MOLECULAR MECHANISMS FOR REGULATION OF GENE EXPRESSION BY LYSOPHOSPHATIDIC ACID IN OVARIAN CARCINOMA CELLS

Lysophosphatidic acid (LPA) is a potent bioactive phospholipid mediator that functions through multiple G protein couple receptors (GPCRs). LPA is elevated in ascites of ovarian cancer patients and is involved in growth, survival and metastasis of ovarian cancer cells. Gene promoter analyses revealed that some LPA-target genes share similar sets of binding sites for prominent transcription factors posing the possibility of a general mechanism for activation of their expression by LPA. Detailed investigation of the mechanisms of regulation of cyclooxygenase 2 (Cox-2), a paradigm of LPA-regulated genes, showed that LPA robustly upregulated the expression of Cox-2 in ovarian cancer cells through multiple receptors. LPA induced rapid increase in Cox-2 mRNA and significantly enhanced the stability of Cox-2 transcript with the support of mRNA binding protein HuR. The effects of LPA on Cox-2 transcriptional activation include essential involvement of transcription factor, C/EBP-b. Further studies on mechanisms of activation of C/EBP-b demonstrated that LPA increased phosphorylation, binding and transcriptional activities of C/EBP-b. In addition, activation of C/EBP-b and LPA-target genes required contribution from EGFR. This novel crosstalk between LPA GPCRs and EGFR in mediating transcription factors activation was further explored by investigating the mechanisms of activation of AP-1 and NF-kB by LPA. Activation of AP-1 family of proteins by LPA relied heavily on basal inputs from EGFR as inhibition of EGFR kinase activity with AG1478 caused significant loss of LPA-induced AP-1 expression, binding and transcription activities. Although HGF and other agonists of RTK only weakly stimulate LPA-target genes and transcription factors in ovarian cancer cells, costimulation with HGF in the presence of AG1478 restored LPA signals to both C/EBP-b and AP-1. This suggests an obligatory role for a RTK in LPA-induced transcriptional activation, not necessarily inputs from EGFR. Interestingly, inhibition of EGFR with AG1478 did not interfere with LPA-induced NF-kB activation. Pharmacological inhibition and molecular targeting revealed that only a subset of G proteins participate in the crosstalk between LPA receptors and EGFR. Collectively, these results demonstrate the presence of at least two signals downstream of LPA receptors: one dependent on basal RTK activity and another mediated directly by LPA GPCRs

Results of surgical excision of urethral prolapse in symptomatic patients

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139115/1/nau23232.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139115/2/nau23232_am.pd

Mechanistic Studies on the Electrochemistry of Glutathione and Homocysteine

This research work has investigated the electrochemistry of glutathione (GSH)and homocysteine (HCSH) in order to develop sensors for these biological thiols.Ru(bpy)33+ and IrCl62− have been used as mediators for the electrooxidation of GSH andHCSH because direct oxidation of these thiols is slow at most conventional electrodes.The electrochemical detection of GSH and HCSH has been pursued because of their biological roles. Concerted proton electron transfer (CPET) and stepwise proton electron transfer(PT/ET) pathways have been observed in the electrooxidation of GSH and HCSH.Oxidation of GSH by Ru(bpy)33+ carried out in deuterated and undeuterated buffered (pH= pD = 5.0) and unbuffered solutions (pH = pD 5.0−9.0) indicates a CPET pathway. AtpH 7.0 buffered solution, the involvement of the buffer was obvious, with rate increasing as the buffer concentration increases − an indication of a general base catalysis. The oxidation of GSH by IrCl62− follows through CPET at pH 7.0 when the optimum concentration of the buffer is established. The plot of the rate vs. buffer concentration gave a curvature at lower buffer concentration and then a plateau at higher concentration,which implies a change in the rate determining step as the buffer concentration increases.At lower buffer concentration, proton transfer was seen to be the rate determining step asthe reduction current increases upon scan rate increase. In the oxidation of HCSH by IrCl62−, CPET was observed at pH = pD values of7.0 and 8.0, whereas PT/ET was seen at pH = pD values of 9.0 and 10. Increase in the buffer concentration at pH 7.0 revealed the contribution of the buffer, in that, the oxidation proceeds more efficiently, seeing that the catalytic peak current shifts more negatively and the peak broadness diminishes. Increase in the temperature for the electrooxidation of HCSH resulted in increase in the rate

A FRACTIONAL ORDER HIV/AIDS MODEL USING CAPUTO-FABRIZIO OPERATOR

Background: HIV is a virus that is directed at destroying the human immune system thereby exposing the human body to the risk of been affected by other common illnesses and if it is not treated, it generates a more chronic illness called AIDS. Materials and Methods: In this paper, we employed the fixed-point theory in developing the uniqueness and existence of a solution of fractional order HIV/AIDS model having Caputo-Fabrizio operator. This approach adopted in this work is not conventional when solving biological models by fractional derivatives. Results: The results showed that the model has two equilibrium points namely, disease-free, and endemic equilibrium points, respectively. We showed conditions necessitating the existence of the endemic equilibrium point and showed that the disease-free equilibrium point is locally asymptotically stable. We also tested the stability of our solution using the iterative Laplace transform method on our model which was also shown stable agreeing with the disease-free equilibrium Conclusions: Numerical simulations of our model showed clear comparison with our analytical results. The numerical solutions show that given fractional operator like the Caputo-Fabrizio operator, it is less noisy and hence plays a major role in making a precise decision and gives room or opportunity (‘freedom’) to use data of specific patients as the model can be easily adjusted to accommodate this, as it a better fit for the patients’ data and provide meaningful predictions. Finally, the result showed the advantage of using fractional order derivative in the analysis of the dynamics of HIV/AIDS over th

