Search

Mitochondrial DNA (mtDNA) associated mitochondrial diseases hold a crucial position but comprehensive and systematic studies are relatively rare. Among the 262 patients of four children's hospitals in China, 96%-point mutations (30 alleles in 11 genes encoding tRNA, rRNA, Complex I and V) and 4%-deletions (seven of ten had not been reported before) were identified as the cause of 14 phenotypes. MILS presented the highest genetic heterogeneity, while the m.3243A G mutation was the only "hotspot" mutation with a wide range of phenotypes. The degrees of heteroplasmy in the leukocytes of MM were higher than MELAS. The heteroplasmy level of patients was higher than that in mild and carrier group, while we found low-level heteroplasmy pathogenic mutations as well. Some homoplasmic variations (e.g., m.9176 T C mutation) are having high incomplete penetrance. For a suspected MELAS, m.3243A G mutation was recommended to detect first; while for a suspected LS, trios-WES and mtDNA genome sequencing by NGS were recommended first in both blood and urine.

Hydrogen sulphide (H2S) inhibits vascular smooth muscle cell (VSMC) proliferation induced by hyperglycaemia and hyperlipidaemia; however, the mechanisms are unclear. Here, we observed lower H2S levels and higher expression of the proliferation‐related proteins PCNA and cyclin D1 in db/db mouse aortae and vascular smooth muscle cells treated with 40 mmol/L glucose and 500 μmol/L palmitate, whereas exogenous H2S decreased PCNA and cyclin D1 expression. The nuclear translocation of mitochondrial pyruvate dehydrogenase complex‐E1 (PDC‐E1) was significantly increased in VSMCs treated with high glucose and palmitate, and it increased the level of acetyl‐CoA and histone acetylation (H3K9Ac). Exogenous H2S inhibited PDC‐E1 translocation from the mitochondria to the nucleus because PDC‐E1 was modified by S‐sulfhydration. In addition, PDC‐E1 was mutated at Cys101. Overexpression of PDC‐E1 mutated at Cys101 increased histone acetylation (H3K9Ac) and VSMC proliferation. Based on these findings, H2S regulated PDC‐E1 S‐sulfhydration at Cys101 to prevent its translocation from the mitochondria to the nucleus and to inhibit VSMC proliferation under diabetic conditions.

To clarify the characteristics and distribution of hospital environmental microbiome associated with confirmed COVID-19 patients. Environmental samples with varying degrees of contamination which were associated with confirmed COVID-19 patients were collected, including 13 aerosol samples collected near eight patients in different wards, five swabs from one patient’s skin and his personal belongings, and two swabs from the surface of positive pressure respiratory protective hood and the face shield from a physician who had close contact with one patient. Metagenomic next-generation sequencing (mNGS) was used to analyze the composition of the microbiome. One of the aerosol samples (near patient 4) was detected positive for COVID-19, and others were all negative. The environmental samples collected in different wards possessed protean compositions and community structures, the dominant genera including Pseudomonas, Corynebacterium, Neisseria, Staphylococcus, Acinetobacter, and Cutibacterium. Top 10 of genera accounted for more than 76.72%. Genera abundance and proportion of human microbes and pathogens radiated outward from the patient, while the percentage of environmental microbes increased. The abundance of the pathogenic microorganism of medical supplies is significantly higher than other surface samples. The microbial compositions of the aerosol collected samples nearby the patients were mostly similar to those from the surfaces of the patient's skin and personal belongings, but the abundance varied greatly. The positive rate of COVID-19 RNA detected from aerosol around patients in general wards was quite low. The ward environment was predominantly inhabited by species closely related to admitted patients. The spread of hospital microorganisms via aerosol was influenced by the patients’ activity.

The treatment of obstructive sleep apnea-hypopnea syndrome targets the narrow anatomic structure of the upper airway (UA) and lacks an effective therapy for UA dilator muscle dysfunction. Long-term hypoxia can cause damage to UA dilator muscles and trigger a vicious cycle. We previously confirmed that hypoxia-inducible factor 1α (HIF-1α) upregulation mediates muscle fatigue in hypoxia condition, but the underlying mechanism remains to be determined. The present study investigated the intrinsic mechanisms and related pathways of HIF-1α that affect myoblast differentiation, with an aim to search for compounds that have protective effects in hypoxic condition. Differentiation of myoblasts was induced under hypoxia, and we found that hypoxia significantly inhibits the differentiation of myoblasts, damages the ultrastructure of mitochondria, and reduces the expression of myogenin, PGC-1β and pAMPKα1. HIF-1α has a negative regulation effect on AMPK. Downregulation of HIF-1α increases the expression of the abovementioned proteins, promotes the differentiation of myoblasts, and protects mitochondrial integrity. In addition, mitochondrial biogenesis occurs during myogenic differentiation. Inhibition of the AMPK pathway inhibits mitochondrial biogenesis, decreases the level of PGC-1β, and increases apoptosis. Resveratrol dimer can reverse the mitochondrial damage induced by AMPK pathway inhibition and decrease myoblast apoptosis. Our results provided a regulatory mechanism for hypoxic injury in genioglossus which may contribute to the pathogenesis and treatment of OSAHS.

Inducer of CBF expression 1 (ICE1), an MYC-like bHLH transcriptional activator, plays an important role in plants under cold stress by regulating the transcriptional expression of downstream cold-responsive genes. The ubiquitination-proteasome pathway mediated by high expression of osmotically responsive gene1 (HOS1) can effectively induce the degradation of ICE1 and decrease the expression of CBFs and their downstream genes under cold stress response in Arabidopsis, but knowledge of ubiquitination regulation of ICE1 by HOS1 is still limited in woody plants. In this study, a E3 ubiquitin ligase gene EcaHOS1 were amplified from Eucalyptus camaldulensis, the protein interactions between EcaICE1 and EcaHOS1 were analyzed. Yeast two-hybrid (Y2H) and bimolecular fluorescence complementation (BiFC) assay results showed that EcaICE1 can interact with the EcaHOS1 protein in the nucleus, and further Y2H assay demonstrated that the 126-185 amino acid region at the N-terminus of the EcaICE1 protein was indispensable for its interaction with EcaHOS1 protein. Moreover, we found that the amino acids at positions 145, 158, and 184 within the key interaction region were the putative phosphorylation sites of EcaICE1 based on bioinformatics analysis, and only the substitution of Serine (Ser) 158 by Alanine (Ala) blocked the protein-protein interactions between EcaICE1 and EcaHOS1 based on Y2H and β-galactosidase activity assays using site-directed mutagenesis. In summary, this is the first report that EcaICE1 can interact with the EcaHOS1 protein in Eucalyptus, and we identified Ser 158 of EcaICE1 as the key putative phosphorylation site for its interaction with the EcaHOS1 protein.

Chronic stress can impair hippocampal neurogenesis, increase neuronal apoptosis, and cause depressive-like behaviors. Our previous studies found that Radix Scutellariae (RS) can rescue the stress-induced neuronal injury, but the mechanism is not clear. Here, we continued to investigate the underlying antidepressant mechanisms of the RS extract. A 7-week chronic unpredictable mild stress (CUMS) procedure was used to establish a murine depression model. 0.75 g/kg or 1.5 g/kg RS was administered daily to the mice during the last 4 weeks. Depressive-like behaviors were evaluated by the sucrose preference test (SPT), forced swimming test (FST), open field test (OFT), and tail suspension test (TST). The neuroprotective effect of RS was evaluated with the expression of hippocampal neuron-related markers and apoptosis-associated proteins by Nissl staining, immunohistochemistry, and western blot. Transforming growth factor-β3 (TGFβ3) pathway-related proteins were detected by western blot. Results showed that RS could ameliorate depressive-like behaviors, increase the expression of the antiapoptotic protein B-cell lymphoma 2 (BCL-2), reduce the expression of the proapoptotic protein BCL-2-associated X (BAX), and increase the number of doublecortin- (DCX-), microtubule-associated protein 2- (MAP2-), and neuronal nucleus- (NeuN-) positive cells in the hippocampus. Moreover, RS could reverse the CUMS-induced decrease of TGFβ3 protein, promote the phosphorylation of SMAD2/3, and increase the expression of downstream NEDD9 protein. These results suggest that RS could exert antidepressant effects via protecting neurons. And the molecular mechanism might be related to the regulation of the TGFβ3-SMAD2/3-NEDD9 pathway.

