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Abstract This study aimed to elucidate the clinical diagnostic value of plasma catecholamines and their metabolites for pheochromocytoma and paraganglioma (PPGL)‐induced secondary hypertension using ultraperformance liquid chromatography‐mass spectrometry (UPLC‐MS/MS). The study population included 155 patients with PPGL that were divided into the PPGL with hypertension (n = 79) and a PPGL without hypertension (n = 76) groups, and 90 healthy volunteers and 90 patients with primary hypertension as the control groups. UPLC‐MS/MS was performed to detect plasma levels of catecholamines and their metabolites, including dopamine, vanillylmandelic acid (VMA), norepinephrine, metanephrine, and normetanephrine. Receiver operating characteristic curves were generated to analyze the diagnostic value of the plasma levels of catecholamines and their metabolites in PPGL‐induced secondary hypertension. Patients in the primary hypertension and PPGL without hypertension groups had higher levels of dopamine, VMA, norepinephrine, metanephrine, and normetanephrine than patients in the normal group (all p

Accumulating evidence underscores exercise as a straightforward and cost-effective lifestyle intervention capable of mitigating the risk and slowing the emergence and progression of Alzheimer’s disease (AD). However, the intricate cellular and molecular mechanisms mediating these exercise-induced benefits in AD remain elusive. The present study delved into the impact of treadmill exercise on memory retrieval performance, hippocampal synaptic plasticity, synaptic morphology, and the expression and activity of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptors (AMPARs) in 6-month-old APP/PS1 mice. APP/PS1 mice (4-month-old males) were randomly assigned to either a treadmill exercise group or a sedentary group, with C57BL/6J mice (4-month-old males) as the control group (both exercise and sedentary). The exercise regimen spanned 8 weeks. Our findings revealed that 8-week treadmill exercise reversed memory retrieval impairment in step-down fear conditioning in 6-month-old APP/PS1 mice. Additionally, treadmill exercise enhanced basic synaptic strength, short-term potentiation (STP), and long-term potentiation (LTP) of the hippocampus in these mice. Moreover, treadmill exercise correlated with an augmentation in synapse numbers, refinement of synaptic structures, and heightened expression and activity of AMPARs. Our findings suggest that treadmill exercise improves behavioral performance and facilitates synaptic transmission by increasing structural synaptic plasticity and the activity of AMPARs in the hippocampus of 6-month-old APP/PS1 mice, which is involved in pre- and postsynaptic processes.

Pigs can be colonized with Salmonella enterica and become established carriers. However, the mechanisms of the host’s response to Salmonella enterica infection are largely unclear. This study was constructed with the Salmonella enterica infection model in vitro using porcine intestinal epithelial cells (IPEC-J2). Transcriptome profiling of IPEC-J2 cells was carried out to characterize the effect of Salmonella enterica infection and lipopolysaccharide (LPS) treatment, in which LPS-induced inflammation was a positive control. At first, Salmonella enterica infection increased the cell apoptosis rate and induced an inflammation response in IPEC-J2. Then, the up-regulated genes were enriched in metabolic pathways, such as those for bile secretion and mineral absorption, while down-regulated genes were enriched in immune-related pathways, such as the Toll-like receptor signaling and p53 signaling pathways. Moreover, we found 368 up-regulated genes and 101 down-regulated genes in common. Then, an integrative analysis of the transcriptomic profile under Salmonella enterica infection and LPS treatment was conducted, and eight up-regulated genes and one down-regulated gene were detected. Among them, AQP8 is one critical gene of the bile secretion pathway, and its mRNA and protein expression were increased significantly under Salmonella enterica infection and LPS treatment. Thus, the AQP8 gene and bile secretion pathway may be important in IPEC-J2 cells under Salmonella enterica infection or LPS treatment.

