Law-Invariant Functionals on General Spaces of Random Variables

We establish general versions of a variety of results for quasiconvex, lower-semicontinuous, and law-invariant functionals. Our results extend well-known results from the literature to a large class of spaces of random variables. We sometimes obtain sharper versions, even for the well-studied case of bounded random variables. Our approach builds on two fundamental structural results for law-invariant functionals: the equivalence of law invariance and Schur convexity, i.e., monotonicity with respect to the convex stochastic order, and the fact that a law-invariant functional is fully determined by its behavior on bounded random variables. We show how to apply these results to provide a unifying perspective on the literature on law-invariant functionals, with special emphasis on quantile-based representations, including Kusuoka representations, dilatation monotonicity, and infimal convolutions

Law-invariant functionals that collapse to the mean

We discuss when law-invariant convex functionals "collapse to the mean". More precisely, we show that, in a large class of spaces of random variables and under mild semicontinuity assumptions, the expectation functional is, up to an affine transformation, the only law-invariant convex functional that is linear along the direction of a nonconstant random variable with nonzero expectation. This extends results obtained in the literature in a bounded setting and under additional assumptions on the functionals. We illustrate the implications of our general results for pricing rules and risk measures

A pH-sensitive stearoyl-PEG-poly(methacryloyl sulfadimethoxine)-decorated liposome system for protein delivery: an application for bladder cancer treatment

Stealth pH-responsive liposomes for the delivery of therapeutic proteins to the bladder epithelium were prepared using methoxy-poly(ethylene glycol)5kDa-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (mPEG5kDa-DSPE) and stearoyl-poly(ethylene glycol)-poly(methacryloyl sulfadimethoxine) copolymer (stearoyl-PEG-polySDM), which possesses an apparent pKa of 7.2. Liposomes of 0.2:0.6:100, 0.5:1.5:100 and 1:3:100 mPEG5kDa-DSPE/stearoyl-PEG-polySDM/(soybean phosphatidylcholine + cholesterol) molar ratios were loaded with bovine serum albumin (BSA) as a protein model. The loading capacity was 1.3% w/w BSA/lipid. At pH 7.4, all liposome formulations displayed a negative zeta-potential and were stable for several days. By pH decrease or addition to mouse urine, the zeta potential strongly decreased, and the liposomes underwent a rapid size increase and aggregation. Photon correlation spectroscopy (PCS) and transmission electron microscopy (TEM) analyses showed that the extent of the aggregation depended on the stearoyl-PEG-polySDM/lipid molar ratio. Cytofluorimetric analysis and confocal microscopy showed that at pH 6.5, the incubation of MB49 mouse bladder cancer cells and macrophages with fluorescein isothiocyanate-labelled-BSA (FITC-BSA) loaded and N-(Lissamine Rhodamine B sulfonyl)-1, 2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine triethylammonium salt (rhodamine-DHPE) labelled 1:3:100 mPEG5kDa-DSPE/stearoyl-PEG-polySDM/lipid molar ratio liposomes resulted in a time-dependent liposome association with the cells. At pH 7.4, the association of BSA-loaded liposomes with the MB49 cells and macrophages was remarkably lower than at pH 6.5. Confocal images of bladder sections revealed that 2 h after the instillation, liposomes at pH 7.4 and control non-responsive liposomes at pH 7.4 or 6.5 did not associate nor delivered FITC-BSA to the bladder epithelium. On the contrary, the pH-responsive liposome formulation set at pH 6.5 and soon administered to mice by bladder instillation showed that, 2 h after administration, the pH-responsive liposomes efficiently delivered the loaded FITC-BSA to the bladder epitheliu

Internet addiction and related clinical problems: a study on italian young adults

The considerable prominence of internet addiction (IA) in adolescence is at least partly explained by the limited knowledge thus far available on this complex phenomenon. In discussing IA, it is necessary to be aware that this is a construct for which there is still no clear definition in the literature. Nonetheless, its important clinical implications, as emerging in recent years, justify the lively interest of researchers in this new form of behavioral addiction. Over the years, studies have associated IA with numerous clinical problems. However, fewer studies have investigated what factors might mediate the relationship between IA and the different problems associated with it. Ours is one such study. The Italian version of the SCL-90 and the IAT were administered to a sample of almost 800 adolescents aged between 16 and 22 years. We found the presence of a significant association between IA and two variables: somatization (\u3b2 = 7.80; p < 0.001) and obsessive-compulsive symptoms (\u3b2 = 2.18; p < 0.05). In line with our hypothesis, the results showed that somatization predicted the relationship between obsessive-compulsive symptoms and IA (\u3b2 = -2.75; t = -3.55; p < 0.001), explaining 24.5% of its variance (\u394R2 = 1.2%; F = 12.78; p < 0.01). In addition, simple slopes analyses revealed that, on reaching clinical significance (+1 SD), somatization showed higher moderation effects in the relationship between obsessive-compulsive symptoms and IA (\u3b2 = 6.13; t = 7.83; p < 0.001). These results appear to be of great interest due to the absence of similar evidence in the literature, and may open the way for further research in the IA field. Although the absence of studies in the literature does not allow us to offer an exhaustive explanation of these results, our study supports current addiction theories which emphasize the important function performed by the enteroceptive system, alongside the more cited reflexive and impulsive systems

