Search

Background: Cardiac fibrosis contributes to end-stage extracellular matrix remodeling and heart failure (HF). Cardiac fibroblasts (CFs) differentiate into myofibroblasts (myoFbs) to preserve the structural integrity of the heart; however, the molecular mechanisms regulating CF transdifferentiation remain poorly understood. Protein arginine deiminase (PAD), which converts arginine to citrulline, has been shown to play a role in myocardial infarction, fibrosis, and HF. This study aimed to investigate the role of PAD in CF differentiation to myoFbs and identify the citrullinated proteins that were associated with phenotypic changes in CFs. Results: Gene expression analysis showed that PAD1 and PAD2 isoforms, but not PAD4 isoforms, were abundant in both CFs and myoFbs, and PAD1 was significantly upregulated in myoFbs. The pan-PAD inhibitor BB-Cl-amidine (BB-Cl) downregulated the mRNA expression of PAD1 and PAD2 as well as the protein expression of the fibrosis marker COL1A1 in CFs and myoFbs. Interestingly, a proteomic approach pointed to the activation of the Nrf2/HO-1 signaling pathway upon BB-Cl treatment in CFs and myoFbs. BB-Cl administration resulted in the upregulation of HO-1 at both the gene and protein levels in CFs and myoFbs. Importantly, the protein citrullination landscape of CFs consisting of 86 novel citrullination sites associated with focal adhesion (FN1(R1054)), inflammation (TAGLN(R12)) and DNA replication (EEF2(R767)) pathways was identified. Conclusions: In summary, we revealed that BB-Cl treatment resulted in increased HO-1 expression via the Nrf2 pathway, which could prevent excessive tissue damage, thereby leading to substantial clinical benefits for the treatment of cardiac fibrosis.

A C-N cross-coupling approach involving oxidative amidations of aromatic aldehydes in the presence of an amide-based nickel(II) pincer catalyst (2) is demonstrated. Upon optimization, quick reaction times (15 min) and an ideal temperature (25 °C) were established and implemented for the conversion of 33 different amide products using only 0.2 mol% of catalyst. Moderate to good turnover numbers (TONs) were obtained for secondary benzamide products, and moderate TONs were obtained for tertiary benzamide products, with the highest turnover number calculated for the 4-chloro-N-(3-phenylpropyl)benzamide product (4i, 309). Gas chromatographic–mass spectrometric (GC–MS) analysis also indicates the formation of alcohols in different reactions, indicating an oxidative amidation process. Kinetic studies were performed by varying the amount of catalyst, aldehyde, LiHMDS base, and amine substrate to determine the order of reaction for each component. Benzaldehyde and benzaldehyde-d6 were reacted with benzylamine, and the kH/kD ratio was determined to understand the rate-determining step. Isotope labeling further revealed that deuterium was being transferred to both the alcohol side product and the target amide product. With the help of kinetic data and UV–visible spectra, a mechanism for the amidation process via the catalyst (2) is proposed through a Ni(I)–Ni(III) pathway.

Abstract Background Pronounced sex differences in the susceptibility and response to SARS-CoV-2 infection remain poorly understood. Emerging evidence has highlighted the potential importance of autoimmune activation in modulating the acute response and recovery trajectories following SARS-CoV-2 exposure. Given that immune-inflammatory activity can be sex-biased in the setting of severe COVID-19 illness, the aim of the study was to examine sex-specific autoimmune reactivity to SARS-CoV-2 in the absence of extreme clinical disease. Methods In this study, we assessed autoantibody (AAB) reactivity to 91 autoantigens previously linked to a range of classic autoimmune diseases in a cohort of 177 participants (65% women, 35% men, mean age of 35) with confirmed evidence of prior SARS-CoV-2 infection based on presence of antibody to the nucleocapsid protein of SARS-CoV-2. Data were compared to 53 pre-pandemic healthy controls (49% women, 51% men). For each participant, socio-demographic data, serological analyses, SARS-CoV-2 infection status and COVID-19 related symptoms were collected by an electronic survey of questions. The symptoms burden score was constructed based on the total number of reported symptoms (N = 21) experienced within 6 months prior to the blood draw, wherein a greater number of symptoms corresponded to a higher score and assigned as more severe burden. Results In multivariable analyses, we observed sex-specific patterns of autoreactivity associated with the presence or absence (as well as timing and clustering of symptoms) associated with prior COVID-19 illness. Whereas the overall AAB response was more prominent in women following asymptomatic infection, the breadth and extent of AAB reactivity was more prominent in men following at least mildly symptomatic infection. Notably, the observed reactivity included distinct antigens with molecular homology with SARS-CoV-2. Conclusion Our results reveal that prior SARS-CoV-2 infection, even in the absence of severe clinical disease, can lead to a broad AAB response that exhibits sex-specific patterns of prevalence and antigen selectivity. Further understanding of the nature of triggered AAB activation among men and women exposed to SARS-CoV-2 will be essential for developing effective interventions against immune-mediated sequelae of COVID-19.

