A genetic and spatial Bayesian analysis of mastitis resistance

A nationwide health card recording system for dairy cattle was introduced in Norway in 1975 (the Norwegian Cattle Health Services). The data base holds information on mastitis occurrences on an individual cow basis. A reduction in mastitis frequency across the population is desired, and for this purpose risk factors are investigated. In this paper a Bayesian proportional hazards model is used for modelling the time to first veterinary treatment of clinical mastitis, including both genetic and environmental covariates. Sire effects were modelled as shared random components, and veterinary district was included as an environmental effect with prior spatial smoothing. A non-informative smoothing prior was assumed for the baseline hazard, and Markov chain Monte Carlo methods (MCMC) were used for inference. We propose a new measure of quality for sires, in terms of their posterior probability of being among the, say 10% best sires. The probability is an easily interpretable measure that can be directly used to rank sires. Estimating these complex probabilities is straightforward in an MCMC setting. The results indicate considerable differences between sires with regards to their daughters disease resistance. A regional effect was also discovered with the lowest risk of disease in the south-eastern parts of Norway.     

Models for Trypanosoma evansi (surra), its control and economic impact on small-hold livestock owners in the Philippines

Simple demographic and infectious disease models of buffaloes and other domestic hosts for animal trypanosomosis (surra) caused by Trypanosoma evansi were developed. The animal models contained deterministic and stochastic elements and were linked to simulate the benefit of control regimes for surra in village domestic animal populations in Mindanao, Philippines. The impact of the disease on host fertility and mortality were key factors in determining the economic losses and net-benefit from the control regimes. If using a high (99%) efficacy drug in surra-moderate to high risk areas, then treating all animals twice each year yielded low prevalence in 2 years; targeted treatment of clinically sick animals, constantly monitored (monthly), required 75% fewer treatments but took longer to reach a low prevalence than treating all animals twice each year. At high drug efficacy both of these treatment strategies increased the benefit over untreated animals by 81%. If drug efficacy declined then the benefit obtained from twice yearly treatment of all animals declined rapidly compared with regular monitoring and targeting treatment to clinically sick animals. The current control regimen applied in the Philippines of annual sero-testing for surra and only treating sero-positive animals provided the lowest net-benefit of all the control options simulated and would not be regarded as effective control. The total net-benefit from effective surra control for a typical village in a moderate/high risk area was 7.9 million pesos per annum (US $158,000). The value added to buffaloes, cattle, horses, goats/sheep and pigs as a result of this control was US $88, $84, $151, $7, $114 per animal/year, respectively.     

Discovery of new low-molecular-weight p53–Mdmx disruptors and their anti-cancer activities

Although several p53–Mdm2-binding disruptors have been identified to date, few studies have been published on p53–Mdmx-interaction inhibitors. In the present study, we demonstrated that o-aminothiophenol derivatives with molecular weights of 200–300 selectively inhibited the p53–Mdmx interaction. S-2-Isobutyramidophenyl 2-methylpropanethioate (K-178) (1c) activated p53, up-regulated the expression of its downstream genes such as p21 and Mdm2, and preferentially inhibited the growth of cancer cells with wild-type p53 over those with mutant p53. Furthermore, we found that the S-isobutyryl-deprotected forms 1b and 3b of 1c and S-2-benzamidophenyl 2-methylpropanethioate (K-181) (3c) preferentially inhibited the p53–Mdmx interaction over the p53–Mdm2 interaction, respectively, by using a Flag-p53 and glutathione S-transferase (GST)-fused protein complex (Mdm2, Mdmx, DAPK1, or PPID). In addition, the interaction of p53 with Mdmx was lost by replacing a sulfur atom with an oxygen atom in 1b and 1c. These results suggest that sulfides such as 1b, 3b, 4b, and 5b interfere with the binding of p53–Mdmx, resulting in the dissociation of the two proteins. Furthermore, the results of oral administration experiments using xenografts in nude mice indicated that 1c reduced the volume of tumor masses to 49.0% and 36.6% that of the control at 100 mg/kg and 150 mg/kg, respectively, in 40 days.     

