SLAB51 Probiotic Formulation Activates SIRT1 Pathway Promoting Antioxidant and Neuroprotective Effects in an AD Mouse Model

The gut-brain axis is a bidirectional communication network functionally linking the gut and the central nervous system (CNS). Based on this, the rational manipulation of intestinal microbiota represents a novel attractive therapeutic strategy for the treatment of CNS-associated disorders. In this study, we explored the properties of a probiotic formulation (namely SLAB51) in counteracting brain oxidative damages associated with Alzheimer's disease (AD). Specifically, transgenic AD mice (3xTg-AD) were treated with SLAB51 and the effects on protein oxidation, neuronal antioxidant defence and repair systems were monitored, with the particular focus on the role of SIRT1-related pathways. We demonstrated that SLAB51 markedly reduced oxidative stress in AD mice brain by activating SIRT1-dependent mechanisms, thus representing a promising therapeutic adjuvant in AD treatment

Functional and morphological adaptations of the digestive system induced by domestication in cats.

Several studies have showed the macroscopic difference in the gastrointestinal tract between the European wildcat (Felis silvestris silvestris) and the domestic cat (Felis silvestris catus). Digestive system in the wildcat is shorter than in domestic species and this feature is considered distinctive in the taxonomic classification of subjects (Schauenberg et al. 1977). This study is a part of a large investigation regarding the microscopic anatomy of the gastrointestinal tract of European wildcat, associated to the study of intestinal microbiome. Its main purpose was to enhance knowledge about this species, to get a comparison with domestic cat, and to evaluate if and how domestication has influenced the functional and morphological development of this apparatus, also n n t ut\u2018s m roflor To this aim we collected, weighted and measured the gastrointestinal tract of twenty European wildcats. Afterwards, intestinal sections were sampled, treated and observed at the microscope in order to evaluate histological characteristics as the villi height and width, crypts depth and wall thickness. Moreover, we wanted to study the intestinal production of an apolipoprotein that is believed directly related to the development of hepatic steatosis, decreasing the amount of lipids deposited in the liver. For this purpose, liver specimens were collected and treated to study histologically the degree of vacuolar degeneration of hepatocytes. Data were analyzed and compared with those of the domestic cats coming from our database. In attempt to evaluate the microbiome, feces and rectal ampulla were collected and sent to the Texas A&M University for pyrosequencing analysis (data not shown). Results demonstrated significant differences in intestinal structure between F. catus and F. s. silvestris. Villi coming from domestic cats were significantly shorter (p<0.0001) and wider (p<0.0142) than in wildcats that showed crypts deeper (p<0.0009). Domestication has led to significant changes in adaptation regarding both behavior and diet. Several studies showed the correlation between diet changes (protein, carbohydrates, and fiber concentration) and morphological adaptation in the gut of different species (Altmann, 1972; Hampson, 1983; Goodlad et al., 1988; Pluske et al., 1996; Sritiawthai et al., 2013). Moreover, data from liver study showed that domestic cat has higher levels of apolipoprotein compared to the wild cat and that the percentage of lipids in the liver was lower in F. catus than in F. s. silvestris. Despite these results, the liver of domestic cat revealed a rate of steatosis higher than in wild cat. Indeed, this pathology proved to be almost absent in wild cats and can be explained by the different nature of the two species diet and microbiome composition. This study revealed that transition from a strictly-carnivorous diet (typical of the wild cat) to an omnivorous type, has modified the nutritional intake considerably and influenced the evolution of the digestive apparatus in domestic cat

Microbiota modulation counteracts Alzheimer's disease progression influencing neuronal proteolysis and gut hormones plasma levels

Gut microbiota has a proven role in regulating multiple neuro-chemical pathways through the highly interconnected gut-brain axis. Oral bacteriotherapy thus has potential in the treatment of central nervous system-related pathologies, such as Alzheimer's disease (AD). Current AD treatments aim to prevent onset, delay progression and ameliorate symptoms. In this work, 3xTg-AD mice in the early stage of AD were treated with SLAB51 probiotic formulation, thereby affecting the composition of gut microbiota and its metabolites. This influenced plasma concentration of inflammatory cytokines and key metabolic hormones considered therapeutic targets in neurodegeneration. Treated mice showed partial restoration of two impaired neuronal proteolytic pathways (the ubiquitin proteasome system and autophagy). Their cognitive decline was decreased compared with controls, due to a reduction in brain damage and reduced accumulation of amyloid beta aggregates. Collectively, our results clearly prove that modulation of the microbiota induces positive effects on neuronal pathways that are able to slow down the progression of Alzheimer's disease

