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Predicting the effects of coding variants is a major challenge. While recent deep-learning models have improved variant effect prediction accuracy, they cannot analyze all coding variants due to dependency on close homologs or software limitations. Here we developed a workflow using ESM1b, a 650-million-parameter protein language model, to predict all ~450 million possible missense variant effects in the human genome, and made all predictions available on a web portal. ESM1b outperformed existing methods in classifying ~150,000 ClinVar/HGMD missense variants as pathogenic or benign and predicting measurements across 28 deep mutational scan datasets. We further annotated ~2 million variants as damaging only in specific protein isoforms, demonstrating the importance of considering all isoforms when predicting variant effects. Our approach also generalizes to more complex coding variants such as in-frame indels and stop-gains. Together, these results establish protein language models as an effective, accurate and general approach to predicting variant effects.

Multidrug-resistant organism (MDRO) colonization is a fundamental challenge in antimicrobial resistance. Limited studies have shown that fecal microbiota transplantation (FMT) can reduce MDRO colonization, but its mechanisms are poorly understood. We conducted a randomized, controlled trial of FMT for MDRO decolonization in renal transplant recipients called PREMIX (NCT02922816). Eleven participants were enrolled and randomized 1:1 to FMT or an observation period followed by delayed FMT if stool cultures were MDRO positive at day 36. Participants who were MDRO positive after one FMT were treated with a second FMT. At last visit, eight of nine patients who completed all treatments were MDRO culture negative. FMT-treated participants had longer time to recurrent MDRO infection versus PREMIX-eligible controls who were not treated with FMT. Key taxa (Akkermansia muciniphila, Alistipes putredinis, Phocaeicola dorei, Phascolarctobacterium faecium, Alistipes species, Mesosutterella massiliensis, Barnesiella intestinihominis, and Faecalibacterium prausnitzii) from the single feces donor used in the study that engrafted in recipients and metabolites such as short-chain fatty acids and bile acids in FMT-responding participants uncovered leads for rational microbiome therapeutic and diagnostic development. Metagenomic analyses revealed a previously unobserved mechanism of MDRO eradication by conspecific strain competition in an FMT-treated subset. Susceptible Enterobacterales strains that replaced baseline extended-spectrum β-lactamase–producing strains were not detectable in donor microbiota manufactured as FMT doses but in one case were detectable in the recipient before FMT. These data suggest that FMT may provide a path to exploit strain competition to reduce MDRO colonization. Editor's summary: Those who must use antibiotic prophylaxis to prevent opportunistic infections are at high risk for intestinal colonization and infection by multi-drug resistant organisms (MDROs). Here, Woodworth and colleagues conducted a randomized controlled trial to compare the safety, efficacy, and strain dynamics of MDRO eradication after bowel preparation plus fecal microbiota transfer (FMT) versus bowel preparation alone in 11 renal transplantation recipients. FMT resulted in faster MDRO decolonization and protected study participants from recurrent infection. In some participants, extended spectrum β-lactamase (ESBL)–producing strains were replaced by non-ESBL strains, suggesting that strain competition rather than eradication may occur after FMT. These findings support the efficacy of FMT and provide valuable insights into the mechanisms by which FMT may lead to MDRO decolonization. —Melissa Norton [ABSTRACT FROM AUTHOR]

In many societies, parents are involved in selecting a spouse for their child, integrating this with decisions about premarital investment such as education. Do spousal preferences of parents and children conflict? We estimate parents' spousal preferences based on survey choices between random profiles, elicited from parents or other relatives who actively search for a spouse on behalf of their adult child in Kunming, China. We simulate marriage outcomes based on preferences for age and education and compare them with patterns in the general population and with the preferences of a survey of students. The common concern that there may be aversion to highly educated or high-earning wives is somewhat corroborated in parents' preferences but not in students' preferences, nor in outcomes, where homogamy is common and wives who are more educated than husbands are as common as husbands who are more educated than wives. Parents prefer wives younger than their husbands, yet most couples are the same age, an outcome consistent with student preferences. Overall, divergences between parental and child preferences exist but are neither major nor very influential in explaining observed outcomes. Fears that highly educated women face diminished marriage prospects appear less serious than often claimed. [ABSTRACT FROM AUTHOR]

