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In everyday life, sound localization entails more than just the extraction and processing of auditory cues. When determining sound position in three dimensions, the brain also considers the available visual information (e.g., visual cues to sound position) and resolves perceptual ambiguities through active listening behavior (e.g., spontaneous head movements while listening). Here, we examined to what extent spontaneous head movements improve sound localization in 3D—azimuth, elevation, and depth—by comparing static vs. active listening postures. To this aim, we developed a novel approach to sound localization based on sounds delivered in the environment, brought into alignment thanks to a VR system. Our system proved effective for the delivery of sounds at predetermined and repeatable positions in 3D space, without imposing a physically constrained posture, and with minimal training. In addition, it allowed measuring participant behavior (hand, head and eye position) in real time. We report that active listening improved 3D sound localization, primarily by ameliorating accuracy and variability of responses in azimuth and elevation. The more participants made spontaneous head movements, the better was their 3D sound localization performance. Thus, we provide proof of concept of a novel approach to the study of spatial hearing, with potentials for clinical and industrial applications.

Background and Purpose Use of unilateral cochlear implant (UCI) is associated with limited spatial hearing skills. Evidence that training these abilities in UCI user is possible remains limited. In this study, we assessed whether a Spatial training based on hand-reaching to sounds performed in virtual reality improves spatial hearing abilities in UCI users Methods Using a crossover randomized clinical trial, we compared the effects of a Spatial training protocol with those of a Non-Spatial control training. We tested 17 UCI users in a head-pointing to sound task and in an audio-visual attention orienting task, before and after each training. Study is recorded in clinicaltrials.gov (NCT04183348). Results During the Spatial VR training, sound localization errors in azimuth decreased. Moreover, when comparing head-pointing to sounds before vs. after training, localization errors decreased after the Spatial more than the control training. No training effects emerged in the audio-visual attention orienting task. Conclusions Our results showed that sound localization in UCI users improves during a Spatial training, with benefits that extend also to a non-trained sound localization task (generalization). These findings have potentials for novel rehabilitation procedures in clinical contexts.

Bullous pemphigoid (BP) is an autoimmune blistering disease that targets the haemidesmosomal proteins, mainly BP180. Extracellular vesicles (EVs) have been demonstrated to carry tissue-specific autoantigens in the setting of autoimmune diseases and transplant organ rejection; this phenomenon was demonstrated to have pathogenic implications in autoimmune diseases and to correlate with transplant rejection severity. The purpose of this study was to identify the presence of BP targeted autoantigens in blister fluid derived EVs. We isolated, by size exclusion chromatography, EVs derived from blisters of BP-patients and from suction blisters of healthy donors. EV characterization was performed by flow cytometry and nanoparticle tracking analysis. Western blot analysis was used to investigate the presence of autoantigens. A suspension enriched in EVs was efficiently obtained from blister fluid from patients and healthy donors. EV-enriched fractions were enriched in particles with a size distribution characterizing small-EVs (main peak was present at 94.5 nm). BP180 was found, by western blot analysis, in EVs derived from blister fluid of 3 out 6 BP patients and in none of EVs isolated from suction blister fluid of healthy donors. BP230 and Dsg1 were not detectable in EVs of any of the samples. No specific clinical characteristics seemed to correlate to the presence of BP180 in EVs. The discovery of BP180 in EVs derived from blister fluid might help understanding BP pathogenesis.

