3‑Hydroxy-Beta-Lactam Inhibitors of Dihydrofolate Synthetase.

The 3-hydroxy-β-lactam (3-HβL) group derived from the natural product tabtoxinine-β-lactam (TβL), an inhibitor of glutamine synthetase, was repurposed to develop an inhibitor of dihydrofolate synthetase (DHFS). We show that replacement of the carboxyl group of -amino-benzoic acid (PABA) with a 3-HβL moiety on the chemical scaffold of a folate mimic results in a potent inhibitor of DHFS. Using a combination of steady-state kinetics, enzyme-coupled assays, and molecular modeling, we validate the essential role of the 3-HβL group in DHFS inhibition.

Monolithically-Integrated van der Waals Synaptic Memory via Bulk Nano-Crystallization.

Owing to the evolution of data-driven technologies, including the large language models, generative artificial intelligence, autonomous driving, and the internet of things requires advanced memory technology. However, conventional memory device structures and fabrication process have significant limitations for high-density integration. Herein, this study reports the monolithically-integrated 1-selector and 1-resistive (1S1R) synaptic memory in van der Waals (vdW) heterostructure, which overcomes the conventional limitations of device integration technologies.

Dominant negative ATP5F1A variants disrupt oxidative phosphorylation causing neurological disorders.

ATP5F1A encodes the α-subunit of complex V of the respiratory chain, which is responsible for mitochondrial ATP synthesis. We describe 6 probands with heterozygous de novo missense ATP5F1A variants that presented with developmental delay, intellectual disability, and movement disorders. All variants were located at the contact points between the α- and β-subunits.

Adaptation invariant concentration discrimination in an insect olfactory system.

Neural responses evoked by a stimulus reduce upon repetition. While this adaptation allows the sensory system to attend to novel cues, does information about the recurring stimulus, particularly its intensity, get compromised? We explored this issue in the locust olfactory system. We found that locusts' innate behavioral response to odorants varied with repetition and stimulus intensity.

Single-neuron datasets for linguistic and semantic processing in the human amygdala and hippocampus.

Understanding linguistic and semantic processing in the human brain involves exploring intricate neural networks. However, it remains unclear whether and how the amygdala and hippocampus are involved in these processes. Here, we recorded single-neuron activity from the human amygdala and hippocampus while neurosurgical patients with intractable epilepsy performed various language tasks.

Proactive control declines while reactive control is preserved across the adult lifespan.

We provide a comprehensive investigation of proactive and reactive control during Stroop task performance with younger, middle-aged, and older adults to test predictions of the dual mechanisms of control framework. A novel color-word vocal response paradigm was utilized with separate proactive, baseline, and reactive conditions, which differed in list-wide and item-specific proportion congruencies, along with matched and randomly alternating color naming and word reading blocks. When compared to baseline, the proactive condition indexes processes that actively maintain goal-relevant information during contexts in which distraction is expected, while the reactive condition indexes dynamic adjustment processes engaged when items associated with high cognitive control demands are unpredictably encountered.

ACLY promotes NK cell effector function by regulating glycolysis and histone acetylation.

Natural killer (NK) cells are innate immune lymphocytes important for host viral and tumor immunity. We investigated the requirement for ATP citrate lyase (ACLY) in NK cell function using an inducible genetic mouse model. ACLY regulates the citrate-malate shuttle, generating cytosolic acetyl-coenzyme A that is primarily used for acetylation or lipid synthesis.

Discontinuation of treatment for alcohol use disorder during pregnancy and postpartum in the United States.

Background: The degree of alcohol use disorder (AUD) treatment utilization during the perinatal period is unknown. We report the prevalence of preconception receipt of medications for AUD (MAUD) and psychosocial interventions (PSY), discontinuation during pregnancy, and postpartum resumption in a multi-state sample, comparing pregnant and nonpregnant people with AUD.

