Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.047
Filtrar
1.
Compr Physiol ; 11(2): 1731-1757, 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-33792901

RESUMEN

The study of microbes has rapidly expanded in recent years due to a surge in our understanding that humans host a plethora of commensal microbes, which reside in their bodies and depending upon their composition, contribute to either normal physiology or pathophysiology. This article provides a general foundation for learning about host-commensal microbial interactions as an emerging area of research. The article is divided into two sections. The first section is dedicated to introducing commensal microbiota and its known effects on the host. The second section is on metabolites, which are biochemicals that the host and the microbes use for bi-directional communication with each other. Together, the sections review what is known about how microbes interact with the host to impact cardiovascular physiology, especially blood pressure regulation. © 2021 American Physiological Society. Compr Physiol 11:1731-1757, 2021.

2.
J Tradit Chin Med ; 41(2): 316-325, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33825413

RESUMEN

OBJECTIVE: To investigate the changes of subcortical gray matter volume and cortical thickness, andexplorethe correlations between regional abnormalities of cortical thickness and cognitive impairment and the effect of modified Bushenyisui decoction ( BSYSD) on the cognitive function of multiple sclerosis (MS). METHODS: This prospective study was approved by the institutional review board. 92 subjects were recruited, including 46 relapsing-remitting multiple sclerosis (RRMS) patients and 46 healthy controls (HC). Of the 46 patients, 22 patients experienced the treatment of BSYSD for half a year. A conventional three-dimensional T1-weighted sequence were acquired for all participants on a 3.0 tesla magnetic resonance system. Basic information, detailed cognitive scales Montreal Cognitive Assessment (MoCA), symbol digit modalities test (SDMT), immediate memory, delayed recall, and long-term recognition were evaluated. Subcortical gray matter volume and cortical thickness weremeasured by FreeSurfer. The correlations between cortical thickness which MS patients showed reduced with respect to HC and cognitive scales wereanalyzed by Pearson correlation in RRMS patients. The influence of modified BSYSD on MS patients' cognition was analyzed by paired T Test. RESULTS: MoCA, immediate memory, delayed recall, and long-term delayed recognition in RRMS were significantly decreased than those of HC. Gray matter atrophy measured by FreeSurfer showed mainly in thalamus and hippocampus of RRMS patients. Compared with HC, the cortical thickness of several regions in frontal lobe, parietal lobe, temporal lobe, hippocampal, cingulate gyrus, and fusiform gyrus of RRMS patients were decreased with significant difference. The regions of cortical thickness thinning related to MoCA, immediate memory, delayed recall, and long-term delayed recognition were temporal lobe and fusiform gyrus. Modified BSYSD could improve MoCA, SDMT, immediate memory, delayed recall, and long-term delayed recognition of MS patients, and it could promote the recovery of cognitive function in MS patients. CONCLUSIONS: Gray matter atrophy and cortical thickness thinning were validated in RRMS. Cortical thickness thinning of temporal lobe and fusiform gyrus strongly related to cognitive deficits in RRMS. The modified BSYSD could promote the recovery of cognitive function in MS.

3.
Oxid Med Cell Longev ; 2021: 5521503, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33815654

RESUMEN

Background: Bu Shen Yi Sui capsule (BSYS) is a traditional Chinese medicine prescription that has shown antineuroinflammatory and neuroprotective effects in treating multiple sclerosis (MS) and its animal model of experimental autoimmune encephalomyelitis (EAE). Microglia play an important role in neuroinflammation. The M1 phenotype of microglia is involved in the proinflammatory process of the disease, while the M2 phenotype plays an anti-inflammatory role. Promoting the polarization of microglia to M2 in MS/EAE is a promising therapeutic strategy. This study is aimed at exploring the effects of BSYS on microglial polarization in mice with EAE. Methods: The EAE model was established by the intraperitoneal injection of pertussis toxin and subcutaneous injection of myelin oligodendrocyte glycoprotein (MOG)35-55 in C57BL/6J mice. The mice were treated with BSYS (3.02 g/kg), FTY720 (0.3 mg/kg), or distilled water by intragastric administration. H&E and LFB staining, transmission electron microscopy, qRT-PCR, immunofluorescence, ELISA, fluorescence in situ hybridization, and western blotting were used to detect the histological changes in myelin, microglial M1/M2 polarization markers, and the expression of key genes involved in EAE. Results and Conclusions. BSYS treatment of EAE mice increased the body weight, decreased the clinical score, and reduced demyelination induced by inflammatory infiltration. BSYS also inhibited the mRNA expression of M1 microglial markers while increasing the mRNA level of M2 markers. Additionally, BSYS led to a marked decrease in the ratio of M1 microglia (iNOS+/Iba1+) and an obvious increase in the number of M2 microglia (Arg1+/Iba1+). In the EAE mouse model, miR-124 expression was decreased, and miR-155 expression was increased, while BSYS treatment significantly reversed this effect and modulated the levels of C/EBP α, PU.1, and SOCS1 (target genes of miR-124 and miR-155). Therefore, the neuroprotective effect of BSYS against MS/EAE was related to promoting microglia toward M2 polarization, which may be correlated with changes in miR-124 and miR-155 in vivo.

