Highlights • Guanabenz extended the lifespan of SOD1 G93A mice. • Guanabenz delayed the disease onset of SOD1 G93A mice. • Guanabenz improved motor performance in SOD1 G93A mice. • Guanabenz ...attenuated motor neuron loss in SOD1 G93A mice. • Guanabenz attenuated ER stress and mitochondrial stress.
Highlights • The Notch pathway was activated in in vitro and in vivo models of ALS. • Suppression of Notch activation reduced the neuronal apoptotic signaling. • Lithium and VPA suppressed Notch ...activation associated with SOD1 mutation. • Lithium–VPA co-treatment had a synergistic effect in the Notch pathway inhibition.
Magnetic cellulose/Fe₃O₄/activated carbon composites (m-Cell/Fe₃O₄/ACCs) were prepared successfully and characterized by X-ray diffraction (XRD), Brunauer–Emmett–Teller (BET), thermogravimetric ...analysis (TGA), scanning electron microscopy (SEM) and vibrating sample magnetometer (VSM). The adsorption of congo red onto the novel m-Cell/Fe₃O₄/ACCs was studied as a function of contact time, initial concentration of congo red, adsorbent dosage, and pH of solution. The saturated magnetization of m-Cell/Fe₃O₄/ACCs reached 48.2emug⁻¹ and the magnetic adsorbent showed characteristics of superparamagnetism, which indicated that m-Cell/Fe₃O₄/ACCs could be separated from treated solution by a magnetic process. A comparison of kinetic models showed that the overall adsorption process was best described by pseudo-second-order kinetic model. Thermodynamic analysis indicated an exothermic nature of adsorption and a spontaneous and favorable process. The m-Cell/Fe₃O₄/ACCs might be a promising candidate of high efficiency, low cost and convenient separation under magnetic field.
Abstract
Superconductivity in the cuprates is found to be intertwined with charge and spin density waves. Determining the interactions between the different types of order is crucial for ...understanding these important materials. Here, we elucidate the role of the charge density wave (CDW) in the prototypical cuprate La
1.885
Sr
0.115
CuO
4
, by studying the effects of large magnetic fields (
H
) up to 24 Tesla. At low temperatures (
T
), the observed CDW peaks reveal two distinct regions in the material: a majority phase with short-range CDW coexisting with superconductivity, and a minority phase with longer-range CDW coexisting with static spin density wave (SDW). With increasing magnetic field, the CDW first grows smoothly in a manner similar to the SDW. However, at high fields we discover a sudden increase in the CDW amplitude upon entering the vortex-liquid state. Our results signify strong coupling of the CDW to mobile superconducting vortices and link enhanced CDW amplitude with local superconducting pairing across the
H
−
T
phase diagram.
Background
Oral fluconazole is used to treat vulvovaginal candidiasis during pregnancy. However, there are concerns regarding the pregnancy outcomes following exposure to fluconazole.
Objectives
To ...evaluate the pregnancy outcomes associated with exposure to oral fluconazole during the first trimester of pregnancy.
Search strategy
A systematic literature search was conducted to identify relevant studies published from inception until April 2019.
Selection criteria
Relevant English‐language citations using the terms oral fluconazole and pregnancy in humans.
Data collection
Two reviewers independently ed data and assessed study quality.
Main results
Oral fluconazole use during the first trimester of pregnancy was marginally associated with an increased risk of congenital malformations (odds ratio OR 1.09, 95% CI 0.99–1.2, P = 0.088; n = 6 studies), whereas in the subgroup analysis, this association existed only for high‐dose users (>150 mg) (OR 1. 19, 95% CI 1.01–1.4, P = 0.039; n = 2). Exposure to fluconazole also increased the risk of heart malformations (OR 1.31, 95% CI 1.09–1.57, P = 0.003; n = 4), cardiac septal defects (OR 1.3, 95% CI 1.1–1.67, P = 0.047; n = 3), and tetralogy of Fallot (OR 3.39 95% CI 1.71–6.74, P < 0.001; n = 2) in the offspring. In addition, exposure to fluconazole was significantly associated with an increased risk of spontaneous abortion (OR 1.99, 95% CI 1.38–2.88, P < 0.001; n = 3).
