The developmental regulator Pax6 is essential for maintenance of islet cell function in the adult mouse pancreas

The transcription factor Pax6 is a developmental regulator with a crucial role in development of the eye, brain, and olfactory system. Pax6 is also required for correct development of the endocrine pancreas and specification of hormone producing endocrine cell types. Glucagon-producing cells are almost completely lost in Pax6-null embryos, and insulin-expressing beta and somatostatin-expressing delta cells are reduced. While the developmental role of Pax6 is well-established, investigation of a further role for Pax6 in the maintenance of adult pancreatic function is normally precluded due to neonatal lethality of Pax6-null mice. Here a tamoxifen-inducible ubiquitous Cre transgene was used to inactivate Pax6 at 6 months of age in a conditional mouse model to assess the effect of losing Pax6 function in adulthood. The effect on glucose homeostasis and the expression of key islet cell markers was measured. Homozygous Pax6 deletion mice, but not controls, presented with all the symptoms of classical diabetes leading to severe weight loss requiring termination of the experiment five weeks after first tamoxifen administration. Immunohistochemical analysis of the pancreata revealed almost complete loss of Pax6 and much reduced expression of insulin, glucagon, and somatostatin. Several other markers of islet cell function were also affected. Notably, strong upregulation in the number of ghrelin-expressing endocrine cells was observed. These findings demonstrate that Pax6 is essential for adult maintenance of glucose homeostasis and function of the endocrine pancreas

Lampreys, the jawless vertebrates, contain three Pax6 genes with distinct expression in eye, brain and pancreas

10.1038/s41598-019-56085-8Scientific Reports911955

Potential for pancreatic maturation of differentiating human embryonic stem cells is sensitive to the specific pathway of definitive endoderm commitment

This study provides a detailed experimental and mathematical analysis of the impact of the initial pathway of definitive endoderm (DE) induction on later stages of pancreatic maturation. Human embryonic stem cells (hESCs) were induced to insulin-producing cells following a directed-differentiation approach. DE was induced following four alternative pathway modulations. DE derivatives obtained from these alternate pathways were subjected to pancreatic progenitor (PP) induction and maturation and analyzed at each stage. Results indicate that late stage maturation is influenced by the initial pathway of DE commitment. Detailed quantitative analysis revealed WNT3A and FGF2 induced DE cells showed highest expression of insulin, are closely aligned in gene expression patterning and have a closer resemblance to pancreatic organogenesis. Conversely, BMP4 at DE induction gave most divergent differentiation dynamics with lowest insulin upregulation, but highest glucagon upregulation. Additionally, we have concluded that early analysis of PP markers is indicative of its potential for pancreatic maturation. © 2014 Jaramillo et al

Functional Redundancy of Two Pax-Like Proteins in Transcriptional Activation of Cyst Wall Protein Genes in Giardia lamblia

The protozoan Giardia lamblia differentiates from a pathogenic trophozoite into an infectious cyst to survive outside of the host. During encystation, genes encoding cyst wall proteins (CWPs) are coordinately induced. Pax family transcription factors are involved in a variety of developmental processes in animals. Nine Pax proteins have been found to play an important role in tissue and organ development in humans. To understand the progression from primitive to more complex eukaryotic cells, we tried to identify putative pax genes in the G. lamblia genome and found two genes, pax1 and pax2, with limited similarity. We found that Pax1 may transactivate the encystation-induced cwp genes and interact with AT-rich initiatior elements that are essential for promoter activity and transcription start site selection. In this study, we further characterized Pax2 and found that, like Pax1, Pax2 was present in Giardia nuclei and it may specifically bind to the AT-rich initiator elements of the encystation-induced cwp1-3 and myb2 genes. Interestingly, overexpression of Pax2 increased the cwp1-3 and myb2 gene expression and cyst formation. Deletion of the C-terminal paired domain or mutation of the basic amino acids of the paired domain resulted in a decrease of nuclear localization, DNA-binding activity, and transactivation activity of Pax2. These results are similar to those found in the previous Pax1 study. In addition, the profiles of gene expression in the Pax2 and Pax1 overexpressing cells significantly overlap in the same direction and ERK1 associated complexes may phosphorylate Pax2 and Pax1, suggesting that Pax2 and Pax1 may be downstream components of a MAPK/ERK1 signaling pathway. Our results reveal functional redundancy between Pax2 and Pax1 in up-regulation of the key encystation-induced genes. These results illustrate functional redundancy of a gene family can occur in order to increase maintenance of important gene function in the protozoan organism G. lamblia

