In early 2020, China experienced a mass outbreak of a novel coronavirus disease (COVID-19). With an aim to evaluate the impact of emission variations on toxic element species in PM2.5 and the health ...risks associated with inhalation exposure during COVID-19, we collected PM2.5 filter samples in Beijing from January 1 to February 28, 2020. Positive matrix factorization (PMF) and a health risk (HR) assessment model were used to assess the health risks of the toxic elements and critical risk sources. The total concentration of eight toxic elements (Se, Cd, Pb, Zn, As, Cu, Ni, and Cr) in Beijing showed a trend of first increasing and then decreasing: full lockdown (322.9 ng m−3) > pre-lockdown (264.2 ng m−3) > partial lockdown (245.3 ng m−3). During the lockdown period, stringent control measures resulted in significant reductions (6−20%) in Zn, Pb, Cd, and Ni levels, while concentrations of Se, As, Cu, and Cr were unexpectedly elevated (14−348%). A total of five sources was identified: traffic emission, coal combustion, dust emission, industrial emission and mixed source of biomass burning and firework combustion. Total carcinogenic risk (TCR) of the selected toxic elements exceeded the US EPA limits for children and adults. As and Cr (IV) were the main contributors to non-carcinogenic and carcinogenic risks, respectively. For source-resolved risks, coal combustion was the main contributor to HI (43%), while industrial emissions were the main cause of TCR (45%). Additionally, increased contributions from coal combustion, biomass burning, and firework combustion during the full lockdown elevated the HI and TCR values.
In most researches of electroosmosis with chemical injection, inorganic salt solutions (calcium chloride (CaCl
2
) solution, sodium silicate (Na
2
SiO
3
) solution) are commonly used as injection ...materials. However, polymer which may be more energy-efficient was seldom used as injection material. This study focused on polyaluminium chloride (PAC, Al
2
(OH)
n
Cl
6-n
m
) solution as injection material to enhance the improvement effect of soil. The effect of different PAC concentrations was evaluated through six laboratory tests. Electrokinetic geosynthetics (EKG) plate was used as electrode material. The results demonstrated that the injection of PAC solution is effective of increasing the soil dewatering, decreasing the energy consumption and shortening the electroosmosis duration. Net final drainage volume had a positive association with introduced Al mass. With the increase of PAC concentration, final drainage volume and introduced Al mass both increased first and then decreased with the optimal concentration of 15%. For the purpose of obtaining maximum drainage and homogeneous consolidation effect, PAC solution of 15% was proved to be the optimal concentration. However, considering the energy consumption, 10% was the optimal concentration. In practical projects, PAC solution of 10~15% concentration can be used considering both energy consumption and improvement effect.
The human ether-a-go-go-related gene (hERG) encodes the K
channel that carries the rapid component of the delayed rectifier current in the human heart. Reduction of hERG activity induced by gene ...mutations or pharmacological inhibition is responsible for the type 2 form of long QT syndrome in patients which can develop into ventricular arrhythmia and sudden cardiac death. Therefore, pharmacological activation of hERG may lead to therapeutic potential for cardiac arrhythmias. In this study we characterized a small and novel compound, N-(2-(tert-butyl)phenyl)-6-(4-chlorophenyl)-4-(trifluoromethyl) nicotinamide, HW-0168, that exhibits potent activation of hERG channel with an EC
of 0.41 ± 0.2 μM. Using whole-cell patch clamp recording of HEK293 cells stably expressed hERG channels, we found that HW-0168 dramatically increased current amplitude about 2.5 folds and slowed down current inactivation about 4 folds. HW-0168 shifted the voltage-dependent channel activation to hyperpolarizing direction about 3.7 mV and the voltage-dependent channel inactivation to depolarizing direction about 9.4 mV. In addition, recording of guinea-pig ventricular cells confirmed that HW-0168 shortened the action potential duration. In conclusion, we identified a novel hERG channel activator HW-0168 that can be used for studying the physiological role of hERG in cardiac myocytes and may be beneficial for treating long QT syndrome.
