Association between social capital and quality of life in older adults with subjective cognitive decline: A cross-sectional study.

BACKGROUND: Subjective cognitive decline (SCD) is increasingly recognized as a clinical and medical risk factor for mild cognitive impairment (MCI) and dementia. Currently, there is little evidence regarding the quality of life (QoL) in older adults with SCD and the impact of social capital on their QoL. AIMS: To examine the perceptions of social capital and QoL among older adults with SCD. METHODS: A total of 325 participants (92.9 % response rate) with a self-reported diagnosis of SCD completed the Chinese version of the 36-item Short-Form Health Survey, the Chinese Shortened Social Capital Scale and the Generalized Anxiety Disorder Scale. A t-test was used to compare the QoL score of our sample with the Chinese norm. Pearson correlation analysis and multivariate linear regression analysis were used to assess the association of social capital with QoL. RESULTS: Social capital were strongly correlated with the total QoL, as well as its physical component summary and mental component summary. The QoL score of older adults with SCD was significantly lower than the Chinese norm (P < 0.001). Multivariate analysis showed that social capital, physical activity, nutrition and anxiety symptoms were factors associated with QoL among older SCD population (P < 0.05). CONCLUSION: The findings of the current study suggest that older adults with SCD may experience lower QoL. Social capital is associated with the QoL in older adults with SCD. These findings have implications for clinicians who work with older adults with SCD.

Physical activity trajectories and their associations with health outcomes in older adults with mild cognitive impairment or dementia: a national cohort study.

BACKGROUND: Physical activity (PA) is a promising non-pharmacological intervention for this population. However, few studies have investigated their PA trajectories, influencing factors, and their relationship with health outcomes. AIMS: The aim was to identify latent trajectories in PA and their determinants in older adults with mild cognitive impairment (MCI) or dementia, as well as to assess the associations between PA trajectories and health outcomes based on the capability-opportunity-motivation behavior model. METHODS: This is a cohort study. Data were obtained from a national cohort study and included participants aged 60 years and older with MCI or dementia. PA trajectories were identified using group-based trajectory modelling. Multinomial logistic regression was conducted to identify the predictors of PA trajectories. Linear regression models were used to assess the associations between PA trajectories and health outcomes. This study adhered to the STROBE checklist for reporting. RESULTS: Three distinct PA trajectories were identified: high-decreasing and rebound class (9.34%), moderate-decreasing class (10.31%), and low-increasing class (80.34%). The logistic regression showed that age, sex, education level, body mass index, residence, depressive symptoms, mobility activities of daily life score, frequency of social activities score were PA predictors. Adjusting for sociodemographic variables, only the high-decreasing and rebound class remained significantly associated with worse self-rated health. DISCUSSION: This study revealed three PA trajectories among older adults with MCI/dementia. Besides sociodemographic variables, addressing physical function and mental health, providing social support are vital for promoting PA in this population.

Inhibition of ATR opposes glioblastoma invasion through disruption of cytoskeletal networks and integrin internalization via macropinocytosis.

BACKGROUND: Glioblastomas have highly infiltrative growth patterns that contribute to recurrence and poor survival. Despite infiltration being a critical therapeutic target, no clinically useful therapies exist that counter glioblastoma invasion. Here, we report that inhibition of ataxia telangiectasia and Rad 3 related kinase (ATR) reduces invasion of glioblastoma cells through dysregulation of cytoskeletal networks and subsequent integrin trafficking. METHODS: Glioblastoma motility and invasion were assessed in vitro and in vivo in response to ATR inhibition (ATRi) and ATR overexpression using time-lapse microscopy, two orthotopic glioblastoma models, and intravital imaging. Disruption to cytoskeleton networks and endocytic processing were investigated via high-throughput, super-resolution and intravital imaging. RESULTS: High ATR expression was associated with significantly poorer survival in clinical datasets while histological, protein expression, and spatial transcriptomics using glioblastoma tumor specimens revealed higher ATR expression at infiltrative margins. Pharmacological inhibition with two different compounds and RNAi targeting of ATR opposed the invasion of glioblastoma, whereas overexpression of ATR drove migration. Subsequent investigation revealed that cytoskeletal dysregulation reduced macropinocytotic internalization of integrins at growth-cone-like structures, resulting in a tumor microtube retraction defect. The biological relevance and translational potential of these findings were confirmed using two orthotopic in vivo models of glioblastoma and intravital imaging. CONCLUSIONS: We demonstrate a novel role for ATR in determining invasion in glioblastoma cells and propose that pharmacological targeting of ATR could have far-reaching clinical benefits beyond radiosensitization.

