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Chronic predator stress (CPS) is an important and ecologically relevant tool for inducing anhedonia in animals, but the neural circuits underlying the associated neurobiological changes remain to be identified. Using cell-type-specific manipulations, we found that corticotropin-releasing hormone (CRH) neurons in the medial subthalamic nucleus (mSTN) enhance struggle behaviors in inescapable situations and lead to anhedonia, predominately through projections to the external globus pallidus (GPe). Recordings of in vivo neuronal activity revealed that CPS distorted mSTN-CRH neuronal responsivity to negative and positive stimuli, which may underlie CPS-induced behavioral despair and anhedonia. Furthermore, we discovered presynaptic inputs from the bed nucleus of the stria terminalis (BNST) to mSTN-CRH neurons projecting to the GPe that were enhanced following CPS, and these inputs may mediate such behaviors. This study identifies a neurocircuitry that co-regulates escape response and anhedonia in response to predator stress. This new understanding of the neural basis of defensive behavior in response to predator stress will likely benefit our understanding of neuropsychiatric diseases.

SARS-CoV-2 spike protein (SARS-2-S) induced cell-cell fusion in uninfected cells may occur in long COVID-19 syndrome, as circulating SARS-2-S or extracellular vesicles containing SARS-2-S (S-EVs) were found to be prevalent in post-acute sequelae of COVID-19 (PASC) for up to 12 months after diagnosis. Although isolated recombinant SARS-2-S protein has been shown to increase the SASP in senescent ACE2-expressing cells, the direct linkage of SARS-2-S syncytia with senescence in the absence of virus infection and the degree to which SARS-2-S syncytia affect pathology in the setting of cardiac dysfunction are unknown. Here, we found that the senescent outcome of SARS-2-S induced syncytia exacerbated heart failure progression. We first demonstrated that syncytium formation in cells expressing SARS-2-S delivered by DNA plasmid or LNP-mRNA exhibits a senescence-like phenotype. Extracellular vesicles containing SARS-2-S (S-EVs) also confer a potent ability to form senescent syncytia without de novo synthesis of SARS-2-S. However, it is important to note that currently approved COVID-19 mRNA vaccines do not induce syncytium formation or cellular senescence. Mechanistically, SARS-2-S syncytia provoke the formation of functional MAVS aggregates, which regulate the senescence fate of SARS-2-S syncytia by TNFα. We further demonstrate that senescent SARS-2-S syncytia exhibit shrinked morphology, leading to the activation of WNK1 and impaired cardiac metabolism. In pre-existing heart failure mice, the WNK1 inhibitor WNK463, anti-syncytial drug niclosamide, and senolytic dasatinib protect the heart from exacerbated heart failure triggered by SARS-2-S. Our findings thus suggest a potential mechanism for COVID-19-mediated cardiac pathology and recommend the application of WNK1 inhibitor for therapy especially in individuals with post-acute sequelae of COVID-19.

Wound infection is becoming a considerable healthcare crisis due to the abuse of antibiotics and the substantial production of multidrug-resistant bacteria. Seawater immersion wounds usually become a mortal trouble because of the infection of Vibrio vulnificus. Bdellovibrio bacteriovorus, one kind of natural predatory bacteria, is recognized as a promising biological therapy against intractable bacteria. Here, we prepared a B. bacteriovorus-loaded polyvinyl alcohol/alginate hydrogel for the topical treatment of the seawater immersion wounds infected by V. vulnificus. The B. bacteriovorus-loaded hydrogel (BG) owned highly microporous structures with the mean pore size of 90 μm, improving the rapid release of B. bacteriovorus from BG when contacting the aqueous surroundings. BG showed high biosafety with no L929 cell toxicity or hemolysis. More importantly, BG exhibited excellent in vitro anti-V. vulnificus effect. The highly effective infected wound treatment effect of BG was evaluated on mouse models, revealing significant reduction of local V. vulnificus, accelerated wound contraction, and alleviated inflammation. Besides the high bacterial inhibition of BG, BG remarkably reduced inflammatory response, promoted collagen deposition, neovascularization and re-epithelization, contributing to wound healing. BG is a promising topical biological formulation against infected wounds.

