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Cancer is a chronic disease that causes the most deaths in the world, being a public health problem nowadays. Even though breast cancer affects the daily lives of patients, many women become resilient after the disease, decreasing the impact of the diagnosis. Based on a positive psychology approach, the concept of co-vitality arises understood as a set of socio-emotional competencies that enhance psychological adaptation. In this sense, emotional intelligence is one of the main protective factors associated with resilience. However, it is not always as beneficial as it seems, and can lead to collateral effects on psychological adjustment. Given this controversy, this study aims to find the specific processes through which the dimensions of Perceived Emotional Intelligence (PEI) (Emotional Attention, Emotional Clarity, and Mood Repair) can act as a risk or protective factor in the development of resilience. The total sample was 167 women (Age: M = 43.26; SD = 12.43), 46.7% were breast cancer survivors, and 53.3% were healthy controls. The selection of women with breast cancer carries out randomly, recruited through the Oncology Units. The sample completed measures of resilience and PEI, through Resilience Scale (Wagnild and Young, 1993) and TMMS-24 (Salovey et al., 1995). The results showed that breast cancer survivors showed higher age and greater levels of resilience and mood repair than healthy women. The mediation analysis revealed that breast cancer survival and PEI predicted 28% of the variance of resilience. The direct effects showed that emotional clarity and mood repair increased resilience levels. Although breast cancer did not predict resilience directly, it does through mood repair by an indirect process. Besides, the analysis showed that emotional attention played a role in vulnerability, decreasing mood repair, and resilience. These research support theories that point to a possible dark side of PEI, thus, a great level of emotional attention makes dark the positive effect of mood repair and personal growth if a clear perception of emotions does not complement it. These results provide empirical support concerning the need to work complementary each dimension of PEI to avoid unwanted effects on intrapersonal adjustment.

Background: Four main clinical phenotypes have been traditionally described in patients mutated in SCN4A, including sodium-channel myotonia (SCM), paramyotonia congenita (PMC), Hypokaliemic type II (HypoPP2), and Hyperkaliemic/Normokaliemic periodic paralysis (HyperPP/NormoPP); in addition, rare phenotypes associated with mutations in SCN4A are congenital myasthenic syndrome and congenital myopathy. However, only scarce data have been reported in literature on large patient cohorts including phenotypes characterized by myotonia and episodes of paralysis.Methods: We retrospectively investigated clinical and molecular features of 80 patients fulfilling the following criteria: (1) clinical and neurophysiological diagnosis of myotonia, or clinical diagnosis of PP, and (2) presence of a pathogenic SCN4A gene variant. Patients presenting at birth with episodic laryngospasm or congenital myopathy-like phenotype with later onset of myotonia were considered as neonatal SCN4A.Results: PMC was observed in 36 (45%) patients, SCM in 30 (37.5%), Hyper/NormoPP in 7 (8.7%), HypoPP2 in 3 (3.7%), and neonatal SCN4A in 4 (5%). The median age at onset was significantly earlier in PMC than in SCM (p < 0.01) and in Hyper/NormoPP than in HypoPP2 (p = 0.02). Cold-induced myotonia was more frequently observed in PMC (n = 34) than in SCM (n = 23) (p = 0.04). No significant difference was found in age at onset of episodes of paralysis among PMC and PP or in frequency of permanent weakness between PP (n = 4), SCM (n = 5), and PMC (n = 10). PP was more frequently associated with mutations in the S4 region of the NaV1.4 channel protein compared to SCM and PMC (p < 0.01); mutations causing PMC were concentrated in the C-terminal region of the protein, while SCM-associated mutations were detected in all the protein domains.Conclusions: Our data suggest that skeletal muscle channelopathies associated with mutations in SCN4A represent a continuum in the clinical spectrum.

Loiasis, caused by the filarial nematode Loa loa, is endemic in Central and West Africa where about 10 million people are infected. There is a scarcity of convenient, commercial diagnostics for L. loa. Microscopy requires trained personnel and has low sensitivity, while the serodiagnosis is currently not standardized. Individual case management is also important in non-endemic countries to treat migrants, expatriates and tourists. We retrospectively compared the performance of a Loa Antibody Rapid Test (RDT) and a commercial ELISA pan-filarial test on 170 patients, 65 with loiasis [8 with eyeworm, 29 with positive microfilaremia, 28 with neither microfilaremia nor history of eyeworm but eosinophilia and history of Calabar swelling (probable loiasis)], 95 with other common parasitic infections and no previous exposure to L. loa (37 with M. perstans, 1 with Brugia sp., 18 with strongyloidiasis, 20 with schistosomiasis, 5 with hookworm, 4 with Ascaris lumbricoides infection, 10 with hyper-reactive malarial splenomegaly), and 10 uninfected controls. The sensitivity of the RDT and of the ELISA were 93.8% (61/65) and 90.8% (59/65), respectively. For the RDT, most of the cross-reactions were observed in patients with M. perstans: 7/37 (18.9%), followed by 1/10 (10%) with hyper-reactive malarial splenomegaly and 1/20 (5%) with schistosomiasis. None of the 27 subjects infected with intestinal nematodes was found positive at this test. The ELISA is meant to be a pan-filarial assay, and reacted extensively with cases of M. perstans (95%), as expected, and also in 11/18 (61.1%) patients with strongyloidiasis and in 3/5 (60%) with hookworm infection. The RDT and the ELISA are both highly sensitive for the diagnosis of loiasis. The main difference lies in the extent of cross-reactivity with other parasites. Considering that the RDT is specifically meant for Loa loa infection, and its high sensitivity, this test could be a useful tool for the diagnosis of occult loiasis.

