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To identify approaches to target DNA repair vulnerabilities in cancer, we discovered nanomolar potent, selective, low molecular weight (MW), allosteric inhibitors of the polymerase function of DNA polymerase Polθ, including ART558. ART558 inhibits the major Polθ-mediated DNA repair process, Theta-Mediated End Joining, without targeting Non-Homologous End Joining. In addition, ART558 elicits DNA damage and synthetic lethality in BRCA1 - or BRCA2 -mutant tumour cells and enhances the effects of a PARP inhibitor. Genetic perturbation screening revealed that defects in the 53BP1/Shieldin complex, which cause PARP inhibitor resistance, result in in vitro and in vivo sensitivity to small molecule Polθ polymerase inhibitors. Mechanistically, ART558 increases biomarkers of single-stranded DNA and synthetic lethality in 53BP1-defective cells whilst the inhibition of DNA nucleases that promote end-resection reversed these effects, implicating these in the synthetic lethal mechanism-of-action. Taken together, these observations describe a drug class that elicits BRCA -gene synthetic lethality and PARP inhibitor synergy, as well as targeting a biomarker-defined mechanism of PARPi-resistance. Polθ has been recently identified as a therapeutic target in cancer but specific inhibitors are currently unavailable. Here, the authors identify small molecule inhibitors of Polθ’s polymerase activity which elicit BRCA1/2 synthetic lethality, enhance the effect of PARP inhibitors and target PARP inhibitor resistance caused by 53BP1/Shieldin pathway defects.

Although forest edges have been studied extensively as an important consequence of fragmentation, a unifying theory of edge influence has yet to be developed. Our objective was to take steps toward the development of such a theory by (1) synthesizing the current knowledge of patterns of forest structure and composition at anthropogenically created forest edges, (2) developing hypotheses about the magnitude and distance of edge influence that consider the ecological processes influencing these patterns, and (3) identifying needs for future research. We compiled data from 44 published studies on edge influence on forest structure and composition in boreal, temperate, and tropical forests. Abiotic and biotic gradients near created forest edges generate a set of primary responses to edge creation. Indirect effects from these primary responses and the original edge gradient perpetuate edge influence, leading to secondary responses. Further changes in vegetation affect the edge environment, resulting in ongoing edge dynamics. We suggest that the magnitude and distance of edge influence are a direct function of the contrast in structure and composition between adjacent communities on either side of the edge. Local factors such as climate, edge characteristics, stand attributes, and biotic factors affect patch contrast. Regional factors define the context within which to assess the ecological significance of edge influence (the degree to which the edge habitat differs from interior forest habitat). Our hypotheses will help predict edge influence on structure and composition in forested ecosystems, an important consideration for conservation. For future research on forest edges in fragmented landscapes, we encourage the testing of our hypotheses, the use of standardized methodology, complete descriptions of study sites, studies on other types of edges, synthesis of edge influence on different components of the ecosystem, and investigations of edges in a landscape context.

Global forest area is declining rapidly, along with degradation of the ecological condition of remaining forests. Hence it is necessary to adopt forest management approaches that can achieve a balance between (1) human management designs based on homogenization of forest structure to efficiently deliver economic values and (2) naturally emerging self-organized ecosystem dynamics that foster heterogeneity, biodiversity, resilience and adaptive capacity. Natural disturbance-based management is suggested to provide such an approach. It is grounded on the premise that disturbance is a key process maintaining diversity of ecosystem structures, species and functions, and adaptive and evolutionary potential, which functionally link to sustainability of ecosystem services supporting human well-being. We review the development, ecological and evolutionary foundations and applications of natural disturbance-based forest management. With emphasis on boreal forests, we compare this approach with two mainstream approaches to sustainable forest management, retention and continuous-cover forestry. Compared with these approaches, natural disturbance-based management provides a more comprehensive framework, which is compatible with current understanding of multiple-scale ecological processes and structures, which underlie biodiversity, resilience and adaptive potential of forest ecosystems. We conclude that natural disturbance-based management provides a comprehensive ecosystem-based framework for managing forests for human needs of commodity production and immaterial values, while maintaining forest health in the rapidly changing global environment.

