Computational prediction of essential genes in an unculturable endosymbiotic bacterium, Wolbachia of Brugia malayi

<p>Abstract</p> <p>Background</p> <p><it>Wolbachia </it>(<it>w</it>Bm) is an obligate endosymbiotic bacterium of <it>Brugia malayi</it>, a parasitic filarial nematode of humans and one of the causative agents of lymphatic filariasis. There is a pressing need for new drugs against filarial parasites, such as <it>B. malayi</it>. As <it>w</it>Bm is required for <it>B. malayi </it>development and fertility, targeting <it>w</it>Bm is a promising approach. However, the lifecycle of neither <it>B. malayi </it>nor <it>w</it>Bm can be maintained <it>in vitro</it>. To facilitate selection of potential drug targets we computationally ranked the <it>w</it>Bm genome based on confidence that a particular gene is essential for the survival of the bacterium.</p> <p>Results</p> <p><it>w</it>Bm protein sequences were aligned using BLAST to the Database of Essential Genes (DEG) version 5.2, a collection of 5,260 experimentally identified essential genes in 15 bacterial strains. A confidence score, the Multiple Hit Score (MHS), was developed to predict each <it>w</it>Bm gene's essentiality based on the top alignments to essential genes in each bacterial strain. This method was validated using a jackknife methodology to test the ability to recover known essential genes in a control genome. A second estimation of essentiality, the Gene Conservation Score (GCS), was calculated on the basis of phyletic conservation of genes across <it>Wolbachia's </it>parent order <it>Rickettsiales</it>. Clusters of orthologous genes were predicted within the 27 currently available complete genomes. Druggability of <it>w</it>Bm proteins was predicted by alignment to a database of protein targets of known compounds.</p> <p>Conclusion</p> <p>Ranking <it>w</it>Bm genes by either MHS or GCS predicts and prioritizes potentially essential genes. Comparison of the MHS to GCS produces quadrants representing four types of predictions: those with high confidence of essentiality by both methods (245 genes), those highly conserved across <it>Rickettsiales </it>(299 genes), those similar to distant essential genes (8 genes), and those with low confidence of essentiality (253 genes). These data facilitate selection of <it>w</it>Bm genes for entry into drug design pipelines.</p

Changes in cerebral vascular reactivity and structure following prolonged exposure to high altitude in humans.

Although high-altitude exposure can lead to neurocognitive impairment, even upon return to sea level, it remains unclear the extent to which brain volume and regional cerebral vascular reactivity (CVR) are altered following high-altitude exposure. The purpose of this study was to simultaneously determine the effect of 3 weeks at 5050 m on: (1) structural brain alterations; and (2) regional CVR after returning to sea level for 1 week. Healthy human volunteers (n = 6) underwent baseline and follow-up structural and functional magnetic resonance imaging (MRI) at rest and during a CVR protocol (end-tidal PCO2 reduced by -10, -5 and increased by +5, +10, and +15 mmHg from baseline). CVR maps (% mmHg(-1)) were generated using BOLD MRI and brain volumes were estimated. Following return to sea level, whole-brain volume and gray matter volume was reduced by 0.4 ± 0.3% (P < 0.01) and 2.6 ± 1.0% (P < 0.001), respectively; white matter was unchanged. Global gray matter CVR and white matter CVR were unchanged following return to sea level, but CVR was selectively increased (P < 0.05) in the brainstem (+30 ± 12%), hippocampus (+12 ± 3%), and thalamus (+10 ± 3%). These changes were the result of improvement and/or reversal of negative CVR to positive CVR in these regions. Three weeks of high-altitude exposure is reflected in loss of gray matter volume and improvements in negative CVR

Extraction of bodily features for gait recognition and gait attractiveness evaluation

This is the author's accepted manuscript. The final publication is available at Springer via http://dx.doi.org/10.1007/s11042-012-1319-2. Copyright @ 2012 Springer.Although there has been much previous research on which bodily features are most important in gait analysis, the questions of which features should be extracted from gait, and why these features in particular should be extracted, have not been convincingly answered. The primary goal of the study reported here was to take an analytical approach to answering these questions, in the context of identifying the features that are most important for gait recognition and gait attractiveness evaluation. Using precise 3D gait motion data obtained from motion capture, we analyzed the relative motions from different body segments to a root marker (located on the lower back) of 30 males by the fixed root method, and compared them with the original motions without fixing root. Some particular features were obtained by principal component analysis (PCA). The left lower arm, lower legs and hips were identified as important features for gait recognition. For gait attractiveness evaluation, the lower legs were recognized as important features.Dorothy Hodgkin Postgraduate Award and HEFCE

Deep Sequencing of Small RNAs in Tomato for Virus and Viroid Identification and Strain Differentiation

Small RNAs (sRNA), including microRNAs (miRNA) and small interfering RNAs (siRNA), are produced abundantly in plants and animals and function in regulating gene expression or in defense against virus or viroid infection. Analysis of siRNA profiles upon virus infection in plant may allow for virus identification, strain differentiation, and de novo assembly of virus genomes. In the present study, four suspected virus-infected tomato samples collected in the U.S. and Mexico were used for sRNA library construction and deep sequencing. Each library generated between 5–7 million sRNA reads, of which more than 90% were from the tomato genome. Upon in-silico subtraction of the tomato sRNAs, the remaining highly enriched, virus-like siRNA pools were assembled with or without reference virus or viroid genomes. A complete genome was assembled for Potato spindle tuber viroid (PSTVd) using siRNA alone. In addition, a near complete virus genome (98%) also was assembled for Pepino mosaic virus (PepMV). A common mixed infection of two strains of PepMV (EU and US1), which shared 82% of genome nucleotide sequence identity, also could be differentially assembled into their respective genomes. Using de novo assembly, a novel potyvirus with less than 60% overall genome nucleotide sequence identity to other known viruses was discovered and its full genome sequence obtained. Taken together, these data suggest that the sRNA deep sequencing technology will likely become an efficient and powerful generic tool for virus identification in plants and animals