Hydrogen sulfide (H2S) plays physiological roles in vascular tone regulation, cytoprotection, and ATP synthesis. HMG-CoA reductase degradation protein (Hrd1), an E3 ubiquitin ligase, is involved in protein trafficking. H2S may play a role in controlling fatty acid uptake in diabetic cardiomyopathy (DCM) in a manner correlated with modulation of Hrd1 S-sulfhydration; however, this role remains to be elucidated. The aim of the present study was to examine whether H2S can attenuate lipid accumulation and to explain the possible mechanisms involved in the regulation of the H2S-Hrd1/VAMP3 pathway. Db/db mice and neonatal rat cardiomyocytes treated with high glucose, palmitate and oleate were used as animal and cellular models of type 2 diabetes, respectively. The expression of cystathionine-γ-lyase (CSE), Hrd1, CD36 and VAMP3 was detected by Western blot analysis. In addition, Hrd1 was mutated at Cys115, and Hrd1 S-sulfhydration was examined using an S-sulfhydration assay. VAMP3 ubiquitylation was investigated by immunoprecipitation. Lipid droplet formation was tested by TEM, BODIPY 493/503 staining and oil red O staining. The expression of CSE and Hrd1 was decreased in db/db mice compared to control mice, whereas CD36 and VAMP3 expression was increased. NaHS administration reduced droplet formation, and exogenous H2S restored Hrd1 expression, modified S-sulfhydration, and decreased VAMP3 expression in the plasma membrane. Using LC-MS/MS analysis, we identified 85 proteins with decreased ubiquitylation, including 3 vesicle-associated membrane proteins, in the cardiac tissues of model db/db mice compared with NaHS-treated db/db mice. Overexpression of Hrd1 mutated at Cys115 diminished VAMP3 ubiquitylation, whereas it increased CD36 and VAMP3 expression and droplet formation. siRNA-mediated Hrd1 deletion increased the expression of CD36 in the cell membrane. These findings suggested that H2S regulates VAMP3 ubiquitylation via Hrd1 S-sulfhydration at Cys115 to prevent CD36 translocation in diabetes.

To cope with their continually fluctuating surroundings, pathovars of the unicellular phytopathogen Pseudomonas syringae have developed rapid and sophisticated signalling networks to sense extracellular stimuli, which allow them to adjust their cellular composition to survive and cause diseases in host plants. Comparative genomic analyses of P. syringae strains have identified various genes that encode several classes of signalling proteins, although how this bacterium directly perceives these environmental cues remains elusive. Recent work has revealed new mechanisms of a cluster of bacterial signal transduction systems that mainly include two-component systems (such as RhpRS, GacAS, CvsRS and AauRS), extracytoplasmic function sigma factors (such as HrpL and AlgU), nucleotide-based secondary messengers, methyl-accepting chemotaxis sensor proteins and several other intracellular surveillance systems. In this review, we compile a list of the signal transduction mechanisms that P. syringae uses to monitor and respond in a timely manner to intracellular and external conditions. Further understanding of these surveillance processes will provide new perspectives from which to combat P. syringae infections.

Alveolar bone defects can arise as a consequence of trauma, infection, periodontal disease, or congenital alveolar fenestration. Many approaches have been employed in an effort to treat or overcome such defects, but the ability to effectively achieve alveolar regeneration remains elusive. Platelet-derived growth factor-BB (PDGF-BB) has been shown to serve as a key factor capable of orchestrating cell proliferation, angiogenesis, and chemoattraction in the context of osteogenic processes. Exactly how PDGF-BB affects human periodontal ligament stem cells (hPDLSCs), however, requires further exploration. In this report, we utilized a lentiviral construct to achieve PDGF-BB overexpression in hPDLSCs, allowing us to establish that this gene was able to enhance the proliferation of these cells and to mediate osteogenic gene upregulation therein. In addition, we established a rat model of alveolar defects that were implanted using different complexes, and then monitored through histological and micro-CT analyses 4 and 8 weeks postsurgery to assess bone repair outcomes. These analyses revealed that a thermosensitive hydrogel was an effective 3D cell culture scaffold, while PDLSCs overexpressing PDGF-BB enhanced bone growth in the context of alveolar bone defects. Together, these results thus indicate that PDGF-BB represents a potent means of promoting stem cell-based alveolar bone tissue regeneration.

An optimized support vector machine model was used to construct a lung cancer diagnosis model based on serological indicators, and a molecular regulation model of Wogonin, a component of Scutellaria baicalensis, was established. Serological indexes of patients were collected, the grid search method was used to identify the optimal penalty coefficient C and parameter g of the support vector machine model, and the benign and malignant auxiliary diagnosis model of isolated pulmonary nodules based on serological indicators was established. The regulatory network and key targets of Wogonin in lung cancer were analyzed by network pharmacology, and key targets were detected by western blot. The relationship between serological susceptibility genes and key targets of Wogonin was established, and the signaling pathway of Wogonin regulating lung cancer was constructed. After support vector machine parameter optimization (C = 90.597, g = 32), the accuracy of the model was 90.8333%, with nine false positives and two false negative cases. Ontology functional analysis of 67 common genes between Wogonin targets and lung cancer–related genes showed that the targets were associated with biological processes involved in peptidye-serine modification and regulation of protein kinase B signaling; cell components in the membrane raft and chromosomal region; and molecular function in protein serine/threonine kinase activity and heme binding. Kyoto Encyclopedia of Genes and Genomes analysis showed that the regulation pathways involved the PI3K-Akt signaling pathway, ERBB signaling pathway, and EGFR tyrosine kinase inhibitor resistance. In vitro analyses using lung cancer cells showed that Wogonin led to significantly increased levels of cleaved caspase-3 and Bad and significantly decreased Bcl-2 expression in a concentration-dependent manner. ErbB4 expression also significantly decreased in lung cancer cells after treatment with Wogonin. A regulatory network of Wogonin regulating lung cancer cell apoptosis was constructed, including the participation of serological susceptibility genes. There is a certain regulatory effect between the serological indexes that can be used in the diagnosis of lung cancer and the key targets of Chinese herbal medicine treatment of lung cancer, which provides a new idea for the diagnosis, treatment and prognosis of clinical lung cancer.

Background: A proper stem cell source is key to muscle injury repair. Dental pulp stem cells (DPSCs) are an available source for the treatment of muscle injury due to their high reproductive and differential activities. However, the application of DPSCs in muscle regeneration is incompletely understood. Noggin, a secreted BMP antagonist promoted by Wnt-1, is required for embryonic myogenesis. Our research is to study whether Noggin can promote myogenic differentiation of DPSCs, and then to investigate the repair effect of Noggin combined with DPSCs in muscle injury.Methods: DPSCs were treated with Noggin to induce myogenic differentiation in vitro. The levels of myogenic markers (MyoD, Desmin, MRF4 and MyHC), and satellite cell markers (Pax3, Pax7, Six1 and Eya2) were detected during this process. Next, we blocked the effect of Noggin by adding BMP, and Samd phosphorylation level was tested. Then, we implanted Noggin-pretreated DPSC combined Matrigel into the mouse tibialis anterior muscle with volumetric muscle loss (VML). After 30-day recovery, morphometric analysis of the tibialis anterior muscle was performed.Results: Noggin effectively increased myotube formation in DPSCs. We also found Noggin accelerated the skeletal myogenic differentiation of DPSCs and promote Pax7+ satellite-like cell generation. These satellite-like cells had the capacity to generate myofibers and could self-renew. Pax7 and Pax3 levels were repressed when blocked the effect of Noggin by adding BMP, and Noggin eliminated the level of BMP/Smad phosphorylation. This suggested that Noggin facilitated the skeletal myogenic differentiation of DPSCs via Smad/Pax7 pathway. Morphometric analysis of muscle cross-sections revealed that DPSCs therapy could increase repair size and decrease scar tissue in tibialis anterior muscle of VML. Moreover, Noggin-treated DPSCs can benefit to Pax7+ satellite cell pool and promote muscle regeneration. Conclusions: This work reveals that Noggin can promote the generation of satellite-like cells for the myogenic process in DPSCs through Smad/Pax7 signaling pathway, and these satellite-like cells bioconstructs might possess a relatively fast capacity to regenerate for muscle injury.

