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1.
Artigo em Inglês | MEDLINE | ID: mdl-33051172

RESUMO

OBJECTIVE: To report outcomes of a surgical technique of eyelid margin splitting and anterior lamellar repositioning with lower eyelid non-entropion trichiasis. METHOD: A total of 13 patients (5 males and 8 females) with lower eyelid non-entropion trichiasis who had undergone eyelid margin splitting and anterior lamellar repositioning at Tongji Hospital from January 2018 to June 2018 were retrospectively reviewed. RESULT: All patients underwent surgery successfully, and 13 patients (23 eyes) were followed up for 9-18 months (mean 12.23±3.14 months). Symptoms were entirely relieved in all patients without the need for further surgery, and all patients were satisfied with the appearance after surgery. The lower lid margin was a flat platform with normal anatomical landmarks, and the lower eyelid eyelashes were no longer in contact with the globe. However, one patient relapsed 7 months after surgery. CONCLUSION: Patients with lower eyelid non-entropion trichiasis can be treated effectively through eyelid margin splitting and anterior lamellar repositioning with inapparent skin scarring.

2.
Clin Genet ; 2020 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-33070343

RESUMO

Multiple morphological abnormalities of the flagella (MMAF) is a genetically heterogeneous disorder leading to male infertility. Recent studies have revealed that DNAH17 variants are associated with MAMF, yet there is no functional evidence in support of their pathnogenicity. Here, we recruited two consanguineous families of Pakistani and Chinese origins, respectively, diagnosed with MMAF. Whole-exome sequencing identified novel homozygous DNAH17 variants, which led to loss of DNAH17 proteins, in the patients. Transmission EM analyses revealed completely disorganized axonemal structure as the predominant anomaly and increased frequencies of missings of microtubule doublet(s) 4-7 in sperm flagella of patients. Similar to those found in patients, Dnah17-/- mice also displayed MMAF phenotype along with completely disorganized axonemal structures. Clusters of disorganized microtubules and outer dense fibers were observed in developing spermatids, indicating impaired sperm flagellar assembly. Besides, we also noticed many elongating spermatids with a deformed nuclear shape and abnormal step 16 spermatids that failed to spermiate, which subsequently underwent apoptosis in Dnah17-null mice. These findings present direct evidence establishing that DNAH17 is a MMAF-related gene in humans and mice, extend the clinical interpretations of DNAH17 variants, and highlight an essential and complex role of DNAH17 in spermatogenesis. This article is protected by copyright. All rights reserved.

3.
Nat Genet ; 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33020666

RESUMO

Here, we present a joint-tissue imputation (JTI) approach and a Mendelian randomization framework for causal inference, MR-JTI. JTI borrows information across transcriptomes of different tissues, leveraging shared genetic regulation, to improve prediction performance in a tissue-dependent manner. Notably, JTI includes the single-tissue imputation method PrediXcan as a special case and outperforms other single-tissue approaches (the Bayesian sparse linear mixed model and Dirichlet process regression). MR-JTI models variant-level heterogeneity (primarily due to horizontal pleiotropy, addressing a major challenge of transcriptome-wide association study interpretation) and performs causal inference with type I error control. We make explicit the connection between the genetic architecture of gene expression and of complex traits and the suitability of Mendelian randomization as a causal inference strategy for transcriptome-wide association studies. We provide a resource of imputation models generated from GTEx and PsychENCODE panels. Analysis of biobanks and meta-analysis data, and extensive simulations show substantially improved statistical power, replication and causal mapping rate for JTI relative to existing approaches.

