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1.
Nat Commun ; 12(1): 4090, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215745

RESUMO

The transition from pluripotent to somatic states marks a critical event in mammalian development, but remains largely unresolved. Here we report the identification of SS18 as a regulator for pluripotent to somatic transition or PST by CRISPR-based whole genome screens. Mechanistically, SS18 forms microscopic condensates in nuclei through a C-terminal intrinsically disordered region (IDR) rich in tyrosine, which, once mutated, no longer form condensates nor rescue SS18-/- defect in PST. Yet, the IDR alone is not sufficient to rescue the defect even though it can form condensates indistinguishable from the wild type protein. We further show that its N-terminal 70aa is required for PST by interacting with the Brg/Brahma-associated factor (BAF) complex, and remains functional even swapped onto unrelated IDRs or even an artificial 24 tyrosine polypeptide. Finally, we show that SS18 mediates BAF assembly through phase separation to regulate PST. These studies suggest that SS18 plays a role in the pluripotent to somatic interface and undergoes liquid-liquid phase separation through a unique tyrosine-based mechanism.

2.
Breast ; 59: 102-109, 2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34225090

RESUMO

BACKGROUND: The COVID-19 pandemic is a significant worldwide health crisis. Breast cancer patients with COVID-19 are fragile and require particular clinical care. This study aimed to identify the clinical characteristics of breast cancer patients with COVID-19 and the risks associated with anti-cancer treatment. METHODS: The medical records of breast cancer patients with laboratory-confirmed COVID-19 were collected among 9559 COVID-19 patients from seven designated hospitals from 13th January to 18th March 2020 in Hubei, China. Univariate and multivariate analyses were performed to assess risk factors for COVID-19 severity. RESULTS: Of the 45 breast cancer patients with COVID-19, 33 (73.3%) developed non-severe COVID-19, while 12 (26.7%) developed severe COVID-19, of which 3 (6.7%) patients died. The median age was 62 years, and 3 (6.7%) patients had stage IV breast cancer. Univariate analysis showed that age over 75 and the Eastern Cooperative Oncology Group (ECOG) score were associated with COVID-19 disease severity (P < 0.05). Multivariate analysis showed that patients who received chemotherapy within 7 days had a significantly higher risk for severe COVID-19 (logistic regression model: RR = 13.886, 95% CI 1.014-190.243, P = 0.049; Cox proportional hazards model: HR = 13.909, 95% CI 1.086-178.150, P = 0.043), with more pronounced neutropenia and higher LDH, CRP and procalcitonin levels than other patients (P < 0.05). CONCLUSIONS: In our breast cancer cohort, the severity of COVID-19 could be associated with baseline factors such as age over 75 and ECOG scores. Chemotherapy within 7 days before symptom onset could be a risk factor for severe COVID-19, reflected by neutropenia and elevated LDH, CRP and procalcitonin levels.

3.
SLAS Discov ; : 24725552211026261, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34192965

RESUMO

The COVID-19 pandemic has clearly brought the healthcare systems worldwide to a breaking point, along with devastating socioeconomic consequences. The SARS-CoV-2 virus, which causes the disease, uses RNA capping to evade the human immune system. Nonstructural protein (nsp) 14 is one of the 16 nsps in SARS-CoV-2 and catalyzes the methylation of the viral RNA at N7-guanosine in the cap formation process. To discover small-molecule inhibitors of nsp14 methyltransferase (MTase) activity, we developed and employed a radiometric MTase assay to screen a library of 161 in-house synthesized S-adenosylmethionine (SAM) competitive MTase inhibitors and SAM analogs. Among six identified screening hits, SS148 inhibited nsp14 MTase activity with an IC50 value of 70 ± 6 nM and was selective against 20 human protein lysine MTases, indicating significant differences in SAM binding sites. Interestingly, DS0464 with an IC50 value of 1.1 ± 0.2 µM showed a bisubstrate competitive inhibitor mechanism of action. DS0464 was also selective against 28 out of 33 RNA, DNA, and protein MTases. The structure-activity relationship provided by these compounds should guide the optimization of selective bisubstrate nsp14 inhibitors and may provide a path toward a novel class of antivirals against COVID-19, and possibly other coronaviruses.