Spatial navigation is one of the most frequently used behavioral paradigms to study memory formation in rodents. Commonly used tasks to study memory are labor-intensive, preventing the simultaneous testing of multiple animals with the tendency to yield a low number of trials, curtailing the statistical power. Moreover, they are not tailored to be combined with neurophysiology recordings because they are not based on overt stereotyped behavioral responses that can be precisely timed. Here we present a novel task to study long-term memory formation and recall during spatial navigation. The task consists of learning sessions during which mice need to find the rewarding port that changes from day to day. Hours after learning, there is a recall session during which mice search for the location of the memorized rewarding port. During the recall sessions, the animals repeatedly poke the remembered port over many trials (up to ∼20) without receiving a reward (i.e., no positive feedback) as a readout of memory. In this task, mice show memory of port locations learned on up to three previous days. This eight-port maze task requires minimal human intervention, allowing for simultaneous and unsupervised testing of several mice in parallel, yielding a high number of recall trials per session over many days, and compatible with recordings of neural activity.

In this paper we analyse a set of socially responsible investment (SRI) indices against their conventional counterparts in the US context. Using a data set that spans the Obama and Trump administrations, we aim to identify whether performance and volatility patterns differ when markets are exposed to political uncertainty and the Global Financial Crisis (GFC). The findings suggest that SRI indices underperform conventional indices, and that the S&P 500 has a significant impact on their behaviour. The CBOE’s Volatility Index (VIX), the US Equity Related Economic Uncertainty Index (EEUi) and the impact of the economic policy uncertainty index (EPUi) are used to consider market volatility and political uncertainty, with VIX emerging as the best indicator to capture market uncertainty. The study signals a positive and significant impact on SRI indices during the first hundred days of the Obama administration with a lack of significant findings for the Trump administration for the period of study. The results for implied volatility reveal similar patterns across all indices.

Non-polymorphic MHC class I-related molecule MR1 presents antigenic bacterial metabolites to mucosal-associated invariant T (MAIT) cells and self-antigens to MR1-restricted T (MR1T) cells. Both MR1-restricted T cell populations are readily identified in healthy individuals, with MAIT cells accounting for 1–10% of circulating T cells, while MR1T cells have frequencies comparable to peptide-specific T cells (

Abstract. While classical nodal mantle cell lymphoma (cMCL) is often associated with involvement of multiple extranodal sites, isolated extranodal disease (ED) at the time of diagnosis is a rare event; data on the outcome of these forms are lacking. On behalf of the European MCL Network, we conducted a retrospective analysis on the clinical characteristics and outcomes of MCL presenting with isolated or predominant ED (MALT MCL). We collected data on 127 patients with MALT MCL diagnosed from 1998 to 2015: 78 patients (61%) were male with a median age of 65 years. The involved sites include: upper airways + Waldeyer ring (40; 32%), gastrointestinal tract (32; 25%), ocular adnexa (17; 13%), oral cavity and salivary glands (17; 13%) and others (13; 1%); 7 patients showed multiple extranodal sites. The median follow-up was 80 months (range: 6–182), 5-year progression-free survival (PFS) was 45% (95% CI: 35–54) and 5-year overall survival (OS) was 71% (95% CI: 62–79). In an explorative setting, we compared MALT MCL with a group of 128 cMCL patients: MALT MCL patients showed a significantly longer PFS and OS compared with nodal cMCL; with a median PFS of 4.5 years vs 2.8 years (p = 0.001) and median OS of 9.8 years vs 6.9 years (p = 0.018), respectively. Patients with MALT MCL at diagnosis showed a more favorable prognosis and indolent course than classical nodal type. This clinical variant of MCL should be acknowledged to avoid possible over-treatment.

Tropheryma whipplei (TW), Helicobacter pylori (HP), and intestinal protozoa (IP) are widespread pathogens with similar routes of transmission and epidemiological risk factors. Epidemiological data on co-infection between TW, HP, and IP are scarce. We aim to more deeply investigate the co-infection rate for these pathogens, evaluating the risk factors and symptoms. Methods: This is a cross-sectional study conducted at the IRCCS Sacro Cuore Don Calabria Hospital in Northern Italy, a referral center for tropical and Whipple’s disease (WD). Stored stool samples from 143 subjects previously tested for TW DNA by real-time PCR were explored for HP and IP DNA detection. The virulence factor cagA was investigated in HP-positive patients. Results: A history of migration was reported significantly more in TW-positive than in negative subjects (34.1% vs. 9.1%, p = 0.001) and in HP-infected than in those non-infected (59.1% vs. 9.1%, p < 0.001). The HP infection rate differed significantly between TW-infected and uninfected groups (31.8% vs. 8.1%, p = 0.001), while no difference was observed for IP infection. Significantly higher TW intestinal colonization was found in HP-infected patients than in non-infected (63.6% vs. 24.8%, p < 0.001). In addition, the proportion of Blastocysts positive finding was also significantly higher in HP-infected than in non-infected (40.9% vs. 17.4%, p = 0.018). Conclusions: The present study is the first to report a high TW and HP co-infection rate. To reduce the risk of morbidity from a chronic infection of either pathogen, clinicians may consider TW-HP molecular screening on the same stool sample for patients with suspected HP disease or WD, particularly in case of travel history.

Pulmonary fibrosis is a pathological fibrotic process affecting the lungs of five million people worldwide. The incidence rate will increase even more in the next years due to the long-COVID-19 syndrome, but a resolving treatment is not available yet and usually prognosis is poor. The emerging role of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling in fibrotic processes has inspired the testing of drugs targeting the PI3K/Akt pathway that are currently under clinical evaluation. This review highlights the progress in understanding the role of PI3K/Akt in the development of lung fibrosis and its causative pathological context, including sepsis as well as acute lung injury (ALI) and its consequent acute respiratory distress syndrome (ARDS). We further summarize current knowledge about PI3K inhibitors for pulmonary fibrosis treatment, including drugs under development as well as in clinical trials. We finally discuss how the design of inhaled compounds targeting the PI3K pathways might potentiate efficacy and improve tolerability.

