Significant challenges to the sustainability of the California coast considering climate change.

Climate change is an existential threat to the environmental and socioeconomic sustainability of the coastal zone and impacts will be complex and widespread. Evidence from California and across the United States shows that climate change is impacting coastal communities and challenging managers with a plethora of stressors already present. Widespread action could be taken that would sustain California's coastal ecosystems and communities. In this perspective, we highlight the main threat to coastal sustainability: the compound effects of episodic events amplified with ongoing climate change, which will present unprecedented challenges to the state. We present two key challenges for California's sustainability in the coastal zone: 1) accelerating sea-level rise combined with storm impacts, and 2) continued warming of the oceans and marine heatwaves. Cascading effects from these types of compounding events will occur within the context of an already stressed system that has experienced extensive alterations due to intensive development, resource extraction and harvesting, spatial containment, and other human use pressures. There are critical components that could be used to address these immediate concerns, including comanagement strategies that include diverse groups and organizations, strategic planning integrated across large areas, rapid implementation of solutions, and a cohesive and policy relevant research agenda for the California coast. Much of this has been started in the state, but the scale could be increased, and timelines accelerated. The ideas and information presented here are intended to help expand discussions to sharpen the focus on how to encourage sustainability of California's iconic coastal region.

Increasing Salt Marsh Elevation Using Sediment Augmentation: Critical Insights from Surface Sediments and Sediment Cores.

Sea-level rise is particularly concerning for tidal wetlands that reside within an area with steep topography or are constrained by human development and alteration of sedimentation. Sediment augmentation to increase wetland elevations has been considered as a potential strategy for such areas to prevent wetland loss over the coming decades. However, there is little information on the best approaches and whether adaptive management actions can mimic natural processes to build sea-level rise resilience. In addition, the lack of information on long-term marsh characteristics, processes, and variability can hamper development of effective augmentation strategies. Here, we assess a case study in a southern California marsh to determine the nature of the pre-existing sediments and variability of the site in relation to sediments applied during an augmentation experiment. Although sediment cores revealed natural variations in the grain size and organic content of sediments deposited at the site over the past 1500 years, the applied sediments were markedly coarser in grain size than prehistoric sediments at the site (100% maximum sand versus 76% maximum sand). The rate of the experimental sediment application (25.1 ± 1.09 cm in ~2 months) was also much more rapid than natural accretion rates measured for the site historically. In contrast, post-augmentation sediment accretion rates on the augmentation site have been markedly slower than pre-augmentation rates or current rates on a nearby control site. The mismatch between the characteristics of the applied sediment and thickness of application and the historic conditions are likely strong contributors to the slow initial recovery of vegetation. Sediment augmentation has been shown to be a useful strategy in some marshes, but this case study illustrates that vegetation recovery may be slow if applied sediments are not similar or at a thickness similar to historic conditions. However, testing adaptation strategies to build wetland elevations is important given the long-term risk of habitat loss with sea-level rise. Lessons learned in the case study could be applied elsewhere.

Large stocks of peatland carbon and nitrogen are vulnerable to permafrost thaw.

Northern peatlands have accumulated large stocks of organic carbon (C) and nitrogen (N), but their spatial distribution and vulnerability to climate warming remain uncertain. Here, we used machine-learning techniques with extensive peat core data (n > 7,000) to create observation-based maps of northern peatland C and N stocks, and to assess their response to warming and permafrost thaw. We estimate that northern peatlands cover 3.7 ± 0.5 million km2 and store 415 ± 150 Pg C and 10 ± 7 Pg N. Nearly half of the peatland area and peat C stocks are permafrost affected. Using modeled global warming stabilization scenarios (from 1.5 to 6 °C warming), we project that the current sink of atmospheric C (0.10 ± 0.02 Pg C⋅y-1) in northern peatlands will shift to a C source as 0.8 to 1.9 million km2 of permafrost-affected peatlands thaw. The projected thaw would cause peatland greenhouse gas emissions equal to ∼1% of anthropogenic radiative forcing in this century. The main forcing is from methane emissions (0.7 to 3 Pg cumulative CH4-C) with smaller carbon dioxide forcing (1 to 2 Pg CO2-C) and minor nitrous oxide losses. We project that initial CO2-C losses reverse after ∼200 y, as warming strengthens peatland C-sinks. We project substantial, but highly uncertain, additional losses of peat into fluvial systems of 10 to 30 Pg C and 0.4 to 0.9 Pg N. The combined gaseous and fluvial peatland C loss estimated here adds 30 to 50% onto previous estimates of permafrost-thaw C losses, with southern permafrost regions being the most vulnerable.

