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Male infertility (MI) and male sexual dysfunction (MSD) can often coexist together due to various interplay factors such as psychosexual, sociocultural and relationship dynamics. The presence of each form of MSD can adversely impact male reproduction and treatment strategies will need to be individualized based on patients’ factors, local expertise, and geographical socioeconomic status. The Asia Pacific Society of Sexual Medicine (APSSM) and the Asian Society of Men’s Health and Aging (ASMHA) aim to provide a consensus statement and practical set of clinical recommendations based on current evidence to guide clinicians in the management of MI and MSD within the Asia-Pacific (AP) region. A comprehensive, narrative review of the literature was performed to identify the various forms of MSD and their association with MI. MEDLINE and EMBASE databases were searched for the following English language articles under the following terms: “low libido”, “erectile dysfunction”, “ejaculatory dysfunction”, “premature ejaculation”, “retrograde ejaculation”, “delayed ejaculation”, “anejaculation”, and “orgasmic dysfunction” between January 2001 to June 2022 with emphasis on published guidelines endorsed by various organizations. This APSSM consensus committee panel evaluated and provided evidence-based recommendations on MI and clinically relevant MSD areas using a modified Delphi method by the panel and specific emphasis on locoregional socioeconomic- cultural issues relevant to the AP region. While variations exist in treatment strategies for managing MI and MSD due to geographical expertise, locoregional resources, and sociocultural factors, the panel agreed that comprehensive fertility evaluation with a multidisciplinary management approach to each MSD domain is recommended. It is important to address individual MI issues with an emphasis on improving spermatogenesis and facilitating reproductive avenues while at the same time, managing various MSD conditions with evidence-based treatments. All therapeutic options should be discussed and implemented based on the patient’s individual needs, beliefs and preferences while incorporating locoregional expertise and available resources.

Introduction: Guilingji, a famous traditional Chinese medicine (TCM) formula, has been used to combat aging and male sexual dysfunction in China for centuries. To date, there has been little evidence-based clinical research on the use of Guilingji to treat idiopathic oligo-asthenoteratozoospermia (OAT), and the therapeutic mechanism from a metabolic perspective needs to be investigated further. Methods: This was a multicenter, double-blind, randomized controlled clinical study of 240 patients with idiopathic OAT recruited from four hospitals between January 2020 and January 2022. Patients were randomly assigned in a 1꞉1 ratio to receive oral Guilingji capsules or placebo for 12 weeks. The total progressive motile sperm count (TPMSC) was considered the primary outcome, and the other sperm parameters, seminal plasma parameters and serum hormones were considered the secondary outcome. A nontargeted metabolomics analysis of serum from OAT patients before and after Guilingji administration was performed by HPLC–MS to identify key metabolites. Furthermore, we used a rat model to show spermatogenesis phenotypes to validate the effect of the key metabolites screened from the patients. Results: At weeks 4, 8 and 12, TPMSC and other sperm parameters were significantly improved in the Guilingji group compared with the placebo group (P

Abstract Background The management of male infertility continues to encounter an array of challenges and constraints, necessitating an in-depth exploration of novel therapeutic targets to enhance its efficacy. As an eight-carbon medium-chain fatty acid, octanoic acid (OCA) shows promise for improving health, yet its impact on spermatogenesis remains inadequately researched. Methods Mass spectrometry was performed to determine the fatty acid content and screen for a pivotal lipid component in the serum of patients with severe spermatogenesis disorders. The sperm quality was examined, and histopathological analysis and biotin tracer tests were performed to assess spermatogenesis function and the integrity of the blood-testis barrier (BTB) in vivo. Cell-based in vitro experiments were carried out to investigate the effects of OCA administration on Sertoli cell dysfunction. This research aimed to elucidate the mechanism by which OCA may influence the function of Sertoli cells. Results A pronounced reduction in OCA content was observed in the serum of patients with severe spermatogenesis disorders, indicating that OCA deficiency is related to spermatogenic disorders. The protective effect of OCA on reproduction was tested in a mouse model of spermatogenic disorder induced by busulfan at a dose 30 mg/kg body weight (BW). The mice in the study were separated into distinct groups and administered varying amounts of OCA, specifically at doses of 32, 64, 128, and 256 mg/kg BW. After evaluating sperm parameters, the most effective dose was determined to be 32 mg/kg BW. In vivo experiments showed that treatment with OCA significantly improved sperm quality, testicular histopathology and BTB integrity, which were damaged by busulfan. Moreover, OCA intervention reduced busulfan-induced oxidative stress and autophagy in mouse testes. In vitro, OCA pretreatment (100 µM) significantly ameliorated Sertoli cell dysfunction by alleviating busulfan (800 µM)-induced oxidative stress and autophagy. Moreover, rapamycin (5 µM)-induced autophagy led to Sertoli cell barrier dysfunction, while OCA administration exerted a protective effect by alleviating autophagy. Conclusions This study demonstrated that OCA administration suppressed oxidative stress and autophagy to alleviate busulfan-induced BTB damage. These findings provide a deeper understanding of the toxicology of busulfan and a promising avenue for the development of novel OCA-based therapies for male infertility.

Abstract The rising demand for freshwater and the challenge of energy scarcity have fueled interest in solar interfacial water evaporation technology, which harnesses solar energy to produce clean water. Attaining high performance with this technology necessitates the development of highly efficient photothermal materials, heat management optimization, and the resolution of salt deposition issues to ensure equipment longevity. Metal-organic frameworks (MOFs) possess large specific surface areas and high porosity, making them ideal for various water treatment applications. In recent years, MOFs have been extensively employed for solar-driven desalination. Here, we review recent developments in the functionalization of MOFs thin films, composites and MOFs-based derivatives and strategies for achieving efficient seawater desalination with MOFs while preventing salt deposition. Furthermore, desalination systems that integrate pollutant degradation and power generation are discussed, which further expand the application scenarios of solar-driven interfacial water evaporation desalination technologies.

Abstract Background Total pelvic exenteration is the ultimate solution for rectovesicovaginal fistula caused by radiation therapy, yet total pelvic exenteration frequently causes intraoperative complications and postoperative complications. These complications are responsible for the dysfunction of lower extremities, impaired quality of life, and even the high long-term morbidity rate, thus multidisciplinary cooperation and early intervention for prevention of complications are necessary. Physical therapy was found to reduce the postoperative complications and promote rehabilitation, yet the effect on how physiotherapy prevents and treats complications after total pelvic exenteration and pelvic lymphadenectomy remains unclear. Case presentation A 50-year-old Chinese woman gradually developed perianal and pelvic floor pain and discomfort, right lower limb numbness, and involuntary vaginal discharge owing to recurrence and metastasis of cervical cancer more than half a year ago. Diagnosed as rectovesicovaginal fistula caused by radiation, she received total pelvic exenteration and subsequently developed severe lower limb edema, swelling pain, obturator nerve injury, and motor dysfunction. The patient was referred to a physiotherapist who performed rehabilitation evaluation and found edema in both lower extremities, right inguinal region pain (numeric pain rate scale 5/10), decreased temperature sensation and light touch in the medial thigh of the right lower limb, decreased right hip adductor muscle strength (manual muscle test 1/5) and right hip flexor muscle strength (manual muscle test 1/5), inability actively to adduct and flex the right hip with knee extension, low de Morton mobility Index score (0/100), and low Modified Barthel Index score (35/100). Routine physiotherapy was performed in 2 weeks, including therapeutic exercises, mechanical stimulation and electrical stimulation as well as manual therapy. The outcomes showed that physiotherapy significantly reduced lower limb pain and swelling, and improved hip range of motion, motor function, and activities of daily living, but still did not prevent thrombosis. Conclusion Standardized physical therapy demonstrates the effect on postoperative complications after total pelvic exenteration and pelvic lymphadenectomy. This supports the necessity of multidisciplinary cooperation and early physiotherapy intervention. Further research is needed to determine the causes of thrombosis after standardized intervention, and more randomized controlled trials are needed to investigate the efficacy of physical therapy after total pelvic exenteration.

