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Fil: Terroba Chambi, Cinthia. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Terroba Chambi, Cinthia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Terroba Chambi, Cinthia. Fleni. Departamento de Neurociencias; Argentina Fil: Bruno, Veronica. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Bruno, Veronica. Fleni. Departamento de Neurociencias; Argentina Fil: Bruno, Veronica. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Medina Escobar, Alex. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Medina Escobar, Alex. Fleni. Departamento de Neurociencias; Argentina Fil: Nanni, Federico. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Nanni, Federico. Fleni. Departamento de Neurociencias; Argentina Fil: Cerquetti, Daniel. Fleni. Departamento de Neurociencias; Argentina Fil: Cerquetti, Daniel. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Rossi, Malco Damián. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Rossi, Malco Damián. Fleni. Departamento de Neurociencias; Argentina Fil: Merello, Marcelo. Fleni. Departamento de Neurociencias; Argentina Fil: Merello, Marcelo. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Merello, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Abstract: Objective - To determine the utility of an electronic diary for registering motor fluctuations and dyskinesia in Parkinson disease (PD). Methods - Free, open-access touch screen software suitable for Android 4.4 or higher, with medication alarms, adjustable intervals, and medication dose settings was developed to evaluate ON-OFF periods and dyskinesia. Prospective evaluation included a first phase conducted to make adjustments concerning motor limitations when using the tablet, as well as for proper motor complication identification, and a second phase of 3 days of use at home with a prior diary training session comparing a modified paper version of Core Assessment Program for Surgical Interventional Therapies in PD and the electronic diary. Results - All patients correctly identified ON-OFF periods and dyskinesia. Rater/patient matching ON-OFF fluctuations ranged between 94% and 100% for evaluations of different motor states. Dyskinesia matching percentage was 100% for patients with dyskinesia interfering with activities of daily living and 88% for those who reported no-interference. No significant differences between paper and electronic diaries were identified when reporting ON-OFF motor states or in the number of errors when filling the diaries. Conclusions - This electronic motor diary proved to be reliable for ON-OFF state and dyskinesia identification and classification. However, no advantage to paper diary has been observed in terms of number of erroneous entries. Based on these results, to improve home motor fluctuations, detection efforts should be directed toward the development of automatic wearable devices rather than digital versions of current available ON-OFF diaries.

INTED 2015, 9 th International Technology, Education and Development Conference, March 2 nd-4 th, 2015-Madrid, Spain, A group of lecturers from diverse areas of knowledge of the University of Alcalá have implemented an experience of teaching innovation based on “reflective diaries”. The students hand in to the lecturer every week their “Weekly Reflection Papers” (WRP), in which they schematically express the most important ideas related with the topic presented during the classes of the previous week. They must include their reflections about the aspects they found especially interesting. After having applied this tool for some academic years we introduced a modification called “Guided Weekly Reflection Papers” (GWRP), where the professors suggest a series of questions on which the students must apply the most significant concepts studied each week. This modification enhances student’s motivation, encourages them to achieve more significant and reflective knowledge and generates interest in emergent topics. However, we often detect that the information management needed to solve the proposed questions in the GWRP is not the most suitable one. Therefore our present work is aimed at helping students develop the necessary skills and acquire a searching criterion in the framework of the information literacy. The strategy was focussed on some important items for the acquisition of information competencies. In this communication we analyze the progress of the GWRP tool and we explore the response of students to the information literacy approach.

The experience gained by our team of educational innovation with the implementation of the “Weekly Reflection Papers” has led us to diversify and make more flexible the employed methodology. The modified tool, applied during the academic year 2010-2011, was called “Guided Weekly Reflection Papers”. The aim of this modification has been the development of certain abilities and skills of the students, with particular emphasis on their ability to integrate, review and apply knowledge in a critical and reflective way. The professors guide the student´s work through a series of questions on which the students must apply the most significant concepts studied each week, to prove the acquisition of such aptitudes and skills.

A group of lecturers from different teaching areas at Alcalá University concern by Innovative Education had implemented during four academic years a learning tool based on “reflective weekly papers”. With the experience gained in this process we have carried out an essential modification in the procedure which provides the students the possibility of a more active and participative learning called Guided Weekly Reflective Papers. In this communication we present the adaptation of this educational method for the first time as a valuable strategy for improving the learning environment in secondary schools, as an extension of its implementation at the University level and as a contribution to the integral formation and meaningful learning of the secondary level students.

Item does not contain fulltext AIMS: Homozygous familial hypercholesterolaemia (HoFH) is a rare life-threatening condition characterized by markedly elevated circulating levels of low-density lipoprotein cholesterol (LDL-C) and accelerated, premature atherosclerotic cardiovascular disease (ACVD). Given recent insights into the heterogeneity of genetic defects and clinical phenotype of HoFH, and the availability of new therapeutic options, this Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society (EAS) critically reviewed available data with the aim of providing clinical guidance for the recognition and management of HoFH. METHODS AND RESULTS: Early diagnosis of HoFH and prompt initiation of diet and lipid-lowering therapy are critical. Genetic testing may provide a definitive diagnosis, but if unavailable, markedly elevated LDL-C levels together with cutaneous or tendon xanthomas before 10 years, or untreated elevated LDL-C levels consistent with heterozygous FH in both parents, are suggestive of HoFH. We recommend that patients with suspected HoFH are promptly referred to specialist centres for a comprehensive ACVD evaluation and clinical management. Lifestyle intervention and maximal statin therapy are the mainstays of treatment, ideally started in the first year of life or at an initial diagnosis, often with ezetimibe and other lipid-modifying therapy. As patients rarely achieve LDL-C targets, adjunctive lipoprotein apheresis is recommended where available, preferably started by age 5 and no later than 8 years. The number of therapeutic approaches has increased following approval of lomitapide and mipomersen for HoFH. Given the severity of ACVD, we recommend regular follow-up, including Doppler echocardiographic evaluation of the heart and aorta annually, stress testing and, if available, computed tomography coronary angiography every 5 years, or less if deemed necessary. CONCLUSION: This EAS Consensus Panel highlights the need for early identification of HoFH patients, prompt referral to specialized centres, and early initiation of appropriate treatment. These recommendations offer guidance for a wide spectrum of clinicians who are often the first to identify patients with suspected HoFH.

Filiació URV: SI Aims: Homozygous familial hypercholesterolaemia (HoFH) is a rare life-threatening condition characterized by markedly elevated circulating levels of low-density lipoprotein cholesterol (LDL-C) and accelerated, premature atherosclerotic cardiovascular disease (ACVD). Given recent insights into the heterogeneity of genetic defects and clinical phenotype of HoFH, and the availability of new therapeutic options, this Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society (EAS) critically reviewed available data with the aim of providing clinical guidance for the recognition and management of HoFH. Methods and results: Early diagnosis ofHoFHand prompt initiation of diet and lipid-lowering therapy are critical. Genetic testing may provide a definitive diagnosis, but if unavailable, markedly elevated LDL-C levels together with cutaneous or tendon xanthomas before 10 years, or untreated elevated LDL-C levels consistent with heterozygous FH in both parents, are suggestive of HoFH.We recommend that patients with suspected HoFH are promptly referred to specialist centres for a comprehensiveACVDevaluation and clinical management. Lifestyle intervention and maximal statin therapy are the mainstays of treatment, ideally started in the first year of life or at an initial diagnosis, often with ezetimibe and other lipid-modifying therapy. As patients rarely achieve LDL-C targets, adjunctive lipoprotein apheresis is recommended where available, preferably started by age 5 and no later than 8 years. The number of therapeutic approaches has increased following approval of lomitapide and mipomersen for HoFH. Given the severity of ACVD, we recommend regular follow-up, including Doppler echocardiographic evaluation of the heart and aorta