4.
Cell Commun Signal ; 18(1): 164, 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33087151

RESUMO

BACKGROUND: Chemotherapy is currently one of the most effective treatments for advanced breast cancer. Anti-microtubule agents, including taxanes, eribulin and vinca-alkaloids are one of the primary major anti-breast cancer chemotherapies; however, chemoresistance remains a problem that is difficult to solve. We aimed to discover novel candidate protein targets to combat chemoresistance in breast cancer. METHODS: A lentiviral shRNA-based high-throughput screening platform was designed and developed to screen the global kinome to find new therapeutic targets in paclitaxel-resistant breast cancer cells. The phenotypes were confirmed with alternative expression in vitro and in vivo. Molecular mechanisms were investigated using global phosphoprotein arrays and expression microarrays. Global microarray analysis was performed to determine TAOK3 and genes that induced paclitaxel resistance. RESULTS: A serine/threonine kinase gene, TAOK3, was identified from 724 screened kinase genes. TAOK3 shRNA exhibited the most significant reduction in IC50 values in response to paclitaxel treatment. Ectopic downregulation of TAOK3 resulted in paclitaxel-resistant breast cancer cells sensitize to paclitaxel treatment in vitro and in vivo. The expression of TAOK3 also was correlated to sensitivity to two other anti-microtubule drugs, eribulin and vinorelbine. Our TAOK3-modulated microarray analysis indicated that NF-κB signaling played a major upstream regulation role. TAOK3 inhibitor, CP43, and shRNA of NF-κB both reduced the paclitaxel resistance in TAOK3 overexpressed cells. In clinical microarray databases, high TAOK3 expressed breast cancer patients had poorer prognoses after adjuvant chemotherapy. CONCLUSIONS: Here we identified TAOK3 overexpression increased anti-microtubule drug resistance through upregulation of NF-κB signaling, which reduced cell death in breast cancer. Therefore, inhibition of the interaction between TAOK3 and NF-κB signaling may have therapeutic implications for breast cancer patients treated with anti-microtubule drugs. Video abstract.

5.
Int J Biol Macromol ; 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33096178

RESUMO

A novel polysaccharide from Siraitia grosvenorii residues (SGP, molecular weight 1.93 × 103 KDa) was isolated and purified. SGP was composed of α-L-Arabinose, α-D-Mannose, α-d-Glucose, α-D-Galactose, Glucuronic acid, and Galacturonic acid with the ratio of 1: 1.92: 3.98: 7.63: 1.85: 7.34. The backbone of SGP was consist of galactoses and linked by α-(1,4)-glycosidic bond. The branch chains including α-1,6 linked glucose branch, α-1,6 linked mannose branch, α-1,3 linked galactose branch and arabinose branched (α-L-Ara(1→). The results of bioactivity experiments suggested that SGP had antioxidant in vitro, especially on scavenging DPPH radicals. Besides, SGP resulted in the decrease of ROS and the percentage of apoptotic and necrotic cells in a dose-dependent manner in H2O2 oxide injury PC12 cells. This research could help to develop the potential value and utilization of Siraitia grosvenorii.

6.
Genet Epidemiol ; 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-33038041

RESUMO

Multiple methods have been proposed to aggregate genetic variants in a gene or a region and jointly test their association with a trait of interest. However, these joint tests do not provide estimates of the individual effect of each variant. Moreover, few methods have evaluated the joint association of multiple variants with DNA methylation. We propose a method based on linear mixed models to estimate the joint and individual effect of multiple genetic variants on DNA methylation leveraging genomic annotations. Our approach is flexible, can incorporate covariates and annotation features, and takes into account relatedness and linkage disequilibrium (LD). Our method had correct Type-I error and overall high power for different simulated scenarios where we varied the number and specificity of functional annotations, number of causal and total genetic variants, frequency of genetic variants, LD, and genetic variant effect. Our method outperformed the family Sequence Kernel Association Test and had more stable estimations of effects than a classical single-variant linear mixed-effect model. Applied genome-wide to the Framingham Heart Study data, our method identified 921 DNA methylation sites influenced by at least one rare or low-frequency genetic variant located within 50 kilobases (kb) of the DNA methylation site.

7.
J Microbiol ; 58(9): 812-820, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32870487

RESUMO

Enterovirus D68 (EVD68) is an emerging pathogen that recently caused a large worldwide outbreak of severe respiratory disease in children. However, the relationship between EVD68 and host cells remains unclear. Caspases are involved in cell death, immune response, and even viral production. We found that caspase-3 was activated during EVD68 replication to induce apoptosis. Caspase-3 inhibitor (Z-DEVD-FMK) inhibited viral production, protected host cells from the cytopathic effects of EVD68 infection, and prevented EVD68 from regulating the host cell cycle at G0/G1. Meanwhile, caspase-3 activator (PAC-1) increased EVD68 production. EVD68 infection therefore activates caspase-3 for virus production. This knowledge provides a potential direction for the prevention and treatment of disease related to EVD68.

