Zika virus (ZIKV) has evolved into a global health threat because of its unexpected causal link to microcephaly. Phylogenetic analysis reveals that contemporary epidemic strains have accumulated ...multiple substitutions from their Asian ancestor. Here we show that a single serine-to-asparagine substitution Ser139→Asn139 (S139N) in the viral polyprotein substantially increased ZIKV infectivity in both human and mouse neural progenitor cells (NPCs) and led to more severe microcephaly in the mouse fetus, as well as higher mortality rates in neonatal mice. Evolutionary analysis indicates that the S139N substitution arose before the 2013 outbreak in French Polynesia and has been stably maintained during subsequent spread to the Americas. This functional adaption makes ZIKV more virulent to human NPCs, thus contributing to the increased incidence of microcephaly in recent ZIKV epidemics.
Amino acids are known regulators of cellular signaling and physiology, but how they are sensed intracellularly is not fully understood. Herein, we report that each aminoacyl-tRNA synthetase (ARS) ...senses its cognate amino acid sufficiency through catalyzing the formation of lysine aminoacylation (K-AA) on its specific substrate proteins. At physiologic levels, amino acids promote ARSs bound to their substrates and form K-AAs on the ɛ-amine of lysines in their substrates by producing reactive aminoacyl adenylates. The K-AA marks can be removed by deacetylases, such as SIRT1 and SIRT3, employing the same mechanism as that involved in deacetylation. These dynamically regulated K-AAs transduce signals of their respective amino acids. Reversible leucylation on ras-related GTP-binding protein A/B regulates activity of the mammalian target of rapamycin complex 1. Glutaminylation on apoptosis signal-regulating kinase 1 suppresses apoptosis. We discovered non-canonical functions of ARSs and revealed systematic and functional amino acid sensing and signal transduction networks.
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•Amino acids modify ɛ-amines of lysines•Each tRNA synthetase is the aminoacyl transferase of its cognate amino acid•Aminoacylations can be reversed by deacetylases•Aminoacylations transmit amino acid signals to regulate cellular functions
He et al. reveal that tRNA synthetases sense sufficiency of amino acids and act as aminoacyl transferases to modify ɛ-amines of lysines in proteins, with leucylation of RagA/B regulating mTORC1 activity and glutaminylation of ASK1 inhibiting apoptosis. Lysine aminoacylation marks are removed by SIRT1 and SIRT3.
The re-emergence of Zika virus (ZIKV) in the Western Hemisphere has resulted in global public health crisis since 2015. ZIKV preferentially infects and targets human neural progenitor cells (hNPCs) ...and causes fetal microcephaly upon maternal infection. hNPCs not only play critical roles during fetal brain development, but also persist in adult brain throughout life. Yet the mechanism of innate antiviral immunity in hNPCs remains largely unknown. Here, we show that ZIKV infection triggers the abundant production of virus-derived small interfering RNAs in hNPCs, but not in the more differentiated progenies or somatic cells. Ablation of key RNAi machinery components significantly enhances ZIKV replication in hNPCs. Furthermore, enoxacin, a broad-spectrum antibiotic that is known as an RNAi enhancer, exerts potent anti-ZIKV activity in hNPCs and other RNAi-competent cells. Strikingly, enoxacin treatment completely prevents ZIKV infection and circumvents ZIKV-induced microcephalic phenotypes in brain organoid models that recapitulate human fetal brain development. Our findings highlight the physiological importance of RNAi-mediated antiviral immunity during the early stage of human brain development, uncovering a novel strategy to combat human congenital viral infections through enhancing RNAi.
NOTCH2NLC GGC repeat expansions were recently identified in neuronal intranuclear inclusion disease (NIID); however, it remains unclear whether they occur in other neurodegenerative disorders. This ...study aimed to investigate the role of intermediate‐length NOTCH2NLC GGC repeat expansions in Parkinson disease (PD). We screened for GGC repeat expansions in a cohort of 1,011 PD patients and identified 11 patients with intermediate‐length repeat expansions ranging from 41 to 52 repeats, with no repeat expansions in 1,134 controls. Skin biopsy revealed phospho‐alpha‐synuclein deposition, confirming the PD diagnosis in 2 patients harboring intermediate‐length repeat expansions instead of NIID or essential tremor. Fibroblasts from PD patients harboring intermediate‐length repeat expansions revealed NOTCH2NLC upregulation and autophagic dysfunction. Our results suggest that intermediate‐length repeat expansions in NOTCH2NLC are potentially associated with PD. ANN NEUROL 2021;89:182–187
As economical traits, food habits domestication can reduce production cost in aquaculture. However, the molecular mechanism underlying food habits domestication has remained elusive. Mandarin fish ...(Siniperca chuatsi) only feed on live prey fish and refuse artificial diets. In the present study, we domesticated mandarin fish to feed on artificial diets. The two groups were obtained, the fish did not eat artificial diets or ate artificial diets during all of the three domestication processes, named Group W or X, respectively.
