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Abstract Reproductive hormones associated with the hypothalamic-pituitary-gonadal (HPG) axis are closely linked to bone homeostasis. In this study, we demonstrate that Gonadotropin inhibitory hormone (GnIH, one of the key reproductive hormones upstream of the HPG axis) plays an indispensable role in regulating bone homeostasis and maintaining bone mass. We find that deficiency of GnIH or its receptor Gpr147 leads to a significant reduction in bone mineral density (BMD) in mice primarily by enhancement of osteoclast activation in vivo and in vitro. Mechanistically, GnIH/Gpr147 inhibits osteoclastogenesis by the PI3K/AKT, MAPK, NF-κB and Nfatc1 signaling pathways. Furthermore, GnIH treatment was able to alleviate bone loss in aging, ovariectomy (OVX) or LPS-induced mice. Moreover, the therapy using green light promotes the release of GnIH and rescues OVX-induced bone loss. In humans, serum GnIH increases and bone resorption markers decrease after green light exposure. Therefore, our study elucidates that GnIH plays an important role in maintaining bone homeostasis via modulating osteoclast differentiation and demonstrates the potential of GnIH therapy or green light therapy in preventing osteoporosis.

Abstract Background Lipid management based on cardiovascular risk level is the cornerstone of primary prevention of coronary artery disease (CAD), while the accuracy and adherence of traditional cardiovascular risk stratification have been questioned. Prevention strategies based on imaging screening for atherosclerotic plaques are found to be more objective and adherent in recent studies. This trial aims to investigate the role of coronary computed tomography angiography (CCTA) in guiding the primary prevention of CAD in a randomized controlled design. Methods Approximately 3400 middle-aged asymptomatic community participants will be recruited and randomized in a 1:1 ratio to a traditional cardiovascular risk score-guided (usual care group) or CCTA-guided (CCTA group) strategy. Participants with cardiovascular disease, prior lipid-lowering therapy, CCTA contraindication, or serious diseases that affect life span will be excluded. The intervention strategy includes blood pressure, blood glucose, and lipid management and lifestyle modifications. Blood pressure and glucose targets and lifestyle modification recommendations keep the same in both strategies, while lipid management is personalized based on traditional risk level or CCTA results, respectively. The primary outcome is the proportion of participants taking lipid-lowering medication regularly at both 6 and 12 months. The secondary outcomes include the proportion of participants achieving low-density lipoprotein cholesterol lowering targets at 12 months, mean changes in lipid levels from baseline to 12 months, barriers to adherence, adverse reactions related to CCTA examination, and cardiovascular events. Discussion The study is the first randomized clinical trial to examine the effectiveness of a CCTA-guided versus a traditional risk score-guided primary prevention strategy in an asymptomatic community-based population. Trial registration ClinicalTrials.gov NCT05725096. Registered on 2 February 2023.

Abstract Background Danggui Shaoyao San (DSS), a frequently prescribed Chinese medicine formula, has demonstrated clinical efficacy in the treatment of Alzheimer’s disease (AD). This study aims to explore the differences in therapeutic effects of DSS and its disassembled prescriptions, Suangan (SG) and Xingan (XG), in treating Alzheimer’s Disease and the mechanism of DSS recovering autophagy in AD. Methods A network pharmacology strategy was employed to delineate the bioactive constituents, associated targets, and regulatory mechanisms of DSS in AD, encompassing in silico target forecasting, the generation and scrutiny of PPI networks, alongside GO and KEGG-based pathway elucidation. An AD mouse model, induced by intracerebroventricular injection of Aβ1–42, was used to evaluate the therapeutic effects of DSS and its disassembled prescriptions on AD. Cognitive function was evaluated using the Morris water maze. Expression levels of inflammatory cytokines were quantified via RT-qPCR and ELISA. Western blotting was used to detect the expression of proteins related to AD pathological markers and the AMPK/mTOR signaling pathway. Results 50 active compounds and 718 HUB genes were screened from relevant databases and literature. KEGG and GO analyses indicated that DSS’s potential mechanisms against AD involved the AMPK/mTOR signaling pathway and mitophagy. In vivo animal model, the results demonstrated that DSS, SG, and XG treatments improved cognitive function and ameliorated neuroinflammation in mice. Additionally, they alleviated the pathological changes of neuronal cells. These treatments also increased the protein level of PSD-95, and decreased levels of APP and p-Tau. Among them, DSS exhibited the best efficacy. Furthermore, DSS, SG, and XG upregulated the expression of LC3, Beclin1, and p-AMPK, while decreasing the expression of P62 and p-mTOR. Conclusions DSS, SG, and XG were found to ameliorate AD-related pathological symptoms in Aβ1−42-injected mice, likely through the AMPK/mTOR autophagy signaling pathway.

