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STUDY QUESTION: Do biallelic deleterious variants of Calreticulin 3 (CALR3) cause fertilization failure (FF), resulting in male infertility in humans? SUMMARY ANSWER: Biallelic mutations in CALR3 were identified in two infertile men from unrelated families and were shown to cause FF associated with failed sperm-zona pellucida (ZP) binding. WHAT IS KNOWN ALREADY: In male mice, the Calr3-knockout has been reported to cause male infertility and FF. However, the mechanism behind this remains unclear in humans. STUDY DESIGN, SIZE, DURATION: Sequencing studies were conducted in a research hospital on samples from Han Chinese families with primary infertility and sperm head deformations to identify the underlying genetic causes. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data from two infertile probands characterized by sperm head deformation were collected through in silico analysis. Sperm cells from the probands were characterized using light and electron microscopy and used to verify the pathogenicity of genetic factors through functional assays. Subzonal insemination (SUZI) and IVF assays were performed to determine the exact pathogenesis of FF. ICSI were administered to overcome CALR3-affected male infertility. MAIN RESULTS AND THE ROLE OF CHANCE: Novel biallelic deleterious mutations in CALR3 were identified in two infertile men from unrelated families. We found one homozygous frameshift CALR3 mutation (M1: c.17_27del, p.V6Gfs*34) and one compound heterozygous CALR3 mutation (M2: c.943A>G, p.N315D; M3: c.544T>C, p.Y182H). These mutations are rare in the general population and cause acrosomal ultrastructural defects in affected sperm. Furthermore, spermatozoa from patients harbouring the CALR3 mutations were unable to bind to the sperm-ZP or they disrupted gamete fusion or prevented oocyte activation. Molecular assays have revealed that CALR3 is crucial for the maturation of the ZP binding protein in humans. Notably, the successful fertilization via SUZI and ICSI attempts for two patients, as well as the normal expression of PLCζ in the mutant sperm, suggests that ICSI is an optimal treatment for CALR3-deficient FF. LIMITATIONS, REASONS FOR CAUTION: The results are based on sperm-related findings from two patients. Further studies are required to gain insight into the developmental stage and function of CALR3 in human testis. WIDER IMPLICATIONS OF THE FINDINGS: Our findings highlight the underlying risk of FF associated with sperm defects and provide a valuable reference for personalized genetic counselling and clinical treatment of these patients. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Key R&D Program of China (2021YFC2700901), Hefei Comprehensive National Science Center Medical-Industrial Integration Medical Equipment Innovation Research Platform Project (4801001202), the National Natural Science Foundation of China (82201803, 82371621, 82271639), Foundation of the Education Department of Anhui Province (gxgwfx2022007), Key Project of Natural Science Research of Anhui Educational Committee (2023AH053287), and the Clinical Medical Research Transformation Project of Anhui Province (202204295107020037). The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.
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Objective: In this study, the impact of inhibiting the PI3K/AKT/NF-κB pathway on lung oxidative damage induced by Echinococcus granulosus cyst fluid was investigated. Methods: Twenty-four mice were randomly assigned to four groups. Three months after inoculation with hydatid cyst segments, mice in group A were treated with intraperitoneal and intratracheal saline injections; mice in group B were administered a caudal vein injection of a PI3K inhibitor, followed by cyst fluid sensitization; mice in group C received an AKT inhibitor via caudal vein, followed by cyst fluid sensitization; and mice in group D were subjected to cyst fluid sensitization without any inhibitor treatment. Cellular changes in lung tissues across all groups were evaluated, including pathological section analysis. Analysis of pulmonary tissue and serum from these mice included the assessment of PI3K/AKT/NF-κB pathway proteins, inflammatory factors, and related mRNA levels. Results: Mice in groups B and C exhibited a higher proportion of M2-type macrophages and significantly lower levels of PI3K/AKT/NF-κB pathway proteins, inflammatory factors (interleukin-6 [IL-6]/tumor necrosis factor-α [TNF-α]), and oxidative markers in lung tissues compared to mice in group D (P < 0.05). Conclusion: Our results in this study indicate that activation of the PI3K/AKT/NF-κB pathway contributed to an increase in the M1 macrophage phenotype, leading to enhanced secretion of peroxidases and inflammatory factors. This mechanism plays a crucial role in the oxidative and inflammatory lung damage associated with allergic reactions to E. granulosus cyst fluid.