8.
Mol Psychiatry ; 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929213

RESUMO

Schizophrenia (SCZ) is a neuropsychiatric disorder with aberrant expression of multiple genes. However, identifying its exact causal genes remains a considerable challenge. The brain-specific transcription factor POU3F2 (POU domain, class 3, transcription factor 2) has been recognized as a risk factor for SCZ, but our understanding of its target genes and pathogenic mechanisms are still limited. Here we report that POU3F2 regulates 42 SCZ-related genes in knockdown and RNA-sequencing experiments of human neural progenitor cells (NPCs). Among those SCZ-related genes, TRIM8 (Tripartite motif containing 8) is located in SCZ-associated genetic locus and is aberrantly expressed in patients with SCZ. Luciferase reporter and electrophoretic mobility shift assays (EMSA) showed that POU3F2 induces TRIM8 expression by binding to the SCZ-associated SNP (single nucleotide polymorphism) rs5011218, which affects POU3F2-binding efficiency at the promoter region of TRIM8. We investigated the cellular functions of POU3F2 and TRIM8 as they co-regulate several pathways related to neural development and synaptic function. Knocking down either POU3F2 or TRIM8 promoted the proliferation of NPCs, inhibited their neuronal differentiation, and impaired the excitatory synaptic transmission of NPC-derived neurons. These results indicate that POU3F2 regulates TRIM8 expression through the SCZ-associated SNP rs5011218, and both genes may be involved in the etiology of SCZ by regulating neural development and synaptic function.

9.
ESC Heart Fail ; 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32909388

RESUMO

AIMS: Heart failure (HF) is associated with several metabolic changes, but it is unknown whether distinct components of the circulating metabolome may be related to cardiac structure and function, and with incident HF in the community. METHODS AND RESULTS: We assayed 217 circulating metabolites in 2336 Framingham Study participants (mean age 55 ± 10 years, 53% women) without HF at baseline. We used linear and Cox regression to relate concentrations of metabolites to left ventricular (LV) diastolic dimension, LV wall thickness, LV ejection fraction, left atrial dimension, LV ventricular mass, and aortic root size cross-sectionally and to incident HF prospectively. Bonferroni-adjusted P-values <0.05 denoted statistical significance. Circulating concentrations of kynurenine [ß = -0.12 cm per standard deviation (SD) increment in normalized residual of metabolite, P = 7.3 × 10-8 ] and aminoadipate (-0.11 cm per SD increment, P = 2.61 × 10-5 ) were associated with left ventricular diastolic dimension, phosphatidylcholine (carbon:double bound = 38:6) with left atrial dimension (0.10 cm per SD increment, P = 9.7 × 10-6 ), and cholesterol ester (carbon:double bound = 20:5) with left atrial dimension (0.10 cm per SD increment, P = 1.4 × 10-5 ) in multivariable-adjusted models. During an average follow-up of 15.8 (range 0.02-23.2) years, 113 participants (5%) were diagnosed with HF with reduced ejection fraction and 106 individuals (5%) with HF with preserved ejection fraction. In multivariable analyses, concentrations of phosphatidylcholine (hazard ratio 0.63, P = 1.3 × 10-5 ) and ornithine (hazard ratio 1.44, P = 0.00014) were associated with HF with reduced ejection fraction. CONCLUSIONS: Several metabolites, including the vasoactive metabolite kynurenine, were related to cardiac structure and function in our sample. Additional research is warranted to confirm our observations and investigate if these metabolites can risk stratify ambulatory individuals.

10.
Water Sci Technol ; 82(1): 120-130, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32910797

RESUMO

In order to investigate the effect of temperatures and operating modes on extracellular polymeric substances (EPS) contents, three sequencing batch reactors (SBRs) were operated at temperatures of 15, 25, and 35 °C (R15 °C, R25 °C, and R35 °C, respectively), with two SBRs operated under alternating anoxic/oxic conditions (RA/O and RO/A, respectively). Results showed that higher contents of tightly bound EPS (TB-EPS) and total EPS appeared in R15 °C, while loosely bound EPS (LB-EPS) dominated in R35 °C. In all three kinds of EPS (LB-EPS, TB-EPS and total EPS) assessed, protein was the main component in R15 °C and R25 °C, while polysaccharides dominated in R35 °C. Moreover, compared with RO/A, RA/O was favorable for the production of the three kinds of EPS. Furthermore, three kinds of EPS and their components were augmented during the nitrification process, while they declined during the denitrification process under all conditions except for R35 °C.


