Tethered hard spheres: A bridge between the fluid and solid phases.

The thermodynamics of hard spheres tethered to a Face-Centered Cubic (FCC) lattice is investigated using event-driven molecular-dynamics. The particle-particle and the particle-tether collision rates are related to the phase space geometry and are used to study the FCC and fluid states. In tethered systems, the entropy can be determined by at least two routes: (i) through integration of the tether collision rates with the tether length rT or (ii) through integration of the particle-particle collision rates with the hard-sphere diameter σ (or, equivalently, the density). If the entropy were an entirely analytic function of rT and σ, these two methods for calculating the entropy should lead to the same results; however, a non-analytic region exists as an extension of the solid-fluid phase transition of the untethered hard-sphere system, and integration paths that cross this region will lead to values for the entropy that depend on the particular path chosen. The difference between the calculated entropies appears to be related to the communal entropy, and the location of the non-analytic region appears to be related to conditions where the regions of phase space associated with the FCC configuration become separated from those associated with the disordered fluid. The non-analytic region is finite in extent, vanishing below rT/a ≈ 0.55, where a is the lattice spacing, and there are many continuous paths that connect the fluid and solid phases that can be used to determine the crystal free energy with respect to the fluid.

Extreme vulnerability of smallholder farmers to agricultural risks and climate change in Madagascar.

Across the tropics, smallholder farmers already face numerous risks to agricultural production. Climate change is expected to disproportionately affect smallholder farmers and make their livelihoods even more precarious; however, there is limited information on their overall vulnerability and adaptation needs. We conducted surveys of 600 households in Madagascar to characterize the vulnerability of smallholder farmers, identify how farmers cope with risks and explore what strategies are needed to help them adapt to climate change. Malagasy farmers are particularly vulnerable to any shocks to their agricultural system owing to their high dependence on agriculture for their livelihoods, chronic food insecurity, physical isolation and lack of access to formal safety nets. Farmers are frequently exposed to pest and disease outbreaks and extreme weather events (particularly cyclones), which cause significant crop and income losses and exacerbate food insecurity. Although farmers use a variety of risk-coping strategies, these are insufficient to prevent them from remaining food insecure. Few farmers have adjusted their farming strategies in response to climate change, owing to limited resources and capacity. Urgent technical, financial and institutional support is needed to improve the agricultural production and food security of Malagasy farmers and make their livelihoods resilient to climate change.

Chronic oscillatory strain induces MLCK associated rapid recovery from acute stretch in airway smooth muscle cells.

A deep inspiration (DI) temporarily relaxes agonist-constricted airways in normal subjects, but in asthma airways are refractory and may rapidly renarrow, possibly due to changes in the structure and function of airway smooth muscle (ASM). Chronic largely uniaxial cyclic strain of ASM cells in culture causes several structural and functional changes in ASM similar to that in asthma, including increases in contractility, MLCK content, shortening velocity, and shortening capacity. However, changes in recovery from acute stretch similar to a DI have not been measured. We have therefore measured the response and recovery to large stretches of cells modified by chronic stretching and investigated the role of MLCK. Chronic, 10% uniaxial cyclic stretch, with or without a strain gradient, was administered for up to 11 days to cultured cells grown on Silastic membranes. Single cells were then removed from the membrane and subjected to 1 Hz oscillatory stretches up to 10% of the in situ cell length. These oscillations reduced stiffness by 66% in all groups (P < 0.05). Chronically strained cells recovered stiffness three times more rapidly than unstrained cells, while the strain gradient had no effect. The stiffness recovery in unstrained cells was completely inhibited by the MLCK inhibitor ML-7, but recovery in strained cells exhibiting increased MLCK was slightly inhibited. These data suggest that chronic strain leads to enhanced recovery from acute stretch, which may be attributable to the strain-induced increases in MLCK. This may also explain in part the more rapid renarrowing of activated airways following DI in asthma.

Airway smooth muscle cell tone amplifies contractile function in the presence of chronic cyclic strain.

Chronic contractile activation, or tone, in asthma coupled with continuous stretching due to breathing may be involved in altering the contractile function of airway smooth muscle (ASM). Previously, we (11) showed that cytoskeletal remodeling and stiffening responses to acute (2 h) localized stresses were modulated by the level of contractile activation of ASM. Here, we investigated if altered contractility in response to chronic mechanical strain was dependent on repeated modulation of contractile tone. Cultured human ASM cells received 5% cyclic (0.3 Hz), predominantly uniaxial strain for 5 days, with once-daily dosing of either sham, forskolin, carbachol, or histamine to alter tone. Stiffness, contractility (KCl), and "relaxability" (forskolin) were then measured as was cell alignment, myosin light-chain phosphorylation (pMLC), and myosin light-chain kinase (MLCK) content. Cells became aligned and baseline stiffness increased with strain, but repeated lowering of tone inhibited both effects (P < 0.05). Strain also reversed a negative tone-modulation dependence of MLCK, observed in static conditions in agreement with previous reports, with strain and tone together increasing both MLCK and pMLC. Furthermore, contractility increased 176% (SE 59) with repeated tone elevation. These findings indicate that with strain, and not without, repeated tone elevation promoted contractile function through changes in cytoskeletal organization and increased contractile protein. The ability of repeated contractile activation to increase contractility, but only with mechanical stretching, suggests a novel mechanism for increased ASM contractility in asthma and for the role of continuous bronchodilator and corticosteroid therapy in reversing airway hyperresponsiveness.

Combined analysis from eleven linkage studies of bipolar disorder provides strong evidence of susceptibility loci on chromosomes 6q and 8q.

Several independent studies and meta-analyses aimed at identifying genomic regions linked to bipolar disorder (BP) have failed to find clear and consistent evidence of linkage regions. Our hypothesis is that combining the original genotype data provides benefits of increased power and control over sources of heterogeneity that outweigh the difficulty and potential pitfalls of the implementation. We conducted a combined analysis using the original genotype data from 11 BP genomewide linkage scans comprising 5,179 individuals from 1,067 families. Heterogeneity among studies was minimized in our analyses by using uniform methods of analysis and a common, standardized marker map and was assessed using novel methods developed for meta-analysis of genome scans. To date, this collaboration is the largest and most comprehensive analysis of linkage samples involving a psychiatric disorder. We demonstrate that combining original genome-scan data is a powerful approach for the elucidation of linkage regions underlying complex disease. Our results establish genomewide significant linkage to BP on chromosomes 6q and 8q, which provides solid information to guide future gene-finding efforts that rely on fine-mapping and association approaches.