Toward expert-level medical question answering with large language models.

Large language models (LLMs) have shown promise in medical question answering, with Med-PaLM being the first to exceed a 'passing' score in United States Medical Licensing Examination style questions. However, challenges remain in long-form medical question answering and handling real-world workflows. Here, we present Med-PaLM 2, which bridges these gaps with a combination of base LLM improvements, medical domain fine-tuning and new strategies for improving reasoning and grounding through ensemble refinement and chain of retrieval.

Transplantation of a genetically modified porcine heart into a live human.

Following our previous experience with cardiac xenotransplantation of a genetically modified porcine heart into a live human, we sought to achieve improved results by selecting a healthier recipient and through more sensitive donor screening for potential zoonotic pathogens. Here we transplanted a 10-gene-edited pig heart into a 58-year-old man with progressive, debilitating inotrope-dependent heart failure due to ischemic cardiomyopathy who was not a candidate for standard advanced heart failure therapies. He was maintained on a costimulation (anti-CD40L, Tegoprubart) blockade-based immunomodulatory regimen.

High-efficiency base editing in the retina in primates and human tissues.

Stargardt disease is a currently untreatable, inherited neurodegenerative disease that leads to macular degeneration and blindness due to loss-of-function mutations in the ABCA4 gene. We have designed a dual adeno-associated viral vector encoding a split-intein adenine base editor to correct the most common mutation in ABCA4 (c.5882G>A, p.

Integrated irrigation and nitrogen optimization is a resource-efficient adaptation strategy for US maize and soybean production.

Climate change poses substantial challenges to agriculture and crop production, but the combined role of nitrogen and water inputs in adaptation has been largely overlooked. Here, by developing regression models using US county-level data (2008-2020), we demonstrate that integrated optimization of irrigation and nitrogen inputs represents the most resource-efficient strategy to offset the climate-related yield losses. Under the 1.

RapA opens the RNA polymerase clamp to disrupt post-termination complexes and prevent cytotoxic R-loop formation.

Following transcript release during intrinsic termination, Escherichia coli RNA polymerase (RNAP) often remains associated with DNA in a post-termination complex (PTC). RNAPs in PTCs are removed from the DNA by the SWI2/SNF2 adenosine triphosphatase (ATPase) RapA. Here we determined PTC structures on negatively supercoiled DNA and with RapA engaged to dislodge the PTC.

Inherent asymmetry of Rpd3S coordinates its nucleosome engagement and association with elongating RNA polymerase II.

The Rpd3S histone deacetylase complex has a crucial role in genomic integrity by deacetylating transcribed nucleosomes following RNA polymerase (Pol) II passage. Cryo-EM studies highlight the importance of asymmetrical Rco1-Eaf3 dimers in nucleosome binding, yet the interaction dynamics with nucleosomal substrates alongside elongating Pol II are poorly understood. Here we demonstrate the essential function of the Rco1 N-terminal intrinsically disordered region (IDR) in modulating Pol II association, in which K/R mutations within the Rco1 IDR impair interaction of Rpd3S with the C-terminal domain (CTD) of Rpb1, without affecting nucleosome recognition or complex integrity.

Identification of CT based radiomic biomarkers for progression free survival in head and neck squamous cell carcinoma.

This study addresses the limited noninvasive tools for Head and Neck Squamous Cell Carcinoma (HNSCC) progression-free survival (PFS) prediction by identifying Computed Tomography (CT)-based biomarkers for predicting prognosis. A retrospective analysis was conducted on data from 203 HNSCC patients. An ensemble feature selection involving correlation analysis, univariate survival analysis, best-subset selection, and the LASSO-Cox algorithm was used to select functional features, which were then used to build final Cox Proportional Hazards models (CPH).

Inactivation of GSK3β by Ser phosphorylation prevents thymocyte necroptosis and impacts Tcr repertoire diversity.

