The genome sequence of <i>Trypanosoma brucei gambiense</i>, causative agent of chronic Human African Trypanosomiasis

&lt;p&gt;&lt;b&gt;Background:&lt;/b&gt; &lt;i&gt;Trypanosoma brucei gambiense&lt;/i&gt; is the causative agent of chronic Human African Trypanosomiasis or sleeping sickness, a disease endemic across often poor and rural areas of Western and Central Africa. We have previously published the genome sequence of a &lt;i&gt;T. b. brucei&lt;/i&gt; isolate, and have now employed a comparative genomics approach to understand the scale of genomic variation between &lt;i&gt;T. b. gambiense&lt;/i&gt; and the reference genome. We sought to identify features that were uniquely associated with &lt;i&gt;T. b. gambiense&lt;/i&gt; and its ability to infect humans.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Methods and findings:&lt;/b&gt; An improved high-quality draft genome sequence for the group 1 &lt;i&gt;T. b. gambiense&lt;/i&gt; DAL 972 isolate was produced using a whole-genome shotgun strategy. Comparison with &lt;i&gt;T. b. brucei&lt;/i&gt; showed that sequence identity averages 99.2% in coding regions, and gene order is largely collinear. However, variation associated with segmental duplications and tandem gene arrays suggests some reduction of functional repertoire in &lt;i&gt;T. b. gambiense&lt;/i&gt; DAL 972. A comparison of the variant surface glycoproteins (VSG) in &lt;i&gt;T. b. brucei&lt;/i&gt; with all &lt;i&gt;T. b. gambiense&lt;/i&gt; sequence reads showed that the essential structural repertoire of VSG domains is conserved across &lt;i&gt;T. brucei&lt;/i&gt;.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; This study provides the first estimate of intraspecific genomic variation within &lt;i&gt;T. brucei&lt;/i&gt;, and so has important consequences for future population genomics studies. We have shown that the &lt;i&gt;T. b. gambiense&lt;/i&gt; genome corresponds closely with the reference, which should therefore be an effective scaffold for any &lt;i&gt;T. brucei&lt;/i&gt; genome sequence data. As VSG repertoire is also well conserved, it may be feasible to describe the total diversity of variant antigens. While we describe several as yet uncharacterized gene families with predicted cell surface roles that were expanded in number in &lt;i&gt;T. b. brucei&lt;/i&gt;, no &lt;i&gt;T. b. gambiense&lt;/i&gt;-specific gene was identified outside of the subtelomeres that could explain the ability to infect humans.&lt;/p&gt

Genome BLAST distance phylogenies inferred from whole plastid and whole mitochondrion genome sequences

BACKGROUND: Phylogenetic methods which do not rely on multiple sequence alignments are important tools in inferring trees directly from completely sequenced genomes. Here, we extend the recently described Genome BLAST Distance Phylogeny (GBDP) strategy to compute phylogenetic trees from all completely sequenced plastid genomes currently available and from a selection of mitochondrial genomes representing the major eukaryotic lineages. BLASTN, TBLASTX, or combinations of both are used to locate high-scoring segment pairs (HSPs) between two sequences from which pairwise similarities and distances are computed in different ways resulting in a total of 96 GBDP variants. The suitability of these distance formulae for phylogeny reconstruction is directly estimated by computing a recently described measure of "treelikeness", the so-called δ value, from the respective distance matrices. Additionally, we compare the trees inferred from these matrices using UPGMA, NJ, BIONJ, FastME, or STC, respectively, with the NCBI taxonomy tree of the taxa under study. RESULTS: Our results indicate that, at this taxonomic level, plastid genomes are much more valuable for inferring phylogenies than are mitochondrial genomes, and that distances based on breakpoints are of little use. Distances based on the proportion of "matched" HSP length to average genome length were best for tree estimation. Additionally we found that using TBLASTX instead of BLASTN and, particularly, combining TBLASTX and BLASTN leads to a small but significant increase in accuracy. Other factors do not significantly affect the phylogenetic outcome. The BIONJ algorithm results in phylogenies most in accordance with the current NCBI taxonomy, with NJ and FastME performing insignificantly worse, and STC performing as well if applied to high quality distance matrices. δ values are found to be a reliable predictor of phylogenetic accuracy. CONCLUSION: Using the most treelike distance matrices, as judged by their δ values, distance methods are able to recover all major plant lineages, and are more in accordance with Apicomplexa organelles being derived from "green" plastids than from plastids of the "red" type. GBDP-like methods can be used to reliably infer phylogenies from different kinds of genomic data. A framework is established to further develop and improve such methods. δ values are a topology-independent tool of general use for the development and assessment of distance methods for phylogenetic inference

