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Feed cost is the main factor affecting the economic benefits of pig industry. Improving the feed efficiency (FE) can reduce the feed cost and improve the economic benefits of pig breeding enterprises. Liver is a complex metabolic organ which affects the distribution of nutrients and regulates the efficiency of energy conversion from nutrients to muscle or fat, thereby affecting feed efficiency. MicroRNAs (miRNAs) are small non-coding RNAs that can regulate feed efficiency through the modulation of gene expression at the post-transcriptional level. In this study, we analyzed miRNA profiling of liver tissues in High-FE and Low-FE pigs for the purpose of identifying key miRNAs related to feed efficiency. A total 212~221 annotated porcine miRNAs and 136~281 novel miRNAs were identified in the pig liver. Among them, 188 annotated miRNAs were co-expressed in High-FE and Low-FE pigs. The 14 miRNAs were significantly differentially expressed (DE) in the livers of high-FE pigs and low-FE pigs, of which 5 were downregulated and 9 were upregulated. Kyoto Encyclopedia of Genes and Genomes analysis of liver DE miRNAs in high-FE pigs and low-FE pigs indicated that the target genes of DE miRNAs were significantly enriched in insulin signaling pathway, Gonadotropin-releasing hormone signaling pathway, and mammalian target of rapamycin signaling pathway. To verify the reliability of sequencing results, 5 DE miRNAs were randomly selected for quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The qRT-PCR results of miRNAs were confirmed to be consistent with sequencing data. DE miRNA data indicated that liver-specific miRNAs synergistically acted with mRNAs to improve feed efficiency. The liver miRNAs expression analysis revealed the metabolic pathways by which the liver miRNAs regulate pig feed efficiency.

Transcription factors (TFs) are proteins that recognize specific DNA fragments in order to decode the genome and ensure its optimal functioning. TFs work at the local and global scales by specifying cell type, cell growth and death, cell migration, organization and timely tasks. We investigate the structure of DNA-binding motifs with the theory of finitely generated groups. The DNA ‘word’ in the binding domain—the motif—may be seen as the generator of a finitely generated group Fdna on four letters, the bases A, T, G and C. It is shown that, most of the time, the DNA-binding motifs have subgroup structures close to free groups of rank three or less, a property that we call ‘syntactical freedom’. Such a property is associated with the aperiodicity of the motif when it is seen as a substitution sequence. Examples are provided for the major families of TFs, such as leucine zipper factors, zinc finger factors, homeo-domain factors, etc. We also discuss the exceptions to the existence of such DNA syntactical rules and their functional roles. This includes the TATA box in the promoter region of some genes, the single-nucleotide markers (SNP) and the motifs of some genes of ubiquitous roles in transcription and regulation.

Electrochemically deposited sensors and DNA biosensors have been widely used in the food industry, and various other fields due to their high sensitivity, fast response, easy operation, no pollution, and low price. A rare earth electrochemically deposited gadolinium ferricyanide thin film modified glassy carbon electrode, and the investigation of electrocatalytic oxidation of guanine by GaHCF/GCE is reported. We deposited electrochemically a rare earth terbium ferricyanide thin film modified glassy carbon electrode. OH was investigated through various characteristics such as capacitance–voltage, Differential Pulse Voltammetric and many more by the comparison of catalytic oxidation signal of guanine with ·OH in Fenton reaction.

Abstract Background Neuroblastoma (NB) is a common extracranial malignancy with high mortality in children. Recently, super-enhancers (SEs) have been reported to play a critical role in the tumorigenesis and development of NB via regulating a wide range of oncogenes Thus, the synthesis and identification of chemical inhibitors specifically targeting SEs are of great urgency for the clinical therapy of NB. This study aimed to characterize the activity of the SEs inhibitor GNE987, which targets BRD4, in NB. Results In this study, we found that nanomolar concentrations of GNE987 markedly diminished NB cell proliferation and survival via degrading BRD4. Meanwhile, GNE987 significantly induced NB cell apoptosis and cell cycle arrest. Consistent with in vitro results, GNE987 administration (0.25 mg/kg) markedly decreased the tumor size in the xenograft model, with less toxicity, and induced similar BRD4 protein degradation to that observed in vitro. Mechanically, GNE987 led to significant downregulation of hallmark genes associated with MYC and the global disruption of the SEs landscape in NB cells. Moreover, a novel candidate oncogenic transcript, FAM163A, was identified through analysis of the RNA-seq and ChIP-seq data. FAM163A is abnormally transcribed by SEs, playing an important role in NB occurrence and development. Conclusion GNE987 destroyed the abnormal transcriptional regulation of oncogenes in NB by downregulating BRD4, which could be a potential therapeutic candidate for NB.

Abstract Background To elucidate the influence of childhood asthma on adult height after consideration of genetic heterogeneity in height. Methods Based on the UK Biobank, we conducted a matched cohort study, including 13,602 European individuals with asthma diagnosed before 18 years old and 136,008 matched unexposed individuals without such an experience. Ascertainment of asthma was based on self-reported data (97.6%) or clinical diagnosis in healthcare registers (2.4%). We studied three height outcomes, including (1) the attained adult height (in centimeters), (2) the height deviation measured as the difference between a person’s rank of genetically determined height (based on generated polygenetic risk score) and their rank of attained adult height in the study population (deviation in % of height order after standardization), and (3) the presence of height deficit comparing genetically determined and attained height (yes or no). We applied linear mixed-effect models to assess the associations of asthma diagnosed at different ages with attained adult height and height deviation, and conditional logistic regression models to estimate the associations of asthma with the risk of height deficit. Results 40.07% (59,944/149,610) of the study participants were born before 1950, and most of them were men (57.65%). After controlling for multiple covariates, childhood asthma was associated with shorter attained adult height, irrespective of age at asthma diagnosis. However, in the analysis of height deviation (deviation in %), we observed the greatest height deviation among individuals with asthma diagnosed before 4 years of age (− 2.57 [95% CI − 4.14 to − 1.00] and − 2.80 [95% CI − 4.06 to − 1.54] for the age of ≤ 2 and 3–4 years, respectively). The magnitude of height deviation in relation to asthma declined thereafter and became null after age 6. Similarly, there was a statistically significant height deficit in relation to an asthma diagnosis at ages ≤ 2 and 3–4 (odds ratios = 1.21, 95% CI 1.04 to 1.40, and 1.15, 95% CI 1.02 to 1.29) but not thereafter. The result pattern was similar when separately analyzing asthma with or without inhaled glucocorticoid (ICS) use, despite that the estimates were consistently stronger among asthma individuals who used ICS. Conclusions Our results suggest a notable association of childhood asthma, primarily asthma diagnosed at an early age, with adult height, after consideration of genetic heterogeneity in height and use of ICS. This finding highlights the need for surveillance on the growth problems among children with asthma.

Abstract Background Genetic variants have been found to influence red blood cell (RBC) susceptibility to hemolytic stress and affect transfusion outcomes and the severity of blood diseases. Males have a higher susceptibility to hemolysis than females, but little is known about the genetic mechanism contributing to the difference. Results To investigate the sex differences in RBC susceptibility to hemolysis, we conducted a sex-stratified genome-wide association study and a genome-wide gene-by-sex interaction scan in a multi-ethnic dataset with 12,231 blood donors who have in vitro osmotic hemolysis measurements during routine blood storage. The estimated SNP-based heritability for osmotic hemolysis was found to be significantly higher in males than in females (0.46 vs. 0.41). We identified SNPs associated with sex-specific susceptibility to osmotic hemolysis in five loci (SPTA1, KCNA6, SLC4A1, SUMO1P1, and PAX8) that impact RBC function and hemolysis. Conclusion Our study established a best practice to identify sex-specific genetic modifiers for sexually dimorphic traits in datasets with mixed ancestries, providing evidence of different genetic regulations of RBC susceptibility to hemolysis between sexes. These and other variants may help explain observed sex differences in the severity of hemolytic diseases, such as sickle cell and malaria, as well as the viability of red cell storage and recovery.

