The rockefeller university

At the start of the pandemic caused by the novel coronavirus (SARS-CoV-2), the Gaucher disease community anticipated that infection with this emerging viral pathogen would be associated with high morbidity and mortality in individuals with this chronic metabolic disorder. Surprisingly, however, preliminary studies suggest that Gaucher disease does not confer a higher risk of severe, life-threatening effects of SARS-CoV-2 infection, and no severe cases have been reported in large cohorts of patients from the United States, Europe and Israel. It is thought that the accumulation of glucocerebroside in the cells of Gaucher patients may promote immune tolerance rather than inflammation on exposure to SARS-CoV-2. We review here the current concepts of Gaucher disease and SARS-CoV-2 infection, focusing particularly on general prevention and vaccination. We also discuss the susceptibility to COVID-19 of patients with inborn errors of type 1 interferon (IFN alpha and IFN omega) immunity.

Recent advances in human naive pluripotent stem cell culture have demonstrated their ability to generate trophectoderm and descendant trophoblast cell types. Moreover, the same cells when cultured in three-dimensional configurations self-organize to generate blastocyst-like structures called blastoids. These discoveries represent a major step forward in modeling early human embryonic development.

Recent advances in synthetic human embryology has provided a previously inexistent molecular portrait of human development. Models of synthetic human embryonic tissues capitalize on the self-organizing capabilities of human embryonic stem cells when they are cultured on biomimetic conditions that simulate in vivo human development. In this Review, we discuss these models and how they have shed light on the early stages of human development including amniotic sac development, gastrulation and neurulation. We discuss the mechanisms underlying the molecular logic of embryonic tissue self-organization that have been dissected using synthetic models of human embryology and explore future challenges in the field. Geared with technological advances in bioengineering, high resolution gene expression and imaging tools, these models are set to transform our understanding of the mechanistic basis of embryonic tissue self-organization during human development and how they may go awry in disease.

Polyphasic sleep is the practice of distributing multiple short sleep episodes across the 24-hour day rather than having one major and possibly a minor (& ldquo;nap & rdquo;) sleep episode each day. While the prevalence of poly phasic sleep is unknown, anecdotal reports suggest attempts to follow this practice are common, particularly among young adults. Polyphasic-sleep advocates claim to thrive on as little as 2 hours of total sleep per day. However, significant concerns have been raised that polyphasic sleep schedules can result in health and safety consequences. We reviewed the literature to identify the impact of polyphasic sleep schedules (excluding nap or siesta schedules) on health, safety, and performance outcomes. Of 40,672 potentially relevant publications, with 2,023 selected for full-text review, 22 relevant papers were retained. We found no evidence supporting benefits from following polyphasic sleep schedules. Based on the current evidence, the consensus opinion is that polyphasic sleep schedules, and the sleep deficiency inherent in those schedules, are associated with a variety of adverse physical health, mental health, and performance outcomes. Striving to adopt a schedule that significantly reduces the amount of sleep per 24 hours and/or fragments sleep into multiple episodes throughout the 24-hour day is not recommended. (c) 2021 The Authors. Published by Elsevier Inc. on behalf of National Sleep Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Maintenance of cell size homeostasis is a property that is conserved throughout eukaryotes. Cell size homeostasis is brought about by the co-ordination of cell division with cell growth and requires restriction of smaller cells from undergoing mitosis and cell division, whilst allowing larger cells to do so. Cyclin-CDK is the fundamental driver of mitosis and therefore ultimately ensures size homeostasis. Here we dissect determinants of CDK activity in vivo to investigate how cell size information is processed by the cell cycle network in fission yeast. We develop a high-throughput single-cell assay system of CDK activity in vivo and show that inhibitory tyrosine phosphorylation of CDK encodes cell size information, with the phosphatase PP2A aiding to set a size threshold for division. CDK inhibitory phosphorylation works synergistically with PP2A to prevent mitosis in smaller cells. Finally, we find that diploid cells of equivalent size to haploid cells exhibit lower CDK activity in response to equal cyclin-CDK enzyme concentrations, suggesting that CDK activity is reduced by increased DNA levels. Therefore, scaling of cyclin-CDK levels with cell size, CDK inhibitory phosphorylation, PP2A, and DNA-dependent inhibition of CDK activity, all inform the cell cycle network of cell size, thus contributing to cell size homeostasis.

