Risk factors for secondary epilepsy following febrile seizures in children: A meta-analysis.

OBJECTIVE: To systematically assess the risk factors for secondary epilepsy in children with febrile seizures, in order to promptly identify early signs of epilepsy and establish a reliable foundation for timely clinical intervention and improved prognosis. METHODS: The databases, including CNKI, WanFang, VIP, CBM, PubMed, Embase, Web of Science, and the Cochrane Library were searched for relevant studies, up to October 2023. Two researchers independently collected and extracted data from selected studies, adhering to predefined criteria. Statistical analysis was performed using Stata 15.0. RESULTS: A total of 23 studies included 714 cases in the case group and 5269 cases in the control group. The results of Meta-analysis showed that preterm birth (OR=3.30, P=0.02), history of perinatal asphyxia (OR=3.94, P=0.001), age at the first seizure < 12 months (OR=2.93, P=0.003), peak temperature < 39℃ (OR=2.51, P<0.001), onset of fever to seizure < 1 h (OR=5.61, P<0.001), Complex FS(OR=4.08, P<0.001), duration of the seizure > 15 min (OR=6.21, P<0.001), Multiple seizures (≥2/episode) in one attack (OR=2.92, P<0.001), focal seizures (OR=2.53, P=0.018), recurrent FS (≥2) (OR=3.49, P<0.001), neurodevelopmental abnormality(OR=8.68, P<0.001), developmental delay(OR=10.04, P<0.001), family history of epilepsy (OR=2.74, P=0.004), family history of FS (OR=2.07, P=0.022), electroencephalogram (EEG) abnormal(OR=4.06, P<0.001)and Brain imaging abnormalities (OR=2.84, P=0.002)were Risk factors for secondary epilepsy following FS in Children. Notably, gender (female) was not a significant factor. CONCLUSIONS: This study provides a comprehensive and systematic discussion of the risk factors associated with secondary epilepsy in children with febrile seizures. It actively formulates intervention measures for modifiable risk factors and conducts early detection and continuous follow-up observation for non-modifiable high-risk children, thereby reducing the risk of epilepsy.

Essential features of weak current for excellent enhancement of NOx reduction over monoatomic V-based catalyst.

Human society is facing increasingly serious problems of environmental pollution and energy shortage, and up to now, achieving high NH3-SCR activity at ultra-low temperatures (<150 °C) remains challenging for the V-based catalysts with V content below 2%. In this study, the monoatomic V-based catalyst under the weak current-assisted strategy can completely convert NOx into N2 at ultra-low temperature with V content of 1.36%, which shows the preeminent turnover frequencies (TOF145 °C = 1.97×10-3 s-1). The improvement of catalytic performance is mainly attributed to the enhancement catalysis of weak current (ECWC) rather than electric field, which significantly reduce the energy consumption of the catalytic system by more than 90%. The further mechanism research for the ECWC based on a series of weak current-assisted characterization means and DFT calculations confirms that migrated electrons mainly concentrate around the V single atoms and increase the proportion of antibonding orbitals, which make the V-O chemical bond weaker (electron scissors effect) and thus accelerate oxygen circulation. The novel current-assisted catalysis in the present work can potentially apply to other environmental and energy fields.

Ngfr+ cholinergic projection from SI/nBM to mPFC selectively regulates temporal order recognition memory.

