Recent decades have been characterized by increasing temperatures worldwide, resulting in an exponential climb in vapor pressure deficit (VPD). VPD has been identified as an increasingly important ...driver of plant functioning in terrestrial biomes and has been established as a major contributor in recent drought-induced plant mortality independent of other drivers associated with climate change. Despite this, few studies have isolated the physiological response of plant functioning to high VPD, thus limiting our understanding and ability to predict future impacts on terrestrial ecosystems. An abundance of evidence suggests that stomatal conductance declines under high VPD and transpiration increases in most species up until a given VPD threshold, leading to a cascade of subsequent impacts including reduced photosynthesis and growth, and higher risks of carbon starvation and hydraulic failure. Incorporation of photosynthetic and hydraulic traits in ‘next-generation’ land-surface models has the greatest potential for improved prediction of VPD responses at the plant- and global-scale, and will yield more mechanistic simulations of plant responses to a changing climate. By providing a fully integrated framework and evaluation of the impacts of high VPD on plant function, improvements in forecasting and long-term projections of climate impacts can be made.
Droughts in a warming climate have become more common and more extreme, making understanding forest responses to water stress increasingly pressing. Analysis of water stress in trees has long focused ...on water potential in xylem and leaves, which influences stomatal closure and water flow through the soil‐plant‐atmosphere continuum. At the same time, changes of vegetation water content (VWC) are linked to a range of tree responses, including fluxes of water and carbon, mortality, flammability, and more. Unlike water potential, which requires demanding in situ measurements, VWC can be retrieved from remote sensing measurements, particularly at microwave frequencies using radar and radiometry. Here, we highlight key frontiers through which VWC has the potential to significantly increase our understanding of forest responses to water stress. To validate remote sensing observations of VWC at landscape scale and to better relate them to data assimilation model parameters, we introduce an ecosystem‐scale analog of the pressure–volume curve, the non‐linear relationship between average leaf or branch water potential and water content commonly used in plant hydraulics. The sources of variability in these ecosystem‐scale pressure‐volume curves and their relationship to forest response to water stress are discussed. We further show to what extent diel, seasonal, and decadal dynamics of VWC reflect variations in different processes relating the tree response to water stress. VWC can also be used for inferring belowground conditions—which are difficult to impossible to observe directly. Lastly, we discuss how a dedicated geostationary spaceborne observational system for VWC, when combined with existing datasets, can capture diel and seasonal water dynamics to advance the science and applications of global forest vulnerability to future droughts.
Changes of vegetation water content (VWC) are linked to a range of tree responses to drought, including fluxes of water and carbon, mortality, flammability, and more, and can be retrieved from microwave remote sensing measurements. We highlight key frontiers through which remotely sensed VWC has the potential to significantly increase our understanding of forest responses to water stress. We argue that separate consideration of diel, seasonal, and decadal timescales can facilitate interpretation of VWC measurements for different process studies, and that VWC observations can be useful for constraining belowground water uptake. To link remotely sensed VWC estimates to plant hydraulic models, the utility and interpretation of ecosystem‐scale pressure‐volume curves are discussed.
Summary
●Plants are characterized by the iso/anisohydry continuum depending on how they regulate leaf water potential (ΨL). However, how iso/anisohydry changes over time in response to year‐to‐year ...variations in environmental dryness and how such responses vary across different regions remains poorly characterized.
●We investigated how dryness, represented by aridity index, affects the interannual variability of ecosystem iso/anisohydry at the regional scale, estimated using satellite microwave vegetation optical depth (VOD) observations. This ecosystem‐level analysis was further complemented with published field observations of species‐level ΨL.
●We found different behaviors in the directionality and sensitivity of isohydricity (σ) with respect to the interannual variation of dryness in different ecosystems. These behaviors can largely be differentiated by the average dryness of the ecosystem itself: in mesic ecosystems, σ decreases in drier years with a higher sensitivity to dryness; in xeric ecosystems, σ increases in drier years with a lower sensitivity to dryness. These results were supported by the species‐level synthesis.
