A New Culture Medium Rich in Phenols Used for Screening Bitter Degrading Strains of Lactic Acid Bacteria to Employ in Table Olive Production.

The olive oil industry recently introduced a novel multi-phase decanter with the "Leopard DMF" series, which gives a by-product called pâté, made up of pulp and olive wastewater with a high content of phenolic substances and without pits. This study aims to create a new culture medium, the Olive Juice Broth (OJB), from DMF pâté, and apply it to select bacteria strains able to survive and degrade the bitter substances normally present in the olive fruit. Thirty-five different bacterial strains of Lactiplantibacillus plantarum from the CREA-IT.PE Collection of Microorganisms were tested. Seven strains characterized by ≥50% growth in OJB (B31, B137, B28, B39, B124, B130, and B51) showed a degradation of the total phenolic content of OJB ≥ 30%. From this set, L. plantarum B51 strain was selected as a starter for table olive production vs. spontaneous fermentation. The selected inoculant effectively reduced the debittering time compared to spontaneous fermentation. Hydroxytyrosol, derived from oleuropein and verbascoside degradation, and tyrosol, derived from ligstroside degradation, were produced faster than during spontaneous fermentation. The OJB medium is confirmed to be useful in selecting bacterial strains resistant to the complex phenolic environment of the olive fruit.

Changes in adolescents with borderline personality features and caregivers after dialectical behaviour multifamily group therapy / Cambios en adolescentes con rasgos de trastorno límite de personalidad y cuidadores tras un grupo multifamiliar de terapia dialéctico conductual

Dialectical Behaviour Therapy (DBT) is an effective treatment for symptoms of Borderline Personality Disorder (BPD) and has been adapted to adolescent population (DBT-A). The objective of this pilot study was to determine if DBT-A skill group as a stand-alone treatment could improve rearing styles and emotion regulation in adolescents with BPD features and their parents. We designed a 12-week skills group intervention with 14 adolescents with BPD features and their caregivers. Participants (81.82% female) ranged in age from 14 to 17 (M= 15.55 SD=.82).We tested the results of the intervention using the non-parametric Wilcoxon test and calculated effect sizes. To understand individual changes, we reported clinical reliable change (CRC). Acceptability of the intervention was also evaluated. The intervention was effective for improving rearing styles (more affectionate and less criticism) in parents and adolescents. Changes in emotion regulation processes were mixed. Some of the changes were stable 6 months after intervention. Participants reported good levels of satisfaction with the intervention. A DBT-A multifamily group intervention could modify potential mechanisms related with the developing BPD as rearing styles. The duration of the intervention could not be enough to improve emotion regulation processes. Developing early interventions with adolescents with BPD features could modify mechanisms that prevent the establishment of BDP. (AU)

La Terapia Dialéctico Conductual (TDC) es efectiva para el tratamiento de los síntomas del Trastorno Límite de Personalidad (TLP) y ha sido adaptada a población adolescente (TDC-A). El objetivo de este estudio piloto fue determinar si el grupo de habilidades de TDC-A como tratamiento independiente podría mejorar los estilos de crianza y la regulación emocional en adolescentes con características de TLP y sus padres. Diseñamos una intervención grupal de habilidades de 12 semanas de duración con 14 adolescentes con características de TLP y sus cuidadores. Los partici-pantes (81.82% mujeres) tenían edades desde 14 a 17 años (M= 15.55 SD= .82).Evaluamos los resultados de la intervención mediante la prueba no paramétrica de Wilcoxon y el cálculo de los tamaños del efecto. Para conocer los cambios individuales, informamos el cambio clínico significativo (CCS). También se evaluó la aceptabilidad de la intervención. La intervención fue efectiva para mejorar los estilos de crianza (más afectivo y menos crítico) en padres y adolescentes. Los cambios en los procesos de regulación emocional fueron mixtos. Algunos de los cambios se mantuvieron estables 6 meses después de la intervención. Los participantes reportaron buenos niveles de satisfacción con la intervención. Una intervención multifamiliar grupal de TDC-A podría modificar los potenciales mecanismos relacionados con el desarrollo del TLP como son los estilos de crianza. La intervención podría no ser suficiente para mejorar los procesos de regulación emocional. Desarrollar una intervención temprana con adolescentes con rasgos de TLP podría modificar los mecanismos que previenen el establecimiento de TLP. (AU)

Dialectical Behavioral Skills Group Therapy for Parents of Adolescents With Borderline Personality Disorder: A Pilot Study.

