Molybdenum sulfides are very attractive noble-metal free electrocatalysts for the hydrogen evolution reaction (HER) from water. Atomic structure and identity of the catalytically active sites have been well established for crystalline molybdenum disulfide (c-MoS 2 ) but not for amorphous molybdenum sulfide (a-MoS x ) which displays significantly higher HER activity compared to its
Broader contextGreat efforts are being focused to search for viable electrocatalysts for the water oxidation reaction (WOR) and the hydrogen evolution reaction (HER) which are preferably composed of only earth-abundant-elements. We report herein two novel ternary suldes, cobalt/nickel-tungsten-suldes, as attractive alternatives to platinum electrocatalysts for the HER. These suldes are easily electrodeposited on conducting electrodes from an aqueous solution of readily available precursors. Implementation of these HER electrocatalysts within a water (photo)electrolysis device is feasible and promising.
The major goal of this review is to summarize recent exciting findings that have been published within the past 10 years that, to our knowledge, have not been presented in detail in previous reviews and that may impact altered follicular development in polycystic ovarian syndrome (PCOS) and premature ovarian failure in women. Specifically, we will cover the following: (1) mouse models that have led to discovery of the derivation of two precursor populations of theca cells in the embryonic gonad; (2) the key roles of the oocyte-derived factor growth differentiation factor 9 on the hedgehog (HH) signaling pathway and theca cell functions; and (3) the impact of the HH pathway on both the specification of theca endocrine cells and theca fibroblast and smooth muscle cells in developing follicles. We will also discuss the following: (1) other signaling pathways that impact the differentiation of theca cells, not only luteinizing hormone but also insulinlike 3, bone morphogenic proteins, the circadian clock genes, androgens, and estrogens; and (2) theca-associated vascular, immune, and fibroblast cells, as well as the cytokines and matrix factors that play key roles in follicle growth. Lastly, we will integrate what is known about theca cells from mouse models, human-derived theca cell lines from patients who have PCOS and patients who do not have PCOS, and microarray analyses of human and bovine theca to understand what pathways and factors contribute to follicle growth as well as to the abnormal function of theca.
Glucokinase (GK) activation as a potential strategy to treat type 2 diabetes (T2D) is well recognized. Compound 1, a glucokinase activator (GKA) lead that we have previously disclosed, caused reversible hepatic lipidosis in repeat-dose toxicology studies. We hypothesized that the hepatic lipidosis was due to the structure-based toxicity and later established that it was due to the formation of a thiourea metabolite, 2. Subsequent SAR studies of 1 led to the identification of a pyrazine-based lead analogue 3, lacking the thiazole moiety. In vivo metabolite identification studies, followed by the independent synthesis and profiling of the cyclopentyl keto- and hydroxyl- metabolites of 3, led to the selection of piragliatin, 4, as the clinical lead. Piragliatin was found to lower pre- and postprandial glucose levels, improve the insulin secretory profile, increase β-cell sensitivity to glucose, and decrease hepatic glucose output in patients with T2D.
In this work, the step-wise oxidation mechanism of nickel (Ni) nanowires is elucidated. Rapid vacancy diffusion plays a signifi cant role at low temperatures in forming heterostructures of nickel oxide (NiO) nanotubes with Ni nanowires. Subsequent investigations of Ni nanowire oxidation at higher temperatures and faster temperature ramp rates show that it is diffi cult to bypass this rapid vacancy diffusion stage, which affects the formation of the fi nal structure. Therefore, it is unlikely to form solid NiO nanowires or NiO nanotubes with uniform wall thickness through the conventional annealing/ oxidation process of Ni nanowires. Instead, a step-wise oxidation process by combining low temperature oxidation with a chemical etching step is utilized to produce for the fi rst time NiO nanotubes with uniform wall thickness from Ni nanowires.
The role of the hedgehog (HH) signaling pathway in ovarian function was examined in transgenic mice in which expression of a dominant active allele of the signal transducer smoothened (SmoM2) was directed to the ovary and Müllerian duct by cre-mediated recombination (Amhr2(cre/+)SmoM2). Mutant mice were infertile and had ovarian and reproductive tract defects. Ovaries contained follicles of all sizes and corpora lutea (CL), but oocytes were rarely recovered from the oviducts of superovulated mice and remained trapped in preovulatory follicles. Measures of luteinization did not differ. Cumulus expansion appeared disorganized, and in vitro analyses confirmed a reduced expansion index. Microarray analysis indicated that expression levels of genes typical of smooth muscle were reduced in mutant mice, and RT-PCR showed that levels of expression of muscle genes were reduced in the nongranulosa, theca-interstitial cell-enriched fraction. Whereas a layer of cells in the outer theca was positively stained for smooth muscle actin in control ovaries, this staining was reduced or absent in mutant ovaries. Expression of a number of genes in granulosa cells that are known to be important for ovulation did not differ in mutants and controls. Expression of components of the HH pathway was observed in both granulosa cells and in the nongranulosa, residual ovarian tissue and changed in response to treatment with equine chorionic gonadotropin/human gonadotropin. The results show that appropriate signaling through the HH pathway is required for development of muscle cells within the theca and that impaired muscle development is associated with failure to release the oocyte at ovulation.
Intrafollicular androgens and cytokines likely comprise a local regulatory loop that impacts GC expression of cytokines and chemokines and the presence of immune cells; this loop is further enhanced in the obese PCOS subtype.
The forkhead box (FOX), FOXO1 and FOXO3, transcription factors regulate multiple functions in mammalian cells. Selective inactivation of the Foxo1 and Foxo3 genes in murine ovarian granulosa cells severely impairs follicular development and apoptosis causing infertility, and as shown here, granulosa cell tumor (GCT) formation. Coordinate depletion of the tumor suppressor Pten gene in the Foxo1/3 strain enhanced the penetrance and onset of GCT formation. Immunostaining and Western blot analyses confirmed FOXO1 and phosphatase and tensin homolog (PTEN) depletion, maintenance of globin transcription factor (GATA) 4 and nuclear localization of FOXL2 and phosphorylated small mothers against decapentaplegic (SMAD) 2/3 in the tumor cells, recapitulating results we observed in human adult GCTs. Microarray and quantitative PCR analyses of mouse GCTs further confirmed expression of specific genes (Foxl2, Gata4, and Wnt4) controlling granulosa cell fate specification and proliferation, whereas others (Emx2, Nr0b1, Rspo1, and Wt1) were suppressed. Key genes (Amh, Bmp2, and Fshr) controlling follicle growth, apoptosis, and differentiation were also suppressed. Inhbb and Grem1 were selectively elevated, whereas reduction of Inha provided additional evidence that activin signaling and small mothers against decapentaplegic (SMAD) 2/3 phosphorylation impact GCT formation. Unexpectedly, markers of Sertoli/epithelial cells (SRY [sex determining region Y]-box 9/keratin 8) and alternatively activated macrophages (chitinase 3-like 3) were elevated in discrete subpopulations within the mouse GCTs, indicating that Foxo1/3/Pten depletion not only leads to GCTs but also to altered granulosa cell fate decisions and immune responses. Thus, analyses of the Foxo1/3/Pten mouse GCTs and human adult GCTs provide strong evidence that impaired functions of the FOXO1/3/PTEN pathways lead to dramatic changes in the molecular program within granulosa cells, chronic activin signaling in the presence of FOXL2 and GATA4, and tumor formation.
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