plasmodium phylogenetic profile an assessment of a predictive tool for protein protein interactions

Motivations. Prediction of protein-protein interactions (PPIs) is a crucial goal for bioinformatics and the increasing availability of sequenced genomes support this challenge. One of the computational tools mostly used for this aim is the phylogenetic profiling, based on the co-conserved proteins identification by local alignments. The master idea is that co-evolving proteins share the same phylogenetic profile and can be grouped functionally. The field of parasite biology received a powerful improvement from post-genomics data. Several approaches have been utilized to predict PPIs for Plasmodium falciparum, including phylogenetic profiling. In contrast, no information about this is available in the case of Plasmodium berghei, even though for this parasite a huge amount of data is now available especially for mutant phenotypes. Methods. A new strategy has been developed to derive phylogenetic profiling. The critical steps of this strategy are: 1) genomes selection; 2) global vs local alignments comparison; 3) mutual information vs correlation coefficients calculation. Agreeing with specific criteria, 774 reference organisms, on 1133 available on Eggnog database (January 2012), were included in the study, a global alignment algorithm, over the mostly used local one, was used to perform proteins identification across the genomes, the Mutual Information and the Correlation Coefficient were calculated and the results were compared. Escherichia coli K12 before, suitable for the assessment of the method, and P. berghei later, were used as target organisms. Results. This analysis offers a new bioinformatical strategy to derive phylogenetic profile of an organism, highlighting on guidelines for the genomes selection, on the performance of different alignment algorithms and mathematical procedures. Moreover, strongly improve the knowledge about P. berghei and offers a new tool for evolution understanding and functional grouping of the proteins of this important biological model

Meristematic connectome: A cellular coordinator of plant responses to environmental signals?

Mechanical stress in tree roots induces the production of reaction wood (RW) and the formation of new branch roots, both functioning to avoid anchorage failure and limb damage. The vascular cambium (VC) is the factor responsible for the onset of these responses as shown by their occurrence when all primary tissues and the root tips are removed. The data presented confirm that the VC is able to evaluate both the direction and magnitude of the mechanical forces experienced before coordinating the most fitting responses along the root axis whenever and wherever these are necessary. The coordination of these responses requires intense crosstalk between meristematic cells of the VC which may be very distant from the place where the mechanical stress is first detected. Signaling could be facilitated through plasmodesmata between meristematic cells. The mechanism of RW production also seems to be well conserved in the stem and this fact suggests that the VC could behave as a single structure spread along the plant body axis as a means to control the relationship between the plant and its environment. The observation that there are numerous morphological and functional similarities between different meristems and that some important regulatory mechanisms of meristem activity, such as homeostasis, are common to several meristems, supports the hypothesis that not only the VC but all apical, primary and secondary meristems present in the plant body behave as a single interconnected structure. We propose to name this structure \u201cmeristematic connectome\u201d given the possibility that the sequence of meristems from root apex to shoot apex could represent a pluricellular network that facilitates long-distance signaling in the plant body. The possibility that the \u201cmeristematic connectome\u201d could act as a single structure active in adjusting the plant body to its surrounding environment throughout the life of a plant is now proposed

NGFS Climate Scenario Database: Technical Documentation V2.2

This document provides technical information on the two datasets behind the NGFS scenarios. It is intended to answer technical questions for those who want to perform analyses on the datasets themselves. It is an update of the Technical Documentation published in June 2020 alongside the first set of NGFS Scenarios. It is therefore aligned with the second set of NGFS Scenarios, released in June 2021

AAV Exploits Subcellular Stress Associated with Inflammation, Endoplasmic Reticulum Expansion, and Misfolded Proteins in Models of Cystic Fibrosis

