Brain activation and connection across resting and motor-task states in patients with generalized tonic-clonic seizures.

AIMS: Motor abnormalities have been identified as one common symptom in patients with generalized tonic-clonic seizures (GTCS) inspiring us to explore the disease in a motor execution condition, which might provide novel insight into the pathomechanism. METHODS: Resting-state and motor-task fMRI data were collected from 50 patients with GTCS, including 18 patients newly diagnosed without antiepileptic drugs (ND_GTCS) and 32 patients receiving antiepileptic drugs (AEDs_GTCS). Motor activation and its association with head motion and cerebral gradients were assessed. Whole-brain network connectivity across resting and motor states was further calculated and compared between groups. RESULTS: All patients showed over-activation in the postcentral gyrus and the ND_GTCS showed decreased activation in putamen. Specifically, activation maps of ND_GTCS showed an abnormal correlation with head motion and cerebral gradient. Moreover, we detected altered functional network connectivity in patients within states and across resting and motor states by using repeated-measures analysis of variance. Patients did not show abnormal connectivity in the resting state, while distributed abnormal connectivity in the motor-task state. Decreased across-state network connectivity was also found in all patients. CONCLUSION: Convergent findings suggested the over-response of activation and connection of the brain to motor execution in GTCS, providing new clues to uncover motor susceptibility underlying the disease.

Mechanisms of angiogenesis in tumour.

Angiogenesis is essential for tumour growth and metastasis. Antiangiogenic factor-targeting drugs have been approved as first line agents in a variety of oncology treatments. Clinical drugs frequently target the VEGF signalling pathway during sprouting angiogenesis. Accumulating evidence suggests that tumours can evade antiangiogenic therapy through other angiogenesis mechanisms in addition to the vascular sprouting mechanism involving endothelial cells. These mechanisms include (1) sprouting angiogenesis, (2) vasculogenic mimicry, (3) vessel intussusception, (4) vascular co-option, (5) cancer stem cell-derived angiogenesis, and (6) bone marrow-derived angiogenesis. Other non-sprouting angiogenic mechanisms are not entirely dependent on the VEGF signalling pathway. In clinical practice, the conversion of vascular mechanisms is closely related to the enhancement of tumour drug resistance, which often leads to clinical treatment failure. This article summarizes recent studies on six processes of tumour angiogenesis and provides suggestions for developing more effective techniques to improve the efficacy of antiangiogenic treatment.

Circulating galectin-3 level association with cardiovascular risk factors during peritoneal dialysis.

OBJECTIVE: Cardiovascular disease (CVD) represents the primary cause of mortality in patients afflicted with end-stage renal disease and undergoing peritoneal dialysis (PD) treatment. Galectin-3 (Gal-3), a molecule known to exhibit a correlation with CVD mortality garners considerable interest. The objective of this study was to explore the potential association between serum Gal-3 levels and other CVD risk factors among PD patients. METHODS: In this cross-sectional study, a total of 114 PD patients with a minimum of 3 months of PD treatment were enrolled. Serum Gal-3 levels were quantified using an enzyme-linked immunosorbent assay. The data of patients with Gal-3 levels higher and lower than 26.744 pg/ml were compared using Mann-Whitney U tests or t tests. Pearson's correlation or Spearman's correlation analysis and multivariate regression were used to assess the associations between the known risk factors for CVD and Gal-3. RESULTS: In comparison to the inter-group baseline data, the low Gal-3 group exhibited a higher glomerular filtration rate (GFR). Gal-3 levels correlate positively with PD duration, B-type natriuretic peptide (BNP), growth differentiation factor 15 (GDF-15), interventricular septal thickness in diastolic (IVST), and left ventricular mass index (LVMI). Conversely, Gal-3 exhibited a negative correlation with albumin levels. Multivariate linear regression analysis demonstrated a positive correlation between Gal-3 levels and BNP, GDF-15, PD duration, IVST and LVMI. Gal-3 levels were negatively correlated with albumin levels. CONCLUSIONS: Gal-3 was strongly associated with BNP, GDF-15, IVST and LVMI in patients undergoing PD treatment. Prospective studies should be carried out to determine whether Gal-3 can be a promising biomarker in predicting increased risk of adverse cardiovascular events in PD patients.

Impact of preoperative antiviral therapy on the prognosis of hepatitis B virus-related hepatocellular carcinoma.

