Nephrogenic Diabetes Insipidus – The Novelly Potential Therapeutic Drugs

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CONTRACT INCENTIVES AND EXCESSIVE NITROGEN USE IN AGRICULTURE

This study examines incentives for input use under tournament contracts. We analyze implications of contract design for nitrate-based environmental externalities generated by agricultural producers. Outcomes are compared from contracts awarded by tournament to those from fixed-payment contracts. Our findings show contract insecurity can distort input use. The model developed in this analysis is applied to a region of the U.S. where tournament-based production is prevalent and groundwater contamination is a problem. We find contract insecurity increases nitrogen use by about 12%, resulting in a 17% increase in nitrate leaching. Implications for contract modification to reduce environmental externalities while maintaining contract incentives are discussed.Crop Production/Industries,

Innate Immune Sensing of a Bacterial Pore-forming Toxin: The Role of the NLRP3 Inflammasome

Gram-positive bacterial infections have risen over recent years and current antibiotic treatments are not always sufficient to control these infections. Specifically, antibiotics target bacteria themselves, but not the bacterially secreted proteins that contribute to bacterial pathogenesis and host tissue damage (i.e. virulence factors). These virulence factors may linger after bacteria are eradicated, making their interaction with the host important to understand for the development of novel therapeutics to supplement antibiotics. One class of virulence factors studied in our laboratory is a large pore-forming toxin family known as the cholesterol-dependent cytolysins (CDC). These exotoxins are secreted by over twenty species of gram-positive bacteria and have been shown to contribute to the virulence of the bacteria that secrete them. We are interested in exploring the pathways initiated by CDC in host innate immune cells such as macrophages and dendritic cells. These cells would be expected to first encounter CDC after bacterial infection and therefore, pathways initiated in these cells by CDC could be targeted for the benefit of the host.We have characterized the mechanism of mature IL-1beta secretion induced by CDC tetanolysin O (TLO) from LPS-primed murine bone marrow-derived macrophages (BMDM). This process is dependent on TLO dose and relies on the caspase-1-containing NLRP3 inflammasome as well as associated signaling pathways, which include ion fluxes and iPLA2 and cathepsin B activities. Furthermore, TLO induces different cell death programs in BMDM that are dependent on TLO dose. High TLO doses induce conventional necrotic cell death while low TLO doses cause NLRP3 inflammasome-dependent and cathepsin B-dependent necrotic cell death that is characterized by lactate dehydrogenase (LDH) and high mobility group box 1 (HMGB1) release. Both IL-1beta and HMGB1 are pro-inflammatory cytokines that contribute to inflammation and may be useful therapeutic targets, in addition to the inflammasome. Finally, susceptibility to CDC-induced cell killing varies based on cell type. In order to determine pathways that might explain these differences, we created a variant murine dendritic cell line resistant to pore formation. Though this cell line has been characterized to some degree, future studies will be needed to pinpoint the pathways responsible for the phenotype observed

E-Professionalism in Undergraduate Nursing Students

Nursing students have been charged criminally or expelled from undergraduate programs for inappropriate social media use. The literature has heavily criticized nursing students for unprofessional use of social media and a lack E-professionalism. The concept of E-professionalism within healthcare is relatively new as more providers use social media, thus it has quickly become an ethical and specialized challenge for nursing. The purpose of this research was to explore E-Professionalism among undergraduate nursing students at a midsize South Western Ontario university. A sample of 136 nursing students participated in this study. Subjects could identify blatant examples of appropriate and inappropriate of social media use but struggled with less obvious violations. Nursing students also lacked the ability to identify regulatory bodies or universities stances on E-professionalism, suggesting that students are learning about E-professionalism outside the academic settings, which may become troublesome when trying to adhere to professional regulations. Changes in current nursing educational practices, surrounding E-professionalism, are suggested and may ultimately contribute to decreased issues with inappropriate social media use for future Registered Nurses

The Landscape of Long Non-Coding RNA Dysregulation and Clinical Relevance in Muscle Invasive Bladder Urothelial Carcinoma.

Bladder cancer is one of the most common cancers in the United States, but few advancements in treatment options have occurred in the past few decades. This study aims to identify the most clinically relevant long non-coding RNAs (lncRNAs) to serve as potential biomarkers and treatment targets for muscle invasive bladder cancer (MIBC). Using RNA-sequencing data from 406 patients in The Cancer Genome Atlas (TCGA) database, we identified differentially expressed lncRNAs in MIBC vs. normal tissues. We then associated lncRNA expression with patient survival, clinical variables, oncogenic signatures, cancer- and immune-associated pathways, and genomic alterations. We identified a panel of 20 key lncRNAs that were most implicated in MIBC prognosis after differential expression analysis and prognostic correlations. Almost all lncRNAs we identified are correlated significantly with oncogenic processes. In conclusion, we discovered previously undescribed lncRNAs strongly implicated in the MIBC disease course that may be leveraged for diagnostic and treatment purposes in the future. Functional analysis of these lncRNAs may also reveal distinct mechanisms of bladder cancer carcinogenesis

Genetic Dissection of Cardiac Remodeling in an Isoproterenol-Induced Heart Failure Mouse Model.