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Echinococcus granulosus , FN-kappa B , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Animales , Echinococcus granulosus/inmunología , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , FN-kappa B/metabolismo , Transducción de Señal , Lesión Pulmonar/inmunología , Lesión Pulmonar/etiología , Lesión Pulmonar/parasitología , Macrófagos/inmunología , Pulmón/inmunología , Pulmón/patología , Pulmón/parasitología , Equinococosis/inmunología , Modelos Animales de Enfermedad , Femenino , Citocinas/metabolismo , Estrés OxidativoRESUMEN
The intrinsic volumetric stress during cycling is the main obstacle for developing Si-based materials as high-energy-density lithium-ion battery anodes. Elastic binders have been demonstrated as an efficient approach to alleviate the stress of Si. Herein, we design a tough 3D hard/soft polymeric network (LPTS) using lithiated poly(acrylic acid), silk sericin, and highly branched tannic acid. Covalent cross-linking provides a robust mechanical strength to endure the large stress. The formed multiple hydrogen bonds with bonding energies between 3.46 and 25 kcal mol-1 can effectively dissipate the stress through sequential hydrogen bond disassociation. The multifunctional LPTS binder maintains the integrity of the Si-based electrodes during repeated discharging/charging. Additionally, Li+ can be transferred via a Li-conducting group (-COOLi), thereby enhancing the ionic conductivity of electrodes. Consequently, the Si/LPTS electrode exhibits an improved initial Coulombic efficiency and excellent durability over 400 cycles. Meanwhile, this binder is also suitable for Si-C anodes, enabling stable cycling at a high areal capacity >3.6 mAh cm-2 and delivering 72.2% capacity retention for the LFP||Si-C/LPTS full cell after 200 cycles. This study provides insight into developing efficient Si-based binders that are facile and low-cost for next-generation high-energy-density systems.
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Introduction: Autism spectrum disorder (ASD) is a group of diseases often characterized by poor sociability and challenges in social communication. The anterior cingulate cortex (ACC) is a core brain region for social function. Whether it contributes to the defects of social communication in ASD and whether it could be physiologically modulated to improve social communication have been poorly investigated. This study is aimed at addressing these questions. Methods: Fragile X mental retardation 1 (FMR1) mutant and valproic acid (VPA)-induced ASD mice were used. Male-female social interaction was adopted to elicit ultrasonic vocalization (USV). Immunohistochemistry was used to evaluate USV-activated neurons. Optogenetic and precise target transcranial magnetic stimulation (TMS) were utilized to modulate anterior cingulate cortex (ACC) neuronal activity. Results: In wild-type (WT) mice, USV elicited rapid expression of c-Fos in the excitatory neurons of the left but not the right ACC. Optogenetic inhibition of the left ACC neurons in WT mice effectively suppressed social-induced USV. In FMR1-/-- and VPA-induced ASD mice, significantly fewer c-Fos/CaMKII-positive neurons were observed in the left ACC following USV compared to the control. Optogenetic activation of the left ACC neurons in FMR1-/- or VPA-pretreated mice significantly increased social activity elicited by USV. Furthermore, precisely stimulating neuronal activity in the left ACC, but not the right ACC, by repeated TMS effectively rescued the USV emission in these ASD mice. Discussion: The excitatory neurons in the left ACC are responsive to socially elicited USV. Their silence mediates the deficiency of social communication in FMR1-/- and VPA-induced ASD mice. Precisely modulating the left ACC neuronal activity by repeated TMS can promote the social communication in FMR1-/- and VPA-pretreated mice.
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The complexities of energy transfer mechanisms in the flagella of mammalian sperm flagella have been intensively investigated and demonstrate significant diversity across species. Enzymatic shuttles, particularly adenylate kinase (AK) and creatine kinase (CK), are pivotal in the efficient transfer of intracellular ATP, showing distinct tissue- and species-specificity. Here, the expression profiles of AK and CK were investigated in mice and found to fall into four subgroups, of which Subgroup III AKs were observed to be unique to the male reproductive system and conserved across chordates. Both AK8 and AK9 were found to be indispensable to male reproduction after analysis of an infertile male cohort. Knockout mouse models showed that AK8 and AK9 were central to promoting sperm motility. Immunoprecipitation combined with mass spectrometry revealed that AK8 and AK9 interact with the radial spoke (RS) of the axoneme. Examination of various human and mouse sperm samples with substructural damage, including the presence of multiple RS subunits, showed that the head of radial spoke 3 acts as an adapter for AK9 in the flagellar axoneme. Using an ATP probe together with metabolomic analysis, it was found that AK8 and AK9 cooperatively regulated ATP transfer in the axoneme, and were concentrated at sites associated with energy consumption in the flagellum. These findings indicate a novel function for RS beyond its structural role, namely, the regulation of ATP transfer. In conclusion, the results expand the functional spectrum of AK proteins and suggest a fresh model regarding ATP transfer within mammalian flagella.