Long-Term Consumption of Green Tea Can Reduce the Degree of Depression in Postmenopausal Women by Increasing Estradiol.

Postmenopausal women face a higher risk of depression due to a combination of social and physiological factors. As a beverage rich in a variety of bioactive substances, green tea has significant effects on metabolism, inflammation and endocrine, and may reduce the risk of depression, but few studies have looked at the effects of green tea on postmenopausal women. Therefore, we designed this study to investigate the effects of long-term green tea consumption on inflammation, endocrine and depression levels in postmenopausal women. We investigated a tea-producing village and eventually included 386 postmenopausal women, both in the tea drinking and control groups. The results showed that there were significant differences in the degree of insomnia, degree of depression, BMI, SII and estradiol between the two groups. And, green tea consumption may reduce the risk of depression through the mediating pathway of sleep, SII and estradiol. In summary, long-term green tea consumption can reduce the risk of depression in postmenopausal women by reducing inflammation and increasing estradiol. This kind of living habit deserves further promotion.

Trends and hotspots in gene research of epilepsy in children: A review and bibliometric analysis from 2010 to 2022.

BACKGROUND: About 70% to 80% of epilepsy cases are related to genetic factors. Genetic research has revealed the genetic etiology and molecular mechanisms of childhood epilepsy, which has increased our understanding of childhood epilepsy. METHODS: We searched the core collection of Web of Science for relevant papers on genetic research on childhood epilepsy published since 2010 on November 30, 2022. In this study, original articles and reviews in English were included. Using CiteSpace and VOSviewer online tools, we conducted a bibliometric analysis of the countries, institutions, journals, co-cited journals, co-cited references, keywords, and research hotspots. RESULTS: We evaluated 2500 literatures on epilepsy genomics in children. Among them, 96 countries published relevant articles, with the United States ranking the most. A total of 389 institutions have contributed relevant publications, and the University of Melbourne has published the most papers. Epilepsy journals were the most commonly cited. The references of papers were clustered into 9 categories: gene testing, epileptic encephalopathy, Dravet syndrome, focal cortical dysplasia, Rolandic epilepsy, copy number variation, ketogenic diet, monogenic epilepsy, and ptt2 mutation. Burst keywords represent the frontier of research, including developmental and epileptic encephalopathy (2021-2022), neurodevelopmental disorders (2020-2022), gene testing (2020-2022), and whole-exome sequencing (2019-2022). CONCLUSION: This study conducted a systematic and objective bibliometric analysis of the literature on epilepsy gene research in children. More importantly, it revealed the hot spot, frontier, and future developmental trends in the field. It will help pediatricians and geneticists further understand the dynamic evolution of genetic research on pediatric epilepsy.

Comparative effectiveness of Chinese herbal injections treating for rotavirus enteritis in children: A systematic review and Bayesian network meta-analysis.

