Disease-Associated Mutations Disrupt Functionally Important Regions of Intrinsic Protein Disorder

The effects of disease mutations on protein structure and function have been extensively investigated, and many predictors of the functional impact of single amino acid substitutions are publicly available. The majority of these predictors are based on protein structure and evolutionary conservation, following the assumption that disease mutations predominantly affect folded and conserved protein regions. However, the prevalence of the intrinsically disordered proteins (IDPs) and regions (IDRs) in the human proteome together with their lack of fixed structure and low sequence conservation raise a question about the impact of disease mutations in IDRs. Here, we investigate annotated missense disease mutations and show that 21.7% of them are located within such intrinsically disordered regions. We further demonstrate that 20% of disease mutations in IDRs cause local disorder-to-order transitions, which represents a 1.7–2.7 fold increase compared to annotated polymorphisms and neutral evolutionary substitutions, respectively. Secondary structure predictions show elevated rates of transition from helices and strands into loops and vice versa in the disease mutations dataset. Disease disorder-to-order mutations also influence predicted molecular recognition features (MoRFs) more often than the control mutations. The repertoire of disorder-to-order transition mutations is limited, with five most frequent mutations (R→W, R→C, E→K, R→H, R→Q) collectively accounting for 44% of all deleterious disorder-to-order transitions. As a proof of concept, we performed accelerated molecular dynamics simulations on a deleterious disorder-to-order transition mutation of tumor protein p63 and, in agreement with our predictions, observed an increased α-helical propensity of the region harboring the mutation. Our findings highlight the importance of mutations in IDRs and refine the traditional structure-centric view of disease mutations. The results of this study offer a new perspective on the role of mutations in disease, with implications for improving predictors of the functional impact of missense mutations

A Catalog of Very Isolated Galaxies from the SDSS Data Release 1

We present a new catalog of isolated galaxies obtained through an automated systematic search. These 2980 isolated galaxies were found in approximately 2099 sq deg of sky in the Sloan Digital Sky Survey Data Release 1 (SDSS DR1) photometry. The selection algorithm, implementing a variation on the criteria developed by Karachentseva in 1973, proved to be very efficient and fast. This catalog will be useful for studies of the general galaxy characteristics. Here we report on our results.Comment: 67 pages, which includes 14 figures. Accepted for publication by A

Optimizing end-labeled free-solution electrophoresis by increasing the hydrodynamic friction of the drag-tag

We study the electrophoretic separation of polyelectrolytes of varying lengths by means of end-labeled free-solution electrophoresis (ELFSE). A coarse-grained molecular dynamics simulation model, using full electrostatic interactions and a mesoscopic Lattice Boltzmann fluid to account for hydrodynamic interactions, is used to characterize the drag coefficients of different label types: linear and branched polymeric labels, as well as transiently bound micelles. It is specifically shown that the label's drag coefficient is determined by its hydrodynamic size, and that the drag per label monomer is largest for linear labels. However, the addition of side chains to a linear label offers the possibility to increase the hydrodynamic size, and therefore the label efficiency, without having to increase the linear length of the label, thereby simplifying synthesis. The third class of labels investigated, transiently bound micelles, seems very promising for the usage in ELFSE, as they provide a significant higher hydrodynamic drag than the other label types. The results are compared to theoretical predictions, and we investigate how the efficiency of the ELFSE method can be improved by using smartly designed drag-tags.Comment: 32 pages, 11 figures, submitted to Macromolecule

Physiotherapy-led telehealth and exercise intervention to improve mobility in older people receiving aged care services (TOP UP): Protocol for a randomised controlled type 1 hybrid effectiveness-implementation trial

Introduction Deteriorating mobility and falls reduce independence and quality of life for older people receiving aged care services. This trial aims to establish effectiveness on the mobility of older people, and explore cost-effectiveness and implementation of a telehealth physiotherapy programme. Method and analysis This type 1 hybrid effectiveness-implementation randomised controlled trial will involve 240 people aged 65+ years receiving aged care services in community or residential settings. Participants will be randomised to either: (1) the Telehealth Physiotherapy for Older People (TOP UP) Program or (2) a wait-list control group. The 6-month intervention includes 10 physiotherapy sessions delivered by videocall (Zoom). The intervention will include the local support of an aged care worker and online exercise resources. Primary outcome is mobility at 6 months post randomisation measured by the Short Physical Performance Battery. Secondary outcomes include rate of falls, sit-to-stand, quality of life, and goal attainment at 6 months after randomisation. Regression models will assess the effect of group allocation on mobility and the other continuously scored secondary outcomes, adjusting for baseline scores. The number of falls per person over 6 months will be analysed using negative binomial regression models to estimate between-group differences. An economic analysis will explore the cost-effectiveness of the TOP UP programme compared with usual care. Implementation outcomes and determinants relating to the intervention's reach, fidelity, exercise dose delivered, adoption, feasibility, acceptability, barriers and facilitators will be explored using mixed methods. Conclusion This is the first trial to investigate the effectiveness, cost-effectiveness and implementation of a physiotherapy intervention in aged care delivered solely by telehealth internationally. The study has strong aged care co-design and governance and is guided by steering and advisory committees that include staff from aged care service providers and end-users. Trial results will be disseminated via peer-reviewed articles, conference presentations and lay summaries. Trial registration number The trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN 12621000734864)

