The Effect of Nicotine on Reproduction and Attachment of Human Gingival Fibroblasts In Vitro

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142127/1/jper0658.pd

Rudimentary G-Quadruplex-Based Telomere Capping In Saccharomyces Cerevisiae

Telomere capping conceals chromosome ends from exonucleases and checkpoints, but the full range of capping mechanisms is not well defined. Telomeres have the potential to form G-quadruplex (G4) DNA, although evidence for telomere G4 DNA function in vivo is limited. In budding yeast, capping requires the Cdc13 protein and is lost at nonpermissive temperatures in cdc13-1 mutants. Here, we use several independent G4 DNA-stabilizing treatments to suppress cdc13-1 capping defects. These include overexpression of three different G4 DNA binding proteins, loss of the G4 DNA unwinding helicase Sgs1, or treatment with small molecule G4 DNA ligands. In vitro, we show that protein-bound G4 DNA at a 3\u27 overhang inhibits 5\u27-\u3e 3\u27 resection of a paired strand by exonuclease I. These findings demonstrate that, at least in the absence of full natural capping, G4 DNA can play a positive role at telomeres in vivo

Pyrimidine biosynthesis is not an essential function for trypanosoma brucei bloodstream forms

<p>Background: African trypanosomes are capable of both pyrimidine biosynthesis and salvage of preformed pyrimidines from the host, but it is unknown whether either process is essential to the parasite.</p> <p>Methodology/Principal Findings: Pyrimidine requirements for growth were investigated using strictly pyrimidine-free media, with or without single added pyrimidine sources. Growth rates of wild-type bloodstream form Trypanosoma brucei brucei were unchanged in pyrimidine-free medium. The essentiality of the de novo pyrimidine biosynthesis pathway was studied by knocking out the PYR6-5 locus that produces a fusion product of orotate phosphoribosyltransferase (OPRT) and Orotidine Monophosphate Decarboxylase (OMPDCase). The pyrimidine auxotroph was dependent on a suitable extracellular pyrimidine source. Pyrimidine starvation was rapidly lethal and non-reversible, causing incomplete DNA content in new cells. The phenotype could be rescued by addition of uracil; supplementation with uridine, 2′deoxyuridine, and cytidine allowed a diminished growth rate and density. PYR6-5−/− trypanosomes were more sensitive to pyrimidine antimetabolites and displayed increased uracil transport rates and uridine phosphorylase activity. Pyrimidine auxotrophs were able to infect mice although the infection developed much more slowly than infection with the parental, prototrophic trypanosome line.</p> <p>Conclusions/Significance: Pyrimidine salvage was not an essential function for bloodstream T. b. brucei. However, trypanosomes lacking de novo pyrimidine biosynthesis are completely dependent on an extracellular pyrimidine source, strongly preferring uracil, and display reduced infectivity. As T. brucei are able to salvage sufficient pyrimidines from the host environment, the pyrimidine biosynthesis pathway is not a viable drug target, although any interruption of pyrimidine supply was lethal.</p&gt

Student performance assessment using clustering techniques

The application of informatics in the university system management allows managers to count with a great amount of data which, rationally treated, can offer significant help for the student programming monitoring. This research proposes the use of clustering techniques as a useful tool of management strategy to evaluate the progression of the students’ behavior by dividing the population into homogeneous groups according to their characteristics and skills. These applications can help both the teacher and the student to improve the quality of education. The selected method is the data grouping analysis by means of fuzzy logic using the Fuzzy C-means algorithm to achieve a standard indicator called Grade, through an expert system to enable segmentation.Universidad de la Costa, 2 Universidad Nacional Experimental Politécnica “Antonio José de Sucre”, Universidad Simón Bolívar, Corporación Universitaria Latinoamericana, Corporación Universitaria Minuto de Dios

