Fever Promotes T Lymphocyte Trafficking via a Thermal Sensory Pathway Involving Heat Shock Protein 90 and α4 Integrins.

Fever is an evolutionarily conserved response that confers survival benefits during infection. However, the underlying mechanism remains obscure. Here, we report that fever promoted T lymphocyte trafficking through heat shock protein 90 (Hsp90)-induced α4 integrin activation and signaling in T cells. By inducing selective binding of Hsp90 to α4 integrins, but not ß2 integrins, fever increased α4-integrin-mediated T cell adhesion and transmigration. Mechanistically, Hsp90 bound to the α4 tail and activated α4 integrins via inside-out signaling. Moreover, the N and C termini of one Hsp90 molecule simultaneously bound to two α4 tails, leading to dimerization and clustering of α4 integrins on the cell membrane and subsequent activation of the FAK-RhoA pathway. Abolishment of Hsp90-α4 interaction inhibited fever-induced T cell trafficking to draining lymph nodes and impaired the clearance of bacterial infection. Our findings identify the Hsp90-α4-integrin axis as a thermal sensory pathway that promotes T lymphocyte trafficking and enhances immune surveillance during infection.

Late-life sleep duration associated with amnestic mild cognitive impairment.

OBJECTIVE: To examine the association between sleep duration in different stages of life and amnestic mild cognitive impairment (aMCI). DESIGN, SETTING, AND PARTICIPANTS: A total of 2472 healthy elderly and 505 patients with aMCI in China were included in this study. The study analyzed the association between aMCI and sleep duration in different stages of life. MEASUREMENTS: We compared sleep duration in different stages of life and analyzed the association between Montreal Cognitive Assessment scores and sleep duration by curve estimation. Logistic regression was used to evaluate the association between aMCI and sleep duration. RESULTS: In the analysis, there were no results proving that sleep duration in youth (P = 0.719, sleep duration < 10 hours; P = 0.999, sleep duration ≥ 10 hours) or midlife (P = 0.898, sleep duration < 9 hours; P = 0.504, sleep duration ≥ 9 hours) had a significant association with aMCI. In the group sleeping less than 7 hours in late life, each hour more of sleep duration was associated with approximately 0.80 of the original risk of aMCI (P = 0.011, odds ratio = 0.80, 95% confidence interval = 0.68-0.95). CONCLUSIONS: Among the elderly sleeping less than 7 hours, there is a decreased risk of aMCI for every additional hour of sleep.

Change lifestyle modification plan/transtheoretical model in non-alcoholic simple fatty liver disease: a pilot randomized study.

BACKGROUND: Non-alcoholic simple fatty liver disease patients have very low compliance with almost all types of physical activities. A transtheoretical model-oriented lifestyle modification plan awakens the patient's consciousness in the pre-intention stage. Aim to evaluate whether a management by stages of change plan based on the Transtheoretical Model and Stages of Change promoted behavior change for patients with non-alcoholic simple fatty liver disease. METHODS: Patients with simple fatty liver diagnosed from July to December 2019 were randomly divided into the transtheoretical model and non-transtheoretical model groups. Primary outcome was change in health belief and health behavior based on questionnaires. Secondary outcomes included changes in blood lipids, body mass indexes, and waist circumference 12-months after intervention. RESULTS: Of 200 enrolled patients 194 were analyzed (non-transtheoretical model group n = 98, transtheoretical model group n = 96). After intervention, total health belief scores (120.91 ± 4.94 vs. 118.82 ± 5.48) and total health behavior scores (131.71 ± 5.87 vs. 119.96 ± 7.12) were higher in the transtheoretical model group (all P < 0.05). Blood lipids, body mass index, and waist circumference more obviously improved in the transtheoretical model group (all P < 0.05). CONCLUSION: A transtheoretical model-based lifestyle modification intervention can be effectively applied to patients with non-alcoholic simple fatty liver. CLINICAL RESEARCH REGISTRATION NUMBER: ChiCTR2100049354. The registration date is August 1, 2021.

DS-GCNs: Connectome Classification using Dynamic Spectral Graph Convolution Networks with Assistant Task Training.

Functional connectivity (FC) matrices measure the regional interactions in the brain and have been widely used in neurological brain disease classification. A brain network, also named as connectome, could form a graph structure naturally, the nodes of which are brain regions and the edges are interregional connectivity. Thus, in this study, we proposed novel graph convolutional networks (GCNs) to extract efficient disease-related features from FC matrices. Considering the time-dependent nature of brain activity, we computed dynamic FC matrices with sliding windows and implemented a graph convolution-based LSTM (long short-term memory) layer to process dynamic graphs. Moreover, the demographics of patients were also used as additional outputs to guide the classification. In this paper, we proposed to utilize the demographic information as extra outputs and to share parameters among three networks predicting subject status, gender, and age, which serve as assistant tasks. We tested the performance of the proposed architecture in ADNI II dataset to classify Alzheimer's disease patients from normal controls. The classification accuracy, sensitivity, and specificity reach 90.0%, 91.7%, and 88.6%, respectively, on ADNI II dataset.