Acetylcholine regulates various cognitive functions through broad cholinergic innervation. However, specific cholinergic subpopulations, circuits and molecular mechanisms underlying recognition memory remain largely unknown. Here we show that Ngfr+ cholinergic neurons in the substantia innominate (SI)/nucleus basalis of Meynert (nBM)-medial prefrontal cortex (mPFC) circuit selectively underlies recency judgements. Loss of nerve growth factor receptor (Ngfr-/- mice) reduced the excitability of cholinergic neurons in the SI/nBM-mPFC circuit but not in the medial septum (MS)-hippocampus pathway, and impaired temporal order memory but not novel object and object location recognition. Expression of Ngfr in Ngfr-/- SI/nBM restored defected temporal order memory. Fiber photometry revealed that acetylcholine release in mPFC not only predicted object encounters but also mediated recency judgments of objects, and such acetylcholine release was absent in Ngfr-/- mPFC. Chemogenetic and optogenetic inhibition of SI/nBM projection to mPFC in ChAT-Cre mice diminished mPFC acetylcholine release and deteriorated temporal order recognition. Impaired cholinergic activity led to a depolarizing shift of GABAergic inputs to mPFC pyramidal neurons, due to disturbed KCC2-mediated chloride gradients. Finally, potentiation of acetylcholine signaling upregulated KCC2 levels, restored GABAergic driving force and rescued temporal order recognition deficits in Ngfr-/- mice. Thus, NGFR-dependent SI/nBM-mPFC cholinergic circuit underlies temporal order recognition memory.

The efficient synthesis of three-membered rings via photo- and electrochemical strategies.

Three-membered rings, such as epoxides, aziridines, oxaziridines, cyclopropenes, vinyloxaziridines, and azirines, are recognized as crucial pharmacophores and building blocks in organic chemistry and drug discovery. Despite the significant advances in the synthesis of these rings through photo/electrochemical methods over the past decade, there has currently been no focused discussion and updated overviews on this topic. Therefore, we presented this review article on the efficient synthesis of three-membered rings using photo- and electrochemical strategies, covering the literature since 2015. In this study, a conceptual overview and detailed discussions were provided to illustrate the advancement of this field. Moreover, a brief discussion outlines the current challenges and opportunities in synthesizing the three-membered rings using these strategies.

Gastroesophageal Reflux Disease and Preterm Birth: Univariate and Multivariate Mendelian Randomization.

Background: Observational studies have established a connection between Gastroesophageal reflux disease (GERD) and preterm birth (PTB). Nevertheless, these correlations can be affected by residual confounding or reverse causality, resulting in ambiguity regarding the connection. The objective of this study was to assess the relationship between genetically predicted GERD and PTB. Methods: Initially, we performed bidirectional univariate Mendelian randomization (UVMR) analysis utilizing publicly accessible genome-wide association studies (GWAS) data. The primary analytical approach employed to determine the causal impact between GERD and PTB is the inverse variance weighted technique (IVW). Subsequently, we utilized multivariate Mendelian randomization (MVMR) to adjust for potential factors that could influence the results, such as body mass index (BMI), maternal smoking around birth, educational attainment, household income, and Townsend deprivation index (TDI). Furthermore, we performed a sequence of comprehensive sensitivity analyses to assess the reliability of our MR findings. Results: The UVMR analysis results showed a significant correlation between GERD and PTB (odds ratio [OR]: 1.810; 95% confidence interval [CI]: 1.344-2.439; P=9.60E-05) in the IVW model, and the Weighted median method (OR=1.591, 95% CI=1.094-2.315, P=0.015) revealed consistent results. The inverse MR findings suggest no causal link between PTB and the incidence of GERD. In addition, the sensitivity analysis did not detect heterogeneity or horizontal pleiotropy, and the "leave-one-out" examination confirmed that the causal estimation is unlikely to be influenced by the single nucleotide polymorphisms (SNPs) effect. The MVMR analysis demonstrated that the causal association between GERD and PTB still existed after considering BMI, maternal smoking around birth, educational attainment, household income, and TDI (OR=1.921, 95% CI=1.401-2.634, P=5.08E-05). Conclusion: This study presents evidence indicating that genetically predicted GERD can heighten the risk of PTB. Therefore, it is advisable to perform focused screening for pregnant women with GERD in order to find the initial signs of PTB and promptly apply intervention strategies to extend the duration of pregnancy.

High-Performance Ultraviolet Photodetectors Based on Nanoporous GaN with a Ga2O3 Single-Crystal Layer.