Methods: Using MarketScan combined commercial and Medicaid claims (2016-2019), we identified individuals with AUD who had continuous insurance coverage throughout pregnancy, classifying those with a live birth as pregnant, and compared their MAUD and PSY patterns to nonpregnant peers matched by age, insurance type, and calendar time.

Fascicular Elastin Impacts Tendon-Specific Ramp-to-Failure and Fatigue Mechanics.

Fascicular elastic fibers have recently been shown to play a significant role in tendon mechanics despite relatively low abundance, leading to increased linear modulus in ramp to failure mechanical testing with elastin knockdown. Despite elastin providing fatigue and recoil properties in a variety of tissues such as vasculature and lungs, its role in tendon fatigue mechanics is largely unknown. Therefore, this study validated and leveraged a novel murine model of local elastin knockout in the limbs (Prx1Cre+;Elnfl/fl) to study the impacts of elastin on tendon stress relaxation, ramp to failure, and fatigue mechanics for functionally distinct Achilles tendons (ATs) and tibialis anterior tendons (TBs).

Oxidative Addition of Aryl Bromides at Palladium(I) to form Palladium(III) Complexes.

Herein, we report the first systematic study of the oxidative addition of aryl bromides to a Pd center to generate organometallic Pd complexes. These isolable Pd complexes stabilized by tetradentate macrocyclic pyridinophane ligands exhibit distinct UV-vis and EPR spectroscopic signatures that allowed for the monitoring of their generation in situ. These ligand scaffolds were sterically and electronically tuned using a modular synthetic approach to probe the kinetic properties and activation parameters of the oxidative addition reaction, and a combination of UV-vis and cryo stopped-flow spectroscopic studies reveal a rapid oxidative addition step occurring at a Pd center.

An unbiased proteomic platform for ATE1-based arginylation profiling.

Protein arginylation is an essential post-translational modification catalyzed by arginyl-tRNA-protein transferase 1 (ATE1) in mammalian systems. Arginylation features a post-translational conjugation of an arginyl to a protein, making it extremely challenging to differentiate from translational arginine residues with the same mass. Here we present a general ATE1-based arginylation profiling platform for the unbiased discovery of arginylation substrates and their precise modification sites.

CeRTS: certainty retrieval token search in large language model clinical information extraction.

Objective: Large language models (LLMs) must effectively communicate their uncertainty to be viable in clinical settings. As such, the need for reliable uncertainty estimation grows increasingly urgent with the expanding use of LLMs for information extraction from electronic health records. Previous token-level uncertainty estimators have only used token probabilities within a single output sequence.

Patterns of maternal and child health services utilization and associated socioeconomic disparities in sub-Saharan Africa.

Under-five mortality remains a global health issue, especially in sub-Saharan Africa, where preventable conditions largely drive the high mortality rates. Understanding the heterogeneity in utilization of reproductive, maternal, newborn, and child health services is crucial for reducing under-five mortality. Here we show that among 9307 under-five mortality cases across 31 sub-Saharan African countries (2014-2024), maternal and child health service utilization falls into three distinct patterns-lowest, medium, and highest.

Ms4a4a deficiency ameliorates plaque pathology in a mouse model of amyloid accumulation.

Introduction: Genome-wide association studies have identified MS4A4A, a microglia-enriched gene, as a modulator of Alzheimer's disease (AD) risk. Common variants in MS4A4A affect AD susceptibility, gene expression, triggering receptor expressed on myeloid cells 2 (TREM2) signaling, and microglial transcriptional states, but the gene's functional role remains unclear.

Methods: Using a novel model, we investigated the impact of Ms4a4a loss in the 5xFAD mouse model of amyloid beta (Aβ) accumulation.

The construct validity of daily cognitive variability.

Cognition is a dynamic process and is subject to substantial variation across short and long timescales. It is becoming common to assess cognition repeatedly over short intervals to determine the correlates and consequences of such "cognitive variability." A high-frequency cognitive assessment approach is also an ideal method for measuring how cognition operates in daily life.

Circulating tumor cells dynamics after CDK4/6 inhibitor for hormone-receptor positive metastatic breast cancer: a biomarker analysis from the PACE phase II study.

