Novel Modulators of Rho Transcriptional Signaling in Cancer.

Rho A and Rho C, members of the Rho GTPase family, have been found to have important roles in the metastases of multiple cancers, including melanoma, prostate, and breast cancer. While Rho GTPases are known to have effects on cell morphology, recent evidence has also demonstrated their ability to affect gene transcription. Many of the current inhibitors of the Rho pathway focus on targeting downstream effectors. However, there are few drugs that target gene transcriptional modulation. Using a cell-based dual Firefly and TK-Renilla luciferase assay, our collaborators in the Neubig laboratory identified a small molecule (1423) that inhibited RhoA/C-stimulated gene expression. Compound 1423 was shown to significantly inhibit gene expression, as well as inhibit the proliferation of a highly metastatic melanoma line and the invasion of PC-3 prostate cancer cells. However, the compound was found to have modest selectivity and significant cytotoxicity. To improve these properties, we examined structure-activity relationships through the synthesis and evaluation of over 100 analogs, focusing on bioisosteric replacement of amide bonds and conformational restriction. We were successful at identifying compounds with improved selectivity for inhibition of RhoA/C-mediated gene transcription and reduced cytotoxicity in comparison to 1423. Finally, we prepared a variety of affinity reagents, which may ultimately provide a novel target for anti-metastatic therapies for cancer. In total, this work advanced 1423 analogs as new inhibitors of the Rho transcriptional signaling pathway.PHDMedicinal ChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/96163/1/jlbe_1.pd

Effect of work boot type on work footwear habits, lower limb pain and perceptions of work boot fit and comfort in underground coal miners

Lower limb injuries are highly prevalent in underground coal mining. Wearing gumboots with inadequate ankle support was thought to contribute to these injuries. Despite the uptake of leather lace-up boots, which provide more ankle support, no recent research could be found investigating the effect of this alternative work boot in underground coal mining. Consequently, this study aimed to determine whether boot type (gumboot, leather lace-up boot) influenced work footwear habits, foot problems, lower limb pain, lower back pain, or perceptions of work boot fit and comfort in underground coal miners. Chi-squared tests were applied to 358 surveys completed by underground coal miners to determine whether responses differed significantly (p \u3c 0.05) according to boot-type. There were no significant between-boot differences in regards to the presence of foot problems, lower limb pain or lower back pain. However, the types of foot problems and locations of foot pain differed according to boot type. Gumboot wearers were also more likely to state that their work boot comfort was either uncomfortable or indifferent, their work boot fit was poor and their current boot did not provide enough support. The introduction of more structured leather lace-up boots appears to have positively influenced the support and fit provided by mining work boots, although foot problems, lower limb pain and lower back pain continue to be reported. Further investigation is recommended to identify which specific boot design features caused these observed differences in work boot fit, comfort and locations of foot pain and how these design features can be manipulated to create an underground coal mining work boot that is comfortable and reduces the high incidence of foot problems and lower limb pain suffered by underground coal miners

Improving management of small natural features on private lands by negotiating the science–policy boundary for Maine vernal pools

Vernal pools are far more important for providing ecosystem services than one would predict based on their small size. However, prevailing resource-management strategies are not effectively conserving pools and other small natural features on private lands. Solutions are complicated by tensions between private property and societal rights, uncertainties over resource location and function, diverse stakeholders, and fragmented regulatory authority. The development and testing of new conservation approaches that link scientific knowledge, stakeholder decision-making, and conservation outcomes are important responses to this conservation dilemma. Drawing from a 15-y history of vernal pool conservation efforts in Maine, we describe the coevolution of pool conservation and research approaches, focusing on how research-based knowledge was produced and used in support of management decisions. As management shifted from reactive, top-down approaches to proactive and flexible approaches, research shifted from an ecology-focused program to an interdisciplinary program based on social-ecological systems. The most effective strategies for linking scientific knowledge with action changed as the decision-makers, knowledge needs, and context for vernal pool management advanced. Interactions among stakeholders increased the extent to which knowledge was coproduced and shifted the objective of stakeholder engagement from outreach to research collaboration and development of innovative conservation approaches. New conservation strategies were possible because of the flexible, solutions-oriented collaborations and trust between scientists and decision-makers (fostered over 15 y) and interdisciplinary, engaged research. Solutions to the dilemma of conserving small natural features on private lands, and analogous sustainability science challenges, will benefit from repeated negotiations of the science-policy boundary

A day in the life of a Ménière’s patient:Understanding the lived experiences and mental health impacts of Ménière’s disease

