ResearchPad - perspectives https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Fluorescence strategies for mapping cell membrane dynamics and structures]]> https://www.researchpad.co/article/elastic_article_13894 Fluorescence spectroscopy has been a cornerstone of research in membrane dynamics and organization. Technological advances in fluorescence spectroscopy went hand in hand with discovery of various physicochemical properties of membranes at nanometric spatial and microsecond timescales. In this perspective, we discuss the various challenges associated with quantification of physicochemical properties of membranes and how various modes of fluorescence spectroscopy have overcome these challenges to shed light on the structure and organization of membranes. Finally, we discuss newer measurement strategies and data analysis tools to investigate the structure, dynamics, and organization of membranes.

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<![CDATA[Perforin and resistance to SARS coronavirus 2]]> https://www.researchpad.co/article/elastic_article_13681 <![CDATA[Compassion in a time of COVID-19]]> https://www.researchpad.co/article/elastic_article_13576 <![CDATA[Recommendations on contingency operations for hospitals in response to COVID-19 cases identified in inpatients – Taiwan]]> https://www.researchpad.co/article/elastic_article_13372 <![CDATA[Managing patients with cancer during the COVID-19 pandemic: frontline experience from Wuhan]]> https://www.researchpad.co/article/elastic_article_13104 <![CDATA[Society and the slow burn of inequality]]> https://www.researchpad.co/article/elastic_article_12977 <![CDATA[Remote monitoring contributes to preventing overwork-related events in health workers at the COVID-19 frontlines]]> https://www.researchpad.co/article/elastic_article_12323 Fighting at the frontlines against the coronavirus disease 2019 (COVID-19) pandemic, the health workers are at high risk of virus infection and overwork-related sudden death and disorders including cardiovascular diseases and stress. When we noticed the increase of overwork-related sudden deaths in physicians and nurses in the first two weeks after lockdown of Wuhan, we organized the ‘Touching Your Heart’ program by remote monitoring, aiming to protect health workers from overwork-related disorders through integrated volunteer work by physicians and medical engineering researchers from Wuhan Huoshenshan Hospital, Nanjing Medical University and Tiangong University. By remotely monitoring the health condition of the medical aid team working at Wuhan Huoshenshan Hospital, the program successfully helped in avoiding severe overwork-related events in them. The result of our program reminded the frontline health workers around the world to take precaution against overworked-related severe events, and showed that precision monitoring is effective in improving work efficiency and maintaining sustainable work force during the emergency situations like a pandemic.

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<![CDATA[Taking care of systemic sclerosis patients during COVID-19 pandemic: rethink the clinical activity]]> https://www.researchpad.co/article/elastic_article_11104 COVID-19 outbreak has quickly spread worldwide, causing a high pressure on the health-care system. In Italy, from March 8, 2020, all the deferrable clinical activities have been suspended to increase the health care offer for COVID-19 patients. The hospital organization has been modified also in order to assure non-COVID-19 patients assistance. The Scleroderma Unit of ASST Pini-CTO Hospital, in Milan, in the region mostly hit by SARS-CoV-2 in Italy, follows more than 600 patients affected by systemic sclerosis (SSc). Patients with SSc need a close follow-up with a regular screening of organ involvement and frequent intravenous treatments. All SSc patients have been educated about ministerial directives to limit COVID-19 spread. The organization of our Scleroderma Unit has been quickly rethought to assure SSc patients assistance in safety for them and for health-care workers during urgent visits or infusion therapies. Using electronic way of communication with frequent virtual contact and guarantying home deliveries of some therapies, we allowed a continuity of care also outside the Hospital.

