The effects of the quality of social relationships and emotion regulation ability on the happiness of introvert individuals

Previous research has shown that extraverts are happier than introverts and, although happy introverts exist, it is unclear under what conditions they can achieve happiness. The aim of the present study is to analyze the quality of social relationships and emotion regulation ability as a possible factor for happiness in introvert individuals. 1006 adults (42% males) completed measures of extraversion, neuroticism, quality of social relationships, emotion regulation ability and happiness. Results shows that introverts have significantly lower happiness, quality of life, quality of social relationship and emotion regulation ability scores than extraverts. Besides, those individuals with high quality social relationships or high emotion regulation ability were happier. Introverts were happier when they had high scores for quality of social relationships and emotion regulation ability, however the effect size was small. These results suggest that emotion regulation and social relationships are important to understand the relationships between introversion and happiness.

The Role of the Transcription Factor Ets1 in Melanocyte Development

Melanocytes, pigment-producing cells, derive from the neural crest (NC), a population of pluripotent cells that arise from the dorsal aspect of the neural tube during embryogenesis. Many genes required for melanocyte development were identified using mouse pigmentation mutants. The deletion of the transcription factor Ets1 in mice results in hypopigmentation; nevertheless, the function of Ets1 in melanocyte development is unknown. The goal of the present study was to establish the temporal requirement and role of Ets1 in murine melanocyte development. In the mouse, Ets1 is widely expressed in developing organs and tissues, including the NC. In the chick cranial NC, Ets1 is required for the expression of Sox10, a transcription factor critical for the development of melanocytes, enteric ganglia, and other NC derivatives. Using a combination of immunofluorescence and cell survival assays Ets1 was found to be required between embryonic days 10 and 11, when it regulates NC cell and melanocyte precursor (melanoblast) survival. Given the requirement of Ets1 for Sox10 expression in the chick cranial NC, a potential interaction between these genes was investigated. Using genetic crosses, a synergistic genetic interaction between Ets1 and Sox10 in melanocyte development was found. Since Sox10 is essential for enteric ganglia formation, the importance of Ets1 on gut innervation was also examined. In mice, Ets1 deletion led to decreased gut innervation, which was exacerbated by Sox10 heterozygosity. At the molecular level, Ets1 was found to activate a Sox10 enhancer critical for Sox10 expression in melanoblasts. Furthermore, mutating Ets1 at a site I characterized in the spontaneous variable spotting mouse pigmentation mutant, led to a 2-fold decrease in enhancer activation. Overexpression and knockdown of Ets1 did not affect Sox10 expression; nonetheless, Ets1 knockdown led to a 6-fold upregulation of the transcription factor Sox9, a gene required for melanocyte and chondrocyte development, but which impairs melanocyte development when its expression is prolonged. Together, these results suggest that Ets1 is required early during melanocyte development for NC cell and melanoblast survival, possibly acting upstream of Sox10. The transcription factor Ets1 may also act indirectly in melanocyte fate specification by repressing Sox9 expression, and consequently cartilage fate.

Infralimbic cortex controls the activity of the hypothalamus-pituitary adrenal axis and the formation of aversive memory: effects of environmental enrichment

The aim of the present study was to investigate the effects of the stimulation and inhibition of the ventral part of the medial prefrontal cortex (infralimbic cortex) on basal and stress-induced plasma levels of corticosterone and on the acquisition of aversive memory in animals maintained in control and environmental enrichment (EE) conditions. Intracortical microinjections of the GABAA antagonist picrotoxin and agonist muscimol were performed in male Wistar rats to stimulate and inhibit, respectively, the activity of the infralimbic cortex. Injections were performed 60 min before foot shock stress and training in the inhibitory avoidance task. Picrotoxin injections into the infralimbic cortex increased basal plasma levels of corticosterone. These increases were higher in EE rats which suggest that EE enhances the control exerted by infralimbic cortex over the hypothalamus-pituitary-adrenal (HPA) axis and corticosterone release. Muscimol injections into the infralimbic cortex reduced the stress-induced plasma levels of corticosterone and the retention latency 24 h after training in the inhibitory avoidance performance in control and EE animals, respectively. These results further suggest that the infralimbic cortex is required for the activation of the HPA axis during stress and for the acquisition of contextual aversive memories.