Massage accelerates brain development and the maturation of visual function

Environmental enrichment (EE) was shown recently to accelerate brain development in rodents. Increased levels of maternal care, and particularly tactile stimulation through licking and grooming, may represent a key component in the early phases of EE. We hypothesized that enriching the environment in terms of body massage may thus accelerate brain development in infants. We explored the effects of body massage in preterm infants and found that massage accelerates the maturation of electroencephalographic activity and of visual function, in particular visual acuity. In massaged infants, we found higher levels of blood IGF-1. Massage accelerated the maturation of visual function also in rat pups and increased the level of IGF-1 in the cortex. Antagonizing IGF-1 action by means of systemic injections of the IGF-1 antagonist JB1 blocked the effects of massage in rat pups. These results demonstrate that massage has an influence on brain development and in particular on visual development and suggest that its effects are mediated by specific endogenous factors such as IGF-1

Manipulating Image Luminance to Improve Eye Gaze and Verbal Behavior in Autistic Children

Autism has been characterized by a tendency to attend to the local visual details over surveying an image to understand the gist–a phenomenon called local interference. This sensory processing trait has been found to negatively impact social communication. Although much work has been conducted to understand these traits, little to no work has been conducted to intervene to provide support for local interference. Additionally, recent understanding of autism now introduces the core role of sensory processing and its impact on social communication. However, no interventions to the end of our knowledge have been explored to leverage this relationship. This work builds on the connection between visual attention and semantic representation in autistic children. In this work, we ask the following research questions: RQ1: Does manipulating image characteristics of luminance and spatial frequency increase likelihood of fixations in hot spots (Areas of Interest) for autistic children? RQ2: Does manipulating low-level image characteristics of luminance and spatial frequency increase the likelihood of global verbal responses for autistic children? We sought to manipulate visual attention as measured by eye gaze fixations and semantic representation of verbal response to the question “What is this picture about?”. We explore digital strategies to offload low-level, sensory processing of global features via digital filtering. In this work, we designed a global filter to reduce image characteristics found to be distracting for autistic people and compared baseline images to featured images in 11 autistic children. Participants saw counterbalanced images way over 2 sessions. Eye gaze in areas of interest and verbal responses were collected and analyzed. We found that luminance in non-salient areas impacted both eye gaze and verbal responding–however in opposite ways (however versus high levels of luminance). Additionally, the interaction of luminance and spatial frequency in areas of interest is also significant. This is the first empirical study in designing an assistive technology aimed to augment global processing that occurs at a sensory-processing and social-communication level. Contributions of this work include empirical findings regarding the quantification of local interference in images of natural scenes for autistic children in real-world settings; digital methods to offload global visual processing to make this information more accessible via insight on the role of luminance and spatial frequency in visual perception of and semantic representation in images of natural scenes

Sunitinib in patients with pre-treated pancreatic neuroendocrine tumors: A real-world study

Introduction: Besides data reported in a Phase-III trial, data on sunitinib in pancreatic Neuroendocrine Tumors (panNETs) are scanty. Aim: To evaluate sunitinib efficacy and tolerability in panNETs patients treated in a real-world setting. Patients and methods: Retrospective analysis of progressive panNETs treated with sunitinib. Efficacy was assessed by evaluating progression-free survival, overall survival, and disease control (DC) rate (stable disease (SD) + partial response + complete response). Data are reported as median (25th\ue2\u80\u9375th IQR). Results: Eighty patients were included. Overall, 71.1% had NET G2, 26.3% had NET G1, and 2.6% had NET G3 neoplasms. A total of 53 patients (66.3%) had received three or more therapeutic regimens before sunitinib, with 24 patients (30%) having been treated with four previous treatments. Median PFS was 10 months. Similar risk of progression was observed between NET G1 and NET G2 tumors (median PFS 11 months and 8 months, respectively), and between patients who had received \ue2\u89\ua5 3 vs \ue2\u89\ua4 2 therapeutic approaches before sunitinib (median PFS 9 months and 10 months, respectively). DC rate was 71.3% and SD was the most frequent observed response, occurring in 43 pts (53.8%). Overall, 59 pts (73.8%) experienced AEs, which were grade 1\ue2\u80\u932 in 43 of them (72.9%), grade 3 in 15 pts (25.4%), and grade 4 in one patient (1.7%). Six pts (7.5%) stopped treatment due to toxicity. Conclusions: The present real-world experience shows that sunitinib is a safe and effective treatment for panNETs, even in the clinical setting of heavily pre-treated, progressive diseases