Inhibition of Non-Homologous End Joining Repair Impairs Pancreatic Cancer Growth and Enhances Radiation Response

Pancreatic ductal adenocarcinoma (PDAC) is amongst the deadliest of human cancers, due to its late diagnosis as well as its intense resistance to currently available therapeutics. To identify mechanisms as to why PDAC are refractory to DNA damaging cytoxic chemotherapy and radiation, we performed a global interrogation of the DNA damage response of PDAC. We find that PDAC cells generally harbor high levels of spontaneous DNA damage. Inhibition of Non-Homologous End Joining (NHEJ) repair either pharmacologically or by RNAi resulted in a further accumulation of DNA damage, inhibition of growth, and ultimately apoptosis even in the absence of exogenous DNA damaging agents. In response to radiation, PDAC cells rely on the NHEJ pathway to rapidly repair DNA double strand breaks. Mechanistically, when NHEJ is inhibited there is a compensatory increase in Homologous Recombination (HR). Despite this upregulation of HR, DNA damage persists and cells are significantly more sensitive to radiation. Together, these findings support the incorporation of NHEJ inhibition into PDAC therapeutic approaches, either alone, or in combination with DNA damaging therapies such as radiation

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Hopefulness predicts resilience after hereditary colorectal cancer genetic testing: a prospective outcome trajectories study

<p>Abstract</p> <p>Background -</p> <p>Genetic testing for hereditary colorectal cancer (HCRC) had significant psychological consequences for test recipients. This prospective longitudinal study investigated the factors that predict psychological resilience in adults undergoing genetic testing for HCRC.</p> <p>Methods -</p> <p>A longitudinal study was carried out from April 2003 to August 2006 on Hong Kong Chinese HCRC family members who were recruited and offered genetic testing by the Hereditary Gastrointestinal Cancer Registry to determine psychological outcomes after genetic testing. Self-completed questionnaires were administered immediately before (pre-disclosure baseline) and 2 weeks, 4 months and 1 year after result disclosure. Using validated psychological inventories, the cognitive style of hope was measured at baseline, and the psychological distress of depression and anxiety was measured at all time points.</p> <p>Results -</p> <p>Of the 76 participating subjects, 71 individuals (43 men and 28 women; mean age 38.9 ± 9.2 years) from nine FAP and 24 HNPCC families completed the study, including 39 mutated gene carriers. Four patterns of outcome trajectories were created using established norms for the specified outcome measures of depression and anxiety. These included chronic dysfunction (13% and 8.7%), recovery (0% and 4.3%), delayed dysfunction (13% and 15.9%) and resilience (76.8% and 66.7%). Two logistic regression analyses were conducted using hope at baseline to predict resilience, with depression and anxiety employed as outcome indicators. Because of the small number of participants, the chronic dysfunction and delayed dysfunction groups were combined into a non-resilient group for comparison with the resilient group in all subsequent analysis. Because of low frequencies, participants exhibiting a recovery trajectory (n = 3 for anxiety and n = 0 for depression) were excluded from further analysis. Both regression equations were significant. Baseline hope was a significant predictor of a resilience outcome trajectory for depression (<it>B </it>= -0.24, <it>p </it>< 0.01 for depression); and anxiety (<it>B </it>= -0.11, <it>p </it>= 0.05 for anxiety).</p> <p>Conclusions -</p> <p>The current findings suggest that hopefulness may predict resilience after HCRC genetic testing in Hong Kong Chinese. Interventions to increase the level of hope may be beneficial to the psychological adjustment of CRC genetic testing recipients.</p

Altered amygdala activation during face processing in Iraqi and Afghanistani war veterans

