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Deciding where to implement actions for biodiversity conservation remains challenging for many reasons, including the increase in maps aimed at prioritizing locations for conservation efforts. Although a growing numbers of maps can create the perception of uncertainty and competing science, a shared set of principles underlie many mapping initiatives. We overlaid the priority areas identified by a subset of maps to assess the extent to which they agree. The comparison suggests that when maps are used without understanding their origin, confusion seems justified: The union of all maps covers 73% of the contiguous United States, whereas the intersection of all maps is at least 3.5%. Our findings support the need to place a strong focus on the principles and premises underpinning the maps and the end users' intentions. We recommend developing a science-based guidance to aid scientists, policymakers, and managers in selecting and applying maps for supporting on-the-ground decisions addressing biodiversity loss and its interconnected crises. [ABSTRACT FROM AUTHOR]

Background: Prolactin receptor (PRLR) is an attractive antibody therapeutic target with expression across a broad population of breast cancers. Antibody efficacy, however, may be limited to subtypes with either PRLR overexpression and/or those where estradiol no longer functions as a mitogen and are, therefore, reliant on PRLR signaling for growth. In contrast a potent PRLR antibody-drug conjugate (ADC) may provide improved therapeutic outcomes extending beyond either PRLR overexpressing or estradiol-insensitive breast cancer populations.Methods: We derived a novel ADC targeting PRLR, ABBV-176, that delivers a pyrrolobenzodiazepine (PBD) dimer cytotoxin, an emerging class of warheads with enhanced potency and broader anticancer activity than the clinically validated auristatin or maytansine derivatives. This agent was tested in vitro and in vivo cell lines and patient derived xenograft models.Results: In both in vitro and in vivo assays, ABBV-176 exhibits potent cytotoxicity against multiple cell line and patient-derived xenograft breast tumor models, including triple negative and low PRLR expressing models insensitive to monomethyl auristatin (MMAE) based PRLR ADCs. ABBV-176, which cross links DNA and causes DNA breaks by virtue of its PBD warhead, also demonstrates enhanced anti-tumor activity in several breast cancer models when combined with a poly-ADP ribose polymerase (PARP) inhibitor, a potentiator of DNA damage.Conclusions: Collectively the efficacy and safety profile of ABBV-176 suggest it may be an effective therapy across a broad range of breast cancers and other cancer types where PRLR is expressed with the potential to combine with other therapeutics including PARP inhibitors. [ABSTRACT FROM AUTHOR]

Conservationists need methods to conserve biological diversity while allowing species and communities to rearrange in response to a changing climate. We developed and tested such a method for northeastern North America that we based on physical features associated with ecological diversity and site resilience to climate change. We comprehensively mapped 30 distinct geophysical settings based on geology and elevation. Within each geophysical setting, we identified sites that were both connected by natural cover and that had relatively more microclimates indicated by diverse topography and elevation gradients. We did this by scoring every 405 ha hexagon in the region for these two characteristics and selecting those that scored >SD 0.5 above the mean combined score for each setting. We hypothesized that these high-scoring sites had the greatest resilience to climate change, and we compared them with sites selected by The Nature Conservancy for their high-quality rare species populations and natural community occurrences. High-scoring sites captured significantly more of the biodiversity sites than expected by chance (p < 0.0001): 75% of the 414 target species, 49% of the 4592 target species locations, and 53% of the 2170 target community locations. Calcareous bedrock, coarse sand, and fine silt settings scored markedly lower for estimated resilience and had low levels of permanent land protection (average 7%). Because our method identifies-for every geophysical setting-sites that are the most likely to retain species and functions longer under a changing climate, it reveals natural strongholds for future conservation that would also capture substantial existing biodiversity and correct the bias in current secured lands. [ABSTRACT FROM AUTHOR]

