Rh(II)-Catalyzed Selective C(sp)-H/C(sp)-H Bonds Cascade Insertion to Construct [6-8-6] Benzo-Fused Scaffold.

The fused eight-membered carbocycles (EMCs) play vital roles in the medicinal and biological investigations of many natural products and marketed drugs. The traditional synthesis of [6-8-6] benzo-fused derivatives involves multistep reactions and low yields, making the development of a one-step synthesis method a more challenging work. Here, we present a novel strategy for one-step construction of [6-8-6] benzo-fused scaffold from propargyl diazoacetates substituted with benzyl-nitrogen heterocyclic ring via Rh(ll)-catalyzed carbene/alkyne metathesis (CAM) and selective C-H bond insertion.

Specific multivalent molecules boost CRISPR-mediated transcriptional activation.

CRISPR/Cas-based transcriptional activators can be enhanced by intrinsically disordered regions (IDRs). However, the underlying mechanisms are still debatable. Here, we examine 12 well-known IDRs by fusing them to the dCas9-VP64 activator, of which only seven can augment activation, albeit independently of their phase separation capabilities.

Early major fracture care in polytrauma-priorities in the context of concomitant injuries: A Delphi consensus process and systematic review.

Background: The timing of major fracture care in polytrauma patients has a relevant impact on outcomes. Yet, standardized treatment strategies with respect to concomitant injuries are rare. This study aims to provide expert recommendations regarding the timing of major fracture care in the presence of concomitant injuries to the brain, thorax, abdomen, spine/spinal cord, and vasculature, as well as multiple fractures.

Survey of Pharmaceutical Industry's Best Practices around In Vitro Transporter Assessment and Implications for Drug Development: Considerations from the International Consortium for Innovation and Quality for Pharmaceutical Development Transporter Working Group.

The International Consortium for Innovation and Quality in Pharmaceutical Development Transporter Working Group had a rare opportunity to analyze a crosspharma collation of in vitro data and assay methods for the evaluation of drug transporter substrate and inhibitor potential. Experiments were generally performed in accordance with regulatory guidelines. Discrepancies, such as not considering the impact of preincubation for inhibition and free or measured in vitro drug concentrations, may be due to the retrospective nature of the dataset and analysis.

Assessment of Retinal Microvasculature and Choroidal Vascularity After Intra-arterial Chemotherapy for Retinoblastoma.

Purpose: To evaluate changes in retinal microvascular density and choroidal vascularity in patients with retinoblastoma (RB) after intra-arterial chemotherapy (IAC).

Design: Retrospective clinical cohort study.

Methods: This study included 12 unilateral RB eyes treated with IAC (RB tumor), 12 contralateral normal eyes (RB fellow), and 12 healthy controls.

Rapid development of double-hit mRNA antibody cocktail against orthopoxviruses.

The Orthopoxvirus genus, especially variola virus (VARV), monkeypox virus (MPXV), remains a significant public health threat worldwide. The development of therapeutic antibodies against orthopoxviruses is largely hampered by the high cost of antibody engineering and manufacturing processes. mRNA-encoded antibodies have emerged as a powerful and universal platform for rapid antibody production.

Promotion of anaerobic biodegradation of azo dye RR2 by different biowaste-derived biochars: Characteristics and mechanism study by machine learning.

The addition of biochar resulted in a 31.5 % to 44.6 % increase in decolorization efficiency and favorable decolorization stability.

Deficiency of Transcription Factor Sp1 Contributes to Hypertrophic Cardiomyopathy.

Background: Hypertrophic cardiomyopathy (HCM) is the most prevalent monogenic heart disorder. However, the pathogenesis of HCM, especially its nongenetic mechanisms, remains largely unclear. Transcription factors are known to be involved in various biological processes including cell growth.

Quartet DNA reference materials and datasets for comprehensively evaluating germline variant calling performance.

Background: Genomic DNA reference materials are widely recognized as essential for ensuring data quality in omics research. However, relying solely on reference datasets to evaluate the accuracy of variant calling results is incomplete, as they are limited to benchmark regions. Therefore, it is important to develop DNA reference materials that enable the assessment of variant detection performance across the entire genome.

Pan-Cancer Single-Nucleus Total RNA Sequencing Using snHH-Seq.

Tumor heterogeneity and its drivers impair tumor progression and cancer therapy. Single-cell RNA sequencing is used to investigate the heterogeneity of tumor ecosystems. However, most methods of scRNA-seq amplify the termini of polyadenylated transcripts, making it challenging to perform total RNA analysis and somatic mutation analysis.

First-in-human trial of SAR107375E, a novel small molecule anticoagulant with dual inhibition of factor Xa and factor IIa.

Background: SAR107375E is a direct dual inhibitor of both Factor Xa and Factor IIa and has shown potent anticoagulation activity in vitro and animals. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending intravenous doses of SAR107375E in healthy Chinese adult subjects.

Methods: In this randomized, double-blind, placebo-controlled trial, 60 healthy Chinese adult subjects were administered intravenously single ascending doses (0.

