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The first webinar of digiNEB.eu project Digital ecosystem for the New EuropeanBauhaus (NEB) took place on December 122022,with high-level representativesof the European Commission, digiNEB.eu project members, and experts inboth digital and NEB ecosystems discussing the role of digital technologies toaccomplish NEB’s main pillars of sustainability, aesthetics and inclusion. The webinar wasdivided into two main parts. The first introductory part illustratedthe digital solutions to expand the NEB's practices among stakeholders and user groups from different contexts. The second part involvedpanellists explaining how to better bring digital solutions to the world of NEB. This post-webinar report highlights the main topics, discussions and results coming from the webinar.

Microduplications involving the MYT1L gene have mostly been described in series of patients with isolated schizophrenia. However, few reports have been published, and the phenotype has still not been well characterized. We sought to further characterize the phenotypic spectrum of this condition by describing the clinical features of patients with a pure 2p25.3 microduplication that included all or part of MYT1L. Through a French national collaboration and a literature review, we assessed a large cohort of patients (n = 43) with pure 2p25.3 microduplications identified by chromosomal microarray analysis. For each case, we recorded clinical data, the microduplication size, and the inheritance pattern. The clinical features were variable and included developmental and speech delays (33%), autism spectrum disorder (23%), mild-to-moderate intellectual disability (21%), schizophrenia (21%), or behavioral disorders (16%). Eleven patients did not have an obvious neuropsychiatric disorder. The microduplications ranged from 62.4 kb to 3.8 Mb in size and led to either duplication of all or part of MYT1L. There were seven cases of intragenic duplication. The inheritance pattern was available for 18 patients: the microduplication was inherited in 13 cases, and all but one of the parents had a normal phenotype. Our comprehensive review and expansion of the phenotypic spectrum associated with 2p25.3 microduplications involving MYT1L (previously linked to schizophrenia) should help clinicians to better assess, counsel and manage affected individuals. MYT1L microduplications are characterized by a spectrum of neuropsychiatric phenotypes with incomplete penetrance and variable expressivity, which are probably due to as-yet unknown genetic and nongenetic modifiers.

On 7 September 2022, HSbooster.eu, the new service for Horizon Europe and Horizon 2020 projects that will support their ability to uptake Standardisation, participated in the “AI and Ethics in Manufacturing” workshop session at the Sustainable Places Conference in Nice, France. This presentation provides an overview of the HSbooster.eu standardisation services offered to closed or ongoing Horizon Europe and Horizon 2020 research and innovation projects. Firstly, Level 1 services provide baseline information on standardisation at an entry point level. Secondly, the proactive service identifies projects where standardisation activities are planned or likely and engages with them to directly map their activities to appropriate SDOs and identify their actual needs. Last, consultancy services offer projects who are interested in contributing to the creation of new standards or revision of existing standards some direct advice from standardisation experts. These services run for up to 3 months and will be extremely practical in nature. Learn more about the HSbooster.eu Open Calls for EU Projects and submit your application. Contact info@hsbooster.eu for more details.

The HSbooster.eu offers three levels of services to bridge the gap between the research and innovation community and the standards world. One of the most crucial aspects of the service matrix is to generate a model that is systematic, replicable and ‘customer’ centric, aiming at a high degree of automation. The automated service (T3.1) is the entry-level service offered by HSbooster.eu, aimed at providing practical guidance and support to steer the research results towards the most promising standardisation pathway. Such guidance is “automated” in the sense that it is spontaneously initiated by the user and offered online, mainly through the project website. Through the proactive service (T3.2) HSbooster.eu actively reaches out and contacts targeted projects where standardisation is deemed attractive and relevant. The proactive service is dialogue-based contrary to the automated service, which is one-way, and the premium service, where it is the expert (EPE) who offers the service and advice. The proactive service is led by the HSbooster.eu consortium and is based on the expertise and relations that the consortium builds upon, as well as the network and sources of information available through the consortium partners. The premium service (T3.3) is the flagship of the HSbooster.eu. The tailormade premium service is based on the effort of a dedicated expert (EPE) who is linked to a specific project within his/her expertise. The HSbooster.eu consortium role in the Premium Service level: • Act as a facilitator to matchmake the expert to the eligible project; • Develop criteria and assigns relevant experts to selected projects, with dedicated templates for experts to use; • Create an evaluation module and feedback system to applicants to monitor results; • Facilitate budget for projects to enrol in SDOs, WGs, and purchase copyrighted material (i.e standards, specifications); • Liaise with EPE for educational purposes on defining their roles and responsibilities. The Service Matrix has five distinct offerings: the EPE, the Open Calls, the Training material, the Standardisation readiness tool and the Mapping tool. The thinking behind the HSbooster.eu is that scalability and automation is key to securing a long-lasting impact of the project that can be sustained beyond its lifetime. Bridging the gap between the R&I community and the standards community will need a continuous effort and the HSbooster.eu is a vital starting point. The HSbooster.eu services will be constantly developed throughout the project lifetime to ensure the coherence and relevance of the offerings.