Background The concept of vulnerability has held a central place in research ethics guidance since its introduction in the United States Belmont Report in 1979. It signals mindfulness for researchers and research ethics boards to the possibility that some participants may be at higher risk of harm or wrong. Despite its important intended purpose and widespread use, there is considerable disagreement in the scholarly literature about the meaning and delineation of vulnerability, stemming from a perceived lack of guidance within research ethics standards. The aim of this study was to assess the concept of vulnerability as it is employed in major national and international research ethics policies and guidelines. Methods We conducted an in-depth analysis of 11 (five national and six international) research ethics policies and guidelines, exploring their discussions of the definition, application, normative justification and implications of vulnerability. Results Few policies and guidelines explicitly defined vulnerability, instead relying on implicit assumptions and the delineation of vulnerable groups and sources of vulnerability. On the whole, we found considerable richness in the content on vulnerability across policies, but note that this relies heavily on the structure imposed on the data through our analysis. Conclusions Our results underscore a need for policymakers to revisit the guidance on vulnerability in research ethics, and we propose that a process of stakeholder engagement would well-support this effort.

Retention harvesting (also called tree retention or structural retention), in which live mature trees are selectively retained within harvested stands at different retention levels and in different patterns (aggregated to dispersed), is increasingly being used to mitigate the negative impacts of forest harvesting on biodiversity. However, the effectiveness of combining different patterns of retention harvesting for conservation and recovery of understory vascular plants in the long term is largely unknown. To address this gap, we compared understory vascular plant diversity, abundance, and composition between aggregated retention and five levels of surrounding dispersed retention (0% [clearcut], 10%, 20%, 50%, 75%) 15 yr postharvest. We also investigated the influence of dispersed retention on the ability of embedded retention patches to support plant communities characteristic of unharvested forests, and whether it varies by patch size of aggregated retention (0.20 ha or 0.46 ha) and position within patches (edge or interior). Species richness, diversity, and cover were higher in the dispersed retention than in the patch retention as the harvested areas favored early-seral plant species. Graminoid cover was greater at the edges than in the interior of large patches. Retention patches as small as 0.2 ha more effectively supported shade-tolerant (forest interior) plant communities when they were surrounded by higher levels of dispersed retention (as compared to patches retained within clearcuts). Overall, the combined use of both aggregated and dispersed retention within a given cut-block benefits both late- and early-seral plant species and thus could effectively conserve understory plant assemblages in harvested landscapes. Sustainable forest management should therefore consider using a range of retention patch sizes combined with varying levels of surrounding dispersed retention in harvest designs to achieve objectives for plant conservation.

Reclamation following oil sands mining in northeastern Alberta (Canada) creates adverse reforestation soil conditions, including extreme pH values. We elucidated pH tolerance limits of boreal plant species and how pH affects nutrient uptake in these plants. We measured growth, gas exchange, and foliar nutrient concentration of 15 common northern boreal forest plants after eight weeks exposure to root zone pH ranging from 5.0 to 9.0. Cluster analyses were used to group these species based on their pH responses. Based on their growth and gas exchange responses to pH, the 15 plant species could be divided into five groups, each of which contained species that commonly co-occur in particular boreal forest site types. For the foliar nutrient responses to pH, the 15 species could be grouped into only two categories; both showed decreases in foliar N, P, Fe and Zn concentration with increasing pH, with a more pronounced effect on the group that included trembling aspen, paper birch and chokecherry. The evidence of differential adaptation to pH by habitat type suggests the importance of soil pH as a factor affecting boreal plant species distribution and could be helpful for selection of species suitable for reclamation of sites with altered soil pH.

