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1.
BMC Plant Biol ; 21(1): 207, 2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-33941091

RESUMO

BACKGROUND: Artificial synthesis of octoploid rapeseed double haploid (DH) induction lines Y3380 and Y3560 was made possible by interspecific hybridization and genome doubling techniques. Production of pure lines by DH induction provides a new way to achieve homozygosity earlier in B.napus. Previously, the mechanism of induction, and whether the induction has obvious maternal genotypic differences or not, are not known so far. RESULTS: In this study, different karyogene and cytoplasmic genotype of B.napus were pollinated with the previously reported DH inducers e.g. Y3380 and Y3560. Our study presents a fine comparison of different cytoplasmic genotypes hybridization to unravel the mechanism of DH induction. Ploidy identification, fertility and SSR marker analysis of induced F1 generation, revealed that ploidy and phenotype of the induced F1 plants were consistent with that type of maternal, rather than paternal parent. The SNP chip analysis revealed that induction efficiency of DH inducers were affected by the karyogene when the maternal cytoplasmic genotypes were the same. However, DH induction efficiency was also affected by cytoplasmic genotype when the karyogenes were same, and the offspring of the ogura cytoplasm showed high frequency inducer gene hybridization or low-frequency infiltration. CONCLUSION: The induction effect is influenced by the interaction between maternal karyogene and cytoplasmic genotype, and the results from the partial hybridization of progeny chromosomes indicate that the induction process may be attributed to the selective elimination of paternal chromosome. This study provides a basis for exploring the mechanism of DH inducer in B.napus, and provides new insights for utilization of inducers in molecular breeding.

2.
Front Immunol ; 12: 645988, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33936064

RESUMO

The molecular mechanisms underlying renal damage of IgA nephropathy (IgAN) remain incompletely defined. Here, single-cell RNA sequencing (scRNA-seq) was applied to kidney biopsies from IgAN and control subjects to define the transcriptomic landscape at single-cell resolution. We presented a comprehensive scRNA-seq analysis of human renal biopsies from IgAN. We showed for the first time that IgAN mesangial cells displayed increased expression of several novel genes including MALAT1, GADD45B, SOX4, and EDIL3, which were related to cell proliferation and matrix accumulation. The overexpressed genes in tubule cells of IgAN were mainly enriched in inflammatory pathways including TNF signaling, IL-17 signaling, and NOD-like receptor signaling. Furthermore, we compared the results of 4 IgAN patients with the published scRNA-Seq data of healthy kidney tissues of three human donors in order to further validate the findings in our study. The results also verified that the overexpressed genes in tubule cells from IgAN patients were mainly enriched in inflammatory pathways including TNF signaling, IL-17 signaling, and NOD-like receptor signaling. The receptor-ligand crosstalk analysis revealed potential interactions between mesangial cells and other cells in IgAN. IgAN patients with overt proteinuria displayed elevated genes participating in several signaling pathways compared with microproteinuria group. It needs to be mentioned that based on number of mesangial cells and other kidney cells analyzed in this study, the results of our study are preliminary and needs to be confirmed on larger number of cells from larger number of patients and controls in future studies. Therefore, these results offer new insight into pathogenesis and identify new therapeutic targets for IgAN.

3.
Environ Sci Technol ; 55(9): 5721-5730, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33797897

RESUMO

Despite the large reduction in anthropogenic activities due to the outbreak of COVID-19, air quality in China has witnessed little improvement and featured great regional disparities. Here, by combining observational data and simulations, this work aims to understand the diverse air quality response in two city clusters, Yangtze River Delta region (YRD) and Pearl River Delta region (PRD), China. Though there was a noticeable drop in primary pollutants in both the regions, differently, the maximum daily 8 h average ozone (O3) soared by 20.6-76.8% in YRD but decreased by 15.5-28.1% in PRD. In YRD, nitrogen oxide (NOx) reductions enhanced O3 accumulation and hence increased secondary aerosol formation. Such an increment in secondary organic and inorganic aerosols under stationary weather reached up to 36.4 and 10.2%, respectively, which was further intensified by regional transport. PRD was quite the opposite. The emission reductions benefited PRD air quality, while regional transport corresponded to an increase of 17.3 and 9.3% in secondary organic and inorganic aerosols, respectively. Apart from meteorology, the discrepancy in O3-VOCs-NOx relationships determined the different O3 responses, indicating that future emission control shall be regionally specific, instead of one-size-fits-all cut. Overall, the importance of regionally coordinated and balanced control strategy for multiple pollutants is highly emphasized.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Ozônio , Poluentes Atmosféricos/análise , China , Cidades , Controle de Doenças Transmissíveis , Monitoramento Ambiental , Humanos , Ozônio/análise , Estações do Ano
4.
Artigo em Inglês | MEDLINE | ID: mdl-33928751