Accumulation of lipid droplets (LDs) induces cardiac dysfunctions in type 2 diabetes patients. Recent studies have shown that hydrogen sulphide (H2S) ameliorates cardiac functions in db/db mice, but its regulation on the formation of LDs in cardiac tissues is unclear. Db/db mice were injected with NaHS (40 μmol·kg‐1) for twelve weeks. H9c2 cells were treated with high glucose (40 mmol/L), oleate (200 µmol/L), palmitate (200 µmol/L) and NaHS (100 µmol/L) for 48 hours. Plasmids for the overexpression of wild‐type Hrd1 and Hrd1 mutated at Cys115 were constructed. The interaction between Hrd1 and DGAT1 and DGAT2, the ubiquitylation level of DGAT1 and 2, the S‐sulfhydration of Hrd1 were measured. Exogenous H2S ameliorated the cardiac functions, decreased ER stress and reduced the number of LDs in db/db mice. Exogenous H2S could elevate the ubiquitination level of DGAT 1 and 2 and increased the expression of Hrd1 in cardiac tissues of db/db mice. The S‐sulfhydration of Hrd1 by NaHS enhanced the interaction between Hrd1 and DGAT1 and 2 to inhibit the formation of LD. Our findings suggested that H2S modified Hrd1 S‐sulfhydration at Cys115 to reduce the accumulation of LDs in cardiac tissues of db/db mice.

Polyethylene glycol (PEG) has previously been reported to improve outcomes of peripheral nerve microsuturing. However, recent studies have challenged this finding. Given its clinical importance, we investigated the potential of PEG as a facilitator of peripheral nerve restoration. The sciatic nerve of 144 rats was transected and submitted either to simple suturing (Group A), PEG-enhanced suturing (Group B), and insertion in an arterial sleeve conduit without PEG (Group C), or with PEG (Group D) in equal numbers. Behavioral recovery was assessed with the sciatic function index (SFI). Nerve impulse conduction was assessed with compound muscle action potentials (CMAPs). Histology comprised standard hematoxylin/eosin staining, electron microscopy and glial cell line-derived neurotrophic factor (GDNF) immunohistochemistry. Expression of GDNF was also assessed with western blotting. Results were evaluated at weeks 1, 4, and 8. PEG treatment significantly improved behavioral recovery and morphology of nerve restoration, particularly in the sleeve conduit group, relative to that of controls. In conclusion, PEG may improve outcomes of peripheral nerve reconstruction.

Background and purpose Hydrogen sulfide (H2 S) plays important roles as a gasotransmitter in pathologies. Increased expression of the E3 ubiquitin ligase, muscle RING finger-1 (MuRF1), may be involved in diabetic cardiomyopathy. Here we have investigated whether and how exogenous H2 S alleviates cardiac muscle degradation through modifications of MuRF1 S-sulfhydration in db/db mice. Experimental approach Neonatal rat cardiomyocytes were treated with high glucose (40 mM), oleate (100 μM), palmitate (400 μM), and NaHS (100 μM) for 72 hr. MuRF1 was silenced with siRNA technology and mutation at Cys44 . Endoplasmic reticulum stress markers, MuRF1 expression, and ubiquitination level were measured. db/db mice were injected with NaHS (39 μmol·kg-1 ) for 20 weeks. Echocardiography, cardiac ultrastructure, cystathionine-γ-lyase, cardiac structure proteins expression, and S-sulfhydration production were measured. Key results H2 S levels and cystathionine-γ-lyase protein expression in myocardium were decreased in db/db mice. Exogenous H2 S reversed endoplasmic reticulum stress, including impairment of the function of cardiomyocytes and structural damage in db/db mice. Exogenous H2 S could suppress the levels of myosin heavy chain 6 and myosin light chain 2 ubiquitination in cardiac tissues of db/db mice, and MuRF1 was modified by S-sulfhydration, following treatment with exogenous H2 S, to reduce the interaction between MuRF1 and myosin heavy chain 6 and myosin light chain 2. Conclusions and implications Our findings suggest that H2 S regulates MuRF1 S-sulfhydration at Cys44 to prevent myocardial degradation in the cardiac tissues of db/db mice. Linked articles This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc.

Solitary fibrous tumours are unusual neoplasms that develop from mesenchymal cells, usually originating from the pleura. A pericardial solitary fibrous tumour is an extremely rare occurrence. We report a 64-year-old woman who presented to the hospital with chief complaints of dyspnoea and abdominal distension. Echocardiography and enhanced computed tomography revealed an intrapericardial tumour with local invasion to the right atrium. Histopathological examination of a biopsy specimen showed a patternless distribution of spindle-shaped cells in a collagen stroma, with a high mitosis rate. Immunohistochemistry was positive for vimentin, CD34, and Bcl-2. The final diagnosis was a pericardial malignant solitary fibrous tumour with right atrial invasion. Surgical resection of the tumour was not performed because of its invasion into the myocardium. We systematically reviewed the literature on cardiac solitary fibrous tumours up to 2019.

We synthesized a series of novel pyrrole- and pyrazole-substituted coumarin derivatives and evaluated their antifungal activity against six phytopathogenic fungi in vitro. The primary assay results demonstrated that some designed compounds displayed potent activities. Among them, compounds 5g, 6a, 6b, 6c, 6d and 6h exhibited more effective control than Osthole against Cucumber anthrax and Alternaria leaf spot. Furthermore, compound 5g displayed stronger antifungal activity against Rhizoctorzia solani (EC50 = 15.4 µg/mL) than positive control Osthole (EC50 = 67.2 µg/mL).

© The Author(s) 2019. A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-Alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2- degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10?6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10?8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models. National Heart, Lung, and Blood Institute; American Heart Association Grant

Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass.Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci.Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms).Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection.Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.

To improve multi-environmental trial (MET) analysis, a compound method—which combines factor analytic (FA) model with additive main effect and multiplicative interaction (AMMI) and genotype main effect plus genotype-by-environment interaction (GGE) biplot—was conducted in this study. The diameter at breast height of 36 open-pollinated (OP) families of Pinus taeda at six sites in South China was used as a raw dataset. The best linear unbiased prediction (BLUP) data of all individual trees in each site was obtained by fitting the spatial effects with the FA method from raw data. The raw data and BLUP data were analyzed and compared by using the AMMI and GGE biplot. BLUP results showed that the six sites were heterogeneous and spatial variation could be effectively fitted by spatial analysis with the FA method. AMMI analysis identified that two datasets had highly significant effects on the site, family, and their interactions, while BLUP data had a smaller residual error, but higher variation explaining ability and more credible stability than raw data. GGE biplot results revealed that raw data and BLUP data had different results in mega-environment delineation, test-environment evaluation, and genotype evaluation. In addition, BLUP data results were more reasonable due to the stronger analytical ability of the first two principal components. Our study suggests that the compound method combing the FA method with the AMMI and GGE biplot could improve the analysis result of MET data in Pinus teada as it was more reliable than direct AMMI and GGE biplot analysis on raw data.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.