Research has indicated the effectiveness of Dialectical behavior therapy in adolescents (DBT-A) with severe emotion dysregulation and other symptoms of Borderline Personality Disorder (BPD). The objective was to determine if DBT skills group with caregivers only could influence in potential mediators of DBT outcomes including rearing styles, emotion regulation and mindfulness skills, evaluated in both parents and adolescents. We implemented a 12-week group intervention based on DBT-A addressed to seven parents of adolescents with features of BPD. We tested differences after treatment using the non-parametric Wilcoxon test and calculated effect sizes. To understand individual changes, we reported clinical reliable change (CRC). The intervention was effective for improving rearing styles, emotion regulation and mindfulness skills in adolescents. Changes were stable after 6 months. The intervention showed good levels of satisfaction reported by parents. A short DBT group-only intervention with caregivers could modify relevant processes related with features of BPD in adolescents. Early interventions with adolescents with symptoms of BPD could prevent the development of BPD influencing in potential mediation mechanisms.

The Usefulness of In Vitro Percutaneous Absorption Experiments Applying the Infinite Dose Technique to Predict In Vivo Plasma Levels: Comparison of Model-Predicted and Observed Plasma Concentrations of Nortriptyline in Rats.

The aims of this study were to evaluate the feasibility of a nortriptyline (NT) formulation for transdermal administration and to assess the usefulness of an estimated kinetic parameter (kout) using the in vitro infinite dose technique to predict in vivo plasma levels when used in combination with pharmacokinetic parameters. To do so, a simple one-compartment model was used to describe the transport of a permeant across a membrane (skin). This model provides relatively simple expressions for the amount of permeant in the skin, the cumulative amount of permeant that crosses the skin, and the flux of permeant, for both the infinite and the finite dose regimens. Transdermal administration of the formulated NT gel to rats resulted in plasma levels of approximately 150 ng/mL between 8 and 30 h post-administration. These levels were higher than the minimum concentration of 40 ng/mL recommended for smoking cessation therapy and slightly higher than the upper limit of the therapeutic range for the treatment of depression in humans. The one-compartment model used to describe transport across the skin was connected to a two-compartment pharmacokinetic model used to predict NT plasma concentrations in rats using the kout determined in vitro and the values of other pharmacokinetic parameters obtained in vivo. The predicted concentrations were close to the observed plasma levels and the time profiles were similar for both types of data. These results show the usefulness of the kout parameter determined in vitro to predict plasma concentrations of drugs administered percutaneously.

AAV-mediated BMP7 gene therapy counteracts insulin resistance and obesity.

Type 2 diabetes, insulin resistance, and obesity are strongly associated and are a major health problem worldwide. Obesity largely results from a sustained imbalance between energy intake and expenditure. Therapeutic approaches targeting metabolic rate may counteract body weight gain and insulin resistance. Bone morphogenic protein 7 (BMP7) has proven to enhance energy expenditure by inducing non-shivering thermogenesis in short-term studies in mice treated with the recombinant protein or adenoviral vectors encoding BMP7. To achieve long-term BMP7 effects, the use of adeno-associated viral (AAV) vectors would provide sustained production of the protein after a single administration. Here, we demonstrated that treatment of high-fat-diet-fed mice and ob/ob mice with liver-directed AAV-BMP7 vectors enabled a long-lasting increase in circulating levels of this factor. This rise in BMP7 concentration induced browning of white adipose tissue (WAT) and activation of brown adipose tissue, which enhanced energy expenditure, and reversed WAT hypertrophy, hepatic steatosis, and WAT and liver inflammation, ultimately resulting in normalization of body weight and insulin resistance. This study highlights the potential of AAV-BMP7-mediated gene therapy for the treatment of insulin resistance, type 2 diabetes, and obesity.

New correlations between ocular parameters and disease severity in Spanish patients with Gaucher's disease Type I.

