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Abstract Mammalian DNA replication relies on various DNA helicase and nuclease activities to ensure accurate genetic duplication, but how different helicase and nuclease activities are properly directed remains unclear. Here, we identify the ubiquitin-specific protease, USP50, as a chromatin-associated protein required to promote ongoing replication, fork restart, telomere maintenance, cellular survival following hydroxyurea or pyridostatin treatment, and suppression of DNA breaks near GC-rich sequences. We find that USP50 supports proper WRN-FEN1 localisation at or near stalled replication forks. Nascent DNA in cells lacking USP50 shows increased association of the DNA2 nuclease and RECQL4 and RECQL5 helicases and replication defects in cells lacking USP50, or FEN1 are driven by these proteins. Consequently, suppression of DNA2 or RECQL4/5 improves USP50-depleted cell resistance to agents inducing replicative stress and restores telomere stability. These data define an unexpected regulatory protein that promotes the balance of helicase and nuclease use at ongoing and stalled replication forks.

Abstract Ring-shaped DNA sliding clamps are essential for DNA replication and genome maintenance. Clamps need to be opened and chaperoned onto DNA by clamp loader complexes (CLCs). Detailed understanding of the mechanisms by which CLCs open and place clamps around DNA remains incomplete. Here, we present a series of six structures of the Escherichia coli CLC bound to an open or closed clamp prior to and after binding to a primer-template DNA, representing the most significant intermediates in the clamp loading process. We show that the ATP-bound CLC first binds to a clamp, then constricts to hold onto it. The CLC then expands to open the clamp with a gap large enough for double-stranded DNA to enter. Upon binding to DNA, the CLC constricts slightly, allowing clamp closing around DNA. These structures provide critical high-resolution snapshots of clamp loading by the E. coli CLC, revealing how the molecular machine works.

Abstract The Permo-Triassic mass extinction was linked to catastrophic environmental changes and large igneous province (LIP) volcanism. In addition to the widespread marine losses, the Permo–Triassic event was the most severe terrestrial ecological crisis in Earth’s history and the only known mass extinction among insects, but the cause of extinction on land remains unclear. In this study, high-resolution Hg concentration records and multiple-archive S-isotope analyses of sediments from the Junggar Basin (China) provide evidence of repeated pulses of volcanic-S (acid rain) and increased Hg loading culminating in a crisis of terrestrial biota in the Junggar Basin coeval with the interval of LIP emplacement. Minor S-isotope analyses are, however, inconsistent with total ozone layer collapse. Our data suggest that LIP volcanism repeatedly stressed end-Permian terrestrial environments in the ~300 kyr preceding the marine extinction locally via S-driven acidification and deposition of Hg, and globally via pulsed addition of CO2.

In recent years, various long non-coding RNAs (lncRNAs) involved in DNA damage response (DDR) have been identified and studied to deepen our understanding. However, there are rare reports on the association between lncRNAs and base excision repair (BER). Our designed DNA microarray identified dozens of functionally unknown lncRNAs, and their transcription levels significantly increased upon exposure to DNA damage inducers. One of them, named LIP (Long noncoding RNA Interacts with PARP-1), exhibited a significant alteration in transcription in response to methyl methanesulfonate (MMS) and temozolomide (TMZ) treatments. LIP knockdown or knockout cell lines are sensitive to MMS and TMZ, indicating that LIP plays a crucial role in DDR. The loss or insufficiency of LIP significantly influences the efficiency of BER in human cells, and it suggests that LIP participates in the BER pathway. The interaction between LIP and a key factor in BER, poly (ADP-ribose) polymerase 1 (PARP-1), has been confirmed. We identified and characterized LIP, a lncRNA, which is involved in DDR, significantly influences BER efficiency, and interacts with the BER key factor PARP-1. This advances our understanding of the connection between lncRNAs and BER, presenting the potential for the discovery of new drug targets.

Abstract Malnutrition underlies almost half of all child deaths globally. Severe Acute Malnutrition (SAM) carries unacceptable mortality, particularly if accompanied by infection or medical complications, including enteropathy. We evaluated four interventions for malnutrition enteropathy in a multi-centre phase II multi-arm trial in Zambia and Zimbabwe and completed in 2021. The purpose of this trial was to identify therapies which could be taken forward into phase III trials. Children of either sex were eligible for inclusion if aged 6–59 months and hospitalised with SAM (using WHO definitions: WLZ

IntroductionThere is a lack of real-world data directly comparing different valve prostheses for transaortic valve replacement (TAVR). We aimed to compare early clinical outcomes at 30-days between the self-expandable Portico valve (Abbott) with the balloon-expandable Edwards Sapien 3 valve (Edwards Lifesciences) (ES3).MethodsOut of 1,901 patients undergoing TAVR between January 2018 and December 2021, all patients who received either Portico valve or ES3 valve via transfemoral TAVR were matched using nearest-neighbor (1:1) propensity scoring. Primary endpoints were single safety endpoints and early safety composite endpoints defined by Valve Academic Research Consortium-2 (VARC-2) criteria. The secondary endpoint was to analyze risk predictors for new permanent pacemaker (PPM) implantation in TAVR.ResultsOut of 661 complete cases, a total of 434 patients were successfully matched based on age, sex, Euro Score II and STS-score. In the matched cohort, 217 received either a Portico or valve and 217 received an ES3 valve. The VARC-2 early safety composite scores indicated a significantly greater overall 30-day safety risk in the Portico group at 9.2% (n = 20) compared to 3.7% (n = 8) in the ES3 group (p = 0.032). The requirement for new permanent pacemaker (PPM) implantation was also higher in the Portico group, at 21.2% (n = 46) vs. 13.4% (n = 29) in the ES3 group (p = 0.042). 30-day mortality was higher was 3.7% (n = 8) in Portico group compared to 0.9% in ES3 group (p = 0.11). Furthermore, implantation of the Portico valve was identified as a significant risk predictor for new PPM implantation, alongside higher age, preprocedural atrioventricular block (AVB) and longer total procedure duration.ConclusionThis study shows significantly higher rates of early clinical complications for Portico valve prostheses compared to ES3. These findings should be especially taken into consideration when selecting valve prosthesis for high-risk patients.

The passive and active L-band system (PALS) is an airborne microwave instrument suite that combines a separate radar and radiometer airborne instrument with a common antenna. PALS has been used for salinity, wind speed, and soil moisture (SM) measurements, which is critical for calibration and validation of the SM active passive satellite brightness temperature measurements. The combined 1.413 GHz radiometer and 1.26 GHz radar measurements can provide high-accuracy SM measurements over vegetated areas. The new upgraded version of the PALS instrument employs a novel single-chain receiver topology and combines the radar and radiometer instruments. The reduced-noise single-chain receiver PALS instrument was deployed on a DC-3 aircraft for SM measurement in the summer of 2019.

