Predicting Carriers of Ongoing Selective Sweeps without Knowledge of the Favored Allele

Methods for detecting the genomic signatures of natural selection have been heavily studied, and they have been successful in identifying many selective sweeps. For most of these sweeps, the favored allele remains unknown, making it difficult to distinguish carriers of the sweep from non-carriers. In an ongoing selective sweep, carriers of the favored allele are likely to contain a future most recent common ancestor. Therefore, identifying them may prove useful in predicting the evolutionary trajectory—for example, in contexts involving drug-resistant pathogen strains or cancer subclones. The main contribution of this paper is the development and analysis of a new statistic, the Haplotype Allele Frequency (HAF) score. The HAF score, assigned to individual haplotypes in a sample, naturally captures many of the properties shared by haplotypes carrying a favored allele. We provide a theoretical framework for computing expected HAF scores under different evolutionary scenarios, and we validate the theoretical predictions with simulations. As an application of HAF score computations, we develop an algorithm (PreCIOSS: Predicting Carriers of Ongoing Selective Sweeps) to identify carriers of the favored allele in selective sweeps, and we demonstrate its power on simulations of both hard and soft sweeps, as well as on data from well-known sweeps in human populations.     

Homology Modeling and Molecular Docking Studies of Glutamate Dehydrogenase (GDH) from Cyanobacterium Synechocystis sp. PCC 6803

Glutamate dehydrogenase (GDH), which is present in most bacteria and eukaryotes’ mitochondria, plays an important role in amino acid metabolism. In g     

In silico design and in vitro expression of novel multiepitope DNA constructs based on HIV-1 proteins and Hsp70 T-cell epitopes

Objectives

Epitope-driven vaccines carrying highly conserved and immunodominant epitopes have emerged as promising approaches to overcome human immunodeficiency virus-1 (HIV-1) infection.

Methods

Two multiepitope DNA constructs encoding T cell epitopes from HIV-1 Gag, Pol, Env, Nef and Rev proteins alone and/or linked to the immunogenic epitopes derived from heat shock protein 70 (Hsp70) as an immunostimulatory agent were designed. In silico analyses were applied including MHC-I and MHC-II binding, MHC-I immunogenicity and antigen processing, population coverage, conservancy, allergenicity, toxicity and hemotoxicity. The peptide-MHC-I/MHC-II molecular docking and cytokine production analyses were carried out for predicted epitopes. The selected highly immunogenic T-cell epitopes were then used to design two multiepitope fusion constructs. Next, prediction of the physicochemical and structural properties, B cell epitopes, and constructs-toll-like receptors (TLRs) molecular docking were performed for each construct. Finally, the eukaryotic expression plasmids harboring totally 12 cytotoxic T Lymphocyte (CTL) and 10 helper T lymphocytes (HTL) epitopes from HIV-1 proteins (i.e., pEGFP-N1-gag-pol-env-nef-rev), and linked to 2 CTL and 2 HTL epitopes from Hsp70 (i.e., pEGFP-N1-hsp70-gag-pol-env-nef-rev) were generated and transfected into HEK-293 T cells for evaluating the percentage of multiepitope peptides expression using flow cytometry and western blotting.

Results

The designed DNA constructs could be successfully expressed in mammalian cells. The expression rates of Gag-Pol-Env-Nef-Rev-GFP and Hsp70-Gag-Pol-Env-Nef-Rev-GFP were about 56–60% as the bands of?~?63 and?~?72 kDa confirmed in western blotting, respectively.

Conclusion

The combined in silico/in vitro methods indicated two multiepitope constructs can be produced and used as probable effective immunogens for HIV-1 vaccine development.

     

Vitamin D Receptor (VDR) Gene Polymorphisms and Risk of Coronary Artery Disease (CAD): Systematic Review and Meta-analysis

Biochemical Genetics - Several studies have noted that vitamin D receptor (VDR) gene polymorphisms are involved in the susceptibility to Coronary artery disease (CAD). Nonetheless, the results have...     

Computational Design and Analysis of a Multi-epitope Against Influenza A virus

International Journal of Peptide Research and Therapeutics - Influenza A viruses are among the most studied viruses, however no effective prevention against influenza infection has been developed....     

Effects of Choline and Magnesium Concurrent Supplementation on Coagulation and Lipid Profile in Patients with Type 2 Diabetes Mellitus: a Pilot Clinical Trial

Biological Trace Element Research - Metabolic failure is associated with dyslipidemia and coagulation which can result in a higher risk of cardiovascular disease (CVD) in type 2 diabetes mellitus...     