Abstract Background Aldehyde dehydrogenase 1A1 (ALDH1A1), a member of aldehyde dehydrogenase family, is a marker of stemness in breast cancer. During tumor progression cancer stem cells (CSCs) have been reported to secrete angiogenic factors to orchestrate the formation of pathological angiogenesis. This vasculature can represent the source of self-renewal of CSCs and the route for further tumor spreading. The aim of the present study has been to assess whether ALDH1A1 controls the output of angiogenic factors in breast cancer cells and regulates tumor angiogenesis in a panel of in vitro and in vivo models. Methods Stemness status of breast cancer cells was evaluated by the ability to form turmorspheres in vitro. A transwell system was used to assess the angiogenic features of human umbilical vein endothelial cells (HUVEC) when co-cultured with breast cancer cells MCF-7 harboring different levels of ALDH1A1. Under these conditions, we survey endothelial proliferation, migration, tube formation and permeability. Moreover, in vivo, MCF-7 xenografts in immunodeficient mice allow to evaluate blood flow, expression of angiogenic factors and microvascular density (MVD). Results In MCF-7 we observed that ALDH1A1 activity conferred stemness property and its expression correlated with an activation of angiogenic factors. In particular we observed a significant upregulation of hypoxia inducible factor-1α (HIF-1α) and proangiogenic factors, such as vascular endothelial growth factor (VEGF). High levels of ALDH1A1, through the retinoic acid pathway, were significantly associated with VEGF-mediated angiogenesis in vitro. Co-culture of HUVEC with ALDH1A1 expressing tumor cells promoted endothelial proliferation, migration, tube formation and permeability. Conversely, downregulation of ALDH1A1 in MCF-7 resulted in reduction of proangiogenic factor release/expression and impaired HUVEC angiogenic functions. In vivo, when subcutaneously implanted in immunodeficient mice, ALDH1A1 overexpressing breast tumor cells displayed a higher expression of VEGF and MVD. Conclusion In breast tumors, ALDH1A1 expression primes a permissive microenvironment by promoting tumor angiogenesis via retinoic acid dependent mechanism. In conclusion, ALDH1A1 might be associated to progression and diffusion of breast cancer.

Abstract Background Lymph node involvement is one of the most important prognostic factors in colon cancer. Twelve is considered the minimum number of lymph nodes necessary to retain reliable tumour staging, but several factors can potentially influence the lymph node harvesting. Emergent surgery for complicated colon cancer (perforation, occlusion, bleeding) could represent an obstacle to reach the benchmark of 12 nodes with an accurate lymphadenectomy. So, an efficient classification system of lymphatic involvement is crucial to define the prognosis, the indication to adjuvant therapy and the follow-up. This is the first study with the aim to evaluate the efficacy of lymph nodes ratio (LNR) and log odds of positive lymph nodes (LODDS) in the prognostic assessment of patients who undergo to urgent surgery for complicated colonic cancer. Methods This is a retrospective study carried out on patients who underwent urgent colonic resection for complicated cancer (occlusion, perforation, bleeding, sepsis). We collected clinical, pathological and follow-up data of 320 patients. Two hundred two patients met the inclusion criteria and were distributed into three groups according to parameter N of TNM, LNR and LODDS. Survival analysis was performed by Kaplan-Meier curves, investigating both overall survival (OS) and disease-free survival (DFS). Results The median number of harvested lymph nodes was 17. In 78.71% (n = 159) of cases, at least 12 lymph nodes were examined. Regarding OS, significant differences from survival curves emerged for ASA score, surgical indication, tumour grading, T parameter, tumour stage, N parameter, LNR and LODDS. In multivariate analysis, only LODDS was found to be an independent prognostic factor. Concerning DFS, we found significant differences between survival curves of sex, surgical indication, T parameter, tumour stage, N parameter, LNR and LODDS, but none of these confirmed its prognostic power in multivariate analysis. Conclusions We found that N, LNR and LODDS are all related to 5-year OS and DFS with statistical significance, but only LODDS was found to be an independent prognostic factor for OS in multivariate analysis.

Stem cells: Proteins in secreted vesicles offer potential therapy Tiny protein-containing vesicles released by partially differentiated stem cells contain a suite of therapeutic proteins that make them a promising alternative to cell-based treatments. Carlos Luzzani from LIAN-CONICET in Buenos Aires, Argentina, and colleagues reprogrammed skin cells to an embryonic-like state, and then coaxed these induced pluripotent stem cells (iPSCs) to form mesenchymal stem/stromal cells (MSCs), a type of adult stem cell that can give rise to bone, muscle and other tissues. The researchers analyzed all the proteins produced by the iPSCs, MSCs and the sub-micron sized bubbles known as extracellular vesicles that each secretes. They found that vesicles from MSCs, but not iPSCs, included a small set of proteins involved in regeneration and immune modulation. These vesicles may provide the regenerative benefits of MSCs without the safety risks of a cell-based therapy.

Abstract Background Trials in rare diseases have many challenges, among which are the need to set up multiple sites in different countries to achieve recruitment targets and the divergent landscape of clinical trial regulations in those countries. Over the past years, there have been initiatives to facilitate the process of international study set-up, but the fruits of these deliberations require time to be operationally in place. FOR-DMD (Finding the Optimum Steroid Regimen for Duchenne Muscular Dystrophy) is an academic-led clinical trial which aims to find the optimum steroid regimen for Duchenne muscular dystrophy, funded by the National Institutes of Health (NIH) for 5 years (July 2010 to June 2015), anticipating that all sites (40 across the USA, Canada, the UK, Germany and Italy) would be open to recruitment from July 2011. However, study start-up was significantly delayed and recruitment did not start until January 2013. Method The FOR-DMD study is used as an example to identify systematic problems in the set-up of international, multi-centre clinical trials. The full timeline of the FOR-DMD study, from funding approval to site activation, was collated and reviewed. Systematic issues were identified and grouped into (1) study set-up, e.g. drug procurement; (2) country set-up, e.g. competent authority applications; and (3) site set-up, e.g. contracts, to identify the main causes of delay and suggest areas where anticipatory action could overcome these obstacles in future studies. Results Time from the first contact to site activation across countries ranged from 6 to 24 months. Reasons of delay were universal (sponsor agreement, drug procurement, budgetary constraints), country specific (complexity and diversity of regulatory processes, indemnity requirements) and site specific (contracting and approvals). The main identified obstacles included (1) issues related to drug supply, (2) NIH requirements regarding contracting with non-US sites, (3) differing regulatory requirements in the five participating countries, (4) lack of national harmonisation with contracting and the requirement to negotiate terms and contract individually with each site and (5) diversity of languages needed for study materials. Additionally, as with many academic-led studies, the FOR-DMD study did not have access to the infrastructure and expertise that a contracted research organisation could provide, organisations often employed in pharmaceutical-sponsored studies. This delay impacted recruitment, challenged the clinical relevance of the study outcomes and potentially delayed the delivery of the best treatment to patients. Conclusion Based on the FOR-DMD experience, and as an interim solution, we have devised a checklist of steps to not only anticipate and minimise delays in academic international trial initiation but also identify obstacles that will require a concerted effort on the part of many stakeholders to mitigate.