Italian adaptation of the brief modified experiences in close relationships scale in a sample of cancer patients: factor analysis and clinical implications

Many previous studies have indicated that the attachment pattern developed during infancy shapes the adult attachment style, which in turn affects responses to stress and help-seeking behaviors. It may be relevant within clinical contexts to have easy-to-administer and rapid tools aimed to investigate attachment dimensions. The current study presents the Italian adaptation of the Brief Modified Experiences in Close Relationships (ECR-M16) – a self-reported measure of the attachment-style dimensions with reference to close others – and assesses its factorial structure. The questionnaire was administered to cancer outpatients. The number of factors to be extracted was calculated via parallel analysis. Subsequently, an exploratory factor analysis was run to calculate the first-order factor structure, which was compared to the original one via Procrustes rotation and Tucker’s coefficient. Finally, a second-order factor structure was calculated by factor analyzing the first-order factor scores. The Italian adaptation of the ECR-M16 is characterized by a first-order factor structure comprising four factors, like the original. The degree of similarity between the two ranges between fair and dissimilar. The second-order factor structure comprises two higher order dimensions, like in the original study. Although partially similar, the two second-order factor structures show relevant differences. A clinically oriented discussion centered on the similarities and differences between the two factor structures is provided, along with indications for future studies

The J2-Immortalized Murine Macrophage Cell Line Displays Phenotypical and Metabolic Features of Primary BMDMs in Their M1 and M2 Polarization State

Macrophages are immune cells that are important for the development of the defensive front line of the innate immune system. Following signal recognition, macrophages undergo activation toward specific functional states, consisting not only in the acquisition of specific features but also of peculiar metabolic programs associated with each function. For these reasons, macrophages are often isolated from mice to perform cellular assays to study the mechanisms mediating immune cell activation. This requires expensive and time-consuming breeding and housing of mice strains. To overcome this issue, we analyzed an in-house J2-generated immortalized macrophage cell line from BMDMs, both from a functional and metabolic point of view. By assaying the intracellular and extracellular metabolism coupled with the phenotypic features of immortalized versus primary BMDMs, we concluded that classically and alternatively immortalized macrophages display similar phenotypical, metabolic and functional features compared to primary cells polarized in the same way. Our study validates the use of this immortalized cell line as a suitable model with which to evaluate in vitro how perturbations can influence the phenotypical and functional features of murine macrophages

The Italian long-term ecosystem research (LTER-Italy) network: results, opportunities, and challenges for coastal transitional ecosystems

1 - The Long-Term Ecosystem Research (LTER) network, now a global reality, was founded on a combination of long-term ecological studies, short-term experiments, and comparisons among sites and eco-domains. 2 - The LTER-Italy network was officially established as a formal member of the LTER international network in 2006, following a wider on-going process in Europe; it currently consists of 22 sites representing the main ecosystem typologies of Italy. Four coastal transitional ecosystem sites are included in the LTER-Italy network: on the northern Peninsula, these include the Venice Lagoon and the lagoons of the Po River Delta, which are characterized by a temperate climate and the influence of tides; and in the southern sector, these include the coastal ecosystems of Sardinia and the Mar Piccolo of Taranto, which are characterized by a Mediterranean climate and the absence of sensible tides. 3 - In this paper, we present and discuss three main issues: the LTER-International and LTER-Europe context, emphasising the most practical issues and activities that must be addressed for the effective organization and maintenance of LTER networks; the history, structure, and perspectives of the national LTER-Italy network; and the opportunities, strengths, and weaknesses related to participation of the LTER-Italy network in the study of coastal transitional ecosystems

The challenge of setting restoration targets for macroalgal forests under climate changes

