Interspecies differences in protein expression do not impact the spatiotemporal regulation of glycoprotein VI mediated activation

Background Accurate protein quantification is a vital prerequisite for generating meaningful predictions when using systems biology approaches, a method that is increasingly being used to unravel the complexities of sub cellular interactions and as part of the drug discovery process. Quantitative proteomics, flow cytometry and western blotting have been extensively used to define human platelet protein copy numbers, yet for mouse platelets, a model widely used for platelet research, evidence is largely limited to a single proteomic dataset in which the total amount of proteins were generally comparatively higher than those found in human platelets. Objectives To investigate the functional implications of discrepancies between levels of mouse and human proteins in the GPVI signalling pathway using a systems pharmacology model of GPVI Methods The protein copy number of mouse platelet receptors was determined using flow cytometry. The Virtual Platelet, a mathematical model of Glycoprotein VI (GPVI) signalling, was used to determine the consequences of protein copy number differences observed between human and mouse platelets. Results and conclusion Despite the small size of mouse platelets compared to human platelets they possessed a greater density of surface receptors alongside a higher concentration of intracellular signalling proteins. Surprisingly the predicted temporal profile of Syk activity was similar in both species with predictions supported experimentally. Super resolution microscopy demonstrates that the spatial distribution of Syk is similar between species, suggesting that the spatial distribution of receptors and signalling molecules in activated platelets, rather than their copy number, is important for signalling pathway regulation

OSS Malicious Package Analysis in the Wild

The open-source software (OSS) ecosystem suffers from various security threats and risks, and malicious packages play a central role in software supply chain (SSC) attacks. Although malware research has a history of over thirty years, less attention has been paid to OSS malware. Its existing research has three limitations: a lack of high-quality datasets, malware diversity, and attack campaign context. In this paper, we first build and curate the largest dataset of 23,425 malicious packages from scattered online sources. We then propose a knowledge graph to represent the OSS malware corpus and conduct malicious package analysis in the wild. Our main findings include (1) it is essential to collect malicious packages from various online sources because there is little data overlap between different sources; (2) despite the sheer volume of SSC attack campaigns, many malicious packages are similar, and unknown/sophisticated attack behaviors have yet to emerge or be detected; (3) OSS malicious package has its distinct life cycle, denoted as {changing->release->detection->removal}, and slightly changing the package (different name) is a widespread attack manner; (4) while malicious packages often lack context about how and who released them, security reports disclose the information about corresponding SSC attack campaigns

AutoFirm: Automatically Identifying Reused Libraries inside IoT Firmware at Large-Scale

The Internet of Things (IoT) has become indispensable to our daily lives and work. Unfortunately, developers often reuse software libraries in the IoT firmware, leading to a major security concern. If vulnerabilities or insecure versions of these libraries go unpatched, a massive number of IoT devices can be impacted. In this paper, we propose the AutoFirm, an automated tool for detecting reused libraries in IoT firmware at a large scale. Specifically, AutoFirm leverages the syntax information (library name and version) to determine whether IoT firmware reuses the libraries. We conduct a large-scale empirical study of reused libraries of IoT firmware, investigating more than 6,900+ firmware and 2,700+ distinct vulnerabilities affecting 11,300+ vulnerable versions from 349 open-source software libraries. Leveraging this diverse information set, we conduct a qualitative assessment of vulnerable library versions to understand security gaps and the misplaced trust of libraries in IoT firmware. Our research reveals that: manufacturers neglected to update outdated libraries for IoT firmware in 67.3\% of cases; on average, outdated libraries persisted for over 1.34 years prior to remediation; vulnerabilities of software libraries have posed server threats to widespread IoT devices.Comment: 13 pages, 20 figure

Correlation between systemic immune inflammatory index and prognosis of patients with hepatic alveolar hydatid disease and establishment of a nomogram prediction model

