Obesity and type 2 diabetes (T2D) are major public health challenges for our generation. Unfortunately, there are no simple answers for the dual epidemics of obesity and T2D. Novel insights and approaches on many fronts are required. One new approach to target disease risk arises from the recognition that risk patterns for both obesity and T2D can originate as a consequence of alterations in growth and metabolism during critical windows of prenatal and early postnatal development. Moreover, obesity, prediabetes, and diabetes in individuals of reproductive age can initiate a vicious cycle, propagating risk to subsequent generations via non-genetic, or epi-genetic and metabolic mechanisms. Thus, understanding mechanisms mediating these effects is an important scientific and clinical goal. More importantly, this concept provides the hope that identification of high-risk individuals for targeted intervention during early childhood and subsequent reproductive life may limit vicious cycles of metabolic risk. Our laboratory is studying mechanisms by which altered nutrition and metabolism can impact offspring, and to identify methods to reverse the impact of adverse exposures on offspring. Using our mouse model, we have demonstrated that mice exposed to transient nutritional alterations during their development go on to develop progressive glucose intolerance, insulin secretory dysfunction, reduced muscle mass, and obesity as adults – the classic phenotype of diabetes risk. Moreover, these F1 mice (both males and females) yield F2 offspring with abnormal glucose tolerance and increased adiposity. These data suggest that environmental exposures alter germ cell epigenetic marks, which may contribute to altered development in F2 offspring and increase risk of chronic disease. We are now testing (in both mice and humans!) whether interventions such as diet, activity, and medications which target specific pathways may reduce transmission of disease risk from one generation to the next.
Bariatric surgery has emerged as a potent strategy to reduce not only body weight but also to reduce plasma glucose levels and induce remission of diabetes, even allowing medication withdrawal. Some patients even develop low blood glucose (hypoglycemia) after bariatric surgery. THese exciting data underscore the importance of gastrointestinal regulation of whole-body metabolism, via pathways which remain incompletely understood. In this project, we are studying the impact of candidate circulating proteins identified via proteomic and metabolomic studies in humans with type 2 diabetes who have had either bariatric surgery or medical management. These candidate proteins are being overexpressed in mice via several approaches, to determine their effect on metabolism, including insulin secretion, in the mouse. The student would work with a postdoctoral fellow in the laboratory to learn needed techniques and analysis of omics data. The student would also have opportunities to interface with clinical studies in this area, as guided by students' interests.
Obesity and type 2 diabetes (T2D) are major public health challenges for our generation. Particularly concerning is the rise in obesity in the pediatric population, the anticipated rise in premature morbidity and mortality with long-standing obesity and costs associated with obesity-related. In parallel, recent projections suggest that prevalence of diabetes is likely to increase to over 25% of the US population by 2050, yielding enormous tolls at individual, public health, and economic levels. Unfortunately, there are no simple answers for the dual epidemics of obesity and T2D. Novel insights and approaches on many fronts are required.
Risk patterns for both obesity and T2D can originate as a consequence of alterations in growth and metabolism during critical windows of prenatal and early postnatal development. Moreover, obesity, prediabetes, and diabetes in individuals of reproductive age can initiate a vicious cycle, propagating risk to subsequent generations via non-genetic, or epi-genetic and metabolic mechanisms. Thus, understanding mechanisms mediating these effects is an important scientific and clinical goal. More importantly, this concept provides the hope that identification of high-risk individuals for targeted intervention during early childhood and subsequent reproductive life may limit vicious cycles of metabolic risk.
One example of nutritionally-mediated transmission of metabolic phenotypes is provided from our laboratory's mouse model in which healthy pregnant mothers (F0) are exposed to modified nutrition during the last third of pregnancy. Their offspring (F1) have a modest 15% reduction in birth weight and experience early postnatal "catch-up growth." Despite normal chow diet after weaning, these UN-exposed mice go on to develop progressive glucose intolerance, insulin secretory dysfunction, reduced muscle mass, and obesity as adults. UN exposed mice have upregulation of lipogenic gene expression in both liver and adipose, increased adipocyte size, and reduced mitochondrial DNA content. We have recently demonstrated that UN-exposed mice also have reduced numbers of myogenic precursor cells, suggesting the possibility that alterations in key stem cell populations may alter developmental trajectories and modify tissue structure/function and repair. The goal of the current study is to examine patterns of transcriptional dysregulation in myoblasts isolated from skeletal muscle from at-risk mice, and in parallel, to identify potential epigenetic mediators resulting from exposure to nutritional stress during pregnancy.
Closed loop insulin pumps are rapidly moving toward reality for clinical diabetes care. While integrationwith continuous glucose monitoring together with integrative algorithms has allowed great improvement in glucose control, factors such as meal initiation, exercise, stress and insulin boluses previously delivered are variables which need to be incorporated into decision-making algorithms to guide improved insulin delivery. This project, a collaboration with Harvard engineers, will inform the development of new insulin delivery algorithms for safer more effective diabetes treatment.
Osataphan S, Macchi C, Singhal G, Chimene-Weiss J, Sales V, Kozuka C, Dreyfuss JM, Pan H, Tangcharoenpaisan Y, Morningstar J, Gerszten R, Patti ME. SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms. JCI Insight. 2019 Mar 07; 4(5). PMID: 30843877.
Franquet E, Watts G, Kolodny GM, Goldfine AB, Patti ME. PET-CT reveals increased intestinal glucose uptake after gastric surgery. Surg Obes Relat Dis. 2019 Jan 25. PMID: 30773442.
Rosen ED, Kaestner KH, Natarajan R, Patti ME, Sallari R, Sander M, Susztak K. Epigenetics and Epigenomics: Implications for Diabetes and Obesity. Diabetes. 2018 10; 67(10):1923-1931. PMID: 30237160.
Grizales AM, Patti ME, Lin AP, Beckman JA, Sahni VA, Cloutier E, Fowler KM, Dreyfuss JM, Pan H, Kozuka C, Lee A, Basu R, Pober DM, Gerszten RE, Goldfine AB. Metabolic Effects of Betaine: A Randomized Clinical Trial of Betaine Supplementation in Prediabetes. J Clin Endocrinol Metab. 2018 08 01; 103(8):3038-3049. PMID: 29860335.
Salehi M, Vella A, McLaughlin T, Patti ME. Hypoglycemia After Gastric Bypass Surgery: Current Concepts and Controversies. J Clin Endocrinol Metab. 2018 08 01; 103(8):2815-2826. PMID: 30101281.
Gonzalez-Franquesa A, Patti ME. Squeezing Flux Out of Fat. Trends Endocrinol Metab. 2018 04; 29(4):201-202. PMID: 29409712.
Laguna Sanz AJ, Mulla CM, Fowler KM, Cloutier E, Goldfine AB, Newswanger B, Cummins M, Deshpande S, Prestrelski SJ, Strange P, Zisser H, Doyle FJ, Dassau E, Patti ME. Design and Clinical Evaluation of a Novel Low-Glucose Prediction Algorithm with Mini-Dose Stable Glucagon Delivery in Post-Bariatric Hypoglycemia. Diabetes Technol Ther. 2018 02; 20(2):127-139. PMID: 29355439.
Arora I, Patti ME. Can reversal of RYGB also reverse hypoglycemia? Mol Metab. 2018 03; 9:1-3. PMID: 29371089.
Fernandes GW, Bocco BMLC, Fonseca TL, McAninch EA, Jo S, Lartey LJ, O-Sullivan I, Unterman TG, Preite NZ, Voigt RM, Forsyth CB, Keshavarzian A, Sinkó R, Goldfine AB, Patti ME, Ribeiro MO, Gereben B, Bianco AC. The Foxo1-Inducible Transcriptional Repressor Zfp125 Causes Hepatic Steatosis and Hypercholesterolemia. Cell Rep. 2018 01 09; 22(2):523-534. PMID: 29320745.
Patti ME. LETTER TO THE EDITOR. Endocr Pract. 2017 10; 23(10):1275. PMID: 29045187.
Mulla CM, Middelbeek RJW, Patti ME. Mechanisms of weight loss and improved metabolism following bariatric surgery. Ann N Y Acad Sci. 2018 Jan; 1411(1):53-64. PMID: 28868615.
Ma H, Sales VM, Wolf AR, Subramanian S, Matthews TJ, Chen M, Sharma A, Gall W, Kulik W, Cohen DE, Adachi Y, Griffin NW, Gordon JI, Patti ME, Isganaitis E. Attenuated Effects of Bile Acids on Glucose Metabolism and Insulin Sensitivity in a Male Mouse Model of Prenatal Undernutrition. Endocrinology. 2017 08 01; 158(8):2441-2452. PMID: 28637315.
Patti ME, Goldfine AB, Hu J, Hoem D, Molven A, Goldsmith J, Schwesinger WH, La Rosa S, Folli F, Kulkarni RN. Heterogeneity of proliferative markers in pancreatic ß-cells of patients with severe hypoglycemia following Roux-en-Y gastric bypass. Acta Diabetol. 2017 Aug; 54(8):737-747. PMID: 28512677.
Sales VM, Ferguson-Smith AC, Patti ME. Epigenetic Mechanisms of Transmission of Metabolic Disease across Generations. Cell Metab. 2017 03 07; 25(3):559-571. PMID: 28273478.
Suhl E, Anderson-Haynes SE, Mulla C, Patti ME. Medical nutrition therapy for post-bariatric hypoglycemia: practical insights. Surg Obes Relat Dis. 2017 May; 13(5):888-896. PMID: 28392017.
Gonzalez-Franquesa A, Patti ME. Insulin Resistance and Mitochondrial Dysfunction. Adv Exp Med Biol. 2017; 982:465-520. PMID: 28551803.
Costa SM, Isganaitis E, Matthews TJ, Hughes K, Daher G, Dreyfuss JM, da Silva GA, Patti ME. Maternal obesity programs mitochondrial and lipid metabolism gene expression in infant umbilical vein endothelial cells. Int J Obes (Lond). 2016 11; 40(11):1627-1634. PMID: 27531045.
Gonzalez-Franquesa A, Burkart AM, Isganaitis E, Patti ME. What Have Metabolomics Approaches Taught Us About Type 2 Diabetes? Curr Diab Rep. 2016 08; 16(8):74. PMID: 27319324.
Goldfine AB, Patti ME. How common is hypoglycemia after gastric bypass? Obesity (Silver Spring). 2016 06; 24(6):1210-1. PMID: 27225595.
Middelbeek RJ, Brown FM, Patti ME. Weight Loss and Health Status after Bariatric Surgery in Adolescents. N Engl J Med. 2016 05 19; 374(20):1988-9. PMID: 27192680.
Mulla CM, Storino A, Yee EU, Lautz D, Sawnhey MS, Moser AJ, Patti ME. Insulinoma After Bariatric Surgery: Diagnostic Dilemma and Therapeutic Approaches. Obes Surg. 2016 Apr; 26(4):874-81. PMID: 26846121; PMCID: PMC4814298.
Burkart AM, Tan K, Warren L, Iovino S, Hughes KJ, Kahn CR, Patti ME. Insulin Resistance in Human iPS Cells Reduces Mitochondrial Size and Function. Sci Rep. 2016 Mar 07; 6:22788. PMID: 26948272; PMCID: PMC4780029.
Ejaz A, Martinez-Guino L, Goldfine AB, Ribas-Aulinas F, De Nigris V, Ribó S, Gonzalez-Franquesa A, Garcia-Roves PM, Li E, Dreyfuss JM, Gall W, Kim JK, Bottiglieri T, Villarroya F, Gerszten RE, Patti ME, Lerin C. Dietary Betaine Supplementation Increases Fgf21 Levels to Improve Glucose Homeostasis and Reduce Hepatic Lipid Accumulation in Mice. Diabetes. 2016 04; 65(4):902-12. PMID: 26858359; PMCID: PMC4806659.
Iovino S, Burkart AM, Warren L, Patti ME, Kahn CR. Myotubes derived from human-induced pluripotent stem cells mirror in vivo insulin resistance. Proc Natl Acad Sci U S A. 2016 Feb 16; 113(7):1889-94. PMID: 26831110; PMCID: PMC4763759.
Makimura H, Stanley TL, Suresh C, De Sousa-Coelho AL, Frontera WR, Syu S, Braun LR, Looby SE, Feldpausch MN, Torriani M, Lee H, Patti ME, Grinspoon SK. Metabolic Effects of Long-Term Reduction in Free Fatty Acids With Acipimox in Obesity: A Randomized Trial. J Clin Endocrinol Metab. 2016 Mar; 101(3):1123-33. PMID: 26691888; PMCID: PMC4803166.
Patti ME, Goldfine AB. The rollercoaster of post-bariatric hypoglycaemia. Lancet Diabetes Endocrinol. 2016 Feb; 4(2):94-6. PMID: 26701701.
Goldfine AB, Patti ME. New lessons from gastric bypass: Impact of glucose-independent islet function. Obesity (Silver Spring). 2015 Oct; 23(10):1942-3. PMID: 26348724; PMCID: PMC4586903.
Middelbeek RJ, James-Todd T, Cavallerano JD, Schlossman DK, Patti ME, Brown FM. Gastric Bypass Surgery in Severely Obese Women With Type 1 Diabetes: Anthropometric and Cardiometabolic Effects at 1 and 5 Years Postsurgery. Diabetes Care. 2015 Jul; 38(7):e104-5. PMID: 26106230; PMCID: PMC4876744.
Beauchamp B, Thrush AB, Quizi J, Antoun G, McIntosh N, Al-Dirbashi OY, Patti ME, Harper ME. Undernutrition during pregnancy in mice leads to dysfunctional cardiac muscle respiration in adult offspring. Biosci Rep. 2015 Apr 10; 35(3). PMID: 26182362; PMCID: PMC4613697.
Beauchamp B, Thrush AB, Quizi J, Antoun G, McIntosh N, Al-Dirbashi OY, Patti ME, Harper ME. Undernutrition during pregnancy in mice leads to dysfunctional cardiac muscle respiration in adult offspring. Biosci Rep. 2015 Apr 10. PMID: 25860649.
Balhara B, Burkart A, Topcu V, Lee YK, Cowan C, Kahn CR, Patti ME. Severe insulin resistance alters metabolism in mesenchymal progenitor cells. Endocrinology. 2015 Jun; 156(6):2039-48. PMID: 25811318; PMCID: PMC4430624.
Isganaitis E, Rifas-Shiman SL, Oken E, Dreyfuss JM, Gall W, Gillman MW, Patti ME. Associations of cord blood metabolites with early childhood obesity risk. Int J Obes (Lond). 2015 Jul; 39(7):1041-8. PMID: 25804930; PMCID: PMC4496296.
Patti ME, Li P, Goldfine AB. Insulin response to oral stimuli and glucose effectiveness increased in neuroglycopenia following gastric bypass. Obesity (Silver Spring). 2015 Apr; 23(4):798-807. PMID: 25755084.
Hivert MF, Perng W, Watkins SM, Newgard CS, Kenny LC, Kristal BS, Patti ME, Isganaitis E, DeMeo DL, Oken E, Gillman MW. Metabolomics in the developmental origins of obesity and its cardiometabolic consequences. J Dev Orig Health Dis. 2015 Apr; 6(2):65-78. PMID: 25631626; PMCID: PMC4406410.
McAninch EA, Jo S, Preite NZ, Farkas E, Mohácsik P, Fekete C, Egri P, Gereben B, Li Y, Deng Y, Patti ME, Zevenbergen C, Peeters RP, Mash DC, Bianco AC. Prevalent polymorphism in thyroid hormone-activating enzyme leaves a genetic fingerprint that underlies associated clinical syndromes. J Clin Endocrinol Metab. 2015 Mar; 100(3):920-33. PMID: 25569702; PMCID: PMC4333048.
Nogiec C, Burkart A, Dreyfuss JM, Lerin C, Kasif S, Patti ME. Metabolic modeling of muscle metabolism identifies key reactions linked to insulin resistance phenotypes. Mol Metab. 2015 Mar; 4(3):151-63. PMID: 25737951; PMCID: PMC4338313.
Perng W, Gillman MW, Fleisch AF, Michalek RD, Watkins SM, Isganaitis E, Patti ME, Oken E. Metabolomic profiles and childhood obesity. Obesity (Silver Spring). 2014 Dec; 22(12):2570-8. PMID: 25251340; PMCID: PMC4236243.
Robertson RP, Bogachus LD, Oseid E, Parazzoli S, Patti ME, Rickels MR, Schuetz C, Dunn T, Pruett T, Balamurugan AN, Sutherland DE, Beilman G, Bellin MD. Assessment of ß-cell mass and a- and ß-cell survival and function by arginine stimulation in human autologous islet recipients. Diabetes. 2015 Feb; 64(2):565-72. PMID: 25187365; PMCID: PMC4303963.
Middelbeek RJ, James-Todd T, Patti ME, Brown FM. Short-term insulin requirements following gastric bypass surgery in severely obese women with type 1 diabetes. Obes Surg. 2014 Sep; 24(9):1442-6. PMID: 24668543; PMCID: PMC4122809.
Bellin MD, Parazzoli S, Oseid E, Bogachus LD, Schuetz C, Patti ME, Dunn T, Pruett T, Balamurugan AN, Hering B, Beilman G, Sutherland DE, Robertson RP. Defective glucagon secretion during hypoglycemia after intrahepatic but not nonhepatic islet autotransplantation. Am J Transplant. 2014 Aug; 14(8):1880-6. PMID: 25039984; PMCID: PMC4440232.
Iovino S, Burkart AM, Kriauciunas K, Warren L, Hughes KJ, Molla M, Lee YK, Patti ME, Kahn CR. Genetic insulin resistance is a potent regulator of gene expression and proliferation in human iPS cells. Diabetes. 2014 Dec; 63(12):4130-42. PMID: 25059784; PMCID: PMC4238001.
Ma H, Patti ME. Bile acids, obesity, and the metabolic syndrome. Best Pract Res Clin Gastroenterol. 2014 Aug; 28(4):573-83. PMID: 25194176; PMCID: PMC4159616.
Beauchamp B, Ghosh S, Dysart MW, Kanaan GN, Chu A, Blais A, Rajamanickam K, Tsai EC, Patti ME, Harper ME. Low birth weight is associated with adiposity, impaired skeletal muscle energetics and weight loss resistance in mice. Int J Obes (Lond). 2015 Apr; 39(4):702-11. PMID: 25091727.
Radford EJ, Ito M, Shi H, Corish JA, Yamazawa K, Isganaitis E, Seisenberger S, Hore TA, Reik W, Erkek S, Peters AHFM, Patti ME, Ferguson-Smith AC. In utero effects. In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism. Science. 2014 Aug 15; 345(6198):1255903. PMID: 25011554.
Goldfine AB, Patti ME. Diabetes improvement following Roux-en-Y gastric bypass: understanding dynamic changes in insulin secretion and action. Diabetes. 2014 May; 63(5):1454-6. PMID: 24757197.
Patti ME, Goldfine AB. Hypoglycemia after gastric bypass: the dark side of GLP-1. Gastroenterology. 2014 Mar; 146(3):605-8. PMID: 24468184.
Wewalka M, Patti ME, Barbato C, Houten SM, Goldfine AB. Fasting serum taurine-conjugated bile acids are elevated in type 2 diabetes and do not change with intensification of insulin. J Clin Endocrinol Metab. 2014 Apr; 99(4):1442-51. PMID: 24432996.
Isganaitis E, Woo M, Ma H, Chen M, Kong W, Lytras A, Sales V, Decoste-Lopez J, Lee KJ, Leatherwood C, Lee D, Fitzpatrick C, Gall W, Watkins S, Patti ME. Developmental programming by maternal insulin resistance: hyperinsulinemia, glucose intolerance, and dysregulated lipid metabolism in male offspring of insulin-resistant mice. Diabetes. 2014 Feb; 63(2):688-700. PMID: 24186867; PMCID: PMC3900545.
Goldfine AB, Patti ME. Diabetes: Bariatric surgery for T2DM--cure, or remission and relapse? Nat Rev Endocrinol. 2014 Jan; 10(1):8-9. PMID: 24165996; PMCID: PMC4160734.
Colaneri A, Wang T, Pagadala V, Kittur J, Staffa NG, Peddada SD, Isganaitis E, Patti ME, Birnbaumer L. A minimal set of tissue-specific hypomethylated CpGs constitute epigenetic signatures of developmental programming. PLoS One. 2013; 8(9):e72670. PMID: 24069155; PMCID: PMC3771925.
Patti ME. Reducing maternal weight improves offspring metabolism and alters (or modulates) methylation. Proc Natl Acad Sci U S A. 2013 Aug 06; 110(32):12859-60. PMID: 23884649; PMCID: PMC3740829.
