Mapping carbon accumulation potential from global natural forest regrowth.

To constrain global warming, we must strongly curtail greenhouse gas emissions and capture excess atmospheric carbon dioxide1,2. Regrowing natural forests is a prominent strategy for capturing additional carbon3, but accurate assessments of its potential are limited by uncertainty and variability in carbon accumulation rates2,3. To assess why and where rates differ, here we compile 13,112 georeferenced measurements of carbon accumulation. Climatic factors explain variation in rates better than land-use history, so we combine the field measurements with 66 environmental covariate layers to create a global, one-kilometre-resolution map of potential aboveground carbon accumulation rates for the first 30 years of natural forest regrowth. This map shows over 100-fold variation in rates across the globe, and indicates that default rates from the Intergovernmental Panel on Climate Change (IPCC)4,5 may underestimate aboveground carbon accumulation rates by 32 per cent on average and do not capture eight-fold variation within ecozones. Conversely, we conclude that maximum climate mitigation potential from natural forest regrowth is 11 per cent lower than previously reported3 owing to the use of overly high rates for the location of potential new forest. Although our data compilation includes more studies and sites than previous efforts, our results depend on data availability, which is concentrated in ten countries, and data quality, which varies across studies. However, the plots cover most of the environmental conditions across the areas for which we predicted carbon accumulation rates (except for northern Africa and northeast Asia). We therefore provide a robust and globally consistent tool for assessing natural forest regrowth as a climate mitigation strategy.

Therapeutic inhibition of USP9x-mediated Notch signaling in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a breast cancer subtype that lacks targeted treatment options. The activation of the Notch developmental signaling pathway, which is a feature of TNBC, results in the secretion of proinflammatory cytokines and the recruitment of protumoral macrophages to the tumor microenvironment. While the Notch pathway is an obvious therapeutic target, its activity is ubiquitous, and predictably, anti-Notch therapies are burdened with significant on-target side effects. Previously, we discovered that, under conditions of cellular stress commonly found in the tumor microenvironment, the deubiquitinase USP9x forms a multiprotein complex with the pseudokinase tribbles homolog 3 (TRB3) that together activate the Notch pathway. Herein, we provide preclinical studies that support the potential of therapeutic USP9x inhibition to deactivate Notch. Using a murine TNBC model, we show that USP9x knockdown abrogates Notch activation, reducing the production of the proinflammatory cytokines, C-C motif chemokine ligand 2 (CCL2) and interleukin-1 beta (IL-1ß). Concomitant with these molecular changes, a reduction in tumor inflammation, the augmentation of antitumor immune response, and the suppression of tumor growth were observed. The pharmacological inhibition of USP9x using G9, a partially selective, small-molecule USP9x inhibitor, reduced Notch activity, remodeled the tumor immune landscape, and reduced tumor growth without associated toxicity. Proving the role of Notch, the ectopic expression of the activated Notch1 intracellular domain rescued G9-induced effects. This work supports the potential of USP9x inhibition to target Notch in metabolically vulnerable tissues like TNBC, while sparing normal Notch-dependent tissues.

Novel Use of Cell Profiling Technology to Visualize Mitochondrial Responses of Humpback Whale Fibroblasts to Chemical Exposure.

Cetaceans are at elevated risk of accumulating persistent and lipophilic environmental contaminants due to their longevity and high proportion of body fat. Despite this, there is a paucity of taxa-specific chemical effect data, in part due to the ethical and logistical constraints in working with highly mobile aquatic species. Advances in cetacean cell culture have opened the door to the application of mainstream in vitro toxicological effect assessment approaches. Image-based cell profiling is a high-throughput, microscopy-based system commonly applied in drug development. It permits the analysis of the xenobiotic effect on multiple cell organelles simultaneously, hereby flagging its potential utility in the evaluation of chemical toxicodynamics. Here we exposed immortalized humpback whale skin fibroblasts (HuWaTERT) to six priority environmental contaminants known to accumulate in the Southern Ocean food web, in order to explore their subcellular organelle responses. Results revealed chemical-dependent modulation of mitochondrial texture, with the lowest observed effect concentrations for chlorpyrifos, dieldrin, trifluralin, and p,p'-dichlorodiphenyldichloroethane of 0.3, 4.1, 9.3, and 19.8 nM, respectively. By contrast, no significant changes were observed upon exposure to endosulfan and lindane. This study contributes the first fixed mitochondrial images of HuWaTERT and constitutes novel, taxa-specific chemical effect data in support of evidence-based conservation policy and management.

