High-throughput screen identifies MAS9 as a novel inhibitor of the C-type lectin receptor-2 (CLEC-2)-podoplanin interaction.

Background And Purpose: The C-type lectin-like receptor-2 (CLEC-2) is a platelet receptor for the endogenous ligand podoplanin. This interaction contributes to several (patho)physiological processes, such as lymphangiogenesis, preservation of blood and lymphatic vessel integrity organ development, and tumour metastasis. Activation of CLEC-2 leads to the phosphorylation of its cytoplasmic hemITAM domain and initiates a signalling cascade involving the kinase Syk.

Potential causal association between gut microbiota, inflammatory cytokines, and acute pancreatitis: A Mendelian randomization study.

Background: Acute pancreatitis (AP) ranks among the most frequently encountered gastrointestinal diseases in the emergency department. Recent studies have increasingly emphasized the substantial connection among gut microbiota, inflammatory cytokines, and AP.

Methods: A two-sample Mendelian randomization (MR) study was conducted using summary statistics of gut microbiota (GM) from the largest available meta-analysis of genome-wide association studies conducted by the MiBioGen consortium (=18,340).

Analysis of risk factors and construction of a predictive model for severe acute pancreatitis complicated by sinistral portal hypertension.

Objective: Sinistral portal hypertension (SPH) is a common complication of severe acute pancreatitis (SAP). Patients with SPH often present asymptomatic, but are at risk of gastrointestinal bleeding and abdominal bleeding due to the presence of varices of the corresponding vessels, which are often fatal. However, there is no prediction model for SAP combined with SPH.

Artificial Bone Materials for Infected Bone Defects: Advances in Antimicrobial Functions.

Infected bone defects, caused by bacterial contamination following disease or injury, result in the partial loss or destruction of bone tissue. Traditional bone transplantation and other clinical approaches often fail to address the therapeutic complexities of these conditions effectively. In recent years, advanced biomaterials have attracted significant attention for their potential to enhance treatment outcomes.

Qingyi decoction and its active ingredients ameliorate acute pancreatitis by regulating acinar cells and macrophages via NF-κB/NLRP3/Caspase-1 pathways.

Background And Purpose: Macrophage infiltration and activation is a critical step during acute pancreatitis (AP). NLRP3 inflammasomes in macrophages plays a critical role in mediating pancreatic inflammatory responses. Qing-Yi Decoction(QYD)has been used for many years in clinical practice of Nankai Hospital combined with traditional Chinese and western medicine treatment of acute pancreatitis.

Poldip2 promotes mtDNA elimination during Drosophila spermatogenesis to ensure maternal inheritance.

Maternal inheritance of mitochondrial DNA (mtDNA) is highly conserved in metazoans. While many species eliminate paternal mtDNA during late sperm development to foster maternal inheritance, the regulatory mechanisms governing this process remain elusive. Through a forward genetic screen in Drosophila, we identified 47 mutant lines exhibiting substantial retention of mtDNA in mature sperm.

Spatial proteomics identifies a CRTC-dependent viral signaling pathway that stimulates production of interleukin-11.

Appropriate cellular recognition of viruses is essential for the generation of an effective innate and adaptive immune response. Viral sensors and their downstream signaling components thus provide a crucial first line of host defense. Many of them exhibit subcellular relocalization upon activation, resulting in the expression of interferon and antiviral genes.

Highly sensitive, breathable, and superhydrophobic dome structure nonwoven-based flexible pressure sensor utilizing machine learning for handwriting recognition.

Wearable devices that incorporate flexible pressure sensors have shown great potential for human-machine interaction, speech recognition, health monitoring, and handwriting recognition. However, achieving high sensitivity, durability, wide detection range, and breathability through cost-effective fabrication remains challenging. Through ultrasound-assisted modification and impregnation-drying, dome-structured nonwovens/rGO/PDMS flexible pressure sensors were developed.

Acute Necrotizing Pancreatitis Complicated with Paroxysmal Nocturnal Haemoglobinuria: A Case Report.