4.
Phys Rev Lett ; 126(25): 251102, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34241495

RESUMO

We perform the three-dimensional lattice simulation of the magnetic field and gravitational wave productions from bubble collisions during the first-order electroweak phase transition. Except for the gravitational wave, the power-law spectrum of the magnetic field strength is numerically calculated for the first time, which is of a broken power-law spectrum: B_{ξ}∝f^{0.91} for the low-frequency region of ff_{⋆} in the thin-wall limit, with the peak frequency being f_{⋆}∼5 Hz at the phase transition temperature 100 GeV. When the hydrodynamics is taken into account, the generated magnetic field strength can reach B_{ξ}∼10^{-7} G at a correlation length ξ∼10^{-7} pc, which may seed the large scale magnetic fields. Our study shows that the measurements of cosmic magnetic field strength and gravitational waves are complementary to probe new physics admitting electroweak phase transition.

5.
Cell Prolif ; : e13085, 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34232542

RESUMO

OBJECTIVES: In this study, we administered immunity-and-matrix regulatory cells (IMRCs) via tail vein (IV) and intracerebroventricular (ICV) injection to 3-month-old 5×FAD transgenic mice to assess the effects of IMRC transplantation on the behaviour and pathology of early-stage Alzheimer's disease (AD). MATERIALS AND METHODS: Clinical-grade human embryonic stem cell (hESC)-derived IMRCs were produced under good manufacturing practice (GMP) conditions. Three-month-old 5×FAD mice were administered IMRCs via IV and ICV injection. After 3 months, the mice were subjected to behavioural tests and electrophysiological analysis to evaluate their cognitive function, memory ability and synaptic plasticity. The effect of IMRCs on amyloid-beta (Aß)-related pathology was detected by thioflavin-S staining and Western blot. Quantitative real-time PCR, ELISA and immunostaining were used to confirm that IMRCs inhibit neuroinflammation. RNA-seq analysis was performed to measure changes in gene expression and perform a pathway analysis in response to IMRC treatment. RESULTS: IMRC administration via tail vein injection significantly ameliorated cognitive deficits in early-stage AD (5×FAD) mice. However, no significant change was observed in the characteristic pathology of AD in the ICV group. Plaque analysis revealed that IMRCs did not influence either plaque deposition or BACE1 expression. In addition, IMRCs inhibited inflammatory responses and reduced microglial activation in vivo. CONCLUSIONS: We have shown that peripheral administration of IMRCs can ameliorate AD pathology and associated cognitive deficits.

6.
Talanta ; 233: 122515, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34215130

RESUMO

In this work, we structured a colorimetric ultrasensitive detection of carcinoembryonic antigen (CEA) based on a proximity hybridization-induced gold nanoparticles (Au NPs) dimers structure. Under the dark-field microscope, this method takes advantage of the distinctive and strong distance-relative localized surface plasmon resonance (LSPR) of Au NPs and their oriented assembly. DNA served as a medium showing wonderful flexibility to label antibody and Au NPs, and tune interparticle spacing as well. Two capture probes were formed by the integration of DNA labeled antibody (DNA1-Ab1 or DNA2-Ab2) and asymmetrically assembled DNA (DNA 3 or DNA 4)- Au NPs via partly hybridization between DNA sequences. In the presence of antigen, the reaction between target protein and capture probes could trigger the generation of immunocomplex which led to the proximity hybridization of the DNA1 and DNA2, and then change the distance of interparticle to form Au NP dimers and thus showed a different color under dark-field microscope. A limit of detection of 14.25 pg/mL was obtained for the detection of CEA, which indicated a promising sensing method in clinical diagnosis of protein biomarkers.


Assuntos
Técnicas Biossensoriais , Nanopartículas Metálicas , Técnicas Eletroquímicas , Ouro , Imunoensaio , Limite de Detecção
7.
Biomed Res Int ; 2021: 9930524, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34258284

RESUMO

Deep venous thrombosis (DVT) is a common complication in patients with lower extremity fractures, causing delays in recovery short-term and possible impacts on quality of life long-term. Early prediction and prevention of thrombosis can effectively reduce patient pain while improving outcomes. Although research on the risk factors for thrombosis is prevalent, there is a stark lack of clinical predictive models for DVT occurrence specifically in patients with lower limb fractures. In this study, we aim to propose a new thrombus prediction model for lower extremity fracture patients. Data from 3300 patients with lower limb fractures were collected from Wuhan Union Hospital and Hebei Third Hospital, China. Patients who met our inclusion criteria were divided into a thrombosis and a nonthrombosis group. A multivariate logistic regression analysis was carried out to identify predictors with obvious effects, and the corresponding formulas were used to establish the model. Model performance was evaluated using a discrimination and correction curve. 2662 patients were included in the regression analysis, with 1666 in the thrombosis group and 996 in the nonthrombosis group. Predictive factors included age, Body Mass Index (BMI), fracture-fixation types, energy of impact at the time of injury, blood transfusion during hospitalization, and use of anticoagulant drugs. The discriminative ability of the model was verified using the C-statistic (0.676). For the convenience of clinical use, a score table and nomogram were compiled. Data from two centers were used to establish a novel thrombus prediction model specific for patients with lower limb fractures, with verified predictive ability.