Mental illness is a global health problem that affects one in four people around the world. Despite its high incidence, there is strong social discrimination towards this population (WHO, 2004). Different professionals encounter, in their daily performance, situations of interaction with these patients and may act as stigma perpetuators if they display negative attitudes of fear and hostility (Roos and Goldner, 2009). Likewise, contact with these mental ill patients will condition their attitudes toward the disease. The aim of this study was to examine the attitudes of future professionals of Health Sciences toward mental ill patients, compared with students of other knowledge fields, and to explore if maintaining contact with these patients can modify these attitudes. The questionnaire “Opinions concerning mental illness” (Ozamiz, 1980) was administered to 820 students (70.37% women and 29.63% men) from different degrees of Health Sciences, and Social and Legal Sciences. This scale assessed global Attitude and five subscales (Negativism, Social Etiology, Authoritarianism, Restrictivism, and Prejudice), obtaining a reliability higher than .7 in Negativism and Social Etiology. Results indicated that Health Sciences students show lower levels of Negativism towards mental ill patients than students in Social and Legal Sciences degrees, regardless of the contact maintained. In addition, students who report contact with these patients have lower levels of Negativism, not differing in a statistically significant way neither in the general Attitude, nor in social Etiology, and regardless of the university degree. These results seem to indicate that negative attitudes toward mental ill patients is lower among Health Sciences students and among students who have contact with this population compared with Social and Legal Science ones.

Emotional management is considered one of the emerging challenges in current society. In this sense, the educational field appears as one of the pioneers designing and implementing of programs to promote its development, favoring in the students’ social and personal skills (Guil and Gil-Olarte, 2007). According to current educational laws in Spain, educational administrations should promote the maximum personal, intellectual, social, and emotional development of students (Organic Educational Law 2/2006, of May 3, modified by the Organic Law 9/2013, of 9 December, for the Improvement of Educational Quality). However, in Middle School (in Spain Secondary Mandatory School, ESO) we find few programs that address this integral development. Moreover, these students have special educational needs in order to achieve academic performance due, among others, to emotional competencies and social skills deficits (Santamaría and Valdés, 2017). Specifically, in Andalusia, students of Basic Vocational Training, usually present high rates of absenteeism, as well as poor motivation, self-concept, self-esteem, and social skills (Junta de Andalucía, 2018). To respond to this situation, we propose a pilot project aimed to increase academic achievement and socio-academic adaptation through emotional competencies. This project has been developed with five students from eighth grade (second year of Spanish ESO) that met the basic criteria to begin Basic Vocational Training next academic year. In this way, students’ emotional competencies will be developed through the reinforcement of instrumental and fundamental curricular subjects, complementary to formal education.

A growing body of research suggests that higher levels of Trait Emotional Intelligence (EI) influence an optimal well-being development and psychological adjustment, such as positive affective states. However, few studies relate these variables considering gender differences. Therefore, the aims of this work are to establish if there are differences according to sex, in each dimension of EI and affective states. Moreover, this study aims to check the existence of relationships between EI and affect, showing the EI contribution as a predictor of affective state, for both, the total sample, and differentiating between men and women. Participants were 467 university students, 82.4% women, with an average age of 21.79 years (SD = 5.19). The TMMS-24 questionnaire was used to measure IE, and affective states were assessed with PANAS. The results showed statistically significant differences (p .05) between men and women in positive affect, being higher for men. In addition, there were statistically significant correlations between EI dimensions and affects (p .01). Regarding the predictive value of EI, the results showed that the three EI dimensions predicted negative affect in both sexes, with an explained variance of 21.2% in women and approximately the doublé in men (37.5%). However, attention and emotional regulation are the variables that predict 16.7% of the variance of positive affect in women, leaving out of the equation to men. The existence of gender differences is demonstrated, not so much in EI dimensions but in the explanatory role of EI in affect, so it has to be taken into consideration in the face of future interventions.

The development of advanced high-strength bainitic steels has been preceded and linked to different metallurgical advances, both in the field of fundamental materials science and in technological fields closer to the production and final application. The diversity and abundance of documents in literature has favored the co-existence of extensive terminology in the context of advanced high-strength steels and bainitic steels. In this work, the concept of advanced high-strength bainitic steels is briefly revisited from a wide perspective, with the aim of highlighting the main limitations and challenges for further development of these microstructures.

Alphaviruses (Togaviridae) are arthropod-borne viruses responsible for several emerging diseases, maintained in nature through transmission between hematophagous arthropod vectors and susceptible vertebrate hosts. Although bats harbor many species of viruses, their role as reservoir hosts in emergent zoonoses has been verified only in a few cases. With bats being the second most diverse order of mammals, their implication in arbovirus infections needs to be elucidated. Reports on arbovirus infections in bats are scarce, especially in South American indigenous species. In this work, we report the genomic detection and identification of two different alphaviruses in oral swabs from bats captured in Northern Uruguay. Phylogenetic analysis identified Río Negro virus (RNV) in two different species: Tadarida brasiliensis (n = 6) and Myotis spp. (n = 1) and eastern equine encephalitis virus (EEEV) in Myotis spp. (n = 2). Previous studies of our group identified RNV and EEEV in mosquitoes and horse serology, suggesting that they may be circulating in enzootic cycles in our country. Our findings reveal that bats can be infected by these arboviruses and that chiropterans could participate in the viral natural cycle as virus amplifiers or dead-end hosts. Further studies are warranted to elucidate the role of these mammals in the biological cycle of these alphaviruses in Uruguay.