Performing transcatheter aortic valve implantation with high implantation technique, i.e. with an aorto-ventricular ratio 60/40, reduces the need of permanent pacemaker implantation. Valve calcification and prosthesis oversizing are predictors of permanent pacemaker implantation, but there are no available data on their role when transcatheter aortic valve implantation is performed with an aorto-ventricular ratio 60/40. The aim of this study was to evaluate the effect of leaflets/annulus calcification and prosthesis oversizing on the incidence of permanent pacemaker implantation after transcatheter aortic valve implantation with a high implantation technique. Transcatheter aortic valve implantation was performed in 48 patients implanting a balloon-expandable transcatheter heart valve with an aorto-ventricular ratio 60/40. Calcium burden was assessed by preprocedural multidetector computed tomography. An invasive electrophysiological study was performed before and after transcatheter aortic valve implantation. Five patients (10.4%) needed permanent pacemaker implantation. At univariate analysis, baseline right bundle branch block and postprocedural PR, QRS and His-ventricular interval elongation significantly predicted permanent pacemaker implantation (p 0.05). Receiver-operating characteristic curve analysis showed a correlation between transcatheter heart valve oversizing and permanent pacemaker implantation need, with the best cut-off being 17% (AUC = 0.72, p = 0.033). Linear regression analysis demonstrated that QRS complex elongation was related to total, left and non-coronary leaflet calcification (p 0.05). This study demonstrates that, when transcatheter aortic valve implantation is performed using a balloon-expandable transcatheter heart valve deployed with an aorto-ventricular ratio 60/40, the presence of leaflets/annulus calcification or the need to oversize the prosthesis correlate with the occurrence of pathological cardiac conduction delays.

The guanaco (Lama guanicoe) was a key staple hunted by foragers throughout the Holocene in southern South America. Stable isotope analyses provide insights about guanaco long-term ecology. Particularly, the characterization of prey habitat and feeding behavior in the past is of the utmost interest for zooarchaeological models. Therefore, we evaluate δ13C and δ15N variation in guanacos inhabiting different C3 plant communities in Tierra del Fuego (Argentina). δ13C and δ15N values derived from bone collagen samples (n = 60), both archeological and modern, serve as geographical markers of forest-steppe environments during the late Holocene. Increased isotopic variation in the middle Holocene could be related either to variations in the terrestrial baseline or to changing dietary behavior of guanacos in a fluctuating environment. Measures of isotopic variability did not clearly correlate to hunting strategies, since areas with similar patterns in the exploitation of guanacos show differences in their isotopic niche size and distribution. Among the samples from the southern coast, there is a strong negative correlation between δ13C and δ15N. This is a trend not observed in herbivores from the forests of continental Patagonia, suggesting that different factors structure natural isotopic variation in guanacos from the Fuegian forest. δ13C and δ15N variation on bone assemblages probably reflect that guanacos fed in confined home-ranges, as it is observed in modern populations, and that hunting activities were developed at patches relatively close to the sites.

Several recent papers have focused on new evidence pointing to the possibility of the mass procurement of guanacos in Fuegian pedestrian hunter-gatherer groups. These works are linked to the excavation of Las Vueltas 1 (northern Tierra del Fuego, Argentina), an archaeological site mainly characterised by a vast guanaco bonebed. This paper is part of that discussion, adding a new line of evidence over the zooarchaeological record using spatial statistics. Our hypothesis considers the formation processes of LV1 were caused by a communal hunting party, which implies the synchronous deposition of the guanaco assemblage in a single event. Consequently, the underlying spatial structure of the bonebed should be clearly identifiable, since neithersuperposition of events nor cleaning patterns are expected. Our proposal embraces an interdisciplinary approach and offers a practical methodology to address the general problem of analysing the spatial structure of an archaeological site, without additional, time-consuming analysis. The results of the different statistical tests have proved to be insightful about the formation processes of the LV1 bonebed, and they are consistent with the initial hypothesis regarding the functionality of the site as a guanaco mass hunting site. Fil: Negre Pérez, Joan. Universitat de Barcelona; España Fil: Santiago, Fernando Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; Argentina Fil: Salemme, Monica Cira. Universidad Nacional de Tierra del Fuego; Argentina

