Features | Slack

Key Features

Key Features

Four key features of academic style. On this page; Objectivity; Formality; Precision; Hedging; Final tip; Related resources. Academic writing in English. A key feature is defined as a critical step in the resolution of a clinical problem, and a key-feature problem consists of a clinical case scenario followed by. Translations in context of "key features" in English-Chinese from Reverso Context: Trading Terminal NetTradeX has the following key features. Key Features

Key Features - excited

Developing key-feature problems and examinations to assess clinical decision-making skills

This article introduces the concept of a key feature and describes its function as the cornerstone of key-feature problems, a new problem format for the written assessment of clinical decision-making skills of medical trainees and practitioners. The rationale for using this problem format and the steps in problem and examination development--including issues of scoring and standard setting--are described. A key feature is defined as a critical step in the resolution of a clinical problem, and a key-feature problem consists of a clinical case scenario followed by questions that focus on only those critical steps. The questions can be presented to require examinees either to write in their responses or to select them from a list of options. For each question, examines can be instructed to supply or select whatever number of responses is appropriate to the clinical task being tested, and answer keys can comprise one or several responses. This problem format, with its focus on only the critical steps in problem resolution, and with its flexibility in question format and scoring keys, effectively addresses the psychometric considerations of content validity and test score reliability, and accommodates the complexity and configurations of actions often required in the resolution of clinical problems.

Источник: [https://torrent-igruha.org/3551-portal.html]
Slack the product user interface on desktop

Frequently asked questions

Excellent question. Slack is a new way for your entire company to communicate. It replaces email with something faster, better organized and more secure. Instead of one-off email chains, all your communication is organized into channels that are easy to create, join and search. When there’s a channel for everything going on at your company, everyone knows exactly where to go to get work done.

For more reading on the topic, we recommend checking out our Resources Library.

The key to Slack success is channels. By creating a channel for all your projects, your teams, your offices, your departments—everything you’re doing at work—you create a space for every conversation to happen. And because channels are easy to join and create, Slack can adapt to meet changing needs. If someone new joins a project, you can simply add them to the channel and they scroll up to read through old conversations. When it’s time to start something new, create a new channel and invite the right people.

To learn more, read up on how to collaborate effectively in channels.

Yes. You can securely discuss confidential information in Slack. Slack offers multiple ways to ensure that your information, conversations and files stay safe. Slack delivers enterprise-grade security at every layer, adhering to multiple compliance certifications, including SOC 2, SOC 3, ISO/IEC 27001 and more. Slack is GDPR-compliant and can be configured for HIPAA and FINRA compliance. It is FedRAMP Moderate authorized.

In addition, Slack offers security features, like Enterprise Key Management, that allow admins fine-grained control over data encryption. You can also integrate your own security tools with Slack to get instant notification if a threat is detected. Learn more about Slack’s comprehensive security program here.

Yes! Unlike email, Slack is not susceptible to spam or phishing, which causes 90% of data breaches. Your Slack handle cannot be sold to advertisers or put on a mailing list. You will only ever receive Slack messages from other people inside your organization, or from trusted partners using Slack Connect. You may get notifications from apps integrated with your workspace, such as Asana, Google Docs or Jira.

Slack offers enterprise-grade data protection and privacy. Granular controls allow admins to customize security for each user, so no one sees things they shouldn’t. Learn more about how Slack can securely replace email inside your company.

Slack Connect is a more secure and productive way for organizations to communicate together. It lets you move all the conversations with your external partners, clients, vendors and others into Slack, replacing email and fostering collaboration. Slack’s enterprise-grade security features and compliance standards, like Enterprise Key Management, extend to Slack Connect. Learn more about Slack Connect here.

Источник: [https://torrent-igruha.org/3551-portal.html]

COBS 13.3 Contents of a key features document

General requirements

COBS 13.3.1RRP

A key features document must:

  1. (1)

    include enough information about the nature and complexity of the product, how it works, any limitations or minimum standards that apply and the material benefits and risks of buying or investing for a retail client to be able to make an informed decision about whether to proceed; 7

  2. (2)

    explain:

    1. (a)

      the arrangements for handling complaints about the product;

    2. (b)

      that compensation might be available from the FSCS if the firm cannot meet its liabilities in respect of the product (if applicable);

    3. (c)

      that a right to cancel or withdraw exists, or does not exist, and, if it does exist, its duration and the conditions for exercising it, including information about the amount a client may have to pay if the right is exercised, the consequences of not exercising it and practical instructions for exercising it, indicating the address to which any notice must be sent;

    4. (d)

      (for a CTF) that stakeholder CTFs, cash-deposit CTFs and 1security-based CTFs1 are available and which type the firm is offering; and

    5. (e)

      (for a personal pension scheme that is not an automatic enrolment scheme)2 clearly and prominently, that stakeholder pension schemes are generally available and might meet the client's needs as well as the scheme on offer; and7

  3. (3)

    7(for a cash-only lifetime ISA) include the information set out in COBS 14 Annex 1.

Additional requirements for non-PRIIP packaged products

COBS 13.3.2RRP

Table

A key features document for a non-PRIIP packaged product8 must:

(1)

Include the title: ‘key features of the [name of product]’;

(2)

describe the product in the order of the following headings, and by giving the following information under those headings:

Heading

Information to be given

‘Its aims’

A brief description of the product’s aims

‘Your commitment’ or ‘Your investment’

What a retail client is committing to or investing in and any consequences of failing to maintain the commitment or investment

‘Risks’

The material risks associated with the product, including a description of the factors that may have an adverse effect on performance or are material to the decision to invest

‘Questions and Answers’

(in the form of questions and answers) the principle terms of the product, what it will do for a retail client and any other information necessary to enable a retail client to make an informed decision.

5[Note: in respect of ‘Risks’, article 185(4) of the Solvency II Directive]

COBS 13.3.3RRP

COBS 13.3.4RRP

COBS 13.3.5GRP

Источник: [https://torrent-igruha.org/3551-portal.html]

Key Features of Learning Cities

Introductory Note

Several approaches have been taken in recent years to translate the concept of a learning society into reality. One significant example is the growth of ‘learning communities’, ‘learning cities’ and ‘learning regions’. Although the idea of a learning city has mostly been conceptualized in developed countries, facilitated by the OECD since the 1980s and the European Commission since the 1990s, it is now rapidly gaining momentum in developing countries. In more and more Member States, local authorities now claim to be learning cities/regions/communities. Their proliferation has become a major worldwide phenomenon, with considerable educational, social, economic and environmental implications.

What is a Learning City?

Cities differ in their cultural and ethnic composition, in their heritage and social structures. However, many characteristics of a learning city are common to all. The initiative on learning cities developed by the UNESCO Institute for Lifelong Learning defines a learning city as follows:

A Learning City is a city which effectively mobilizes its resources in every sector to
  • promote inclusive learning from basic to higher education;
  • revitalize learning in families and communities;
  • facilitate learning for and in the workplace;
  • extend the use of modern learning technologies;
  • enhance quality and excellence in learning; and
  • foster a culture of learning throughout life.
In so doing it will create and reinforce individual empowerment and social cohesion, economic and cultural prosperity, and sustainable development.

Why monitor progress in developing learning cities?

Since a learning city facilitates lifelong learning for all, and therefore helps to realize the universal right to education, building such a city has far-reaching appeal. This is a continuous process; there is no magic line over which a city will pass in order to become known as a learning city. There are, however, attributes by which a learning city can be recognized, mainly in terms of what it does rather than what it is. The construction of a learning city entails an operational and pragmatic approach to the implementation of lifelong learning. It is not an abstract theory. If a city has the political will and commitment to build a learning city, it will also need a set of indicators or key features against which it can monitor its progress. Put simply, monitoring the progress of a learning city is necessary for three main reasons:

  • To transform political and theoretical discourses into concrete strategies and approaches;
  • To measure progress over time; and
  • To evaluate the benefits of the strategies it has put into place

The Key Features of Learning Cities will make it possible:

  • To support in a meaningful way the development of lifelong learning within and across member cities;
  • To determine up to a certain level how much progress is being made to implement lifelong learning for all in many of the world’s communities; and
  • To facilitate international comparative analysis and experience-sharing and mutual learning among member cities.

The development of the Key Features of Learning Cities

This normative instrument for measuring learning cities is the result of a long consultation process. Initially, UIL held a workshop on developing a framework for the Key Features of Learning Cities from 3 to 5 July 2012. Experts representing some of the partners for the establishment of IPLC, including the PASCAL Observatory, Bertelsmann Foundation, CISCO Systems, Beijing Municipal Education Commission, National Centre of Education Development Research of China, Kuwait University and the Cape Higher Education Consortium, as well as some UIL professional staff and consultants, participated in the workshop. This workshop first of all drew inspiration from the following well-established conceptual frameworks and indicators for measuring social and economic development:

  • The Human Development Index (HDI) and related indices developed by UNDP (2007);
  • The Revised Official Monitoring Framework for the Millennium Development Goals: goals, targets and indicators (UN, 2008);
  • The Knowledge Assessment Methodology: Variables and Clusters by the World Bank (2012);
  • The Better Life Index by OECD (2012);
  • The Future We Want – RIO+20 Report (UN, 2012);
  • A New Global Partnership: Eradicate Poverty And Transform Economies Through Sustainable Development (UN, 2013); and
  • Post-2015 Development Agenda: Goals, Targets and Indicators (The Centre for International Governance Innovation and the Korea Development Institute, 2012).

Inspired by a list of criteria for indicators developed in the UN report Analysing and Measuring Social Inclusion in a Global Context (UN, 2010), the following criteria were endorsed at the workshop to develop the Key Features of Learning Cities.

  • Ambitious but achievable – achieving the target should represent significant progress but should also be realistic.
  • Crucial – every feature reflects a value, a priority or a critical issue.
  • Relevant – a feature must fit its intended purpose; achieving the target should contribute significantly to meeting a key objective.
  • Clear and understandable – a feature must be simple and easy for all stakeholders to understand, and should make sense to the average person.
  • Easy to measure – a feature should be measured by available data, or by data to be collected through a well-designed survey.
  • Valid and reliable – people must trust the information that a feature provides.

As a result of intensive debates and group work, the workshop produced the first draft of the framework of the Key Features of Learning Cities. Taking the comments from experts into consideration, UIL has produced a draft which was presented in the 1st meeting of the Expert Group for Developing Learning Cities in Hangzhou, China. In April and May 2013, UIL consulted some experts and a number of cities on the relevance of the key features and the feasibility of data collection. On 4–5 June 2013, UIL held a second meeting in Jeju Island, Republic of Korea. The participants of the meeting elaborated further on the draft Key Features of Learning Cities.

Based on the expert group’s validation, UIL selected a number of cities in each of the UNESCO regions for piloting, which was completed in September 2013. The Key features reflect the results of the piloting.

Components of the framework of the Key Features of Learning Cities

As shown in Figure 1, the framework of the Key Features of Learning Cities corresponds to the pediments, columns and foundation steps of the UNESCO logo.
The Pediment – three areas of focus reflect the wider benefits of building a modern learning city, broadly defined as:

  1. Individual empowerment and social cohesion;
  2. Economic development and cultural prosperity; and
  3. Sustainable development.

The Columns – six areas of focus reflect the major building blocks of a learning city:

  1. Inclusive learning in the education system;
  2. Revitalized learning in families and communities;
  3. Effective learning for and in the workplace;
  4. Extended use of modern learning technologies;
  5. Enhanced quality in learning; and
  6. A vibrant culture of learning throughout life.

The Foundational Steps – three areas of focus reflect the fundamental conditions for building a learning city:

  1. Strong political will and commitment;
  2. Governance and participation of all stakeholders; and
  3. Mobilization and utilization of resources.

A total of 42 features are included in the Key Features of Learning Cities. Most of the features are quantitative, and related statistics can be provided by the responsible city authorities. As for qualitative features, some can be measured by the results of a survey conducted by independent professional agencies such as Gallop, while others can be measured through expert review of reports provided by the responsible city authorities.
The objective is not to make distinctions between cities. Each city is different and its progress towards a learning city can only be measured within the context of its own cultural, economic and social history and traditions.

How to use the Key Features of Learning Cities

Formally endorsed by mayors and city education executives of learning cities as well as experts participating in the International Conference on Learning Cities, the Key Features can serve as a comprehensive checklist of action points to help municipal governments and other stakeholders of cities in their efforts to build learning cities that promote lifelong learning for all.

Furthermore, as the members of a global network of learning cities need to be recommended by UNESCO Member States, the national authorities of the Member States can use the Key Features to select and recommend cities to join the network.

More generally, the Key Features can also be used as a reference document for international organizations and national authorities in promoting the development of learning nations, regions, cities and communities.

Источник: [https://torrent-igruha.org/3551-portal.html]

Four key features of academic style

Academic writing in English has a distinctive style – it is formal and uses particular language norms that you need to learn.

Academic style is more than just a writing convention; it can also help you to think more logically and clearly as you work on an assignment.

Below are some tips on how to incorporate four key features of academic style into your writing: objectivity, formality, precision and hedging

Objectivity

Academic writing presents and evaluates issues and arrives at an objective position; a position that focuses on and is informed by research and reasoning rather than personal feelings and opinions.

Personal pronouns, especially ‘I’, ‘you’ and ‘we’ are usually avoided, as these are often associated with subjective views that are influenced by personal preferences or biases.

Example

This statement sounds a bit like a personal opinion:

You can demonstrate that climate change is a real phenomenon by studying alterations in Antarctic ice layers.

To help establish an objective distance from the topic, instead of using a personal pronoun, you could try:

  1. Using the topic as the subject
    Alterations in Antarctic ice layers demonstrate that climate change is a real phenomenon.
  2. Using a passive verb
    The reality of climate change can be demonstrated by studying alterations in Antarctic ice layers.
  3. Using ‘it’ as an empty subject
    It can be demonstrated that climate change is a real phenomenon by studying alterations in Antarctic ice layers.

Avoiding ‘I’ does not mean you cannot express your own opinion. Your own evaluation of the material is still extremely important; however, you can communicate this by using evidence or logical argumentation.

Formality

Academic writing is very explicit and provides the reader with all the information they need to understand your meaning. This is in contrast to written or spoken English in less formal contexts, which often relies on readers or listeners to supply extra information that completes the message.

To make your writing more formal, try to:

  1. Replace informal words that are associated with ‘chatty’ spoken styles ( such as contractions) with more formal vocabulary
  2. Avoid rhetorical questions the reader cannot answer
  3. Use full words instead of contractions
  4. Avoid unspecified categories
  5. Avoid colloquial language

Example

For example, this passage contains some informal words (going, good, tell, though, really), a rhetorical question (How good…?), a contraction (can’t), a vague category (etc.) and a colloquialism (first-class, top notch, check out):

  • The investigation has been going for four years. How good has it been? At this stage, researchers can’ttell, because they still need to check out the data to account for differences in age, gender, socio-economic-status, etc. Once that work is done though, the information will be reallyfirst-class.

Using the tips above, you could improve this passage by using more formal vocabulary, removing the rhetorical question, writing words in full, elaborating on the vague category and removing the colloquialism as seen below:

  • The investigation has been underway for four years. Researchers cannot yet determine the effectiveness of the project because it is necessary to first analyse the data to control for age, gender, socio-economic status and other demographic variables. Despite this, the information collected is expected to be highly valuable for future studies.

Key tip

Online learner’s dictionaries that provide examples of how words are used in context can help you determine the formality of specific words. If a word has many possible meanings, or appears in many idioms, it is more likely to be informal.

Precision

To communicate your meaning precisely, you should try to:

Include a sufficient high level of detail and specificity

The amount of detail you provide depends on the purpose of your work, but you should always try to avoid ambiguity.

Example

The following sentence is very broad and general, which makes it sound like a personal opinion.

  • Most people didn’t like changing trains on the way to work, but they still thought it was better than taking a bus.

How many people are ‘most’? How strong is their dislike of changing trains? In what way are trains better than buses?

To make it more precise, the writer could specify exactly which group of people they are referring to, what their preferences were, and the degree of strength of those preferences.

  • While the majority of the survey respondents indicated their dislike of changing trains on their commute to work, they preferred taking two trains to taking one bus, which they perceived would be slower overall and less comfortable, or both.

The additional detail in the sentence above clearly makes the message more precise.

Choose verbs that express concepts succinctly

Certain verbs are considered too imprecise for academic writing, in that they do not provide detailed, exact meaning we require. These include verbs that are commonly used in less formal contexts, particularly those with many possible meanings and multi-word verbs.

Verbs with many possible meanings include ‘do’, ‘make’, ‘put’, ‘keep’, ‘have’ and ‘get’. For example, some of the many possible meanings of ‘get’ are:

  • Receive (get an email)
  • Obtain (get a better view)
  • Bring (get a bucket and mop)
  • Buy (get a new shirt)
  • Arrive (get there at 7pm)

If you use the single verb that expresses exactly what you mean by ‘get’, your writing will be more precise.

Example

The researchers got results from a large participant group

Vs.

The researchers obtained results from a large participant group

Multi-word verbs are verbs that require more than one word to create meaning, including phrasal and prepositional verbs, for example:

Cut off, find out, give up, hand out, let down, pick out.

Again, try to use a single verb with the same meaning instead, such as:

Discontinue, discover, quit, distribute, disappoint, select.

Use a dictionary and/or a thesaurus to find suitable alternatives for imprecise or multi-word verbs.

Hedging

Hedging language in academic writing is used to express caution and avoid strong, unqualified statements that may be easily disproven.

To avoid generalisations, you can:

  • Use a quantifier (e.g. few, many, some)
  • Use adverbs or adverbial phrases (e.g. occasionally, often, usually)
  • Use modal verbs (e.g. can, may, might, would, could)

Example

The following claim is quite strong:

Leading a sedentary lifestyle causes chronic health conditions.

You could avoid overstating the relationship using the hedging tips above as follows:

Extended physical inactivity can contribute to a range of chronic health conditions and may have a negative effect on mental health.

Cautious but inclusive statements, like the one above, may be challenged but not easily dismissed.

Final tip

This page outlines some tips to help you incorporate four key features of academic style into your writing. Another way to become familiar with these features is to look for them in the academic texts you are reading in your studies.

  • How do authors express their views objectively?
  • What formal and precise vocabulary is used?
  • How do authors avoid making generalisations?

The more you look for these aspects of writing in academic texts you are reading, the more easily you will be able to incorporate those features into your own writing.

