Promiscuous prediction and conservancy analysis of CTL binding epitopes of HCV 3a viral proteome from Punjab Pakistan: an In Silico Approach

<p>Abstract</p> <p>Background</p> <p>HCV is a positive sense RNA virus affecting approximately 180 million people world wide and about 10 million Pakistani populations. HCV genotype 3a is the major cause of infection in Pakistani population. One of the major problems of HCV infection especially in the developing countries that limits the limits the antiviral therapy is the long term treatment, high dosage and side effects. Studies of antigenic epitopes of viral sequences of a specific origin can provide an effective way to overcome the mutation rate and to determine the promiscuous binders to be used for epitope based subunit vaccine design. An <it>in silico </it>approach was applied for the analysis of entire HCV proteome of Pakistani origin, aimed to identify the viral epitopes and their conservancy in HCV genotypes 1, 2 and 3 of diverse origin.</p> <p>Results</p> <p>Immunoinformatic tools were applied for the predictive analysis of HCV 3a antigenic epitopes of Pakistani origin. All the predicted epitopes were then subjected for their conservancy analysis in HCV genotypes 1, 2 and 3 of diverse origin (worldwide). Using freely available web servers, 150 MHC II epitopes were predicted as promiscuous binders against 51 subjected alleles. E2 protein represented the 20% of all the predicted MHC II epitopes. 75.33% of the predicted MHC II epitopes were (77-100%) conserve in genotype 3; 47.33% and 40.66% in genotype 1 and 2 respectively. 69 MHC I epitopes were predicted as promiscuous binders against 47 subjected alleles. NS4b represented 26% of all the MHC I predicted epitopes. Significantly higher epitope conservancy was represented by genotype 3 i.e. 78.26% and 21.05% for genotype 1 and 2.</p> <p>Conclusions</p> <p>The study revealed comprehensive catalogue of potential HCV derived CTL epitopes from viral proteome of Pakistan origin. A considerable number of predicted epitopes were found to be conserved in different HCV genotype. However, the number of conserved epitopes in HCV genotype 3 was significantly higher in contrast to its conservancy in HCV genotype 1 and 2. Despite of the lower conservancy in genotype 1 and 2, all the predicted epitopes have important implications in diagnostics as well as CTL-based rational vaccine design, effective for most population of the world and especially the Pakistani Population.</p

Skeletal growth in class II malocclusion from childhood to adolescence: does the profile straighten?

BACKGROUND There is relatively little appreciation of the changes in maxillary-mandibular relationships occurring during adolescence among subjects with normal and increased overjet. The aim of this study was to assess differences in changes in maxillo-mandibular relationships during the adolescent growth period based on the presence of a normal ( 4 mm) overjet in childhood. Our hypothesis was that there is no difference in the change of the A point, nasion, B point (ANB) angle during growth between these two overjet groups. Lateral cephalograms were obtained from 65 subjects taken from the American Association of Orthodontists Foundation (AAOF) Craniofacial Growth Legacy Collections Project. Cephalograms were obtained at ages 7-10 (T0) and 14-17 (T1) with allocation into two groups based on baseline overjet (> 4 mm: group 1, 2-4 mm: group 2). Random effects linear regression was used to account for multiple within -patient measurements with dependent variables including antero-posterior skeletal pattern (based on sella, nasion, A point (SNA); sella, nasion, B point (SNB); and ANB angles). RESULTS We included a similar number of males (n = 34; 52.3%) and females (n = 31; 47.7%). The mean ANB was higher at baseline in group 1 (5.42, SD 2.16°) than in group 2 (3.08, SD 1.91°). The hypothesis was rejected as the ANB angle reduced by 1.92° more in the larger overjet group with the association being statistically significant after accounting for age and gender (P  4 mm overjet group compared to the 2-4 mm group (0.857°, P = 0.271; 95% CI - 0.669 to 2.383). The SNB angle increased by 1.15° more in the higher overjet group but there was only weak evidence of an association (P = 0.086; 95% CI - 2.464 to 0.164). CONCLUSIONS A slight straightening of the facial profile was observed in both groups with a statistically significant greater reduction in ANB arising in the group with larger baseline overjet. This translated into a marginal reduction in the overjet in this group

