is the major intracellular degradation system, by which cytoplasmic materials are delivered to and degraded in the lyso- some. As a quality control mechanism for cytoplasmic proteins and organelles, ...autophagy plays important roles in a variety of human diseases, including neurodegenerative diseases, cancer, cardiovascular disease, diabetes and infectious and inflammatory diseases. The discovery of ATG genes and the dissection of the signaling pathways involved in regulating autophagy have greatly enriched our knowledge on the occurrence and development of this lysosomal degradation pathway. In addition to its role in degradation, autophagy may also promote a type of programmed cell death that is different from apoptosis, termed type II programmed cell death. Owing to the dual roles of autophagy in cell death and the specificity of diseases, the exact mechanisms of autophagy in various diseases require more investigation. The application of autophagy inhibitors and activators will help us understand the regulation of autophagy in human diseases, and provide insight into the use of autophagy-targeted drugs. In this review, we summarize the latest research on autophagy inhibitors and activators and discuss the possibility of their application in human disease therapy.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Objective
Inflammatory injury plays a critical role in intracerebral hemorrhage (ICH)‐induced secondary brain injury. However, the upstream events that initiate inflammatory responses following ICH ...remain elusive. Our previous studies suggested that Toll‐like receptor 4 (TLR4) may be the upstream signal that triggers inflammatory injury in ICH. In addition, recent clinical findings indicated that both TLR2 and TLR4 may participate in ICH‐induced brain injury. However, it is unclear how TLR2 functions in ICH‐induced inflammatory injury and how TLR2 interacts with TLR4.
Methods
The role of TLR2 and TLR2/TLR4 heterodimerization in ICH‐induced inflammatory injury was investigated in both in vivo and in vitro models of ICH.
Results
TLR2 mediated ICH‐induced inflammatory injury, which forms a heterodimer with TLR4 in both in vivo and in vitro models of ICH. Hemoglobin (Hb), but not other blood components, triggered inflammatory injury in ICH via assembly of TLR2/TLR4 heterodimers. MyD88 (myeloid differentiation primary response gene 88), but not TRIF (Toll/IR‐1 domain–containing adaptor protein inducing interferon‐beta), was required for ICH‐induced TLR2/TLR4 heterodimerization. Mutation of MyD88 Arg196 abolished the TLR2/TLR4 heterodimerization.
Interpretation
Our results suggest that a novel TLR2/TLR4 heterodimer induced by Hb initiates inflammatory injury in ICH. Interfering with the assembly of the TLR2/TLR4 heterodimer may be a novel target for developing effective treatment of ICH. Ann Neurol 2014;75:876–889
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
As of June 1, 2020, coronavirus disease 2019 (COVID-19) has caused more than 6,000,000 infected persons and 360,000 deaths globally. Previous studies revealed pregnant women with COVID-19 had similar ...clinical manifestations to nonpregnant women. However, little is known about the outcome of neonates born to infected women.
In this retrospective study, we studied 29 pregnant women with COVID-19 infection delivered in 2 designated general hospitals in Wuhan, China between January 30 and March 10, 2020, and 30 neonates (1 set of twins). Maternal demographic characteristics, delivery course, symptoms, and laboratory tests from hospital records were extracted. Neonates were hospitalized if they had symptoms (5 cases) or their guardians agreed to a hospitalized quarantine (13 cases), whereas symptom-free neonates also could be discharged after birth and followed up through telephone (12 cases). For hospitalized neonates, laboratory test results and chest X-ray or computed tomography (CT) were extracted from hospital records. The presence of antibody of SARS-CoV-2 was assessed in the serum of 4 neonates. Among 29 pregnant COVID-19-infected women (13 confirmed and 16 clinical diagnosed), the majority had higher education (56.6%), half were employed (51.7%), and their mean age was 29 years. Fourteen women experienced mild symptoms including fever (8), cough (9), shortness of breath (3), diarrhea (2), vomiting (1), and 15 were symptom-free. Eleven of 29 women had pregnancy complications, and 27 elected to have a cesarean section delivery. Of 30 neonates, 18 were admitted to Wuhan Children's Hospital for quarantine and care, whereas the other 12 neonates discharged after birth without any symptoms and had normal follow-up. Five hospitalized neonates were diagnosed as COVID-19 infection (2 confirmed and 3 suspected). In addition, 12 of 13 other hospitalized neonates presented with radiological features for pneumonia through X-ray or CT screening, 1 with occasional cough and the others without associated symptoms. SARS-CoV-2 specific serum immunoglobulin M (IgM) and immunoglobulin G (IgG) were measured in 4 neonates and 2 were positive. The limited sample size limited statistical comparison between groups.
In this study, we observed COVID-19 or radiological features of pneumonia in some, but not all, neonates born to women with COVID-19 infection. These findings suggest that intrauterine or intrapartum transmission is possible and warrants clinical caution and further investigation.
Chinese Clinical Trial Registry, ChiCTR2000031954 (Maternal and Perinatal Outcomes of Women with coronavirus disease 2019 (COVID-19): a multicenter retrospective cohort study).
