The de novo design and synthesis of yeast chromosome XIII facilitates investigations on aging.

In the era of synthetic biology, design, construction, and utilization of synthetic chromosomes with unique features provide a strategy to study complex cellular processes such as aging. Herein, we successfully construct the 884 Kb synXIII of Saccharomyces cerevisiae to investigate replicative aging using these synthetic strains. We verify that up-regulation of a rRNA-related transcriptional factor, RRN9, positively influence replicative lifespan.

Enhancing transcription-replication conflict targets ecDNA-positive cancers.

Extrachromosomal DNA (ecDNA) presents a major challenge for cancer patients. ecDNA renders tumours treatment resistant by facilitating massive oncogene transcription and rapid genome evolution, contributing to poor patient survival. At present, there are no ecDNA-specific treatments.

Determining the Relationship Between Corneal Stiffening and Tissue Dehydration After Corneal Cross-Linking.

Purpose: To quantify corneal cross-linking (CXL)-induced stiffening via mechanical testing to estimate the impact of changes in hydration levels (H) and evaluate depth-dependent tissue hydration after CXL.

Methods: Eighty-three porcine corneal buttons were divided into three groups: Standard protocol CXL (S-CXL), accelerated CXL (A-CXL), and untreated (nonirradiated riboflavin-only) controls. Samples were hydrated or dehydrated to modulate H and dynamic mechanical analyzer compression tests were performed to measure Young's modulus (E).

NINJ1 regulates plasma membrane fragility under mechanical tension.

Plasma membrane integrity is vital not only for cell survival but also nearly all aspects of cell functioning1. Mechanical stress can cause plasma membrane damage2, but it is not known whether there are large molecules (proteins) that control plasma membrane integrity. Here we constructed a 384-well cellular stretch system that delivers precise, reproducible mechanical strain to adherent cells.

Single phage proteins sequester signals from TIR and cGAS-like enzymes.

Prokaryotic anti-phage immune systems use TIR and cGAS-like enzymes to produce 1''-3'-glycocyclic ADP-ribose (1''-3'-gcADPR) and cyclic dinucleotide (CDN) and cyclic trinucleotide (CTN) signalling molecules, respectively, which limit phage replication. However, how phages neutralize these distinct and common systems is largely unclear. Here we show that the Thoeris anti-defence proteins Tad1 and Tad2 both achieve anti-cyclic-oligonucleotide-based anti-phage signalling system (anti-CBASS) activity by simultaneously sequestering CBASS cyclic oligonucleotides.

CAR-Macrophage Therapy Alleviates Myocardial Ischemia-Reperfusion Injury.

Background: Given the growing acknowledgment of the detrimental effects of excessive myocardial fibrosis on pathological remodeling after myocardial ischemia-reperfusion injury (I/R), targeting the modulation of myocardial fibrosis may offer protective and therapeutic advantages. However, effective clinical interventions and therapies that target myocardial fibrosis remain limited. As a promising chimeric antigen receptor (CAR) cell therapy, whether CAR macrophages (CAR-Ms) can be used to treat I/R remains unclear.

Atrasentan in Patients with IgA Nephropathy.

Background: Patients with IgA nephropathy and severe proteinuria have a high lifetime risk of kidney failure. The efficacy and safety of the selective endothelin type A receptor antagonist atrasentan in reducing proteinuria in patients with IgA nephropathy are incompletely understood.

Methods: We are conducting a phase 3, multinational, double-blind, randomized, controlled trial involving adults with biopsy-proven IgA nephropathy, a total urinary protein excretion of at least 1 g per day, and an estimated glomerular filtration rate of at least 30 ml per minute per 1.

Alternative Complement Pathway Inhibition with Iptacopan in IgA Nephropathy.

Background: The alternative complement pathway plays a key role in the pathogenesis of IgA nephropathy. Iptacopan specifically binds to factor B and inhibits the alternative pathway.

Methods: In this phase 3, double-blind, randomized, placebo-controlled trial, we enrolled adults with biopsy-confirmed IgA nephropathy and proteinuria (defined as a 24-hour urinary protein-to-creatinine ratio of ≥1 [with protein and creatinine both measured in grams]) despite optimized supportive therapy.

Multi-omics analysis reveals the key factors involved in the severity of the Alzheimer's disease.

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder with a global impact, yet its pathogenesis remains poorly understood. While age, metabolic abnormalities, and accumulation of neurotoxic substances are potential risk factors for AD, their effects are confounded by other factors. To address this challenge, we first utilized multi-omics data from 87 well phenotyped AD patients and generated plasma proteomics and metabolomics data, as well as gut and saliva metagenomics data to investigate the molecular-level alterations accounting the host-microbiome interactions.