Abnormal Behavior and Cortical Connectivity Deficits in Mice Lacking Usp9x.

Genetic association studies have identified many factors associated with neurodevelopmental disorders such as autism spectrum disorder (ASD). However, the way these genes shape neuroanatomical structure and connectivity is poorly understood. Recent research has focused on proteins that act as points of convergence for multiple factors, as these may provide greater insight into understanding the biology of neurodevelopmental disorders. USP9X, a deubiquitylating enzyme that regulates the stability of many ASD-related proteins, is one such point of convergence. Loss of function variants in human USP9X lead to brain malformations, which manifest as a neurodevelopmental syndrome that frequently includes ASD, but the underlying structural and connectomic abnormalities giving rise to patient symptoms is unknown. Here, we analyzed forebrain-specific Usp9x knockout mice (Usp9x-/y) to address this knowledge gap. Usp9x-/y mice displayed abnormal communication and social interaction behaviors. Moreover, the absence of Usp9x culminated in reductions to the size of multiple brain regions. Diffusion tensor magnetic resonance imaging revealed deficits in all three major forebrain commissures, as well as long-range hypoconnectivity between cortical and subcortical regions. These data identify USP9X as a key regulator of brain formation and function, and provide insights into the neurodevelopmental syndrome arising as a consequence of USP9X mutations in patients.

Conceptual Links between Landscape Diversity and Diet Diversity: A Roadmap for Transdisciplinary Research.

Malnutrition linked to poor quality diets affects at least 2 billion people. Forests, as well as agricultural systems linked to trees, are key sources of dietary diversity in rural settings. In the present article, we develop conceptual links between diet diversity and forested landscape mosaics within the rural tropics. First, we summarize the state of knowledge regarding diets obtained from forests, trees, and agroforests. We then hypothesize how disturbed secondary forests, edge habitats, forest access, and landscape diversity can function in bolstering dietary diversity. Taken together, these ideas help us build a framework illuminating four pathways (direct, agroecological, energy, and market pathways) connecting forested landscapes to diet diversity. Finally, we offer recommendations to fill remaining knowledge gaps related to diet and forest cover monitoring. We argue that better evaluation of the role of land cover complexity will help avoid overly simplistic views of food security and, instead, uncover nutritional synergies with forest conservation and restoration.

Direct evidence using a controlled greenhouse study for threshold effects of soil organic matter on crop growth.

Soil organic matter (SOM) is a key indicator of soil fertility, and building SOM is assumed to decrease reliance on external inputs and ensure stable crop production. Recent syntheses of field data support this assumption with positive SOM-productivity relationships that asymptote at ~4% SOM. Teasing out the directionality of this relationship-the extent to which SOM increases crop growth vs. greater growth leading to higher SOM concentrations-requires controlled experimentation. To disentangle this causative pathway, we conducted a greenhouse experiment whereby we manipulated SOM concentrations from 1% to 9% and evaluated whether the SOM-productivity relationship differed for spring wheat (Triticum aestivum, L.) under nitrogen fertilization crossed with irrigation due to the expectation that SOM buffers the effects of reduced fertilization and/or irrigation. We found that higher concentrations of SOM led to greater productivity (measured as aboveground biomass) up to a threshold of 5% SOM, after which productivity declined across all treatments. These declines occurred despite the fact that indicators of soil health (water-holding capacity, microbial biomass, and bulk density) improved linearly with increasing SOM concentrations. That is, improvements in soil properties did not translate to gains in productivity at the highest SOM levels. Nitrogen fertilization led to greater productivity across all treatments, but to a greater relative extent at lower SOM levels, where we found that productivity on unfertilized soils with 4% SOM matched that of fertilized soils with 2% SOM. Differences in productivity on unfertilized soils due to irrigation emerged at higher SOM levels (>5%), highlighting SOM's role in water retention. Our results demonstrate that building SOM leads to improved growth of a globally important crop; however, our results also indicated a pronounced SOM threshold, after which crop growth declined. This underscores the need to develop optimal SOM targets for desired agricultural and environmental outcomes.