BACKGROUND: For chronic hepatitis B virus (HBV) infection patients, increasing evidence has demonstrated the effectiveness of expanding the indications and applicable population for antiviral therapy. However, the expanded indication of antiviral therapy for hepatocellular carcinoma (HCC) remains to be further explored. METHODS: 196 HBV-related HCC patients who received radical hepatectomy and nucleos(t)ide analogues (NAs) therapy at Sichuan Provincial People's Hospital were enrolled in this study. HCC recurrence, overall survival (OS), early virological (VR) and biochemical responses (BR) of patients were compared between different NAs therapy and the use of anti-programmed cell death protein 1 (PD-1) therapy. RESULTS: NAs therapy at different timing of surgery was a strong independent risk factor for postoperative recurrence and overall mortality of HBV-related HCC patients. Furthermore, in HCC patients who received postoperative anti-PD-1 therapy, patients with HBV DNA < 1000 copy/mL had significantly better recurrence-free survival (RFS) and OS than those with HBV DNA ≥ 1000 copy/mL (HR: 7.783; P = 0.002; HR: 6.699; P < 0.001). However, the differences of RFS and OS rates between entecavir group and tenofovir disoproxil fumarate group were not statistically significant. Similar results were also observed in the rates of early VR, BR and combined VR and BR. CONCLUSION: Timely and reasonable preoperative NAs therapy showed clinical benefit in improving the prognosis of patients with HBV-related HCC, even in the case of normal alanine aminotransferase (ALT) level and negative hepatitis e antigen (HBeAg). Furthermore, a possible synergistic effect between antiviral therapy and anti-PD-1 therapy was founded and need further verification.

Integrated clinical and prognostic analyses of mTOR/Hippo pathway core genes in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most aggressive and dismal cancers globally. Emerging evidence has established that mTOR and Hippo pathways are oncogenic drivers of HCC. However, the prognostic value of these pathways in HCC remains unclear. In this study, we aimed to develop a gene signature utilizing the mTOR/Hippo genes for HCC prognostication. A multiple stage strategy was employed to screen, and a 12-gene signature based on mTOR/Hippo pathways was constructed to predict the prognosis of HCC patients. The risk scores calculated by the signature were inversely correlated with patient prognosis. Validation of the signature in independent cohort confirmed its predictive power. Further analysis revealed molecular differences between high and low-risk groups at genomic, transcriptomic, and protein-interactive levels. Moreover, immune infiltration analysis revealed an immunosuppressive state in the high-risk group. Finally, the gene signature could predict the sensitivity to current chemotherapeutic drugs. This study demonstrated that combinatorial mTOR/Hippo gene signature was a robust and independent prognostic tool for survival prediction of HCC. Our findings not only provide novel insights for the molecular understandings of mTOR/Hippo pathways in HCC, but also have important clinical implications for guiding therapeutic strategies.

Evaluating the response and adaptation of urban stormwater systems to changed rainfall with the CMIP6 projections.

Climate change is altering urban rainfall characteristics, leading to extreme urban stormwater and, particularly, more frequent flooding. Due to the uncertainty of climate change, the responses of urban drainage systems to climate change are becoming more complicated. This complexity makes it difficult for decision makers to assess whether urban infrastructure is sufficiently resilient to cope with flood risks. In this study, the Xiao Zhai area, a high-density urban area of China, was used as an example. A quantitative method for assessing these risks and the resilience of urban drainage systems to future urban stormwater was developed. First, based on the Coupled Model Intercomparison Project Phase 6 (CMIP6), the variation and uncertainty of future rainfall in the study area were analysed. A high-fidelity hydro-hydraulic model was developed to analyse the influence of climate change on future urban stormwater. Finally, the relationship between urban flood risk and the resilience of urban drainage systems was evaluated. The results show that the temporal distribution of future rainfall from 2023 to 2100 is relatively uniform. However, the number of heavy rainfall events increases significantly during this period. The flood risk caused by future rainfall was one level higher than the historical flood risk. For example, the flood risk caused by future 5a rainfall is equal to the flood risk from historical 10a rainfall. The correlations between the spatial distributions of flood risk and resilience are 0.49-0.63. Urban drainage systems urgently need to be improved and refined in areas with flood risk and low resilience to become more resilient to climate change. Rational planning of grey-green rainwater facilities in flood risk and low resilience areas can improve the rainwater system's resilience to 0.67-0.95 for climate change.