RESUMO

AIMS: To explore the different patterns of C-peptide decline in patients with and without partial remission of newly diagnosed type 1 diabetes (T1D). MATERIALS AND METHODS: A total of 298 patients with new-onset T1D were followed up regularly at 3 months' interval to investigate the loss of C-peptide. Partial remission was determined by postprandial C-peptide ≥300 pmol/L or insulin dose-adjusted A1c ≤ 9 in the absence of C-peptide. Beta-cell function was defined as preserved, residual or failed by postprandial C-peptide of ≥200 pmol/L, 50-200 pmol/L or ≤50 pmol/L, respectively. RESULTS: Altogether, 199 out of 298 patients (125 adults) had partial remission. The pattern of C-peptide change in patients with partial remission was three-phasic, demonstrating an upward trend followed by a downward trend of fast first and then slow, while the pattern in patients without partial remission was biphasic, showing an initial fast fall and a subsequent slower decrease. The patterns remained consistent when patients were stratified by the age of onset. At 3 years, there were 71% of the patients with partial remission still had preserved or residual beta-cell function, while 89% of the patients who had no partial remission developed beta-cell function failure. In patients whose partial remission ended, the average C-peptide was still higher than duration-matched patients without partial remission. CONCLUSIONS: Patients with partial remission of T1D have a distinct three-phasic pattern of C-peptide decline, other than the widely recognized biphasic pattern. The effect of partial remission still exist​s after remission ends.

5.
Mol Med Rep ; 23(6)2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33846809

RESUMO

Preeclampsia is a pregnancy disorder that is primarily associated with maternal and neonatal or fetal morbidity and mortality. The discovery of dysregulated microRNAs (miRs) and their roles in preeclampsia has provided new insight into the mechanisms involved in pregnancy­related disorders. In the present study, quantitative PCR demonstrated that the expression levels of miR­524­5p were lower in patients with preeclampsia than those in normal pregnant women. Cell Counting Kit­8 and Transwell assays indicated that overexpression of miR­524­5p promoted the proliferation and invasion of HTR­8/SVneo cells, whereas inhibition of miR­524­5p suppressed HTR­8/SVneo cell proliferation and invasion. Furthermore, NUMB endocytic adaptor protein (NUMB), a negative regulator of the Notch signaling pathway and a target gene of miR­524­5p, limited the effects of miR­524­5p on HTR­8/SVneo cell invasion and migration. The present study demonstrated that miR­524­5p regulated the proliferation and invasion of HTR­8/SVneo cells at least partly by targeting NUMB to regulate the Notch signaling pathway.

6.
Immunol Lett ; 2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33895173

RESUMO

Ubiquitin-specific peptidases7 (USP7) participates in the regulation of various metabolic and immune disorders. However, the role of USP7 in lupus nephritis (LN) remains unknown. The current study set out to elucidate the regulatory role of USP7 in LN together with JMJD3 and NF-κB. SLE MRL/LPR mice and mouse glomerular mesangial cells SV40 MES 13 cells were employed for in vivo or vitro experiments. USP7, JMJD3 and NF-κB expression in MRL/LPR mice were detected, followed by investigation of their functions in the proliferation of mesangial cells and mesangial matrix. Subsequently, the interaction among USP7, JMJD3 and NF-κB was determined by means of ChIP and co-immunoprecipitation assay. The results indicated that USP7, JMJD3, p-NF-κB p65 were all highly-expressed in MRL/LPR mice. USP7 promoted the proliferation of mesangial cells and mesangial matrix, and stabilized the JMJD3 protein via deubiquitination in SV40 MES 13 cells. Meanwhile, silencing of JMJD3 inhibited the promotive effect of USP7 on the proliferation of mesangial cells and mesangial matrix. Furthermore, JMJD3 increased the expression of NF-κB p65 through demethylation, whereas silencing JMJD3 alleviated the proliferation of mesangial cells and mesangial matrix. Lastly, NF-κB p65 was proved to aggravate LN pathogenesis. Altogether, our findings highlighted that USP7 promoted the occurrence of LN by regulating the NF-κB p65 signaling pathway via stabilization of JMJD3.

