Oncogenic context shapes the fitness landscape of tumor suppression.

Tumors acquire alterations in oncogenes and tumor suppressor genes in an adaptive walk through the fitness landscape of tumorigenesis. However, the interactions between oncogenes and tumor suppressor genes that shape this landscape remain poorly resolved and cannot be revealed by human cancer genomics alone. Here, we use a multiplexed, autochthonous mouse platform to model and quantify the initiation and growth of more than one hundred genotypes of lung tumors across four oncogenic contexts: KRAS G12D, KRAS G12C, BRAF V600E, and EGFR L858R.

Drug and gut microbe relationships: Moving beyond antibiotics.

Our understanding of drug-microbe relationships has evolved from viewing microbes as mere drug producers to a dynamic, modifiable system where they can serve as drugs or targets of precision pharmacology. This review highlights recent findings on the gut microbiome, particularly focusing on four aspects of research: (i) drugs for bugs, covering recent strategies for targeting gut pathogens; (ii) bugs as drugs, including probiotics; (iii) drugs from bugs, including postbiotics; and (iv) bugs and drugs, discussing additional types of drug-microbe interactions. This review provides a perspective on future translational research, including efficient companion diagnostics in pharmaceutical interventions.

Digital Twin-Enabled Personalized Nutrition Improves Metabolic Dysfunction-Associated Fatty Liver Disease in Type 2 Diabetes: Results of a 1-Year Randomized Controlled Study.

Objective: Postprandial hyperglycemia drives insulin resistance and inflammation, leading to metabolic dysfunction-associated fatty liver disease (MAFLD). Prediction of postprandial glycemic responses by digital twin (DT) technology can fashion a personalized nutrition, activity, and sleep to treat type 2 diabetes (T2D) and MAFLD. This study examines the effects of DT-enabled personalized nutrition, activity, and sleep on glycemic status, surrogate markers of MAFLD, and magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) in patients with T2D.

Comparative study of the plasma pharmacokinetics and tissue residues of trimethoprim in silky fowls and 817 broilers after single oral administration.

A comparative study was performed to investigate the differences in plasma pharmacokinetics (PKs) and tissue residues of trimethoprim (TMP) between silky fowls and 817 broilers. The 2 breeds of chickens received compound sulfadiazine suspension by gavage at 20 mg/kg (measured as TMP). Blood and tissue samples were collected at predetermined time points.

Prognostic Value of Coronary CT Angiography-derived Fractional Flow Reserve on 3-year Outcomes in Patients with Stable Angina.

Background The prognostic value of coronary CT angiography (CTA)-derived fractional flow reserve (FFR) beyond 1-year outcomes and in patients with high levels of coronary artery calcium (CAC) is uncertain. Purpose To assess the prognostic value of coronary CTA-derived FFR test results on 3-year clinical outcomes in patients with coronary stenosis and among a subgroup of patients with high levels of CAC. Materials and Methods This study represents a 3-year follow-up of patients with new-onset stable angina pectoris who were consecutively enrolled in the Assessing Diagnostic Value of Noninvasive CT-FFR in Coronary Care, known as ADVANCE (ClinicalTrials.

A Novel Vectorized Curved Road Representation Based Aerial Guided Unmanned Vehicle Trajectory Planning.

Unmanned vehicles frequently encounter the challenge of navigating through complex mountainous terrains, which are characterized by numerous unknown continuous curves. Drones, with their wide field of view and ability to vertically displace, offer a potential solution to compensate for the limited field of view of ground vehicles. However, the conventional approach of path extraction solely provides pixel-level positional information.

Implications of Public Interest in Colonoscopy: Analysis of Google Trends Data From 12 European Countries.

Introduction: Colorectal cancer (CRC) is one of the deadliest diseases in the European Union. Colonoscopy remains the gold standard of CRC screening. Analysis of colonoscopy-related Google Trends (GT; Google LLC, Mountain View, California, United States) data could provide useful information regarding interest in colonoscopy and potential barriers making patients unwilling to attend screening programs.

Universal DNA methylation age across mammalian tissues.

Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.