The utilization of a nanoporous (NP) GaN fabricated by electrochemical etching has been demonstrated to be effective in the fabrication of a high-performance ultraviolet (UV) photodetector (PD). However, the NP-GaN PD typically exhibits a low light-dark current ratio and slow light response speed. In this study, we present three types of UV PDs based on an unetched GaN, NP-GaN distributed Bragg reflector (DBR), and NP-GaN-DBR with a Ga2O3 single-crystal film (Ga2O3/NP-GaN-DBR). The unetched GaN PD does not exhibit a significant photoresponse. Compared to the NP-GaN-DBR PD device, the Ga2O3/NP-GaN-DBR PD demonstrates a larger light-dark current ratio (6.14 × 103) and higher specific detectivity (8.9 × 1010 Jones) under 365 nm at 5 V bias due to its lower dark current (3.0 × 10-10 A). This reduction in the dark current can be attributed to the insertion of the insulating Ga2O3 between the metal and the NP-GaN-DBR, which provides a thicker barrier thickness and higher barrier height. Additionally, the Ga2O3/NP-GaN-DBR PD device exhibits shorter rise/decay times (0.33/0.23 s) than the NP-GaN-DBR PD, indicating that the growth of a Ga2O3 layer on the DBR effectively reduces the trap density within the NP-GaN DBR structure. Although the device with a Ga2O3 layer presents low photoresponsivity (0.1 A/W), it should be feasible to use Ga2O3 as a dielectric layer based on the above-mentioned reasons.

A causal relationship between particulate matter 2.5 and obesity and its related indicators: a Mendelian randomization study of European ancestry.

Background: In recent years, the prevalence of obesity has continued to increase as a global health concern. Numerous epidemiological studies have confirmed the long-term effects of exposure to ambient air pollutant particulate matter 2.5 (PM2.5) on obesity, but their relationship remains ambiguous. Methods: Utilizing large-scale publicly available genome-wide association studies (GWAS), we conducted univariate and multivariate Mendelian randomization (MR) analyses to assess the causal effect of PM2.5 exposure on obesity and its related indicators. The primary outcome given for both univariate MR (UVMR) and multivariate MR (MVMR) is the estimation utilizing the inverse variance weighted (IVW) method. The weighted median, MR-Egger, and maximum likelihood techniques were employed for UVMR, while the MVMR-Lasso method was applied for MVMR in the supplementary analyses. In addition, we conducted a series of thorough sensitivity studies to determine the accuracy of our MR findings. Results: The UVMR analysis demonstrated a significant association between PM2.5 exposure and an increased risk of obesity, as indicated by the IVW model (odds ratio [OR]: 6.427; 95% confidence interval [CI]: 1.881-21.968; P FDR = 0.005). Additionally, PM2.5 concentrations were positively associated with fat distribution metrics, including visceral adipose tissue (VAT) (OR: 1.861; 95% CI: 1.244-2.776; P FDR = 0.004), particularly pancreatic fat (OR: 3.499; 95% CI: 2.092-5.855; PFDR =1.28E-05), and abdominal subcutaneous adipose tissue (ASAT) volume (OR: 1.773; 95% CI: 1.106-2.841; P FDR = 0.019). Furthermore, PM2.5 exposure correlated positively with markers of glucose and lipid metabolism, specifically triglycerides (TG) (OR: 19.959; 95% CI: 1.269-3.022; P FDR = 0.004) and glycated hemoglobin (HbA1c) (OR: 2.462; 95% CI: 1.34-4.649; P FDR = 0.007). Finally, a significant negative association was observed between PM2.5 concentrations and levels of the novel obesity-related biomarker fibroblast growth factor 21 (FGF-21) (OR: 0.148; 95% CI: 0.025-0.89; P FDR = 0.037). After adjusting for confounding factors, including external smoke exposure, physical activity, educational attainment (EA), participation in sports clubs or gym leisure activities, and Townsend deprivation index at recruitment (TDI), the MVMR analysis revealed that PM2.5 levels maintained significant associations with pancreatic fat, HbA1c, and FGF-21. Conclusion: Our MR study demonstrates conclusively that higher PM2.5 concentrations are associated with an increased risk of obesity-related indicators such as pancreatic fat content, HbA1c, and FGF-21. The potential mechanisms require additional investigation.

