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1.
Aging (Albany NY) ; 132021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33819187

RESUMO

Myocardial infarction (MI) is one of the leading causes of death. Wilms' tumor 1-associating protein (WTAP), one of the components of the m6A methyltransferase complex, has been shown to affect gene expression via regulating mRNA modification. Although WTAP has been implicated in various diseases, its role in MI is unclear. In this study, we found that hypoxia/reoxygenation (H/R) time-dependently increased WTAP expression, which in turn promoted endoplasmic reticulum (ER) stress and apoptosis, in human cardiomyocytes (AC16). H/R effects on ER stress and apoptosis were all blocked by silencing of WTAP, promoted by WTAP overexpression, and ameliorated by administration of ER stress inhibitor, 4-PBA. We then investigated the underlying molecular mechanism and found that WTAP affected m6A methylation of ATF4 mRNA to regulate its expression, and that the inhibitory effects of WTAP on ER stress and apoptosis were ATF4 dependent. Finally, WTAP's effects on myocardial I/R injury were confirmed in vivo. WTAP promoted myocardial I/R injury through promoting ER stress and cell apoptosis by regulating m6A modification of ATF4 mRNA. These findings highlight the importance of WTAP in I/R injury and provide new insights into therapeutic strategies for MI.

2.
Zhongguo Zhen Jiu ; 41(3): 243-6, 2021 Mar 12.
Artigo em Chinês | MEDLINE | ID: mdl-33798303

RESUMO

OBJECTIVE: To compare the clinical therapeutic effect on coronavirus disease 2019 (COVID-19) with insomnia between the combined treatment of baduanjin and auricular point sticking therapy and the medication with oral estazolam on the base of the conventional treatment. METHODS: A total of 90 patients with COVID-19 accompanied with insomnia were randomly divided into an observation group (45 cases, 3 cases dropped off) and a control group (45 cases). In the observation group, baduanjin, a traditional Chinese fitness activity, was practiced everyday. Besides, auricular point sticking therapy was exerted at ear-shenmen (TF 4), subcortex (AT 4), heart (CO 15), occiput (AT 3), etc. These auricular points were pressed and kneaded three times a day, 30 s at each point each time, consecutively for 12 days. In the control group, estazolam tablets were prescribed for oral administration, 1 mg, once daily, consecutively for 12 days. Before and after treatment, the score of Pittsburgh sleep quality index (PSQI), the score of self-rating anxiety scale (SAS), the score of self-rating depression scale (SDS) and the score of symptoms in traditional Chinese medicine (TCM) were observed in the two groups and the clinical therapeutic effect was evaluated. RESULTS: After treatment, the scores of every item and the total scores in PSQI were all reduced as compared with those before treatment in the two groups (P<0.01). The scores of sleep time and sleep efficiency in the observation group were lower than those in the control group after treatment (P<0.05). SAS scores and SDS scores in the observation group and SAS score in the control group after treatment were all reduced as compared with those before treatment (P<0.01), and SDS score in the observation group was lower than that in the control group (P<0.01). After treatment, in the observation group, the score of each of the symptoms of TCM, i.e. unsound sleep, irritability and hot temper, profuse sputum and sticky feeling in the mouth, bitter taste in the mouth and foul breath, abdominal distention and poor appetite, as well as lassitude was reduced as compared with that before treatment successively (P<0.01), and the scores aforementioned (excepted for the unsound sleep) in the observation group were all lower than the control group (P<0.05). The total effective rates were 83.3% (35/42) in the observation group and 84.4% (38/45) in the control group, without statistical difference in comparison (P>0.05). CONCLUSION: The combined treatment of baduanjin and auricular point sticking therapy improves sleep quality, the conditions of anxiety and depression and the symptoms in TCM for patients of COVID-19 with insomnia. The therapeutic effect of this combined treatment is better than the oral administration of estazolam.