Neuronal hyperactivity is a key abnormality in early stage Alzheimer's disease (AD). Medial entorhinal cortex (mEC) plays a vital role in memory function and is affected early in AD. Growing evidence indicates benefits of regular exercise on memory and cognitive function in humans with AD, although, the underlying mechanisms are not clear. Therefore, this study was designed to test the effects of 16 weeks treadmill exercise on spatial learning memory and the underlying cellular mechanisms in 6-month-old 3xTg-AD mice. Whole-cell patch clamp was used to examine neuronal intrinsic excitability, spontaneous excitatory postsynaptic currents (sEPSCs) and spontaneous inhibitory postsynaptic currents (sIPSCs) of mEC layer II/III pyramidal neurons in the following groups: wild type (WT + sham), 3xTg-AD (AD+sham), WT receiving exercise (WT + Ex), and AD receiving exercise (AD+Ex). We found that at a behavioral level, treadmill exercise decreased working memory errors in radial arm maze (RAM) test in 6-month-old AD mice. At a cellular level, we found that treadmill exercise prevented the abnormal increase in mEC pyramidal neuron input resistance and action potential firing in 6-month-old 3xTg-AD mice compared with WT + sham and AD+Ex mice; further, sEPSC amplitude and frequency were normal in AD+Ex but overactive in AD+sham; additionally, GABAergic inhibition was normal in AD+Ex mice but reduced in AD+sham. In conclusion, our results indicate that treadmill exercise improves spatial learning memory and prevents network hyperexcitability in mEC by reducing pyramidal neuronal intrinsic excitability and normalizing excitatory and inhibitory synaptic transmission in 3xTg-AD mice.

Background: Exercise can effectively attenuate withdrawal symptoms and reduce relapse, but it is unknown whether exercise of different intensities produces different results. This study aimed to systematically review the effects of different exercise intensities on withdrawal symptoms among people with substance use disorder (SUD).Methods: Systematic searches for randomized controlled trials (RCTs) on exercise, SUD, and abstinence symptoms were conducted via electronic databases, including PubMed, up to June 2022. Study quality was evaluated using the Cochrane Risk of Bias tool (RoB 2.0) for assessment of risk of bias in randomized trials. The meta-analysis was performed by calculating the standard mean difference (SMD) in outcomes of interventions involving light-, moderate-, and high-intensity exercise for each individual study using Review Manager version 5.3 (RevMan 5.3).Results: In total, 22 RCTs (n = 1,537) were included. Overall, exercise interventions had significant effects on withdrawal symptoms, but the effect size varied with exercise intensity and by outcome measure (i.e., for different negative emotions). Light-, moderate-, and high-intensity exercise reduced cravings after the intervention [SMD = −0.71, 95% CI = (−0.90, −0.52)], and there were no statistical differences between the subgroups (p > 0.05). Light-, moderate-, and high-intensity exercise reduced depression after the intervention [light, SMD = −0.33, 95% CI = (−0.57, −0.09); moderate, SMD = −0.64, 95% CI = (−0.85, −0.42); high, SMD = −0.25, 95% CI = (−0.44, −0.05)], with moderate-intensity exercise producing the best effect (p < 0.05). Only light- and moderate-intensity exercise relieved anxiety after the intervention [light, SMD = −0.48, 95% CI = (−0.71, −0.26); moderate, SMD = −0.58, 95% CI = (−0.85, −0.31)]. Only high-intensity exercise worked in alleviating stress [SMD = −1.13, 95% CI = (−2.22, −0.04)]. Both irritability and restlessness could be improved by light- and moderate-intensity exercise [irritability, SMD = −0.74, 95% CI = (−0.98, −0.50); restless, SMD = −0.72, 95% CI = (−0.98, −0.47)], and there were no statistical differences between the subgroups (p > 0.05). Moderate- and high-intensity exercise decreased withdrawal syndrome after the intervention [moderate, SMD = −0.30, 95% CI = (−0.55, −0.05); high, SMD = −1.33, 95% CI = (−1.90, −0.76)], with high-intensity exercise producing the best effects (p < 0.01).Conclusion: Overall, exercise leads to improvements in withdrawal symptoms in individuals with SUD, but these effects vary significantly between the exercise of different intensities and according to the type of withdrawal symptoms. Moderate-intensity exercise has the greatest benefits in improving depression and anxiety; high-intensity exercise has the greatest benefits in improving withdrawal syndrome.Systematic Review Registration:www.crd.york.ac.uk/PROSPERO/, identifier, CRD42022343791

