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Background: The major safety concern of the clinical application of wild type FGF19 (FGF19WT) emerges given that its extended treatment causes hepatocellular carcinoma. Therefore, we previously generated a safer FGF19 variant - FGF19ΔKLB, which have same effects on glycemic control and bile acid production but much less mitogenic activity. However, it remains unclear as to whether FGF19ΔKLB ameliorates intrahepatic cholestasis. Results: We found that, similar to that of FGF19WT, the chronic administration of FGF19ΔKLB protects mice from cholestatic liver injury in these two models. The therapeutic benefits of FGF19ΔKLB on cholestatic liver damage are attributable, according to the following mechanistic investigation, to the reduction of BA production, liver inflammation, and fibrosis. More importantly, FGF19ΔKLB did not induce any tumorigenesis effects during its prolonged treatment. Conclusions: Together, our findings raise hope that FGF19ΔKLB may represent a useful therapeutic strategy for the treatment of intrahepatic cholestasis. [ABSTRACT FROM AUTHOR]

Background: Mutations in the signal transducers and activators of transcription 3 (STAT3) gene result in hyper-IgE syndrome(HIES), a rare immunodeficiency that causes abnormalities in immune system, bones and teeth. However, the role of Stat3 in development of dental hard tissues was yet to investigate. Methods: In this study, a transgenic mouse of conditional knockout of Stat3 in dental mesenchymal cells (Osx-Cre; Stat3fl/fl, Stat3 CKO) was made. The differences of postnatal tooth development between control and Stat3 CKO mice were compared by histology, µCT and scanning electron microscopy. Result: Compared with the control, Stat3 CKO mice were presented with remarkable abnormal tooth phenotypes characterized by short root and thin dentin in molars and incisors. The enamel defects were also found on mandibular incisors. showed that Ki67-positive cells significantly decreased in dental mesenchymal of Stat3 CKO mice. In addition, β-catenin signaling was reduced in Hertwig's epithelial root sheath (HERS) and odontoblasts of Stat3 CKO mice. Conclusions: Our results suggested that Stat3 played an important role in dental hard tissues development, and Stat3 may regulate dentin and tooth root development through the β-catenin signaling pathway. [ABSTRACT FROM AUTHOR]

Background: The outbreak of the 2009 H1N1 influenza pandemic (H1N1pdm) affected thousands of people in Mexico and the United States, and spread rapidly throughout the world from April 2009 to July 2010. To explore the age-specific prevalence of seroprotection against H1N1pdm infection, we estimated pre-existing humoral and cellular immunities of residents in Northern China against H1N1pdm and seasonal H1N1 virus in an age-dependent manner.Methods: Anonymous serum samples were collected from 1425 to 1434 adult healthy individuals before and after the pandemic outbreak, and then grouped by birth year 1913-1990. The antibody titers of H1N1pdm and seasonal H1N1 were determined using microneutralization (MN) assays, and the proportion of seropositive was estimated based on the year of birth. Separately, another 63 blood samples were collected in 2006 and prepared for analysis of virus specific memory B and IFN-γ+ T cells using the ELISpot assays.Results: The prevalence of pre-existing H1N1pdm-specific sero-antibodies in the elderly population (>60 years old) was 7.8%. The younger group, aged 19 to 60 years, exhibited a significant increase in seropositivity for H1N1pdm after the pandemic (4.9% before pandemic and 18.9% after pandemic, p < 0.05). The prevalence of H1N1pdm specific MBCs before the pandemic in the elderly (>60 years) and younger populations (<60 years) was 38% (8/21) and 48% (20/42), respectively (p = 0.6). The IFN-γ+ T cell responses to the pandemic and seasonal viruses were significantly lower in the elder group than those in the younger group (<60 years) (p < 0.05).Conclusions: Pre-existing serum antibodies and memory B cells against H1N1pdm were low in all age group, whereas diminished memory T cell responses to this virus were observed in the elderly population both before and after the pandemic. [ABSTRACT FROM AUTHOR]

Background Inherited genetic defects play an important role in congenital hearing loss, contributing to about 60% of deafness occurring in infants. Hereditary nonsyndromic hearing loss is highly heterogeneous, and most patients with a presumed genetic etiology lack a specific molecular diagnosis. Methods By whole exome sequencing, we identified responsible gene of family 4794 with autosomal recessively nonsyndromic hearing loss (ARNSHL). We also used DNA from 56 Chinese familial patients with ARNSHL (autosomal recessive nonsyndromic hearing loss) and 108 ethnicity-matched negative samples to perform extended variants analysis. Results We identified MYO15A c.IVS25 + 3G > A and c.8375 T > C (p.V2792A) as the diseasecausing mutations. Both mutations co-segregated with hearing loss in family 4794, but were absent in the 56 index patients and 108 ethnicity-matched controls. Conclusions Our results demonstrated that the hearing loss of family 4794 was caused by novel compound heterozygous mutations in MYO15A. [ABSTRACT FROM AUTHOR]

