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Objective: Chinese medicine formulae possess the potential for cholestasis treatment. This study aimed to explore the underlying mechanisms of San-Huang-Chai-Zhu formula (SHCZF) against cholestasis. Methods: The major chemical compounds of SHCZF were identified by high-performance liquid chromatography. The bioactive compounds and targets of SHCZF, and cholestasis-related targets were obtained from public databases. Intersected targets of SHCZF and cholestasis were visualized by Venn diagram. The protein-protein interaction and compound-target networks were established by Cytoscape according to the STRING database. The biological functions and pathways of potential targets were characterized by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. The biological process-target-pathway network was constructed by Cytoscape. Finally, the interactions between biological compounds and hub target proteins were validated via molecular docking. Results: There 7 major chemical compounds in SHCZF. A total of 141 bioactive compounds and 83 potential targets were screened for SHCZF against cholestasis. The process of SHCZF against cholestasis was mainly involved in AGE-RAGE signaling pathway in diabetic complications, fluid shear stress and atherosclerosis, and drug metabolism-cytochrome P450. ALB, IL6, AKT1, TP53, TNF, MAPK3, APOE, IL1B, PPARG, and PPARA were the top 10 hub targets. Molecular docking showed that bioactive compounds of SHCZF had a good binding affinity with hub targets. Conclusions: This study predicted that the mechanisms of SHCZF against cholestasis mainly involved in AGE-RAGE signaling pathway in diabetic complications, fluid shear stress and atherosclerosis, and drug metabolism-cytochrome P450. Moreover, APOE, AKT1, and TP53 were the critical hub targets for bioactive compounds of SHCZF. [ABSTRACT FROM AUTHOR]

Background and objective: We aimed to predict the targets and signal pathways of Xiao-Chai-Hu-Tang (XCHT) in the treatment of colorectal cancer (CRC) based on network pharmacology, just as well as to further analyze its anti-CRC material basis and mechanism of action. Methods: We adopted Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) and Traditional Chinese Medicine Integrated Database (TCMID) databases to screen the active ingredients and potential targets of XCHT. CRC-related targets were retrieved by analyzing published microarray data (accession number GSE110224) from the Gene Expression Omnibus (GEO) database. The common targets were used to construct the "herb-active ingredient-target" network using the Cytoscape 3.8.0 software. Next, we constructed and analyzed protein-to-protein interaction (PPI) using BisoGenet and CytoNCA plug-in in Cytoscape. We then performed Gene Ontology (GO) functional and the Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analyses of target genes using the R package of clusterProfiler. Furthermore, we used the AutoDock Tools software to conduct molecular docking studies on the active ingredients and key targets to verify the network pharmacological analysis results. Results: We identified a total of 71 active XCHT ingredients and 20 potential anti-CRC targets. The network analysis revealed quercetin, stigmasterol, kaempferol, baicalein, and acacetin as potential key compounds, and PTGS2, NR3C2, CA2, and MMP1 as potential key targets. The active ingredients of XCHT interacted with most CRC disease targets. We showed that XCHT's therapeutic effect was attributed to its synergistic action (multi-compound, multi-target, and multi-pathway). Our GO enrichment analysis showed 46 GO entries, including 20 biological processes, 6 cellular components, and 20 molecular functions. We identified 11 KEGG signaling pathways, including the IL-17, TNF, Toll-like receptor, and NF-kappa B signaling pathways. Our results showed that XCHT could play a role in CRC treatment by regulating different signaling pathways. The molecular docking experiment confirmed the correlation between five core compounds (quercetin, stigmasterol, kaempferol, baicalein, and acacetin) just as well as PTGS2, NR3C2, CA2, and MMP1. Conclusion: In this study, we described the potential active ingredients, possible targets, and key biological pathways responsible for the efficacy of XCHT in CRC treatment, providing a theoretical basis for further research. [ABSTRACT FROM AUTHOR]

Background: Clozapine is widely regarded as a highly efficacious psychotropic drug that is largely underused worldwide. Recent disproportionality analyses and nationwide case-control studies suggested a potential association between clozapine use and hematological malignancy (HM). Nevertheless, the absolute rate difference is not well-established due to the absence of analytic cohort studies. The clinical significance of such a potential risk remains unclear. Methods and findings: We extracted data from a territory-wide public healthcare database from January 2001 to August 2022 in Hong Kong to conduct a retrospective cohort study of anonymized patients aged 18+ years with a diagnosis of schizophrenia who used clozapine or olanzapine (drug comparator with highly similar chemical structure and pharmacological mechanisms) for 90+ days, with at least 2 prior other antipsychotic use records within both groups. Weighted by inverse probability of treatment (IPTW) based on propensity scores, Poisson regression was used to estimate the incidence rate ratio (IRR) of HM between clozapine and olanzapine users. The absolute rate difference was also estimated. In total, 9,965 patients with a median follow-up period of 6.99 years (25th to 75th percentile: 4.45 to 10.32 years) were included, among which 834 were clozapine users. After IPTW, the demographic and clinical characteristics of clozapine users were comparable to those of olanzapine users. Clozapine users had a significant weighted IRR of 2.22 (95% confidence interval (CI) [1.52, 3.34]; p < 0.001) for HM compared to olanzapine users. The absolute rate difference was estimated at 57.40 (95% CI [33.24, 81.55]) per 100,000 person-years. Findings were consistent across subgroups by age and sex. Sensitivity analyses all supported the robustness of the results and showed good specificity to HM but no other cancers. The main limitation of this observational study is the potential residual confounding effects that could have arisen from the lack of randomization in clozapine or olanzapine use. Conclusions: Absolute rate difference in HM incidence associated with clozapine is small despite a 2-fold elevated rate. Given the rarity of HM and existing blood monitoring requirements, more restrictive indication for clozapine or special warnings may not be necessary. Yuqi Hu, Le Gao and colleagues compare the incidence of haematological malignancies between clozapine and olanzapine users using territory-wide electronic health records from Hong Kong public health facilities. Author summary: Why was this study done?: Preliminary epidemiologic evidence has been reported on an elevated risk of hematological malignancy (HM) associated with clozapine use. The clinical significance (or insignificance) of such a risk is yet to be determined. Analytic cohort studies are needed to estimate the rate difference, i.e., number of additional cases associated with clozapine use, in addition to rate ratios. What did the researchers do and find?: Using the territory-wide electronic health records from Hong Kong public healthcare facilities, we built a retrospective cohort to compare the incidence of HM between clozapine and olanzapine users. Similar with previous research, we found a 2-fold elevated rate of HM in clozapine users. Nevertheless, the rate difference between clozapine and olanzapine users were small, i.e., approximately 1 additional case of HM in every 1,700 person-year of exposure to clozapine. What do these findings mean?: The previously observed elevated risk of HM associated with clozapine is supported by territory-wide data in Hong Kong. The absolute rate difference is small and, given existing risk mitigation measures for hematological abnormalities, does not necessitate additional restrictions on the indication of clozapine or special warnings. As the assignment of clozapine versus olanzapine use in this cohort was not randomized, there may be underlying factors that are related to both clozapine use (versus olanzapine) and HM that gave rise to the observed association but were not considered. [ABSTRACT FROM AUTHOR]

To identify differences in human immunodeficiency virus (HIV) risky behavior and healthy practices between rural and urban men who have sex with men (MSM) in Southeast China, a cross-sectional study was conducted on MSM aged ≥ 18 years recruited from four community-based organizations (CBOs) in seven cities in Zhejiang Province between October 2022 and March 2023. An electronic survey questionnaire was completed by the study participants to collect HIV risky behavior and healthy practices. The chi-square test and multiple logistic regression were used for analysis. Among the 1,993 MSM participants, 21.1% (420) were rural MSM. Compared with urban MSM, rural MSM was more likely to have a low level of education (high school and below; 46.2% vs. 40.2%, p = 0.028) and a low annual income (≤ 90,000 RMB; 71.2% vs. 64.7%, p = 0.013). Multiple logistic regression showed that, compared with urban MSM in the past 6 months behaviors, rural MSM had lower odds of finding casual sex partners on the Internet (adjusted odds ratio [aOR]: 0.790, 95% confidence interval [CI]: 0.633–0.986), using stimulants with online casual sex partners (aOR: 0.688, 95% CI: 0.506–0.936), and high odds of ever having sex with a female (aOR: 1.460, 95% CI:1.036–2.058). Rural MSM reported lower odds of an HIV knowledge score of 2–3 (aOR: 0.586, 95% CI: 0.454–0.756), HIV testing more than twice (aOR: 0.583, 95% CI: 0.455–0.748), and obtaining four to five types of HIV information (aOR: 0.661, 95% CI: 0.529–0.826), as well as higher odds of high/very high awareness of HIV infection risk (aOR: 2.312, 95% CI: 1.638–3.263), compared to urban MSM. Rural MSM and urban MSM reported discrepancies in HIV risky behavior, HIV knowledge and HIV-related healthy practices. Paying more attention to HIV risky behavior and improving healthy practices in rural areas may help to prevent HIV transmission. [ABSTRACT FROM AUTHOR]

