Visualizing elements of Sha[3] in genus 2 jacobians

Mazur proved that any element xi of order three in the Shafarevich-Tate group of an elliptic curve E over a number field k can be made visible in an abelian surface A in the sense that xi lies in the kernel of the natural homomorphism between the cohomology groups H^1(k,E) -> H^1(k,A). However, the abelian surface in Mazur's construction is almost never a jacobian of a genus 2 curve. In this paper we show that any element of order three in the Shafarevich-Tate group of an elliptic curve over a number field can be visualized in the jacobians of a genus 2 curve. Moreover, we describe how to get explicit models of the genus 2 curves involved.Comment: 12 page

N-body simulations of gravitational dynamics

We describe the astrophysical and numerical basis of N-body simulations, both of collisional stellar systems (dense star clusters and galactic centres) and collisionless stellar dynamics (galaxies and large-scale structure). We explain and discuss the state-of-the-art algorithms used for these quite different regimes, attempt to give a fair critique, and point out possible directions of future improvement and development. We briefly touch upon the history of N-body simulations and their most important results.Comment: invited review (28 pages), to appear in European Physics Journal Plu

Withdrawal of maintenance therapy for cytomegalovirus retinitis in AIDS patients exhibiting immunological response to HAART

BACKGROUND: Before the introduction of highly active antiretroviral therapy (HAART), CMV retinitis was a common complication in patients with advanced HIV disease and the therapy was well established; it consisted of an induction phase to control the infection with ganciclovir, followed by a lifelong maintenance phase to avoid or delay relapses. METHODS: To determine the safety of CMV maintenance therapy withdrawal in patients with immune recovery after HAART, 35 patients with treated CMV retinitis, on maintenance therapy, with CD4+ cell count greater than 100 cells/mm³ for at least three months, but almost all patients presented these values for more than six months and viral load < 30000 copies/mL, were prospectively evaluated for the recurrence of CMV disease. Maintenance therapy was withdrawal at inclusion, and patients were monitored for at least 48 weeks by clinical and ophthalmologic evaluations, and by determination of CMV viremia markers (antigenemia-pp65), CD4+/CD8+ counts and plasma HIV RNA levels. Lymphoproliferative assays were performed on 26/35 patients. RESULTS: From 35 patients included, only one had confirmed reactivation of CMV retinitis, at day 120 of follow-up. No patient returned positive antigenemia tests. No correlation between lymphoproliferative assays and CD4+ counts was observed. CONCLUSION: CMV retinitis maintenance therapy discontinuation is safe for those patients with quantitative immune recovery after HAART

Universal DNA methylation age across mammalian tissues

DATA AVAILABILITY STATEMENT : The individual-level data from the Mammalian Methylation Consortium can be accessed from several online locations. All data from the Mammalian Methylation Consortium are posted on Gene Expression Omnibus (complete dataset, GSE223748). Subsets of the datasets can also be downloaded from accession numbers GSE174758, GSE184211, GSE184213, GSE184215, GSE184216, GSE184218, GSE184220, GSE184221, GSE184224, GSE190660, GSE190661, GSE190662, GSE190663, GSE190664, GSE174544, GSE190665, GSE174767, GSE184222, GSE184223, GSE174777, GSE174778, GSE173330, GSE164127, GSE147002, GSE147003, GSE147004, GSE223943 and GSE223944. Additional details can be found in Supplementary Note 2. The mammalian data can also be downloaded from the Clock Foundation webpage: https://clockfoundation.org/MammalianMethylationConsortium. The mammalian methylation array is available through the non-profit Epigenetic Clock Development Foundation (https://clockfoundation.org/). The manifest file of the mammalian array and genome annotations of CpG sites can be found on Zenodo (10.5281/zenodo.7574747). All other data supporting the findings of this study are available from the corresponding author upon reasonable request. The chip manifest files, genome annotations of CpG sites and the software code for universal pan-mammalian clocks can be found on GitHub95 at https://github.com/shorvath/MammalianMethylationConsortium/tree/v2.0.0. The individual R code for the universal pan-mammalian clocks, EWAS analysis and functional enrichment studies can be also found in the Supplementary Code.SUPPLEMENTARY MATERIAL 1 : Supplementary Tables 1–3 and Notes 1–6.SUPPLEMENTARY MATERIAL 2 : Reporting SummarySUPPLEMENTARY MATERIAL 3 : Supplementary Data 1–14.SUPPLEMENTARY MATERIAL 4 : Supplementary Code.Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.https://www.nature.com/nataginghj2024Zoology and EntomologySDG-15:Life on lan

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Surf Wave Hydrodynamics in the Coastal Environment

