Diffusion tensor imaging combined with chemical shift-encoded sequence to quantify the adaptive changes of calf muscles in amateur marathoners.

PURPOSE: Calf muscles play an important role in marathon race, and the incidence of injury is high in this process. This study prospectively quantified diffusion tensor metrics, muscle fat fraction (MFF) and cross-sectional area (CSA) of calf muscles induced by endurance exercise in amateur marathoners, and the potential mechanisms underlying the changes in these parameters were analyzed. METHOD: In this prospective study, 35 marathoners (27 males, 8 females; mean age (standard deviation, SD), 38.92 (4.83) years) and 26 controls (18 males, 8 females; mean age (SD), 38.35 (6.75) years) underwent magnetic resonance imaging (MRI) from September 2022 to March 2023. The diffusion tensor eigenvalues (λ1, λ2, λ3), radial diffusivity (RD), fractional anisotropy (FA), MFF and CSA of calf muscles were compared between marathoners and controls. A binary logistic regression model with gender correction was performed analyze the relationship between marathon exercise and DTI parameters, CSA and MFF of calf muscles. RESULTS: Interobserver agreement was good (κ = 0.71). The results of binary logistic regression model with gender correction showed that the regression coefficients of FA values in anterior group of calf (AC), soleus (SOL), medial gastrocnemius (MG) and lateral gastrocnemius (LG) were negative, and the odds ratios (OR) were 0.33, 0.45, 0.35, 0.05, respectively (P < 0.05). The OR of RD in SOL and λ2 in external group of calf (EC) were relatively higher, 3.74 and 3.26, respectively (P < 0.05). CSA was greater in SOL of marathoners, with an OR value of 1.00(P < 0.05). The MFF in AC and LG was lower in marathoners and OR of two indexes were -0.69 and -0.59, respectively (P < 0.05). CONCLUSIONS: Diffusion tensor imaging (DTI) combined with chemical shift-encoded sequence can noninvasively detect and quantify the adaptive changes of calf muscle morphology, microstructure and tissue composition induced by long-term running training in amateur marathoners.

Design, Synthesis, and Activity Evaluation of Fluorine-Containing Scopolamine Analogues as Potential Antidepressants.

This study aimed to develop novel rapid-acting antidepressants with sustained efficacy and favorable safety profiles. We designed and synthesized a series of fluorine-containing scopolamine analogues and evaluated their antidepressant potential. In vitro cytotoxicity assays showed that most of these compounds exhibited minimal toxicity against neuronal and non-neuronal mammalian cell lines (IC50 > 100 µM). The antidepressant activities of the compounds were evaluated using the tail suspension test, and S-3a was identified as a lead compound with potent and sustained antidepressant effects. Behaviorally, S-3a alleviated depressive symptoms in mice and displayed a higher cognitive safety margin than scopolamine. Toxicological assessments confirmed S-3a's safety, while pharmacokinetics showed a rapid clearance (half-life: 16.6 min). Mechanistically, S-3a antagonized M1 receptors and elevated BDNF levels, suggesting its potential as an antidepressant for further exploration.

Differences in ingestion and biodegradation of the melamine formaldehyde plastic by yellow mealworms Tenebrio molitor and superworms Zophobas atratus, and the prediction of functional gut microbes.

Plastics biodegradation by insect larvae is considered as a new strategy for plastic wastes treatment. To uncover the biodegradation of a more complex chemical polymer of melamine formaldehyde (MF) by insect larvae, two worm species of yellow mealworm Tenebrio molitor and superworm Zophobas atratus were fed on MF foam as sole diet for 45 days with sole bran diet as control. Although the MF foam consumption by yellow mealworms of 0.38 mg/d/g-larvae was almost 40% higher than that by superworms of 0.28 mg/d/g-larvae, a similar decrease of survival rates in both species were obtained at about 58%, indicating the adverse effects on their growth. Depolymerization and biodegradation of MF foam occurred in both larval guts, but was more extensive in yellow mealworms. MF foam sole diet influenced gut bacterial and fungal microbiomes of both larvae species, which were assessed by Illumina MiSeq on day 45. Compared to the bran-fed group, both gut bacterial and fungal communities significantly changed in MF-fed groups, but differed in the two larvae species. The results demonstrated a strong association between the distinctive gut microbiome and MF foam degradation, such as unclassified Enterobacteriaceae, Hyphopichia and Issatchenkia. However, sole MF foam diet negatively influenced worms, like lower survival rates and gut abnormalities. In summary, MF foam could be degraded by both yellow mealworms and superworms, albeit with adverse effects. Gut microbes were strongly associated to MF foam degradation, especially the gut fungi.