Background: Rotavirus enteritis (RVE) accounts for 37% of all death in children (<5 years) with diarrhea. Chinese herbal injections (CHIs) have drawn more attention from practitioners because of the valid effects for RVE. However, the most beneficial one has not yet been determined. Methods: Eight databases were searched from their inception up to September 3rd, 2022. The primary outcome was clinical effective rate and the secondary outcomes were time for disappearance of diarrhea, time of defervescence, time for disappearance of vomiting, and adverse drug reactions or adverse drug events. OpenBUGS 3.2.3 and STATA 14.0 software were employed to carry out the NMA. Results: 58 randomized controlled trials (RCTs) with 6436 child patients were included in this Bayesian NMA. Four CHIs were investigated including Yanhuning injection (YHN), Xiyanping injection (XYP), Reduning injection (RDN), and Zedoary Turmeric Oil injection (ZTO). The results showed that YHN [OR=6.16, 95% CI (4.39, 8.77)] had a superior effect in improving clinical effective rate compared to Ribavirin based on Western medicine (WM). According to SUCRA values, YHN (84.1%) ranked highest. As for the secondary outcomes, XYP was the better intervention in shortening the time for disappearance of diarrhea. Regarding time for defervescence, RDN had obvious advantages and also performed well in time for disappearance of vomiting. Conclusion: CHIs combined with WM could be beneficial than Ribavirin in improving clinical effective rate, and YHN was the optimum treatment. From the comprehensive evaluations of both the clinical effective rate and other outcomes, YHN also indicated a favorable therapeutic effect in RVE. Study registration: PROSPERO, CRD42022357149.

The XINDI Study: A Randomized Phase III Clinical Trial Evaluating the Efficacy and Safety of Safinamide as Add-On Therapy to Levodopa in Chinese Patients with Parkinson's Disease with Motor Fluctuations.

BACKGROUND: Levodopa remains the gold standard for the treatment of Parkinson's disease, but its long-term use is associated with motor complications whose management is still a significant challenge. Safinamide is a multimodal drug with proven efficacy as an adjunct to levodopa. OBJECTIVE: The objective of this study was to investigate the efficacy and safety of safinamide as an add-on to levodopa in Chinese patients with Parkinson's disease with motor fluctuations. METHODS: The XINDI study was a phase III, randomized, double-blind, placebo-controlled, multicenter study, with a 2-week screening period and a 16-week treatment period. The starting dose of safinamide (or placebo) was 50 mg once daily, increased to 100 mg once daily at day 15. Patients aged ≥  18 years, with idiopathic Parkinson's disease of >3 years duration, Hoehn and Yahr stage 1-4, and daily OFF time ≥  1.5 h, were eligible. Patients should follow a stable oral levodopa regimen and may receive concomitant treatment with stable doses of other anti-Parkinson drugs, except monoamine oxidase-B inhibitors. Patients with severe disabling peak-dose or biphasic dyskinesia, unpredictable or widely swinging fluctuations, other forms of parkinsonism, a history of dementia or severe cognitive dysfunction, major psychiatric illnesses, and/or clinically significant medical illnesses were excluded. The primary efficacy endpoint was the change from baseline to week 16 in the mean daily OFF time. Secondary efficacy endpoints included the Unified Parkinson's Disease Rating Scale, the Numerical Rating Scale, the Clinical Global Impression scale, and the 39-Item Parkinson's Disease Questionnaire scale. The statistical analysis of the efficacy parameters was conducted using an analysis of co-variance, except for the Clinical Global Impression scale scores that were assessed using the Wilcoxon-Mann-Whitney test. Safety was evaluated through the frequency of adverse events and serious adverse events, physical examination, vital signs, 12-lead electrocardiograms, and laboratory exams. All safety endpoints were summarized using descriptive statistics. RESULTS: The trial enrolled 307 patients. At week 16, the difference in the change of the mean total daily OFF time between safinamide and placebo groups was 1.10 h (p < 0.0001). This change was significantly greater in the safinamide group starting from week 2, suggesting a rapid onset of drug efficacy. ON time, Unified Parkinson's Disease Rating Scale, Clinical Global Impression scale, and the 39-Item Parkinson's Disease Questionnaire showed statistically significant improvements. There were no significant between-group differences for adverse events or serious adverse events. CONCLUSIONS: Safinamide, as add-on therapy to levodopa, significantly reduced motor fluctuations and improved motor symptoms and quality of life of Chinese patients with idiopathic Parkinson's disease. The improvements observed in the Unified Parkinson's Disease Rating Scale total and motor scores were also clinically significant. No safety concerns were identified, confirming the good tolerability profile of the drug. CLINICAL TRIAL REGISTRATION: NCT03881371, registered on 19 March, 2019, https://clinicaltrials.gov/NCT03881371 .

