Mycobacteriumsmegmatis bio¢lm formationand slidingmotility are a¡ected by the serine/threonine protein kinase PknF

Eighteen ‘eukaryotic-like’ serine/threonine kinases are present in the Mycobacterium smegmatis genome. One of them encoded by the ORF 3677 demonstrates high similarity to the Mycobacterium tuberculosis protein kinase PknF. A merodiploid strain was generated, which showed reduced growth associated with irregular cell structure. The merodiploid strain displayed altered colony morphology, defective slidingmotility and biofilm formation. These data indicate a role for PknF in biofilm formation, possibly associated with alterations in glycopeptidolipid composition

Area and Power efficient booth’s Multipliers Based on Non-Redundant Radix-4Signed-Digit Encoding

In this paper, we introduce an architecture of pre-encoded multipliers for Digital Signal Processing applications based on off-line encoding of coefficients. To this extend, the Non-Redundant radix-4 Signed-Digit (NR4SD) encoding technique, which uses the digit values {-1, 0, +1, +2} or {-2,-1,0,+1}, is proposed leading to a multiplier design with less complex partial products implementation. Extensive experimental analysis verifies that the proposed pre-encoded NR4SD multipliers, including the coefficients memory, are more area and power efficient than the conventional Modified Booth scheme

A genetically engineered thermally responsive sustained release curcumin depot to treat neuroinflammation.

Radiculopathy, a painful neuroinflammation that can accompany intervertebral disc herniation, is associated with locally increased levels of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα). Systemic administration of TNF antagonists for radiculopathy in the clinic has shown mixed results, and there is growing interest in the local delivery of anti-inflammatory drugs to treat this pathology as well as similar inflammatory events of peripheral nerve injury. Curcumin, a known antagonist of TNFα in multiple cell types and tissues, was chemically modified and conjugated to a thermally responsive elastin-like polypeptide (ELP) to create an injectable depot for sustained, local delivery of curcumin to treat neuroinflammation. ELPs are biopolymers capable of thermally-triggered in situ depot formation that have been successfully employed as drug carriers and biomaterials in several applications. ELP-curcumin conjugates were shown to display high drug loading, rapidly release curcumin in vitro via degradable carbamate bonds, and retain in vitro bioactivity against TNFα-induced cytotoxicity and monocyte activation with IC50 only two-fold higher than curcumin. When injected proximal to the sciatic nerve in mice via intramuscular (i.m.) injection, ELP-curcumin conjugates underwent a thermally triggered soluble-insoluble phase transition, leading to in situ formation of a depot that released curcumin over 4days post-injection and decreased plasma AUC 7-fold

Diverse Clinical Isolates of Mycobacterium tuberculosis Develop Macrophage-Induced Rifampin Tolerance.

The Mycobacterium tuberculosis lineage 4 strains CDC1551 and H37Rv develop tolerance to multiple antibiotics upon macrophage residence. To determine whether macrophage-induced tolerance is a general feature of clinical M. tuberculosis isolates, we assessed macrophage-induced drug tolerance in strains from lineages 1-3, representing the other predominant M. tuberculosis strains responsible for tuberculosis globally. All 3 lineages developed isoniazid tolerance. While lineage 1, 3, and 4 strains developed rifampin tolerance, lineage 2 Beijing strains did not. Their failure to develop tolerance may be explained by their harboring of a loss-of-function mutation in the Rv1258c efflux pump that is linked to macrophage-induced rifampicin tolerance

Understanding the Role of PknJ in Mycobacterium tuberculosis: Biochemical Characterization and Identification of Novel Substrate Pyruvate Kinase A

Reversible protein phosphorylation is a prevalent signaling mechanism which modulates cellular metabolism in response to changing environmental conditions. In this study, we focus on previously uncharacterized Mycobacterium tuberculosis Ser/Thr protein kinase (STPK) PknJ, a putative transmembrane protein. PknJ is shown to possess autophosphorylation activity and is also found to be capable of carrying out phosphorylation on the artificial substrate myelin basic protein (MyBP). Previous studies have shown that the autophosphorylation activity of M. tuberculosis STPKs is dependent on the conserved residues in the activation loop. However, our results show that apart from the conventional conserved residues, additional residues in the activation loop may also play a crucial role in kinase activation. Further characterization of PknJ reveals that the kinase utilizes unusual ions (Ni2+, Co2+) as cofactors, thus hinting at a novel mechanism for PknJ activation. Additionally, as shown for other STPKs, we observe that PknJ possesses the capability to dimerize. In order to elucidate the signal transduction cascade emanating from PknJ, the M. tuberculosis membrane-associated protein fraction is treated with the active kinase and glycolytic enzyme Pyruvate kinase A (mtPykA) is identified as one of the potential substrates of PknJ. The phospholabel is found to be localized on serine and threonine residue(s), with Ser37 identified as one of the sites of phosphorylation. Since Pyk is known to catalyze the last step of glycolysis, our study shows that the fundamental pathways such as glycolysis can also be governed by STPK-mediated signaling

