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Abstract Introduction Chronic obstructive pulmonary disease (COPD) is a frequent cause of morbidity and mortality. Dysregulated and enhanced immune-inflammatory responses have been described in COPD. Recent data showed impaired immune responses and, in particular, of interferon (IFNs) signaling pathway in these patients. Aim To evaluate in peripheral lung of COPD patients, the expression of some of the less investigated key components of the innate immune responses leading to IFN productions including: IFN-receptors (IFNAR1/IFNAR2), IRF-3 and MDA-5. Correlations with clinical traits and with the inflammatory cell profile have been assessed. Methods Lung specimens were collected from 58 subjects undergoing thoracic surgery: 22 COPD patients, 21 smokers with normal lung function (SC) and 15 non-smoker controls (nSC). The expression of IFNAR1, IFNAR2, IRF-3 and MDA-5, of eosinophils and activated NK cells (NKp46+) were quantified in the peripheral lung by immunohistochemistry. Results A significant increase of IRF-3 + alveolar macrophages were observed in COPD and SC compared with nSC subjects. However, in COPD patients, the lower the levels of IRF-3 + alveolar macrophages the lower the FEV1 and the higher the exacerbation rate. The presence of chronic bronchitis (CB) was also associated with low levels of IRF-3 + alveolar macrophages. NKp46 + cells, but not eosinophils, were increased in COPD patients compared to nSC patients (p

Fluid inclusions are a window into deep geological fluids, providing unique access to their nature and composition. The isotopic composition of CO2 and CH4 hosted in fluid inclusions is a powerful proxy to assess the origin and transformation of deep geological fluids, giving insights into carbon sources, fluxes, and degassing in a wide variety of geodynamic settings. Over the last 5 decades, techniques have been developed to extract fluid inclusions from their host minerals and measure their bulk composition. These techniques are often challenged by analytical artifacts including high blank levels of CO2 and CH4, fluid re-speciation, gas adsorption, and diffusion. Since these processes may alter the pristine composition of gases liberated from fluid inclusions, rigorous protocols are needed in order to evaluate the isotopic integrity of the extracted volatile species. In this study, we introduce new protocols for bulk off-line fluid inclusion extraction for the analysis of δ13C-CH4 and δ13C-CO2 using a Cavity Ring-Down Spectroscopy (CRDS) analyser (Picarro G2201-i). Two mechanical fluid extraction techniques are compared: ball milling in ZrO2 jars and sample crushing in a stainless steel sealed tube under a hydraulic press. Blanks and isotopically labelled tests with the ball milling technique suggest that rotation speed, grinding stock filling degree and filling type alter the CH4 and CO2 concentrations and isotopic compositions measured by the CRDS analyser. In contrast, the crushing technique does not generate measurable quantities of blank CH4 and CO2. The protocols presented in this study allow to extract, detect, and analyse δ13C of CH4 and CO2 for concentrations above 10 and 1,000 ppm respectively. Interlaboratory experiments allowed to replicate previously measured δ13C-CH4 values in natural fluid inclusions within 1‰ with both extraction techniques. This study highlights the potential of combining simple bulk off-line fluid inclusion extraction techniques with a CRDS analyser for δ13C analysis of CO2 and CH4 without gas separation being required.

Abstract Background A growing body of evidence clearly documents the benefits of integrated systems approaches to protecting and promoting the safety, health and well-being of workers. The purpose of this study is to provide a holistic view of the work ability of employees of an Italian University Hospital measuring their resources in relation to job demands. In particular, it examines socio-demographics, family and organizational antecedents of health professionals’ work ability. Methods A survey was conducted to assess the work ability of healthcare professionals, including physicians, nurses and administrative staff, working at the University Hospital of Modena (Italy). The data collection allows us to get a sample of 443 workers, who correspond to 11% of the target population. The data were analyzed using preliminary statistics on the main characteristics of the sample in terms of work ability, socio-demographic variables, family and organizational characteristics. In addition, logit models of the likelihood of having high work ability were estimated using SPSS version 25. Results Work ability decreases with increasing age, comorbidity, high body mass index, having at least one child under 5 and/or a dependent adult, having a poor work-life balance, and doing more than 20 h of housework. Specific job resources can significantly promote work ability, including relationship-oriented leadership, autonomy in decision making and individuals’ skill match. The nursing profession is associated with a low work ability. Finally, a significant gender gap has been documented. Women find it more difficult to reconcile life and work, especially when they have children of preschool age and work in professions with greater responsibilities, as in the case of women doctors, who experience lower work capacity. Conclusions Our results suggest that it is necessary to consider other factors, in addition to age, that are equally relevant in influencing work ability. Consequently, organisational interventions could be implemented to improve the work ability of all workers. In addition, we propose targeted interventions for groups at risk of reduced work capacity, in particular older workers (45 years and over), nurses, women with children of preschool age and in the position of physician.

Abstract Background The recent pandemic outbursts, due to SARS-CoV-2, have highlighted once more the central role of the inflammatory process in the propagation of viral infection. The main consequence of COVID-19 is the induction of a diffuse pro-inflammatory state, also defined as a cytokine storm, which affects different organs, but mostly the lungs. We aimed to prove the efficacy of cinnamaldehyde, the active compound of cinnamon, as an anti-inflammatory compound, able to reduce SARS-CoV-2 induced cytokine storm. Results We enrolled 53 COVID-19 patients hospitalized for respiratory failure. The cohort was composed by 39 males and 13 females, aged 65.0 ± 9.8 years. We reported that COVID-19 patients have significantly higher IL-1β and IL-6 plasma levels compared to non-COVID-19 pneumonia patients. In addition, human mononuclear cells (PBMCs) isolated from SARS-CoV-2 infected patients are significantly more prone to release pro-inflammatory cytokines upon stimuli. We demonstrated, using in vitro cell models, that macrophages are responsible for mediating the pro-inflammatory cytokine storm while lung cells support SARS-CoV-2 replication upon viral infection. In this context, cinnamaldehyde administration significantly reduces SARS-CoV-2-related inflammation by inhibiting NLRP3 mediated IL-1β release in both PBMCs and THP-1 macrophages, as well as viral replication in CaLu-3 epithelial cells. Lastly, aerosol-administered cinnamaldehyde was able to significantly reduce IL-1β release in an in vivo lung-inflammatory model. Conclusion The obtained results suggest the possible use of cinnamaldehyde as a co-adjuvant preventive treatment for COVID-19 disease together with vaccination, but also as a promising dietary supplement to reduce, more broadly, viral induced inflammation.

