Direct BMP2/4 signaling through BMP receptor IA regulates fetal thymocyte progenitor homeostasis and differentiation to CD4+CD8+double-positive cell

BMP2/4 signaling is required for embryogenesis and involved in thymus morphogenesis and T-lineage differentiation. In vitro experiments have shown that treatment of thymus explants with exogenous BMP4 negatively regulated differentiation of early thymocyte progenitors and the transition from CD4−CD8− (DN) to CD4+CD8+ (DP). Here we show that in vivo BMP2/4 signaling is required for fetal thymocyte progenitor homeostasis and expansion, but negatively regulates differentiation from DN to DP cell. Unexpectedly, conditional deletion of BMPRIA from fetal thymocytes (using the Cre-loxP system and directing excision to hematopoietic lineage cells with the Vav promoter) demonstrated that physiological levels of BMP2/4 signaling directly to thymocytes through BMPRIA are required for normal differentiation and expansion of early fetal DN thymocytes. In contrast, the arrest in early thymocyte progenitor differentiation caused by exogenous BMP4 treatment of thymus explants is induced in part by direct signaling to thymocytes through BMPRIA, and in part by indirect signaling through non-hematopoietic cells. Analysis of the transition from fetal DN to DP cell, both by ex vivo analysis of conditional BMPRIA-deficient thymocytes and by treatment of thymus explants with the BMP4-inhibitor Noggin demonstrated that BMP2/4 signaling is a negative regulator at this stage. We showed that at this stage of fetal T-cell development BMP2/4 signals directly to thymocytes through BMPRIA

Ferroelectric Nanotubes

We report the independent invention of ferroelectric nanotubes from groups in several countries. Devices have been made with three different materials: lead zirconate-titanate PbZr1-xTixO3 (PZT); barium titanate BaTiO3; and strontium bismuth tantalate SrBi2Ta2O9 (SBT). Several different deposition techniques have been used successfully, including misted CSD (chemical solution deposition) and pore wetting. Ferroelectric hysteresis and high optical nonlinearity have been demonstrated. The structures are analyzed via SEM, TEM, XRD, AFM (piezo-mode), and SHG. Applications to trenching in Si dynamic random access memories, ink-jet printers, and photonic devices are discussed. Ferroelectric filled pores as small as 20 nm in diameter have been studied

A look at new therapeutic opportunities in patients with non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, and is considered to be the liver manifestation of metabolic syndrome. Currently, there is no etiotropic treatment of NAFLD, so an active research for new methods of treatment is underway. In the meantime, drugs are used to treat comorbid conditions, such as dyslipidemia, arterial hypertension, obesity, type 2 diabetes, which are present in varying degrees in patients. This review considers medications that are used in patients with NAFLD and related concomitant features, and also describes new strategies for regressing changes in liver tissue in NAFLD. In our opinion, one of the promising groups of drugs are agonists of the farnesoid X receptor (FXR). FXR belongs to the group of nuclear receptors, which are ligand-activated transcription factors that regulate the genes involved in metabolism. FXR agonists can claim to be a new promising drug for the treatment of NAFLD and related diseases influencing carbohydrate metabolism, fat metabolism, bile acid metabolism, as well as inflammatory processes in the liver to ensure metabolic homeostasis

BMP signaling negatively regulates bone mass through sclerostin by inhibiting the canonical Wnt pathway

Bone morphogenetic proteins (BMPs) are known to induce ectopic bone. However, it is largely unknown how BMP signaling in osteoblasts directly regulates endogenous bone. This study investigated the mechanism by which BMP signaling through the type IA receptor (BMPR1A) regulates endogenous bone mass using an inducible Cre-loxP system. When BMPR1A in osteoblasts was conditionally disrupted during embryonic bone development, bone mass surprisingly was increased with upregulation of canonical Wnt signaling. Although levels of bone formation markers were modestly reduced, levels of resorption markers representing osteoclastogenesis were severely reduced, resulting in a net increase in bone mass. The reduction of osteoclastogenesis was primarily caused by Bmpr1a-deficiency in osteoblasts, at least through the RANKL-OPG pathway. Sclerostin (Sost) expression was downregulated by about 90% and SOST protein was undetectable in osteoblasts and osteocytes, whereas the Wnt signaling was upregulated. Treatment of Bmpr1a-deficient calvariae with sclerostin repressed the Wnt signaling and restored normal bone morphology. By gain of Smad-dependent BMPR1A signaling in mice, Sost expression was upregulated and osteoclastogenesis was increased. Finally, the Bmpr1a-deficient bone phenotype was rescued by enhancing BMPR1A signaling, with restoration of osteoclastogenesis. These findings demonstrate that BMPR1A signaling in osteoblasts restrain endogenous bone mass directly by upregulating osteoclastogenesis through the RANKL-OPG pathway, or indirectly by downregulating canonical Wnt signaling through sclerostin, a Wnt inhibitor and a bone mass mediator