Patti ME. Intergenerational programming of metabolic disease: evidence from human populations and experimental animal models. Cell Mol Life Sci. 2013 May; 70(9):1597-608. PMID: 23435955; PMCID: PMC3625497.
Sales V, Patti ME. The Ups and Downs of Insulin Resistance and Type 2 Diabetes: Lessons from Genomic Analyses in Humans. Curr Cardiovasc Risk Rep. 2013 Feb 01; 7(1):46-59. PMID: 23459395.
Simonen M, Dali-Youcef N, Kaminska D, Venesmaa S, Käkelä P, Pääkkönen M, Hallikainen M, Kolehmainen M, Uusitupa M, Moilanen L, Laakso M, Gylling H, Patti ME, Auwerx J, Pihlajamäki J. Conjugated bile acids associate with altered rates of glucose and lipid oxidation after Roux-en-Y gastric bypass. Obes Surg. 2012 Sep; 22(9):1473-80. PMID: 22638681; PMCID: PMC4426904.
Radford EJ, Isganaitis E, Jimenez-Chillaron J, Schroeder J, Molla M, Andrews S, Didier N, Charalambous M, McEwen K, Marazzi G, Sassoon D, Patti ME, Ferguson-Smith AC. An unbiased assessment of the role of imprinted genes in an intergenerational model of developmental programming. PLoS Genet. 2012; 8(4):e1002605. PMID: 22511876.
Pihlajamäki J, Lerin C, Kaminska D, Venesmaa S, Itkonen P, Boes T, Floss T, Schroeder J, Dearie F, Crunkhorn S, Burak F, Jimenez-Chillaron JC, Kuulasmaa T, Miettinen P, Park PJ, Nasser I, Zhao Z, Zhang Z, Xu Y, Wurst W, Ren H, Morris AJ, Stamm S, Goldfine AB, Laakso M, Patti ME. Response to Brosch et al. Cell Metab. 2012 Mar 07; 15(3):267-269. PMID: 25960695.
Pihlajamäki J, Lerin C, Itkonen P, Boes T, Floss T, Schroeder J, Dearie F, Crunkhorn S, Burak F, Jimenez-Chillaron JC, Kuulasmaa T, Miettinen P, Park PJ, Nasser I, Zhao Z, Zhang Z, Xu Y, Wurst W, Ren H, Morris AJ, Stamm S, Goldfine AB, Laakso M, Patti ME. Expression of the splicing factor gene SFRS10 is reduced in human obesity and contributes to enhanced lipogenesis. Cell Metab. 2011 Aug 03; 14(2):208-18. PMID: 21803291; PMCID: PMC3167228.
Bezy O, Tran TT, Pihlajamäki J, Suzuki R, Emanuelli B, Winnay J, Mori MA, Haas J, Biddinger SB, Leitges M, Goldfine AB, Patti ME, King GL, Kahn CR. PKCd regulates hepatic insulin sensitivity and hepatosteatosis in mice and humans. J Clin Invest. 2011 Jun; 121(6):2504-17. PMID: 21576825; PMCID: PMC3104767.
Jin W, Goldfine AB, Boes T, Henry RR, Ciaraldi TP, Kim EY, Emecan M, Fitzpatrick C, Sen A, Shah A, Mun E, Vokes V, Schroeder J, Tatro E, Jimenez-Chillaron J, Patti ME. Increased SRF transcriptional activity in human and mouse skeletal muscle is a signature of insulin resistance. J Clin Invest. 2011 Mar; 121(3):918-29. PMID: 21393865; PMCID: PMC3049368.
Halperin F, Patti ME, Skow M, Bajwa M, Goldfine AB. Continuous glucose monitoring for evaluation of glycemic excursions after gastric bypass. J Obes. 2011; 2011:869536. PMID: 21331295; PMCID: PMC3038694.
Ferguson-Smith AC, Patti ME. You are what your dad ate. Cell Metab. 2011 Feb 02; 13(2):115-7. PMID: 21284975.
da-Silva WS, Ribich S, Arrojo e Drigo R, Castillo M, Patti ME, Bianco AC. The chemical chaperones tauroursodeoxycholic and 4-phenylbutyric acid accelerate thyroid hormone activation and energy expenditure. FEBS Lett. 2011 Feb 04; 585(3):539-44. PMID: 21237159.
Goldfine AB, Gerwien RW, Kolberg JA, O'Shea S, Hamren S, Hein GP, Xu XM, Patti ME. Biomarkers in fasting serum to estimate glucose tolerance, insulin sensitivity, and insulin secretion. Clin Chem. 2011 Feb; 57(2):326-37. PMID: 21149503.
Reubi JC, Perren A, Rehmann R, Waser B, Christ E, Callery M, Goldfine AB, Patti ME. Glucagon-like peptide-1 (GLP-1) receptors are not overexpressed in pancreatic islets from patients with severe hyperinsulinaemic hypoglycaemia following gastric bypass. Diabetologia. 2010 Dec; 53(12):2641-5. PMID: 20835917.
Patti ME, Goldfine AB. Hypoglycaemia following gastric bypass surgery--diabetes remission in the extreme? Diabetologia. 2010 Nov; 53(11):2276-9. PMID: 20730413.
Patti ME. Rehashing endocannabinoid antagonists: can we selectively target the periphery to safely treat obesity and type 2 diabetes? J Clin Invest. 2010 Aug; 120(8):2646-8. PMID: 20664166; PMCID: PMC2912207.
Hall JA, Ribich S, Christoffolete MA, Simovic G, Correa-Medina M, Patti ME, Bianco AC. Absence of thyroid hormone activation during development underlies a permanent defect in adaptive thermogenesis. Endocrinology. 2010 Sep; 151(9):4573-82. PMID: 20660060.
Castillo M, Freitas BC, Rosene ML, Drigo RA, Grozovsky R, Maciel RM, Patti ME, Ribeiro MO, Bianco AC. Impaired metabolic effects of a thyroid hormone receptor beta-selective agonist in a mouse model of diet-induced obesity. Thyroid. 2010 May; 20(5):545-53. PMID: 20406106; PMCID: PMC2941403.
Zelezniak A, Pers TH, Soares S, Patti ME, Patil KR. Metabolic network topology reveals transcriptional regulatory signatures of type 2 diabetes. PLoS Comput Biol. 2010 Apr 01; 6(4):e1000729. PMID: 20369014; PMCID: PMC2848542.
Halperin F, Patti ME, Goldfine AB. Glucagon treatment for post-gastric bypass hypoglycemia. Obesity (Silver Spring). 2010 Sep; 18(9):1858-60. PMID: 20168313; PMCID: PMC4465911.
Patti ME, Corvera S. The role of mitochondria in the pathogenesis of type 2 diabetes. Endocr Rev. 2010 Jun; 31(3):364-95. PMID: 20156986; PMCID: PMC3365846.
Espinoza DO, Boros LG, Crunkhorn S, Gami H, Patti ME. Dual modulation of both lipid oxidation and synthesis by peroxisome proliferator-activated receptor-gamma coactivator-1alpha and -1beta in cultured myotubes. FASEB J. 2010 Apr; 24(4):1003-14. PMID: 19906680; PMCID: PMC2845426.
Pihlajamäki J, Boes T, Kim EY, Dearie F, Kim BW, Schroeder J, Mun E, Nasser I, Park PJ, Bianco AC, Goldfine AB, Patti ME. Thyroid hormone-related regulation of gene expression in human fatty liver. J Clin Endocrinol Metab. 2009 Sep; 94(9):3521-9. PMID: 19549744; PMCID: PMC2741713.
Wang XL, Suzuki R, Lee K, Tran T, Gunton JE, Saha AK, Patti ME, Goldfine A, Ruderman NB, Gonzalez FJ, Kahn CR. Ablation of ARNT/HIF1beta in liver alters gluconeogenesis, lipogenic gene expression, and serum ketones. Cell Metab. 2009 May; 9(5):428-39. PMID: 19416713.
Sutherland AP, Zhang H, Zhang Y, Michaud M, Xie Z, Patti ME, Grusby MJ, Zhang WJ. Zinc finger protein Zbtb20 is essential for postnatal survival and glucose homeostasis. Mol Cell Biol. 2009 May; 29(10):2804-15. PMID: 19273596; PMCID: PMC2682054.
Apovian CM, Cummings S, Anderson W, Borud L, Boyer K, Day K, Hatchigian E, Hodges B, Patti ME, Pettus M, Perna F, Rooks D, Saltzman E, Skoropowski J, Tantillo MB, Thomason P. Best practice updates for multidisciplinary care in weight loss surgery. Obesity (Silver Spring). 2009 May; 17(5):871-9. PMID: 19396065; PMCID: PMC2859198.
Isganaitis E, Jimenez-Chillaron J, Woo M, Chow A, DeCoste J, Vokes M, Liu M, Kasif S, Zavacki AM, Leshan RL, Myers MG, Patti ME. Accelerated postnatal growth increases lipogenic gene expression and adipocyte size in low-birth weight mice. Diabetes. 2009 May; 58(5):1192-200. PMID: 19208909; PMCID: PMC2671035.
Jin W, Patti ME. Genetic determinants and molecular pathways in the pathogenesis of Type 2 diabetes. Clin Sci (Lond). 2009 Jan; 116(2):99-111. PMID: 19076063.
Grozovsky R, Ribich S, Rosene ML, Mulcahey MA, Huang SA, Patti ME, Bianco AC, Kim BW. Type 2 deiodinase expression is induced by peroxisomal proliferator-activated receptor-gamma agonists in skeletal myocytes. Endocrinology. 2009 Apr; 150(4):1976-83. PMID: 19036883; PMCID: PMC2659265.
Jimenez-Chillaron JC, Isganaitis E, Charalambous M, Gesta S, Pentinat-Pelegrin T, Faucette RR, Otis JP, Chow A, Diaz R, Ferguson-Smith A, Patti ME. Intergenerational transmission of glucose intolerance and obesity by in utero undernutrition in mice. Diabetes. 2009 Feb; 58(2):460-8. PMID: 19017762; PMCID: PMC2628621.
Doria A, Patti ME, Kahn CR. The emerging genetic architecture of type 2 diabetes. Cell Metab. 2008 Sep; 8(3):186-200. PMID: 18762020; PMCID: PMC4267677.
Ruddock MW, Stein A, Landaker E, Park J, Cooksey RC, McClain D, Patti ME. Saturated fatty acids inhibit hepatic insulin action by modulating insulin receptor expression and post-receptor signalling. J Biochem. 2008 Nov; 144(5):599-607. PMID: 18713797.
Isshiki K, He Z, Maeno Y, Ma RC, Yasuda Y, Kuroki T, White GS, Patti ME, Weir GC, King GL. Insulin regulates SOCS2 expression and the mitogenic effect of IGF-1 in mesangial cells. Kidney Int. 2008 Dec; 74(11):1434-43. PMID: 19008912; PMCID: PMC2644821.
Woo M, Patti ME. Diabetes risk begins in utero. Cell Metab. 2008 Jul; 8(1):5-7. PMID: 18590686.
Crunkhorn S, Patti ME. Links between thyroid hormone action, oxidative metabolism, and diabetes risk? Thyroid. 2008 Feb; 18(2):227-37. PMID: 18279023.
Goldfine AB, Mun EC, Devine E, Bernier R, Baz-Hecht M, Jones DB, Schneider BE, Holst JJ, Patti ME. Patients with neuroglycopenia after gastric bypass surgery have exaggerated incretin and insulin secretory responses to a mixed meal. J Clin Endocrinol Metab. 2007 Dec; 92(12):4678-85. PMID: 17895322.
Crunkhorn S, Dearie F, Mantzoros C, Gami H, da Silva WS, Espinoza D, Faucette R, Barry K, Bianco AC, Patti ME. Peroxisome proliferator activator receptor gamma coactivator-1 expression is reduced in obesity: potential pathogenic role of saturated fatty acids and p38 mitogen-activated protein kinase activation. J Biol Chem. 2007 May 25; 282(21):15439-50. PMID: 17416903.
Oge A, Isganaitis E, Jimenez-Chillaron J, Reamer C, Faucette R, Barry K, Przybyla R, Patti ME. In utero undernutrition reduces diabetes incidence in non-obese diabetic mice. Diabetologia. 2007 May; 50(5):1099-108. PMID: 17370059.
Arikawa E, Ma RC, Isshiki K, Luptak I, He Z, Yasuda Y, Maeno Y, Patti ME, Weir GC, Harris RA, Zammit VA, Tian R, King GL. Effects of insulin replacements, inhibitors of angiotensin, and PKCbeta's actions to normalize cardiac gene expression and fuel metabolism in diabetic rats. Diabetes. 2007 May; 56(5):1410-20. PMID: 17363743.
Jimenez-Chillaron JC, Patti ME. To catch up or not to catch up: is this the question? Lessons from animal models. Curr Opin Endocrinol Diabetes Obes. 2007 Feb; 14(1):23-9. PMID: 17940415.
Hernandez-Valencia M, Patti ME. A thin phenotype is protective for impaired glucose tolerance and related to low birth weight in mice. Arch Med Res. 2006 Oct; 37(7):813-7. PMID: 16971218.
Jimenez-Chillaron JC, Hernandez-Valencia M, Lightner A, Faucette RR, Reamer C, Przybyla R, Ruest S, Barry K, Otis JP, Patti ME. Reductions in caloric intake and early postnatal growth prevent glucose intolerance and obesity associated with low birthweight. Diabetologia. 2006 Aug; 49(8):1974-84. PMID: 16761107.
Tiffin N, Adie E, Turner F, Brunner HG, van Driel MA, Oti M, Lopez-Bigas N, Ouzounis C, Perez-Iratxeta C, Andrade-Navarro MA, Adeyemo A, Patti ME, Semple CA, Hide W. Computational disease gene identification: a concert of methods prioritizes type 2 diabetes and obesity candidate genes. Nucleic Acids Res. 2006; 34(10):3067-81. PMID: 16757574; PMCID: PMC1475747.
Goldfine AB, Beckman JA, Betensky RA, Devlin H, Hurley S, Varo N, Schonbeck U, Patti ME, Creager MA. Family history of diabetes is a major determinant of endothelial function. J Am Coll Cardiol. 2006 Jun 20; 47(12):2456-61. PMID: 16781373.
Ilany J, Bilan PJ, Kapur S, Caldwell JS, Patti ME, Marette A, Kahn CR. Overexpression of Rad in muscle worsens diet-induced insulin resistance and glucose intolerance and lowers plasma triglyceride level. Proc Natl Acad Sci U S A. 2006 Mar 21; 103(12):4481-6. PMID: 16537411; PMCID: PMC1450197.
Goldfine AB, Crunkhorn S, Costello M, Gami H, Landaker EJ, Niinobe M, Yoshikawa K, Lo D, Warren A, Jimenez-Chillaron J, Patti ME. Necdin and E2F4 are modulated by rosiglitazone therapy in diabetic human adipose and muscle tissue. Diabetes. 2006 Mar; 55(3):640-50. PMID: 16505226.
Myers MG, Patti ME, Leshan RL. Hitting the target: leptin and perinatal nutrition in the predisposition to obesity. Endocrinology. 2005 Oct; 146(10):4209-10. PMID: 16166232.
Patti ME, McMahon G, Mun EC, Bitton A, Holst JJ, Goldsmith J, Hanto DW, Callery M, Arky R, Nose V, Bonner-Weir S, Goldfine AB. Severe hypoglycaemia post-gastric bypass requiring partial pancreatectomy: evidence for inappropriate insulin secretion and pancreatic islet hyperplasia. Diabetologia. 2005 Nov; 48(11):2236-40. PMID: 16195867.
Halperin F, Beckman JA, Patti ME, Trujillo ME, Garvin M, Creager MA, Scherer PE, Goldfine AB. The role of total and high-molecular-weight complex of adiponectin in vascular function in offspring whose parents both had type 2 diabetes. Diabetologia. 2005 Oct; 48(10):2147-54. PMID: 16091909.
Tseng YH, Butte AJ, Kokkotou E, Yechoor VK, Taniguchi CM, Kriauciunas KM, Cypess AM, Niinobe M, Yoshikawa K, Patti ME, Kahn CR. Prediction of preadipocyte differentiation by gene expression reveals role of insulin receptor substrates and necdin. Nat Cell Biol. 2005 Jun; 7(6):601-11. PMID: 15895078.
Gordon LB, Harten IA, Patti ME, Lichtenstein AH. Reduced adiponectin and HDL cholesterol without elevated C-reactive protein: clues to the biology of premature atherosclerosis in Hutchinson-Gilford Progeria Syndrome. J Pediatr. 2005 Mar; 146(3):336-41. PMID: 15756215.
Yechoor VK, Patti ME, Ueki K, Laustsen PG, Saccone R, Rauniyar R, Kahn CR. Distinct pathways of insulin-regulated versus diabetes-regulated gene expression: an in vivo analysis in MIRKO mice. Proc Natl Acad Sci U S A. 2004 Nov 23; 101(47):16525-30. PMID: 15546994; PMCID: PMC534529.
Patti ME, Kahn BB. Nutrient sensor links obesity with diabetes risk. Nat Med. 2004 Oct; 10(10):1049-50. PMID: 15459705.
Patti ME. Gene expression in humans with diabetes and prediabetes: what have we learned about diabetes pathophysiology? Curr Opin Clin Nutr Metab Care. 2004 Jul; 7(4):383-90. PMID: 15192439.
Patti ME. Gene expression in the pathophysiology of type 2 diabetes mellitus. Curr Diab Rep. 2004 Jun; 4(3):176-81. PMID: 15132881.
Blüher M, Patti ME, Gesta S, Kahn BB, Kahn CR. Intrinsic heterogeneity in adipose tissue of fat-specific insulin receptor knock-out mice is associated with differences in patterns of gene expression. J Biol Chem. 2004 Jul 23; 279(30):31891-901. PMID: 15131119.
Patti ME, Butte AJ, Crunkhorn S, Cusi K, Berria R, Kashyap S, Miyazaki Y, Kohane I, Costello M, Saccone R, Landaker EJ, Goldfine AB, Mun E, DeFronzo R, Finlayson J, Kahn CR, Mandarino LJ. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Proc Natl Acad Sci U S A. 2003 Jul 08; 100(14):8466-71. PMID: 12832613; PMCID: PMC166252.
Combs TP, Berg AH, Rajala MW, Klebanov S, Iyengar P, Jimenez-Chillaron JC, Patti ME, Klein SL, Weinstein RS, Scherer PE. Sexual differentiation, pregnancy, calorie restriction, and aging affect the adipocyte-specific secretory protein adiponectin. Diabetes. 2003 Feb; 52(2):268-76. PMID: 12540596.
Yechoor VK, Patti ME, Saccone R, Kahn CR. Coordinated patterns of gene expression for substrate and energy metabolism in skeletal muscle of diabetic mice. Proc Natl Acad Sci U S A. 2002 Aug 06; 99(16):10587-92. PMID: 12149437.
Fraenkel PG, Rutkove SB, Matheson JK, Fowkes M, Cannon ME, Patti ME, Atkins MB, Gollob JA. Induction of myasthenia gravis, myositis, and insulin-dependent diabetes mellitus by high-dose interleukin-2 in a patient with renal cell cancer. J Immunother. 2002 Jul-Aug; 25(4):373-8. PMID: 12142560.
Orban T, Landaker E, Ruan Z, Cordeman TP, Weitgasser R, Bonner-Weir S, Jackson RA, Patti ME. High-fructose diet preserves beta-cell mass and prevents diabetes in nonobese diabetic mice: A potential role for increased insulin receptor substrate-2 expression. Metabolism. 2001 Nov; 50(11):1369-76. PMID: 11699059.
Rosas HD, Goodman J, Chen YI, Jenkins BG, Kennedy DN, Makris N, Patti M, Seidman LJ, Beal MF, Koroshetz WJ. Striatal volume loss in HD as measured by MRI and the influence of CAG repeat. Neurology. 2001 Sep 25; 57(6):1025-8. PMID: 11571328.
Goldfine AB, Patti ME, Zuberi L, Goldstein BJ, LeBlanc R, Landaker EJ, Jiang ZY, Willsky GR, Kahn CR. Metabolic effects of vanadyl sulfate in humans with non-insulin-dependent diabetes mellitus: in vivo and in vitro studies. Metabolism. 2000 Mar; 49(3):400-10. PMID: 10726921.
Cusi K, Maezono K, Osman A, Pendergrass M, Patti ME, Pratipanawatr T, DeFronzo RA, Kahn CR, Mandarino LJ. Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. J Clin Invest. 2000 Feb; 105(3):311-20. PMID: 10675357; PMCID: PMC377440.
Patti ME. Nutrient modulation of cellular insulin action. Ann N Y Acad Sci. 1999 Nov 18; 892:187-203. PMID: 10842663.
Patti ME, Virkamäki A, Landaker EJ, Kahn CR, Yki-Järvinen H. Activation of the hexosamine pathway by glucosamine in vivo induces insulin resistance of early postreceptor insulin signaling events in skeletal muscle. Diabetes. 1999 Aug; 48(8):1562-71. PMID: 10426374.
Koval JA, Maezono K, Patti ME, Pendergrass M, DeFronzo RA, Mandarino LJ. Effects of exercise and insulin on insulin signaling proteins in human skeletal muscle. Med Sci Sports Exerc. 1999 Jul; 31(7):998-1004. PMID: 10416561.
Patti ME, Brambilla E, Luzi L, Landaker EJ, Kahn CR. Bidirectional modulation of insulin action by amino acids. J Clin Invest. 1998 Apr 01; 101(7):1519-29. PMID: 9525995.
Patti ME, Kahn CR. The insulin receptor--a critical link in glucose homeostasis and insulin action. J Basic Clin Physiol Pharmacol. 1998; 9(2-4):89-109. PMID: 10212828.
Smith-Hall J, Pons S, Patti ME, Burks DJ, Yenush L, Sun XJ, Kahn CR, White MF. The 60 kDa insulin receptor substrate functions like an IRS protein (pp60IRS3) in adipose cells. Biochemistry. 1997 Jul 08; 36(27):8304-10. PMID: 9204876.
Patti ME, Kahn CR. Lessons from transgenic and knockout animals about noninsulin-dependent diabetes mellitus. Trends Endocrinol Metab. 1996 Nov; 7(9):311-9. PMID: 18406764.
Goldfine AB, Simonson DC, Folli F, Patti ME, Kahn CR. In vivo and in vitro studies of vanadate in human and rodent diabetes mellitus. Mol Cell Biochem. 1995 Dec 6-20; 153(1-2):217-31. PMID: 8927042.
Goldfine AB, Simonson DC, Folli F, Patti ME, Kahn CR. Metabolic effects of sodium metavanadate in humans with insulin-dependent and noninsulin-dependent diabetes mellitus in vivo and in vitro studies. J Clin Endocrinol Metab. 1995 Nov; 80(11):3311-20. PMID: 7593444.
Patti ME, Sun XJ, Bruening JC, Araki E, Lipes MA, White MF, Kahn CR. 4PS/insulin receptor substrate (IRS)-2 is the alternative substrate of the insulin receptor in IRS-1-deficient mice. J Biol Chem. 1995 Oct 20; 270(42):24670-3. PMID: 7559579.
Araki E, Lipes MA, Patti ME, Brüning JC, Haag B, Johnson RS, Kahn CR. Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature. 1994 Nov 10; 372(6502):186-90. PMID: 7526222.


