Urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) are important targets for the development of uric acid-lowering drugs. We previously showed that the flexible linkers of URAT1 inhibitors ...could enhance their potency. In this study we designed and synthesized CDER167, a novel RDEA3710 analogue, by introducing a linker (methylene) between the naphthalene and pyridine rings to increase flexibility, and characterized its pharmacological and pharmacokinetics properties in vitro and in vivo. We showed that CDER167 exerted dual-target inhibitory effects on both URAT1 and GLUT9: CDER167 concentration-dependently inhibited the uptake of
C-uric acid in URAT1-expressing HEK293 cells with an IC
value of 2.08 ± 0.31 μM, which was similar to that of RDEA3170 (its IC
value was 1.47 ± 0.23 μM). Using site-directed mutagenesis, we demonstrated that CDER167 might interact with URAT1 at S35 and F365. In GLUT9-expressing HEK293T cells, CDER167 concentration-dependently inhibited GLUT9 with an IC
value of 91.55 ± 15.28 μM, whereas RDEA3170 at 100 μM had no effect on GLUT9. In potassium oxonate-induced hyperuricemic mice, oral administration of CDER167 (10 mg·kg
· d
) for 7 days was more effective in lowering uric acid in blood and significantly promoted uric acid excretion in urine as compared with RDEA3170 (20 mg·kg
· d
) administered. The animal experiment proved the safety of CDER167. In addition, CDER167 displayed better bioavailability than RDEA3170, better metabolic stability and no hERG toxicity at 100 μM. These results suggest that CDER167 deserves further investigation as a candidate antihyperuricemic drug targeting URAT1 and GLUT9.
The influence of different replacement ratios of steel-slag powder as cement-replacement material on the fracture performance of concrete is studied in this paper. A three-point bending fracture test ...is carried out on slag powder-cement-based concrete (SPC)-notched beams with steel-slag powder as cementitious materials, partially replacing cement (0%, 5%, 10%, 15%, and 20%). Load-deflection curves and load-crack-opening displacement curves of SPC-notched beams with five different replacement ratios of steel-slag powder were obtained. The effects of different steel-slag-powder replacement ratios on the fracture properties (fracture energy, fracture toughness, and double-K fracture parameters) of the SPC were analyzed and discussed. The results showed that the incorporation of appropriate steel-slag powder can affect the fracture performance of SPC. Compared with concrete without steel-slag powder, adding appropriate steel-slag powder can effectively improve the bond performance between aggregate and matrix because the steel-slag powder contains hydration activity substances such as calcium oxide and aluminium trioxide. The fracture energy and fracture toughness of SPC increased and then decreased with the increase in steel-slag-powder replacement ratios, and the SPC concrete showed best fracture performance with a 5% steel slag powder replacement ratio. Its fracture energy increases by 13.63% and fracture toughness increases by 53.22% compared with NC.
Inspired by the typical two-dimensional (2D) black-phosphorene-type structure with
mm2
point-group symmetry, the structural stability, electronic structure, and intrinsic piezoelectricity of 2D ...ternary GaXY (X = Se and Te; Y = Cl, Br, and I) monolayers are systematically studied by the first-principles density functional theory. Our calculations show that these ternary monolayer compounds exhibit desirable dynamical and thermal stabilities and a large variety of bandgaps. The calculated piezoelectric coefficients
d
11
is as large as 15.57 pm/V for GaTeF, and the largest
d
12
reaches to 3.78 pm/V for GaSeI. It is worth noting that the
e
ij
and
d
ij
coefficients of GaXY monolayers display anisotropic periodic trends with respect to the constituent elements, which could be interpreted by a linear correlation between the piezoelectric coefficients and the differences in anionic polarizabilities
α
X
or
α
Y
. It is found that
d
11
of GaXY monolayers is directly proportional to
(
α
X
-
α
Y
)
, while
d
12
is inversely proportional to
(
α
X
-
α
Y
)
. Such anisotropic correlation could be applicable to elucidate the origin of the piezoelectricity in other 2D ternary compounds.
Graphical abstract
Urbanization in China is rapidly proceeding, but rural-to-urban migration and its association with overweight and obesity is not well studied. This study aimed to explore the age at arrival, duration ...of migration, and the corresponding association with overweight/obesity in Yi migrants in China.
A cross-sectional study was conducted in rural and urban areas in 2015 in Sichuan province, China. Demographic characteristics, lifestyle factors, and anthropometry were collected. General linear regression models were used to assess the effect of duration of migration (1-10, 11-20, 21-30, and >30 years) on body mass index (BMI). Multi-variable logistic regression was used to examine the association between duration of migration and overweight/obesity (BMI ≥ 25 kg/m2).
