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1.
J Clin Invest ; 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34128834

RESUMO

Disordered lysosomal/autophagy pathways initiate and drive pancreatitis, but the underlying mechanisms and links to disease pathology are poorly understood. Here, we show that mannose-6-phosphate (M6P) pathway of hydrolase delivery to lysosomes critically regulates pancreatic acinar cell cholesterol metabolism. Ablation of the Gnptab gene coding for a key enzyme in M6P pathway disrupted acinar cell cholesterol turnover, causing accumulation of non-esterified cholesterol in lysosomes/autolysosomes, its' depletion in the plasma membrane, and upregulation of cholesterol synthesis and uptake. We found similar dysregulation of acinar cell cholesterol, and a decrease in GNPTAB levels, in both WT experimental pancreatitis and human disease. The mechanisms mediating pancreatic cholesterol dyshomeostasis in Gnptab-/- and experimental models involve disordered endolysosomal system, resulting in impaired cholesterol transport through lysosomes and blockage of autophagic flux. By contrast, in Gnptab-/- liver the endolysosomal system and cholesterol homeostasis were largely unaffected. Gnptab-/- mice developed spontaneous pancreatitis. Normalization of cholesterol metabolism by pharmacologic means alleviated responses of experimental pancreatitis, particularly trypsinogen activation, the disease hallmark. The results reveal the essential role of M6P pathway in maintaining exocrine pancreas homeostasis and function, and implicate cholesterol disordering in the pathogenesis of pancreatitis.

2.
Toxicol Ind Health ; 37(5): 251-259, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34078187

RESUMO

This study investigated hepatic oxidative damage in rats following long-term manganese (Mn) exposure and clarified the underlying mechanisms. Forty-eight rats (SPF, male) were randomly assigned to receive low (10 mg/kg, n = 16) or high doses of Mn (50 mg/kg, n = 16) or sterilized distilled water (control group, n = 16). Rats were euthanized after 12 months, and liver Mn levels and histopathological changes were determined. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and liver malondialdehyde (MDA), glutathione peroxidase (GSH-PX), nuclear factor E2-related factor-2 (Nrf2), heme oxygenase-1 (HO-1), and NAD(P)H quinine oxidoreductase-1 (NQO1) levels were also determined. The Mn concentration and relative liver weights were significantly higher in the high-dose Mn group than in the control and low-dose Mn exposure groups. Low-dose Mn exposure resulted in mild expansion of hepatic sinuses and intact nuclei, whereas high-dose exposure led to pathological alterations in hepatocytes. High-dose Mn treatment significantly increased AST, ALT, and MDA activities and decreased GSH-PX activity. Additionally, liver Nrf2, HO-1, and NQO1 protein expression were markedly reduced by Mn exposure. Under the study conditions, long-term low-dose Mn exposure resulted in slight pathological changes in liver structure, but high-dose Mn exposure affected both liver structure and function, which might be related to the inhibition of Nrf2 expression, suppression of the transcription of its underlying antioxidant genes, and down regulation of the corresponding proteins. Consequently, the antioxidant capacity in the rat liver was weakened.

3.
Front Public Health ; 9: 671400, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34079787

RESUMO

The prevalence and related factors of mental health impact among medical staffs who experienced the second wave of the COVID-19 pandemic in China is unknown. Therefore, this survey was conducted to investigate the prevalence and related factors of depressive, anxiety, acute stress, and insomnia symptoms in medical staffs in Kashi, Xinjiang, China during the second wave of the COVID-19 pandemic. A cross-sectional online survey was conducted among medical staffs working in First People's Hospital of Kashi, Xinjiang. The questionnaire collected demographic data and self-design questions related to the COVID-19 pandemic. The Impact of Events Scale-6, the Insomnia Severity Index, the Patient Health Questionnaire-9, the Generalized Anxiety Disorder Scale-7, the Perceived Social Support Scale, the Chinese Big Five Personality Inventory-15, and the Trait Coping Style Questionnaire were used to measure psychological symptoms or characteristics. Binary logistic regression was carried out to examine the associations between socio-demographic factors and symptoms of depression, anxiety, stress, and insomnia. In total, data from 123 participants were finally included, among which the prevalence rate of depressive, anxiety, acute stress, and insomnia symptoms is 60.2, 49.6, 43.1, and 41.1%, respectively. The regression model revealed that minority ethnicity, being worried about infection, spending more time on following pandemic information, and neurotic personality were positively associated with the mental health symptoms, while extraversion personality, higher education level, and better social support were negatively associated. In our study, the prevalence of mental health impact was high among medical staffs in Kashi, China who experienced the second wave of the COVID-19 pandemic. Several factors were found to be associated with mental health conditions. These findings could help identify medical staffs at risk for mental health problems and be helpful for making precise mental health intervention policies during the resurgence. Our study may pave way for more research into Xinjiang during the COVID-19 pandemic.


