Stapled Peptides as HIF‐1α/p300 Inhibitors: Helicity Enhancement in the Bound State Increases Inhibitory Potency

Protein–protein interactions (PPIs) control virtually all cellular processes and have thus emerged as potential targets for development of molecular therapeutics. Peptide‐based inhibitors of PPIs are attractive given that they offer recognition potency and selectivity features that are ideal for function, yet, they do not predominantly populate the bioactive conformation, frequently suffer from poor cellular uptake and are easily degraded, for example, by proteases. The constraint of peptides in a bioactive conformation has emerged as a promising strategy to mitigate against these liabilities. In this work, using peptides derived from hypoxia‐inducible factor 1 (HIF‐1α) together with dibromomaleimide stapling, we identify constrained peptide inhibitors of the HIF‐1α/p300 interaction that are more potent than their unconstrained sequences. Contrary to expectation, the increased potency does not correlate with an increased population of an α‐helical conformation in the unbound state as demonstrated by experimental circular dichroism analysis. Rather, the ability of the peptide to adopt a bioactive α‐helical conformation in the p300 bound state is better supported in the constrained variant as demonstrated by molecular dynamics simulations and circular dichroism difference spectra

Semantic inferentialism as (a form of) active externalism

Within contemporary philosophy of mind, it is taken for granted that externalist accounts of meaning and mental content are, in principle, orthogonal to the matter of whether cognition itself is bound within the biological brain or whether it can constitutively include parts of the world. Accordingly, Clark and Chalmers (Analysis 58(1):7–19, 1998) distinguish these varieties of externalism as ‘passive’ and ‘active’ respectively. The aim here is to suggest that we should resist the received way of thinking about these dividing lines. With reference to Brandom’s (1994, 2000, Inquiry 47:236–253, 2008) broad semantic inferentialism, we show that a theory of meaning can be at the same time a variety of active externalism. While we grant that supporters of other varieties of content externalism (e.g., Putnam 1975 and Burge (Philosophical Review 95:3–45, 1986) can deny active externalism, this is not an option for semantic inferentialists: On this latter view, the role of the environment (both in its social and natural form) is not ‘passive’ in the sense assumed by the alternative approaches to content externalism

What two models may teach us about duality violations in QCD

Though the operator product expansion is applicable in the calculation of current correlation functions in the Euclidean region, when approaching the Minkowskian domain, violations of quark-hadron duality are expected to occur, due to the presence of bound-state or resonance poles. In QCD finite-energy sum rules, contour integrals in the complex energy plane down to the Minkowskian axis have to be performed, and thus the question arises what the impact of duality violations may be. The structure and possible relevance of duality violations is investigated on the basis of two models: the Coulomb system and a model for light-quark correlators which has already been studied previously. As might yet be naively expected, duality violations are in some sense "maximal" for zero-width bound states and they become weaker for broader resonances whose poles lie further away from the physical axis. Furthermore, to a certain extent, they can be suppressed by choosing appropriate weight functions in the finite-energy sum rules. A simplified Ansatz for including effects of duality violations in phenomenological QCD sum rule analyses is discussed as well.Comment: 17 pages, 6 figures; version to appear in JHE

The effects of childbirth on the pelvic-floor

Basically, vaginal delivery is associated with the risk of pelvic floor damage. The pelvic floor sequelae of childbirth includes anal incontinence, urinary incontinence and pelvic organ prolapse. Pathophysiology, incidence and risk factors for the development of the respective problems are reviewed. Where possible, recommendations for reducing the risk of pelvic floor damage are given

Mechanisms of Esophago-Pharyngeal Acid Regurgitation in Human Subjects

Esophago-pharyngeal regurgitation is implicated in various otolaryngologic and respiratory disorders. The pathophysiological mechanisms causing regurgitation are still largely unknown

Restrictive ID policies: implications for health equity

We wish to thank Synod Community Services for their critical work to develop, support, and implement a local government-issued ID in Washtenaw County, MI. We also thank Yousef Rabhi of the Michigan House of Representatives and Janelle Fa'aola of the Washtenaw ID Task Force, Lawrence Kestenbaum of the Washtenaw County Clerk's Office, Sherriff Jerry Clayton of the Washtenaw County Sherriff's Office, and the Washtenaw ID Task Force for their tireless commitment to developing and supporting the successful implementation of the Washtenaw ID. Additionally, we thank Vicenta Vargas and Skye Hillier for their contributions to the Washtenaw ID evaluation. We thank the Curtis Center for Research and Evaluation at the University of Michigan School of Social Work, the National Center for Institutional Diversity at the University of Michigan, and the University of California-Irvine Department of Chicano/Latino Studies and Program in Public Health for their support of the Washtenaw ID community-academic research partnership. Finally, we thank the reviewers for their helpful comments on earlier drafts of this manuscript. (Curtis Center for Research and Evaluation at the University of Michigan School of Social Work; National Center for Institutional Diversity at the University of Michigan; University of California-Irvine Department of Chicano/Latino Studies; Program in Public Health)https://link.springer.com/content/pdf/10.1007/s10903-017-0579-3.pdfPublished versio

