Envisioning Creative Collaboration between Faculty and Technologists

Faculty developers must often mediate conflicts resulting from differences between seemingly mutually exclusive cultures that university technolo gists and university teachers inhabit. Activity theory embraces workplace conflict as normal and as contributing to organizing health and adapta tion, in contrast to a functionalist approach that focuses on how to maintain system equilibrium. Engestrom’s (1987) interpretation of activity theory provides a theoretically informed framework for under standing different forms of human activity, mediated by culturally mol ded rules, values, and division of labor, without suffering from the polarizing effects of an us-versus-them approach

Counseling Athletes Who Use Performance-Enhancing Drugs: A New Conceptual Framework Linked to Clinical Practice

Doping, the use of performance-enhancing drugs by athletes, is a major concern that the media have publicized prominently. Sport governing bodies currently use two primary methods to dissuade athletes from doping: punishment and didactic education. Neither of these approaches has eradicated doping from competitive athletics because the practice appears to be increasing. Including clinical interventions in systemic campaigns that address this problem would be efficacious. The current article provides a conceptual framework that addresses doping from a psychologist’s perspective and then operationalizes this framework, all the while identifying the unique environment in which athletes function. Practical interventions for working with clients who dope are identified, as are possible future research paths that could benefit work with this population

Cosmic Calibration: Constraints from the Matter Power Spectrum and the Cosmic Microwave Background

Several cosmological measurements have attained significant levels of maturity and accuracy over the last decade. Continuing this trend, future observations promise measurements of the statistics of the cosmic mass distribution at an accuracy level of one percent out to spatial scales with k~10 h/Mpc and even smaller, entering highly nonlinear regimes of gravitational instability. In order to interpret these observations and extract useful cosmological information from them, such as the equation of state of dark energy, very costly high precision, multi-physics simulations must be performed. We have recently implemented a new statistical framework with the aim of obtaining accurate parameter constraints from combining observations with a limited number of simulations. The key idea is the replacement of the full simulator by a fast emulator with controlled error bounds. In this paper, we provide a detailed description of the methodology and extend the framework to include joint analysis of cosmic microwave background and large scale structure measurements. Our framework is especially well-suited for upcoming large scale structure probes of dark energy such as baryon acoustic oscillations and, especially, weak lensing, where percent level accuracy on nonlinear scales is needed.Comment: 15 pages, 14 figure

Whole genome sequencing of experimental hybrids supports meiosis-like sexual recombination in Leishmania

Hybrid genotypes have been repeatedly described among natural isolates of Leishmania, and the recovery of experimental hybrids from sand flies co-infected with different strains or species of Leishmania has formally demonstrated that members of the genus possess the machinery for genetic exchange. As neither gamete stages nor cell fusion events have been directly observed during parasite development in the vector, we have relied on a classical genetic analysis to determine if Leishmania has a true sexual cycle. Here, we used whole genome sequencing to follow the chromosomal inheritance patterns of experimental hybrids generated within and between different strains of L. major and L. infantum. We also generated and sequenced the first experimental hybrids in L. tropica. We found that in each case the parental somy and allele contributions matched the inheritance patterns expected under meiosis 97–99% of the time. The hybrids were equivalent to F1 progeny, heterozygous throughout most of the genome for the markers that were homozygous and different between the parents. Rare, non-Mendelian patterns of chromosomal inheritance were observed, including a gain or loss of somy, and loss of heterozygosity, that likely arose during meiosis or during mitotic divisions of the progeny clones in the fly or culture. While the interspecies hybrids appeared to be sterile, the intraspecies hybrids were able to produce backcross and outcross progeny. Analysis of 5 backcross and outcross progeny clones generated from an L. major F1 hybrid, as well as 17 progeny clones generated from backcrosses involving a natural hybrid of L. tropica, revealed genome wide patterns of recombination, demonstrating that classical crossing over occurs at meiosis, and allowed us to construct the first physical and genetic maps in Leishmania. Altogether, the findings provide strong evidence for meiosis-like sexual recombination in Leishmania, presenting clear opportunities for forward genetic analysis and positional cloning of important genes.</div

A Large-scale 3D Micromechanical Computational Myocardium Model

The right ventricle (RV) of the heart experiences substantial adaptions in structure and mechanical properties under pulmonary arterial hypertension (PAH). Developing computational models of RV myocardium can provide crucial insight into the factors influencing the onset, progression, and potential reversibility of post-PAH remodeling. However, knowledge of the mechanical interactions between myocardial constituents like myofibers and extracellular matrix (ECM) collagen, previously shown to be essential for capturing tissue behavior, remains incomplete, necessitating a micromechanical framework to link tissue-scale mechanical behavior to myocardial microanatomy. We developed a micromechanical finite element (FE) model leveraging high-fidelity imaging of myocardial microstructure to elucidate micro-scale myofiber-collagen interactions and their contribution to bulk tissue properties. We generated a 1.1-million tetrahedral mesh from a confocal microscopy dataset of a 204x204x40 μm myocardium sample. The material behaviors of the myofiber and ECM were modeled with hyperelastic, anisotropic, nearly incompressible constitutive forms derived from previous structurally-based models. The FE model was used to simulate physiologically informed equibiaxial and non-equibiaxial planar biaxial deformations, and the material parameters were fitted to the total stress-strain response of our previously developed tissue- scale model. Simulations were performed on the Stampede2 supercomputer at the Texas Advanced Computing Center using the finite element solver FEniCS, parallelized over 68 processors. We then employed a multiscale homogenization technique to predict tissue-level (5x5x0.7-mm) biaxial behavior from the localized micromechanical response via emulation of the tissue-scale histological structure and experimental biaxial deformation protocols. Recapitulation of the myocardial microanatomy successfully reproduced the tissue-level results in all deformation modes, suggesting that the micro-scale arrangement of myofibers and ECM is a primary mechanism driving myofiber-collagen coupling at the bulk tissue level. This work establishes the feasibility of incorporating microanatomy into high-fidelity supercomputer-based modeling of myocardium to investigate post-PAH remodeling of the cardiac microstructure and identify mechanical attributes critical to heart disease therapies

