A novel Ebola virus (EBOV) first identified in March 2014 has infected more than 25,000 people in West Africa, resulting in more than 10,000 deaths. Preliminary analyses of genome sequences of 81 ...EBOV collected from March to June 2014 from Guinea and Sierra Leone suggest that the 2014 EBOV originated from an independent transmission event from its natural reservoir followed by sustained human-to-human infections. It has been reported that the EBOV genome variation might have an effect on the efficacy of sequence-based virus detection and candidate therapeutics. However, only limited viral information has been available since July 2014, when the outbreak entered a rapid growth phase. Here we describe 175 full-length EBOV genome sequences from five severely stricken districts in Sierra Leone from 28 September to 11 November 2014. We found that the 2014 EBOV has become more phylogenetically and genetically diverse from July to November 2014, characterized by the emergence of multiple novel lineages. The substitution rate for the 2014 EBOV was estimated to be 1.23 × 10(-3) substitutions per site per year (95% highest posterior density interval, 1.04 × 10(-3) to 1.41 × 10(-3) substitutions per site per year), approximating to that observed between previous EBOV outbreaks. The sharp increase in genetic diversity of the 2014 EBOV warrants extensive EBOV surveillance in Sierra Leone, Guinea and Liberia to better understand the viral evolution and transmission dynamics of the ongoing outbreak. These data will facilitate the international efforts to develop vaccines and therapeutics.
Overexpression of ANXA1 and EphA2 has been linked to various cancers and both proteins have attracted considerable attention for the development of new anticancer drugs. Here we report that ANXA1 ...competes with Cbl for binding EphA2 and increases its stability by inhibiting Cbl-mediated EphA2 ubiquitination and degradation in nasopharyngeal carcinoma (NPC). Binding of ANXA1 to EphA2 promoted NPC cell growth and metastasis
and
by elevating EphA2 levels and increasing activity of EphA2 oncogenic signaling (pS897-EphA2). Expression of ANXA1 and EphA2 was positively correlated and both were significantly higher in NPC tissues than in the normal nasopharyngeal epithelial tissues. Patients with high expression of both proteins presented poorer disease-free survival and overall survival relative to patients with high expression of one protein alone. Furthermore, amino acid residues 20-30aa and 28-30aa of the ANXA1 N-terminus bound EphA2. An 11 amino acid-long ANXA1-derived peptide (EYVQTVKSSKG) was developed on the basis of this N-terminal region, which disrupted the connection of ANXA1 with EphA2, successfully downregulating EphA2 expression and dramatically suppressing NPC cell oncogenicity
and in mice. These findings suggest that ANXA1 promotes NPC growth and metastasis via binding and stabilization of EphA2 and present a strategy for targeting EphA2 degradation and treating NPC with a peptide. This therapeutic strategy may also be extended to other cancers with high expression of both proteins. SIGNIFICANCE: These findings show that EphA2 is a potential target for NPC therapeutics and an ANXA1-derived peptide suppresses NPC growth and metastasis. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/20/4386/F1.large.jpg.
Aloe barbadensis Miller (Aloe vera) is widely used for healthy foods, medical and cosmetic products, while its leaf skin is usually treated as industrial waste. To have a profound understanding of ...the polysaccharides in the leaf skin of Aloe vera, crude polysaccharide was extracted from the leaf skin of Aloe vera and purified into three fractions, designated as ASP-4N, ASP-6N and ASP-8N, using gradient ammonium sulfate precipitation. The physicochemical properties and structural characteristics of ASP-4N were systematically investigated by methylation analysis and 1D/2D NMR spectroscopy. Results showed that decreasing contents of neutral sugar (79%–74%) were detected among the three fractions, with the concentration increasing of ammonium sulfate used for precipitation. Small amounts of protein and uronic acid were also detected by colorimetric method. Homogeneity identified by high performance gel permeation chromatography (HPGPC) indicated that the three fractions were highly purified. The relative weight average molecular weights for ASP-4N, ASP-6N and ASP-8N were 339, 130 and 67.6 kDa, successively. Monosaccharide compositions and characteristic FT-IR spectra of these fractions suggested the presence of typical acetylated glucomannan and the ratios of mannose/glucose were 19.13, 8.97 and 2.96, successively. Further structural analysis of ASP-4N suggested that it was a highly acetylated (1 → 4)-β-glucomannan. There was also some (1 → 3)-β-Manp mixed in the backbone.
