Challenges, advances, and opportunities in RNA structural biology by Cryo-EM.

RNAs are remarkably versatile molecules that can fold into intricate three-dimensional (3D) structures to perform diverse cellular and viral functions. Despite their biological importance, relatively few RNA 3D structures have been solved, and our understanding of RNA structure-function relationships remains in its infancy. This limitation partly arises from challenges posed by RNA's complex conformational landscape, characterized by structural flexibility, formation of multiple states, and a propensity to misfold.

Constraints on anomalous Higgs boson couplings from its production and decay using the WW channel in proton-proton collisions at .

A study of the anomalous couplings of the Higgs boson to vector bosons, including -violation effects, has been conducted using its production and decay in the WW channel. This analysis is performed on proton-proton collision data collected with the CMS detector at the CERN LHC during 2016-2018 at a center-of-mass energy of 13 TeV, and corresponds to an integrated luminosity of 138 . The different-flavor dilepton final state is analyzed, with dedicated categories targeting gluon fusion, electroweak vector boson fusion, and associated production with a W or Z boson.

Glycosphingolipid synthesis mediates immune evasion in KRAS-driven cancer.

Cancer cells frequently alter their lipids to grow and adapt to their environment. Despite the critical functions of lipid metabolism in membrane physiology, signalling and energy production, how specific lipids contribute to tumorigenesis remains incompletely understood. Here, using functional genomics and lipidomic approaches, we identified de novo sphingolipid synthesis as an essential pathway for cancer immune evasion.

Kv1.1 channels help set the pace.

JGP study (Si et al. https://doi.org/10.

Bone controls browning of white adipose tissue and protects from diet-induced obesity through Schnurri-3-regulated SLIT2 secretion.

The skeleton has been suggested to function as an endocrine organ controlling whole organism energy balance, however the mediators of this effect and their molecular links remain unclear. Here, utilizing Schnurri-3 (Shn3) mice with augmented osteoblast activity, we show Shn3mice display resistance against diet-induced obesity and enhanced white adipose tissue (WAT) browning. Conditional deletion of Shn3 in osteoblasts but not adipocytes recapitulates lean phenotype of Shn3mice, indicating this phenotype is driven by skeleton.

The Ruminant Telomere-to-Telomere (RT2T) Consortium.

Telomere-to-telomere (T2T) assemblies reveal new insights into the structure and function of the previously 'invisible' parts of the genome and allow comparative analyses of complete genomes across entire clades. We present here an open collaborative effort, termed the 'Ruminant T2T Consortium' (RT2T), that aims to generate complete diploid assemblies for numerous species of the Artiodactyla suborder Ruminantia to examine chromosomal evolution in the context of natural selection and domestication of species used as livestock.

A Novel Case of IFNAR1 Deficiency Identified a Common Canonical Splice Site Variant in DOCK8 in Western Polynesia: The Importance of Validating Variants of Unknown Significance in Under-Represented Ancestries.

Advanced genomic technologies such as whole exome or whole genome sequencing have improved diagnoses and disease outcomes for individuals with genetic diseases. Yet, variants of unknown significance (VUS) require rigorous validation to establish disease causality or modification, or to exclude them from further analysis. Here, we describe a young individual of Polynesian ancestry who in the first 13 mo of life presented with SARS-CoV-2 pneumonia, severe enterovirus meningitis and adenovirus gastroenteritis, and severe adverse reaction to MMR vaccination.

A new generation of nanobody research tools using improved mass spectrometry-based discovery methods.

Single-domain antibodies ("nanobodies") derived from the variable region of camelid heavy-chain only antibody variants have proven to be widely useful tools for research, therapeutic, and diagnostic applications. In addition to traditional display techniques, methods to generate nanobodies using direct detection by mass spectrometry and DNA sequencing have been highly effective. However, certain technical challenges have limited widespread application.

