A polymer-like ultrahigh-strength metal alloy.

Futuristic technologies such as morphing aircrafts and super-strong artificial muscles depend on metal alloys being as strong as ultrahigh-strength steel yet as flexible as a polymer. However, achieving such 'strong yet flexible' alloys has proven challenging because of the inevitable trade-off between strength and flexibility. Here we report a Ti-50.

Development and validation of a clinical breast cancer tool for accurate prediction of recurrence.

Given high costs of Oncotype DX (ODX) testing, widely used in recurrence risk assessment for early-stage breast cancer, studies have predicted ODX using quantitative clinicopathologic variables. However, such models have incorporated only small cohorts. Using a cohort of patients from the National Cancer Database (NCDB, n = 53,346), we trained machine learning models to predict low-risk (0-25) or high-risk (26-100) ODX using quantitative estrogen receptor (ER)/progesterone receptor (PR)/Ki-67 status, quantitative ER/PR status alone, and no quantitative features.

Accuracy of Modern Intraocular Lens Formulas in Highly Myopic Eyes Implanted With Plate-Haptic Intraocular Lenses.

Purpose: To evaluate the predictive accuracy of modern intraocular lens (IOL) formulas and axial length (AL) adjusted traditional IOL formulas, including Wang-Koch and Cooke-modified AL (CMAL) method, in long eyes with plate-haptic IOLs, and to compare refractive prediction error variances with C-loop IOLs.

Design: Retrospective consecutive case series study.

Methods: Data from 391 eyes with Zeiss 509 M and 302 eyes with Alcon SN6CWS implants in highly myopic patients, following cataract surgery from January 2019 to November 2023, were collected.

Single-Molecule Spatial Transcriptomics of Human Thoracic Aortic Aneurysms Uncovers Calcification-Related -Expressing Smooth Muscle Cells.

Background: Although single-cell RNA-sequencing is commonly applied to dissect the heterogeneity in human tissues, it involves the preparation of single-cell suspensions via cell dissociation, causing loss of spatial information. In this study, we employed high-resolution single-cell transcriptome imaging to reveal rare smooth muscle cell (SMC) types in human thoracic aortic aneurysm (TAA) tissue samples.

Methods: Single-molecule spatial distribution of transcripts from 140 genes was analyzed in fresh-frozen human TAA samples with region and sex-matched controls.

Breast cancer PDxO cultures for drug discovery and functional precision oncology.

Patient-derived xenografts (PDXs) have clinical value but are time-, cost-, and labor-intensive and thus ill-suited for large-scale experiments. Here, we present a protocol to convert PDX tumors into PDxOs for long-term cultures amenable to moderate-throughput drug screens, including in-depth PDxO validation. We describe steps for PDxO preparation and mouse cell removal.

DT-109 ameliorates nonalcoholic steatohepatitis in nonhuman primates.

Nonalcoholic steatohepatitis (NASH) prevalence is rising with no pharmacotherapy approved. A major hurdle in NASH drug development is the poor translatability of preclinical studies to safe/effective clinical outcomes, and recent failures highlight a need to identify new targetable pathways. Dysregulated glycine metabolism has emerged as a causative factor and therapeutic target in NASH.

Mutations in the MET tyrosine kinase domain and resistance to tyrosine kinase inhibitors in non-small-cell lung cancer.

Background: The Mesenchymal epithelial transition factor (MET) gene encodes a receptor tyrosine kinase with pleiotropic functions in cancer. MET exon 14 skipping alterations and high-level MET amplification are oncogenic and targetable genetic changes in patients with non-small-cell lung cancer (NSCLC). Resistance to tyrosine kinase inhibitors (TKIs) has been a major challenge for targeted therapies that impairs their clinical efficacies.

Lp-PLA (Lipoprotein-Associated Phospholipase A) Deficiency Lowers Cholesterol Levels and Protects Against Atherosclerosis in Rabbits.

Background: Elevated plasma Lp-PLA (lipoprotein-associated phospholipase A) activity is closely associated with an increased risk of cardiovascular events. However, whether and how Lp-PLA is directly involved in the pathogenesis of atherosclerosis is still unclear. To examine the hypothesis that Lp-PLA could be a potential preventative target of atherosclerosis, we generated Lp-PLA knockout rabbits and investigated the pathophysiological functions of Lp-PLA.

Induction of glutathione biosynthesis by glycine-based treatment mitigates atherosclerosis.

