Detecting the direction of a signal on high-dimensional spheres: Non-null and Le Cam optimality results

We consider one of the most important problems in directional statistics, namely the problem of testing the null hypothesis that the spike direction $\theta$ of a Fisher-von Mises-Langevin distribution on the $p$-dimensional unit hypersphere is equal to a given direction $\theta_0$. After a reduction through invariance arguments, we derive local asymptotic normality (LAN) results in a general high-dimensional framework where the dimension $p_n$ goes to infinity at an arbitrary rate with the sample size $n$, and where the concentration $\kappa_n$ behaves in a completely free way with $n$, which offers a spectrum of problems ranging from arbitrarily easy to arbitrarily challenging ones. We identify various asymptotic regimes, depending on the convergence/divergence properties of $(\kappa_n)$, that yield different contiguity rates and different limiting experiments. In each regime, we derive Le Cam optimal tests under specified $\kappa_n$ and we compute, from the Le Cam third lemma, asymptotic powers of the classical Watson test under contiguous alternatives. We further establish LAN results with respect to both spike direction and concentration, which allows us to discuss optimality also under unspecified $\kappa_n$. To investigate the non-null behavior of the Watson test outside the parametric framework above, we derive its local asymptotic powers through martingale CLTs in the broader, semiparametric, model of rotationally symmetric distributions. A Monte Carlo study shows that the finite-sample behaviors of the various tests remarkably agree with our asymptotic results.Comment: 47 pages, 4 figure

The different roles of ‘design process champions’ for digital libraries in African higher education

The concept of design stakeholders is central to effective design of digital libraries. We report on research findings that identified the presence of a key subset of stakeholders which we term ‘design process champions’. Our findings have identified that these champions can change interaction patterns and the eventual output of the other stakeholders (project participants) in the design process of digital library projects. This empirical research is based upon 38 interviews with key stakeholders and a review of documentary evidence in ten innovative digital library design projects (e.g. mobile clinical libraries) located in three African universities in Kenya, Uganda and South Africa. Through a grounded theory approach two different types of the ‘design process champions’ emerged from the data with varying levels of effectiveness in the design process: (i) domain champions and (ii) multidisciplinary champions. The domain champions assume a ‘siloed’ approach of engagement while the multidisciplinary champions take on a participatory engagement throughout the design process. A discussion of the implications of information specialists functioning as domain champions is highlighted. We conclude by suggesting that the multidisciplinary champions’ approach is particularly useful in supporting sustainability of digital library design projects

The Two Different Isoforms of the RSC Chromatin Remodeling Complex Play Distinct Roles in DNA Damage Responses

The RSC chromatin remodeling complex has been implicated in contributing to DNA double-strand break (DSB) repair in a number of studies. Both survival and levels of H2A phosphorylation in response to damage are reduced in the absence of RSC. Importantly, there is evidence for two isoforms of this complex, defined by the presence of either Rsc1 or Rsc2. Here, we investigated whether the two isoforms of RSC provide distinct contributions to DNA damage responses. First, we established that the two isoforms of RSC differ in the presence of Rsc1 or Rsc2 but otherwise have the same subunit composition. We found that both rsc1 and rsc2 mutant strains have intact DNA damage-induced checkpoint activity and transcriptional induction. In addition, both strains show reduced non-homologous end joining activity and have a similar spectrum of DSB repair junctions, suggesting perhaps that the two complexes provide the same functions. However, the hypersensitivity of a rsc1 strain cannot be complemented with an extra copy of RSC2, and likewise, the hypersensitivity of the rsc2 strain remains unchanged when an additional copy of RSC1 is present, indicating that the two proteins are unable to functionally compensate for one another in DNA damage responses. Rsc1, but not Rsc2, is required for nucleosome sliding flanking a DNA DSB. Interestingly, while swapping the domains from Rsc1 into the Rsc2 protein does not compromise hypersensitivity to DNA damage suggesting they are functionally interchangeable, the BAH domain from Rsc1 confers upon Rsc2 the ability to remodel chromatin at a DNA break. These data demonstrate that, despite the similarity between Rsc1 and Rsc2, the two different isoforms of RSC provide distinct functions in DNA damage responses, and that at least part of the functional specificity is dictated by the BAH domains

Alendronate increases BMD at appendicular and axial skeletons in patients with established osteoporosis

