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Any opacification of the lens can be defined as cataracts, and lens epithelium cells play a crucial role in guaranteeing lens transparency by maintaining its homeostasis. Although several causative genes of congenital cataracts have been reported, the mechanisms underlying lens opacity remain unclear. In this study, a large family with congenital cataracts was collected and genetic analysis revealed a pathological mutation (c.3857 C > T, p.T1287I) in the GBF1 gene; all affected individuals in the family carried this heterozygous mutation, while unaffected family members did not. Functional studies in human lens epithelium cell line revealed that this mutation led to a reduction in GBF1 protein levels. Knockdown of endogenous GBF1 activated XBP1s in the unfolded protein response signal pathway, and enhances autophagy in an mTOR-independent manner. Heterozygous Gbf1 knockout mice also displayed typic cataract phenotype. Together, our study identified GBF1 as a novel causative gene for congenital cataracts. Additionally, we found that GBF1 deficiency activates the unfolded protein response and leads to enhanced autophagy, which may contribute to lens opacity.
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AIMS: To examine chain mediating effect of discharge readiness and self-efficacy between quality of discharge teaching and self-management in patients after percutaneous coronary intervention (PCI). BACKGROUND: Although self-management after PCI has significant benefits in controlling risk factors and delaying disease progression, the status of self-management remains unoptimistic. A large number of studies have explored the close relationship between the quality of discharge teaching and patients self-management, but little is known about the underlying mechanisms. METHODS: The cross-sectional samples was collected from a tertiary hospital in China. Self-reported questionnaires were used to assess quality of discharge teaching, discharge readiness, self-efficacy and self-management. Pearson correlation analysis and mediation effect analysis were used for statistical analysis. REPORTING METHOD: The study used the STROBE checklist for reporting. RESULTS: A total of 198 patients with a mean age of 64.99 ± 11.32 (34-85) were included. The mean score of self-management was 88.41 ± 11.82. Quality of discharge teaching, discharge readiness, self-efficacy and self-management were all positively correlated. Mediation effect analysis showed that the mediating effects of discharge readiness, self-efficacy, discharge readiness and self-efficacy between quality of discharge teaching and self-management were 0.157, 0.177 and 0.049, respectively, accounting for 21.96%, 24.76% and 6.85% of the total effect. CONCLUSION: The quality of discharge teaching for patients after PCI not only directly affects self-management, but also can indirectly affect self-management through discharge readiness and self-efficacy. RELEVANCE TO CLINICAL PRACTICE: To improve the life quality of patients after PCI, medical staff should pay attention to the influence of self-management of quality of discharge teaching, and develop intervention strategies based on the path of discharge readiness and self-efficacy. PATIENT OR PUBLIC CONTRIBUTION: Questionnaires filled out by patients were used to understand the association between quality of discharge teaching, discharge readiness, self-efficacy and self-management.
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BACKGROUND: Early embryonic arrest and fragmentation (EEAF) is a common cause of female infertility, but the genetic causes remain to be largely unknown. CIP2A encodes the cellular inhibitor of PP2A, playing a crucial role in mitosis and mouse oocyte meiosis. METHODS: Exome sequencing and Sanger sequencing were performed to identify candidate causative genes in patients with EEAF. The pathogenicity of the CIP2A variant was assessed and confirmed in cultured cell lines and human oocytes through Western blotting, semi-quantitative RT-PCR, TUNEL staining, and fluorescence localization analysis. FINDINGS: We identified CIP2A (c.1510C > T, p.L504F) as a novel disease-causing gene in human EEAF from a consanguineous family. L504 is highly conserved throughout evolution. The CIP2A variant (c.1510C > T, p.L504F) reduced the expression level of the mutant CIP2A protein, leading to the abnormal aggregation of mutant CIP2A protein and cell apoptosis. Abnormal aggregation of CIP2A protein and chromosomal dispersion occurred in the patient's oocytes and early embryos. We further replicated the patient phenotype by knockdown CIP2A in human oocytes. Additionally, CIP2A deficiency resulted in decreased levels of phosphorylated ERK1/2. INTERPRETATION: We first found that the CIP2A loss-of-function variant associate with female infertility characterized by EEAF. Our findings suggest the uniqueness and importance of CIP2A gene in human oocyte and early embryo development. FUNDING: This work was supported by National Key Research and Development Program of China (2023YFC2706302), the National Natural Science Foundation of China (81000079, 81170165, and 81870959), the HUST Academic Frontier Youth Team (2016QYTD02), and the Key Research of Huazhong University of Science and Technology, Tongji Hospital (2022A20).
