Pre-Meal Whey Protein Alters Postprandial Insulinemia by Enhancing β-Cell Function and Reducing Insulin Clearance in T2D

CONTEXT: Treatments that reduce postprandial glycemia (PPG) independent of stimulating insulin secretion are appealing for the management of type 2 diabetes (T2D). Consuming pre-meal whey protein (WP) reduces PPG by delaying gastric emptying and increasing plasma insulin concentrations. However, its effects on β-cell function and insulin kinetics remains unclear. OBJECTIVE: To examine the PPG-regulatory effects of pre-meal WP by modeling insulin secretion rates (ISR), insulin clearance, and β-cell function. METHODS: This was a single-blind, randomized, placebo-controlled, crossover design study in 18 adults with T2D (HbA1c, 56.7 ± 8.8 mmol/mol) who underwent 2 240-minute mixed-meal tolerance tests. Participants consumed WP (15 g protein) or placebo (0 g protein) 10 minutes before a mixed-macronutrient breakfast meal. PPG, pancreatic islet, and incretin hormones were measured throughout. ISR was calculated by C-peptide deconvolution. Estimates of insulin clearance and β-cell function were modeled from glucose, insulin, and ISR. Changes in PPG incremental area under the curve (iAUC; prespecified) and insulin clearance (post hoc) were measured. RESULTS: β-cell function was 40% greater after WP (P = .001) and was accompanied with a -22% reduction in postprandial insulin clearance vs placebo (P < .0001). Both the peak change and PPG iAUC were reduced by WP (-1.5 mmol/L and -16%, respectively; both P < .05). Pre-meal WP augmented a 5.9-fold increase in glucagon and glucagon-like peptide 1 iAUC (both P < .0001), and a 1.5-fold increase in insulin iAUC (P < .001). Although the plasma insulin response was greater following WP, ISR was unaffected (P = .133). CONCLUSION: In adults with T2D, pre-meal WP reduced PPG by coordinating an enhancement in β-cell function with a reduction in insulin clearance. This enabled an efficient postprandial insulinemic profile to be achieved without requiring further β-cell stimulation.Trial registry ISRCTN ID: ISRCTN17563146 Website link: www.isrctn.com/ISRCTN17563146

Immune-mediated competition in rodent malaria is most likely caused by induced changes in innate immune clearance of merozoites

Malarial infections are often genetically diverse, leading to competitive interactions between parasites. A quantitative understanding of the competition between strains is essential to understand a wide range of issues, including the evolution of virulence and drug resistance. In this study, we use dynamical-model based Bayesian inference to investigate the cause of competitive suppression of an avirulent clone of Plasmodium chabaudi (AS) by a virulent clone (AJ) in immuno-deficient and competent mice. We test whether competitive suppression is caused by clone-specific differences in one or more of the following processes: adaptive immune clearance of merozoites and parasitised red blood cells (RBCs), background loss of merozoites and parasitised RBCs, RBC age preference, RBC infection rate, burst size, and within-RBC interference. These processes were parameterised in dynamical mathematical models and fitted to experimental data. We found that just one parameter μ, the ratio of background loss rate of merozoites to invasion rate of mature RBCs, needed to be clone-specific to predict the data. Interestingly, μ was found to be the same for both clones in single-clone infections, but different between the clones in mixed infections. The size of this difference was largest in immuno-competent mice and smallest in immuno-deficient mice. This explains why competitive suppression was alleviated in immuno-deficient mice. We found that competitive suppression acts early in infection, even before the day of peak parasitaemia. These results lead us to argue that the innate immune response clearing merozoites is the most likely, but not necessarily the only, mediator of competitive interactions between virulent and avirulent clones. Moreover, in mixed infections we predict there to be an interaction between the clones and the innate immune response which induces changes in the strength of its clearance of merozoites. What this interaction is unknown, but future refinement of the model, challenged with other datasets, may lead to its discovery