Este artículo contiene 10 páginas, 5 figuras, 1 tabla.The process of site selection and spatial planning has received scarce attention in the scientific literature dealing with marine restoration, suggesting the need to better address how spatial planning tools could guide restoration interventions. In this study, for the first time, the consequences of adopting different restoration targets and criteria on spatial restoration prioritization have been assessed at a regional scale, including the consideration of climate changes. We applied the decision-support tool Marxan, widely used in systematic conservation planning on Mediterranean macroalgal forests. The loss of this habitat has been largely documented, with limited evidences of natural recovery. Spatial priorities were identified under six planning scenarios, considering three main restoration targets to reflect the objectives of the EU Biodiversity Strategy for 2030. Results show that the number of suitable sites for restoration is very limited at basin scale, and targets are only achieved when the recovery of 10% of regressing and extinct macroalgal forests is planned. Increasing targets translates into including unsuitable areas for restoration in Marxan solutions, amplifying the risk of ineffective interventions. Our analysis supports macroalgal forests restoration and provides guiding principles and criteria to strengthen the effectiveness of restoration actions across habitats. The constraints in finding suitable areas for restoration are discussed, and recommendations to guide planning to support future restoration interventions are also included.This study was funded by the EASME–EMFF (Sustainable Blue Economy) Project AFRIMED (http://afrimed-project.eu/, grant agreement N. 789059), supported by the European Community.Peer reviewe

Macrophages and neutrophils as major source of B-cells activating factors in H. pylori associated diseases

