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The investigation of gene regulation therapeutics for the treatment of skin-related diseases is rarely explored in part due to inefficient systemic delivery. In this study, a bottlebrush polymer-antisense oligonucleotide (ASO) conjugate, termed pacDNA, designed to target IL-17 receptor A (IL-17RA), which is involved in psoriasis pathogenesis is presented. Systemic administration of pacDNA led to its accumulation in epidermis, dermis, and hypodermis of mouse skin, reduced IL-17RA gene expression in skin, and significantly reversed the development of imiquimod (IMQ)-induced psoriasis in a mouse model. These findings highlight the potential of the pacDNA as a promising nanoconstruct for systemic oligonucleotide delivery to the skin and for treating psoriasis and other skin-related disorders through systemic administration.
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Costal eutrophication leads to increased sulfide levels in sediments, which has been identified as a major cause of the global decline in seagrass beds. The seagrass Thalassia hemprichii, a dominant tropical species in the Indo-Pacific, is facing a potential threat from sulfide, which can be easily reduced from sulfate in porewater under the influence of global climate change and eutrophication. However, its metabolic response and tolerance mechanisms to high sulfide remain unclear. Thus, the current study investigated the physiological responses and programmed metabolic networks of T. hemprichii through a three-week mesocosm experiment, integrating physiology, stable isotope, widely targeted metabolomics, transcriptomics, and microbial diversity assessments. High sulfide reduced the sediment microbial diversity, while increased sediment sulfate reduced bacterial abundance and δ34S. The exposure to sulfide enhanced root δ34S while decreased leaf δ34S in T. hemprichii. High sulfide was shown to inhibit photosynthesis via damaging PSII, which further reduced ATP production. In response, abundant up-regulated differentially expressed genes in energy metabolism, especially in oxidative phosphorylation, were activated to compensate high energy requirement. High sulfide also promoted autophagy by overexpressing the genes related to phagocytosis and phagolysosome. Meanwhile, metabolomic profiling revealed that the contents of many primary metabolites, such as carbohydrates and amino acids, were reduced in both leaves and roots, likely to provide more energy and synthesize stress-responsive secondary metabolites. Genes related to nitrate reduction and transportation were up-regulated to promote N uptake for sulfide detoxification. High sulfide levels specifically enhanced thiamine in roots, while increased jasmonic acid and flavonoid levels in leaves. The distinct differences in metabolism between roots and leaves might be related to sulfide levels and the growth-defense trade-off. Collectively, our work highlights the specific mechanisms underlying the response and tolerance of T. hemprichii to high sulfide, providing new insights into seagrass strategies for resisting sulfide.
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Drosophila melanogaster crystal cells are a specialized type of blood cells for innate immune process upon injury. Under normal conditions, crystal cells rarely proliferate and constitute a small proportion of fly blood cells. Notch signaling has been known to guide the cell fate determination of crystal cells and maintain their survival. Here, we reported that protein phosphatase V (PpV), the unique catalytic subunit of protein phosphatase 6 in Drosophila, is a novel regulator of crystal cell proliferation and integrity. We found that PpV proteins highly accumulated in crystal cells in the larval hematopoietic organ termed the lymph gland. Silencing PpV using RNA interference led to increased crystal cell proliferation in a Notch-independent manner and induced crystal cell rupture dependent on Notch signaling. Moreover, additive PpV prevented the rupture of crystal cells in lymph glands upon a needle injury, suggesting the involvement of PpV in wound healing. Altogether, our results indicated that PpV plays a dual role in lymph glands, preventing crystal cell proliferation to limit the cell number, as well as inhibiting crystal cell rupture to maintain their survival.