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<![CDATA[Resetting the Narrative in Australian Aboriginal and Torres Strait Islander Nutrition Research]]> https://www.researchpad.co/article/elastic_article_10006 As the oldest continuous living civilizations in the world, Aboriginal and Torres Strait Islander peoples have strength, tenacity, and resilience. Initial colonization of the landscape included violent dispossession and removal of people from Country to expand European land tenure and production systems, loss of knowledge holders through frontier violence, and formal government policies of segregation and assimilation designed to destroy ontological relationships with Country and kin. The ongoing manifestations of colonialism continue to affect food systems and food knowledges of Aboriginal peoples, and have led to severe health inequities and disproportionate rates of nutrition-related health conditions. There is an urgent need to collaborate with Aboriginal and Torres Strait Islander peoples to address nutrition and its underlying determinants in a way that integrates Aboriginal and Torres Strait Islander peoples’ understandings of food and food systems, health, healing, and well-being. We use the existing literature to discuss current ways that Australian Aboriginal and Torres Strait Islander peoples are portrayed in the literature in relation to nutrition, identify knowledge gaps that require further research, and propose a new way forward.

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<![CDATA[Premature Deaths, Statistical Lives, and Years of Life Lost: Identification, Quantification, and Valuation of Mortality Risks]]> https://www.researchpad.co/article/elastic_article_8263 Mortality effects of exposure to air pollution and other environmental hazards are often described by the estimated number of “premature” or “attributable” deaths and the economic value of a reduction in exposure as the product of an estimate of “statistical lives saved” and a “value per statistical life.” These terms can be misleading because the number of deaths advanced by exposure cannot be determined from mortality data alone, whether from epidemiology or randomized trials (it is not statistically identified). The fraction of deaths “attributed” to exposure is conventionally derived as the hazard fraction (R – 1)/R, where R is the relative risk of mortality between high and low exposure levels. The fraction of deaths advanced by exposure (the “etiologic” fraction) can be substantially larger or smaller: it can be as large as one and as small as 1/e (≈0.37) times the hazard fraction (if the association is causal and zero otherwise). Recent literature reveals misunderstanding about these concepts. Total life years lost in a population due to exposure can be estimated but cannot be disaggregated by age or cause of death. Economic valuation of a change in exposure‐related mortality risk to a population is not affected by inability to know the fraction of deaths that are etiologic. When individuals facing larger or smaller changes in mortality risk cannot be identified, the mean change in population hazard is sufficient for valuation; otherwise, the economic value can depend on the distribution of risk reductions.

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<![CDATA[How did “flatten the curve” become “flatten the economy?” A perspective from the United States of America]]> https://www.researchpad.co/article/elastic_article_7321 The coronavirus SARS-CoV-2 (COVID-19) pandemic offers many medical, economic, societal, and cultural challenges. The response by individual states in the United States of America varies, but with the common initial impetus for all being to “flatten the curve,” which was intended to delay infections and spread the burden and impact on hospitals and medical systems. Starting with that intention, the responses by states has included many major steps not taken in prior pandemics. Those steps have significantly adversely affected hospitals rather than support them, and the overall impact has been to “flatten the economy” rather than just to “flatten the curve.” Many state governors have stated that their decisions are “science-led” and “data driven” but the reality is that there is not relevant experimental data. The progression of decisions during the early pandemic decisions is traced, and the basis of decisions based in science or herd mentality is discussed. Experiences are not experiments, and experiences are not founded in the scientific process. Medical and government leaders must be vigilant to recognize the limitations of available data in responding to unique circumstances.