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•Three polysaccharide fractions were purified from the leaf skin of Aloe vera using gradient ammonium sulfate precipitation.•Their molecular weights were decreasing from 339 kDa to 67.6 kDa with the increase of ammonium sulfate concentration.•Glucose and mannose with different ratios were found in the three fractions.•One of the three fractions was identified to be acetylated β-(1 → 4)-glucomannan.
The location and shape detection of water-bearing structures, such as karst caves and faults, is significant for water inrush early warning during tunnel construction. The direct current (DC) ...resistivity method is widely employed in detecting the water-bearing structure for the large difference in resistivity between the water-bearing structure and the surrounding rock. The fixed inversion mesh pattern is one of the most used methods in the DC resistivity inversion, and its inversion results are highly dependent on the inversion mesh. It is challenging to build a high-quality inversion mesh for the uncertainty in the morphogenesis of water-bearing structures. To address this issue, the idea of adaptive inversion is introduced to reduce the dependence of inversion on model regularization constraints. An adaptive inversion method with the variable mesh is proposed. First, the adaptive mesh optimization method with variable mesh is used to identify the region of the water-bearing structure. Second, based on the polyhedral grid's decomposability, the identified region's divided grid is gradually encrypted as the inversion iterations proceed. A series of numerical simulations are carried out to evaluate the detecting effect on the water-bearing structure of the proposed method, and the results proved that it depicts the position and morphology of water-bearing structures more precisely compared to the fixed inversion grid pattern. Additionally, an on-site application was conducted for the Central Yunnan Water Diversion Project. The result indicates that there is a significant low resistance anomaly exits in the range of 12 + 053 ∼ 12 + 068, which is verified by drilling to be a water-rich fault with a high risk of water and mud inrush. Overall, the method proposed in this study provides a better understanding of the sudden surge of water disaster prevention and control in tunnels.
Water inrush represents a significant hazard in karst tunnels, and the water-resistant rock mass plays a pivotal role in water inrush incidents. It is of great significance to explore the coupled ...hydro-mechanical failure process of water-resistant rock mass under excavation. A series of triaxial compression tests with different pressure conditions and loading rates were conducted in this study to investigate progressive failure characteristics and permeability evolution of limestone specimens. The experimental findings demonstrate that loading rate and confining pressure significantly influence progressive failure characteristics and permeability evolution. Additionally, a decreasing-then-increasing trend is observed in the crack initiation threshold (
σ
ci
), and the crack damage threshold (
σ
cd
) exhibits a decreasing tendency. The resulting
σ
ci
/
σ
p
ratio increases while the
σ
cd
/
σ
p
ratio decreases, indicating a diminishing stable fracture development stage. In general, permeability experiences an increase within an order of magnitude during the progressive failure of rock specimens, and the permeability of the rock mass decreases with rising initial confining pressure. The rate of deformation induced over the duration of permeability measurement exhibits a positive correlation with the stress ratio. Lastly, we propose a potential hysteresis water inrush mechanism, drawing upon the aforementioned observations. It is deduced that the creation, expansion, and ultimate penetration of fractures within the rock mass, resulting from the combined effects of excavation stress disturbance and changed pore pressure, give rise to water inrush events in karst tunnels.
Highlights
Study of progressive failure characteristics and permeability evolution of limestone.
Loading rate and confining pressure significantly influence progressive failure characteristics.
Permeability experiences an increase within an order of magnitude.
