Effects of interactive global changes on methane uptake in an annual grassland.

The future size of the terrestrial methane (CH4) sink of upland soils remains uncertain, along with potential feedbacks to global warming. Much of the uncertainty lies in our lack of knowledge about potential interactive effects of multiple simultaneous global environmental changes. Field CH4 fluxes and laboratory soil CH4 consumption were measured five times during 3 consecutive years in a California annual grassland exposed to 8 years of the full factorial combination of ambient and elevated levels of precipitation, temperature, atmospheric CO2 concentration, and N deposition. Across all sampling dates and treatments, increased precipitation caused a 61% reduction in field CH4 uptake. However, this reduction depended quantitatively on other global change factors. Higher precipitation reduced CH4 uptake when temperature or N deposition (but not both) increased, and under elevated CO2 but only late in the growing season. Warming alone also decreased CH4 uptake early in the growing season, which was partly explained by a decrease in laboratory soil CH4 consumption. Atmospheric CH4 models likely need to incorporate nonadditive interactions, seasonal interactions, and interactions between methanotrophy and methanogenesis. Despite the complexity of interactions we observed in this multifactor experiment, the outcome agrees with results from single‐factor experiments: an increased terrestrial CH4 sink appears less likely than a reduced one

Testing interactive effects of global environmental changes on soil nitrogen cycling

Responses of soil nitrogen (N) cycling to simultaneous and potentially interacting global environmental changes are uncertain. Here, we investigated the combined effects of elevated CO2, warming, increased precipitation and enhanced N supply on soil N cycling in an annual grassland ecosystem as part of the Jasper Ridge Global Change Experiment (CA, USA). This field experiment included four treatments-CO2, temperature, precipitation, nitrogen-with two levels per treatment (ambient and elevated), and all their factorial combinations replicated six times. We collected soil samples after 7 and 8 years of treatments, and measured gross rates of N mineralization, N immobilization and nitrification, along with potential rates of ammonia oxidation, nitrite oxidation and denitrification. We also determined the main drivers of these microbial activities (soil ammonium and nitrate concentrations, soil moisture, soil temperature, soil pH, and soil CO2 efflux, as an indicator of soil heterotrophic activity). We found that gross N mineralization responded to the interactive effects of the CO2, precipitation and N treatments: N addition increased gross N mineralization when CO2 and precipitation were either both at ambient or both at elevated levels. However, we found limited evidence for interactions among elevated CO2, warming, increased precipitation, and enhanced N supply on the other N cycling processes examined: statistically significant interactions, when found, tended not to persist across multiple dates. Soil N cycling responded mainly to single-factor effects: long-term N addition increased gross N immobilization, potential ammonia oxidation and potential denitrification, while increased precipitation depressed potential nitrite oxidation and increased potential ammonia oxidation and potential denitrification. In contrast, elevated CO2 and modest warming did not significantly affect any of these microbial N transformations. These findings suggest that global change effects on soil N cycling are primarily additive, and therefore generally predictable from single factor studies

Safety of AAV Factor IX Peripheral Transvenular Gene Delivery to Muscle in Hemophilia B Dogs

Muscle represents an attractive target tissue for adeno-associated virus (AAV) vector–mediated gene transfer for hemophilia B (HB). Experience with direct intramuscular (i.m.) administration of AAV vectors in humans showed that the approach is safe but fails to achieve therapeutic efficacy. Here, we present a careful evaluation of the safety profile (vector, transgene, and administration procedure) of peripheral transvenular administration of AAV-canine factor IX (cFIX) vectors to the muscle of HB dogs. Vector administration resulted in sustained therapeutic levels of cFIX expression. Although all animals developed a robust antibody response to the AAV capsid, no T-cell responses to the capsid antigen were detected by interferon (IFN)-γ enzyme-linked immunosorbent spot (ELISpot). Interleukin (IL)-10 ELISpot screening of lymphocytes showed reactivity to cFIX-derived peptides, and restimulation of T cells in vitro in the presence of the identified cFIX epitopes resulted in the expansion of CD4+FoxP3+IL-10+ T-cells. Vector administration was not associated with systemic inflammation, and vector spread to nontarget tissues was minimal. At the local level, limited levels of cell infiltrates were detected when the vector was administered intravascularly. In summary, this study in a large animal model of HB demonstrates that therapeutic levels of gene transfer can be safely achieved using a novel route of intravascular gene transfer to muscle

