The XRCC1 phosphate-binding pocket binds poly (ADP-ribose) and is required for XRCC1 function

Poly (ADP-ribose) is synthesized at DNA single-strand breaks and can promote the recruitment of the scaffold protein, XRCC1. However, the mechanism and importance of this process has been challenged. To address this issue, we have characterized the mechanism of poly (ADP-ribose) binding by XRCC1 and examined its importance for XRCC1 function. We show that the phosphate-binding pocket in the central BRCT1 domain of XRCC1 is required for selective binding to poly (ADP-ribose) at low levels of ADP-ribosylation, and promotes interaction with cellular PARP1. We also show that the phosphate-binding pocket is required for EGFP-XRCC1 accumulation at DNA damage induced by UVA laser, H2O2, and at sites of sub-nuclear PCNA foci, suggesting that poly (ADP-ribose) promotes XRCC1 recruitment both at single-strand breaks globally across the genome and at sites of DNA replication stress. Finally, we show that the phosphate-binding pocket is required following DNA damage for XRCC1-dependent acceleration of DNA single-strand break repair, DNA base excision repair, and cell survival. These data support the hypothesis that poly (ADP-ribose) synthesis promotes XRCC1 recruitment at DNA damage sites and is important for XRCC1 function

Considerations when assessing endurance in combat sport athletes

Combat sports encompass a range of sports, each involving physical combat between participants. Such sports are unique, with competitive success influenced by a diverse range of physical characteristics. Effectively identifying and evaluating each characteristic is essential for athletes and support staff alike. Previous research investigating the relationship between combat sports performance and measures of strength and power is robust. However, research investigating the relationship between combat sports performance and assessments of endurance is less conclusive. As a physical characteristic, endurance is complex and influenced by multiple factors including mechanical efficiency, maximal aerobic capacity, metabolic thresholds, and anaerobic capacities. To assess endurance of combat sports athletes, previous research has employed methods ranging from incremental exercise tests to circuits involving sports-specific techniques. These tests range in their ability to discern various physiological attributes or performance characteristics, with varying levels of accuracy and ecological validity. In fact, it is unclear how various physiological attributes influence combat sport endurance performance. Further, the sensitivity of sports specific skills in performance based tests is also unclear. When developing or utilizing tests to better understand an athletes\u27 combat sports-specific endurance characteristic, it is important to consider what information the test will and will not provide. Additionally, it is important to determine which combination of performance and physiological assessments will provide the most comprehensive picture. Strengthening the understanding of assessing combat sport-specific endurance as a physiological process and as a performance metric will improve the quality of future research and help support staff effectively monitor their athlete\u27s characteristics

Inverse Problems in a Bayesian Setting

In a Bayesian setting, inverse problems and uncertainty quantification (UQ) --- the propagation of uncertainty through a computational (forward) model --- are strongly connected. In the form of conditional expectation the Bayesian update becomes computationally attractive. We give a detailed account of this approach via conditional approximation, various approximations, and the construction of filters. Together with a functional or spectral approach for the forward UQ there is no need for time-consuming and slowly convergent Monte Carlo sampling. The developed sampling-free non-linear Bayesian update in form of a filter is derived from the variational problem associated with conditional expectation. This formulation in general calls for further discretisation to make the computation possible, and we choose a polynomial approximation. After giving details on the actual computation in the framework of functional or spectral approximations, we demonstrate the workings of the algorithm on a number of examples of increasing complexity. At last, we compare the linear and nonlinear Bayesian update in form of a filter on some examples.Comment: arXiv admin note: substantial text overlap with arXiv:1312.504

HEPCloud, a New Paradigm for HEP Facilities: CMS Amazon Web Services Investigation

Historically, high energy physics computing has been performed on large purpose-built computing systems. These began as single-site compute facilities, but have evolved into the distributed computing grids used today. Recently, there has been an exponential increase in the capacity and capability of commercial clouds. Cloud resources are highly virtualized and intended to be able to be flexibly deployed for a variety of computing tasks. There is a growing nterest among the cloud providers to demonstrate the capability to perform large-scale scientific computing. In this paper, we discuss results from the CMS experiment using the Fermilab HEPCloud facility, which utilized both local Fermilab resources and virtual machines in the Amazon Web Services Elastic Compute Cloud. We discuss the planning, technical challenges, and lessons learned involved in performing physics workflows on a large-scale set of virtualized resources. In addition, we will discuss the economics and operational efficiencies when executing workflows both in the cloud and on dedicated resources.Comment: 15 pages, 9 figure