PurposeDue to its fast growth, cross-border e-commerce (CBEC) is becoming a popular internationalization model, especially in those destination markets with impressive e-commerce development like China. However, CBEC also brings new logistics challenges and uncertainty. This paper aims to understand how companies cope with logistics uncertainty in this field and whether the different types of uncertainty influence the risk management strategies adopted to face them.Design/methodology/approachA survey targeting online exporters to China and third-party forwarding logistics service providers (3PFLs) is conducted. A structural equation model (SEM) analysis is performed to test the possible relationship between the adopted risk management strategies and the types of uncertainty. The type, industry and size of the company, as well as the distance between the company's home country and China, are used as control variables in the study. Survey results are enriched via interviews with some of the respondents.FindingsThe risk management strategies adopted are dependent on the type of logistics uncertainty that the companies face and, to a minor extent, on the industry the company operates in. Conversely, no significant influence is exerted by other types of control factors, i.e. home country, company size or company type.Originality/valueThe paper investigates logistics uncertainty and risk management approaches in the novel context of CBEC. A systematic review of relevant sources of uncertainty is offered to help both scholars and practitioners understand the current complexities of CBEC. From a theoretical perspective, the paper models the investigated concepts in light of the contingency approach. From a practical perspective, results can be of interest since the list of proposed items can support risk identification and evaluation while the interviews with managers can provide insights on risk management practices.

Due to the collective attention towards global environmental challenges, the rise in fuel prices, the risk of drivers’ shortage, and the new legal developments limiting the hours of service on frequently congested roads, developing efficient and effective intermodal freight transport networks is becoming an increasingly important success factor for companies to manage their supply chains. However, many factors hinder the smooth implementation of intermodal systems, such as the high number of operators to be involved, the duplication of handling activities and transit times at the intersection of each transport mode, and the lack of information sharing among the different transport modes and companies. To overcome such barriers, Intelligent Communication Systems (ICS) have increasingly been applied to activities within the nodes (warehouses, transit points) and arches (transport routes) of distribution networks, providing several benefits, such as real-time visibility and tracking, more precise, reliable and efficient data collection, and document exchange. One of the key elements that can guarantee the successful design and implementation of an intermodal transport system is the integration of the various systems and actors involved along the process. This paper aims to contribute to this issue by presenting some of the results of the “ITS Italy 2020” project, an applied research initiative financed by the Italian Government to foster the diffusion of Intelligent Transport Systems (ITS). More specifically, we illustrate a prototype solution, based on a software that allows managing and monitoring freight transport along an intermodal network, thus overcoming some barriers currently limiting intermodal transport implementation. The prototype can communicate with devices and sensors put on board the vehicle or load, and track sensors positioned along the road. The solution integrates all the other systems involved by collecting and publishing information, managing events, and sending messages.

This study evaluates the implementation costs of cloud-based booking platforms (CBBPs) to manage vehicle queues in warehouses and investigates how cloud-based booking platforms support inter-organizational logistics processes. To understand the impact of CBBPs, we interviewed logistics managers concerning the structure of the CBBP processes, salient platform features, and their effects on inter-organizational dynamics. In addition, we conducted an analytical modeling simulation to compute the economic impact of each investment scenario. Our results show that CBBP benefits, and their financial viability, are sensitive to the size of a company and the selected decision driver (cost vs. time optimization). Hence, our findings challenge the standard view that adopting digital technologies in inter-organizational settings is an easy task.