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Impacts of different operational parameters on function microbes were evaluated.•Function microbiomes included the distinct and overlapping components.•The set of minimal “core microbiome” is ...detectable (ca. 40%).•Organic loading rate shaped finer microbial networks than hydraulic retention time.•Firmicutes is the most connected node with biogas production.
Understanding of how anaerobic digestion (AD)-related microbiomes are constructed by operational parameters or their interactions within the biochemical process is limited. Using high-throughput sequencing and molecular ecological network analysis, this study shows the succession of AD-related microbiome hosting diverse members of the phylum Actinobacteria, Bacteroidetes, Euryarchaeota, and Firmicutes, which were affected by organic loading rate (OLR) and hydraulic retention time (HRT). OLR formed finer microbial network modules than HRT (12 vs. 6), suggesting the further subdivision of functional components. Biomarkers were also identified in OLR or HRT groups (e.g. the family Actinomycetaceae, Methanosaetaceae and Aminiphilaceae). The most pair-wise link between Firmicutes and biogas production indicates the keystone members based on network features can be considered as markers in the regulation of AD. A set of 40% species (“core microbiome”) were similar across different digesters. Such noteworthy overlap of microbiomes indicates they are generalists in maintaining the ecological stability of digesters.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
•Metagenomic approach revealed the effects of antibiotics on anaerobic digestion.•Antibiotics impacted archaeal community and genes encoding fatty acid degradation.•All methanogenesis pathways were ...influenced by antibiotics pressure.•Antibiotics increased the antimicrobial resistant risks of digested sludge.•Positive association among antibiotics, ARG and specific microbe were found.
Continuous stirred-tank digesters with tetracyclines and sulfonamides were operated to investigate the impacts of antibiotic pressure on sludge anaerobic digestion. The versatile methanogen Methanosarcinales and strictly hydrogenotrophic methanogen Methanobacteriales increased and decreased by 21.1% and 10.9% under antibiotic pressure, respectively. KEGG analysis revealed that hydrogenotrophic and acetoclastic methanogenesis pathways were all affected. The decrease in abundance of function genes involved in lipid metabolism, carbohydrate metabolism, and fatty acid degradation, would lead to a reduction in methane production by 25%. Network analysis indicated positive associations among tetracycline residuals, abundance of resistance genes (ARGs), and specific member of potential hosts. Over 1000 ARG subtypes were widely detected in sludge, including macrolide (28%), tetracycline (24%), fluoroquinolone (20%), and peptide (20%) resistance genes. AD process exposed to long-term antibiotic would increase the diversity and abundance of ARG, enhance the association of ARG with specific microbes, and select bacteria able to perform chemotaxis mechanism.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
RNA methylation is emerging as an important regulator of gene expression. Dysregulation of methyltransferase that is essential for RNA modification contributes to the development and progression of ...human cancers. Here we show that methyltransferase-like 1 (METTL1) is upregulated in hepatocellular carcinoma (HCC) and exhibits oncogenic activities via PTEN/AKT signaling pathway. High expression of METTL1 is correlated with larger tumor size, higher serum AFP level, tumor vascular invasion, and poor prognosis in two independent cohorts containing 892 patients with HCC. Multivariate analyses suggest METTL1 as an independent factor for unfavorable overall survival. In vitro studies demonstrate that METTL1 overexpression promotes cell proliferation and migration, whereas its knockdown results in opposite phenotypes. Gene set enrichment analysis (GSEA) indicates PTEN pathway is activated in patients with low METTL1 expression. Ectopic expression of PTEN or inhibition of AKT activity significantly attenuates the METTL1-mediated malignant phenotypes. In clinical samples, METTL1 expression is reversely associated with PTEN expression. Combination of low METTL1 expression and high PTEN expression is significantly correlated with overall survival, more so than either METTL1 or PTEN expression alone. Collectively, our data suggest that METTL1 serves as a promising prognostic biomarker and that targeting METTL1/PTEN axis may provide therapeutic potential in HCC intervention.
Key messages
METTL1 is upregulated in HCC and correlated with poor outcomes.
METTL1 promotes cell proliferation and migration in HCC.
METTL1 exerts oncogenic activities via suppression of PTEN signaling.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Spread of antibiotic resistance genes (ARGs) originating from sewage sludge is highlighted as an eminent health threat. This study established a thermophilic anaerobic digester using one-step startup ...strategy to quickly remove tetracycline and sulfonamides resistance genes from sewage sludge. At least 20days were saved in the startup period from mesophilic to thermophilic condition. Based on the results of 16S rDNA amplicons sequencing and predicted metagenomic method, the successful startup largely relied on the fast colonization of core thermophilic microbial population (e.g. Firmicutes, Proteobacteria, Actinobacteria). Microbial metabolic gene pathways for substrate degradation and methane production was also increased by one-step mode. In addition, real-time quantitative PCR approach revealed that most targeted tetracycline and sulfonamides resistance genes ARGs (sulI, tetA, tetO, tetX) were substantially removed during thermophilic digestion (removal efficiency>80%). Network analysis showed that the elimination of ARGs was attributed to the decline of their horizontal (intI1 item) and vertical (potential hosts) transfer-related elements under high-temperature. This research demonstrated that rapid startup thermophilic anaerobic digestion of wastewater solids would be a suitable technology for reducing quantities of various ARGs.
