Epigenetic priming promotes acquisition of tyrosine kinase inhibitor resistance and oncogene amplification in human lung cancer.

In mammalian cells, gene copy number is tightly controlled to maintain gene expression and genome stability. However, a common molecular feature across cancer types is oncogene amplification, which promotes cancer progression by drastically increasing the copy number and expression of tumor-promoting genes. For example, in tyrosine kinase inhibitor (TKI)-resistant lung adenocarcinoma (LUAD), oncogene amplification occurs in over 40% of patients' tumors.

Mechanism for local attenuation of DNA replication at double-strand breaks.

DNA double-strand breaks (DSBs) disrupt the continuity of the genome, with consequences for malignant transformation. Massive DNA damage can elicit a cellular checkpoint response that prevents cell proliferation. However, how highly aggressive cancer cells, which can tolerate widespread DNA damage, respond to DSBs alongside continuous chromosome duplication is unknown.

Preoperative SGLT2 Inhibitor Use and Postoperative Diabetic Ketoacidosis.

Importance: Case reports of postoperative diabetic ketoacidosis in patients using sodium-glucose cotransporter 2 inhibitor (SGLT2i) medications underlie guidance by the US Food and Drug Administration to withhold SGLT2i medication for at least 3 days prior to surgery. Given the potential negative consequences associated with preoperative medication withholding, a large-scale evaluation of the risk of diabetic ketoacidosis in this population is needed.

Objective: To estimate the association between preoperative SGLT2i medication use and postoperative diabetic ketoacidosis in a population of patients who underwent a variety of emergency surgeries.

Brain aging and rejuvenation at single-cell resolution.

Brain aging leads to a decline in cognitive function and a concomitant increase in the susceptibility to neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. A key question is how changes within individual cells of the brain give rise to age-related dysfunction. Developments in single-cell "omics" technologies, such as single-cell transcriptomics, have facilitated high-dimensional profiling of individual cells.

Spatial transcriptomic clocks reveal cell proximity effects in brain ageing.

Old age is associated with a decline in cognitive function and an increase in neurodegenerative disease risk. Brain ageing is complex and is accompanied by many cellular changes. Furthermore, the influence that aged cells have on neighbouring cells and how this contributes to tissue decline is unknown.

Engineered extrachromosomal oncogene amplifications promote tumorigenesis.

Focal gene amplifications are among the most common cancer-associated mutations but have proven challenging to engineer in primary cells and model organisms. Here we describe a general strategy to engineer large (more than 1 Mbp) focal amplifications mediated by extrachromosomal DNAs (ecDNAs) in a spatiotemporally controlled manner in cells and in mice. By coupling ecDNA formation with expression of selectable markers, we track the dynamics of ecDNA-containing cells under physiological conditions and in the presence of specific selective pressures.

Racial and Ethnic Disparities in Failure-to-Rescue After Postoperative Sepsis After Noncardiac Surgery.

Background: Sepsis disproportionately affects marginalized communities. This study aims to evaluate racial and ethnic disparities in failure-to-rescue (FTR) after postoperative sepsis.

Methods: This cross-sectional study used data from the American College of Surgeons National Surgical Quality Improvement Program for patients who underwent inpatient noncardiac surgery between 2018 and 2021.

A proteome-wide quantitative platform for nanoscale spatially resolved extraction of membrane proteins into native nanodiscs.

The native membrane environment profoundly influences every aspect of membrane protein (MP) biology. Despite this, the most prevalent method of studying MPs uses detergents to disrupt and remove this vital membrane context, impeding our ability to decipher the local molecular context and its effect. Here we develop a membrane proteome-wide platform that enables rapid spatially resolved extraction of target MPs directly from cellular membranes into native nanodiscs that maintain the local membrane context, using a library of membrane-active polymers.

Interaction of methyl-CpG-binding protein 2 (MeCP2) with distinct enhancers in the mouse cortex.

Mutations in methyl-CpG-binding protein 2 (MeCP2) cause Rett syndrome. MeCP2 is thought to regulate gene transcription by binding to methylated DNA broadly across the genome. Here, using cleavage under target and release under nuclease (CUT&RUN) assays in the adult mouse cortex, we show that MeCP2 strongly binds to specific gene enhancers that we call MeCP2-binding hotspots (MBHs).

CRISPR-Cas9 screens reveal regulators of ageing in neural stem cells.