The docking protein p140Cap negatively regulates tumour cell features. Its relevance on breast cancer patient survival, as well as its ability to counteract relevant cancer signalling pathways, are not fully understood. Here we report that in patients with ERBB2-amplified breast cancer, a p140Cap-positive status associates with a significantly lower probability of developing a distant event, and a clear difference in survival. p140Cap dampens ERBB2-positive tumour cell progression, impairing tumour onset and growth in the NeuT mouse model, and counteracting epithelial mesenchymal transition, resulting in decreased metastasis formation. One major mechanism is the ability of p140Cap to interfere with ERBB2-dependent activation of Rac GTPase-controlled circuitries. Our findings point to a specific role of p140Cap in curbing the aggressiveness of ERBB2-amplified breast cancers and suggest that, due to its ability to impinge on specific molecular pathways, p140Cap may represent a predictive biomarker of response to targeted anti-ERBB2 therapies., p140Cap adaptor proteins interfere with adhesion and growth factor-dependent signalling in cancer cells but the mechanisms are unclear. Here the authors show that p140Cap interferes with ERBB2-dependent activation of Rac GTPase-controlled circuitries reducing metastasis and cancer progression.

Nature Communications 8: Article number: 14797 (2017); Published online 16 March 2017; Updated 30 March 2018 In the original version of this Article, the affiliation details for Anna Sapino were incorrectly given as Department of Medical Sciences, University of Torino, 10126 Torino, Italy instead ofCandiolo Cancer Institute-FPO, IRCCS, Str.

The archaeological record of the northern steppe in Tierra del Fuego (Argentina) is characterized by the occurrence of concentrations of archaeological material at the ground surface, coming from gullies and deflation hollows related to shallow lake coastal environments. This particular distribution becomes a challenge concerning the study of siteformation processes, particularly in relation to the burial andexhumation of archaeological materials. Bone assemblages coming from three archaeological contexts (Tres Marías, Amalia 4 and Arturo 1) are analysed here, pointing to the features, damage and stability or movements that reveal their taphonomic histories. Geomorphological landscapes vary from each site, being represented by deflation hollows close to shallow lakes as well as gullies originating from the coastitself. The faunal assemblages are mostly dominated by Lama guanicoe bones. Variability in taxonomic composition, weathering profiles, mobility and stability of materials, as well as evidence of anthropic modifications, among other records, demonstrate the existence of different depositional events.The high variability observed suggests that several pre- andpost-depositional processes were involved; thus, it results incomplex taphonomic histories and low integrity that maketheir interpretation difficult in terms of human activities. Fil: Oria, Jimena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; Argentina Fil: Salemme, Monica Cira. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; Argentina. Universidad Nacional de Tierra del Fuego; Argentina Fil: Vazquez, Martin Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; Argentina

The class B MADS-box genes belong to two distinct functional groups: the AP3/DEF-like and the PI/GLO-like sub-families. In orchids, AP3/DEF-like genes are present in four copies, each with a different role in floral organ formation, which is described in the "orchid code" model. Interestingly, the orchid PI/GLO-like genes are present in two copies in Orchidinae, whereas they are described as single copy in the other orchid lineages. The two PI/GLO-like paralogs have site-specific different selective constraints; in addition, they show relaxation of purifying selection when compared to the single-copy lineages. In this study, we present a comparative analysis of the expression patterns of the two PI/GLO-like paralogs, OrcPI and OrcPI2, in floral tissues of Orchis italica in different developmental stages using real-time PCR. The two genes show similar expression profiles in the tissue examined, with differences detectable between immature and mature inflorescence. In all cases, OrcPI2 is expressed at a higher level than OrcPI. Real-time PCR results reveal that the co-expression of the two duplicated loci could have a fully or partially redundant function. The possible evolutionary fate of OrcPI and OrcPI2 is discussed as well as their involvement in ovary development.

Endoscopic submucosal dissection (ESD) is gaining popularity worldwide in the treatment of neoplastic lesions of the gastrointestinal tract. However, the experience in Western countries is quite limited and restricted to large or academic centers. Besides, this approach requires an optimal pathological assessment. The aim of this study was to report our experience with colonic ESD using a new device that allows complete handling of the resected specimens and especially of lateral margins, for pathological analysis. In a 1-year period, 14 patients (6 men, 8 women, age range 50-82 years) underwent colonic ESD in a non-academic hospital. The endoscopic procedure was carried out successfully en bloc in more than 90 % of cases. Perforation requiring surgery occurred in one patient (7 %). Pathological assessment with the new device allowed entire and complete examination of both the deep and lateral margins of the excised specimens. Colonic ESD is a viable option for non-surgical treatment of large bowel lesions even in relatively small centers and in non-academic settings. The new device allows good handling of the specimens, and it seems to be useful for the entire examination of the resection margins.

