Search

Personalized surgery; Tertiary hospital; Virtual planning Cirugía personalizada; Hospital terciario; Planificación virtual Cirurgia personalitzada; Hospital terciari; Planificació virtual Personalized surgery (PS) involves virtual planning (VP) and the use of 3D printing technology to design and manufacture custom-made elements to be used during surgery. The widespread use of PS has fostered a paradigm shift in the surgical process. A recent analysis performed in our hospital—along with several studies published in the literature—showed that the extensive use of PS does not preclude the lack of standardization in the process. This means that despite the widely accepted use of this technology, standard individual roles and responsibilities have not been properly defined, and this could hinder the logistics and cost savings in the PS process. The aim of our study was to describe the method followed and the outcomes obtained for the creation of a PS service for the Oral and Maxillofacial Surgery Unit that resolves the current absence of internal structure, allows for the integration of all professionals involved and improves the efficiency and quality of the PS process. We performed a literature search on the implementation of PS techniques in tertiary hospitals and observed a lack of studies on the creation of PS units or services in such hospitals. Therefore, we believe that our work is innovative and has the potential to contribute to the implementation of PS units in other hospitals.

By 2000 the European Union (EU) had recognized that its innovation capacity was underperforming in comparison to similar competitors and trading partners. Although the EU has made an effort to stimulate public research and development (R&D) through policy tools like Pre-Commercial Procurement (PCP) and Public Procurement of Innovation (PPI), starting with the 2000 Lisbon strategy and continuing through the 2021 updated Guidance on Innovation Procurement, there has remained a gap in knowledge of and use of these tools, in particular within health care. The past decades have seen an explosion in the number and use of digital technologies across the entire spectrum of health care. Demand-driven R&D has lagged here, while new digital health R&D has largely been driven by the supply side in a linear fashion, which can have disappointing results. PCP and PPI could have big impacts on the development and uptake of innovative health technology. The Platform for Innovation of Procurement and Procurement of Innovation (PiPPi) project was a Horizon 2020-funded project that ran from December 2018 to May 2022 with a consortium including seven of Europe’s premier research hospitals and the Catalan Agency for Health Information. To promote PCP and PPI, PiPPi established a virtual Community of Practice (CoP) that brings together all stakeholder groups to share and innovate around unmet health care needs. This commentary presents a brief history of PCP and PPI in Europe with a focus on digital innovation in health care before introducing the PiPPi project and its value proposition.

IntroductionThe assessment of current technologies needs a more holistic approach to obtain accurate recommendations for decision-making. The VALues In Doing Assessments of health TEchnologies (VALIDATE) methodology considers that facts and values from all stakeholders need to be included in the scoping of an assessment to gather the comprehensive information needed for unbiased decision-making. This report aimed to explore how to properly assess the integrated care of patients with aortic valve stenosis (AVS) using the VALIDATE approach.MethodsA literature review was conducted, and 11 semi-structured interviews were performed with various hospital-based healthcare professionals (cardiac surgeon, clinical cardiologist, interventional cardiologist, anesthetist, process coordinator nurse, and others) and patients. Content analysis was used for data analysis and integration.ResultsThe literature review showed that the cardiology and cardiac surgery perspectives were dominant in 90 percent of the articles and present in the remaining ten percent. The perspectives of other specialties (anesthesiology, primary care, and psychology) were included in three percent of the articles and patient perspectives were included in nine percent. Interviewing and considering the perspectives of the different stakeholders involved in the care pathway identified the following indicators that should be included in the assessment care for patients with AVS: difficulties associated with late diagnosis of AVS; the need to incorporate a multidisciplinary approach in patient risk assessment; the importance of geriatric evaluations; considering patient (and family and caregiver) preferences for type of treatment; the importance of following up pharmaceutical treatment and palliative care; use of telemonitoring; and digital exclusion of patients with respect to the use of apps for prehabilitation and rehabilitation.ConclusionsThe stakeholders interviewed were involved in different steps of the care pathway and had differing needs, some of which were not found in the literature. The indicators suggested for inclusion in the assessment differed according to type of stakeholder and their involvement in the care pathway. Therefore, this case study exemplifies the VALIDATE method and endorses the need for multistakeholder involvement in eliciting values when scoping the assessment of a complex technology.