<p>Abstract</p> <p>Background</p> <p>To identify high-risk patients and provide pharmacological treatment is one of the effective approaches in prevention of osteoporotic fractures. This study investigated the effect of 12-month Alendronate treatment on bone mineral density (BMD) and bone turnover biochemical markers in postmenopausal women with one or more non-traumatic fractures, i.e. patients with established osteoporosis.</p> <p>Methods</p> <p>A total of 118 Hong Kong postmenopausal Chinese women aged 50 to 75 with low-energy fracture at distal radius (Colles' fracture) were recruited for BMD measurement at lumbar spine and non-dominant hip using Dual-Energy X-ray Absorptiometry (DXA). 47 women with BMD T-score below -2 SD at either side were identified as patients with established osteoporosis and then randomized into Alendronate group (n = 22) and placebo control group (n = 25) for BMD measurement at spine and hip using DXA and distal radius of the non-fracture side by peripheral quantitative computed tomography (pQCT), and bone turnover markers, including bone forming alkaline phosphatase (BALP) and bone resorbing urinary Deoxypyridinoline (DPD). All measurements were repeated at 6 and 12 months.</p> <p>Results</p> <p>Alendronate treatment significantly increased BMD, more in weight-bearing skeletons (5.1% at spine and 2.5% at hip) than in non-weight bearing skeleton (0.9% at distal radius) after 12 months treatment. Spine T-score was significant improved in Alendronate group (p < 0.01) (from -2.2 to -1.9) but not in control placebo group. The Alendronate treatment effect was explained by significant suppression of bone turnover.</p> <p>Conclusion</p> <p>12 months Alendronate treatment was effective to increase BMD at both axial and appendicular skeletons in postmenopausal women with established osteoporosis.</p

Morphology of the earliest reconstructable tetrapod Parmastega aelidae.

The known diversity of tetrapods of the Devonian period has increased markedly in recent decades, but their fossil record consists mostly of tantalizing fragments1-15. The framework for interpreting the morphology and palaeobiology of Devonian tetrapods is dominated by the near complete fossils of Ichthyostega and Acanthostega; the less complete, but partly reconstructable, Ventastega and Tulerpeton have supporting roles2,4,16-34. All four of these genera date to the late Famennian age (about 365-359 million years ago)-they are 10 million years younger than the earliest known tetrapod fragments5,10, and nearly 30 million years younger than the oldest known tetrapod footprints35. Here we describe Parmastega aelidae gen. et sp. nov., a tetrapod from Russia dated to the earliest Famennian age (about 372 million years ago), represented by three-dimensional material that enables the reconstruction of the skull and shoulder girdle. The raised orbits, lateral line canals and weakly ossified postcranial skeleton of P. aelidae suggest a largely aquatic, surface-cruising animal. In Bayesian and parsimony-based phylogenetic analyses, the majority of trees place Parmastega as a sister group to all other tetrapods

Improved RAD51 binders through motif shuffling based on the modularity of BRC repeats.

This is the final version. Available from the National Academy of Sciences via the DOI in this record. SI Appendix contains detailed descriptions of the cloning of bacterial expression constructs for the 64 shuffled BRC peptide variants, cloning of mammalian expression constructs, and notes on the soluble expression of the shuffled BRC peptide variants. Also included is a description of ITC used to cross-validate the microfluidic measurements, single concentration point measurements carried out with microfluidics, and exemplary titrations carried out by microfluidics. The fluorescence anisotropy data obtained for the 64 separate titrations as well as the Matlab script used in the analysis have been uploaded as separate files. The supplementary data also contain an analysis on the effect of shuffling of BRC peptides and in particular on the effect of the exact shuffle cutoff point placement. X-ray crystallography electron density map images, data collection, and refinement statistics are also to be found in SI Appendix. Additional cell images highlighting the pan-nuclear signal of RAD51 are also included in SI Appendix. The coordinates and corresponding structure factors for the monomeric RAD51:BRC8-2 complex have been deposited to the PDB under accession code 6HQU. As described previously (49), the transformation from intensity maps into anisotropy values from image data was carried out with a custom Matlab code available on GitHub (https://github.com/quantitativeimaging/icetropy). A custom Matlab script used to fit Kd values for the unlabeled competitive GB1-BRC peptides can be found in SI Appendix, Datasets S1–S4. All other study data are included in the article and/or supporting information.Exchanges of protein sequence modules support leaps in function unavailable through point mutations during evolution. Here we study the role of the two RAD51-interacting modules within the eight binding BRC repeats of BRCA2. We created 64 chimeric repeats by shuffling these modules and measured their binding to RAD51. We found that certain shuffled module combinations were stronger binders than any of the module combinations in the natural repeats. Surprisingly, the contribution from the two modules was poorly correlated with affinities of natural repeats, with a weak BRC8 repeat containing the most effective N-terminal module. The binding of the strongest chimera, BRC8-2, to RAD51 was improved by -2.4 kCal/mol compared to the strongest natural repeat, BRC4. A crystal structure of RAD51:BRC8-2 complex shows an improved interface fit and an extended β-hairpin in this repeat. BRC8-2 was shown to function in human cells, preventing the formation of nuclear RAD51 foci after ionizing radiation.Biotechnology and Biological Sciences Research CouncilEuropean Research CouncilMarie Curie Research GrantCancer Research UKEngineering and Physical Sciences Research CouncilEngineering and Physical Sciences Research CouncilWellcome TrustWellcome TrustMedical Research CouncilMedical Research CouncilSchweizerischer Nationalfond

Theoretical study of the insulating oxides and nitrides: SiO2, GeO2, Al2O3, Si3N4, and Ge3N4

