Tridimensional model structure and patterns of molecular evolution of Pepino mosaic virus TGBp3 protein

<p>Abstract</p> <p>Background</p> <p><it>Pepino mosaic virus </it>(PepMV) is considered one of the most dangerous pathogens infecting tomatoes worldwide. The virus is highly diverse and four distinct genotypes, as well as inter-strain recombinants, have already been described. The isolates display a wide range on symptoms on infected plant species, ranging from mild mosaic to severe necrosis. However, little is known about the mechanisms and pattern of PepMV molecular evolution and about the role of individual proteins in host-pathogen interactions.</p> <p>Methods</p> <p>The nucleotide sequences of the triple gene block 3 (TGB3) from PepMV isolates varying in symptomatology and geographic origin have been analyzed. The modes and patterns of molecular evolution of the TGBp3 protein were investigated by evaluating the selective constraints to which particular amino acid residues have been subjected during the course of diversification. The tridimensional structure of TGBp3 protein has been modeled <it>de novo </it>using the Rosetta algorithm. The correlation between symptoms development and location of specific amino acids residues was analyzed.</p> <p>Results</p> <p>The results have shown that TGBp3 has been evolving mainly under the action of purifying selection operating on several amino acid sites, thus highlighting its functional role during PepMV infection. Interestingly, amino acid 67, which has been previously shown to be a necrosis determinant, was found to be under positive selection.</p> <p>Conclusions</p> <p>Identification of diverse selection events in TGB3p3 will help unraveling its biological functions and is essential to an understanding of the evolutionary constraints exerted on the <it>Potexvirus </it>genome. The estimated tridimensional structure of TGBp3 will serve as a platform for further sequence, structural and function analysis and will stimulate new experimental advances.</p

Human resources for health care delivery in Tanzania: a multifaceted problem

BACKGROUND: Recent years have seen an unprecedented increase in funds for procurement of health commodities in developing countries. A major challenge now is the efficient delivery of commodities and services to improve population health. With this in mind, we documented staffing levels and productivity in peripheral health facilities in southern Tanzania. METHOD: A health facility survey was conducted to collect data on staff employed, their main tasks, availability on the day of the survey, reasons for absenteeism, and experience of supervisory visits from District Health Teams. In-depth interview with health workers was done to explore their perception of work load. A time and motion study of nurses in the Reproductive and Child Health (RCH) clinics documented their time use by task. RESULTS: We found that only 14% (122/854) of the recommended number of nurses and 20% (90/441) of the clinical staff had been employed at the facilities. Furthermore, 44% of clinical staff was not available on the day of the survey. Various reasons were given for this. Amongst the clinical staff, 38% were absent because of attendance to seminar sessions, 8% because of long-training, 25% were on official travel and 20% were on leave. RCH clinic nurses were present for 7 hours a day, but only worked productively for 57% of time present at facility. Almost two-third of facilities had received less than 3 visits from district health teams during the 6 months preceding the survey. CONCLUSION: This study documented inadequate staffing of health facilities, a high degree of absenteeism, low productivity of the staff who were present and inadequate supervision in peripheral Tanzanian health facilities. The implications of these findings are discussed in the context of decentralized health care in Tanzania

Cysteinyl leukotrienes: multi-functional mediators in allergic rhinitis

Cysteinyl leukotrienes (CysLTs) are a family of inflammatory lipid mediators synthesized from arachidonic acid by a variety of cells, including mast cells, eosinophils, basophils, and macrophages. This article reviews the data for the role of CysLTs as multi-functional mediators in allergic rhinitis (AR). We review the evidence that: (1) CysLTs are released from inflammatory cells that participate in AR, (2) receptors for CysLTs are located in nasal tissue, (3) CysLTs are increased in patients with AR and are released following allergen exposure, (4) administration of CysLTs reproduces the symptoms of AR, (5) CysLTs play roles in the maturation, as well as tissue recruitment, of inflammatory cells, and (6) a complex inter-regulation between CysLTs and a variety of other inflammatory mediators exists.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75432/1/j.1365-2222.2006.02498.x.pd

Missense mutation of Brain Derived Neurotrophic Factor (BDNF) alters neurocognitive performance in patients with mild traumatic brain injury: a longitudinal study