Ca2+ transients on the T cell surface trigger rapid integrin activation in a timescale of seconds.

One question in lymphocyte homing is how integrins are rapidly activated to enable immediate arrest of fast rolling lymphocytes upon encountering chemokines at target vascular beds given the slow chemokine-induced integrin inside-out activation. Herein we demonstrate that chemokine CCL25-triggered Ca2+ influx induces T cell membrane-proximal external Ca2+ concentration ([Ca2+]ex) drop in 6 s from physiological concentration 1.2 mM to 0.3 mM, a critical extracellular Ca2+ threshold for inducing αLß2 activation, triggering rapid αLß2 activation and T cell arrest before occurrence of αLß2 inside-out activation. Talin knockdown inhibits the slow inside-out activation of αLß2 but not [Ca2+]ex drop-triggered αLß2 quick activation. Blocking Ca2+ influx significantly suppresses T cell rolling-to-arrest transition and homing to skin lesions in a mouse psoriasis model, thus alleviating skin inflammation. [Ca2+]ex decrease-triggered rapid integrin activation bridges the gap between initial chemokine stimulation and slow integrin inside-out activation, ensuring immediate lymphocyte arrest and subsequent diapedesis on the right location.

Spatiotemporal patterns of early afterdepolarizations underlying abnormal T-wave morphologies in a tissue model of the Purkinje-ventricular system.

Sudden cardiac death (SCD) is a leading cause of death worldwide, and the majority of SCDs are caused by acute ventricular arrhythmias (VAs). Early afterdepolarizations (EADs) are an important trigger of VA under pathological conditions, e.g., inherited or acquired long QT syndrome (LQTS). However, it remains unclear how EAD events at the cellular level are spatially organized at the tissue level to induce and maintain ventricular arrhythmias and whether the spatial-temporal patterns of EADs at the tissue level are associated with abnormal T-wave morphologies that are often observed in LQTS, such as broad-based, notched or bifid; late appearance; and pointed T-waves. Here, a tissue model of the Purkinje-ventricular system (PVS) was developed to quantitatively investigate the complex spatial-temporal dynamics of EADs during T-wave abnormalities. We found that (1) while major inhibition of ICaL can substantially reduce the excitability of the PVS leading to conduction failures, moderate ICaL inhibition can promote occurrences of AP alternans at short cycle lengths (CLs), and EAD events preferentially occur with a major reduction of IKr (>50%) at long CLs; (2) with a minor reduction of ICaL, spatially synchronized steady-state EAD events with inverted and biphasic T-waves can be "weakened" into beat-to-beat concurrences of spatially synchronized EADs and T-wave alternans, and as pacing CLs increase, beat-to-beat concurrences of localized EADs with late-appearing and pointed T-wave morphologies can be observed; (3) under certain conditions, localized EAD events in the midmyocardium may trigger slow uni-directional electric propagation with inverted (antegrade) or upright (retrograde) broad-based T-waves; (4) spatially discordant EADs were typically characterized by desynchronized spontaneous onsets of EAD events between two groups of PVS tissues with biphasic T-wave morphologies, and they can evolve into spatially discordant oscillating EAD patterns with sustained or self-terminated alternating EAD and electrocardiogram (ECG) patterns. Our results provide new insights into the spatiotemporal aspects of the onset and development of EADs and suggest possible mechanistic links between the complex spatial dynamics of EADs and T-wave morphologies.

Autocrine pro-legumain promotes breast cancer metastasis via binding to integrin αvß3.

Tumor metastasis is the leading cause of cancer-associated mortality. Unfortunately, the underlying mechanism of metastasis is poorly understood. Expression of legumain (LGMN), an endo-lysosomal cysteine protease, positively correlates with breast cancer metastatic progression and poor prognosis. Here, we report that LGMN is secreted in the zymogen form by motile breast cancer cells. Through binding to cell surface integrin αvß3 via an RGD motif, the autocrine pro-LGMN activates FAK-Src-RhoA signaling in cancer cells and promotes cancer cell migration and invasion independent of LGMN protease activity. Either silencing LGMN expression or mutationally abolishing pro-LGMN‒αvß3 interaction significantly inhibits cancer cell migration and invasion in vitro and breast cancer metastasis in vivo. Finally, we developed a monoclonal antibody against LGMN RGD motif, which blocks pro-LGMN‒αvß3 binding, and effectively suppresses cancer cell migration and invasion in vitro and breast cancer metastasis in vivo. Thus, disruption of pro-LGMN‒integrin αvß3 interaction may be a potentially promising strategy for treating breast cancer metastasis.

Mucin-Like Domain of Mucosal Addressin Cell Adhesion Molecule-1 Facilitates Integrin α4ß7-Mediated Cell Adhesion Through Electrostatic Repulsion.