Asthma and risk of adverse pregnancy outcomes: A Mendelian randomization study.

Background: Multiple empirical investigations have indicated a connection between asthma and adverse pregnancy outcomes (APOs). Nevertheless, the effects of asthma on APOs remain uncertain. Methods: We performed bi-directional Univariable Mendelian randomization (UVMR) analyses using combined information obtained from genome-wide association studies (GWAS) data that is publicly accessible. The principal approach used to analyze the causal association between asthma or age when diagnosed and APOs was the inverse variance weighted (IVW) method. The two types of data regarding exposure originate from the IEU Open GWAS project, which includes 56,167 and 47,222 European asthma patients, respectively. The data of four APOs were acquired via the GWAS dataset of the FinnGen collaboration. In addition, we implemented multivariable Mendelian randomization (MVMR), controlling for confounding factors such as smoking status, frequent drinking, body mass index (BMI), and live birth quantity. Furthermore, we executed several meticulous sensitivity studies to ascertain the reliability of our MR results. Results: Following the implementation of the Bonferroni adjustment, the UVMR assessment revealed that in the IVW model, asthma was significantly linked to an elevated risk of spontaneous abortion (SA) (odds ratio [OR]: 1.115; 95 % confidence interval [CI]: 1.031-1.206; P = 0.006) and gestational diabetes mellitus (GDM) (OR: 1.125; 95 % CI: 1.037-1.220; P = 0.005). However, there was no causal correlation between asthma and preterm birth (PTB) (OR: 0.979; 95 % CI: 0.897-1.068; P = 0.629) or preeclampsia (PE) (OR: 1.059; 95 % CI: 0.951-1.179; P = 0.297). After adjusting for confounding factors, including smoking status, frequent drinking, BMI, and live birth quantity, the MVMR analysis shows a statistically significant causal relationship between asthma and SA or GDM. Furthermore, our investigation's findings did not reveal a substantial correlation between the age of asthma onset based on genetics and the likelihood of SA or GDM. The inverse MR outcomes indicate a lack of causal connection linking APOs to the incidence of asthma. The validity of these findings were verified by sensitivity analyses. Conclusions: The evidence provided by this study proves that genetically determined asthma is linked to a higher likelihood of SA and GDM. Further research is required to examine potential pathways. However, no conclusive evidence has been found to support the increased risk of SA and GDM in early asthma diagnosis or the interaction between asthma and PTB or PE, indicating that confounding factors may affect the results of previous observational studies.

Serum Branched-Chain Amino Acids and Long-Term Complications of Liver Cirrhosis: Evidence from a Population-Based Prospective Study.

BACKGROUND AND AIMS: The role of serum branched-chain amino acids (BCAAs) in long-term liver cirrhosis complication events remains unclear. We aimed to evaluate the associations between serum BCAAs and the risk of liver-related events. METHODS: We included a total of 64,005 participants without liver cirrhosis complication events at baseline from the UK Biobank. Cox proportional hazards regression models were utilized to estimate multivariable hazard ratios (HRs) and 95% CIs for the incidence of liver cirrhosis complication events, adjusting for potential confounders, including sociodemographic and lifestyle factors. Relationships between serum BCAAs and liver cirrhosis complications were examined using nonparametrically restricted cubic spline regression. RESULTS: During a median follow-up of 12.7 years, 583 participants developed liver cirrhosis complication events. The multivariable Cox regression model suggested that total BCAAs (HR = 0.88, 95% CI 0.82-0.95), serum leucine (HR = 0.88, 95% CI 0.81-0.95), serum isoleucine (HR = 0.88, 95% CI 0.82-0.96), and serum valine (HR = 0.87, 95% CI 0.82-0.96) were all independent protective factors for liver cirrhosis complications after adjustment for sociodemographic and lifestyle factors. Cox models with restricted cubic splines showed U-shaped associations between serum valine and liver cirrhosis complication incidence. Serum total BCAA and isoleucine concentrations might reduce the risk of liver cirrhosis complications by raising the risk of (type 2 diabetes mellitus) T2DM. CONCLUSION: Lower serum BCAA levels exacerbate the long-term risk of liver cirrhosis complications. Future studies should confirm these findings and identify the biological pathways of these associations.