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The study aimed to investigate the extended effects and interrelations of corneal biomechanics, corneal optical density (COD), corneal thickness (CT), and intraocular pressure (IOP) following cataract surgery. Sixteen eyes were analyzed prospectively. The Corneal Visualization Scheimpflug Technology (Corvis ST) device assessed corneal biomechanics, while the Pentacam AxL® (Pentacam) measured COD and CT. Postoperative data were collected around six months after surgery, with a subgroup analysis of data at nine months. The Pearson correlation was used to examine the relationship between surgical-induced changes in corneal biomechanics and COD. At six months, significant postoperative differences were observed in various biomechanical indices, including uncorrected IOP (IOPuct) and biomechanics-corrected IOP (bIOP). However, many indices lost statistical significance by the nine-month mark, suggesting the reversibility of postoperative corneal changes. Postoperative COD increased at the anterior layer of the 2-6 mm annulus and incision site. The changes in COD correlated with certain biomechanical indices, including maximal (Max) deformative amplitude (DA) and stiffness parameter (SP). In conclusion, despite significant immediate postoperative changes, corneal biomechanics, COD, and IOP experienced a gradual recovery process following cataract surgery. Clinicians should maintain vigilance for any unusual changes during the short-term observation period to detect abnormalities early.
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The alterations in DNA methylation and transcriptome in trophoblast cells under conditions of low oxygen and oxidative stress have major implications for pregnancy-related disorders. However, the exact mechanism is still not fully understood. In this study, we established models of hypoxia (H group) and oxidative stress (HR group) using HTR-8/SVneo trophoblast cells and performed combined analysis of genome-wide DNA methylation changes using reduced representation bisulphite sequencing and transcriptome expression changes using RNA sequencing. Our findings revealed that the H group exhibited a higher number of differentially methylated genes and differentially expressed genes than the HR group. In the H group, only 0.90% of all differentially expressed genes displayed simultaneous changes in DNA methylation and transcriptome expression. After the threshold was expanded, this number increased to 6.29% in the HR group. Notably, both the H group and HR group exhibited concurrent alterations in DNA methylation and transcriptome expression within Axon guidance and MAPK signalling pathway. Among the top 25 differentially methylated KEGG pathways in the promoter region, 11 pathways were commonly enriched in H group and HR group, accounting for 44.00%. Among the top 25 KEGG pathways in transcriptome with significant differences between the H group and HR group, 10 pathways were consistent, accounting for 40.00%. By integrating our previous data on DNA methylation from preeclamptic placental tissues, we identified that the ANKRD37 and PFKFB3 genes may contribute to the pathogenesis of preeclampsia through DNA methylation-mediated transcriptome expression under hypoxic conditions.
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Hipoxia de la Célula , Metilación de ADN , Estrés Oxidativo , Transcriptoma , Trofoblastos , Humanos , Trofoblastos/metabolismo , Estrés Oxidativo/genética , Transcriptoma/genética , Hipoxia de la Célula/genética , Línea Celular , Femenino , Embarazo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Fosfofructoquinasa-2/genética , Fosfofructoquinasa-2/metabolismoRESUMEN
BACKGROUND: Local brain tissue can suffer from ischaemia/reperfusion (I/R) injury, which lead to vascular endothelial damage. The peptide δ opioid receptor (δOR) agonist [D-ala2, D-leu5]-Enkephalin (DADLE) can reduce apoptosis caused by acute I/R injury in brain microvascular endothelial cells (BMECs). OBJECTIVE: This study aims to explore the mechanism by which DADLE enhances the level of mitophagy in BMECs by upregulating the expression of transient receptor potential vanilloid subtype 4 (TRPV4). METHODS: BMECs were extracted and made to undergo oxygen-glucose deprivation/reoxygenation (OGD/R) accompanied by DADLE. RNA-seq analysis revealed that DADLE induced increased TRPV4 expression. The CCK-8 method was used to assess the cellular viability; quantitative PCR (qPCR) was used to determine the mRNA expression of Drp1; western blot was used to determine the expression of TRPV4 and autophagy-related proteins; and calcium imaging was used to detect the calcium influx. Autophagosomes in in the cells' mitochondria were observed by using transmission electron microscopy. ELISA was used to measure ATP content, and a JC-1 fluorescent probe was used to detect mitochondrial membrane potential. RESULTS: When compared with the OGD/R group, OGD/R+DADLE group showed significantly enhanced cellular viability; increased expression of TRPV4, Beclin-1, LC3-II/I, PINK1 and Parkin; decreased p62 expression; a marked rise in calcium influx; further increases in mitophagy, an increase in ATP synthesis and an elevation of mitochondrial membrane potential. These protective effects of DADLE can be blocked by a TRPV4 inhibitor HC067047 or RNAi of TRPV4. CONCLUSION: DADLE can promote mitophagy in BMECs through TRPV4, improving mitochondrial function and relieving I/R injury.