Purpose The purpose of this paper is to support companies’ risk-informed selection of a logistics solution to operate in China via cross-border e-commerce (CBEC). Design/methodology/approach Decision theory is applied to the recent field of CBEC. This theoretic setup involves a decision maker who must choose among a set of alternatives, whose consequences depend on uncertain factors (Savage, 1954). The study develops an activity-based model to calculate logistics costs in a deterministic setting. Simulations and probabilistic sensitivity analyses are later performed to evaluate the impact of uncertainty. Findings There are four main solutions to enter China, determined by the adopted international transport mean and the presence of a local warehouse. The most important risk factors affecting the choice of the logistics solution are change of CBEC regulation, product value, expected service level and demand level. Originality/value From a theoretical perspective, this study improves CBEC literature, so far characterised by descriptive papers, often lacking industry focus or empirical exploration. It also provides new application opportunities for decision theory, whereas previous contributions have proposed different theoretical approaches, such as transaction cost or institutional theory. From a practical viewpoint, the paper is the first to compare the costs of the main logistics solutions to sell online to China, by taking uncertainty into account. The results can be used to better understand the differences among solutions and identify the most critical parameters. Finally, this research provides some observations for policy implementation.

Building on the resource-based view (RBV) perspective of the firm and firms’ competitive capabilities, this study examines the digital export drivers as means for firms to exploit opportunities brought about by digital technologies in their B2C digital marketing activities. By leveraging a unique dataset covering 102 Italy-based firms of different sizes (small, medium, and large), active in three different sectors (design and furniture, fashion, and food and beverage), this work examines the role of firm resources to support internationalization via digital channels. We find that: (1) SMEs do not suffer from a weaker propensity to engage with digital export despite resources constraints; (2) firms leveraging digital technologies are more likely to enhance their digital export, regardless of firm size; (3) digital capabilities are critical as firms employing an e-commerce manager have a higher propensity to undertake digital export than firms relying on a traditional export manager, regardless of firm size.

El efecto de la revolución digital ha sido escasamente abordado en la internacionalización de las PYME. Este artículo muestra que solo unas pocas empresas italianas en los sectores de la alimentación y la moda utilizan el comercio electrónico para la internacionalización. Las barreras son tanto tradicionales -los costes asociados a la logística y la adaptación a diferentes culturas- como las asociadas con el desconocimiento de los mercados digitales extranjeros, los requisitos legales para el comercio electrónico y el desconocimiento de los canales digitales o de los sistemas de pago en línea.

With the rise in global consumption and the consequent intensive demand for global resources, the attention of scholars and practitioners towards greener supply chains has grown over the years. In this context, this study has two main aims. The first is to offer an up-to-date literature review of the ways in which sustainability is pursued in diverse settings, based on the sector, the geographical area, and the level of adoption of digital technologies of a company. The second aim is to identify the research gaps in this field, and to suggest directions for future investigations. The results of the structured literature review reveal that, although developed and developing countries tend to focus on different types of sustainable interventions, three factors are consistently considered to be crucial for the success of a sustainable initiative in global supply chains. These factors are the collaboration along the supply chain, the commitment of the top management, and the presence of environmentally-oriented policies or regulations. These three factors complicate the decision-making process that is needed to implement sustainable practices. Therefore, we suggest ways in which to design future research that better capture the real challenges of making environmentally conscious decisions, leveraging on the concepts of the Intertwined Supply Network (ISN) and the cognitive frame.

PurposeThis paper reviews scientific publications in the field of logistics underlying cross-border e-commerce (CBEC) to China. A focus on the role played in this complex process by other countries of the Greater China is carried out. The purpose of this paper is to outline directions for future research to encourage CBEC development.Design/methodology/approachThe review is based on 32 papers published from 2002 to 2016 in international peer-reviewed journals or proceedings of international conferences, retrieved from bibliographic databases and science search engines.FindingsCBEC to China is gaining increasing interest, as shown by the rising amount of publications from 2013 onwards. Within these contributions, however, studies specifically investigating the relation between logistics and e-commerce, commonly acknowledged as critical, seem to lack. Many contributions are descriptive and do not provide specific insights on how to manage the complexities of CBEC logistics in this region. Stemming from the review, a set of possible development areas are identified, including distribution network design, i.e. deciding how to shape the CBEC distribution structure, and logistics outsourcing, i.e. determining whether to manage logistics activities in-house or through third parties.Originality/valueTo the extent of the authors’ knowledge, this paper is the first one to classify the existing body of knowledge on logistics supporting CBEC. Its main contribution is the critical identification of current research gaps and the proposal of key themes for future research. From a managerial perspective, it helps export and logistics managers identify the key challenges of managing CBEC logistics to Greater China.