Deformation induced by permeability measurement exhibits a positive correlation with the stress ratio.
Investigation of water inrush mechanism linking construction disturbance and pore pressure.
Background
Maternal smoking during pregnancy may be associated with low birth weight (LBW) in offspring and global risk estimates have not been summarized previously. We aimed to systematically ...explore evidence regarding maternal smoking and the LBW risk in offspring globally and examine possible causes of heterogeneity across relevant studies.
Methods
Comprehensive search of PubMed, Ovid Embase, Ovid Medline (R), and Web of science from inception until October 2021 was carried out. A random-effects meta-analysis was used to estimate the pooled odds ratio (OR) and corresponding 95% confidence interval (CI). Restricted cubic spline analysis with three knots was used to further examine the dose–response relationship.
Results
Literature searches yielded 4940 articles, of which 53 met inclusion criteria (comprising 55 independent studies). Maternal smoking during pregnancy was significantly associated with the risk of LBW in offspring (OR = 1.89, 95% CI = 1.80–1.98). Furthermore, an obvious dose–response relationship between the amount of cigarettes daily smoked in pregnancy and the risk of LBW in offspring was observed. The results of subgroup analyses indicated that the risk of maternal smoking on LBW was larger in more recently conducted studies (
P
= 0.020) and longer period of active smoking during pregnancy (
P
= 0.002). No evidence of publication bias was found.
Conclusions
In summary, maternal smoking in pregnancy was significantly associated with a higher risk of LBW in offspring on a global scale. The risk of maternal smoking on infant LBW seems to be increasing over time, and was higher with longer smoking duration throughout pregnancy and more cigarettes smoked daily.
Cisplatin-based concurrent chemoradiotherapy is currently considered to be the standard treatment regimen for patients with advanced nasopharyngeal carcinoma, but has well known side-effects such as ...gastrointestinal reactions, nephrotoxicity, and ototoxicity. Nedaplatin was developed to decrease the toxic effects induced by cisplatin, and in this trial we assessed whether a nedaplatin-based concurrent chemoradiotherapy regimen was non-inferior to a cisplatin-based regimen in patients with locoregional, stage II–IVB nasopharyngeal carcinoma.
We did an open-label, non-inferiority, phase 3, randomised, controlled trial at two centres in China. Patients aged 18–65 years with non-keratinising stage II–IVB (T1–4N1–3 or T3–4N0) nasopharyngeal carcinoma, a Karnofsky score of at least 70, and adequate haematological, renal, and hepatic function were randomly assigned (1:1) to receive intravenously either nedaplatin 100 mg/m2 or cisplatin 100 mg/m2 on days 1, 22, and 43 for three cycles concurrently with intensity-modulated radiotherapy. Randomisation was done manually using a computer-generated random number code and patients were stratified by treatment centre and clinical stage. Patients and clinicians were not masked to treatment allocation. The primary endpoint was progression-free survival at 2 years; non-inferiority was shown if the upper limit of the 95% CI for the difference in 2-year progression-free survival between the two groups did not exceed 10%. Analyses were by both intention to treat and per protocol, including all patients who received at least one complete cycle of chemotherapy. This trial is registered with ClinicalTrials.gov, number NCT01540136, and is currently in follow-up.
