Binding constant of cell adhesion receptors and substrate-immobilized ligands depends on the distribution of ligands

Cell-cell adhesion and the adhesion of cells to tissues and extracellular matrix, which are pivotal for immune response, tissue development, and cell locomotion, depend sensitively on the binding constant of receptor and ligand molecules anchored on the apposing surfaces. An important question remains of whether the immobilization of ligands affects the affinity of binding with cell adhesion receptors. We have investigated the adhesion of multicomponent membranes to a flat substrate coated with immobile ligands using Monte Carlo simulations of a statistical mesoscopic model with biologically relevant parameters. We find that the binding of the adhesion receptors to ligands immobilized on the substrate is strongly affected by the ligand distribution. In the case of ligand clusters, the receptor-ligand binding constant can be significantly enhanced due to the less translational entropy loss of lipid-raft domains in the model cell membranes upon the formation of additional complexes. For ligands randomly or uniformly immobilized on the substrate, the binding constant is rather decreased since the receptors localized in lipid-raft domains have to pay an energetic penalty in order to bind ligands. Our findings help to understand why cell-substrate adhesion experiments for measuring the impact of lipid rafts on the receptor-ligand interactions led to contradictory results

Distress and anhedonia as predictors of depression treatment outcome: A secondary analysis of a randomized clinical trial

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record Two core features of depression include depressed mood (heightened distress) and anhedonia (reduced pleasure). Despite their centrality to depression, studies have not examined their contribution to treatment outcomes in a randomized clinical trial providing mainstream treatments like antidepressant medications (ADM) and cognitive therapy (CT). We used baseline distress and anhedonia derived from a factor analysis of the Mood and Anxiety Symptom Questionnaire to predict remission and recovery in 433 individuals with recurrent/chronic major depressive disorder. Patients were provided with only ADM or both ADM and CT. Overall, higher baseline distress and anhedonia predicted longer times to remission within one year and recovery within three years. When controlling for treatment condition, distress improved prediction of outcomes over and above anhedonia, while anhedonia did not improve prediction of outcomes over and above distress. Interactions with treatment condition demonstrated that individuals with higher distress and anhedonia benefited from receiving CT in addition to ADM, whereas there was no added benefit of CT for individuals with lower distress and anhedonia. Assessing distress and anhedonia prior to treatment may help select patients who will benefit most from CT in addition to ADM. For the treatments and outcome measures tested, utilizing distress to guide treatment planning may yield the greatest benefit. Trial registration: clinicaltrials.gov Identifier: NCT00057577.National Institute of Mental Healt

A universal model for mobility and migration patterns

Introduced in its contemporary form by George Kingsley Zipf in 1946, but with roots that go back to the work of Gaspard Monge in the 18th century, the gravity law is the prevailing framework to predict population movement, cargo shipping volume, inter-city phone calls, as well as bilateral trade flows between nations. Despite its widespread use, it relies on adjustable parameters that vary from region to region and suffers from known analytic inconsistencies. Here we introduce a stochastic process capturing local mobility decisions that helps us analytically derive commuting and mobility fluxes that require as input only information on the population distribution. The resulting radiation model predicts mobility patterns in good agreement with mobility and transport patterns observed in a wide range of phenomena, from long-term migration patterns to communication volume between different regions. Given its parameter-free nature, the model can be applied in areas where we lack previous mobility measurements, significantly improving the predictive accuracy of most of phenomena affected by mobility and transport processes.Comment: Main text and supplementary informatio

Human HERC5 restricts an early stage of HIV-1 assembly by a mechanism correlating with the ISGylation of Gag