The Italian Rare Pancreatic Exocrine Cancer Initiative

INTRODUCTION: Exocrine pancreatic cancers include common type pancreatic ductal adenocarcinoma and cystic neoplasms, which account for 85% and 10% of cases, respectively. The remaining 5% are rare histotypes, comprising adenosquamous carcinoma, acinar cell carcinoma, signet ring cell carcinoma, medullary carcinoma, pancreatoblastoma, hepatoid carcinoma, undifferentiated carcinoma and its variant with osteoclast-like giant cells, solid pseudopapillary carcinoma, and carcinosarcoma. Due to their low incidence, little knowledge is available on their clinical and molecular features as well as on treatment choices. The national initiative presented here aims at the molecular characterization of series of rare histotypes for which therapeutic and follow-up data are available. METHODS: A nationwide Italian Rare Pancreatic Cancer (IRaPaCa) task force whose first initiative is a multicentric retrospective study involving 21 Italian cancer centers to retrieve histologic material and clinical and treatment data of at least 100 patients with rare exocrine pancreatic cancers has been created. After histologic revision by a panel of expert pathologists, DNA and RNA from paraffin tissues will be investigated by next-generation sequencing using molecular pathway-oriented and immune-oriented mutational and expression profiling panels constructed availing of the information from the International Cancer Genome Consortium. Bioinformatic analysis of data will drive validation studies by immunohistochemistry and in situ hybridization, as well as nanostring assays. CONCLUSIONS: We expect to gather novel data on rare pancreatic cancer types that will be useful to inform the design of therapeutic choices

Geological map of the Tocomar Basin (Puna Plateau, NW Argentina): Implication for the geothermal system investigation

This paper presents a detailed geological map at the 1:20,000 scale of the Tocomar basin in the Central Puna (north-western Argentina), which extends over an area of about 80 km2 and displays the spatial distribution of the Quaternary deposits and the structures that cover the Ordovician basement and the Tertiary sedimentary and volcanic units. The new dataset includes litho-facies descriptions, stratigraphic and structural data and new 234U/230Th ages for travertine rocks. The new reconstructed stratigraphic framework, along with the structural analysis, has revealed the complex evolution of a small extensional basin including a period of prolonged volcanic activity with different eruptive centres and styles. The geological map improves the knowledge of the geology of the Tocomar basin and the local interplay between orogen-parallel thrusts and orogen-oblique fault systems. This contribution represents a fundamental support for in depth research and also for encouraging geothermal exploration and exploitation in the Puna Plateau regionFil: Filipovich, Ruben Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Bio y Geociencias del NOA. Universidad Nacional de Salta. Facultad de Ciencias Naturales. Museo de Ciencias Naturales. Instituto de Bio y Geociencias del NOA; ArgentinaFil: Baez, Walter Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Bio y Geociencias del NOA. Universidad Nacional de Salta. Facultad de Ciencias Naturales. Museo de Ciencias Naturales. Instituto de Bio y Geociencias del NOA; ArgentinaFil: Groppelli, Gianluca. CNR Istituto di Geologia Ambientale e Geoingegneria; ItaliaFil: Ahumada, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Bio y Geociencias del NOA. Universidad Nacional de Salta. Facultad de Ciencias Naturales. Museo de Ciencias Naturales. Instituto de Bio y Geociencias del NOA; ArgentinaFil: Aldega, Luca. Università degli Studi di Roma "La Sapienza"; ItaliaFil: Becchio, Raul Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Bio y Geociencias del NOA. Universidad Nacional de Salta. Facultad de Ciencias Naturales. Museo de Ciencias Naturales. Instituto de Bio y Geociencias del NOA; ArgentinaFil: Berardi, Gabriele. Università Roma Tre III; ItaliaFil: Bigi, Sabina. Università degli Studi di Roma "La Sapienza"; ItaliaFil: Caricchi. Chiara. Istituto Nazionale di Geofisica e Vulcanologia; ItaliaFil: Chiodi, Agostina Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Bio y Geociencias del NOA. Universidad Nacional de Salta. Facultad de Ciencias Naturales. Museo de Ciencias Naturales. Instituto de Bio y Geociencias del NOA; ArgentinaFil: Corrado, Sveva. Università Roma Tre III; ItaliaFil: De Astis, Gianfilippo. Istituto Nazionale di Geofisica e Vulcanologia; ItaliaFil: De Benedetti, Arnaldo Angelo. Università Roma Tre III; ItaliaFil: Invernizzi, Chiara. Universita Degli Di Camerino; ItaliaFil: Norini, Gianluca. CNR Istituto di Geologia Ambientale e Geoingegneria; ItaliaFil: Soligo, Michele. Università Roma Tre III; ItaliaFil: Taviani, Sara. University of Milano-Bicocca; ItaliaFil: Viramonte, Jose German. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Bio y Geociencias del NOA. Universidad Nacional de Salta. Facultad de Ciencias Naturales. Museo de Ciencias Naturales. Instituto de Bio y Geociencias del NOA; ArgentinaFil: Giordano, Guido. CNR Istituto di Geologia Ambientale e Geoingegneria; Italia. Università Roma Tre III; Itali

