In C2C12 myotubes and in mouse muscle, mutant constitutively activated STAT3-induced muscle fiber atrophy and exacerbated wasting in cachexia. Conversely, inhibiting STAT3 pharmacologically with JAK or STAT3 inhibitors or

genetically with dominant negative STAT3 and short hairpin STAT3 reduced muscle atrophy downstream of IL-6 or cancer. These results indicate that STAT3 is a primary mediator of muscle wasting in cancer cachexia and other conditions of high IL-6 family signaling. Thus STAT3 could represent a novel therapeutic target for the preservation of skeletal muscle in cachexia.”
“Diphenyl diselenide [(PhSe)(2)], an organoselenium compound, presents toxicological effects in rat pups, manifested by the appearance of seizure episodes. The aim of this study was to carry out the determination and quantification of (PhSe)(2) in plasma, liver and brain of rat pups after oral administration (p.o) Cytoskeletal Signaling inhibitor of this compound (500 mg/kg).

The second objective of this study was to correlate the latency to the appearance for the first seizure episode with (PhSe)(2) plasma, liver and brain levels. Analysis of (PhSe)(2) in plasma, liver and brain samples was performed by gas chromatography/flame ionized detector system (GC/FID). The average levels of (PhSe)(2) in plasma, liver and brain of rat pups were 3.67, 5.07 and BKM120 purchase 1.15 mu g/ml, respectively, at 20.58 min post dosing, the latency media for the first seizure episode. (PhSe)(2) levels in plasma did not correlate with the latency for the first seizure episode induced by this compound. A significant negative correlation between the latency for the first seizure episode and the levels of (PhSe)(2) liver and brain of rat pups was found. It demonstrates that rat pups which Rapamycin had highest levels of (PhSe)(2) in liver and brain showed the shortest latency for the first seizure episode.”
“In inside-out bovine heart sarcolemmal vesicles, p-chloromercuribenzenesulfonate (PCMBS) and n-ethylmaleimide (NEM) fully inhibited MgATP up-regulation of the

Na+/Ca2+ exchanger (NCX1) and abolished the MgATP-dependent PtdIns-4,5P2 increase in the NCX1-PtdIns-4,5P2 complex; in addition, these compounds markedly reduced the activity of the PtdIns(4)-5kinase. After PCMBS or NEM treatment, addition of dithiothreitol (DTT) restored a large fraction of the MgATP stimulation of the exchange fluxes and almost fully restored PtdIns(4)-5kinase activity; however, in contrast to PCMBS, the effects of NEM did not seem related to the alkylation of protein SH groups. By itself DTT had no effect on the synthesis of PtdIns-4,5P2 but affected MgATP stimulation of NCX1: moderate inhibition at 1 mM MgATP and 1 mu M Ca2+ and full inhibition at 0.25 mM MgATP and 0.2 mu M Ca2+. In addition, DDT prevented coimmunoprecipitation of NCX1 and PtdIns(4)-5kinase.

As part of the investigation of that outbreak, we compared the efficacies of 11 different contact lens solutions against cysts of A. castellanii, A. polyphaga, and A. hatchetti (the isolates of all species were genotype T4), which were

isolated in 2007 from specimens obtained during the outbreak investigation. The data, generated with A. castellanii, A. GM6001 manufacturer polyphaga, and A. hatchetti cysts, suggest that the two contact lens solutions containing hydrogen peroxide were the only solutions that showed any disinfection ability, with 0% and 66% growth, respectively, being detected with A. castellanii and 0% and 33% growth, respectively, being detected with A. polyphaga. There was no statistically significant difference in disinfection efficacy between the 11 solutions for A. hatchetti.”
“The (pro)renin receptor (P)RR is a receptor for renin and prorenin, not only allowing local production of angiotensin I from angiotensinogen, but also inducing intracellular Selleckchem Elafibranor signaling.

