Migration feedback yields novel critical transitions and emergent ecotypes in connected populations

Biological populations live and evolve in spatially extended and heterogeneous environments. From gut microbiota to antibiotic resistant bacteria, spatial heterogeneity of selection pressure can profoundly affect evolution. Yet, the effects of heterogeneity depend upon the migration patterns by which organisms explore their environment. We present a simple and general model of evolution on a network of interconnected habitats, showing that migration feedback through a heterogeneous environment generates non-local niches to which emergent ecotypes specialize. Varying migration rates induces both continuous and discontinuous phase transitions at which ecotypes exchange stability. These transitions result in ecotype extinction or emergence, which may have significant health implications. At the discontinuous transitions, there is no population decline to warn of an impending tipping point, yet the statistics of population fluctuations encode a warning signal of an approaching transition. We find that the discontinuous phase transitions arise via a novel mechanism of simultaneous transcritical bifurcations. Interestingly, these transitions show a `fine structure', analogous to that of atomic spectra, when a symmetry of the competitive interactions is broken. The ecological nature of the phase transitions implies that feasible experiments could explore the predicted behaviors, potentially using the fine-structure as a tool to measure the type and strength of interactions between organisms.Comment: 11 pages, 3 figure

Geometric Signatures of Switching Behavior in Mechanobiology

The proteins involved in cells' mechanobiological processes have evolved specialized and surprising responses to applied forces. Biochemical transformations that show catch-to-slip switching and force-induced pathway switching serve important functions in cell adhesion, mechano-sensing and signaling, and protein folding. We show that these switching behaviors are generated by singularities in the flow field that describes force-induced deformation of bound and transition states. These singularities allow for a complete characterization of switching mechanisms in 2-dimensional (2D) free energy landscapes, and provide a path toward elucidating novel forms of switching in higher dimensional models. Remarkably, the singularity that generates a catch-slip switch occurs in almost every 2D free energy landscape, implying that almost any bond admitting a 2D model will exhibit catch-slip behavior under appropriate force. We apply our analysis to models of P-selectin and antigen extraction to illustrate how these singularities provide an intuitive framework for explaining known behaviors and predicting new behaviors.Comment: 6 pages, 3 figure

Tropical tele-connections to the Mediterranean climate and weather

Some strong natural fluctuations of climate in the Eastern Mediterranean (EM) region are shown to be connected to the major tropical systems. Potential relations between EM rainfall extremes to tropical systems, e.g. El Niño, Indian Monsoon and hurricanes, are demonstrated. For a specific event, high resolution modelling of the severe flood on 3-5 December 2001 in Israel suggests a relation to hurricane Olga. In order to understand the factors governing the EM climate variability in the summer season, the relationship between extreme summer temperatures and the Indian Monsoon was examined. Other tropical factors like the Red-Sea Trough system and the Saharan dust are also likely to contribute to the EM climate variability

Modulation of Glucagon Receptor Pharmacology by Receptor Activity-modifying Protein-2 (RAMP2).

The glucagon and glucagon-like peptide-1 (GLP-1) receptors play important, opposing roles in regulating blood glucose levels. Consequently, these receptors have been identified as targets for novel diabetes treatments. However, drugs acting at the GLP-1 receptor, although having clinical efficacy, have been associated with severe adverse side-effects, and targeting of the glucagon receptor has yet to be successful. Here we use a combination of yeast reporter assays and mammalian systems to provide a more complete understanding of glucagon receptor signaling, considering the effect of multiple ligands, association with the receptor-interacting protein receptor activity-modifying protein-2 (RAMP2), and the role of individual G protein α-subunits. We demonstrate that RAMP2 alters both ligand selectivity and G protein preference of the glucagon receptor. Importantly, we also uncover novel cross-reactivity of therapeutically used GLP-1 receptor ligands at the glucagon receptor that is abolished by RAMP2 interaction. This study reveals the glucagon receptor as a previously unidentified target for GLP-1 receptor agonists and highlights a role for RAMP2 in regulating its pharmacology. Such previously unrecognized functions of RAMPs highlight the need to consider all receptor-interacting proteins in future drug development.This work was supported by a Warwick Impact Fund (C.W., G.L.), the BBSRC (G.L. - BB/G01227X/1), (T.S., G.R., D.R. - BB/F008392/1), (D.P. - BB/M007529/1 and BB/M000176/1), Warwick Research Development Fund (C.W., G.L.) grant number (RD13301) and the Birmingham Science City Research Alliance (G.L).This is the final version of the article. It first appeared from ASBMB at http://dx.doi.org/10.1074/jbc.M114.62460

