Expression and function of alpha(v)beta(3) and alpha(v)beta(5) integrins in the developing pancreas: roles in the adhesion and migration of putative endocrine progenitor cells.

Cell-cell and cell-matrix interactions play a critical role in tissue morphogenesis and in homeostasis of adult tissues. The integrin family of adhesion receptors regulates cellular interactions with the extracellular matrix, which provides three-dimensional information for tissue organization. It is currently thought that pancreatic islet cells develop from undifferentiated progenitors residing within the ductal epithelium of the fetal pancreas. This process involves cell budding from the duct, migration into the surrounding mesenchyme, differentiation, and clustering into the highly organized islet of Langerhans. Here we report that alpha(v)beta(3) and alpha(v)beta(5), two integrins known to coordinate epithelial cell adhesion and movement, are expressed in pancreatic ductal cells and clusters of undifferentiated cells emerging from the ductal epithelium. We show that expression and function of alpha(v)beta(3) and alpha(v)beta(5) integrins are developmentally regulated during pancreatic islet ontogeny, and mediate adhesion and migration of putative endocrine progenitor cells both in vitro and in vivo in a model of pancreatic islet development. Moreover, we demonstrate the expression of fibronectin and collagen IV in the basal membrane of pancreatic ducts and of cell clusters budding from the ductal epithelium. Conversely, expression of vitronectin marks a population of epithelial cells adjacent to, or emerging from, pancreatic ducts. Thus, these data provide the first evidence for the contribution of integrins alpha(v)beta(3) and alpha(v)beta(5) and their ligands to morphogenetic events in the human endocrine pancreas

Sex-Specific Effects of Prenatal Stress on Bdnf Expression in Response to an Acute Challenge in Rats : a Role for Gadd45β

Exposure to early adversities represents a major risk factor for psychiatric disorders. We have previously shown that exposure to prenatal stress (PNS) in rats alters the developmental expression of brain-derived neurotrophic factor (Bdnf) with a specific temporal profile. However, exposure to early-life stress is known to alter the ability to cope with challenging events later in life, which may contribute to the enhanced vulnerability to stress-related disorders. Since Bdnf is also an important player for activity-dependent plasticity, we investigated whether the exposure to PNS in rats could alter Bdnf responsiveness to an acute challenge at adulthood. We found that exposure to PNS produces significant changes in Bdnf responsiveness with brain region- and gender-specific selectivity. Indeed, exposure to an acute stress upregulates Bdnf expression in the prefrontal cortex, but not in the hippocampus, of control animals. Moreover, such modulatory activity is selectively impaired in PNS female rats, an effect that was associated with changes in the modulation of the DNA demethylase Gadd45\u3b2. Our results suggest that exposure to PNS may reprogram gene transcription through epigenetic mechanisms reducing the ability to cope under adverse conditions, a trait that is disrupted in psychiatric diseases

ECM signaling regulates collective cellular dynamics to control pancreas branching morphogenesis

During pancreas development, epithelial buds undergo branching morphogenesis to form an exocrine and endocrine gland. Proper morphogenesis is necessary for correct lineage allocation of pancreatic progenitors; however, the cellular events underlying pancreas morphogenesis are unknown. Here, we employed time-lapse microscopy and fluorescent labeling of cells to analyze cell behaviors associated with pancreas morphogenesis. We observed that outer bud cells adjacent to the basement membrane are pleomorphic and rearrange frequently; additionally, they largely remain in the outer cell compartment even after mitosis. These cell behaviors and pancreas branching depend on cell contacts with the basement membrane, which induce actomyosin cytoskeleton remodeling via integrin-mediated activation of FAK/Src signaling. We show that integrin signaling reduces E-cadherin-mediated cell-cell adhesion in outer cells and provide genetic evidence that this regulation is necessary for initiation of branching. Our study suggests that regulation of cell motility and adhesion by local niche cues initiates pancreas branching morphogenesis

Safety and efficacy of apremilast through 104 weeks in patients with moderate to severe psoriasis who continued on apremilast or switched from etanercept treatment: findings from the LIBERATE study