Colloidal Jamming by Interfacial Self-Assembled Polymers: A Robust Route for Ultrahigh Efficient Encapsulation.

The control of cargo phase-transfer is of interest for many applications in science and technology. Herein, we report a simple, versatile and robust method to block the phase-transfer of cargo colloids by interfacial self-assembled amphiphilic polymer molecules. After simply increasing the concentration of amphiphilic polymers, the orientation of interfacial polymer molecules changed from flat to upright, forming a thick three-dimensional polymer layer at the oil-water interface. Even under fierce external force, this thick interfacial layer robustly prevented the phase-transfer of cargo colloids, resulting in an ultrahigh encapsulation efficiency (up to 97.1 %) for proteins and peptides. One single injection of high insulin-loaded microcomposites (58.3 wt%) kept the blood glucose level within the normoglycemic state for 10 days in type 1 diabetic rats. The mass of administrated amphiphilic polymers was 1889 times smaller than that of microcomposites prepared with non-amphiphilic ones.

Hierarchical multi-class Alzheimer's disease diagnostic framework using imaging and clinical features.

Due to the clinical continuum of Alzheimer's disease (AD), the accuracy of early diagnostic remains unsatisfactory and warrants further research. The objectives of this study were: (1) to develop an effective hierarchical multi-class framework for clinical populations, namely, normal cognition (NC), early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI), and AD, and (2) to explore the geometric properties of cognition-related anatomical structures in the cerebral cortex. A total of 1,670 participants were enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, comprising 985 participants (314 NC, 208 EMCI, 258 LMCI, and 205 AD) in the model development set and 685 participants (417 NC, 110 EMCI, 83 LMCI, and 75 AD) after 2017 in the temporal validation set. Four cortical geometric properties for 148 anatomical structures were extracted, namely, cortical thickness (CTh), fractal dimension (FD), gyrification index (GI), and sulcus depth (SD). By integrating these imaging features with Mini-Mental State Examination (MMSE) scores at four-time points after the initial visit, we identified an optimal subset of 40 imaging features using the temporally constrained group sparse learning method. The combination of selected imaging features and clinical variables improved the multi-class performance using the AdaBoost algorithm, with overall accuracy rates of 0.877 in the temporal validation set. Clinical Dementia Rating (CDR) was the primary clinical variable associated with AD-related populations. The most discriminative imaging features included the bilateral CTh of the dorsal part of the posterior cingulate gyrus, parahippocampal gyrus (PHG), parahippocampal part of the medial occipito-temporal gyrus, and angular gyrus, the GI of the left inferior segment of the insula circular sulcus, and the CTh and SD of the left superior temporal sulcus (STS). Our hierarchical multi-class framework underscores the utility of combining cognitive variables with imaging features and the reliability of surface-based morphometry, facilitating more accurate early diagnosis of AD in clinical practice.

Edge Constraint and Location Mapping for Liver Tumor Segmentation from Nonenhanced Images.