The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing annually, and emerging evidence suggests that the gut microbiota plays a causative role in the development of NAFLD. However, the role of gut microbiota in the development of NAFLD remains unclear and warrants further investigation. Thus, C57BL/6J mice were fed a high-fat diet (HFD), and we found that the HFD significantly induced obesity and increased the accumulation of intrahepatic lipids, along with alterations in serum biochemical parameters. Moreover, it was observed that the HFD also impaired gut barrier integrity. It was revealed via 16S rRNA gene sequencing that the HFD increased gut microbial diversity, which enriched Colidextribacter, Lachnospiraceae-NK4A136-group, Acetatifactor, and Erysipelatoclostridium. Meanwhile, it reduced the abundance of Faecalibaculum, Muribaculaceae, and Coriobacteriaceae-UCG-002. The predicted metabolic pathways suggest that HFD enhances the chemotaxis and functional activity of gut microbiota pathways associated with flagellar assembly, while also increasing the risk of intestinal pathogen colonization and inflammation. And the phosphotransferase system, streptomycin biosynthesis, and starch/sucrose metabolism exhibited decreases. These findings reveal the composition and predictive functions of the intestinal microbiome in NAFLD, further corroborating the association between gut microbiota and NAFLD while providing novel insights into its potential application in gut microbiome research for NAFLD patients.

Objective:This study aimed to distinguish the risk variables of nonalcoholic fatty liver disease (NAFLD) and to construct a prediction model of NAFLD in visceral fat obesity in Japanese adults.MethodsThis study is a historical cohort study that included 1,516 individuals with visceral obesity. All individuals were randomly divided into training group and validation group at 70% (n = 1,061) and 30% (n = 455), respectively. The LASSO method and multivariate regression analysis were performed for selecting risk factors in the training group. Then, overlapping features were selected to screen the effective and suitable risk variables for NAFLD with visceral fatty obesity, and a nomogram incorporating the selected risk factors in the training group was constructed. Then, we used the C-index, calibration plot, decision curve analysis, and cumulative hazard analysis to test the discrimination, calibration, and clinical meaning of the nomogram. At last, internal validation was used in the validation group.ResultsWe contract a nomogram and validated it using easily available and cost-effective parameters to predict the incidence of NAFLD in participants with visceral fatty obesity, including ALT, HbA1c, body weight, FPG, and TG. In training cohort, the area under the ROC was 0.863, with 95% CI: 0.84–0.885. In validation cohort, C-index was 0.887, with 95%CI: 0.857–0.888. The decision curve analysis showed that the model's prediction is more effective. Decision curve analysis of the training cohort and validation cohort showed that the predictive model was more effective in predicting the risk of NAFLD in Japanese patients with visceral fatty obesity. To help researchers and clinicians better use the nomogram, our online version can be accessed at https://xy2yyjzyxk.shinyapps.io/NAFLD/.ConclusionsMost patients with visceral fatty obesity have a risk of NALFD, but some will not develop into it. The presented nomogram can accurately identify these patients at high risk.

Perfect boron nitride (BN) nanotubes are chemically inert, and hardly considered as catalysts. Nevertheless, metal wire encapsulated BN nanotubes show extraordinarily high chemical activity. We report nickel (Ni) nanowire encapsulated BN(8.0) and BN(9.0) nanotubes toward O2 activation and CO oxidization on the basis of first-principles calculations. Our results suggest that Ni wire encapsulated BN(8.0) and BN(9.0) nanotubes can easily adsorb and activate O2 molecules to form peroxo or superoxo species exothermically. Meanwhile, superoxo species are ready to react with CO molecules forming OCOO intermediate state and finally yielding CO2 molecules. Meanwhile, the rate-limiting step barrier is only 0.637 eV, implying excellent performance for CO oxidation on Ni nanowire encapsulated BN nanotubes. Furthermore, encapsulation of nickel wire improves the catalytic activity of BN nanotubes by facilitating electron transfer from Ni wire to BN nanotubes, which facilitates the adsorption of highly electronegative O2 molecules and subsequent CO oxidation. This study provides a practical and efficient strategy for activating O2 on a metal encapsulated BN nanotube toward CO oxidation.