Purpose: In the past few years China has experienced a significant growth of both its economy and the adoption of technologies. With 310 billion dollars turnover it has become one of the biggest B2C ecommerce markets in the world (WorldPay 2015). As Chinese consumers are generally leaned towards buying international brands, entering this market while exploiting the rising trend of online and mobile commerce adoption might be an interesting opportunity for western fashion companies. However, the ultimate success of an e-commerce initiative is strictly dependent on the effectiveness of the distribution process. Geographical and cultural distance, expected service level, tariff and non-tariff barriers are some of the elements making this activity more complex in a global environment. The aim of this paper is to provide a quantitative model to compare different logistic solutions underlying a B2C e-commerce initiative in China. The analysis takes the perspective of a European firm operating in the apparel industry. Research Approach: The paper has an empirical approach. It presents an Activity-based model to quantify the logistics costs of three logistics solutions that can be adopted to sell online in an international context. The alternatives have been identified through interviews and context data have been derived from case studies. The model has been eventually validated by industry experts and practitioners. The considered logistics options are (i) distribution from a warehouse located in China, (ii) distribution through a sorting hub located in China, and (iii) distribution from a warehouse in the Country of origin through express couriers. By elaborating some specific data (e.g. weight and volume of the garment) as inputs, the model returns the distributive solution associated to the lowest logistics costs. In addition, a sensitivity analysis is provided to take into account variations in both the annual demand of the item and its value. Originality: This study simultaneously addresses three major subjects which are relevant for a fashion company, i.e. the design of a logistics strategy, the use of e-commerce and the implementation of an internationalisation project. A preliminary literature review has revealed that these themes have largely been debated as stand-alone topics while the “intersection” of these fields has not been adequately investigated yet. Research Impact: The present study contributes to create knowledge in the field of technology-driven internationalisation strategies. At the same time, it paves the way to additional meaningful research that can be originated by addressing some of its limitations. For instance, one of the hints for future research on this topic is to evaluate the impact of product returns which can be complex to manage at an international level. Practical Impact: The main beneficiaries of this study are producers and/or retailers operating in the apparel industry. They can learn some of the logistics alternatives to serve the promising Chinese B2C e-commerce market and identify the most efficient strategy for them.

This paper addresses an identified need of quantitative models in the rising field of omni-channel (OC) purchasing sustainability. It contributes with a detailed assessment of the environmental impact of two processes, click and collect (C&C) and mobile shopping in store (MSiS), highlighting the weight of logistics activities. An activity-based model is developed and applied to a base case, that best represents the average purchasing process in the apparel industry, considering both the retailer's and the customer's perspectives. Sensitivity analyses are performed as well. Results show that MSiS is less sustainable than C&C, mainly due to the heavier impact of transport. For both configurations, the most critical parameter is the distance between the customer house and the store, whereas the customer profile and the location of the customer house (urban vs. extra-urban area) are additional significant factors for MSiS. The results of this study are also compared to previous research in the field of e-commerce environmental sustainability.

The predominant molecular symptom of aging is the accumulation of altered gene products. Moreover, several conditions including protein, lipid or glucose oxidation disrupt redox homeostasis and lead to accumulation of unfolded or misfolded proteins in the aging brain. Alzheimer's and Parkinson's diseases or Friedreich ataxia are neurological diseases sharing, as a common denominator, production of abnormal proteins, mitochondrial dysfunction and oxidative stress, which contribute to the pathogenesis of these so called "protein conformational diseases". The central nervous system has evolved the conserved mechanism of unfolded protein response to cope with the accumulation of misfolded proteins. As one of the main intracellular redox systems involved in neuroprotection, the vitagene system is emerging as a neurohormetic potential target for novel cytoprotective interventions. Vitagenes encode for cytoprotective heat shock proteins (Hsp) Hsp70 and heme oxygenase-1, as well as thioredoxin reductase and sirtuins. Nutritional studies show that ageing in animals can be significantly influenced by dietary restriction. Thus, the impact of dietary factors on health and longevity is an increasingly appreciated area of research. Reducing energy intake by controlled caloric restriction or intermittent fasting increases lifespan and protects various tissues against disease. Genetics has revealed that ageing may be controlled by changes in intracellular NAD/NADH ratio regulating sirtuin, a group of proteins linked to aging, metabolism and stress tolerance in several organisms. Recent findings suggest that several phytochemicals exhibit biphasic dose responses on cells with low doses activating signaling pathways that result in increased expression of vitagenes encoding survival proteins, as in the case of the Keap1/Nrf2/ARE pathway activated by curcumin and NAD/NADH-sirtuin-1 activated by resveratrol. Consistently, the neuroprotective roles of dietary antioxidants including curcumin, acetyl-l-carnitine and carnosine have been demonstrated through the activation of these redox-sensitive intracellular pathways. Although the notion that stress proteins are neuroprotective is broadly accepted, still much work needs to be done in order to associate neuroprotection with specific pattern of stress responses. In this review the importance of vitagenes in the cellular stress response and the potential use of dietary antioxidants in the prevention and treatment of neurodegenerative disorders is discussed. © 2008 Springer Science+Business Media, LLC.