The advantages of fish such as high propulsion efficiency, strong maneuverability and low environmental disturbance have sparked extensive research on bionic robotic fish by both domestic and international scholars. The basic-level gait control method and closed-loop motion control method are currently two hot topics in research on robotic fish control. According to the propulsion mode classification method, this paper summarizes the prototype development and performance of various robotic fish, introduces the research progress of the propulsion mechanisms and hydrodynamics of robotic fish, focuses on two basic gait control ideas, namely the trajectory approximation method and central pattern generator （CPG）, and summarizes the typical closed-loop motion control method. The CPG method has stronger flexibility, stability and operability, and it is easy to introduce feedback items and achieve closed-loop control, for which it plays a leading role in the basic gait control of robotic fish; while the improved learning-based control method and hybrid control method combining multiple methods based on the significant characteristics of robotic fish have broader development prospects, which is in line with the development direction of intelligent biomimetic robotic fish. Establishing a reasonable gait control system and an accurate and efficient closed-loop motion control system based on working conditions and motion requirements is the key to improving the overall performance of robotic fish.

Recent research emphasised the indispensable role of histone lactylation in the activation of hepatic stellate cells. The VHL mutation is extremely common in clear cell renal cell carcinoma, which normally causes a metabolic shift in cancer cells and increases lactate production, eventually creating a lactate-enriched tumour microenvironment. Cancer-associated fibroblasts (CAFs) promote tumour progression, which is also vital in clear cell renal cell carcinoma. Therefore, this study investigated histone lactylation in CAFs and its impact on patient survival. Multiomics technology was employed to determine the role of histone lactylation-related genes in the evolution of CAFs which correlated with the function and molecular signatures of CAFs. The results suggested that TIMP1 was the hub gene of histone lactylation-related genes in clear cell renal cell carcinoma.

Abstract Background Central nervous system (CNS) tumors are the most common solid tumors in children and the leading cause of cancer-related death in the latter. Currently, the incidence rate exceeds that of leukemia and ranks first in the incidence of malignant tumors in children. Methods The epidemiological data on childhood CNS tumors were collected from the Chinese Cancer Registry Annual Report. The annual percent change (APC) of incidence and mortality-rate changes were estimated via Joinpoint regression. Due to a lack of pertinent data, we performed a system review on the clinical-pathological characteristics in Chinese publications. Results There was no significant increase in the incidence rate (APC: -0.1, 95% CI: -1.5 to 1.3), but there was a significant increase in the mortality rate (APC: 1.8, 95% CI: 0.3 to 3.4) for childhood CNS tumors. In the subgroup analysis, there were significant increases in both the incidence and mortality rates in rural areas (APC in the incidence: 6.2, 95% CI: 2.4 to 10.2; APC in mortality: 4.4, 95% CI: 0.4 to 8.4). The most common location and type of childhood CNS were, respectively, the cerebral hemisphere (25.5%, 95% CI: 21.7% to 29.4%) and astrocytomas (26.8%, 95% CI: 23.9% to 29.6%). Conclusions The epidemiological trends, and the relevant prediction, highlighted the need to pay continual attention to childhood CNS tumors, and the clinicopathology evinced its own distinctive characteristics. Timely detection and effective treatment must be further promoted regarding childhood CNS tumors with a view to decreasing the disease burden, especially in rural areas.

Abstract How early life experience is translated into storable epigenetic information leading to behavioral changes remains poorly understood. Here we found that Zika virus (ZIKV) induced-maternal immune activation (MIA) imparts offspring with anxiety- and depression-like behavior. By integrating bulk and single-nucleus RNA sequencing (snRNA-seq) with genome-wide 5hmC (5-hydroxymethylcytosine) profiling and 5mC (5-methylcytosine) profiling in prefrontal cortex (PFC) of ZIKV-affected male offspring mice, we revealed an overall loss of 5hmC and an increase of 5mC levels in intragenic regions, associated with transcriptional changes in neuropsychiatric disorder-related genes. In contrast to their rapid initiation and inactivation in normal conditions, immediate-early genes (IEGs) remain a sustained upregulation with enriched expression in excitatory neurons, which is coupled with increased 5hmC and decreased 5mC levels of IEGs in ZIKV-affected male offspring. Thus, MIA induces maladaptive methylome remodeling in brain and selectively regulates neuronal activity gene methylation linking to emotional behavioral abnormalities in offspring.

Abstract Because cognitive fatigue (CF) is common and debilitating following brain injury or disease we investigated the relationships among CF, behavioral performance, and cerebral activation within and across populations by combining the data from two cross-sectional studies. Individuals with multiple sclerosis (MS) were included to model CF resulting from neurological disease; individuals who had sustained a traumatic brain injury (TBI) were included to model CF resulting from neurological insult; both groups were compared with a control group (Controls). CF was induced while neuroimaging data was acquired using two different tasks. CF significantly differed between the groups, with the clinical groups reporting more CF than Controls—a difference that was statistically significant for the TBI group and trended towards significance for the MS group. The accrual of CF did not differ across the three groups; and CF ratings were consistent across tasks. Increasing CF was associated with longer response time for all groups. The brain activation in the caudate nucleus and the thalamus was consistently correlated with CF in all three groups, while more dorsally in the caudate, activation differed across the groups. These results suggest the caudate and thalamus to be central to CF while more dorsal aspects of the caudate may be sensitive to damage associated with particular types of insult.

Alzheimer’s disease (AD) is a complex neurodegenerative disorder and the most common form of dementia. There are two main types of AD: familial and sporadic. Familial AD is linked to mutations in amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2). On the other hand, sporadic AD is the more common form of the disease and has genetic, epigenetic, and environmental components that influence disease onset and progression. Investigating the epigenetic mechanisms associated with AD is essential for increasing understanding of pathology and identifying biomarkers for diagnosis and treatment. Chemical covalent modifications on DNA and RNA can epigenetically regulate gene expression at transcriptional and post-transcriptional levels and play protective or pathological roles in AD and other neurodegenerative diseases.

Introduction: Atrial fibrillation (AF) is the most common cardiac arrhythmia, which is clinically identified with irregular and rapid heartbeat rhythm. AF puts a patient at risk of forming blood clots, which can eventually lead to heart failure, stroke, or even sudden death. Electrocardiography (ECG), which involves acquiring bioelectrical signals from the body surface to reflect heart activity, is a standard procedure for detecting AF. However, the occurrence of AF is often intermittent, costing a significant amount of time and effort from medical doctors to identify AF episodes. Moreover, human error is inevitable, as even experienced medical professionals can overlook or misinterpret subtle signs of AF. As such, it is of critical importance to develop an advanced analytical model that can automatically interpret ECG signals and provide decision support for AF diagnostics.Methods: In this paper, we propose an innovative deep-learning method for automated AF identification using single-lead ECGs. We first extract time-frequency features from ECG signals using continuous wavelet transform (CWT). Second, the convolutional neural networks enhanced with residual learning (ReNet) are employed as the functional approximator to interpret the time-frequency features extracted by CWT. Third, we propose to incorporate a multi-branching structure into the ResNet to address the issue of class imbalance, where normal ECGs significantly outnumber instances of AF in ECG datasets.Results and Discussion: We evaluate the proposed Multi-branching Resnet with CWT (CWT-MB-Resnet) with two ECG datasets, i.e., PhysioNet/CinC challenge 2017 and ECGs obtained from the University of Oklahoma Health Sciences Center (OUHSC). The proposed CWT-MB-Resnet demonstrates robust prediction performance, achieving an F1 score of 0.8865 for the PhysioNet dataset and 0.7369 for the OUHSC dataset. The experimental results signify the model’s superior capability in balancing precision and recall, which is a desired attribute for ensuring reliable medical diagnoses.

