The syndrome of multiple morphological abnormalities of the sperm flagella (MMAF) is one of the most serious kinds of sperm defects, leading to asthenoteratozoospermia and male infertility. In this study, we use whole-exome sequencing to identify genetic factors that account for male infertility in a patient born from a consanguineous Pakistani couple. A homozygous frameshift mutation (c.1399_1402del; p.Gln468ArgfsTer2) in axonemal dynein light chain domain containing 1 ( AXDND1 ) was identified in the patient. Sanger sequencing data showed that the mutation was cosegregated recessively with male infertility in this family. Papanicolaou staining and scanning electron microscopy analysis of the sperm revealed severely abnormal flagellar morphology in the patient. Immunofluorescence and western blot showed undetectable AXDND1 expression in the sperm of the patient. Transmission electron microscopy analysis showed disorganized sperm axonemal structure in the patient, particularly missing the central pair of microtubules. Immunofluorescence staining showed the absence of sperm-associated antigen 6 (SPAG6) and dynein axonemal light intermediate chain 1 (DNALI1) signals in the sperm flagella of the patient. These findings indicate that AXDND1 is essential for the organization of flagellar axoneme and provide direct evidence that AXDND1 is a MMAF gene in humans, thus expanding the phenotypic spectrum of AXDND1 frameshift mutations.
Humans ; Male ; Sperm Tail/ultrastructure* ; Frameshift Mutation ; Infertility, Male/pathology* ; Pakistan ; Pedigree ; Consanguinity ; Axonemal Dyneins/genetics* ; Adult ; Spermatozoa ; Exome Sequencing

Diabetes, a metabolic disease stemming from impaired or defective insulin secretion, ranks among the most severe chronic illnesses globally. While several approved drugs exist for its treatment, they often come with multiple side effects. Therefore, there is a pressing need for safe and effective anti-diabetic medications. Traditional Chinese medicine has recognized Lycium barbarum (LB; goji berry) plant, commonly known as "wolfberry fruit" in China, for over 2,000 years. Natural compounds derived from LB show promise in reducing diabetes levels. Although research on the impact of LB on diabetes is still limited, our review aims to explore the potential of LB in reducing the risk of diabetes and examine the underlying mechanisms involved. LB can modulate diabetes through various pathways, such as inhibiting α-amylase and α-glucosidase activities, promoting β-cell proliferation, stimulating insulin secretion, inhibiting glucagon secretion, improving insulin resistance and glucose tolerance, and enhancing antioxidant and anti-inflammatory activities. Additionally, LB improves gut flora and immunomodulation, further aiding diabetes management. These findings highlight the potential clinical utility of LB in managing diabetes and its complications within the framework of evidence-based modern medicine.

Hepatocellular carcinoma (HCC) is one of the most common malignancies and is a major cause of cancer-related mortalities worldwide (Forner et al., 2018; He et al., 2023). Sarcopenia is a syndrome characterized by an accelerated loss of skeletal muscle (SM) mass that may be age-related or the result of malnutrition in cancer patients (Cruz-Jentoft and Sayer, 2019). Preoperative sarcopenia in HCC patients treated with hepatectomy or liver transplantation is an independent risk factor for poor survival (Voron et al., 2015; van Vugt et al., 2016). Previous studies have used various criteria to define sarcopenia, including muscle area and density. However, the lack of standardized diagnostic methods for sarcopenia limits their clinical use. In 2018, the European Working Group on Sarcopenia in Older People (EWGSOP) renewed a consensus on the definition of sarcopenia: low muscle strength, loss of muscle quantity, and poor physical performance (Cruz-Jentoft et al., 2019). Radiological imaging-based measurement of muscle quantity or mass is most commonly used to evaluate the degree of sarcopenia. The gold standard is to measure the SM and/or psoas muscle (PM) area using abdominal computed tomography (CT) at the third lumbar vertebra (L3), as it is linearly correlated to whole-body SM mass (van Vugt et al., 2016). According to a "North American Expert Opinion Statement on Sarcopenia," SM index (SMI) is the preferred measure of sarcopenia (Carey et al., 2019). The variability between morphometric muscle indexes revealed that they have different clinical relevance and are generally not applicable to broader populations (Esser et al., 2019).
Humans ; Aged ; Sarcopenia/diagnostic imaging* ; Carcinoma, Hepatocellular/diagnostic imaging* ; Muscle, Skeletal/diagnostic imaging* ; Deep Learning ; Prognosis ; Radiomics ; Liver Neoplasms/diagnostic imaging* ; Retrospective Studies