Travel in spectacular fashion from Switzerland to Italy on the highest railway in the alps. You can choose to continue your journey by Bernina Express bus through Italy and past Lake Como to Lugano in Switzerland – from glaciers to palm trees!
Board the Bernina Express from Chur, Davos or St Moritz. Reservations are required in 1st and 2nd class carriages which offer great views from the panoramic carriages.
A minibar service offers tasty snacks and refreshing drinks during your journey. Take this trip as far as Tirano (Italy) as a return day excursion. Lunch is available in Poschiavo or Tirano. Choose to extend your journey by panoramic bus from Tirano, along the banks of Lake Como, to Lugano, for an overnight stay there.
On the Montebello Curve, travellers will get a glimpse of Morteratsch glacier, Piz Palue and Piz Bernina as the train makes a 180 degrees turn. Picture perfect!
From Glaciers to Palm Trees. You travel over viaducts, past glaciers before descending to the milder climates of Italy.


Construction began in 1960. Opened September 1963.
Richard Hart from National Helicopter Service says there were three deaths during the construction. Information posted inside the Tramway station say there were no deaths during construction. (Bit of controversy?) Checked Desert Sun and found two articles. One with two injured helicopter pilots, one with an injured worked. No deaths reported.
Response on 6/30/17 - "That was a long time ago, we might still have some useful information and we could supply aerial filming services should you need current footage."
Dianne Rothenberg - Miss Tramwayland 1970 - where is she?


