The role of the proximal small intestine in improvements in diabetes resolution and insulin sensitivity following bariatric surgery in type 2 diabetes

Bariatric surgery is an effective, rapid, and durable treatment for obesity and type 2 diabetes mellitus (T2DM). Roux-en Y Gastric Bypass (RYGB) resolves T2DM in 80% of cases, while gastric banding (LAGB) resolves T2DM in only 45%. One significant difference between RYGB and LAGB is the bypassing of the proximal small intestine in RYGB. Inadequate insulin secretion and insulin resistance are well known contributors to T2DM and both improve following RYGB. To determine if RYGB produces greater improvements in insulin secretion and insulin sensitivity than LAGB in T2DM, we studied obese, T2DM, Caucasian women who underwent RYGB (N=9) or LAGB (N=3). Insulin secretion (AIRg) and insulin sensitivity (Si) were measured pre- and 1-wk post-surgery by Minimal Model analysis following an insulin modified intravenous glucose tolerance test (IVGTT). Post-surgery analysis at 1-wk eliminates the potential contribution of differences in weight loss or food consumption as these are rigorously controlled for 1 wk following these surgical procedures. There was a trend (p = 0.053) for an increase in Si from pre-surgery to 1-wk post-surgery, but there was no difference in Si between surgical groups (RYGB, Pre: 0.85 ± 0.15 and 1-wk: 2.30 ± 0.43) and (LAGB, Pre: 1.32 ± 0.26 and 1-wk: 1.67± 0.60). There was a trend for an Interaction (p = 0.056) in AIRg with an increase in RYGB (Pre: 42.0 ± 23.3 and 1-wk: 94.7 ± 52.6), but decrease among LAGB (Pre: 519.7 ± 392.9 and 1-wk: 391.8 ± 291.6) with surgery. There was also a trend (p = 0.067) for a greater AIRg in LAGB compared to RYGB regardless of surgery status. These results in obese, T2DM, Caucasian women suggest that insulin sensitivity may be increased similarly in RYGB and LAGB questioning the role of the proximal small intestine bypass in the reversal of insulin sensitivity following bariatric surgery. In contrast, improvements in insulin secretion may be greater in RYGB than LAGB. Additional gastric banding patients are required to provide adequate power for statistical analysis.  M.S

Exploring the Future of Human Factors Education; Online Learning, MOOCs, Next Generation Standards, and the Technological Skills We Need to Impart

The objective of this panel was to examine how the future of human factors education is changing given the influx of technology, a push for online learning, and adapting to the changing market. The panel will begin by Heather Lum briefly giving an overview and the precipice for this discussion panel. The panelists then provided their views and experiences regarding this topic. Kelly Steelman will discuss the potential for MOOCs and other online formats to create faster and more flexible postgraduate programs. Christina Frederick will discuss her perspectives on the technological skills we should be equipping our human factors graduates with to be successful. Nathan Sonnenfeld will give his unique take on this as an undergraduate student currently obtaining a human factors education. Susan Amato-Henderson will discuss the Next Generation Science Standards and the ramifications for educators. Lastly, Thomas Smith will focus on the advantages and disadvantages of online learning at the K-12 level. Dr. Lum will foster discussion among the panelists and questions from the general audience. Discussion time: 90 minutes

