Discovery, Optimization, and Evaluation of Non-Nucleoside SARS-CoV-2 NSP14 Inhibitors.

We recently reported the discovery of TDI-015051, a first-in-class small-molecule inhibitor of the SARS-CoV-2 guanine-N7 methyltransferase nonstructural protein 14 (NSP14). NSP14 plays a critical role in viral RNA cap synthesis and its inhibition represents a novel antiviral approach. Utilizing systematic structure-activity relationship studies, potent non-nucleoside-based inhibitors with single-digit nanomolar cellular activity were identified from an HTS hit lacking cellular activity.

Quaternary Habitat Fluctuations and Demographic Dynamics in Turtles Inferred From Environmental Niche Modelling and Whole Genome Data.

Quaternary climatic fluctuations had a substantial influence on ecosystems, species distribution, phenology and genetic diversity, driving extinction, adaptation and demographic shifts during glacial periods and postglacial expansions. Integration of genomic data and environmental niche modelling can provide valuable insights on how organisms responded to past environmental variations and contribute to assessing vulnerability and resilience to ongoing climatic challenges. Among vertebrates, turtles are particularly vulnerable to habitat changes because of distinctive life history traits and the effect of environmental conditions on physiology and survival.

Platelet Activation and a Platelet Biosignature Are Associated With Cardiovascular Risk in Patients With Controlled Psoriasis.

Background: The underlying mechanisms of atherosclerosis and strategies for identifying high cardiovascular risk in psoriasis are incompletely understood. Platelet activity is increased in psoriasis and induces vascular dysfunction. We investigated the platelet phenotype and platelet transcriptome as one potential mechanism to explain cardiovascular risk in psoriasis.

Human inborn errors of type I interferon-independent intrinsic immunity in nonleukocytic cells.

'Intrinsic immunity' is often used to refer to mechanisms of host defense operating in nonleukocytic cells. This term can refer to the intrinsic capacity of an individual cell to fend off invading microbes without help from other cells or of a group of similar cells to fend off invading microbes without help from other cell types. The intrinsic capacity of individual cells to defend themselves against invading microbes without assistance has received little attention and is the topic of this review.

Opportunities and considerations for using artificial intelligence in bioinformatics education.

Artificial intelligence (AI) tools and techniques are undoubtedly being used in bioinformatics education, reflecting broader trends in education. However, many instructors and learners may be unaware of the full scope of potential uses for these tools within bioinformatics education, as well as effective practices for using them. Building on discussions held at the 6th Global Bioinformatics Education Summit, this perspective article provides insights about ways that AI might be used to generate or adapt instructional content, provide personalized help for learners, and automate assessment and grading.

Chromosome-level genome assembly of the Tyrrhenian tree frog (Hyla sarda).

The Tyrrhenian tree frog (Hyla sarda) is a small cryptically coloured amphibian found in Corsica, Sardinia, and the Tuscan Archipelago. Investigation into the species' evolutionary history has revealed phenotypic changes triggered by glaciation-induced range expansion, but understanding the genetic basis of this trait variation has been hampered by the lack of a reference genome. To address this, we assembled a chromosome-level genome of Hyla sarda using PacBio HiFi long reads, Bionano optical maps, and Hi-C data.

Transcriptional Interference Gates Monogenic Odorant Receptor Expression in Ants.

Communication is crucial to social life, and in ants, it is mediated primarily through olfaction. Ants have more odorant receptor (OR) genes than any other group of insects, generated through tandem duplications that produce large genomic arrays of related genes. However, how olfactory sensory neurons produce a single functional OR from these arrays remains unclear.

A Toolkit for Mapping and Modulating Neurotransmission at Single-Cell Resolution.

Understanding the organization and regulation of neurotransmission at the level of individual neurons and synapses requires tools that can track and manipulate transmitter-specific vesicles . Here, we present a suite of genetic tools in to fluorescently label and conditionally ablate the vesicular transporters for glutamate, GABA, acetylcholine, and monoamines. Using a structure-guided approach informed by protein topology and evolutionary conservation, we engineered endogenously tagged versions for each transporter that maintain their physiological function while allowing for cell-specific, bright, and stable visualization.

