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BackgroundInsulin resistance is associated with atrial remodeling as well as atrial fibrillation (AF). However, there was limited evidence on the relationship of triglyceride-glucose index (TyG) index, a simple, valuable marker of insulin resistance, with AF. Thus, we aimed to investigate the association between TyG index and AF among hospitalized patients.MethodsA retrospective observational study was conducted in Daping Hospital, which included 356 hospitalized patients from the Department of Cardiology. Clinical and biochemical parameters were collected from electronic medical records and AF was diagnosed from electrocardiogram (ECG) findings.ResultsWe found that the TyG index was significantly higher in the AF group than in the group without AF. Multivariate logistic regression revealed that hypertension (OR = 1.756, 95%CI 1.135-2.717, P = 0.011) and TyG index (OR = 2.092, 95%CI 1.412-3.100, P

Amphioxus (e.g., Branchiostoma belcheri, Bb) has recently emerged as a new model for studying the origin and evolution of vertebrate immunity. Mammalian lymphocyte-specific tyrosine kinase (Lck) plays crucial roles in T cell activation, differentiation and homeostasis, and is reported to phosphorylate both the ITIM and ITSM of PD-1 to induce the recruitment of phosphatases and thus the inhibitory function of PD-1. Here, we identified and cloned the amphioxus homolog of human Lck. By generating and using an antibody against BbLck, we found that BbLck is expressed in the amphioxus gut and gill. Through overexpression of BbLck in Jurkat T cells, we found that upon TCR stimulation, BbLck was subjected to tyrosine phosphorylation and could partially rescue Lck-dependent tyrosine phosphorylation in Lck-knockdown T cells. Mass spectrometric analysis of BbLck immunoprecipitates from immunostimulants-treated amphioxus, revealed a BbLck-associated membrane-bound receptor LRR (BbLcLRR). By overexpressing BbLcLRR in Jurkat T cells, we demonstrated that BbLcLRR was tyrosine phosphorylated upon TCR stimulation, which was inhibited by Lck knockdown and was rescued by overexpression of BbLck. By mutating single tyrosine to phenylalanine (Y-F), we identified three tyrosine residues (Y539, Y655, and Y690) (3Y) of BbLcLRR as the major Lck phosphorylation sites. Reporter gene assays showed that overexpression of BbLcLRR but not the BbLcLRR-3YF mutant inhibited TCR-induced NF-κB activation. In Lck-knockdown T cells, the decline of TCR-induced IL-2 production was reversed by overexpression of BbLck, and this reversion was inhibited by co-expression of BbLcLRR but not the BbLcLRR-3YF mutant. Sequence analysis showed that the three tyrosine-containing sequences were conserved with the tyrosine-based inhibition motifs (ITIMs) or ITIM-like motifs. And TCR stimulation induced the association of BbLcLRR with tyrosine phosphatases SHIP1 and to a lesser extent with SHP1/2. Moreover, overexpression of wild-type BbLcLRR but not its 3YF mutant inhibited TCR-induced tyrosine phosphorylation of multiple signaling proteins probably via recruiting SHIP1. Thus, we identified a novel immunoreceptor BbLcLRR, which is phosphorylated by Lck and then exerts a phosphorylation-dependent inhibitory role in TCR-mediated T-cell activation, implying a mechanism for the maintenance of self-tolerance and homeostasis of amphioxus immune system and the evolutionary conservatism of Lck-regulated inhibitory receptor pathway.

Abstract The well-defined mammalian slp76-signalosome is crucial for T-cell immune response, yet whether slp76-signalosome exists in invertebrates and how it evolved remain unknown. Here we investigated slp76-signalosome from an evolutionary perspective in amphioxus Branchiostoma belcheri (bb). We proved slp76-signalosome components bbslp76, bbGADS and bbItk are present in amphioxus and bbslp76 interacts with bbGADS and bbItk, but differences exist between the interaction manners within slp76-signalosome components of amphioxus and human (h). Specifically, bbslp76 has a unique WW-domain that blocked its association with hItk and decreased TCR-induced tyrosine-phosphorylation and NFAT-activation. Deletion of WW-domain shifted the constitutive association between bbslp76 and hPLCγ1 to a TCR-enhanced association. Among slp76-signalosome, the interaction between slp76 and PLCγ1 is the most conserved and the binding between Itk and slp76 evolved from constitutive to stimulation-regulated. Sequence alignment and 3D structural analysis of slp76-signalosome molecules from keystone species indicated slp76 evolved into a more unfolded and flexible adaptor due to lack of WW-domain and several low-complexity-regions (LCRs) while GADS turned into a larger protein by a LCR gain, thus preparing more space for nucleating the coevolving slp76-signalosome. Altogether, through deletion of WW-domain and manipulation of LCRs, slp76-signalosome evolves from a rigid and stimulation-insensitive to a more flexible and stimulation-responding complex.