Intriguingly, (P)RR is also called ATP6AP2 because a (P)RR fragment was demonstrated to be associated with vacuolar-type H+-ATPase (V-ATPase), which is of importance for the maintenance of intracellular pH. Recent studies implicate that deletion of (P)RR results in the dysfunction of V-ATPase, suggesting that the (P)RR is essential for its role as a proton pump. Furthermore, the novel function of (P)RR as an adaptor protein between the Wnt receptor complex and the V-ATPase was discovered. Thus, (P)RR is a multi-functional molecule with functions beyond renin and prorenin. This review focuses on the current knowledge and issues of (P)RR and V-ATPase.”
“The aim of this study was to assess ten plants from the Congolese pharmacopoeia for their analgesic activity as well as their cytotoxicity, in order to validate their traditional use. Thirty-three extracts were obtained in 3 different solvents (Water, Ethanol, DCM) from these

ten plants selected after an ethnobotanic survey in the region of the Pool (Congo Brazzaville): Leonotis selleck chemical nepetaefolia (Lamiaceae), Manotes pruinosa (Connaraceae), Spilanthes uliginosa (Asteraceae), Hymenocardia ulmoides (Euphorbiaceae), Celosia trigyna (Amaranthaceae), Cogniauxia podolaena (Cucurbitaceae), Brillantaisia patula (Acanthaceae), Urena lobata (Malvaceae), Mitracarpus scaber (Rubiaceae), Triumfetta rhomboidea (Tiliaceae). The writhing test (Siegmund Chemical Test) was used for the pharmacological screening. The cytotoxicity of all the extracts was tested on KB (Human epidermoid carcinoma) and Vero (African green monkey kidney) cell lines with taxotere as positive control. A TLC chemical screening of the extracts was carried out to detect the major chemical classes present in the plants.

Both these proteins are present on only mature WPBs, and this rab/effector complex appears to anchor these WPBs to peripheral actin. Depletion of either the Rab or its effector results in a loss of peripheral WPB localization, and this destabilization is coupled with an increase in both

basal and stimulated secretion. The VWF released from Rab27a-depleted cells is less multimerized, and the VWF strings seen under flow find more are shorter. Our results indicate that this Rab/effector complex controls peripheral distribution and prevents release of incompletely processed WPB content. (Blood. 2009;113:5010-5018)”
“The invasion of monocytes into the subendothelium space plays an important role in the early stage of atherosclerosis. Cilostazol, a specific phosphodiesterase type III (PDE3) inhibitor, has been shown to exhibit anti-atherosclerotic effect. The present study aimed to investigate the modulating effects of cilostazol on monocyte invasion and the gene expressions of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1. We found that PMA significantly increased the invasive ability and the MMP-9 activity of THP-1 cells, as analyzed by matrix invasion assay and gelatin zymography, respectively. The increased expression of MMP-9 was demonstrated at both

the RNA and protein levels by RT/real-time PCR and western blot analysis. These changes were markedly inhibited by cilostazol in a dose-dependent LB-100 order manner, which also could be observed when cAMP analog was used. On the contrary, the expression of TIMP-1, an inhibitor of MMP-9, was significantly upregulated by cilostazol dose dependently at both the RNA and protein levels. Reverse zymography further confirmed the increase of TIMP-1 activity after cilostazol treatment. The increase of TIMP-1 by cilostazol, however, was not cAMP-dependent. Cilostazol reduced the

MMP-9 promoter activity and suppressed the nuclear translocation of NF-kappa Selleck Bromosporine B, indicating that the inhibitory effect of cilostazol is at the transcriptional level. In conclusion, the present study provides an additional mechanism underlying the anti-atherosclerotic effect of cilostazol by inhibiting the monocyte invasion and modulating the gene expressions of MMP-9 and TIMP-1 in monocytes upon differentiating to macrophages. (C) 2011 Elsevier B.V. All rights reserved.”
“Most cases of a predisposition to venous thrombosis are caused by resistance to activated protein C, associated in 95% of cases with the Factor V Leiden allele (FVL or R506Q). Several recent studies report a further increased risk of thrombosis by an association between the AB alleles of the ABO blood group and Factor V Leiden. The present study investigated this association with deep vein thrombosis (DVT) in individuals treated at the Hemocentro de Pernambuco in northeastern Brazil.

