Interactions between BRCA2 and RAD51 for promoting homologous recombination in Leishmania infantum.

In most organisms, the primary function of homologous recombination (HR) is to allow genome protection by the faithful repair of DNA double-strand breaks. The vital step of HR is the search for sequence homology, mediated by the RAD51 recombinase, which is stimulated further by proteins mediators such as the tumor suppressor BRCA2. The biochemical interplay between RAD51 and BRCA2 is unknown in Leishmania or Trypanosoma. Here we show that the Leishmania infantum BRCA2 protein possesses several critical features important for the regulation of DNA recombination at the genetic and biochemical level. A BRCA2 null mutant, generated by gene disruption, displayed genomic instability and gene-targeting defects. Furthermore, cytological studies show that LiRAD51 can no longer localize to the nucleus in this mutant. The Leishmania RAD51 and BRCA2 interact together and the purified proteins bind single-strand DNA. Remarkably, LiBRCA2 is a recombination mediator that stimulates the invasion of a resected DNA double-strand break in an undamaged template by LiRAD51 to form a D-loop structure. Collectively, our data show that LiBRCA2 and LiRAD51 promote HR at the genetic and biochemical level in L. infantum, the causative agent of visceral leishmaniasis

A Framework for Understanding Selection Bias in Real-World Healthcare Data

Using administrative patient-care data such as Electronic Health Records and medical/pharmaceutical claims for population-based scientific research has become increasingly common. With vast sample sizes leading to very small standard errors, researchers need to pay more attention to potential biases in the estimates of association parameters of interest, specifically to biases that do not diminish with increasing sample size. Of these multiple sources of biases, in this paper, we focus on understanding selection bias. We present an analytic framework using directed acyclic graphs for guiding applied researchers to dissect how different sources of selection bias may affect their parameter estimates of interest. We review four easy-to-implement weighting approaches to reduce selection bias and explain through a simulation study when they can rescue us in practice with analysis of real world data. We provide annotated R codes to implement these methods

Learning to segment clustered amoeboid cells from brightfield microscopy via multi-task learning with adaptive weight selection

Detecting and segmenting individual cells from microscopy images is critical to various life science applications. Traditional cell segmentation tools are often ill-suited for applications in brightfield microscopy due to poor contrast and intensity heterogeneity, and only a small subset are applicable to segment cells in a cluster. In this regard, we introduce a novel supervised technique for cell segmentation in a multi-task learning paradigm. A combination of a multi-task loss, based on the region and cell boundary detection, is employed for an improved prediction efficiency of the network. The learning problem is posed in a novel min-max framework which enables adaptive estimation of the hyper-parameters in an automatic fashion. The region and cell boundary predictions are combined via morphological operations and active contour model to segment individual cells. The proposed methodology is particularly suited to segment touching cells from brightfield microscopy images without manual interventions. Quantitatively, we observe an overall Dice score of 0.93 on the validation set, which is an improvement of over 15.9% on a recent unsupervised method, and outperforms the popular supervised U-net algorithm by at least $5.8\%$ on average

A tetragonal core with asymmetric iron environments supported solely by bis(μ-OH){μ-(O-H···O)} bridging and terminal pyridine amide (N, O) coordination: a new member of the tetrairon(III) family

Room-temperature aerobic reaction of [Fe(MeCN)4][ClO4]2 with 1,3-bis(2-pyridinecarboxamido)propane (H2bpp) yields the tetrairon(III) complex [Fe4(H2bpp)4(μ-OH)2(μ-OHO)][ClO4]7·2H2O·xMeCN (1·xMeCN, 0≤x≤3). Crystal structure determination reveals that 1·3MeCN is a new member of the tetrairon(III) family, bridged solely by two hydroxido ligands and a localized {O-H···O}3- bridging unit. The properties of the "tetragonal" core [Fe4(μ-OH)2{μ-(O-H···O)}]7+ have been investigated by variable-temperature magnetic and Mossbauer spectroscopic measurements. Successful modeling of the data has revealed asymmetric iron environments and three types of magnetic exchange interactions [through μ-OH and μ-O/μ-OH of μ-(O-H···O) bridges]. This tetragonal core is a valuable addition to the tetrairon(III) cluster family from inorganic and bioinorganic perspectives

Does the Blazar Gamma-Ray Spectrum Harden with Increasing Flux? Analysis of 9 Years of EGRET Data