The African Light Source (AfLS) project is now almost eight years old. This article assesses the history, current context and future of the project. There is by now considerable momentum in building the user community, including deep training, facilitating access to current facilities, growing the scientific output, scientific networks and growing the local laboratory-scale research infrastructure. The Conceptual Design Report for the AfLS is in its final editing stages. This document specifies the socio-economic and scientific rationales and the technical aspects amongst others. The AfLS is supported by many national and Pan-African scientific professional bodies and voluntary associates across many scientific disciplines, and there are stakeholders throughout the continent and beyond. The current roadmap phases have expanded to include national and Pan-African level conversations with policy makers through new Strategic Task Force groups. The document summarizes this progress and discusses the future of the project.

We present a genome assembly from an individual male Boloria euphrosyne (the Pearl-bordered Fritillary; Arthropoda; Insecta; Lepidoptera; Nymphalidae). The genome sequence is 400.4 megabases in span. Most of the assembly is scaffolded into 31 chromosomal pseudomolecules, including the Z sex chromosome. The mitochondrial genome has also been assembled and is 15.17 kilobases in length. Gene annotation of this assembly on Ensembl identified 19,138 protein coding genes.

IntroductionInterpersonal synchronization involves the alignment of behavioral, affective, physiological, and brain states during social interactions. It facilitates empathy, emotion regulation, and prosocial commitment. Mental disorders characterized by social interaction dysfunction, such as Autism Spectrum Disorder (ASD), Reactive Attachment Disorder (RAD), and Social Anxiety Disorder (SAD), often exhibit atypical synchronization with others across multiple levels. With the introduction of the “second-person” neuroscience perspective, our understanding of interpersonal neural synchronization (INS) has improved, however, so far, it has hardly impacted the development of novel therapeutic interventions.MethodsTo evaluate the potential of INS-based treatments for mental disorders, we performed two systematic literature searches identifying studies that directly target INS through neurofeedback (12 publications; 9 independent studies) or brain stimulation techniques (7 studies), following PRISMA guidelines. In addition, we narratively review indirect INS manipulations through behavioral, biofeedback, or hormonal interventions. We discuss the potential of such treatments for ASD, RAD, and SAD and using a systematic database search assess the acceptability of neurofeedback (4 studies) and neurostimulation (4 studies) in patients with social dysfunction.ResultsAlthough behavioral approaches, such as engaging in eye contact or cooperative actions, have been shown to be associated with increased INS, little is known about potential long-term consequences of such interventions. Few proof-of-concept studies have utilized brain stimulation techniques, like transcranial direct current stimulation or INS-based neurofeedback, showing feasibility and preliminary evidence that such interventions can boost behavioral synchrony and social connectedness. Yet, optimal brain stimulation protocols and neurofeedback parameters are still undefined. For ASD, RAD, or SAD, so far no randomized controlled trial has proven the efficacy of direct INS-based intervention techniques, although in general brain stimulation and neurofeedback methods seem to be well accepted in these patient groups.DiscussionSignificant work remains to translate INS-based manipulations into effective treatments for social interaction disorders. Future research should focus on mechanistic insights into INS, technological advancements, and rigorous design standards. Furthermore, it will be key to compare interventions directly targeting INS to those targeting other modalities of synchrony as well as to define optimal target dyads and target synchrony states in clinical interventions.

Emotions in animals may be expressed by arousal and understanding this often relies upon the monitoring of their behaviour. Under human care, animals’ arousal states may be linked to husbandry decisions, whereby animals may display arousal responses to scheduled events such as feeding and human interaction. Here, we investigate vocal correlates of arousal associated with public presentations of bottlenose dolphins (Tursiops spp.) in human care by comparing vocal production rates and characteristics between high and low arousal contexts. Elevated arousal during the day compared with overnight was characterised by increased signature and non-signature whistle production. High intensity broadband crack vocalisations were produced less than whistles during the day and did not correlate with increased arousal around presentation times. Three of ten dolphins increased signature whistle production before and/or after presentation sessions, indicating elevated arousal and variation in individual responses. Many individuals elevated minimum frequency and suppressed maximum frequency of signature whistles in a way that correlated with higher arousal contexts, indicating that these may therefore be good indicators of changes in arousal state. Overall, our study demonstrates that passive acoustic monitoring can provide a useful indication of arousal linked to husbandry decisions, and that individual variation in vocal responses, likely linked to personality, is important to consider.

Abstract Background In European axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) clinical registries, we aimed to investigate commonalities and differences in (1) set-up, clinical data collection; (2) data availability and completeness; and (3) wording, recall period, and scale used for selected patient-reported outcome measures (PROMs). Methods Data was obtained as part of the EuroSpA Research Collaboration Network and consisted of (1) an online survey and follow-up interview, (2) upload of real-world data, and (3) selected PROMs included in the online survey. Results Fifteen registries participated, contributing 33,948 patients (axSpA: 21,330 (63%), PsA: 12,618 (37%)). The reported coverage of eligible patients ranged from 0.5 to 100%. Information on age, sex, biological/targeted synthetic disease-modifying anti-rheumatic drug treatment, disease duration, and C-reactive protein was available in all registries with data completeness between 85% and 100%. All PROMs (Bath Ankylosing Spondylitis Disease Activity and Functional Indices, Health Assessment Questionnaire, and patient global, pain and fatigue assessments) were more complete after 2015 (68–86%) compared to prior (50–79%). Patient global, pain and fatigue assessments showed heterogeneity between registries in terms of wording, recall periods, and scale. Conclusion Important heterogeneity in registry design and data collection across fifteen European axSpA and PsA registries was observed. Several core measures were widely available, and an increase in data completeness of PROMs in recent years was identified. This study might serve as a basis for examining how differences in data collection across registries may impact the results of collaborative research in the future.

Abstract Organic Cation Transporter 1 (OCT1) plays a crucial role in hepatic metabolism by mediating the uptake of a range of metabolites and drugs. Genetic variations can alter the efficacy and safety of compounds transported by OCT1, such as those used for cardiovascular, oncological, and psychological indications. Despite its importance in drug pharmacokinetics, the substrate selectivity and underlying structural mechanisms of OCT1 remain poorly understood. Here, we present cryo-EM structures of full-length human OCT1 in the inward-open conformation, both ligand-free and drug-bound, indicating the basis for its broad substrate recognition. Comparison of our structures with those of outward-open OCTs provides molecular insight into the alternating access mechanism of OCTs. We observe that hydrophobic gates stabilize the inward-facing conformation, whereas charge neutralization in the binding pocket facilitates the release of cationic substrates. These findings provide a framework for understanding the structural basis of the promiscuity of drug binding and substrate translocation in OCT1.