Neurotrophic factor GDNF promotes survival of salivary stem cells

Stem cell-based regenerative therapy is a promising treatment for head and neck cancer patients that suffer from chronic dry mouth (xerostomia) due to salivary gland injury from radiation therapy. Current xerostomia therapies only provide temporary symptom relief, while permanent restoration of salivary function is not currently feasible. Here, we identified and characterized a stem cell population from adult murine submandibular glands. Of the different cells isolated from the submandibular gland, this specific population, Lin-CD24+c-Kit+Sca1+, possessed the highest capacity for proliferation, self renewal, and differentiation during serial passage in vitro. Serial transplantations of this stem cell population into the submandibular gland of irradiated mice successfully restored saliva secretion and increased the number of functional acini. Gene-expression analysis revealed that glial cell line-derived neurotrophic factor (Gdnf) is highly expressed in Lin-CD24+c-Kit+Sca1+ stem cells. Furthermore, GDNF expression was upregulated upon radiation therapy in submandibular glands of both mice and humans. Administration of GDNF improved saliva production and enriched the number of functional acini in submandibular glands of irradiated animals and enhanced salisphere formation in cultured salivary stem cells, but did not accelerate growth of head and neck cancer cells. These data indicate that modulation of the GDNF pathway may have potential therapeutic benefit for management of radiation-induced xerostomia

The RGD Domain of Human Osteopontin Promotes Tumor Growth and Metastasis through Activation of Survival Pathways

BACKGROUND:Human osteopontin (OPN), a known tumor associated protein, exists in different isoforms, whose function is unclear. It also possesses a RGD domain, which has been implicated in diverse function. Here, we use genetic approaches to systematically investigate the function of the RGD domain in different OPN isoforms on tumor progression and metastasis for 2 different solid tumor models. METHODOLOGY/PRINCIPAL FINDINGS:Using isoform-specific qRT-PCR, we found that OPN-A and B were the main isoforms overexpressed in evaluated human tumors, which included 4 soft tissue sarcomas, 24 lung and 30 head and neck carcinomas. Overexpression of either OPN-A or B in two different cell types promoted local tumor growth and lung metastasis in SCID mouse xenografts. However, expression of either isoform with the RGD domain either mutated or deleted decreased tumor growth and metastasis, and resulted in increased apoptosis by TUNEL staining. In vitro, whereas mutation of the RGD domain did not affect cell-cell adhesion, soft agar growth or cell migration, it increased apoptosis under hypoxia and serum starvation. This effect could be mitigated when the RGD mutant cells were treated with condition media containing WT OPN. Mechanistically, the RGD region of OPN inhibited apoptosis by inducing NF-kappaB activation and FAK phosphorylation. Inhibition of NF-kappaB (by siRNA to the p65 subunit) or FAK activation (by a inhibitor) significantly increased apoptosis under hypoxia in WT OPN cells, but not in RGD mutant cells. CONCLUSION/SIGNIFICANCE:Unlike prior reports, our data suggest that the RGD domain of both OPN-A and B promote tumor growth and metastasis mainly by protecting cells against apoptosis under stressed conditions and not via migration or invasion. Future inhibitors directed against OPN should target multiple isoforms and should inhibit cell survival mechanisms that involve the RGD domain, FAK phosphorylation and NF-kappaB activation

THE REAL McCOIL: A method for the concurrent estimation of the complexity of infection and SNP allele frequency for malaria parasites.

As many malaria-endemic countries move towards elimination of Plasmodium falciparum, the most virulent human malaria parasite, effective tools for monitoring malaria epidemiology are urgent priorities. P. falciparum population genetic approaches offer promising tools for understanding transmission and spread of the disease, but a high prevalence of multi-clone or polygenomic infections can render estimation of even the most basic parameters, such as allele frequencies, challenging. A previous method, COIL, was developed to estimate complexity of infection (COI) from single nucleotide polymorphism (SNP) data, but relies on monogenomic infections to estimate allele frequencies or requires external allele frequency data which may not available. Estimates limited to monogenomic infections may not be representative, however, and when the average COI is high, they can be difficult or impossible to obtain. Therefore, we developed THE REAL McCOIL, Turning HEterozygous SNP data into Robust Estimates of ALelle frequency, via Markov chain Monte Carlo, and Complexity Of Infection using Likelihood, to incorporate polygenomic samples and simultaneously estimate allele frequency and COI. This approach was tested via simulations then applied to SNP data from cross-sectional surveys performed in three Ugandan sites with varying malaria transmission. We show that THE REAL McCOIL consistently outperforms COIL on simulated data, particularly when most infections are polygenomic. Using field data we show that, unlike with COIL, we can distinguish epidemiologically relevant differences in COI between and within these sites. Surprisingly, for example, we estimated high average COI in a peri-urban subregion with lower transmission intensity, suggesting that many of these cases were imported from surrounding regions with higher transmission intensity. THE REAL McCOIL therefore provides a robust tool for understanding the molecular epidemiology of malaria across transmission settings