7.
Nat Med ; 2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33888900

RESUMO

An effective vaccine is needed to end the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Here, we assess the preliminary safety, tolerability and immunogenicity data from an ongoing single-center (in Jiangsu province, China), parallel-group, double-blind phase 1 trial of the vaccine candidate BNT162b1 in 144 healthy SARS-CoV-2-naive Chinese participants. These participants are randomized 1:1:1 to receive prime and boost vaccinations of 10 µg or 30 µg BNT162b1 or placebo, given 21 d apart, with equal allocation of younger (aged 18-55 years) and older adults (aged 65-85 years) to each treatment group (ChiCTR2000034825). BNT162b1 encodes the SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD) and is one of several messenger RNA-based vaccine candidates under clinical investigation. Local reactions and systemic events were generally dose dependent, transient and mild to moderate. Fever was the only grade 3 adverse event. BNT162b1 induced robust interferon-γ T cell responses to a peptide pool including the RBD in both younger and older Chinese adults, and geometric mean neutralizing titers reached 2.1-fold (for younger participants) and 1.3-fold (for the older participants) that of a panel of COVID-19 convalescent human sera obtained at least 14 d after positive SARS-CoV-2 polymerase chain reaction test. In summary, BNT162b1 has an acceptable safety profile and produces high levels of humoral and T cell responses in an Asian population.

8.
JCI Insight ; 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33848263

RESUMO

Left ventricular hypertrophy (LVH) is a primary feature of cardiovascular complications in chronic kidney disease (CKD) patients. MiRNA-30 is an important posttranscriptional regulator of LVH, but it is unknown whether miRNA-30 participates in the process of CKD-induced LVH. In the present study, we found that CKD not only results in LVH but also suppresses miRNA-30 expression in the myocardium. Rescue of cardiomyocyte-specific miRNA-30 attenuates LVH in CKD rats without altering CKD progression. Importantly, in vivo and in vitro knockdown of miRNA-30 in cardiomyocytes leads to cardiomyocyte hypertrophy by upregulating the calcineurin signalling directly. Furthermore, CKD-related detrimental factors, such as fibroblast growth factor-23 (FGF-23), uraemic toxin, angiotensin-II (Ang-II) and transforming growth factor-ß (TGF-ß), suppress cardiac miRNA-30 expression, while miRNA-30 supplementation blunts cardiomyocyte hypertrophy induced by such factors. These results uncover a novel mechanism of CKD-induced LVH and provide a potential therapeutic target for CKD patients with LVH.

9.
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.