BACKGROUND: Gaucher's disease is associated with a high variety of structural and functional abnormalities in the eye, which do not always affect visual acuity. The purpose of this study was to analyse ocular features in Spanish patients with Gaucher's disease type I, and to investigate their possible correlation with phenotypic and burden parameters of this entity. METHODS: This cross-sectional observational study compared parameters belonging to 18 eyes from 9 Spanish patients with Gaucher's disease Type I with 80 eyes from 40 healthy controls. Complete ophthalmological examination included choroidal and retinal thickness maps with swept source optical coherence tomography. Systemic analysis included genotype, plasmatic biomarkers, [ferritin, chemokine ligand 18 (CCL18) and chitotriosidase (ChT)] and severity scoring systems results ["Gaucher Disease Severity Score Index Type I" (GauSSI-I) and "Gaucher disease severity scoring system" (GD-DS3)]. RESULTS: Nine subjects (18 eyes) were cases (female: 55.5%, mean age 45 years; male: 44.5%, mean age 36 years) and 40 subjects (80 eyes) were controls (female: 49%, mean age 50 years; male: 51%, mean age 55 years). There were no statistically significant differences when comparing ocular parameters (visual acuity; axial length, refractive errors, corneal parameters, lens, retinal and choroidal thickness) between case and control subjects (p>0.05). A statistically significant moderate correlation was observed between lower retinal thickness and choroidal quadrants thickness and greater disease severity scores. A lower central retinal thickness also correlates with higher biological plasmatic levels, and has a statistically significant association with the most affected patient with genotype N370S/Del 55pb. Conversely, higher pachymetry involves a more severe plasmatic concentration of biomarkers. CONCLUSIONS: Our results suggest that pachymetry, and retinal and choroidal thickness, are associated with burden biomarkers and disease severity index scores in Spanish patients with Gaucher's disease Type I.

Seven-year follow-up of durability and safety of AAV CNS gene therapy for a lysosomal storage disorder in a large animal.

Delivery of adeno-associated viral vectors (AAVs) to cerebrospinal fluid (CSF) has emerged as a promising approach to achieve widespread transduction of the central nervous system (CNS) and peripheral nervous system (PNS), with direct applicability to the treatment of a wide range of neurological diseases, particularly lysosomal storage diseases. Although studies in small animal models have provided proof of concept and experiments in large animals demonstrated feasibility in bigger brains, there is not much information on long-term safety or durability of the effect. Here, we report a 7-year study in healthy beagle dogs after intra-CSF delivery of a single, clinically relevant dose (2 × 1013 vg/dog) of AAV9 vectors carrying the canine sulfamidase, the enzyme deficient in mucopolysaccharidosis type IIIA. Periodic monitoring of CSF and blood, clinical and neurological evaluations, and magnetic resonance and ultrasound imaging of target organs demonstrated no toxicity related to treatment. AAV9-mediated gene transfer resulted in detection of sulfamidase activity in CSF throughout the study. Analysis at tissue level showed widespread sulfamidase expression and activity in the absence of histological findings in any region of encephalon, spinal cord, or dorsal root ganglia. Altogether, these results provide proof of durability of expression and long-term safety for intra-CSF delivery of AAV-based gene transfer vectors encoding therapeutic proteins to the CNS.

Treatment of skeletal and non-skeletal alterations of Mucopolysaccharidosis type IVA by AAV-mediated gene therapy.

Mucopolysaccharidosis type IVA (MPSIVA) or Morquio A disease, a lysosomal storage disorder, is caused by N-acetylgalactosamine-6-sulfate sulfatase (GALNS) deficiency, resulting in keratan sulfate (KS) and chondroitin-6-sulfate accumulation. Patients develop severe skeletal dysplasia, early cartilage deterioration and life-threatening heart and tracheal complications. There is no cure and enzyme replacement therapy cannot correct skeletal abnormalities. Here, using CRISPR/Cas9 technology, we generate the first MPSIVA rat model recapitulating all skeletal and non-skeletal alterations experienced by patients. Treatment of MPSIVA rats with adeno-associated viral vector serotype 9 encoding Galns (AAV9-Galns) results in widespread transduction of bones, cartilage and peripheral tissues. This led to long-term (1 year) increase of GALNS activity and whole-body correction of KS levels, thus preventing body size reduction and severe alterations of bones, teeth, joints, trachea and heart. This study demonstrates the potential of AAV9-Galns gene therapy to correct the disabling MPSIVA pathology, providing strong rationale for future clinical translation to MPSIVA patients.

Multisensory integration in cortical regions responding to locomotion-related visual and somatomotor signals.