Lower circulating levels of glycine are consistently reported in association with cardiovascular disease (CVD), but the causative role and therapeutic potential of glycine in atherosclerosis, the underlying cause of most CVDs, remain to be established. Here, following the identification of reduced circulating glycine in patients with significant coronary artery disease (sCAD), we investigated a causative role of glycine in atherosclerosis by modulating glycine availability in atheroprone mice. We further evaluated the atheroprotective potential of DT-109, a recently identified glycine-based compound with dual lipid/glucose-lowering properties.

Macrophage-derived IGF-1 protects the neonatal intestine against necrotizing enterocolitis by promoting microvascular development.

Necrotizing enterocolitis (NEC) is a deadly bowel necrotic disease of premature infants. Low levels of plasma IGF-1 predispose premature infants to NEC. While increasing evidence suggests that defective perinatal intestinal microvascular development plays a role in NEC, the involved mechanism remains incompletely understood.

Glaucoma and risk factors three years after congenital cataract surgery.

Background: This study aimed to identify the incidence of and risk factors for postoperative glaucoma-related adverse events at various time points after congenital cataract surgery.

Methods: This retrospective cohort study enrolled 259 eyes from 174 patients (surgical age ≤ 7 years) who underwent congenital cataract surgery. All surgical procedures were conducted at the Eye Hospital of Wenzhou Medical University between May 2011 and March 2019.

Epidemiologic and Genetic Associations of Erythropoietin With Blood Pressure, Hypertension, and Coronary Artery Disease.

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Endothelial TFEB (Transcription Factor EB) Improves Glucose Tolerance via Upregulation of IRS (Insulin Receptor Substrate) 1 and IRS2.

Objective: Vascular endothelial cells (ECs) play a critical role in maintaining vascular homeostasis. Aberrant EC metabolism leads to vascular dysfunction and metabolic diseases. TFEB (transcription factor EB), a master regulator of lysosome biogenesis and autophagy, has protective effects on vascular inflammation and atherosclerosis.

Glycine-based treatment ameliorates NAFLD by modulating fatty acid oxidation, glutathione synthesis, and the gut microbiome.

Nonalcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis (NASH) has reached epidemic proportions with no pharmacological therapy approved. Lower circulating glycine is consistently reported in patients with NAFLD, but the causes for reduced glycine, its role as a causative factor, and its therapeutic potential remain unclear. We performed transcriptomics in livers from humans and mice with NAFLD and found suppression of glycine biosynthetic genes, primarily alanine-glyoxylate aminotransferase 1 ().

MiCas9 increases large size gene knock-in rates and reduces undesirable on-target and off-target indel edits.

Gene editing nuclease represented by Cas9 efficiently generates DNA double strand breaks at the target locus, followed by repair through either the error-prone non-homologous end joining or the homology directed repair pathways. To improve Cas9's homology directed repair capacity, here we report the development of miCas9 by fusing a minimal motif consisting of thirty-six amino acids to spCas9. MiCas9 binds RAD51 through this fusion motif and enriches RAD51 at the target locus.

BAF60a Deficiency in Vascular Smooth Muscle Cells Prevents Abdominal Aortic Aneurysm by Reducing Inflammation and Extracellular Matrix Degradation.

Objective: Currently, there are no approved drugs for abdominal aortic aneurysm (AAA) treatment, likely due to limited understanding of the primary molecular mechanisms underlying AAA development and progression. BAF60a-a unique subunit of the SWI/SNF (switch/sucrose nonfermentable) chromatin remodeling complex-is a novel regulator of metabolic homeostasis, yet little is known about its function in the vasculature and pathogenesis of AAA. In this study, we sought to investigate the role and underlying mechanisms of vascular smooth muscle cell (VSMC)-specific BAF60a in AAA formation.

Brown Adipocyte-Specific PPARγ (Peroxisome Proliferator-Activated Receptor γ) Deletion Impairs Perivascular Adipose Tissue Development and Enhances Atherosclerosis in Mice.

Objective- Perivascular adipose tissue (PVAT) contributes to vascular homeostasis by producing paracrine factors. Previously, we reported that selective deletion of PPARγ (peroxisome proliferator-activated receptor γ) in vascular smooth muscle cells resulted in concurrent loss of PVAT and enhanced atherosclerosis in mice. To address the causal relationship between loss of PVAT and atherosclerosis, we used BA-PPARγ-KO (brown adipocyte-specific PPARγ knockout) mice.

