Latent epigenetic programs in Müller glia contribute to stress and disease response in the retina.

Previous studies have demonstrated the dynamic changes in chromatin structure during retinal development correlate with changes in gene expression. However, those studies lack cellular resolution. Here, we integrate single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) with bulk data to identify cell-type-specific changes in chromatin structure during human and murine development.

Impact of the clinically approved BTK inhibitors on the conformation of full-length BTK and analysis of the development of BTK resistance mutations in chronic lymphocytic leukemia.

Inhibition of Bruton's tyrosine kinase (BTK) has proven to be highly effective in the treatment of B-cell malignancies such as chronic lymphocytic leukemia (CLL), autoimmune disorders, and multiple sclerosis. Since the approval of the first BTK inhibitor (BTKi), Ibrutinib, several other inhibitors including Acalabrutinib, Zanubrutinib, Tirabrutinib, and Pirtobrutinib have been clinically approved. All are covalent active site inhibitors, with the exception of the reversible active site inhibitor Pirtobrutinib.

Assembly of the Tricyclic Core of Alopecurone C by Asymmetric Donor/Donor Carbene C-H Insertion.

Two routes to assemble the complete tricyclic core of alopecurone C are described. In the first-generation route, an efficient synthesis of the "eastern" half of the target, including a decagram-scale rhodium-catalyzed C-H insertion reaction, was developed. When this route proved intractable for assembling the final flavanone ring, a successful second-generation route was developed from a flavanone precursor (naringenin) employing a later stage C-H insertion.

Lessons learned from 20 years of preclinical testing in pediatric cancers.

Programs for preclinical testing of targeted cancer agents in murine models of childhood cancers have been supported by the National Cancer Institute (NCI) since 2004. These programs were established to work collaboratively with industry partners to address the paucity of targeted agents for pediatric cancers compared with the large number of agents developed and approved for malignancies primarily affecting adults. The distinctive biology of pediatric cancers and the relatively small numbers of pediatric cancer patients are major challenges for pediatric oncology drug development.

Exploration of Chemical Space Through Automated Reasoning.

The vast size of composition space poses a significant challenge for materials chemistry: exhaustive enumeration of potentially interesting compositions is typically infeasible, hindering assessment of important criteria ranging from novelty and stability to cost and performance. We report a tool, Comgen, for the efficient exploration of composition space, which makes use of logical methods from computer science used for proving theorems. We demonstrate how these techniques, which have not previously been applied to materials discovery, can enable reasoning about scientific domain knowledge provided by human experts.

La Substitution into the Melilite Derivative CaGaO: Prediction, Synthesis and Ionic Conductivity.

Melilite-type gallates of general formula REAEGaO are of interest for their ability to host mobile interstitial oxide ions in [GaO] layers. The crystal structure of CaGaO is closely related to melilite, with [GaO] layers stacked in a more complex way to accommodate an additional 0.5 interlayer cations per formula unit, suggesting the potential for similar oxide ion conduction behavior.

Navigation through high-dimensional chemical space: discovery of BaY[SiO]O and BaY[SiO].

Two compounds were discovered in the well-studied BaO-YO-SiO phase field. Two different experimental routines were used for the exploration of this system due to the differences of synthetic conditions and competition with a glass field. The first phase BaY[SiO]O was isolated through a combination of energy dispersive X-ray spectroscopy analysis and diffraction techniques which guided the exploration.

Alterations in visible light exposure modulate platelet function and regulate thrombus formation.

Background: Variations in light exposure are associated with changes in inflammation and coagulation. The impact of light spectra on venous thrombosis (VT) and arterial thrombosis is largely unexplored.

Objectives: To investigate the impact of altering light spectrum on platelet function in thrombosis.

Protein is expressed in all major organs after intravenous infusion of mRNA-lipid nanoparticles in swine.

delivery of mRNA is promising for the study of gene expression and the treatment of diseases. Lipid nanoparticles (LNPs) enable efficient delivery of mRNA constructs, but protein expression has been assumed to be limited to the liver. With specialized LNPs, delivery to extrahepatic tissue occurs in small animal models; however, it is unclear if global delivery of mRNA to all major organs is possible in humans because delivery may be affected by differences in innate immune response and relative organ size.

Suppressing upregulation of fibrinogen after polytrauma mitigates thrombosis in mice.