ObjectiveThis study aimed to analyze the trends in Hepatitis A incidence associated with age, period, and birth cohorts from 2007 to 2021 in Jiangsu Province, China, and projects the future burden through 2031.MethodsData on Hepatitis A cases in Jiangsu Province from 2007 to 2021 were obtained from the National Notifiable Disease Reporting System. Joinpoint regression analysis identified significant changes in incidence trends. The age-period-cohort model assessed the effects of age, period, and cohort on Hepatitis A incidence rates. Projections for 2022–2031 were generated using the Bayesian age-period-cohort model.ResultsFrom 2007 to 2021, Hepatitis A incidence in Jiangsu Province significantly declined, with an average annual percent change (AAPC) of −10.77%. The decline was more pronounced in males (AAPC = −12.87%) compared to females (AAPC = −7.46%). The overall net drift was −10.61% (95% CI: −11.14% to −10.07%), the net drift for males was −12.77% (95% CI: −13.40% to −12.13%), which was higher than that for females at −7.27% (95% CI: −7.93% to −6.60%). The local drift indicates the incidence of hepatitis A decreased gradually, with the rate of decline slowing in the later period. Descriptive analysis revealed the highest incidence of Hepatitis A cases in the 40–59 age group, while age-period-cohort analysis indicated higher incidence rates in younger individuals. The cohort effect showed a continuous decline from the earliest cohort in 1923–1927 (Overall RR = 64.93, 95% CI: 42.55 to 99.07) to the most recent cohort in 1993–1997 (Overall RR = 0.008, 95% CI: 0.004 to 0.01). But Bayesian age-period-cohort model projections for 2022–2031 suggest that incidence rates will remain low, though they may slightly increase by 2031, with peak incidence shifting to the 60–64 age group.ConclusionThe incidence of Hepatitis A in Jiangsu Province has significantly decreased from 2007 to 2021, primarily due to public health measures and vaccination programs. Future efforts should focus on maintaining vaccination coverage and improving sanitation and hygiene practices to sustain these achievements.

Background The computed tomography angiography enhancement ratio (CTA‐ER), calculated through the net water uptake formula, is a valuable predictive tool for detecting adverse events after stroke. However, limited research has investigated the correlation between CTA‐ER and the prognosis of patients receiving endovascular treatment. Therefore, we aimed to examine whether CTA‐ER could predict favorable outcomes in patients undergoing endovascular treatment. Methods We conducted a retrospective study enrolling patients with acute anterior circulation large‐vessel occlusive stroke undergoing endovascular treatment between January 2016 and January 2023. All patients received noncontrast computed tomography and computed tomography angiography scans upon admission. Multivariate logistic regression analysis and receiver operator characteristic curve were used to assess the predictive efficacy in determining favorable outcomes. The favorable outcome at 90 days was a modified Rankin scale score of 0 to 2. Results A total of 206 participants (median age, 68 [60–77] years; 77 women) were included in the study, with 82 (39.8%) individuals demonstrating favorable outcomes. Patients with favorable outcomes had lower noncontrast computed tomography net water uptake (6.42% versus 7.76%; P < 0.001) and CTA‐ER (8.31% versus 10.56%; P < 0.001). Multivariate logistic regression analysis identified that CTA‐ER was a significant predictor for favorable outcomes (P

In the drug discovery process, time and costs are the most typical problems resulting from the experimental screening of drug-target interactions (DTIs). To address these limitations, many computational methods have been developed to achieve more accurate predictions. However, identifying DTIs mostly rely on separate learning tasks with drug and target features that neglect interaction representation between drugs and target. In addition, the lack of these relationships may lead to a greatly impaired performance on the prediction of DTIs. Aiming at capturing comprehensive drug-target representations and simplifying the network structure, we propose an integrative approach with a convolution broad learning system for the DTI prediction (ConvBLS-DTI) to reduce the impact of the data sparsity and incompleteness. First, given the lack of known interactions for the drug and target, the weighted K-nearest known neighbors (WKNKN) method was used as a preprocessing strategy for unknown drug-target pairs. Second, a neighborhood regularized logistic matrix factorization (NRLMF) was applied to extract features of updated drug-target interaction information, which focused more on the known interaction pair parties. Then, a broad learning network incorporating a convolutional neural network was established to predict DTIs, which can make classification more effective using a different perspective. Finally, based on the four benchmark datasets in three scenarios, the ConvBLS-DTI's overall performance out-performed some mainstream methods. The test results demonstrate that our model achieves improved prediction effect on the area under the receiver operating characteristic curve and the precision-recall curve.

Despite substantial evidence suggesting that hydrogen gas (H2) can enhance osmotic tolerance in plants, the conventional supply method of hydrogen-rich water (HRW) poses challenges for large-scale agricultural applications. Recently, magnesium hydride (MgH2), a hydrogen storage material in industry, has been reported to yield beneficial effects in plants. This study aimed to investigate the effects and underlying mechanisms of MgH2 in plants under osmotic stress. Mung bean seedlings were cultured under control conditions or with 20% polyethylene glycol (PEG)-6000, with or without MgH2 addition (0.01 g L−1). Under our experimental conditions, the MgH2 solution maintained a higher H2 content and longer retention time than HRW. Importantly, PEG-stimulated endogenous H2 production was further triggered by MgH2 application. Further results revealed that MgH2 significantly alleviated the inhibition of seedling growth and reduced oxidative damage induced by osmotic stress. Pharmacological evidence suggests the MgH2-reestablished redox homeostasis was associated with activated antioxidant systems, particularly the ascorbate–glutathione cycle. The above observations were further supported by the enhanced activities and gene transcriptional levels of ascorbate peroxidase, monodehydroascorbate reductase, dehydroascorbate reductase, and glutathione reductase. Overall, this study demonstrates the importance of MgH2 in mitigating osmotic stress in mung bean seedlings, providing novel insights into the potential agricultural applications of hydrogen storage materials.