The assembly of Tcrb and Tcra genes require double negative (DN) thymocytes to undergo multiple rounds of programmed DNA double-strand breaks (DSBs), followed by their efficient repair. However, mechanisms governing cell cycle checkpoints and specific survival pathways during the repair process remain unclear. Here, we report high-resolution scRNA-seq analyses of individually sorted mouse DN3 and DN4 thymocytes, which reveals a G2M cell cycle checkpoint, in addition to the known G1 checkpoint, during Tcrb and Tcra recombination.

Decreased impulsiveness and MEG normalization after AI-digital therapy in ADHD children: a RCT.

Attention-deficit/hyperactivity disorder (ADHD) presents with symptoms like impulsiveness, inattention, and hyperactivity, often affecting children's academic and social functioning. Non-pharmacological interventions, such as digital cognitive therapy, are emerging as complementary treatments for ADHD. The randomized controlled trial explored the impact of an AI-driven digital cognitive program on impulsiveness, inattentiveness, and neurophysiological markers in 41 children aged 8-12 with ADHD.

Maternal effects in the model system Daphnia: the ecological past meets the epigenetic future.

Maternal effects have been shown to play influential roles in many evolutionary and ecological processes. However, understanding how environmental stimuli induce within-generation responses that transverse across generations remains elusive, particularly when attempting to segregate confounding effects from offspring genotypes. This review synthesizes literature regarding resource- and predation-driven maternal effects in the model system Daphnia, detailing how the maternal generation responds to the environmental stimuli and the maternal effects seen in the offspring generation(s).

Population-level amplification of gene regulation by programmable gene transfer.

Engineering cells to sense and respond to environmental cues often focuses on maximizing gene regulation at the single-cell level. Inspired by population-level control mechanisms like the immune response, we demonstrate dynamic control and amplification of gene regulation in bacterial populations using programmable plasmid-mediated gene transfer. By regulating plasmid loss rate, transfer rate and fitness effects via Cas9 endonuclease, F conjugation machinery and antibiotic selection, we modulate the fraction of plasmid-carrying cells, serving as an amplification factor for single-cell-level regulation.

Quantitative magnetization transfer and g-ratio imaging of white matter myelin in early psychotic spectrum disorders.

Myelin abnormalities in white matter have been implicated in the pathophysiology of psychotic spectrum disorders (PSD), which are characterized by brain dysconnectivity as a core feature. Among evidence from in vivo MRI studies, diffusion imaging findings have largely supported disrupted white matter integrity in PSD; however, they are not specific to myelin changes. Using a multimodal imaging approach, the current study aimed to further delineate myelin and microstructural changes in the white matter of a young PSD cohort.

Lymphatic collection and cell isolation from mouse models for multiomic profiling.

Premetastatic cancer cells often spread from the primary lesion through the lymphatic vasculature and, clinically, the presence or absence of lymph node metastases impacts treatment decisions. However, little is known about cancer progression via the lymphatic system or of the effect that the lymphatic environment has on cancer progression. This is due, in part, to the technical challenge of studying lymphatic vessels and collecting lymph fluid.

Sialic acid aptamer and RNA in situ hybridization-mediated proximity ligation assay for spatial imaging of glycoRNAs in single cells.

Glycosylated RNAs (glycoRNAs) have recently emerged as a new class of molecules of substantial interest owing to their potential roles in cellular processes and diseases. However, studying glycoRNAs is challenging owing to the lack of effective research tools including, but not limited to, imaging techniques to study the spatial distribution of glycoRNAs. Recently, we reported the development of a glycoRNA imaging technique, called sialic acid aptamer and RNA in situ hybridization-mediated proximity ligation assay (ARPLA), to visualize sialic acid-containing glycoRNAs with high sensitivity and specificity.

Longitudinal genomic profiling using liquid biopsies in metastatic nonsquamous NSCLC following first line immunotherapy.

Tumor genomic profiling is often limited to one or two timepoints due to the invasiveness of tissue biopsies, but longitudinal profiling may provide deeper clinical insights. Using ctDNA data from IMpower150 study, we examined genetic changes in metastatic non-squamous NSCLC post-first-line immunotherapy. Mutations were most frequently detected in TP53, KRAS, SPTA1, FAT3, and LRP1B at baseline and during treatment.