<p>Abstract</p> <p>Background</p> <p>The identification and characterization of several interferon (IFN)-induced cellular HIV-1 restriction factors, defined as host cellular proteins or factors that restrict or inhibit the HIV-1 life cycle, have provided insight into the IFN response towards HIV-1 infection and identified new therapeutic targets for HIV-1 infection. To further characterize the mechanism underlying restriction of the late stages of HIV-1 replication, we assessed the ability of IFNbeta-induced genes to restrict HIV-1 Gag particle production and have identified a potentially novel host factor called HECT domain and RCC1-like domain-containing protein 5 (HERC5) that blocks a unique late stage of the HIV-1 life cycle.</p> <p>Results</p> <p>HERC5 inhibited the replication of HIV-1 over multiple rounds of infection and was found to target a late stage of HIV-1 particle production. The E3 ligase activity of HERC5 was required for blocking HIV-1 Gag particle production and correlated with the post-translational modification of Gag with ISG15. HERC5 interacted with HIV-1 Gag and did not alter trafficking of HIV-1 Gag to the plasma membrane. Electron microscopy revealed that the assembly of HIV-1 Gag particles was arrested at the plasma membrane, at an early stage of assembly. The mechanism of HERC5-induced restriction of HIV-1 particle production is distinct from the mechanism underlying HIV-1 restriction by the expression of ISG15 alone, which acts at a later step in particle release. Moreover, HERC5 restricted murine leukemia virus (MLV) Gag particle production, showing that HERC5 is effective in restricting Gag particle production of an evolutionarily divergent retrovirus.</p> <p>Conclusions</p> <p>HERC5 represents a potential new host factor that blocks an early stage of retroviral Gag particle assembly. With no apparent HIV-1 protein that directly counteracts it, HERC5 may represent a new candidate for HIV/AIDS therapy.</p

A pathway-based association analysis model using common and rare variants

How various genetic effects in combination affect susceptibility to certain disease states continues to be a major area of methodological research. Various rare variant models have been proposed, in response to a common failure to either identify or validate biologically driven causal genetic variants in genome-wide association studies. Adopting the idea that multiple rare variants may effectively produce a combined effect equal to a single common variant effect through common linkage with this variant, we construct a pathway-based genetic association analysis model using both common and rare variants. This genetic model is applied to the disease status of unrelated individuals in replication 1 from Genetic Analysis Workshop 17. In this simulated example, we were able to identify several pathways that were potentially associated with the disease status and found that common variants showed stronger genetic effect than rare variants

Falling behind: life expectancy in US counties from 2000 to 2007 in an international context

<p>Abstract</p> <p>Background</p> <p>The United States health care debate has focused on the nation's uniquely high rates of lack of insurance and poor health outcomes relative to other high-income countries. Large disparities in health outcomes are well-documented in the US, but the most recent assessment of county disparities in mortality is from 1999. It is critical to tracking progress of health reform legislation to have an up-to-date assessment of disparities in life expectancy across counties. US disparities can be seen more clearly in the context of how progress in each county compares to international trends.</p> <p>Methods</p> <p>We use newly released mortality data by age, sex, and county for the US from 2000 to 2007 to compute life tables separately for each sex, for all races combined, for whites, and for blacks. We propose, validate, and apply novel methods to estimate recent life tables for small areas to generate up-to-date estimates. Life expectancy rates and changes in life expectancy for counties are compared to the life expectancies across nations in 2000 and 2007. We calculate the number of calendar years behind each county is in 2000 and 2007 compared to an international life expectancy time series.</p> <p>Results</p> <p>Across US counties, life expectancy in 2007 ranged from 65.9 to 81.1 years for men and 73.5 to 86.0 years for women. When compared against a time series of life expectancy in the 10 nations with the lowest mortality, US counties range from being 15 calendar years ahead to over 50 calendar years behind for men and 16 calendar years ahead to over 50 calendar years behind for women. County life expectancy for black men ranges from 59.4 to 77.2 years, with counties ranging from seven to over 50 calendar years behind the international frontier; for black women, the range is 69.6 to 82.6 years, with counties ranging from eight to over 50 calendar years behind. Between 2000 and 2007, 80% (men) and 91% (women) of American counties fell in standing against this international life expectancy standard.</p> <p>Conclusions</p> <p>The US has extremely large geographic and racial disparities, with some communities having life expectancies already well behind those of the best-performing nations. At the same time, relative performance for most communities continues to drop. Efforts to address these issues will need to tackle the leading preventable causes of death.</p