Between Jan 16, 2012, and July 16, 2014, we randomly assigned 402 patients to nedaplatin-based (n=201) or cisplatin-based (n=201) concurrent chemoradiotherapy. In the intention-to-treat population, 2-year progression-free survival was 89·9% (95% CI 85·8–94·0) in the cisplatin group and 88·0% (83·5–94·5) in the nedaplatin group, with a difference of 1·9% (95% CI −4·2 to 8·0; pnon-inferiority=0·0048). In the per-protocol analysis (cisplatin group, n=197; nedaplatin group, n=196), 2-year progression-free survival was 89·7% (95% CI 85·4–94·0) in the cisplatin group and 88·7% (84·2–94·5) in the nedaplatin group, with a difference of 1·0% (95% CI −5·2 to 7·0; pnon-inferiority=0·0020). A significantly higher frequency of grade 3 or 4 vomiting (35 18% of 198 in the cisplatin group vs 12 6% of 200 in the nedaplatin group, p<0·0001), nausea (18 9% vs four 2%, p=0·0021), and anorexia (53 27% vs 26 13%, p=0·00070) was observed in the cisplatin group compared with the nedaplatin group. 11 (6%) patients in the nedaplatin group had grade 3 or 4 thrombocytopenia compared with four (2%) in the cisplatin group (p=0·065). Patients in the cisplatin group had a higher frequency of any grade or grade 3 or 4 late auditory or hearing toxicities than did patients in the nedaplatin group (grade 3 or 4: three 2% in the nedaplatin group vs 11 6% in the cisplatin group, p=0·030). No patients died from treatment-related causes.
Our findings show that nedaplatin-based concurrent chemoradiotherapy represents an alternative doublet treatment strategy to cisplatin-based concurrent chemoradiotherapy for patients with locoregional, advanced nasopharyngeal carcinoma. Further investigations are needed to explore the potential use of this treatment as induction or adjuvant chemotherapy or in combination with other agents.
National Key R&D Program of China, National Natural Science Foundation of China, Sun Yat-sen University Clinical Research 5010 Program, Sci-Tech Project Foundation of Guangzhou City, National Key Basic Research Program of China, Special Support Plan of Guangdong Province, Sci-Tech Project Foundation of Guangdong Province, Health & Medical Collaborative Innovation Project of Guangzhou City, National Science & Technology Pillar Program during the Twelfth Five-year Plan Period, PhD Start-up Fund of Natural Science Foundation of Guangdong Province, Cultivation Foundation for the Junior Teachers in Sun Yat-sen University, and Fundamental Research Funds for the Central Universities.
Supplementation of certain bioactive dietary fibers could alleviate obesity induced by a high-fat diet, whereas whether the responses of different polysaccharides are consistent remains unclear. ...Consequently, we selected ten representative types of bioactive dietary fibers, including β-glucan, arabinoxylan, glucomannan, xanthan gum, guar gum, apple pectin, carrageenan, arabinogalactan, inulin, xylan and compared their anti-obesity effects through combining the physiology, genomics, and metabolomics with the obese rat model. We found that supplementation with β-glucan, arabinoxylan, xanthan gum, guar gum, apple pectin, carrageenan, inulin and xylan significantly reduced the bodyweight and dyslipidemia, whereas glucomannan and arabinogalactan did not affect serum lipids and bodyweight control in obese rats, respectively. Besides, apple pectin, β-glucan and arabinoxylan improved the greater biomarkers (15, 17 and 18 kinds) which were relevant to obesity, and the bioactive dietary fibers associated with elevated glycerophospholipids levels and regulation of glycerophospholipid metabolism. Moreover, the abundance of beneficial bacteria Akkermansia, Butyricimonas, Oscillospira, Ruminococcus, Prevotella were enriched by dietary fibers with various degrees, furthering exhibited benefits on obesity. It was also found that increased Butyricimonas (including glucomannan, xanthan gum, guar gum, xylan, apple pectin, arabinogalactan) and Prevotella (except for xanthan gum and inulin) showed negative with dyslipidemia factors notably (TC, TG, LDL-C), positive with glycerophospholipids (like phosphatidylcholine), therefore promoted the improvement of host metabolism and relief in dyslipidemia. In brief, our study revealed that different dietary fibers have an impact on gut microbiota then mediating metabolic benefits in obese rats, and these interactions could be considered as targets for diet personalized.
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•Dietary fibers showed benefits in decrease of the bodyweight and dyslipidemia.•β-glucan reversed most physiological indicators which have a risk with obesity.•Apple pectin, β-glucan and arabinoxylan regulated greater biomarkers to improve host metabolism.•Dietary fibers enriched the beneficial bacteria in favor of alleviating obesity.