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Promoters are one of the most critical elements in regulating gene expression. They are considered essential biotechnological tools for heterologous protein production. The one most widely used in plants is the 35S promoter from cauliflower mosaic virus. However, our study for the first time discovered the 35S promoter reduced the expression of exogenous proteins under increased antibiotic stress. We discovered an endogenous strong promoter from duckweed named LpSUT2 that keeps higher initiation activity under antibiotic stress. Stable transformation in duckweed showed that the gene expression of eGFP in the LpSUT2:eGFP was 1.76 times that of the 35S:eGFP at 100 mg.L-1 G418 and 6.18 times at 500 mg.L-1 G418. Notably, with the increase of G418 concentration, the gene expression and the fluorescence signal of eGFP in the 35S:eGFP were weakened, while the LpSUT2:eGFP only changed slightly. This is because, under high antibiotic stress, the 35S promoter was methylated, leading to the gene silencing of the eGFP gene. Meanwhile, the LpSUT2 promoter was not methylated and maintained high activity. This is a previously unknown mechanism that provides us with new insights into screening more stable promoters that are less affected by environmental stress. These outcomes suggest that the LpSUT2 promoter has a high capacity to initiate the expression of exogenous proteins. In conclusion, our study provides a promoter tool with potential application for plant genetic engineering and also provides new insights into screening promoters.
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COVID-19 , Servicio de Urgencia en Hospital , Triaje , Humanos , COVID-19/diagnóstico , COVID-19/epidemiología , Triaje/métodos , Masculino , Femenino , Persona de Mediana Edad , SARS-CoV-2 , Anciano , Pandemias , AdultoRESUMEN
Differentiated thyroid cancer (DTC) is the predominant type of thyroid cancer, with some patients experiencing relapse, distant metastases, or refractoriness, revealing limited treatment options. Chimeric antigen receptor (CAR)-modified Natural Killer (NK) cells are revolutionary therapeutic agents effective against various resistant cancers. Thyroid-stimulating hormone receptor (TSHR) expression in DTC provides a unique tumor-specific target for CAR therapy. Here, we developed an innovative strategy for treating DTC using modified NK-92 cells armed with a TSHR-targeted CAR. The modified cells showed enhanced cytotoxicity against TSHR-positive DTC cell lines and exhibited elevated degranulation and cytokine release. After undergoing irradiation, the cells effectively halted their proliferative capacity while maintaining potent targeted killing ability. Transfer of these irradiation-treated cells into NSG mice with DTC tumors resulted in profound tumor suppression. NK-92 cells modified with TSHR-CAR offer a promising, off-the-shelf option for advancing DTC immunotherapy.
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Células Asesinas Naturales , Receptores Quiméricos de Antígenos , Receptores de Tirotropina , Neoplasias de la Tiroides , Receptores de Tirotropina/inmunología , Receptores de Tirotropina/metabolismo , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/terapia , Neoplasias de la Tiroides/inmunología , Humanos , Animales , Células Asesinas Naturales/inmunología , Línea Celular Tumoral , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/metabolismo , Ratones , Diferenciación Celular , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Endogámicos NOD , Proliferación Celular , Citotoxicidad Inmunológica , Inmunoterapia Adoptiva/métodosRESUMEN
With the advantages of lightweight and low thermal conductivity properties, polymeric foams are widely employed as thermal insulation materials for energy-saving buildings but suffer from inherent flammability. Flame-retardant coatings hold great promise for improving the fire safety of these foams without deteriorating the mechanical-physical properties of the foam. In this work, four kinds of sulfur-based flame-retardant copolymers are synthesized via a facile radical copolymerization. The sulfur-containing monomers serve as flame-retardant agents including vinyl sulfonic acid sodium (SPS), ethylene sulfonic acid sodium (VS), and sodium p-styrene sulfonate (VSS). Additionally, 2-hydroxyethyl acrylate (HEA) and 4-hydroxybutyl acrylate are employed to enable a strong interface adhesion with polymeric foams through interfacial H-bonding. By using as-synthesized waterborne flame-retardant polymeric coating with a thickness of 600 µm, the coated polyurethane foam (PUF) can achieve a desired V-0 rating during the vertical burning test with a high limiting oxygen index (LOI) of >31.5 vol%. By comparing these sulfur-containing polymeric fire-retardant coatings, poly(VS-co-HEA) coated PUF demonstrates the best interface adhesion capability and flame-retardant performance, with the lowest peak heat release rate of 166 kW m-2 and the highest LOI of 36.4 vol%. This work provides new avenues for the design and performance optimization of advanced fire-retardant polymeric coatings.
