Infection with laboratory-attenuated rabies virus (RABV) enhances blood-brain barrier (BBB) permeability, which has been demonstrated to be an important factor for host survival, since it allows ...immune effectors to enter the central nervous system (CNS) and clear RABV. To probe the mechanism by which RABV infection enhances BBB permeability, the expression of tight junction (TJ) proteins in the CNS was investigated following intracranial inoculation with laboratory-attenuated or wild-type (wt) RABV. BBB permeability was significantly enhanced in mice infected with laboratory-attenuated, but not wt, RABV. The expression levels of TJ proteins (claudin-5, occludin, and zonula occludens-1) were decreased in mice infected with laboratory-attenuated, but not wt, RABV, suggesting that enhancement of BBB permeability is associated with the reduction of TJ protein expression in RABV infection. RABV neither infects the brain microvascular endothelial cells (BMECs) nor modulates the expression of TJ proteins in BMECs. However, brain extracts prepared from mice infected with laboratory-attenuated, but not wt, RABV reduced TJ protein expression in BMECs. It was found that brain extracts from mice infected with laboratory-attenuated RABV contained significantly higher levels of inflammatory chemokines/cytokines than those from mice infected with wt RABV. Pathway analysis indicates that gamma interferon (IFN-γ) is located in the center of the cytokine network in the RABV-infected mouse brain, and neutralization of IFN-γ reduced both the disruption of BBB permeability in vivo and the downregulation of TJ protein expression in vitro. These findings indicate that the enhancement of BBB permeability and the reduction of TJ protein expression are due not to RABV infection per se but to virus-induced inflammatory chemokines/cytokines.
Previous studies have shown that infection with only laboratory-attenuated, not wild-type, rabies virus (RABV) enhances blood-brain barrier (BBB) permeability, allowing immune effectors to enter the central nervous system (CNS) and clear RABV from the CNS. This study investigated the mechanism by which RABV infection enhances BBB permeability. It was found that RABV infection enhances BBB permeability by downregulation of tight junction (TJ) protein expression in the brain microvasculature. It was further found that it is not RABV infection per se but the chemokines/cytokines induced by RABV infection that downregulate the expression of TJ proteins and enhance BBB permeability. Blocking some of these cytokines, such as IFN-γ, ameliorated both the disruption of BBB permeability and the downregulation of TJ protein expression. These studies may provide a foundation for developing therapeutics for clinical rabies, such as medication that could be used to enhance BBB permeability.
An interatomic potential for the Al-Tb alloy around the composition of Al
90
Tb
10
is developed using the deep neural network (DNN) learning method. The atomic configurations and the corresponding ...total potential energies and forces on each atom obtained from
ab initio
molecular dynamics (AIMD) simulations are collected to train a DNN model to construct the interatomic potential for the Al-Tb alloy. We show that the obtained DNN model can well reproduce the energies and forces calculated by AIMD simulations. Molecular dynamics (MD) simulations using the DNN interatomic potential also accurately describe the structural properties of the Al
90
Tb
10
liquid, such as partial pair correlation functions (PPCFs) and bond angle distributions, in comparison with the results from AIMD simulations. Furthermore, the developed DNN interatomic potential predicts the formation energies of the crystalline phases of the Al-Tb system with an accuracy comparable to
ab initio
calculations. The structure factors of the Al
90
Tb
10
metallic liquid and glass obtained by MD simulations using the developed DNN interatomic potential are also in good agreement with the experimental X-ray diffraction data. The development of short-range order (SRO) in the Al
90
Tb
10
liquid and the undercooled liquid is also analyzed and three dominant SROs,
i.e.
, Al-centered distorted icosahedron (DISICO) and Tb-centered '3661' and '15551' clusters, respectively, are identified.
The developed deep neural network (DNN) potential can describe the structural properties of the Al
90
Tb
10
liquid and the formation energies of Al-Tb crystals with the accuracy of
ab initio
calculations.
•Expression of complement components, C1q and C3, is increased in the EAE hippocampus.•Genetic loss of C3 prevents synapse elimination in the EAE hippocampus.•Loss of C3, but not C1qa, reduces ...microglial activation and EAE motor impairments.•C3 knockout protects memory and freezing behavior after contextual fear conditioning in EAE.
Multiple sclerosis (MS) is an inflammatory, neurodegenerative disease of the CNS characterized by both grey and white matter injury. Microglial activation and a reduction in synaptic density are key features of grey matter pathology that can be modeled with MOG35-55 experimental autoimmune encephalomyelitis (EAE). Complement deposition combined with microglial engulfment has been shown during normal development and in disease as a mechanism for pruning synapses. We tested whether there is excess complement production in the EAE hippocampus and whether complement-dependent synapse loss is a source of degeneration in EAE using C1qa and C3 knockout mice. We found that C1q and C3 protein and mRNA levels were elevated in EAE mice. Genetic loss of C3 protected mice from EAE-induced synapse loss, reduced microglial activation, decreased the severity of the EAE clinical score, and protected memory/freezing behavior after contextual fear conditioning. C1qa KO mice with EAE showed little to no change on these measurements compared to WT EAE mice. Thus, pathologic expression and activation of the early complement pathway, specifically at the level of C3, contributes to hippocampal grey matter pathology in the EAE.
