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The Slack channel (KCNT1, Slo2.2) is a sodium-activated and chloride-activated potassium channel that regulates heart rate and maintains the normal excitability of the nervous system. Despite intense interest in the sodium gating mechanism, a comprehensive investigation to identify the sodium-sensitive and chloride-sensitive sites has been missing. In the present study, we identified two potential sodium-binding sites in the C-terminal domain of the rat Slack channel by conducting electrophysical recordings and systematic mutagenesis of cytosolic acidic residues in the rat Slack channel C terminus. In particular, by taking advantage of the M335A mutant, which results in the opening of the Slack channel in the absence of cytosolic sodium, we found that among the 92 screened negatively charged amino acids, E373 mutants could completely remove sodium sensitivity of the Slack channel. In contrast, several other mutants showed dramatic decreases in sodium sensitivity but did not abolish it altogether. Furthermore, molecular dynamics (MD) simulations performed at the hundreds of nanoseconds timescale revealed one or two sodium ions at the E373 position or an acidic pocket composed of several negatively charged residues. Moreover, the MD simulations predicted possible chloride interaction sites. By screening predicted positively charged residues, we identified R379 as a chloride interaction site. Thus, we conclude that the E373 site and the D863/E865 pocket are two potential sodium-sensitive sites, while R379 is a chloride interaction site in the Slack channel.SIGNIFICANCE STATEMENTThe research presented here identified two distinct sodium and one chloride interaction sites located in the intracellular C-terminal domain of the Slack (Slo2.2, KCNT1) channel. Identification of the sites responsible for the sodium and chloride activation of the Slack channel sets its gating property apart from other potassium channels in the BK channel family. This finding sets the stage for future functional and pharmacological studies of this channel.

Background: Sex disparities in acute large vessel occlusion (LVO) following endovascular treatment (EVT) have been recently reported. However, there is uncertainty about the effect of sex differences on functional outcomes after EVT, particularly in an Asian population. The present study aimed to compare the clinical and safety outcomes between men and women with anterior circulation LVO treated with EVT. Methods: We analyzed data from the ANGEL-ACT (Endovascular Treatment Key Technique and Emergency Work Flow Improvement of Acute Ischemic Stroke: a Prospective Multicenter Registry Study) Registry, which was conducted at 111 hospitals from 26 provinces in China between November 2017 and March 2019. Men and women with anterior circulation LVO treated with EVT were matched using propensity scores. After a 1:1 propensity score matching, we compared the clinical outcomes including 90-day ordinal modified Rankin Scale distribution (primary outcome), procedure duration, successful reperfusion, symptomatic intracranial hemorrhage, and mortality. Furthermore, we explored sex modification on the primary outcome in subgroup analysis. Results: Of 1321 patients, 483 (36.6%) were women and 838 (63.4%) were men. The mean age for women and men were 68 and 62 years old, respectively. Among 578 patients identified after matching, there were no sex differences (men versus women) in 90-day ordinal modified Rankin Scale distribution (median [interquartile range], 4 [1–5] versus 3 [1–5], P =0.464), successful reperfusion (86.5% versus 91.0%, P =0.089), symptomatic intracranial hemorrhage (6.5% versus 7.9%, P =0.512), and mortality within 90 days (17.7% versus 17.0%, P =0.826). However, men had a longer median procedure duration than women (86 [52–128] versus 72 [48–110] minutes, β=14.51, [95% CI, 4.19–24.84]; P =0.006). Subgroup analysis showed that in patients with National Institutes of Health Stroke Scale score P for interaction=0.032). Conclusions: Overall, this matched-control study from the ANGEL-ACT study showed similar clinical outcomes between men and women with anterior circulation LVO treated with EVT. However, in the subgroup of patients presenting with lower stroke severity (ie, National Institutes of Health Stroke Scale score Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03370939.

