Site-saturation mutagenesis of 500 human protein domains.

Missense variants that change the amino acid sequences of proteins cause one-third of human genetic diseases. Tens of millions of missense variants exist in the current human population, and the vast majority of these have unknown functional consequences. Here we present a large-scale experimental analysis of human missense variants across many different proteins.

Middle Meningeal Artery Embolization for Nonacute Subdural Hematoma.

Background: The effect of embolization of the middle meningeal artery in patients with subacute or chronic subdural hematoma is uncertain.

Methods: We performed a multicenter, open-label, randomized trial in China, involving patients with symptomatic nonacute subdural hematoma with mass effect. Patients were assigned to undergo burr-hole drainage or receive nonsurgical treatment at the surgeon's discretion, and patients in each group were then randomly assigned, in a 1:1 ratio, to undergo middle meningeal artery embolization with liquid embolic material or to receive usual care.

Discovery of electrophilic degraders that exploit SAr chemistry.

Targeted covalent inhibition (TCI) and targeted protein degradation (TPD) have proven effective in pharmacologically addressing formerly 'undruggable' targets. Integration of both methodologies has resulted in the development of electrophilic degraders where recruitment of a suitable E3 ubiquitin ligase is achieved through formation of a covalent bond with a cysteine nucleophile. Expanding the scope of electrophilic degraders requires the development of electrophiles with tempered reactivity that enable selective ligase recruitment and reduce cross-reactivity with other cellular nucleophiles.

Efficacy and safety of HAIC-FOLFOX plus tyrosine kinase inhibitors and immune checkpoint inhibitors as first-line treatment for unresectable advanced hepatocellular carcinoma: A systematic review and meta-analysis.

Background: Advanced hepatocellular carcinoma (HCC) has been treated with targeted therapy, immunotherapy, or a combination of both, however, the overall clinical efficacy is still unsatisfactory. Hepatic arterial infusion chemotherapy (HAIC), as a localized treatment modality, has demonstrated favorable therapeutic efficacy in patients with advanced HCC accompanied by portal vein tumor thrombus and extensive intrahepatic metastasis. In recent years, the combination of HAIC with immune and targeted therapy has gradually gained acceptance in East Asian countries.

Combination of Different Sectional Elastography Techniques with Age to Optimize the Downgrading of Breast BI-RAIDS Class 4a Nodules.

Objective: This study aims to optimize the downgrading of BI-RADS class 4a nodules by combining various sectional elastography techniques with age.

Materials And Methods: We performed conventional ultrasonography, strain elastography (SE), and shear wave elastography (SWE) on patients. Quantitative parameters recorded included age, cross-sectional and longitudinal area ratios (C-EI/B, L-EI/B), strain rate ratios (C-SR, L-SR), overall average elastic modulus values (C-Emean1, L-Emean1), five-point average elastic modulus values (C-Emean2, L-Emean2), and maximum elastic modulus values (C-Emax, L-Emax).

[Clinical efficacy and safety of liposomal amphotericin B in the salvage treatment of invasive fungal disease in patients with hematological diseases].

To investigate the efficacy and safety of liposomal amphotericin B (L-AmB) for the salvage treatment of invasive fungal disease (IFD) in patients with hematological diseases. Data were retrospectively collected from 80 patients with hematological issues treated with L-AmB between June 2023 and December 2023 after failure of previous antifungal therapy. Baseline patient information, clinical efficacy, and factors affecting the efficacy of L-AmB were analyzed by logistic regression.

Generative models for synthetic data generation: application to pharmacokinetic/pharmacodynamic data.

The generation of synthetic patient data that reflect the statistical properties of real data plays a fundamental role in today's world because of its potential to (i) be enable proprietary data access for statistical and research purposes and (ii) increase available data (e.g., in low-density regions-i.

Boosting the Formation of Brønsted Acids on Flame-made WO/ZrO for Glucose Conversion.