Objective: Chronic obstructive pulmonary disease (COPD) is one of the main causes of morbidity and mortality in the United States. Oxidative stress due to cigarette smoking seems to be one of the major driving mechanisms in COPD pathogenesis. Since the scavenger receptor B1 (SR-B1) appears to play a key role in med iating the uptake for ɑ-tocopherol and other antioxidants in lung tissue, we aimed to investigate its role in COPD pathogenesis. Methods: Lung tissue biopsies were obtained from 12 subjects; 6 of these had a diagnosis of COPD in a stable clinical state, the others 6 were current (n = 1) or ex-smokers (n = 5) with normal lung function (controls). 4-Hydroxynonenal (4-HNE)–SR-B1 adducts were detected by immunoprecipitation. ɑ-tocopherol concentration was determined by HPLC. Results: SR-B1 levels were lower in COPD patients and these results par allel with lower levels of vitamin E in lung tissue found in COPD patients . This effect can be the consequence of oxidative posttranslational modifications, confirmed by the binding of the peroxidation product 4-HNE to SR-B1 possibly leading to its degradation. Conclusions: The loss of SR-B1 may be involved in lung ɑ-tocopherol content decrease with the consequence of making lung tissue more susceptible to oxidative damage as suggested by the SR-B1–4-HNE adduct formation, and more prone to COPD development. Thus, our findings suggest a novel role of SR-B1 in pathomechani sms underlying COPD. Significance statement Chronic obstructive pulmonary disease (COPD) is one of the main causes of morbidity and mortality in the United States. Oxidative stress has been suggested to be the major driving mechanism in COPD pathogenesis. Loss of scavenger receptor BI (SR-B1) significantly decreases tocopherol lung content making lung tissue more susceptible to oxidative damage. The results of our study show that SR-B1 levels were lower in COPD patients and these results parallel with lower levels of vitamin E in lung tissue. Our findings suggest a novel role of SR- B1 in pathomechanisms underlying COPD.

Abstract Background SARS-CoV-2 breakthrough infections (BI) after vaccine booster dose are a relevant public health issue. Methods Multicentric longitudinal cohort study within the ORCHESTRA project, involving 63,516 health workers (HW) from 14 European settings. The study investigated the cumulative incidence of SARS-CoV-2 BI after booster dose and its correlation with age, sex, job title, previous infection, and time since third dose. Results 13,093 (20.6%) BI were observed. The cumulative incidence of BI was higher in women and in HW aged 130 days. Conclusions The risk of BI after booster is significantly reduced by previous infection, heterologous vaccination, and older ages. Immunosuppression is relevant for increased BI incidence. Time elapsed from booster affects BI severity, confirming the public health usefulness of booster. Further research should focus on BI trend after 4th dose and its relationship with time variables across the epidemics.

Abstract Background Pulmonary arterial hypertension (PAH) encompasses a group of diseases characterized by raised pulmonary vascular resistance, resulting from vascular remodelling and inflammation. Bromodomain and extra-terminal (BET) proteins are required for the expression of a subset of NF-κB-induced inflammatory genes which can be inhibited by the BET mimic JQ1+. We hypothesised that JQ+ would supress TNFα-driven inflammatory responses in human pulmonary vascular cells from PAH patients. Methods Immunohistochemical staining of human peripheral lung tissue (N = 14 PAH and N = 12 non-PAH) was performed for the BET proteins BRD2 and 4. Human pulmonary microvascular endothelial cells (HPMEC) and pulmonary artery smooth muscle cells (HPASMC) from PAH patients (N = 4) and non-PAH controls (N = 4) were stimulated with TNFα in presence or absence of JQ1+ or its inactive isomer JQ1–. IL-6 and -8 mRNA was measured by RT-qPCR and protein levels by ELISA. Chromatin immunoprecipitation analysis was performed using EZ-ChIP™ and NF-κB p65 activation determined using a TransAm kit. MTT assay was used to measure cell viability. Results Nuclear staining of BRD2 and BRD4 was significantly (p

Objectives: Bezlotoxumab (BEZ) is a promising tool for preventing the recurrence of Clostridioides difficile infection (rCDI). The aim of the study was to emulate, in a real-world setting, the MODIFY trials in a cohort of participants with multiple risk factors for rCDI treated with BEZ in addition to the standard of care (SoC) versus SoC alone. Methods: A multicenter cohort study was conducted including 442 patients with Clostridioides difficile infection from 2018 to 2022, collected from 18 Italian centers. The main outcome was the 30-day occurrence of rCDI. The secondary outcomes were (i) all-cause mortality at 30 days (ii) and the composite outcome (30-day recurrence and/or all-cause death). Results: rCDI at day 30 occurred in 54 (12%): 11 in the BEZ + SoC group and 43 treated with SoC alone (8% vs 14%, odds ratio [OR] = 0.58, 95% confidence interval [CI]: 0.31-1.09, P = 0.09). The difference between BEZ + SoC versus SoC was statistically significant after controlling for confounding factors (adjusted OR = 0.40, 95% CI: 018-0.88, P = 0.02) and even more using the composite outcome (adjusted OR = 0.35, 95% CI: 0.17-0.73, P = 0.005). Conclusion: Our study confirms the efficacy of BEZ + SoC for the prevention of rCDI and death in a real-world setting. BEZ should be routinely considered among participants at high risk of rCDI regardless of age, type of Clostridioides difficile infection therapy (vancomycin vs fidaxomicin), and number of risk factors.

Within the 9th European Framework programme, since 2021 EUROfusion is operating five tokamaks under the auspices of a single Task Force called ‘Tokamak Exploitation’. The goal is to benefit from the complementary capabilities of each machine in a coordinated way and help in developing a scientific output scalable to future largre machines. The programme of this Task Force ensures that ASDEX Upgrade, MAST-U, TCV, WEST and JET (since 2022) work together to achieve the objectives of Missions 1 and 2 of the EUROfusion Roadmap: i) demonstrate plasma scenarios that increase the success margin of ITER and satisfy the requirements of DEMO and, ii) demonstrate an integrated approach that can handle the large power leaving ITER and DEMO plasmas. The Tokamak Exploitation task force has therefore organized experiments on these two missions with the goal to strengthen the physics and operational basis for the ITER baseline scenario and for exploiting the recent plasma exhaust enhancements in all four devices (PEX: Plasma EXhaust) for exploring the solution for handling heat and particle exhaust in ITER and develop the conceptual solutions for DEMO. The ITER Baseline scenario has been developed in a similar way in ASDEX Upgrade, TCV and JET. Key risks for ITER such as disruptions and run-aways have been also investigated in TCV, ASDEX Upgrade and JET. Experiments have explored successfully different divertor configurations (standard, super-X, snowflakes) in MAST-U and TCV and studied tungsten melting in WEST and ASDEX Upgrade. The input from the smaller devices to JET has also been proven successful to set-up novel control schemes on disruption avoidance and detachment.

This work presents the first analysis of the disruptive locked mode (LM) triggered by the dynamics of a confinement change. It shows that, under certain conditions, the LM threshold during the transient is significantly lower than expected from steady states. We investigate the sensitivity to a controlled n = 1 error field (EF) activated prior to the L-H transition in the COMPASS tokamak, at q _95 ∼ 3, β _N ∼ 1, and using EF coils on the high-field side of the vessel. A threshold for EF penetration subsequent to the L-H transition is identified, which shows no significant trend with density or applied torque, and is an apparent consequence of the reduced intrinsic rotation of the 2/1 mode during this transient phase. This finding challenges the assumption made in theoretical and empirical works that natural mode rotation can be predicted by global plasma parameters and urges against using any parametric EF penetration scaling derived from steady-state experiments to define the EF correction strategy in the entire discharge. Furthermore, even at EFs below the identified penetration threshold, disruptive locking of sawtooth-seeded 2/1 tearing modes is observed after about 30% of L-H transitions without external torque.

