MiR-378b Modulates -Induced Upper Genital Tract Pathology.

Genital infection causes severe reproductive pathologies such as salpingitis and pelvic inflammatory disease that can lead to tubal factor infertility. MicroRNAs (miRNAs) are evolutionarily conserved regulators of mammalian gene expression in development, immunity and pathophysiologic processes during inflammation and infection, including infection. Among the miRNAs involved in regulating host responses and pathologic outcome of infection, we have shown that miR-378b was significantly differentially expressed during primary infection and reinfection.

Aryl hydrocarbon receptor in mesenchymal stromal cells: new frontiers in AhR biology.

Mesenchymal stromal cells (MSCs) are nonhematopoietic cells that have been clinically explored as investigational cellular therapeutics for tissue injury regeneration and immune-mediated diseases. Their pharmaceutical properties arise from activation of endogenous receptors and transcription factors leading to a paracrine effect which mirror the biology of progenitors from which they arise. The aryl hydrocarbon receptor (AhR) is a transcription factor that has been extensively studied as an environmental sensor for xenobiotics, but recent findings suggest it can modulate immunological functions.

S100A6 is a positive regulator of PPP5C-FKBP51-dependent regulation of endothelial calcium signaling.

I is a cation current permeating the ISOC channel. In pulmonary endothelial cells, I activation leads to formation of inter-endothelial cell gaps and barrier disruption. The immunophilin FK506-binding protein 51 (FKBP51), in conjunction with the serine/threonine protein phosphatase 5C (PPP5C), inhibits I .

VU0810464, a non-urea G protein-gated inwardly rectifying K (K 3/GIRK) channel activator, exhibits enhanced selectivity for neuronal K 3 channels and reduces stress-induced hyperthermia in mice.

Background And Purpose: G protein-gated inwardly rectifying K (K 3) channels moderate the activity of excitable cells and have been implicated in neurological disorders and cardiac arrhythmias. Most neuronal K 3 channels consist of K 3.1 and K 3.

Discovery, synthesis and characterization of a series of (1-alkyl-3-methyl-1H-pyrazol-5-yl)-2-(5-aryl-2H-tetrazol-2-yl)acetamides as novel GIRK1/2 potassium channel activators.

The present study describes the discovery and characterization of a series of 5-aryl-2H-tetrazol-3-ylacetamides as G protein-gated inwardly-rectifying potassium (GIRK) channels activators. Working from an initial hit discovered during a high-throughput screening campaign, we identified a tetrazole scaffold that shifts away from the previously reported urea-based scaffolds while remaining effective GIRK1/2 channel activators. In addition, we evaluated the compounds in Tier 1 DMPK assays and have identified a (3-methyl-1H-pyrazol-1-yl)tetrahydrothiophene-1,1-dioxide head group that imparts interesting and unexpected microsomal stability compared to previously-reported pyrazole head groups.

The Antitumor Drug LB-100 Is a Catalytic Inhibitor of Protein Phosphatase 2A (PPP2CA) and 5 (PPP5C) Coordinating with the Active-Site Catalytic Metals in PPP5C.

LB-100 is an experimental cancer therapeutic with cytotoxic activity against cancer cells in culture and antitumor activity in animals. The first phase I trial (NCT01837667) evaluating LB-100 recently concluded that safety and efficacy parameters are favorable for further clinical testing. Although LB-100 is widely reported as a specific inhibitor of serine/threonine phosphatase 2A (PP2AC/), we could find no experimental evidence in the published literature demonstrating the specific engagement of LB-100 with PP2A , in cultured cells, or in animals.

Analgesic Effects of the GIRK Activator, VU0466551, Alone and in Combination with Morphine in Acute and Persistent Pain Models.

G protein-gated inwardly rectifying potassium (GIRK) channels are potassium-selective ion channels. As their name suggests, GIRK channels are effectors of G G protein-couple receptors whereby activation of these GPCRs leads to increased GIRK channel activity resulting in decreased cellular excitability. In this way, GIRK channels play diverse roles in physiology as effectors of G-coupled GPCRs: peacemaking in the heart rate, modulation of hormone secretion in endocrine tissues, as well as numerous CNS functions including learning, memory, and addiction/reward.

REPRODUCTIVE HORMONE PATTERNS IN MALE AND FEMALE COWNOSE RAYS ( RHINOPTERA BONASUS) IN AN AQUARIUM SETTING AND CORRELATION TO ULTRASONOGRAPHIC STAGING.