ABSTRACT Importance The phenotypes of ATP1A3 gene mutations are diverse. Relapsing encephalopathy with cerebellar ataxia and fever‐induced paroxysmal weakness and encephalopathy (FIPWE) are considered non‐classical phenotypes caused by p.Arg756 mutations of ATP1A3. Objective To summarize the clinical manifestations, treatment, and follow‐up of Chinese patients with p.Arg756 mutations of ATP1A3. Methods We analyzed the clinical features, treatment, and genotypes of eight children with p.Arg756 mutations of ATP1A3 who were treated in Beijing Children's Hospital from January 2014 to December 2019. Results Eight patients (six boys and two girls) were included; seven had been misdiagnosed with encephalitis. The age of onset ranged from 0.8 to 4.5 years. All patients had encephalopathy and had at least one episode of FIPWE. Cerebellar ataxia was present in nine episodes. Reversible splenial lesions of the corpus callosum were found in two patients in the acute phase. Three types of heterozygous ATP1A3 mutations were found: c.2267G > T (p.R756L) (patient 3 [P3]), c.2266C > T (p.R756C) (P2 and P4), and c.2267G > A (p.R756H) (P1, P5, P6, P7, and P8). Six mutations were de novo; two mutations were inherited. Both patients with p.R756C and one patient (P7) with p.R756H had four episodes of severe ataxia as the main manifestations. However, in the other three episodes, limb weakness was more prominent than ataxia. P5 with p.R756H exhibited overlap with FIPWE and rapid‐onset dystonia‐parkinsonism. Interpretation Acute encephalopathy followed by febrile disease was characteristic of the disease in patients with p.Arg756 mutations of ATP1A3. However, the weakness and ataxia were variable. Phenotypic crossover and overlap were observed among these patients.

Abstract Recent studies uncovered the emerging roles of SAPCD2 (suppressor anaphase-promoting complex domain containing 2) in several types of human cancer. However, the functions and underlying mechanisms of SAPCD2 in the progression of neuroblastoma (NB) remain elusive. Herein, through integrative analysis of public datasets and regulatory network of GSK-J4, a small-molecule drug with anti-NB activity, we identified SAPCD2 as an appealing target with a high connection to poor prognosis in NB. SAPCD2 promoted NB progression in vitro and in vivo. Mechanistically, SAPCD2 could directly bind to cytoplasmic E2F7 but not E2F1, alter the subcellular distribution of E2F7 and regulate E2F activity. Among the E2F family members, the roles of E2F7 in NB are poorly understood. We found that an increasing level of nuclear E2F7 was induced by SAPCD2 knockdown, thereby affecting the expression of genes involved in the cell cycle and chromosome instability. In addition, Selinexor (KTP-330), a clinically available inhibitor of exportin 1 (XPO1), could induce nuclear accumulation of E2F7 and suppress the growth of NB. Overall, our studies suggested a previously unrecognized role of SAPCD2 in the E2F signaling pathway and a potential therapeutic approach for NB, as well as clues for understanding the differences in subcellular distribution of E2F1 and E2F7 during their nucleocytoplasmic shuttling.

Abstract Background Acute kidney injury (AKI) is associated with high morbidity and mortality. Multiple urinary biomarkers have been identified to be associated with the prediction of AKI and outcomes. However, the accuracy of these urinary biomarkers for AKI and associated outcomes has not been clearly defined, especially in heterogeneous populations. The aims of the study were to compare the ability of 10 existing or potential urinary biomarkers to predict AKI and pediatric intensive care unit (PICU) mortality and validate urinary tissue inhibitor of metalloproteinases-1 (uTIMP-1) as a better biomarker for early prediction in heterogeneous critically ill children. Methods A derivation-validation approach with separate critically ill cohorts was designed. We first conducted a prospective cohort study to determine the ability of 10 urinary biomarkers serially measured in 123 children during the first 7 days of PICU stay to predict AKI and PICU mortality (derivation study) and further validated the better biomarker of uTIMP-1 in a separate cohort of 357 critically ill children (validation study). AKI diagnosis was based on KDIGO classification with serum creatinine and urine output. PICU mortality was defined as all-cause mortality. Results In the derivation cohort, 17 of 123 (13.8%) children developed AKI stage 3 or died during the PICU stay, and both the initial and peak uTIMP-1 displayed the highest AUCs of 0.87 (0.79–0.94) and 0.90 (0.84–0.96), respectively, for predicting AKI stage 3 or death. In the validation cohort, 78 of 357 (21.8%) developed AKI during the first week after admission, and 38 (10.6%) died during the PICU stay. The initial uTIMP-1 level was validated to be independently associated with AKI (AOR = 2.88, 95% CI 1.97–4.21), severe AKI (AOR = 2.62, 95% CI 1.78–3.88), AKI stage 3 (AOR = 2.94, 95% CI 1.84–4.68) and PICU mortality (AOR = 1.92, 95% CI 1.11–3.30) after adjustment for potential confounders. The predictive values of uTIMP-1 for AKI, severe AKI, AKI stage 3 and PICU mortality were 0.80 (0.74–0.86), 0.83 (0.77–0.89), 0.84 (0.77–0.92) and 0.83 (0.76–0.89), respectively. Conclusions Urinary TIMP-1 levels have been identified and validated to be independently associated with AKI and PICU mortality in independent prospective cohorts and may be an early potential indicator of AKI and PICU mortality in critically ill children.

Abstract Background Childhood abuse and neglect have been associated with premenstrual disorders (PMDs), including premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD). However, the associations of other adverse childhood experiences (ACEs) and the cumulative number of ACEs with PMDs remain to be explored. Methods To evaluate the associations of the cumulative number and types of ACEs with PMDs, we conducted a cross-sectional analysis with a subsample of menstruating women within the Stress-And-Gene-Analysis (SAGA) cohort, assessed for PMDs and ACEs (N=11,973). The cumulative and individual exposure of 13 types of ACEs was evaluated by a modified ACE-International Questionnaire. A modified version of the Premenstrual Symptom Screening Tool was used to identify probable cases of PMDs, further sub-grouped into PMS and PMDD. Prevalence ratios (PRs) of PMDs in relation to varying ACEs were estimated using Poisson regression. Results At a mean age of 34.0 years (standard deviation (SD) 9.1), 3235 (27%) met the criteria of probable PMDs, including 2501 (21%) for PMS and 734 (6%) for PMDD. The number of ACEs was linearly associated with PMDs (fully-adjusted PR 1.12 per ACE, 95% CI 1.11–1.13). Specifically, the PR for PMDs was 2.46 (95% CI 2.21–2.74) for women with 4 or more ACEs compared with women with no ACEs. A stronger association was observed for probable PMDD compared to PMS (p for difference

Abstract Super-refractory status epilepticus (SRSE) is a serious and life-threatening neurological condition. Ketogenic diet (KD) is a diet characterized by high fat, low carbohydrate, and moderate protein. As KD shows effectiveness in controlling seizures in more than half of SRSE patients, it can be a treatment option for SRSE. Currently, KD treatment for SRSE is based on personal experience and observational evidence has been published. In the context of a lack of a validated guideline, we convened a multicenter expert panel within the China Association Against Epilepsy (CAAE) Ketogenic Diet Commission to work out the Chinese expert recommendations on KD for SRSE. We summarize and discuss the latest clinical practice of KD for SRSE in critical care settings. Recommendations are given on patient selection, the timing of KD, diet implementation, and follow-up. More research data are needed in this area to support better clinical practice.