This work deals with the analysis of the energy performance and the environmental impact of a Heating, Ventilation and Air Conditioning (HVAC) system based on an innovative Air-to-Water electrical Heat Pump (AWHP) using propane (R290) as the refrigerant. A building of the University of Bologna located in Forlì (North of Italy) is considered for replacing a condensing gas boiler and a conventional chiller with an AWHP using R290. To evaluate the efficiency of the existing heating system and the potential savings linked to the adoption of the propane AWHP, the building energy model was created and calibrated by collecting monthly thermal and electrical consumptions as a function of the actual climate data. In this paper, the main features of the R290-based AWHP are described in detail by emphasising the device performance as a function of the operating conditions (i.e., air and water temperature and speed of the scroll compressor). A series of scenarios have been studied to evaluate the energy performance of the propane AWHP with respect to the reference scenario under various operating conditions. The results show that while the total primary energy demand increases adopting the propane AWHP with respect to the case of a gas boiler, the non-renewable primary energy fraction decreases significantly, with a dramatic increase in the renewable quote. From an economic point of view, lower annual costs are obtained by adopting a propane AWHP coupled to fan coils, mainly when the electrical heat pump is used in a thermally insulated building in which a photovoltaic system is installed.

Mitochondrial metabolism has been associated with tumourigenesis in acute myeloid leukaemia (AML) and currently considered as a potential therapeutic target. Here, the authors show, in patients with AML, that germline mutations in mitochondrial complex I are mutually exclusive with somatic mutations in the metabolic enzyme IDH1, and find IDH1 mutant cells have increased sensitivity to complex I inhibitors.

Introduction: The impact of long-COVID-19 syndrome is rather variable, since it is influenced by several residual confounders. This study aimed to investigate the prevalence of long COVID-19 in healthcare workers (HCWs) from four university hospitals in north-eastern Italy: Trieste, Padua, Verona, and Modena-Reggio Emilia. Methods: During the period June 2022–August 2022, HCWs were surveyed for past COVID-19 infections, medical history, and any acute as well as post-COVID-19 symptoms. The prevalence of long COVID-19 was estimated at 30–60 days or 61+ days since first negative swab following first and second COVID-19 episode. Furthermore, the risk of long COVID-19 was investigated by multivariable logistic regression. Results were expressed as the adjusted odds ratio (aOR) with a 95% confidence interval (95%CI). Results: 5432 HCWs returned a usable questionnaire: 2401 were infected with SARS-CoV-2 at least once, 230 were infected at least twice, and 8 were infected three times. The prevalence of long COVID-19 after a primary COVID-19 infection was 24.0% at 30–60 days versus 16.3% at 61+ days, and 10.5% against 5.5% after the second SARS-CoV-2 event. The most frequent symptoms after a first COVID-19 event were asthenia (30.3%), followed by myalgia (13.7%), cough (12.4%), dyspnea (10.2%), concentration deficit (8.1%), headache (7.3%), and anosmia (6.5%), in decreasing order of prevalence. The risk of long COVID-19 at 30–60 days was significantly higher in HCWs hospitalized for COVID-19 (aOR = 3.34; 95%CI: 1.62; 6.89), those infected with SARS-CoV-2 during the early pandemic waves—namely the Wuhan (aOR = 2.16; 95%CI: 1.14; 4.09) or Alpha (aOR= 2.05; 95%CI: 1.25; 3.38) transmission periods—and progressively increasing with viral shedding time (VST), especially 15+ days (aOR = 3.20; 95%CI: 2.07; 4.94). Further determinants of long COVID-19 at 30–60 days since primary COVID-19 event were female sex (aOR = 1.91; 95%CI: 1.30; 2.80), age >40 years, abnormal BMI, or administrative services (reference category). In contrast, HCWs vaccinated with two doses before their primary infection (aOR = 0.57; 95%CI: 0.34; 0.94), undergraduate students, or postgraduate medical trainees were less likely to experience long COVID-19 at 30–60 days. Apart from pandemic waves, the main determinants of long COVID-19 at 30–60 days were confirmed at 61+ days. Conclusions: The risk of long COVID-19 following primary infection increased with the severity of acute disease and VST, especially during the initial pandemic waves, when more virulent viral strains were circulating, and susceptibility to SARS-CoV-2 was higher since most HCWs had not been infected yet, COVID-19 vaccines were still not available, and/or vaccination coverage was still building up. The risk of long COVID-19 therefore decreased inversely with humoral immunity at the individual level. Nevertheless, the prevalence of long COVID-19 was remarkably lower after SARS-CoV-2 reinfections regardless of vaccination status, suggesting that hybrid humoral immunity did not increase protection against the syndrome compared to immunity mounted by either natural infection or vaccination separately. Since the risk of long COVID-19 is currently low with Omicron and patients who developed the syndrome following SARS-CoV-2 infection in the early pandemic waves tend to return to a state of full health with time, a cost-effective approach to screen post-COVID-19 symptoms during the Omicron time could be restricted to vulnerable individuals developing severe disease and/or with prolonged VST.

Dalbavancin represents a promising treatment for cardiovascular prosthetic infections due to its prolonged half-life, bactericidal activity, large spectrum of activity, and excellent biofilm penetration. However, the use of dalbavancin in this setting is limited, and only a few cases have performed therapeutic drug monitoring (TDM) analysis to optimize dosage in suppressive treatments longer than 4 weeks. Our retrospective case series reports the use of dalbavancin in a small cohort of patients with cardiovascular prosthetic infections (cardiac implantable electronic device infections (CEDIs), prosthetic valve endocarditis (PVE), prosthetic vascular graft infections (PVGIs)) treated with dalbavancin as sequential therapy. From May 2019 to May 2023, 14 patients were included: eight cases of PVE (57.1%), seven cases of PVGI (50%), three cases of CEDI (21.4%), and four cases with overlap of infection sites (28.6%). The main pathogen was Staphylococcus aureus (35.7%). Prosthesis replacement was obtained in four patients (28.6%). The median time between symptom onset and the end of treatment was 15 weeks (IQR 7–53), with a median duration of dalbavancin therapy of 8 weeks (IQR 1 to 45 weeks) and 3.5 doses per patient. Among patients managed with TDM-guided strategy, dalbavancin infusion intervals ranged from 4 to 9 weeks. The median length of follow-up was 65 weeks (IQR 23 to 144 weeks). Clinical success was achieved in 10 cases (76.9%); all clinical failures occurred in patients with the implant retained. Among patients monitored by TDM, clinical success was 87.5% vs. 60% in patients treated without TDM. Because of pharmacokinetic individual variability, dalbavancin TDM-guided administration could improve clinical outcomes by individualizing dosing and selecting dosing intervals. This case series seems to suggest a promising role of long-term suppressive dalbavancin treatment for difficult-to-treat cardiovascular prosthesis infection, also with limited surgical indications.

The present paper reports a new application: the voltammetric determination in herbal medicines of ultra-trace thallium(I), in the presence of lead(II), tin(II) and antimony(III) as interfering metals, by square wave anodic stripping voltammetry (SWASV). A conventional three-electrodes voltammetric cell was employed with a stationary hanging mercury drop electrode (HMDE) as working electrode and a platinum electrode and an Ag|AgCl|KClsatd. electrode as auxiliary and reference electrodes, respectively. The supporting electrolyte was 0.5 mol L−1 ammonium citrate buffer pH 6.5 + 7.3·10−3 mol L−1 EDTA-Na2. The analytical procedure was verified by the analysis of the standard reference materials: spinach Leaves NIST-SRM 1570a and tomato leaves NIST-SRM 1573a from National Institute of Standards and Technology. Precision and trueness, expressed as relative standard deviation and relative error, respectively, were generally lower than 7% in all cases. Once set up on the standard reference materials, the analytical procedure was transferred and applied to herbal medicines samples—Taraxacun officinale weber, Eucalyptus globulus and Harpagophytum procumbens DC—sold on the market. A critical comparison with spectroscopic measurements is also discussed.