Background Livestock grazing and ‘overabundance’ of large wild herbivores in forested areas have long been perceived as conflicting with the aims of both silviculture and forest conservation; however, certain kinds of herbivory can help to maintain habitat values in forest ecosystems. Management of mammalian herbivory in protected forests can, therefore, be a critical tool for biodiversity conservation. The primary aim of this systematic review was to examine how forest vegetation and invertebrates are affected by manipulation of the grazing/browsing pressure by livestock or wild ungulates. The ultimate purpose was to investigate whether such manipulation is useful for conserving or restoring biodiversity in forest set-asides. Methods We considered studies of manipulated ungulate herbivory in forests anywhere within the boreal and temperate zones, not only in protected areas but also in production forest. Non-intervention or alternative levels of intervention were used as comparators. Relevant outcomes included abundance, diversity and composition of plants and invertebrates, tree regeneration, and performance of focal/target species. Studies were mainly selected from a recent systematic map of the evidence on biodiversity effects of forest management relevant to protected areas. Additional studies were identified through updated searches online and in bibliographies of existing reviews. Relevant studies were critically appraised, and studies with low or unclear validity were excluded from the review. Quantitative outcomes were extracted from 103 articles, and summary effect sizes were derived by meta-analysis. Results Most of the 144 studies included in the review had been conducted in North America, Europe or Australia/New Zealand. The intervention most commonly studied was experimental exclusion (or enclosure) of wild and/or domestic ungulates by fencing. Other studies examined culling of wild ungulates or compared forests long grazed by livestock to ungrazed forests. Effects on vegetation and invertebrates were reported in 135 and 23 of the studies, respectively. We found negative responses to herbivory in the abundance of understorey vegetation as a whole, woody understorey and bryophytes, and also in the species richness of woody understorey vegetation, whereas the richness of forbs and bryophytes responded positively. Several effects depended on ungulate origins: Understorey abundance responded negatively to livestock and to ungulates introduced into the wild, but not to native ones. In contrast, understorey species richness responded positively to livestock but not to wild ungulates. The duration and intensity of herbivory had few significant effects on vegetation—exceptions included woody understorey abundance and richness, which decreased with increasing duration and intensity, respectively. Among invertebrates we found negative responses to herbivory in the abundance of lepidopterans and spiders, but no significant effects on species richness. Conclusions Our review revealed a large body of high-validity experimental studies on impacts of ungulate herbivory in forests. This evidence confirmed that manipulation of such herbivory is often highly influential on tree regeneration and on the abundance, diversity and composition of understorey vegetation. Nevertheless, we also identified important knowledge gaps—we found few studies of boreal areas, long-term herbivory effects, impacts on bryophytes, lichens and invertebrates, and effects of manipulation less radical than total exclusion of ungulates.

We used repeat oblique photography to quantify and determine the drivers of vegetation change, particularly forest closure and encroachment, in the Rocky Mountains of southern Alberta, Canada, from the beginning of the twentieth century to the present. We classified the landscape into seven distinct vegetation types (closed‐canopy conifer forest, broadleaf deciduous forest, mixedwood forest, open‐canopy woodlands, shrublands, grasslands and meadows, non‐vegetated) and assessed vegetation change between the two time periods. We found that closed‐canopy coniferous forest, broadleaf deciduous forest, and mixedwood forest increased on an area basis by 35%, 45%, and 80%, respectively, over this time period; concomitantly, grasslands and open‐canopy woodlands declined by 25% and 39%, respectively. Overall, 28% of the landscape was in a more advanced successional state in 2008 as compared to the early twentieth century. The Montane and Subalpine Natural Subregions (NSR) experienced the most change (42% and 26%, respectively, in a more advanced successional state). The loss of open‐canopy woodlands was observed across the entire landscape, while grassland and meadow losses were most acute in the Subalpine and Alpine NSRs. The probability of vegetation change to a more advanced successional condition was greater at higher elevations and in areas receiving lower amounts of solar insolation. The changes observed are consistent with what we would expect to see due to lengthening of fire return intervals. Understanding the magnitude of change in vegetation types and the drivers of this change is important for the development of effective contemporary ecosystem management and restoration practices.