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Autoantígenos , Infertilidad Femenina , Péptidos y Proteínas de Señalización Intracelular , Proteínas de la Membrana , Oocitos , Humanos , Femenino , Autoantígenos/genética , Autoantígenos/metabolismo , Infertilidad Femenina/genética , Infertilidad Femenina/patología , Infertilidad Femenina/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Oocitos/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Apoptosis/genética , Mutación con Pérdida de Función , Adulto , Secuenciación del Exoma , Animales , Linaje , RatonesRESUMEN
Prenatal lethality associated with mouse knockout of Mettl16, a recently identified RNA N6-methyladenosine (m6A) methyltransferase, has hampered characterization of the essential role of METTL16-mediated RNA m6A modification in early embryonic development. Here, using cross-species single-cell RNA sequencing analysis, we found that during early embryonic development, METTL16 is more highly expressed in vertebrate hematopoietic stem and progenitor cells (HSPCs) than other methyltransferases. In Mettl16-deficient zebrafish, proliferation capacity of embryonic HSPCs is compromised due to G1/S cell cycle arrest, an effect whose rescue requires Mettl16 with intact methyltransferase activity. We further identify the cell-cycle transcription factor mybl2b as a directly regulated by Mettl16-mediated m6A modification. Mettl16 deficiency resulted in the destabilization of mybl2b mRNA, likely due to lost binding by the m6A reader Igf2bp1 in vivo. Moreover, we found that the METTL16-m6A-MYBL2-IGF2BP1 axis controlling G1/S progression is conserved in humans. Collectively, our findings elucidate the critical function of METTL16-mediated m6A modification in HSPC cell cycle progression during early embryonic development.
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Células Madre Hematopoyéticas , Metiltransferasas , Metilación de ARN , Proteínas de Unión al ARN , Factores de Transcripción , Pez Cebra , Animales , Humanos , Ratones , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/genética , Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Proliferación Celular , Desarrollo Embrionario/genética , Regulación del Desarrollo de la Expresión Génica , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/citología , Metiltransferasas/metabolismo , Metiltransferasas/genética , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Pez Cebra/metabolismo , Pez Cebra/embriología , Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Metilación de ARN/genéticaRESUMEN
DEAH-Box Helicase 38 (DHX38) is a pre-mRNA splicing factor and also a disease-causing gene of autosomal recessive retinitis pigmentosa (arRP). The role of DHX38 in the development and maintenance of the retina remains largely unknown. In this study, by using the dhx38 knockout zebrafish model, we demonstrated that Dhx38 deficiency causes severe differentiation defects and apoptosis of retinal progenitor cells (RPCs) through disrupted mitosis and increased DNA damage. Furthermore, we found a significant accumulation of R-loops in the dhx38-deficient RPCs and human cell lines. Finally, we found that DNA replication stress is the prerequisite for R-loop-induced DNA damage in the DHX38 knockdown cells. Taken together, our study demonstrates a necessary role of DHX38 in the development of retina and reveals a DHX38/R-loop/replication stress/DNA damage regulatory axis that is relatively independent of the known functions of DHX38 in mitosis control.
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Cerebral cavernous malformation (CCM) is a vascular malformation of the central nervous system and mainly characterized by enlarged capillary cavities without intervening brain parenchyma. Genetic studies have identified three disease-causing genes (CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10) responsible for CCM. Here, we characterized a four-generation family diagnosed with CCM and identified a novel heterozygous mutation c.1159C>T, p.Q387X in KRIT1 gene by whole exome sequencing and Sanger sequencing. The Q387X mutation resulted in premature termination of KRIT1 protein, which was predicted to be deleterious by the ACMG/AMP 2015 guideline. Our results provide novel genetic evidence support that KRIT1 mutations cause CCM, and are helpful to the treatment and genetic diagnosis of CCM.
