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Background Certain post-translational modifications to histones, including H3K4me3, as well as binding sites for the transcription factor STAT1, predict the site of integration of exogenous gamma-retroviruses with great accuracy and cell-type specificity. Statistical methods that were used to identify chromatin features that predict exogenous gamma-retrovirus integration site selection were exploited here to determine whether cell type-specific chromatin markers are enriched in the vicinity of endogenous retroviruses (ERVs). Results Among retro-elements in the human genome, the gamma-retrovirus HERV-H was highly associated with H3K4me3, though this association was only observed in embryonic stem (ES) cells (p < 10 -300 ) and, to a lesser extent, in induced pluripotent stem (iPS) cells. No significant association was observed in nearly 40 differentiated cell types, nor was any association observed with other retro-elements. Similar strong association was observed between HERV-H and the binding sites within ES cells for the pluripotency transcription factors NANOG, OCT4, and SOX2. NANOG binding sites were located within the HERV-H 5 ′ LTR itself. OCT4 and SOX2 binding sites were within 1 kB and 2 kB of the 5 ′ LTR, respectively. In keeping with these observations, HERV-H RNA constituted 2% of all poly A RNA in ES cells. As ES cells progressed down a differentiation pathway, the levels of HERV-H RNA decreased progressively. RNA-Seq datasets showed HERV-H transcripts to be over 5 kB in length and to have the structure 5 ′ LTR- gag - pro -3 ′ LTR, with no evidence of splicing and no intact open reading frames. Conclusion The developmental regulation of HERV-H expression, the association of HERV-H with binding sites for pluripotency transcription factors, and the extremely high levels of HERV-H RNA in human ES cells suggest that HERV-H contributes to pluripotency in human cells. Proximity of HERV-H to binding sites for pluripotency transcription factors within ES cells might be due to retention of the same chromatin features that determined the site of integration of the ancestral, exogenous, gamma-retrovirus that gave rise to HERV-H in the distant past. Retention of these markers, or, alternatively, recruitment of them to the site of the established provirus, may have acted post-integration to fix the provirus within the germ-line of the host species. Either way, HERV-H RNA provides a specific marker for pluripotency in human cells.

\"Numerous Hindu and Buddhist kingdoms flourished in Southeast Asia from the 5th to the 9th century, yet until recently few concrete details were known about them. Lost Kingdoms reveals newly discovered architectural and sculptural relics from this region, which provide key insights into the formerly mysterious kingdoms. The first publication to use sculpture as a lens to explore this period of Southeast Asian history, Lost Kingdoms offers a significant contribution and a fresh approach to the study of cultures in Cambodia, Thailand, Burma, and other countries\"--Distributor's website.

This article studies inference for the average treatment effect in randomized controlled trials with covariate-adaptive randomization. Here, by covariate-adaptive randomization, we mean randomization schemes that first stratify according to baseline covariates and then assign treatment status so as to achieve \"balance\" within each stratum. Our main requirement is that the randomization scheme assigns treatment status within each stratum so that the fraction of units being assigned to treatment within each stratum has a well behaved distribution centered around a proportion π as the sample size tends to infinity. Such schemes include, for example, Efron's biased-coin design and stratified block randomization. When testing the null hypothesis that the average treatment effect equals a prespecified value in such settings, we first show the usual two-sample t-test is conservative in the sense that it has limiting rejection probability under the null hypothesis no greater than and typically strictly less than the nominal level. We show, however, that a simple adjustment to the usual standard error of the two-sample t-test leads to a test that is exact in the sense that its limiting rejection probability under the null hypothesis equals the nominal level. Next, we consider the usual t-test (on the coefficient on treatment assignment) in a linear regression of outcomes on treatment assignment and indicators for each of the strata. We show that this test is exact for the important special case of randomization schemes with , but is otherwise conservative. We again provide a simple adjustment to the standard errors that yields an exact test more generally. Finally, we study the behavior of a modified version of a permutation test, which we refer to as the covariate-adaptive permutation test, that only permutes treatment status for units within the same stratum. When applied to the usual two-sample t-statistic, we show that this test is exact for randomization schemes with and that additionally achieve what we refer to as \"strong balance.\" For randomization schemes with , this test may have limiting rejection probability under the null hypothesis strictly greater than the nominal level. When applied to a suitably adjusted version of the two-sample t-statistic, however, we show that this test is exact for all randomization schemes that achieve \"strong balance,\" including those with . A simulation study confirms the practical relevance of our theoretical results. We conclude with recommendations for empirical practice and an empirical illustration. Supplementary materials for this article are available online.

