Mitochondrial autophagy in ischemic aged livers

Mitochondrial autophagy (mitophagy) is a central catabolic event for mitochondrial quality control. Defective or insufficient mitophagy, thus, can result in mitochondrial dysfunction, and ultimately cell death. There is a strong causal relationship between ischemia/reperfusion (I/R) injury and mitochondrial dysfunction following liver resection and transplantation. Compared to young patients, elderly patients poorly tolerate I/R injury. Accumulation of abnormal mitochondria after I/R is more prominent in aged livers than in young counterparts. This review highlights how altered autophagy is mechanistically involved in age-dependent hypersensitivity to reperfusion injury

Organization of the human intestine at single-cell resolution

The intestine is a complex organ that promotes digestion, extracts nutrients, participates in immune surveillance, maintains critical symbiotic relationships with microbiota and affects overall healt

Novel APC promoter and exon 1B deletion and allelic silencing in three mutation-negative classic familial adenomatous polyposis families

BACKGROUND: The overwhelming majority (approximately 80%) of individuals with classic familial adenomatous polyposis (FAP) exhibit mutations in the coding sequence of the adenomatous polyposis coli (APC) tumor suppressor gene. Families without detectable APC mutations are unable to benefit from the use of genetic testing for clinical management of this autosomal dominant syndrome. METHODS: We used exome sequencing and linkage analysis, coupled with second-generation sequencing of the APC locus including non-coding regions to investigate three APC mutation-negative classical FAP families. RESULTS: We identified a novel ~11 kb deletion localized 44 kb upstream of the transcription start site of APC that encompasses the APC 1B promoter and exon. This deletion was present only in affected family members of one kindred with classical FAP. Furthermore, this same deletion with identical breakpoints was found in the probands of two additional APC mutation-negative classical FAP kindreds. Phasing analysis of single nucleotide polymorphisms (SNPs) around the deletion site in the three probands showed evidence of a shared haplotype, suggesting a common founder deletion in the three kindreds. SNP analysis within the coding sequence of APC, revealed that this ~11 kb deletion was accompanied by silencing of one of the APC alleles in blood-derived RNA of affected individuals. CONCLUSIONS: These results support the causal role of a novel promoter deletion in FAP and suggest that non-coding deletions, identifiable using second-generation sequencing methods, may account for a significant fraction of APC mutation-negative classical FAP families

Plasma n-3 and n-6 fatty acid profiles and their correlations to hair coat scores in horses kept under Malaysian conditions

A survey was carried out to determine the relationship between plasma fatty acid profiles and hair coat scores of horses kept under Malaysian conditions. Thirty-seven Thoroughbred horses with an average age of seven years were included in this study. The surveyed population comprised 27 geldings and 10 mares from the Kuala Lumpur City Hall stables at Titiwangsa (TTW, n=7) and Bandar Tun Razak (BTR, n=7), the Equine Unit, Universiti Putra Malaysia (UPM, n=7), the Royal Malaysian Police stables (RMP, n=8) and the Selangor Turf Club (STC, n=8). Plasma and feed fatty acid profiles were determined using gas chromatography and the hair coat score determined using a seven-point scoring system (1=worst hair coat condition; 7=best hair coat condition). Results showed that feed and plasma fatty acids profiles were variable across sampling locations. The n-6:n-3 ratios in feeds ranged from 6.8 (BTR) to 17.2 (UPM). Only plasma oleic and linolenic acids were different (P<0.05) across sampling locations. The STC horses had the best hair coat score (median score=7, P<0.05). It was found that total n-3 fatty acids were highly correlated with hair coat scores ( rho =0.686, P<0.01). A significant inverse correlation between n-6:n-3 ratio and hair coat scores ( rho =-0.755, P<0.01) was also noted. This meant that increasing plasma n-3 fatty acids and decreasing n-6:n-3 ratios were associated with better hair coat scores in these horses

Characteristics Associated with Utilization of Asthma-Related Traditional Chinese Medicine Services among Asthma Children in Taiwan: A Nationwide Cohort Study

Introduction. Previous studies have demonstrated the advantages of TCM use among asthmatic children. However, there is a paucity of epidemiologic reports on features of TCM users among asthmatic children. This cohort study aimed to investigate child&apos;s, parent&apos;s, and provider&apos;s characteristics associated with the use of asthma-related TCM services among newly diagnosed asthmatic children. Materials and Methods. A nationally representative cohort of one million National Health Insurance beneficiaries was used. The newly diagnosed asthma children who received asthma medication from western medicine providers from 2005 to 2010 were selected as our sample for analysis. Generalized estimating equation was applied to identify the child&apos;s, parents&apos; , and provider&apos;s characteristics associated with the use of asthma-related TCM among the newly diagnosed asthmatic children. Results. Of 20,080 children who were enrolled and followed up for one year, 4,034 children used TCM for asthma-related treatment. Children with prior experience of TCM, pre-school and school aged children, boys, those with more severe asthma or poorer health, with higher income parents were more likely to use asthma-related TCM. Herbal medicine was the most common modality among asthmatic children. Conclusions. There were only 20% newly diagnosed asthmatic children using TCM. The findings may shed light on possible integration of TCM with western medicine services

A compendium of chromatin contact maps reveals spatially active regions in the human genome