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Adenosina Trifosfato , Adenilato Quinasa , Axonema , Ratones Noqueados , Motilidad Espermática , Cola del Espermatozoide , Animales , Adenilato Quinasa/metabolismo , Masculino , Ratones , Axonema/metabolismo , Motilidad Espermática/fisiología , Cola del Espermatozoide/metabolismo , Adenosina Trifosfato/metabolismo , Humanos , Metabolismo Energético , Espermatozoides/metabolismo , Flagelos/metabolismo , Creatina Quinasa/metabolismo , Infertilidad Masculina/metabolismo , Infertilidad Masculina/genéticaRESUMEN
BACKGROUND AND AIMS: Human studies about short-chain fatty acids (SCFAs), the gut microbiome, and Type 2 diabetes (T2DM) are limited. Here we explored the association between SCFAs and T2DM and the effects of gut microbial diversity on glucose status in rural populations. METHODS AND RESULTS: We performed a cross-sectional study from the Henan Rural Cohort and collected stool samples. Gut microbiota composition and faecal SCFA concentrations were measured by 16S rRNA and GC-MS. The population was divided based on the tertiles of SCFAs, and logistic regression models assessed the relationship between SCFAs and T2DM. Generalized linear models tested the interactions between SCFAs and gut microbial diversity on glucose indicators (glucose, HbAlc and insulin). Compared to the lowest tertile of total SCFA, acetate and butyrate, the highest tertile exhibited lower T2DM prevalence, with ORs and 95% CIs of 0.291 (0.085-0.991), 0.160 (0.044-0.574) and 0.171 (0.047-0.620), respectively. Restricted cubic spline demonstrated an approximately inverse S-shaped association. We also noted interactions of the ACE index with the highest tertile of valerate on glucose levels (P-interaction = 0.022) and the Shannon index with the middle tertile of butyrate on insulin levels (P-interaction = 0.034). Genus Prevotella_9 and Odoribacter were inversely correlated with T2DM, and the genus Blautia was positively associated with T2DM. These bacteria are common SCFA-producing members. CONCLUSIONS: Inverse S-shaped associations between SCFAs (total SCFA, acetate, and butyrate) and T2DM were observed. Valerate and butyrate modify glucose status with increasing gut microbial diversity.
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Bacterias , Biomarcadores , Glucemia , Diabetes Mellitus Tipo 2 , Ácidos Grasos Volátiles , Heces , Microbioma Gastrointestinal , Salud Rural , Humanos , Diabetes Mellitus Tipo 2/microbiología , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Masculino , Persona de Mediana Edad , Estudios Transversales , Femenino , China/epidemiología , Ácidos Grasos Volátiles/metabolismo , Heces/microbiología , Heces/química , Glucemia/metabolismo , Bacterias/clasificación , Bacterias/aislamiento & purificación , Bacterias/metabolismo , Bacterias/genética , Biomarcadores/sangre , Prevalencia , Factores de Riesgo , Ribotipificación , Adulto , Anciano , Medición de Riesgo , Hemoglobina Glucada/metabolismo , Insulina/sangre , Intestinos/microbiologíaRESUMEN
OBJECTIVE: This study aimed to investigate the relationship between dietary branched-chain amino acids (BCAAs) and the risk of developing hypertension. METHODS: A cohort study of 14,883 Chinese adults without hypertension at baseline with were followed for an average of 8.9 years. Dietary intakes of BCAAs, including Ile, Leu, and Val, were collected using 3-day 24-h meal recall and household condiment weighing. Cox proportional hazards regression, restricted cubic splines, interaction analysis, and sensitivity analysis were used to assess the relationship between dietary BCAAs and risk of developing self-reported hypertension, adjusting for age, gender, region, body mass index (BMI), smoking and drinking status, physical activity, energy intake, salt intake. RESULTS: Among 14,883 study subjects, 6386(42.9%) subjects aged ≥ 45 years at baseline, 2692 (18.1%) had new-onset hypertension during the study period, with a median age of 56 years. High levels of dietary BCAAs were associated with an increased risk of new-onset hypertension. Compared with the 41st-60th percentile, multivariable adjusted hazard ratio (HR) for new-onset hypertension was 1.16 (95% CI 1.01-1.32) for dietary BCAAs 61st-80th percentiles, 1.30 (1.13-1.50) for 81st-95th, 1.60 (1.32-1.95) for 96th-100th. The cut-off value of new-onset hypertension risk, total BCAAs, Ile, Leu, and Val were 15.7 g/day, 4.1 g/day, 6.9 g/day, 4.6 g/day, respectively, and the proportion of the population above these intake values were 13.9%, 13.1%, 15.4%, and 14.4%, respectively. Age, BMI, and salt intake had an interactive effect on this relationship (P < 0.001). CONCLUSION: There was a significant positive association between total dietary BCAAs, Ile, Leu, Val intake and the risk of developing hypertension, after adjustment for confounders. This relationship was influenced by age, BMI, and salt intake. Further research is needed to clarify the mechanism and potential role of BCAAs in the pathogenesis of hypertension.