4.
Materials (Basel) ; 14(7)2021 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-33805027

RESUMEN

In this paper, the stability of large-size graded crushed stone used for road base or cushioning under repeated load is investigated. Using an in-house developed device, large-size crushed stone mix was compacted and molded by the vibration and rotary compaction method. Cyclic rotating axial compression was applied, and the shakedown theory was used to study the cumulative deformation of the large-size crushed stone specimens. The effects of gradation parameters on the cumulative strain and stability behavior were analyzed, and the critical stability and failure loads were determined according to the shakedown theory. The test results indicate that there are three obvious instability behavior stages of large-size graded crushed stone under cyclic rotating axial compression: elastic stability, plastic creep, and incremental plastic failure. Large-size graded crushed stone has a higher critical stability load stiffness than conventional-size graded crushed stone. The critical shakedown load of the specimen is mainly affected by the skeleton structure performance, and the critical failure load by the properties of the crushed stone material. Increasing the content and compactness of large-size crushed stone in the specimen can improve the stiffness and stability performance, and to achieve improvements, the content of large-size crushed stone should be controlled between 22% and 26%. The critical shakedown load increases with the increase in the California bearing ratio (CBR) value, while, on the other hand, the CBR value has little relationship with the critical failure load.

5.
Muscle Nerve ; 2021 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-33831220

RESUMEN

INTRODUCTION: Intensive care unit-acquired weakness (ICUAW) is a severe neuromuscular complication of critical illness. Serum lactate is a useful biomarker in critically ill patients. The relationship between serum lactate level and ICUAW remains controversial. This study evaluated whether hyperlactacidemia (lactate level>2 mmol/L) was an independent risk factor for ICUAW in critically ill adult patients. Methods An observational cohort study was performed in a general multidisciplinary intensive care unit (ICU). Sixty-eight consecutive adult critically ill patients without preexisting neuromuscular disease or a poor pre-ICU functional status whose length of ICU stay was seven or more days were evaluated. Patients were screened daily for signs of awakening. Muscle strength assessment using the Medical Research Council score was performed on the first day a patient was considered awake. Patients with clinical muscle weakness were considered to have ICUAW. RESULTS: Among the 68 patients who achieved a satisfactory state of consciousness, the diagnosis of ICUAW was made in 30 patients (44.1%). After multivariate analysis, hyperlactacidemia (P=0.02), APACHE II score (P=0.04), duration of mechanical ventilation (P=0.02), and the use of norepinephrine (P=0.04) were found to be significantly associated with the development of ICUAW in critically ill patients. DISCUSSION: This study shows a number of risk factors to be significantly associated with the development of ICUAW in critically ill adults. These factors should be considered when building early prediction models or designing prevention strategies for ICUAW in future studies.