Radial transport of runaway electrons (REs) in tokamaks is affected by the presence of magnetic perturbations, either caused by internal magnetohydrodynamic instabilities or induced by external coils. The magnetic field configuration inside the plasma volume consists in general of intact magnetic surfaces alternated with magnetic islands and stochastic layers, which make the usual diffusive approach, based on the Rechester–Rosenbluth formula, inadequate to the study of transport. Here the fractional diffusion approach is employed to model RE transport in presence of intrinsic magnetic perturbations (magnetic islands) in the flat-top phase of RE-dedicated discharges on COMPASS tokamak. The character of RE transport is found to be subdiffusive. The degree of subdiffusion is evaluated by running simulations with the ORBIT code and a time-fractional diffusion equation is applied to calculate the time evolution of RE particle number. The results are compared with the observed RE losses, estimated from the time integrated neutron signal.

Indole-containing acyloins are either key intermediates of many antimicrobial/antiviral natural products or building blocks in the synthesis of biologically active molecules. As such, access to structurally diverse indole-containing acyloins has attracted considerable attention. In this report, we present a pilot study of using biotransformation to provide acyloins that contain various indole substituents. The biotransformation system contains the tryptophan synthase standalone β-subunit variant, PfTrpB6, generated from directed evolution in the literature; a commercially available L-amino acid oxidase (LAAO); and the thiamine-diphosphate (ThDP)-dependent enzyme NzsH, encoded in the biosynthetic gene cluster (nzs) of the bacterial carbazole alkaloid natural product named neocarazostatin A. The utilization of the first two enzymes, the PfTrpB variant and LAAO, is designed to provide structurally diverse indole 3-pyruvate derivatives as donor substrates for NzsH-catalysed biotransformation to provide acyloin derivatives. Our results demonstrate that NzsH displays a considerable substrate profile toward donor substrates for production of acyloins with different indole ring systems, suggesting that NzsH could be further explored as a potential biocatalyst via directed evolution to improve the catalytic efficiency in the future.

Introduction: Abdominoplasty involves not only aesthetic characteristics but abdominal wall structural reconstruction. This study aimed to illustrate the authors' experience with abdominoplasty, focusing on the scar's aesthetic results and the evolution of application of the block resection technique of Professor Ronaldo Pontes (RP). Methods: The study included a series of retrospective cases of 124 patients treated between March 2014 and March 2017 who underwent RP block abdominoplasty. Results: In our studies, a minimal incidence of complications and a small number of healing alterations were noted with the RP block technique compared to those found in the literature. Conclusion: A técnica descrita e suas variantes atendem a necessidade de diversos tipos de casos e garantem cirurgias seguras e eficazes, com resultados muito satisfatórios, sendo uma técnica reprodutível.

Conocer al autor de una obra nos permite entenderla mejor, por esto nos hemos acercado a Andrés García de Céspedes no sólo a través de los autores que lo han estudiado, sino también de las fuentes directas. Él trabajó en el campo de las ciencias siendo matemático, cosmógrafo y astrónomo; también fue inventor y artífice de instrumentos astronómicos y matemáticos. Además, fue Piloto Mayor de la Casa de la Contratación de Sevilla, Cosmógrafo Mayor del Consejo de Indias, clérigo y supuestamente capitán. A través de los siglos su controvertida personalidad y calidad de sus obras han contrapuesto las opiniones de expertos. Su tenacidad y metodología, que lo llevaron algunas veces a apropiarse de ideas de otros cosmógrafos e inclusive a adjudicarse obras que no eran suyas, le permitieron lograr un reconocimiento en la historia de la navegación. Abstract Knowing the author of a work allows us to understand it better. This is why we have approached Andrés García de Céspedes, not only through the authors who have studied him, but also from the primary sources. He worked intensely in the field of sciences being a mathematician, cosmographer and astronomer. He was also the inventor and architect of astronomical and mathematical instruments. In addition, he was a Major Pilot of the House of Trade of Seville, Major Cosmographer of the Council of Indies, cleric and captain. Over the centuries his controversial personality and the quality of his works have contrasted the opinions of several experts. His tenacity and methodology, which sometimes led him to appropriate the ideas of other cosmographers and even by awarding works that were not his own, allowed him to achieve recognition in the history of navigation.

Al acercarnos al manuscrito del Regimiento de tomar la altura del polo en la mar y cosas tocantes a la navegación observamos dos tipos de caligrafía, lo cual representaba un posible problema de autoría. Además, en la obra se encuentran detalles que nos hicieron pensar que era un texto interpo-lado y en cuatro folios hay una rúbrica que inicialmente la atribuimos al autor; otro aspecto que nos llamaba la atención era la alteración de la fecha que aparece en la portada. Decidimos analizar el manuscrito con la finalidad de formular una explicación a estos hallazgos, te-niendo como objetivo principal comprobar la autoría de la obra; para ello primero necesitábamos iden-tificar la escritura de A. García de Céspedes y los capítulos escritos por él, por tanto era determinante distinguir sus rasgos caligráficos. Para los objetivos propuestos, procedimos con la única alternativa metodológica para este caso: comparar otros manuscritos del autor y de algunos cosmógrafos y pilotos mayores anteriores y contemporáneos a él. A través del estudio se ha podido individuar el texto que él escribió, confirmar que el regimiento es un libro escrito a dos manos con capítulos interpolados por el mismo autor y que el contenido de varios de ellos refleja la influencia de otros expertos. También hemos descubierto que el texto base se redactó cuatro años antes de la fecha que aparece en la portada y hemos podido comprobar que la rúbrica no es suya. Además de las conclusiones antes señaladas, el estudio nos ha ofrecido un resultado inesperado: un manuscrito que está registrado con el nombre de García de Céspedes no fue escrito por él, éste sería el tercero, ya que otros investigadores indicaron dos obras hace algunos años.

Background: The research aimed to investigate the incidence of SARS-CoV-2 breakthrough infections and their determinants in a large European cohort of more than 60,000 health workers. Methods: A multicentric retrospective cohort study, involving 12 European centers, was carried out within the ORCHESTRA project, collecting data up to 18 November 2021 on fully vaccinated health workers. The cumulative incidence of SARS-CoV-2 breakthrough infections was investigated with its association with occupational and social–demographic characteristics (age, sex, job title, previous SARS-CoV-2 infection, antibody titer levels, and time from the vaccination course completion). Results: Among 64,172 health workers from 12 European health centers, 797 breakthrough infections were observed (cumulative incidence of 1.2%). The primary analysis using individual data on 8 out of 12 centers showed that age and previous infection significantly modified breakthrough infection rates. In the meta-analysis of aggregated data from all centers, previous SARS-CoV-2 infection and the standardized antibody titer were inversely related to the risk of breakthrough infection (p = 0.008 and p = 0.007, respectively). Conclusion: The inverse correlation of antibody titer with the risk of breakthrough infection supports the evidence that vaccination plays a primary role in infection prevention, especially in health workers. Cellular immunity, previous clinical conditions, and vaccination timing should be further investigated.