Serine proteases play varied and manifold roles in important biological, physiological, and pathological processes. These include viral, bacterial, and parasitic infection, allergic sensitization, tumor invasion, and metastasis. The use of activity-based profiling has been foundational in pinpointing the precise roles of serine proteases across this myriad of processes. A broad range of serine protease-targeted activity-based probe (ABP) chemotypes have been developed and we have recently introduced biotinylated and “clickable” peptides containing P1 N-alkyl glycine arginine N-hydroxy succinimidyl (NHS) carbamates as ABPs for detection/profiling of trypsin-like serine proteases. This present study provides synthetic details for the preparation of additional examples of this ABP chemotype, which function as potent irreversible inhibitors of their respective target serine protease. We describe their use for the activity-based profiling of a broad range of serine proteases including trypsin, the trypsin-like protease plasmin, chymotrypsin, cathepsin G, and neutrophil elastase (NE), including the profiling of the latter protease in clinical samples obtained from patients with cystic fibrosis.

The factors that are associated with myeloma precursor condition progression are not well understood. Here the authors find that monoclonal gammopathies of undetermined significance and smoldering myelomas that did not progress to multiple myelomas have a distinct genomic profile and emerge later in the patient’s life.

The trypsin-like proteases (TLPs) play widespread and diverse roles, in a host of physiological and pathological processes including clot dissolution, extracellular matrix remodelling, infection, angiogenesis, wound healing and tumour invasion/metastasis. Moreover, these enzymes are involved in the disruption of normal lung function in a range of respiratory diseases including allergic asthma where several allergenic proteases have been identified. Here, we report the synthesis of a series of peptide derivatives containing an N-alkyl glycine analogue of arginine, bearing differing electrophilic leaving groups (carbamate and triazole urea), and demonstrate their function as potent, irreversible inhibitors of trypsin and TLPs, to include activities from cockroach extract. As such, these inhibitors are suitable for use as activity probes (APs) in activity-based profiling (ABP) applications.

In the last two decades, proteases have become a primary and vital target in drug discovery [...]

Cell culture systems have greatly expanded our understanding of how bacterial pathogens target signaling pathways to manipulate the host and cause infection. Advances in genetic engineering have allowed for the creation of fluorescent protein readouts within signaling pathways, but these techniques have been underutilized in pathogen biology. Here, we genetically engineered a lung cell line with fluorescent reporters for extracellular signal-related kinase (ERK) and the downstream transcription factor FOS-related antigen 1 (Fra1) and evaluated signaling after inoculation with pathogenic and non-pathogenic bacteria. Cells were inoculated with 100 colony-forming units of Acinetobacter baylyi, Klebsiella pneumoniae, Pseudomonas aeruginosa, Streptococcus agalactiae, or Staphylococcus epidermidis and imaged in a multi-mode reader. The alamarBlue cell viability assay was used as a reference test and showed that pathogenic P. aeruginosa induced significant (p < 0.05) cell death after 8 h in both wild-type and engineered cell lines compared to non-pathogenic S. epidermidis. In engineered cells, we found that Fra1 signaling was disrupted in as little as 4 h after inoculation with bacterial pathogens compared to delayed disruption in signaling by non-pathogenic S. epidermidis. Overall, we demonstrate that low levels of pathogenic versus non-pathogenic bacteria can be rapidly and sensitively screened based on ERK-Fra1 signaling.