Saponins as therapeutic candidates for atherosclerosis.

Drug development for atherosclerosis, the underlying pathological state of ischemic cardiovascular diseases, has posed a longstanding challenge. Saponins, classified as steroid or triterpenoid glycosides, have shown promising therapeutic potential in the treatment of atherosclerosis. Through an exhaustive examination of scientific literature spanning from May 2013 to May 2023, we identified 82 references evaluating 37 types of saponins in terms of their prospective impacts on atherosclerosis. These studies suggest that saponins have the potential to ameliorate atherosclerosis by regulating lipid metabolism, inhibiting inflammation, suppressing apoptosis, reducing oxidative stress, and modulating smooth muscle cell proliferation and migration, as well as regulating gut microbiota, autophagy, endothelial senescence, and angiogenesis. Notably, ginsenosides exhibit significant potential and manifest essential pharmacological attributes, including lipid-lowering, anti-inflammatory, anti-apoptotic, and anti-oxidative stress effects. This review provides a comprehensive examination of the pharmacological attributes of saponins in atherosclerosis, with particular emphasis on their role in the regulation of lipid metabolism regulation and anti-inflammatory effects. Thus, saponins may warrant further investigation as a potential therapy for atherosclerosis. However, due to various reasons such as low oral bioavailability, the clinical application of saponins in the treatment of atherosclerosis still needs further exploration.

Tiaogan daozhuo formula attenuates atherosclerosis via activating AMPK -PPARγ-LXRα pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Tiaogan Daozhuo Formula (TGDZF) is a common formulation against atherosclerosis, however, there is limited understanding of its therapeutic mechanism. AIM OF THIS STUDY: To examine the effectiveness of TGDZF in the treatment of atherosclerosis and to explore its mechanisms. MATERIALS AND METHODS: In ApoE-/- mice, atherosclerosis was induced by a high-fat diet for 12 weeks and treated with TGDZF at different doses. The efficacy of TGDZF in alleviating atherosclerosis was evaluated by small animal ultrasound and histological methods. Lipid levels were measured by biochemical methods. The capacity of cholesterol efflux was tested with a cholesterol efflux assay in peritoneal macrophage, and the expression of AMPKα1, PPARγ, LXRα, and ABCA1 was examined at mRNA and protein levels. Meanwhile, RAW264.7-derived macrophages were induced into foam cells by ox-LDL, and different doses of TGDZF-conducting serum were administered. Similarly, we examined differences in intracellular lipid accumulation, cholesterol efflux rate, and AMPKα1, PPARγ, LXRα, and ABCA1 levels following drug intervention. Finally, changes in the downstream molecules were evaluated following the inhibition of AMPK by compound C or PPARγ silencing by small interfering RNA. RESULTS: TGDZF administration reduced aortic plaque area and lipid accumulation in aortic plaque and hepatocytes, and improved the serum lipid profiles of ApoE-/- mice. Further study revealed that its efficacy was accompanied by an increase in cholesterol efflux rate and the expression of PPARγ, LXRα, and ABCA1 mRNA and protein, as well as the promotion of AMPKα1 phosphorylation. Moreover, similar results were caused by the intervention of TGDZF-containing serum in vitro experiments. Inhibition of AMPK and PPARγ partially blocked the regulatory effect of TGDZF, respectively. CONCLUSIONS: TGDZF alleviated atherosclerosis and promoted cholesterol efflux from macrophages by activating the AMPK-PPARγ-LXRα-ABCA1 pathway.

Event-Triggered Interval Observer Fault Detection and Isolation for Multiagent Systems.

This article investigates an event-triggered interval observer (ETIO) fault detection and isolation method for multiagent systems. First, an event-triggered mechanism is developed to reduce unnecessary communication transmission. Then, a distributed ETIO is designed by combining an interval observer and the proposed event-triggered mechanism. Furthermore, for achieving the desired tradeoff between the robustness to disturbances and the sensitivity to faults, the ETIO is formulated as a multiobjective optimization with l1 / H∞ performance. Second, a bank of ETIOs are interpreted to isolate the faulty agent on a local agent using only the output information from itself and its neighbors. Comparison result with the existing method is given to highlight the superiority of our methodology. Finally, the multiunmanned aerial vehicles system is utilized as the case research, and specific simulation results are presented.