A total of 3056 Yi people (1894 Yi farmers and 1162 Yi migrants) aged 20 to 80 years were enrolled. After adjusting for age, sex, and other potential confounders, Yi migrants had 1.71 kg/m2 (95% confidence interval CI: 1.36-2.06) higher BMI and a 2.13-fold (95% CI: 1.71-2.65) higher risk of overweight/obesity than Yi farmers. In Yi migrants, stratified by age at arrival, no significant association between duration of migration and overweight/obesity was observed in those who were 0 to 20 years old at arrival. In comparison, in migrants >20 years old at arrival, compared with the reference group (1-10 years), long-term migration (>30 years) was found to be associated with overweight/obesity after adjustment (odds ratio: 1.85, 95% CI: 1.04-3.29).
Yi migrants were observed to have greater risk of overweight/obesity than Yi farmers. In Yi migrants, the risk of overweight/obesity increased according to the duration of migration, especially in those who were older upon their arrival.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to the outbreak of pneumonia in Wuhan. The virus is highly infectious. Patients with cancer might be susceptible to the viral ...infection because of the immunosuppressive state cause by therapies on tumors.
We present the clinical features of four cancer patients who were infected with SARS-CoV-2 in late January of 2020 in our hospital. Cases 1 and 3 were diagnosed as mild and common type of coronavirus disease 2019 (COVID-2019) and survived from the viral infection. They acquired SARS-CoV-2 infection during their staying in hospital under radiotherapy and surgery of the tumors. Cases 2 and 4 suffered from severe type of COVID-19, and Case 2 was dead owning to the advanced age, uncontrolled chronic B cell lymphocytic leukemia and many other underlying diseases. The immunosuppressive state induced by liver transplantation and anti-rejection therapy might contribute to the severity of COVID-19 in Case 4, who suffered from hepatitis B related hepatocellular carcinoma. However, Case 4 was recovered from COVID-19 after a combination therapy against virus, bacteria and fungi, and also respiratory support. Nearly all patients showed a decrease in lymphocytes including total CD3
T cells, B cells, and natural killer cells after infection of the virus.
The severity of COVID-19 might be influenced by immune system state and underlying diseases in cancer patients. And the treatment of SARS-CoV-2 infection in cancer patients is challenged by the immunosuppressive state of these patients under chemotherapy or surgery.
Acute mountain sickness is caused by sub-acute hypoxia in healthy individuals going rapidly to altitude. Both tissue hypoxia in vitro and whole-body hypoxia in vivo have been found to promote the ...release of reactive oxygen species. Nitronyl nitroxide can trap free radicals such as ·NO or ·OH, and may therefore be efficient protective agents. This study assessed the ability of nitronyl nitroxide to against acute mountain sickness as a free radical scavenger in acute high-altitude hypoxia mice model. Normobaric hypoxia and hypobaric hypoxia model were used to estimate the protect effects of nitronyl nitroxide against acute mountain sickness. Low pressure oxygen compartment system was used to stimulate high-altitude hypobaric hypoxia environment. Mice in nitronyl nitroxide groups survived longer than acetazolamide group in normobaric hypoxia test. Hydrogen peroxide (H2O2) and malondialdehyde (MDA) increased in both cerebrum and myocardium in vehicle group. The results indicated more radicals were generated during high-altitude hypobaric hypoxia environment. In therapeutic groups H2O2 and MDA were significantly reduced while the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) were similar to normal group. These results demonstrated that nitronyl nitroxide was an efficient tissue radical scavenger and a potential protective agent for acute mountain sickness.
Abstract Objective To evaluate the psychometric properties of the 6-item Kessler psychological distress scale (K6) in screening for serious mental illness (SMI) among undergraduates in a major ...comprehensive university in China. Method The K6 was self-completed by 8289 randomly sampled participants. A group of them ( n = 222) were re-assessed using K6 and interviewed using the Chinese version of Composite International Diagnostic Interview 3.1 (CIDI-3.1). Results The test–retest reliability of the K6 scale was 0.79, the Cronbach's alpha was 0.84, and its area under the receiver operating curve (AUC) for diagnosing CIDI-3.1 SMI was 0.85 (95% CI = 0.80–0.90). For the optimal cut-off of K6 (12/13), the sensitivity (SEN), specificity (SPE), positive predictive value (PPV), negative predictive value (NPV), and classification accuracy (AC) were 0.83, 0.79, 0.60, 0.93, and 0.80, respectively. The 12-month prevalence of SMI was estimated as 3.97% using this optimal cut-off. Binary logistic regression analysis (including gender, ethnicity, grade, number of siblings and family residency location) showed that only family residency location in rural areas compared to urban areas was significantly associated with more SMI. Conclusions This study documented the value of using the K6 for detecting SMI in Chinese undergraduate populations and supported its cross-cultural reliability and validity.