10.
Huan Jing Ke Xue ; 42(5): 2101-2109, 2021 May 08.
Artigo em Chinês | MEDLINE | ID: mdl-33884779

RESUMO

To explore the concentrations, characteristics, and sources of organic aerosols in winter in Beijing, atmospheric fine particulate matter (PM2.5) samples were collected from November 10, 2016 to December 10, 2016. One hundred and twenty-nine particulate organic matters (POM) were quantified by gas chromatography-mass spectrometry, accounting for approximately 9.3%±1.2% of the total concentration of organic matter. The most abundant class was sugar, among which levoglucosan alone accounted for 18% of the quantified organic matter mass. The next most abundant classes were alkanoic acids, normal alkanes, dicarboxylic acids, and polycyclic aromatic hydrocarbons. The influence of winter heating and biomass burning emissions on organic aerosols in winter in Beijing was analyzed by the characteristics of the molecular markers in the POM. Compared with those during the non-heating period, the concentrations and proportions of hopane species, which are tracers for fossil fuels, increased in the organic matters during the heating period. Moreover, the influence of coal burning emissions on the distribution of hopane species was enhanced. The species with the maximum concentration and carbon predominance index in n-alkanes also reflected the influence of enhanced fossil fuel emissions. The results of the concentration-weighted trajectory model for levoglucosan, a tracer for biomass combustion, suggested that straw burning pollution in the surrounding areas of Beijing would affect the composition of organic aerosols in Beijing via airmass transport. A molecular marker-based chemical mass balance model was used to apportion the sources of organic carbon in the winter of 2016 in Beijing, and the results were compared with those of research in 2006 to quantify the changes in the source contributions over 10 years. The contribution of motor vehicles increased significantly in 2016 compared with that in 2006, whereas the contribution of coal burning and wood burning decreased to a large extent. The contribution of cooking emissions could not be ignored. Therefore, the control of motor vehicle and cooking emissions is of great importance to reduce the problem of PM2.5 pollution in winter in Beijing.

11.
Front Immunol ; 12: 625672, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33841408

RESUMO

Background: Rapidly progressive glomerulonephritis caused by antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is typically characterized as pauci-immune glomerulonephritis. However, immune complex (IC) deposition in the glomerulus has been reported in a growing number of studies. Here, we assess the presence of glomerular immune deposits alongside renal outcome in myeloperoxidase (MPO)-ANCA associated glomerulonephritis (MPO-ANCA GN). Methods: Clinical and histopathologic characteristics of 97 patients with MPO-ANCA GN classified by renal biopsy from January 2008 to December 2019 were extracted retrospectively from electronic medical records. The extent of immune deposits in the kidney (C3, C4, C1q, IgA, IgG, IgM) at diagnosis were analyzed by immunofluorescence (IF). Patients were followed up for a median period of 15 months. The response to treatment and outcomes of renal and histological lesion changes were also assessed. Results: In our study, 41% (40/97) of patients showed positive IF (≥2+) for at least one of the six immunoglobulin or complement components tested. Patients with IC deposits showed higher levels of serum creatinine (p=0.025), lower platelet counts (p=0.009), lower serum complement C3 (sC3) (≤790 ml/L) (p=0.013) and serum IgG (p=0.018) than patients with pauci-immune (PI) deposition at diagnosis. End-stage renal disease was negatively associated with eGFR (HR 0.885, 95% CI 0.837 to 0.935, p<0.0001), platelet count (HR 0.996, 95% CI 0.992 to 1.000, p=0.046) and serum globulin (HR 0.905, 95% CI 0.854 to 0.959, p=0.001). Patients with lower sC3 levels showed a worse renal outcome than the patients with normal sC3 at diagnosis (p=0.003). Analysis of the components of the renal deposits found that patients with IgG deposits exhibited a poorer renal outcome compared to patients that were IgG negative (p=0.028). Moreover, Bowman's capsule rupture occurred less frequently in patients with IgM deposition compared with IgM negative counterparts (p=0.028). Vascular lesions and granuloma-like lesions had been seen more frequently in cases with IgA deposition than those without IgA deposition (p=0.03 and 0.015, respectively). Conclusion: In conclusion, patients with immune complex deposits in the kidney showed less platelet count, lower sC3 and sIgG levels, and higher serum creatinine levels. Patients with low sC3 at initial and with continued low sC3 during the treatment displayed a trend toward poorer kidney survival. Moreover, the IC group showed a worse renal outcome than the PI group, further enforcing the present strategy of introducing complement targeted therapies in AAV.