Assuntos
Distúrbios do Início e da Manutenção do Sono , Ansiedade/epidemiologia , China/epidemiologia , Estudos Transversais , Depressão/epidemiologia , Humanos , Corpo Clínico , Pandemias , Prevalência , Distúrbios do Início e da Manutenção do Sono/epidemiologia
4.
Phys Chem Chem Phys ; 2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34105559

RESUMO

The efficiency of cascade reactions, which consist of multiple chemical transformations that occur in a single pot without purification steps, is limited by the transport efficiency of intermediates between adjacent steps. Electrostatic channeling is a proven strategy for intermediate transfer in natural chemical cascades, but implementation into artificial cascades remains a challenge. Here, we combine infrequent metadynamics (InMetaD), umbrella sampling (US), and kinetic Monte Carlo (KMC) models to computationally study the transfer mechanism of glucose-6-phosphate (G6P) on a poly-arginine peptide bridging hexokinase (HK) and glucose-6-dehydrogenase (G6PDH). Transport of G6P by hopping in the presence of poly-arginine peptides is shown to be a rare event, and InMetaD is used to compute the hopping activation energy. US simulations capture the configurational change in the desorption process and enable the determination of the desorption energy. Parameterized by these results, a KMC model is used to estimate transport efficiency for the bridged enzyme complex. Results are compared to a similar complex using a poly-lysine bridge, using kinetic lag time as a metric. Even at a high ionic strength of 120 mM, poly-arginine peptides may be capable of more efficient transport as compared to poly-lysine, with a predicted lag time of 6 seconds for poly-arginine, compared to a previously reported lag time of 59 seconds for poly-lysine. This work indicates that poly-arginine peptides may be an improved bridge structure for electrostatic channeling of anionic intermediates.

5.
Environ Int ; 154: 106564, 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33964723

RESUMO

BACKGROUND: Ecologic analyses suggest that living in areas with higher levels of ambient fine particulate matter air pollution (PM2.5) is associated with higher risk of adverse COVID-19 outcomes. Studies accounting for individual-level health characteristics are lacking. METHODS: We leveraged the breadth and depth of the US Department of Veterans Affairs national healthcare databases and built a national cohort of 169,102 COVID-19 positive United States Veterans, enrolled between March 2, 2020 and January 31, 2021, and followed them through February 15, 2021. Annual average 2018 PM2.5 exposure, at an approximately 1 km2 resolution, was linked with residential street address at the year prior to COVID-19 positive test. COVID-19 hospitalization was defined as first hospital admission between 7 days prior to, and 15 days after, the first COVID-19 positive date. Adjusted Poisson regression assessed the association of PM2.5 with risk of hospitalization. RESULTS: There were 25,422 (15.0%) hospitalizations; 5,448 (11.9%), 5,056 (13.0%), 7,159 (16.1%), and 7,759 (19.4%) were in the lowest to highest PM2.5 quartile, respectively. In models adjusted for State, demographic and behavioral factors, contextual characteristics, and characteristics of the pandemic a one interquartile range increase in PM2.5 (1.9 µg/m3) was associated with a 10% (95% CI: 8%-12%) increase in risk of hospitalization. The association of PM2.5 and risk of hospitalization among COVID-19 individuals was present in each wave of the pandemic. Models of non-linear exposure-response suggested increased risk at PM2.5 concentrations below the national standard 12 µg/m3. Formal effect modification analyses suggested higher risk of hospitalization associated with PM2.5 in Black people compared to White people (p = 0.045), and in those living in socioeconomically disadvantaged neighborhoods (p < 0.001). CONCLUSIONS: Exposure to higher levels of PM2.5 was associated with increased risk of hospitalization among COVID-19 infected individuals. The risk was evident at PM2.5 levels below the regulatory standards. The analysis identified those of Black race and those living in disadvantaged neighborhoods as population groups that may be more susceptible to the untoward effect of PM2.5 on risk of hospitalization in the setting of COVID-19.