Contact guidance is a powerful topographical cue that induces persistent directional cell migration. Healthy tissue stroma is characterized by a meshwork of wavy extracellular matrix (ECM) fiber bundles, whereas metastasis-prone stroma exhibit less wavy, more linear fibers. The latter topography correlates with poor prognosis, whereas more wavy bundles correlate with benign tumors. We designed nanotopographic ECM-coated substrates that mimic collagen fibril waveforms seen in tumors and healthy tissues to determine how these nanotopographies may regulate cancer cell polarization and migration machineries. Cell polarization and directional migration were inhibited by fibril-like wave substrates above a threshold amplitude. Although polarity signals and actin nucleation factors were required for polarization and migration on low-amplitude wave substrates, they did not localize to cell leading edges. Instead, these factors localized to wave peaks, creating multiple "cryptic leading edges" within cells. On high amplitude wave substrates, retrograde flow from large cryptic leading edges depolarized stress fibers and focal adhesions and inhibited cell migration. On low-amplitude wave substrates, actomyosin contractility overrode the small cryptic leading edges and drove stress fiber and focal adhesion orientation along the wave axis to mediate directional migration. Cancer cells of different intrinsic contractility depolarized at different wave amplitudes, and cell polarization response to wavy substrates could be tuned by manipulating contractility. We propose that ECM fibril waveforms with sufficiently high amplitude around tumors may serve as "cell polarization barriers," decreasing directional migration of tumor cells, which could be overcome by up-regulation of tumor cell contractility.

Background: Hidradenitis suppurativa (HS), also known as acne inversa, is a chronic, painful, and burdensome inflammatory disease manifesting in nodules and abscesses, with progression to chronically draining tunnels in later-stage disease. Objective: We sought to determine whether HS tunnels are immunologically active participants in disease activity. Methods: Skin biopsy specimens were obtained by using ultrasound guidance in untreated patients with HS and those enrolled in an open-label study of brodalumab (ClinicalTrials.gov identifier NCT03960268) for patients with moderate-to-severe HS. Results: Immunohistochemistry of HS biopsy specimens demonstrated that the epithelialized HS tunnels recapitulate the psoriasiform epidermal hyperplasia morphology of the overlying epidermis, displaying molecular inflammation, including S100A7 (psoriasin) positivity, as well as features of epidermal skin, including loricrin, filaggrin, lipocalin-2, and Melan-A positive cells. Tunnels were associated with increased infiltration of T cells, dendritic cells, and neutrophils; formation of neutrophil extracellular traps, and increased expression of psoriasiform proinflammatory cytokines. Unsupervised hierarchical clustering demonstrated a separation of HS samples based on the presence or absence of tunnels. Tunnels isolated by microdissection had higher levels of epithelium derived inflammatory cytokines compared with the overlying epidermis and healthy controls. Clinically, the size and draining of the tunnels were decreased with treatment with the IL-17RA antagonist brodalumab. Conclusion: These data suggest that tunnels are a source of inflammation in HS. (J Allergy Clin Immunol 2021;147:2213-24.)

Cytotoxic T lymphocytes (CTLs) represent key immune effectors of the host response against chronic viruses, due to their cytotoxic response to virus-infected cells. In response to this selection pressure, viruses may accumulate escape mutations that evade CTL-mediated control. To study the emergence of CTL escape mutations, we employed the murine chronic infection model of lymphocytic choriomeningitis virus (LCMV). We developed an amplicon-based next-generation sequencing pipeline to detect low frequency mutations in the viral genome and identified non-synonymous mutations in the immunodominant LCMV CTL epitope, GP33-41, in infected wildtype mice. Infected Rag2-deficient mice lacking CTLs did not contain such viral mutations. By using transgenic mice with T cell receptors specific to GP33-41, we characterized the emergence of viral mutations in this epitope under varying selection pressure. We investigated the two most abundant viral mutations by employing reverse genetically engineered viral mutants encoding the respective mutations. These experiments provided evidence that these mutations prevent activation and expansion of epitope-specific CD8 T cells. Our findings on the mutational dynamics of CTL escape mutations in a widely-studied viral infection model contributes to our understanding of how chronic viruses interact with their host and evade the immune response. This may guide the development of future treatments and vaccines against chronic infections.

The International Society for Stem Cell Research has updated its Guidelines for Stem Cell Research and Clinical Translation in order to address advances in stem cell science and other relevant fields, together with the associated ethical, social, and policy issues that have arisen since the last update in 2016. While growing to encompass the evolving science, clinical applications of stem cells, and the increasingly complex implications of stem cell research for society, the basic principles underlying the Guidelines remain unchanged, and they will continue to serve as the standard for the field and as a resource for scientists, regulators, funders, physicians, and members of the public, including patients. A summary of the key updates and issues is presented here.