This study comprehensively examined the accumulation of cadmium (Cd) in soybeans grown in low- and high-Cd soils around the high geological background areas in Guizhou province. The aim was to analyze the relationship between soybean Cd and soil pH and soil Cd, alongside assessing the potential carcinogenic and non-carcinogenic risks associated with Cd in soybeans. Cd content of soybeans cultivated in the high-Cd area (0.430 mg/kg) was significantly higher than that in low-Cd areas (0.156 mg/kg) (P < 0.05). Biological concentration factors (BCFs) of soybean for Cd in low- and high-Cd areas were 0.282 and 0.314, respectively, with no significant differences (P > 0.05). Multiple linear regression results indicated that soil pH was a determining factor for Cd accumulation in soybeans in both areas. Furthermore, soil pH and soil Cd could accurately predict Cd accumulation in soybeans according to the neural network model. These findings suggest that regulating soil pH could reduce Cd accumulation in soybeans in areas with high geological background. In both areas, there was no significant non-carcinogenic risk for the adult population (HQ value < 1) through soybean consumption. However, according to the Monte Carlo model, the percentage of Cd in soybeans exceeding the acceptable range (CR value > 1.00 × 10 −04) in areas was 99.18%, indicating an unacceptable carcinogenic risk for the adult population. Our discussion revealed that reducing the soybean intake and increasing soil pH did not effectively lower the carcinogenic risk of Cd in soybeans to an acceptable range (CR value ≤ 1.00 × 10 −04). These findings necessitate further exploration of alternative remediation strategies to ensure the safe production of soybeans, such as screening for low-Cd accumulation soybean varieties and implementing the combined remediation strategies. [ABSTRACT FROM AUTHOR]

The non-axisymmetric problem caused by the fluid sloshing in the tank of a mining concrete mixing tank truck during driving is affected by the excitation of complex road surfaces. The fluid sloshing is coupled with the dynamics of the vehicle body due to the excitation of the complex road surface. The traditional hydraulic drive proportional integral differential (PID) control method is not effective in dealing with such problems, which can easily lead to accidents such as overturning. To improve the accuracy and stability of the hydraulic drive control system, this paper proposes an optimized particle filter PID adaptive control method based on the elastic firefly (FA) algorithm to accelerate the convergence speed of control parameter optimization, and then analyzes its hydraulic drive control characteristics and structural applications, and discusses step steering and double lane change modes are simulated under filling rates of 1.5 and 2.0, respectively. The experimental results show that compared with traditional PID control, the proposed adaptive control method can significantly reduce the average speed error of hydraulic drive control to 0.03km/h and the maximum speed error to 0.17km/h. It also improves the control tracking performance and stability. The practicality of the adaptive hydraulic drive is verified in the filling rate experiments under step steering and double-lane shifting conditions. It has important reference value for the practical application of hydraulic drive control optimization of mining concrete mixing transport tank trucks. [ABSTRACT FROM AUTHOR]

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) can be triggered by infectious agents including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the impact of the coronavirus disease 2019 (COVID-19) pandemic on ME/CFS prevalence is not well characterized. Methods: In this population-based cross-sectional study, we enrolled a stratified random sample of 9,825 adult participants in the Kaiser Permanente Northern California (KPNC) integrated health system from July to October 2022 to assess overall ME/CFS-like illness prevalence and the proportion that were identified following COVID-19 illness. We used medical record and survey data to estimate the prevalence of ME/CFS-like illness based on self-reported symptoms congruent with the 2015 Institute of Medicine ME/CFS criteria. History of COVID-19 was based on a positive SARS-CoV-2 nucleic acid amplification test or ICD-10 diagnosis code in the medical record, or self-report of prior COVID-19 on a survey. Results: Of 2,745,374 adults in the eligible population, an estimated 45,892 (95% confidence interval [CI]: 32,869, 58,914) or 1.67% (CI 1.20%, 2.15%) had ME/CFS-like illness. Among those with ME/CFS-like illness, an estimated 14.12% (CI 3.64%, 24.6%) developed the illness after COVID-19. Among persons who had COVID-19, those with ME/CFS-like illness after COVID-19 were more likely to be unvaccinated and to have had COVID-19 before June 1, 2021. All persons with ME/CFS-like illness had significant impairment in physical, mental, emotional, social, and occupational functioning compared to persons without ME/CFS-like illness. Conclusions: In a large, integrated health system, 1.67% of adults had ME/CFS-like illness and 14.12% of all persons with ME/CFS-like illness developed it after COVID-19. Though COVID-19 did not substantially increase ME/CFS-like illness in the KPNC population during the study time period, ME/CFS-like illness nevertheless affects a notable portion of this population and is consistent with estimates of ME/CFS prevalence in other populations. Additional attention is needed to improve awareness, diagnosis, and treatment of ME/CFS. [ABSTRACT FROM AUTHOR]

Meningococcal vaccination in Chinese national immunization program (NIP) includes polysaccharide vaccine against Neisseria meningitidis serogroup A (MPV-A) and polysaccharide vaccine against Neisseria meningitidis serogroup A and C(MPV-AC). This study aimed to assess the cost-effectiveness of an alternative strategy using polysaccharide conjugate vaccine against Neisseria meningitidis serogroup A,C,W,Y(MCV-ACWY) and polysaccharide vaccine against Neisseria meningitidis serogroup A,C,W,Y(MPV-ACWY). From a societal perspective, we constructed a decision tree-Markov model to simulate the economic and health consequences of meningococcal disease in a 2023 birth cohort with the current meningococcal vaccination strategy and the alternative. Parameters of epidemiology, vaccine efficacy, cost, and utility were extracted from database and previous literatures. The sensitivity analysis was implemented to evaluate the robustness of the model. Compared to the current practice, the alternative strategy could avoid 513 meningococcal disease cases, 53 sequelae and 47 deaths. The ICER was estimated at $16899.81 /QALY, under the threshold of one time of the GDP per capita of Zhejiang province in 2023. The incidence of meningococcemia, the incidence of meningococcal meningitis, the case fatality of meningococcemia, the vaccine efficacy of MCV-ACWY and the price of MCV-ACWY would influence the cost-effectiveness of the meningococcal vaccination strategies. At the threshold, the probability of cost-effectiveness was 14.76% for the current strategy and 55.98% for the alternative strategy, respectively. The current meningococcal vaccination strategy had effectively prevented meningococcal disease at a low cost, but with limited serogroup coverage. Strategy using MCV-ACWY and MPV-ACWY could increase health benefits at a substantial cost at a cost-effective manner. [ABSTRACT FROM AUTHOR]

Dynamic properties are essential for microtubule (MT) physiology. Current techniques for in vivo imaging of MTs present intrinsic limitations in elucidating the isotype-specific nuances of tubulins, which contribute to their versatile functions. Harnessing the power of the AlphaFold2 pipeline, we engineered a strategy for the minimally invasive fluorescence labeling of endogenous tubulin isotypes or those harboring missense mutations. We demonstrated that a specifically designed 16-amino acid linker, coupled with sfGFP11 from the split-sfGFP system and integration into the H1-S2 loop of tubulin, facilitated tubulin labeling without compromising MT dynamics, embryonic development, or ciliogenesis in Caenorhabditis elegans. Extending this technique to human cells and murine oocytes, we visualized MTs with the minimal background fluorescence and a pathogenic tubulin isoform with fidelity. The utility of our approach across biological contexts and species set an additional paradigm for studying tubulin dynamics and functional specificity, with implications for understanding tubulin-related diseases known as tubulinopathies. GFP-tagged tubulins have been widely used to monitor and visualize tubulin isotypes, but this is known to interfere with their cellular functions. This study describes a functional labeling strategy, guided by AlphaFold2 structural predictions, to label endogenous tubulins across diverse species while preserving functionality. [ABSTRACT FROM AUTHOR]

Foot-and-mouth disease (FMD) is a severe, highly contagious viral disease of livestock that has a significant economic impact on domestic animals and threatens wildlife survival in China and border countries. However, effective surveillance and prevention of this disease is often incomplete and unattainable due to the cost, the great diversity of wildlife hosts, the changing range and dynamics, and the diversity of FMDV. In this study, we used predictive models to reveal the spread and risk of FMD in anticipation of identifying key nodes to control its spread. For the first time, the spatial distribution of FMD serotype O was predicted in western China and border countries using a niche model, which is a combination of eco-geographic, human, topographic, and vegetation variables. The transboundary least-cost pathways (LCPs) model for ungulates in the study area were also calculated. Our study indicates that FMD serotype O survival is seasonal at low altitudes (March and June) and more sensitive to temperature differences at high altitudes. FMD serotype O risk was higher in Central Asian countries and both were highly correlated with the population variables. Ten LCPs were obtained representing Pakistan, Kazakhstan, Kyrgyzstan, and China. [ABSTRACT FROM AUTHOR]

Background: Evidence supports the use of hand-based metacarpophalangeal joint (MCPJ) blocking splints as an intervention for trigger finger (TF). In practice, finger-based relative motion (RM) splints are also implemented without evidence. Purpose: This randomized comparative trial (RCT) aims to evaluate implementation of MCPJ blocking and RM splints for effectiveness, function, occupational performance and wearability after 6 weeks of TF management. Methods and analysis: Priori analysis determined 36 individuals were needed for random assignment to the RM or MCPJ blocking splint groups. Individuals must be aged ≥21 years, and diagnosed with TF involving ≥1 finger. For blinding purposes, the primary author screens for eligibility, fabricates the splints and educates. Therapist A administers the primary outcome measures Week-1 and Week-6—stage of stenosing tenosynovitis and secondary outcome measures- number of triggering events in 10 active fists, visual analog scales (VAS) for pain, splint comfort and satisfaction, Disabilities of the Arm, Shoulder and Hand, and Canadian Occupational Performance Measure. Therapist B in Week-3 instructs participants in deep tissue massage and administers splint wearability VASs. The RM pencil test is used to determine the affected finger(s) MCPJ splint position i.e., more extension or flexion based on participant response. The MCPJ blocking splint holds the MCPJ in a neutral position. Analysis involves a mixed-effects ANOVA to compare Week-1 and Week-6 primary and secondary outcomes. Results: Recruitment and data collection are ongoing. Discussion: Biomechanically RM splints control tendon excursion and reduce passive tendon tension while allowing unencumbered finger motion and hand function. Hence clinicians use RM splints as an intervention for TF, despite the lack of implementation evidence. This RCT implements a function-focused as well as patient-centered approach with partial blinding of assessors and participants. Conclusion: We anticipate that this study will provide evidence for the implementation of RM splints to manage adults with TF. Trial registration: Clinical trial registration This trial is registered with ClinicalTrials.gov (NCT05763017). [ABSTRACT FROM AUTHOR]