Single-cell profiling reveals the heterogeneity of NK cells during anti-PD-1 therapy in non-small-cell lung cancer.

BACKGROUND: The efficacy of immune checkpoint inhibitors remains limited in non-small cell lung cancer (NSCLC). Natural killer (NK) cells serve as the key element of innate immunity and play an important role in anti-tumor immunity, the impact of NK cells on efficacy of anti-PD-1 therapy in NSCLC is worth exploring. METHODS: We analyzed single-cell transcriptome data derived from biopsies of NSCLC patients receiving anti-PD-1 treatment. Immune cell subtypes were identified and further cell-cell communication were analyzed and verified. RESULTS: We observed totally 6 distinct NK cells clusters in NSCLC infiltrating immune cells. It's worth noting that enrichment of immature NK cells was found in responsive group. A series of marker genes of immature NK cells were associated with anti-PD-1 response and related to immune regulation processes such as antigen processing, Th1, Th17 cells activation. Moreover, effector CD8+ T cells were significantly enriched in responsive group and showed similar trajectories with immature NK cells. Cell-cell communication analysis showed that immature NK cells showed strong interactions with Th17 cells and effector CD8+ T cells. Furthermore, when validating the expression of immature NK cells marker genes, we found that CXCR4 was associated with enriched infiltration of CD8+ T cells. CONCLUSIONS: In conclusion, immature NK cells may facilitate the efficacy of anti-PD-1 therapy by interacting with Th1 cells, Th17 cells and enhancing infiltration of effector CD8+ T cells. Our data suggested that NK cells could be a promising target to improve the prognosis of NSCLC patients.

Non-invasive assessment of liver fibrosis by serum metabolites in non-human primates and human patients.

Liver fibrosis, a rising cause of chronic liver diseases, could eventually develop into cirrhosis and liver failure. Current diagnosis of liver fibrosis relies on pathological examination of hepatic tissues acquired from percutaneous biopsy, which may produce invasive injuries. Here, for non-invasive assessment of liver fibrosis, we applied comparative multi-omics in non-human primates (rhesus macaques) and subsequent serum biopsy in human patients. Global transcriptomics showed significant gene enrichment of metabolism process, in parallel with oxidative stress and immune responses in fibrotic primates. Targeted metabolomics were concordant with transcriptomic patterns, identifying elevated lipids and porphyrin metabolites during hepatic fibrosis. Importantly, liquid biopsy results validated that specific metabolites in the serum (e.g., biliverdin) were highly diagnostic to distinguish human patients from healthy controls. Findings describe the interconnected transcriptional and metabolic network in primate liver fibrosis and provide potential indices for non-invasive detection of liver fibrosis in humans.

Outpatient Parenteral Antibiotic Therapy for Diabetic Foot Osteomyelitis in an Uninsured and Underinsured Cohort.

Background: Diabetic foot osteomyelitis (DFO) is usually treated with prolonged outpatient parenteral antibiotic therapy (OPAT). Evaluation and treatment of non-antibiotic aspects of DFO (e.g., peripheral artery disease [PAD]) are also recommended. There is limited data regarding OPAT practice patterns and outcomes for DFO. Methods: Single-center observational study of patients receiving OPAT for DFO in a large United States public hospital between January 2017 and July 2019. We abstracted data regarding microbiology test, antibiotics, clinical outcomes, and non-antibiotic DFO management. Results: Ninety-six patients were included and some had >1 DFO-OPAT course during the study period (106 DFO-OPAT courses included). No culture was obtained in 40 (38%) of courses. Methicillin-resistant S. aureus (MRSA) was cultured in 15 (14%) and P. aeruginosa in 1 (1%) of DFO-OPAT courses. An antibiotic with MRSA activity (vancomycin or daptomycin) was used in 79 (75%) of courses and a parenteral antibiotic with anti-pseudomonal activity was used in 7 (6%) of courses. Acute kidney injury occurred in 19 (18%) DFO-OPAT courses. An ankle-brachial index measurement was obtained during or 6 months prior to the first DFO-OPAT course for 44 (49%) of patients. Forty-two (44%) patients died or had an amputation within 12 months of their initial hospital discharge. Conclusions: We found high rates of empiric antibiotic therapy for DFO and low uptake of the non-antibiotic aspects of DFO care. Better implementation of microbiological tests for DFO in addition to stronger integration of infectious disease and non-infectious diseases care could improve DFO outcomes.