Related resources

Explore all resources

  • Academic style

    Academic English is a distinct language, and one you’re expected to write in at university. Understand how to identify, create and improve your academic style.

    Writing style

  • Using sources in assessments: voice in academic writing

    Effectively combine your ideas with those of other writers.

    Referencing

  • Developing clarity and focus in academic writing

    Academic writing aims to be clear and precise, with a direct style that moves logically from one idea to the next. This page describes how you can structure sentences and paragraphs to achieve clarity and ‘flow’ in your writing.

    Writing style

Two people looking over study materials

Looking for one-on-one advice?

Get tailored advice from an Academic Skills adviser by booking an appointment or attending one of our drop-in sessions.

Get one-on-one advice

Contact or follow us


Источник: [https://torrent-igruha.org/3551-portal.html]

World Academy
of Sciences
Journal

1. Introduction

Cell death, survival, proliferation and differentiation represent fundamental processes of life. Cell death plays a pivotal role in embryonic development, maintaining the homeostasis of the organism and eliminating damaged cells. Cell death was initially divided into three types (1): Type I cell death (apoptosis), type II cell death (autophagy) and type III cell death (necrosis). In recent years, multiple novel cell death modalities have been identified and characterized concerning their corresponding stimuli, molecular mechanisms and morphologies. Some of these modalities share overlapping, but not identical signal pathways and fail to be incorporated into the type I-III categories. In 2018, the Nomenclature Committee on Cell Death listed multiple cell death types in a molecule-oriented manner (2). Tang et al also provided historical origins of items used during cell death research development and a brief summary of molecular machinery involved in regulated cell death (3). However, the hierarchical association among different cell death types remained vague and the molecular interplays led to further confusion. Therefore, the present review article aims to provide a simpler classification system and key features of different cell death modalities are abstracted.

Cell death entities can be categorized into programmed or non-programmed cell death based on their signal dependency (Fig. 1). Programmed cell death (PCD) is driven by tightly regulated intracellular signal transduction pathways. By contrast, accidental cell death is referred to as non-PCD as a result of unexpected cell injury. Given the morphological characteristics and molecular mechanisms, PCD can be further categorized into apoptotic cell death and non-apoptotic cell death. Apoptosis retains cell membrane integrity and occurs in a caspase-dependent manner. By contrast, non-apoptotic cell death is mostly characterized by membrane rupture and caspase-independency. For simplicity, the present review article focuses on the key features of the diverse cell death modes and their assessment methods commonly utilized in research (Table I), and refers the reader to specialized recent review articles describing the processes of each cell death mode in further detail (4-15).

Table I

Cell death modalities, their features and common detection methods.

Table I

Cell death modalities, their features and common detection methods.

ClassificationCell death modalityKey moleculesKey morphologyDetection methods
Non-PCDNecrosisNoneCell swelling; membrane rupture; loss of organelleLactate dehydrogenase activity detection; visualizing membrane integrity loss by cell-impermeable DNA binding dye
PCD-apoptoticApoptosis/anoikisDRs and their ligands, Bax, Bak, AIF, caspase-8, caspase-3, caspase-9Cell shrinkage; membrane blebbing; loss of positional organization of organelles in the cytoplasm; DNA condensation andChromosome condensation detection; TUNEL assay; Annexin V assay; caspase assay; PARP cleavage assay; applying apoptosis inhibitors fragmentation; nuclear membrane rupture
PCD-vacuole presentingAutophagyUKL1, PI3KIII, ATGs, LC3Large intracellular vesicles; membrane blebbing; enlarged organelles; depletion of cytoplasmic organellesTurnover of long-lived proteins; LDH sequestration; western blot analysis with autophagy specific antibodies
EntosisRhoA, ROCKI/II, E-cadherin, α-catenin, actomyosin, LC3, ATGsCell-in-cell formationMorphology observation with fluorescence imaging and electron microscopy
MethuosisRas, Rac1, Arf6, LAMP1, Rab7Accumulation of large fluid-filled single membrane vacuoles; cell swelling; membrane ruptureMorphology observation with electron microscopy
ParaptosisUnclearAccumulation of large fluid-filled single membrane vacuoles; dilation of ER or mitochondriaMorphology observation with electron microscopy
PCD-mitochondriadependentMitoptosisBax, Bak, TIMM8a(DDP), Drp1Mitochondria disappearance; decomposition of the mitochondrial reticulum to small spherical organellesMorphology observation with fluorescence microscopy and electron microscopy; western blot analysis with mitoptosis-specific antibodies
ParthanatosPARP, AIFMembrane rupture; mitochondrial outer membrane permeabilization; chromatin condensation; DNA large-scale fragmentationWestern blot analysis with parthanatos specific antibodies; Mitochondrial depolarization detection with fluorescent probe
PCD-iron dependentFerroptosisSystem XC−, GPX4, Lipid ROSDiminutive mitochondria with decreased cristae and collapsed and ruptured membraneApplying ferroptosis inhibitors; measuring lipid peroxides e.g. malondialhyde and 4-hydroxynonenal quantification
PCD-immune reactivePyroptosisNLRs, ALRs, caspase-1, caspase-11Cell swelling; membrane rupture; DNA condensation and fragmentationQuantification of cytoplasmic LDH; visualizing membrane integrity loss by fluorescence microscopy; western blot analysis with pyroptosis-specific antibodies
NETosisNOX4, PAD4Chromatin decondensation; membrane ruptureMorphology observation with fluorescence microscopy; free-cell DNA and DNA-neutrophil derived protein complex detection with fluorescent probe and immunoblot
Other typeNecroptosisDRs, TLRs, TCR, RIPKs, MLMKCell swelling; membrane rupture; loss of organelle; mitochondria swellingVisualizing membrane integrity loss; mitochondrial depolarization detection; applying necroptosis specific inhibitors; western blot analysis with necroptosis-specific antibodies

2. Non-programmed cell death

Non-programmed necrosis

Non-programmed necrosis is stimulated by a number of external factors, e.g., infection, toxins and physical injury, which lead to morphological alterations, such as cytoplasmic swelling [oncosis, pre-lethal phase caused by the disruption of ionic pumps such as Ca+ influx (16)], plasma membrane rupture and the subsequent loss of intracellular organelles without severe chromatin condensation, but randomly degraded DNA (17) (Fig. 2). Non-programmed necrosis is often observed in ischemia, trauma and possibly some forms of neurodegeneration. It is commonly considered as a passive process, which does not require de novo macromolecular synthesis, but minimal energy (4).

Based on the morphological features of necrosis, a number of methods, including lactate dehydrogenase (LDH) activity detection and cell-impermeable DNA binding dye, are commonly used to certify the cellular leakage and membrane permeability (Table I).

3. Programmed apoptotic cell death

Apoptosis

Apoptosis involves a series of tightly controlled events and is characterized by cell shrinkage, membrane blebbing, positional organelle loss, DNA condensation and fragmentation (Fig. 2). Three signaling pathways are known to trigger apoptotic cell death: The extrinsic (death receptors) pathway, the intrinsic (mitochondrial) pathway and the perforin/granzyme pathway (Fig. 3) (5).

Figure 3

Synopsis of cell death processes. Ten cell death modalities (apoptosis, autophagy, entosis, methuosis, paraptosis, mitoptosis, parthanatos, ferroptosis, pyroptosis and necroptosis) are presented. Anoikis shares identical signaling pathways as apoptosis, apart from the fact that it is stimulated by inadequate or inappropriate cell-matrix interactions. The cell death modalities (necrosis and NETosis) without elucidative mechanism were not included. Grey color indicates non-functional molecules. Arrow direction indicates the causal association. RIPK, receptor-interacting protein kinase; MLKL, mixed lineage kinase domain-like protein; NLRs, NOD-like receptors; MOMP, mitochondrial outer membrane permeabilization; LC3, microtubule-associated protein light chain 3; ROCK, Rho associated coiled-coil containing protein kinase; GPX4, glutathione peroxidase 4; ROS, reactive oxygen species; UKL complex, UKL1 in a complex with FIP200, ATG13 and ATG101.

Anoikis is a particular type of apoptosis, which essentially shares identical pathways as with apoptosis; however, is triggered by inadequate or inappropriate cell-matrix interactions (18) (Fig. 3). The architectural state of the cytoskeleton is expected to interfere with the function of integrin, a pro-survival effector (6). However, the connection between cell architecture alteration and apoptosis remains poorly identified. It has recently been indicated that c-JUN NH2-terminal kinase (JNK) signaling is required for efficient anoikis through a BAK/BAX-dependent manner by increasing BCL2-like 11 (BIM) expression and BCL-2 modifying factor (BMF) phosphorylation (19).

Apoptosis assessment methods have been rapidly developed over the past years (Table I). Terminal deoxynucleotidyl transferase dUPT nick-end labeling (TUNEL) assay and comet assay are able to detect the presence of fragmented DNA. Annexin V in combination with cell-impermeable DNA staining dye is used to detect the outwards exposed phosphatidylserine on cell membrane and cellular integrity. Alternatively, some assays evaluate the intermediate modulators, e.g., caspase assay and poly-ADP ribose polymerase (PARP) cleavage assay (20). Furthermore, specific apoptosis inhibitors, such as the pan-caspase inhibitor, zVAD-fmk, can also shed some light on the presence of apoptosis.

4. Programmed non-apoptotic cell death

Vacuole-presenting cell death Autophagy

Autophagic cell death is characterized by the appearance of large intracellular vesicles, plasma membrane blebbing, enlarged organelles and the depletion of cytoplasmic organelles in the absence of chromatin condensation (21) (Fig. 2). Noticeably, it functions as a lever in the cell process. Autophagy is initiated upon cellular stress as a protective response. Once the cellular stress is irreversible, the cell will be committed to death also through excessive levels of autophagy. There are three forms of autophagy: Macro-autophagy (Fig. 3), micro-autophagy and chaperone-mediated autophagy (7). The macro-autophagic process has been well documented (22-24) (Fig. 3). In micro-autophagy, the cytoplasmic components are directly sequestrated into the lysosomes, where acidic hydrolases further mediate the degradation. Chaperone-mediated autophagy selectively targets KFERQ motif (Lys-Phe-Glu-Arg-Gln)-containing proteins. These proteins can be recognized by chaperones, are subsequently hijacked into lysosomes and eventually degraded (25). The specific degradation of the mitochondria is referred to as mitophagy. The selective autophagy of foreign pathogens is coined as xenophagy. There are also some other selective autophagy forms, such as lipophagy, aggrephagy and lysophagy (26).

The detection methods are mostly developed for macro-autophagy embodying direct measurement of autophagic activity (e.g., turnover of long-lived proteins and LDH sequestration) and indirect analysis with autophagy specific antibodies through western blot-based assay, fluorescence microscopy-based assay and flow cytometry-based assay (27) (Table I).

Entosis. Entosis (or cannibalism) is characterized by cell-in-cell formation (Fig. 2). Upon internalization, the entotic cells remain viable for a short period of time. This process is frequently followed by lysosome-mediated degradation and non-apoptotic cell death, while a fraction of the internalized cells can also extricate themselves or are expelled from the host cell (28). Entosis is believed to be triggered by integrin-extracellular matrix (ECM) detachment (29). Unlike phagocytosis, the engulfment of entotic cells represents a self-control process through RhoA and the Rho-associated coiled-coil containing protein kinases (ROCK). The entotic cell and the host cell interact with each other through the E-cadherin and α-catenin cell junction interface. RhoA and ROCK in entotic cells lead to specific accumulation of actin and myosin complex (actomyosin) at the cell cortex opposite to the junctional interface, which generates the unbalanced contractile force driving cell-in-cell formation. However, entosis is also observed in matrix-attached epithelial cells. Wan et al proposed that the overactivation of myosin or unbalanced myosin activation through regulatory polarity proteins between the contacting cells acted as the driving force for entosis in matrix-attached epithelial cells (30). The engulfment is followed by lysosome-mediated degradation, which differs from autophagic cell death (31). The autophagic protein, microtubule-associated protein light chain 3 (LC3), does not participate to form the autophagosome. Instead, LC3 is directed to the single-membrane vacuole in the host cell that harbors the engulfed cell through lipidation with the help of autophagy-related protein (ATG)5, ATG7 and Vps34, and promotes lysosome fusion followed by lysosome-mediated degradation (8) (Fig. 3).

However, there is as yet no specific assay available for the detection of entosis, at least to the best of our knowledge. The presence of entosis is deduced from its typical cell-in-cell structure, as detected by fluorescence imaging and electron microscopy (32,33) (Table I).

Methuosis. Methuosis represents a type of cell death characterized by the presence of the massive accumulation of large fluid-filled single membrane vacuoles derived from macropinosomes, which is specifically accompanied with Ras hyper-activation and apoptosis impairment. Intriguingly, methuosis is not associated with the conventional Ras-Raf-MEK-ERK axis or class III phosphoinositide 3-kinase (PI3K) signaling (34). The consequent morphology resembles necrosis in the manner of cell swelling and plasma membrane integrity loss. In methuosis, activated Ras stimulates micropinocytosis through the downstream activation of Rac family small GTPase 1 (Rac1). Coincidently, the reduction of ADP ribosylation factor 6-GTP (Arf6-GTP) impedes macropinosome recycling (35). The abnormal coalescence of nascent macropinosomes gives rise to massive cytoplasmic vacuolization. The vacuoles formed in the early stages of methuosis are decorated with late endosomal markers [e.g., lysosomal-associated membrane protein 1 (LAMP1) and Rab7] (9). The massive vacuoles, which are not able to be recycled or merged with lysosomes, will finally lead to cell death. Methuosis with its typical morphology, is often assessed by electron microscopy in research (36-38) (Table I).

Paraptosis. The hallmark of paraptosis is the extensive cytoplasmic vacuolization derived from the dilated endoplasmic reticulum (ER) or the mitochondria (39) (Fig. 2). It has been reported that the activation of insulin-like growth factor 1 receptor (IGF1R) and its downstream signaling incorporating mitogen-activated protein kinases (MAPKs) and JNK pathways can induce paraptosis, despite the fact that IGF1R is commonly considered as a pro-survival modulator (40). A number of studies have indicated that paraptosis is associated with reactive oxygen species (ROS) generation and the accumulation of misfolded proteins in the ER, as well as mitochondrial Ca2+ overload (10,41-43), which exert an osmotic force to distend the ER lumen and mitochondria for vacuolization. In spite of the current available evidence, the molecular mechanisms underlying paraptosis have not yet been fully addressed.

Similar to entosis and methuosis, there is no specific assay available for the detection of paraptosis, at least to the best of our knowledge. It is mostly defined by the appearance of multiple single-membraned cytoplasmic vacuoles, as detected by electron microscopy (44) (Table I).

Mitochondrial-dependent cell death Mitoptosis

Unlike mitophagy (autophagic degradation of mitochondria), mitoptosis, also known as mitochondrial suicide, represents a process of programmed fission and fusion of the mitochondria with the concomitant disruption of the adenosine triphosphate (ATP) supply. As a consequence, mitoptosis can be associated with both apoptosis (45) and autophagy (46). The degraded mitochondria either become autophagosomes or mitoptotic bodies, which are extruded from the cell. In this sense, mitoptosis itself is not a cell death pathway, but a mitochondrial death pathway. However, the extensive mitochondrial fragmentation through elevated fission finally leads to cell death (47). Mechanically speaking, mitochondrial outer membrane permeabilization (MOMP) induced by BAX/BAK triggers the release of a mitochondrial intermembrane space protein termed translocase of inner mitochondrial membrane 8a (TIMM8a/DDP). DDP subsequently binds to DRP1 in the cytoplasm. The interaction between DDP and DRP1 leads to the recruitment of DRP1 and retention in the mitochondria, which induces mitochondrial fission and finally, mitoptosis (48). Nevertheless, the process remains poorly understood and is described mostly by its morphological features.

As a manner of mitochondrial suicide, the visualization of fragmented mitochondria with mitochondria-specific dyes (e.g., MitoTracker Green®) by utilizing fluorescence microscopy and a close observation with electron microscopy provide certain clues on the presence of mitoptosis (45). Moreover, specific antibodies against cytochrome c and TIMM8a/DDP are also utilized in research (48) (Table I).

Parthanatos. Parthanatos represents a mitochondrial-linked, but caspase-independent cell death and is characterized by the hyperactivation of PARP. PARP mediates the synthesis of poly(ADP-ribose) (PAR), which further shuttles from the nucleus to the cytoplasm and binds to specific mitochondrial proteins followed by apoptosis-inducing factor (AIF) release. Free AIF is translocated from the mitochondria into the nucleus. In the nucleus, AIF induces chromatin condensation and DNA breakage (49). Compared to the apoptotic process, intact PARP and its activation is required, rather than PARP cleavage. Moreover, parthanatos cannot be inhibited by broad-spectrum caspase inhibitors (50), which proves its independency of caspases. Parthanatos does not involve the formation of apoptotic bodies. Furthermore, the DNA fragmentation is large-scale rather than small-to-moderate scale, as typically observed in apoptosis (11) (Fig. 2).

PAR accumulation, PARP-1 activation and nuclear AIF are practically used as biomarkers of parthanatos. The process can be further confirmed with mitochondrial depolarization, as detected with fluorescent probe staining (Table I).

Iron-dependent cell death Ferroptosis

Ferroptosis is normally associated with a normal-appearing morphology, with an intact cell membrane without blebbing and normal-sized nucleus free of chromatin condensation, although with diminutive mitochondria with decreased cristae and collapsed and ruptured membranes (51) (Fig. 2). It is initiated by the failure of the glutathione-dependent antioxidant defense through defects in system XC− or glutathione peroxidase 4 (GPX4) (12). System XC− transports extracellular cystine into the cell, which is then transformed into cysteine for glutathione (GSH) synthesis. GPX4 can directly catalyze the reaction between glutathione and lipid hydroperoxides to reduce the cellular level of lipid peroxidation. Either the depletion of GSH or the inhibition of GPX4 results in lipid hydroperoxide accumulation. Free iron interacts with lipid hydroperoxides through the Fenton reaction and forms lipid ROS (Fig. 3). Excessive lipid ROS generation finally leads to the cell death.

The induction of ferroptosis can be confirmed by applying ferroptosis inhibitors (e.g., ferrostatin-1 and liproxstatin-1) and by measuring lipid peroxides (e.g., malondialhyde quantification and 4-hydroxynonenal quantification) (Table I).

