Development of a TSR-based method for understanding structural relationships of cofactors and local environments in photosystem I.

Background: All chemical forms of energy and oxygen on Earth are generated via photosynthesis where light energy is converted into redox energy by two photosystems (PS I and PS II). There is an increasing number of PS I 3D structures deposited in the Protein Data Bank (PDB). The Triangular Spatial Relationship (TSR)-based algorithm converts 3D structures into integers (TSR keys).

Personalised estimation of exposure to ambient air pollution and application in a longitudinal cohort analysis of cognitive function in London-dwelling older adults.

Background: Accurate estimates of personal exposure to ambient air pollution are difficult to obtain and epidemiological studies generally rely on residence-based estimates, averaged spatially and temporally, derived from monitoring networks or models. Few epidemiological studies have compared the associated health effects of personal exposure and residence-based estimates.

Objective: To evaluate the association between exposure to air pollution and cognitive function using exposure estimates taking mobility and location into account.

Multiplex genome editing eliminates lactate production without impacting growth rate in mammalian cells.

The Warburg effect, which describes the fermentation of glucose to lactate even in the presence of oxygen, is ubiquitous in proliferative mammalian cells, including cancer cells, but poses challenges for biopharmaceutical production as lactate accumulation inhibits cell growth and protein production. Previous efforts to eliminate lactate production in cells for bioprocessing have failed as lactate dehydrogenase is essential for cell growth. Here, we effectively eliminate lactate production in Chinese hamster ovary and in the human embryonic kidney cell line HEK293 by simultaneous knockout of lactate dehydrogenases and pyruvate dehydrogenase kinases, thereby removing a negative feedback loop that typically inhibits pyruvate conversion to acetyl-CoA.

A phase I study of the CDK4/6 inhibitor ribociclib combined with gemcitabine in patients with advanced solid tumors.

Background: Based on preclinical data showing addition of CDK4/6 inhibitors to gemcitabine was synergistic, ribociclib was evaluated in combination with gemcitabine to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT).

Methods: In this single arm multicohort phase I trial, we evaluated the safety and efficacy of ribociclib plus gemcitabine in patients with advanced solid tumors. Patients received gemcitabine intravenously on days 1 and 8 followed by ribociclib days 8-14, with treatment repeated every 3 weeks.

Evolutionary plasticity and functional repurposing of the essential metabolic enzyme MoeA.

MoeA, also known as gephyrin in higher eukaryotes, is an enzyme essential for molybdenum cofactor (Moco) biosynthesis and involved in GABA and GlyR receptor clustering at the synapse in animals. We recently discovered that Actinobacteria have a repurposed version of MoeA (Glp) linked to bacterial cell division. Since MoeA exists in all domains of life, our study explores how it gained multifunctionality over time.

Stable centromere association of the yeast histone variant Cse4 requires its essential N-terminal domain.

Chromosome segregation relies on kinetochores that assemble on specialized centromeric chromatin containing a histone H3 variant. In budding yeast, a single centromeric nucleosome containing Cse4 assembles at a sequence-defined 125 bp centromere. Yeast centromeric sequences are poor templates for nucleosome formation in vitro, suggesting the existence of mechanisms that specifically stabilize Cse4 nucleosomes in vivo.

Structure of transmembrane AMPA receptor regulatory protein subunit γ2.

Transmembrane AMPA receptor regulatory proteins (TARPs) are claudin-like proteins that tightly regulate AMPA receptors (AMPARs) and are fundamental for excitatory neurotransmission. With cryo-electron microscopy (cryo-EM) we reconstruct the 36 kDa TARP subunit γ2 to 2.3 Å, which points to structural diversity among TARPs.

Enabling next-generation engineered TCR-T therapies based on high-throughput TCR discovery from diagnostic tumor biopsies.

Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) can mediate tumor regression, including complete and durable responses, in a range of solid cancers, most notably in melanoma. However, its wider application and efficacy has been restricted by the limited accessibility, proliferative capacity and effector function of tumor-specific TIL. Here, we develop a platform for the efficient identification of tumor-specific TCR genes from diagnostic tumor biopsies, including core-needle biopsies frozen in a non-viable format, to enable engineered T cell therapy.