Heme oxygenase (HO) and cyclooxygenase (COX) are two hemeproteins involved in the regulation of several functions in the nervous system. Heme oxygenase is the enzyme responsible for the degradation of heme into ferrous iron, carbon monoxide (CO), and biliverdin, the latter being further reduced in bilirubin (BR) by biliverdin reductase. Heme oxygenase-derived CO is a gaseous neuromodulator and plays an important role in the synaptic plasticity, learning and memory processes, as well as in the regulation of hypothalamic neuropeptide release, whereas BR is an endogenous molecules with antioxidant and anti-nitrosative activities. Cyclooxygenase is considered a pro-inflammatory enzyme as free radicals and prostaglandins (PGs) are produced during its catalytic cycle. Although PGs are also involved in a variety of physiologic conditions including angiogenesis, hemostasis, or regulation of kidney function, upregulation of COX and increase in PGs levels are a common feature of neuroinflammation. In the brain, a functional interplay exists between HO and COX. Heme oxygenase regulates COX activity by reducing the intracellular heme content or by generating CO, which stimulates PGE2 release. Increased levels of PGs, free radicals, and the associated oxidative stress serve in the brain as a trigger for the induction of HO isoforms which increases cellular antioxidant defenses to counteract oxidative damage. The importance of the interaction between HO and COX in the regulation of physiologic brain functions, and its relevance to neuroprotective or neurodegenerative mechanisms are discussed. © 2006 Wiley-Liss, Inc.

In the present study, we investigated the effect of Ginkgo biloba extract, EGb 761, and one of its components, bilobalide, on gene expression of subunit 1 of mitochondrial NADH dehydrogenase (ND1) in PC12 cells. By Northern blot analysis we found a ∼2-fold significant increase in ND1 mRNA level, after 48 and 72 h exposure to 100 μg/ml EGb 761 and to 10 μg/ml bilobalide. We also evaluated, by oxygraphy measurements, mitochondrial respiration during state 3 and state 4. In cells treated with EGb 761 and bilobalide for 48 and 72 h, state 4 respiration was significantly decreased, and the respiratory control ratio was increased. These results provide evidence that EGb 761 and bilobalide exert their protective effects by up-regulating mitochondrial ND1 gene expression and by decreasing state 4 respiration, whose increase is thought to be responsible for oxidative damage.

A study was undertaken in rats to evaluate the effects of short-term oral ethanol administration on the levels of fatty acid ethyl esters (FAEE) in brain and peripheral organs in the presence and absence of pretreatment with L-carnitine. Administration of ethanol to rats for seven days resulted in fatty acid ethyl ester formation, particularly in the heart and brain, but also in the kidney and liver. FAEE generation was associated with a significant increase of GSH transferase activity. Treatment with L-carnitine significantly reduced both FAEE and GSH transferase activity, and these effects were associated with a significant decrease in alcohol blood concentrations. The present evidence supports the hypothesis that fatty acid ethyl esters could be mediators involved in the production of alcohol-dependent syndromes. Administration of L-carnitine through an increment in lipid metabolism and turnover, and by the modulation of cellular antioxidant enzymes, greatly reduces these metabolic abnormalities supporting its potential usefulness as a pharmacological tool in alcoholism management.