A Genome-Wide Association Study Identifies Susceptibility Variants for Type 2 Diabetes in Han Chinese

To investigate the underlying mechanisms of T2D pathogenesis, we looked for diabetes susceptibility genes that increase the risk of type 2 diabetes (T2D) in a Han Chinese population. A two-stage genome-wide association (GWA) study was conducted, in which 995 patients and 894 controls were genotyped using the Illumina HumanHap550-Duo BeadChip for the first genome scan stage. This was further replicated in 1,803 patients and 1,473 controls in stage 2. We found two loci not previously associated with diabetes susceptibility in and around the genes protein tyrosine phosphatase receptor type D (PTPRD) (P = 8.54×10−10; odds ratio [OR] = 1.57; 95% confidence interval [CI] = 1.36–1.82), and serine racemase (SRR) (P = 3.06×10−9; OR = 1.28; 95% CI = 1.18–1.39). We also confirmed that variants in KCNQ1 were associated with T2D risk, with the strongest signal at rs2237895 (P = 9.65×10−10; OR = 1.29, 95% CI = 1.19–1.40). By identifying two novel genetic susceptibility loci in a Han Chinese population and confirming the involvement of KCNQ1, which was previously reported to be associated with T2D in Japanese and European descent populations, our results may lead to a better understanding of differences in the molecular pathogenesis of T2D among various populations

Profiling the mental health of diabetic patients: a cross-sectional survey of Zimbabwean patients

Objective The burden of diabetes mellitus has exponentially increased in low resource settings. Patients with diabetes are more likely to exhibit poor mental health which negatively affects treatment outcomes. However, patients with high levels of social support (SS) are likely to report optimal mental health. We sought to determine how SS affects the report of psychiatric morbidity and health-related quality of life (HRQoL) in 108 diabetic patients in Harare, Zimbabwe. Results The average age of participants was 54.1 (SD 18.6) years. Most of the participants were; females (69.4%), married (51.9%), and were of low level of income (43.5%). 37.1% of the participants exhibited signs of psychiatric morbidity [mean Shona Symptoms Questionnaire score—6.7 (SD 3.2)]. Further, patients also reported lower HRQoL [mean EQ-5D-VAS score—64.1 (SD 15.3)] and high levels of SS [mean Multidimensional Scale of Perceived Social Support score—43.7 (SD 11.5)]. Patients who received greater amount of SS had optimal mental health. Being female, unmarried, lower education attainment, having more comorbid conditions, being diagnosed with type 2 diabetes and having been diagnosed of diabetes for a longer duration were associated with poorer mental health. It is important to develop context-specific interventions to improve diabetic patients’ mental health

Determining the porosity and water impregnation in irradiated graphite

International audienceImpurities in nuclear graphite can become neutron-activated during operation, generating radionuclides and leading to modifications in the microstructure of the graphite due to fast neutrons. The long-term disposal of nuclear graphite waste requires collecting data on the behaviour of long-lived radionuclides in disposal conditions (water-saturated). The release of radionuclides in solution depends on a number of physicochemical processes such as water ingress into the graphite structure (radionuclides sites), as well as the solubilisation and transport of radionuclides in solution through the graphite pores. Analysis of the impregnation (impregnation speed, impregnation rate) of water in the porous graphite environment represents one of the main parameters that will greatly influence the physicochemical processes controlling the release of radionuclides in solution. For this reason, the impregnation of irradiated samples from the G2 and St Laurent A2 (SLA2) gas-cooled graphite-moderated reactors was studied, as was the distribution of the porosity. Results show that the geometric density of the samples decreases after irradiation, which is expressed as an increase in the total porosity or more precisely in the open porosity. This means that irradiated graphite is mainly a macroporous solid. Nuclear graphite becomes a more hydrophobic material with its open porosity filled by water in just a few days. This is due to the presence of functional groups on the pore surface