Calculations have been performed for carbon nanoribbons (CNRs) with zigzag edges containing one substitutional nitrogen atom per 154 carbon atoms, using ab initio density functional theory. It is ...found that the formation energies of these nanoribbons depend on the nitrogen doping site, as do the electrical properties. The doping nitrogen atom energetically prefers to distribute near the nanoribbon edges, and there is an impurity state below or above the Fermi level for the nitrogen-doped CNR, which depends on the nitrogen doping site. Also, the distribution of non-bonding electrons of nitrogen atom depends on the nitrogen doping site.
Intra-abdominal infection is a common complication of blunt abdominal trauma. Early detection and intervention can reduce the incidence of intra-abdominal infection and improve patients’ prognoses. ...This study aims to construct a clinical model predicting postsurgical intra-abdominal infection after blunt abdominal trauma.
This study is a retrospective analysis of 553 patients with blunt abdominal trauma from the Department of General Surgery of 7 medical centers (2011–2021). A 7:3 ratio was used to assign patients to the derivation and validation cohorts. Patients were divided into 2 groups based on whether intra-abdominal infection occurred after blunt abdominal trauma. Multivariate logistic regression and least absolute shrinkage and selection operator regression were used to select variables to establish a nomogram. The nomogram was evaluated, and the validity of the model was further evaluated by the validation cohort.
A total of 113 were diagnosed with intra-abdominal infection (20.4%). Age, prehospital time, C-reactive protein, injury severity score, operation duration, intestinal injury, neutrophils, and antibiotic use were independent risk factors for intra-abdominal infection in blunt abdominal trauma patients (P < .05). The area under the receiver operating curve (area under the curve) of derivation cohort and validation cohort was 0.852 (95% confidence interval, 0.784–0.912) and 0.814 (95% confidence interval, 0.751–0.902). The P value for the Hosmer-Lemeshow test was .135 and .891 in the 2 cohorts. The calibration curve demonstrated that the nomogram had a high consistency between prediction and practical observation. The decision curve analysis also showed that the nomogram had a better potential for clinical application. To facilitate clinical application, we have developed an online at https://nomogramcgz.shinyapps.io/IAIrisk/.
The nomogram is helpful in predicting the risk of postoperative intra-abdominal infection in patients with blunt abdominal trauma and provides guidance for clinical decision-making and treatment.
Hypoxia drives aging and promotes age-related cognition and hearing functional decline. Despite the role of erythrocytes in oxygen (O2) transport, their role in the onset of aging and age-related ...cognitive decline and hearing loss (HL) remains undetermined. Recent studies revealed that signaling through the erythrocyte adenosine A2B receptor (ADORA2B) promotes O2 release to counteract hypoxia at high altitude. However, nothing is known about a role for erythrocyte ADORA2B in age-related functional decline. Here, we report that loss of murine erythrocyte-specific ADORA2B (eAdora2b-/-) accelerates early onset of age-related impairments in spatial learning, memory, and hearing ability. eAdora2b-/- mice display the early aging-like cellular and molecular features including the proliferation and activation of microglia and macrophages, elevation of pro-inflammatory cytokines, and attenuation of hypoxia-induced glycolytic gene expression to counteract hypoxia in the hippocampus (HIP), cortex, or cochlea. Hypoxia sufficiently accelerates early onset of cognitive and cochlear functional decline and inflammatory response in eAdora2b-/- mice. Mechanistically, erythrocyte ADORA2B-mediated activation of AMP-activated protein kinase (AMPK) and bisphosphoglycerate mutase (BPGM) promotes hypoxic and metabolic reprogramming to enhance production of 2,3-bisphosphoglycerate (2,3-BPG), an erythrocyte-specific metabolite triggering O2 delivery. Significantly, this finding led us to further discover that murine erythroblast ADORA2B and BPGM mRNA levels and erythrocyte BPGM activity are reduced during normal aging. Overall, we determined that erythrocyte ADORA2B-BPGM axis is a key component for anti-aging and anti-age-related functional decline.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this work, a novel friction stir diffusion bonding (FSDB) method was proposed to eliminate hook when joining thin sheets. Three tools, with several convex-vortex pins were innovatively designed to ...improve the diffusion bonding effect of the lap interface. Results showed that sound joints, excellently bonded at the lap interface and without hook, were obtained. The lap interfaces on the joints welded using the T-tool and F-tool almost remained intact, thereby indicating that they were formed by diffusion bonding. The material flow behavior was also simulated by FLUENT software and the results showed that the material flow along thickness was significantly enhanced by increasing the pin number. The joint welded by the T-tool showed shear fracture mode. Sound bonding was formed at the lap interface when using the F-tool and thus the joint showed tensile fracture.