Metamodel-assisted design optimization of piezoelectric flex transducer for maximal bio-kinetic energy conversion

Energy Harvesting Devices (EHD) have been widely used to generate electrical power from the bio-kinetic energy of human body movement. A novel Piezoelectric Flex Transducer (PFT) based on the Cymbal device has been proposed by Daniels et al. (2013) for the purpose of energy harvesting. To further improve the efficiency of the device, optimal design of the PFT for maximum output power subject to stress and displacement constraints is carried out in this paper. Sequential Quadratic Programming (SQP) on metamodels generated with Genetic Programming from a 140-point optimal Latin hypercube design of experiments is used in the optimization. Finally, the optimal design is validated by finite element simulations. The simulations show that the magnitude of the electrical power generated from this optimal PFT harvesting device can be up to 6.5 mw when a safety design factor of 2.0 is applied

Climate warming, marine protected areas and the ocean-scale integrity of coral reef ecosystems

Coral reefs have emerged as one of the ecosystems most vulnerable to climate variation and change. While the contribution of a warming climate to the loss of live coral cover has been well documented across large spatial and temporal scales, the associated effects on fish have not. Here, we respond to recent and repeated calls to assess the importance of local management in conserving coral reefs in the context of global climate change. Such information is important, as coral reef fish assemblages are the most species dense vertebrate communities on earth, contributing critical ecosystem functions and providing crucial ecosystem services to human societies in tropical countries. Our assessment of the impacts of the 1998 mass bleaching event on coral cover, reef structural complexity, and reef associated fishes spans 7 countries, 66 sites and 26 degrees of latitude in the Indian Ocean. Using Bayesian meta-analysis we show that changes in the size structure, diversity and trophic composition of the reef fish community have followed coral declines. Although the ocean scale integrity of these coral reef ecosystems has been lost, it is positive to see the effects are spatially variable at multiple scales, with impacts and vulnerability affected by geography but not management regime. Existing no-take marine protected areas still support high biomass of fish, however they had no positive affect on the ecosystem response to large-scale disturbance. This suggests a need for future conservation and management efforts to identify and protect regional refugia, which should be integrated into existing management frameworks and combined with policies to improve system-wide resilience to climate variation and change

Comparison of the CDC Backpack aspirator and the Prokopack aspirator for sampling indoor- and outdoor-resting mosquitoes in southern Tanzania.

BACKGROUND\ud \ud Resting mosquitoes can easily be collected using an aspirating device. The most commonly used mechanical aspirator is the CDC Backpack aspirator. Recently, a simple, and low-cost aspirator called the Prokopack has been devised and proved to have comparable performance. The following study evaluates the Prokopack aspirator compared to the CDC backpack aspirator when sampling resting mosquitoes in rural Tanzania.\ud \ud METHODS\ud \ud Mosquitoes were sampled in- and outdoors of 48 typical rural African households using both aspirators. The aspirators were rotated between collectors and households in a randomized, Latin Square design. Outdoor collections were performed using artificial resting places (large barrel and car tyre), underneath the outdoor kitchen (kibanda) roof and from a drop-net. Data were analysed with generalized linear models.\ud \ud RESULTS\ud \ud The number of mosquitoes collected using the CDC Backpack and the Prokopack aspirator were not significantly different both in- and outdoors (indoors p = 0.735; large barrel p = 0.867; car tyre p = 0.418; kibanda p = 0.519). The Prokopack was superior for sampling of drop-nets due to its smaller size. The number mosquitoes collected per technician was more consistent when using the Prokopack aspirator. The Prokopack was more user-friendly: technicians preferred using the it over the CDC backpack aspirator as it weighs considerably less, retains its charge for longer and is easier to manoeuvre.\ud \ud CONCLUSIONS\ud \ud The Prokopack proved in the field to be more advantageous than the CDC Backpack aspirator. It can be self assembled using simple, low-cost and easily attainable materials. This device is a useful tool for researchers or vector-control surveillance programs operating in rural Africa, as it is far simpler and quicker than traditional means of sampling resting mosquitoes. Further longitudinal evaluations of the Prokopack aspirator versus the gold standard pyrethrum spray catch for indoor resting catches are recommended