The special characteristics of ocean ecosystems, such as the high salinity and pressure, low temperature, and nutrition, makes marine microorganisms diverse in species, gene composition, and ecological functions. Recent advances in molecular biology techniques, together with the ongoing developments in bioinformatic and automatic technologies, have highlighted the scientific studies on marine microbial ecology, eliminating the total reliance on classical cultivation-based techniques. This review systematically summarizes the innovative aspects of a field investigation of marine microorganisms. It covers various cutting-edge sampling approaches employed in the field, highlighting the in situ high-fidelity sampling strategies with practical applications. Particular emphasis is placed on the molecular analyses for marine ecology based on recently developed omics technologies. The key technical issues and substantial contribution of the contemporary instrumental analyses are discussed accordingly. It provides references for the in situ surveys of complex biogeochemical processes from marine microorganisms to ecosystems, relying on the development of new technical concepts and scientific methodologies in field investigations.

Recurrent implantation failure (RIF) is a challenging scenario from different standpoints. This study aimed to investigate its correlation with the endometrial metabolic characteristics. Transcriptomics data of 70 RIF and 99 normal endometrium tissues were retrieved from the Gene Expression Omnibus database. Common differentially expressed metabolism-related genes were extracted and various enrichment analyses were applied. Then, RIF was classified using a consensus clustering approach. Three machine learning methods were employed for screening key genes, and they were validated through the RT-qPCR experiment in the endometrium of 10 RIF and 10 healthy individuals. Receiver operator characteristic (ROC) curves were generated and validated by 20 RIF and 20 healthy individuals from Peking University People’s Hospital. We uncovered 109 RIF-related metabolic genes and proposed a novel two-subtype RIF classification according to their metabolic features. Eight characteristic genes (SRD5A1, POLR3E, PPA2, PAPSS1, PRUNE, CA12, PDE6D, and RBKS) were identified, and the area under curve (AUC) was 0.902 and the external validated AUC was 0.867. Higher immune cell infiltration levels were found in RIF patients and a metabolism-related regulatory network was constructed. Our work has explored the metabolic and immune characteristics of RIF, which paves a new road to future investigation of the related pathogenic mechanisms.

Abstract Background An increased susceptibility to COVID-19 has been suggested for individuals with neurodegenerative diseases, but data are scarce from longitudinal studies. Methods In this community-based cohort study, we included 96,275 participants of the UK Biobank who had available SARS-CoV-2 test results in Public Health England. Of these, 2617 had a clinical diagnosis of neurodegenerative diseases in the UK Biobank inpatient hospital data before the outbreak of COVID-19 (defined as January 31st, 2020), while the remaining participants constituted the reference group. We then followed both groups from January 31st, 2020 to June 14th, 2021 for ascertainment of COVID-19 outcomes, including any COVID-19, inpatient care for COVID-19, and COVID-19 related death. Logistic regression was applied to estimate the association between neurogenerative disease and risks of COVID-19 outcomes, adjusted for multiple confounders and somatic comorbidities. Results We observed an elevated risk of COVID-19 outcomes among individuals with a neurodegenerative disease compared with the reference group, corresponding to a fully adjusted odds ratio of 2.47 (95%CI 2.25–2.71) for any COVID-19, 2.18 (95%CI 1.94–2.45) for inpatient COVID-19, and 3.67 (95%CI 3.11–4.34) for COVID-19 related death. Among individuals with a positive test result for SARS-CoV-2, individuals with neurodegenerative diseases had also a higher risk of COVID-19 related death than others (fully adjusted odds ratio 2.08; 95%CI 1.71–2.53). Conclusion Among UK Biobank participants who received at least one test for SARS-CoV-2, a pre-existing diagnosis of neurodegenerative disease was associated with a subsequently increased risk of COVID-19, especially COVID-19 related death.

Abstract Fibroblast growth factor-21 (FGF-21) performs a wide range of biological functions in organisms. Here, we report for the first time that FGF-21 suppresses thrombus formation with no notable risk of bleeding. Prophylactic and therapeutic administration of FGF-21 significantly improved the degree of vascular stenosis and reduced the thrombus area, volume and burden. We determined the antithrombotic mechanism of FGF-21, demonstrating that FGF-21 exhibits an anticoagulant effect by inhibiting the expression and activity of factor VII (FVII). FGF-21 exerts an antiplatelet effect by inhibiting platelet activation. FGF-21 enhances fibrinolysis by promoting tissue plasminogen activator (tPA) expression and activation, while inhibiting plasminogen activator inhibitor 1 (PAI-1) expression and activation. We further found that FGF-21 mediated the expression and activation of tPA and PAI-1 by regulating the ERK1/2 and TGF-β/Smad2 pathways, respectively. In addition, we found that FGF-21 inhibits the expression of inflammatory factors in thrombosis by regulating the NF-κB pathway.

Abstract Background Cancer patients experience increased risk of death from accident and suicide. Cognitive impairment induced by cancer-related inflammation and stress-related psychiatric symptoms may be underlying mechanisms. We therefore studied the association between use of nonsteroidal anti-inflammatory drugs (NSAIDs) and risk of these outcomes. Methods Following a cohort of 388,443 cancer patients diagnosed between October 2005 and December 2014 in Sweden, we ascertained dispense of aspirin or non-aspirin NSAIDs from 3 months before cancer diagnosis onward and defined the on-medication period as from date of drug dispense until the prescribed dosage was consumed. Follow-up time outside medicated periods and time from unexposed patients were defined as off-medication periods. We used Cox models to estimate hazard ratios (HRs) of death due to suicide or accident, by comparing the on-medication periods with off-medication periods. Results In total, 29.7% of the cancer patients had low-dose aspirin dispensed and 29.1% had non-aspirin NSAIDs dispensed. Patients with aspirin use were more likely to be male than patients without aspirin use. Compared with off-medication periods, there was a 22% lower risk of accidental death (N = 651; HR 0.78, 95% confidence interval [CI]: 0.70 to 0.87) during on-medication periods with aspirin. The use of aspirin was not associated with risk of suicide (N = 59; HR 0.96, 95% CI: 0.66 to 1.39). No association was noted between use of non-aspirin NSAIDs and the risk of suicide (N = 13; HR 0.95, 95% CI: 0.42 to 2.18) or accidental death (N = 59; HR 0.92, 95% CI: 0.68 to 1.26). Conclusions Intake of low-dose aspirin after cancer diagnosis was associated with a lower risk of unnatural deaths among cancer patients.

Chinese rice wine (Huangjiu) has a long history and has been popular in China for thousands of years. During Huangjiu fermentation, many kinds of microorganisms are involved and hundreds of metabolites are produced, which form its unique aroma. The composition of the Huangjiu microbiome has a strong influence on the flavor and quality of the final consumer product. Therefore, this review summarizes the research progress on the main components, quality control indicators and flavor compounds, as well as potential hazards during the fermentation of Huangjiu. The influence of the dominant microbial species on the Huangjiu fermentation, the sensory qualities and the formation of harmful substances are discussed. This helps to provide a theoretical basis for modification of the Huangjiu microbiome to improve control of the fermentation process and the overall sensory quality of the final product.

Benefiting from free labeling pixel-level samples, weakly supervised semantic segmentation (WSSS) is making progress in automatically extracting building from high-resolution (HR) remote sensing (RS) imagery. For WSSS methods, generating high-quality pseudomasks is crucial for accurate building extraction.To improve the performance of generating pseudomasks by using image-level labels, this article proposes a weakly supervised building extraction method by combining adversarial climbing and gated convolution. The proposed method optimizes class activation maps (CAMs) by using adversarial climbing strategy, generates accurate class boundary maps by introducing a gated convolution module, and further refines building pseudomasks by fusing pairing semantic affinities and CAMs with a random walk strategy. Experimental results on three datasets—two ISPRS datasets and a self-annotated dataset—demonstrate that the proposed approach outperformed SOTA WSSS methods, leading to improvement of building extraction from HR RS imager. This article provides a new approach for optimizing pseudomasks generation, and a methodological reference for the applications of weakly supervised on RS images.