Ageing is becoming an increasingly serious problem; therefore, there is an urgent need to find safe and effective anti-ageing drugs. Aims: To investigate the effects of Bazi Bushen capsule (BZBS) on the senescence of mesenchymal stem cells (MSCs) and explore its mechanism of action. Methods: Network pharmacology was used to predict the targets of BZBS in delaying senescence in MSCs. For in vitro studies, MSCs were treated with D-gal, BZBS, and NMN, and cell viability, cell senescence, stemness-related genes, and cell cycle were studied using cell counting kit-8 (CCK-8) assay, SA-β-galactosidase (SA-β-gal) staining, Quantitative Real-Time PCR (qPCR) and flow cytometry (FCM), respectively. Alkaline phosphatase (ALP), alizarin red, and oil red staining were used to determine the osteogenic and lipid differentiation abilities of MSCs. Finally, the expression of senescence-related genes and cyclin-related factors was detected by qPCR and western blotting. Results: Network pharmacological analysis suggested that BZBS delayed cell senescence by interfering in the cell cycle. Our in vitro studies suggested that BZBS could significantly increase cell viability (P

Summary: N-α-acetyltransferase D (NatD) mediates N-α-terminal acetylation of histone H4 (Nt-Ac-H4), but its role in breast cancer metastasis remains unknown. Here, we show that depletion of NatD directly represses the expression of FOXA2, and is accompanied by a significant reduction in Nt-Ac-H4 enrichment at the FOXA2 promoter. We show that NatD is commonly upregulated in primary breast cancer tissues, where its expression level correlates with FOXA2 expression, enhanced invasiveness, and poor clinical outcomes. Furthermore, we show that FOXA2 promotes the migration and invasion of breast cancer cells by activating MMP14 expression. MMP14 is also upregulated in breast cancer tissues, where its expression level correlates with FOXA2 expression and poor clinical prognosis. Our study shows that the NatD-FOXA2-MMP14 axis functions as a key signaling pathway to promote the migratory and invasive capabilities of breast cancer cells, suggesting that NatD is a critical epigenetic modulator of cell invasion during breast cancer progression.

Abstract High-quality graphene-based van der Waals superlattices are crucial for investigating physical properties and developing functional devices. However, achieving homogeneous wafer-scale graphene-based superlattices with controlled twist angles is challenging. Here, we present a flat-to-flat transfer method for fabricating wafer-scale graphene and graphene-based superlattices. The aqueous solution between graphene and substrate is removed by a two-step spinning-assisted dehydration procedure with the optimal wetting angle. Proton-assisted treatment is further used to clean graphene surfaces and interfaces, which also decouples graphene and neutralizes the doping levels. Twist angles between different layers are accurately controlled by adjusting the macroscopic stacking angle through their wafer flats. Transferred films exhibit minimal defects, homogeneous morphology, and uniform electrical properties over wafer scale. Even at room temperature, robust quantum Hall effects are observed in graphene films with centimetre-scale linewidth. Our stacking transfer method can facilitate the fabrication of graphene-based van der Waals superlattices and accelerate functional device applications.

Summary: TDP-43 is an RNA/DNA-binding protein that forms aggregates in various brain disorders. TDP-43 engages in many aspects of RNA metabolism, but its molecular roles in regulating genes and transposable elements (TEs) have not been extensively explored. Chronic TDP-43 knockdown impairs cell proliferation and cellular responses to DNA damage. At the molecular level, TDP-43 chronic deficiency affects gene expression either locally or distally by concomitantly altering the crosstalk between R-loops and 5-hydroxymethylcytosine (5hmC) in gene bodies and long-range enhancer/promoter interactions. Furthermore, TDP-43 knockdown induces substantial disease-relevant TE activation by influencing their R-loop and 5hmC homeostasis in a locus-specific manner. Together, our findings highlight the genomic roles of TDP-43 in modulating R-loop-5hmC coordination in coding genes, distal regulatory elements, and TEs, presenting a general and broad molecular mechanism underlying the contributions of proteinopathies to the etiology of neurodegenerative disorders.

Abstract Mono‐methylation of histone H3 on Lys 4 (H3K4me1), which is catalyzed by histone‐lysine N‐methyltransferase 2D (KMT2D), serves as an important epigenetic regulator in transcriptional control. In this study, the authors identify early B‐cell factor 2 (EBF2) as a binding protein of H3K4me1. Combining analyses of RNA‐seq and ChIP‐seq data, the authors further identify killin (KLLN) as a transcriptional target of KMT2D and EBF2 in pancreatic ductal adenocarcinoma (PDAC) cells. KMT2D‐dependent H3K4me1 and EBF2 are predominantly over‐lapped proximal to the transcription start site (TSS) of KLLN gene. Comprehensive functional assays show that KMT2D and EBF2 cooperatively inhibit PDAC cells proliferation, migration, and invasion through upregulating KLLN. Such inhibition on PDAC progression is also achieved through increasing H3K4me1 level by GSK‐LSD1, a selective inhibitor of lysine‐specific demethylase 1 (LSD1). Taken together, these findings reveal a new mechanism underlying PDAC progression and provide potential therapeutic targets for PDAC treatment.

Chronic heart failure (CHF) is a key part of cardiovascular continuum. Under the guidance of the theory of vessel-collateral doctrine, the present study proposes therapeutic benefits of Qili Qiangxin (QLQX) capsules, an innovative Chinese medicine, on chronic heart failure. The studies show that multiple targets of the drug on CHF, including enhancing myocardial systole, promoting urine excretion, inhibiting excessive activation of the neuroendocrine system, preventing ventricular remodeling by inhibiting inflammatory response, myocardial fibrosis, apoptosis and autophagy, enhancing myocardial energy metabolism, promoting angiogenesis, and improving endothelial function. Investigation on the effects and mechanism of the drug is beneficial to the treatment of chronic heart failure (CHF) through multiple targets and/or signaling pathways. Meanwhile, it provides new insights to further understand other refractory diseases in the cardiovascular continuum, and it also has an important theoretical and practical significance in enhancing prevention and therapeutic effect of traditional Chinese medicine for these diseases.

Summary: O-GlcNAc transferase (OGT) acts in the development of various cancers, but its role in clear cell renal cell carcinoma (ccRCC) remains unclear. In this study, we found that OGT was upregulated in ccRCC and this upregulation was associated with a worse survival. Moreover, OGT promoted the proliferation, clone formation, and invasion of VHL-mutated ccRCC cells. Mechanistically, OGT increased the protein level of hypoxia-inducible factor-2α (HIF-2α) (the main driver of the clear cell phenotype) by repressing ubiquitin‒proteasome system-mediated degradation. Interestingly, the OGT/HIF-2α axis conferred ccRCC a high sensitivity to ferroptosis. In conclusion, OGT promotes the progression of VHL-mutated ccRCC by inhibiting the degradation of HIF-2α, and agents that can modulate the OGT/HIF-2α axis may exert therapeutic effects on mutated VHL ccRCC.