Hymenopteran parasitoids generally show a haplo-diploid sex determination system. Haploid males are produced from unfertilized eggs, whereas diploid females develop from fertilized eggs (arrhenotokous). In some cases, diploid females develop from unfertilized eggs (thelytokous). Diglyphus wani (Hymenoptera: Eulophidae) is a biological control agent for agromyzid leafminers and have arrhenotokous and thelytokous strains. However, the morphological characteristics of two strains of D. wani are so similar that it is difficult to accurately distinguish them based on morphology. Here, a rapid molecular identification method was developed based on the mitochondrial gene cytochrome c oxidase I (COI) and one-step multiplex PCR. Two primer combinations, PC1 (Ar-F1/Th-F1/WR2) and PC2 (Ar-F1/Th-F4/WR2), were designed and repeatedly screened to distinguish two strains simultaneously, of which two special forward primers Th-F1/Th-F4 were used for the thelytokous strain and one special forward primer Ar-F1 was used for the arrhenotokous strain. In addition, a common reverse primer, WR2, was used for both strains. The PC1 and PC2 PCR assays were effective in distinguishing the two strains at different developmental stages and field colonies. This method provides a reliable, highly sensitive, and cost-effective tool for the rapid identification of the two strains of D. wani.

Paracetamol (acetaminophen) is an over the counter drug that is often used in suicide attempts. We have developed a SERS based assay that allows for the quantification of paracetamol and its three major metabolites.

Accelerating the sluggish anode reaction in a Zn-air battery can improve its energy efficiency, but the large-scale development of this battery is hindered by the lack of bifunctional catalysts. Herein, we designed a one-step carbonization strategy for synthesizing monodispersed Co nanoparticles supported on N-doped carbon nanotube (Co/CNT), which shows excellent bifunctional electrocatalytic performance with long-term durability for oxygen reduction reaction/oxygen evolution reaction. The formation of carbon substrates from the carbonization of nitrogenous organic molecules are benefit to capture more Co nanoparticles though strong metal-substrate interaction, then construct high-density effective active sites of the Lewis base for accelerating the electrocatalytic reaction process. To verify its superior performance, a rechargeable Zn-air battery with a Co/CNT air electrode was subsequently constructed. The battery exhibits an open-circuit voltage of 1.41 V and a specific discharge capacity of 835.2 mAh/g

Let $ \mu $ be a positive Borel measure on the interval $ [0, 1) $. The Hankel matrix $ \mathcal{H}_{\mu} = (\mu_{n, k})_{n, k\geq 0} $ with entries $ \mu_{n, k} = \mu_{n+k} $, where $ \mu_{n} = \int_{[0, 1)}t^nd\mu(t) $, formally induces the operator as follows: \begin{document}$ \mathcal{DH}_\mu(f)(z) = \sum\limits_{n = 0}^\infty\left(\sum\limits_{k = 0}^\infty \mu_{n,k}a_k\right)(n+1)z^n , \; z\in \mathbb{D}, $\end{document} where $ f(z) = \sum_{n = 0}^\infty a_nz^n $ is an analytic function in $ \mathbb{D} $. In this article, we characterize those positive Borel measures on $ [0, 1) $ such that $ \mathcal{DH}_\mu $ is bounded (resp., compact) from Bergman spaces $ \mathcal{A}^p $ into Hardy spaces $ H^q $, where $ 0 < p, q < \infty $.

A thin-film cross-vertical double-layer electrode array is uniquely proposed, and this flexible sensor device can be combined with signal processing links and display terminals to form a complete usable maritime sensing system.

In this paper, we investigate the effects of ambient air pollution (AAP) on the spread of influenza in an AAP-dependent dynamic influenza model. The value of this study lies in two aspects. Mathematically, we establish the threshold dynamics in the term of the basic reproduction number $ \mathcal{R}_0 $: If $ \mathcal{R}_0 < 1 $, the disease will go to extinction, while if $ \mathcal{R}_0 > 1 $, the disease will persist. Epidemiologically, based on the statistical data in Huaian, China, we find that, in order to control the prevalence of influenza, we must increase the vaccination rate, the recovery rate and the depletion rate, and decrease the rate of the vaccine wearing off, the uptake coefficient, the effect coefficient of AAP on transmission rate and the baseline rate. To put it simply, we must change our traveling plan and stay at home to reduce the contact rate or increase the close-contact distance and wear protective masks to reduce the influence of the AAP on the influenza transmission.

