The rockefeller university

Transitions across ecological boundaries, such as those separating freshwater from the sea, are major drivers of phenotypic innovation and biodiversity. Despite their importance to evolutionary history, we know little about the mechanisms by which such transitions are accomplished. To help shed light on these mechanisms, we generated the first high-quality, near-complete assembly and annotation of the genome of the American shad (Alosa sapidissima), an ancestrally diadromous (migratory between salinities) fish in the order Clupeiformes of major cultural and historical significance. Among the Clupeiformes, there is a large amount of variation in salinity habitat and many independent instances of salinity boundary crossing, making this taxon well-suited for studies of mechanisms underlying ecological transitions. Our initial analysis of the American shad genome reveals several unique insights for future study including: (i) that genomic repeat content is among the highest of any fish studied to date; (ii) that genome-wide heterozygosity is low and may be associated with range-wide population collapses since the 19th century; and (iii) that natural selection has acted on the branch leading to the diadromous genus Alosa. Our analysis suggests that functional targets of natural selection may include diet, particularly lipid metabolism, as well as cytoskeletal remodeling and sensing of salinity changes. Natural selection on these functions is expected in the transition from a marine to diadromous life history, particularly in the tolerance of nutrient- and ion-devoid freshwater. We anticipate that our assembly of the American shad genome will be used to test future hypotheses on adaptation to novel environments, the origins of diadromy, and adaptive variation in life history strategies, among others.

Many real-world data sets live on high-dimensional Stiefel and Grassmannian manifolds, V-k(R-N) and Gr(k, R-N), respectively, and benefit from projection onto lower-dimensional Stiefel (respectively, Grassmannian) manifolds. In this work, we propose an algorithm called principal Stiefel coordinates to reduce data dimensionality from V-k(R-N) to V-k(R-n) in an O(k)-equivariant manner (k <= n << N). We begin by observing that each element alpha is an element of V-n(R-N) defines an isometric embedding of V-k(R-n) into V-k(R-N). Next, we optimize for such an embedding map that minimizes data fit error by warm-starting with the output of principal component analysis (PCA) and applying gradient descent. Then we define a continuous and O(k)-equivariant map pi(alpha) that acts as a ''closest point operator" to project the data onto the image of V-k(R-n) in V-k(R-N) under the embedding determined by alpha, while minimizing distortion. Because this dimensionality reduction is O(k)-equivariant, these results extend to Grassmannian manifolds as well. Lastly, we show that the PCA output globally minimizes projection error in a noiseless setting, but that our algorithm achieves a meaningfully different and improved outcome when the data does not lie exactly on the image of a linearly embedded lower-dimensional Stiefel manifold as above. Multiple numerical experiments using synthetic and real-world data are performed.

QuestionCan investigators agree on morphological definitions and methods of assessment for lesions in clinical trials for hidradenitis suppurativa (HS)?FindingThrough a modified Delphi process involving expert dermatologists, consensus was achieved on 11 morphologic lesion definitions and on 16 of 18 statements guiding standardized HS lesion assessments.MeaningConsensus on detailed morphologic definitions to support classification of HS lesions and guidance that standardizes assessment of these lesions can be implemented in study protocols and investigator trainings with the goal of improving accuracy and reliability of investigator ratings in clinical trials for HS. This consensus statement establishes consensus-based morphological definitions of hidradenitis suppurativa (HS) lesions and guidance statements that standardize investigator lesion assessments for implementation in clinical trials. ImportanceAccurate classification and reliability in assessment for lesions of hidradenitis suppurativa (HS) by investigators is critical to the determination of responder status and to overall data quality in clinical trials.ObjectiveTo establish consensus-based morphological definitions of HS lesions and guidance statements that standardize investigator lesion assessments for implementation in clinical trials.Evidence ReviewHealth professionals (primarily dermatologists) with expertise in the measurement of HS disease activity as well as novice raters completed a preliminary questionnaire in which participants were asked to assess images of HS lesions and provide qualitative feedback on their decision making. Based on this feedback, detailed morphologic definitions for lesions and guidance statements that standardize lesion assessments were formulated and presented for consensus voting in 2 electronic Delphi surveys. A virtual group discussion after round 1 supported participants in round 2 voting.FindingsResponse rates were 84.7% (50 of 59), 86.0% (43 of 50), and 90.9% (40 of 44) in the preliminary, electronic Delphi round 1, and electronic Delphi round 2 surveys, respectively. Morphological definitions for 11 lesion types achieved the prespecified 70% consensus threshold, with 9 definitions reaching at least 90% agreement. After 2 electronic Delphi rounds, 16 of 18 guidance statements achieved the prespecified consensus threshold, with 13 statements receiving endorsement from more than 80% of participants. Two guidance statements related to assessment of tunneled plaques with multiple openings and assessment of scalp lesions failed to reach consensus.Conclusions and RelevanceCommon morphologic definitions and guidance that standardize assessment of HS lesions can be implemented in clinical trial protocols and investigator trainings with the goals of improving accuracy and reliability of investigator ratings.

Psychological stress and its sequelae pose a major challenge to public health. Immune activation is conventionally thought to aggravate stress-related mental diseases such as anxiety disorders and depression. Here, we sought to identify potentially beneficial consequences of immune activation in response to stress. We showed that stress led to increased interleukin (IL)-22 production in the intestine as a result of stress-induced gut leakage. IL-22 was both necessary and sufficient to attenuate stress-induced anxiety behaviors in mice. More specifically, IL-22 gained access to the septal area of the brain and directly suppressed neuron activation. Furthermore, human patients with clinical depression displayed reduced IL-22 levels, and exogenous IL- 22 treatment ameliorated depressive-like behavior elicited by chronic stress in mice. Our study thus identifies a gut-brain axis in response to stress, whereby IL-22 reduces neuronal activation and concomitant anxiety behavior, suggesting that early immune activation can provide protection against psychological stress.