Amidst the digital transformation of education, the essence of the human touch in online teaching remains pivotal. Despite growing literature, there remains a significant gap in understanding how the human element in online teaching directly influences student engagement and learning outcomes, especially in diverse educational contexts. This study develops a quantifiable index capturing the essence of humanized online teaching and investigates the determinants influencing this humanization. Additionally, an index encapsulating students' online learning experiences, as perceived by their instructors, has been constructed. Bridging these indices, the research unravels the intricate relationship between the humanization of online teaching and the resulting student experiences in the virtual realm. Sourced from a self-constructed questionnaire and encompassing responses from 152 instructors across 22 Malaysian institutions, the data revealed an average incorporation of 81.38% humanized online teaching elements. Key determinants, such as subject matter, teaching experience, Internet quality, and platform choices, emerged as significant influences. A regression model showed approximately 31.7% (R-squared = 0.317, p<0.001) of the variation in the dependent variable. A significant moderate positive correlation (r = 0.423, p<0.001) between the Humanized Online Teaching Index and the Students' Online Learning Experiences Index highlights the intertwined nature of humanized instructional methodologies and enhanced student engagement in online settings. Though contextualised during the coronavirus disease-2019 pandemic, the study's implications transcend the immediate circumstances, offering transformative insights for future online teaching methodologies and enhancing student experiences in the evolving digital age. [ABSTRACT FROM AUTHOR]

Introduction: Individualized treatment of spinal deformity is needed for adolescent idiopathic scoliosis (AIS), and the integration of pelvic rotation correction based on proprioceptive neuromuscular facilitation (PNF) into regular physiotherapy may be a promising approach. However, few high-quality studies have investigated its effects. This study aimed to evaluate the efficacy of pelvic rotation correction combined with Schroth exercises in the treatment of mild AIS. Methods: This was a randomized controlled trial. Forty-two AIS patients were randomly divided into experimental and control groups. Both groups underwent 20 therapeutic sessions over 24 weeks. All patients (n = 42) performed Schroth exercises at each session. In addition, the experimental group (n = 21) also participated in a pelvic rotation correction program based on PNF at each session. The primary outcome was the concave/convex ratio of hipbone widths, and the secondary outcomes included the Cobb angle, trunk rotation angle, self-perception, apical vertebral translation, and apical vertebral rotation. Patients were evaluated before and after 24 weeks of intervention. Results: There was a significant between-group difference in the change from baseline between the experimental and control groups for the following parameters: concave/convex ratio 2.89% (95% confidence interval [CI], 1.58 to 4.20, P<0.001), trunk rotation angle −1.26° (95% CI, −2.20 to −0.32; P = 0.01), and apical vertebral rotation improved by at least one class from baseline in 3 patients (14.3%) in the control group and 9 patients (42.9%) in the experimental group (P = 0.04). While Cobb angle −1.60° (95% CI, −7.75 to 0.54; P = 0.14), self-image 0.149 (95% CI, 0.001 to 0.297; P = 0.049), apical vertebral translation −0.58 mm (95% CI, −3.83 to 2.67; P = 0.72), and pelvic obliquity 0.10° (95% CI, −0.21 to 0.41; P = 0.52) did not differ significantly. Conclusions: Pelvic rotation correction combined with Schroth exercises more effectively improved pelvic axial rotation and other spinal deformities, including trunk rotation and apical vertebral rotation, than Schroth exercises alone in the treatment of mild AIS. [ABSTRACT FROM AUTHOR]

Inflammasomes play pivotal roles in inflammation by processing and promoting the secretion of IL-1β. Caspase-1 is involved in the maturation of IL-1β and IL-18, while human caspase-4 specifically processes IL-18. Recent structural studies of caspase-4 bound to Pro-IL-18 reveal the molecular basis of Pro-IL-18 activation by caspase-4. However, the mechanism of caspase-1 processing of pro-IL-1β and other IL-1β-converting enzymes remains elusive. Here, we observed that swine Pro-IL-1β (sPro-IL-1β) exists as an oligomeric precursor unlike monomeric human Pro-IL-1β (hPro-IL-1β). Interestingly, Seneca Valley Virus (SVV) 3C protease cleaves sPro-IL-1β to produce mature IL-1β, while it cleaves hPro-IL-1β but does not produce mature IL-1β in a specific manner. When the inflammasome is blocked, SVV 3C continues to activate IL-1β through direct cleavage in porcine alveolar macrophages (PAMs). Through molecular modeling and mutagenesis studies, we discovered that the pro-domain of sPro-IL-1β serves as an 'exosite' with its hydrophobic residues docking into a positively charged 3C protease pocket, thereby directing the substrate to the active site. The cleavage of swine IL-1β (sIL-1β) generates a monomeric and active form of sIL-1β, initiating the downstream signaling. Thus, these studies provide IL-1β is an inflammatory sensor that directly detects viral protease through an independent pathway operating in parallel with host inflammasomes. Author summary: IL-1β is a key inflammatory mediator, crucial for immune responses and pathological inflammation. Upon the assembly of large complexes by NOD-like receptors, caspase-1 serves as the endogenous enzyme that cleaves pro-IL-1β in activate IL-1β. Previous studies have identified IL-1β is an innate immune sensor of group A Streptococcus (GAS) protease SpeB. However, whether IL-1β is an inflammatory sensor for viral proteases remains unclear. Here, we report that Seneca Valley Virus (SVV) 3C protease functions as an unconventional IL-1β-converting enzyme (ICE), specifically and directly cleaving and processing swine pro-IL-1β but not human pro-IL-1β. The cleaved IL-1β is bioactive, consistent with the function of mature IL-1β. This finding reveals a novel virus-mediated activation mechanism of IL-1β and may influence the host's inflammatory response. [ABSTRACT FROM AUTHOR]

High-quality, chromosome-scale genomes are essential for genomic analyses. Analyses, including 3D genomics, epigenetics, and comparative genomics rely on a high-quality genome assembly, which is often accomplished with the assistance of Hi-C data. Curation of genomes reveal that current Hi-C-assisted scaffolding algorithms either generate ordering and orientation errors or fail to assemble high-quality chromosome-level scaffolds. Here, we offer the software Puzzle Hi-C, which uses Hi-C reads to accurately assign contigs or scaffolds to chromosomes. Puzzle Hi-C uses the triangle region instead of the square region to count interactions in a Hi-C heatmap. This strategy dramatically diminishes scaffolding interference caused by long-range interactions. This software also introduces a dynamic, triangle window strategy during assembly. Initially small, the window expands with interactions to produce more effective clustering. Puzzle Hi-C outperforms available scaffolding tools. [ABSTRACT FROM AUTHOR]

Objective: Winter-over expeditioners in Antarctica are challenged by various environmental and psycho-social stress factors, which may induce psychophysiological changes. The autonomic nervous system (ANS) plays a crucial role in the adaptation process under stress. However, the relationship between ANS activity and the mood states of expeditioners remains largely unexplored. This study aims to uncover the pattern of ANS adjustment under extreme Antarctic environments and provide new insights into the correlations between ANS activity and mood state changes, which may provide scientific data for medical interventions. Methods: Fourteen expeditioners at Zhongshan Station participated in this study. The study was conducted during four representative periods: pre-Antarctica, Antarctica-1 (pre-winter), Antarctica-2 (winter), and Antarctica-3 (summer). The heart rate variability (HRV) of the expeditioners was continuously measured for 24 hours to evaluate ANS activity. Plasma levels of catecholamines were tested by ELISA. Mood states were assessed by the Profile of Mood States (POMS) scale. Results: HRV analysis showed a disturbance of ANS during winter and summer periods. For frequency domain parameters, very low frequency (VLF), low frequency (LF), high frequency (HF), and total power (TP) significantly increased during the second half of the mission. Especially, LF/HF ratio decreased during summer, indicating the predominance of vagal tone. Results of the time domain analysis showed increased heart rate variability during the austral winter and summer. Plasma epinephrine (E) significantly increased during residence in Antarctica. Compared with pre-Antarctica, the vigor, depression, and anger scores of the expeditioners decreased significantly during the austral summer. Notably, the depression score showed a moderate positive correlation with LF/HF, while weak negative correlations with other HRV indicators, including TP, VLF, and LF. Anger score showed a moderate positive correlation with LF/HF and weak negative correlations with the average normal-to-normal (NN) interval, and the root mean square of differences between adjacent RR intervals (RMSSD). Plasma E level weakly correlated with the average NN interval. Conclusion: Prolonged residence in Antarctica increased the ANS activities and shifted the cardiac autonomic modulation towards vagal predominance. The alteration of HRV correlated with mood states and plasma epinephrine levels. [ABSTRACT FROM AUTHOR]

The third author's name is spelled incorrectly. The correct name is: Jiangchao Zhao. The correct citation is: Galena AE, Chai J, Zhao J, Bednarzyk M, Perez D, Ochrietor JD, et al. (2022) The effects of fermented vegetable consumption on the composition of the intestinal microbiota and levels of inflammatory markers in women: A pilot and feasibility study. PLoS ONE 17(10): e0275275. https://doi.org/10.1371/journal.pone.0275275.By Amy E. Galena; Jianmin Chai; Jiangchao Zhao; Michele Bednarzyk; Doreen Perez; Judith D. Ochrietor; Alireza Jahan-Mihan and Andrea Y. ArikawaReported by Author; Author; Author; Author; Author; Author; Author; Author [Extracted from the article]