Abstract Background To determine the safety and efficacy of biological agents used in the treatment of systemic lupus erythematosus (SLE) in adults. Methods Systematic review and meta-analysis following PRISMA guidelines. Data sources MEDLINE (through Pubmed), EMBASE, Cochrane library, Clinicaltrials.gov, Australianclinicaltrials.gov.au, ANZCTR.org.au and WHO International Clinical Trials Registry Platform for studies published from 20 May 2021 and 15 years prior. A grey literature search was performed and completed on 31 May 2021. Study criteria Phase II, III or quasi randomised controlled trials, studies with only cerebral or cutaneous lupus were excluded. Data extraction: Two authors independently screened studies for eligibility, extracted, reviewed data for accuracy, and used the Cochrane tool to assess risk of bias. Results Forty-four studies were identified, consisting of 15 groups of drugs and 25 different biological agents, totalling 16,889 patients. The main outcomes assessed included Systemic Lupus Erythematosus Responder Index (SRI), BILAG-Based Composite Lupus Assessment (BICLA) and combined combined/partial renal remission (CRR/PRR). Four groups of biologics were found to improve outcomes. Anti-interferons: Anifrolumab increased BICLA response and SRI 5 to 8, decreased prednisone dosages, with increased herpes zoster infections, but fewer serious adverse events. Sifalimumab improved SRI but also increased herpes zoster infections. Anti BAFF/BLyS and/or APRIL: Belimumab consistently improved SRI 4, decreased prednisone dosages, increased combined CRR/PRR, and had no adverse safety outcomes. Tabalumab increased SRI 5 at 52 weeks with no steroid sparing effect but was associated with increased infusion related adverse events. Telitacicept improved SRI 4 at 52 weeks, with no increased adverse events, though data was rather sparse. Anti CD-20 monoclonal antibody, Obinutuzumab increased combined CRR/PRR at 1 and 2 years. Anti IL12/23 monoclonal antibody, Ustekinumab, increased SRI 4 to 6, but not BICLA at 24 weeks, with no concerning safety outcomes. Conclusion Multiple biologic agents are shown in high quality studies to have a significant therapeutic impact on outcomes in SLE.

Thermal transients of small or thermally well-conducting components typically relax with a very short time constant. In some cases, the fastest changes occur on a time scale of a few tens to hundreds of microseconds. Providing a sampling rate higher than 1 kHz is challenging, even for modern infrared cameras. This work presents a periodic non-uniform sampling technique for measuring thermographic transients, which increases the effective sampling rate by one order of magnitude to 10 kHz, resulting in a temporal resolution of 100 μs. The practical application of this technique captures parts of the thermal transient that would otherwise be missed for standard sampling rates. The results confirm the algorithm’s ability to enhance the effective sampling rate, providing a more detailed thermal analysis of rapid transient processes in small-scale electronic components.

Abstract Background In Tanzania little is known about how the respiratory system of small-holder fish vendors is affected by occupational exposure to biomass smoke and other associated factors. This study assessed the prevalence of lung obstruction and associated factors among small-holder fish vendors along coastal areas in Tanzania. Methods A cross-sectional descriptive study was conducted in Bagamoyo and Kunduchi fish markets along coastal areas of Tanzania. Environmental air pollutant levels and composition were measured using a hand-held device. A standardized questionnaire was used to assess respiratory symptoms while EasyOne spirometer was used to test for lung function among small-holder fish vendors. Chronic Obstructive Pulmonary Disease (COPD) was defined as FEV1/FVC below the lower limit of normal. Data were analyzed using STATA Version 17. Descriptive statistics was performed and logistic regression analysis was used to determine factors that are associated with poor lung function presented as crude and adjusted odds ratio and their 95% confidence intervals. Results A total of 103 participants were included in the study who were predominantly males 82 (79.6%). The participants’ mean age was 35.47 (± 8.77 SD) years. The hourly average concentration levels of PM1, PM2.5, PM10, and CO exposure during fish frying were 653.6 (± 206.3 SD) μg/m3, 748.48 (± 200.6 SD) μg/m3, 798.66 (± 181.71 SD) μg/m3 and 62.6 (± 12.3 SD) ppm respectively which are higher than the WHO recommended limits. The prevalence of COPD was found to be 32.04% (95% CI 0.23–0.42). Most of the participants reported respiratory symptoms like coughing, wheezing, sputum production and breathlessness during performing their daily activities. Conclusion Findings suggest that three out of ten participants had COPD and the major environmental air pollutants (PMs and CO) concentration levels were too high, suggesting that occupational exposure to biomass smoke may be a risk factor. This calls for effective approaches to reduce exposure and prevent known acute and chronic respiratory diseases that are associated with such exposure to air pollutants. Also the study calls for follow up or cohort studies to be conducted in this area.

Abstract Weather regimes have been defined over multiple regions and used in a range of practical applications, including subseasonal‐to‐seasonal forecasting and climate model evaluation. Despite their widespread use, the extent to which regimes reflect physical modes of the atmosphere is seldom investigated. Here, we adopt a year‐round classification of four North American weather regimes, with a fifth “no regime” class, and leverage dynamical systems theory to investigate their dynamical properties. We find that when the atmospheric flow is assigned to a regime, it displays persistent characteristics and a lifecycle‐like temporal evolution. We further find that, regardless of season, these characteristics are enhanced when the atmospheric flow displays a comparatively strong projection onto the cluster‐mean of the regime to which it is assigned (while the reverse is true for a weaker projection). We interpret these results as evidence that the four North American weather regimes are physically‐meaningful, with a clear dynamical footprint.

Abstract Apicomplexa are ancient and diverse organisms which have been poorly characterized by modern genomics. To better understand the evolution and diversity of these single-celled eukaryotes, we sequenced the genome of Ophryocystis elektroscirrha, a parasite of monarch butterflies, Danaus plexippus. We contextualize our newly generated resources within apicomplexan genomics before answering longstanding questions specific to this host-parasite system. To start, the genome is miniscule, totaling only 9 million bases and containing fewer than 3,000 genes, half the gene content of two other sequenced invertebrate-infecting apicomplexans, Porospora gigantea and Gregarina niphandrodes. We found that O. elektroscirrha shares different orthologs with each sequenced relative, suggesting the true set of universally conserved apicomplexan genes is very small indeed. Next, we show that sequencing data from other potential host butterflies can be used to diagnose infection status as well as to study diversity of parasite sequences. We recovered a similarly sized parasite genome from another butterfly, Danaus chrysippus, that was highly diverged from the O. elektroscirrha reference, possibly representing a distinct species. Using these two new genomes, we investigated potential evolutionary response by parasites to toxic phytochemicals their hosts ingest and sequester. Monarch butterflies are well-known to tolerate toxic cardenolides thanks to changes in the sequence of their Type II ATPase sodium pumps. We show that Ophryocystis completely lacks Type II or Type 4 sodium pumps, and related proteins PMCA calcium pumps show extreme sequence divergence compared to other Apicomplexa, demonstrating new avenues of research opened by genome sequencing of non-model Apicomplexa.

