The current therapies to treat hepatitis B virus (HBV) infection are limited. Recently, clustered regularly interspaced short palindromic repeat (CRISPR) systems, originally identified in bacteria ...and archaea, have been found to consist of an RNA-based adaptive immune system that degrades complimentary sequences of invading plasmids and viruses. Here, we studied the effects of the CRISPR/CRISPR-associated Cas9 system that was targeted to the surface antigen (HBsAg)-encoding region of HBV, both in a cell culture system and in vivo. The HBsAg levels in the media of the cells and in the sera of mice were analyzed by a quantitative enzyme-linked immunosorbent assay. The HBV DNA levels were assessed by quantitative PCR and HBsAg expression in mouse livers was assessed by an immunohistochemical assay. The amount of HBsAg secreted in the cell culture and mouse serum was reduced by CRISPR/Cas9 treatment. Immunohistochemistry analyses showed almost no HBsAg-positive cells in the liver tissue of CRISPR/Cas9-S1+X3-treated mice. The CRISPR/Cas9 system efficiently produced mutations in HBV DNA. Thus, CRISPR/Cas9 inhibits HBV replication and expression in vitro and in vivo and may constitute a new therapeutic strategy for HBV infection.
The prevalence of diabetes in China is among the highest in the world. For this reason, findings from the 2016 Global Burden of Disease (GBD) study were used to calculate the burden of hyperglycaemia ...and diabetes in China.
Following the general analytical strategy used in GBD 2016, diabetes prevalence and mortality were analyzed by age and gender. Trends in disability-adjusted life years (DALYs) due to diabetes were assessed in 33 province-level administrative units from 1990 to 2016, and similar data were provided for chronic kidney disease (CKD) related to diabetes and, as an overall summarizing measure, for hyperglycaemia expressed as high fasting plasma glucose (HFPG).
From 1990 to 2016, all-age prevalence of diabetes rose from 3.7% to 6.6%, and all-age diabetes and diabetes-related CKD mortality rates increased by 63.5% and 33.3%, respectively, with both rates increasing more rapidly in diabetes patients aged 15–49 years than in any other age groups. In 2016, HFPG became China's sixth leading cause of DALYs, and the attributable DALYs burden was 1802.3/100,000 population. Although the number of diabetes DALYs increased by 95% from 1990 to 2016, age-standardized diabetes DALYs rates increased by only 2.3%. Also, from 1990 to 2016, rates of age-standardized DALYs due to diabetes decreased in 14 provinces, but increased in 19 provinces. High BMI Scores and diets low in whole grains, nuts and seeds were the most important risk factors for diabetes in 2016.
Diabetes and hyperglycaemia constitute a huge health burden in China. The substantial increase in diabetes-related burden represents an ongoing challenge, given the rapidly ageing Chinese population. Thus, a targeted control and preventative strategy needs to be developed at risk factor level to reduce this burden.
Although many studies on lepidopteran pheromone‐binding proteins (PBPs)/ general odorant‐binding proteins (GOBPs) have been reported, the functional differentiation within and between the two ...odorant‐binding protein (OBP) subclasses is still elusive. Here we conducted a comparative study on three SexiPBPs and two SexiGOBPs in Spodoptera exigua. Results showed that all five SexiPBP/GOBP genes have the same intron numbers and conserved exon/intron splice sites. Reverse transcription PCR results showed that these five SexiPBP/GOBPs were primarily expressed in antennae of both sexes and some were also detected in other tissues. Further, quantitative real‐time PCR showed that five SexiPBP/GOBPs had different sex‐biased expression patterns, with PBP1 being highly male‐biased (5.96‐fold difference) and PBP3 slightly female‐biased (2.43‐fold difference), while PBP2 and two GOBPs were approximately sex‐equivalent (the absolute value < 1.90‐fold difference). Binding assays showed that all three SexiPBPs could bind all six sex pheromone components, but SexiPBP1 had much higher affinities dissociation constant (Kᵢ) < 1.10 μM than did the other two SexiPBPs (Kᵢ > 1.20 μM). Very intriguingly, SexiGOBP2 displayed even stronger binding to five sex pheromone components (Kᵢ < 0.40 μM) than SexiPBP1. In contrast, SexiGOBP1 only exhibited weak binding to three alcohol‐pheromone components. Similar results were obtained for tested pheromone analogues. In addition, each of SexiPBP/GOBPs selectively bound some plant odorants with considerable affinities (Kᵢ < 10.0 μM). Taken together, of the three SexiPBPs, SexiPBP1 may play the most important role in female sex pheromone reception, and additionally all three SexiPBPs can detect some plant odorants, while SexiGOBP2 may be involved in the detection of female sex pheromones in addition to plant odorants. The results strongly suggest functional differentiation within and between the two OBP sub‐classes.