Considerations When Assessing Endurance in Combat Sport Athletes

Combat sports encompass a range of sports, each involving physical combat between participants. Such sports are unique, with competitive success influenced by a diverse range of physical characteristics. Effectively identifying and evaluating each characteristic is essential for athletes and support staff alike. Previous research investigating the relationship between combat sports performance and measures of strength and power is robust. However, research investigating the relationship between combat sports performance and assessments of endurance is less conclusive. As a physical characteristic, endurance is complex and influenced by multiple factors including mechanical efficiency, maximal aerobic capacity, metabolic thresholds, and anaerobic capacities. To assess endurance of combat sports athletes, previous research has employed methods ranging from incremental exercise tests to circuits involving sports-specific techniques. These tests range in their ability to discern various physiological attributes or performance characteristics, with varying levels of accuracy and ecological validity. In fact, it is unclear how various physiological attributes influence combat sport endurance performance. Further, the sensitivity of sports specific skills in performance based tests is also unclear. When developing or utilizing tests to better understand an athletes’ combat sports-specific endurance characteristic, it is important to consider what information the test will and will not provide. Additionally, it is important to determine which combination of performance and physiological assessments will provide the most comprehensive picture. Strengthening the understanding of assessing combat sport-specific endurance as a physiological process and as a performance metric will improve the quality of future research and help support staff effectively monitor their athlete’s characteristics

Facial onset sensory and motor neuronopathy: new cases, cognitive changes and pathophysiology

Purpose of review To improve our clinical understanding of facial onset sensory and motor neuronopathy (FOSMN). Recent findings We identified 29 new cases and 71 literature cases, resulting in a cohort of 100 patients with FOSMN. During follow-up, cognitive and behavioral changes became apparent in 8 patients, suggesting that changes within the spectrum of frontotemporal dementia (FTD) are a part of the natural history of FOSMN. Another new finding was chorea, seen in 6 cases. Despite reports of autoantibodies, there is no consistent evidence to suggest an autoimmune pathogenesis. Four of 6 autopsies had TAR DNA-binding protein (TDP) 43 pathology. Seven cases had genetic mutations associated with neurodegenerative diseases. Summary FOSMN is a rare disease with a highly characteristic onset and pattern of disease progression involving initial sensory disturbances, followed by bulbar weakness with a cranial to caudal spread of pathology. Although not conclusive, the balance of evidence suggests that FOSMN is most likely to be a TDP-43 proteinopathy within the amyotrophic lateral sclerosis–FTD spectrum

Inhibitory mechanisms on dry anaerobic digestion: Ammonia, hydrogen and propionic acid relationship

Inhibitory pathways in dry anaerobic digestion are still understudied and current knowledge on wet processes cannot be easily transferred. This study forced instability in pilot-scale digesters by operating at short retention times (40 and 33 days) in order to understand inhibition pathways over long term operation (145 days). The first sign of inhibition at elevated total ammonia concentrations (8 g/l) was a headspace hydrogen level over the thermodynamic limit for propionic degradation, causing propionic accumulation. The combined inhibitory effect of propionic and ammonia accumulation resulted in further increased hydrogen partial pressures and n-butyric accumulation. The relative abundance of Methanosarcina increased while that of Methanoculleus decreased as digestion deteriorated. It was hypothesized that high ammonia, total solids and organic loading rate inhibited syntrophic acetate oxidisers, increasing their doubling time and resulting in its wash out, which in turn inhibited hydrogenotrophic methanogenesis and shifted the predominant methanogenic pathway towards acetoclastic methanogenesis at free ammonia over 1.5 g/l. C/N increases to 25 and 29 reduced inhibitors accumulation but did not avoid inhibition or the washout of syntrophic acetate oxidising bacteria