Role for CD4+ CD25+ Regulatory T Cells in Reactivation of Persistent Leishmaniasis and Control of Concomitant Immunity

Reactivation of dormant infections causes an immense burden of morbidity and mortality in the world at large. Reactivation can occur as a result of immunosuppression, environmental insult, or aging; however, the cause of reactivation of such infections is often not clear. We have previously shown that persistence of the parasite Leishmania major is controlled by endogenous CD4+ CD25+ regulatory T (T reg) cells. In this report, we show that despite efficient parasite clearance at secondary sites of infection, Leishmania superinfection can cause disease reactivation at the primary site. Our results strongly suggest that T reg cells, whose numbers increase in sites of reactivation, are directly responsible for such reactivation. Depletion of CD25+ cells at the time of secondary challenge prevented disease reactivation at the site of persistent infection while strengthening the expression of immunity at the site of secondary challenge. Finally, transfer of T reg cells purified from infected mice into chronically infected mice was sufficient to trigger disease reactivation and prevent the expression of an effector memory response. Our results demonstrate that after persistence is achieved, an equilibrium between T reg cells and effector lymphocytes, which can be disturbed by superinfection, controls the efficiency of recall immune responses and disease reactivation

Gene expression in Leishmania is regulated predominantly by gene dosage

ABSTRACT Leishmania tropica, a unicellular eukaryotic parasite present in North and East Africa, the Middle East, and the Indian subcontinent, has been linked to large outbreaks of cutaneous leishmaniasis in displaced populations in Iraq, Jordan, and Syria. Here, we report the genome sequence of this pathogen and 7,863 identified protein-coding genes, and we show that the majority of clinical isolates possess high levels of allelic diversity, genetic admixture, heterozygosity, and extensive aneuploidy. By utilizing paired genome-wide high-throughput DNA sequencing (DNA-seq) with RNA-seq, we found that gene dosage, at the level of individual genes or chromosomal “somy” (a general term covering disomy, trisomy, tetrasomy, etc.), accounted for greater than 85% of total gene expression variation in genes with a 2-fold or greater change in expression. High gene copy number variation (CNV) among membrane-bound transporters, a class of proteins previously implicated in drug resistance, was found for the most highly differentially expressed genes. Our results suggest that gene dosage is an adaptive trait that confers phenotypic plasticity among natural Leishmania populations by rapid down- or upregulation of transporter proteins to limit the effects of environmental stresses, such as drug selection. IMPORTANCE Leishmania is a genus of unicellular eukaryotic parasites that is responsible for a spectrum of human diseases that range from cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL) to life-threatening visceral leishmaniasis (VL). Developmental and strain-specific gene expression is largely thought to be due to mRNA message stability or posttranscriptional regulatory networks for this species, whose genome is organized into polycistronic gene clusters in the absence of promoter-mediated regulation of transcription initiation of nuclear genes. Genetic hybridization has been demonstrated to yield dramatic structural genomic variation, but whether such changes in gene dosage impact gene expression has not been formally investigated. Here we show that the predominant mechanism determining transcript abundance differences (>85%) in Leishmania tropica is that of gene dosage at the level of individual genes or chromosomal somy

Envisioning Creative Collaboration Between Faculty and Technologists

Faculty developers must often mediate the conflicts resulting from the differences between the seemingly mutually exclusive cultures that university technologists and university teachers inhabit. Activity Theory embraces workplace conflict as normal and as contributing to organization health and adaptation, in contrast to a functionalist approach which focuses on how to maintain system equilibrium. Engeström’s (1987) interpretation of Activity Theory provides a theoretically informed framework for understanding different forms of human activity, mediated by culturally molded rules, values, and division of labor, without suffering from the polarizing effects of an “Us vs Them” approach

Deficiency in β1,3-Galactosyltransferase of a Leishmania major Lipophosphoglycan Mutant Adversely Influences the Leishmania-Sand Fly Interaction

To study the function of side chain oligosaccharides of the cell-surface lipophosphoglycan (LPG), mutagenized Leishmania major defective in side chain biosynthesis were negatively selected by agglutination with the monoclonal antibody WIC79.3, which recognizes the galactose-containing side chains of L. major LPG. One such mutant, called Spock, lacked the ability to bind significantly to midguts of the natural L. major vector, Phlebotomus papatasi, and to maintain infection in the sand fly after excretion of the digested bloodmeal. Biochemical characterization of Spock LPG revealed its structural similarity to the LPG of Leishmania donovani, a species whose inability to bind to and maintain infections in P. papatasi midguts has been strongly correlated with the expression of a surface LPG lacking galactose-terminated oligosaccharide side chains. An in vitro galactosyltransferase assay using wild-type or Spock membranes was used to determine that the defect in Spock LPG biosynthesis is a result of defective beta1,3-galactosyltransferase activity as opposed to a modification of LPG, which would prevent it from serving as a competent substrate for galactose addition. The results of these experiments show that Spock lacks the beta1, 3-galactosyltransferase for side chain addition and that the LPG side chains are required for L. major to bind to and to produce transmissible infection in P. papatasi