Investigating Transcriptional Control of Specialized Gene Expression in Plants

Specialized or secondary metabolism is a collection of pathways and small molecules that, while beneficial to an organism, are not strictly necessary for survival. Plants use secondary metabolites to, among other things, attract pollinators, defend against biotic and abiotic stressors, and form symbioses. Natural products from plants have seen an increase in scientific interest as many of these compounds have implications for human use. One of the main limitations in natural product research is the inability to produce relevant compounds in heterologous hosts or cell tissue culture, as some intermediate steps in the biosynthetic pathways are limited to a specific tissue or cell type. In this work, my collaborators and I work to address some of the larger challenges that come from this limitation, largely through the lens of transcriptional control of gene expression. My colleagues and I began by using machine learning in the model plant Arabidopsis thaliana to explore the primary determinants of tissue specific gene expression. A pair of predictive models were built using precise transcriptomic and chromatin accessibility data; models of this type—L1-regularized logistic regression models—allow the user to extract the factors determined to be important for making the predictions. We found that most of the highly weighted factors for both models are sequence motifs, with actively transcribed promoters having a general openness of the chromatin. Next, we investigated what factors affect biosynthesis of the chemotherapeutic compound vinblastine and its key intermediates in the medicinal plant Catharanthus roseus. Using a combination of metabolomics and gene expression analysis, we found that both plant variety and hormonal treatment are critical components in determining metabolite production levels. Additionally, we found that these factors have an impact on expression levels of master regulators and key biosynthetic pathway genes

Implementing a pilot leadership course for internal medicine residents: design considerations, participant impressions, and lessons learned

Background: Effective clinical leadership is associated with better patient care. We implemented and evaluated a pilot clinical leadership course for second year internal medicine residents at a large United States Academic Medical Center that is part of a multi-hospital health system. Methods: The course met weekly for two to three hours during July, 2013. Sessions included large group discussions and small group reflection meetings. Topics included leadership styles, emotional intelligence, and leading clinical teams. Course materials were designed internally and featured “business school style” case studies about everyday clinical medicine which explore how leadership skills impact care delivery. Participants evaluated the course’s impact and quality using a post-course survey. Questions were structured in five point likert scale and free text format. Likert scale responses were converted to a 1-5 scale (1 = strongly disagree; 3 = neither agree nor disagree; 5 = strongly agree), and means were compared to the value 3 using one-way T-tests. Responses to free text questions were analyzed using the constant comparative method. Results: All sixteen pilot course participants completed the survey. Participants overwhelmingly agreed that the course provided content and skills relevant to their clinical responsibilities and leadership roles. Most participants also acknowledged that taking the course improved their understanding of their strengths and weaknesses as leaders, different leadership styles, and how to manage interpersonal conflict on clinical teams. 88% also reported that the course increased their interest in pursuing additional leadership training. Conclusions: A clinical leadership course for internal medicine residents designed by colleagues, and utilizing case studies about clinical medicine, resulted in significant self-reported improvements in clinical leadership competencies. Electronic supplementary material The online version of this article (doi:10.1186/s12909-014-0257-2) contains supplementary material, which is available to authorized users

United on Sunday: The effects of secular rituals on social bonding and affect

Religious rituals are associated with health benefits, potentially produced via social bonding. It is unknown whether secular rituals similarly increase social bonding. We conducted a field study with individuals who celebrate secular rituals at Sunday Assemblies and compared them with participants attending Christian rituals. We assessed levels of social bonding and affect before and after the rituals. Results showed the increase in social bonding taking place in secular rituals is comparable to religious rituals. We also found that both sets of rituals increased positive affect and decreased negative affect, and that the change in positive affect predicted the change in social bonding observed. Together these results suggest that secular rituals might play a similar role to religious ones in fostering feelings of social connection and boosting positive affect

Blocking mu-opioid receptors inhibits social bonding in rituals

Religious rituals are universal human practices that play a seminal role in community bonding. In two experiments, we tested the role of mu-opioids as the active factor fostering social bonding. We used a mu-opioid blocker (naltrexone) in two double-blind studies of rituals from different religious traditions. We found the same effect across both studies, with naltrexone leading to significantly lower social bonding compared with placebo. These studies suggest that mu-opioids play a significant role in experiences of social bonding within ritual contexts

Biological mechanisms of aging predict age-related disease co-occurrence in patients