As there is no contrast enhancement, the liver tumor area in nonenhanced MRI exists with blurred edges and low contrast, which greatly affects the speed and accuracy of liver tumor diagnosis. As a result, precise segmentation of liver tumor from nonenhanced MRI has become an urgent and challenging task. In this paper, we propose an edge constraint and localization mapping segmentation model (ECLMS) to accurately segment liver tumor from nonenhanced MRI. It consists of two parts: localization network and dual-branch segmentation network. We build the localization network, which generates prior coarse masks to provide position mapping for the segmentation network. This part enhances the ability of the model to localize liver tumor in nonenhanced images. We design a dual-branch segmentation network, where the main decoding branch focuses on the feature representation in the core region of the tumor and the edge decoding branch concentrates on capturing the edge information of the tumor. To improve the ability of the model for capturing detailed features, sSE blocks and dense upward connections are introduced into it. We design the bottleneck multiscale module to construct multiscale feature representations using kernels of different sizes while integrating the location mapping of tumor. The ECLMS model is evaluated on a private nonenhanced MRI dataset that comprises 215 different subjects. The model achieves the best Dice coefficient, precision, and accuracy of 90.23%, 92.25%, and 92.39%, correspondingly. The effectiveness of our model is demonstrated by experiment results, and our model reaches superior results in the segmentation task of nonenhanced liver tumor compared to existing segmentation methods.

G protein-coupled receptor 17 restricts rabies virus replication via BAK-mediated apoptosis.

Rabies, caused by rabies virus (RABV), is an ancient zoonotic disease that significantly affects human and animal health throughout the world. RABV causes acute encephalitis in mammals with a high fatality rate in developing countries. G protein-coupled receptor 17 (GPR17) is a vital gene in the central nervous system (CNS) that plays important roles in demyelinating diseases and ischemia brain. However, it is still unclear whether GPR17 participates in the regulation of RABV infection. Here, we found that upregulation or activation of GPR17 can reduce the virus titer; conversely, the inactivation or silence of GPR17 led to increased RABV replication in N2a cells. The recombinant RABV expressing GPR17 (rRABV-GPR17) showed reduced replication capacity compared to the parent virus rRABV. Moreover, overexpression of GPR17 can attenuate RABV pathogenicity in mice. Further study demonstrated that GPR17 suppressed RABV replication via BAK-mediated apoptosis. Our findings uncover an unappreciated role of GPR17 in suppressing RABV infection, where GPR17 mediates cell apoptosis to limit RABV replication and may be an attractive candidate for new therapeutic interventions in the treatment of rabies.

Identification of vascular dementia and Alzheimer's disease hub genes expressed in the frontal lobe and temporal cortex by weighted co-expression network analysis and construction of a protein-protein interaction.

Background: It is difficult to distinguish cognitive decline due to AD from that sustained by cerebrovascular disease in view of the great overlap. It is uncertain in the molecular biological pathway behind AD and VaD.Objective: Our study aimed to explore the hub molecules and their associations with each other to identify potential biomarkers and therapeutic targets for the AD and VaD.Methods: We screened the differentially expressed genes of AD and VaD, used weighted gene co-expression network analysis and then constructed a VaD-AD-specific protein-protein interaction network with functional annotation to their related metabolic pathways. Finally, we performed a ROC curve analysis of hub proteins to get an idea about their diagnostic value.Results: In the frontal lobe and temporal cortex, hub genes were identified. With regard to VaD, there were only three hub genes which encoded the neuropeptides, SST, NMU and TAC1. The AUC of these genes were 0.804, 0.768 and 0.779, respectively. One signature was established for these three hub genes with AUC of 0.990. For the identification of AD and VaD, all hub genes were receptors. These genes included SH3GL2, PROK2, TAC3, HTR2A, MET, TF, PTH2R CNR1, CHRM4, PTPN3 and CRH. The AUC of these genes were 0.853, 0.859, 0.796, 0.775, 0.706, 0.677, 0.696, 0.668 and 0.652, respectively. The other signature was built for eleven hub genes with AUC of 0.990.Conclusion: In the frontal lobe and temporal cortex regions, hub genes are used as diagnostic markers, which may provide insight into personalized potential biomarkers and therapeutic targets for patients with VaD and AD.

Detection of four foodborne pathogens based on magnetic separation multiplex PCR and capillary electrophoresis.