6.
Chemosphere ; 278: 130416, 2021 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-33831683

RESUMEN

A new integrated source-specific risk model and site-specific blood lead levels (BLLs) of 0-6 children were introduced to comprehensive understand the status of the toxic metals in soil-dust-plant total environment from a Coal-Gas industrial city, NW China. 144 samples were collected and ten toxic metals (As, Ba, Co, Cr, Cu, Mn, Ni, Sr, Pb, and Zn) were screened by XRF and ICP-MS. It was found that the occurrences of toxic metals deferred in the different medium, such as Co, Cu, Pb, and Zn observed the trend of accumulating in soil and plant compared to clustered distributions of Cr, Mn and Ni preferred to accumulate in dust. However, few bioaccumulations observed in Ulmus pumila L. Toxic metals distributions in majority of sites influenced by coal combustion mixed sources and industrial activities posed the high integrated ecological risks and caused significant non-carcinogenic and carcinogenic integrated risks for local 0-6 children identified by new integrated source-specific risk model, especially observed in the priority contaminants Co and Pb. The site-specific BLLs confirmed that younger children fewer than 4 lived in the north region were more vulnerable to priority Pb pollution as their BLLs above 50 µg/L, almost up to 80 µg/L. Although proportions of source-specific risks to toxic metals changed in soil and dust, the critical sources from coal combustions and industrial activities posed the most important contribution to the local risks. Therefore, effective strategies targeting at critical sources on coal industries should be conducted to reduce risks, and mostly emphasize on the north hotspot areas.

7.
J Ethnopharmacol ; : 114103, 2021 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-33836259

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Zuojin Pill (ZJP) has been a classic prescription for the treatment of gastrointestinal diseases in China since ancient times. But its effect on non-steroidal anti-inflammatory drugs (NSAIDs) induced gastric injury (GI) is still uncharted. AIM OF THE STUDY: This study aims to investigate the therapeutic effect and molecular mechanism of ZJP on indomethacin (IDO) induced gastric injury. MATERIALS AND METHODS: GI was induced in rat by oral administration of 5mg/kg IDO. Then the rats were treated with ZJP (1.26, 2.52, 5.04g/kg, ig). The changes of food intake, body weight, gastric pH and general state observation were carried out to determine the improvement of ZJP in IDO-induced GI: HE staining and AB-PAS staining was analyzed to characterize the thickness of gastric mucosa and micro mucosal injury; in order to elucidate the effect of ZJP on IDO-induced inflammatory injury, the inflammatory infiltration of gastric tissue was observed by MPO immunohistochemical method, and the contents of TNF-α, IL-6 and IL-10 were measured. Furthermore, the regulatory mechanism of ZJP in treating IDO-induced GI was predicted with the help of network pharmacology, and the expression levels of key proteins ERK, p-ERK, P38, p-P38, JNK, p-JNK were determined to elucidate the molecular mechanism of ZJP. RESULTS: Current data strongly demonstrated that ZJP alleviated food intake reduction, weight loss and gastric injury caused by IDO and made gastric pH and mucosal thickness return to normal. In addition, ZJP could reduce the level of MPO to alleviate the inflammatory infiltration of gastric tissue. Simultaneously, ZJP could down regulate the expression of TNF-α and IL-6 and up regulate the expression of IL-10 to reduce the damage caused by inflammatory, and create a healing environment. Furthermore, ZJP could significantly inhibit the phosphorylation of ERK, p38 and JNK, which leaded to the increase of inflammatory factors and the damage of gastric mucosa. CONCLUSION: ZJP improved local inflammation by inhibiting MAPK signaling pathway, and had a good therapeutic effect on IDO-induced GI. This study has reference significance for the study of ZJP in the prevention and treatment of NSAID induced gastric injury. In addition, ZJP may be a new treatment option for the prevention and treatment of NSAID induced gastric disease.

8.
J Am Soc Nephrol ; 2021 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-33788701

RESUMEN

BACKGROUND: The Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guideline used eGFR and urinary albumin-creatinine ratio (ACR) to categorize risks for CKD prognosis. The utility of KDIGO's stratification of major CVD risks and predictive ability beyond traditional CVD risk prediction scores are unknown. METHODS: To evaluate CVD risks on the basis of ACR and eGFR (individually, together, and in combination using the KDIGO risk categories) and with the atherosclerotic cardiovascular disease (ASCVD) score, we studied 115,366 participants in the China Cardiometabolic Disease and Cancer Cohort study. Participants (aged ≥40 years and without a history of cardiovascular disease) were examined prospectively for major CVD events, including nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death. RESULTS: During 415,111 person-years of follow-up, 2866 major CVD events occurred. Incidence rates and multivariable-adjusted hazard ratios of CVD events increased significantly across the KDIGO risk categories in ASCVD risk strata (all P values for log-rank test and most P values for trend in Cox regression analysis <0.01). Increases in c statistic for CVD risk prediction were 0.01 (0.01 to 0.02) in the overall study population and 0.03 (0.01 to 0.04) in participants with diabetes, after adding eGFR and log(ACR) to a model including the ASCVD risk score. In addition, adding eGFR and log(ACR) to a model with the ASCVD score resulted in significantly improved reclassification of CVD risks (net reclassification improvements, 4.78%; 95% confidence interval, 3.03% to 6.41%). CONCLUSIONS: Urinary ACR and eGFR (individually, together, and in combination using KDIGO risk categories) may be important nontraditional risk factors in stratifying and predicting major CVD events in the Chinese population.

