Reporting the biodiversity impacts of greenhouse gas emissions.

There are increasing demands for organisations and governments to report their biodiversity impacts, yet there are limited methods to account for the consequences of emitting greenhouse gases on global biodiversity. We use published evidence to derive a conversion factor of approximately 2.3 × 10-7 species expected to be committed to extinction per tCO2 e emitted. We demonstrate how this conversion factor can be used to account for emissions-related biodiversity impacts of organisations and nations.

Spatial variation in avian bill size is associated with temperature extremes in a major radiation of Australian passerines.

Morphology is integral to body temperature regulation. Recent advances in understanding of thermal physiology suggest a role of the avian bill in thermoregulation. To explore the adaptive significance of bill size for thermoregulation we characterized relationships between bill size and climate extremes. Most previous studies focused on climate means, ignoring frequencies of extremes, and do not reflect thermoregulatory costs experienced over shorter time scales. Using 79 species (9847 museum specimens), we explore how bill size variation is associated with temperature extremes in a large and diverse radiation of Australasian birds, Meliphagides, testing a series of predictions. Overall, across the continent, bill size variation was associated with both climate extremes and means and was most strongly associated with winter temperatures; associations at the level of climate zones differed from continent-wide associations and were complex, yet consistent with physiology and a thermoregulatory role for avian bills. Responses to high summer temperatures were nonlinear suggesting they may be difficult to detect in large-scale continental analyses using previous methodologies. We provide strong evidence that climate extremes have contributed to the evolution of bill morphology in relation to thermoregulation and show the importance of including extremes to understand fine-scale trait variation across space.

Habitat-based biodiversity assessment for ecosystem accounting in the Murray-Darling Basin.

Understanding how biodiversity is changing over space and time is crucial for well-informed decisions that help retain Earth's biological heritage over the long term. Tracking changes in biodiversity through ecosystem accounting provides this important information in a systematic way and readily enables linking to other relevant environmental and economic data to provide an integrated perspective. We derived biodiversity accounts for the Murray-Darling Basin, Australia's largest catchment. We assessed biodiversity change from 2010 to 2015 for all vascular plants, all waterbirds, and 10 focal species. We applied a scalable habitat-based assessment approach that combined expected patterns in the distribution of biodiversity from spatial biodiversity models with a time series of spatially complete data on habitat condition derived from remote sensing. Changes in biodiversity from 2010 to 2015 varied across regions and biodiversity features. For the entire Murray-Darling Basin, the expected persistence of vascular plants increased slightly from 2010 to 2015 (from 86.8% to 87.1%), mean species richness of waterbirds decreased slightly (from 12.5 to 12.3 species), whereas for the focal species the estimated area of habitat increased for 8 species and decreased for 1 species. Regions in the north of the Murray-Darling Basin generally had decreases in biodiversity from 2010 to 2015, whereas in the south biodiversity was stable or increased. Our results demonstrate the benefits of habitat-based biodiversity assessments in providing fully scalable biodiversity accounts across different biodiversity features, consistent with the United Nations System of Environmental Economic Accounting - Ecosystem Accounting (SEEA EA) framework.

Evaluación de la Biodiversidad con base en el Hábitat para la Contabilización de Ecosistemas en la Cuenca Murray-Darling Resumen El conocimiento sobre cómo está cambiando la biodiversidad en el tiempo y en el espacio es crucial para las decisiones bien informadas que ayudan a retener la herencia biológica de la Tierra a largo plazo. El seguimiento de cambios en la biodiversidad mediante la contabilidad de los ecosistemas proporciona esta información importante de manera sistémica y permite fácilmente la conexión con otros datos ambientales y económicos relevantes para proporcionar una perspectiva integrada. Derivamos la contabilidad de la biodiversidad para la Cuenca Murray-Darling, la mayor cuenca de Australia. Analizamos los cambios en la biodiversidad entre 2010 y 2015 de todas las plantas vasculares, todas las aves acuáticas y diez especies focales. Aplicamos una estrategia de evaluación basada en el hábitat que combinó los patrones esperados en la distribución de la biodiversidad a partir de modelos espaciales de la biodiversidad con una serie temporal de datos espacialmente completos derivados de la teledetección de la condición del hábitat. Los cambios en la biodiversidad entre 2010 y 2015 variaron entre las regiones y las características de la biodiversidad. Para toda la Cuenca Murray-Darling, la persistencia esperada de las plantas vasculares incrementó ligeramente durante los años de estudio (de 86.8% a 87.1%), la riqueza promedio de especies de aves acuáticas disminuyó un poco (de 12.5 a 12.3 especies), mientras que el área estimada del hábitat de las especies focales incrementó para ocho especies y disminuyó para una. Las regiones al norte de la cuenca tuvieron disminuciones generalizadas de la biodiversidad entre 2010 y 2015, mientras al sur, la biodiversidad se mantuvo estable o incrementó. Nuestros resultados demuestran los beneficios que tienen las evaluaciones de la biodiversidad basadas en el hábitat para proporcionar una contabilidad de la biodiversidad completamente escalable entre las diferentes características de la biodiversidad, acorde con la estructura del Sistema de Contabilidad Económico-Ambiental - Contabilidad de los Ecosistemas (SEEA EA) de las Naciones Unidas.

