DNA double-strand breaks (DSBs) can arise from multiple sources, including exposure to ionizing radiation. The repair of DSBs involves both posttranslational modification of nucleosomes and ...concentration of DNA-repair proteins at the site of damage. Consequently, nucleosome packing and chromatin architecture surrounding the DSB may limit the ability of the DNA-damage response to access and repair the break. Here, we review early chromatin-based events that promote the formation of open, relaxed chromatin structures at DSBs and that allow the DNA-repair machinery to access the spatially confined region surrounding the DSB, thereby facilitating mammalian DSB repair.
Following birth, the breast-fed infant gastrointestinal tract is rapidly colonized by a microbial consortium often dominated by bifidobacteria. Accordingly, the complete genome sequence of ...Bifidobacterium longum subsp. infantis ATCC15697 reflects a competitive nutrient-utilization strategy targeting milk-borne molecules which lack a nutritive value to the neonate. Several chromosomal loci reflect potential adaptation to the infant host including a 43 kbp cluster encoding catabolic genes, extracellular solute binding proteins and permeases predicted to be active on milk oligosaccharides. An examination of in vivo metabolism has detected the hallmarks of milk oligosaccharide utilization via the central fermentative pathway using metabolomic and proteomic approaches. Finally, conservation of gene clusters in multiple isolates corroborates the genomic mechanism underlying milk utilization for this infant-associated phylotype.
We tracked over time the conductance switching of single and bundled phenylene ethynylene oligomers isolated in matrices of alkanethiolate monolayers. The persistence times for isolated and bundled ...molecules in either the ON or OFF switch state range from seconds to tens of hours. When the surrounding matrix is well ordered, the rate at which the inserted molecules switch is low. Conversely, when the surrounding matrix is poorly ordered, the inserted molecules switch more often. We conclude that the switching is a result of conformational changes in the molecules or bundles, rather than electrostatic effects of charge transfer.
Abstract
Using existing data can be a reliable and cost-effective way to predict species distributions, and particularly useful for recovering or expanding species. We developed a current gray wolf (
...Canis lupus
) distribution model for the western Great Lakes region, USA, and evaluated the spatial transferability of single-state models to the region. This study is the first assessment of transferability in a wide-ranging carnivore, as well as one of few developed for large spatial extents. We collected 3500 wolf locations from winter surveys in Minnesota (2017–2019), Wisconsin (2019–2020), and Michigan (2017–2020). We included 10 variables: proportion of natural cover, pastures, and crops; distance to natural cover, agriculture, developed land, and water; major and minor road density; and snowfall (1-km res.). We created a regional ensemble distribution by weight-averaging eight models based on their performance. We also developed single-state models, and estimated spatial transferability using two approaches: state cross-validation and extrapolation. We assessed performance by quantifying correlations, receiver operating characteristic curves (ROC), sensitivities, and two niche similarity indices. The regional area estimated to be most suitable for wolves during winter (threshold = maximum sensitivity/specificity) was 106,465 km
2
(MN = 48,083 km
2
, WI = 27,757 km
2
, MI = 30,625 km
2
) and correctly predicted 88% of wolf locations analyzed. Increasing natural cover and distance to crops were consistently important for determining regional and single-state wolf distribution. Extrapolation (vs. cross-validation) produced results with the greatest performance metrics, and were most similar to the regional model, yet good internal performance was unrelated to greater extrapolation performance. Factors influencing species distributions are scale-dependent and can vary across areas due to behavioral plasticity. When extending inferences beyond the current occurrence of individuals, assessing variation in ecology such as habitat selection, as well as methodological factors including model performance, will be critical to avoid poor scientific interpretations and develop effective conservation applications. In particular, accurate distribution models for recovering or recovered carnivores can be used to develop plans for habitat management, quantify potential of unoccupied habitat, assess connectivity modeling, and mitigate conflict, facilitating long-term species persistence.
Silent cerebral ischemia (SCI) has been reported in 14% of cases after catheter ablation of atrial fibrillation (AF) with radiofrequency (RF) energy and discontinuation of warfarin before AF ablation ...procedures.
The purpose of this study was to determine whether periprocedural anticoagulation management affects the incidence of SCI after RF ablation using an open irrigated catheter.