El objetivo de este trabajo fue obtener datos cuantitativos sobre la investigación clínica en la Argentina. Para esto consultamos la base MEDLINE de la Biblioteca Nacional de los EE.UU. que contiene más de 18 millones de referencias en revistas científicas y donde son listadas 5400 publicaciones en 39 idiomas. En el 2009, casi 850 000 trabajos fueron citados en MEDLINE y la Argentina contribuyó con el 0.33% y de ellos 90% en inglés. El número de trabajos publicados en castellano ha ido disminuyendo en los últimos años, un hecho que también se observa en otros idiomas como el alemán, francés, portugués, entre otros. Utilizando las herramientas que provee MEDLINE buscamos trabajos que podrían ser catalogados como de investigación clínica. Para esto acotamos la búsqueda con la palabra "patient" en el texto" y "hospital" en la dirección de los autores. A lo largo de los últimos 10 años, el 16% de los trabajos publicados desde la Argentina contienen la palabra "patient" y esto se reduce a la mitad si se exige que los trabajos hayan sido realizados en un hospital. El número de trabajos en castellano con estas restricciones es aún menor. El aumento en los artículos enviados desde la Argentina ha seguido la curva ascendente del total de trabajos en MEDLINE y este crecimiento ha sido a expensas de la investigación básica, ya que el porcentaje de trabajos clínicos se ha mantenido constante. En conclusión, este trabajo intenta aportar una información que no tenemos respecto a los trabajos de biomedicina en la Argentina. The aim of this paper was to provide quantitative data about clinical investigation in Argentina. We searched MEDLINE which is the U.S. National Library of Medicine's bibliographic database that contains more than 18 million references to journal articles in life sciences; 5400 journals in 39 languages are listed. In 2009 almost 850 000 papers were cited in MEDLINE and Argentina provided 0.33% of them, 90% of these in English. The number of papers published in Spanish is diminishing every year and similar results are observed with the German, French and other languages. Using the tools provided by MEDLINE we searched for papers that could be classified as clinical. We restricted our search to the word "patients" in the text and "hospital" in the address provided by the authors. Along the last 10 years, from 2000 to 2009, about 16% of the papers published from Argentina contain the word "patient" and this percentage is reduced to half if we combine the word "patient" with the word "hospital" in the address. If we search for papers written in Spanish with these two restrictions the number is much lower. The number of articles from Argentina followed the upward trend in the total of articles cited in MEDLINE in the last 10 years. This local increase was due to basic investigation papers because the percentage of clinical articles was relatively constant during these years. In conclusion, these data provide a survey of an area with scanty quantitative information. Fil: Kotsias, Basilio Aristides. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Medicas; Argentina

Introduction Intestinal parasitoses affect millions of people worldwide, especially children of developing countries. In Argentina, the prevalence of these infections varies among areas according to socio-economic and climatic variability. This study aimed to evaluate the prevalence of intestinal parasitoses and risk factors in child and youth populations from neighbourhoods of La Plata (Buenos Aires province, Argentina) affected by occasional floods, including a serious flood in 2013. Methods Serial stool samples and anal swabs of 398 individuals were processed using techniques of sedimentation and flotation. Socio-economic variables were surveyed using a semi-structured questionnaire and the land use/cover was determined by classification of a satellite image. Results Of all examined individuals, 70.9% were parasitized by at least one of the 12 parasites identified. The most prevalent species were Blastocystis sp. (42.7%), Enterobius vermicularis (34.7%) and Giardia lamblia (17.6%). Infection risk factors included houses built with makeshift materials and dirt floors; lack of piped water and public waste collection service, bed-sharing and living in the non-urban area. >70.3% of the participants that lived within, Graphical abstract Intestinal parasitoses are still a serious public health problem and that they are strongly associated with socio-economic conditions and land use/cover.Unlabelled Image, Highlights • >70% of children and youth were parasitized. • 12 parasitic species were identified. • Blastocystis sp., Giardia lamblia and Enterobius vermicularis were the most prevalent species. • Intestinal parasitoses are strongly associated with socio-economic conditions. • Land use/cover was an important infection risk.

In this study, our aim is to assess the role played by autophagy and its inhibition in the different PDAC cellular compartments, and its involvement in chemo-resistance using primary human pancreatic cancer-derived cells (PCC) and Cancer Associated Fibroblasts (CAF). Autophagy flux, as measured by LC3-I and -II in the presence of Chloroquine, showed a variable level in PCC and CAFs. We found no correlation between autophagy level and degree of tumor differentiation. Association of Chloroquine with gemcitabine, 5FU, oxaliplatin, irinotecan and docetaxel revealed that its effect on survival is cell- and drug-dependent in vitro and in vivo. In addition, we demonstrated that autophagy in CAFs can play an important role in sensitizing PDAC to anticancer treatments since its inhibition increased the resistance of PCCs to gemcitabine. In conclusion, this work clearly shows a heterogeneity in the effect of Chloroquine and highlights a role of CAFs autophagy in sensitizing tumors to treatments. It also reveals that the role of autophagy is more complex than expected in PDAC as well as its sensitivity to treatments. Fil: Molejon, Maria Ines. Institut National de la Santé et de la Recherche Médicale; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Ciencias de la Tierra y Ambientales de La Pampa. Universidad Nacional de La Pampa. Facultad de Ciencias Exactas y Naturales. Instituto de Ciencias de la Tierra y Ambientales de La Pampa; Argentina Fil: Swayden, Mirna. Institut National de la Santé et de la Recherche Médicale; Francia Fil: Fanale, Daniele. 3 Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy.; Argentina. University of Palermo. Department of Surgical, Oncological and Oral Sciences; Italia Fil: Bintz, Jennifer. Institut National de la Santé et de la Recherche Médicale; Francia Fil: Gayet, Odile. Institut National de la Santé et de la Recherche Médicale; Francia Fil: Soubeyran, Philippe. Institut National de la Santé et de la Recherche Médicale; Francia Fil: Iovanna, Juan Lucio. Institut National de la Santé et de la Recherche Médicale; Francia

During a survey of saprophytic microfungi on decomposing woody, herbaceous debris and soil from different regions in Southern Europe, a wide range of interesting species of asexual ascomycetes were found. Phylogenetic analyses based on partial gene sequences of SSU, LSU and ITS proved that most of these fungi were related to Sordariomycetes and Dothideomycetes and to lesser extent to Leotiomycetes and Eurotiomycetes. Four new monotypic orders with their respective families are proposed here, i.e. Lauriomycetales, Lauriomycetaceae; Parasympodiellales, Parasympodiellaceae; Vermiculariopsiellales, Vermiculariopsiellaceae and Xenospadicoidales, Xenospadicoidaceae. One new order and three families are introduced here to accommodate orphan taxa, viz. Kirschsteiniotheliales, Castanediellaceae, Leptodontidiaceae and Pleomonodictydaceae. Furthermore, Bloxamiaceae is validated. Based on morphology and phylogenetic affinities Diplococcium singulare, Trichocladium opacum and Spadicoides atra are moved to the new genera Paradiplococcium, Pleotrichocladium and Xenospadicoides, respectively. Helicoon fuscosporum is accommodated in the genus Magnohelicospora. Other novel genera include Neoascotaiwania with the type species N. terrestris sp. nov., and N. limnetica comb. nov. previously accommodated in Ascotaiwania; Pleomonodictys with P. descalsii sp. nov. as type species, and P. capensis comb. nov. previously accommodated in Monodictys; Anapleurothecium typified by A. botulisporum sp. nov., a fungus morphologically similar to Pleurothecium but phylogenetically distant; Fuscosclera typified by F. lignicola sp. nov., a meristematic fungus related to Leotiomycetes; Pseudodiplococcium typified by P. ibericum sp. nov. to accommodate an isolate previously identified as Diplococcium pulneyense; Xyladictyochaeta typified with X. lusitanica sp. nov., a foliicolous fungus related to Xylariales and similar to Dictyochaeta, but distinguished by polyphialidic conidiogenous cells produced on setiform conidiophores. Other novel species proposed are Brachysporiella navarrica, Catenulostroma lignicola, Cirrenalia iberica, Conioscypha pleiomorpha, Leptodontidium aureum, Pirozynskiella laurisilvatica, Parasympodiella lauri and Zanclospora iberica. To fix the application of some fungal names, lectotypes and/or epitypes are designated for Magnohelicospora iberica, Sporidesmium trigonellum, Sporidesmium opacum, Sporidesmium asperum, Camposporium aquaticum and Psilonia atra.