BackgroundVoxel-mirrored homotopic connectivity (VMHC) is utilized to assess the functional connectivity of neural networks by quantifying the similarity between corresponding regions in the bilateral hemispheres of the brain. The exploration of VMHC abnormalities in basal ganglia ischemic stroke (BGIS) patients across different cerebral hemispheres has been limited. This study seeks to establish a foundation for understanding the functional connectivity status of both brain hemispheres in BGIS patients through the utilization of VMHC analysis utilizing resting-state functional magnetic resonance imaging (rs-fMRI).MethodsThis study examined a total of 38 patients with left basal ganglia ischemic stroke (LBGIS), 44 patients with right basal ganglia ischemic stroke (RBGIS), and 41 individuals in a healthy control (HC) group. Rs-fMRI studies were performed on these patients, and the pre-processed rs-fMRI data were analyzed using VMHC method. Subsequently, the VMHC values were compared between three groups using a one-way ANOVA and post hoc analysis. Correlation analysis with clinical scales was also conducted.ResultsThe results indicated that compared to the HC group, significant differences were detected in postcentral gyrus, extending to precentral gyrus in both BGIS groups. Post hoc analysis showed that in the pairwise ROI-based comparison, individuals with LBGIS and RBGIS exhibited reduced VMHC values compared to HC groups. There was no significant difference between the LBGIS and RBGIS groups. In the LBGIS group, the VMHC value showed a negative correlation with NIHSS and a positive correlation with BI.ConclusionThe analysis of VMHC in rs-fMRI revealed a pattern of brain functional remodeling in patients with unilateral BGIS, marked by reduced synchronization and coordination between hemispheres. This may contribute to the understanding of the neurological mechanisms underlying motor dysfunction in these patients.

BackgroundThe optimal dose of tenecteplase vs. alteplase for acute ischemic stroke (AIS) has yet to be established. Therefore, we included the latest randomized controlled trials (RCT) to assess the efficacy and safety of different doses of tenecteplase vs. alteplase for AIS within 4.5 hours of symptom onset.MethodsLiterature was searched in PubMed, Cochrane Library, Embase, Web of Science, and clinical trial registries until February 12, 2023. Odds ratios (OR) with 95% credible intervals (CrI) were estimated using Bayesian network meta-analysis (NMA). Treatments were ranked based on efficacy and safety using the surface under the cumulative ranking curve (SUCRA).ResultsEleven RCTs with 5,475 patients were included. Tenecteplase 0.25 mg/kg and alteplase 0.9 mg/kg had significantly higher rates of excellent functional outcome (tenecteplase: OR, 1.85; 95% CrI, 1.44–2.37; alteplase: OR, 1.60; 95% CrI, 1.29–1.97) and good functional outcome (tenecteplase: OR, 1.54; 95% CrI, 1.19–1.98; alteplase: OR, 1.40; 95% CrI, 1.14–1.74) than placebo, despite an increased risk of symptomatic intracranial hemorrhage. Furthermore, the NMA (OR, 1.16; 95% CrI, 1.01–1.33) and the pairwise meta-analysis (OR, 1.16; 95% CI, 1.02–1.33; P = 0.03) indicated that tenecteplase 0.25 mg/kg was superior to alteplase 0.9 mg/kg in excellent functional outcome. Alteplase 0.9 mg/kg (OR, 2.54; 95% CrI, 1.45–8.08) significantly increased the risk of any intracranial hemorrhage compared with placebo. SUCRA results demonstrated that tenecteplase 0.25 mg/kg ranked first and tenecteplase 0.4 mg/kg ranked last in efficacy outcomes.ConclusionsThe NMA indicated that tenecteplase 0.25 mg/kg and alteplase 0.9 mg/kg are safe and significantly improve clinical outcomes in patients with AIS within 4.5 h of symptom onset. Furthermore, tenecteplase 0.25 mg/kg provides more benefit and has the potential to replace alteplase 0.9 mg/kg in AIS treatment.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/index.php, identifier: CRD42022343948.