Intelligent in-cell electrophysiology: Reconstructing intracellular action potentials using a physics-informed deep learning model trained on nanoelectrode array recordings.

Intracellular electrophysiology is essential in neuroscience, cardiology, and pharmacology for studying cells' electrical properties. Traditional methods like patch-clamp are precise but low-throughput and invasive. Nanoelectrode Arrays (NEAs) offer a promising alternative by enabling simultaneous intracellular and extracellular action potential (iAP and eAP) recordings with high throughput.

Factors Associated With Prolonged Venous Transit in Large Vessel Occlusion Acute Ischemic Strokes.

Background And Purpose: Prolonged venous transit (PVT), derived from computed tomography perfusion (CTP) time-to-maximum (T) maps, reflects compromised venous outflow (VO) in acute ischemic stroke due to large vessel occlusion (AIS-LVO). Poor VO is associated with worse clinical outcomes, but pre-treatment markers predictive of PVT are not well described.

Methods: We conducted a retrospective analysis of 189 patients with anterior circulation AIS-LVO who underwent baseline CT evaluation, including non-contrast CT, CT angiography, and CTP.

Static and dynamic connectivity structure of white-matter functional networks across the adult lifespan.

Aging of the human brain involves intricate biological processes, resulting in complex changes in structure and function. While the effects of aging on gray matter (GM) connectivity are extensively studied, white matter (WM) functional changes have received comparatively less attention. This study examines age-related WM functional dynamics using resting-state fMRI across the adult lifespan.

Characterizing the microstructural transition at the gray matter-white matter interface: Implementation and demonstration of age-associated differences.

Background: The cortical gray matter-white matter interface (GWI) is a natural transition zone where the composition of brain tissue abruptly changes and is a location for pathologic change in brain disorders. While diffusion magnetic resonance imaging (dMRI) is a reliable and well-established technique to characterize brain microstructure, the GWI is difficult to assess with dMRI due to partial volume effects and is normally excluded from such studies.

Methods: In this study, we introduce an approach to characterize the dMRI microstructural profile across the GWI and to assess the sharpness of the microstructural transition from cortical gray matter (GM) to white matter (WM).

Stepwise order in protein complex assembly: approaches and emerging themes.

Protein-based nanomachines drive every cellular process. An explosion of high-resolution structures of multiprotein complexes has improved our understanding of what these machines look like and how they work, but we still know relatively little about how they assemble in living cells. For example, it has only recently been appreciated that many complexes assemble co-translationally, with at least one subunit still undergoing active translation while already interacting with other subunits.

Gut microbial GABA imbalance emerges as a metabolic signature in mild autism spectrum disorder linked to overrepresented Escherichia.

Gut microbiota (GM) alterations have been implicated in autism spectrum disorder (ASD), yet the specific functional architecture remains elusive. Here, employing multi-omics approaches, we investigate stool samples from two distinct cohorts comprising 203 children with mild ASD or typical development. In our screening cohort, regression-based analysis for metabolomic profiling identifies an elevated γ-aminobutyric acid (GABA) to glutamate (Glu) ratio as a metabolic signature of ASD, independent of age and gender.

Gut microbiota and short-chain fatty acids signatures in postmenopausal osteoporosis patients: A retrospective study.

Studies have shown that gut microbiota (GM) and its metabolites, short-chain fatty acids (SCFAs), are associated with the development of postmenopausal osteoporosis (PMO). This study explored the clinical and laboratory evidence of the relationship of GM and SCFAs to PMO and attempted to determine the potential mechanism of action. 18 patients (Collected from the First Affiliated Hospital of Guangdong Pharmaceutical University between January 2021 and August 2021) were included in this retrospective study, including 10 PMO women and 8 healthy young women as the healthy control (HC) group from Guangzhou, China.

Rhythmic Exercises Before Basketball Training: A Study on Motor Skills, Static Balance, and Reaction Speed in School-Aged Children.

Racil, G, Padulo, J, Trabelsi, Y, Frizziero, A, Russo, L, and Migliaccio, GM. Rhythmic exercises before basketball training: A study on motor skills, static balance, and reaction speed in school-aged children. J Strength Cond Res 38(12): e761-e768, 2024-The aim of this study was to investigate the effects of combining rhythmic exercises with basketball training on the improvement of basic motor and physical skills in children.

