The Circular Economy (CE) has received considerable attention as an approach that promises to reconcile ecological systems and economic growth. In spite of its increased popularity, little is known ...about the implementation struggles of incumbent firms across industrial sectors. Furthermore, although the notion of circular production systems is at the intersection of different research areas such as sustainable product design, sustainable supply chains, and reverse logistics, knowledge on how these concepts combine to ease or impede firms' transition towards circularity is scarce. To shed light on these gaps, I used multiple case studies from Cradle to Cradle certified companies in the textile industry in Europe. By employing qualitative research, I identified a set of factors along the textile value chain, from product design to take-back and reprocessing, that are crucial in expediting or delaying a firm's aspirations to develop a circular product. The main contribution of this paper is the dynamic understanding of how certain collaborative supplier-buyer innovation factors (i.e., supply chain position, power balance, and a shared vision) coupled with complex aspects in product design, namely in basic materials, architecture, and functionality, combine to determine the output speed and quantity of circular products to be sold, taken back, and ultimately regenerated.
By means of a system dynamics computer simulation model, this paper analyzes the systemic effects of combining multiple product design and business model strategies for slowing and closing resource ...loops in a circular economy. In the model, green (i.e., recycled) and brown (i.e., traditional linear) products, as well as products under a PSS model, flow in a closed-loop supply chain. The model structure covers issues related to product design, product use and replacement, second-hand use, product discard, and finally, collection and processing for product recycling. Results from this research provide insights into the relationship between design considerations at the beginning of a product's life and their implications for the product's take-back stage when a new manufacturing cycle begins. The main contributions of this paper are the considerations of time delays and reinforcing feedback loops in the design of an effective closed-loop supply chain.
Treatment of breast cancer with trastuzumab is complicated by cardiotoxicity in up to 34% of the patients. In most patients, trastuzumab-induced cardiotoxicity (TIC) is reversible: left ventricular ...ejection fraction (LVEF) improves after trastuzumab withdrawal and with, or sometimes without, initiation of heart failure (HF) therapy. The reversibility of TIC, however, is not foreseeable, and identification of patients at risk and of those who will not recover from cardiac dysfunction is crucial. The usefulness of troponin I (TNI) in the identification of patients at risk for TIC and in the prediction of LVEF recovery has never been investigated.
In total, 251 women were enrolled. TNI was measured before and after each trastuzumab cycle. LVEF was evaluated at baseline, every 3 months during trastuzumab therapy, and every 6 months afterward. In case of TIC, trastuzumab was discontinued, and HF treatment with enalapril and carvedilol was initiated. TIC was defined as LVEF decrease of > 10 units and below 50%. Recovery from TIC was defined as LVEF increase above 50%.
TIC occurred in 42 patients (17%) and was more frequent in patients with TNI elevation (TNI+; 62% v 5%; P < .001). Twenty-five patients (60%) recovered from TIC. LVEF recovery occurred less frequently in TNI+ patients (35% v 100%; P < .001). At multivariate analysis, TNI+ was the only independent predictor of TIC (hazard ratio HR, 22.9; 95% CI, 11.6 to 45.5; P < .001) and of lack of LVEF recovery (HR, 2.88; 95% CI,1.78 to 4.65; P < .001).
TNI+ identifies trastuzumab-treated patients who are at risk for cardiotoxicity and are unlikely to recover from cardiac dysfunction despite HF therapy.
Immunotherapy with chimeric antigen receptor (CAR)-expressing T cells that target the disialoganglioside GD2 expressed on tumor cells may be a therapeutic option for patients with high-risk ...neuroblastoma.
In an academic, phase 1-2 clinical trial, we enrolled patients (1 to 25 years of age) with relapsed or refractory, high-risk neuroblastoma in order to test autologous, third-generation GD2-CAR T cells expressing the inducible caspase 9 suicide gene (GD2-CART01).