Assuntos
Matriz Extracelular de Substâncias Poliméricas , Esgotos , Reatores Biológicos , Nitrificação , Temperatura
11.
Cell Death Dis ; 11(9): 781, 2020 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-32951003

RESUMO

Drug-induced liver injury is the major cause of acute liver failure. However, the underlying mechanisms seem to be multifaceted and remain poorly understood, resulting in few effective therapies. Here, we report a novel mechanism that contributes to acetaminophen-induced hepatotoxicity through the induction of ferroptosis, a distinctive form of programmed cell death. We subsequently identified therapies protective against acetaminophen-induced liver damage and found that (+)-clausenamide ((+)-CLA), an active alkaloid isolated from the leaves of Clausena lansium (Lour.) Skeels, inhibited acetaminophen-induced hepatocyte ferroptosis both in vivo and in vitro. Consistently, (+)-CLA significantly alleviated acetaminophen-induced or erastin-induced hepatic pathological damages, hepatic dysfunctions and excessive production of lipid peroxidation both in cultured hepatic cell lines and mouse liver. Furthermore, treatment with (+)-CLA reduced the mRNA level of prostaglandin endoperoxide synthase 2 while it increased the protein level of glutathione peroxidase 4 in hepatocytes and mouse liver, confirming that the inhibition of ferroptosis contributes to the protective effect of (+)-CLA on drug-induced liver damage. We further revealed that (+)-CLA specifically reacted with the Cys-151 residue of Keap1, which blocked Nrf2 ubiquitylation and resulted in an increased Nrf2 stability, thereby leading to the activation of the Keap1-Nrf2 pathway to prevent drug-induced hepatocyte ferroptosis. Our studies illustrate the innovative mechanisms of acetaminophen-induced liver damage and present a novel intervention strategy to treat drug overdose by using (+)-CLA.

12.
Genome Med ; 12(1): 84, 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-32988399

RESUMO

BACKGROUND: Mitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. However, the mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation. METHODS: To investigate this hypothesis, we assessed the relationship between mtDNA-CN and nDNA methylation in 2507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings, we assayed an additional 2528 participants from the Cardiovascular Health Study (CHS) (N = 533) and Framingham Heart Study (FHS) (N = 1995). We further assessed the effect of experimental modification of mtDNA-CN through knockout of TFAM, a regulator of mtDNA replication, via CRISPR-Cas9. RESULTS: Thirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance (P < 5 × 10- 8). Meta-analysis across all cohorts identified six mtDNA-CN-associated CpGs at genome-wide significance (P < 5 × 10- 8). Additionally, over half of these CpGs were associated with phenotypes known to be associated with mtDNA-CN, including coronary heart disease, cardiovascular disease, and mortality. Experimental modification of mtDNA-CN demonstrated that modulation of mtDNA-CN results in changes in nDNA methylation and gene expression of specific CpGs and nearby transcripts. Strikingly, the "neuroactive ligand receptor interaction" KEGG pathway was found to be highly overrepresented in the ARIC cohort (P = 5.24 × 10- 12), as well as the TFAM knockout methylation (P = 4.41 × 10- 4) and expression (P = 4.30 × 10- 4) studies. CONCLUSIONS: These results demonstrate that changes in mtDNA-CN influence nDNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling.