Large differences in projected future annual precipitation increases in North America exists across 27 CMIP6 models under four emission scenarios. These differences partly arise from weak representations of land-atmosphere interactions. Here we demonstrate an emergent constraint relationship between annual growth rates of future precipitation and growth rates of historical temperature. The original CMIP6 projections show 0.49% (SSP126), 0.98% (SSP245), 1.45% (SSP370) and 1.92% (SSP585) increases in precipitation per decade. Combining observed warming trends, the constrained results show that the best estimates of future precipitation increases are more likely to reach 0.40–0.48%, 0.83–0.93%, 1.29–1.45% and 1.70–1.87% respectively, implying an overestimated future precipitation increases across North America. The constrained results also are narrow the corresponding uncertainties (standard deviations) by 13.8–31.1%. The overestimated precipitation growth rates also reveal an overvalued annual growth rates in temperature (6.0–13.2% or 0.12–0.37°C) and in total evaporation (4.8–14.5%) by the original models' predictions. These findings highlight the important role of temperature for accurate climate predictions, which is important as temperature from current climate models' simulations often still have systematic errors. [ABSTRACT FROM AUTHOR]

Influenza A viruses (IAVs) continue to pose a huge threat to public health, and their prevention and treatment remain major international issues. Neuraminidase (NA) is the second most abundant surface glycoprotein on influenza viruses, and antibodies to NA have been shown to be effective against influenza infection. In this study, we generated a monoclonal antibody (mAb), named FNA1, directed toward N1 NAs. FNA1 reacted with H1N1 and H5N1 NA, but failed to react with the NA proteins of H3N2 and H7N9. In vitro, FNA1 displayed potent antiviral activity that mediated both NA inhibition (NI) and blocking of pseudovirus release. Moreover, residues 219, 254, 358, and 388 in the NA protein were critical for FNA1 binding to H1N1 NA. However, further validation is necessary to confirm whether FNA1 mAb is indeed a good inhibitor against NA for application against H1N1 and H5N1 viruses. [ABSTRACT FROM AUTHOR]

Fuchs endothelial corneal dystrophy (FECD) is an age-related cause of vision loss, and the most common repeat expansion-mediated disease in humans characterised to date. Up to 80% of European FECD cases have been attributed to expansion of a non-coding CTG repeat element (termed CTG18.1) located within the ubiquitously expressed transcription factor encoding gene, TCF4. The non-coding nature of the repeat and the transcriptomic complexity of TCF4 have made it extremely challenging to experimentally decipher the molecular mechanisms underlying this disease. Here we comprehensively describe CTG18.1 expansion-driven molecular components of disease within primary patient-derived corneal endothelial cells (CECs), generated from a large cohort of individuals with CTG18.1-expanded (Exp+) and CTG 18.1-independent (Exp-) FECD. We employ long-read, short-read, and spatial transcriptomic techniques to interrogate expansion-specific transcriptomic biomarkers. Interrogation of long-read sequencing and alternative splicing analysis of short-read transcriptomic data together reveals the global extent of altered splicing occurring within Exp+ FECD, and unique transcripts associated with CTG18.1-expansions. Similarly, differential gene expression analysis highlights the total transcriptomic consequences of Exp+ FECD within CECs. Furthermore, differential exon usage, pathway enrichment and spatial transcriptomics reveal TCF4 isoform ratio skewing solely in Exp+ FECD with potential downstream functional consequences. Lastly, exome data from 134 Exp- FECD cases identified rare (minor allele frequency <0.005) and potentially deleterious (CADD>15) TCF4 variants in 7/134 FECD Exp- cases, suggesting that TCF4 variants independent of CTG18.1 may increase FECD risk. In summary, our study supports the hypothesis that at least two distinct pathogenic mechanisms, RNA toxicity and TCF4 isoform-specific dysregulation, both underpin the pathophysiology of FECD. We anticipate these data will inform and guide the development of translational interventions for this common triplet-repeat mediated disease. Author summary: Fuchs endothelial corneal dystrophy (FECD) leads to vision loss and is the most common repeat expansion-mediated disease characterised to date; most individuals with FECD harbour a non-coding CTG repeat expansion within the gene TCF4. FECD represents an important paradigm for other rare and devastating neurological repeat-mediated diseases, given its relatively mild and tissue-specific nature. Intriguingly, despite TCF4 being ubiquitously expressed, individuals with FECD only experience corneal disease, and the biological reason for this tissue-specificity remains elusive. Here, we use tissue from 31 individuals with FECD to perform complementary long-read, short-read and spatial transcriptomic analyses to enhance our understanding of mechanisms underpinning this disease. These data highlight that at least two mechanisms, RNA toxicity and TCF4 isoform dysregulation, underlie the disease state in affected corneal cells. Furthermore, TCF4 isoform skewing, with evidence of downregulation, suggests this mechanism in part may explain the unique vulnerability of the cornea. In addition, 7/134 FECD expansion negative cases were identified to harbour rare and potentially deleterious TCF4 variants, further supporting the hypothesis that dysregulation of TCF4 may be key to FECD pathophysiology. Biological insights presented here will guide the development of personalised FECD therapies and may inform the development of repeat-expansion mediated therapies more broadly. [ABSTRACT FROM AUTHOR]

Objective: The two commonly used diagnostic methods for taurodontism are susceptible to aging changes, mastication wear and other factors. Therefore, this study proposed an improved diagnostic method for taurodontism, and compared it with the previous two methods as a supplement for taurodontism diagnosis. Methods: The included patients were aged 10–89 years and admitted to the Department of Stomatology of Hebei Eye Hospital from June 1, 2022 to May 31, 2023. Eighty cone-beam computed tomography images were divided equally into 4 groups: 10–29, 30–49, 50–69, and 70–89 years old. The right mandibular first molars were selected as measurement objects. Firstly, |BD| and taurodontism index (TI)-related parameters were measured using Shifman and Chanannel's method and crown-body(CB) and root (R) lengths was measured by Seow and Lai's method. The improved method used the length from the cementoenamel junction(CEJ) to the root bifurcation point(body, B)and the root length(root, R)as the measurement objects. Finally, TI, CB/R ratios, and B/R ratios were calculated according to the formulas given below. One-way ANOVA analysis was mainly used to compare the differences in the values, indices and ratios of taurodontism among different age groups (p<0.05). Results: With the increase of age, |BD| and TI values decreased significantly (p<0.01). The CB/R ratios of 70–89 years group were significantly lower than those of the other three groups (p<0.01). Ratios derived from the improved method were significantly lower in the 70–89 years than in 10–29 years group (p<0.05). Conclusions: The |BD| and TI parameters proposed by Shifman and channel are significantly influenced by age. The measurements of Seow and Lai (CB/R ratios) were less affected by age compared with those of the former. The improved method(B/R ratios) was least affected by age, which would reduce error and bias in the measurement of taurodontism and obtain more objective results in older patients. [ABSTRACT FROM AUTHOR]

The expanding urbanization of coastal areas has led to increased ocean sprawl, which has had both physical and chemical adverse effects on marine and coastal ecosystems. To maintain the health and functionality of these ecosystems, it is imperative to develop effective solutions. One such solution involves the use of biodegradable polymers as bioactive coatings to enhance the bioreceptivity of marine and coastal infrastructures. Our study aimed to explore two main objectives: (1) investigate PHA-degrading bacteria on polymer-coated surfaces and in surrounding seawater, and (2) comparing biofilm colonization between surfaces with and without the polymer coating. We applied poly(3-hydroxybutyrate) [P(3HB)) coatings on concrete surfaces at concentrations of 1% and 6% w/v, with varying numbers of coating cycles (1, 3, and 6). Our findings revealed that the addition of P(3HB) indeed promoted accelerated biofilm growth on the coated surfaces, resulting in an occupied area approximately 50% to 100% larger than that observed in the negative control. This indicates a remarkable enhancement, with the biofilm expanding at a rate roughly 1.5 to 2 times faster than the untreated surfaces. We observed noteworthy distinctions in biofilm growth patterns based on varying concentration and number of coating cycles. Interestingly, treatments with low concentration and high coating cycles exhibited comparable biofilm enhancements to those with high concentrations and low coating cycles. Further investigation into the bacterial communities responsible for the degradation of P(3HB) coatings identified mostly common and widespread strains but found no relation between the concentration and coating cycles. Nevertheless, this microbial degradation process was found to be highly efficient, manifesting noticeable effects within a single month. While these initial findings are promising, it's essential to conduct tests under natural conditions to validate the applicability of this approach. Nonetheless, our study represents a novel and bio-based ecological engineering strategy for enhancing the bioreceptivity of marine and coastal structures. [ABSTRACT FROM AUTHOR]

The multikinase inhibitor sorafenib is the standard first-line treatment for advanced hepatocellular carcinoma (HCC), but many patients become sorafenib-resistant (SR). This study investigated the efficacy of another kinase inhibitor, regorafenib (Rego), as a second-line treatment. We produced SR HCC cells, wherein the PI3K-Akt, TNF, cAMP, and TGF-beta signaling pathways were affected. Acute Rego treatment of these cells reversed the expression of genes involved in TGF-beta signaling but further increased the expression of genes involved in PI3K-Akt signaling. Additionally, Rego reversed the expression of genes involved in nucleosome assembly and epigenetic gene expression. Weighted gene co-expression network analysis (WGCNA) revealed four differentially expressed long non-coding RNA (DElncRNA) modules that were associated with the effectiveness of Rego on SR cells. Eleven putative DElncRNAs with distinct expression patterns were identified. We associated each module with DEmRNAs of the same pattern, thus obtaining DElncRNA/DEmRNA co-expression modules. We discuss the potential significance of each module. These findings provide insights and resources for further investigation into the potential mechanisms underlying the response of SR HCC cells to Rego. [ABSTRACT FROM AUTHOR]

