Nitrogen (N) is an essential macronutrient for plants and a major limiting factor for plant growth and crop production. Nitrate is the main source of N available to plants in agricultural soils and ...in many natural environments. Sustaining agricultural productivity is of paramount importance in the current scenario of increasing world population, diversification of crop uses, and climate change. Plant productivity for major crops around the world, however, is still supported by excess application of N-rich fertilizers with detrimental economic and environmental impacts. Thus, understanding how plants regulate nitrate uptake and metabolism is key for developing new crops with enhanced N use efficiency and to cope with future world food demands. The study of plant responses to nitrate has gained considerable interest over the last 30 years. This review provides an overview of key findings in nitrate research, spanning biochemistry, molecular genetics, genomics, and systems biology. We discuss how we have reached our current view of nitrate transport, local and systemic nitrate sensing/signaling, and the regulatory networks underlying nitrate-controlled outputs in plants. We hope this summary will serve not only as a timeline and information repository but also as a baseline to define outstanding questions for future research.
Although breast cancer stem cells (BCSCs) display plasticity transitioning between quiescent mesenchymal-like (M) and proliferative epithelial-like (E) states, how this plasticity is regulated by ...metabolic or oxidative stress remains poorly understood. Here, we show that M- and E-BCSCs rely on distinct metabolic pathways and display markedly different sensitivities to inhibitors of glycolysis and redox metabolism. Metabolic or oxidative stress generated by 2DG, H2O2, or hypoxia promotes the transition of ROSlo M-BCSCs to a ROShi E-state. This transition is reversed by N-acetylcysteine and mediated by activation of the AMPK-HIF1α axis. Moreover, E-BCSCs exhibit robust NRF2-mediated antioxidant responses, rendering them vulnerable to ROS-induced differentiation and cytotoxicity following suppression of NRF2 or downstream thioredoxin (TXN) and glutathione (GSH) antioxidant pathways. Co-inhibition of glycolysis and TXN and GSH pathways suppresses tumor growth, tumor-initiating potential, and metastasis by eliminating both M- and E-BCSCs. Exploiting metabolic vulnerabilities of distinct BCSC states provides a novel therapeutic approach targeting this critical tumor cell population.
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•E- and M-BCSCs have divergent sensitivities to glycolysis or redox metabolism inhibition•Hypoxic or oxidant stress promotes M to E state transition by activating AMPK-HIF1α•E-BCSCs are more oxidative (OXPHOS) and reliant on NRF2 antioxidant responses•Co-inhibition of glycolysis and TXN and GSH pathways targets both M- and E-BCSCs
Luo et al. report that metabolic stressors modulate breast cancer stem cell (BCSC) state dynamics through ROS-mediated activation of the AMPK-HIF1α axis. They further describe the metabolic pathways and vulnerabilities of epithelial- and mesenchymal-like BCSCs and build a conceptual framework to effectively target both BCSC states in PDX and systemic metastasis models of TNBC.
A consensus conference on multiple system atrophy (MSA) in 1998 established criteria for diagnosis that have been accepted widely. Since then, clinical, laboratory, neuropathologic, and imaging ...studies have advanced the field, requiring a fresh evaluation of diagnostic criteria. We held a second consensus conference in 2007 and present the results here.
Experts in the clinical, neuropathologic, and imaging aspects of MSA were invited to participate in a 2-day consensus conference. Participants were divided into five groups, consisting of specialists in the parkinsonian, cerebellar, autonomic, neuropathologic, and imaging aspects of the disorder. Each group independently wrote diagnostic criteria for its area of expertise in advance of the meeting. These criteria were discussed and reconciled during the meeting using consensus methodology.
The new criteria retain the diagnostic categories of MSA with predominant parkinsonism and MSA with predominant cerebellar ataxia to designate the predominant motor features and also retain the designations of definite, probable, and possible MSA. Definite MSA requires neuropathologic demonstration of CNS alpha-synuclein-positive glial cytoplasmic inclusions with neurodegenerative changes in striatonigral or olivopontocerebellar structures. Probable MSA requires a sporadic, progressive adult-onset disorder including rigorously defined autonomic failure and poorly levodopa-responsive parkinsonism or cerebellar ataxia. Possible MSA requires a sporadic, progressive adult-onset disease including parkinsonism or cerebellar ataxia and at least one feature suggesting autonomic dysfunction plus one other feature that may be a clinical or a neuroimaging abnormality.
These new criteria have simplified the previous criteria, have incorporated current knowledge, and are expected to enhance future assessments of the disease.
Hypofractionated radiotherapy has an intrinsically different normal tissue and tumor radiobiology. The results of a prospective trial of stereotactic body radiotherapy (SBRT) for prostate cancer with ...long-term patient-reported toxicity and tumor control rates are presented.
From 2003 through 2009, 67 patients with clinically localized low-risk prostate cancer were enrolled. Treatment consisted of 36.25 Gy in 5 fractions using SBRT with the CyberKnife as the delivery technology. No patient received hormone therapy. Patient self-reported bladder and rectal toxicities were graded on the Radiation Therapy Oncology Group scale (RTOG).