Glyphosate exposure and GM seed rollout unequally reduced perinatal health.

The advent of herbicide-tolerant genetically modified (GM) crops spurred rapid and widespread use of the herbicide glyphosate throughout US agriculture. In the two decades following GM-seeds' introduction, the volume of glyphosate applied in the United States increased by more than 750%. Despite this breadth and scale, science and policy remain unresolved regarding the effects of glyphosate on human health.

ClaPEPCK4: target gene for breeding innovative watermelon germplasm with low malic acid and high sweetness.

Malic acid markedly affects watermelon flavor. Reducing the malic acid content can significantly increase the sweetness of watermelon. An effective solution strategy is to reduce watermelon malic acid content through molecular breeding technology.

A study on the variation of cytokine and electrolyte levels in rhesus macaques, cynomolgus monkeys, and Assamese macaques.

Background: Non-human primates (NPHs), such as rhesus macaques, cynomolgus monkeys, and Assamese macaques, play a crucial role in biomedical research. However, baseline cytokine and electrolyte data for these three species, particularly data stratified by age and sex, are limited. Therefore, the aim of this study was to establish and analyze age- and sex-specific cytokine and electrolyte profiles in these three species.

Phase I Dose Volume Escalation of Rectally Administered PC-1005 to Assess Safety, Pharmacokinetics, and Antiviral Pharmacodynamics as a Multipurpose Prevention Technology (MTN-037).

Background: On demand, topical PrEP is desired by those preferring episodic, nonsystemic PrEP. PC-1005 gel (MIV-150, zinc, and carrageenan) exhibits in vitro antiviral HIV-1, human papillomavirus (HPV), and herpes simplex virus type 2 (HSV-2) activity, attractive for a multipurpose prevention technology candidate. We evaluated the safety, pharmacokinetics, and antiviral effect of rectally applied PC-1005.

A deoxyfluoroalkylation-aromatization strategy to access fluoroalkyl arenes.

Fluoroalkyl arenes (Ar-R) are valuable substructures present in several FDA-approved drugs, patents, agrochemicals, and materials, and complementary strategies that enable access to a broad spectrum of Ar-R compounds benefit these applied fields. Herein, we report a deoxyfluoroalkylation-aromatization strategy to convert cyclohexanones into broad-spectrum Ar-R containing compounds. Generally, the fluoroalkyl sources were activated to participate in a 1,2-addition reaction followed by aromatization in a sequence that contrasts more common preparations of these Ar-R compounds, such as (i) transition-metal catalyzed cross-coupling reactions of aryl electrophiles and nucleophiles, and (ii) radical fluoroalkylation reactions of C-H bonds of arenes.

Serendipitous Discovery of Dearomatized Dimers in Anthracene Derivative Oxidation.

We present the serendipitous discovery of an unusual dimer formed from anthracene-derived polyarenes. Unlike the typical oxidative coupling of substituted aromatic scaffolds, the reaction yielded a dearomatized enone dimer as the sole product. This dearomatized motif, notably, does not undergo the commonly observed rearomatization, and no biaryl products were detected.

Discovery of Peptidic Siderophore Degradation by Screening Natural Product Profiles in Marine-Derived Bacterial Mono- and Cocultures.

Coral reefs are hotspots of marine biodiversity, which results in the synthesis of a wide variety of compounds with unique molecular scaffolds, and bioactivities, rendering reefs an ecosystem of interest. The chemodiversity stems from the intricate relationships between inhabitants of the reef, as the chemistry produced partakes in intra- and interspecies communication, settlement, nutrient acquisition, and defense. However, the coral reefs are declining at an unprecedented rate due to climate change, pollution, and increased incidence of pathogenic diseases.

Molecular dynamics model of mechanophore sensors for biological force measurement.

Cellular forces regulate an untold spectrum of living processes, such as cell migration, gene expression, and ion conduction. However, a quantitative description of mechanical control remains elusive due to the lack of general, live-cell tools to measure discrete forces between biomolecules. Here we introduce a computational pipeline for force measurement that leverages well-defined, tunable release of a mechanically activated small molecule fluorophore.