Characterization of the Onset, Progression, and Reversibility of Morphological Changes in Mouse Lung after Pharmacological Inhibition of Leucine-Rich Kinase 2 Kinase Activity.

Gain-of-function mutations in leucine-rich kinase 2 (LRRK2) are associated with increased incidence of Parkinson disease (PD); thus, pharmacological inhibition of LRRK2 kinase activity is postulated as a disease-modifying treatment of PD. Histomorphological changes in lungs of nonhuman primates (NHPs) treated with small-molecule LRRK2 kinase inhibitors have brought the safety of this treatment approach into question. Although it remains unclear how LRRK2 kinase inhibition affects the lung, continued studies in NHPs prove to be both cost- and resource-prohibitive. To develop a tractable alternative animal model platform, we dosed male mice in-diet with the potent, highly selective LRRK2 kinase inhibitor MLi-2 and induced histomorphological changes in lung within 1 week. Oral bolus dosing of MLi-2 at a frequency modeled to provide steady-state exposure equivalent to that achieved with in-diet dosing induced type II pneumocyte vacuolation, suggesting pulmonary changes require sustained LRRK2 kinase inhibition. Treating mice with MLi-2 in-diet for up to 6 months resulted in type II pneumocyte vacuolation that progressed only modestly over time and was fully reversible after withdrawal of MLi-2. Immunohistochemical analysis of lung revealed a significant increase in prosurfactant protein C staining within type II pneumocytes. In the present study, we demonstrated the kinetics for onset, progression, and rapid reversibility of chronic LRRK2 kinase inhibitor effects on lung histomorphology in rodents and provide further evidence for the derisking of safety and tolerability concerns for chronic LRRK2 kinase inhibition in PD. SIGNIFICANCE STATEMENT: We have defined a mouse model by which the on-target lung effects of leucine-rich kinase 2 (LRRK2) kinase inhibition can be monitored, whereas previous in vivo testing relied solely on nonhuman primates. Data serve to derisk long-term treatment with LRRK2 kinase inhibitors, as all lung changes were mild and readily reversible.

Reconciling global priorities for conserving biodiversity habitat.

Degradation and loss of natural habitat is the major driver of the current global biodiversity crisis. Most habitat conservation efforts to date have targeted small areas of highly threatened habitat, but emerging debate suggests that retaining large intact natural systems may be just as important. We reconcile these perspectives by integrating fine-resolution global data on habitat condition and species assemblage turnover to identify Earth's high-value biodiversity habitat. These are areas in better condition than most other locations predicted to have once supported a similar assemblage of species and are found within both intact regions and human-dominated landscapes. However, only 18.6% of this high-value habitat is currently protected globally. Averting permanent biodiversity loss requires clear, spatially explicit targets for retaining these unprotected high-value habitats.

Projecting impacts of global climate and land-use scenarios on plant biodiversity using compositional-turnover modelling.