Tumor necrosis factor alpha induces NOX2-dependent reactive oxygen species production in hypothalamic paraventricular nucleus neurons following angiotensin II infusion.

There is evidence that tumor necrosis factor alpha (TNFα) influences autonomic processes coordinated within the hypothalamic paraventricular nucleus (PVN), however, the signaling mechanisms subserving TNFα's actions in this brain area are unclear. In non-neuronal cell types, TNFα has been shown to play an important role in canonical NADPH oxidase (NOX2)-mediated production of reactive oxygen species (ROS), molecules also known to be critically involved in hypertension. However, little is known about the role of TNFα in NOX2-dependent ROS production in the PVN within the context of hypertension.

Enhanced Recognition of a Herbal Compound Epiberberine by a DNA Quadruplex-Duplex Structure.

The small molecule epiberberine (EPI) is a natural alkaloid with versatile bioactivities against several diseases including cancer and bacterial infection. EPI can induce the formation of a unique binding pocket at the 5' side of a human telomeric G-quadruplex (HTG) sequence with four telomeric repeats (Q4), resulting in a nanomolar binding affinity ( approximately 26 nM) with significant fluorescence enhancement upon binding. It is important to understand (1) how EPI binding affects HTG structural stability and (2) how enhanced EPI binding may be achieved through the engineering of the DNA binding pocket.

A reporter virus particle seroneutralization assay for tick-borne encephalitis virus overcomes ELISA limitations.

Tick-borne encephalitis (TBE) virus is the most prevalent tick-transmitted orthoflavivirus in Europe. Due to the nonspecific nature of its symptoms, TBE is primarily diagnosed by ELISA-based detection of specific antibodies in the patient serum. However, cross-reactivity between orthoflaviviruses complicates the diagnosis.

The Orphan G Protein-Coupled Receptor GPR52 is a Novel Regulator of Breast Cancer Multicellular Organization.

G protein-coupled receptors (GPCRs) are the largest class of membrane-bound receptors and transmit critical signals from the extracellular to the intracellular spaces. Transcriptomic data of resected breast tumors shows that low mRNA expression of the orphan GPCR GPR52 correlates with reduced overall survival in breast cancer patients, leading to the hypothesis that loss of GPR52 supports breast cancer progression. CRISPR-Cas9 was used to knockout GPR52 in human triple-negative breast cancer (TNBC) cell lines MDA-MB-468 and MDA-MB-231, and in the non-cancerous breast epithelial cell line, MCF10A.

G-quadruplexes are a source of vulnerability in deficient granule cell progenitors and medulloblastoma.

Biallelic pathogenic variants in the essential DNA repair gene causes Fanconi anemia, complementation group FA-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 SHH activation, but the type of DNA lesions that require the function of the BRCA2 to prevent tumorigenesis remains unknown.

De Novo Genes.

Although the majority of annotated new genes in a given genome appear to have arisen from duplication-related mechanisms, recent studies have shown that genes can also originate de novo from ancestrally nongenic sequences. Investigating de novo-originated genes offers rich opportunities to understand the origin and functions of new genes, their regulatory mechanisms, and the associated evolutionary processes. Such studies have uncovered unexpected and intriguing facets of gene origination, offering novel perspectives on the complexity of the genome and gene evolution.

Mechanism of PCNA loading by Ctf18-RFC for leading-strand DNA synthesis.

The proliferating cell nuclear antigen (PCNA) clamp encircles DNA to hold DNA polymerases (Pols) to DNA for processivity. The Ctf18-RFC PCNA loader, a replication factor C (RFC) variant, is specific to the leading-strand Pol (Polε). We reveal here the underlying mechanism of Ctf18-RFC specificity to Polε using cryo-electron microscopy and biochemical studies.

Dopamine biases decisions by limiting temporal integration.

