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Both increases in temperature and changes in precipitation may limit future tree growth, but rising atmospheric CO₂ could offset some of these stressors through increased plant Water Use Efficiency (WUE). The net balance between the negative impacts of climate change and positive effects of CO₂ on tree growth is crucial for ecotones, where increased climate stress could drive mortality and shifts in range. Here, we quantify the effects of climate, stand structure, and rising CO₂ on both annual tree-ring growth increment and intrinsic WUE (iWUE) at a savanna-forest boundary in the Upper Midwest United States. Taking a Bayesian hierarchical modelling approach, we find that plant iWUE increased by ~ 16–23% over the course of the twentieth century, but on average, tree-ring growth increments do not significantly increase. Consistent with higher iWUE under increased CO₂ and recent wetting, we observe a decrease in sensitivity of tree growth to annual precipitation, leading to ~ 35–41% higher growth under dry conditions compared to trees of similar size in the past. However, an emerging interaction between summer maximum temperatures and annual precipitation diminishes the water-savings benefit under hot and dry conditions. This decrease in precipitation sensitivity, and the interaction between temperature and precipitation are strongest in open canopy microclimates, suggesting that stand structure may modulate response to future changes. Overall, while higher iWUE may provide some water savings benefits to growth under normal drought conditions, near-term future temperature increases combined with drought events could drive growth declines of about 50%.

Great hope is being placed in the ability of forest ecosystems to contribute to greenhouse gas (GHG) emission reduction targets to limit global warming. Many nations plan to rely on forest-based climate mitigation activities to create additional and long-term carbon sequestration. Here, we take a critical look at the state of the policy and ecology surrounding forest-based natural climate solutions (NCS), with a focus on temperate forests of the United States (US). We first provide a high-level overview of carbon accounting, including key concepts used in the monitoring, reporting and verification of forest-based NCS. Second, we provide a high-level overview of forest carbon dynamics, including pools and fluxes, and drivers of their change. We then identify gaps in the current systems of GHG accounting, and between current ambitions and basic forest ecology. Improved use of data in models provides a path forward to better assessment and anticipation of forest-based climate mitigation. We illustrate this with the creation of a climate-sensitive forestry model, using tree-ring time series data. This climate-sensitive forest simulator will improve planning of site-level climate mitigation activities in the US by providing more realistic expectations of the carbon sequestration potential of forests undergoing climate change. Our review highlights the sobering complexity and uncertainty surrounding forest carbon dynamics, along with the need to improve carbon accounting. If we are to expect forests to play the significant emissions reduction role that is currently planned, we should view immediate emissions reductions as critical to preserve the climate mitigation capacity of forest ecosystems.

Historically, closed eastern forests transitioned into open savannas and prairies in the U.S. Midwest, but this transition is poorly understood. To investigate the eastern boundary of the prairie-forest ecotone, we conducted a case study of historic and modern vegetation patterns of the Yellow River watershed in northwest Indiana. Historic vegetation came from the Public Land Survey notes collected in the early 1800s, whereas modern vegetation came from the Forest Inventory Analysis and USGS National Land Cover Database. We mapped vegetation data using GIS to reconstruct the region's past and current forest composition and structure. We also mapped climate, topography, and soil composition across the watershed to investigate the relationship between historic vegetation and environmental gradients. We found a sharp transition in the presettlement forest structure and composition, with dense deciduous forests in the eastern portion of our study area and open oak savannas in the west. The savanna ecosystem dominated in sandy well-drained soils and was at a slightly lower elevation than the adjacent closed forest. Modest environmental changes accompanied major vegetation changes in the past, which might suggest fire and hydrological patterns helped maintain the sharp ecotone. By contrast the modern forest shows no difference in tree density and composition across the watershed, which is consistent with major land use and hydrology changes in the watershed since settlement. On the modern landscape, land that was historically closed forest now has higher agricultural productivity compared to land that was historically savanna, whereas the historic savanna currently supports more mesic forest. These results suggest the environmental gradient continues to subtly shape the landscape. Though land use change has largely removed the closed mixed hardwood forests and oak savannas from this area, a better understanding of the historic vegetation and the conditions that supported it can help inform land management and restoration, as well as reveal ecological processes that drive vegetation transitions.

Atmospheric carbon dioxide concentration ([CO₂]) is increasing, which increases leaf-scale photosynthesis and intrinsic water-use efficiency. These direct responses have the potential to increase plant growth, vegetation biomass, and soil organic matter; transferring carbon from the atmosphere into terrestrial ecosystems (a carbon sink). A substantial global terrestrial carbon sink would slow the rate of [CO₂] increase and thus climate change. However, ecosystem CO₂ responses are complex or confounded by concurrent changes in multiple agents of global change and evidence for a [CO₂]-driven terrestrial carbon sink can appear contradictory. Here we synthesize theory and broad, multidisciplinary evidence for the effects of increasing [CO₂] (iCO₂) on the global terrestrial carbon sink. Evidence suggests a substantial increase in global photosynthesis since pre-industrial times. Established theory, supported by experiments, indicates that iCO₂ is likely responsible for about half of the increase. Global carbon budgeting, atmospheric data, and forest inventories indicate a historical carbon sink, and these apparent iCO₂ responses are high in comparison to experiments and predictions from theory. Plant mortality and soil carbon iCO₂ responses are highly uncertain. In conclusion, a range of evidence supports a positive terrestrial carbon sink in response to iCO₂, albeit with uncertain magnitude and strong suggestion of a role for additional agents of global change.