Background: Thiamine-responsive megaloblastic anemia syndrome (TRMA) is a rare autosomal recessive hereditary disease due to mutations in SLC19A2. Some cases show familial inheritance.Case report: A female patient (from a gravida 1, para 1 mother) of 3.5 years of age was admitted to the Pediatric Hematology Department of Xianyang Caihong Hospital in June 2019. The patient had severe anemia, acupoint-size bleeding spots, and a few ecchymoses all over her body, as well as astigmatism and hyperopia. Hearing was normal. The patient had diabetes. Bone marrow biopsy suggested a myelodysplastic syndrome. The patient had a c.515G>A (p.G172D) homozygous mutation of SLC19A2 (NM_006996), indicating TRMA. Genetic testing revealed that the two alleles were inherited from her mother alone due to maternal uniparental isodisomy (UPD). The patient was treated with thiamine and a subcutaneous injection of insulin. The patient recovered well and was discharged. She continued thiamine and insulin at the same dose and was followed once a month. The last follow-up on September 15, 2020, showed no anemia or bleeding. She had a sound hearing and normal blood routine and fasting glucose levels. Hyperopia and astigmatism did not improve.Conclusion: The patient had TRMA induced by the c.515G>A (p.G172D) homozygous mutation of SLC19A2 inherited through maternal UPD. The genetic diagnosis of TRMA is of significance for guiding clinical treatment. Early treatment with exogenous thiamine can improve some of the clinical features of TRMA.

Background: Hypertriglyceridemia has emerged as a critical coronary artery disease (CAD) risk factor. Rare loss-of function (LoF) variants in apolipoprotein C-III have been reported to reduce triglycerides (TG) and are cardioprotective in American Indians and Europeans. However, there is a lack of data in other Europeans and non-Europeans. Also, whether genetically increased plasma TG due to ApoC-III is causally associated with increased CAD risk is still unclear and inconsistent. The objectives of this study were to verify the cardioprotective role of earlier reported six LoF variants of APOC3 in South Asians and other multi-ethnic cohorts and to evaluate the causal association of TG raising common variants for increasing CAD risk. Methods: We performed gene-centric and Mendelian randomization analyses and evaluated the role of genetic variation encompassing APOC3 for affecting circulating TG and the risk for developing CAD. Results: One rare LoF variant (rs138326449) with a 37% reduction in TG was associated with lowered risk for CAD in Europeans (p = 0.007), but we could not confirm this association in Asian Indians (p = 0.641). Our data could not validate the cardioprotective role of other five LoF variants analysed. A common variant rs5128 in the APOC3 was strongly associated with elevated TG levels showing a p-value 2.8 × 10− 424. Measures of plasma ApoC-III in a small subset of Sikhs revealed a 37% increase in ApoC-III concentrations among homozygous mutant carriers than the wild-type carriers of rs5128. A genetically instrumented per 1SD increment of plasma TG level of 15 mg/dL would cause a mild increase (3%) in the risk for CAD (p = 0.042). Conclusions: Our results highlight the challenges of inclusion of rare variant information in clinical risk assessment and the generalizability of implementation of ApoC-III inhibition for treating atherosclerotic disease. More studies would be needed to confirm whether genetically raised TG and ApoC-III concentrations would increase CAD risk. Ministry of Health (MOH) National Medical Research Council (NMRC) Published version AIDHS/SDS: The Sikh Diabetes Study/ Asian Indian Diabetic Heart Study was supported by NIH grants-R01DK082766; R01DK118427 (NIDDK) and NOT-HG11-009 (NHGRI) and grants from Presbyterian Health Foundation and Harald Hamm Diabetes Center of Oklahoma. Sequencing services were provided through the RS&G Service by the Northwest Genomics Center at the University of Washington, Department of Genome Sciences, under US Federal Government contract number HHSN268201100037C from the National Heart, Lung, and Blood Institute of the NIH. LOLIPOP: The LOLIPOP study is supported by the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre Imperial College Healthcare NHS. Trust, the British Heart Foundation (S.P./04/002), the Medical Research Council (G0601966, G0700931), the Wellcome Trust (084723/Z/08/Z, 090532 & 098381) the NIHR (RP-PG-0407-10371), the NIHR Official Development Assistance (ODA, award 16/136/68), the European Union FP7 (EpiMigrant, 279143) and H2020 programs (iHealth-T2D, 643774). We acknowledge the support of the MRC-PHE Centre for Environment and Health, and the NIHR Health Protection Research Unit on Health Impact of Environmental Hazards. The work was carried out in part at the NIHR/Wellcome Trust Imperial Clinical Research Facility. The views expressed are those of the author(s) and not necessarily those of the Imperial College Healthcare NHS. Trust, the NHS, the NIHR, or the Department of Health. We thank the participants and research staff who made the study possible. JC is supported by the Singapore Ministry of Health’s National Medical Research Council under its Singapore Translational Research Investigator (STaR) Award (NMRC/ STaR/0028/2017). SAMAFS: SAMAFS is supported in part by National Institutes of Health (NIH) grants P01 HL045522, R01 DK047482, DK053889, R01 HL113323, R37 MH059490, and T2D-GENES Consortium grants (U01 DK085524, U01 DK085584, U01 DK085501, U01 DK085526, and U01 DK085545). We thank the participants of the San Antonio Family Heart Study and the San Antonio Family Diabetes/Gallbladder Study for their continued cooperation and participation in our research programs. MISS-OLIVER: The OLIVER and MISS are partly supported by NIH grants -R01DK082766 funded by the National Institute of Health (NIDDK), Presbyterian Health Foundation Grants, the College of Medicine Alumni Association grant, and Leinbach Seed Grant from the University of Oklahoma Health Sciences Center. The authors thank all the participants of MISS-OLIVER participants and are grateful for their contribution to this study. UKBB: YT is supported by a Funai Overseas Scholarship from the Funai Foundation for Information Technology and the Stanford University School of Medicine. MAR is partially supported by Stanford University and a National Institute of Health center for Multi-and Trans-ethnic Mapping of Mendelian and Complex Diseases grant (5 U01 HG009080) and partially supported by the National Human Genome Research Institute (NHGRI) of the National Institutes of Health (NIH) under award R01HG010140.

A series of fluorinated 7-hydroxycoumarin derivatives containing an oxime ether moiety have been designed, synthesized and evaluated for their antifungal activity. All the target compounds were determined by 1H-NMR, 13C-NMR, FTIR and HR-MS spectra. The single-crystal structures of compounds 4e, 4h, 5h and 6c were further confirmed using X-ray diffraction. The antifungal activities against Botrytis cinerea (B. cinerea), Alternariasolani (A. solani), Gibberella zeae (G. zeae), Rhizoctorzia solani (R. solani), Colletotrichum orbiculare (C. orbiculare) and Alternaria alternata (A. alternata) were evaluated in vitro. The preliminary bioassays showed that some of the designed compounds displayed the promising antifungal activities against the above tested fungi. Strikingly, the target compounds 5f and 6h exhibited outstanding antifungal activity against B. cinerea at 100 &mu, g/mL, with the corresponding inhibition rates reached 90.1 and 85.0%, which were better than the positive control Osthole (83.6%) and Azoxystrobin (46.5%). The compound 5f was identified as the promising fungicide candidate against B. cinerea with the EC50 values of 5.75 &mu, g/mL, which was obviously better than Osthole (33.20 &mu, g/mL) and Azoxystrobin (64.95 &mu, g/mL). Meanwhile, the compound 5f showed remarkable antifungal activities against R. solani with the EC50 values of 28.96 &mu, g/mL, which was better than Osthole (67.18 &mu, g/mL) and equivalent to Azoxystrobin (21.34 &mu, g/mL). The results provide a significant foundation for the search of novel fluorinated 7-hydroxycoumarin derivatives with good antifungal activity.