Abstract Background Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease characterized by development of autoantibodies and multiorgan involvement. Kidney involvement, termed lupus nephritis, has major impact on life expectancy. It is increasingly recognized that SLE is likely a common clinical manifestation of pathophysiologically diverse processes, and lupus nephritis has similarly been associated with several distinct immunological processes. We compared the immune cell phenotypes of individuals with SLE in the presence or absence of nephritis. Methods Cryopreserved peripheral blood mononuclear cells from SLE patients with and without kidney involvement underwent flow cytometric analysis to identify major populations in T cells, B cells and myeloid lineages. Results We compared the frequencies of lymphocyte populations in 69 SLE patients without nephritis, 20 SLE patients with nephritis, and 92 healthy blood donors. Patients with SLE and lupus nephritis (LN) had reduced marginal zone B cells (P

A novel trimethyltin(IV) complex (Me3SnL), derived from 3-(4-methyl-2-oxoquinolin-1(2H)-yl)propanoate ligand, has been synthesized and characterized by elemental microanalysis, UV/Vis spectrophotometry, FT-IR and multinuclear (1H, 13C and 119Sn) NMR spectroscopies. Furthermore, the structure of the ligand precursor HL was solved using SC-XRD (single-crystal X-ray diffraction). The prediction of UV/Vis and NMR spectra by quantum-chemical methods was performed and compared to experimental findings. The protein binding affinity of Me3SnL towards BSA was determined by spectrofluorometric titration and subsequent molecular docking simulations. Me3SnL has been evaluated for its in vitro anticancer activity against three human cell lines, MCF-7 (breast adenocarcinoma), A375 (melanoma) and HCT116 (colorectal carcinoma), and three mouse tumor cell lines, 4T1 (breast carcinoma), B16 (melanoma) and CT26 (colon carcinoma), using MTT and CV assays. The strong inhibition of A375 cell proliferation, ROS/RNS upregulation and robust lipid peroxidation lead to autophagic cell death upon treatment with Me3SnL.

Summary: Phages and lipids in human milk (HM) may benefit preterm infant health by preventing gastrointestinal pathobiont overgrowth and microbiome modulation. Lipid association may promote vertical transmission of phages to the infant. Despite this, interrelationships between lipids and phages are poorly characterized in preterm HM. Shotgun metagenomics and untargeted lipidomics of phage and lipid profiles from 99 preterm HM samples reveals that phages are abundant and prevalent from the first week and throughout the first 100 days of lactation. Phage-host richness of preterm HM increases longitudinally. Core phage communities characterized by Staphylococcus- and Propionibacterium-infecting phages are significantly correlated with long-chain fatty acid abundances over lactational age. We report here a phage-lipid interaction in preterm HM, highlighting the potential importance of phage carriage in preterm HM. These results reveal possible strategies for phage carriage in HM and their importance in early-life microbiota development.

Abstract In Europe, the increase in temperatures caused by climate change has been particularly fast in the cold season. Although the magnitude of this change is relatively well known, less research has been done on how the increase of temperatures is manifested in different large‐scale weather types, called weather regimes. For example, one could expect that the weather patterns in which air is flowing from the rapidly‐warming Arctic would have warmed faster than other weather patterns in recent decades. Here we show that such an asymmetric warming actually occurs in the four Euro‐Atlantic weather regimes. In northern Europe, the weather regime which is typically associated with cold airmasses from the Arctic (NAO–) has warmed about 25% faster than the cold‐season days on average, and about 60% faster than the regime where the air flows from the North Atlantic (NAO+). Consequently, the weather regime that on average brings the coldest weather is warming the fastest in a large part of northern Europe. In contrast, the weather regime that typically brings the warmest weather has warmed the slowest, especially in the continental Europe. Our results provide a new perspective on the reported decrease of sub‐seasonal temperature variability.

Rotaviruses are causative agents of diarrhea in humans and animals. Currently, the species rotavirus A-J (RVA-RVJ) and the putative species RVK and RVL are defined, mainly based on their genome sequence identities. RVK strains were first identified in 2019 in common shrews (Sorex aranaeus) in Germany; however, only short sequence fragments were available so far. Here, we analyzed the complete coding regions of strain RVK/shrew-wt/GER/KS14–0241/2013, which showed highest sequence identities with RVC. The amino acid sequence identity of VP6, which is used for rotavirus species definition, reached only 51% with other rotavirus reference strains thus confirming classification of RVK as a separate species. Phylogenetic analyses for the deduced amino acid sequences of all 11 virus proteins showed, that for most of them RVK and RVC formed a common branch within the RVA-like phylogenetic clade. Only the tree for the highly variable NSP4 showed a different branching; however, with very low bootstrap support. Comparison of partial nucleotide sequences of other RVK strains from common shrews of different regions in Germany indicated a high degree of sequence variability (61–97% identity) within the putative species. These RVK strains clustered separately from RVC genotype reference strains in phylogenetic trees indicating diversification of RVK independent from RVC. The results indicate that RVK represents a novel rotavirus species, which is most closely related to RVC.

Here, Rouet et al. present a strategy for the identification of broadly neutralising antibodies against SARS-CoV-2 receptor binding domain from peripheral blood mononuclear cells of convalescent patients, which enabled the identification of a new class 6 epitope.

This article presents an analysis of P-band radio signal propagation through forest based on 3D Numerical Method of Maxwell's equations (NMM3D). The simulation domain of the forested region covers an area of 35.8 × 35.8 m2 that includes 112–121 coniferous trees with a height in the range of 8–16 m. The modeled trees have primary and secondary branches to account for their impact on scattering and attenuation at P-band. The fast hybrid method (FHM) has been successfully developed to complete the NMM3D full wave simulations of trees with efficient use of CPU time and memory. The accuracy of the proposed FHM model is validated by comparing scattered fields to that of FEKO for the case with nine trees. To account for the seasonal variation of water content in trees and hence dielectric constant, the wave scattering model is applied to a range of dielectric constants. Analysis of the P-band signal propagation is performed by computing the average loss and correlation of the transmission fields. The results show that the transmissivities are about 0.9 for winter conditions (low dielectric constant) and about 0.7 for summer conditions (high dielectric constant). Simulations with randomly positioned trees (off the periodic grid) demonstrate that the transmissivity shows a maximum variation of 4.3% relative to the nonrandomly positioned trees. The correlation analysis of P-band radio signals with two different dielectric constants indicates a high correlation amplitude above 0.89 and a phase change of less than 6°. A sensitivity analysis is carried out for a range of tree heights and trunk radii.

Cryo-EM structures of E. coli F1Fo ATP synthase highlight the role of the inhibitory ε subunit in regulating the torsional movement of the central stalk within the Fo motor and central stalk flexibility in coupling the F1 and Fo motors.

Background Sexual selection and conflicts within and between sexes promote morphological diversity of reproductive traits within species. Variation in the morphology of diagnostic reproductive characters within species offer an excellent opportunity to study these evolutionary processes as drivers of species diversification. The African monarch, Danaus chrysippus (Linnaeus, 1758), is widespread across Africa. The species is polytypic, with the respective geographical ranges of the four colour morphs only overlapping in East Africa. Furthermore, some of the populations host an endosymbiotic bacterium, Spiroplasma, which induces son-killing and distorts the local host population sex-ratio, creating sexual conflicts between the females seeking to optimize their fecundity and the limited mating capacity of the rare males. Methods We dissected females from Kenya, Rwanda and South Africa, where Spiroplasma vary in presence and prevalence (high, variable and absent, respectively), and conducted microscopy imaging of their reproductive organs. We then characterized the effect of population, female body size, and female mating status, on the size and shape of different genitalia characters of the D. chrysippus female butterflies. Results We showed that although the general morphology of the organs is conserved in D. chrysippus, female genitalia vary in size and shape between and within populations. The virgin females have smaller organs, while the same organs were expanded in mated females. Females from highly female-biased populations, where the male-killing Spiroplasma is prevalent, also have a larger area of their corpus bursae covered with signa structures. However, this pattern occurs because a larger proportion of the females remains virgin in the female-biased populations rather than because of male depletion due to the symbiont, as males from sex-ratio distorted populations did not produce significantly smaller nutritious spermatophores.