Core mitochondrial genes are down-regulated during SARS-CoV-2 infection of rodent and human hosts.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins bind to host mitochondrial proteins, likely inhibiting oxidative phosphorylation (OXPHOS) and stimulating glycolysis. We analyzed mitochondrial gene expression in nasopharyngeal and autopsy tissues from patients with coronavirus disease 2019 (COVID-19). In nasopharyngeal samples with declining viral titers, the virus blocked the transcription of a subset of nuclear DNA (nDNA)-encoded mitochondrial OXPHOS genes, induced the expression of microRNA 2392, activated HIF-1α to induce glycolysis, and activated host immune defenses including the integrated stress response.

Deep Learning Approach for the Discovery of Tumor-Targeting Small Organic Ligands from DNA-Encoded Chemical Libraries.

DNA-Encoded Chemical Libraries (DELs) have emerged as efficient and cost-effective ligand discovery tools, which enable the generation of protein-ligand interaction data of unprecedented size. In this article, we present an approach that combines DEL screening and instance-level deep learning modeling to identify tumor-targeting ligands against carbonic anhydrase IX (CAIX), a clinically validated marker of hypoxia and clear cell renal cell carcinoma. We present a new ligand identification and hit-to-lead strategy driven by machine learning models trained on DELs, which expand the scope of DEL-derived chemical motifs.

Genomic assessment of invasion dynamics of SARS-CoV-2 Omicron BA.1.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) now arise in the context of heterogeneous human connectivity and population immunity. Through a large-scale phylodynamic analysis of 115,622 Omicron BA.1 genomes, we identified >6,000 introductions of the antigenically distinct VOC into England and analyzed their local transmission and dispersal history.

Large language models encode clinical knowledge.

Large language models (LLMs) have demonstrated impressive capabilities, but the bar for clinical applications is high. Attempts to assess the clinical knowledge of models typically rely on automated evaluations based on limited benchmarks. Here, to address these limitations, we present MultiMedQA, a benchmark combining six existing medical question answering datasets spanning professional medicine, research and consumer queries and a new dataset of medical questions searched online, HealthSearchQA.

OME-Zarr: a cloud-optimized bioimaging file format with international community support.

A growing community is constructing a next-generation file format (NGFF) for bioimaging to overcome problems of scalability and heterogeneity. Organized by the Open Microscopy Environment (OME), individuals and institutes across diverse modalities facing these problems have designed a format specification process (OME-NGFF) to address these needs. This paper brings together a wide range of those community members to describe the cloud-optimized format itself-OME-Zarr-along with tools and data resources available today to increase FAIR access and remove barriers in the scientific process.

Surface electromyographic wheel speed skate protocol and its potential in athletes' performance analysis and injury prevention.

Background: Speed skating is a discipline that involves cyclical and repetitive movements that make athletes susceptible to injuries, especially in the groin. In professional athletes, during a season, it was found that about 20% had overuse injuries with significant consequences during the competitive season due to long recovery times. Currently, new technological tools allow the measurement of multiple parameters and, through a panel of data deriving from various measurements, provide a valuable aid for training and rehabilitative purposes.

Data Management 101 for drug developers: A peek behind the curtain.

In drug development a frequently used phrase is "data-driven". Just as high-test gas fuels a car, so drug development "runs on" high-quality data; hence, good data management practices, which involve case report form design, data entry, data capture, data validation, medical coding, database closure, and database locking, are critically important. This review covers the essentials of clinical data management (CDM) for the United States.

Faster sorting algorithms discovered using deep reinforcement learning.

Fundamental algorithms such as sorting or hashing are used trillions of times on any given day. As demand for computation grows, it has become critical for these algorithms to be as performant as possible. Whereas remarkable progress has been achieved in the past, making further improvements on the efficiency of these routines has proved challenging for both human scientists and computational approaches.

Camera trapping expands the view into global biodiversity and its change.

