Chemical physics insight of PPy-based modified ion exchange membranes: a fundamental approach

Four commercially available, cost-effective ion exchange membranes (two cationic and two anionic exchange membranes, CEMs and AEMs, respectively) were modified to mitigate crossover phenomena of the redox active species typically observed in Aqueous Organic Redox Flow Batteries (AORFB) systems. The modification strategy was carried out using a pyrrole(Py)-based polymer which successfully reduced the permeation of two redox active organic molecules, a viologen derivative (named BP7 throughout this study) and TEMPOL, by an order of magnitude. Additionally, modified membranes showed not significant changes in ion conductivity, with negligible effect on the electrical conductivity of the membranes at a given conditions. The morphology, physicochemical, mechanical, and electrochemical properties of the membranes were determined to evaluate the impact of these modifications. AEMs modified in this manner were found to have optimal properties, showing an increase in ion exchange capacity while maintaining excellent mechanical stability and unaltered permselectivity. Additionally, the diffusion boundary layer of these AEMs was slightly extended, which suggests a greater double layer stability for ion exchange processes than in the case of CEMs. Our work shows that these modified membranes could be an appealing approach for AORFB applicationsThis work has been funded by the European Union under the HIGREEW project, Affordable High-performance Green Redox Flow batteries (Grant agreement no. 875613). H2020: LC-BAT-4-2019875613

Micro-manufacturing : research, technology outcomes and development issues

Besides continuing effort in developing MEMS-based manufacturing techniques, latest effort in Micro-manufacturing is also in Non-MEMS-based manufacturing. Research and technological development (RTD) in this field is encouraged by the increased demand on micro-components as well as promised development in the scaling down of the traditional macro-manufacturing processes for micro-length-scale manufacturing. This paper highlights some EU funded research activities in micro/nano-manufacturing, and gives examples of the latest development in micro-manufacturing methods/techniques, process chains, hybrid-processes, manufacturing equipment and supporting technologies/device, etc., which is followed by a summary of the achievements of the EU MASMICRO project. Finally, concluding remarks are given, which raise several issues concerning further development in micro-manufacturing

Treatment challenges in and outside a specialist network setting: Pancreatic neuroendocrine tumours

Pancreatic Neuroendocrine Neoplasms comprise a group of rare tumours with special biology, an often indolent behaviour and particular diagnostic and therapeutic requirements. The specialized biochemical tests and radiological investigations, the complexity of surgical options and the variety of medical treatments that require individual tailoring, mandate a multidisciplinary approach that can be optimally achieved through an organized network. The present study describes currents concepts in the management of these tumours as well as an insight into the challenges of delivering the pathway in and outside a Network

Testicular germ-cell tumours and penile squamous cell carcinoma: Appropriate management makes the difference

Germ-cell tumours (GCT) of the testis and penile squamous cell carcinoma (PeSCC) are a rare and a very rare uro-genital cancers, respectively. Both tumours are well defined entities in terms of management, where specific recommendations - in the form of continuously up-to-dated guide lines-are provided. Impact of these tumour is relevant. Testicular GCT affects young, healthy men at the beginning of their adult life. PeSCC affects older men, but a proportion of these patients are young and the personal consequences of the disease may be devastating. Deviation from recommended management may be a reason of a significant prognostic worsening, as proper treatment favourably impacts on these tumours, dramatically on GCT and significantly on PeSCC. RARECAREnet data may permit to analyse how survivals may vary according to geographical areas, histology and age, leading to assume that non-homogeneous health-care resources may impact the cure and definitive outcomes. In support of this hypothesis, some epidemiologic datasets and clinical findings would indicate that survival may improve when appropriate treatments are delivered, linked to a different accessibility to the best health institutions, as a consequence of geographical, cultural and economic barriers. Finally, strong clues based on epidemiological and clinical data support the hypothesis that treatment delivered at reference centres or under the aegis of a qualified multi-institutional network is associated with a better prognosis of patients with these malignancies. The ERN EURACAN represents the best current European effort to answer this clinical need