Soil-based microorganisms assume a direct and crucial role in the promotion of soil health, quality and fertility, all factors known to contribute heavily to the quality and yield of agricultural products. Cover cropping, used in both traditional and organic farming, is a particularly efficient and environmentally favorable tool for manipulating microbiome composition in agricultural soils and has had clear benefits for soil quality and crop output. Several long-term investigations have evaluated the influence of multi-mix (multiple species) cover crop treatments on soil health and microbial diversity. The present study investigated the short-term effects of a seven species multi-mix cover crop treatment on soil nutrient content and microbial diversity, compared to a single-mix cover crop treatment and control. Analysis of 16S sequencing data of isolated soil DNA revealed that the single-mix cover crop treatment decreased overall microbial abundance and diversity, whereas the control and multi-mix treatments altered the overall microbial composition in similar fluctuating trends. Furthermore, we observed significant changes in specific bacteria belonging to the phyla Acidobacteria, Actinobacteria, Planctomycetes, Proteobacteria and Verrucombicrobia for all treatments, but only the single-mix significantly decreased in abundance of the selected bacteria over time. Our findings indicate that the control and multi-mix treatments are better at maintaining overall microbial composition and diversity compared to the single-mix. Further study is required to elucidate the specific difference between the treatment effect of the multi-mix treatment and the control, given that their microbial composition changes over time were similar but they diverge into two populations of unique bacterial types by the end of this short-term study. [ABSTRACT FROM AUTHOR]

Both parents and offspring have evolved mating preferences that enable them to select mates and children‐in‐law to maximize their inclusive fitness. The theory of parent–offspring conflict predicts that preferences for potential mates may differ between parents and offspring: individuals are expected to value biological quality more in their own mates than in their offspring's mates and to value investment potential more in their offspring's mates than in their own mates. We tested this hypothesis in China using a naturalistic ‘marriage market’ where parents actively search for marital partners for their offspring. Parents gather at a public park to advertise the characteristics of their adult children, looking for a potential son or daughter‐in‐law. We presented 589 parents and young adults from the city of Kunming (Yunnan, China) with hypothetical mating candidates varying in their levels of income (proxy for investment potential) and physical attractiveness (proxy for biological quality). We found some evidence of a parent–offspring conflict over mate choice, but only in the case of daughters, who evaluated physical attractiveness as more important than parents. We also found an effect of the mating candidate's sex, as physical attractiveness was deemed more valuable in a female potential mate by parents and offspring alike. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 59-year-old right-handed woman presented with an encephalopathy and her family reported a two-week history of worsening cognition and confusion, with two months' history of deteriorating gait. It revealed the characteristic magnetic resonance findings of linear perivascular enhancement.

The availability of high-throughput genomic data has led to several challenges in recent genetic association studies, including the large number of genetic variants that must be considered and the computational complexity in statistical analyses. Tackling these problems with a marker-set study such as SNP-set analysis can be an efficient solution. To construct SNP-sets, we first propose a clustering algorithm, which employs Hamming distance to measure the similarity between strings of SNP genotypes and evaluates whether the given SNPs or SNP-sets should be clustered. A dendrogram can then be constructed based on such distance measure, and the number of clusters can be determined. With the resulting SNP-sets, we next develop an association test HDAT to examine susceptibility to the disease of interest. This proposed test assesses, based on Hamming distance, whether the similarity between a diseased and a normal individual differs from the similarity between two individuals of the same disease status. In our proposed methodology, only genotype information is needed. No inference of haplotypes is required, and SNPs under consideration do not need to locate in nearby regions. The proposed clustering algorithm and association test are illustrated with applications and simulation studies. As compared with other existing methods, the clustering algorithm is faster and better at identifying sets containing SNPs exerting a similar effect. In addition, the simulation studies demonstrated that the proposed test works well for SNP-sets containing a large proportion of neutral SNPs. Furthermore, employing the clustering algorithm before testing a large set of data improves the knowledge in confining the genetic regions for susceptible genetic markers. [ABSTRACT FROM AUTHOR]