Risk factors associated with age at onset of Parkinson's disease in the UK Biobank.

Substantial evidence shown that the age at onset (AAO) of Parkinson's disease (PD) is a major determinant of clinical heterogeneity. However, the mechanisms underlying heterogeneity in the AAO remain unclear. To investigate the risk factors with the AAO of PD, a total of 3156 patients with PD from the UK Biobank were included in this study. We evaluated the effects of polygenic risk scores (PRS), nongenetic risk factors, and their interaction on the AAO using Mann-Whitney U tests and regression analyses. We further identified the genes interacting with nongenetic risk factors for the AAO using genome-wide environment interaction studies. We newly found physical activity (P < 0.0001) was positively associated with AAO and excessive daytime sleepiness (P < 0.0001) was negatively associated with AAO, and reproduced the positive associations of smoking and non-steroidal anti-inflammatory drug intake and the negative association of family history with AAO. In the dose-dependent analyses, smoking duration (P = 1.95 × 10-6), coffee consumption (P = 0.0150), and tea consumption (P = 0.0008) were positively associated with AAO. Individuals with higher PRS had younger AAO (P = 3.91 × 10-5). In addition, we observed a significant interaction between the PRS and smoking for AAO (P = 0.0316). Specifically, several genes, including ANGPT1 (P = 7.17 × 10-7) and PLEKHA6 (P = 4.87 × 10-6), may influence the positive relationship between smoking and AAO. Our data suggests that genetic and nongenetic risk factors are associated with the AAO of PD and that there is an interaction between the two.

VarCards2: an integrated genetic and clinical database for ACMG-AMP variant-interpretation guidelines in the human whole genome.

VarCards, an online database, combines comprehensive variant- and gene-level annotation data to streamline genetic counselling for coding variants. Recognising the increasing clinical relevance of non-coding variations, there has been an accelerated development of bioinformatics tools dedicated to interpreting non-coding variations, including single-nucleotide variants and copy number variations. Regrettably, most tools remain as either locally installed databases or command-line tools dispersed across diverse online platforms. Such a landscape poses inconveniences and challenges for genetic counsellors seeking to utilise these resources without advanced bioinformatics expertise. Consequently, we developed VarCards2, which incorporates nearly nine billion artificially generated single-nucleotide variants (including those from mitochondrial DNA) and compiles vital annotation information for genetic counselling based on ACMG-AMP variant-interpretation guidelines. These annotations include (I) functional effects; (II) minor allele frequencies; (III) comprehensive function and pathogenicity predictions covering all potential variants, such as non-synonymous substitutions, non-canonical splicing variants, and non-coding variations and (IV) gene-level information. Furthermore, VarCards2 incorporates 368 820 266 documented short insertions and deletions and 2 773 555 documented copy number variations, complemented by their corresponding annotation and prediction tools. In conclusion, VarCards2, by integrating over 150 variant- and gene-level annotation sources, significantly enhances the efficiency of genetic counselling and can be freely accessed at http://www.genemed.tech/varcards2/.

Prioritizing de novo potential non-canonical splicing variants in neurodevelopmental disorders.