The expansion in the repertoire of genes linked to thoracic aortic aneurysms (TAA) has revolutionised our understanding of the disease process. The clinical benefits of such progress are numerous, particularly helping our understanding of non-syndromic hereditary causes of TAA (HTAAD) and further refinement in the subclassification of disease. Furthermore, the understanding of aortic biomechanics and mechanical homeostasis has been significantly informed by the discovery of deleterious mutations and their effect on aortic phenotype. The drawbacks in genetic testing in TAA lie with the inability to translate genotype to accurate prognostication in the risk of thoracic aortic dissection (TAD), which is a life-threatening condition. Under current guidelines, there are no metrics by which those at risk for dissection with normal aortic diameters may undergo preventive surgery. Future research lies with more advanced genetic diagnosis of HTAAD and investigation of the diverse pathways involved in its pathophysiology, which will i) serve to improve our understanding of the underlying mechanisms, ii) improve guidelines for treatment and iii) prevent complications for HTAAD and sporadic aortopathies.

As an important moving element in the machine structure, the crossbeam determines the dynamic characteristics of the machine in X or Y axis, which directly affects the machining efficiency and quality of the machine. The most typical expression of dynamic characteristics is acceleration, and the acceleration is inversely proportional to the mass of the moving parts, so reducing the mass of the moving parts while ensuring the stiffness is an important part of optimizing the machine structure. To address the problem that the cross beam of HIMT50 vertical machining center has structural redundancy, which leads to bad dynamic characteristics, the cross beam is firstly modeled in 3D, and its static and dynamic characteristics are analyzed by Abaqus software, and the data are applied to the optimization module to optimize the structure by topology optimization method. The optimization results show that the deformation and low-order amplitude of the crossbeam are improved with the reduction of its mass, which provides a theoretical basis and reference value for optimizing the crossbeam structure, reducing the overall manufacturing cost and improving the machining efficiency of the machine tool.

Type A acute aortic dissection (TAAAD) is a dangerous and complicated condition with a high death rate before hospital treatment. Patients who are fortunate to receive prompt surgical treatment still face high in-hospital mortality. A series of post-operative complications further affects the prognosis. Post-operative pneumonia (POP) also leads to great morbidity and mortality. This study aimed to identify the prevalence as well as the risk factors for POP in TAAAD patients and offer references for clinical decisions to further improve the prognosis of patients who survived the surgical procedure.The study enrolled 89 TAAAD patients who underwent surgical treatment in Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei province, China from December 2020 to July 2021 and analyzed the perioperative data and outcomes of these patients. Logistic regression analyses were used to identify the risk factors for POP.In the study, 31.5% of patients developed POP. Patients with POP had higher proportions of severe oxygenation damage, pneumothorax, reintubation, tracheotomy, renal replacement therapy, arrhythmia, gastrointestinal bleeding, and longer duration of mechanical ventilation, fever, ICU stay, and length of stay (all with P0.05). The in-hospital mortality was 2.3%. Smoking, preoperative white blood cells, and intraoperative transfusion were the independent risk factors for POP in TAAAD.Patients who underwent TAAAD surgery suffered poorer outcomes when they developed POP. Furthermore, patients with risk factors should be treated with caution.

Percolation, describing critical behaviors of phase transition in a geometrical context, prompts wide investigations in natural and social networks as a fundamental model. The introduction of quantum-intrinsic interference and tunneling brings percolation into quantum regime with more fascinating phenomena and unique features, which, however, hasn't been experimentally explored yet. Here we present an experimental demonstration of quantum transport in hexagonal percolation lattices by successfully mapping such large-scale porous structures into a photonic chip using femtosecond laser direct writing techniques. A quantum percolation threshold of 80% is observed in the prototyped laser-written lattices with up to 1,600 waveguides, which is significantly larger than the classical counterpart of 63%. We also investigate the spatial confinement by localization parameters and exhibit the transition from ballistic to diffusive propagation with the decrease of the occupation probability. Direct observation of quantum percolation may deepen the understanding of the relation among materials, quantum transport, geometric quenching, disorder and localization, and inspire applications for quantum technologies., 21 pages, 5 figures, 1 table, comments welcome