A total of 27 children with heavily pretreated neuroblastoma (12 with refractory disease, 14 with relapsed disease, and 1 with a complete response at the end of first-line therapy) were enrolled and received GD2-CART01. No failure to generate GD2-CART01 was observed. Three dose levels were tested (3-, 6-, and 10×10
CAR-positive T cells per kilogram of body weight) in the phase 1 portion of the trial, and no dose-limiting toxic effects were recorded; the recommended dose for the phase 2 portion of the trial was 10×10
CAR-positive T cells per kilogram. Cytokine release syndrome occurred in 20 of 27 patients (74%) and was mild in 19 of 20 (95%). In 1 patient, the suicide gene was activated, with rapid elimination of GD2-CART01. GD2-targeted CAR T cells expanded in vivo and were detectable in peripheral blood in 26 of 27 patients up to 30 months after infusion (median persistence, 3 months; range, 1 to 30). Seventeen children had a response to the treatment (overall response, 63%); 9 patients had a complete response, and 8 had a partial response. Among the patients who received the recommended dose, the 3-year overall survival and event-free survival were 60% and 36%, respectively.
The use of GD2-CART01 was feasible and safe in treating high-risk neuroblastoma. Treatment-related toxic effects developed, and the activation of the suicide gene controlled side effects. GD2-CART01 may have a sustained antitumor effect. (Funded by the Italian Medicines Agency and others; ClinicalTrials.gov number, NCT03373097.).
Long-lasting effects of undernutrition Martins, Vinicius J B; Toledo Florêncio, Telma M M; Grillo, Luciane P ...
International journal of environmental research and public health,
06/2011, Letnik:
8, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Undernutrition is one of the most important public health problems, affecting more than 900 million individuals around the World. It is responsible for the highest mortality rate in children and has ...long-lasting physiologic effects, including an increased susceptibility to fat accumulation mostly in the central region of the body, lower fat oxidation, lower resting and postprandial energy expenditure, insulin resistance in adulthood, hypertension, dyslipidaemia and a reduced capacity for manual work, among other impairments. Marked changes in the function of the autonomic nervous system have been described in undernourished experimental animals. Some of these effects seem to be epigenetic, passing on to the next generation. Undernutrition in children has been linked to poor mental development and school achievement as well as behavioural abnormalities. However, there is still a debate in the literature regarding whether some of these effects are permanent or reversible. Stunted children who had experienced catch-up growth had verbal vocabulary and quantitative test scores that did not differ from children who were not stunted. Children treated before 6 years of age in day-hospitals and who recovered in weight and height have normal body compositions, bone mineral densities and insulin production and sensitivity.
Accurate paleo-latitudinal reconstructions of the Intertropical Convergence Zone (ITCZ) are necessary for understanding tropical hydroclimate and atmospheric circulation. Paleoclimate models and ...records suggest that as global temperatures increase, the ITCZ should migrate towards the warmer hemisphere. Many uncertainties remain regarding the magnitude of this migration, and few studies have focused on the Central Equatorial Pacific (CEP). Here, we use eolian dust records recovered from three locations in the CEP to address changes in dust provenance across the paleo ITCZ since the last glacial maximum (LGM). Radiogenic isotope compositions of Nd and Pb show that dust delivered to the CEP was sourced mainly from two regions: East Asia and South America. From these data we deduced that since Marine Oxygen Isotope Stage 2 (MIS2) the ITCZ has migrated north to its modern position, being displaced by as much as 7°, to as little as 2.5°. We find that the ITCZ migrated further north during the early Holocene (∼9 kyr), reaching its position furthest north during the mid-Holocene warm interval (∼7 kyr), based on an increase in South American dust at the northernmost sites.
•There are clear changes in the source of dust supplied to the CEP before and after the deglaciation.•ITCZ position was at least 2.5° further south during MIS2 than that today.•The ITCZ migrated north during the Holocene, reaching its modern position after the mid-Holocene.•The main source of dust at 7°N in the CEP is Asian Loess.•The main source of dust at the equator is South America.
Protecting riparian vegetation around streams is vital in reducing the detrimental effects of environmental change on freshwater ecosystems and in maintaining aquatic biodiversity. Thus, identifying ...ecological thresholds is useful for defining regulatory limits and for guiding the management of riparian zones towards the conservation of freshwater biota.
Using nationwide data on fish and invertebrates occurring in small Brazilian streams, we estimated thresholds of native vegetation loss in which there are abrupt changes in the occurrence and abundance of freshwater bioindicators and tested whether there are congruent responses among different biomes, biological groups and riparian buffer sizes.
