BACKGROUND: Slow neurotransmission including DARPP-32 signalling is implicated in substance use disorders (SUDs) by experimental systems but not yet in the human aetiology. PPP1R12B, encoding another protein in the DARPP-32 family, hasn't been studied in the brain. METHODS: Brain-regional gene activity was assessed in three different animal models of SUDs for mRNA level alterations. Genetic associations were assessed by meta-analysis of pre-existing dbGaP GWAS datasets for main effects and epistasis with known genetic risks, followed by cell type-specific pathway delineation. Parkinson's disease (PD) was included as a dopamine-related disease control for SUDs. FINDINGS: In animal models of SUDs, environmentally-altered PPP1R12B expression sex-dependently involves motivation-related brain regions. In humans with polysubstance abuse, meta-analysis of pre-existing datasets revealed that PPP1R12B and PPP1R1B, although expressed in dopamine vs. dopamine-recipient neurons, exerted similar interactions with known genetic risks such as ACTR1B and DRD2 in men but with ADH1B, HGFAC and DRD3 in women. These interactions reached genome-wide significances (Pmeta<10-20) for SUDs but not for PD (disease selectivity: P = 4.8 × 10-142, OR = 6.7 for PPP1R12B; P = 8.0 × 10-8, OR = 2.1 for PPP1R1B). CADM2 was the common risk in the molecular signalling regardless of gender and cell type. INTERPRETATION: Gender-dependant slow neurotransmission may convey both genetic and environmental vulnerabilities selectively to SUDs. FUNDING: Grants from National Institute on Drug Abuse (NIDA) and National Institute on Alcohol Abuse and Alcoholism (NIAAA) of U.S.A. and National Natural Science Foundation of China (NSFC).
- MeSH
- celogenomová asociační studie MeSH
- dopaminem a cAMP regulovaný fosfoprotein 32 genetika metabolismus MeSH
- genetická epistáze * MeSH
- genetická heterogenita MeSH
- genetická predispozice k nemoci MeSH
- genové regulační sítě MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- mozek metabolismus patologie MeSH
- myši MeSH
- náchylnost k nemoci MeSH
- nervový přenos genetika MeSH
- orgánová specificita genetika MeSH
- poruchy spojené s užíváním psychoaktivních látek diagnóza etiologie metabolismus MeSH
- proteinfosfatasa 1 genetika metabolismus MeSH
- regulace genové exprese MeSH
- sexuální faktory MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
In recent years, a lot of scientific interest has focused on cancer immunotherapy. Although chronic inflammation has been described as one of the hallmarks of cancer, acute inflammation can actually trigger the immune system to fight diseases, including cancer. Toll-like receptor (TLR) ligands have long been used as adjuvants for traditional vaccines and it seems they may also play a role enhancing efficiency of tumor immunotherapy. The aim of this perspective is to discuss the effects of TLR stimulation in cancer, expression of various TLRs in different types of tumors, and finally the role of TLRs in anti-cancer immunity and tumor rejection.
- MeSH
- adaptorové proteiny signální transdukční metabolismus MeSH
- imunita * MeSH
- lidé MeSH
- ligandy MeSH
- nádory etiologie metabolismus patologie terapie MeSH
- orgánová specificita genetika imunologie MeSH
- regulace genové exprese u nádorů MeSH
- toll-like receptory agonisté genetika metabolismus MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Research Support, N.I.H., Extramural MeSH
The physiological function of the pancreas is controlled by the circadian clock. The aim of this study was to determine whether aging-induced changes in glucose homeostasis affect properties of the circadian clock in the pancreas and/or its sensitivity to disturbances in environmental lighting conditions. mPer2Luc mice aged 24-26 months developed hyperinsulinemic hypoglycaemia, which was likely due to the Pclo-mediated insulin hyper-secretion and Slc2a2-mediated glucose transport impairment in the pancreas, and due to the alterations in Pp1r3c-related glycogen storage and Sgk1-related glucose transport in the liver. In the pancreatic tissue, aging affected clock gene expression only marginally, it upregulated Bmal1 and downregulated Clock expression. Whereas aging significantly impaired the circadian clock in lung explants, which were used as a control tissue, the properties of the pancreatic clock in vitro were not affected. The data suggest a non-circadian role of Bmal1 in changes of pancreatic function that occur during aging. Additionally, the pancreatic clock was more sensitive to exposure of animals to constant light conditions. These findings provide an explanation for the previously demonstrated relationship between disturbances in the circadian system and disordered glucose homeostasis, including diabetes mellitus type 2, in subjects exposed to long-term shift work.