BackgroundAlthough procurement of innovation is an established policy tool used to stimulate collaboration between supply- and demand-side entities during the development of new technologies, there is little scientific literature describing the process as applied in health care settings. Furthermore, what literature exists contains inconsistencies of terms, definitions, and/or concepts related to procurement of innovation. This protocol details our process for a systematic scoping review to describe the current scope of literature and to provide terminology clarification.MethodsA search strategy will be used to search PubMed, EMBASE [OVID], CINAHL [EBSCO], PsycINFO [ProQUEST], ABI/INFORM, ISI Web of Knowledge, EBSCO, JSTOR, the Cochrane Database of Systematic Reviews, and Google Scholar; grey literature, non-scientific reports, policy documents and expert recommendations will also be considered as additional sources for texts. Two researchers will screen titles and abstracts for inclusion/exclusion criteria, followed by full texts. We will extract the following data, if applicable: title, authors, date, author affiliations, country, journal/publication characteristics, setting, aims/purpose, methodology, sample characteristics, assessment/evaluation tools, outcome parameters, key findings, relevance, and terminology usage/definitions. Results will be presented narratively and visually.DiscussionThis paper describes the steps of our proposed systematic scoping review to identify and analyse scientific and non-scientific literature related to procurement of innovation and/or innovation of procurement in health care settings, with a particular focus on digital health technologies. Results are intended to demonstrate the current scope of literature, to provide clarity in language and therefore to serve as a first step for further research in this growing field.

Protein-protein interactions (PPIs) are crucial in many biological processes. The first step towards the molecular characterisation of PPIs implies the charting of their interfaces, that is, the surfaces mediating the interaction. To this end, we present here iFrag, a sequence-based computational method that infers possible interacting regions between two proteins by searching minimal common sequence fragments of the interacting protein pairs. By utilising the sequences of two interacting proteins (queries), iFrag derives a two-dimensional matrix computing a score for each pair of residues that relates to the presence of similar regions in interolog protein pairs. The scoring matrix is represented as a heat map reflecting the potential interface regions in both query proteins. Unlike existing approaches, iFrag does not require three-dimensional structural information or multiple sequence alignments and can even predict small interaction sites consisting only of few residues. Thus, predicted interfaces range from short fragments composed of few residues to domains of proteins, depending on available information on PPIs, as we demonstrate in several examples. Moreover, as a proof of concept, we include the experimental validation on the successful prediction of a peptide competing with the aggregation of β-amyloid in Alzheimer's disease. iFrag is freely accessible at http://sbi.imim.es/iFrag.

The activation of N-Methyl D-Aspartate Receptor (NMDAR) by glutamate is crucial in the nervous system function, particularly in memory and learning. NMDAR is composed by two GluN1 and two GluN2 subunits. GluN2B has been reported to participate in the prevalent NMDAR subtype at synapses, the GluN1/2A/2B. Here we studied the regulation of GluN2B expression in cortical neurons finding that glutamate up-regulates GluN2B translation through the action of nitric oxide (NO), which induces the phosphorylation of the eukaryotic translation initiation factor 2 α (eIF2α). It is a process mediated by the NO-heme-regulated eIF2α kinase (HRI), as the effect was avoided when a specific HRI inhibitor or a HRI small interfering RNA (siHRI) were used. We found that the expressed GluN2B co-localizes with PSD-95 at the postsynaptic ending, which strengthen the physiological relevance of the proposed mechanism. Moreover the receptors bearing GluN2B subunits upon NO stimulation are functional as high Ca2+ entry was measured and increases the co-localization between GluN2B and GluN1 subunits. In addition, the injection of the specific HRI inhibitor in mice produces a decrease in memory retrieval as tested by the Novel Object Recognition performance. Summarizing our data suggests that glutamatergic stimulation induces HRI activation by NO to trigger GluN2B expression and this process would be relevant to maintain postsynaptic activity in cortical neurons. This work was supported by the Plan Estatal de I+D+I 2013-2016 and the ISCIII-Subdirección/nGeneral de Evaluación y Fomento de la Investigación (Grants PI13/00408; PI13/00135; Red HERACLES RD12/0042/0014) and FEDER Funds; the Spanish Ministry of Economy and Competitiveness (SAF2014-52228-R; SAF2015-69762-R; BFU2015-68568-P); MINECO (PCIN-2014-105); Fundació la Marató de TV3 (20134030 and 20140210); FONDECYT 3140355 (ERF),/n1120512 (AAR) and 3120015 (LVR)