Treatment challenges in and outside a network setting: Head and neck cancers

Head and neck cancer (HNC) is a rare disease that can affect different sites and is characterized by variable incidence and 5-year survival rates across Europe. Multiple factors need to be considered when choosing the most appropriate treatment for HNC patients, such as age, comorbidities, social issues, and especially whether to prefer surgery or radiation-based protocols. Given the complexity of this scenario, the creation of a highly specialized multidisciplinary team is recommended to guarantee the best oncological outcome and prevent or adequately treat any adverse effect. Data from literature suggest that the multidisciplinary team-based approach is beneficial for HNC patients and lead to improved survival rates. This result is likely due to improved diagnostic and staging accuracy, a more efficacious therapeutic approach and enhanced communication across disciplines. Despite the benefit of MTD, it must be noted that this approach requires considerable time, effort and financial resources and is usually more frequent in highly organized and high-volume centers. Literature data on clinical research suggest that patients treated in high-accrual centers report better treatment outcomes compared to patients treated in low-volume centers, where a lower radiotherapy-compliance and worst overall survival have been reported. There is general agreement that treatment of rare cancers such as HNC should be concentrated in high volume, specialized and multidisciplinary centers. In order to achieve this goal, the creation of international collaboration network is fundamental. The European Reference Networks for example aim to create an international virtual advisory board, whose objectives are the exchange of expertise, training, clinical collaboration and the reduction of disparities and enhancement of rationalize migration across Europe. The purpose of our work is to review all aspects and challenges in and outside this network setting planned for the management of HNC patients

Differential Scanning Fluorometry Signatures as Indicators of Enzyme Inhibitor Mode of Action: Case Study of Glutathione S-Transferase

Differential scanning fluorometry (DSF), also referred to as fluorescence thermal shift, is emerging as a convenient method to evaluate the stabilizing effect of small molecules on proteins of interest. However, its use in the mechanism of action studies has received far less attention. Herein, the ability of DSF to report on inhibitor mode of action was evaluated using glutathione S-transferase (GST) as a model enzyme that utilizes two distinct substrates and is known to be subject to a range of inhibition modes. Detailed investigation of the propensity of small molecule inhibitors to protect GST from thermal denaturation revealed that compounds with different inhibition modes displayed distinct thermal shift signatures when tested in the presence or absence of the enzyme's native co-substrate glutathione (GSH). Glutathione-competitive inhibitors produced dose-dependent thermal shift trendlines that converged at high compound concentrations. Inhibitors acting via the formation of glutathione conjugates induced a very pronounced stabilizing effect toward the protein only when GSH was present. Lastly, compounds known to act as noncompetitive inhibitors exhibited parallel concentration-dependent trends. Similar effects were observed with human GST isozymes A1-1 and M1-1. The results illustrate the potential of DSF as a tool to differentiate diverse classes of inhibitors based on simple analysis of co-substrate dependency of protein stabilization

Electrostatic Effects in the Folding of the SH3 Domain of the c-Src Tyrosine Kinase: pH-Dependence in 3D-Domain Swapping and Amyloid Formation