Accreting Black Holes

This chapter provides a general overview of the theory and observations of black holes in the Universe and on their interpretation. We briefly review the black hole classes, accretion disk models, spectral state classification, the AGN classification, and the leading techniques for measuring black hole spins. We also introduce quasi-periodic oscillations, the shadow of black holes, and the observations and the theoretical models of jets.Comment: 41 pages, 18 figures. To appear in "Tutorial Guide to X-ray and Gamma-ray Astronomy: Data Reduction and Analysis" (Ed. C. Bambi, Springer Singapore, 2020). v3: fixed some typos and updated some parts. arXiv admin note: substantial text overlap with arXiv:1711.1025

Entanglement entropy of black holes

The entanglement entropy is a fundamental quantity which characterizes the correlations between sub-systems in a larger quantum-mechanical system. For two sub-systems separated by a surface the entanglement entropy is proportional to the area of the surface and depends on the UV cutoff which regulates the short-distance correlations. The geometrical nature of the entanglement entropy calculation is particularly intriguing when applied to black holes when the entangling surface is the black hole horizon. I review a variety of aspects of this calculation: the useful mathematical tools such as the geometry of spaces with conical singularities and the heat kernel method, the UV divergences in the entropy and their renormalization, the logarithmic terms in the entanglement entropy in 4 and 6 dimensions and their relation to the conformal anomalies. The focus in the review is on the systematic use of the conical singularity method. The relations to other known approaches such as 't Hooft's brick wall model and the Euclidean path integral in the optical metric are discussed in detail. The puzzling behavior of the entanglement entropy due to fields which non-minimally couple to gravity is emphasized. The holographic description of the entanglement entropy of the black hole horizon is illustrated on the two- and four-dimensional examples. Finally, I examine the possibility to interpret the Bekenstein-Hawking entropy entirely as the entanglement entropy.Comment: 89 pages; an invited review to be published in Living Reviews in Relativit

Does advancing male age influence the expression levels and localisation patterns of phospholipase C zeta (PLCζ) in human sperm?

Socio-economic factors have led to an increasing trend for couples to delay parenthood. However, advancing age exerts detrimental effects upon gametes which can have serious consequences upon embryo viability. While such effects are well documented for the oocyte, relatively little is known with regard to the sperm. One fundamental role of sperm is to activate the oocyte at fertilisation, a process initiated by phospholipase C zeta (PLCζ), a sperm-specific protein. While PLCζ deficiency can lead to oocyte activation deficiency and infertility, it is currently unknown whether the expression or function of PLCζ is compromised by advancing male age. Here, we evaluate sperm motility and the proportion of sperm expressing PLCζ in 71 males (22–54 years; 44 fertile controls and 27 infertile patients), along with total levels and localisation patterns of PLCζ within the sperm head. Three different statistical approaches were deployed with male age considered both as a categorical and a continuous factor. While progressive motility was negatively correlated with male age, all three statistical models concurred that no PLCζ–related parameter was associated with male age, suggesting that advancing male age is unlikely to cause problems in terms of the sperm’s fundamental ability to activate an oocyt

SIDEKICK: Genomic data driven analysis and decision-making framework

<p>Abstract</p> <p>Background</p> <p>Scientists striving to unlock mysteries within complex biological systems face myriad barriers in effectively integrating available information to enhance their understanding. While experimental techniques and available data sources are rapidly evolving, useful information is dispersed across a variety of sources, and sources of the same information often do not use the same format or nomenclature. To harness these expanding resources, scientists need tools that bridge nomenclature differences and allow them to integrate, organize, and evaluate the quality of information without extensive computation.</p> <p>Results</p> <p>Sidekick, a genomic data driven analysis and decision making framework, is a web-based tool that provides a user-friendly intuitive solution to the problem of information inaccessibility. Sidekick enables scientists without training in computation and data management to pursue answers to research questions like "What are the mechanisms for disease X" or "Does the set of genes associated with disease X also influence other diseases." Sidekick enables the process of combining heterogeneous data, finding and maintaining the most up-to-date data, evaluating data sources, quantifying confidence in results based on evidence, and managing the multi-step research tasks needed to answer these questions. We demonstrate Sidekick's effectiveness by showing how to accomplish a complex published analysis in a fraction of the original time with no computational effort using Sidekick.</p> <p>Conclusions</p> <p>Sidekick is an easy-to-use web-based tool that organizes and facilitates complex genomic research, allowing scientists to explore genomic relationships and formulate hypotheses without computational effort. Possible analysis steps include gene list discovery, gene-pair list discovery, various enrichments for both types of lists, and convenient list manipulation. Further, Sidekick's ability to characterize pairs of genes offers new ways to approach genomic analysis that traditional single gene lists do not, particularly in areas such as interaction discovery.</p