Microglia hyperactivation is an important cause of neuroinflammation in Alzheimer's disease (AD). Paeoniflorin (PF), ferulic acid (FA), and atractylenolide III (ATL) are potent in anti-inflammation and neuroprotection. Multiple components can act on different targets simultaneously to exert synergistic therapeutic effects and exploring the synergistic potential between compounds is an important area of research. We investigated the effects of PF, FA, and ATL, alone or in combination, on LPS-induced neuroinflammation and autophagy in BV2 microglia cells. We found that PF, FA, and ATL, alone or in combination, significantly reduced the production of inflammatory factors such as IL-6, IL-1β, and TNF-α, especially in the PF + FA + ATL group, which performed the best. In addition, the combination of PF, FA, and ATL significantly increased the expression of autophagy-related proteins p-AMPK, p-ULK1, Beclin1, LC3, and TFEB and decreased the expression of p62. Moreover, the restoration of autophagic flux by the combination of PF, FA, and ATL was abrogated by the addition of the autophagy inhibitor Wortmannin. In conclusion, PF, FA, and ATL have a synergistic effect in reducing LPS-induced inflammatory factor release from BV2 microglia cells, and its protective effect may be through activation of the AMPK/ULK1/TFEB autophagic signaling pathway.

Abstract Objectives Besides plaque enhancement grade, the incremental value of enhancement-related high-resolution MRI features in defining culprit plaques needs further evaluation. This study was focused on assessing whether plaque enhancement features contribute to culprit plaque identification and further risk stratification. Methods We retrospectively studied patients who experienced an acute ischaemic stroke and transient ischaemic attack due to intracranial atherosclerosis from 2016 to 2022. The enhancement features included enhancement grade, enhanced length, and enhancement quadrant. Associations between plaque enhancement features and culprit plaques, as well as diagnostic value, were investigated using logistic regression and receiver operating characteristic analyses. Results Overall, 287 plaques were identified, of which 231 (80.5%) and 56 (19.5%) were classified as culprit and non-culprit plaques, respectively. Comparison of the pre- and post-enhancement images revealed enhanced length longer than the plaque length in 46.32% of the culprit plaques. Multivariate logistic regression showed that enhanced length longer than plaque length (OR 6.77; 95% CI 2.47–18.51) and grade II enhancement (OR 7.00; 95% CI 1.69–28.93) were independently associated with culprit plaques. The area under the curve value for the combination of stenosis and plaque enhancement grade for the diagnosis of culprit plaques was 0.787, which increased significantly to 0.825 on the addition of enhanced length longer than the plaque length (p = 0.026 for DeLong’s test). Conclusions Enhanced length longer than the plaque length and grade II enhancement were independently associated with culprit plaques. The combination of the enhanced plaque features resulted in better culprit plaque identification.

Fibrosis could happen in every organ, leading to organic malfunction and even organ failure, which poses a serious threat to global health. Early treatment of fibrosis has been reported to be the turning point, therefore, exploring potential correlates in the pathogenesis of fibrosis and how to reverse fibrosis has become a pressing issue. As a mechanism-sensitive cationic calcium channel, Piezo1 turns on in response to changes in the lipid bilayer of the plasma membrane. Piezo1 exerts multiple biological roles, including inhibition of inflammation, cytoskeletal stabilization, epithelial-mesenchymal transition, stromal stiffness, and immune cell mechanotransduction, interestingly enough. These processes are closely associated with the development of fibrotic diseases. Recent studies have shown that deletion or knockdown of Piezo1 attenuates the onset of fibrosis. Therefore, in this paper we comprehensively describe the biology of this gene, focusing on its potential relevance in pulmonary fibrosis, renal fibrosis, pancreatic fibrosis, and cardiac fibrosis diseases, except for the role of drugs (agonists), increased intracellular calcium and mechanical stress using this gene in alleviating fibrosis.

ObjectiveThis study attempts to analyze the spatial clustering and spatial-temporal distribution characteristics of hepatitis E (HE) at the county (city and district) level in Jiangsu province to provide a scientific basis for the prevention and control of HE.MethodThe information on HE cases reported in the Chinese Center for Disease Control and Prevention Information System from 2005 to 2020 was collected for spatial autocorrelation analysis and spatial-temporal clustering analysis.ResultFrom 2005 to 2020, 48,456 HE cases were reported in Jiangsu province, with an average annual incidence rate of 3.87/100,000. Male cases outnumbered female cases (2.46:1), and the incidence was highest in the 30–70 years of age group (80.50%). Farmers accounted for more than half of all cases (59.86%), and in terms of the average annual incidence, the top three cities were all in Zhenjiang city. Spatial autocorrelation analysis showed that Global Moran's I of HE incidence varied from 0.232 to 0.513 for the years. From 2005 to 2020, 31 counties (cities and districts) had high and statistically significant HE incidence, and two clustering areas were detected by spatial-temporal scanning.ConclusionHE incidence in Jiangsu province from 2005 to 2020 was stable, with age and gender differences, regional clustering, and spatial-temporal clustering. Further investigation of HE clustering areas is necessary to formulate corresponding targeted prevention and control measures.