BackgroundTo explore the evaluation value of systemic immune inflammation index (SII) in the prognosis of patients with alveolar hydatid disease, and establish a nomogram prediction model.MethodsCollect the clinical data of 351 patients undergoing hepatic alveolar hydatid surgery admitted to the Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Qinghai University from January 2015 to December 2020, calculate the SII value, and use the receiver operating characteristic curve (ROC curve) to determine According to the optimal clinical cut-off value of SII, patients were divided into two groups with high SII and low SII, and the relationship between SII and clinicopathological factors and prognosis of patients with alveolar echinococcosis was analyzed. Establish a nomogram prediction model based on independent risk factors for patient prognosis, and evaluate the prediction accuracy and discrimination ability of the nomogram through the consistency index (C-index) and calibration curve. The result is through the use of bootstrapping validation with 1,000 re-sampling Method for internal verification.ResultsThe ROC curve was used to determine the optimal cut-off value of SII before operation 761.192, and patients were divided into low SII group (n = 184) cases and high SII group (n = 167) cases. The 1, 3, and 5-year survival rates of patients with hepatic alveolar hydatid in the low SII group and the high SII group were 98.90%, 96.90%, 86.50% and 98.20%, 72.50%, 40.30%, respectively. The survival rate of worm disease patients was significantly better than that of the high SII group, and the overall survival rate difference between the two groups was statistically significant (P < 0.001). Multivariate Cox regression model analysis results showed that intraoperative blood loss (HR = 1.810, 95%CI: 1.227–2.668, P = 0.003), SII (HR = 5.011, 95%CI: 3.052–8.228, P < 0.001), Complications (HR = 1.720, 95%CI: 1.162–2.545, P = 0.007) are independent risk factors for the prognosis of patients with alveolar hydatid disease. Draw a nomogram and include statistically significant factors in the multivariate Cox regression model to predict the overall survival rate of patients with alveolar hydatid disease at 1, 3, and 5 years. The survival probability calibration curve is displayed. The nomogram is compared with The actual results have a high degree of agreement. The concordance index (C-index) of the nomogram model in the modeling sample is 0.777, and the C-index in the verification sample is 0.797, indicating that the nomogram model of this study has good accuracy and discrimination.ConclusionsSII has a clear correlation to the prognosis of patients with alveolar echinococcosis. The nomogram prediction model constructed on this basis is beneficial to the clinically individualized analysis of the patient's prognosis

Lymphatic blood filling in CLEC-2-deficient mouse models

C-type lectin-like receptor 2 (CLEC-2) is considered as a potential drug target in settings of wound healing, inflammation, and infection. A potential barrier to this is evidence that CLEC-2 and its ligand podoplanin play a critical role in preventing lymphatic vessel blood filling in mice throughout life. In this study, this aspect of CLEC-2/podoplanin function is investigated in more detail using new and established mouse models of CLEC-2 and podoplanin deficiency, and models of acute and chronic vascular remodeling. We report that CLEC-2 expression on platelets is not required to maintain a barrier between the blood and lymphatic systems in unchallenged mice, post-development. However, under certain conditions of chronic vascular remodeling, such as during tumorigenesis, deficiency in CLEC-2 can lead to lymphatic vessel blood filling. These data provide a new understanding of the function of CLEC-2 in adult mice and confirm the essential nature of CLEC-2-driven platelet activation in vascular developmental programs. This work expands our understanding of how lymphatic blood filling is prevented by CLEC-2-dependent platelet function and provides a context for the development of safe targeting strategies for CLEC-2 and podoplanin

Exploring the causal role of plasma metabolites and metabolite ratios in prostate cancer: a two-sample Mendelian randomization study

BackgroundProstate cancer (PCa), the most prevalent malignant neoplasm in males, involves complex biological mechanisms and risk factors, many of which remain unidentified. By employing a novel two-sample Mendelian randomization (MR) approach, this study aims to elucidate the causal relationships between the circulating metabolome and PCa risk, utilizing comprehensive data on genetically determined plasma metabolites and metabolite ratios.MethodsFor the MR analysis, we utilized data from the GWAS Catalog database to analyze 1,091 plasma metabolites and 309 ratios in relation to PCa outcomes within two independent GWAS datasets. The inverse variance weighted (IVW) method was the primary approach for determining the existence of the causal relationship, supplemented by additional MR methods for heterogeneity, pleiotropy, and cross-validation. The false discovery rate (FDR) and Bonferroni correction were applied to identify the most significant causative associations. Additionally, reverse MR and Steiger filtering were conducted to ascertain whether PCa influenced the observed metabolite levels. Furthermore, metabolic pathway analysis was conducted with MetaboAnalyst 6.0 software.ResultsIn the MR analysis, our findings reveal three overlapped metabolite ratios (arginine to glutamate, phosphate to uridine, and glycerol to mannitol/sorbitol) inversely associated with PCa risk. Following FDR correction (FDR < 0.05), cysteinylglycine disulfide was identified as a potential reducer of PCa risk, whereas Uridine and N-acetyl-L-glutamine (NAG) were pinpointed as potential risk factors. Notably, NAG (OR 1.044; 95% CI 1.025–1.063) emerged as a metabolite with significant causal influence, as confirmed by stringent Bonferroni correction (P < 0.05/1400). Steiger’s directionality test (P < 0.001) and reverse MR confirmed the proposed causal direction. Furthermore, metabolic pathway analysis revealed a significant association between the “Glutathione Metabolism” pathway and PCa development.ConclusionThis study provides novel insights into the potential causal effects of plasma metabolites and metabolite ratios on PCa. The identified metabolites and ratios could serve as candidate biomarkers, contributing to the elucidation of PCa’s biological mechanisms