9.
Biomed Pharmacother ; 138: 111490, 2021 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-33773465

RESUMEN

This study was aimed to explore the mechanism of rutaecarpine (RUT) on ethanol-induced gastric ulcer (GU) in mice by integrated approaches. At first, the efficacy was determined through the macroscopic and microscopic state of stomach tissue and the expression levels of GU-related factors. Then, the serum metabolomics method based on UPLC-Q-TOF/MS was used to explore the specific metabolites and metabolic pathways. Finally, the upstream key protein targets of these specific metabolites were analyzed by network pharmacology and verified by PCR to explore the potential mechanism. RUT alleviated the histological and pathological damage of gastric tissue caused by ethanol, and could remarkably ameliorate the level of GU-related factors. Subsequently, a total of 7 potential metabolites involved in 9 metabolic pathways were identified by metabolomics analysis. Then, a 'component-targets-metabolites' interaction network was constructed, and therefore 4 key target proteins (PLA2G1B, PDE5A, MIF and SRC) that may regulate the specific metabolites were obtained. This case was further verified by the results of PCR. ALL the above results strongly demonstrated that RUT exerted a gastroprotective effect against GU. And it is the first time to combine metabolomics combined with network pharmacology to elucidate the mechanism of RUT on GU, which may be related to the regulation of energy metabolism, oxidative stress, and inflammation, and these pathways may be regulated through the upstream protein PLA2G1B, PDE5A, MIF and SRC.

10.
Artículo en Inglés | MEDLINE | ID: mdl-33783706

RESUMEN

Obtaining accurate data on reference crop evapotranspiration (ET0) is important for agricultural water management. A novel Gaussian exponential model (GEM) was developed in this study to predict ET0 with limited climatic data. The GEM was further compared with the M5 model tree (M5T), extreme learning machine (ELM), and boosted trees (BT) model under local and regional scenarios. Daily meteorological data during 1997-2016 from four stations in Northeast China were used to develop and validate the model. The results showed that the models considering solar radiation and relative humidity demonstrated considerably higher accuracy than those using other inputs. The GEM demonstrated higher accuracy among the four machine learning models for different stations. The accuracy of GEM under local scenarios was higher than that under regional scenarios with the root mean square error (RMSE) reducing by 0.025-0.046 mm/d, relative root mean square error (RRMSE) reducing by 0.879-2.022%, coefficient of efficiency (Ens) increasing by 0.008-0.026, the coefficients of determination (R2) increasing by 0.008-0.026, and mean absolute error (MAE) reducing by 0.015-0.033 mm/d. The GEM considering solar radiation had the highest accuracy with the global performance indicator (GPI) of 1.876. It can also be seen from the Taylor diagrams that the GEM has the the lowest standard deviation and mean square error and the highest correlation coefficient with the standard values. In general, the GEM considering solar radiation had the lowest error and the highest consistency and could be recommended for ET0 simulation for Northeast China.

11.
Int J Cardiol ; 2021 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-33667580

RESUMEN

BACKGROUND: Excessive adiposity in adulthood is positively associated with the risk of cardiovascular disease (CVD). However, it is less studied how the risk is separately explained by early adulthood weight and later weight change, especially in Asian ancestries. METHODS: This study included 121160 participants in a large population-based cohort in China. Body weight at 20 and 40 years of age wase self-reported. Information on CVD history was obtained through standard questionnaires. RESULTS: The odds ratios (ORs) were 1.20 (95% CI, 1.10-1.31) for coronary heart disease (CHD), 1.74 (95% CI, 1.36-2.22) for myocardial infarction (MI), 1.14 (95% CI, 0.99-1.32) for stroke and 1.21 (95% CI, 1.12-1.31) for total CVD among individuals with early overweight, and became more prominent for early obesity. Meanwhile, A moderate weight gain of 2.5 kg between early adulthood and midlife significantly increased the risk of CHD (OR: 1.18, 95% CI: 1.05-1.32), stroke (OR: 1.19, 95% CI: 1.03-1.38) and total CVD (OR: 1.15, 95% CI: 1.04-1.27), and the risk escalated with higher amounts of weight gain. Conversely, a weight loss of 2.5 kg conferred lower risk of CVD compared with a stable weight. In further cross-analysis, participants with early adulthood overweight or obesity and significant weight gain afterwards exhibited the greatest risk of CVD. CONCLUSIONS: High early adulthood BMI and subsequent weight gain had both independent and combined effect on the risk of CVD after midlife. Therefore, weight management should start before early adulthood, and emphasized throughout adulthood for CVD prevention.