8.
mBio ; : e0138221, 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34253066

RESUMO

Bacterial cell division, with a few exceptions, is driven by FtsZ through a treadmilling mechanism to remodel and constrict the rigid peptidoglycan (PG) layer. Yet different organisms may differ in the composition of the cell division complex (divisome). In the filamentous cyanobacterium Anabaena sp. strain PCC 7120, hetF is required for the initiation of the differentiation of heterocysts, cells specialized in N2 fixation under combined-nitrogen deprivation. In this study, we demonstrate that hetF is expressed in vegetative cells and necessary for cell division under certain conditions. Under nonpermissive conditions, cells of a ΔhetF mutant stop dividing, consistent with increased levels of HetF under similar conditions in the wild type. Furthermore, HetF is a membrane protein located at midcell and cell-cell junctions. In the absence of HetF, FtsZ rings are still present in the elongated cells; however, PG remodeling is abolished. This phenotype is similar to that observed with the inhibition of the septal PG synthase FtsI. We further reveal that HetF is recruited to or stabilized at the divisome by interacting with FtsI and that this interaction is necessary for HetF function in cell division. Our results indicate that HetF is a member of the divisome depending mainly on light intensity and reveal distinct features of the cell division machinery in cyanobacteria that are of high ecological and environmental importance. IMPORTANCE Cyanobacteria shaped the Earth's evolutionary history and are still playing important roles for elementary cycles in different environments. They consist of highly diverse species with different cell shapes, sizes, and morphologies. Although these properties are strongly affected by the process of cytokinesis, the mechanism remains largely unexplored. Using different approaches, we demonstrate that HetF is a new component of the cell division machinery under certain environmental conditions in the filamentous cyanobacterium Anabaena sp. strain PCC 7120. The common and diverged characteristics of cell division in prokaryotes reflect the evolutionary history of different bacteria as an adaptive measure to proliferate under certain environmental conditions. As a protein for cell differentiation, the recruitment of HetF to the septum illustrates such an adaptive mechanism in cyanobacteria.

9.
Molecules ; 26(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208577

RESUMO

Metal-organic frameworks (MOFs) have been rapidly developed for their broad applications in many different chemistry and materials fields. In this work, a multi-dentate building block 5-(4-(tetrazol-5-yl)phenyl)-isophthalic acid (H3L) containing tetrazole and carbolxylate moieties was employed for the synthesis of a two-dimensional (2D) lanthanide MOF [La(HL)(DMF)2(NO3)] (DMF = N,N-dimethylformamide) (1) under solvothermal condition. The fluorescent sensing application of 1 was investigated. 1 exhibits high sensitivity recognition for antibiotic nitrofurantoin (Ksv: 3.0 × 103 M-1 and detection limit: 17.0 µM) and amino acid l-tyrosine (Ksv: 1.4 × 104 M-1 and detection limit: 3.6 µM). This work provides a feasible detection platform of 2D MOFs for highly sensitive discrimination of antibiotics and amino acids.


Assuntos
Elementos da Série dos Lantanídeos/química , Nitrofurantoína/química , Tirosina/química , Antibacterianos/química , Cristalografia por Raios X/métodos , Corantes Fluorescentes/química , Estruturas Metalorgânicas/química , Nitrofurantoína/metabolismo , Tirosina/metabolismo
10.
Breast ; 59: 102-109, 2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: covidwho-1283953