Factors influencing terrestriality in primates of the Americas and Madagascar

Among mammals, the order Primates is exceptional in having a high taxonomic richness in which the taxa are arboreal, semiterrestrial, or terrestrial. Although habitual terrestriality is pervasive among the apes and African and Asian monkeys (catarrhines), it is largely absent among monkeys of the Americas (platyrrhines), as well as galagos, lemurs, and lorises (strepsirrhines), which are mostly arboreal. Numerous ecological drivers and species-specific factors are suggested to set the conditions for an evolutionary shift from arboreality to terrestriality, and current environmental conditions may provide analogous scenarios to those transitional periods. Therefore, we investigated predominantly arboreal, diurnal primate genera from the Americas and Madagascar that lack fully terrestrial taxa, to determine whether ecological drivers (habitat canopy cover, predation risk, maximum temperature, precipitation, primate species richness, human population density, and distance to roads) or species-specific traits (body mass, group size, and degree of frugivory) associate with increased terrestriality. We collated 150,961 observation hours across 2,227 months from 47 species at 20 sites in Madagascar and 48 sites in the Americas. Multiple factors were associated with ground use in these otherwise arboreal species, including increased temperature, a decrease in canopy cover, a dietary shift away from frugivory, and larger group size. These factors mostly explain intraspecific differences in terrestriality. As humanity modifies habitats and causes climate change, our results suggest that species already inhabiting hot, sparsely canopied sites, and exhibiting more generalized diets, are more likely to shift toward greater ground use.Fil: Eppley, Timothy M.. San Diego Zoo Wildlife Alliance; Estados Unidos. Portland State University; Estados UnidosFil: Hoeks, Selwyn. Radboud Universiteit Nijmegen; Países BajosFil: Chapman, Colin A.. University of KwaZulu-Natal; Sudáfrica. Wilson Center; Estados Unidos. Northwest University; China. The George Washington University; Estados UnidosFil: Ganzhorn, Jörg U.. Universitat Hamburg; AlemaniaFil: Hall, Katie. Sedgwick County Zoo; Estados UnidosFil: Owen, Megan A.. San Diego Zoo Wildlife Alliance; Estados UnidosFil: Adams, Dara B.. Humboldt State University; Estados Unidos. Ohio State University; Estados UnidosFil: Allgas, Néstor. Asociación Neotropical Primate Conservation Perú; PerúFil: Amato, Katherine R.. Northwestern University; Estados UnidosFil: Andriamahaihavana, McAntonin. Université D'antananarivo; MadagascarFil: Aristizabal, John F.. Universidad Autónoma de Ciudad Juárez; México. Universidad de los Andes; ColombiaFil: Baden, Andrea L.. City University of New York; Estados Unidos. New York Consortium In Evolutionary Primatology; Estados UnidosFil: Balestri, Michela. Oxford Brookes University (oxford Brookes University);Fil: Barnett, Adrian A.. University Of Roehampton; Reino Unido. Universidade Federal de Pernambuco; BrasilFil: Bicca Marques, Júlio César. Pontificia Universidade Católica do Rio Grande do Sul; BrasilFil: Bowler, Mark. University Of Suffolk; Reino Unido. San Diego Zoo Wildlife Alliance; Estados UnidosFil: Boyle, Sarah A.. Rhodes College; Estados UnidosFil: Brown, Meredith. University of Calgary; CanadáFil: Caillaud, Damien. University of California at Davis; Estados UnidosFil: Calegaro Marques, Cláudia. Universidade Federal do Rio Grande do Sul; BrasilFil: Campbell, Christina J.. California State University Northridge (calif. State Univ. Northridge);Fil: Campera, Marco. Oxford Brookes University (oxford Brookes University);Fil: Campos, Fernando A.. University of Texas at San Antonio; Estados UnidosFil: Cardoso, Tatiane S.. Museu Paraense Emílio Goeldi; BrasilFil: Carretero Pinzón, Xyomara. Proyecto Zocay; ColombiaFil: Champion, Jane. University of Calgary; CanadáFil: Chaves, Óscar M.. Universidad de Costa Rica; Costa RicaFil: Chen Kraus, Chloe. University of Yale; Estados UnidosFil: Colquhoun, Ian C.. Western University; CanadáFil: Dean, Brittany. University of Calgary; CanadáFil: Kowalewski, Miguel Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Centro de Ecología Aplicada del Litoral. Universidad Nacional del Nordeste. Centro de Ecología Aplicada del Litoral; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales "Bernardino Rivadavia". Estación Biológica de Usos Múltiples (Sede Corrientes); Argentin