Background: Each year in China, 30,000 babies are born with congenital hearing impairment. However, the molecular etiology of hearing impairment in the Yunnan Province population where more than 52 minorities live has not been thoroughly investigated. To provide appropriate genetic testing and counseling to these families, we investigated the molecular etiology of nonsyndromic deafness in this population.Methods: Unrelated students with hearing loss (n = 235) who attended Kunming Huaxia secondary specialized school in Yunnan enrolled in this study. Three prominent deafness-related genes, GJB2, SLC26A4 and mtDNA 12S rRNA, were analyzed. High-resolution temporal bone computed tomography (CT) scan examinations were performed in 100 cases, including 16 cases with SLC26A4 gene variants, and 37 minorities and 47 Han cases without any SLC26A4 gene mutation.Results: The GJB2 mutation was detected in 16.67% (7/42) of minority patients and 17.62% (34/193) of Chinese Han patients (P > 0.05). 235delC was the hotspot mutation in nonsyndromic hearing loss (NSHL) patients, whereas 35delG was not found. The 431_450del19 mutation was detected for the first time in Han NSHL patients, which resulted in a premature stop codon and changed the protein. The SLC26A4 mutation was found in 9.52% (4/42) of minority patients and 9.84% (19/193) of Han Chinese patients (P > 0.05). The frequencies of mtDNA 12S rRNA mutation in minority and Han Chinese patients were 11.90% (5/42) and 7.77% (15/193; P > 0.05), respectively. Sixteen (16/23, 69.57%) patients with SLC26A4 mutations received temporal bone CT scan, and 14 patients were diagnosed with enlarged vestibular aqueducts (EVAs); the other 2 patients had normal inner ear development. The ratio of EVA in the minorities was 14.63% (6/41).Conclusions: In this study, a total of 35.74% deaf patients showed evidence of genetic involvement, based on either genetic screening or family history; 17.45%, 9.79%, and 8.51% of the patients were determined to have inherited hearing impairment caused by GJB2, SLC26A4, and mtDNA 1555A > G mutations. There was no significant difference in deafness associated gene mutational spectrum and frequency between the Yunnan minority and Han patients. [ABSTRACT FROM AUTHOR]

Background: We studied the effects of single nucleotide polymorphisms (SNPs) in the metabotropic glutamate receptor 3 (GRM3) gene on brain N-acetylaspartate (NAA) concentrations and executive function (EF) skills in non-smoking, active alcoholics, and evaluated associations between these variables. Methods: SNPs (rs6465084, rs1468412, and rs2299225) in GRM3 were genotyped in 49 male, non-smoking, alcohol-dependent patients and 45 healthy control subjects using ligase detection reactions. NAA/creatine (Cr) ratios in left prefrontal gray matter (GM) and white matter (WM), left parietal GM, left parietal WM, and cerebellar vermis regions were measured by Proton 1 H Magnetic resonance spectroscopy (MRS). EF was measured by the Wisconsin Card Sorting Test (WCST). Results: Compared to controls, alcoholics had lower NAA/Cr ratios in prefrontal GM and WM regions and performed more poorly on all EF tests (P < 0.001). Alcoholics with the A/A genotype for SNP rs6465084 had lower NAA/Cr ratios in prefrontal GM and WM regions and had poorer EF skills than alcoholics who were G-carriers for this SNP (P < 0.01). Non-alcoholics with the A/A genotype for rs6465084 also had lower NAA/Cr levels in prefrontal GM and made more random errors in the WCST than G-carriers (P < 0.01). The A/A genotype group for SNP rs6465084 was significantly different from the G carriers for the variables of NAA/Cr ratios and WCST scores in both alcoholics and controls (P < 0.05). Alcoholics who were T-carriers for rs1468412 had lower NAA/Cr ratios in prefrontal GM and showed poorer EF skills (P < 0.05). No effects of rs2299225 genotype on NAA/Cr or executive skills were observed. NAA/Cr in left prefrontal regions correlated with certain parameters of EF testing in both alcoholics and controls (P < 0.05), but the significance of this correlation among alcoholics disappeared after adjustment for the effects of genotype. Conclusions: Our results provide evidence that glutamate system dysfunction may play a role in the prefrontal functional abnormalities seen in alcohol dependence. It is possible that certain GRM3 SNP genotypes (the A/A genotype of rs6465084 and the T allele of rs1468412) may further lower NAA/Cr levels and EF skills in addition to the effect of alcohol. [ABSTRACT FROM AUTHOR]