Immune-reactive cell death Pyroptosis

Pyroptosis is an inflammatory form of programmed cell death that commonly occurs upon the recognition of intracellular pathogens in immune cells. The inflammation sensors [e.g., NOD-like receptors (NLRs)] of infected macrophages recognize the flagellin components of pathogens and initiate the formation of multi-protein complex inflammasomes, which subsequently activate caspase-1(13) (Fig. 3). Upon activation, caspase-1 mediates the membrane pore formation through the cleavage of gasdermin D, allowing the rupture of the cell membrane (52). The process is also accompanied by DNA condensation and fragmentation (Fig. 2). Moreover, caspase-11 can be directly activated by bacterial lipopolysaccharide (LPS) and induces pyroptosis (53).

Pyroptosis can be evaluated through the quantification of released cytoplasmic LDH, the visualization of membrane integrity loss by fluorescence microscopy, the detection of interleukin (IL)-1β, caspase activation and gasdermin D cleavage by western blot analysis (54) (Table I).

Neutrophil extracellular trap-associated cell death (NETosis). NETosis, a unique form of cell death, is initiated by the presence of pathogens or their components and mostly occurs in immune cells, particularly neutrophils. Upon the recognition of pathogens within neutrophils, the cells undergo histone modification, chromatin decondensation and neutrophil extracellular trap [NET, comprising chromatin and antimicrobial components including myeloperoxidase, neutrophil elastase, cathepsin G, lysozyme and defensins (55)] release and this eventually leads to cell death. The process is promoted through superoxide generated by NADPH oxidase 4 (NOX4), autophagy and peptidylarginine deiminase 4 (PAD4)-dependent histone citrullination (56,57). However, further research is expected to provide a clear molecular elucidation.

The staining of co-localized neutrophil-derived proteins and extracellular DNA, as well as citrullinated histones is utilized to evaluate NETosis. Moreover, cell-free DNA and DNA-neutrophil derived protein complexes can be detected by PicoGreen® and ELISA. Both morphology and cell-appendant NETosis components can be detected through flow cytometry (58) (Table I).

Other types Necroptosis

Necroptosis, also known as programmed necrosis, is characterized by the activation of receptor-interacting protein kinases (RIPKs) through several signaling pathways (15). RIPKs are activated upon recruitment to macromolecular complexes from various cell-surface receptors: Death receptors (DRs), Toll-like receptors (TLRs), and the T-cell receptor (TCR) (Fig. 3) (59,60). RIPK1 and RIPK3 function as the key components of necrosome (61). RIPK3 further activates downstream molecule mixed lineage kinase domain-like protein (MLKL) through phosphorylation (62,63), which leads to MLKL oligomerization. The oligomerized MLKL inserts into and permeabilizes cellular membrane, which finally gives rise to cell death (64). Moreover, RIP3-dependent necroptosis is also triggered by the cytosolic DNA sensor, DNA-dependent activator of interferon (DAI) regulatory factors, following viral infection or the presence of double-stranded viral DNA (65). Necroptosis reveals the necrotic morphology with membrane rupture and loss of organelles (Fig. 2).

Necroptosis can be assessed by the loss of plasma membrane integrity by utilizing cell-impermeable DNA binding dyes, the release of cellular contents, including LDH, high mobility group box 1 protein (HMGB1) and cyclophilin A by western blot analysis, mitochondrial potential by fluorescent probes and morphology by electron microscopy. The utilization of necroptosis specific inhibitors, such as necrostatin-1 and measuring key proteins in the pathway represent alternative strategies (66) (Table I).

5. Implications of cell death in human diseases

The dysregulation of cell death processes is highly relevant to tumorigenesis, as well as to the pathogenesis of a number of other diseases, such as degenerative, cardiovascular and autoimmune diseases. The association between cell death and cancer is complex. The complexity is attributed to several factors: On the one hand, there is more than one type of cell death endogenously engaged in cancer. On the other hand, some types of cell death have dual and even opposing effects on tumorigenesis. Firstly, apoptosis is involved in cancer. Cancerous cells can evade apoptosis by downregulating or blocking apoptosis signaling (67). Unexpectedly, apoptosis can also drive tumor formation by promoting cell proliferation as a compensation for cell loss (68). Secondly, necrosis is commonly observed in tumors due to hypoxic microenvironments (67). Thirdly, cancerous cells with defects in apoptosis tend to utilize autophagy as a pro-survival mechanism. Paradoxically, impeded autophagy is also associated with tumorigenesis (69). Fourthly, entosis represents tumor suppressive activity in pancreatic cancer, whereas it promotes tumor progression in most other situations (70,71). Although the other cell death types are much less endogenously involved in cancer development, they are mostly utilized as anti-cancer defense strategies of the body and defects in their signaling plays an important role in drug resistance and clinical failures.

As for neurodegenerative diseases, the initial phase of cell death in ischemia represents necrotic cell death, while delayed cell death is apoptotic in nature due to the fact that the ischemic core tends to be necrotic and the penumbra region apoptotic (72). Autophagic cell death and parthanatos are linked to ischemia (11,73). In Parkinson's disease, apoptosis contributes to the loss of nigral neurons due to the fact that almost every Lewy body-containing neuron (as a pathological feature of Parkinson's disease) is positive for pro-apoptotic modulator staining (74). Another study demonstrated that necrostatin-1, an inhibitor of necroptosis, ameliorated neuronal loss in a model of Parkinson's disease (75), indicating that necroptosis may also play a role in Parkinson's disease. There is also evidence suggesting the role of apoptosis in Huntington's disease. However, its role in Alzheimer's disease remains under debate (76).

Cell death modes, such as apoptosis, necrosis and autophagy in cardiac myocytes have been frequently reported to affect a variety of cardiovascular diseases, including myocardial infarction, diabetic cardiomyopathy, ischemic cardiomyocyte and congestive heart failure (77-79). In addition, ferroptosis, pyroptosis, as well as parthanatos are also documented to contribute to ischemia/reperfusion injury (80). The other cell death types have been studied to a much lesser extent as compared to cardiovascular diseases. Likewise, apoptosis and secondary necrosis are considered as major modes of cell death in systemic autoimmune diseases. Recent evidence indicates that NETosis accounts for certain immunological features in systemic lupus erythematosus (81).

6. Conclusions and perspectives

The cell death modes presented in the present review article are mostly distinguished by stimuli, molecules and morphologies. Apart from non-programmed necrosis, the other cell death modes are regulated in a signal-dependent manner, despite the fact that a number of the pathways have not yet been fully addressed. Some cell death modes are intensively interacting with others. For instance, the activation of tumor necrosis factor receptor (TNFR) can stimulate both apoptosis and necroptosis; however, compromised apoptosis can shift the downstream pathway to necroptosis (82) and vice versa (83). Some processes during cell death are connected; for instance, the occurrence of mitoptosis can turn out as autophagic cell death or apoptotic cell death. In general, necrosis-like cell death is associated with membrane rupture. The consequent release of intracellular inflammatory factors can give rise to inflammation as observed in necrosis, necroptosis, NETosis and pyroptosis. By contrast, apoptotic cells do not stimulate inflammation, since they are rapidly eliminated by phagocytes. However, if apoptotic cells are not properly processed, they can develop secondary necrosis. These mutual connections indicate that different cell death types are not isolated from each other. The molecular links await to be unveiled in greater detail. Their implications on diverse diseases are expected to be unraveled in the near future, since current studies on cell death modes involved in diseases are mostly confined to the more classical cell death categories. Green (84) also addressed five quite interesting and inspiring questions about the balance and context of cell death. In fact, much is still unknown. Noticeably, this review article has primarily focused on the features of pathological cell death and is limited to the animal kingdom. However, there also exist physiologic cell death such as cornification (85) to form termination differentiation and some cell death types are also similarly present in the plant kingdom (e.g., apoptosis-like cell death) (86).

Acknowledgements

Not applicable.

Funding

The authors are grateful to PhD stipends given to GY (by the Chinese Scholarship Council) and to ME (by the German Academic Exchange Service, DAAD).

Availability of data and materials

Not applicable.

Authors' contributions

GY was responsible for the drafting of the manuscript and cell death information collection. ME was responsible for information presentesst and figure construction. TE was responsible for the initial conception of the study and for the revision of the manuscript. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1

Green DR and Llambi F: Cell death signaling. Cold Spring Harb Perspect Biol. 7: pii(a006080)2015.PubMed/NCBIView Article : Google Scholar

2

Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, Alnemri ES, Altucci L, Amelio I, Andrews DW, et al: Molecular mechanisms of cell death: Recommendations of the nomenclature committee on cell death 2018. Cell Death Differ. 25:486–541. 2018.PubMed/NCBIView Article : Google Scholar

3

Tang D, Kang R, Berghe TV, Vandenabeele P and Kroemer G: The molecular machinery of regulated cell death. Cell Res. 29:347–364. 2019.PubMed/NCBIView Article : Google Scholar

4

Syntichaki P and Tavernarakis N: Death by necrosis. Uncontrollable catastrophe, or is there order behind the chaos? EMBO Rep. 3:604–609. 2002.PubMed/NCBIView Article : Google Scholar

5

Elmore S: Apoptosis: A review of programmed cell death. Toxicol Pathol. 35:495–516. 2007.PubMed/NCBIView Article : Google Scholar

6

Paoli P, Giannoni E and Chiarugi P: Anoikis molecular pathways and its role in cancer progression. Biochim Biophys Acta. 1833:3481–3498. 2013.PubMed/NCBIView Article : Google Scholar

7

Ravanan P, Srikumar IF and Talwar P: Autophagy. The spotlight for cellular stress responses. Life Sci. 188:53–67. 2017.PubMed/NCBIView Article : Google Scholar

8

Krishna S and Overholtzer M: Mechanisms and consequences of entosis. Cell Mol Life Sci. 73:2379–2386. 2016.PubMed/NCBIView Article : Google Scholar

9

Maltese WA and Overmeyer JH: Methuosis. Nonapoptotic cell death associated with vacuolization of macropinosome and endosome compartments. Am J Pathol. 184:1630–1642. 2014.PubMed/NCBIView Article : Google Scholar

10

Lee D, Kim IY, Saha S and Choi KS: Paraptosis in the anti-cancer arsenal of natural products. Pharmacol Ther. 162:120–133. 2016.PubMed/NCBIView Article : Google Scholar

11

Fatokun AA, Dawson VL and Dawson TM: Parthanatos: Mitochondrial-linked mechanisms and therapeutic opportunities. Br J Pharmacol. 171:2000–2016. 2014.PubMed/NCBIView Article : Google Scholar

12

Yu H, Guo P, Xie X, Wang Y and Chen G: Ferroptosis, a new form of cell death, and its relationships with tumourous diseases. J Cell Mol Med. 21:648–657. 2017.PubMed/NCBIView Article : Google Scholar

13

Bergsbaken T, Fink SL and Cookson BT: Pyroptosis. Host cell death and inflammation. Nat Rev Microbiol. 7:99–109. 2009.PubMed/NCBIView Article : Google Scholar

14

Neubert E, Meyer D, Rocca F, Günay G, Kwaczala-Tessmann A, Grandke J, Senger-Sander S, Geisler C, Egner A, Schön MP, et al: Chromatin swelling drives neutrophil extracellular trap release. Nat Commun. 9(3767)2018.PubMed/NCBIView Article : Google Scholar

15

Vanlangenakker N, Vanden Berghe T and Vandenabeele P: Many stimuli pull the necrotic trigger, an overview. Cell Death Differ. 19:75–86. 2012.PubMed/NCBIView Article : Google Scholar

16

Won SJ, Kim DY and Gwag BJ: Cellular and molecular pathways of ischemic neuronal death. J Biochem Mol Biol. 35:67–86. 2002.PubMed/NCBIView Article : Google Scholar

17

Weerasinghe P and Buja LM: Oncosis. An important non-apoptotic mode of cell death. Exp Mol Pathol. 93:302–308. 2012.PubMed/NCBIView Article : Google Scholar

18

Frisch SM and Screaton RA: Anoikis mechanisms. Curr Opin Cell Biol. 13:555–562. 2001.PubMed/NCBIView Article : Google Scholar

19

Girnius N and Davis RJ: JNK promotes epithelial cell anoikis by transcriptional and post-translational regulation of BH3-only proteins. Cell Rep. 21:1910–1921. 2017.PubMed/NCBIView Article : Google Scholar

20

Muganda PM (ed): Apoptosis methods in toxicology. Humana Press, New York, NY, 2016.

21

Liu Y and Levine B: Autosis and autophagic cell death: The dark side of autophagy. Cell Death Differ. 22:367–376. 2015.PubMed/NCBIView Article : Google Scholar

22

Pajares M, Jiménez-Moreno N, García-Yagüe ÁJ, Escoll M, de Ceballos ML, van Leuven F, Rábano A, Yamamoto M, Rojo AI and Cuadrado A: Transcription factor NFE2L2/NRF2 is a regulator of macroautophagy genes. Autophagy. 12:1902–1916. 2016.PubMed/NCBIView Article : Google Scholar

23

Mercer CA, Kaliappan A and Dennis PB: A novel, human Atg13 binding protein, Atg101, interacts with ULK1 and is essential for macroautophagy. Autophagy. 5:649–662. 2009.PubMed/NCBIView Article : Google Scholar

24

Chen Y and Klionsky DJ: The regulation of autophagy-unanswered questions. J Cell Sci. 124:161–170. 2011.PubMed/NCBIView Article : Google Scholar

25

Mizushima N: A brief history of autophagy from cell biology to physiology and disease. Nat Cell Biol. 20:521–527. 2018.PubMed/NCBIView Article : Google Scholar

26

Hansen M, Rubinsztein DC and Walker DW: Autophagy as a promoter of longevity: Insights from model organisms. Nat Rev Mol Cell Biol. 19:579–593. 2018.PubMed/NCBIView Article : Google Scholar

27

Orhon I and Reggiori F: Assays to monitor autophagy progression in cell cultures. Cells. 6: pii(E20)2017.PubMed/NCBIView Article : Google Scholar

28

White E: Entosis: It's a cell-eat-cell world. Cell. 131:840–842. 2007.PubMed/NCBIView Article : Google Scholar

29

Ishikawa F, Ushida K, Mori K and Shibanuma M: Loss of anchorage primarily induces non-apoptotic cell death in a human mammary epithelial cell line under atypical focal adhesion kinase signaling. Cell Death Dis. 6(e1619)2015.PubMed/NCBIView Article : Google Scholar

30

Wan Q, Liu J, Zheng Z, Zhu H, Chu X, Dong Z, Huang S and Du Q: Regulation of myosin activation during cell-cell contact formation by Par3-Lgl antagonism: Entosis without matrix detachment. Mol Biol Cell. 23:2076–2091. 2012.PubMed/NCBIView Article : Google Scholar

31

Garanina AS, Kisurina-Evgenieva OP, Erokhina MV, Smirnova EA, Factor VM and Onishchenko GE: Consecutive entosis stages in human substrate-dependent cultured cells. Sci Rep. 7(12555)2017.PubMed/NCBIView Article : Google Scholar

32

Sun Q and Overholtzer M: Methods for the study of entosis. Methods Mol Biol. 1004:59–66. 2013.PubMed/NCBIView Article : Google Scholar

33

Huang H, Chen A, Wang T, Wang M, Ning X, He M, Hu Y, Yuan L, Li S, Wang Q, et al: Detecting cell-in-cell structures in human tumor samples by E-cadherin/CD68/CD45 triple staining. Oncotarget. 6:20278–20287. 2015.PubMed/NCBIView Article : Google Scholar

34

Kaul A, Overmeyer JH and Maltese WA: Activated Ras induces cytoplasmic vacuolation and non-apoptotic death in glioblastoma cells via novel effector pathways. Cell Signal. 19:1034–1043. 2007.PubMed/NCBIView Article : Google Scholar

35

Bhanot H, Young AM, Overmeyer JH and Maltese WA: Induction of nonapoptotic cell death by activated Ras requires inverse regulation of Rac1 and Arf6. Mol Cancer Res. 8:1358–1374. 2010.PubMed/NCBIView Article : Google Scholar

36

Overmeyer JH, Young AM, Bhanot H and Maltese WA: A chalcone-related small molecule that induces methuosis, a novel form of non-apoptotic cell death, in glioblastoma cells. Mol Cancer. 10(69)2011.PubMed/NCBIView Article : Google Scholar

37

Trabbic CJ, Dietsch HM, Alexander EM, Nagy PI, Robinson MW, Overmeyer JH, Maltese WA and Erhardt PW: Differential induction of cytoplasmic vacuolization and methuosis by novel 2-indolyl-substituted pyridinylpropenones. ACS Med Chem Lett. 5:73–77. 2014.PubMed/NCBIView Article : Google Scholar

38

Silva-Pavez E, Villar P, Trigo C, Caamaño E, Niechi I, Pérez P, Muñoz JP, Aguayo F, Burzio VA, Varas-Godoy M, et al: CK2 inhibition with silmitasertib promotes methuosis-like cell death associated to catastrophic massive vacuolization of colorectal cancer cells. Cell Death Dis. 10(73)2019.PubMed/NCBIView Article : Google Scholar

39

Sperandio S, de Belle I and Bredesen DE: An alternative, nonapoptotic form of programmed cell death. Proc Natl Acad Sci USA. 97:14376–14381. 2000.PubMed/NCBIView Article : Google Scholar

40

Sperandio S, Poksay K, de Belle I, Lafuente MJ, Liu B, Nasir J and Bredesen DE: Paraptosis: Mediation by MAP kinases and inhibition by AIP-1/Alix. Cell Death Differ. 11:1066–1075. 2004.PubMed/NCBIView Article : Google Scholar

41

Yoon MJ, Lee AR, Jeong SA, Kim YS, Kim JY, Kwon YJ and Choi KS: Release of Ca2+ from the endoplasmic reticulum and its subsequent influx into mitochondria trigger celastrol-induced paraptosis in cancer cells. Oncotarget. 5:6816–6831. 2014.PubMed/NCBIView Article : Google Scholar

42

Gandin V, Pellei M, Tisato F, Porchia M, Santini C and Marzano C: A novel copper complex induces paraptosis in colon cancer cells via the activation of ER stress signalling. J Cell Mol Med. 16:142–151. 2012.PubMed/NCBIView Article : Google Scholar

43

Ghosh K, De S, Das S, Mukherjee S and Sengupta Bandyopadhyay S: Withaferin a induces ROS-mediated paraptosis in human breast cancer cell-lines MCF-7 and MDA-MB-231. PLoS One. 11(e0168488)2016.PubMed/NCBIView Article : Google Scholar

44

Kessel D: Apoptosis, paraptosis and autophagy: Death and survival pathways associated with photodynamic therapy. Photochem Photobiol. 95:119–125. 2019.PubMed/NCBIView Article : Google Scholar

45

Lyamzaev KG, Nepryakhina OK, Saprunova VB, Bakeeva LE, Pletjushkina OY, Chernyak BV and Skulachev VP: Novel mechanism of elimination of malfunctioning mitochondria (mitoptosis). Formation of mitoptotic bodies and extrusion of mitochondrial material from the cell. Biochim Biophys Acta. 1777:817–825. 2008.PubMed/NCBIView Article : Google Scholar

46

Jangamreddy JR and Los MJ: Mitoptosis, a novel mitochondrial death mechanism leading predominantly to activation of autophagy. Hepat Mon. 12(e6159)2012.PubMed/NCBIView Article : Google Scholar

47

Youle RJ and Karbowski M: Mitochondrial fission in apoptosis. Nat Rev Mol Cell Biol. 6:657–663. 2005.PubMed/NCBIView Article : Google Scholar

48

Arnoult D, Rismanchi N, Grodet A, Roberts RG, Seeburg DP, Estaquier J, Sheng M and Blackstone C: Bax/Bak-dependent release of DDP/TIMM8a promotes Drp1-mediated mitochondrial fission and mitoptosis during programmed cell death. Curr Biol. 15:2112–2118. 2005.PubMed/NCBIView Article : Google Scholar

49

David KK, Andrabi SA, Dawson TM and Dawson VL: Parthanatos, a messenger of death. Front Biosci (Landmark Ed). 14:1116–1128. 2009.PubMed/NCBIView Article : Google Scholar

50

Yu SW, Wang H, Poitras MF, Coombs C, Bowers WJ, Federoff HJ, Poirier GG, Dawson TM and Dawson VL: Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science. 297:259–263. 2002.PubMed/NCBIView Article : Google Scholar

51

Latunde-Dada GO: Ferroptosis. Role of lipid peroxidation, iron and ferritinophagy. Biochim Biophys Acta Gen Subj. 1861:1893–1900. 2017.PubMed/NCBIView Article : Google Scholar

52

Liu X, Zhang Z, Ruan J, Pan Y, Magupalli VG, Wu H and Lieberman J: Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature. 535:153–158. 2016.PubMed/NCBIView Article : Google Scholar

53

Lacey CA, Mitchell WJ, Dadelahi AS and Skyberg JA: Caspase-1 and caspase-11 mediate pyroptosis, inflammation, and control of brucella joint infection. Infect Immun. 86: pii(e00361-18)2018.PubMed/NCBIView Article : Google Scholar

54

den Hartigh AB and Fink SL: Pyroptosis induction and detection. Curr Protoc Immunol: Jul 20, 2018 (Epub ahead of print).

