The rockefeller university

As scholars envision a new regulatory or statutory neurorights schema it is important to imagine unintended consequences if reforms are implemented before their implications are fully understood. This paper critically evaluates provisions proposed for a new Chilean Constitution and evaluates this movement against efforts to improve the diagnosis of, and treatment for, individuals with disorders of consciousness within the broader context of disability law, international human rights, and a capabilities approach to health justice as advanced by Amartya Sen and Martha Nussbaum. Framed in this way, any neurorights regime would need to satisfy several criteria. First it would be obliged to balance both positive and negative rights in the furtherance of human capabilities. Second, it would need to be future oriented and informed about the science it sought to regulate and not fall prey to science fiction fantasies that remain ungrounded in reality. Third, it would need to be specific and avoid generalizations that would lead to conceptual confusion and litigation that could delay scientific progress. Finally, it would need to harmonize novel neurorights with long-established norms in international disability and human rights law. A failure to meet these criteria will destine any novel neurorights regime to the periphery. At this juncture Chile's nascent constitutional venture into neurorights fails to satisfy these criteria. While there yet may be a role for a more capacious and bivalent articulation of neurorights that account for capabilities and precedent, the current Chilean neurorights reforms are vague and premature. As such they should undergo additional scholarly scrutiny and should not be adopted by other jurisdictions.

BG24, a VRC01-class broadly neutralizing antibody (bNAb) against HIV-1 Env with relatively few somatic hypermutations (SHMs), represents a promising target for vaccine strategies to elicit CD4-binding site (CD4bs) bNAbs. To understand how SHMs correlate with BG24 neutralization of HIV-1, we report 4.1 angstrom and 3.4 angstrom single-particle cryo-EM structures of two inferred germline (iGL) BG24 precursors complexed with engineered Env-based immunogens lacking CD4bs N-glycans. Structures reveal critical Env contacts by BG24(iGL) and identify antibody light chain structural features that impede Env recognition. In addition, biochemical data and cryo-EM structures of BG24(iGL) variants bound to Envs with CD4bs glycans present provide insights into N-glycan accommodation, including structural modes of light chain adaptations in the presence of the N276(gp120) glycan. Together, these findings reveal Env regions critical for germline antibody recognition and potential sites to alter in immunogen design.

Microbial source tracking analysis has emerged as a widespread technique for characterizing the properties of complex microbial communities. However, this analysis is currently limited to source environments sampled in a specific study. In order to expand the scope beyond one single study and allow the exploration of source environments using large databases and repositories, such as the Earth Microbiome Project, a source selection procedure is required. Such a procedure will allow differentiating between contributing environments and nuisance ones when the number of potential sources considered is high. Here, we introduce STENSL (microbial Source Tracking with ENvironment SeLection), a machine learning method that extends common microbial source tracking analysis by performing an unsupervised source selection and enabling sparse identification of latent source environments. By incorporating sparsity into the estimation of potential source environments, STENSL improves the accuracy of true source contribution, while significantly reducing the noise introduced by noncontributing ones. We therefore anticipate that source selection will augment microbial source tracking analyses, enabling exploration of multiple source environments from publicly available repositories while maintaining high accuracy of the statistical inference. IMPORTANCE Microbial source tracking is a powerful tool to characterize the properties of complex microbial communities. However, this analysis is currently limited to source environments sampled in a specific study. In many applications there is a clear need to consider source selection over a large array of microbial environments, external to the study. To this end, we developed STENSL (microbial Source Tracking with ENvironment SeLection), an expectation-maximization algorithm with sparsity that enables the identification of contributing sources among a large set of potential microbial environments. With the unprecedented expansion of microbiome data repositories such as the Earth Microbiome Project, recording over 200,000 samples from more than 50 types of categorized environments, STENSL takes the first steps in performing automated source exploration and selection. STENSL is significantly more accurate in identifying the contributing sources as well as the unknown source, even when considering hundreds of potential source environments, settings in which state-of-the-art microbial source tracking methods add considerable error.