Background: Polytrauma results in systemic inflammation and increased circulating fibrinogen, which increases the risk of microvascular and macrovascular thrombosis that contributes to secondary organ damage and venous thromboembolism (VTE). There are no clinically approved agents to prevent hyperfibrinogenemia after polytrauma. We hypothesized that preventing the increase in fibrinogen levels after polytrauma would suppress thrombosis.

fusion proteins deregulate gene networks controlling mitochondrial translation in pediatric rhabdomyosarcoma.

Alveolar rhabdomyosarcoma (ARMS) patients harboring PAX3-FOXO1 and PAX7-FOXO1 fusion proteins exhibit a greater incidence of tumor relapse, metastasis, and poor survival outcome, thereby underscoring the urgent need to develop effective therapies to treat this subtype of childhood cancer. To uncover mechanisms that contribute to tumor initiation, we developed a novel muscle progenitor model and used epigenomic approaches to unravel genome re-wiring events mediated by PAX3/7 fusion proteins. Importantly, these regulatory mechanisms are conserved across established ARMS cell lines, primary tumors, and orthotopic-patient derived xenografts.

Recognition and order of multiple sidechains by metal-organic framework enhances the separation of hexane isomers.

Porous materials perform molecular sorting, separation and transformation by interaction between their framework structures and the substrates. Proteins also interact with molecules to effect chemical transformations, but rely on the precise sequence of the amino acid building units along a common polypeptide backbone to maximise their performance. Design strategies that positionally order sidechains over a defined porous framework to diversify the internal surface chemistry would enhance control of substrate processing.

Risk factors associated with medical encounters in ultramarathon race starters - Data from 103,131 race starters over 90 km: SAFER XLI.

Objectives: To identify the risk factors associated with all medical encounters (MEs) and serious/life-threatening MEs (SLMEs) during the Comrades Marathon.

Design: Prospective cohort study, with cross-sectional analyses.

Methods: During the 2014-2019 Comrades Marathon, all MEs (including SLMEs) were recorded in 103,131 starters.

Single cell transcriptomic profiling identifies tumor-acquired and therapy-resistant cell states in pediatric rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is a pediatric tumor that resembles undifferentiated muscle cells; yet the extent to which cell state heterogeneity is shared with human development has not been described. Using single-cell/nucleus RNA sequencing from patient tumors, patient-derived xenografts, primary in vitro cultures, and cell lines, we identify four dominant muscle-lineage cell states: progenitor, proliferative, differentiated, and ground cells. We stratify these RMS cells/nuclei along the continuum of human muscle development and show that they share expression patterns with fetal/embryonal myogenic precursors rather than postnatal satellite cells.

Evolutionary conservation of VSX2 super-enhancer modules in retinal development.

Super-enhancers (SEs) are expansive regions of genomic DNA that regulate the expression of genes involved in cell identity and cell fate. We recently identified developmental stage- and cell type-specific modules within the murine Vsx2 SE. Here, we show that the human VSX2 SE modules have similar developmental stage- and cell type-specific activity in reporter gene assays.

Enhancement of Low Temperature Superionic Conductivity by Suppression of Li Site Ordering in LiSiGeSI.

Ge substitution into the recently discovered superionic conductor LiSiSI is demonstrated by synthesis of LiSiGeSI, where x≤1.2. The anion packing and tetrahedral silicon location of LiSiSI are retained upon substitution.

Reporting and analysis of sex in vascular surgery research.

Objective: To examine sex in human vascular surgery research by quantifying the inclusion and analysis of sex-based data in high-impact vascular surgery journals.

Methods: A bibliographic review of original articles published in the European Journal of Vascular and Endovascular Surgery, Journal of Vascular Surgery, JVS: Venous and Lymphatic Disorders, Journal of Endovascular Therapy, and Annals of Vascular Surgery from January 1, 2018, to December 31, 2020, and from January 1, 2023, to December 31, 2023, was conducted. Abstracted data included sex-based data analysis, inclusion of sex as a variable in multivariable analysis, inclusion of sex as an independent variable, and a discussion of sex-based results.

Sex, training variables, history of chronic disease, and chronic injury are risk factors associated with a history of exercise-associated muscle cramping in 10,973 ultramarathon race entrants: a safer XXXVIII study.

Background: The prevalence of a history of exercise-associated muscle cramping (hEAMC) among ultramarathon runners is high. While the Comrades is one of the most popular mass community-based participation ultramarathons (90 km) globally, research on the epidemiology, clinical characteristics, and risk factors of entrants' lifetime hEAMC are scarce. This research aimed to describe the epidemiology, clinical characteristics, and risk factors of hEAMC among Comrades Marathon entrants.