6.
Huan Jing Ke Xue ; 42(6): 2908-2916, 2021 Jun 08.
Artigo em Chinês | MEDLINE | ID: mdl-34032090

RESUMO

In this study, the functional material SZVI-SA is successfully prepared to efficiently remove Cr(Ⅵ) from water. This composite, with micron zero-valent iron (ZVI) as its core, is sulfurized and loaded by sodium alginate (SA). Some parameters affecting the Cr(Ⅵ) removal are also tested, including the type and mass fraction of chelating agents as well as S/Fe. SEM-EDS, TEM, XRD, and XPS are used to characterize and analyze the material. The results show that 7% Fe3+ is most suitable as the chelating agent for sodium alginate, and a S/Fe ratio of 3.5 and drying temperature of 70℃ are the ideal formation conditions. The effect of SZVI-SA on the removal of Cr(Ⅵ) is in line with the secondary adsorption rate model, mainly affected by the availability of binding sites. The active ingredient was identified as FeS, and the specific surface area can reach 97.83 m2·g-1. Many pores, especially micropores, are present in this material and in addition to Cr(Ⅵ), SZVI-SA was found to effectively remove Cr(Ⅲ) and Fe(Ⅲ) from the test solution. Overall, the Cr(Ⅵ)-removal efficiency was 92%; the removal mechanism is mainly via redox reactions; and the main reducing active substances are Fe2+, S2-, and S22-. Following the reaction of Fe(Ⅲ) and Cr(Ⅲ), Fe(OH)3 and Cr(OH)3 are formed and Cr2O3 precipitation separation occurs.

7.
J Am Heart Assoc ; 10(11): e020237, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34013739

RESUMO

Background The frequency of the initial short-term decline in estimated glomerular filtration rate (eGFR), eGFR dip, following initiation of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and its clinical implications in real-world practice are not clear. Methods and Results We built a cohort of 36 638 new users of SGLT2i and 209 025 new users of other antihyperglycemics. Inverse probability weighting was used to estimate the excess rate of eGFR dip, risk of the composite cardiovascular outcome of nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, or all-cause mortality, and risk of the composite kidney outcome of eGFR decline >50%, end-stage kidney disease, or all-cause mortality. In the first 6 months of therapy, compared with other antihyperglycemics, excess rates of eGFR dip >10% and eGFR dip >30% were 9.86 (95% CI: 8.83-11.00) and 1.15 (0.70-1.62) per 100 SGLT2i users, respectively. In mediation analyses that accounted for eGFR dipping, SGLT2i use was associated with reduced risk of cardiovascular and kidney outcomes (hazard ratio, 0.92 [0.84-0.99] and 0.78 [0.71-0.87], respectively); the magnitude of the association reduced by eGFR dipping was small for both outcomes. SGLT2i was associated with reduced risk of both outcomes in those with higher than average probability of eGFR dip >10% or 30%. Compared with discontinuation, continued use of SGLT2i at 6 months was associated with reduced risk of cardiovascular and kidney outcomes in those with no eGFR dip or eGFR dip ≤10%, in those with eGFR dip >10%, and in those with eGFR dip >30%. Conclusions The salutary association of SGLT2i with cardiovascular and kidney outcomes was maintained regardless of eGFR dipping; concerns about eGFR dipping should not preclude use, and occurrence of eGFR dip after SGLT2i initiation may not warrant discontinuation.