The latest Josh Hawley commercial shows Senator Claire McCaskill, presumably at a volunteer gathering, remark that if she gets good turnout in St. Louis County, she can "give up a few votes in the bootheel." See it here.
Tag line: Prop D's a bargain to keep my family and yours safer.
Former Sen. Jolie Justus' announced that she's back in the KC mayor's race. See the video here.
She likely jumps to the top of the polling.
For your prep, take a look at the 2016 Senate 22 map here. Trump won Senate 22 by 35 points! Yowza.
Robert Butler's Facebook ads (see them here): he's endorsed by the Fraternal Order of Police; Wieland took the most gifts from lobbyists; proven champion for labor; and gets healthcare because wife Miriam is a nurse.
Paul Wieland's Facebook ads (see them here): Bring Jobs Home Act; opioid crisis; anti-eminent domain; stood up to insurance companies; stood up to towing companies; stood up to 911 tax; record school funding; pro-Trump's wall.
Republicans watch too many legal rulings reversing their legislative work and they'll take another run at the non-partisan court plan. Just sayin….
Quaker Window Products announced a $65 million expansion in Eldon Missouri yesterday. One of the reasons they cited – in addition to a "quality workforce" – was a new economic development tool from SB 564 which offers a special rate on energy. Quaker Windows is the first company to apply for the incentive, which allows for up to a 40% rate cut under certain criteria for up to five years.
To Jessica Winschel Grove who starts at St. Louis Community College on Monday as Associate for Board Relations reporting to the chancellor. She has been Vice President of Business Development at the Missouri Biotechnology Association.
The "camel nose/voucher" argument for allowing a mixed delivery system that includes private and public educators for Pre-K is just plain wrong. Public funds already go to early care and education providers outside of traditional districts. Public/private collaboration is good policy that benefits children, families and local communities.
The St. Louis Regional Chamber seeks Manager Government Affairs. "Represents the interests of the Regional Chamber with government officials, agencies and external audiences as the Chamber's primary contact with government at the regional, state and federal levels. Influences the passage, defeat and modification of legislation and administrative actions as needed to achieve the Chamber's public policy goals and objectives…" See it here.
Jeffrey Brooks, Bill Gamble, Cynthia Gamble, Kathryn Gamble, David Jackson, Sarah Schlemeier and Sarah Topp added Swope Health Services.
Jeffrey Brooks, Cynthia Gamble, and Sarah Topp deleted Saint Louis Zoo Association.
Jeffrey Brooks, Cynthia Gamble, and Jorgen Schlemeier deleted Journey to New Life Inc.
Jeffrey Brooks deleted Criminal Justice Ministry, Luetkenhaus Properties, and Empower Missouri.
David Jackson deleted Missouri Association Of County Dev Disabilities Services.
Jason Klumb deleted McCarthy Buildings Company, Bannister Transformation and Development, and Kansas City Area Development Council.
Vote For Your Library - $10,000 from John Sherman.
Vote For Your Library - $10,000 from Civic Council of Kansas City.
Majority Forward - $25,000 from WSCEW PAC.
Majority Forward - $10,000 from Centene Management Company LLC.
SaferMO.Com - $10,000 from MFA Oil.
Missouri Insurance Political Action Committee - $7,500 from RGA Enterprise Services Company.
MO Insurance Coalition PAC - $7,500 from RGA Enterprise Services Company.
Humane Society Legislative Fund of Missouri PAC - $15,000 from Chuck Laue.
Major Brands Political Action Committee - $25,000 from Susan McCollum.
Happy birthdays to Rep. Jason Chipman and Rick Francis, Charles Schlottach, Bridget Halquist, Dave Chilenski, Mavis Busiek, Jeff Mazur, and Alexandria Zumsteg.
Saturday: Larry Pleus, Linda Black, and John Mayfield.
Sunday: Jeremy LaFaver and Casey Guersey.