This report presents a unique case of acute necrotizing pancreatitis(ANP) concomitant with paroxysmal nocturnal hemoglobinuria(PNH), a combination that has not been documented in existing literature. The impact of PNH on ANP and its treatment remains uncertain due to the lack of consensus. The case described herein involves a patient who exhibited both ANP and PNH, subsequently experiencing splanchnic vein thrombosis (SVT), resulting in substantial intra-abdominal and gastrointestinal hemorrhaging.

Two mitochondrial DNA polymorphisms modulate cardiolipin binding and lead to synthetic lethality.

Genetic screens have been used extensively to probe interactions between nuclear genes and their impact on phenotypes. Probing interactions between mitochondrial genes and their phenotypic outcome, however, has not been possible due to a lack of tools to map the responsible polymorphisms. Here, using a toolkit we previously established in Drosophila, we isolate over 300 recombinant mitochondrial genomes and map a naturally occurring polymorphism at the cytochrome c oxidase III residue 109 (CoIII) that fully rescues the lethality and other defects associated with a point mutation in cytochrome c oxidase I (CoI).

Quantitative proteomics defines mechanisms of antiviral defence and cell death during modified vaccinia Ankara infection.

Modified vaccinia Ankara (MVA) virus does not replicate in human cells and is the vaccine deployed to curb the current outbreak of mpox. Here, we conduct a multiplexed proteomic analysis to quantify >9000 cellular and ~80% of viral proteins throughout MVA infection of human fibroblasts and macrophages. >690 human proteins are down-regulated >2-fold by MVA, revealing a substantial remodelling of the host proteome.

Trivalent nanobody-based ligands mediate powerful activation of GPVI, CLEC-2, and PEAR1 in human platelets whereas FcγRIIA requires a tetravalent ligand.

Background: Clustering of the receptors glycoprotein receptor VI (GPVI), C-type lectin-like receptor 2 (CLEC-2), low-affinity immunoglobulin γ Fc region receptor II-a (FcγRIIA), and platelet endothelial aggregation receptor 1 (PEAR1) leads to powerful activation of platelets through phosphorylation of tyrosine in their cytosolic tails and initiation of downstream signaling cascades. GPVI, CLEC-2, and FcγRIIA signal through YxxL motifs that activate Syk. PEAR1 signals through a YxxM motif that activates phosphoinositide 3-kinase.

Milton assembles large mitochondrial clusters, mitoballs, to sustain spermatogenesis.

Mitochondria are dynamic organelles that undergo frequent remodeling to accommodate developmental needs. Here, we describe a striking organization of mitochondria into a large ball-like structure adjacent to the nucleus in premeiotic spermatocytes, which we term "mitoball". Mitoballs are transient structures that colocalize with the endoplasmic reticulum, Golgi bodies, and the fusome.

Thromboelastography parameters in chronic viral liver disease and liver resection: a retrospective study.

Introduction: Thromboelastography (TEG) provides a global assessment of haemostasis and is potentially applicable to liver disease. The present study aimed to explore the utility of TEG for the evaluation of patients with chronic viral liver disease, which has previously not been investigated.

Methods: Demographic characteristics and TEG parameters were collected before surgery.

Divalent nanobodies to platelet CLEC-2 can serve as agonists or antagonists.

CLEC-2 is a target for a new class of antiplatelet agent. Clustering of CLEC-2 leads to phosphorylation of a cytosolic YxxL and binding of the tandem SH2 domains in Syk, crosslinking two receptors. We have raised 48 nanobodies to CLEC-2 and crosslinked the most potent of these to generate divalent and tetravalent nanobody ligands.

Influence of Confining Pressure on Nonlinear Failure Characteristics of Coal Subjected to Triaxial Compression.

The stress of a coal seam increases with an increase in the mining depth, which makes the failure mechanism of a coal mass more complex. To reveal the deformation and failure law of deep coal, a series of triaxial experiments was carried out via laboratory experiments and numerical simulation experiments to analyze the influence of the confining stress on the nonlinear failure characteristics of coal. Based on the crack-propagation model, the values for the inelastic flexibility and the damage variable were calculated.