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Retardadores de Llama , Polímeros , Poliuretanos , Azufre , Poliuretanos/química , Polímeros/química , Azufre/química , Retardadores de Llama/análisis , IncendiosRESUMEN
BACKGROUND: The goal was to develop a risk assessment model for predicting red blood cell (RBC) transfusion in neonatal patients to assist hospital blood supply departments in providing small portions of RBCs to those requiring RBC transfusion on time. METHODS: Clinical information was collected from 1,201 children admitted to the neonatal unit. Clinical factors associated with predicting RBC transfusion were screened, and prediction models were developed using stepwise and multifactorial logistic regression analyses, followed by the evaluation of prediction models using receiver operating characteristic curves, calibration curves, and decision curve analysis (DCA). RESULTS: Overall, 81 neonatal patients were transfused with RBCs, and the variables of gestational age at birth, age < 1 month, receipt of mechanical ventilation, and infant anemia were included in the final prediction model. The area under the curve of the prediction model was 0.936 (0.921 - 0.949), which was significantly higher than that of the individual indicators of gestational age at birth, age at admission < 1 month, receipt of mechanical ventilation, and infant anemia (p < 0.001). DCA showed a standardized net benefit for the possible risk of infant RBC transfusion at 0.1 - 1.0. CONCLUSIONS: We developed a risk assessment model to predict the risk of RBC transfusion in neonatal patients that can effectively assess the risk of RBC transfusion in children.
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Anemia , Transfusión de Eritrocitos , Recién Nacido , Lactante , Niño , Humanos , Transfusión de Eritrocitos/efectos adversos , Anemia/diagnóstico , Anemia/terapia , Edad Gestacional , Eritrocitos , Medición de RiesgoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Psoraleae Fructus (PF), the dried fruit of Psoralea corylifolia L., is a commonly used traditional medicine that has contributed to the treatment of orthopedic diseases for thousands of years in China. However, recent PF-related liver injury reports have drawn widespread attention regarding its potential hepatotoxicity risks. AIM OF THE STUDY: This study was aimed to evaluate the long-term efficacy and chronic toxicity of PF using a 26-week administration experiment on rats in order to simulate the clinical usage situation. MATERIALS AND METHODS: The PF aqueous extract was consecutively administrated to rats daily at dosages of 0.7, 2.0, and 5.6 g/kg (equivalent to 1-8 times the clinical doses for humans) for as long as 26 weeks. Samples were collected after 13, 26, and 32 weeks (withdrawal for 6 weeks) since the first administration. The chronic toxicity of PF was evaluated by conventional toxicological methods, and the efficacy of PF was evaluated by osteogenic effects in the natural growth process. RESULTS: In our experiments, only the H group (5.6 g/kg) for 26-week PF treatment demonstrated liver or kidney injury, which the injuries were reversible after 6 weeks of withdrawal. Notably, the PF treatment beyond 13 weeks showed significant benefits for bone growth and development in rats, with a higher benefit-risk ratio in female rats. CONCLUSIONS: PF displayed a promising benefit-risk ratio in the treatment and prevention of osteoporosis, a disease that lacks effective medicine so far. This is the first study to elucidate the benefit-risk balance associated with clinical dosage and long-term use of PF, thereby providing valuable insights for rational clinical use and risk control of PF.