Sensorineural hearing loss has been reported as an extraintestinal manifestation of inflammatory bowel disease, especially in adult patients with ulcerative colitis. However, to date only a few series have been reported in the literature, and none from Italy. The aim of the present investigation was to assess the prevalence of symptomatic sensorineural hearing loss in Italian patients with ulcerative colitis.We retrospectively assessed the charts of all patients with ulcerative colitis who underwent otolaryngologic investigation in a 10-year period.Complete charts of 57 patients were available for the observation period. Reasons for head and neck investigation were transient, mild hearing loss and sporadic vertigo. Clinical and instrumental head and neck examination was unremarkable in all but one woman who complained of mild hearing loss without vertigo or tinnitus, in whom sensorineural hearing loss was diagnosed.In our series, sensorineural hearing loss was found in less than 2 % of adult patients with ulcerative colitis evaluated in a department of otolaryngology. Systematic evaluation for this extraintestinal manifestation should not be carried out unless hearing loss is present.

Isoflavones are a group of natural phytoestrogens including the compound genistein. Health beneficial effects have been attributed to the consumption of this compound, but the fact that it has estrogen-like activity has raised doubts regarding its potential risk in infants, newborns, or in the fetus and placenta during pregnancy. This work is aimed at studying genistein effects on Ca2+ handling by smooth muscle cells of the human umbilical artery (HUA). Using fluorometric techniques, we found that in these cells genistein reduces the intracellular Ca2+ peak produced by serotonin. The same result could be demonstrated in absence of extracellular Ca2+, suggesting that the isoflavone reduces Ca2+ release from the sarcoplasmic reticulum. Force measurement experiments strengthen these results, since genistein reduced the peak force attained by intact HUA rings stimulated by serotonin in a Ca2+-free solution. Moreover, genistein induced the relaxation of HUA rings precontracted either with serotonin or a depolarizing high-extracellular K+ solution, hinting at a reduction of extracellular Ca2+ entry to the cell. This was confirmed by whole-cell patch-clamp experiments where it was shown that the isoflavone inhibits ionic currents through voltage-operated Ca2+ channels. In summary, we show that genistein inhibits two mechanisms that could increase intracellular Ca2+ in human umbilical smooth muscle cells, behaving in this way as a potential vasorelaxing substance of fetal vessels. Taking into account that genistein is able to cross the placental barrier, these data show that isoflavones may have important implications in the regulation of feto-maternal blood flow in pregnant women who consume soy-derived products as part of their meals., Facultad de Ciencias Exactas

The gain of reactive saccades was manipulated in 17 subjects using a target-jump paradigm. Following adaptation three sub-groups were formed: (1) rest 15 min in the dark, eyes closed; (2) perform self-generated saccades for 15 min; (3) perform reactive saccades for 15 min. The series of saccades were the same in groups 2 and 3 (amplitude, sequence), except that group 3 performed fewer saccades (same number as the lowest number of saccades performed by one subject in group 2). Neither the rest period nor the series of self-generated saccades affected the adapted gain. The series of reactive saccades generated, by contrast, quick de-adaptation. These results support the conclusion that the gain of self-generated and reactive saccades is independently controlled.

The multitude of potential drug targets emerging from genome sequencing demands new approaches to drug discovery. A chemogenomics strategy, which involves the generation of small-molecule compounds that can be used both as tools to probe biological mechanisms and as leads for drug-property optimization, provides a highly parallel, industrialized solution. Key to the success of this strategy is an integrated suite of chemi-informatics applications that can allow the rapid and directed optimization of chemical compounds with drug-like properties using 'just-in-time' combinatorial chemical synthesis. An effective embodiment of this process requires new computational and data-mining tools that cover all aspects of library generation, compound selection and experimental design, and work effectively on a massive scale.