Chromatin plays a critical role in faithful implementation of gene expression programs. Different post-translational modifications (PTMs) of histone proteins reflect the underlying state of gene activity, and many chromatin proteins write, erase, bind, or are repelled by, these histone marks. One such protein is UpSET, the Drosophila homolog of yeast Set3 and mammalian KMT2E (MLL5). Here, we show that UpSET is necessary for the proper balance between active and repressed states. Using CRISPR/Cas-9 editing, we generated S2 cells that are mutant for upSET. We found that loss of UpSET is tolerated in S2 cells, but that heterochromatin is misregulated, as evidenced by a strong decrease in H3K9me2 levels assessed by bulk histone PTM quantification. To test whether this finding was consistent in the whole organism, we deleted the upSET coding sequence using CRISPR/Cas-9, which we found to be lethal in both sexes in flies. We were able to rescue this lethality using a tagged upSET transgene, and found that UpSET protein localizes to transcriptional start sites (TSS) of active genes throughout the genome. Misregulated heterochromatin is apparent by suppressed position effect variegation of the wm4 allele in heterozygous upSET-deleted flies. Using nascent-RNA sequencing in the upSET-mutant S2 lines, we show that this result applies to heterochromatin genes generally. Our findings support a critical role for UpSET in maintaining heterochromatin, perhaps by delimiting the active chromatin environment.

Author(s): Alison Farrell; Charlotte Wang; Ushma Savla Triallelic inheritance Bardet-Biedl syndrome (BBS) is a rare genetically heterogeneous disorder that displays a collection of phenotypes including pigmentary retinal dystrophy, obesity, polydactyly, [...]

Author(s): Leila Alland; Tanguy Chouard; Kristine Novak; Bernd Pulverer; Charlotte Wang Sporadic cancer model Researchers have developed a novel gene-targeting procedure to create mice that more closely recapitulate the spontaneous [...]

Author(s): Bernd Pulverer; Karen Birmingham; Simon Nobel; Charlotte Wang; Kristine Novak Leptin attenuates heroin craving A study recently published in the 15 February edition of The Journal of Neuroscience suggests [...]

Author(s): Charlotte Wang The process of neurogenesis, now recognized to be an ongoing process in adult mammalian brain, requires a specific molecular environment that neuroscientists are only beginning to understand. [...]

The article focuses on the similarities of the Christian right in the U.S. and the Muslim conservative party in Turkey on their views about God, gender and political religion. It discusses their stand on rebuilding and defending their own land by binding the opposing sexes in divine union. Information is given on the emergence of religious nationalism in both countries. It explains the connection between public love of nation and private way in which husbands and wives love each other.

X-chromosome dosage compensation by the MSL (male-specific lethal) complex is required in Drosophila melanogaster to increase gene expression from the single male X to equal that of both female X chromosomes. Instead of focusing solely on protein complexes released from DNA, here we used chromatin-interacting protein MS (ChIP-MS) to identify MSL interactions on cross-linked chromatin. We identified MSL-enriched histone modifications, including histone H4 Lys16 acetylation and histone H3 Lys36 methylation, and CG4747, a putative Lys36-trimethylated histone H3 (H3K36me3)-binding protein. CG4747 is associated with the bodies of active genes, coincident with H3K36me3, and is mislocalized in the Set2 mutant lacking H3K36me3. CG4747 loss of function in vivo results in partial mislocalization of the MSL complex to autosomes, and RNA interference experiments confirm that CG4747 and Set2 function together to facilitate targeting of the MSL complex to active genes, validating the ChIP-MS approach. [ABSTRACT FROM AUTHOR]

Long noncoding RNAs (lncRNAs) have important regulatory roles and can function at the level of chromatin. To determine where lncRNAs bind to chromatin, we developed capture hybridization analysis of RNA targets (CHART), a hybridization-based technique that specifically enriches endogenous RNAs along with their targets from reversibly cross-linked chromatin extracts. CHART was used to enrich the DNA and protein targets of endogenous lncRNAs from flies and humans. This analysis was extended to genome-wide mapping of roX2, a well-studied ncRNA involved in dosage compensation in Drosophila. CHART revealed that roX2 binds at specific genomic sites that coincide with the binding sites of proteins from the male-specific lethal complex that affects dosage compensation. These results reveal the genomic targets of roX2 and demonstrate how CHART can be used to study RNAs in a manner analogous to chromatin immunoprecipitation for proteins. [ABSTRACT FROM AUTHOR]