12.
Int J Biol Sci ; 17(3): 848-860, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33767593

RESUMEN

CD151 impacts various signaling pathways in different cancers, and promotes colorectal cancer (CRC) cell malignancy by yet undefined mechanisms. This study aimed to comprehensively assess CD151's function in CRC. CD151 levels were significantly higher in CRC tissues and cells compared with controls in the tissue microarray. Cell viability, migration and invasion were suppressed by CD151 downregulation in CRC cells. Consistently, mouse xenografts were inhibited by CD151 silencing. RNA-seq revealed that multiple genes were significantly altered by CD151 knockdown in cultured CRC cells and xenografts. Particularly, transforming growth factor ß1 (TGFß1), carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) and leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) alongside CD151 were downregulated both in vitro and in vivo. Co-immunoprecipitation and mass spectrometry results were validated by qRT-PCR and immunoblot. Moreover, pull-down assay and immunofluorescence confirmed the associations of TGFß1, CEACAM6 and LGR5 with CD151. This study demonstrated CEACAM6, LGR5 and Wnt pathway suppression by CD151 silencing might occur through TGFß1 regulation, offering a comprehensive view of CD151's roles in colorectal carcinogenesis. Our findings provide an insight into the CD151-involved signaling network in CRC oncogenesis, which could be utilized to design novel targeted therapies against CD151-based signaling in treatment for CRC.

13.
J Steroid Biochem Mol Biol ; 210: 105859, 2021 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-33677016

RESUMEN

Androgens are essential for prostate cancer development. However, steroidogenesis has mainly been investigated in a limited number of prostate cancer cell lines, leading to varied conclusions and elusive clinical significance. Here, we established an ex vivo research platform with fresh biopsy samples transiently cultured with tritium- labelled androgens to trace steroidogenesis in prostate tissues and investigate its potential clinical application. DHEA was confirmed as the major precursor for androgen synthesis in the prostate. Significant amounts of oxidized DHEA and 5α-androstanedione were generated from DHEA in prostate biopsy samples. Prostatic steroidogenesis was independent of other clinical factors. Furthermore, prostatic steroidogenesis was suppressed after androgen deprivation therapy but increased upon treatment resistance, indicating that prostatic steroidogenesis was affected by clinical treatments. Overall, we provide an accessible research platform to characterize steroidogenesis in prostate tissue and indicate the correlation between prostatic steroidogenesis and disease progression.

14.
J Med Chem ; 64(6): 2851-2877, 2021 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-33656892

RESUMEN

Proteostasis is the process of regulating intracellular proteins to maintain the balance of the cell proteome, which is crucial for cancer cell survival. Several proteases located in the cytoplasm, mitochondria, lysosome, and extracellular environment have been identified as potential antitumor targets because of their involvement in proteostasis. Although the discovery of small-molecule inhibitors targeting proteases faces particular challenges, rapid advances in chemical biology and structural biology, and the new technology of drug discovery have facilitated the development of promising protease modulators. In this review, the protein structure and function of important tumor-related proteases and their inhibitors are presented. We also provide a prospective on advances and the outlook of new drug strategies that target these proteases.