The homing of lymphocytes from blood to gut-associated lymphoid tissue is regulated by interaction between integrin α4ß7 with mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) expressed on the endothelium of high endothelial venules (HEVs). However, the molecular basis of mucin-like domain, a specific structure of MAdCAM-1 regulating integrin α4ß7-mediated cell adhesion remains obscure. In this study, we used heparan sulfate (HS), which is a highly acidic linear polysaccharide with a highly variable structure, to mimic the negative charges of the extracellular microenvironment and detected the adhesive behaviors of integrin α4ß7 expressing 293T cells to immobilized MAdCAM-1 in vitro. The results showed that HS on the surface significantly promoted integrin α4ß7-mediated cell adhesion, decreased the percentage of cells firmly bound and increased the rolling velocities at high wall shear stresses, which was dependent on the mucin-like domain of MAdCAM-1. Moreover, breaking the negative charges of the extracellular microenvironment of CHO-K1 cells expressing MAdCAM-1 with sialidase inhibited cell adhesion and rolling velocity of 293T cells. Mechanistically, electrostatic repulsion between mucin-like domain and negative charges of the extracellular microenvironment led to a more upright conformation of MAdCAM-1, which facilitates integrin α4ß7-mediated cell adhesion. Our findings elucidated the important role of the mucin-like domain in regulating integrin α4ß7-mediated cell adhesion, which could be applied to modulate lymphocyte homing to lymphoid tissues or inflammatory sites.

Prediction of hypertension, hyperglycemia and dyslipidemia from retinal fundus photographs via deep learning: A cross-sectional study of chronic diseases in central China.

Retinal fundus photography provides a non-invasive approach for identifying early microcirculatory alterations of chronic diseases prior to the onset of overt clinical complications. Here, we developed neural network models to predict hypertension, hyperglycemia, dyslipidemia, and a range of risk factors from retinal fundus images obtained from a cross-sectional study of chronic diseases in rural areas of Xinxiang County, Henan, in central China. 1222 high-quality retinal images and over 50 measurements of anthropometry and biochemical parameters were generated from 625 subjects. The models in this study achieved an area under the ROC curve (AUC) of 0.880 in predicting hyperglycemia, of 0.766 in predicting hypertension, and of 0.703 in predicting dyslipidemia. In addition, these models can predict with AUC>0.7 several blood test erythrocyte parameters, including hematocrit (HCT), mean corpuscular hemoglobin concentration (MCHC), and a cluster of cardiovascular disease (CVD) risk factors. Taken together, deep learning approaches are feasible for predicting hypertension, dyslipidemia, diabetes, and risks of other chronic diseases.

Deletion/insertion polymorphisms of the prion protein gene (PRNP) in gayal (Bos frontalis).

Resistance to fatal disease bovine spongiformencephalopathy (BSE), due to misfolded prion protein in cattle, is associated with a 23-bp indel polymorphism in the putative promoter and a 12-bp indel in intron 1 of the PRNP gene. Gayal (Bos frontalis) is an important semiwild bovid species and of great conservation concern, but till today these indel polymorphisms have not been evaluated in gayals. Therefore, we collected 225 samples of gayals and evaluated the genetic indel polymorphism in the two regions of this PRNP gene. The results revealed high allelic frequencies of insertions at these indel sites: 0.909 and 0.667 for, respectively, the 23 bp and 12 bp indels, both also with significant genotype frequencies (χ2: 9.81; 23 bp and χ2: 43.56; 12 bp). At the same time, the haplotype data showed indel polymorphisms with extremely low deletion (0.01) in both regions of the PRNP gene. We compared these data with those reported for healthy and BSE-affected cattle (Bos taurus) breeds from two European countries, Germany and Switzerland, and significant difference (P <0.001) was observed between BSE-affected as well as the healthy cattle. Further, our data were also extensively compared with previous reports on BSE and highly significant (P<0.001) outcomes were observed. This result suggested negligible genetic susceptibility to BSE in gayals. To the best of our knowledge, this study is the first comprehensive deciphering information about the PRNP indel polymorphisms of 23 bp and 12 bp in gayals, a semiwild species of China.

Bile acids evoke placental inflammation by activating Gpbar1/NF-κB pathway in intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic disorder with potentially deleterious consequences for fetuses. Although a clear correlation between the elevated levels of maternal serum bile acids and deficient fetal outcome has been established in clinical practice, the underlying mechanisms remain elusive. Herein, we report that bile acids induce NF-κB pathway activation via G protein-coupled bile acid receptor 1 (Gpbar1), with consequent upregulation of inflammatory genes in trophoblasts, leading to aberrant leukocyte infiltration and inflammation in placenta. Ursodeoxycholic acid (UDCA), a drug used clinically to treat ICP, competes with other bile acids for binding with Gpbar1 and thus inhibits bile acid-induced inflammatory response in trophoblasts and improves fetal survival in pregnant rats with obstructive cholestasis. Notably, inhibition of NF-κB by andrographolide is more effective than UDCA in benefiting placentas and fetuses. Thus, anti-inflammation therapy targeting Gpbar1/NF-κB pathway could be effective in suppressing bile acid-induced inflammation and alleviating ICP-associated fetal disorders.