88 research outputs found

    Analyses of 32 Loci Clarify Phylogenetic Relationships among Trypanosoma cruzi Lineages and Support a Single Hybridization prior to Human Contact

    Get PDF
    Trypanosoma cruzi is the protozoan parasite that causes Chagas disease, a major health problem in Latin America. The genetic diversity of this parasite has been traditionally divided in two major groups: T. cruzi I and II, which can be further divided in six major genetic subdivisions (subgroups TcI-TcVI). T. cruzi I and II seem to differ in important biological characteristics, and are thought to represent a natural division relevant for epidemiological studies and development of prophylaxis. Having a correct reconstruction of the evolutionary history of T. cruzi is essential for understanding the potential connection between the genetic and phenotypic variability of T. cruzi with the different manifestations of Chagas disease. Here we present results from a comprehensive phylogenetic analysis of T. cruzi using more than 26 Kb of aligned sequence data. We show strong evidence that T. cruzi II (TcII-VI) is not a natural evolutionary group but a paraphyletic lineage and that all major lineages of T. cruzi evolved recently (<3 million years ago [mya]). Furthermore, the sequence data is consistent with one major hybridization event having occurred in this species recently (< 1 mya) but well before T. cruzi entered in contact with humans in South America

    HIV-infected T cells are migratory vehicles for viral dissemination

    Get PDF
    After host entry through mucosal surfaces, HIV-1 disseminates to lymphoid tissues to establish a generalized infection of the immune system. The mechanisms by which this virus spreads among permissive target cells locally during early stages of transmission, and systemically during subsequent dissemination are not known1. In vitro studies suggest that formation of virological synapses (VSs) during stable contacts between infected and uninfected T cells greatly increases the efficiency of viral transfer2. It is unclear, however, if T cell contacts are sufficiently stable in vivo to allow for functional synapse formation under the conditions of perpetual cell motility in epithelial3 and lymphoid tissues4. Here, using multiphoton intravital microscopy (MP-IVM), we examined the dynamic behavior of HIV-infected T cells in lymph nodes (LNs) of humanized mice. We found that most productively infected T cells migrated robustly, resulting in their even distribution throughout the LN cortex. A subset of infected cells formed multinucleated syncytia through HIV envelope (Env)-dependent cell fusion. Both uncoordinated motility of syncytia as well as adhesion to CD4+ LN cells led to the formation of long membrane tethers, increasing cell lengths to up to 10 times that of migrating uninfected T cells. Blocking the egress of migratory T cells from LNs into efferent lymph, and thus interrupting T cell recirculation, limited HIV dissemination and strongly reduced plasma viremia. Thus, we have found that HIV-infected T cells are motile, form syncytia, and establish tethering interactions that may facilitate cell-to-cell transmission through VSs. While their migration in LNs spreads infection locally, T cell recirculation through tissues is important for efficient systemic viral spread, suggesting new molecular targets to antagonize HIV infection

    Shotgun Sequencing Analysis of Trypanosoma cruzi I Sylvio X10/1 and Comparison with T. cruzi VI CL Brener

    Get PDF
    Trypanosoma cruzi is the causative agent of Chagas disease, which affects more than 9 million people in Latin America. We have generated a draft genome sequence of the TcI strain Sylvio X10/1 and compared it to the TcVI reference strain CL Brener to identify lineage-specific features. We found virtually no differences in the core gene content of CL Brener and Sylvio X10/1 by presence/absence analysis, but 6 open reading frames from CL Brener were missing in Sylvio X10/1. Several multicopy gene families, including DGF, mucin, MASP and GP63 were found to contain substantially fewer genes in Sylvio X10/1, based on sequence read estimations. 1,861 small insertion-deletion events and 77,349 nucleotide differences, 23% of which were non-synonymous and associated with radical amino acid changes, further distinguish these two genomes. There were 336 genes indicated as under positive selection, 145 unique to T. cruzi in comparison to T. brucei and Leishmania. This study provides a framework for further comparative analyses of two major T. cruzi lineages and also highlights the need for sequencing more strains to understand fully the genomic composition of this parasite

    Spanish version of the Oral Health Impact Profile (OHIP-Sp)

