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31.
Erica Bree Rosenblum Timothy Y. James Kelly R. Zamudio Thomas J. Poorten Dan Ilut David Rodriguez Jonathan M. Eastman Katy Richards-Hrdlicka Suzanne Joneson Thomas S. Jenkinson Joyce E. Longcore Gabriela Parra Olea Luís Felipe Toledo Maria Luz Arellano Edgar M. Medina Silvia Restrepo Sandra Victoria Flechas Lee Berger Cheryl J. Briggs Jason E. Stajich 《Proceedings of the National Academy of Sciences of the United States of America》2013,110(23):9385-9390
Understanding the evolutionary history of microbial pathogens is critical for mitigating the impacts of emerging infectious diseases on economically and ecologically important host species. We used a genome resequencing approach to resolve the evolutionary history of an important microbial pathogen, the chytrid Batrachochytrium dendrobatidis (Bd), which has been implicated in amphibian declines worldwide. We sequenced the genomes of 29 isolates of Bd from around the world, with an emphasis on North, Central, and South America because of the devastating effect that Bd has had on amphibian populations in the New World. We found a substantial amount of evolutionary complexity in Bd with deep phylogenetic diversity that predates observed global amphibian declines. By investigating the entire genome, we found that even the most recently evolved Bd clade (termed the global panzootic lineage) contained more genetic variation than previously reported. We also found dramatic differences among isolates and among genomic regions in chromosomal copy number and patterns of heterozygosity, suggesting complex and heterogeneous genome dynamics. Finally, we report evidence for selection acting on the Bd genome, supporting the hypothesis that protease genes are important in evolutionary transitions in this group. Bd is considered an emerging pathogen because of its recent effects on amphibians, but our data indicate that it has a complex evolutionary history that predates recent disease outbreaks. Therefore, it is important to consider the contemporary effects of Bd in a broader evolutionary context and identify specific mechanisms that may have led to shifts in virulence in this system.Emerging infectious diseases (EIDs) pose significant challenges for human health, agricultural crops, and economically and ecologically important populations in nature (1–4). The incidence of EIDs has been steadily rising over the last several decades (5, 6), and EIDs are of particular concern in an increasingly globalized world. For example, the majority of human EIDs is zoonoses that originate in wildlife (5) and subsequently, create a significant burden for global economies and public health (7, 8). Therefore, scientific efforts to understand and respond to EIDs are critical in diverse fields from biomedicine to conservation biology.Although EIDs result from a complex interplay of factors, many studies focus primarily on the emergence of novel microbial pathogens. There are, in fact, high-profile examples of EIDs caused by the rapid appearance of novel, hypervirulent, or host-switching strains (9–11), but EIDs are not always caused by rapid or recent evolution of the pathogen itself. Virulence itself is an emergent property of microbe–host–environment interactions (12). Thus, EIDs can result from shifts in any factor—or combination of factors—in the microbe–host–environment epidemiological triangle (13). Characterizing the evolutionary history of emerging pathogens is, thus, critical, allowing us to determine whether observed EIDs result from rapid, recent shifts in organisms with pathogenic potential.Chytridiomycosis is an EID responsible for declines in amphibian species around the world. The chytrid fungus Batrachochytrium dendrobatidis (Bd) was discovered and linked to amphibian declines in 1998 (14, 15). Chytridiomycosis is caused by Bd and kills amphibians by disrupting the integrity of their skin, a physiologically important organ that is involved in gas exchange, electrolyte balance, hydration, and protection from other pathogens (16, 17). Bd infects hundreds of species of amphibians, is found on all continents where amphibians occur, and is responsible for declines and extirpations in a diversity of amphibian hosts (18).Soon after Bd was discovered, researchers proposed two competing hypotheses for the emergence of chytridiomycosis. The emerging pathogen hypothesis posited that a novel disease agent caused chytridiomycosis, and the endemic pathogen hypothesis proposed that an environmental shift disrupted a previously benign microbe–host interaction (19). Over the years, spatiotemporal and genetic data have supported the emerging pathogen hypothesis (reviewed in refs. 20 and 21). Spatiotemporal data provided clear evidence that Bd arrived and