Mouse SNP Miner: an annotated database of mouse functional single nucleotide polymorphisms

BACKGROUND: The mapping of quantitative trait loci in rat and mouse has been extremely successful in identifying chromosomal regions associated with human disease-related phenotypes. However, identifying the specific phenotype-causing DNA sequence variations within a quantitative trait locus has been much more difficult. The recent availability of genomic sequence from several mouse inbred strains (including C57BL/6J, 129X1/SvJ, 129S1/SvImJ, A/J, and DBA/2J) has made it possible to catalog DNA sequence differences within a quantitative trait locus derived from crosses between these strains. However, even for well-defined quantitative trait loci (<10 Mb) the identification of candidate functional DNA sequence changes remains challenging due to the high density of sequence variation between strains. DESCRIPTION: To help identify functional DNA sequence variations within quantitative trait loci we have used the Ensembl annotated genome sequence to compile a database of mouse single nucleotide polymorphisms (SNPs) that are predicted to cause missense, nonsense, frameshift, or splice site mutations (available at ). For missense mutations we have used the PolyPhen and PANTHER algorithms to predict whether amino acid changes are likely to disrupt protein function. CONCLUSION: We have developed a database of mouse SNPs predicted to cause missense, nonsense, frameshift, and splice-site mutations. Our analysis revealed that 20% and 14% of missense SNPs are likely to be deleterious according to PolyPhen and PANTHER, respectively, and 6% are considered deleterious by both algorithms. The database also provides gene expression and functional annotations from the Symatlas, Gene Ontology, and OMIM databases to further assess candidate phenotype-causing mutations. To demonstrate its utility, we show that Mouse SNP Miner successfully finds a previously identified candidate SNP in the taste receptor, Tas1r3, that underlies sucrose preference in the C57BL/6J strain. We also use Mouse SNP Miner to derive a list of candidate phenotype-causing mutations within a previously uncharacterized QTL for response to morphine in the 129/Sv strain

The Transition from Proliferation to Differentiation Is Delayed in Satellite Cells from Mice Lacking MyoD

AbstractSatellite cells from adult rat muscle coexpress proliferating cell nuclear antigen and MyoD upon entry into the cell cycle, suggesting that MyoD plays a role during the recruitment of satellite cells. Moreover, the finding that muscle regeneration is compromised in MyoD−/− mice, has provided evidence for the role of MyoD during myogenesis in adult muscle. In order to gain further insight into the role of MyoD during myogenesis in the adult, we compared satellite cells from MyoD−/− and wildtype mice as they progress through myogenesis in single-myofiber cultures and in tissue-dissociated cell cultures (primary cultures). Satellite cells undergoing proliferation and differentiation were traced immunohistochemically using antibodies against various regulatory proteins. In addition, an antibody against the mitogen-activated protein kinases ERK1 and ERK2 was used to localize the cytoplasm of the fiber-associated satellite cells regardless of their ability to express specific myogenic regulatory factor proteins. We show that during the initial days in culture the myofibers isolated from both the MyoD−/− and the wildtype mice contain the same number of proliferating, ERK+ satellite cells. However, the MyoD−/− satellite cells continue to proliferate and only a very small number of cells transit into the myogenin+ state, whereas the wildtype cells exit the proliferative compartment and enter the myogenin+ stage. Analyzing tissue-dissociated cultures of MyoD−/− satellite cells, we identified numerous cells whose nuclei were positive for the Myf5 protein. In contrast, quantification of Myf5+ cells in the wildtype cultures was difficult due to the low level of Myf5 protein present. The Myf5+ cells in the MyoD−/− cultures were often positive for desmin, similar to the MyoD+ cells in the wildtype cultures. Myogenin+ cells were identified in the MyoD−/− primary cultures, but their appearance was delayed compared to the wildtype cells. These “delayed” myogenin+ cells can express other differentiation markers such as MEF2A and cyclin D3 and fuse into myotubes. Taken together, our studies suggest that the presence of MyoD is critical for the normal progression of satellite cells into the myogenin+, differentiative state. It is further proposed that the Myf5+/MyoD− phenotype may represent the myogenic stem cell compartment which is capable of maintaining the myogenic precursor pool in the adult muscle