Aging is the main challenge that humanity will face on the near future. Brain aging is associated with cognitive deficiencies and is the main risk factor for Alzheimer’s Disease (AD). AD is the most common neurodegenerative disease leading to dementia caused by the aggregation of amyloid-β peptide (Aβ). In this thesis, we have shown that neuronal aging leads to alteration in the ganglioside membrane content. Specifically, increased levels of GM1 ganglioside in membrane leads to a decrease in the calcium entry through NMDA receptors and a reduction of dendritic spines. Overall, pointing a role in the alterations in learning and memory associated to aging. On the other hand, we have showed the inhibitory effect of the human gamma immunoglobulins (IgG) in Aβ aggregation through the antigen-binding fragment (Fab), which binds to Aβ blocking fibrillation progression. L’envelliment de la població és i serà un gran repte per la nostra societat en els pròxims anys. L’envelliment cerebral està associat amb deficiències cognitives i és el principal factor de risc pel desenvolupament de la malaltia d’Alzheimer. L’Alzheimer és la malaltia neurodegenerativa que més freqüentment provoca demència i és causada per l’agregació del pèptid β-amiloide (Aβ). En aquesta tesis hem demostrat que l’envelliment neuronal condueix a alteracions en el contingut de gangliòsids de les membranes. Particularment, l’increment del gangliòsid GM1 en la membrana condueix a una disminució en l’entrada de calci a través dels receptors de NMDA i a una reducció de les espines dendrítiques. En conjunt, indicant el rol de GM1 en les alteracions en l’aprenentatge i la memòria que es produeixen en l’envelliment. Per una altra banda, hem demostrat l’efecte inhibitori de gamma immunoglobulina humana (IgG) en la inhibició de l’agregació de l’Aβ a través del contacte del fragment d’unió a l’antigen (Fab). Fab s’uneix a Aβ inhibint la progressió de la fibril·lació.

Anxiety disorders are often associated with an inability to extinguish learned fear responses. The hypocretin/orexin system is involved in the regulation of emotional states and could also participate in the consolidation and extinction of aversive memories. Using hypocretin receptor-1 and hypocretin receptor-2 antagonists, hypocretin-1 and hypocretin-2 peptides, and hypocretin receptor-1 knockout mice, we investigated the role of the hypocretin system in cue- and context-dependent fear conditioning and extinction. Hypocretins were crucial for the consolidation of fear conditioning, and this effect was mainly observed in memories with a high emotional component. Notably, after the acquisition of fear memory, hypocretin receptor-1 blockade facilitated fear extinction, whereas hypocretin-1 administration impaired this extinction process. The extinction-facilitating effects of the hypocretin receptor-1 antagonist SB334867 were associated with increased expression of cFos in the basolateral amygdala and the infralimbic cortex. Intra-amygdala, but neither intra-infralimbic prefrontal cortex nor intra-dorsohippocampal infusion of SB334867 enhanced fear extinction. These results reveal a key role for hypocretins in the extinction of aversive memories and suggest that hypocretin receptor-1 blockade could represent a novel therapeutic target for the treatment of diseases associated with inappropriate retention of fear, such as post-traumatic stress disorder and phobias. This work was supported by the Instituto de Salud Carlos III grants, #PI13/00042 and #RD12/0028/0023 (RTA-RETICS), by the Spanish Ministry of Science #SAF2011-29864, the/nCatalan Government (SGR2009-00731), and by the Catalan Institution for Research and Advanced Studies (ICREA Academia program). África Flores is a recipient of a predoctoral fellowship from the Spanish Ministry of Education.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the pathological aggregation of the amyloid-β peptide (Aβ). Monomeric soluble Aβ can switch from helicoidal to β-sheet conformation, promoting its assembly into oligomers and subsequently to amyloid fibrils. Oligomers are highly toxic to neurons and have been reported to induce synaptic transmission impairments. The progression from oligomers to fibrils forming senile plaques is currently considered a protective mechanism to avoid the presence of the highly toxic oligomers. Protein nitration is a frequent post-translational modification under AD nitrative stress conditions. Aβ can be nitrated at tyrosine 10 (Y10) by peroxynitrite. Based on our analysis of ThT binding, Western blot and electron and atomic force microscopy, we report that Aβ nitration stabilizes soluble, highly toxic oligomers and impairs the formation of fibrils. We propose a mechanism by which fibril elongation is interrupted upon Y10 nitration: Nitration disrupts fibril-forming folds by preventing H14-mediated bridging, as shown with an Aβ analog containing a single residue (H to E) replacement that mimics the behavior of nitrated Aβ related to fibril formation and neuronal toxicity. The pathophysiological role of our findings in AD was highlighted by the study of these nitrated oligomers on mouse hippocampal neurons, where an increased NMDAR-dependent toxicity of nitrated Aβ oligomers was observed. Our results show that Aβ nitrotyrosination is a post-translational modification that increases Aβ synaptotoxicity. SIGNIFICANCE STATEMENT: We report that nitration (i.e., the irreversible addition of a nitro group) of the Alzheimer-related peptide amyloid-β (Aβ) favors the stabilization of highly toxic oligomers and inhibits the formation of Aβ fibrils. The nitrated Aβ oligomers are more toxic to neurons due to increased cytosolic calcium levels throughout their action on NMDA receptors. Sustained elevated calcium levels trigger excitotoxicity, a characteristic event in Alzheimer's disease. This work was supported by Spanish Plan Estatal de I+D+I 2013-2016 and the ISCIII-Subdirección General de Evaluación y Fomento de la Investigación Grants PI13/00408 and Red HERACLES RD12/0042/0014 and FEDER Funds, Spanish Ministerio de Economía y Competitividad BIO2014-57518-R, BIO2014-52872-R, and AGL2014-52395-C2-2-R and FEDER Funds, the Generalitat de Catalunya (Spain) 2014-SGR-938, and Chilean Funds for Science CONICYTPFB 12/2007 and FONDECYT N° 1160724. A.P.-M. was the recipient of the Universitat Autònoma de Barcelona-Programa Banco de Santander Fellowship

