Cryptosporidium Priming Is More Effective than Vaccine for Protection against Cryptosporidiosis in a Murine Protein Malnutrition Model

Cryptosporidium is a major cause of severe diarrhea, especially in malnourished children. Using a murine model of C. parvum oocyst challenge that recapitulates clinical features of severe cryptosporidiosis during malnutrition, we interrogated the effect of protein malnutrition (PM) on primary and secondary responses to C. parvum challenge, and tested the differential ability of mucosal priming strategies to overcome the PM-induced susceptibility. We determined that while PM fundamentally alters systemic and mucosal primary immune responses to Cryptosporidium, priming with C. parvum (106 oocysts) provides robust protective immunity against re-challenge despite ongoing PM. C. parvum priming restores mucosal Th1-type effectors (CD3+CD8+CD103+ T-cells) and cytokines (IFNγ, and IL12p40) that otherwise decrease with ongoing PM. Vaccination strategies with Cryptosporidium antigens expressed in the S. Typhi vector 908htr, however, do not enhance Th1-type responses to C. parvum challenge during PM, even though vaccination strongly boosts immunity in challenged fully nourished hosts. Remote non-specific exposures to the attenuated S. Typhi vector alone or the TLR9 agonist CpG ODN-1668 can partially attenuate C. parvum severity during PM, but neither as effectively as viable C. parvum priming. We conclude that although PM interferes with basal and vaccine-boosted immune responses to C. parvum, sustained reductions in disease severity are possible through mucosal activators of host defenses, and specifically C. parvum priming can elicit impressively robust Th1-type protective immunity despite ongoing protein malnutrition. These findings add insight into potential correlates of Cryptosporidium immunity and future vaccine strategies in malnourished children

The Dawn of Open Access to Phylogenetic Data

The scientific enterprise depends critically on the preservation of and open access to published data. This basic tenet applies acutely to phylogenies (estimates of evolutionary relationships among species). Increasingly, phylogenies are estimated from increasingly large, genome-scale datasets using increasingly complex statistical methods that require increasing levels of expertise and computational investment. Moreover, the resulting phylogenetic data provide an explicit historical perspective that critically informs research in a vast and growing number of scientific disciplines. One such use is the study of changes in rates of lineage diversification (speciation - extinction) through time. As part of a meta-analysis in this area, we sought to collect phylogenetic data (comprising nucleotide sequence alignment and tree files) from 217 studies published in 46 journals over a 13-year period. We document our attempts to procure those data (from online archives and by direct request to corresponding authors), and report results of analyses (using Bayesian logistic regression) to assess the impact of various factors on the success of our efforts. Overall, complete phylogenetic data for ~60% of these studies are effectively lost to science. Our study indicates that phylogenetic data are more likely to be deposited in online archives and/or shared upon request when: (1) the publishing journal has a strong data-sharing policy; (2) the publishing journal has a higher impact factor, and; (3) the data are requested from faculty rather than students. Although the situation appears dire, our analyses suggest that it is far from hopeless: recent initiatives by the scientific community -- including policy changes by journals and funding agencies -- are improving the state of affairs

WNT signalling in prostate cancer

Genome sequencing and gene expression analyses of prostate tumours have highlighted the potential importance of genetic and epigenetic changes observed in WNT signalling pathway components in prostate tumours-particularly in the development of castration-resistant prostate cancer. WNT signalling is also important in the prostate tumour microenvironment, in which WNT proteins secreted by the tumour stroma promote resistance to therapy, and in prostate cancer stem or progenitor cells, in which WNT-β-catenin signals promote self-renewal or expansion. Preclinical studies have demonstrated the potential of inhibitors that target WNT receptor complexes at the cell membrane or that block the interaction of β-catenin with lymphoid enhancer-binding factor 1 and the androgen receptor, in preventing prostate cancer progression. Some WNT signalling inhibitors are in phase I trials, but they have yet to be tested in patients with prostate cancer

Etiological spectrum and treatment outcome of Obstructive jaundice at a University teaching Hospital in northwestern Tanzania: A diagnostic and therapeutic challenges