Reproductive management of cownose rays ( Rhinoptera bonasus) under professional care plays an important role in conservation of the species, but hormone and ultrasonographic analyses of their 12-mo reproductive cycle have not been documented previously. Plasma reproductive hormone concentrations (17B-estradiol, progesterone, testosterone, and androstenedione) were measured monthly via radioimmunoassay for 1 yr in an aquarium-managed population of adult females ( n = 15) and males ( n = 5). Ultrasounds of the uterus were performed each month at the time of sample collection to identify gestation stage (0-5) based on a previously developed in-house staging system.

Selective Activation of N,N'-Diacyl Rhodamine Pro-fluorophores Paired with Releasing Enzyme, Porcine Liver Esterase (PLE).

This study reports the synthesis and testing of a family of rhodamine pro-fluorophores and an enzyme capable of converting pro-fluorophores to Rhodamine 110. We prepared a library of simple N,N'-diacyl rhodamines and investigated porcine liver esterase (PLE) as an enzyme to activate rhodamine-based pro-fluorophores. A PLE-expressing cell line generated an increase in fluorescence rapidly upon pro-fluorophore addition demonstrating the rhodamine pro-fluorophores are readily taken up and fluorescent upon PLE-mediated release.

Serine/threonine phosphatase 5 (PP5C/PPP5C) regulates the ISOC channel through a PP5C-FKBP51 axis.

Pulmonary endothelial cells express a store-operated calcium entry current ( I), which contributes to inter-endothelial cell gap formation. I is regulated by a heterocomplex of proteins that includes the immunophilin FKBP51. FKBP51 inhibits I by mechanisms that are not fully understood.

PP1:Tautomycetin Complex Reveals a Path toward the Development of PP1-Specific Inhibitors.

Selective inhibitors for each serine/threonine phosphatase (PPP) are essential to investigate the biological actions of PPPs and to guide drug development. Biologically diverse organisms (e.g.

Discovery and Characterization of 1H-Pyrazol-5-yl-2-phenylacetamides as Novel, Non-Urea-Containing GIRK1/2 Potassium Channel Activators.

The G protein-gated inwardly-rectifying potassium channels (GIRK, K3) are a family of inward-rectifying potassium channels, and there is significant evidence supporting the roles of GIRKs in a number of physiological processes and as potential targets for numerous indications. Previously reported urea containing molecules as GIRK1/2 preferring activators have had significant pharmacokinetic (PK) liabilities. Here we report a novel series of 1H-pyrazolo-5-yl-2-phenylacetamides in an effort to improve upon the PK properties.

Fifty Shades of African Lightness: A Bio-psychosocial Review of the Global Phenomenon of Skin Lightening Practices.

Skin-lightening is an aesthetic practice of global concern. By adopting a biopsycho-social approach, we consider the interplay between the biological, psychological and social factors that underpin the circulation and consumption of skin lighteners in South Africa. This paper reflects on biological aspects of skin lightening, interpersonal relationships, individual beliefs and expectations about the maintenance of health and well being that informs cosmetic practices.

Crystal structures and mutagenesis of PPP-family ser/thr protein phosphatases elucidate the selectivity of cantharidin and novel norcantharidin-based inhibitors of PP5C.

Cantharidin is a natural toxin and an active constituent in a traditional Chinese medicine used to treat tumors. Cantharidin acts as a semi-selective inhibitor of PPP-family ser/thr protein phosphatases. Despite sharing a common catalytic mechanism and marked structural similarity with PP1C, PP2AC and PP5C, human PP4C was found to be insensitive to the inhibitory activity of cantharidin.

Challenges in Exploratory Methods for Tuberculosis Research in South Africa.

Haunted by a legacy of apartheid governance that left millions in material poverty, South Africa has among the highest tuberculosis (TB) morbidity and mortality rates in the world. Our Social Markers of TB research project shared a vision of working with ethnographic research methods to understand TB-infected persons, their families, care providers, and social networks. We argue that felt and enacted TB stigma and the related HIV-TB stigma impaired our ability to collect the necessary data for a full portrait of TB-infected persons and their lived conditions.

Development and validation of a thallium flux-based functional assay for the sodium channel NaV1.7 and its utility for lead discovery and compound profiling.