Nowadays, the growing interest in gathering physiological data and human behavior in everyday life scenarios is paralleled by an increase in wireless devices recording brain and body signals. However, the technical issues that characterize these solutions often limit the full brain-related assessments in real-life scenarios. Here we introduce the Biohub platform, a hardware/software (HW/SW) integrated wearable system for multistream synchronized acquisitions. This system consists of off-the-shelf hardware and state-of-art open-source software components, which are highly integrated into a high-tech low-cost solution, complete, yet easy to use outside conventional labs. It flexibly cooperates with several devices, regardless of the manufacturer, and overcomes the possibly limited resources of recording devices. The Biohub was validated through the characterization of the quality of (i) multistream synchronization, (ii) in-lab electroencephalographic (EEG) recordings compared with a medical-grade high-density device, and (iii) a Brain-Computer-Interface (BCI) in a real driving condition. Results show that this system can reliably acquire multiple data streams with high time accuracy and record standard quality EEG signals, becoming a valid device to be used for advanced ergonomics studies such as driving, telerehabilitation, and occupational safety.

In organic agriculture, synthetic pesticides and treatments are substituted by natural remedies with interesting success for product yield and environmental outcomes, but the safety of these bio-based products needs to be assessed in vertebrate and human models. Therefore, in this paper we assessed the safety profile of sweet chestnut (Castanea sativa) wood distillate (WD) on the different cellular components of tissues implied in transcutaneous absorption. We investigated the viability of different cell lines mimicking the skin (HaCaT keratinocytes), mucosa (A431), connective (normal human dermal fibroblasts, NHDF) and vascular (human umbilical vein endothelial cells, HUVEC) tissues after exposure to increasing concentrations (0.04–0.5%, v/v, corresponding to 1:2800–1:200 dilutions) of WD. A short exposure to increasing doses of WD was well tolerated up to the highest concentration. Instead, following a prolonged treatment, a concentration dependent cytotoxic effect was observed. Notably, a different behavior was found with the various cell lines, with higher sensitivity to cytotoxicity by the cells with higher proliferation rate and reduced doubling time (human keratinocytes). Moreover, to exclude an inflammatory effect at the not cytotoxic WD concentrations, the expression of the main inducible markers of inflammation, cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1), were assessed, and no improvement was found both after brief and prolonged exposure. In conclusion, our data exclude any inflammatory and cytotoxic effect at the lowest WD concentrations, namely 0.07% and 0.04%, mimicking some recommended dilutions of the product and the potential exposure doses for the operators in agriculture. Nevertheless, higher concentrations showed a safe profile for short time usage, but caution should be used by farmers following persistent product exposure.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

This work considered the influence of the duration of olive storage on the chemical and sensory properties of extra virgin olive oil. In total, 228 batches of olives collected during three successive crop seasons were sampled in seven industrial mills; information about olive batches (variety, harvest date) was collected, together with the produced oils. Four classes of storage times were considered: ≤24 h, 2–3 days, 4–6 days, ≥7 days. The oils’ quality parameters free acidity, peroxide number and K232 increased significantly as storage duration increased, while phenolic content decreased significantly, with a resulting effect on oil stability. The fatty acid composition was not affected by the olive storage period, while α-tocopherol, lutein and β-carotene content decreased as storage duration lengthened. Finally, the main positive sensory attributes (olive fruity, green notes, bitter and pungency) underwent a statistically significant reduction with the increase in storage duration, while the intensity of defects increased, suggesting that the duration of olive storage has an important effect on the quality of the final oil.

Abstract Background A small number of patients affected by Neutral Lipid Storage Diseases (NLSDs: NLSD type M with Myopathy and NLSD type I with Ichthyosis) have been described in various ethnic groups worldwide. However, relatively little is known about the progression and phenotypic variability of the disease in large specific populations. The aim of our study was to assess the natural history, disability and genotype-phenotype correlations in Italian patients with NLSDs. Twenty-one patients who satisfied the criteria for NLSDs were enrolled in a retrospective cross-sectional study to evaluate the genetic aspects, clinical signs at onset, disability progression and comorbidities associated with this group of diseases. Results During the clinical follow-up (range: 2–44 years, median: 17.8 years), two patients (9.5%, both with NLSD-I) died of hepatic failure, and a further five (24%) lost their ability to walk or needed help when walking after a mean period of 30.6 years of disease. None of the patients required mechanical ventilation. No patient required a heart transplant, one patient with NLSD-M was implanted with a cardioverter defibrillator for severe arrhythmias. Conclusion The genotype/phenotype correlation analysis in our population showed that the same gene mutations were associated with a varying clinical onset and course. This study highlights peculiar aspects of Italian NLSD patients that differ from those observed in Japanese patients, who were found to be affected by a marked hypertrophic cardiopathy. Owing to the varying phenotypic expression of the same mutations, it is conceivable that some additional genetic or epigenetic factors affect the symptoms and progression in this group of diseases.

Pediatric Acute Megakaryoblastic Leukemia not associated to Down Syndrome (non-DS AMKL) is a rare disease with a dismal prognosis. Around 15% of patients carry the chromosomal translocation t(1;22) that originates the fusion oncogene RBM15-MKL1, which is linked to an earlier disease onset (median of 6 months of age) and arises in utero. Here we report the generation of two hPSC cell lines constitutively expressing the oncogene RBM15-MKL1, resulting in an increased expression of known RBM15-MKL1 gene targets. These cell lines represent new disease models of pediatric AMKL to study the impact of the RBM15-MKL1 oncogene on human embryonic hematopoietic development.