Departures From Axisymmetric Morphology and Dynamics in Spiral Galaxies

New HI synthesis data have been obtained for six face-on galaxies with the Very Large Array. These data and reanalyses of three additional data sets make up a sample of nine face-on galaxies analyzed for deviations from axisymmetry in morphology and dynamics. This sample represents a subsample of galaxies already analyzed for morphological symmetry properties in the R-band. Four quantitative measures of dynamical nonaxisymmetry are compared to one another and to the quantitative measures of morphological asymmetry in HI and R-band to investigate the relationships between nonaxisymmetric morphology and dynamics. We find no significant relationship between asymmetric morphology and most of the dynamical measures in our sample. A possible relationship is found, however, between morphology and dynamical position angle differences between approaching and receding sides of the galaxy.Comment: 24 pages, 19 figures, AASTeX, accepted for publication in AJ, postscript figures available at ftp://culebra.tn.cornell.edu/pub/david/figures.tar.g

Planck pre-launch status: HFI beam expectations from the optical optimisation of the focal plane

Planck is a European Space Agency (ESA) satellite, launched in May 2009, which will map the cosmic microwave background anisotropies in intensity and polarisation with unprecedented detail and sensitivity. It will also provide full-sky maps of astrophysical foregrounds. An accurate knowledge of the telescope beam patterns is an essential element for a correct analysis of the acquired astrophysical data. We present a detailed description of the optical design of the High Frequency Instrument (HFI) together with some of the optical performances measured during the calibration campaigns. We report on the evolution of the knowledge of the pre-launch HFI beam patterns when coupled to ideal telescope elements, and on their significance for the HFI data analysis procedure

The HI content of the Eridanus group of galaxies

The HI content of galaxies in the Eridanus group is studied using the GMRT observations and the HIPASS data. A significant HI deficiency up to a factor of 2-3 is observed in galaxies in the high galaxy density regions. The HI deficiency in galaxies is observed to be directly correlated with the local projected galaxy density, and inversely correlated with the line-of-sight radial velocity. Furthermore, galaxies with larger optical diameters are predominantly in the lower galaxy density regions. It is suggested that the HI deficiency in Eridanus is due to tidal interactions. In some galaxies, evidences of tidal interactions are seen. An important implication is that significant evolution of galaxies can take place in the group environment. In the hierarchical way of formation of clusters via mergers of groups, a fraction of the observed HI deficiency in clusters could have originated in groups. The co-existence of S0's and severely HI deficient galaxies in the Eridanus group suggests that galaxy harassment is likely to be an effective mechanism for transforming spirals to S0's.Comment: 21 pages; Accepted for publication in Journal of Astroph. & Astron. March, 200

ACBAR: The Arcminute Cosmology Bolometer Array Receiver

We describe the Arcminute Cosmology Bolometer Array Receiver (ACBAR); a multifrequency millimeter-wave receiver designed for observations of the Cosmic Microwave Background (CMB) and the Sunyaev-Zel'dovich effect in clusters of galaxies. The ACBAR focal plane consists of a 16-pixel, background-limited, 240 mK bolometer array that can be configured to observe simultaneously at 150, 220, 280, and 350 GHz. With 4-5' FWHM Gaussian beam sizes and a 3 degree azimuth chop, ACBAR is sensitive to a wide range of angular scales. ACBAR was installed on the 2 m Viper telescope at the South Pole in January 2001. We describe the design of the instrument and its performance during the 2001 and 2002 observing seasons.Comment: 59 pages, 16 figures -- updated to reflect version published in ApJ

GMRT HI observations of the Eridanus group of galaxies

The GMRT HI 21cm-line observations of galaxies in the Eridanus group are presented. The Eridanus group, at a distance of ~23 Mpc, is a loose group of \~200 galaxies. The group extends more than 10 Mpc in projection. The velocity dispersion of the galaxies in the group is ~240 km/s. The galaxies are clustered into different sub-groups. The overall population mix of the group is 30% (E+S0) and 70% (Sp+Irr). The observations of 57 Eridanus galaxies were carried out with the GMRT for ~200 hour. HI emission was detected from 31 galaxies. The channel rms of ~1.0 mJy beam^{-1} was achieved for most of the image-cubes made with 4 hour of data. The corresponding HI column density sensitivity (3-sigma) is ~1x10^{20} cm^{-2} for a velocity-width of ~13.4 km/s. The 3-sigma detection limit of HI mass is ~1.2x10^{7} M_sun for a line-width of 50 km/s. Total HI images, HI velocity fields, global HI line profiles, HI mass surface densities, HI disk parameters and HI rotation curves are presented. The velocity fields are analysed separately for the approaching and the receding sides of the galaxies. This data will be used to study the HI and the radio continuum properties, the Tully-Fisher relations, the dark matter halos, and the kinematical and HI lopsidedness in galaxies.Comment: 75 pages including HI atlas; Accepted for publication in Journal of Astroph. & Astron. March, 200