Assisted oocyte activation (AOA) has been proposed as an effective technique to overcome the problem of impaired fertilization after intracytoplasmic sperm injection (ICSI) but the safety of AOA remains a concern. We aimed to investigate if AOA induces imprinting effects on embryos. We used 13 cleavage embryos, nine blastocysts, and eight placentas from 15 patients. The subjects were divided into six groups by tissue type and with or without AOA. The methylation levels of imprinted genes (H19, paternally expressed gene [PEG3] and small nuclear ribonucleoprotein polypeptide N [SNRPN]) were tested by pyrosequencing. We observed different methylation levels among cleavage embryos. The variability was much more remarkable between cleavage embryos than blastocysts and placenta tissues. The methylation levels were especially higher in SNRPN and lower in the H19 gene in AOA embryos than those without AOA. No significant difference was found either among blastocysts or among placenta tissues regardless of AOA. The methylation levels of the three genes in blastocysts were very similar to those in the placenta. Compared to conventional ICSI, AOA changed imprinting methylation rates at H19 and SNRPN in cleavage embryos but not in the blastocyst stage and placenta. We recommend that blastocyst transfer should be considered for patients undergoing AOA during in vitro fertilization.

Background and aimImplantable cardiac monitors (ICM) can facilitate the detection of asymptomatic atrial fibrillation episodes. We performed a systematic review and meta-analysis to investigate whether ICM can prevent stroke in patients with prior stroke and risk factors for stroke.MethodsThis study included randomized controlled trials comparing ICM with conventional (non-ICM) external cardiac monitoring in patients with prior stroke and risk factors for stroke. We searched Medline, Embase, and CENTRAL from inception until January 5, 2022, without language restriction. Quantitative pooling of the data was undertaken using a random-effects model. The primary outcome was ischemic stroke at the longest follow-up.ResultsFour trials comprising 7237 patients were included. ICM was significantly associated with decreased risk of ischemic stroke (RR 0.76; 95% CI, 0.59-0.97; moderate-quality evidence) in patients with prior stroke and risk factors for stroke. ICM was associated with higher detection of atrial fibrillation (RR 4.21, 95% CI 2.26-7.85) and use of oral anticoagulants (RR 2.29, 95% CI 2.07-2.55).ConclusionsICM results in a significantly lower risk of ischemic stroke than conventional (non-ICM) external cardiac monitoring in patients with prior stroke and risk factors for stroke. Due to the clinical heterogeneity of study population and limited related studies, more trials were needed to furtherly explore the topic in patients with prior stroke or high risk of stroke.

The morbidity and mortality of myocardial infarction (MI) are increasing worldwide. Mesenchymal stem cells (MSCs) are multipotent stem cells with self-renewal and differentiation capabilities that are essential in tissue healing and regenerative medicine. However, the low implantation and survival rates of transplanted cells hinder the widespread clinical use of stem cells. Exosomes are naturally occurring nanovesicles that are secreted by cells and promote the repair of cardiac function by transporting noncoding RNA and protein. In recent years, MSC-derived exosomes have been promising cell-free treatment tools for improving cardiac function and reversing cardiac remodeling. This review describes the biological properties and therapeutic potential of exosomes and summarizes some engineering approaches for exosomes optimization to enhance the targeting and therapeutic efficacy of exosomes in MI.

Background. Arising from T progenitor cells, T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignant tumor, accounting for 15% of childhood ALL and 25% of adult ALL. Composing of putative enhancers in close genomic proximity, super enhancer (SE) is critical for cell identity and the pathogenesis of multiple cancers. Belonging to the cytosolute linker protein group, FYB1 is essential for TCR signaling and extensively studied in terms of tumor pathogenesis and metastasis. Dissecting the role of FYN binding protein 1 (FYB1) in T-ALL holds the potential to improve the treatment outcome and prognosis of T-ALL. Methods. In this study, SEs were explored using public H3K27ac ChIP-seq data derived from T-ALL cell lines, AML cell lines and hematopoietic stem and progenitor cells (HSPCs). Downstream target of FYB1 gene was identified by RNA-seq. Effects of shRNA-mediated downregulation of FYB1 and immunoglobulin lambda-like polypeptide 1 (IGLL1) on self-renewal of T-ALL cells were evaluated in vitro and/or in vivo. Results. As an SE-driven gene, overexpression of FYB1 was observed in T-ALL, according to the Cancer Cell Line Encyclopedia database. In vitro, knocking down FYB1 led to comprised growth and enhanced apoptosis of T-ALL cells. In vivo, downregulation of FYB1 significantly decreased the disease burden by suppressing tumor growth and improved survival rate. Knocking down FYB1 resulted in significantly decreased expression of IGLL1 that was also an SE-driven gene in T-ALL. As a downstream target of FYB1, IGLL1 exerted similar role as FYB1 in inhibiting growth of T-ALL cells. Conclusion. Our results suggested that FYB1 gene played important role in regulating self-renewal of T-ALL cells by activating IGLL1, representing a promising therapeutic target for T-ALL patients.

ObjectiveTo compare the rerupture rate after conservative treatment, open repair, and minimally invasive surgery management of acute Achilles tendon ruptures.DesignSystematic review and network meta-analysis.Data sourcesWe searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from inception to August 2022.MethodsRandomised controlled trials involving different treatments for Achilles tendon rupture were included. The primary outcome was rerupture. Bayesian network meta-analysis with random effects was used to assess pooled relative risks (RRs) and 95% confidence intervals. We evaluated the heterogeneity and publication bias.ResultsThirteen trials with 1465 patients were included. In direct comparison, there was no difference between open repair and minimally invasive surgery for rerupture rate (RR, 0.72, 95% CI 0.10-4.4; I2 = 0%; Table 2). Compared to the conservative treatment, the RR was 0.27 (95% CI 0.10-0.62, I2 = 0%) for open repair and 0.14 (95% CI 0.01-0.88, I2 = 0%) for minimally invasive surgery. The network meta-analysis had obtained the similar results as the direct comparison.ConclusionBoth open repair and minimally invasive surgery were associated with a significant reduction in rerupture rate compared with conservative management, but no difference in rerupture rate was found comparing open repair and minimally invasive surgery.

Introduction The role of COVID-19 vaccination on the mental health of the general population remains poorly understood. This study aims to assess the short-term change in depressive and anxiety symptoms in relation to COVID-19 vaccination among Swedish adults. Methods A prospective study of 7,925 individuals recruited from ongoing cohort studies at the Karolinska Institutet, Stockholm, Sweden, or through social media campaigns, with monthly data collections on self-reported depressive and anxiety symptoms from December 2020 to October 2021 and COVID-19 vaccination from July to October 2021. Prevalence of depressive and anxiety symptoms (defined as a self-reported total score of ≥10 in PHQ-9 and GAD-7, respectively) was calculated one month before, one month after the first dose, and, if applicable, one month after the second dose. For individuals not vaccinated or choosing not to report vaccination status (unvaccinated individuals), we selected three monthly measures of PHQ-9 and GAD-7 with 2-month intervals in-between based on data availability. Results 5,079 (64.1%) individuals received two doses of COVID-19 vaccine, 1,977 (24.9%) received one dose, 305 (3.9%) were not vaccinated, and 564 (7.1%) chose not to report vaccination status. There was a lower prevalence of depressive and anxiety symptoms among vaccinated, compared to unvaccinated individuals, especially after the second dose. Among individuals receiving two doses of vaccine, the prevalence of depressive and anxiety symptoms was lower after both first (aRR = 0.82, 95%CI 0.76–0.88 for depression; aRR = 0.81, 95%CI 0.73–0.89 for anxiety) and second (aRR = 0.79, 95%CI 0.73–0.85 for depression; aRR = 0.73, 95%CI 0.66–0.81 for anxiety) dose, compared to before vaccination. Similar results were observed among individuals receiving only one dose (aRR = 0.76, 95%CI 0.68–0.84 for depression; aRR = 0.82, 95%CI 0.72–0.94 for anxiety), comparing after first dose to before vaccination. Conclusions We observed a short-term improvement in depressive and anxiety symptoms among adults receiving COVID-19 vaccines in the current pandemic. Our findings provide new evidence to support outreach campaigns targeting hesitant groups.