During real-world locomotion, in order to be able to move along a path or avoid an obstacle, continuous changes in self-motion direction (i.e. heading) are needed. Control of heading changes during locomotion requires the integration of multiple signals (i.e., visual, somatomotor, vestibular). Recent fMRI studies have shown that both somatomotor areas (human PEc [hPEc], human PE [hPE], primary somatosensory cortex [S-I]) and egomotion visual regions (cingulate sulcus visual area [CSv], posterior cingulate area [pCi], posterior insular cortex [PIC]) respond to either leg movements and egomotion-compatible visual stimulations, suggesting a role in the analysis of both visual attributes of egomotion and somatomotor signals with the aim of guiding locomotion. However, whether these regions are able to integrate egomotion-related visual signals with somatomotor inputs coming from leg movements during heading changes remains an open question. Here we used a combined approach of individual functional localizers and task-evoked activity by fMRI. In thirty subjects we first localized three egomotion areas (CSv, pCi, PIC) and three somatomotor regions (S-I, hPE, hPEc). Then, we tested their responses in a multisensory integration experiment combining visual and somatomotor signals relevant to locomotion in congruent or incongruent trials. We used an fMR-adaptation paradigm to explore the sensitivity to the repeated presentation of these bimodal stimuli in the six regions of interest. Results revealed that hPE, S-I and CSv showed an adaptation effect regardless of congruency, while PIC, pCi and hPEc showed sensitivity to congruency. PIC exhibited a preference for congruent trials compared to incongruent trials. Areas pCi and hPEc exhibited an adaptation effect only for congruent and incongruent trials, respectively. PIC, pCi and hPEc sensitivity to the congruency relationship between visual (locomotion-compatible) cues and (leg-related) somatomotor inputs suggests that these regions are involved in multisensory integration processes, likely in order to guide/adjust leg movements during heading changes.

Lower visual field preference for the visuomotor control of limb movements in the human dorsomedial parietal cortex.

Visual cues coming from the lower visual field (VF) play an important role in the visual guidance of upper and lower limb movements. A recently described region situated in the dorsomedial parietal cortex, area hPEc (Pitzalis et al. in NeuroImage 202:116092, 2019), might have a role in integrating visually derived information with somatomotor signals to guide limb interaction with the environment. In macaque, it has been demonstrated that PEc receives visual information mostly from the lower visual field but, to date, there has been no systematic investigation of VF preference in the newly defined human homologue of macaque area PEc (hPEc). Here we examined the VF preferences of hPEc while participants performed a visuomotor task implying spatially directed delayed eye-, hand- and foot-movements towards different spatial locations within the VF. By analyzing data as a function of the different target locations towards which upcoming movements were planned (and then executed), we observed the presence of asymmetry in the vertical dimension of VF in area hPEc, being this area more strongly activated by limb movements directed towards visual targets located in the lower compared to the upper VF. This result confirms the view, first advanced in macaque monkey, that PEc is involved in processing visual information to guide body interaction with the external environment, including locomotion. We also observed a contralateral dominance for the lower VF preference in the foot selective somatomotor cortex anterior to hPEc. This result might reflect the role of this cortex (which includes areas PE and S-I) in providing highly topographically organized signals, likely useful to achieve an appropriate foot posture during locomotion.

Preference for locomotion-compatible curved paths and forward direction of self-motion in somatomotor and visual areas.

During locomotion, leg movements define the direction of walking (forward or backward) and the path one is taking (straight or curved). These aspects of locomotion produce characteristic visual motion patterns during movement. Here, we tested whether cortical regions responding to either egomotion-compatible visual motion, or leg movements, or both, are sensitive to these locomotion-relevant aspects of visual motion. We compared a curved path (typically the visual feedback of a changing direction of movement in the environment) to a linear path for simulated forward and backward motion in an event-related fMRI experiment. We used an individual surface-based approach and two functional localizers to define (1) six egomotion-related areas (V6+, V3A, intraparietal motion area [IPSmot], cingulate sulcus visual area [CSv], posterior cingulate area [pCi], posterior insular cortex [PIC]) using the flow field stimulus and (2) three leg-related cortical regions (human PEc [hPEc], human PE [hPE] and primary somatosensory cortex [S-I]) using a somatomotor task. Then, we extracted the response from all these regions with respect to the main event-related fMRI experiment, consisting of passive viewing of an optic flow stimulus, simulating a forward or backward direction of self-motion in either linear or curved path. Results showed that some regions have a significant preference for the curved path motion (hPEc, hPE, S-I, IPSmot) or a preference for the forward motion (V3A), while other regions have both a significant preference for the curved path motion and for the forward compared to backward motion (V6+, CSv, pCi). We did not find any significant effects of the present stimuli in PIC. Since controlling locomotion mainly means controlling changes of walking direction in the environment during forward self-motion, such a differential functional profile among these cortical regions suggests that they play a differentiated role in the visual guidance of locomotion.

