Hemodynamic alterations in liver cirrhosis

In cirrhotic patients, portal hypertension is often associated with a hyperdynamic circulatory syndrome, with high cardiac output and reduced systemic vascular resistance and arterial pressure. The hyperdynamic circulatory syndrome is due to arterial vasodilation that mainly occurs in the splanchnic circulation, while vascular resistance in the other circulatory districts is normal or increased, accordingly with the degree of portal hypertension, liver impairment and activation of the renin-aldosterone and sympathetic nervous system. The mechanism(s) leading to splanchnic vasodilation is unclear. A favored hypothesis translocation of intestinal bacteria and/or some their products, such as endotoxin, into the interstitial space in the splanchnic organs results in the local release of vasodilating factors such as nitric oxide, carbon monoxide and others.     

Spectrometric studies on stability of tenuazonic acid (TeA) solution in organic solvents

The stability of tenuazonic acid solution at different temperatures and storage times was studied using methanol, methanol-water (8:2 v/v), benzene and benzene-acetonitrile (98:2 v/v) as solvents. Solutions were analysed by a spectrometric method TeA U.V.-spectrum was recorded. Results indicated that the optimum temperature for long-time storage period of tenuazonic acid solution in any solvent assayed is -20°C. Benzene and benzene-acetonitrile (98:2 v/v) could be advised to make tenuazonic acid solution which will be stored less than 2 months at 4°C. Methanol and methanolwater (8:2 v/v) are not recommended because a low stability of TeA solution in this solvents.     

QSAR study for a novel series of ortho monosubstituted phenoxy analogues of alpha1-adrenoceptor antagonist WB4101

A number of (S)- and (R)-2-[(2-phenoxyethyl)aminomethyl]-1,4-benzodioxanes unsubstituted or ortho monosubstituted at the phenoxy moiety were synthesized and tested in binding assays on the alpha(1a)-AR, alpha(1b)-AR, alpha(1d)-AR and the 5-HT(1A) receptor. The affinity values of the new compounds 1-16 were compared with those of the enantiomers of the 2,6-dimethoxyphenoxy analogue, the well-known alpha(1) antagonist WB4101, finding that the unsubstituted derivative (S)-1 and the o-methyl, the o-t-butyl, the o-fluoro and the o-methoxy derivatives, (S)-2, (S)-4, (S)-8 and (S)-16, respectively, display a significantly specific 5-HT(1A) affinity, very close, with the exception of (S)-4, to the almost nanomolar one of (S)-WB4101. Otherwise, sensible affinity decreases were recorded for the three alpha(1)-AR subtypes. A classical quantitative structure-activity relationship (Hansch) analysis was successfully applied to compounds (S)-1 to (S)-16 and (S)-WB4101 to rationalize such binding data.     

Is the Mg2+-ATP-dependent proton pumping activity of the synaptic vesicles a factor involved in the cerebral hypoxia?

The changes in the Mg²⁺-dependent V-type ATPase activity and the Mg²⁺-ATP-dependent H⁺ pumping activity of the synaptic vesicles from the cerebral cortex of rats submitted to intermittent chronic (4 weeks) mild or severe hypoxia were evaluated. The adaptation to the chronic severe hypoxia increases both the ATPase and the H⁺ pumping activities which are inhibited by NEM with an exponential relationship between the IC₅₀ values and the in vivo O₂ concentration. The Mg²⁺-dependent increase in H⁺ pumping activity of synaptic vesicles from the rats subjected to in vivo chronic hypoxia may be antagonized by nigericin (dissipating ΔpH) and by FCCP (dissipating ΔpH and Δ_ΨSV). In contrast, valinomycin (dissipating the Δ_ΨSV and facilitating an enhancement in ΔpH) increases in vitro the H⁺ pumping activity that is inhibited by the addition of high concentration of K gluconate (reducing the rate of K⁺ efflux). The preincubation of vesicles from hypoxic rats with FCCP, but not with nigericin, inhibits the valinomycin-increased H⁺ pumping activity.l-glutamate increases the H⁺ pumping activity in synaptic vesicles from the cerebral cortex of chronic hypoxic rats, whereas other amino acids (i.e.,l-aspartate andl-homocysteate) and glutamate analogs (i.e., quisqualate and ibotenate) are ineffective. The adaptation to both chronic intermittent severe hypoxia and in vivo treatment with posatireline causes a decrease in the Mg²⁺-ATPase activity consistent with the decrease in the H⁺ pumping one of the synaptic vesicles. The addition of nigericin into incubation medium magnifies the decrease in the H⁺ pumping activity, while the addition of FCCP is ineffective, suggesting that the treatment with posatireline interferes with the Δ_ΨSV component in the of the synaptic vesicles from rats submitted to chronic hypoxia. The results of the in vivo and in vitro experiments suggest that in the synaptic vesicles from hypoxic rats the Δ_ΨSV component in may be most effective in increasing the Mg²⁺-ATP-dependent H⁺ pumping activity.     