Mean thresholds of native vegetation cover loss varied widely among biomes, buffer sizes and biological groups: ranging from 0.5% to 77.4% for fish, from 2.9% to 37.0% for aquatic invertebrates and from 3.8% to 43.2% for a subset of aquatic invertebrates. Confidence intervals for thresholds were wide, but the minimum values of these intervals were lower for the smaller riparian buffers (50 and 100 m) than larger ones (200 and 500 m), indicating that land use should be kept away from the streams. Also, thresholds occurred at a lower percentage of riparian vegetation loss in the smaller buffers, and were critically lower for invertebrates: reducing only 6.5% of native vegetation cover within a 50‐m riparian buffer is enough to cross thresholds for invertebrates.
Synthesis and applications. The high variability in biodiversity responses to loss of native riparian vegetation suggests caution in the use of a single riparian width for conservation actions or policy definitions nationwide. The most sensitive bioindicators can be used as early warning signals of abrupt changes in freshwater biodiversity. In practice, maintaining at least 50‐m wide riparian reserves on each side of streams would be more effective to protect freshwater biodiversity in Brazil. However, incentives and conservation strategies to protect even wider riparian reserves (~100 m) and also taking into consideration the regional context will promote a greater benefit. This information should be used to set conservation goals and to create complementary mechanisms and policies to protect wider riparian reserves than those currently required by the federal law.
Resumo
Proteger a vegetação no entorno de riachos é vital para reduzir os efeitos das mudanças ambientais sobre os ecossistemas aquáticos e para a manutenção de sua biodiversidade. Assim, a identificação de limiares ecológicos é útil para regular os limites de uso e para orientar o manejo de zonas ripárias, visando a conservação da biota aquática.
Usando dados de peixes e invertebrados aquáticos de pequenos riachos do Brasil, nós estimamos os limiares de perda de vegetação nativa nos quais ocorrem mudanças abruptas na ocorrência e abundância de bioindicadores aquáticos. Também testamos se existem respostas congruentes entre os diferentes biomas, grupos biológicos e áreas de vegetação ripária (buffers).
Os valores médios dos limiares de perda de vegetação nativa variaram marcadamente entre biomas, tamanhos de buffer e grupos biológicos: entre 0,5% e 77,4% para peixes, entre 2,9% e 37,0% para invertebrados aquáticos e entre 3,8% e 43,2% para um subconjunto de invertebrados aquáticos. Os intervalos de confiança dos limiares foram amplos, mas os valores mínimos dos intervalos foram reduzidos para os menores buffers ripários (50 e 100 m) em comparação com os maiores (200 e 500 m), indicando que o uso do solo deve ser mantido longe dos riachos. Além disso, os limiares ocorreram em menores porcentagens de perda de vegetação ripária nos buffers menores, e foram criticamente baixos para invertebrados aquáticos: uma redução de apenas 6,5% da cobertura de vegetação nativa no buffer ripário de 50 m é suficiente para ultrapassar os limiares de perda de invertebrados.
Síntese e aplicações. A elevada variabilidade dos limiares de declínio abrupto da biodiversidade aquática em resposta a perda de vegetação ripária nativa sugere cautela no uso de uma largura única de proteção ripária para ações de conservação e definição de políticas nacionais. Os bioindicadores mais sensíveis podem ser usados como sinais precoces que alertam a aproximação de mudanças abruptas na biodiversidade aquática. Na prática, manter reservas ripárias (áreas de preservação permanente—APP) de pelo menos 50 m de largura, em ambos os lados dos riachos, parece ser mais efetivo em proteger a biodiversidade de água doce do Brasil. Contudo, incentivos e estratégias de conservação que protejam reservas ripárias ainda maiores (~100 m de largura) e que levem em consideração o contexto regional podem promover um maior benefício. Essas informações podem ser usadas para definir metas de conservação e para criar mecanismos e políticas complementares para proteger reservas ripárias (APP) ainda maiores do que aquelas atualmente requeridas pela lei federal.
The high variability in biodiversity responses to loss of native riparian vegetation suggests caution in the use of a single riparian width for conservation actions or policy definitions nationwide. The most sensitive bioindicators can be used as early warning signals of abrupt changes in freshwater biodiversity. In practice, maintaining at least 50‐m wide riparian reserves on each side of streams would be more effective to protect freshwater biodiversity in Brazil. However, incentives and conservation strategies to protect even wider riparian reserves (~100 m) and also taking into consideration the regional context will promote a greater benefit. This information should be used to set conservation goals and to create complementary mechanisms and policies to protect wider riparian reserves than those currently required by the federal law.