Assuntos
Terapia por Acupuntura , Distúrbios do Início e da Manutenção do Sono , Pontos de Acupuntura , Humanos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Distúrbios do Início e da Manutenção do Sono/etiologia , Resultado do Tratamento
3.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(2): 547-552, 2021 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-33812429

RESUMO

OBJECTIVE: To explore the clinical features, prognosis and survival of patients with IgD multiple myeloma (MM). METHODS: The clinical data of 20 patients with IgD MM was analyzed retrospectively. The prognostic factors and survival analysis was carried out. We summarized their clinical characteristics. The survival analysis was carried out by Kaplan-Meier method, and the prognostic factor were analyzed by using log-rank test for single factor analysis of observation index. Variables of P<0.15 in single factor analysis were enrolled in multifactor cox regression analysis. RESULTS: IgD MM patients accounted for 4.3% of all MM patients in the same period, among which 80% were male, the median age of patients was 57.5(35-77) years old, 90% of the patients belongs to λ light chain type. At the time of diagnosis, 18 patients (90%) were in DS-Ⅲ stages, while 10 patients were in ISS-Ⅲ stage. The first clinical manifestations were fatigue, bone pain, kidney function impairment, anemia (Hb<100 g/L) in 14 cases (70%), 12 cases (60%) with osteolytic bone destruction≥3, combined with renal impairment in 8 cases (40%), and elevated blood calcium in 11 cases (51.4%). In only 5 patients the ratio of albumin to globntin was inverted, hypoalbuminemia accounted for 40%, and globulin increase accounted for only 15%. FISH results showed that the positive rate of 1q21 amplification (50%) was the highest, and it was easy to occur at the same time as other cytogenetic abnormalities. Extramedullary infiltration occurred in 4 cases (20%). The analysis of prognostic factors showed that only the increase of lactate dehydrogenase (LDH) level was an independent poor prognostic factor for IgD MM patients. Extramedullary infiltration and various cytogenetic abnormalities were found in 2 IgD MM patients with primary drug resistance, suggesting that extramedullary infiltration and various cytogenetic abnormalities may be prognostic factors, but the difference was not statistically significant, Which maybe related to the small sample size. All 20 patients were treated with bortezomib-containing regimen, of which 19 patients were evaluated, 17 patients (89.4%) showed effective, including CR+VGPR (52.6%), PR (31.5%), MR (5.3%), 2 patients primary drug resistance. The median PFS and OS was 9.5 and 10.5 months, respectively. CONCLUSION: IgD MM is a rare and invasive disease. Increased LDH is an independent prognostic factor. Bortizomib-containing regimen can improve the prognosis of IgD MM patients.


Assuntos
Mieloma Múltiplo , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Imunoglobulina D , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
5.
Artigo em Inglês | MEDLINE | ID: mdl-33829761

RESUMO

The integration of reactive oxygen species (ROS)-involved molecular dynamic therapy (MDT) and photodynamic therapy (PDT) holds great promise for enhanced anticancer effects. Herein, we report a biodegradable tumor microenvironment-responsive nanoplatform composed of sinoporphyrin sodium (SPS) photosensitizer-loaded zinc peroxide nanoparticles (SPS@ZnO2 NPs), which can enhance the action of ROS through the production of hydrogen peroxide (H2O2) and singlet oxygen (1O2) for MDT and PDT, respectively, and the depletion of glutathione (GSH). Under these conditions, SPS@ZnO2 NPs show excellent MDT/PDT synergistic therapeutic effects. We demonstrate that the SPS@ZnO2 NPs quickly degrade to H2O2 and endogenous Zn2+ in an acidic tumor environment and produce toxic 1O2 with 630 nm laser irradiation both in vitro and in vivo. Anticancer mechanistic studies show that excessive production of ROS damages lysosomes and mitochondria and induces cellular apoptosis. We show that SPS@ZnO2 NPs increase the uptake and penetration depth of photosensitizers in cells. In addition, the fluorescence of SPS is a powerful diagnostic tool for the treatment of tumors. The depletion of intracellular GSH through H2O2 production and the release of cathepsin B enhance the effectiveness of PDT. This theranostic nanoplatform provides a new avenue for tumor microenvironment-responsive and ROS-involved therapeutic strategies with synergistic enhancement of antitumor activity.

6.
J Exp Med ; 218(5)2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-33710283

RESUMO

The role of the PYHIN family member absent in melanoma 2 (AIM2), another important inflammasome sensor, in EAE remains unclear. In this study, we found that AIM2 negatively regulates the pathogenesis of EAE independent of inflammasome activation. AIM2 deficiency enhanced microglia activation and infiltration of peripheral immune cells into the CNS, thereby promoting neuroinflammation and demyelination during EAE. Mechanistically, AIM2 negatively regulates the DNA-PK-AKT3 in microglia to control neuroinflammation synergistically induced by cGAS and DNA-PK. Administration of a DNA-PK inhibitor reduced the severity of the EAE. Collectively, these findings identify a new role for AIM2 in controlling the onset of EAE. Furthermore, delineation of the underlying inflammasome-independent mechanism highlights cGAS and DNA-PK signaling as potential targets for the treatment of heterogeneous MS.

