We assessed how the role of genes genetic causation in causing maturity-onset diabetes of the young (MODY) alters the response to an oral glucose tolerance test (OGTT).
We studied OGTT in 362 MODY ...subjects, from seven European centres; 245 had glucokinase gene mutations and 117 had Hepatocyte Nuclear Factor -1 alpha ( HNF-1alpha) gene mutations.
BMI and age were similar in the genetically defined groups. Fasting plasma glucose (FPG) was less than 5.5 mmol/l in 2 % glucokinase subjects and 46 % HNF-1 alpha subjects ( p < 0.0001). Glucokinase subjects had a higher FPG than HNF-1 alpha subjects (means +/- SD 6.8 +/- 0.8 vs 6.0 +/- 1.9 mmol/l, p < 0.0001), a lower 2-h value (8.9 +/- 2.3 vs 11.2 +/- 5.2 mmol/l, p < 0.0001) and a lower OGTT increment (2-h - fasting) (2.1 +/- 2.3 vs 5.2 +/- 3.9 mmol/l, p < 0.0001). The relative proportions classified as diabetic depended on whether fasting (38 % vs 22 %, glucokinase vs HNF-1 alpha) or 2-h values (19 % vs 44 %) were used. Fasting and 2-h glucose values were not correlated in the glucokinase subjects ( r = -0.047, p = 0.65) but were strongly correlated in HNF-1 alpha subjects ( r = 0.8, p < 0.001). Insulin concentrations were higher in the glucokinase subjects throughout the OGTT.
The genetic cause of the beta-cell defect results in clear differences in both the fasting glucose and the response to an oral glucose load and this can help diagnostic genetic testing in MODY. OGTT results reflect not only the degree of hyperglycaemia but also the underlying cause.
Diabet. Med. 29, 479–487 (2012)
Aim To explore the putative association of new‐onset diabetes and the soluble urokinase plasminogen activator receptor (suPAR), which is a new and stable plasma ...marker of immune function and low‐grade inflammation. This association has been previously suggested by using the less sensitive International Classification of Disease system to detect incident diabetes in the Danish MONICA 10 cohort.
Methods The Danish National Diabetes Register enabled more accurate identification of incident diabetes during a median follow‐up of 13.8 years in the Danish MONICA 10 cohort (n = 2353 generally healthy individuals). The soluble urokinase plasminogen activator receptor was measured by the ELISA method. To fulfil model assumptions, outcome analyses were stratified by age, and further by smoking, owing to the interaction between the soluble urokinase plasminogen activator receptor and smoking on new‐onset diabetes (P < 0.0001).
Results New‐onset diabetes (n = 182) was associated with increased soluble urokinase plasminogen activator receptor levels (P = 0.013). Among 699 middle‐aged (41 and 51 years) and 564 older (61 and 71 years) non‐smokers, participants in the upper soluble urokinase plasminogen activator receptor quartile had a sex‐ and age‐adjusted relative risk of 6.01 (95% CI 2.17–16.6, P < 0.0006) and relative risk of 3.25 (95% CI 1.51–6.98, P = 0.0025), respectively, for new‐onset diabetes compared with participants in the lowest quartile. This relationship remained significant after additional adjustments for C‐reactive protein and leukocytes or fasting glucose and insulin or BMI (P < 0.05). The soluble urokinase plasminogen activator receptor was not related to incident diabetes among smokers (P ≥ 0.85).
Conclusions In these explorative analyses, the soluble urokinase plasminogen activator receptor associated independently with incident diabetes in non‐smokers, supporting an immune origin of Type 2 diabetes. Competing disease risk may explain lack of association among smokers.
The outer atmosphere of the first generations of low-mass (M < 0.8 M ) stars retain to a great extent the original chemical composition of the interstellar medium (ISM) at the time and place of their ...birth. The composition of this pristine gas represents the nucleosynthesis of the very first massive stars, that produced and ejected the first heavy elements into the early ISM. Thus a detailed abundance analysis of low-mass, metal-poor stars can help us track these gasses and provide insight into the formation processes that took place in the very early stages of our Galaxy. Preliminary result of a 25-star homogeneously analysed sample of metal- poor candidates from the Hamburg ESO survey is presented. The main focus is on the most metal-poor stars of the sample; stars with Fe H < −4. The abundance pattern of these ultra metal-poor (UMP) stars is used to extract key information of the earliest ongoing formation processes (ranging from hydrostatic burning to neutron-capture processes).