In this solo podcast episode, I reflect on the previous, eventful discussion with Tor Hyams about defining and pursuing music industry success, one in which Tor rejected the notion that engaging in the kindie artist community could lead in the direction of a successful entertainment career. Having given that interview some time and space where I could engage with the ideas it yielded, I offer my detailed, experience based counterpoint to Tor's assertions.
Grammy-nominated producer and festival promoter Tor Hyams attained his phenomenal kindie success after having already established a career in the entertainment industry and built relationships with celebrities which opened up avenues for his kindie endeavors that are not available to most do-it-yourselfers.
In this podcast interview, Tor challenges you to take stock in what you're trying to accomplish in your career, gives you pieces of what worked for him that can be applied to what you want to do, and puts you through a real gut check as to whether this is a career for you, a passion project or a hobby. There's in-depth discussion of the major players in the children's entertainment world (Disney, Nickelodeon and PBS) and what it may take to put your work in a position to be of interest to these players.
We also discuss the gap between what kindie artists expect as career gains from time and effort spent among communities of children's artists and what they actually get.
This podcast episode, sponsored by KindieComm, features Kaitlin and Tommy from the Alphabet Rockers, talking about how they started their new web TV series and some ways that you as a kindie artist can get your big project from idea to reality.
Listen in Apple Podcasts here.


Stoned driving can be as serious a problem as drunk driving.
Fatal accidents involving stoned drivers have soared in the state of Washington since marijuana was legalized there, according to a study from the AAA Foundation for Traffic Safety. But it's difficult to determine whether a high-on-pot driver is too impaired to drive, according to a separate study from the same group.
Fatal crashes involving drivers who recently used marijuana more than doubled in 2014. Pot was involved in 17% of fatal crashes in Washington in 2014, up from 8% in 2013 -- the year before recreational marijuana was allowed there.
"The significant increase in fatal crashes involving marijuana is alarming," said Peter Kissinger, CEO of the foundation, which funds scientifically rigorous studies for the drivers organization. "Washington serves as an eye-opening case study for what other states may experience with road safety after legalizing the drug."
"There is understandably a strong desire by both lawmakers and the public to create legal limits for marijuana impairment, in the same manner as we do with alcohol," said Marshall Doney, AAA's CEO. "In the case of marijuana, this approach is flawed and not supported by scientific research. It's simply not possible today to determine whether a driver is impaired based solely on the amount of the drug in their body."
The study was criticized by the National Cannabis Industry Association, which pointed to a different study, by the Transportation Department, which found that drivers who drivers who are drunk have a much greater increase in the risk of being in an accident than drivers who used marijuana.
"All this report really shows is that more people in Washington State are likely consuming cannabis, and thus might have some THC in their systems at the time of an accident. But since having THC in your system tells us nothing about your potential impairment, it would be like a report showing how many people involved in accidents had drunk a beer in the last week," said Taylor West, deputy director of the group.
AAA said the key result of the studies are that it's important that drivers be aware that marijuana can greatly impair driving ability.
"Whether the use of marijuana is legal or not, all motorists should avoid driving while impaired," said the group. "Just because a drug is legal does not mean it is safe to use while operating a motor vehicle. Drivers who get behind the wheel while impaired put themselves and others on the road at risk."
Another problem with testing for THC is that it requires a blood test, which can take up to two hours to be administered. That's much longer than the roadside breath tests used to test blood alcohol levels. And THC levels can decline significantly in those two hours, making results suspect.


In this Article: On iPhone Android Community Q&A. This wikiHow teaches you how to view chats stored in your archive for WhatsApp on your iPhone or Android.... WhatsApp now has a setting which allows you to hide chat in WhatsApp. This post will share the steps to achieve that on Android, iOS and Windows. After the chat is hidden it is also possible to show back the hidden chats when desired.
Can you Permanently Delete Messages on Whatsapp?
9/01/2016�� Queen �Banishes� Meghan From Palace After She�s Caught Pulling Unforgivable Stunt - Duration: 5:25. LATEST NEWS Recommended for you... WhatsApp now has a setting which allows you to hide chat in WhatsApp. This post will share the steps to achieve that on Android, iOS and Windows. After the chat is hidden it is also possible to show back the hidden chats when desired.
In this Article: On iPhone Android Community Q&A. This wikiHow teaches you how to view chats stored in your archive for WhatsApp on your iPhone or Android.
WhatsApp now has a setting which allows you to hide chat in WhatsApp. This post will share the steps to achieve that on Android, iOS and Windows. After the chat is hidden it is also possible to show back the hidden chats when desired.
This feature is, however, only available for the android users that are currently running under 7.0 or above OS, so if you�re wondering- how to read deleted whatsapp messages on iphone- am afraid, there isn�t any way, yet. Furthermore, the users could only recover texts, which means you cannot retrieve any media files whatsoever.


