DNA DSB repair pathway choice: an orchestrated handover mechanism

DNA double strand breaks (DSBs) are potential lethal lesions but can also lead to chromosome rearrangements, a step promoting carcinogenesis. DNA non-homologous end-joining (NHEJ) is the major DSB rejoining process and occurs in all cell cycle stages. Homologous recombination (HR) can additionally function to repair irradiation-induced two-ended DSBs in G2 phase. In mammalian cells, HR predominantly uses a sister chromatid as a template for DSB repair; thus HR functions only in late S/G2 phase. Here, we review current insight into the interplay between HR and NHEJ in G2 phase. We argue that NHEJ represents the first choice pathway, repairing approximately 80% of X-ray-induced DSBs with rapid kinetics. However, a subset of DSBs undergoes end resection and repair by HR. 53BP1 restricts resection, thereby promoting NHEJ. During the switch fromNHEJ to HR, 53BP1 is repositioned to the periphery of enlarged irradiation-induced foci (IRIF) via a BRCA1-dependent process. K63-linked ubiquitin chains, which also form at IRIF, are also repositioned as well as receptor-associated protein 80 (RAP80), a ubiquitin binding protein. RAP80 repositioning requires POH1, a proteasome component. Thus, the interfacing barriers to HR, 53BP1 and RAP80 are relieved by POH1 and BRCA1, respectively. Removal of RAP80 from the IRIF core is required for loss of the ubiquitin chains and 53BP1, and for efficient replication protein A foci formation. We propose that NHEJ is used preferentially to HR because it is a compact process that does not necessitate extensive chromatin changes in the DSB vicinity

Lack of Protection following Passive Transfer of Polyclonal Highly Functional Low-Dose Non-Neutralizing Antibodies

Recent immune correlates analysis from the RV144 vaccine trial has renewed interest in the role of non-neutralizing antibodies in mediating protection from infection. While neutralizing antibodies have proven difficult to induce through vaccination, extra-neutralizing antibodies, such as those that mediate antibody-dependent cellular cytotoxicity (ADCC), are associated with long-term control of infection. However, while several non-neutralizing monoclonal antibodies have been tested for their protective efficacy in vivo, no studies to date have tested the protective activity of naturally produced polyclonal antibodies from individuals harboring potent ADCC activity. Because ADCC-inducing antibodies are highly enriched in elite controllers (EC), we passively transferred highly functional non-neutralizing polyclonal antibodies, purified from an EC, to assess the potential impact of polyclonal non-neutralizing antibodies on a stringent SHIV-SF162P3 challenge in rhesus monkeys. Passive transfer of a low-dose of ADCC inducing antibodies did not protect from infection following SHIV-SF162P3 challenge. Passively administered antibody titers and gp120-specific, but not gp41-specific, ADCC and antibody induced phagocytosis (ADCP) were detected in the majority of the monkeys, but did not correlate with post infection viral control. Thus these data raise the possibility that gp120-specific ADCC activity alone may not be sufficient to control viremia post infection but that other specificities or Fc-effector profiles, alone or in combination, may have an impact on viral control and should be tested in future passive transfer experiments

Attribution-based motivation treatment efficacy in an online learning environment for students who differ in cognitive elaboration

Attribution-based motivation treatments can boost performance in competitive achievement settings (Perry and Hamm 2017), yet their efficacy relative to mediating processes and affect-based treatments remains largely unexamined. In a two-semester, pre-post, randomized treatment study (n = 806), attributional retraining (AR) and stress-reduction (SR) treatments were administered in an online learning environment to first-year college students who differed in cognitive elaboration (low, high). Low elaborators who received AR outperformed their SR peers by nearly a letter grade on a class test assessed 5 months post-treatment. Path analysis revealed this AR-performance linkage was mediated by causal attributions, perceived control, and positive and negative achievement emotions in a hypothesized causal sequence. Results advance the literature by showing AR (vs. SR) improved performance indirectly via cognitive and affective process variables specified by Weiner’s (1985a, 2012) attribution theory of motivation and emotion

A Role for Behavior in the Relationships Between Depression and Hostility and Cardiovascular Disease Incidence, Mortality, and All-Cause Mortality: the Prime Study.

BACKGROUND: Behavioral factors are important in disease incidence and mortality and may explain associations between mortality and various psychological traits. PURPOSE: These analyses investigated the impact of behavioral factors on the associations between depression, hostility and cardiovascular disease(CVD) incidence, CVD mortality, and all-cause mortality. METHODS: Data from the PRIME Study (N = 6953 men) were analyzed using Cox proportional hazards models, following adjustment for demographic and biological CVD risk factors, and other psychological traits, including social support. RESULTS: Following initial adjustment, both depression and hostility were significantly associated with both mortality outcomes (smallest SHR = 1.24, p < 0.001). Following adjustment for behavioral factors, all relationships were attenuated both when accounting for and not accounting for other psychological variables. Associations with all-cause mortality remained significant (smallest SHR = 1.14, p = 0.04). Of the behaviors included, the most significant contribution to outcomes was found for smoking, but a role was also found for fruit and vegetable intakes and high alcohol consumption. CONCLUSIONS: These findings demonstrate well-known associations between depression, hostility, and mortality and suggest the potential importance of behaviors in explaining these relationships