Nations have committed to ambitious conservation targets in response to accelerating rates of global biodiversity loss. Anticipating future impacts is essential to inform policy decisions for achieving these targets, but predictions need to be of sufficiently high spatial resolution to forecast the local effects of global change. As part of the intercomparison of biodiversity and ecosystem services models of the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services, we present a fine-resolution assessment of trends in the persistence of global plant biodiversity. We coupled generalized dissimilarity models, fitted to >52 million records of >254 thousand plant species, with the species-area relationship, to estimate the effect of land-use and climate change on global biodiversity persistence. We estimated that the number of plant species committed to extinction over the long term has increased by 60% globally between 1900 and 2015 (from ~10,000 to ~16,000). This number is projected to decrease slightly by 2050 under the most optimistic scenario of land-use change and to substantially increase (to ~18,000) under the most pessimistic scenario. This means that, in the absence of climate change, scenarios of sustainable socio-economic development can potentially bring extinction risk back to pre-2000 levels. Alarmingly, under all scenarios, the additional impact from climate change might largely surpass that of land-use change. In this case, the estimated number of species committed to extinction increases by 3.7-4.5 times compared to land-use-only projections. African regions (especially central and southern) are expected to suffer some of the highest impacts into the future, while biodiversity decline in Southeast Asia (which has previously been among the highest globally) is projected to slow down. Our results suggest that environmentally sustainable land-use planning alone might not be sufficient to prevent potentially dramatic biodiversity loss, unless a stabilization of climate to pre-industrial times is observed.

A Brain Penetrant Mutant IDH1 Inhibitor Provides In Vivo Survival Benefit.

Mutations in IDH1 are highly prevalent in human glioma. First line treatment is radiotherapy, which many patients often forego to avoid treatment-associated morbidities. The high prevalence of IDH1 mutations in glioma highlights the need for brain-penetrant IDH1 mutant-selective inhibitors as an alternative therapeutic option. Here, we have explored the utility of such an inhibitor in IDH1 mutant patient-derived models to assess the potential therapeutic benefits associated with intracranial 2-HG inhibition. Treatment of mutant IDH1 cell line models led to a decrease in intracellular 2-HG levels both in vitro and in vivo. Interestingly, inhibition of 2-HG production had no effect on in vitro IDH1 mutant glioma cell proliferation. In contrast, IDH1 mutant-selective inhibitors provided considerable survival benefit in vivo. However, even with near complete inhibition of intratumoral 2-HG production, not all mutant glioma models responded to treatment. The results suggest that disruption of 2-HG production with brain-penetrant inhibitors in IDH1 mutant gliomas may have substantial patient benefit.

Portable x-ray fluorescence for the analysis of chromium in nail and nail clippings.

Assessment of chromium content in human nail or nail clippings could serve as an effective biomarker of chromium status. The feasibility of a new portable x-ray fluorescence (XRF) approach to chromium measurement was investigated through analysis of nail and nail clipping phantoms. Five measurements of 180s (real time) duration were first performed on six whole nail phantoms having chromium concentrations of 0, 2, 5, 10, 15, and 20µg/g. Using nail clippers, these phantoms were then converted to nail clippings, and assembled into different mass groups of 20, 40, 60, 80, and 100mg for additional measurements. The amplitude of the chromium Kα characteristic x-ray energy peak was examined as a function of phantom concentration for all measurement conditions to create a series of calibration lines. The minimum detection limit (MDL) for chromium was also calculated for each case. The chromium MDL determined from the whole nail intact phantoms was 0.88±0.03µg/g. For the clipping phantoms, the MDL ranged from 1.2 to 3.3µg/g, depending on the mass group analyzed. For the 40mg clipping group, the MDL was 1.2±0.1µg/g, and higher mass collections did not improve upon this result. This MDL is comparable to chromium concentration levels seen in various studies involving human nail clippings. Further improvements to the portable XRF technique would be required to detect chromium levels expected from the lower end of a typical population.

Assessing arsenic and selenium in a single nail clipping using portable X-ray fluorescence.

The feasibility of measuring arsenic and selenium contents in a single nail clipping was investigated using a small-focus portable X-ray fluorescence (XRF) instrument with monochromatic excitation beams. Nail clipping phantoms supplemented with arsenic and selenium to produce materials with 0, 5, 10, 15, and 20µg/g were used for calibration purposes. In total, 10 different clippings were analyzed at two different measurement positions. Energy spectra were fit with detection peaks for arsenic Kα, selenium Kα, arsenic Kß, selenium Kß, and bromine Kα characteristic X-rays. Data analysis was performed under two distinct conditions of fitting constraint. Calibration lines were established from the amplitude of each of the arsenic and selenium peaks as a function of the elemental contents in the clippings. The slopes of the four calibration lines were consistent between the two conditions of analysis. The calculated minimum detection limit (MDL) of the method, when considering the Kα peak only, ranged from 0.210±0.002µg/g selenium under one condition of analysis to 0.777±0.009µg/g selenium under another. Compared with previous portable XRF nail clipping studies, MDLs were substantially improved for both arsenic and selenium. The new measurement technique had the additional benefits of being short in duration (~3min) and requiring only a single nail clipping. The mass of the individual clipping used did not appear to play a major role in signal strength, but positioning of the clipping is important.