Branching in long-lived plants can cause scarring at the base and affect wood density, which greatly inhibits wood yield and quality. Eucalyptus urophylla is one of the most important commercial forest tree species in South China, with diverse branch number and branch angles under different genetic backgrounds. However, the main elements and regulatory mechanisms associated with different branching traits in E. urophylla remain unclear. To identify the factors that may influence branching, the transcriptome and metabolome were performed on the shoot apex (SA), lateral shoot apex (LSA), and stem segment at the 5th axillary bud from the shoot apex (S1) in lines ZQUC14 (A) and LDUD26 (B), with A exhibiting a smaller Ba than B. A total of 307.3 million high-quality clean reads and nine hormones were identified from six libraries. Several differentially expressed regulatory factors were identified between the two genotypes of E. urophylla. The Kyoto Encyclopedia of Genes and Genomes pathways were enriched in plant hormone signal transduction, plant hormone biosynthesis and their transport pathways. Furthermore, gene expression pattern analysis identified genes that were significantly downregulated or upregulated in S1 relative to the SA and LSA segments, and the plant hormone signal transduction pathway was constructed to explain branching development. This study clarified the main plant hormones and genes underlying branch numbers and angles of E. urophylla, confirmed that ABA and SA could promote a larger branch angle and smaller branch number, while IAA has an opposite function. Numbers of key candidate genes involved in plant hormone signal transduction were found in the positive regulation of branch formation. These novel findings should aid molecular breeding of branching in Eucalyptus.

Monoterpenoid alkaloids are well known for their broad and excellent biological activities, but their extremely low content and complex chemical structure limit their practical application. This study used the biosynthetic precursor genipin as a basic material to conduct a biomimetic synthesis of iridoid alkaloids. The structures of the iridoid alkaloids were characterized by 1H and 13C NMR spectroscopy and high-resolution mass spectrometry, and their fungicidal and insecticidal activities were evaluated. Bioassay results indicated that iridoid alkaloids possess good to excellent activities against phytopathogenic fungi, diamondback moth, bean aphid, and spider mite. Compound 3s had the most promising activity against three important phytopathogenic fungi Fusarium graminearum (LC50 value of 34.5 μg/mL with a 95% confidence interval of 33.4-35.5 μg/mL), Rhizoctonia solani (18 μg/mL, 15.7-20.8 μg/mL), and Botrytis cinerea (26 μg/mL, 22.4-30.4 μg/mL), thereby emerging as a potential new fungicidal lead. The structure-activity relationship research has shown that the electrical property and steric hindrance sizes of iridoid alkaloids apparently influence fungicidal activity. Moreover, compound 3n exhibited good insecticidal activity against diamondback moth with an LC50 (35.6 μg/mL, 95% confidence interval 19.0-66.6 μg/mL) comparable to that of the commercial insecticide rotenone (35.4 μg/mL, 95% confidence interval 22.2-56.4 μg/mL). This outcome indicates that this compound deserves further study as a potential lead for development of new insecticides.

We propose a photonic crystal fiber (PCF) sensor based on graphene oxide (GO) composite film modification to simultaneously measure the multi-parameter sensing characteristics of humidity, temperature, and glucose concentration. The GO-polyvinyl alcohol (PVA) composite film is used to measure the humidity-sensing characteristics of the sensor, and the glucose oxidase composite film is used to measure the sensing characteristics of the glucose concentration, respectively. Experiment results show that the sensitivities of the temperature of the GO-PVA coating structure are 0.037 nm/°C, 0.047 nm/°C, and 0.031 nm/°C; the sensitivities of humidity are 0.059 nm/%RH, 0.121 nm/%RH, and 0.047 nm/%RH; and the sensitivities of the glucose concentration of the GO-GOD coating structure are 0.028 nm/(g/L), 0.049 nm/(g/L), and 0.010 nm/(g/L) for three interference dips, respectively. The structure is simple to manufacture and can be used as a sensor for detecting multiple parameters. It can be widely used in biomedicine, environmental monitoring, and other fields.

We assembled an ancestrally diverse collection of genome-wide association studies of type 2 diabetes (T2D) in 180,834 cases and 1,159,055 controls (48.9% non-European descent). We identified 277 loci at genome-wide significance (p-8), including 237 attaining a more stringent trans-ancestry threshold (p-9), which were delineated to 338 distinct association signals. Trans-ancestry meta-regression offered substantial enhancements to fine-mapping, with 58.6% of associations more precisely localised due to population diversity, and 54.4% of signals resolved to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying foundations for functional investigations. Trans-ancestry genetic risk scores enhanced transferability across diverse populations, providing a step towards more effective clinical translation to improve global health.

Background The discovery of robust and trans-ethnically replicated DNA methylation markers of metabolic phenotypes, has hinted at a potential role of epigenetic mechanisms in lipid metabolism. However, DNA methylation and the lipid compositions and lipid concentrations of lipoprotein sizes have been scarcely studied. Here, we present an epigenome-wide association study (EWAS) (N = 5414 total) of mostly lipid-related metabolic measures, including a fine profiling of lipoproteins. As lipoproteins are the main players in the different stages of lipid metabolism, examination of epigenetic markers of detailed lipoprotein features might improve the diagnosis, prognosis, and treatment of metabolic disturbances. Results We conducted an EWAS of leukocyte DNA methylation and 226 metabolic measurements determined by nuclear magnetic resonance spectroscopy in the population-based KORA F4 study (N = 1662) and replicated the results in the LOLIPOP, NFBC1966, and YFS cohorts (N = 3752). Follow-up analyses in the discovery cohort included investigations into gene transcripts, metabolic-measure ratios for pathway analysis, and disease endpoints. We identified 161 associations (p value −10), covering 16 CpG sites at 11 loci and 57 metabolic measures. Identified metabolic measures were primarily medium and small lipoproteins, and fatty acids. For apolipoprotein B-containing lipoproteins, the associations mainly involved triglyceride composition and concentrations of cholesterol esters, triglycerides, free cholesterol, and phospholipids. All associations for HDL lipoproteins involved triglyceride measures only. Associated metabolic measure ratios, proxies of enzymatic activity, highlight amino acid, glucose, and lipid pathways as being potentially epigenetically implicated. Five CpG sites in four genes were associated with differential expression of transcripts in blood or adipose tissue. CpG sites in ABCG1 and PHGDH showed associations with metabolic measures, gene transcription, and metabolic measure ratios and were additionally linked to obesity or previous myocardial infarction, extending previously reported observations. Conclusion Our study provides evidence of a link between DNA methylation and the lipid compositions and lipid concentrations of different lipoprotein size subclasses, thus offering in-depth insights into well-known associations of DNA methylation with total serum lipids. The results support detailed profiling of lipid metabolism to improve the molecular understanding of dyslipidemia and related disease mechanisms.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most common antibody-mediated encephalitis. There are several studies on B cell repertoire of anti-NMDAR encephalitis in Caucasians. Here, the cerebrospinal fluid (CSF) samples of 12 Chinese patients with first-episode anti-NMDAR encephalitis were collected to investigate the B cell receptor (BCR) binding to NMDAR by single cell amplification of BCR and Sanger sequencing. BCR data of healthy persons, and of patients with anti-leucine-rich glioma inactivated 1 (anti-LGI1) encephalitis, multiple sclerosis (MS), and neuromyelitis optica spectrum disorder (NMOSD) from the public databases were used as control. A heavy chain common clone IGHV1-18*04,IGHD1-26*01/ IGHD2-2*03/IGHD2-8*01, IGHJ3*02_(CDR3) ARVGSKYGFETFDI was found in 11 of 12 enrolled patients but not in the comparison data set. In addition, 4 shared clonotypes were found among these patients, and three of them contained the common clone. This study also revealed that the antibody gene family usage preference between patients and healthy controls were different, while they had similar antibody mutation rate. Our findings may have potential clinical implications for the diagnosis of anti-NMDAR encephalitis.