ABSTRACT Heptose metabolites including ADP-d-glycero-β-d-manno-heptose (ADP-heptose) are involved in bacterial lipopolysaccharide and cell envelope biosynthesis. Recently, heptoses were also identified to have potent proinflammatory activity on human cells as novel microbe-associated molecular patterns. The gastric pathogenic bacterium Helicobacter pylori produces heptose metabolites, which it transports into human cells through its Cag type 4 secretion system. Using H. pylori as a model, we have addressed the question of how proinflammatory ADP-heptose biosynthesis can be regulated by bacteria. We have characterized the interstrain variability and regulation of heptose biosynthesis genes and the modulation of heptose metabolite production by H. pylori, which impact cell-autonomous proinflammatory human cell activation. HldE, a central enzyme of heptose metabolite biosynthesis, showed strong sequence variability between strains and was also variably expressed between strains. Amounts of gene transcripts in the hldE gene cluster displayed intrastrain and interstrain differences, were modulated by host cell contact and the presence of the cag pathogenicity island, and were affected by carbon starvation regulator A (CsrA). We reconstituted four steps of the H. pylori lipopolysaccharide (LPS) heptose biosynthetic pathway in vitro using recombinant purified GmhA, HldE, and GmhB proteins. On the basis of one- and two-dimensional nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry, the structures of major reaction products were identified as β-d-ADP-heptose and β-heptose-1-monophosphate. A proinflammatory heptose-monophosphate variant was also identified for the first time as a novel cell-active product in H. pylori bacteria. Separate purified HldE subdomains and variant HldE allowed us to uncover additional strain variation in generating heptose metabolites. IMPORTANCE Bacterial heptose metabolites, intermediates of lipopolysaccharide (LPS) biosynthesis, are novel microbe-associated molecular patterns (MAMPs) that activate proinflammatory signaling. In the gastric pathogen Helicobacter pylori, heptoses are transferred into host cells by the Cag type IV secretion system, which is also involved in carcinogenesis. Little is known about how H. pylori, which is highly strain variable, regulates heptose biosynthesis and downstream host cell activation. We report here that the regulation of proinflammatory heptose production by H. pylori is strain specific. Heptose gene cluster activity is modulated by the presence of an active cag pathogenicity island (cagPAI), contact with human cells, and the carbon starvation regulator A. Reconstitution with purified biosynthesis enzymes and purified bacterial lysates allowed us to biochemically characterize heptose pathway products, identifying a heptose-monophosphate variant as a novel proinflammatory metabolite. These findings emphasize that the bacteria use heptose biosynthesis to fine-tune inflammation and also highlight opportunities to mine the heptose biosynthesis pathway as a potential therapeutic target against infection, inflammation, and cancer.

The degree of spin–orbit alignment in a population of binary stars can be determined from measurements of their orbital inclinations and rotational broadening of their spectral lines. Alignment in a face-on binary guarantees low rotational broadening, while alignment in an edge-on binary maximizes the rotational broadening. In contrast, if spin–orbit angles ( ψ ) are random, rotational broadening should not depend on orbital inclination. Using this technique, we investigated a sample of 2727 astrometric binaries from Gaia DR3 with F-type primaries and orbital periods between 50 and 1000 days (separations 0.3–2.7 au). We found that ψ is strongly associated with e , the orbital eccentricity. When e < 0.15, the mean spin–orbit angle is $\langle \psi \rangle ={6.9}_{-4.1}^{+5.4}$ degrees, while for e > 0.7, it rises to $\langle \psi \rangle ={46}_{-24}^{+26}$ degrees. These results suggest that some binaries are affected by processes during their formation or evolution that excite both orbital eccentricity and inclination.

Here, the authors study adaptation to altitude in 518 whole genomes from two species of tropical butterflies. They find repeated genetic differentiation within species, little molecular parallelism between these species, and introgression from closely related species, concluding that standing genetic variation promotes parallel local adaptation.

Understanding how DNA double strand breaks (DSBs) form and are repaired in the genome depends on their accurate measurement. Here the authors describe INDUCE-seq; a DSB-detection method that simultaneously measures physiological and induced breaks throughout the genome.

Salmonella enterica subspecies enterica serovar Dublin (S. Dublin) is a host-adapted serovar causing enteritis and/or systemic diseases in cattle. As the serovar is not host-restricted, it may cause infections in other animals, including humans with severe illness and higher mortality rates than other non-typhoidal serovars. As human infections are mainly caused by contaminated milk, milk products and beef, information on the genetic relationship of S. Dublin strains from cattle and food should be evaluated. Whole-genome sequencing (WGS) of 144 S. Dublin strains from cattle and 30 strains from food origin was performed. Multilocus sequence typing (MLST) revealed mostly sequence type ST-10 from both, cattle and food isolates. In total, 14 of 30 strains from food origin were clonally related to at least one strain from cattle, as detected by core-genome single nucleotide polymorphisms typing as well as core-genome MLST. The remaining 16 foodborne strains fit into the genome structure of S. Dublin in Germany without outliers. WGS proved to be a powerful tool not only to gain information on the epidemiology of Salmonella strains but also to detect clonal relations between organisms isolated from different stages of production. This study has shown a high genetic correlation between S. Dublin strains from cattle and food and, therefore, the potential to cause human infections. S. Dublin strains of both origins share an almost identical set of virulence factors, emphasizing their potential to cause severe clinical manifestations in animals, but also in humans and thus the need for effective control of S. Dublin in a farm-to-fork strategy.