As a kind of traditional Chinese medicine,which has a medicinal site of rhizomes,contains rich active ingredients,mainly including steroidal saponins,flavonoids,phenols,stilbenes,organic acids and other compounds,which together give a wide range of pharmacological effects,including anti-inflammatory,antibacterial,anti-tumor,hypolipidemic,hypoglycemic,and so on.In recent years,with the continuous development of modern science and technology,the research on Smilacis chinae rhizoma has been deepening,and the pharmacological mechanism of its active ingredients has been gradually revealed.This paper reviews the research progress on the active ingredients and pharmacological effects of Smilacis chinae rhizoma over the last few years at home and abroad,in order to provide a scientific basis for further development and utilization of Smilacis chinae rhizoma,and inject new vitality into the modernization and international development of traditional Chinese medicine.

Background/Aims: We performed a systematic review and meta-analysis evaluating the symptomatic response rate to antibiotics in patients with small intestinal bacterial overgrowth (SIBO). Similarly, we performed a meta-analysis on the symptomatic response to antibiotics in irritable bowel syndrome (IBS) patients with and without SIBO. Methods: MEDLINE, EMBASE, Web of Science, and Cochrane databases were searched from inception to March 2021. Randomized controlled trials and prospective studies reporting dichotomous outcomes were included. Results: There were 6 studies included in the first meta-analysis comparing the efficacy of antibiotics to placebo or no antibiotic. This included 196 patients, of whom 101 received antibiotics and 95 received placebo or no antibiotics. Significantly more patients improved with antibiotics (relative risk [95% CI] = 2.46 [1.33-4.55], P = 0.004). There were 4 studies included in the analysis comparing symptomatic response rates in IBS patients with or without SIBO with 266 IBS patients, of whom 172 had SIBO and 94 did not. The pooled response rate for symptomatic response was 51.2% in the SIBO group vs 23.4% in the no SIBO group, respectively. Significantly more IBS patients with SIBO responded to antibiotics compared to those without SIBO (relative risk [95% CI] = 2.07 [1.40-3.08], P = 0.0003). Conclusions Antibiotics appear to be efficacious in treating SIBO, although small sample sizes and poor data quality limit this interpretation. Symptomatic response rates also appear to be higher in IBS patients with SIBO. This may be the first example of precision medicine in IBS as opposed to our current empiric treatment approach. Large-multicenter studies are needed to verify the results.

The mammalian carboxylesterase 1 (Ces1/CES1) family comprises several enzymes that hydrolyze many xenobiotic chemicals and endogenous lipids. To investigate the pharmacological and physiological roles of Ces1/CES1, we generated Ces1 cluster knockout (Ces1 ^-/- ) mice, and a hepatic human CES1 transgenic model in the Ces1 ^-/- background (TgCES1). Ces1 ^-/- mice displayed profoundly decreased conversion of the anticancer prodrug irinotecan to SN-38 in plasma and tissues. TgCES1 mice exhibited enhanced metabolism of irinotecan to SN-38 in liver and kidney. Ces1 and hCES1 activity increased irinotecan toxicity, likely by enhancing the formation of pharmacodynamically active SN-38. Ces1 ^-/- mice also showed markedly increased capecitabine plasma exposure, which was moderately decreased in TgCES1 mice. Ces1 ^-/- mice were overweight with increased adipose tissue, white adipose tissue inflammation (in males), a higher lipid load in brown adipose tissue, and impaired blood glucose tolerance (in males). These phenotypes were mostly reversed in TgCES1 mice. TgCES1 mice displayed increased triglyceride secretion from liver to plasma, together with higher triglyceride levels in the male liver. These results indicate that the carboxylesterase 1 family plays essential roles in drug and lipid metabolism and detoxification. Ces1 ^-/- and TgCES1 mice will provide excellent tools for further study of the in vivo functions of Ces1/CES1 enzymes.