Gerard Ill-Raga et al., © 2014. Ischemic stroke is an acute vascular event that compromises neuronal viability, and identification of the pathophysiological mechanisms is critical for its correct management. Ischemia produces increased nitric oxide synthesis to recover blood flow but also induces a free radical burst. Nitric oxide and superoxide anion react to generate peroxynitrite that nitrates tyrosines. We found that fibrinogen nitrotyrosination was detected in plasma after the initiation of ischemic stroke in human patients. Electron microscopy and protein intrinsic fluorescence showed that in vitro nitrotyrosination of fibrinogen affected its structure. Thromboelastography showed that initially fibrinogen nitrotyrosination retarded clot formation but later made the clot more resistant to fibrinolysis. This result was independent of any effect on thrombin production. Immunofluorescence analysis of affected human brain areas also showed that both fibrinogen and nitrotyrosinated fibrinogen spread into the brain parenchyma after ischemic stroke. Therefore, we assayed the toxicity of fibrinogen and nitrotyrosinated fibrinogen in a human neuroblastoma cell line. For that purpose we measured the activity of caspase-3, a key enzyme in the apoptotic pathway, and cell survival. We found that nitrotyrosinated fibrinogen induced higher activation of caspase 3. Accordingly, cell survival assays showed a more neurotoxic effect of nitrotyrosinated fibrinogen at all concentrations tested. In summary, nitrotyrosinated fibrinogen would be of pathophysiological interest in ischemic stroke due to both its impact on hemostasis - it impairs thrombolysis, the main target in stroke treatments - and its neurotoxicity that would contribute to the death of the brain tissue surrounding the infarcted area., This work was supported by the Spanish Ministry of Science and Innovation (SAF2012-38140; SAF 2009-10365); Fondo de Investigación Sanitaria (FIS PI13/00408, FIS PI13/00864, CP04-00112, PS09/00664 and Red HERACLES RD12/0042/0014, RD12/0042/0016 and RD12/0042/0020); FEDER Funds; Generalitat de Catalunya (SGR09-1369); and Fundació la Marató de TV3 (100310)