Background/Aim: Alpha-fetoprotein (AFP) had been used as a prognostic factor in hepatocellular carcinoma but it was unknown what level of AFP could predict the survival of patients with ruptured hepatocellular carcinoma (rHCC) after resection. This retrospective study was to identify the best cutoff value of AFP for this prediction. Methods: Data of patients having hepatectomy for rHCC from 1989 to 2015 were reviewed. The receiver operating characteristic curve and Youden’s index were used to identify the cutoff value of AFP affecting survival. The patients were then divided into two groups by the cutoff for comparison. Results: Totally 114 patients were included. An AFP level of 256 ng/ml was found to affect survival (area under curve 63.1%, 95% confidence interval 0.514–0.748, p = 0.027; sensitivity 0.6, specificity 0.706). The 114 patients were divided into Group A (AFP < 256 ng/ml, n = 56) and Group B (AFP ≥ 256 ng/ml, n = 58). The median AFP level was 13.0 ng/ml (range, 2–253 ng/ml) in Group A and 11206.5 ng/ml (range, 259–481,000 ng/ml) in Group B (p

Abstract Aims Assessing frailty and sarcopenia is considered a valuable cornerstone of perioperative risk stratification in advanced heart failure patients. The lack of an international consensus on a diagnostic standard impedes its implementation in the clinical routine. This study aimed to compare the feasibility and prognostic impact of different assessment tools in patients undergoing continuous‐flow left ventricular assist device (cf‐LVAD) implantation. Methods and results We prospectively compared feasibility and prognostic values of six frailty/sarcopenia assessment methods in 94 patients prior to cf‐LVAD implantation: bioelectrical impedance analysis (BIA), computed tomography (CT)‐based measurement of two muscle areas/body surface area [erector spinae muscle (TMESA/BSA) and iliopsoas muscle (TPA/BSA)], physical performance tests [grip strength, 6 min walk test (6MWT)] and Rockwood Clinical Frailty Scale (RCFS). Six‐month mortality and/or prolonged ventilation time >95 h was defined as the primary endpoint. BIA and CT showed full feasibility (100%); physical performance and RCFS was limited due to patients' clinical status (feasibility: 87% grip strength, 62% 6MWT, 88% RCFS). Phase angle derived by BIA showed the best results regarding the prognostic value for 6 month mortality and/or prolonged ventilation time >95 h (odds ratio (OR) 0.66 [95% confidence interval (CI): 0.46–0.92], P = 0.019; area under the curve (AUC) 0.65). It provided incremental value to the clinical risk assessment of EuroSCORE II: C‐index of the combined model was 0.75 [95% CI; 0.651–0.848] compared with C‐index of EuroSCORE II alone, which was 0.73 (95% CI: 0.633–0.835). Six‐month survival was decreased in patients with reduced body cell mass derived by BIA or reduced muscle area in the CT scan compared with patients with normal values: body cell mass 65% (95% CI: 51.8–81.6%) vs. 83% (95% CI: 74.0–93.9%); P = 0.03, TMESA/BSA 65% (95% CI: 51.2–82.2%) vs. 82% (95% CI: 73.2–93.0%); P = 0.032 and TPA/BSA 66% (95% CI: 53.7–81.0%) vs. 85% (95% CI: 75.0–95.8%); P = 0.035. Conclusions Bioelectrical impedance analysis parameters and CT measurements were shown to be suitable to predict 6‐month mortality and/or prolonged ventilation time >95 h in patients with advanced heart failure prior to cf‐LVAD implantation. Phase angle had the best predictive capacity and sarcopenia diagnosed by reduced body cell mass in BIA or muscle area in CT was associated with a decreased 6 month survival.

Abstract Lipids play essential roles in the hepatitis C virus (HCV) life cycle and patients with chronic HCV infection display disordered lipid metabolism which resolves following successful anti-viral therapy. It has been proposed that HCV genotype 3 (HCV-G3) infection is an independent risk factor for hepatocellular carcinoma and evidence suggests lipogenic proteins are involved in hepatocarcinogenesis. We aimed to characterise variation in host lipid metabolism between participants chronically infected with HCV genotype 1 (HCV-G1) and HCV-G3 to identify likely genotype-specific differences in lipid metabolism. We combined several lipidomic approaches: analysis was performed between participants infected with HCV-G1 and HCV-G3, both in the fasting and non-fasting states, and after sustained virological response (SVR) to treatment. Sera were obtained from 112 fasting patients (25% with cirrhosis). Serum lipids were measured using standard enzymatic methods. Lathosterol and desmosterol were measured by gas-chromatography mass spectrometry (MS). For further metabolic insight on lipid metabolism, ultra-performance liquid chromatography MS was performed on all samples. A subgroup of 13 participants had whole body fat distribution determined using in vivo magnetic resonance imaging and spectroscopy. A second cohort of (non-fasting) sera were obtained from HCV Research UK for comparative analyses: 150 treatment naïve patients and 100 non-viraemic patients post-SVR. HCV-G3 patients had significantly decreased serum apoB, non-HDL cholesterol concentrations, and more hepatic steatosis than those with HCV-G1. HCV-G3 patients also had significantly decreased serum levels of lathosterol, without significant reductions in desmosterol. Lipidomic analysis showed lipid species associated with reverse cholesterol transport pathway in HCV-G3. We demonstrated that compared to HCV-G1, HCV-G3 infection is characterised by low LDL cholesterol levels, with preferential suppression of cholesterol synthesis via lathosterol, associated with increasing hepatic steatosis. The genotype-specific lipid disturbances may shed light on genotypic variations in liver disease progression and promotion of hepatocellular cancer in HCV-G3.

The National Aeronautics and Space Administration Soil Moisture Active Passive (SMAP) mission has been validating its soil moisture (SM) products since the start of data production on March 31, 2015. Prior to launch, the mission defined a set of criteria for core validation sites (CVS) that enable the testing of the key mission SM accuracy requirement (unbiased root-mean-square error 3/m3). The validation approach also includes other (“sparse network”) in situ SM measurements, satellite SM products, model-based SM products, and field experiments. Over the past six years, the SMAP SM products have been analyzed with respect to these reference data, and the analysis approaches themselves have been scrutinized in an effort to best understand the products’ performance. Validation of the most recent SMAP Level 2 and 3 SM retrieval products (R17000) shows that the L-band (1.4 GHz) radiometer-based SM record continues to meet mission requirements. The products are generally consistent with SM retrievals from the European Space Agency Soil Moisture Ocean Salinity mission, although there are differences in some regions. The high-resolution (3-km) SM retrieval product, generated by combining Copernicus Sentinel-1 data with SMAP observations, performs within expectations. Currently, however, there is limited availability of 3-km CVS data to support extensive validation at this spatial scale. The most recent (version 5) SMAP Level 4 SM data assimilation product providing surface and root-zone SM with complete spatio–temporal coverage at 9-km resolution also meets performance requirements. The SMAP SM validation program will continue throughout the mission life; future plans include expanding it to forested and high-latitude regions.

Remote sensing of sea surface salinity (SSS) near land is difficult due to land contamination. In this article, we assess SSS retrieved from the soil moisture active passive (SMAP) mission in coastal region. SMAP SSS products from the Jet Propulsion Laboratory (JPL), and from the remote sensing systems (RSS) are collocated with in situ data collected by saildrones during the North American West Coast Survey. Satellite and saildrone salinity measurements reveal consistent large-scale features: the fresh water (low SSS) assocciated with the Columbia River discharge, and the relatively salty water (high SSS) near Baja California associated with regional upwelling. The standard deviation of the difference for collocations with SMAP Level 3 (eight days average) between 40 and 100 km from land is 0.51 (0.56) psu for JPL V5 (RSS V4 70 km). This is encouraging for the potential application of SMAP SSS in monitoring coastal zone freshwater particularly where there exists large freshwater variance. We analyze the different land correction approaches independently developed at JPL and RSS using SMAP level 2 matchups. We found that JPL's land correction method is more promising in pushing SMAP SSS retrieval towards land. For future improvement, we suggest implementing dynamic land correction versus the current climatology-based static land correction to reduce uncertainty in estimating land contribution. In level 2 to level 3 processing, a more rigorous quality control may help to eliminate outliers and deliver reliable level 3 products without over-smoothing, which is important in resolving coastal processes such as fronts or upwelling.