Biomechanical cue within the tissue microenvironment is known to play a critical role in regulating cell behaviors and maintaining tissue homeostasis. As hydrostatic pressure often increases in biliary system under pathological states, we investigated the effect of the moderate elevation of the hydrostatic pressure on biliary epithelial cells, especially on the epithelial-mesenchymal transition (EMT). Human intrahepatic biliary epithelial cells were loaded to hydrostatic pressure using a commercial device. We found that loading the cells to 50 mmHg hydrostatic pressure induced obvious morphological changes and significantly upregulated vimentin, ZEB1, and pSmad2/3, fibronectin, and collagen 1α. All changes induced by hydrostatic pressure loading were effectively mitigated by either ROCK inhibitor (Y-27632) or ALK5 inhibitor (SB-431542). Our in vitro experimental data suggests that hydrostatic pressure loading induces EMT of cholangiocytes through RhoA/ROCK and TGF-β/Smad pathways. Elevated hydrostatic pressure in biliary duct system under pathological states may promote the biliary epithelial cells shifting to profibrotic and mesenchymal characteristics. [ABSTRACT FROM AUTHOR]

Background: The Compeer Model, which was originally designed to match individuals recovering from mental illness with volunteers from their community, served as the basis for the development of the buddy program. However, limited research was available related to the buddy program among older adults in a Malaysian context. Aim: The study aimed to identify the effectiveness of the buddy program training module to enhance the daily living function, social participation and emotional status of older adults in residential aged care homes. Methods: A quasi-experimental study was conducted with 30 pairs of buddies and older adults for both the experimental group and control group in two randomly selected residential aged care homes. The buddies in the experimental group received the buddy program training module related to activities of daily living (basic and instrumental) while the buddy-older adults pairs in the control group continued to perform their usual daily life activities in residential aged care homes. Baselines were performed before intervention and at eight weeks post-intervention. Results: Over the eight weeks, for the older adults in the experimental group, there was a significant main effect of time after the intervention on BADL (p = 0.010). There were no significant interaction effects for the experiment group and control group on IADL and social participation. Also, there were no significant interaction effects for all domains in emotional status: depression, anxiety and stress. For buddies, there was a significant interaction effect for depression (p = 0.045) in the control group. Conclusions: The buddy program training module can be used as a guideline for older adults with more significant disabilities in residential aged care homes in managing activities of daily living. Future studies could be implemented to explore the intergenerational buddy program among older adults and young children in the community. [ABSTRACT FROM AUTHOR]

Researchers conducted an investigation by tornado simulator to study the impact of wind angle on the aerodynamic characteristics of a reduced (1:150) high-speed train model using six-dimensional force/torque sensor. The reduced scale model size can match the relative size relationship between high-speed train and tornado vortex core in real condition. Results show that the wind angle affects the mean value and standard deviation of the force and moment coefficient of the high-speed train at the same radial position. The variations of the mean value and standard deviation of the pitching moment coefficient of the high-speed train carriage model at 60°and 90°are different from that at other wind angles. The variations of the mean value of the pitching moment coefficient of the high-speed train head model at 0°, 15°and 30°are different from that at other wind angles. The variations of the standard deviation of the pitching moment coefficient of the high-speed train head model at 60°,75°and 90°are different from that at other wind angles. This research will help the further study of the operation safety of high-speed train in the event of a tornado impacting a high-speed train network. [ABSTRACT FROM AUTHOR]

Introduction: Healthcare utilization often favors the higher-socioeconomic status (SES) and having chronic diseases may exacerbate this inequality. This study aims to examine the trends in health service use over time, the effect of SES on healthcare utilization, and the role of chronic diseases in this association. Methods: Data used in this study were from the China Health and Retirement Longitudinal Study (CHARLS) in 2011, 2013, 2015, and 2018, which is the first nationally representative survey of the middle-aged and older. The sample included people aged 45 years and older who responded to all the waves. A total of 10,922 adults were included in this study. Healthcare utilization was categorized into outpatient and inpatient service use and SES was measured by per-capita household expenditure. A multilevel zero-inflated negative binomial regression model was performed to analyze outpatient and inpatient service use, separately. Results: The rates of outpatient service use in 2011, 2013, 2015, and 2018 were 19.11%, 21.45%, 20.12%, and 16.32%, respectively, while the rates of inpatient service use were 8.40%, 13.04%, 14.17%, and 18.79%, respectively. Compared to individuals in the lowest quintile of per-capita household expenditure, those in higher quintiles had higher odds of outpatient service use (Q2: odds ratio = 1.233, p < 0.0001; Q3: 1.416, p < 0.0001; Q4: 1.408, p < 0.0001; or Q5: 1.439, p < 0.0001) and higher rates of inpatient service use (Q2: incidence rate ratio = 1.273, p < 0.0001; Q3: 1.773, p < 0.0001; Q4: 2.071, p < 0.0001; or Q5: 1.992, p < 0.0001). Additionally, having morbidity generally increased healthcare utilization, but did not play a significant role in moderating the relationship between SES and healthcare utilization. Conclusions: Healthcare utilization rates were overall low in China, but relatively high for people in higher quintiles of per-capita household expenditure or those with morbidity, compared to their counterparts. Policy actions are required to provide more health education to the public, to further optimize health insurance schemes targeting outpatient services, especially for the low-SES, and to establish new health delivery models for NCD management in the primary health care setting. [ABSTRACT FROM AUTHOR]

Purpose: To investigate human corneal epithelial cell and fibroblast migration and growth factor secretion after rose bengal photodynamic therapy (RB-PDT) and the effect of conditioned medium (CM). Methods: A human corneal epithelial cell line (HCE-T), human corneal fibroblasts (HCF) and keratoconus fibroblasts (KC-HCF) have been used. Twenty-four hours after RB-PDT (0.001% RB concentration, 565 nm wavelength illumination, 0.17 J/cm2 fluence) cell migration rate using scratch assay and growth factor concentrations in the cell culture supernatant using ELISA have been determined. In addition, the effect of CM has been observed. Results: RB-PDT significantly reduced migration rate in all cell types, compared to controls (p≤0.02). Migration rate of HCE-T cultures without RB-PDT (untreated) was significantly higher using HCF CM after RB-PDT, than using HCF CM without RB-PDT (p<0.01). Similarly, untreated HCF displayed a significantly increased migration rate with HCE-T CM after RB-PDT, compared to HCE-T CM without treatment (p<0.01). Furthermore, illumination alone and RB-PDT significantly decreased keratinocyte growth factor (KGF) concentration in HCF and KC-HCF supernatant, and RB-PDT significantly decreased soluble N-Cadherin (SN-Cad) concentration in HCF supernatant, compared to controls (p<0.01 for all). In HCE-T CM, RB-PDT increased hepatocyte growth factor (HGF) and basic fibroblast growth factor (FGFb) concentration (p≤0.02), while decreasing transforming growth factor β (TGF-β) concentration (p<0.01). FGFb concentration increased (p<0.0001) and TGF-β concentration decreased (p<0.0001) in HCF CM, by RB-PDT. Epidermal growth factor (EGF), HGF, and TGF-β concentration decreased (p≤0.03) and FGFb concentration increased (p<0.01) in KC-HCF CM, using RB-PDT. Conclusions: HCE-T, HCF and KC-HCF migration rate is reduced 24 hours after RB-PDT. In contrast, HCE-T migration is enhanced using HCF CM after RB-PDT, and HCF migration rate is increased through HCE-T CM following RB-PDT. Modulation of EGF, KGF, HGF, FGFb, TGF-β and N-Cadherin secretion through RB-PDT may play an important role in corneal wound healing. [ABSTRACT FROM AUTHOR]

The spatial spillover of urban innovation has increasingly become an important factor affecting urban total factor productivity (TFP) growth. Based on the panel data of 108 cities in the Yangtze River Economic Belt from 2004 to 2020, this paper illustrates the spatial-temporal evolution trend of urban innovation and manufacturing total factor productivity and uses the spatial Dubin model to study the direct and indirect effects of urban innovation on manufacturing total factor productivity. The main conclusions are as follows:(1)Spatial correlation and heterogeneity between urban innovation and manufacturing total factor productivity prove to be significant in the Yangtze River Economic Belt;(2)Urban innovation has a significant positive impact on manufacturing total factor productivity and has a positive spillover effect on surrounding cities; (3)The effect of urban innovation on manufacturing total factor productivity varies with time and region;(4) Mechanism analysis shows that talent agglomeration significantly promotes the positive impact of urban innovation on manufacturing total factor productivity, while the spillover effect is insignificant. [ABSTRACT FROM AUTHOR]

During COVID-19 pandemic several public health measures were implemented by diverse countries to reduce the risk of COVID-19, including social distancing. Here we collected the minimal distance recommended by each country for physical distancing at the onset of the pandemic and aimed to examine whether it had an impact on the outbreak dynamics and how this specific value was chosen. Despite an absence of data on SARS-CoV-2 viral transmission at the beginning of the pandemic, we found that most countries recommended physical distancing with a precise minimal distance, between one meter/three feet and two meters/six feet. 45% of the countries advised one meter/three feet and 49% advised a higher minimal distance. The recommended minimal distance did not show a clear correlation with reproduction rate nor with the number of new cases per million, suggesting that the overall COVID-19 dynamics in each country depended on multiple interacting factors. Interestingly, the recommended minimal distance correlated with several cultural parameters: it was higher in countries with larger interpersonal distance between two interacting individuals in non-epidemic conditions, and it correlated with civil law systems, and with currency. This suggests that countries which share common conceptions such as civil law systems and currency unions tend to adopt the same public health measures. [ABSTRACT FROM AUTHOR]

