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Hirschsprung disease (HSCR), one of several neurocristopathies in children, is characterized by nerve loss in the large intestine and is mainly treated by surgery, which causes severe complications. Enteric neural crest‐derived cell (ENCC) transplantation is a potential therapeutic strategy; however, so far with poor efficacy. Here, we assessed whether and how fecal microbiota transplantation (FMT) could improve ENCC transplantation in a rat model of hypoganglionosis; a condition similar to HSCR, with less intestinal innervation. We found that the hypoganglionosis intestinal microenvironment negatively influenced the ENCC functional phenotype in vitro and in vivo. Combining 16S rDNA sequencing and targeted mass spectrometry revealed microbial dysbiosis and reduced short‐chain fatty acid (SCFA) production in the hypoganglionic gut. FMT increased the abundance of Bacteroides and Clostridium, SCFA production, and improved outcomes following ENCC transplantation. SCFAs alone stimulated ENCC proliferation, migration, and supported ENCC transplantation. Transcriptome‐wide mRNA sequencing identified MAPK signaling as the top differentially regulated pathway in response to SCFA exposure, and inhibition of MEK1/2 signaling abrogated the SCFA‐mediated effects on ENCC. This study demonstrates that FMT improves cell therapy for hypoganglionosis via short‐chain fatty acid metabolism‐induced MEK1/2 signaling. Synopsis: Fecal microbiota transplantation synergy with enteric neural crest‐derived cell transplantation is tested in a rat model of hypoganglianosis to provide a non‐surgical treatment option of neurocristopathies including Hirschsprung disease. The intestinal microenvironment in a rat model of hypoganglionosis negatively influences enteric neural crest‐derived cell (ENCC) proliferation and migrationFecal microbiota transplantation (FMT) relieves hypoganglionosis symptoms and promotes ENCC transplantation in vitro and vivo.Some genera, particularly Bacteroides and Clostridium, increased after FMT, which coincided with short‐chain fatty acid (SCFA) production.SCFA exposure stimulated ENCC proliferation, migration, and supported ENCC transplantation in the treatment of hypoganglionosis via the MEK1/2 signaling pathway. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?Long non‐coding RNAs (lncRNAs) are widely involved in the progression of Hirschsprung's disease (HSCR), but the role of actin filament associated protein 1 antisense RNA1 (AFAP1‐AS1), an lncRNA, in HSCR has not been explored before.What is the main finding and its importance?Downregulation of AFAP1‐AS1 blocks enteric neural crest stem cell proliferation, differentiation, migration and invasion and promotes the occurrence of HSCR via the miR‐195/E2F3 axis, indicating thatAFAP1‐AS might be a potential biomarker for HSCR patients. Long non‐coding RNAs (lncRNAs) are involved in several human disorders. Nevertheless, it remains unclear whether they are implicated in the phenotypes of enteric neural crest stem cells (ENCSCs) in Hirschsprung's disease (HSCR). Therefore, we designed this study to explore the pathogenicity of AFAP1‐AS1 for HSCR. Microarray analysis and bioinformatic tools were used to screen out the differentially lncRNAs and microRNAs (miRNAs) in patients with HSCR. Small interference RNA transfection was applied to carry out functional experiments in ENCSCs. Cellular activities were detected by cell counting kit‐8, 5‐ethynyl‐2′‐deoxyuridine, Transwell assays and flow cytometry. Finally, rescue experiments were performed to examine the cofunction of AFAP1‐AS1 and miR‐195 and of miR‐195 and E2F transcription factor 3 (E2F3). AFAP1‐AS1 was reduced in HSCR patients. Meanwhile, knockdown of AFAP1‐AS1 reduced the cell migratory and proliferative capacities and facilitated cell apoptosis along with G0/G1 phase arrest. E2F3 was diminished when miR‐195 was upregulated, and AFAP1‐AS1 inhibition reduced its ability to bind to miR‐195. Altogether, AFAP1‐AS1 silencing acts as an endogenous RNA by interacting with miR‐195 to alter E2F3 expression, thus conferring repressive effects on ENCSC activity and promoting HSCR progression. [ABSTRACT FROM AUTHOR]