Foodborne pathogen contamination is a major safety issue for many foods and is causing concern worldwide. In this study, a detection system based on magnetic separation, multiplex PCR (MPCR) and capillary electrophoresis (CE) technologies was developed for the simultaneous detection of four foodborne pathogens. Magnetic separation technology is used to rapidly capture pathogenic bacteria in food samples, and then a combination of MPCR and CE can be used to greatly increase detection sensitivity. The detection limit for bacterial DNA reached 10-5 -10-7  ng µL-1 and in the analysis of mocked food samples, the assay showed good sensitivity for bacterial detection ranging from 101 to 105 CFU mL-1 with excellent specificity. Compared to similar detection methodologies, this technique avoids the need for time-consuming enrichment cultures, is more sensitive, and can be used to assay simultaneously four foodborne pathogens.

Virus-Like Vesicles Based on Semliki Forest Virus-Containing Rabies Virus Glycoprotein Make a Safe and Efficacious Rabies Vaccine Candidate in a Mouse Model.

Rabies is a fatal zoonosis that causes encephalitis in mammals, and vaccination is the most effective method to control and eliminate rabies. Virus-like vesicles (VLVs), which are characterized as infectious, self-propagating membrane-enveloped particles composed of only Semliki Forest virus (SFV) replicase and vesicular stomatitis virus glycoprotein (VSV-G), have been proven safe and efficient as vaccine candidates. However, previous studies showed that VLVs containing rabies virus glycoprotein (RABV-G) grew at relatively low titers in cells, impeding their potential use as a rabies vaccine. In this study, we constructed novel VLVs by transfection of a mutant SFV RNA replicon encoding RABV-G. We found that these VLVs could self-propagate efficiently in cell culture and could evolve to high titers (approximately 108 focus-forming units [FFU]/ml) by extensive passaging 25 times in BHK-21 cells. Furthermore, we found that the evolved amino acid changes in SFV nonstructural protein 1 (nsP1) at positions 470 and 482 was critical for this high-titer phenotype. Remarkably, VLVs could induce robust type I interferon (IFN) expression in BV2 cells and were highly sensitive to IFN-α. We found that direct inoculation of VLVs into the mouse brain caused reduced body weight loss, mortality, and neuroinflammation compared with the RABV vaccine strain. Finally, it could induce increased generation of germinal center (GC) B cells, plasma cells (PCs), and virus-neutralizing antibodies (VNAs), as well as provide protection against virulent RABV challenge in immunized mice. This study demonstrated that VLVs containing RABV-G could proliferate in cells and were highly evolvable, revealing the feasibility of developing an economic, safe, and efficacious rabies vaccine. IMPORTANCE VLVs have been shown to represent a more versatile and superior vaccine platform. In previous studies, VLVs containing the Semliki Forest virus replicase (SFV nsP1 to nsP4) and rabies virus glycoprotein (RABV-G) grew to relatively low titers in cells. In our study, we not only succeeded in generating VLVs that proliferate in cells and stably express RABV-G, but the VLVs that evolved grew to higher titers, reaching 108 FFU/ml. We also found that nucleic acid changes at positions 470 and 482 in nsP1 were vital for this high-titer phenotype. Moreover, the VLVs that evolved in our studies were highly attenuated in mice, induced potent immunity, and protected mice from lethal RABV infection. Collectively, our study showed that high titers of VLVs containing RABV-G were achieved, demonstrating that these VLVs could be an economical, safe, and efficacious rabies vaccine candidate.

Activities of daily living as a longitudinal moderator of the effect of autonomic dysfunction on anxiety and depression of Parkinson's patients.