Background. Complex regulation exists between tumor metabolism and M2 macrophages. Long noncoding RNAs (lncRNAs) are famous for their wide regulatory role. This study aimed to identify the lncRNAs involved in the crosstalk between tumor metabolism and M2 macrophages. Methods. The Cancer Genome Atlas was responsible for the public data. R software was responsible for the analysis of public data. Results. Based on the input expression profile, we quantified the M2 macrophage infiltration using the CIBERSORT algorithm and found that M2 macrophages were a risk factor for lung cancer. Also, we found that M2 macrophages were correlated with multiple metabolism pathways. Then, 67 lncRNAs involved in both M2 macrophages and related metabolism pathways were identified. A prognosis signature based on AC027288.3, AP001189.3, FAM30A, GAPLINC, LINC00578, and LINC01936 was established, which had good prognosis prediction ability. The clinical parameters and risk score were combined into a nomogram plot for better prediction of the patient’s prognosis. A high fit of actual survival and nomogram-predicted survival was found using the calibration plot. Moreover, in low-risk patients, immunotherapy was more effective, while cisplatin and docetaxel were more effective in high-risk patients. Biological enrichment analysis indicated pathways of notch signaling, TGF-β signaling, interferon alpha response, and interferon-gamma response were activated in the high-risk group. Meanwhile, the risk score was associated with tumor metabolism and M2 macrophages. Also, we found that the promoting effect of CAPLINC on M2 macrophage polarization might act through multiple metabolism pathways. Conclusions. Our result can provide new insights into the interaction between M2 macrophages and tumor metabolism, as well as the involved lncRNAs, which can provide the direction for future studies.

Colorectal cancer (CRC) is one of the most common cancers, with a high mortality rate, and is a major burden on human health worldwide. Gut microbiota regulate human immunity and metabolism through producing numerous metabolites, which act as signaling molecules and substrates for metabolic reactions in various biological processes. The importance of host-gut microbiota interactions in immunometabolic mechanisms in CRC is increasingly recognized, and interest in modulating the microbiota to improve patient’s response to therapy has been raising. However, the specific mechanisms by which gut microbiota interact with immunotherapy and radiotherapy remain incongruent. Here we review recent advances and discuss the feasibility of gut microbiota as a regulatory target to enhance the immunogenicity of CRC, improve the radiosensitivity of colorectal tumor cells and ameliorate complications such as radiotoxicity. Currently, great breakthroughs in the treatment of non-small cell lung cancer and others have been achieved by radioimmunotherapy, but radioimmunotherapy alone has not been effective in CRC patients. By summarizing the recent preclinical and clinical evidence and considering regulatory roles played by microflora in the gut, such as anti-tumor immunity, we discuss the potential of targeting gut microbiota to enhance the efficacy of radioimmunotherapy in CRC and expect this review can provide references and fresh ideas for the clinical application of this novel strategy.

ObjectiveThis study aimed to explore the clinical characteristics and differential diagnosis of patients with autoimmune pancreatitis (AIP) and pancreatic cancer to prevent misdiagnosis and mistreatment.MethodsThe clinical data of patients with AIP with suspected pancreatic or bile duct malignancy and pancreatic cancer were retrospectively analyzed. The risk factors and the diagnostic value of IgG4 and Tbil levels before treatment for AIP was investigated. Moreover, the imaging features and response to hormone therapy were analyzed.ResultsAIP was commonly observed in men. Compared to patients with pancreatic cancer, the incidence of poor appetite and weight loss and carbohydrate antigen 19-9 (CA19-9) level was lower in patients with AIP, while the immunoglobulin G4 (IgG4) level was higher (p

Human infancy is characterized by most rapid regional cerebral blood flow (rCBF) increases across lifespan and emergence of a fundamental brain system default-mode network (DMN). However, how infant rCBF changes spatiotemporally across the brain and how the rCBF increase supports emergence of functional networks such as DMN remains unknown. Here, by acquiring cutting-edge multi-modal MRI including pseudo-continuous arterial-spin-labeled perfusion MRI and resting-state functional MRI of 48 infants cross-sectionally, we elucidated unprecedented 4D spatiotemporal infant rCBF framework and region-specific physiology–function coupling across infancy. We found that faster rCBF increases in the DMN than visual and sensorimotor networks. We also found strongly coupled increases of rCBF and network strength specifically in the DMN, suggesting faster local blood flow increase to meet extraneuronal metabolic demands in the DMN maturation. These results offer insights into the physiological mechanism of brain functional network emergence and have important implications in altered network maturation in brain disorders.

BackgroundSARS-CoV-2 invades human cells and leads to COVID-19 by direct associating with angiotensin converting enzyme 2 (ACE2) receptors, the level of which may be increased by treatment with angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs). This meta-analysis aimed to explore the impact of ACEI/ARB treatment on the clinical outcomes of patients with COVID-19 infections among population in the East-Asia region.MethodsWe collected clinical data published from January 2000 to May 2022 in the English databases including PubMed, Embase, and the Cochrane Library. Two reviewers independently screened and identified studies that met the prespecified criteria. Review Manager 5.3 software was used to perform the meta-analysis.ResultsA total of 28 articles were included in this analysis. The results showed that patients who were prescribed with ACEI/ARB had a shorter duration of hospital stay [MD = -2.37, 95%CI (-3.59, -1.14), P = 0.000 2] and a lower mortality rate [OR = 0.61, 95% CI (0.52, 0.70), PConclusionsThis meta-analysis suggested that the use of ACEI/ARB was not associated with adverse clinical outcomes in East-Asian Covid-19 patients and a reduced mortality and shorter duration of hospital stay among East-Asian population (especially for female subjects) was found. Thus, ACEI/ARB should be continued in patients infected by Covid-19.

BackgroundAnlotinib may boost the efficacy of pancreatic cancer (PC) treatment if timely added to the GS regimen (Gemcitabine, Tegafur-gimeracil-oteracil potassium); however, no data has been published. This study evaluated the safety and efficacy of anlotinib in combination with the GS regimen(hereafter referred to as the A+GS regimen) in the first-line treatment of patients with unresectable or metastatic PC.MethodsPatients with unresectable or metastatic PC treated at Yueyang Central Hospital and Yueyang People’s Hospital between October 2018 and June 2022 were enrolled in this retrospective real-world investigation. Treatment efficacy was evaluated based on the overall survival (OS), progression-free survival (PFS), disease control rate (DCR), and objective response rate (ORR), while the treatment safety was assessed by the frequency of major adverse events (AEs).ResultsSeventy-one patients were included in this study, 41 in the GS group and 30 in the A+GS group. The A+GS group had a longer mPFS than the GS group (12.0 months (95% CI, 6.0–18.0) and 6.0 months (95% CI, 3.0–8.1)), respectively (P = 0.005). mOS was longer in the GS+A group) when compared with the GS group (17.0 months (95%CI, 14.0–20.0) and 10.0 months (95% CI, 7.5–12.5)), respectively (P = 0.018). The GS+A group had higher ORR (50.0% vs 26.8%, P = 0.045) and DCR (83.3% vs 58.5%, P = 0.026). Furthermore, there were no grade 4-5 AEs and no treatment-related deaths, and no discernible increase in AEs in the GS+A group when compared with the GS group.ConclusionThe A+GS regimen therapy holds great promise in managing treatment-naive advanced PC, except that future prospective studies with larger sample sizes and multiple centers are required to determine its efficacy and safety.