El projecte “PROJECTE CONSTRUCTIU DE LA ESTACIÓ DEPURADORA D’AIGÜES RESIDUALS DE CARME I COL∙LECTORS EN ALTA” te com objectiu determinar i definir les actuacions necessàries per la concentració i tractament de les aigües residuals urbanes i industrials del nucli urbà de Carme, a l’Anoia. En la redacció del projecte l'obra s'ha considerat en la seva totalitat, entenent‐se que totes les instal∙lacions complementàries i les pròpies de depuració han estat contemplades en el projecte, de forma que una vegada executada estaria en condicions d'ésser lliurada i posada en servei per l’ús públic. Això implica el disseny de la pròpia planta de depuració, la construcció del col∙lector en alta per la connexió amb els col∙lectors en baixa municipals i la restitució de l’abocament, jardineria, vials, tancament, etc., així com totes aquelles obres necessàries per un bon funcionament de les instal∙lacions. La Generalitat de Catalunya, en exercici de les competències estatutàriament assumides en matèria de desenvolupament legislatiu i de gestió del medi ambient, així com l’exclusiva sobre aprofitaments hidràulics quan les aigües discorrin íntegrament dins de Catalunya, va aprovar la Llei 19/1991, del 7 de novembre, de reforma de la Junta de Sanejament, posteriorment modificada per la Llei 7/1994. Aquesta Llei reservava al Govern de la Generalitat l’aprovació del Pla de Sanejament de Catalunya i en regulava la tramitació, així com el contingut mínim. El Govern, en la sessió del 7 de novembre del 1995, va aprovar el Pla de Sanejament de Catalunya, en compliment de la Directiva 91/271/CEE, del Consell, del 21 de maig del 1991, sobre el tractament d’aigües residuals urbanes, modificada per la Directiva 98/15/CE, de la Comissió, del 27 de febrer, i de la normativa bàsica estatal, tot i avançant‐se en el calendari de les actuacions previstes per la legislació esmentada. El 10 de setembre del 2002, del Govern de la Generalitat, va aprovar el primer desenvolupament territorial del Programa de Sanejament d’Aigües Residuals Urbanes. En data del 20 de juny del 2006, s’aprova per acord del Govern de Catalunya la resolució MAH/2370/2006 per la que s’aprova el (2n) Programa de Sanejament d’Aigües Residuals Urbanes (PSARU 2005). En data 20 de juny de 2007, el Consell d’Administració de l’Agència Catalana de l’Aigua actualitza el anterior programa. El projecte actual està emmarcat en l’última actualització de l’ACA del PSARU 2005, com una actuació urgent, per tal d’assolir els objectius en relació al sanejament de les aigües residuals procedents de nuclis urbans, ateses la Directiva 91/271/CEE i la Directiva 2000/60/CE, del 23 d’octubre, per la qual s’estableix un marc comunitari d’actuació en l’àmbit de la política d’aigües, així com la normativa bàsica estatal. En aquest Programa de Sanejament d’Aigües Residuals Urbanes es planteja l’assoliment dels objectius de qualitat de l’aigua definits en la legislació vigent. En conseqüència, preveu les mesures a adoptar per part de l’Administració de la Generalitat de Catalunya en relació al sanejament de les aigües residuals urbanes per tal que, en relació als nuclis de més de 2.000 habitants o equivalents, s’acabin de complir els nivells de tractament que estableix la Directiva 91/271/CEE, i que, en relació als nuclis de menys de 2.000 habitants o equivalents, es realitzi un tractament adequat de les aigües residuals per tal que s’assoleixi un bon estat de les masses d’aigua superficials, en consonància amb els objectius de qualitat que el Programa incorpora com a valors de referència, en els termes previstos en la Directiva marc d’aigües i en el Text refós de la Llei d’aigües. A banda dels antecedents legislatius, la població de Carme té unes particularitats per les que és prioritària la redacció i execució del present projecte. Aquestes particularitats radiquen en les característiques del sistema de clavegueram, així com en el fet que tot i el poc cabal d’aigua de la riera en les temporades seques, les aigües residuals s’aboquen actualment directament a la riera sense cap mena de tractament previ. Això, tenint en compte que la riera travessa en els seus diferents meandres tota la localitat, provoca greus problemes de olors i salut pública. A més de la contaminació i problemes mediambientals que això suposa per un paratge de la bellesa de la vall de Carme. Pel que fa a la xarxa de clavegueram, la seva peculiaritat radica en que el nucli urbà es travessat per un reg patrimonial públic, que fa la funció de reg d’alguns dels horts urbans del poble, però arrel de la desordenada urbanització recent, fa també les funcions de claveguera i recol∙lecció d’aigües residuals. Aquesta barreja de les aigües de reg amb les aigües negres, provoca com es evident, diversos problemes, però el més important va ser l’aparició d’un brot de gastroenteritis per Sighella que afectà 8 habitats del poble al Octubre del 2007. La sighellosi, també coneguda com a Disenteria Bacil∙lar, és una malaltia infecto‐contagiosa actualment eradicada als països desenvolupats. Aquesta malaltia es relaciona amb la contaminació per aigües fecals de la xarxa de distribució d’aigua potable o per contaminació de l’aigua de reg de verdures o hortalisses. Aquesta problemàtica de salut pública, juntament amb els problemes mediambientals abans mencionats fan urgents l’execució d’un nou Pla Director de Clavegueram executat el 2008, i el present projecte constructiu del sistema de Tractament de les aigües residuals. Els annexos corresponents de la memòria contenen informació addicional sobre el sistema de Sanejament de Carme i les problemàtiques que això comporta.