The gray matter volume of the amygdala is correlated with the perception of melodic intervals: a voxel-based morphometry study

Music is not simply a series of organized pitches, rhythms, and timbres, it is capable of evoking emotions. In the present study, voxel-based morphometry (VBM) was employed to explore the neural basis that may link music to emotion. To do this, we identified the neuroanatomical correlates of the ability to extract pitch interval size in a music segment (i.e., interval perception) in a large population of healthy young adults (N = 264). Behaviorally, we found that interval perception was correlated with daily emotional experiences, indicating the intrinsic link between music and emotion. Neurally, and as expected, we found that interval perception was positively correlated with the gray matter volume (GMV) of the bilateral temporal cortex. More important, a larger GMV of the bilateral amygdala was associated with better interval perception, suggesting that the amygdala, which is the neural substrate of emotional processing, is also involved in music processing. In sum, our study provides one of first neuroanatomical evidence on the association between the amygdala and music, which contributes to our understanding of exactly how music evokes emotional responses

Resection of the liver for colorectal carcinoma metastases - A multi-institutional study of long-term survivors

In this review of a collected series of patients undergoing hepatic resection for colorectal metastases, 100 patients were found to have survived greater than five years from the time of resection. Of these 100 long-term survivors, 71 remain disease-free through the last follow-up, 19 recurred prior to five years, and ten recurred after five years. Patient characteristics that may have contributed to survival were examined. Procedures performed included five trisegmentectomies, 32 lobectomies, 16 left lateral segmentectomies, and 45 wedge resections. The margin of resection was recorded in 27 patients, one of whom had a positive margin, nine of whom had a less than or equal to 1-cm margin, and 17 of whom had a greater than 1-cm margin. Eighty-one patients had a solitary metastasis to the liver, 11 patients had two metastases, one patient had three metastases, and four patients had four metastases. Thirty patients had Stage C primary carcinoma, 40 had Stage B primary carcinoma, and one had Stage A primarycarcinoma. The disease-free interval from the time of colon resection to the time of liver resection was less than one year in 65 patients, and greater than one year in 34 patients. Three patients had bilobar metastases. Four of the patients had extrahepatic disease resected simultaneously with the liver resection. Though several contraindications to hepatic resection have been proposed in the past, five-year survival has been found in patients with extrahepatic disease resected simultaneously, patients with bilobar metastases, patients with multiple metastases, and patients with positive margins. Five-year disease-free survivors are also present in each of these subsets. It is concluded that five-year survival is possible in the presence of reported contraindications to resection, and therefore that the decision to resect the liver must be individualized. © 1988 American Society of Colon and Rectal Surgeons

Using modeling to understand how athletes in different disciplines solve the same problem: Swimming versus running versus speed skating

Every new competitive season offers excellent examples of human locomotor abilities, regardless of the sport. As a natural consequence of competitions, world records are broken every now and then. World record races not only offer spectators the pleasure of watching very talented and highly trained athletes performing muscular tasks with remarkable skill, but also represent natural models of the ultimate expression of human integrated muscle biology, through strength, speed, or endurance performances. Given that humans may be approaching our species limit for muscular power output, interest in how athletes improve on world records has led to interest in the strategy of how limited energetic resources are best expended over a race. World record performances may also shed light on how athletes in different events solve exactly the same problem-minimizing the time required to reach the finish line. We have previously applied mathematical modeling to the understanding of world record performances in terms of improvements in facilities/equipment and improvements in the athletes' physical capacities. In this commentary, we attempt to demonstrate that differences in world record performances in various sports can be explained using a very simple modeling process

Predictors of pain interference and potential gain from intervention in community dwelling adults with joint pain: A prospective cohort study.

INTRODUCTION: There is little research on identifying modifiable risk factors that predict future interference of pain with daily activity in people with joint pain, and the estimation of the corresponding population attributable risk (PAR). The present study therefore investigated modifiable predictors of pain interference and estimated maximum potential gain from intervention in adults with joint pain. METHODS: A population-based cohort aged ≥50 years was recruited from eight general practices in North Staffordshire, UK. Participants (n = 1878) had joint pain at baseline lasting ≥3 months and indicated no pain interference. Adjusted associations of self-reported, potentially modifiable prognostic factors (body mass index, anxiety/depressive symptoms, widespread pain, inadequate joint pain control, physical inactivity, sleep problems, smoking and alcohol intake) with onset of pain interference 3 years later were estimated via Poisson regression, and corresponding PAR estimates were obtained. RESULTS: Inadequate joint-specific pain control, insomnia and infrequent walking were found to be independently significantly associated with the onset of pain interference after 3 years, with associated PARs of 6.3% (95% confidence interval -0.3, 12.4), 7.6% (-0.4, 15.0) and 8.0% (0.1, 15.2), respectively, with only the PAR for infrequent walking deemed statistically significant. The PAR associated with insomnia, infrequent walking and inadequate control of joint pain simultaneously was 20.3% (8.6, 30.4). CONCLUSIONS: There is potential to reduce moderately the onset of pain interference from joint pain in the over-50s if clinical and public health interventions targeted pain management and insomnia, and promoted an active lifestyle. However, most of the onset of significant pain interference in the over-50s, would not be prevented, even assuming that these factors could be eliminated