IntroductionThe outbreak and spread of the pandemics have been an issue of critical concern globally, posing a significant threat to the health sector globally. This study aimed to examine the basic knowledge and attitudes toward the recommended protective measures at different times, respond to the COVID-19 pandemic, and provide recommendations for developing targeted strategies and measures for preventing and controlling public health emergencies.MethodsThe study used self-filled questionnaires to examine the public's knowledge, attitudes, and practices on COVID-19 at two different period, from 20 to 31 March 2020 (the beginning period) and 22–27 April 2022 (the regular epidemic prevention and control period). Descriptive and quantitative analyses were used for statistical analysis.Results and discussionThe survey collected 2375 valid questionnaires. A comparison of the two periods reveals that as the epidemic continued over a long period, the level of knowledge, attitudes toward preventive measures, risk perceptions, and adoption behavior of the respondents at the beginning of the epidemic were significantly higher than during the regular epidemic prevention and control period. With the upsurge in the spread of the epidemic, the public needs a multi-channel, targeted, and all-round guidance and information on prevention and control of the COVID-19, and internalizes knowledge into individual's behavior of actively responding to diseases.When the epidemic lasts for a long time, the relevant agencies should strengthen their monitoring role to promote public compliance with the recommended measures.

PurposeTo evaluate the influence of GATA3 rs3824662 on pre-B-cell acute lymphoblastic leukemia (pre-B-cell ALL) susceptibility and long-term prognosis in Han Chinese children with pre-B-cell ALL treated with the CCLG-2008 protocol at the Children’s Hospital of Soochow University.MethodsA total of 256 patients with childhood pre-B-cell ALL under the CCLG-2008 protocol were enrolled in this study, and 174 healthy children were used as case controls. GATA3 rs3824662 genotyping was performed using a polymerase chain reaction, followed by Sanger sequencing. The association of genotype with clinical characteristics, treatment response, adverse events, and outcomes were analyzed.ResultsThe A allele frequency of GATA3 rs3824662 in patients with pre-B cell ALL was significantly higher than that in healthy children (OR = 1.41, 95% CI = 1.042–1.908; P = 0.026). Among patients with pre-B-cell ALL, the GATA3 rs3824662 AA genotype was associated with poor prednisolone response and high blast cell burden on day 15 of the induction therapy (P = 0.011 and 0.007, respectively). Patients with the rs3824662 AA variant suffered more episodes of sepsis than those with the CC or CA variants (P = 0.021). The GATA3 rs3824662 AA genotype was significantly associated with sepsis [hazard ratio (HR) = 3.375; P = 0.01]. No significant differences were found in the cumulative incidence of relapse, overall survival, and event-free survival among all genotypes.ConclusionGATA3 rs3824662 was associated with susceptibility in Han Chinese children with pre-B-cell ALL and could be a possible risk factor for poor early treatment response and treatment-related sepsis.

Spinosyns are natural broad-spectrum biological insecticides with a double glycosylated polyketide structure that are produced by aerobic fermentation of the actinomycete, Saccharopolyspora spinosa. However, their large-scale overproduction is hindered by poorly understood bottlenecks in optimizing the original strain, and poor adaptability of the heterologous strain to the production of spinosyn. In this study, we genetically engineered heterologous spinosyn-producer Streptomyces albus J1074 and optimized the fermentation to improve the production of spinosad (spinosyn A and spinosyn D) based on our previous work. We systematically investigated the result of overexpressing polyketide synthase genes (spnA, B, C, D, E) using a constitutive promoter on the spinosad titer in S. albus J1074. The supply of polyketide synthase precursors was then increased to further improve spinosad production. Finally, increasing or replacing the carbon source of the culture medium resulted in a final spinosad titer of ∼70 mg/L, which is the highest titer of spinosad achieved in heterologous Streptomyces species. This research provides useful strategies for efficient heterologous production of natural products.

Abstract Background The limited ovicidal activity of currently available acaricides is a significant obstacle to efficacious scabies treatment. Several essential oils or their respective components have proved to be active against the eggs of arthropods, mainly lice and ticks. Information on the activity of these oils and/or components against the eggs of mites remains very limited. The aim of this study was to assess the activity of six terpenes (carvacrol, eugenol, geraniol, citral, terpinen-4-ol and linalool) commonly found in essential oils against the eggs of Sarcoptes scabiei. Methods Sarcoptes eggs were exposed to paraffin oil containing 1, 2.5, or 5% of each terpene tested. After a 12-h exposure period, the eggs were washed and placed in paraffin oil for hatching. Embryonic development following treatment was assessed every day to determine the stage of developmental arrest. Results The median effective concentration to obtain 50% egg mortality (EC50) was 0.5, 0.9, 2.0, 4.8, 5.1 and 9.8% for carvacrol, eugenol, geraniol, citral, terpinen-4-ol and linalool, respectively. The microscopic images of eggs after each treatment indicated that these six terpenes may act by penetrating through the aeropyles on the egg surface. Conclusions In conclusion, carvacrol, eugenol and geraniol possess significant ovicidal activities, which should be considered as promising ovicidal agents for the treatment of scabies. Graphical Abstract

Abstract Background Castleman disease (CD) is a group of rare lymphoproliferative diseases with common lymph node histological features that can easily be misdiagnosed as infections, multiple autoimmune diseases, and malignant tumors. Case presentation Here we report a rare case of a Chinese male with refractory ascites for two years and was eventually diagnosed as CD. Conclusions The challenges in diagnosis of CD arise from the large differential, clinical heterogeneity and our limited understanding of pathology. In case of rare ascites, CD needs to be considered.

High-grade serous ovarian cancer (HGSOC) harbours aberrant epigenetic features, including DNA methylation. In this study we delineate pathways and networks altered by DNA methylation and associated with HGSOC initiation and progression to a platinum-resistant state. By including tumours from patients who had been treated with the hypomethylating agent (HMA) guadecitabine, we also addressed the role of HMAs in treatment of HGSOC. Tumours from patients with primary (platinum-naïve) HGSOC (n = 20) were compared to patients with recurrent platinum-resistant HGSOC and enrolled in a recently completed clinical trial (NCT01696032). Human ovarian surface epithelial cells (HOSE; n = 5 samples) served as normal controls. Genome-wide methylation profiles were determined. DNA methyltransferase (DNMT) expression levels were examined by immunohistochemistry and correlated with clinical outcomes. Cancer-related and tumorigenesis networks were enriched among differentially methylated genes (DMGs) in primary OC vs. HOSE. When comparing platinum-resistant and primary tumours, 452 CpG island (CGI)-containing gene promoters acquired DNA methylation; of those loci, decreased (P