Recent studies suggest a functional diversity of native alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate-type glutamate receptor channels (AMPARs). In several types of interneurons, AMPARs are characterized by higher Ca2+ permeability and faster kinetics than AMPARs in principal cells. We studied the expression profile of AMPAR subunits in the hippocampal parvalbumin (PV)- and calretinin (CR)-positive cells, which represent different populations of non-principal cells. To this end, non-radioactive in situ hybridization with AMPAR subunit specific cRNAs was combined with immunocytochemistry for PV or CR. Double-immunolabelling using antibodies against AMPAR subunits and PV or CR was also performed. PV-containing neurons represent a fairly homogeneous population of cells expressing high levels of GluR-A and GluR-D mRNAs, moderate levels of GluR-C and low levels of GluR-B mRNAs in all the examined regions of hippocampus. The vast majority of CR-containing cells have a much lower expression of GluR-A, -C and -D mRNA than PV-positive neurons, although similarly featuring low levels of GluR-B mRNA. Only a subpopulation of CR-containing cells, the spiny neurons of the dentate gyrus and CA3 region of the hippocampus were characterized by a strong expression of GluR-A and -D subunit mRNAs. The differential pattern found for the AMPAR subunit mRNA expression was confirmed by immunocytochemistry at protein level. Despite the common feature of low GluR-B subunit expression, PV- and CR-containing interneurons differ with respect to the density and combination of their expressed AMPAR subunits. The different combination of subunits might subserve different properties of the AMPA channels featured by these cell types, with implications for the functioning of the hippocampal network.

In the present study we evaluated the effects of NO synthase (NOS) induction on the regulation of cytochrome c oxidase (CO) and F0F1-ATPase subunit expression in astroglial and mixed cortical cell cultures. In mixed cortical cell cultures, 18 h of treatment with lipopolysaccharide (LPS, 0.1 microgram/mL) plus interferon-gamma (INF-gamma, 10 U/mL) caused an increase of mRNAs for CO-I, F0F1-ATPase 6 and also for iNOS at 20 DIV. The induction of both CO-I and F0F1-ATPase 6 was abolished by the NOS inhibitor N-monomethyl-L-arginine (NMMA) or by the enzymatic scavenger superoxide dismutase/catalase (SOD/CAT). In primary astroglial cell cultures, treatment for 18 h with increasing concentrations of LPS and INF gamma, produced an increase in the amount of mitochondrial encoded CO-I and -II subunits, with no significant modifications of nuclear encoded subunit IV. An increase was also observed at level of transcription for CO-I and -II, and F0F1-ATPase 6 mRNAs. These effects were abolished by addition of NMMA or SOD/CAT. mRNA induction of CO-I was higher in mixed cortical than in astroglial cell cultures while that of F0F1-ATPase 6 was similar in both cell types. These results suggest that the expression of mitochondrial encoded subunits (CO-I, CO-II and F0F1-ATPase 6) is up-regulated in response to oxygen and NO reactive species. The activity of cytochrome c oxidase decreased after LPS/INF gamma treatment in both astroglial and mixed cortical cultures. The activity of ATP synthase was unmodified, while ATP content drastically decreased after LPS/INF gamma treatment, in both astroglial and mixed cortical cultures. The enzymatic activities of catalase and Mn-SOD (mitochondrial) showed a significant increase after LPS/INF gamma treatment, which was abolished by NMMA.

In the present study we analyzed the age-dependent changes of mRNA levels for cytochrome c oxidase and F0F1-ATP synthase subunits in rat cerebral cortex and cerebellum. To establish whether the regulation of expression is transcriptional or post-transcriptional, the results were compared to those related to protein subunits levels, of the same enzymatic complexes, previously observed. The different patterns of age-related changes of mRNA subunits, in particular the lower increments, compared with those related to protein subunits, indicate that post-transcriptional mechanisms of regulation might be involved in the coordinated expression of the various subunits of each complex. Northern blotting analyses of RNA from the cerebellum of rats at the various ages, showed also differences in age-dependent patterns of transcription between cerebral cortex and cerebellum. Moreover, the major age-dependent changes of mitochondrial-encoded subunits, compared with the nuclear-encoded ones, previously observed at proteins level, occur also during transcription.

