MLKL-mediated endothelial necroptosis drives vascular damage and mortality in systemic inflammatory response syndrome.

The hypersecretion of cytokines triggers life-threatening systemic inflammatory response syndrome (SIRS), leading to multiple organ dysfunction syndrome (MODS) and mortality. Although both coagulopathy and necroptosis have been identified as important factors in the pathogenesis of SIRS, the specific cell types that undergo necroptosis and the interrelationships between coagulopathy and necroptosis remain unclear. In this study, we utilized visualization analysis via intravital microscopy to demonstrate that both anticoagulant heparin and nonanticoagulant heparin (NAH) pretreatment protect mice against TNF-α-induced mortality in SIRS.

Altered Cell Clusters and Upregulated Aqp1 in Connexin 50 Knockout Lens Epithelium.

Purpose: To characterize the heterogeneity and cell clusters of postnatal lens epithelial cells (LECs) and to investigate the downstream targets of connexin 50 (Cx50) in the regulation of lens homeostasis and lens growth. To determine differentially expressed genes (DEGs) in the connexin 50 knockout (Cx50KO) lens epithelial cells that shed light on novel mechanism underlying the cataract and small size of the Cx50KO lenses.

Methods: Single-cell RNA sequencing (scRNA-seq) of lens epithelial cells isolated from one-month-old Cx50KO and wild-type (WT) mice were performed.

Designing novel ice creams using nut oil emulsion gels based on blueberry pectin and CaCl as fat replacers: Insights from physicochemical and sensory properties.

This study aimed to utilize blueberry pectin and calcium chloride to design a gel network structure for loading nut oils (peanut and walnut oil, respectively). The optimization of emulsion gel preparation was conducted through orthogonal experiments, utilizing the oil-holding ratio and gel strength as critical indicators. The emulsion gel was applied to the ice cream production.

Triple oxygen isotope reveals insolation-forced tropical moisture cycles.

Tropical oceans are the main global water vapor and latent heat sources, but their responses to radiative forcing remain unclear. Here, we investigate oceanic moisture dynamics of the western tropical Pacific (WTP) over the past 210,000 years through an approach of planktonic foraminiferal triple oxygen isotope (Δ'O). The Δ'O record is dominated by the precession cycles (~23,000 years), with lower values reflecting higher humidity in concert with higher Northern Hemisphere summer insolation.

Small-molecule GSDMD agonism in tumors stimulates antitumor immunity without toxicity.

Gasdermin-mediated inflammatory cell death (pyroptosis) can activate protective immunity in immunologically cold tumors. Here, we performed a high-throughput screen for compounds that could activate gasdermin D (GSDMD), which is expressed widely in tumors. We identified 6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline (DMB) as a direct and selective GSDMD agonist that activates GSDMD pore formation and pyroptosis without cleaving GSDMD.

Tumor editing suppresses innate and adaptive antitumor immunity and is reversed by inhibiting DNA methylation.

Cancer cells edit gene expression to evade immunosurveillance. However, genome-wide studies of gene editing during early tumorigenesis are lacking. Here we used single-cell RNA sequencing in a breast cancer genetically engineered mouse model (GEMM) to identify edited genes without bias.

A novel chemical probe based on the salamo-Co(II) complex for the highly selective fluorescence detection of tyrosine.

A new and rare Salamo-Co(II) complex probe L-Co was designed and synthesised. The structure of the [Co(L)(μ-OAc)(MeOH)]⋅2HO complex was obtained by X-ray diffraction experiments. Three Co(II) atoms are in a line in the complex, and all Co(II) atoms form a 6-coordinated octahedral configuration.

Upregulation of the Ca1.3 channel in inner hair cells by interleukin 6-dependent inflammaging contributes to age-related hearing loss.

Age-related hearing loss (AHL) is the most common sensory disorder amongst the older population. Inflammaging is a ≈chronic low-grade inflammation that worsens with age and is an early sign of AHL; however, the underlying mechanisms remain unclear. We used electrophysiological and genetic approaches to establish the importance of interleukin 6 (IL-6)-dependent inflammation in AHL.