Obstructive jaundice poses diagnostic and therapeutic challenges to general surgeons practicing in resource-limited countries. This study was undertaken to highlight the etiological spectrum, treatment outcome of obstructive jaundice in our setting and to identify prognostic factors for morbidity and mortality. This was a descriptive prospective study which was conducted at Bugando Medical Centre between July 2006 and June 2010. All patients with a clinical diagnosis of obstructive jaundice were, after informed consent for the study, consecutively enrolled into the study. Data were collected using a pre-tested structured questionnaire and analyzed using SPSS computer software version 11.5. A total of 116 patients were studied. Females outnumbered males by a ratio of 1.3:1. Patients with malignant obstructive jaundice were older than those of benign type. Ca head of pancreas was the commonest malignant cause of jaundice where as choledocholithiasis was the commonest benign cause. Abdominal ultrasound was the only diagnostic imaging done in all patients and revealed dilated intra and extra-hepatic ducts, common bile stones and abdominal masses in 56.2%, 78.9%, 58.1% and 72.4% of the cases respectively. A total of 110 (94.8%) patients underwent surgical treatment and the remaining 6 (5.2%) patients were unfit for surgery. The complication rate was 22.4% mainly surgical site infections. The mean hospital stay and mortality rate were 14.54 days and 15.5% respectively. A low haematocrit and presence of postoperative sepsis were the main predictors of the hospital stay (P < 0.001), whereas age > 60 years, prolonged duration of jaundice, malignant causes and presence of postoperative complications mainly sepsis significantly predicted mortality (P < 0.001). Obstructive jaundice in our setting is more prevalent in females and the cause is mostly malignant. The result of this study suggests that early diagnosis and treatment plays an important role in the prognosis of patients with obstructive jaundice

Production of phi mesons at mid-rapidity in sqrt(s_NN) = 200 GeV Au+Au collisions at RHIC

We present the first results of meson production in the K^+K^- decay channel from Au+Au collisions at sqrt(s_NN) = 200 GeV as measured at mid-rapidity by the PHENIX detector at RHIC. Precision resonance centroid and width values are extracted as a function of collision centrality. No significant variation from the PDG accepted values is observed. The transverse mass spectra are fitted with a linear exponential function for which the derived inverse slope parameter is seen to be constant as a function of centrality. These data are also fitted by a hydrodynamic model with the result that the freeze-out temperature and the expansion velocity values are consistent with the values previously derived from fitting single hadron inclusive data. As a function of transverse momentum the collisions scaled peripheral.to.central yield ratio RCP for the is comparable to that of pions rather than that of protons. This result lends support to theoretical models which distinguish between baryons and mesons instead of particle mass for explaining the anomalous proton yield.Comment: 326 authors, 24 pages text, 23 figures, 6 tables, RevTeX 4. To be submitted to Physical Review C as a regular article. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Exploring Action Dynamics as an Index of Paired-Associate Learning

Much evidence exists supporting a richer interaction between cognition and action than commonly assumed. Such findings demonstrate that short-timescale processes, such as motor execution, may relate in systematic ways to longer-timescale cognitive processes, such as learning. We further substantiate one direction of this interaction: the flow of cognition into action systems. Two experiments explored match-to-sample paired-associate learning, in which participants learned randomized pairs of unfamiliar symbols. During the experiments, their hand movements were continuously tracked using the Nintendo Wiimote. Across learning, participant arm movements are initiated and completed more quickly, exhibit lower fluctuation, and exert more perturbation on the Wiimote during the button press. A second experiment demonstrated that action dynamics index novel learning scenarios, and not simply acclimatization to the Wiimote interface. Results support a graded and systematic covariation between cognition and action, and recommend ways in which this theoretical perspective may contribute to applied learning contexts

Oncogene Activation Induces Metabolic Transformation Resulting in Insulin-Independence in Human Breast Cancer Cells

