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1.
Front Immunol ; 12: 635018, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33936047

RESUMO

Objective: Bacterial and viral infectious triggers are linked to spondyloarthritis (SpA) including psoriatic arthritis (PsA) development, likely via dendritic cell activation. We investigated spinal entheseal plasmacytoid dendritic cells (pDCs) toll-like receptor (TLR)-7 and 9 activation and therapeutic modulation, including JAK inhibition. We also investigated if COVID-19 infection, a potent TLR-7 stimulator triggered PsA flares. Methods: Normal entheseal pDCs were characterized and stimulated with imiquimod and CpG oligodeoxynucleotides (ODN) to evaluate TNF and IFNα production. NanoString gene expression assay of total pDCs RNA was performed pre- and post- ODN stimulation. Pharmacological inhibition of induced IFNα protein was performed with Tofacitinib and PDE4 inhibition. The impact of SARS-CoV2 viral infection on PsA flares was evaluated. Results: CD45+HLA-DR+CD123+CD303+CD11c- entheseal pDCs were more numerous than blood pDCs (1.9 ± 0.8% vs 0.2 ± 0.07% of CD45+ cells, p=0.008) and showed inducible IFNα and TNF protein following ODN/imiquimod stimulation and were the sole entheseal IFNα producers. NanoString data identified 11 significantly upregulated differentially expressed genes (DEGs) including TNF in stimulated pDCs. Canonical pathway analysis revealed activation of dendritic cell maturation, NF-κB signaling, toll-like receptor signaling and JAK/STAT signaling pathways following ODN stimulation. Both tofacitinib and PDE4i strongly attenuated ODN induced IFNα. DAPSA scores elevations occurred in 18 PsA cases with SARS-CoV2 infection (9.7 ± 4 pre-infection and 35.3 ± 7.5 during infection). Conclusion: Entheseal pDCs link microbes to TNF/IFNα production. SARS-CoV-2 infection is associated with PsA Flares and JAK inhibition suppressed activated entheseal plasmacytoid dendritic Type-1 interferon responses as pointers towards a novel mechanism of PsA and SpA-related arthropathy.

2.
Spectrochim Acta A Mol Biomol Spectrosc ; 258: 119862, 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33957448

RESUMO

In this work, we use density functional theory and time dependent density functional theory to explore the ESIPT and TICT process of 6-(1H-Benzoimidazol-2-yl)-2,3-dimethoxy-phenol (BIDOP) in cyclohexane (CHX) and tetrahydrofuran (THF) solvent, respectively. It reveals that ESIPT process of BIDOP can occur in both CHX and THF solvent at the first excited state with similar reaction barrier. Remarkably, compared to barrierless from keto (K*) to TICT state of BIDOP in THF solvent, the reaction barrier between K* and TICT state is up to 20.28 kcal/mol for in CHX that TICT process is inhibited in CHX solvent. The absence of nonradiative decay TICT state of BIDOP in CHX solvent induces higher fluorescence in CHX compared to in THF solvent. These findings indicate that CHX solvent can effectively enhance fluorescence of BIDOP. Our study highlights a convenient approach for enhancing fluorescence and is significant for photophysics and photobiology field.

3.
Life (Basel) ; 11(3)2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33809095

RESUMO

De novo variants (DNVs) are critical to the treatment of neurodevelopmental disorders (NDDs). However, effectively identifying candidate genes in small cohorts is challenging in most NDDs because of high genetic heterogeneity. We hypothesised that integrating DNVs from multiple NDDs with genetic similarity can significantly increase the possibility of prioritising the candidate gene. We catalogued 66,186 coding DNVs in 50,028 individuals with nine types of NDDs in cohorts with sizes spanning from 118 to 31,260 from Gene4Denovo database to validate this hypothesis. Interestingly, we found that integrated DNVs can effectively increase the number of prioritised candidate genes for each disorder. We identified 654 candidate genes including 481 shared candidate genes carrying putative functional variants in at least two disorders. Notably, 13.51% (65/481) of shared candidate genes were prioritised only via integrated analysis including 44.62% (29/65) genes validated in recent large cohort studies. Moreover, we estimated that more novel candidate genes will be prioritised with the increase in cohort size, in particular for some disorders with high putative functional DNVs per individual. In conclusion, integrated DNVs may increase the power of prioritising candidate genes, which is important for NDDs with small cohort size.