Downscaling land-use data to provide global 30″ estimates of five land-use classes.

Land-use change is one of the biggest threats to biodiversity globally. The effects of land use on biodiversity manifest primarily at local scales which are not captured by the coarse spatial grain of current global land-use mapping. Assessments of land-use impacts on biodiversity across large spatial extents require data at a similar spatial grain to the ecological processes they are assessing. Here, we develop a method for statistically downscaling mapped land-use data that combines generalized additive modeling and constrained optimization. This method was applied to the 0.5° Land-use Harmonization data for the year 2005 to produce global 30″ (approx. 1 km(2)) estimates of five land-use classes: primary habitat, secondary habitat, cropland, pasture, and urban. The original dataset was partitioned into 61 bio-realms (unique combinations of biome and biogeographical realm) and downscaled using relationships with fine-grained climate, land cover, landform, and anthropogenic influence layers. The downscaled land-use data were validated using the PREDICTS database and the geoWiki global cropland dataset. Application of the new method to all 61 bio-realms produced global fine-grained layers from the 2005 time step of the Land-use Harmonization dataset. Coarse-scaled proportions of land use estimated from these data compared well with those estimated in the original datasets (mean R (2): 0.68 ± 0.19). Validation with the PREDICTS database showed the new downscaled land-use layers improved discrimination of all five classes at PREDICTS sites (P < 0.0001 in all cases). Additional validation of the downscaled cropping layer with the geoWiki layer showed an R (2) improvement of 0.12 compared with the Land-use Harmonization data. The downscaling method presented here produced the first global land-use dataset at a spatial grain relevant to ecological processes that drive changes in biodiversity over space and time. Integrating these data with biodiversity measures will enable the reporting of land-use impacts on biodiversity at a finer resolution than previously possible. Furthermore, the general method presented here could be useful to others wishing to downscale similarly constrained coarse-resolution data for other environmental variables.

Discovery of biomarkers predictive of GSI response in triple-negative breast cancer and adenoid cystic carcinoma.

UNLABELLED: Next-generation sequencing was used to identify Notch mutations in a large collection of diverse solid tumors. NOTCH1 and NOTCH2 rearrangements leading to constitutive receptor activation were confined to triple-negative breast cancers (TNBC; 6 of 66 tumors). TNBC cell lines with NOTCH1 rearrangements associated with high levels of activated NOTCH1 (N1-ICD) were sensitive to the gamma-secretase inhibitor (GSI) MRK-003, both alone and in combination with paclitaxel, in vitro and in vivo, whereas cell lines with NOTCH2 rearrangements were resistant to GSI. Immunohistochemical staining of N1-ICD in TNBC xenografts correlated with responsiveness, and expression levels of the direct Notch target gene HES4 correlated with outcome in patients with TNBC. Activating NOTCH1 point mutations were also identified in other solid tumors, including adenoid cystic carcinoma (ACC). Notably, ACC primary tumor xenografts with activating NOTCH1 mutations and high N1-ICD levels were sensitive to GSI, whereas N1-ICD-low tumors without NOTCH1 mutations were resistant. SIGNIFICANCE: NOTCH1 mutations, immunohistochemical staining for activated NOTCH1, and HES4 expression are biomarkers that can be used to identify solid tumors that are likely to respond to GSI-based therapies.

Continent-wide risk assessment for the establishment of nonindigenous species in Antarctica.