Abstract Background Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder that frequently exhibits low-grade inflammation, pro-oxidant activity, and gut dysbiosis. PCOS has become one of the leading causes of female infertility worldwide. Recently, omega-3 polyunsaturated fatty acids (PUFAs) have been proven to benefit metabolic disorders in PCOS patients. However, its roles in the regulation of metabolic and endocrinal balances in PCOS pathophysiology are not clear. In the present study, we aimed to explore how omega-3 PUFAs alleviate ovarian dysfunction and insulin resistance in mice with dehydroepiandrosterone (DHEA)-induced PCOS by modulating the gut microbiota. Methods We induced PCOS in female mice by injecting them with DHEA and then treated them with omega-3 PUFAs. 16S ribosomal DNA (rDNA) amplicon sequencing, fecal microbiota transplantation (FMT) and antibiotic treatment were used to evaluate the role of microbiota in the regulation of ovarian functions and insulin resistance (IR) by omega-3 PUFAs. To further investigate the mechanism of gut microbiota on omega-3-mediated ovarian and metabolic protective effects, inflammatory and oxidative stress markers in ovaries and thermogenic markers in subcutaneous and brown adipose tissues were investigated. Results We found that oral supplementation with omega-3 PUFAs ameliorates the PCOS phenotype. 16S rDNA analysis revealed that omega-3 PUFA treatment increased the abundance of beneficial bacteria in the gut, thereby alleviating DHEA-induced gut dysbiosis. Antibiotic treatment and FMT experiments further demonstrated that the mechanisms underlying omega-3 benefits likely involve direct effects on the ovary to inhibit inflammatory cytokines such as IL-1β, TNF-α and IL-18. In addition, the gut microbiota played a key role in the improvement of adipose tissue morphology and function by decreasing multilocular cells and thermogenic markers such as Ucp1, Pgc1a, Cited and Cox8b within the subcutaneous adipose tissues. Conclusion These findings indicate that omega-3 PUFAs ameliorate androgen-induced gut microbiota dysbiosis. The gut microbiota plays a key role in the regulation of omega-3-mediated IR protective effects in polycystic ovary syndrome mice. Moreover, omega-3 PUFA-regulated improvements in the ovarian dysfunction associated with PCOS likely involve direct effects on the ovary to inhibit inflammation. Our findings suggest that omega-3 supplementation may be a promising therapeutic approach for the treatment of PCOS by modulating gut microbiota and alleviating ovarian dysfunction and insulin resistance.

Evaporated mother liquor of gas field wastewater (EML-GFW) is a form of wastewater generated by the triple-effect evaporation treatment of gas field wastewater containing complex pollutants. In this study, four metal sulfides, CuS, ZnS, MoS2, and WS2, were used to strengthen the Fenton process in EML-GFW treatment. The optimum Fenton/ZnS process for the highest removal of TOC from EML-GFW was achieved at the initial pH of 3.0 and in a mixture of FeSO4·7H2O:ZnS:H2O2 in the ratio of 30 g/L:10 g/L:1.2 mol/L, with a TOC removal efficiency of 74.5%. The organic components analysis of EML-GFW over four distinct periods demonstrated that the presence of N,N-dimethylethanolamine (DMEA) persisted and accounted for the greatest proportion of pollutants, identifying it as the characteristic pollutant. The TOC removal mechanism by Fenton/ZnS was revealed via analysis of organic materials obtained from the Fenton/ZnS process, tert-butanol quenching experiment, and illumination experiment. ZnS-generated hole–electron pairs under illumination, which promoted the reduction of Fe3+ to Fe2+, followed by an acceleration of •OH generation, thus improving TOC removal efficiency. The Fenton/ZnS process improved the treatment of EML-GFW in the laboratory, providing strong data support and theoretical guidance for expanding this technology at the gas field project site. HIGHLIGHTS The optimization of the Fenton/ZnS process was based on the actual wastewater.; The TOC removal efficiency of EML-GFW reached 74.5% by the optimum Fenton/ZnS process.; ZnS accelerated the production of •OH, increasing the removal efficiency of TOC.; This work was meaningful for the wastewater treatment at the gas field project site.;

Abstract In recent years, the postponement of childbearing has become a critical social issue. Male fertility is negatively associated with age because of testis aging. Spermatogenesis is impaired with age, but the molecular mechanism remains unknown. The dynamic posttranslational modification O-linked N-acetylglucosamine (O-GlcNAc), which is a type of monosaccharide modification, has been shown to drive the process of aging in various systems, but it has not yet been investigated in the testis and male reproductive aging. Thus, this study aims to investigate the alteration of O-GlcNAc with aging and explore the role of O-GlcNAc in spermatogenesis. Here, we demonstrate that the decline in spermatogenesis in aged mice is associated with elevation of O-GlcNAc. O-GlcNAc is specifically localized in differentiating spermatogonia and spermatocytes, indicating its crucial role in meiotic initiation and progression. Mimicking the age-related elevation of O-GlcNAc in young mice by disabling O-GlcNAcase (OGA) using the chemical inhibitor Thiamet-G can recapitulate the impairment of spermatogenesis in aged mice. Mechanistically, the elevation of O-GlcNAc in the testis leads to meiotic pachytene arrest due to defects in synapsis and recombination. Furthermore, decreasing O-GlcNAc in aged testes using an O-GlcNAc transferase (OGT) inhibitor can partially rescue the age-related impairment of spermatogenesis. Our results highlight that O-GlcNAc, as a novel posttranslational modification, participates in meiotic progression and drives the impairment of spermatogenesis during aging.

Abstract n-3 PUFAs are classic antioxidant that can be used to treat follicular dysplasia and hyperinsulinemia caused by excessive oxidative stress in PCOS women. To investigate the effect of n-3 PUFA supplementation on the oocyte quality of polycystic ovary syndrome (PCOS) mice during in vitro maturation, a PCOS mouse model was established by dehydroepiandrosterone (DHEA). The GV oocytes of the control and PCOS groups were collected and cultured in vitro with or without n-3 PUFAs. After 14 h, the oocytes were collected. Our data demonstrated that the oocyte maturation rate of PCOS mice significantly increased after the addition of 50 µM n-3 PUFAs. The results of immunofluorescence showed that the abnormal rates of spindles and chromosomes in the PCOS + n-3 PUFA group were lower than those in the PCOS group. The mRNA expression of an antioxidant-related gene (Sirt1) and DNA damage repair genes (Brca1/Msh2) was found to be significantly rescued after n-3 treatment. Additionally, the results of living cell staining showed that the addition of n-3 PUFAs could reduce the levels of reactive oxygen species and mitochondrial superoxide in PCOS oocytes. In conclusion, the addition of 50 µM n-3 PUFAs during the in vitro maturation of PCOS mouse oocytes can improve the maturation rate by reducing the level of oxidative stress and the rate of spindle/chromosome abnormalities, providing valuable support during the IVM process.

Abstract Genomic studies have demonstrated a high frequency of genetic alterations in components of the SWI/SNF complex including the core subunit SMARCA4. However, the mechanisms of tumorigenesis driven by SMARCA4 mutations, particularly in colorectal cancer (CRC), remain largely unknown. In this study, we identified a specific, hotspot mutation in SMARCA4 (c. 3721C>T) which results in a conversion from arginine to tryptophan at residue 1157 (R1157W) in human CRC tissues associated with higher-grade tumors and controls CRC progression. Mechanistically, we found that the SMARCA4R1157W mutation facilitated its recruitment to PRMT1-mediated H4R3me2a (asymmetric dimethylation of Arg 3 in histone H4) and enhanced the ATPase activity of SWI/SNF complex to remodel chromatin in CRC cells. We further showed that the SMARCA4R1157W mutant reinforced the transcriptional expression of EGFR and TNS4 to promote the proliferation of CRC cells and patient-derived tumor organoids. Importantly, we demonstrated that SMARCA4R1157W CRC cells and mutant cell-derived xenografts were more sensitive to the combined inhibition of PRMT1 and SMARCA4 which act synergistically to suppress cell proliferation. Together, our findings show that SMARCA4-R1157W is a critical activating mutation, which accelerates CRC progression through facilitating chromatin recruitment and remodeling. Our results suggest a potential precision therapeutic strategy for the treatment of CRC patients carrying the SMARCA4R1157W mutation.