Nutritional requirements of the critically ill patient

Objective: Given the inaccessibility of indirect calorimetry, intensive care units generally use predictive equations or recommendations that are established by international societies to determine energy expenditure. The aim of the present study was to compare the energy expenditure of critically ill patients, as determined using indirect calorimetry, to the values obtained using the Harris-Benedict equation. Methods: A retrospective observational study was conducted at the Intensive Care Unit 1 of the Centro Hospitalar do Porto. The energy requirements of hospitalized critically ill patients as determined using indirect calorimetry were assessed between January 2003 and April 2012. The accuracy (± 10% difference between the measured and estimated values), the mean differences and the limits of agreement were determined for the studied equations. Results: Eighty-five patients were assessed using 288 indirect calorimetry measurements. The following energy requirement values were obtained for the different methods: 1,753.98±391.13 kcal/ day (24.48 ± 5.95 kcal/kg/day) for indirect calorimetry and 1,504.11 ± 266.99 kcal/day (20.72±2.43 kcal/kg/day) for the HarrisBenedict equation. The equation had a precision of 31.76% with a mean difference of -259.86 kcal/day and limits of agreement between -858.84 and 339.12 kcal/day. Sex (p=0.023), temperature (p=0.009) and body mass index (p< 0.001) were found to significantly affect energy expenditure Conclusion: The Harris-Benedict equation is inaccurate and tends to underestimate energy expenditure. In addition, the Harris-Benedict equation is associated with significant differences between the predicted and true energy expenditure at an individual level

Concurrent validity of the Swedish version of the life-space assessment questionnaire

BACKGROUND: The Life-Space Assessment (LSA), developed in the USA, is an instrument focusing on mobility with respect to reaching different areas defined as life-spaces, extending from the room where the person sleeps to mobility outside one's hometown. A newly translated Swedish version of the LSA (LSA-S) has been tested for test-retest reliability, but the validity remains to be tested. The purpose of the present study was to examine the concurrent validity of the LSA-S, by comparing and correlating the LSA scores to other measures of mobility. METHOD: The LSA was included in a population-based study of health, functioning and mobility among older persons in Sweden, and the present analysis comprised 312 community-dwelling participants. To test the concurrent validity, the LSA scores were compared to a number of other mobility-related variables, including the Short Physical Performance Battery (SPPB) as well as "stair climbing", "transfers", "transportation", "food shopping", "travel for pleasure" and "community activities". The LSA total mean scores for different levels of the other mobility-related variables, and measures of correlation were calculated. RESULTS: Higher LSA total mean scores were observed with higher levels of all the other mobility related variables. Most of the correlations between the LSA and the other mobility variables were large (r = 0.5-1.0) and significant at the 0.01 level. The LSA total score, as well as independent life-space and assistive life-space correlated with transportation (0.63, 0.66, 0.64) and food shopping (0.55, 0.58, 0.55). Assistive life-space also correlated with SPPB (0.47). With respect to maximal life-space, the correlations with the mobility-related variables were generally lower (below 0.5), probably since this aspect of life-space mobility is highly influenced by social support and is not so dependent on the individual's own physical function. CONCLUSION: LSA was shown to be a valid measure of mobility when using the LSA total, independent LS or assistive LSA.