Sacubitril/Valsartan in Pediatric Heart Failure (PANORAMA-HF): A Randomized, Multicenter, Double-Blind Trial.

Background: Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), is an established treatment for heart failure (HF) with reduced left ventricular ejection fraction. It has not been rigorously compared with angiotensin-converting enzyme inhibitors in children. PANORAMA-HF (Prospective Trial to Assess the Angiotensin Receptor Blocker Neprilysin Inhibitor LCZ696 Versus Angiotensin-Converting Enzyme Inhibitor for the Medical Treatment of Pediatric HF) is a randomized, double-blind trial that evaluated the pharmacokinetics and pharmacodynamics (PK/PD), safety, and efficacy of sacubitril/valsartan versus enalapril in children 1 month to <18 years of age with HF attributable to systemic left ventricular systolic dysfunction (LVSD).

Prediction of Donor Heart Acceptance for Transplant and Its Clinical Implications: Results From The Donor Heart Study.

Background: Despite a shortage of potential donors for heart transplant in the United States, most potential donor hearts are discarded. We evaluated predictors of donor heart acceptance in the United States and applied machine learning methods to improve prediction.

Methods: We included a nationwide (2005-2020) cohort of potential heart donors in the United States (n=73 948) from the Scientific Registry of Transplant Recipients and a more recent (2015-2020) rigorously phenotyped cohort of potential donors from DHS (Donor Heart Study; n=4130).

C2H2-zinc-finger transcription factors bind RNA and function in diverse post-transcriptional regulatory processes.

Cys2-His2 zinc-finger proteins (C2H2-ZNFs) constitute the largest class of DNA-binding transcription factors (TFs) yet remain largely uncharacterized. Although certain family members, e.g.

Bacterial killing and the dimensions of bacterial death.

Bacteria can be dead, alive, or exhibit slowed or suspended life forms, making bacterial death difficult to establish. Here, agar-plating, microscopic-counting, SYTO9/propidium-iodide staining, MTT-conversion, and bioluminescence-imaging were used to determine bacterial death upon exposure to different conditions. Rank correlations between pairs of assay outcomes were low, indicating different assays measure different aspects of bacterial death.

Cross-regulations of two connected domains form a mechanical circuit for steady force transmission during clathrin-mediated endocytosis.

Mechanical forces are transmitted from the actin cytoskeleton to the membrane during clathrin-mediated endocytosis (CME) in the fission yeast Schizosaccharomyces pombe. End4p directly transmits force in CME by binding to both the membrane (through the AP180 N-terminal homology [ANTH] domain) and F-actin (through the talin-HIP1/R/Sla2p actin-tethering C-terminal homology [THATCH] domain). We show that 7 pN force is required for stable binding between THATCH and F-actin.

Structures of Th aqueous solutions: insights from AIMD and metadynamics simulations.

Solution chemistry of actinide ions is critical to understanding the solvation behaviors and hydrolysis process. Using tetravalent thorium ion Th as a representative example, we investigate the local structures and dynamic behaviors of hydrated Th ions by molecular dynamics (AIMD) simulations using the recently developed norm-conserving pseudopotentials and basis sets optimized for actinides (J.-B.

Agonist antibody to guanylate cyclase receptor NPR1 regulates vascular tone.

Heart failure is a leading cause of morbidity and mortality. Elevated intracardiac pressures and myocyte stretch in heart failure trigger the release of counter-regulatory natriuretic peptides, which act through their receptor (NPR1) to affect vasodilation, diuresis and natriuresis, lowering venous pressures and relieving venous congestion. Recombinant natriuretic peptide infusions were developed to treat heart failure but have been limited by a short duration of effect.

The pathogenesis of IgA nephropathy and implications for treatment.

IgA nephropathy (IgAN) is a common form of primary glomerulonephritis and represents an important cause of chronic kidney disease globally, with observational studies indicating that most patients are at risk of developing kidney failure within their lifetime. Several research advances have provided insights into the underlying disease pathogenesis, framed by a multi-hit model whereby an increase in circulating IgA1 that lacks galactose from its hinge region - probably derived from the mucosal immune system - is followed by binding of specific IgG and IgA antibodies, generating immune complexes that deposit within the glomeruli, which triggers inflammation, complement activation and kidney damage. Although treatment options are currently limited, new therapies are rapidly emerging that target different pathways, cells and mediators involved in the disease pathogenesis, including B cell priming in the gut mucosa, the cytokines APRIL and BAFF, plasma cells, complement activation and endothelin pathway activation.