A search is presented for an extended Higgs sector with two new particles, X and., in the process X ->phi phi ->(gamma gamma)(gamma gamma).Novel neural networks classify events with diphotons that are merged and determine the diphoton masses. The search uses LHC proton-proton collision data at root s = 13 TeV collected with the CMS detector, corresponding to an integrated luminosity of 138 fb(-1). No evidence of such resonances is seen. Upper limits are set on the production cross section for m(X) between 300 and 3000 GeV and m.=m(X) between 0.5% and 2.5%, representing the most sensitive search in this channel.

Human endogenous retroviruses (HERVs) occupy a large portion of the human genome. Most HERVs are transcriptionally silent, but they can be reactivated during pathological states such as viral infection and certain cancers. The HERV-K HML-2 clade includes elements that recently integrated have in the human germ line and often contain intact open reading frames that possibly support peptide and protein expression. Understanding HERV-K-host interactions and their potential as biomarkers is problematic due to the high similarity among different elements. Previously, we described a long-read single molecule real-time sequencing (PacBio) strategy to analyze HERV-K RNA expression profiles in different cell types. However, identifying HERV-K HML-2 proteins accurately is difficult without robust and reliable methods and reagents. Here we present a new approach to characterize the HML-2 elements that (a) are being translated and (b) produce enough protein to be detected and identified by mass spectrometry. Our data reveal that RNA expression profiling alone cannot accurately predict which HML-2 elements are responsible for protein production, as we observe several differences between the highest expressed RNAs and the elements that are the predominant source of HERV-K HML-2 protein synthesis. These studies represent an important advance toward untangling the complexity of HERV-K-host interactions.

Background Immunological disturbances (anti-type I IFN auto-antibody production, cytokine storm, lymphopenia, T-cell hyperactivation and exhaustion) are responsible for disease exacerbation during severe COVID-19 infections.Methods In this study, we set up a prospective, randomised clinical trial (ClinicalTrials.gov ID: NCT04751643) and performed therapeutic plasma exchange (TPE) in severe COVID-19 patients in order to decrease excess cytokines and auto-antibodies and to assess whether adding TPE to the standard treatment (ST, including corticosteroids plus high-flow rate oxygen) could help restore immune parameters and limit the progression of acute respiratory distress syndrome (ARDS).Results As expected, performing TPE decreased the amount of anti-type I IFN auto-antibodies and improved the elimination or limited the production of certain inflammatory mediators (IL-18, IL-7, CCL2, CCL3, etc.) circulating in the blood of COVID-19 patients, compared to ST controls. Interestingly, while TPE did not influence changes in ARDS parameters throughout the protocol, it proved more effective than ST in reversing lymphopenia, preventing T-cell hyperactivation and reducing T-cell exhaustion, notably in a fraction of TPE patients who had an early favourable respiratory outcome. TPE also restored appropriate numbers of CD4+ and CD8+ T-cell memory populations and increased the number of circulating virus-specific T cells in these patients.Conclusion Our results therefore indicate that the addition of TPE sessions to the standard treatment accelerates immune cell recovery and contributes to the development of appropriate antiviral T-cell responses in some patients with severe COVID-19 disease.

Medical interventions often require timed series of doses, thus necessitating accurate medical record-keeping. In many global settings, these records are unreliable or unavailable at the point of care, leading to less effective treatments or disease prevention. Here we present an invisible-to-the-naked-eye on-patient medical record-keeping technology that accurately stores medical information in the patient skin as part of microneedles that are used for intradermal therapeutics. We optimize the microneedle design for both a reliable delivery of messenger RNA (mRNA) therapeutics and the near-infrared fluorescent microparticles that encode the on-patient medical record-keeping. Deep learning-based image processing enables encoding and decoding of the information with excellent temporal and spatial robustness. Long-term studies in a swine model demonstrate the safety, efficacy and reliability of this approach for the co-delivery of on-patient medical record-keeping and the mRNA vaccine encoding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This technology could help healthcare workers make informed decisions in circumstances where reliable record-keeping is unavailable, thus contributing to global healthcare equity.

Congenital hydrocephalus, characterized by cerebral ventriculomegaly, is among the most common and least understood paediatric neurosurgical disorders.We have identified, in the largest assembled cerebral ventriculomegaly cohort (2697 parent-proband trios), an exome-wide significant enrichment of protein-altering de novo variants in LDB1 (P = 1.11 x 10-15). Eight unrelated patients with ventriculomegaly, developmental delay and dysmorphic features harboured loss-of-function de novo variants that truncate carboxy-terminal LIM interaction domain of LDB1, which regulates assembly of LIM homeodomain-containing transcriptional modulators.Integrative multiomic analyses suggest that LDB1 is a key transcriptional regulator in ventricular neuroprogenitors through its binding to LIM-homeodomain proteins, including SMARCC1 and ARID1B. Indeed, LIM-homeodomain-containing genes carry a disproportionate burden of protein-damaging de novo variants in our cohort, with SMARCC1 (P = 5.83 x 10-9) and ARID1B (P = 1.80 x 10-17) surpassing exome-wide significance thresholds.These data identify LBD1 as a novel neurodevelopmental disorder gene and suggest that an LDB1-regulated transcriptional programme is essential for human brain morphogenesis. Allington et al. identify an enrichment of de novo variants in LDB1 in children with a neurodevelopmental syndrome featuring cerebral ventriculomegaly. The findings highlight the importance of an LDB1-regulated transcriptional network in brain morphogenesis, and suggest that exome sequencing may be useful in evaluating patients.