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.     

Foliar treatment of potassium nitrate modulates the fermentative and sucrose metabolizing pathways in contrasting maize genotypes under water logging stress

Physiology and Molecular Biology of Plants - The effect of potassium nitrate on the status of fermentative and sucrose metabolizing pathways was studied in two maize (Zea mays L.) genotypes, viz.,...     

Virmid: accurate detection of somatic mutations with sample impurity inference

Detection of somatic variation using sequence from disease-control matched data sets is a critical first step. In many cases including cancer, however, it is hard to isolate pure disease tissue, and the impurity hinders accurate mutation analysis by disrupting overall allele frequencies. Here, we propose a new method, Virmid, that explicitly determines the level of impurity in the sample, and uses it for improved detection of somatic variation. Extensive tests on simulated and real sequencing data from breast cancer and hemimegalencephaly demonstrate the power of our model. A software implementation of our method is available at http://sourceforge.net/projects/virmid/.     

Reprever: resolving low-copy duplicated sequences using template driven assembly

Genomic sequence duplication is an important mechanism for genome evolution, often resulting in large sequence variations with implications for disease progression. Although paired-end sequencing technologies are commonly used for structural variation discovery, the discovery of novel duplicated sequences remains an unmet challenge. We analyze duplicons starting from identified high-copy number variants. Given paired-end mapped reads, and a candidate high-copy region, our tool, Reprever, identifies (a) the insertion breakpoints where the extra duplicons inserted into the donor genome and (b) the actual sequence of the duplicon. Reprever resolves ambiguous mapping signatures from existing homologs, repetitive elements and sequencing errors to identify breakpoint. At each breakpoint, Reprever reconstructs the inserted sequence using profile hidden Markov model (PHMM)-based guided assembly. In a test on 1000 artificial genomes with simulated duplication, Reprever could identify novel duplicates up to 97% of genomes within 3 bp positional and 1% sequence errors. Validation on 680 fosmid sequences identified and reconstructed eight duplicated sequences with high accuracy. We applied Reprever to reanalyzing a re-sequenced data set from the African individual NA18507 to identify >800 novel duplicates, including insertions in genes and insertions with additional variation. polymerase chain reaction followed by capillary sequencing validated both the insertion locations of the strongest predictions and their predicted sequence.     

Fosfomycin Permeation through the Outer Membrane Porin OmpF

Fosfomycin is a frequently prescribed drug in the treatment of acute urinary tract infections. It enters the bacterial cytoplasm and inhibits the biosynthesis of peptidoglycans by targeting the MurA enzyme. Despite extensive pharmacological studies and clinical use, the permeability of fosfomycin across the bacterial outer membrane is largely unexplored. Here, we investigate the fosfomycin permeability across the outer membrane of Gram-negative bacteria by electrophysiology experiments as well as by all-atom molecular dynamics simulations including free-energy and applied-field techniques. Notably, in an electrophysiological zero-current assay as well as in the molecular simulations, we found that fosfomycin can rapidly permeate the abundant Escherichia coli porin OmpF. Furthermore, two triple mutants in the constriction region of the porin have been investigated. The permeation rates through these mutants are slightly lower than that of the wild type but fosfomycin can still permeate. Altogether, this work unravels molecular details of fosfomycin permeation through the outer membrane porin OmpF of E. coli and moreover provides hints for understanding the translocation of phosphonic acid antibiotics through other outer membrane pores.     

Video Capsule Endoscopy in Patients with Chronic Abdominal Pain with or without Associated Symptoms: A Retrospective Study

Background

Chronic abdominal pain (CAP) is a common indication for gastroenterology referrals. More insidious causes of CAP isolated to the small bowel, such as malignancies and Crohn’s disease, are rising in incidence and causing more gastroenterologists to evaluate their patients with video capsule endoscopy (VCE). However, the role of VCE in patients with CAP is still unclear.

Aims

We assessed the efficacy of VCE in patients with CAP and whether it led to findings that contributed to disease management and meaningful interventions.

Methods

This retrospective study evaluated 607 capsule endoscopy studies at an open referral endoscopy unit. Ninety of the studies were for CAP. These studies were compared to those performed for other indications to compare diagnostic yield. In addition, we investigated whether VCE led to an intervention that improved clinical outcomes.

