Development of in vivo flux analysis of hepatic glucose production in Type 2 Diabetes

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2008.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Vita.Includes bibliographical references (p. 289-300).Metabolic diseases are an increasing health concern in the developed world. Type 2 Diabetes, (T2D) affects over 100 million people worldwide and significantly contributes to chronic diseases such as atherosclerosis and kidney failure. This condition is characterized by deregulation of glucose homeostasis through the development of insulin resistance, manifested as increased glucose production in the liver. Hepatic gluconeogenesis provides de novo formation of glucose from three carbon precursors such as glycerol, lactate, pyruvate and alanine. The upregulation of this pathway underlies the persistent hyperglycemia observed in diabetic patients. We have developed stable isotope tracer methods to reconstruct hepatic glucose production fluxes by infusion of [13C, 2H]-glycerol and mass spectrometry analysis of plasma metabolites. Using this methodology we observe physiologic changes in liver cell lines and primary hepatocyte cultures in the presence of hormones insulin/glucagon and in response to gluconeogenic precursor availability. We put forth the hypothesis that in the presence of glycerol as a gluconeogenic substrate, glucose-6-phosphatase has an important role in modulating metabolic flux through upper gluconeogenesis. Infusion of simultaneous tracer combinations in vivo including a novel [U-13C,2H5]-glycerol allow detailed net flux and reversibility reconstruction of upper gluconeogenesis to an unprecedented degree in a single experiment. We deployed the developed methods to probe glucose overproduction in the liver insulin receptor knockout (LIRKO) transgenic model of Type 2 Diabetes, and found unexpected similarities in the metabolic flux profile not observed by genomic, protein or metabolite measurements.(cont.) Our results underscore the importance of flux measurement as a physiologic parameter akin to gene and protein expression in revealing the metabolic phenotype of cells, tissues and organisms. These methods have the potential to contribute as clinical assays to characterize excess glucose production as well as in drug development for new targets to control hepatic glucose production.by José O. Alemán.Ph.D

Histologic features of bone regenerated by means of negative pressure in the context of odontogenic keratocyst

Propósito: El objetivo de la presente investigación es describir las características histológicas del hueso regenerado mediante presión negativa (sugosteogénesis) en un grupo de pacientes con diagnóstico de queratoquiste odontogénico (QO) sometidos a descompresión activa y sugosteogénesis por distracción (ADDS) en nuestra institución. Materiales y métodos: Los autores diseñaron un estudio retrospectivo de serie de casos. La población incluyó pacientes con diagnóstico histológico de queratoquiste odontogénico en los que se realizó descompresión activa y sugosteogénesis por distracción seguida de enucleación. Todos los pacientes fueron atendidos y seguidos desde julio de 2019 hasta enero de 2021. La investigación fue aprobada por la Junta de Revisión Institucional, y observó la Declaración de Helsinki sobre protocolo médico. Las variables de este estudio incluyeron la edad, el sexo, la localización anatómica (mandíbula o maxilar) y las características histológicas del hueso regenerado mediante presión negativa. Las características histológicas se definieron como consistentes o inconsistentes con hueso maduro viable. Resultados: Se consideraron las biopsias óseas de 6 pacientes. En total, el 83,33% de los pacientes eran varones y el 16,66% mujeres. El cien por cien de las muestras óseas sometidas a presión negativa mostraban características de hueso maduro viable. Conclusiones: En este estudio, las características histológicas del hueso sometido a presión negativa demostraron las características normales del hueso maduro normal. 2022, El/los autor/es, bajo licencia exclusiva de Springer-Verlag GmbH Alemania, parte de Springer Nature.Purpose: The objective of the present research is to describe the histologic features of the bone regenerated by means of negative pressure (sugosteogenesis) in a group of patients diagnosed with odontogenic keratocyst (OKC) who underwent active decompression and distraction sugosteogenesis (ADDS) at our institution. Materials and methods: The authors designed a retrospective case series study. The population included patients with a histologic diagnosis of odontogenic keratocyst in whom active decompression and distraction sugosteogenesis followed by enucleation was performed. All patients were seen and followed from July 2019 to January 2021. The investigation was approved by the Institutional Review Board, and it observed the Declaration of Helsinki on medical protocol. Variables of this study included age, gender, anatomic location (mandible or maxilla), and histologic characteristics of the bone regenerated by means of negative pressure. Histologic features were defined as being consistent or inconsistent with viable mature bone. Results: Bone biopsies of 6 patients were considered. In total, 83.33% of patients were males and 16.66% females. One hundred percent of the bone samples subjected to negative pressure showed features of viable mature bone. Conclusions: In this study, the histological features of the bone subjected to negative pressure demonstrated the normal characteristics of the mature, normal bone. © 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature

A Graphene Acid - TiO2 Nanohybrid as Multifunctional Heterogeneous Photocatalyst for the Synthesis of 1,3,4-Oxadiazoles