Abstract
We report an unusual pressure-induced superconducting state that coexists with an antiferromagnetic ordering of Eu
2+
moments and shows a large upper critical field comparable to the Pauli ...paramagnetic limit in EuTe
2
. In concomitant with the emergence of superconductivity with
T
c
≈ 3–5 K above
P
c
≈ 6 GPa, the antiferromagnetic transition temperature
T
N
(
P
) experiences a quicker rise with the slope increased dramatically from d
T
N
/d
P
= 0.85(14) K/GPa for
P
≤
P
c
to 3.7(2) K/GPa for
P
≥
P
c
. Moreover, the superconducting state can survive in the spin-flop state with a net ferromagnetic component of the Eu
2+
sublattice under moderate magnetic fields
μ
0
H
≥ 2 T. Our findings establish the pressurized EuTe
2
as a rare magnetic superconductor possessing an intimated interplay between magnetism and superconductivity.
Aim
To identify core bacterial communities and volatile compounds and to investigate their relationships in Doubanjiang, a Chinese traditional red pepper paste.
Methods and Results
Two main ...culture‐independent methods, polymerase chain reaction‐denaturing gradient gel electrophoresis (PCR‐DGGE) and MiSeq sequencing technique, were used to investigate bacterial composition. Headspace solid‐phase microextraction combined with gas chromatography‐mass spectrometry (HS‐SPME‐GC‐MS) was used to isolate and identify volatile organic compounds. Partial least squares (PLS) regression and correlation coefficients analyses were used for elucidating the relationship between core bacterial community and volatile compounds.
Conclusions
Lactic acid bacteria (LAB) and Enterobacteriaceae family were identified primarily by the PCR‐DGGE fingerprinting. Furthermore, the core microbiome (>1% average relative abundance) were indentified by Miseq sequencing technique, which mainly assigned to Proteobacteria, Cyanobacteria and Firmicutes phyla. For volatile profile, a total of 29 volatile compounds were identified by HP‐SPME‐GC‐MS, mainly alcohols, esters, aldehydes, ketones and phenols. PLS regression and Pearson's correlation coefficients analyses revealed highly covariable relationships between volatile compounds and bacterial taxa. Notably, Pseudomonas most highly significantly associated with 3‐methyl butanal, 2‐methyl butanal, benzeneacetaldehyde and 2‐acetylpyrrole (P < 0·001), and significantly correlated with 5‐methylfurfural and 5‐methyl‐2‐phenyl‐2‐hexenal (P < 0·01).
Significance and Impact of the Study
Core bacterial communities were identified and the relationship between bacterial taxa and flavour compounds was revealed, these results could be beneficial for improving the quality of Doubanjiang.
Eight survey cruises in different seasons have been conducted in the Yellow Sea (YS) and East China Sea (ECS) during the period from 2000 to 2008. Suspended sediment concentration (SSC) and ...hydrological data were collected during each cruise. Data analysis showed that total suspended sediment mass was approximately 0.18 × 10
9 tons in the surveyed area during spring and autumn seasons. Highly turbid waters were found in the shallow waters between the Subei coast, the Changjiang estuary and the Zhejiang coast with seasonal variations.
The investigation provided convincing evidence that suspended sediments were transported from the Subei coast and the southern entrance of the Yellow Sea Trough to the central YS. Muddy patches were found at the sea bed when tidal currents were too weak to erode the bottom sediments and water column stratification and eddies provided favorable conditions for trapping the fine-grained suspended sediments.
The investigation indicated that the different front may have different effect on sediment transport during different seasons. The front between the Yellow Sea Cold Water and the coastal water in the Subei coast appeared to trap the high SSC sediments on the shallow water side of the front. During summer, the front along the Zhejiang coast seemed to prevent suspended sediments from transport across the front due to circulation in the front zone and upwelling along the Zhejiang coast. During winter, sediments were likely transported across the front to the central continental shelf of the ECS with the help of the downwelling and lateral Ekman transport driven by monsoon winds.
► We collect abundant in-situ data from 8 cruises during 2000–2008. ► We discuss the seasonal sediment transport and possible mechanism. ► Suspended sediments are transported from the Subei coast to the central Yellow Sea. ► A new explanation is given on the formation of muddy patches in the region. ► The different front may have different effect on sediment transport during different seasons.
Adenosine monophosphate-activated protein kinase (AMPK) acts as a major sensor of cellular energy status in cancers and is critically involved in cell sensitivity to anticancer agents. Here, we ...showed that AMPK was inactivated in lymphoma and related to the upregulation of the mammalian target of rapamycin (mTOR) pathway. AMPK activator metformin potentially inhibited the growth of B- and T-lymphoma cells. Strong antitumor effect was also observed on primary lymphoma cells while sparing normal hematopoiesis ex vivo. Metformin-induced AMPK activation was associated with the inhibition of the mTOR signaling without involving AKT. Moreover, lymphoma cell response to the chemotherapeutic agent doxorubicin and mTOR inhibitor temsirolimus was significantly enhanced when co-treated with metformin. Pharmacologic and molecular knock-down of AMPK attenuated metformin-mediated lymphoma cell growth inhibition and drug sensitization. In vivo, metformin induced AMPK activation, mTOR inhibition and remarkably blocked tumor growth in murine lymphoma xenografts. Of note, metformin was equally effective when given orally. Combined treatment of oral metformin with doxorubicin or temsirolimus triggered lymphoma cell autophagy and functioned more efficiently than either agent alone. Taken together, these data provided first evidence for the growth-inhibitory and drug-sensitizing effect of metformin on lymphoma. Selectively targeting mTOR pathway through AMPK activation may thus represent a promising new strategy to improve treatment of lymphoma patients.