Correlation between the parameters of contingent negative variation and characteristics of variational pulsometry in Parkinsonian patients

In patients suffering from Parkinson's disease (PD), we analyzed correlations between the parameters of contingent negative variation (CNV) and data of variational pulsometry (according to the measurements of R-R ECG intervals). Studies were carried out on 35 patients (group PD), 49 to 74 years old, with the stage of disease of 1.5 to 3.0 according to the Hoehn-Yahr international classification. In the course of CNV recording (i.e., in the state of a certain functional loading), we observed significant negative correlations between the integral magnitude (area) of this potential and indices of variational pulsometry (RMSSD, SDNN, C. var, and HF) that characterize the intensity of parasympathetic (respiratory) influences on the cardiovascular system. In the control group, such correlations were absent. We found significant correlations between the autonomic balance, CNV magnitude, and stage of PD reflecting the level of generalization of the pathological process. In the subgroup of patients with the PD stage 1.5 to 2.0, significant changes in the mean values of indices of parasympathetic influences during recording of the CNV were not observed, while in another subgroup (the PD stage 2.5 to 3.0), these values increased significantly (P < 0.05 and P < 0.01). If the estimates of the PD stage were low, the CNV area demonstrated greater values (P < 0.01). The disturbance of coordination of muscle-to-muscle interactions in the PD group is, probably, an important factor responsible for parasympathetic dysregulation and suppression of the CNV generation. We found positive correlation between the intensity of parasympathetic influences in the course of CNV recording and the level of postural disorders (r = 0.37, P < 0.05). On the contrary, the CNV magnitude demonstrated a negative correlation with the intensity of these disorders (r = −0.36, P < 0.05), as well as with the level of postural instability (r = −0.55, P < 0.001). We hypothesize that alterations of the autonomic balance and the activity of those cerebral structures, which are responsible for the motor readiness, result, to a significant extent, from weakening of the activity of the noradrenergic system due to degenerative processes developing in cells of the locus coeruleus. The impairment of the latter structure, together with degeneration of neurons of the substantia nigra and a decrease in the level of nigro-striatal dopamine, underlies the pathomorphological pattern of PD. Neirofiziologiya/Neurophysiology, Vol. 40, No. 3, pp. 242–253, May–June, 2008.     

CircRNA has_circ_0006427 suppresses the progression of lung adenocarcinoma by regulating miR-6783–3p/DKK1 axis and inactivating Wnt/β-catenin signaling pathway

Recently, circular RNAs (circRNAs) are identified as a novel class of noncoding RNAs playing important roles in human malignant tumors. However, the regulatory function of circRNA in lung adenocarcinoma (LUAD) is still largely unknown. Present study aimed to explore the role of circ_0006427 in LUAD progression. Firstly, the downregulation of circ_0006427 in LUAD tissues and cell lines was revealed by microarray analysis and qRT-PCR analysis. And we also confirmed the circ_0006427 as a prognostic target in LUAD patients. Functionally, overexpression of circ_0006427 effectively suppressed cell proliferation, migration and invasion. Mechanistically, circ_0006427 was found to be predominantly located in the cytoplasm of LUCA cell, and was further revealed to positively regulate DKK1 in LUAD by sponging miR-6783–3p. KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis and western blot analysis revealed that circ_0006427 inactivated Wnt/β-catenin signaling pathway by upregulating DKK1. At last, rescue assays proved the function of circ_0006427/miR-6783–3p/DKK1 axis in LUAD progression. In conclusion, our study revealed that circ_0006427 suppressed lung adenocarcinoma progression through regulating miR-6783–3p/DKK1 axis.     