BACKGROUND: Genomic variants outside of the canonical splicing site (±2) may generate abnormal mRNA splicing, which are defined as non-canonical splicing variants (NCSVs). However, the clinical interpretation of NCSVs in neurodevelopmental disorders (NDDs) is largely unknown. METHODS: We investigated the contribution of NCSVs to NDDs from 345,787 de novo variants (DNVs) in 47,574 patients with NDDs. We performed functional enrichment and protein-protein interaction analysis to assess the association between genes carrying prioritised NCSVs and NDDs. Minigene was used to validate the impact of NCSVs on mRNA splicing. FINDINGS: We observed significantly more NCSVs (p = 0.02, odds ratio [OR] = 2.05) among patients with NDD than in controls. Both canonical splicing variants (CSVs) and NCSVs contributed to an equal proportion of patients with NDD (0.76% vs. 0.82%). The candidate genes carrying NCSVs were associated with glutamatergic synapse and chromatin remodelling. Minigene successfully validated 59 of 79 (74.68%) NCSVs that led to abnormal splicing in 40 candidate genes, and 9 of the genes (ARID1B, KAT6B, TCF4, SMARCA2, SHANK3, PDHA1, WDR45, SCN2A, SYNGAP1) harboured recurrent NCSVs with the same variant present in more than two unrelated patients with NDD. Moreover, 36 of 59 (61.02%) NCSVs are novel clinically relevant variants, including 34 unreported and 2 clinically conflicting interpretations or of uncertain significance NCSVs in the ClinVar database. INTERPRETATION: This study highlights the common pathology and clinical importance of NCSVs in unsolved patients with NDD. FUNDING: The present study was funded by grants from the National Natural Science Foundation of China, China Postdoctoral Science Foundation, the Hunan Youth Science and Technology Innovation Talent Project, the Provincial Natural Science Foundation of Hunan, The Scientific Research Program of FuRong laboratory, and the Natural Science Project of the University of Anhui Province.

Estimation of soil water and organic matter content in medium and low yield fields of Ningxia Yellow River Irrigation area based on hyperspectral information.

Accurately obtaining soil water and organic matter content is of great significance for improving soil qua-lity in croplands with medium to low yield. We explored the estimation effect of fractional order differentiation (FOD) combined with different spectral indices on soil water and organic matter content in medium and low yield croplands of Ningxia Yellow River Irrigation Area. After root mean square transformation of field measured hyperspectral reflectance, we used 0-2 FOD (with a step length of 0.25) to construct difference index (DI), ratio index (RI), product index (PI), sum index (SI), generalized difference index (GDI), and nitrogen planar domain index (NPDI) and to select the optimal spectral index based on the correlation coefficients between six spectral indices with soil water and organic matter contents. We constructed a model for estimating soil water and organic matter content based on partial least squares regression (PLSR) and support vector machine (SVM). The results showed that the correlation between soil water and organic matter content and spectral information was effectively improved after FOD transformation compared with the original spectrum, with maximum increases of 0.1785 and 0.1713, respectively. The soil water content sensitive bands were mainly in the range of 400-630 and 1350-1940 nm, while the sensitive bands of organic matter content were mainly at 460-850, 1530-1910, and 2060-2310 nm. The accuracy of SVM model was significantly higher than that of PLSR, and the soil water content estimation model based on 1.75-order NPDI-SVM reached the highest precision, with a validation determination coefficient (Rp2) of 0.970, root mean square error (RMSE) of 1.615, and relative percent deviation (RPD) of 4.211. The organic matter content estimation model based on 0.5 order DI-SVM had the best performance, with Rp2, RMSE and RPD of 0.983, 0.701 and 5.307, respectively. Our results could provide data and technological support for soil water and nutrient monitoring, quality improvement, and graphics creating in similar area with medium to low yield fields.

Inversion of soil water and salt information based on UAV hyperspectral remote sensing and machine lear-ning.

Accurate diagnosis of water and salt information in saline agricultural lands is crucial for long-term soil quality improvement and arable land conservation. In this study, we extracted field-scale vegetation canopy spectral information by UAV hyperspectral information, transforming the reflectance (R) to standard normal variate transformation (SNV), multiplicative scatter correction (MSC), first derivative of reflectance (FDR) and second derivative of reflectance (SDR). We determined the optimal spectral transformation forms of soil water content (SWC), soil pH, and soil salt content (SSC) by the maximum absolute correlation coefficient (MACC), and extracted the feature bands by competitive adaptive reweighted sampling (CARS). We constructed an inversion model of soil water and salt information by partial least squares regression (PLSR), random forest (RF), and extreme gradient boosting (XGBoost). The results showed that R, FDR and MSC were the best spectral transformation types for soil water content, soil pH, and soil salt content, and the corresponding MACC were 0.730, 0.472 and 0.654, respectively. The CARS algorithm effectively eliminated the irrelevant variables, optimally selecting 16-17 feature bands from 150 spectral bands. Both soil water content and soil pH performed best with XGBoost model, achieving determination coefficient of validation (Rp2) 0.927 and 0.743, and the relative percentage difference (RPD) amounted to 3.93 and 2.45. For soil salt content, the RF model emerged as the best inversion method with Rp2 and RPD of 0.427 and 1.64, respectively. The study could provide a reference solution for the integrated remote sensing monitoring of soil water and salt information in space and sky, serving as a scientific guide for the amelioration and sustainable management of saline lands.