Chemical constituents from Macleaya cordata (Willd) R. Br. and their phenotypic functions against a Parkinson's disease patient-derived cell line.

Cytological profiling (CP) assay against a human olfactory neuroshpere-derived (hONS) cell line using a library of traditional Chinese medicinal plant extracts gave indications that the ethanolic extract of Macleaya cordata (Willd) R. Br. elicited strong perturbations to various cellular components. Further chemical investigation of this extract resulted in the isolation of two new benzo[c]phenanthridine alkaloids, (6R)-10-methoxybocconoline (1) and 6-(1-hydroxyethyl)-10-methoxy-5,6-dihydrochelerythrine (2). Their planar structures were elucidated by extensive 1D and 2D NMR studies, together with MS data. The absolute configuration for position C-6 of 1 and relative configurations for position C-6 and C-1' of 2 were assigned by density functional theory (DFT) calculations of ECD and NMR data, respectively. Also isolated were fourteen known metabolites, including ten alkaloids (3-12) and four coumaroyl-containing compounds (13-16). Cytological profiling of the isolates against Parkinson's Disease (PD) patient-derived olfactory cells revealed bocconoline (3) and 6-(1-hydroxyethyl)-5,6-dihydrochelerythrine (4) significantly perturbated the features of cellular organelles including early endosomes, mitochondria and autophagosomes. Given that hONS cells from PD patients model some functional aspects of the disease, the results suggested that these phenotypic profiles may have a role in the mechanisms underlying PD and signified the efficacy of CP in finding potential chemical tools to study the biological pathways in PD.

A Grand Challenge. 3. Unbiased Phenotypic Function of Metabolites from Australia Plants Gloriosa superba and Alangium villosum against Parkinson's Disease.

As part of a continuing research program aiming to identify chemical probes to interrogate Parkinson's disease (PD), we have investigated the Australian plants Gloriosa superba and Alangium villosum. The chemical investigations of G. superba resulted in the isolation of four new alkaloids, ß-lumicolchicosides A-C (1-3) and γ-lumicolchicoside A (4), together with four lumicolchicine derivatives (5-8) and six colchicine analogues (9-14) as known structures. The chemical investigations of A. villosum resulted in the isolation of four new benzoquinolizidine N-oxides, tubulosine Nß5-oxide (15), isotubulosine Nα5-oxide (16), 9-demethyltubulosine Nß5-oxide (17), and 9-demethylisotubulosine Nα5-oxide (18), together with five known benzoquinolizidine alkaloids (19-23). The chemical structures of the new compounds (1-4 and 15-18) were characterized unambiguously by extensive analysis of their NMR and MS data. Unbiased multidimensional profiling was used to investigate the phenotypic profiles of all of the metabolites. The results show that the lead probes have different effects on cellular organelles that are implicated in PD in patient-derived cells.

Investigating the role of CRIPTO-1 (TDGF-1) in glioblastoma multiforme U87 cell line.