Using transcriptome and metabolome analysis, we investigated the differentially expressed genes and metabolites between the two groups, and found three common pathways related to food habit domestication, including retinol metabolism, glycerolipid metabolism, and biosynthesis of unsaturated fatty acids pathways. Furthermore, the western blotting and bisulfite sequencing PCR analysis were performed. The gene expression of TFIIF and histone methyltransferase ezh1 were significantly increased and decreased in the fish of Group X, respectively. The total DNA methylation levels of TFIIF gene and tri-methylation of histone H3 at lysine 27 (H3K27me3) were significantly higher and lower in the fish of Group X, respectively.
It was speculated that mandarin fish which could feed on artificial diets, might be attributed to the lower expression of ezh1, resulting in the decreased level of H3K27me3 and increased level of DNA methylation of TFIIF gene. The high expression of TFIIF gene might up-regulate the expression of genes in retinol metabolism, glycerolipid metabolism and glycerophosphoric metabolism pathways. Our study indicated the relationship between the methylation of DNA and histone and food habits domestication, which might be a novel molecular mechanism of food habits domestication in animals.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Erianin is a small‐molecule compound that is isolated from Dendrobium chrysotoxum Lindl. In recent years, it has been found to have evident antitumor activity in various cancers, such as bladder ...cancer, cervical cancer, and nasopharyngeal carcinoma. In this study, we assessed the effect of erianin on lung cancer in terms of cell growth inhibition and the related mechanism. First, erianin at a concentration of less than 1 nmol/L exhibited cytotoxicity in H1975, A549, LLC lung cancer cells, did not cause marked growth inhibition in normal lung and kidney cells, induced obvious apoptosis and G2/M phase arrest of cells, and inhibited the migration and invasion of lung cancer cells in vitro. Second, in a mouse xenograft model of lewis lung cancer (LLC), oral administration of erianin (50, 35, and 10 mg kg−1 day−1 for 12 days) substantially inhibited nodule growth, reduced the fluorescence counts of lewis cells and the percentage vascularity of tumor tissues, increased the number of apoptotic tumor cells, the thymus indices, up‐regulated the levels of interleukin (IL)‐2 and tumor necrosis factor‐α (TNF‐α), decreased IL‐10 levels and the spleen index, and enhanced immune function. Lastly, the possible targets of erianin were determined by molecular docking and verified via western blot assay. The results indicated that erianin may achieve the above effects via inhibiting the phosphoinositide 3‐kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway in vitro and vivo. Taken together, the results showed that erianin had obvious antitumor effects via inhibiting the PI3K/Akt/mTOR pathway in vitro and vivo and may have potential clinical value for the treatment of lung cancer.
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•Bifunctional Co-doped UiO-66 nanoparticle was synthesized by a one-step method.•Effects of tetracycline on adsorption capacity were investigated.•Mechanisms and tetracycline ...intermediates of photodegradation was described.•Tetracycline in real samples were removed efficiently.
In this study, a novel recyclable Co-doped UiO-66 nanoparticle was synthesized by a one-step solvothermal method. A high adsorption capacity of 224.1 mg g−1 was obtained by the CoUiO-1 nanoparticle, then the adsorbed tetracycline (TC) molecules could be removed more than 94% of initial concentration under simulative sunlight irradiation. The adsorptive ability and photocatalytic performance of CoUiO-1 nanoparticle were about 7.6 and 6.9 times higher than the pristine UiO-66, respectively. The adsorption capacity of CoUiO-1 nanoparticle was sensitive to adsorbent dosage, coexisting ions, solution pH values and initial TC concentrations. Pseudo-second-order and Freundlich models fitted well with the adsorption process. Thermodynamic study indicated the TC adsorption on CoUiO-1 nanoparticle was a spontaneous and exothermic process. TC photodegradation experiment showed that the Co-doped modification expanded light absorption and facilitated charge separation of UiO-66, which was beneficial to enhance photocatalytic performance. The mechanism of TC photodegradation by Co-doped UiO-66 nanoparticle was investigated. Moreover, a plausible degradation pathway for TC was proposed. The high removal efficiencies of CoUiO-1 nanoparticle were obtained towards real samples including tap water, river water and pharmaceutical wastewater. Therefore, the novel Co-doped MOFs photocatalytic adsorbent showed great potential in wastewater treatment.