Connectivity between coral reefs is critical to ensure their resilience and persistence against disturbances. It is driven by ocean currents, which often have very complex patterns within reef systems. Only biophysical models that simulate both the fine-scale details of ocean currents and the life-history traits of larvae transported by these currents can help to estimate connectivity in large reef systems. Here we use the unstructured-mesh coastal ocean model SLIM that locally achieves a spatial resolution of ~100 m, 10 times finer than existing models, over the entire Florida Reef Tract (FRT). It allows us to simulate larval dispersal between the ~1,000 reefs composing the FRT. By using different connectivity measures and clustering methods, we have identified two major connectivity pathways, one originating on the westernmost end of the outer shelf and the other originating on the inner shelf, North of the Lower Keys. We introduce new connectivity indicators, based on the PageRank algorithm, to show that protection efforts should be focused on the most upstream reefs of each pathway, while reefs best suited for restoration are more evenly spread between the Lower and Upper Keys. We identify one particular reef, North of Vaca Key, that is a major stepping stone in the connectivity network. Our results are the first reef-scale connectivity estimates for the entire FRT. Such fine-scale information can provide knowledge-based decision support to allocate conservation and restoration resources optimally.

BackgroundVancomycin is a commonly used antibiotic with potent activity against Gram-positive organisms, but prolonged use and high doses can lead to toxicity. While vancomycin-associated nephrotoxicity is widely reported, few cases of ototoxicity have been described. The objective of this study was to determine the prevalence of negative changes in audiograms in patients receiving long-term intravenous (IV) vancomycin and to identify high-risk patients who need audiogram monitoring.MethodsThis was an IRB approved, cross-sectional study performed at an academic medical center from 1/2012-3/2019. Patients who were prescribed IV vancomycin for ≥ 14 days and had baseline and follow-up weekly audiometry were included. All data was extracted from the electronic medical record. The primary endpoint was worsening audiogram while on vancomycin. Descriptive and bivariate statistics were used to describe the patient population.Results424 patients were screened for inclusion; 92 received at least two audiograms while on vancomycin. Fifty-three percent of patients were men, the median (IQR) patient age was 44 (34-58) years, and 8% of patients had an estimated Cockcroft-Gault creatinine clearance ≤ 30 mL/min or received hemodialysis. The median (IQR) vancomycin exposure up until the last recorded audiogram was 30 (17-42) days. Vancomycin indications were: 53 (58%) bone and joint infections, 17 (18%) infective endocarditis, 10 (11%) bacteremia, 12 (13%) other infections. Seven (8%) patients experienced a worsening change in hearing from baseline, two (2%) of them suffered mild loss, two (2%) had mild to moderate loss, and three (3%) developed moderate-to-severe hearing loss. In bivariate analyses, no variables were found to be associated with a worsening change in audiogram, including baseline abnormal audiogram, age ≥ 40 years, elevated serum vancomycin levels, or vancomycin doses ≥ 4 grams/day.ConclusionsThe prevalence of negative changes in audiograms among patients receiving long-term intravenous vancomycin was low. The utility of routine audiogram testing in this population remains questionable except in high-risk patients; however, larger prospective studies with controls may be warranted to further explore the risk of ototoxicity.

There are many calls to use the COVID 19 crisis as an opportunity for transforming to a future trajectory that is more equitable and environmentally sustainable. What is lacking is a cohesive framework for bringing these calls together. We propose that such transitions could be informed by lessons from three decades of scholarship on abrupt and surprising change in systems of humans and nature. Over time, many social-ecological systems exhibit cycles of change consisting of sequential patterns of growth, development, crisis, and reorganization. A critical phase in the cycle is the brief period after crisis when novelty and innovation can change the future trajectory. Without being prepared for this window of opportunity, deep, systemic change may be unachievable. We propose a three-step process to identify the major drivers of the global system that need to be changed: (1) identifying what society values; (2) identifying the determinants of these valued variables; and (3) identifying the underlying drivers of the determinants and how they need to be changed. A tentative list of five such drivers are identified and discussed: (i) the economic system, (ii) homogenization, (iii) human population growth, size, and densities, (iv) consumption patterns, human ethics, and behavior, and (v) governance. They are linked to seven questions relating to how we might proceed in addressing the drivers. If response to the crisis merely reinforces the existing system, its incompatibility with the natural world and its propensity to increase inequity and conflict will likely increase fragility and lead to another version of the present calamity. If it is a deliberately transformed system that emerges its future will depend on the reorganization process, and the way the system is guided into the future. What is needed is a deliberate, fundamental cultivation of emergence to enable transformation toward better futures in order to avoid an inevitable deepening of a system that ultimately is worse for all.