In the present study, we examined the

expression of the EphB6 variant (EphB6v) in a panel of brain tumor cell lines and glioblastoma tissues and we found that EphB6v was preferentially expressed in malignant brain tumors, such as glioblastomas and anaplastic astrocytomas. The EphB6v has a unique 54 amino acid sequence at the C-terminal that is not found in normal EphB6. Therefore, we attempted to identify antigenic peptides unique to EphB6v for immunotherapy. The two EphB6v-derived peptides exhibited the ability to bind to human leukocyte antigen (HLA)-A0201 molecules, and https://www.selleckchem.com/products/ro-3306.html each of them was able to induce cytotoxic T lymphocytes in vitro in the peripheral blood mononuclear cells of HLA-A2(+) glioma patients. The cytotoxicity was mediated by peptide-specific CD8(+) T cells in an HLA-A2-restricted manner. The expression of EphB6v was also observed in different types of cancer (e.g. lung, colon, stomach, liver and pancreatic) cells. Taken together, the two peptides derived from EphB6v might be appropriate targets for peptide-based specific immunotherapy for HLA-A2(+) patients

with various cancers. (Cancer Sci 2008; 99: 1656-1662)”
“The osteoinductive growth factor, bone morphogenetic protein-2 (BMP-2), is capable of inducing de novo bone formation after implantation. A nanoparticulate Selleckchem VX-809 (NP) system was developed for BMP-2 delivery based on NPs fabricated from bovine serum albumin (BSA) and stabilized by polyethylenimine (PEI) coating. In this study, the pharmacokinetics and osteoinductivity of BMP-2 delivered with different BSA NP formulations were determined by subcutaneous

implantation in rats. A 7-day pharmacokinetics study showed that PEI coating on NPs effectively reduced the initial burst release of BMP-2 and prolonged the BMP-2 retention at implantation site. However, the uncoated BMP-2 NPs (BMP-2 loading of 1.44% w/w) were able to induce a robust ectopic bone formation, while no bone formation was found by the BMP-2 NPs coated with PEI. The toxicity of the PEI used for NP coating was determined to be the reason for lack of osteoinduction. Increasing BMP-2 loading (up to 5.76% w/w) was then employed to formulate NPs; with lower PEI content: the higher BMP-2 loading was found p38 protein kinase to better promote induction of de novo bone. Our findings indicated that PEI coating on BSA NPs was effective for controlling BMP-2 release from NPs, but the toxicity of cationic PEI was a concern for the osteoinductive activity, which should be alleviated by further optimization of NP formulations. (C) 2009 Elsevier Ltd. All rights reserved.”
“Multidrug-resistant Plasmodium falciparum malaria parasites pose a threat to effective drug control, even to artemisinin-based combination therapies (ACTs). Here we used linkage group selection and Solexa whole-genome resequencing to investigate the genetic basis of resistance to component drugs of ACTs.

Treatment for this disease is still under investigation. Mucuna pruriens (L.), is a traditional herbal medicine, used in India since 1500 B.C., as a neuroprotective agent. In this present study, we evaluated the therapeutic effects of aqueous extract of M. pruriens (Mp) seed in Parkinsonian mouse model developed by chronic exposure to paraquat (PQ). Results of our study revealed that the nigrostriatal

portion of Parkinsonian mouse brain showed significantly increased levels of nitrite, malondialdehyde (MDA) and reduced levels of catalase compared to the control. Bucladesine solubility dmso In the Parkinsonian mice hanging time was decreased, whereas narrow beam walk time and foot printing errors were increased.\n\nTreatment with aqueous seed extract of Mp significantly increased the catalase activity and decreased the MDA and nitrite level, compared to untreated Parkinsonian mouse brain. Mp treatment also improved the behavioral ACY-738 abnormalities. It increased hanging time, whereas it decreased narrow beam walk time and foot printing error compared to untreated Parkinsonian mouse brain.\n\nFurthermore, we observed a significant reduction

in tyrosine hydroxylase (TH) immunoreactivity in the substantia nigra (SN) and striatum region of the brain, after treatment with PQ which was considerably restored by the use of Mp seed extract. Our result suggested that Mp seed extract treatment significantly reduced the PQ induced neurotoxicity as evident by decrease in oxidative damage, physiological abnormalities and immunohistochemical changes in the Parkinsonian mouse. (C) 2013 Elsevier Ltd. All rights reserved.”
“Background: Though recent reports have indicated a higher prevalence of latent tuberculosis infection (LTBI) in laboratory personnel selleck inhibitor than in other healthcare workers, these studies included only a limited number of laboratory personnel. Methods: We have thus focused on the laboratory personnel, who had a high level of exposure to specimens from patients with TB. We recruited 173 laboratory personnel and performed QuantiFERON-TB Gold In-Tube test (QFT-G) and tuberculin skin test (TST). Results: QFT-G was positive in 21.4% of the enrolled laboratory personnel, and TST was positive