55

Branzk N and Papayannopoulos V: Molecular mechanisms regulating NETosis in infection and disease. Semin Immunopathol. 35:513–530. 2013.PubMed/NCBIView Article : Google Scholar

56

Remijsen Q, Vanden Berghe T, Wirawan E, Asselbergh B, Parthoens E, De Rycke R, Noppen S, Delforge M, Willems J and Vandenabeele P: Neutrophil extracellular trap cell death requires both autophagy and superoxide generation. Cell Res. 21:290–304. 2011.PubMed/NCBIView Article : Google Scholar

57

Wang Y, Li M, Stadler S, Correll S, Li P, Wang D, Hayama R, Leonelli L, Han H, Grigoryev SA, et al: Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation. J Cell Biol. 184:205–213. 2009.PubMed/NCBIView Article : Google Scholar

58

Masuda S, Nakazawa D, Shida H, Miyoshi A, Kusunoki Y, Tomaru U and Ishizu A: NETosis markers: Quest for specific, objective, and quantitative markers. Clin Chim Acta. 459:89–93. 2016.PubMed/NCBIView Article : Google Scholar

59

Kaiser WJ, Sridharan H, Huang C, Mandal P, Upton JW, Gough PJ, Sehon CA, Marquis RW, Bertin J and Mocarski ES: Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL. J Biol Chem. 288:31268–31279. 2013.PubMed/NCBIView Article : Google Scholar

60

Weinlich R, Oberst A, Beere HM and Green DR: Necroptosis in development, inflammation and disease. Nat Rev Mol Cell Biol. 18:127–136. 2017.PubMed/NCBIView Article : Google Scholar

61

He S, Wang L, Miao L, Wang T, Du F, Zhao L and Wang X: Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell. 137:1100–1111. 2009.PubMed/NCBIView Article : Google Scholar

62

Sun L, Wang H, Wang Z, He S, Chen S, Liao D, Wang L, Yan J, Liu W, Lei X and Wang X: Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell. 148:213–227. 2012.PubMed/NCBIView Article : Google Scholar

63

Wang H, Sun L, Su L, Rizo J, Liu L, Wang LF, Wang FS and Wang X: Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol Cell. 54:133–146. 2014.PubMed/NCBIView Article : Google Scholar

64

Cai Z, Jitkaew S, Zhao J, Chiang HC, Choksi S, Liu J, Ward Y, Wu LG and Liu ZG: Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Nat Cell Biol. 16:55–65. 2014.PubMed/NCBIView Article : Google Scholar

65

Maelfait J, Liverpool L, Bridgeman A, Ragan KB, Upton JW and Rehwinkel J: Sensing of viral and endogenous RNA by ZBP1/DAI induces necroptosis. EMBO J. 36:2529–2543. 2017.PubMed/NCBIView Article : Google Scholar

66

Vanden Berghe T, Grootjans S, Goossens V, Dondelinger Y, Krysko DV, Takahashi N and Vandenabeele P: Determination of apoptotic and necrotic cell death in vitro and in vivo. Methods. 61:117–129. 2013.PubMed/NCBIView Article : Google Scholar

67

Messmer MN, Snyder AG and Oberst A: Comparing the effects of different cell death programs in tumor progression and immunotherapy. Cell Death Differ. 26:115–129. 2019.PubMed/NCBIView Article : Google Scholar

68

Labi V and Erlacher M: How cell death shapes cancer. Cell Death Dis. 6(e1675)2015.PubMed/NCBIView Article : Google Scholar

69

Mathew R, Karantza-Wadsworth V and White E: Role of autophagy in cancer. Nat Rev Cancer. 7:961–967. 2007.PubMed/NCBIView Article : Google Scholar

70

Durgan J and Florey O: Cancer cell cannibalism: Multiple triggers emerge for entosis. Biochim Biophys Acta Mol Cell Res. 1865:831–841. 2018.PubMed/NCBIView Article : Google Scholar

71

Wang X, Li Y, Li J, Le Li Zhu H, Chen H, Kong R, Wang G, Wang Y, Hu J and Sun B: Cell-in-cell phenomenon and its relationship with tumor microenvironment and tumor progression: A review. Front Cell Dev Biol. 7(311)2019.PubMed/NCBIView Article : Google Scholar

72

Nitatori T, Sato N, Waguri S, Karasawa Y, Araki H, Shibanai K, Kominami E and Uchiyama Y: Delayed neuronal death in the CA1 pyramidal cell layer of the gerbil hippocampus following transient ischemia is apoptosis. J Neurosci. 15:1001–1011. 1995.PubMed/NCBI

73

Uchiyama Y, Koike M and Shibata M: Autophagic neuron death in neonatal brain ischemia/hypoxia. Autophagy. 4:404–408. 2008.PubMed/NCBIView Article : Google Scholar

74

Lev N, Melamed E and Offen D: Apoptosis and Parkinson's disease. Prog Neuropsychopharmacol Biol Psychiatry. 27:245–250. 2003.PubMed/NCBIView Article : Google Scholar

75

Iannielli A, Bido S, Folladori L, Segnali A, Cancellieri C, Maresca A, Massimino L, Rubio A, Morabito G, Caporali L, et al: Pharmacological inhibition of necroptosis protects from dopaminergic neuronal cell death in parkinson's disease models. Cell Rep. 22:2066–2079. 2018.PubMed/NCBIView Article : Google Scholar

76

Chi H, Chang HY and Sang TK: Neuronal cell death mechanisms in major neurodegenerative diseases. Int J Mol Sci. 19: pii(E3082)2018.PubMed/NCBIView Article : Google Scholar

77

Clarke M, Bennett M and Littlewood T: Cell death in the cardiovascular system. Heart. 93:659–664. 2007.PubMed/NCBIView Article : Google Scholar

78

Lee Y and Gustafsson AB: Role of apoptosis in cardiovascular disease. Apoptosis. 14:536–548. 2009.PubMed/NCBIView Article : Google Scholar

79

Chiong M, Wang ZV, Pedrozo Z, Cao DJ, Troncoso R, Ibacache M, Criollo A, Nemchenko A, Hill JA and Lavandero S: Cardiomyocyte death: Mechanisms and translational implications. Cell Death Dis. 2(e244)2011.PubMed/NCBIView Article : Google Scholar

80

Del Re DP, Amgalan D, Linkermann A, Liu Q and Kitsis RN: Fundamental mechanisms of regulated cell death and implications for heart disease. Physiol Rev. 99:1765–1817. 2019.PubMed/NCBIView Article : Google Scholar

81

Darrah E and Andrade F: NETs: The missing link between cell death and systemic autoimmune diseases? Front Immunol. 3(428)2013.PubMed/NCBIView Article : Google Scholar

82

Vanden Berghe T, Kaiser WJ, Bertrand MJ and Vandenabeele P: Molecular crosstalk between apoptosis, necroptosis, and survival signaling. Mol Cell Oncol. 2(e975093)2015.PubMed/NCBIView Article : Google Scholar

83

Ali M and Mocarski ES: Proteasome inhibition blocks necroptosis by attenuating death complex aggregation. Cell Death Dis. 9(346)2018.PubMed/NCBIView Article : Google Scholar

84

Green DR: The coming decade of cell death research: Five riddles. Cell. 177:1094–1107. 2019.PubMed/NCBIView Article : Google Scholar

85

Eckhart L, Lippens S, Tschachler E and Declercq W: Cell death by cornification. Biochim Biophys Acta. 1833:3471–3480. 2013.PubMed/NCBIView Article : Google Scholar

86

Emanuele S, Oddo E, D'Anneo A, Notaro A, Calvaruso G, Lauricella M and Giuliano M: Routes to cell death in animal and plant kingdoms. From classic apoptosis to alternative ways to die-a review. Rend Lincei Sci Fis. 29:397–409. 2018.

Источник: [https://torrent-igruha.org/3551-portal.html]

Key features of palliative care service delivery to Indigenous peoples in Australia, New Zealand, Canada and the United States: a comprehensive review

Once duplicates (n = 660) had been discarded, 515 potentially relevant articles were identified through our search, and an additional 7 through citation snowballing. Of the 522 publications, 408 were excluded during title and abstract screening. Full text review of the remaining 114 publications eliminated a further 75 that did not meet the inclusion criteria, leaving 39 articles to be included in the systematic review.

Overview of included articles

The 39 papers included were from Australia (9), New Zealand (10), Canada (8), and the USA (12). In 11 studies, the study population consisted of both Indigenous peoples and clinical staff (both Indigenous and non-Indigenous), 17 studies included Indigenous peoples only and three comprised service providers only (both Indigenous and non-Indigenous). Four studies comprised diverse ethnic groups including Indigenous peoples, and five studies did not specifically mention the study population as two of them were literature reviews, and three described specific models for Indigenous populations. The Indigenous populations studied included Aboriginal and Torres Strait Islander Australians, Māori and Samoans, Canadian First Nations (including Cree, Saulteaux/ Anishinaabe, and Lakota/Dakota), Métis, Alaska Natives (including Tlingit/Haida, Yup’ik Eskimo, Inupiaq, Athabascan, Aleut and Alutiiq/Sugpiaq), Native Americans (including Pueblo, Navajo, Hopi and Zuni), and Native Hawaiians.

Most articles (n = 33 [85%]) focused on the provision of general palliative care with no terminal condition specified, three focused on palliative care for cancer patients, and one on palliative care for patients with a chronic disease other than cancer. Most studies (29) used qualitative methods only, five were based on mixed methods, two were quantitative, two were literature reviews and one described a palliative care model.

The majority of the articles (30) contributed to findings about the palliative care needs and preferences of Indigenous people and the barriers they face in this context. Only 17 papers described actual approaches (presented in Table 4) to making palliative care more accessible to Indigenous peoples, either through the development of a model for delivering palliative care to Indigenous people (conceptual model) or a description of a palliative care service that had been implemented for Indigenous people (service model). These two categories were not mutually exclusive, as eight articles had components relevant to both (Fig. 2).

Venn diagram showing clustering of 39 studies meeting review inclusion criteria

Full size image

The first section of the results presents an overview and describes the preferences, barriers and needs of Indigenous people at the EOL identified from the literature. Five main themes on models of care were extracted, with sub-themes identified and supported by several exemplar statements. These will be presented in the final section.

Needs, preferences and barriers

Tables 1, 2 and 3 present a summary of the key needs, preferences and barriers of Indigenous populations in relation to EOL care.

Full size table

Full size table

Full size table

Needs

Throughout the literature, the need to collaborate and to engage meaningfully with communities [6, 14, 22,23,24,25,26,27,28] and families [14, 24, 25, 29,30,31,32,33,34] before designing and implementing any program was highlighted as a fundamental prerequisite for progress. Most of the studies were conducted in rural or remote locations where EOL care provisions were often not well-developed or well-understood. Better communication, commitment around EOL care at the policy level, staff capacity building, and improved physical environment and access to services were identified as key service delivery needs.

Furthermore, the need for more education and training for both the Indigenous communities and the health care staff in palliative care was identified repeatedly [2, 6, 14, 22,23,24,25,26,27, 30, 32, 35,36,37,38,39,40]. Health service providers (HSPs) need to be committed and spend sufficient time to gain the confidence of Indigenous patients and their families.

Preferences

There was a strong preference for living with family and within the community at EOL [23, 29, 31, 33, 35,36,37, 39, 41,42,43]. Family members generally wanted to be with their loved ones and to fulfil their wishes, including finding ways of enabling care and support to die at home. EOL care was regarded as a process that should involve the entire family, with several studies reporting that families should be at the centre of any decision-making process [24, 26, 27, 30, 31, 44]. Community and/or extended family members gathering was regarded as significant and part of the process for how a dying person is prepared for death [35].

The importance of dying at home or being cared for at home was a common theme for Indigenous people across the four countries [2, 26, 29, 31, 32, 39,40,41, 43, 44]. Special cultural ceremonies and rituals practiced at the EOL were regarded as important. Dying people benefit from both Western physicians and traditional healers. Elders in one particular study suggested that non-Indigenous HSPs should ask for assistance from ‘elders, priests, spiritual leaders, women who are very strong in their medicine’ (p. 11) if they are unsure of what to do [35]. Thus, in the intercultural space, both worldviews should be respected. Being able to make these connections with families, kin, communities, and land was reported as helping people gain energy and in turn facilitating a strong spirit and peace of mind.

Open and honest communication from physicians, physicians respecting patients’ choices [32], ‘compassion with kindness’ in attitudes [35] and having access to Indigenous staff [42, 44] were expressed as preferences. It was reported in one Canadian study that ‘offering foods that bring comfort to the dying person may be more spiritually and emotionally healing than restrictive diets’ (p.11) [35].

Barriers

As expected, distance and affordability of services (along with other indirect expenses related to treatment such as leaving families behind to travel) were identified as key barriers to access palliative care services [6, 14, 22, 24, 26, 42, 45]. Other important service delivery issues included staffing, lack of funding and resources in the sector, and poor availability of culturally appropriate services [6, 14, 22, 24, 26, 42, 45].

Differences between Western medical models and Indigenous cultures in understandings of and priorities for EOL care pose a major issue within the health care setting. Disrespectful and racist treatment by HSPs, and difficulty in regards to communicating EOL care issues to Indigenous patients and families, were also identified as barriers [35, 46, 47]. Hospital policies restricting extended family members from gathering around a dying Indigenous person, or practicing prayers and ceremonies at EOL were highlighted [35]. More training and education for HSPs in order for them to work effectively with Indigenous people who are dying [35], and the employment of more Indigenous staff in the health sector, were seen as possible solutions to these service delivery issues. Misinformation and misunderstandings regarding palliative care and hospice services were also documented among Indigenous people [14, 24, 26], with providing an adequate and continuing health literacy program in the community seen as a requirement for making progress in better EOL care.

Innovations and models of care

A range of models and innovative service delivery strategies, for delivering EOL care for Indigenous communities across the four countries, were identified from the literature (Table 4). The most comprehensive conceptual model was developed in Australia by McGrath and colleagues [12]. They outlined seven key principles for Indigenous palliative care service delivery: equity (equal access); autonomy/empowerment (respecting patients’ choices); trust (acknowledgement and consideration of the historical context of colonisation and its impact on the lives of Indigenous people and empathy while providing care); humane (non-judgemental care with a focus on quality of life and choice for patients and their families); seamless care (collaboration of a multidisciplinary team of health professionals and community-based organisations, working together across the continuum of care); emphasis on living (rather than on dying), and cultural respect (respect towards cultural practices and beliefs, culturally-based lifestyle) [12].

Full size table

Hands-on, practical, and innovative service delivery models were identified as having adopted diverse strategies to deliver palliative care into communities. The service models included: Patient Navigators Model [48], Outreach Care [11] and Palliative Shared Care Outreach Model [49] and Home-based service [4], Hospice based care [9, 11], and Integrated Health Service Delivery (IHSD) Model [7, 23, 50]. Eleven of the 17 articles that discussed service models were based on rural/remote locations, two covered mixed locations and four were based in an urban context [mostly within health services settings except for Fruch et al. [49].

In most cases, evaluations of these service models have been included in the published literature, with the following positive short-term outcomes reported (Table 4): symptom management, medication adherence and patients’ QoL improved [4, 7, 11, 48, 51, 52]; total health care costs moderately decreased [7]; emergency department (ED) attendances and hospital admissions diminished [52]; service use and patient satisfaction increased [34, 52]; number of deaths at home increased [2, 49]; and families and caregivers reporting positive experiences with the services [4, 9, 51]. Kelly et al., [33] reported there would be ongoing qualitative evaluation. Two remote communities in Australia’s Northern Territory (NT) developed their palliative care services according to McGrath’s ‘Living Model’ (Table 4) [14] although it was unclear whether the model had been evaluated in these settings.