Abstract: Parkinson’s disease (PD) is a common neurodegenerative disease of unknown etiology. Evidence suggests a role for protein misfolding in disease pathogenesis. One pathologic feature observed in dopaminergic neurons is the intracytoplasmic eosinophilic inclusions known as Lewy bodies. One component of Lewy bodies, the presynaptic protein, α-synuclein forms oligomers and higher order aggregates and is proposed to be involved in dopaminergic neuronal death. In an effort to discriminate between α-synuclein conformational forms as well as design potential disruptors of pathogenic misfolding we panned a human phage antibody library for anti-synuclein single chain antibodies (scFvs). We identified six scFvs which recognize different conformers of α-synuclein in both an ELISA and Western blot analysis. These scFvs may further our understanding of α-synuclein’s role in PD. [Copyright &y& Elsevier]

This paper examines the effects of including place of origin, place of current residence and place of migration in the Sewell-Hauser basic model of socioeconomic achievement and particularly focuses on the effect on earnings. The analysis is based on data from the Wisconsin longitudinally study of 1957 high school seniors. The inclusion of the residential variables markedly increases the explained variance in earnings, but does not alter the effects of the socioeconomic and ability variables on earnings. Further analysis indicate that current residence is particularly important in accounting for earnings. Earnings are positively related to size of place of current residence, even after adjusting for other variables. The earnings of men living in rural communities, especially those living on farms, are low compared with all other respondents. [ABSTRACT FROM AUTHOR]

Presents research notes related to heart failure. Use of beta-andrenergic receptor blocker for heart failure; Cause of the enlargement of the heart; Benefits of the drug statins.

The article presents information related to some important researches. After a meal, pancreatic secretion of insulin tells peripheral tissues, mainly skeletal muscle and fat, to take up glucose. In type 2 diabetes, this signal is impaired by "resistance" of peripheral tissues to insulin. In 1995, researchers were quietly introduced to a molecule, now known as adiponectin, that would later emerge as a promising link between obesity and insulin resistance. The way people think about metabolic regulation has been changed, with the discovery of the transcriptional coactivator PGC-1α in 1998.

Abstract: The aim of this study was to investigate the prevalence of common geriatric conditions in a tertiary medical center. We conducted a cross-sectional, hospital-wide survey of 455 inpatients, aged 65 and older, from 24 medical and surgical units of a 2200-bed urban academic medical center in Taiwan. Patients were screened in face-to-face interviews for 15 geriatric conditions. The prevalence of geriatric conditions was determined and compared by medical versus surgical services. Our sample of participants had a mean age of 75.3±6.1 years (±S.D.), range=65–92. The prevalence of geriatric conditions ranged from 5% (pressure ulcers) to 57% (polypharmacy; taking>5 prescriptions). The majority was visually impaired (74%) and complained of sleep disturbance during their hospital stay (58%). Prevalence rates of certain geriatric conditions differed significantly between medical and surgical units, suggesting that care should address not only common conditions but also those with higher rates on different units. Furthermore, high rates of geriatric conditions indicate strong needs for care that does not fit into traditional disease models of medicine. Care should be better targeted to address different risks for geriatric conditions of medical versus surgical geriatric inpatients in acute care settings. [Copyright &y& Elsevier]

Summary: The Drosophila MSL complex associates with active genes specifically on the male X chromosome to acetylate histone H4 at lysine 16 and increase expression approximately 2-fold. To date, no DNA sequence has been discovered to explain the specificity of MSL binding. We hypothesized that sequence-specific targeting occurs at “chromatin entry sites,” but the majority of sites are sequence independent. Here we characterize 150 potential entry sites by ChIP-chip and ChIP-seq and discover a GA-rich MSL recognition element (MRE). The motif is only slightly enriched on the X chromosome (∼2-fold), but this is doubled when considering its preferential location within or 3′ to active genes (>4-fold enrichment). When inserted on an autosome, a newly identified site can direct local MSL spreading to flanking active genes. These results provide strong evidence for both sequence-dependent and -independent steps in MSL targeting of dosage compensation to the male X chromosome. [Copyright &y& Elsevier]