The aberrant micro-RNA (miR) expression has been reported to play a vital role in proliferation and tumorigenesis and of several human cancers. MicroRNA-365 (miR-365) has been shown to exhibit tumor-suppressive or oncogenic role in several human cancers. Nonetheless, little is known about its growth regulatory role in human multiple myeloma. The present study characterized the regulatory control exercised by miR-365 in multiple myeloma. The results showed significant (P

Lung cancer continues to be the leading cause of cancer-related deaths worldwide due to its high incidence, malignant behaviour and lack of major advancements in treatment strategy. The occurrence and development of lung cancer is closely related to inflammation. Thus, we conducted the present study to investigate the effects of IL-38 (interleukin-38), a newly identified anti-inflammatory factor, on non-small cell lung cancer (NSCLC), which accounts for about 85% of all lung cancers. We first evaluated the IL-38 expression in 384 pairs of NSCLC samples and their adjacent normal mucosa by real-time PCR, ELISA (enzyme-linked immunoassay) and tissue microarrays. Then the role of IL-38 on patient survival rates, cancer progression and their sensitivity to chemotherapy drugs was assessed. IL-38 was barely expressed in the NSCLC tissues but highly expressed in the adjacent normal tissues. The downregulation of IL-38 was significantly correlated with the results of the American Joint Committee on Cancer stage and degree of differentiation, and it was also shown to be an independent prognostic indicator of disease-free survival and overall survival for patients with NSCLC. Overexpression of IL-38 in NSCLC cells suppressed cell migration, invasion, proliferation and colony formation through suppressing β-catenin. IL-38 inhibited NSCLC formation in a mice model and sensitized the cancer cells to chemotherapy drugs. Our results show that IL-38 plays an inhibitory role in NSCLC development and functions as a novel prognostic indicator and a potential therapeutic target.

Background: The role of macro and micro nutrients have been reported in various plant. However, in perennial trees, the function of multiple elements to different genotypes remain to be elucidated. This study aimed at deciphering the genetic architecture of physiological differences under different nutrient levels between the high- and low-growth genotypes. Results: Our results showed that growth traits of both genotypes at nutrient starvation treatment was much lower than that at nutrient abundant treatment, indicating that nutrient is essential for plant growth. However, tree height, crown width, and fresh weight of different tissues of ZQUA44 were much higher than that of ZQUB15 at the three nutrient levels, implicating the genetic basis of different trees is another factor that varied the phenotypic performance. The differentially expressed genes (DEGs) were clustered into 6 subclusters depending on different expression pattern. Functional annotation of DEGs from different subclusters showed that DEGs involved in glutathione metabolism, flavonoid biosynthesis and stilbenoid, diarylheptanoid and gingerol biosynthesis may responsible for nutrient starvation across different genotypes, while DEGs involved in carotenoid biosynthesis and starch and sucrose metabolism may have diverse function in different genotypes. The DEGs encoding MYB_related may responsible for nutrient deficiency of all the genotypes, while B3 may play different functions in different genotypes. Conclusion: Our results demonstrate that different genotypes may form different metabolic pathways to coordinate plant keeping survival when they face abiotic stresses. Furthermore, we elucidate DEGs that may widely responsible for nutrient deficiency in different treatments and DEGs that play different functions in different genotypes. Finally, our funding provide adequate nutrient supply for Eucalyptus.

Eucalyptus urophylla is a commercially important wood crop plantation species due to its rapid growth, biomass yield, and use as bioenergy feedstock. We characterized the genetic diversity and population structure of 332 E. urophylla individuals from 19 geographically defined E. urophylla populations with a reliability of 14,468 single-nucleotide polymorphisms (SNPs). We compared the patterns of genetic variation among these 19 populations. High levels of genetic diversity were observed throughout the 19 E. urophylla populations based on genome-wide SNP data (HE = 0.2677 to 0.3487). Analysis with STRUCTURE software, principal component analysis (PCA), and a neighbor-joining (NJ) tree indicated that E. urophylla populations could be divided into three groups, and weak population structure was observed with pairwise genetic differentiation (FST) values ranging from − 0.09 to 0.074. The low genetic diversity and shallow genetic differentiation found within the 19 populations may be a consequence of their pollination system and seed dispersal mechanism. In addition, 55 core germplasms of E. urophylla were constructed according to the genetic marker data. The genome-wide SNPs we identified will provide a valuable resource for further genetic improvement and effective use of the germplasm resources.

Muscle atrophy occurs in many pathological states, including cancer, diabetes and sepsis, whose results primarily from accelerated protein degradation and activation of the ubiquitin‐proteasome pathway. Expression of Muscle RING finger 1 (MuRF1), an E3 ubiquitin ligase, was increased to induce the loss of muscle mass in diabetic condition. However, hydrogen sulphide (H2S) plays a crucial role in the variety of physiological functions, including antihypertension, antiproliferation and antioxidant. In this study, db/db mice and C2C12 myoblasts treated by high glucose and palmitate and oleate were chose as animal and cellular models. We explored how exogenous H2S attenuated the degradation of skeletal muscle via the modification of MuRF1 S‐sulfhydration in db/db mice. Our results show cystathionine‐r‐lyase expression, and H2S level in skeletal muscle of db/db mice was reduced. Simultaneously, exogenous H2S could alleviate ROS production and reverse expression of ER stress protein markers. Exogenous H2S could decrease the ubiquitination level of MYOM1 and MYH4 in db/db mice. In addition, exogenous H2S reduced the interaction between MuRF1 with MYOM1 and MYH4 via MuRF1 S‐sulfhydration. Based on these results, we establish that H2S prevented the degradation of skeletal muscle via MuRF1 S‐sulfhydration at the site of Cys44 in db/db mice.

Neural stem cells (NSCs) can generate new neurons to repair brain injury and central nervous system disease by promoting neural regeneration. MicroRNAs (miRNAs) involve in neural development, brain damage, and neurological diseases repair. Recent reports show that several miRNAs express in NSCs and are important to neurogenesis. Neurites play a key role in NSC-related neurogenesis. However, the mechanism of NSC neurite generation is rarely studied. We surprisingly noticed that the neurites increased after bone morphogenetic protein (BMP) treatment in rat NSCs. This process was accompanied by the dynamic change of miRNA-29. Then we discovered that miR-29a regulated neural neurites in rat hippocampus NSCs. Overexpression of miR-29a reduced the cell soma area and promoted the neurite outgrowth of NSCs. Cell soma area became small, whereas the number of neurite increased. Moreover, neurite complexity increased dramatically, with more primary and secondary branches after miR-29a overexpression. In addition, miR-29a overexpression still maintained the stemness of NSCs. Besides, we identified that miR-29a can promote the neurite outgrowth by targeting extracellular matrix-related genes like Fibrillin 1 (Fbn1), Follistatin-like 1 (Fstl1), and laminin subunit gamma 2 (Lamc2). These findings may provide a novel role of miR-29a to regulate neurite outgrowth and development of NSCs. We also offered a possible theoretical basis to the migration mechanism of NSCs in brain development and damage repair.

A series of coumarin-3-carboxamides/hydrazides have been designed and synthesized, all the target compounds were evaluated in vitro for their antifungal activity against Botrytis cinerea, Alternaria solani, Gibberella zeae, Rhizoctorzia solani, Cucumber anthrax and Alternaria leaf spot, some of the designed compounds 4a-4g exhibited potential activity in the primary assays, this highlighted by the compounds 4a, 4d, 4e and 4f, EC50 values of which against Rhizoctorzia solani were as low as 1.80 μg/mL, 2.50 μg/mL, 2.25 μg/mL and 2.10 μg/mL, respectively, exhibiting more effective control with that of the positive control than Boscalid. Furthermore, compounds 4a and 4e represented equivalent antifungal activity with Boscalid against Botrytis cinerea.

Streptochlorin, a small indole alkaloid isolated from marine Streptomyces sp., exhibits a wide range of potent biological activities. An efficient and economic synthetic protocol for streptochlorin has been developed and validated, 4 steps from indole in a total yield of 45%, and further applied for the synthesis of its analogues. Biological testing showed that most of the target compounds exhibited potential antifungal activity in the primary assays, especially compounds 6, 7 and 9c were the most active ones, representing effective activity against the phytopathogenic fungi screened in preliminary test and might be explored for the study of mode of action in the future.