Cripto-1 has been implicated in a number of human cancers. Although there is high potential for a role of Cripto-1 in glioblastoma multiforme (GBM) pathogenesis and progression, few studies have tried to define its role in GBM. These studies were limited in that Cripto-1 expression was not studied in detail in relation to markers of cancer initiation and progression. Therefore, these correlative studies allowed limited interpretation of Criptos-1's effect on the various aspects of GBM development using the U87 GBM cell line. In this study, we sought to delineate the role of Cripto-1 in facilitating pathogenesis, stemness, proliferation, invasion, migration and angiogenesis in GBM. Our findings show that upon overexpressing Cripto-1 in U87 GBM cells, the stemness markers Nanog, Oct4, Sox2, and CD44 increased expression. Similarly, an increase in Ki67 was observed demonstrating Cripto-1's potential to induce cellular proliferation. Likewise, we report a novel finding that increased expression of the markers of migration and invasion, Vimentin and Twist, correlated with upregulation of Cripto-1. Moreover, Cripto-1 exposure led to VEGFR-2 overexpression along with higher tube formation under conditions promoting endothelial growth. Taken together our results support a role for Cripto-1 in the initiation, development, progression, and maintenance of GBM pathogenesis. The data presented here are also consistent with a role for Cripto-1 in the re-growth and invasive growth in GBM. This highlights its potential use as a predictive and diagnostic marker in GBM as well as a therapeutic target.

De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations.

Mutations in more than a hundred genes have been reported to cause X-linked recessive intellectual disability (ID) mainly in males. In contrast, the number of identified X-linked genes in which de novo mutations specifically cause ID in females is limited. Here, we report 17 females with de novo loss-of-function mutations in USP9X, encoding a highly conserved deubiquitinating enzyme. The females in our study have a specific phenotype that includes ID/developmental delay (DD), characteristic facial features, short stature, and distinct congenital malformations comprising choanal atresia, anal abnormalities, post-axial polydactyly, heart defects, hypomastia, cleft palate/bifid uvula, progressive scoliosis, and structural brain abnormalities. Four females from our cohort were identified by targeted genetic testing because their phenotype was suggestive for USP9X mutations. In several females, pigment changes along Blaschko lines and body asymmetry were observed, which is probably related to differential (escape from) X-inactivation between tissues. Expression studies on both mRNA and protein level in affected-female-derived fibroblasts showed significant reduction of USP9X level, confirming the loss-of-function effect of the identified mutations. Given that some features of affected females are also reported in known ciliopathy syndromes, we examined the role of USP9X in the primary cilium and found that endogenous USP9X localizes along the length of the ciliary axoneme, indicating that its loss of function could indeed disrupt cilium-regulated processes. Absence of dysregulated ciliary parameters in affected female-derived fibroblasts, however, points toward spatiotemporal specificity of ciliary USP9X (dys-)function.

Grb2-Mediated Recruitment of USP9X to LAT Enhances Themis Stability following Thymic Selection.

Themis is a new component of the TCR signaling machinery that plays a critical role during T cell development. The positive selection of immature CD4+CD8+ double-positive thymocytes and their commitment to the CD4+CD8- single-positive stage are impaired in Themis-/- mice, suggesting that Themis might be important to sustain TCR signals during these key developmental processes. However, the analysis of Themis mRNA levels revealed that Themis gene expression is rapidly extinguished during positive selection. We show in this article that Themis protein expression is increased in double-positive thymocytes undergoing positive selection and is sustained in immature single-positive thymocytes, despite the strong decrease in Themis mRNA levels in these subsets. We found that Themis stability is controlled by the ubiquitin-specific protease USP9X, which removes ubiquitin K48-linked chains on Themis following TCR engagement. Biochemical analyses indicate that USP9X binds directly to the N-terminal CABIT domain of Themis and indirectly to the adaptor protein Grb2, with the latter interaction enabling recruitment of Themis/USP9X complexes to LAT, thereby sustaining Themis expression following positive selection. Together, these data suggest that TCR-mediated signals enhance Themis stability upon T cell development and identify USP9X as a key regulator of Themis protein turnover.