13.
Mol Psychiatry ; 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32826963

RESUMO

Genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms (SNPs) associated with bipolar disorder (BD), but what the causal variants are and how they contribute to BD is largely unknown. In this study, we used FUMA, a GWAS annotation tool, to pinpoint potential causal variants and genes from the latest BD GWAS findings, and performed integrative analyses, including brain expression quantitative trait loci (eQTL), gene coexpression network, differential gene expression, protein-protein interaction, and brain intermediate phenotype association analysis to identify the functions of a prioritized gene and its connection to BD. Convergent lines of evidence prioritized protein-coding gene G Protein Nucleolar 3 (GNL3) as a BD risk gene, with integrative analyses revealing GNL3's roles in cell proliferation, neuronal functions, and brain phenotypes. We experimentally revealed that BD-related eQTL SNPs rs10865973, rs12635140, and rs4687644 regulate GNL3 expression using dual luciferase reporter assay and CRISPR interference experiment in human neural progenitor cells. We further identified that GNL3 knockdown and overexpression led to aberrant neuronal proliferation and differentiation, using two-dimensional human neural cell cultures and three-dimensional forebrain organoid model. This study gathers evidence that BD-related genetic variants regulate GNL3 expression which subsequently affects neuronal proliferation and differentiation.

14.
Artigo em Inglês | MEDLINE | ID: mdl-32750957

RESUMO

Recent advances in the development of multivariate analysis methods have led to the application of multivariate pattern analysis (MVPA) to investigate the interactions between brain regions using graph theory (functional connectivity, FC) and decode visual categories from functional magnetic resonance imaging (fMRI) data from a continuous multicategory paradigm. To estimate stable FC patterns from fMRI data, previous studies required long periods in the order of several minutes, in comparison to the human brain that categories visual stimuli within hundreds of milliseconds. Constructing short-time dynamic FC patterns in the order of milliseconds and decoding visual categories is a relatively novel concept. In this study, we developed a multivariate decoding algorithm based on FC patterns and applied it to magnetoencephalography (MEG) data. MEG data were recorded from participants presented with image stimuli in four categories (faces, scenes, animals and tools). MEG data from 17 participants demonstrate that short-time dynamic FC patterns yield brain activity patterns that can be used to decode visual categories with high accuracy. Our results show that FC patterns change over the time window, and FC patterns extracted in the time window of 0~200 ms after the stimulus onset were most stable. Further, the categorizing accuracy peaked (the mean binary accuracy is above 78.6% at individual level) in the FC patterns estimated within the 0~200 ms interval. These findings elucidate the underlying connectivity information during visual category processing on a relatively smaller time scale and demonstrate that the contribution of FC patterns to categorization fluctuates over time.

15.
Am J Hum Genet ; 107(3): 514-526, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32791035

RESUMO

Multiple morphological abnormalities of the sperm flagella (MMAF) is a severe form of asthenoteratozoospermia. Although recent studies have revealed several MMAF-associated genes and demonstrated MMAF to be a genetically heterogeneous disease, at least one-third of the cases are still not well understood for their etiology. Here, we identified bi-allelic loss-of-function variants in CFAP58 by using whole-exome sequencing in five (5.6%) unrelated individuals from a cohort of 90 MMAF-affected Chinese men. Each of the men harboring bi-allelic CFAP58 variants presented typical MMAF phenotypes. Transmission electron microscopy demonstrated striking flagellar defects with axonemal and mitochondrial sheath malformations. CFAP58 is predominantly expressed in the testis and encodes a cilia- and flagella-associated protein. Immunofluorescence assays showed that CFAP58 localized at the entire flagella of control sperm and predominantly concentrated in the mid-piece. Immunoblotting and immunofluorescence assays showed that the abundances of axoneme ultrastructure markers SPAG6 and SPEF2 and a mitochondrial sheath protein, HSP60, were significantly reduced in the spermatozoa from men harboring bi-allelic CFAP58 variants. We generated Cfap58-knockout mice via CRISPR/Cas9 technology. The male mice were infertile and presented with severe flagellar defects, consistent with the sperm phenotypes in MMAF-affected men. Overall, our findings in humans and mice strongly suggest that CFAP58 plays a vital role in sperm flagellogenesis and demonstrate that bi-allelic loss-of-function variants in CFAP58 can cause axoneme and peri-axoneme malformations leading to male infertility. This study provides crucial insights for understanding and counseling of MMAF-associated asthenoteratozoospermia.