Fluorine-18 fluorodeoxyglucose positron emission tomography with computed tomography attenuation correction (PET-CT) in myeloma can detect and enumerate focal lesions by the quantitative characterization of metabolic activity. The aim of this study was to determine the prognostic significance of the suppression of PET-CT activity at a number of time points post therapy initiation: day 7, post induction, post transplant, and at maintenance therapy. As part of the TT4-6 trial series, 596 patients underwent baseline PET-CT and were evaluated serially during their disease course using peak standardized uptake values above background red marrow signal. We demonstrate that the presence of more than 3 focal lesions at presentation identifies a group of patients with an adverse progression-free survival and overall survival. At day 7 of therapy, patients with complete focal lesion signal suppression revert to the same prognosis as those with no lesions at diagnosis. At later time points, the continued suppression of signal remains prognostically important. We conclude that for newly diagnosed patients with focal lesions, treatment until these lesions are suppressed is an important therapeutic goal as the prognosis of these patients is the same as those without lesions at diagnosis. (clinicaltrials.gov identifiers: 00734877, 02128230, 00869232, 00871013).

Glucocorticoids are potent inhibitors of angiogenesis in the rodent in vivo and in vitro but the mechanism by which this occurs has not been determined. Administration of glucocorticoids is used to treat a number of conditions in horses but the angiogenic response of equine vessels to glucocorticoids and, therefore, the potential role of glucocorticoids in pathogenesis and treatment of equine disease, is unknown. This study addressed the hypothesis that glucocorticoids would be angiostatic both in equine and murine blood vessels.The mouse aortic ring model of angiogenesis was adapted to assess the effects of cortisol in equine vessels. Vessel rings were cultured under basal conditions or exposed to: foetal bovine serum (FBS; 3%); cortisol (600 nM), cortisol (600nM) plus FBS (3%), cortisol (600nM) plus either the glucocorticoid receptor antagonist RU486 or the mineralocorticoid receptor antagonist spironolactone. In murine aortae cortisol inhibited and FBS stimulated new vessel growth. In contrast, in equine blood vessels FBS alone had no effect but cortisol alone, or in combination with FBS, dramatically increased new vessel growth compared with controls. This effect was blocked by glucocorticoid receptor antagonism but not by mineralocorticoid antagonism. The transcriptomes of murine and equine angiogenesis demonstrated cortisol-induced down-regulation of inflammatory pathways in both species but up-regulation of pro-angiogenic pathways selectively in the horse. Genes up-regulated in the horse and down-regulated in mice were associated with the extracellular matrix. These data call into question our understanding of glucocorticoids as angiostatic in every species and may be of clinical relevance in the horse.

OBJECTIVES/SPECIFIC AIMS: 1) Determine the mutational landscape, including translocation, mutations and mutational signatures as well as copy number variations of pPCL and identify significant differences to non pPCL MM. 2) Determine whether genetic changes pertinent to pPCL could be explored as therapeutic targets to improve the dismal prognosis of this patient population. METHODS/STUDY POPULATION: Samples from overall 19 pPCL patients that presented to the Myeloma Center, UAMS between 2000-2018 were used for this study. We performed gene expression profiling (GEP; Affymetrix U133 Plus 2.0) of matched circulating peripheral PCs and bone marrow (BM) PCs from 13 patients. Whole exome sequencing (WES) was performed on purified CD138+ PCs from BM aspirates from 19 pPCL patients with a median depth of 61x. CD34+ sorted cells, taken at the time of stem cell harvest from the same 19 patients, were used as controls. Translocations and mutations were called using Manta and Strelka and annotated as previously reported. Copy number was determined by Sequenza. RESULTS/ANTICIPATED RESULTS: 1) GEP from the BM and circulating peripheral PCs showed that the expression patterns of the two samples from each individual clustered together, indicating that circulating PCs and BM PCs in pPCL result from the same clone and are biologically clearly related. 2) The clinical characteristics from the patient cohort used for WES analysis were as follows: median age was 58 years (range 36–77), females accounted for 74% (14/19), an elevated creatinine level was found in 78% (14/18) and an elevated LDH level in 71% (10/14). All patients presented with an ISS stage of III. Median OS of the whole dataset was poor at 22 months, which is consistent with OS from previously reported pPCL cohorts. 3) Primary Immunoglobulin translocations were common and identified in 63% (12/19) of patients, including MAF translocations, which are known to carry high risk in 42% (8/19) of patients [t(14;16), 32% and t(14;20), 10%] followed by t(11;14) (16%) and t(4;14) (10%). Furthermore, 32% (6/19) of patients had at least one MYC translocation, which are known to play a crucial role in disease progression. 4) The mutational burden of pPCL consisted of a median of 98 non-silent mutations per sample, suggesting that the mutational landscape of pPCL is highly complex and harbors more coding mutations than non-pPCL MM. 5) Driver mutations, that previously have been described in non-pPCL MM showed a different prevalence and distribution in pPCL, including KRAS and TP53 with 47% (9/19) and 37% (7/19) affected patients respectively compared to 21% and 5% in non-PCL MM. PIK3CA (5%), PRDM1 (10%), EP300 (10%) and NF1 (10%) were also enriched in the pPCL group compared to previously reported cases in non-pPCL MM. 6) Biallelic inactivation of TP53 – a feature of Double Hit myeloma - was found in 6/19 (32%) samples, indicating a predominance of high risk genomic features compared to non-pPCL MM. Furthermore, analysis of mutational signatures in pPCL showed that aberrant APOBEC activity was highly prevalent only in patients with a MAF translocation, but not in other translocation groups. DISCUSSION/SIGNIFICANCE OF IMPACT: In conclusion we present one of the first WES datasets on pPCL with the largest patient cohort reported to date and show that pPCL is a highly complex disease. The aggressive disease behavior can, at least in part, be explained by a high prevalence of MAF and MYC translocations, TP53 and KRAS mutations as well as bi-allelic inactivation of TP53. It is of interest that only KRAS but not NRAS mutations are highly enriched in pPCL. From all highly prevalent genomic alterations in pPCL, only KRAS mutations offer a potential for already available therapeutically targeting with MEK inhibitors, which should be further explored.