Determination of the maximum steady state of lactate (MLSS) in saliva: An alternative to blood lactate determination

Based on previous research which shows parallelism between the saliva and blood lactate response during incremental exercise, we hypothesized that a "maximum salivary lactate steady state" (saliva-MLSS) might exist. Thus, the aim of the present investigation was to establish 1) which lower limit for the increase in salivary lactate concentration during a constant workload (i.e., from the 10th to the 20th min) test could be used to determine the saliva-MLSS and 2) if the exercise intensity corresponding to the saliva-MLSS is identical to that evoking the (blood) MLSS. Twelve male amateur athletes of mean (+/-SD) age 24+/-5 year were selected for the study. Based on the results of a previous maximal cycle ergometer test for lactate threshold (LT) determination, each subject performed consecutive constant workload tests of 20-min duration on separate days for MLSS determination, Blood and saliva (25 mu l) samples were collected at 0, 10, and 20 min during the tests for lactate determination. A Student's t-test for paired data demonstrated that a salivary lactate increase of 0.8 mM corresponded to the saliva-MLSS. At this value, indeed, no significant differences were observed between the mean (V) over dot O-2, and W values corresponding to the MLSS and the saliva-MLSS. In conclusion, the present findings indicate that 0.8 mM is the lower limit for the increase in saliva lactate concentration during a constant load test and thus is that which might be used as a reference to determine saliva-MLSS. Furthermore, saliva-MLSS might be used as an alternative to MLSS determination in blood samples.

Characteristics of microRNAs and their potential relevance for the diagnosis and therapy of the acute respiratory distress syndrome: from bench to bedside

Acute respiratory distress syndrome (ARDS) is a complex disease associated with high morbidity and mortality. Biomarkers and specific pharmacologic treatment of the syndrome are lacking. MicroRNAs (miRNAs) are small (∼19–22 nucleotides) noncoding RNA molecules whose function is the regulation of gene expression. Their uncommon biochemical characteristics (eg, their resistance to degradation because of extreme temperature and pH fluctuations, freeze-thaw cycles, long storage times in frozen conditions, and RNAse digestion) and their presence in a wide range of different biological fluids and the relatively low number of individual miRNAs make these molecules good biomarkers in different clinical conditions. In addition, miRNAs are suitable therapeutic targets as their expression can be modulated by different available strategies. The aim of the present review is to offer clinicians a global perspective of miRNA, covering their structure and nomenclature, biogenesis, effects on gene expression, regulation of expression, and features as disease biomarkers and therapeutic targets, with special attention to ARDS. Because of the early stage of research on miRNAs applied to ARDS, attention has been focused on how knowledge sourced from basic and translational research could inspire future clinical studies.

An investigation of the relationship between the components of tumour microenvironment, signal transduction pathways and outcome in breast cancer