Assuntos
Anormalidades Múltiplas/genética , Astenozoospermia/genética , Axonema/genética , Infertilidade Masculina/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Anormalidades Múltiplas/patologia , Alelos , Animais , Astenozoospermia/fisiopatologia , Axonema/patologia , Sistemas CRISPR-Cas/genética , Proteínas de Ciclo Celular/genética , Homozigoto , Humanos , Infertilidade Masculina/patologia , Mutação com Perda de Função/genética , Perda de Heterozigosidade/genética , Masculino , Camundongos , Camundongos Knockout , Proteínas dos Microtúbulos/genética , Mitocôndrias/genética , Cauda do Espermatozoide/metabolismo , Cauda do Espermatozoide/patologia , Testículo/metabolismo , Testículo/patologia , Sequenciamento Completo do Exoma
16.
PLoS One ; 15(8): e0236869, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32745127

RESUMO

Many factors influence the incidence of type 2 diabetes mellitus (T2DM). Here, we investigated the associations between socio-demographic characteristics and familial history with the 5-year incidence of T2DM in a family-based study conducted in Brazil. T2DM was defined as baseline fasting blood glucose ≥ 126 mg/dL or the use of any hypoglycaemic drug. We excluded individuals with T2DM at baseline or if they did not attend two examination cycles. After exclusions, we evaluated a sample of 1,125 participants, part of the Baependi Heart Study (BHS). Mixed-effects logistic regression models were used to assess T2DM incident given different characteristics. At the 5-year follow-up, the incidence of T2DM was 6.7% (7.2% men and 6.3% women). After adjusting for age, sex, and education status, the model that combined marital and occupation status, skin color, and familial history of T2DM provided the best prediction for T2DM incidence. Only marital status was independently associated with T2DM incidence. Individuals that remained married, despite having significantly increased their weight, were significantly less likely to develop diabetes than their divorced counterparts.


Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Estado Civil , Adulto , Glicemia/análise , Brasil , Grupos de Populações Continentais , Diabetes Mellitus Tipo 2/diagnóstico , Educação , Feminino , Humanos , Hipertensão , Incidência , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Obesidade , Fatores de Risco , População Rural
17.
Biotechnol Lett ; 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32757151

RESUMO

The purification and characterization of PGM (Phosphoglucomutase) from Cordyceps militaris (C. militaris) was investigated. PGM was purified using a combination of ultrafiltration, salting-out and ion exchange chromatography resulting in 4.23-fold enhancement of activity with a recovery of 20.01%. Molecular mass was 50.01 kDa by SDS-PAGE. The optimal activity was achieved at pH 7.5 and 30 °C with NADPH as substrate. The results showed that SDS, DTT Li+, Cu2+, Na+, Mn2+ and Al3+ were effective PGM inhibitors; whereas glycerol, Zn2+, Mg2+, Ca2+, Fe2+ and Fe3+ could enhance the activity of PGM, and the Km and Vmax values were 11.62 mmol/L and 416.67 U/mL, respectively. At the same time, qRT-PCR was used to test the changes of mRNA transcription level of PGM gene encoding under two fermentation conditions: basic medium and optimized medium. The relative quantitative results of PGM target genes resulting in 2.60-fold enhancement than the control group.

18.
Circ Res ; 127(10): 1253-1260, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-32842915

RESUMO

RATIONALE: A sedentary lifestyle is associated with increased risk for cardiovascular disease (CVD). Smartwatches enable accurate daily activity monitoring for physical activity measurement and intervention. Few studies, however, have examined physical activity measures from smartwatches in relation to traditional risk factors associated with future risk for CVD. OBJECTIVE: To investigate the association of habitual physical activity measured by smartwatch with predicted CVD risk in adults. METHODS AND RESULTS: We enrolled consenting FHS (Framingham Heart Study) participants in an ongoing eFHS (electronic Framingham Heart Study) at the time of their FHS research center examination. We provided participants with a smartwatch (Apple Watch Series 0) and instructed them to wear it daily, which measured their habitual physical activity as the average daily step count. We estimated the 10-year predicted risk of CVD using the American College of Cardiology/American Heart Association 2013 pooled cohort risk equation. We estimated the association between physical activity and predicted risk of CVD using linear mixed effects models adjusting for age, sex, wear time, and familial structure. Our study included 903 eFHS participants (mean age 53±9 years, 61% women, 9% non-White) who wore the smartwatch ≥5 hours per day for ≥30 days. Median daily step count was similar among men (7202 with interquartile range 3619) and women (7260 with interquartile range 3068; P=0.52). Average 10-year predicted CVD risk was 4.5% (interquartile range, 6.1%) for men and 1.2% (interquartile range, 2.2%) for women (P=1.3×10-26). Every 1000 steps higher habitual physical activity was associated with 0.18% lower predicted CVD risk (P=3.2×10-4). The association was attenuated but remained significant after further adjustment for body mass index (P=0.01). CONCLUSIONS: In this community-based sample of adults, higher daily physical activity measured by a study smartwatch was associated with lower predicted risk of CVD. Future research should examine the longitudinal association of prospectively measured daily activity and incident CVD.

