Cholesterol in the cargo membrane amplifies tau inhibition of kinesin-1-based transport.

Intracellular cargos are often membrane-enclosed and transported by microtubule-based motors in the presence of microtubule-associated proteins (MAPs). Whereas increasing evidence reveals how MAPs impact the interactions between motors and microtubules, critical questions remain about the impact of the cargo membrane on transport. Here we combined in vitro optical trapping with theoretical approaches to determine the effect of a lipid cargo membrane on kinesin-based transport in the presence of MAP tau. Our results demonstrate that attaching kinesin to a fluid lipid membrane reduces the inhibitory effect of tau on kinesin. Moreover, adding cholesterol, which reduces kinesin diffusion in the cargo membrane, amplifies the inhibitory effect of tau on kinesin binding in a dosage-dependent manner. We propose that reduction of kinesin diffusion in the cargo membrane underlies the effect of cholesterol on kinesin binding in the presence of tau, and we provide a simple model for this proposed mechanism. Our study establishes a direct link between cargo membrane cholesterol and MAP-based regulation of kinesin-1. The cholesterol effects uncovered here may more broadly extend to other lipid alterations that impact motor diffusion in the cargo membrane, including those associated with aging and neurological diseases.

Tuning ensemble-averaged cargo run length via fractional change in mean kinesin number.

The number of motors carrying cargos in biological cells is not well-defined, instead varying from cargo to cargo about a statistical mean. Predictive understanding of motility in cells therefore requires quantitative insights into mixed ensembles of cargos. Toward this goal, here we employed Monte Carlo simulations to investigate statistical ensembles of cargos carried by a Poisson-distributed number of motors. Focusing on the key microtubule-based motor kinesin-1, our simulations utilized experimentally determined single-kinesin characteristics and alterations in kinesin's on- and off-rates caused by cellular factors and/or physical load. We found that a fractional increase in mean kinesin number enhances the ensemble-averaged cargo run length and amplifies run-length sensitivity to changes in single-kinesin on-rate and off-rate. These tuning effects can be further enhanced as solution viscosity increases over the range reported for cells. Together, our data indicate that the physiological range of kinesin number sensitively tunes the motility of mixed cargo populations. These effects have rich implications for quantitative and predictive understanding of cellular motility and its regulation.

Cooperative financial institutions: A review of the literature.

Financial cooperatives play an important role in the financial systems of many countries. They act as a safe haven for deposits and are major sources of credit for households and small- and medium-sized firms. A not-for-profit orientation (in many cases) and a focus on maximising benefits to members have ensured the enduring popularity and sustainability of financial cooperatives. This is particularly evident since the global financial crisis when financial cooperatives continued to extend credit to members as many profit-orientated commercial banks restricted credit to households and firms. The overarching theme of the first part of this review is the structural and behavioural characteristics of financial cooperatives. In this part we consider, the origin and diffusion of financial cooperatives, network arrangements, the business model, relationship banking, balancing the interest of members, tax treatment and regulatory framework. The second part has performance and contribution to the real economy as the overarching theme. In this part we consider, efficiency and sustainability, mergers, acquisitions and failures, the benefits (and challenges) of FinTech and the contribution of financial cooperatives to the real economy including during times of crisis. The paper concludes with a summary of what we now know (and do not know) about financial cooperatives and provides suggestions as to where future research may usefully concentrate.

Cargo diffusion shortens single-kinesin runs at low viscous drag.

Molecular motors such as kinesin-1 drive active, long-range transport of cargos along microtubules in cells. Thermal diffusion of the cargo can impose a randomly directed, fluctuating mechanical load on the motor carrying the cargo. Recent experiments highlighted a strong asymmetry in the sensitivity of single-kinesin run length to load direction, raising the intriguing possibility that cargo diffusion may non-trivially influence motor run length. To test this possibility, here we employed Monte Carlo-based simulations to evaluate the transport of cargo by a single kinesin. Our simulations included physiologically relevant viscous drag on the cargo and interrogated a large parameter space of cytoplasmic viscosities, cargo sizes, and motor velocities that captures their respective ranges in living cells. We found that cargo diffusion significantly shortens single-kinesin runs. This diffusion-based shortening is countered by viscous drag, leading to an unexpected, non-monotonic variation in run length as viscous drag increases. To our knowledge, this is the first identification of a significant effect of cargo diffusion on motor-based transport. Our study highlights the importance of cargo diffusion and load-detachment kinetics on single-motor functions under physiologically relevant conditions.

Does debt affect health? Cross country evidence on the debt-health nexus.

We investigate the relationship between aggregate household debt and aggregate health outcomes across 17 European countries over the period 1995 to 2012. Using a dataset of country-level standardized and objective measures of household debt, health outcomes and a rich set of control variables, we estimate an instrumental variable (GMM) model to address possible reverse causality concerns. We find that aggregate household debt affects health outcomes, and that this varies by the maturity of debt. Both short and medium-term debt has a positive effect on health outcomes. Long-term unsecured debt and mortgage debt are associated with poorer health outcomes. These findings are robust after controlling for alternative measures of health and debt. Overall, the results suggest that aggregate household debt is an important determinant of aggregate health outcomes across countries.