Structural serology of polyclonal antibody responses to mRNA-1273 and NVX-CoV2373 COVID-19 vaccines.

Current COVID-19 vaccines are largely limited in their ability to induce broad, durable immunity against emerging viral variants. Design and development of improved vaccines utilizing existing platforms requires an in-depth understanding of the antigenic and immunogenic properties of available vaccines. Here we examined the antigenicity of two of the original COVID-19 vaccines, mRNA-1273 and NVX-CoV2373, by electron microscopy-based polyclonal epitope mapping (EMPEM) of serum from immunized non-human primates (NHPs) and clinical trial donors.

Experimental and computational investigations of RNA duplexes containing N7-regioisomers of adenosine and LNA-adenosine.

Although glycosidic bonds in purines typically involve the N9 position, the chemical synthesis of adenosine produces N7-ribofuranosyladenine (7A) as a kinetically favorable ribosylation product. Similarly, in the synthesis of LNA-adenosine (AL), a minor product, N7-LNA-adenosine (7AL), is observed. While extensive research has focused on investigating the properties of N9-regioisomers of adenosine, 7A has been largely overlooked and considered as a side-product.

The International Bathymetric Chart of the Arctic Ocean Version 5.0.

Knowledge about seafloor depth, or bathymetry, is crucial for various marine activities, including scientific research, offshore industry, safety of navigation, and ocean exploration. Mapping the central Arctic Ocean is challenging due to the presence of perennial sea ice, which limits data collection to icebreakers, submarines, and drifting ice stations. The International Bathymetric Chart of the Arctic Ocean (IBCAO) was initiated in 1997 with the goal of updating the Arctic Ocean bathymetric portrayal.

Exploring the pathways between depression, anxiety, stress, and quality of life on life satisfaction: a path analysis approach.

Background: Life satisfaction, one promising health asset, is associated with reduced risk of several chronic diseases and mortality. Mental health conditions and quality of life (QoL) are important aspects of well-being in late life and are significantly associated with life satisfaction. Despite the complex interrelationships between mental health, QoL and life satisfaction, the current literature has evaluated the simple association between them and failed to consider the complex pathways among these variables, especially among the older population.

Maternal separation stress increases alcohol preference regardless of DNA methylation and histone acetylation or methylation in the amygdala.

Alcohol use disorder (AUD) is a condition with multifactorial causes, including biopsychosocial factors. Childhood exposure to stress may increase susceptibility to AUD in adulthood. Despite its significance, the interaction between stress and AUD remains unclear.

Dulce Digital-Me: results of a randomized comparative trial of static versus adaptive digital interventions for Latine adults with diabetes.

Objective: To compare the effectiveness of a static, text-based diabetes education and support intervention (Dulce Digital, DD) versus a dynamic approach with personalized feedback and goal setting (Dulce Digital-Me, DD-Me) in improving diabetes outcomes.

Design And Methods: Comparative effectiveness trial in 310 Latine adults with poorly managed type 2 diabetes in a Federally Qualified Health Center in Southern California, randomized to DD, DD-Me-Auto (algorithm-driven text-based personalized feedback), or DD-Me-Tel (coach delivered personalized feedback). Changes in HbA1c (primary outcome), low-density lipoprotein-cholesterol, systolic blood pressure, and patient-reported outcomes were examined across 6 and 12 months, with the primary comparison being DD versus DD-Me (combined automated and telephonic).

Impact of Bindarit, a CCL2 Chemokine Synthesis Inhibitor, on Macrophage-Based Biofouling and Continuous Glucose Monitoring .

Continuous glucose monitoring (CGM) using implantable glucose sensors is a critical tool in the management of diabetes. Unfortunately, current commercial glucose sensors have limited performance and lifespans , considered to be due to sensor-induced tissue reactions (inflammation, fibrosis, and vessel regression). Previously, our laboratory utilized monocyte/macrophage (Mo/MQ) deficient and depleted mice to establish a causal relationship between Mo/MQ accumulation and inflammation in glucose sensor performance .

Absorption, single-dose and steady-state metabolism, excretion, and pharmacokinetics of adagrasib, a KRAS inhibitor.

Objective: This study investigated absorption, metabolism, and excretion of adagrasib after a single oral 600 mg dose (1 µCi [C]-adagrasib) in 7 healthy subjects and compared the metabolite profile to the profile at steady-state in 4 patients dosed at 600 mg twice daily.

Methods: Plasma, urine, and feces were collected post [C]-adagrasib administration and total radioactivity and pooled sample metabolite profiles were determined. Adagrasib pharmacokinetics were determined in plasma and urine.