Bmal1 in Perivascular Adipose Tissue Regulates Resting-Phase Blood Pressure Through Transcriptional Regulation of Angiotensinogen.

Background: The perivascular adipose tissue (PVAT) surrounding vessels constitutes a distinct functional integral layer of the vasculature required to preserve vascular tone under physiological conditions. However, there is little information on the relationship between PVAT and blood pressure regulation, including its potential contributions to circadian blood pressure variation.

Methods: Using unique brown adipocyte-specific aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1) and angiotensinogen knockout mice, we determined the vasoactivity of homogenized PVAT in aortic rings and how brown adipocyte peripheral expression of Bmal1 and angiotensinogen in PVAT regulates the amplitude of diurnal change in blood pressure in mice.

Macrophage exosomes as natural nanocarriers for protein delivery to inflamed brain.

Recent work has stimulated interest in the use of exosomes as nanocarriers for delivery of small drugs, RNAs, and proteins to the central nervous system (CNS). To overcome the blood-brain barrier (BBB), exosomes were modified with brain homing peptides that target brain endothelium but likely to increase immune response. Here for the first time we demonstrate that there is no need for such modification to penetrate the BBB in mammals.

Small Intracranial Aneurysms: Diagnostic Accuracy of CT Angiography.

Purpose To assess the accuracy of computed tomographic (CT) angiography for diagnosis of cerebral aneurysms 5 mm or smaller, with digital subtraction angiography (DSA) as the reference standard, in a large patient cohort Materials and Methods This retrospective study was approved by the local institutional review board with a waiver of written informed consent. A total of 1366 patients who underwent cerebral CT angiography followed by DSA were included. The performance of CT angiography for depiction of aneurysms was evaluated by two readers on a per-patient and per-aneurysm basis and based on size of aneurysm, location, and status of rupture.

Beneficial Role of Erythrocyte Adenosine A2B Receptor-Mediated AMP-Activated Protein Kinase Activation in High-Altitude Hypoxia.

Background: High altitude is a challenging condition caused by insufficient oxygen supply. Inability to adjust to hypoxia may lead to pulmonary edema, stroke, cardiovascular dysfunction, and even death. Thus, understanding the molecular basis of adaptation to high altitude may reveal novel therapeutics to counteract the detrimental consequences of hypoxia.

Cas9-Assisted Targeting of CHromosome segments CATCH enables one-step targeted cloning of large gene clusters.

The cloning of long DNA segments, especially those containing large gene clusters, is of particular importance to synthetic and chemical biology efforts for engineering organisms. While cloning has been a defining tool in molecular biology, the cloning of long genome segments has been challenging. Here we describe a technique that allows the targeted cloning of near-arbitrary, long bacterial genomic sequences of up to 100 kb to be accomplished in a single step.

In vivo evidence of pathogenicity of VPS35 mutations in the Drosophila.

Mutations of VPS35, a component of the retromer complex have been associated with late onset familial Parkinson's disease. The D620N mutation in VPS35 appears to be most prevalent, however, P316S was found in two cases within the same family and a control, whereas L774M was identified in 6 cases and 1 control. In vivo evidence of their pathogenicity is lacking.

Pulmonary embolism and renal vein thrombosis in patients with nephrotic syndrome: prospective evaluation of prevalence and risk factors with CT.

Purpose: To prospectively determine the prevalence of pulmonary embolism ( PE pulmonary embolism ) and renal vein thrombosis ( RVT renal vein thrombosis ) with computed tomography (CT) and to identify markers predictive of PE pulmonary embolism and/or RVT renal vein thrombosis in a large consecutive cohort of patients with nephrotic syndrome.

Materials And Methods: This study was approved by the local institutional review board, and all patients or their guardians provided written informed consent. Consecutive patients with nephrotic syndrome (24-hour urine protein > 3.

Large-scale phosphotyrosine proteomic profiling of rat renal collecting duct epithelium reveals predominance of proteins involved in cell polarity determination.

Although extensive phosphoproteomic information is available for renal epithelial cells, previous emphasis has been on phosphorylation of serines and threonines with little focus on tyrosine phosphorylation. Here we have carried out large-scale identification of phosphotyrosine sites in pervanadate-treated native inner medullary collecting ducts of rat, with a view towards identification of physiological processes in epithelial cells that are potentially regulated by tyrosine phosphorylation. The method combined antibody-based affinity purification of tyrosine phosphorylated peptides coupled with immobilized metal ion chromatography to enrich tyrosine phosphopeptides, which were identified by LC-MS/MS.