In Alzheimer's disease (AD), neurodegenerative signals such as amyloid-beta (Aβ) and the precursors of neurotrophins, outbalance neurotrophic signals, causing synaptic dysfunction and ...neurodegeneration. The neurotrophin receptor p75 (p75NTR) is a receptor of Aβ and mediates Aβ-induced neurodegenerative signals. The shedding of its ectodomain from the cell surface is physiologically regulated; however, the function of the diffusible p75NTR ectodomain (p75ECD) after shedding remains largely not known. Here, we show that p75ECD levels in cerebrospinal fluid and in the brains of Alzheimer's patients and amyloid-beta precursor protein (APP)/PS1 transgenic mice were significantly reduced, due to inhibition of the sheddase-tumor necrosis factor-alpha-converting enzyme by Aβ. Restoration of p75ECD to the normal level by brain delivery of the gene encoding human p75ECD before or after Aβ deposition in the brain of APP/PS1 mice reversed the behavioral deficits and AD-type pathologies, such as Aβ deposit, apoptotic events, neuroinflammation, Tau phosphorylation and loss of dendritic spine, neuronal structures and synaptic proteins. Furthermore, p75ECD can also reduce amyloidogenesis by suppressing β-secretase expression and activities. Our data demonstrate that p75ECD is a physiologically neuroprotective molecule against Aβ toxicity and would be a novel therapeutic target and biomarker for AD.
Background and purpose
Previous studies suggested that the overall burden of prior infections contributes to cardiovascular diseases and stroke. In the present study, the association between ...infectious burden (IB) and Alzheimer's disease (AD) was examined.
Methods
Antibody titers to common infectious pathogens including cytomegalovirus (CMV), herpes simplex virus type 1 (HSV‐1), Borrelia burgdorferi, Chlamydophila pneumoniae and Helicobacter pylori were measured by enzyme‐linked immunosorbent assay in 128 AD patients and 135 healthy controls. IB was defined as a composite serological measure of exposure to these common pathogens.
Results
Seropositivities toward zero−two, three and four−five of these pathogens were found in 44%, 40% and 16% of healthy controls but in 20%, 44% and 36% of AD patients, respectively. IB, bacterial burden and viral burden were independently associated with AD after adjusting for age, gender, education, APOE genotype and various comorbidities. Mini‐Mental State Examination scores were negatively correlated with IB in all cases. Serum beta‐amyloid protein (Aβ) levels (i.e. Aβ40, Aβ42 and total Aβ) and inflammatory cytokines (i.e. interferon‐γ, tumor necrosis factor α, interleukin‐1β and interleukin‐6) in individuals exposed to four−five infectious pathogens were significantly higher than those exposed to zero−two or three pathogens.
Conclusions
IB consisting of CMV, HSV‐1, B. burgdorferi, C. pneumoniae and H. pylori is associated with AD. This study supports the role of infection/inflammation in the etiopathogenesis of AD.
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Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme that generates NADPH to maintain reduced glutathione (GSH), which scavenges reactive oxygen species (ROS) to protect cancer cell from ...oxidative damage. In this study, we mainly investigate the potential roles of G6PD in colorectal cancer (CRC) development and chemoresistance. We discover that G6PD is overexpressed in CRC cells and patient specimens. High expression of G6PD predicts poor prognosis and correlated with poor outcome of oxaliplatin-based first-line chemotherapy in patients with CRC. Suppressing G6PD decreases NADPH production, lowers GSH levels, impairs the ability to scavenge ROS levels, and enhances oxaliplatin-induced apoptosis in CRC via ROS-mediated damage in vitro. In vivo experiments further shows that silencing G6PD with lentivirus or non-viral gene delivery vector enhances oxaliplatin anti-tumor effects in cell based xenografts and PDX models. In summary, our finding indicated that disrupting G6PD-mediated NADPH homeostasis enhances oxaliplatin-induced apoptosis in CRC through redox modulation. Thus, this study indicates that G6PD is a potential prognostic biomarker and a promising target for CRC therapy.
Aims
This study aimed to investigate the antimicrobial resistance (AMR) profiles and genotypes of Streptococcus suis from Jiangxi Province, China.