Growing threats to biodiversity demand timely, detailed information on species occurrence, diversity and abundance at large scales. Camera traps (CTs), combined with computer vision models, provide an efficient method to survey species of certain taxa with high spatio-temporal resolution. We test the potential of CTs to close biodiversity knowledge gaps by comparing CT records of terrestrial mammals and birds from the recently released Wildlife Insights platform to publicly available occurrences from many observation types in the Global Biodiversity Information Facility.

A pilot study of closed-loop neuromodulation for treatment-resistant post-traumatic stress disorder.

The neurophysiological mechanisms in the human amygdala that underlie post-traumatic stress disorder (PTSD) remain poorly understood. In a first-of-its-kind pilot study, we recorded intracranial electroencephalographic data longitudinally (over one year) in two male individuals with amygdala electrodes implanted for the management of treatment-resistant PTSD (TR-PTSD) under clinical trial NCT04152993. To determine electrophysiological signatures related to emotionally aversive and clinically relevant states (trial primary endpoint), we characterized neural activity during unpleasant portions of three separate paradigms (negative emotional image viewing, listening to recordings of participant-specific trauma-related memories, and at-home-periods of symptom exacerbation).

A temperate Earth-sized planet with tidal heating transiting an M6 star.

Temperate Earth-sized exoplanets around late-M dwarfs offer a rare opportunity to explore under which conditions planets can develop hospitable climate conditions. The small stellar radius amplifies the atmospheric transit signature, making even compact secondary atmospheres dominated by N or CO amenable to characterization with existing instrumentation. Yet, despite large planet search efforts, detection of low-temperature Earth-sized planets around late-M dwarfs has remained rare and the TRAPPIST-1 system, a resonance chain of rocky planets with seemingly identical compositions, has not yet shown any evidence of volatiles in the system.

Winners and Losers: Species under the Pressure of Climate Change.

(1) Bioclimatic factors have a proven effect on species distributions in terrestrial, marine, or freshwater ecosystems. Because of anthropogenic effects, the changes in these variables are accelerated; thus, the knowledge of the impact has great importance from a conservation point of view. Two endemic dragonflies, the Balkan Goldenring () and the Two-Toothed Goldenring (), confined to the hilly and mountainous regions in Europe, are classified as "Near Threatened" according to the IUCN Red List.

OME-Zarr: a cloud-optimized bioimaging file format with international community support.

A growing community is constructing a next-generation file format (NGFF) for bioimaging to overcome problems of scalability and heterogeneity. Organized by the Open Microscopy Environment (OME), individuals and institutes across diverse modalities facing these problems have designed a format specification process (OME-NGFF) to address these needs. This paper brings together a wide range of those community members to describe the cloud-optimized format itself -- OME-Zarr -- along with tools and data resources available today to increase FAIR access and remove barriers in the scientific process.

Selective ablation of primary and paracrine senescent cells by targeting iron dyshomeostasis.

Senescent cells can spread the senescent phenotype to other cells by secreting senescence-associated secretory phenotype factors. The resulting paracrine senescent cells make a significant contribution to the burden of senescent cell accumulation with age. Previous efforts made to characterize paracrine senescence are unreliable due to analyses being based on mixed populations of senescent and non-senescent cells.

Identifying COVID-19 Vaccine Deserts and Ways to Reduce Them: A Digital Tool to Support Public Health Decision-Making.

A private-academic partnership built the Vaccine Equity Planner (VEP) to help decision-makers improve geographic access to COVID-19 vaccinations across the United States by identifying vaccine deserts and facilities that could fill those deserts. The VEP presented complex, updated data in an intuitive form during a rapidly changing pandemic situation. The persistence of vaccine deserts in every state as COVID-19 booster recommendations develop suggests that vaccine delivery can be improved.

Sleep and seizure risk in epilepsy: bed and wake times are more important than sleep duration.

Sleep duration, sleep deprivation and the sleep-wake cycle are thought to play an important role in the generation of epileptic activity and may also influence seizure risk. Hence, people diagnosed with epilepsy are commonly asked to maintain consistent sleep routines. However, emerging evidence paints a more nuanced picture of the relationship between seizures and sleep, with bidirectional effects between changes in sleep and seizure risk in addition to modulation by sleep stages and transitions between stages.