RESUMO

BACKGROUND: The COVID-19 pandemic is a significant worldwide health crisis. Breast cancer patients with COVID-19 are fragile and require particular clinical care. This study aimed to identify the clinical characteristics of breast cancer patients with COVID-19 and the risks associated with anti-cancer treatment. METHODS: The medical records of breast cancer patients with laboratory-confirmed COVID-19 were collected among 9559 COVID-19 patients from seven designated hospitals from 13th January to 18th March 2020 in Hubei, China. Univariate and multivariate analyses were performed to assess risk factors for COVID-19 severity. RESULTS: Of the 45 breast cancer patients with COVID-19, 33 (73.3%) developed non-severe COVID-19, while 12 (26.7%) developed severe COVID-19, of which 3 (6.7%) patients died. The median age was 62 years, and 3 (6.7%) patients had stage IV breast cancer. Univariate analysis showed that age over 75 and the Eastern Cooperative Oncology Group (ECOG) score were associated with COVID-19 disease severity (P < 0.05). Multivariate analysis showed that patients who received chemotherapy within 7 days had a significantly higher risk for severe COVID-19 (logistic regression model: RR = 13.886, 95% CI 1.014-190.243, P = 0.049; Cox proportional hazards model: HR = 13.909, 95% CI 1.086-178.150, P = 0.043), with more pronounced neutropenia and higher LDH, CRP and procalcitonin levels than other patients (P < 0.05). CONCLUSIONS: In our breast cancer cohort, the severity of COVID-19 could be associated with baseline factors such as age over 75 and ECOG scores. Chemotherapy within 7 days before symptom onset could be a risk factor for severe COVID-19, reflected by neutropenia and elevated LDH, CRP and procalcitonin levels.

11.
BMC Cardiovasc Disord ; 21(1): 345, 2021 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-34273963

RESUMO

BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia in patients with chronic kidney disease (CKD) and acute coronary syndrome (ACS). This study aimed to explore the frequency and impact of AF on clinical outcomes in CKD patients with ACS. METHODS: CKD inpatients with ACS between November 2014 and December 2018 were included based on the improving care for cardiovascular disease in China-ACS (CCC-ACS) project. Included patients were divided into an AF group and a non-AF group according to the discharge diagnosis. Multivariable logistic regression was used to adjust for potential confounders. RESULTS: A total of 16,533 CKD patients with ACS were included. A total of 1418 (8.6%) patients had clinically recognized AF during hospitalization, 654 of whom had an eGFR of 45 to < 60 ml/min/1.73 m2, and 764 had an estimated glomerular filtration rate (eGFR) < 45 ml/min/1.73 m2. Compared with the non-AF group, the AF group had a higher risk of in-hospital mortality [OR 1.250; 95% CI (1.001-1.560), P = 0.049] and major adverse cardiovascular events (MACEs) [OR 1.361; 95% CI (1.197-1.547), P < 0.001]. We also found that compared with patients with eGFR 45 to < 60 ml/min/1.73 m2, patients with eGFR < 45 ml/min/1.73 m2 had a 1.512-fold increased risk of mortality and a 1.435-fold increased risk of MACEs. CONCLUSIONS: AF was a risk factor affecting the short-term prognosis of ACS patients in the CKD population. Furthermore, the lower the eGFR, the higher the risk of in-hospital mortality and MACEs in CKD patients with ACS. TRIAL REGISTRY: Clinicaltrial.gov, NCT02306616. Registered 29 November 2014, https://clinicaltrials.gov/ct2/show/NCT02306616?term=NCT02306616&draw=2&rank=1.