Physical exercise improves memory and cognition in physiological aging and Alzheimer’s disease (AD), but the mechanisms remain poorly understood. Here, we test the hypothesis that Aβ oligomer accumulation, neuroinflammation, and glial cell activation may lead to disruption of synaptic transmission in the prefrontal cortex of 3 × Tg-AD Mice, resulting in impairment of learning and memory. On the other hand, treadmill exercise could prevent the pathogenesis and exert neuroprotective effects. Here, we used immunohistochemistry, western blotting, enzyme-linked immunosorbent assay, and slice electrophysiology to analyze the levels of GSK3β, Aβ oligomers (Aβ dimers and trimers), pro-inflammatory cytokines (IL-1β, IL-6, and TNFα), the phosphorylation of CRMP2 at Thr514, and synaptic currents in pyramidal neurons in the prefrontal cortex. We show that 12-week treadmill exercise beginning in three-month-old mice led to the inhibition of GSK3β kinase activity, decreases in the levels of Aβ oligomers, pro-inflammatory cytokines (IL-1β, IL-6, and TNFα), and the phosphorylation of CRMP2 at Thr514, reduction of microglial and astrocyte activation, and improvement of excitatory and inhibitory synaptic transmission of pyramidal neurons in the prefrontal cortex of 3 × Tg-AD Mice. Thus, treadmill exercise reduces neuroinflammation, glial cell activation and improves synaptic transmission in the prefrontal cortex in 3 × Tg-AD mice, possibly related to the inhibition of GSK3β kinase activity.

BackgroundTranslocase of inner mitochondrial membrane 17A (TIMM17A) is overexpressed in breast cancer (BRCA), and upregulation can increase the aggressiveness of BRCA cells. This study examined the influence of the TIMM17A gene network on BRCA outcome.MethodsExpression levels of TIMM17A were compared between normal and tumor tissues from the OncomineTM database, and the association with patient survival was analyzed using Kaplan–Meier Plotter. Clinical factors influencing TIMM17A expression were studied by UALCAN. cBioPotal was then used to identify genes interacting with TIMM17A, and network relationships were assessed using the R clusterProfiler package. The association between TIMM17A mutation and mRNA expression in BRCA was examined using the LinkFinder application in LinkedOmics, and coexpressed genes were assessed for functional enrichment using the LinkInterpreter application. Furthermore, TIMM17A expression correlation with cell cycle phase distribution was performed by flow cytometry. Finally, the target networks of kinases, microRNAs (miRNAs), and transcription factors were identified using GeneMANIA. The expression and correlation of potential miRNAs and targets were further validated in BRCA cell lines by qRT-PCR.ResultsExpression of TIMM17A was significantly elevated in BRCA compared with normal tissue (p < 0.05), and overexpression was associated with both poor overall survival (OS) and shorter distant metastasis-free survival (DMFS) (p < 0.05). Expression of TIMM17A was not associated with age, sex, BRCA subclass, clinical stage, or patient ethnicity. The coexpressed TIMM17A network was enriched in genes targeted by cell cycle regulators such as CDK1, miR-331, and E2F family transcription factors (FDR < 0.001). Furthermore, flow cytometry revealed a strong association between higher TIMM17A expression and faster cell cycle progression in these BRCA cell lines. In addition, expression of TIMM17A protein was correlated with CDK1 protein expression in BRCA cell lines as measured by western blotting.ConclusionElevated TIMM17A expression accelerates the progression of BRCA, thereby reducing OS and DMFS. The TIMM17A-associated networks identified here provide clues to the molecular pathogenesis of BRCA and potential targets for BRCA treatment.