Identification of simple sequence repeat markers for sweetpotato weevil resistance

The development of sweetpotato [Ipomoea batatas (L.) Lam] germplasm with resistance to sweetpotato weevil (SPW) requires an understanding of the biochemical and genetic mechanisms of resistance to optimize crop resistance. The African sweetpotato landrace, ‘New Kawogo’, was reported to be moderately resistant to two species of SPW, Cylas puncticollis and Cylas brunneus. Resistance has been associated with the presence of hydroxycinnamic acids esters (HCAs), but the underlying genetic basis remains unknown. To determine the genetic basis of this resistance, a bi-parental sweetpotato population from a cross between the moderately resistant, white-fleshed ‘New Kawogo’ and the highly susceptible, orange-fleshed North American variety ‘Beauregard’ was evaluated for SPW resistance and genotyped with simple sequence repeat (SSR) markers to identify weevil resistance loci. SPW resistance was measured on the basis of field storage root SPW damage severity and total HCA ester concentrations. Moderate broad sense heritability (H2 = 0.49) was observed for weevil resistance in the population. Mean genotype SPW severity scores ranged from 1.0 to 9.0 and 25 progeny exhibited transgressive segregation for SPW resistance. Mean genotype total HCA ester concentrations were significantly different (P < 0.0001). A weak but significant correlation (r = 0.103, P = 0.015) was observed between total HCA ester concentration and SPW severity. A total of five and seven SSR markers were associated with field SPW severity and total HCA ester concentration, respectively. Markers IBS11, IbE5 and IbJ544b showed significant association with both field and HCA-based resistance, representing potential markers for the development of SPW resistant sweetpotato cultivars

Evidence of Yersinia pestis DNA from fleas in an endemic plague area of Zambia

BACKGROUND: Yersinia pestis is a bacterium that causes plague which infects a variety of mammals throughout the world. The disease is usually transmitted among wild rodents through a flea vector. The sources and routes of transmission of plague are poorly researched in Africa, yet remains a concern in several sub-Saharan countries. In Zambia, the disease has been reported on annual basis with up to 20 cases per year, without investigating animal reservoirs or vectors that may be responsible in the maintenance and propagation of the bacterium. In this study, we undertook plague surveillance by using PCR amplification of the plasminogen activator gene in fleas. FINDINGS: Xenopsylla species of fleas were collected from 83 rodents trapped in a plague endemic area of Zambia. Of these rodents 5 had fleas positive (6.02%) for Y. pestis plasminogen activator gene. All the Y. pestis positive rodents were gerbils. CONCLUSIONS: We conclude that fleas may be responsible in the transmission of Y. pestis and that PCR may provide means of plague surveillance in the endemic areas of Zambia

A large scale survey reveals that chromosomal copy-number alterations significantly affect gene modules involved in cancer initiation and progression

Background Recent observations point towards the existence of a large number of neighborhoods composed of functionally-related gene modules that lie together in the genome. This local component in the distribution of the functionality across chromosomes is probably affecting the own chromosomal architecture by limiting the possibilities in which genes can be arranged and distributed across the genome. As a direct consequence of this fact it is therefore presumable that diseases such as cancer, harboring DNA copy number alterations (CNAs), will have a symptomatology strongly dependent on modules of functionally-related genes rather than on a unique "important" gene. Methods We carried out a systematic analysis of more than 140,000 observations of CNAs in cancers and searched by enrichments in gene functional modules associated to high frequencies of loss or gains. Results The analysis of CNAs in cancers clearly demonstrates the existence of a significant pattern of loss of gene modules functionally related to cancer initiation and progression along with the amplification of modules of genes related to unspecific defense against xenobiotics (probably chemotherapeutical agents). With the extension of this analysis to an Array-CGH dataset (glioblastomas) from The Cancer Genome Atlas we demonstrate the validity of this approach to investigate the functional impact of CNAs. Conclusions The presented results indicate promising clinical and therapeutic implications. Our findings also directly point out to the necessity of adopting a function-centric, rather a gene-centric, view in the understanding of phenotypes or diseases harboring CNAs.Spanish Ministry of Science and Innovation (grant BIO2008-04212)Spanish Ministry of Science and Innovation (grant FIS PI 08/0440)GVA-FEDER (PROMETEO/2010/001)Red Temática de Investigación Cooperativa en Cáncer (RTICC) (grant RD06/0020/1019)Instituto de Salud Carlos III (ISCIII)Spanish Ministry of Science and InnovationSpanish Ministry of Health (FI06/00027