The predictability of neurocognitive outcomes in patients with traumatic brain injury is not straightforward. The extent and nature of recovery in patients with mild traumatic brain injury (mTBI) are usually heterogeneous and not substantially explained by the commonly known demographic and injury-related prognostic factors despite having sustained similar injuries or injury severity. Hence, this study evaluated the effects and association of the Brain Derived Neurotrophic Factor (BDNF) missense mutations in relation to neurocognitive performance among patients with mTBI. 48 patients with mTBI were prospectively recruited and MRI scans of the brain were performed within an average 10.1 (SD 4.2) hours post trauma with assessment of their neuropsychological performance post full Glasgow Coma Scale (GCS) recovery. Neurocognitive assessments were repeated again at 6 months follow-up. The paired t-test, Cohen’s d effect size and repeated measure ANOVA were performed to delineate statistically significant differences between the groups [wildtype G allele (Val homozygotes) vs. minor A allele (Met carriers)] and their neuropsychological performance across the time point (T1 = baseline/ admission vs. T2 = 6th month follow-up). Minor A allele carriers in this study generally performed more poorly on neuropsychological testing in comparison wildtype G allele group at both time points. Significant mean differences were observed among the wildtype group in the domains of memory (M = -11.44, SD = 10.0, p = .01, d = 1.22), executive function (M = -11.56, SD = 11.7, p = .02, d = 1.05) and overall performance (M = -6.89 SD = 5.3, p = .00, d = 1.39), while the minor A allele carriers showed significant mean differences in the domains of attention (M = -11.0, SD = 13.1, p = .00, d = .86) and overall cognitive performance (M = -5.25, SD = 8.1, p = .01, d = .66).The minor A allele carriers in comparison to the wildtype G allele group, showed considerably lower scores at admission and remained impaired in most domains across the timepoints, although delayed signs of recovery were noted to be significant in the domains attention and overall cognition. In conclusion, the current study has demonstrated the role of the BDNF rs6265 Val66Met polymorphism in influencing specific neurocognitive outcomes in patients with mTBI. Findings were more detrimentally profound among Met allele carriers

Catalytic residues in hydrolases: analysis of methods designed for ligand-binding site prediction

The comparison of eight tools applicable to ligand-binding site prediction is presented. The methods examined cover three types of approaches: the geometrical (CASTp, PASS, Pocket-Finder), the physicochemical (Q-SiteFinder, FOD) and the knowledge-based (ConSurf, SuMo, WebFEATURE). The accuracy of predictions was measured in reference to the catalytic residues documented in the Catalytic Site Atlas. The test was performed on a set comprising selected chains of hydrolases. The results were analysed with regard to size, polarity, secondary structure, accessible solvent area of predicted sites as well as parameters commonly used in machine learning (F-measure, MCC). The relative accuracies of predictions are presented in the ROC space, allowing determination of the optimal methods by means of the ROC convex hull. Additionally the minimum expected cost analysis was performed. Both advantages and disadvantages of the eight methods are presented. Characterization of protein chains in respect to the level of difficulty in the active site prediction is introduced. The main reasons for failures are discussed. Overall, the best performance offers SuMo followed by FOD, while Pocket-Finder is the best method among the geometrical approaches

Nucleases as a barrier to gene silencing in the cotton boll weevil, Anthonomus grandis.

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Cholera- and Anthrax-Like Toxins Are among Several New ADP-Ribosyltransferases

Chelt, a cholera-like toxin from Vibrio cholerae, and Certhrax, an anthrax-like toxin from Bacillus cereus, are among six new bacterial protein toxins we identified and characterized using in silico and cell-based techniques. We also uncovered medically relevant toxins from Mycobacterium avium and Enterococcus faecalis. We found agriculturally relevant toxins in Photorhabdus luminescens and Vibrio splendidus. These toxins belong to the ADP-ribosyltransferase family that has conserved structure despite low sequence identity. Therefore, our search for new toxins combined fold recognition with rules for filtering sequences – including a primary sequence pattern – to reduce reliance on sequence identity and identify toxins using structure. We used computers to build models and analyzed each new toxin to understand features including: structure, secretion, cell entry, activation, NAD+ substrate binding, intracellular target binding and the reaction mechanism. We confirmed activity using a yeast growth test. In this era where an expanding protein structure library complements abundant protein sequence data – and we need high-throughput validation – our approach provides insight into the newest toxin ADP-ribosyltransferases