Breast cancer, the most commonly diagnosed type of cancer in women, is a major cause of morbidity and mortality in the western world. Well-established risk factors of breast cancer are mostly related to women’s reproductive history, such as early menarche, late first pregnancy and late menopause. Survival rates have improved due to a combination of factors, including better health education, early detection with large-scale use of screening mammogram, improved surgical techniques, as well as widespread use of adjuvant therapy. At initial presentation, clinicopathological features of breast cancer such as age, nodal status, tumour size, tumour grade, and hormonal receptor status are considered to be the standard prognostic and predictive markers of patient survival, and are used to guide appropriate treatment strategies. Lymphovascular invasion (LBVI), including lymphatic (LVI) and blood (BVI) vessel invasion, has been reported to be prognostic and merit accurate evaluation, particularly in patients with node negative tumours who might benefit from adjuvant chemotherapy. There is a lack of standard assessment and agreement on distinguishing LVI from BVI despite the major challenges in the field. A systematic review of the literatures, examining methods of detection and the prognostic significance of LBVI, LVI and BVI, was carried out. The majority of studies used haematoxylin and eosin (H&E) and classical histochemistry to identify LVI and BVI. Only few recent studies used immunohistochemistry (IHC) staining of the endothelium lining lymphatic and blood vessels, and were able to show clear differences between LVI and BVI. The prognostic significance of LBVI and LVI was well-documented and strongly associated with aggressive features of breast tumours, while the prognostic value and the optimal detection method of BVI were unclear. Assessment and prognostic value of LBVI on H&E sections (LBVIH&E) was examined and compared to that of LVI and BVI detected using IHC with D2-40 for LVI (LVID2–40) and Factor VIII for BVI (BVIFVIII) in patients with breast cancer including node negative and triple negative patients (n=360). LBVIH&E, LVID2–40 and BVIFVIII were present in 102 (28%), 127 (35%) and 59 (16%) patients respectively. In node negative patients (206), LBVIH&E, LVID2–40 and BVIFVIII were present in 41 (20%), 53 (26%) and 21 (10%) respectively. In triple negative patients (102), LBVIH&E, LVID2–40 and BVIFVIII were present in 35 (29%), 36 (35%) and 14 (14%) respectively. LBVIH&E, LVID2–40 and BVIFVIII were all significantly associated with tumour recurrence in all cohorts. On multivariate survival analysis, only LVID2–40 and BVIFVIII were independent predictors of cancer specific survival (CSS) in the whole cohort (P=0.022 and P<0.001 respectively), node negative (P=0.008 and P=0.001 respectively) and triple negative patients (P=0.014 and P<0.001 respectively). Assessment of LVI and BVI by IHC, using D2-40 and Factor VIII, improves prediction of outcome in patients with node negative and triple negative breast cancer and was superior to the conventional detection method. Breast cancer is recognised as a complex molecular disease and histologically identical tumours may have highly variable outcomes, including different responses to therapy. Therefore, there is a compelling need for new prognostic and predictive markers helpful of selecting patients at risk and patients with aggressive diseases who might benefit from adjuvant and targeted therapy. It is increasingly recognised that the development and progression of human breast cancer is not only determined by genetically abnormal cells, but also dependent on complex interactions between malignant cells and the surrounding microenvironment. This has led to reconsider the features of tumour microenvironment as potential predictive and prognostic markers. Among these markers, tumour stroma percentage (TSP) and tumour budding, as well as local tumour inflammatory infiltrate have received recent attention. In particular, the local environment of cytokines, proteases, angiogenic and growth factors secreted by inflammatory cells and stromal fibroblasts has identified crucial roles in facilitating tumour growth, and metastasis of cancer cells through lymphatic and/or blood vessel invasion. This might help understand the underlying process promoting tumour invasion into these vessels. An increase in the proportion of tumour stroma and an increase in the dissociation of tumour cells have been associated with poorer survival in a number of solid tumours, including breast cancer. However, the interrelationship between these variables and other features of the tumour microenvironment in different subgroups of breast cancer are not clear. Also, whether their prognostic values are independent of other components of the tumour microenvironment have yet to be identified. Therefore, the relationship between TSP, clinicopathological characteristics and outcome in patients with invasive ductal breast cancer, in particular node negative and triple negative disease was examined in patients with invasive ductal breast cancer (n=361). The TSP was assessed on the haematoxylin and eosin-stained tissue sections. With a cut-off value of 50% TSP, patients with ≤50% stroma were classified as the low-TSP group and those with >50% stroma were classified as the high-TSP group. A total of 109 (30%) patients had high TSP. Patients with high TSP were old age (P=0.035), had involved lymph node (P=0.049), Her-2 positive tumours (P=0.029), low-grade peri-tumoural inflammatory infiltrate (P=0.034), low CD68+ macrophage infiltrate (P<0.001), low CD4+ (P=0.023) and low CD8+ T-lymphocytes infiltrate (P=0.017), tumour recurrence (P=0.015) and shorter CSS (P<0.001). In node negative patients (n=207), high TSP was associated with low CD68+ macrophage infiltrate (P=0.001), low CD4+ (P=0.040) and low CD8+ T-lymphocytes infiltrate (P=0.016) and shorter CSS (P=0.005). In triple negative patients (n=103), high TSP was associated with increased tumour size (P=0.017) high tumour grade (P=0.014), low CD8+ T-lymphocytes infiltrate (P=0.048) and shorter CSS (P=0.041). The 15-year cancer specific survival rate was 79% vs 21% in the low-TSP group vs high-TSP group. On multivariate survival analysis, a high TSP was associated with reduced CSS in the whole cohort (P=0.007), node negative patients (P=0.005) and those who received systemic adjuvant therapy (P=0.016), independent of other pathological characteristics including local host inflammatory responses. Therefore, a high TSP in invasive ductal breast cancer was associated with recurrence and poorer long-term survival. The inverse relation with the tumour inflammatory infiltrate highlights the importance of the amount of tumour stroma on immunological response in patients with invasive ductal breast cancer. Implementing this simple and reproducible parameter in routine pathological examination may help optimise risk stratification in patients with breast cancer. Similarly, the relationship between tumour budding, clinicopathological characteristics and outcome was examined in patients with invasive ductal breast cancer (n=474), using routine pathological sections. Tumour budding was associated with several adverse pathological characteristics, including positive lymph node (P=0.009), presence of LVI (P<0.001), and high TSP (P=0.001) and low-grade general peri-tumural inflammatory infiltrative (P=0.002). In node negative patients, a high tumour budding was associated with presence of LVI (P<0.001) and low-grade general peri-tumural inflammatory infiltrative (P=0.038). On multivariate survival analysis, tumour budding was associated with reduced CSS (P=0.001), independent of nodal status, tumour necrosis, CD8+ and CD138+ inflammatory cells infiltrate, LVI, BVI and TSP. Furthermore, tumour budding was independently associated with reduced CSS in node negative patients (P=0.004) and in those who have low TSP (P=0.003) and high-grade peri-tumoural inflammatory infiltrative (P=0.012). A high tumour budding was significantly associated with shorter CSS in luminal B and triple negative breast cancer subtypes (all P<0.001). Therefore, tumour budding was a significant predictor of poor survival in patients with invasive ductal breast cancer, independent of adverse pathological characteristics and components of tumour microenvironment. These results suggest that tumour budding may promote disease progression through a direct effect on local and distant invasion into lymph nodes and lymphatic vessels. Therefore, detection of tumour buds at the stroma invasive front might therefore represent a morphologic link between tumour progression, lymphatic invasion, spread of tumour cells to regional lymph nodes, and the establishment of metastatic dissemination. Given the potential importance of the tumour microenvironment, the characterisation of intracellular signalling pathways is important in the tumour microenvironment and is of considerable interest. One plausible signalling molecule that links tumour stroma, inflammatory cell infiltrate and tumour budding is the signal transducer and activator of transcription (STAT). The relationship between total and phosphorylated STAT1 (ph-STAT1), and total and ph-STAT3 tumour cell expression, components of tumour microenvironment and survival in patients with invasive ductal breast cancer was examined. IHC of total and ph-STAT1/STAT3 was performed on tissue microarray of 384 breast cancer specimens. Cellular STAT1 and cellular STAT3 expression at both cytoplasmic and nuclear locations were combined and identified as STAT1/STAT3 tumour cell expression. These results were then related to CSS and phenotypic features of the tumour and host. A high ph-STAT1 and a high ph-STAT3 tumour cell expression was associated with increased ER (P=0.001 and P<0.001 respectively) and PR (all P<0.05), reduced tumour grade (P=0.015 and P<0.001 respectively) and necrosis (all P=0.001). Ph-STAT1 was associated with increased general peri-tumoural inflammatory infiltrate (P=0.007) and ph-STAT3 was associated with lower CD4+ T-lymphocyte infiltrate (P=0.024). On multivariate survival analysis, including both ph-STAT1 and ph-STAT3 tumour cell expression, only high ph-STAT3 tumour cell expression was significantly associated with improved CSS (P=0.010) independent of other tumour and host-based factors. In patients with high necrosis grade, high ph-STAT3 tumour cell expression was independent predictor of improved CSS (P=0.021). Ph-STAT1 and ph-STAT3 were also significantly associated with improved cancer specific survival in luminal A and B subtypes. STAT1 and STAT3 tumour cell expression appeared to be an important determinant of favourable outcome in patients with invasive ductal breast cancer. The present results suggest that STATs may affect disease outcome through direct impact on tumour cells, and the surrounding microenvironment. The above observations of the present thesis point to the importance of the tumour microenvironment in promoting tumour budding, LVI and BVI. The observations from STATs work may suggest that an important driving mechanism for the above associations is the presence of tumour necrosis, probably secondary to hypoxia. Further work is needed to examine the interaction of other molecular pathways involved in the tumour microenvironment, such as HIF and NFkB in patients with invasive ductal breast cancer.