The immobilization of TiO2 nanoparticles on graphene acid (GA), a conductive graphene derivative densely functionalized with COOH groups, is presented. The interaction between the carboxyl groups of the surface and the titanium precursor leads to a controlled TiO2 heterogenization on the nanosheet according to microscopic and spectroscopic characterizations. Electronic communication shared among graphene and semiconductor nanoparticles shifts the hybrid material optical features toward less energetic radiation but maintaining the conductivity. Therefore, GA-TiO2 is employed as heterogeneous photocatalyst for the synthesis of 2,5-disubstituted 1,3,4-oxadiazoles using ketoacids and hydrazides as substrates. The material presented enhanced photoactivity compared to bare TiO2, being able to yield a large structural variety of oxadiazoles in reaction times as fast as 1 h with full recyclability and stability. The carbocatalytic character of GA is the responsible for the substrates condensation and the GA-TiO2 light interaction ability is able to photocatalyze the cyclization to the final 1,3,4-oxadiazoles, demonstrating the optimal performance of this multifunctional photocatalytic materialFinancial support was provided by the Spanish Government (RTI2018-095038-B-I00), FotoaArt “Comunidad de Madrid”, and European Structural Funds (S2018/NMT-4367) proyectos sinérgicos I+D (Y2020/NMT-6469) and Comunidad Autónoma de Madrid (SI1/PJI/2019-00237). M.B. and M.B. thank the Spanish MICINN for the Juan de la Cierva Incorporación contracts (IJC2019-042157-I and IJC2019- 042430-I). We also acknowledge the electron microscopy analysis from CNME. This work was supported by the national project NovaCO2 (PID2020-118593RB-C22) funded by MCIN/AEI/10.13039/50110001103

Circulating MIR148A associates with sensitivity to adiponectin levels in human metabolic surgery for weight loss

Objective: We sought to discover secreted biomarkers to monitor the recovery of physiological adiponectin levels with metabolic surgery, focusing on epigenetic changes that might predict adiponectin function. Design: We conducted a prospective observational study of patients undergoing metabolic surgery by Roux-en-Y Gastric Bypass (RYGB) for weight loss in a single center (IRB GHS # 1207-27). Methods: All patients (n = 33; 27 females; 6 males) signed informed consent. Metabolites, adiponectin and MIR148A were measured in fasting plasma. We followed MIQE for transcript profiles. Results: Patients lost on average 47 ± 12% excess BMI (%EBMI) after 12 weeks. Adiponectin pre, post or delta (post minus pre) did not correlate with %EBMIL. A decrease in adiponectin following weight loss surgery was observed in a subset of patients, chi-square test of independence rejects the null hypotheses that the liver DNA methyltransferase 1 (DNMT1) and delta adiponectin are independent (chi-square statistics χ2 = 6.9205, P = 0.00852, n = 33), as well as MIR148A and delta adiponectin are independent (chi-square statistics χ2 = 9.6823, P = 0.00186, n = 33). The presence of plasma MIR148A allows identification of patients that appear to be adiponectin insensitive at baseline. Conclusion: We combined the presence of plasma MIR148A, the concentration of total adiponectin and the expression of DNA methyltransferase 1 (DNMT1) in liver biopsy tissue to identify patients with non-physiological adiponectin. Weight loss and physical activity interventions complemented with the new method presented here could serve to monitor the physiological levels of adiponectin, thought to be important for long-term weight loss maintenance

Fecal microbiota and bile acid interactions with systemic and adipose tissue metabolism in diet-induced weight loss of obese postmenopausal women

Microbiota and bile acids in the gastrointestinal tract profoundly alter systemic metabolic processes. In obese subjects, gradual weight loss ameliorates adipose tissue inflammation and related systemic changes. We assessed how rapid weight loss due to a very low calorie diet (VLCD) affects the fecal microbiome and fecal bile acid composition, and their interactions with the plasma metabolome and subcutaneous adipose tissue inflammation in obesity. We performed a prospective cohort study of VLCD-induced weight loss of 10% in ten grades 2-3 obese postmenopausal women in a metabolic unit. Baseline and post weight loss evaluation included fasting plasma analyzed by mass spectrometry, adipose tissue transcription by RNA sequencing, stool 16S rRNA sequencing for fecal microbiota, fecal bile acids by mass spectrometry, and urinary metabolic phenotyping by H-NMR spectroscopy. Outcome measures included mixed model correlations between changes in fecal microbiota and bile acid composition with changes in plasma metabolite and adipose tissue gene expression pathways. Alterations in the urinary metabolic phenotype following VLCD-induced weight loss were consistent with starvation ketosis, protein sparing, and disruptions to the functional status of the gut microbiota. We show that the core microbiome was preserved during VLCD-induced weight loss, but with changes in several groups of bacterial taxa with functional implications. UniFrac analysis showed overall parallel shifts in community structure, corresponding to reduced abundance of the genus Roseburia and increased Christensenellaceae;g__ (unknown genus). Imputed microbial functions showed changes in fat and carbohydrate metabolism. A significant fall in fecal total bile acid concentration and reduced deconjugation and 7-α-dihydroxylation were accompanied by significant changes in several bacterial taxa. Individual bile acids in feces correlated with amino acid, purine, and lipid metabolic pathways in plasma. Furthermore, several fecal bile acids and bacterial species correlated with altered gene expression pathways in adipose tissue. VLCD dietary intervention in obese women changed the composition of several fecal microbial populations while preserving the core fecal microbiome. Changes in individual microbial taxa and their functions correlated with variations in the plasma metabolome, fecal bile acid composition, and adipose tissue transcriptome