DNA conformational dynamics in the context-dependent non-CG CHH methylation by plant methyltransferase DRM2.

DNA methylation provides an important epigenetic mechanism that critically regulates gene expression, genome imprinting, and retrotransposon silencing. In plants, DNA methylation is prevalent not only in a CG dinucleotide context but also in non-CG contexts, namely CHG and CHH (H = C, T, or A) methylation. It has been established that plant non-CG DNA methylation is highly context dependent, with the +1- and +2-flanking sequences enriched with A/T nucleotides.

White Matter Hyperintensity Volume and Poststroke Cognition: An Individual Patient Data Pooled Analysis of 9 Ischemic Stroke Cohort Studies.

Background: White matter hyperintensities (WMH) are associated with cognitive dysfunction after ischemic stroke. Yet, uncertainty remains about affected domains, the role of other preexisting brain injury, and infarct types in the relation between WMH burden and poststroke cognition. We aimed to disentangle these factors in a large sample of patients with ischemic stroke from different cohorts.

Anti-Epstein-Barr Virus BNLF2b for Mass Screening for Nasopharyngeal Cancer.

Background: Population screening of asymptomatic persons with Epstein-Barr virus (EBV) DNA or antibodies has improved the diagnosis of nasopharyngeal carcinoma and survival among affected persons. However, the positive predictive value of current screening strategies is unsatisfactory even in areas where nasopharyngeal carcinoma is endemic.

Methods: We designed a peptide library representing highly ranked B-cell epitopes of EBV coding sequences to identify novel serologic biomarkers for nasopharyngeal carcinoma.

Systems pharmacology dissection of pharmacological mechanisms of Xiaochaihu decoction against human coronavirus.

Background: Although coronavirus disease 2019 (COVID-19) pandemic is still rage worldwide, there are still very limited treatments for human coronaviruses (HCoVs) infections. Xiaochahu decoction (XCHD), which is one of the traditional Chinese medicine (TCM) prescriptions in Qingfeipaidu decoction (QFPDD), is widely used for COVID-19 treatment in China and able to relieve the symptoms of fever, fatigue, anorexia, and sore throat. To explore the role and mechanisms of XCHD against HCoVs, we presented an integrated systems pharmacology framework in this study.

Immune Repertoire Profiling Reveals Its Clinical Application Potential and Triggers for Neuromyelitis Optica Spectrum Disorders.

Background And Objectives: Neuromyelitis optica spectrum disorders (NMOSD) is widely recognized as a CNS demyelinating disease associated with AQP4-IgG (T cell-dependent antibody), and its trigger is still unclear. In addition, although the treatment of NMOSD currently can rely on traditional immunosuppressive and modulating agents, effective methods to predict the efficacy of these therapeutics are lacking.

Methods: In this study, high-throughput T-cell receptor (TCR) sequencing was performed on peripheral blood from 151 pretreatment patients with AQP4-IgG NMOSD and 151 healthy individuals.

High-sensitivity troponins and mortality in the general population.

Aims: Cardiac troponin T and I can be measured using a number of high-sensitivity (hs) assays. This study aimed to characterize correlations between four such assays and test their comparative associations with mortality.

Methods And Results: Among adults without cardiovascular disease in the 1999-2004 National Health and Nutrition Examination Survey, hs-troponin T was measured using one assay (Roche) and hs-troponin I using three assays (Abbott, Siemens, and Ortho).

Study on surface thermal oxidation of silicon carbide irradiated by pulsed laser using reactive molecular dynamics.

Pulsed lasers are a powerful tool for fabricating silicon carbide (SiC) that has a hard and brittle nature, but oxidation is usually unavoidable. This study presents an exploration of the oxidation mechanism of 4H-SiC in oxygen and water under different temperatures via reactive force field molecular dynamics. Single pulse irradiation experiments were conducted to study the oxygen content of the laser-affected zone through energy dispersive x-ray spectrometry.

A potent, broadly protective vaccine against SARS-CoV-2 variants of concern.

Since the first outbreak in December 2019, SARS-CoV-2 has been constantly evolving and five variants have been classified as Variant of Concern (VOC) by the World Health Organization (WHO). These VOCs were found to enhance transmission and/or decrease neutralization capabilities of monoclonal antibodies and vaccine-induced antibodies. Here, we successfully designed and produced a recombinant COVID-19 vaccine in CHO cells at a high yield.

Rethinking Annotation Granularity for Overcoming Shortcuts in Deep Learning-based Radiograph Diagnosis: A Multicenter Study.

Purpose: To evaluate the ability of fine-grained annotations to overcome shortcut learning in deep learning (DL)-based diagnosis using chest radiographs.

Materials And Methods: Two DL models were developed using radiograph-level annotations (disease present: yes or no) and fine-grained lesion-level annotations (lesion bounding boxes), respectively named CheXNet and CheXDet. A total of 34 501 chest radiographs obtained from January 2005 to September 2019 were retrospectively collected and annotated regarding cardiomegaly, pleural effusion, mass, nodule, pneumonia, pneumothorax, tuberculosis, fracture, and aortic calcification.