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Hipertensión , Cloruro de Sodio Dietético , Adulto , Humanos , Persona de Mediana Edad , Estudios de Cohortes , Estudios Prospectivos , Aminoácidos de Cadena Ramificada , Hipertensión/epidemiologíaRESUMEN
Evidence of the relationship between fecal short-chain fatty acids (SCFA) levels, dietary quality and type 2 diabetes mellitus (T2DM) in rural populations is limited. Here, we aimed to investigate the association between fecal SCFA levels and T2DM and the combined effects of dietar quality on T2DM in rural China. In total, 100 adults were included in the case-control study. Dietary quality was assessed by the Alternate Healthy Eating Index 2010 (AHEI-2010), and SCFA levels were analysed using the GC-MS system. Generalised linear regression was conducted to calculate the OR and 95 % CI to evaluate the effect of SCFA level and dietary quality on the risk of T2DM. Finally, an interaction was used to study the combined effect of SCFA levels and AHEI-2010 scores on T2DM. T2DM participants had lower levels of acetic and butyric acid. Generalised linear regression analysis revealed that the OR (95 % CI) of the highest acetic and butyric acid levels were 0·099 (0·022, 0·441) and 0·210 (0·057, 0·774), respectively, compared with the subjects with the lowest tertile of level. We also observed a significantly lower risk of T2DM with acetic acid levels > 1330·106 µg/g or butyric acid levels > 585·031 µg/g. Moreover, the risks of higher acetic and butyric acid levels of T2DM were 0·007 (95 % CI: 0·001, 0·148), 0·005 (95 % CI: 0·001, 0·120) compared with participants with lower AHEI-2010 scores (all P < 0·05). Acetate and butyrate levels may be important modifiable beneficial factors affecting T2DM in rural China. Improving dietary quality for body metabolism balance should be encouraged to promote good health.
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Diabetes Mellitus Tipo 2 , Dieta , Ácidos Grasos Volátiles , Heces , Población Rural , Humanos , Estudios de Casos y Controles , China/epidemiología , Ácidos Grasos Volátiles/análisis , Ácidos Grasos Volátiles/metabolismo , Femenino , Masculino , Persona de Mediana Edad , Heces/química , Adulto , Factores de Riesgo , Dieta Saludable , Ácido Butírico/análisis , Anciano , Estudios de CohortesRESUMEN
Pseudouridine, one of the most abundant RNA modifications, is synthesized by stand-alone or RNA-guided pseudouridine synthases. Here, we comprehensively mapped pseudouridines in rRNAs, tRNAs and small RNAs in the archaeon Sulfolobus islandicus and identified Cbf5-associated H/ACA RNAs. Through genetic deletion and in vitro modification assays, we determined the responsible enzymes for these modifications. The pseudouridylation machinery in S. islandicus consists of the stand-alone enzymes aPus7 and aPus10, and six H/ACA RNA-guided enzymes that account for all identified pseudouridines. These H/ACA RNAs guide the modification of all eleven sites in rRNAs, two sites in tRNAs, and two sites in CRISPR RNAs. One H/ACA RNA shows exceptional versatility by targeting eight different sites. aPus7 and aPus10 are responsible for modifying positions 13, 54 and 55 in tRNAs. We identified four atypical H/ACA RNAs that lack the lower stem and the ACA motif and confirmed their function both in vivo and in vitro. Intriguingly, atypical H/ACA RNAs can be modified by Cbf5 in a guide-independent manner. Our data provide the first global view of pseudouridylation in archaea and reveal unexpected structures, substrates, and activities of archaeal H/ACA RNPs.