Effects of Matrices on the Structure and Properties of Composite Films of Soy Protein Isolates/Xanthan Gum

The structures and properties of the composite films formed by soy protein isolate (SPI) and xanthan gum (XG) with different other matrices were investigated. The composite films were prepared with SPI and XG by adding sodium alginate (SA), carboxymethyl cellulose (CMC), gelatin (GEL), pectin (PEC) and agar (Agar), respectively. The thickness, mechanical properties, oxygen permeability and opacity of the composite films were measured, and their structures were characterized. The results showed that the thicknesses of composite films with 1.5 g of different other matrices were significantly higher (P<0.05) than the film of SPI/XG, and the maximum tensile strength was 5.90±0.32 MPa for SPI/XG-Agar film (P<0.05), the oxygen permeabilities of them were significantly reduced (P<0.05), and the lowest opacity was 0.45±0.09 Abs600/mm for SPI/XG-Agar film (P<0.05). The photograph of SEM showed that the surface of SPI/XG-Agar composite film was flat, smooth and free of particles, while the other composite films were with particles and folds on the surface. The infrared spectroscopy analysis showed that there was good compatibility between all the matrices. The results of tensile strength, opacity and SEM for the SPI/XG-Agar film were superior to other films

A Bi-Functional Anti-Thrombosis Protein Containing Both Direct-Acting Fibrin(ogen)olytic and Plasminogen-Activating Activities

Direct-acting fibrin(ogen)olytic agents such as plasmin have been proved to contain effective and safety thrombolytic potential. Unfortunately, plasmin is ineffective when administered by the intravenous route because it was neutralized by plasma antiplasmin. Direct-acting fibrin(ogen)olytic agents with resistance against antiplasmin will brighten the prospect of anti-thrombosis. As reported in ‘Compendium of Materia Medica’, the insect of Eupolyphaga sinensis Walker has been used as traditional anti-thrombosis medicine without bleeding risk for several hundreds years. Currently, we have identified a fibrin(ogen)olytic protein (Eupolytin1) containing both fibrin(ogen)olytic and plasminogen-activating (PA) activities from the beetle, E. sinensis. Objectives: To investigate the role of native and recombinant eupolytin1 in fibrin(ogen)olytic and plasminogen-activating processes. Methods and Results: Using thrombus animal model, eupolytin1 was proved to contain strong and rapid thrombolytic ability and safety in vivo, which are better than that of urokinase. Most importantly, no bleeding complications were appeared even the intravenous dose up to 0.12 µmol/kg body weight (3 times of tested dose which could completely lyse experimental thrombi) in rabbits. It is the first report of thrombolytic agents containing both direct-acting fibrin(ogen)olytic and plasminogen-activating activities. Conclusions: The study identified novel thrombolytic agent with prospecting clinical potential because of its bi-functional merits containing both plasmin- and PA-like activities and unique pharmacological kinetics in vivo

Simultaneous Quantitation of Oxidized and Reduced Glutathione via LC-MS/MS: An Insight into the Redox State of Hematopoietic Stem Cells