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Lung cancer is a common malignant tumor disease with high clinical disability and death rates. Currently, lung cancer diagnosis mainly relies on manual pathology section analysis, but the low efficiency and subjective nature of manual film reading can lead to certain misdiagnoses and omissions. With the continuous development of science and technology, artificial intelligence (AI) has been gradually applied to imaging diagnosis. Although there are reports on AI-assisted lung cancer diagnosis, there are still problems such as small sample size and untimely data updates. Therefore, in this study, a large amount of recent data was included, and meta-analysis was used to evaluate the value of AI for lung cancer diagnosis. With the help of STATA16.0, the value of AI-assisted lung cancer diagnosis was assessed by specificity, sensitivity, negative likelihood ratio, positive likelihood ratio, diagnostic ratio, and plotting the working characteristic curves of subjects. Meta-regression and subgroup analysis were used to investigate the value of AI-assisted lung cancer diagnosis. The results of the meta-analysis showed that the combined sensitivity of the AI-aided diagnosis system for lung cancer diagnosis was 0.87 [95% CI (0.82, 0.90)], specificity was 0.87 [95% CI (0.82, 0.91)] (CI stands for confidence interval.), the missed diagnosis rate was 13%, the misdiagnosis rate was 13%, the positive likelihood ratio was 6.5 [95% CI (4.6, 9.3)], the negative likelihood ratio was 0.15 [95% CI (0.11, 0.21)], a diagnostic ratio of 43 [95% CI (24, 76)] and a sum of area under the combined subject operating characteristic (SROC) curve of 0.93 [95% CI (0.91, 0.95)]. Based on the results, the AI-assisted diagnostic system for CT (Computerized Tomography), imaging has considerable diagnostic accuracy for lung cancer diagnosis, which is of significant value for lung cancer diagnosis and has greater feasibility of realizing the extension application in the field of clinical diagnosis.
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Inteligencia Artificial , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Sensibilidad y EspecificidadRESUMEN
Acinetobacter baumannii (A. baumannii) is a Gram-negative opportunistic pathogen widely attached to the surface of medical instruments, making it one of the most common pathogens of nosocomial infection, and often leading to cross-infection and co-infection. Due to the extensive antibiotic and pan-resistance, A. baumannii infection is facing fewer treatment options in the clinic. Therefore, the prevention and treatment of A. baumannii infection have become a tricky global problem. The requirement for research and development of the new strategy is urgent. Now, non-antibiotic treatment strategies are urgently needed. This review describes the research on A. baumannii vaccines and antibacterial adjuvants, discusses the advantages and disadvantages of different candidate vaccines tested in vitro and in vivo, especially subunit protein vaccines, and shows the antibacterial efficacy of adjuvant drugs in monotherapy.
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Male infertility, a global public health problem, exhibits complex pathogenic causes and genetic factors deserve further discovery and study. We identified a novel homozygous missense mutation c.224A > C (p.D75A) in ACTL7A gene in two infertile brothers with teratozoospermia by whole-exome sequencing (WES). In vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) showed fertilization failure of the two affected couples. The three-dimensional (3D) models showed that a small section of α-helix transformed into random coil in the mutant ACTL7A protein and mutant amino acid lacked a hydrogen bond with Ser170 amino acid. Immunofluorescence revealed that ACTL7A protein was degraded in sperms of patients. Transmission electron microscopy (TEM) analysis of sperms from the infertile patients showed that the irregular perinuclear theca (PT) and acrosomal ultrastructural defects. Furthermore, ACTL7A mutation caused abnormal localization and reduced the expression of PLCZ1 in sperms of the patients, which may be the key reasons for the fertilization failure after ICSI. Our findings expand the spectrum of ACTL7A mutations and provide novel theoretical basis for genetic counseling.