in 33.3%. The agreement between the two tests was fair (kappa = 0.234). In multivariate analyses, household contact with TBpatients (P = 0.013), the laboratory sections of microbiology (P = 0.045) and chemistry/ immunology (P = 0.014) were shown to be significantly associated with positive QFT-G results. Conclusion: Our data show a high prevalence of TST and QFT-G positivity in laboratory personnel and emphasize the importance of LTBI screening for laboratory personnel. In BCG-vaccinated populations with an intermediate incidence setting, QFT-G seems to be superior to TST as a screening tool for the detection of LTBI. Further study, including results of follow-up tests will be helpful for confirmation of our findings. J. Clin. Lab. Anal. 25: 382-388, 2011.

Recent data suggest that dendritic cells in lymph nodes are more prone to apoptosis, which correlates with disease progression. In addition, plasmacytoid dendritic cells isolated from blood showed a semi-mature phenotype after HIV-1 exposure, which coincided

with persistent IFN-alpha secretion. Emerging data show that semi-mature dendritic cells induce regulatory T cells Selleckchem Bcl-2 inhibitor and suppress effector function. There may therefore be mechanisms by which HIV-1 affects dendritic cell immune stimulation and, in doing so, interferes with the elicitation of anti-HIV-1 responses.\n\nSummary\n\nUnderstanding how dendritic cells are functionally altered during

HIV-1 infection is crucial for the development of new immune-therapy strategies including approaches to target dendritic cells with antigen in vivo or ex vivo to induce efficient adaptive anti-HIV immunity.”
“Magnetic and magnetocaloric properties of the intermetallic compound TbAgAl have been investigated. Temperature dependence of magnetization data revealed that TbAgAl exhibits magnetic ordering at 59 K and possesses competing ferromagnetic-antiferromagnetic BMS-754807 clinical trial interactions, which leads to the formation of Griffiths-like phase. The field dependence of magnetization data shows the existence of a metamagnetic-like transition at a critical field of 10 kOe. Unusually potent relaxation effects are seen in the time dependence of magnetization data in the ordered phase. The presence of spin-glass-like state is found to affect magnetocaloric properties of this compound.”
“The present manuscript reports the design, synthesis and characterization of three star-shaped polymers consisting Cilengitide ic50 of three different arylimides such as perylene (PR)-, naphthalene (NT)- and benzene (BZ) tetracarboxylicdiimide as core and polyfluorene

(PF) as arms. Chemical structure of star-shaped polymers was aimed at broadening as much as possible their absorption profile. Arylimide cored star polymers (PF-BZ, PF-NT and PF-PR) were prepared through palladium catalyzed Suzuki polycondensation to tune the band gap of the polymers. The prepared polymers were characterized by elemental analysis, NMR, GPC, UV-Vis, photoluminescence and cyclic voltammetry studies. Electrochemical and optical responses of three polymers revealed the lowering of band gap from linear PF to star-shaped polymers. TCSPC study confirmed the partial energy transfer from PF arms to arylimide cores. The unexpected keto defect in linear PF was also reduced by preparation of star polymer with large arylimide cores. TGA exhibited the enhancement of thermal stability of star polymer than linear PF.

Limitations and suggestions for further study are discussed.”
“The deep sea is the largest biome of the biosphere. The knowledge of the spatial variability of deep-sea biodiversity is one of the main challenges

of marine ecology and evolutionary biology. The choice of the observational spatial scale is assumed to play a key role for understanding processes structuring the deep-sea benthic communities and one of the most typical features of marine biodiversity distribution is the existence of bathymetric gradients. However, Torin 2 the analysis of biodiversity bathymetric gradients and the associated changes in species composition (beta diversity) typically compared large depth ranges (with intervals of 500 to 1000 or even 2000 m depth among sites). To test whether significant changes