Methods and Results
A total of 314 nasal swab ...samples were collected from clinically healthy pigs, with a positive isolation rate of S. suis of 34·08%. Antimicrobial susceptibility testing showed that more than 80% of the isolates were susceptible to vancomycin, penicillin, minocycline and chloramphenicol. A high frequency of resistance to clindamycin, tetracycline, clarithromycin and erythromycin was observed. All of the isolates were resistant to three or more categories of antimicrobials. The erm(B) and tet(O) served as the most frequent genotypes that contributed to lincosamide, macrolide and tetracycline resistances. A part of macrolide‐resistant genotypes could not exhibit specific phenotypes. Finally, integrative and conjugative elements (ICEs) were identified in 28·97% of the isolates.
Conclusions
The multidrug resistance of S. suis has widely emerged in Jiangxi Province. The most prevalent resistance genes and genotypes were similar to those in other regions or countries. The presence of ICEs is increasing the risk of horizontal transfer of AMR genes.
Significance and Impact of the Study
The findings could provide guidance for the rational use of antimicrobial drugs and be helpful for monitoring the AMR information of S. suis in China.
The CDEX-1 experiment conducted a search of low-mass (< 10GeV/c super(2)) weakly interacting massive particles dark matter at the China Jinping Underground Laboratory using a p-type point-contact ...germanium detector with a fiducial mass of 915 g at a physics analysis threshold of 475 eVee. We report the hardware setup, detector characterization, data acquisition, and analysis procedures of this experiment. No excess of unidentified events is observed after the subtraction of the known background. Using 335.6 kg-days of data, exclusion constraints on the weakly interacting massive particle-nucleon spin-independent and spin-dependent couplings are derived.
This paper reviews the recent research and development of clay-based polymer nanocomposites. Clay minerals, due to their unique layered structure, rich intercalation chemistry and availability at low ...cost, are promising nanoparticle reinforcements for polymers to manufacture low-cost, lightweight and high performance nanocomposites. We introduce briefly the structure, properties and surface modification of clay minerals, followed by the processing and characterization techniques of polymer nanocomposites. The enhanced and novel properties of such nanocomposites are then discussed, including mechanical, thermal, barrier, electrical conductivity, biodegradability among others. In addition, their available commercial and potential applications in automotive, packaging, coating and pigment, electrical materials, and in particular biomedical fields are highlighted. Finally, the challenges for the future are discussed in terms of processing, characterization and the mechanisms governing the behaviour of these advanced materials.
A simplified analysis method based on the damage evolution mechanism of rock mass is proposed to predict the possible excavation damaged zone around a tunnel. The formation of an excavation damaged ...zone is dependent on three main aspects: time-dependent macroscopic stress field during excavation, constitutive model under unloading condition, and initial microcracks. The excavation process is simplified as a time-dependent increase of the radius. For the tunnel problem, the tangential stress is under loading, while the radial stress is under unloading condition. As the macroscopic stress redistribution, the constitutive relationships which can take unloading state into account are coupled in this model. Then, in order to simulation the damage evolution process of surrounding rock mass, the sliding crack model and equivalent crack method are adopted. The different constitutive curve between loading and unloading state is discussed through examples. The efficiency of the proposed model is verified with the experimental and numerical simulation data available. The results of the proposed analytical model are in good agreement with the test results and, therefore, this model can be used in the preliminary tunnel design to evaluate tunnel stability, especially for the tunnel engineering at high geostress zone.
•A constitutive accounting for geostress and unloading process are adopted here.•The difference of constitutive curve between loading and unloading state are shown in this paper.•Effects of initial microcracks on the evolution of damage zone are discussed.
Polymer nanocomposites offer a wide range of promising applications because of their much enhanced properties arising from the reinforcement of nanoparticles. However, further development of such ...nanomaterials depends on the fundamental understanding of their hierarchical structures and behaviors which requires multiscale modeling and simulation strategies to provide seamless coupling among various length and time scales. In this review, we first introduce some computational methods that have been applied to polymer nanocomposites, covering from molecular scale (e.g., molecular dynamics, Monte Carlo), microscale (e.g., Brownian dynamics, dissipative particle dynamics, lattice Boltzmann, time-dependent Ginzburg–Landau method, dynamic density functional theory method) to mesoscale and macroscale (e.g., micromechanics, equivalent-continuum and self-similar approaches, finite element method). Then, we discuss in some detail their applications to various aspects of polymer nanocomposites, including the thermodynamics and kinetics of formation, molecular structure and dynamics, morphology, processing behaviors, and mechanical properties. Finally, we address the importance of multiscale simulation strategies in the understanding and predictive capabilities of polymer nanocomposites in which few studies have been reported. The present review aims to summarize the recent advances in the fundamental understanding of polymer nanocomposites reinforced by nanofillers (e.g., spherical nanoparticles, nanotubes, clay platelets) and stimulate further research in this area.