La endocarditis infecciosa (EI) es una enfermedad poco frecuente pero severa, dada por una infección del endocardio. La incidencia anual oscila entre 3 y 7 por cada 100 000 personas-año, con una tasa de mortalidad general del 25%. Los estafilococos y los estreptococos representaron aproximadamente un 80% de los casos de EI. Los enterococos son la tercera causa, aportando aproximadamente 5% a 18% de todos los casos, y se vinculan cada vez más al contacto con la atención médica. El número creciente de dispositivos electrónicos cardiovasculares e implantes de válvulas protésicas, junto con los frecuentes procedimientos invasivos diagnósticos o terapéuticos en las personas ancianas, también podrían contribuir al incremento de EI en esta población. Los hemocultivos y los hallazgos ecocardiográficos son la piedra angular del diagnóstico de EI, confirmado o rechazado de acuerdo con los criterios modificados de Duke. Otras modalidades de imagenología tales como la Tomografía Computarizada Cardíaca (TCC), la Resonancia Magnética Cardíaca (RMC) y la Tomografía por Emisión de Positrones – Tomografía Computarizada con 18F-fluorodeoxiglucosa (18F-FDG PET/TC) pueden determinar un diagnóstico más preciso e identificar muchas de las complicaciones asociadas a la endocarditis. Aquí describimos un paciente con una válvula aórtica protésica y EI por EF. Una RM del cerebro y la columna vertebral y una 18F-FDG PET/TC practicadas durante la hospitalización evidenciaron embolia periférica multiorgánica silenciosa. Además, el examen por cultivo de la muestra quirúrgica valvular reveló Staphylococcus aureus sensible a la meticilina (SASM), sugestivo de endocarditis polimicrobiana. Algunos autores demostraron un posible falso positivo del cultivo valvular dado por contaminación postoperatoria. Ya que los cultivos contaminados generalmente producen microorganismos compatibles con la endocarditis, tales como estafilococos coagulasa negativos y estreptococos del grupo viridans, le puede resultar difícil al médico no tratar al paciente. Este caso representa la necesidad de tener un alto nivel de sospecha para diagnosticar la EI. La valoración multimodal mejora el diagnóstico y permite detectar complicaciones. Además, un equipo multidisciplinario y los centros especializados determinan un mejor desenlace para el paciente.

Introduction Cigarette smoking and oxidative stress are common risk factors for the multi-morbidities associated with chronic obstructive pulmonary disease (COPD). Elevated levels of advanced glycation endproducts (AGE) increase the risk of cardiovascular disease (CVD) comorbidity and mortality. The enzyme fructosamine-3-kinase (FN3K) reduces this risk by lowering AGE levels.Methods The distribution and expression of FN3K protein in lung tissues from stable COPD and control subjects, as well as an animal model of COPD, was assessed by immunohistochemistry. Serum FN3K protein and AGE levels were assessed by ELISA in patients with COPD exacerbations receiving metformin. Genetic variants within the FN3K and FN3K-RP genes were evaluated for associations with cardiorespiratory function in the Subpopulations and Intermediate Outcome Measures in COPD Study cohort.Results This pilot study demonstrates that FN3K expression in the blood and human lung epithelium is distributed at either high or low levels irrespective of disease status. The percentage of lung epithelial cells expressing FN3K was higher in control smokers with normal lung function, but this induction was not observed in COPD patients nor in a smoking model of COPD. The top five nominal FN3K polymorphisms with possible association to decreased cardiorespiratory function (p

Advances in nanotechnology have opened up new horizons in nanomedicine through the synthesis of new composite nanomaterials able to tackle the growing drug resistance in bacterial strains. Among these, nanosilver antimicrobials sow promise for use in the treatment of bacterial infections. The use of polydopamine (PDA) as a biocompatible carrier for nanosilver is appealing; however, the synthesis and functionalization steps used to obtain Ag-PDA nanoparticles (NPs) are complex and require time-consuming cleanup processes. Post-synthesis treatment can also hinder the stability and applicability of the material, and dry, offline characterization is time-consuming and unrepresentative of real conditions. The optimization of Ag-PDA preparation and purification together with well-defined characterization are fundamental goals for the safe development of these new nanomaterials. In this paper, we show the use of field-flow fractionation with multi-angle light scattering and spectrophotometric detection to improve the synthesis and quality control of the production of Ag-PDA NPs. An ad hoc method was able to monitor particle growth in a TLC-like fashion; characterize the species obtained; and provide purified, isolated Ag-PDA nanoparticles, which proved to be biologically active as antibacterial agents, while achieving a short analysis time and being based on the use of green, cost-effective carriers such as water.

Bioindicator plants are species that have the capacity to linearly uptake some elements (metal and metalloids) from the growing substrate, thus reflecting their concentration in the soil. Many factors can influence the uptake of these elements by plants, among which is the simultaneous presence of several metals, a common situation in contaminated or natural soils. A novel approach that can be used to validate the bioindication ability of a species growing on a polymetallic substrate is the design of experiment (DoE) approach. The aim of the present study was to apply the DoE in full factorial mode to model the Cu, Cd, Pb, Zn, and Cr bioindication capacity of Polygonum aviculare, used as the model plant. The results showed that P. aviculare has the ability to bioindicate Cd and Cr with a linear uptake (from 0.35 to 6.66, and 0.1 to 3.4 mg kg−1, respectively) unaffected by the presence of other metals. Conversely, the uptake of Pb, Cu, and Zn is strongly influenced by the presence of all the studied metals, making their concentration in the plant shoot not proportional to that of the soil. In conclusion, these preliminary results confirmed that the DoE can be used to predict the bioindicator abilities of a plant for several elements at the same time and to evaluate the interactions that can be established between variables in the growing medium and in the plant itself. However, more studies including other plant species are needed to confirm the effectiveness of this method.

Introduction: Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) assessment is mandatory for the single agent pembrolizumab treatment of patients with advanced non-small cell lung cancer (NSCLC). PD-L1 testing has been validated and is currently certified only on formalin-fixed paraffin-embedded materials but not on cytological smears. Unfortunately, a significant proportion of patients, having only cytological material available, cannot be tested for PD-L1 and treated with pembrolizumab. In this study, we aimed to validate PD-L1 IHC on cytological smears prospectively by comparing clone SP263 staining in 150 paired histological samples and cytological smears of NSCLC patients. Methods: We prospectively enrolled 150 consecutive advanced NSCLC patients. The clone SP263 was selected as, in a previous study of our group, it showed higher accuracy compared with clones 28-8 and 22-C3, with good cyto-histological agreement using a cut-off of 50%. For cyto-histological concordance, we calculated the kappa coefficient using two different cut-offs according to the percentage of PD-L1 positive neoplastic cells (