Mode of action of a surfactant–polymer formulation to support performance of the entomopathogenic nematode Steinernema carpocapsae for control of diamondback moth larvae (Plutella xylostella)

The use of entomopathogenic nematodes on cabbage leaves against larvae of the diamondback moth (DBM) Plutella xylostella requires the addition of formulation adjuvants to achieve satisfying control. Without adjuvants nematodes settle in the tank mix of backpack sprayers causing uneven distribution. The polymers arabic and guar gum, alginate and xanthan were used in concentrations between 0.05 and 0.3% to retard sedimentation of Steinernema carpocapsae. Arabic gum had no effect, guar gum prevented sedimentation at 0.3% but the effect dropped significantly at lower concentration. At 0.05%, xanthan prevented nematode sedimentation better than alginate. Deposition of nematodes on the leaves was significantly increased by the addition of any of the polymers. Spraying nematodes on leaves with an inclination of 45° without the addition of any formulation resulted in 70% run-off. Adding 0.2% alginate or xanthan reduced the losses to <20%. The use of a surfactant–polymer formulation significantly reduced defoliation by DBM larvae. Visual examinations provided evidence that nematodes are not ingested by DBM larvae. Invasion of S. carpocapsae is an active process via the anus. The function of the formulation is not to prolong nematode survival, but to provide environmental conditions which enable rapid invasion of the nematodes. Nematode performance was improved by selection of the best surfactant in combination with xanthan and by optimisation of the concentrations of the surfactant Rimulgan® and the polymer xanthan. The best control results were achieved with Rimulgan® at 0.3% together with 0.3% xanthan, causing DBM mortality of >90% at 80% relative humidity and >70% at 60%. The formulation lowered the LC₅₀ from 12 to 1 nematode/larva. The viscosity of the surfactant–polymer formulations correlated well with nematode efficacy, prevention of sedimentation and adherence to the leave. This physical parameter can therefore be recommended for improvement of nematode formulations to be used for foliar application against DBM.     

Accurate MS-based Rab10 Phosphorylation Stoichiometry Determination as Readout for LRRK2 Activity in Parkinson's Disease

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Highlights

• •MS-based clinical assay that accurately determines phospho Rab10 occupancy.
• •Stable isotope labeled phosphopeptide injected as a standard with endogenous tryptic phospho Rab peptide for accurate ratio determination.
• •Determination of pRab levels in neutrophils of Parkinson disease patients.
• •Relevance of pRab levels as marker of PD.

     

Sensory Neurons Contacting the Cerebrospinal Fluid Require the Reissner Fiber to Detect Spinal Curvature In Vivo

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Effect of secondary anchor amino acid substitutions on the immunogenic properties of an HLA-A*0201-restricted T cell epitope derived from the Trypanosoma cruzi KMP-11 protein

The TcTLE peptide (TLEEFSAKL) is a CD8⁺ T cell HLA-A*0201-restricted epitope derived from the Trypanosoma cruzi KMP-11 protein that is efficiently processed, presented and recognized by CD8⁺ T cells from chagasic patients. Since the immunogenic properties of wild-type epitopes may be enhanced by suitable substitutions in secondary anchor residues, we have studied the effect of introducing specific mutations at position 3, 6 and 7 of the TcTLE peptide. Mutations (E3L, S6V and A7F) were chosen on the basis of in silico predictions and in vitro assays were performed to determine the TcTLE-modified peptide binding capacity to the HLA-A*0201 molecule. In addition, the functional activity of peptide-specific CD8⁺ T cells in HLA-A2⁺ chagasic patients was also interrogated. In contrast to bioinformatics predictions, the TcTLE-modified peptide was found to have lower binding affinity and stability than the original peptide. Nevertheless, CD8⁺ T cells from chronic chagasic patients recognized the TcTLE-modified peptide producing TNF-α and INF-γ and expressing CD107a/b, though in less extension than the response triggered by the original peptide. Overall, although the amino acids at positions 3, 6 and 7 of TcTLE are critical for the peptide affinity, they have a limited effect on the immunogenic properties of the TcTLE epitope.