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Seudouridina , ARN de Archaea , ARN de Transferencia , Sulfolobus , Seudouridina/metabolismo , Sulfolobus/genética , Sulfolobus/metabolismo , ARN de Transferencia/metabolismo , ARN de Transferencia/genética , ARN de Archaea/genética , ARN de Archaea/metabolismo , ARN de Archaea/química , ARN Ribosómico/metabolismo , ARN Ribosómico/genética , Proteínas Arqueales/metabolismo , Proteínas Arqueales/genética , Procesamiento Postranscripcional del ARN , ARN Guía de Sistemas CRISPR-Cas/genética , ARN Guía de Sistemas CRISPR-Cas/metabolismo , Transferasas Intramoleculares/genética , Transferasas Intramoleculares/metabolismoRESUMEN
PURPOSE: To investigate the association between low-carbohydrate diet scores (LCDs) and the risk of type 2 diabetes in rural China. METHODS: A total of 38,100 adults were included in the Henan Rural Cohort Study. Macronutrient intake was assessed via a validated food-frequency questionnaire to create low-carbohydrate diet (LCD) scores. Multivariate logistic regression models and subgroup analysis were performed to estimate the odds ratio (OR) and 95% confidence interval (95% CI). RESULTS: After multivariable adjustment, participants with a high total low-carbohydrate diet score have a high risk of T2D (extreme-quartile OR = 1.23, 95% CI: 1.04-1.41; P = 0.007), whereas plant-based LCD score is not related to T2D risk. Among individuals with a BMI < 24 (extreme-quartile OR = 1.22, 95% CI: 1.01-1.47; P < 0.001) or high levels of physical activity (extreme-quartile OR = 1.42, 95% CI: 1.17-1.72; P < 0.001), the animal-based LCD score is positively correlated with the risk of T2D. CONCLUSION: Among Chinese rural populations, high-fat-low carbohydrate diet is associated with an increased risk of type 2 diabetes. High intake of animal protein and fat also increases T2D risk in those who are overweight or have high physical activity.
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Diabetes Mellitus Tipo 2 , Dieta Baja en Carbohidratos , Población Rural , Humanos , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Masculino , China/epidemiología , Persona de Mediana Edad , Población Rural/estadística & datos numéricos , Adulto , Estudios de Cohortes , Anciano , Factores de Riesgo , Índice de Masa Corporal , Pueblos del Este de AsiaRESUMEN
The gut microbiota establishment in young ruminants has a profound impact on their adult production performance. However, the critical phase for the succession of the gut microbial composition and metabolic profiles of juvenile sika deer still needs to be further investigated. Here, we analyzed the fecal microbiota and metabolites of juvenile sika deer during the birth (D1), transition (D42), and rumination (D70) periods based on 16S rRNA sequencing and gas chromatography-time-of-flight mass spectrometry (GC-TOF-MS). The results showed that the fecal bacteria and metabolites composition were significantly different in D1 compared to D42 and D70, and the number of OTUs and the Shannon index were significantly higher in D70 than in D1 (p < 0.05). The relative abundances of Lactobacillus, Lactococcus, and Lachnoclostridium showed a significant increase in D1 compared to D42 and D70, whereas the relative abundances of Ruminococcaceae UCG-005, Ruminococcaceae UCG-010, Ruminococcaceae UCG-014, Christensenellaceae R-7, and Eubacterium coprostanoligenes group were significantly decreased in D1 compared to D42 and D70 (p < 0.05). The amounts of serine, phenylalanine, aspartic acid, ornithine, citrulline, creatine, isoleucine, galactose, and ribose in the feces were significantly higher in D1 compared to D42 and D70. In contrast, the concentrations of cortexolone, resveratrol, piceatannol, fumaric acid, alpha-ketoglutarate, glycerol, uracil-5-carboxylic acid, and maleic acid were significantly decreased in D1. The enrichment analysis showed that amino acid metabolism and carbohydrate metabolism were significantly changed in D1 compared to D42 and D70. The glycine, serine and threonine metabolism; alanine, aspartate and glutamate metabolism; arginine biosynthesis; glyoxylate and dicarboxylate metabolism; citrate cycle; and pyruvate metabolism were significantly enriched across the three periods (p < 0.05). In conclusion, our results suggested that the birth-transition period is a critical phase for the gut bacterial community and metabolic function shift in juvenile sika deer.
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Per- and polyfluoroalkyl substances (PFASs) are widely used in industrial production, causing potential health risks to the residents living around chemical industrial plants; however, the lack of data on population exposure and adverse effects impedes our understanding and ability to prevent risks. In this study, we performed screening and association analysis on exogenous PFAS pollutants and endogenous small-molecule metabolites in the serum of elderly residents living near industrial plants. Exposure levels of 11 legacy and novel PFASs were determined. PFOA and PFOS were major contributors, and PFNA, PFHxS, and 6:2 Cl-PFESA also showed high detection frequencies. Association analysis among PFASs and 287 metabolites identified via non-target screening was performed with adjustments of covariates and false discovery rate. Strongly associated metabolites were predominantly lipid and lipid-like molecules. Steroid hormone biosynthesis, primary bile acid biosynthesis, and fatty-acid-related pathways, including biosynthesis of unsaturated fatty acids, linoleic acid metabolism, α-linolenic acid metabolism, and fatty acid biosynthesis, were enriched as the metabolic pathways associated with mixed exposure to multiple PFASs, providing metabolic explanation and evidence for the potential mediating role of adverse health effects as a result of PFAS exposure. Our study achieved a comprehensive screening of PFAS exposure and associated metabolic profiling, demonstrating the promising application for integrated analysis of exposome and metabolome.