Olive Pâté by Multi-Phase Decanter as Potential Source of Bioactive Compounds of Both Nutraceutical and Anticancer Effects.

In the oil sector, a novelty in the centrifugal extraction system is represented by the multi-phase decanters (DMF) that work without adding process water and with the advantage of recovering a dried pomace and a by-product, called "pâté", consisting of the pulp and its vegetation water, without traces of stone. The pâté has a high content of phenolic compounds, mainly represented by secoiridoids and verbascoside. The present work investigated the efficacy of two different ways of debittering (by sequential filtrations and spontaneous fermentation) of DMF pâté from three olive cultivars (Olea europaea L. "Leccino", "Carboncella" and "Tortiglione") to make the pâté edible, and, contemporary, investigated also the effect of its phenolic bioactive extracts on pathogenic bacteria and colon cancer cell model. Daily filtrations of pâté of the three cultivars have been shown to be more efficient in phenolic degradation. The activity of the indigenous microflora on the other hand takes a longer time to degrade the phenolic component and therefore to de-bitter it. None of pâté showed antibacterial activity. Colorimetric assay MTS for cell viability and metabolic activity tested on colon cancer cells CaCo2 and HCT116 suggest a potential beneficial effect of the dried extracts probably related to the modulation of gene expression under these treatments.

Table Olives Fermented in Iodized Sea Salt Brines: Nutraceutical/Sensory Properties and Microbial Biodiversity.

This research aimed to study the influence of different brining processes with iodized and noniodized salt on mineral content, microbial biodiversity, sensory evaluation and color change of natural fermented table olives. Fresh olives of Olea europaea Carolea and Leucocarpa cvs. were immersed in different brines prepared with two different types of salt: the PGI "Sale marino di Trapani", a typical sea salt, well known for its taste and specific microelement content, and the same salt enriched with 0.006% of KIO3. PGI sea salt significantly enriches the olive flesh in macroelements as Na, K and Mg, and microelements such as Fe, Mn, Cu and Zn. Instead, Ca decreases, P remains constant, while iodine is present in trace amounts. In the olives fermented in iodized-PGI sea salt brine, the iodine content reached values of 109 µg/100 g (Carolea cv.) and 38 µg/100 g (Leucocarpa cv.). The relationships between the two varieties and the mineral composition were explained by principal component analysis (PCA) and cluster analysis (CA). Furthermore, analyzing the fermenting brines, iodine significantly reduces the microbial load, represented only by yeasts, both in Carolea cv. and in Leucocarpa cv. Candida is the most representative genus. The sensory and color properties weren't significantly influenced by iodized brining. Only Carolea cv. showed significative difference for b* parameter and, consequently, for C value. Knowledge of the effects of iodized and noniodized brining on table olives will be useful for developing new functional foods, positively influencing the composition of food products.

Performance of 18F-fluciclovine PET/MR in the evaluation of osseous metastases from castration-resistant prostate cancer.

PURPOSE: 18F-Fluciclovine is indicated for evaluation of suspected prostate cancer (PCa) biochemical recurrence. There are few studies investigating fluciclovine with PET/MR and none evaluated osseous metastases. Our aim was to assess the performance of 18F-fluciclovine PET/MR (fluciclovine-PET/MR) for detecting osseous metastases in patients with castration-resistant prostate cancer (CRPC). We also investigated possible correlations between SUVmax and ADCmean. METHODS: We evaluated 8 patients with CRPC metastatic to bones, some before and some after radium therapy, who underwent 13 fluciclovine-PET/MR studies. We analyzed the performance of radionuclide bone scan (RBS), MR alone, fluciclovine-PET alone, and fluciclovine-PET/MR in detecting osseous metastases. Lesion size, characteristics (early sclerotic, late sclerotic, mixed, lytic), SUVmax, and ADCmean were assessed. The reference standard was a combination of clinical information and correlation with both prior and follow-up imaging. RESULTS: Of 347 metastatic bony lesions in 13 studies, 238/347 (68%) were detected by fluciclovine-PET alone, 286/347 (82%) by RBS, 344/347 (99%) by MR alone, and 347/347 (100%) by fluciclovine-PET/MR. Fluciclovine-PET/MR and MR had the best performance (p < 0.001). There was no statistically significant difference between fluciclovine-PET/MR and MR alone (p = 0.25). Fluciclovine-PET had a lower detection rate especially with late sclerotic lesions (p < 0.001). There was a moderate inverse correlation between lesion SUVmax and ADCmean (r = - 0.49; p < 0.001). CONCLUSIONS: This study suggests that fluciclovine-PET/MR and MR have high sensitivity for detecting osseous metastases in CRPC. Fluciclovine-PET alone underperformed in detecting late sclerotic lesions. The inverse correlation between SUVmax and ADCmean suggests a possible relationship between tumor metabolism and cellularity.

