The stalking ground: Some varieties of human conduct seen in and through a frame of ritual.

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Building Large Phylogenetic Trees on Coarse-Grained Parallel Machines

Abstract Phylogenetic analysis is an area of computational biology concerned with the reconstruction of evolutionary relationships between organisms, genes, and gene families. Maximum likelihood evaluation has proven to be one of the most reliable methods for constructing phylogenetic trees. The huge computational requirements associated with maximum likelihood analysis means that it is not feasible to produce large phylogenetic trees using a single processor. We have completed a fully cross platform coarse-grained distributed application, DPRml, which overcomes many of the limitations imposed by the current set of parallel phylogenetic programs. We have completed a set of efficiency tests that show how to maximise efficiency while using the program to build large phylogenetic trees. The software is publicly available under the terms of the GNU general public licence from the system webpage at http://www.cs.nuim.ie/distributed

Molecular Identity and Spatial Topography of Transient A-type Potassium Channels in the Rostral Nucleus of the Solitary Tract

The potent hedonic properties of tastes strongly affect dietary selection and are linked to clinical conditions associated with overconsumption and obesity. Understanding how taste is represented and processed in the brain is thus important to promote human health. CNS gustatory processing begins in the rostral nucleus of the solitary tract (rNST). Factors influencing the output signal from the rNST to areas that control ingestive behavior include the synaptic interactions of neurons within the nucleus and the intrinsic membrane properties of the neurons themselves. In particular, transient A-type potassium channels, which produce an outward IA current, have been shown to modulate sensory signals in both the caudal and rostral poles of the NST. However, the molecular identity of the IA channel on the two major phenotypes of neurons within the rNST, GABAergic interneurons and glutamatergic projection neurons, as well as the distribution of these channels within the different subdivisions of the rNST remains unclear. Previous literature suggest that IA is concentrated on non-GABAergic projection neurons in the central subdivision of rNST, while the channels are absent on GABAergic neurons in the ventral subdivision. However, we recently found that a subpopulation of GABAergic neurons do contain IA. Consequently, IA current is not exclusive to non-GABAergic projection cells, but exists on both cell phenotypes. In the present study, immunohistochemical and pharmacological approaches were used to identify the molecular identity of the potassium channel contributing to IA in the rNST and to describe its location within the nucleus. These data suggest that Kv4.3, a member of the Kv4 family, is primarily responsible for the IA current. Furthermore, it was observed that this channel is evenly distributed throughout the rNST, predominately in the neuropil, rather than on the cell soma. Pharmacologically blocking the IA channel using a toxin specific to the Kv4 family had similar effects on both GABAergic and non-GABAergic neurons. In both cell phenotypes the toxin reduced the first-spike delay and IA current amplitude seen in cells with IA. Because the expression of IA is sensitive to inhibition, we are exploring the interaction between IA and inhibition in sensory processing in the rNST.Research Supported by the NIH NIDCD Grant: ROIDC016112 Grant: R21DC013676Academic Major: Biolog

USP4 Auto-Deubiquitylation Promotes Homologous Recombination.

Repair of DNA double-strand breaks is crucial for maintaining genome integrity and is governed by post-translational modifications such as protein ubiquitylation. Here, we establish that the deubiquitylating enzyme USP4 promotes DNA-end resection and DNA repair by homologous recombination. We also report that USP4 interacts with CtIP and the MRE11-RAD50-NBS1 (MRN) complex and is required for CtIP recruitment to DNA damage sites. Furthermore, we show that USP4 is ubiquitylated on multiple sites including those on cysteine residues and that deubiquitylation of these sites requires USP4 catalytic activity and is required for USP4 to interact with CtIP/MRN and to promote CtIP recruitment and DNA repair. Lastly, we establish that regulation of interactor binding by ubiquitylation occurs more generally among USP-family enzymes. Our findings thus identify USP4 as a novel DNA repair regulator and invoke a model in which ubiquitin adducts regulate USP enzyme interactions and functions.Research in the S.P.J. laboratory is funded by CRUK Program Grant C6/A11224, CRUK Project Grant C6/A14831 and the European Community Seventh Framework Program grant agreement no. HEALTH-F2-2010-259893 (DDResponse). R.N. was funded by the Daiichi Sankyo Foundation of Life Sciences fellowship. Cancer Research UK Grant C6946/A14492 and Wellcome Trust Grant WT092096 provided core infrastructure funding. S.P.J receives his salary from the University of Cambridge, supplemented by CRUK. The John Fell Fund 133/075 and the Wellcome Trust grant 097813/Z/11/Z funded research performed by B.M.K and R.K..This is the final version of the article. It was first available from Elsevier via http://dx.doi.org/10.1016/j.molcel.2015.09.01

Highly disordered histone H1-DNA model complexes and their condensates.

Disordered proteins play an essential role in a wide variety of biological processes, and are often posttranslationally modified. One such protein is histone H1; its highly disordered C-terminal tail (CH1) condenses internucleosomal linker DNA in chromatin in a way that is still poorly understood. Moreover, CH1 is phosphorylated in a cell cycle-dependent manner that correlates with changes in the chromatin condensation level. Here we present a model system that recapitulates key aspects of the in vivo process, and also allows a detailed structural and biophysical analysis of the stages before and after condensation. CH1 remains disordered in the DNA-bound state, despite its nanomolar affinity. Phase-separated droplets (coacervates) form, containing higher-order assemblies of CH1/DNA complexes. Phosphorylation at three serine residues, spaced along the length of the tail, has little effect on the local properties of the condensate. However, it dramatically alters higher-order structure in the coacervate and reduces partitioning to the coacervate phase. These observations show that disordered proteins can bind tightly to DNA without a disorder-to-order transition. Importantly, they also provide mechanistic insights into how higher-order structures can be exquisitely sensitive to perturbation by posttranslational modifications, thus broadening the repertoire of mechanisms that might regulate chromatin and other macromolecular assemblies