Coccidioidomycosis Incidence in Arizona Predicted by Seasonal Precipitation

The environmental mechanisms that determine the inter-annual and seasonal variability in incidence of coccidioidomycosis are unclear. In this study, we use Arizona coccidioidomycosis case data for 1995–2006 to generate a timeseries of monthly estimates of exposure rates in Maricopa County, AZ and Pima County, AZ. We reveal a seasonal autocorrelation structure for exposure rates in both Maricopa County and Pima County which indicates that exposure rates are strongly related from the fall to the spring. An abrupt end to this autocorrelation relationship occurs near the the onset of the summer precipitation season and increasing exposure rates related to the subsequent season. The identification of the autocorrelation structure enabled us to construct a “primary” exposure season that spans August-March and a “secondary” season that spans April–June which are then used in subsequent analyses. We show that October–December precipitation is positively associated with rates of exposure for the primary exposure season in both Maricopa County (R = 0.72, p = 0.012) and Pima County (R = 0.69, p = 0.019). In addition, exposure rates during the primary exposure seasons are negatively associated with concurrent precipitation in Maricopa (R = −0.79, p = 0.004) and Pima (R = −0.64, p = 0.019), possibly due to reduced spore dispersion. These associations enabled the generation of models to estimate exposure rates for the primary exposure season. The models explain 69% (p = 0.009) and 54% (p = 0.045) of the variance in the study period for Maricopa and Pima counties, respectively. We did not find any significant predictors for exposure rates during the secondary season. This study builds on previous studies examining the causes of temporal fluctuations in coccidioidomycosis, and corroborates the “grow and blow” hypothesis

Pdx1 Is Post-Translationally Modified In vivo and Serine 61 Is the Principal Site of Phosphorylation

Maintaining sufficient levels of Pdx1 activity is a prerequisite for proper regulation of blood glucose homeostasis and beta cell function. Mice that are haploinsufficient for Pdx1 display impaired glucose tolerance and lack the ability to increase beta cell mass in response to decreased insulin signaling. Several studies have shown that post-translational modifications are regulating Pdx1 activity through intracellular localization and binding to co-factors. Understanding the signaling cues converging on Pdx1 and modulating its activity is therefore an attractive approach in diabetes treatment. We employed a novel technique called Nanofluidic Proteomic Immunoassay to characterize the post-translational profile of Pdx1. Following isoelectric focusing in nano-capillaries, this technology relies on a pan specific antibody for detection and it therefore allows the relative abundance of differently charged protein species to be examined simultaneously. In all eukaryotic cells tested we find that the Pdx1 protein separates into four distinct peaks whereas Pdx1 protein from bacteria only produces one peak. Of the four peaks in eukaryotic cells we correlate one of them to a phosphorylation Using alanine scanning and mass spectrometry we map this phosphorylation to serine 61 in both Min6 cells and in exogenous Pdx1 over-expressed in HEK293 cells. A single phosphorylation is also present in cultured islets but it remains unaffected by changes in glucose levels. It is present during embryogenesis but is not required for pancreas development

Life satisfaction and resilience in medical school – a six-year longitudinal, nationwide and comparative study

BACKGROUND: This study examined the relationship between life satisfaction among medical students and a basic model of personality, stress and coping. Previous studies have shown relatively high levels of distress, such as symptoms of depression and suicidal thoughts in medical undergraduates. However despite the increased focus on positive psychological health and well-being during the past decades, only a few studies have focused on life satisfaction and coping in medical students. This is the first longitudinal study which has identified predictors of sustained high levels of life satisfaction among medical students. METHODS: This longitudinal, nationwide questionnaire study examined the course of life satisfaction during medical school, compared the level of satisfaction of medical students with that of other university students, and identified resilience factors. T-tests were used to compare means of life satisfaction between and within the population groups. K-means cluster analyses were applied to identify subgroups among the medical students. Analysis of Variance (ANOVA) and logistic regression analyses were used to compare the subgroups. RESULTS: Life satisfaction decreased during medical school. Medical students were as satisfied as other students in the first year of study, but reported less satisfaction in their graduation year. Medical students who sustained high levels of life satisfaction perceived medical school as interfering less with their social and personal life, and were less likely to use emotion focused coping, such as wishful thinking, than their peers. CONCLUSION: Medical schools should encourage students to spend adequate time on their social and personal lives and emphasise the importance of health-promoting coping strategies

Alpha-Synuclein Cell-to-Cell Transfer and Seeding in Grafted Dopaminergic Neurons In Vivo