4.
J Nat Prod ; 2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33890470

RESUMO

The protein chromosome region maintenance 1 (CRM1) is an important nuclear export factor and drug target in diseases such as cancer and viral infections. Several plant-derived CRM1 inhibitors including plumbagin and oridonin possess potent antitumor activities. However, their modes of CRM1 inhibition remain unclear. Here, a multimutant CRM1 was engineered to enable crystallization of these two small molecules in its NES groove. Plumbagin and oridonin share the same three conjugation sites in CRM1. In solution, these two inhibitors targeted more CRM1 sites and inhibited its activity through promoting its aggregation, in addition to directly targeting the NES groove. While the plumbagin-bound NES groove resembles the NES-bound groove state, the oridonin complex reveals for the first time a more open NES groove. The observed greater NES groove dynamics may improve cargo loading through a "capture-and-tighten" mechanism. This work thus provides new insights on the mechanism of CRM1 inhibition by two natural products and a structural basis for further development of these or other CRM1 inhibitors.

5.
Chin Med J (Engl) ; 2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33883412

RESUMO

BACKGROUND: Since 2019, a novel coronavirus named 2019 novel coronavirus (2019-nCoV) has emerged worldwide. Apart from fever and respiratory complications, acute kidney injury has been observed in a few patients with coronavirus disease 2019. Furthermore, according to recent findings, the virus has been detected in urine. Angiotensin-converting enzyme II (ACE2) has been proposed to serve as the receptor for the entry of 2019-nCoV, which is the same as that for the severe acute respiratory syndrome. This study aimed to investigate the possible cause of kidney damage and the potential route of 2019-nCoV infection in the urinary system. METHODS: We used both published kidney and bladder cell atlas data and new independent kidney single-cell RNA sequencing data generated in-house to evaluate ACE2 gene expression in all cell types in healthy kidneys and bladders. The Pearson correlation coefficients between ACE2 and all other genes were first generated. Then, genes with r values larger than 0.1 and P values smaller than 0.01 were deemed significant co-expression genes with ACE2. RESULTS: Our results showed the enriched expression of ACE2 in all subtypes of proximal tubule (PT) cells of the kidney. ACE2 expression was found in 5.12%, 5.80%, and 14.38% of the proximal convoluted tubule cells, PT cells, and proximal straight tubule cells, respectively, in three published kidney cell atlas datasets. In addition, ACE2 expression was also confirmed in 12.05%, 6.80%, and 10.20% of cells of the proximal convoluted tubule, PT, and proximal straight tubule, respectively, in our own two healthy kidney samples. For the analysis of public data from three bladder samples, ACE2 expression was low but detectable in bladder epithelial cells. Only 0.25% and 1.28% of intermediate cells and umbrella cells, respectively, had ACE2 expression. CONCLUSION: This study has provided bioinformatics evidence of the potential route of 2019-nCoV infection in the urinary system.