To date, only few mutations in the mitochondrial DNA (mtDNA)-encoded ND2 subunit of Complex I have been reported, usually presenting a severe phenotype characterized by early onset encephalomyopathy and early death. In this report, we describe a new mutation in the MTND2 gene in a 21-year-old man with a mild myopathic phenotype characterized by exercise intolerance and increased plasma lactate at rest. Electromyography and brain NMR were normal, and no cardiac involvement was present. Muscle biopsy showed a massive presence of ragged red – COX-positive fibres, with enlarged mitochondria containing osmiophilic inclusions. Biochemical assays revealed a severe isolated complex I deficiency. We identified a novel, heteroplasmic mutation m.4831G>A in the MTND2 gene, causing the p.Gly121Asp substitution in the ND2 protein. The mutation was present in the 95% of mitochondrial genomes from patient's muscle tissue, at a lower level in cells from the urinary tract and at a lowest level in lymphocytes from patient's blood; the base substitution was absent in fibroblasts and in the tissues from proband's healthy mother and brother. The specific skeletal muscle tissue involvement can explain the childhood-onset and the relatively benign, exclusively myopathic course of the disease.

As the recent edition of the Wittgenstein’s Whewell’s Court Lectures shows, Wittgenstein mentioned Hume several times in the series of lectures on belief. Towards the end of the Thirties, in fact, he came across Hume’s Abstract of the Treatise, a pamphlet that Piero Sraffa and John Maynard Keynes had ‘discovered’ at the end of 1933, re-edited in 1937 and finally published in March 1938 – Sraffa, with whom Wittgenstein had an intense intercourse in 1938-1941, donated him a copy. A lexical analysis of excerpts of Wittgenstein’s ET 1940 lectures strongly suggests that he read the Abstract in March-May 1940, and shows that some of the issues he discussed in his lectures at that time revolve around the peculiar definition that Hume gave in that text of the feeling of belief.

The olive fruit fly is worldwide considered a major harmful pest of the olive agroecosystem. In Italy, the fruit fly infestation is traditionally countered by spraying chemical insecticides (e.g., dimethoate), but due to the recent ban of dimethoate by the Reg EU2019/1090 and the increasing awareness of consumers of food sustainability, the interest in developing chemical-free alternatives to pesticides, such as the use of particle-films, is rising. A field experiment was conducted to assess the effect of different particle films (kaolin-base and zeolitite-base) on leaf gas exchanges and leaf optical properties. Results showed that with the dust accumulation on the leaves’ surface, photosynthesis, stomatal conductance, transpiration and water use efficiency were significantly lower in kaolin-treated olive trees compared to those treated with zeolitite and to the control, while olive trees treated with zeolitite showed physiological parameters similar to the untreated plants. Microstructural differences of different particle film on the leaf and olive surfaces emerged by ESEM observations also influenced leaf optical properties. Oils produced by zeolitite-treated plants show higher intensities of gustatory and olfactory secondary flavors compared to kaolin and test oils.

Preservation of vascular wall integrity against degenerative processes associated with ageing, fat-rich diet and metabolic diseases is a timely therapeutical challenge. The loss of endothelial function and integrity leads to cardiovascular diseases and multiorgan inflammation. The protective effects of the H2S-donor erucin, an isothiocyanate purified by Eruca sativa Mill. seeds, were evaluated on human endothelial and vascular smooth muscle cells. In particular, erucin actions were evaluated on cell viability, ROS, caspase 3/7, inflammatory markers levels and the endothelial hyperpermeability in an inflammatory model associated with high glucose concentrations (25 mM, HG). Erucin significantly prevented the HG-induced decrease in cell viability as well as the increase in ROS, caspase 3/7 activation, and TNF-α and IL-6 levels. Similarly, erucin suppressed COX-2 and NF-κB upregulation associated with HG exposure. Erucin also caused a significant inhibition of p22phox subunit expression in endothelial cells. In addition, erucin significantly prevented the HG-induced increase in endothelial permeability as also confirmed by the quantification of the specific markers VE-Cadherin and ZO-1. In conclusion, our results assess anti-inflammatory and antioxidant effects by erucin in vascular cells undergoing HG-induced inflammation and this protection parallels the preservation of endothelial barrier properties.

The fine control of inflammation following injury avoids fibrotic scars or impaired wounds. Due to side effects by anti-inflammatory drugs, the research is continuously active to define alternative therapies. Among them, physical countermeasures such as photobiomodulation therapy (PBMT) are considered effective and safe. To study the cellular and molecular events associated with the anti-inflammatory activity of PBMT by a dual-wavelength NIR laser source, human dermal fibroblasts were exposed to a mix of inflammatory cytokines (IL-1β and TNF-α) followed by laser treatment once a day for three days. Inducible inflammatory key enzymatic pathways, as iNOS and COX-2/mPGES-1/PGE2, were upregulated by the cytokine mix while PBMT reverted their levels and activities. The same behavior was observed with the proangiogenic factor vascular endothelial growth factor (VEGF), involved in neovascularization of granulation tissue. From a molecular point of view, PBMT retained NF-kB cytoplasmatic localization. According to a change in cell morphology, differences in expression and distribution of fundamental cytoskeletal proteins were observed following treatments. Tubulin, F-actin, and α-SMA changed their organization upon cytokine stimulation, while PBMT reestablished the basal localization. Cytoskeletal rearrangements occurring after inflammatory stimuli were correlated with reorganization of membrane α5β1 and fibronectin network as well as with their upregulation, while PBMT induced significant downregulation. Similar changes were observed for collagen I and the gelatinolytic enzyme MMP-1. In conclusion, the present study demonstrates that the proposed NIR laser therapy is effective in controlling fibroblast activation induced by IL-1β and TNF-α, likely responsible for a deleterious effect of persistent inflammation.

The vascular endothelium consists of a single layer of squamous endothelial cells (ECs) lining the inner surface of blood vessels. Nowadays, it is no longer considered as a simple barrier between the blood and vessel wall, but a central hub to control blood flow homeostasis and fulfill tissue metabolic demands by furnishing oxygen and nutrients. The endothelium regulates the proper functioning of vessels and microcirculation, in terms of tone control, blood fluidity, and fine tuning of inflammatory and redox reactions within the vessel wall and in surrounding tissues. This multiplicity of effects is due to the ability of ECs to produce, process, and release key modulators. Among these, gasotransmitters such as nitric oxide (NO) and hydrogen sulfide (H2S) are very active molecules constitutively produced by endotheliocytes for the maintenance and control of vascular physiological functions, while their impairment is responsible for endothelial dysfunction and cardiovascular disorders such as hypertension, atherosclerosis, and impaired wound healing and vascularization due to diabetes, infections, and ischemia. Upregulation of H2S producing enzymes and administration of H2S donors can be considered as innovative therapeutic approaches to improve EC biology and function, to revert endothelial dysfunction or to prevent cardiovascular disease progression. This review will focus on the beneficial autocrine/paracrine properties of H2S on ECs and the state of the art on H2S potentiating drugs and tools.