Several people with Parkinson’s disease have been treated with intrastriatal grafts of fetal dopaminergic neurons. Following autopsy, 10–22 years after surgery, some of the grafted neurons contained Lewy bodies similar to those observed in the host brain. Numerous studies have attempted to explain these findings in cell and animal models. In cell culture, α-synuclein has been found to transfer from one cell to another, via mechanisms that include exosomal transport and endocytosis, and in certain cases seed aggregation in the recipient cell. In animal models, transfer of α-synuclein from host brain cells to grafted neurons has been shown, but the reported frequency of the event has been relatively low and little is known about the underlying mechanisms as well as the fate of the transferred α-synuclein. We now demonstrate frequent transfer of α-synuclein from a rat brain engineered to overexpress human α-synuclein to grafted dopaminergic neurons. Further, we show that this model can be used to explore mechanisms underlying cell-to-cell transfer of α-synuclein. Thus, we present evidence both for the involvement of endocytosis in α-synuclein uptake in vivo, and for seeding of aggregation of endogenous α-synuclein in the recipient neuron by the transferred α-synuclein. Finally, we show that, at least in a subset of the studied cells, the transmitted α-synuclein is sensitive to proteinase K. Our new model system could be used to test compounds that inhibit cell-to-cell transfer of α-synuclein and therefore might retard progression of Parkinson neuropathology

Oncostatin M promotes STAT3 activation, VEGF production, and invasion in osteosarcoma cell lines

<p>Abstract</p> <p>Background</p> <p>We have previously demonstrated that both canine and human OSA cell lines, as well as 8 fresh canine OSA tumor samples, exhibit constitutive phosphorylation of STAT3, and that this correlates with enhanced expression of matrix metalloproteinase-2 (MMP2). While multiple signal transduction pathways can result in phosphorylation of STAT3, stimulation of the cytokine receptor gp130 through either IL-6 or Oncostatin M (OSM) is the most common mechanism through which STAT3 is activated. The purpose of this study was to evaluate the role of IL-6 and OSM stimulation on both canine and human OSA cell lines to begin to determine the role of these cytokines in the biology of OSA.</p> <p>Methods</p> <p>RT-PCR and Western blotting were used to interrogate the consequences of OSM and IL-6 stimulation of OSA cell lines. OSA cells were stimulated with OSM and/or hepatocyte growth factor (HGF) and the effects on MMP2 activity (gel zymography), proliferation (CyQUANT), invasion (Matrigel transwell assay), and VEGF production (Western blotting, ELISA) were assessed. The small molecule STAT3 inhibitor LLL3 was used to investigate the impact of STAT3 inhibition following OSM stimulation of OSA cells.</p> <p>Results</p> <p>Our data demonstrate that the OSM receptor (OSMR), but not IL-6 or its receptor, is expressed by all human and canine OSA cell lines and canine OSA tumor samples; additionally, OSM expression was noted in all tumor samples. Treatment of OSA cell lines with OSM induced phosphorylation of STAT3, Src, and JAK2. OSM stimulation also resulted in a dose dependent increase in MMP2 activity and VEGF expression that was markedly reduced following treatment with the small molecule STAT3 inhibitor LLL3. Lastly, OSM stimulation of OSA cell lines enhanced invasion through Matrigel, particularly in the presence of rhHGF. In contrast, both OSM and HGF stimulation of OSA cell lines did not alter their proliferative capacity.</p> <p>Conclusions</p> <p>These data indicate OSM stimulation of human and canine OSA cells induces STAT3 activation, thereby enhancing the expression/activation of MMP2 and VEGF, ultimately promoting invasive behavior and tumor angiogenesis. As such, OSM and its receptor may represent a novel target for therapeutic intervention in OSA.</p

Depression in medical students: insights from a longitudinal study

Background: Factors associated with depression of medical students are poorly understood. The purpose of this study is to determine the prevalence of depression in medical students, its change during the course, if depression persists for affected students, what are the factors associated with depression and how these factors change over time. Methods: A prospective, longitudinal observational study was conducted at the Medical School of the University of Minho, Portugal, between academic years 2009-2010 to 2012-2013. We included students who maintained their participation by annually completing a questionnaire including Beck Depression Inventory (BDI). Anxiety and burnout were assessed using the State Trait Anxiety Inventory and Maslach Burnout Inventory. Surveys on socio-demographic variables were applied to evaluate potential predictors, personal and academic characteristics and perceived difficulties. ANOVA with multiple comparisons were used to compare means of BDI score. The medical students were organized into subgroups by K-means cluster analyses. ANOVA mixed-design repeated measurement was performed to assess a possible interaction between variables associated with depression. Results: The response rate was 84, 92, 88 and 81% for academic years 2009-2010, 2010-2011,2011-2012 and 2012/2013, respectively. Two hundred thirty-eight medical students were evaluated longitudinally. For depression the prevalence ranged from 21.5 to 12.7% (academic years 2009/2010 and 2012/2013). BDI scores decreased during medical school. 19.7% of students recorded sustained high BDI over time. These students had high levels of trait-anxiety and choose medicine for anticipated income and prestige, reported more relationship issues, cynicism, and decreased satisfaction with social activities. Students with high BDI scores at initial evaluation with low levels of trait-anxiety and a primary interest in medicine as a career tended to improve their mood and reported reduced burnout, low perceived learning problems and increased satisfaction with social activities at last evaluation. No difference was detected between men and women in the median BDI score over time. Conclusions: Our findings suggest that personal factors (anxiety traits, medicine choice factors, relationship patterns and academic burnout) are relevant for persistence of high levels of BDI during medical training. Medical schools need to identity students who experience depression and support then, as early as possible, particularly when depression has been present over time.info:eu-repo/semantics/publishedVersio