●Our study suggests that how plants adjust their water use across years – as revealed by their interannual variability in isohydricity – depends on the dryness of plants’ living environment. This finding advances our understanding of plant responses to drought at regional scales.
Remotely sensed microwave observations of vegetation optical depth (VOD) have been widely used for examining vegetation responses to climate. Nevertheless, the relative impacts of phenological ...changes in leaf biomass and water stress on VOD have not been explicitly disentangled. In particular, determining whether leaf water potential (ψL) affects VOD may allow these data sets as a constraint for plant hydraulic models. Here we test the sensitivity of VOD to variations in ψL and present a conceptual framework that relates VOD to ψL and total biomass including leaves, whose dynamics are measured through leaf area index, and woody components. We used measurements of ψL from three sites across the US—a mixed deciduous forests in Indiana and Missouri and a piñon‐juniper woodland in New Mexico—to validate the conceptual model. The temporal dynamics of X‐band VOD were similar to those of the VOD signal estimated from the new conceptual model with observed ψL (R2 = 0.6–0.8). At the global scale, accounting for a combination of biomass and estimated ψL (based on satellite surface soil moisture data) increased correlations with VOD by ~ 15% and 30% compared to biomass and water potential, respectively. In wetter regions with denser and taller canopy heights, VOD has a higher correlation with leaf area index than with water stress and vice versa in drier regions. Our results demonstrate that variations in both phenology and ψL must be considered to accurately interpret the dynamics of VOD observations for ecological applications.
Key Points
A new conceptual model of microwave vegetation optical depth dynamics in terms of leaf area index and leaf water potential was developed
The conceptual model was validated using leaf water potential measurements at two mixed deciduous forests and a pinion‐juniper woodland
Globally, the suggested framework increased the correlation of water potential (leaf area index) with observed VOD by ~30% (~15%)
Xerostomia, or the feeling of dry mouth, is a significant side effect of radiation therapy for patients with head and neck cancer (HNC). Preliminary data suggest that mesenchymal stromal/stem cells ...(MSCs) can improve salivary function. We performed a first-in-human pilot study of interferon gamma (IFNγ)-stimulated autologous bone marrow-derived MSCs, or MSC(M), for the treatment of radiation-induced xerostomia (RIX). Here we present the primary safety and secondary efficacy endpoints.
A single-center pilot clinical trial was conducted investigating the safety and tolerability of autologous IFNγ-stimulated MSC(M). The study was conducted under an approved Food and Drug Administration Investigational New Drug application using an institutional review board-approved protocol (NCT04489732). Patients underwent iliac crest bone marrow aspirate and MSC(M) were isolated, cultured, stimulated with IFNγ and cryopreserved for later use. Banked cells were thawed and allowed to recover in culture before patients received a single injection of 10 × 10
MSC(M) into the right submandibular gland under ultrasound guidance. The primary objective was determination of safety and tolerability by evaluating dose-limiting toxicity (DLT). A DLT was defined as submandibular pain >5 on a standard 10-point pain scale or any serious adverse event (SAE) within 1 month after injection. Secondary objectives included analysis of efficacy as measured by salivary quantification and using three validated quality of life instruments. Quantitative results are reported as mean and standard deviation.
Six patients with radiation-induced xerostomia who had completed radiation at least 2 years previously (average 7.8 years previously) were enrolled in the pilot study. The median age was 71 (61-74) years. Five (83%) patients were male. Five patients (83%) were treated with chemoradiation and one patient (17%) with radiation alone. Grade 1 pain was seen in 50% of patients after submandibular gland injection; all pain resolved within 4 days. No patients reported pain 1 month after injection, with no SAE or other DLTs reported 1 month after injection. The analysis of secondary endpoints demonstrated a trend of increased salivary production. Three patients (50%) had an increase in unstimulated saliva at 1 and 3 months after MSC(M) injection. Quality of life surveys also showed a trend toward improvement.
