Mouse RAD54 affects DNA double-strand break repair and sister chromatid exchange

Cells can achieve error-free repair of DNA double-strand breaks (DSBs) by homologous recombination through gene conversion with or without crossover. In contrast, an alternative homology-dependent DSB repair pathway, single-strand annealing (SSA), results in deletions. In this study, we analyzed the effect of mRAD54, a gene involved in homologous recombination, on the repair of a site-specific I-SceI-induced DSB located in a repeated DNA sequence in the genome of mouse embryonic stem cells. We used six isogenic cell lines differing solely in the orientation of the repeats. The combination of the three recombination-test substrates used discriminated among SSA, intrachromatid gene conversion, and sister chromatid gene conversion. DSB repair was most efficient for the substrate that allowed recovery of SSA events. Gene conversion with crossover, indistinguishable from long tract gene conversion, preferentially involved the sister chromatid rather than the repeat on the same chromatid. Comparing DSB repair in mRAD54 wild-type and knockout cells revealed direct evidence for a role of mRAD54 in DSB repair. The substrate measuring SSA showed an increased efficiency of DSB repair in the absence of mRAD54. The substrate measuring sister chromatid gene conversion showed a decrease in gene conversion with and without crossover. Consistent with this observation, DNA damage-induced sister chromatid exchange was reduced in mRAD54-deficient cells. Our results suggest that mRAD54 promotes gene conversion with predominant use of the sister chromatid as the repair template at the expense of error-prone SSA

Forecasting spatio‑temporal variation in residential burglary with the integrated Laplace approximation framework: Effects of crime generators, street networks, and prior crimes

Objectives - We investigate the spatio-temporal variation of monthly residential burglary frequencies across neighborhoods as a function of crime generators, street network features and temporally and spatially lagged burglary frequencies. In addition, we evaluate the per-formance of the model as a forecasting tool. Methods - We analyze 48 months of police-recorded residential burglaries across 20 neigh-borhoods in Amsterdam, the Netherlands, in combination with data on the locations of urban facilities (crime generators), frequencies of other crime types, and street network data. We apply the Integrated Laplace Approximation method, a Bayesian forecasting framework that is less computationally demanding than prior frameworks. Results - The local number of retail stores, the number of street robberies perpetrated and the closeness of the local street network are positively related to residential burglary. Inclu-sion of a general spatio-temporal interaction component significantly improves forecasting performance, but inclusion of spatial proximity or temporal recency components does not.DiscussionOur findings on crime generators and street network characteristics support evi-dence in the literature on environmental correlates of burglary. The significance of spatio-temporal interaction indicates that residential burglary is spatio-temporally concentrated. Our finding that recency and proximity of prior burglaries do not contribute to the perfor-mance of the forecast, probably indicates that relevant spatio-temporal interaction is lim-ited to fine-grained spatial and temporal units of analysis, such as days and street blocks. Discussion - Our findings on crime generators and street network characteristics support evidence in the literature on environmental correlates of burglary. The significance of spatio-temporal interaction indicates that residential burglary is spatio-temporally concentrated. Our finding that recency and proximity of prior burglaries do not contribute to the performance of the forecast, probably indicates that relevant spatio-temporal interaction is limited to fine-grained spatial and temporal units of analysis, such as days and street blocks

Amplification of IGH/MYC fusion in clinically aggressive IGH/BCL2-positive germinal center B-cell lymphomas

Activation of an oncogene via its juxtaposition to the IGH locus by a chromosomal translocation or, less frequently, by genomic amplification is considered a major mechanism of B-cell lymphomagenesis. However, amplification of an IGH/oncogene fusion, coined a complicon, is a rare event in human cancers and has been associated with poor outcome and resistance to treatment. In this article are descriptions of two cases of germinal-center-derived B-cell lymphomas with IGH/BCL2 fusion that additionally displayed amplification of an IGH/MYC fusion. As shown by fluorescence in situ hybridization, the first case contained a IGH/MYC complicon in double minutes, whereas the second case showed a BCL2/IGH/MYC complicon on a der(8)t(8;14)t(14;18). Additional molecular cytogenetic and mutation analyses revealed that the first case also contained a chromosomal translocation affecting the BCL6 oncogene and a biallelic inactivation of TP53. The second case harbored a duplication of REL and acquired a translocation affecting IGL and a biallelic inactivation of TP53 during progression. Complicons affecting Igh/Myc have been reported previously in lymphomas of mouse models simultaneously deficient in Tp53 and in genes of the nonhomologous end-joining DNA repair pathway. To the best of our knowledge, this is the first time that IGH/MYC complicons have been reported in human lymphomas. Our findings imply that the two mechanisms resulting in MYC deregulation, that is, translocation and amplification, can occur simultaneously

Ultra-low noise supercontinuum source for ultra-high resolution optical coherence tomography at 1300 nm