The dialogue between trophectoderm cells of the conceptus and epithelial cells of the endometrium is critical to CL maintenance and embryo survival. The signal transduction mechanisms by which bovine ...interferon (IFN)-τ regulates cyclooxygenase (COX)-2 expression and secretion of prostaglandin F
2α (PGF
2α) in bovine endometrial (BEND) cells is examined. Stimulation of Protein Kinase C with a phorbol ester (phorbol 12, 13 dibutyrate PDBu) activates COX-2 gene expression and PGF
2α secretion via the mitogen-activated protein kinase (MAPK) pathway. Interferon-τ attenuates PDBu activation of PGF
2α secretion, but this inhibitory effect appears to be independent of the MAPK pathway. Embryonic IFN-τ, acting through a Type I IFN receptor, activates the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway resulting in activation or repression of interferon-stimulated genes. Experimental evidence is provided that IFN-τ regulation of STATs regulates gene expression of COX-2 in a manner that decreases secretion of PGF
2α. Maternal regulation of the antiluteolytic pathway is discussed relative to the ability of the polyunsaturated fatty acid, eicosapentaenoic (EPA), to decrease endometrial secretion of PGF
2α and progesterone to increase both conceptus development and IFN-τ secretion.
The phorboxazoles are mixed non-ribosomal peptide synthase/polyketide synthase biosynthetic products that embody polyketide domains joined via two serine-derived oxazole moieties. Total syntheses of ...phorboxazole A and analogues have been developed that rely upon the convergent coupling of three fragments via biomimetically inspired de novo oxazole formation. First, the macrolide-containing domain of phorboxazole A was assembled from C3−C17 and C18−C30 building blocks via formation of the C16−C18 oxazole, followed by macrolide ring closure involving an intramolecular Still−Genarri olefination at C2−C3. Alternatively, a ring-closing metathesis process was optimized to deliver the natural product’s (2Z)-acrylate with remarkable geometrical selectivity. The C31−C46 side-chain domain was then appended to the macrolide by a second serine amide-derived oxazole assembly. Minimal deprotection then afforded phorboxazole A. This generally effective strategy was then dramatically abbreviated by employing a total synthesis approach wherein both of the natural product’s oxazole moieties were installed simultaneously. A key bis-amide precursor to the bis-oxazole was formed in a chemoselective one-pot, bis-amidation sequence without the use of amino or carboxyl protecting groups. Thereafter, both oxazoles were formed from the key C18 and C31 bis-N-(1-hydroxyalkan-2-yl)amide in a simultaneous fashion, involving oxidation−cyclodehydrations. This synthetic strategy provides a total synthesis of phorboxazole A in 18% yield over nine steps from C3−C17 and C18−C30 synthetic fragments. It illustrates the utility of a synthetic design to form a mixed non-ribosomal peptide synthase/polyketide synthase biosynthetic product based upon biomimetic oxazole formation initiated by amide bond formation to join synthetic building blocks.
Magnetoelectric properties displayed in multiferroics are generally associated with complex magnetic orders. This complexity often results in a delicate balance between several geometrically ...frustrated magnetic exchange interactions. Applying pressure will thus unbalance this equilibrium and strongly affect the multiferroic properties. In this paper, we study the effect of pressure on magnetism in three particular members of the RMn2O5 multiferroics (R = Gd, Sm, and Nd) with interesting magnetic orders. Using powder neutron diffraction, we studied the evolution of their magnetic structures as a function of pressure. Despite their singular properties with respect to the other compositions, we demonstrate that these three members present the same pressure-induced commensurate phase (PCM) with the propagation wave vector qPCM=(12,0,12). Furthermore, the stabilization of the PCM phase under pressure can be explained by a similar mechanism. We ultimately conclude that the different origin of the CM and PCM phases of these three compounds are related to the competition of only two superexchange interactions, namely J1 and J6.
Transmission electron microscopy (TEM) makes it possible to obtain insight into the structure, composition and reactivity of photocatalysts, which are of fundamental interest for sustainable energy ...research. Such insight can be used for further material optimization. Here, we combine conventional TEM analysis of photocatalysts with environmental TEM (ETEM) and photoactivation using light. Two novel types of TEM specimen holder that enable in situ illumination are developed to study light-induced phenomena in photoactive materials, systems and photocatalysts at the nanoscale under working conditions. The technological development of the holders is described and two representative photo-induced phenomena are studied: the photodegradation of Cu2O and the photodeposition of Pt onto a GaN:ZnO photocatalyst.