DeBouganin Diabody Fusion Protein Overcomes Drug Resistance to ADCs Comprised of Anti-Microtubule Agents.

Antibody drug conjugates (ADC), comprised of highly potent small molecule payloads chemically conjugated to a full-length antibody, represent a growing class of therapeutic agents. The targeting of cytotoxic payloads via the specificity and selectivity of the antibody has led to substantial clinical benefits. However, ADC potency can be altered by mechanisms of resistance such as overexpression of efflux pumps or anti-apoptotic proteins. DeBouganin is a de-immunized variant of bouganin, a ribosome-inactivating protein (RIP) that blocks protein synthesis, thereby leading to apoptosis. When conjugated to trastuzumab (T-deB), deBouganin was more potent than ado-trastuzumab-emtansine (T-DM1) and unaffected by resistance mechanisms to which DM1 is susceptible. To further highlight the differentiating mechanism of action of deBouganin, HCC1419 and BT-474 tumor cells that survived T-DM1 or trastuzumab-MMAE (T-MMAE) treatment were treated with an anti-HER2 C6.5 diabody-deBouganin fusion protein or T-deB. C6.5 diabody-deBouganin and T-deB were potent against HCC1419 and BT-474 cells that were resistant to T-DM1 or T-MMAE killing. The resistant phenotype involved MDR pumps, Bcl-2 family members, and the presence of additional unknown pathways. Overall, the data suggest that deBouganin is effective against tumor cell resistance mechanisms selected in response to ADCs composed of anti-microtubule payloads.

Science-policy processes for transboundary water governance.

In this policy perspective, we outline several conditions to support effective science-policy interaction, with a particular emphasis on improving water governance in transboundary basins. Key conditions include (1) recognizing that science is a crucial but bounded input into water resource decision-making processes; (2) establishing conditions for collaboration and shared commitment among actors; (3) understanding that social or group-learning processes linked to science-policy interaction are enhanced through greater collaboration; (4) accepting that the collaborative production of knowledge about hydrological issues and associated socioeconomic change and institutional responses is essential to build legitimate decision-making processes; and (5) engaging boundary organizations and informal networks of scientists, policy makers, and civil society. We elaborate on these conditions with a diverse set of international examples drawn from a synthesis of our collective experiences in assessing the opportunities and constraints (including the role of power relations) related to governance for water in transboundary settings.

Climate Change and water in Southwestern North America special feature: water, climate change, and sustainability in the southwest.

The current Southwest drought is exceptional for its high temperatures and arguably the most severe in history. Coincidentally, there has been an increase in forest and woodland mortality due to fires and pathogenic outbreaks. Although the high temperatures and aridity are consistent with projected impacts of greenhouse warming, it is unclear whether the drought can be attributed to increased greenhouse gases or is a product of natural climatic variability. Climate models indicate that the 21st century will be increasingly arid and droughts more severe and prolonged. Forest and woodland mortality due to fires and pathogens will increase. Demography and food security dictate that water demand in the Southwest will remain appreciable. If projected population growth is twinned with suburb-centered development, domestic demands will intensify. Meeting domestic demands through transference from agriculture presents concerns for rural sustainability and food security. Environmental concerns will limit additional transference from rivers. It is unlikely that traditional supply-side solutions such as more dams will securely meet demands at current per-capita levels. Significant savings in domestic usage can be realized through decreased applications of potable water to landscaping, but this is a small fraction of total regional water use, which is dominated by agriculture. Technical innovations, policy measures, and market-based solutions that increase supply and decrease water demand are all needed. Meeting 21st-century sustainability challenges in the Southwest will also require planning, cooperation, and integration that surpass 20th-century efforts in terms of geographic scope, jurisdictional breadth, multisectoral engagement, and the length of planning timelines.

