Recognition of abasic sites and single base bulges in DNA by a metalloinsertor

Abasic sites and single base bulges are thermodynamically destabilizing DNA defects that can lead to cancerous transformations if left unrepaired by the cell. Here we discuss the binding properties with abasic sites and single base bulges of Rh(bpy)_2(chrysi)^(3+), a complex previously shown to bind thermodynamically destabilized mismatch sites via metalloinsertion. Photocleavage experiments show that Rh(bpy)_2(chrysi)^(3+) selectively binds abasic sites with affinities of 1−4 × 10^6 M^(−1); specific binding is independent of unpaired base identity but is somewhat contingent on sequence context. Single base bulges are also selectively bound and cleaved, but in this case, the association constants are significantly lower (~10^5 M^(−1)), and the binding is dependent on both unpaired base identity and bulge sequence context. A wide variety of evidence, including strand scission asymmetry, binding enantiospecificity, and MALDI-TOF cleavage fragment analysis, suggests that Rh(bpy)_2(chrysi)^(3+) binds abasic sites, like mismatches, through insertion of the bulky chrysi ligand into the base pair stack from the minor groove side and ejection of the unpaired base. At single base bulge sites, a similar, though not identical, metalloinsertion mode is suggested. The recognition of abasic sites and single base bulges with bulky metalloinsertors holds promise for diagnostic and therapeutic applications

Targeting Abasic Sites and Single Base Bulges in DNA with Metalloinsertors

The site-specific recognition of abasic sites and single base bulges in duplex DNA by sterically expansive rhodium metalloinsertors has been investigated. Through DNA photocleavage experiments, Rh(bpy)_2(chrysi)^(3+) is shown to bind both abasic sites and single base bulges site-specifically and, upon irradiation, to cleave the backbone of the defect-containing DNA. Photocleavage titrations reveal that the metal complex binds DNA containing an abasic site with high affinity (2.6(5) × 10^6 M^(−1)), comparably to the metalloinsertor and a CC mismatch. The complex binds single base bulge sites with lower affinity (∼10^5 M^(−1)). Analysis of cleavage products and the correlation of affinities with helix destabilization suggest that Rh(bpy)_2(chrysi)^(3+) binds both lesions via metalloinsertion, as observed for Rh binding at mismatched sites, a binding mode in which the mismatched or unpaired bases are extruded from the helix and replaced in the base stack by the sterically expansive ligand of the metalloinsertor

A Qualitative Analysis of Gabapentin Misuse and Diversion Among People Who Use Drugs in Appalachian Kentucky

Gabapentin, an anticonvulsant and analgesic for postherpetic neuralgia, has been thought to have no abuse potential despite numerous published reports to the contrary. Gabapentin has been linked with impaired driving and opioid use, highlighting the need to more fully understand its risk profile. Thirty-three individuals reporting recent nonmedical use of gabapentin were recruited from two ongoing longitudinal studies of drug users in Appalachian Kentucky to participate in focus groups. Four sessions were held (two in the community and two in jail settings), during which participants responded to questions regarding their personal experiences with gabapentin misuse. Focus group participants were similar to other gabapentin users in the larger cohort studies with respect to demographics and drug use behaviors. Overall, the sample reported having initiated gabapentin more than 10 years earlier after having it prescribed for a legitimate, though generally off-label, medical indication (e.g., pain, anxiety, opioid detoxification). Participants reported use of gabapentin in combination with buprenorphine, other opioids, cocaine, and caffeine to produce sought-after central nervous system effects (e.g., muscle relaxation, pain reduction, sleep induction, feeling drunk, and feeling “high”). Focus group responses highlighted the low cost of gabapentin for the purpose of getting high and noted increasing popularity in the community, particularly over the last 2 years. Gabapentin was a prominent drug of abuse in two cohorts of the primarily opioid-using individuals. Providers should be aware of gabapentin’s abuse potential, and a reexamination of the need for scheduling is warranted

Incidence of falls among adults with cerebral palsy: a cohort study using primary care data

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154463/1/dmcn14444_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154463/2/dmcn14444-sup-0001-AppendixS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154463/3/dmcn14444.pd