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Ácidos Alcanesulfónicos , Contaminantes Ambientales , Fluorocarburos , Humanos , Anciano , Fluorocarburos/análisis , Contaminantes Ambientales/análisis , Metabolómica , Ácidos GrasosRESUMEN
BACKGROUND: 3â¯M syndrome is first reported in 1975ï¼which characterized by severe pre- and postnatal growth retardation, skeletal malformation and facial dysmorphism. These three genes (CUL7, OBSL1 and CCDC8) have been identified to be respond for 3â¯M syndrome, of which CUL7 is accounting for approximately 70%. To date, the molecular mechanism underlying the pathogenesis of 3â¯M syndrome remains poorly understood. Previous studies showed that no Cul7-/- mice could survive after birth, because of growth retardation at late gestational stage and respiratory distress after birth. The establishment of the animal model of cartilage specific Cul7 knockout mice (Cul7fl/fl;Col2a1-CreERT2 mice) has confirmed that Cul7fl/fl;Col2a1-CreERT2 mice can be selective in a time- and tissue-dependent manner, which can provide an experimental basis for further research on severe genetic diseases related to growth plates. OBJECTIVE: To establish a model of Cul7fl/fl;Col2a1-CreERT2 mice based on Cre/LoxP system, and to further observe its phenotype and morphological changes in growth plate. METHODS: The Cul7fl/fl;Col2a1-CreERT2 mice were taken as the experimental group, while the genotype of Cul7fl/+;Col2a1-CreERT2 mice were used as the control group. The gross morphological features and X-ray films of limbs in the two groups were observed every week for 3-6 consecutive weeks, and the length of the mice from nose to the tail, the length of femur and tibia were recorded. In the meantime, The histological morphology of tibial growth plates was compared between the two groups. RESULTS: A preliminary model of Cul7fl/fl;Col2a1-CreERT2 mice was established. The Cul7fl/fl;Col2a1-CreERT2 mice had abnormally short and deformed limbs (P<0.05), increased thickness of growth plate, the disorderly arranged chondrocyte columns, decreased number of cells in the proliferation zone, changes in the shape from flat to round, obviously expanded extracellular matrix, and disordered arrangement, thickening and loosening of bone trabecula at the proximal metaphysis of the femur. CONCLUSIONS: The knockout of Cul7 gene may affect both the proliferation of chondrocytes and the endochondral osteogenesis, confirming that Cul7 is essential for the normal development of bone in the body.
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Anomalías Múltiples , Enanismo , Placa de Crecimiento , Discapacidad Intelectual , Hipotonía Muscular , Retinitis Pigmentosa , Columna Vertebral/anomalías , Ratones , Animales , Ratones Noqueados , Condrocitos , Trastornos del Crecimiento , Proteínas Cullin/genéticaRESUMEN
BACKGROUND: High-sodium intake is one of the most important risk factors for hypertension and cardiovascular disease, yet reliable national estimates of sodium intake in Chinese adults have not been reported. OBJECTIVES: We estimated 24-h urinary sodium and potassium excretion and population daily sodium and potassium intake of Chinese adults for the first time at a national level. METHODS: A nationally representative cross-sectional survey was conducted to collect 24-h urine specimens from Chinese adults aged ≥18 y as part of the China National Nutrition Survey 2015. Finally, 10,114 participants (4932 males and 5182 females) with complete 24-h urine specimens were included in the analysis. Estimates of mean urinary electrolyte excretion and demographic, socioeconomic, and health characteristics were used with weighted coefficients that accounted for sample selection probabilities, poststratification weighting, and nonresponse rates. RESULTS: The estimation of overall weighted mean 24-h urinary sodium excretion was 4121 mg (95% confidence interval [CI]: 3993, 4250), 4155 mg (95% CI: 3993, 4317) in males and 4081 mg (95% CI: 3953, 4209) in females (P for sex difference = 0.36). Overall mean 24-h urinary potassium excretion was 1534 mg (95% CI: 1492, 1577), 1468 mg (95% CI: 1424, 1513) in males and 1614 mg (95% CI: 1569-1660) in females (P for sex difference <0.001). Mean 24-h urinary sodium excretion was significantly higher in rural adults (4350 mg; 95% CI: 4217, 4483) than in urban residents (3909 mg; 95% CI: 3739, 4080; P < 0.001), and in northern residents (4388 mg; 95% CI: 4237, 4539) than in southern residents (3998 mg; 95% CI: 3832, 4163; P = 0.002). CONCLUSIONS: The first nationwide survey with 24-h urine collection confirmed that mean sodium intake in Chinese adults was more than twice the upper limit, whereas mean potassium intake was <60% of the lower limit, recommended by the World Health Organization. Urgent measures should be taken to reduce sodium intake and increase potassium intake in China.