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Infertilidad Masculina , Semen , Humanos , Masculino , Infertilidad Masculina/genética , Inyecciones de Esperma Intracitoplasmáticas/métodos , Fertilización In Vitro , MutaciónRESUMEN
Carbapenem-resistant Klebsiella pneumoniae are distributed worldwide. This study aimed to characterize a hypervirulent tigecycline-resistant and carbapenem-resistant Klebsiella pneumoniae strain, XJ-K2, collected from a patient's blood. We tested antimicrobial susceptibility, virulence, and whole-genome sequencing (WGS) on strain XJ-K2. WGS data were used to identify virulence and resistance genes and to perform multilocus sequence typing (MLST) and phylogenetic analysis. Three novel plasmids, including a pLVPK-like virulence plasmid (pXJ-K2-p1) and two multiple resistance plasmids (pXJ-K2-KPC-2 and pXJ-K2-p3), were discovered in strain XJ-K2. The IncFII(pCRY) plasmid pXJ-K2-p3 carried the dfrA14, sul2, qnrS1, blaLAP-2, and tet(A) resistance genes. The IncFII(pHN7A8)/IncR plasmid pXJ-K2-KPC-2 also carried a range of resistance elements, containing rmtB, blaKPC-2, blaTEM-1, blaCTX-M-65, and fosA3. MLST analysis revealed that strain XJ-K2 belonged to sequence type 11 (ST11). Seven complete phage sequences and many virulence genes were found in strain XJ-K2. Meanwhile, antimicrobial susceptibility tests and G. mellonella larval infection models confirmed the extensively drug resistance (XDR) and hypervirulence of KJ-K2. To our knowledge, this is the first observation and description of the ST11 hypervirulent tigecycline- and carbapenem-resistant K. pneumoniae strain co-carrying blaKPC-2 and the tet(A) in a patient's blood in China. Further investigation is needed to understand the resistance and virulence mechanisms of this significant hypervirulent tigecycline- and carbapenem-resistant strain.
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Enterobacteriaceae Resistentes a los Carbapenémicos , Infecciones por Klebsiella , Humanos , Tigeciclina/farmacología , Klebsiella pneumoniae , Antibacterianos/farmacología , Infecciones por Klebsiella/epidemiología , Infecciones por Klebsiella/microbiología , Tipificación de Secuencias Multilocus , Filogenia , beta-Lactamasas/genética , Carbapenémicos/farmacología , Plásmidos/genética , Enterobacteriaceae Resistentes a los Carbapenémicos/genéticaRESUMEN
Mutations in the Actl7a gene have been reported to lead to male infertility; however, the detailed mechanism of this phenomenon remains unknown. In this study, we constructed Actl7a gene knockout (KO) mice and found that Actl7a deficiency led to malformed formation of sperm acrosomes, male infertility, fertilization failure during in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), and reduced sperm-zona pellucida (ZP) binding ability. Moreover, we found that the localization of the zona pellucida binding protein (ZPBP) was altered in the sperm of Actl7a homozygous KO male mice, which may affect the sperm-zona pellucida binding ability. ACTL7A and ZPBP could form complex, which may be involved in acrosomal formation. Further studies found that localization and expression of the PLCZ1 protein were abnormal in misshapen sperm, leading to reduced calcium oscillations in oocytes. Herein, we provide more detailed mechanisms underlining Actl7a deficiency and male infertility.
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Infertilidad Masculina , Interacciones Espermatozoide-Óvulo , Animales , Fertilización/genética , Fertilización In Vitro , Humanos , Infertilidad Masculina/genética , Infertilidad Masculina/metabolismo , Masculino , Ratones , Oocitos/metabolismo , Semen , Inyecciones de Esperma Intracitoplasmáticas , Interacciones Espermatozoide-Óvulo/genética , Espermatozoides/metabolismo , Zona Pelúcida/metabolismoRESUMEN
ZP1 is a critical glycoprotein in the formation of the zona pellucida. It plays an indispensable role in the maturation of oocytes. To identify the causative gene of empty follicle syndrome (EFS) in a patient from a consanguineous family, whole-exome sequencing was performed in the proband. We identified a novel homozygous nonsense mutation c.1260C > G (p. Tyr420X) in the ZP1 gene from two primary infertile patients. Western blot showed that Y420X mutation in ZP1 gene produced a truncated protein. However, the mutation had no significant effect on subcellular localization of the mutant protein. Our findings confirmed the important role of the ZP1 gene in human female reproduction, enriched the mutation spectrums of ZP1 gene, and expanded its applications in the clinical and molecular diagnoses of EFS.