Abstract Hand, foot, and mouth disease (HFMD) is a serious disease burden in the Asia–Pacific region, including China. This study calculated the transmissibility of HFMD at county levels in Jiangsu Province, China, analyzed the differences of transmissibility and explored the possible influencing factors of its transmissibility. We built a mathematical model for seasonal characteristics of HFMD, estimated the effective reproduction number (R eff ), and compared the incidence rate and transmissibility in different counties using non-parametric tests, rapid cluster analysis and rank-sum ratio in 97 counties in Jiangsu Province from 2015 to 2020. The average daily incidence rate was between 0 and 4 per 100,000 people in Jiangsu Province from 2015–2020. The Quartile of R eff in Jiangsu Province from 2015 to 2020 was 1.54 (0.49, 2.50). Rugao District and Jianhu District had the highest transmissibility according to the rank-sum ratio. R eff generally decreased in 2017 and increased in 2018 in most counties, and the median level of R eff was the lowest in 2017 (P

As a hallmark of inflammatory bowel disease (IBD), elevated intestinal epithelial cell (IEC) death compromises the gut barrier, activating the inflammatory response and triggering more IEC death. However, the precise intracellular machinery that prevents IEC death and breaks this vicious feedback cycle remains largely unknown. Here, we report that Grb2-associated binder 1 (Gab1) expression is decreased in patients with IBD and inversely correlated with IBD severity. Gab1 deficiency in IECs accounted for the exacerbated colitis induced by dextran sodium sulfate owing to sensitizing IECs to receptor-interaction protein kinase 3–mediated (RIPK3-mediated) necroptosis, which irreversibly disrupted the homeostasis of the epithelial barrier and promoted intestinal inflammation. Mechanistically, Gab1 negatively regulated necroptosis signaling through inhibiting the formation of RIPK1/RIPK3 complex in response to TNF-α. Importantly, administration of RIPK3 inhibitor revealed a curative effect in epithelial Gab1-deficient mice. Further analysis indicated mice with Gab1 deletion were prone to inflammation-associated colorectal tumorigenesis. Collectively, our study defines a protective role for Gab1 in colitis and colitis-driven colorectal cancer by negatively regulating RIPK3-dependent necroptosis, which may serve as an important target to address necroptosis and intestinal inflammation–related disease.

Multimodal rail transit systems integration and interconnection can solve frequent transfer problems and better adapt to disequilibrium passenger flow and space. It is an inevitable choice in the development of various rail transit systems. Firstly, this paper proposes a novel train service plan design model in the scenario of multimodal rail transit systems integration and interconnection. Our model takes into account the costs of both passengers and enterprises, and passengers travel time is converted into cost using passengers’ nonworking time value coefficient. The model contains some conventional constraints such as passenger flow, station capacity, and line carrying capacity. It also considers whether the transportation capacity of different lines is matched, that is, the constraint of capacity matching degree. Secondly, an improved harmonic search algorithm (IHSA) is designed to solve the problem, and a numerical experiment is used to prove the performance of the proposed method. Our research result shows that the model and algorithm proposed in this paper is effective, which can help overcome the drawbacks of the existing independent operation mode of different rail transit systems. This study is also applicable to the scenario of other kinds of rail transit systems integration and interconnection.

Due to high transport efficiency, reduced transfer time, and various other advantages, the joint operation of different rail transit systems emerges as the optimal choice for rail transit systems. This article mainly studies the line-planning problem under the line-sharing operation mode between metro and suburban railway. First, a complex multiobjective programming model is established to maximize the net profit of two operating companies and the time savings of passengers. The constraints of this model encompass passenger flow, available vehicles, line carrying capacity, station capacity, cross-line configuration, departure frequency, and variable value range. Second, the linear weighted sum method is introduced to consolidate three objective functions into a single one, while utilizing the improved artificial bee colony (IABC) algorithm to address the line-planning problem. Besides, the traditional artificial bee colony (TABC) algorithm and the simulated annealing (SA) algorithm are provided as comparison groups to solve the same numerical example problem. The results demonstrate significant reductions in travel time by adopting the line-sharing operation mode. In addition, the IABC algorithm exhibits better solution quality and higher efficiency than both the TABC and SA algorithms. The proposed method proves to be valuable in formulating and optimizing the line plan.

ObjectivesSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineage B.1.617.2 (also named the Delta variant) was declared as a variant of concern by the World Health Organization (WHO). This study aimed to describe the outbreak that occurred in Nanjing city triggered by the Delta variant through the epidemiological parameters and to understand the evolving epidemiology of the Delta variant.MethodsWe collected the data of all COVID-19 cases during the outbreak from 20 July 2021 to 24 August 2021 and estimated the distribution of serial interval, basic and time-dependent reproduction numbers (R0 and Rt), and household secondary attack rate (SAR). We also analyzed the cycle threshold (Ct) values of infections.ResultsA total of 235 cases have been confirmed. The mean value of serial interval was estimated to be 4.79 days with the Weibull distribution. The R0 was 3.73 [95% confidence interval (CI), 2.66–5.15] as estimated by the exponential growth (EG) method. The Rt decreased from 4.36 on 20 July 2021 to below 1 on 1 August 2021 as estimated by the Bayesian approach. We estimated the household SAR as 27.35% (95% CI, 22.04–33.39%), and the median Ct value of open reading frame 1ab (ORF1ab) genes and nucleocapsid protein (N) genes as 25.25 [interquartile range (IQR), 20.53–29.50] and 23.85 (IQR, 18.70–28.70), respectively.ConclusionsThe Delta variant is more aggressive and transmissible than the original virus types, so continuous non-pharmaceutical interventions are still needed.