Portuguese Version of the Suicidal Behaviors Questionnaire-Revised: Validation Data and the Establishment of a Cut-Score for Screening Purposes

The aim of the present study is to provide validation data regarding the Portuguese version of the Suicidal Behaviors Questionnaire Revised in nonclinical individuals. Two studies were undertaken with two different nonclinical samples in order to demonstrate reliability, concurrent, predictive, and construct validity, and in order to establish an appropriate cut-score for nonclinical individuals. A sample of 810 community adults participated in Study 1. Results from this study provided information regarding scale internal consistency, exploratory and confirmatory factor analysis, and concurrent validity. Receiver operating characteristic curve analysis established a cut-off score to be used for screening purposes with nonclinical individuals. A sample of 440 young adults participated in Study 2, which demonstrated scale score internal consistency and 5-month predictive validity. Further, 5-month test-retest reliability was also evaluated and the correlations of SBQ-R scale scores with two other measures that assess constructs related to suicidality, depression and psychache, were also performed. In addition, confirmatory factor analysis was undertaken to demonstrate the robustness of the result obtained in Study 1. Overall, findings supported the psychometric appropriateness of the Portuguese Suicidal Behaviors Questionnaire-Revise

Interspecies study of the enteric nervous system and related pathologies

The enteric nervous system (ENS) modulates a number of digestive functions including well known ones, i.e. motility, secretion, absorption and blood flow, along with other critically relevant processes, i.e. immune responses of the gastrointestinal (GI) tract, gut microbiota and epithelial barrier . The characterization of the anatomical aspects of the ENS in large mammals and the identification of differences and similarities existing between species may represent a fundamental basis to decipher several digestive GI diseases in humans and animals. In this perspective, the aim of the present thesis is to highlight the ENS anatomical basis and pathological aspects in different mammalian species, such as horses, dogs and humans. Firstly, I designed two anatomical studies in horses:  “Excitatory and inhibitory enteric innervation of horse lower esophageal sphincter”.  “Localization of 5-hydroxytryptamine 4 receptor (5-HT4R) in the equine enteric nervous system”. Then I focused on the enteric dysfunctions, including:  A primary enteric aganglionosis in horses: “Extrinsic innervation of the ileum and pelvic flexure of foals with ileocolonic aganglionosis”.  A diabetic enteric neuropathy in dogs: “Quantification of nitrergic neurons in the myenteric plexus of gastric antrum and ileum of healthy and diabetic dogs”.  An enteric neuropathy in human neurological patients: “Functional and neurochemical abnormalities in patients with Parkinson's disease and chronic constipation”. The physiology of the GI tract is characterized by a high complexity and it is mainly dependent on the control of the intrinsic nervous system. ENS is critical to preserve body homeostasis as reflect by its derangement occurring in pathological conditions that can be lethal or seriously disabling to humans and animals. The knowledge of the anatomy and the pathology of the ENS represents a new important and fascinating topic, which deserves more attention in the veterinary medicine field.

Numerical modeling and experimental validation of the recrystallization behaviour in the extrusion of 6XXX aluminum alloys