    Get PDF
    BACKGROUND: The need for appraisal of oral health-related quality of life has been increasingly recognized over the last decades. The aims of this study were to develop a Spanish version (OHIP-Sp) of the Oral Health Impact Profile and to evaluate its convergent and discriminative validity, and its internal consistency. METHODS: The original 49-items OHIP was translated to Spanish, revised for understanding and semantics by two independent dentists, and then translated back to English by an independent bilingual dentist. The data originated in a cross sectional study conducted among high school students from the Province of Santiago, Chile. The study group was sampled using a multistage random cluster procedure yielding 9,203 students aged 12–21 years. All selected students were invited to participate and all filled a questionnaire with information on socio-demographic factors; oral health related behaviors; and self-reported oral health status (good, fair or poor). From this group, 9,163 students also accepted to fill a detailed questionnaire on socio-economic indicators and to receive a clinical examination comprising direct recordings of clinical attachment levels (CAL) in molars and incisors, tooth loss, and the presence of necrotizing ulcerative gingival lesions. RESULTS: The participation rate and the questionnaire completeness were high with OHIP-Sp total scores being computed for 9,133 subjects. Self-perceived oral health status was associated with the total OHIP-Sp score and all its domains (Spearman rank correlation). The OHIP-Sp total score was also directly associated with the 4 dental outcomes investigated (Mann-Whitney test) and the largest impact was found for the outcomes, 'tooth loss' with a mean OHIP-Sp score = 13.5 and 'CAL >= 3 mm' with a mean OHIP-Sp score = 13.0. CONCLUSION: The OHIP-Sp revealed suitable convergent and discriminative validity and appropriate internal consistency (Cronbach's α). Further studies on OHIP-Sp warrant the inclusion of populations with a higher disease burden; and the use of test-retest reliability exercises to evaluate the stability of the test

    The eClinical Care Pathway Framework: A novel structure for creation of online complex clinical care pathways and its application in the management of sexually transmitted infections.

    Get PDF
    Despite considerable international eHealth impetus, there is no guidance on the development of online clinical care pathways. Advances in diagnostics now enable self-testing with home diagnosis, to which comprehensive online clinical care could be linked, facilitating completely self-directed, remote care. We describe a new framework for developing complex online clinical care pathways and its application to clinical management of people with genital chlamydia infection, the commonest sexually transmitted infection (STI) in England.Using the existing evidence-base, guidelines and examples from contemporary clinical practice, we developed the eClinical Care Pathway Framework, a nine-step iterative process. Step 1: define the aims of the online pathway; Step 2: define the functional units; Step 3: draft the clinical consultation; Step 4: expert review; Step 5: cognitive testing; Step 6: user-centred interface testing; Step 7: specification development; Step 8: software testing, usability testing and further comprehension testing; Step 9: piloting. We then applied the Framework to create a chlamydia online clinical care pathway (Online Chlamydia Pathway).Use of the Framework elucidated content and structure of the care pathway and identified the need for significant changes in sequences of care (Traditional: history, diagnosis, information versus Online: diagnosis, information, history) and prescribing safety assessment. The Framework met the needs of complex STI management and enabled development of a multi-faceted, fully-automated consultation.The Framework provides a comprehensive structure on which complex online care pathways such as those needed for STI management, which involve clinical services, public health surveillance functions and third party (sexual partner) management, can be developed to meet national clinical and public health standards. The Online Chlamydia Pathway's standardised method of collecting data on demographics and sexual behaviour, with potential for interoperability with surveillance systems, could be a powerful tool for public health and clinical management.UKCRC Translational Infection Research (TIR) Initiative supported by the Medical Research Council, eSTI2 Consortium (Grant Number G0901608)

    GWAS for executive function and processing speed suggests involvement of the CADM2 gene

    Get PDF
    To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32 070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.Molecular Psychiatry advance online publication, 14 April 2015; doi:10.1038/mp.2015.37

    How reproducible are surface areas calculated from the BET equation?

    Get PDF
    Porosity and surface area analysis play a prominent role in modern materials science. At the heart of this sits the Brunauer-Emmett-Teller (BET) theory, which has been a remarkably successful contribution to the field of materials science. The BET method was developed in the 1930s for open surfaces but is now the most widely used metric for the estimation of surface areas of micro- and mesoporous materials. Despite its widespread use, the calculation of BET surface areas causes a spread in reported areas, resulting in reproducibility problems in both academia and industry. To prove this, for this analysis, 18 already-measured raw adsorption isotherms were provided to sixty-one labs, who were asked to calculate the corresponding BET areas. This round-robin exercise resulted in a wide range of values. Here, the reproducibility of BET area determination from identical isotherms is demonstrated to be a largely ignored issue, raising critical concerns over the reliability of reported BET areas. To solve this major issue, a new computational approach to accurately and systematically determine the BET area of nanoporous materials is developed. The software, called "BET surface identification" (BETSI), expands on the well-known Rouquerol criteria and makes an unambiguous BET area assignment possible

    Simulation of dynamic bubble spectra in tissues

    No full text
    Decompression sickness (DCS) is the result of bubble formation in the body due to excessive/rapid reduction in the ambient pressure. Existing models relate the decompression stress either to the inert gas load or to the size of a single bubble in a tissue compartment. This paper presents a model that uses the gas exchange equations combined with bubble dissolution physics and population balance equations to produce a new mathematical framework for DCS modeling. This framework, the population balance model for decompression sickness (PBMDS), simulates the number of bubbles with their corresponding size distributions in a compartmental tissue array, The model has a modular structure that enables one to explore different modeling results with respect to key aspects of DCS, such as gas exchange, nucleation, and surface tension. The paper's goal is to present the derivation of PBMDS in detail, however, three simple application case studies are provided. The aim of these case studies is to suggest that PBMDS supplies additional information on bubble distribution while supporting the results from current practice
    corecore