A 1,200-year perspective of 21st century drought in southwestern North America.

A key feature of anticipated 21st century droughts in Southwest North America is the concurrence of elevated temperatures and increased aridity. Instrumental records and paleoclimatic evidence for past prolonged drought in the Southwest that coincide with elevated temperatures can be assessed to provide insights on temperature-drought relations and to develop worst-case scenarios for the future. In particular, during the medieval period, ∼AD 900-1300, the Northern Hemisphere experienced temperatures warmer than all but the most recent decades. Paleoclimatic and model data indicate increased temperatures in western North America of approximately 1 °C over the long-term mean. This was a period of extensive and persistent aridity over western North America. Paleoclimatic evidence suggests drought in the mid-12th century far exceeded the severity, duration, and extent of subsequent droughts. The driest decade of this drought was anomalously warm, though not as warm as the late 20th and early 21st centuries. The convergence of prolonged warming and arid conditions suggests the mid-12th century may serve as a conservative analogue for severe droughts that might occur in the future. The severity, extent, and persistence of the 12th century drought that occurred under natural climate variability, have important implications for water resource management. The causes of past and future drought will not be identical but warm droughts, inferred from paleoclimatic records, demonstrate the plausibility of extensive, severe droughts, provide a long-term perspective on the ongoing drought conditions in the Southwest, and suggest the need for regional sustainability planning for the future.

Pre-Younger Dryas megafaunal extirpation at Rancho La Brea linked to fire-driven state shift.

The cause, or causes, of the Pleistocene megafaunal extinctions have been difficult to establish, in part because poor spatiotemporal resolution in the fossil record hinders alignment of species disappearances with archeological and environmental data. We obtained 172 new radiocarbon dates on megafauna from Rancho La Brea in California spanning 15.6 to 10.0 thousand calendar years before present (ka). Seven species of extinct megafauna disappeared by 12.9 ka, before the onset of the Younger Dryas. Comparison with high-resolution regional datasets revealed that these disappearances coincided with an ecological state shift that followed aridification and vegetation changes during the Bølling-Allerød (14.69 to 12.89 ka). Time-series modeling implicates large-scale fires as the primary cause of the extirpations, and the catalyst of this state shift may have been mounting human impacts in a drying, warming, and increasingly fire-prone ecosystem.

A phase II study of oportuzumab monatox: an immunotoxin therapy for patients with noninvasive urothelial carcinoma in situ previously treated with bacillus Calmette-Guérin.

PURPOSE: A phase II study was performed to assess the efficacy and tolerability of intravesical oportuzumab monatox in patients with urothelial carcinoma in situ of the bladder. Bacillus Calmette-Guérin treatment had previously failed in all patients. MATERIALS AND METHODS: A total of 46 patients received 1 induction cycle of 6 (cohort 1) or 12 (cohort 2) weekly intravesical oportuzumab monatox (VB4-845) instillations of 30 mg, followed by up to 3 maintenance cycles of 3 weekly administrations every 3 months. RESULTS: A complete response to oportuzumab monatox was seen in 9 of 22 patients (41%) in cohort 1 and 9 of 23 (39%) in cohort 2 at the 3-month evaluation. A total of 20 patients (44%) achieved a complete response. Two other patients without carcinoma in situ who achieved a complete response were not included in the study due to the development of noninvasive papillary (Ta) disease. Median time to recurrence in patients who achieved a complete response was 274 and 408 days in cohorts 1 and 2, respectively. Overall 7 patients (16%) remained disease-free. Post-study assessment demonstrated that these patients were still disease-free at last followup (18 to 25 months). The most common adverse events were mild to moderate reversible bladder symptoms. CONCLUSIONS: Oportuzumab monatox was effective and well tolerated in patients with bacillus Calmette-Guérin refractory carcinoma in situ of the bladder. These results demonstrate the clinical benefit of oportuzumab monatox and support its continued development for the second line treatment of nonmuscle invasive bladder cancer.