A difficulty in measuring sustainable development is integrating measures of its key components (environment, economic, and social) in a way that allows comparison and assessment of tradeoffs and communication of results. This article presents a trial implementation of a sustainability measure called Inclusive Wealth. We do this by constructing an experimental model to estimate sustainable development through the measurement of capital stocks (built, human, natural, and resilience) in the Goulburn-Broken Catchment in Australia. By trialing the model over the period 1991–2001, we address practical issues associated with identifying capital stocks, estimating shadow prices, addressing risk, assessing intragenerational equity, and dealing with price changes. Results are presented as the basis for discussing hurdles to the implementation of regional sustainability measures and for highlighting outstanding theoretical and methodological issues that need resolution for sustainability measures to become a practical policy tool.

Many bacterial and viral pathogens (or their toxins), including Pseudomonas aeruginosa exotoxin A, require processing by host pro-protein convertases such as furin to cause disease. We report the development of a novel irreversible inhibitor of furin (QUB-F1) consisting of a diphenyl phosphonate electrophilic warhead coupled with a substrate-like peptide (RVKR), that also includes a biotin tag, to facilitate activity-based profiling/visualisation. QUB-F1 displays greater selectivity for furin, in comparison to a widely used exemplar compound (furin I) which has a chloromethylketone warhead coupled to RVKR, when tested against the serine trypsin-like proteases (trypsin, prostasin and matriptase), factor Xa and the cysteine protease cathepsin B. We demonstrate QUB-F1 does not prevent P. aeruginosa exotoxin A-induced airway epithelial cell toxicity; in contrast to furin I, despite inhibiting cell surface furin-like activity to a similar degree. This finding indicates additional proteases, which are sensitive to the more broad-spectrum furin I compound, may be involved in this process.

Background The recurrent immunoglobulin translocation, t(4;14)(p16;q32) occurs in 15% of multiple myeloma patients and is associated with poor prognosis, through an unknown mechanism. The t(4;14) up-regulates fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET domain (MMSET) genes. The involvement of MMSET in the pathogenesis of t(4;14) multiple myeloma and the mechanism or genes deregulated by MMSET upregulation are still unclear.Design and Methods The expression of MMSET was analyzed using a novel antibody. The involvement of MMSET in t(4;14) myelomagenesis was assessed by small interfering RNA mediated knockdown combined with several biological assays. In addition, the differential gene expression of MMSET-induced knockdown was analyzed with expression microarrays. MMSET gene targets in primary patient material was analyzed by expression microarrays.Results We found that MMSET isoforms are expressed in multiple myeloma cell lines, being exclusively up-regulated in t(4;14)-positive cells. Suppression of MMSET expression affected cell proliferation by both decreasing cell viability and cell cycle progression of cells with the t(4;14) translocation. These findings were associated with reduced expression of genes involved in the regulation of cell cycle progression (e.g. CCND2, CCNG1, BRCA1, AURKA and CHEK1), apoptosis (CASP1, CASP4 and FOXO3A) and cell adhesion (ADAM9 and DSG2). Furthermore, we identified genes involved in the latter processes that were differentially expressed in t(4;14) multiple myeloma patient samples.Conclusions In conclusion, dysregulation of MMSET affects the expression of several genes involved in the regulation of cell cycle progression, cell adhesion and survival.