Summary: Solid tumors have developed robust ferroptosis resistance. The mechanism underlying ferroptosis resistance regulation in solid tumors, however, remains elusive. Here, we report that the hypoxic tumor microenvironment potently promotes ferroptosis resistance in solid tumors in a hypoxia-inducible factor 1α (HIF-1α)-dependent manner. In combination with HIF-2α, which promotes tumor ferroptosis under hypoxia, HIF-1α is the main driver of hypoxia-induced ferroptosis resistance. Mechanistically, HIF-1α-induced lactate contributes to ferroptosis resistance in a pH-dependent manner that is parallel to the classical SLC7A11 and FSP1 systems. In addition, HIF-1α also enhances transcription of SLC1A1, an important glutamate transporter, and promotes cystine uptake to promote ferroptosis resistance. In support of the role of hypoxia in ferroptosis resistance, silencing HIF-1α sensitizes mouse solid tumors to ferroptosis inducers. In conclusion, our results reveal a mechanism by which hypoxia drives ferroptosis resistance and identify the combination of hypoxia alleviation and ferroptosis induction as a promising therapeutic strategy for solid tumors.

Lens epithelium-derived growth factor (LEDGF/p75) is a reader of epigenetic marks and a potential target for therapeutic intervention. Its involvement in human immunodeficiency virus (HIV) integration and the development of leukemia driven by MLL (also known as KMT2A) gene fusion make it an attractive candidate for drug development. However, exploration of LEDGF/p75 as an epigenetic reader of H3K36me3 in tumors is limited. Here, for the first time, we analyze the role of LEDGF/p75 in multiple cancers via multiple online databases and in vitro experiments. We used pancancer bulk sequencing data and online tools to analyze correlations of LEDGF/p75 with prognosis, genomic instability, DNA damage repair, prognostic alternative splicing, protein interactions, and tumor immunity. In summary, the present study identified that LEDGF/p75 may serve as a prognostic predictor for tumors such as adrenocortical carcinoma, kidney chromophobe, liver hepatocellular carcinoma, pancreatic adenocarcinoma, skin cutaneous melanoma, and clear cell renal cell carcinoma (ccRCC). In addition, in vitro experiments and gene microarray sequencing were performed to explore the function of LEDGF/p75 in ccRCC, providing new insights into the pathogenesis of the nonmutated SETD2 ccRCC subtype.

Background: Many factors were reported associated with the pregnancy rate of intrauterine insemination (IUI), which played key role is still debated. Aims: The aim of this study was to explore related clinical pregnancy outcome factor in IUI cycles of non-male factor. Settings and Design: The clinical data of 1232 IUI cycles in 690 couples experiencing infertility who attended the Reproductive Center of Jinling Hospital between July 2015 and November 2021 were retrospectively analysed. Materials and Methods: Female and male age, body mass index (BMI), anti-Müllerian hormone (AMH), male semen parameters before and after wash, endometrial thickness (EMT), artificial insemination timing and ovarian stimulation (OS) protocols were compared between the pregnant group and the non-pregnant group in order to explore any correlation. Statistical Analysis Used: Continuous variables were analysed using independent-samples t-test, and Chi-square test was used for comparison of measurement data between the two groups. P 4.5 ng/ml, EMT between 8 and 12 mm and letrozole + human menopausal gonadotropin stimulation with higher clinical pregnancy. However, there were no differences between the pregnant group and the non-pregnant group amongst the female and male age, BMI, hormones on baseline and day of human chorionic gonadotrophin, number of ovulated oocytes, sperm parameters before and after wash, treatment protocols and the timing of IUI (P > 0.05). Furthermore, there were 240 couples who not pregnant received one or more cycles of in vitro fertilisation/intracytoplasmic sperm injection/ pre-implantation genetic technology treatment, and another 182 couples forgo follow-up treatment. Conclusion: The results of the present study demonstrate that the clinical IUI pregnancy rate is correlated with the factors of female AMH, EMT and OS protocol; more studies and samples are necessary to evaluate whether other factors affect pregnancy rate.

Aims: To explore the new indications and key mechanism of Bazi Bushen capsule (BZBS) by network pharmacology and in vitro experiment. Methods: The ingredients library of BZBS was constructed by retrieving multiple TCM databases. The potential target profiles of the components were predicted by target prediction algorithms based on different principles, and validated by using known activity data. The target spectrum of BZBS with high reliability was screened by considering the source of the targets and the node degree in compound-target (C-T) network. Subsequently, new indications for BZBS were predicted by disease ontology (DO) enrichment analysis and initially validated by GO and KEGG pathway enrichment analysis. Furthermore, the target sets of BZBS acting on AD signaling pathway were identified by intersection analysis. Based on STRING database, the PPI network of target was constructed and their node degree was calculated. Two Alzheimer's disease (AD) cell models, BV-2 and SH-SY5Y, were used to preliminarily verify the anti-AD efficacy and mechanism of BZBS in vitro. Results: In total, 1499 non-repeated ingredients were obtained from 16 herbs in BZBS formula, and 1320 BZBS targets with high confidence were predicted. Disease enrichment results strongly suggested that BZBS formula has the potential to be used in the treatment of AD. GO and KEGG enrichment results provide a preliminary verification of this point. Among them, 113 functional targets of BZBS belong to AD pathway. A PPI network containing 113 functional targets and 1051 edges for the treatment of AD was constructed. In vitro experiments showed that BZBS could significantly reduce the release of TNF-α and IL-6 and the expression of COX-2 and PSEN1 in Aβ25-35-induced BV-2 cells, which may be related to the regulation of ERK1/2/NF-κB signaling pathway. BZBS reduced the apoptosis rate of Aβ25-35 induced SH-SY5Y cells, significantly increased mitochondrial membrane potential, reduced the expression of Caspase3 active fragment and PSEN1, and increased the expression of IDE. This may be related to the regulation of GSK-3β/β-catenin signaling pathway. Conclusions: BZBS formula has a potential use in the treatment of AD, which is achieved through regulation of ERK1/2, NF-κB signaling pathways, and GSK-3β/β-catenin signaling pathway. Furthermore, the network pharmacology technology is a feasible drug repurposing strategy to reposition new clinical use of approved TCM and explore the mechanism of action. The study lays a foundation for the subsequent in-depth study of BZBS in the treatment of AD and provides a basis for its application in the clinical treatment of AD.

AbstractBackground Although ERAS Program had some advantages in laparoscopic distal gastrectomy (LDG), its efficacy and safety remained unclear. We conducted a systematic review and meta-analysis to assess the efficacy and safety of the ERAS group and the traditional care (TC) group in LDG.Methods Multiple databases were retrieved from 1 January 2000 to 30 April 2023. The risk ratio (RR), standardized mean difference (SMD) and their 95% confidence interval (CI) were used to estimate the results.Results Our meta-analysis contained 17 randomized controlled trials (RCTs) studies, which comprised 1468 patients. Regarding efficacy, the ERAS group had significantly shorter postoperative time to first flatus (SMD = −1.29 [95% CI: −1.68, −0.90]), shorter time to first defecation (SMD = −1.26 [95% CI: −1.90, −0.61]), shorter hospital stays (SMD = −0.99 [95% CI: −1.34, −0.63]), and lower hospitalization costs (SMD = −1.17 [95% CI: −1.86, −0.48]) compared to the TC group. Furthermore, in the ERAS group, C-reactive protein levels were lower on postoperative days 1, 3 or 4, and 7; albumin levels were higher on postoperative days 3 or 4 and 7; and interleukin-6 levels were lower on postoperative days 1 and 3. Regarding safety, the overall postoperative complication rate was lower in the ERAS group (RR: 0.76 [95% CI: 0.60, 0.97]), but there was no significant difference in the individual postoperative complication rate. Other indicators were also not statistically significant.Conclusion The combination of ERAS Program with laparoscopy surgery was safe and effective for the perioperative management of patients with distal gastric cancer.

