Discovery of small molecules against porcine reproductive and respiratory syndrome virus replication by targeting NendoU activity.

Unlabelled: Porcine reproductive and respiratory syndrome (PRRS) remains a major threat to animal health and causes substantial economic losses worldwide. The nonstructural protein 11 (NSP11) of the causative agent, PRRS virus (PRRSV), contains a highly conserved nidoviral uridylate-specific endoribonuclease (NendoU) domain essential for viral replication and immune evasion. Targeting NSP11 offers a novel approach to antiviral intervention.

NaP-TRAP reveals the regulatory grammar in 5'UTR-mediated translation regulation during zebrafish development.

The cis-regulatory elements encoded in an mRNA determine its stability and translational output. While there has been a considerable effort to understand the factors driving mRNA stability, the regulatory frameworks governing translational control remain more elusive. We have developed a novel massively parallel reporter assay (MPRA) to measure mRNA translation, named Nascent Peptide Translating Ribosome Affinity Purification (NaP-TRAP).

Untrimmed ITS2 metabarcode sequences cause artificially reduced abundances of specific fungal taxa.

Unlabelled: Advances in DNA metabarcoding have greatly expanded our knowledge of microbial communities in recent years. Pipelines and parameters have been tested extensively for bacterial metabarcoding using the 16S rRNA gene and best practices are largely established. For fungal metabarcoding using the internal transcribed spacer (ITS) gene, however, only a few studies have considered how such pipelines and parameters can affect community prediction.

DICE: fast and accurate distance-based reconstruction of single-cell copy number phylogenies.

Somatic copy number alterations (sCNAs) are valuable phylogenetic markers for inferring evolutionary relationships among tumor cell subpopulations. Advances in single-cell DNA sequencing technologies are making it possible to obtain such sCNAs datasets at ever-larger scales. However, existing methods for reconstructing phylogenies from sCNAs are often too slow for large datasets.

Genomes of two invasive species (hemlock woolly adelgid and pineapple gall adelgid) enable characterization of nicotinic acetylcholine receptors.

Two invasive hemipteran adelgids cause widespread damage to North American conifers. (the hemlock woolly adelgid) has decimated and (the Eastern and Carolina hemlocks, respectively). was introduced from East Asia and reproduces parthenogenetically in North America, where it can kill trees rapidly.

Comprehensive single-cell aging atlas of healthy mammary tissues reveals shared epigenomic and transcriptomic signatures of aging and cancer.

Aging is the greatest risk factor for breast cancer; however, how age-related cellular and molecular events impact cancer initiation is unknown. In this study, we investigated how aging rewires transcriptomic and epigenomic programs of mouse mammary glands at single-cell resolution, yielding a comprehensive resource for aging and cancer biology. Aged epithelial cells exhibit epigenetic and transcriptional changes in metabolic, pro-inflammatory and cancer-associated genes.

An Early-Life Disruption of Gut Microbiota Has Opposing Effects on Parasite Resistance in Two Host Species.

Gut microbiota regulate multiple aspects of host health, including metabolism and the development of the immune system. However, we still know relatively little about how the gut microbiota influences host responses to parasitism in wild organisms, particularly whether host-microbiota interactions contribute to variation in parasitism across host species. The goal of this study was to determine the role of gut microbiota in shaping how birds respond to nest parasites and investigate whether this relationship varies between host species.

Genes Regulate Purkinje Cell Diversity in Cerebellar Development and Evolution.

Mammalian cerebellar development is thought to be influenced by distinct Purkinje cell (PC) subtypes. However, the degree of PC heterogeneity and the molecular drivers of this diversity have remained unclear, hindering efforts to manipulate PC diversification and assess its role in cerebellar development. Here, we demonstrate the critical role of genes in cerebellar development by regulating PC diversification.

Turnover of retroelements and satellite DNA drives centromere reorganization over short evolutionary timescales in Drosophila.

Centromeres reside in rapidly evolving, repeat-rich genomic regions, despite their essential function in chromosome segregation. Across organisms, centromeres are rich in selfish genetic elements such as transposable elements and satellite DNAs that can bias their transmission through meiosis. However, these elements still need to cooperate at some level and contribute to, or avoid interfering with, centromere function.

Alternative splicing is coupled to gene expression in a subset of variably expressed genes.

Numerous factors regulate alternative splicing of human genes at a co-transcriptional level. However, how alternative splicing depends on the regulation of gene expression is poorly understood. We leveraged data from the Genotype-Tissue Expression (GTEx) project to show a significant association of gene expression and splicing for 6874 (4.