Nucleotide-dependent conformational changes direct peptide export by the transporter associated with antigen processing.

The transporter associated with antigen processing (TAP) delivers peptide antigens from the cytoplasm into the endoplasmic reticulum (ER) for loading onto major histocompatibility complex class I (MHC-I) molecules. To examine the mechanisms of peptide transport and release into the ER, we determined cryo-electron microscopy structures of the human TAP heterodimer in multiple functional states along the transport cycle. In the inward-facing conformation, when the peptide translocation cavity within the TAP heterodimer is exposed to the cytosol, ATP binding strengthened intradomain assembly.

SPECTREM Phase 3b Clinical Trial Results Through Week 16: Guselkumab Efficacy and Safety for the Treatment of Low Body Surface Area, Moderate Psoriasis With High-Impact Site Involvement.

Background: Patients with psoriasis affecting a low percentage of their body surface area (BSA) are underrepresented in clinical studies and may face substantial disease burden if high-impact sites are affected.

Objectives: SPECTREM is a Phase 3b, randomized, placebo-controlled study evaluating guselkumab efficacy and safety in participants with low BSA (2%-15%), moderate (Investigator's Global Assessment [IGA]=3) plaque psoriasis involving ≥1 high-impact site (scalp, face, genitals, intertriginous areas).

Methods: Eligible participants were randomized 2:1 to receive guselkumab 100 mg or placebo at Week 0 and Week 4, then every 8 weeks.

A Comprehensive Account of the Breeding Systems of the Fire Ant .

When animals reproduce in social groups, the potential for conflict and cooperation is shaped by the number of reproductive individuals (breeders), their relatedness to one another, and division of reproduction among them. These features comprise species' "breeding systems." Despite their importance, breeding systems are poorly characterized in most social animals, and detailed accounts for single species are rare.

Persistent Genomic Erosion in Whooping Cranes Despite Demographic Recovery.

Integrating in-situ (wild) and ex-situ (captive) conservation efforts can mitigate genetic diversity loss and help prevent extinction of endangered wild populations. The whooping crane (Grus americana) experienced severe population declines in the 18th century, culminating in a collapse to ~20 individuals by 1944. Legal protections and conservation actions have since increased the census population from a stock of 16 individuals to approximately 840 individuals, yet the impact on genomic diversity remains unclear.

G-quadruplexes as a source of vulnerability in BRCA2deficient granule cell progenitors and medulloblastoma.

Biallelic pathogenic variants in the essential DNA repair gene cause Fanconi anemia complementation group D1. Patients in this group are highly prone to develop embryonal tumors, most commonly medulloblastoma arising from the cerebellar granule cell progenitors (GCPs). GCPs undergo high proliferation in the postnatal cerebellum under Sonic Hedgehog (SHH) activation, but the type of DNA lesions that require the function of the BRCA2 to prevent tumorigenesis remains unknown.

Spatiotemporal profiling reveals the impact of caloric restriction in the aging mammalian brain.

Caloric restriction (CR) is a well-studied intervention that extends lifespan and slows cognitive decline across species, yet the specific cell populations and molecular pathways involved remain elusive. In this study, we profiled >500,000 cells from 36 control and CR mouse brains across three age groups with EasySci single-nucleus transcriptomics and performed imaging-free IRISeq spatial transcriptomics on twelve brain sections from CR and control aged mice. We thereby explored the impact of CR in >300 cellular states and 11 brain regions.

A non-catalytic role for RFC in PCNA-mediated processive DNA synthesis.

The ring-shaped sliding clamp PCNA enables DNA polymerases to perform processive DNA synthesis during replication and repair. The loading of PCNA onto DNA is catalyzed by the ATPase clamp loader RFC. Using a single-molecule platform to visualize the dynamic interplay between PCNA and RFC on DNA, we unexpectedly discovered that RFC continues to associate with PCNA after loading, contrary to the conventional view.

Inference of germinal center evolutionary dynamics via simulation-based deep learning.