Hepatitis E has placed a heavy burden on China, especially in Jiangsu Province, so accurately predicting the incidence of hepatitis E benefits to alleviate the medical burden. In this paper, we propose a new attentive bidirectional long short-term memory network (denoted as BiLSTM–Attention) to predict the incidence of hepatitis E for all 13 cities in Jiangsu Province, China. Besides, we also explore the performance of adding meteorological factors and the Baidu (the most widely used Chinese search engine) index as additional training data for the prediction of our BiLSTM–Attention model. SARIMAX, GBDT, LSTM, BiLSTM, and BiLSTM–Attention models are tested in this study, based on the monthly incidence rates of hepatitis E, meteorological factors, and the Baidu index collected from 2011 to 2019 for the 13 cities in Jiangsu province, China. From January 2011 to December 2019, a total of 29,339 cases of hepatitis E were detected in all cities in Jiangsu Province, and the average monthly incidence rate for each city is 0.359 per 100,000 persons. Root mean square error (RMSE) and mean absolute error (MAE) are used for model selection and performance evaluation. The BiLSTM–Attention model considering meteorological factors and the Baidu index has the best performance for hepatitis E prediction in all cities, and it gets at least 10% improvement in RMSE and MAE for all 13 cities in Jiangsu province, which means the model has significantly improved the learning ability, generalizability, and prediction accuracy when comparing with others.

Abstract Background During the period of the coronavirus disease 2019 (COVID-19) outbreak, strong intervention measures, such as lockdown, travel restriction, and suspension of work and production, may have curbed the spread of other infectious diseases, including natural focal diseases. In this study, we aimed to study the impact of COVID-19 prevention and control measures on the reported incidence of natural focal diseases (brucellosis, malaria, hemorrhagic fever with renal syndrome [HFRS], dengue, severe fever with thrombocytopenia syndrome [SFTS], rabies, tsutsugamushi and Japanese encephalitis [JE]). Methods The data on daily COVID-19 confirmed cases and natural focal disease cases were collected from Jiangsu Provincial Center for Disease Control and Prevention (Jiangsu Provincial CDC). We described and compared the difference between the incidence in 2020 and the incidence in 2015–2019 in four aspects: trend in reported incidence, age, sex, and urban and rural distribution. An autoregressive integrated moving average (ARIMA) (p, d, q) × (P, D, Q) s model was adopted for natural focal diseases, malaria and severe fever with thrombocytopenia syndrome (SFTS), and an ARIMA (p, d, q) model was adopted for dengue. Nonparametric tests were used to compare the reported and the predicted incidence in 2020, the incidence in 2020 and the previous 4 years, and the difference between the duration from illness onset date to diagnosed date (DID) in 2020 and in the previous 4 years. The determination coefficient (R 2) was used to evaluate the goodness of fit of the model simulation. Results Natural focal diseases in Jiangsu Province showed a long-term seasonal trend. The reported incidence of natural focal diseases, malaria and dengue in 2020 was lower than the predicted incidence, and the difference was statistically significant (P

Background and Aims: The Cancer Genome Atlas (TCGA) project has identified HER2 mutations or amplification in 7% of colon cancers. In addition to HER2 mutations, colon cancer patients also possess co-occurring mutations in genes such as APC. Here, we investigated the role of HER2 and APC mutations on the crypt-villus architecture of the intestinal epithelium, localization of secretory cells, and expression of intestinal stem cell markers. Methods: We generated a HER2 transgenic mouse (HER2V777L Tg) possessing an activating mutation commonly found in colorectal cancer patients, HER2V777L, using transcription activator-like effector nucleases–based gene editing technology. We expressed the HER2V777L transgene in mouse small intestine and colon using Lgr5-Cre and Villin-Cre recombinases. In addition, we analyzed Lgr5-Cre; APCmin; HER2V777L Tg mice by morphologic and gene expression assays on intestinal sections and organoids derived from the epithelium. Results: HER2V777L expression resulted in hypertrophic crypt formation with expanded zones of proliferation. Proximal intestinal villi showed increased abundance of multiple differentiated lineages including extensive intermediate cell differentiation, as evidenced by MUC2/MMP7 co-immunofluorescence and transmission electron microscopy. HER2V777L expression in the context of APC loss resulted in further enhancement and expansion of the proliferative crypt compartment. Conclusions: We established an epithelial intrinsic role for HER2V777L on enhanced cellular proliferation. Additionally, we determined that HER2 and APC mutations, when combined, promote enhanced proliferation of intestinal crypts.

In neurodegenerative diseases, microglial activation and neuroinflammation are essential for the control and progression of neurodegenerative diseases. Mitigating microglium-induced inflammation is one strategy for hindering the progression of neurodegenerative diseases. Ferulic acid (FA) is an effective anti-inflammatory agent, but its potential role and regulation mechanism in neuroinflammatory reactions have not been fully studied. In this study, the neuroinflammation model was established by lipopolysaccharide (LPS), and the inhibitory effect of FA on neuroinflammation of BV2 microglia was studied. The results showed that FA significantly reduced the production and expression of reactive oxygen species (ROS), tumor necrosis factor-α (TNF-α), leukocyte-6 (IL-6) and interleukin-1β (IL-1β). We further studied the mechanism of FA’s regulation of LPS-induced BV2 neuroinflammation and found that FA can significantly reduce the expression of mTOR in BV2 microglia induced by LPS, and significantly increase the expression of AMPK, indicating that FA may have an anti-inflammatory effect by activating the AMPK/mTOR signaling pathway to regulate the release of inflammatory mediators (such as NLRP3, caspase-1 p20 and IL-1β). We further added an autophagy inhibitor (3-MA) and an AMPK inhibitor (compound C, CC) for reverse verification. The results showed that FA’s inhibitory effects on TNF-α, IL-6 and IL-1β and its regulatory effect on AMPK/mTOR were destroyed by 3-MA and CC, which further indicated that FA’s inhibitory effect on neuroinflammation is related to its activation of the AMPK/mTOR autophagy signaling pathway. In a word, our experimental results show that FA can inhibit LPS-induced neuroinflammation of BV2 microglia by activating the AMPK/mTOR signaling pathway, and FA may be a potential drug for treating neuroinflammatory diseases.