To explore the clinical characteristics and prognosis of the new coronavirus 2019-nCoV patients combined with cardiovascular disease （CVD).
A retrospective analysis was performed on 112 COVID-19 ...patients with CVD admitted to the western district of Union Hospital in Wuhan, from January 20, 2020 to February 15, 2020. They were divided into critical group (ICU,
=16) and general group (
=96) according to the severity of the disease and patients were followed up to the clinical endpoint. The observation indicators included total blood count, C-reactive protein (CRP), arterial blood gas analysis, myocardial injury markers, coagulation function, liver and kidney function, electrolyte, procalcitonin (PCT), B-type natriuretic peptide (BNP), blood lipid, pulmonary CT and pathogen detection.
Compared with the general group, the lymphocyte count (0.74 (0.34, 0.94)×10
/L vs. 0.99 (0.71, 1.29)×10
/L,
=0.03) was extremely lower in the critical group, CRP (106.98 (81.57, 135.76) mg/L vs. 34.34 (9.55,76.54) mg/L,
<0.001) and PCT (0.20 (0.15,0.48) μg/L vs. 0.11 (0.06,0.20) μg/L,
<0.001) were significantly higher in the critical group. The BMI of the critical group was significantly higher than that of the general group (25.5 (23.0, 27.5) kg/m
vs. 22.0 (20.0, 24.0) kg/m
，
=0.003). Patients were further divided into non-survivor group (17, 15.18%) group and survivor group (95, 84.82%). Among the non-survivors, there were 88.24% (15/17) patients with BMI> 25.0 kg/m
, which was significantly higher than that of survivors (18.95% (18/95),
<0.001). Compared with the survived patients, oxygenation index (130 (102, 415) vs. 434 (410, 444),
<0.001) was significantly lower and lactic acid (1.70 (1.30, 3.00) mmol/L vs. 1.20 (1.10, 1.60) mmol/L,
<0.001) was significantly higher in the non-survivors. There was no significant difference in the proportion of ACEI/ARB medication between the critical group and the general group or between non-survivors and survivors （all
>0.05).
COVID-19 patients combined with CVD are associated with a higher risk of mortality. Critical patients are characterized with lower lymphocyte counts. Higher BMI are more often seen in critical patients and non-survivor. ACEI/ARB use does not affect the morbidity and mortality of COVID-19 combined with CVD. Aggravating causes of death include fulminant inflammation, lactic acid accumulation and thrombotic events.
Sperm-associated antigen 5 (SPAG5) is involved in various biological processes. However, the roles of SPAG5 in bladder urothelial carcinoma (BUC) are unknown. This study showed that upregulation of ...SPAG5 was detected frequently in primary BUC tissues, and was associated with significantly worse survival among the 112 patients that underwent radical cystectomy (RC). Up and downregulating the expression of SPAG5 enhanced or inhibited, respectively, the proliferation of BUC cells in vitro and in vivo, and suppressed or enhanced, respectively, apoptosis in vitro and in vivo. Moreover, SPAG5 increased the resistance of BUC cells to chemotherapy-induced apoptosis. Mechanistic investigations showed that SPAG5 promotes proliferation and suppresses apoptosis in BUC at least partially via upregulating Wnt3 through activating the AKT/mTOR signaling pathway. The importance of the SPAG5/AKT-mTOR/Wnt3 axis identified in BUC cell models was confirmed via immunohistochemical analysis of a cohort of human BUC specimens that underwent RC. Collectively, our data suggested that in patients with BUC who underwent RC, high SPAG5 expression is associated with poor survival. In addition, targeting SPAG5 might represent a novel therapeutic strategy to improve the survival of patients with BUC.
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