Structures, mechanisms, and kinetic advantages of the SgrAI filament forming mechanism.

This review documents investigations leading to the unprecedented discovery of filamentation as a mode of enzyme regulation in the type II restriction endonuclease SgrAI. Filamentation is defined here as linear or helical polymerization of a single enzyme as occurs for SgrAI, and has now been shown to occur in many other enzyme systems, including conserved metabolic enzymes. In the case of SgrAI, filamentation activates the DNA cleavage rate by up to 1000-fold and also alters the enzyme's DNA sequence specificity.

Two decades of three-dimensional movement data from adult female northern elephant seals.

Northern elephant seals (Mirounga angustirostris) have been integral to the development and progress of biologging technology and movement data analysis, which continue to improve our understanding of this and other species. Adult female elephant seals at Año Nuevo Reserve and other colonies along the west coast of North America were tracked annually from 2004 to 2020, resulting in a total of 653 instrument deployments. This paper outlines the compilation and curation process of these high-resolution diving and location data, now accessible in two Dryad repositories.

An acidic microenvironment produced by the V-type ATPase of Euprymna scolopes promotes specificity during Vibrio fischeri recruitment.

Animals often acquire their microbial symbionts from the environment, but the mechanisms underlying how specificity of the association is achieved are poorly understood. We demonstrate that the conserved proton pump, V-type ATPase (VHA), plays a key role in the establishment of the model light-organ symbiosis between the squid Euprymna scolopes and its bacterial partner, Vibrio fischeri. Recruitment of V.

Association between cardiovascular health and perceived quality of life in ethnically diverse adults: insights from the Community of Mine study using the American Heart Association's Life's Simple 7.

Purpose: The association between cardiovascular health (CVH) with perceived quality of life (PQoL) and variations by sex and Hispanic ethnicity is not well understood.

Methods: This study included 583 participants (42% Hispanic, 56% female, mean age 59 years). Linear regression modeled the covariate-adjusted associations between CVH, using the combined 7 components of Life's Simple 7 (LS7; ideal and intermediate, compared to poor), and PQoL (total and physical, social, and cognitive health domains).

Trends in Sudden Cardiac Death Among Adults Aged 25 to 44 Years in the United States: An Analysis of 2 Large US Databases.

Background: Sudden cardiac death (SCD) in early adults aged 25 to 44 years represents an important and unexpected cause of death. We assessed trends in SCD-related mortality in the United States from 1999 to 2020 among early adults to determine differences by sex, ethnoracial groups, urbanization, and census region.

Methods And Results: Mortality data were retrieved from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) data set from 1999 to 2020.

Exploiting the DCAF16-SPIN4 interaction to identify DCAF16 ligands for PROTAC development.

Traditional small molecule drugs often target protein activity directly, but challenges arise when proteins lack suitable functional sites. An alternative approach is targeted protein degradation (TPD), which directs proteins to cellular machinery for proteolytic degradation. Recent studies have identified additional E3 ligases suitable for TPD, expanding the potential of this approach.

IP6, PF74 affect HIV-1 capsid stability through modulation of hexamer-hexamer tilt angle preference.

The HIV-1 capsid is an irregularly shaped protein complex containing the viral genome and several proteins needed for integration into the host cell genome. Small molecules, such as the drug-like compound PF-3450074 (PF74) and the anionic sugar inositolhexakisphosphate (IP6), are known to impact capsid stability, although the mechanisms through which they do so remain unknown. In this study, we employed atomistic molecular dynamics simulations to study the impact of molecules bound to hexamers at the central pore (IP6) and the FG-binding site (PF74) on the interface between capsid oligomers.

Contrasteric Glycosylations of Cotylenol and 1,2-Diols by Virtual Linker Selection.

Many terpene glycosides exhibit contrasteric patterns of 1,2-diol glycosylation in which the more hindered alcohol bears a sugar; protection of the less hindered alcohol only increases steric repulsion. Here, we report a method for contrasteric glycosylation using a new sugar-linker that forms a cleavable, 10-membered ring with high efficiency, leading to syntheses of cotylenin E, J, and ISIR-050. Linker selection was aided by DFT calculations of side reactions and stereoselectivity, as well as conformational analyses using autoDFT, a Python script that converts SMILES strings to DFT-optimized conformational ensembles.

Palladium Bisphosphine Monoxide Complexes: Synthesis, Scope, Mechanism, and Catalytic Relevance.