A practical and open source implementation of IEC 61850-7-2 for IED monitoring applications

A new open source mapping of IEC 61850-7-2 to web services has been defined and implemented. This work is useful for rapidly implementing user interfaces—particularly web-based interfaces—for monitoring and controlling Intelligent Electronic Devices (IEDs) from multiple vendors. The web service mapping has been implemented using the Hypertext Transfer Protocol (HTTP), with a message format in JavaScript Object Notation (JSON). This approach requires a simple and ubiquitous software stack for its implementation, which is a significant advantage over existing client-server communications mappings. The use of an open source paradigm allows for the rapid iteration and refinement of the design, implementation, and testing of the internal details of the proposed protocol stack, in a collaborative manner. These developments are of immediate interest to users of IEC 61850 and are particularly relevant to the IEC 61850 standardization process

Association of insulin resistance and non-alcoholic fatty liver disease

BACKGROUND: The number of patients with chronic metabolic disorders such as obesity, type 2 diabetes mellitus (T2D) and non-alcoholic fatty liver disease (NAFLD) is growing at an alarming rate worldwide in both developed and developing countries. In the world, the prevalence of NAFLD is approaching 25%. Among patients with T2D, 70–80% are diagnosed with NAFLD. Insulin resistance (IR) is recognized as one of the main pathogenetic factors in the development of the most common chronic liver disease — NAFLD.AIM: Our search work was aimed at determining the contribution of the degree of IR to the progression of NAFLD; compare the gold standard for the determination of IR (clamp) and the mathematical model (HOMA-IR).METHODS: An observational one-stage open comparative study was conducted on the basis of the case-control principle. The objects of the study were overweight and obese patients who had not previously been diagnosed carbohydrate metabolism disorders, without secondary causes of fat accumulation in the liver. During the examination, clinical and laboratory studies were carried out, IR indices (M-index, HOMA-IR index) were obtained, a diagnosis of carbohydrate metabolism disturbance (or its absence) was made, a liver biopsy was made, morphological and clinical diagnoses were made.RESULTS: The analysis included information about 60 patients, they are divided into 3 groups: without NAFLD (7 people), with steatosis (18 people), with non-alcoholic steatohepatitis (NASH) (35 people), groups are comparable by age, gender, and body mass index (BMI), glycated hemoglobin. When assessing the degree of IR using the hyperinsulinemic euglycemic clamp test, 19 showed a severe degree of IR, 28 had a moderate degree, 8 had a mild degree, and 5 had no IR. In the three studied groups, the median IR corresponded to an average degree and did not significantly differ. When comparing the gold standard for determining IR and the mathematical model (HOMA-IR) in the studied groups, an negative significant correlation was revealed (p = 0,0001).CONCLUSIONS: In the course of our study, no correlation was found between the degree of IR and the severity of NAFLD. This result allows us to think about other pathogenetic factors that affect the progression of NAFLD

Ultrafast optical generation of coherent phonons in CdTe1-xSex quantum dots

We report on the impulsive generation of coherent optical phonons in CdTe0.68Se0.32 nanocrystallites embedded in a glass matrix. Pump probe experiments using femtosecond laser pulses were performed by tuning the laser central energy to resonate with the absorption edge of the nanocrystals. We identify two longitudinal optical phonons, one longitudinal acoustic phonon and a fourth mode of a mixed longitudinal-transverse nature. The amplitude of the optical phonons as a function of the laser central energy exhibits a resonance that is well described by a model based on impulsive stimulated Raman scattering. The phases of the coherent phonons reveal coupling between different modes. At low power density excitations, the frequency of the optical coherent phonons deviates from values obtained from spontaneous Raman scattering. This behavior is ascribed to the presence of electronic impurity states which modify the nanocrystal dielectric function and, thereby, the frequency of the infrared-active phonons

