Beta cell adaptation to pregnancy requires prolactin action on both beta and non-beta cells.

Pancreatic islets adapt to insulin resistance of pregnancy by up regulating ß-cell mass and increasing insulin secretion. Previously, using a transgenic mouse with global, heterozygous deletion of prolactin receptor (Prlr+/-), we found Prlr signaling is important for this adaptation. However, since Prlr is expressed in tissues outside of islets as well as within islets and prolactin signaling affects ß-cell development, to understand ß-cell-specific effect of prolactin signaling in pregnancy, we generated a transgenic mouse with an inducible conditional deletion of Prlr from ß-cells. Here, we found that ß-cell-specific Prlr reduction in adult mice led to elevated blood glucose, lowed ß-cell mass and blunted in vivo glucose-stimulated insulin secretion during pregnancy. When we compared gene expression profile of islets from transgenic mice with global (Prlr+/-) versus ß-cell-specific Prlr reduction (ßPrlR+/-), we found 95 differentially expressed gene, most of them down regulated in the Prlr+/- mice in comparison to the ßPrlR+/- mice, and many of these genes regulate apoptosis, synaptic vesicle function and neuronal development. Importantly, we found that islets from pregnant Prlr+/- mice are more vulnerable to glucolipotoxicity-induced apoptosis than islets from pregnant ßPrlR+/- mice. These observations suggest that down regulation of prolactin action during pregnancy in non-ß-cells secondarily and negatively affect ß-cell gene expression, and increased ß-cell susceptibility to external insults.

HSP25 Vaccination Attenuates Atherogenesis via Upregulation of LDLR Expression, Lowering of PCSK9 Levels and Curbing of Inflammation.

[Figure: see text].

Modulating the optical and magnetic properties of geometrically frustrated ZnV2O4 by the introduction of indium (nonmagnetic ions), iron, and chromium (magnetic ions).

The current study is aimed at understanding the effects of diluting the magnetic properties of a geometrically frustrated normal spinel, ZnV2O4, with the incorporation of nonmagnetic In3+ in place of V3+. Samples with the formula, ZnV2-xInxO4 (x = 0.00, 0.25, 0.50, 1.00 and 1.50), were synthesized following an epoxide mediated gel method and characterized extensively. The monophasic cubic spinel structure was retained up to 50 mol% of vanadium with indium, beyond which phase separation took place. The occupancy of indium at the octahedral site and the near-linear increment of the cubic unit cell constant were confirmed from the successful structural refinements. The optical bandgap increased from 2.80 (ZnV2O4) to 3.06, 3.19, and 3.35 eV for x values of 0.25, 0.50, and 1.00 in ZnV2-xInxO4. ZnVInO4 exhibited paramagnetic behavior down to 2 K in both the field-dependent and temperature-dependent magnetic measurements. However, the magnetization values were lower than those of ZnV2O4. A frustration index of 42 was estimated for ZnVInO4. Samples containing magnetic Cr3+ and Fe3+ ions in place of V3+ were synthesized and characterized to compare and contrast the magnetic ions' influence. For both chromium and iron substituted samples, the optical bandgap was higher than that of ZnV2O4. ZnVCrO4 showed an antiferromagnetic ordering of spins with a TN of 12.3 K. In contrast, the randomization of Zn, V, and Fe among the available crystallographic sites increased the ferrimagnetic transition temperature (TF) to 31.9 K. ZnVInO4 catalyzed the photodegradation of rhodamine-6G under UV-vis radiation to a greater extent than ZnVCrO4 and ZnVFeO4.

Unlike estrogens that increase PCSK9 levels post-menopause HSP27 vaccination lowers cholesterol levels and atherogenesis due to divergent effects on PCSK9 and LDLR.