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.Concepts of social practice are increasingly being used to understand experiences of everyday life, particularly in relation to consumption and healthy lifestyles. This paper builds on this in the context of lives disrupted and reshaped by chronic illness. It uses social practice theory to examine the lived experiences of individuals with Ménière’s disease; a long-term progressive vestibular disorder, defined by episodes of severe and debilitating vertigo, aural fullness, tinnitus and sensorineural hearing loss. Drawing on the findings of 20 in-depth narrative interviews with Ménière’s patients, and eight spousal/partner interviews, we explore the impacts of the condition on sensory, temporal, spatial and social dimensions of the body. In doing so, we highlight the intensely embodied sensory and emotional work required to maintain connections between the ‘competences’, ‘materials’ and ‘meanings’ that constitute and sustain the performance of both mundane and meaningful social practices over time. As connections between these elements of social practice are disrupted during more active phases of the condition, affected individuals may be defected from old practices and recruited to new ones, often requiring both time and social support to find meaning or pleasure in these alternative ways of being in the world.Many thanks go to all the study participants for sharing their experiences; Mr. David Whinney (Ear Nose and Throat Consultant at Royal Cornwall Hospital Treliske), Clinical Project Advisor; the Ménière’s Society for funding the study; and PenCLAHRC (the National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care South West Peninsula) for providing follow-on funding. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, the Department of Health or the Ménière’s Society. We would also like to thank the two anonymous reviewers for their valuable feedback on an earlier draft of this paper

Confirmed feasibility of a satellite tracker attachment method on small juvenile hawksbill turtles Eretmochelys imbricata

Satellite trackers can be used for studying sea turtle movement, illuminating their migrations and behaviours. However, many studies have focused on adult turtles, with uneven species representation, despite the importance of understanding movement and habitat use of turtles at all life-stages. Furthermore, few publications detail successful satellite tracker attachment methods, particularly for juveniles. Smaller-sized juvenile sea turtles often have an irregularly shaped carapace and are fast growing, rendering the attachment of rigid trackers in a safe and durable manner challenging. Juvenile hawksbill turtles’ specific carapace shape and imbricated scute arrangement further complicate satellite tracker attachment compared to juveniles of other turtle species. This study’s objective was to confirm the feasibility of an attachment method that would allow small-sized juvenile hawksbill turtles (~267-345 mm curved carapace length) to continue growing, without tracker loss or damage to underlying scutes. Replica trackers were made of resin (simulating Wildlife Computer Spot-387 trackers), and attached with epoxy, silicone and neoprene, using a technique modified from those used on neonate loggerheads and Kemp’s ridleys. Throughout the study (3.5 mo), replica trackers remained attached, the turtles grew up to 114% heavier and 25% longer, and all turtles appeared clinically healthy and active. Furthermore, all scutes were undamaged after tracker removal. As a critically endangered species, the paucity of data on hawksbill turtles, and specifically juveniles, can hinder evidence-based management decision-making. The improved ability to satellite track juvenile hawksbills can, therefore, help better our understanding of their ecology and inform management and conservation practices for this species

The microRNA landscape of MYCN-amplified neuroblastoma

MYCN gene amplification and upregulated expression are major hallmarks in the progression of high-risk neuroblastoma. MYCN expression and function in modulating gene synthesis in neuroblastoma is controlled at virtually every level, including poorly understood regulation at the post-transcriptional level. MYCN modulates the expression of various microRNAs including the miR-17-92 cluster. MYCN mRNA expression itself is subjected to the control by miRNAs, most prominently the miR-17-92 cluster that balances MYCN expression by feed-back regulation. This homeostasis seems disturbed in neuroblastoma where MYCN upregulation coincides with severely increased expression of the miR-17-92 cluster. In the presented study, we applied high-throughput next generation sequencing to unravel the miRNome in a cohort of 97 neuroblastomas, representing all clinical stages. Aiming to reveal the MYCN-dependent miRNome, we evaluate miRNA expression in MYCN-amplified as well as none amplified tumor samples. In correlation with survival data analysis of differentially expressed miRNAs, we present various putative oncogenic as well as tumor suppressive miRNAs in neuroblastoma. Using microRNA trapping by RNA affinity purification, we provide a comprehensive view of MYCN-regulatory miRNAs in neuroblastoma-derived cells, confirming a pivotal role of the miR-17-92 cluster and moderate association by the let-7 miRNA family. Attempting to decipher how MYCN expression escapes elevated expression of inhibitory miRNAs, we present evidence that RNA-binding proteins like the IGF2 mRNA binding protein 1 reduce miRNA-directed downregulation of MYCN in neuroblastoma. Our findings emphasize the potency of post-transcriptional regulation of MYCN in neuroblastoma and unravel new avenues to pursue inhibition of this potent oncogene.Publikationsfonds ML