Abstract Background Exposure to combat can have a significant impact across a wide array of domains, and may manifest as post-traumatic stress disorder (PTSD), a debilitating mental illness that is associated with neural and affective sequelae. This study tested the hypothesis that combat-exposed individuals with and without PTSD, relative to healthy control subjects with no history of PTSD or combat exposure, would show amygdala hyperactivity during performance of a well-validated face processing task. We further hypothesized that differences in the prefrontal cortex would best differentiate the combat-exposed groups with and without PTSD. Methods Twelve men with PTSD related to combat in Operations Enduring Freedom and/or Iraqi Freedom, 12 male combat-exposed control patients with a history of Operations Enduring Freedom and/or Iraqi Freedom combat exposure but no history of PTSD, and 12 healthy control male patients with no history of combat exposure or PTSD completed a face-matching task during functional magnetic resonance imaging. Results The PTSD group showed greater amygdala activation to fearful versus happy faces than both the combat-exposed control and healthy control groups. Both the PTSD and the combat-exposed control groups showed greater amygdala activation to all faces versus shapes relative to the healthy control group. However, the combat-exposed control group relative to the PTSD group showed greater prefrontal/parietal connectivity with the amygdala, while the PTSD group showed greater connectivity with the subgenual cingulate. The strength of connectivity in the PTSD group was inversely related to avoidance scores. Conclusions These observations are consistent with the hypothesis that PTSD is associated with a deficiency in top-down modulation of amygdala activation by the prefrontal cortex and shows specific sensitivity to fearful faces

Recovering Dietary Information from Extant and Extinct Primates Using Plant Microremains

When reconstructing the diets of primates, researchers often rely on several well established methods, such as direct observation, studies of discarded plant parts, and analysis of macrobotanical remains in fecal matter. Most of these studies can be performed only on living primate groups, however, and the diets of extinct, subfossil, and fossil groups are known only from proxy methods. Plant microremains, tiny plant structures with distinctive morphologies, can record the exact plant foods that an individual consumed. They can be recovered from recently deceased and fossil primate samples, and can also be used to supplement traditional dietary analyses in living groups. Here I briefly introduce plant microremains, provide examples of how they have been successfully used to reconstruct the diets of humans and other species, and describe methods for their application in studies of primate dietary ecology

Investigation of the role of gas hydrates in continental slope stability west of Fiordland, New Zealand

Sediment weakening due to increased local pore fluid pressure is interpreted to be the cause of a submarine landslide that has been seismically imaged off the southwest coast of New Zealand. Data show a distinct and continuous bottom‐simulating reflection (BSR)—a seismic phenomena indicative of the presence of marine gas hydrate—below the continental shelf from water depths of c. 2400 m to c. 750 m, where it intersects the seafloor. Excess pore fluid pressure (EPP) generated in a free gas zone below the base of gas hydrate stability is interpreted as being a major factor in the slope's destabilisation. Representative sediment strength characteristics have been applied to limit‐equilibrium methods of slope stability analysis with respect to the Mohr‐Coulomb failure criterion to develop an understanding of the feature's sensitivity to EPP. EPP has been modelled with representative material properties (internal angle of friction, bulk soil unit weight and cohesion) to show the considerable effect it has on stability. The best estimate of average EPP being solely responsible for failure is 1700 kPa, assuming a perfectly elastic body above a pre‐defined failure surface in a static environment

Increased Nucleotide Diversity with Transient Y Linkage in Drosophila americana

Recombination shapes nucleotide variation within genomes. Patterns are thought to arise from the local recombination landscape, influencing the degree to which neutral variation experiences hitchhiking with selected variation. This study examines DNA polymorphism along Chromosome 4 (element B) of Drosophila americana to identify effects of hitchhiking arising as a consequence of Y-linked transmission. A centromeric fusion between the X and 4(th) chromosomes segregates in natural populations of D. americana. Frequency of the X-4 fusion exhibits a strong positive correlation with latitude, which has explicit consequences for unfused 4(th) chromosomes. Unfused Chromosome 4 exists as a non-recombining Y chromosome or as an autosome proportional to the frequency of the X-4 fusion. Furthermore, Y linkage along the unfused 4 is disrupted as a function of the rate of recombination with the centromere. Inter-population and intra-chromosomal patterns of nucleotide diversity were assayed using six regions distributed along unfused 4(th) chromosomes derived from populations with different frequencies of the X-4 fusion. No difference in overall level of nucleotide diversity was detected among populations, yet variation along the chromosome exhibits a distinct pattern in relation to the X-4 fusion. Sequence diversity is inflated at loci experiencing the strongest Y linkage. These findings are inconsistent with the expected reduction in nucleotide diversity resulting from hitchhiking due to background selection or selective sweeps. In contrast, excessive polymorphism is accruing in association with transient Y linkage, and furthermore, hitchhiking with sexually antagonistic alleles is potentially responsible