A FAIR guide for data providers to maximise sharing of human genomic data

It is generally acknowledged that, for reproducibility and progress of human genomic research, data sharing is critical. For every sharing transaction, a successful data exchange is produced between a data consumer and a data provider. Providers of human genomic data (e.g., publicly or privately funded repositories and data archives) fulfil their social contract with data donors when their shareable data conforms to FAIR (findable, accessible, interoperable, reusable) principles. Based on our experiences via Repositive (https://repositive.io), a leading discovery platform cataloguing all shared human genomic datasets, we propose guidelines for data providers wishing to maximise their shared data’s FAIRness. Citation: Corpas M, Kovalevskaya NV, McMurray A, Niel

Strong mitochondrial DNA support for a Cretaceous origin of modern avian lineages

<p>Abstract</p> <p>Background</p> <p>Determining an absolute timescale for avian evolutionary history has proven contentious. The two sources of information available, paleontological data and inference from extant molecular genetic sequences (colloquially, 'rocks' and 'clocks'), have appeared irreconcilable; the fossil record supports a Cenozoic origin for most modern lineages, whereas molecular genetic estimates suggest that these same lineages originated deep within the Cretaceous and survived the K-Pg (Cretaceous-Paleogene; formerly Cretaceous-Tertiary or K-T) mass-extinction event. These two sources of data therefore appear to support fundamentally different models of avian evolution. The paradox has been speculated to reflect deficiencies in the fossil record, unrecognized biases in the treatment of genetic data or both. Here we attempt to explore uncertainty and limit bias entering into molecular divergence time estimates through: (i) improved taxon (<it>n </it>= 135) and character (<it>n = </it>4594 bp mtDNA) sampling; (ii) inclusion of multiple cladistically tested internal fossil calibration points (<it>n </it>= 18); (iii) correction for lineage-specific rate heterogeneity using a variety of methods (<it>n </it>= 5); (iv) accommodation of uncertainty in tree topology; and (v) testing for possible effects of episodic evolution.</p> <p>Results</p> <p>The various 'relaxed clock' methods all indicate that the major (basal) lineages of modern birds originated deep within the Cretaceous, although temporal intraordinal diversification patterns differ across methods. We find that topological uncertainty had a systematic but minor influence on date estimates for the origins of major clades, and Bayesian analyses assuming fixed topologies deliver similar results to analyses with unconstrained topologies. We also find that, contrary to expectation, rates of substitution are not autocorrelated across the tree in an ancestor-descendent fashion. Finally, we find no signature of episodic molecular evolution related to either speciation events or the K-Pg boundary that could systematically mislead inferences from genetic data.</p> <p>Conclusion</p> <p>The 'rock-clock' gap has been interpreted by some to be a result of the vagaries of molecular genetic divergence time estimates. However, despite measures to explore different forms of uncertainty in several key parameters, we fail to reconcile molecular genetic divergence time estimates with dates taken from the fossil record; instead, we find strong support for an ancient origin of modern bird lineages, with many extant orders and families arising in the mid-Cretaceous, consistent with previous molecular estimates. Although there is ample room for improvement on both sides of the 'rock-clock' divide (e.g. accounting for 'ghost' lineages in the fossil record and developing more realistic models of rate evolution for molecular genetic sequences), the consistent and conspicuous disagreement between these two sources of data more likely reflects a genuine difference between estimated ages of (i) stem-group origins and (ii) crown-group morphological diversifications, respectively. Further progress on this problem will benefit from greater communication between paleontologists and molecular phylogeneticists in accounting for error in avian lineage age estimates.</p