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Infertilidad Femenina , Enfermedades del Ovario , Humanos , Femenino , Glicoproteínas de la Zona Pelúcida/genética , Infertilidad Femenina/genética , Infertilidad Femenina/metabolismo , Codón sin Sentido/metabolismo , Zona Pelúcida , Enfermedades del Ovario/genética , Enfermedades del Ovario/metabolismo , Oocitos/metabolismo , MutaciónRESUMEN
Multiple morphological abnormalities of the sperm flagella (MMAF), characteristic with bent, short, coiled, absent, and abnormal caliber flagella, is an important basis of male infertility. Genetic factors account for a large proportion of patients with MMAF. The fibrous sheath interacting protein 2 (FSIP2) has a significant function in the spermatogenesis and flagellar motility. In our study, a novel compound heterozygous mutation (c.1494C > A, p.C498* and c.11020_11024del, p.Tyr3675Cysfs*3) in FSIP2 gene was identified in an infertile male patient with MMAF. H&E staining presented typical MMAF phenotype and thick neck, midpiece in the patient's sperm cells. Transmission electron microscopy observation showed abnormal mitochondrial arrangement and disorganization and dysplastic of the fibrous sheath (FS), which were verified again under light microscopy. Immunofluorescence (IF) analysis of FISP2 expression showed that FSIP2 was absent in the flagellum of the patient's sperm cells. Our findings will be helpful to the precise diagnosis of MMAF and male infertility and enrich the mutational spectrum of FSIP2 gene.
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Dineínas Axonemales , Infertilidad Masculina , Proteínas de Plasma Seminal , Cola del Espermatozoide , Espermatozoides , Dineínas Axonemales/genética , Heterocigoto , Humanos , Infertilidad Masculina/genética , Masculino , Mutación , Proteínas de Plasma Seminal/genética , Espermatozoides/anomalíasRESUMEN
Zona pellucida (ZP) which is an extracellular matrix consisting of ZP1, ZP2, ZP3, and ZP4 plays a vital role in oocyte maturity, early embryonic development, and fertilization process. Any alterations of structure or function may lead to the abnormal formation of ZP and female infertility. Two novel heterozygous mutations c.1859G > A (p.Cys620Tyr) and c.1421 T > C (p.Leu474Pro) in ZP2 gene were recognized in three patients from two unrelated families with abnormal ZP and female infertility in this study. The expression constructs carrying wild-type ZP2 gene, c.1859G > A (p.Cys620Tyr) mutant ZP2 gene, and c.1421 T > C (p.Leu474Pro) mutant ZP2 gene were transfected into CHO cells respectively. There was a remarkable decrease in the expression of p.Cys620Tyr mutant protein with western blot. In addition, secretion of p.Leu474Pro mutant protein in the culture medium reduced markedly compared with that of wild-type ZP2 protein. Furthermore, co-immunoprecipitation showed that the p.Leu474Pro mutation affected the interaction between ZP2 and ZP3. Prediction of three-dimensional (3D) structure of the proteins showed that p.Cys620Tyr mutation altered the disulfide bond of ZP2 protein and may affect its function. These findings extend the ranges of mutations of ZP2 gene. Meanwhile, it will be helpful to the precise diagnosis of abnormal ZP.
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Infertilidad Femenina , Zona Pelúcida , Animales , Cricetinae , Cricetulus , Disulfuros/análisis , Disulfuros/metabolismo , Femenino , Humanos , Infertilidad Femenina/genética , Infertilidad Femenina/metabolismo , Proteínas Mutantes/análisis , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutación , Oocitos/metabolismo , Embarazo , Glicoproteínas de la Zona Pelúcida/genéticaRESUMEN
PURPOSE: The aim of this study was to identify the disease-causing mutations found in three infertile female patients who were diagnosed with abnormal zona pellucida (ZP) and empty follicle syndrome (EFS). METHODS: We performed whole-exome sequencing and Sanger sequencing to identify and verify the disease-causing mutations. Additionally, we performed Western blotting and mini-gene splicing assay to assess the effects of the mutations. RESULTS: We identified two novel compound heterozygous mutations in the ZP2 gene, a patient with an abnormal ZP carrying a novel compound heterozygous mutation (c.1695-2A>G and c.1831G>T, p.V611F) and a patient with EFS carrying a novel compound heterozygous mutation (c.1695-2A>G and c.1924 C>T, p.R642*). Furthermore, we identified a patient with typical abnormal ZP carrying a novel heterozygous mutation (c.400G>T, p.A134S) in the ZP3 gene. The splice site mutation (c.1695-2A>G) can cause abnormal pre-mRNA splicing that inserts an extra sequence of 61 bp in the mRNA of ZP2, and the missense mutation (c.1831G>T) can cause a decrease of ZP2 protein in HEK293 cells. CONCLUSION: We identified three novel mutations in the ZP2 gene and the ZP3 gene in three Chinese female patients with infertility. Our study expands the spectrum of ZP gene mutations and phenotypes and thus is beneficial in the genetic diagnosis of infertility in females.