Injection of autologous IFNγ-stimulated MSC(M) into a singular submandibular gland of patients with RIX is safe and well tolerated in this pilot study. A trend toward an improvement in secondary endpoints of salivary quantity and quality of life was observed. This first-in-human study provides support for further investigation into IFNγ-stimulated MSC(M) injected in both submandibular glands as an innovative approach to treat RIX and improve quality of life for patients with HNC.
An exponential rise in the atmospheric vapour pressure deficit (VPD) is among the most consequential impacts of climate change in terrestrial ecosystems. Rising VPD has negative and cascading effects ...on nearly all aspects of plant function including photosynthesis, water status, growth and survival. These responses are exacerbated by land-atmosphere interactions that couple VPD to soil water and govern the evolution of drought, affecting a range of ecosystem services including carbon uptake, biodiversity, the provisioning of water resources and crop yields. However, despite the global nature of this phenomenon, research on how to incorporate these impacts into resilient management regimes is largely in its infancy, due in part to the entanglement of VPD trends with those of other co-evolving climate drivers. Here, we review the mechanistic bases of VPD impacts at a range of spatial scales, paying particular attention to the independent and interactive influence of VPD in the context of other environmental changes. We then evaluate the consequences of these impacts within key management contexts, including water resources, croplands, wildfire risk mitigation and management of natural grasslands and forests. We conclude with recommendations describing how management regimes could be altered to mitigate the otherwise highly deleterious consequences of rising VPD.
Xerostomia, or dry mouth, is a common side effect of head and neck radiation. Current treatment options for radiation-induced xerostomia are generally supportive in nature. Adult stem cells are the ...ultimate source for replenishment of salivary gland tissue. Bone marrow-derived mesenchymal stromal cells (BM-MSCs) are a viable cell-based therapy for xerostomia. We have undertaken studies enabling U.S. Food and Drug Administration Investigational New Drug status, demonstrating the normal phenotype, intact functionality, and pro-growth secretome of interferon-γ (IFNγ)-stimulated BM-MSCs taken from patients with head and neck cancer who have undergone radiation ± chemotherapy. Here we present the protocol of MARSH, a first-in-human clinical trial of bone marrow-derived, IFNγ-activated BM-MSCs for the treatment of radiation-induced xerostomia.
This single-center phase 1 dose-escalation with expansion cohort, non-placebo-controlled study will assess the safety and tolerability of BM-MSCs for the treatment of radiation-induced xerostomia in patients who had head and neck cancer. The phase 1 dose-escalation study will be a 3 + 3 design with staggered enrollment. A total of 21 to 30 subjects (9 to 18 in phase 1 study, 12 in expansion cohort) will be enrolled. The primary endpoint is determining the recommended phase 2 dose (RP2D) of IFNγ-stimulated BM-MSCs to enable further studies on the efficacy of BM-MSCs. Patients' bone marrow will be aspirated, and BM-MSCs will be expanded, stimulated with IFNγ, and injected into the submandibular gland. The RP2D will be determined by dose-limiting toxicities occurring within 1 month of BM-MSC injection. Secondary outcomes of saliva amounts and composition, ultrasound of salivary glands, and quality of life surveys will be taken at 3-, 6-, 12-, and 24-month visits.
Autotransplantation of IFNγ-stimulated BM-MSCs in salivary glands after radiation therapy or chemoradiation therapy may provide an innovative remedy to treat xerostomia and restore quality of life. This is the first therapy for radiation-induced xerostomia that may be curative.
World Health Organization International Clinical Trials Registry Platform: NCT04489732.
Salivary dysfunction is a significant side effect of radiation therapy for head and neck cancer (HNC). Preliminary data suggests that mesenchymal stromal cells (MSCs) can improve salivary function. ...Whether MSCs from HNC patients who have completed chemoradiation are functionally similar to those from healthy patients is unknown. We performed a pilot clinical study to determine whether bone marrow-derived MSCs MSC(M) from HNC patients could be used for the treatment of RT-induced salivary dysfunction.