Genetic, environmental, and pharmacological interventions into the aging process can confer resistance to multiple age-related diseases in laboratory animals, including rhesus monkeys. These findings imply that individual mechanisms of aging might contribute to the co-occurrence of age-related diseases in humans and could be targeted to prevent these conditions simultaneously. To address this question, we text mined 917,645 literature abstracts followed by manual curation and found strong, non-random associations between age-related diseases and aging mechanisms in humans, confirmed by gene set enrichment analysis of GWAS data. Integration of these associations with clinical data from 3.01 million patients showed that age-related diseases associated with each of five aging mechanisms were more likely than chance to be present together in patients. Genetic evidence revealed that innate and adaptive immunity, the intrinsic apoptotic signaling pathway and activity of the ERK1/2 pathway were associated with multiple aging mechanisms and diverse age-related diseases. Mechanisms of aging hence contribute both together and individually to age-related disease co-occurrence in humans and could potentially be targeted accordingly to prevent multimorbidity

Depression and Anxiety among Iraqi Women: A Systematic Review

Background and objective: Maternal mental health is considered an important subject among leading public health experts. Women are two to three times more likely to be diagnosed with mental illness compared to men. According to the World Health Organization, depression will be the biggest contributor to burden of disease among women by 2020. Chronic stress, experiencing war, and history of abuse are associated with mental illness. Iraq has experienced years of challenging circumstances due to the political and social environment as well as physical barriers to health care services. This paper presents findings from literature about mental illness among Iraqi women. Methods: A comprehensive literature review was conducted using PubMed, Google Scholar, and EBSCO Academic Search Complete to identify studies focused on mental illness in Iraq. Search terms included: maternal, anxiety, depression, Iraq, Middle Eastern and North African region, and women. Cross-sectional, cohort, and case-control studies were included. Results: Five papers were found that focused exclusively on mental illness in Iraq. Two described maternal mental illness and three focused on mental illness in the general population, with two of the three including information specific to women. Results suggest that the rate of mental illness among Iraqi women is not different from women in other countries. However, because there is a difference of seven years between the Iraqifocused study and other global studies, additional new research is required to best compare rates. Interestingly, Iraqi women experience maternal mental illness at higher rates than other women. While the global average rate for mental illness in pregnancy or the postpartum period is estimated at 15-20%, 37.5% of Iraqi women experience anxiety and 28.5% experience depression. Conclusion: Additional study focusing on women’s health and maternal mental health is necessary to describe women at highest risk for mental illness and to inform strategies

Policy Recommendations for Meeting the Grand Challenge to Ensure Healthy Development for All Youth

This brief was created forSocial Innovation for America’s Renewal, a policy conference organized by the Center for Social Development in collaboration with the American Academy of Social Work & Social Welfare, which is leading theGrand Challenges for Social Work initiative to champion social progress. The conference site includes links to speeches, presentations, and a full list of the policy briefs

The calcilytic agent NPS 2143 rectifies hypocalcemia in a mouse model with an activating calcium-sensing-receptor (CaSR) mutation:relevance to autosomal dominant hypocalcemia type 1 (ADH1)

Autosomal dominant hypocalcemia type 1 (ADH1) is caused by germline gain-of-function mutations of the calcium-sensing receptor (CaSR) and may lead to symptomatic hypocalcemia, inappropriately low serum parathyroid hormone (PTH) concentrations and hypercalciuria. Negative allosteric CaSR modulators, known as calcilytics, have been shown to normalise the gain-of-function associated with ADH-causing CaSR mutations in vitro and represent a potential targeted therapy for ADH1. However, the effectiveness of calcilytic drugs for the treatment of ADH1-associated hypocalcemia remains to be established. We have investigated NPS 2143, a calcilytic compound, for the treatment of ADH1 by in vitro and in vivo studies involving a mouse model, known as Nuf, which harbors a gain-of-function CaSR mutation, Leu723Gln. Wild-type (Leu723) and Nuf mutant (Gln723) CaSRs were expressed in HEK293 cells and the effect of NPS 2143 on their intracellular calcium responses determined by flow cytometry. NPS 2143 was also administered as a single intraperitoneal bolus to wild-type and Nuf mice and plasma concentrations of calcium and PTH, and urinary calcium excretion measured. In vitro administration of NPS 2143 decreased the intracellular calcium responses of HEK293 cells expressing the mutant Gln723 CaSR in a dose-dependent manner, thereby rectifying the gain-of-function associated with the Nuf mouse CaSR mutation. Intraperitoneal injection of NPS 2143 in Nuf mice led to significant increases in plasma calcium and PTH without elevating urinary calcium excretion. These studies of a mouse model with an activating CaSR mutation demonstrate NPS 2143 to normalize the gain-of-function causing ADH1, and improve the hypocalcemia associated with this disorder