Atmospheric carbon dioxide concentration ([CO2]) is increasing, which increases leaf-scale photosynthesis and intrinsic water-use efficiency. These direct responses have the potential to increase plant growth, vegetation biomass, and soil organic matter; transferring carbon from the atmosphere into terrestrial ecosystems (a carbon sink). A substantial global terrestrial carbon sink would slow the rate of [CO2] increase and thus climate change. However, ecosystem CO2 responses are complex or confounded by concurrent changes in multiple agents of global change and evidence for a [CO2]-driven terrestrial carbon sink can appear contradictory. Here we synthesize theory and broad, multidisciplinary evidence for the effects of increasing [CO2] (iCO2) on the global terrestrial carbon sink. Evidence suggests a substantial increase in global photosynthesis since pre-industrial times. Established theory, supported by experiments, indicates that iCO2 is likely responsible for about half of the increase. Global carbon budgeting, atmospheric data, and forest inventories indicate a historical carbon sink, and these apparent iCO2 responses are high in comparison to experiments and predictions from theory. Plant mortality and soil carbon iCO2 responses are highly uncertain. In conclusion, a range of evidence supports a positive terrestrial carbon sink in response to iCO2, albeit with uncertain magnitude and strong suggestion of a role for additional agents of global change.

Atmospheric carbon dioxide concentration ([CO2]) is increasing, which increases leaf-scale photosynthesis and intrinsic water-use efficiency. These direct responses have the potential to increase plant growth, vegetation biomass, and soil organic matter; transferring carbon from the atmosphere into terrestrial ecosystems (a carbon sink). A substantial global terrestrial carbon sink would slow the rate of [CO2] increase and thus climate change. However, ecosystem CO2-responses are complex or confounded by concurrent changes in multiple agents of global change and evidence for a [CO2]-driven terrestrial carbon sink can appear contradictory. In this work, we synthesise theory and broad, multi-disciplinary evidence for the effects of increasing [CO2] (iCO2) on the global terrestrial carbon sink. Evidence suggests a substantial increase in global photosynthesis since pre-industry. Established theory, supported by experiments, indicates that iCO2 is likely responsible for about half of the increase. Global carbon budgeting, atmospheric data, and forest inventories indicate a historical carbon sink, and these apparent iCO2-responses are high in comparison with experiments and theory. Plant mortality and soil carbon iCO2-responses are highly uncertain. In conclusion, a range of evidence supports a positive terrestrial carbon sink in response to iCO2, albeit with uncertain magnitude and strong suggestion of a role for additional agents of global change.

Ongoing anthropogenic changes, such as land-use change, climate changes, and direct effects of CO2, can alter vegetation structure, composition, and growth rates. If these changes are substantial, they may redistribute forest biomes, with downstream feedbacks onto terrestrial carbon storage, climate, and availability of natural resources. Species and ecosystems at the edge of current distributions, such as at the boundary between savannas and closed forests, may be the most vulnerable to these environmental changes. In this dissertation I explore the long term effects of anthropogenic changes on the structure, composition, function of vegetation at a savanna-forest boundary. We use historical vegetation survey data from both the 1800’s and today to test whether vegetation had multiple stable states within the same environmental space in the past, and to determine if long-term changes in land-use and management drove a vegetation state shift. We find that past vegetation had a multiple stable vegetation states of open savanna and closed forests likely maintained by disturbance-vegetation feedbacks. But ongoing fire suppression and logging have created and maintained modern vegetation in a single closed forest state. We show that disturbance is a strong predictor of aboveground biomass in the past, but only has a negligible effect on aboveground biomass on the present landscape. Strong residual taxa relationships that are unexplained by relationships with the environment were common in the past vegetation, but have since disappeared from the modern landscape. While it is likely that modern systems will be maintained as mostly closed forests by continued land management, future projections for the region indicate much hotter and potentially drier growing seasons, questioning how long vegetation will remain forested. Positive effects of increases CO2 on plant water use efficiency (WUE) could aid forest resilience to future drought conditions, but may be complicated by climate changes. To test whether combined changes in CO2 and climate have a positive or negative effect on growth, I use Bayesian models of annual tree ring growth and WUE. We find that CO2 increases plant WUE, driving precipitation sensitivity declines, but the negative impacts of increasing summer temperatures outweigh any positive impacts of higher WUE. Long-term ecosystem model runs simulate similar increase in WUE and declines in precipitation sensitivity by plant functional types over the 20th century, but do not always agree on either the direction or magnitude of overall growth changes or changes in temperature sensitivity. Overall, the historical perspective provided in this dissertation demonstrates that a combination of land-use, climate changes, and CO2 can drive very different vegetation structure, composition, and functional response to climates that would not be predictable from modern vegetation-environment relationships alone. As a result, future forecasting efforts might be improved by including the disturbance processes, species compositional feedbacks, and non-stationary climate responses highlighted in this dissertation.