15.
Biomed Pharmacother ; 137: 111373, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33761599

RESUMEN

Psoriasis is a chronic, inflammatory autoimmune disease mediated by T cells, and characterized with abnormal proliferation and differentiation of keratinocytes, and inflammatory infiltration. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway has been identified to play essential roles in mediating various of biological processes, and is closely related to autoimmune diseases. Dendritic cells (DCs) are important antigen presenting cells and play an important regulatory role in T cells. The proliferation, differentiation and function of DCs are regulated by JAK and FMS-like tyrosine kinase 3 (FLT3) signal pathways. Flonoltinib maleate (FM), a high selectivity dual JAK2/FLT3 inhibitor with IC50 values of 0.8 nM and 15 nM for JAK2 and FLT3, respectively, was developed by our laboratory. Moreover, FM was a potent JAK2 inhibitor with 863-fold and 696-fold selectivity over JAK1 and JAK3, respectively. In this study, the anti-psoriasis activity of FM was evaluated both in vitro and in vivo. FM effectively inhibited the proliferation of HaCaT, the inflammatory keratinocyte induced by M5 and markedly suppressed the generation and differentiation of DCs from bone marrow (BM), and inhibited the expression of FLT3 in DCs in vitro. FM effectively inhibited the ear thickening and improved the pathological changes of the ear in interleukin (IL)-23-induced psoriasis-like acanthosis mouse model. Further in keratin 14-vascular endothelial growth factor (K14-VEGF) transgenic homozygous mice model, FM could obviously improve the psoriatic symptom and pathological changes, significantly inhibit the generations of Th1 and Th17 cells in the spleen, and the accumulations of DCs in the ears. FM could also significantly reduce the expression of various inflammatory factors both in C57BL/6 and K14-VEGF mice ears, and the serum of K14-VEGF mice. Mechanism revealed that FM effectively suppressed the phosphorylation of JAK2, STAT3 and STAT5 in inflammatory keratinocytes and the mice ears of C57BL/6 and K14-VEGF, as well as the phosphorylation of FLT3 in K14-VEGF mice ears. In conclusion, FM plays an excellent anti-psoriasis activity, including inhibiting keratinocyte proliferation and regulating inflammatory response through inhibiting JAK2 and FLT3 signaling pathway.

16.
J Thorac Oncol ; 2021 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-33722707

RESUMEN

INTRODUCTION: Metastasis is the primary cause of lung cancer-related death. Nevertheless, the underlying molecular mechanisms and evolutionary patterns of lung cancer metastases are still elusive. METHODS: We performed whole-exome sequencing for 40 primary tumors (PTs) and 61 metastases from 47 patients with lung cancer, of which 40 patients had paired PTs and metastases. The PT-metastasis genomic divergence, metastatic drivers, timing of metastatic dissemination, and evolutionary origins were analyzed using appropriate statistical tools and mathematical models. RESULTS: There were various degrees of genomic heterogeneity when comparing the paired primary and metastatic lesions or comparing metastases of different sites. Multiple metastasis-selected/enriched genetic alterations were found, such as MYC amplification, NKX2-1 amplification, RICTOR amplification, arm 20p gain, and arm 11p loss, and these results were were also featured in a meta-analysis cross-validated using an independent cohort from Memorial Sloan-Kettering Cancer Center database. To elucidate the metastatic seeding time, we applied a metastatic model and found 61.1% of the tumors were late dissemination, in which the metastatic seeding happened approximately 2.74 years before clinical detection. One exception was lymph node metastases whose dissemination time was relatively early. By analyzing the evolutionary origins, we reported that nonlymph node metastases were mainly seeded by the PT (87.5%) rather than the earlier colonized lymph node metastases. CONCLUSIONS: Our results shed light on the molecular features that potentially drive lung cancer metastases. The distinct temporospatial pattern of disease progression revealed that lung cancer was susceptible to either late dissemination or indolent early lymph node metastases, leaving a potential time window to minimize metastases by early cancer detection.

17.
J Clin Invest ; 131(6)2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33720048

RESUMEN

Chronic HIV-1 infection is generally characterized by progressive CD4+ T cell depletion due to direct and bystander death that is closely associated with persistent HIV-1 replication and an inflammatory environment in vivo. The mechanisms underlying the loss of CD4+ T cells in patients with chronic HIV-1 infection are incompletely understood. In this study, we simultaneously monitored caspase-1 and caspase-3 activation in circulating CD4+ T cells, which revealed that pyroptotic and apoptotic CD4+ T cells are distinct cell populations with different phenotypic characteristics. Levels of pyroptosis and apoptosis in CD4+ T cells were significantly elevated during chronic HIV-1 infection, and decreased following effective antiretroviral therapy. Notably, the occurrence of pyroptosis was further confirmed by elevated gasdermin D activation in lymph nodes of HIV-1-infected individuals. Mechanistically, caspase-1 activation closely correlated with the inflammatory marker expression and was shown to occur through NLRP3 inflammasome activation driven by virus-dependent and/or -independent ROS production, while caspase-3 activation in CD4+ T cells was more closely related to T cell activation status. Hence, our findings show that NLRP3-dependent pyroptosis plays an essential role in CD4+ T cell loss in HIV-1-infected patients and implicate pyroptosis signaling as a target for anti-HIV-1 treatment.