Contrast enhancement boost improves the image quality of CT angiography derived from 80-kVp cerebral CT perfusion data.

Rationale And Objective: To investigate the impact of the contrast enhancement boost (CE-boost) technique on the image quality of CT angiography (CTA) derived from 80-kVp cerebral CT perfusion (CTP) data, and to compare it with conventional CTA as well as other currently employed methods for enhancing CTA images, such as CTA and CTA extracted from CTP.

Materials And Methods: The data of forty-seven patients who underwent CTP at 80 kVp were retrospectively collected. Four sets of images: CTA, CTA, CTA, and CE-boost images.

Curcumin attenuates lupus nephritis by inhibiting neutrophil migration via PI3K/AKT/NF-κB signalling pathway.

Objective: To investigate the role of curcumin in the treatment of lupus nephritis (LN) by inhibiting the migration of neutrophils and the underlying mechanism involved.

Methods: Two lupus mouse models, MRL/lpr mice and R848-treated mice, were treated with 50 mg/kg curcumin by intraperitoneal injection. H&E and Masson staining were used to estimate histopathological changes in the kidney.

Co-Transplantation-Based Human-Mouse Chimeric Brain Models to Study Human Glial-Glial and Glial-Neuronal Interactions.

Human-mouse chimeric brain models, generated by transplanting human induced pluripotent stem cell (hiPSC)-derived neural cells, are valuable for studying the development and function of human neural cells in vivo. Understanding glial-glial and glial-neuronal interactions is essential for unraveling the complexities of brain function and developing treatments for neurological disorders. To explore these interactions between human neural cells within an intact brain environment, we employe a co-transplantation strategy involving the engraftment of hiPSC-derived neural progenitor cells along with primitive macrophage progenitors into the neonatal mouse brain.

Ovarian function in patients with systemic lupus erythematosus: Pathogenesis, drug application and prospective therapies.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease in which multiple organs are damaged that prevails in fertile women. Currently, glucocorticoids and immunosuppressants are widely used to treat SLE patients. However, ovarian dysfunction occurs following the use of these drugs in women with SLE.

First insights into the age of the giant ice deposits in the Eisriesenwelt cave (Austria).

Frozen water is the most widespread type of ice present in ice caves and forms ice stalagmites and stalactites as well as floor ice, which is often several meters thick. Organic macroremains are commonly rare in this type of cave ice, which makes it difficult to establish a chronology and severely limits the use of such ice deposits as paleoenvironmental archives. Here, the chronology of such ice deposits in the inner part of the glaciated Eisriesenwelt, one of the world's largest ice caves located in the European Alps of Austria, is determined by a combination of radiocarbon and Th dating of cryogenic calcite.

Potent human neutralizing antibodies against Nipah virus derived from two ancestral antibody heavy chains.

Nipah virus (NiV) is a World Health Organization priority pathogen and there are currently no approved drugs for clinical immunotherapy. Through the use of a naïve human phage-displayed Fab library, two neutralizing antibodies (NiV41 and NiV42) targeting the NiV receptor binding protein (RBP) were identified. Following affinity maturation, antibodies derived from NiV41 display cross-reactivity against both NiV and Hendra virus (HeV), whereas the antibody based on NiV42 is only specific to NiV.

A Trisomy 21-linked Hematopoietic Gene Variant in Microglia Confers Resilience in Human iPSC Models of Alzheimer's Disease.

While challenging, identifying individuals displaying resilience to Alzheimer's disease (AD) and understanding the underlying mechanism holds great promise for the development of new therapeutic interventions to effectively treat AD. Down syndrome (DS), or trisomy 21, is the most common genetic cause of AD. Interestingly, some people with DS, despite developing AD neuropathology, show resilience to cognitive decline.

Identification and Characterization of Retinitis Pigmentosa in a Novel Mouse Model Caused by PDE6B-T592I.