12.
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
13.
Ir J Med Sci ; 2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33733397

RESUMO

BACKGROUND: Determining how many female patients who underwent breast imaging meet the eligibility criteria for genetic testing for familial pancreatic cancer (FPC). METHODS: A total of 42,904 patients seen at the Newton-Wellesley Hospital between 2007 and 2009 were retrospectively reviewed. The first four categories were based on pancreatic cancer-associated syndromes: (1) hereditary breast and ovarian cancer (HBOC), (2) Lynch syndrome (LS), (3) familial atypical multiple mole melanoma (FAMMM), and (4) family history of FPC (FH-FPC). PancPRO (5) and MelaPRO (6) categories were based on risk scores from Mendelian risk prediction tool. RESULTS: Exactly 4445 of 42,904 patients were found to be in at least one of the six risk categories. About 5.7% of patients were classified as being at high risk for HBOC, 2.3% as being at high risk for LS, 0.1% as being at high risk for FAMMM, 0.1% as being at high risk for FH-FPC, 2.7% as being at high risk based on PancPRO, and 0.2% as being at high risk based on MelaPRO. CONCLUSION: About 10.4% of the female patients were classified as being at high risk for FPC. This finding emphasizes the importance of applying criteria to the general population, in order to ensure that individuals with high risk are identified early.

14.
Environ Toxicol ; 36(6): 1195-1205, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33720504

RESUMO

In this study, healthy Wuchang bream (Megalobrama amblycephala) juveniles were exposed to 0, 5, 10, 20 and 30 mg/L total ammonia nitrogen for 30 days to elucidate toxic effects and mechanisms of ammonia on growth performance involved with the regulation of growth hormone/insulin-like growth factor (GH/IGF) and hypothalamic-pituitary-thyroid (HPT) axes. Our results showed that the increasing total ammonia nitrogen concentrations caused dose-depend decreases in the weight gain and specific growth rate but increases in the food conversion ratio and mortality in juvenile bream, indicating growth inhibitory effects induced by ammonia. Concurrently, GH, IGF-1 at protein and mRNA levels were significantly decreased in ammonia exposure groups (p < .05), while serum thyroid stimulating hormone, free thyroxine, free triiodothyronine levels were significantly reduced only in fish exposed to higher concentrations of 20 and 30 mg/L ammonia (p < .05), suggesting that ammonia exposure could perturb both GH/IGF-axis and HPT-axis functions. Furthermore, transcriptional levels of extracellular regulated protein kinases 2 (erk2), phosphatidylinositol 3-kinase (pi3k), protein kinase B (akt), target of rapamycin (tom) and ribosomal protein S6 kinase-polypeptide 1(s6k1) in the dorsal muscle were significantly down-regulated in the fish exposed to ammonia (p < .05). This fact indicated that MAPK/ERK pathway and PI3K/AKT pathway should be responsible for the growth inhibition. Combining the results of spearman correlation coefficient, it should be noted that the GH/IGF axis played a more important role in regulating the growth than the HPT axis in Wuchang bream under persistent ammonia stress.


Assuntos
Amônia , Somatomedinas , Amônia/toxicidade , Animais , Regulação para Baixo , Hormônio do Crescimento , Fator de Crescimento Insulin-Like I/genética , Fosfatidilinositol 3-Quinases
15.
Biomolecules ; 11(2)2021 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-33671480

RESUMO

The resurrection plants Myrothamnus flabellifolia can survive long term severe drought and desiccation conditions and soon recover after rewatering. However, few genes related to such excellent drought tolerance and underlying molecular mechanism have been excavated. WRKY transcription factors play critical roles in biotic and abiotic stress signaling, in which WRKY70 functions as a positive regulator in biotic stress response but a negative regulator in abiotic stress signaling in Arabidopsis and some other plant species. In the present study, the functions of a dehydration-induced MfWRKY70 of M. flabellifolia participating was investigated in the model plant Arabidopsis. Our results indicated that MfWRKY70 was localized in the nucleus and could significantly increase tolerance to drought, osmotic, and salinity stresses by promoting root growth and water retention, as well as enhancing the antioxidant enzyme system and maintaining reactive oxygen species (ROS) homeostasis and membrane-lipid stability under stressful conditions. Moreover, the expression of stress-associated genes (P5CS, NCED3 and RD29A) was positively regulated in the overexpression of MfWRKY70 Arabidopsis. We proposed that MfWRKY70 may function as a positive regulator for abiotic stress responses and can be considered as a potential gene for improvement of drought and salinity tolerance in plants.

