Cargo adaptors regulate stepping and force generation of mammalian dynein-dynactin.

Cytoplasmic dynein is an ATP-driven motor that transports intracellular cargos along microtubules. Dynein adopts an inactive conformation when not attached to a cargo, and motility is activated when dynein assembles with dynactin and a cargo adaptor. It was unclear how active dynein-dynactin complexes step along microtubules and transport cargos under tension. Using single-molecule imaging, we showed that dynein-dynactin advances by taking 8 to 32-nm steps toward the microtubule minus end with frequent sideways and backward steps. Multiple dyneins collectively bear a large amount of tension because the backward stepping rate of dynein is insensitive to load. Recruitment of two dyneins to dynactin increases the force generation and the likelihood of winning against kinesin in a tug-of-war but does not directly affect velocity. Instead, velocity is determined by cargo adaptors and tail-tail interactions between two closely packed dyneins. Our results show that cargo adaptors modulate dynein motility and force generation for a wide range of cellular functions

Anisotropic Small-Polaron Hopping In W:Bivo4 Single Crystals

DC electrical conductivity, Seebeck and Hall coefficients are measured between 300 and 450 K on single crystals of monoclinic bismuth vanadate that are doped n-type with 0.3% tungsten donors (W:BiVO4). Strongly activated small-polaron hopping is implied by the activation energies of the Arrhenius conductivities (about 300 meV) greatly exceeding the energies characterizing the falls of the Seebeck coefficients' magnitudes with increasing temperature (about 50 meV). Small-polaron hopping is further evidenced by the measured Hall mobility in the ab-plane (10(-1) cm(2) V-1 s(-1) at 300 K) being larger and much less strongly activated than the deduced drift mobility (about 5 x 10(-5) cm(2) V-1 s(-1) at 300 K). The conductivity and n-type Seebeck coefficient is found to be anisotropic with the conductivity larger and the Seebeck coefficient's magnitude smaller and less temperature dependent for motion within the ab-plane than that in the c-direction. These anisotropies are addressed by considering highly anisotropic next-nearest-neighbor (approximate to 5 angstrom) transfers in addition to the somewhat shorter (approximate to 4 angstrom), nearly isotropic nearest-neighbor transfers. (C) 2015 AIP Publishing LLC.U.S. Department of Energy (DOE), DE-FG02-09ER16119Welch Foundation Grant F-1436Hemphill-Gilmore Endowed FellowshipNSF MIRT DMR 1122603Chemical EngineeringTexas Materials InstituteChemistr

Pre-diagnostic prescription patterns in bladder and renal cancer: a longitudinal linked data study

Background: Understanding pre-diagnostic prescribing activity could reveal windows during which more timely cancer investigation and detection may occur. Aim: To examine prescription patterns for common urological clinical features prior to renal and bladder cancer diagnoses. Design and setting: We performed a retrospective cohort study using electronic primary care and cancer registry data on patients with bladder and renal cancer diagnosed between April 2012–December 2015 in England. Method: We analysed primary care prescriptions up to 2 years pre-diagnosis for five groups of clinical features (irritative urological symptoms, obstructive symptoms, urinary tract infections, genital infections, atrophic vaginitis). Poisson regressions estimating the inflection point, from which the rate of prescriptions increased from baseline, were used to identify the start of diagnostic windows during which cancer could be detected. Results: 48,094 prescriptions for 5,322 patients were analysed. Inflection points for an increase in UTI prescriptions were identified 9 months pre-diagnosis for renal (CI:5.3–12.7) and bladder (CI:7.4–10.6) cancers. For bladder cancer, the change in UTI antibiotic prescription rates occurred four months earlier in women (11 months, CI:9.7–12.3) than men (7 months, CI:5.4–8.6). No inflection points were identified, and so no diagnostic windows could be defined, for other clinical features. Conclusion: Prescription rates for UTIs increased 9 months before bladder and renal cancer diagnosis, indicating that there is potential to expedite diagnosis of these cancers in patients presenting with features of UTI. The greatest opportunity for more timely diagnosis may be in women with bladder cancer, who experienced the earliest increase in UTI prescription rate