The SH3 domain of the c-Src tyrosine kinase (c-Src-SH3) aggregates to form intertwined dimers and amyloid fibrils at mild acid pHs. In this work, we show that a single mutation of residue Gln128 of this SH3 domain has a significant effect on: (i) its thermal stability; and (ii) its propensity to form amyloid fibrils. The Gln128Glu mutant forms amyloid fibrils at neutral pH but not at mild acid pH, while Gln128Lys and Gln128Arg mutants do not form these aggregates under any of the conditions assayed. We have also solved the crystallographic structures of the wild-type (WT) and Gln128Glu, Gln128Lys and Gln128Arg mutants from crystals obtained at different pHs. At pH 5.0, crystals belong to the hexagonal space group P6522 and the asymmetric unit is formed by one chain of the protomer of the c-Src-SH3 domain in an open conformation. At pH 7.0, crystals belong to the orthorhombic space group P212121, with two molecules at the asymmetric unit showing the characteristic fold of the SH3 domain. Analysis of these crystallographic structures shows that the residue at position 128 is connected to Glu106 at the diverging β-turn through a cluster of water molecules. Changes in this hydrogen-bond network lead to the displacement of the c-Src-SH3 distal loop, resulting also in conformational changes of Leu100 that might be related to the binding of proline rich motifs. Our findings show that electrostatic interactions and solvation of residues close to the folding nucleation site of the c-Src-SH3 domain might play an important role during the folding reaction and the amyloid fibril formation.This research was funded by the Spanish Ministry of Science and Innovation and Ministry of Economy and Competitiveness and FEDER (EU): BIO2009-13261-C02-01/02 (ACA); BIO2012-39922-C02-01/02 (ACA); CTQ2013-4493 (JLN) and CSD2008-00005 (JLN); Andalusian Regional Government (Spain) and FEDER (EU): P09-CVI-5063 (ACA); and Valentian Regional Government (Spain) and FEDER (EU): Prometeo 2013/018 (JLN). Data collection was supported by European Synchrotron Radiation Facility (ESRF), Grenoble, France: BAG proposals MX-1406 (ACA) and MX-1541 (ACA); and ALBA (Barcelona, Spain) proposals 2012010072 (ACA) and 2012100378 (ACA)