spread through geographic regions where it was not present historically (22–24). Early genetic studies also found very little genetic differentiation in Bd with no geographic signal, consistent with a recent, rapid spread of a novel disease agent (25–27). Recently, genetic and genomic data have been used to describe a geographically widespread Bd lineage [termed the global panzootic lineage (GPL)] (28) and several putatively endemic Bd lineages (28–30). However, different studies have used different methods and focused sampling in different parts of the world, precluding integration across studies to determine the evolutionary history leading to the emergence of Bd as a global threat to amphibians.Here, we present whole-genome sequencing from a global panel of Bd isolates to show that Bd has a historically deeper and more complex evolutionary history than previously appreciated. We sequenced Bd genomes from around the world and also, a non-Bd chytrid outgroup that does not attack amphibians [Homolaphlyctis polyrhiza (Hp)] (31). Our focus was primarily on the evolutionary dynamics of Bd in the Americas, because many of the most devastating outbreaks have occurred in the New World. We address outstanding questions about the origins, genetic diversity, and genome structure of Bd that can be resolved using whole-genome data. We also integrate our genomic data with those data from a previous study with complementary geographic sampling (28). Our results reveal that the evolutionary history of Bd is complex, with multiple divergent lineages, heterogeneous patterns of genomic evolution, and no simple link between a single evolutionary event and observed amphibian declines. 相似文献
32.
CMV drives the expansion of highly functional memory T cells expressing NK‐cell receptors in renal transplant recipients 下载免费PDF全文
Nandini Makwana Bree Foley Sonia Fernandez Silvia Lee Ashley Irish Hanspeter Pircher Patricia Price 《European journal of immunology》2017,47(8):1324-1334
Cytomegalovirus (CMV) is a common opportunistic infection encountered in renal transplant recipients (RTRs) and may be reactivated without symptoms at any time post‐transplant. We describe how active and latent CMV affect T‐cell subsets in RTRs who are stable on maintenance therapy. T‐cell responses to CMV were assessed in RTRs (n = 54) >2 years post‐transplant, and healthy controls (n = 38). Seven RTRs had CMV DNA detectable in plasma. CMV antibody and DNA aligned with increased proportions of CD8+ T cells and reduced CD4/CD8 ratios. This paralleled an expansion of effector memory T‐cell (TEM), terminally differentiated T‐cell (TEMRA) and CD57+ TEMRA cell populations. Expression of NK‐cell receptors, LIR‐1 and KLRG1 on CD4+ and CD8+ CD57+ TEM and TEMRA cells correlated with elevated interferon‐γ and cytotoxic responses to anti‐CD3 and increased cytotoxic responses to CMV phosphoprotein (pp) 65 in RTRs who carried CMV DNA. CD8+ T cells from all CMV seropositive RTRs responded efficiently to CMV immediate early (IE) ‐1 peptides. The data show that latent and active CMV infection can alter T‐cell subsets in RTRs many years after transplantation, and up‐regulate T‐cell expression of NK‐cell receptors. This may enhance effector responses of CD4+ and CD8+ T cells against CMV. 相似文献
33.
J. Melissas E. de Bree G. Schoretsanitis D. D. Tsiftsis 《Acta chirurgica Belgica》2013,113(5):559-563
Purpose : In the ongoing effort to improve patient treatment, a deeper understanding of the symptomatology, physical signs and management options of rare splenic, non-traumatic, benign diseases is extremely important. Patients and Methods : The records of eight consecutive patients with benign splenic conditions, other than injury and abscess, were reviewed retrospectively in order to analyse the clinical presentation, diagnostic methodology and therapeutic procedures applied in these rare conditions.Of the eight patients, three were diagnosed with splenic hydatid cyst, two with pseudocysts, one with splenic epider-moid cyst, one with wandering spleen and one with infraction of an ectopic spleen with situs inversus of other intraabdominal organs.Results : Upper abdominal pain was the most common presenting symptom and a tender palpable mass in the left upper abdominal quadrant, the predominant clinical finding. Pre-operative CT scanning confirmed the diagnosis in six patients, but failed to reveal the splenic pathology in the remaining two cases. Seven patients underwent splenectomy while saving splenic parenchyma was feasible in only one patient (12,5%).Conclusions : Splenic, non-traumatic, benign diseases have vague clinical presentation and may create diagnostic difficulties. Although spleen saving intervention can be applied in selected cases, splenectomy would be required in most patients. 相似文献
34.