Background The rapid expansion of next-generation sequencing (NGS) technologies has generated vast amounts of genomic data, creating a growing demand for secure, scalable, and accessible tools to support variant interpretation. However, many existing solutions are command-line based, rely on cloud or server infrastructures that may pose data privacy risks, lack flexibility in supporting both VCF, CSV and TSV formats, or struggle to handle the scale and complexity of modern genomic datasets. There is a clear need for a user-friendly, locally operated application capable of efficiently processing annotated variant data for large-scale cohort level analysis. Results We introduce GenMasterTable, a free, secure, and cross-platform desktop application designed to simplify variant analysis through an intuitive graphical user interface (GUI). As the first tool to enable comprehensive cohort-level analysis from VCF, CSV to TSV files, GenMasterTable provides advanced functionality for concatenation, filtering, summarizing, and visualizing large-scale annotated datasets. Tailored for users without programming expertise, it enables rapid and accurate exploration of genetic variants, making it a practical solution for both research and clinical settings. Conclusion GenMasterTable addresses critical limitations in current variant analysis workflows by combining usability, data security, and scalability. Its support for multiple input formats and locally executed operations empowers clinicians, geneticists, and researchers to perform comprehensive variant analysis efficiently without the need for programming expertise.

Nudging or ‘choice architecture’ refers to strategic changes in the environment that are anticipated to alter people’s behaviour in a predictable way, without forbidding any options or significantly changing their economic incentives. Nudging strategies may be used to promote healthy eating behaviour. However, to date, the scientific evidence has not been systematically reviewed to enable practitioners and policymakers to implement, or argue for the implementation of, specific measures to support nudging strategies. This systematic review investigated the effect of positional changes of food placement on food choice. In total, seven scientific databases were searched using relevant keywords to identify interventions that manipulated food position (proximity or order) to generate a change in food selection, sales or consumption, among normal-weight or overweight individuals across any age group. From 2576 identified articles, fifteen articles comprising eighteen studies met our inclusion criteria. This review has identified that manipulation of food product order or proximity can influence food choice. Such approaches offer promise in terms of impacting on consumer behaviour. However, there is a need for high-quality studies that quantify the magnitude of positional effects on food choice in conjunction with measuring the impact on food intake, particularly in the longer term. Future studies should use outcome measures such as change in grams of food consumed or energy intake to quantify the impact on dietary intake and potential impacts on nutrition-related health. Research is also needed to evaluate potential compensatory behaviours secondary to such interventions.

Despite its central role in the control of plant architecture, strigolactone has been recognized as a phytohormone only 15 years ago. Together with auxin, it regulates shoot branching in response to genetically encoded programs, as well as environmental cues. A central determinant of shoot architecture is apical dominance, i.e., the tendency of the main shoot apex to inhibit the outgrowth of axillary buds. Hence, the execution of apical dominance requires long-distance communication between the shoot apex and all axillary meristems. While the role of strigolactone and auxin in apical dominance appears to be conserved among flowering plants, the mechanisms involved in bud activation may be more divergent, and include not only hormonal pathways but also sugar signaling. Here, we discuss how spatial aspects of SL biosynthesis, transport, and sensing may relate to apical dominance, and we consider the mechanisms acting locally in axillary buds during dormancy and bud activation.