Influence of iron filing waste on the performance of warm mix asphalt

Recently, interest in the use of projectiles in research on recycling waste materials for construction applications has grown. Using recycled materials for the construction of asphalt concrete pavement, in the meantime, has become a topic of research due to its significant benefits, such as cost savings and reduced environmental impacts. This study reports on comprehensive experimental research conducted using a typical mechanical milling waste, iron filing waste (IFW), as an alternative fine aggregate for warm mix asphalt (WMA) for pavement wearing surface applications. A type of IFW from a local machine workshop was used to replace the conventional fine aggregate, fine natural sand (FNS), at percentages of 25%, 50% 75%, and 100% by the weight of FNS of the size passing sieve No. 50. Experimental tests were conducted on the mixes to compare their Marshall properties, resilient moduli, rutting and fatigue resistance, and moisture susceptibility. Finally, a performance analysis was carried out using the VESYS 5W software on the constructed pavement using the IFW mixes. Both the experiment and the modeling work demonstrated that IFW can be an effective alternative resource for replacing natural fine aggregate in WMA concrete and provided details on the optimum rate based on the comprehensive data obtained first hand

How Much Does Effortful Thinking Underlie Observers’ Reactions to Victimization?

From blaming to helping innocent victims, just-world research has revealed that observers react to victimization in a variety of ways. Recent research suggests that such responses to victimization require effortful thought, whereas other research has shown that people can react to these situations intuitively. Along with manipulating just-world threat, across seven experiments, we manipulated or measured participants’ level of mental processing before assessing judgments of victim derogation, blame, willingness to help, and ultimate justice reasoning. The effect of just-world threat on these responses held constant over a range of manipulations/measures, suggesting that the processes involved in maintaining a belief in a just world are not restricted to the rational, deliberative level of mental processing but also occur intuitively

Residual effects of natural Zn chelates on navy bean response, Zn leaching and soil status

greenhouse experiment was conducted on weakly acidic and calcareous soils to evaluate the aging and residual effects of three natural organic Zn chelates [Zn-ethylenediaminedisuccinate (Zn-EDDS), Zn-polyhydroxyphenylcarboxylate and Zn-aminelignosulfonate] each administered in a single application to a first navy bean (Phaseolus vulgaris L.) crop at several different Zn application rates. In a second navy bean crop, we determined the following parameters: the extent of Zn leaching, the amount of available Zn remaining in soils, the amount of easily leachable Zn, the size of Zn fractions in soils, the pH and redox potential, the dry matter yield, and the soluble and total Zn concentrations in plants. The residual effect after 2 years of Zn fertilization mainly depended on the aging effect of Zn chelates and losses due to Zn leaching. The data relating to the evolution from the first to the second crop showed that the aging effect was noticeable in the calcareous soil. In the latter soil, the Zn-S,S-EDDS treatments showed greater decreases in the Zn uptake by plants than the other Zn treatments and the greatest Zn uptake by plants occurred when Zn was applied as Zn-aminelignosulfonate (10 mg Zn kg−1 rate, 6.85 mg Zn per lysimeter; 5 mg Zn kg−1 rate, 3.36 mg Zn per lysimeter). In contrast, in the calcareous soil, the maximum amount of Zn uptake, for the three chelates was 0.82 mg Zn per lysimeter. Consequently, a further application of Zn would be needed to prevent Zn deficiencies in the plants of a subsequent crop. The behaviour of the pH and Eh parameters in the soils and leachates did not depend on the natural Zn sources applied. In this study, the easily leachable Zn estimated by BaCl2 extraction was not adequate to predict Zn leaching from the soils in subsequent crops

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

What do the australian black summer fires signify for the global fire crisis?

The 2019–20 Australian fire season was heralded as emblematic of the catastrophic harm wrought by climate change. Similarly extreme wildfire seasons have occurred across the globe in recent years. Here, we apply a pyrogeographic lens to the recent Australian fires to examine the range of causes, impacts and responses. We find that the extensive area burnt was due to extreme climatic circumstances. However, antecedent hazard reduction burns (prescribed burns with the aim of reducing fuel loads) were effective in reducing fire severity and house loss, but their effectiveness declined under extreme weather conditions. Impacts were disproportionately borne by socially disadvantaged regional communities. Urban populations were also impacted through prolonged smoke exposure. The fires produced large carbon emissions, burnt fire-sensitive ecosystems and exposed large areas to the risk of biodiversity decline by being too frequently burnt in the future. We argue that the rate of change in fire risk delivered by climate change is outstripping the capacity of our ecological and social systems to adapt. A multi-lateral approach is required to mitigate future fire risk, with an emphasis on reducing the vulnerability of people through a reinvigoration of community-level capacity for targeted actions to complement mainstream fire management capacity