IntroductionInflammation play important roles in the initiation and progression of acute lung injury (ALI), acute respiratory distress syndrome (ARDS), septic shock, clotting dysfunction, or even death associated with SARS-CoV-2 infection. However, the pathogenic mechanisms underlying SARS-CoV-2-induced hyperinflammation are still largely unknown.MethodsThe animal model of septic shock and ALI was established after LPS intraperitoneal injection or intratracheal instillation. Bone marrow-derived macrophages (BMDMs) from WT and BPOZ-2 KO mouse strains were harvested from the femurs and tibias of mice. Immunohistology staining, ELISA assay, coimmunoprecipitation, and immunoblot analysis were used to detect the histopathological changes of lung tissues and the expression of inflammatory factors and protein interaction.Results and conclusionsWe show a distinct mechanism by which the SARS-CoV-2 N (SARS-2-N) protein targets Bood POZ-containing gene type 2 (BPOZ-2), a scaffold protein for the E3 ubiquitin ligase Cullin 3 that we identified as a negative regulator of inflammatory responses, to promote NLRP3 inflammasome activation. We first demonstrated that BPOZ-2 knockout (BPOZ-2 KO) mice were more susceptible to lipopolysaccharide (LPS)-induced septic shock and ALI and showed increased serum IL-1β levels. In addition, BMDMs isolated from BPOZ-2 KO mice showed increased IL-1β production in response to NLRP3 stimuli. Mechanistically, BPOZ-2 interacted with NLRP3 and mediated its degradation by recruiting Cullin 3. In particular, the expression of BPOZ-2 was significantly reduced in lung tissues from mice infected with SARS-CoV-2 and in cells overexpressing SARS-2-N. Importantly, proinflammatory responses triggered by the SARS-2-N were significantly blocked by BPOZ-2 reintroduction. Thus, we concluded that BPOZ-2 is a negative regulator of the NLPR3 inflammasome that likely contributes to SARS-CoV-2-induced hyperinflammation.

Dysregulation of lipid metabolism and transport contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Here the authors identify GP73 as a TBC-domain Rab GTPase-activating protein that regulates very low-density lipoprotein export and promotes NAFLD development in mice.

As a critical immune checkpoint molecule, PD-L1 is expressed at significantly higher levels in multiple neoplastic tissues compared to normal ones. PD-L1/PD-1 axis is a critical target for tumor immunotherapy, blocking the PD-L1/PD-1 axis is recognized and has achieved unprecedented success in clinical applications. However, the clinical efficacy of therapies targeting the PD-1/PD-L1 pathway remains limited, emphasizing the need for the mechanistic elucidation of PD-1/PD-L1 expression. In this study, we found that RNF125 interacted with PD-L1 and regulated PD-L1 protein expression. Mechanistically, RNF125 promoted K48-linked polyubiquitination of PD-L1 and mediated its degradation. Notably, MC-38 and H22 cell lines with RNF125 knockout, transplanted in C57BL/6 mice, exhibited a higher PD-L1 level and faster tumor growth than their parental cell lines. In contrast, overexpression of RNF125 in MC-38 and H22 cells had the opposite effect, resulting in lower PD-L1 levels and delayed tumor growth compared with parental cell lines. In addition, immunohistochemical analysis of MC-38 tumors with RNF125 overexpression showed significantly increased infiltration of CD4+, CD8+ T cells and macrophages. Consistent with these findings, analyses using The Cancer Genome Atlas (TCGA) public database revealed a positive correlation of RNF125 expression with CD4+, CD8+ T cell and macrophage tumor infiltration. Moreover, RNF125 expression was significantly downregulated in several human cancer tissues, and was negatively correlated with the clinical stage of these tumors, and patients with higher RNF125 expression had better clinical outcomes. Our findings identify a novel mechanism for regulating PD-L1 expression and may provide a new strategy to increase the efficacy of immunotherapy.

The rapid diagnosis and detection of respiratory bacteria at the early stage can effectively control the epidemic spread and bacterial infection. Here, we designed a rapid, ultrasensitive, and quantitative lateral flow immunoassay (LFA) strip for simultaneous detection of respiratory bacteria S. aureus and S. pneumoniae. In this assay, the surface enhanced Raman scattering (SERS) tags were designed through combining magnetite Raman enhancement nanoparticle Fe3O4@Au/DTNB and recognition element 4-mercaptophenylboronic acid (4-MPBA). Further, 4-MPBA could capture multiple bacteria in a complex environmental solution. Based on the strategies, Fe3O4@Au/DTNB-mediated magnetic enrichment and 4-MPBA-mediated universal capture capabilities improved the detection sensitivity, the limits of detection for S. aureus and S. pneumoniae were as low as 8 and 13 CFU mL−1, respectively, which were more sensitive than those of colloidal gold method. The Fe3O4@Au/DTNB/Au/4-MPBA-LFA also exhibited good reproducibility, excellent specificity, and high recovery rates in sputum samples, indicating its potential application in the detection of respiratory bacteria samples.