6.
Zhen Ci Yan Jiu ; 46(3): 194-200, 2021 Mar 25.
Artigo em Chinês | MEDLINE | ID: mdl-33798291

RESUMO

OBJECTIVE: To explore the effect of moxibustion at "Zusanli"(ST36) and "Shenshu"(BL23) on synovitis, and expressions of miR-155, Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), interlukine(IL-1) receptor-associated kinase (IRAK1), tumor necrosis factor receptor-associated factor 6 (TRAF6), nuclear factor κB (NF-κB), IL-1ß, tumor necrosis factor receptor (TNF)-α and IL-6 mRNA and protein of synovial membrane in rheumatoid arthritis (RA) rats, so as to explore its mechanism underlying improvement of RA. METHODS: A total of 48 male Wistar rats were randomly divided into normal control, model, moxibustion and antagonist groups (n=12 rats in each group). The RA model was replicated by placing the rats in a wind, cold and wet environment and injection of Freund's complete adjuvant (CFA, 0.5 mL) into the right hindlimb foot plantar. Moxibustion was applied to bilateral ST36 and BL23 for 30 min, once daily for 21 consecutive days. Rats of the antagonist group was treated by injection of TLR4 antagonist (TAK-242, 1 mg/mL, 0.1 mg/kg) via tail vein, once per day for consecutive 21 d. The joint swelling degree (JSD) and arthritis index (AI, red swelling scale) were determined, and the expression levels of various indicators of miR-155, and TLR4, myeloid MyD88, IRAK1, TRAF6, NF-κB, IL-1ß, TNF-α and IL-6 mRNA and protein were assayed by quantitative real time-PCR and Western blot, separately. RESULTS: Compared with the normal control group, the JSD and AI, and the expression levels of synovial miR-155, TLR4, MyD88, IRAK1, TRAF6, NF-κB, IL-1ß, TNF-α and IL-6 mRNA and protein were significantly increased in the model group (P<0.01). Compared with the model group, the increased levels of JSD and AI, and the expression levels of synovial miR-155, TLR4, MyD88, IRAK1, TRAF6, NF-κB, IL-1ß, TNF-α and IL-6 mRNA and protein were notably down-regulated in both moxibustion and antagonist groups (P<0.01). The effects of moxibustion were evidently superior to the antagonist in down-regulating the abovementioned indexes (P<0.01), except TLR4 mRNA and protein. CONCLUSION: Moxibustion at ST36 and BL23 can reduce the synovitis of RA rats, which is related to its effects in suppressing the expressions of miR-155, TLR4, MyD88, IRAK1, TRAF6, NF-κB, IL-1ß, TNF-α and IL-6 mRNA and protein (i.e., inhibition of miR-155/TLR4/NF-κB signaling).


Assuntos
Artrite Reumatoide , MicroRNAs , Moxibustão , Sinovite , Animais , Artrite Reumatoide/genética , Artrite Reumatoide/terapia , Masculino , MicroRNAs/genética , NF-kappa B/genética , Ratos , Ratos Wistar , Receptor 4 Toll-Like/genética
7.
Int J Nanomedicine ; 16: 2833-2847, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33883894

RESUMO

Introduction: Peptides can be rationally designed as non-covalent inhibitors for molecularly targeted therapy. However, it remains challenging to efficiently deliver the peptides into the targeted cells, which often severely affects their therapeutic efficiency. Methods: Herein, we created a novel non-covalent peptide inhibitor against nuclear export factor CRM1 by a structure-guided drug design method and targetedly delivered the peptide into cancer cells by a nanoparticle-mediated gene expression system for use as a cancer therapy. Results: The nuclear export signal (NES)-optimized CRM1 peptide inhibitor colocalized with CRM1 to the nuclear envelope and inhibited nuclear export in cancer cell lines in vitro. The crystal structures of the inhibitors complexed with CRM1 were solved. In contrast to the covalent inhibitors, the peptides were similarly effective against cells harboring the CRM1 C528S mutation. Moreover, a plasmid encoding the peptides was delivered by a iRGD-modified nanoparticle to efficiently target and transfect the cancer cells in vivo after intravenous administration. The peptides could be selectively expressed in the tumor, resulting in the efficient inhibition of subcutaneous melanoma xenografts without obvious systemic toxicity. Discussion: This work provides an effective strategy to design peptide-based molecularly targeted therapeutics, which could lead to the development of future targeted therapy.


Assuntos
Espaço Intracelular/metabolismo , Carioferinas/antagonistas & inibidores , Melanoma Experimental/tratamento farmacológico , Nanopartículas/química , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Células A549 , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Sequência de Aminoácidos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Técnicas de Transferência de Genes , Proteínas de Fluorescência Verde/metabolismo , Células HeLa , Humanos , Carioferinas/química , Carioferinas/metabolismo , Melanoma Experimental/patologia , Proteínas Mutantes/metabolismo , Mutação/genética , Nanopartículas/ultraestrutura , Sinais de Exportação Nuclear , Peptídeos/química , Ligação Proteica/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/química , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteínas não Estruturais Virais/química
8.
J Plant Physiol ; 261: 153418, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33887526

RESUMO

Plant electrical signals, an early event in the plant-stimulus interaction, rapidly transmit information generated by the stimulus to other organs, and even the whole plant, to promote the corresponding response and trigger a regulatory cascade. In recent years, many promising state-of-the-art technologies applicable to study plant electrophysiology have emerged. Research focused on expression of genes associated with electrical signals has also proliferated. We propose that it is appropriate for plant electrical signals to be considered in the form of a "plant electrophysiological phenotype". This review synthesizes research on plant electrical signals from a novel, interdisciplinary perspective, which is needed to improve the efficient aggregation and use of plant electrical signal data and to expedite interpretation of plant electrical signals.