Background Aortic stenosis (AS) in combination with left ventricular outflow tract obstruction (LVOTO) has occasionally been reported. However, making a precise diagnosis and successfully treating ...this combination is challenging due to the hemodynamic interaction between the two conditions. Case summary A 56-year-old male patient who had been diagnosed with severe AS and asymmetric left ventricular hypertrophy underwent aortic valve replacement (AVR) and a conventional septal myectomy. Immediately after the procedure, significant systolic anterior motion and mitral regurgitation developed, necessitating a surgical mitral edge-to-edge repair. Ten days after the procedure, the patient developed hematuria and LVOTO, which was confirmed by echocardiography. Because the LVOTO might have been the cause of the hematuria, the patient underwent alcohol septal ablation, but this had little effect. Three months later, a transapical beating-heart septal myectomy (TA-BSM) was performed in our hospital. Postoperatively, the LVOTO had been significantly ameliorated and the hematuria had resolved. Conclusion For patients with AS and LVOTO due to a hypertrophic interventricular septum, inadequate amelioration of the LVOTO after AVR may lead to severe hemolytic hematuria. TA-BSM is a minimally invasive, safe, and effective surgical procedure for ameliorating LVOTO in patients with aortic valve prostheses.
Intestinal microbiota has been confirmed to influencing the pharmacokinetic processes of a variety of oral drugs. However, the pharmacokinetic effects of the gut microbiota on cyclosporine A, a drug ...with a narrow therapeutic window, remain to be studied.
Twenty-one rats were randomly divided into three groups: (a) control group (CON), (b) antibiotic treatment group (ABT) and (c) fecal microbe transplantation group (FMT). The ABT group was administrated with water containing multiple antibiotics to deplete microorganisms. FMT was with the same treatment, followed by oral administration of conventional rat fecal microorganisms for normalization.
The bioavailability of CSA increased by 155.6% after intestinal microbes were consumed by antibiotics. After intestinal microbiota reconstruction by fecal transplantation, the increased bioavailability was significantly reduced and basically returned to the control group level. Changes in gut microbiota alter the protein expression of CYP3A1, UGT1A1 and P-gp in liver. The expressions of these three proteins in ABT group were significantly lower than those in CON and FMT groups. The relative abundance of
and
was negatively correlated with CSA bioavailability while the relative abundance of
and
was negatively correlated with CSA bioavailability.
Intestinal microbiota affects the pharmacokinetics of CSA by regulating the expression of CYP3A1, UGT1A1 and P-GP.
The purposes of this study were to identify physiological and genetic factors that contributed to variability of pemetrexed (PEM) exposure and to optimize the dosing regimens for Chinese non-small ...cell lung carcinoma patients. A prospective population pharmacokinetics (PPK) research was performed in this population. The PEM concentrations of 192 plasma samples from 116 in-hospital patients were detected. All patients were genotyped for polymorphisms. The PPK model of PEM was developed. The pharmacokinetic behavior of PEM was described by a two-compartment model with first-order elimination. The population typical values were as follows: clearance (CL) 8.29 L/h, intercompartmental clearance (Q) 0.10 L/h, central volume of distribution (V1) 18.94 L and peripheral volume of distribution (V2) 5.12 L. Creatinine clearance (CrCl) was identified as a covariate to CL, and ERCC1 (rs3212986) and CYP3A5 (rs776746) gene polymorphisms as covariates to Q. By using empirical body surface area (BSA)-based dosing strategy, PEM exposure decreased with the elevation of CrCl. Contrarily, CrCl-based dosing strategy exhibited a satisfactory efficacy of achieving the target PEM exposure. BSA-based dosing regimen in current clinic practice is not suitable to achieve the target exposure in PEM chemotherapy of Chinese NSCLC patients. Alternatively, renal function-based dosing strategy is suggested.
Usher syndrome (USH) is a group of disorders manifested as retinitis pigmentosa and bilateral sensorineural hearing loss, with or without vestibular dysfunction. Here, we recruited three Chinese ...families affected with autosomal recessive USH for detailed clinical evaluations and for mutation screening in the genes associated with inherited retinal diseases. Using targeted next-generation sequencing (NGS) approach, three new alleles and one known mutation in MYO7A gene were identified in the three families. In two families with USH type 1, novel homozygous frameshift variant p.Pro194Hisfs*13 and recurrent missense variant p.Thr165Met were demonstrated as the causative mutations respectively. Crystal structural analysis denoted that p.Thr165Met would very likely change the tertiary structure of the protein encoded by MYO7A. In another family affected with USH type 2, novel biallelic mutations in MYO7A, c.1343+1G>A;2837T>G or p.?;Met946Arg, were identified with clinical significance. Because MYO7A, to our knowledge, has rarely been correlated with USH type 2, our findings therefore reveal distinguished clinical phenotypes associated with MYO7A. We also conclude that targeted NGS is an effective approach for genetic diagnosis for USH, which can further provide better understanding of genotype-phenotype relationship of the disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The hierarchical porous SiOC ceramics (HPSCs) have been prepared by the pyrolysis of precursors (the mixture of dimethicone and KH-570) and polyacrylonitrile nanofibers (porous template). The HPSCs ...possess hierarchical porous structure with a BET surface area of 51.4 m
2
/g and have a good anti-oxidation property (only 5.1 wt.% weight loss). Owing to the porous structure, the HPSCs deliver an optimal reflection loss value of − 47.9 dB at 12.24 GHz and an effective absorption bandwidth of 4.56 GHz with a thickness of 2.3 mm. The amorphous SiOC, SiO
x
, and free carbon components within SiOC make contributions to enhancing dipolar polarization. Besides, the abundant interfaces between SiOC and carbon nanofibers (CNFs) are favorable for improving interfacial polarization. The conductive loss arisen from cross-linked CNFs can also boost the microwave absorption performance.