The causes of amyotrophic lateral sclerosis (ALS) are mostly undefined; however, excitotoxic injury and astrogliosis may contribute to motor neuron (MN) degeneration. Group I metabotropic glutamate (mGlu) receptors are over-expressed in reactive astrocytes in ALS, but the functional significance of this over-expression is presently unknown. We examined the role of group I mGlu receptors on excitotoxic death of spinal cord MNs grown in cultures enriched of astrocytes bearing a reactive phenotype. A prolonged exposure to the selective non-competitive mGlu5 receptor antagonist MPEP reduced AMPA-mediated toxicity and cobalt uptake in MNs. Expression levels of the GluR1 (but not GluR2) AMPA receptor subunit and levels of brain-derived neurotrophic factor (BDNF) were reduced in mixed spinal cord cultures pretreated with MPEP. In addition, neuroprotection by MPEP was less than additive with that produced by a neutralizing anti-BDNF antibody and a treatment with exogenous BDNF masked the protective effect of MPEP, suggesting that mGlu5 receptors and BDNF converge in facilitating excitotoxic MN death. The protective effect of MPEP was absent in cultures with a reduced number of astrocytes. We suggest that blocking astrocytic mGlu5 receptors is a potential therapeutic strategy in ALS. © 2011 Elsevier Inc.

The widely accepted oxidative stress theory of aging postulates that aging results from accumulation of oxidative damage. A prediction of this theory is that, among species, differential rates of aging may be apparent on the basis of intrinsic differences in oxidative damage accrual. Although widely accepted, there is a growing number of exceptions to this theory, most contingently related to genetic model organism investigations. Proteins are one of the prime targets for oxidative damage and cysteine residues are particularly sensitive to reversible and irreversible oxidation. The adaptation and survival of cells and organisms requires the ability to sense proteotoxic insults and to coordinate protective cellular stress response pathways and chaperone networks related to protein quality control and stability. The toxic effects that stem from the misassembly or aggregation of proteins or peptides, in any cell type, are collectively termed proteotoxicity. Despite the abundance and apparent capacity of chaperones and other components of homeostasis to restore folding equilibrium, the cell appears poorly adapted for chronic proteotoxic stress which increases in cancer, metabolic and neurodegenerative diseases. Pharmacological modulation of cellular stress response pathways has emerging implications for the treatment of human diseases, including neurodegenerative disorders, cardiovascular disease, and cancer. A critical key to successful medical intervention is getting the dose right. Achieving this goal can be extremely challenging due to human inter-individual variation as affected by age, gender, diet, exercise, genetic factors and health status. The nature of the dose response in and adjacent to the therapeutic zones, over the past decade has received considerable advances. The hormetic dose-response, challenging long-standing beliefs about the nature of the dose-response in a lowdose zone, has the potential to affect significantly the design of pre-clinical studies and clinical trials as well as strategies for optimal patient dosing in the treatment of numerous diseases. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing stress responses, including carnitines. This paper describes in mechanistic detail how hormetic dose responses are mediated for endogenous cellular defense pathways, including the possible signaling mechanisms by which the carnitine system, by interplaying metabolism, mitochondrial energetics and activation of critical vitagenes, modulates signal transduction cascades that confer cytoprotection against chronic degenerative damage associated to aging and neurodegenerative disorders.

Poly(ADP-ribose) polymerases (PARPs) play a crucial role in DNA damage surveillance through their nick sensor functions. Since PARPs' over activation leads to an excessive consumption of NAD(+) and ATP depletion, these enzymes also are involved in the early events of programmed cell death as well as in necrosis. In order to verify the protective action of L: -carnosine and trehalose against NO induced cell death, in the present study we examined their effects on the expression of PARP-1, PARP-2 and iNOS in primary rat astrocyte and oligodendrocyte cells, treated with lipopolysaccharide (LPS) and interferon gamma (INFγ), through semi-quantitative PCR and western analysis. To further characterize the molecular mechanisms underlying L-carnosine and trehalose action, we measured cell viability, nitrite production and LDH release. The data obtained clearly demonstrate that in the stress model employed L-carnosine and trehalose down regulate PARP-1 and PARP-2 expression in both cell phenotypes, thus suggesting their possible application in clinical trials.