Interrelationship between Sleep and Exercise: A Systematic Review

Although a substantial body of literature has explored the relationship between sleep and exercise, comprehensive reviews and definitive conclusions about the impact of exercise interventions on sleep are lacking. Electronic databases were searched for articles published between January 2013 and March 2017. Studies were included if they possessed either objective or subjective measures of sleep and an exercise intervention that followed the guidelines recommended by the American College of Sports Medicine. Thirtyfour studies met these inclusion criteria. Twenty-nine studies concluded that exercise improved sleep quality or duration; however, four found no difference and one reported a negative impact of exercise on sleep. Study results varied most significantly due to participants' age, health status, and the mode and intensity of exercise intervention. Mixed findings were reported for children, adolescents, and young adults. Interventions conducted with middle-aged and elderly adults reported more robust results. In these cases, exercise promoted increased sleep efficiency and duration regardless of the mode and intensity of activity, especially in populations suffering from disease. Our review suggests that sleep and exercise exert substantial positive effects on one another; however, to reach a true consensus, the mechanisms behind these observations must first be elucidated

Motivations for innovation in the built environment: new directions for research

Innovation in the built environment involves multiple actors with diverse motivations. Policy-makers find it difficult to promote changes that require cooperation from these numerous and dispersed actors and to align their sometimes divergent interests. Established research traditions on the economics and management of innovation pay only limited attention to stakeholder choices, engagement and motivation. This paper reviews the insights that emerge as research in these traditions comes into contact with work on innovation from sociological and political perspectives. It contributes by highlighting growing areas of research on user involvement in complex innovation, collective action, distributed innovation and transition management. To differing extents, these provide approaches to incorporate the motivations of different actors into theoretical understanding. These indicate new directions for research that promise to enrich understanding of innovation

Future making and visual artefacts : an ethnographic study of a design project

Current research on strategizing and organizing has explored how practitioners make sense of an uncertain future, but provides limited explanations of how they actually make a realizable course of action for the future. A focus on making rather than sensemaking brings into view the visual artefacts that practitioners use in giving form to what is ‘not yet’ – drawings, models and sketches. We explore how visual artefacts are used in making a realizable course of action, by analysing ethnographic data from an architectural studio designing a development strategy for their client. We document how visual artefacts become enrolled in practices of imagining, testing, stabilizing and reifying, through which abstract imaginings of the future are turned into a realizable course of action. We then elaborate on higher-order findings that are generalizable to a wide range of organizational settings, and discuss their implications for future research in strategizing and organizing. This paper contributes in two ways: first, it offers future making as an alternative perspective on how practitioners orient themselves towards the future (different from current perspectives such as foreseeing, future perfect thinking and wayfinding). Second, it advances our understanding of visual artefacts and their performativity in the making of organizational futures

Comprehensive resequence analysis of a 97 kb region of chromosome 10q11.2 containing the MSMB gene associated with prostate cancer

Genome-wide association studies of prostate cancer have identified single nucleotide polymorphism (SNP) markers in a region of chromosome 10q11.2, harboring the microseminoprotein-β (MSMB) gene. Both the gene product of MSMB, the prostate secretory protein 94 (PSP94) and its binding protein (PSPBP), have been previously investigated as serum biomarkers for prostate cancer progression. Recent functional work has shown that different alleles of the significantly associated SNP in the promoter of MSMB found to be associated with prostate cancer risk, rs10993994, can influence its expression in tumors and in vitro studies. Since it is plausible that additional variants in this region contribute to the risk of prostate cancer, we have used next-generation sequencing technology to resequence a ~97-kb region that includes the area surrounding MSMB (chr10: 51,168,025–51,265,101) in 36 prostate cancer cases, 26 controls of European origin, and 8 unrelated CEPH individuals in order to identify additional variants to investigate in functional studies. We identified 241 novel polymorphisms within this region, including 142 in the 51-kb block of linkage disequilibrium (LD) that contains rs10993994 and the proximal promoter of MSMB. No sites were observed to be polymorphic within the exons of MSMB