text:
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Veterans Affairs Changes Course, Allowing Religious Displays at VA Facilities Nationwide
Steve Warren
The US Department of Veterans Affairs (VA) recently announced it has updated its policies "permitting religious literature, symbols and displays at VA facilities to protect religious liberty for veterans and families while ensuring inclusivity and non-discrimination."
The department's move aims to simplify and clarify the VA's policies on religious symbols, and spiritual and pastoral care, which have been interpreted in different ways at various VA facilities across the country in recent years, leading to much confusion.
The changes to the policies went into effect at all VA facilities on July 3. They will help ensure that patrons within the VA have access to religious literature and symbols at chapels as requested and protect representations of faith in publicly accessible displays at facilities throughout the department, according to a government press release.
The changes include:
Allow the inclusion in appropriate circumstances of religious content in publicly accessible displays at VA facilities.
Allow patients and their guests to request and be provided religious literature, symbols, and sacred texts during visits to VA chapels and during their treatment at VA.
Allow VA to accept donations of religious literature, cards, and symbols at its facilities and distribute them to VA patrons under appropriate circumstances or to a patron who requests them.
"We want to make sure that all of our Veterans and their families feel welcome at VA, no matter their religious beliefs. Protecting religious liberty is a key part of how we accomplish that goal," said VA Secretary Robert Wilkie.
"These important changes will bring simplicity and clarity to our policies governing religious and spiritual symbols, helping ensure we are consistently complying with the First Amendment to the US Constitution at thousands of facilities across the department."
Bible Returned to 'Missing Man' Table in VA Hospital
In May, First Liberty Institute, a non-profit, religious liberty law firm, sent a letter to the VA urging a policy clarification after the Military Religious Freedom Foundation (MRFF) filed a lawsuit challenging a POW/MIA Remembrance display at the Manchester VA Medical Center that includes a Bible. First Liberty's client, the Northeast POW/MIA Network, is the organization responsible for creating and maintaining that POW/MIA remembrance display.
The Bible in question was returned to the display after the hospital received many complaints from patients and their families asking that the Bible be brought back. The Bible was returned with an apology by Curt Cashour, press secretary for the Department of Veterans Affairs.
The new policy now in effect at all VA facilities was a bit of good news to Mike Berry, director of military affairs at First Liberty.
"This new VA policy is a welcome breath of fresh air," he said. "The Supreme Court recently upheld the constitutionality of religious displays with historic roots such as those commonly found in VA facilities. We commend the VA for taking this necessary and positive action."
As CBN News reported, the US Supreme Court recently reaffirmed the important role religion plays in the lives of many Americans and its consistency with Constitutional principles.
This includes the following values: a display that follows in the longstanding tradition of monuments, symbols, and practices; respect and tolerance of differing views; and endeavors to achieve inclusivity and non-discrimination.
Building Homes for Injured Veterans While They Rebuild Their Lives
Why This Man Mowed Lawns for Veterans and Single Moms in All 50 States
'Nerves of Steel' Pilot Who Landed Stricken Plane, Inspires Couples During Wilderness Marriage Seminar
Amazon Pulls Reparative Therapy Books Offering Healing for Gays, Bans Former LGBT Authors»
«Facing Calls for Resignation, Labor Secretary Acosta Defends Handling of Epstein Case

redpajama_set_name: RedPajamaCommonCrawl


text:
[![NPM version][npm-image]][npm-url]
[![build status][travis-image]][travis-url]
[![Test coverage][coveralls-image]][coveralls-url]
[![Downloads][downloads-image]][downloads-url]
[![js-standard-style][standard-image]][standard-url]

## Installation
```bash
$ npm install core-manifests
```

## Usage
```js

```

## License
[MIT](https://tldrlegal.com/license/mit-license)

[npm-image]: https://img.shields.io/npm/v/core-manifests.svg?style=flat-square
[npm-url]: https://npmjs.org/package/core-manifests
[travis-image]: https://img.shields.io/travis/yoshuawuyts/core-manifests.svg?style=flat-square
[travis-url]: https://travis-ci.org/yoshuawuyts/core-manifests
[coveralls-image]: https://img.shields.io/coveralls/yoshuawuyts/core-manifests.svg?style=flat-square
[coveralls-url]: https://coveralls.io/r/yoshuawuyts/core-manifests?branch=master
[downloads-image]: http://img.shields.io/npm/dm/core-manifests.svg?style=flat-square
[downloads-url]: https://npmjs.org/package/core-manifests
[standard-image]: https://img.shields.io/badge/code%20style-standard-brightgreen.svg?style=flat-square
[standard-url]: https://github.com/feross/standard

redpajama_set_name: RedPajamaGithub


The Michigan High School Athletic Association recently released participation numbers for the 2014-15 school year.
The MHSAA reports that 40,088 student-athletes participated in high school football last year, which was a 1.4% decrease from the 2013-14 school year. According to a news release is the percentage decrease was less than those between the 2011-12 and 2013-14 school years.
The decrease from 2011-12 to 2012-13 was 3.7%. Football participation dropped 2% between 2012-13 and 2013-14.


Mel Gibson's ultra-violet film Hacksaw Ridge is both a terrifying depiction of warfare and a peaceful examination of one man's commitment to faith. Andrew Garfield gives a captivating performance, despite the film's somewhat flawed script.
Mel Gibson steps behind the camera once again to direct Hacksaw Ridge, an ultra-violent war film that's based on the true story of Desmond Doss — a medic soldier that helped change the war without ever picking up a rifle.
Gibson's film focuses on the character of Desmond Doss (Andrew Garfield) and his connection to God and his belief of wanting to join the war and serve his country, but by doing so without ever taking a single life. Doss refuses to take weapons training class and almost gets tossed into military prison because of his strong beliefs.
Hacksaw Ridge may look like another ultra-violet war film and while it is definitely violent and full of warfare — it's also an examination of one man's faith and morality. The film's first half is spent away from the battlefield and spread out across boot camp training and spending time in Doss' hometown.
It is there where he meets his eventual wife Dorothy (Teresa Palmer) and it is there where he discovers his want to become a medic in the War. Mel Gibson does his best directing from a script that's not without its flaws. Hacksaw Ridge might feel cliched and riddled with a lack of consistency and that's mostly fine, because Gibson's ability to elevate the story is the true saving grace, paired with Andrew Garfield's stubborn, but determined performance.
Garfield's stereotypical babyface actually helps him in the film, managing to make the character believable, yet likable, despite his viewpoint from an outsiders point of view. A good portion consists of outsiders' perspective on Doss and their ability to trust him and understand his point of view and both Gibson and Garfield do a splendid job keeping Doss level-headed and sympathetic, without making him downright pathetic or ignorant.
The film's later moments that take place on the battlefield will without a doubt elicit tears from those more prone to crying at the cinema and that's because the film's story really is a marvelous one and one that gives us a slightly different look at World War II.
Gibson doesn't cut any corners either, leaving endless amounts of blood and body parts on the dirty ridge as dozens, if not hundreds of men go to war in one of the most grueling films to depict such an event. Gibson's ability to capture the frantic hellfire of war in a way that's tragic for both sides is to be noted and commended. This isn't just another God Bless USA depiction of war and instead an eye-opening look at the military and its views on warfare and what is expected of a soldier.
The way Doss is treated early on in the film is somewhat expected, but then carried out in ways that I was not aware of.
Hacksaw Ridge might not be the best war film ever made, but it's definitely a strong one that gives us a starring performance worthy of watching the whole way through. The film's central focus is different enough to separate the film from other countless other WWII films, yet Gibson manages to bring enough action and warfare to surely please those looking for a film that presents the ugliest and sometimes most realistic parts of war.
And yet it doesn't feel like a complete bummer, because of Desmond Doss and his incredibly motivating true story that helped save the lives of so many men and prove that all soldiers are an important part of war and not just those looking to kill.


BRAND NEW - Renovated Lincoln Park Dream Studio - In Unit Laundry!
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This apartment is a two room studio with in unit laundry. It is a gut rehab apartment which features stainless steel appliances, granite counter tops, cherry cabinets in the kitchen. The bathroom features a glass tiled shower, a vanity with storage and quartz countertops. Also featured is a walk-in closet in most studios, brand new wood floors and new windows.


As it is Spirituality day at Coppull Parish Primary School today, some of the children made a bow and arrow, on their arrow they wrote something that they wanted to be forgiven for or someone they wanted to forgive; and fired it away.
Phoebe and Natasha worked together to make a den and then made bird feeders using the knives to slice apples up, they then threaded string through the middle of the apples and hung them from their den.
Marcus, Alfie, Alex, Bailey and Alfie worked together as a team to build a den together.