12.
Mol Med Rep ; 24(3)2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34278483

RESUMO

As a calcineurin inhibitor, tacrolimus is commonly used as a first­line immunosuppressant in organ transplant recipients. Post­transplantation diabetes mellitus (PTDM) is a common complication following kidney transplantation and is associated with immunosuppressant drugs, such as tacrolimus. PTDM caused by tacrolimus may be related to its influence on insulin secretion and insulin resistance. However, the specific mechanism has not been fully elucidated. The aim of the present study was to investigate whether the PI3K/Akt/mTOR signaling pathway served an important role in the pathogenesis of PTDM induced by tacrolimus. In the present study, the Cell Counting Kit­8 assay was used to measure the effect of tacrolimus on the viability of Min6 mouse insulinoma cells. The effects of tacrolimus on the insulin secretion and the activity of caspase­3 of Min6 cells stimulated by glucose exposure were measured by ELISA. Superoxide dismutase (SOD) and malondialdehyde (MDA) levels were measured using WST­8 and thiobarbituric acid assays, respectively. The effects of tacrolimus on the mRNA expression levels of PI3K, Akt and mTOR were detected by reverse transcription­quantitative PCR (RT­qPCR), whereas the protein expression levels of PI3K, Akt, mTOR, phosphorylated (p)­AKT and p­mTOR in Min6 cells were assessed using western blotting. The present data indicated that, compared with the control group, 5, 25 and 50 ng/ml tacrolimus treatment could inhibit the insulin secretion of Min6 cells stimulated by glucose solution, and 50 ng/ml tacrolimus could notably decrease the stimulation index (P<0.05). Moreover, 50 ng/ml tacrolimus markedly increased the activity of caspase­3 by 175.1% (P<0.05), it also decreased the SOD activity (P<0.01) and increased MDA levels (P<0.05). The RT­qPCR results demonstrated that the mRNA expression levels of PI3K, Akt and mTOR were downregulated by 25 and 50 ng/ml tacrolimus (P<0.01). Furthermore, the western blotting results suggested that tacrolimus had no significant effects on the expression levels of total PI3K, Akt and mTOR proteins (P>0.05), but 25 and 50 ng/ml tacrolimus could significantly inhibit the expression levels of p­Akt and p­mTOR (P<0.01). In conclusion, tacrolimus decreased the activity and insulin secretion of pancreatic ß cells and induced the apoptosis of islet ß cells by inhibiting the mRNA expression levels of PI3K, Akt and mTOR and reducing the phosphorylation of Akt and mTOR proteins in the PI3K/Akt/mTOR signaling pathway, which may ultimately lead to the occurrence of diabetes mellitus, and may be considered as one of the specific mechanisms of PTDM caused by tacrolimus.

13.
Andrologia ; : e14191, 2021 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-34278587

RESUMO

The aim of this study is to do a study of cryoinjury and ischaemic injury on testicular graft during cryopreservation and transplantation. According to time at 1, 3, 7 and 14 days after transplantation, the grafts were collected for immunohistochemistry assay for CD34 (blood vessel marker), VEGF (neoangiogenesis marker), caspase-3 (apoptosis marker) MAGE-A4 (germ cell marker). A significant increase was observed in the density of VEGF-positive blood vessels on day 3, reached a peak on day 7. On post-transplant day 3, a sharp increase occurred in the rate of spermatogonia-expressing caspase-3 until the day 7. At 14th day after transplantation, the spermatogonia number per round tubule of nonfrozen grafts was 41 ± 5.9% from that of fresh control tissues, while, in frozen-thawed grafts, the spermatogonia number per round tubule was 36.8 ± 4.6% from that of fresh control tissues. In testicular grafts, angiogenesis initiated reperfusion from day 3, and the formation of new blood vessel generally is completed about 7 days after transplantation. Angiogenesis in grafts after transplantation plays a crucial role in the restoration of function. Therefore, minimising ischaemic injury as well as improvement of cryopreservation protocols are needed to improve testicular graft after freezing, thawing and grafting.

14.
Clin Pharmacol Ther ; 2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34287856

RESUMO

Our previous study showed that parenteral anticoagulation therapy (PACT) in the context of aggressive antiplatelet therapy failed to improve clinical outcomes in patients undergoing percutaneous coronary intervention (PCI) for non-ST-segment elevation acute coronary syndrome (NSTE-ACS). However, the roles of PACT in patients managed medically remains unknown. This observational cohort study enrolled NSTE-ACS patients receiving medical therapy from November 2014 to June 2017 in the Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome project. Eligible patients were included in the PACT group and non-PACT group. The primary outcomes were in-hospital all-cause mortality and major bleeding. The secondary outcome included minor bleeding. Among 23,726 patients, 8,845 eligible patients who received medical therapy were enrolled. After adjusting the potential confounders, PACT was not associated with a lower risk of in-hospital all-cause mortality (adjusted odds ratio [OR], 1.25, 95% confidence interval [CI], 0.92-1.71, P = 0.151). Additionally, PACT did not increase the incidence of major bleeding or minor bleeding (major bleeding: adjusted OR, 1.04, 95% CI, 0.80-1.35, P = 0.763, minor bleeding: adjusted OR, 1.27, 95% CI, 0.91-1.75, P = 0.156). The propensity score analysis confirmed the primary analyses. In patients with NSTE-ACS receiving antiplatelet therapy, PACT was not associated with a lower risk of in-hospital all-cause mortality or a higher bleeding risk in NSTE-ACS patients receiving non-invasive therapies and concurrent antiplatelet strategies. Randomized clinical trials are warranted to reevaluate the safety and efficacy of PACT in all NSTE-ACS patients who receive noninvasive therapies and current antithrombotic strategies.