Intravascular ultrasound (IVUS)-guided percutaneous coronary intervention (PCI) has been reported to significantly reduce major adverse cardiac events (MACEs) compared with angiography-guided PCI. We ...aimed to explore whether there were racial differences regarding the beneficial effects of IVUS-guided PCI. Randomized controlled trials for comparison of clinical outcomes between IVUS-guided and angiography-guided PCI were retrieved from PubMed, Web of Science, Embase, and the Cochrane Library from inception to March 15, 2023. The clinical outcomes included MACE, all-cause mortality, myocardial infarction (MI), target vessel revascularization (TVR), target lesion revascularization (TLR), and stent thrombosis (ST). Finally, 18 randomized controlled trials were included in this study (8 in East Asian patients and 10 in Western patients). Results showed that IVUS-guided PCI was associated with a significant reduction of MACE, TVR, TLR, and ST, but not all-cause mortality and MI in both East Asian and Western patients. The reduction of MACE was more significant in East Asian patients (odds ratio OR 0.57, 95% confidence interval CI 0.46 to 0.70) than that in Western patients (OR 0.83, 95% CI 0.67 to 1.02). Meta-regression analysis revealed that the country the study was performed in (East Asian vs Western countries) was associated with significant heterogeneity between groups, suggesting that racial differences existed (p = 0.033). In conclusion, IVUS-guided PCI was associated with a lower risk of MACE, TLR, TVR, and ST, but not all-cause mortality and MI in both East Asians and Westerners. East Asians benefited more than Westerners upon using IVUS-guided PCI in reducing MACE, suggesting that racial differences do exist between different imaging methods. Larger-sample studies are warranted for further clarification of our findings.
Currently, there are no approved specific antiviral agents for novel coronavirus disease 2019 (COVID-19). In this study, 10 severe patients confirmed by real-time viral RNA test were enrolled ...prospectively. One dose of 200 mL of convalescent plasma (CP) derived from recently recovered donors with the neutralizing antibody titers above 1:640 was transfused to the patients as an addition to maximal supportive care and antiviral agents. The primary endpoint was the safety of CP transfusion. The second endpoints were the improvement of clinical symptoms and laboratory parameters within 3 d after CP transfusion. The median time from onset of illness to CP transfusion was 16.5 d. After CP transfusion, the level of neutralizing antibody increased rapidly up to 1:640 in five cases, while that of the other four cases maintained at a high level (1:640). The clinical symptoms were significantly improved along with increase of oxyhemoglobin saturation within 3 d. Several parameters tended to improve as compared to pretransfusion, including increased lymphocyte counts (0.65 × 109/L vs. 0.76 × 109/L) and decreased C-reactive protein (55.98 mg/L vs. 18.13 mg/L). Radiological examinations showed varying degrees of absorption of lung lesions within 7 d. The viral load was undetectable after transfusion in seven patients who had previous viremia. No severe adverse effects were observed. This study showed CP therapy was well tolerated and could potentially improve the clinical outcomes through neutralizing viremia in severe COVID-19 cases. The optimal dose and time point, as well as the clinical benefit of CP therapy, needs further investigation in larger well-controlled trials.
A new series of dinuclear lanthanide complexes, Ln 2 (Hshi) 2 DBM 4 ·2DMF (Ln = Sm, Eu, Gd, Dy, Nd and Yb) were synthesized using H 3 shi (H 3 shi = salicylhydroxamic acid) and a β-diketonate ligand ...(DBM = dibenzoylmethanide). The two Ln( iii ) ions in the molecules are bridged by a salicylhydroxamic ligand with a rigid configuration. The structures of the isostructural complexes 1–6 were determined by single-crystal X-ray crystallography. The optical properties of the complexes can be simply enhanced by doping methods. White-light emission materials can be obtained from a single component (Sm 3+ ) by adjusting the excitation wavelength. The lifetimes and quantum yields of the luminescence were also determined.
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