16.
Mol Ther ; 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33677093

RESUMO

Hypertrophic growth of cardiomyocytes is one of the major compensatory responses in the heart after physiological or pathological stimulation. Protein synthesis enhancement, which is mediated by the translation of messenger RNAs, is one of the main features of cardiomyocyte hypertrophy. Although the transcriptome shift caused by cardiac hypertrophy induced by different stimuli has been extensively investigated, translatome dynamics in this cellular process has been less studied. Here, we generated a nucleotide-resolution translatome as well as transcriptome data from isolated primary cardiomyocytes undergoing hypertrophy. More than 10,000 open reading frames (ORFs) were detected from the deep sequencing of ribosome-protected fragments (Ribo-seq), which orchestrated the shift of the translatome in hypertrophied cardiomyocytes. Our data suggest that rather than increase the translational rate of ribosomes, the increased efficiency of protein synthesis in cardiomyocyte hypertrophy was attributable to an increased quantity of ribosomes. In addition, more than 100 uncharacterized short ORFs (sORFs) were detected in long noncoding RNA genes from Ribo-seq with potential of micropeptide coding. In a random test of 15 candidates, the coding potential of 11 sORFs was experimentally supported. Three micropeptides were identified to regulate cardiomyocyte hypertrophy by modulating the activities of oxidative phosphorylation, the calcium signaling pathway, and the mitogen-activated protein kinase (MAPK) pathway. Our study provides a genome-wide overview of the translational controls behind cardiomyocyte hypertrophy and demonstrates an unrecognized role of micropeptides in cardiomyocyte biology.

17.
BMC Pregnancy Childbirth ; 21(1): 177, 2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33663436

RESUMO

BACKGROUND: Preeclampsia is characterized by an excessive inflammatory response. Recent studies have shown that vagus nerve stimulation (VNS) has anti-inflammatory properties in vivo. This study aims to investigate whether VNS is safe for use during pregnancy and to explore the therapeutic potential and underlying mechanisms of VNS in PE. METHODS: Pregnant Sprague-Dawley rats were randomly chosen to receive N-nitro-L-arginine methyl ester (L-NAME)-containing water (preeclampsia-like mouse model) or saline (normal pregnancy control) daily at gestational days 14.5-20.5. VNS and the α7nAChR antagonist methyllycaconitine citrate (MLA, 1 mg/kg/d) were given daily at the same time. RESULTS: VNS decreased the high systolic blood pressure and urinary protein observed in the PE rats. In addition, VNS mitigated abnormal pregnancy outcomes. Moreover, VNS alleviated the inflammatory response by decreasing the levels of inflammatory cytokines. VNS significantly increased the expression of α7nAChR and attenuated the activation of NF-κB p65 in the placenta. DISCUSSION: Our findings indicate that maternal VNS treatment is safe during pregnancy and has a protective effect in a pregnant rat model of preeclampsia induced by L-NAME.

18.
Front Immunol ; 12: 648917, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33777046

RESUMO

Background: The treatment modalities for pancreatic ductal adenocarcinoma (PDAC) are limited and unsatisfactory. Although many novel drugs targeting the tumor microenvironment, such as immune checkpoint inhibitors, have shown promising efficacy for some tumors, few of them significantly prolong the survival of patients with PDAC due to insufficient knowledge on the tumor microenvironment. Methods: A single-cell RNA sequencing (scRNA-seq) dataset and seven PDAC cohorts with complete clinical and bulk sequencing data were collected for bioinformatics analysis. The relative proportions of each cell type were estimated using the gene set variation analysis (GSVA) algorithm based on the signatures identified by scRNA-seq or previous literature. Results: A meta-analysis of 883 PDAC patients showed that neutrophils are associated with worse overall survival (OS) for PDAC, while CD8+ T cells, CD4+ T cells, and B cells are related to prolonged OS for PDAC, with marginal statistical significance. Seventeen cell categories were identified by clustering analysis based on single-cell sequencing. Among them, CD8+ T cells and NKT cells were universally exhausted by expressing exhaustion-associated molecular markers. Interestingly, signatures of CD8+ T cells and NKT cells predicted prolonged OS for PDAC only in the presence of "targets" for pyroptosis and ferroptosis induction. Moreover, a specific state of T cells with overexpression of ribosome-related proteins was associated with a good prognosis. In addition, the hematopoietic stem cell (HSC)-like signature predicted prolonged OS in PDAC. Weighted gene co-expression network analysis identified 5 hub genes whose downregulation may mediate the observed survival benefits of the HSC-like signature. Moreover, trajectory analysis revealed that myeloid cells evolutionarily consisted of 7 states, and antigen-presenting molecules and complement-associated genes were lost along the pseudotime flow. Consensus clustering based on the differentially expressed genes between two states harboring the longest pseudotime span identified two PDAC groups with prognostic differences, and more infiltrated immune cells and activated immune signatures may account for the survival benefits. Conclusion: This study systematically investigated the prognostic implications of the components of the PDAC tumor microenvironment by integrating single-cell sequencing and bulk sequencing, and future studies are expected to develop novel targeted agents for PDAC treatment.