Although antibody levels progressively decrease following SARS-CoV-2 infection, the immune memory persists for months. Thus, individuals who naturally contracted SARS-CoV-2 are expected to develop a more rapid and sustained response to COVID-19 vaccines than naïve individuals. In this study, we analyzed the dynamics of the antibody response to the BNT162b2 mRNA COVID-19 vaccine in six healthcare workers who contracted SARS-CoV-2 in March 2020, in comparison to nine control subjects without a previous infection. The vaccine was well tolerated by both groups, with no significant difference in the frequency of vaccine-associated side effects, with the exception of local pain, which was more common in previously infected subjects. Overall, the titers of neutralizing antibodies were markedly higher in response to the vaccine than after natural infection. In all subjects with pre-existing immunity, a rapid increase in anti-spike receptor-binding domain (RBD) IgG antibodies and neutralizing antibody titers was observed one week after the first dose, which seemed to act as a booster. Notably, in previously infected individuals, neutralizing antibody titers 7 days after the first vaccine dose were not significantly different from those observed in naïve subjects 7 days after the second vaccine dose. These results suggest that, in previously infected people, a single dose of the vaccine might be sufficient to induce an effective response.

The importance of the qualitative characteristics of information from the annual financial statements must not be ignored also within the interim financial statements, given that their development is determined primarily by the utility and appropriateness of information and data provided to internal and external users. This article focuses on those aspects of a qualitative nature that concentre on professional accountants in the preparation of financial reporting and the challenges they face are based on professional judgment. The article also compares the Romanian accounting framework with the European and international ones, regarding the treatment of qualitative characteristics of accounting information.

It is unclear how the microenvironment of the aorta-gonad-mesonephros influences haematopoietic stem cell (HSC) production early in mouse development. Here, Souilhol et al. use an in vitroaggregate system as a tool to understand how several pathways, BMP, SCF and Shh, may regulate HSC production.

The molecular pathways involving p21 and mTORC1 are frequently deregulated in head and neck squamous cell carcinomas (HNSCC). Here, Llanos et al. report a mechanism that regulates p21 stability through the mTORC1/4E-BP1 pathway independently of p53, and show that the mechanism is prevalent in HNSCC.

In this paper, simulations of a ship travelling on a given oceanic route were performed by a weather routing system to provide a large realistic navigation data set, which could represent a collection of data obtained on board a ship in operation. This data set was employed to train a neural network computing system in order to predict ship speed and fuel consumption. The model was trained using the Levenberg–Marquardt backpropagation scheme to establish the relation between the ship speed and the respective propulsion configuration for the existing sea conditions, i.e., the output torque of the main engine, the revolutions per minute of the propulsion shaft, the significant wave height, and the peak period of the waves, together with the relative angle of wave encounter. Additional results were obtained by also using the model to train the relationship between the same inputs used to determine the speed of the ship and the fuel consumption. A sensitivity analysis was performed to analyze the artificial neural network capability to forecast the ship speed and fuel oil consumption without information on the status of the engine (the revolutions per minute and torque) using as inputs only the information of the sea state. The results obtained with the neural network model show very good accuracy both in the prediction of the speed of the vessel and the fuel consumption.

Here, we assessed whether 36 single nucleotide polymorphisms (SNPs) within the TNFSF4 and MAPKAPK2 loci influence the risk of developing invasive aspergillosis (IA). We conducted a two-stage case control study including 911 high-risk patients diagnosed with hematological malignancies that were ascertained through the aspBIOmics consortium. The meta-analysis of the discovery and replication populations revealed that carriers of the TNFSF4rs7526628T/T genotype had a significantly increased risk of developing IA (p = 0.00022). We also found that carriers of the TNFSF4rs7526628T allele showed decreased serum levels of TNFSF14 protein (p = 0.0027), and that their macrophages had a decreased fungicidal activity (p = 0.048). In addition, we observed that each copy of the MAPKAPK2rs12137965G allele increased the risk of IA by 60% (p = 0.0017), whereas each copy of the MAPKAPK2rs17013271T allele was estimated to decrease the risk of developing the disease (p = 0.0029). Mechanistically, we found that carriers of the risk MAPKAPK2rs12137965G allele showed increased numbers of CD38+IgM-IgD- plasmablasts in blood (p = 0.00086), whereas those harboring two copies of the allele had decreased serum concentrations of thymic stromal lymphopoietin (p = 0.00097). Finally, we also found that carriers of the protective MAPKAPK2rs17013271T allele had decreased numbers of CD27-IgM-IgD- B cells (p = 0.00087) and significantly lower numbers of CD14+ and CD14+CD16- cells (p = 0.00018 and 0.00023). Altogether, these results suggest a role of the TNFSF4 and MAPKAPK2 genes in determining IA risk.

Psychogenic non-epileptic seizures (PNES) or dissociative seizures are found under the umbrella headings of functional/dissociative neurological disorders (FND) in psychiatric classifications (DSM-5; ICD-11). PNES are not characterized by any specific ictal or postictal EEG abnormalities. Patients with PNES can present with motor or non-motor symptoms, frequently associated with a change in the level of consciousness. PNES duration is variable, often longer than that of epileptic seizures. Prolonged PNES, sometimes termed PNES status, involve continuous or repetitive events that exceed 30 min. Prolonged PNES are often misdiagnosed as an epileptic event and are often inappropriately treated with high doses of antiseizure drugs. In this report, we describe two adolescent patients who presented with prolonged PNES characterized by generalized hypertonic posturing and low levels of consciousness. Despite multiple presentation to the Emergency department, and multiple normal video-EEG, the patients were misdiagnosed with epilepsy and were inappropriately treated with antiseizure medications. Both patients presented psychiatric comorbidity, consisting of a major depressive disorder, obsessive-compulsive symptoms, social withdrawal, difficulty of social interaction, and anxious-perfectionist personality traits. The episodes of prolonged PNES gradually declined within 18 months in both patients.