15.
J Cancer Res Ther ; 17(3): 695-701, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34269301

RESUMO

Objectives: The aim of the study was to compare the relative diagnostic utility of low-dose computed tomography (LDCT) and standard-dose computed tomography (SDCT)-guided lung biopsy approaches. Materials and Methods: The PubMed, Embase, and Cochrane Library databases were searched for relevant studies published through August 2020. Data pertaining to endpoints including technical success, diagnostic performance, operative time, radiation dose, and complications, were extracted, and meta-analysis was performed using RevMan v5.3. Results: Three retrospective analyses and three randomized controlled trials, were included. The studies included 1977 lung lesions across 1927 patients who underwent LDCT-guided lung biopsy, and 887 lung lesions across 879 patients who underwent SDCT-guided lung biopsy. No significant differences were observed between these LDCT and SDCT groups with respect to the rates of technical success (99.0% vs. 99.5%, odds ratio [OR]: 1.82, P = 0.35,), diagnostic yield (79.6% vs. 76.2%, OR: 0.93, P = 0.47), diagnostic accuracy (96.1% vs. 96.1%, OR: 0.93, P = 0.69), operative time (mean difference [MD]: 1.04, P = 0.30), pneumothorax (19.9% vs. 21.3%, OR: 0.92, P = 0.43) or hemoptysis (4.6% vs. 5.8%, OR: 1.14, P = 0.54). Patients in the LDCT group received a significantly lower radiation dose (MD: ‒209.87, P < 0.00001) than patients in the SDCT group. Significant heterogeneity was observed with respect to the operative duration and radiation dose endpoints (I2 = 84% and 100%, respectively). Conclusions: Relative to SDCT-guided lung biopsy, an LDCT-guided approach is equally safe and can achieve comparable diagnostic efficacy while exposing patients to lower doses of radiation.

16.
J Hypertens ; 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34269332

RESUMO

BACKGROUND: Hypertension grows into a serious public health problem among young adults, linking to a set of life-threatening cardiovascular diseases (CVDs). Young adults are not well represented in current knowledge about the CVDs burden attributable to hypertension. METHODS: In this analysis of data from the GBD (Global Burden of Disease) study 2019, we focus on young adults and provide the first comprehensive and comparative assessment of the hypertension attributable CVDs burden, in terms of its mortality and years of living with disability (YLD) from 1990 to 2019, stratified by location, sex, and development status. RESULTS: Globally in 2019, the death and YLD numbers caused by hypertension-related CVDs were 640 239 and 2 717 474 in young adults, marking a 43.0 and 86.6% increase from 1990, respectively. The corresponding mortality rate dropped by 10.5%, whereas the YLD rate increased by 16.8% during the same period. V-shaped association between CVDs burden and social development status was observed. The largest burden and the most pronounced increase were borne by middle-income countries, while high-income countries had the lowest death/YLD rate with a quicker annual decline. Men largely outpaced women in hypertension attributable CVDs mortality. Ischemic heart disease and stroke were the leading cause for death and YLD burden, correspondingly. CONCLUSIONS: Hypertension attributable CVDs burden in young adults has greatly increased from 1990 to 2019, with considerably spatiotemporal and sexual heterogeneity. The largest burden was borne by middle-income countries, especially by men. Establishment of geographically and sexually tailored strategies were needed to prevent hypertension-related CVDs in young adults.

17.
Molecules ; 26(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201870

RESUMO

Flavonoids in Rosa sterilis were studied. The flavonoids in Rosa sterilis were extracted by ultrasonic method, and the extraction conditions were modeled and optimized by response the surface methodology and the artificial intelligence method. The results show that the ultrasonic method can effectively extract total flavonoids, and the extraction rate is close to the prediction value of ANN-GA algorithm, which proves the rationality of the model. The order of the effects of the parameters on the experiment was material liquid ratio > extraction power > extraction time > ethanol concentration. In addition, the scavenging effects of flavonoids on DPPH, O2-· and ·OH were also determined, and these indicated that flavonoids have strong antioxidant activities. The kinetics of the extraction process was studied by using the data of the extraction process, and it was found that the extraction process conformed to Fick's first law.