Bart de Keizer Gerard C. Krijger F. Tessa Ververs Robert J. J. van Es Remco de Bree Stefan Willems 《Nuclear Medicine and Molecular Imaging》2017,51(4):360-361
A patient with a history of adenoid cystic carcinoma of the nasal cavity presented himself with bone pain and an elevated PSA level. On suspicion of metastatic prostate cancer a 68Ga-PSMA PET-CT was performed. The PET-CT showed numerous lung and non-sclerotic bone metastasis. Biopsy of a bone metastasis was performed and pathology showed adenoid cystic carcinoma instead of prostate cancer. Immunohistochemical PSMA staining of the primary tumour showed intense PSMA expression in adenoid cystic carcinoma tumour cells. Because of the high PSMA expression of adenoid cystic carcinoma, 68Ga-PSMA PET-CT might be a promising imaging modality for this malignancy. 相似文献
35.
Cailotto C Costes LM van der Vliet J VAN Bree SH VAN Heerikhuize JJ Buijs RM Boeckxstaens GE 《Neurogastroenterology and motility》2012,24(2):191-e93
Background The cholinergic anti‐inflammatory pathway is proposed to be part of the so‐called vago‐vagal ‘inflammatory reflex’. The aim of this study is to provide neuro‐anatomical evidence to support the existence of a functional neuronal circuit and its activation in response to intestinal inflammation. Methods The expression of c‐fos was evaluated at different levels of the neurocircuitry in the course of postoperative ileus (POI) in a mouse model. Specific activation of the motor neurons innervating the inflamed intestine and the spleen was monitored by retrograde tracing using cholera toxin‐b. The role of the vagal afferent pathway nerve was evaluated by selective vagal denervation of the intestine. Key Results Abdominal surgery resulted in subtle inflammation of the manipulated intestine at 24 h (late phase), but not after 2 and 6 h (early) after surgery. This local inflammation was associated with activation of neurons in the nucleus of the solitary tract and in the dorsal nucleus of the vagus. The vagal output mainly targeted the inflamed zone: 42% of motor neurons innervating the intestine expressed c‐fos IR in contrast to 7% of those innervating the spleen. Vagal denervation of the intestine abolished c‐fos expression in the brain nuclei involved in the neuronal network activated by intestinal inflammation. Conclusions & Inferences Our data demonstrate that intestinal inflammation triggers a vagally mediated circuit leading mainly to activation of vagal motor neurons connected to the inflamed intestine. These findings for the first time provide neuro‐anatomical evidence for the existence of the endogenous ‘inflammatory reflex’ and its activation during inflammation. 相似文献
36.
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38.
Ralph J Abi-Habib Ravibhushan Singh Stephen H Leppla John J Greene Yan Ding Bree Berghuis Nicholas S Duesbery Arthur E Frankel 《Clinical cancer research》2006,12(24):7437-7443
PURPOSE: Anthrax Lethal Toxin (LeTx), composed of protective antigen and lethal factor, catalytically cleaves mitogen-activated protein kinase (MAPK) kinases and inhibits the MAPK signaling pathways. The majority of metastatic melanomas possess the V599E BRAF mutation, which constitutively activates MAPK1/2 signaling. LeTx is cytotoxic to BRAF mutant melanoma cell lines in vitro, whereas most normal cells are resistant to this toxin. In this study, we determine the in vivo potency and safety of systemically administered LeTx. EXPERIMENTAL DESIGN: A s.c. xenograft melanoma model in athymic nude mice was treated with different i.p. doses of LeTx. RESULTS: In this study, we show that in vivo systemic LeTx treatment of s.c. xenograft melanoma tumors in athymic nude mice yields partial and complete tumor regressions with minor toxicity to mice. When animal toxicity was observed, we did not find any histologic evidence of tissue damage. CONCLUSIONS: LeTx is one of the rare targeted agents to produce complete remissions of human melanomas in an animal model and thus warrants further preclinical development. 相似文献
39.