Previous fluid-structure interaction (FSI) studies on carotid bifurcation focused on the effect of wall compliance on the predicted hemodynamic features in normal or atherosclerotic carotid arteries. However, FSI study on patient-specific post-stent carotid model is still lacking, and to the authors knowledge no such a study has been reported so far. This study attempts to simulate the full-scale patient-specific post- stent carotid bifurcation geometry with the hope to understand the effect of wall compliance on hemodynamic quantities. The FSI model was based on patient-specific geometry consisting of three components i.e., the carotid artery wall and stent as the solid domain, and blood in the fluid domain. Full FSI simulations incorporating patient-specific boundary conditions at the inlet and outlets, and realistic homogenous incompressible carotid wall and stent were completed to evaluate the flow patterns and wall shear stress. The FSI simulation results were compared with the corresponding rigid-wall model. The quantitative difference in time-averaged wall shear stress (TAWSS) distribution between the FSI and rigid-wall models shows that FSI model predicted 8% less of the area in the low TAWSS band (

Alzheimer's disease (AD) is the most common neurodegenerative disease and has an insidious onset. Exploring the characteristics and mechanism of the early symptoms of AD plays a critical role in the early diagnosis and intervention of AD. Here we found that depressive-like behavior and short-term spatial memory dysfunction appeared in APPswe/PS1dE9 mice (AD mice) as early as 9-11 weeks of age. Electrophysiological analysis revealed excitatory/inhibitory (E/I) imbalance in the prefrontal cortex (PFC). This E/I imbalance was induced by significant reduction in the number and activity of parvalbumin interneurons (PV

Children with intracranial germ cell tumors may present premature sexual development via either gonadotrophin-releasing hormone (GnRH)-dependent cause or GnRH-independent cause. We conducted a single-center retrospective study on 37 precocious puberty (PP) patients with intracranial germ cell tumors and 25 age-matched prepubertal patients with elevated human chorionic gonadotropin (hCG) levels. Classification of PP was derived from hCG, gonadotropin and sex steroid levels and their changes. Five boys were assigned to GnRH-dependent group (G1). Thirty-one boys and one girl were assigned to GnRH-independent group (G2) with a median hCG of 76.75 (8.29–2747) IU/L. Seven boys and 18 girls were conducted as controls, with a median hCG of 17.12 (2.91–1062) IU/L. Patients in G1 had constant pubertal LH and testosterone levels after tumor complete response. Patients in G2 had hCG levels that decreased simultaneously with testosterone/estradiol levels, prior to tumor regression. The differences in hCG levels and the gender ratio were significant between G2 and controls (P = 0.006 and P 0.001, separately). Among intracranial germ cell tumor patients with positive hCG, boys with significantly higher hCG levels more easily developed PP. Our results suggest that GnRH-independent PP commonly regresses together with tumor regression. In comparison, results were inconclusive in tying tumor regression to the regression of GnRH-dependent PP.

Background and purposeSymptomatic intracranial atherosclerotic stenosis (sICAS) is associated with a considerable risk of recurrent stroke despite contemporarily optimal medical treatment. Severity of luminal stenosis in sICAS and its haemodynamic significance quantified with computational fluid dynamics (CFD) models were associated with the risk of stroke recurrence. We aimed to develop and compare stroke risk prediction nomograms in sICAS, based on vascular risk factors and these metrics.MethodsPatients with 50%–99% sICAS confirmed in CT angiography (CTA) were enrolled. Conventional vascular risk factors were collected. Severity of luminal stenosis in sICAS was dichotomised as moderate (50%–69%) and severe (70%–99%). Translesional pressure ratio (PR) and wall shear stress ratio (WSSR) were quantified via CTA-based CFD modelling; the haemodynamic status of sICAS was classified as normal (normal PR&WSSR), intermediate (otherwise) and abnormal (abnormal PR&WSSR). All patients received guideline-recommended medical treatment. We developed and compared performance of nomograms composed of these variables and independent predictors identified in multivariate logistic regression, in predicting the primary outcome, recurrent ischaemic stroke in the same territory (SIT) within 1 year.ResultsAmong 245 sICAS patients, 20 (8.2%) had SIT. The D2H2A nomogram, incorporating diabetes, dyslipidaemia, haemodynamic status of sICAS, hypertension and age ≥50 years, showed good calibration (P for Hosmer-Lemeshow test=0.560) and discrimination (C-statistic 0.73, 95% CI 0.60 to 0.85). It also had better performance in risk reclassification and provided larger net benefits in decision curve analysis, compared with nomograms composed of conventional vascular risk factors only, and plus the severity of luminal stenosis in sICAS. Sensitivity analysis in patients with anterior-circulation sICAS showed similar results.ConclusionsThe D2H2A nomogram, incorporating conventional vascular risk factors and the haemodynamic significance of sICAS as assessed in CFD models, could be a useful tool to stratify sICAS patients for the risk of recurrent stroke under contemporarily optimal medical treatment.