ObjectiveThe aim of this study was to investigate the spontaneous regional neural activity abnormalities in patients with acute basal ganglia ischemic stroke (BGIS) using a multifrequency bands regional homogeneity (ReHo) method and to explore whether the alteration of ReHo values was associated with clinical characteristics.MethodsIn this study, 34 patients with acute BGIS and 44 healthy controls (HCs) were recruited. All participants were examined by resting-state functional magnetic resonance imaging (rs-fMRI). The ReHo method was used to detect the alterations of spontaneous neural activities in patients with acute BGIS. A two-sample t-test comparison was performed to compare the ReHo value between the two groups, and a Pearson correlation analysis was conducted to assess the relationship between the regional neural activity abnormalities and clinical characteristics.ResultsCompared with the HCs, the patients with acute BGIS showed increased ReHo in the left caudate and subregions such as the right caudate and left putamen in conventional frequency bands. In the slow-5 frequency band, patients with BGIS showed decreased ReHo in the left medial cingulum of BGIS compared to the HCs and other subregions such as bilateral caudate and left putamen. No brain regions with ReHo alterations were found in the slow-4 frequency band. Moreover, we found that the ReHo value of left caudate was positively correlated with the NIHSS score.ConclusionOur findings revealed the alterations of ReHo in patients with acute BGIS in a specific frequency band and provided a new insight into the pathogenesis mechanism of BGIS. This study demonstrated the frequency-specific characteristics of ReHo in patients with acute BGIS, which may have a positive effect on the future neuroimaging studies.

Objective. The purpose of this study was to investigate the characteristics of different frequency bands in the spontaneous brain activity among patients with acute basal ganglia ischemic stroke (BGIS). Methods. In the present study, thirty-four patients with acute BGIS and forty-four healthy controls were examined by resting-state functional magnetic resonance imaging (rs-fMRI) from May 2019 to December 2020. Two amplitude methods including amplitude of low-frequency fluctuations (ALFF) and fractional ALFF (fALFF) calculated in three frequency bands (conventional frequency band: 0.01-0.08 Hz; slow-5 frequency band: 0.01-0.027 Hz; and slow-4 frequency band: 0.027-0.073 Hz) were conducted to evaluate the spontaneous brain activity in patients with acute BGIS and healthy controls (HCs). Gaussian Random Field Theory (GRF, voxel p

Lung cancer related hypercoagulability could increase the risk of ischemic stroke. Routine coagulation tests may have limited capacity in evaluating hypercoagulability. The aim of this study was to investigate the ability of thromboelastography (TEG) in the identification of hypercoagulability in patients with lung cancer and cryptogenic ischemic stroke (LCIS). Between January 2016 and December 2018, whole citrated blood from LCIS patients (n = 35) and age- and gender-matched lung cancer patients and healthy volunteers were used for TEG and routine coagulation tests. The coagulation indicator and clinical data were compared among the 3 groups. There were 27/35 (77.14%) on TEG and 18/35 (51.43%) on routine coagulation tests of LCIS patients who had evidence of hypercoagulability. The detection rate of hypercoagulability by TEG in LCIS patients was higher than routine coagulation tests ( P = 0.018). Comparing with lung cancer patients and healthy controls, LCIS patients have a significantly higher maximum amplitude (MA), fibrinogen, and D-dimer. Multivariate analysis showed that D-dimer and MA were significantly associated with ischemic stroke in lung cancer patients. ROC curve showed that the area under the curve of TEG (0.790 ± 0.048, 95% CI: 0.697-0.864) was significantly higher than routine coagulation tests (0.673 ± 0.059, 95% CI: 0.572-0.763) ( P = 0.04) in identifying hypercoagulability in LCIS patients. Therefore, TEG could identify hypercoagulability in LCIS patients and healthy controls. Identification of hypercoagulability in lung cancer patients by TEG may be helpful to prevent the occurrence of LCIS.

Objective To investigate the independent risk factors and potential predictors of bladder cancer-related ischemic stroke (BCRIS). Methods This was a multi-center retrospective study including patients with active bladder cancer and acute ischemic stroke without traditional stroke risk factors (BCRIS group), and sex- and age-matched patients with active bladder cancer alone (control group). Data were collected between January 2006 and December 2018. Uni- and multivariate analyses were performed to identify independent risk factors for BCRIS. The predictive performance of these risk factors was assessed using receiver operating characteristic (ROC) curves. Results Records were retrospectively reviewed from 60 BCRIS patients and 120 bladder cancer controls. Univariate analysis revealed that serum D-dimer and carcinoembryonic antigen (CEA) levels and the platelet and neutrophil counts were significantly higher in BCRIS patients compared with controls. Multivariate analysis identified the three above-mentioned variables as independent risk factors for BCRIS. The product of all three factors gave the largest area under the ROC curve. Conclusions Elevated serum D-dimer and CEA levels and increased platelet count were independent risk factors for BCRIS, and the cut-off value based on the product of the three independent risk factors (≥2,640,745.29) could serve as a potential predictor of BCRIS.