The Energetic Gamma-Ray Experiment Telescope (EGRET) on the Compton Gamma-Ray Observatory (CGRO) discovered gamma-ray emission from more than 67 blazars during its 9 yr lifetime. We conducted an exhaustive search of the EGRET archives and selected all the blazars that were observed multiple times and were bright enough to enable a spectral analysis using standard power-law models. The sample consists of 18 flat-spectrum radio quasars(FSRQs), 6 low-frequency peaked BL Lac objects (LBLs) and 2 high-frequency peaked BL Lac objects (HBLs). We do not detect any clear pattern in the variation of spectral index with flux. Some of the blazars do not show any statistical evidence for spectral variability. The spectrum hardens with increasing flux in a few cases. There is also evidence for a flux-hardness anticorrelation at low fluxes in five blazars. The well-observed blazars (3C 279, 3C 273, PKS 0528+134, PKS 1622-297 PKS 0208-512) do not show any overall trend in the long-term spectral dependence on flux, but the sample shows a mixture of hard and soft states. We observed a previously unreported spectral hysteresis at weekly timescales in all three FSRQs for which data from flares lasting for ~(3-4) weeks were available. All three sources show a counterclockwise rotation, despite the widely different flux profiles. We analyze the observed spectral behavior in the context of various inverse Compton mechanisms believed to be responsible for emission in the EGRET energy range. Our analysis uses the EGRET skymaps that were regenerated to include the changes in performance during the mission

Comparison of techniques for eliciting views and judgements in decision-making

1. Decision‐making is a complex process that typically includes a series of stages: identifying the issue, considering possible options, making judgements and then making a decision by combining information and values. The current status quo relies heavily on the informational aspect of decision‐making with little or no emphasis on the value positions that affect decisions. 2. There is increasing realization of the importance of adopting rigorous methods for each stage such that the information, views and judgements of stakeholders and experts are used in a systematic and repeatable manner. Though there are several methodological textbooks which discuss a plethora of social science techniques, it is hard to judge the suitability of any given technique for a given decision problem. 3. In decision‐making, the three critical aspects are “what” decision is to be made, “who” makes the decisions and “how” the decisions are made. The methods covered in this paper focus on “how” decisions can be made. We compare six techniques: Focus Group Discussion (FGD), Interviews, Q methodology, Multi‐criteria Decision Analysis (MCDA), Nominal Group Technique and the Delphi technique specifically in the context of biodiversity conservation. All of these techniques (with the exception of MCDA) help in understanding human values and the underlying perspectives which shape decisions. 4. Based on structured reviews of 423 papers covering all six methods, we compare the conceptual and logistical characteristics of the methods, and map their suitability for the different stages of the decision‐making process. While interviews and FGD are well‐known, techniques such the Nominal Group technique and Q methodology are relatively under‐used. In situations where conflict is high, we recommend using the Q methodology and Delphi technique to elicit judgements. Where conflict is low, and a consensus is needed urgently, the Nominal Group technique may be more suitable. 5. We present a nuanced synthesis of methods aimed at users. The comparison of the different techniques might be useful for project managers, academics or practitioners in the planning phases of their projects and help in making better informed methodological choices.N.M. was funded by the Fondation Wiener Anspach and the Scriven post doctoral fellowship. J.H. is funded by the Belgian National Fund for Research (FRS‐FNRS) and the KLIMOS‐ACROPOLIS project. N.T.O. was funded by Cambridge Overseas Trusts, The Wildlife Conservation Society, Wildlife Conservation Network and WildiZe Foundation. B.A.E. is funded by EU Horizon 2020 ESMERALDA Project, grant agreement no. 642007. W.J.S. is funded by Arcadia

Value-based care in surgery : implications in crisis and beyond

Over the past 2 years, surgeons and surgical systems have demonstrated an ability to rapidly adopt value-driven care, triage patients and make evidence-based decisions in response to crisis. Building on these successes, this paper explores a framework to expand these advances in creating a value-based approach to patient care through clinician leadership and state-wide clinical networks

Digital Doppler-cancellation servo for ultra-stable optical frequency dissemination over fiber

Progress made in optical references, including ultra-stable Fabry-Perot cavities, optical frequency combs and optical atomic clocks, have driven the need for ultra-stable optical fiber networks. Telecom-wavelength ultra-pure optical signal transport has been demonstrated on distances ranging from the laboratory scale to the continental scale. In this manuscript, we present a Doppler-cancellation setup based on a digital phase-locked loop for ultra-stable optical signal dissemination over fiber. The optical phase stabilization setup is based on a usual heterodyne Michelson-interferometer setup, while the Software Defined Radio (SDR) implementation of the phase-locked loop is based on a compact commercial board embedding a field programmable gate array, analog-to-digital and digital-to-analog converters. Using three different configurations including an undersampling method, we demonstrate a 20 m long fiber link with residual fractional frequency instability as low as $10^{-18}$ at 1000 s, and an optical phase noise of $-70$ dBc/Hz at 1 Hz with a telecom frequency carrier.Comment: 11 pages, 6 figure