Background: Healthcare workers (HCWs) are at increased risk of tuberculosis infection (TBI). We estimated the prevalence and incidence of TBI and risk factors among HCWs in Bangladeshi hospitals to target TB infection prevention and control (IPC) interventions. Methods: During 2013–2016, we conducted a longitudinal study among HCWs in four chest disease hospitals. At baseline, we administered a questionnaire on sociodemographic and occupational factors for TB, tuberculin skin tests (TST) in all hospitals, and QuantiFERON ®-TB Gold in-Tube (QFT-GIT) tests in one hospital. We assessed factors associated with baseline TST positivity (induration ≥10mm), TST conversion (induration increase ≥10mm from baseline), baseline QFT-GIT positivity (interferon-gamma ≥0.35 IU/mL), and QFT-GIT conversion (interferon-gamma <0.35 IU/mL to ≥0.35 IU/mL). We included factors with a biologically plausible relationship with TBI identified in prior studies or having an association (p = <0.20) in the bivariate analyses with TST positivity or QFT-GIT positivity in multivariable generalized linear models. The Kaplan-Meier was used to estimate the cumulative TBI incidence rate per 100 person-years. Results: Of the 758 HCWs invited, 732 (97%) consented to participate and 731 completed the one-step TST, 40% had a positive TST result, and 48% had a positive QFT-GIT result. In multivariable models, HCWs years of service 11–20 years had 2.1 (95% CI: 1.5–3.0) times higher odds of being TST-positive and 1.6 (95% CI 1.1–2.5) times higher odds of QFT-GIT-positivity at baseline compared with those working ≤10 years. HCWs working 11–20 years in pulmonary TB ward had 2.0 (95% CI: 1.4–2.9) times higher odds of TST positivity, and those >20 years had 2.5 (95% CI: 1.3–4.9) times higher odds of QFT-GIT-positivity at baseline compared with those working <10 years. TBI incidence was 4.8/100 person-years by TST and 4.2/100 person-years by QFT-GIT. Females had 8.5 (95% CI: 1.5–49.5) times higher odds of TST conversion than males. Conclusions: Prevalent TST and QFT-GIT positivity was associated with an increased number of years working as a healthcare worker and in pulmonary TB wards. The incidence of TBI among HCWs suggests ongoing TB exposure in these facilities and an urgent need for improved TB IPC in chest disease hospitals in Bangladesh. [ABSTRACT FROM AUTHOR]

Background: Migraine is a primary neurological headache. Treatment of this condition includes medications; however, these medications, when given for a longer duration, can have side effects. If migraine is left untreated or undiagnosed, it is reported that around 2.5% of individuals with migraine may develop to have a chronic condition. This study aims to analyse the preliminary effectiveness of aerobic training on migraine pain level, sleep quality, quality of life, and resting-state brain waves among university students with migraine symptoms. Methodology: 88 university students with migraine symptoms are the target participants. 4 of 5 on the Migraine Screen Questionnaire, 5 of 7 on the International Classification of Headache Disorders 3rd edition (ICHD-3), and both genders aged 18–40 years will be included. The participants with a score of more than or equal to 5 on the visual aura rating scale, diagnosed with a secondary headache, pregnancy, medication for neurological and cardiorespiratory conditions, and unwilling to participate will be excluded. Based on the disability questionnaire, the participants will be randomly assigned to either of the three groups. The primary outcome is resting-state electroencephalography (EEG) brain, and the secondary outcomes are sleep quality, quality of life, and migraine pain level. The post-test assessments will be performed at week 6. Result: After the primary EEG analysis using MATLAB, the amplitude, frequency, frequency band ratio, and power spectrum density will be analysed. Mixed design analysis and intention-to-treat analysis will be used to assess the efficacy of aerobic training. Discussion: Migraines can be unpredictable, sometimes occurring without symptoms. If underdiagnosed or over-looked, it encompasses a serious of long-term effects. Hence with appropriate intervention, the symptoms can be prevented from worsening. But there is an unmet need for evidence-based non-pharmacological approaches to complement pharmacotherapy in migraine prevention. Moreover, an exercise intervention may be more suitable for people with migraine considering their tendency toward inactivity. Although some studies developed exercise programs for untrained patients with migraine, the outcome was primarily in terms of exercise capacity rather than the primary characteristics and secondary brain wave/ sleep quality changes, indicating the need for this study. [ABSTRACT FROM AUTHOR]

This study investigated the potential impacts of depressive rats' maternal behavior as an early life stress on the outcome of offspring as an adulthood. Offspring from the same mother were divided into two groups, half of them were fostered or remained by a depressive mother, and the other half remained or fostered by a control mother, respectively. The results showed that offspring fostered by depressive mothers presented significant depressive behaviors. Meanwhile, depressive mothers engaged in more grooming during the light cycle, but less off-the-pup behavior during the dark phase. In conclusion, offspring exposed to a postnatal depressive maternal environment developed a depressive-like behavior. Contrarily, postpartum maternal behaviors play an essential role, which might determine the outcome of the next generation. Furthermore, the appropriate timing of postpartum maternal caring sequences, which might eliminate prenatal stressful influences, was recognized and might be a promising approach for reducing children's predisposition to mental disorders in their life time. [ABSTRACT FROM AUTHOR]

RNA viruses cause numerous infectious diseases in humans and animals. The crosstalk between RNA viruses and the innate DNA sensing pathways attracts increasing attention. Recent studies showed that the cGAS-STING pathway plays an important role in restricting RNA viruses via mitochondria DNA (mtDNA) mediated activation. However, the mechanisms of cGAS mediated innate immune evasion by RNA viruses remain unknown. Here, we report that seneca valley virus (SVV) protease 3C disrupts mtDNA mediated innate immune sensing by cleaving porcine cGAS (pcGAS) in a species-specific manner. Mechanistically, a W/Q motif within the N-terminal domain of pcGAS is a unique cleavage site recognized by SVV 3C. Three conserved catalytic residues of SVV 3C cooperatively contribute to the cleavage of pcGAS, but not human cGAS (hcGAS) or mouse cGAS (mcGAS). Additionally, upon SVV infection and poly(dA:dT) transfection, pcGAS and SVV 3C colocalizes in the cells. Furthermore, SVV 3C disrupts pcGAS-mediated DNA binding, cGAMP synthesis and interferon induction by specifically cleaving pcGAS. This work uncovers a novel mechanism by which the viral protease cleaves the DNA sensor cGAS to evade innate immune response, suggesting a new antiviral approaches against picornaviruses. Author summary: While the effect of cGAS on counteracting DNA viruses has been extensively studied, how cGAS restricts RNA viruses and how RNA viruses combat cGAS-mediated immune surveillance are largely unknown. Here, we show that picornavirus, seneca valley virus (SVV), infection causes the leakage of mitochondrial DNA into cytosol for cGAS activation, while SVV 3C protease cleaves porcine cGAS (pcGAS) in a species-specific manner to disrupt pcGAS-mediated DNA sensing, cGAMP synthesis and interferon induction. Importantly, we identify a W/Q motif within the N-terminal domain of pcGAS, which is unique among other species for SVV 3C cleavage. Three conserved catalytic residues of SVV 3C cooperatively contribute to the cleavage of pcGAS. These findings unravel a novel strategy for viral evasion of cGAS-mediated innate restriction. [ABSTRACT FROM AUTHOR]

This paper proposes a novel hybrid algorithm, named Multi-Strategy Hybrid Harris Hawks Tunicate Swarm Optimization Algorithm (MSHHOTSA). The primary objective of MSHHOTSA is to address the limitations of the tunicate swarm algorithm, which include slow optimization speed, low accuracy, and premature convergence when dealing with complex problems. Firstly, inspired by the idea of the neighborhood and thermal distribution map, the hyperbolic tangent domain is introduced to modify the position of new tunicate individuals, which can not only effectively enhance the convergence performance of the algorithm but also ensure that the data generated between the unknown parameters and the old parameters have a similar distribution. Secondly, the nonlinear convergence factor is constructed to replace the original random factor c1 to coordinate the algorithm's local exploitation and global exploration performance, which effectively improves the ability of the algorithm to escape extreme values and fast convergence. Finally, the swarm update mechanism of the HHO algorithm is introduced into the position update of the TSA algorithm, which further balances the local exploitation and global exploration performance of the MSHHOTSA. The proposed algorithm was evaluated on eight standard benchmark functions, CEC2019 benchmark functions, four engineering design problems, and a PID parameter optimization problem. It was compared with seven recently proposed metaheuristic algorithms, including HHO and TSA. The results were analyzed and discussed using statistical indicators such as mean, standard deviation, Wilcoxon's rank sum test, and average running time. Experimental results demonstrate that the improved algorithm (MSHHOTSA) exhibits higher local convergence, global exploration, robustness, and universality than BOA, GWO, MVO, HHO, TSA, ASO, and WOA algorithms under the same experimental conditions. [ABSTRACT FROM AUTHOR]