Testing different 3D techniques using geometric morphometrics: Implications for cranial fluctuating asymmetry in humans

This study aimed to test the performance of 3D digitizer, CT scanner, and surface scanner in detecting cranial fluctuating asymmetry. Sets of 32 landmarks (6 in the midline and 13 bilateral) were acquired from 14 archeological crania using a 3D digitizer, and from 3D models generated from a CT scanner and surface scanner using Viewbox 4. Levels of shape variation were analyzed in MorphoJ using Procrustes analysis of variance and Principal component analysis. Intra-observer error accounted for 1.7%, 1.8%, and 4.5% of total shape variation for 3D digitizer, CT scanner, and surface scanner respectively. Fluctuating asymmetry accounted for 15%–16% of total shape variation. Variation between techniques accounted for 18% of total shape variation. We found a higher level of missing landmarks in our surface scan data than for both 3D digitizer and CT scanner data, and both 3D model-based techniques sometimes obscured taphonomic damage. All three 3D techniques are appropriate for measuring cranial fluctuating asymmetry. We advise against combining data collected with different techniques.     

Characterization of Nine Novel Mutations in the CD40 Ligand Gene in Patients with X-Linked Hyper IgM Syndrome of Various Ancestry

X-linked immunodeficiency with hyper-IgM (HIGMX-1) is a rare disorder caused by defective expression of the CD40 ligand (CD40L) by activated T lymphocytes, resulting in inefficient T-B cell cooperation and failure of B cells to undergo immunoglobulin isotype switch. In the present work, we describe nine patients of various ancestry who bear different mutations in the X chromosome–specific CD40L gene. Two of the mutations were nonsense mutations, one each resulting in premature stop codons at amino acid residues 39 and 140. Three patients had single point missense mutations, one each at codons 126, 140, and 144. Another patient had a 4-bp genomic deletion in exon 2, resulting in a frameshift and premature termination. Three patients showed insertions, one each of 1, 2, and 4 nt, probably because of polymerase slippage, resulting in frameshift mutation and premature termination. Overall, these observations confirm the heterogeneity of mutations in HIGMX-1. However, the identification of two patients whose mutation involves codon 140 (previously shown to be altered in two other unrelated subjects) suggests that this may be a hotspot of mutation in HIGMX-1. In two additional patients with clinical and immunological features indistinguishable from canonical HIGMX-1, no mutation was detected in the coding sequence, in the 5' flanking region, or in the 3' UTR.     

mTORC1 stimulates cell growth through SAM synthesis and m6A mRNA-dependent control of protein synthesis

1. Download : Download high-res image (109KB)
2. Download : Download full-size image

     

Whole-genome sequence analysis reveals differences in population management and selection of European low-input pig breeds

Background

A major concern in conservation genetics is to maintain the genetic diversity of populations. Genetic variation in livestock species is threatened by the progressive marginalisation of local breeds in benefit of high-output pigs worldwide. We used high-density SNP and re-sequencing data to assess genetic diversity of local pig breeds from Europe. In addition, we re-sequenced pigs from commercial breeds to identify potential candidate mutations responsible for phenotypic divergence among these groups of breeds.

Results

Our results point out some local breeds with low genetic diversity, whose genome shows a high proportion of regions of homozygosis (>50%) and that harbour a large number of potentially damaging mutations. We also observed a high correlation between genetic diversity estimates using high-density SNP data and Next Generation Sequencing data (r = 0.96 at individual level). The study of non-synonymous SNPs that were fixed in commercial breeds and also in any local breed, but with different allele, revealed 99 non-synonymous SNPs affecting 65 genes. Candidate mutations that may underlie differences in the adaptation to the environment were exemplified by the genes AZGP1 and TAS2R40. We also observed that highly productive breeds may have lost advantageous genotypes within genes involve in immune response – e.g. IL12RB2 and STAB1–, probably as a result of strong artificial in the intensive production systems in pig.

Conclusions

The high correlation between genetic diversity computed with the 60K SNP and whole genome re-sequence data indicates that the Porcine 60K SNP Beadchip provides reliable estimates of genomic diversity in European pig populations despite the expected bias. Moreover, this analysis gave insights for strategies to the genetic characterization of local breeds. The comparison between re-sequenced local pigs and re-sequenced commercial pigs made it possible to report candidate mutations to be responsible for phenotypic divergence among those groups of breeds. This study highlights the importance of low input breeds as a valuable genetic reservoir for the pig production industry. However, the high levels of ROHs, inbreeding and potentially damaging mutations emphasize the importance of the genetic characterization of local breeds to preserve their genomic variability.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-601) contains supplementary material, which is available to authorized users.