Postdoctoral Opportunities for Nursing PhD Graduates: A Resource Guide

Before completing a nursing PhD program, doctoral students are encouraged to seek out and apply for a position in one of many, often highly competitive postdoctoral programs. These programs include the more traditional National Institutes of Health (NIH) funded experiences, such as the T32, as well as the nontraditional institution funded positions, including the associate faculty role. Graduates often need guidance on which postdoctoral programs are available, the resources each program offers to promote development of the applicant’s program of research, the disadvantages of each program, and what each program uses as benchmarks for success. This article summarizes both traditional and nontraditional postdoctoral positions including the T32, F32, F99/K00, T90/R90, research supplements, associate faculty, research associate, and hospital-affiliated postdoctoral positions. This article updates previous papers describing postdoctoral opportunities and offers a starting place to aide PhD students planning their postgraduate activities in seeking and evaluating these positions

Nonlinear analysis of a fractional reaction diffusion model for tumour invasion

Mathematical models in general an

COVID-19-related suicides in Bangladesh due to lockdown and economic factors: case study evidence from media reports

The incidence and mortality of the coronavirus-2019 disease (COVID-19) have increased dramatically around the world. The effects of COVID-19 pandemic are not limited to health, but also have a major impact on the social and economic aspects. Meanwhile, developing and less developed countries are arguably experiencing more severe crises than developed countries, with many small and medium-sized businesses being disrupted and even bankrupt (Fernandes 2020). Consequently, some individuals’ mental health is very fragile (Lin 2020). Sahoo et al. (2020) reported some of the psychological consequences in India (the neighboring country of Bangladesh) including self-harm due to COVID-19 misinformation. Moreover, impacts on mental health (e.g., depression, anxiety, panic, and traumatic stress) can also occur due to the lack of accurate information (Rajkumar 2020; Sahoo et al. 2020; Tandon 2020). In addition, pandemic-related restraints (e.g., spatial distancing, isolation, home quarantine, etc.) is impacting on economic sustainability and well-being, which may induce psychological mediators, such as sadness, worry, fear, anger, annoyance, frustration, guilt, helplessness, loneliness, and nervousness (Mukhtar 2020; Mamun and Griffiths 2020a). These mediators are also distinctive features of psychological suffering that individuals can experience during and after pandemics (Ahorsu et al. 2020; Pakpour and Griffiths 2020). Without early economic interventions, such mental health issues can facilitate suicidal behaviors among some individuals (Arafat and Mamun 2019; Mamun and Griffiths 2020b, c; Jahan et al. 2020), because economic recession, unemployment, and poverty are strongly associated with severe psychological comorbidities such as suicidal behaviors (Goldman-Mellor et al. 2010; Oyesanya et al. 2015; Rafi et al. 2019). There is one prior study that has examined COVID-19-related suicide in Bangladesh (Mamun and Griffiths 2020a)

Cyclic AMP increases COX-2 expression via mitogen-activated kinase in human myometrial cells

Cyclic AMP (cAMP) is the archetypal smooth muscle relaxant, mediating the effects of many hormones and drugs. However, recently PGI2, acting via cAMP/PKA, was found to increase contraction-associated protein expression in myometrial cells and to promote oxytocin-driven myometrial contractility. Cyclo-oxygenase-2 (COX-2) is the rate-limiting enzyme in prostaglandin synthesis, which is critical to the onset and progression of human labour. We have investigated the impact of cAMP on myometrial COX-2 expression, synthesis and activity. Three cAMP agonists (8-bromo-cAMP, forskolin and rolipram) increased COX-2 mRNA expression and further studies confirmed that this was associated with COX-2 protein synthesis and activity (increased PGE2 and PGI2 in culture supernatant) in primary cultures of human myometrial cells. These effects were neither reproduced by specific agonists nor inhibited by specific inhibitors of known cAMP-effectors (PKA, EPAC and AMPK). We then used shRNA to knockdown the same effectors and another recently described cAMP-effector PDZ-GEF1-2, without changing the response to cAMP. We found that MAPK activation mediated the cAMP effects on COX-2 expression and that PGE2 acts through EP-2 to activate MAPK and increase COX-2. These data provide further evidence in support of a dual role for cAMP in the regulation of myometrial function

Effect of acute citalopram on self-referential emotional processing and social cognition in healthy volunteers

This study was funded by the UK National Productivity Investment Fund awarded to C.H. through the GW4 BioMed Medical Research Council Doctoral Training Partnership. This study was supported by the National Institute for Health Research (NIHR) Oxford Health Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR or the Department of Health. ICMJE forms are in the supplementary material, available online at https://doi.org/10.1192/bjo.2020.107.Peer reviewedPublisher PD