Recent global crises reveal an emerging pattern of causation that could increasingly characterize the birth and progress of future global crises. A conceptual framework identifies this pattern’s deep causes, intermediate processes, and ultimate outcomes. The framework shows how multiple stresses can interact within a single social-ecological system to cause a shift in that system’s behavior, how simultaneous shifts of this kind in several largely discrete social-ecological systems can interact to cause a far larger intersystemic crisis, and how such a larger crisis can then rapidly propagate across multiple system boundaries to the global scale. Case studies of the 2008-2009 financial-energy and food-energy crises illustrate the framework. Suggestions are offered for future research to explore further the framework’s propositions.

Globalization, the process by which local social-ecological systems (SESs) are becoming linked in a global network, presents policy scientists and practitioners with unique and difficult challenges. Although local SESs can be extremely complex, when they become more tightly linked in the global system, complexity increases very rapidly as multi-scale and multi-level processes become more important. Here, we argue that addressing these multi-scale and multi-level challenges requires a collection of theories and models. We suggest that the conceptual domains of sustainability, resilience, and robustness provide a sufficiently rich collection of theories and models, but overlapping definitions and confusion about how these conceptual domains articulate with one another reduces their utility. We attempt to eliminate this confusion and illustrate how sustainability, resilience, and robustness can be used in tandem to address the multi-scale and multi-level challenges associated with global change.

Statement of the problem : Subjects with psychosis are at risk for metabolic syndrome, mainly secondary to antipsychotic treatment although overeating also plays a role. The hypothalamic–pituitary–adrenal axis, which is involved in visceral obesity, may also affect energy balance through affecting energy intake and the risk for stress-induced hyperphagia. The main aim of the study was to study the association between salivary cortisol, overeating, and obesity in a sample of subjects with early psychosis. Methods : We evaluated 53 participants (mean age: 23.5 years, 42% females) who were attending to the Early Psychosis Program from Reus (HPU Institut Pere Mata, Tarragona, Spain). All participants met criteria for a psychotic disorder or were considered at risk mental states after administration of the Schedules of Clinical Assessment in Neuropsychiatry (SCAN) or the Comprehensive Assessment of At Risk Mental States (CAARMS). Dietary habits were assessed by a dietician who administered the Eating Disorders module of the SCAN to explore two types of overeating: (1) Grazing, defined as repeatedly eating small amounts of food between mean meals (2) Binging, defined as consuming large quantities of food in a very short period of time. As grazing and binging can coexist in the same patient, we recoded overeating in four categories: (1) no overeating, (2) only grazing, (3) only binging and (4) grazing and binging. BMI and waist circumference were registered. A fasting morning saliva sample (9 h) was obtained. Salivary cortisol levels were determined by ELISA. Statistical analyses were performed with SPSS v.17.0. Kruskal–Wallis test was used to test differences between groups in continuous variables. Chi-squared tests were used to test differences between groups in categorical data. Results : Of 53 participants, 37 (69.8%) reported grazing and/or binging. Salivary cortisol was not associated with BMI or waist circumference. Of all participants, the group reporting both grazing and binging showed increased salivary cortisol levels (p = 0.004) and greater BMI (p=0.035). Conclusions : In young participants with early psychosis, overeating (coexistence of grazing and binging episodes) is associated with greater BMI and increased morning salivary cortisol levels.

We present some insights on the use and interpretation of resilience ideas that arose in a conference on "Society's Resilience in Withstanding Disaster." Three points in particular have relevance for those interested in resilience in social-ecological systems: (1) Time as a threshold vs. avoiding quick fixes; (2) Trading risks: specified vs. general resilience; (3) Response origination: building local general resilience, and general resilience in central agencies. In the latter the need is to allow improvisation, and failure, during times of crisis.