Mycobacterium avium sp. avium (MAA), M. avium sp. hominissuis (MAH), and M. avium sp. paratuberculosis (MAP) are the main members of the M. avium complex (MAC) causing diseases in several hosts. The aim of this study was to describe the genetic diversity of MAC isolated from different hosts. Twenty-six MAH and 61 MAP isolates were recovered from humans and cattle, respectively. GenoType CM® and IS1311-PCR were used to identify Mycobacterium species. The IS901-PCR was used to differentiate between MAH and MAA, while IS900-PCR was used to identify MAP. Genotyping was performed using a mycobacterial interspersed repetitive-unit-variable-number tandem-repeat (MIRU-VNTR) scheme (loci: 292, X3, 25, 47, 3, 7, 10, 32) and patterns (INMV) were assigned according to the MAC-INMV database (http://mac-inmv.tours.inra.fr/). Twenty-two (22/26, 84·6%) MAH isolates were genotyped and 16 were grouped into the following, INMV 92, INMV 121, INMV 97, INMV 103, INMV 50, and INMV 40. The loci X3 and 25 showed the largest diversity (D: 0·5844), and the global discriminatory index (Hunter and Gaston discriminatory index, HGDI) was 0·9300. MAP (100%) isolates were grouped into INMV 1, INMV 2, INMV 11, INMV 8, and INMV 5. The HGDI was 0·6984 and loci 292 and 7 had the largest D (0·6980 and 0·5050). MAH presented a higher D when compared with MAP. The MIRU-VNTR was a useful tool to describe the genetic diversity of both MAH and MAP as well as to identify six new MAH patterns that were conveniently reported to the MAC-INMV database. It was also demonstrated that, in the geographical region studied, human MAC cases were produced by MAH as there was no MAA found among the human clinical samples., Facultad de Ciencias Veterinarias, Centro de Diagnóstico e Investigaciones Veterinarias

// Javier A. Menendez 1,2 , Nuria Folguera-Blasco 3 , Elisabet Cuyas 1,2 , Salvador Fernandez-Arroyo 4 , Jorge Joven 4 and Tomas Alarcon 3,5,6,7 1 ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Catalonia, Spain 2 Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI), Salt, Catalonia, Spain 3 Computational and Mathematical Biology Research Group, Centre de Recerca Matematica (CRM), Barcelona, Spain 4 Unitat de Recerca Biomedica, Hospital Universitari de Sant Joan, IISPV, Universitat Rovira i Virgili, Campus of International Excellence Southern Catalonia, Reus, Spain 5 Institucio Catalana d’Estudis i Recerca Avancats (ICREA), Barcelona, Spain 6 Departament de Matematiques, Universitat Autonoma de Barcelona, Barcelona, Spain 7 Barcelona Graduate School of Mathematics (BGSMath), Barcelona, Spain Correspondence to: Javier A. Menendez, email: // Tomas Alarcon, email: // Keywords : BRCA1, geroncogenesis, metabolism, cancer, metformin, Gerotarget Received : January 22, 2016 Accepted : February 21, 2016 Published : March 02, 2016 Abstract The geroncogenesis hypothesis postulates that the decline in metabolic cellular health that occurs naturally with aging drives a “field effect” predisposing normal tissues for cancer development. We propose that mutations in the cancer susceptibility genes BRCA1 / 2 might trigger “accelerated geroncogenesis” in breast and ovarian epithelia. By speeding up the rate at which the metabolic threshold becomes “permissive” with survival and expansion of genomically unstable pre-tumoral epithelial cells, BRCA haploinsufficiency-driven metabolic reprogramming would operate as a bona fide oncogenic event enabling malignant transformation and tumor formation in BRCA carriers. The metabolic facet of BRCA1 one-hit might involve tissue-specific alterations in acetyl-CoA, α-ketoglutarate, NAD + , FAD, or S-adenosylmethionine, critical factors for de/methylation or de/acetylation dynamics in the nuclear epigenome. This in turn might induce faulty epigenetic reprogramming at the “install phase” that directs cell-specific differentiation of breast/ovarian epithelial cells, which can ultimately determine the penetrance of BRCA defects during developmental windows of susceptibility. This model offers a framework to study whether metabolic drugs that prevent or revert metabolic reprogramming induced by BRCA haploinsufficiency might displace the “geroncogenic risk” of BRCA carriers to the age typical for those without the mutation. The identification of the key nodes that directly communicate changes in cellular metabolism to the chromatin in BRCA haploinsufficient cells may allow the epigenetic targeting of genomic instability using exclusively metabolic means. The validation of accelerated geroncogenesis as an inherited “one-hit” metabolic “field effect” might offer new strategies to therapeutically revisit the apparently irreversible genetic-hereditary fate of women with hereditary breast-ovarian cancer syndrome.

Hyaluronan, the main glycosaminoglycan of extracellular matrices, is concentrated in tissues with high cell proliferation and migration rates. In cancer, hyaluronan expression is altered and it becomes fragmented into low-molecular-weight forms,affecting mechanisms associated with cell proliferation, invasion, angiogenesis and multidrug resistance. Here, we analyzed the effect of low-molecular-weight hyaluronan on the response of T lymphoma, osteosarcoma, and mammary adenocarcinoma cell lines to the antineoplastic drug doxorubicin, and whether co-treatment with hyaluronan and doxorubicin modified the behavior of endothelial cells. Our aim was to associate the hyaluronan-doxorubicin response with angiogenic alterations in these tumors. After hyaluronan and doxorubicin co-treatment, hyaluronan altered drug accumulation and modulated the expression of ATP-binding cassette transporters in T-cell lymphoma cells. In contrast, no changes in drug accumulation were observed in cells from solid tumors, indicating that hyaluronan might not affect drug efflux. However, when we evaluated the effect on angiogenic mechanisms, the supernatant from tumor cells treated with doxorubicin exhibited a pro-angiogenic effect on endothelial cells.Hyaluronan-doxorubicin co-treatment increased migration and vessel formation inendothelial cells. This effect was independent of vascular endothelial growth factor but related to fibroblast growth factor-2 expression. Besides, we observed a proangiogenic effect on endothelial cells during hyaluronan and doxorubicin co-treatment in the in vivo murine model of T-cell lymphoma. Our results demonstrate for the first time that hyaluronan is a potential modulator of doxorubicin response by mechanisms that involve not only drug efflux but also angiogenic processes, providing an adverse tumor stroma during chemotherapy. Fil: Vitale, Daiana Luján. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina Fil: Spinelli, Fiorella Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina Fil: del Dago, Daiana Alejandra Ayelén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina Fil: Icardi, Antonella. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina Fil: Demarchi, Gianina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina Fil: Caon, Ilaria. Universitá degli Studio dell’Insubria; Italia Fil: García, Mariana Gabriela. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina Fil: Bolontrade, Marcela Fabiana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Passi, Alberto. Universitá degli Studio dell’Insubria; Italia Fil: Cristina, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina Fil: Alaniz, Laura Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina

Data on the impact of the recently recommended maternal pertussis vaccination are promising, but still insufficient to universalise this approach. We thus compared the epidemiological data prior to the implementation of this vaccination strategy in Argentina (2012) with the figures reported after 2012. During that 2010–2016 period, two outbreaks occurred, one in 2011 and another in 2016. In the former, the incidence was 6.9/100 000 inhabitants and the casefatality rate 2.6%. Thereafter, a decline in incidence was detected until 2014. During 2015 and 2016 an increase in the incidence transpired, but this rise was fortunately not accompanied by one in the case fatality ratio. Indeed, in 2016 the case fatality ratio was the lowest (0.6%). Moreover, during the 2016 outbreak, the incidence (3.9/100 000 inhabitants) and the case severity detected in the most vulnerable population (infants 0–2 months) were both lower than those in 2011. Consistent with this pattern, in 2016, in the most populated province of Argentina (Buenos Aires), the case percentage with laboratory-positive results indicating a high number of symptoms (59.1% of the total cases) diminished compared with that detected in the 2011 outbreak without maternal immunisation (71.9%). Using the mathematical model of pertussis transmission we previously designed, we assessed the effect of vaccination during pregnancy on infant incidence. From comparisons between the epidemiological data made through calculations, emerged the possibility that vaccinating women during pregnancy would benefit the infants beyond age 2 months, specifically in the 2–12-month cohort., Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas, Facultad de Ciencias Exactas

The activity and circulation of influenza viruses in Argentina was studied during 2012 as part of the Argentinean Surveillance for Influenza and other Respiratory Viruses, in the context of Global Influenza Surveillance. The antigenicity and molecular characteristics of haemagglutinins (HA) of circulating influenza A and B viruses were analysed to assess the emergence of virus variants. Susceptibility to oseltamivir and zanamivir was evaluated by enzymatic assay and results were backed-up by sequencing of the neuraminidase (NA) genes. During the 2012 season, influenza virus circulation in Argentina was detected from weeks 24 to 51. The HA sequences of the studied A(H1N1)pdm09 subtype viruses segregated in a different genetic group compared to those identified during the 2009 pandemic, although they were still closely related antigenically to the vaccine virus A/California/07/2009. The HA sequences of the A(H3N2) viruses analysed fell into the A/Victoria/208/2009 clade, genetic group 3C. A mixed circulation of virus variants belonging to B/Victoria and B/Yamagata lineages was detected, with B/Victoria being dominant. All viruses tested were sensitive to oseltamivir and zanamivir except one. This isolate, an A(H1N1)pdm09 virus possessing the substitution NA-N295S, showed highly reduced inhibition by oseltamivir and reduced inhibition by zanamivir. Virological and epidemiological surveillance remains critical for detection of evolving influenza viruses. Fil: Benedetti, Estefanía. Direccion Nacional de Instituto de Investigacion. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbran". Instituto Nacional de Enfermedades Infecciosas. Departamento de Virologia; Argentina. Organizacion Mundial de la Salud; Argentina Fil: Daniels , R. S.. The Francis Crick institute; Reino Unido Fil: Pontoriero, Andrea. Direccion Nacional de Instituto de Investigacion. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbran". Instituto Nacional de Enfermedades Infecciosas. Departamento de Virologia; Argentina. Organizacion Mundial de la Salud; Argentina Fil: Russo, M. L.. Organizacion Mundial de la Salud; Argentina. Direccion Nacional de Instituto de Investigacion. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbran". Instituto Nacional de Enfermedades Infecciosas. Departamento de Virologia; Argentina Fil: Avaro, Martin. Direccion Nacional de Instituto de Investigacion. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbran". Instituto Nacional de Enfermedades Infecciosas. Departamento de Virologia; Argentina. Organizacion Mundial de la Salud; Argentina Fil: Czech, Andrea. Direccion Nacional de Instituto de Investigacion. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbran". Instituto Nacional de Enfermedades Infecciosas. Departamento de Virologia; Argentina. Organizacion Mundial de la Salud; Argentina Fil: Campos, Ana. Direccion Nacional de Instituto de Investigacion. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbran". Instituto Nacional de Enfermedades Infecciosas. Departamento de Virologia; Argentina. Organizacion Mundial de la Salud; Argentina Fil: Periolo, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Organizacion Mundial de la Salud; Argentina. Direccion Nacional de Instituto de Investigacion. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbran". Instituto Nacional de Enfermedades Infecciosas. Departamento de Virologia; Argentina Fil: Gregory, V.. The Francis Crick institute; Reino Unido Fil: McCauley, J.W.. The Francis Crick institute; Reino Unido Fil: Baumeister, Elsa. Organizacion Mundial de la Salud; Argentina. Direccion Nacional de Instituto de Investigacion. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbran". Instituto Nacional de Enfermedades Infecciosas. Departamento de Virologia; Argentina

Celiac disease is caused by intolerance to cereal gluten proteins, and HLA-DQ molecules are involved in the disease pathogenesis by presentation of gluten peptides to CD4+ T cells. The α- or β-chain sharing HLA molecules DQ2.5, DQ2.2, and DQ7.5 display different risks for the disease. It was recently demonstrated that T cells of DQ2.5 and DQ2.2 patients recognize distinct sets of gluten epitopes, suggesting that these two DQ2 variants select different peptides for display. To explore whether this is the case, we performed a comprehensive comparison of the endogenous self-peptides bound to HLA-DQ molecules of B-lymphoblastoid cell lines. Peptides were eluted from affinity-purified HLA molecules of nine cell lines and subjected to quadrupole orbitrap mass spectrometry and MaxQuant software analysis. Altogether, 12,712 endogenous peptides were identified at very different relative abundances. Hierarchical clustering of normalized quantitative data demonstrated significant differences in repertoires of peptides between the three DQ variant molecules. The neural network-based method, NNAlign, was used to identify peptide-binding motifs. The binding motifs of DQ2.5 and DQ7.5 concurred with previously established binding motifs. The binding motif of DQ2.2 was strikingly different from that of DQ2.5 with position P3 being a major anchor having a preference for threonine and serine. This is notable as three recently identified epitopes of gluten recognized by T cells of DQ2.2 celiac patients harbor serine at position P3. This study demonstrates that relative quantitative comparison of endogenous peptides sampled from our protein metabolism by HLA molecules provides clues to understand HLA association with disease. Fil: Bergseng, Elin. University of Oslo; Noruega Fil: Dørum, Siri. University of Oslo; Noruega Fil: Arntzen, Magnus Ø.. University of Oslo; Noruega Fil: Nielsen, Morten. Technical University of Denmark; Dinamarca. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina Fil: Nygård, Ståle. University of Oslo; Noruega Fil: Buus, Søren. Universidad de Copenhagen; Dinamarca Fil: de Souza, Gustavo A.. University of Oslo; Noruega Fil: Sollid, Ludvig M.. University of Oslo; Noruega