Display omitted
•Rapid startup of thermophilic digester saved 20days.•Most antibiotic resistance genes were removed during thermophilic digestion.•Network of antibiotic resistance genes and potential hosts were presented.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract
Radial velocity (RV) is among the most fundamental physical quantities obtainable from stellar spectra and is rather important in the analysis of time-domain phenomena. LAMOST ...Medium-resolution Survey (MRS) DR7 contains five million single-exposure stellar spectra with spectral resolution
R
∼ 7500. However, the temporal variation of the RV zero-points (RVZPs) of the MRS, which makes the RVs from multiple epochs inconsistent, has not been addressed. In this paper, we measure the RVs of 3.8 million single-exposure spectra (for 0.6 million stars) with signal-to-noise ratios (S/N) higher than 5 based on the cross-correlation function method, and propose a robust method to self-consistently determine the RVZPs exposure by exposure for each spectrograph with the help of Gaia DR2 RVs. Such RVZPs are estimated for 3.6 million RVs and can reach a mean precision of ∼0.38 km s
−1
. The result of the temporal variation of RVZPs indicates that our algorithm is efficient and necessary before we use the absolute RVs to perform time-domain analyses. Validating the results with APOGEE DR16 shows that our absolute RVs can reach an overall precision of 0.84/0.80 km s
−1
in the blue/red arm at 50 < S/N < 100 and of 1.26/1.99 km s
−1
at 5 < S/N < 10. The cumulative distribution function of the standard deviations of multiple RVs (
N
obs
≥ 8) for 678 standard stars reaches 0.45/0.54, 1.07/1.39, and 1.45/1.86 km s
−1
in the blue/red arm at the 50%, 90%, and 95% levels, respectively. Catalogs of the RVs, RVZPs, and selected candidate RV standard stars are available at
https://github.com/hypergravity/paperdata
.
Since numerous RNAs and RBPs prevalently localize to active chromatin regions, many RNA‐binding proteins (RBPs) may be potential transcriptional regulators. RBPs are generally thought to regulate ...transcription via noncoding RNAs. Here, we describe a distinct, dual mechanism of transcriptional regulation by the previously uncharacterized tRNA‐modifying enzyme, hTrmt13. On one hand, hTrmt13 acts in the cytoplasm to catalyze 2'‐O‐methylation of tRNAs, thus regulating translation in a manner depending on its tRNA‐modification activity. On the other hand, nucleus‐localized hTrmt13 directly binds DNA as a transcriptional co‐activator of key epithelial–mesenchymal transition factors, thereby promoting cell migration independent of tRNA‐modification activity. These dual functions of hTrmt13 are mutually exclusive, as it can bind either DNA or tRNA through its CHHC zinc finger domain. Finally, we find that hTrmt13 expression is tightly associated with poor prognosis and survival in diverse cancer patients. Our discovery of the noncatalytic roles of an RNA‐modifying enzyme provides a new perspective for understanding epitranscriptomic regulation.
Synopsis
tRNA methyltransferases regulate translation through tRNA modification, while chromatin‐associated RBPs are thought to regulate transcription primarily though lncRNAs. Here, human tRNA methyltransferase hTrmt13 is found to have an unexpected additional nuclear function in regulating transcription.
Cytoplasmic hTrmt13 regulates protein translation dependent on its tRNA 2’‐O‐methylation activity.
Nuclear hTrmt13 directly binds DNA to promote transcription, independent of its catalytic activity.
Nuclear hTrmt13 promotes cell migration and cancer metastasis by acting as a transcriptional co‐activator.
hTrmt13 regulates gene expression via translation in the cytoplasm, but also by acting in a non‐catalytic manner as a transcriptional coactivator.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Traumatic brain injury (TBI) survivors suffer from long-term disability and neuropsychiatric sequelae due to irreparable brain tissue destruction. However, there are still few efficient therapies to ...promote neurorestoration in damaged brain tissue. This study aimed to investigate whether the pro-oncogenic gene ski can promote neurorestoration after TBI. We established a ski-overexpressing experimental TBI mouse model using adenovirus-mediated overexpression through immediate injection after injury. Hematoxylin-eosin staining, MRI-based 3D lesion volume reconstruction, neurobehavioral tests, and analyses of neuronal regeneration and astrogliosis were used to assess neurorestorative efficiency. The effects of ski overexpression on the proliferation of cultured immature neurons and astrocytes were evaluated using imaging flow cytometry. The Ski protein level increased in the perilesional region at 3 days post injury. ski overexpression further elevated Ski protein levels up to 14 days post injury. Lesion volume was attenuated by approximately 36-55% after ski overexpression, with better neurobehavioral recovery, more newborn immature and mature neurons, and less astrogliosis in the perilesional region. Imaging flow cytometry results showed that ski overexpression elevated the proliferation rate of immature neurons and reduced the proliferation rate of astrocytes. These results show that ski can be considered a novel neurorestoration-related gene that effectively promotes neurorestoration, facilitates neuronal regeneration, and reduces astrogliosis after TBI.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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