Generation of isogenic models of Angelman syndrome and Prader-Willi syndrome in CRISPR/Cas9-engineered human embryonic stem cells.

Angelman syndrome (AS) and Prader-Willi syndrome (PWS), two distinct neurodevelopmental disorders, result from loss of expression from imprinted genes in the chromosome 15q11-13 locus most commonly caused by a megabase-scale deletion on either the maternal or paternal allele, respectively. Each occurs at an approximate incidence of 1/15,000 to 1/30,000 live births and has a range of debilitating phenotypes. Patient-derived induced pluripotent stem cells (iPSCs) have been valuable tools to understand human-relevant gene regulation at this locus and have contributed to the development of therapeutic approaches for AS.

Reconstruction of the human amylase locus reveals ancient duplications seeding modern-day variation.

Previous studies suggested that the copy number of the human salivary amylase gene, , correlates with starch-rich diets. However, evolutionary analyses are hampered by the absence of accurate, sequence-resolved haplotype variation maps. We identified 30 structurally distinct haplotypes at nucleotide resolution among 98 present-day humans, revealing that the coding sequences of copies are evolving under negative selection.

Enhanced Plasma Stability and Potency of Aryl/Acyloxy Prodrugs of a BTN3A1 Ligand.

While ester-based phosphonate prodrugs excel at delivering payloads into cells, their instability in plasma is a hurdle for their advancement. Here, we synthesized new aryl/acyloxy prodrugs of a phosphonate BTN3A1 ligand. We evaluated their phosphoantigen potency by flow cytometry and ELISA and their plasma and cellular metabolism by LC-MS.

Plateau depolarizations in spontaneously active neurons detected by calcium or voltage imaging.

In calcium imaging studies, Ca transients are commonly interpreted as neuronal action potentials (APs). However, our findings demonstrate that robust optical Ca transients primarily stem from complex "AP-Plateaus", while simple APs lacking underlying depolarization envelopes produce much weaker photonic signatures. Under challenging in vivo conditions, these "AP-Plateaus" are likely to surpass noise levels, thus dominating the Ca recordings.

Selective degradation of phage RNAs by the Csm6 ribonuclease provides robust type III CRISPR immunity in Streptococcus thermophilus.

Type III CRISPR immune systems bind viral or plasmid RNA transcripts and activate Csm3/Cmr4 and Cas10 nucleases to uniquely cleave both invader RNA and DNA, respectively. Additionally, type III effector complexes generate cyclic oligoadenylate (cOA) signaling molecules to activate trans-acting, auxiliary Csm6/Csx1 ribonucleases, previously proposed to be non-specific in their in vivo RNA cleavage preference. Despite extensive in vitro studies, the nuclease requirements of type III systems in their native contexts remain poorly understood.

Integrated multi-omics analysis of zinc-finger proteins uncovers roles in RNA regulation.

RNA interactome studies have revealed that hundreds of zinc-finger proteins (ZFPs) are candidate RNA-binding proteins (RBPs), yet their RNA substrates and functional significance remain largely uncharacterized. Here, we present a systematic multi-omics analysis of the DNA- and RNA-binding targets and regulatory roles of more than 100 ZFPs representing 37 zinc-finger families. We show that multiple ZFPs are previously unknown regulators of RNA splicing, alternative polyadenylation, stability, or translation.

Cytoskeletal mechanisms regulating attaching/effacing bacteria interactions with host cells: It takes a village to build the pedestal.

The actin cytoskeleton is a key cellular structure subverted by pathogens to infect and survive in or on host cells. Several pathogenic strains of Escherichia coli, such as enteropathogenic E. coli (EPEC) and enterohemorrhagic E.

Actomyosin contraction in the follicular epithelium provides the major mechanical force for follicle rupture during ovulation.

Ovulation is critical for sexual reproduction and consists of the process of liberating fertilizable oocytes from their somatic follicle capsules, also known as follicle rupture. The mechanical force for oocyte expulsion is largely unknown in many species. Our previous work demonstrated that ovulation, as in mammals, requires the proteolytic degradation of the posterior follicle wall and follicle rupture to release the mature oocyte from a layer of somatic follicle cells.

Autoregulated splicing of β programs T cell fate in response to antigen-receptor stimulation.

T cell receptor (TCR) sensitivity to peptide-major histocompatibility complex (MHC) dictates T cell fate. Canonical models of TCR sensitivity cannot be fully explained by transcriptional regulation. In this work, we identify a posttranscriptional regulatory mechanism of TCR sensitivity that guides alternative splicing of TCR signaling transcripts through an evolutionarily ultraconserved poison exon (PE) in the RNA-binding protein (RBP) TRA2β in mouse and human.