Results

Overall, the number of abnormal findings in CAP patients was significantly lower than VCE performed for other indications (24.4% vs 39.0%, respectively p = 0.009). When patients with CAP presented with other pertinent clinical findings (e.g. nausea, weight loss, anemia, history of in inflammatory bowel disease, etc.), the likelihood of an abnormal finding increased to a level that was not different from those who received VCE for other indications (27.1%, p = 0.10). The findings from VCE lead to changed management and improved outcomes in 16.2% of CAP patients with associated symptoms. However, the subgroup that benefited the most were those who had a prior history of Crohn’s disease. Patients with CAP who did not have any associated symptoms continued to have a significantly lower abnormal finding rate compared to those who received VCE for other indications (19.4%, p = 0.03) and VCE rarely led to a change in management that would improve outcomes (5.6%).

Conclusions

VCE for CAP has a lower rate of abnormal findings than other indications. However, VCE is a useful diagnostic tool that can help provide a possible etiology of CAP in patients with associated symptoms. However, a change in management from VCE is likely to be limited to those with a history of Crohn’s disease.     

Protein identification using top-down

In the last two years, because of advances in protein separation and mass spectrometry, top-down mass spectrometry moved from analyzing single proteins to analyzing complex samples and identifying hundreds and even thousands of proteins. However, computational tools for database search of top-down spectra against protein databases are still in their infancy. We describe MS-Align+, a fast algorithm for top-down protein identification based on spectral alignment that enables searches for unexpected post-translational modifications. We also propose a method for evaluating statistical significance of top-down protein identifications and further benchmark various software tools on two top-down data sets from Saccharomyces cerevisiae and Salmonella typhimurium. We demonstrate that MS-Align+ significantly increases the number of identified spectra as compared with MASCOT and OMSSA on both data sets. Although MS-Align+ and ProSightPC have similar performance on the Salmonella typhimurium data set, MS-Align+ outperforms ProSightPC on the (more complex) Saccharomyces cerevisiae data set.     

Conservation of Dynamics Associated with Biological Function in an Enzyme Superfamily

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Exogenous application of calcium chloride in wheat genotypes alleviates negative effect of drought stress by modulating antioxidant machinery and enhanced osmolyte accumulation

Plants use various mechanisms to cope with drought constraints at morphological, physiological, and biochemical level by means of different adaptive mechanisms. All organisms use a network of signal transduction pathways to control their metabolism and to adapt to the environment. Among these pathways, calcium (Ca²⁺) ions play an important role as a universal second messenger. Calcium has unique properties and universal ability to transmit diverse signals that trigger primary physiological actions in the cell in response to hormones, pathogens, and stress factors. Calcium plays a fundamental role in regulating the polar growth of cells and tissues and participates in plant adaptation to various stress factors. This study was conducted to examine the role of Ca²⁺ in ameliorating the adverse effect of drought stress responses in two contrasting wheat genotypes, HD 2733 (drought sensitive) and HD 2987 (drought tolerant), differing in their drought tolerance. The plants were treated with mannitol or Hoagland solution and then supplemented with CaCl₂ (10 mM). Measurements of seed germination, shoot growth, and chlorophyll content showed that calcium treatment increased all these factors in tolerant genotype (HD 2987) under induced stress condition. Drought stress reduced relative water content, osmolyte, and soluble sugar accumulation in both the genotypes, but CaCl₂ supplementation increased all the components under stress condition in HD 2987 as compared to HD 2733. The oxidative damage caused by induced stress was lower in HD 2987 compared to HD 2733 genotypes as assessed by their higher photosynthetic capacity and lower electrolyte leakage, malondialdehyde (MDA) content as well as H₂O₂ accumulation. Less accumulation of superoxide and H₂O₂ was also observed in HD 2987 genotype after CaCl₂ supplementation combined with mannitol treatment. In addition, the enhanced accumulation of calcium in the HD 2987 genotype is correlated with the higher activities of antioxidant enzymes than HD 2733 genotype under similar stress conditions. Our findings provide evidence of the protective role of exogenous calcium in conferring better tolerance against mannitol-induced drought stress in wheat genotypes, which could be useful as genetic stock to develop wheat tolerant varieties in breeding programs.