in alpha and beta diversity occur also at fine-scale bathymetric gradients (i.e., within few hundred-meter depth intervals) the variability of deep-sea nematode biodiversity and assemblage composition along a bathymetric transect (200-1200 m depth) with intervals of 200 m among sampling depths, was investigated. A hierarchical sampling strategy for the analysis of nematode species richness, beta diversity, functional (trophic) diversity, and related environmental variables, was used. The results indicate the lack of significant differences in taxonomic and functional diversity across sampling depths, but the presence of high beta diversity at all spatial scales investigated: AZD5153 cell line between cores collected from the same box corer (on average 56%), among deployments at the same depth (58%), and between all sampling depths (62%). Such high beta diversity is influenced by the presence of small-scale patchiness in the deep sea and is also related to the large number of rare or very rare species (typically accounting for > 80% of total species richness). Moreover, the number of ubiquitous nematode species across all sampling depths is quite low (ca. 15%). Multiple regression analyses provide evidence

that such patterns could be related to the different availability, composition and size spectra of food particles in the sediments. Additionally, though to a lesser extent, our results indicate, that GSK923295 mw selective predation can influence the nematode trophic composition. These findings suggest that a multiple scale analysis based on a nested sampling design could significantly improve our knowledge of bathymetric patterns of deepsea biodiversity and its drivers. (C) 2013 Elsevier Ltd. All rights reserved.”
“Portable EEG units are key tools in epilepsy diagnosis. Current systems could be made physically smaller and longer lasting by the inclusion of online data reduction methods to reduce the power required for storage or transmission of the EEG data.

Frequently, optimal environmental conditions favour production of more costly

CH structures whilst economical and reliable CL structures are produced under less favourable conditions. In this study we explore (1) the effect of light and water on the reproductive phenology and (2) the effect of pollen supplementation on resource allocation to seeds in SNS-032 supplier the cleistogamous weed Ruellia nudiflora.\n\nMethods Split-plot field experiments were carried out to assess the effect of shade (two levels: ambient light vs. a reduction of 50 %) and watering (two levels: non-watered vs. watered) on the onset, end and duration of the production of three reproductive structures: CH flowers, CH fruit and CL fruit. We also looked at the effect of these environmental factors on biomass allocation to seeds (seed weight) from obligately self-pollinated flowers (CL), open-pollinated

CH flowers and pollen-supplemented CH flowers.\n\nKey Results CH structures were produced for a briefer period and ended earlier under shaded conditions. These conditions also resulted in an earlier production of CL fruit. Shaded conditions also produced greater biomass allocation to CH seeds receiving extra pollen.\n\nConclusions Sub-optimal (shaded) conditions resulted in a briefer production period of CH structures whilst these same conditions resulted in an earlier production of CL structures. However, under sub-optimal conditions, plants

also allocated more resources to seeds sired from CH flowers receiving large pollen loads. Earlier production of reproductive this website structures and relatively larger seed might improve subsequent success of CL and pollen-supplemented CH seeds, respectively.”
“Background: The dose-response relationship is a fundamental pharmacological parameter necessary to determine therapeutic thresholds. Epi-allelic hypomorphic analysis using RNA interference (RNAi) can similarly correlate target gene dosage with cellular phenotypes. This however requires a set of RNAi triggers empirically determined to attenuate target gene expression to different levels. Results: In order to improve our ability to incorporate epi-allelic analysis into target validation studies, we developed a novel flow cytometry-based Smad pathway functional screening approach (CellSelectRNAi) to achieve unbiased selection of shRNAs from high-coverage libraries that knockdown target gene expression to predetermined levels. Employing a Gaussian probability model we calculated that knockdown efficiency is inferred from shRNA sequence frequency profiles derived from sorted hypomorphic cell populations. We used this approach to generate a hypomorphic epi-allelic cell series of shRNAs to reveal a functional threshold for the tumor suppressor p53 in normal and transformed cells.