Irradiation neutronique du graphite a basse temperature cas du reacteur G1

National audienceDans le cœur des réacteurs de type Uranium Naturel Graphite Gaz (UNGG), du graphite était utilisé en tant que modérateur et réflecteur de neutrons. Ce matériau irradié durant le fonctionnement de ces réacteurs constituera une part importante des déchets nucléaires après les opérations de démantèlement. Ils contiennent notamment plusieurs radionucléides « dimensionnants » pour la gestion à long terme de ces déchets dont le 3H, le 14C et le 36Cl. Les objectifs des études de caractérisation des graphites nucléaires irradiés sont principalement de comprendre et de quantifier les évolutions du graphite après le passage en réacteur en fonction des paramètres de fonctionnement. Ces données sont particulièrement utiles à des études de modélisation de l'irradiation neutronique du graphite. Par ailleurs, ces études peuvent également aider à la compréhension des phénomènes de migration en condition de stockage des radionucléides actuellement présents dans les déchets de graphite. Le réacteur G1 du Commissariat à l'Energie Atomique (CEA) de Marcoule fût le premier réacteur de la filière UNGG. Construit en 1955, ce dernier a été exploité entre janvier 1956 et septembre 1968. Une particularité de ce réacteur était que le caloporteur utilisé était de l'air à température ambiante. Celui-ci était injecté à partir d'une fente médiane à l'empilement graphite du réacteur. La température de fonctionnement y était donc moins élevée (20 - 230°C) que dans les autres réacteurs UNGG. Par ailleurs, dix-huit opérations de recuit ont été réalisées pour dissiper l'énergie Wigner accumulée dans le graphite au cours de la vie du réacteur. De par ses conditions particulières de fonctionnement (basse température, recuits hors irradiation), il est intéressant d'étudier l'impact de l'irradiation neutronique sur le graphite nucléaire dans ce réacteur. Ainsi, les évolutions de structure et de nanostructure ont été étudiées par microspectrométrie Raman et Microscopie Electronique à Transmission (MET). En termes de résultat, (1) les échantillons prélevés dans le réacteur G1 sont relativement très impactés aux échelles étudiées par l’irradiation neutronique notamment en raison de la basse température de fonctionnement du réacteur et (2) la distribution des défauts d’irradiation n'est pas identique à ce qui a été observé sur les échantillons des réacteurs précédemment étudiés [1]. La température d’irradiation étant le principal changement, quelques interprétations seront proposées quant à la contribution de ce paramètre sur les évolutions de l'organisation multi-échelle du graphite lors du passage en réacteur. [1]J. Pageot et al., Carbon 105 2016, 77-89

Recrystallization of amorphous ion implanted silicon carbide after thermal annealing

Single crystals of 6H-SiC were implanted at room temperature with 4-MeV Au ions to a fluence of 1015cm 2. Raman spectra showed that full amorphization was achieved. The recrystallization process was studied by micro-Raman spectrometry after isochronal thermal annealing between 700 and 1500 C. The spectra permitted the evolution upon annealing of Si-C bonds, and also of Si-Si and C-C bonds, to be followed. Amorphous phase relaxation takes place below 700 C; then recrystallization of the 6H polytype sets in at 700 C. At 900 C crystallites with different crystalline states are formed. Moreover, Raman spectra provide evidence of graphitic nanocluster formation at 1500 C