Demyelination is a common pathological feature of a large number of neurodegenerative diseases including multiple sclerosis and Huntington's disease (HD). Laquinimod (LAQ) has been found to have therapeutic effects on multiple sclerosis and HD. However, the mechanism underlying LAQ's therapeutic effects remains unknown. Using HD mice that selectively express mutant huntingtin in oligodendrocytes and show demyelination, we found that LAQ reduces the Ser259 phosphorylation on myelin regulatory factor (MYRF), an oligodendrocyte‐specific transcription factor promoting the expression of myelin‐associated genes. The reduced MYRF phosphorylation inhibits MYRF's binding to mutant huntingtin and increases the expression of myelin‐associated genes. We also found that PRKG2, a cGMP‐activated protein kinase subunit II, promotes the Ser259‐MYRF phosphorylation and that knocking down PRKG2 increased myelin‐associated protein's expression in HD mice. Our findings suggest that PRKG2‐regulated phosphorylation of MYRF is involved in demyelination and can serve as a potential therapeutic target for reducing demyelination. Synopsis: Laquinimod reduces Ser259 phosphorylation of myelin regulatory factor and its binding to mutant huntingtin, alleviating expression of myelin‐associated genes and demyelination caused by mutant huntingtin in oligodendrocytes. Laquinimod alleviates the phenotypes and pathology of HD mice expressing mutant HTT in oligodendrocytes.Laquinimod inhibits the interaction of mutant HTT with MYRF by reducing the phosphorylation of MYRF and restores the expression of myelin genes.Reducing the phosphorylation of MYRF by knocking down PRKG2 increases the expression of myelin genes in HD mice. [ABSTRACT FROM AUTHOR]

So far, the mechanism that links mitochondrial dysfunction to PDX1 inhibition in the pathogenesis of pancreatic β cell dysfunction under diabetic condition remains largely unclear. This study determined the role of mitochondrial protein FAM3A in regulating PDX1 expression in pancreatic β cells using gain‐ and loss‐of function methods in vitro and in vivo. Within pancreas, FAM3A is highly expressed in β, α, δ, and pp cells of islets. Islet FAM3A expression was correlated with insulin expression under physiological and diabetic conditions. Mice with specific knockout of FAM3A in islet β cells exhibited markedly blunted insulin secretion and glucose intolerance. FAM3A‐deficient islets showed significant decrease in PDX1 expression, and insulin expression and secretion. FAM3A overexpression upregulated PDX1 and insulin expressions, and augmented insulin secretion in cultured islets and β cells. Mechanistically, FAM3A enhanced ATP production to elevate cellular Ca2+ level and promote insulin secretion. Furthermore, FAM3A‐induced ATP release activated CaM to function as a co‐activator of FOXA2, stimulating PDX1 gene transcription. In conclusion, FAM3A plays crucial roles in controlling PDX1 and insulin expressions in pancreatic β cells. Inhibition of FAM3A will trigger mitochondrial dysfunction to repress PDX1 and insulin expressions. [ABSTRACT FROM AUTHOR]

