DNA DSB repair pathway choice: an orchestrated handover mechanism

DNA double strand breaks (DSBs) are potential lethal lesions but can also lead to chromosome rearrangements, a step promoting carcinogenesis. DNA non-homologous end-joining (NHEJ) is the major DSB rejoining process and occurs in all cell cycle stages. Homologous recombination (HR) can additionally function to repair irradiation-induced two-ended DSBs in G2 phase. In mammalian cells, HR predominantly uses a sister chromatid as a template for DSB repair; thus HR functions only in late S/G2 phase. Here, we review current insight into the interplay between HR and NHEJ in G2 phase. We argue that NHEJ represents the first choice pathway, repairing approximately 80% of X-ray-induced DSBs with rapid kinetics. However, a subset of DSBs undergoes end resection and repair by HR. 53BP1 restricts resection, thereby promoting NHEJ. During the switch fromNHEJ to HR, 53BP1 is repositioned to the periphery of enlarged irradiation-induced foci (IRIF) via a BRCA1-dependent process. K63-linked ubiquitin chains, which also form at IRIF, are also repositioned as well as receptor-associated protein 80 (RAP80), a ubiquitin binding protein. RAP80 repositioning requires POH1, a proteasome component. Thus, the interfacing barriers to HR, 53BP1 and RAP80 are relieved by POH1 and BRCA1, respectively. Removal of RAP80 from the IRIF core is required for loss of the ubiquitin chains and 53BP1, and for efficient replication protein A foci formation. We propose that NHEJ is used preferentially to HR because it is a compact process that does not necessitate extensive chromatin changes in the DSB vicinity

Finite element modelling of pellet-clad interaction during operational transients

A finite element model of pellet-clad interaction in advanced gas cooled reactor fuel experiencing extended reduced power operations is presented. The model considers a 1/8th segment of fuel and overlaying cladding bonded to it. A radial crack is introduced to the pellet, this is able to open and close, straining a section of cladding above the crack. In addition, circumferential cracks in the fuel pellet result in a sliver of fuel being bonded to the cladding; this sliver of fuel contains hairline radial cracks, known as ladder cracks, the opening and closing of which are modelled. Finally, the model predicts the creep strain at the tip of an incipient crack in the cladding, ahead of the radial crack in the fuel pellet. Results show that the crack tip creep strain is strongly dependent on the model of ladder cracking chosen

Effects of upwelling duration and phytoplankton growth regime on dissolved-oxygen levels in an idealized Iberian Peninsula upwelling system

Abstract. We apply a coupled modelling system composed of a state-of-the-art hydrodynamical model and a low-complexity biogeochemical model to an idealized Iberian Peninsula upwelling system to identify the main drivers of dissolved-oxygen variability and to study its response to changes in the duration of the upwelling season and in the phytoplankton growth regime. We find that the export of oxygenated waters by upwelling front turbulence is a major sink for nearshore dissolved oxygen. In our simulations of summer upwelling, when the phytoplankton population is generally dominated by diatoms whose growth is boosted by nutrient input, net primary production and air–sea exchange compensate dissolved-oxygen depletion by offshore export over the shelf. A shorter upwelling duration causes a relaxation of upwelling winds and a decrease in offshore export, resulting in a slight increase of net dissolved-oxygen enrichment in the coastal region as compared to longer upwelling durations. When phytoplankton is dominated by groups less sensitive to nutrient inputs, growth rates decrease, and the coastal region becomes net heterotrophic. Together with the physical sink, this lowers the net oxygenation rate of coastal waters, which remains positive only because of air–sea exchange. These findings help in disentangling the physical and biogeochemical controls of dissolved oxygen in upwelling systems and, together with projections of increased duration of upwelling seasons and phytoplankton community changes, suggest that the Iberian coastal upwelling region may become more vulnerable to hypoxia and deoxygenation. This research has been supported by the IDEX UNITI – University of Toulouse (TEASAO IDEX UNITI – Univer- sity of Toulouse)

Optimal search strategies for identifying sound clinical prediction studies in EMBASE

BACKGROUND: Clinical prediction guides assist clinicians by pointing to specific elements of the patient's clinical presentation that should be considered when forming a diagnosis, prognosis or judgment regarding treatment outcome. The numbers of validated clinical prediction guides are growing in the medical literature, but their retrieval from large biomedical databases remains problematic and this presents a barrier to their uptake in medical practice. We undertook the systematic development of search strategies ("hedges") for retrieval of empirically tested clinical prediction guides from EMBASE. METHODS: An analytic survey was conducted, testing the retrieval performance of search strategies run in EMBASE against the gold standard of hand searching, using a sample of all 27,769 articles identified in 55 journals for the 2000 publishing year. All articles were categorized as original studies, review articles, general papers, or case reports. The original and review articles were then tagged as 'pass' or 'fail' for methodologic rigor in the areas of clinical prediction guides and other clinical topics. Search terms that depicted clinical prediction guides were selected from a pool of index terms and text words gathered in house and through request to clinicians, librarians and professional searchers. A total of 36,232 search strategies composed of single and multiple term phrases were trialed for retrieval of clinical prediction studies. The sensitivity, specificity, precision, and accuracy of search strategies were calculated to identify which were the best. RESULTS: 163 clinical prediction studies were identified, of which 69 (42.3%) passed criteria for scientific merit. A 3-term strategy optimized sensitivity at 91.3% and specificity at 90.2%. Higher sensitivity (97.1%) was reached with a different 3-term strategy, but with a 16% drop in specificity. The best measure of specificity (98.8%) was found in a 2-term strategy, but with a considerable fall in sensitivity to 60.9%. All single term strategies performed less well than 2- and 3-term strategies. CONCLUSION: The retrieval of sound clinical prediction studies from EMBASE is supported by several search strategies