[Growth decline characteristics of Picea schrenkiana at different altitudes in Yili River Basin, western Tian-shan Mountains, Xinjiang, China]. / 新疆天山西部伊犁河流域不同海拔雪岭云杉生长衰退特征.

Picea schrenkiana is the dominant tree species in Ili River Basin located in the western Tianshan Mountains of Xinjiang. We investigated the growth decline characteristics of P. schrenkiana at different altitudes (1800, 2300 and 2800 m) based on tree-ring index (TRI) and percentage growth change (GC), aiming to understand the growth response of P. schrenkiana to drought events at different altitudes and the impacts of altitude on tree growth decline in this region. The results showed that P. schrenkiana experienced multiple decline events at low-altitude (1800 m). TRI and GC identified inconsistent occurrence time of the decline events. The variations of TRI indicated that P. schrenkiana at low-altitude experienced two large-scale declines during 1927-1933 and 2017-2014, respectively. The variations of GC identified four decline events, including 1891-1893, 1924-1926, 1973-1975, and 2004-2009. The radial growth of P. schrenkiana across altitudes from low to high was significantly affected by the Palmer drought severity index (PDSI) of the previous growing season. The impact of current PDSI on P. schrenkiana during the growing season initially enhanced but later decreased with increasing altitude. In the extreme drought year 1917, the magnitude of growth decline increased with altitude. At low-altitude (1800 m), the TRI was 0.65, which was 35% lower than the normal level. At mid-altitude (2300 m) and high-altitude (2800 m), it was 0.56 and 0.54, respectively, being 40% lower than the average level. The drought event in 1917 had a 2-year legacy effect on the growth of P. schrenkiana at all the altitudes, with the TRI in 1920 recovered to exceeding 0.9, being close to the normal level. The impact of altitude on drought-induced forest decline was significant. Tree growth in low-altitude areas was more vulnerable to drought events due to the relatively poorer water and temperature conditions at low-altitude, which could lead to multiple large-scale decline events. In mid- and high-altitude areas, where hydrothermal conditions were more favorable, trees could experience even more severe decline during extreme droughts.

Psychological distress and uterine fibroids: a bidirectional two-sample mendelian randomization study.

BACKGROUND: Observational data indicates a connection between emotional discomfort, such as anxiety and depression, and uterine fibroids (UFs). However, additional investigation is required to establish the causal relationship between them. Hence, we assessed the reciprocal causality between four psychological disorders and UFs utilizing two-sample Mendelian randomization (MR). METHODS: To evaluate the causal relationship between four types of psychological distress (depressive symptoms, severe depression, anxiety or panic attacks, mood swings) and UFs, bidirectional two-sample MR was employed, utilizing single nucleotide polymorphisms (SNPs) associated with these conditions. Both univariate MR (UVMR) and multivariate MR (MVMR) primarily applied inverse variance weighted (IVW) as the method for estimating potential causal effects. Complementary approaches such as MR Egger, weighted median, simple mode, and weighted mode were utilized to validate the findings. To assess the robustness of our MR results, we conducted sensitivity analyses using Cochran's Q-test and the MR Egger intercept test. RESULTS: The results of our UVMR analysis suggest that genetic predispositions to depressive symptoms (Odds Ratio [OR] = 1.563, 95% Confidence Interval [CI] = 1.209-2.021, P = 0.001) and major depressive disorder (MDD) (OR = 1.176, 95% CI = 1.044-1.324, P = 0.007) are associated with an increased risk of UFs. Moreover, the IVW model showed a nominally significant positive correlation between mood swings (OR: 1.578; 95% CI: 1.062-2.345; P = 0.024) and UFs risk. However, our analysis did not establish a causal relationship between UFs and the four types of psychological distress. Even after adjusting for confounders like body mass index (BMI), smoking, alcohol consumption, and number of live births in the MVMR, the causal link between MDD and UFs remained significant (OR = 1.217, 95% CI = 1.039-1.425, P = 0.015). CONCLUSIONS: Our study presents evidence supporting the causal relationship between genetic susceptibility to MDD and the incidence of UFs. These findings highlight the significance of addressing psychological health issues, particularly depression, in both the prevention and treatment of UFs.