Hydrogen sulfide (H2S) is involved in diverse physiological functions, such as anti-hypertension, anti-proliferation, regulating ATP synthesis, and reactive oxygen species production. Sirtuin 3 (SIRT3) is a NAD + -dependent deacetylase that regulates mitochondrial energy metabolism. The role of H2S in energy metabolism in diabetic cardiomyopathy (DCM) may be related to regulate SIRT3 expression; however, this role remains to be elucidated. We hypothesized that exogenous H2S could switch cardiac energy metabolic substrate preference by lysine acetylation through promoting the expression of SIRT3 in cardiac tissue of db/db mice. Db/db mice, neonatal rat cardiomyocytes, and H9c2 cell line with the treatment of high glucose, oleate, and palmitate were used as animal and cellular models of type 2 diabetes. Using LC-MS/MS, we identified 76 proteins that increased acetylation, including 8 enzymes related to fatty acid β-oxidation and 7 enzymes of the tricarboxylic acid (TCA) cycle in the db/db mice hearts compared to those with the treatment of NaHS. Exogenous H2S restored the expression of NAMPT and the ratio of NAD+/NADH enhanced the expression and activity of SIRT3. As a result of activation of SIRT3, the acetylation level and activity of fatty acid β-oxidation enzyme LCAD and the acetylation of glucose oxidation enzymes PDH, IDH2, and CS were reduced which resulted in activation of PDH, IDH2, and CS. Our finding suggested that H2S induced a switch in cardiac energy substrate utilization from fatty acid β-oxidation to glucose oxidation in DCM through regulating SIRT3 pathway.

Introduction: Cardiac amyloidosis is one of the several systemic manifestations of amyloidosis. It is a relatively uncommon disease. Patients with cardiac amyloidosis clinically present with rapidly progressive heart failure. Case Presentation: We present a case of 64-year-old man with multiple episodes of chest discomfort accompanied sometimes with dyspnoea for the past several months. A non-specific ST-T changes with low voltage limb leads on ECG, a diastolic dysfunction with preserved ejection fraction on echocardiography, increased troponin and BNP, increased serum λ/κ light chain ratio led us to highly suspect amyloidosis with cardiac involvement. Abdominal fat pad biopsy confirmed the amyloid type change of subcutaneous fat, with immunohistochemistry revealing Lambda positive. After confirmed diagnosis of primary systemic amyloidosis with cardiac involvement, patient completed six cycles of chemotherapy with bortezomib and dexamethasone. The patient showed significant improvements after chemotherapy and supportive therapy. Conclusion: Amyloidosis is relatively fatal disease. Patients often have a short life expectancy after symptom onset. Early diagnosis is crucial to proper management and better prognosis.

A biosensor modified by graphene oxide (GO)–glucose oxidase (GOD) for glucose detection is proposed and demonstrated. Gluconic acid and H2O2 are produced by the reaction between GOD and glucose, and due to the large change of the refractive index (RI) around the sensor, the drift of the interference valleys appears in the transmission spectrum clearly. With this method, a symmetric lateral-offset sensor based on photonic crystal fiber (PCF) is fabricated. Response characteristics of glucose concentration are tested in the range of 10 g/L to 70 g/L. Experimental results show that the sensitivity to glucose concentration can be represented by a quadratic curve, and it has good sensitivity as well as linearity. The temperature sensitivities in the range of 5 °C–30 °C are 0.061 nm/°C and 0.159 nm/°C, which can realize dual-parameter measurement. The biosensor has broad application prospects in the fields of environmental detection and drug research.

// Lijie Sun 1,2,* , Yan Li 1,2,* , Xiuzhi Jia 1,2,* , Qi Wang 1,2 , Yue Li 3 , Minghui Hu 4 , Linlu Tian 1,2 , Jinfeng Yang 1,2 , Wenjing Xing 1,2 , Weihua Zhang 5 , Jingtao Wang 6 , Hongwei Xu 1,2 , Lihua Wang 7 , Dekai Zhang 3 and Huan Ren 1,2 1 Department of Immunology, Harbin Medical University, Harbin, China 2 Key Laboratory of Infection & Immunity, Heilongjiang Province, Harbin, China 3 Center for Infectious and Inflammatory Disease, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, TX, USA 4 Department of Clinical Laboratory, The Affiliated Hospital to Qingdao University, Qingdao, China 5 Department of Pathophysiology, Harbin Medical University, Harbin, China 6 Department of Epidemiology and Biostatistics, The Public Health Institute, Harbin Medical University, Harbin, China 7 Department of Neuroscience, The Second Hospital Affiliated to Harbin Medical University, Harbin, China Correspondence to: Huan Ren, email: // Dekai Zhang, email: // Lihua Wang, email: // Keywords : interferon-gamma, astrocyte, interleukin-6, apoptosis, neuroinflammation, Immunology and Microbiology Section, Immune response, Immunity Received : November 21, 2016 Accepted : March 22, 2017 Published : April 09, 2017 Abstract Inflammation eliminates pathogenic infections while also threatening the integrity of the central nervous system. In this study, using in vivo and in vitro models of acute neuroinflammation, we investigated the mechanisms by which inflammation and astrocytes affect neuronal apoptosis. The in vitro model mimicked acute neuroinflammation by incubation in IFN-γ-containing media with primary cultured cerebellar granule neurons, with or without cultured astrocytes. This quickly induced neuronal apoptosis characterized by cleaved caspase-3 expression, Hoechst 33342 staining, and intercellular Ca 2+ influx, whereas the presence of astrocytes significantly protected neurons from these effects. IFN-γ in the inflammation media also promoted astrocyte secretion of IL-6, essential for protection. The supernatants of rat peripheral blood mononuclear cells stimulated by lymphocyte mitogen lipopolysaccharide or concanavalin A were used as inflammation media to verify the results. The in vivo model involved a peripheral challenge with lipopolysaccharide, with or without recombinant IFN-γ, in C57BL/6 mice. This confirmed the in vitro results: anti-IFN-γ antibodies exacerbated the acute course of neuroinflammation and led to neurocyte apoptosis in vivo . The pro-inflammatory cytokine IFN-γ provided neuroprotection during acute neuroinflammation via induction of astrocyte-secreted IL-6. The findings provide novel insights into the mechanisms of neuroprotection by IFN-γ during acute neuroinflammation, and may impact therapies for inflammation-related central nervous system injury and disease.

// Jiayin An 1, * , Xiangdong Pei 1, * , Zhenle Zang 1 , Zheng Zhou 1 , Jintao Hu 1 , Xin Zheng 1 , Yin Zhang 1 , Jiaojiang He 2 , Lian Duan 3 , Rufei Shen 3 , Weihua Zhang 4 , Feng Zhu 5 , Song Li 1 and Hui Yang 1 1 Multidisciplinary Center for Pituitary Adenomas of Chongqing, Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China 2 Department of Neurosurgery, Lanzhou General Hospital of Chinese People’s Liberation Army, Lanzhou, China 3 Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing, China 4 Department of Biology and Biochemistry, College of Natural Sciences and Mathematics, University of Houston, Houston, Texas, USA 5 Innovative Drug Research Centre, University of Chongqing, Chongqing, China * These authors have contributed equally to this work Correspondence to: Hui Yang, email: huiyangxinqiao@163.com Song Li, email: dlisong3@163.com Keywords: metformin, growth hormone-secreting pituitary adenoma, proliferation, ATF3, STAT3 Received: June 11, 2016 Accepted: February 06, 2017 Published: March 25, 2017 ABSTRACT Metformin is an anti-hyperglycemic agent used to treat diabetes, and recent evidence suggests it has antitumor efficacy. Because growth hormone-secreting pituitary adenoma (GH-PA) patients have a high incidence of diabetes frequently treated with metformin, we assessed the antitumor effect of metformin on GH-PA. We found that metformin effectively inhibited proliferation and induced apoptosis in the GH-PA cell line GH3. We detected a decrease in mitochondrial membrane potential (MMP), an increase in expression of pro-apoptotic proteins, and a decrease in expression of an anti-apoptotic protein in metformin-treated GH3 cells, which suggests involvement of the mitochondrial-mediated apoptosis pathway. Inhibition of AMPK, which is activated by metformin, failed to reverse the antiproliferative effect. ATF3 was upregulated by metformin, and its knockdown significantly reduced metformin-induced apoptosis. In addition, GH secretion was inhibited by metformin through suppression of STAT3 activity independently of AMPK. Metformin also significantly suppressed cellular proliferation and GH secretion in primary human GH-PA cells. Metformin also significantly inhibited GH3 cell proliferation and GH secretion in vivo . ATF3 upregulation and p-STAT3 downregulation were confirmed in xenografts. These findings suggest metformin is a potentially promising therapeutic agent for the treatment of GH-PA, particularly in patients with diabetes.