The double-floor storage tank can overcome the disadvantages of severe corrosion and strong leakage concealment of the traditional single-floor storage tank, but its upper floor is at the risk of fatigue failure under cyclic loading. Therefore, an axisymmetric model was established based on the structure and load symmetry for the vertical double-floor storage tank with annular grille structure. Through finite element analysis on the fatigue life of storage tanks during long-term service, the distribution of safety factor and fatigue life of the tanks out of service was studied in detail under the conditions of different bottom supports, grille spacing and thickness-to-width ratios of grille. The results show that the tank wall bottom is the most vulnerable part. Under the same grille arrangement and loading, the support mode with the floor connected by angle steel has higher fatigue reliability. Besides, the grille spacing and the thickness-to-width ratio have significant impact on the overall fatigue reliability of storage tanks. With the decrease of grille spacing and the thickness-to-width ratio, the overall safety factor and fatigue life of storage tanks increase, and their fatigue reliability also increases. Generally, the research results could provide a theoretical basis and technical reference for the structural design and optimization of vertical double-floor storage tanks.

Abstract Exploring the functions of human-specific genes (HSGs) is challenging due to the lack of a tractable genetic model system. Testosterone is essential for maintaining human spermatogenesis and fertility, but the underlying mechanism is unclear. Here, we identified Cancer/Testis Antigen gene family 47 (CT47) as an essential regulator of human-specific spermatogenesis by stabilizing arginine methyltransferase 5 (PRMT5). A humanized mouse model revealed that CT47 functions to arrest spermatogenesis by interacting with and regulating CT47/PRMT5 accumulation in the nucleus during the leptotene/zygotene-to-pachytene transition of meiosis. We demonstrate that testosterone induces nuclear depletion of CT47/PRMT5 and rescues leptotene-arrested spermatocyte progression in humanized testes. Loss of CT47 in human embryonic stem cells (hESCs) by CRISPR/Cas9 led to an increase in haploid cells but blocked the testosterone-induced increase in haploid cells when hESCs were differentiated into haploid spermatogenic cells. Moreover, CT47 levels were decreased in nonobstructive azoospermia. Together, these results established CT47 as a crucial regulator of human spermatogenesis by preventing meiosis initiation before the testosterone surge.

Reduced expression of myosin phosphatase target subunit 1 (MYPT1) is critical for the development of vasculogenic erectile dysfunction and a natural compound, lotusine, is found to increase MYPT1 expression and rescue penile smooth muscle function.

Abstract Background Aberrant expression of circular RNAs (circRNAs) contributes to the initiation and progression of human malignancies, but the underlying mechanisms remain largely elusive. Methods High-throughput sequencing was performed to screen aberrantly expressed circRNAs or miRNAs in colorectal cancer (CRC) and adjacent normal tissues. A series of gain- and loss-of-function studies were conducted to evaluate the biological behaviors of CRC cells. RNA pulldown, mass spectrometry, RIP, qRT-PCR, Western blot, luciferase reporter assays and MeRIP-seq analysis were further applied to dissect the detailed mechanisms. Results Here, a novel circRNA named circEZH2 (hsa_circ_0006357) was screened out by RNA-seq in CRC tissues, whose expression is closely related to the clinicpathological characteristics and prognosis of CRC patients. Biologically, circEZH2 facilitates the proliferation and migration of CRC cells in vitro and in vivo. Mechanistically, circEZH2 interacts with m6A reader IGF2BP2 and blocks its ubiquitination-dependent degradation. Meanwhile, circEZH2 could serve as a sponge of miR-133b, resulting in the upregulation of IGF2BP2. Particularly, circEZH2/IGF2BP2 enhances the stability of CREB1 mRNA, thus aggravating CRC progression. Conclusions Our findings not only reveal the pivotal roles of circEZH2 in modulating CRC progression, but also advocate for attenuating circEZH2/miR-133b/IGF2BP2/ CREB1 regulatory axis to combat CRC.

Tumor cells can evade attack by phagocytes by upregulating the self-marker CD47. The mechanisms underlying tumor CD47 upregulation, however, remain unclear. Here, we report that human lung adenocarcinoma CD47 is upregulated by interferon-γ (IFN-γ), the level in the tumor microenvironment of which is markedly increased after tumor metastasis and chemotherapy. The IFN-γ receptor is expressed in various human lung adenocarcinoma tissues regardless of the CD47 protein expression, and lung adenocarcinoma CD47 expression is significantly enhanced following tumor metastasis or chemotherapy treatment. In line with this, CD47 expression in various lung cancer cells is markedly increased by IFN-γ treatment. Mechanistically, IFN-γ promotes CD47 expression by activating interferon regulatory factor-1 (IRF-1), which binds to an IRF-1-binding domain within the CD47 promoter region and increases CD47 transcription. Functionally, IFN-γ-enhanced CD47 expression facilitates human lung cancer cell invasion both in vitro and in vivo, whereas IFN-γ-induced CD47 upregulation and cancer metastasis are blocked by mutating the IRF-1-binding site within the CD47 promoter. Our results reveal IFN-γ-enhanced CD47 expression as a novel mechanism promoting human lung adenocarcinoma progression.

Abstract Background Prostate cancer (PCa) is the most frequently diagnosed malignancy in men, and its mechanism remains poorly understood. Therefore, it is urgent to discover potential novel diagnostic biomarkers and therapeutic targets that can potentially facilitate the development of efficient anticancer strategies. Methods A series of functional in vitro and in vivo experiments were conducted to evaluate the biological behaviors of PCa cells. RNA pulldown, Western blot, luciferase reporter, immunohistochemistry and chromatin immunoprecipitation assays were applied to dissect the detailed underlying mechanisms. High-throughput sequencing was performed to screen for differentially expressed circRNAs in PCa and adjacent normal tissues. Results Upregulation of protein arginine methyltransferase 5 (PRMT5) is associated with poor progression-free survival and the activation of multiple signaling pathways in PCa. PRMT5 inhibits the transcription of CAMK2N1 by depositing the repressive histone marks H4R3me2s and H3R8me2s on the proximal promoter region of CAMK2N1, and results in malignant progression of PCa both in vitro and in vivo. Moreover, the expression of circSPON2, a candidate circRNA in PCa tissues identified by RNA-seq, was found to be associated with poor clinical outcomes in PCa patients. Further results showed that circSPON2 induced PCa cell proliferation and migration, and that the circSPON2-induced effects were counteracted by miR-331-3p. Particularly, circSPON2 acted as a competitive endogenous RNA (ceRNA) of miR-331-3p to attenuate the repressive effects of miR-331-3p on its downstream target PRMT5. Conclusions Our findings showed that the epigenetic regulator PRMT5 aggravates PCa progression by inhibiting the transcription of CAMK2N1 and is modulated by the circSPON2/miR-331-3p axis, which may serve as a potential therapeutic target for patients with aggressive PCa.

Summary: Ovarian granulosa cells (GCs) in the follicle are the important mediator of steroidogenesis and foster oocyte maturation. Evidences suggested that the function of GCs could be regulated by S-palmitoylation. However, the role of S-palmitoylation of GCs in ovarian hyperandrogenism remains elusive. Here, we demonstrated that the protein from GCs in ovarian hyperandrogenism phenotype mouse group exhibits lower palmitoylation level compared with that in the control group. Using S-palmitoylation-enriched quantitative proteomics, we identified heat shock protein isoform α (HSP90α) with lower S-palmitoylation levels in ovarian hyperandrogenism phenotype group. Mechanistically, S-palmitoylation of HSP90α modulates the conversion of androgen to estrogens via the androgen receptor (AR) signalling pathway, and its level is regulated by PPT1. Targeting AR signaling by using dipyridamole attenuated ovarian hyperandrogenism symptoms. Our data help elucidate ovarian hyperandrogenism from perspective of protein modification and provide new evidence showing that HSP90α S-palmitoylation modification might be a potential pharmacological target for ovarian hyperandrogenism treatment.