In Vivo Gene Therapy for Mucopolysaccharidosis Type III (Sanfilippo Syndrome): A New Treatment Horizon.

For most lysosomal storage diseases (LSDs), there is no cure. Gene therapy is an attractive tool for treatment of LSDs caused by deficiencies in secretable lysosomal enzymes, in which neither full restoration of normal enzymatic activity nor transduction of all cells of the affected organ is necessary. However, some LSDs, such as mucopolysaccharidosis type III (MPSIII) diseases or Sanfilippo syndrome, represent a difficult challenge because patients suffer severe neurodegeneration with mild somatic alterations. The disease's main target is the central nervous system (CNS) and enzymes do not efficiently cross the blood-brain barrier (BBB) even if present at very high concentration in circulation. No specific treatment has been approved for MPSIII. In this study, we discuss the adeno-associated virus (AAV) vector-mediated gene transfer strategies currently being developed for MPSIII disease. These strategies rely on local delivery of AAV vectors to the CNS either through direct intraparenchymal injection at several sites or through delivery to the cerebrospinal fluid (CSF), which bathes the whole CNS, or exploit the properties of certain AAV serotypes capable of crossing the BBB upon systemic administration. Although studies in small and large animal models of MPSIII diseases have provided evidence supporting the efficacy and safety of all these strategies, there are considerable differences between the different routes of administration in terms of procedure-associated risks, vector dose requirements, sensitivity to the effect of circulating neutralizing antibodies that block AAV transduction, and potential toxicity. Ongoing clinical studies should shed light on which gene transfer strategy leads to highest clinical benefits while minimizing risks. The development of all these strategies opens a new horizon for treatment of not only MPSIII and other LSDs but also of a wide range of neurological diseases.

A putative human homologue of the macaque area PEc.

The cortical area PEc is anatomically and functionally well-defined in macaque, but it is unknown whether it has a counterpart in human. Since we know that macaque PEc, but not the nearby posterior regions, hosts a lower limb representation, in an attempt to recognize a possible human PEc we looked for the existence of leg representations in the human parietal cortex using individual cortical surface-based analysis, task-evoked paradigms and resting-state functional connectivity. fMRI images were acquired while thirty-one participants performed long-range leg movements through an in-house MRI-compatible set-up. We revealed the existence of multiple leg representations in the human dorsomedial parietal cortex, here defined as S-I (somatosensory-I), hPE (human PE, in the postcentral sulcus), and hPEc (human PEc, in the anterior precuneus). Among the three "leg" regions, hPEc had a unique functional profile, in that it was the only one responding to both arm and leg movements, to both hand-pointing and foot pointing movements, and to flow field visual stimulation, very similar to macaque area PEc. In addition, hPEc showed functional connections with the somatomotor regions hosting a lower limb representation, again as in macaque area PEc. Therefore, based on similarity in brain position, functional organization, cortical connections, and relationship with the neighboring areas, we propose that this cortical region is the human homologue of macaque area PEc.

Walking-related locomotion is facilitated by the perception of distant targets in the extrapersonal space.

The Gibsonian notion of affordance has been massively employed in cognitive sciences to characterize the tight interdependence between hand-related actions, manipulable objects and peripersonal space. A behavioural facilitation effect, indeed, is observed for grasping actions directed to objects located in the 'reachable' peripersonal space. Relevantly, this relationship is supported by dedicated neural systems in the brain. The original notion of affordance, however, was directly inspired by real-time interactions between animals and their extended natural environment. Consistently, also the extrapersonal space representation can be significantly modulated by action-related factors, and the brain contains dedicated systems for the representation of topographical space and navigation. Here we examined whether a facilitation effect could be also described for a walking-related action in the far extrapersonal space. To this aim, we employed a go/no-go paradigm requiring subjects to execute a footstep ahead in response to pictures of a virtual reality environment containing objects located at different distances (near, far) and eccentricities (central, peripheral). A walking-related, facilitation effect for distant extrapersonal locations was found, suggesting an automatic trigger of walking by positions that preferentially guide spatial exploration. Based on the parallelism with the literature on micro-affordances, we propose that this effect can be described in terms of "macro-affordances".