Stochastic wave models play a central role in our present-day wave modelling capabilities. They are frequently used to compute wave statistics, to generate boundary conditions and to include wave effects in coupled model systems. Historically, such models were developed to predict the wave field evolution in deep water where the conditions of Gaussianity generally hold. However, in recent decades, such models have been applied to the shallower coastal environment where the stochastic representation of the dominant wave physics becomes questionable. This is primarily due to the increased influence of wave nonlinearity and the additional depth-induced wave processes that are dominant in this region.Unfortunately, the two most dominant wave processes in the surf zone: depth-induced wave breaking and nonlinear triad wave-wave interactions are also the least well represented and understood. This is due to both their complexity and the scarcity of analytical solutions for realistic wave fields. As such, they represent a significant obstacle in the accurate modelling of the wave dynamics in the coastal region. Providing accurate representations of these wave processes is essential to answering the questions demanded from stochastic wave models from coastal engineers for coastal management and design. Such advancements are necessary to improve our understanding of wave-induced processes, to reduce costs in managing the coastal environment and to tackle contemporary issues such as uncertainties with respect to increased sea level rise.Due to the complexity of depth-induced wave breaking, a complete representation of this wave process does not exist for both stochastic and deterministic modelling frameworks. Although there is extensive literature on the subject of parameterizing depth-induced wave breaking in a stochastic sense, these parameterizations are inconsistent with theory, observations and (deterministic) model predictions. In particular, present-day modelling defaults perform poorly over (near-)horizontal bathymetries with over-enhanced wave dissipation of locally-generated waves and insufficient dissipation of swell waves. Equally, nonlinear triad wave-wave interactions are poorly represented in stochastic wave models due to the problem of closure and the impractical computational expense of more accurate representations. In particular, the most commonly applied parameterization in the wave literature incorrectly predicts the evolution of the spectral shape, and the convergence to an equilibrium high-frequency tail deep in the surf zone. Correctly resolving these issues is essential for the management of many of the activities occurring at the coast; from the design of coastal defenses to feasibility studies for wave energy converters, from port operation and availability to vessel navigation, from understanding the ecology at the coast to the fisheries, and from managing leisure and tourism to safety at the coast. In this work, we investigate the process of depth-induced wave breaking through a comprehensive analysis of the literature and a comparison of modelling performance. Here, we use an extensive set of wave observations representing a large range of wave conditions and bathymetric profiles. The analysis demonstrates that no currently available depth-induced breaking source term is capable of sufficiently representing the process of depth-induced wave breaking. This is shown to be in agreement with the wave literature with parameterizations either over-predicting wave dissipation for locally generated waves or under-predicting wave dissipation for non-locally generated waves over (near-)horizontal bathymetries. To address this issue, a new joint scaling using both local wave and bathymetric conditions is proposed. Using both the normalized characteristic wave number and local bottom slope unifies two approaches prevalent in the wave literature. This is shown to improve the model performance for the dissipation of both locally and non-locally generated waves over (near-)horizontal bathymetries. Furthermore, the validity of the assumption that wave dissipation can be modelled as analogous to a 1D dissipative bore is explored. Subsequently, a heuristic directional modification is introduced for depth-induced wave breaking dissipation models. This directionally partitions the 2D spectrum into several directional partitions that are assumed to be unidirectional. Model results demonstrate that the effect of the directional partitioning is to reduce the dissipation of wave energy and to enhance the significant wave height; in agreement with field measurements. Not only is this modification shown to be applicable to the joint wave breaking parameterization proposed in this study, but also for well-established parameterizations. The effects of both the proposed scaling and directional modification are then reviewed from an operational context and are compared to state-of-the-art source terms, field observations and a hypothetical storm representative of Dutch design conditions. Such design conditions are expected to be representative of design conditions found globally. In an environment where storm intensities may be increasing, for example due to global warming, the results of wave breaking models near the coast under such extreme conditions become of greater relevance. The influence of wave breaking models in coupled model systems is anticipated to provide important new insights in understanding the various wave-driven processes along our coasts. Next, the representation of the nonlinear triad wave-wave interactions in stochastic wave models is reviewed. In particular, the collinear approximation used to transform 1D triad source terms for implementation in 2D stochastic wave models is revisited. These approximations are necessitated by considerations of computational efficiency. The conventional collinear approximation is shown to be inconsistent at the unidirectional limit and to be a primary source of modelling error. Instead of converging to the values predicted by the 1D triad source terms at the unidirectional limit, the energy transfers as computed by stochastic wave models are shown to become unbounded. This results in a dimensional calibration coefficient which is at least an order of magnitude smaller than that found in the wave literature. Consequently, for directional wave conditions, 1D triad source terms implemented with the conventional collinear approximation insufficiently capture the wave evolution. To address this problem, a new collinear approximation is presented which accounts for the wave energy contained within a finite directional bandwidth. This collinear approximation is shown to converge correctly at the unidirectional limit and to agree well with predictions from a second-order accurate deterministic wave model. In particular, better agreement is shown in the modelling prediction of the spectral shape and related integral parameters, e.g. wave period, under idealized wave conditions. Under certain conditions, these error reductions are shown to be more significant than differences between the underlying triad models.The contribution of this work demonstrates that while the underlying theory underpinning stochastic wave modelling in the coastal environment still remains questionable, the accurate determination of wave statistics in the coastal zone is tenable. With the advancements presented in this study, the new source terms correspond better with the current wave literature and are shown to provide significant steps forward over existing default source terms. The developments presented here are anticipated to form the foundation for future source term research, and to be used for the representation of the dominant wave physics in the coastal environment in operational wave models.Environmental Fluid Mechanic