Luca Ricciardi,1,* Jessica Dal Col,1,* Paolo Casolari,2 Domenico Memoli,1 Valeria Conti,1 Alessandro Vatrella,1 Becky M Vonakis,3 Alberto Papi,2 Gaetano Caramori,4 Cristiana Stellato1,3 1Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Salerno, Italy; 2Interdipartimental Study Center for Inflammatory and Smoke-related Airway Diseases (CEMICEF), Cardiorespiratory and Internal Medicine Section, University of Ferrara, Ferrara, Italy; 3Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 4Department of Biomedical Sciences, Dentistry and Morphological and Functional Imaging (BIOMORF), University of Messina, Messina, Italy *These authors contributed equally to this work Purpose: Inflammatory gene expression is modulated by posttranscriptional regulation via RNA-binding proteins (RBPs), which regulate mRNA turnover and translation by binding to conserved mRNA sequences. Their role in COPD is only partially defined. This study evaluated RBPs tristetraprolin (TTP), human antigen R (HuR), and AU-rich element-binding factor 1 (AUF-1) expression using lung tissue from COPD patients and control subjects and probed their function in epithelial responses in vitro. Patients and methods: RBPs were detected by immunohistochemistry in bronchial and peripheral lung samples from mild-to-moderate stable COPD patients and age/smoking history-matched controls; RBPs and RBP-regulated genes were evaluated by Western blot, ELISA, protein array, and real-time PCR in human airway epithelial BEAS-2B cell line stimulated with hydrogen peroxide, cytokine combination (cytomix), cigarette smoke extract (CSE), and following siRNA-mediated silencing. Results were verified in a microarray database from bronchial brushings of COPD patients and controls. RBP transcripts were measured in peripheral blood mononuclear cell samples from additional stable COPD patients and controls. Results: Specific, primarily nuclear immunostaining for the RBPs was detected in structural and inflammatory cells in bronchial and lung tissues. Immunostaining for AUF-1, but not TTP or HuR, was significantly decreased in bronchial epithelium of COPD samples vs controls. In BEAS-2B cells, cytomix and CSE stimulation reproduced the RBP pattern while increasing expression of AUF-1-regulated genes, interleukin-6, CCL2, CXCL1, and CXCL8. Silencing expression of AUF-1 reproduced, but not enhanced, target upregulation induced by cytomix compared to controls. Analysis of bronchial brushing-derived transcriptomic confirmed the selective decrease of AUF-1 in COPD vs controls and revealed significant changes in AUF-1-regulated genes by genome ontology. Conclusion: Downregulated AUF-1 may be pathogenic in stable COPD by altering posttranscriptional control of epithelial gene expression. Keywords: airway epithelium, AUF-1, COPD, inflammation, posttranscriptional gene regulation

Communal strife is one of the most noteworthy political phenomenon in India at present. Since the Bharatiya Janata Party’s (BJP) return to power in 2014 India’s political climate worsened: attacks on religious minorities, in particular Muslims, and low caste members are the order of the day. At the same time, the relations between India and Pakistan are at one of their most critical stages: in February 2019 indeed a fifth Indo-Pakistani war almost broke out and thereafter the relations between the two countries are very tense. Communalism in India dates back to the colonial times. Subsequent failures to resolve the problem of an increasing enmity between Hindu and Muslim community led to India’s partition and to recurrent riots within the country. Communalism is often ascribed to religious causes, whereas religion is just a powerful mobilization tool. This essay aims to prove that the causes of apparently religious conflicts are economic, social and political. This applies in particular to India, as a strongly multiethnic country, but to any other multiethnic context as well. In order to fight communalism, its real causes should be addressed.

Abstract Backbround COPD is a common, highly debilitating disease of the airways, primarily caused by smoking. Chronic inflammation and structural remodelling are key pathological features of this disease caused, in part, by the aberrant function of airway smooth muscle (ASM). We have previously demonstrated that hydrogen sulfide (H2S) can inhibit ASM cell proliferation and CXCL8 release, from cells isolated from non-smokers. Methods We examined the effect of H2S upon ASM cells from COPD patients. ASM cells were isolated from non-smokers, smokers and patients with COPD (n = 9). Proliferation and cytokine release (IL-6 and CXCL8) of ASM was induced by FCS, and measured by bromodeoxyuridine incorporation and ELISA, respectively. Results Exposure of ASM to H2S donors inhibited FCS-induced proliferation and cytokine release, but was less effective upon COPD ASM cells compared to the non-smokers and smokers. The mRNA and protein expression of the enzymes responsible for endogenous H2S production (cystathionine-β-synthase [CBS] and 3-mercaptopyruvate sulphur transferase [MPST]) were inhibited by H2S donors. Finally, we report that exogenous H2S inhibited FCS-stimulated phosphorylation of ERK–1/2 and p38 mitogen activated protein kinases (MAPKs), in the non-smoker and smoker ASM cells, with little effect in COPD cells. Conclusions H2S production provides a novel mechanism for the repression of ASM proliferation and cytokine release. The ability of COPD ASM cells to respond to H2S is attenuated in COPD ASM cells despite the presence of the enzymes responsible for H2S production.

Background: Hop cultivation requires an abundant quantity of nutrients to reach higher cone yield and quality. The aim of this work was the evaluation of different fertilization plans to obtain an improvement in product quality. Methods: Foliar analysis, anatomical analysis through the use of light microscope and SEM; physiological measurements through atLEAF, Handy PEA and spectrophotometry, were carried out to determine chlorophyll content, carotenoids and photosynthetic efficiency in two periods (t1, t2) for four experimental treatments and a Control (Treat 1, Treat 2, Treat 3, Treat 4, Untreat). Leaf texture (texture analyzer), color (colorimeter), DPPH activity (spectrophotometer), bitter acid content (HPLC-UV) and essential oil yields (steam distillation) and cone yields were measured. Results: Treat 2 showed the best performance: (i) in leaves, in terms of texture, chlorophyll content and color; (ii) in cones, with 6.98% of alpha acids, 1.78% of oil yield and 3.55 kg of fresh cones per plants. Conclusion: The fertilization plans caused alteration in micro and macro elements content in hop leaves and in the composition of hop cones. In our conditions, the best fertilization plan, in terms of cone productivity and quality, was Treat 2, highlighting the value of a customized organic foliar fertilization plan for hop cultivation.

Abstract We describe a novel ERBB1/EGFR somatic mutation (p. C329R; c.985 T > C) identified in a patient with JAK2V617F Polycythaemia Vera (PV). This substitution affects a conserved cysteine residue in EGFR domain 2 and leads to the formation of a ligand-independent covalent receptor dimer, associated with increased transforming potential. Aberrant signalling from the EGFRC329R receptor is cell type-dependent and in the TF1.8 erythroid cell line expression of this mutant suppresses EPO-induced differentiation. Clonal analysis shows that the dominant JAK2V617F-positive clone in this PV patient harbors EGFRC329R, thus this mutation may contribute to clonal expansion. Somatic mutations affecting other ERBB and related receptor tyrosine kinases are observed in myeloproliferative neoplasms (MPN), and we show elevated EGFR levels in MPN samples, consistent with previous reports. Thus activation of this group of receptors, via multiple mechanisms, may contribute to clonal growth and survival of the JAK2V617F disease clone in MPN.

Marine endophytic fungi from under-explored locations are a promising source for the discovery of new bioactivities. Different endophytic fungi were isolated from plants and marine organisms collected from Wadi El-Natrun saline lakes and the Red Sea near Hurghada, Egypt. The isolated strains were grown on three different media, and their ethyl acetate crude extracts were evaluated for their antimicrobial activity against a panel of pathogenic bacteria and fungi as well as their antioxidant properties. Results showed that most of the 32 fungal isolates initially obtained possessed antimicrobial and antioxidant activities. The most potent antimicrobial extracts were applied to three different cellulose containing fabrics to add new multifunctional properties such as ultraviolet protection and antimicrobial functionality. For textile safety, the toxicity profile of the selected fungal extract was evaluated on human fibroblasts. The 21 strains displaying bioactivity were identified on molecular basis and selected for chemical screening and dereplication, which was carried out by analysis of the MS/MS data using the Global Natural Products Social Molecular Networking (GNPS) platform. The obtained molecular network revealed molecular families of compounds commonly produced by fungal strains, and in combination with manual dereplication, further previously reported metabolites were identified as well as potentially new derivatives.

