Examining Landscape Factors Influencing Relative Distribution of Mosquito Genera and Frequency of Virus Infection

Mosquito-borne infections cause some of the most debilitating human diseases, including yellow fever and malaria, yet we lack an understanding of how disease risk scales with human-driven habitat changes. We present an approach to study variation in mosquito distribution and concomitant viral infections on the landscape level. In a pilot study we analyzed mosquito distribution along a 10-km transect of a West African rainforest area, which included primary forest, secondary forest, plantations, and human settlements. Variation was observed in the abundance of Anopheles, Aedes,Culex, and Uranotaenia mosquitoes between the different habitat types. Screening of trapped mosquitoes from the different habitats led to the isolation of five uncharacterized viruses of the families Bunyaviridae, Coronaviridae, Flaviviridae, and Rhabdoviridae, as well as an unclassified virus. Polymerase chain reaction screening for these five viruses in individual mosquitoes indicated a trend toward infection with specific viruses in specific mosquito genera that differed by habitat. Based on these initial analyses, we believe that further work is indicated to investigate the impact of anthropogenic landscape changes on mosquito distribution and accompanying arbovirus infection

Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy.

Sphingolipid imbalance is the culprit in a variety of neurological diseases, some affecting the myelin sheath. We have used whole-exome sequencing in patients with undetermined leukoencephalopathies to uncover the endoplasmic reticulum lipid desaturase DEGS1 as the causative gene in 19 patients from 13 unrelated families. Shared features among the cases include severe motor arrest, early nystagmus, dystonia, spasticity, and profound failure to thrive. MRI showed hypomyelination, thinning of the corpus callosum, and progressive thalamic and cerebellar atrophy, suggesting a critical role of DEGS1 in myelin development and maintenance. This enzyme converts dihydroceramide (DhCer) into ceramide (Cer) in the final step of the de novo biosynthesis pathway. We detected a marked increase of the substrate DhCer and DhCer/Cer ratios in patients' fibroblasts and muscle. Further, we used a knockdown approach for disease modeling in Danio rerio, followed by a preclinical test with the first-line treatment for multiple sclerosis, fingolimod (FTY720, Gilenya). The enzymatic inhibition of Cer synthase by fingolimod, 1 step prior to DEGS1 in the pathway, reduced the critical DhCer/Cer imbalance and the severe locomotor disability, increasing the number of myelinating oligodendrocytes in a zebrafish model. These proof-of-concept results pave the way to clinical translation

Comprehensive prediction of chromosome dimer resolution sites in bacterial genomes

<p>Abstract</p> <p>Background</p> <p>During the replication process of bacteria with circular chromosomes, an odd number of homologous recombination events results in concatenated dimer chromosomes that cannot be partitioned into daughter cells. However, many bacteria harbor a conserved dimer resolution machinery consisting of one or two tyrosine recombinases, XerC and XerD, and their 28-bp target site, <it>dif</it>.</p> <p>Results</p> <p>To study the evolution of the <it>dif/</it>XerCD system and its relationship with replication termination, we report the comprehensive prediction of <it>dif </it>sequences <it>in silico </it>using a phylogenetic prediction approach based on iterated hidden Markov modeling. Using this method, <it>dif </it>sites were identified in 641 organisms among 16 phyla, with a 97.64% identification rate for single-chromosome strains. The <it>dif </it>sequence positions were shown to be strongly correlated with the GC skew shift-point that is induced by replicational mutation/selection pressures, but the difference in the positions of the predicted <it>dif </it>sites and the GC skew shift-points did not correlate with the degree of replicational mutation/selection pressures.</p> <p>Conclusions</p> <p>The sequence of <it>dif </it>sites is widely conserved among many bacterial phyla, and they can be computationally identified using our method. The lack of correlation between <it>dif </it>position and the degree of GC skew suggests that replication termination does not occur strictly at <it>dif </it>sites.</p

A Phenotypic Profile of the Candida albicans Regulatory Network

Candida albicans is a normal resident of the gastrointestinal tract and also the most prevalent fungal pathogen of humans. It last shared a common ancestor with the model yeast Saccharomyces cerevisiae over 300 million years ago. We describe a collection of 143 genetically matched strains of C. albicans, each of which has been deleted for a specific transcriptional regulator. This collection represents a large fraction of the non-essential transcription circuitry. A phenotypic profile for each mutant was developed using a screen of 55 growth conditions. The results identify the biological roles of many individual transcriptional regulators; for many, this work represents the first description of their functions. For example, a quarter of the strains showed altered colony formation, a phenotype reflecting transitions among yeast, pseudohyphal, and hyphal cell forms. These transitions, which have been closely linked to pathogenesis, have been extensively studied, yet our work nearly doubles the number of transcriptional regulators known to influence them. As a second example, nearly a quarter of the knockout strains affected sensitivity to commonly used antifungal drugs; although a few transcriptional regulators have previously been implicated in susceptibility to these drugs, our work indicates many additional mechanisms of sensitivity and resistance. Finally, our results inform how transcriptional networks evolve. Comparison with the existing S. cerevisiae data (supplemented by additional S. cerevisiae experiments reported here) allows the first systematic analysis of phenotypic conservation by orthologous transcriptional regulators over a large evolutionary distance. We find that, despite the many specific wiring changes documented between these species, the general phenotypes of orthologous transcriptional regulator knockouts are largely conserved. These observations support the idea that many wiring changes affect the detailed architecture of the circuit, but not its overall output

Assessment of Yellow Fever Epidemic Risk: An Original Multi-criteria Modeling Approach

