Two-step nucleation in a binary mixture of patchy particles

Nucleation in systems with a metastable liquid–gas critical point is the prototypical example of a two-step nucleation process in which the appearance of the critical nucleus is preceded by the formation of a liquid-like density fluctuation. So far, the majority of studies on colloidal and protein crystallization have focused on one-component systems, and we are lacking a clear description of two-step nucleation processes in multicomponent systems, where critical fluctuations involve coupled density and concentration inhomogeneities. Here, we examine the nucleation process of a binary mixture of patchy particles designed to nucleate into a diamond lattice. By combining Gibbs-ensemble simulations and direct nucleation simulations over a wide range of thermodynamic conditions, we are able to pin down the role of the liquid–gas metastable phase diagram on the nucleation process. In particular, we show that the strongest enhancement of crystallization occurs at an azeotropic point with the same stoichiometric composition of the crystal

Towards a genealogy of migrant struggles and rescue. The memory of solidarity at the Alpine border

This article advances a genealogy of migrant struggles and citizens solidarity practices, with a focus on the French-Italian migrant passage. It contends that scholarship has mainly mobilised a spatial approach to migrant struggles, while the temporality of solidarity and the collective memory of struggles have remained under-theorised. Then, the article moves on by focusing on the French-Italian Alpine border and it analyses the longstanding history of migrants’ passages there and, jointly, the mobilisations that took place in that area over the last decades exploring how these sedimented a citizen collective memory of solidarity practices. The final section deals with the history of mountain rescue at the French-Italian Alpine border and shows how migrants were saved by volunteers. The piece concludes by arguing that an insight into the memory of migrant struggles and solidarity practices enables foregrounding the transversal alliances which have been built between migrants and citizens and unsettling binary opposition between the former and the latter

The pyruvate kinase activator mitapivat reduces hemolysis and improves anemia in a \u3b2-thalassemia mouse model

Anemia in \u3b2-thalassemia is related to ineffective erythropoiesis and reduced red cell survival. Excess free heme and accumulation of unpaired \u3b1-globin chains impose substantial oxidative stress on \u3b2-thalassemic erythroblasts and erythrocytes, impacting cell metabolism. We hypothesized that increased pyruvate kinase activity induced by mitapivat (AG-348) in the Hbbth3/+ mouse model for \u3b2-thalassemia would reduce chronic hemolysis and ineffective erythropoiesis through stimulation of red cell glycolytic metabolism. Oral mitapivat administration ameliorated ineffective erythropoiesis and anemia in Hbbth3/+ mice. Increased ATP, reduced reactive oxygen species production, and reduced markers of mitochondrial dysfunction associated with improved mitochondrial clearance suggested enhanced metabolism following mitapivat administration in \u3b2-thalassemia. The amelioration of responsiveness to erythropoietin resulted in reduced soluble erythroferrone, increased liver Hamp expression, and diminished liver iron overload. Mitapivat reduced duodenal Dmt1 expression potentially by activating the pyruvate kinase M2-HIF2\u3b1 axis, representing a mechanism additional to Hamp in controlling iron absorption and preventing \u3b2-thalassemia\u2013related liver iron overload. In ex vivo studies on erythroid precursors from patients with \u3b2-thalassemia, mitapivat enhanced erythropoiesis, promoted erythroid maturation, and decreased apoptosis. Overall, pyruvate kinase activation as a treatment modality for \u3b2-thalassemia in preclinical model systems had multiple beneficial effects in the erythropoietic compartment and beyond, providing a strong scientific basis for further clinical trials

Fyn kinase is a novel modulator of erythropoietin signaling and stress erythropoiesis.