Conclusions
Oral fluconazole use during the first trimester of pregnancy appears to be associated with heart malformations and spontaneous abortion, but a causal link cannot be proven.
Tweetable
Oral fluconazole during the first trimester of pregnancy may be associated with unfavourable pregnancy outcomes.
Tweetable
Oral fluconazole during the first trimester of pregnancy may be associated with unfavourable pregnancy outcomes.
Summary
The aim of the current study was to use a Bayesian network meta-analysis to evaluate the relative benefits and risks of balloon kyphoplasty (BK), percutaneous vertebroplasty (PVP), and ...non-surgical treatment (NST) for patients with osteoporotic vertebral compression fractures (OVCFs). The results demonstrate that for pain and functional status, PVP was significantly better than NST, while the three treatments did not significantly differ in other outcomes.
Introduction
BK, PVP, and NST are widely used to treat OVCFs, but preferable treatment is unknown. The aim of the current study was to use a Bayesian network meta-analysis to evaluate the relative benefits and risks of BK, PVP, and NST for patients with OVCFs.
Methods
PubMed, EMBASE, and the Cochrane Library were screened. Based on the preplanned eligibility criteria, we screened and included randomized controlled trials that compared BK, PVP, and NST in treating patients with OVCFs. The risk of bias for individual studies was appraised. The data were pooled using a Bayesian network meta-analysis and a traditional direct comparison meta-analysis.
Results
Of the 1057 relevant studies, 15 were eligible and included. Compared with NST, PVP significantly reduced pain, Oswestry Disability Index (ODI), and Roland–Morris Disability Questionnaire (RMDQ). The comparative efficacy of BK and PVP was similar for pain (mean difference (MD) 0.51, 95% credible interval (CrI) − 0.35 to 1.4), ODI (MD 0.11, 95% CrI − 13 to 13), and RMDQ (MD 1.2, 95% CrI − 2.7 to 5.4). The European Quality of Life–5 Dimensions (EQ–5D) and Physical Component Summary subscales of the Medical Outcomes Study 36-Item Short-Form General Health Survey (SF-36 PCS) did not differ significantly. There were also no substantial differences in the risks of subsequent vertebral fractures, adjacent vertebral fractures, and re-fractures at the treated level across all comparators. The results of pairwise meta-analyses were almost consistent with those of network meta-analyses. The treatment ranking indicated that PVP had the highest probability of being the most effective for pain, ODI, RMDQ, and EQ-5D. BK had the highest probability of improving SF-36 PCS and of reducing the risk of subsequent vertebral fractures and re-fractures at the treated level. NST was ranked first in preventing adjacent vertebral fractures.
Conclusion
PVP was the most effective method for improving pain, functional status, and quality of life (based on EQ-5D). BK emerged as the best intervention for decreasing the risk of subsequent vertebral fractures and re-fractures at the treated level. NST could be ranked first in reducing adjacent vertebral fractures. The future directions of OVCFs treatment will depend on the outcomes of additional and larger randomized trials in comparing BK with PVP.
Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) represents a paradigm shift in the treatment of non-small cell lung cancer (NSCLC) patients and has been the first-line therapy ...in clinical practice. While erlotinib, gefitinib and afatinib have achieved superior efficacy in terms of progression-free survival and overall survival compared with conventional chemotherapy in NSCLC patients, most people inevitably develop acquired resistance to them, which presents another challenge in the treatment of NSCLC. The mechanisms of acquired resistance can be classified as three types: target gene mutation, bypass signaling pathway activation and histological transformation. And the most common mechanism is T790M which accounts for approximately 50% of all subtypes. Many strategies have been explored to overcome the acquired resistance to EGFR TKI. Continuation of EGFR TKI beyond progressive disease is confined to patients in asymptomatic stage when the EGFR addiction is still preserved in some subclones. While the combination of EGFR TKI and chemotherapy or other targeted agents has improved the survival benefit in EGFR TKI resistant patients, there are controversies within them. The next-generation EGFR TKI and immunotherapy represent two novel directions for overcoming acquired resistance and have achieved promising efficacy. Liquid biopsy provides surveillance of the EGFR mutation by disclosing the entire genetic landscape but tissue biopsy is still indispensable because of the considerable rate of false-negative plasma.