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Potasio , Sodio en la Dieta , Adulto , Humanos , Masculino , Femenino , Estudios Transversales , Sodio , Encuestas Nutricionales , ChinaRESUMEN
Aqueous electrolytes have become a research hotspot because of their high safety and low cost, while the inevitable ionization phenomenon of water in aqueous solution leads to the existence of competitive ions (H+) except the active ions. In this article, we take aqueous Na base electrolyte as an example to clear the ion competition behavior by modeling, simulating together with experimental verification. First, the reaction tendency of the two ions (Na+ and H+) is obtained by calculating the Gibbs energy change of the reaction. Furthermore, the properties of electrolytes with different concentrations including transportation are obtained by modeling. After that, relevant experiments are also proceeded to verify the simulation results. Then, the ion competition behavior is analyzed by in situ observation by controlling the constant concentration of Na+: the high concentration of Na+ can reduce the proportion of H+ and reduce the competitiveness of H+; a high concentration of Na+ causes the increased viscosity and reduces the ion diffusion. Based on this, the correlation between ion competitiveness and ion ratio is also confirmed by keeping the concentration of Na+ unchanged and adjusting the concentration of H+ (adjusting pH). The influence of the ion competition phenomenon (Na+ and H+) is the reaction characteristics of the substance itself and the ratio of ion concentration. Finally, the electrochemical performance is further verified in 3,4,9,10-perylene tetracarboxylic dianhydride (PTCDI) symmetric cells and in full-cells with vanadium phosphate sodium (NVP) as the cathode and PTCDI as the anode.
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The application of metal batteries is seriously affected by active ions transport and deposition stability during operation. This article takes water-based Zn metal electrodes as an example to analyze the factors that affect ion distribution and the impact of ion distribution on electrodeposition morphology through electrochemical model simulation calculation, in situ observation and electrochemical experiment: 1) high concentration will reduce the concentration polarization and the overpotential; 2) The passage of active ions through channels are facilitated by small anion (Cl-) rather than bigger one (SO4 2-), which means small deposition overpotential; 3) The transportability-reaction properties of cations (Zn2+, Li+, Na+ and H+) depends on their concentration, solvent coordination structure, and the energy changes during redox reactions. Based on the diffusion and reaction properties, a Li+ coupled Zn2+ electrolyte is designed to achieve the rapid transportation of doped ions to cover uneven growth sites and maintain a stable interface for the steady deposition of active Zn2+, guiding the interface design for high stability metal batteries in addition to the traditional addition of organic solvents.
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Cattleyak is a typically male sterile species. The meiosis process is blocked and the scarcity of spermatogenic stems cells are both contributing factors to the inability of male cattleyak to produce sperm. While Glial cell line-derived neurotrophic factor (GDNF) is the first discovered growth factor known to promote the proliferation and self-renewal of spermatogenic stem cells, its relationship to the spermatogenesis arrest of cattleyak remains unclear. In this report, we studied the differential expression of GDNF in the testis of yak and cattleyak, and discussed the optimal concentration of GDNF in the culture medium of undifferentiated spermatogonia (UDSPG) of cattleyak in vitro and the effect of GDNF on the proliferation of cattleyak UDSPG. The results indicated that GDNF expression in the testicular tissue of cattleyak was inferior to that of yak. Moreover, the optimum value for the UDSPG in vitro culture was determined to be 20-30 ng/mL for cattleyak. In vitro, the proliferation activity of UDSPG was observed to increase with additional GDNF due to the up-regulation of proliferation-related genes and the down-regulation of differentiation-related genes. We hereby report that the scarcity of cattleyak UDSPG is due to insufficient expression of GDNF, and that the addition of GDNF in vitro can promote the proliferation of cattleyak UDSPG by regulating the expression of genes related to proliferation and differentiation. This work provides a new insight to solve the issue of spermatogenic arrest in cattleyak.