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Medicamentos Herbarios Chinos , Fabaceae , Psoralea , Humanos , Ratas , Femenino , Animales , Frutas , Oportunidad Relativa , Hígado , Medicamentos Herbarios Chinos/toxicidadRESUMEN
Purpose: Analyze the relationship between changes in the proportion of X-chromosome deletions and clinical manifestations in children with Turner syndrome (TS). Methods: X-chromosome number abnormalities in 8,635 children with growth retardation were identified using fluorescence in situ hybridization (FISH). Meanwhile, the relationship between the proportion of X-chromosome deletions and the clinical manifestations of TS, such as face and body phenotype, cardiovascular, renal, and other comorbidities in children with TS was analyzed. Results: A total of 389 children had X-chromosome number abnormalities, with an average age at diagnosis of 9.2 years. There was a significant increase in diagnoses around the ages of 3 and 7 years and highest number of diagnoses at 10 years of age. 130 with XO (complete loss of an X-chromosome), 205 with XO/XX, 8 with XO/XXX, 23 with XO/XX/XXX, 19 with XO/XY, and 4 with XO/XY/XYY. Body and facial phenotypes increased with higher mosaicism proportions, with a relatively high correlation shown with Pearson correlation analysis (r = 0.26, p = 1.7e-06). The incidence of congenital heart malformations was 25.56%, mainly involving a bicuspid aortic valve, and were more common in patients who had complete loss of an X-chromosome. However, this relationship was not present for renal disease (p = 0.26), central nervous system, thyroid, or liver disease. Conclusion: The mosaicism (XO/XX) is the most common karyotype of TS in screened cases. The phenotypes in children with TS may increase with the proportion of X-chromosome deletions, but the renal disease and comorbidities did not show the same characteristics.
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Enfermedades Renales , Síndrome de Turner , Niño , Humanos , Síndrome de Turner/complicaciones , Síndrome de Turner/epidemiología , Síndrome de Turner/genética , Deleción Cromosómica , Hibridación Fluorescente in Situ , Cromosomas Humanos X/genética , Cariotipificación , Enfermedades Renales/genéticaRESUMEN
Ribosomal protein 25 (RPS25) has been related to male fertility diseases in humans. However, the role of RPS25 in spermatogenesis has yet to be well understood. RpS25 is evolutionarily highly conserved from flies to humans through sequence alignment and phylogenetic tree construction. In this study, we found that RpS25 plays a critical role in Drosophila spermatogenesis and its knockdown leads to male sterility. Examination of each stage of spermatogenesis from RpS25-knockdown flies showed that RpS25 was not required for initial germline cell divisions, but was required for spermatid elongation and individualization. In RpS25-knockdown testes, the average length of cyst elongation was shortened, the spermatid nuclei bundling was disrupted, and the assembly of individualization complex from actin cones failed, resulting in the failure of mature sperm production. Our data revealed an essential role of RpS25 during Drosophila spermatogenesis through regulating spermatid elongation and individualization.
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Proteínas de Drosophila , Drosophila , Animales , Humanos , Masculino , Drosophila/genética , Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Filogenia , Semen/metabolismo , Espermátides/metabolismo , Espermatogénesis/genética , Espermatozoides/metabolismo , Testículo/metabolismoRESUMEN
Tripartite Motif 14 (TRIM14) is an oncoprotein that belongs to the E3 ligase TRIM family, which is involved in the progression of various tumors except for non-small cell lung carcinoma (NSCLC). However, little is currently known regarding the function and related mechanisms of TRIM14 in NSCLC. Here, we found that the TRIM14 protein was downregulated in lung adenocarcinoma tissues compared with the adjacent tissues, which can suppress tumor cell proliferation and migration both in vitro and in vivo. Moreover, TRIM14 can directly bind to glutamine fructose-6-phosphate amidotransferase 1 (GFAT1), which in turn results in the degradation of GFAT1 and reduced O-glycosylation levels. GFAT1 is a key enzyme in the rate-limiting step of the hexosamine biosynthetic pathway (HBP). Replenishment of N-acetyl-d-glucosamine can successfully reverse the inhibitory effect of TRIM14 on the NSCLC cell growth and migration as expected. Collectively, our data revealed that TRIM14 suppressed NSCLC cell proliferation and migration through ubiquitination and degradation of GFAT1, providing a new regulatory role for TRIM14 on HBP.