Clinical predictors of antipsychotic treatment resistance: Development and internal validation of a prognostic prediction model by the STRATA-G consortium

Introduction Our aim was to, firstly, identify characteristics at first-episode of psychosis that are associated with later antipsychotic treatment resistance (TR) and, secondly, to develop a parsimonious prediction model for TR. Methods We combined data from ten prospective, first-episode psychosis cohorts from across Europe and categorised patients as TR or non-treatment resistant (NTR) after a mean follow up of 4.18 years (s.d. = 3.20) for secondary data analysis. We identified a list of potential predictors from clinical and demographic data recorded at first-episode. These potential predictors were entered in two models: a multivariable logistic regression to identify which were independently associated with TR and a penalised logistic regression, which performed variable selection, to produce a parsimonious prediction model. This model was internally validated using a 5-fold, 50-repeat cross-validation optimism-correction. Results Our sample consisted of N = 2216 participants of which 385 (17 %) developed TR. Younger age of psychosis onset and fewer years in education were independently associated with increased odds of developing TR. The prediction model selected 7 out of 17 variables that, when combined, could quantify the risk of being TR better than chance. These included age of onset, years in education, gender, BMI, relationship status, alcohol use, and positive symptoms. The optimism-corrected area under the curve was 0.59 (accuracy = 64 %, sensitivity = 48 %, and specificity = 76 %). Implications Our findings show that treatment resistance can be predicted, at first-episode of psychosis. Pending a model update and external validation, we demonstrate the potential value of prediction models for TR.Funding: This work was supported by a Stratified Medicine Programme grant to JHM from the Medical Research Council (grant number MR/L011794/1 which funded the research and supported S.E.S., D.A., A.F.P, L.K., R.M.M., D.S., J.T.R.W, & J.H.M.); funding from the National Institute for Health Research Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King's College London to D.A. and D.S; and funding from the Collaboration for Leadership in Applied Health Research and Care (CLAHRC) South London at King's College Hospital National Health Service Foundation Trust to S.E.S. The views expressed are those of the author(s) and not necessarily those of the Medical Research Council, National Health Service, the National Institute for Health Research, or the Department of Health. The AESOP (London, UK) cohort was funded by the UK Medical Research Council (Ref: G0500817). The Belfast (UK) cohort was funded by the Research and Development Office of Northern Ireland. The Bologna (Italy) cohort was funded by the European Community's Seventh Framework Program under grant agreement (agreement No.HEALTH-F2-2010–241909, Project EU-GEI). The GAP (London, UK) cohort was funded by the UK National Institute of Health Research(NIHR) Specialist Biomedical Research Centre for Mental Health, South London and Maudsley NHS Mental Health Foundation Trust (SLaM) and the Institute of Psychiatry, Psychology, and Neuroscience at King's College London; Psychiatry Research Trust; Maudsley Charity Research Fund; and the European Community's Seventh Framework Program grant (agreement No. HEALTH-F2-2009-241909, Project EU-GEI). The Lausanne (Switzerland) cohort was funded by the Swiss National Science Foundation (no. 320030_135736/1 to P.C. and K.Q.D., no 320030-120686, 324730-144064 and 320030-173211 to C.B.E and P.C., and no 171804 to LA); National Center of Competence in Research (NCCR) “SYNAPSY - The Synaptic Bases of Mental Diseases” from the Swiss National Science Foundation (no 51AU40_125759 to PC and KQD); and Fondation Alamaya (to KQD). The Oslo (Norway) cohort was funded by the Research Council of Norway (#223273/F50, under the Centers of Excellence funding scheme, #300309, #283798) and the South-Eastern Norway Regional Health Authority (#2006233, #2006258, #2011085, #2014102, #2015088 to IM, #2017-112). The Paris (France) cohort was funded by European Community's Seventh Framework Program grant (agreement No. HEALTH-F2-2010–241909, Project EU-GEI). The Prague (Czech Republic) cohort was funded by the Ministry of Health of the Czech Republic (Grant Number: NU20-04-00393). The Santander (Spain) cohort was funded by the following grants (to B.C.F): Instituto de Salud Carlos III, FIS 00/3095, PI020499, PI050427, PI060507, Plan Nacional de Drogas Research Grant 2005-Orden sco/3246/2004, and SENY Fundatio Research Grant CI 2005-0308007, Fundacion Marques de Valdecilla A/02/07 and API07/011. SAF2016-76046-R and SAF2013-46292-R (MINECO and FEDER). The West London (UK) cohort was funded The Wellcome Trust (Grant Number: 042025; 052247; 064607)