Trans-crop applications of atypical R genes for multipathogen resistance.

Genetic resistance to plant diseases is essential for global food security. Significant progress has been achieved for plant disease-resistance (R) genes comprising nucleotide-binding domain, leucine-rich repeat-containing receptors (NLRs), and membrane-localized receptor-like kinases or proteins (RLKs/RLPs), which we refer to as typical R genes. However, there is a knowledge gap in how non-receptor-type or atypical R genes contribute to plant immunity. Here, we summarize resources and technologies facilitating the study of atypical R genes, examine diverse atypical R proteins for broad-spectrum resistance, and outline potential approaches for trans-crop applications of atypical R genes. Studies of atypical R genes are important for a holistic understanding of plant immunity and the development of novel strategies in disease control and crop improvement.

Association between biological aging and the risk of mortality in individuals with non-alcoholic fatty liver disease: A prospective cohort study.

BACKGROUND: The biological process of aging plays an important role in nonalcoholic fatty liver disease (NAFLD) development. However, epidemiological evidence about the association of biological aging with mortality risk among people with NAFLD is limited. METHODS: A total of 2199 participants with NAFLD from the National Health and Nutrition Examination Surveys (NHANES) III were included. The outcomes were all-cause and cause-specific (cardiovascular disease [CVD], cancer, and diabetes) mortality. We computed three BA measures, the Klemera-Doubal method (KDM) age, Phenotypic age, and homeostatic dysregulation (HD), by using 18 age-associated clinical biomarkers, and assessed their associations with mortality risk using Cox proportional hazards (CPH) models. RESULTS: After a median follow-up of 16 years, a total of 1077 deaths occurred. People with NAFLD who died during follow-up period exhibited higher baseline biological age (BA) and biological age accelerations (BAAs). The multivariate-adjusted CPH suggested that a one-standard deviation (SD) increase in KDM age acceleration, Phenotypic age acceleration, or HD was associated with a 3 %, 7 %, or 39 % elevated risk of all-cause mortality, respectively. The results of age-varying HRs showed that the associations of KDM age accelerations (AAs) and Phenotypic AAs with all-cause mortality appeared to be stronger in people with NAFLD younger than 45 years. CONCLUSIONS: Biological aging was positively associated with both all-cause and cause-specific mortality among people with NAFLD, particularly among younger individuals.

Machine-learning-based plasma metabolomic profiles for predicting long-term complications of cirrhosis.