Asunto(s)
Factor Neurotrófico Derivado de la Línea Celular Glial , Espermatogonias , Masculino , Animales , Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Factor Neurotrófico Derivado de la Línea Celular Glial/farmacología , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Semen/metabolismo , Testículo , Proliferación CelularRESUMEN
@#[摘 要] 目的：探究野生型水疱性口炎病毒印第安纳株（VSV-IN）对小鼠三阴性乳腺癌4T1细胞移植模型小鼠的免疫调节及肿瘤转移的影响。方法：VSV以MOI=1、MOI=10、MOI=100感染4T1细胞12、24、48 h后，CCK-8法检测4T1细胞死亡率，划痕愈合实验检测细胞迁移能力，qPCR检测细胞中E-cadherin、MMP-2、MMP-9 mRNA的表达。于雌性BALB/c小鼠脂肪垫接种1×106个/mL的4T1细胞0.1 mL，构建4T1细胞荷瘤小鼠模型，待小鼠肿瘤体积达200 mm3，分别向移植瘤内注射PBS、紫杉醇（TAX）（15 mg/kg）、VSV-IN（1×106 pfu/只），每周1次。给药4次后，处死小鼠、剥离完整移植瘤组织，测量肿瘤体积及质量，肺组织病理切片经H-E染色后观察肿瘤肺部转移结节，流式细胞术检测脾组织中T细胞亚群比例，ELISA法检测小鼠血清IL-6及TNF-α水平，利用GEPIA在线分析乳腺肿中迁移相关蛋白mRNA的表达，免疫组化法检测肿瘤中MMP-2、MMP-9与E-cadherin的表达，利用蛋白-蛋白对接技术预测VSV-IN的G蛋白、M蛋白与ERK2、E-cadherin的亲和力。结果：经MOI=10、100的VSV-IN处理48 h后，4T1细胞死亡率显著高于对照组（均P<0.01）；与对照组相比，VSV-IN组（MOI=10）细胞迁移率明显降低（P<0.01），MMP-9 mRNA的相对表达量明显降低（P<0.05）；与对照组小鼠相比，VSV-IN组移植瘤生长较对照组减缓且终点体积显著减小（P<0.05），VSV-IN组小鼠肺转移结节数量显著减少[（12.86±1.86） vs （24±3.67）个，P<0.01]，脾内CD4+ T、CD8+ T细胞比例显著升高（均P<0.05），血清TNF-α、IL-6含量显著升高（均P<0.01）；GEPIA分析发现在乳腺癌中E-cadherin、MMP-9表达水平均高于癌旁组织（P<0.05）；VSV-IN组小鼠肿瘤细胞内MMP-9表达明显低于对照组（P<0.05）；VSV-IN的G、M蛋白与ERK2的结合自由能分别为–11.7 kcal/mol、–6.4 kcal/mol。结论：野生型VSV-IN可抑制4T1细胞荷瘤小鼠的移植瘤生长及转移，这可能与其促进抗肿瘤免疫及调控迁移相关蛋白表达有关。
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Previous studies exploring the relationship between dietary potassium and magnesium intake and the risk of type 2 diabetes mellitus (T2DM) have yielded inconsistent results and the lack evidence from rural China. Therefore, we aimed to investigate the association between dietary potassium and magnesium intake and the risk of T2DM in rural China. Data was collected from the Henan Rural Cohort Study in 2017. A validated semi-quantitative food frequency questionnaire assessed dietary potassium and magnesium intake. Logistic regression models were used to calculate odds ratio (ORs) and 95% confidence intervals (CIs) to evaluate the effect of dietary potassium, magnesium and the potassium-magnesium ratio on the risk of T2DM. A total of 38384 individuals were included in the study, and 3616 participants developed T2DM. Logistic regression analysis revealed that the OR (95% CI) of the highest versus dietary potassium and magnesium and potassium-magnesium ratio intakes were 0.67 (0.59, 0.75), 0.76 (0.67, 0.88), and 0.57 (0.50, 0.66), respectively, compared to the subjects with the lowest quartile of intakes. In addition, gender partially influences the relationship between dietary magnesium and T2DM prevalence (P-interaction = 0.042). The group with the highest dietary potassium and dietary magnesium intake had the lowest risk of T2DM, with an OR (95% CI) of 0.63 (0.51-0.77). Dietary potassium and magnesium intake are important modifiable risk factors for T2DM in rural China. Dietary potassium intake > 1.8g/day, dietary magnesium intake > 358.6mg/day and < 414.7mg/day and potassium-magnesium ratio >5.1 should be encouraged to prevent better and manage T2DM.
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The commercial application of lithium-sulfur (Li-S) batteries has faced obstacles, including challenges related to low sulfur utilization, structural degradation resulting from electrode volume expansion, and migration of polysulfide lithium (LiPSs). Herein, Co1-xS/3D-Ti3C2Tx composites with three-dimensional (3D) multilayered structures are used as separator modification materials for Li-S batteries to solve these problems. The multilevel layered structure of Co1-xS/3D-Ti3C2Tx establishes an efficient electron and Li+ transfer path, alleviates the volume change during the battery charge-discharge process, and enhances the stability of the structure. In addition, the battery assembled with the modified separator shows excellent discharge capacity and cycle stability at 0.5 C and could maintain a high discharge capacity after 500 cycles. This work provides a method for designing highly dispersed metal sulfide nanoparticles on MXenes and extends the application of MXenes-based composites in electrochemical energy storage.