We discovered an empirical relationship between the logarithm of mean excitation energy (ln Im) and the effective atomic number (EAN) of human tissues, which allows for computing patient-specific ...proton stopping power ratios (SPRs) using dual-energy CT (DECT) imaging. The accuracy of the DECT method was evaluated for 'standard' human tissues as well as their variance. The DECT method was compared to the existing standard clinical practice-a procedure introduced by Schneider et al at the Paul Scherrer Institute (the stoichiometric calibration method). In this simulation study, SPRs were derived from calculated CT numbers of known material compositions, rather than from measurement. For standard human tissues, both methods achieved good accuracy with the root-mean-square (RMS) error well below 1%. For human tissues with small perturbations from standard human tissue compositions, the DECT method was shown to be less sensitive than the stoichiometric calibration method. The RMS error remained below 1% for most cases using the DECT method, which implies that the DECT method might be more suitable for measuring patient-specific tissue compositions to improve the accuracy of treatment planning for charged particle therapy. In this study, the effects of CT imaging artifacts due to the beam hardening effect, scatter, noise, patient movement, etc were not analyzed. The true potential of the DECT method achieved in theoretical conditions may not be fully achievable in clinical settings. Further research and development may be needed to take advantage of the DECT method to characterize individual human tissues.
Summary
Background
Dupilumab is an antibody against interleukin‐4 receptor α, used in the treatment of atopic dermatitis (AD).
Objectives
To evaluate the efficacy and safety of dupilumab in adult ...Chinese patients with moderate‐to‐severe AD.
Methods
In this randomized, double‐blind, placebo‐controlled, parallel‐group, phase III study, conducted between December 2018 and February 2020, patients with AD received dupilumab (300 mg) or placebo once every 2 weeks for 16 weeks, and were followed up for 12 weeks. The primary efficacy endpoint was the proportion of patients with both an Investigator’s Global Assessment score of 0–1 and a reduction from baseline of ≥ 2 points at week 16.
Results
Overall, 165 patients (mean age 30·6 years; 71·5% male patients) were randomized; 82 patients were randomized to dupilumab and 83 patients were randomized to placebo. At week 16, 26·8% of patients in the dupilumab group and 4·8% of patients in the placebo group achieved the primary endpoint difference 22·0%, 95% confidence interval (CI) 11·37–32·65; P < 0·001. Compared with placebo, higher proportions of patients in the dupilumab group achieved ≥ 75% reduction in the Eczema Area and Severity Index score (57·3% vs. 14·5%; difference 42·9%, 95% CI 29·75–55·97; P < 0·001) and had ≥ 3‐point (52·4% vs. 9·6%; difference 42·8%, 95% CI 30·26–55·34; P < 0·001) and ≥ 4‐point (39·0% vs. 4·8%; difference 34·2%, 95% CI 22·69–45·72; P < 0·001) reductions in weekly average daily peak daily pruritus numerical rating scale scores. The incidence of treatment‐emergent adverse events during the treatment period was similar in the two groups. The incidence of conjunctivitis, allergic conjunctivitis and injection site reaction was higher in the dupilumab group than in the placebo group.
Conclusions
In adult Chinese patients, dupilumab was effective in improving the signs and symptoms of AD and demonstrated a favourable safety profile.
What is already known about this topic?
Two randomized, placebo‐controlled phase III trials (SOLO 1 and SOLO 2) have demonstrated that dupilumab is effective and safe when used in the treatment of atopic dermatitis in adults.
However, very few Chinese participants were included and, therefore, the efficacy and safety of dupilumab in this population is unclear.
What does this study add?
The findings of this randomized, placebo‐controlled phase III trial show that dupilumab is effective in improving the signs and symptoms of atopic dermatitis in adult Chinese patients and has a favourable safety profile in this population.
Plain language summary available online
Alpha-tocopheryl succinate (alpha-TOS) is a selective inducer of apoptosis in cancer cells, which involves the accumulation of reactive oxygen species (ROS). The molecular target of alpha-TOS has not ...been identified. Here, we show that alpha-TOS inhibits succinate dehydrogenase (SDH) activity of complex II (CII) by interacting with the proximal and distal ubiquinone (UbQ)-binding site (Q(P) and Q(D), respectively). This is based on biochemical analyses and molecular modelling, revealing similar or stronger interaction energy of alpha-TOS compared to that of UbQ for the Q(P) and Q(D) sites, respectively. CybL-mutant cells with dysfunctional CII failed to accumulate ROS and underwent apoptosis in the presence of alpha-TOS. Similar resistance was observed when CybL was knocked down with siRNA. Reconstitution of functional CII rendered CybL-mutant cells susceptible to alpha-TOS. We propose that alpha-TOS displaces UbQ in CII causing electrons generated by SDH to recombine with molecular oxygen to yield ROS. Our data highlight CII, a known tumour suppressor, as a novel target for cancer therapy.
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