Development of ensemble learning models for prognosis of hepatocellular carcinoma patients underwent postoperative adjuvant transarterial chemoembolization.

Background: Postoperative adjuvant transarterial chemoembolization (PA-TACE) has been increasing widely used to improve the prognosis of hepatocellular carcinoma (HCC) patients. However, clinical outcomes vary from patient to patient, which calls for individualized prognostic prediction and early management. Methods: A total of 274 HCC patients who underwent PA-TACE were enrolled in this study. The prediction performance of five machine learning models was compared and the prognostic variables of postoperative outcomes were identified. Results: Compared with other machine learning models, the risk prediction model based on ensemble learning strategies, including Boosting, Bagging, and Stacking algorithms, presented better prediction performance for overall mortality and HCC recurrence. Moreover, the results showed that the Stacking algorithm had relatively low time consumption, good discriminative ability, and the best prediction performance. In addition, according to time-dependent ROC analysis, the ensemble learning strategies were found to perform well in predicting both OS and RFS for the patients. Our study also found that BCLC Stage, hsCRP/ALB and frequency of PA-TACE were relatively important variables in both overall mortality and recurrence, while MVI contributed more to the recurrence of the patients. Conclusion: Among the five machine learning models, the ensemble learning strategies, especially the Stacking algorithm, could better predict the prognosis of HCC patients following PA-TACE. Machine learning models could also help clinicians identify the important prognostic factors that are clinically useful in individualized patient monitoring and management.

Construction and application of sponge city resilience evaluation system: a case study in Xi'an, China.

Urban vulnerability is evident when highly complex flood risks overlap with diverse cities, and it is important to enhance the resilience of cities to flood shocks. In this study, a sponge city resilience assessment system is established considering engineering, environmental and social indicators, and the grey relational analysis method (GRA) is used to quantify sponge city resilience. At the same time, a multi-objective optimization model is established based on the three dimensions of water ecological environment, drainage safety, and waterlogging safety. The optimal configuration of grey-green infrastructure is weighed by combining the ideal point method, aiming to ensure that cities effectively reduce flood risk through the optimal configuration scheme. Taking the Xiaozhai area in Xi'an as the study area, the evaluation results show that the grey relational degree (GRD) of the resilience indexes of the original scheme is between 0.390 and 0.661 under the seven different return periods, while the optimization scheme ranges from 0.648 to 0.765, with the best sponge city resilience at a return period of 2a. Compared with the original scheme, the optimized sponge city resilience level increases from level II to nearly level I in the low return period and from level IV to level II in the high return period, indicating that city's ability to cope with waterlogging and pollution is enhanced significantly. Besides, the main factor affecting the sponge city resilience is the runoff control rate, followed by pollutant load reduction rate, which can provide a methodological framework for the assessment and improvement of sponge city resilience.

[Circular RNA ame_circ_000115 regulates expression of genes in larval gusts of Apis mellifera ligustica stressed by Ascosphaera apis].

Circular RNAs (circRNAs) are a new class of non-coding RNAs, which have been confirmed to regulate insect gene expression and immune response through multiple manners such as competing endogenous RNA (ceRNA) regulatory network. Currently, function of circRNA in honey bee immune response remains unclear. In this study, PCR and Sanger sequencing were performed to validate the back splicing (BS) site of ame_circ_000115 (in short ac115). RT-qPCR was used to detect the expression profile of ac115 in larval guts of Apis mellifera ligustica stressed by Ascosphaera apis. Dual-luciferase reporter gene assay was conducted to verify the binding relationship between ac115 and ame-miR-13b. Interference of ac115 in larval guts was carried out by feeding specific siRNA, followed by determination of the effect of ac115 interference on expression of six genes relevant to host immune response. The results confirmed the existence of BS site within ac115. Compared with the un-inoculated group, the expression of ac115 in 4-day-old larval gut of the A. apis-inoculated group was up-regulated with extreme significance (P < 0.000 1), while that in 5- and 6-day-old larval guts were significantly up-regulated (P < 0.05). The brightness of specific band for ac115 in 4-, 5- and 6-day-old larval guts of the siRNA-circ_000115-fed group gradually became weak, whereas that of the siRNA-scrambl-fed group was pretty high without obvious variation. Compared with that of the siRNA-scramble-fed group, the expression of ac115 in 4-day-old larval gut of the siRNA-circ_000115-fed group was significantly down-regulated (P < 0.05), whereas that of the 5- and 6-day-old larval guts were down-regulated with extreme significance (P < 0.001). Ame-miR-13b was truly existed and expressed in A. m. ligustica larval guts, and there was true binding relationship between ac115 and ame-miR-13b. Compared with that of the siRNA-scramble-fed group, the expression of antimicrobial peptide genes hymenoptaecin and abaecin in 6-day-old larval gut of the siRNA-circ_000115-fed group was significantly up-regulated (P < 0.05), while that of ecdysone receptor (Ecr) was down-regulated with extreme significance (P < 0.01). These results indicate that ac115 is truly expressed in A. m. ligustica larval guts, BS site truly exists within ac115, and effective interference of ac115 in A. m. ligustica larval guts can be achieved via feeding siRNA. Moreover, ac115 potentially regulates Ecr expression through adsorption of ame-miR-13b and expression of hymenoptaecin and abaecin using a non-ceRNA manner, further participating in host stress-response.