A Transgenic Model Reveals the Role of Klotho in Pancreatic Cancer Development and Paves the Way for New Klotho-Based Therapy

Klotho; Càncer de pàncrees; Supressor del tumorKlotho; Cáncer de páncreas; Supresor de tumorKlotho; Pancreatic cancer; Tumor suppressorKlotho is an anti-aging transmembrane protein, which can be shed and can function as a hormone. Accumulating data indicate that klotho is a tumor suppressor in a wide array of malignancies, and designate the subdomain KL1 as the active region of the protein towards this activity. We aimed to study the role of klotho as a tumor suppressor in pancreatic ductal adenocarcinoma (PDAC). Bioinformatics analyses of The Cancer Genome Atlas (TCGA) datasets revealed a correlation between the survival of PDAC patients, levels of klotho expression, and DNA methylation, and demonstrated a unique hypermethylation pattern of klotho in pancreatic tumors. The in vivo effects of klotho and KL1 were examined using three mouse models. Employing a novel genetic model, combining pancreatic klotho knockdown with a mutation in Kras, the lack of klotho contributed to PDAC generation and decreased mousece survival. In a xenograft model, administration of viral particles carrying sKL, a spliced klotho isoform containing the KL1 domain, inhibited pancreatic tumors. Lastly, treatment with soluble sKL prolonged survival of Pdx1-Cre; KrasG12D/+;Trp53R172H/+ (KPC) mice, a model known to recapitulate human PDAC. In conclusion, this study provides evidence that klotho is a tumor suppressor in PDAC. Furthermore, these data suggest that the levels of klotho expression and DNA methylation could have prognostic value in PDAC patients, and that administration of exogenous sKL may serve as a novel therapeutic strategy to treat PDAC.This project was funded by the The Sami and Tova Sagol Foundation for the Study of Aging, the Margaret Stultz foundation for Pancreatic Cancer Research, the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Ministerio de Ciencia e Innovación ‘Proyectos I+D+I 2019, to M.C., (grant number PID2019-104034RB-I00) and by the TASMC excellence fund. to I.W

Neutrinos From Individual Gamma-Ray Bursts in the BATSE Catalog

We calculate the neutrino emission from individual gamma-ray bursts observed by the BATSE detector on the Compton Gamma-Ray Observatory. Neutrinos are produced by photoproduction of pions when protons interact with photons in the region where the kinetic energy of the relativistic fireball is dissipated allowing the acceleration of electrons and protons. We also consider models where neutrinos are predominantly produced on the radiation surrounding the newly formed black hole. From the observed redshift and photon flux of each individual burst, we compute the neutrino flux in a variety of models based on the assumption that equal kinetic energy is dissipated into electrons and protons. Where not measured, the redshift is estimated by other methods. Unlike previous calculations of the universal diffuse neutrino flux produced by all gamma-ray bursts, the individual fluxes (compiled at http://www.arcetri.astro.it/~dafne/grb/) can be directly compared with coincident observations by the AMANDA telescope at the South Pole. Because of its large statistics, our predictions are likely to be representative for future observations with larger neutrino telescopes.Comment: 49 pages, 7 figures. Accepted for publication in Astroparticle Physic

Immune cell C/EBPβ deficiency is associated with hepatic mononuclear defects and spontaneous hepatitis but not steatohepatitis induced liver fibrosis