The three-dimensional configuration of DNA is integral to all nuclear processes in eukaryotes, yet our knowledge of the chromosome architecture is still limited. Genome-wide chromosome conformation capture studies have uncovered features of chromatin organization in cultured cells, but genome architecture in human tissues has yet to be explored. Here, we report the most comprehensive survey to date of chromatin organization in human tissues. Through integrative analysis of chromatin contact maps in 21 primary human tissues and cell types, we find topologically associating domains highly conserved in different tissues. We also discover genomic regions that exhibit unusually high levels of local chromatin interactions. These frequently interacting regions (FIREs) are enriched for super-enhancers and are near tissue specifically expressed genes. They display strong tissue-specificity in local chromatin interactions. Additionally, FIRE formation is partially dependent on CTCF and the Cohesin complex. We further show that FIREs can help annotate the function of non-coding sequence variants

Elevated plasma level of visfatin/pre-b cell colony-enhancing factor in male oral squamous cell carcinoma patients

Objectives: Visfatin, also known as nicotiamide phosphoribosyltransferase or pre-B cell colony enhancing factor, is a pro-inflammatory cytokine whose serum level is increased in various cancers. In this study, we investigated whether plasma visfatin levels were altered in patients with oral squamous cell carcinoma (OSCC). The relation ship between plasma visfatin levels and the pretreatment hematologic profile was also explored. Study Design: Plasma visfatin concentrations were measured through ELISA in OSCC patients and control sub- D esign: Plasma visfatin concentrations were measured through ELISA in OSCC patients and control sub- esign: Plasma visfatin concentrations were measured through ELISA in OSCC patients and control sub jects. A total of 51 patients with OSCC and 57 age- and body mass index (BMI)-matched control subjects were studied. All study subjects were male. Results: Plasma visfatin was found to be elevated in patients with OSCC (7.0 ± 4.5 vs. 4.8 ± 1.9 ng/ml, p = 0.002). Multiple logistic regression analysis revealed visfatin as an independent association factor for OSCC, even after full adjustment of known biomarkers. Visfatin level was significantly correlated with white blood cell (WBC) count, neutrophil count, and hematocrit (all p < 0.05). In addition, WBC count, neutrophil count, and visfatin gradually increased with stage progression, and hematocrit gradually decreased with stage progression (all p < 0.05). Conclusion: Increased plasma visfatin levels were associated with OSCC, independent of risk factors, and were cor related with inflammatory biomarkers. These data suggest that visfatin may act through inflammatory reactions to play an important role in the pathogenesis of OSC

Genome-wide identification and functional analysis of Apobec-1-mediated C-to-U RNA editing in mouse small intestine and liver

BackgroundRNA editing encompasses a post-transcriptional process in which the genomically templated sequence is enzymatically altered and introduces a modified base into the edited transcript. Mammalian C-to-U RNA editing represents a distinct subtype of base modification, whose prototype is intestinal apolipoprotein B mRNA, mediated by the catalytic deaminase Apobec-1. However, the genome-wide identification, tissue-specificity and functional implications of Apobec-1-mediated C-to-U RNA editing remain incompletely explored.ResultsDeep sequencing, data filtering and Sanger-sequence validation of intestinal and hepatic RNA from wild-type and Apobec-1-deficient mice revealed 56 novel editing sites in 54 intestinal mRNAs and 22 novel sites in 17 liver mRNAs, all within 3' untranslated regions. Eleven of 17 liver RNAs shared editing sites with intestinal RNAs, while 6 sites are unique to liver. Changes in RNA editing lead to corresponding changes in intestinal mRNA and protein levels for 11 genes. Analysis of RNA editing in vivo following tissue-specific Apobec-1 adenoviral or transgenic Apobec-1 overexpression reveals that a subset of targets identified in wild-type mice are restored in Apobec-1-deficient mouse intestine and liver following Apobec-1 rescue. We find distinctive polysome profiles for several RNA editing targets and demonstrate novel exonic editing sites in nuclear preparations from intestine but not hepatic apolipoprotein B RNA. RNA editing is validated using cell-free extracts from wild-type but not Apobec-1-deficient mice, demonstrating that Apobec-1 is required.ConclusionsThese studies define selective, tissue-specific targets of Apobec-1-dependent RNA editing and show the functional consequences of editing are both transcript- and tissue-specific

Dual lactate clearance in the viability assessment of livers donated after circulatory death with ex situ normothermic machine perfusion

Perfusate lactate clearance (LC) is considered one of the useful indicators of liver viability assessment during normothermic machine perfusion (NMP); however, the applicable scope and potential mechanisms of LC remain poorly defined in the setting of liver donation after circulatory death. Methods: The ex situ NMP of end-ischemic human livers was performed using the OrganOx Metra device. We further studied the extracellular signal-regulated kinases (phospho-extracellular signal-regulated kinase1/2 [pERK1/2]) pathway and several clinical parameters of these livers with successful LC (sLC, n = 5) compared with non-sLC (nLC, n = 5) in the perfusate (\u3c2.2 mmol/L at 2 h, n = 5, rapid retrieval without normothermic regional perfusion). Results: We found the pERK1/2 level was substantially higher in the nLC livers than in the sLC livers (n = 5) at 2- and 6-h NMP ( Conclusions: The dual LC in perfusate and bile can be helpful in evaluating the hypoxic injury of hepatocytes and cholangiocytes during the NMP of donation after circulatory death in liver donors