Dengue virus NS5 protein plays multiple functions in the cytoplasm of infected cells, enabling viral RNA replication and counteracting host antiviral responses. Here, we demonstrate a novel function of NS5 in the nucleus where it interferes with cellular splicing. Using global proteomic analysis of infected cells together with functional studies, we found that NS5 binds spliceosome complexes and modulates endogenous splicing as well as minigene-derived alternative splicing patterns. In particular, we show that NS5 alone, or in the context of viral infection, interacts with core components of the U5 snRNP particle, CD2BP2 and DDX23, alters the inclusion/exclusion ratio of alternative splicing events, and changes mRNA isoform abundance of known antiviral factors. Interestingly, a genome wide transcriptome analysis, using recently developed bioinformatics tools, revealed an increase of intron retention upon dengue virus infection, and viral replication was improved by silencing specific U5 components. Different mechanistic studies indicate that binding of NS5 to the spliceosome reduces the efficiency of pre-mRNA processing, independently of NS5 enzymatic activities. We propose that NS5 binding to U5 snRNP proteins hijacks the splicing machinery resulting in a less restrictive environment for viral replication.

Porcine reproductive and respiratory syndrome virus (PRRSV) is known to suppress the type I interferon (IFNs-α/β) response during infection. PRRSV also activates the NF-κB signaling pathway, leading to the production of proinflammatory cytokines during infection. In swine farms, co-infections of PRRSV and other secondary bacterial pathogens are common and exacerbate the production of proinflammatory cytokines, contributing to the porcine respiratory disease complex (PRDC) which is clinically a severe disease. Previous studies identified the non-structural protein 1β (nsp1β) of PRRSV-2 as an IFN antagonist and the nucleocapsid (N) protein as the NF-κB activator. Further studies showed the leucine at position 126 (L126) of nsp1β as the essential residue for IFN suppression and the region spanning the nuclear localization signal (NLS) of N as the NF-κB activation domain. In the present study, we generated a double-mutant PRRSV-2 that contained the L126A mutation in the nsp1β gene and the NLS mutation (ΔNLS) in the N gene using reverse genetics. The immunological phenotype of this mutant PRRSV-2 was examined in porcine alveolar macrophages (PAMs) in vitro and in young pigs in vivo. In PAMs, the double-mutant virus did not suppress IFN-β expression but decreased the NF-κB-dependent inflammatory cytokine productions compared to those for wild-type PRRSV-2. Co-infection of PAMs with the mutant PRRSV-2 and Streptococcus suis (S . suis) also reduced the production of NF-κB-directed inflammatory cytokines. To further examine the cytokine profiles and the disease severity by the mutant virus in natural host animals, 6 groups of pigs, 7 animals per group, were used for co-infection with the mutant PRRSV-2 and S . suis . The double-mutant PRRSV-2 was clinically attenuated, and the expressions of proinflammatory cytokines and chemokines were significantly reduced in pigs after bacterial co-infection. Compared to the wild-type PRRSV-2 and S . suis co-infection control, pigs coinfected with the double-mutant PRRSV-2 exhibited milder clinical signs, lower titers and shorter duration of viremia, and lower expression of proinflammatory cytokines. In conclusion, our study demonstrates that genetic modification of the type I IFN suppression and NF-κB activation functions of PRRSV-2 may allow us to design a novel vaccine candidate to alleviate the clinical severity of PRRS-2 and PRDC during bacterial co-infection.

This study investigates the impact of an efficacy-focused virtual reality (VR) intervention designed according to instructional design principles on eating behavior. In the preregistered intervention study, psychology students were randomly assigned to nine seminar blocks. Employing parallel design, they were allocated to either a VR intervention to experience the environmental impact of food behavior (1) and alter the future by revising food choices (2) or to a passive control condition. The data from 123 participants (78% female, mean age 25.03, SD  = 6.4) were analyzed to investigate the effect of the VR intervention on dietary footprint measured from 1 week before to 1 week after the intervention. The VR intervention decreased individual dietary footprints ( d  = 0.4) significantly more than the control condition. Similarly, the VR condition increased response efficacy and knowledge to a larger extent compared to the control. For knowledge, the effect persisted for 1 week. The VR intervention had no impact on intentions, self-efficacy, or psychological distance. Additional manipulation of normative feedback enhanced self-efficacy; however, manipulation of geographical framing did not influence psychological distance. This research received no financial support from any funding agency and was registered on 15/09/2021 at Open Science Foundation with the number https://doi.org/10.17605/OSF.IO/2AXF3 .