Normal breast epithelial cells require insulin and EGF for growth in serum-free media. We previously demonstrated that over expression of breast cancer oncogenes transforms MCF10A cells to an insulin-independent phenotype. Additionally, most breast cancer cell lines are insulin-independent for growth. In this study, we investigated the mechanism by which oncogene over expression transforms MCF10A cells to an insulin-independent phenotype. Analysis of the effects of various concentrations of insulin and/or IGF-I on proliferation of MCF10A cells demonstrated that some of the effects of insulin were independent from those of IGF-I, suggesting that oncogene over expression drives a true insulin-independent proliferative phenotype. To test this hypothesis, we examined metabolic functions of insulin signaling in insulin-dependent and insulin-independent cells. HER2 over expression in MCF10A cells resulted in glucose uptake in the absence of insulin at a rate equal to insulin-induced glucose uptake in non-transduced cells. We found that a diverse set of oncogenes induced the same result. To gain insight into how HER2 oncogene signaling affected increased insulin-independent glucose uptake we compared HER2-regulated gene expression signatures in MCF10A and HER2 over expressing MCF10A cells by differential analysis of time series gene expression data from cells treated with a HER2 inhibitor. This analysis identified genes specifically regulated by the HER2 oncogene, including VAMP8 and PHGDH, which have known functions in glucose uptake and processing of glycolytic intermediates, respectively. Moreover, these genes specifically implicated in HER2 oncogene-driven transformation are commonly altered in human breast cancer cells. These results highlight the diversity of oncogene effects on cell regulatory pathways and the importance of oncogene-driven metabolic transformation in breast cancer

A supramolecular helix that disregards chirality

The functions of complex crystalline systems derived from supramolecular biological and non-biological assemblies typically emerge from homochiral programmed primary structures via first principles involving secondary, tertiary and quaternary structures. In contrast, heterochiral and racemic compounds yield disordered crystals, amorphous solids or liquids. Here, we report the self-assembly of perylene bisimide derivatives in a supramolecular helix that in turn self-organizes in columnar hexagonal crystalline domains regardless of the enantiomeric purity of the perylene bisimide. We show that both homochiral and racemic perylene bisimide compounds, including a mixture of 21 diastereomers that cannot be deracemized at the molecular level, self-organize to form single-handed helical assemblies with identical single-crystal-like order. We propose that this high crystalline order is generated via a cogwheel mechanism that disregards the chirality of the self-assembling building blocks. We anticipate that this mechanism will facilitate access to previously inaccessible complex crystalline systems from racemic and homochiral building blocks

The Changing Epidemiology of Murray Valley Encephalitis in Australia: The 2011 Outbreak and a Review of the Literature

Murray Valley encephalitis virus (MVEV) is the most serious of the endemic arboviruses in Australia. It was responsible for six known large outbreaks of encephalitis in south-eastern Australia in the 1900s, with the last comprising 58 cases in 1974. Since then MVEV clinical cases have been largely confined to the western and central parts of northern Australia. In 2011, high-level MVEV activity occurred in south-eastern Australia for the first time since 1974, accompanied by unusually heavy seasonal MVEV activity in northern Australia. This resulted in 17 confirmed cases of MVEV disease across Australia. Record wet season rainfall was recorded in many areas of Australia in the summer and autumn of 2011. This was associated with significant flooding and increased numbers of the mosquito vector and subsequent MVEV activity. This paper documents the outbreak and adds to our knowledge about disease outcomes, epidemiology of disease and the link between the MVEV activity and environmental factors. Clinical and demographic information from the 17 reported cases was obtained. Cases or family members were interviewed about their activities and location during the incubation period. In contrast to outbreaks prior to 2000, the majority of cases were non-Aboriginal adults, and almost half (40%) of the cases acquired MVEV outside their area of residence. All but two cases occurred in areas of known MVEV activity.This outbreak continues to reflect a change in the demographic pattern of human cases of encephalitic MVEV over the last 20 years. In northern Australia, this is associated with the increasing numbers of non-Aboriginal workers and tourists living and travelling in endemic and epidemic areas, and also identifies an association with activities that lead to high mosquito exposure. This outbreak demonstrates that there is an ongoing risk of MVEV encephalitis to the heavily populated areas of south-eastern Australia