How Broken DNA Finds Its Template for Repair: A Computational Approach

Homologous recombination (HR) is the process by which a double-strand break in DNA is repaired using an identical donor template. Despite rapid progress in identifying the functions of the proteins that mediate HR, little is known about how broken DNA finds its homologous template. This process, coined homology search, has been difficult to monitor experimentally. Therefore, we present here a computational approach to model the effect of subnuclear positioning and chromatin dynamics on homology search. We found that, in our model, homology search occurs more efficiently if both the cut site and its template are at the nuclear periphery, whereas restricting the movement of the template or the break alone to the periphery markedly increases the time of the search. Immobilization of either component at any position slows down the search. Based on these results, we propose a new model for homology search, the facilitated random search model, which predicts that the search is random, but that nuclear organization and dynamics strongly influence its speed and efficiency

Baylisascaris Procyonis Exposure Case Study

We report a case of exposure to raccoon feces found to be contaminated with baylisascaris procyonis. The exposure was recognized early enough by the family to allow prophylaxis with albendazole. Because of the potential fatal or neurologically catastrophic effects of this disease immediate treatment is indicated. This is started in advance of environmental studies that are done to determine if the feces is indeed contaminated

A longitudinal resting-state functional connectivity analysis on trauma exposure and post-traumatic stress symptoms in older individuals

BACKGROUND: Given the present demographic shift towards an aging society, there is an increased need to investigate the brain's functional connectivity in the context of aging. Trauma exposure and post-traumatic stress disorder (PTSD) symptoms are factors known to impact healthy aging and have been reported to be associated with functional connectivity differences. In the present study, we examined and compared differences in within-default mode network (DMN), within-salience network (SN) and between-DMN-SN functional connectivity, between trauma-exposed individuals with and without PTSD symptoms as well as non-traumatized individuals in a non-clininical older adult sample. METHODS: Resting state functional MRI and behavioral data is taken from the Longitudinal Healthy Aging Brain Database Project (LHAB). For the present analysis, participants who completed the questionnaires on trauma exposure and PTSD symptoms (N = 110 individuals of which n = 50 individuals reported previous trauma exposure and n = 25 individuals reported PTSD symptoms; mean age = 70.55 years, SD = 4.82) were included. RESULTS: The reporting of PTSD symptoms relative to no symptoms was associated with lower within-DMN connectivity, while on a trend level trauma-exposed individuals showed higher within-SN connectivity compared to non-trauma exposed individuals. Consistent with existing models of healthy aging, between-DMN-SN functional connectivity showed an increase across time in older age. CONCLUSION: Present results suggest that alterations in within-DMN and within-SN functional connectivity also occur in non-treatment seeking older adult populations with trauma exposure and in association with PTSD symptoms. These changes manifest, alongside altered between-DMN-SN functional connectivity, in older age supposedly independent of aging-related functional desegregation

Impact of historical land‐use changes on greenhouse gas exchange in the U.S. Great Plains, 1883–2003

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/117205/1/eap20112141105.pd

Combined use of satellite estimates and rain gauge observations to generate high‐quality historical rainfall time series over Ethiopia

Climate data are used in a number of applications including climate risk management and adaptation to climate change. However, the availability of climate data, particularly throughout rural Africa, is very limited. Available weather stations are unevenly distributed and mainly located along main roads in cities and towns. This imposes severe limitations to the availability of climate information and services for the rural community where, arguably, these services are needed most. Weather station data also suffer from gaps in the time series. Satellite proxies, particularly satellite rainfall estimate, have been used as alternatives because of their availability even over remote parts of the world. However, satellite rainfall estimates also suffer from a number of critical shortcomings that include heterogeneous time series, short time period of observation, and poor accuracy particularly at higher temporal and spatial resolutions. An attempt is made here to alleviate these problems by combining station measurements with the complete spatial coverage of satellite rainfall estimates. Rain gauge observations are merged with a locally calibrated version of the TAMSAT satellite rainfall estimates to produce over 30-years (1983-todate) of rainfall estimates over Ethiopia at a spatial resolution of 10 km and a ten-daily time scale. This involves quality control of rain gauge data, generating locally calibrated version of the TAMSAT rainfall estimates, and combining these with rain gauge observations from national station network. The infrared-only satellite rainfall estimates produced using a relatively simple TAMSAT algorithm performed as good as or even better than other satellite rainfall products that use passive microwave inputs and more sophisticated algorithms. There is no substantial difference between the gridded-gauge and combined gauge-satellite products over the test area in Ethiopia having a dense station network; however, the combined product exhibits better quality over parts of the country where stations are sparsely distributed

Ecosystem dynamics of crop‐pasture rotations in a fifty‐year field experiment in Southern South America: Century model and field results.

The Century model was used to simulate soil C and N cycling and crop produc- tion dynamics in an ongoing field experiment in Uruguay (started in 1963). The model was calibrated using observed data from three treatments (crop or crop–pasture rotations) and validated with a fourth treatment. The model correctly predicted the impact of different treatments on microbial biomass, N mineralization, soil respi- ration, and crop yields. The model and observed data show that soil respiration, N mineralization, soil C, and crop yields increase with increasing plant-derived C inputs caused by increasing the frequency of pastures in the rotations. This is one of the first papers that show the strong positive correlation of observed soil C with plant C soil inputs to field-observed microbial biomass, soil respiration, and N mineralization. The results also showed that reducing tillage and transitioning to a no-till system increased soil C and reduced soil erosion. The main path of soil C losses was het- erotrophic microbial respiration, which accounted for 66% of the total C lost in a continuous crop rotation and no fertilizers, 71% in a continuous crop rotation with fertilizers, and 86% in a crop–pasture rotation with fertilizers. Model results from a degraded cropping system showed that adding grass–clover (Trifolium spp.) pastures greatly increased plant production and soil C, whereas reducing the frequency of grass–clover pastures in high-fertility cropping systems from 50% of the time to 25% reduces crop yields and soil C. Including cover crops substantially increases crop production and maintains soil C in high-fertility and degraded cropping systems

Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size

Stem cells reside in a specialized niche that regulates their abundance and fate. Components of the niche have generally been defined in terms of cells and signaling pathways. We define a role for a matrix glycoprotein, osteopontin (OPN), as a constraining factor on hematopoietic stem cells within the bone marrow microenvironment. Osteoblasts that participate in the niche produce varying amounts of OPN in response to stimulation. Using studies that combine OPN-deficient mice and exogenous OPN, we demonstrate that OPN modifies primitive hematopoietic cell number and function in a stem cell–nonautonomous manner. The OPN-null microenvironment was sufficient to increase the number of stem cells associated with increased stromal Jagged1 and Angiopoietin-1 expression and reduced primitive hematopoietic cell apoptosis. The activation of the stem cell microenvironment with parathyroid hormone induced a superphysiologic increase in stem cells in the absence of OPN. Therefore, OPN is a negative regulatory element of the stem cell niche that limits the size of the stem cell pool and may provide a mechanism for restricting excess stem cell expansion under conditions of niche stimulation

Am J Blood Res

The Ikaros transcription factor is crucial for many aspects of hematopoiesis. Loss of function mutations in IKZF1, the gene encoding Ikaros, have been implicated in adult and pediatric B cell acute lymphoblastic leukemia (B-ALL). These mutations result in haploinsufficiency of the Ikaros gene in approximately half of the cases. The remaining cases contain more severe or compound mutations that lead to the generation of dominant-negative proteins or complete loss of function. All IKZF1 mutations are associated with a poor prognosis. Here we review the current genetic, clinical and mechanistic evidence for the role of Ikaros as a tumor suppressor in B-ALL

Week 96 Extension Results of a Phase 3 Study Evaluating Long-Acting Cabotegravir with Rilpivirine for HIV-1 Treatment

BACKGROUND: ATLAS (NCT02951052), a phase 3, multicenter, open-label study, demonstrated that switching to injectable cabotegravir (CAB) with rilpivirine (RPV) long-acting dosed every 4 weeks was noninferior at week (W) 48 to continuing three-drug daily oral current antiretroviral therapy (CAR). Results from the W 96 analysis are presented. METHODS AND DESIGN: Participants completing W 52 of ATLAS were given the option to withdraw, transition to ATLAS-2M (NCT03299049), or enter an Extension Phase to continue long-acting therapy (Long-acting arm) or switch from CAR to long-acting therapy (Switch arm). Endpoints assessed at W 96 included proportion of participants with plasma HIV-1 RNA less than 50 copies/ml, incidence of confirmed virologic failure (CVF; two consecutive HIV-1 RNA ≥200 copies/ml), safety and tolerability, pharmacokinetics, and patient-reported outcomes. RESULTS: Most participants completing the Maintenance Phase transitioned to ATLAS-2M (88%, n = 502/572). Overall, 52 participants were included in the W 96 analysis of ATLAS; of these, 100% (n = 23/23) and 97% (n = 28/29) in the Long-acting and Switch arms had plasma HIV-1 RNA less than 50 copies/ml at W 96, respectively. One participant had plasma HIV-1 RNA 50 copies/ml or higher in the Switch arm (173 copies/ml). No participants met the CVF criterion during the Extension Phase. No new safety signals were identified. All Switch arm participants surveyed preferred long-acting therapy to their previous daily oral regimen (100%, n = 27/27). CONCLUSION: In this subgroup of ATLAS, 98% (n = 51/52) of participants at the Extension Phase W 96 analysis maintained virologic suppression with long-acting therapy. Safety, efficacy, and participant preference results support the therapeutic potential of long-acting CAB+RPV treatment for virologically suppressed people living with HIV-1

Selenoprotein gene nomenclature

The human genome contains 25 genes coding for selenocysteine-containing proteins (selenoproteins). These proteins are involved in a variety of functions, most notably redox homeostasis. Selenoprotein enzymes with known functions are designated according to these functions: TXNRD1, TXNRD2, and TXNRD3 (thioredoxin reductases), GPX1, GPX2, GPX3, GPX4 and GPX6 (glutathione peroxidases), DIO1, DIO2, and DIO3 (iodothyronine deiodinases), MSRB1 (methionine-R-sulfoxide reductase 1) and SEPHS2 (selenophosphate synthetase 2). Selenoproteins without known functions have traditionally been denoted by SEL or SEP symbols. However, these symbols are sometimes ambiguous and conflict with the approved nomenclature for several other genes. Therefore, there is a need to implement a rational and coherent nomenclature system for selenoprotein-encoding genes. Our solution is to use the root symbol SELENO followed by a letter. This nomenclature applies to SELENOF (selenoprotein F, the 15 kDa selenoprotein, SEP15), SELENOH (selenoprotein H, SELH, C11orf31), SELENOI (selenoprotein I, SELI, EPT1), SELENOK (selenoprotein K, SELK), SELENOM (selenoprotein M, SELM), SELENON (selenoprotein N, SEPN1, SELN), SELENOO (selenoprotein O, SELO), SELENOP (selenoprotein P, SeP, SEPP1, SELP), SELENOS (selenoprotein S, SELS, SEPS1, VIMP), SELENOT (selenoprotein T, SELT), SELENOV (selenoprotein V, SELV) and SELENOW (selenoprotein W, SELW, SEPW1). This system, approved by the HUGO Gene Nomenclature Committee, also resolves conflicting, missing and ambiguous designations for selenoprotein genes and is applicable to selenoproteins across vertebrates