BACKGROUND: CCAAT/enhancer-binding protein ß (C/EBPß) is a transcription factor known to be involved in macrophage differentiation and function, steatohepatitis and liver fibrosis. METHODS: Immune restricted C/EBPß deficient and control mice were investigated in steady-state and in the CDA-HFD steatohepatitis model. Mice were assessed for weight change, liver biochemical profile, histology and hepatic phagocytes composition. RESULTS: Flow cytometry analysis of hepatic nonparenchymal cells revealed reduced numbers of hepatic monocytes and Kupffer cells and an increase in hepatic MHC class II positive myeloid cells in immune cells restricted C/EBPß deficient mice. Immune-restricted C/EBPß deficiency resulted in decreased weight gain and appearance of mild spontaneous liver inflammation. Nevertheless, In the CDA-HFD steatohepatitis model, immune restricted C/EBPß deficient and proficient mice exhibit similar grade of hepatic steatosis, liver enzymes levels and fibrosis stage. CONCLUSIONS: Immune-restricted C/EBPß deficiency leads to significant alteration in hepatic mononuclear phagocytes composition associated with spontaneous mild hepatitis. Steatohepatitis associated fibrosis is not dependent on C/EBPß expression by immune cells

Infection by a foliar endophyte elicits novel arabidopside-based plant defence reactions in its host, Cirsium arvense

Endophytic fungi live asymptomatically within plants. They are usually regarded as non-pathogenic or even mutualistic, but whether plants respond antagonistically to their presence remains unclear, particularly in the little-studied associations between endophytes and nong-raminoid herbaceous plants. We investigated the effects of the endophyte Chaetomium cochlioides on leaf chemistry in Cirsium arvense. Plants were sprayed with spores; leaf material from both subsequent new growth and the sprayed leaves was analysed 2 wk later. Infection frequency was 91% and63% for sprayed and new growth, respectively, indicating that C. cochlioides rapidly infects new foliage. Metabolomic analyses revealed marked changes in leaf chemistry with infection, especially in new growth. Changes in several novel oxylipin metabolites were detected, including arabi-dopsides reported here for the first time in a plant species other than Arabidopsis thaliana,and a jasmonate-containing galactolipid. The production of these metabolites in response to endophyte presence, particularly in newly infected foliage, suggests that endophytes elicit similar chemical responses in plants to those usually produced following wounding, herbivory and pathogen invasion. Whether en-dophytes benefit their hosts may depend on a complex series of chemically mediated interactions between the plant, the endophyte, other microbial colonists and natural enemies

Mean first-passage time of surface-mediated diffusion in spherical domains

We present an exact calculation of the mean first-passage time to a target on the surface of a 2D or 3D spherical domain, for a molecule alternating phases of surface diffusion on the domain boundary and phases of bulk diffusion. The presented approach is based on an integral equation which can be solved analytically. Numerically validated approximation schemes, which provide more tractable expressions of the mean first-passage time are also proposed. In the framework of this minimal model of surface-mediated reactions, we show analytically that the mean reaction time can be minimized as a function of the desorption rate from the surface.Comment: to appear in J. Stat. Phy

Incidência do míldio em cebola sob adubação mineral e orgânica.

Analisou-se a relação entre adubação mineral e orgânica sobre a incidência de míldio (Peronospora destructor) em cebola (Allium cepa). O trabalho constituiu-se de dois experimentos localizados em Ituporanga, conduzidos entre agosto e dezembro de 1998. O experimento 1, com fontes orgânicas, constou dos tratamentos: esterco de suínos, esterco de aves, composto, esterco de peru e húmus, na dosagem de 75 kg/ha de N; esterco de suínos, na dosagem de 37,5 kg/ha de N; adubação mineral, 30-120-60 kg/ha de N-P2O5-K2O; 60-240-120 kg/ha de N-P2O5-K2O e testemunha sem adubação. O experimento 2 constou dos tratamentos: fontes minerais, 30-120-60 kg/ha de N-P2O5-K2O; 90-360-180 kg/ha de N-P2O5-K2O; 75 kg/ha de N; 225 kg/ha de N; 80 kg/ha de P2O5; 240 kg/ha de P2O5; 60 kg/ha de K2O; 180 kg/ha de K2O; esterco de suínos + fosfato natural, em três combinações, 7,9+0,1, 15,7+0,2 e 47,2+0,6 t/ha, respectivamente; testemunha sem adubação. Não houve diferença entre as fontes mineral e orgânica sobre a incidência de míldio. A relação entre nutrientes e doença foi variável entre datas de amostragem e distinta para fontes minerais e orgânicas