Purpose: Circulating tumor cells (CTCs) are biomarkers associated with poor prognosis and treatment resistance in hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (MBC). This analysis evaluates the prognostic role of baseline CTC enumeration and its interaction with treatment regimens in patients progressing on CDK4/6 inhibitors.

Experimental Design: The PACE trial is a phase II, multicenter, randomized study of HR+/HER2- MBC patients experiencing progression on aromatase inhibitors (AI) and CDK4/6 inhibitors.

Clinically significant improvement in health-related quality of life (EQ-5D-5 L) after endoscopic spine surgery.

Purpose: This study aims to define the minimal clinically important difference (MCID) and substantial clinical benefit (SCB) for EQ-5D-5 L and identify factors associated with clinical benefit achievement after Full Endoscopic Spine Surgery (FESS).

Methods: This is a retrospective analysis of a multicentric prospective study that included adults who underwent FESS for lumbar degenerative spine disease. Patients were monitored postoperatively via a smartphone application, PROMs including EQ-5D-5 L and Oswestry Disability Index (ODI), were collected preoperatively and one-year postoperatively.

Chain Formation and Addition Drive the Debye Relaxation of Methanol.

The Debye relaxation in alcohols has generally been attributed to "collective motion" driven by hydrogen bonding, but the molecular mechanism of relaxation has yet to be conclusively identified. Taking methanol as a model alcohol, we apply an oscillating electric field in molecular dynamics simulations to directly evaluate the molecular motions and identify the mechanism. Methanol forms short-lived chains of hydrogen-bonded molecules through the hydroxyl group.

Interrater Reliability of Pediatric Respiratory Auscultation Findings.

Objective: To evaluate the interrater reliability of pediatric auscultatory findings as assessed by pediatric emergency medicine (PEM) physicians.

Methods: We conducted a multicenter survey of physicians in 6 academic PEM divisions in the United States. Respondents listened to 15 audio clips of pediatric auscultatory sounds and classified them as normal or as having 1 or more adventitious sounds.

Rheumatologic and Autoimmune Features of Inborn Errors of Immunity: Implications for Diagnosis and Management.

Inborn errors of immunity (IEI) are monogenic disorders of the immune system that frequently present with autoimmunity or autoinflammation, necessitating multi-specialty care. In many cases, patients may present for rheumatologic evaluation prior to a genetic diagnosis, highlighting the need for recognition of an underlying IEI with immune dysregulation. Here, we review IEI that can present with rheumatologic and autoimmune complications and the role of genetic testing for establishing a molecular diagnosis and devising personalized treatment plans to improve patient outcomes.

The Femoral Head Edema Zone: A Novel Classification Scheme to Better Predict Osteonecrosis Progression.

Background: This study proposed a new classification, the Edema Zone classification, that uses Magnetic Resonance Imaging (MRI) images to grade the extent of edema in osteonecrosis of the femoral head (ONFH). The purpose of the study was 1) to examine how the Edema Zone classification compared to the Japanese Investigation Committee (JIC) classification's prognostic ability for early conversion to total hip arthroplasty (THA), and 2) to determine how accurately and reliably the Edema Zone classification performed as a classification system.

Methods: This was a retrospective study of hips that converted to THA from a core decompression within 26 months compared to hips that received only core decompression.

Creating Favorable Pt/Co Interfaces via a Two-Step Approach for Constructing Highly Durable PtCo Intermetallic Fuel Cell Catalysts.

Structurally ordered PtCo intermetallics are one of the most promising oxygen-reduction catalysts in proton exchange membrane fuel cells (PEMFCs) due to their intrinsically improved catalytic activity and stability relative to PtCo solid-solution alloys. However, increasing the heating temperature to achieve a desirable high degree of ordering results in severe particle agglomeration and low mass activity and stability. Herein, a two-step synthesis approach is developed to create an L1-PtCo intermetallic structure with an increased ordering degree and well-dispersed ultrafine particles.