Dysfunction of degradation machineries causes cancers, including hepatocellular carcinoma (HCC). Overexpression of cyclin D1 in HCC has been reported. We previously reported that autophagy ...preferentially recruits and degrades the oncogenic microRNA (miR)‐224 to prevent HCC. Therefore, in the present study, we attempted to clarify whether cyclin D1 is another oncogenic factor selectively regulated by autophagy in HCC tumorigenesis. Initially, we found an inverse correlation between low autophagic activity and high cyclin D1 expression in tumors of 147 HCC patients and three murine models, and these results taken together revealed a correlation with poor overall survival of HCC patients, indicating the importance of these two events in HCC development. We found that increased autophagic activity leads to cyclin D1 ubiquitination and selective recruitment to the autophagosome (AP) mediated by a specific receptor, sequestosome 1 (SQSTM1), followed by fusion with lysosome and degradation. Autophagy‐selective degradation of ubiquitinated cyclin D1 through SQSTM1 was confirmed using cyclin D1/ubiquitin binding site (K33‐238R) and phosphorylation site (T286A) mutants, lentivirus‐mediated silencing autophagy‐related 5 (ATG5), autophagy‐related 7 (ATG7), and Sqstm1 knockout cells. Functional studies revealed that autophagy‐selective degradation of cyclin D1 plays suppressive roles in cell proliferation, colony, and liver tumor formation. Notably, an increase of autophagic activity by pharmacological inducers (amiodarone and rapamycin) significantly suppressed tumor growth in both the orthotopic liver tumor and subcutaneous tumor xenograft models. Our findings provide evidence of the underlying mechanism involved in the regulation of cyclin D1 by selective autophagy to prevent tumor formation. Conclusion: Taken together, our data demonstrate that autophagic degradation machinery and the cell‐cycle regulator, cyclin D1, are linked to HCC tumorigenesis. We believe these findings may be of value in the development of alternative therapeutics for HCC patients. (Hepatology 2018;68:141‐154).
Preclinical and clinical studies have suggested a neuroprotective effect of remote ischemic conditioning (RIC), which involves repeated occlusion/release cycles on bilateral upper limb arteries; ...however, robust evidence in patients with ischemic stroke is lacking.
To assess the efficacy of RIC for acute moderate ischemic stroke.
This multicenter, open-label, blinded-end point, randomized clinical trial including 1893 patients with acute moderate ischemic stroke was conducted at 55 hospitals in China from December 26, 2018, through January 19, 2021, and the date of final follow-up was April 19, 2021.
Eligible patients were randomly assigned within 48 hours after symptom onset to receive treatment with RIC (using a pneumatic electronic device and consisting of 5 cycles of cuff inflation for 5 minutes and deflation for 5 minutes to the bilateral upper limbs to 200 mm Hg) for 10 to 14 days as an adjunct to guideline-based treatment (n = 922) or guideline-based treatment alone (n = 971).
The primary end point was excellent functional outcome at 90 days, defined as a modified Rankin Scale score of 0 to 1. All end points had blinded assessment and were analyzed on a full analysis set.
Among 1893 eligible patients with acute moderate ischemic stroke who were randomized (mean SD age, 65 10.3 years; 606 women 34.1%), 1776 (93.8%) completed the trial. The number with excellent functional outcome at 90 days was 582 (67.4%) in the RIC group and 566 (62.0%) in the control group (risk difference, 5.4% 95% CI, 1.0%-9.9%; odds ratio, 1.27 95% CI, 1.05-1.54; P = .02). The proportion of patients with any adverse events was 6.8% (59/863) in the RIC group and 5.6% (51/913) in the control group.
Among adults with acute moderate ischemic stroke, treatment with remote ischemic conditioning compared with usual care significantly increased the likelihood of excellent neurologic function at 90 days. However, these findings require replication in another trial before concluding efficacy for this intervention.
ClinicalTrials.gov Identifier: NCT03740971.