The ERA-EDTA Registry Annual Report 2018 : A summary

Funding Information: The ERA-EDTA Registry is funded by the ERA-EDTA. This article was written by A.K. et al. on behalf of the ERA-EDTA Registry, which is an official body of the ERA-EDTA. In addition, V.S.S. reports grants from ERA-EDTA, during the conduct of the study; S.B. reports personal fees from Astra Zeneca, outside the submitted work; P.F. reports personal fees from Baxter, outside the submitted work; and K.J.J. reports grants from ERA-EDTA, during the conduct of the study. Publisher Copyright: © The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.Background. The European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry collects data on kidney replacement therapy (KRT) via national and regional renal registries in Europe and countries bordering the Mediterranean Sea. This article summarizes the 2018 ERA-EDTA Registry Annual Report, and describes the epidemiology of KRT for kidney failure in 34 countries. Methods. Individual patient data on patients undergoing KRT in 2018 were provided by 34 national or regional renal registries and aggregated data by 17 registries. The incidence and prevalence of KRT, the kidney transplantation activity and the survival probabilities of these patients were calculated. Results. In 2018, the ERA-EDTA Registry covered a general population of 636 million people. Overall, the incidence of KRT for kidney failure was 129 per million population (p.m.p.), 62% of patients were men, 51% were 65 years of age and 20% had diabetes mellitus as cause of kidney failure. Treatment modality at the onset of KRT was haemodialysis (HD) for 84%, peritoneal dialysis (PD) for 11% and pre-emptive kidney transplantation for 5% of patients. On 31 December 2018, the prevalence of KRT was 897 p.m.p., with 57% of patients on HD, 5% on PD and 38% living with a kidney transplant. The transplant rate in 2018 was 35 p.m.p.: 68% received a kidney from a deceased donor, 30% from a living donor and for 2% the donor source was unknown. For patients commencing dialysis during 2009-13, the unadjusted 5-year survival probability was 42.6%. For patients receiving a kidney transplant within this period, the unadjusted 5-year survival probability was 86.6% for recipients of deceased donor grafts and 93.9% for recipients of living donor grafts.Peer reviewe

Fe solubility, growth mechanism, and luminescence of Fe doped ZnO nanowires and nanorods grown by evaporation-deposition

Fe dopedZnO nanowires,nanorods, and urchin-like nanostructures have been grown using an evaporation-deposition method with compacted mixtures of ZnS and Fe_2O_3 powders, with different Fe contents as precursors. Treatments at 950 °C under argon flow lead to the growth of irondopednanowires,nanorods, and other nanostructures on the surface of the compacted sample. The incorporation of iron into the nanostructures has been investigated via energy dispersive spectroscopy as well as by cathodoluminescence in a scanning electron microscope and photoluminescence in an optical microscope. The iron content in the structures is limited to the range of 0.5–0.7 at.% and does not depend on the content in the precursor. Bright and dark field imaging and twist contour analysis via transmission electron microscopy support the possibility of a dislocation driven growth of the nanowires

Phylogenetic analysis of some members of the subgenus Persea (Persea, Lauraceae)

"The avocado belongs to the genus Persea, which is one of the most controversial genera of the Lauraceae family, since the relationships within the subgenus Persea are not clear and only recognized two species, Persea americana and Persea schiedeana. It

Crédito para el desarrollo rural en Nicaragua : un enfoque institucional sobre la experiencia del fondo de desarrollo local

El conocimiento provee información a nuestros modelos subjetivos para aprehender la realidad, o sea, para estructurarle y darle sentido y dirección. Define las percepciones de lrealidad y valora o desvalora los proyectos estratégicos y las acciones de los actores sociales. Conocimiento es poder. Lógicamente, el proceso social de producción del conocimiento constituye un campo de batalla discursiva, una arena social permanente donde se mezclan innovacionecreativas y conflictos de intereses. Para países como Nicaragua, el discurso que se produce sobre el desarrollo, y que circula en el mundo de las universidades y las agencias de desarrollo --desde las multilaterales hasta las no gubernamentales-- constituye, evidentemente, un campo de batalla discursiva de primera importancia. De hecho, con base en su retórica y sus modelos subjetivos dominantes se dibuja un panorama de la "realidad", sobre el cual se define el universo de las acciones y políticas deseables y viables