Background Apremilast, an oral phosphodiesterase‐4 inhibitor, has demonstrated efficacy in patients with moderate to severe psoriasis. Objective To evaluate long‐term efficacy and safety of apremilast in biologic‐naive patients with moderate to severe plaque psoriasis and safety of switching from etanercept to apremilast in the phase 3b LIBERATE trial. Methods Two hundred fifty patients were randomized to placebo, apremilast 30 mg BID or etanercept 50 mg QW through Week 16; thereafter, all patients continued or switched to apremilast through Week 104 (extension phase). Skin, scalp and nail involvement at Weeks 16, 52 and 104 were assessed using the Psoriasis Area and Severity Index (PASI; 0–72), Scalp Physician Global Assessment (ScPGA; 0–5) and Nail Psoriasis Severity Index (NAPSI; 0–8); patient‐reported outcomes (PROs) were assessed using the Dermatology Life Quality Index (DLQI; 0–32) and pruritus visual analog scale (VAS; 0–100 mm). Results The apremilast‐extension phase (Weeks 16–104) included 226 patients in the placebo/apremilast (n = 73), apremilast/apremilast (n = 74) and etanercept/apremilast (n = 79) groups, and at Week 104, 50.7%, 45.9% and 51.9% of these patients, respectively, maintained ≥75% reduction from baseline in PASI score (based on last‐observation‐carried‐forward analysis). Across treatment groups, ScPGA 0 (clear) or 1 (minimal) was achieved by 50.0%–59.2% of patients; NAPSI mean change from baseline was −48.1% to −51.1%; DLQI score ≤5 was achieved by 66.0%–72.5% of patients; and pruritus VAS mean change from baseline was −24.4 to −32.3. AEs in ≥5% of patients (diarrhoea, nausea, nasopharyngitis, upper respiratory tract infection and headache) did not increase with prolonged apremilast exposure. Conclusions Apremilast demonstrated significant and sustained improvements in skin, scalp, nails and PROs (pruritus and quality of life) over 104 weeks in patients with moderate to severe plaque psoriasis. Safety was consistent with the known safety profile of apremilast

Trehalose administration in C57BL/6N old mice affects healthspan improving motor learning and brain anti-oxidant defences in a sex-dependent fashion: a pilot study

Aim of this study was to characterize the effects of oral trehalose administration (2%w/v) on healthspan in old mice. Trehalose was administered in drinking water for 1 month to male and female C57BL/6N mice aged 25-months. After behavioral phenotyping (grip strength, beam walking and rotarod tests), autophagy (LC3-II/actin) and oxidative stress were tested in the cerebral cortex and gastrocnemius muscle. The latter parameter was indirectly assessed by evaluating carbonyl groups added to proteins as a result of oxidative reactions, in addition to central levels of NRF2 protein, a transcription factor that regulates the expression of antioxidant enzymes. In comparison with sex-matched controls, trehalose-treated males performed better in motor planning and coordination tasks. This behavioral phenotype was associated with an activation of the ubiquitin-proteasome system, autophagy and antioxidant defences in cerebral cortex. Independently from trehalose administration, females were characterized by better motor performance and showed higher levels of ubiquitinated proteins and NRF2 in cerebral cortex, suggesting an up-regulation of basal antioxidant defences. In conclusion, trehalose was effective in counteracting some aspects of age-related decay, with specific effects in male and female subjects

Ion-pairing chromatography and amine derivatization provide complementary approaches for the targeted LC-MS analysis of the polar metabolome.

Liquid chromatography coupled to mass spectrometry is a key metabolomics/metabonomics technology. Reversed-phase liquid chromatography (RPLC) is very widely used as a separation step, but typically has poor retention of highly polar metabolites. Here, we evaluated the combination of two alternative methods for improving retention of polar metabolites based on 6-aminoquinoloyl-N-hydroxysuccinidimyl carbamate derivatization for amine groups, and ion-pairing chromatography (IPC) using tributylamine as an ion-pairing agent to retain acids. We compared both of these methods to RPLC and also to each other, for targeted analysis using a triple-quadrupole mass spectrometer, applied to a library of ca. 500 polar metabolites. IPC and derivatization were complementary in terms of their coverage: combined, they improved the proportion of metabolites with good retention to 91%, compared to just 39% for RPLC alone. The combined method was assessed by analyzing a set of liver extracts from aged male and female mice that had been treated with the polyphenol compound ampelopsin. Not only were a number of significantly changed metabolites detected, but also it could be shown that there was a clear interaction between ampelopsin treatment and sex, in that the direction of metabolite change was opposite for males and females

Use of infrared thermography (IRT) in equine assisted interventions: physiological aspects

Infrared imaging thermography (IRT) is a technique widely used in wildlife studies and the assessment of animal welfare is among its fields of application. The heat emitted from superficial capillaries changes as blood flow is under control of the autonomic nervous system. For this reason, cutaneous temperature on selected areas can be considered as a good indicator of the health status and welfare of a particular individual. These changes in heat emitted can be quantified using IRT. The system consists of an infrared camera FLIR A65 (640 512 pixel, uncooled microbolometer detector, thermal sensitivity 0.05 \ub0C) with a 7\ub0 and 13\ub0 angle of view germanium tele lenses and a dedicated laptop. In the case of chimpanzees\u2019 studies, most of the available data derive from subjects kept in small enclosures, with little ecological validity. The aim of this research was to develop an infrared method allowing the acquisition of thermographic videos and images of animals at long distance. The system was tested on a group of eleven chimpanzees, in semi-natural conditions, housed at Parco Natura Viva in Bussolengo (Verona). The study ran between April and December 2016. Images and videos were shot at distance greater than 10 meters, during the everyday chimpanzees\u2019 life. The accuracy and repeatability of measurements was that typically reserved to the image acquisition with closer subjects at indoor conditions. Through this system it was possible to detect temperature variations in face layers by distinguishing the facial features of the subject. Thus, despite the distance from the animals, thanks to the good resolution of the system, the cutaneous temperatures were detected. In conclusion, IRT could be able to non-invasively detect different autonomic responses of the chimpanzees to different situations, suggesting that this system could be a valuable tool to study the chimpanzee\u2019s behavior and welfare at long distance