Pressure-driven membranes-based desalination provides an effective and promising strategy to deal with the worldwide fresh water crisis. However, some drawbacks are still restricting their wider ...applications. Therefore, it still remains a great challenge to explore the novel technologies to develop new types of pressure-driven desalination membranes and to improve the properties of the present ones. Layer-by-layer (LBL) assembly technology, which can produce charged thin films on molecular levels by adsorbing oppositely charged polyelectrolytes and/or other nano-species via different interactions, provides a tunable and facile method to tailor separation membranes with desired properties. Moreover, LBL assembly has shown great potential for exploring multifunctional pressure-driven desalination membranes including reverse osmosis (RO) and forward osmosis (FO) membranes. This review aims to give a comprehensive discussion and comment on the state-of-the-art developments of LBL assembled technology applied on the pressure-driven desalination membranes, mainly focusing on RO and FO membranes. It is sincerely expected that this review can provide a scientific view and give some fundamental clues for acquiring new methodologies for the exploration of pressure-driven desalination membranes with preferable performances based on LBL assembly technology.
•Discussion of reverse osmosis (RO) and forward osmosis (FO) desalination membranes.•Layer-by-Layer assembly technology applied on RO and FO desalination membranes.•Perspective of LBL assembly technology on RO and FO desalination membranes.
Anthropogenic environments have been implicated in enrichment and exchange of antibiotic resistance genes and bacteria. Here we study the impact of confined and controlled swine farm environments on ...temporal changes in the gut microbiome and resistome of veterinary students with occupational exposure for 3 months. By analyzing 16S rRNA and whole metagenome shotgun sequencing data in tandem with culture-based methods, we show that farm exposure shapes the gut microbiome of students, resulting in enrichment of potentially pathogenic taxa and antimicrobial resistance genes. Comparison of students' gut microbiomes and resistomes to farm workers' and environmental samples revealed extensive sharing of resistance genes and bacteria following exposure and after three months of their visit. Notably, antibiotic resistance genes were found in similar genetic contexts in student samples and farm environmental samples. Dynamic Bayesian network modeling predicted that the observed changes partially reverse over a 4-6 month period. Our results indicate that acute changes in a human's living environment can persistently shape their gut microbiota and antibiotic resistome.
The characteristics of municipal solid waste incineration (MSWI) fly ash, surface leaching toxicity and successive leaching concentration of heavy metals from MSWI fly ash-cement hardened pastes were ...studied. And, the relationships between leaching concentrations of heavy metals and leaching time were also discussed. Experimental results showed that immobilization effect of cement on MSWI fly ash is good. Even if MSWI fly ash-cement hardened pastes were damaged, the leaching toxicity is still in a safety range. In early leaching stage, the surface leaching rate is relatively a little high, up to 10
−5–10
−4
cm
d
−1 order of magnitude, in the later time of leaching, its rate rapidly declined, down to 10
−7. Most of leached heavy metals are produced at early ages. The leaching concentration of heavy metals and leaching time has strong positive relationships. In factual utilizing circumstances, heavy metals’ leaching from MSWI fly ash-cement hardened pastes is a very slow and gradually diluting process. The leaching toxicity of heavy metals is far lower than that of the National Standard of China, and minimum harmful matters can be contained and released in the environment. Reusing of MSWI fly ash as partial replacement for cement in concrete mixes is potentially feasible.
Sepsis-induced myocardial dysfunction represents a major cause of death. Alamandine is an important biologically active peptide. The present study evaluated whether alamandine improves cardiac ...dysfunction, inflammation, and apoptosis, and affects the signaling pathways involved in these events. Experiments were carried out in mice treated with lipopolysaccharide (LPS) or alamandine, and in neonatal rat cardiomyocytes. Alamandine increased the ejection fraction and fractional shortening, both of which were decreased upon LPS infusion in mice. LPS and alamandine reduced blood pressure, and increased the expression of inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) in the heart in mice. The LPS-induced decrease in α-myosin heavy chain (MHC) and β-MHC, and increase in S100 calcium binding protein A8 (S100A8) and S100A9, were reversed by alamandine pre-treatment. Alamandine pre-treatment prevented LPS-induced myocardial inflammation, apoptosis and autophagy. LPS increased p-ERK, p-JNK, and p-p38 levels, which were inhibited by alamandine. Dibutyryl cyclic AMP (db-cAMP) increased p-ERK, p-JNK, and p-p38 levels, and reversed the inhibitory effects of alamandine on the LPS-induced increase in p-ERK, p-JNK, and p-p38. Moreover, db-cAMP reduced the expression of α-MHC and β-MHC in cardiomyocytes, and reversed the almandine-induced attenuation of the LPS-induced decrease in α-MHC and β-MHC. These results indicate that alamandine attenuates LPS-induced cardiac dysfunction, resulting in increased cardiac contractility, and reduced inflammation, autophagy, and apoptosis. Furthermore, alamandine attenuates sepsis induced by LPS via inhibiting the mitogen-activated protein kinases (MAPKs) signaling pathways.