Identificación del índice de vulnerabilidad territorial a partir de modelos jerárquicos y heurísticos aplicando SOA

Auxiliar de InvestigaciónEn el proyecto se realiza el diseño y desarrollo de 4 servicios web implementando los modelos de toma de decisión (AHP, AHP FUZZY, ELECTRE y PROMETHEE), encargados de procesar datos obtenidos en campo en la primera fase del proyecto que se realizó a través de encuestas, formatos de entrevistas, talleres y metodologías de análisis. Los datos se procesaran de acuerdo al modelo de toma de decisión seleccionado, generando como resultado final un indicador de vulnerabilidad territorial.PregradoIngeniero de Sistema

Integrating Multiple Genetic Detection Methods to Estimate Population Density of Social and Territorial Carnivores

Spatial capture–recapture models can produce unbiased estimates of population density, but sparse detection data often plague studies of social and territorial carnivores. Integrating multiple types of detection data can improve estimation of the spatial scale parameter (σ), activity center locations, and density. Noninvasive genetic sampling is effective for detecting carnivores, but social structure and territoriality could cause differential detectability among population cohorts for different detection methods. Using three observation models, we evaluated the integration of genetic detection data from noninvasive hair and scat sampling of the social and territorial coyote (Canis latrans). Although precision of estimated density was improved, particularly if sharing σ between detection methods was appropriate, posterior probabilities of σ and posterior predictive checks supported different σ for hair and scat observation models. The resulting spatial capture–recapture model described a scenario in which scat‐detected individuals lived on and around scat transects, whereas hair‐detected individuals had larger σ and mostly lived off of the detector array, leaving hair but not scat samples. A more supported interpretation is that individual heterogeneity in baseline detection rates (λ0) was inconsistent between detection methods, such that each method disproportionately detected different population cohorts. These findings can be attributed to the sociality and territoriality of canids: Residents may be more likely to strategically mark territories via defecation (scat deposition), and transients may be more likely to exhibit rubbing (hair deposition) to increase mate attraction. Although this suggests that reliance on only one detection method may underestimate population density, integrating multiple sources of genetic detection data may be problematic for social and territorial carnivores. These data are typically sparse, modeling individual heterogeneity in λ0 and/or σ with sparse data is difficult, and positive bias can be introduced in density estimates if individual heterogeneity in detection parameters that is inconsistent between detection methods is not appropriately modeled. Previous suggestions for assessing parameter consistency of σ between detection methods using Bayesian model selection algorithms could be confounded by individual heterogeneity in λ0 in noninvasive detection data. We demonstrate the usefulness of augmenting those approaches with calibrated posterior predictive checks and plots of the posterior density of activity centers for key individuals

Impact of financial inclusion in low- and middle-income countries: a systematic review of reviews

Financial inclusion programmes seek to increase access to financial services such as credit, savings, insurance and money transfers and so allow poor and low-income households in low- and middle-income countries to enhance their welfare, grasp opportunities, mitigate shocks, and ultimately escape poverty. This systematic review of reviews assesses the evidence on economic, social, behavioural and gender-related outcomes from financial inclusion. It collects and appraises all of the existing meta-studies - that is systematic reviews and meta-analyses - of the impact of financial inclusion. The authors first analyse the strength of the methods used in those meta-studies, then synthesise the findings from those that are of a sufficient quality, and finally, report the implications for policy, programming, practice and further research arising from the evidence. Eleven studies are included in the analysis

Proteins with Complex Architecture as Potential Targets for Drug Design: A Case Study of Mycobacterium tuberculosis

Lengthy co-evolution of Homo sapiens and Mycobacterium tuberculosis, the main causative agent of tuberculosis, resulted in a dramatically successful pathogen species that presents considerable challenge for modern medicine. The continuous and ever increasing appearance of multi-drug resistant mycobacteria necessitates the identification of novel drug targets and drugs with new mechanisms of action. However, further insights are needed to establish automated protocols for target selection based on the available complete genome sequences. In the present study, we perform complete proteome level comparisons between M. tuberculosis, mycobacteria, other prokaryotes and available eukaryotes based on protein domains, local sequence similarities and protein disorder. We show that the enrichment of certain domains in the genome can indicate an important function specific to M. tuberculosis. We identified two families, termed pkn and PE/PPE that stand out in this respect. The common property of these two protein families is a complex domain organization that combines species-specific regions, commonly occurring domains and disordered segments. Besides highlighting promising novel drug target candidates in M. tuberculosis, the presented analysis can also be viewed as a general protocol to identify proteins involved in species-specific functions in a given organism. We conclude that target selection protocols should be extended to include proteins with complex domain architectures instead of focusing on sequentially unique and essential proteins only