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Infertilidad Femenina , Enfermedades del Ovario , Glicoproteínas de la Zona Pelúcida , Femenino , Células HEK293 , Humanos , Infertilidad Femenina/genética , Infertilidad Femenina/metabolismo , Mutación/genética , Oocitos/metabolismo , Enfermedades del Ovario/genética , Enfermedades del Ovario/metabolismo , Zona Pelúcida/metabolismo , Glicoproteínas de la Zona Pelúcida/genéticaRESUMEN
Background: COVID-19 (coronavirus disease 2019) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seriously endangers people's lives. The variation in SARS-CoV-2 makes the research and development of vaccines and specific drugs particularly important. However, the prevention and diagnosis of COVID-19 cannot be underestimated in the control of the epidemic. Case Presentation: We introduced a 65-year-old female patient who was diagnosed with COVID-19. The SARS-CoV-2 nucleic acid test result of this patient was positive again during treatment. It took 85 days from the first symptom to the final cure. According to the known reports, she is currently the patient with the longest virus shedding in Sichuan Province, China. Due to the patient's special condition, she was treated in four hospitals before and after, and she was diagnosed with type 2 diabetes mellitus (T2DM) and right lung metastatic adenocarcinoma. We fully introduced the patient's epidemiological history, diagnosis, testing, and treatment process. The patient was finally discharged from the hospital under the treatment of antiviral, hypoglycaemic, anti-anxiety, and a combination of Chinese and Western medicine. Conclusions: The epidemic is still rampant, and we should not relax our efforts in the prevention and control of viruses. For the elderly, especially those who are suffering from complications or vulnerable to diseases, it is recommended to extend the observation time. Additionally, medical workers should pay attention to the mental state of patients.
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Hypertension, diabetes mellitus, and coronary artery disease are common comorbidities and dangerous factors for infection and serious COVID-19. Polymorphisms in genes associated with comorbidities may help observe susceptibility and disease severity variation. However, specific genetic factors and the extent to which they can explain variation in susceptibility of severity are unclear. Therefore, we evaluated candidate genes associated with COVID-19 and hypertension, diabetes mellitus, and coronary artery disease. In particular, we performed searches against OMIM, NCBI, and other databases, protein-protein interaction network construction, and GO and KEGG pathway enrichment analyses. Results showed that the associated overlapping genes were TLR4, NLRP3, MBL2, IL6, IL1RN, IL1B, CX3CR1, CCR5, AGT, ACE, and F2. GO and KEGG analyses yielded 302 GO terms (q < 0.05) and 29 signaling pathways (q < 0.05), respectively, mainly including coronavirus disease-COVID-19 and cytokine-cytokine receptor interaction. IL6 and AGT were central in the PPI, with 8 and 5 connections, respectively. In this study, we identified 11 genes associated with both COVID-19 and three comorbidities that may contribute to infection and disease severity. The key genes IL6 and AGT are involved in regulating immune response, cytokine activity, and viral infection. Therefore, RAAS inhibitors, AGT antisense nucleotides, cytokine inhibitors, vitamin D, fenofibrate, and vaccines regulating non-immune and immune factors could be potential strategies to prevent and cure COVID-19. The study provides a basis for further investigation of genes and pathways with predictive value for the risk of infection and prognosis and could help guide drug and vaccine development to improve treatment efficacy and the development of personalised treatments, especially for COVID-19 individuals with common comorbidities.