Factors influencing terrestriality in primates of the Americas and Madagascar

Among mammals, the order Primates is exceptional in having a high taxonomic richness in which the taxa are arboreal, semiterrestrial, or terrestrial. Although habitual terrestriality is pervasive among the apes and African and Asian monkeys (catarrhines), it is largely absent among monkeys of the Americas (platyrrhines), as well as galagos, lemurs, and lorises (strepsirrhines), which are mostly arboreal. Numerous ecological drivers and species-specific factors are suggested to set the conditions for an evolutionary shift from arboreality to terrestriality, and current environmental conditions may provide analogous scenarios to those transitional periods. Therefore, we investigated predominantly arboreal, diurnal primate genera from the Americas and Madagascar that lack fully terrestrial taxa, to determine whether ecological drivers (habitat canopy cover, predation risk, maximum temperature, precipitation, primate species richness, human population density, and distance to roads) or species-specific traits (bodymass, group size, and degree of frugivory) associate with increased terrestriality. We collated 150,961 observation hours across 2,227 months from 47 species at 20 sites in Madagascar and 48 sites in the Americas. Multiple factors were associated with ground use in these otherwise arboreal species, including increased temperature, a decrease in canopy cover, a dietary shift away from frugivory, and larger group size. These factors mostly explain intraspecific differences in terrestriality. As humanity modifies habitats and causes climate change, our results suggest that species already inhabiting hot, sparsely canopied sites, and exhibiting more generalized diets, are more likely to shift toward greater ground use

Malaria protection due to sickle haemoglobin depends on parasite genotype.

Host genetic factors can confer resistance against malaria1, raising the question of whether this has led to evolutionary adaptation of parasite populations. Here we searched for association between candidate host and parasite genetic variants in 3,346 Gambian and Kenyan children with severe malaria caused by Plasmodium falciparum. We identified a strong association between sickle haemoglobin (HbS) in the host and three regions of the parasite genome, which is not explained by population structure or other covariates, and which is replicated in additional samples. The HbS-associated alleles include nonsynonymous variants in the gene for the acyl-CoA synthetase family member2-4 PfACS8 on chromosome 2, in a second region of chromosome 2, and in a region containing structural variation on chromosome 11. The alleles are in strong linkage disequilibrium and have frequencies that covary with the frequency of HbS across populations, in particular being much more common in Africa than other parts of the world. The estimated protective effect of HbS against severe malaria, as determined by comparison of cases with population controls, varies greatly according to the parasite genotype at these three loci. These findings open up a new avenue of enquiry into the biological and epidemiological significance of the HbS-associated polymorphisms in the parasite genome and the evolutionary forces that have led to their high frequency and strong linkage disequilibrium in African P. falciparum populations