The enzyme poly(ADP-ribose)polymerase (PARP) has a leader role in the DNA damage survey mechanisms by its nick-sensor function, but it is also involved in the early events of the programmed cell death, particularly during inflammatory injury, as a coactivator of NF-kB. In the present study, we evaluated the PARP involvement in the mechanisms of protection and/or cell death in rat astroglial cell cultures during the early phase of proinflammatory commitment after lipopolysaccharide and interferon gamma treatment. According with the recent findings that PARP-1 phosphorylation by MAPK/ERK-2 pathway seems to modulate PARP activation, in time course experiments we demonstrated that a very early PARP activation and expression is able to trigger a cell death pathway, DNA damage independent, during strong proinflammatory insults, maintaining its role of guardian of the genome stability only during the normal cell cycling.

Oxidative stress has been suggested to play a main role in the pathogenesis of type 2 diabetes mellitus and its complications. As a consequence of this increased oxidative status, a cellular-adaptive response occurs requiring functional chaperones, antioxidant production, and protein degradation. This study was designed to evaluate systemic oxidative stress and cellular stress response in patients suffering from type 2 diabetes–induced nephropathy and in age-matched healthy subjects. Systemic oxidative stress has been evaluated by measuring advanced glycation end-products (pentosidine), protein oxidation (protein carbonyls [DNPH]), and lipid oxidation (4-hydroxy-2-nonenal [HNE] and F2-isoprostanes) in plasma, lymphocytes, and urine, whereas the lymphocyte levels of the heat shock proteins (Hsps) heme oxygenase-1 (HO-1), Hsp70, and Hsp60 as well as thioredoxin reductase-1 (TrxR-1) have been measured to evaluate the systemic cellular stress response. We found increased levels of pentosidine (P < 0.01), DNPH (P < 0.05 and P < 0.01), HNE (P < 0.05 and P < 0.01), and F2-isoprostanes (P < 0.01) in all the samples from type 2 diabetic patients with nephropathy with respect to control group. This was paralleled by a significant induction of cellular HO-1, Hsp60, Hsp70, and TrxR-1 (P < 0.05 and P < 0.01). A significant upregulation of both HO-1 and Hsp70 has been detected also in lymphocytes from type 2 diabetic patients without uraemia. Significant positive correlations between DNPH and Hsp60, as well as between the degree of renal failure and HO-1 or Hsp70, also have been found in diabetic uremic subjects. In conclusion, patients affected by type 2 diabetes complicated with nephropathy are under condition of systemic oxidative stress, and the induction of Hsp and TrxR-1 is a maintained response in counteracting the intracellular pro-oxidant status.

At the end of the 1980s, it was clearly demonstrated that cells produce nitric oxide and that this gaseous molecule is involved in the regulation of the cardiovascular, immune and nervous systems, rather than simply being a toxic pollutant. In the CNS, nitric oxide has an array of functions, such as the regulation of synaptic plasticity, the sleep-wake cycle and hormone secretion. Particularly interesting is the role of nitric oxide as a Janus molecule in the cell death or survival mechanisms in brain cells. In fact, physiological amounts of this gas are neuroprotective, whereas higher concentrations are clearly neurotoxic.

Increasing evidence suggests a critical role for oxidative and nitrosative stress in the pathogenesis of most important neurodegenerative disorders. Parkinson's disease (PD) is a neurodegenerative disease characterized by a severe depletion in number of dopaminergic cells of the substantia nigra (SN). Administration of L-DOPA (LD) is the more effective treatment for patients with PD. However, the vast majority of patients suffer LD-related complications, which represent the major problem in the clinical management of PD. In the present study, LD administration to rats resulted in a significant dose-dependent increase in Hsp70 synthesis which was specific for the SN. The amount of 70 kDa protein increased after 6 h treatment reaching the maximal induction after 24-48 h. Induction of Hsp70 in the SN was associated with a significant increase in constitutive Hsc70 and mitochondrial Hsp60 stress proteins, and with increased expression of mitochondrial complex I whereas no significant changes were found in the activity of complex IV. In the same experimental conditions, a significant decrease in reduced glutathione was observed, which was associated with an increased content of oxidized glutathione content as well as nitric oxide (NO) synthase activity, NO metabolites and nitrotyrosine immunoreactivity. Interestingly, Hsp70 induction, iNOS up-regulation and nitrotyrosine formation have been confirmed also in SN and striatum of rats treated with LD and carbidopa, this latter being an inhibitor of the peripheral DOPA decarboxylase. Our data are in favor of the importance of the heat shock signal pathway as a basic mechanism of defense against neurotoxicity elicited by free radical oxygen and nitrogen species produced in aging and neurodegenerative disorders.