Després de treballar durant gaire bé un any en una empresa de logística on es realitzen entregues exprés en menys d’una hora a la ciutat de Barcelona vam veure la necessitat de trobar un sistema que pogués ajustar el número de transportistes disponibles en cada moment a les necessitats dels clients. Tot això podria portar a reduir les incidències i augmentar el marge operacional per així oferir major planificació i facturació als transportistes. Per aconseguir un sistema que ens pogués dimensionar la xarxa vam buscar xarxes similars o que si més no poguessin inspirar-nos. Les xarxes de taxis respondrien aquestes característiques i ens vam inspirar en el model de Carlos F. Daganzo. La nostra xarxa no transportarà persones si no comandes i a més a més cada transportista podrà transportar més d’una comanda simultàniament, el mateix que succeeix amb l’UberPool amb persones. El model que hem posat a prova sorgeix de restringir el temps total de les comandes a 60 minuts i permetre que en portin més d’una simultàniament. Així tindrem en compte velocitats, distancies, temps de recollida i entrega, previsió de la demanda ... A més a més mitjançant el factor d’actualització que dependrà dels nous clients, l’estacionalitat i el creixement orgànic dels clients podrem ajustar-nos millor a la realitat. Un cop aplicat el nostre model el vam posar a prova a la xarxa real i vam obtenir el feedback durant 7 dies, això ens va permetre extreure el dimensionament requerit per la xarxa en cada moment i poder-lo comparar amb el que nosaltres havíem aplicat. Ens vam adonar que en els moments que el nostre model no s’ajustava era a causa d’una previsió de la demanda errònia. Així doncs vam provar el nostre model amb la demanda real i vam comprovar que s’ajustava a les necessitats de la xarxa. L’aplicació del nostre model va portar a augmentar un 4% el marge operacional, reduir les incidències en les operacions i optimitzar la utilització dels transportistes. Amb la millora de la previsió de la demanda encara es podrien aconseguir més millores tant per l’empresa com pels transportistes ja que la xarxa s’adaptaria encara millor a les necessitats. Així doncs l’obtenció del model ha servit per poder dimensionar la xarxa de forma automàtica setmana rere setmana i poder anar millorant el model en totes les seves febleses. Después de trabajar durante casi un año en una empresa de logística donde se realizan entregas exprés en menos de una hora en la Ciudad de Barcelona vimos la necesidad de encontrar un sistema que pudiese ajustar el número de transportistas disponibles en cada momento a las necesidades de los clientes. Todo esto podría llevar a la reducción de las incidencias y al aumentó del margen operacional para así poder ofrecer una mayor planificación y facturación a los transportistas. Para conseguir un sistema que nos pudiese dimensionar la red buscamos redes similares o que como mínimo pudiesen inspirarnos. Las redes de taxis responderían a estas características i nos inspiramos en el modelo de Carlos F.Daganzo. Nuestra red no transportará personas si no pedidos y además cada transportista podrá transportar más de un pedido simultáneamente, lo mismo que sucede con UberPool con personas. El modelo que hemos puesto a prueba surge de restringir el tiempo total de los pedidos a 60 minutos y permitir que lleven más de uno simultáneamente. Así tendremos en cuenta velocidades, distancias, tiempo de recogida y entrega, previsión de la demanda… Además mediante el factor de actualización que dependerá de los nuevos clientes, la estacionalidad y el crecimiento orgánico de los clientes podremos ajustarnos mejor a la realidad. Una vez aplicado nuestro modelo lo pusimos a prueba con la red real y obtuvimos el feedback durante 7 días, esto nos permitió extraer el dimensionamiento necesario para la red en cada momento y poderlo comparar con el que nosotros habíamos aplicado. Nos dimos cuenta que en los momentos que nuestro modelo no se ajustaba era a causa de una previsión de la demanda errónea. Así probamos nuestro modelo con la demanda real y pudimos comprobar que se ajustaba a las necesidades de la red. La aplicación del nuestro modelo hizo aumentar un 4% el margen operacional, redujo las incidencias en las operaciones y optimizó la utilización de los transportistas. Con la mejora de la previsión de la demanda aún se podrían conseguir más mejoras tanto para la empresa como para los transportistas ya que la red se adaptaría aún mejor a las necesidades. Así la obtención del modelo ha servido para poder dimensionar la red de forma automática semana tras semana y poder ir mejorando el modelo en todos sus puntos débiles. After working for almost a year in a logistics company where express deliveries are done in less than an hour in Barcelona. We saw the need to find a system that could adjust the number of available carriers at any time to the needs of the customers. All this would reduce incidents and increased the operational margin to be able to offer a greater planning and billing to the carriers. To achieve a system that ajust the network we search similar networks or at least inspire us. Taxi networks would respond to these characteristics and we were inspired by the model of Carlos F. Daganzo. Our network does not transport people, it will transport packages and in addition each carrier will be able to transport more than one order simultaneously, as it happens with UberPool with people. The model that we have tested comes from restricting the total order time to 60 minutes and allowing them to carry more than one package simultaneously. Thus we will use speeds, distances, collection and delivery time, demand forecast ... Also with the updating factor we can adjust better to reality, this will depend on the new customers, the seasonality and organic growth of the customers. Once we applied our model we tested it with the real network and obtained the feedback for 7 days, this allowed us to extract the necessary adjustment for the network at each moment and to be able to compare it with the one that we had applied. We realized that at times when our model did not fit was because of a wrong demand forecast. So we tested our model with real demand and we were able to verify that it fit the needs of the network. The model application increased the operating margin by 4%, reduced operational incidents and optimized the use of carriers. By improving demand forecast, more improvements could be achieved both for the company and for the carriers as the network would adapt even better to the needs. Finally the model has provided an automatic adjustment week after week and to be able to improve the model in all its weak points.