Falls are a leading reason for older people presenting to the emergency department (ED), and many experience further falls. Little evidence exists to guide secondary prevention in this population. This randomised controlled trial (RCT) investigated whether a 6-month telephone-based patient-centred program-RESPOND-had an effect on falls and fall injuries in older people presenting to the ED after a fall. Community-dwelling people aged 60-90 years presenting to the ED with a fall and planned for discharge home within 72 hours were recruited from two EDs in Australia. Participants were enrolled if they could walk without hands-on assistance, use a telephone, and were free of cognitive impairment (Mini-Mental State Examination > 23). Recruitment occurred between 1 April 2014 and 29 June 2015. Participants were randomised to receive either RESPOND (intervention) or usual care (control). RESPOND comprised (1) home-based risk assessment; (2) 6 months telephone-based education, coaching, goal setting, and support for evidence-based risk factor management; and (3) linkages to existing services. Primary outcomes were falls and fall injuries in the 12-month follow-up. Secondary outcomes included ED presentations, hospital admissions, fractures, death, falls risk, falls efficacy, and quality of life. Assessors blind to group allocation collected outcome data via postal calendars, telephone follow-up, and hospital records. There were 430 people in the primary outcome analysis-217 randomised to RESPOND and 213 to control. The mean age of participants was 73 years; 55% were female. Falls per person-year were 1.15 in the RESPOND group and 1.83 in the control (incidence rate ratio [IRR] 0.65 [95% CI 0.43-0.99]; P = 0.042). There was no significant difference in fall injuries (IRR 0.81 [0.51-1.29]; P = 0.374). The rate of fractures was significantly lower in the RESPOND group compared with the control (0.05 versus 0.12; IRR 0.37 [95% CI 0.15-0.91]; P = 0.03), but there were no significant differences in other secondary outcomes between groups: ED presentations, hospitalisations or falls risk, falls efficacy, and quality of life. There were two deaths in the RESPOND group and one in the control group. No adverse events or unintended harm were reported. Limitations of this study were the high number of dropouts (n = 93); possible underreporting of falls, fall injuries, and hospitalisations across both groups; and the relatively small number of fracture events. In this study, providing a telephone-based, patient-centred falls prevention program reduced falls but not fall injuries, in older people presenting to the ED with a fall. Among secondary outcomes, only fractures reduced. Adopting patient-centred strategies into routine clinical practice for falls prevention could offer an opportunity to improve outcomes and reduce falls in patients attending the ED. Australian New Zealand Clinical Trials Registry (ACTRN12614000336684).

Increasing environmental concerns with forestry have led to mounting interest in mixedwood management as a possible strategy to achieve a diversity of ecological and productivity goals within the context of sustainable forest management. This review focuses on the effects of mixedwoods on biodiversity including understory plants, birds, soil fauna, and ectomycorrhizae (ECM). It examines stand-level species diversity and composition but particularly focuses on the regional scale (gamma diversity) by examining evidence for the occurrence of mixedwood-indicator species. The main conclusions are as follows: (i) The existence of different tree species in the canopy is associated with provision of a greater diversity of microhabitats allowing for the addition of understory plant species associated with each canopy species. However, there is little evidence for the existence of understory plant species uniquely associated with mixedwoods. (ii) Some bird species require or prefer the presence of different tree species within a landscape or within a stand. Mixed forest stands and landscapes are thus critical to support populations of these species. (iii) A few studies showed a positive effect of mixed stands or mixed litters on some groups of soil organisms, but high variability makes it difficult to draw firm conclusions about any potential benefits of mixedwoods for biodiversity of soil fauna. (iv) Some ECM taxa are associated with multiple hosts, and could thus benefit from availability of multiple possible host species found in mixed forest stands. Several studies confirmed that there was a greater abundance of multiple-host ECM taxa in mixedwoods.