The SARS-CoV-2 vaccine NVX-CoV2373 is a protein-based vaccine that might circumvent the difficulties in distributing mRNA vaccines to regions with limited access to cold-chain and refrigeration. However, the NVX-CoV2373-induced T cell and antibody responses remain poorly understood. In this issue of the JCI, Moderbacher et al. characterized SARS-CoV-2-specific CD4(+) and CD8(+) T cell responses elicited by one or two doses of NVX-CoV2373 in individuals enrolled in a phase I/IIa trial. Substantially increased spike-specific CD4(+) and T follicular helper cells were found after the first or second vaccine dose, with some individuals developing a modest spike-specific CD8(+) T cell response. Correlation analysis revealed an association between spike-specific CD4(+) T cells and neutralizing antibody titers. Notably, preexisting T cell immunity showed negligible effects on NVX-CoV2373-induced T cell responses. These findings indicate that the protein-based vaccine NVX-CoV2373 induces robust T cell immunity capable of recognizing SARS-CoV-2 antigens and supporting humoral immune responses.

Multiple coronaviruses have emerged independently in the past 20 years that cause lethal human diseases. Al-though vaccine development targeting these viruses has been accelerated substantially, there remain patients requiring treatment who cannot be vaccinated or who experience breakthrough infections. Understanding the common host factors necessary for the life cycles of coronaviruses may reveal conserved therapeutic targets. Here, we used the known substrate specificities of mammalian protein kinases to deconvolute the sequence of phosphorylation events mediated by three host protein kinase families (SRPK, GSK-3, and CK1) that coordinately phosphorylate a cluster of serine and threonine residues in the viral N protein, which is required for viral rep-lication. We also showed that loss or inhibition of SRPK1/2, which we propose initiates the N protein phosphor-ylation cascade, compromised the viral replication cycle. Because these phosphorylation sites are highly conserved across coronaviruses, inhibitors of these protein kinases not only may have therapeutic potential against COVID-19 but also may be broadly useful against coronavirus-mediated diseases.

The menopause is a midlife endocrinological process that greatly affects women's central nervous system functions. Over the last 2 decades numerous clinical studies have addressed the influence of ovarian hormone decline on neurological disorders like Parkinson's disease and Alzheimer's disease. However, the findings in support of a role for age at menopause, type of menopause and hormone replacement therapy on Parkinson's disease onset and its core features show inconsistencies due to the heterogeneity in the study design. Here, we provide a unified overview of the clinical literature on the influence of menopause and ovarian hormones on Parkinson's disease. We highlight the possible sources of conflicting evidence and gather considerations for future observational clinical studies that aim to explore the neurological impact of menopause-related features in Parkinson's disease.

Introduction: Generalized pustular psoriasis (GPP) is a rare, severe, clinically heterogeneous disease characterized by flares of widespread, noninfectious, macroscopically visible pustules that occur with or without systemic inflammation, and are associated with significant morbidity and mortality. Historically, GPP has been classified as a variant of psoriasis vulgaris (PV, or plaque psoriasis); however, accumulating evidence indicates that these are distinct conditions, requiring different treatment approaches. Areas covered: In this perspective article we review evidence that supports the classification of GPP as distinct from PV. Expert opinion: The histopathologic and clinical appearance of GPP is distinct from that of PV and fundamental differences exist between the two conditions in terms of genetic causes and expression-related mechanisms of disease development. GPP results from dysregulation of the innate immune system, with disruption of the interleukin (IL)-36 inflammatory pathway, induction of inflammatory keratinocyte responses, and recruitment of neutrophils. PV is driven by the adaptive immune system, with a key role played by IL-17. Considering GPP as a separate disease will enable greater focus on its specific pathogenesis and the needs of patients. Many treatments for PV have insufficient efficacy in GPP and a therapeutic approach developed specifically for GPP might lead to better patient outcomes. PLAIN LANGUAGE SUMMARY Generalized pustular psoriasis (GPP) is a rare disease. During episodes of worsening disease, the immune system attacks the skin. This causes large areas of skin to become red and painful, pus-filled blisters suddenly form. Some people with GPP have a history of another, more common, skin condition called psoriasis vulgaris (PV). People with PV develop patches of scaly, itchy skin. In the past, GPP was classed as a type of PV and treated with the same medicines. However, these medicines do not work well in GPP. Researchers now understand more about what causes GPP and how it differs from PV. GPP can cause medical problems throughout the body, leading to life-threatening complications. This means that people with GPP often need urgent medical treatment in hospitals. People with PV are mostly treated outside of hospitals. Any other medical problems are not usually due to PV itself. Researchers have found several genes that are altered in people with GPP and PV, and they differ between the two diseases. For example, changes in a gene called IL36RN are common in GPP but are not seen in PV. The skin of people with these two diseases also looks different under a microscope. Knowing more about GPP and how it differs from PV will help people with GPP to be diagnosed more quickly. It will also help researchers to develop new medicines specifically for GPP, so people can receive better treatment in the future.