Background: In C. elegans there are two well-defined TGFβ-like signaling pathways. The Sma/Mab pathway affects body size morphogenesis, male tail development and spicule formation while the Daf pathway regulates entry into and exit out of the dauer state. To identify additional factors that modulate TGFβ signaling in the Sma/Mab pathway, we have undertaken a genetic screen for small animals and have identified kin-29. Results: kin-29 encodes a protein with a cytoplasmic serine-threonine kinase and a novel Cterminal domain. The kinase domain is a distantly related member of the EMK (ELKL motif kinase) family, which interacts with microtubules. We show that the serine-threonine kinase domain has in vitro activity. kin-29 mutations result in small animals, but do not affect male tail morphology as do several of the Sma/Mab signal transducers. Adult worms are smaller than the wild-type, but also develop more slowly. Rescue by kin-29 is achieved by expression in neurons or in the hypodermis. Interaction with the dauer pathway is observed in double mutant combinations, which have been seen with Sma/Mab pathway mutants. We show that kin-29 is epistatic to the ligand dbl-1, and lies upstream of the Sma/Mab pathway target gene, lon-1. Conclusion: kin-29 is a new modulator of the Sma/Mab pathway. It functions in neurons and in the hypodermis to regulate body size, but does not affect all TGFβ outputs, such as tail morphogenesis. [ABSTRACT FROM AUTHOR]

Background: Infantile eczema is an immunological disease that is characterized by itchy and dry skin. Recent studies have suggested that gut microbiota (GM) plays a role in the development and progression of eczema. To further evaluate this potential link, we collected feces from 19 infants with eczema and 14 infants without eczema and analyzed the molecular discrepancies between the two groups using 16S rDNA analysis., Results: Bacteroidaceae and Deinococcaceae were significantly enriched in eczema infants, and Bacteroidaceae was potentially involved in autoimmune diseases by promoting the Th17 (T helper cell 17) secretion of IL-17 (interleukin-17). In the infants without eczema, the co-abundance network featured three core nodes: Clostridiaceae, Veillonellaceae, and Lactobacillaceae, all of which were lacking in the infants with eczema. Furthermore, our data suggested that Enterobacteriaceae was the core of the co-abundance network for the diseased subjects., Conclusions: GM is closely connected to the human immune system, and the dysbiotic GM network plays a role in eczema. This study furthered our understanding of the dynamic GM network and its correlation to the occurrence of eczema.

Background: Superoxide dismutase (SOD) is an essential enzyme of the plant antioxidant system that responds to oxidative stresses caused by adverse conditions. Banana is an important staple and economic crop in tropical and subtropical regions. However, its growth and yield are constantly affected by various abiotic stresses. To analyze the roles of distinct SOD genes under various stresses, a detailed characterization and analysis of the SOD gene family in Cavendish banana is indispensable., Methods: The presence and structure of the SOD family genes were experimentally verified using 5'/3' RACE-PCR, reverse transcription PCR and PCR. Then, their syntenic relationships, conserved motifs and phylogenetic relationships were analyzed using software. Cis-elements present in the promoters were predicted via PlantCARE. And the expression levels under abiotic and hormonal stresses were determined using real-time quantitative polymerase chain reaction., Results: In total, 25 'Tianbaojiao' SOD cDNAs (MaSODs), which encoded six Cu/ZnSODs, four MnSODs and two FeSODs, were cloned. The 12 MaSOD genes were divided into four groups based on their conserved motifs, which corroborated their classifications based on gene-structure patterns and subcellular localizations. Eleven MaSOD promoters were isolated and found to contain many cis-acting elements involved in stress responses. Gene expression analysis showed that 11 out of the 12 MaSODs were expressed in all tested tissues (leaf, pseudostem and root), whereas MaCSD2B was expressed only in leaves and roots. Specific MaSOD members exhibited different expression patterns under abiotic and hormonal treatments. Among the 12 MaSOD genes, MaCSD1D was the only one that responded to all eight treatments, suggesting that this gene plays a predominant role in reactive oxygen species scavenging caused by various stresses in banana., Conclusions: A genome-wide analysis showed that the 'Tianbaojiao' banana harbored an expanded SOD gene family. Whole genome duplication, segmental duplication and complex transcriptional regulation contributed to the gene expansion and mRNA diversity of the MaSODs. The expression patterns of distinct MaSOD genes showed that they are important responses to different abiotic and hormonal stresses in banana.