Importance: Pathogenic variants in the RBM20 gene are associated with aggressive dilated cardiomyopathy (DCM). Recently, RBM20 was found to be associated with left ventricular non‐compaction cardiomyopathy (LVNC). Thus far, only five families with LVNC have been reported to carry variants in RBM20. It remains unknown whether the variants in RBM20 associated with DCM can also cause LVNC. Objective: To elucidate the causative RBM20 variant in two unrelated patients with both LVNC and DCM, and to identify the clinical characteristics associated with variants in RBM20. Methods: Trio whole‐exome sequencing (WES) was performed. Variants were filtered and classified in accordance with the guidelines of the American College of Medical Genetics and Genomics (ACMG). Results: We identified two distinct de novo variants in RBM20 (one per patient) in these two patients with LVNC. Both variants have been reported in patients with DCM, without the LVNC phenotype. Patient 1 was an 11‐year‐old girl who had DCM, LVNC, and heart failure; the ratio of noncompacted‐to‐compacted myocardium was 2.7:1. A de novo heterozygous variant c.1907G>A (p.Arg636His) in exon 9 was identified in this patient. Patient 2 was a 13‐year‐old boy who had clinical phenotypes identical to those of Patient 1; the ratio of noncompacted‐to‐compacted myocardium was 3.2:1 in this patient. WES revealed a de novo heterozygous variant c.1909A>G (p.Ser637Gly) in exon 9. Both variants were previously characterized as pathogenic, and our study classified them as pathogenic variants based on the ACMG guidelines. Interpretation: We found that two patients with LVNC had variants in RBM20. Our results extended the clinical spectrum of the two RBM20 variants and illustrated that the same variant in RBM20 can cause DCM, with or without the LVNC phenotype. [ABSTRACT FROM AUTHOR]

Physiological and pathophysiological differences exist between the left and right kidneys; however, the molecular bases for these differences remain unknown. Since miRNAs are involved in kidney function and the development of kidney diseases, we examined their differential expression through miRNA profiling of the left and right kidneys of normal mice. We find that 36 miRNAs exhibit higher expression, whereas 22 miRNAs show lower expression in the left than the right kidneys in mice under physiological condition. Ten miRNAs were further examined by quantitative PCR assays, and four of them with high expression level were confirmed by Northern blot. Through bioinformatic analysis, we dissected the function and network of the differentially expressed miRNAs, providing insights into the physiological and pathophysiological differences between the left and the right kidneys. [ABSTRACT FROM AUTHOR]

Family with sequence similarity three member C (FAM3C) (interleukin‐like EMT inducer [ILEI]), heat shock factor 1 (HSF1) and Ying‐Yang 1 (YY1) have been independently reported to be involved in the pathogenesis of various cancers. However, whether they are coordinated to trigger the development of cancer remains unknown. This study determined the role and mechanism of YY1 and HSF1 in FAM3C‐induced proliferation and migration of breast cancer cells. In human MDA‐MB‐231 breast cancer cell line, transforming growth factor‐β (TGFβ) up‐regulated FAM3C, HSF1 and YY1 expressions. FAM3C overexpression promoted the proliferation and migration of MDA‐MB‐231 cells with YY1 and HSF1 up‐regulation, whereas FAM3C silencing exerted the opposite effects. FAM3C inhibition repressed TGFβ‐induced HSF1 activation, and proliferation and migration of breast cancer cells. YY1 was shown to directly activate HSF1 transcription to promote the proliferation and migration of breast cancer cells. YY1 silencing blunted FAM3C‐ and TGFβ‐triggered activation of HSF1‐Akt‐Cyclin D1 pathway, and proliferation and migration of breast cancer cells. Inhibition of HSF1 blocked TGFβ‐, FAM3C‐ and YY1‐induced proliferation and migration of breast cancer cells. YY1 and HSF1 had little effect on FAM3C expression. Similarly, inhibition of HSF1 also blunted FAM3C‐ and TGFβ‐promoted proliferation and migration of human breast cancer BT‐549 cells. In human breast cancer tissues, FAM3C, YY1 and HSF1 protein expressions were increased. In conclusion, FAM3C activated YY1‐HSF1 signalling axis to promote the proliferation and migration of breast cancer cells. Furthermore, novel FAM3C‐YY1‐HSF1 pathway plays an important role in TGFβ‐triggered proliferation and migration of human breast cancer MDA‐MB‐231 cells. [ABSTRACT FROM AUTHOR]

