The AMC Linear Disability Score in patients with newly diagnosed Parkinson disease

Objective: The aim of this study was to examine the clinimetric properties of the AMC Linear Disability Score (ALDS), a new generic disability measure based on Item Response Theory, in patients with newly diagnosed Parkinson disease (PD).\ud \ud Methods: A sample of 132 patients with PD was evaluated using the Hoehn and Yahr (H&Y), the Unified PD Rating Scale motor examination, the Schwab and England scale (S&E), the Short Form–36, the PD Quality of Life Questionnaire, and the ALDS.\ud \ud Results: The internal consistency reliability of the ALDS was good ([alpha] = 0.95) with 55 items extending the sufficient item-total correlation criterion (r > 0.20). The ALDS was correlated with other disability measures (r = 0.50 to 0.63) and decreasingly associated with measures reflecting impairments (r = 0.36 to 0.37) and mental health (r = 0.23 to -0.01). With regard to know-group validity, the ALDS indicated that patients with more severe PD (H&Y stage 3) were more disabled than patients with mild (H&Y stage 1) or moderate PD (H&Y stage 2) (p < 0.0001). The ALDS discriminated between more or less severe extrapyramidal symptoms (p = 0.001) and patients with postural instability showed lower ALDS scores compared to patients without postural instability (p = < 0.0001). Compared to the S&E (score 100% = 19%), the ALDS showed less of a ceiling effect (5%).\ud \ud Conclusion: The AMC Linear Disability Score is a flexible, feasible, and clinimetrically promising instrument to assess the level of disability in patients with newly diagnosed Parkinson disease

Protein Evolution in Yeast Transcription Factor Subnetworks

When averaged over the full yeast protein–protein interaction and transcriptional regulatory networks, protein hubs with many interaction partners or regulators tend to evolve significantly more slowly due to increased negative selection. However, genome-wide analysis of protein evolution in the subnetworks of associations involving yeast transcription factors (TFs) reveals that TF hubs do not tend to evolve significantly more slowly than TF non-hubs. This result holds for all four major types of TF hubs: interaction hubs, regulatory in-degree and out-degree hubs, as well as co-regulatory hubs that jointly regulate target genes with many TFs. Furthermore, TF regulatory in-degree hubs tend to evolve significantly more quickly than TF non-hubs. Most importantly, the correlations between evolutionary rate (KA/KS) and degrees for TFs are significantly more positive than those for generic proteins within the same global protein–protein interaction and transcriptional regulatory networks. Compared to generic protein hubs, TF hubs operate at a higher level in the hierarchical structure of cellular networks, and hence experience additional evolutionary forces (relaxed negative selection or positive selection through network rewiring). The striking difference between the evolution of TF hubs and generic protein hubs demonstrates that components within the same global network can be governed by distinct organizational and evolutionary principles.National Natural Science Foundation of China (10801131, 10631070); National Science Foundation (DGE-0654108); Pharmaceutical Research and Manufacturers of America Foundation (Research Starter Grant in Informatics); K. C. Wong Education Foundatio

An effectual template bank for the detection of gravitational waves from inspiralling compact binaries with generic spins

We report the construction of a three-dimensional template bank for the search for gravitational waves from inspiralling binaries consisting of spinning compact objects. The parameter space consists of two dimensions describing the mass parameters and one "reduced-spin" parameter, which describes the secular (non-precessing) spin effects in the waveform. The template placement is based on an efficient stochastic algorithm and makes use of the semi-analytical computation of a metric in the parameter space. We demonstrate that for "low-mass" ($m_1 + m_2 \lesssim 12\,M_\odot$) binaries, this template bank achieves effective fitting factors $\sim0.92$--$0.99$ towards signals from generic spinning binaries in the advanced detector era over the entire parameter space of interest (including binary neutron stars, binary black holes, and black hole-neutron star binaries). This provides a powerful and viable method for searching for gravitational waves from generic spinning low-mass compact binaries. Under the assumption that spin magnitudes of black-holes [neutron-stars] are uniformly distributed between 0--0.98 [0 -- 0.4] and spin angles are isotropically distributed, the expected improvement in the average detection volume (at a fixed signal-to-noise-ratio threshold) of a search using this reduced-spin bank is $\sim20-52\%$, as compared to a search using a non-spinning bank.Comment: Minor changes, version appeared in Phys. Rev.

Formation of regulatory modules by local sequence duplication

Turnover of regulatory sequence and function is an important part of molecular evolution. But what are the modes of sequence evolution leading to rapid formation and loss of regulatory sites? Here, we show that a large fraction of neighboring transcription factor binding sites in the fly genome have formed from a common sequence origin by local duplications. This mode of evolution is found to produce regulatory information: duplications can seed new sites in the neighborhood of existing sites. Duplicate seeds evolve subsequently by point mutations, often towards binding a different factor than their ancestral neighbor sites. These results are based on a statistical analysis of 346 cis-regulatory modules in the Drosophila melanogaster genome, and a comparison set of intergenic regulatory sequence in Saccharomyces cerevisiae. In fly regulatory modules, pairs of binding sites show significantly enhanced sequence similarity up to distances of about 50 bp. We analyze these data in terms of an evolutionary model with two distinct modes of site formation: (i) evolution from independent sequence origin and (ii) divergent evolution following duplication of a common ancestor sequence. Our results suggest that pervasive formation of binding sites by local sequence duplications distinguishes the complex regulatory architecture of higher eukaryotes from the simpler architecture of unicellular organisms