text:
Last edited by Faucage
8 edition of Texas Kingdoms found in the catalog.
by Robert W. Broomall
Published August 29, 1989 by Fawcett .
Romance of the Three Kingdoms (simplified Chinese: 三国演义; traditional Chinese: 三國演義; pinyin: Sānguó Yǎnyì) is a 14th-century historical novel attributed to Luo is set in the turbulent years towards the end of the Han dynasty and the Three Kingdoms period in Chinese history, starting in AD and ending with the reunification of the land in Author: Luo Guanzhong. Small Kingdoms book description (Description is for The Best American Mystery Stories ) "With so many great authors contributing to this fiction collection it doesn't take detecting skills to discover the gem. And every story dazzles These stories, in prose both elegant and compelling, get to the heart of why people do what they.
Golden Kingdoms creates new understandings of ancient American art through a thematic exploration of indigenous ideas of value and luxury. Central to the book is the idea of the exchange of materials and ideas across regions and across time: works of great value would often be transported over long distances, or passed down over generations, in. Parents need to know that Sky Raiders is the first book in the Five Kingdoms series from fantasy author Brandon Mull, who developed a big fan base from his Fablehaven and Beyonders series. If kids have already read some of Mull's books, they'll find the start of this series less violent and just a little less complex than 's one moment of gore that's more "eww" than .
Romance of the Three Kingdoms Books Free Online [ Home –> Links –> Three Kingdoms Literature –> Read Books Online ] You are viewing the Read Books Online category of our Three Kingdoms community link directory. We provide this directory to make researching the Three Kingdoms period, Chinese history, the Romance of the Three Kingdoms novel and even . George R.R. Martin wrote specifi cally for this book Perfectly timed for the holiday season, The World of Ice and Fire is a must-have for long-time fans, new readers, and viewers of the HBO series Game of Thrones. A Bantam Hardcover and eBook • On sale: 10/28/ • HC: | $/$C • E: | $/$CFile Size: 6MB.
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Texas Kingdoms by Robert W. Broomall Download PDF EPUB FB2
"Texas Kingdoms" is the year story of two men, a woman, and a town. Will Stewart and Chance Evans come to Texas inon their way to the California gold fields. Will is poor and determined to make something of himself; Chance is a gambler, determined to separate fools from their money/5(48).
Texas Kingdoms is the year story of two men, a woman, and a town. Will Stewart and Chance Evans come to Texas inon their way to the California gold fields. Will is poor and determined to make something of himself; Chance is a gambler, determined to separate fools from their money/5.
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Free shipping over $ Check out this great listen on A new collection of short stories from Charlaine Harris, the number-one New York Times best-selling author of the Sookie Stackhouse books, the basis for HBO's True Blood, and the Midnight Crossroad series, the inspiration for Midnight, Texas on NBC.
Five Kingdoms has 16 entries in the series. Borrow eBooks, audiobooks, and videos from thousands of public libraries worldwide. So yeah. Three Kingdoms is more or less the Chinese equivalent of the Illiad, or perhaps Shakespeare, in that it's one of the cornerstones of Chinese n in the 14 th century, Three Kingdoms details the chaos and battles and drama that arose at the end of the Han dynasty, some centuries before.
So even at the time it was written, Three Kingdoms was. The long drive. The rise of the cattle kingdom coincided with the spread of the railroads across the country.
InTexas ranchers drove their herds of longhorn cattle north to the railhead at Sedalia, Missouri, for shipment to the slaughter and packinghouses in the East. As the railroads moved west, the terminus of the long drive moved with. Pre-Order Now: Small Kingdoms and Other Stories Coming Soon: Small Kingdoms and Other Stories brings together beloved #1 New York Times bestseller Charlaine Harris's deliciously twisted tales about two people with specialized talents making a small town high school into a place like no other.
The Records of the Three Kingdoms, also known as Sanguo zhi, contains 65 volumes and aboutChinese characters broken into three books. The Book of Wei contains 30 volumes, the Book of Shu 15 volumes, while the Book of Wu contains 20 volumes.
Each volume is organised in the form of one or more : Chen Shou. A new collection of linked short stories from Charlaine Harris, the #1 New York Times bestselling author of the Sookie Stackhouse books, the basis for HBO's True Blood, and the Midnight Crossroad series, the inspiration for Midnight, Texas on NBC.
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The Cattle Boom started mainly with the Texas longhorn which was the time when Spanish settlers in the s brought their cattle to California and Texas. Later, the cattle were mixed with English breeds and created the Texas longhorn.
These types of cattle were very tough and had horns up to five feet across. Settlers preferred to raise them. Kingdoms Connected Music Group LLC is a Texas Domestic Limited-Liability Company (Llc) filed on Ap The company's filing status is listed as In Existence and its File Number is The Registered Agent on file for this company is Law Office Of Deborah E.
Johnson and is located at Knollbrook Lane, Fort Worth, TX Founded: Texas Destiny (Texas Trilogy Book 1) PDF Book Download Online; Fire Dancer's Captive PDF Book Download Online; Girls On The Line: A Novel PDF Book Download Online A Falling Kingdoms Novel and read Gathering Darkness: A Falling Kingdoms Novel online books in format PDF.
Get also books in EPUB and Mobi Format. Check out other translated. Kingdom's Edge is an action/adventure allegory of the life of Christ where swords, knights and battles are biblically symbolic.
It is told by Cedric, a young peasant who is doomed to a life of hopelessness and despair, until he meets the "stranger." The stranger takes Cedric under his tutelage and trains him in the art of the sword, for this man is a true "Master of the Sword.".Brandon Mull is the author of the New York Times, USA TODAY, and Wall Street Journal bestselling Beyonders and Fablehaven series, as well as the bestselling Five Kingdoms, Candy Shop Wars, and Dragonwatch series.
He resides in Utah, in a happy little valley near the mouth of a canyon. Brandon's greatest regret is that he has but one life to give for Gondor. Small Kingdoms and Other Stories - Ebook written by Charlaine Harris. Read this book using Google Play Books app on your PC, android, iOS devices.
Download for offline reading, highlight, bookmark or take notes while you read Small Kingdoms and Other Stories/5(4).
texasbestchambers.com - Texas Kingdoms book © 2020


text:
import numpy.testing as npt
from pymc3.tests import backend_fixtures as bf
from pymc3.backends import ndarray, text

class TestText0dSampling(bf.SamplingTestCase):
    backend = text.Text
    name = 'text-db'
    shape = ()

class TestText1dSampling(bf.SamplingTestCase):
    backend = text.Text
    name = 'text-db'
    shape = 2

class TestText2dSampling(bf.SamplingTestCase):
    backend = text.Text
    name = 'text-db'
    shape = (2, 3)

class TestText0dSelection(bf.SelectionTestCase):
    backend = text.Text
    name = 'text-db'
    shape = ()

class TestText1dSelection(bf.SelectionTestCase):
    backend = text.Text
    name = 'text-db'
    shape = 2

class TestText2dSelection(bf.SelectionTestCase):
    backend = text.Text
    name = 'text-db'
    shape = (2, 3)

class TestTextDumpLoad(bf.DumpLoadTestCase):
    backend = text.Text
    load_func = staticmethod(text.load)
    name = 'text-db'
    shape = (2, 3)

class TestTextDumpFunction(bf.BackendEqualityTestCase):
    backend0 = backend1 = ndarray.NDArray
    name0 = None
    name1 = 'text-db'
    shape = (2, 3)

    @classmethod
    def setUpClass(cls):
        super(TestTextDumpFunction, cls).setUpClass()
        text.dump(cls.name1, cls.mtrace1)
        with cls.model:
            cls.mtrace1 = text.load(cls.name1)

class TestTraceToDf(bf.ModelBackendSampledTestCase):
    backend = ndarray.NDArray
    name = 'text-db'
    shape = (2, 3)

    def test_strace_to_df(self):
        mtrace = self.mtrace
        df = text._strace_to_df(mtrace._straces[0])
        self.assertEqual(len(mtrace), df.shape[0])

        checked = False
        for varname in self.test_point.keys():
            vararr = mtrace.get_values(varname, chains=0)
            ## With `shape` above, only one variable has to have that
            ## `shape`.
            if vararr.shape[1:] != self.shape:
                continue
            npt.assert_equal(vararr[:, 0, 0], df[varname + '__0_0'].values)
            npt.assert_equal(vararr[:, 1, 0], df[varname + '__1_0'].values)
            npt.assert_equal(vararr[:, 1, 2], df[varname + '__1_2'].values)
            checked = True
        self.assertTrue(checked)

class TestNDArrayTextEquality(bf.BackendEqualityTestCase):
    backend0 = ndarray.NDArray
    name0 = None
    backend1 = text.Text
    name1 = 'text-db'
    shape = (2, 3)

def test_create_flat_names_0d():
    shape = ()
    result = text._create_flat_names('x', shape)
    expected = ['x']
    assert result == expected
    assert text._create_shape(result) == shape

def test_create_flat_names_1d():
    shape = 2,
    result = text._create_flat_names('x', shape)
    expected = ['x__0', 'x__1']
    assert result == expected
    assert text._create_shape(result) == shape

def test_create_flat_names_2d():
    shape = 2, 3
    result = text._create_flat_names('x', shape)
    expected = ['x__0_0', 'x__0_1', 'x__0_2',
                'x__1_0', 'x__1_1', 'x__1_2']
    assert result == expected
    assert text._create_shape(result) == shape

def test_create_flat_names_3d():
    shape = 2, 3, 4
    assert text._create_shape(text._create_flat_names('x', shape)) == shape


text:
Making Sense of Race
by Edward DuttonEdward Dutton
Cutting through the contradictions, euphemisms, and misconceptions, Edward Dutton carefully and systematically refutes the arguments against the concept of "race," demonstrating that it is as much a proper biological category as "species."Making Sense of Race takes us on a journey through the fascinating world of evolved physical and mental racial differences, presenting us with the most up-to-date discoveries on the consistent ways in which races differ in significant traits as a result of being adapted to different ecologies. Intelligence, personality, genius, religiousness, sex appeal, puberty, menopause, ethnocentrism, ear-wax, and even the nature of dreams . . . Making Sense of Race will tell you everything you ever wanted to know about race, but might have been afraid to ask.
Edward Dutton is a prolific researcher and commentator, who has published widely in the field of evolutionary psychology. He is Editor at Washington Summit Publishers and Professor of Evolutionary Psychology at Asbiro University in Łódź, Poland. Dutton is the author of many books, including J. Philippe Rushton: A Life History Perspective (2018), Race Differences in Ethnocentrism (2019), and Islam: An Evolutionary Perspective (2020).
Praise for Edward Dutton and Making Sense of Race
"Edward Dutton's new book, Making Sense of Race, is a godsend at a time when the university curriculum effectively censors human nature from much of the humanities and social sciences. This information, which comes wrapped in prodigious layers of data, is presented in a highly accessible, often funny, style. It should be required reading for all students of anthropology, sociology, gender studies, and politics. Those thirsting for knowledge about race-an inescapable and ever more destabilizing feature of our globalizing world -should dip into this Jolly Heretic of a book. Whether laughing out loud or marveling at new facts about human biodiversity, Making Sense of Race is a riveting read."
-Dr. Frank Salter
Author of On Genetic Interests: Family, Ethnicity, and Humanity in an Age of Mass Migration
"Edward Dutton is one of the liveliest and most engaging of this new generation of academic dissidents. . . . [He is] what Bill Nye the Science Guy would be, if that gentleman dared to present the human sciences with uninhibited objectivity."
-John Derbyshire
Washington Summit Publishers