An IRB-approved pilot clinical study was undertaken on HNC patients with xerostomia who had completed treatment two or more years prior. Patients underwent iliac crest bone marrow aspirate and MSC(M) were isolated and cultured. Culture-expanded MSC(M) were stimulated with IFNγ and cryopreserved prior to reanimation and profiling for functional markers by flow cytometry and ELISA. MSC(M) were additionally injected into mice with radiation-induced xerostomia and the changes in salivary gland histology and salivary production were examined.
A total of six subjects were enrolled. MSC(M) from all subjects were culture expanded to > 20 million cells in a median of 15.5 days (range 8–20 days). Flow cytometry confirmed that cultured cells from HNC patients were MSC(M). Functional flow cytometry demonstrated that these IFNγ-stimulated MSC(M) acquired an immunosuppressive phenotype. IFNγ-stimulated MSC(M) from HNC patients were found to express GDNF, WNT1, and R-spondin 1 as well as pro-angiogenesis and immunomodulatory cytokines. In mice, IFNγ-stimulated MSC(M) injection after radiation decreased the loss of acinar cells, decreased the formation of fibrosis, and increased salivary production.
MSC (M) from previously treated HNC patients can be expanded for auto-transplantation and are functionally active. Furthermore IFNγ-stimulated MSC(M) express proteins implicated in salivary gland regeneration. This study provides preliminary data supporting the feasibility of using autologous MSC(M) from HNC patients to treat RT-induced salivary dysfunction
Abstract How genetic variations in the dopamine transporter (DAT) combined with exposure to environmental toxins modulate the risk of Parkinson's disease remains unclear. Using unbiased stereology in ...DAT knock-down mice (DAT-KD) and wild-type (WT) littermates, we found that decreased DAT caused a loss of tyrosine hydroxylase–positive (dopaminergic) neurons in subregions of the substantia nigra pars compacta at 3–4 days, 5 weeks, and 18 months of age. Both genotypes lost dopaminergic neurons with age and remaining neurons at 11 months were resilient to paraquat/maneb. In 5-week-old mice, the toxins decreased substantia nigra pars compacta dopaminergic neurons in both genotypes but less in DAT-KD. Regional analysis revealed striking differences in the subsets of neurons affected by low DAT, paraquat/maneb, and aging. In particular, we show that a potentially protective effect of low DAT against toxin exposure is not sufficient to reduce death of all nigrostriatal dopaminergic neurons. Thus, different regional vulnerability of nigrostriatal dopaminergic neurons may contribute to an increased risk of developing Parkinson's disease when multiple factors are combined.
Several methods to expand and activate (EA) NK cells ex vivo have been developed for the treatment of relapsed or refractory cancers. Infusion of fresh NK cells is generally preferred to the infusion ...of cryopreserved/thawed (C/T) NK cells because of concern that cryopreservation diminishes NK cell activity. However, there has been little head-to-head comparison of the functionality of fresh versus C/T NK cell products.
We evaluated activity of fresh and C/T EA NK cells generated by interleukin (IL)-15, IL-2 and CD137L expansion.
Analysis of C/T NK cell products demonstrated decreased recovery of viable CD56+ cells, but the proportion of NK cells in the C/T EA NK cell product did not decrease compared with the fresh EA NK cell product. Fresh and C/T EA NK cells demonstrated increased granzyme B compared with NK cells pre-expansion, but only fresh EA NK cells showed increased NKG2D. Compared with fresh EA NK cells, cytotoxic ability of C/T EA NK cells was reduced, but C/T EA NK cells remained potently cytotoxic against tumor cells via both antibody-independent and antibody-dependent mechanisms within 4 h post-thaw. Fresh EA NK cells generated high levels of gamma interferon (IFN-γ), which was abrogated by JAK1/JAK2 inhibition with ruxolitinib, but C/T EA NK cells showed lower IFN-γ unaffected by JAK1/JAK2 inhibition.
Usage of C/T EA NK cells may be an option to provide serial “boost” NK cell infusions from a single apheresis to maximize NK cell persistence and potentially improve NK-induced responses to refractory cancer.
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