A fractal nature for polymerized laminin

Polylaminin (polyLM) is a non-covalent acid-induced nano- and micro-structured polymer of the protein laminin displaying distinguished biological properties. Polylaminin stimulates neuritogenesis beyond the levels achieved by ordinary laminin and has been shown to promote axonal regeneration in animal models of spinal cord injury. Here we used confocal fluorescence microscopy (CFM), scanning electron microscopy (SEM) and atomic force microscopy (AFM) to characterize its three-dimensional structure. Renderization of confocal optical slices of immunostained polyLM revealed the aspect of a loose flocculated meshwork, which was homogeneously stained by the antibody. On the other hand, an ordinary matrix obtained upon adsorption of laminin in neutral pH (LM) was constituted of bulky protein aggregates whose interior was not accessible to the same anti-laminin antibody. SEM and AFM analyses revealed that the seed unit of polyLM was a flat polygon formed in solution whereas the seed structure of LM was highly heterogeneous, intercalating rod-like, spherical and thin spread lamellar deposits. As polyLM was visualized at progressively increasing magnifications, we observed that the morphology of the polymer was alike independently of the magnification used for the observation. A search for the Hausdorff dimension in images of the two matrices showed that polyLM, but not LM, presented fractal dimensions of 1.55, 1.62 and 1.70 after 1, 8 and 12 hours of adsorption, respectively. Data in the present work suggest that the intrinsic fractal nature of polymerized laminin can be the structural basis for the fractal-like organization of basement membranes in the neurogenic niches of the central nervous system.This work was supported by a grant from the Brazilian National Research Council (CNPq; 476772/2008-7) to TCS. MSS acknowledges support from the European Research Council through ERC - 306990. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Hochman Méndez, C.; Cantini ., M.; Moratal Pérez, D.; Salmerón Sánchez, M.; Coelho-Sampaio, T. (2014). A fractal nature for polymerized laminin. PLoS ONE. 9(10):109388-1-109388-11. https://doi.org/10.1371/journal.pone.0109388S109388-1109388-11910Durbeej, M. (2009). Laminins. Cell and Tissue Research, 339(1), 259-268. doi:10.1007/s00441-009-0838-2Miner, J. H., & Yurchenco, P. D. (2004). LAMININ FUNCTIONS IN TISSUE MORPHOGENESIS. Annual Review of Cell and Developmental Biology, 20(1), 255-284. doi:10.1146/annurev.cellbio.20.010403.094555Yurchenco, P. D. (2010). Basement Membranes: Cell Scaffoldings and Signaling Platforms. Cold Spring Harbor Perspectives in Biology, 3(2), a004911-a004911. doi:10.1101/cshperspect.a004911Hohenester, E., & Yurchenco, P. D. (2013). Laminins in basement membrane assembly. Cell Adhesion & Migration, 7(1), 56-63. doi:10.4161/cam.21831Freire, E., & Coelho-Sampaio, T. (2000). Self-assembly of Laminin Induced by Acidic pH. Journal of Biological Chemistry, 275(2), 817-822. doi:10.1074/jbc.275.2.817Freire, E., Sant’Ana Barroso, M. M., Klier, R. N., & Coelho-Sampaio, T. (2011). Biocompatibility and Structural Stability of a Laminin Biopolymer. Macromolecular Bioscience, 12(1), 67-74. doi:10.1002/mabi.201100125Freire, E. (2002). Structure of laminin substrate modulates cellular signaling for neuritogenesis. Journal of Cell Science, 115(24), 4867-4876. doi:10.1242/jcs.00173Hochman-Mendez, C., Lacerda de Menezes, J. R., Sholl-Franco, A., & Coelho-Sampaio, T. (2013). Polylaminin recognition by retinal cells. Journal of Neuroscience Research, 92(1), 24-34. doi:10.1002/jnr.23298Menezes, K., Ricardo Lacerda de Menezes, J., Assis Nascimento, M., de Siqueira Santos, R., & Coelho-Sampaio, T. (2010). Polylaminin, a polymeric form of laminin, promotes regeneration after spinal cord injury. The FASEB Journal, 24(11), 4513-4522. doi:10.1096/fj.10-157628Barroso, M. M. S., Freire, E., Limaverde, G. S. C. S., Rocha, G. M., Batista, E. J. O., Weissmüller, G., … Coelho-Sampaio, T. (2008). Artificial Laminin Polymers Assembled in Acidic pH Mimic Basement Membrane Organization. Journal of Biological Chemistry, 283(17), 11714-11720. doi:10.1074/jbc.m709301200Freire, E. (2004). Sialic acid residues on astrocytes regulate neuritogenesis by controlling the assembly of laminin matrices. Journal of Cell Science, 117(18), 4067-4076. doi:10.1242/jcs.01276Hausdorff, F. (1918). Dimension und �u�eres Ma�. Mathematische Annalen, 79(1-2), 157-179. doi:10.1007/bf01457179Soille, P., & Rivest, J.