PDE 7 Inhibitors: New Potential Drugs for the Therapy of Spinal Cord Injury

BACKGROUND: Primary traumatic mechanical injury to the spinal cord (SCI) causes the death of a number of neurons that to date can neither be recovered nor regenerated. During the last years our group has been involved in the design, synthesis and evaluation of PDE7 inhibitors as new innovative drugs for several neurological disorders. Our working hypothesis is based on two different facts. Firstly, neuroinflammation is modulated by cAMP levels, thus the key role for phosphodiesterases (PDEs), which hydrolyze cAMP, is undoubtedly demonstrated. On the other hand, PDE7 is expressed simultaneously on leukocytes and on the brain, highlighting the potential crucial role of PDE7 as drug target for neuroinflammation. METHODOLOGY/PRINCIPAL FINDINGS: Here we present two chemically diverse families of PDE7 inhibitors, designed using computational techniques such as virtual screening and neuronal networks. We report their biological profile and their efficacy in an experimental SCI model induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. We have selected two candidates, namely S14 and VP1.15, as PDE7 inhibitors. These compounds increase cAMP production both in macrophage and neuronal cell lines. Regarding drug-like properties, compounds were able to cross the blood brain barrier using parallel artificial membranes (PAMPA) methodology. SCI in mice resulted in severe trauma characterized by edema, neutrophil infiltration, and production of a range of inflammatory mediators, tissue damage, and apoptosis. Treatment of the mice with S14 and VP1.15, two PDE7 inhibitors, significantly reduced the degree of spinal cord inflammation, tissue injury (histological score), and TNF-α, IL-6, COX-2 and iNOS expression. CONCLUSIONS/SIGNIFICANCE: All these data together led us to propose PDE7 inhibitors, and specifically S14 and VP1.15, as potential drug candidates to be further studied for the treatment of SCI

Instabilities in the wake of an inclined prolate spheroid

We investigate the instabilities, bifurcations and transition in the wake behind a 45-degree inclined 6:1 prolate spheroid, through a series of direct numerical simulations (DNS) over a wide range of Reynolds numbers (Re) from 10 to 3000. We provide a detailed picture of how the originally symmetric and steady laminar wake at low Re gradually looses its symmetry and turns unsteady as Re is gradually increased. Several fascinating flow features have first been revealed and subsequently analysed, e.g. an asymmetric time-averaged flow field, a surprisingly strong side force etc. As the wake partially becomes turbulent, we investigate a dominating coherent wake structure, namely a helical vortex tube, inside of which a helical symmetry alteration scenario was recovered in the intermediate wake, together with self-similarity in the far wake.Comment: Book chapter in "Computational Modeling of Bifurcations and Instabilities in Fluid Dynamics (A. Gelfgat ed.)", Springe

Stingless bee honey protects against lipopolysaccharide induced-chronic subclinical systemic inflammation and oxidative stress by modulating Nrf2, NF-κB and p38 MAPK

Background: Epidemiological and experimental studies have extensively indicated that chronic subclinical systemic inflammation (CSSI) and oxidative stress are risk factors for several chronic diseases, including cancer, arthritis, type 2 diabetes, and cardiovascular and neurodegenerative diseases. This study examined the protective effect of stingless bee honey (SBH) supplementation against lipopolysaccharide (LPS)-induced CSSI, pointing to the possible involvement of NF-κB, p38 MAPK and Nrf2 signaling. Methods: CSSI was induced in male Sprague Dawley rats by intraperitoneal injection of LPS three times per week for 28 days, and SBH (4.6 and 9.3 g/kg/day) was supplemented for 30 days. Results: LPS-induced rats showed significant leukocytosis, and elevated serum levels of CRP, TNF-α, IL-1β, IL-6, IL-8, MCP-1, malondialdehyde (MDA) and 8-hydroxy-2′-deoxyguanosine (8-OHdG), accompanied with diminished antioxidants. Treatment with SBH significantly ameliorated inflammatory markers, MDA and 8-OHdG, and enhanced antioxidants in LPS-induced rats. In addition, SBH decreased NF-κB p65 and p38 MAPK, and increased Nrf2 expression in the liver, kidney, heart and lung of LPS-induced rats. Furthermore, SBH prevented LPS-induced histological and functional alterations in the liver, kidney, heart and lung of rats. Conclusion: SBH has a substantial protective role against LPS-induced CSSI in rats mediated via amelioration of inflammation, oxidative stress and NF-κB, p38 MAPK and Nrf2 signaling