Impacts of climate change on plant diseases – opinions and trends

There has been a remarkable scientific output on the topic of how climate change is likely to affect plant diseases in the coming decades. This review addresses the need for review of this burgeoning literature by summarizing opinions of previous reviews and trends in recent studies on the impacts of climate change on plant health. Sudden Oak Death is used as an introductory case study: Californian forests could become even more susceptible to this emerging plant disease, if spring precipitations will be accompanied by warmer temperatures, although climate shifts may also affect the current synchronicity between host cambium activity and pathogen colonization rate. A summary of observed and predicted climate changes, as well as of direct effects of climate change on pathosystems, is provided. Prediction and management of climate change effects on plant health are complicated by indirect effects and the interactions with global change drivers. Uncertainty in models of plant disease development under climate change calls for a diversity of management strategies, from more participatory approaches to interdisciplinary science. Involvement of stakeholders and scientists from outside plant pathology shows the importance of trade-offs, for example in the land-sharing vs. sparing debate. Further research is needed on climate change and plant health in mountain, boreal, Mediterranean and tropical regions, with multiple climate change factors and scenarios (including our responses to it, e.g. the assisted migration of plants), in relation to endophytes, viruses and mycorrhiza, using long-term and large-scale datasets and considering various plant disease control methods

An open-source database for the synthesis of soil radiocarbon data: International Soil Radiocarbon Database (ISRaD) version 1.0

Radiocarbon is a critical constraint on our estimates of the timescales of soil carbon cycling that can aid in identifying mechanisms of carbon stabilization and destabilization and improve the forecast of soil carbon response to management or environmental change. Despite the wealth of soil radiocarbon data that have been reported over the past 75 years, the ability to apply these data to global-scale questions is limited by our capacity to synthesize and compare measurements generated using a variety of methods. Here, we present the International Soil Radiocarbon Database (ISRaD; http://soilradiocarbon.org, last access: 16 December 2019), an open-source archive of soil data that include reported measurements from bulk soils, distinct soil carbon pools isolated in the laboratory by a variety of soil fractionation methods, samples of soil gas or water collected interstitially from within an intact soil profile, CO2 gas isolated from laboratory soil incubations, and fluxes collected in situ from a soil profile. The core of ISRaD is a relational database structured around individual datasets (entries) and organized hierarchically to report soil radiocarbon data, measured at different physical and temporal scales as well as other soil or environmental properties that may also be measured and may assist with interpretation and context. Anyone may contribute their own data to the database by entering it into the ISRaD template and subjecting it to quality assurance protocols. ISRaD can be accessed through (1) a web-based interface, (2) an R package (ISRaD), or (3) direct access to code and data through the GitHub repository, which hosts both code and data. The design of ISRaD allows for participants to become directly involved in the management, design, and application of ISRaD data. The synthesized dataset is available in two forms: the original data as reported by the authors of the datasets and an enhanced dataset that includes ancillary geospatial data calculated within the ISRaD framework. ISRaD also provides data management tools in the ISRaD-R package that provide a starting point for data analysis; as an open-source project, the broader soil community is invited and encouraged to add data, tools, and ideas for improvement. As a whole, ISRaD provides resources to aid our evaluation of soil dynamics across a range of spatial and temporal scales. The ISRaD v1.0 dataset is archived and freely available at https://doi.org/10.5281/zenodo.2613911 (Lawrence et al., 2019).Max Planck Institute for Biogeochemistry; European Research CouncilEuropean Research Council (ERC) [695101]; USGS Land Change Science mission area; US Department of AgricultureUnited States Department of Agriculture (USDA) [2018-67003-27935]; US Geological Survey Powell Center for the working group on Soil Carbon Storage and FeedbacksOpen access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Predicting In-Hospital Mortality in Patients Undergoing Percutaneous Coronary Intervention

Background Standardization of risk is critical in benchmarking and quality improvement efforts for percutaneous coronary interventions (PCI). In 2018, the CathPCI Registry was updated to include additional variables to better classify higher-risk patients. Objectives We sought to develop a model for predicting in-hospital mortality risk following PCI incorporating these additional variables. Methods Data from 706,263 PCIs performed between 7/2018-6/2019 at 1,608 sites were used to develop and validate a new full and pre-catheterization model to predict in-hospital mortality, and a simplified bedside risk score. The sample was randomly split into a development (70%, n=495,005) and validation cohort (30%, n=211,258). We created 1,000 bootstrapped samples of the development cohort and used stepwise selection logistic regression on each sample. The final model included variables that were selected in at least 70% of the bootstrapped samples and those identified a priori due to clinical relevance. Results In-hospital mortality following PCI varied based on clinical presentation. Procedural urgency, cardiovascular instability, and level of consciousness after cardiac arrest were most predictive of in-hospital mortality. The full model performed well, with excellent discrimination (c-index: 0.943) in the validation cohort and good calibration across different clinical and procedural risk cohorts. The median hospital risk-standardized mortality rate was 1.9% and ranged from 1.1% to 3.3% (interquartile range: 1.7%-2.1%). Conclusions The risk of mortality following PCI can be predicted in contemporary practice by incorporating variables that reflect clinical acuity. This model, which includes data previously not captured, is a valid instrument for risk stratification and for quality improvement efforts