-F. (1996). On the Validity of Fractal Dimension Measurements in Image Analysis. Journal of Visual Communication and Image Representation, 7(3), 217-229. doi:10.1006/jvci.1996.0020Theiler, J. (1990). Estimating fractal dimension. Journal of the Optical Society of America A, 7(6), 1055. doi:10.1364/josaa.7.001055Otsu, N. (1979). A Threshold Selection Method from Gray-Level Histograms. IEEE Transactions on Systems, Man, and Cybernetics, 9(1), 62-66. doi:10.1109/tsmc.1979.4310076Iranfar, H., Rajabi, O., Salari, R., & Chamani, J. (2012). Probing the Interaction of Human Serum Albumin with Ciprofloxacin in the Presence of Silver Nanoparticles of Three Sizes: Multispectroscopic and ζ Potential Investigation. The Journal of Physical Chemistry B, 116(6), 1951-1964. doi:10.1021/jp210685qPalmero, C. Y., Miranda-Alves, L., Sant’Ana Barroso, M. M., Souza, E. C. L., Machado, D. E., Palumbo-Junior, A., … Nasciutti, L. E. (2013). The follicular thyroid cell line PCCL3 responds differently to laminin and to polylaminin, a polymer of laminin assembled in acidic pH. Molecular and Cellular Endocrinology, 376(1-2), 12-22. doi:10.1016/j.mce.2013.05.020Behrens, D. T., Villone, D., Koch, M., Brunner, G., Sorokin, L., Robenek, H., … Hansen, U. (2012). The Epidermal Basement Membrane Is a Composite of Separate Laminin- or Collagen IV-containing Networks Connected by Aggregated Perlecan, but Not by Nidogens. Journal of Biological Chemistry, 287(22), 18700-18709. doi:10.1074/jbc.m111.336073Colognato, H., Winkelmann, D. A., & Yurchenco, P. D. (1999). Laminin Polymerization Induces a Receptor–Cytoskeleton Network. The Journal of Cell Biology, 145(3), 619-631. doi:10.1083/jcb.145.3.619Liesi, P., & Silver, J. (1988). Is astrocyte laminin involved in axon guidance in the mammalian CNS? Developmental Biology, 130(2), 774-785. doi:10.1016/0012-1606(88)90366-1Zhou, F. C. (1990). Four patterns of laminin-immunoreactive structure in developing rat brain. Developmental Brain Research, 55(2), 191-201. doi:10.1016/0165-3806(90)90200-iGarcia-Abreu, J., Cavalcante, L. A., & Neto, V. M. (1995). Differential patterns of laminin expression in lateral and medial midbrain glia. NeuroReport, 6(5), 761-764. doi:10.1097/00001756-199503270-00014Kazanis, I., & ffrench-Constant, C. (2011). Extracellular matrix and the neural stem cell niche. Developmental Neurobiology, 71(11), 1006-1017. doi:10.1002/dneu.20970Mercier F, Schnack J, Chaumet MSG (2011) Chapter 4 Fractones: home and conductors of the neural stem cell niche. In: Seki, T., Sawamoto, K., Parent, J. M., Alvarez-Buylla, A., (Eds.) Neurogenesis in the adult brain I: neurobiology. Springer. pp 109–133.CAVALCANTIADAM, E., MICOULET, A., BLUMMEL, J., AUERNHEIMER, J., KESSLER, H., & SPATZ, J. (2006). Lateral spacing of integrin ligands influences cell spreading and focal adhesion assembly. European Journal of Cell Biology, 85(3-4), 219-224. doi:10.1016/j.ejcb.2005.09.011Frith, J. E., Mills, R. J., & Cooper-White, J. J. (2012). Lateral spacing of adhesion peptides influences human mesenchymal stem cell behaviour. Journal of Cell Science, 125(2), 317-327. doi:10.1242/jcs.087916Hernández, J. C. R., Salmerón Sánchez, M., Soria, J. M., Gómez Ribelles, J. L., & Monleón Pradas, M. (2007). Substrate Chemistry-Dependent Conformations of Single Laminin Molecules on Polymer Surfaces are Revealed by the Phase Signal of Atomic Force Microscopy. Biophysical Journal, 93(1), 202-207. doi:10.1529/biophysj.106.102491Douet, V., Kerever, A., Arikawa-Hirasawa, E., & Mercier, F. (2013). Fractone-heparan sulphates mediate FGF-2 stimulation of cell proliferation in the adult subventricular zone. Cell Proliferation, 46(2), 137-145. doi:10.1111/cpr.12023Nikolova, G., Strilic, B., & Lammert, E. (2007). The vascular niche and its basement membrane. Trends in Cell Biology, 17(1), 19-25. doi:10.1016/j.tcb.2006.11.005Yurchenco, P. D., Amenta, P. S., & Patton, B. L. (2004). Basement membrane assembly, stability and activities observed through a developmental lens. 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Diminishing benefits of urban living for children and adolescents’ growth and development