This article describes the use of an original modeling approach to assess the risk of yellow fever (YF) epidemics. YF is a viral hemorrhagic fever responsible in past centuries for devastating outbreaks. Since the 1930s, a vaccine has been available that protects the individual for at least 10 years, if not for life. However, immunization of populations in African countries was gradually discontinued after the 1960s. With the decrease in immunity against YF in African populations the disease reemerged in the 1980s. In 2005, WHO, UNICEF, and the GAVI Alliance decided to support preventive vaccination of at-risk populations in West African endemic countries in order to tackle the reemergence of YF and reduce the risk of urban YF outbreaks. Financial resources were made available to scale up a global YF vaccine stockpile and to support countries with limited resources in the management of preventive vaccination campaigns. This article describes the process we used to determine the most at-risk populations using a mathematical model to prioritize targeted immunization campaigns. We believe that this approach could be useful for other diseases for which decision making process is difficult because of limited data availability, complex risk variables, and a need for rapid decisions and implementation

Revised Lithostratigraphy of the Sonsela Member (Chinle Formation, Upper Triassic) in the Southern Part of Petrified Forest National Park, Arizona

BACKGROUND: Recent revisions to the Sonsela Member of the Chinle Formation in Petrified Forest National Park have presented a three-part lithostratigraphic model based on unconventional correlations of sandstone beds. As a vertebrate faunal transition is recorded within this stratigraphic interval, these correlations, and the purported existence of a depositional hiatus (the Tr-4 unconformity) at about the same level, must be carefully re-examined. METHODOLOGY/PRINCIPAL FINDINGS: Our investigations demonstrate the neglected necessity of walking out contacts and mapping when constructing lithostratigraphic models, and providing UTM coordinates and labeled photographs for all measured sections. We correct correlation errors within the Sonsela Member, demonstrate that there are multiple Flattops One sandstones, all of which are higher than the traditional Sonsela sandstone bed, that the Sonsela sandstone bed and Rainbow Forest Bed are equivalent, that the Rainbow Forest Bed is higher than the sandstones at the base of Blue Mesa and Agate Mesa, that strata formerly assigned to the Jim Camp Wash beds occur at two stratigraphic levels, and that there are multiple persistent silcrete horizons within the Sonsela Member. CONCLUSIONS/SIGNIFICANCE: We present a revised five-part model for the Sonsela Member. The units from lowest to highest are: the Camp Butte beds, Lot's Wife beds, Jasper Forest bed (the Sonsela sandstone)/Rainbow Forest Bed, Jim Camp Wash beds, and Martha's Butte beds (including the Flattops One sandstones). Although there are numerous degradational/aggradational cycles within the Chinle Formation, a single unconformable horizon within or at the base of the Sonsela Member that can be traced across the entire western United States (the "Tr-4 unconformity") probably does not exist. The shift from relatively humid and poorly-drained to arid and well-drained climatic conditions began during deposition of the Sonsela Member (low in the Jim Camp Wash beds), well after the Carnian-Norian transition

Worldwide comparison of survival from childhood leukaemia for 1995–2009, by subtype, age, and sex (CONCORD-2): a population-based study of individual data for 89 828 children from 198 registries in 53 countries

Background Global inequalities in access to health care are reflected in differences in cancer survival. The CONCORD programme was designed to assess worldwide differences and trends in population-based cancer survival. In this population-based study, we aimed to estimate survival inequalities globally for several subtypes of childhood leukaemia. Methods Cancer registries participating in CONCORD were asked to submit tumour registrations for all children aged 0-14 years who were diagnosed with leukaemia between Jan 1, 1995, and Dec 31, 2009, and followed up until Dec 31, 2009. Haematological malignancies were defined by morphology codes in the International Classification of Diseases for Oncology, third revision. We excluded data from registries from which the data were judged to be less reliable, or included only lymphomas, and data from countries in which data for fewer than ten children were available for analysis. We also excluded records because of a missing date of birth, diagnosis, or last known vital status. We estimated 5-year net survival (ie, the probability of surviving at least 5 years after diagnosis, after controlling for deaths from other causes [background mortality]) for children by calendar period of diagnosis (1995-99, 2000-04, and 2005-09), sex, and age at diagnosis (< 1, 1-4, 5-9, and 10-14 years, inclusive) using appropriate life tables. We estimated age-standardised net survival for international comparison of survival trends for precursor-cell acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML). Findings We analysed data from 89 828 children from 198 registries in 53 countries. During 1995-99, 5-year agestandardised net survival for all lymphoid leukaemias combined ranged from 10.6% (95% CI 3.1-18.2) in the Chinese registries to 86.8% (81.6-92.0) in Austria. International differences in 5-year survival for childhood leukaemia were still large as recently as 2005-09, when age-standardised survival for lymphoid leukaemias ranged from 52.4% (95% CI 42.8-61.9) in Cali, Colombia, to 91.6% (89.5-93.6) in the German registries, and for AML ranged from 33.3% (18.9-47.7) in Bulgaria to 78.2% (72.0-84.3) in German registries. Survival from precursor-cell ALL was very close to that of all lymphoid leukaemias combined, with similar variation. In most countries, survival from AML improved more than survival from ALL between 2000-04 and 2005-09. Survival for each type of leukaemia varied markedly with age: survival was highest for children aged 1-4 and 5-9 years, and lowest for infants (younger than 1 year). There was no systematic difference in survival between boys and girls. Interpretation Global inequalities in survival from childhood leukaemia have narrowed with time but remain very wide for both ALL and AML. These results provide useful information for health policy makers on the effectiveness of health-care systems and for cancer policy makers to reduce inequalities in childhood survival