The cGMP-phosphodiesterase 6 beta subunit (PDE6B) is an essential component in the phototransduction pathway for light responses in photoreceptor cells. PDE6B gene mutations cause the death of rod photoreceptors, named as hereditary retinitis pigmentosa (RP) in humans and retinal degeneration (RD) in rodents. Here, we report a new RD model, identified from a phenotypic screen of N-ethyl-N-nitrosourea (ENU)-induced mutant mice, which displays retinal degeneration caused by a point mutation in the gene that results in PDE6B-T592I mutant protein.

ABIN1 (Q478) is Required to Prevent Hematopoietic Deficiencies through Regulating Type I IFNs Expression.

A20-binding inhibitor of NF-κB activation (ABIN1) is a polyubiquitin-binding protein that regulates cell death and immune responses. Although Abin1 is located on chromosome 5q in the region commonly deleted in patients with 5q minus syndrome, the most distinct of the myelodysplastic syndromes (MDSs), the precise role of ABIN1 in MDSs remains unknown. In this study, mice with a mutation disrupting the polyubiquitin-binding site (Abin1 ) is generated.

Gasdermin D permeabilization of mitochondrial inner and outer membranes accelerates and enhances pyroptosis.

Gasdermin D (GSDMD)-activated inflammatory cell death (pyroptosis) causes mitochondrial damage, but its underlying mechanism and functional consequences are largely unknown. Here, we show that the N-terminal pore-forming GSDMD fragment (GSDMD-NT) rapidly damaged both inner and outer mitochondrial membranes (OMMs) leading to reduced mitochondrial numbers, mitophagy, ROS, loss of transmembrane potential, attenuated oxidative phosphorylation (OXPHOS), and release of mitochondrial proteins and DNA from the matrix and intermembrane space. Mitochondrial damage occurred as soon as GSDMD was cleaved prior to plasma membrane damage.

Treatment of autosomal dominant retinitis pigmentosa caused by RHO-P23H mutation with high-fidelity Cas13X in mice.

Mutations in (RHO) gene commonly cause autosomal dominant retinitis pigmentosa (adRP) without effective therapeutic treatment so far. Compared with genomic DNA-targeting CRISPR-Cas9 system, Cas13 edits RNA for therapeutic applications, avoiding the risk of causing permanent changes in the genome. In particular, a compact and high-fidelity Cas13X (hfCas13X) recently has been developed to degrade targeted RNA with minimal collateral effects and could also be packaged in a single adeno-associated virus for efficient delivery.

Holocene climate change in southern Oman deciphered by speleothem records and climate model simulations.

Qunf Cave oxygen isotope (δO) record from southern Oman is one of the most significant of few Holocene Indian summer monsoon cave records. However, the interpretation of the Qunf δO remains in dispute. Here we provide a multi-proxy record from Qunf Cave and climate model simulations to reconstruct the Holocene local and regional hydroclimate changes.

Structure-Based Discovery of a Novel Allosteric Inhibitor against Human Dopamine Transporter.

Human dopamine transporter (hDAT) regulates the reuptake of extracellular dopamine (DA) and is an essential therapeutic target for central nervous system (CNS) diseases. The allosteric modulation of hDAT has been identified for decades. However, the molecular mechanism underlying the transportation is still elusive, which hinders the rational design of allosteric modulators against hDAT.

Lightweight polyurethane composite foam for electromagnetic interference shielding with high absorption characteristic.

Due to the rapid growth of electronic equipment technology, efficient electromagnetic shielding materials are needed for equipment and human protection. Among them, foam shielding materials with absorption as the primary mechanism have higher application value than highly reflective materials. Highly absorbing shielding materials can reduce the secondary pollution caused by electromagnetic wave reflection.

Lipopolysaccharide and Glycolipoprotein Coordinately Triggered Necroptosis Contributes to the Pathogenesis of Leptospira Infection in Mice.

Leptospirosis is a recurring but neglected zoonotic disease caused by pathogenic Leptospira. The explicit underlying mechanism of necroptosis and its role in Leptospira infection have not yet been elucidated. Here we reported that leptospiral pathogen-associated molecular patterns, lipopolysaccharide, and glycolipoprotein activate the necroptotic RIPK1-RIPK3-MLKL cascade through the TLR4 signaling pathway in mouse macrophages.