Resilience thinking addresses the dynamics and development of complex social-ecological systems (SES). Three aspects are central: resilience, adaptability and transformability. These aspects interrelate across multiple scales. Resilience in this context is the capacity of a SES to continually change and adapt yet remain within critical thresholds. Adaptability is part of resilience. It represents the capacity to adjust responses to changing external drivers and internal processes and thereby allow for development along the current trajectory (stability domain). Transformability is the capacity to cross thresholds into new development trajectories. Transformational change at smaller scales enables resilience at larger scales. The capacity to transform at smaller scales draws on resilience from multiple scales, making use of crises as windows of opportunity for novelty and innovation, and recombining sources of experience and knowledge to navigate social-ecological transitions. Society must seriously consider ways to foster resilience of smaller more manageable SESs that contribute to Earth System resilience and to explore options for deliberate transformation of SESs that threaten Earth System resilience.

Resilience and vulnerability represent two related yet different approaches to understanding the response of systems and actors to change; to shocks and surprises, as well as slow creeping changes. Their respective origins in ecological and social theory largely explain the continuing differences in approach to social-ecological dimensions of change. However, there are many areas of strong convergence. This paper explores the emerging linkages and complementarities between the concepts of resilience and vulnerability to identify areas of synergy. We do this with regard to theory, methodology, and application. The paper seeks to go beyond just recognizing the complementarities between the two approaches to demonstrate how researchers are actively engaging with each field to coproduce new knowledge, and to suggest promising areas of complementarity that are likely to further research and action in the field.

Anthropogenic pressures on the Earth System have reached a scale where abrupt global environmental change can no longer be excluded. We propose a new approach to global sustainability in which we define planetary boundaries within which we expect that humanity can operate safely. Transgressing one or more planetary boundaries may be deleterious or even catastrophic due to the risk of crossing thresholds that will trigger non-linear, abrupt environmental change within continental- to planetary-scale systems. We have identified nine planetary boundaries and, drawing upon current scientific understanding, we propose quantifications for seven of them. These seven are climate change (CO2 concentration in the atmosphere

This paper is a work-in-progress account of ideas and propositions about resilience in social-ecological systems. It articulates our understanding of how these complex systems change and what determines their ability to absorb disturbances in either their ecological or their social domains. We call them "propositions" because, although they are useful in helping us understand and compare different social-ecological systems, they are not sufficiently well defined to be considered formal hypotheses. These propositions were developed in two workshops, in 2003 and 2004, in which participants compared the dynamics of 15 case studies in a wide range of regions around the world. The propositions raise many questions, and we present a list of some that could help define the next phase of resilience-related research.

The concept of resilience has evolved considerably since Holling's (1973) seminal paper. Different interpretations of what is meant by resilience, however, cause confusion. Resilience of a system needs to be considered in terms of the attributes that govern the system's dynamics. Three related attributes of social-ecological systems (SESs) determine their future trajectories: resilience, adaptability, and transformability. Resilience (the capacity of a system to absorb disturbance and reorganize while undergoing change so as to still retain essentially the same function, structure, identity, and feedbacks) has four components - latitude, resistance, precariousness, and panarchy - most readily portrayed using the metaphor of a stability landscape. Adaptability is the capacity of actors in the system to influence resilience (in a SES, essentially to manage it). There are four general ways in which this can be done, corresponding to the four aspects of resilience. Transformability is the capacity to create a fundamentally new system when ecological, economic, or social structures make the existing system untenable. The implications of this interpretation of SES dynamics for sustainability science include changing the focus from seeking optimal states and the determinants of maximum sustainable yield (the MSY paradigm), to resilience analysis, adaptive resource management, and adaptive governance.

Increasing interest in regime shifts in ecological and linked social-ecological systems (SESs) has placed a strong focus on the thresholds of change. However, research into this topic has been hampered by a lack of empirical data. This paper describes a developing database established to address this need. The database is freely available and comprises a set of summarized published examples and a searchable bibliographic database of publications on the topic. Thresholds in the database are characterized in terms of a standardized set of 24 descriptors, including the variables along which they occur, the variables that change, and the factors that have driven the change. Readers are encouraged to contribute new examples. Examples range from conceptual models to empirical evidence. The former predominate in the literature and, although they make valuable contributions and will continue to be included, the intention is build up the number of examples based on data. Examples are presented in terms of whether the threshold occurs in the ecological system, the social system, or both, and the direction of interactions between systems. The paper concludes with some initial observations on thresholds based on the examples included so far, and poses some questions for future research. Research on a typology of thresholds is a priority topic in the emerging area of "sustainability science" and it requires a rich database of empirical data.