The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) remains a lethal malignancy despite much progress concerning its molecular characterization. PDA tumours harbour four signature somatic mutations in addition to numerous lower frequency genetic events of uncertain significance. Here we use Sleeping Beauty (SB) transposon-mediated insertional mutagenesis in a mouse model of pancreatic ductal preneoplasia to identify genes that cooperate with oncogenic Kras(G12D) to accelerate tumorigenesis and promote progression. Our screen revealed new candidate genes for PDA and confirmed the importance of many genes and pathways previously implicated in human PDA. The most commonly mutated gene was the X-linked deubiquitinase Usp9x, which was inactivated in over 50% of the tumours. Although previous work had attributed a pro-survival role to USP9X in human neoplasia, we found instead that loss of Usp9x enhances transformation and protects pancreatic cancer cells from anoikis. Clinically, low USP9X protein and messenger RNA expression in PDA correlates with poor survival after surgery, and USP9X levels are inversely associated with metastatic burden in advanced disease. Furthermore, chromatin modulation with trichostatin A or 5-aza-2'-deoxycytidine elevates USP9X expression in human PDA cell lines, indicating a clinical approach for certain patients. The conditional deletion of Usp9x cooperated with Kras(G12D) to accelerate pancreatic tumorigenesis in mice, validating their genetic interaction. We propose that USP9X is a major tumour suppressor gene with prognostic and therapeutic relevance in PDA.

Seizures are regulated by ubiquitin-specific peptidase 9 X-linked (USP9X), a de-ubiquitinase.

Epilepsy is a common disabling disease with complex, multifactorial genetic and environmental etiology. The small fraction of epilepsies subject to Mendelian inheritance offers key insight into epilepsy disease mechanisms; and pathologies brought on by mutations in a single gene can point the way to generalizable therapeutic strategies. Mutations in the PRICKLE genes can cause seizures in humans, zebrafish, mice, and flies, suggesting the seizure-suppression pathway is evolutionarily conserved. This pathway has never been targeted for novel anti-seizure treatments. Here, the mammalian PRICKLE-interactome was defined, identifying prickle-interacting proteins that localize to synapses and a novel interacting partner, USP9X, a substrate-specific de-ubiquitinase. PRICKLE and USP9X interact through their carboxy-termini; and USP9X de-ubiquitinates PRICKLE, protecting it from proteasomal degradation. In forebrain neurons of mice, USP9X deficiency reduced levels of Prickle2 protein. Genetic analysis suggests the same pathway regulates Prickle-mediated seizures. The seizure phenotype was suppressed in prickle mutant flies by the small-molecule USP9X inhibitor, Degrasyn/WP1130, or by reducing the dose of fat facets a USP9X orthologue. USP9X mutations were identified by resequencing a cohort of patients with epileptic encephalopathy, one patient harbored a de novo missense mutation and another a novel coding mutation. Both USP9X variants were outside the PRICKLE-interacting domain. These findings demonstrate that USP9X inhibition can suppress prickle-mediated seizure activity, and that USP9X variants may predispose to seizures. These studies point to a new target for anti-seizure therapy and illustrate the translational power of studying diseases in species across the evolutionary spectrum.

Historical foundations and future directions in macrosystems ecology.

Macrosystems ecology is an effort to understand ecological processes and interactions at the broadest spatial scales and has potential to help solve globally important social and ecological challenges. It is important to understand the intellectual legacies underpinning macrosystems ecology: How the subdiscipline fits within, builds upon, differs from and extends previous theories. We trace the rise of macrosystems ecology with respect to preceding theories and present a new hypothesis that integrates the multiple components of macrosystems theory. The spatio-temporal anthropogenic rescaling (STAR) hypothesis suggests that human activities are altering the scales of ecological processes, resulting in interactions at novel space-time scale combinations that are diverse and predictable. We articulate four predictions about how human actions are "expanding", "shrinking", "speeding up" and "slowing down" ecological processes and interactions, and thereby generating new scaling relationships for ecological patterns and processes. We provide examples of these rescaling processes and describe ecological consequences across terrestrial, freshwater and marine ecosystems. Rescaling depends in part on characteristics including connectivity, stability and heterogeneity. Our STAR hypothesis challenges traditional assumptions about how the spatial and temporal scales of processes and interactions operate in different types of ecosystems and provides a lens through which to understand macrosystem-scale environmental change.