MXene-BN-Introduced Artificial SEI to Inhibit Dendrite Growth of Lithium Metal Batteries.

Lithiophilic substrates have been shown to improve the electrochemical performance of lithium metal anodes. The MXene-BN/Cu 3D current collector was prepared by a filtration method. The artificial solid electrolyte interface (SEI) layer composed of Li3N and LiF was formed on the surface of MXene-BN/Cu during the Li deposition process. Volume changes can be effectively relieved by this special 3D structure. The artificial SEI film reduced the critical dendrite growth length, inhibited Li dendrite growth, and stabilized the electrochemical cycle. MXene-BN/Cu exhibited highly reversible cycling properties during lithium metal deposition with a high Coulombic efficiency of ∼ 98.0% over 500 cycles. Furthermore, LiBH4 was produced during the Li deposition process. This study presents a promising strategy for developing dendrite-free Li anodes for use in lithium metal batteries.

DDIT4 is essential for DINP-induced autophagy of ovarian granulosa cells.

As one of the most important phthalates, di-isononyl phthalate (DINP) has been widely used as a common plasticizer in the food and personal care products sectors. In our previous study, we found that DINP can induce autophagy of ovarian granulosa cells; while the underlying mechanism is unclear. In the study, we showed that DINP exposure could induce autophagy of ovarian granulosa cells and KGN cells, accompanied with the increase in the mRNA and protein level of DDIT4. Furthermore, overexpression of DDIT4 were shown to induce autophagy of KGN cells; while knockdown of DDIT4 inhibited DINP-induced autophagy, implying that DDIT4 played an important role in DINP-induced autophagy of ovarian granulosa cells. There were three putative binding sites of transcription factor ATF4 in the promoter region of DDIT4 gene, suggesting that DDIT4 might be regulated by ATF4. Herein, we found that overexpression of ATF4 could upregulate the expression of DDIT4 in KGN cells, while knockdown of ATF4 inhibited its expression. Subsequently, ATF4 was identified to bind to the promoter region of DDIT4 gene and promote its transcription. The expression of ATF4 was also increased in the DINP-exposed granulosa cells, and ATF4 overexpression promoted autophagy of KGN cells; whereas knockdown of ATF4 alleviated DINP-induced upregulation of DDIT4 and autophagy of the cells. Taken together, DINP triggered autophagy of ovarian granulosa cells through activating ATF4/DDIT4 signals.

Fisher-Information-Matrix-Based USBL Cooperative Location in USV-AUV Networks.

With the development of underwater technology and the increasing demand for ocean development, more and more intelligent equipment is being applied to underwater scientific missions. Specifically, autonomous underwater vehicle (AUV) clusters are being used for their flexibility and the advantages of carrying communication and detection units, often performing underwater tasks in formation. In order to locate AUVs with high precision, we introduce an unmanned surface vehicle (USV) with global positioning system (GPS) and propose a USV-AUV network. Furthermore, we propose an ultra-short baseline (USBL) acoustic cooperative location scheme with an orthogonal array, which is based on underwater communication with sonar. Based on the derivation of the Fisher information matrix formula under Cartesian parameters, we analyze the positioning accuracy of AUVs in different positions under the USBL positioning mode to derive the optimal array of the AUV formation. In addition, we propose a USV path planning scheme based on Dubins path planning functions to assist in locating the AUV formation. The simulation results verify that the proposed scheme can ensure the positioning accuracy of the AUV formation and help underwater research missions.

Association between ovarian reserve and spontaneous miscarriage and their shared genetic architecture.