AIMS: The estrogen-inducible protein Heat Shock Protein 27 (HSP27) as well as anti-HSP27 antibodies are elevated in healthy subjects compared to cardiovascular disease patients. Vaccination of ApoE-/- mice with recombinant HSP25 (rHSP25, the murine ortholog), boosts anti- HSP25 levels and attenuates atherogenesis. As estrogens promote HSP27 synthesis, cellular release and blood levels, we hypothesize that menopause will result in loss of HSP27 atheroprotection. Hence, the rationale for this study is to compare the efficacy of rHSP25 vaccination vs. estradiol (E2) therapy for the prevention of post-menopausal atherogenesis. METHODS AND RESULTS: ApoE-/- mice subjected to ovariectomy (OVX) showed a 65 % increase atherosclerotic burden compared to sham mice after 5 weeks of a high fat diet. Relative to vaccination with rC1, a truncated HSP27 control peptide, atherogenesis was reduced by 5-weekly rHSP25 vaccinations (-43 %), a subcutaneous E2 slow release pellet (-52 %) or a combination thereof (-82 %). Plasma cholesterol levels declined in parallel with the reductions in atherogenesis, but relative to rC1/OVX mice plasma PCSK9 levels were 52 % higher in E2/OVX and 41 % lower in rHSP25/OVX mice (p < 0.0001 for both). Hepatic LDLR mRNA levels did not change with E2 treatment but increased markedly with rHSP25 vaccination. Conversely, hepatic PCSK9 mRNA increased 148 % with E2 treatment vs. rC1/OVX but did not change with rHSP25 vaccination. In human HepG2 hepatocytes E2 increased PCSK9 promoter activity 303 %, while the combination of [rHSP27 + PAb] decreased PCSK9 promoter activity by 64 %. CONCLUSION: The reduction in post-OVX atherogenesis and cholesterol levels with rHSP25 vaccination is associated with increased LDLR but not PCSK9 expression. Surprisingly, E2 therapy attenuates atherogenesis and cholesterol levels post-OVX without altering LDLR but increases PCSK9 expression and promoter activity. This is the first documentation of increased PCSK9 expression with E2 therapy and raises questions about balancing physiological estrogenic / PCSK9 homeostasis and targeting PCSK9 in women - are there effects beyond cholesterol?

Understanding the role of ionic flux on the polarity of the exposed surfaces of ZnO.

The role of ionic flux in controlling the polarity of the surfaces of ZnO was evaluated, both experimentally and theoretically. Zinc oxide was synthesized by controlled decomposition of zinc oxalate nanorods in the presence of ionic flux. The degree of preferred orientation for a specific plane, for the ZnO structures, was observed by calculating the texture coefficient. The presence of flux (NaCl, KCl, a mixture of NaCl-KCl and Na2SO4) during decomposition of the oxalate precursor led to the preferential growth of (112[combining macron]0) planes. The value of texture coefficient was found to be high for the (112[combining macron]0) plane when the decomposition was carried out in the presence of a mixture of NaCl and KCl when compared to their counterparts. A decrease in the value of texture coefficient for the (112[combining macron]0) plane was observed when Na2SO4 was used as a flux, which was similar to the value obtained for ZnO synthesized in the absence of flux. The observations from the analysis of texture coefficient were correlated with the photocatalytic degradation of rhodamine B dye, by making use of the fact that the nature of exposed surfaces influences the catalytic activity of a material. On-site Coulomb correlation corrected density functional theory (DFT + U)-based computational studies were performed to get theoretical insight into the role of the ionic flux in surface reconstructions. The surface energies for different ZnO surfaces were computed in the presence and absence of the ionic flux. It was revealed that the pristine (101[combining macron]0) surface is more stable compared to pristine (112[combining macron]0) by 0.04 J m-2 (surface energy), however the scenario changes in the presence of the ionic flux and (112[combining macron]0) becomes more stable by 0.03 J m-2. This indeed corroborated with our experimental observations and explained the fundamental role of ionic flux on the polarity of exposed surfaces of ZnO.