9.
Chin Med J (Engl) ; 134(8): 935-943, 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33879756

RESUMO

BACKGROUND: Since 2019, a novel coronavirus named 2019 novel coronavirus (2019-nCoV) has emerged worldwide. Apart from fever and respiratory complications, acute kidney injury has been observed in a few patients with coronavirus disease 2019. Furthermore, according to recent findings, the virus has been detected in urine. Angiotensin-converting enzyme II (ACE2) has been proposed to serve as the receptor for the entry of 2019-nCoV, which is the same as that for the severe acute respiratory syndrome. This study aimed to investigate the possible cause of kidney damage and the potential route of 2019-nCoV infection in the urinary system. METHODS: We used both published kidney and bladder cell atlas data and new independent kidney single-cell RNA sequencing data generated in-house to evaluate ACE2 gene expression in all cell types in healthy kidneys and bladders. The Pearson correlation coefficients between ACE2 and all other genes were first generated. Then, genes with r values larger than 0.1 and P values smaller than 0.01 were deemed significant co-expression genes with ACE2. RESULTS: Our results showed the enriched expression of ACE2 in all subtypes of proximal tubule (PT) cells of the kidney. ACE2 expression was found in 5.12%, 5.80%, and 14.38% of the proximal convoluted tubule cells, PT cells, and proximal straight tubule cells, respectively, in three published kidney cell atlas datasets. In addition, ACE2 expression was also confirmed in 12.05%, 6.80%, and 10.20% of cells of the proximal convoluted tubule, PT, and proximal straight tubule, respectively, in our own two healthy kidney samples. For the analysis of public data from three bladder samples, ACE2 expression was low but detectable in bladder epithelial cells. Only 0.25% and 1.28% of intermediate cells and umbrella cells, respectively, had ACE2 expression. CONCLUSION: This study has provided bioinformatics evidence of the potential route of 2019-nCoV infection in the urinary system.


Assuntos
/metabolismo , Rim/metabolismo , Análise de Célula Única , Bexiga Urinária/metabolismo , Expressão Gênica , Humanos , Análise de Sequência de RNA
10.
Front Immunol ; 12: 610019, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33679746

RESUMO

Objectives: We theorized that myelodysplastic syndrome (MDS) with somatic mutations and karyotype abnormalities are associated with autoinflammation, and that the presence of autoinflammatory disease affected prognosis in MDS. Methods: One hundred thirty-four MDS patients were assessed for the prevalence of autoinflammatory complications and its link with karyotypes and somatic mutation status. Autoinflammatory complications were described either as well-defined autoinflammatory diseases (AD) or undifferentiated "autoinflammatory disease" (UAD) (defined as CRP over 10.0 mg/L on five consecutive occasions, taken at separate times and not explained by infection). Several patient characteristics including demographic, clinical, laboratory, cytogenetics charts, and outcomes, were compared between different groups. Results: Sixty-two (46.3%) patients had an autoinflammatory complication manifesting as arthralgia (43.5% vs. 23.6%, p = 0.0146), arthritis (30.6% vs. 15.3%, p = 0.0340), skin rash (27.4% vs. 12.5%, p = 0.0301), pleuritis (14.5% vs. 4.2%, p = 0.0371) and unexplained fever (27.4% vs. 0%, p < 0.0001). AD were found in 7.4% of MDS patients (with polymyalgia rheumatic being the most frequently one). Classical autoimmune diseases were found only in 4 MDS patients (3.0%). Transcription factor pathway mutations (RUNX1, BCOR, WTI, TP53) (OR 2.20 [95%CI 1.02-4.75], p = 0.0451) and abnormal karyotypes (OR 2.76 [95%CI 1.22-6.26], p = 0.0153) were associated with autoinflammatory complications. Acute leukaemic transformation was more frequent in MDS patients with autoinflammatory features than those without (27.4% vs. 9.7%, p = 0.0080). Conclusions: Autoinflammatory complications are common in MDS. Somatic mutations of transcription factor pathways and abnormal karyotypes are associated with greater risk of autoinflammatory complications, which are themselves linked to malignant transformation and a worse prognosis.