Cognitive dysfunction is a core symptom common in psychiatric disorders including depression that is primarily managed by antidepressants lacking efficacy in improving cognition. In this study, we ...report a novel dual serotonin transporter and voltage-gated potassium Kv7/KCNQ/M-channel inhibitor D01 (a 2-methyl-3-aryloxy-3-heteroarylpropylamines derivative) that exhibits both anti-depression effects and improvements in cognition. D01 inhibits serotonin transporters (Ki = 30.1 ± 6.9 nmol/L) and M channels (IC50 = 10.1 ± 2.4 μmol/L). D01 also reduces the immobility duration in the mouse FST and TST assays in a dose-dependent manner without a stimulatory effect on locomotion. Intragastric administrations of D01 (20 and 40 mg/kg) can significantly shorten the immobility time in a mouse model of chronic restraint stress (CRS)-induced depression-like behavior. Additionally, D01 dose-dependently improves the cognitive deficit induced by CRS in Morris water maze test and increases the exploration time with novel objects in normal or scopolamine-induced cognitive deficits in mice, but not fluoxetine. Furthermore, D01 reverses the long-term potentiation (LTP) inhibition induced by scopolamine. Taken together, our findings demonstrate that D01, a dual-target serotonin reuptake and M channel inhibitor, is highly effective in the treatment-resistant depression and cognitive deficits, thus holding potential for development as therapy of depression with cognitive deficits.
Compound D01, a novel dual serotonin transporter and M-channel inhibitor, is effective in alleviating depression and improving cognitive function, thus holding developmental potential for therapy of depression with cognitive deficits. Display omitted
Retinitis pigmentosa (RP) is the most common form of inherited retinal dystrophy presenting remarkable genetic heterogeneity. Genetic annotations would help with better clinical assessments and ...benefit gene therapy, and therefore should be recommended for RP patients. This report reveals the disease causing mutations in two RP pedigrees with confusing inheritance patterns using whole exome sequencing (WES).
Twenty-five participants including eight patients from two families were recruited and received comprehensive ophthalmic evaluations. WES was applied for mutation identification. Bioinformatics annotations, intrafamilial co-segregation tests, and in silico analyses were subsequently conducted for mutation verification.
All patients were clinically diagnosed with RP. The first family included two siblings born to parents with consanguineous marriage; however, no potential pathogenic variant was found shared by both patients. Further analysis revealed that the female patient carried a recurrent homozygous C8ORF37 p.W185*, while the male patient had hemizygous OFD1 p.T120A. The second family was found to segregate mutations in two genes, TULP1 and RP1. Two patients born to consanguineous marriage carried homozygous TULP1 p.R419W, while a recurrent heterozygous RP1 p.L762Yfs*17 was found in another four patients presenting an autosomal dominant inheritance pattern. Crystal structural analysis further indicated that the substitution from arginine to tryptophan at the highly conserved residue 419 of TULP1 could lead to the elimination of two hydrogen bonds between residue 419 and residues V488 and S534. All four genes, including C8ORF37, OFD1, TULP1 and RP1, have been previously implicated in RP etiology.
Our study demonstrates the coexistence of diverse inheritance modes and mutations affecting distinct disease causing genes in two RP families with consanguineous marriage. Our data provide novel insights into assessments of complicated pedigrees, reinforce the genetic complexity of RP, and highlight the need for extensive molecular evaluations in such challenging families with diverse inheritance modes and mutations.
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