Timed inhibition of CDC7 increases CRISPR-Cas9 mediated templated repair.

Repair of double strand DNA breaks (DSBs) can result in gene disruption or gene modification via homology directed repair (HDR) from donor DNA. Altering cellular responses to DSBs may rebalance editing outcomes towards HDR and away from other repair outcomes. Here, we utilize a pooled CRISPR screen to define host cell involvement in HDR between a Cas9 DSB and a plasmid double stranded donor DNA (dsDonor). We find that the Fanconi Anemia (FA) pathway is required for dsDonor HDR and that other genes act to repress HDR. Small molecule inhibition of one of these repressors, CDC7, by XL413 and other inhibitors increases the efficiency of HDR by up to 3.5 fold in many contexts, including primary T cells. XL413 stimulates HDR during a reversible slowing of S-phase that is unexplored for Cas9-induced HDR. We anticipate that XL413 and other such rationally developed inhibitors will be useful tools for gene modification

Accretion of Planetary Material onto Host Stars

Accretion of planetary material onto host stars may occur throughout a star's life. Especially prone to accretion, extrasolar planets in short-period orbits, while relatively rare, constitute a significant fraction of the known population, and these planets are subject to dynamical and atmospheric influences that can drive significant mass loss. Theoretical models frame expectations regarding the rates and extent of this planetary accretion. For instance, tidal interactions between planets and stars may drive complete orbital decay during the main sequence. Many planets that survive their stars' main sequence lifetime will still be engulfed when the host stars become red giant stars. There is some observational evidence supporting these predictions, such as a dearth of close-in planets around fast stellar rotators, which is consistent with tidal spin-up and planet accretion. There remains no clear chemical evidence for pollution of the atmospheres of main sequence or red giant stars by planetary materials, but a wealth of evidence points to active accretion by white dwarfs. In this article, we review the current understanding of accretion of planetary material, from the pre- to the post-main sequence and beyond. The review begins with the astrophysical framework for that process and then considers accretion during various phases of a host star's life, during which the details of accretion vary, and the observational evidence for accretion during these phases.Comment: 18 pages, 5 figures (with some redacted), invited revie

Why Robots Should Be Social: Enhancing Machine Learning through Social Human-Robot Interaction.

Social learning is a powerful method for cultural propagation of knowledge and skills relying on a complex interplay of learning strategies, social ecology and the human propensity for both learning and tutoring. Social learning has the potential to be an equally potent learning strategy for artificial systems and robots in specific. However, given the complexity and unstructured nature of social learning, implementing social machine learning proves to be a challenging problem. We study one particular aspect of social machine learning: that of offering social cues during the learning interaction. Specifically, we study whether people are sensitive to social cues offered by a learning robot, in a similar way to children's social bids for tutoring. We use a child-like social robot and a task in which the robot has to learn the meaning of words. For this a simple turn-based interaction is used, based on language games. Two conditions are tested: one in which the robot uses social means to invite a human teacher to provide information based on what the robot requires to fill gaps in its knowledge (i.e. expression of a learning preference); the other in which the robot does not provide social cues to communicate a learning preference. We observe that conveying a learning preference through the use of social cues results in better and faster learning by the robot. People also seem to form a "mental model" of the robot, tailoring the tutoring to the robot's performance as opposed to using simply random teaching. In addition, the social learning shows a clear gender effect with female participants being responsive to the robot's bids, while male teachers appear to be less receptive. This work shows how additional social cues in social machine learning can result in people offering better quality learning input to artificial systems, resulting in improved learning performance

Changes in the distribution of red foxes (Vulpes vulpes) in urban areas in Great Britain: findings and limitations of a media-driven nationwide survey

Urbanization is one of the major forms of habitat alteration occurring at the present time. Although this is typically deleterious to biodiversity, some species flourish within these human-modified landscapes, potentially leading to negative and/or positive interactions between people and wildlife. Hence, up-to-date assessment of urban wildlife populations is important for developing appropriate management strategies. Surveying urban wildlife is limited by land partition and private ownership, rendering many common survey techniques difficult. Garnering public involvement is one solution, but this method is constrained by the inherent biases of non-standardised survey effort associated with voluntary participation. We used a television-led media approach to solicit national participation in an online sightings survey to investigate changes in the distribution of urban foxes in Great Britain and to explore relationships between urban features and fox occurrence and sightings density. Our results show that media-based approaches can generate a large national database on the current distribution of a recognisable species. Fox distribution in England and Wales has changed markedly within the last 25 years, with sightings submitted from 91% of urban areas previously predicted to support few or no foxes. Data were highly skewed with 90% of urban areas having <30 fox sightings per 1000 people km-2. The extent of total urban area was the only variable with a significant impact on both fox occurrence and sightings density in urban areas; longitude and percentage of public green urban space were respectively, significantly positively and negatively associated with sightings density only. Latitude, and distance to nearest neighbouring conurbation had no impact on either occurrence or sightings density. Given the limitations associated with this method, further investigations are needed to determine the association between sightings density and actual fox density, and variability of fox density within and between urban areas in Britain