Objective To assess progress towards the elimination of trans-fatty acids (TFA) in foods after the 2008 Pan American Health Organization (PAHO) recommendation of virtual elimination of TFA in Latin America. Design A descriptive, comparative analysis of foods that were likely to contain TFA and were commonly consumed in four cities in Latin America. Setting San José (Costa Rica), Mexico City (Mexico), Rio de Janeiro (Brazil), Buenos Aires (Argentina). Subjects Foods from each city were sampled in 2011; TFA content was analysed using GC. TFA of selected foods was also monitored in 2016. Results In 2011-2016, there was a significant decrease in the content of TFA in the sampled foods across all sites, particularly in Buenos Aires (from 12·6-34·8 % range in 2011-2012 to nearly 0 % in 2015-2016). All sample products met the recommended levels of TFA content set by the PAHO. TFA were replaced with a mixture of saturated and unsaturated fats. Conclusions Our results indicate a virtual elimination of TFA from major food sources in the cities studied. This could be due to a combination of factors, including recommendations by national and global public health authorities, voluntary and/or mandatory food reformulation made by the food industry. Fil: Monge Rojas, Rafael. Instituto Costarricense de Investigación y Enseñanza en Nutrición y Salud; Costa Rica Fil: Colón Ramos, Uriyoán. The George Washington University; Estados Unidos Fil: Jacoby, Enrique. Pan American Health Organization; Estados Unidos Fil: Alfaro, Thelma. Instituto Costarricense de Investigación y Enseñanza en Nutrición y Salud; Costa Rica Fil: Tavares Do Carmo, Maria Das Graças. Universidade Federal do Rio de Janeiro; Brasil Fil: Villalpando, Salvador. Instituto Nacional de Salud Pública. Centro de Investigación en Nutrición y Salud; México Fil: Bernal, Claudio Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas; Argentina

Ring finger protein 146 (Iduna) facilitates DNA repair and protects against cell death induced by NMDA receptor-mediated glutamate excitotoxicity or by cerebral ischemia. Neuroprotectin D1 (NPD1), a docosahexaenoic acid (DHA)-derived lipid mediator, promotes cell survival under uncompensated oxidative stress (UOS). Our data demonstrate that NPD1 potently upregulates Iduna expression and provides remarkable cell protection against UOS. Iduna, which was increased by the lipid mediator, requires the presence of the poly(ADP-ribose) (PAR) sites. Moreover, astrocytes and neurons in the penumbra display an enhanced abundance of Iduna, followed by remarkable neurological protection when DHA, a precursor of NPD1, is systemically administered 1 h after 2 h of ischemic stroke. These findings provide a conceptual advancement for survival of neural cells undergoing challenges to homeostasis because a lipid mediator, made 'on demand,' modulates the abundance of a critically important protein for cell survival. Fil: Belayev, Ludmila. Louisiana State University Health Sciences Center; Estados Unidos Fil: Mukherjee, Pranab K. Louisiana State University Health Sciences Center; Estados Unidos Fil: Balaszczuk, Veronica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones y Estudio sobre Cultura y Sociedad. Centro de Investigaciones de la Facultad de Psicología - Grupo Vinculado CIPSI; Argentina. Louisiana State University Health Sciences Center; Estados Unidos Fil: Calandria, Jorgelina M. Louisiana State University Health Sciences Center; Estados Unidos Fil: Obenaus, Andre. Loma Linda University Adventist Health Sciences Center; Estados Unidos Fil: Khoutorova, Larissa. Louisiana State University Health Sciences Center; Estados Unidos Fil: Hong, Sung-Ha. Louisiana State University Health Sciences Center; Estados Unidos Fil: Bazan, Nicolas G.. Louisiana State University Health Sciences Center; Estados Unidos

Neovascular retinopathies are leading causes of irreversible blindness. Although vascular endothelial growth factor (VEGF) inhibitors have been established as the mainstay of current treatment, clinical management of these diseases is still limited. As retinal impairment involves abnormal neovascularization and neuronal degeneration, we evaluated here the involvement of galectin-1 in vascular and non-vascular alterations associated with retinopathies, using the oxygen-induced retinopathy (OIR) model. Postnatal day 17 OIR mouse retinas showed the highest neovascular profile and exhibited neuro-glial injury as well as retinal functional loss, which persisted until P26 OIR. Concomitant to VEGF up-regulation, galectin-1 was highly expressed in P17 OIR retinas and it was mainly localized in neovascular tufts. In addition, OIR induced remodelling of cell surface glycophenotype leading to exposure of galectin-1-specific glycan epitopes. Whereas VEGF returned to baseline levels at P26, increased galectin-1 expression persisted until this time period. Remarkably, although anti-VEGF treatment in P17 OIR improved retinal vascularization, neither galectin-1 expression nor non-vascular and functional alterations were attenuated. However, this functional defect was partially prevented in galectin-1-deficient (Lgals1-/-) OIR mice, suggesting the importance of targeting both VEGF and galectin-1 as non-redundant independent pathways. Supporting the clinical relevance of these findings, we found increased levels of galectin-1 in aqueous humor from patients with proliferative diabetic retinopathy and neovascular glaucoma. Thus, using an OIR model and human samples, we identified a role for galectin-1 accompanying vascular and non-vascular retinal alterations in neovascular retinopathies. Fil: Ridano, Magali Evelin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina Fil: Subirada Caldarone, Paula Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina Fil: Paz, Maria Constanza. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina Fil: Lorenc, Valeria Erika. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina Fil: Stupirski, Juan Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Gramajo, Ana Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad Ejecutora Instituto de Nanociencia y Nanotecnología. Unidad Ejecutora Instituto de Nanociencia y Nanotecnología - Nodo Bariloche | Comisión Nacional de Energía Atómica. Unidad Ejecutora Instituto de Nanociencia y Nanotecnología. Unidad Ejecutora Instituto de Nanociencia y Nanotecnología - Nodo Bariloche; Argentina Fil: Luna, José Domingo. Clinica de Ojos Romagosa, Fundacion Ver; Argentina Fil: Croci Russo, Diego Omar. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina Fil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad Nacional de Córdoba. Facultad de Cs.exactas Físicas y Naturales. Departamento de Química. Cátedra de Química Biologica; Argentina Fil: Garcia Sanchez, Maria Candela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina

We previously reported the association of HSPA1A and HSPB1 with high-grade astrocytomas, suggesting that these proteins might be involved in disease outcome and response to treatment. With the aim to better understand the resistance/susceptibility processes associated to temozolomide (TMZ) treatment, the current study was performed in three human malignant glioma cell lines by focusing on several levels: (a) apoptotic index and senescence, (b) DNA damage, and (c) interaction of HSPB1 with players of the DNA damage response. Three human glioma cell lines, Gli36, U87, and DBTRG, were treated with TMZ evaluating cell viability and survival, apoptosis, senescence, and comets (comet assay). The expression of HSPA (HSPA1A and HSPA8), HSPB1, O6-methylguanine-DNA methyltransferase (MGMT), MLH1, and MSH2 was determined by immunocytochemistry, immunofluorescence, and Western blot. Immunoprecipitation was used to analyze protein interaction. The cell lines exhibited differences in viability, apoptosis, and senescence after TMZ administration. We then focused on Gli36 cells (relatively unstudied) which showed very low recovery capacity following TMZ treatment, and this was related to high DNA damage levels; however, the cells maintained their viability. In these cells, MGMT, MSH2, HSPA, and HSPB1 levels increased significantly after TMZ administration. In addition, MSH2 and HSPB1 proteins appeared co-localized by confocal microscopy. This co-localization increased after TMZ treatment, and in immunoprecipitation analysis, MSH2 and HSPB1 appeared interacting. In contrast, HSPB1 did not interact with MGMT. We show in glioma cells the biological effects of TMZ and how this drug affects the expression levels of heat shock proteins (HSPs), MGMT, MSH2, and MLH1. In Gli36 cells, the results suggest that interactions between HSPB1 and MSH2, including co-nuclear localization, may be important in determining cell sensitivity to TMZ. Fil: Castro, Gisela Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina Fil: Cayado Gutiérrez, Niubys de Los Milagros. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina Fil: Zoppino, Felipe Carlos Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina Fil: Fanelli, Mariel Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina Fil: Cuello Carrión, Fernando Darío. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina Fil: Sottile Fleury, Mayra Lis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina Fil: Nadin, Silvina Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina Fil: Ciocca, Daniel Ramon. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina

Macrophage plasticity is critical for controlling inflammation including thoseproduced by helminth infections, where alternatively activated macrophages (AAM)are accumulated in tissues. AAM expressing the co-inhibitory molecule programmeddeath ligand 2 (PD-L2), which is capable of binding programmed death 1 (PD-1) expressed on activated T cells, have been demonstrated in different parasiticinfections. However, the role of PD-L2 during F. hepatica infection has not yet beenexplored. We observed that F. hepatica infection or a F. hepatica total extract (TE)injection increased the expression of PD-L2 on peritoneal macrophages. In addition,the absence of PD-L2 expression correlated with an increase in susceptibility to F.hepatica infection, as evidenced by the shorter survival and increased liver damageobserved in PD-L2 deficient (KO) mice. We assessed the contribution of the PD-L2pathway to Th2 polarization during this infection, and found that the absence of PD-L2caused a diminished Th2 type cytokine production by TE stimulated splenocytes fromPD-L2 KO infected compared with WT mice. Besides, splenocytes and intrahepaticleukocytes from infected PD-L2 KO mice showed higher levels of IFN-γ than thosefrom WT mice. Arginase expression and activity and IL-10 production were reducedin macrophages from PD-L2 KO mice compared to those from WT mice, revealing astrong correlation between PD-L2 expression and AAM polarization. Taken together,our data indicate that PD-L2 expression in macrophages is critical for AAM inductionand the maintenance of an optimal balance between the Th1- and Th2-type immuneresponses to assure host survival during F. hepatica infection. Fil: Stempin, Cinthia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina Fil: Motran, Claudia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina Fil: Aoki, Maria del Pilar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina Fil: Falcón, Cristian Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina Fil: Cerban, Fabio Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina Fil: Cervi, Laura Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina

// Elisabet Cuyas 1, 2, * , Salvador Fernandez-Arroyo 3, * , Tomas Alarcon 4, 5, 6, 7 , Ruth Lupu 8, 9 , Jorge Joven 3 , Javier A. Menendez 1, 2 1 ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Catalonia, Spain 2 Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI), Girona, Catalonia, Spain 3 Unitat de Recerca Biomedica, Hospital Universitari de Sant Joan, IISPV, Universitat Rovira i Virgili, Campus of International Excellence Southern Catalonia, Reus, Spain 4 Institucio Catalana d'Estudis i Recerca Avancats (ICREA), Barcelona, Spain 5 Computational and Mathematical Biology Research Group, Centre de Recerca Matematic (CRM), Barcelona, Spain 6 Departament de Matematiques, Universitat Autonoma de Barcelona, Barcelona, Spain 7 Barcelona Graduate School of Mathematics (BGSMath), Barcelona, Spain 8 Mayo Clinic, Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Rochester, MN, USA 9 Mayo Clinic Cancer Center, Rochester, MN, USA * These authors contributed equally to this work Correspondence to: Javier A. Menendez, email: jmenendez@iconcologia.net , jmenendez@idibgi.org Keywords: BRCA1, hereditary breast cancer, breast cancer susceptibility, bioenergetics, glutamine Received: January 22, 2016 Accepted: May 12, 2016 Published: May 31, 2016 ABSTRACT We hypothesized that women inheriting one germline mutation of the BRCA1 gene (“one-hit”) undergo cell-type-specific metabolic reprogramming that supports the high biosynthetic requirements of breast epithelial cells to progress to a fully malignant phenotype. Targeted metabolomic analysis was performed in isogenic pairs of nontumorigenic human breast epithelial cells in which the knock-in of 185delAG mutation in a single BRCA1 allele leads to genomic instability. Mutant BRCA1 one-hit epithelial cells displayed constitutively enhanced activation of biosynthetic nodes within mitochondria. This metabolic rewiring involved the increased incorporation of glutamine- and glucose-dependent carbon into tricarboxylic acid (TCA) cycle metabolite pools to ultimately generate elevated levels of acetyl-CoA and malonyl-CoA, the major building blocks for lipid biosynthesis. The significant increase of branched-chain amino acids (BCAAs) including the anabolic trigger leucine, which can not only promote protein translation via mTOR but also feed into the TCA cycle via succinyl-CoA, further underscored the anabolic reprogramming of BRCA1 haploinsufficient cells. The anti-diabetic biguanide metformin “reversed” the metabolomic signature and anabolic phenotype of BRCA1 one-hit cells by shutting down mitochondria-driven generation of precursors for lipogenic pathways and reducing the BCAA pool for protein synthesis and TCA fueling. Metformin-induced restriction of mitochondrial biosynthetic capacity was sufficient to impair the tumor-initiating capacity of BRCA1 one-hit cells in mammosphere assays. Metabolic rewiring of the breast epithelium towards increased anabolism might constitute an unanticipated and inherited form of metabolic reprogramming linked to increased risk of oncogenesis in women bearing pathogenic germline BRCA1 mutations. The ability of metformin to constrain the production of mitochondrial-dependent biosynthetic intermediates might open a new avenue for “starvation” chemopreventive strategies in BRCA1 carriers.

Runx1 participation in epithelial mammary cells is still under review. Emerging data indicates that Runx1 could be relevant for breast tumor promotion. However, to date no studies have specifically evaluated the functional contribution of Runx1 to control gene expression in mammary epithelial tumor cells. It has been described that Runx1 activity is defined by protein context interaction. Interestingly, Foxp3 is a breast tumor suppressor gene. Here we show that endogenous Runx1 and Foxp3 physically interact in normal mammary cells and this interaction blocks Runx1 transcriptional activity. Furthermore we demonstrate that Runx1 is able to bind to R-spondin 3 (RSPO3) and Gap Junction protein Alpha 1 (GJA1) promoters. This binding upregulates Rspo3 oncogene expression and downregulates GJA1 tumor suppressor gene expression in a Foxp3-dependent manner. Moreover, reduced Runx1 transcriptional activity decreases tumor cell migration properties. Collectively, these data provide evidence of a new mechanism for breast tumor gene expression regulation, in which Runx1 and Foxp3 physically interact to control mammary epithelial cell gene expression fate. Our work suggests for the first time that Runx1 could be involved in breast tumor progression depending on Foxp3 availability. Fil: Recouvreux, Sol. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Grasso, Esteban Nicolas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Echeverria, Pablo Christian. Universidad de Ginebra; Suiza. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Rocha Viegas, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Castilla, Lucio Hernán. University Of Massachussets. Medical School; Estados Unidos Fil: Schere Levy, Carolina Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Tocci, Johanna Melisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Kordon, Edith Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina Fil: Rubinstein, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina

Background Detection of drug-resistant tuberculosis is essential for the control of the disease but it is often hampered by the limitation of transport and storage of samples from remote locations to the reference laboratory. We performed a retrospective field study to evaluate the performance of four supports enabling the transport and storage of samples to be used for molecular detection of drug resistance using the GenoType MTBDRplus. Methods Two hundred Mycobacterium tuberculosis strains were selected and spotted on slides, FTA cards, GenoCards, and in ethanol. GenoType MTBDRplus was subsequently performed with the DNA extracted from these supports. Sensitivity and specificity were calculated and compared to the results obtained by drug susceptibility testing. Results For all supports, the overall sensitivity and specificity for detection of resistance to RIF was between 95% and 100%, and for INH between 95% and 98%. Conclusion The four transport and storage supports showed a good sensitivity and specificity for the detection of resistance to RIF and INH in M. tuberculosis strains using the GenoType MTBDRplus. These supports can be maintained at room temperature and could represent an important alternative cost-effective method useful for rapid molecular detection of drugresistant TB in low-resource settings. Fil: Rabodoarivelo, Marie Sylvianne. University of Ghent; Bélgica Fil: Imperiale, Belén Rocío. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Provincia de Buenos Aires. Ministerio de Salud. Hospital "Dr. Antonio A. Cetrángolo"; Argentina Fil: Andrianiavomikotroka, Rina. Institut Pasteur de Madagascar; Madagascar Fil: Brandao, Angela. Fundación Oswaldo Cruz; Brasil Fil: Kumar, Parveen. All India Institute of Medical Sciences; India Fil: Singh, Sarman. All India Institute of Medical Sciences; India Fil: Ferrazoli, Lucilaine. Instituto Adolfo Lutz Núcleo de Tuberculose e Micobacteriosis Sao Paulo; Brasil Fil: Morcillo, Nora. Provincia de Buenos Aires. Ministerio de Salud. Hospital "Dr. Antonio A. Cetrángolo"; Argentina Fil: Rasolofo, Voahangy. Institut Pasteur de Madagascar; Madagascar Fil: Palomino, Juan Carlos. University of Ghent; Bélgica Fil: Vandamme, Peter. University of Ghent; Bélgica Fil: Martin, Anandi. University of Ghent; Bélgica

Little is known about long-lasting measles protective immunity when exposure to wild-type or vaccine measles virus precedes HIV infection. The results obtained suggest that measles immunity wanes and the lowest measles geometric mean titres (GMT) were significantly associated with measles vaccine-induced immunity in individuals that later developed HIV infection (86% prevalence, GMT 164 mIU/ml) compared to naturally induced immunity in HIV-infected adults (100% prevalence, GMT 340 mIU/ml, P= 0·0082) or non-HIV infected adults (100%, GMT 724 mIU/ml, P= 0·0001), and vaccine-induced immunity in non-HIV-infected adults (100%, GMT 347 mIU/ml, P= 0·017). The study was conducted in an area without wild-type virus circulation since 2000. The absence of virus circulating may alter the paradigm of lifelong immunity to measles virus after vaccination. As the proportion of HIV-infected individuals possessing only vaccine-induced immunity continues to grow, checking the status of measles immunity in this group is strongly recommended Fil: Isa, Maria Beatriz. Universidad Nacional de Córdoba. Facultad de Medicina. Instituto de Virología; Argentina. Universidad Catolica de Córdoba. Facultad de Medicina. Clinica Universitaria Reina Fabiola; Argentina Fil: Pavan, Jorge Victorio. Universidad Nacional de Córdoba. Facultad de Medicina. Instituto de Virología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Sicilia Don, Paola Ermelinda. Universidad Nacional de Córdoba. Facultad de Medicina. Instituto de Virología; Argentina Fil: Grutadauria, S.. Sanatorio Allende; Argentina Fil: Martinez, Laura Cecilia. Universidad Nacional de Córdoba. Facultad de Medicina. Instituto de Virología; Argentina Fil: Giordano, Miguel Oscar. Universidad Nacional de Córdoba. Facultad de Medicina. Instituto de Virología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Masachessi, Gisela. Universidad Nacional de Córdoba. Facultad de Medicina. Instituto de Virología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Barril, Patricia Angelica. Universidad Nacional de Córdoba. Facultad de Medicina. Instituto de Virología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Nates, Silvia Viviana. Universidad Nacional de Córdoba. Facultad de Medicina. Instituto de Virología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Obesity has become a pandemic disease in the last 40 years. The WHO estimates that the population with overweight has nearly tripled since 1975, and the tendency is still growing. These data have an impact on health and on country's healthcare costs. Obesity is a chronic disease of multifactorial origin that is associated to other pathophysiological conditions such as Type 2 Diabetes mellitus. Obesity appears due to an imbalance in the energy metabolism, which is primarily regulated by the hypothalamus, the central structure responsible for integrating signals from the periphery and orchestrating a homeostatic response. In the last years, research has been focused on the molecular mechanisms and the hypothalamic nuclei involved in the dysregulation of energy homeostasis of obesity in order to identify potential therapeutic targets. This thesis studies the role of the protein carnitine palmitoyltransferase 1c (CPT1c), a neuronal energy sensor, in the regulation of energy homeostasis within the hypothalamus in response to different metabolic challenges. Recently, its expression in the ventromedial nucleus of the hypothalamus (VMH) has been found as necessary for the activation of thermogenesis in brown adipose tissue (BAT) in response to a high-fat diet. The most abundant neuronal population of the VMH nucleus are SF1 neurons. Thus, we have generated a new genetic mouse model deficient in CPT1c in these neurons (SF1-CPT1c-KO) to explore the specific function of the protein in these neurons. At the same time, we have studied the role of CPT1c in the central response to long-chain fatty acids (LCFAs). First, we defined the differential effects that saturated and unsaturated LCFAs have on food intake, body weight and brown adipose tissue thermogenesis, as well as the hypothalamic nuclei involved and the possible signalling pathways involved, in wild-type mice (WT). Then we evaluated the same effects on mice deficient for CPT1c (CPT1c-KO). Results of this thesis showed, on the one hand, that CPT1c in the SF1 neurons is necessary for the metabolic adaptation, facilitating that the peripheral tissues use fat but not glucose as the energy substrate, during the first days of high-fat diet administration and under fasting or cold exposure situation. On the other hand, we have defined that centrally administered LCFAs differently activate satiety and BAT thermogenesis depending on the level of saturation. We have also identified that the hypothalamic nuclei arcuate, paraventricular and VMH are mediators of unsaturated LCFA signals and that LCFAs differently activate the AMPK-ACC axis and FAS expression depending on the level of saturation. Finally, we have described that CPT1c is involved in this axis. Overall, our results confirm the important role of CPT1c under metabolic challenges and provide new knowledge of the central processes underlying obesity development. L’obesitat s’ha convertit en una pandèmia en els últims 40 anys. L’OMS estima que la població amb sobreprès gairebé s’ha triplicat des del 1975, i la tendència continua creixent. Aquestes dades tenen un gran impacte tant en la salut com en la despesa sanitària d’un país. L’obesitat és una malaltia crònica d’origen multifactorial que va lligada a altres condicions patològiques, com la Diabetis mellitus tipus 2. L’obesitat apareix degut a un desequilibri en el metabolisme energètic de l’organisme, el qual està estretament regulat per l’hipotàlem, encarregat d’integrar senyals de la perifèria i donar una resposta homeostàtica. En els últims anys, s’ha investigat sobre els mecanismes moleculars i els nuclis de l'hipotàlem implicats en la desregulació de la homeòstasis energètica per poder reconèixer possibles dianes terapèutiques. Aquesta tesi està centrada en estudiar el paper de la proteïna carnitina palmitoil transferasa 1c (CPT1c), un sensor energètic neuronal, en la regulació de la homeòstasis energètica en l’hipotàlem com a resposta a diferents reptes metabòlics. Recentment, la seva expressió en el nucli ventral de l’hipotàlem (VMH) ha estat assenyalada com a necessària per a l’activació de la termogènesis del teixit adipós marró en resposta a una alimentació rica en greixos. La població neuronal més abundant del nucli VMH són les neurones SF1. Així doncs, hem generat un nou model genètic de ratolí que no expressa CPT1c en aquestes neurones (SF1- CPT1c-KO) per poder conèixer-ne la funció concreta en aquesta població neuronal. Paral·lelament, també hem estudiat el paper de la CPT1c en la resposta central als àcids grassos de cadena llarga (AGCL). Primerament, hem definit l’efecte diferencial dels AGCL saturats i insaturats en la ingesta, el control del pes i la termogènesis del teixit adipós marró, així com els nuclis hipotalàmics implicats i les possibles rutes de senyalització involucrades, en ratolins salvatge (WT) , i seguidament hem avaluat aquests efectes en ratolins deficients per aquesta proteïna (CPT1c-KO). Els resultats de la tesi evidencien, per una banda, que la CPT1c en les neurones SF1 del VMH és necessària per una l’adaptació metabòlica, facilitant que els teixits perifèrics utilitzin preferentment els greixos com a substrat energètic en comptes de la glucosa, durant els primers dies d’exposició a la dieta grassa, en una situació de dejú o en l’exposició al fred. Per altra banda, hem confirmat que els àcids grassos administrats centralment activen de forma diferencial la sacietat i la termogènesis del teixit adipós marró depenent del grau de saturació/insaturació de la seva cadena alifàtica. També hem identificat els nuclis hipotalàmics arcuat, paraventricular i VMH com a mediadors d’aquesta senyal i l’activació diferent de l’eix AMPK-ACC i la proteïna FAS segons el nivell de saturació dels àcids grassos de cadena llarga. Finalment, hem descrit que la proteïna CPT1c es troba implicada en aquest eix. En el seu conjunt, els resultats obtinguts confirmen el paper important de la CPT1c davant de reptes metabòlics, i aporta nous coneixements dels processos centrals durant el desenvolupament de l’obesitat.