BACKGROUND AND AIMS: The complications of liver cirrhosis occur after long asymptomatic stages of progressive fibrosis and are generally diagnosed late. We aimed to develop a plasma metabolomic-based score tool to predict these events. APPROACH AND RESULTS: We enrolled 64,005 UK biobank participants with metabolomic profiles. Participants were randomly divided into the training (n=43,734) and validation cohorts (n=20,271). Liver cirrhosis complications were defined as hospitalization for liver cirrhosis or presentation with HCC. An interpretable machine-learning framework was applied to learn the metabolomic states extracted from 168 circulating metabolites in the training cohort. An integrated nomogram was developed and compared to conventional and genetic risk scores. We created 3 groups: low-risk, middle-risk, and high-risk through selected cutoffs of the nomogram. The predictive performance was validated through the area under a time-dependent receiver operating characteristic curve (time-dependent AUC), calibration curves, and decision curve analysis. The metabolomic state model could accurately predict the 10-year risk of liver cirrhosis complications in the training cohort (time-dependent AUC: 0.84 [95% CI: 0.82-0.86]), and outperform the fibrosis-4 index (time-dependent AUC difference: 0.06 [0.03-0.10]) and polygenic risk score (0.25 [0.21-0.29]). The nomogram, integrating metabolomic state, aspartate aminotransferase, platelet count, waist/hip ratio, and smoking status showed a time-dependent AUC of 0.930 at 3 years, 0.889 at 5 years, and 0.861 at 10 years in the validation cohort, respectively. The HR in the high-risk group was 43.58 (95% CI: 27.08-70.12) compared with the low-risk group. CONCLUSIONS: We developed a metabolomic state-integrated nomogram, which enables risk stratification and personalized administration of liver-related events.

Evolutionary dynamics and comparative pathogenicity of clade 2.3.4.4b H5 subtype avian influenza viruses, China, 2021-2022.

The recent concurrent emergence of H5N1, H5N6, and H5N8 avian influenza viruses (AIVs) has led to significant avian mortality globally. Since 2020, frequent human-animal interactions have been documented. To gain insight into the novel H5 subtype AIVs (i.e., H5N1, H5N6 and H5N8), we collected 6102 samples from various regions of China between January 2021 and September 2022, and identified 41 H5Nx strains. Comparative analyses on the evolution and biological properties of these isolates were conducted. Phylogenetic analysis revealed that the 41 H5Nx strains belonged to clade 2.3.4.4b, with 13 related to H5N1, 19 to H5N6, and 9 to H5N8. Analysis based on global 2.3.4.4b viruses showed that all the viruses described in this study were likely originated from H5N8, exhibiting a heterogeneous evolutionary history between H5N1 and H5N6 during 2015-2022 worldwide. H5N1 showed a higher rate of evolution in 2021-2022 and more sites under positive selection pressure in 2015-2022. The antigenic profiles of the novel H5N1 and H5N6 exhibited notable variations. Further hemagglutination inhibition assay suggested that some A(H5N1) viruses may be antigenically distinct from the circulating H5N6 and H5N8 strains. Mammalian challenge assays demonstrated that the H5N8 virus (21GD001_H5N8) displayed the highest pathogenicity in mice, followed by the H5N1 virus (B1557_H5N1) and then the H5N6 virus (220086_H5N6), suggesting a heterogeneous virulence profile of H5 AIVs in the mammalian hosts. Based on the above results, we speculate that A(H5N1) viruses have a higher risk of emergence in the future. Collectively, these findings unveil a new landscape of different evolutionary history and biological characteristics of novel H5 AIVs in clade 2.3.4.4b, contributing to a better understanding of designing more effective strategies for the prevention and control of novel H5 AIVs.

Comparative analysis of tropomyosin allergenicity in three different species of molluscs: insights into the role of amino acid composition in IgE epitopes.

Limited research has been conducted on the differences in allergenicity among Alectryonella plicatula tropomyosin (ATM), Haliotis discus hannai tropomyosin (HTM), and Mimachlamys nobilis tropomyosin (MTM) in molluscs. Our study aimed to comprehensively analyze and compare their immunoreactivity, sensitization, and allergenicity while simultaneously elucidating the underlying molecular mechanisms involved. We assessed the immune binding activity of TM utilizing 86 sera from allergic patients and evaluated sensitization and allergenicity through two different types of mouse models. The dot-blot and basophil activation test assays revealed strong immunoreactivity for HTM, ATM, and MTM, with HTM exhibiting significantly lower levels compared to ATM. In the BALB/c mouse sensitization model, all TM groups stimulated the production of specific antibodies, elicited IgE-mediated immediate hypersensitivity responses, and caused an imbalance in the IL-4/IFN-γ ratio. Similarly, in the BALB/c mouse model of food allergy, all TM variants induced IgE-mediated type I hypersensitivity responses, leading to the development of food allergies characterized by clinical symptoms and an imbalance in the IL-4/IFN-γ ratio. The stimulation ability of sensitization and the severity of food allergies consistently ranked as ATM > MTM > HTM. Through an in-depth analysis of non-polar amino acid frequency and polar hydrogen bonds, HTM exhibited higher frequencies of non-polar amino acids in its amino acid sequence and IgE epitopes, in comparison with ATM and MTM. Furthermore, HTM demonstrated a lower number of polar hydrogen bonds in IgE epitopes. Overall, HTM exhibited the lowest allergenic potential in both allergic patients and mouse models, likely due to its lower polarity in the amino acid sequence and IgE epitopes.