Based on the realistic concerns about the improvement of the quality of agricultural foods (agri-foods), the optimal supply quality and price subsidy strategies of producers and sellers for the two-level agricultural supply chain, composed of a producer and a seller, are studied. The differences in the quality safety, price, and market demand of agri-foods in the supply chain are compared and analyzed. The study found that the maximum profit of supply chain participants decreases with the increase of price elasticity of demand. When the quality of agri-foods is upgraded in a producer-led manner, the quality of agri-foods in the supply chain does not undergo substantial improvement, and the maximum profit of agri-foods operators is insensitive to the price elasticity of demand at this time. When the seller-led quality upgrading is launched, the maximum profit of the producer decreases with the increase of the quality elasticity of demand, the maximum profit of the seller increases with the increase of the quality elasticity of demand, and the total profit of the supply chain also increases with the increase of the quality elasticity of demand under the centralized decision situation. The quality and safety of agri-foods as well as the overall profit of the supply chain can be improved most effectively under the centralized control decision with the goal of maximizing the supply chain benefits. In terms of quality and price, quality improvement actions of agri-foods driven by supply-side producers are less effective than those driven by demand-side consumption. In addition, cost-sharing contracts can significantly improve the quality of agri-foods in the supply chain and make them more “high-quality and low-price” than before the adoption of cost-sharing contracts.

In industrial steel plate production, process parameters and steel grade composition significantly influence the microstructure and mechanical properties of the steel produced. But determining the exact relationship between process parameters and mechanical properties is a challenging process. This work aimed to devise a deep learning model, to predict mechanical properties of industrial steel plate including yield strength (YS), ultimate tensile strength (UTS), elongation (EL), and impact energy (Akv); based on the process parameters as well as composition of raw steel, and apply it online to a real steel manufacturing plant. An optimal deep neural network (DNN) model was formulated with 27 inputs parameters, 2 hidden layers each having 200 nodes and 4 output parameters (27 × 200 × 200 × 4) with an initial learning rate 0.0001, using Adam optimizer and subjected to Z pre-processing method, to yield an accurate model with R2 = 0.907. The tuned DNN model, had a root mean square error of 21.06 MPa, 16.67 MPa, 2.36%, and 39.33 J, and root mean square percentage error of 4.7%, 2.9%, 7.7%, and 16.2%, for YS, UTS, EL and Akv respectively. Through comparative analysis, it was found that the accuracy of DNN model was higher than other classic machine learning algorithms. To interpret the model assumptions and findings, several local linear models were devised and analyzed to establish the link between process parameters and mechanical properties. Finally the tuned DNN model was deployed in the real-steel plant for online monitoring and control of steel mechanical properties, and to guide the production of targeted steel plates with tailored mechanical properties.

Alzheimer’s disease (AD) is characterized by deficits in learning and memory. A pathological feature of AD is the alterations in the number and size of synapses, axon length, dendritic complexity, and dendritic spine numbers in the hippocampus and prefrontal cortex. Treadmill exercise can enhance synaptic plasticity in mouse or rat models of stroke, ischemia, and dementia. The aim of this study was to examine the effects of treadmill exercise on learning and memory, and structural synaptic plasticity in 3×Tg-AD mice, a mouse model of AD. Here, we show that 12 weeks treadmill exercise beginning in three-month-old mice improves spatial working memory in six-month-old 3×Tg-AD mice, while non-exercise six-month-old 3×Tg-AD mice exhibited impaired spatial working memory. To investigate potential mechanisms for the treadmill exercise-induced improvement of spatial learning and memory, we examined structural synaptic plasticity in the hippocampus and prefrontal cortex of six-month-old 3×Tg-AD mice that had undergone 12 weeks of treadmill exercise. We found that treadmill exercise led to increases in synapse numbers, synaptic structural parameters, the expression of synaptophysin (Syn, a presynaptic marker), the axon length, dendritic complexity, and the number of dendritic spines in 3×Tg-AD mice and restored these parameters to similar levels of non-Tg control mice without treadmill exercise. In addition, treadmill exercise also improved these parameters in non-Tg control mice. Strengthening structural synaptic plasticity may represent a potential mechanism by which treadmill exercise prevents decline in spatial learning and memory and synapse loss in 3×Tg-AD mice.