7.
J Clin Neurosci ; 86: 10-17, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33775311

RESUMO

BACKGROUND: Endovascular thrombectomy (EVT) is the first-line treatment for patients with acute ischemic stroke (AIS). However, the optimal anesthetic modality during EVT is unclear. Therefore, this systematic review and meta-analysis is aimed to summarize the current literatures from RCTs to provide new clinical evidence of choosing anesthetic modality for AIS patients when receiving EVT. METHODS: Literature search was conducted in following databases, EMBASE, MEDLINE, Web of Science, and the Cochrane Library, for relevant randomized controlled trials (RCTs) comparing general anesthesia (GA) and conscious sedation (CS) for AIS patients during EVT. We used the Cochrane Collaboration criteria for assessment of risk bias of included studies. The heterogeneity of outcomes was assessed by I2statistic. RESULTS: 5 RCTs with 498 patients were included. GA was conducted in 251 patients and CS in 247 patients. EVT under GA in AIS patients had higher rates of successful recanalization (RR: 1.13, 95% CI: 1.04-1.23; P = 0.004; I2 = 40.6%) and functional independence at 3 months (RR: 1.28, 95% CI: 1.05-1.55; P = 0.013; I2 = 18.2%) than CS. However, GA was associated with higher risk of mean arterial pressure (MAP) drop (RR: 1.71, 95% CI: 1.19-2.47; P < 0.01; I2 = 80%) and pneumonia (RR: 2.32, 95% CI: 1.23-4.37; P = 0.009; I2 = 33.5%). There was no difference between GA and CS groups in mortality at 3 months, interventional complications, intracerebral hemorrhage and cerebral infarction after 30 days. CONCLUSIONS: GA was superior over CS in successful recanalization and functional independence at 3 months when performing EVT in AIS patients. However, GA was associated with higher risk of MAP drop and pneumonia. Therefore, results of ongoing RCTs will provide new clinical evidence of anesthetic modality selection during EVT in the future.

8.
Eye (Lond) ; 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33767408

RESUMO

OBJECTIVES: To investigate the differences in lncRNAs expression in whole blood between diabetic retinopathy (DR) patients and healthy subjects, and to evaluate the potential value of lncRNAs as a diagnostic biomarker for proliferative diabetic retinopathy (PDR). METHODS: A series of 34 PDR patients, 34 patients with non-proliferative DR (NPDR) and 34 healthy participants were enroled. Differentially expressed lncRNAs were demonstrated using high-throughput sequencing and validated using qRT-PCR. Gene Ontology (GO) was performed to explore the possible biological function of the differentially expressed lncRNAs. lncRNA/mRNA coexpression network was built to determine the targets of differentially expressed lncRNAs. Receiver operating characteristic (ROC) analysis was utilized to evaluate the diagnostic value of lncRNAs for PDR. RESULTS: We identified 175 and 179 differentially expressed lncRNAs in PDR patients compared with control samples and NPDR patients, respectively. GO analysis showed that the various metabolic processes were possibly influenced by these dysregulated lncRNAs. Using the differently expressed lncRNAs data, we further identified 82 overlapping lncRNAs in PDR patients with NPDR and control subjects. Part of these overlapping lncRNAs was significantly correlated with nuclear factor kappa B (NF-κB) and Wnt signal pathways. ROC curves were constructed for two upregulated lncRNAs and the ROC analysis indicated that both of them had potential diagnostic value and could distinguish PDR from control subjects and NPDR patients. CONCLUSIONS: LncRNAs expression was altered in PDR patients compared with NPDR and control subjects. Moreover, it provides a resource that lncRNAs might be novel diagnostic and prognostic biomarker for PDR.