FAM3B, also known as PANcreatic DERived factor (PANDER), promotes gluconeogenesis and lipogenesis in hepatocytes. However, the underlying mechanism(s) still remains largely unclear. This study determined the mechanism of PANDER‐induced FOXO1 activation in hepatocytes. In mouse livers and cultured hepatocytes, PANDER protein is located in both the cytoplasm and nucleus. Nuclear PANDER distribution was increased in the livers of obese mice. In cultured mouse and human hepatocytes, PANDER was co‐localized with FOXO1 in the nucleus. PANDER directly interacted with FOXO1 in mouse and human hepatocytes. PANDER overexpression enhanced PANDER‐FOXO1 interaction, and detained FOXO1 in the nucleus upon insulin stimulation in hepatocytes. With the increase in PANDER‐FOXO1 interaction, PANDER overexpression upregulated the expression of gluconeogenic genes and promoted gluconeogenesis in both human and mouse hepatocytes. Luciferase reporter assays further revealed that PANDER augmented the transcriptional activity of FOXO1 on gluconeogenic genes. Moreover, PANDER overexpression also interfered the binding of AS1842856, a specific FOXO1 inhibitor, with FOXO1, and impaired its inhibitory effects on gluconeogenic gene expression and gluconeogenesis in hepatocytes. siRNA mediated‐silencing of FOXO1 inhibited PANDER‐promoted gluconeogenic gene expression and glucose production in hepatocytes. In conclusion, PANDER protein is abundantly present in the nucleus, where it functions as a new co‐activator of FOXO1 to induce gluconeogenic gene expression in hepatocytes. [ABSTRACT FROM AUTHOR]

Summary: Over 450 structurally distinct fatty acids are synthesized by plants. We have developed PlantFAdb.org, an internet‐based database that allows users to search and display fatty acid composition data for over 9000 plants. PlantFAdb includes more than 17 000 data tables from >3000 publications and hundreds of unpublished analyses. This unique feature allows users to easily explore chemotaxonomic relationships between fatty acid structures and plant species by displaying these relationships on dynamic phylogenetic trees. Users can navigate between order, family, genus and species by clicking on nodes in the tree. The weight percentage of a selected fatty acid is indicated on phylogenetic trees and clicking in the graph leads to underlying data tables and publications. The display of chemotaxonomy allows users to quickly explore the diversity of plant species that produce each fatty acid and that can provide insights into the evolution of biosynthetic pathways. Fatty acid compositions and other parameters from each plant species have also been compiled from multiple publications on a single page in graphical form. Links provide simple and intuitive navigation between fatty acid structures, plant species, data tables and the publications that underlie the datasets. In addition to providing an introduction to this resource, this report illustrates examples of insights that can be derived from PlantFAdb. Based on the number of plant families and orders that have not yet been surveyed we estimate that a large number of novel fatty acid structures are still to be discovered in plants. Significance Statement: Within the plant kingdom several hundred different fatty acid structures are synthesized and many of these have important applications in industry, nutrition, pharmacy and cosmetics. The PlantFAdb website and database compiles data from over 3000 publications on more than 9000 plants and allows users to explore connections between fatty acid structures and plant species by displaying these relationships on dynamic phylogenetic trees. [ABSTRACT FROM AUTHOR]