The Evolution of Compact Binary Star Systems

We review the formation and evolution of compact binary stars consisting of white dwarfs (WDs), neutron stars (NSs), and black holes (BHs). Binary NSs and BHs are thought to be the primary astrophysical sources of gravitational waves (GWs) within the frequency band of ground-based detectors, while compact binaries of WDs are important sources of GWs at lower frequencies to be covered by space interferometers (LISA). Major uncertainties in the current understanding of properties of NSs and BHs most relevant to the GW studies are discussed, including the treatment of the natal kicks which compact stellar remnants acquire during the core collapse of massive stars and the common envelope phase of binary evolution. We discuss the coalescence rates of binary NSs and BHs and prospects for their detections, the formation and evolution of binary WDs and their observational manifestations. Special attention is given to AM CVn-stars -- compact binaries in which the Roche lobe is filled by another WD or a low-mass partially degenerate helium-star, as these stars are thought to be the best LISA verification binary GW sources.Comment: 105 pages, 18 figure

Integrin-Blocking Antibodies Delay Keratinocyte Re-Epithelialization in a Human Three-Dimensional Wound Healing Model

The α6β4 integrin plays a significant role in tumor growth, angiogenesis and metastasis through modulation of growth factor signaling, and is a potentially important therapeutic target. However, α6β4-mediated cell-matrix adhesion is critical in normal keratinocyte attachment, signaling and anchorage to the basement membrane through its interaction with laminin-5, raising potential risks for targeted therapy. Bioengineered Human Skin Equivalent (HSE), which have been shown to mimic their normal and wounded counterparts, have been used here to investigate the consequences of targeting β4 to establish toxic effects on normal tissue homeostasis and epithelial wound repair. We tested two antibodies directed to different β4 epitopes, one adhesion-blocking (ASC-8) and one non-adhesion blocking (ASC-3), and determined that these antibodies were appropriately localized to the basal surface of keratinocytes at the basement membrane interface where β4 is expressed. While normal tissue architecture was not altered, ASC-8 induced a sub-basal split at the basement membrane in non-wounded tissue. In addition, wound closure was significantly inhibited by ASC-8, but not by ASC-3, as the epithelial tongue only covered 40 percent of the wound area at 120 hours post-wounding. These results demonstrate β4 adhesion-blocking antibodies may have adverse effects on normal tissue, whereas antibodies directed to other epitopes may provide safer alternatives for therapy. Taken together, we conclude that these three-dimensional tissue models provide a biologically relevant platform to identify toxic effects induced by candidate therapeutics, which will allow generation of findings that are more predictive of in vivo responses early in the drug development process

Outer Membrane Vesicles Derived from Escherichia coli Induce Systemic Inflammatory Response Syndrome

Sepsis, characterized by a systemic inflammatory state that is usually related to Gram-negative bacterial infection, is a leading cause of death worldwide. Although the annual incidence of sepsis is still rising, the exact cause of Gram-negative bacteria-associated sepsis is not clear. Outer membrane vesicles (OMVs), constitutively secreted from Gram-negative bacteria, are nano-sized spherical bilayered proteolipids. Using a mouse model, we showed that intraperitoneal injection of OMVs derived from intestinal Escherichia coli induced lethality. Furthermore, OMVs induced host responses which resemble a clinically relevant condition like sepsis that was characterized by piloerection, eye exudates, hypothermia, tachypnea, leukopenia, disseminated intravascular coagulation, dysfunction of the lungs, hypotension, and systemic induction of tumor necrosis factor-α and interleukin-6. Our study revealed a previously unidentified causative microbial signal in the pathogenesis of sepsis, suggesting OMVs as a new therapeutic target to prevent and/or treat severe sepsis caused by Gram-negative bacterial infection