Conservationists have proposed methods for adapting to climate change that assume species distributions are primarily explained by climate variables. The key idea is to use the understanding of species-climate relationships to map corridors and to identify regions of faunal stability or high species turnover. An alternative approach is to adopt an evolutionary timescale and ask ultimately what factors control total diversity, so that over the long run the major drivers of total species richness can be protected. Within a single climatic region, the temperate area encompassing all of the Northeastern U.S. and Maritime Canada, we hypothesized that geologic factors may take precedence over climate in explaining diversity patterns. If geophysical diversity does drive regional diversity, then conserving geophysical settings may offer an approach to conservation that protects diversity under both current and future climates. Here we tested how well geology predicts the species diversity of 14 US states and three Canadian provinces, using a comprehensive new spatial dataset. Results of linear regressions of species diversity on all possible combinations of 23 geophysical and climatic variables indicated that four geophysical factors; the number of geological classes, latitude, elevation range and the amount of calcareous bedrock, predicted species diversity with certainty (adj. R² = 0.94). To confirm the species-geology relationships we ran an independent test using 18,700 location points for 885 rare species and found that 40% of the species were restricted to a single geology. Moreover, each geology class supported 5-95 endemic species and chi-square tests confirmed that calcareous bedrock and extreme elevations had significantly more rare species than expected by chance (P<0.0001), strongly corroborating the regression model. Our results suggest that protecting geophysical settings will conserve the stage for current and future biodiversity and may be a robust alternative to species-level predictions. [ABSTRACT FROM AUTHOR]

1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and its analogues have been shown to inhibit proliferation of human cancer cells mediated by vitamin D receptor (VDR). The over-expression of 25-hydroxyvitamin D-24-hydroxylase (CYP24A1), an enzyme involved in the metabolism of 1,25(OH)2D3 and its analogues, is associated with poor prognosis of some human cancers. In this study, we employed real-time reverse transcription PCR to examine the expression of VDR and CYP24A1 mRNA in a cohort of human breast, lung, colon and ovary tumor samples. We found that CYP24A1 mRNA was significantly up-regulated in colon, ovary and lung tumors, but down-regulated in breast tumor relative to the analogous normal tissues. As a comparison, VDR mRNA was modestly down-regulated in colon, breast and lung tumors, but highly up-regulated in ovarian tumors. Treatment of two breast cancer cell lines, SW-620 and MCF-7, and one colon cancer cell line, HT-29, by 1,25(OH)2D3 for 48 h profoundly stimulated CYP24A1 mRNA expression (EC50=0.6, 0.8 and 29.5 nM in SW-620, HT-29 and MCF-7, respectively), but did not significantly affect VDR mRNA expression. Growth as assessed by DNA synthesis was modestly arrested by 1,25(OH)2D3 after 72 h of incubation, but was not altered after a 5-day incubation period. These data suggest that the VDR signaling pathway may be compromised via the modulation of CYP24A1 and VDR in human tumors. [ABSTRACT FROM AUTHOR]

Connectivity models are useful tools that improve the ability of researchers and managers to plan land use for conservation and preservation. Most connectivity models function in a point-to-point or patch-to-patch fashion, limiting their use for assessing connectivity over very large areas. In large or highly fragmented systems, there may be so many habitat patches of interest that assessing connectivity among all possible combinations is prohibitive. To overcome these conceptual and practical limitations, we hypothesized that minor adaptation of the Circuitscape model can allow the creation of omnidirectional connectivity maps illustrating flow paths and variations in the ease of travel across a large study area. We tested this hypothesis in a 24,300 km2 study area centered on the Montérégie region near Montréal, Québec. We executed the circuit model in overlapping tiles covering the study region. Current was passed across the surface of each tile in orthogonal directions, and then the tiles were reassembled to create directional and omnidirectional maps of connectivity. The resulting mosaics provide a continuous view of connectivity in the entire study area at the full original resolution. We quantified differences between mosaics created using different tile and buffer sizes and developed a measure of the prominence of seams in mosaics formed with this approach. The mosaics clearly show variations in current flow driven by subtle aspects of landscape composition and configuration. Shown prominently in mosaics are pinch points, narrow corridors where organisms appear to be required to traverse when moving through the landscape. Using modest computational resources, these continuous, fine-scale maps of nearly unlimited size allow the identification of movement paths and barriers that affect connectivity. This effort develops a powerful new application of circuit models by pinpointing areas of importance for conservation, broadening the potential for addressing intriguing questions about resource use, animal distribution, and movement. [ABSTRACT FROM AUTHOR]

Discusses studies in biodiversity conservation focusing on animal species, populations, ecosystems, landscapes, and other levels of biological organization. Biodiversity on small and large geographic scales; Description of functional conservation areas and how to determine this environmental function; Challenges faced by conservationists; Case study of the Yampa River in Colorado; Conclusions and comments.