9.
Microb Pathog ; 154: 104825, 2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33689812

RESUMO

The study aimed to induce the white-opaque-gray tri-stable transformation in clinical C. albicans and to explore their potential pathogenicity. Sixty-four clinical strains were used to induce the white, opaque and gray cells of C. albicans. Secreted aspartyl proteinases (Sap) activity of the three phenotypes was then measured, and a vulvovaginal candidiasis (VVC) animal model was constructed. Of the 64 clinical strains, only 3 strains successfully underwent white-gray-opaque tri-stable transformation, and the three strains all belonged to MTL homozygous strains. Pz values in white, opaque and gray phenotypes were 0.834 ± 0.012, 0.707 ± 0.036, and 0.628 ± 0.002, respectively, which indicated that the cells with gray phenotype had higher Sap activity. After inoculation of different fungal suspension, the fungal colony count in descending order was as follows: gray phenotype, opaque phenotype and white phenotype. After treated with fluconazole for 3 days or 10 days, the fungal colony counts were significantly decreased compared with that before treatment (P < 0.05). The Sap activity and pathogenicity of gray cells in C. albicans were the strongest, followed by opaque cells and white cells. Additionally, white, gray and opaque phenotypic cells were all susceptible to fluconazole.

10.
Bioorg Med Chem Lett ; 40: 127968, 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33753264

RESUMO

A series of 5-phenyloxazole-2-carboxylic acid derivatives were synthesized, and their structure-activity relationships (SARs) were studied. N,5-diphenyloxazole-2-carboxamides 6, 7, and 9, which mimicked ABT751, showed improved cytotoxicity compared with ABT751. Compound 9 exhibited the highest antiproliferative activities against Hela A549, and HepG2 cancer cell lines, with IC50 values of 0.78, 1.08, and 1.27 µM, respectively. Furthermore, compound 9 showed selectivity for human cancer cells over normal cells, and this selectivity was greater than those of ABT751 and colchicine. Preliminary mechanism studies suggested that compound 9 inhibited tubulin polymerization and led to cell cycle arrest at G2/M phase. Molecular docking studies indicated that compound 9 bound to the colchicine binding site of tubulin. Our findings provided insights into useful SARs for further structural modification of inhibitors of tubulin polymerization.

11.
Huan Jing Ke Xue ; 42(3): 1065-1072, 2021 Mar 08.
Artigo em Chinês | MEDLINE | ID: mdl-33742902

RESUMO

With the rapid development of China's economy and society, the polycyclic aromatic hydrocarbon (PAH) pollution of surface soil has attracted increasing attention. Based on a systematic review, this study identified 166 relevant papers (published from 2000 to 2020) dealing with the contamination of 16 PAHs in the surface soil of China and summarized the pollution level, temporal, and spatial distribution influencing factors of PAHs with statistics, spatial interpolation analysis, and source analysis methods. The results showed that the surface soil of China has been polluted by human-caused PAHs, with a median concentration of 675.70 µg·kg-1. Although the overall condition is good, some sampling points have been seriously polluted. Among the monomers of PAHs, the concentrations of fluoranthene (Fla) and pyrene (Pyr) are high, while acenaphthylene (Acy) and acenaphthene (Ace) are relatively low. During the survey period, the concentration data of surface soil PAHs are generally within the moderate pollution levels of 313.10-1070.45 µg·kg-1, while the annual changes of PAHs do not show obvious fluctuations and are less affected by oil production and consumption. Statistics and spatial interpolation results show that PAH pollution in the surface soil of China has regional characteristics, where the concentration decreases in order from northwest, north, east, northeast, southwest, and south-central China. The pollution level in most provinces is "contaminated" or "weakly contaminated." From the source analysis results, PAH pollution in surface soils in most areas of China comes from the high-temperature combustion of fossil fuels such as petroleum, biomass, and coal. Heilongjiang and some northwestern regions (e.g., Xinjiang and Tibet) were mainly represented by oil source pollution. Such results could provide a reference for soil environmental management and PAH pollution control in China.