8.
Zhongguo Zhong Yao Za Zhi ; 46(8): 1967-1972, 2021 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-33982506

RESUMO

The article summarized the relevant researches on the clinical orientation of Chinese patent medicines, and put forward the post-marking principle and strategies of the clinical orientation. The principle could be illustrated by four criteria: overall design, step-by-step implementation, from easiness to hardness, gradual concentration. The strategies were as follows: first carrying out the projects with little cost of money and time, and then the projects requiring much cost of money and time, so that the possibility of fai-lure would be put forward at an early stage to reduce the loss caused by research failure as much as possible by consolidating the research projects with less investment at the early stage and gradually increasing the research projects with more investment at the later stage. On this basis, the "three dimensions and four stages" key technology was proposed for the post-marketing clinical orientation of traditional Chinese medicine. Medicines, diseases and patients were the "three dimensions", so we should understand the features and interaction of the target indications, symptoms and population to establish a three-dimensional clinical positioning coordinate system. "Four stages" were the four steps of clues analyzing, hypothesis orientation, preliminary verification and clinical validation. Each latter stage should be started after full completion of the former one, and the latter stage results shall be used to validate and revise the former clinical orientational hypothesis, continuously forming a feedback circle. Based on the sufficient verification of previous study, prospective clinical trials were implemented at last to get the best evidence-based evidence of clinical orientational hypothesis.


Assuntos
Medicamentos de Ervas Chinesas , Medicina Tradicional Chinesa , Humanos , Marketing , Medicamentos sem Prescrição , Estudos Prospectivos
9.
Zhongguo Zhong Yao Za Zhi ; 46(8): 1973-1979, 2021 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-33982507

RESUMO

At present, the value evaluation of Chinese patent medicines is in the exploratory stage, and a clinical value evaluation system that can reflect the characteristics of traditional Chinese medicine has not been established. This article investigates four universal drug value tools from abroad, namely, evidence rating matrix, cancer value label, patient-perspective value framework and multiple criteria decision analysis advance value framework. The evidence rating matrix is used to measure the benefits and risks of different treatment measures, and the net health benefit is used as the best estimate point to evaluate the value of treatment; the cancer value label is mainly used to weigh the economic value and innovative value of drug treatment programs of different anti-tumor drugs by matrix composed the ratio between the expected result and the cost; the patient-perspective value framework emphasizes the evaluation of the value of different healthcare intervention methods from the patient's perspective; multiple criteria decision analysis advance value framework measures the value of drugs or measures from multiple dimensions. Combined with the characteristics of the above universal drug value evaluation tools and the correlation research of domestic drug value evaluation, the paper proposes to analyze the characteristics of Chinese patent medicine value evaluation from the six dimensions of effectiveness, safety, innovation, economy, suitability and accessibility of Chinese patent medicine, and expounds the strategy of constructing Chinese patent medicine value evaluation tool, so as to provide reference for the drug value evaluation and decision-making application of Chinese patent medicine.


Assuntos
Medicamentos de Ervas Chinesas , China , Humanos , Medicina Tradicional Chinesa , Medicamentos sem Prescrição
10.
Zhongguo Zhong Yao Za Zhi ; 46(8): 1988-1993, 2021 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-33982509

RESUMO

Classical Chinese patent medicines(CPMs) are a kind of modern preparation developed from the experience of compatibility and application about ancient prescriptions. Its rich history of human use and reliable clinical efficacy imply the unique theoretical essence and precious value of traditional Chinese medicine(TCM). With the development of evidence-based medicine and the improvement of medical policy, it is particularly urgent to evaluate the clinical values of post-marketing classical CPMs. In this paper, some problems on the clinical value evaluation of CPMs would be described, and it is considered that the simplified evaluation procedures can lead to the lack of evidence for evaluating clinical value of CPMs, causing the difficulty in evaluating the quality of CPM, lack of R&D motivation of enterprises, low content of science and technology, and poor international development. Based on this background, it points out that the clinical value evaluation is the core of the post-marketing evaluation of the classical CPMs, and the eva-luation should be based on the direction of literature research and the latest practice. We should adhere to the research mode of combination disease with syndrome, and select the appropriate type of trials, with clinical efficacy, health economic benefits and safety eva-luation as the main content of the studies, in order to refine the indications and standardize the clinical positioning. Clinical value eva-luation is the basis and main content of post-marketing comprehensive researches on classic and famous CPMs to clarify their clinical value, obtain the conditions for continued marketingand standardize their clinical application, so as to optimize the evidence and quality service of classic and famous CPMs and inherit the core value concept of Chinese medicine.