Advances in gene therapy for muscular dystrophies

Duchenne muscular dystrophy (DMD) is a recessive lethal inherited muscular dystrophy caused by mutations in the gene encoding dystrophin, a protein required for muscle fibre integrity. So far, many approaches have been tested from the traditional gene addition to newer advanced approaches based on manipulation of the cellular machinery either at the gene transcription, mRNA processing or translation levels. Unfortunately, despite all these efforts, no efficient treatments for DMD are currently available. In this review, we highlight the most advanced therapeutic strategies under investigation as potential DMD treatments

Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is an incurable X-linked muscle-wasting disease caused by mutations in the dystrophin gene. Gene therapy using highly functional microdystrophin genes and recombinant adeno-associated virus (rAAV) vectors is an attractive strategy to treat DMD. Here we show that locoregional and systemic delivery of a rAAV2/8 vector expressing a canine microdystrophin (cMD1) is effective in restoring dystrophin expression and stabilizing clinical symptoms in studies performed on a total of 12 treated golden retriever muscular dystrophy (GRMD) dogs. Locoregional delivery induces high levels of microdystrophin expression in limb musculature and significant amelioration of histological and functional parameters. Systemic intravenous administration without immunosuppression results in significant and sustained levels of microdystrophin in skeletal muscles and reduces dystrophic symptoms for over 2 years. No toxicity or adverse immune consequences of vector administration are observed. These studies indicate safety and efficacy of systemic rAAV-cMD1 delivery in a large animal model of DMD, and pave the way towards clinical trials of rAAV-microdystrophin gene therapy in DMD patients

Genome-wide identification of FoxO-dependent gene networks in skeletal muscle during C26 cancer cachexia

BACKGROUND: Evidence from cachectic cancer patients and animal models of cancer cachexia supports the involvement of Forkhead box O (FoxO) transcription factors in driving cancer-induced skeletal muscle wasting. However, the genome-wide gene networks and associated biological processes regulated by FoxO during cancer cachexia are unknown. We hypothesize that FoxO is a central upstream regulator of diverse gene networks in skeletal muscle during cancer that may act coordinately to promote the wasting phenotype. METHODS: To inhibit endogenous FoxO DNA-binding, we transduced limb and diaphragm muscles of mice with AAV9 containing the cDNA for a dominant negative (d.n.) FoxO protein (or GFP control). The d.n.FoxO construct consists of only the FoxO3a DNA-binding domain that is highly homologous to that of FoxO1 and FoxO4, and which outcompetes and blocks endogenous FoxO DNA binding. Mice were subsequently inoculated with Colon-26 (C26) cells and muscles harvested 26 days later. RESULTS: Blocking FoxO prevented C26-induced muscle fiber atrophy of both locomotor muscles and the diaphragm and significantly spared force deficits. This sparing of muscle size and function was associated with the differential regulation of 543 transcripts (out of 2,093) which changed in response to C26. Bioinformatics analysis of upregulated gene transcripts that required FoxO revealed enrichment of the proteasome, AP-1 and IL-6 pathways, and included several atrophy-related transcription factors, including Stat3, Fos, and Cebpb. FoxO was also necessary for the cancer-induced downregulation of several gene transcripts that were enriched for extracellular matrix and sarcomere protein-encoding genes. We validated these findings in limb muscles and the diaphragm through qRT-PCR, and further demonstrate that FoxO1 and/or FoxO3a are sufficient to increase Stat3, Fos, Cebpb, and the C/EBPβ target gene, Ubr2. Analysis of the Cebpb proximal promoter revealed two bona fide FoxO binding elements, which we further establish are necessary for Cebpb promoter activation in response to IL-6, a predominant cytokine in the C26 cancer model. CONCLUSIONS: These findings provide new evidence that FoxO-dependent transcription is a central node controlling diverse gene networks in skeletal muscle during cancer cachexia, and identifies novel candidate genes and networks for further investigation as causative factors in cancer-induced wasting.R01 AR060217 - NIAMS NIH HHS; R01 AR060209 - NIAMS NIH HHS; T32 HD043730 - NICHD NIH HHS; R00 HL098453 - NHLBI NIH HHS; R00HL098453 - NHLBI NIH HHS; R01AR060209 - NIAMS NIH HHS; R01AR060217 - NIAMS NIH HH