Ion channels are critical for life, and they are targets of numerous drugs. The sequencing of the human genome has revealed the existence of hundreds of different ion channel subunits capable of forming thousands of ion channels. In the face of this diversity, we only have a few selective small-molecule tools to aid in our understanding of the role specific ion channels in physiology which may in turn help illuminate their therapeutic potential.

UV-B radiation impacts shoot tissue pigment composition in Allium fistulosum L. cultigens.

Plants from the Allium genus are valued worldwide for culinary flavor and medicinal attributes. In this study, 16 cultigens of bunching onion (Allium fistulosum L.) were grown in a glasshouse under filtered UV radiation (control) or supplemental UV-B radiation [7.

Synthesis, structural and spectroscopic characterization, catalytic properties, and thermal transformations of new cyclic di- and trisiloxanediolato tantalum complexes.

The reaction between Ta(OEt)5 and 1,1,3,3-tetramethyl-1,3-disiloxanediol, (HOSiMe2OSiMe2OH), leads to new siloxy complexes in which the dimeric nature of Ta(OEt)5 is maintained with both bridging ethoxide and disiloxanediolato bridges. With equal amounts of the reagents, two terminal OEt groups are replaced to form [Ta(OEt)2]2(mu-OEt)2(mu-OSiMe2OSiMe2O)2, 1, whereas with an excess of diol, the remaining terminal OEt groups are also replaced but with a trisiloxanediolato unit to form [Ta(OSiMe2OSiMe2OSiMe2O)]2(mu-OEt)2(mu-OSiMe2OSiMe2O)2, 2. Complexes 1 and 2 catalyze the transformation of HOSiMe2OSiMe2OH to polysiloxanes.

Three new phases in the K/Cu/Th/S system: KCuThS3, K2Cu2ThS4, and K3Cu3Th2S7.

Synthetic exploration of K/Cu/Th/S quaternary phase space has yielded three new compounds: KCuThS3 (I), K2Cu2ThS4 (II), and K3Cu3Th2S7 (III). All three phases are semiconductors with optical band gaps of 2.95, 2.

Structural characterization of the first hydroxo-bridged plutonium compound, (PuO(2))(2)(IO(3))(mu(2)-OH)(3).

The hydrothermal reaction of a (239)Pu(IV) stock solution in the presence of iodic acid and 1 M KOH produces reddish-brown single crystals of (PuO(2))(2)(IO(3))(OH)(3). The structure consists of two-dimensional layers forming in the ac plane and is the first single-crystal structure of plutonium(VI) connected through hydroxide anions. The additional linkage of plutonium centers is completed through iodate ligands.

Synthesis and characterization of two quaternary thorium chalcophosphates: Cs4Th2P6S18 and Rb7Th2P6Se21.

Two new thorium chalcophosphates have been synthesized by the reactive flux method and characterized by single-crystal X-ray diffraction, diffuse reflectance, and Raman spectroscopy: Cs4Th2P6S18 (I); Rb7Th2P6Se21 (II). Compound I crystallizes as colorless blocks in the triclinic space group P1 (No. 2) with a = 12.

Synthesis and characterization of AU2Se6 (A = K, Cs).

Two new ternary uranium selenides, AU(2)Se(6) (A = K, Cs), were prepared using the reactive flux method. Single crystal X-ray diffraction was performed on single crystals. The compounds crystallize in the orthorhombic Immm space group, Z = 2.

Higher order speciation effects on plutonium L(3) X-ray absorption near edge spectra.

Pu L(3) X-ray near edge absorption spectra for Pu(0-VII) are reported for more than 60 chalcogenides, chlorides, hydrates, hydroxides, nitrates, carbonates, oxy-hydroxides, and other compounds both as solids and in solution, and substituted in zirconolite, perovskite, and borosilicate glass. This large database extends the known correlations between the energy and shape of these spectra from the usual association of the XANES with valence and site symmetry to higher order chemical effects. Because of the large number of compounds of these different types, a number of novel and unexpected behaviors are observed, such as effects resulting from the medium and disorder that can be as large as those from valence.

The effects of topical ocular application of 0.25% demecarium bromide on serum acetylcholinesterase levels in normal dogs.

Objective: To assess the effects of topical ocular application of 0.25% demecarium bromide on serum acetylcholinesterase (AChE) levels in normal dogs.

Animals: Nine adult mixed breed dogs weighing between 18 and 27 kg.