STUDY QUESTION: Can potential mechanisms involved in the likely concurrence of diminished ovarian reserve (DOR) and miscarriage be identified using genetic data? SUMMARY ANSWER: Concurrence between ovarian reserve and spontaneous miscarriage was observed, and may be attributed to shared genetic risk loci enriched in antigen processing and presentation and autoimmune disease pathways. WHAT IS KNOWN ALREADY: Previous studies have shown that lower serum anti-Müllerian hormone (AMH) levels are associated with increased risk of embryo aneuploidy and spontaneous miscarriage, although findings have not been consistent across all studies. A recent meta-analysis suggested that the association between DOR and miscarriage may not be causal, but rather a result of shared underlying causes such as clinical conditions or past exposure. Motivated by this hypothesis, we conducted the present analysis to explore the concurrence between DOR and miscarriage, and to investigate potential mechanisms using genetic data. STUDY DESIGN, SIZE, DURATION: Three data sources were used in the study: the clinical IVF data were retrospectively collected from an academically affiliated Reproductive Medicine Center (17 786 cycles included); the epidemiological data from the UK Biobank (UKB), which is a large-scale, population-based, prospective cohort study (35 316 white women included), were analyzed; and individual-level genotype data from the UKB were extracted for further analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: There were three modules of analysis. First, clinical IVF data were used to test the association between ovarian reserve biomarkers and the subsequent early spontaneous miscarriage risk. Second, the UKB data were used to test the association of spontaneous miscarriage history and early menopause. Third, individual-level genotype data from the UKB were analyzed to identify specific pleiotropic genes which affect the development of miscarriage and menopause. MAIN RESULTS AND THE ROLE OF CHANCE: In the analysis of clinical IVF data, the risk of early spontaneous miscarriage was 1.57 times higher in the group with AMH < 1.1 ng/ml group (P < 0.001), 1.62 times for antral follicular count <5 (P < 0.001), and 1.39 times for FSH ≥10 mIU/ml (P < 0.001) in comparison with normal ovarian reserve groups. In the analysis of UKB data, participants with a history of three or more miscarriages had a one-third higher risk of experiencing early menopause (odds ratio: 1.30, 95% CI 1.13-1.49, P < 0.001), compared with participants without spontaneous miscarriage history. We identified 158 shared genetic risk loci that affect both miscarriage and menopause, which enrichment analysis showed were involved in antigen processing and presentation and autoimmune disease pathways. LIMITATIONS, REASONS FOR CAUTION: The analyses of the UKB data were restricted to participants of European ancestry, as 94.6% of the cohort were of white ethnicity. Further studies are needed in non-white populations. Additionally, maternal age at the time of spontaneous miscarriage was not available in the UKB cohort, therefore we adjusted for age at baseline assessment in the models instead. It is known that miscarriage rate in IVF is higher compared to natural conception, highlighting a need for caution when generalizing our findings from the IVF cohort to the general population. WIDER IMPLICATIONS OF THE FINDINGS: Our findings have implications for IVF clinicians in terms of patient counseling on the prognosis of IVF treatment, as well as for genetic counseling regarding miscarriage. Our results highlight the importance of further research on the shared genetic architecture and common pathophysiological basis of DOR and miscarriage, which may lead to new therapeutic opportunities. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Hunan Youth Science and Technology Innovation Talent Project (2020RC3060), the International Postdoctoral Exchange Fellowship Program (Talent-Introduction Program, YJ20220220), the fellowship of China Postdoctoral Science Foundation (2022M723564), and the Natural Science Foundation of Hunan Province, China (2023JJ41016). This work has been accepted for poster presentation at the 39th Annual Meeting of ESHRE, Copenhagen, Denmark, 25-28 June 2023 (Poster number: P-477). The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Identifying Network Biomarkers in Early Diagnosis of Hepatocellular Carcinoma via miRNA-Gene Interaction Network Analysis.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly heterogeneous cancer at the histological level. Despite the emergence of new biological technology, advanced-stage HCC remains largely incurable. The prediction of a cancer biomarker is a key problem for targeted therapy in the disease. METHODS: We performed a miRNA-gene integrated analysis to identify differentially expressed miRNAs (DEMs) and genes (DEGs) of HCC. The DEM-DEG interaction network was constructed and analyzed. Gene ontology enrichment and survival analyses were also performed in this study. RESULTS: By the analysis of healthy and tumor samples, we found that 94 DEGs and 25 DEMs were significantly differentially expressed in different datasets. Gene ontology enrichment analysis showed that these 94 DEGs were significantly enriched in the term "Liver" with a statistical p-value of 1.71 × 10-26. Function enrichment analysis indicated that these genes were significantly overrepresented in the term "monocarboxylic acid metabolic process" with a p-value = 2.94 × 10-18. Two sets (fourteen genes and five miRNAs) were screened by a miRNA-gene integrated analysis of their interaction network. The statistical analysis of these molecules showed that five genes (CLEC4G, GLS2, H2AFZ, STMN1, TUBA1B) and two miRNAs (hsa-miR-326 and has-miR-331-5p) have significant effects on the survival prognosis of patients. CONCLUSION: We believe that our study could provide critical clinical biomarkers for the targeted therapy of HCC.