BACKGROUND The present study aimed to investigate the effects of dietary synbiotic supplementation on growth performance, carcass composition, meat quality and muscular antioxidant capacity, and mineral contents in broilers. Accordingly, 96 day-old male broiler chicks (Arbor Acres Plus; Aviagen, Huntsville, AL, USA) were randomly allocated to two groups, and each group consisted of six replicates with eight chicks each. Birds were fed a corn-soybean meal basal diet supplemented with either 0 or 1.5 g kg−1 synbiotic, consisting of probiotics ( Bacillus subtilis, Bacillus licheniformis and Clostridium butyricum) and prebiotics (yeast cell wall and xylooligosaccharide) from 1 to 42 days of age. RESULTS Compared with the control group, supplementation with a synbiotic increased average daily gain ( P < 0.05) but reduced feed/gain ratio ( P < 0.01) in broilers from 1 to 42 days of age. Similalrly, dietary synbiotic inclusion increased breast yield ( P < 0.05) but decreased abdominal fat ( P < 0.01) in broilers. The breast muscle pH value at 24 h postmortem in broilers was elevated with the incorporation of synbiotic ( P < 0.05). By contrast, synbiotic supplementation lowered the cooking loss during heat treatment in a water bath, malondialdehyde content, and total Cr content in the thigh muscle in broilers ( P < 0.05). CONCLUSION Dietary synbiotic supplementation into the diet of broilers may be an effective method for improving growth performance and carcass compositions, resulting in the production of meat with a favorable quality and oxidative stability. © 2017 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

Pure magnesium (Mg) was implanted intramedullary into the femur of streptozotocin (STZ)-induced diabetic rats to investigate its effect on bone growth after 6 weeks degradation. The experimental results showed that the femoral BMD in diabetic rats was significantly lower than that in controls ( p < 0.01) but restored notably by Mg implantation. The contents of calcium (Ca), phosphorus (P), Mg, zinc (Zn), potassium (K), strontium (Sr), and sulfur (S) in bone of diabetic group were significantly lower than those in controls but remarkably increased with implantation of Mg. The residual weight calculation showed that 29.41% of Mg was degraded in vivo. The energy dispersive X-ray spectroscopy (EDS) analysis showed that the reaction layer on the surface of the Mg implant mainly consisted of C, Ca, O, P, and Mg. Besides, serum Mg level was significantly decreased in diabetic group compared with the control group but increased by Mg treatment. Also, there were no significant differences in body weight and blood glucose, as well as blood glycosylated hemoglobin (HbAIc%), serum Ca, alanine aminitransperase (ALT), aspartate aminotransferase (AST), uric acid (UA), nonesterified fatty acid (NEFA), cholinesterase (CHE), and creatinine (CR) levels between diabetic and Mg-implanted rats. The study indicated that Mg implant had no obvious toxicity in STZ-induced diabetic rats and may act as a potential agent to treat osteoporosis. © 2011 Wiley Periodicals, Inc. J Biomed Mater Res Part A:, 2011. [ABSTRACT FROM AUTHOR]

The histone chaperone SET encoded by the SET gene, which is also known as template-activating factor Iβ (TAF-Iβ), is a multifunctional molecule that is involved in many biological phenomena such as histone binding, nucleosome assembly, chromatin remodelling, replication, transcription and apoptosis. A truncated SET/TAF-IβΔN protein that lacked the first 22 residues of the N-terminus but contained the C-terminal acidic domain and an additional His6 tag at the C-terminus was overexpressed in Escherichia coli and crystallized by the hanging-drop vapour-diffusion method using sodium acetate as precipitant at 283 K. The crystals diffracted to 2.7 Å resolution and belonged to space group P43212. [ABSTRACT FROM AUTHOR]

Transfer RNA (tRNA) (m(7)G46) methyltransferase (TrmB) belongs to the Rossmann-fold methyltransferase (RFM) family and uses S-adenosyl-L-methionine (SAM) as the methyl-group donor to catalyze the formation of N(7)-methylguanosine (m(7)G) at position 46 in the variable loop of tRNAs. After attempts to crystallize full-length Escherichia coli TrmB (EcTrmB) failed, a truncated protein lacking the first 32 residues of the N-terminus but with an additional His(6) tag at the C-terminus was crystallized by the hanging-drop vapour-diffusion method using polyethylene glycol 3350 (PEG 3350) as precipitant at 283 K. An X-ray diffraction data set was collected using a single flash-cooled crystal that belonged to space group P2(1).