Objectives: Family caregivers play a fundamental role in the care of the older blunt trauma patient. We aim to identify risk factors for negative and positive experiences of caregiving among family caregivers. Design: Prospective, nationwide, multi-center cohort study. Setting and participants: 110 family caregivers of Singaporeans aged≥55 admitted for unintentional blunt trauma with an Injury Severity Score (ISS) or New Injury Severity Score (NISS)≥10 were assessed for caregiving-related negative (disturbed schedule and poor health, lack of family support, lack of finances) and positive (esteem) experiences using the modified-Caregiver Reaction Assessment (m-CRA) three months post-injury. Methods: The association between caregiver and patient factors, and the four m-CRA domains were evaluated via linear regression. Results: Caregivers of retired patients and caregivers of functionally dependent patients (post-injury Barthel score <80) reported a worse experience in terms of disturbed schedule and poor health (β-coefficient 0.42 [95% Confidence Interval 0.10, 0.75], p =.01; 0.77 [0.33, 1.21], p =.001), while male caregivers and caregivers who had more people in the household reported a better experience (-0.39 [-0.73, -0.06], p =.02; -0.16 [-0.25, -0.07], p =.001). Caregivers of male patients, retired patients, and patients living in lower socioeconomic housing were more likely to experience lack of family support (0.28, [0.03, -0.53], p =.03; 0.26, [0.01, 0.52], p =.05; 0.34, [0.05, -0.66], p =.02). In the context of lack of finances, caregivers of male patients and caregivers of functionally dependent patients reported higher financial strain (0.74 [0.31, 1.17], p =.001; 0.84 [0.26, 1.43], p =.01). Finally, caregivers of male patients reported higher caregiver esteem (0.36 [0.15, 0.57], p =.001). Conclusions and implications: Negative and positive experiences of caregiving among caregivers of older blunt trauma patients are associated with pre-injury disability and certain patient and caregiver demographics. These factors should be considered when planning the post-discharge support of older blunt trauma patients. [ABSTRACT FROM AUTHOR]

Conservation of crop wild relatives is critical for plant breeding and food security. The lack of clarity on the genetic factors that lead to endangered status or extinction create difficulties when attempting to develop concrete recommendations for conserving a citrus wild relative: the wild relatives of crops. Here, we evaluate the conservation of wild kumquat (Fortunella hindsii) using genomic, geographical, environmental, and phenotypic data, and forward simulations. Genome resequencing data from 73 accessions from the Fortunella genus were combined to investigate population structure, demography, inbreeding, introgression, and genetic load. Population structure was correlated with reproductive type (i.e., sexual and apomictic) and with a significant differentiation within the sexually reproducing population. The effective population size for one of the sexually reproducing subpopulations has recently declined to ~1,000, resulting in high levels of inbreeding. In particular, we found that 58% of the ecological niche overlapped between wild and cultivated populations and that there was extensive introgression into wild samples from cultivated populations. Interestingly, the introgression pattern and accumulation of genetic load may be influenced by the type of reproduction. In wild apomictic samples, the introgressed regions were primarily heterozygous, and genome-wide deleterious variants were hidden in the heterozygous state. In contrast, wild sexually reproducing samples carried a higher recessive deleterious burden. Furthermore, we also found that sexually reproducing samples were self-incompatible, which prevented the reduction of genetic diversity by selfing. Our population genomic analyses provide specific recommendations for distinct reproductive types and monitoring during conservation. This study highlights the genomic landscape of a wild relative of citrus and provides recommendations for the conservation of crop wild relatives. Author summary: Conservation genomics offers a comprehensive approach to understand the underlying genetic and environmental factors affecting the conservation of species. Despite its importance, the conservation genomics of most crop wild relatives remains poorly understood. In this study, we investigated the population fragmentation, inbreeding, gene flow, and genetic load of a citrus wild relative, Fortunella hindsii, using a combination of genomic, geographical, environmental, and phenotypic data, as well as forward simulations. Fortunella hindsii, listed on the registry of National Key Protected Wild Plants in China, has two types of reproduction, sexual and apomictic. Conservation genomics provided insights into the genetic diversity and structure, which are critical for developing effective conservation strategies. Our analysis also helped to assess the risks of hybridization and introgression from cultivated to wild populations. We found that different patterns of introgression and genetic load may be influenced by reproductive type; for example, deleterious variants may hide in the heterozygous state in apomictic populations. Sexually reproducing samples with the self-incompatibility mechanism can prevent rapid loss of genetic diversity caused by selfing. This study serves as an example of conservation genomics and the importance of utilizing important wild relatives of crops to inform broader conservation efforts. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to evaluate the performance of the D-index, a calculated measure of neutropenic burden, in predicting the risk of invasive fungal infections (IFIs) in acute myeloid leukemia (AML) patients. Methods: A retrospective study of adult AML patients who received the first induction chemotherapy and developed febrile neutropenia was conducted. Clinical characteristics, laboratory data, and the calculation of the D-index and cumulative D-index (c-D-index) were collected and analyzed between patients with and without IFIs. Results: A total of 101 patients were included, with 16 (15.8%) patients who developed IFIs. Clinical characteristics, antifungal prophylaxis, and AML cytogenetic risk were similar between patients with or without IFIs. The results showed that the D-index and c-D-index were more effective in predicting IFIs than the duration of neutropenia. With the D-index cutoff of 7083, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 81.3%, 83.5%, 48.2%, and 95.9%, respectively. c-D-index at 5625 revealed sensitivity, specificity, PPV, and NPV for IFIs of 68.8%, 68.2%, 28.9%, and 92.1%, respectively. Using this cutoff of c-D-index, patients without IFIs were overtreated with an antifungal regimen in 45 (52.9%) cases. Conclusion: The D-index and c-D-index were helpful indicators for defining the risk of IFIs in AML patients with febrile neutropenia. [ABSTRACT FROM AUTHOR]

Background: The coronavirus disease 2019 (COVID-19) pandemic has resulted in changes in lifestyle habits and experiences of mental health outcomes, some of which were possibly related to weight gain, leading to an increase in the prevalence of obesity, which is associated with the development of several severe diseases. Concerns regarding weight gain and its impact on health outcomes are prevalent worldwide, with obesity being one of the highest causes of mortality in current society. Methods: A self-reported questionnaire collected data from participants aged 18 years of age and above from 26 countries and regions worldwide. Post-hoc multiple logistic regression analyses have been done to evaluate the association between demographic and socioeconomic factors, and the perspectives that were identified to be associated with weight gain. Results: Participants belonging to a younger age group; with a higher level of education; living in an urban area; living with family members; employed full-time; and had obesity were found to be more vulnerable to weight gain. After adjusting for socio-demographic factors, participants who were quarantined; exercised less prior to the pandemic; consumed unhealthy foods; and reported negative thoughts such as helplessness and the perceived risk of COVID-19, were more likely to experience weight gain; while negative thoughts such as having no means of control over the COVID-19 pandemic and the consequences of the COVID-19 pandemic will have great personal effect were associated with females, students, and people living in the rural area. Conclusions: Weight gain risk during the pandemic was significantly associated with certain socio-demographic and COVID-19 related factors. To improve public health outcomes, future research should conduct a longitudinal evaluation on the effects of COVID-19 experiences upon health choices. Streamlined mental support should also be provided to the vulnerable groups which were prone to negative thoughts that were associated with weight gain. [ABSTRACT FROM AUTHOR]

Stimulator-of-interferon gene (STING) is a vital element of the innate immune system against DNA viruses. Optimal activation of STING is crucial for maintaining immune homeostasis and eliminating invading viruses, and the oligomerization of STING is an essential prerequisite for STING activation. However, the mechanism of cGAMP-induced STING oligomerization in ER remains unclear. Selenoproteins are crucial for various physiological processes. Here, we identified that the endoplasmic reticulum (ER)-located transmembrane selenoprotein K (SELENOK) was induced during virus infection and facilitated innate immune responses against herpes simplex virus-1 (HSV-1). Mechanistically, SELENOK interacts with STING in the ER and promotes STING oligomerization, which in turn promotes its translocation from the ER to the Golgi. Consequently, Selenok deficiency suppresses STING-dependent innate responses and facilitates viral replication in vivo. Thus, the control of STING activation by selenium-mediated SELENOK expression will be a priming therapeutic strategy for the treatment of STING-associated diseases. Author summary: Selenoproteins are crucial for various physiological processes. Most selenoproteins locate in the cytoplasm and regulate redox pathways to protect cells from oxidative stress. However, the potential roles of transmembrane selenoproteins are largely unknown. Here, we identified Selenoprotein K (SELENOK), an ER-located transmembrane selenoprotein, as a physiological enhancer of STING-dependent antiviral innate immunity. SELENOK is upregulated during viral infection and enhances STING oligomerization to facilitate the activation of the cGAS-STING pathway and suppress viral replication. These results will be valuable for understanding the physiological roles of transmembrane selenoproteins in immunity. Furthermore, as aberrant STING activation has been linked to various pathological conditions, control of STING activity by SELENOK may be a prime therapeutic strategy. [ABSTRACT FROM AUTHOR]