An approach for the identification of targets specific to bone metastasis using cancer genes interactome and gene ontology analysis

Metastasis is one of the most enigmatic aspects of cancer pathogenesis and is a major cause of cancer-associated mortality. Secondary bone cancer (SBC) is a complex disease caused by metastasis of tumor cells from their primary site and is characterized by intricate interplay of molecular interactions. Identification of targets for multifactorial diseases such as SBC, the most frequent complication of breast and prostate cancers, is a challenge. Towards achieving our aim of identification of targets specific to SBC, we constructed a 'Cancer Genes Network', a representative protein interactome of cancer genes. Using graph theoretical methods, we obtained a set of key genes that are relevant for generic mechanisms of cancers and have a role in biological essentiality. We also compiled a curated dataset of 391 SBC genes from published literature which serves as a basis of ontological correlates of secondary bone cancer. Building on these results, we implement a strategy based on generic cancer genes, SBC genes and gene ontology enrichment method, to obtain a set of targets that are specific to bone metastasis. Through this study, we present an approach for probing one of the major complications in cancers, namely, metastasis. The results on genes that play generic roles in cancer phenotype, obtained by network analysis of 'Cancer Genes Network', have broader implications in understanding the role of molecular regulators in mechanisms of cancers. Specifically, our study provides a set of potential targets that are of ontological and regulatory relevance to secondary bone cancer.Comment: 54 pages (19 pages main text; 11 Figures; 26 pages of supplementary information). Revised after critical reviews. Accepted for Publication in PLoS ON

Parathyroid hormone induces bone cell motility and loss of mature osteocyte phenotype through L-calcium channel dependent and independent mechanisms

Parathyroid Hormone (PTH) can exert both anabolic and catabolic effects on the skeleton, potentially through expression of the PTH type1 receptor (PTH1R), which is highly expressed in osteocytes. To determine the cellular and molecular mechanisms responsible, we examined the effects of PTH on osteoblast to osteocyte differentiation using primary osteocytes and the IDG-SW3 murine cell line, which differentiate from osteoblast to osteocyte-like cells in vitro and express GFP under control of the dentin matrix 1 (Dmp1) promoter. PTH treatment resulted in an increase in some osteoblast and early osteocyte markers and a decrease in mature osteocyte marker expression. The gene expression profile of PTH-treated Day 28 IDG-SW3 cells was similar to PTH treated primary osteocytes. PTH treatment induced striking changes in the morphology of the Dmp1-GFP positive cells in IDG-SW3 cultures and primary cells from Dmp1-GFP transgenic mice. The cells changed from a more dendritic to an elongated morphology and showed increased cell motility. E11/gp38 has been shown to be important for cell migration, however, deletion of the E11/gp38/podoplanin gene had no effect on PTH-induced motility. The effects of PTH on motility were reproduced using cAMP, but not with protein kinase A (PKA), exchange proteins activated by cAMP (Epac), protein kinase C (PKC) or phosphatidylinositol-4,5-bisphosphonate 3-kinase (Pi3K) agonists nor were they blocked by their antagonists. However, the effects of PTH were mediated through calcium signaling, specifically through L-type channels normally expressed in osteoblasts but decreased in osteocytes. PTH was shown to increase expression of this channel, but decrease the T-type channel that is normally more highly expressed in osteocytes. Inhibition of L-type calcium channel activity attenuated the effects of PTH on cell morphology and motility but did not prevent the downregulation of mature osteocyte marker expression. Taken together, these results show that PTH induces loss of the mature osteocyte phenotype and promotes the motility of these cells. These two effects are mediated through different mechanisms. The loss of phenotype effect is independent and the cell motility effect is dependent on calcium signaling.Matthew Prideaux, Sarah L. Dallas, Ning Zhao, Erica D. Johnsrud, Patricia A. Veno, Dayong Guo, Yuji Mishina, Stephen E. Harris, Lynda F. Bonewal