The microstructure of 6XXX aluminum alloys deeply affects mechanical, crash, corrosion and aesthetic properties of extruded profiles. Unfortunately, grain structure evolution during manufacturing processes is a complex phenomenon because several process and material parameters such as alloy chemical composition, temperature, extrusion speed, tools geometries, quenching and thermal treatment parameters affect the grain evolution during the manufacturing process. The aim of the present PhD thesis was the analysis of the recrystallization kinetics during the hot extrusion of 6XXX aluminum alloys and the development of reliable recrystallization models to be used in FEM codes for the microstructure prediction at a die design stage. Experimental activities have been carried out in order to acquire data for the recrystallization models development, validation and also to investigate the effect of process parameters and die design on the microstructure of the final component. The experimental campaign reported in this thesis involved the extrusion of AA6063, AA6060 and AA6082 profiles with different process parameters in order to provide a reliable amount of data for the models validation. A particular focus was made to investigate the PCG defect evolution during the extrusion of medium-strength alloys such as AA6082. Several die designs and process conditions were analysed in order to understand the influence of each of them on the recrystallization behaviour of the investigated alloy. From the numerical point of view, innovative models for the microstructure prediction were developed and validated over the extrusion of industrial-scale profiles with complex geometries, showing a good matching in terms of the grain size and surface recrystallization prediction. The achieved results suggest the reliability of the developed models and their application in the industrial field for process and material properties optimization at a die-design stage.

Evaluation of the transcriptomic response of an Alzheimer's disease murine model induced at different ages: searching for predictors

Alzheimer’s disease (AD) is a chronic, progressive neurodegenerative disease, characterized by the impairment of mnesic and cognitive functions, that represents the most frequent type of dementia in older people worldwide. Aging is the most important risk factor for the sporadic form of the pathology and it is associated to the progressive impairment of the proteostasis network. The endoplasmic reticulum (ER), the main cellular actor involved in proteostasis, appears significantly compromised in AD due to the accumulation of β-amyloid (Aβ) protein and phosphorylated-tau protein. Increasing proteins misfolding activates a specific cellular response known as Unfolded Protein response (UPR) which orchestrates the recovery of ER function. The aim of the present study was to investigate the role of UPR and aging process in a murine model of AD induced by intracerebroventricular (i.c.v.) injection of Aβ1-42 oligomers at 3 or 18 months. The oligomers injection in aged animals caused the increased of memory impairment, oxidative stress, and the depletion of glutathione reserve. Furthermore, the RNA-sequencing analysis was performed and the bioinformatic analysis showed the enrichment of several pathways involved in neurodegeneration and protein regulations. The following analysis highlighted the significant dysregulation of the three branches of the UPR, the protein kinase RNA-like ER kinase (PERK), inositol-requiring protein 1α (IRE1α) and activating transcription factor 6 (ATF-6). In turn, ER stress affected the PI3K/Akt/Gsk3β and MAPK/ERK pathways, highlighting Mapkapk5 as a potential marker of the neurodegenerative process, which regulation could lead to the definition of new pharmacological and neuroprotective strategies to counteract AD.

The book of Qohelet. A digital scholarly edition of the hebrew text

The objective of the present dissertation is a born-digital critical edition of the Hebrew Old Testament book of Qohelet. The edition is based on an extensive collation of variant readings from indirect sources – the Septuagint, the Peshitta, the works of St. Jerome (the Vulgate and the Commentary), and the Targum – as well as from direct sources such as the Qumran fragments and Hebrew medieval manuscripts. The ultimate goal of the edition is (a) to reproduce the earliest textual form, the Archetype, that can be reconstructed on the basis of the available evidence; and (b) to propose a rehabilitation of the Original of the Author by resorting, when necessary, to conjectural emendation. We date the Archetype to the II century BCE, corresponding to the date of Hebrew fragments from Qumran, while we place the Original between the V and III centuries BCE. Unlike previous critical editions of Qohelet, ours follows the so-called eclectic model, which involves the reconstitution of a critical text and the preparation of an apparatus of secondary variants. Our edition includes, moreover, new data, taken both from primary literature, such as the recently published Göttingen Septuagint, and from up-to-date studies and critical commentaries on the text of Qohelet. The work is made up of five main parts: an introduction, which sets forth the rationale of the edition and the methodology adopted; the collation, where the variants are listed in their original language; the commentary, where they are extensively discussed; the critical text accompanied by the apparatus, which presents a selection of authentic Hebrew variants taken from the collation; and finally, a translation of the critical text. The edition uses the mark-up language of the Text Encoding Initiative (TEI). It is realized in pdf, via LaTeX, and will be available in digital form, via the TEI-Publisher editor.

