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Product-Service System (PSS) design methodologies have been extensively researched during the past years. Various tools and methods have been established for the incorporation of sustainability and system-oriented lifecycle thinking in the design of PSS. This paper presents an integrated collaborative platform that aspires to conceptualize a new landscape of modular product-services that will be tracked throughout their lifecycle using a network of smart sensors enabling the extraction of useful value. The concept is based on a series of distinct components supported by a common semantic knowledge base, enabling the seamless collaboration of partners of multiple disciplines for the realization of product-services. Moreover, a set of services are used, which are integrated with the sensor network to return information about the performance of the PSS to the customers and the product designer, supporting them in the decision making process. Finally, an application of the proposed methodology in an industrial scenario is presented. [ABSTRACT FROM AUTHOR]

• Atypical antipsychotics dramatically reduce the severity of EAE, the main animal model of MS. • Antipsychotics suppress the production of proinflammatory cytokines. • Clozapine reduces myeloid and T cell activation more than other antipsychotics. • Further research is needed to allow clinical testing on MS patients. The high efficacy of atypical antipsychotics (AAP) in treating diverse psychiatric disorders has been partly attributed to their capacity to curb neuroinflammation, a shared aspect of these diseases. These immunomodulatory properties of AAP have lately been explored in the context of multiple sclerosis (MS), an autoimmune demyelinating disease of the CNS. This study aimed to review in vivo studies reporting on the therapeutic effects of AAP both in EAE, the main animal model of MS and in cuprizone-induced demyelination. For that matter we conducted a literature search and a screening process that eventually yielded 8 eligible studies. All studies agreed on the efficiency of AAP to dramatically reduce EAE severity and delay its onset, while suppressing the production of numerous inflammatory cytokines. Clozapine showcased similar yet more intense effects than risperidone, quetiapine and olanzapine, significantly attenuating CD4 T cell infiltration and myeloid cell activation, while upregulating Tregs. Clozapine also downregulated chemokines responsible for the migration of immune cells in the CNS and caused dopamine receptor levels in the brain of EAE mice to rise. Taken together, these findings unanimously attest to the anti-inflammatory and immunomodulatory properties of AAP, suggesting that their therapeutic potential expands beyond their current neuropsychiatric applications. Despite the salutary effects of AAP in MS reported in vivo , a clinical trial of clozapine on MS patients failed to confirm preclinical findings due to low acceptability of AAP and early participant withdrawal. Although preclinical evidence unquestionably supports the multifaceted beneficial properties of AAP in MS, further investigation is required to elucidate the pharmacodynamic profile of these agents and allow for their proper clinical testing on MS patients. [ABSTRACT FROM AUTHOR]

Abstract: We isolated a chick homologue of BM88 (cBM88), a cell-intrinsic nervous system-specific protein and examined the expression of BM88 mRNA and protein in the developing brain, spinal cord and peripheral nervous system of the chick embryo by in situ hybridization and immunohistochemistry. cBM88 is widely expressed in the developing central nervous system, both in the ventricular and mantle zones where precursor and differentiated cells lie, respectively. In the spinal cord, particularly strong cBM88 expression is detected ventrally in the motor neuron area. cBM88 is also expressed in the dorsal root ganglia and sympathetic ganglia. In the early neural tube, cBM88 is first detected at HH stage 15 and its expression increases with embryonic age. At early stages, cBM88 expression is weaker in the ventricular zone (VZ) and higher in the mantle zone. At later stages, when gliogenesis persists instead of neurogenesis, BM88 expression is abolished in the VZ and cBM88 is restricted in the neuron-containing mantle zone of the neural tube. Association of cBM88 expression with cells of the neuronal lineage in the chick spinal cord was demonstrated using a combination of markers characteristic of neuronal or glial precursors, as well as markers of differentiated neuronal, oligodendroglial and astroglial cells. In addition to the spinal cord, cBM88 is expressed in the HH stage 45 (embryonic day 19) brain, including the telencephalon, diencephalon, mesencephalon, optic tectum and cerebellum. BM88 is also widely expressed in the mouse embryonic CNS and PNS, in both nestin-positive neuroepithelial cells and post-mitotic βIII-tubulin positive neurons. [Copyright &y& Elsevier]

Abstract: A permanent solution in order to remediate a heavily contaminated soil is washing it utilizing the appropriate reagents. The study presented in this paper deals with the washing of a soil highly polluted by mining and metallurgical activities. Pollution consists of slags, sulphur compound waste and various low grade lead condensates, all rich in heavy metals and metalloids (Pb, As, Cu, Zn, Mn and Fe). Soil was washed with deionized water, 6, 3, 2 and 1M HCl, 6M H2SO4, 6M HNO3 and 0.1M Na2EDTA. High extraction efficiency was achieved with respect to hydrochloric acid even at the lowest concentration; the solubility of pollutants in nitric acid was low, while sulphuric acid was proven to be problematic with respect to lead. Mobilization of metals and metalloids under DI water effect was minimal indicating that the elements fraction that is weakly bound to soil particles is insignificant. Furthermore, a kinetic study was undertaken, utilizing 1M HCl and 0.1M Na2EDTA. Results illustrated that 1M HCl was more effective for intermediate mixing times (up to 4h) while 0.1M Na2EDTA was better applicable to short mixing times (<1h) and low pH values (pH<7.1). 1M HCl was proven to be very effective for the removal of pollutants from contaminated soil but the high metal content of the resulting solution necessitates further treatment for the retention of metals. [Copyright &y& Elsevier]