We aimed to understand the genetic control of cardiac remodeling using an isoproterenol-induced heart failure model in mice, which allowed control of confounding factors in an experimental setting. We characterized the changes in cardiac structure and function in response to chronic isoproterenol infusion using echocardiography in a panel of 104 inbred mouse strains. We showed that cardiac structure and function, whether under normal or stress conditions, has a strong genetic component, with heritability estimates of left ventricular mass between 61% and 81%. Association analyses of cardiac remodeling traits, corrected for population structure, body size and heart rate, revealed 17 genome-wide significant loci, including several loci containing previously implicated genes. Cardiac tissue gene expression profiling, expression quantitative trait loci, expression-phenotype correlation, and coding sequence variation analyses were performed to prioritize candidate genes and to generate hypotheses for downstream mechanistic studies. Using this approach, we have validated a novel gene, Myh14, as a negative regulator of ISO-induced left ventricular mass hypertrophy in an in vivo mouse model and demonstrated the up-regulation of immediate early gene Myc, fetal gene Nppb, and fibrosis gene Lgals3 in ISO-treated Myh14 deficient hearts compared to controls

Investigating in vitro anticancer properties of Malaysian rainforest plants: Acalypha wilkesiana Müll, Arg. Archidendron ellipticum (Blume) Hassk. Duabanga grandiflora Walp. Pseuduvaria macrophylla (Oliv.) Merr

Malaysia is ranked the 12th richest country for its biological diversity of plant species by the Convention on Biological Diversity and this project aims to contribute to existing knowledge of Malaysian rainforest plants, Acalypha wilkesiana, Duabanga grandiflora, Archidendron ellipticum and Pseuduvaria macrophylla, for the treatment of cancer. A. wilkesiana (Euphorbiaceae) whole plant EtOH and EtOAc extracts inhibited growth of breast cancer MDA-MB-468 cells (GI50: 22.7 and 15.9 μg/ml) and revealed preference over non-transformed MRC5 fibroblasts (GI50: 46.6 and 53.3 μg/ml, respectively). EtOH and HEX extracts were able to impair cell survival and colony-forming abilities in MDA-MB-468 cells after 24 h. Detection of increased MDA-MB-468 sub-G1 cell populations after 48 h treatment to EtOH and HEX extracts, suggest that cells may be undergoing apoptosis. A. ellipticum (Leguminosae) crude polar bark and leaf extracts inhibited MDA-MB-468 cell growth (GI50 of bark EtOH, EtOAc extracts: 1.7 and 40.4 μg/ml, respectively and leaf EtOH and EtOAc extracts: 9.3 and 9.3 μg/ml, respectively). However, MDA-MB-468 cell growth was unaffected by HEX extracts (> 200 μg/ml). Separation of crude extracts revealed sub-fractions of greater activity, in particular a 50-fold enhanced potency in sub-fractions of HEX extract thus overcoming masking or antagonistic activity in the crude mixture. Following 24 h, bark and leaf extracts impaired MDA-MB-468 cells’ proliferative and colony-forming abilities at 1X and 2X GI50 values suggesting significant damage was induced leading to observed cellular senescence and inhibition of cell proliferation. After 48 h exposure to EtOH and HEX extracts, MDA-MB-468 cells accumulated cellular damage, possibly affecting microtubule functions resulted in activation of apoptosis as shown by increased of sub-G1 and G2/M MDA-MB-468 cell populations and presence of phosphatidyl serine on the outer membrane of cells. Modest levels of flavonoid and phenolic compounds were found in bark and leaf extracts, which correlated to moderate level of free radical scavenging activity observed. D. grandiflora (Lythraceae) bark and leaf extracts revealed growth inhibitory effects against colorectal cancer HCT116 cells (GI50 of bark Water, EtOH, EtOAc and HEX extracts: 42.4, 37.5, 21.69 and 28.9 μg/ml, respectively; leaf Water, EtOH, EtOAc and HEX extracts GI50: 38.0, 40.9, 24.7 and > 200 μg/ml, respectively). Separation of crude bark extracts resulted in fractions of greater activity, whereas separation of leaf extracts revealed reduced activity suggesting synergistic activity in the mixture. Following 24 h, bark and leaf extracts impaired HCT116 cells’ proliferative and colony-forming abilities at 1X and 2X GI50 values indicating significant damage incurred leading to observed cellular senescence and cell proliferation inhibition. After 48 h exposure to D. grandiflora extracts, increased sub-G1 HCT116 cell population and a G1/0 cell cycle block accompanied by decreased S and G2/M cell populations were measured. Detection of phosphatidyl serine on cells’ outer membrane and activated apoptotic caspase 3 protein confirmed D. grandiflora extracts induced apoptosis. Highest levels of flavonoid and phenolic compounds were found in polar bark and leaf D. grandiflora extracts, which may correlate to the highest free radical scavenging activity measured. P. macrophylla (Annonaceae) extracts collectively displayed greatest HCT116 cell growth inhibition (EtOH, EtOAc and HEX extracts GI50: 5.2, 1.6 and 5.4 μg/ml) and separation of EtOH and EtOAc extracts revealed even greater activity in sub-fractions. After 24 h, polar extracts at 2X GI50 completely impaired HCT116 cells’ proliferative and colony-forming abilities suggesting extract-induced significant damage led to inability of cells to proliferate. Analysis of cell cycle distribution revealed increased sub-G1 HCT116 cell population and high levels of early apoptotic HCT116 cells following 48 h exposure to P. macrophylla extracts coupled with detection of caspase 3 activation confirming execution of apoptosis. Modest levels of flavonoid and phenolic compounds were detected in EtOH, EtOAc and HEX extracts, which correlated to modest free radical scavenging activity. The findings in this project should justify further separation and in vitro investigations

Large-scale land acquisitions in Zambia: Evidence to inform policy

Land in Zambia plays a vital role in sustaining livelihoods, ensuring food security and reducing poverty. If people are not able to access land (including communal interests, such as lands for grazing or access to water resources), they will be unable to secure rights over their land, participate in decisions over land that they occupy or use, or undertake diverse activities that improve their livelihoods, such as farming and fishing. This can contribute to increased poverty levels and may lead to food insecurity. Promoting good land governance in the process of allocating land for development and managing the different interests and competing claims to land is essential in protecting the livelihoods of many Zambians who depend on land