Statins, bone, and neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is a dominantly inherited multi-system disorder. Major features include pigmentary abnormalities, benign tumors of the nerve sheath (neurofibromas), malignant tumors, learning disabilities, and skeletal dysplasia. The NF1 gene functions as a tumor suppressor, but haploinsuffiency probably accounts for some aspects of the non-tumor phenotype. The protein product, neurofibromin, is a Ras GTPase-activating protein, and various Ras pathway inhibitors are being tested in preclinical models and clinical trials for effectiveness in treating NF1 complications. This month in BMC Medicine, a paper by Kolanczyk et al describes a preclinical mouse model for tibial dysplasia and provides evidence that the drug lovastatin – in use to treat cardiovascular disease – may be beneficial, opening the door to clinical trials in humans

Managing the Socially Marginalized: Attitudes Towards Welfare, Punishment and Race

Welfare and incarceration policies have converged to form a system of governance over socially marginalized groups, particularly racial minorities. In both of these policy areas, rehabilitative and social support objectives have been replaced with a more punitive and restrictive system. The authors examine the convergence in individual-level attitudes concerning welfare and criminal punishment, using national survey data. The authors\u27 analysis indicates a statistically significant relationship between punitive attitudes toward welfare and punishment. Furthermore, accounting for the respondents\u27 racial attitudes explains the bivariate relationship between welfare and punishment. Thus, racial attitudes seemingly link support for punitive approaches to opposition to welfare expenditures. The authors discuss the implications of this study for welfare and crime control policies by way of the conclusion

Index tracking with utility enhanced weighting

Passive index investing involves investing in a fund that replicates a market index. Enhanced indexation uses the returns of an index as a reference point and aims at outperforming this index. The motivation behind enhanced indexing is that the indices and portfolios available to academics and practitioners for asset pricing and benchmarking are generally inefficient and, thus, susceptible to enhancement. In this paper we propose a novel technique based on the concept of cumulative utility area ratios and the Analytic Hierarchy Process (AHP) to construct enhanced indices from the DJIA and S&P500. Four main conclusions are forthcoming. First, the technique, called the utility enhanced tracking technique (UETT), is computationally parsimonious and applicable for all return distributions. Second, if desired, cardinality constraints are simple and computationally parsimonious. Third, the technique requires only infrequent rebalancing, monthly at the most. Finally, the UETT portfolios generate consistently higher out-of-sample utility profiles and after-cost returns for the fully enhanced portfolios as well as for the enhanced portfolios adjusted for cardinality constraints. These results are robust to varying market conditions and a range of utility functions

The Impact of HAART on the Respiratory Complications of HIV Infection: Longitudinal Trends in the MACS and WIHS Cohorts

Objective: To review the incidence of respiratory conditions and their effect on mortality in HIV-infected and uninfected individuals prior to and during the era of highly active antiretroviral therapy (HAART). Design: Two large observational cohorts of HIV-infected and HIV-uninfected men (Multicenter AIDS Cohort Study [MACS]) and women (Women's Interagency HIV Study [WIHS]), followed since 1984 and 1994, respectively. Methods: Adjusted odds or hazards ratios for incident respiratory infections or non-infectious respiratory diagnoses, respectively, in HIV-infected compared to HIV-uninfected individuals in both the pre-HAART (MACS only) and HAART eras; and adjusted Cox proportional hazard ratios for mortality in HIV-infected persons with lung disease during the HAART era. Results: Compared to HIV-uninfected participants, HIV-infected individuals had more incident respiratory infections both pre-HAART (MACS, odds ratio [adjusted-OR], 2.4; 95% confidence interval [CI], 2.2-2.7; p<0.001) and after HAART availability (MACS, adjusted-OR, 1.5; 95%CI 1.3-1.7; p<0.001; WIHS adjusted-OR, 2.2; 95%CI 1.8-2.7; p<0.001). Chronic obstructive pulmonary disease was more common in MACS HIV-infected vs. HIV-uninfected participants pre-HAART (hazard ratio [adjusted-HR] 2.9; 95%CI, 1.02-8.4; p = 0.046). After HAART availability, non-infectious lung diseases were not significantly more common in HIV-infected participants in either MACS or WIHS participants. HIV-infected participants in the HAART era with respiratory infections had an increased risk of death compared to those without infections (MACS adjusted-HR, 1.5; 95%CI, 1.3-1.7; p<0.001; WIHS adjusted-HR, 1.9; 95%CI, 1.5-2.4; p<0.001). Conclusion: HIV infection remained a significant risk for infectious respiratory diseases after the introduction of HAART, and infectious respiratory diseases were associated with an increased risk of mortality. © 2013 Gingo et al