Morphogenesis of hierarchical vascular networks depends on the integration of multiple biomechanical signals by endothelial cells, the cells lining the interior of blood vessels. Expansion of ...vascular networks arises through sprouting angiogenesis, a process involving extensive cell rearrangements and collective cell migration. Yet, the mechanisms controlling angiogenic collective behavior remain poorly understood. Here, we show this collective cell behavior is regulated by non-canonical Wnt signaling. We identify that Wnt5a specifically activates Cdc42 at cell junctions downstream of ROR2 to reinforce coupling between adherens junctions and the actin cytoskeleton. We show that Wnt5a signaling stabilizes vinculin binding to alpha-catenin, and abrogation of vinculin in vivo and in vitro leads to uncoordinated polarity and deficient sprouting angiogenesis in
. Our findings highlight how non-canonical Wnt signaling coordinates collective cell behavior during vascular morphogenesis by fine-tuning junctional mechanocoupling between endothelial cells.
•We exhaustively evaluate two GPU strategies for evolutionary machine learning systems.•We use synthetic datasets to thoroughly explore the space of problem characteristics.•The findings of the ...evaluation on synthetic datasets translate to real-world problems.•Our findings help avoiding a blind trial-and-error calibration of GPU data mining code.
Graphics Processing Units (GPUs) are effective tools for improving the efficiency of many computationally demanding algorithms. GPUs have been particularly effective at speeding up the evaluation stage of evolutionary machine learning systems. The speedups obtained in these tasks, depend on many factors: dataset characteristics, the parallel strategy of the GPU code and the fit of the GPU code within the rest of the learning system. A solid understanding of all these factors is required to choose and adjust the most suitable GPU strategy in different scenarios. In this paper we present a large-scale performance evaluation of two GPU strategies for speeding up the evaluation of evolutionary machine learning systems. We use highly-tuneable synthetic problems to exhaustively explore the space of problem characteristics and determine the type of problems where each strategy performs best. The lessons learnt from this extensive evaluation are further confirmed by running experiments on a broad range of real-world datasets. Through this thorough evaluation we obtain a solid understanding of the capabilities and limitations of the evaluated GPU strategies for boosting the efficiency of evolutionary machine learning systems.
Mitochondrial translation normally requires formylation of the initiator tRNA‐met, a reaction catalyzed by the enzyme formyltransferase, Fmt1p and MTFMT in Saccharomyces cerevisiae and human ...mitochondria, respectively. Yeast fmt1 mutants devoid of Fmt1p, however, can synthesize all mitochondrial gene products by initiating translation with a non‐formylated methionyl‐tRNA. Yeast synthetic respiratory‐deficient fmt1 mutants have uncovered several factors suggested to play a role in translation initiation with non‐formylated methionyl‐tRNA. Here, we present evidence that Msc6p, a member of the pentatricopeptide repeat (PPR) motif family, is another essential factor for mitochondrial translation in fmt1 mutants. The PPR motif is characteristic of RNA‐binding proteins found in chloroplasts and plant and fungal mitochondria, and is generally involved in RNA stability and transport. Moreover, in the present study, we show that the respiratory deficiency of fmt1msc6 double mutants can be rescued by overexpression of the yeast mitochondrial initiation factor mIF‐2, encoded by IFM1. The role of Msc6p in translational initiation is further supported by pull‐down assays showing that it transiently interacts with mIF‐2. Altogether, our data indicate that Msc6p is an important factor in mitochondrial translation with an auxiliary function related to the mIF‐2‐dependent formation of the initiation complex.
In wild‐type (wt), yeast mitochondrial translation initiation normally requires the recognition of formylated fMet‐tRNAfMet by the mitochondrial initiation factor 2 (mIF‐2). Msc6p, a protein with pentatricopeptide repeat motifs, is necessary for mitochondrial translation initiation in yeast mutants devoid of the enzyme formyltransferase (∆fmt1). Our data indicate that Msc6p is an important auxiliary factor for mIF‐2‐dependent initiation of translation on mitoribosomes
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