The signaling cascade induced by the interaction of erythropoietin (EPO) with its receptor (EPO-R) is a key event of erythropoiesis. We present here data indicating that Fyn, a Src-family-kinase, participates in the EPO signaling-pathway, since Fyn-/- mice exhibit reduced Tyr-phosphorylation of EPO-R and decreased STAT5-activity. The importance of Fyn in erythropoiesis is also supported by the blunted responsiveness of Fyn-/- mice to stress erythropoiesis. Fyn-/- mouse erythroblasts adapt to reactive oxygen species (ROS) by activating the redox-related-transcription-factor Nrf2. However, since Fyn is a physiologic repressor of Nrf2, absence of Fyn resulted in persistent-activation of Nrf2 and accumulation of nonfunctional proteins. ROS-induced over-activation of Jak2-Akt-mTOR-pathway and repression of autophagy with perturbation of lysosomal-clearance were also noted. Treatment with Rapamycin, a mTOR-inhibitor and autophagy activator, ameliorates Fyn-/- mouse baseline erythropoiesis and erythropoietic response to oxidative-stress. These findings identify a novel multimodal action of Fyn in the regulation of normal and stress erythropoiesis

Tools for Semi-automated Landform Classification: A Comparison in the Basilicata Region (Southern Italy)

Recent advances in spatial methods of digital elevation model (DEMs) analysis have addressed many research topics on the assessment of morphometric parameters of the landscape. Development of computer algorithms for calculating the geomorphometric properties of the Earth’s surface has allowed for expanding of some methods in the semi-automatic recognition and classification of landscape features. In such a way, several papers have been produced, documenting the applicability of the landform classification based on map algebra. The Topographic Position Index (TPI) is one of the most widely used parameters for semi-automated landform classification using GIS software. The aim was to apply the TPI classes for landform classification in the Basilicata Region (Southern Italy). The Basilicata Region is characterized by an extremely heterogeneous landscape and geological features. The automated landform extraction, starting from two different resolution DEMs at 20 and 5 m-grids, has been carried out by using three different GIS software: Arcview, Arcmap, and SAGA. Comparison of the landform maps resulting from each software at a different scale has been realized, furnishing at the end the best landform map and consequently a discussion over which is the best software implementation of the TPI method

Violent behavior of patients living in psychiatric residential facilities: A comparison of male patients with different violence histories

People with severe mental disorders and a history of violence are often seen as a difficult-to-manage segment of the population. In addition, this group is usually characterized by a high risk of crime recidivism, and poor compliance with community and aftercare programs. To investigate a sample of male patients living in Residential Facilities (RFs) with a history of violent behavior against people and to compare their characteristics with those of never-violent residents; to analyze the associations between aggressive behaviors in the last two years and a history of previous violence; and, to assess the predictors of aggressive behaviors. This study is part of a prospective observational cohort study which involved 23 RFs in Northern Italy. A comprehensive set of sociodemographic, clinical, and treatment-related information was gathered, and standardized assessments were administered to each participant. Also a detailed assessment of aggressive behaviors in the past two years was carried out. The study involved 268 males: 81 violent and 187 never-violent. Compared to never-violent patients, violent patients were younger, with a higher proportion of personality disorders, and have displayed an increased number of aggressive behaviors in the last two years. The presence of a history of violent behavior in the past significantly increases the probability of committing aggressive acts in the future

Peroxiredoxin-2 plays a pivotal role as multimodal cytoprotector in the early phase of pulmonary hypertension

Pulmonary-artery-hypertension (PAH) is a life-threatening and highly invalidating chronic disorder. Chronic oxidation contributes to lung damage and disease progression. Peroxiredoxin-2 (Prx2) is a typical 2-cysteine (Cys) peroxiredoxin but its role on lung homeostasis is yet to be fully defined. Here, we showed that Prx2 mice displayed chronic lung inflammatory disease associated with (i) abnormal pulmonary vascular dysfunction; and (ii) increased markers of extracellular-matrix remodeling. Hypoxia was used to induce PAH. We focused on the early phase PAH to dissect the role of Prx2 in generation of PAH. Hypoxic Prx2 mice showed (i) amplified inflammatory response combined with cytokine storm; (ii) vascular activation and dysfunction; (iii) increased PDGF-B lung levels, as marker of extracellular-matrix deposition and remodeling; and (iv) ER stress with activation of UPR system and autophagy. Rescue experiments with in vivo the administration of fusedrecombinant- PEP-Prx2 show a reduction in pulmonary inflammatory vasculopathy and in ER stress with down-regulation of autophagy. Thus, we propose Prx2 plays a pivotal role in the early stage of PAH as multimodal cytoprotector, targeting oxidation, inflammatory vasculopathy and ER stress with inhibition of autophagy. Collectively, our data indicate that Prx2 is able to interrupt the hypoxia induced vicious cycle involving oxidation-inflammationautophagy in the pathogenesis of PAH