text:
Radix Addressing The "Blockchain Trilemma" With Asset-Oriented DeFi & Web3 Infrastructure
Chances are you have frequently heard how mainstream decentralized finance (DeFi) needs more scalability, composability, and security. But achieving all three of these features isn't exactly possible with the existing blockchain tech stack.
That's because most legacy blockchains were designed to operate in standalone environments and cater to specific use cases. Providing limitless scalability alongside frictionless composability without compromising security is a complicated task for developers, primarily because existing infrastructure isn't well-equipped for this approach.
However, thanks to Radix's technology breakthrough, we now have a full-stack solution that guarantees all three key aspects: scalability, composability, and security. The Radix team has successfully overcome the shortcomings of existing DeFi infrastructure by reinventing smart contracts with a native-level asset-oriented model, allowing developers to efficiently (and quickly) build a wide range of dApps and protocols.
The Radix project consists of industry leaders and innovators with decades of experience across some of the most prominent brands like Microsoft, Y Combinator, Visa, Nvidia, and ConsenSys, to name a few.
It is also important to note that Radix isn't another project that was developed overnight. Led by founder Dan Hughes and CEO Piers Ridyard, Radix's core development team has been working on a full-stack solution for DeFi for the last nine years. The multi-feature Radix ecosystem results from years of assessment, experimentation, and optimization - all aimed at overcoming the limitations of present-day DeFi protocols and applications.
A Full-Stack Ecosystem for DeFi to Thrive
There is no denying that the tools that exist in today's DeFi space are largely inadequate. Because developers need to build everything from scratch, it takes years for developers to become competent enough in a specific smart contract language to develop dApps and protocols that can contribute towards a secure, composable, scalable, and user-friendly DeFi ecosystem.
But before we dig deeper into Radix's solution, let's take a quick look at what "composability" is and why it matters so much for DeFi.
In DeFi, composability refers to the ability of different financial tools and services to work together in a seamless and interconnected way. This means that users can combine various DeFi products and services, such as lending and borrowing platforms, stablecoins, and exchanges, to create customized financial solutions that meet their specific needs.
Radix takes this concept a step further with "atomic composability." Within the blockchain ecosystem, atomicity refers to the concept that a single transaction can contain several sub-transactions like token calls, transfers, and requests from other dApps, DEXs, and DeFi protocols. For "atomicity" to work, all sub-transactions that are part of the main transaction must be accurate, or else the entire transaction fails.
The problem is that existing layer-1 and layer-2 solutions focus more on solving the scalability problem for blockchains while compromising atomic composability and security. Besides, the standalone design of most blockchains hinders developers from implementing atomic composability at scale.
Realizing these shortcomings, the Radix team developed a full-stack solution that not only provides developers with everything they need to build extraordinarily complex DeFi apps and protocols but also allows them to do it quickly, easily, and cost-efficiently.
That said, Radix's full-stack solution consists of a novel consensus mechanism (Cerberus), the infrastructure (Radix Engine) that combines execution and assets with consensus, and a new smart contract programming language (Scrypto) designed specifically to simplify DeFi and Web3 development.
Radix CEO Piers Ridyard recently shared insights on the working principle of the Radix ecosystem. He explained, "Cerberus is the world's first consensus algorithm that does not break atomic composability as it scales. Radix Engine makes Web 3.0 code easy to build and deploy. And to make things even easier, we've created a programming language specifically for the needs of Web 3.0 and DeFi, and it's called Scrypto, the next part of the Radix stack that makes Web 3.0 easy to build and deploy."
"The developer experience with Scrypto powered by the Radix Engine and Cerberus is so delightful and intuitive that users, developers, and entrepreneurs can be confident that the powerful DApps that they want to use, build, and run are secure," notes Ridyard. "All of this is only made possible with the full Radix technology stack - a technology stack where the programming language, execution environment, and consensus have all been designed to work perfectly together for Web3 and DeFi."
Put simply, Radix provides developers with the required tools and infrastructure to build a wide range of dApps and protocols by mixing existing code and logic. The Radix Engine gives developers access to easy-to-integrate models for dApps and protocols, backed by its asset-oriented approach and highly-scalable consensus architecture.
Radix takes a different approach to existing solutions, making assets the global feature of the platform itself, eliminating the need to implement multiple tokens at the smart contract level. It effectively addresses the four core areas that the DeFi and Web3 ecosystems need to go mainstream: composability, security, reusability, and ease of use.
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text:
HomeMan UnitedManchester United vs Manchester City: Red Devils' One-On-One Analysis
Manchester United vs Manchester City: Red Devils' One-On-One Analysis
December 10, 2017 Juan Pablo Aravena Man United, Manchester City, Match Reports 0
Manchester United had a golden chance to shrink Manchester City's advantage at the top of the English Premier League standings, but they missed it. Even though City didn't have their best performance, they still defeated The Red Devils 2-1 at Old Trafford. As a result, Pep Guardiola's men now have an 11-point lead at the top of the standings.
How did the Manchester United players fare in this game? Read on to find out!
David De Gea – 6
It's hard to put this defeat on De Gea's shoulders. The Spanish goalkeeper could not do much in any of the two goals he conceded, as both came due to defensive mistakes and City's ability to execute set-piece situations. De Gea finished the game with five saves throughout the game.
Antonio Valencia – 5
Valencia was not able to shine as he has done it in past encounters against top opposition. Knowing he could not leave too many spaces on the defensive end due to the threat of City's wingers, Valencia was not a reliable attacking option on the right flank. He had a few crosses here and there, but for the most part he spent the game containing te opposing playmakers.
Chris Smalling – 7
The former Fulham star got the start due to the injuries of Eric Bailly and Phil Jones, and he responded beautifully to the challenge. Even though United lost the game, Smalling was a huge presence at the back. For instance, Smalling limited the impact of Gabriel Jesus while the Brazilian was out there. He also looked pretty active overall, and his numbers backed that up since he finished with seven clearances, four tackles, three interceptions, and one blocked shot.
Marcos Rojo – 4
If Smalling was the team's best defender, then we could easily qualify Rojo as the weaker link on United's defensive line during this game. The Argentina international looked inaccurate on his touches, his positioning was subpar, and lost several duels. To make things more complicated, he left the game with an injury during half time and was replaced by Victor Lindelöf.
Ashley Young – 6
Ashley Young could deserve some of the blame for Manchester City's first goal, but he still managed to fill the stat sheet and produce on both ends of the pitch. He finished with four clearances, four tackles and four interceptions. Young proved he should remain as a decent left-back choice for United, at least in the short-term picture.
Ander Herrera – 5
Ander Herrera took Paul Pogba's role in this game, but the Spaniard simply couldn't thrive and struggled on both ends of the pitch. He looked overmatched physically by players such as Fernnadinho and Fabian Delph, while struggling to represent a creative threat. He just wasn't good, and there is no doubt United fans missed Pogba here. Ander registered a high number of interceptions (five) and tackles (four), but fans certainly expected more from the former Athletic Bilbao star.
Nemanja Matic – 6
Another game, another solid display for Matic. The Serbian international does not shine going forward and excels defensively, so he once again focused on that side of the ball against City. Matic managed to limit the impact of Kevin de Bruyne at times, but we have seen better performances from him in the past. He needs to get back to his early-season form.
Anthony Martial – 6
Martial didn't have the influence Marcus Rashford had in the game (more on him later) but he still produced a strong display on the right wing. The French only registered one shot on target and one key pass, but still managed to complicate the opposing defence from time to time.
Jesse Lingard – 5
Lingard has been one of the best players for Manchester United during the past few weeks. However, he couldn't repeat his past performances in this game. He looked overmatched, and failed to represent much of a threat in the final meters. To make things even worst for him, he could have done something to prevent City's first goal.
Marcus Rashford – 7
Rashford might be a youngster who is not even old enough to drink in several places in the world, but that hasn't stopped him to dazzle every time he steps on a football pitch. Sunday's game against Manchester City wasn't the exception, as the England international took advantage of a big defensive mistake to score coolly past Ederson. Rahsford played mostly on the left wing, and was one of the team's biggest attacking threats. Unfortunately, his efforts weren't enough.
Romelu Lukaku – 4
If you want to know how bad Lukaku was in this game, then the stats do not tell the whole story. The Belgian came close to equalise late in the second half, but uncharacteristically he played a big part on the two goals United conceded. He lost an easy aerial duel in the first half, and his deflection from a free kick early in the second half resulted in City's winning goal. He needs to play better soon, because his recent performances have not been up to his standards.
Victor Lindelöf replaced the injured Marcos Rojo during half time, and he failed to thrive. The same goes for Zlatan Ibrahimovic and Juan Mata, as both players entered the pitch too late to turn things around.
5 points to summarise Manchester United's season
May 24, 2015 Stretford-end 0
Jose Mourinho Wants "Life-Long Deal" For David De Gea
Will a World Cup star be heading to Manchester United this summer?


text:
Addressing the Most Important Weakness of Conservative-Libertarian Public Interest Law
By Ilya Somin on December 10, 2009 7:58 pm in Conservatism, Federalist Society, Libertarianism, Public Interest Law
I recently renewed my membership in the Federalist Society, and got a mailing asking to sign up with the Fed Soc Pro Bono Center. I was only vaguely aware of this organization's existence, even though it is a potentially important effort to address the most important shortcoming of conservative and libertarian public interest law. Perhaps it will be more successful in that effort, if more people learn about it.
Over the last 30 years, conservative and libertarian public interest firms such as the Institute for Justice, the Center for Individual Rights, and the Pacific Legal Foundation have mounted a strong challenge to the previously dominant legal left, and won some important legal victories for property rights, economic liberties, and limits on government power. However, right of center public interest law suffers from a key weakness: the paucity of lawyers available to conduct follow-up litigation to enforce favorable precedents. Even the most important federal and state supreme court decisions don't change the legal landscape all by themselves; they usually require extensive follow-up litigation to make sure that government officials comply and that their principles are enforced in other cases where similar issues come up. Often, the people victimized by government violations of constitutional rights are poor, politically weak, or unable to engage in protracted litigation to vindicate their rights. This is true in the area of property rights, and many others of interest to libertarians and conservatives. Left-liberal scholars and activists have long understood this crucial lesson, and they have created an extensive network to facilitate follow-up litigation to enforce their high court legal victories. In almost every major law firm, there are lawyers who do small-bore pro bono cases on behalf of various left-wing causes. These cases often build on and enforce favorable appellate decisions.
By contrast, conservatives and libertarians have been slow to grasp this point and act on it. That isn't just my opinion. It's also the view of Steven Teles, author of the leading academic work on right of center public interest law, and also of prominent leaders of conservative and libertarian public interest organizations, such as Chip Mellor, President of the Institute for Justice and the leaders of CIR (interviewed in Teles' book).
The Fed Soc Pro Bono Center is a thoughtful effort to address the problem. The premise is simple: interested lawyers sign up at the Center's website, and give their contact information, areas of expertise (e.g. – property rights, First Amendment, religious liberties, criminal law), what kind of work they can do (trial, appellate, etc.), and how much time they have per month. The Center then matches them up with public interest firms and other organizations that are looking for lawyers to work on specific cases (these organizations can also sign up at the website, and provide information about their needs). I doubt that the Pro Bono Center can cure the greatest weakness of conservative/libertarian public interest law all by itself. But it's a step in the right direction. IJ's Human Action Network is an older, somewhat similar initiative (but one that doesn't have an explicit case-matching system).
Most lawyers, especially those working at large firms, have at least some time to do pro bono work. Indeed, senior partners often encourage junior associates to so such work because it is a great way for younger lawyers to get useful experience. At many firms, partners are happy to have associates take on such work even if they don't necessarily agree with its ideological orientation; after all, it's still valuable experience that can benefit the firm when the associate uses what he or she has learned in later work for paying clients. Obviously, there are also career benefits to the lawyer himself. Getting useful litigation experience can help your career, and it's often easier for a young lawyer to get major responsibility on a pro bono matter than in a case on behalf of a paying client.
Conservative and libertarian law students often ask me what they can do to promote the cause of free markets and limited government if they are unable or unwilling to go into public interest law or academia. Here's my answer to that perennial question: They also serve who litigate unglamorous but essential follow-up cases. Few important legal precedents ever amount to much without them.
CONFLICT OF INTEREST WATCH: I have done various pro bono work for the Institute for Justice myself, and serve on one of the Federalist Society's practice group executive committees (an unpaid position).
"Stossel" premieres tonight on Fox Business Channel
Bats Stall Wind Farm


The Durham Arts Council is a 501(c)(3) nonprofit and local arts agency dedicated to supporting the arts in Durham and surrounding areas, since 1954. Each year DAC serves more than 400,000 visitors and program participants, 2,000 artists, and 300 arts and cultural organizations through classes, artist residencies, exhibits, festivals, grants programs, technical support, creative economy initiatives, arts advocacy and information services. Durham Arts Council, Inc. is a catalyst in the cultural development of Durham – it leads, inspires, and promotes excellence in and access to the creation, experience and active support of the arts for all the people of our community.