Steroid hormones released from manure agricultural application are a matter of global concern. The residual levels of steroid hormones were studied in a typical intensive vegetable cultivation area ...in northeast China, with a long history of heavy manure application. Seven steroids (estrone, 17α-estradiol, 17β-estradiol, estriol, testosterone, androstendione and progesterone) were analyzed from soil sampled from vegetable greenhouses, from sediments and water from the adjacent drainage ditch and from the groundwater. The results showed that target steroids were detected in the soil samples, with detection frequencies varying from 3.13 to 100%. The steroid concentrations varied substantially in soils, ranging from below the detection limit to 109.7μg·kg−1. Three steroids—progesterone, androstendione and estrone—were found to have relatively high residue concentrations in soil, with maximum concentrations of 109.7, 9.83 and 13.30μg·kg−1, respectively. In adjacent groundwater, all the steroids, with the exception of estrone, were detected in one or more of the 13 groundwater samples. The concentrations of steroids in groundwater ranged from below the method detection limit to 2.38ng·L−1. Six of the seven (excluding androstendione) were detected in drainage ditch water samples, with concentrations ranging from below the detection limit to 14ng·L−1. Progesterone, androstendione and estrone accumulated relatively easily in soils; their concentrations in groundwater were lower than those of other steroids. The concentrations of testosterone and estriol were relatively low in soil, while in groundwater were higher than those of other steroids. The residual levels of steroids in soil and groundwater showed a clear spatial variation in the study area. The residual levels of steroid hormones in soil varied substantially between differently planted greenhouses.
Accumulation of steroid hormones in (a) greenhouse soil, (b) ditch sediment, (c) ditch water and (d) groundwater. Display omitted
•Seven steroids were detected in soil and adjacent drainage ditch sediment.•Six steroids were found in drainage ditch water and groundwater.•Progesterone, androstendione and estrone accumulated relatively easily in soils.•Testosterone and estriol were easily leached to groundwater.•Concentrations of steroids in soil and groundwater were highly spatially variable.
The geological conditions in Yunnan Province, China, are intricate, and numerous challenges are anticipated during tunnel excavation. The goal of this study was to develop a high resolution detection ...approach combining probe drilling and horizontal cross-hole resistivity tomography to interpret water conducting channels ahead of the tunnel. A complex section of the Xianglu Mountain tunnel was taken as an example. Drilling data from 10 boreholes are used to establish the initial resistivity model ahead of the tunnel face. The utilization of drilling data as a priori information refines the horizontal cross-borehole resistivity tomography imaging results, providing a more accurate depiction of the subsurface conditions. In practical applications, the use of multiple boreholes for high resolution detection via probe drilling analysis and horizontal cross-hole resistivity tomography is relatively uncommon in complex underground environments and represents an engineering innovation. At the Xianglu Mountain tunnel site, 13 electrical resistivity tomography (ERT) profiles were executed to thoroughly assess the geological conditions. A 3-D resistivity model was constructed via interpolation of this dataset. The 3-D resistivity model not only facilitated precise estimation of the 3-D hydrogeological environment at the Xianglu Mountain tunnel site but also enhanced the accuracy of identifying the water conducting channels by revealing low-resistivity interconnected zones. This approach offers a precise guide for determining the location of the critical water conducting channels and for optimizing grouting treatment strategies based on the characterization, geometry, resistivity spatial distribution, and hydrogeological conditions of the studied zones. The acquired results, which are in good accordance with the reality of the studied area in terms of locating the water conducting channels, can be utilized to develop preventative techniques for water and mud inrush disasters during tunnel construction.
•A high resolution detection approach to investigate the tunnel is applied.•The approach combines probe drilling and horizontal cross-hole resistivity tomography.•Water conducting channel characteristics in tunnel are investigated.•The tunnel successfully passed through the water-rich fault area.
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