A decline in cardiovascular modulation is a feature of the normal aging process and associated with cardiovascular diseases (CVDs) such as hypertension and stroke. Exercise training is known to promote cardiovascular adaptation in young animals and positive effects on motor and cognitive capabilities, as well as on brain plasticity for all ages in mice. Here, we examine the question of whether aerobic exercise interventions may impact the GABAergic neurons of the paraventricular nucleus (PVN) in aged rats which have been observed to have a decline in cardiovascular integration function. In the present study, young (2 months) and old (24 months) male Wistar rats were divided into young control (YC), old sedentary, old low frequency exercise (20 m/min, 60 min/day, 3 days/week, 12 weeks) and old high frequency exercise (20 m/min, 60 min/day, 5 days/week, 12 weeks). Exercise training indexes were obtained, including resting heart rate (HR), blood pressure (BP), plasma norepinephrine (NE), and heart weight (HW)-to-body weight (BW) ratios. The brain was removed and processed according to the immunofluorescence staining and western blot used to analyze the GABAergic terminal density, the proteins of GAD67, GABAA receptor and gephyrin in the PVN. There were significant changes in aged rats compared with those in the YC. Twelve weeks aerobic exercise training has volume-dependent ameliorated effects on cardiovascular parameters, autonomic nervous activities and GABAergic system functions. These data suggest that the density of GABAergic declines in the PVN is associated with imbalance in autonomic nervous activities in normal aging. Additionally, aerobic exercise can rescue aging-related an overactivity of the sympathetic nervous system and induces modifications the resting BP and HR to lower values via improving the GABAergic system in the PVN.

PURPOSE:The role of exercise to prevent or reverse aging-induced cognitive decline has been widely reported. This neuroprotection is associated with changes in the synaptic structure plasticity. However, the mechanisms of exercise-induced synaptic plasticity in the aging brain are still unclear. Thus, the aim of the present study is to investigate the aging-related alterations of Rho-GTPase and the modulatory influences of exercise training. METHODS:Young and old rats were used in this study. Old rats were subjected to different schedules of aerobic exercise (12 m/min, 60 min/d, 3d/w or 5d/w) or kept sedentary for 12 w. After 12 w of aerobic exercise, the synapse density in the cortex and hippocampus was detected with immunofluorescent staining using synaptophysin as a marker. The total protein levels of RhoA, Rac1, Cdc42 and cofilin in the cortex and hippocampus were detected with Western Blot. The activities of RhoA, Rac1 and Cdc42 were determined using a pull down assay. RESULTS:We found that synapse loss occurred in aging rats. However, the change of expression and activity of RhoA, Rac1 and Cdc42 was different in the cortex and hippocampus. In the cortex, the expression and activity of Rac1 and Cdc42 was greatly increased with aging, whereas there were no changes in the expression and activity of RhoA. In the hippocampus, the expression and activity of Rac1 and Cdc42 was greatly decreased and there were no changes in the expression and activity of RhoA. As a major downstream substrate of the Rho GTPase family, the increased expression of cofilin was only observed in the cortex. High frequency exercise ameliorated all aging-related changes in the cortex and hippocampus. CONCLUSIONS:These data suggest that aerobic exercise reverses synapse loss in the cortex and hippocampus in aging rats, which might be related to the regulation of Rho GTPases.

Sn- or Ge-doped hematite thin films were fabricated by annealing alloyed films for the purpose of photoelectrochemical (PEC) water splitting. The alloyed films were deposited on FTO glass by magnetron sputtering and their compositions were controlled by the target. The morphology, crystalline structure, optical properties, and photocatalytic activities have been investigated. The SEM observation showed that uniform, large area arrays of nanoflakes formed after thermal oxidation. The incorporation of doping elements into the hematite structure was confirmed by XRD. The photocurrent density-voltage characterization illustrated that the nanoflake films of Sn-doped hematite exhibited high PEC performance and the Sn concentration was optimized about 5%. The doped Ge4+ ions were proposed to occupy the empty octahedral holes and their effect on PEC performance of hematite is smaller than that of tin ions.