Genome-wide association studies (GWAS) have identified more than 160 susceptibility loci for colorectal cancer (CRC). The effects of these variants, particularly their mechanisms, however, remain unclear. In this study, a comprehensive functional annotation of CRC-related GWAS signals was firstly conducted to identify the potential causal variants. We found that the SNP rs7229639 in intron 3 of SMAD7 at 18q21.1 might serve as a putative functional variant in CRC. The SNP rs7229639 is located in a region with evidence of regulatory potential. Dual-luciferase reporter assays revealed that three other SNPs (rs77544449, rs60385309 and rs72917785), in strong linkage disequilibrium (LD) with rs7229639, exhibited allele-specific enhancer activity, of which one of the target genes may conceivably be LIPG, as suggested by eQTL association data and Hi-C data. We also verified that LIPG promoted malignancy of CRC cells in vitro, with supporting clinical data indicating that LIPG is upregulated and correlated with a poor prognosis in CRC. Finally, pitavastatin was observed to exhibit an anti-CRC activity and modest inhibition of LIPG mRNA levels. Collectively, our data suggest that these functional variants at 18q21.1 are involved in the pathogenesis of CRC by modulating enhancer activity, and possibly LIPG expression, thus indicating a promising therapeutic target for CRC. The results of functional annotation in our investigation could also serve as an inventory for CRC susceptibility SNPs and offer guides for post-GWAS downstream functional studies.

Objective: To describe the epidemiological characteristics of norovirus outbreaks in Jiangsu Province, utilize the total attack rate (TAR) and transmissibility (Runc) as the measurement indicators of the outbreak, and a statistical difference in risk factors associated with TAR and transmissibility was compared. Ultimately, this study aimed to provide scientific suggestions to develop the most appropriate prevention and control measures.Method: We collected epidemiological data from investigation reports of all norovirus outbreaks in Jiangsu Province from 2012 to 2018 and performed epidemiological descriptions, sequenced the genes of the positive specimens collected that were eligible for sequencing, created a database and calculated the TAR, constructed SEIAR and SEIARW transmission dynamic models to calculate Runc, and performed statistical analyses of risk factors associated with the TAR and Runc.Results: We collected a total of 206 reported outbreaks, of which 145 could be used to calculate transmissibility. The mean TAR in was 2.6% and the mean Runc was 12.2. The epidemiological characteristics of norovirus outbreaks showed an overall increasing trend in the number of norovirus outbreaks from 2012 to 2018; more outbreaks in southern Jiangsu than northern Jiangsu; more outbreaks in urban areas than in rural areas; outbreaks occurred mostly in autumn and winter. Most of the sites where outbreaks occurred were schools, especially primary schools. Interpersonal transmission accounted for the majority. Analysis of the genotypes of noroviruses revealed that the major genotypes of the viruses changed every 3 years, with the GII.2 [P16] type of norovirus dominating from 2016 to 2018. Statistical analysis of TAR associated with risk factors found statistical differences in all risk factors, including time (year, month, season), location (geographic location, type of settlement, type of premises), population (total number of susceptible people at the outbreak site), transmission route, and genotype (P < 0.05). Statistical analysis of transmissibility associated with risk factors revealed that only transmissibility was statistically different between sites.Conclusions: The number of norovirus outbreaks in Jiangsu Province continues to increase during the follow-up period. Our findings highlight the impact of different factors on norovirus outbreaks and identify the key points of prevention and control in Jiangsu Province.

Overlap between the pathogenesis of posterior reversible encephalopathy syndrome and that of cerebrovascular disease can confound their clinical and radiological presentations, posing a diagnostic challenge. This article presents a literature review and discussion of the clinical manifestations, pathological mechanisms, and imaging manifestations of subarachnoid hemorrhage and vasculitis leading to posterior reversible encephalopathy syndrome, coexistence of posterior reversible encephalopathy syndrome with reversible cerebral vasoconstriction syndrome, and hemorrhage and infarction secondary to posterior reversible encephalopathy syndrome. The findings show that posterior reversible encephalopathy syndrome shares some overlapping pathophysiological mechanisms with cerebrovascular disease. Importantly, neuroimaging plays an important role in identifying this entity in a timely manner and differentiating it from other diseases.