12.
Eur J Neurol ; 2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33686758

RESUMO

BACKGROUND AND PURPOSE: The Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) was developed using Rasch methodology. This scale has been demonstrated as a reliable outcome measure of amyotrophic lateral sclerosis (ALS) trials. To date, there are no similar interval-weighted scales to assess disability in ALS patients. The current study aimed to validate a Chinese version of the ROADS via Rasch methodology. METHODS: The Chinese version of the ROADS was obtained through a standardized forward-backward translation and cultural adaptation. ALS patients were recruited from the Department of Neurology of Peking University Third Hospital in Beijing, China to complete the ROADS and the revised ALS Functional Rating Scale (ALSFRS-R). Overall, 254 participants with ALS finished the Chinese scale. Rasch analysis was performed on the ROADS for validation and the ALSFRS-R for comparison. RESULTS: The Chinese version of the ROADS was modified according to the statistical results. A final 28-question scale was constructed that fulfilled all the requirements of the Rasch model with proper validity and reliability. Furthermore, the ROADS showed improved item targeting compared to the ALSFRS-R. Conversely, the ALSFRS-R did not fit the Rasch model expectations due to misfit values and disordered thresholds for all 12 items. CONCLUSIONS: The Chinese adaptation of the ROADS is a linearly weighted scale that specifically captures overall disability in ALS patients. This scale indicates a wider range of item difficulties and better responsiveness than the ALSFRS-R. The ROADS could be used as a valuable tool for use in ALS trials and in the clinic in Chinese settings.

13.
J Mater Chem B ; 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33666636

RESUMO

Multifunctional contrast-enhanced agents suitable for application in surgical navigation by taking advantage of the merits of their diverse imaging modalities at different surgical stages are highly sought-after. Herein, an amphipathic polymer composed of aggregation-induced emission fluorogens (AIEgens) and Gd3+ chelates was successfully synthesized and assembled into ultrasound responsive microbubbles (AIE-Gd MBs) to realize potential tri-modal contrast-enhanced ultrasound (US) imaging, magnetic resonance imaging (MRI), and AIEgen-based fluorescence imaging (FI) during the perioperative period. Through ultrasound targeted microbubble destruction (UTMD) and cavitation effect, the as-prepared AIE-Gd MBs went through a MBs-to-nanoparticles (NPs) conversion, which not only resulted in targeted accumulation in tumor tissues but also led to stronger fluorescence being exhibited due to the more aggregated AIE-Gd molecules in the NPs. As a proof-of-concept, our work proposes a strategy of US-lit-up AIEgens in tumors which could offer a simple and powerful tool for surgical navigation in the future.

14.
Syst Rev ; 10(1): 66, 2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33663590

RESUMO

BACKGROUND: Stroke is the second leading cause of death worldwide, and 53.4% of stroke survivors suffer from post-stroke cognitive impairment. Post-stroke cognitive impairment can increase hospitalization rate and cost of care and decrease the quality of life of stroke patients. To date, multiple cognitive rehabilitation interventions have been tested in stroke populations with post-stroke cognitive impairment. However, the most efficacious intervention has not been established. This systematic review aims to compare the efficacy of cognitive rehabilitation interventions for patients with post-stroke cognitive impairment. METHODS: We will search MEDLINE, EMBASE, CENTRAL, PsycINFO, CINAHL, PubMed, and clinical trial registries to identify eligible randomized clinical trials with no restrictions in the date of publication and language. Studies conducted with patients aged 18 or over, with the presence of cognitive impairment after being diagnosed with stroke will be included. Studies will be restricted to randomized controlled trials comparing a cognitive rehabilitation intervention with another intervention. The primary outcome is any clinical changes in the general or specific cognitive domain (e.g., executive function, attention, memory, or perception). The secondary outcomes that will be collected include adverse effects (e.g., stroke, disability, or mortality) and quality of life. Two independent reviewers will assess articles to identify trials eligible for inclusion. Data extraction and risk of bias assessment of the included studies will also be done independently. Any discrepancies will be solved by discussion, or a third reviewer will be consulted if necessary. A meta-analysis will be carried out if appropriate. DISCUSSION: This systematic review for patients with post-stroke cognitive impairment will assess the efficacy of cognitive rehabilitation interventions. And our results will help clinical decision-making and support the development of clinical practice guidelines. TRIAL REGISTRATION: Systematic review registration: PROSPERO CRD42020173988.

