26 research outputs found

    Ontogeny of hallucal metatarsal rigidity and shape in the rhesus monkey (Macaca mulatta) and chimpanzee (Pan troglodytes)

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    Life history variables including the timing of locomotor independence, along with changes in preferred locomotor behaviors and substrate use during development, influence how primates use their feet throughout ontogeny. Changes in foot function during development, in particular the nature of how the hallux is used in grasping, can lead to different structural changes in foot bones. To test this hypothesis, metatarsal midshaft rigidity [estimated from the polar second moment of area (J) scaled to bone length] and cross-sectional shape (calculated from the ratio of maximum and minimum second moments of area, Imax /Imin ) were examined in a cross-sectional ontogenetic sample of rhesus macaques (Macaca mulatta; n = 73) and common chimpanzees (Pan troglodytes; n = 79). Results show the hallucal metatarsal (Mt1) is relatively more rigid (with higher scaled J-values) in younger chimpanzees and macaques, with significant decreases in relative rigidity in both taxa until the age of achieving locomotor independence. Within each age group, Mt1 rigidity is always significantly higher in chimpanzees than macaques. When compared with the lateral metatarsals (Mt2-5), the Mt1 is relatively more rigid in both taxa and across all ages; however, this difference is significantly greater in chimpanzees. Length and J scale with negative allometry in all metatarsals and in both species (except the Mt2 of chimpanzees, which scales with positive allometry). Only in macaques does Mt1 midshaft shape significantly change across ontogeny, with older individuals having more elliptical cross-sections. Different patterns of development in metatarsal diaphyseal rigidity and shape likely reflect the different ways in which the foot, and in particular the hallux, functions across ontogeny in apes and monkeys

    Rapid expression and purification of the hepatitis delta virus antigen using the methylotropic yeast Pichia pastoris

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    Objective: Patients with dual hepatitis B (HBV) and hepatitis D (HDV) virus infection are at an increased risk of progression to liver cirrhosis and hepatocellular carcinoma than patients with a single viral infection. Treatment of viral hepatitis due to dual HBV/HDV infection represents a challenge. Currently there is no vaccine against HDV. Recombinant production of HDV antigen (HDAg) is the first step towards a potential vaccine candidate and the development of assays for HDV detection. Results: This study demonstrates the expression of one HDAg isoform, S-HDAg, in Pichia pastoris. A recombinant vector carrying a tagged gene encoding S-HDAg under the control of the methanol-inducible promoter AOX1 was designed and integrated into P. pastoris X33. The protein, which was purified using a Ni2+ affinity column and eluted at 100-150 mM imidazole, has potential as a recombinant antigen for further study

    Global Analysis of the Evolution and Mechanism of Echinocandin Resistance in Candida glabrata

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    The evolution of drug resistance has a profound impact on human health. Candida glabrata is a leading human fungal pathogen that can rapidly evolve resistance to echinocandins, which target cell wall biosynthesis and are front-line therapeutics for Candida infections. Here, we provide the first global analysis of mutations accompanying the evolution of fungal drug resistance in a human host utilizing a series of C. glabrata isolates that evolved echinocandin resistance in a patient treated with the echinocandin caspofungin for recurring bloodstream candidemia. Whole genome sequencing identified a mutation in the drug target, FKS2, accompanying a major resistance increase, and 8 additional non-synonymous mutations. The FKS2-T1987C mutation was sufficient for echinocandin resistance, and associated with a fitness cost that was mitigated with further evolution, observed in vitro and in a murine model of systemic candidemia. A CDC6-A511G(K171E) mutation acquired before FKS2-T1987C(S663P), conferred a small resistance increase. Elevated dosage of CDC55, which acquired a C463T(P155S) mutation after FKS2-T1987C(S663P), ameliorated fitness. To discover strategies to abrogate echinocandin resistance, we focused on the molecular chaperone Hsp90 and downstream effector calcineurin. Genetic or pharmacological compromise of Hsp90 or calcineurin function reduced basal tolerance and resistance. Hsp90 and calcineurin were required for caspofungin-dependent FKS2 induction, providing a mechanism governing echinocandin resistance. A mitochondrial respiration-defective petite mutant in the series revealed that the petite phenotype does not confer echinocandin resistance, but renders strains refractory to synergy between echinocandins and Hsp90 or calcineurin inhibitors. The kidneys of mice infected with the petite mutant were sterile, while those infected with the HSP90-repressible strain had reduced fungal burden. We provide the first global view of mutations accompanying the evolution of fungal drug resistance in a human host, implicate the premier compensatory mutation mitigating the cost of echinocandin resistance, and suggest a new mechanism of echinocandin resistance with broad therapeutic potential

    Immunodeficiency and Autoimmune Enterocolopathy Linked to NFAT5 Haploinsufficiency

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    The link between autoimmune diseases and primary immunodeficiency syndromes has been increasingly appreciated. Immunologic evaluation of a young man with autoimmune enterocolopathy and unexplained infections revealed evidence of immunodeficiency, including IgG subclass deficiency, impaired Ag-induced lymphocyte proliferation, reduced cytokine production by CD8(+) T lymphocytes, and decreased numbers of NK cells. Genetic evaluation identified haploinsufficiency of NFAT5, a transcription factor regulating immune cell function and cellular adaptation to hyperosmotic stress, as a possible cause of this syndrome. Inhibition or deletion of NFAT5 in normal human and murine cells recapitulated several of the immune deficits identified in the patient. These results provide evidence of a primary immunodeficiency disorder associated with organ-specific autoimmunity linked to NFAT5 deficiency

    Immunodeficiency and Autoimmune Enterocolopathy Linked to NFAT5 Haploinsufficiency

    No full text
    The link between autoimmune diseases and primary immunodeficiency syndromes has been increasingly appreciated. Immunologic evaluation of a young man with autoimmune enterocolopathy and unexplained infections revealed evidence of immunodeficiency, including IgG subclass deficiency, impaired antigen-induced lymphocyte proliferation, reduced cytokine production by CD8(+) T lymphocytes, and decreased numbers of natural killer (NK) cells. Genetic evaluation identified haploinsufficiency of NFAT5, a transcription factor regulating immune cell function and cellular adaptation to hyperosmotic stress, as a possible cause of this syndrome. Inhibition or deletion of NFAT5 in normal human and murine cells recapitulated several of the immune deficits identified in the patient. These results provide evidence of a primary immunodeficiency disorder associated with organ-specific autoimmunity linked to NFAT5 deficiency
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