Abstract Background Circular RNAs (circRNAs), a novel class of poorly conserved non-coding RNAs that regulate gene expression, are highly enriched in the human brain. Despite increasing discoveries of circRNA function in human neurons, the circRNA landscape and function in developing human oligodendroglia, the myelinating cells that govern neuronal conductance, remains unexplored. Meanwhile, improved experimental and computational tools for the accurate identification of circRNAs are needed. Results We adopt a published experimental approach for circRNA enrichment and develop CARP (CircRNA identification using A-tailing RNase R approach and Pseudo-reference alignment), a comprehensive 21-module computational framework for accurate circRNA identification and quantification. Using CARP, we identify developmentally programmed human oligodendroglia circRNA landscapes in the HOG oligodendroglioma cell line, distinct from neuronal circRNA landscapes. Numerous circRNAs display oligodendroglia-specific regulation upon differentiation, among which a subclass is regulated independently from their parental mRNAs. We find that circRNA flanking introns often contain cis-regulatory elements for RNA editing and are predicted to bind differentiation-regulated splicing factors. In addition, we discover novel oligodendroglia-specific circRNAs that are predicted to sponge microRNAs, which co-operatively promote oligodendroglia development. Furthermore, we identify circRNA clusters derived from differentiation-regulated alternative circularization events within the same gene, each containing a common circular exon, achieving additive sponging effects that promote human oligodendroglia differentiation. Conclusions Our results reveal dynamic regulation of human oligodendroglia circRNA landscapes during early differentiation and suggest critical roles of the circRNA-miRNA-mRNA axis in advancing human oligodendroglia development.

Let $ f: V(G)\cup E(G)\rightarrow \{1, 2, \dots, k\} $ be a total $ k $ -coloring of $ G $. Define a weight function on total coloring as $ \phi(x) = f(x)+\sum\limits_{e\ni x}f(e)+\sum\limits_{y\in N(x)}f(y), $ where $ N(x) = \{y\in V(G)|xy\in E(G)\} $. If $ \phi(x)\neq \phi(y) $ for any edge $ xy\in E(G) $, then $ f $ is called a neighbor full sum distinguishing total $ k $ -coloring of $ G $. The smallest value $ k $ for which $ G $ has such a coloring is called the neighbor full sum distinguishing total chromatic number of $ G $ and denoted by fgndi $ _{\sum}(G) $. Suppose that $ H = T\cup C $ is a Halin graph, where $ T $ and $ C $ are called the characteristic tree and the adjoint cycle, respectively. Let $ V_0\subseteq V(H)\setminus V(C) $ and each vertex in $ V_0 $ is adjacent to some vertices on $ C $. In this paper, we prove that the neighbor full sum distinguishing total chromatic number of two types of Halin graphs are not more than three: (i) 3-regular Halin graphs and (ii) every vertex of $ V_0 $ of a Halin graph with degree at least 4. The above results support a conjecture that fgndi $ _{\sum}(G)\leq 3 $ for any connected graph $ G $ of order at least three (Chang et al., 2022).

Traditional approaches for diagnosing Alzheimer’s disease (AD) such as brain imaging and cerebrospinal fluid are invasive and expensive. It is desirable to develop a useful diagnostic tool by exploiting biomarkers obtained from peripheral tissues due to their noninvasive and easily accessible characteristics. However, the capacity of using DNA methylation data in peripheral blood for predicting AD progression is rarely known. It is also challenging to develop an efficient prediction model considering the complex and high-dimensional DNA methylation data in a longitudinal study. Here, we develop two multi-task deep autoencoders, which are based on the convolutional autoencoder and long short-term memory autoencoder to learn the compressed feature representation by jointly minimizing the reconstruction error and maximizing the prediction accuracy. By benchmarking on longitudinal DNA methylation data collected from the peripheral blood in Alzheimer’s Disease Neuroimaging Initiative, we demonstrate that the proposed multi-task deep autoencoders outperform state-of-the-art machine learning approaches for both predicting AD progression and reconstructing the temporal DNA methylation profiles. In addition, the proposed multi-task deep autoencoders can predict AD progression accurately using only the historical DNA methylation data and the performance is further improved by including all temporal DNA methylation data.Availability:: https://github.com/lichen-lab/MTAE.

BackgroundThere is a lack of in-depth analysis regarding the disease burden of childhood cancer in China. Indeed, this is the first time the topic has been addressed in detail. Drawing on population-based data for the past 30 years, this study systematically analyzes the composition and long-term trend of this disease burden in China.MethodsGBD 2019 contained population-based data from 1990 to 2019 and was prepared using Microsoft Excel 2016. We used AAPC and ARIMA models for trend analysis and prediction formulation.ResultsIn 2019, there were 45,601 new cases, 9,156 cancer deaths, and 782,530 DALYs in China. From 1990 to 2019, leukemia, together with brain and CNS cancer, invariably ranked highest in terms of new cases, cancer deaths, and DALYs. Leukemia accounted for more than 50%, but decreased over time. By contrast, the proportions for brain and CNS cancer increased. There were significant decreases in the overall incidence, mortality, and DALY rates in China, but these were still higher than the corresponding global average levels. Considering all types of childhood cancer, the incidence rate of testicular cancer showed the biggest increase, and the mortality and DALY rates of leukemia showed the largest decrease. In terms of different age groups, the overall incidence rate of childhood cancers increased in 0 to 4 age group, but it decreased in 5 to 14 age groups. The overall mortality and DALY rates of childhood cancers decreased in all four age groups. Over the next 10 years, the overall incidence rate of childhood cancer will increase, but the overall mortality and DALY rates will decrease. The increase in malignant skin melanoma will comprise the largest rise in the incidence, while the decrease for leukemia will be the largest fall in the incidence, cancer deaths, and DALYs.ConclusionThe disease burden of all childhood cancers in China remains highly serious, especially for certain types of cancer and certain age groups. China should focus more emphatically on the incidence of childhood cancer in future, and it must consistently strengthen investment in the relevant research and medical resources to reduce the disease burden in this field.

Blood-testis barrier (BTB) damage promotes spermatogenesis dysfunction, which is a critical cause of male infertility. Dyslipidemia has been correlated with male infertility, but the major hazardous lipid and the underlying mechanism remains unclear. In this study, we firstly discovered an elevation of palmitic acid (PA) and a decrease of inhibin B in patients with severe dyszoospermia, which leaded us to explore the effects of PA on Sertoli cells. We observed a damage of BTB by PA. PA penetration to endoplasmic reticulum (ER) and its damage to ER structures were exhibited by microimaging and dynamic observation, and consequent ER stress was proved to mediate PA-induced Sertoli cell barrier disruption. Remarkably, we demonstrated a critical role of aberrant protein palmitoylation in PA-induced Sertoli cell barrier dysfunction. An ER protein, Calnexin, was screened out and was demonstrated to participate in this process, and suppression of its palmitoylation showed an ameliorating effect. We also found that ω-3 poly-unsaturated fatty acids down-regulated Calnexin palmitoylation, and alleviated BTB dysfunction. Our results indicate that dysregulated palmitoylation induced by PA plays a pivotal role in BTB disruption and subsequent spermatogenesis dysfunction, suggesting that protein palmitoylation might be therapeutically targetable in male infertility.

Let $ f $ be a proper total $ k $-coloring of a simple graph $ G $ from $ V(G)\cup E(G) $ to $ \{1, 2, \dots, k\} $, let $ C(u, f) $ be the set of the colors assigned to the edges incident with $ u $, and let $ n_d(G) $ and $ \Delta(G) $ denote the number of all vertices of degree $ d $ and the maximum degree in $ G $, respectively. We call $ f $ a (2)-vertex distinguishing total $ k $-coloring ($ k $-(2)-vdc for short) if $ C(u, f)\neq C(v, f) $ and $ C(u, f)\cup \{f(u)\}\neq C(v, f)\cup \{f(v)\} $ for distinct vertices $ u, v\in V(G) $. The minimum number $ k $ of colors required for which $ G $ admits a $ k $-(2)-vdc is denoted by $ \chi''_{2s}(G) $. In this paper, we show that a tree $ T $ with $ n_2(T)\leq n_1(T) $ has $ \chi''_{2s}(T) = n_1(T) $ if and only if $ T $ is not a tree with $ D(T) = 2, 3 $ or $ n_1(T) = \Delta(T) $, where $ D(T) $ is the diameter of tree $ T $.