Background: The disease burden of hepatitis E remains high. We used a new method (richness, diversity, evenness, and similarity analyses) to classify cities according to the occupational classification of hepatitis E patients across regions in China and compared the results of cluster analysis.Methods: Data on reported hepatitis E cases from 2008 to 2018 were collected from 24 cities (9 in Jilin Province, 13 in Jiangsu Province, Xiamen City, and Chuxiong Yi Autonomous Prefecture). Traditional statistical methods were used to describe the epidemiological characteristics of hepatitis E patients, while the new method and cluster analysis were used to classify the cities by analyzing the occupational composition across regions.Results: The prevalence of hepatitis E in eastern China (Jiangsu Province) was similar to that in the south (Xiamen City) and southwest of China (Chuxiong Yi Autonomous Prefecture), but higher than that in the north (Jilin Province). The age of hepatitis E patients was concentrated between 41 and 60 years, and the sex ratio ranged from 1:1.6 to 1:3.4. Farming was the most highly prevalent occupation; other sub-prevalent occupations included retirement, housework and unemployment. The incidence of occupations among migrant workers, medical staff, teachers, and students was moderate. There were several occupational types with few or no records, such as catering industry, caregivers and babysitters, diaspora children, childcare, herders, and fishing (boat) people. The occupational similarity of hepatitis E was high among economically developed cities, such as Nanjing, Wuxi, Baicheng, and Xiamen, while the similarity was small among cities with large economic disparities, such as Nanjing and Chuxiong Yi Autonomous Prefecture. A comparison of the classification results revealed more similarities and some differences when using these two methods.Conclusion: In China, the factors with the greatest influence on the prevalence of hepatitis E are living in the south, farming as an occupation, being middle-aged or elderly, and being male. The 24 cities we studied were highly diverse and moderately similar in terms of the occupational distribution of patients with hepatitis E. We confirmed the validity of the new method on in classifying cities according to their occupational composition by comparing it with the clustering method.

Tobacco smoking is an established risk factor for squamous cell carcinoma (SCC). We obtained smoking-related SCC, including cervical SCC (CSCC), esophageal SCC (ESCC), head and neck SCC (HNSC), and lung SCC (LUSC), from The Cancer Genome Atlas (TCGA) database to investigate the association between smoking status (reformed and current smoking) and prognosis. We found that reformed smokers had a better prognosis than current smokers in CSCC (p = 0.003), HNSC (p = 0.019), and LUSC (p < 0.01) cohorts. Then, we selected LUSC cohorts as the training cohort and other SCC cohorts as the test cohorts. Function analysis revealed that homologous recombination (HR) was the most significant pathway involved in smoking-induced LUSC. Moreover, the effect of cross-talk between the smoking status and HR deficiency (HRD) on the prognosis was further evaluated, revealing that quitting smoking with high HRD scores could significantly improve patients’ prognosis (p < 0.01). To improve prognosis prediction and more effectively screen suitable populations for platinum drugs and poly-ADP-ribose polymerase (PARP) inhibitors, we constructed a risk score model using smoking- and HRD-related genes in LUSC. The risk score model had high power for predicting 2-, 3-, and 5-year survival (p < 0.01, AUC = 0.67, 0.66, and 0.66). In addition, the risk scores were an independent risk factor for LUSC (HR = 2.34, 95%CI = 1.70–3.23). The practical nomogram was also built using the risk score, smoking status, and other clinical information with a good c-index (0.72, 95%CI = 0.70–0.74). Finally, we used other TCGA SCC cohorts to confirm the reliability and validity of the risk score model (p < 0.01 and AUC > 0.6 at 2, 3, and 5 years in CSCC and HNSC cohorts). In conclusion, the present study suggested that smoking cessation should be a part of smoking-related SCC treatment, and also provided a risk score model to predict prognosis and improve the effectiveness of screening the platinum/PARP population.

Treatment for peripheral nerve injury remains limited. The inherent differences between motor and sensory nerve fibers in peripheral nerves should be considered to improve the effects of clinical treatment of peripheral nerve injury. In this study, we investigated the differences in protein expression and ultrastructure between the cutaneous and muscular branches of the femoral nerve in rats. Our results suggest that the cutaneous branch of the femoral nerve mainly contains sensory nerve fibers and few motor nerve fibers; Correspondingly, many motor nerve fibers and few sensory nerve fibers were observed in the muscular branch of the femoral nerve, which indicate that two branches of femoral nerve are mixed nerve. The mean thickness of the myelin sheath and basement membrane of the medullated fibers in the muscular branch of the femoral nerve was greater than that of the cutaneous branch of the femoral nerve. However, the cutaneous branch has a larger G-ratio. Gene Ontology enrichment analysis revealed that the cellular component term extracellular space was the most highly enriched, and more genes were upregulated in the muscular branch of the femoral nerve. Meanwhile, the expression of key proteins were validated by Western Blot, and immunofluorescence targets the expression of key proteins, which is consistent with the enrichment analysis of Gene Ontology. In conclusion, inherent differences in protein expression and ultrastructure were observed between the cutaneous and muscular branches of the femoral nerve in rats, which should be considered in future studies on the treatment of peripheral nerve injuries.

Objective This study was conducted to assess the cost-effectiveness of hepatitis E vaccination of elderly population in the sporadic regions in China. Methods We used a decision tree-Markov model to evaluate the cost-effectiveness of 3 kinds of hepatitis E virus vaccination strategies from societal perspectives. Parameter estimates were obtained from published researches and experts' opinion. The time horizon was 16 years, and the discounted rate was 3% annually. Costs are expressed in 2016 US dollars. Results The universal vaccination strategy had an incremental cost-effectiveness ratio (ICER) of US$ 8475.90 per QALY gained versus no vaccination. The implementation of screening and vaccination strategy would have an ICER of US$ 4044.28, compared with no vaccination. The vaccination was cost-effective (ICER< 3 times China's per capital gross domestic product/quality-adjusted life years). The QALY of asymptomatic infection, vaccine coverage and vaccine protection are the important parameters impacting the ICER in one-way sensitivity analysis and screening and vaccination being the dominant strategy in probabilistic sensitivity analysis. Conclusion This analysis indicates that screening and vaccination is the most cost-effective hepatitis E intervention strategy of elderly population in sporadic region in China.