Motivations bias our responses to stimuli, producing behavioural outcomes that match our needs and goals. Here we describe a mechanism behind this phenomenon: adjusting the time over which stimulus-derived information is permitted to accumulate towards a decision. As a Drosophila copulation progresses, the male becomes less likely to continue mating through challenges.

Multiplexed mapping of the interactome of GPCRs with receptor activity-modifying proteins.

Receptor activity-modifying proteins (RAMPs) form complexes with G protein-coupled receptors (GPCRs) and may regulate their cellular trafficking and pharmacology. RAMP interactions have been identified for about 50 GPCRs, but only a few GPCR-RAMP complexes have been studied in detail. To elucidate a comprehensive GPCR-RAMP interactome, we created a library of 215 dual epitope-tagged (DuET) GPCRs representing all GPCR subfamilies and coexpressed each GPCR with each of the three RAMPs.

Adult neurogenesis improves spatial information encoding in the mouse hippocampus.

Adult neurogenesis is a unique form of neuronal plasticity in which newly generated neurons are integrated into the adult dentate gyrus in a process that is modulated by environmental stimuli. Adult-born neurons can contribute to spatial memory, but it is unknown whether they alter neural representations of space in the hippocampus. Using in vivo two-photon calcium imaging, we find that male and female mice previously housed in an enriched environment, which triggers an increase in neurogenesis, have increased spatial information encoding in the dentate gyrus.

Ant social network structure is highly conserved across species.

The ecological success of social insects makes their colony organization fascinating to scientists studying collective systems. In recent years, the combination of automated behavioural tracking and social network analysis has deepened our understanding of many aspects of colony organization. However, because studies have typically worked with single species, we know little about interspecific variation in network structure.

Pharmacokinetics and pharmacodynamics of itepekimab in adults with moderate-to-severe atopic dermatitis: Results from two terminated phase II trials.

Interleukin-33 (IL-33) is a proinflammatory alarmin cytokine released by damaged epithelial tissue cells that initiates and amplifies both type 1 and type 2 inflammatory cascades. A role for IL-33 in atopic dermatitis (AD; a chronic, relapsing type 2 inflammatory disease of the skin) has been proposed. Itepekimab is a novel human IgG4P monoclonal antibody against IL-33, currently in clinical development for chronic obstructive pulmonary disease (COPD).

Observation of the ϒ(3S) Meson and Suppression of ϒ States in Pb-Pb Collisions at sqrt[s_{NN}]=5.02 TeV.

The production of ϒ(2S) and ϒ(3S) mesons in lead-lead (Pb-Pb) and proton-proton (pp) collisions is studied in their dimuon decay channel using the CMS detector at the LHC. The ϒ(3S) meson is observed for the first time in Pb-Pb collisions, with a significance above 5 standard deviations. The ratios of yields measured in Pb-Pb and pp collisions are reported for both the ϒ(2S) and ϒ(3S) mesons, as functions of transverse momentum and Pb-Pb collision centrality.

Gaps in the coordination of care for people living with dementia.

Background: One-third of people living with dementia (PLWD) have highly fragmented care (i.e., care spread across many ambulatory providers without a dominant provider).

Exclusive Characteristics of the p.E555K Dominant-Negative Variant in Autosomal Dominant E47 Deficiency.

Purpose: Transcription factor 3 (TCF3) encodes 2 transcription factors generated by alternative splicing, E12 and E47, which contribute to early lymphocyte differentiation. In humans, autosomal dominant (AD) E47 transcription factor deficiency is an inborn error of immunity characterized by B-cell deficiency and agammaglobulinemia. Only the recurrent de novo p.

Search for and production in the final state using proton-proton collisions at .

A search for and production in the final state is presented, where H is the standard model (SM) Higgs boson. The search uses an event sample of proton-proton collisions corresponding to an integrated luminosity of 133 collected at a center-of-mass energy of 13 with the CMS detector at the CERN LHC. The analysis introduces several novel techniques for deriving and validating a multi-dimensional background model based on control samples in data.