BACKGROUND: There is no clear time point for the onset of depression and anxiety in Parkinson's disease (PD), and their atypical physical symptoms often overlap with other nonmotor symptoms. Autonomic dysfunction usually appears earlier than motor symptoms, seriously impairing activities of daily living (ADL), even quality of life. Whether autonomic dysfunction can affect depression and anxiety in PD patients through ADL is still unclear. METHODS: We conducted three progressive autoregressive mediation models to evaluate whether ADL may mediate the association between autonomic symptom burden, where the mediation chain with autonomic function as an independent variable, ADL as a mediating variable, and anxiety and depression as dependent variables. The ADL of PD patients were measured by the Scales for Outcomes in Parkinson's disease-Autonomic (SCOPA-AUT) and Modified Schwab and England ADL scale, respectively, and the status of depression and anxiety were measured by the Geriatric Depression Scale (GDS) and State-Trait Anxiety Inventory (STAI). RESULTS: There were 338 PD patients, including 220 males and 118 females. Demographic information, including age, gender, and education level, were not correlated with the depression and anxiety. Model III had the smallest AIC (AIC = 12,669.89), and the cross-lagged relations were not statistically significant, so we selected Model II as the optimal model. In Model II, longitudinal autoregressive mediated effect and longitudinal mediated effect of autonomic dysfunction affecting anxiety and depression through ADL were not statistically significant, suggesting longitudinal changes of autonomic dysfunction were independent of anxiety and depression through ADL. Contemporaneous mediated effects of autonomic dysfunction affecting anxiety and depression through ADL were statistically significant, suggesting contemporaneous autonomic dysfunction may contribute to anxiety and depression through ADL. CONCLUSIONS: Targeted prevention and intervention measures for autonomic dysfunction and ADL should be taken to preserve and improve self-perceived life satisfaction in the clinical practice and preventive health care of PD.

An Optimized Model of Hypertrophic Preconditioning Confers Cardioprotection in the Mouse.

BACKGROUND: Conventional models of hypertrophic preconditioning (C-HP) can be established surgically through transverse aortic constriction (TAC) → deconstriction (De-TAC) → reconstriction (Re-TAC) characterized by dynamic afterload while it exerts technical difficulty on operators and poses high mortality during perioperative period in mice. We aimed to introduce an optimized method for obtaining a hypertrophic preconditioning (O-HP) model for further study on cardiac hypertrophy. METHODS: Ninety mice were divided into four groups: sham, TAC, C-HP, and O-HP. The sham group was exerted on three-time thoracotomies. The TAC group experienced twice thoracotomies and one TAC operation. C-HP and O-HP groups were given TAC, De-TAC, and Re-TAC operation at day 0, day 3, and day 7 in conventional and optimized method, respectively. We optimized the operating procedure in O-HP mice compared with the C-HP group by (1) leaving a ∼3-cm suture fixed in the subcutaneous layer after aortic constriction in TAC surgery (2) using two small forceps to untie the constriction knot instead of cutting it in the De-TAC operation. Ultrasound biomicroscopy was used for hemodynamics and cardiac function detection. Four weeks after the third surgery, all mice were sacrificed and pathology was analyzed among four groups. RESULTS: Four weeks after Re-TAC, the survival of O-HP mice was 63.3% while that of C-HP was 26.7%. Ultrasound biomicroscopy showed a successful establishment of HP models. C-HP and O-HP mice had improved cardiac structure and function indicated by left ventricular end-systolic diameter, left ventricular end-systolic posterior wall thickness, left ventricular ejection fraction, and left ventricular fractional shortening than the TAC group. Pathological analysis showed O-HP as well as C-HP had less hypertrophy than the TAC mice. CONCLUSIONS: Our results provide a rapid, safe, efficient, and reproducible method for optimized establishment of the HP model, which will facilitate studies for early intervention and prevention of left ventricular hypertrophy and heart failure.

The path linking disease severity and cognitive function with quality of life in Parkinson's disease: the mediating effect of activities of daily living and depression.