Exosomes derived from human adipose mesenchymal stem cells ameliorate hepatic fibrosis by inhibiting PI3K/Akt/mTOR pathway and remodeling choline metabolism.

Liver fibrosis is a chronic liver disease with the presence of progressive wound healing response caused by liver injury. Currently, there are no approved therapies for liver fibrosis. Exosomes derived from human adipose mesenchymal stem cells (hADMSCs-Exo) have displayed a prominent therapeutic effect on liver diseases. However, few studies have evaluated therapeutic effect of hADMSCs-Exo in liver fibrosis and cirrhosis, and its precise mechanisms of action remain unclear. Herein, we investigated anti-fibrotic efficacy of hADMSCs-Exo in vitro and in vivo, and identified important metabolic changes and the detailed mechanism through transcriptomic and metabolomic profiling. We found hADMSCs-Exo could inhibit the proliferation of activated hepatic stellate cells through aggravating apoptosis and arresting G1 phase, effectively inhibiting the expression of profibrogenic proteins and epithelial-to-mesenchymal transition (EMT) in vitro. Moreover, it could significantly block collagen deposition and EMT process, improve liver function and reduce liver inflammation in liver cirrhosis mice model. The omics analysis revealed that the key mechanism of hADMSCs-Exo anti-hepatic fibrosis was the inhibition of PI3K/AKT/mTOR signaling pathway and affecting the changes of metabolites in lipid metabolism, and mainly regulating choline metabolism. CHPT1 activated by hADMSCs-Exo facilitated formation and maintenance of vesicular membranes. Thus, our study indicates that hADMSCs-Exo can attenuate hepatic stellate cell activation and suppress the progression of liver fibrosis, which holds the significant potential of hADMSCs-Exo for use as extracellular nanovesicles-based therapeutics in the treatment of liver fibrosis and possibly other intractable chronic liver diseases.

ST8SIA6-AS1 contributes to hepatocellular carcinoma progression by targeting miR-142-3p/HMGA1 axis.

Hepatocellular carcinoma (LIHC) accounts for 90% of all liver cancers and is a serious health concern worldwide. Long noncoding RNAs (lncRNAs) have been observed to sponge microRNAs (miRNAs) and participate in the biological processes of LIHC. This study aimed to evaluate the role of the ST8SIA6-AS1-miR-142-3p-HMGA1 axis in regulating LIHC progression. RT-qPCR and western blotting were performed to determine the levels of ST8SIA6-AS1, miR-142-3p, and HMGA1 in LIHC. The relationship between ST8SIA6-AS1, miR-142-3p, and HMGA1 was assessed using luciferase assay. The role of the ST8SIA6-AS1-miR-142-3p-HMGA1 axis was evaluated in vitro using LIHC cells. Expression of ST8SIA6-AS1 and HMGA1 was significantly upregulated, whereas that of miR-142-3p was markedly lowered in LIHC specimens and cells. ST8SIA6-AS1 accelerated cell growth, invasion, and migration and suppressed apoptosis in LIHC. Notably, ST8SIA6-AS1 inhibited HMGA1 expression by sponging miR-142-3p in LIHC cells. In conclusion, sponging of miR-142-3p by ST8SIA6-AS1 accelerated the growth of cells while preventing cell apoptosis in LIHC cells, and the inhibitory effect of miR-142-3p was abrogated by elevating HMGA1 expression. The ST8SIA6-AS1-miR-142-3p-HMGA1 axis represents a potential target for the treatment of patients with LIHC.