The Impact of Quarantine and Physical Distancing Following COVID-19 on Mental Health : Study Protocol of a Multicentric Italian Population Trial

The COVID-19 pandemic and its related containment measures-mainly physical distancing and isolation-are having detrimental consequences on the mental health of the general population worldwide. In particular, frustration, loneliness, and worries about the future are common reactions and represent well-known risk factors for several mental disorders, including anxiety, affective, and post-traumatic stress disorders. The vast majority of available studies have been conducted in China, where the pandemic started. Italy has been severely hit by the pandemic, and the socio-cultural context is completely different from Eastern countries. Therefore, there is the need for methodologically rigorous studies aiming to evaluate the impact of COVID-19 and quarantine measures on the mental health of the Italian population. In fact, our results will help us to develop appropriate interventions for managing the psychosocial consequences of pandemic. The "COVID-IT-mental health trial" is a no-profit, not-funded, national, multicentric, cross-sectional population-based trial which has the following aims: a) to evaluate the impact of COVID-19 pandemic and its containment measures on mental health of the Italian population; b) to identify the main areas to be targeted by supportive long-term interventions for the different categories of people exposed to the pandemic. Data will be collected through a web-platform using validated assessment tools. Participants will be subdivided into four groups: a) Group 1-COVID-19 quarantine group. This group includes the general population which are quarantined but not isolated, i.e., those not directly exposed to contagion nor in contact with COVID-19+ individuals; b) Group 2-COVID-19+ group, which includes isolated people directly/indirectly exposed to the virus; c) Group 3-COVID-19 healthcare staff group, which includes first- and second-line healthcare professionals; d) Group 4-COVID-19 mental health, which includes users of mental health services and all those who had already been diagnosed with a mental disorder. Mental health services worldwide are not prepared yet to manage the short- and long-term consequences of the pandemic. It is necessary to have a clear picture of the impact that this new stressor will have on mental health and well-being in order to develop and disseminate appropriate interventions for the general population and for the other at-risk groups

Loneliness in Young Adults During the First Wave of COVID-19 Lockdown: Results From the Multicentric COMET Study

The COVID-19 pandemic has affected the mental and physical health of the general population at any age, but it is expected to have a protracted and severe consequences for younger populations. The pandemic has had several consequences on mental health including anger and irritability, depressive symptoms and somatic complaints, insomnia, lack of motivation, and loneliness. In particular, loneliness and its related negative feelings are thought to be particularly pronounced during young adulthood because of the many social changes that young people deal with during this period of life. Therefore, it is essential to evaluate the type of impact of the pandemic on the mental health of young people and their levels of loneliness experienced during the first phase of the lockdown. Based on the largest Italian study on the effects of the COVID-19 pandemic on the mental health of general population, in this paper we aim to: (1) describe the levels of loneliness in a national sample of Italian young adults aged 18–34 years, during the first wave of lockdown in 2020; (2) evaluate the clinical and socio-demographic differences in young adults reporting low vs. high levels of loneliness; (3) assess the role of clinical symptomatology, coping strategies, levels of resilience, and duration of lockdown as possible predictors of loneliness. The final sample consists of 8,584 people, mainly female (72.6%), single, with a mean age of 26.4 (±4.4) years. The mean score at the UCLA was 47.5 (±13.6), with 27% (N = 2,311) of respondents exceeding the cut-off for high levels of loneliness. High levels of loneliness were predicted by the presence of avoidant coping strategies, such as self-distraction (Beta coefficient, B = 0.369, 95% Confidence Interval, CI = 0.328–0.411), venting (B = 0.245, 95% CI = 0.197–0.293), denial (B = 0.110, 95% CI = 0.061–0.159), and emotional disengagement (B = 0.133, 95% CI = 0.080–0.185). Weeks of exposure to the pandemic were significantly associated with worsening of loneliness (p < 0.000). There is currently considerable interest in trying to reduce loneliness, both within the context of COVID-19 and more generally. Our results highlight that young people are at a higher risk of developing loneliness and suggest that more interventions and practical guidelines are needed