BACKGROUND: Research on quality of life (QOL) with Parkinson's disease (PD) has examined direct influencing factors, not mediators. The study aim was to explore whether PD severity and poor cognitive function may decrease physical and mental QOL by reducing activities of daily living (ADL) and increasing depression in sequence. METHODS: We conducted a cross-sectional questionnaire study of 150 PD hospital patients in China. PD severity, cognitive function, ADL, depression, and QOL were evaluated. We used structural equation modeling to analyze the mediating effects of ADL and depression on the association between PD severity/cognition and the physical health and mental health component summary scores measured by the SF36 quality of life instrument. RESULTS: There was a significant mediating effect of PD severity on physical health via ADL and depression (95% CI: - 0.669, - 0.026), and a significant direct effect (p < 0.001). The mediating effect of PD severity on mental health via ADL and depression was significant (95% CI: - 2.135, - 0.726), but there was no direct effect (p = 0.548). There was a significant mediating effect of cognitive function on physical health via ADL and depression (95% CI: 0.025, 0.219) and a significant direct effect (p < 0.001). The mediating effect of cognitive function on mental health via ADL and depression was significant (95% CI: 0.256, 0.645), but there was no direct effect (p = 0.313). The physical health models showed a partial mediation, and the mental health models showed a complete mediation, of ADL and depression. CONCLUSIONS: PD severity and cognitive function increase depression by reducing ADL, leading to lower QOL, and directly or indirectly affect physical health and mental health through different pathways.

Antibody neutralization of SARS-CoV-2 through ACE2 receptor mimicry.

Understanding the mechanism for antibody neutralization of SARS-CoV-2 is critical for the development of effective therapeutics and vaccines. We recently isolated a large number of monoclonal antibodies from SARS-CoV-2 infected individuals. Here we select the top three most potent yet variable neutralizing antibodies for in-depth structural and functional analyses. Crystal structural comparisons reveal differences in the angles of approach to the receptor binding domain (RBD), the size of the buried surface areas, and the key binding residues on the RBD of the viral spike glycoprotein. One antibody, P2C-1F11, most closely mimics binding of receptor ACE2, displays the most potent neutralizing activity in vitro and conferred strong protection against SARS-CoV-2 infection in Ad5-hACE2-sensitized mice. It also occupies the largest binding surface and demonstrates the highest binding affinity to RBD. More interestingly, P2C-1F11 triggers rapid and extensive shedding of S1 from the cell-surface expressed spike glycoprotein, with only minimal such effect by the remaining two antibodies. These results offer a structural and functional basis for potent neutralization via disruption of the very first and critical steps for SARS-CoV-2 cell entry.

A novel antiviral lncRNA, EDAL, shields a T309 O-GlcNAcylation site to promote EZH2 lysosomal degradation.

BACKGROUND: The central nervous system (CNS) is vulnerable to viral infection, yet few host factors in the CNS are known to defend against invasion by neurotropic viruses. Long noncoding RNAs (lncRNAs) have been revealed to play critical roles in a wide variety of biological processes and are highly abundant in the mammalian brain, but their roles in defending against invasion of pathogens into the CNS remain unclear. RESULTS: We report here that multiple neurotropic viruses, including rabies virus, vesicular stomatitis virus, Semliki Forest virus, and herpes simplex virus 1, elicit the neuronal expression of a host-encoded lncRNA EDAL. EDAL inhibits the replication of these neurotropic viruses in neuronal cells and rabies virus infection in mouse brains. EDAL binds to the conserved histone methyltransferase enhancer of zest homolog 2 (EZH2) and specifically causes EZH2 degradation via lysosomes, reducing the cellular H3K27me3 level. The antiviral function of EDAL resides in a 56-nt antiviral substructure through which its 18-nt helix-loop intimately contacts multiple EZH2 sites surrounding T309, a known O-GlcNAcylation site. EDAL positively regulates the transcription of Pcp4l1 encoding a 10-kDa peptide, which inhibits the replication of multiple neurotropic viruses. CONCLUSIONS: Our findings show that a neuronal lncRNA can exert an effective antiviral function via blocking a specific O-GlcNAcylation that determines EZH2 lysosomal degradation, rather than the traditional interferon-dependent pathway.

Correction: Genetic variability of human adenovirus type 7 circulating in mainland China.

[This corrects the article DOI: 10.1371/journal.pone.0232092.].