We show, however, that bacterium-like and phage-like genes sequenced by the N. vectensis genome project tend to cluster on separate scaffolds, which typically do not include eukaryotic genes and differ from the latter in their GC contents. Quisinostat supplier Moreover, most of the bacterium-like genes in N. vectensis either lack introns or the introns annotated in such genes are false predictions that, when translated, often restore the missing portions of their predicted protein products. In a freshwater

cnidarian, Hydra, for which a proteobacterial endosymbiont is known, these gene features have been used to delineate the DNA of that endosymbiont sampled by the genome sequencing project. We predict that a large fraction of bacterium-like genes identified in the N. vectensis genome similarly are drawn from the contemporary bacterial consorts of the starlet sea anemone. These uncharacterized bacteria associated with N. vectensis are a proteobacterium click here and a representative of the phylum Bacteroidetes,

each represented in the database by an apparently random sample of informational and operational genes. A substantial portion of a putative bacteriophage genome was also detected, which would be especially unlikely to have been transferred to a eukaryote.”
“The catalytic oxidation of phenolic substrates by polyphenoloxidase (PPO) causes pericarp browning of postharvest rambutan fruit. In the present study, PPO and its endogenous substrates were extracted from rambutan pericarp tissues (RPT). The substrate extracts were sequentially partitioned with ethyl acetate and n-butanol. The analysis of total phenolic content showed that the most phenolic compounds were distributed in ethyl acetate fraction. By high-performance liquid chromatography (HPLC),

(-)-epicatechin see more (EC) and proanthocyanidin A2 (PA2) were identified from this fraction. After reacting with rambutan PPO, EC turned brown rapidly within 10 min, indicating that it was a significant endogenous substrate. Although PA2 could also be oxidized by the PPO, it turned brown very slowly. In addition, because EC and PA2 were continually catalyzed into browning products by PPO during storage of the fruit at 4 and 25 degrees C, their contents in RPT gradually declined with the extended storage time. It was further observed that both substrate contents in rambutan fruit storing at 25 degrees C decreased more rapidly than that storing at 4 degrees C, suggesting that low temperature inhibited the catalytic oxidation of substrates so as to slow down pericarp browning.”
“The Regulation on Advanced Therapies (Regulation (EC) 1394/2007) establishes a new scientific committee, the Committee for Advanced Therapies (CAT), at the European Medicines Agency.

As temperature decreases from 296 K to 183 K (23 A degrees C to -90 A degrees C), the formation life for cracking about pit and EXCO corrosion perimeters increases, microstructure scale crack growth rates PFTα decrease in the range from 20 to 500 mu m beyond the corrosion topography,

and long crack growth rates similarly decline. Fatigue crack surface features correlate with reduced hydrogen embrittlement with decreasing temperature fed by localized H produced during precorrosion for pit and EXCO-proximate cracks, as well as by crack tip H produced by water vapor reaction during stressing for all crack sizes. The importance of the former H source increases with decreasing temperature for cracks sized below 200 mu m. Decreasing temperature to 223 K (-50 A degrees C) eliminates the contribution of environmental H through interaction of reduced water vapor pressure

in equilibrium with ice and reduced H diffusion. The Knudsen flow model and exposure parameter, , enables improved modeling of temperature dependent crack propagation, but does not fully describe low temperature fatigue behavior due to possible rate limitation by H diffusion. Further decreases in MSC da/dN to 183 K (-90 A degrees C) are related to reduced mobility of the corrosion-precharged H which SN-38 ic50 may associate with vacancies from dissolution. Crack formation, and growth rates correlate with either elastic stress intensity range or cyclic crack tip opening displacement, and are available to predict corrosion effects on airframe fatigue for the important low temperature regime. DOI: 10.1007/s11661-012-1374-3 (C) The Minerals, Metals & Materials Society and ASM International 2012″
“Chemical cues constitute much of the language of life in the sea. Our understanding of biotic interactions and their effects on marine ecosystems will advance more rapidly if this language is studied

and understood. Here, I review how chemical cues regulate critical aspects of the behavior of marine organisms from bacteria to phytoplankton to benthic invertebrates and water column fishes. Proteasome assay These chemically mediated interactions strongly affect population structure, community organization, and ecosystem function. Chemical cues determine foraging strategies, feeding choices, commensal associations, selection of mates and habitats, competitive interactions, and transfer of energy and nutrients within and among ecosystems. In numerous cases, the indirect effects of chemical signals on behavior have as much or more effect on community Structure and function as the direct effects of consumers and pathogens. Chemical cues are critical for understanding marine systems, but their omnipresence and impact are inadequately recognized.”
“We tested the hypothesis that trees have measurable effects on infiltrability, macroporosity, and preferential flows in agrosilvopastoral systems. Managing agricultural systems for water conservation is a critical component of sustainable systems.