We studied the amount of time required for treadmill familiarisation in older people and also whether familiarised treadmill walking could be generalised to overground walking. Sixteen healthy volunteers over 65 years of age walked on a level overground walkway and on a treadmill at the same speed for up to 15 min. A motion measurement system was used to measure the sagittal-plane kinematics of the knee and cadence during overground walking and after 0, 2, 4, 6, 8, 10, 12 and 14 min of treadmill walking. Older adults had not familiarised to the treadmill within 15 min as many participants continued to hold the treadmill’s handrails and as reliability and absolute difference scores were still changing. Participants were most familiarised after 14 min on the treadmill. Furthermore, treadmill walking after 14 min was not closely related to overground walking in older adults, with measures on the treadmill only being able to predict knee angles during overground to within 8.0°, or cadence to within 16.6 steps/min with 95% confidence. Treadmill walking in older adults after a single 15-min training session could not be generalised to overground walking. [Copyright &y& Elsevier]

Alzheimer's disease (AD) is the most common form of dementia worldwide, characterized by a progressive decline in a variety of cognitive and non-cognitive functions. The amyloid beta protein cascade hypothesis places the formation of amyloid beta protein aggregates on the first position in the complex pathological cascade leading to neurodegeneration, and therefore AD might be considered to be a protein-misfolding disease. The Ubiquitin Proteasome System (UPS), being the primary protein degradation mechanism with a fundamental role in the maintenance of proteostasis, has been identified as a putative therapeutic target to delay and/or to decelerate the progression of neurodegenerative disorders that are characterized by accumulated/aggregated proteins. The purpose of this study was to test if the activation of proteasome in vivo can alleviate AD pathology. Specifically by using two compounds with complementary modes of proteasome activation and documented antioxidant and redox regulating properties in the 5xFAD transgenic mice model of AD, we ameliorated a number of AD related deficits. Shortly after proteasome activation we detected significantly reduced amyloid-beta load correlated with improved motor functions, reduced anxiety and frailty level. Essentially, to our knowledge this is the first report to demonstrate a dual activation of the proteasome and its downstream effects. In conclusion, these findings open up new directions for future therapeutic potential of proteasome-mediated proteolysis enhancement. Image 1 • Proteasome function is impaired in Alzheimer's disease (AD). • Two compounds transcriptionally and structurally activate proteasome in 5xFAD mice. • Proteasome activation is followed by a decrease in amyloid-beta (Aβ) load. • Reduced amount of Aβ correlates with significantly improved behavior and frailty level. • Proteasome activation represents a promising intervention for alleviating AD pathology. [ABSTRACT FROM AUTHOR]

Failure of the mammalian central nervous system (CNS) to regenerate effectively after injury leads to mostly irreversible functional impairment. Gold nanoparticles (AuNPs) are promising candidates for drug delivery in combination with tissue-compatible reagents, such as polyethylene glycol (PEG). PEG administration in CNS injury models has received interest for potential therapy, but toxicity and low bioavailability prevents clinical application. Here we show that intraspinal delivery of PEG-functionalized 40-nm-AuNPs at early stages after mouse spinal cord injury is beneficial for recovery. Positive outcome of hind limb motor function was accompanied by attenuated inflammatory response, enhanced motor neuron survival, and increased myelination of spared or regrown/sprouted axons. No adverse effects, such as body weight loss, ill health, or increased mortality were observed. We propose that PEG-AuNPs represent a favorable drug-delivery platform with therapeutic potential that could be further enhanced if PEG-AuNPs are used as carriers of regeneration-promoting molecules. [ABSTRACT FROM AUTHOR]

Abstract: The objective of this study was to evaluate the effects of two commercially available semen extenders on the motility of cryopreserved goat sperm and to simplify the cryopreservation protocol. Individual goat ejaculates were split and processed in parallel for freezing in either commercially available soy-based extender (Bioxcell®) or egg yolk-based extender (Irvine TYB). Sperm quality was assessed using total and progressive sperm motility, measured by computer-assisted sperm analysis (CASA). Total motility was higher for samples processed in soy-based extender, both at pre-freeze (P = 0.002) and at post-thaw (P < 0.0001). Progressive motility was higher for semen processed in soy extender at post-thaw (P < 0.0001). Approximately 10% of samples processed in egg yolk-based extender had a large (> 50%) reduction in total motility prior to freezing. However, this type of extreme reduction in pre-freeze motility did not occur in semen samples processed in soy extender. In addition, the use of soy-based extender eliminated the need for a time-consuming sperm washing protocol. We concluded that a commercially available soy-based extender was superior to an egg yolk-based extender in preserving motility of cryopreserved goat sperm, using a two-step method. [Copyright &y& Elsevier]