Supercontinuum (SC) sources are of great interest for many applications due to their ultra-broad optical bandwidth, good beam quality and high power spectral density [1]. In particular, the high average power over large bandwidths makes SC light sources excellent candidates for ultra-high resolution optical coherence tomography (UHR-OCT) [2-5]. However, conventional SC sources suffer from high pulse-to-pulse intensity fluctuations as a result of the noise-sensitive nonlinear effects involved in the SC generation process [6-9]. This intensity noise from the SC source can limit the performance of OCT, resulting in a reduced signal-to-noise ratio (SNR) [10-12]. Much work has been done to reduce the noise of the SC sources for instance with fiber tapers [7,8] or increasing the repetition rate of the pump laser for averaging in the spectrometer [10,12]. An alternative approach is to use all-normal dispersion (ANDi) fibers [13,14] to generate SC light from well-known coherent nonlinear processes [15-17]. In fact, reduction of SC noise using ANDi fibers compared to anomalous dispersion SC pumped by sub-picosecond pulses has been recently demonstrated [18], but a cladding mode was used to stabilize the ANDi SC. In this work, we characterize the noise performance of a femtosecond pumped ANDi based SC and a commercial SC source in an UHR-OCT system at 1300 nm. We show that the ANDi based SC presents exceptional noise properties compared to a commercial source. An improvement of ~5 dB in SNR is measured in the UHR-OCT system, and the noise behavior resembles that of a superluminiscent diode. This preliminary study is a step forward towards development of an ultra-low noise SC source at 1300 nm for ultra-high resolution OCT

Mood and anxiety disorders across the adult lifespan: a European perspective

BACKGROUND: The World Mental Health Survey Initiative (WMHSI) has advanced our understanding of mental disorders by providing data suitable for analysis across many countries. However, these data have not yet been fully explored from a cross-national lifespan perspective. In particular, there is a shortage of research on the relationship between mood and anxiety disorders and age across countries. In this study we used multigroup methods to model the distribution of 12-month DSM-IV/CIDI mood and anxiety disorders across the adult lifespan in relation to determinants of mental health in 10 European Union (EU) countries. METHOD: Logistic regression was used to model the odds of any mood or any anxiety disorder as a function of age, gender, marital status, urbanicity and employment using a multigroup approach (n = 35500). This allowed for the testing of specific lifespan hypotheses across participating countries. RESULTS: No simple geographical pattern exists with which to describe the relationship between 12-month prevalence of mood and anxiety disorders and age. Of the adults sampled, very few aged ≥ 80 years met DSM-IV diagnostic criteria for these disorders. The associations between these disorders and key sociodemographic variables were relatively homogeneous across countries after adjusting for age. CONCLUSIONS: Further research is required to confirm that there are indeed stages in the lifespan where the reported prevalence of mental disorders is low, such as among younger adults in the East and older adults in the West. This project illustrates the difficulties in conducting research among different age groups simultaneously

Adaptation Strategies for Personalized Gait Neuroprosthetics

Personalization of gait neuroprosthetics is paramount to ensure their efficacy for users, who experience severe limitations in mobility without an assistive device. Our goal is to develop assistive devices that collaborate with and are tailored to their users, while allowing them to use as much of their existing capabilities as possible. Currently, personalization of devices is challenging, and technological advances are required to achieve this goal. Therefore, this paper presents an overview of challenges and research directions regarding an interface with the peripheral nervous system, an interface with the central nervous system, and the requirements of interface computing architectures. The interface should be modular and adaptable, such that it can provide assistance where it is needed. Novel data processing technology should be developed to allow for real-time processing while accounting for signal variations in the human. Personalized biomechanical models and simulation techniques should be developed to predict assisted walking motions and interactions between the user and the device. Furthermore, the advantages of interfacing with both the brain and the spinal cord or the periphery should be further explored. Technological advances of interface computing architecture should focus on learning on the chip to achieve further personalization. Furthermore, energy consumption should be low to allow for longer use of the neuroprosthesis. In-memory processing combined with resistive random access memory is a promising technology for both. This paper discusses the aforementioned aspects to highlight new directions for future research in gait neuroprosthetics.AK is funded by a faculty endowment by adidas AG. MA, SKH, NM, MN, RJQ, R-DR, RJT are supported by NSF CPS grant 1739800, VA Merit Reviews A2275-R and 3056, and the NIH (5T32EB004314-15, R01 NS040547-13). MS and AG are funded by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (Grant agreement No. 803035). AJd-A, JMF-L, and JCM are supported by coordinated grants RTI2018-097290-B-C31/C32/C33 (TAILOR project) funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe”. MR is funded by the Lo3-ML project by the Federal Ministry for Education, Science and Technology (BMBF) (Funding No. 16ES1142K). AC, SS, and MV were supported by the European Research Council (ERC) under the project NGBMI (759370), the Einstein Stiftung Berlin, the ERA-NET NEURON project HYBRIDMIND (BMBF, 01GP2121A and -B) and the BMBF project NEO (13GW0483C)

Access to infertility consultations: what women tell us about it?

The main objective of the present paper is to evaluate the perception of women concerning the barriers and access to infertility consultations. Socio cultural and economic access to infertility consultations is detached and three municipalities of the northwest of Portugal were chosen as an example of a peripheral country. A quantitative/qualitative study was done with 60 women. Three dimensions were evaluated: geographic and structural and functional access; economic access; and sociocultural access. The main barriers were mainly identified in the last two dimensions. The economic access was the less well evaluated by women being the cost of treatment (medication, and concentration of costs in a short period) difficult to bear. This can justify a greater involvement of the Portuguese Government, by developing policies for the reimbursement of part of the costs. Also, some changes in structural and functional access must be done with special regard to the separation of the infertility consultations from the reproductive medicine section. The setting of the teams, with a follow-up by the same team of health professionals is also needed