Developmental differences in children’s interpersonal emotion regulation

Previous research on interpersonal emotion regulation (ER) in childhood has been rather unsystematic, focusing mainly on children’s prosocial behaviour, and has been conducted in the absence of an integrative emotion theoretical framework. The present research relied on the interpersonal affect classification proposed by Niven, Totterdell, and Holman (2009) to investigate children’s use of different interpersonal ER strategies. The study drew on two samples: 180 parents of children aged between 3 and 8 years reported about a situation where their child was able to change what another person was feeling in order to make them feel better. In addition, 126 children between 3- and 8-years old answered two questions about how they could improve others’ mood. Results from both samples showed age differences in children’s use of interpersonal ER strategies. As expected, ‘affective engagement’ (i.e., focusing on the person or the problem) and ‘cognitive engagement’ (i.e., appraising the situation from a different perspective) were mainly used by 7-8 years-old, whereas ‘attention’ (i.e., distracting and valuing) was most used by 3-4 and 5-6 years-old. ‘Humor’ (i.e., laughing with the target) remained stable across the different age groups. The present research provides more information about the developmental patterns for each specific interpersonal emotion regulation strategy

The Evolution of Compact Binary Star Systems

We review the formation and evolution of compact binary stars consisting of white dwarfs (WDs), neutron stars (NSs), and black holes (BHs). Binary NSs and BHs are thought to be the primary astrophysical sources of gravitational waves (GWs) within the frequency band of ground-based detectors, while compact binaries of WDs are important sources of GWs at lower frequencies to be covered by space interferometers (LISA). Major uncertainties in the current understanding of properties of NSs and BHs most relevant to the GW studies are discussed, including the treatment of the natal kicks which compact stellar remnants acquire during the core collapse of massive stars and the common envelope phase of binary evolution. We discuss the coalescence rates of binary NSs and BHs and prospects for their detections, the formation and evolution of binary WDs and their observational manifestations. Special attention is given to AM CVn-stars -- compact binaries in which the Roche lobe is filled by another WD or a low-mass partially degenerate helium-star, as these stars are thought to be the best LISA verification binary GW sources.Comment: 105 pages, 18 figure

Biodiversity seen through the perspective of insects: 10 simple rules on methodological choices and experimental design for genomic studies

Massively parallel DNA sequencing opens up opportunities for bridging multiple temporal and spatial dimensions in biodiversity research, thanks to its efficiency to recover millions of nucleotide polymorphisms. Here, we identify the current status, discuss the main challenges, and look into future perspectives on biodiversity genomics focusing on insects, which arguably constitute the most diverse and ecologically important group among all animals. We suggest 10 simple rules that provide a succinct step-by-step guide and best-practices to anyone interested in biodiversity research through the study of insect genomics. To this end, we review relevant literature on biodiversity and evolutionary research in the field of entomology. Our compilation is targeted at researchers and students who may not yet be specialists in entomology or molecular biology. We foresee that the genomic revolution and its application to the study of non-model insect lineages will represent a major leap to our understanding of insect diversity

A randomized clinical trial of a peri-operative behavioral intervention to improve physical activity adherence and functional outcomes following total knee replacement

<p>Abstract</p> <p>Background</p> <p>Total knee replacement (TKR) is a common and effective surgical procedure to relieve advanced knee arthritis that persists despite comprehensive medical treatment. Although TKR has excellent technical outcomes, significant variation in patient-reported functional improvement post-TKR exists. Evidence suggests that consistent post-TKR exercise and physical activity is associated with functional gain, and that this relationship is influenced by emotional health. The increasing use of TKR in the aging US population makes it critical to find strategies that maximize functional outcomes.</p> <p>Methods/Design</p> <p>This randomized clinical trial (RCT) will test the efficacy of a theory-based telephone-delivered Patient Self-Management Support intervention that seeks to enhance adherence to independent exercise and activity among post- TKR patients. The intervention consists of 12 sessions, which begin prior to surgery and continue for approximately 9 weeks post-TKR. The intervention condition will be compared to a usual care control condition using a randomized design and a probabilistic sample of men and women. Assessments are conducted at baseline, eight weeks, and six- and twelve- months. The project is being conducted at a large healthcare system in Massachusetts. The study was designed to provide greater than 80% power for detecting a difference of 4 points in physical function (SF36/Physical Component Score) between conditions (standard deviation of 10) at six months with secondary outcomes collected at one year, assuming a loss to follow up rate of no more than 15%.</p> <p>Discussion</p> <p>As TKR use expands, it is important to develop methods to identify patients at risk for sub-optimal functional outcome and to effectively intervene with the goal of optimizing functional outcomes. If shown efficacious, this peri-TKR intervention has the potential to change the paradigm for successful post-TKR care. We hypothesize that Patient Self-Management Support to enhance adherence to independent activity and exercise will enhance uniform, optimal improvement in post-TKR function and patient autonomy, the ultimate goals of TKR.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00566826">NCT00566826</a></p