Background: X linked cone-rod dystrophy (CORDX) is a recessive retinal disease characterised by progressive dysfunction of photoreceptors. It is genetically heterogeneous, showing linkage to three X ...chromosomal loci. CORDX1 is caused by mutations in the RPGR gene (Xp21.1), CORDX2 is located on Xq27.2-28, and we recently localised CORDX3 to Xp11.4-q13.1. We aimed to identify the causative gene behind the CORDX3 phenotype. Methods: All 48 exons of the CACNA1F gene were screened for mutations by DNA sequencing. RNA from cultured lymphoblasts and peripheral blood activated T lymphocytes was analysed by RT-PCR and sequencing. Results: A novel CACNA1F mutation, IVS28-1 GCGTC>TGG, in the splice acceptor site of intron 28 was identified. Messenger RNA studies indicated that the identified mutation leads to altered splicing of the CACNA1F transcript. Aberrant splice variants are predicted to result in premature termination and deletions of the encoded protein, Cav1.4 α1 subunit. Conclusion:CACNA1F mutations cause the retinal disorder, incomplete congenital stationary night blindness (CSNB2), although mutations have also been detected in patients with divergent diagnoses. Our results indicate that yet another phenotype, CORDX3, is caused by a mutation in CACNA1F. Clinically, CORDX3 shares some features with CSNB2 but is distinguishable from CSNB2 in that it is progressive, can begin in adulthood, has no nystagmus or hyperopic refraction, has only low grade astigmatism, and in dark adaptation lacks cone threshold and has small or no elevation of rod threshold. Considering all features, CORDX3 is more similar to other X chromosomal cone-rod dystrophies than to CSNB2.
Heterogeneous bi-magnetic nanostructured systems have had a sustained interest during the last decades owing to their unique magnetic properties and the wide range of derived potential applications. ...However, elucidating the details of their magnetic properties can be rather complex. Here, a comprehensive study of Fe
O
/Mn
O
core/shell nanoparticles using polarized neutron powder diffraction, which allows disentangling the magnetic contributions of each of the components, is presented. The results show that while at low fields the Fe
O
and Mn
O
magnetic moments averaged over the unit cell are antiferromagnetically coupled, at high fields, they orient parallel to each other. This magnetic reorientation of the Mn
O
shell moments is associated with a gradual evolution with the applied field of the local magnetic susceptibility from anisotropic to isotropic. Additionally, the magnetic coherence length of the Fe
O
cores shows some unusual field dependence due to the competition between the antiferromagnetic interface interaction and the Zeeman energies. The results demonstrate the great potential of the quantitative analysis of polarized neutron powder diffraction for the study of complex multiphase magnetic materials.
Aims: This study elucidates the mechanisms by which a nonbacteriocinogenic Carnobacterium piscicola inhibits growth of Listeria monocytogenes.
Methods and Results: Listeria monocytogenes was ...exposed to live cultures of a bacteriocin‐negative variant of C. piscicola A9b in co‐culture, in a diffusion chamber system, and to a cell‐free supernatant. Suppression of maximum cell density (0–3·5 log units) of L. monocytogenes was proportional to initial levels of C. pisciola (103–107 CFU ml−1). Cell‐to‐cell contact was not required to cause inhibition. The cell‐free C. piscicola supernatant caused a decrease in L. monocytogenes maximum cell density, which was abolished by glucose addition but not by amino acid, vitamin or mineral addition. The fermentate also gave rise to a longer lag phase and a reduction in growth rate. These effects were independent of glucose and may have been caused by acetate production by C. piscicola. 2D gel‐electrophoretic patterns of L. monocytogenes exposed to C. piscicola or to L. monocytogenes fermentate did not differ. Treatment with C. piscicola fermentate resulted in down‐regulation (twofold) of genes involved in purine‐ or pyrimidine metabolism, and up‐regulation (twofold) of genes from the regulon for vitamin B12 biosynthesis and propanediol and ethanolamine utilization.
Conclusions: A nonbacteriocinogenic C. piscicola reduced growth of L. monocytogenes partly by glucose depletion.
Significance and Impact of the Study: Understanding the mechanism of microbial interaction enhances prediction of growth in mixed communities as well as use of bioprotective principles for food preservation.
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