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<![CDATA[On the horizon—the value and promise of the global pipeline of Alzheimer's disease therapeutics]]> https://www.researchpad.co/article/elastic_article_7057 The recent failure of several late‐stage Alzheimer's disease (AD) clinical trials focused on amyloid beta (Aβ) highlights the challenges of finding effective disease‐modifying therapeutics. Despite major advances in our understanding of the genetic risk factors of disease and the development of clinical biomarkers, and that not all Aβ‐based approaches are equivalent, these failures may engender skepticism regarding the value of the AD pipeline.MethodsTo investigate these concerns, we compiled a database of current Phase 2 and 3 trials based on disease‐modifying targets through a query of the National Institutes of Health's ClinicalTrials.gov. We then assessed the financial value of the pipeline. Financial modeling utilized risk‐adjusted net present value (rNPV) measurements and included sensitivity analyses to help inform the drug development process.ResultsResults indicate that the preponderance of current Phase 3 trials were indeed targeting Aβ, with only 15% addressing other targets. In contrast, the pipeline of Phase 2 trials was more diverse. The estimated rNPV of Phase 2 and 3 therapeutics was estimated to be $338 billion over 10 years. This figure increased to a theoretical cumulative value of $788 billion when incorporating the assumption that diagnostics will be developed to identify individuals at high risk for developing AD. Results from model sensitivity analyses showed that speed of market penetration and patient access contributed the most weight to financial value. In contrast, decreasing drug development costs had minimal impact on rNPV.DiscussionThese findings argue in favor of conducting thorough biomarker‐driven Phase 2 proof of concept studies to avoid prematurely advancing assets into Phase 3. Insights from these analyses are also discussed in the context of the financial ecosystem needed to maintain a healthy AD pipeline. ]]> <![CDATA[Epigenetic regulation of kidney progenitor cells]]> https://www.researchpad.co/article/elastic_article_6506 Representative scheme of epigenetic regulation of kidney progenitors within a nephrogenic niche during kidney development. Epigenetic mechanisms involved in kidney organogenesis include DNA methylation, histone acetylation, chromatin remodeling complexes, and versatile noncoding RNAs. These mechanisms are mediated by special epigenetic modifiers and play important roles in the regulation of self‐renewal maintenance and differentiation of three types of kidney progenitors during kidney development

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<![CDATA[Phenotypic Plasticity: From Theory and Genetics to Current and Future Challenges]]> https://www.researchpad.co/article/Nea9f736f-6409-4bc1-b929-d1b9296f21a4 Phenotypic plasticity is defined as the property of organisms to produce distinct phenotypes in response to environmental variation. While for more than a century, biologists have proposed this organismal feature to play an important role in evolution and the origin of novelty, the idea has remained contentious. Plasticity is found in all domains of life, but only recently has there been an increase in empirical studies. This contribution is intended as a fresh view and will discuss current and future challenges of plasticity research, and the need to identify associated molecular mechanisms. After a brief summary of conceptual, theoretical, and historical aspects, some of which were responsible for confusion and contention, I will formulate three major research directions and predictions for the role of plasticity as a facilitator of novelty. These predictions result in a four-step model that, when properly filled with molecular mechanisms, will reveal plasticity as a major factor of evolution. Such mechanistic insight must be complemented with comparative investigations to show that plasticity has indeed created novelty and innovation. Together, such studies will help develop a true developmental evolutionary biology.

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<![CDATA[The ABC of Major Histocompatibility Complexes and T Cell Receptors in Health and Disease]]> https://www.researchpad.co/article/Nffb610d1-9f53-4e4d-8276-844e9f10f6c7 A seminal discovery of major histocompatibility complex (MHC) restriction in T cell recognition by Peter Doherty and Rolf Zinkernagel has led to 45 years of exciting research on the mechanisms governing peptide MHC (pMHC) recognition by T cell receptors (TCRs) and their importance in health and disease. T cells provide a significant level of protection against viral, bacterial, and parasitic infections, as well as tumors, hence, the generation of protective T cell responses is a primary goal for cell-mediated vaccines and immunotherapies. Understanding the mechanisms underlying generation of optimal high-avidity effector T cell responses, memory development, maintenance, and recall is of major importance for the rational design of preventative and therapeutic vaccines/immunotherapies. In this review, we summarize the lessons learned over the last four decades and outline our current understanding of the basis and consequences of pMHC/TCR interactions on T cell development and function, and TCR diversity and composition, driving better clinical outcomes and prevention of viral escape. We also discuss the current models of T cell memory formation and determinants of immunodominant T cell responses in animal models and humans. As TCR composition and diversity can affect both the protective capacity of T cells and protection against viral escape, defining the spectrum of TCR selection has implications for improving the functional efficacy of effector T cell responsiveness and memory formation.