B cells and the antibodies they produce are vital to health and survival, motivating research on the details of the mutational and evolutionary processes in the germinal centers (GCs) from which mature B cells arise. It is known that B cells with higher affinity for their cognate antigen (Ag) will, on average, tend to have more offspring. However the exact form of this relationship between affinity and fecundity, which we call the "affinity-fitness response function", is not known.

The challenge of chromatin model comparison and validation: A project from the first international 4D Nucleome Hackathon.

The computational modeling of chromatin structure is highly complex due to the hierarchical organization of chromatin, which reflects its diverse biophysical principles, as well as inherent dynamism, which underlies its complexity. Chromatin structure modeling can be based on diverse approaches and assumptions, making it essential to determine how different methods influence the modeling outcomes. We conducted a project at the NIH-funded 4D Nucleome Hackathon on March 18-21, 2024, at The University of Washington in Seattle, USA.

RNA-Seq dataset of wild type and PRC2 mutant mouse embryonic stem cells undergoing ground state conversion.

Mouse embryonic stem cells (mESCs) represent an exceptional model for understanding how transcriptional responses are regulated by signalling pathways during development. Treatment with a cocktail of MEK and GSK3β inhibitors ("2i") induces ground state pluripotency, characterized by increased self-renewal, reduced DNA methylation, and uniformly high expression of pluripotency markers. Polycomb Repressive Complex 2 (PRC2) is a key developmental regulator controlling stem cell self-renewal and differentiation decisions, and altered expression of PRC2 target genes is a signature of 2i-mediated ground state conversion.

Engineered bacteria launch and control an oncolytic virus.

The ability of bacteria and viruses to selectively replicate in tumours has led to synthetic engineering of new microbial therapies. Here we design a cooperative strategy whereby Salmonella typhimurium bacteria transcribe and deliver the Senecavirus A RNA genome inside host cells, launching a potent oncolytic viral infection. 'Encapsidated' by bacteria, the viral genome can further bypass circulating antiviral antibodies to reach the tumour and initiate replication and spread within immune mice.

The genome sequence of (Chiroptera, Phyllostomidae, Stenodermatinae; Olfers, 1818).

We present a genome assembly from an individual male (Chordata; Mammalia; Chiroptera; Phyllostomidae). The genome sequence is 2.15 in span.

Melanin-Concentrating Hormone (MCH): Role in Mediating Reward-Motivated and Emotional Behavior and the Behavioral Disturbances Produced by Repeated Exposure to Reward Substances.

Clinical and animal studies suggest that multiple brain systems are involved in mediating reward-motivated and related emotional behavior including the consumption of commonly used drugs and palatable food, and there is evidence that the repeated ingestion of or exposure to these rewarding substances may in turn stimulate these brain systems to produce an overconsumption of these substances along with co-occurring emotional disturbances. To understand this positive feedback loop, this review focuses on a specific population of hypothalamic peptide neurons expressing melanin-concentrating hormone (MCH), which are positively related to dopamine reward and project to forebrain areas that mediate this behavior. It also examines neurons expressing the peptide hypocretin/orexin (HCRT) that are anatomically and functionally linked to MCH neurons and the molecular systems within these peptide neurons that stimulate their development and ultimately affect behavior.

Brown adipose tissue machine learning nnU-Net V2 network using TriDFusion (3DF).

Background: Recent advances in machine learning have revolutionized medical imaging. Currently, identifying brown adipose tissue (BAT) relies on manual identification and segmentation on Fluorine- fluorodeoxyglucose positron emission tomography/computed tomography (F-FDG PET/CT) scans. However, the process is time-consuming, especially for studies involving a large number of cases, and is subject to bias due to observer dependency.

Clonal expansion and diversification of germinal center and memory B cell responses to booster immunization in primates.

Effective vaccines elicit B cell clonal expansion in germinal centers (GCs) that produce memory B cells and antibody-secreting plasma cells. In mice, memory B cells rarely re-enter GCs upon boosting and instead differentiate into plasma cells. However, mouse circulating memory constitutes only 1%-2% of B cells, compared to 30%-50% in primates.