An extensive theoretical study is performed for wide bandgap crystalline oxides and nitrides, namely, SiO_{2}, GeO_{2}, Al_{2}O_{3}, Si_{3}N_{4}, and Ge_{3}N_{4}. Their important polymorphs are considered which are for SiO_{2}: $\alpha$-quartz, $\alpha$- and $\beta$-cristobalite and stishovite, for GeO_{2}: $\alpha$-quartz, and rutile, for Al_{2}O_{3}: $\alpha$-phase, for Si_{3}N_{4} and Ge_{3}N_{4}: $\alpha$- and $\beta$-phases. This work constitutes a comprehensive account of both electronic structure and the elastic properties of these important insulating oxides and nitrides obtained with high accuracy based on density functional theory within the local density approximation. Two different norm-conserving \textit{ab initio} pseudopotentials have been tested which agree in all respects with the only exception arising for the elastic properties of rutile GeO_{2}. The agreement with experimental values, when available, are seen to be highly satisfactory. The uniformity and the well convergence of this approach enables an unbiased assessment of important physical parameters within each material and among different insulating oxide and nitrides. The computed static electric susceptibilities are observed to display a strong correlation with their mass densities. There is a marked discrepancy between the considered oxides and nitrides with the latter having sudden increase of density of states away from the respective band edges. This is expected to give rise to excessive carrier scattering which can practically preclude bulk impact ionization process in Si_{3}N_{4} and Ge_{3}N_{4}.Comment: Published version, 10 pages, 8 figure

The SWR1 Histone Replacement Complex Causes Genetic Instability and Genome-Wide Transcription Misregulation in the Absence of H2A.Z

The SWR1 complex replaces the canonical histone H2A with the variant H2A.Z (Htz1 in yeast) at specific chromatin regions. This dynamic alteration in nucleosome structure provides a molecular mechanism to regulate transcription, gene silencing, chromosome segregation and DNA repair. Here we show that genetic instability, sensitivity to drugs impairing different cellular processes and genome-wide transcriptional misregulation in htz1Δ can be partially or totally suppressed if SWR1 is not formed (swr1Δ), if it forms but cannot bind to chromatin (swc2Δ) or if it binds to chromatin but lacks histone replacement activity (swc5Δ and the ATPase-dead swr1-K727G). These results suggest that in htz1Δ the nucleosome remodelling activity of SWR1 affects chromatin integrity because of an attempt to replace H2A with Htz1 in the absence of the latter. This would impair transcription and, either directly or indirectly, other cellular processes. Specifically, we show that in htz1Δ, the SWR1 complex causes an accumulation of recombinogenic DNA damage by a mechanism dependent on phosphorylation of H2A at Ser129, a modification that occurs in response to DNA damage, suggesting that the SWR1 complex impairs the repair of spontaneous DNA damage in htz1Δ. In addition, SWR1 causes DSBs sensitivity in htz1Δ; consistently, in the absence of Htz1 the SWR1 complex bound near an endonuclease HO-induced DSB at the mating-type (MAT) locus impairs DSB-induced checkpoint activation. Our results support a stepwise mechanism for the replacement of H2A with Htz1 and demonstrate that a tight control of this mechanism is essential to regulate chromatin dynamics but also to prevent the deleterious consequences of an incomplete nucleosome remodelling

Lighting during grow-out and Salmonella in broiler flocks

<p>Abstract</p> <p>Background</p> <p>Lighting is used during conventional broiler grow-out to modify bird behaviour to reach the goals of production and improve bird welfare. The protocols for lighting intensity vary. In a field study, we evaluated if the lighting practices impact the burden of <it>Salmonella </it>in broiler flocks.</p> <p>Methods</p> <p>Conventional grow-out flocks reared in the states of Alabama, Mississippi and Texas, USA in 2003 to 2006 were sampled 1 week before harvest (<it>n </it>= 58) and upon arrival for processing (<it>n </it>= 56) by collecting feathered carcass rinsate, crop and one cecum from each of 30 birds, and during processing by collecting rinsate of 30 carcasses at pre-chilling (<it>n </it>= 56) and post-chilling points (<it>n </it>= 54). Litter samples and drag swabs of litter were collected from the grow-out houses after bird harvest (<it>n </it>= 56). Lighting practices for these flocks were obtained with a questionnaire completed by the growers. Associations between the lighting practices and the burden of <it>Salmonella </it>in the flocks were tested while accounting for variation between the grow-out farms, their production complexes and companies.</p> <p>Results</p> <p>Longer relative duration of reduced lights during the grow-out period was associated with reduced detection of <it>Salmonella </it>on the exterior of birds 1 week before harvest and on the broiler carcasses at the post-chilling point of processing. In addition, starting reduced lights for ≥18 hours per day later in the grow-out period was associated with decreased detection of <it>Salmonella </it>on the exterior of broilers arriving for processing and in the post-harvest drag swabs of litter from the grow-out house.</p> <p>Conclusions</p> <p>The results of this field study show that lighting practices implemented during broiler rearing can impact the burden of <it>Salmonella </it>in the flock. The underlying mechanisms are likely to be interactive.</p