Herpes simplex virus (HSV) receptor engagement activates phospholipid scramblase triggering Akt translocation to the outer leaflet of the plasma membrane where its subsequent phosphorylation promotes viral entry. We hypothesize that this previously unrecognized outside-inside signaling pathway is employed by other viruses and that cell-impermeable kinase inhibitors could provide novel antivirals. We synthesized a cell-impermeable analog of staurosporine, CIMSS, which inhibited outer membrane HSV-induced Akt phosphorylation and blocked viral entry without inducing apoptosis. CIMSS also blocked the phosphorylation of 3-phosphoinositide dependent protein kinase 1 and phospholipase C gamma, which were both detected at the outer leaflet following HSV exposure. Moreover, vesicular stomatitis virus pseudotyped with SARS-CoV-2 spike protein (VSV-S), but not native VSV or VSV pseudotyped with Ebola virus glycoprotein, triggered this scramblase-Akt outer membrane signaling pathway. VSV-S and native SARS-CoV-2 infection were inhibited by CIMSS. Thus, CIMSS uncovered unique extracellular kinase processes linked to HSV and SARS-CoV-2 entry. A cell-impermeable analog of staurosporine blocks phosphorylation events at the outer leaflet of the plasma membrane, which prevents herpes simplex virus and SARS-CoV-2 entry without inducing apoptosis.

Neuromyelitis optica spectrum disorders (NMOSD) are rare, debilitating autoimmune diseases of the central nervous system. Many NMOSD patients have antibodies to Aquaporin-4 (AQP4). Prior studies show associations of NMOSD with individual Human Leukocyte Antigen (HLA) alleles and with mutations in the complement pathway and potassium channels. HLA allele associations with NMOSD are inconsistent between populations, suggesting complex relationships between the identified alleles and risk of disease. We used a retrospective case-control approach to identify contributing genetic variants in patients who met the diagnostic criteria for NMOSD and their unaffected family members. Potentially deleterious variants identified in NMOSD patients were compared to members of their families who do not have the disease and to existing databases of human genetic variation. HLA sequences from patients from Belgrade, Serbia, were compared to the frequency of HLA haplotypes in the general population in Belgrade. We analyzed exome sequencing on 40 NMOSD patients and identified rare inherited variants in the complement pathway and potassium channel genes. Haplotype analysis further detected two haplotypes, HLA-A*01, B*08, DRB1*03 and HLA-A*01, B*08, C*07, DRB1*03, DQB1*02, which were more prevalent in NMOSD patients than in unaffected individuals. In silico modeling indicates that HLA molecules within these haplotypes are predicted to bind AQP4 at several sites, potentially contributing to the development of autoimmunity. Our results point to possible autoimmune and neurodegenerative mechanisms that cause NMOSD, and can be used to investigate potential NMOSD drug targets.

Embryogenesis is guided by a limited set of signaling pathways dynamically expressed in different places. How a context-dependent signaling response is generated has been a central question of developmental biology, which can now be addressed with in vitro models of human embryos that are derived from embryonic stem cells (hESCs). Our previous work demonstrated that during early stages of hESC differentiation, cells chronicle signaling hierarchy. Only cells that have been exposed (primed) by WNT signaling can respond to subsequent activin exposure and differentiate to mesendodermal (ME) fates. Here, we show that WNT priming does not alter SMAD2 binding nor its chromatin opening but, instead, acts by inducing the expression of the SMAD2 co-factor EOMES. Expression of EOMES is sufficient to replace WNT upstream of activin-mediated ME differentiation, thus unveiling the mechanistic basis for priming and cellular memory in early development.