Invasive alien species are among the primary causes of biodiversity change globally, with the risks thereof broadly understood for most regions of the world. They are similarly thought to be among the most significant conservation threats to Antarctica, especially as climate change proceeds in the region. However, no comprehensive, continent-wide evaluation of the risks to Antarctica posed by such species has been undertaken. Here we do so by sampling, identifying, and mapping the vascular plant propagules carried by all categories of visitors to Antarctica during the International Polar Year's first season (2007-2008) and assessing propagule establishment likelihood based on their identity and origins and on spatial variation in Antarctica's climate. For an evaluation of the situation in 2100, we use modeled climates based on the Intergovernmental Panel on Climate Change's Special Report on Emissions Scenarios Scenario A1B [Nakicenovic N, Swart R, eds (2000) Special Report on Emissions Scenarios: A Special Report of Working Group III of the Intergovernmental Panel on Climate Change (Cambridge University Press, Cambridge, UK)]. Visitors carrying seeds average 9.5 seeds per person, although as vectors, scientists carry greater propagule loads than tourists. Annual tourist numbers (∼33,054) are higher than those of scientists (∼7,085), thus tempering these differences in propagule load. Alien species establishment is currently most likely for the Western Antarctic Peninsula. Recent founder populations of several alien species in this area corroborate these findings. With climate change, risks will grow in the Antarctic Peninsula, Ross Sea, and East Antarctic coastal regions. Our evidence-based assessment demonstrates which parts of Antarctica are at growing risk from alien species that may become invasive and provides the means to mitigate this threat now and into the future as the continent's climate changes.

Evidence of mTOR Activation by an AKT-Independent Mechanism Provides Support for the Combined Treatment of PTEN-Deficient Prostate Tumors with mTOR and AKT Inhibitors.

Activation of the phosphoinositide 3-kinase pathway is commonly observed in human prostate cancer. Loss of function of phosphatase and tensin homolog (PTEN) is associated with the activation of AKT and mammalian target of rapamycin (mTOR) in many cancer cell lines as well as in other model systems. However, activation of mTOR is also dependent of kinases other than AKT. Here, we show that activation of mTOR is not dependent on AKT in a prostate-specific PTEN-deficient mouse model of prostate cancer. Pathway bifurcation of AKT and mTOR was noted in both mouse and human prostate tumors. We demonstrated for the first time that cotargeting mTOR and AKT with ridaforolimus/MK-8669 and M1K-2206, respectively, delivers additive antitumor effects in vivo when compared to single agents. Our preclinical data suggest that the combination of AKT and mTOR inhibitors might be more effective in treating prostate cancer patients than current treatment regimens or either treatment alone.

De novo discovery of a gamma-secretase inhibitor response signature using a novel in vivo breast tumor model.

Notch pathway signaling plays a fundamental role in normal biological processes and is frequently deregulated in many cancers. Although several hypotheses regarding cancer subpopulations most likely to respond to therapies targeting the Notch pathway have been proposed, clinical utility of these predictive markers has not been shown. To understand the molecular basis of gamma-secretase inhibitor (GSI) sensitivity in breast cancer, we undertook an unbiased, de novo responder identification study using a novel genetically engineered in vivo breast cancer model. We show that tumors arising from this model are heterogeneous on the levels of gene expression, histopathology, growth rate, expression of Notch pathway markers, and response to GSI treatment. In addition, GSI treatment of this model was associated with inhibition of Hes1 and proliferation markers, indicating that GSI treatment inhibits Notch signaling. We then identified a pretreatment gene expression signature comprising 768 genes that is significantly associated with in vivo GSI efficacy across 99 tumor lines. Pathway analysis showed that the GSI responder signature is enriched for Notch pathway components and inflammation/immune-related genes. These data show the power of this novel in vivo model system for the discovery of biomarkers predictive of response to targeted therapies, and provide a basis for the identification of human breast cancers most likely to be sensitive to GSI treatment.

Inhibition of tumor growth progression by antiandrogens and mTOR inhibitor in a Pten-deficient mouse model of prostate cancer.

Androgen receptors have been shown to play a critical role in prostate cancer. We used ultrasound imaging techniques to track tumor response to antiandrogen and rapamycin treatment in a prostate-specific Pten-deleted mouse model of cancer. Depletion of androgens by either surgical or chemical castration significantly inhibited tumor growth progression without altering the activation of Akt and mammalian target of rapamycin (mTOR). We also showed for the first time that targeting mTOR along with antiandrogen treatment exhibited additive antitumor effects in vivo when compared with single agents. Our preclinical data suggest that combination of antiandrogens with mTOR inhibitors might be more effective in treating androgen-dependent prostate cancer patients.