Summary
Anti‐neurofascin‐155 (NF155) antibodies have been observed in two cases with neuromyelitis optica spectrum disorders (NMOSD). This study investigated the prevalence of anti‐NF155 antibodies ...in patients with NMOSD and the clinical features of anti‐NF155 antibody‐positive patients. Sera from 129 patients with NMOSD were screened with anti‐NF155 antibodies by cell‐based assay (CBA) and re‐examined using immunostaining of teased mouse sciatic nerve fibres. Fifty‐six patients with multiple sclerosis (MS) and 50 healthy controls (HC) were also enrolled for detecting anti‐NF155 antibodies. A total of 12.40% (16 of 129) of patients with NMOSD were positive for anti‐NF155 antibodies confirmed by both CBA and immunostaining. Immunoglobulin (Ig) G1 was the predominant subclass. However, none of 56 MS patients or 50 HC were positive for anti‐NF155 antibodies. Anti‐NF155 antibody‐positive NMOSD patients had a higher proportion of co‐existing with autoimmune diseases (p < 0.001) and higher positive rates of serum non‐organ‐specific autoantibodies, including anti‐SSA antibodies (p < 0.001), anti‐SSB antibodies (p = 0.008), anti‐Ro‐52 antibodies (p < 0.001) and rheumatoid factor (p < 0.001). Five anti‐NF155 antibody‐positive NMOSD patients who took part in the nerve conduction study showed mildly abnormal results. Differences in some nerve conduction study parameters were observed between anti‐NF155 antibody‐positive and negative patients. Anti‐NF155 antibodies occurred in a small proportion of NMOSD patients. Anti‐NF155 antibody‐positive NMOSD patients tended to co‐exist with autoimmune diseases.
12.40% (16/129) of patients with NMOSD were positive for anti‐NF155 antibodies confirmed by both CBA and immunostaining. Anti‐NF155 antibody‐positive NMOSD patients had a higher proportion of coexisting with autoimmune diseases and higher positive rates of serum non‐organ‐specific autoantibodies. Anti‐NF155 antibody‐positive NMOSD patients tended to coexist with autoimmune diseases.
Imbalances in gut microbiota composition are linked to hypertension, host metabolic abnormalities, systemic inflammation, and other conditions. In the present study, we examined the changes of gut ...microbiota in women with early-onset preeclampsia (PE) and in normotensive, uncomplicated pregnant women during late pregnancy and at 1 and 6 weeks postpartum.
Gut microbiota profiles of women with PE and healthy pregnant women in the third trimester and at 1 and 6 weeks postpartum were assessed by 16S rRNA gene amplicon sequencing. Plasma levels of interleukin-6 (IL-6), intestinal fatty acid-binding protein (I-FABP), zonulin, and lipopolysaccharide (LPS) were measured in the third trimesters.
At the genus level, 8 bacterial genera were significantly enriched in the antepartum samples of PE patients compared to healthy controls, of which
, and
represented the major variances in PE microbiomes. Conversely, 5 genera, including
, and
, were significantly depleted in antepartum PE samples. Maternal blood pressure and liver enzyme levels were positively correlated to the PE-enriched genera such as
, and
, while the fetal features (e.g., Apgar score and newborn birth weight) were positively correlated with PE-depleted genera and negatively correlated with PE-enriched genera. Moreover, maternal blood IL-6 level was positively associated with gut
and
, whereas LPS level was negatively associated with
. In terms of postpartum women, both the gut microbial composition and the PE-associated microbial alterations were highly consistent with those of the antepartum women.