11.
BMC Genomics ; 22(1): 167, 2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33750312

RESUMO

BACKGROUND: Suaeda glauca (S. glauca) is a halophyte widely distributed in saline and sandy beaches, with strong saline-alkali tolerance. It is also admired as a landscape plant with high development prospects and scientific research value. The S. glauca chloroplast (cp) genome has recently been reported; however, the mitochondria (mt) genome is still unexplored. RESULTS: The mt genome of S. glauca were assembled based on the reads from Pacbio and Illumina sequencing platforms. The circular mt genome of S. glauca has a length of 474,330 bp. The base composition of the S. glauca mt genome showed A (28.00%), T (27.93%), C (21.62%), and G (22.45%). S. glauca mt genome contains 61 genes, including 27 protein-coding genes, 29 tRNA genes, and 5 rRNA genes. The sequence repeats, RNA editing, and gene migration from cp to mt were observed in S. glauca mt genome. Phylogenetic analysis based on the mt genomes of S. glauca and other 28 taxa reflects an exact evolutionary and taxonomic status of S. glauca. Furthermore, the investigation on mt genome characteristics, including genome size, GC contents, genome organization, and gene repeats of S. gulaca genome, was investigated compared to other land plants, indicating the variation of the mt genome in plants. However, the subsequently Ka/Ks analysis revealed that most of the protein-coding genes in mt genome had undergone negative selections, reflecting the importance of those genes in the mt genomes. CONCLUSIONS: In this study, we reported the mt genome assembly and annotation of a halophytic model plant S. glauca. The subsequent analysis provided us a comprehensive understanding of the S. glauca mt genome, which might facilitate the research on the salt-tolerant plant species.

12.
Nat Metab ; 3(3): 352-365, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33723463

RESUMO

It has been suggested that new beta cells can arise from specific populations of adult pancreatic progenitors or facultative stem cells. However, their existence remains controversial, and the conditions under which they would contribute to new beta-cell formation are not clear. Here, we use a suite of mouse models enabling dual-recombinase-mediated genetic tracing to simultaneously fate map insulin-positive and insulin-negative cells in the adult pancreas. We find that the insulin-negative cells, of both endocrine and exocrine origin, do not generate new beta cells in the adult pancreas during homeostasis, pregnancy or injury, including partial pancreatectomy, pancreatic duct ligation or beta-cell ablation with streptozotocin. However, non-beta cells can give rise to insulin-positive cells after extreme genetic ablation of beta cells, consistent with transdifferentiation. Together, our data indicate that pancreatic endocrine and exocrine progenitor cells do not contribute to new beta-cell formation in the adult mouse pancreas under physiological conditions.


Assuntos
Diferenciação Celular , Células Secretoras de Insulina/citologia , Pâncreas/citologia , Envelhecimento , Animais , Proliferação de Células , Homeostase , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Camundongos
13.
Oncogene ; 40(17): 3060-3071, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33782545

RESUMO

Recombinant adeno-associated viruses (rAAVs) are well-established vectors for delivering therapeutic genes. However, previous reports have suggested that wild-type AAV is linked to hepatocellular carcinoma, raising concern with the safety of rAAVs. In addition, a recent long-term follow-up study in canines, which received rAAVs for factor VIII gene therapy, demonstrated vector integration into the genome of liver cells, reviving the uncertainty between AAV and cancer. To further explore this relationship, we performed large-scale molecular epidemiology of AAV in resected tumor samples and non-lesion tissues collected from 413 patients, reflecting nine carcinoma types: breast carcinoma, rectal cancer, pancreas carcinoma, brain tumor, hepatoid adenocarcinoma, hepatocellular carcinoma, gastric carcinoma, lung squamous, and adenocarcinoma. We found that over 80% of patients were AAV-positive among all nine types of carcinoma examined. Importantly, the AAV sequences detected in patient-matched tumor and adjacent non-lesion tissues showed no significant difference in incidence, abundance, and variation. In addition, no specific AAV sequences predominated in tumor samples. Our data shows that AAV genomes are equally abundant in tumors and adjacent normal tissues, but lack clonality. The finding critically adds to the epidemiological profile of AAV in humans, and provides insights that may assist rAAV-based clinical studies and gene therapy strategies.