Implications of including a magnetic ion (Cr3+ and Fe3+) at the vanadium site in a geometrically frustrated spinel MgV2O4: magnetic and catalytic properties.

The vanadium sublattice in a geometrically frustrated MgV2O4 is substituted partially with Cr3+ and Fe3+. With a successful Rietveld refinement of the powder X-ray diffraction patterns of MgVCrO4 and MgVFeO4, Cr and Fe occupy the octahedral sites of a spinel structure. Extensive field-dependent and temperature magnetic measurements on these samples reveal exciting results. MgV2O4 remains paramagnetic till 3 K, with a small divergence at around 20 K between ZFC and FC data. MgVCrO4 exhibits antiferromagnetic behavior with a Néel temperature of 13.6 K. MgVFeO4 shows spin-glass behavior resulting from the frustration with a glass transition temperature of 194 K. This sample shows a typical ferromagnetic behavior, with a coercivity of 194.5 Oe within an applied field of ±2 kOe. All three systems have been found to have a frustration index in the range of 1-25, and the effective magnetic moment decreases in the order MgVFeO4 > MgVCrO4 > MgV2O4. While the inclusion of chromium does not alter the bandgap of MgV2O4, iron substitution increases the bandgap. The partial replacement of V3+ with Cr3+ and Fe3+ increases the catalytic ability of the system in terms of the oxidative degradation of methylene blue dye. The catalytic efficiency follows the order MgVFeO4 > MgVCrO4 > MgV2O4, matching well with the trend noticed in the porosity, surface area, and redox ability of Fe3+, Cr3+ and V3+ in these samples. The degradation pathway has been followed by analyzing the intermediates from these experiments by mass spectrometry, and a plausible mechanism is proposed.

Lrrc55 is a novel prosurvival factor in pancreatic islets.

Pancreatic islets adapt to the increase in insulin demand during pregnancy by upregulating ß-cell number, insulin synthesis, and secretion. These changes require prolactin receptor (PrlR) signaling, as mice with PrlR deletion are glucose intolerant with a lower ß-cell mass. Prolactin also prevents ß-cell apoptosis. Many genes participate in these adaptive changes in the islet, and Lrrc55 is one of the most upregulated genes with unknown function in islets. Because Lrrc55 expression increases in parallel to the increase in ß-cell number and insulin production during pregnancy, we hypothesize that Lrrc55 might regulate ß-cell proliferation/apoptosis (thus ß-cell number) and insulin synthesis. Here, we found that Lrrc55 expression was upregulated by >60-fold during pregnancy in a PrlR-dependent manner, and this increase was restricted only to the islets. Overexpression of Lrrc55 in ß-cells had minimal effect on ß-cell proliferation and glucose-stimulated insulin secretion but protected ß-cells from glucolipotoxicity-induced reduction in insulin gene expression. Moreover, Lrrc55 protects ß-cells from glucolipotoxicity-induced apoptosis, with upregulation of prosurvival signals and downregulation of proapoptotic signals of the endoplasmic reticulum (ER) stress pathway. Furthermore, Lrrc55 attenuated calcium depletion induced by glucolipotoxicity, which may contribute to its antiapoptotic effect. Hence our findings suggest that Lrrc55 is a novel prosurvival factor that is upregulated specifically in islets during pregnancy, and it prevents conversion of adaptive unfolded protein response to unresolved ER stress and apoptosis in ß-cells. Lrrc55 could be a potential therapeutic target in diabetes by reducing ER stress and promoting ß-cell survival.

Metastable Bi2Zr2O7 with Pyrochlore-like Structure: Stabilization, Oxygen Ion Conductivity, and Catalytic Properties.