Consecutive patients undergoing RF ablation for AF without warfarin discontinuation and receiving heparin bolus before transseptal catheterization (group I, n = 146) were compared with a group of patients who had protocol deviation in terms of maintaining the therapeutic preprocedural international normalized ratio (patients with subtherapeutic INR) and/or failure to receive pretransseptal heparin bolus infusion and/or ≥2 consecutive ACT measurements <300 seconds (noncompliant population, group II, n = 134) and with a group of patients undergoing RF ablation with warfarin discontinuation bridged with low molecular weight heparin (group III, n = 148). All patients underwent preablation and postablation (within 48 hours) diffusion magnetic resonance imaging.
SCI was detected in 2% of patients (3/146) in group I, 7% (10/134) in group II, and 14% (21/148) in group III (P <.001). “Therapeutic INR” was strongly associated with a lower prevalence of postprocedural silent cerebral ischemia (SCI). Multivariable analysis demonstrated nonparoxysmal AF (odds ratio 3.8, 95% confidence interval 1.5–9.7, P = .005) and noncompliance to protocol (odds ratio 2.8, 95% confidence interval 1.5–5.1, P <.001 to be significant predictors of ischemic events.
Strict adherence to an anticoagulation protocol significantly reduces the prevalence of SCI after catheter ablation of AF with RF energy.
Detailed angle and energy resolved measurements of positrons ejected from the back of a gold target that was irradiated with an intense picosecond duration laser pulse reveal that the positrons are ...ejected in a collimated relativistic jet. The laser-positron energy conversion efficiency is ∼2×10{-4}. The jets have ∼20 degree angular divergence and the energy distributions are quasimonoenergetic with energy of 4 to 20 MeV and a beam temperature of ∼1 MeV. The sheath electric field on the surface of the target is shown to determine the positron energy. The positron angular and energy distribution is controlled by varying the sheath field, through the laser conditions and target geometry.
Neuroticism is a personality trait of fundamental importance for psychological well-being and public health. It is strongly associated with major depressive disorder (MDD) and several other ...psychiatric conditions. Although neuroticism is heritable, attempts to identify the alleles involved in previous studies have been limited by relatively small sample sizes. Here we report a combined meta-analysis of genome-wide association study (GWAS) of neuroticism that includes 91 370 participants from the UK Biobank cohort, 6659 participants from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and 8687 participants from a QIMR (Queensland Institute of Medical Research) Berghofer Medical Research Institute (QIMR) cohort. All participants were assessed using the same neuroticism instrument, the Eysenck Personality Questionnaire-Revised (EPQ-R-S) Short Form's Neuroticism scale. We found a single-nucleotide polymorphism-based heritability estimate for neuroticism of ∼15% (s.e.=0.7%). Meta-analysis identified nine novel loci associated with neuroticism. The strongest evidence for association was at a locus on chromosome 8 (P=1.5 × 10(-15)) spanning 4 Mb and containing at least 36 genes. Other associated loci included interesting candidate genes on chromosome 1 (GRIK3 (glutamate receptor ionotropic kainate 3)), chromosome 4 (KLHL2 (Kelch-like protein 2)), chromosome 17 (CRHR1 (corticotropin-releasing hormone receptor 1) and MAPT (microtubule-associated protein Tau)) and on chromosome 18 (CELF4 (CUGBP elav-like family member 4)). We found no evidence for genetic differences in the common allelic architecture of neuroticism by sex. By comparing our findings with those of the Psychiatric Genetics Consortia, we identified a strong genetic correlation between neuroticism and MDD and a less strong but significant genetic correlation with schizophrenia, although not with bipolar disorder. Polygenic risk scores derived from the primary UK Biobank sample captured ∼1% of the variance in neuroticism in the GS:SFHS and QIMR samples, although most of the genome-wide significant alleles identified within a UK Biobank-only GWAS of neuroticism were not independently replicated within these cohorts. The identification of nine novel neuroticism-associated loci will drive forward future work on the neurobiology of neuroticism and related phenotypes.