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•The in situ stress redistribution in underground blasts is a dynamic process.•Dynamic stress redistribution generates larger EDZ than that in quasi-static condition.•Dynamic stress ...redistribution dominates EDZ for the blasts in high-stressed rocks.•PPV threshold for blast damage increases firstly and then decreases as in situ stress increases.
When underground cavities are created in initially stressed rock masses by the drill and blast method, an unwanted excavation damage zone (EDZ) is induced around the cavities due to the combined effects of in-situ stress redistribution and blast loading. During rock fragmentation by blasting, the in-situ stress on blast-created excavation boundaries is suddenly released. The in-situ stress redistribution is a dynamic process that starts from the transient release of stress and reaches a final static stress state after excavation. For a circular tunnel that is excavated underground by full-face millisecond delay blasting, 2D finite element simulation is performed to investigate the rock damage induced by the dynamic in-situ stress redistribution and blast loading. The critical peak particle velocity (PPV) for the initiation of blast damage in pre-stressed rock masses is also numerically studied. The results show that the transient stress release generates additional stress waves, resulting in a larger damage zone compared with that following quasi-static stress redistribution. The effect that the additional stress waves have on rock damage becomes more obvious as the in-situ stress levels and excavation dimensions increase and as the stress release duration decreases. Blast-induced tensile stress in the circumferential direction of a tunnel is neutralized by compressive in-situ stress. In deep-buried or high-stressed tunnel excavation, dynamic stress redistribution is responsible for the formation of EDZ; the critical PPV for the initiation of blast damage first increases and then decreases with an increase in the in-situ stress. Therefore, in underground blasting excavation, the factors that affect the level of in-situ stress such as tunnel depths should be considered with respect to the blasting vibration standards and damage criteria.
Summary
Background
Coronavirus disease 2019 (COVID-19) is a global pandemic but the follow-up data of discharged patients was barely described.
Aim
To investigate clinical outcomes, distribution of ...quarantine locations and the infection status of the contacts of COVID-19 patients after discharge.
Design
A prospective cohort study.
Methods
Demographics, baseline characteristics of 131 COVID-19 patients discharged from 3 February 2020 to 21 February 2020 in Wuhan, China were collected and analyzed by reviewing the medical records retrospectively. Post-hospitalization data related to clinical outcomes, quarantine locations and close contact history were obtained by following up the patients every week up to 4 weeks.
Results
Fifty-three (40.05%) patients on discharge had cough (29.01%), fatigue (7.63%), expectoration (6.11%), chest tightness (6.11%), dyspnea (3.82%), chest pain (3.05%) and palpitation (1.53%). These symptoms constantly declined in 4 weeks post-discharge. Transient fever recurred in 11 (8.4%) patients. Among the discharged patients, 78 (59.5%) underwent chest CT and 2 (1.53%) showed deterioration. A total of 94 (71.8%) patients received SARS-CoV-2 retest and 8 (6.10%) reported positive. Seven (2.29%) patients were readmitted because of fever or positive SARS-CoV-2 retest. After discharge, 121 (92.37%) and 4 (3.05%) patients were self-quarantined at home or community spots, respectively, after a close contact with 167 persons in total who were free of COVID-19 at the endpoint of study.
Conclusion
The majority of COVID-19 patients after discharge were in the course of recovery. Readmission was required in rare cases due to suspected recurrence of COVID-19. Although no contacted infection observed, appropriate self-quarantine and regular re-examination are necessary, particularly for those who have recurred symptoms.
Severe malaria is caused by the apicomplexan parasite
Despite decades of research, the distinct biology of these parasites has made it challenging to establish high-throughput genetic approaches to ...identify and prioritize therapeutic targets. Using transposon mutagenesis of
in an approach that exploited its AT-rich genome, we generated more than 38,000 mutants, saturating the genome and defining mutability and fitness costs for over 87% of genes. Of 5399 genes, our study defined 2680 genes as essential for optimal growth of asexual blood stages in vitro. These essential genes are associated with drug resistance, represent leading vaccine candidates, and include approximately 1000
-conserved genes of unknown function. We validated this approach by testing proteasome pathways for individual mutants associated with artemisinin sensitivity.
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