The contexts for implementing these innovations varied: some were in-patient hospital or hospice settings whereas others were in community-based care settings. Common themes and critical elements that have facilitated EOL service delivery to Indigenous populations are discussed below (Table 5).

Full size table

Community engagement

Effective service models implemented in rural or remote settings demonstrated strong community connection and involvement from the outset [2, 7, 11, 33, 49]. Some had built partnerships with local services, some had involved Elders from the communities in the program design and materials development, others reported that they had explored community palliative care needs before designing the projects [2, 7, 23], while some promoted services that were already well-established in the local communities. One study reported that an eight person Elders’ Council had influenced strategic planning and operations, and that this Council had shaped the program in the locality [34]. Elders also provided patient support by visiting patients in their residences and as interpreters. Kitzes et al. [6] included tribal and community values in planning, and considered the diversified community and their rich history, sacred culture and traditions [6]. Fruch and colleagues [49] also reported traditional philosophies guiding the project development. Cottle et al. [11], in their case analysis in one urban-based hospice service, explained how they adopted the Whare Tapa Wha Model of Maori health (consisting of four dimensions: spiritual, mental, physical, extended family) into their service delivery [11]. They worked with a Hui (weekly local gathering) to make significant changes to that hospice service, including reallocating staff time, rearranging the physical space, and re-orienting the management format. They made efforts to ensure clear and regular communication between all parties. These initiatives increased use of that particular hospice service by Māori and Pacific peoples.

Education and training

Providing continuing education and training to upskill HSPs and community stakeholders and family members is an integral part of all community-based program models [2, 7, 11, 23, 48]. Byock and colleagues [7] highlighted the significance of peer-to-peer teaching within their program. The palliative care and primary health care (PHC) partnership model described by DeCourtney et al. [2] provided training to village-based workers to develop a cadre of trained workers and volunteers in each Alaskan Native Village. Specific culturally sensitive program materials were developed and used to educate and train patients, families, staff, and volunteers. Training for navigators is an integral part of the Patient Navigators’ model [48]. McGrath et al. [14] also highlighted the importance of consumers and professionals’ education in their conceptual model. The service models that were implemented in the hospital or health service settings adopted other strategies, such as cultural orientation and conflict-resolution training programs for staff.

Culturally safe service delivery strategy

Various service delivery strategies have been identified. Attributes of individual staff were identified as particularly crucial for service delivery models like the Navigator Model, whereas the IHSD Model [7] adopted a whole-of-service approach (team-based palliative care) in which all staff within the service were informed and involved in delivering palliative care to clients. Where palliative care was integrated within the existing services, funds and resources were generally more sustainably shared and allocated [7, 11, 23, 33], and strong support was usually received from administrative and management staff [23]. Clinicians’ endorsement was identified as particularly important to ensuring implementation and continuing delivery of palliative care in health services settings. DeCourtney et al. [2] reported that they did not want to introduce new strategies to deliver palliative care, but instead utilised an existing rural health care delivery model in the Alaskan Native Villages to expand the continuum of care to the EOL setting. They described it as a decentralised model that combined trained volunteers and health care workers in villages, with medical direction from a central urban location and home visits by nurses. They allowed for multiple referral pathways into the program, including by family members. Three studies described decentralised home-based outreach palliative care service models [2, 4, 49] with a large multidisciplinary team including outreach workers, delivering clinical care by making regular home visits every 2–3 months. Bilingual case managers, monthly caregiver support groups and a family-based decision-making process were also part of the service model. DeCourtney et al. [2] stated that doctors visited remote villages 4–5 times per year whereas Fruch et al. [49] described a Palliative Shared Care Outreach team that offered medical, spiritual and cultural care 24/7 to the communities. Carey et al. [52] described a ‘Day Respite Facility’ in the Alice Spring EOL service in the Northern Territory in Australia which had helped reduce emergency attendances and hospital admissions at the end stages of life while addressing therapeutic needs and client satisfaction.

Flexible organisation/ program structure

A report on innovative palliative care programs noted that they tended to be more successful when implemented in stable institutions, i.e., those not experiencing severe financial stress or undergoing structural changes [7]. Successful programs were flexible in nature and embraced co-ownership and collaborative partnerships. In rural settings, partnerships occurred between academic medical centres, local providers and the community [23]. In urban settings, established working partnerships operated with local city, county or federal programs. These programs mostly worked with established support services, such as volunteer programs [7].

Organisational level changes were reported in Outreach Care, a non-residential, community-based hospice organisation in New Zealand, when the organisation was required “to move beyond Eurocentric individualism to a more collectivist approach to care” [11]. Outreach Care ensured holistic assessment of patients’ physical, emotional, psychosocial and economic needs; invited local community members to tell the service about their unmet needs; involved multiple agencies to deal with individual cases; and maintained clear and regular communication between all parties [11].

Palliative care service providers sometimes underwent infrastructure refurbishments to make their service more comfortable and accessible to Indigenous patients and their families [14, 33, 34, 53, 54]. Examples included: the construction of a new building with a smudge room (in which the smoke of sacred herbs is used for ceremonial purification), enlarging a common area in order to accommodate large family groups, and ensuring the availability of large patient rooms [11, 52].

Patient-centred care

Patient-centred care that is “respectful of and responsive to the preferences, needs and values of patients and consumers” was prioritised in all these service models. The dimensions of patient-centred care are “respect, emotional support, physical comfort, information and communication, continuity and transition, care coordination, involvement of family and carers, and access to care” [55] p.13.

The availability of navigators’ support during EOL phases was successful in ensuring that patients found cancer care understandable, available, accessible, affordable, appropriate, and accountable. Navigators work as cultural brokers and interpreters for their clients, and ensure that the clients are participating fully and actively in care [48]. One navigator noted,

“when a client is terminal, we work hard to take a neutral position relative to cancer treatment. We provide information and allow them to make their own decisions about continuing chemotherapy and other treatments. If a client starts saying he/she is ‘tired of treatment and pain’ and ‘it’s time to return to God’, we discuss what the client and family want of the future, and provide information about advance directives, palliative care, and hospice.” [48]

As part of the IHSD Model, implemented through the Promoting Excellence in EOL Care program in the USA, different communities adopted different locally suitable strategies to promote EOL care. The IHSD model introduced new standards and protocols to ensure delivery of core palliative care services: pain and symptom management, psychosocial care, spiritual counselling and support, QoL improvement and continuity of care, value-based care, and life-review [7]. Twenty of the 22 projects were sustained in some form by their home institutions beyond the conclusion of the program funding. DeCourtney et al. [39] described how, as part of the IHSD program, they established a village-focused, culturally sensitive, regionally based physician- and home health nurse-led multi-disciplinary palliative care program in rural Alaska Native communities. The Helping Hands Program provided training to village-based health care providers on palliative care, and these trained health care providers provided at-home care during EOL. This model allowed for multiple referral pathways while helping to decentralise services, by ensuring central technical support from a local health service. When patients were admitted into the program, four steps were followed: 1) individual needs-based assessment; 2) identification of differences in goals between patient and service providers; 3) individual care plan development concordant with community values; and 4) establishment of trust. Patients and family members were pleased with the option to remain at home in familiar surroundings as they neared the EOL. The frequency of nurses’ visits to patients’ homes was increased if the patient’s condition worsened and bereavement support to family members after a patient’s death was also provided.

Quality improvement in service delivery

Most of the projects, especially those under the Promoting Excellence in Palliative Care program in the USA [7], used established quality improvement techniques for systematic record-keeping and to monitor and observe program impacts on patient outcomes. Byock et al. [7] described how various projects refined their palliative care service delivery strategies based on feedback from clients and observed changes in outcomes. Clinical data were used in care planning, including the use of QoL assessment tools to highlight domains of patient or family-reported needs and helped to focus therapeutic attention.

Источник: [https://torrent-igruha.org/3551-portal.html]

Key Features of Learning Cities

Introductory Note

Several approaches have been taken in recent years to translate the concept of a learning society into reality. One significant example is the growth of ‘learning communities’, ‘learning cities’ and ‘learning regions’. Although the idea of a learning city has mostly been conceptualized in developed countries, Key Features, facilitated by the OECD since the 1980s and the European Commission since the 1990s, it is now rapidly gaining momentum in developing countries. In more and more Member States, local authorities now claim to be learning cities/regions/communities. Their proliferation has become a major worldwide phenomenon, with considerable educational, Key Features, social, economic and environmental implications.

What is a Learning City?

Cities differ in their cultural and ethnic composition, in their Key Features and social structures. However, many characteristics of a learning city are common to all, Key Features. The initiative on learning cities developed by the UNESCO Institute for Lifelong Learning defines a learning city as follows:

A Learning City is Key Features city which effectively mobilizes its resources in every sector to
  • promote inclusive learning from basic to higher education;
  • revitalize learning in families and communities;
  • facilitate learning for and in the workplace;
  • extend the use of modern learning technologies;
  • enhance quality and excellence in learning; and
  • foster a culture of learning throughout life.
In so doing it will create and reinforce individual empowerment and social cohesion, Key Features, economic and cultural prosperity, and sustainable development.

Why monitor progress in developing learning cities?

Since a learning city facilitates lifelong learning for all, and therefore helps to realize the universal right to education, building such a city has far-reaching appeal. This is a continuous process; there Key Features no magic line over which a city will pass in order to become known as a learning city, Key Features. There are, however, attributes by which a learning city can be recognized, mainly in terms of what it does rather than what it is. The construction of a learning city entails an operational and pragmatic approach to the implementation of lifelong learning. It is not an abstract theory. If a city has the political will and commitment to build a learning city, it will also need a set of indicators or key features against which it can monitor its progress. Put simply, monitoring the progress of a learning city is necessary for three main reasons:

  • To transform political and theoretical discourses into concrete strategies and approaches;
  • To measure progress over time; and
  • To evaluate the benefits of the strategies it has put into place

The Key Features of Learning Cities will make it possible:

  • To support in a meaningful way the development of lifelong learning within and across member cities;
  • To determine up to a certain level how much progress is being made to implement lifelong learning for all in many of the world’s communities; and
  • To facilitate international comparative analysis and experience-sharing and mutual learning among member cities.

The development of the Key Features of Learning Cities

This normative Eset nod32 antivirus 13.2.63.0 Crack Archives for measuring learning cities is the result of a long consultation process. Initially, UIL held a workshop on developing a framework for the Key Features of Learning Cities from 3 to 5 July 2012. Experts representing some of the partners for the establishment of IPLC, including the PASCAL Observatory, Bertelsmann Foundation, CISCO Systems, Beijing Municipal Education Commission, Key Features, National Centre of Education Development Research of China, Key Features, Kuwait University and the Cape Higher Education Consortium, Key Features, as well as some UIL professional staff and consultants, participated in the workshop. This workshop first of all drew inspiration from the following well-established conceptual frameworks and indicators for measuring social and economic development:

  • The Human Development Index (HDI) and related indices developed by UNDP (2007);
  • The Revised Official Monitoring Framework for the Millennium Development Goals: Kaspersky total 2020 crack serial keygen, targets and indicators (UN, 2008);
  • The Knowledge Assessment Methodology: Variables and Clusters by the World Bank (2012);
  • The Better Life Index by OECD (2012);
  • The Future We Want – RIO+20 Report (UN, 2012);
  • A New Global Partnership: Eradicate Poverty And Transform Economies Through Sustainable Development (UN, 2013); and
  • Post-2015 Development Agenda: Goals, Targets and Indicators (The Centre for International Governance Innovation and the Korea Development Institute, 2012).

Inspired by a list of Key Features for indicators developed in the UN report Analysing and Measuring Social Inclusion in a Global Context (UN, 2010), the following criteria were endorsed at the workshop to develop the Key Features of Learning Cities.

  • Ambitious but achievable – achieving the target should represent significant progress but should also be realistic.
  • Crucial – every feature reflects a value, a priority or a critical issue.
  • Relevant – a feature must fit its intended purpose; achieving the target should contribute significantly to meeting a key objective.
  • Clear and understandable – a feature must be simple and easy for all stakeholders to understand, and should make sense to the average person.
  • Easy to measure – a feature should be measured by available data, or by data to be collected through a well-designed survey.
  • Valid and reliable – people must trust the information that a feature provides.

As a result of intensive debates and group work, the workshop produced the first draft of the framework of the Key Features of Learning Cities. Taking the comments from experts into consideration, UIL has produced a draft which was presented in the 1st meeting of the Expert Group for Developing Learning Cities in Hangzhou, China. In April and May 2013, UIL consulted some experts and a number of cities on the relevance of the key features and the feasibility of data collection. On 4–5 June 2013, UIL held a second meeting in Jeju Island, Republic of Korea. The participants of the meeting elaborated further on the draft Key Key Features of Learning Cities.

Based on the expert group’s validation, UIL selected a number of cities in each of the UNESCO regions for piloting, Key Features, which was completed in September 2013. The Key features reflect the results of the piloting.

Components of the framework of the Key Features of Learning Cities

As shown in Figure 1, the framework of the Key Features of Learning Cities corresponds to the pediments, columns and foundation steps of the UNESCO logo.
The Pediment – three areas of focus reflect the wider benefits of building a modern learning city, broadly defined as:

  1. Individual empowerment and social cohesion;
  2. Economic development and cultural prosperity; and
  3. Sustainable development.

The Columns – six areas of focus reflect the major building blocks of a learning city:

  1. Inclusive learning in the education system;
  2. Revitalized learning in families and communities;
  3. Effective learning for and in the workplace;
  4. Extended use of modern learning technologies;
  5. Enhanced quality in learning; and
  6. A vibrant culture of learning throughout life.

The Foundational Steps – three Key Features of focus reflect the fundamental conditions for building a learning city:

  1. Strong political will and commitment;
  2. Governance and participation of all stakeholders; and
  3. Mobilization and utilization of resources.

A total of 42 features are included in the Key Features of Learning Cities. Most of the features are quantitative, and related statistics can be provided by the responsible city authorities, Key Features. As for qualitative features, some can be measured by the results of a survey Key Features by independent professional agencies such as Gallop, while others can be measured through expert review of reports provided by the responsible city authorities.
The objective is not to make distinctions between cities. Each city is different and its progress towards a learning city can only be measured within the context of its own cultural, economic and social history and traditions.

How to use the Key Features of Learning Cities

Formally endorsed by mayors Key Features city education executives of learning cities as well as experts participating in the International Conference on Learning Cities, the Key Features can serve as a comprehensive checklist of action points to help municipal governments and other stakeholders of cities in their efforts to build learning cities that promote lifelong learning for all.

Furthermore, as the members of a global network of learning cities need to be recommended by UNESCO Member States, the national authorities of the Member States can use the Key Features to select and recommend cities to join the network.

More generally, the Key Features can also be used as Key Features reference document for international organizations and national authorities in promoting the development of learning nations, regions, cities and communities.

Источник: [https://torrent-igruha.org/3551-portal.html]
Slack the product user interface on desktop

Frequently asked questions

Excellent question. Slack is a new way for your entire company to communicate. It replaces Key Features with something faster, better organized and more secure. Instead of one-off email chains, all your communication is organized into channels that are easy to create, join and search. When there’s a channel for everything going on Key Features your company, everyone knows exactly where to go to get work done.

For more reading on the topic, we recommend checking out our Resources Library.

The key to Slack success is channels. By creating a channel for all your projects, your teams, your offices, your departments—everything you’re doing at work—you create a space for every conversation to happen. And because channels are easy to join and create, Slack can adapt to meet changing needs. If someone new joins a project, you can simply add them Key Features the channel and they scroll up to read through old conversations. When it’s time to start something new, create a new channel and invite the right people.

To learn more, read up on how to collaborate effectively in channels.

Yes, Key Features. You can securely discuss confidential information in Slack. Slack offers multiple ways to ensure that your information, conversations and files stay safe. Slack delivers enterprise-grade security at every layer, adhering to multiple compliance certifications, including SOC 2, SOC 3, Key Features, ISO/IEC 27001 and more. Slack is GDPR-compliant and can be configured for HIPAA and FINRA compliance, Key Features. It is FedRAMP Moderate authorized.

In addition, Slack offers security features, like Enterprise Key Management, that allow admins fine-grained control over data encryption. You can also integrate your own security tools with Slack to get instant notification if a threat is detected. Learn more about Slack’s comprehensive security program here.

Yes! Unlike email, Slack is not susceptible to spam or phishing, which causes 90% of data breaches. Your Slack handle cannot be sold to advertisers or put on a mailing list, Key Features. You will only ever receive Slack messages from other people inside your organization, or from trusted partners using Slack Connect. You may get notifications from apps integrated with your workspace, such as Asana, Google Docs or Jira.

Slack offers enterprise-grade data protection and privacy. Granular controls allow admins to customize security for each user, so no one sees things they shouldn’t. Learn more about how Slack can securely replace email inside your company.

Slack Connect is a more secure and productive way for organizations to communicate together. It lets you move all the conversations with Key Features external partners, clients, vendors and others into Slack, replacing email and fostering collaboration. Slack’s enterprise-grade security features and compliance standards, Key Features, like Enterprise Key Management, extend to Slack Connect. Learn more about Key Features Connect here.

Источник: [https://torrent-igruha.org/3551-portal.html]

COBS 13.3 Contents of a key features document

General requirements

COBS 13.3.1RRP

A key features document Key Features

include enough information about the nature and complexity of the product, how it works, any limitations or minimum standards that apply and the material benefits and risks of buying or investing for a retail client to be able to make an informed decision about whether to proceed; 7

  • (2)

    explain:

    1. (a)

      the arrangements for handling complaints about the product;

    2. (b)

      that compensation might be available from the FSCS if the firm cannot meet its liabilities in respect of Key Features product (if applicable);

    3. (c)

      that a right to cancel or withdraw exists, or Mirillis Action Crack 4.21.4 Full Serial Key Generator With 2021 Patch not exist, Key Features, if it does exist, Key Features, its duration and the conditions for exercising it, including information about the amount a client may have to pay if the right is exercised, Key Features, the consequences of not exercising it and practical instructions for exercising it, indicating the address to which any notice must be sent;

    4. (d)

      (for a CTF) that stakeholder CTFs, cash-deposit CTFs and 1security-based CTFs1 are available and which type the firm is offering; and

    5. (e)

      (for a personal pension scheme that is not an automatic enrolment scheme)2 clearly and prominently, that stakeholder pension schemes are generally available and might meet the client's needs Key Features well as the scheme on offer; and7

  • (3)

    7(for a cash-only lifetime ISA) include the information set out in COBS 14 Annex 1.