Different bacterial and fungal community patterns in restored habitats in coal-mining subsidence areas.

Soil microbiota, which plays a fundamental role in ecosystem functioning, is sensitive to environmental changes. Studying soil microbial ecological patterns can help to understand the consequences of environmental disturbances on soil microbiota and hence ecosystem services. The different habitats with critical environmental gradients generated through the restoration of coal-mining subsidence areas provide an ideal area to explore the response of soil microbiota to environmental changes. Here, based on high-throughput sequencing, we revealed the patterns of soil bacterial and fungal communities in habitats with different land-use types (wetland, farmland, and grassland) and with different restored times which were generated during the ecological restoration of a typical coal-mining subsidence area in Jining City, China. The α-diversity of bacterial was higher in wetland than in farmland and grassland, while that of fungi had no discrepancy among the three habitats. The ß-diversity of bacterial community in the grassland was lower than in the farmland, and fungal community was significant different in all three habitats, showing wetland, grassland, and farmland from high to low. The ß-diversity of the bacterial community decreased with restoration time while that of the fungal community had no significant change in the longer-restoration-time area. Furthermore, soil electrical conductivity was the most important driver for both bacterial and fungal communities. Based on the taxonomic difference among different habitats, we identified a group of biomarkers for each habitat. The study contributes to understand the microbial patterns during the ecological restoration of coal-mining subsidence areas, which has implications for the efficient ecological restoration of subsidence areas.

Analyzing the cellular and molecular atlas of ovarian mesenchymal cells provides a strategy against female reproductive aging.

Ovarian mesenchymal cells (oMCs) constitute a distinct microenvironment that supports folliculogenesis under physiological conditions. Supplementation of exogenous non-ovarian mesenchymal-related cells has been reported to be an efficient approach to improve ovarian functions. However, the development and cellular and molecular characteristics of endogenous oMCs remain largely unexplored. In this study, we surveyed the single-cell transcriptomic landscape to dissect the cellular and molecular changes associated with the aging of oMCs in mice. Our results showed that the oMCs were composed of five ovarian differentiated MC (odMC) populations and one ovarian mesenchymal progenitor (oMP) cell population. These cells could differentiate into various odMCs via an oMP-derived route to construct the ovarian stroma structures. Comparative analysis revealed that ovarian aging was associated with decreased quantity of oMP cells and reduced quality of odMCs. Based on the findings of bioinformatics analysis, we designed different strategies involving supplementation with young oMCs to examine their effects on female fertility and health. Our functional investigations revealed that oMCs supplementation prior to ovarian senescence was the optimal method to improve female fertility and extend the reproductive lifespan of aged females in the long-term.

Evolving trends in drug overdose mortality in the USA from 2000 to 2020: an age-period-cohort analysis.

Background: Drug overdose deaths in the USA have increased rapidly in the past 20 years, and understanding patterns and trends in mortality is essential to develop policy responses. This study aimed to determine whether cohort patterns in mortality due to drug overdose have changed in the past two decades and assess these patterns by race and sex. Methods: The national records of accidental drug overdose death were extracted from Centers for Disease Control and Prevention, National Center for Health Statistics Mortality Data for 2000-2020. Age-period-cohort analysis was performed to examine independent effects of age, period and birth cohort on accidental drug overdose mortality. Findings: The number of accidental drug overdose deaths increased by 622% between 2000 and 2020, and age-standardized mortality rates increased nearly four-fold in both men and women. Age-period-cohort decomposition found rapid increases in mortality since 2012 in men and women, with higher mortality risk in cohorts born after 1990. The fastest increase occurred in Black Americans since 2012, and Americans of all races born after 1975 had significantly higher mortality risk, with mortality risk increasing rapidly in more recent cohorts. The peak of mortality has shifted from the 40-59 age group to the 30-40 year age group in the past decade. Interpretation: The burden of drug overdose mortality has shifted to younger Americans, and a new generation of Americans are at significantly higher and rapidly increasing risk of overdose death. Urgent action is needed to prevent an entire generation of young people being consigned to decades of preventable mortality. Funding: None.