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Carcinoma de Pulmón de Células no Pequeñas , Movimiento Celular , Proliferación Celular , Glutamina-Fructosa-6-Fosfato Transaminasa (Isomerizadora) , Hexosaminas , Neoplasias Pulmonares , Proteínas de Motivos Tripartitos , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Glutamina-Fructosa-6-Fosfato Transaminasa (Isomerizadora)/metabolismo , Glutamina-Fructosa-6-Fosfato Transaminasa (Isomerizadora)/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Proteínas de Motivos Tripartitos/metabolismo , Proteínas de Motivos Tripartitos/genética , Hexosaminas/biosíntesis , Hexosaminas/metabolismo , Animales , Ratones , Regulación Neoplásica de la Expresión Génica , Progresión de la Enfermedad , Ubiquitinación , Línea Celular Tumoral , Masculino , Ratones Desnudos , Femenino , Glicosilación , Ratones Endogámicos BALB C , Vías Biosintéticas , Péptidos y Proteínas de Señalización IntracelularRESUMEN
Cadmium (Cd) is a common and toxic non-essential heavy metal that must be effectively treated to reduce its threat to the environment and public health. Adsorption with an adsorbent, such as agricultural waste, is widely used to remove heavy metals from wastewater. Sweet potato, the sixth most abundant food crop worldwide, produces a large amount of waste during postharvest processing that could be used as an economic adsorbent. In this study, the feasibility of using sweet potato residue (SPR) as an adsorbent for Cd2+ adsorption was assessed. To enhance the removal rate, SPR was modified with NaOH, and the effects of the modification and adsorption conditions on the removal of Cd2+ from wastewater were investigated. The results showed that modified sweet potato residue (MSPR) could be adapted to various pH and temperatures of simulated wastewater, implying its potential for multi-faceted application. Under optimized conditions, the removal of Cd2+ by MSPR was up to 98.94% with a maximum adsorption capacity of 19.81 mg g-1. Further investigation showed that the MSPR exhibited rich functional groups, a loose surface, and a mesoporous structure, resulting in advantageous characteristics for the adsorption of Cd2+. In addition, the MSPR adsorbed Cd2+ by complexation, ion exchange, and precipitation during a monolayer chemisorption adsorption process. This work demonstrates a sustainable and environment friendly strategy for Cd2+ removal from wastewater and a simple approach for the preparation of MSPR and also revealed the adsorption mechanism of Cd2+ by MSPR, thus providing a suitable adsorbent and strategy for the removal of other heavy metals.
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OBJECTIVE: This study aimed to examine rheumatoid arthritis (RA) risk associated with hormonal and reproductive factors in women from the large cohort of the UK Biobank. METHODS: Data on hormonal and reproductive factors in women were collected from a prospective cohort of 223 526 UK Biobank participants. The potential relationship between reproductive factors and RA risk was assessed using restricted cubic spline. Hazard ratios (HR) were estimated using Cox proportional hazard regressions. RESULTS: During a median follow-up of 12.39 years, 3313 women with RA were identified. Age at menarche >14 years was associated with a greater RA risk (HR 1.13, 95% CI 1.02 to 1.26) compared with menarche at 13. The multiple adjusted HR for RA in women with menopause at <45 years was 1.46. Reproductive years <33 increased the risk of RA (HR 1.39, 95% CI 1.21 to 1.59). Compared with those with 2 children, women with ≥4 children were associated with a higher risk of RA (HR 1.18, 95% CI 1.04 to 1.34). Women who had a hysterectomy (HR 1.40, 95% CI 1.25 to 1.56) or oophorectomy (HR 1.21, 95% CI 1.08 to 1.35) had a higher risk of RA than those without a hysterectomy or oophorectomy. Both hormone replacement therapy (HRT) use (HR 1.46, 95% CI 1.35 to 1.57) and HRT duration (HR 1.02, 95% CI 1.01 to 1.03) were associated with a higher risk of RA. CONCLUSIONS: Some hormonal and reproductive factors were associated with a higher risk of RA. Hormonal and reproductive factors should be considered in risk assessment and formulating management plans in female patients with RA.