GNE myopathy is an autosomal recessive muscular disorder of young adults characterized by progressive skeletal muscle weakness and wasting. It is caused by a mutation in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene, which encodes a key enzyme in sialic acid biosynthesis. The mutated hypofunctional GNE is associated with intracellular accumulation of amyloid β-peptide (Aβ) in patient muscles through as yet unknown mechanisms. We found here for the first time that an experimental reduction in sialic acid favors Aβ1-42 endocytosis in C2C12 myotubes, which is dependent on clathrin and heparan sulfate proteoglycan. Accordingly, Aβ1-42 internalization in myoblasts from a GNE myopathy patient was enhanced. Next, we investigated signal changes triggered by Aβ1-42 that may underlie toxicity. We observed that p-Akt levels are reduced in step with an increase in apoptotic markers in GNE myopathy myoblasts compared to control myoblasts. The same results were experimentally obtained when Aβ1-42 was overexpressed in myotubes. Hence, we propose a novel disease mechanism whereby hyposialylation favors Aβ1-42 internalization and the subsequent apoptosis in myotubes and in skeletal muscle from GNE myopathy patients. This work was supported by Fundació la Marató de TV3 (100310); Supported by the Plan Estatal de I+D+I 2013-2016 and the ISCIII-Subdirección General de Evaluación y Fomento de la Investigación (Grants PI13/00408, PI08/00574 and Red HERACLES RD12/0042/0014) and FEDER; Generalitat de Catalunya (SGR09-1369).

AIMS: Hippocampus is the brain center for memory formation, a process that requires synaptogenesis. However, hippocampus is dramatically compromised in Alzheimer's disease due to the accumulation of amyloid β-peptide, whose production is initiated by β-site APP Cleaving Enzyme 1 (BACE1). It is known that pathological stressors activate BACE1 translation through the phosphorylation of the eukaryotic initiation factor-2α (eIF2α) by GCN2, PERK, or PKR kinases, leading to amyloidogenesis. However, BACE1 physiological regulation is still unclear. Since nitric oxide (NO) participates directly in hippocampal glutamatergic signaling, we investigated the neuronal role of the heme-regulated eukaryotic initiation factor eIF2α kinase (HRI), which can bind NO by a heme group, in BACE1 translation and its physiological consequences. RESULTS: We found that BACE1 is expressed on glutamate activation with NO being the downstream effector by triggering eIF2α phosphorylation, as it was obtained by Western blot and luciferase assay. It is due to the activation of HRI by NO as assayed by Western blot and immunofluorescence with an HRI inhibitor and HRI siRNA. BACE1 expression was early detected at synaptic spines, contributing to spine growth and consolidating the hippocampal memory as assayed with mice treated with HRI or neuronal NO synthase inhibitors. INNOVATION: We provide the first description that HRI and eIF2α are working in physiological conditions in the brain under the control of nitric oxide and glutamate signaling, and also that BACE1 has a physiological role in hippocampal function. CONCLUSION: We conclude that BACE1 translation is controlled by NO through HRI in glutamatergic hippocampal synapses, where it plays physiological functions, allowing the spine growth and memory consolidation. Supported by the Plan Estatal de I+D+i 2013-2016 and the ISCIII-Subdirección General de Evaluación y Fomento de la Investigación (Grants PI13/00408, BFU2012-33500 and Red HERACLES RD12/0042/0014) and FEDER Funds; Generalitat de Catalunya (SGR09-1369); and Fundació la Marató de TV3 (100310).

// Victoria Valls-Comamala 1 , Biuse Guivernau 1 , Jaume Bonet 2 , Marta Puig 1 , Alex Peralvarez-Marin 3 , Ernest Palomer 1 , Xavier Fernandez-Busquets 4, 5 , Xavier Altafaj 6 , Marta Tajes 7 , Albert Puig-Pijoan 8 , Ruben Vicente 1 , Baldomero Oliva 2 and Francisco J. Munoz 1 1 Laboratory of Molecular Physiology, Faculty of Health and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain 2 Laboratory of Structural Bioinformatics (GRIB), Faculty of Health and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain 3 Unitat de Biofisica, Departament de Bioquimica i de Biologia Molecular, Facultat de Medicina, Universitat Autonoma de Barcelona, Barcelona, Spain 4 Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain 5 ISGlobal, Barcelona Centre for International Health Research, Hospital Clinic-Universitat de Barcelona, Barcelona, Spain 6 Bellvitge Biomedical Research Institute (IDIBELL) - Unit of Neuropharmacology and Pain, University of Barcelona, Barcelona, Spain 7 Heart Diseases Biomedical Research Group, IMIM-Hospital del Mar Medical Research Institute, Barcelona, Spain 8 Servei de Neurologia, Hospital del Mar-IMIM-Parc de Salut Mar, Barcelona, Spain Correspondence to: Francisco J. Munoz, email: paco.munoz@upf.edu Keywords: Alzheimer’s disease, amyloid, immunoglobulin, Fab, oligomers Received: December 22, 2016 Accepted: March 22, 2017 Published: April 13, 2017 ABSTRACT The amyloid beta-peptide (Aβ) plays a leading role in Alzheimer’s disease (AD) physiopathology. Even though monomeric forms of Aβ are harmless to cells, Aβ can aggregate into β-sheet oligomers and fibrils, which are both neurotoxic. Therefore, one of the main therapeutic approaches to cure or delay AD onset and progression is targeting Aβ aggregation. In the present study, we show that a pool of human gamma immunoglobulins (IgG) protected cortical neurons from the challenge with Aβ oligomers, as assayed by MTT reduction, caspase-3 activation and cytoskeleton integrity. In addition, we report the inhibitory effect of IgG on Aβ aggregation, as shown by Thioflavin T assay, size exclusion chromatography and atomic force microscopy. Similar results were obtained with Palivizumab, a human anti-sincitial virus antibody. In order to dissect the important domains, we cleaved the pool of human IgG with papain to obtain Fab and Fc fragments. Using these cleaved fragments, we functionally identified Fab as the immunoglobulin fragment inhibiting Aβ aggregation, a result that was further confirmed by an in silico structural model. Interestingly, bioinformatic tools show a highly conserved structure able to bind amyloid in the Fab region. Overall, our data strongly support the inhibitory effect of human IgG on Aβ aggregation and its neuroprotective role.