18.
Plant Cell ; 33(1): 104-128, 2021 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-33751093

RESUMEN

Grain filling in maize (Zea mays) is regulated by a group of spatiotemporally synchronized transcription factors (TFs), but the factors that coordinate their expression remain unknown. We used the promoter of the grain filling-specific TF gene Opaque2 (O2) to screen upstream regulatory factors and identified a B3 domain TF, ZmABI19, that directly binds to the O2 promoter for transactivation. zmabi19 mutants displayed developmental defects in the endosperm and embryo, and mature kernels were opaque and reduced in size. The accumulation of zeins, starch and lipids dramatically decreased in zmabi19 mutants. RNA sequencing revealed an alteration of the nutrient reservoir activity and starch and sucrose metabolism in zmabi19 endosperms, and plant phytohormone signal transduction and lipid metabolism in zmabi19 embryos. Chromatin immunoprecipitation followed by sequencing coupled with differential expression analysis identified 106 high-confidence direct ZmABI19 targets. ZmABI19 directly regulates multiple key grain filling TFs including O2, Prolamine-box binding factor 1, ZmbZIP22, NAC130, and Opaque11 in the endosperm and Viviparous1 in the embryo. A number of phytohormone-related genes were also bound and regulated by ZmABI19. Our results demonstrate that ZmABI19 functions as a grain filling initiation regulator. ZmABI19 roles in coupling early endosperm and embryo development are also discussed.

19.
Sci Total Environ ; 779: 146283, 2021 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-33752001

RESUMEN

Spatio-temporal distributions of air pollution and population are two important factors influencing the patterns of mortality and diseases. Past studies have quantified the adverse effects of long-term exposure to air pollution. However, the dynamic changes of air pollution levels and population mobility within a day are rarely taken into consideration, especially in metropolitan areas. In this study, we use the high-resolution PM2.5 data from the micro-air monitoring stations, and hourly population mobility simulated by the heatmap based on Location Based Service (LBS) big data to evaluate the hourly active PM2.5 exposure in a typical Chinese metropolis. The dynamic "active population exposure" is compared spatiotemporally with the static "census population exposure" based on census data. The results show that over 12 h on both study periods, 45.83% of suburbs' population-weighted exposure (PWE) is underestimated, while 100% of rural PWE and more than 34.78% of downtown's PWE are overestimated, with the relative difference reaching from -11 µg/m3 to 7 µg/m3. More notably, the total PWE of the active population at morning peak hours on weekdays is worse than previously realized, about 12.41% of people are exposed to PM2.5 over 60 µg/m3, about twice as much as that in census scenario. The commuters who live in the suburbs and work in downtown may suffer more from PM2.5 exposure and uneven environmental resource distribution. This study proposes a new approach of calculating population exposure which can also be extended to quantify other environmental issues and related health burdens.

20.
EMBO J ; : e106632, 2021 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-33739466

RESUMEN

HIV-1 latency is a major obstacle to achieving a functional cure for AIDS. Reactivation of HIV-1-infected cells followed by their elimination via immune surveillance is one proposed strategy for eradicating the viral reservoir. However, current latency-reversing agents (LRAs) show high toxicity and low efficiency, and new targets are needed to develop more promising LRAs. Here, we found that the histone chaperone CAF-1 (chromatin assembly factor 1) is enriched on the HIV-1 long terminal repeat (LTR) and forms nuclear bodies with liquid-liquid phase separation (LLPS) properties. CAF-1 recruits epigenetic modifiers and histone chaperones to the nuclear bodies to establish and maintain HIV-1 latency in different latency models and primary CD4+ T cells. Three disordered regions of the CHAF1A subunit are important for phase-separated CAF-1 nuclear body formation and play a key role in maintaining HIV-1 latency. Disruption of phase-separated CAF-1 bodies could be a potential strategy to reactivate latent HIV-1.

SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...