Abstract Background Acute myeloid leukemia (AML) is a myeloid neoplasm accounts for 7.6% of hematopoietic malignancies. AML is a complex disease, and understanding its pathophysiology is contributing to the improvement in the treatment and prognosis of AML. In this study, we assessed the expression profile and molecular functions of CCAAT enhancer binding protein gamma (CEBPG), a gene implicated in myeloid differentiation and AML progression. Methods shRNA mediated gene interference was used to down-regulate the expression of CEBPG in AML cell lines, and knockdown efficiency was detected by RT-qPCR and western blotting. The effect of knockdown on the growth of AML cell lines was evaluated by CCK-8. Western blotting was used to detect PARP cleavage, and flow cytometry were used to determine the effect of knockdown on apoptosis of AML cells. Genes and pathways affected by knockdown of CEBPG were identified by gene expression analysis using RNA-seq. One of the genes affected by knockdown of CEBPG was Eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1), a known repressor of translation. Knockdown of EIF4EBP1 was used to assess its potential role in AML progression downstream of CEBPG. Results We explored the ChIP-Seq data of AML cell lines and non-AML hematopoietic cells, and found CEBPG was activated through its distal enhancer in AML cell lines. Using the public transcriptomic dataset, the Cancer Cell Line Encyclopedia (CCLE) and western blotting, we also found CEBPG was overexpressed in AML. Moreover, we observed that CEBPG promotes AML cell proliferation by activating EIF4EBP1, thus contributing to the progression of AML. These findings indicate that CEBPG could act as a potential therapeutic target for AML patients. Conclusion In summary, we systematically explored the molecular characteristics of CEBPG in AML and identified CEBPG as a potential therapeutic target for AML patients. Our findings provide novel insights into the pathophysiology of AML and indicate a key role for CEBPG in promoting AML progression.

Abstract Background Depression imposes immense public health burden, demonstrating an urgent need of the identification of modifiable risk factors. Only a few cohort studies have analyzed the association between Mediterranean dietary pattern (MDP) and depression but with mixed results. We examined the impact of MDP on clinically ascertained depression in a large population-based dataset. Methods In 1991/92, detailed information on diet, using a food frequency questionnaire, and potential confounding factors (body weight, height, educational attainment, smoking, previous diabetes and hypertension, and physical activity) was collected, in a random sample of 49,261 Swedish women aged 29-49. Adherence to MDP was calculated. Clinical depression was extracted from the National Patient Register. Study participants were followed up through 2012. Results During an average follow-up of 20.4 years, 1677 incident cases of depression were diagnosed. We observed a lower risk of depression for medium (score 4-5) and high (6-9) adherence to MDP, compared with low (0-3) adherence (Medium: hazard ratio (HR) = 0.90, 95% confidence interval (CI) = 0.81-1.00; High: HR = 0.82, 95%CI = 0.71-0.94). Per unit increase of adherence, the risk of depression was reduced by 5% (HR = 0.95, 95%CI = 0.92-0.98). The association became stronger when restricting to severe form of depression (HR = 0.51, 95%CI = 0.33-0.76). The HRs were higher from age 50 onward both over the first and the second 10-year follow-up period, compared with before age 50, indicating stronger association with increasing age. Results remained after extensive sensitivity analyses. Conclusion Higher adherence to a Mediterranean diet at middle age was associated with a lower risk of depression later in life among Swedish women.

China has become the world’s largest producer and consumer of energy, and ranks first in its wind and solar power installation capacity. However, serious wind and solar curtailment in China has significantly hindered the development and utilization of renewable energy. To address problems in the consumption of renewable energy, this paper analyzes four key factors affecting the capacity of power generated from renewable energy sources: power balance, power regulation performance, transmission capacity, and load level. Focusing on these bottlenecks, we propose seven solutions: centralized and distributed development of renewable energy, improving the peak-load regulation flexibility of thermal power, increasing the proportion of gas turbines and pumped-hydropower storage, construction of transmission channels and a flexible smart grid developing demand response and virtual power plants, adopting new energy active support and energy storage, and establishing appropriate policies and market mechanisms. The Chinese Government and energy authorities have issued a series of policies and measures, and in the past three years, China has had remarkable achievements in the adoption of renewable energy. The rate of idle wind capacity decreased from 17% in 2016 to 7% in 2018, and that of solar decreased from 10% in 2016 to 3% in 2018.

ObjectiveAge-related decline within the noradrenergic system is associated with reduced cognition. The β-adrenoceptors are widely expressed in the brain as well as in the peripheral. Medications targeting β-adrenoceptor activity have been widely used in older adults. The aim of this study was to explore the associations between β-adrenoceptor acting drugs and the risk of dementia in the older population.MethodsThe subjects' information was collected from the electronic medical record (EMR) database. A propensity score matching strategy was conducted to select control participants for users of β2-agonists or β-antagonists. Logistic regression analysis was performed to estimate the risk of dementia with the use of β2-agonists or β-antagonists.ResultsA total of 1,429 participants in the EMR database were included in the study. The use of β2-agonists was strongly associated with a decreased risk of dementia [OR = 0.324, 95% confidence interval (CI): 0.149–0.707, P = 0.005]. This decreased risk showed a statistically significant inverse time-dependent pattern (Ptrend = 0.014). However, the use of non-selective β-antagonists significantly correlated with an increased dementia risk (OR = 1.961, 95% CI: 1.144–3.359, P = 0.014), although no time-dependent manner was found (Ptrend = 0.220). There was no association between selective β1-antagonists usage and dementia risk (OR = 1.114, P = 0.625).ConclusionThe use of β-adrenoceptor acting drugs seems to be associated with the risk of dementia. Pharmacological interventions modulating β2-adrenoceptor activity might be a potential target in therapeutics for dementia.

IntroductionTissue-resident macrophages (TRMs) are highly heterogeneous and have a complex and important role in tissue support, homeostasis, and function. The heterogeneity, maintenance, and function of TRMs, as one of the major immune cells in the ovary, are not well understood.MethodsApplication of flow cytometry, Parabiosis, Fate mapping, Macrophage depletion, etc.ResultsHere, we described two distinct macrophage subsets, F4/80hiCD11bint and F4/80intCD11bhi, with different phenotypic characteristics in the ovary of mice. The F4/80hiCD11bint population contained a distinct CD206+ subgroup and highly expressed CD81, while the F4/80intCD11bhi subset showed higher expression of CCR2 and TLR2. Notably, Ly6c+ macrophages were present almost exclusively in the F4/80intCD11bhi subpopulation. Combining in vivo fate mapping and parabiotic mouse models, we characterized the longevity and replenishment of the two macrophage populations. We found that both the F4/80hiCD11bint and F4/80intCD11bhi subsets were ovary-resident. Importantly, the F4/80hiCD11bint macrophages acted as a self-maintaining and long-lived population with a modest monocyte contribution at a steady state, and the F4/80intCD11bhi subpopulation had a relatively short lifespan with a greater contribution from monocytes. After macrophage ablation, disturbance of estradiol secretion and ovarian hemorrhage due to damaged vascular integrity was observed in mice.DiscussionOur data provide critical insights into ovarian macrophage heterogeneity and highlight the strategic role of TRMs in ovarian homeostasis and physiology.

With the development of high-throughput sequencing technology, the scale of single-cell RNA sequencing (scRNA-seq) data has surged. Its data are typically high-dimensional, with high dropout noise and high sparsity. Therefore, gene imputation and cell clustering analysis of scRNA-seq data is increasingly important. Statistical or traditional machine learning methods are inefficient, and improved accuracy is needed. The methods based on deep learning cannot directly process non-Euclidean spatial data, such as cell diagrams. In this study, we developed scGAEGAT, a multi-modal model with graph autoencoders and graph attention networks for scRNA-seq analysis based on graph neural networks. Cosine similarity, median L1 distance, and root-mean-squared error were used to measure the gene imputation performance of different methods for comparison with scGAEGAT. Furthermore, adjusted mutual information, normalized mutual information, completeness score, and Silhouette coefficient score were used to measure the cell clustering performance of different methods for comparison with scGAEGAT. Experimental results demonstrated promising performance of the scGAEGAT model in gene imputation and cell clustering prediction on four scRNA-seq data sets with gold-standard cell labels.