Alzheimer's disease (AD) is characterized by the oxidative stress generated from amyloid β-peptide (Aβ) aggregates. It produces protein nitrotyrosination, after the reaction with nitric oxide to form peroxynitrite, being triosephosphate isomerase (TPI) one of the most affected proteins. TPI is a glycolytic enzyme that catalyzes the interconversion between glyceraldehyde 3-phosphate (GAP) and dihydroxyacetone phosphate (DHAP). Methylglyoxal (MG) is a by-product of TPI activity whose production is triggered when TPI is nitrotyrosinated. MG is harmful to cells because it glycates proteins. Here we found protein glycation when human neuroblastoma cells were treated with Aβ. Moreover glycation was also observed when neuroblastoma cells overexpressed mutated TPI where Tyr165 or Tyr209, the two tyrosines close to the catalytic center, were changed by Phe in order to mimic the effect of nitrotyrosination. The pathological relevance of these findings was studied by challenging cells with Aβ oligomers and MG. A significant decrease in mitochondrial transmembrane potential, one of the first apoptotic events, was obtained. Therefore, increasing concentrations of MG were assayed searching for MG effect in neuronal apoptosis. We found a decrease of the protective Bcl2 and an increase of the proapoptotic caspase-3 and Bax levels. Our results suggest that MG is triggering apoptosis in neurons and it would play a key role in AD neurodegeneration. This work was supported by the Plan Estatal de I+D+i 2013-2016 and the ISCIII-Subdirección General de Evaluación y Fomento de la Investigación (Grants PI13/00408, and Red HERACLES RD12/0042/0014) and FEDER Funds; the virtual physiological human (VPH) NoE (FP7-ICT-2007-2-223920), the Spanish Ministry of Science and Innovation (CTQ2008-00755; BFU2006-28430-E/BMC and RETIC COMBIOMED RD07/0067/0001); Generalitat de Catalunya (AGAUR BE-2 10240); and La Marató de TV3 (Nº 100310).

Dendritic spines are actin-rich protrusions from the dendritic shaft, considered to be the locus where most synapses occur, as they receive the vast majority of excitatory connections in the central nervous system (CNS). Interestingly, hippocampal spines are plastic structures that contain a dense array of molecules involved in postsynaptic signaling and synaptic plasticity. Since changes in spine shape and size are correlated with the strength of excitatory synapses, spine morphology directly reflects spine function. Therefore several neuropathologies are associated with defects in proteins located at the spines. The present work is focused on the spine actin cytoskeleton attending to its structure and function mainly in glutamatergic neurons. It addresses the study of the structural plasticity of dendritic spines associated with long-term potentiation (LTP) and the mechanisms that underlie learning and memory formation. We have integrated the current knowledge on synaptic proteins to relate this plethora of molecules with actin and actin-binding proteins. We further included recent findings that outline key uncharacterized proteins that would be useful to unveil the real ultrastructure and function of dendritic spines. Furthermore, this review is directed to understand how such spine diversity and interplay contributes to the regulation of spine morphogenesis and dynamics. It highlights their physiological relevance in the brain function, as well as it provides insights for pathological processes affecting dramatically dendritic spines, such as Alzheimer's disease. This work was supported by the Plan Estatal de I+D+i 2013-2016 and the ISCIII Subdirección General de Evaluación y Fomento de la Investigación (Grants PI13/00408, PI10/00587 and Red HERACLES RD12/0042/0014) and FEDER Funds; FEDER Funds; Generalitat de Catalunya (SGR09-1369); and Fundació la Marató de TV3 (100310).