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<![CDATA[A Disquisition on MHC Restriction and T Cell Recognition in Five Acts]]> https://www.researchpad.co/article/N94b7c308-084b-45bb-a8bc-9907a639be2b The seminal discovery in the early 1970s, credited to Peter Doherty and Rolf Zinkernagel, of major histocompatibility complex (MHC) restriction exhibited by cytotoxic T cells represented a major conceptual advance in understanding antigen recognition by conventional T cells. This advance also led to other major new insights into the ontogeny and immunobiology of T cells and catalyzed a renaissance in viral immunology. In this commentary in honor of Peter Doherty, I offer five brief reflections on different aspects of the phenomenon of MHC restriction and the process by which it was discovered and explained. In the first of these sections, I offer a reinterpretation of MHC restriction that reframes the constraints on self-MHC recognition in terms of the probabilities of recognizing a given nominal antigen peptide in the context of an MHC molecule that is nonself on the basis of differing in amino acid sequence from the self-restriction element at one or more positions. Subsequent sections address: (i) the ways in which general ideas, developed subsequent to the discovery of MHC restriction, about the intricacies of antigen recognition by antibodies apply to T cell receptors binding to MHC/peptide complexes; (ii) how to reconcile the existence of MHC restriction with the impressive magnitude of T cell responses to nonself MHC antigens; (iii) the possible relevance to MHC restriction and immune system function of ideas from mathematical logic that relate to the consequences of self-reference; and (iv) the implications for the philosophy of science of MHC restriction and the processes of its discovery and acceptance within the immunology research community.

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<![CDATA[Elucidating Specificity Opens a Window to the Complexity of Both the Innate and Adaptive Immune Systems]]> https://www.researchpad.co/article/Nfcd24800-f125-4f5c-9e69-a6588b3cb9d0 Science is a tedious and painstaking business. Many discoveries are considered incremental, individually not necessarily earth shattering, but collectively providing the critical broad framework on which pivotal insights can emerge. Transformational discoveries spring from this knowledge legacy of others and spur a fervent discovery process, often driven by technological developments. The seminal discovery of major histocompatibility class restriction I (MHCI) and its role in antiviral infections by Doherty and Zinkernagel in 1974 was one such discovery—the key that unlocked the treasure chest to the rich tapestry of the diversity of the immune system. An army of researchers have teased apart the different elements of the immune response, which now brings us to a deeper understanding of immune memory and protective immunity. In this process, it has uncovered a multitude of cell types that bridge the innate and adaptive arms of the immune system—blurring the line between these two branches—and ultimately fortifying the development of long-term immune protection.

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<![CDATA[MHC Restriction: Where Are We Now?]]> https://www.researchpad.co/article/Na895b435-62ef-43b1-8111-7daf2f2f158c <![CDATA[国际多学科肺癌组织病理新分类解读]]> https://www.researchpad.co/article/5c052c56d5eed0c4848a7efa <![CDATA[On the dynamics of the human endocrine pancreas and potential consequences for the development of type 1 diabetes]]> https://www.researchpad.co/article/N2cccfed8-f359-4739-ab58-815ddd924c89

Little is known about the human islet life span, and beta-cell neogenesis is generally considered rare in adults. However, based on available data on beta-cell proliferation, calculations can be made suggesting that the dynamics of the endocrine pancreas is considerable even during adulthood, with islet neogenesis and a sustained increase in size of already formed islets. Islet-associated hemorrhages, frequently observed in most mammals including humans, could account for a considerable loss of islet parenchyma balancing the constant beta-cell proliferation. Notably, in subjects with type 1 diabetes, periductal accumulation of leukocytes and fibrosis is frequently observed, findings that are likely to negatively affect islet neogenesis from endocrine progenitor cells present in the periductal area. Impaired neogenesis would disrupt the balance, result in loss of islet mass, and eventually lead to beta-cell deficiency and compromised glucose metabolism, with increased islet workload and blood perfusion of remaining islets. These changes would impose initiation of a vicious circle further increasing the frequency of vascular events and hemorrhages within remaining islets until the patient eventually loses all beta-cells and becomes c-peptide negative.

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