The effect of service satisfaction and spiritual well-being on the quality of life of patients with schizophrenia.

Quality of life (QOL) has been considered an important outcome measure in psychiatric research and determinants of QOL have been widely investigated. We aimed at detecting predictors of QOL at baseline and at testing the longitudinal interrelations of the baseline predictors with QOL scores at a 1-year follow-up in a sample of patients living in Residential Facilities (RFs). Logistic regression models were adopted to evaluate the association between WHOQoL-Bref scores and potential determinants of QOL. In addition, all variables significantly associated with QOL domains in the final logistic regression model were included by using the Structural Equation Modeling (SEM). We included 139 patients with a diagnosis of schizophrenia spectrum. In the final logistic regression model level of activity, social support, age, service satisfaction, spiritual well-being and symptoms' severity were identified as predictors of QOL scores at baseline. Longitudinal analyses carried out by SEM showed that 40% of QOL follow-up variability was explained by QOL at baseline, and significant indirect effects toward QOL at follow-up were found for satisfaction with services and for social support. Rehabilitation plans for people with schizophrenia living in RFs should also consider mediators of change in subjective QOL such as satisfaction with mental health services

Regulatory T cell frequency in patients with melanoma with different disease stage and course, and modulating effects of high-dose interferon-α 2b treatment

<p>Abstract</p> <p>Background</p> <p>High-dose interferon-alpha 2b (IFN-α 2b) is the only approved systemic therapy in the United States for the adjuvant treatment of melanoma. The study objective was to explore the immunomodulatory mechanism of action for IFN-α 2b by measuring serum regulatory T cell (Treg), serum transforming growth factor-β (TGF-β), interleukin (IL)-10, and autoantibody levels in patients with melanoma treated with the induction phase of the high-dose IFN-α 2b regimen.</p> <p>Methods</p> <p>Patients with melanoma received IFN-α 2b administered intravenously (20 MU/m²each day from day 1 to day 5 for 4 consecutive weeks). Serum Treg levels were measured as whole lymphocytes in CD4⁺cells using flow cytometry while TGF-β, IL-10, and autoantibody levels were measured using enzyme-linked immunosorbent assays.</p> <p>Results</p> <p>Twenty-two patients with melanoma received IFN-α 2b treatment and were evaluated for Treg levels. Before treatment, Treg levels were significantly higher in patients with melanoma when compared with data from 20 healthy subjects (<it>P </it>= 0.001; Mann-Whitney test). Although a trend for reduction of Treg levels following IFN-α 2b treatment was observed (average decrease 0.29% per week), statistical significance was not achieved. Subgroup analyses indicated higher baseline Treg levels for stage III versus IV disease (<it>P </it>= 0.082), early recurrence versus no recurrence (<it>P </it>= 0.017), deceased versus surviving patients (<it>P = </it>0.021), and preoperative neoadjuvant versus postoperative adjuvant treatment groups (not significant). No significant effects were observed on the levels of TGF-β, IL-10, and autoantibodies in patients with melanoma treated with IFN-α 2b.</p> <p>Conclusions</p> <p>Patients with melanoma in this study showed increased basal levels of Treg that may be relevant to their disease and its progression. Treg levels shifted in patients with melanoma treated with IFN-α 2b, although no firm conclusions regarding the role of Tregs as a marker of treatment response or outcome can be made at present.</p