Downregulation of Mcl-1 has anti-inflammatory pro-resolution effects and enhances bacterial clearance from the lung

Phagocytes not only coordinate acute inflammation and host defense at mucosal sites, but also contribute to tissue damage. Respiratory infection causes a globally significant disease burden and frequently progresses to acute respiratory distress syndrome, a devastating inflammatory condition characterized by neutrophil recruitment and accumulation of protein-rich edema fluid causing impaired lung function. We hypothesized that targeting the intracellular protein myeloid cell leukemia 1 (Mcl-1) by a cyclin-dependent kinase inhibitor (AT7519) or a flavone (wogonin) would accelerate neutrophil apoptosis and resolution of established inflammation, but without detriment to bacterial clearance. Mcl-1 loss induced human neutrophil apoptosis, but did not induce macrophage apoptosis nor impair phagocytosis of apoptotic neutrophils. Neutrophil-dominant inflammation was modelled in mice by either endotoxin or bacteria (Escherichia coli). Downregulating inflammatory cell Mcl-1 had anti-inflammatory, pro-resolution effects, shortening the resolution interval (R(i)) from 19 to 7 h and improved organ dysfunction with enhanced alveolar–capillary barrier integrity. Conversely, attenuating drug-induced Mcl-1 downregulation inhibited neutrophil apoptosis and delayed resolution of endotoxin-mediated lung inflammation. Importantly, manipulating lung inflammatory cell Mcl-1 also accelerated resolution of bacterial infection (R(i); 50 to 16 h) concurrent with enhanced bacterial clearance. Therefore, manipulating inflammatory cell Mcl-1 accelerates inflammation resolution without detriment to host defense against bacteria, and represents a target for treating infection-associated inflammation

Integrated Risk Assessment for the Blue Economy

With the anticipated boom in the ‘blue economy’ and associated increases in industrialization across the world’s oceans, new and complex risks are being introduced to ocean ecosystems. As a result, conservation and resource management increasingly look to factor in potential interactions among the social, ecological and economic components of these systems. Investigation of these interactions requires interdisciplinary frameworks that incorporate methods and insights from across the social and biophysical sciences. Risk assessment methods, which have been developed across numerous disciplines and applied to various real-world settings and problems, provide a unique connection point for cross-disciplinary engagement. However, research on risk is often conducted in distinct spheres by experts whose focus is on narrow sources or outcomes of risk. Movement toward a more integrated treatment of risk to ensure a balanced approach to developing and managing ocean resources requires cross-disciplinary engagement and understanding. Here, we provide a primer on risk assessment intended to encourage the development and implementation of integrated risk assessment processes in the emerging blue economy. First, we summarize the dominant framework for risk in the ecological/biophysical sciences. Then, we discuss six key insights from the long history of risk research in the social sciences that can inform integrated assessments of risk: (1) consider the subjective nature of risk, (2) understand individual social and cultural influences on risk perceptions, (3) include diverse expertise, (4) consider the social scales of analysis, (5) incorporate quantitative and qualitative approaches, and (6) understand interactions and feedbacks within systems. Finally, we show how these insights can be incorporated into risk assessment and management, and apply them to a case study of whale entanglements in fishing gear off the United States west coast

Nautical Research Platform for Water-Bound Experiments

Conducting research in lakes and rivers requires large crews and heavy-duty equipment, making even simple tests more costly and time consuming. Newer research methods are evolving constantly as new technology enables more precise and accessible experiments to be conducted. The need for simple execution of water-bound experiments exists and must be addressed to aid our understanding of these environments. We at the Microgravity Undergraduate Research Team have taken our previous research in autonomous Unmanned Surface Vehicles (USVs) and applied our efforts to relieving this problem. Our current research aims to provide a universal platform for research and experiments to be conducted in lakes and rivers, where we can then expand our efforts to more broad applications. The design allows for remote-control navigation by one user and easy portability. To address precision in experimentation, we have integrated autonomous GPS waypoint navigation which removes user error in sensitive measurements. The most important factor in its design is modularity; the ability to accommodate a wide range of equipment for research. Our platform succeeds in making water-bound experiments more accessible and more precise for a multitude of potential applications

Self-interest, foreign need and good governance: are bilateral investment treaty programs similar to aid allocation?