Study of the urinary biomarkers of synthetic cannabinoid receptor agonists (SCRAs) for the forensic unequivocal proof of consumption: medico-legal implications for drug abuse prevention

Introduction. Synthetic cannabinoid receptor agonists (SCRAs) represent the widest group of New Psychoactive Substances (NPS) and, around 2021-2022, new compounds emerged on the market. The aims of the present research were to identify suitable urinary markers of Cumyl-CB-MEGACLONE, Cumyl-NB-MEGACLONE, Cumyl-NB-MINACA, 5F-EDMB-PICA, EDMB-PINACA and ADB-HEXINACA, to present data on their prevalence and to adapt the methodology from the University of Freiburg to the University of Bologna. Materials and methods. Human phase-I metabolites detected in 46 authentic urine samples were confirmed in vitro with pooled human liver microsomes (pHLM) assays, analyzed by liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-qToF-MS). Prevalence data were obtained from urines collected for abstinence control programs. The method to study SCRAs metabolism in use at the University of Freiburg was adapted to the local facilities, tested in vitro with 5F-EDMB-PICA and applied to the study of ADB-HEXINACA metabolism. Results. Metabolites built by mono, di- and tri-hydroxylation were recommended as specific urinary biomarkers to monitor the consumption of SCRAs bearing a cumyl moiety. Monohydroxylated and defluorinated metabolites were suitable proof of 5F-EDMB-PICA consumption. Products of monohydroxylation and amide or ester hydrolysis, coupled to monohydroxylation or ketone formation, were recognized as specific markers for EDMB-PINACA and ADB-HEXINACA. The LC-qToF-MS method was successfully adapted to the University of Bologna, as tested with 5F-EDMB-PICA in vitro metabolites. Prevalence data showed that 5F-EDMB-PINACA and EDMB-PINACA were more prevalent than ADB-HEXINACA, but for a limited period. Conclusion. Due to undetectability of parent compounds in urines and to shared metabolites among structurally related compounds, the identification of specific urinary biomarkers as unequivocal proofs of SCRAs consumption remains challenging for forensic laboratories. Urinary biomarkers are necessary to monitor SCRAs abuse and prevalence data could help in establishing tailored strategies to prevent their spreading, highlighting the role for legal medicine as a service to public health.

Simulation of the Earth's radiation budget by the European Centre for Medium-Range Weather Forecasts 40-year reanalysis (ERA40)

The radiation budget simulated by the European Centre for Medium-Range Weather Forecasts (ECMWF) 40-year reanalysis (ERA40) is evaluated for the period 1979–2001 using independent satellite data and additional model data. This provides information on the quality of the radiation products and indirect evaluation of other aspects of the climate produced by ERA40. The climatology of clear-sky outgoing longwave radiation (OLR) is well captured by ERA40. Underestimations of about 10 W m−2 in clear-sky OLR over tropical convective regions by ERA40 compared to satellite data are substantially reduced when the satellite sampling is taken into account. The climatology of column-integrated water vapor is well simulated by ERA40 compared to satellite data over the ocean, indicating that the simulation of downward clear-sky longwave fluxes at the surface is likely to be good. Clear-sky absorbed solar radiation (ASR) and clear-sky OLR are overestimated by ERA40 over north Africa and high-latitude land regions. The observed interannual changes in low-latitude means are not well reproduced. Using ERA40 to analyze trends and climate feedbacks globally is therefore not recommended. The all-sky radiation budget is poorly simulated by ERA40. OLR is overestimated by around 10 W m−2 over much of the globe. ASR is underestimated by around 30 W m−2 over tropical ocean regions. Away from marine stratocumulus regions, where cloud fraction is underestimated by ERA40, the poor radiation simulation by ERA40 appears to be related to inaccurate radiative properties of cloud rather than inaccurate cloud distributions.