PE diagnosed in the third trimester of pregnancy is associated with a disrupted gut microbiota composition compared with uncomplicated pregnant women, which are associated with maternal clinical features (blood pressure level and liver dysfunction) and newborn birth weight. Moreover, these antepartum alterations in gut microbiota persisted 6 weeks postpartum.
Previous studies investigated the potential mechanism of embolic stroke of undetermined source (ESUS) from extracranial artery plaque, but there has been no study other than a case report on ...high-risk intracranial plaque in ESUS.
The aim of this study was to investigate the issue by evaluating the morphology and composition of intracranial plaque in patients with ESUS and small-vessel disease (SVD) using 3.0-T high-resolution magnetic resonance imaging.
Two hundred forty-three consecutive patients with ESUS and 160 patients with SVD-associated stroke between January 2015 and December 2019 were retrospectively enrolled. Multidimensional parameters involving the presence of plaque on both sides, including remodeling index (RI), plaque burden, presence of discontinuity of plaque surface, thick fibrous cap, intraplaque hemorrhage, and complicated American Heart Association type VI plaque at the maximal luminal narrowing site, were evaluated using intracranial high-resolution magnetic resonance imaging.
Among 243 patients with ESUS, the prevalence of intracranial plaque was much higher in the ipsilateral than the contralateral side (63.8% vs. 42.8%; odds ratio OR: 5.25; 95% confidence interval CI: 2.83 to 9.73), a finding that was not evident in patients with SVD (35.6% vs. 30.6%; OR: 2.14; 95% CI: 0.87 to 5.26; p = 0.134). Logistic analysis showed that RI was independently associated with ESUS in model 1 (OR: 2.329; 95% CI: 1.686 to 3.217; p < 0.001) and model 2 (OR: 2.295; 95% CI: 1.661 to 3.172; p < 0.001). RI alone with an optimal cutoff of 1.162, corresponding to an area under the curve of 0.740, had good diagnostic efficiency for ESUS.
The present study supports an etiologic role of high-risk nonstenotic intracranial plaque in ESUS.
Overweight and obesity in preschoolers might develop into childhood and even adulthood obesity. Overweight and obesity have been shown to be negatively related with cardiorespiratory fitness (CRF) in ...children and adults but few studies did among preschoolers. We aimed to evaluate whether excess body adipose is negatively associated with CRF in both the submaximal and maximal effort of preschool children in exercise testing and to examine if there is difference to achieve maximal effort during exercise testing between preschoolers with normal and excess body adipose.
Data of 106 preschoolers aged 4-6 that received symptom-limited treadmill exercise testing was analyzed. Anthropometry was measured by vector bioelectrical impedance analysis. Excess body adipose was defined as (1) 'overweight' and 'obesity' by body mass index (BMI), (2) fat mass index (FMI) greater than the sex- and age-specific 75th percentile of whole subjects, and (3) fat-free mass index (FFMI) smaller than the sex- and age-specific 25th percentile. CRF was indicated by metabolic equivalent (MET) at anaerobic threshold (AT MET), peak MET, oxygen uptake efficiency slope (OUES) calculated by the 50% (OUES-50) and the entire (OUES-100) duration of the exercise testing.
Preschoolers with excess body adipose by three different definitions (BMI, FMI, and FFMI) all had poorer ability to perform maximal effort (p = 0.004, 0.043, and 0.007, respectively). Preschoolers with excess body adipose by BMI and FFMI classifications had lower OUES-50 (p = 0.018, and 0.001, respectively), and lower OUES-100 (p = 0.004, and 0.001, respectively) than peers with normal body adipose during exercise testing while those with excess body adipose by FMI classification showed no significant differences from peers with normal body adipose in both OUES-50 and OUES-100.
Preschoolers with excess body adipose had lower CRF significantly during treadmill exercise testing. Weight control and health promotion should start as early as possible.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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