The upregulation of reactive oxygen species (ROS) is a primary cause of cardiomyocyte apoptosis in diabetes cardiomyopathy (DCM). Mitofusin-2 (Mfn-2) is a key protein that bridges the mitochondria and endoplasmic reticulum (ER). Hydrogen sulfide (H2S)-mediated cardioprotection is related to antioxidant effects. The present study demonstrated that H2S inhibited the interaction between the ER and mitochondrial apoptotic pathway. This study investigated cardiac function, ultrastructural changes in the ER and mitochondria, apoptotic rate using TUNEL, and the expression of ER stress-associated proteins and mitochondrial apoptotic proteins in cardiac tissues in STZ-induced type I diabetic rats treated with or without NaHS (donor of H2S). Mitochondria of cardiac tissues were isolated, and MPTP opening and cytochrome c (cyt C) and Mfn-2 expression were also detected. Our data showed that hyperglycemia decreased the cardiac function by ultrasound cardiogram, and the administration of exogenous H2S ameliorated these changes. We demonstrated that the expression of ER stress sensors and apoptotic rates were elevated in cardiac tissue of DCM and cultured H9C2 cells, but the expression of these proteins was reduced following exogenous H2S treatment. The expression of mitochondrial apoptotic proteins, cyt C, and mPTP opening was decreased following treatment with exogenous H2S. In our experiment, the expression and immunofluorescence of Mfn-2 were both decreased after transfection with Mfn-2-siRNA. Hyperglycemia stimulated ER interactions and mitochondrial apoptotic pathways, which were inhibited by exogenous H2S treatment through the regulation of Mfn-2 expression.

Patterns of habitat use profoundly influence interactions among wildlife species and ecological communities, the sustainability of species and the stability of populations. The Eurasian lynx Lynx lynx, sable Martes zibellina, moose Alces alces, roe deer Capreolus pygargus and mountain hare Lepus timidus are sympatric carnivore and herbivore species in Hanma Nature Reserve in the Greater Khingan Mountains, northeastern China. We conducted snow track sample plot surveys of these mammals during the winter of 2012–2013 and analyzed habitat selection characteristics and interspecific interactions. We screened the preferred habitat variables of each species and predicted their potential occurrence probability by generalized linear mixed model (GLMM) and further, selected the best model of each species that incorporated other species' potential occurrence probability in GLMM. Our results showed that when we only considered habitat factors in the model: 1) river valley was the most favored habitat factor in winte...

SUMOylation in plants is associated with biotic and abiotic stress responses, flowering and other aspects of development, and ICE1 protein SUMOylation by SUMO E3 ligase SIZ1 plays important roles in plant cold tolerance. Here, we reported the subcellular localization of EcaICE1 and its interaction with EcaSIZ1 in Eucalyptus camaldulensis. The genes EcaICE1 and EcaSIZ1 were isolated by homologous cloning. The subcellular localization analysis showed that EcaICE1 was located in nucleus. Bimolecular fluorescence complementation (BiFC) analysis revealed that EcaICE1 could interact with EcaSIZ1 in the nucleus of Nicotiana benthamiana leaves. Moreover, yeast two-hybrid assay confirmed that the amino acid region from position 84 to 126 in EcaICE1 was critical for the strong transactivation activity of EcaICE1 and that the C terminal region from position 361 to 557 in EcaICE1 was the key region for its interaction with EcaSIZ1 by using different truncated lengths of non-transactivation activity of EcaICE1 as the bait protein. Collectively, our results showed that EcaICE1 may have a SUMOylation pathway similar to Arabidopsis thaliana.

To understand the recovery of the biological functions of washed soil, we studied changes in the microbial communities of soils washed with 10 or 60 mmol kg−1 ethylenediaminetetraacetic acid (EDTA) for 90 d of incubation. The relative abundance of tolerant or degrading species decreased, while that of microorganisms with chemical autotrophic ability increased as the incubation time increased. The changes in the enzyme activity followed different trends. As an intracellular enzyme, dehydrogenase was initially most severely damaged by the washing process but could recover over time, while the activity of urease increased after washing with EDTA, which may be related to the use of N as a nutrient source by microorganisms. Phosphatase did not significantly change over time. The redundancy discriminant analyses indicated that there were distinct factors driving such changes in the soils washed with different EDTA dosages. For the soil washed with 10 mmol kg−1 EDTA, bacteria with tolerance or degradation capacity of toxic pollutants, such as Nocardioidaceae, played a more important role in the recovery of soil functions; therefore, the EDTA stress indicator was the main driving factor. However, in the soil washed with 60 mmol kg−1 EDTA, chemolithoautotrophic bacteria, such as Nitrososphaeraceae, exerted a greater influence on the recovery of biological functions due to the higher loss of nutrients and EDTA residue; therefore, the main driving factor was the nutrients supply.

Publisher's version (útgefin grein)., In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding., This paper is the work of the ROHgen consortium. We thank the Sigma T2D Consortium, whose members are detailed in Supplementary Note 3. We thank the UK Biobank Resource, approved under application 19655; we acknowledge funding from the UK Medical Research Council Human Genetics Unit and MRC Doctoral Training Programme in Precision Medicine. We also thank Neil Robertson, Wellcome Trust Centre for Human Genetics, Oxford, for use of his author details management software, Authorial. Finally, we thank all the participants, researchers and funders of ROHgen cohorts. Cohort-specific acknowledgements are in Supplementary Data 2; personal acknowledgements and disclosures are in Supplementary Note 2. We thank Rachel Edwards for administrative assistance.

Considering the high Zn content of municipal sewage sludge and its competition with Cd during plant uptake due to their similar properties, the presence of Zn in sludge-derived biochar (SDBC) may affect Cd immobilization and uptake by plants. To confirm this, SDBC samples with different Zn contents were prepared and characterized. Their Cd immobilization behavior was studied by conducting batch sorption experiments, and their effects on Cd uptake by lettuce were explored by conducting hydroponic experiments. The results reveal that some Zn contained in the sewage sludge was transformed into ZnO during pyrolysis. The Brunauer-Emmett-Teller (BET) surface area of the SDBC samples containing 2324 mg kg−1 Zn (BC-2324) was 18.3 m2 g−1, which was 132% larger than that of the samples containing 1438 mg kg−1 Zn (BC-1438). The SDBC samples containing 1901 mg kg−1 (BC-1901) exhibited the highest Langmuir sorption capacity of 3476 mg kg−1, which is 115% higher than that of SB-1438. Furthermore, the lettuce remedied with SB-1901 exhibited 44% more biomass; lower peroxidase, catalase, and malondialdehyde activity; and 18.4% less Cd in the leaves of the lettuce than the lettuce remedied with BC-1438, suggesting the potential benefits of using Zn-rich SDBC for soil amendment.