Tungstate-zirconium oxide catalysts (WO/ZrO) with much higher concentrations of Brønsted acid sites (BAS) and a bigger ratio of Brønsted to Lewis acid sites (B/L) than achievable by conventional impregnation (IM) were synthesized using single-step flame spray pyrolysis (FSP). The rapid quenching and short residence time inherent to FSP prevent the accumulation of W atoms on the ZrO support and thus provide an excellent surface dispersion of WO species. As a result, FSP-made WO/ZrO (FSP-WO/ZrO) has a much higher surface concentration of three-dimensional Zr-WO clusters than corresponding materials prepared by conventional impregnation (IM-WO/ZrO).

Combined inhibition of KRAS and mTORC1 kinase is synergistic in non-small cell lung cancer.

Current KRAS (OFF) inhibitors that target inactive GDP-bound KRAS cause responses in less than half of patients and these responses are not durable. A class of RAS (ON) inhibitors that targets active GTP-bound KRAS blocks ERK signaling more potently than the inactive-state inhibitors. Sensitivity to either class of agents is strongly correlated with inhibition of mTORC1 activity.

Uncoupling histone modification crosstalk by engineering lysine demethylase LSD1.

Biochemical crosstalk between two or more histone modifications is often observed in epigenetic enzyme regulation, but its functional significance in cells has been difficult to discern. Previous enzymatic studies revealed that Lys14 acetylation of histone H3 can inhibit Lys4 demethylation by lysine-specific demethylase 1 (LSD1). In the present study, we engineered a mutant form of LSD1, Y391K, which renders the nucleosome demethylase activity of LSD1 insensitive to Lys14 acetylation.

Microneedle-based sampling of dermal interstitial fluid using a vacuum-assisted skin patch.

Interstitial fluid (ISF) contains a wealth of biomolecules, yet it is underutilized for diagnostic testing due to a lack of rapid and simple techniques for collecting abundant amounts of fluid. Here, we report a simple and minimally invasive technique for rapidly sampling larger quantities of ISF from human skin. A microneedle array is used to generate micropores in skin from which ISF is extracted using a vacuum-assisted skin patch.

Penpulimab, an anti-PD-1 antibody, for heavily pretreated metastatic nasopharyngeal carcinoma: a single-arm phase II study.

Penpulimab is an anti-programmed cell death-1 (PD-1) IgG1 antibody with no Fc gamma receptor (FcγR) binding activity, and thus theoretically reduced immune-related adverse events (irAEs) while maintaining efficacy. This single-arm, phase II trial conducted across 20 tertiary care centers in China enrolled adult patients with metastatic nasopharyngeal carcinoma (NPC) who had failed two or more lines of previous systemic chemotherapy. Patients received 200-mg penpulimab intravenously every 2 weeks (4 weeks per cycle) until disease progression or intolerable toxicities.

Unraveling the Structure-Activity-Stability Relationship over Gallium-Promoted HZSM-5 Nanocrystalline Aggregates for Propane Aromatization.

The aromatization of light alkane is an important process for increasing the aromatic production and utilization efficiency of light alkane resources simultaneously. Herein, Ga-modified HZSM-5 catalysts were prepared and investigated by a series of characterization techniques such as X-ray diffraction, nuclear magnetic resonance spectroscopy, transmission electron microscopy, N adsorption-desorption, and NH temperature-programmed desorption to study their physicochemical properties. The catalytic performance in propane aromatization was also tested.

Intensive Ambulance-Delivered Blood-Pressure Reduction in Hyperacute Stroke.

Background: Treatment of acute stroke, before a distinction can be made between ischemic and hemorrhagic types, is challenging. Whether very early blood-pressure control in the ambulance improves outcomes among patients with undifferentiated acute stroke is uncertain.

Methods: We randomly assigned patients with suspected acute stroke that caused a motor deficit and with elevated systolic blood pressure (≥150 mm Hg), who were assessed in the ambulance within 2 hours after the onset of symptoms, to receive immediate treatment to lower the systolic blood pressure (target range, 130 to 140 mm Hg) (intervention group) or usual blood-pressure management (usual-care group).

An ensemble penalized regression method for multi-ancestry polygenic risk prediction.

Great efforts are being made to develop advanced polygenic risk scores (PRS) to improve the prediction of complex traits and diseases. However, most existing PRS are primarily trained on European ancestry populations, limiting their transferability to non-European populations. In this article, we propose a novel method for generating multi-ancestry Polygenic Risk scOres based on enSemble of PEnalized Regression models (PROSPER).