Background: Some recent studies suggest that children and adolescents with different neurodevelopmental disorders perform worse in emotions recognition through facial expressions (ER) compared with typically developing peers. This impairment is also described in children with Specific Learning Disorders (SLD), compromising their scholastic achievement, social functioning, and quality of life. The purpose of our study is to evaluate ER skills in children and adolescents with SLD compared to a control group without learning disorders, and correlate them with intelligence and executive functions. Materials and Methods: Our work is a cross-sectional observational study. Sixty-three children and adolescents aged between 8 and 16 years, diagnosed with SLD, and 32 sex/age-matched controls without learning disorders were recruited. All participants were administered standardized neuropsychological tests, evaluating facial emotion recognition (NEPSY-II), executive functions (EpiTrack Junior), and intelligence profile (WISC-IV). Results: Emotion recognition mean score was significantly lower in the SLD group than in the controls group on the Mann–Whitney U test for unpaired samples (p < 0.001). The SLD group performed significantly lower than the control group in their abilities to identify neutral expressions, happiness, sadness, anger, and fear compared to controls (p < 0.001). ER scores were positively correlated to the executive functions scores. There was no correlation with the Total Intelligence Quotient scores but there is a significant positive correlation with Working Memory Index and Processing Speed Index measured by WISC.IV. Conclusion: Our study showed that children and adolescents with Specific Learning Disorders have facial emotion recognition impairment when compared with a group of peers without learning disorders. ER abilities were independent of their global intelligence but potentially related to executive functions.

Background: The estimation of Plasmodium falciparum parasitaemia can vary according to the method used. Recently, droplet digital PCR (ddPCR) has been proposed as a promising approach in the molecular quantitation of Plasmodium, but its ability to predict the actual parasitaemia on clinical samples has not been largely investigated. Moreover, the possibility of applying the ddPCR-sensitive method to serum samples has never been explored. Methods: We used, for the first time, ddPCR on both blood and serum to detect the DNA of P. falciparum in 52 paired samples from 26 patients. ddPCR was compared with loop-mediated isothermal amplification (LAMP) and rtPCR. The correlation between the ddPCR results, microscopy, and clinical parameters was examined. Results: ddPCR and microscopy were found to be strongly correlated (ρ(26) = 0.83111, p < 0.0001) in blood. Samples deviating from the correlation were partially explained by clinical parameters. In serum samples, ddPCR revealed the best performance in detecting P. falciparum DNA, with 77% positive samples among malaria subjects. Conclusion: Absolute quantitation by ddPCR can be a flexible technique for Plasmodium detection, with potential application in the diagnosis of malaria. In particular, ddPCR is a powerful approach for Plasmodium DNA analysis on serum when blood samples are unavailable.

Drug-loaded, PEGylated, organic-modified silica (ORMOSIL) nanoparticles prepared by microemulsion condensation of vinyltriethoxysilane (VTES) were investigated as potential nanovectors for cancer therapy. To target cancer stem cells, anti-CD44v6 antibody and hyaluronic acid (HA) were conjugated to amine-functionalized PEGylated ORMOSIL nanoparticles through thiol-maleimide and amide coupling chemistries, respectively. Specific binding and uptake of conjugated nanoparticles were studied on cells overexpressing the CD44v6 receptor. Cytotoxicity was subsequently evaluated in the same cells after the uptake of the nanoparticles. Internalization of nanocarriers loaded with the anticancer drug 3N-cyclopropylmethyl-7-phenyl-pyrrolo- quinolinone (MG2477) into cells resulted in a substantial increase of the cytotoxicity with respect to the free formulation. Targeting with anti-CD44v6 antibodies or HA yielded nanoparticles with similar effectiveness, in their optimized formulation.

Há trinta anos, exatamente em 1988, a Empresa Catarinense de Pesquisa Agropecuária S.A./Empasc, atual Epagri, lançava o primeiro número da revista Agropecuária Catarinense. A RAC, como periódico técnico-científico, além de registrar as pesquisas de seu próprio corpo de investigadores, ao longo dos anos também abriu espaço para difundir trabalhos de profissionais de outras instituições, como cientistas de universidades federais e estaduais, pesquisadores da Embrapa e técnicos de entidades diversas.

The definition “unconventional T cells” identifies T lymphocytes that recognize non-peptide antigens presented by monomorphic antigen-presenting molecules. Two cell populations recognize lipid antigens and small metabolites presented by CD1 and MR1 molecules, respectively. A third cell population expressing the TCR Vγ9Vδ2 is stimulated by small phosphorylated metabolites. In the recent past, we have learnt a lot about the selection, tissue distribution, gene transcription programs, mode of expansion after antigen recognition, and persistence of these cells. These studies depict their functions in immune homeostasis and diseases. Current investigations are revealing that unconventional T cells include distinct sub-populations, which display unexpected similarities to classical MHC-restricted T cells in terms of TCR repertoire diversity, antigen specificity variety, functional heterogeneity, and naïve-to-memory differentiation dynamic. This review discusses the latest findings with a particular emphasis on these T cells, which appear to be more conventional than previously appreciated, and with the perspective of using CD1 and MR1-restricted T cells in vaccination and immunotherapy.

Magnetic resonance imaging techniques measuring in vivo brain perfusion and integrity of the blood-brain barrier have developed rapidly in the past decade, resulting in a wide range of available methods. This review first discusses their principles, possible pitfalls, and potential for quantification and outlines clinical application in neurological disorders. Then, we focus on the endothelial cells of the blood-brain barrier, pointing out their contribution in regulating vascular tone by production of vasoactive substances. Finally, the role of these substances in brain hypoperfusion in multiple sclerosis is discussed.