Development of a GMP Phase III purification process for VB4-845, an immunotoxin expressed in E. coli using high cell density fermentation.

VB4-845 is a recombinant immunotoxin comprised of an anti-epithelial cell adhesion molecule (EpCAM) scFv fused to a truncated form of the bacterial toxin, Pseudomonas exotoxin A. VB4-845, purified from TB fed-batch fermentation, showed clinical efficacy when administered locally to treat non-muscle invasive bladder cancer (NMIBC) and squamous cell carcinomas of the head and neck (SCCHN). Here, we describe the implementation of an Escherichia coli high cell density (HCD) cultivation and purification process for VB4-845. HCD cultivation was a prerequisite for achieving higher yields necessary for Phase III clinical trials and commercialization. Using this process, the VB4-845 titer in the supernatant was increased by 30-fold over the original TB fed-batch cultivation. To obtain clinical grade material, a process involving a five-step column purification procedure was implemented and led to an overall recovery of ∼ 40%. VB4-845 purity of >97% was achieved after the first three columns following the removal of low-molecular weight product-related impurities and aggregates. Endotoxins were effectively separated from VB4-845 on the Q-columns and by washing the Ni-column with a detergent buffer while host cell proteins were removed using ceramic hydroxyapatite. Comparability studies demonstrated that the purified product from the Phase III process was identical to the Phase II reference standard produced using TB fed-batch fermentation.

Fluorescence-guided tumor detection with a novel anti-EpCAM targeted antibody fragment: Preclinical validation.

Tumor-specific fluorescent imaging agents are moving towards the clinic, supporting surgeons with real-time intraoperative feedback about tumor locations. The epithelial cell adhesion molecule (EpCAM) is considered as one of the most promising tumor-specific proteins due its high overexpression on epithelial-derived cancers. This study describes the development and evaluation of EpCAM-F800, a novel fluorescent anti-EpCAM antibody fragment, for intraoperative tumor imaging. Fab production, conjugation to the fluorophore IRDye 800CW, and binding capacities were determined and validated using HPLC, spectrophotometry and cell-based assays. In vivo, dose escalation-, blocking-, pharmacokinetic- and biodistribution studies (using both fluorescence and radioactivity) were performed, next to imaging of clinically relevant orthotopic xenografts for breast and colorectal cancer. EpCAM-F800 targets EpCAM with high specificity in vitro, which was validated using in vivo blocking experiments with a 10x higher dose of unlabeled Fab. The optimal dose range for fluorescence tumor detection in mice was 1-5 nmol (52-260 µg), which corresponds to a human equivalent dose of 0.2-0.8 mg/kg. Biodistribution showed high accumulation of EpCAM-F800 in tumors and metabolizing organs. Breast and colorectal tumors could clearly be visualized within 8 h post-injection and up to 96 h, while the agent already showed homogenous tumor distribution within 4 h. The blood half-life was 4.5 h. This study describes the development and evaluation of a novel EpCAM-targeting agent and the feasibility to visualize breast and colorectal tumors by fluorescence imaging during resections. EpCAM-F800 will be translated for clinical use, considering its abundance in a broad range of tumor types.

Three-dimensional imaging of the intact mouse cochlea by fluorescent laser scanning confocal microscopy.

The complex anatomy of the mammalian cochlea is most readily understood by representation in three-dimensions. However, the cochlea is often sectioned to minimize the effects of its anatomic complexity and optical properties on image acquisition by light microscopy. We have found that optical aberrations present in the decalcified cochlea can be greatly reduced by dehydration through graded ethanols followed by clearing with a mixture of five parts methyl salicylate and three parts benzyl benzoate (MSBB). Clearing the cochlea with MSBB enables acquisition of high-resolution images with multiple fluorescent labels, through the full volume of the cochlea by laser scanning confocal microscopy. The resulting images are readily applicable to three-dimensional morphometric analysis and volumetric visualizations. This method promises to be particularly useful for three-dimensional characterization of anatomy, innervation and expression of genes or proteins in the many new animal models of hearing and balance generated by genetic manipulation. Furthermore, the MSBB is compatible with most non-protein fluorophores used for histological labeling, and may be removed with traditional transitional solvents to allow subsequent epoxy embedding for sectioning.