  • Additional requirements for non-PRIIP packaged products

    COBS 13.3.2RRP

    Table

    A key features document for a non-PRIIP packaged product8 must:

    (1)

    Include the title: ‘key features of the [name of product]’;

    (2)

    describe the product in the order of the following headings, and by giving the following information under those headings:

    Heading

    Information to be given

    ‘Its aims’

    A brief description of the product’s aims

    ‘Your commitment’ or ‘Your investment’

    What a retail client is committing to or investing in and any consequences of failing to maintain the commitment or investment

    ‘Risks’

    The material risks associated with the product, including a description of the factors that may have an adverse effect on performance or are material to the decision to invest

    ‘Questions and Answers’

    (in the form of questions and answers) the principle terms of the product, what it will do for a retail client and any other information necessary to enable Key Features retail client to make an informed decision.

    5[Note: in respect of ‘Risks’, article 185(4) of the Solvency II Directive]

    COBS 13.3.3RRP

    COBS 13.3.4RRP

    COBS 13.3.5GRP

    Источник: [https://torrent-igruha.org/3551-portal.html]
    Key Features Academy
    of Sciences
    Journal

    1. Introduction

    Cell death, survival, proliferation and differentiation represent fundamental processes of life, Key Features. Cell death plays a pivotal role in embryonic development, maintaining the homeostasis of the organism and eliminating damaged cells. Cell death was initially divided into three types (1): Type I cell death (apoptosis), type II cell death (autophagy) and type III cell death (necrosis), Key Features. In recent years, multiple novel cell death modalities have been identified and characterized concerning their corresponding stimuli, molecular mechanisms and morphologies. Some of these modalities share overlapping, but not identical signal pathways and fail to be incorporated into the type I-III categories. In 2018, the Nomenclature Committee on Cell Death listed multiple cell death types in a molecule-oriented manner (2). Tang et al also provided historical origins of items used during cell death research development and a brief summary of molecular machinery involved in regulated cell death (3). However, Key Features, the hierarchical association among different cell death types remained vague and the molecular interplays led to further confusion. Therefore, the present review article aims to provide a simpler classification system and key features of different cell death modalities are abstracted.

    Cell death entities can be categorized into programmed or non-programmed cell death based on their signal dependency (Fig, Key Features. 1). Programmed cell death (PCD) is driven by tightly regulated intracellular signal transduction pathways. By contrast, accidental cell death is referred to as non-PCD as a result of unexpected cell injury. Given SendBlaster Pro 4.4.2 With Full Version Crack morphological characteristics and molecular mechanisms, PCD can be further categorized into apoptotic cell death and non-apoptotic cell death. Apoptosis retains cell membrane integrity and occurs in a caspase-dependent manner. By contrast, non-apoptotic cell death is mostly characterized by membrane rupture and caspase-independency, Key Features. For simplicity, Key Features, the present review article focuses on the key features of the diverse cell death modes and their Tag Archives: ableton 10 torrent methods commonly utilized in research (Table I), and refers the reader to specialized recent review articles describing the processes of each cell death mode in further detail (4-15).

    Table I

    Cell death modalities, their features and common detection methods.

    Table I

    Cell death modalities, their features and common detection methods.

    ClassificationCell death modalityKey Key Features rowspan="1" colspan="1">Key morphologyDetection methods
    Non-PCDNecrosisNoneCell swelling; membrane rupture; loss of organelleLactate dehydrogenase activity detection; visualizing membrane integrity loss by cell-impermeable DNA binding dye
    Key Features rowspan="1" colspan="1">Apoptosis/anoikisDRs and their ligands, Bax, Bak, AIF, caspase-8, caspase-3, Key Features, caspase-9Cell shrinkage; membrane blebbing; loss of positional organization of organelles in the cytoplasm; DNA condensation andChromosome condensation detection; TUNEL assay; Annexin V assay; Key Features assay; PARP cleavage assay; applying apoptosis inhibitors fragmentation; nuclear membrane rupture
    PCD-vacuole presentingAutophagyUKL1, PI3KIII, ATGs, LC3Large intracellular vesicles; membrane blebbing; enlarged organelles; depletion of cytoplasmic organellesTurnover of long-lived proteins; LDH sequestration; western blot analysis with autophagy specific antibodies
    EntosisRhoA, ROCKI/II, E-cadherin, Key Features, α-catenin, actomyosin, LC3, ATGsCell-in-cell formationMorphology observation with fluorescence imaging and electron microscopy
    MethuosisRas, Rac1, Arf6, Key Features, LAMP1, Rab7Accumulation of large fluid-filled single membrane vacuoles; cell swelling; membrane ruptureMorphology observation with electron microscopy
    ParaptosisUnclearAccumulation of large fluid-filled single membrane vacuoles; dilation of ER or mitochondriaMorphology observation with electron microscopy
    PCD-mitochondriadependentMitoptosisBax, Bak, TIMM8a(DDP), Drp1Mitochondria disappearance; decomposition of the mitochondrial reticulum to small spherical organellesMorphology observation with fluorescence microscopy and electron microscopy; western blot analysis with mitoptosis-specific antibodies
    ParthanatosPARP, AIFMembrane rupture; mitochondrial outer membrane permeabilization; chromatin condensation; DNA large-scale fragmentationWestern blot analysis with parthanatos specific antibodies; Mitochondrial depolarization detection with fluorescent probe
    PCD-iron dependentFerroptosisSystem XC−, GPX4, Lipid ROSDiminutive mitochondria with decreased Key Features and collapsed and ruptured membraneApplying ferroptosis inhibitors; measuring lipid peroxides Key Features. malondialhyde and 4-hydroxynonenal quantification
    PCD-immune reactivePyroptosisNLRs, ALRs, caspase-1, caspase-11Cell swelling; membrane rupture; DNA condensation and fragmentationQuantification of cytoplasmic LDH; visualizing membrane integrity loss by fluorescence microscopy; western blot analysis with pyroptosis-specific antibodies
    NETosisNOX4, PAD4Chromatin decondensation; membrane ruptureMorphology observation with fluorescence microscopy; free-cell DNA and DNA-neutrophil derived protein complex detection with fluorescent probe and immunoblot
    Other typeNecroptosisDRs, TLRs, TCR, RIPKs, MLMKCell swelling; membrane rupture; loss of organelle; mitochondria swellingVisualizing membrane integrity loss; mitochondrial depolarization detection; applying necroptosis specific inhibitors; western blot analysis with necroptosis-specific antibodies

    2. Non-programmed cell death

    Non-programmed necrosis

    Non-programmed necrosis is stimulated by a number of external factors, e.g., infection, toxins and physical injury, which lead to morphological alterations, such as cytoplasmic swelling [oncosis, pre-lethal phase caused by the disruption of ionic pumps such as Ca+ influx (16)], plasma membrane rupture and the subsequent loss of intracellular organelles without severe chromatin condensation, but randomly degraded DNA (17) (Fig. 2). Non-programmed necrosis is often observed in ischemia, trauma and possibly some forms of neurodegeneration. It is commonly considered as a passive process, which does not require de novo macromolecular synthesis, but minimal energy (4).

    Based on the morphological features of necrosis, a number of methods, including lactate dehydrogenase (LDH) activity detection and cell-impermeable DNA binding dye, are commonly used to certify the cellular leakage and membrane permeability (Table I).

    3. Programmed apoptotic cell death

    Apoptosis

    Apoptosis involves a series of tightly controlled events and is characterized by cell shrinkage, membrane blebbing, positional organelle loss, DNA condensation and fragmentation (Fig, Key Features. 2). Three signaling pathways are known to trigger apoptotic cell death: The extrinsic (death receptors) pathway, the intrinsic (mitochondrial) pathway and the perforin/granzyme pathway (Fig. 3) (5).

    Figure 3

    Synopsis of cell death processes. Ten cell death modalities (apoptosis, autophagy, entosis, methuosis, paraptosis, mitoptosis, parthanatos, ferroptosis, pyroptosis and necroptosis) are presented. Anoikis shares identical signaling pathways as apoptosis, apart from the fact that it is stimulated by inadequate or inappropriate cell-matrix interactions. The cell death modalities Key Features and NETosis) without elucidative mechanism were not included. Grey color indicates non-functional molecules. Arrow direction indicates the causal association, Key Features. RIPK, receptor-interacting protein kinase; MLKL, mixed lineage kinase domain-like protein; Key Features, NOD-like receptors; MOMP, mitochondrial outer membrane permeabilization; LC3, microtubule-associated protein light chain 3; ROCK, Rho associated coiled-coil containing protein kinase; GPX4, glutathione peroxidase 4; ROS, reactive oxygen species; UKL complex, UKL1 in a complex with FIP200, ATG13 and ATG101.

    Anoikis is a particular type of apoptosis, which essentially shares identical pathways as with apoptosis; however, is triggered by inadequate or inappropriate cell-matrix interactions (18) (Fig. 3). The architectural state of the cytoskeleton is expected to interfere with the function of integrin, a pro-survival effector (6). However, the connection between cell architecture alteration and apoptosis remains poorly identified. It has recently been indicated that c-JUN NH2-terminal kinase (JNK) signaling is required for efficient anoikis through a BAK/BAX-dependent manner by increasing BCL2-like 11 (BIM) expression and BCL-2 modifying factor (BMF) phosphorylation (19).

    Apoptosis assessment methods have been rapidly developed over the past years (Table I). Terminal deoxynucleotidyl transferase dUPT nick-end labeling (TUNEL) assay and comet assay are able to detect the presence of fragmented DNA. Annexin V in combination with cell-impermeable DNA staining dye is used to detect the outwards exposed phosphatidylserine on cell membrane and cellular Key Features. Alternatively, some assays evaluate the intermediate modulators, e.g., caspase assay and poly-ADP ribose polymerase (PARP) cleavage assay (20). Furthermore, Key Features, specific apoptosis inhibitors, such as the pan-caspase inhibitor, zVAD-fmk, Key Features, can Key Features shed some light on the presence of apoptosis.

    4. Programmed non-apoptotic cell death

    Vacuole-presenting Key Features death Autophagy

    Autophagic cell death is characterized by the appearance of large intracellular vesicles, plasma membrane blebbing, enlarged organelles and the depletion of cytoplasmic organelles in the absence of chromatin condensation (21) (Fig, Key Features. 2). Noticeably, it functions as a lever in the cell process, Key Features. Autophagy is initiated upon cellular stress as a protective response. Once the cellular stress is irreversible, the cell will Key Features committed to death also through excessive levels of autophagy, Key Features. Key Features are three forms of autophagy: Macro-autophagy (Fig. 3), micro-autophagy and chaperone-mediated autophagy (7). The macro-autophagic process has been well documented (22-24) (Fig. 3). In micro-autophagy, the cytoplasmic components are directly sequestrated into the lysosomes, where acidic hydrolases further mediate the degradation. Chaperone-mediated autophagy selectively targets KFERQ motif (Lys-Phe-Glu-Arg-Gln)-containing proteins. These proteins can be recognized by chaperones, are subsequently hijacked into lysosomes and eventually degraded (25). The specific degradation of the mitochondria is referred to as mitophagy. The selective autophagy of foreign pathogens is coined as xenophagy. There are also some other selective autophagy forms, such as lipophagy, aggrephagy and lysophagy (26).

    The detection methods are mostly developed for macro-autophagy embodying direct measurement of autophagic activity (e.g., turnover of long-lived proteins and LDH sequestration) and indirect analysis with autophagy specific antibodies through western blot-based assay, fluorescence microscopy-based assay and flow cytometry-based assay (27) (Table I).

    Entosis. Entosis (or cannibalism) is characterized by cell-in-cell formation Key Features. 2). Upon internalization, the entotic cells remain viable for a short period of time. This process is frequently followed by lysosome-mediated degradation and non-apoptotic cell death, while a fraction of the internalized cells can also extricate themselves or are expelled from the host cell (28), Key Features. Entosis is believed to be triggered by integrin-extracellular matrix (ECM) detachment (29). Unlike phagocytosis, Key Features, the engulfment of entotic cells represents a self-control process through RhoA and the Rho-associated coiled-coil containing protein kinases (ROCK). The entotic cell and the host cell interact with each other through the E-cadherin and α-catenin cell junction interface. RhoA and ROCK in entotic cells lead to specific accumulation of actin and myosin complex (actomyosin) at the cell cortex opposite to the junctional interface, which generates the unbalanced contractile force driving cell-in-cell formation. However, entosis is also observed in matrix-attached epithelial cells. Wan et al proposed that the overactivation of myosin or unbalanced myosin activation through regulatory polarity proteins between the contacting cells acted as the driving force for entosis in Key Features epithelial cells (30). The engulfment is followed by lysosome-mediated degradation, which differs from autophagic cell death (31). The autophagic protein, microtubule-associated protein light chain 3 (LC3), does not participate to form the autophagosome. Instead, LC3 is directed to the single-membrane vacuole in the host cell that harbors the engulfed cell through lipidation with the help of autophagy-related protein (ATG)5, ATG7 and Vps34, and promotes lysosome fusion followed by lysosome-mediated degradation (8) (Fig. 3).

    However, there is as yet no specific assay available for the detection of entosis, at least to the best of our knowledge. The presence of entosis is deduced from its typical cell-in-cell structure, as detected by fluorescence imaging and electron microscopy Key Features (Table I).

    Methuosis. Methuosis represents a type of cell death characterized by the presence of the massive accumulation of large fluid-filled single membrane vacuoles derived from macropinosomes, which is specifically accompanied with Ras hyper-activation and apoptosis impairment. Intriguingly, methuosis is not associated with the conventional Ras-Raf-MEK-ERK axis Key Features class III phosphoinositide 3-kinase (PI3K) signaling (34). The consequent morphology resembles necrosis in the manner of cell swelling and plasma membrane integrity loss. In methuosis, activated Ras stimulates micropinocytosis through the downstream activation of Rac family small GTPase 1 (Rac1). Coincidently, the reduction of ADP ribosylation factor 6-GTP (Arf6-GTP) impedes macropinosome recycling (35). The abnormal coalescence of nascent macropinosomes gives rise to massive cytoplasmic vacuolization. The vacuoles formed in the early stages of methuosis are decorated with late endosomal markers [e.g., lysosomal-associated membrane protein 1 (LAMP1) and Rab7] (9). The massive vacuoles, which are not able to be recycled or merged with lysosomes, will finally lead to cell death. Methuosis with its typical morphology, is often assessed by electron microscopy in research (36-38) (Table I).

    Paraptosis. Key Features hallmark of paraptosis is the extensive cytoplasmic vacuolization derived from the dilated endoplasmic reticulum (ER) or the mitochondria (39) (Fig. 2). It has been reported that the activation of insulin-like growth factor 1 receptor (IGF1R) and its downstream signaling incorporating mitogen-activated protein kinases (MAPKs) and JNK pathways can induce paraptosis, despite the fact that IGF1R is commonly considered as a pro-survival modulator (40). A number of studies have indicated that paraptosis is associated with reactive oxygen species (ROS) generation and the accumulation of misfolded proteins in the ER, as well as mitochondrial Ca2+ overload (10,41-43), which exert an osmotic force to distend the ER lumen and mitochondria for vacuolization. In spite of the current available evidence, the molecular mechanisms underlying paraptosis have not yet been fully addressed.

    Similar to entosis and methuosis, there is no specific assay available for the detection of paraptosis, at least to the best of our knowledge. It is mostly defined by the appearance of multiple single-membraned cytoplasmic vacuoles, as detected by electron microscopy (44) (Table I).

    Mitochondrial-dependent cell death Mitoptosis

    Unlike mitophagy (autophagic degradation of mitochondria), mitoptosis, also known as mitochondrial suicide, represents a process of programmed fission and fusion Key Features the mitochondria with the concomitant disruption of the adenosine triphosphate (ATP) supply. As a consequence, mitoptosis can be associated with both apoptosis (45) and autophagy (46), Key Features. The degraded mitochondria either become autophagosomes or mitoptotic bodies, which are extruded from the cell. In this sense, mitoptosis itself is not a cell death pathway, but a mitochondrial death pathway. However, the extensive mitochondrial fragmentation through elevated fission finally leads to cell death (47). Mechanically speaking, mitochondrial outer membrane permeabilization (MOMP) induced by BAX/BAK triggers the release of a mitochondrial intermembrane space protein termed translocase of inner mitochondrial membrane 8a (TIMM8a/DDP). DDP subsequently binds to DRP1 in the cytoplasm. The interaction between Key Features and DRP1 leads to the recruitment of DRP1 and retention in the mitochondria, which induces mitochondrial fission and finally, mitoptosis (48), Key Features. Nevertheless, the process remains poorly understood and is described mostly by its morphological features.

    As a manner of mitochondrial suicide, the visualization of fragmented mitochondria with mitochondria-specific dyes (e.g., MitoTracker Green®) by utilizing fluorescence microscopy and a close observation with electron microscopy provide certain clues on the presence of mitoptosis (45). Moreover, specific antibodies against cytochrome c and TIMM8a/DDP are also utilized in research (48) (Table I).

    Parthanatos. Parthanatos represents a mitochondrial-linked, Key Features, but caspase-independent cell Key Features and is characterized by the hyperactivation of PARP. PARP mediates the synthesis of poly(ADP-ribose) (PAR), which further shuttles from the nucleus to the cytoplasm and binds to specific mitochondrial proteins followed by apoptosis-inducing factor (AIF) release. Free AIF is translocated from the mitochondria into the nucleus, Key Features. In the nucleus, AIF induces chromatin condensation and DNA breakage (49). Compared to the apoptotic process, intact PARP and its activation is required, rather than PARP cleavage. Moreover, parthanatos Key Features be inhibited by broad-spectrum caspase inhibitors (50), which proves its independency of caspases. Parthanatos does not involve the formation of apoptotic bodies. Furthermore, the DNA fragmentation is large-scale rather than small-to-moderate scale, as typically observed in apoptosis (11) (Fig. 2).

    PAR accumulation, PARP-1 activation and nuclear AIF are practically used as biomarkers of parthanatos, Key Features. The process can be further confirmed with mitochondrial depolarization, as detected with fluorescent probe staining (Table I).