The cytokine APRIL (A proliferation inducing ligand) and the cytokine BLyS (B lymphocyte simulator) are two recently discovered factors that belong to the TNF-(tumor necrosis factor) family. Since their discovery, these cytokines have been intensively studied for their role in B cells biology. Indeed, APRIL and BLyS are involved in the maturation of B cells, but, most importantly, they increase the survival and proliferation of these cells. However, the effect of these cytokines is amplified in neoplastic B cells in lymphomas, and self-reactive B cells in autoimmune diseases. In particular, it has been demonstrated that APRIL is over-expressed in different types of lymphoma, whereas BLyS is very abundant in serum and tissues of patients with different types of autoimmune diseases, such as, rheumatoid arthritis or systemic lupus erythematous. In our study, we evaluated the role of these cytokines in two diseases caused by the bacterium Helicobacter pylori (H. pylori): MALT lymphoma (I) and autoimmune gastritis (AIG) (II). (I) the development of lymphoid follicles with germinal centers and an acquired MALT (mucosa-associated lymphoid tissue) are characteristic of H. pylori-induced gastritis. These MALT represents a pre-neoplastic condition associated with infection, which can evolve into a B-cell lymphoma. It is currently unclear which cytokines or soluble factors promote B cell activation and the genesis of lymphoma during H. pylori infection. In our study, we have demonstrated that gastric MALT lymphoma is characterized by high expression of APRIL. Furthermore, APRIL is over-expressed also in a pre-MALT situation, suggesting that this cytokine may be involved in the induction, as well as in the proliferation of the lymphoma. Further analysis allowed us to identify the macrophages as the main source of APRIL in this type of cancer. We confirmed this observation by in vitro experiments, suggesting that H. pylori is able to induce the secretion of APRIL by macrophages. We have also shown that the contribution to APRIL secretion is supported also by tumour infiltrating T cells specific for H. pylori. Thus, we have demonstrated that H. pylori is able to induce APRIL secretion by macrophage in a direct way, following in vitro infection, but even in an undirect way, mediated by H. pylori-specific T lymphocytes. Our data represent the first evidence of the involvement of APRIL in the development of MALT lymphoma in H. pylori infected patients. Moreover, we identified macrophages as key cells in this process. (II) Among the diseases caused by H. pylori there is also AIG. It has recently been reported that the cytokine BLyS plays a pivotal role in the pathogenesis of two different models of autoimmune disease (collagen induced arthritis and experimental autoimmun encephalomyelitis); in these works, it has been demonstrated that BLyS induce naive T cells to differentiate into the Th17 phenotype. These effector T cells, produce IL-17 and they play a crucial role in the pathogenesis and maintenance of several autoimmune diseases. Thus, given that it is established that H. pylori infection is associated with a Th17 response, we wondered to investigate whether the BLyS/Th17 axis is involved in the development of AIG following H. pylori-infection. To test this hypothesis, we have considered H. pylori-induced chronic gastritis as a model for our analysis because it is the typical inflammatory context that might evolve AIG in susceptible patients. We have demonstrated that patients with chronic gastritis not only present, as expected, a Th17-enriched cellular infiltrate in gastric mucosa, but also that in these biopses there is a significant expression of BLyS. Noteworthy, after the eradication of the bacterium there is a marked reduction of both BLyS and IL-17 cytokines in gastric mucosa, underlining the crucial role of H. pylori in the axis BLyS/Th17. We have also shown that BLyS is able to activate in vitro monocytes and macrophages, inducing the secretion of IL-1β, IL-6, TGF-β and IL-23 by these cells: all these cytokines are fundamental for Th17 cells differentiation. In addition, we identified neutrophils as a possible source of BLyS in gastric mucosa. Indeed, H. pylori-stimulated neutrophils secrete a great amount of BLyS in vitro. Accordingly, there are evidence that neutrophils represent a great percentage of cellular infiltrate during H. pylori-sustained inflammation. Therefore, we hypothesized a model for AIG development of following H. pylori-infection: the bacterium stimulates gastric mucosa-infiltrating neutrophils to release BLyS. BLyS, in turn could on one hand lead to the survival of autoreactive B cells (characterized by auto-antibodies production), but on the other hand, it might also acts on monocytes/macrophages (which are also abundant in the inflammatory infiltrate) for the induction of pro-Th17 cytokines. The Th17-pro-inflammatory profile may increase inflammation and worsen the tissue damage which is typically found in patients with AIG. However, this study is still in progress and many things remain to be understood to validate this model. We first of all need to identify BLyS-expressing cells in chronic gastritis; to this aim different double-immunohistochemistry staining with specific markers for different immune cell types are currently underway. In addition, the results of immunohistochemical analysis will be corroborated with in vitro experiments aimed to: i) confirm the ability of cells, identified by immunohistochemistry, to secrete BLyS following stimulation with H. pylori, ii) confirm the role of BLyS in the differentiation of Th17 cells. Although this second study is currently ongoing, we have demonstrated that H. pylori might create a cytokine microenvironment which can drive the development of MALT lymphoma or AIG. In particular, we have shown that H. pylori is able to induce the production and release of BLyS and APRIL by macrophages and neutrophils, respectively, in two diseases characterized by dysfunction of B cells. These data may suggest that targeting these cytokines may be a new additional therapeutic approach for the treatment of AIG and MALT lymphomaLa citochina APRIL (A proliferation inducing ligand) e la citochina BLyS (B lymphocyte simulator) sono due fattori, scoperti recentemente, facenti parte della famiglia dei TNF (tumour necrosis factor). Dalla loro scoperta entrambe queste citochine sono state intensivamente studiate