19.
Nat Prod Res ; : 1-9, 2020 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-32686492

RESUMO

A novel water-soluble polysaccharide, named ICP-1, was isolated and purified by Sephadex G-200 after extracting the crude polysaccharide (ICP) from Imperial Chrysanthemum. The structural characterization of ICP-1 was determined by physical and chemical methods, FT-IR, NMR, SEM, HPGPC, periodate oxidation, Smith degradation, methylation and Congo red test. Then, acid production and proliferation of lactic acid bacteria and the tolerance tests of simulated gastrointestinal fluid were measured to investigate the activity of prebiotic potential. The results showed that ICP-1 was an acidic hetero-polysaccharide with an average molecular weight of 2.98 × 103 kDa and a specific optical rotation of +155°. The glycosyl residues of ICP-1 were composed of (1→), (1→4) and (1→6) glucose, (1→5) arabinose, (1→4) galacturonic acid and (1→3,6) mannose. Besides, ICP-1 can speed up the acid production of lactic acid bacteria and promote the growth and proliferation of lactic acid bacteria effectively.

20.
Am J Hum Genet ; 107(2): 330-341, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32619401

RESUMO

Sperm malformation is a direct factor for male infertility. Multiple morphological abnormalities of the flagella (MMAF), a severe form of asthenoteratozoospermia, are characterized by immotile spermatozoa with malformed and/or absent flagella in the ejaculate. Previous studies indicated genetic heterogeneity in MMAF. To further define genetic factors underlying MMAF, we performed whole-exome sequencing in a cohort of 90 Chinese MMAF-affected men. Two cases (2.2%) were identified as carrying bi-allelic missense DNAH8 variants, variants which were either absent or rare in the control human population and were predicted to be deleterious by multiple bioinformatic tools. Re-analysis of exome data from a second cohort of 167 MMAF-affected men from France, Iran, and North Africa permitted the identification of an additional male carrying a DNAH8 homozygous frameshift variant. DNAH8 encodes a dynein axonemal heavy-chain component that is expressed preferentially in the testis. Hematoxylin-eosin staining and electron microscopy analyses of the spermatozoa from men harboring bi-allelic DNAH8 variants showed a highly aberrant morphology and ultrastructure of the sperm flagella. Immunofluorescence assays performed on the spermatozoa from men harboring bi-allelic DNAH8 variants revealed the absent or markedly reduced staining of DNAH8 and its associated protein DNAH17. Dnah8-knockout male mice also presented typical MMAF phenotypes and sterility. Interestingly, intracytoplasmic sperm injections using the spermatozoa from Dnah8-knockout male mice resulted in good pregnancy outcomes. Collectively, our experimental observations from humans and mice demonstrate that DNAH8 is essential for sperm flagellar formation and that bi-allelic deleterious DNAH8 variants lead to male infertility with MMAF.


Assuntos
Anormalidades Múltiplas/genética , Dineínas do Axonema/genética , Flagelos/genética , Variação Genética/genética , Infertilidade Masculina/genética , Cauda do Espermatozoide/patologia , Alelos , Animais , Estudos de Coortes , Exoma/genética , Feminino , Homozigoto , Humanos , Masculino , Camundongos , Camundongos Knockout , Espermatozoides/anormalidades , Testículo/anormalidades , Sequenciamento Completo do Exoma/métodos
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