Background: Intracranial hemorrhage (ICH) is the most devastating complication of recombinant tissue plasminogen activator (rtPA) treatment in acute ischemic stroke patients. Data on rtPA-associated asymptomatic ICH (aICH) are limited. Objectives: To determine the incidence, risk factors, characteristics, management, and clinical outcome of rtPA-associated aICH. Methods: The data were retrieved from the Chiang Mai University Hospital Stroke Registry between 1995 and 2019. Consecutive ischemic stroke patients were included if they were 18 or older and received rtPA. Study outcomes were the incidence and characteristics of aICH, management, 90-day modified Rankin scale (mRS), National Institute of Health Stroke Scale (NIHSS), Barthel index, and all-cause mortality. Results: Of 725 rtPA treated patients, 166 (16.0%, 95% confidence interval [CI] 13.4–18.9) had aICH, 50 (6.9%, 95% CI 5.2–9.0) had symptomatic ICH (sICH). Patients with aICH had more hemorrhagic infarctions (HI) compared to sICH (81.9% vs 2.0%, P-value < 0.001). Fresh Frozen Plasma and cryoprecipitate were the most common blood products used to reverse the anticoagulant effect in sICH. Craniotomy was performed in 1% and 60% of patients who had aICH and sICH. At 90 days, patients who had aICH had poorer clinical outcomes (mRS, NIHSS and Barthel index) as compared to those without ICH. Compared to non-ICH patients, aICH patients were associated with increased risk of 90-day mortality, the hazard ratio (HR), 3.7, 95% CI 1.6–8.9. Conclusions: The rtPA-associated aICH increased the risk of morbidity and mortality outcomes. Further treatment consensus, guideline generation, or clinical trials focusing on the treatment of rtPA-associated aICH may be required. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and poor prognosis. Emerging evidence suggests that epigenetic alterations play a crucial role in HCC, suggesting epigenetic inhibition as a promising therapeutic approach. Indeed, the bromodomain and extra-terminal (BET) inhibitors inhibit the proliferation and invasion of various cancers but still lack a strong mechanistic rationale. Here, we identified the differentially expressed mRNAs (DEmRNAs) and lncRNAs (DElncRNAs) in human HCC cell line HepG2 treated with the BET inhibitors, JQ1, OTX015, or ABBV-075. We analyzed the correlation between DEmRNAs and DElncRNAs in common for the three inhibitors based on their expression profiles and performed functional annotation pathway enrichment analysis. Most of these shared DEmRNAs and DElncRNAs, including some novel transcripts, were downregulated, indicating decreased proliferation/adhesion and increased apoptosis/inflammation. Our study suggests that BET proteins play a crucial role in regulating cancer progression-related genes and provide a valuable resource for novel putative biomarkers and therapeutic targets in HCC. [ABSTRACT FROM AUTHOR]

Objective: To compare two agents that can induce a rat model of temporomandibular joint osteoarthritis (TMJOA) by chemical induction: monosodium iodoacetate (MIA) and collagenase type 2 (Col-2). We wished to ascertain the best agent for assessing drug-delivery systems (DDSs). Method: Male Wistar rats underwent intra-articular injection with MIA or Col-2. They were manipulated for 30 days. The head withdrawal threshold (HWT), immunohistological assessment, and positron emission tomography (PET) were used to evaluate the relevance of our models. Results: For both the MIA and Col-2 groups, pain persisted for 30 days after injection. Change in the HWT showed that Col-2 elicited a strong action initially that decreased progressively. MIA had a constant action upon pain behavior. Histology of TMJ tissue from both groups showed progressive degradation of TMJ components. Conclusions: MIA and Col-2 induced orofacial pain by their local chemical action on TMJs. However, based on a prolonged and greater sustained effect on the pain threshold, persistent histological changes, and imaging results, MIA appeared to be more suitable for creation of a rat model of TMJOA for the study of DDSs. [ABSTRACT FROM AUTHOR]

In order to expand the high added value of waste chilli stems and the recycling of green resources, cellulose in chilli stems was extracted by nitric acid–ethanol method, and nanocellulose was prepared by sulfuric acid hydrolysis method. The results showed that the cellulose content was between 15% and 34.5%. Under the optimum experimental conditions of 60% sulfuric acid concentration, 60°C reaction temperature and 120 min reaction time, the average yield of nanocellulose was 36.42% ±1.36%. Prepared cellulose and nanocellulose had been characterized using scanning electron microscopy, fourier-transform infrared, and x-ray diffraction analysis. The research indicated that the biscuits with acceptable overall quality could be prepared by using the dosage of nanocellulose (7%), and the corresponding biscuits had regular appearance and relatively smooth surface. The total dietary fiber content was positively correlated with different nanocellulose content. Through mice experiments, it was found that the consumption of biscuits containing nanocellulose could significantly reduce the food intake of mice and inhibit the weight growth of mice. Therefore, the research showed that whole wheat biscuits with nanocellulose could be regarded as food rich in dietary fiber. These results provided a basis for exploring the green resource recycling of chilli stems in food processing. [ABSTRACT FROM AUTHOR]

Background: Despite the conflicting data, the positivity of antiphospholipid antibodies (aPL) in cancer patients may be associated with an increased risk of thrombosis. Objective: To identify the prevalence and impact of aPL on venous thromboembolic events (VTE) and arterial thrombosis (ATE) in ambulatory cancer patients Methods: In this single-center, prospective cohort study, we enrolled newly diagnosed ambulatory cancer patients receiving chemotherapy. Non-cancer controls were age- and sex-matched. Participants were evaluated for aPL. Primary outcomes were the composite outcome of VTE or ATE and the prevalence of aPL positivity in cancer patients. Secondary outcomes included the risk of VTE and ATE in cancer patients and all-cause mortality at six-month follow-up duration. Results: There were 137 cases and 137 controls with mean age of 56.0±12.3 and 55.5±12.1 years, respectively. Cancer patients were more likely to have positive aPL compared to controls, with the risk difference of 9.4% (95%CI 1.5 to 17.5). Composite of ATE or VTE occurred in 9 (6.6%) in cancer patients and 2 (1.5%) in controls. Cancer patients with aPL positivity were associated with higher risk of ATE or VTE (risk ratio [RR] 3.6, 95% CI 1.04–12.4). Positive LA in cancer patients were associated with higher risk of composites of ATE or VTE (RR 5.3 95%CI 1.3–21.0), whereas the anti-β2-GPI positivity were associated with increased risk of VTE (RR 4.7, 95%CI 1.1–19.2). Conclusion: aPL was more prevalent in active cancer patients and positive aPL in cancer patients was associated with arterial or venous thrombosis. [ABSTRACT FROM AUTHOR]

COVID-19, as a global health crisis, has triggered the fear emotion with unprecedented intensity. Besides the fear of getting infected, the outbreak of COVID-19 also created significant disruptions in people's daily life and thus evoked intensive psychological responses indirect to COVID-19 infections. In this study, we construct a panel expressed fear database tracking the universe of social media posts (16 million) generated by 536 thousand individuals between January 1st, 2019 and August 31st, 2020 in China. We employ deep learning techniques to detect expressions of fear emotion within each post, and then apply topic model to extract the major topics of fear expressions in our sample during the COVID-19 pandemic. Our unique database includes a comprehensive list of topics, not being limited to post centering around COVID-19. Based on this database, we find that sleep disorders ("nightmare" and "insomnia") take up the largest share of fear-labeled posts in the pre-pandemic period (January 2019-December 2019), and significantly increase during the COVID-19. We identify health and work-related concerns are the two major sources of non-COVID fear during the pandemic period. We also detect gender differences, with females having higher fear towards health topics and males towards monetary concerns. Our research shows how applying fear detection and topic modeling techniques on posts unrelated to COVID-19 can provide additional policy value in discerning broader societal concerns during this COVID-19 crisis. [ABSTRACT FROM AUTHOR]

Due to different nucleotide preferences at target sites, no single Cas9 is capable of editing all sequences. Thus, this highlights the need to establish a Cas9 repertoire covering all sequences for efficient genome editing. Cas9s with simple protospacer adjacent motif (PAM) requirements are particularly attractive to allow for a wide range of genome editing, but identification of such Cas9s from thousands of Cas9s in the public database is a challenge. We previously identified PAMs for 16 SaCas9 orthologs. Here, we compared the PAM-interacting (PI) domains in these orthologs and found that the serine residue corresponding to SaCas9 N986 was associated with the simple NNGG PAM requirement. Based on this discovery, we identified five additional SaCas9 orthologs that recognize the NNGG PAM. We further identified three amino acids that determined the NNGG PAM requirement of SaCas9. Finally, we engineered Sha2Cas9 and SpeCas9 to generate high-fidelity versions of Cas9s. Importantly, these natural and engineered Cas9s displayed high activities and distinct nucleotide preferences. Our study offers a new perspective to identify SaCas9 orthologs with NNGG PAM requirements, expanding the Cas9 repertoire. Due to different nucleotide preferences at target sites, no single Cas9 is capable of editing all sequences. This study identifies variants in the PAM-interacting domain of natural SaCas9 orthologs that recognize a simple NNGG PAM, and demonstrates that introducing these variants can confer NNGG PAM recognition, expanding the Cas9 repertoire. [ABSTRACT FROM AUTHOR]

Background: The prevailing consensus from large epidemiological studies is that breastfeeding is associated with improved IQ and cognitive functioning in later childhood and adolescence. Current research is exploring the association between breastfeeding and early brain development in preterm infants. Objective: To explore the differences in brain gray matter between breastmilk-fed and formula-fed preterm infants using structural and functional magnetic resonance imaging. Methods: A convenience sample of breastmilk-fed preterm infants(n = 34) and formula-fed infants (n = 22) aged approximately 32 weeks. At near term-equivalent age, MR scanning was performed. Gray matter structural and functional differences between the two groups were assessed using MATLAB software for voxel-based morphometry (VBM) and amplitude of low-frequency fluctuation (ALFF) analysis. Results: Maternal and neonatal demographic characteristics showed no significant difference between the two groups. Breastmilk-fed infants had greater regional gray matter volume on MRI than formula-fed infants in multiple brain regions, including the bilateral frontal lobe (BA11, BA46), right temporal lobe (BA37), and left caudate nucleus, at a statistical threshold of p<0.01 (AlphaSim corrected) with a cluster size of >40 voxels. Compared with formula-fed infants, breastmilk-fed infants showed increased brain activation on fMRI in the right superior temporal gyrus (BA41). Conclusion: Breastmilk-fed infants had greater regional gray matter development and increased regional gray matter function compared with formula-fed infants at near term-equivalent age, suggesting breastmilk feeding in the early period after birth may have some degree of influence on early brain development in preterm infants. [ABSTRACT FROM AUTHOR]