Els ritmes biològics tenen un paper important en l’adaptació fisiològica i metabòlica de l’organisme un moment del dia, ritme circadià, o de l’any, ritme estacional. Els senyals o moduladors externs anomenats zeitgebers, com la llum o el menjar, tenen un paper crucial en la reprogramació o alteració d'aquestes oscil·lacions. L'alteració del ritme circadià deguda als estils de vida moderns, com ara els canvis en els cicles de llum/foscor o els patrons dietètics, s'ha relacionat amb el desenvolupament de trastorns metabòlics. En aquest context, els compostos fenòlics com les proantocianidines (PACs) han demostrat exercir efectes beneficiosos sobre els trastorns metabòlics. A més, els polifenols han demostrat la seva capacitat per modular alguns components del sistema del rellotge. De fet, la interacció dels compostos fenòlics amb els ritmes biològics ha estat assenyalada recentment pel nostre grup com un mecanisme potencial implicat en els efectes beneficiosos. Aleshores, l'objectiu d'aquesta tesi va ser dilucidar si els PACs actuen a través dels ritmes biològics i investigar si aquests compostos fenòlics poden restaurar els ritmes biològics en diferents situacions de pertorbació, com els canvis en els cicles de llum/foscor o en els patrons dietètics. Per això, es van estudiar els ritmes circadians de rates Fischer 344 sanes i amb dieta de cafeteria (CAF), els efectes de diferents situacions de pertorbació d'aquests ritmes i les propietats dels PACs per restaurar aquestes pertorbacions. Los ritmos biológicos desempeñan un papel importante en la adaptación fisiológica y metabólica del organismo a momento del día, ritmo circadiano, o del año, ritmo estacional. Las señales o moduladores externos llamados zeitgebers, como la luz o la comida, desempeñan un papel crucial en la reprogramación o alteración de estas oscilaciones. La alteración del ritmo circadiano debida a los estilos de vida modernos, como los cambios en los ciclos de luz/oscuridad o los patrones dietéticos, se ha relacionado con el desarrollo de trastornos metabólicos. En este contexto, los compuestos fenólicos como las proantocianidinas (PACs) han demostrado ejercer efectos beneficiosos sobre los trastornos metabólicos. Además, los polifenoles han demostrado su capacidad para modular algunos componentes del sistema del reloj. De hecho, la interacción de los compuestos fenólicos con los ritmos biológicos ha sido señalada recientemente por nuestro grupo como un mecanismo potencial implicado en sus efectos beneficiosos. Entonces, el objetivo de esta tesis fue dilucidar si los PACs actúan a través de los ritmos biológicos e investigar si estos compuestos fenólicos pueden restaurar los ritmos biológicos en diferentes situaciones de perturbación, como los cambios en los ciclos de luz-oscuridad o en los patrones dietéticos. Para ello, se estudiaron los ritmos circadianos de ratas Fischer 344 sanas y con dieta de cafetería (CAF), los efectos de diferentes situaciones de perturbación de estos ritmos y las propiedades de los PACs para restaurar estas perturbaciones. Biological rhythms play an important role in the physiological and metabolic adaptation of the organism to the time of day, circadian rhythm, or year, seasonal rhythm. External cues or modulators called zeitgebers, such as light or food, play a crucial role in the reprogramming or altering these oscillations. Circadian rhythm disruption due to modern lifestyles such as changes in light/dark cycles or dietary patterns has been related to the development of metabolic disorders. In this context, phenolic compounds such as proanthocyanidins (PACs) have demonstrate to exert beneficial effects on metabolic disorders. Moreover, polyphenols have shown their capacity to modulate some components of the clock system. Indeed, the interaction of phenolic compounds with biological rhythms has been recently pointed out by our group as a potential mechanism involved in their beneficial effects. Then, the aim of this thesis was to elucidate whether PACs act through biological rhythms and to investigate whether these phenolic compounds can restore biological rhythms in different perturbation situations, such as changes in light-dark cycles or in dietary patterns. For this, circadian rhythms of healthy and cafeteria (CAF) diet obese Fischer 344 rats, the effects of different situations of perturbation of these rhythms and the properties of PACs to restore these disruptions were studied. CAF diet caused disruption of central clock genes and alteration of metabolism circadian rhythms. PACs demonstrated to act as zeitgebers mitigating the circadian disruption, notably the restoration of the circadian rhythm of melatonin

Objective: This paper proposes a novel approach for automatic left ventricle (LV) quantification using convolutional neural networks (CNN). Methods: The general framework consists of one CNN for detecting the LV, and another for tissue classification. Also, three new deep learning architectures were proposed for LV quantification. These new CNNs introduce the ideas of sparsity and depthwise separable convolution into the U-net architecture, as well as, a residual learning strategy level-to-level. To this end, we extend the classical U-net architecture and use the generalized Jaccard distance as optimization objective function. Results: The CNNs were trained and evaluated with 140 patients from two public cardiovascular magnetic resonance datasets (Sunnybrook and Cardiac Atlas Project) by using a 5-fold cross-validation strategy. Our results demonstrate a suitable accuracy for myocardial segmentation ($\sim$0.9 Dice's coefficient), and a strong correlation with the most relevant physiological measures: 0.99 for end-diastolic and end-systolic volume, 0.97 for the left myocardial mass, 0.95 for the ejection fraction and 0.93 for the stroke volume and cardiac output. Conclusion: Our simulation and clinical evaluation results demonstrate the capability and merits of the proposed CNN to estimate different structural and functional features such as LV mass and EF which are commonly used for both diagnosis and treatment of different pathologies. Significance: This paper suggests a new approach for automatic LV quantification based on deep learning where errors are comparable to the inter- and intra-operator ranges for manual contouring. Also, this approach may have important applications on motion quantification., Accepted in Computer Methods and Programs in Biomedicine. https://www.sciencedirect.com/science/article/pii/S0169260718311696?via%3Dihub