An Orthotopic Resection Surgical Technique Using an Inferior Infracolic Approach for Laparoscopic Pancreaticoduodenectomy.

The no-touch isolation technique has been widely used in cancer surgery as a strategy to prevent cancer cells from spreading; however, it is difficult to apply in laparoscopic pancreaticoduodenectomy (LPD). Here, we describe an orthotopic resection surgical technique that applies a no-touch principle for LPD and can help with the in situ resection of tumors. In implementing this surgical strategy, Kocher's maneuver was not performed first. Instead, after the exploration of the abdominal cavity, the distal stomach and the pancreatic neck were transected. Then, the dissection of the uncinate process of the pancreas, the duodenum, and the superior mesenteric vein and artery is carried out via an inferior infracolic approach. Finally, the pancreatic head and duodenum were removed in situ. Among the 41 patients who underwent this technique, two (4.9%) required conversion to open surgery due to uncontrolled bleeding. The average operative time was 335 min (248-1055 min). The mean estimated blood loss was 300 mL (50-1250 mL). Two patients (4.9%) underwent combined PV resection and reconstruction; six patients (14.6%) required a blood transfusion; two patients (4.9%) suffered from postoperative bleeding; two patients (4.9%) suffered from Grade B pancreatic fistulas; one patient (2.4%) suffered from bile leakage; and three patients (7.3%) suffered from abdominal fluid collection. No patients died during the perioperative period. Therefore, orthotopic LPD using an inferior infracolic approach is safe and feasible for patients with malignant pancreatic head and periampullary tumors. However, further investigations are required to elucidate its oncological benefits.

ITGA5 and ITGB1 contribute to Sorafenib resistance by promoting vasculogenic mimicry formation in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is labeled with high mortality and tolerance to chemotherapy. Sorafenib has been the first-line treatment option in HCC patients for past decades, while the therapeutic effect was limited in almost HCC patients. METHODS: In this study, we analyzed public omics data of HCC patients with different responses to Sorafenib treatment. To confirm the role of integrins A5 and B1 (ITGA5 and ITGB1) in Sorafenib resistance, we generated the Sorafenib-resistant (Sor-R) cell lines and cells overexpressing ITGA5 or ITGB1. Hypoxia level was measured using Hypoxy probe by flow cytometry, while vasculogenic mimicry was detected and quantified by CD31 and periodic acid schiff staining. RESULTS: Hypoxia was upregulated in non-responsive patients, accompanied with genes involved in encoding extracellular matrix components and angiogenesis such as ITGA5 and ITGB1. Sor-R hepatoma cell lines were constructed to measure expression and role of candidate genes. ITGA5 and ITGB1 were augmented in Sor-R cells. Upregulation of ITGA5 or ITGB1 reduced the sensitivity to Sorafenib in HepG2 and Huh7 cells, aggravated the hypoxic condition and resulted in formation of vascular mimicry. CONCLUSIONS: These findings suggested that hypoxia associated vascular mimicry account for non-response to Sorafenib treatment in HCC patients. ITGA5 and ITGB1 may serve as effective predictors of HCC patients' outcome after Sorafenib treatment, which also provides a new target for HCC patients resistant to Sorafenib.

Epigenome-wide association study of BMI in Black populations from InterGEN and GENOA.