UDP-glucuronosyltransferase and sulfotransferase polymorphisms, sex hormone concentrations, and tumor receptor status in breast cancer patients

INTRODUCTION: UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) enzymes are involved in removing sex hormones from circulation. Polymorphic variation in five UGT and SULT genes – UGT1A1 ((TA)(6)/(TA)(7)), UGT2B4 (Asp(458)Glu), UGT2B7 (His(268)Tyr), UGT2B15 (Asp(85)Tyr), and SULT1A1 (Arg(213)His) – may be associated with circulating sex hormone concentrations, or the risk of an estrogen receptor-negative (ER(-)) or progesterone receptor-negative (PR(-)) tumor. METHODS: Logistic regression analysis was used to estimate the odds ratios of an ER(- )or PR(- )tumor associated with polymorphisms in the genes listed above for 163 breast cancer patients from a population-based cohort study of women in western Washington. Adjusted geometric mean estradiol, estrone, and testosterone concentrations were calculated within each UGT and SULT genotype for a subpopulation of postmenopausal breast cancer patients not on hormone therapy 2–3 years after diagnosis (n = 89). RESULTS: The variant allele of UGT1A1 was associated with reduced risk of an ER(- )tumor (P for trend = 0.03), and variants of UGT2B15 and SULT1A1 were associated with non-statistically significant risk reductions. There was some indication that plasma estradiol and testosterone concentrations varied by UGT2B15 and SULT1A1 genotypes; women with the UGT2B15 Asp/Tyr and Tyr/Tyr genotypes had higher concentrations of estradiol than women with the Asp/Asp genotype (P = 0.004). Compared with women with the SULT1A1 Arg/Arg and Arg/His genotypes, women with the His/His genotype had elevated concentrations of testosterone (P = 0.003). CONCLUSIONS: The risk of ER(- )breast cancer tumors may vary by UGT or SULT genotype. Further, plasma estradiol and testosterone concentrations in breast cancer patients may differ depending on some UGT and SULT genotypes

Development and Validation of a Surgical Workload Measure: The Surgery Task Load Index (SURG-TLX)

Background: The purpose of the present study was to develop and validate a multidimensional, surgery-specific workload measure (the SURG-TLX), and to determine its utility in providing diagnostic information about the impact of various sources of stress on the perceived demands of trained surgical operators. As a wide range of stressors have been identified for surgeons in the operating room, the current approach of considering stress as a unidimensional construct may not only limit the degree to which underlying mechanisms may be understood but also the degree to which training interventions may be successfully matched to particular sources of stress. Methods: The dimensions of the SURG-TLX were based on two current multidimensional workload measures and developed via focus group discussion. The six dimensions were defined as mental demands, physical demands, temporal demands, task complexity, situational stress, and distractions. Thirty novices were trained on the Fundamentals of Laparoscopic Surgery (FLS) peg transfer task and then completed the task under various conditions designed to manipulate the degree and source of stress experienced: task novelty, physical fatigue, time pressure, evaluation apprehension, multitasking, and distraction. Results: The results were supportive of the discriminant sensitivity of the SURG-TLX to different sources of stress. The sub-factors loaded on the relevant stressors as hypothesized, although the evaluation pressure manipulation was not strong enough to cause a significant rise in situational stress. Conclusions: The present study provides support for the validity of the SURG-TLX instrument and also highlights the importance of considering how different stressors may load surgeons. Implications for categorizing the difficulty of certain procedures, the implementation of new technology in the operating room (man-machine interface issues), and the targeting of stress training strategies to the sources of demand are discussed. Modifications to the scale to enhance clinical utility are also suggested. © 2011 The Author(s).published_or_final_versionSpringer Open Choice, 21 Feb 201