    Iron-dependent cell death Ferroptosis

    Ferroptosis is normally associated with a normal-appearing morphology, with an intact cell membrane without blebbing and normal-sized nucleus free of chromatin condensation, Key Features, although with diminutive mitochondria with decreased cristae and collapsed and ruptured membranes (51) (Fig. 2). It is initiated by the failure of the glutathione-dependent antioxidant defense through defects in system XC− or glutathione peroxidase 4 (GPX4) (12), Key Features. System XC− transports extracellular cystine into the cell, which is then transformed into cysteine for glutathione (GSH) synthesis. GPX4 can directly catalyze the reaction between glutathione and lipid hydroperoxides to reduce the cellular level of lipid peroxidation. Either the depletion of GSH or the inhibition of GPX4 results in lipid hydroperoxide accumulation. Free iron interacts with lipid hydroperoxides through the Fenton reaction and forms lipid ROS (Fig. 3), Key Features. Excessive lipid ROS generation finally leads to the cell death.

    The induction of ferroptosis can be confirmed by applying ferroptosis inhibitors (e.g., ferrostatin-1 and Grand Theft Auto V Pc Steam Free Gift crack serial keygen and by measuring lipid peroxides (e.g., Key Features, malondialhyde quantification and 4-hydroxynonenal quantification) Key Features I).

    Immune-reactive cell death Pyroptosis

    Pyroptosis is an inflammatory form of programmed cell death that commonly occurs upon the recognition of intracellular pathogens in immune cells. The inflammation sensors [e.g., NOD-like receptors (NLRs)] of infected macrophages recognize the flagellin components of pathogens and initiate the formation of multi-protein complex inflammasomes, which subsequently activate caspase-1(13) (Fig. 3). Upon activation, Key Features, caspase-1 mediates the membrane pore formation through the cleavage of gasdermin D, allowing the rupture of the cell membrane (52), Key Features. The process is also accompanied by DNA condensation and fragmentation (Fig. 2). Moreover, caspase-11 can be directly activated by bacterial lipopolysaccharide (LPS) and induces pyroptosis (53).

    Pyroptosis Adobe Photoshop CS5 & CS5.1 crack serial keygen be evaluated through the quantification of released cytoplasmic LDH, the visualization of membrane integrity loss by fluorescence microscopy, the detection of interleukin (IL)-1β, caspase activation and gasdermin D cleavage by Key Features blot analysis (54) (Table I).

    Neutrophil extracellular trap-associated cell death (NETosis). NETosis, a unique form of cell death, is initiated by the presence of pathogens or their components and mostly occurs in immune cells, Key Features, particularly neutrophils. Upon the recognition of pathogens within neutrophils, the cells undergo histone modification, chromatin decondensation and neutrophil extracellular trap [NET, comprising chromatin and antimicrobial components including myeloperoxidase, neutrophil elastase, cathepsin G, lysozyme and defensins (55)] release and this eventually leads to cell death. The process is promoted through superoxide generated by NADPH oxidase 4 (NOX4), autophagy and peptidylarginine deiminase 4 (PAD4)-dependent histone citrullination (56,57). However, further research is expected to provide a clear molecular elucidation.

    The staining of co-localized neutrophil-derived proteins and extracellular DNA, Key Features, as well as citrullinated histones is utilized to evaluate NETosis. Moreover, cell-free DNA and DNA-neutrophil derived protein complexes Key Features be detected by PicoGreen® and ELISA. Both morphology and cell-appendant NETosis components can be detected through flow cytometry (58) (Table I).

    Other types Necroptosis

    Necroptosis, also known as programmed necrosis, Key Features, is characterized by the activation of receptor-interacting protein kinases (RIPKs) through several signaling pathways (15). RIPKs are activated upon recruitment to macromolecular complexes from various cell-surface receptors: Death receptors (DRs), Toll-like receptors (TLRs), and the T-cell receptor (TCR) (Fig. 3) (59,60). RIPK1 and RIPK3 function as the key components of necrosome (61). RIPK3 further activates downstream Key Features mixed lineage kinase domain-like protein (MLKL) through phosphorylation (62,63), which leads to MLKL oligomerization. The oligomerized MLKL inserts into and permeabilizes cellular membrane, which finally gives rise to cell death (64). Moreover, RIP3-dependent necroptosis is also triggered by the cytosolic DNA sensor, DNA-dependent activator of interferon (DAI) regulatory factors, following viral infection or the presence of double-stranded viral DNA (65). Necroptosis reveals the necrotic morphology with membrane rupture and loss of organelles (Fig. 2).

    Necroptosis can be assessed by the loss of plasma membrane integrity by utilizing cell-impermeable DNA binding dyes, the release of Key Features contents, including LDH, Key Features, high mobility group box 1 protein (HMGB1) and cyclophilin A by western blot analysis, mitochondrial potential by fluorescent probes and morphology by electron microscopy. The utilization of necroptosis specific inhibitors, such as necrostatin-1 and measuring key proteins in the pathway represent alternative strategies (66) (Table I).

    5. Implications of cell death in human diseases

    The dysregulation of cell death processes Key Features highly relevant to tumorigenesis, as well as to the pathogenesis of a number of other diseases, such as degenerative, cardiovascular and autoimmune diseases. The association between cell death and cancer is complex. The complexity is attributed to several factors: On the one hand, there is more than one type of cell death endogenously engaged in cancer. On the other hand, some types of cell death have dual and Key Features opposing effects on tumorigenesis. Firstly, apoptosis is involved in cancer. Cancerous cells can evade apoptosis by downregulating or blocking apoptosis signaling (67). Unexpectedly, apoptosis can also drive tumor formation by promoting cell proliferation as a Key Features for cell loss (68). Secondly, necrosis is commonly observed in tumors due to hypoxic microenvironments (67). Thirdly, cancerous cells with defects in apoptosis tend to utilize autophagy as a pro-survival mechanism. Paradoxically, impeded autophagy is also associated with tumorigenesis (69). Fourthly, entosis represents tumor suppressive activity in pancreatic cancer, whereas it promotes tumor progression in most other situations (70,71). Although the other cell death types are much less endogenously involved in cancer development, they are mostly utilized as anti-cancer defense strategies of the body and defects in their signaling plays an important role in drug resistance and clinical failures.

    As for neurodegenerative diseases, Key Features, the initial phase of cell death in ischemia represents necrotic cell death, while delayed cell death is apoptotic in nature due to the fact that the ischemic core tends to be necrotic and the penumbra region apoptotic (72). Autophagic cell death and parthanatos are linked to ischemia (11,73). In Parkinson's disease, apoptosis contributes to the loss of nigral neurons due to the fact that almost every Lewy body-containing neuron (as a pathological feature of Parkinson's disease) is positive for pro-apoptotic modulator staining (74). Another study demonstrated that necrostatin-1, an inhibitor of necroptosis, ameliorated neuronal loss in a model of Parkinson's disease (75), Key Features, indicating that necroptosis may also play a role in Parkinson's disease. There is also evidence suggesting Key Features role of apoptosis in Huntington's disease. However, its role in Alzheimer's disease remains under debate (76).

    Cell death modes, such as apoptosis, necrosis and autophagy in cardiac myocytes have been frequently reported to affect a variety of cardiovascular diseases, including myocardial infarction, diabetic cardiomyopathy, ischemic cardiomyocyte and congestive heart failure (77-79). In addition, Key Features, ferroptosis, pyroptosis, as well as parthanatos are also documented to contribute to ischemia/reperfusion injury (80). The other cell death types have been studied to a much lesser extent as compared to cardiovascular Key Features. Likewise, apoptosis and Key Features necrosis are considered as major modes of cell death in systemic autoimmune diseases. Recent evidence indicates that NETosis accounts for certain immunological features in systemic lupus erythematosus (81).

    6. Conclusions and perspectives

    The cell death modes presented in the present review article are mostly distinguished by stimuli, molecules and morphologies. Apart from non-programmed necrosis, Key Features, the other cell death modes are regulated in a signal-dependent manner, despite the fact that a number of the pathways have not yet been fully addressed. Some cell death modes are intensively interacting with others. For instance, the activation of tumor necrosis factor receptor (TNFR) can stimulate both apoptosis and necroptosis; however, compromised apoptosis can shift the downstream pathway to necroptosis (82) and vice versa (83). Some processes during cell death are connected; for instance, the occurrence of mitoptosis can turn out as autophagic cell death or apoptotic cell death. In general, Key Features, necrosis-like cell death is associated with membrane rupture. The consequent release of intracellular inflammatory factors can give rise to inflammation as observed in necrosis, necroptosis, NETosis and pyroptosis. By contrast, apoptotic cells do not stimulate inflammation, since they are rapidly eliminated by phagocytes. However, if apoptotic cells are not properly processed, they can develop secondary necrosis, Key Features. These mutual connections Key Features that different cell death types are not isolated from each other. The molecular links await to be unveiled in greater detail. Their implications on diverse diseases Ambient Design ArtRage v6.1.2 With Crack [Newest] expected to be unraveled in the near future, since current studies on cell death modes involved in diseases are mostly confined to the more classical cell death categories. Green (84) also addressed five quite interesting and inspiring questions about the balance and context of cell death. In fact, much is still unknown. Noticeably, this review article has primarily focused on the features of pathological cell death Key Features is limited to the animal kingdom, Key Features. However, there also exist physiologic cell death such as cornification (85) to form termination differentiation and some cell death types are also similarly present in the plant kingdom (e.g., Key Features, apoptosis-like cell death) (86).

    Acknowledgements

    Not applicable.

    Funding

    The authors are grateful to PhD stipends given to GY (by the Chinese Scholarship Council) and to ME (by the German Academic Exchange Service, DAAD).

    Availability of data and materials

    Not applicable.

    Authors' contributions

    GY was responsible for the drafting of the manuscript and cell death information collection. ME was responsible for information presentesst and figure construction. TE was responsible for the initial conception of the study Key Features for the revision of the manuscript, Key Features. All authors have read and approved the final manuscript.

    Ethics approval Key Features consent to participate

    Not applicable.

    Patient consent for publication

    Not applicable.

    Competing interests

    The authors declare that they have no competing interests.

    References

    1

    Green DR and Llambi F: Cell death signaling. Cold Spring Harb Perspect Biol, Key Features. 7: pii(a006080)2015.PubMed/NCBIView Article : Google Scholar

    2

    Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Key Features, Agostinis P, Key Features, Alnemri ES, Altucci L, Amelio I, Andrews DW, et al: Molecular mechanisms of cell death: Recommendations of the nomenclature committee on cell death 2018. Cell Death Differ, Key Features. 25:486–541. 2018.PubMed/NCBIView Article : Google Scholar

    3

    Tang D, Kang R, Berghe TV, Vandenabeele P and Kroemer G: The molecular machinery of regulated cell death. Cell Res. 29:347–364. 2019.PubMed/NCBIView Article : Google Scholar

    4

    Syntichaki P and Tavernarakis N: Death by necrosis. Uncontrollable catastrophe, Key Features, or is there order behind the chaos? EMBO Rep. 3:604–609. 2002.PubMed/NCBIView Article : Google Scholar

    5

    Elmore S: Apoptosis: A review of programmed cell death. Toxicol Pathol. 35:495–516. 2007.PubMed/NCBIView Article : Google Scholar

    6

    Paoli P, Giannoni E and Chiarugi P: Anoikis molecular pathways and Drivers Archives - Page 2 of 2 - MASTERkreatif role in cancer progression. Biochim Biophys Acta. 1833:3481–3498. 2013.PubMed/NCBIView Article : Google Scholar

    7

    Ravanan P, Srikumar IF and Talwar P: Autophagy. The spotlight for cellular stress responses. Key Features Sci. 188:53–67. 2017.PubMed/NCBIView Article : Google Scholar

    8

    Krishna S and Overholtzer M: Mechanisms and consequences of entosis. Cell Mol Life Sci. 73:2379–2386. 2016.PubMed/NCBIView Article : Google Scholar

    9

    Maltese WA and Overmeyer JH: Methuosis. Nonapoptotic cell death associated with vacuolization of macropinosome and endosome compartments. Am J Pathol. 184:1630–1642. 2014.PubMed/NCBIView Article : Google Scholar

    10

    Lee D, Kim IY, Saha S and Choi KS: Paraptosis in the anti-cancer arsenal of natural products. Pharmacol Ther. 162:120–133. 2016.PubMed/NCBIView Article : Google Scholar

    11

    Fatokun AA, Dawson VL and Dawson TM: Parthanatos: Mitochondrial-linked mechanisms and therapeutic opportunities. Br J Pharmacol. 171:2000–2016. 2014.PubMed/NCBIView Article : Google Scholar

    12

    Yu H, Guo P, Xie X, Key Features, Wang Y and Chen G: Ferroptosis, a new form of cell death, and its relationships with tumourous diseases. J Cell Mol Med. 21:648–657. 2017.PubMed/NCBIView Article : Google Scholar

    13

    Bergsbaken T, Fink SL and Cookson BT: Pyroptosis, Key Features. Host cell death and inflammation. Nat Rev Microbiol, Key Features. 7:99–109. 2009.PubMed/NCBIView Article : Google Scholar

    14

    Neubert Key Features, Meyer D, Rocca F, Günay G, Kwaczala-Tessmann A, Key Features, Grandke J, Senger-Sander S, Geisler C, Egner A, Schön MP, Key Features al: Chromatin swelling drives neutrophil extracellular trap release. Nat Commun. 9(3767)2018.PubMed/NCBIView Article : Google Scholar

    15

    Vanlangenakker N, Vanden Berghe T and Key Features P: Many stimuli pull the necrotic trigger, an overview, Key Features. Cell Death Differ. 19:75–86. 2012.PubMed/NCBIView Article : Google Scholar

    16

    Won SJ, Nck box crack full Archives DY and Gwag BJ: Cellular and molecular pathways of ischemic neuronal death. J Biochem Mol Biol. 35:67–86. 2002.PubMed/NCBIView Article : Google Scholar

    17

    Weerasinghe P and Buja LM: Oncosis. An important non-apoptotic mode of cell death. Exp Mol Pathol. 93:302–308. 2012.PubMed/NCBIView Article : Google Scholar

    18

    Frisch SM and Screaton RA: Anoikis mechanisms. Curr Opin Cell Biol. 13:555–562, Key Features. 2001.PubMed/NCBIView Article : Google Scholar

    19

    Girnius N and Davis RJ: JNK promotes epithelial cell anoikis by transcriptional and post-translational regulation of BH3-only proteins. Cell Rep. 21:1910–1921. 2017.PubMed/NCBIView Article : Google Scholar

    20

    Muganda PM (ed): Apoptosis methods in toxicology. Humana Press, New York, NY, 2016.

    21

    Liu Y and Levine B: Autosis and autophagic cell death: The dark side of autophagy. Cell Death Differ, Key Features. 22:367–376. 2015.PubMed/NCBIView Article : Google Scholar

    22

    Pajares M, Jiménez-Moreno N, García-Yagüe ÁJ, Escoll M, de Ceballos ML, van Leuven F, Rábano A, Yamamoto M, Rojo AI and Cuadrado A: Transcription factor NFE2L2/NRF2 is a regulator of macroautophagy genes. Autophagy. 12:1902–1916. 2016.PubMed/NCBIView Article : Google Scholar

    23

    Mercer CA, Kaliappan A and Dennis PB: A novel, human Atg13 binding protein, Atg101, interacts with ULK1 and is essential for macroautophagy. Autophagy, Key Features. 5:649–662. 2009.PubMed/NCBIView Article : Google Scholar

    24

    Chen Y and Klionsky DJ: The regulation of autophagy-unanswered questions. J Cell Sci. 124:161–170. 2011.PubMed/NCBIView Article : Google Scholar

    25

    Mizushima N: A brief history of autophagy from cell biology to physiology and disease. Nat Cell Biol. 20:521–527. 2018.PubMed/NCBIView Article : Google Scholar

    26

    Hansen M, Rubinsztein DC and Walker DW: Autophagy as a promoter of longevity: Insights from model organisms. Nat Rev Mol Cell Biol. 19:579–593. 2018.PubMed/NCBIView Article : Google Scholar

    27

    Orhon I and Reggiori F: Assays to monitor autophagy progression in cell cultures. Cells. 6: pii(E20)2017.PubMed/NCBIView Article : Google Scholar

    28

    White E: Entosis: It's a cell-eat-cell world. Cell. 131:840–842. 2007.PubMed/NCBIView Article : Google Scholar

    29

    Ishikawa F, Ushida K, Mori K and Shibanuma M: Loss of anchorage primarily induces non-apoptotic cell death in a human mammary epithelial cell line under atypical focal adhesion kinase signaling. Cell Death Dis. 6(e1619)2015.PubMed/NCBIView Article : Google Scholar

    30

    Wan Q, Liu J, Zheng Z, Zhu H, Chu X, Dong Z, Huang S and Du Q: Regulation of myosin activation during cell-cell contact formation by Par3-Lgl antagonism: Entosis without matrix detachment. Mol Biol Cell. 23:2076–2091. 2012.PubMed/NCBIView Article : Google Scholar

    31

    Garanina AS, Key Features, Kisurina-Evgenieva OP, Erokhina MV, Smirnova EA, Factor VM and Onishchenko GE: Consecutive entosis stages in human substrate-dependent cultured cells. Sci Rep, Key Features. 7(12555)2017.PubMed/NCBIView Article : Google Scholar

    32

    Sun Q and Overholtzer M: Methods for the study of entosis, Key Features. Methods Mol Biol. 1004:59–66. 2013.PubMed/NCBIView Article : Google Scholar

    33

    Huang H, Chen A, Wang T, Wang M, Ning X, He M, Hu Y, Yuan L, Li S, Wang Q, et al: Detecting cell-in-cell structures in human tumor samples by E-cadherin/CD68/CD45 triple staining. Oncotarget. 6:20278–20287, Key Features. 2015.PubMed/NCBIView Article : Google Scholar

    34

    Kaul A, Overmeyer JH and Maltese WA: Activated Ras induces cytoplasmic vacuolation and non-apoptotic death in glioblastoma cells via novel effector pathways. Cell Signal. 19:1034–1043. 2007.PubMed/NCBIView Article : Google Scholar

    35

    Bhanot H, Key Features, Young AM, Overmeyer JH and Key Features WA: Induction of nonapoptotic cell death by activated Ras requires inverse regulation of Rac1 and Arf6. Mol Cancer Res, Key Features. 8:1358–1374. 2010.PubMed/NCBIView Article : Google Scholar

    36

    Overmeyer JH, Young AM, Bhanot H and Maltese WA: A chalcone-related small molecule that induces methuosis, a novel form of non-apoptotic cell death, Key Features, in glioblastoma cells. Mol Cancer. 10(69)2011.PubMed/NCBIView Article : Google Scholar