per il loro ruolo nello sviluppo dei linfociti B. Infatti sia APRIL che BLyS sono coinvolte nella maturazione delle cellule B, ma è stato anche dimostrato che ne aumentano la sopravvivenza e la proliferazione. L’effetto di queste citochine risulta però amplificato su cellule B neoplastiche, che caratterizzano i linfomi, e sulle cellule B auto-reattive, che giocano un ruolo cruciale nelle patologie autoimmuni. In particolare, è stato dimostrato che APRIL risulta sovraespressa specificamente in diversi tipi di linfoma, mentre BLyS è molto abbondante nel siero e nei tessuti di pazienti affetti da diversi tipi di patologie autoimmuni, come ad esempio, l’artrite reumatoide, o il lupus eritematoso sistemico. Nel nostro studio abbiamo valutato il ruolo di queste citochine in due patologie causate dal batterio Helicobacter pylori (H. pylori): i linfomi tipo MALT (I) e la gastrite autoimmune (II). (I) L’infiammazione causata da H. pylori è caratterizzata da una massiva infiltrazione di cellule, che però non riescono ad contrastare efficacemente la crescita batterica. Questo porta molto facilmente alla cronicizzazione dell’infezione che porta allo sviluppo di follicoli linfatici con centri germinativi. Questo follicoli costituiscono una sorta di organo linfoide associato alla mucosa gastrica detto MALT (tessuto linfatico mucosa-associato). L’acquisizione del MALT rappresenta una condizione pre-neoplastica associata all’infezione da H. pylori, che può evolvere verso un linfoma a cellule B. Attualmente non è noto quali citochine o fattori solubili promuovano l’attivazione delle cellule B e la genesi del linfoma a seguito dell’infezione da H. pylori. Nel nostro studio, abbiamo dimostrato che nel linfoma gastrico di tipo MALT sono espressi alti livelli di APRIL. Inoltre, APRIL risulta sovraepresso anche in una situazione pre-MALT, suggerendo che questa citochina possa essere coinvolta anche nell’induzione, oltre che nel mantenimento del linfoma. Un’analisi approfondita ci ha in seguito permesso di identificare la popolazione macrofagica come fonte principale di APRIL in questo tipo di tumore. Abbiamo poi confermato con esperimenti in vitro che H. pylori è in grado di indurre la secrezione di APRIL da parte dei macrofagi. Abbiamo infine dimostrato che anche le cellule T, specifiche per H. pylori, possono indurre i macrofagi a secernere APRIL. I nostri dati rappresentano la prima evidenza di un coinvolgimento della citochina APRIL nello sviluppo del linfoma MALT in pazienti con infezione da H. pylori e identificano nei macrofagi le cellule chiave nel processo. (II) Tra le malattie che conseguono all’infezione da H. pylori c’è la gastrite autoimmune. E’ stato recentemente dimostrato il ruolo determinante della citochina BLyS in due differenti modelli di malattia autoimmune; BLyS infatti indurrebbe i linfociti T naive a differenziare verso il fenotipo Th17. Queste cellule T effettrici, producono IL-17 e giocano un ruolo cruciale nella genesi e nel mantenimento di numerose patologie autoimmuni. Con queste premesse, abbiamo voluto verificare se nella gastrite autoimmune da H. pylori fosse coinvolto l’asse BLyS/Th17, anche alla luce del fatto che era già noto che l’infezione da H. pylori si associa ad una risposta Th17. Per valutare questa possibilità abbiamo utilizzato come modello di studio la gastrite cronica indotta da H. pylori, in quanto essa può costituire il contesto da cui evolve la gastrite autoimmune. Abbiamo dimostrato che pazienti con gastrite cronica non solo presentano, come atteso, una mucosa riccamente infiltrata di linfociti Th17, ma quest’ultima è anche caratterizzata da una significativa espressione della citochina BLyS. Degno di nota il fatto che l’eradicazione del batterio si accompagna ad una riduzione di entrambe le citochine, BLyS e IL-17, nella mucosa dei pazienti, a sottolineare il ruolo determinante del batterio nel sostenere l’asse BLyS/Th17. Inoltre, abbiamo dimostrato che BLyS è in grado attivare in vitro monociti e macrofagi e di indurre la secrezione da parte di queste cellule di IL-1β, IL-6, TGF-β and Il23, tutte citochine coinvolte nel differenziamento delle cellule Th17. In aggiunta abbiamo identificato i neutrofili come potenziale fonte di BLyS nella mucosa gastrica. Infatti, neutrofili stimolati in vitro con H. pylori secernono grandi quantitativi di BLyS ed inoltre sono dimostrati essere la maggior componente dell’infiltrato cellulare nell’infezione di H. pylori. Quindi, abbiamo ipotizzato un modello di sviluppo della gastrite autoimmune a seguito dell’infezione di H. pylori: il batterio stimolerebbe i neutrofili infiltranti la mucosa gastrtica a rilasciare BLyS. BLyS, potrebbe da un lato indurre la sopravvivenza delle cellule B autoreattive (con relativa produzione di auto-anticorpi), ma anche agire sui monociti/macrofagi (anch’essi abbondanti nell’infilatrato infiammatorio) inducendo la secrezione di citochine che portano al differenziamento delle cellule Th17. Il profilo pro-infiammatorio delle cellule Th17, potrebbe aumentare l’infiammazione e peggiorare il danno tissutale tipicamente riscontrato nei pazienti con gastrite autoimmune. Tuttavia, questo studio è tuttora in corso d’opera e molte cose restano da capire per validare questo modello. Bisogna innanzitutto identificare le cellule esprimenti BLyS nella gastrite cronica; a questo scopo,diverse prove di co-immunoistochimica con marcatori specifici per i diversi tipi di cellule del sistema immunitario sono attualmente in corso. Inoltre, i risultati delle immunoistochimiche saranno corroborati con esperimenti in vitro mirati a: i) confermare la capacità delle cellule, identificate per immunoistochimica, di secernere BLyS a seguito di stimolazione con H. pylori; ii) confermare il ruolo di BLyS nel differenziamento delle cellule Th17. Ancorché questo secondo studio sia attualmente in corso, riteniamo plausibile proporre l’idea generale che H. pylori possa creare un microambiente citochinico favorevole allo sviluppo sia del linfoma tipo MALT che della gastrite autoimmune. In particolare, abbiamo dimostrato che questo batterio è in grado di indurre la produzione ed il rilascio di APRIL e BLyS da parte di macrofagi e neutrofili rispettivamente, in due patologie caratterizzate da una disfunzione delle cellule B. Questi dati potrebbero suggerire che terapie mirate verso queste citochine potrebbero diventare un nuovo approccio terapeutico per la cura del MALT linfoma e della gastrite autoimmun