19.
Int Urol Nephrol ; 2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33675470

RESUMO

PURPOSE: Anti-neutrophil cytoplasmic autoantibody-associated vasculitis (AAV) is predominantly a disease of the elderly, and the incidence increases with age. However, there are few data focusing on the clinical features in elderly onset AAV, especially in very elderly onset AAV in China. The aim of this study was to explore whether elderly onset AAV shows any specific clinical features and outcomes in Chinese patients. METHODS: We performed a retrospective study in Xiangya Hospital, a mixed tertiary medical center in south China. A total of 177 patients presenting with AAV were included between January 1, 2010 and December 31, 2017. Patients were divided into younger group (age < 65 years) and older group (age ≥ 65 years) which was sub-divided into elderly group (age 65-74 years) and very elderly group (age ≥ 75 years). And their medical records were analyzed by retrospective review. RESULTS: We found patients in the very elderly group had more chest and cardiovascular involvement (P = 0.033 and P = 0.017). Older AAV patients had less renal involvement and lower serum C4 level (P = 0.013 and P = 0.003). Very elderly AAV patients had lower platelet counts. Patients in the younger group had a higher level of BVAS among three groups (P < 0.05 younger group vs. very elderly group; P < 0.05 younger group vs. elderly group). There were no significant difference in the proportion of ESRD patients among the three groups (P = 0.473). Patients in the very elderly group had the poorest patient survival (P = 0.002). CONCLUSION: Older AAV patients had less renal involvement, lower serum C4 level and BVAS. The very elderly group got the most chest and cardiovascular involvement and had lower platelet counts. Older age is associated with higher mortality in AAV patients.

20.
Cell Death Dis ; 12(2): 162, 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33558466

RESUMO

Hepatocellular carcinoma (HCC) is a common high-mortality cancer, mainly due to diagnostic difficulties during its early clinical stages. In this study, we aimed to identify genes that are important for HCC diagnosis and treatment, and we investigated the underlying mechanism of prognostic differences. Differentially expressed genes (DEGs) were identified by using the limma package, and receiver operating characteristic curve analysis was performed to identify diagnostic markers for HCC. Bioinformatics and clinical specimens were used to assess epithelial cell transforming 2 (ECT2) in terms of expression, prognostic value, pathways, and immune correlations. In vitro experiments were used to investigate the underlying mechanism and function of ECT2, and the results were confirmed through in vivo experiments. The integrated analysis revealed 53 upregulated DEGs, and one candidate biomarker for diagnosis (ECT2) was detected. High expression of ECT2 was found to be an independent prognostic risk factor for HCC. ECT2 expression showed a strong correlation with tumor-associated macrophages. We found that ECT2 overexpression increased the migration and proliferation of HCC cells. It also promoted the expression of PLK1, which subsequently interacted with PTEN and interfered with its nuclear translocation, ultimately enhancing aerobic glycolysis and promoting M2 macrophage polarization. M2 macrophages suppress the functions of NK cells and T cells, and this was confirmed in the in vivo experiments. Overall, ECT2 may promote the polarization of M2 macrophages by enhancing aerobic glycolysis and suppressing the functions of immune cells. ECT2 could serve as a candidate diagnostic and prognostic biomarker for HCC.

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