Equimolar concentrations of Zr4+ and Bi3+ were chelated with ethylenediaminetetraacetic acid ligand with the purpose of using it as a precursor to generate pyrochlore-like Bi2Zr2O7. When the X-ray amorphous precursor was calcined at 750 °C for 3 h in air, pyrochlore-like product with superstructure reflections was identified by powder X-ray diffraction (PXRD) along with one minor reflection due to ß-Bi2O3. This phase was found to be metastable from additional experiments conducted by varying calcination conditions. Structural refinement of PXRD pattern by Le Bail method in Fd3̅ m space group yielded cubic lattice constant of 10.8421(27) Å. Flower-petal-like morphology of the sample was evident in its field-emission scanning electron microscopy image and energy-dispersive X-ray analysis performed at various locations of the specimen confirmed nearly equal concentration of zirconium and bismuth. Six bands at 260, 320, 448, 531, 597, and 828 cm-1 were observed for this sample in its Raman spectrum and supported our claim of pyrochlore-like structure. Indexation of bright spots present in selected area electron diffraction pattern and observed distances of lattice fringes in high-resolution transmission electron microscopy image were in conformity with the results from PXRD measurements. Absorbance maxima at 312, 372, and 423 nm with a broad tailing stretching up to visible region was noticed in the UV-visible spectrum of this sample. Direct band gap of 2 eV was estimated for this sample from Tauc plot. The oxygen ion conductivity of the sample in the temperature range of 333-773 K was examined, and the highest conductivity at 773 K was 3.071 × 10-6 S/cm. From activation energy estimation and dielectric loss analysis, thermally activated process related to the mobility of oxygen ion vacancy was found responsible for the observed ionic conductivity. A similar conclusion was reached after careful analysis of dielectric spectroscopy data of this sample. High surface area (125.04 m2/g) and mesoporosity (pore diameter of 3.81 nm) were possessed by this sample, which paved way for studying its catalytic role in the reduction of nitroaromatics and carcinogenic Cr6+. Cyclability experiments showed the retainment of catalytic activity up to five cycles by the sample without undergoing any structural change.

Prophylactic salpingo-oophorectomy & surgical menopause for inherited risks of cancer: the need to identify biomarkers to assess the theoretical risk of premature coronary artery disease.

BACKGROUND: Some women with genetic risk of breast and/or ovarian cancer (e.g., BRCA1/2) opt to undergo prophylactic salpingo-oophorectomy (PSO, or surgical removal of the ovaries & fallopian tubes) in order to reduce their risk of cancer. As a consequence, these women experience "surgical menopause" - accompanied by more severe climacteric symptoms that occur in a much shorter time frame. While the risk of coronary artery disease (CAD) rises with menopause, little is known about how the sudden loss of ovarian function from PSO alters the whole-body physiology, and whether it predisposes women to premature CAD. METHODS/DESIGN: To manage CAD risk there is a prerequisite for reliable biomarkers that can help guide risk assessment and therapeutic interventions. To address these needs, this prospective, observational cohort study will evaluate surrogate markers reflective of CAD health in women experiencing surgical menopause after PSO. Twenty women representing each of the following groups will be enrolled over 3 years (total participants = 240): (i) pre-menopausal PSO, (ii) post-menopausal PSO, (iii) pre-menopausal women undergoing other pelvic surgery, and (iv) pre-menopausal controls (no surgery). All participants will provide blood plasma samples pre- and 1, 3, 6, & 12 months post-operatively, with serial samples collectively assessed for measurements of the study's primary endpoints of interest. These include a hormone profile (estradiol, follicle stimulating hormone (FSH), luteinizing hormone (LH), and progesterone) and both conventional (lipid profile) and novel biomarkers (Heat Shock Protein 27 (HSP27), HSP27-antibodies (HSP27 Ab), proprotein convertase subtilisin/kexin 9 (PCSK9), inflammatory cytokines) of CAD. Another aspect of this study is the measurement and analysis of retinal vessel diameters - an emerging physiological parameter reflective of CAD risk. Finally, a patient engagement exercise will result in the drafting of patient-generated questionnaires that address the well-being and health concerns of these women as they transition through premature menopause and work with our research team to identify and discuss their health priorities. DISCUSSION: The protocol of our planned study investigating the effects of PSO on CAD is described herein. Characterization of novel CAD markers in women experiencing surgical menopause will yield new insights into the role of the functional ovary in modulating lipid parameters and other CAD risk factors such as HSP27 and HSP27 Ab.