Background: This study is part of the Stroke Investigative Research and Educational Network (SIREN), the largest study of stroke patients in Africa to date, with computed tomography (CT) or magnetic resonance (MR) imaging data for each patient to confirm stroke. Prior imaging studies performed using high-field MR (≥1.5T) have shown that white matter hyperintensities (WMH), signs of microangiopathy in the subcortical brain, are correlated with many stroke risk factors as well as poor stroke outcomes. The aim of this study was the evaluation of MR images (0.3T–1.5T) from the SIREN study to determine associations between WMH volumes in West African patients and both stroke outcomes and stroke risk factors identified in the SIREN study. Materials and methods: Brain MR images of 130 Western African stroke patients (age ​= ​57.87 ​± ​14.22) were processed through Lesion Segmentation Toolbox of the Statistical Parametric Mapping software to extract all areas of hyperintensity in the brain. WMH was separated from stroke lesion hyperintensity and WMH volume was computed and summed. A stepwise linear regression and multivariate analysis was performed between patients’ WMH volume and sociodemographic and clinical indices. Results: Multivariate analysis showed that high WMH volume was statistically significantly positively correlated with age (β ​= ​0.44, p ​= ​0.001), waist/hip ratio (β ​= ​0.22, p ​= ​0.03), and platelet count (β ​= ​0.19, p ​= ​0.04) after controlling for head size in a Western African stroke population. Conclusion: Associations between WMH and age and waist/hip ratio previously identified in Western countries were demonstrated for the first time in a resource-limited, homogeneous black African community using low-field MR scanners.

Jojoba (Simmondsia chinensis (Link) C.K. Schneid) is a dioecious plant in desert and semi-desert areas, e.g., the Ismailia Desert in Egypt. Jojoba oil (JJBO) is a natural slight yellow oil with the functions of skin barrier repairing and wound healing, which is dermally applied as a traditional medication or cosmetic in the Middle East. The objective of this study was to prepare JJBO dry nanoemulsion powders (JNDs) and investigate their anti-acute lung injury effects. JJBO nanoemulsions (JNEs) were prepared and then lyophilized to JNDs and the properties and simulated lung deposition were measured. Rat acute lung injury (ALI) models were established after intratracheal (i.t.) administration of lipopolysaccharide (LPS) or hydrogen peroxide (H2O2). JNDs and dexamethasone (DXM) solutions were also i.t. administered to the rats. The pathological states of lung tissues were checked. Inflammatory and oxidative factors in the lung tissues were determined using ELISA methods. NF-κB p65 and caspase-3 were measured with a Western blotting method and an immunohistochemical method, respectively. JNDs had an appropriate mass median aerodynamic diameter (MMAD) of 4.17 µm and a fine particle fraction (FPF) of 39.11%. JNDs showed higher anti-inflammatory effect on LPS-induced ALI than DXM with a decrease in total protein content and down-regulation of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and NF-κB p65. JNDs also showed higher anti-inflammatory and anti-oxidation effect on H2O2-induced ALI than DXM with elimination of reactive oxygen species (ROS), increasing of superoxide dismutase (SOD), decrease in of lipid peroxide malondialdehyde (MDA) and glutathione (GSH), and inhibition of caspase-3 expression. Moreover, i.t. JNDs attenuated bleeding and infiltrations of the inflammatory cells in the two ALI models. JNDs are a promising natural oil-contained inhalable medication for the treatment of LPS- or H2O2-induced ALI.

The research on service supply chain has attracted more and more focus from both academia and industrial community. In a service supply chain, the selection of supplier portfolio is an important and difficult problem due to the fact that a supplier portfolio may include multiple suppliers from a variety of fields. To address this problem, we propose a novel supplier portfolio selection method based on a well known machine learning approach, i.e., Ranking Neural Network (RankNet). In the proposed method, we regard the problem of supplier portfolio selection as a ranking problem, which integrates a large scale of decision making features into a ranking neural network. Extensive simulation experiments are conducted, which demonstrate the feasibility and effectiveness of the proposed method. The proposed supplier portfolio selection model can be applied in a real corporation easily in the future.