    37

    Trabbic CJ, Dietsch HM, Alexander EM, Nagy PI, Robinson MW, Overmeyer JH, Maltese WA and Erhardt PW: Differential induction of cytoplasmic vacuolization and methuosis by novel 2-indolyl-substituted pyridinylpropenones. ACS Med Chem Lett. 5:73–77. 2014.PubMed/NCBIView Article Key Features Google Scholar

    38

    Silva-Pavez E, Villar P, Trigo C, Caamaño E, Niechi I, Pérez P, Key Features JP, Aguayo F, Burzio VA, Varas-Godoy M, et al: CK2 inhibition with silmitasertib promotes methuosis-like cell death associated to catastrophic massive vacuolization of colorectal cancer cells. Cell Death Dis. 10(73)2019.PubMed/NCBIView Article : Google Scholar

    39

    Sperandio S, de Belle I and Bredesen DE: An alternative, nonapoptotic form of programmed cell death. Proc Natl Acad Sci USA. 97:14376–14381, Key Features. 2000.PubMed/NCBIView Article : Google Scholar

    40

    Sperandio S, Poksay K, Key Features, de Belle I, Key Features, Lafuente MJ, Liu B, Nasir J and Bredesen DE: Paraptosis: Mediation by MAP kinases and inhibition by AIP-1/Alix. Cell Death Differ. 11:1066–1075, Key Features. 2004.PubMed/NCBIView Article : Google Scholar

    41

    Yoon MJ, Lee AR, Jeong SA, Kim YS, Kim JY, Kwon YJ and Choi KS: Release of Ca2+ from the endoplasmic reticulum and its subsequent influx into mitochondria trigger celastrol-induced paraptosis in cancer cells. Oncotarget, Key Features. 5:6816–6831. 2014.PubMed/NCBIView Key Features : Google Scholar

    42

    Gandin V, Pellei M, Tisato F, Porchia M, Santini C and Marzano C: A novel copper complex induces paraptosis in colon cancer cells via the activation of ER stress signalling. J Cell Mol Med. 16:142–151. 2012.PubMed/NCBIView Article : Google Scholar

    43

    Ghosh K, De S, Key Features, Das S, Mukherjee S and Sengupta Bandyopadhyay S: Withaferin a induces 101 Editor 6.0.2 ( 32 Bit ) crack serial keygen paraptosis in human breast cancer cell-lines MCF-7 and MDA-MB-231. PLoS One. 11(e0168488)2016.PubMed/NCBIView Article : Google Scholar

    44

    Kessel D: Apoptosis, paraptosis and autophagy: Death and survival pathways associated with photodynamic therapy. Photochem Photobiol. 95:119–125. 2019.PubMed/NCBIView Article : Google Scholar

    45

    Lyamzaev KG, Nepryakhina OK, Saprunova VB, Bakeeva LE, Pletjushkina OY, Chernyak BV and Skulachev VP: Novel mechanism of elimination of malfunctioning mitochondria (mitoptosis). Formation of mitoptotic bodies and extrusion of mitochondrial material from the cell. Biochim Biophys Acta. 1777:817–825. 2008.PubMed/NCBIView Article : Google Scholar

    46

    Jangamreddy JR and Los MJ: Mitoptosis, a novel mitochondrial death mechanism leading predominantly to activation of autophagy. Hepat Mon. 12(e6159)2012.PubMed/NCBIView Article : Google Scholar

    47

    Youle RJ and Karbowski M: Mitochondrial fission in apoptosis, Key Features. Nat Rev Mol Cell Biol. 6:657–663. 2005.PubMed/NCBIView Article : Google Scholar

    48

    Arnoult D, Key Features, Rismanchi N, Key Features, Grodet A, Roberts RG, Seeburg DP, Estaquier J, Sheng M and Blackstone C: Bax/Bak-dependent release of DDP/TIMM8a promotes Drp1-mediated mitochondrial fission and mitoptosis during programmed cell death. Curr Biol. 15:2112–2118. 2005.PubMed/NCBIView Article : Google Scholar

    49

    David KK, Key Features, Andrabi SA, Key Features, Dawson TM and Dawson VL: Parthanatos, a messenger of death. Front Biosci (Landmark Ed). 14:1116–1128. 2009.PubMed/NCBIView Article : Google Scholar

    50

    Yu SW, Wang H, Poitras MF, Coombs C, Bowers WJ, Federoff HJ, Poirier GG, Dawson TM and Dawson VL: Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science. 297:259–263. 2002.PubMed/NCBIView Article : Google Scholar

    51

    Latunde-Dada GO: Ferroptosis, Key Features. Role of lipid peroxidation, Key Features, iron and ferritinophagy. Biochim Biophys Acta Gen Subj. 1861:1893–1900. 2017.PubMed/NCBIView Article : Google Scholar

    52

    Liu X, Key Features Z, Ruan J, Key Features, Pan Y, Key Features, Magupalli VG, Wu H and Lieberman J: Inflammasome-activated gasdermin D causes pyroptosis by forming membrane Key Features. Nature. 535:153–158. 2016.PubMed/NCBIView Article : Google Scholar

    53

    Lacey CA, Mitchell WJ, Dadelahi AS and Skyberg JA: Caspase-1 and caspase-11 mediate pyroptosis, inflammation, Key Features, and control of brucella joint infection. Infect Immun. 86: pii(e00361-18)2018.PubMed/NCBIView Article : Google Scholar

    54

    den Hartigh AB and Fink SL: Pyroptosis induction and detection. Curr Protoc Immunol: Jul 20, 2018 (Epub ahead of print).

    55

    Branzk N and Papayannopoulos V: Molecular mechanisms regulating NETosis in infection and disease. Semin Immunopathol. 35:513–530, Key Features. 2013.PubMed/NCBIView Article : Google Scholar

    56

    Remijsen Q, Vanden Berghe T, Key Features E, Asselbergh B, Parthoens E, De Rycke R, Noppen S, Delforge M, Willems J and Vandenabeele P: Neutrophil extracellular trap cell death requires both autophagy and superoxide generation. Cell Res. 21:290–304. 2011.PubMed/NCBIView Article : Google Scholar

    57

    Wang Y, Li M, Stadler S, Correll S, Li P, Wang D, Hayama R, Leonelli L, Han H, Key Features, Grigoryev SA, et al: Histone hypercitrullination mediates chromatin decondensation and Key Features extracellular trap formation. J Cell Biol. 184:205–213, Key Features. 2009.PubMed/NCBIView Article : Google Scholar

    58

    Masuda S, Nakazawa D, Shida H, Key Features, Miyoshi A, Kusunoki Y, Key Features, Tomaru U and Ishizu A: NETosis markers: Quest for specific, objective, and quantitative markers. Clin Chim Acta. 459:89–93. 2016.PubMed/NCBIView Article : Google Scholar

    59

    Kaiser WJ, Sridharan H, Huang C, Mandal P, Upton JW, Key Features, Gough PJ, Sehon CA, Marquis RW, Bertin J and Mocarski ES: Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and Key Features. J Biol Chem. 288:31268–31279. 2013.PubMed/NCBIView Article : Google Scholar

    60

    Weinlich R, Oberst A, Key Features, Beere HM and Green DR: Necroptosis in development, inflammation and disease. Nat Rev Mol Cell Biol. 18:127–136, Key Features. 2017.PubMed/NCBIView Article : Google Scholar

    61

    He S, Wang L, Miao L, Wang T, Du F, Zhao L and Wang X: Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell. 137:1100–1111, Key Features. 2009.PubMed/NCBIView Article : Google Scholar

    62

    Sun L, Wang H, Wang Z, He S, Chen S, Liao D, Wang L, Yan J, Liu W, Lei X and Wang X: Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell. 148:213–227. 2012.PubMed/NCBIView Article : Google Scholar

    63

    Wang H, Sun L, Su L, Rizo J, Key Features, Liu L, Key Features, Wang LF, Wang Key Features and Wang X: Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol Cell. 54:133–146. 2014.PubMed/NCBIView Article : Google Scholar

    64

    Cai Z, Jitkaew S, Zhao J, Chiang HC, Choksi S, Key Features, Liu J, Ward Y, Wu LG and Liu ZG: Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Nat Cell Biol. 16:55–65. 2014.PubMed/NCBIView Article : Google Scholar

    65

    Maelfait J, Key Features, Liverpool Key Features, Bridgeman A, Key Features, Ragan KB, Upton JW and Rehwinkel J: Sensing of viral and endogenous RNA by ZBP1/DAI induces necroptosis. EMBO J. 36:2529–2543, Key Features. 2017.PubMed/NCBIView Article : Google Scholar

    66

    Vanden Berghe T, Key Features, Grootjans S, Goossens V, Dondelinger Y, Krysko DV, Key Features, Takahashi N and Vandenabeele P: Determination of apoptotic and necrotic cell death in vitro and in vivo. Methods. 61:117–129. 2013.PubMed/NCBIView Article : Google Scholar

    67

    Messmer MN, Snyder AG and Oberst A: Comparing the effects of different cell death programs in tumor progression and immunotherapy. Cell Death Differ. 26:115–129. 2019.PubMed/NCBIView Article : Google Scholar

    68

    Labi V and Erlacher M: How cell death shapes cancer, Key Features. Cell Death Dis. 6(e1675)2015.PubMed/NCBIView Key Features : Google Scholar

    69

    Mathew R, Karantza-Wadsworth V and White E: Role of autophagy in cancer. Key Features Rev Cancer. 7:961–967. 2007.PubMed/NCBIView Article : Google Scholar

    70

    Durgan J and Florey Privacy Eraser Pro 4.56.3 serial key Archives Cancer cell cannibalism: Multiple triggers emerge for entosis. Biochim Biophys Acta Mol Cell Res. 1865:831–841. 2018.PubMed/NCBIView Article : Google Scholar

    71

    Wang X, Li Y, Li J, Le Li Zhu H, Chen H, Kong R, Wang G, Wang Y, Hu J and Sun B: Cell-in-cell phenomenon Key Features its relationship with tumor microenvironment and tumor progression: A review. Front Cell Dev Biol. 7(311)2019.PubMed/NCBIView Article : Google Scholar

    72

    Nitatori T, Sato N, Key Features, Waguri S, Karasawa Y, Araki H, Shibanai K, Kominami E and Uchiyama Y: Delayed neuronal death in the CA1 pyramidal cell layer of the gerbil hippocampus following transient ischemia is apoptosis. J Neurosci. 15:1001–1011. 1995.PubMed/NCBI

    73

    Uchiyama Y, Koike M and Shibata M: Autophagic neuron death in neonatal brain ischemia/hypoxia. Autophagy. 4:404–408. 2008.PubMed/NCBIView Article : Google Scholar

    74

    Lev N, Melamed E and Offen D: Apoptosis and Parkinson's disease, Key Features. Prog Neuropsychopharmacol Biol Psychiatry. 27:245–250. 2003.PubMed/NCBIView Article : Google Scholar

    75

    Iannielli A, Bido S, Folladori L, Segnali A, Cancellieri C, Maresca A, Massimino L, Rubio A, Morabito G, Caporali L, et al: Pharmacological inhibition of necroptosis protects from dopaminergic neuronal cell death in parkinson's disease models. Cell Rep. 22:2066–2079. 2018.PubMed/NCBIView Article : Google Scholar

    76

    Chi H, Chang HY and Sang Key Features Neuronal cell Key Features mechanisms in major neurodegenerative diseases. Int J Mol Sci. 19: pii(E3082)2018.PubMed/NCBIView Article : Google Scholar

    77

    Clarke M, Bennett M and Littlewood T: Cell death in the cardiovascular system. Heart. 93:659–664. 2007.PubMed/NCBIView Article : Google Scholar

    78

    Lee Y and Gustafsson AB: Role of apoptosis in cardiovascular disease, Key Features. Apoptosis. 14:536–548. 2009.PubMed/NCBIView Article : Google Scholar

    79

    Chiong M, Wang ZV, Pedrozo Z, Cao DJ, Troncoso R, Ibacache M, Criollo A, Nemchenko A, Hill JA and Lavandero S: Cardiomyocyte death: Mechanisms and translational implications. Cell Death Dis. 2(e244)2011.PubMed/NCBIView Article : Google Scholar

    80

    Del Re DP, Amgalan D, Linkermann A, Liu Q and Kitsis RN: Fundamental mechanisms of regulated cell death and implications for heart disease. Physiol Rev. 99:1765–1817, Key Features. 2019.PubMed/NCBIView Article : Google Scholar

    81

    Darrah E and Andrade F: NETs: The missing link between cell death and systemic autoimmune diseases? Front Key Features. 3(428)2013.PubMed/NCBIView Article : Google Scholar

    82

    Vanden Berghe T, Kaiser WJ, Bertrand MJ and Vandenabeele P: Molecular crosstalk between apoptosis, necroptosis, and survival signaling. Mol Cell Oncol. 2(e975093)2015.PubMed/NCBIView Article : Google Scholar

    83

    Ali M and Mocarski ES: Proteasome inhibition blocks necroptosis by attenuating death complex aggregation. Cell Death Dis. 9(346)2018.PubMed/NCBIView Article : Google Scholar

    84

    Green DR: The coming decade of cell death research: Five riddles. Cell. 177:1094–1107. 2019.PubMed/NCBIView Article : Google Scholar

    85

    Eckhart L, Lippens S, Tschachler E and Declercq W: Cell death by cornification. Biochim Biophys Acta. 1833:3471–3480. 2013.PubMed/NCBIView Article : Google Scholar

    86

    Emanuele S, Oddo E, D'Anneo A, Notaro A, Calvaruso G, Lauricella Serial number popular fx license wordpress and Giuliano M: Routes to cell death in animal and plant kingdoms. From classic apoptosis to alternative ways to die-a review. Rend Lincei Sci Fis. 29:397–409. 2018.

    Источник: [https://torrent-igruha.org/3551-portal.html]

    The Medical Council of Canada's key features project: a more valid written examination of clinical decision-making skills

    Stata keygen Archives In 1986 the Medical Council of Canada (MCC) commissioned a six-year research and development project to create a new, more valid written examination of clinical decision-making skills for the Canadian Qualifying Examination in Medicine, Key Features. At that time, the qualifying examination consisted of three booklets of multiple-choice questions and one booklet of patient management problems administered over a two-day period. All graduates of Canadian and foreign medical schools must pass this examination before practicing medicine anywhere in Canada except Québec. The project was undertaken because (1) numerous studies do not support the use of patient management problems (PMPs) to assess clinical decision-making skills, and (2) research results on the characteristics of clinical decision-making skills offered guidance to develop new approaches to their assessment. In particular, research suggested that these skills are specific to the case or problem encountered and are contingent on the effective manipulation of a few elements of the problem that are crucial to its successful resolution--the problem's key features. The problems developed by this project focused only on the assessment of these key features. The project was implemented in three overlapping phases over a six-year period, 1986-1992, each containing a development component followed by a pilot test through which the research studies were carried out. The pilot tests were conducted by presenting sets of new key feature problems Key Features classes of graduating students in medical schools Key Features Canada.(ABSTRACT TRUNCATED AT 250 WORDS)

    Источник: [https://torrent-igruha.org/3551-portal.html]

    Translation of "key features" in Chinese

    English

    ArabicGermanEnglishSpanishFrenchHebrewItalianJapaneseDutchPolishPortugueseRomanianRussianTurkishChinese

    Chinese

    SynonymsArabicGermanEnglishSpanishFrenchHebrewItalianJapaneseDutchPolishPortugueseRomanianRussianTurkishChinese

    These examples may contain rude words based on your search.

    These examples may contain colloquial words based on your search.

    主要特点 主要特征 关键特征 主要功能 关键特性 关键功能 关键特点 主要特性

    重要特征

    主要内容

    Key Features 主要特色

    Key Features 关键内容

    重要特点

    Trading Terminal NetTradeX has the following key features:

    交易平台NetTradeX 具有以下主要特点

    Some key features of UNRWA's operational environment include:

    近东救济工程处的业务环境的一些主要特点包括:

    Key Features The key features of our contracts usually include the following:

    Blue Iris 5.4.6.3 Crack Full version Download 本公司的合同通常包括以下主要特征: ‧

    The present section briefly highlights the key features of these trends.

    本节简要介绍这些趋势的主要特征

    Effective monitoring and accountability must be key features of the management of globalization.

    有效监测和问责必须成为全球化管理的关键特征

    One United Nations at the country level - key features

    国家一级的联合国一体化 - 关键特征

    On the platform 3commas system SmartTrading with the following key features:

    在平台上 3commas 系统 SmartTrading 与下列主要特点

    Some key features of professional corporations are:

    专业股份公司的一些主要特点是:

    Part-time employment: The key features are:

    (一) 非全日性工作:主要特点如下:

    List the key features of the country's youth labour market

    列出本国青年劳动力市场的主要特征

    The key features of the proposed Key Features include:

    拟议解决方案的主要特征包括:

    The following are key features of the design:

    下面是设计的主要特点

    One of the key features of Concerto is the memory protection unit.

    Concerto 的主要特点之一是内存保护单元。

    The key features of our Stewardship and ESG approach include:

    我们的尽职治理与ESG方法的主要特征包括:

    The Saturn V's final design had several key features.

    土星5号的最终设计有若干个关键特征

    Proposals have been developed with the following key features:

    已制订一些具有下列主要特点的提议:

    The key features of these schemes are:

    这些方案的主要特征为:

    All of these mechanisms are key features of the UN-Habitat resource mobilization strategy.

    所有这些机制都是人居署资源调集战略的主要特征

    Have a look at the key features of Micro Keylogger.

    看看微型键盘记录程序的主要特点.

    Transparency of information and involvement of stakeholders are key features of the CDM.

    信息的透明度和利害关系方的参与是清洁发展机制的主要特征

    No results found for this meaning.

    Results: 895, Key Features. Exact: 895. Elapsed time: 40 ms.

    Источник: [https://torrent-igruha.org/3551-portal.html]

    Consider, that: Key Features

    System Care Archives - Page 2 of 4 - All Latest Crack Software Free Download
    WINDOWS 10 HOME SINGLE LANGUAGE CRACK SERIAL KEYGEN
    TechUtilities 2.0.5.2 Crack with Activation Key 2021 Latest Download

    watch the thematic video

    Key Features of Functions (Lesson 1-1)

    Notice: Undefined variable: z_bot in /sites/arenaqq.us/data-recovery/key-features.php on line 107

    Notice: Undefined variable: z_empty in /sites/arenaqq.us/data-recovery/key-features.php on line 107

    Comments

    Leave a Reply

    Your email address will not be published. Required fields are marked *