Assuntos
Medicamentos de Ervas Chinesas , Medicamentos sem Prescrição , China , Humanos , Marketing , Medicina Tradicional Chinesa
11.
Zhongguo Zhong Yao Za Zhi ; 46(8): 1994-1998, 2021 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-33982510

RESUMO

Post-marketing evaluation of traditional Chinese medicine(TCM) is an important research stage in the life cycle of a drug, and the add-on-design is a common method for its post-marketing evaluation. This article introduces the basic concept of add-on-design, and points out that it is suitable for use based on the principles of medical ethics when the standard treatment should not be interrupted. The post-marketing evaluation of TCM should be carried out based on human experience and in compliance with regulations and ethics. The clinical values of TCM, such as the therapeutic effect for disease, improvement of disease symptoms, improvement in quality of life, as well as the synergism and toxicity attenuation of combined use of TCM and chemical drugs, should be fully reflected through the clinical trials designed with add-on-design. The key points of add-on-design are accurate clinical positioning, scientific estimation of sample size, and rigorous standard treatment. Standard treatment should be a recognized one, consistent and stable; appropriate and recognized efficacy indicators and targeted safety indicators should be selected; the design and operation of clinical research scheme should meet the requirements of randomization and blind method, with special emphasis on the production of qualified placebo. The add-on-design has the advantages that the rights and interests of the subjects are adequately protected. Besides, the research conclusions are easily put into clinical application. But there are also many difficulties, such as the influence of confounding bias, the "ceiling" effect of clinical efficacy, and the difficulty of interpretation of adverse events. Therefore, a rigorous research quality assu-rance system should be established, and the quality control of evaluation consistency of researchers should be emphasized to ensure strict quality control in the research process.


Assuntos
Medicamentos de Ervas Chinesas , Medicina Tradicional Chinesa , Humanos , Marketing , Controle de Qualidade , Qualidade de Vida
12.
Zhongguo Zhong Yao Za Zhi ; 46(8): 2010-2015, 2021 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-33982513

RESUMO

This paper introduced the basic definition, application scope, advantages and challenges of the master protocol, basket design, umbrella design and platform trial, and put forward the idea of using master protocol, basket design and umbrella design in Chinese medicine(CM) by considering the characteristics of CM and research experiences. The author pointed out that master protocol, basket design and umbrella design, as a high-efficiency research and design strategy, can be used in the clinical research on the treatment of the same disease with different therapies, the treatment of different diseases with the same therapy and the combination of diseases and CM syndromes. In particular, the exploration from the classification of CM syndromes can supplement the gaps in the cli-nical research on CM syndromes. In the application of such designs, it is also necessary to pay attention to their potential challenges and develop reasonable and feasible plans on research implementation, management and statistical analysis in advance to meet these challenges.


Assuntos
Medicina Tradicional Chinesa , Medicina de Precisão , Suplementos Nutricionais , Registros , Projetos de Pesquisa
13.
Sci Rep ; 11(1): 10348, 2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-33990647

RESUMO

A mathematical model based on heat and mass transfer processes in the porous wick of electronic cigarettes was established to describe the atomization of e-liquids according to max liquid temperature, vaporization rate and thermal efficiency in a single puff. Dominant capillary-evaporation effects were defined in the model to account for the effects of electrical power, e-liquid composition and porosity of the wick material on atomization and energy transmission processes. Liquid temperature, vaporization rate, and thermal efficiency were predicted using the mathematical model in 64 groups, varying with electrical power, e-liquid composition and wick porosity. Experimental studies were carried out using a scaled-model test bench to validate the model's prediction. A higher PG/VG ratio in the e-liquid promoted energy transfer for vaporization, and the e-liquid temperature was comparatively reduced at a relatively high power, which was helpful to avoid atomizer overheating. Compared with the other factors, wick porosity affected the thermal efficiency more significantly. The vaporization rate increased with a higher wick porosity in a certain range. The modelling results suggested that a greater wick porosity and a higher PG ratio in e-liquids helped to improve the overall thermal efficiency.