As an important mode of open innovation, crowdsourcing can effectively integrate external resources, enabling enterprises to obtain stronger competitiveness and more benefits at a faster speed and lower cost. However, this mode has inevitable intellectual property protection challenges, especially on contest-based crowdsourcing platforms. Previous studies mostly focused on the protection of the rights of sponsors while ignoring the rights of workers, rarely paying attention to sponsor fraud, which may reduce the enthusiasm of participants and eventually turn crowdsourcing;' into a lemon market. This study proposes several fraud detection models to address this problem on contest-based crowdsourcing platforms. Furthermore, this paper explores and compares the value of four types of information as deception cues in crowdsourcing contexts via data mining technology and machine learning methods. The results benefit participants in crowdsourcing markets and contribute to fraud detection research and open innovation in the knowledge economy.

To maintain energy supply to the brain, a direct energy source called adenosine triphosphate (ATP) is produced by oxidative phosphorylation and aerobic glycolysis of glucose in the mitochondria and cytoplasm. Brain glucose metabolism is reduced in many neurodegenerative diseases, including Alzheimer’s disease (AD), where it appears presymptomatically in a progressive and region-specific manner. Following dysregulation of energy metabolism in AD, many cellular repair/regenerative processes are activated to conserve the energy required for cell viability. Glucose metabolism plays an important role in the pathology of AD and is closely associated with the tricarboxylic acid cycle, type 2 diabetes mellitus, and insulin resistance. The glucose intake in neurons is from endothelial cells, astrocytes, and microglia. Damage to neurocentric glucose also damages the energy transport systems in AD. Gut microbiota is necessary to modulate bidirectional communication between the gastrointestinal tract and brain. Gut microbiota may influence the process of AD by regulating the immune system and maintaining the integrity of the intestinal barrier. Furthermore, some therapeutic strategies have shown promising therapeutic effects in the treatment of AD at different stages, including the use of antidiabetic drugs, rescuing mitochondrial dysfunction, and epigenetic and dietary intervention. This review discusses the underlying mechanisms of alterations in energy metabolism in AD and provides potential therapeutic strategies in the treatment of AD.

In this paper, a new honeycomb plate box-type hollow roof structure is prepared. The failure mode and mechanical properties of the box-type hollow roof structure were analyzed by bearing capacity test and numerical analysis. The validity of the numerical analysis model is verified by comparing the results of bearing capacity test with the results of the complete coordinated model and the coupled model analysis. The results show that the failure mode of the specimen is tensile failure of the surface plate of the honeycomb plate with strengthened frame and buckling instability of the plate near the joint. The box-type hollow roof structure has good ductility. The results of static analysis and nonlinear buckling analysis of the honeycomb plate box-type hollow roof structure are carried out by coupling model are more consistent with the results of bearing capacity test.

Gastric cancer (GC) is a global health problem. As a complicated heterogeneous disease, The Cancer Genome Atlas (TCGA) Research Network recognized four subtypes of GC, including Epstein-Barr virus (EBV)-positive GC (EBVaGC), which accounts for approximately 9% of all GC cases. The response to immunotherapy in GC is limited, and whether EBV status is a predictor of immunotherapy remains controversial.The differential gene expression analysis was utilized to compare the gene expression between the EBV-positive group and the EBV-negative group in the TCGA-Stomach Adenocarcinoma (TCGA-STAD) cohort. Weighted gene co-expression network analysis (WGCNA), protein-protein interaction (PPI) network analysis, and gene functional enrichment analysis were used to investigate the most pivotal hub genes and their roles. The "Estimation of Stromal and Immune cells in Malignant Tumours using Expression data" (ESTIMATE) and CIBERSORT algorithms were performed to infer the immune compositions of tissue samples. Furthermore, quantitative real-time polymerase chain reaction (RT-qPCR) and survival analysis were used to validate the expression and prognosis of these hub genes in Sun Yat-sen University Cancer Center (SYSUCC) cohort. A GC cohort that received anti-programmed cell death 1 (PD-1) therapy was used to analyze the predicted efficacy based on the expression of hub genes.There is a total of 1,686 differentially expressed genes (DEGs) between the EBV-positive group and EBV-negative group, and WGCNA identified a yellow-colored module that was most related to EBV features. Functional enrichment analysis of 144 genes in this yellow module demonstrated that these genes primarily performed immune-related functions, and PPI network analysis through the CytoHubba plug-in identified 11 hub genes in the network. The RT-qPCR results in the SYSUCC cohort further validated that the hub genes were all increased in the EBV-positive group. Finally, we found that a potential classifier was associated with the efficacy of immunotherapy based on the expression of these 11 hub genes.Our study identified several hub genes associated with EBV status that are closely related to the immune microenvironmental features of EBVaGC and may be used as molecular markers for predicting the immune response in GC.