Oligofructose as an adjunct in treatment of diabetes in NOD mice.

In type 1 diabetes, restoration of normoglycemia can be achieved if the autoimmune attack on beta cells ceases and insulin requirement is met by the residual beta cells. We hypothesize that an adjunctive therapy that reduces insulin demand by increasing insulin sensitivity will improve the efficacy of an immunotherapy in reversing diabetes. We tested the gut microbiota-modulating prebiotic, oligofructose (OFS), as the adjunctive therapy. We treated non-obese diabetic mice with an immunotherapy, monoclonal anti-CD3 antibody (aCD3), with or without concurrent dietary supplement of OFS. After 8 weeks of OFS supplement, the group that received both aCD3 and OFS (aCD3 + OFS) had a higher diabetes remission rate than the group that received aCD3 alone. The aCD3 + OFS group had higher insulin sensitivity accompanied by reduced lymphocytic infiltrate into the pancreatic islets, higher beta-cell proliferation rate, higher pancreatic insulin content, and secreted more insulin in response to glucose. The addition of OFS also caused a change in gut microbiota, with a higher level of Bifidobacterium and lower Clostridium leptum. Hence, our results suggest that OFS can potentially be an effective therapeutic adjunct in the treatment of type 1 diabetes by improving insulin sensitivity and beta-cell function, leading to improved glycemic control.

Prolactin as an Adjunct for Type 1 Diabetes Immunotherapy.

Type 1 diabetes is caused by autoimmune destruction of ß-cells. Although immunotherapy can restore self-tolerance thereby halting continued immune-mediated ß-cell loss, residual ß-cell mass and function is often insufficient for normoglycemia. Using a growth factor to boost ß-cell mass can potentially overcome this barrier and prolactin (PRL) may fill this role. Previous studies have shown that PRL can stimulate ß-cell proliferation and up-regulate insulin synthesis and secretion while reducing lymphocytic infiltration of islets, suggesting that it may restore normoglycemia through complementary mechanisms. Here, we test the hypothesis that PRL can improve the efficacy of an immune modulator, the anticluster of differentiation 3 monoclonal antibody (aCD3), in inducing diabetes remission by up-regulating ß-cell mass and function. Diabetic nonobese diabetic (NOD) mice were treated with a 5-day course of aCD3 with or without a concurrent 3-week course of PRL. We found that a higher proportion of diabetic mice treated with the aCD3 and PRL combined therapy achieved diabetes reversal than those treated with aCD3 alone. The aCD3 and PRL combined group had a higher ß-cell proliferation rate, an increased ß-cell fraction, larger islets, higher pancreatic insulin content, and greater glucose-stimulated insulin release. Lineage-tracing analysis found minimal contribution of ß-cell neogenesis to the formation of new ß-cells. Although we did not detect a significant difference in the number or proliferative capacity of T cells, we observed a higher proportion of insulitis-free islets in the aCD3 and PRL group. These results suggest that combining a growth factor with an immunotherapy may be an effective treatment paradigm for autoimmune diabetes.

Integrating techniques to re-establish dentogingival esthetics.

The aim of this article was to report the clinical case of a male patient of 20 years with hyperpigmented gingiva and moderate fluorosis, whose smile was reestablished by the use of a laser assisted depigmentation procedure, an enamel microabrasion technique, followed by at-home bleaching and subsequent remineralization therapy. The association of these techniques presented excellent results and the patient was satisfied. All techniques are painless, fast and easy to perform, in addition to preserving the hard and soft dental structure. Treatment showed immediate and permanent results; these techniques must be divulged among professionals and their patients.