14.
Zhongguo Zhong Yao Za Zhi ; 46(8): 1999-2003, 2021 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-33982511

RESUMO

Traditional Chinese medicines(TCMs) have certain limitations in the clinical research design in their post-marketing evaluation, so that randomized controlled programs cannot be strictly implemented in some studies, while the objective performance criteria is a reasonable external controlled research method that has been gradually recognized at home and abroad in recent years in addition to randomized controlled trial(RCT) method. It is more mature in medical devices, surgery and other research fields, but there is no relevant report in the field of post-marketing evaluation of Chinese patent medicines. In this paper, the application prospect of the objective performance criteria and the problems were discussed in the field of post-marketing evaluation of TCM. The characteristics of as TCM are more consistent with the scope of the objective performance criteria, the application of the objective performance criteria in post-marketing evaluation of Chinese patent medicines, especially in single arm research, can break through the limitations of existing conventional clinical research methods, and improve the level of evidence, with good feasibility and advantages. However, in the application process, we should pay attention to the key issues such as the selection of index, research population, follow-up period and the reference selection, to ensure the quality of research. This research group has carried out some exploration and practice in the field of post-marketing evaluation of TCM injections by using single arm combined with the objective performance criteria, hoping to establish the key technology in this field, and provide certain research and design reference for the secondary development of Chinese patent medicines.


Assuntos
Medicamentos de Ervas Chinesas , Medicina Tradicional Chinesa , Marketing , Medicamentos sem Prescrição , Vigilância de Produtos Comercializados , Ensaios Clínicos Controlados Aleatórios como Assunto
15.
J Hazard Mater ; 417: 125932, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-34020353

RESUMO

Genetic improvement could play a significant role in enhancing the Cd accumulation, translocation and tolerance in plants. In this study, for the first time, we constructed transgenic tall fescue overexpressing a class II (CII) sHSP gene FaHSP17.8-CII, which enhanced Cd tolerance and the root-to-shoot Cd translocation. After exposed to 400 µM CdCl2, two FaHSP17.8-CII overexpressing lines (OE#3 and OE#7) exhibited 30% and 40% more shoot fresh weight, respectively, relative to the wild-type (WT). Both transgenic lines showed higher tolerance to Cd, as evidenced by lower levels of electrolyte leakage and malondialdehyde compared to the WT plants under Cd stress. FaHSP17.8-CII overexpression increased shoot Cd contents 49-59% over the WT plants. The Cd translocation factor of root-to-shoot in OE grasses was 69-85% greater than WT under Cd stress. Furthermore, overexpression of FaHSP17.8-CII reduced Cd-induced damages of chloroplast ultra-structure and chlorophyll synthesis, and then improved photosystem II (PSII) function under Cd stress, which resulted in less reactive oxygen species (ROS) accumulation in OE grasses than that in WT exposed to Cd stress. The study suggests a novel FaHSP17.8-CII-PSII-ROS module to understand the mechanisms of Cd detoxification and tolerance, which provides a new strategy to improve phytoremediation efficiency in Cd-stressed grasses.

16.
Org Biomol Chem ; 19(18): 3960-3982, 2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-33978039

RESUMO

Bridged polycycles are privileged molecular skeletons with wide occurrence in bioactive natural products and pharmaceuticals. Therefore, they have been the pursing target molecules of numerous chemists. The rapid and convenient generation of sp3-rich complex three-dimensional molecular skeletons from simple and easily available aromatics has made dearomatization a highly valuable synthetic tool for the construction of rigid and challenging bridged rings. This review summarizes the-state-of-the-art advances of dearomatization strategies in the application of bridged ring formation, discusses their advantages and limitations and the in-depth mechanism, and highlights their synthetic value in the total synthesis of natural products. We wish this review will provide an important reference for medicinal and synthetic chemists and will inspire further development in this intriguing research area.