Thermal barrier coatings (TBCs) can effectively protect the alloy substrate of hot components in aeroengines or land-based gas turbines by the thermal insulation and corrosion/erosion resistance of the ceramic top coat. However, the continuous pursuit of a higher operating temperature leads to degradation, delamination, and premature failure of the top coat. Both new ceramic materials and new coating structures must be developed to meet the demand for future advanced TBC systems. In this paper, the latest progress of some new ceramic materials is first reviewed. Then, a comprehensive spalling mechanism of the ceramic top coat is summarized to understand the dependence of lifetime on various factors such as oxidation scale growth, ceramic sintering, erosion, and calcium-magnesium-aluminium-silicate (CMAS) molten salt corrosion. Finally, new structural design methods for high-performance TBCs are discussed from the perspectives of lamellar, columnar, and nanostructure inclusions. The latest developments of ceramic top coat will be presented in terms of material selection, structural design, and failure mechanism, and the comprehensive guidance will be provided for the development of next-generation advanced TBCs with higher temperature resistance, better thermal insulation, and longer lifetime.

Background: The role of stroke etiology subtype in patients with acute large vessel occlusion on the occurrence of hemorrhagic transformation (HT) after endovascular treatment is poorly studied, and which factors mediate their relationship remains largely unknown. We utilized nationwide registry data to explore the association of stroke subtype (cardioembolism versus large artery atherosclerosis) with HT and to identify the possible mediators. Methods: A total of 1015 subjects were selected from the ANGEL-ACT registry (Endovascular Treatment Key Technique and Emergency Work Flow Improvement of Acute Ischemic Stroke)—a prospective consecutive cohort of acute large vessel occlusion patients undergoing endovascular treatment at 111 hospitals in China between November 2017 and March 2019—and divided into large artery atherosclerosis (n=538) and cardioembolism (n=477) according to the Trial of ORG 10172 in Acute Stroke Treatment criteria. The types of HT included any intracerebral hemorrhage (ICH), parenchymal hematoma, and symptomatic ICH within 24 hours after endovascular treatment. The association between stroke subtype and HT was analyzed using a logistic regression model. Mediation analysis was done to assess how much of the effect of stroke subtype on HT was mediated through the identified mediators. Results: Stroke subtype (cardioembolism versus large artery atherosclerosis) was associated with increased risk of any ICH (29.8% versus 16.5%; odds ratio, 2.03 [95% CI, 1.22–3.36]), parenchymal hematoma (14.3% versus 5.4%; odds ratio, 2.90 [95% CI, 1.38–6.13]), and symptomatic ICH (9.9% versus 4.7%; odds ratio, 2.59 [95% CI, 1.09–6.16]) after adjustment for potential confounders. The more thrombectomy passes in cardioembolism patients had a significant mediation effect on the association of stroke subtype with increased risk of HT (any ICH, 15.9%; parenchymal hematoma, 13.4%; symptomatic ICH, 14.2%, respectively). Conclusions: Stroke subtype is an independent risk factor for HT within 24 hours following endovascular treatment among acute large vessel occlusion patients. Mediation analyses propose that stroke subtype contributes to HT partly through thrombectomy pass, suggesting a possible pathomechanistic link. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03370939.