The effects of key parameters on locked mode induced disruption (LMiD) are investigated in EAST experiments. The experimental data for locked mode are collected from 2015 to 2022 when the externally ...applied resonant magnetic perturbation is successfully employed in EAST. In this dataset, ∼42% of the total shots are LMiD, while the remaining 58% are LM without disruption. To better analyze the LMiD, an intuitive physical process is proposed. The LMiD process can be divided into two stages, the evolution of magnetic islands and the loss of plasma stored energy. The LMiD can also be related to the evolution of the other 8 physical quantities. On the basis of this physical process analysis, the time scale and the influencing factors for LMiD are investigated using statistical analysis. It is found that the density (ne), the distance from the magnetic island outer boundary to the plasma last closed surface (dedge), the loop-voltage (Vloop), and the plasma core electron temperature (Te), which are consistent with the intuitive physical model, are key parameters to LMiD. In addition, other potentially important parameters, the relevant reasons, and statistical analysis on the parameter intervals where rapid disruption with greater harmfulness occurred have also been investigated.
The objective was to determine the effects of prebiotics and synbiotics on adults with functional constipation (FC). Medline, Embase and the Cochrane Library were searched for literature published up ...to February 2015. We selected randomized controlled trials (RCTs) that reported administration of prebiotics or synbiotics to adults with FC. The end points included stool frequency, stool consistency and other symptoms related to constipation. Mean differences (MD) or standard mean differences (SMD) were used for continuous outcomes and risk ratios for discontinuous outcomes using a random-effects model. The Cochrane Risk of Bias Tool was used to determine the quality of the trials. Funnel plots and Egger's test were used to analyze for publication bias. We included 5 RCTs involving 199 patients who were administered prebiotics and 8 RCTs involving 825 patients who were administered synbiotics. Prebiotics increased weekly stool frequency (MD: 1.01bowel movements/week, 95% CI: 0.04-1.99) and improved stool consistency (SMD: -0.59, 95% CI: -1.16 to -0.02). Subgroup analysis showed specific effects for galacto-oligosaccharides on stool frequency, consistency, ease of defecation and abdominal pain. Synbiotics significantly improved stool frequency (MD: 1.15bowel movements/week, 95% CI: 0.58-1.71), consistency (SMD: 0.63, 95% CI: 0.33-0.92) and reduced whole-gut transit time (MD: 13.52, 95% CI: -26.56 to -0.49) in patients with FC. Subgroup analysis showed specific effects for fructo-oligosaccharides and probiotic combinations on stool frequency, consistency, straining defecation and bloating. Galacto-oligosaccharides and synbiotics made up of fructo-oligosaccharides with probiotic combinations may improve stool frequency, consistency and some other symptoms related to constipation.
Heavy ion radiotherapy has shown great promise for cancer therapy. Understanding the cellular response mechanism to heavy ion radiation is required to explore measures of overcoming devastating side ...effects. Here, we performed a quantitative proteomic analysis to investigate the mechanism of carbon ion irradiation on human AHH-1 lymphoblastoid cells. We identified 4602 proteins and quantified 4569 proteins showing high coverage in the mitochondria. Data are available via ProteomeXchange with identifier PXD008351. After stringent filtering, 290 proteins were found to be significantly up-regulated and 16 proteins were down-regulated. Functional analysis revealed that these up-regulated proteins were enriched in the process of DNA damage repair, mitochondrial ribosome, and particularly mitochondrial respiratory chain, accounting for approximately 50% of the accumulated proteins. Bioinformatics and functional analysis demonstrated that these up-regulated mitochondrial respiratory chain proteins enhanced ATP production and simultaneously reactive oxygen species release. More importantly, increased reactive oxygen species led to secondary organelle injury and lagged DNA double-strand breaks. Consistently, the expression of antioxidant enzymes was up-regulated for free radical scavenging. The mechanism of lagged secondary injury originated from disturbances in the mitochondrial respiratory chain. Our results provided a novel target for cell self-repair against heavy ion radiation-induced cellular damage.
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