15.
J Integr Med ; 19(2): 111-119, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33589406

RESUMO

BACKGROUND: Shenyankangfu Tablet (SYKFT) is a Chinese patent medicine that has been used widely to decrease proteinuria and the progression of chronic kidney disease. OBJECTIVE: This trial compared the efficacy and safety of SYKFT, for the control of proteinuria in primary glomerulonephritis patients, against the standard drug, losartan potassium. DESIGN, SETTING, PARTICIPANTS AND INTERVENTION: This was a multicenter, double-blind, randomized, controlled clinical trial. Primary glomerulonephritis patients, aged 18-70 years, with blood pressure ≤ 140/90 mmHg, estimated glomerular filtration rate (eGFR) ≥ 45 mL/min per 1.73 m2, and 24-hour proteinuria level of 0.5-3.0 g, were recruited in 41 hospitals across 19 provinces in China and were randomly divided into five groups: SYKFT, losartan potassium 50 mg or 100 mg, SYKFT plus losartan potassium 50 mg or 100 mg. MAIN OUTCOME MEASURES: The primary outcome was change in the 24-hour proteinuria level, after 48 weeks of treatment. RESULTS: A total of 735 participants were enrolled. The percent decline of urine protein quantification in the SYKFT group after 48 weeks was 8.78% ± 2.56% (P = 0.006) more than that in the losartan 50 mg group, which was 0.51% ± 2.54% (P = 1.000) less than that in the losartan 100 mg group. Compared with the losartan potassium 50 mg group, the SYKFT plus losartan potassium 50 mg group had a 13.39% ± 2.49% (P < 0.001) greater reduction in urine protein level. Compared with the losartan potassium 100 mg group, the SYKFT plus losartan potassium 100 mg group had a 9.77% ± 2.52% (P = 0.001) greater reduction in urine protein. With a superiority threshold of 15%, neither was statistically significant. eGFR, serum creatinine and serum albumin from the baseline did not change statistically significant. The average change in TCM syndrome score between the patients who took SYKFT (-3.00 [-6.00, -2.00]) and who did not take SYKFT (-2.00 [-5.00, 0]) was statistically significant (P = 0.003). No obvious adverse reactions were observed in any group. CONCLUSION: SYKFT decreased the proteinuria and improved the TCM syndrome scores of primary glomerulonephritis patients, with no change in the rate of decrease in the eGFR. SYKFT plus losartan potassium therapy decreased proteinuria more than losartan potassium therapy alone. TRIAL REGISTRATION NUMBER: NCT02063100 on ClinicalTrials.gov.

16.
Andrologia ; 53(3): e13980, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33528066

RESUMO

Transducin (ß)-like 1 X-linked receptor 1 (TBL1XR1) is an evolutionarily conserved protein related to spermatozoa. To clarify its role and mechanism of action in spermatozoa, qRT-PCR was used to analyse the expression of TBL1XR1 in human spermatozoa and mouse testes. The mice were established as an animal model by injecting the mice testes with small interfering RNA against TBL1XR1 or control siRNA. Our results indicated that deficiency of TBL1XR1 in mice reduced the motility of spermatozoa and disrupted the histone-to-protamine transition. We also found the decreased expression of TBL1XR1 in the spermatozoa of human patients with asthenozoospermia (AZ) compared with that in the spermatozoa of healthy males. Moreover, we carried out chromatin immunoprecipitation analyses and found that genes downstream of TBL1XR1 were related to sperm motility. Thus, TBL1XR1 might be related to sperm motility and might function through its downstream genes. Our data highlight the role of TBL1XR1 involved in spermatozoa and provide new molecular insights into the intricate systems required for male fertility.