Summary Background Patients with isolated locoregional recurrences (ILRR) of breast cancer have a high risk of distant metastasis and death from breast cancer. We aimed to establish whether adjuvant ...chemotherapy improves the outcome of such patients. Methods The CALOR trial was a pragmatic, open-label, randomised trial that accrued patients with histologically proven and completely excised ILRR after unilateral breast cancer who had undergone a mastectomy or lumpectomy with clear surgical margins. Eligible patients were enrolled from hospitals worldwide and were centrally randomised (1:1) to chemotherapy (type selected by the investigator; multidrug for at least four courses recommended) or no chemotherapy, using permuted blocks, and stratified by previous chemotherapy, oestrogen-receptor and progesterone-receptor status, and location of ILRR. Patients with oestrogen-receptor-positive ILRR received adjuvant endocrine therapy, radiation therapy was mandated for patients with microscopically involved surgical margins, and anti- HER2 therapy was optional. The primary endpoint was disease-free survival. All analyses were by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00074152. Findings From Aug 22, 2003, to Jan 31, 2010, 85 patients were randomly assigned to receive chemotherapy and 77 were assigned to no chemotherapy. At a median follow-up of 4·9 years (IQR 3·6–6 ·0), 24 (28%) patients had disease-free survival events in the chemotherapy group compared with 34 (44%) in the no chemotherapy group. 5-year disease-free survival was 69% (95% CI 56–79) with chemotherapy versus 57% (44–67) without chemotherapy (hazard ratio 0·59 95% CI 0·35–0·99; p=0·046). Adjuvant chemotherapy was significantly more effective for women with oestrogen-receptor-negative ILRR (pinteraction =0·046), but analyses of disease-free survival according to the oestrogen-receptor status of the primary tumour were not statistically significant (pinteraction =0·43). Of the 81 patients who received chemotherapy, 12 (15%) had serious adverse events. The most common adverse events were neutropenia, febrile neutropenia, and intestinal infection. Interpretation Adjuvant chemotherapy should be recommended for patients with completely resected ILRR of breast cancer, especially if the recurrence is oestrogen-receptor negative. Funding US Department of Health and Human Services, Swiss Group for Clinical Cancer Research (SAKK), Frontier Science and Technology Research Foundation, Australian and New Zealand Breast Cancer Trials Group, Swedish Cancer Society, Oncosuisse, Cancer Association of South Africa, Foundation for Clinical Research of Eastern Switzerland (OSKK), Grupo Español de Investigación en Cáncer de Mama (GEICAM), and the Dutch Breast Cancer Trialists' Group (BOOG).
Objective:Low-dose testosterone has been shown to improve depression symptom severity, fatigue, and sexual function in small studies in women not formally diagnosed with major depressive disorder. ...The authors sought to determine whether adjunctive low-dose transdermal testosterone improves depression symptom severity, fatigue, and sexual function in women with antidepressant-resistant major depression. A functional MRI (fMRI) substudy examined effects on activity in the anterior cingulate cortex (ACC), a brain region important in mood regulation.Methods:The authors conducted an 8-week randomized double-blind placebo-controlled trial of adjunctive testosterone cream in 101 women, ages 21–70, with antidepressant-resistant major depression. The primary outcome measure was depression symptom severity as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary endpoints included fatigue, sexual function, and safety measures. The primary outcome of the fMRI substudy (N=20) was change in ACC activity.Results:The participants’ mean age was 47 years (SD=14) and their mean baseline MADRS score was 26.6 (SD=5.9). Eighty-seven (86%) participants completed 8 weeks of treatment. MADRS scores decreased in both study arms from baseline to week 8 (testosterone arm: from 26.8 SD=6.3 to 15.3 SD=9.6; placebo arm: from 26.3 SD=5.4 to 14.4 SD=9.3), with no significant difference between groups. Improvement in fatigue and sexual function did not differ between groups, nor did side effects. fMRI results showed a relationship between ACC activation and androgen levels before treatment but no difference in ACC activation with testosterone compared with placebo.Conclusions:Adjunctive transdermal testosterone, although well tolerated, was not more effective than placebo in improving symptoms of depression, fatigue, or sexual dysfunction. Imaging in a subset of participants demonstrated that testosterone did not result in greater activation of the ACC.
AIM: Understanding how ecological and evolutionary processes together determine patterns of biodiversity remains a central aim in biology. Guided by ecological theory, we use data from multiple ...arthropod lineages across the Hawaiian archipelago to explore the interplay between ecological (population dynamics, dispersal, trophic interactions) and evolutionary (genetic structuring, adaptation, speciation, extinction) processes. Our goal is to show how communities develop from the dynamic feedbacks that operate at different temporal and spatial scales. LOCATION: The Hawaiian islands (19â22°âN, 155â160°âW). METHODS: We synthesize genetic data from selected arthropods across the Hawaiian archipelago to determine the relative role of dispersal and in situ differentiation across the island chronosequence. From four sites on three high islands with geological ages ranging from â1âMyr. Herbivoreâplant communities only transiently achieve statistical steady state during assembly, presumably due to incomplete assembly from dispersal in the early stages, and the increasing influence of island ontogeny on older islands.
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