Barriers to infection act at multiple levels to prevent viruses, bacteria, and parasites from commandeering host cells for their own purposes. An intriguing hypothesis is that if a cell experiences stress, such as that elicited by inflammation, endoplasmic reticulum (ER) expansion, or misfolded proteins, then subcellular barriers will be less effective at preventing viral infection. Here we have used models of cystic fibrosis (CF) to test whether subcellular stress increases susceptibility to adeno-associated virus (AAV) infection. In human airway epithelium cultured at an air/liquid interface, physiological conditions of subcellular stress and ER expansion were mimicked using supernatant from mucopurulent material derived from CF lungs. Using this inflammatory stimulus to recapitulate stress found in diseased airways, we demonstrated that AAV infection was significantly enhanced. Since over 90% of CF cases are associated with a misfolded variant of Cystic Fibrosis Transmembrane Conductance Regulator (ΔF508-CFTR), we then explored whether the presence of misfolded proteins could independently increase susceptibility to AAV infection. In these models, AAV was an order of magnitude more efficient at transducing cells expressing ΔF508-CFTR than in cells expressing wild-type CFTR. Rescue of misfolded ΔF508-CFTR under low temperature conditions restored viral transduction efficiency to that demonstrated in controls, suggesting effects related to protein misfolding were responsible for increasing susceptibility to infection. By testing other CFTR mutants, G551D, D572N, and 1410X, we have shown this phenomenon is common to other misfolded proteins and not related to loss of CFTR activity. The presence of misfolded proteins did not affect cell surface attachment of virus or influence expression levels from promoter transgene cassettes in plasmid transfection studies, indicating exploitation occurs at the level of virion trafficking or processing. Thus, we surmised that factors enlisted to process misfolded proteins such as ΔF508-CFTR in the secretory pathway also act to restrict viral infection. In line with this hypothesis, we found that AAV trafficked to the microtubule organizing center and localized near Golgi/ER transport proteins. Moreover, AAV infection efficiency could be modulated with siRNA-mediated knockdown of proteins involved in processing ΔF508-CFTR or sorting retrograde cargo from the Golgi and ER (calnexin, KDEL-R, β-COP, and PSMB3). In summary, our data support a model where AAV exploits a compromised secretory system and, importantly, underscore the gravity with which a stressed subcellular environment, under internal or external insults, can impact infection efficiency

Transfection of IL-10 expression vectors into endothelial cultures attenuates α4β7-dependent lymphocyte adhesion mediated by MAdCAM-1

BACKGROUND: Enhanced expression of MAdCAM-1 (mucosal addressin cell adhesion molecule-1) is associated with the onset and progression of inflammatory bowel disease. The clinical significance of elevated MAdCAM-1 expression is supported by studies showing that immunoneutralization of MAdCAM-1, or its ligands reduce inflammation and mucosal damage in models of colitis. Interleukin-10 (IL-10) is an endogenous anti-inflammatory and immunomodulatory cytokine that has been shown to prevent inflammation and injury in several animal studies, however clinical IL-10 treatment remains insufficient because of difficulties in the route of IL-10 administration and its biological half-life. Here, we examined the ability of introducing an IL-10 expression vector into endothelial cultures to reduce responses to a proinflammatory cytokine, TNF-α METHODS: A human IL-10 expression vector was transfected into high endothelial venular ('HEV') cells (SVEC4-10); we then examined TNF-α induced lymphocyte adhesion to lymphatic endothelial cells and TNF-α induced expression of MAdCAM-1 and compared these responses to control monolayers. RESULTS: Transfection of the IL-10 vector into endothelial cultures significantly reduced TNF-α induced, MAdCAM-1 dependent lymphocyte adhesion (compared to non-transfected cells). IL-10 transfected endothelial cells expressed less than half (46 ± 6.6%) of the MAdCAM-1 induced by TNF-α (set as 100%) in non-transfected (control) cells. CONCLUSION: Our results suggest that gene therapy of the gut microvasculature with IL-10 vectors may be useful in the clinical treatment of IBD

Regulation of pH During Amelogenesis

During amelogenesis, extracellular matrix proteins interact with growing hydroxyapatite crystals to create one of the most architecturally complex biological tissues. The process of enamel formation is a unique biomineralizing system characterized first by an increase in crystallite length during the secretory phase of amelogenesis, followed by a vast increase in crystallite width and thickness in the later maturation phase when organic complexes are enzymatically removed. Crystal growth is modulated by changes in the pH of the enamel microenvironment that is critical for proper enamel biomineralization. Whereas the genetic bases for most abnormal enamel phenotypes (amelogenesis imperfecta) are generally associated with mutations to enamel matrix specific genes, mutations to genes involved in pH regulation may result in severely affected enamel structure, highlighting the importance of pH regulation for normal enamel development. This review summarizes the intra- and extracellular mechanisms employed by the enamel-forming cells, ameloblasts, to maintain pH homeostasis and, also, discusses the enamel phenotypes associated with disruptions to genes involved in pH regulation