Deletion of a Malaria Invasion Gene Reduces Death and Anemia, in Model Hosts

Malaria parasites induce complex cellular and clinical phenotypes, including anemia, cerebral malaria and death in a wide range of mammalian hosts. Host genes and parasite ‘toxins’ have been implicated in malarial disease, but the contribution of parasite genes remains to be fully defined. Here we assess disease in BALB/c mice and Wistar rats infected by the rodent malaria parasite Plasmodium berghei with a gene knock out for merozoite surface protein (MSP) 7. MSP7 is not essential for infection but in P. falciparum, it enhances erythrocyte invasion by 20%. In vivo, as compared to wild type, the P. berghei Δmsp7 mutant is associated with an abrogation of death and a decrease from 3% to 2% in peak, circulating parasitemia. The Δmsp7 mutant is also associated with less anemia and modest increase in the size of follicles in the spleen. Together these data show that deletion of a single parasite invasion ligand modulates blood stage disease, as measured by death and anemia. This work is the first to assess the contribution of a gene present in all plasmodial species in severe disease

Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT≥20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration

γδ T lymphocytes from cystic fibrosis patients and healthy donors are high TNF-α and IFN-γ-producers in response to Pseudomonas aeruginosa

BACKGROUND: γδ T cells have an important immunoregulatory and effector function through cytokine release. They are involved in the responses to Gram-negative bacterium and in protection of lung epithelium integrity. On the other hand, they have been implicated in airway inflammation. METHODS: The aim of the present work was to study intracytoplasmic IL-2, IL-4, IFN-γ and TNF-α production by γδ and αβ T lymphocytes from cystic fibrosis patients and healthy donors in response to Pseudomonas aeruginosa (PA). Flow cytometric detection was performed after peripheral blood mononuclear cells (PBMC) culture with a cytosolic extract from PA and restimulation with phorbol ester plus ionomycine. Proliferative responses, activation markers and receptor usage of γδ T cells were also evaluated. RESULTS: The highest production of cytokine was of TNF-α and IFN-γ, γδ being better producers than αβ. No differences were found between patients and controls. The Vγ9δ2 subset of γδ T cells was preferentially expanded. CD25 and CD45RO expression by the αβ T subset and PBMC proliferative response to PA were defective in cystic fibrosis lymphocytes. CONCLUSION: Our results support the hypothesis that γδ T lymphocytes play an important role in the immune response to PA and in the chronic inflammatory lung reaction in cystic fibrosis patients. They do not confirm the involvement of a supressed Th1 cytokine response in the pathogenesis of this disease

Genome Wide Analysis of Inbred Mouse Lines Identifies a Locus Containing Ppar-γ as Contributing to Enhanced Malaria Survival

The genetic background of a patient determines in part if a person develops a mild form of malaria and recovers, or develops a severe form and dies. We have used a mouse model to detect genes involved in the resistance or susceptibility to Plasmodium berghei malaria infection. To this end we first characterized 32 different mouse strains infected with P. berghei and identified survival as the best trait to discriminate between the strains. We found a locus on chromosome 6 by linking the survival phenotypes of the mouse strains to their genetic variations using genome wide analyses such as haplotype associated mapping and the efficient mixed-model for association. This new locus involved in malaria resistance contains only two genes and confirms the importance of Ppar-γ in malaria infection