Ecological resilience is a powerful heuristic for ecosystem management in the context of rapid environmental change. Significant efforts are underway to improve the resilience of biodiversity and ecological function to extreme events and directional change across all types of landscapes, from intact natural systems to highly modified landscapes such as cities and agricultural regions. However, identifying management strategies likely to promote ecological resilience remains a challenge. In this article, we present seven core dimensions to guide long-term and large-scale resilience planning in highly modified landscapes, with the objective of providing a structure and shared vocabulary for recognizing opportunities and actions likely to increase resilience across the whole landscape. We illustrate application of our approach to landscape-scale ecosystem management through case studies from two highly modified California landscapes, Silicon Valley and the Sacramento–San Joaquin Delta. We propose that resilience-based management is best implemented at large spatial scales and through collaborative, cross-sector partnerships. [ABSTRACT FROM AUTHOR]

Describing the physical habitat diversity of stream types is important for understanding stream ecosystem complexity, but also prioritizing management of stream ecosystems, especially those that are rare. We developed a stream classification system of six physical habitat layers (size, gradient, hydrology, temperature, valley confinement, and substrate) for approximately 1 million stream reaches within the Eastern United States in order to conduct an inventory of different types of streams and examine stream diversity. Additionally, we compare stream diversity to patterns of anthropogenic disturbances to evaluate associations between stream types and human disturbances, but also to prioritize rare stream types that may lack natural representation in the landscape. Based on combinations of different layers, we estimate there are anywhere from 1,521 to 5,577 different physical types of stream reaches within the Eastern US. By accounting for uncertainty in class membership, these estimates could range from 1,434 to 6,856 stream types. However, 95% of total stream distance is represented by only 30% of the total stream habitat types, which suggests that most stream types are rare. Unfortunately, as much as one third of stream physical diversity within the region has been compromised by anthropogenic disturbances. To provide an example of the stream classification’s utility in management of these ecosystems, we isolated 5% of stream length in the entire region that represented 87% of the total physical diversity of streams to prioritize streams for conservation protection, restoration, and biological monitoring. We suggest that our stream classification framework could be important for exploring the diversity of stream ecosystems and is flexible in that it can be combined with other stream classification frameworks developed at higher resolutions (meso- and micro-habitat scales). Additionally, the exploration of physical diversity helps to estimate the rarity and patchiness of riverscapes over large region and assist in conservation and management. [ABSTRACT FROM AUTHOR]

The authors share their perspective on the future of landscape conservation. They argue on the importance of landscape conservation cooperatives (LCC) as a step in the application of systematic conservation planning and in the promotion of connectivity and persistence in wildlife conservation. They express support to the capability of LCCs to achieve outcomes including climate change mitigation, land use change, biodiversity and ecosystem-service goals.

ABT-700 is a therapeutic antibody against the hepatocyte growth factor receptor (MET). At doses or regimens that lead to exposures exceeding optimum in vivo, the efficacy of ABT-700 is unexpectedly reduced. We hypothesized that this reduction in efficacy was due to a "prozone-like" effect in vivo. A prozone-like effect, which is a reduction in efficacy beyond optimum exposure, is caused due a mechanism similar to the generation of false negative flocculation tests by excessive antibody titres. In vitro, we demonstrate that at higher ABT-700 concentrations, this "prozone-like" effect is mediated by a progressive conversion from bivalent to ineffective monovalent binding of the antibody. In vivo, the efficacy of ABT-700 is dependent on an optimum range of exposure as well. Our data suggest that the "prozone-like" effect is operative and independent of target expression. ABT-700 dose, regimen, exposure, and tumor burden are interdependent variables influencing the "prozone-like" effect and mediating and in vivo efficacy. By optimization of dosage and regimen we demonstrate that the "prozone-like" effect can be alleviated and ABT-700 efficacy at varying tumor loads can be further extended in combination with cisplatin. Our results suggest that optimization of exposure taking tumor burden into account may alleviate "prozone-like" effects without compromising efficacy. [ABSTRACT FROM AUTHOR]