Unprecedented breakthroughs have been made in cancer immunotherapy in recent years. Particularly immune checkpoint inhibitors have fostered hope for patients with cancer. However, immunotherapy still exhibits certain limitations, such as a low response rate, limited efficacy in certain populations, and adverse events in certain tumors. Therefore, exploring strategies that can improve clinical response rates in patients is crucial. Tumor-associated macrophages (TAMs) are the predominant immune cells that infiltrate the tumor microenvironment and express a variety of immune checkpoints that impact immune functions. Mounting evidence indicates that immune checkpoints in TAMs are closely associated with the prognosis of patients with tumors receiving immunotherapy. This review centers on the regulatory mechanisms governing immune checkpoint expression in macrophages and strategies aimed at improving immune checkpoint therapies. Our review provides insights into potential therapeutic targets to improve the efficacy of immune checkpoint blockade and key clues to developing novel tumor immunotherapies.

IntroductionThoracic endovascular aortic repair (TEVAR) of the arch is challenging given its complex geometry and the involvement of supra-aortic arteries. Different branched endografts have been designed for use in this region, but their haemodynamic performance and the risk for post-intervention complications are not yet clear. This study aims to examine aortic haemodynamics and biomechanical conditions following TVAR treatment of an aortic arch aneurysm with a two-component single-branched endograft.MethodsComputational fluid dynamics and finite element analysis were applied to a patient-specific case at different stages: pre-intervention, post-intervention and follow-up. Physiologically accurate boundary conditions were used based on available clinical information.ResultsComputational results obtained from the post-intervention model confirmed technical success of the procedure in restoring normal flow to the arch. Simulations of the follow-up model, where boundary conditions were modified to reflect change in supra-aortic vessel perfusion observed on the follow-up scan, predicted normal flow patterns but high levels of wall stress (up to 1.3M MPa) and increased displacement forces in regions at risk of compromising device stability. This might have contributed to the suspected endoleaks or device migration identified at the final follow up.DiscussionOur study demonstrated that detailed haemodynamic and biomechanical analysis can help identify possible causes for post-TEVAR complications in a patient-specific setting. Further refinement and validation of the computational workflow will allow personalised assessment to aid in surgical planning and clinical decision making.

Background Chronic cerebral ischemia induces white matter injury (WMI) contributing to cognitive decline. Both astrocytes and microglia play vital roles in the demyelination and remyelination processes, but the underlying mechanism remains unclear. This study aimed to explore the influence of the chemokine CXCL5 on WMI and cognitive decline in chronic cerebral ischemia and the underlying mechanism. Methods Bilateral carotid artery stenosis (BCAS) model was constructed to mimic chronic cerebral ischemia in 7–10 weeks old male mice. Astrocytic Cxcl5 conditional knockout (cKO) mice were constructed and mice with Cxcl5 overexpressing in astrocytes were generated by stereotactic injection of adeno-associated virus (AAV). WMI was evaluated by magnetic resonance imaging (MRI), electron microscopy, histological staining and western blotting. Cognitive function was examined by a series of neurobehavioral tests. The proliferation and differentiation of oligodendrocyte progenitor cells (OPCs), phagocytosis of microglia were analyzed via immunofluorescence staining, western blotting or flow cytometry. Results CXCL5 was significantly elevated in the corpus callosum (CC) and serum in BCAS model, mainly expressed in astrocytes, and Cxcl5 cKO mice displayed improved WMI and cognitive performance. Recombinant CXCL5 (rCXCL5) had no direct effect on the proliferation and differentiation of OPCs in vitro. Astrocytic specific Cxcl5 overexpression aggravated WMI and cognitive decline induced by chronic cerebral ischemia, while microglia depletion counteracted this effect. Recombinant CXCL5 remarkably hindered microglial phagocytosis of myelin debris, which was rescued by inhibition of CXCL5 receptor C-X-C motif chemokine receptor 2 (CXCR2). Conclusion Our study revealed that astrocyte-derived CXCL5 aggravated WMI and cognitive decline by inhibiting microglial phagocytosis of myelin debris, suggesting a novel astrocyte-microglia circuit mediated by CXCL5-CXCR2 signaling in chronic cerebral ischemia.

Plants alert immune systems by recognizing the fungal pathogen cell wall component chitin via pattern recognition cell surface receptors. Successful fungal pathogens escape the perception by deacetylating chitin to chitosan, which is also necessary for fungal cell development and virulence.