GJ 367 is a bright ( V ≈ 10.2) M1 V star that has been recently found to host a transiting ultra-short period sub-Earth on a 7.7 hr orbit. With the aim of improving the planetary mass and radius and unveiling the inner architecture of the system, we performed an intensive radial velocity follow-up campaign with the HARPS spectrograph—collecting 371 high-precision measurements over a baseline of nearly 3 yr—and combined our Doppler measurements with new TESS observations from sectors 35 and 36. We found that GJ 367 b has a mass of M _b = 0.633 ± 0.050 M _⊕ and a radius of R _b = 0.699 ± 0.024 R _⊕ , corresponding to precisions of 8% and 3.4%, respectively. This implies a planetary bulk density of ρ _b = 10.2 ± 1.3 g cm ^−3 , i.e., 85% higher than Earth’s density. We revealed the presence of two additional non-transiting low-mass companions with orbital periods of ∼11.5 and 34 days and minimum masses of ${M}_{{\rm{c}}}\sin {i}_{{\rm{c}}}$ = 4.13 ± 0.36 M _⊕ and ${M}_{{\rm{d}}}\sin {i}_{{\rm{d}}}$ = 6.03 ± 0.49 M _⊕ , respectively, which lie close to the 3:1 mean motion commensurability. GJ 367 b joins the small class of high-density planets, namely the class of super-Mercuries, being the densest ultra-short period small planet known to date. Thanks to our precise mass and radius estimates, we explored the potential internal composition and structure of GJ 367 b, and found that it is expected to have an iron core with a mass fraction of ${0.91}_{-0.23}^{+0.07}$ . How this iron core is formed and how such a high density is reached is still not clear, and we discuss the possible pathways of formation of such a small ultra-dense planet.

Misalignments between planetary orbits and the equatorial planes of their host stars are clues about the formation and evolution of planetary systems. Earlier work found evidence for a peak near 90° in the distribution of stellar obliquities, based on frequentist tests. We performed hierarchical Bayesian inference on a sample of 174 planets for which either the full three-dimensional stellar obliquity has been measured (72 planets) or for which only the sky-projected stellar obliquity has been measured (102 planets). We investigated whether the obliquities are best described by a Rayleigh distribution or by a mixture of a Rayleigh distribution representing well-aligned systems and a different distribution representing misaligned systems. The mixture models are strongly favored over the single-component distribution. For the misaligned component, we tried an isotropic distribution and a distribution peaked at 90° and found the evidence to be essentially the same for both models. Thus, our Bayesian inference engine did not find strong evidence favoring a “perpendicular peak,” unlike the frequentist tests. We also investigated selection biases that affect the inferred obliquity distribution, such as the bias of the gravity-darkening method against obliquities near 0° or 180°. Further progress in characterizing the obliquity distribution will probably require the construction of a more homogeneous and complete sample of measurements.

Tuberculosis (TB) is among diseases of global health importance with Sub Saharan Africa (SSA) accounting for 25% of the global TB burden. TB prevalence among miners in SSA is estimated at 3,000–7,000/100,000, which is about 3 to 10-times higher than in the general population. The study’s objective was to determine the prevalence of TB and associated risk factors among mining communities in Mererani, northern Tanzania. This was a cross-sectional study conducted from April 2019 to November 2021 involving current Small Scale Miners (SSM) and the General Community (GC). A total of 660 participants, 330 SSM and 330 GC were evaluated for the presence of TB. Data were analysed using Statistical Package for the Social Sciences (SPSS) database (IBM SPSS Statistics Version 27.0.0.0). Binary logistic regression (Generalized Linear Mixed Model) was used to determine the association between TB and independent predictors. Prevalence of TB was 7%, about 24-times higher than the national prevalence of 0.295%. Participants from the general community had higher prevalence of TB 7.9% than SSM (6.1%). Both for SSM and the GC, TB was found to be associated with: lower education level (aOR = 3.62, 95%CI = 1.16–11.28), previous lung disease (aOR = 4.30, 95%CI = 1.48–12.53) and having symptoms of TB (aOR = 3.24, 95%CI = 1.38–7.64). Specifically for the SSM, TB was found to be associated with Human Immunodeficiency Virus (HIV) infection (aOR = 8.28, 95%CI = 1.21–56.66). Though significant progress has been attained in the control of the TB epidemic in Tanzania, still hot spots with significantly high burden of TB exists, including miners. More importantly, populations surrounding the mining areas, are equally affected, and needs more engagement in the control of TB so as to realize the Global End TB targets of 2035.

Hybridization is frequent in the wild but it is unclear when admixture events lead to predictable outcomes and if so, at what timescale. We show that selection led to correlated sorting of genetic variation rapidly after admixture in 3 hybrid Formica aquilonia × F. polyctena ant populations. Removal of ancestry from the species with the lowest effective population size happened in all populations, consistent with purging of deleterious load. This process was modulated by recombination rate variation and the density of functional sites. Moreover, haplotypes with signatures of positive selection in either species were more likely to fix in hybrids. These mechanisms led to mosaic genomes with comparable ancestry proportions. Our work demonstrates predictable evolution over short timescales after admixture in nature. Hybridization between species is frequent in the wild but it is unclear when admixture events lead to predictable outcomes and if so, at what timescale. This study shows that selection contributes to correlated sorting of genetic variation across three independent hybrid wood ant populations in less than 50 generations.

High-intensity focused ultrasound (HIFU) has been shown to be a valuable tool in the management of small liver tumors such as hepatocellular carcinoma (HCC). It has been shown to be a safe and effective means to ablate small HCC even in the presence of advanced cirrhosis. This review examines the challenges faced during HIFU ablation when the target tumors are located in difficult locations such as the liver dome, close to the rib cage, near large blood vessels or the heart, or adjacent to hollow viscera; and the special maneuvers employed to tackle such lesions.

Abstract Background Local sequence context is known to have an impact on the mutational pattern seen in cancer. The RAS genes and a smoking carcinogen, Benzo[a]pyrene diol epoxide (BPDE), have been utilised to explore these context effects. BPDE is known to form an adduct at the guanines in a number of RAS gene sites, KRAS codons 12, 13 and 14, NRAS codon 12, and HRAS codons 12 and 14. Results Molecular modelling techniques, along with multivariate analysis, have been utilised to determine the sequence influenced differences between BPDE-adducted RAS gene sequences as well as the local distortion caused by the adducts. Conclusions We conclude that G:C > T:A mutations at KRAS codon 12 in the tumours of lung cancer patients (who smoke), proposed to be predominantly caused by BPDE, are due to the effect of the interaction methyl group at the C5 position of the thymine base in the KRAS sequence with the BPDE carcinogen investigated causing increased distortion. We further suggest methylated cytosine would have a similar effect, showing the importance of methylation in cancer development.