Separating two probability distributions from a mixture model that is made up of the combinations of the two is essential to a wide range of applications. For example, in information retrieval (IR), there often exists a mixture distribution consisting of a relevance distribution that we need to estimate and an irrelevance distribution that we hope to get rid of. Recently, a distribution separation method (DSM) was proposed to approximate the relevance distribution, by separating a seed irrelevance distribution from the mixture distribution. It was successfully applied to an IR task, namely pseudo-relevance feedback (PRF), where the query expansion model is often a mixture term distribution. Although initially developed in the context of IR, DSM is indeed a general mathematical formulation for probability distribution separation. Thus, it is important to further generalize its basic analysis and to explore its connections to other related methods. In this article, we first extend DSM’s theoretical analysis, which was originally based on the Pearson correlation coefficient, to entropy-related measures, including the KL-divergence (Kullback–Leibler divergence), the symmetrized KL-divergence and the JS-divergence (Jensen–Shannon divergence). Second, we investigate the distribution separation idea in a well-known method, namely the mixture model feedback (MMF) approach. We prove that MMF also complies with the linear combination assumption, and then, DSM’s linear separation algorithm can largely simplify the EM algorithm in MMF. These theoretical analyses, as well as further empirical evaluation results demonstrate the advantages of our DSM approach.

Quantum theory has been applied in a number of fields outside physics, e.g., cognitive science and information retrieval (IR). Recently, it has been shown that quantum theory can subsume various key IR models into a single mathematical formalism of Hilbert vector spaces. While a series of quantum-inspired IR models has been proposed, limited effort has been devoted to verify the existence of the quantum-like phenomenon in real users’ information retrieval processes, from a real user study perspective. In this paper, we aim to explore and model the quantum interference in users’ relevance judgement about documents, caused by the presentation order of documents. A user study in the context of IR tasks have been carried out. The existence of the quantum interference is tested by the violation of the law of total probability and the validity of the order effect. Our main findings are: (1) there is an apparent judging discrepancy across different users and document presentation orders, and empirical data have violated the law of total probability; (2) most search trials recorded in the user study show the existence of the order effect, and the incompatible decision perspectives in the quantum question (QQ) model are valid in some trials. We further explain the judgement discrepancy in more depth, in terms of four effects (comparison, unfamiliarity, attraction and repulsion) and also analyse the dynamics of document relevance judgement in terms of the evolution of the information need subspace.

Recently, Quantum Theory (QT) has been employed to advance the theory of Information Retrieval (IR). Various analogies between QT and IR have been established. Among them, a typical one is applying the idea of photon polarization in IR tasks, e.g., for document ranking and query expansion. In this paper, we aim to further extend this work by constructing a new superposed state of each document in the information need space, based on which we can incorporate the quantum interference idea in query expansion. We then apply the new quantum query expansion model to session search, which is a typical Web search task. Empirical evaluation on the large-scale Clueweb12 dataset has shown that the proposed model is effective in the session search tasks, demonstrating the potential of developing novel and effective IR models based on intuitions and formalisms of QT.

Acrylonitrile-butadiene-styrene (ABS) material is widely used as a protective rigid shell and impact absorber in bike helmets, providing vital protection against head injuries under specific working conditions. However, ABS aging in helmets could affect the safety factor of helmets and shorten the service life. Exploring the transformation during aging process for real assembled helmets made of ABS out shells is crucial for the investigation and fabrication of high performance helmets. Herein, the effect of long-term aging on the physical properties of practical helmets made of ABS outer shells has been discussed systematically. Four different types of helmets were subjected to different aging conditions, i.e., outdoor environment, ultraviolet exposure, hot air, and humid-heat conditions. The impact property and stiffness tests were carried out as a function of aging time and aging conditions. The measured helmets were capable of meeting engineering tolerances when aged under outdoor, ultraviolet, and hot air conditions, and could deliver competitive mechanical performance to their pristine helmets. Yet, after aging under humid-heat for 800 h, the helmets showed an obvious decrease in impact strength, gloss, and stiffness. The influence of different aging conditions was further investigated by thermal and spectral characterizations. The study might provide some valuable advice for helmet performance evaluation. [ABSTRACT FROM AUTHOR]