Two-orbital SU(N) magnetism with ultracold alkaline-earth atoms

Fermionic alkaline-earth atoms have unique properties that make them attractive candidates for the realization of novel atomic clocks and degenerate quantum gases. At the same time, they are attracting considerable theoretical attention in the context of quantum information processing. Here we demonstrate that when such atoms are loaded in optical lattices, they can be used as quantum simulators of unique many-body phenomena. In particular, we show that the decoupling of the nuclear spin from the electronic angular momentum can be used to implement many-body systems with an unprecedented degree of symmetry, characterized by the SU(N) group with N as large as 10. Moreover, the interplay of the nuclear spin with the electronic degree of freedom provided by a stable optically excited state allows for the study of spin-orbital physics. Such systems may provide valuable insights into strongly correlated physics of transition metal oxides, heavy fermion materials, and spin liquid phases.Comment: 15 pages, 10 figures. V2: extended experimental accessibility and Kondo sections in the main text (including new Fig. 5b) and in the Methods; reorganized other parts; added reference

The skeletal phenotype of chondroadherin deficient mice

Chondroadherin, a leucine rich repeat extracellular matrix protein with functions in cell to matrix interactions, binds cells via their a2b1 integrin as well as via cell surface proteoglycans, providing for different sets of signals to the cell. Additionally, the protein acts as an anchor to the matrix by binding tightly to collagens type I and II as well as type VI. We generated mice with inactivated chondroadherin gene to provide integrated studies of the role of the protein. The null mice presented distinct phenotypes with affected cartilage as well as bone. At 3–6 weeks of age the epiphyseal growth plate was widened most pronounced in the proliferative zone. The proteome of the femoral head articular cartilage at 4 months of age showed some distinct differences, with increased deposition of cartilage intermediate layer protein 1 and fibronectin in the chondroadherin deficient mice, more pronounced in the female. Other proteins show decreased levels in the deficient mice, particularly pronounced for matrilin-1, thrombospondin-1 and notably the members of the a1-antitrypsin family of proteinase inhibitors as well as for a member of the bone morphogenetic protein growth factor family. Thus, cartilage homeostasis is distinctly altered. The bone phenotype was expressed in several ways. The number of bone sialoprotein mRNA expressing cells in the proximal tibial metaphysic was decreased and the osteoid surface was increased possibly indicating a change in mineral metabolism. Micro-CT revealed lower cortical thickness and increased structure model index, i.e. the amount of plates and rods composing the bone trabeculas. The structural changes were paralleled by loss of function, where the null mice showed lower femoral neck failure load and tibial strength during mechanical testing at 4 months of age. The skeletal phenotype points at a role for chondroadherin in both bone and cartilage homeostasis, however, without leading to altered longitudinal growth

Interleukin-1 regulates multiple atherogenic mechanisms in response to fat feeding

Background: Atherosclerosis is an inflammatory process that develops in individuals with known risk factors that include hypertension and hyperlipidaemia, influenced by diet. However, the interplay between diet, inflammatory mechanisms and vascular risk factors requires further research. We hypothesised that interleukin-1 (IL-1) signaling in the vessel wall would raise arterial blood pressure and promote atheroma. Methodology/Principal Findings: Apoe(-/-) and Apoe(-/-)/IL-1R1(-/-) mice were fed high fat diets for 8 weeks, and their blood pressure and atherosclerosis development measured. Apoe(-/-)/IL-R1(-/-) mice had a reduced blood pressure and significantly less atheroma than Apoe(-/-) mice. Selective loss of IL-1 signaling in the vessel wall by bone marrow transplantation also reduced plaque burden (p<0.05). This was associated with an IL-1 mediated loss of endothelium-dependent relaxation and an increase in vessel wall Nox 4. Inhibition of IL-1 restored endothelium-dependent vasodilatation and reduced levels of arterial oxidative stress. Conclusions/Significance: The IL-1 cytokine system links atherogenic environmental stimuli with arterial inflammation, oxidative stress, increased blood pressure and atherosclerosis. This is the first demonstration that inhibition of a single cytokine can block the rise in blood pressure in response to an environmental stimulus. IL-1 inhibition may have profound beneficial effects on atherogenesis in man