18.
Curr Atheroscler Rep ; 23(9): 50, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: covidwho-1296964

RESUMO

PURPOSE OF REVIEW: This review highlights late-breaking science presented at the Virtual American College of Cardiology Scientific Sessions 2021 that demonstrated advancements in preventative cardiology and introduced novel therapeutic modalities for the management of chronic kidney disease, heart failure, and COVID-19. RECENT FINDINGS: The studies reviewed include clinical trials that assessed the use of dapagliflozin in patients with respiratory failure due to COVID-19 (DARE-19 trial); evinacumab for patients with severe hypertriglyceridemia and pancreatitis; effect of genotype-guided oral P2y12 inhibitors vs conventional clopidogrel on long-term ischemic outcomes after percutaneous coronary intervention (TAILOR-PCI trial); anticoagulation in patients hospitalized with COVID-19 (ACTION trial); atorvastatin vs placebo in patients with COVID-19 admitted to the ICU (INSPIRATION-S trial); rehabilitation therapy in older acute heart failure patients (REHAB-HF trial); and aspirin dosing: a patient-centric trial assessing benefits and long-term effectiveness (ADAPTABLE trial). In addition, we review the results of the American College of Cardiology Global Heart Attack Initiative (GHATI). Finally, we discuss the secondary analysis of the STRENGTH trial assessing the association of achieved levels of omega-3 fatty acid levels and major cardiovascular outcomes. The studies presented at the virtual American College of Cardiology Scientific Session 2021 represent remarkable contributions in the field of cardiovascular disease and prevention.

19.
SLAS Discov ; : 24725552211026261, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: covidwho-1290310

RESUMO

The COVID-19 pandemic has clearly brought the healthcare systems worldwide to a breaking point, along with devastating socioeconomic consequences. The SARS-CoV-2 virus, which causes the disease, uses RNA capping to evade the human immune system. Nonstructural protein (nsp) 14 is one of the 16 nsps in SARS-CoV-2 and catalyzes the methylation of the viral RNA at N7-guanosine in the cap formation process. To discover small-molecule inhibitors of nsp14 methyltransferase (MTase) activity, we developed and employed a radiometric MTase assay to screen a library of 161 in-house synthesized S-adenosylmethionine (SAM) competitive MTase inhibitors and SAM analogs. Among six identified screening hits, SS148 inhibited nsp14 MTase activity with an IC50 value of 70 ± 6 nM and was selective against 20 human protein lysine MTases, indicating significant differences in SAM binding sites. Interestingly, DS0464 with an IC50 value of 1.1 ± 0.2 µM showed a bisubstrate competitive inhibitor mechanism of action. DS0464 was also selective against 28 out of 33 RNA, DNA, and protein MTases. The structure-activity relationship provided by these compounds should guide the optimization of selective bisubstrate nsp14 inhibitors and may provide a path toward a novel class of antivirals against COVID-19, and possibly other coronaviruses.

20.
Artigo em Inglês | MEDLINE | ID: mdl-34263300

RESUMO

AIMS: Previous observations revealed a negative association between low-density lipoprotein cholesterol (LDL-C) and clinical outcomes following myocardial infarction, i.e., the lower level the higher mortality, which was referred to as lipid paradox. We sought to re-evaluate this association in ST-elevation myocardial infarction (STEMI) in contemporary practice. METHODS AND RESULTS: We examined the association between admission LDL-C and in-hospital mortality among 44 563 STEMI patients enrolled from 2014 to 2019 in a nationwide registry in China. A total of 43 covariates, which were temporally classified into the following three domains were used for adjustment: (i) pre-admission characteristics; (ii) percutaneous coronary intervention (PCI)-related variables; and (iii) other in-hospital medications. In-hospital mortality was 2.01% (897/44 563). When no covariate adjustment was performed, an inversely 'J-shaped' curve was observed between admission LDL-C levels and in-hospital mortality by restricted cubic spline in logistic regression, with a threshold value of <75 mg/dL that associated with increased risk for in-hospital mortality. However, a gradual attenuation for this association was noted when step-wise adjustments were performed, with the threshold values for LDL-C decreasing from 75 mg/dL to 70 mg/dL after accounting for pre-admission characteristics, further to 65 mg/dL after accounting for PCI-related variables, and finally to no statistical association after further adjustment for other in-hospital medications. CONCLUSIONS: In a nationwide registry in China, our findings do not support the lipid paradox in terms of in-hospital mortality in STEMI patients in contemporary practice. Previous findings in this scenario are possibly due to inadequate control for confounders.

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