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COVID-19/genética , COVID-19/epidemiología , Comorbilidad , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/genética , Complicaciones de la Diabetes/epidemiología , Complicaciones de la Diabetes/genética , Humanos , Hipertensión/complicaciones , Hipertensión/epidemiología , Hipertensión/genética , Mutación , Mapas de Interacción de ProteínasRESUMEN
Mendelian susceptibility to mycobacterial disease (MSMD) is a rare monogenetic disease, which is characterized by susceptibility to some weakly virulent mycobacteria. Here, we explored the pathogenic genes and molecular mechanisms of MSMD patients. We recruited three patients diagnosed with MSMD from two families. Two novel mutations (c.1228A > G, p.K410E and c.2071A > G, p.M691V) in STAT1 gene were identified from two families. The translocation of K410E mutant STAT1 protein into nucleus was not affected. The binding ability between gamma-activating sequence (GAS) and K410E mutant STAT1 protein was significantly reduced, which will reduce the interaction between STAT1 protein with the promoters of target genes. The M691V mutant STAT1 protein cannot translocate into the nucleus after IFN-γ stimulation, which will affect the STAT1 protein form gamma-activating factors (GAF) and bind the GAS in the promoter region of downstream target genes. Taken together, our results showed that the mutation of K410E led to impaired binding of STAT1 to target DNA, and the mutation of M691V prevented the transport of STAT1 into the nucleus, which led to MSMD. Together, we identified two novel mutations (c.1228A > G, p.K410E and c.2071A > G, p.M691V) in STAT1 gene in MSMD patients, and deciphered the molecular mechanism of MSMD caused by STAT1 mutations.
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Predisposición Genética a la Enfermedad , Mutación/genética , Infecciones por Mycobacterium/genética , Infecciones por Mycobacterium/microbiología , Factor de Transcripción STAT1/genética , Secuencia de Aminoácidos , Secuencia de Bases , Núcleo Celular/metabolismo , ADN/metabolismo , Femenino , Células HEK293 , Células HeLa , Humanos , Masculino , Proteínas Mutantes/química , Proteínas Mutantes/genética , Linaje , Unión Proteica , Dominios Proteicos , Transporte de Proteínas , Factor de Transcripción STAT1/química , Factor de Transcripción STAT1/metabolismo , Fracciones Subcelulares/metabolismoRESUMEN
OBJECTIVE: Oral hypoglycemic drugs for the treatment of gestational diabetes mellitus (GDM) are still controversial because they can pass through the placenta. The purpose of this meta-analysis is to evaluate the safety and effectiveness of oral hypoglycemic drugs. METHODS: PubMed, Ovid Embase, Web of Science, and Cochrane databases were systematically searched (inception to 20 April 2021). Rev Man 5.0 was used to analyze the data. A random-effects model was used to compute the summary risk estimates. RESULTS: There were 26 randomized controlled trials (RCTs) involving 4921 GDM patients which were included in this meta-analysis. Compared with metformin, insulin had a significant increase in the risk of preeclampsia (odds ratio [OR], 1.61; 95% confidence interval [CI], 1.06 to 2.45; I2=40%; p < .05), hypertension (OR, 1.42; 95% CI, 1.02 to 1.99; I2=0%; p < .05), hypoglycemia (OR, 3.93; 95% CI, 1.27 to 12.19; I2=0%; p < .05), neonatal hypoglycemia (OR, 1.92; 95% CI, 1.34 to 2.76; I2=41%; p < .0001), neonatal jaundice (OR, 2.70; 95% CI, 1.12 to 6.52; I2=0%; p < .05), and Neonatal Intensive Care Unit Admission (OR, 1.46; 95% CI, 1.09 to 1.95; I2=39%; p < .05), but the risk of neonatal macrosomia (OR, 1.67; 95% CI, 1.12 to 2.40; I2=0%; p < .05) and neonatal injury (OR, 0.70; 95% CI, 0.55 to 0.89; I2=0%; p < .01) is lower. CONCLUSIONS: Metformin is comparable with insulin in glycemic control and neonatal outcomes and has the potential to replace insulin therapy in clinical practice. Glyburide is behind metformin and insulin, and more RCTs are needed to verify its safety.