CUREs in Biochemistry—Where We Are and Where We Should Go

Integration of research experience into classroom is an important and vital experience for all undergraduates. These course-based undergraduate research experiences (CUREs) have grown from independent instructor lead projects to large consortium driven experiences. The impact and importance of CUREs on students at all levels in biochemistry was the focus of a National Science Foundation funded think tank. The state of biochemistry CUREs and suggestions for moving biochemistry forward as well as a practical guide (supplementary material) are reported here

Emission-Line Galaxy Surveys as Probes of the Spatial Distribution of Dwarf Galaxies. I. The University of Michigan Survey

Objective-prism surveys which select galaxies on the basis of line-emission are extremely effective at detecting low-luminosity galaxies and constitute some of the deepest available samples of dwarfs. In this study, we confirm that emission-line galaxies (ELGs) in the University of Michigan (UM) objective-prism survey (MacAlpine et al. 1977-1981) are reliable tracers of large-scale structure, and utilize the depth of the samples to examine the spatial distribution of low-luminosity (M$_{B} >$ -18.0) dwarfs relative to higher luminosity giant galaxies (M$_{B} \leq$ -18.0) in the Updated Zwicky Catalogue (Falco et al. 1999). New spectroscopic data are presented for 26 UM survey objects. We analyze the relative clustering properties of the overall starbursting ELG and normal galaxy populations, using nearest neighbor and correlation function statistics. This allows us to determine whether the activity in ELGs is primarily caused by gravitational interactions. We conclude that galaxy-galaxy encounters are not the sole cause of activity in ELGs since ELGs tend to be more isolated and are more often found in the voids when compared to their normal galaxy counterparts. Furthermore, statistical analyses performed on low-luminosity dwarf ELGs show that the dwarfs are less clustered when compared to their non-active giant neighbors. The UM dwarf samples have greater percentages of nearest neighbor separations at large values and lower correlation function amplitudes relative to the UZC giant galaxy samples. These results are consistent with the expectations of galaxy biasing.Comment: 17 pages, 4 tables, 10 figures. Accepted for publication in the Ap

Infrared Properties of a Complete Sample of Star-Forming Dwarf Galaxies

We present a study of a large, statistically complete sample of star-forming dwarf galaxies using mid-infrared observations from the {\it Spitzer Space Telescope}. The relationships between metallicity, star formation rate (SFR) and mid-infrared color in these systems show that the galaxies span a wide range of properties. However, the galaxies do show a deficit of 8.0 \um\ polycyclic aromatic hydrocarbon emission as is apparent from the median 8.0 \um\ luminosity which is only 0.004 \lstarf\ while the median $B$-band luminosity is 0.05 \lstarb. Despite many of the galaxies being 8.0 \um\ deficient, there is about a factor of 4 more extremely red galaxies in the [3.6] $-$ [8.0] color than for a sample of normal galaxies with similar optical colors. We show correlations between the [3.6] $-$ [8.0] color and luminosity, metallicity, and to a lesser extent SFRs that were not evident in the original, smaller sample studied previously. The luminosity--metallicity relation has a flatter slope for dwarf galaxies as has been indicated by previous work. We also show a relationship between the 8.0 \um\ luminosity and the metallicity of the galaxy which is not expected given the competing effects (stellar mass, stellar population age, and the hardness of the radiation field) that influence the 8.0 \um\ emission. This larger sample plus a well-defined selection function also allows us to compute the 8.0 \um\ luminosity function and compare it with the one for the local galaxy population. Our results show that below 10$^{9}$ $L$\solar, nearly all the 8.0 \um\ luminosity density of the local universe arises from dwarf galaxies that exhibit strong \ha\ emission -- i.e., 8.0 \um\ and \ha\ selection identify similar galaxy populations despite the deficit of 8.0 \um\ emission observed in these dwarfs.Comment: 13 pages, 11 figures, Published in Ap

Challenges in lifestyle and community interventions research

Earlier this year the BMC portfolio was enriched by a new journal BMC Obesity. Here, we present the aims and objectives of the section on Lifestyle and Community Interventions. Innovative research is needed. Preventing or managing obesity requires addressing different determinants across multiple levels where diverse levers and stakeholders can play a critical role. Interactions of these determinants within and between systems need to be studied. How to leverage, manage and measure this complexity underlies the innovation that is needed in the next generation of obesity interventions. The ambition of the Lifestyle and Community Interventions section is to provide a space for innovative research, including research that falls outside the traditional comfort zone. We welcome studies of heterogeneous designs, including those of qualitative, quantitative, mixed and systems methodologies. Studies of interest include not only outcomes research of interventions but also process evaluation, cost effectiveness or cost-benefit analysis, and implementation and dissemination research. Innovations that integrate diverse intervention levers or combine primary and secondary levels of prevention are particularly encouraged. The general aim of BMC Obesity’ s Lifestyle and Community Interventions section is to advance our ability to decide on what combinations of approaches will be required to effectively and equitably prevent obesity