17.
Int J Infect Dis ; 108: 81-88, 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33862209

RESUMO

BACKGROUND: Although phenotypic drug susceptibility testing (DST) of Mycobacterium tuberculosis (Mtb) takes up to 6-8 weeks, little is known about how drug susceptibility is affected during this period. METHODS: We performed a prospective cohort study to investigate the development of drug resistance (DR) during turnaround time (TAT), including 359 pulmonary tuberculosis (PTB) patients with a baseline DST result of an Mtb isolate collected at TB diagnosis and a follow-up DST result of an Mtb isolate collected when baseline DST result was available between 2013 and 2018. Whole-genome sequencing (WGS) was used to differentiate between acquired drug resistance, exogenous reinfection, and mixed infection. RESULTS: Among the studied patients, during TAT for DST, 116 (32.3%) developed DR to four first-line drugs (rifampicin, isoniazid, pyrazinamide, ethambutol). Among 116 pairs of isolates included for WGS, 21 pairs were classified as acquired drug resistance with single nucleotide polymorphisms (SNPs) differences less than 12. Four pairs with an intermediate SNPs differences displayed minor differences in related genotypes and were assessed as mixed infection. The remaining 91 pairs had high SNPs differences consistent with exogenous reinfection. CONCLUSIONS: The exogenous reinfection of drug-resistant strains played a vital role in the development of DR of Mtb isolates during TAT for DST, highlighting the need for both rapid DST methods and improved infection control.

18.
FASEB J ; 35(5): e21455, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33913197

RESUMO

Mammal's milk is an abundantly foremost source of proteins, lipids, and micronutrients for human nutrition and health. Understanding the molecular mechanisms underlying synthesis of milk components provides practical benefits to improve the milk quality via systematic breeding program in mammals. Through RNAi with EEF1D in primary bovine mammary epithelial cells, we phenotypically observed aberrant formation of cytoplasmic lipid droplets and significantly decreased milk triglyceride level by 37.7%, and exploited the mechanisms by which EEF1D regulated milk lipid synthesis via insulin (PI3K-Akt), AMPK, and PPAR pathways. In the EEF1D CRISPR/Cas9 knockout mice, incompletely developed mammary glands at 9th day postpartum with small or unformed lumens, and significantly decreased triglyceride concentration in milk by 23.4% were observed, as well as the same gene expression alterations in the three pathways. For dairy cattle, we identified a critical regulatory mutation modifying EEF1D transcription activity, which interpreted 7% of the genetic variances of milk lipid yield and percentage. Our findings highlight the significance of EEF1D in mammary gland development and milk lipid synthesis in mammals.

19.
Nature ; 594(7862): 259-264, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33887749

RESUMO

The acute clinical manifestations of COVID-19 have been well characterized1,2, but the post-acute sequelae of this disease have not been comprehensively described. Here we use the national healthcare databases of the US Department of Veterans Affairs to systematically and comprehensively identify 6-month incident sequelae-including diagnoses, medication use and laboratory abnormalities-in patients with COVID-19 who survived for at least 30 days after diagnosis. We show that beyond the first 30 days of illness, people with COVID-19 exhibit a higher risk of death and use of health resources. Our high-dimensional approach identifies incident sequelae in the respiratory system, as well as several other sequelae that include nervous system and neurocognitive disorders, mental health disorders, metabolic disorders, cardiovascular disorders, gastrointestinal disorders, malaise, fatigue, musculoskeletal pain and anaemia. We show increased incident use of several therapeutic agents-including pain medications (opioids and non-opioids) as well as antidepressant, anxiolytic, antihypertensive and oral hypoglycaemic agents-as well as evidence of laboratory abnormalities in several organ systems. Our analysis of an array of prespecified outcomes reveals a risk gradient that increases according to the severity of the acute COVID-19 infection (that is, whether patients were not hospitalized, hospitalized or admitted to intensive care). Our findings show that a substantial burden of health loss that spans pulmonary and several extrapulmonary organ systems is experienced by patients who survive after the acute phase of COVID-19. These results will help to inform health system planning and the development of multidisciplinary care strategies to reduce chronic health loss among individuals with COVID-19.

20.
J Integr Plant Biol ; 2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33913600

RESUMO

CRISPR/Cas system has been widely used for precise gene editing in plants. However, simultaneous gene editing of multiple homoeoalleles remains challenging, especially in self-incompatible polyploid plants. Here, we simultaneously introduced targeted mutations in all three homoeoalleles of two genes in the self-incompatible allohexaploid tall fescue, using both CRISPR/Cas9 and LbCas12a (LbCpf1) systems. Loss-of-function mutants of FaPDS exhibited albino leaves, while knockout of FaHSP17.9 resulted in impaired heat resistance in T0 generation of tall fescue. Moreover, these mutations were inheritable. Our findings demonstrate the feasibility of generating loss-of-function mutants in a T0 generation polyploid perennial grasses using CRISPR/Cas systems. This article is protected by copyright. All rights reserved.

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