Immune checkpoint inhibitors (ICPIs) are considered one of the most important breakthroughs in cancer treatment of the past decade; notably, different studies of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have reported impressive clinical activity and durable responses in patients with advanced non-small cell lung cancer (NSCLC). These findings have led to the changing of the current therapeutic algorithm of advanced NSCLC, adding a new standard first-line treatment option for patients with PD-L1-positive tumors. Pembrolizumab, a highly selective anti-PD-1 humanized monoclonal antibody, was approved by the United States Food and Drug Administration (US FDA) in October 2016 for previously untreated metastatic NSCLC patients whose tumors have high PD-L1 expression, tumor proportion score (TPS) ⩾ 50%, as well as for metastatic NSCLC patients whose tumors express PD-L1 with TPS ⩾ 1% progressing on or after platinum-based chemotherapy. However, many issues remain outstanding, mainly regarding the identification of an optimal biomarker which can help selecting patients more likely to respond to ICPIs. In this review, we discuss the clinical results obtained so far with the anti-PD-1 pembrolizumab in advanced NSCLC, commenting on the role of PD-L1 as a predictive factor and providing an update of the future perspectives.

In recent years, heavy metals (HMs) levels in soil and vegetation have increased considerably due to traffic pollution. These pollutants can be taken up from the soil through the root system. The ability of plants to accumulate HMs into their tissues can therefore be used to monitor soil pollution. The aim of this study was to test the ruderal species Senecio vulgaris L., Polygonum aviculare L., and Poa annua L., as possible candidates for biomonitoring Cu, Zn, Cd, Cr, Ni and Pb in multiple environments. The soils analyzed in this work came from three different environments (urban, woodland, and ultramafic), and therefore deeply differed for their metal content, texture, pH, and organic matter (OM) content. All urban soils were characterized by high OM content and presence of anthropogenic metals like Pb, Zn, Cd, and Cu. Woodland soils were sandy and characterized by low metal content and low OM content, and ultramafic soils had high Ni and Cr content. This soil variability affected the bioindication properties of the three studied species, leading to the exclusion of most metals (Zn, Cu, Cr, Cd, and Pb) and one species (P. aviculare) due to the lack of linear relations between metal in soil and metal in plants. Senecio vulgaris and Poa annua, conversely, appeared to be good indicators of Ni in all the soils tested. A high linear correlation between total Ni in soil and Ni concentration in P. annua shoots (R2 = 0.78) was found and similar results were achieved for S. vulgaris (R2 = 0.88).

3D cylindrical layered scaffolds with anisotropic mechanical properties were prepared according to a new and simple method, which involves gelatin foaming, deposition of foamed strips, in situ crosslinking, strip rolling and lyophilization. Different genipin concentrations were tested in order to obtain strips with different crosslinking degrees and a tunable stability in biological environment. Before lyophilization, the strips were curled in a concentric structure to generate anisotropic spiral-cylindrical scaffolds. The scaffolds displayed significantly higher values of stress at break and of the Young modulus in compression along the longitudinal than the transverse direction. Further improvement of the mechanical properties was achieved by adding strontium-substituted hydroxyapatite (Sr-HA) to the scaffold composition and by increasing genipin concentration. Moreover, composition modulated also water uptake ability and degradation behavior. The scaffolds showed a sustained strontium release, suggesting possible applications for the local treatment of abnormally high bone resorption. This study demonstrates that assembly of layers of different composition can be used as a tool to obtain scaffolds with modulated properties, which can be loaded with drugs or biologically active molecules providing properties tailored upon the needs.

Abstract The importance of NF‐κB activation and deficient anti‐viral interferon induction in the pathogenesis of rhinovirus‐induced asthma exacerbations is poorly understood. We provide the first in vivo evidence in man and mouse that rhinovirus infection enhanced bronchial epithelial cell NF‐κB p65 nuclear expression, NF‐κB p65 DNA binding in lung tissue and NF‐κB‐regulated airway inflammation. In vitro inhibition of NF‐κB reduced rhinovirus‐induced pro‐inflammatory cytokines but did not affect type I/III interferon induction. Rhinovirus‐infected p65‐deficient mice exhibited reduced neutrophilic inflammation, yet interferon induction, antiviral responses and virus loads were unaffected, indicating that NF‐κB p65 is required for pro‐inflammatory responses, but redundant in interferon induction by rhinoviruses in vivo. Conversely, IFNAR1−/− mice exhibited enhanced neutrophilic inflammation with impaired antiviral immunity and increased rhinovirus replication, demonstrating that interferon signalling was critical to antiviral immunity. We thus provide new mechanistic insights into rhinovirus infection and demonstrate the therapeutic potential of targeting NF‐κB p65 (to suppress inflammation but preserve anti‐viral immunity) and type I IFN signalling (to enhance deficient anti‐viral immunity) to treat rhinovirus‐induced exacerbations of airway diseases. See accompanying article http://dx.doi.org/10.1002/emmm.201202032

Most breast cancer risk factors are associated with prolonged exposure of the mammary gland to high levels of estrogens. The actions of estrogens are predominantly mediated by two receptors, ERα and ERβ, which act as transcription factors binding with high affinity to estrogen response elements in the promoter region of target genes. However, most target genes do not contain the consensus estrogen response elements, but rather degenerated palindromic sequences showing one or more mutations and other ER-binding sites such as AP-1 and SP-1. Using the differential display reverse transcription-polymerase chain reaction technique, our group identified several genes differentially expressed in normal tissue and in ER-positive and ER-negative primary breast tumors. One of the genes shown to be down-regulated in breast tumors compared to normal breast tissue was the PHLDA1 (Pleckstrin homology-like domain, family A, member 1). In the present study, we investigated the potential of PHLDA1 to be regulated by estrogen via ER in MCF-7 breast cancer cells. The promoter region of PHLDA1 shows an imperfect palindrome, an AP-1- and three SP-1-binding sites potentially regulated by estrogens. We also assessed the effects of 17β-estradiol on PHLDA1 mRNA expression in MCF-7 breast cancer cells. MCF-7 cells exposed to 10 nM 17β-estradiol showed more than 2-fold increased expression of the PHLDA1 transcripts compared to control cells (P = 0.05). The anti-estrogen ICI 182,780 (1 µM) inhibited PHLDA1 mRNA expression and completely abolished the effect of 10 nM 17β-estradiol on PHLDA1 expression (P < 0.05), suggesting that PHLDA1 is regulated by estrogen via ER.

Most breast cancer risk factors are associated with prolonged exposure of the mammary gland to high levels of estrogens. The actions of estrogens are predominantly mediated by two receptors, ERα and ERβ, which act as transcription factors binding with high affinity to estrogen response elements in the promoter region of target genes. However, most target genes do not contain the consensus estrogen response elements, but rather degenerated palindromic sequences showing one or more mutations and other ER-binding sites such as AP-1 and SP-1. Using the differential display reverse transcription-polymerase chain reaction technique, our group identified several genes differentially expressed in normal tissue and in ER-positive and ER-negative primary breast tumors. One of the genes shown to be down-regulated in breast tumors compared to normal breast tissue was the PHLDA1 (Pleckstrin homology-like domain, family A, member 1). In the present study, we investigated the potential of PHLDA1 to be regulated by estrogen via ER in MCF-7 breast cancer cells. The promoter region of PHLDA1 shows an imperfect palindrome, an AP-1- and three SP-1-binding sites potentially regulated by estrogens. We also assessed the effects of 17β-estradiol on PHLDA1 mRNA expression in MCF-7 breast cancer cells. MCF-7 cells exposed to 10 nM 17β-estradiol showed more than 2-fold increased expression of the PHLDA1 transcripts compared to control cells (P = 0.05). The anti-estrogen ICI 182,780 (1 µM) inhibited PHLDA1 mRNA expression and completely abolished the effect of 10 nM 17β-estradiol on PHLDA1 expression (P < 0.05), suggesting that PHLDA1 is regulated by estrogen via ER.