Experimental validation of computerised models of clustering of platelet glycoprotein receptors that signal via tandem SH2 domain proteins.

The clustering of platelet glycoprotein receptors with cytosolic YxxL and YxxM motifs, including GPVI, CLEC-2 and PEAR1, triggers activation via phosphorylation of the conserved tyrosine residues and recruitment of the tandem SH2 (Src homology 2) domain effector proteins, Syk and PI 3-kinase. We have modelled the clustering of these receptors with monovalent, divalent and tetravalent soluble ligands and with transmembrane ligands based on the law of mass action using ordinary differential equations and agent-based modelling. The models were experimentally evaluated in platelets and transfected cell lines using monovalent and multivalent ligands, including novel nanobody-based divalent and tetravalent ligands, by fluorescence correlation spectroscopy.

REC drives recombination to repair double-strand breaks in animal mtDNA.

Mechanisms that safeguard mitochondrial DNA (mtDNA) limit the accumulation of mutations linked to mitochondrial and age-related diseases. Yet, pathways that repair double-strand breaks (DSBs) in animal mitochondria are poorly understood. By performing a candidate screen for mtDNA repair proteins, we identify that REC-an MCM helicase that drives meiotic recombination in the nucleus-also localizes to mitochondria in Drosophila.

Measurement of tigecycline in dried blood spots by LC-MS/MS and comparison tigecycline concentrations between whole blood and plasma.

Rationale: An LC-MS/MS method was established to measure tigecycline in dried blood spots (DBSs).

Methods: The DBS specimens obtained by applying 30 μl of blood to filter paper were extracted with hydrogen oxide and subsequently precipitated protein with perchloric acid, then the extract was directly analyzed by liquid chromatography tandem mass spectrometry. A Hypersil GOLD aQ column was utilized for separating the analytes, and detection was carried out in positive and selective reaction monitoring modes.

Anti-GPVI nanobody blocks collagen- and atherosclerotic plaque-induced GPVI clustering, signaling, and thrombus formation.

Background: The collagen receptor glycoprotein VI (GPVI) is an attractive antiplatelet target due to its critical role in thrombosis but minor involvement in hemostasis.

Objective: To investigate GPVI receptor involvement in platelet activation by collagen-I and atherosclerotic plaque using novel blocking and non-blocking anti-GPVI nanobodies (Nbs).

Methods: Nb effects on GPVI-mediated signaling and function were assessed by western blot and whole blood thrombus formation under flow.

CLEC-2 Supports Platelet Aggregation in Mouse but not Human Blood at Arterial Shear.

C-type lectin-like receptor 2 (CLEC-2) is highly expressed on platelets and a subpopulation of myeloid cells, and is critical in lymphatic development. CLEC-2 has been shown to support thrombus formation at sites of inflammation, but to have a minor/negligible role in hemostasis. This identifies CLEC-2 as a promising therapeutic target in thromboinflammatory disorders, without hemostatic detriment.

[Value of red blood cell distribution width in evaluating the severity of illness of novel coronavirus Delta variant].

Objective: To explore the value of red blood cell distribution width (RDW) in evaluating the severity of patients infected with novel coronavirus Delta variant.

Methods: A total of 28 patients infected with novel coronavirus Delta variant in designated hospital treated by the First Affiliated Hospital of Xi'an Jiaotong University medical team from December 2021 to January 2022 were enrolled (23 cases of common type, 4 severe and 1 critical cases). The detailed clinical data of patients was collected.

Katacine Is a New Ligand of CLEC-2 that Acts as a Platelet Agonist.

Background:  CLEC-2 is a platelet receptor with an important role in thromboinflammation but a minor role in hemostasis. Two endogenous ligands of CLEC-2 have been identified, the transmembrane protein podoplanin and iron-containing porphyrin hemin, which is formed following hemolysis from red blood cells. Other exogenous ligands such as rhodocytin have contributed to our understanding of the role of CLEC-2.