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Artritis Reumatoide , Niño , Humanos , Femenino , Adolescente , Estudios Prospectivos , Artritis Reumatoide/complicaciones , Artritis Reumatoide/epidemiología , Medición de Riesgo , Biobanco del Reino UnidoRESUMEN
Successful completion of spermatogenesis is crucial for the perpetuation of the species. In Drosophila, spermatid individualization, a process involving changes in mitochondrial structure and function is critical to produce functional mature sperm. Ant2, encoding a mitochondrial adenine nucleotide translocase, is highly expressed in male testes and plays a role in energy metabolism in the mitochondria. However, its molecular function remains unclear. Here, we identified an important role of Ant2 in spermatid individualization. In Ant2 knockdown testes, spermatid individualization complexes composed of F-actin cones exhibited a diffuse distribution, and mature sperms were absent in the seminal vesicle, thus leading to male sterility. The most striking effects in Ant2-knockdown spermatids were decrease in tubulin polyglycylation and disruption of proper mitochondria derivatives function. Excessive apoptotic cells were also observed in Ant2-knockdown testes. To further investigate the phenotype of Ant2 knockdown in testes at the molecular level, complementary transcriptome and proteome analyses were performed. At the mRNA level, 868 differentially expressed genes were identified, of which 229 genes were upregulated and 639 were downregulated induced via Ant2 knockdown. iTRAQ-labeling proteome analysis revealed 350 differentially expressed proteins, of which 117 proteins were upregulated and 233 were downregulated. The expression of glutathione transferase (GstD5, GstE5, GstE8, and GstD3), proteins involved in reproduction were significantly regulated at both the mRNA and protein levels. These results indicate that Ant2 is crucial for spermatid maturation by affecting mitochondrial morphogenesis.
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Proteínas de Drosophila , Drosophila melanogaster , Espermatogénesis , Animales , Masculino , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Drosophila melanogaster/crecimiento & desarrollo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Testículo/metabolismo , Translocador 2 del Nucleótido Adenina/metabolismo , Translocador 2 del Nucleótido Adenina/genética , Espermátides/metabolismoRESUMEN
BACKGROUND: Methylmalonic acidemia (MMA) is the most common organic acidemia in China, and isolated MMA accounts for approximately 30 % of all types of MMA. Common variants of the MMUT gene vary greatly around the world. The present study aims to determine the high-frequency and novel genetic variants of the MMUT gene in the Henan population of China and evaluate the prognosis of patients carrying the c.1663G>A (p.Ala555Thr) variant. METHODS: We performed next-generation sequencing for 41 patients with isolated MMA screened by tandem mass spectrometry (MS/MS) and analysed the genetic results. We also evaluated the prognosis of patients with the c.1663G>A variant. We used Jalview software for multispecies sequence alignment and Missense3D and DynaMut to predict the protein function of the detected novel variants. RESULTS: A total of 43 variants from 41 patients with isolated MMA were detected, of which c.1663G>A (14.63 %), c.729_730insTT (10.98 %), and c.1106G>A (8.53 %) are high-frequency variants of the MMUT gene in the Henan population. The patients carrying the c.1663G>A variant tended to be responsive to vitamin B12, have a low mortality rate. We also identified 5 novel variants (c.479C>T, c.811G>C, c.965T>A, c.1142G>A and c.1667C>T). CONCLUSION: The rare variant c.1663G>A is prevalent in the Henan population, and infants with this variant tend to have good prognosis. Our findings, especially novel variants, will help broaden the spectrum of genetic variants and facilitate clinical diagnosis and genetic counselling for affected families.