Ischemic Stroke (IS) is a major disease which greatly threatens human health. Recent studies showed sex-specific outcomes and mechanisms of cerebral ischemic stroke. This study aimed to identify the ...key changes of gene expression between male and female IS in humans.
Gene expression dataset GSE22255, including peripheral blood samples, was downloaded from the Gene Expression Omnibus (GEO) dataset. Differentially Expressed Genes (DEGs) with a LogFC>1, and a P-value <0.05 were screened by BioConductor R package and grouped in female, male and overlap DEGs for further bioinformatic analysis. Gene Ontology (GO) functional annotation, Protein-Protein Interaction (PPI) network, "Molecular Complex Detection" (MCODE) modules, CytoNCA (cytoscape network centrality analysis) essential genes and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway interrelation analysis were performed.
In a total of 54,665 genes, 185 (73 ups and 112 downs) DEGs in the female dataset, 461 DEGs (297 ups and 164 downs) in the male dataset, within which 118 DEGs overlapped (7 similar changes in female and male, 111 opposite changes in female and male) were obtained from the GSE22255 dataset. Female, male and overlapping DEGs enriched for similar cellular components and molecular function. Male DEGs enriched for divergent biological processes from female and overlapping DEGs. Sex-specific and overlapping DEGs were put into the PPI network. Overlapping genes such as IL6, presented opposite changes and were mainly involved in cytokine-cytokine receptor interactions, the TNF-signalling pathway, etc.
The analysis of sex-specific DEGs from GEO human blood samples showed that not only specific but also opposite DEG alterations in the female and male stroke genome wide dataset. The results provided an overview of sex-specific mechanisms, which might provide insight into stroke and its biomarkers and lead to sex-specific prognosis and treatment strategies in future clinical practice.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Several preclinical studies have reported the rapid antidepressant effects of N-methyl-D-aspartate receptor (NMDAR) antagonists, although the underlying mechanisms are still unclear. Death-associated ...protein kinase 1 (DAPK1) couples GluN2B subunits at extrasynaptic sites to regulate NMDAR channel conductance. In the present study, we found that chronic unpredictable stress (CUS) induced extracellular glutamate accumulation, accompanied by an increase in the DAPK1-NMDAR interaction, the high expression of DAPK1 and phosphorylated GluN2B at Ser1303, a decrease in phosphorylated DAPK1 at Ser308 and synaptic protein deficits in the rat medial prefrontal cortex (mPFC). CUS also enhanced GluN2B-mediated NMDA currents and extrasynaptic responses that were induced by bursts of high-frequency stimulation, which may be associated with the loss of astrocytes and low expression of glutamate transporter-1 (GLT-1). The blockade of GLT-1 in the mPFC was sufficient to induce depressive-like behavior and cause similar molecular changes. Selective GluN2B antagonist, DAPK1 knockdown by adeno-associated virus-mediated short-hairpin RNA or a pharmacological inhibitor, and the uncoupling of DAPK1 from the NMDAR GluN2B subunit produced rapid antidepressant-like effects and reversed CUS-induced alterations in the mPFC. The inhibition of DAPK1 and its interaction with GluN2B subunit in the mPFC also rescued CUS-induced depressive-like behavior 7 days after treatment. A selective GluN2B antagonist did not have rewarding effects in the conditioned place preference paradigm. Altogether, our findings suggest that the DAPK1 interaction with the NMDAR GluN2B subunit acts as a critical component in the pathophysiology of depression and is a potential target for new antidepressant treatments.
IntroductionBulimia nervosa (BN) is a disorder with high health and socioeconomic burdens that typically arises in late adolescence and early adulthood. Previous neuroimaging studies have found ...functional brain changes in patients with BN. This study aims to review the latest neurobiological evidence from studies of individuals with BN, examine the consistency of these findings and evaluate the food addiction hypothesis of the disease.Methods and analysisA systematic search will be performed using the Cochrane Library, PubMed, Embase and Web of Science databases, covering the period from database inception to 30 November 2021. Two researchers will be responsible for study selection, quality assessment and data extraction. The anisotropic effect size version of the signed differential mapping method will be used to conduct a coordinate-based meta-analysis. Publication bias will be examined with the Egger test. The quality of studies will be evaluated using the Newcastle-Ottawa Scale.Ethics and disseminationNo ethics approval is required for this is a systematic review protocol and does not require the collection of primary data. Findings will be disseminated through peer-reviewed journal or related conferences.PROSPERO registration numberCRD42022307233.
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