17.
Clin Cancer Res ; 27(6): 1734-1743, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33414138

RESUMO

PURPOSE: Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare but lethal subtype of RCC. Little is known about the genomic profile of FH-deficient RCC, and the therapeutic options for advanced disease are limited. To this end, we performed a comprehensive genomics study to characterize the genomic and epigenomic features of FH-deficient RCC. EXPERIMENTAL DESIGN: Integrated genomic, epigenomic, and molecular analyses were performed on 25 untreated primary FH-deficient RCCs. Complete clinicopathologic and follow-up data of these patients were recorded. RESULTS: We identified that FH-deficient RCC manifested low somatic mutation burden (median 0.58 mutations per megabase), but with frequent somatic copy-number alterations. The majority of FH-deficient RCCs were characterized by a CpG sites island methylator phenotype, displaying concerted hypermethylation at numerous CpG sites in genes of transcription factors, tumor suppressors, and tumor hallmark pathways. However, a few cases (20%) with low metastatic potential showed relatively low DNA methylation levels, indicating the heterogeneity of methylation pattern in FH-deficient RCC. Moreover, FH-deficient RCC is potentially highly immunogenic, characterized by increased tumor T-cell infiltration but high expression of immune checkpoint molecules in tumors. Clinical data further demonstrated that patients receiving immune checkpoint blockade-based treatment achieved improved progression-free survival over those treated with antiangiogenic monotherapy (median, 13.3 vs. 5.1 months; P = 0.03). CONCLUSIONS: These results reveal the genomic features and provide new insight into potential therapeutic strategies for FH-deficient RCC.

18.
Nat Commun ; 12(1): 674, 2021 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-33514698

RESUMO

Transcriptionally mature and immature ß-cells co-exist within the adult islet. How such diversity contributes to insulin release remains poorly understood. Here we show that subtle differences in ß-cell maturity, defined using PDX1 and MAFA expression, contribute to islet operation. Functional mapping of rodent and human islets containing proportionally more PDX1HIGH and MAFAHIGH ß-cells reveals defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, the presence of increased numbers of PDX1HIGH and MAFAHIGH ß-cells leads to dysregulation of gene pathways involved in metabolic processes. Using a chemogenetic disruption strategy, differences in PDX1 and MAFA expression are shown to depend on islet Ca2+ signaling patterns. During metabolic stress, islet function can be restored by redressing the balance between PDX1 and MAFA levels across the ß-cell population. Thus, preserving heterogeneity in PDX1 and MAFA expression, and more widely in ß-cell maturity, might be important for the maintenance of islet function.


Assuntos
Secreção de Insulina/fisiologia , Células Secretoras de Insulina/metabolismo , Animais , Cálcio/metabolismo , Células Cultivadas , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Feminino , Técnicas de Introdução de Genes , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Fatores de Transcrição Maf Maior/genética , Fatores de Transcrição Maf Maior/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Modelos Animais , Cultura Primária de Células , Transativadores/genética , Transativadores/metabolismo
19.
Spectrochim Acta A Mol Biomol Spectrosc ; 249: 119327, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33360566

RESUMO

The spectroscopic properties of 3-(benzo[d]-thiazol-2-yl)-2-hydroxy-5-methoxy benzaldehyde molecule were investigated [J. Phys. Chem. A 2019, 123, 10246-10253]. The result shows that the excited-state intramolecular proton transfer (ESIPT) was driven toward the N center over the O center. In this research, the density functional theory and time-dependent density functional theory method were used to calculate molecule structures. Through our calculations, the ESIPT process toward N atom is proved to be feasible. Moreover, the emission peak we obtained of ESIPT process from the OH proton to aldehyde O atom is located at 564 nm, which is attributed to 500 nm in previous research. From the potential energy curves, the 0.35 kcal/mol energy barrier indicates the ESIPT process could occur when excited to S1 state from the OH proton to aldehyde O atom. In addition, the frontier molecular orbitals analysis and IR spectrum were also calculated. Finally, we revise the direction of BTHMB molecule, the two directions of ESIPT are both feasible when excited to S1 state.

20.
Nat Commun ; 11(1): 6121, 2020 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-33257686

RESUMO

Modified Vaccinia Ankara (MVA) is a highly attenuated poxvirus vector that is widely used to develop vaccines for infectious diseases and cancer. We demonstrate the construction of a vaccine platform based on a unique three-plasmid system to efficiently generate recombinant MVA vectors from chemically synthesized DNA. In response to the ongoing global pandemic caused by SARS coronavirus-2 (SARS-CoV-2), we use this vaccine platform to rapidly produce fully synthetic MVA (sMVA) vectors co-expressing SARS-CoV-2 spike and nucleocapsid antigens, two immunodominant antigens implicated in protective immunity. We show that mice immunized with these sMVA vectors develop robust SARS-CoV-2 antigen-specific humoral and cellular immune responses, including potent neutralizing antibodies. These results demonstrate the potential of a vaccine platform based on synthetic DNA to efficiently generate recombinant MVA vectors and to rapidly develop a multi-antigenic poxvirus-based SARS-CoV-2 vaccine candidate.

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