Bilateral investment treaties (BITs) have become the most important legal mechanism for the encouragement and governance of foreign direct investment (FDI) in developing countries. Yet practically no systematic evidence exists on what motivates capital-exporting developed countries to sign BITs earlier with some developing countries than with others, if at all. The theoretical framework from the aid allocation literature suggests that developed countries pursue a mixture of self-interest, foreign need and, possibly, good governance. We find evidence that both economic interests of developed countries’ foreign investors and political interests of developed countries determine their scheduling of BITs. However, foreign need as measured by per capita income is also a factor, whereas good governance by and large does not matter. These results suggest that BIT programs can be explained employing the same framework successfully applied to the allocation of aid. At the same time, self-interest seems to be substantively more important than developing country need when it comes to BITs

Economic Geography and Human Rights

This is a working paper.This paper investigates the geo-political and international economic aspects of human rights performance using a pooled cross-section time-series data set. We start with simple descriptive accounts of the recent geographic history of human rights performance. We then test for basic economic effects of income and then apply tools from the spatial economics literature to examine the degree to which clusters of relative human rights performance exist. Using spatial weighting models we analyse the spatial impact of proximity and human rights performance of neghbours on overall levels of human rights performance. Unlike previous studies, our approach treats this spatial impact as partly endogenous: one country’s human rights performance may affect its neighbours through a variety of potential geographical spillover mechanisms. The spatial weighting models take into account size and distance of neighbours in order to compare each country’s human rights performance with what would be predicted by regression on a weighted average of its neighbours’ performance. The findings sugest that there are (a) geographical clusters of human rights performance and (b) size and proximity effects for human rights performance, both of which have significant implications for the promotion and protection of human rights

Balloon Dilation of the Eustachian Tube: 12-Month Follow-up of the Randomized Controlled Trial Treatment Group

Objective: Obstructive eustachian tube dysfunction (OETD) affects up to 5% of adults; however, available treatment strategies have limitations. It was previously reported that balloon dilation of the eustachian tube (BDET) with the eustachian tube balloon catheter + medical management (MM) results in a significantly higher proportion of subjects with normalized tympanograms versus MM alone at 6- and 24-week follow-up. The current analysis extends these initial findings by investigating the durability of BDET + MM treatment outcomes through 52 weeks. Study Design: Prospective cohort follow-up study from the treatment group in a previously reported multicenter randomized controlled trial. Setting: Twenty-one investigational sites across the United States. Subjects and Methods: Here we report on secondary and exploratory endpoints for patients with OETD who previously failed MM and were randomized to the BDET + MM cohort. Analyses of tympanogram outcomes are reported by ear, unless specified otherwise, as a more accurate measure of durability of the procedure over time. Results: Among subjects randomized to BDET + MM, the overall number with normalized tympanograms and ETDQ-7 scores (Eustachian Tube Dysfunction Questionnaire–7) remained comparable to those reported at 6- versus 52-week follow-up: tympanograms, 73 of 143 (51.0%) versus 71 of 128 (55.5%); ETDQ-7, 79 of 142 (55.6%) versus 71 of 124 (57.3%). The overall number of ears with normalized tympanograms also remained comparable, with 117 of 204 (57%) versus 119 of 187 (63.6%). Conclusions: The present study suggests that the beneficial effects of BDET + MM on tympanogram normalization and symptoms of subjects with refractory OETD demonstrate significant durability that is clinically relevant through 52 weeks

Dye Encapsulation in Polynorbornene Micelles

The encapsulation efficiency of high-<i>T</i>_g polynorbornene micelles was probed with a hydrophobic dye 2,6-diiodoboron-dipyrromethene (BODIPY). Changes in the visible absorption spectra of aggregated versus monomeric dye molecules provided a probe for assessing encapsulation. Polynorbornene micelles are found to be capable of loading up to one BODIPY dye per ten polymers. As the hydrophilic block size increased in the polymeric amphiphiles, more of the dye was incorporated within the micelles. This result is consistent with the dye associating with the polymer backbone in the shell of the micelles. The encapsulation rate varied significantly with temperature, and a slight dependence on micellar morphology was also noted. Additionally, we report a 740 μs triplet lifetime for the encapsulated BODIPY dye. The lifetime is the longest ever recorded for a BODIPY triplet excited state at room temperature and is attributed to hindered triplet–triplet annihilation in the high-viscosity micellar shell