Abstract: In neurogenesis, little is known about signal transduction pathways upstream of gene expression however, mounting evidence suggests that calcium release from internal stores plays a critical role. We have previously demonstrated that BM88 is a neuronal lineage-specific regulator of cell cycle exit and differentiation; we now report a link between BM88 and calcium signaling. Calcium imaging experiments revealed that P2Y-induced calcium mobilization is diminished in mouse neuroblastoma Neuro 2a cells stably transfected with BM88 (N2A-BM88 cells) as compared with N2A cells or N2A cells differentiated with retinoic acid. This effect is not restricted to N2A cells but is also observed in HeLa cells that are transiently transfected with BM88, indicating that cells of both neural and non-neural origin respond similarly. Further, activation of P2Y1 but not purinergic P2X receptors induces proliferation of N2A and to a lesser extent of N2A-BM88 cells. Conversely, knockdown of BM88 facilitates N2A cell proliferation both under stimulating and non-stimulating conditions. Importantly, N2A-BM88 cells are less susceptible to apoptosis triggered by C2-ceramide and exhibit reduced C2-ceramide-induced intracellular calcium release. Higher calcium uptake from mitochondria and/or lower calcium levels inside the endoplasmic reticulum may explain the reduced calcium mobilization in response to BM88. Overall, our data reveal a novel signaling mechanism by which BM88 interferes with calcium release from inositol 1,4,5-trisphosphate-sensitive stores and exerts anti-proliferative and anti-apoptotic functions. [Copyright &y& Elsevier]

HSP90 is a ubiquitously expressed molecular chaperone that controls the folding, assembly, intracellular disposition, and proteolytic turnover of many proteins, most of which are involved in signal transduction processes. Recently, a surface form of HSP90 has been identified and associated with cell migration events. In this paper, we explore the interaction of surface HSP90 with HER-2, a receptor-like glycoprotein and member of the ErbB family of receptor tyrosine kinases that play central roles in cellular proliferation, differentiation, and migration as well as in cancer progress. The involvement of HSP90 in the regulation of HER-2 has been attributed so far to receptor stabilization via interaction with its cytoplasmic kinase domain. Here we present evidence, using glutathione S-transferase pull-down and transfection assays, for a novel interaction between surface HSP90 and the extracellular domain of HER-2. Specific disruption of this interaction using mAb 4C5, a function-blocking monoclonal antibody against HSP90, inhibits cell invasion accompanied by altered actin dynamics in human breast cancer cells under ligand stimulation conditions with heregulin. Additionally, disruption of surface HSP90/HER-2 interaction leads to inhibition of heregulin-induced HER-2-HER-3 heterodimer formation, reduced HER-2 phosphorylation, and impaired downstream kinase signaling. Interestingly, this disruption does not affect HER-2 internalization. Our data suggest that surface HSP90 is involved in heregulin-induced HER-2 activation and signaling, leading to cytoskeletal rearrangement, essential for cell invasion. [ABSTRACT FROM AUTHOR]

Control of cell cycle progression/exit and differentiation of neuronal precursors is of paramount importance during brain development. BM88 is a neuronal protein associated with terminal neuron-generating divisions in vivo and is implicated in mechanisms underlying neuronal differentiation. Here we have used mouse neuroblastoma Neuro 2a cells as an in vitro model of neuronal differentiation to dissect the functional properties of BM88 by implementing gain- and loss-of-function approaches. We demonstrate that stably transfected cells overexpressing BM88 acquire a neuronal phenotype in the absence of external stimuli, as judged by enhanced expression of neuronal markers and neurite outgrowth-inducing signaling molecules, In addition, cell cycle measurements involving cell growth assays, BrdUrd incorporation, and fluorescence-activated cell sorting analysis revealed that the BM88-transfected cells have a prolonged G1 phase, most probably corresponding to cell cycle exit at the G0 restriction point, as compared with controls. BM88 overexpression also results in increased levels of the cell cycle regulatory protein p53, and accumulation of the hypophosphorylated form of the retinoblastoma protein leading to cell cycle arrest, with concomitant decreased levels and, in many cells, cytoplasmic localization of cyclin D1. Conversely, BM88 gene silencing using RNA interference experiments resulted in acceleration of cell proliferation accompanied by impairment of retinoic acid-induced neuronal differentiation of Neuro 2a cells. Taken together, our results suggest that BM88 plays an essential role in regulating cell cycle exit and differentiation of Neuro 2a cells toward a neuronal phenotype and further support its involvement in the proliferation/differentiation transition of neural stem/progenitor cells during embryonic development. [ABSTRACT FROM AUTHOR]