Cellular and organismal function of choline metabolism.

Choline is an essential micronutrient critical for cellular and organismal homeostasis. As a core component of phospholipids and sphingolipids, it is indispensable for membrane architecture and function. Additionally, choline is a precursor for acetylcholine, a key neurotransmitter, and betaine, a methyl donor important for epigenetic regulation.

Oxidative toxicity mediated oophoritis alters ovarian growth in Channa punctatus under prolonged exposure to herbicide, paraquat dichloride.

Herbicide paraquat dichloride, a potent redox agent found its way to natural water bodies and influences their health; however, its impact on the reproductive health of fish is potentially less studied and requires clear investigation. This study was conducted to elucidate its effect on the gonadal health of female fish, Channa punctatus over 60 days. The 96-h LC of test herbicide was calculated as 0.

Consuming a modified Mediterranean ketogenic diet reverses the peripheral lipid signature of Alzheimer's disease in humans.

Background: Alzheimer's disease (AD) is a major neurodegenerative disorder with significant environmental factors, including diet and lifestyle, influencing its onset and progression. Although previous studies have suggested that certain diets may reduce the incidence of AD, the underlying mechanisms remain unclear.

Method: In this post-hoc analysis of a randomized crossover study of 20 elderly adults, we investigated the effects of a modified Mediterranean ketogenic diet (MMKD) on the plasma lipidome in the context of AD biomarkers, analyzing 784 lipid species across 47 classes using a targeted lipidomics platform.

Streptomyces secretes a siderophore that sensitizes competitor bacteria to phage infection.

To overtake competitors, microbes produce and secrete secondary metabolites that kill neighbouring cells and sequester nutrients. This metabolite-mediated competition probably evolved in complex microbial communities in the presence of viral pathogens. We therefore hypothesized that microbes secrete natural products that make competitors sensitive to phage infection.

Enterobactin inhibits microbiota-dependent activation of AhR to promote bacterial sepsis in mice.

Sepsis is a major cause of morbidity and mortality, but our understanding of the mechanisms underlying survival or susceptibility is limited. Here, as pathogens often subvert host defence mechanisms, we hypothesized that this might influence the outcome of sepsis. We used microbiota analysis, faecal microbiota transplantation, antibiotic treatment and caecal metabolite analysis to show that gut-microbiota-derived tryptophan metabolites including indoles increased host survival in a mouse model of Serratia marcescens sepsis.

A hybrid machine learning approach for the personalized prognostication of aggressive skin cancers.

Accurate prognostication guides optimal clinical management in skin cancer. Merkel cell carcinoma (MCC) is the most aggressive form of skin cancer that often presents in advanced stages and is associated with poor survival rates. There are no personalized prognostic tools in use in MCC.

A multi-kinase inhibitor screen identifies inhibitors preserving stem-cell-like chimeric antigen receptor T cells.

Chimeric antigen receptor T cells (CAR T cells) with T stem (T) cell-like phenotypic characteristics promote sustained antitumor effects. We performed an unbiased and automated high-throughput screen of a kinase-focused compound set to identify kinase inhibitors (KIs) that preserve human T cell-like CAR T cells. We identified three KIs, UNC10225387B, UNC10225263A and UNC10112761A, that combined in vitro increased the frequency of CD45RACCR7TCF1 T cell-like CAR T cells from both healthy donors and patients with cancer.

β-Glucan reprograms neutrophils to promote disease tolerance against influenza A virus.

Disease tolerance is an evolutionarily conserved host defense strategy that preserves tissue integrity and physiology without affecting pathogen load. Unlike host resistance, the mechanisms underlying disease tolerance remain poorly understood. In the present study, we investigated whether an adjuvant (β-glucan) can reprogram innate immunity to provide protection against influenza A virus (IAV) infection.