【Objective】 To compare the clinical efficacy of robot-assisted and open surgery in the treatment of renal carcinoma with inferior vena cava cancer thrombus, and to analyze the safety and feasibility of robot-assisted radical nephrectomy. 【Methods】 Clinical data of 55 patients surgically treated for renal carcinoma with Mayo Ⅰ-Ⅲ inferior vena cava tumor thrombus during Dec.2015 and Dec.2021 were retrospectively analyzed. Based on the operation methods, the patients were divided into the robotic surgery group (n=36) and open surgery group (n=19). The perioperative data, oncological results and survival of the two groups were compared. 【Results】 All operations were successful. The median operation time was 176 (IQR:137-234) min, and grade Ⅲ and above complications occurred in 9(16.4%) cases. The robotic surgery group had lower intraoperative blood loss [300 (IQR:200-625) mL vs.1 000 (IQR:600-1 184) mL] and blood transfusion ratio [(20/36) vs. (18/19)] than the open surgery group, but higher postoperative hemoglobin level[109(98-120) g/L vs. 90(84-100) g/L]. During a median follow-up of 26 (IQR:19-39) months, 19(34.5%) patients developed new metastases and 12(21.8%) patients died. The postoperative tumor-specific survival (HR=0.39, 95%CI:0.13-1.16, P=0.090) and overall survival (HR=0.71, 95%CI:0.22-2.23,P=0.554) were not significantly different between the two groups. 【Conclusion】 There are no significant differences in the incidence of postoperative complications, tumor-specific survival and overall survival between robot-assisted and open surgery for Mayo Ⅰ-Ⅲ inferior vena cava tumor thrombus, but the intraoperative blood loss in robotic group is lower than that in the open surgery group.

OBJECTIVE: The study aimed to estimate the benchmark dose (BMD) of coke oven emissions (COEs) exposure based on mitochondrial damage with the mitochondrial DNA copy number (mtDNAcn) as a biomarker. METHODS: A total of 782 subjects were recruited, including 238 controls and 544 exposed workers. The mtDNAcn of peripheral leukocytes was detected through the real-time fluorescence-based quantitative polymerase chain reaction. Three BMD approaches were used to calculate the BMD of COEs exposure based on the mitochondrial damage and its 95% confidence lower limit (BMDL). RESULTS: The mtDNAcn of the exposure group was lower than that of the control group (0.60 ± 0.29 vs. 1.03 ± 0.31; P < 0.001). A dose-response relationship was shown between the mtDNAcn damage and COEs. Using the Benchmark Dose Software, the occupational exposure limits (OELs) for COEs exposure in males was 0.00190 mg/m ³. The OELs for COEs exposure using the BBMD were 0.00170 mg/m ³ for the total population, 0.00158 mg/m ³ for males, and 0.00174 mg/m ³ for females. In possible risk obtained from animal studies (PROAST), the OELs of the total population, males, and females were 0.00184, 0.00178, and 0.00192 mg/m ³, respectively. CONCLUSION Based on our conservative estimate, the BMDL of mitochondrial damage caused by COEs is 0.002 mg/m ³. This value will provide a benchmark for determining possible OELs.
Male ; Female ; Animals ; Coke ; Polycyclic Aromatic Hydrocarbons ; DNA Copy Number Variations ; Benchmarking ; Occupational Exposure/analysis* ; DNA, Mitochondrial/genetics* ; DNA Damage

Wound healing is a dynamic process that involves a series of molecular and cellular events aimed at replacing devitalized and missing cellular components and/or tissue layers. Recently, extracellular vesicles (EVs), naturally cell-secreted lipid membrane-bound vesicles laden with biological cargos including proteins, lipids, and nucleic acids, have drawn wide attention due to their ability to promote wound healing and tissue regeneration. However, current exploitation of EVs as therapeutic agents is limited by their low isolation yields and tedious isolation processes. To circumvent these challenges, bioinspired cell-derived nanovesicles (CDNs) that mimic EVs were obtained by shearing mesenchymal stem cells (MSCs) through membranes with different pore sizes. Physical characterisations and high-throughput proteomics confirmed that MSC-CDNs mimicked MSC-EVs. Moreover, these MSC-CDNs were efficiently uptaken by human dermal fibroblasts and demonstrated a dose-dependent activation of MAPK signalling pathway, resulting in enhancement of cell proliferation, cell migration, secretion of growth factors and extracellular matrix proteins, which all promoted tissue regeneration. Of note, MSC-CDNs enhanced angiogenesis in human dermal microvascular endothelial cells in a 3D PEG-fibrin scaffold and animal model, accelerating wound healing in vitro and in vivo. These findings suggest that MSC-CDNs could replace both whole cells and EVs in promoting wound healing and tissue regeneration.