15.
Phys Rev Lett ; 126(7): 072001, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33666473

RESUMO

We present for the first time complete next-to-next-to-leading-order coefficient functions to match flavor nonsinglet quark correlation functions in position space, which are calculable in lattice QCD, to parton distribution functions (PDFs). Using PDFs extracted from experimental data and our calculated matching coefficients, we predict valence-quark correlation functions that can be confronted by lattice QCD calculations. The uncertainty of our predictions is greatly reduced with higher order matching coefficients. By performing Fourier transformation, we also obtain matching coefficients for corresponding quasi-PDFs and pseudo-PDFs. Our method of calculations can be readily generalized to evaluate the matching coefficients for sea-quark and gluon correlation functions, making the program to extract partonic structure of hadrons from lattice QCD calculations comparable with and complementary to that from experimental measurements.

16.
Front Med ; 2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33687643

RESUMO

Tocilizumab has been reported to attenuate the "cytokine storm" in COVID-19 patients. We attempted to verify the effectiveness and safety of tocilizumab therapy in COVID-19 and identify patients most likely to benefit from this treatment. We conducted a randomized, controlled, open-label multicenter trial among COVID-19 patients. The patients were randomly assigned in a 1:1 ratio to receive either tocilizumab in addition to standard care or standard care alone. The cure rate, changes of oxygen saturation and interference, and inflammation biomarkers were observed. Thirty-three patients were randomized to the tocilizumab group, and 32 patients to the control group. The cure rate in the tocilizumab group was higher than that in the control group, but the difference was not statistically significant (94.12% vs. 87.10%, rate difference 95% CI-7.19%-21.23%, P = 0.4133). The improvement in hypoxia for the tocilizumab group was higher from day 4 onward and statistically significant from day 12 (P = 0.0359). In moderate disease patients with bilateral pulmonary lesions, the hypoxia ameliorated earlier after tocilizumab treatment, and less patients (1/12, 8.33%) needed an increase of inhaled oxygen concentration compared with the controls (4/6, 66.67%; rate difference 95% CI-99.17% to-17.50%, P = 0.0217). No severe adverse events occurred. More mild temporary adverse events were recorded in tocilizumab recipients (20/34, 58.82%) than the controls (4/31, 12.90%). Tocilizumab can improve hypoxia without unacceptable side effect profile and significant influences on the time virus load becomes negative. For patients with bilateral pulmonary lesions and elevated IL-6 levels, tocilizumab could be recommended to improve outcome.

17.
Artigo em Inglês | MEDLINE | ID: mdl-33710420

RESUMO

Methyl siloxanes are widely found in the environment, but little is known about the distributions of these chemicals in soils especially in areas where they are manufactured. We determined the concentrations of four cyclic (D3-D6) and 13 linear methyl siloxanes (L4-L16) in the soils from a siloxane-manufacturing site in China; the total concentrations of these 17 siloxanes (TSi) in the soils were 17.1-3,191 (median, 134) ng/g. We did not find extremely high concentrations of siloxanes in the soils. The median concentrations of total cyclic siloxanes (TCSi) were approximately sevenfold higher than those of total linear congeners. Hexamethylcyclotrisiloxane and octamethylcyclotetrasiloxane contributed a median of 59.7% and 20.3% of the TSi concentrations, respectively. Higher concentrations of soil TCSi were found in the silicone-manufacturing area relative to the other study areas. Source analysis indicated that industrial activities contributed substantially to soil siloxanes, in addition to the contribution of the siloxane emissions from specific consumer products. We calculated that the median values of daily TSi intakes through soil ingestion were 0.021 and 0.138 ng/kg-body weight/day for adults and children, respectively, under high exposure scenarios. Although our estimated daily intakes of the chemicals from soils were low, more research is required to improve our understanding of the health risks posed to humans exposed to siloxanes through other pathways.