Ozcan R Kayikcioglu Iryna Falkenstein Linguen Cheng Igor Kozak Laurie La Bree Stanley P Azen Flossie Wong-Staal Nicholas F Paoni William R Freeman 《Journal of ocular pharmacology and therapeutics》2006,22(1):1-9
PURPOSE: The aim of this study was to evaluate the efficacy of hammerhead ribozyme to the proliferating cell nuclear antigen (PCNA-Rz) and 5-fluorouracil (5-FU) in experimental choroidal neovascularization (CNV) model in rats. METHODS: Laser was used to induce CNV in each eye of 44 rats. For angiography studies, injections of either a mixture of PCNA-Rz 10 microg/microL and 5-FU 1.5 microg/microL, versus the same dose of either drug alone versus a control injection of Hanks' Balanced Salt Solution (HBSS) were performed. We also studied this regimen to evaluate scar size and volume. RESULTS: There was significantly less angiographic leakage for the treated eyes compared to the controls by 3.53 grading points (P = 0.0005); CNV leakage was reduced in the combination group compared to 5-FU alone by 1.75 grading units (P = 0.04) and compared to PCNARz by 2.22 grading units (P = 0.07). The scar size and volume were smaller (diameter 354.6 +/- 174.2 microm vs 477.3 +/- 157.0 microm), (thickness 52.7 +/- 43.0 microm versus 79.6 +/- 46.2 microm) with a reduction in scar volume of 44.8%. CONCLUSIONS: Subretinal injection of PCNA-Rz and 5-FU mixture is more effective as treatment of laser-induced CNV, than either drug alone. The majority of the antiangiogenic effect is a result of 5-FU activity with a contribution by the PCNA ribozyme. 相似文献
40.
Effects of exercise and disuse on bone remodeling, bone mass, and biomechanical competence in spontaneously diabetic female rats 总被引:8,自引:0,他引:8
Diabetes is associated with low bone formation. In this study we investigate the effect of additional or reduced mechanical loading on indices of bone formation and resorption, bone mass, and biomechanical properties in spontaneously diabetic BB rats. Female diabetic (mean age 13 weeks) and age-matched control rats were each allocated to three experimental groups: no-intervention; supervised running exercise program (Ex); and unloading induced by unilateral sciatic neurectomy (USN). The study period was 8 weeks. We measured biochemical parameters of bone formation (plasma osteocalcin) and resorption (urinary deoxypyridinoline [Dpd]); bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) at middiaphyseal and metaphyseal regions of the femur; histomorphometry of the proximal tibial metaphysis (PTM); and biomechanical properties of the femur (neck, diaphysis, and metaphysis) and lumbar vertebra (L-5). In nondiabetic rats, Ex did not affect parameters of bone formation/resorption and BMD, and had little effect on biomechanical properties. USN increased Dpd excretion, whereas there was a decreased trabecular bone formation rate (BFR) on morphometry of PTM in both paralyzed and intact limbs. Compared with intact limbs, paralyzed limbs of USN rats showed decreased trabecular bone volume at the PTM, and decreased BMD and biomechanical properties at the distal femoral metaphysis (DFM) and, to a lesser extent, femoral neck. Diabetic rats of the three experimental groups had low plasma osteocalcin levels and Dpd excretion, as well as low BFR on morphometry. The BMD and biomechanical properties of both femur and L-5 were unchanged in diabetic rats. Diabetic Ex rats, however, showed a lower maximum load and stress at DFM than control Ex rats. Diabetic USN rats showed no increase in Dpd excretion; their paralyzed limbs showed decreased maximum load at DFM, but there was no significant decrease in trabecular bone volume at PTM or BMD at DFM. Thus, the running exercise does not affect low bone formation in diabetic rats; however, trabecular bone loss caused by disuse is less pronounced in diabetic rats, probably as a result of low bone resorption. 相似文献