- MeSH
- cirkadiánní hodiny * účinky záření MeSH
- cirkadiánní proteiny Period metabolismus MeSH
- glukosa metabolismus MeSH
- homeostáza * MeSH
- játra metabolismus MeSH
- kolon metabolismus MeSH
- myši MeSH
- orgánová specificita genetika MeSH
- pankreas metabolismus účinky záření MeSH
- proteiny CLOCK genetika metabolismus MeSH
- regulace genové exprese účinky záření MeSH
- stárnutí metabolismus MeSH
- světlo MeSH
- transkripční faktory ARNTL genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
MAIN CONCLUSION: In tobacco, three sequence variants of the TERT gene have been described. We revealed unbalanced levels of TERT variant transcripts in vegetative tobacco tissues and enhanced TERT transcription and telomerase activity in reproductive tissues. Telomerase is a ribonucleoprotein complex responsible for the maintenance of telomeres, structures delimiting ends of linear eukaryotic chromosomes. In the Nicotiana tabacum (tobacco) allotetraploid plant, three sequence variants (paralogs) of the gene coding for the telomerase reverse transcriptase subunit (TERT) have been described, two of them derived from the maternal N. sylvestris genome (TERT_Cs, TERT_D) and one originated from the N. tomentosiformis paternal genome (TERT_Ct). In this work, we analyzed the transcription of TERT variants in correlation with telomerase activity in tobacco tissues. High and approximately comparable levels of TERT_Ct and TERT_Cs transcripts were detected in seedlings, roots, flower buds and leaves, while the transcript of the TERT_D variant was markedly underrepresented. Similarly, in N. sylvestris tissues, TERT_Cs transcript significantly predominated. A specific pattern of TERT transcripts was found in samples of tobacco pollen with the TERT_Cs variant clearly dominating particularly at the early stage of pollen development. Detailed analysis of TERT_C variants representation in functionally distinct fractions of pollen transcriptome revealed their prevalence in large ribonucleoprotein particles encompassing translationally silent mRNA; only a minority of TERT_Ct and TERT_Cs transcripts were localized in actively translated polysomes. Histones of the TERT_C chromatin were decorated predominantly with the euchromatin-specific epigenetic modification in both telomerase-positive and telomerase-negative tobacco tissues. We conclude that the existence and transcription pattern of tobacco TERT paralogs represents an interesting phenomenon and our results indicate its functional significance. Nicotiana species have again proved to be appropriate and useful model plants in telomere biology studies.
- MeSH
- buněčné jádro genetika MeSH
- chromatinová imunoprecipitace MeSH
- euchromatin metabolismus MeSH
- genetická transkripce MeSH
- genetická variace * MeSH
- histony metabolismus MeSH
- messenger RNA genetika metabolismus MeSH
- orgánová specificita genetika MeSH
- polyribozomy metabolismus MeSH
- posttranslační úpravy proteinů MeSH
- pylová láčka růst a vývoj MeSH
- regulace genové exprese u rostlin * MeSH
- tabák genetika MeSH
- telomerasa genetika metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
Cephalochordates, the sister group of vertebrates + tunicates, are evolving particularly slowly. Therefore, genome comparisons between two congeners of Branchiostoma revealed so many conserved noncoding elements (CNEs), that it was not clear how many are functional regulatory elements. To more effectively identify CNEs with potential regulatory functions, we compared noncoding sequences of genomes of the most phylogenetically distant cephalochordate genera, Asymmetron and Branchiostoma, which diverged approximately 120-160 million years ago. We found 113,070 noncoding elements conserved between the two species, amounting to 3.3% of the genome. The genomic distribution, target gene ontology, and enriched motifs of these CNEs all suggest that many of them are probably cis-regulatory elements. More than 90% of previously verified amphioxus regulatory elements were re-captured in this study. A search of the cephalochordate CNEs around 50 developmental genes in several vertebrate genomes revealed eight CNEs conserved between cephalochordates and vertebrates, indicating sequence conservation over >500 million years of divergence. The function of five CNEs was tested in reporter assays in zebrafish, and one was also tested in amphioxus. All five CNEs proved to be tissue-specific enhancers. Taken together, these findings indicate that even though Branchiostoma and Asymmetron are distantly related, as they are evolving slowly, comparisons between them are likely optimal for identifying most of their tissue-specific cis-regulatory elements laying the foundation for functional characterizations and a better understanding of the evolution of developmental regulation in cephalochordates.
- MeSH
- bezlebeční genetika MeSH
- Chordata genetika MeSH
- fylogeneze MeSH
- genom MeSH
- konzervovaná sekvence genetika MeSH
- kopinatci genetika MeSH
- molekulární evoluce * MeSH
- orgánová specificita genetika MeSH
- regulační oblasti nukleových kyselin genetika MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Ixodes ricinus is a tick that transmits the pathogens of Lyme and several arboviral diseases. Pathogens invade the tick midgut, disseminate through the hemolymph, and are transmitted to the vertebrate host via the salivary glands; subverting these processes could be used to interrupt pathogen transfer. Here, we use massive de novo sequencing to characterize the transcriptional dynamics of the salivary and midgut tissues of nymphal and adult I. ricinus at various time points after attachment on the vertebrate host. Members of a number of gene families show stage- and time-specific expression. We hypothesize that gene expression switching may be under epigenetic control and, in support of this, identify 34 candidate proteins that modify histones. I. ricinus-secreted proteins are encoded by genes that have a non-synonymous to synonymous mutation rate even greater than immune-related genes. Midgut transcriptome (mialome) analysis reveals several enzymes associated with protein, carbohydrate, and lipid digestion, transporters and channels that might be associated with nutrient uptake, and immune-related transcripts including antimicrobial peptides. This publicly available dataset supports the identification of protein and gene targets for biochemical and physiological studies that exploit the transmission lifecycle of this disease vector for preventative and therapeutic purposes.
