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

Development of cognitive enhancers based on inhibition of insulin-regulated aminopeptidase

The peptides angiotensin IV and LVV-hemorphin 7 were found to enhance memory in a number of memory tasks and reverse the performance deficits in animals with experimentally induced memory loss. These peptides bound specifically to the enzyme insulin-regulated aminopeptidase (IRAP), which is proposed to be the site in the brain that mediates the memory effects of these peptides. However, the mechanism of action is still unknown but may involve inhibition of the aminopeptidase activity of IRAP, since both angiotensin IV and LVV-hemorphin 7 are competitive inhibitors of the enzyme. IRAP also has another functional domain that is thought to regulate the trafficking of the insulin-responsive glucose transporter GLUT4, thereby influencing glucose uptake into cells. Although the exact mechanism by which the peptides enhance memory is yet to be elucidated, IRAP still represents a promising target for the development of a new class of cognitive enhancing agents

T-cell Subsets and Antifungal Host Defenses

It has been long appreciated that protective immunity against fungal pathogens is dependent on activation of cellular adaptive immune responses represented by T lymphocytes. The T-helper (Th)1/Th2 paradigm has proven to be essential for the understanding of protective adaptive host responses. Studies that have examined the significance of regulatory T cells in fungal infection, and the recent discovery of a new T-helper subset called Th17 have provided crucial information for understanding the complementary roles played by the various T-helper lymphocytes in systemic versus mucosal antifungal host defense. This review provides an overview of the role of the various T-cell subsets during fungal infections and the reciprocal regulation between the T-cell subsets contributing to the tailored host response against fungal pathogens

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

Search for rare quark-annihilation decays, B --> Ds(*) Phi

We report on searches for B- --> Ds- Phi and B- --> Ds*- Phi. In the context of the Standard Model, these decays are expected to be highly suppressed since they proceed through annihilation of the b and u-bar quarks in the B- meson. Our results are based on 234 million Upsilon(4S) --> B Bbar decays collected with the BABAR detector at SLAC. We find no evidence for these decays, and we set Bayesian 90% confidence level upper limits on the branching fractions BF(B- --> Ds- Phi) Ds*- Phi)<1.2x10^(-5). These results are consistent with Standard Model expectations.Comment: 8 pages, 3 postscript figues, submitted to Phys. Rev. D (Rapid Communications

Involvement of glomerular renin−angiotensin system (RAS) activation in the development and progression of glomerular injury

Recently, there has been a paradigm shift away from an emphasis on the role of the endocrine (circulating) renin−angiotensin system (RAS) in the regulation of the sodium and extracellular fluid balance, blood pressure, and the pathophysiology of hypertensive organ damage toward a focus on the role of tissue RAS found in many organs, including kidney. A tissue RAS implies that RAS components necessary for the production of angiotensin II (Ang II) reside within the tissue and its production is regulated within the tissue, independent of the circulating RAS. Locally produced Ang II plays a role in many physiological and pathophysiological processes such as hypertension, inflammation, oxidative stress, and tissue fibrosis. Both glomerular and tubular compartments of the kidney have the characteristics of a tissue RAS. The purpose of this article is to review the recent advances in tissue RAS research with a particular focus on the role of the glomerular RAS in the progression of renal disease

Role of deficits in pathogen recognition receptors in infection susceptibility

This work was supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (NORTE-01-0145-FEDER-000013), and the Fundação para a Ciência e Tecnologia (FCT) (IF/00735/2014 to A.C. and SFRH/BPD/96176/2013 to C.C.

Effects of Short-Term Continuous Montmorency Tart Cherry Juice Supplementation in Participants with Metabolic Syndrome

© 2020 Springer-Verlag. The final publication is available at Springer via https://doi.org/10.1007/s00394-020-02355-5Purpose: Metabolic Syndrome (MetS) augments the incidence of cardiovascular disease by two-fold and type II diabetes mellitus by five-fold. Montmorency tart cherries are rich in phytochemicals shown to improve biomarkers related to cardio-metabolic health in humans. This study aimed to examine cardio-metabolic responses after 7-days Montmorency tart cherry juice (MTCJ) supplementation and also acute on short-term supplementation responses to a single bolus, in humans with MetS. Methods: In a randomised, single-blind, placebo-controlled, crossover trial, 12 participants with MetS (50 ± 10 years; 6M/6F), consumed MTCJ or placebo (PLA) for 7 days. Blood-based and functional cardio-metabolic biomarkers were measured pre- and post-supplementation, and acute responses measured pre-bolus and up to 5 h post-bolus on the 7th day. Results: 24-h ambulatory systolic (P = 0.016), diastolic (P = 0.009) blood pressure and mean arterial pressure (P = 0.041) were significantly lower after 7-days MTCJ supplementation compared to PLA. Glucose (P = 0.038), total cholesterol (P = 0.036), LDL (P = 0.023) concentrations, total cholesterol:HDL ratio (P = 0.004) and respiratory exchange ratio values (P = 0.009) were significantly lower after 6-days MTCJ consumption compared to PLA. Conclusions: This study revealed for the first time in humans that MTCJ significantly improved 24-h BP, fasting glucose, total cholesterol and total cholesterol:HDL ratio, and also lowered resting respiratory exchange ratio compared to a control group. Responses demonstrated clinically relevant improvements on aspects of cardio-metabolic function, emphasising the potential efficacy of MTCJ in preventing further cardio-metabolic dysregulation in participants with MetS. Registered at clinicaltrials.gov (NCT03619941).Peer reviewedFinal Accepted Versio

Genome-Wide Analysis Reveals a Complex Pattern of Genomic Imprinting in Mice

Parent-of-origin–dependent gene expression resulting from genomic imprinting plays an important role in modulating complex traits ranging from developmental processes to cognitive abilities and associated disorders. However, while gene-targeting techniques have allowed for the identification of imprinted loci, very little is known about the contribution of imprinting to quantitative variation in complex traits. Most studies, furthermore, assume a simple pattern of imprinting, resulting in either paternal or maternal gene expression; yet, more complex patterns of effects also exist. As a result, the distribution and number of different imprinting patterns across the genome remain largely unexplored. We address these unresolved issues using a genome-wide scan for imprinted quantitative trait loci (iQTL) affecting body weight and growth in mice using a novel three-generation design. We identified ten iQTL that display much more complex and diverse effect patterns than previously assumed, including four loci with effects similar to the callipyge mutation found in sheep. Three loci display a new phenotypic pattern that we refer to as bipolar dominance, where the two heterozygotes are different from each other while the two homozygotes are identical to each other. Our study furthermore detected a paternally expressed iQTL on Chromosome 7 in a region containing a known imprinting cluster with many paternally expressed genes. Surprisingly, the effects of the iQTL were mostly restricted to traits expressed after weaning. Our results imply that the quantitative effects of an imprinted allele at a locus depend both on its parent of origin and the allele it is paired with. Our findings also show that the imprinting pattern of a locus can be variable over ontogenetic time and, in contrast to current views, may often be stronger at later stages in life

EMT-Induced Stemness and Tumorigenicity Are Fueled by the EGFR/Ras Pathway

10.1371/journal.pone.0070427PLoS ONE88-POLN