Fatigue, including cognitive fatigue, is one of the most debilitating symptoms reported by persons with multiple sclerosis (pwMS). Cognitive fatigue has been associated with disruptions in striato-thalamo-cortical and frontal networks, but what remains unknown is how the rate at which pwMS become fatigued over time relates to microstructural properties within the brain. The current study aims to fill this gap in knowledge by investigating how cognitive fatigue rate relates to white matter and basal ganglia microstructure in a sample of 62 persons with relapsing-remitting MS. Participants rated their level of cognitive fatigue at baseline and after each block (x7) of a within-scanner cognitive fatigue inducing task. The slope of the regression line of all eight fatigue ratings was designated as “cognitive fatigue rate.” Diffusional kurtosis imaging maps were processed using tract-based spatial statistics and regional analyses (i.e., basal ganglia) and associated with cognitive fatigue rate. Results showed cognitive fatigue rate to be related to several white matter tracts, with many having been associated with basal ganglia connectivity or the previously proposed “fatigue network.” In addition, cognitive fatigue rate was associated with the microstructure within the putamen, though this did not survive multiple comparisons correction. Our approach of using cognitive fatigue rate, rather than trait fatigue, brings us closer to understanding how brain pathology may be impacting the experience of fatigue in the moment, which is crucial for developing interventions. These results hold promise for continuing to unpack the complex construct that is cognitive fatigue.

Introduction Morphological evaluation is used to select embryos for in vitro fertilisation. However, it does not fully reflect the implantation potential. Preimplantation genetic testing for aneuploidies (PGT-A) can detect embryonic aneuploidy, but biopsy procedure is invasive. Currently, a non-invasive PGT (ni-PGT) approach using spent medium is being evaluated. However, the clinical benefit of ni-PGT has not been clearly demonstrated. A multicentre randomised trial is needed to verify whether ni-PGT can be an new effective tool for evaluating embryos.Methods and analysis Overall, 1148 couples aged 35~42 (women) receiving in vitro fertilization–intracytoplasmic sperm injection are planned to be enrolled. Couples will be digitally randomised to (1) ni-PGT and (2) conventional morphology groups at a 1:1 treatment ratio. The primary outcome will be the ongoing pregnancy rate related to the first transfer cycle within 6 months after oocyte retrieval.Ethics and dissemination The study protocol is approved by the Ethics Committee of Peking University Third Hospital and the participating hospitals. The results will be disseminated through international conferences and scientific journals.Trial registration number NCT04339166.

Controlling the trapping process is one of the important themes in the study of random walk in real complex systems. We studied two types of random walks that are different from the traditional random walk on a directed weighted network. The first type of random walk is the weighted random walk controlled by the weight θ, and the other is the delayed-weighted random walk affected by both delay probability p and weight θ. Furthermore, we derived analytically the average trapping time (ATT) measuring the efficiency of the two types of trapping processes; the result shows that the ATT grows sub-linearly, linearly, and super-linearly with the network order when the weight satisfies θ32 , respectively. The weight θ of the directed network can be adjusted by direction, the delay parameter p only changes the pre-factor of the ATT, and the weight θ modifies both the pre-factor and scaling of the ATT.

Abstract Here we report a case of a 16q24.3 microdeletion KBG syndrome (KBGS) in a fetus. The absence of a well‐defined phenotype poses a challenge for genetic diagnosis. This report demonstrated that the high‐risk chromosome 21 trisomy could be the first manifestation of KBGS, as observed in this case.

Background: The emergence of castration resistance is fatal for patients with prostate cancer (PCa); however, there is still a lack of effective means to detect the early progression. In this study, a novel combined nomogram was established to predict the risk of progression related to castration resistance.Methods: The castration-resistant prostate cancer (CRPC)-related differentially expressed genes (DEGs) were identified by R packages “limma” and “WGCNA” in GSE35988-GPL6480 and GSE70768-GPL10558, respectively. Relationships between DEGs and progression-free interval (PFI) were analyzed using the Kaplan–Meier method in TCGA PCa patients. A multigene signature was built by lasso-penalized Cox regression analysis, and assessed by the receiver operator characteristic (ROC) curve and Kaplan–Meier curve. Finally, the univariate and multivariate Cox regression analyses were used to establish a combined nomogram. The prognostic value of the nomogram was validated by concordance index (C-index), calibration plots, ROC curve, and decision curve analysis (DCA).Results: 15 CRPC-related DEGs were identified finally, of which 13 genes were significantly associated with PFI and used as the candidate genes for modeling. A two-gene (KIFC2 and BCAS1) signature was built to predict the risk of progression. The ROC curve indicated that 5-year area under curve (AUC) in the training, testing, and whole TCGA dataset was 0.722, 0.739, and 0.731, respectively. Patients with high-risk scores were significantly associated with poorer PFI (p < 0.0001). A novel combined nomogram was successfully established for individualized prediction integrating with T stage, Gleason score, and risk score. While the 1-year, 3-year, and 5-year AUC were 0.76, 0.761, and 0.762, respectively, the good prognostic value of the nomogram was also validated by the C-index (0.734), calibration plots, and DCA.Conclusion: The combined nomogram can be used to predict the individualized risk of progression related to castration resistance for PCa patients and has been preliminarily verified to have good predictive ability.

Using asymmetric topology cryptography to encrypt networks on the basis of topology coding is a new topic of cryptography, which consists of two major elements, i.e., topological structures and mathematical constraints. The topological signature of asymmetric topology cryptography is stored in the computer by matrices that can produce number-based strings for application. By means of algebra, we introduce every-zero mixed graphic groups, graphic lattices, and various graph-type homomorphisms and graphic lattices based on mixed graphic groups into cloud computing technology. The whole network encryption will be realized by various graphic groups.

Abstract Background Aberrant changes in epigenetic mechanisms such as histone modifications play an important role in cancer progression. PRMT1 which triggers asymmetric dimethylation of histone H4 on arginine 3 (H4R3me2a) is upregulated in human colorectal cancer (CRC) and is essential for cell proliferation. However, how this dysregulated modification might contribute to malignant transitions of CRC remains poorly understood. Methods In this study, we integrated biochemical assays including protein interaction studies and chromatin immunoprecipitation (ChIP), cellular analysis including cell viability, proliferation, colony formation, and migration assays, clinical sample analysis, microarray experiments, and ChIP-Seq data to investigate the potential genomic recognition pattern of H4R3me2s in CRC cells and its effect on CRC progression. Results We show that PRMT1 and SMARCA4, an ATPase subunit of the SWI/SNF chromatin remodeling complex, act cooperatively to promote colorectal cancer (CRC) progression. We find that SMARCA4 is a novel effector molecule of PRMT1-mediated H4R3me2a. Mechanistically, we show that H4R3me2a directly recruited SMARCA4 to promote the proliferative, colony-formative, and migratory abilities of CRC cells by enhancing EGFR signaling. We found that EGFR and TNS4 were major direct downstream transcriptional targets of PRMT1 and SMARCA4 in colon cells, and acted in a PRMT1 methyltransferase activity-dependent manner to promote CRC cell proliferation. In vivo, knockdown or inhibition of PRMT1 profoundly attenuated the growth of CRC cells in the C57BL/6 J-ApcMin/+ CRC mice model. Importantly, elevated expression of PRMT1 or SMARCA4 in CRC patients were positively correlated with expression of EGFR and TNS4, and CRC patients had shorter overall survival. These findings reveal a critical interplay between epigenetic and transcriptional control during CRC progression, suggesting that SMARCA4 is a novel key epigenetic modulator of CRC. Our findings thus highlight PRMT1/SMARCA4 inhibition as a potential therapeutic intervention strategy for CRC. Conclusion PRMT1-mediated H4R3me2a recruits SMARCA4, which promotes colorectal cancer progression by enhancing EGFR signaling.