The Directed Dominating Set Problem: Generalized Leaf Removal and Belief Propagation

A minimum dominating set for a digraph (directed graph) is a smallest set of vertices such that each vertex either belongs to this set or has at least one parent vertex in this set. We solve this hard combinatorial optimization problem approximately by a local algorithm of generalized leaf removal and by a message-passing algorithm of belief propagation. These algorithms can construct near-optimal dominating sets or even exact minimum dominating sets for random digraphs and also for real-world digraph instances. We further develop a core percolation theory and a replica-symmetric spin glass theory for this problem. Our algorithmic and theoretical results may facilitate applications of dominating sets to various network problems involving directed interactions.Comment: 11 pages, 3 figures in EPS forma

Morphometry of the Cranial Base in Subjects with Class III Malocclusion

The significance of the cranial base in the development of Class III malocclusion remains uncertain. The purpose of this study was to determine whether the form of the cranial base differs between prepubertal Class I and Class III subjects. Lateral cephalographs of 73 children of European-American descent aged between 5 and 11 years with Class III malocclusion were compared with those of their counterparts with a normal, Class I molar occlusion. The cephalographs were traced, checked, and subdivided into seven age- and sex-matched groups. Average geometries, scaled to an equivalent size, were generated based on 13 craniofacial landmarks by means of Procrustes analysis, and these configurations were statistically tested for equivalence. Bivariate and multivariate analyses utilizing 5 linear and angular measurements were undertaken to corroborate the Procrustes analysis. Graphical analysis, utilizing thin-plate spline and finite element methods, was performed for localization of differences in cranial base morphology. Results indicated that cranial base morphology differed statistically for all age-wise comparisons. Graphical analysis revealed that the greatest differences in morphology occurred in the posterior cranial base region, which generally consisted of horizontal compression, vertical expansion, and size contraction. The sphenoidal region displayed expansion, while the anterior regions showed shearing and local increases in size. It is concluded that the shape of the cranial base differs in subjects with Class III malocclusion compared with the normal Class I configuration, due in part to deficient orthocephalization, or failure of the cranial base to flatten during development.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/67377/2/10.1177_00220345970760021101.pd

Functional Diversity and Structural Disorder in the Human Ubiquitination Pathway

The ubiquitin-proteasome system plays a central role in cellular regulation and protein quality control (PQC). The system is built as a pyramid of increasing complexity, with two E1 (ubiquitin activating), few dozen E2 (ubiquitin conjugating) and several hundred E3 (ubiquitin ligase) enzymes. By collecting and analyzing E3 sequences from the KEGG BRITE database and literature, we assembled a coherent dataset of 563 human E3s and analyzed their various physical features. We found an increase in structural disorder of the system with multiple disorder predictors (IUPred - E1: 5.97%, E2: 17.74%, E3: 20.03%). E3s that can bind E2 and substrate simultaneously (single subunit E3, ssE3) have significantly higher disorder (22.98%) than E3s in which E2 binding (multi RING-finger, mRF, 0.62%), scaffolding (6.01%) and substrate binding (adaptor/substrate recognition subunits, 17.33%) functions are separated. In ssE3s, the disorder was localized in the substrate/adaptor binding domains, whereas the E2-binding RING/HECT-domains were structured. To demonstrate the involvement of disorder in E3 function, we applied normal modes and molecular dynamics analyses to show how a disordered and highly flexible linker in human CBL (an E3 that acts as a regulator of several tyrosine kinase-mediated signalling pathways) facilitates long-range conformational changes bringing substrate and E2-binding domains towards each other and thus assisting in ubiquitin transfer. E3s with multiple interaction partners (as evidenced by data in STRING) also possess elevated levels of disorder (hubs, 22.90% vs. non-hubs, 18.36%). Furthermore, a search in PDB uncovered 21 distinct human E3 interactions, in 7 of which the disordered region of E3s undergoes induced folding (or mutual induced folding) in the presence of the partner. In conclusion, our data highlights the primary role of structural disorder in the functions of E3 ligases that manifests itself in the substrate/adaptor binding functions as well as the mechanism of ubiquitin transfer by long-range conformational transitions. © 2013 Bhowmick et al