Median follow-up was 2.7 years. There were no grade 4 toxicities. Radiation Therapy Oncology Group Grade 3, 2, and 1 bladder toxicities were seen in 3% (2 patients), 5% (3 patients), and 23% (13 patients) respectively. Dysuria exacerbated by urologic instrumentation accounted for both patients with Grade 3 toxicity. Urinary incontinence, complete obstruction, or persistent hematuria was not observed. Rectal Grade 3, 2, and 1 toxicities were seen in 0, 2% (1 patient), and 12.5% (7 patients), respectively. Persistent rectal bleeding was not observed. Low-grade toxicities were substantially less frequent with QOD vs. QD dose regimen (p = 0.001 for gastrointestinal and p = 0.007 for genitourinary). There were two prostate-specific antigen (PSA), biopsy-proven failures with negative metastatic workup. Median PSA at follow-up was 0.5 ± 0.72 ng/mL. The 4-year Kaplan-Meier PSA relapse-free survival was 94% (95% confidence interval, 85%-102%).
Significant late bladder and rectal toxicities from SBRT for prostate cancer are infrequent. PSA relapse-free survival compares favorably with other definitive treatments. The current evidence supports consideration of stereotactic body radiotherapy among the therapeutic options for localized prostate cancer.
Earth System Models (ESMs) are essential tools for understanding and predicting global change, but they cannot explicitly resolve hillslope‐scale terrain structures that fundamentally organize water, ...energy, and biogeochemical stores and fluxes at subgrid scales. Here we bring together hydrologists, Critical Zone scientists, and ESM developers, to explore how hillslope structures may modulate ESM grid‐level water, energy, and biogeochemical fluxes. In contrast to the one‐dimensional (1‐D), 2‐ to 3‐m deep, and free‐draining soil hydrology in most ESM land models, we hypothesize that 3‐D, lateral ridge‐to‐valley flow through shallow and deep paths and insolation contrasts between sunny and shady slopes are the top two globally quantifiable organizers of water and energy (and vegetation) within an ESM grid cell. We hypothesize that these two processes are likely to impact ESM predictions where (and when) water and/or energy are limiting. We further hypothesize that, if implemented in ESM land models, these processes will increase simulated continental water storage and residence time, buffering terrestrial ecosystems against seasonal and interannual droughts. We explore efficient ways to capture these mechanisms in ESMs and identify critical knowledge gaps preventing us from scaling up hillslope to global processes. One such gap is our extremely limited knowledge of the subsurface, where water is stored (supporting vegetation) and released to stream baseflow (supporting aquatic ecosystems). We conclude with a set of organizing hypotheses and a call for global syntheses activities and model experiments to assess the impact of hillslope hydrology on global change predictions.
Plain Language Summary
Hillslopes are key landscape features that organize water availability on land. Valley bottoms are wetter than hilltops, and sun‐facing slopes are warmer and drier than shaded ones. This hydrologic organization leads to systematic differences in soil and vegetation between valleys and hilltops, and between sunny and shady slopes. Although these patterns are fundamental to understanding the structures and functions of water and terrestrial ecosystems, they are too fine grained to be represented in global‐scale Earth System Models. Here we bring together Critical Zone scientists who study the interplay of vegetation, the porous upper layer of the continental crust from vegetation to bedrock, and moisture dynamics deep into the weathered bedrock underlying hillslopes and Earth System Model scientists who develop global models, to ask: Do hillslope‐scale processes matter to predicting global change? The answers will help scientists understand where and why hillslopes matter, and to better predict how terrestrial ecosystems, including societies, may affect and be affected by our rapidly changing planet.
Key Points
Lateral flow from ridges to valleys, and contrasts between sunny and shady slopes organize water, energy and vegetation across landscapes
These processes may affect Earth System Model predictions of terrestrial water storage and fluxes, as well as ecosystem resilience to stress
The greatest knowledge gap is the subsurface structure; Critical Zone science can offer new insights into terrestrial water storage/fluxes
•Melanogenesis stimulates expression of HIF-1α and downstream regulators of metabolism.•Melanogenesis affects expression of stress related genes.•Advanced melanomas show increased expression of ...HIF-1α protein.•Advanced melanomas show increased expression of membrane-bound GLUT-1.
To study the effect of melanogenesis on HIF-1α expression and attendant pathways, we used stable human and hamster melanoma cell lines in which the amelanotic vs. melanotic phenotypes are dependent upon the concentration of melanogenesis precursors in the culture media. The induction of melanin pigmentation led to significant up-regulation of HIF-1α, but not HIF-2α, protein in melanized cells for both lines. Similar upregulation of nuclear HIF-1α was observed in excisions of advanced melanotic vs. amelanotic melanomas. In cultured cells, melanogenesis also significantly stimulated expression of classical HIF-1-dependent target genes involved in angiogenesis and cellular metabolism, including glucose metabolism and stimulation of activity of key enzymes in the glycolytic pathway. Several other stress related genes containing putative HRE consensus sites were also upregulated by melanogenesis, concurrently with modulation of expression of HIF-1-independent genes encoding for steroidogenic enzymes, cytokines and growth factors. Immunohistochemical studies using a large panel of pigmented lesions revealed that higher levels of HIF-1α and GLUT-1 were detected in advanced melanomas in comparison to melanocytic nevi or thin melanomas localized to the skin. However, the effects on overall or disease free survival in melanoma patients were modest or absent for GLUT-1 or for HIF-1α, respectively. In conclusion, induction of the melanogenic pathway leads to robust upregulation of HIF-1-dependent and independent pathways in cultured melanoma cells, suggesting a key role for melanogenesis in regulation of cellular metabolism.
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