- MeSH
- anotace sekvence MeSH
- časové faktory MeSH
- fylogeneze MeSH
- genetická transkripce * MeSH
- klíště klasifikace genetika MeSH
- orgánová specificita genetika MeSH
- polymorfismus genetický MeSH
- shluková analýza MeSH
- slinné žlázy metabolismus MeSH
- stanovení celkové genové exprese MeSH
- střeva metabolismus MeSH
- transkriptom MeSH
- výpočetní biologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Intramural MeSH
Nuclear receptors (NRs), or nuclear hormone receptors (NHRs), are transcription factors that regulate development and metabolism of most if not all animal species. Their regulatory networks include conserved mechanisms that are shared in-between species as well as mechanisms that are restricted to certain phyla or even species. In search for conserved members of the NHR family in Schmidtea mediterranea, we identified a molecular signature of a class of NRs, NR2E1, in the S. mediterranea genome and cloned its complete cDNA coding sequence. The derived amino acid sequence shows a high degree of conservation of both DNA-binding domain and ligand- binding domain and a remarkably high homology to vertebrate NR2E1 and C. elegans NHR-67. Quantitative PCR detected approximately ten-fold higher expression of Smed-tlx-1 in the proximal part of the head compared to the tail region. The expression of Smed-tlx-1 is higher during fed state than during fasting. Smed-tlx-1 down-regulation by RNA interference affects the ability of the animals to maintain body plan and induces defects of brain, eyes and body shape during fasting and re-growing cycles. These results suggest that SMED-TLX-1 is critical for tissue and body plan maintenance in planaria.
- MeSH
- fylogeneze MeSH
- klonování DNA MeSH
- lidé MeSH
- molekulární sekvence - údaje MeSH
- omezení příjmu potravy fyziologie MeSH
- orgánová specificita genetika MeSH
- proteiny červů genetika chemie metabolismus MeSH
- receptory cytoplazmatické a nukleární genetika chemie metabolismus MeSH
- regulace genové exprese MeSH
- RNA interference MeSH
- rozvržení tělního plánu genetika MeSH
- sekvence aminokyselin MeSH
- sekvenční seřazení MeSH
- stravovací zvyklosti fyziologie MeSH
- Turbellaria embryologie fyziologie genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
Hemojuvelin (Hjv) is an essential component of the pathway regulating hepcidin (Hamp1) gene expression. Mice with targeted disruption of the Hjv gene (Hjv-/- mice) fail to upregulate hepatic Hamp1 expression following iron overload. The main aim of the study was to determine whether the Hjv protein is also necessary for Hamp1 downregulation. In addition, sex differences in Hamp1 expression in Hjv-/- mice were also examined. Male and female Hjv-/- mice (129SvJ background) were used for the experiments, tissue Hamp1 and Hamp2 mRNA content was determined by real-time PCR. Hepatic Hamp1 mRNA content in male Hjv-/- mice was low (0.6% of Hjv+/+ males), however, female Hjv-/- mice displayed only moderately reduced (to 17%) Hamp1 mRNA levels. Hepatic non-heme iron concentration was similar in Hjv-/- mice of both sexes. Disruption of the Hjv gene did not affect Hamp1 mRNA content in the myocardium or Hamp2 mRNA content in the pancreas. Single phlebotomy resulted in significant reduction of Hamp1 mRNA in both male and female Hjv+/+ mice (to 17% and 27% of controls respectively), measured 20 h after treatment. In Hjv-/- mice, phlebotomy decreased Hamp1 mRNA content to 46% in males and to 11% in females. Bleeding also significantly decreased (to 16%) hepatic Hamp2 mRNA levels in Hjv-/- females. The obtained results indicate that the pathway mediating hepcidin downregulation by phlebotomy does not require functional hemojuvelin protein. In addition, they confirm a significant effect of sex on hepcidin gene expression.
- MeSH
- financování organizované MeSH
- flebotomie MeSH
- kationické antimikrobiální peptidy biosyntéza MeSH
- krvácení metabolismus MeSH
- lidé MeSH
- membránové proteiny nedostatek MeSH
- mutace MeSH
- myši knockoutované MeSH
- myši MeSH
- orgánová specificita genetika MeSH
- pohlavní dimorfismus MeSH
- regulace genové exprese genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