U.S. Pacific coastal wetland resilience and vulnerability to sea-level rise.

We used a first-of-its-kind comprehensive scenario approach to evaluate both the vertical and horizontal response of tidal wetlands to projected changes in the rate of sea-level rise (SLR) across 14 estuaries along the Pacific coast of the continental United States. Throughout the U.S. Pacific region, we found that tidal wetlands are highly vulnerable to end-of-century submergence, with resulting extensive loss of habitat. Using higher-range SLR scenarios, all high and middle marsh habitats were lost, with 83% of current tidal wetlands transitioning to unvegetated habitats by 2110. The wetland area lost was greater in California and Oregon (100%) but still severe in Washington, with 68% submerged by the end of the century. The only wetland habitat remaining at the end of the century was low marsh under higher-range SLR rates. Tidal wetland loss was also likely under more conservative SLR scenarios, including loss of 95% of high marsh and 60% of middle marsh habitats by the end of the century. Horizontal migration of most wetlands was constrained by coastal development or steep topography, with just two wetland sites having sufficient upland space for migration and the possibility for nearly 1:1 replacement, making SLR threats particularly high in this region and generally undocumented. With low vertical accretion rates and little upland migration space, Pacific coast tidal wetlands are at imminent risk of submergence with projected rates of rapid SLR.

Sea-level rise, habitat loss, and potential extirpation of a salt marsh specialist bird in urbanized landscapes.

Sea-level rise (SLR) impacts on intertidal habitat depend on coastal topology, accretion, and constraints from surrounding development. Such habitat changes might affect species like Belding's savannah sparrows (Passerculus sandwichensis beldingi; BSSP), which live in high-elevation salt marsh in the Southern California Bight. To predict how BSSP habitat might change under various SLR scenarios, we first constructed a suitability model by matching bird observations with elevation. We then mapped current BSSP breeding and foraging habitat at six estuarine sites by applying the elevation-suitability model to digital elevation models. To estimate changes in digital elevation models under different SLR scenarios, we used a site-specific, one-dimensional elevation model (wetland accretion rate model of ecosystem resilience). We then applied our elevation-suitability model to the projected digital elevation models. The resulting maps suggest that suitable breeding and foraging habitat could decline as increased inundation converts middle- and high-elevation suitable habitat to mudflat and subtidal zones. As a result, the highest SLR scenario predicted that no suitable breeding or foraging habitat would remain at any site by 2100 and 2110. Removing development constraints to facilitate landward migration of high salt marsh, or redistributing dredge spoils to replace submerged habitat, might create future high salt marsh habitat, thereby reducing extirpation risk for BSSP in southern California.

Integrating the social, hydrological and ecological dimensions of freshwater health: The Freshwater Health Index.

Degradation of freshwater ecosystems and the services they provide is a primary cause of increasing water insecurity, raising the need for integrated solutions to freshwater management. While methods for characterizing the multi-faceted challenges of managing freshwater ecosystems abound, they tend to emphasize either social or ecological dimensions and fall short of being truly integrative. This paper suggests that management for sustainability of freshwater systems needs to consider the linkages between human water uses, freshwater ecosystems and governance. We present a conceptualization of freshwater resources as part of an integrated social-ecological system and propose a set of corresponding indicators to monitor freshwater ecosystem health and to highlight priorities for management. We demonstrate an application of this new framework -the Freshwater Health Index (FHI) - in the Dongjiang River Basin in southern China, where stakeholders are addressing multiple and conflicting freshwater demands. By combining empirical and modeled datasets with surveys to gauge stakeholders' preferences and elicit expert information about governance mechanisms, the FHI helps stakeholders understand the status of freshwater ecosystems in their basin, how ecosystems are being manipulated to enhance or decrease water-related services, and how well the existing water resource management regime is equipped to govern these dynamics over time. This framework helps to operationalize a truly integrated approach to water resource management by recognizing the interplay between governance, stakeholders, freshwater ecosystems and the services they provide.

Accuracy and Precision of Tidal Wetland Soil Carbon Mapping in the Conterminous United States.