Egomotion-related visual areas respond to active leg movements.

Monkey neurophysiology and human neuroimaging studies have demonstrated that passive viewing of optic flow stimuli activates a cortical network of temporal, parietal, insular, and cingulate visual motion regions. Here, we tested whether the human visual motion areas involved in processing optic flow signals simulating self-motion are also activated by active lower limb movements, and hence are likely involved in guiding human locomotion. To this aim, we used a combined approach of task-evoked activity and resting-state functional connectivity by fMRI. We localized a set of six egomotion-responsive visual areas (V6+, V3A, intraparietal motion/ventral intraparietal [IPSmot/VIP], cingulate sulcus visual area [CSv], posterior cingulate sulcus area [pCi], posterior insular cortex [PIC]) by using optic flow. We tested their response to a motor task implying long-range active leg movements. Results revealed that, among these visually defined areas, CSv, pCi, and PIC responded to leg movements (visuomotor areas), while V6+, V3A, and IPSmot/VIP did not (visual areas). Functional connectivity analysis showed that visuomotor areas are connected to the cingulate motor areas, the supplementary motor area, and notably to the medial portion of the somatosensory cortex, which represents legs and feet. We suggest that CSv, pCi, and PIC perform the visual analysis of egomotion-like signals to provide sensory information to the motor system with the aim of guiding locomotion.

FGF21 gene therapy as treatment for obesity and insulin resistance.

Prevalence of type 2 diabetes (T2D) and obesity is increasing worldwide. Currently available therapies are not suited for all patients in the heterogeneous obese/T2D population, hence the need for novel treatments. Fibroblast growth factor 21 (FGF21) is considered a promising therapeutic agent for T2D/obesity. Native FGF21 has, however, poor pharmacokinetic properties, making gene therapy an attractive strategy to achieve sustained circulating levels of this protein. Here, adeno-associated viral vectors (AAV) were used to genetically engineer liver, adipose tissue, or skeletal muscle to secrete FGF21. Treatment of animals under long-term high-fat diet feeding or of ob/ob mice resulted in marked reductions in body weight, adipose tissue hypertrophy and inflammation, hepatic steatosis, inflammation and fibrosis, and insulin resistance for > 1 year. This therapeutic effect was achieved in the absence of side effects despite continuously elevated serum FGF21. Furthermore, FGF21 overproduction in healthy animals fed a standard diet prevented the increase in weight and insulin resistance associated with aging. Our study underscores the potential of FGF21 gene therapy to treat obesity, insulin resistance, and T2D.

Disease correction by AAV-mediated gene therapy in a new mouse model of mucopolysaccharidosis type IIID.

Gene therapy is a promising therapeutic alternative for Lysosomal Storage Disorders (LSD), as it is not necessary to correct the genetic defect in all cells of an organ to achieve therapeutically significant levels of enzyme in body fluids, from which non-transduced cells can uptake the protein correcting their enzymatic deficiency. Animal models are instrumental in the development of new treatments for LSD. Here we report the generation of the first mouse model of the LSD Muccopolysaccharidosis Type IIID (MPSIIID), also known as Sanfilippo syndrome type D. This autosomic recessive, heparan sulphate storage disease is caused by deficiency in N-acetylglucosamine 6-sulfatase (GNS). Mice deficient in GNS showed lysosomal storage pathology and loss of lysosomal homeostasis in the CNS and peripheral tissues, chronic widespread neuroinflammation, reduced locomotor and exploratory activity and shortened lifespan, a phenotype that closely resembled human MPSIIID. Moreover, treatment of the GNS-deficient animals with GNS-encoding adeno-associated viral (AAV) vectors of serotype 9 delivered to the cerebrospinal fluid completely corrected pathological storage, improved lysosomal functionality in the CNS and somatic tissues, resolved neuroinflammation, restored normal behaviour and extended lifespan of treated mice. Hence, this work represents the first step towards the development of a treatment for MPSIIID.