Most conservation planning to date has focused on protecting today's biodiversity with the assumption that it will be tomorrow's biodiversity. However, modern climate change has already resulted in distributional shifts of some species and is projected to result in many more shifts in the coming decades. As species redistribute and biotic communities reorganize, conservation plans based on current patterns of biodiversity may fail to adequately protect species in the future. One approach for addressing this issue is to focus on conserving a range of abiotic conditions in the conservation-planning process. By doing so, it may be possible to conserve an abiotically diverse 'stage' upon which evolution will play out and support many actors (biodiversity). We reviewed the fundamental underpinnings of the concept of conserving the abiotic stage, starting with the early observations of von Humboldt, who mapped the concordance of abiotic conditions and vegetation, and progressing to the concept of the ecological niche. We discuss challenges posed by issues of spatial and temporal scale, the role of biotic drivers of species distributions, and latitudinal and topographic variation in relationships between climate and landform. For example, abiotic conditions are not static, but change through time-albeit at different and often relatively slow rates. In some places, biotic interactions play a substantial role in structuring patterns of biodiversity, meaning that patterns of biodiversity may be less tightly linked to the abiotic stage. Furthermore, abiotic drivers of biodiversity can change with latitude and topographic position, meaning that the abiotic stage may need to be defined differently in different places. We conclude that protecting a diversity of abiotic conditions will likely best conserve biodiversity into the future in places where abiotic drivers of species distributions are strong relative to biotic drivers, where the diversity of abiotic settings will be conserved through time, and where connectivity allows for movement among areas providing different abiotic conditions. [ABSTRACT FROM AUTHOR]

Aurora kinase B inhibitors induce apoptosis secondary to polyploidization and have entered clinical trials as an emerging class of neocytotoxic chemotherapeutics. We demonstrate here that polyploidization neutralizes Mcl-1 function, rendering cancer cells exquisitely dependent on Bcl-XL/-2. This "addiction" can be exploited therapeutically by combining aurora kinase inhibitors and the orally bioavailable BH3 mimetic, ABT-263, which inhibits Bcl-XL, Bcl-2, and Bcl-w. The combination of ABT-263 with aurora B inhibitors produces a synergistic loss of viability in a range of cell lines of divergent tumor origin and exhibits more sustained tumor growth inhibition in vivo compared with aurora B inhibitor monotherapy. These data demonstrate that Bcl-XL/-2 is necessary to support viability during polyploidization in a variety of tumor models and represents a druggable molecular vulnerability with potential therapeutic utility. [ABSTRACT FROM AUTHOR]

Abstract: Formalin-fixed paraffin-embedded (FFPE) tissue samples are a potentially valuable resource of expression information for medical research, but are under-utilized due to degradation and modification of the RNA. Using a random primer-based RNA amplification strategy, we have evaluated multiple protocols for the extraction and isolation of RNA from FFPE samples. We found that the RecoverAll RNA isolation procedure with three or four slices (ten-microns in thickness), supplemented with additional DNAse, gave optimal results. RNA integrity as assessed by Agilent Bioanalyzer, and amplification of the 28S ribosomal RNA, were predictive for the number of genes detected on Affymetrix arrays. We obtained expression data for colon and lung tumor and normal FFPE samples and matched frozen samples and found a high correlation between frozen and matched FFPE samples (R 2 between 0.82 and 0.89), while the signature sets in tumor versus normal comparisons were also quite similar. QPCR confirmed all 16 of the differential expression results from the microarrays that we tested. Differentially expressed signature genes from tumor versus matched normal FFPE tissue from colon and lung were identified as cancer-related, with 95 colon tumor and 67 lung tumor genes identified, respectively. [Copyright &y& Elsevier]

Reports the lessons learned from implementing the planning framework of The Nature Conservancy (TNC) as a model for the agencies and institutions around the world facing challenges in conservation planning. Discussion of the TNC seven-step plan, which identifies a network of lands and waters for conserving the elements of biodiversity within an ecoregion; Citation of relevant scientific literature that supports the importance of each step; Benefits of the conservation plan.

We have previously identified poly(ADP-ribose) polymerase-1 (PARP-1) as a coactivator for the human T cell leukemia virus type I (HTLV-I) transcription activator Tax. While PARP-1 is believed to contribute to DNA repair, PARP-1 has been described as a coactivator for other transcription factors. Recent evidence suggests that PARP-1 forms complexes on cellular promoters, so we investigated PARP-1 complexes on the HTLV-I Tax responsive elements (TxREs) using an end-blocked DNA binding assay. We observed sequence-specific binding of PARP-1 to the TxREs. The DNA binding domain of PARP-1 was fused to the transcriptional activation domain of VP16, and this fusion protein activated the HTLV-I promoter in a TxRE-dependent manner. Internal, sequence-specific binding of PARP-1 to DNA provides a mechanism for transcriptional regulation of the HTLV-I promoter. The mechanism of PARP-1 function in the HTLV-I system may have common mechanistic steps with other cellular promoters, including the formation of active complexes on the promoter. [Copyright &y& Elsevier]