Recent studies in transition metal catalysis employing chelating phosphines have suggested a role for partial ligand oxidation in formation of the catalytically active species, with potentially widespread relevance in a number of catalytic systems. We examine the internal redox reaction of Pd(bisphosphine)X (X = Cl, OAc, ) complexes to reveal previously underexplored aspects of bisphosphine monoxides (BPMOs), including evaluation of ligand structure and development of general reaction conditions to access a collection of structurally diverse BPMO precatalysts based on organopalladium oxidative addition complexes. In particular, a series of Pd(BPMO)(R)(X) (R = aryl, alkyl; X = I, Br) oxidative addition complexes bearing 24 different BPMO ligands were characterized by NMR and X-ray crystallography.

Genomic and transmission dynamics of the 2024 Marburg virus outbreak in Rwanda.

The ongoing outbreak of Marburg virus disease in Rwanda marks the third largest historically, although it has shown the lowest fatality rate. Genomic analysis of samples from 18 cases identified a lineage with limited internal diversity, closely related to a 2014 Ugandan case. Our findings suggest that the Rwandan lineage diverged decades ago from a common ancestor shared with diversity sampled from bats in Uganda.

Guardians at the Gate: Optimization of Small Molecule Entry Inhibitors of Ebola and Marburg Viruses.

Ebola and Marburg (EBOV and MARV) filoviral infections lead to fatal hemorrhagic fevers and have caused over 30 outbreaks in the last 50 years. Currently, there are no FDA-approved small molecule therapeutics for effectively treating filoviral diseases. To address this unmet medical need, we have conducted a systematic structural optimization of an early lead compound, -(4-(4-methylpiperidin-1-yl)-3-(trifluoromethyl)phenyl)-4-(morpholinomethyl)benzamide (), borne from our previously reported hit-to-lead effort.

Structural basis for gene silencing by siRNAs in humans.

Small interfering RNAs (siRNAs) guide mRNA cleavage by human Argonaute2 (hAgo2), leading to targeted gene silencing. Despite their laboratory and clinical impact, structural insights into human siRNA catalytic activity remain elusive. Here, we show that disrupting siRNA 3'-end binding by hAgo2 accelerates target cleavage and stabilizes its catalytic conformation, enabling detailed structural analysis.

Modulation of antigen delivery and lymph node activation in nonhuman primates by saponin adjuvant saponin/monophosphoryl lipid A nanoparticle.

Saponin-based vaccine adjuvants are potent in preclinical animal models and humans, but their mechanisms of action remain poorly understood. Here, using a stabilized HIV envelope trimer immunogen, we carried out studies in nonhuman primates (NHPs) comparing the most common clinical adjuvant aluminum hydroxide (alum) with saponin/monophosphoryl lipid A nanoparticles (SMNP), an immune-stimulating complex-like adjuvant. SMNP elicited substantially stronger humoral immune responses than alum, including 7-fold higher peak antigen-specific germinal center B-cell responses, 18-fold higher autologous neutralizing antibody titers, and higher levels of antigen-specific plasma and memory B cells.

Distinct autoregulatory roles of ELFN1 intracellular and extracellular domains on membrane trafficking, synaptic localization, and dimerization.

Synaptic adhesion molecules are essential components of the synapse, yet the diversity of these molecules and their associated functions remain to be fully characterized. Extracellular leucine rich repeat and fibronectin type III domain containing 1 (ELFN1) is a postsynaptic adhesion molecule in the brain that has been increasingly implicated in human neurological disease. ELFN1 is best known for trans-synaptically modulating group III metabotropic glutamate receptors (mGluRs).

Aspirin modulates generation of procoagulant phospholipids in cardiovascular disease, by regulating LPCAT3.

Enzymatically oxygenated phospholipids (eoxPL) from lipoxygenases (LOX) or cyclooxygenase (COX) are prothrombotic. Their generation in arterial disease, and their modulation by cardiovascular therapies is unknown. Furthermore, the Lands cycle acyl-transferases that catalyze their formation are unidentified.

The RodentGPOmics Atlas: a comprehensive database of rodent biology for genomes and pathogens.

Rodents represent the most abundant order of mammals, exhibiting remarkable diversity in morphology, habitats, behaviors, and hosted pathogens. Significant attention is currently focused on rodents as experimental animals for biomedical research. However, numerous aspects of rodents remain unexplored, such as their potential in unconventional biomedical models, molecular underpinnings of intriguing complex phenotypes, adaptations to environment or climate change, and host-pathogen interactions and arms race evolution.