Numerous pediatric neurogenetic diseases may be optimally treated by in utero gene therapy (IUGT); but advancing such treatments requires animal models that recapitulate developmental physiology relevant to humans. One disease that could benefit from IUGT is the autosomal recessive motor neuron disease spinal muscular atrophy (SMA). Current SMA gene-targeting therapeutics are more efficacious when delivered shortly after birth, however postnatal treatment is rarely curative in severely affected patients. IUGT may provide benefit for SMA patients. In previous studies, we developed a large animal porcine model of SMA using AAV9 to deliver a short hairpin RNA (shRNA) directed at porcine survival motor neuron gene (Smn) mRNA on postnatal day 5. Here, we aimed to model developmental features of SMA in fetal piglets and to demonstrate the feasibility of prenatal gene therapy by delivering AAV9-shSmn in utero. Saline (sham), AAV9-GFP, or AAV9-shSmn was injected under direct ultrasound guidance between gestational ages 77–110 days. We developed an ultrasound-guided technique to deliver virus under direct visualization to mimic the clinic setting. Saline injection was tolerated and resulted in viable, healthy piglets. Litter rejection occurred within seven days of AAV9 injection for all other rounds. Our real-world experience of in utero viral delivery followed by AAV9-related fetal rejection suggests that the domestic sow may not be a viable model system for preclinical in utero AAV9 gene therapy studies.

Limited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations. This is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity. 1383 female patient records with BC and COVID-19 were included in the analysis, the median age was 61 years, and median follow-up was 90 days. Multivariable analysis revealed higher odds of COVID-19 severity for older age (aOR per decade, 1.48 [95% CI, 1.32-1.67]); Black patients (aOR 1.74; 95 CI 1.24-2.45), Asian Americans and Pacific Islander patients (aOR 3.40; 95 CI 1.70-6.79) and Other (aOR 2.97; 95 CI 1.71-5.17) racial/ethnic groups; worse ECOG performance status (ECOG PS ≥2: aOR, 7.78 [95% CI, 4.83-12.5]); pre-existing cardiovascular (aOR, 2.26 [95% CI, 1.63-3.15])/pulmonary comorbidities (aOR, 1.65 [95% CI, 1.20-2.29]); diabetes mellitus (aOR, 2.25 [95% CI, 1.66-3.04]); and active and progressing cancer (aOR, 12.5 [95% CI, 6.89-22.6]). Hispanic ethnicity, timing, and type of anti-cancer therapy modalities were not significantly associated with worse COVID-19 outcomes. The total all-cause mortality and hospitalization rate for the entire cohort was 9% and 37%, respectively however, it varied according to the BC disease status. Using one of the largest registries on cancer and COVID-19, we identified patient and BC-related factors associated with worse COVID-19 outcomes. After adjusting for baseline characteristics, underrepresented racial/ethnic patients experienced worse outcomes compared to non-Hispanic White patients. This study was partly supported by National Cancer Institute grant number P30 CA068485 to Tianyi Sun, Sanjay Mishra, Benjamin French, Jeremy L Warner; P30-CA046592 to Christopher R Friese; P30 CA023100 for Rana R McKay; P30-CA054174 for Pankil K Shah and Dimpy P Shah; KL2 TR002646 for Pankil Shah and the American Cancer Society and Hope Foundation for Cancer Research (MRSG-16-152-01-CCE) and P30-CA054174 for Dimpy P Shah. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH). The funding sources had no role in the writing of the manuscript or the decision to submit it for publication. CCC19 registry is registered on ClinicalTrials.gov, NCT04354701.

Image-guided percutaneous biopsy has largely replaced excisional biopsy of mammographic lesions. Vacuum-assisted core biopsy has improved sampling of such lesions. The objectives of this study were to define the accuracy of the vacuum-assisted 11-gauge stereotactic core biopsy in sampling of atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS) and to define histologic and mammographic features of target lesions, which predict sampling errors. Between October 1996 and March 2000, 1341 patients underwent stereotactic 11-gauge vacuum-assisted biopsy. Patients with ADH or DCIS were encouraged to undergo excisional biopsy. Surgical excision of 37 ADH lesions revealed 5 missed DCIS lesions and 1 missed invasive cancer. Twelve of 91 DCIS lesions were upstaged to invasive cancer upon excision. The underestimation rate was highest in patients with DCIS when the target lesion for biopsy was a zone of calcifications >1.5 cm. No correlation existed between the histologic features of DCIS lesions diagnosed by stereotactic biopsy and the presence of infiltrating disease on excision. Vacuum-assisted 11-gauge stereotactic core biopsy understages 13.2% and 13.5% of DCIS and ADH lesions, respectively. In patients with DCIS found by stereotactic biopsy, a target zone of calcifications >1.5 cm is associated with a higher underestimation rate of infiltrating disease.