Ageing impairs the ability of neural stem cells (NSCs) to transition from quiescence to proliferation in the adult mammalian brain. Functional decline of NSCs results in the decreased production of new neurons and defective regeneration following injury during ageing. Several genetic interventions have been found to ameliorate old brain function, but systematic functional testing of genes in old NSCs-and more generally in old cells-has not been done.

Spatiotemporal transcriptomic profiling and modeling of mouse brain at single-cell resolution reveals cell proximity effects of aging and rejuvenation.

Old age is associated with a decline in cognitive function and an increase in neurodegenerative disease risk. Brain aging is complex and accompanied by many cellular changes. However, the influence that aged cells have on neighboring cells and how this contributes to tissue decline is unknown.

SPRITE: improving spatial gene expression imputation with gene and cell networks.

Motivation: Spatially resolved single-cell transcriptomics have provided unprecedented insights into gene expression in situ, particularly in the context of cell interactions or organization of tissues. However, current technologies for profiling spatial gene expression at single-cell resolution are generally limited to the measurement of a small number of genes. To address this limitation, several algorithms have been developed to impute or predict the expression of additional genes that were not present in the measured gene panel.

Restoration of neuronal progenitors by partial reprogramming in the aged neurogenic niche.

Partial reprogramming (pulsed expression of reprogramming transcription factors) improves the function of several tissues in old mice. However, it remains largely unknown how partial reprogramming impacts the old brain. Here we use single-cell transcriptomics to systematically examine how partial reprogramming influences the subventricular zone neurogenic niche in aged mouse brains.

Variability in Intraoperative Opioid and Nonopioid Utilization During Intracranial Surgery: A Multicenter, Retrospective Cohort Study.

Background: Key goals during intracranial surgery are to facilitate rapid emergence and extubation for early neurologic evaluation. Longer-acting opioids are often avoided or administered at subtherapeutic doses due to their perceived risk of sedation and delayed emergence. However, inadequate analgesia and increased postoperative pain are common after intracranial surgery.

Principled and interpretable alignability testing and integration of single-cell data.

Single-cell data integration can provide a comprehensive molecular view of cells, and many algorithms have been developed to remove unwanted technical or biological variations and integrate heterogeneous single-cell datasets. Despite their wide usage, existing methods suffer from several fundamental limitations. In particular, we lack a rigorous statistical test for whether two high-dimensional single-cell datasets are alignable (and therefore should even be aligned).

TISSUE: uncertainty-calibrated prediction of single-cell spatial transcriptomics improves downstream analyses.

Whole-transcriptome spatial profiling of genes at single-cell resolution remains a challenge. To address this limitation, spatial gene expression prediction methods have been developed to infer the spatial expression of unmeasured transcripts, but the quality of these predictions can vary greatly. Here we present Transcript Imputation with Spatial Single-cell Uncertainty Estimation (TISSUE) as a general framework for estimating uncertainty for spatial gene expression predictions and providing uncertainty-aware methods for downstream inference.

A Cost and Waste-Savings Comparison Between Single-Use and Reusable Pulse Oximetry Sensors Across US Operating Rooms.

Background: Operating room (OR) expenditures and waste generation are a priority, with several professional societies recommending the use of reprocessed or reusable equipment where feasible. The aim of this analysis was to compare single-use pulse oximetry sensor stickers ("single-use stickers") versus reusable pulse oximetry sensor clips ("reusable clips") in terms of annual cost savings and waste generation across all ORs nationally.

Methods: This study did not involve patient data or research on human subjects.

Dynamic visualization of high-dimensional data.

Dimensionality reduction (DR) is commonly used to project high-dimensional data into lower dimensions for visualization, which could then generate new insights and hypotheses. However, DR algorithms introduce distortions in the visualization and cannot faithfully represent all relations in the data. Thus, there is a need for methods to assess the reliability of DR visualizations.

Association of Patient Race and Hospital with Utilization of Regional Anesthesia for Treatment of Postoperative Pain in Total Knee Arthroplasty: A Retrospective Analysis Using Medicare Claims.

Background: Regional anesthesia for total knee arthroplasty has been deemed high priority by national and international societies, and its use can serve as a measure of healthcare equity. The association between utilization of regional anesthesia for postoperative pain and (1) race and (2) hospital in patients undergoing total knee arthroplasty was estimated. The hypothesis was that Black patients would be less likely than White patients to receive regional anesthesia, and that variability in regional anesthesia would more likely be attributable to the hospital where surgery occurred than race.