Colon cancer therapy by focusing on colon cancer stem cells and their tumor microenvironment

Despite many advances and optimization in colon cancer treatment, tumor recurrence and metastases make the development of new therapies necessary. Colon cancer stem cells (CCSCs) are considered as the main triggering factor of cancer progression, recurrence, and metastasis. CCSCs as a result of accumulated genetic and epigenetic alterations and also complex interconnection with the tumor microenvironment (TME) can evolve and convert to full malignant cells. Mounting evidence suggests that in cancer therapy both CCSCs and non-CCSCs in TME have to be regarded to break through the limitation of current therapies. In this regard, stem cell capabilities of some non-CCSCs may arise inside the TME condition. Therefore, a deep knowledge of regulatory mechanisms, heterogeneity, specific markers, and signaling pathways of CCSCs and their interconnection with TME components is needed to improve the treatment of colorectal cancer and the patient's life quality. In this review, we address current different targeted therapeutic options that target cell surface markers and signaling pathways of CCSCs and other components of TME. Current challenges and future perspectives of colon cancer personalized therapy are also provided here. Taken together, based on the deep understanding of biology of CCSCs and using three-dimensional culture technologies, it can be possible to reach successful colon cancer eradication and improvise combination targeted therapies against CCSCs and TME.     

The effect of different salts (heavy metals) on the mycelium growth of Nematophagus fungi

Environmental pollution in addition to direct damage on plant growth, with the destruction of biological control agents, causes indirect damage to plants. The aim of this research was to study the effects of different concentrations (0, 500, 1000, 1500 and 2000 ppm) of heavy metals including Ag, Co, Cu, Fe, Hg, Mn, Pb and Zn on the mycelial growth and to assess the fungicidal or fungistatic effects of these salts on five Nematophagus fungi including Trichoderma harzianum (T8), Trichoderma virens (T21), Trichoderma hamatum (T9), Pochonia chlamydosporia var. chlamydosporia and Arthrobotrys oligospora. The results show that Ag, Co, Cu, Fe and Hg could stop the mycelium growth of all fungi, but Mn, Pb and Zn cannot inhibit the growth of these fungi completely. Among the first group, Hg and Cu stopped the growth of fungi even in 500 ppm. Among these metals that inhibit the growth of fungi, Cu has fungistatic effect and others have fungicide effect. The experiment was conducted in vitro condition, using potato dextrose agar (PDA) under complete randomised design with four replications. The data of mycelium growth were recorded at seven days after inoculation at 25 ± 2°C.     

Prevention of Contrast-Induced Acute Kidney Injury: Is Simple Oral Hydration Similar To Intravenous? A Systematic Review of the Evidence

Background

Pre-procedural intravenous fluid administration is an effective prophylaxis measure for contrast-induced acute kidney injury. For logistical ease, the oral route is an alternative to the intravenous. The objective of this study was to compare the efficacy of the oral to the intravenous route in prevention of contrast-induced acute kidney injury.

Study Design

A systematic review and meta-analysis of randomised trials with a stratified analysis and metaregression. Databases included MEDLINE (1950 to November 23 2011), EMBASE (1947 to week 47 2011), Cochrane CENTRAL (3^rd quarter 2011). Two reviewers identified relevant trials and abstracted data.

Settings and Population

Trials including patients undergoing a contrast enhanced procedure.

Selection Criteria

Randomised controlled trial; adult (>18 years) population; comparison of oral versus intravenous volume expansion.

Intervention

Oral route of volume expansion compared to the intravenous route.

Outcomes

Any measure of acute kidney injury, need for renal replacement therapy, hospitalization and death.

Results

Six trials including 513 patients met inclusion criteria. The summary odds ratio was 1.19 (95% CI 0.46, 3.10, p = 0.73) suggesting no difference between the two routes of volume expansion. There was significant heterogeneity (Cochran’s Q = 11.65, p = 0.04; I² = 57). In the stratified analysis, inclusion of the five studies with a prespecified oral volume expansion protocol resulted in a shift towards oral volume expansion (OR 0.75, 95% CI 0.37, 1.50, p = 0.42) and also resolved the heterogeneity (Q = 3.19, P = 0.53; I² = 0).

Limitations

Small number of studies identified; lack of hard clinical outcomes.

Conclusion

The oral route may be as effective as the intravenous route for volume expansion for contrast-induced acute kidney injury prevention. Adequately powered trials with hard endpoints should be done given the potential advantages of oral (e.g. reduced patient burden and cost) over intravenous volume expansion.