Dementias Platform UK: Bringing genetics into life.

INTRODUCTION: The Dementias Platform UK (DPUK) Data Portal is a data repository bringing together a wide range of cohorts. Neurodegenerative dementias are a group of diseases with highly heterogeneous pathology and an overlapping genetic component that is poorly understood. The DPUK collection of independent cohorts can facilitate research in neurodegeneration by combining their genetic and phenotypic data. METHODS: For genetic data processing, pipelines were generated to perform quality control analysis, genetic imputation, and polygenic risk score (PRS) derivation with six genome-wide association studies of neurodegenerative diseases. Pipelines were applied to five cohorts. DISCUSSION: The data processing pipelines, research-ready imputed genetic data, and PRS scores are now available on the DPUK platform and can be accessed upon request though the DPUK application process. Harmonizing genome-wide data for multiple datasets increases scientific opportunity and allows the wider research community to access and process data at scale and pace.

Soft mechano-chemistry of molecular hubs in mitotic spindle: biomechanics and mechanical proofreading at microtubule ends.

A microtubule (MT) is a long stiff tube-shaped filament formed by a hierarchical organization of a large number of tubulin protein molecules. These filaments constitute a major structural component of the scaffold of a multi-component macromolecular machine called mitotic spindle. The plus ends of the MTs are tethered to some specific binding partners by molecular tethers while those of some others are crosslinked by crosslinking molecules. Because of the non-covalent binding involved in the tethering and crosslinking, the attachments formed are intrinsically 'soft'. These attachments are transient because these can get ruptured spontaneously by thermal fluctuations. By implementing in silico the standard protocols of in vitro molecular force spectroscopy, we compute the lifetimes of simple theoretical models of these attachments. The mean lifetime is essentially a mean first-passage time. The stability of cross-linked antiparallel MTs is shown to decrease monotonically with increasing tension, a characteristic of all 'slip-bonds'. This is in sharp contrast to the nonmonotonic variation of the mean lifetime with tension, a mechanical fingerprint of 'catch-bonds', displayed by the MTs tethered to two distinct binding partners. We mention plausible functional implications of these observations in the context of mechanical proofreading.

Molecular force spectroscopy of kinetochore-microtubule attachment in silico: Mechanical signatures of an unusual catch bond and collective effects.

Measurement of the lifetime of attachments formed by a single microtubule (MT) with a single kinetochore (kt) in vitro under force-clamp conditions had earlier revealed a catch-bond-like behavior. In the past, the physical origin of this apparently counterintuitive phenomenon was traced to the nature of the force dependence of the (de)polymerization kinetics of the MTs. Here, first the same model MT-kt attachment is subjected to external tension that increases linearly with time until rupture occurs. In our force-ramp experiments in silico, the model displays the well known "mechanical signatures" of a catch bond probed by molecular force spectroscopy. Exploiting this evidence, we have further strengthened the analogy between MT-kt attachments and common ligand-receptor bonds in spite of the crucial differences in their underlying physical mechanisms. We then extend the formalism to model the stochastic kinetics of an attachment formed by a bundle of multiple parallel microtubules with a single kt considering the effect of rebinding under force-clamp and force-ramp conditions. From numerical studies of the model we predict the trends of variation of the mean lifetime and mean rupture force with the increasing number of MTs in the bundle. Both the mean lifetime and the mean rupture force display nontrivial nonlinear dependence on the maximum number of MTs that can attach simultaneously to the same kt.