Abstract Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by extraordinary heterogeneity, due to the complex pathogenesis and diverse manifestations. Stratification of patients for therapy and prognosis represents a major challenge to manage SLE. Conventional biomarkers for disease diagnosis and activity assessment provide very limited insight into immunological pathogenesis and therapeutic response rates. The advancement of “omics” technologies including genomics, transcriptomics, proteomics, and metabolomics has constituted an unprecedented opportunity to characterize the immunopathological landscape in individual patients with SLE. Indeed, genomic studies reveal a subset of SLE patients carrying one or more functional single nucleotide polymorphisms (SNPs) underlying immune dysregulation while transcriptomic studies have revealed subgroups in SLE patients showing distinct signatures for Type I interferon (TI‐IFN) pathway activation or aberrant differentiation of B cells into plasma cells. This review will summarize results from the latest studies using omics technology to understand SLE heterogeneity. In addition, we propose that the application of artificial intelligence, such as by machine learning‐based nonlinear dimensionality reduction method uniform manifold approximation and projection (UMAP) can further strengthen the analysis of omics big data. The combination of new technology and novel analysis pipeline can lead to breakthroughs in stratifying SLE patients for a better monitoring of disease activity and more precise design of treatment regime, not only for conventional immunosuppression but also novel immunotherapies targeting B‐cell activating factor (BAFF), TI‐IFN, and interleukin 2 (IL‐2).

Spinal muscular atrophy (SMA) is a neuromuscular disorder due to degeneration of spinal cord motor neurons caused by deficiency of the ubiquitously expressed SMN protein. Here, we present a retinal vascular defect in patients, recapitulated in SMA transgenic mice, driven by failure of angiogenesis and maturation of blood vessels. Importantly, the retinal vascular phenotype was rescued by early, systemic SMN restoration therapy in SMA mice. We also demonstrate in patients an unfavorable imbalance between endothelial injury and repair, as indicated by increased circulating endothelial cell counts and decreased endothelial progenitor cell counts in blood circulation. The cellular markers of endothelial injury were associated with disease severity and improved following SMN restoration treatment in cultured endothelial cells from patients. Finally, we demonstrated autonomous defects in angiogenesis and blood vessel formation, secondary to SMN deficiency in cultured human and mouse endothelial cells, as the underlying cellular mechanism of microvascular pathology. Our cellular and vascular biomarker findings indicate microvasculopathy as a fundamental feature of SMA. Our findings provide mechanistic insights into previously described SMA microvascular complications, and highlight the functional role of SMN in the periphery, including the vascular system, where deficiency of SMN can be addressed by systemic SMN-restoring treatment.

Abstract Variability in atmospheric river (AR) frequency can drive hydrometeorological extremes with broad societal impacts. Mitigating the impacts of increased or decreased AR frequency requires forewarning weeks to months ahead. A key driver of Northern Hemisphere wintertime mid‐latitude subseasonal‐to‐seasonal climate variability is the stratospheric polar vortex. Here, we quantify AR frequency, landfall, genesis, and termination depending on the strength of the lower stratospheric polar vortex. We find large differences between weak and strong vortex states consistent with a latitudinal shift of the eddy‐driven jet, with the greatest differences over the British Isles, Scandinavia, and Iberia. Significant differences are also found for the Pacific Northwest of North America. Most of the seasonal‐scale stratospheric modulation of precipitation over Europe is explained by modulation of ARs. Our results provide potentially useful statistics for extended‐range prediction, and highlight the importance of ARs in bringing about the precipitation response to anomalous vortex states.

We report on a 72 years old male patient with recurrent heart failure hospitalizations caused by severe mitral regurgitation due to severe restriction of the posterior mitral leaflet treated with the transfemoral mitral valve replacement (TMVR) system Cardiovalve. Immediate interventional success was obtained resulting in a quick mobilization and discharge.

Soil moisture is an essential parameter to understand crop conditions throughout the growing season. Collecting soil moisture data by field observation is labor-intensive, especially when attempting to obtain Conterminous United States (CONUS) geographic coverage. In addition, using soil moisture for assessing current and future crop conditions is best realized by combining soil moisture estimates with concurrent observations of crop conditions. However, until recently, this capability has not been available to the public. In this paper, we present an interoperable data service application system, the Crop Condition and Soil Moisture Analytics (Crop-CASMA) system, that facilitates the retrieval, analysis, visualization, and sharing of soil moisture data for the CONUS. This system delivers a variety of satellite remote sensing based data products that are derived from Soil Moisture Active Passive (SMAP) Level-4 data and SMAP Thermal Hydraulic disaggregation of Soil Moisture (THySM) data, as well as vegetation index data derived from Moderate Resolution Imaging Spectroradiometer (MODIS) observations. To make services interoperable and reusable, all data products are disseminated via Open Geospatial Consortium (OGC) Web Map Service (WMS) and Web Coverage Service (WCS) interface standards. Additionally, a suite of geoprocessing operations, such as geospatial statistics, time-series profile generation, PDF map production, and image composition, has been implemented in the OGC Web Processing Service (WPS) interface standard. The implementation shows the proposed web service system can significantly simplify the mapping and quantitative analysis of soil moisture and crop condition over U.S. cropland. In addition, it is interoperable with GIS software and has been successfully integrated with web-based applications.

BackgroundIn most cases of transcatheter valve embolization and migration (TVEM), the embolized valve remains in the aorta after implantation of a second valve into the aortic root. There is little data on potential late complications such as valve thrombosis or aortic wall alterations by embolized valves.AimsThe aim of this study was to analyze the incidence of TVEM in a large cohort of patients undergoing transcatheter aortic valve implantation (TAVI) and to examine embolized valves by computed tomography (CT) late after TAVI.MethodsThe patient database of our center was screened for cases of TVEM between July 2009 and July 2021. To identify risk factors, TVEM cases were compared to a cohort of 200 consecutive TAVI cases. Out of 35 surviving TVEM patients, ten patients underwent follow-up by echocardiography and CT.Results54 TVEM occurred in 3757 TAVI procedures, 46 cases were managed percutaneously. Horizontal aorta (odds ratio [OR] 7.51, 95% confidence interval [CI] 3.4–16.6, p < 0.001), implantation of a self-expanding valve (OR 4.63, 95% CI 2.2–9.7, p < 0.01) and a left ventricular ejection fraction < 40% (OR 2.94, 95% CI 1.1–7.3, p = 0.016) were identified as risk factors for TVEM. CT scans were performed on average 26.3 months after TAVI (range 2–84 months) and detected hypoattenuated leaflet thickening (HALT) in two patients as well as parts of the stent frame protruding into the aortic wall in three patients.ConclusionTVEM represents a rare complication of TAVI. Follow up-CT detected no pathological findings requiring intervention.