Optimal growth and development in childhood and adolescence is crucial for lifelong health and well-being1–6. Here we used data from 2,325 population-based studies, with measurements of height and weight from 71 million participants, to report the height and body-mass index (BMI) of children and adolescents aged 5–19 years on the basis of rural and urban place of residence in 200 countries and territories from 1990 to 2020. In 1990, children and adolescents residing in cities were taller than their rural counterparts in all but a few high-income countries. By 2020, the urban height advantage became smaller in most countries, and in many high-income western countries it reversed into a small urban-based disadvantage. The exception was for boys in most countries in sub-Saharan Africa and in some countries in Oceania, south Asia and the region of central Asia, Middle East and north Africa. In these countries, successive cohorts of boys from rural places either did not gain height or possibly became shorter, and hence fell further behind their urban peers. The difference between the age-standardized mean BMI of children in urban and rural areas was <1.1 kg m–2 in the vast majority of countries. Within this small range, BMI increased slightly more in cities than in rural areas, except in south Asia, sub-Saharan Africa and some countries in central and eastern Europe. Our results show that in much of the world, the growth and developmental advantages of living in cities have diminished in the twenty-first century, whereas in much of sub-Saharan Africa they have amplified

Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128·9 million children, adolescents, and adults.

BACKGROUND: Underweight, overweight, and obesity in childhood and adolescence are associated with adverse health consequences throughout the life-course. Our aim was to estimate worldwide trends in mean body-mass index (BMI) and a comprehensive set of BMI categories that cover underweight to obesity in children and adolescents, and to compare trends with those of adults. METHODS: We pooled 2416 population-based studies with measurements of height and weight on 128·9 million participants aged 5 years and older, including 31·5 million aged 5-19 years. We used a Bayesian hierarchical model to estimate trends from 1975 to 2016 in 200 countries for mean BMI and for prevalence of BMI in the following categories for children and adolescents aged 5-19 years: more than 2 SD below the median of the WHO growth reference for children and adolescents (referred to as moderate and severe underweight hereafter), 2 SD to more than 1 SD below the median (mild underweight), 1 SD below the median to 1 SD above the median (healthy weight), more than 1 SD to 2 SD above the median (overweight but not obese), and more than 2 SD above the median (obesity). FINDINGS: Regional change in age-standardised mean BMI in girls from 1975 to 2016 ranged from virtually no change (-0·01 kg/m2 per decade; 95% credible interval -0·42 to 0·39, posterior probability [PP] of the observed decrease being a true decrease=0·5098) in eastern Europe to an increase of 1·00 kg/m2 per decade (0·69-1·35, PP>0·9999) in central Latin America and an increase of 0·95 kg/m2 per decade (0·64-1·25, PP>0·9999) in Polynesia and Micronesia. The range for boys was from a non-significant increase of 0·09 kg/m2 per decade (-0·33 to 0·49, PP=0·6926) in eastern Europe to an increase of 0·77 kg/m2 per decade (0·50-1·06, PP>0·9999) in Polynesia and Micronesia. Trends in mean BMI have recently flattened in northwestern Europe and the high-income English-speaking and Asia-Pacific regions for both sexes, southwestern Europe for boys, and central and Andean Latin America for girls. By contrast, the rise in BMI has accelerated in east and south Asia for both sexes, and southeast Asia for boys. Global age-standardised prevalence of obesity increased from 0·7% (0·4-1·2) in 1975 to 5·6% (4·8-6·5) in 2016 in girls, and from 0·9% (0·5-1·3) in 1975 to 7·8% (6·7-9·1) in 2016 in boys; the prevalence of moderate and severe underweight decreased from 9·2% (6·0-12·9) in 1975 to 8·4% (6·8-10·1) in 2016 in girls and from 14·8% (10·4-19·5) in 1975 to 12·4% (10·3-14·5) in 2016 in boys. Prevalence of moderate and severe underweight was highest in India, at 22·7% (16·7-29·6) among girls and 30·7% (23·5-38·0) among boys. Prevalence of obesity was more than 30% in girls in Nauru, the Cook Islands, and Palau; and boys in the Cook Islands, Nauru, Palau, Niue, and American Samoa in 2016. Prevalence of obesity was about 20% or more in several countries in Polynesia and Micronesia, the Middle East and north Africa, the Caribbean, and the USA. In 2016, 75 (44-117) million girls and 117 (70-178) million boys worldwide were moderately or severely underweight. In the same year, 50 (24-89) million girls and 74 (39-125) million boys worldwide were obese. INTERPRETATION: The rising trends in children's and adolescents' BMI have plateaued in many high-income countries, albeit at high levels, but have accelerated in parts of Asia, with trends no longer correlated with those of adults. FUNDING: Wellcome Trust, AstraZeneca Young Health Programme