18.
J Virol ; 2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33692215

RESUMO

Within a year after its emergence, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 100 million people worldwide with a death toll over 2 million. Vaccination remains the best hope to ultimately put this pandemic to an end. Here, using Trimer-Tag technology, we produced both wild-type (WT) and furin site mutant (MT) S-Trimers for COVID-19 vaccine studies. Cryo-EM structures of the WT and MT S-Trimers, determined at 3.2 Å and 2.6 Å respectively, revealed that both antigens adopt a tightly closed conformation and their structures are essentially identical to that of the previously solved full-length WT S protein in detergent. The tightly closed conformation is stabilized by fatty acid and polysorbate 80 binding at the receptor binding domains (RBDs) and the N terminal domains (NTDs) respectively. Additionally, we identified an important pH switch in the WT S-Trimer that shows dramatic conformational change and accounts for its increased stability at lower pH. These results validate Trimer-Tag as a platform technology in production of metastable WT S-Trimer as a candidate for COVID-19 subunit vaccine.IMPORTANCEEffective vaccine against SARS-CoV-2 is critical to end the COVID-19 pandemic. Here, using Trimer-Tag technology, we are able to produce stable and large quantities of WT S-Trimer, a subunit vaccine candidate for COVID-19 with high safety and efficacy from animal and Phase 1 clinical trial studies. Cryo-EM structures of the S-Trimer subunit vaccine candidate show that it predominately adopts tightly closed pre-fusion state, and resembles that of the native and full-length spike in detergent, confirming its structural integrity. WT S-Trimer is currently being evaluated in global Phase 2/3 clinical trial. Combining with published structures of the S protein, we also propose a model to dissect the conformation change of the spike protein before receptor binding.

19.
Trials ; 22(1): 216, 2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33736674

RESUMO

BACKGROUND: Acute pharyngitis and tonsillitis are common respiratory diseases for which children seek medical care. Their main clinical manifestation is sore throat which interferes with patients' quality of life. However, there is no proven effective or safe method to treat it. It is necessary to find an excellent strategy to reduce sore throat and reduce the burden of acute illness. We designed the randomized controlled trial with the characteristics of traditional Chinese medicine (TCM) to determine the clinical positioning of Kai-Hou-Jian spray (children's type) (KHJS) through evidence-based research. This trial aims to evaluate the immediate analgesic efficacy of KHJS on sore throat caused by acute pharyngitis and tonsillitis (wind-heat syndrome/heat exuberance in lung and stomach syndrome) in children and to observe its safety. METHODS/DESIGN: This is a prospective, multicenter, randomized, double-blind, parallel-group, placebo-controlled trial. It will include 240 children with acute pharyngitis/tonsillitis from 7 study sites across China. All participants are randomly assigned to two parallel treatment groups, one with KHJS and the other with placebo sprays, for 5 consecutive days. The primary outcome is the time of analgesic onset. Secondary outcomes include duration of analgesic effect, area under time curve of 0-3 h Wong-Baker FACES Pain Rating Scale (WBS) score (AUC0-3 h), rate of analgesic onset, rate of disappearance of sore throat, changes of WBS score (in days), effective rate of pharyngeal signs, and effective rate of TCM syndrome. The incidence of adverse events during the trial is the primary safety outcome. In addition, vital signs and laboratory tests before and after medication are monitored. DISCUSSION: To our knowledge, this will be the first clinical trial to explore the immediate analgesic efficacy of a Chinese patent medicine spray for acute pharyngitis/tonsillitis induced sore throat in children in a multicenter, randomized, double-blinded, parallel-group, placebo-controlled manner. Not only might it prove the efficacy and safety of KHJS in the treatment of sore throat caused by acute pharyngitis/tonsillitis in children, but it might also provide evidence for the treatment of acute sore throat with Chinese herbal medicine. TRIAL REGISTRATION: A multicenter, randomized, double-blind, very low-dose, parallel controlled trial for the immediate analgesic effect and safety of Kai-Hou- Jian spray (children's type) in the treatment of sore throat caused by acute pharyngitis and tonsillitis in children. Chinese Clinical Trial Registry ChiCTR2000031599 . Registered on 5 April 2020.

20.
J Org Chem ; 2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33729800

RESUMO

Hydroboration reactions of carboxylic acids using sodium aminodiboranate (NaNH2[BH3]2, NaADBH) to form primary alcohols were systematically investigated, and the reduction mechanism was elucidated experimentally and computationally. The transfer of hydride ions from B atoms to C atoms, the key step in the mechanism, was theoretically illustrated and supported by experimental results. The intermediates of NH2B2H5, PhCH═CHCOOBH2NH2BH3-, PhCH═CHCH2OBO, and the byproducts of BH4-, NH2BH2, and NH2BH3- were identified and characterized by 11B and 1H NMR. The reducing capacity of NaADBH was found between that of NaBH4 and LiAlH4. We have thus found that NaADBH is a promising reducing agent for hydroboration because of its stability and easy handling. These reactions exhibit excellent yields and good selectivity, therefore providing alternative synthetic approaches for the conversion of carboxylic acids to primary alcohols with a wide range of functional group tolerance.

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