Approaches to natural resource management are often based on a presumed ability to predict probabilistic responses to management and external drivers such as climate. They also tend to assume that the manager is outside the system being managed. However, where the objectives include long-term sustainability, linked social-ecological systems (SESs) behave as complex adaptive systems, with the managers as integral components of the system. Moreover, uncertainties are large and it may be difficult to reduce them as fast as the system changes. Sustainability involves maintaining the functionality of a system when it is perturbed, or maintaining the elements needed to renew or reorganize if a large perturbation radically alters structure and function. The ability to do this is termed "resilience." This paper presents an evolving approach to analyzing resilience in SESs, as a basis for managing resilience. We propose a framework with four steps, involving close involvement of SES stakeholders. It begins with a stakeholder-led development of a conceptual model of the system, including its historical profile (how it got to be what it is) and preliminary assessments of the drivers of the supply of key ecosystem goods and services. Step 2 deals with identifying the range of unpredictable and uncontrollable drivers, stakeholder visions for the future, and contrasting possible future policies, weaving these three factors into a limited set of future scenarios. Step 3 uses the outputs from steps 1 and 2 to explore the SES for resilience in an iterative way. It generally includes the development of simple models of the system's dynamics for exploring attributes that affect resilience. Step 4 is a stakeholder evaluation of the process and outcomes in terms of policy and management implications. This approach to resilience analysis is illustrated using two stylized examples.

Global change is the net effect of individual and interactive effects of changes in land use, atmospheric composition, biological diversity, and climate. A synthesis of the past six years' activities of the Global Change and Terrestrial Ecosystems project of the IGBP (International Geosphere-Biosphere Programme) deals with global change effects as ecosystem responses and living with global change. Ecosystem responses are considered in terms of changes in function and vegetation composition/structure. Field experiments of elevated CO2 effects on aboveground biomass show, on average, a positive effect on biomass, ranging from -20% to +80%. Some early predictions of CO2 effects (C3 vs. C4 plants, N-fixers, C:N in litter) are not generally supported, and it is necessary to consider the interactive effects of changes in CO2, temperature, and nitrogen. Dynamic global vegetation models involving transient changes show that biomes will not shift as intact entities. Significant changes in vegetation, especially in high latitudes, are likely over the next century, and changes in disturbance regimes will be most important. Based on forecast changes in land use, vegetation structure, and ecosystem physiology, the terrestrial biosphere will probably become a source rather than a sink for carbon over the next century. Because of land use change, the terrestrial biosphere of the 21st century will probably be further impoverished in species richness and substantially reorganized. More natural ecosystems will be in an early successional state or converted to production systems. The biosphere will be generally weedier and structurally simpler, with fewer areas in an ecologically complex old-growth state. Temperate crop production will probably increase slightly because of CO2 increases (5-7% for wheat for average field conditions), but crop production in the tropics may decline in some areas. Land use change will have the greatest effect on pastures and rangelands; due to a required >2% annual increase in crop production to meet the expanding human population, there will be increased incursion of cropland into rangelands.

The purpose of this essay is to define and refine the concepts of stability and resilience and to demonstrate their value in understanding the behavior of exploited systems. Some ecological systems display several possible stable states. They may also show a hysteresis effect in which, even after a long time, the state of the system may be partly determined by its history. The concept of resilience depends upon our objectives, the types of disturbances that we anticipate, control measures that are available, and the time scale of interest.

How can middle-level educators improve reading achievement when digitized texts and tests manage their instruction? Experienced Osage Middle School reading teachers and school administrators addressed this question as they examined their Istation reading curriculum, and higher education faculty partners were invited to portray this work. Teaching to standardized tests, assigning low interest texts, and even digitizing controlled reading instruction were accepted practices at Osage Middle School. This portrait of reform illustrates how these practices were successfully resisted and reconstructed in just one academic year. The Osage educators' resistance was portrayed in three stages. First, the school's accepted literacy practices were named as digitized managed events that diminished educator authority. Then co-investigations of new reading instruction deconstructed these accepted practices. Eventually the new reading instruction practices transformed the school's reading curriculum. Possibilities for further research suggested by the Osage Middle School reform portrait include examining the invisibility of low achieving readers, investigating the paradoxes of managing controlled instruction, and testing the utility of collaborative educator inquiry.