Establishment of a mild cognitive impairment risk model in middle-aged and older adults: a longitudinal study.

BACKGROUND: Early identification individuals at high risk of mild cognitive impairment (MCI) is essential for prevention and intervention strategies of dementia, such as Alzheimer's disease. MCI prediction considering the interdependence of predictors in longitudinal data needs to be further explored. We aimed to employ machine learning (ML) to develop and verify a prediction model of MCI. METHODS: In a longitudinal population-based cohort of China Health and Retirement Longitudinal Study (CHARLS), 8390 non-MCI participants were enrolled. The diagnosis of MCI was based on the aging-associated cognitive decline (AACD), and 13 factors (gender, education, marital status, residence, diabetes, hypertension, depression, hearing impairment, social isolation, physical activity, drinking status, body mass index and expenditure) were finally selected as predictors. We implemented a long short-term memory (LSTM) to predict the MCI risks in middle-aged and older adults within 7 years. The Receiver Operating Characteristic curve (ROC) and calibration curve were used to evaluate the performance of the model. RESULTS: Through 7 years of follow-up, 1925 participants developed MCI. The model for all incident MCI achieved an AUC of 0.774, and its deployment to the participants followed 2, 4, and 7 years achieved results of 0.739, 0.747, and 0.750, respectively. The model was well-calibrated with predicted probabilities plotted against the observed proportions of cognitive impairment. Education level, gender, marital status, and depression contributed most to the prediction of MCI. CONCLUSIONS: This model could be widely applied to medical institutions, even in the community, to identify middle-aged and older adults at high risk of MCI.

Spinocerebellar Ataxia Type 3 Pathophysiology-Implications for Translational Research and Clinical Studies.

The spinocerebellar ataxias (SCA) comprise a group of inherited neurodegenerative diseases. Machado-Joseph Disease (MJD) or spinocerebellar ataxia 3 (SCA3) is the most common autosomal dominant form, caused by the expansion of CAG repeats within the ataxin-3 (ATXN3) gene. This mutation results in the expression of an abnormal protein containing long polyglutamine (polyQ) stretches that confers a toxic gain of function and leads to misfolding and aggregation of ATXN3 in neurons. As a result of the neurodegenerative process, SCA3 patients are severely disabled and die prematurely. Several screening approaches, e.g., druggable genome-wide and drug library screenings have been performed, focussing on the reduction in stably overexpressed ATXN3(polyQ) protein and improvement in the resultant toxicity. Transgenic overexpression models of toxic ATXN3, however, missed potential modulators of endogenous ATXN3 regulation. In another approach to identify modifiers of endogenous ATXN3 expression using a CRISPR/Cas9-modified SK-N-SH wild-type cell line with a GFP-T2A-luciferase (LUC) cassette under the control of the endogenous ATXN3 promotor, four statins were identified as potential activators of expression. We here provide an overview of the high throughput screening approaches yet performed to find compounds or genomic modifiers of ATXN3(polyQ) toxicity in different SCA3 model organisms and cell lines to ameliorate and halt SCA3 progression in patients. Furthermore, the putative role of cholesterol in neurodegenerative diseases (NDDs) in general and SCA3 in particular is discussed.