Antigen discovery technologies have largely focused on major histocompatibility complex (MHC) class I-restricted human T cell receptors (TCRs), leaving methods for MHC class II-restricted and mouse TCR reactivities relatively undeveloped. Here we present TCR mapping of antigenic peptides (TCR-MAP), an antigen discovery method that uses a synthetic TCR-stimulated circuit in immortalized T cells to activate sortase-mediated tagging of engineered antigen-presenting cells (APCs) expressing processed peptides on MHCs. Live, tagged APCs can be directly purified for deconvolution by sequencing, enabling TCRs with unknown specificity to be queried against barcoded peptide libraries in a pooled screening context. TCR-MAP accurately captures self-reactivities or viral reactivities with high throughput and sensitivity for both MHC class I-restricted and class II-restricted TCRs. We elucidate problematic cross-reactivities of clinical TCRs targeting the cancer/testis melanoma-associated antigen A3 and discover targets of myocarditis-inciting autoreactive T cells in mice. TCR-MAP has the potential to accelerate T cell antigen discovery efforts in the context of cancer, infectious disease and autoimmunity., (© 2024. The Author(s).)

This paper studies how people make decisions over preventive behaviors under ambiguity (i.e., Knightian uncertainty) where they do not even know the probability of a loss. In the context of the current COVID-19 pandemic, scientific uncertainty makes it hard to evaluate not only whether one will be infected, but also probabilities such as the infection rate. We constructed a simple model and demonstrated how its effect was heterogeneous depending on ambiguity-attitudes. Motivated by the model, we further conducted a survey experiment in Japan where we manipulated the information regarding scientific uncertainty on COVID-19. We found that higher ambiguity induced by scientific uncertainty increased the level of social distancing among ambiguity-loving people, but such evidence was nonexistent for ambiguity-averse counterparts., Supplementary Information: The online version contains supplementary material available at 10.1007/s42973-022-00120-3., (© Japanese Economic Association 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

T cell recognition of specific antigens mediates protection from pathogens and controls neoplasias, but can also cause autoimmunity. Our knowledge of T cell antigens and their implications for human health is limited by the technical limitations of T cell profiling technologies. Here, we present T-Scan, a high-throughput platform for identification of antigens productively recognized by T cells. T-Scan uses lentiviral delivery of antigen libraries into cells for endogenous processing and presentation on major histocompatibility complex (MHC) molecules. Target cells functionally recognized by T cells are isolated using a reporter for granzyme B activity, and the antigens mediating recognition are identified by next-generation sequencing. We show T-Scan correctly identifies cognate antigens of T cell receptors (TCRs) from viral and human genome-wide libraries. We apply T-Scan to discover new viral antigens, perform high-resolution mapping of TCR specificity, and characterize the reactivity of a tumor-derived TCR. T-Scan is a powerful approach for studying T cell responses., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A properly designed distance-based measure can capture informative genetic differences among individuals with different phenotypes and can be used to detect variants responsible for the phenotypes. To detect associated variants, various tests have been designed to contrast genetic dissimilarity or similarity scores of certain subject groups in different ways, among which the most widely used strategy is to quantify the difference between the within-group genetic dissimilarity/similarity ( i.e. , case-case and control-control similarities) and the between-group dissimilarity/similarity ( i.e. , case-control similarities). While it has been noted that for common variants, the within-group and the between-group measures should all be included; in this work, we show that for rare variants, comparison based on the two within-group measures can more effectively quantify the genetic difference between cases and controls. The between-group measure tends to overlap with one of the two within-group measures for rare variants, although such overlap is not present for common variants. Consequently, a dissimilarity or similarity test that includes the between-group information tends to attenuate the association signals and leads to power loss. Based on these findings, we propose a dissimilarity test that compares the degree of SNP dissimilarity within cases to that within controls to better characterize the difference between two disease phenotypes. We provide the statistical properties, asymptotic distribution, and computation details for a small sample size of the proposed test. We use simulated and real sequence data to assess the performance of the proposed test, comparing it with other rare-variant methods including those similarity-based tests that use both within-group and between-group information. As similarity-based approaches serve as one of the dominating approaches in rare-variant analysis, our results provide some insight for the effective detection of rare variants., (Copyright © 2018 by the Genetics Society of America.)