Mutations in USP9X are associated with X-linked intellectual disability and disrupt neuronal cell migration and growth.

With a wealth of disease-associated DNA variants being recently reported, the challenges of providing their functional characterization are mounting. Previously, as part of a large systematic resequencing of the X chromosome in 208 unrelated families with nonsyndromic X-linked intellectual disability, we identified three unique variants (two missense and one protein truncating) in USP9X. To assess the functional significance of these variants, we took advantage of the Usp9x knockout mouse we generated. Loss of Usp9x causes reduction in both axonal growth and neuronal cell migration. Although overexpression of wild-type human USP9X rescued these defects, all three USP9X variants failed to rescue axonal growth, caused reduced USP9X protein localization in axonal growth cones, and (in 2/3 variants) failed to rescue neuronal cell migration. Interestingly, in one of these families, the proband was subsequently identified to have a microdeletion encompassing ARID1B, a known ID gene. Given our findings it is plausible that loss of function of both genes contributes to the individual's phenotype. This case highlights the complexity of the interpretations of genetic findings from genome-wide investigations. We also performed proteomics analysis of neurons from both the wild-type and Usp9x knockout embryos and identified disruption of the cytoskeleton as the main underlying consequence of the loss of Usp9x. Detailed clinical assessment of all three families with USP9X variants identified hypotonia and behavioral and morphological defects as common features in addition to ID. Together our data support involvement of all three USP9X variants in ID in these families and provide likely cellular and molecular mechanisms involved.

Spermatogonial deubiquitinase USP9X is essential for proper spermatogenesis in mice.

USP9X (ubiquitin-specific peptidase 9, X chromosome) is the mammalian orthologue of Drosophila deubiquitinase fat facets that was previously shown to regulate the maintenance of the germ cell lineage partially through stabilizing Vasa, one of the widely conserved factors crucial for gametogenesis. Here, we demonstrate that USP9X is expressed in the gonocytes and spermatogonia in mouse testes from newborn to adult stages. By using Vasa-Cre mice, germ cell-specific conditional deletion of Usp9x from the embryonic stage showed no abnormality in the developing testes by 1 week and no appreciable defects in the undifferentiated and differentiating spermatogonia at postnatal and adult stages. Interestingly, after 2 weeks, Usp9x-null spermatogenic cells underwent apoptotic cell death at the early spermatocyte stage, and then, caused subsequent aberrant spermiogenesis, which resulted in a complete infertility of Usp9x conditional knockout male mice. These data provide the first evidence of the crucial role of the spermatogonial USP9X during transition from the mitotic to meiotic phases and/or maintenance of early meiotic phase in Usp9x conditional knockout testes.

Discontinuity in the responses of ecosystem processes and multifunctionality to altered soil community composition.

Ecosystem management policies increasingly emphasize provision of multiple, as opposed to single, ecosystem services. Management for such "multifunctionality" has stimulated research into the role that biodiversity plays in providing desired rates of multiple ecosystem processes. Positive effects of biodiversity on indices of multifunctionality are consistently found, primarily because species that are redundant for one ecosystem process under a given set of environmental conditions play a distinct role under different conditions or in the provision of another ecosystem process. Here we show that the positive effects of diversity (specifically community composition) on multifunctionality indices can also arise from a statistical fallacy analogous to Simpson's paradox (where aggregating data obscures causal relationships). We manipulated soil faunal community composition in combination with nitrogen fertilization of model grassland ecosystems and repeatedly measured five ecosystem processes related to plant productivity, carbon storage, and nutrient turnover. We calculated three common multifunctionality indices based on these processes and found that the functional complexity of the soil communities had a consistent positive effect on the indices. However, only two of the five ecosystem processes also responded positively to increasing complexity, whereas the other three responded neutrally or negatively. Furthermore, none of the individual processes responded to both the complexity and the nitrogen manipulations in a manner consistent with the indices. Our data show that multifunctionality indices can obscure relationships that exist between communities and key ecosystem processes, leading us to question their use in advancing theoretical understanding--and in management decisions--about how biodiversity is related to the provision of multiple ecosystem services.