OBJECTIVE: Obesity is a significant public health concern across the globe. Research investigating epigenetic mechanisms related to obesity and obesity-associated conditions has identified differences that may contribute to cellular dysregulation that accelerates the development of disease. However, few studies include Black women, who experience the highest incidence of obesity and early onset of cardiometabolic disorders. METHODS: The association of BMI with epigenome-wide DNA methylation (DNAm) was examined using the 850K Illumina EPIC BeadChip in two Black populations (Intergenerational Impact of Genetic and Psychological Factors on Blood Pressure [InterGEN], n = 239; and The Genetic Epidemiology Network of Arteriopathy [GENOA] study, n = 961) using linear mixed-effects regression models adjusted for batch effects, cell type heterogeneity, population stratification, and confounding factors. RESULTS: Cross-sectional analysis of the InterGEN discovery cohort identified 28 DNAm sites significantly associated with BMI, 24 of which had not been previously reported. Of these, 17 were replicated using the GENOA study. In addition, a meta-analysis, including both the InterGEN and GENOA cohorts, identified 658 DNAm sites associated with BMI with false discovery rate < 0.05. In a meta-analysis of Black women, we identified 628 DNAm sites significantly associated with BMI. Using a more stringent significance threshold of Bonferroni-corrected p value 0.05, 65 and 61 DNAm sites associated with BMI were identified from the combined sex and female-only meta-analyses, respectively. CONCLUSIONS: This study suggests that BMI is associated with differences in DNAm among women that can be identified with DNA extracted from salivary (discovery) and peripheral blood (replication) samples among Black populations across two cohorts.

Transcriptome-Wide Characterization of piRNAs during the Developmental Process of European Honey-Bee Larval Guts.

piRNAs play pivotal roles in maintaining genome stability, regulating gene expression, and modulating development and immunity. However, there are few piRNA-associated studies on honey-bees, and the regulatory role of piRNAs in the development of bee guts is largely unknown. Here, the differential expression pattern of piRNAs during the developmental process of the European honey-bee (Apis mellifera) larval guts was analyzed, followed by investigation of the regulatory network and the potential function of differentially expressed piRNAs (DEpiRNAs) in regulating gut development. A total of 843 piRNAs were identified in the larval guts of A. mellifera; among these, 764 piRNAs were shared by 4- (Am4 group), 5- (Am5 group), and 6-day-old (Am6 group) larval guts, while 11, 67, and one, respectively, were unique. The first base of piRNAs in each group had a cytosine (C) bias. Additionally, 61 up-regulated and 17 down-regulated piRNAs were identified in the "Am4 vs. Am5" comparison group, further targeting 9, 983 genes, which were involved in 50 GO terms and 142 pathways, while two up-regulated and five down-regulated piRNAs were detected in the "Am5 vs. Am6" comparison group, further targeting 1, 936 genes, which were engaged in 41 functional terms and 101 pathways. piR-ame-742536 and piR-ame-856650 in the "Am4 vs. Am5" comparison group as well as piR-ame-592661 and piR-ame-31653 in the "Am5 vs. Am6" comparison group were found to link to the highest number of targets. Further analysis indicated that targets of DEpiRNAs in these two comparison groups putatively regulate seven development-associated signaling pathways, seven immune-associated pathways, and three energy metabolism pathways. Moreover, the expression trends of five randomly selected DEpiRNAs were verified based on stem-loop RT-PCR and RT-qPCR. These results were suggestive of the overall alteration of piRNAs during the larval developmental process and demonstrated that DEpiRNAs potentially modulate development-, immune-, and energy metabolism-associated pathways by regulating the expression of corresponding genes via target binding, further affecting the development of A. mellifera larval guts. Our data offer a novel insight into the development of bee larval guts and lay a basis for clarifying the underlying mechanisms.

Umbilical cord blood-derived mesenchymal stem cells transplantation decreases incidence of liver cancer in end-stage liver disease patients: a retrospective analysis over 5 years.

OBJECTIVE: To investigate effects of umbilical cord blood-derived mesenchymal stem cells (UC-MSCs) transplantation on the risks of liver cancers in end-stage liver disease (ESLD) patients. METHODS: Data of 45 ESLD patients received UC-MSCs transplantation (UC-MSCs group) and 50 ESLD patients received non-UC-MSCs transplantation (non-UC-MSCs group) were retrospectively analyzed, and they were followed up for 5 years. RESULTS: The incidence of liver cancer was much lower in UC-MSCs group than that in the non-UC-MSCs group (12% vs 2.2%, P=0.008). The survival rate of patients was significantly higher in the UC-MSCs group than that in the non-UC-MSCs group during the five years follow-up (P=0.043). The inflammation and fibrosis scores were lower in the UC-MSCs group than those in the non-UC-MSCs group (P<0.036). Compared with the non-UC-MSCs group, the UC-MSCs group showed largely improved liver cirrhosis degree and lower Child-Pugh scores (P<0.05). CONCLUSIONS: UC-MSCs transplantation is able to decrease the risks of liver cancers in ESLD patients, which might work by inhibiting inflammation.