Cellular redox balance plays a significant role in the regulation of hematopoietic stem-progenitor cell (HSC/MPP) self-renewal and differentiation. Unregulated changes in cellular redox homeostasis are associated with the onset of most hematological disorders. However, accurate measurement of the redox state in stem cells is difficult because of the scarcity of HSC/MPPs. Glutathione (GSH) constitutes the most abundant pool of cellular antioxidants. Thus, GSH metabolism may play a critical role in hematological disease onset and progression. A major limitation to studying GSH metabolism in HSC/MPPs has been the inability to measure quantitatively GSH concentrations in small numbers of HSC/MPPs. Current methods used to measure GSH levels not only rely on large numbers of cells, but also rely on the chemical/structural modification or enzymatic recycling of GSH and therefore are likely to measure only total glutathione content accurately. Here, we describe the validation of a sensitive method used for the direct and simultaneous quantitation of both oxidized and reduced GSH via liquid chromatography followed by tandem mass spectrometry (LC-MS/MS) in HSC/MPPs isolated from bone marrow. The lower limit of quantitation (LLOQ) was determined to be 5.0 ng/mL for GSH and 1.0 ng/mL for GSSG with lower limits of detection at 0.5 ng/mL for both glutathione species. Standard addition analysis utilizing mouse bone marrow shows that this method is both sensitive and accurate with reproducible analyte recovery. This method combines a simple extraction with a platform for the high-throughput analysis, allows for efficient determination of GSH/GSSG concentrations within the HSC/MPP populations in mouse, chemotherapeutic treatment conditions within cell culture, and human normal/leukemia patient samples. The data implicate the importance of the modulation of GSH/GSSG redox couple in stem cells related diseases

Room-temperature quantum interference in single perovskite quantum dot junctions

钙钛矿材料由于其高量子产率、载流子迁移率和独特的光致发光特性而在光电材料领域存在诸多潜在的重要应用。研究钙钛矿材料在纳米尺度下电荷输运的独特尺寸效应对钙钛矿光电器件的设计和开发具有重要的指导意义。洪文晶教授课题组基于机械可控裂结技术自主研发了具有皮米级位移调控灵敏度和飞安级电学测量精度的精密科学仪器，对南开大学李跃龙副教授团队合成的钙钛矿量子点进行了深入表征，研究工作成功将量子干涉的研究体系拓展至在光电领域具有重要应用的钙钛矿材料领域，为未来制备基于量子干涉效应的新型钙钛矿器件提供了一种全新的思路。 这一跨学科国际合作研究工作是在化学化工学院洪文晶教授、英国Lancaster 大学物理系Colin J. Lambert教授以及南开大学电子信息与光电工程学院李跃龙副教授的共同指导下完成的。化工系硕士研究生郑海宁、Lancaster University大学Songjun Hou博士、南开大学硕士研究生辛晨光为论文第一作者。博士后林禄春，博士研究生谭志冰、郑珏婷，硕士研究生蒋枫、张珑漪，本科生何文翔、李庆民等参与了论文的研究工作。刘俊扬特任副研究员、师佳副教授和萨本栋微纳米研究院杨扬副教授也参与了部分指导工作。The studies of quantum interference effects through bulk perovskite materials at the Ångstrom scale still remain as a major challenge. Herein, we provide the observation of roomtemperature quantum interference effects in metal halide perovskite quantum dots (QDs) using the mechanically controllable break junction technique. Single-QD conductance measurements reveal that there are multiple conductance peaks for the CH3NH3PbBr3 and CH3NH3PbBr2.15Cl0.85 QDs, whose displacement distributions match the lattice constant of QDs, suggesting that the gold electrodes slide through different lattice sites of the QD via Auhalogen coupling. We also observe a distinct conductance ‘jump’ at the end of the sliding process, which is further evidence that quantum interference effects dominate charge transport in these single-QD junctions. This conductance ‘jump’ is also confirmed by our theoretical calculations utilizing density functional theory combined with quantum transport theory. Our measurements and theory create a pathway to exploit quantum interference effects in quantum-controlled perovskite materials.This work was supported by the National Key R&D Program of China (2017YFA0204902, 2014DFE60170, 2018YFB1500105), the National Natural Science Foundation of China (Nos. 21673195, 21503179, 21490573, 61674084, 61874167), the Open Fund of the Key Laboratory of Optical Information Science & Technology (Nankai University) of China, the Fundamental Research Funds for the Central Universities of China (63181321, 63191414, 96173224), and the 111 Project (B16027), the Tianjin Natural Science Foundation (17JCYBJC41400), FET Open project 767187—QuIET, the EU project BAC-TO-FUEL and the UK EPSRC projects EP/N017188/1, EP/M014452/1. 该工作得到国家重点研发计划课题（2017YFA0204902）、国家自然科学基金（21673195、21503179、21490573）、厦门大学“人工智能分析引擎”双一流重大专项等项目的资助，也得到了固体表面物理化学国家重点实验室、能源材料化学协同创新中心的支持