The Vps35 D620N mutation linked to Parkinson's disease disrupts the cargo sorting function of retromer.

The retromer is a trimeric cargo-recognition protein complex composed of Vps26, Vps29 and Vps35 associated with protein trafficking within endosomes. Recently, a pathogenic point mutation within the Vps35 subunit (D620N) was linked to the manifestation of Parkinson's disease (PD). Here, we investigated details underlying the molecular mechanism by which the D620N mutation in Vps35 modulates retromer function, including examination of retromer's subcellular localization and its capacity to sort cargo. We show that expression of the PD-linked Vps35 D620N mutant redistributes retromer-positive endosomes to a perinuclear subcellular localization and that these endosomes are enlarged in both model cell lines and fibroblasts isolated from a PD patient. Vps35 D620N is correctly folded and binds Vps29 and Vps26A with the same affinity as wild-type Vps35. While PD-linked point mutant Vps35 D620N interacts with the cation-independent mannose-6-phosphate receptor (CI-M6PR), a known retromer cargo, we find that its expression disrupts the trafficking of cathepsin D, a CI-M6PR ligand and protease responsible for degradation of α-synuclein, a causative agent of PD. In summary, we find that the expression of Vps35 D620N leads to endosomal alterations and trafficking defects that may partly explain its action in PD.

Nrf2: a modulator of Parkinson's disease?

Parkinson's disease (PD) is a complex multifactorial disorder that has been associated with the processes of oxidative stress. In the absence of curative therapies, modification of the neurodegenerative process-including the manipulation of endogenous antioxidant pathways-is the focus of intensive research. Recently, genetic and pharmacological accretion of the transcription factor, and phase II antioxidant 'master regulator' Nrf2, has shown to demonstrably mitigate the toxic neuronal effects of parkinsonian agents such as MPP(+), rotenone, and hydrogen peroxide in vitro and in vivo. Furthermore, baseline genetic variability in Nrf2-dependant pathways may promote neuronal susceptibility to exogenous agents and correlate with PD onset within certain populations. While contemporary evidence directly implicating Nrf2 in the pathogenesis of PD is not conclusive and likely contingent upon the evaluation of complex interacting factors-including genetic variation and a history of environmental exposures-it remains a promising target for therapeutic benefit in the modulation of oxidative stress.

Opposing effects of different soil organic matter fractions on crop yields.

Soil organic matter is critical to sustainable agriculture because it provides nutrients to crops as it decomposes and increases nutrient- and water-holding capacity when built up. Fast- and slow-cycling fractions of soil organic matter can have different impacts on crop production because fast-cycling fractions rapidly release nutrients for short-term plant growth and slow-cycling fractions bind nutrients that mineralize slowly and build up water-holding capacity. We explored the controls on these fractions in a tropical agroecosystem and their relationship to crop yields. We performed physical fractionation of soil organic matter from 48 farms and plots in western Kenya. We found that fast-cycling, particulate organic matter was positively related to crop yields, but did not have a strong effect, while slower-cycling, mineral-associated organic matter was negatively related to yields. Our finding that slower-cycling organic matter was negatively related to yield points to a need to revise the view that stabilization of organic matter positively impacts food security. Our results support a new paradigm that different soil organic matter fractions are controlled by different mechanisms, potentially leading to different relationships with management outcomes, like crop yield. Effectively managing soils for sustainable agriculture requires quantifying the effects of specific organic matter fractions on these outcomes.