Patients with severe traumatic peripheral nerve injury (PNI) always suffer from incomplete recovery and poor functional outcome. Physical exercise-based rehabilitation, as a non-invasive interventional strategy, has been widely acknowledged to improve PNI recovery by promoting nerve regeneration and relieving pain. However, effects of exercise on chronic plastic changes following severe traumatic PNIs have been limitedly discussed. In this study, we created a long-gap sciatic nerve transection followed by autograft bridging in rats and tested the therapeutic functions of treadmill running with low intensity and late initiation. We demonstrated that treadmill running effectively facilitated nerve regeneration and prevented muscle atrophy and thus improved sensorimotor functions and walking performance. Furthermore, exercise could reduce inflammation at the injured nerve as well as prevent the overexpression of TRPV1, a pain sensor, in primary afferent sensory neurons. In the central nervous system, we found that PNI induced transcriptive changes at the ipsilateral lumber spinal dorsal horn, and exercise could reverse the differential expression for genes involved in the Notch signaling pathway. In addition, through neural imaging techniques, we found volumetric, microstructural, metabolite, and neuronal activity changes in supraspinal regions of interest (i.e., somatosensory cortex, motor cortex, hippocampus, etc.) after the PNI, some of which could be reversed through treadmill running. In summary, treadmill running with late initiation could promote recovery from long-gap nerve transection, and while it could reverse maladaptive plasticity after the PNI, exercise may also ameliorate comorbidities, such as chronic pain, mental depression, and anxiety in the long term.

Mutations in CAD gene, encoding a multifunctional enzyme involved in de novo pyrimidine biosynthesis, has been reported to be associated with early-onset epileptic encephalopathy (EOEE). Herein, we generated an induced pluripotent stem cell (iPSC) line from the skin fibroblasts of a five-year-old boy with CAD deficiency, presented with developmental delay, refractory epilepsy, anemia with anisopoikilocytosis, and dramatic responsive to supplementation with oral uridine, carrying biallelic mutations, c.108delC (p.Tyr36Tyrfs*15) and c.3775G>A (p.Val1259Met) in CAD. These iPSCs exhibited stable amplification, expressed pluripotent markers, and differentiated spontaneously into three germ layers in vitro.

The origins of preexisting SARS-CoV-2 cross-reactive antibodies and their potential impacts on vaccine efficacy have not been fully clarified. In this study, we demonstrated that S2 was the prevailing target of the preexisting S protein cross-reactive antibodies in both healthy human and SPF mice. A dominant antibody epitope was identified on the connector domain of S2 (1147-SFKEELDKYFKNHT-1160, P144), which could be recognized by preexisting antibodies in both human and mouse. Through metagenomic sequencing and fecal bacteria transplant, we demonstrated that the generation of S2 cross-reactive antibodies was associated with commensal gut bacteria. Furthermore, six P144 reactive monoclonal antibodies were isolated from naïve SPF mice and were proven to cross-react with commensal gut bacteria collected from both human and mouse. A variety of cross-reactive microbial proteins were identified using LC-MS, of which E. coli derived HSP60 and HSP70 proteins were confirmed to be able to bind to one of the isolated monoclonal antibodies. Mice with high levels of preexisting S2 cross-reactive antibodies mounted higher S protein specific binding antibodies, especially against S2, after being immunized with a SARS-CoV-2 S DNA vaccine. Similarly, we found that levels of preexisting S2 and P144-specific antibodies correlated positively with RBD binding antibody titers after two doses of inactivated SARS-CoV-2 vaccination in human. Collectively, our study revealed an alternative origin of preexisting S2-targeted antibodies and disclosed a previously neglected aspect of the impact of gut microbiota on host anti-SARS-CoV-2 immunity.

Salidroside, the main bioactive compound isolated from the plant source of Rhodiola rosea L, possesses broad-spectrum pharmacological activities, but suffers from the low cell membranes permeability and alimentary absorption due to its high polarity. Therefore, a whole-cell catalytic strategy for the synthesis of salidroside esters was explored to improve its lipophilicity. The results showed that Aspergillus oryzae demonstrated the highest biocatalytic activity among the microbial strains tested. For the synthesis of salidroside caprylate, the optimum conditions of reaction medium, Aspergillus oryzae amount, molar ratio of vinyl caprylate to salidroside and reaction temperature were acetone, 30 mg/ml, 10°C and 40°C, respectively. Under these conditions, the initial reaction rate was 15.36 mM/h, and substrate conversion and regioselectivity all reached 99%. Moreover, the results indicated that although various 6′-monoesters derivatives of salidroside were exclusively obtained with excellent conversions (96%–99%), the reaction rate varied greatly with different chain-length acyl donors. This study details an efficient and cost-effective biocatalytic approach for the synthesis of salidroside esters by using Aspergillus oryzae as a catalyst for the first time. Considering the whole cell catalytic efficiency and operational stability, this strategy may provide a new opportunity to develop green industrial processes production for ester derivatives of salidroside and its analogues.

BackgroundRetroperitoneal liposarcoma (RPLS) is a variety of soft tissue sarcoma that originates from mesenchymal cells. A tumor measuring greater than 30 cm is called a “giant liposarcoma.” A part of the neoplasm tends to grow in size, recur locally, or metastasize distantly. In those with such a condition, long-term survival is uncommon. Therefore, it is necessary to present a uniform and optimized program to improve the prognosis.MethodsBy successfully treating a multiple-recurrent giant retroperitoneal dedifferentiated liposarcoma (RP DDLPS) in July 2010, we hope to devise more comprehensive strategies to improve diagnosis, therapy, and outcome.ResultsIn July 2010, we thoroughly resected a giant multifocal RPLS with a concomitant part of the gastric wall. The histopathological examination revealed a high-grade (grade III) dedifferentiated liposarcoma. The patient was discharged uneventfully on the 15th postoperative day. She relapsed after 16 months and needed another complete excision. After 9 months, she died after the fourth recidive. The patient had experienced four recurrences and underwent operations with 15 years of follow-up.ConclusionsThe above demonstrates that we were able to successfully treat the multirecurrent giant RPLS, despite the patient’s poor medical condition, with meticulous management. Moreover, this indicates that long-term survival could be achieved for high-grade RP DDLPS.

Testicular germ cell tumours (TGCTs) respond well to cisplatin-based therapy. However, cisplatin resistance and poor outcomes do occur. It has been suggested that a shift towards DNA hypermethylation mediates cisplatin resistance in TGCT cells, although there is little direct evidence to support this claim. Here we utilized a series of isogenic cisplatin-resistant cell models and observed a strong association between cisplatin resistance in TGCT cells and a net increase in global CpG and non-CpG DNA methylation spanning regulatory, intergenic, genic and repeat elements. Hypermethylated loci were significantly enriched for repressive DNA segments, CTCF and RAD21 sites and lamina associated domains, suggesting that global nuclear reorganization of chromatin structure occurred in resistant cells. Hypomethylated CpG loci were significantly enriched for EZH2 and SUZ12 binding and H3K27me3 sites. Integrative transcriptome and methylome analyses showed a strong negative correlation between gene promoter and CpG island methylation and gene expression in resistant cells and a weaker positive correlation between gene body methylation and gene expression. A bidirectional shift between gene promoter and gene body DNA methylation occurred within multiple genes that was associated with upregulation of polycomb targets and downregulation of tumour suppressor genes. These data support the hypothesis that global remodelling of DNA methylation is a key factor in mediating cisplatin hypersensitivity and chemoresistance of TGCTs and furthers the rationale for hypomethylation therapy for refractory TGCT patients.