The idea of safety region was introduced into the rolling bearing condition monitoring. The safety region estimation and the state identification of the rolling bearing operational were performed by the comprehensive utilization of Empirical Mode Decomposition (EMD), Principal Component Analysis (PCA), and the Least Square Support Vector Machine (LSSVM). The collected vibration data was segmented according to a certain time interval, and then the Intrinsic Mode Functions (IMFs) of each piece of the data were obtained by EMD. The control limits of two statistical variables extracted by PCA were presented as state characteristics. The safety region estimation for the rolling bearing operational status was performed by two-class LSSVM. The states of normal bearing, ball fault, inner race fault, and outer race fault were identified by the multi-class LSSVM. The results show that the estimation accuracy for both the safety region and the states identification reached 95%, and that the validity of the proposed method was verified.

The application of the multi-scale intrinsic mode function permutation entropy and extreme learning machine classifiers in railway rolling bearing fault diagnosis is here proposed in this article. The original signal is first denoised using wavelet de-noising as a pre-filter, which improves the subsequent decomposition into a number of intrinsic mode functions using ensemble empirical mode decompose. Second, the multi-scale intrinsic mode function permutation entropy is extracted as feature parameters. Finally, the extracted features are entered into extreme learning machine for an automated fault diagnosis procedure. Case studies have been carried out to evaluate the validity of the approach. The results demonstrate its effectiveness for diagnosis of faults in railway rolling bearings.

Sentiment analysis is one of the most important tasks in natural language processing. The goal of sentiment analysis is to classify the text-based sentiment tendencies by extracting text features. The quality of the classification can be assessed by the accuracy, precision and recall of the classification. So it is very important to design efficient tools or models to carry out the classification process. In this paper, we build a novel model, integrating the dealing method of Bidirectional Encoder Representation from Transformers (BERT), Bidirectional Long Short - Term Memory (Bi-LSTM) and the Multi-Head Attention (MHA), building an MHA based, integrating BERT and Bi-LSTM, Sentiment Analysis Model (MHA-BB-SAM). The model concludes two layers, the embedding layer and the Bi-LSTM layer. In the embedding layer, BERT is used to pre-process the text and train the required word vectors. In the Bi-LSTM layer, Bi-LSTM network is utilized to catch the order information of the context. Multi-Head Attention (MHA) is introduced to enhance the ability to capture the long-distance text features. The novel model is tested on two corpuses, SemEval-2020 corpus and College Learners' Spoken English Corpus (COLSEC). The computing results prove the high performance of the model. The approach presented in this paper can provide a reference for the sentiment analysis work. [ABSTRACT FROM AUTHOR]

The title compound, C21H25NO2, adopts a Z conformation about the C=C double bond. The molecular structure is stabilized by an intramolecular N—H...O hydrogen bond and the dihedral angle between the aromatic ring planes is 76.04 (12)°. The atoms of the ethyl substituent are disordered over two sets of sites in a 0.60 (2):0.40 (2) ratio.

Histone modifications, including lysine methylation, are epigenetic marks that influence many biological pathways. Accordingly, many methyltransferases have critical roles in various biological processes, and their dysregulation is often associated with cancer. However, the biological functions and regulation of many methyltransferases are unclear. Here, we report that a human homolog of the methyltransferase SET (SU(var), enhancer of zeste, and trithorax) domain containing 3 (SETD3) is cell cycle-regulated; SETD3 protein levels peaked in S phase and were lowest in M phase. We found that the-isoform of the tumor suppressor F-box and WD repeat domain containing 7 (FBXW7β) specifically mediates SETD3 degradation. Aligning the SETD3 sequence with those of well known FBXW7 substrates, we identified six potential non-canonical Cdc4 phosphodegrons (CPDs), and one of them, CPD1, is primarily phosphorylated by the kinase glycogen synthase kinase 3 (GSK3β), which is required for FBXW7β-mediated recognition and degradation. Moreover, depletion or inhibition of GSK3β or FBXW7β resulted in elevated SETD3 levels. Mutations of the phosphorylated residues in CPD1 of SETD3 abolished the interaction between FBXW7β and SETD3 and prevented SETD3 degradation. Our data further indicated that SETD3 levels positively correlated with cell proliferation of liver cancer cells and liver tumorigenesis in a xenograft mouse model, and that overexpression of FBXW7β counteracts the SETD3's tumorigenic role. We also show that SETD3 levels correlate with cancer malignancy, indicated by SETD3 levels that the 54 liver tumors are 2-fold higher than those in the relevant adjacent tissues. Collectively, these data elucidated that a GSK3β-FBXW7β-dependent mechanism controls SETD3 protein levels during the cell cycle and attenuates its oncogenic role in liver tumorigenesis. [ABSTRACT FROM AUTHOR]

Considering the deficiencies of the Co-training algorithm including redundancy and sufficient conditions, diversity measurers of classifier, combined label rules, unoptimizable classifier during model updating process etc., a multi-view collaborative semi-supervised classification algorithm based on diversity measurers of the classifier with the combination of agreement and disagreement label rules (Co-AgDiag) is proposed. This algorithm uses a combination of agreement and disagreement label rules during the labelling unlabelled data process by judging whether the two classifiers are consistent and considering the diversity threshold in order to improve the performance of the classifier. During the process of generating classifier and model updating, we employed the diversity rule of classifier to update the model in order to judge the performance of the two classifiers. The experimental results on UCI datasets demonstrate the effectively and feasibility of the proposed algorithm for multi-view classification problems. [ABSTRACT FROM AUTHOR]