MUSSEL: Enhanced Bayesian polygenic risk prediction leveraging information across multiple ancestry groups.

Polygenic risk scores (PRSs) are now showing promising predictive performance on a wide variety of complex traits and diseases, but there exists a substantial performance gap across populations. We propose MUSSEL, a method for ancestry-specific polygenic prediction that borrows information in summary statistics from genome-wide association studies (GWASs) across multiple ancestry groups via Bayesian hierarchical modeling and ensemble learning. In our simulation studies and data analyses across four distinct studies, totaling 5.

Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer.

Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations. RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS and NRAS, with affinity for both mutant and wild-type variants. More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS.

CD151 Maintains Endolysosomal Protein Quality to Inhibit Vascular Inflammation.

Background: Tetraspanin CD151 is highly expressed in endothelia and reinforces cell adhesion, but its role in vascular inflammation remains largely unknown.

Methods: In vitro molecular and cellular biological analyses on genetically modified endothelial cells, in vivo vascular biological analyses on genetically engineered mouse models, and in silico systems biology and bioinformatics analyses on CD151-related events.

Results: Endothelial ablation of leads to pulmonary and cardiac inflammation, severe sepsis, and perilous COVID-19, and endothelial CD151 becomes downregulated in inflammation.

The Production Splitting Method of Offshore Multilayer Combined Water Flooding Gas Wells with Gas Dissolving.

Offshore gas reservoirs are characterized by thin interlayers, high production, few wells, etc., and are often exploited by multilayer combined mining, whereas the production dynamics of multilayer gas reservoirs are very different from those of single-layer gas reservoirs. Therefore, clarifying the gas production contribution of each layer in multilayer combined gas reservoirs is an important prerequisite for analyzing the potential of gas reservoirs and realizing efficient development.

Remote Ischemic Conditioning With Medical Management or Reperfusion Therapy for Acute Ischemic Stroke: A Systematic Review and Meta-Analysis.

Background And Objectives: Remote ischemic conditioning (RIC) is a low-cost, accessible, and noninvasive neuroprotective treatment strategy, but its efficacy and safety in acute ischemic stroke are controversial. With the publication of several randomized controlled trials (RCTs) and the recent results of the RESIST trial, it may be possible to identify the patient population that may (or may not) benefit from RIC. This systematic review and meta-analysis aims to evaluate the effectiveness and safety of RIC in patients with ischemic stroke receiving different treatments by pooling data of all randomized controlled studies to date.

Clonal hematopoiesis of indeterminate potential is associated with acute kidney injury.

Age is a predominant risk factor for acute kidney injury (AKI), yet the biological mechanisms underlying this risk are largely unknown. Clonal hematopoiesis of indeterminate potential (CHIP) confers increased risk for several chronic diseases associated with aging. Here we sought to test whether CHIP increases the risk of AKI.

LI-RADS CT and MRI Ancillary Feature Association with Hepatocellular Carcinoma and Malignancy: An Individual Participant Data Meta-Analysis.

Background The independent contribution of each Liver Imaging Reporting and Data System (LI-RADS) CT or MRI ancillary feature (AF) has not been established. Purpose To evaluate the association of LI-RADS AFs with hepatocellular carcinoma (HCC) and malignancy while adjusting for LI-RADS major features through an individual participant data (IPD) meta-analysis. Materials and Methods Medline, Embase, Cochrane Central Register of Controlled Trials, and Scopus were searched from January 2014 to January 2022 for studies evaluating the diagnostic accuracy of CT and MRI for HCC using LI-RADS version 2014, 2017, or 2018.

Single Bolus r-SAK Before Primary PCI for ST-Segment-Elevation Myocardial Infarction.

Background: It is uncertain whether adjunctive thrombolysis is beneficial for patients with ST-segment-elevation myocardial infarction undergoing percutaneous coronary intervention (PCI) within 120 minutes of presentation. This study was to determine whether in patients presenting with ST-segment-elevation myocardial infarction a single bolus recombinant staphylokinase (r-SAK) before timely PCI leads to improved patency of the infarct-related artery and reduces the infarct size.

Methods: This is an open-label, prospective, multicenter, randomized study.