Tidal wetlands produce long-term soil organic carbon (C) stocks. Thus for carbon accounting purposes, we need accurate and precise information on the magnitude and spatial distribution of those stocks. We assembled and analyzed an unprecedented soil core dataset, and tested three strategies for mapping carbon stocks: applying the average value from the synthesis to mapped tidal wetlands, applying models fit using empirical data and applied using soil, vegetation and salinity maps, and relying on independently generated soil carbon maps. Soil carbon stocks were far lower on average and varied less spatially and with depth than stocks calculated from available soils maps. Further, variation in carbon density was not well-predicted based on climate, salinity, vegetation, or soil classes. Instead, the assembled dataset showed that carbon density across the conterminous united states (CONUS) was normally distributed, with a predictable range of observations. We identified the simplest strategy, applying mean carbon density (27.0 kg C m-3), as the best performing strategy, and conservatively estimated that the top meter of CONUS tidal wetland soil contains 0.72 petagrams C. This strategy could provide standardization in CONUS tidal carbon accounting until such a time as modeling and mapping advancements can quantitatively improve accuracy and precision.

Author Correction: Accuracy and Precision of Tidal Wetland Soil Carbon Mapping in the Conterminous United States.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Ultrastructural analysis of aminoglycoside-induced hair cell death in the zebrafish lateral line reveals an early mitochondrial response.

Loss of the mechanosensory hair cells in the auditory and vestibular organs leads to hearing and balance deficits. To investigate initial, in vivo events in aminoglycoside-induced hair cell damage, we examined hair cells from the lateral line of the zebrafish, Danio rerio. The mechanosensory lateral line is located externally on the animal and therefore allows direct manipulation and observation of hair cells. Labeling with vital dyes revealed a rapid response of hair cells to the aminoglycoside neomycin. Similarly, ultrastructural analysis revealed structural alteration among hair cells within 15 minutes of neomycin exposure. Animals exposed to a low, 25-microM concentration of neomycin exhibited hair cells with swollen mitochondria, but little other damage. Animals treated with higher concentrations of neomycin (50-200 microM) had more severe and heterogeneous cellular changes, as well as fewer hair cells. Both necrotic-like and apoptotic-like cellular damage were observed. Quantitation of the types of alterations observed indicated that mitochondrial defects appear earlier and more predominantly than other structural alterations. In vivo monitoring demonstrated that mitochondrial potential decreased following neomycin treatment. These results indicate that perturbation of the mitochondrion is an early, central event in aminoglycoside-induced damage.

Little Ice Age climatic erraticism as an analogue for future enhanced hydroclimatic variability across the American Southwest.

The American Southwest has experienced a series of severe droughts interspersed with strong wet episodes over the past decades, prompting questions about future climate patterns and potential intensification of weather disruptions under warming conditions. Here we show that interannual hydroclimatic variability in this region has displayed a significant level of non-stationarity over the past millennium. Our tree ring-based analysis of past drought indicates that the Little Ice Age (LIA) experienced high interannual hydroclimatic variability, similar to projections for the 21st century. This is contrary to the Medieval Climate Anomaly (MCA), which had reduced variability and therefore may be misleading as an analog for 21st century warming, notwithstanding its warm (and arid) conditions. Given past non-stationarity, and particularly erratic LIA, a 'warm LIA' climate scenario for the coming century that combines high precipitation variability (similar to LIA conditions) with warm and dry conditions (similar to MCA conditions) represents a plausible situation that is supported by recent climate simulations. Our comparison of tree ring-based drought analysis and records from the tropical Pacific Ocean suggests that changing variability in El Niño Southern Oscillation (ENSO) explains much of the contrasting variances between the MCA and LIA conditions across the American Southwest. Greater ENSO variability for the 21st century could be induced by a decrease in meridional sea surface temperature gradient caused by increased greenhouse gas concentration, as shown by several recent climate modeling experiments. Overall, these results coupled with the paleo-record suggests that using the erratic LIA conditions as benchmarks for past hydroclimatic variability can be useful for developing future water-resource management and drought and flood hazard mitigation strategies in the Southwest.