Background. Inhalation of thermal water with antioxidant properties is empirically used for COPD. Aims. To evaluate the effects of sulphurous thermal water (reducing agents) on airway oxidant stress and clinical outcomes in COPD. Methods. Forty moderate-to-severe COPD patients were randomly assigned to receive 12-day inhalation with sulphurous thermal water or isotonic saline. Patients were assessed for superoxide anion (O2-) production in the exhaled breath condensate and clinical outcomes at recruitment, the day after the conclusion of the 12-day inhalation treatment, and one month after the end of the inhalation treatment. Results. Inhalation of reducing agents resulted in a significant reduction of O2- production in exhaled breath condensate of COPD patients at the end of the inhalatory treatment and at followup compared to baseline. A significant improvement in the COPD assessment test (CAT) questionnaire was shown one month after the end of the inhalatory treatment only in patients receiving sulphurous water. Conclusion. Thermal water inhalation produced an in vivo antioxidant effect and improvement in health status in COPD patients. Larger studies are required in order to evaluate whether inhalation of thermal water is able to modify relevant clinical outcomes of the disease (the study was registered at clinicaltrial.gov—identifier: NCT01664767).

To assess activation of the inflammatory transcription factor NF-kappa B (NF-κB) in human idiopathic pulmonary arterial hypertension (PAH).Idiopathic PAH is a severe progressive disease characterized by pulmonary vascular remodeling and excessive proliferation of vascular cells. Increasing evidence indicates that inflammation is important in disease pathophysiology.NF-κB-p65 and CD68, CD20 and CD45 were measured by immunohistochemistry and confocal microscopy on lung specimens from patients with idiopathic PAH (n = 12) and controls undergoing lung surgery (n = 14). Clinical data were recorded for all patients including invasive pulmonary hemodynamics for the PAH patients. Immunohistochemical images were analyzed by blinded observers to include standard pulmonary vascular morphometry; absolute macrophage counts/mm(2) and p65-positivity (p65+) using composite images and image-analysis software; and cytoplasmic:nuclear p65+ of individual pulmonary arterial endothelial and smooth muscle cells (PASMC) in 10-20 pulmonary arteries or arterioles per subject. The expression of ET-1 and CCL5 (RANTES) in whole lung was determined by RT-qPCR.Macrophage numbers were increased in idiopathic PAH versus controls (49.0±4.5 vs. 7.95±1.9 macrophages/100 mm(2), p

The Hamiltonian character of the ray tracing equations describing the propagation of the Lower Hybrid Wave (LHW) in a magnetic confined plasma device (tokamak) is investigated in order to study the evolution of the parallel wave number along the propagation path. The chaotic diffusion of the “time-averaged” parallel wave number at higher values (with respect to that launched by the antenna at the plasma edge) has been evaluated, in order to find an explanation of the filling of the spectral gap (Fisch, 1987) by “Hamiltonian chaos” in the Lower Hybrid Current Drive (LHCD) experiments (Fisch, 1978). The present work shows that the increase of the parallel wave number \(n_{\parallel}\) due to toroidal effects, in the case of the typical plasma parameters of the Frascati Tokamak Upgrade (FTU) experiment, is insufficient to explain the filling of the spectral gap, and the consequent current drive and another mechanism must come into play to justify the wave absorption by Landau damping. Analytical calculations have been supplemented by a numerical algorithm based on the symplectic integration of the ray equations implemented in a ray tracing code, in order to preserve exactly the symplectic character of a Hamiltonian flow.

Programmed mRNA localization to specific subcellular compartments for localized translation is a fundamental mechanism of post-transcriptional regulation that affects many, and possibly all, mRNAs in eukaryotes. We describe here a systematic approach to identify the RNA cargoes associated with the cytoskeletal motor proteins of Saccharomyces cerevisiae in combination with live-cell 3D super-localization microscopy of endogenously tagged mRNAs. Our analysis identified widespread association of mRNAs with cytoskeletal motor proteins, including association of Myo3 with mRNAs encoding key regulators of actin branching and endocytosis such as WASP and WIP. Using conventional fluorescence microscopy and expression of MS2-tagged mRNAs from endogenous loci, we observed a strong bias for actin patch nucleator mRNAs to localize to the cell cortex and the actin patch in a Myo3- and F-actin dependent manner. Use of a double-helix point spread function (DH-PSF) microscope allowed super-localization measurements of single mRNPs at a spatial precision of 25 nm in x and y and 50 nm in z in live cells with 50 ms exposure times, allowing quantitative profiling of mRNP dynamics. The actin patch mRNA exhibited distinct and characteristic diffusion coefficients when compared to a control mRNA. In addition, disruption of F-actin significantly expanded the 3D confinement radius of an actin patch nucleator mRNA, providing a quantitative assessment of the contribution of the actin cytoskeleton to mRNP dynamic localization. Our results provide evidence for specific association of mRNAs with cytoskeletal motor proteins in yeast, suggest that different mRNPs have distinct and characteristic dynamics, and lend insight into the mechanism of actin patch nucleator mRNA localization to actin patches.

The T lymphocyte-mediated immune response to Mycobacterium tuberculosis infection in the parietal pleura of patients with tuberculous pleurisy is unknown. The aim of this study was to investigate the immune response in the parietal pleura of tuberculous pleurisy compared with nonspecific pleuritis. We have measured the numbers of inflammatory cells particularly T-cell subsets (Th1/Th2/Th17/Treg cells) in biopsies of parietal pleura obtained from 14 subjects with proven tuberculous pleurisy compared with a control group of 12 subjects with nonspecific pleuritis. The number of CD3+, CD4+ and CCR4+ cells and the expression of RORC2 mRNA were significantly increased in the tuberculous pleurisy patients compared with the nonspecific pleuritis subjects. The number of toluidine blue+ cells, tryptase+ cells and GATA-3+ cells was significantly decreased in the parietal pleura of patients with tuberculous pleurisy compared with the control group of nonspecific pleuritis subjects. Logistic regression with receiver operator characteristic (ROC) analysis for the three single markers was performed and showed a better performance for GATA-3 with a sensitivity of 75%, a specificity of 100% and an AUC of 0.88. There was no significant difference between the two groups of subjects in the number of CD8, CD68, neutrophil elastase, interferon (IFN)-γ, STAT4, T-bet, CCR5, CXCR3, CRTH2, STAT6 and FOXP3 positive cells. Elevated CD3, CD4, CCR4 and Th17 cells and decreased mast cells and GATA-3+ cells in the parietal pleura distinguish patients with untreated tuberculous pleurisy from those with nonspecific pleuritis.

M. bovis BCG is used clinically in the immunotherapy treatment of superficial bladder cancer to prevent progression to invasive disease, leading in some cases to a severe localized inflammation or disseminated infections. For this reason, an accurate and early identification of this particular microorganism is clinically relevant.We describe a case-report of bladder cancer with a urine culture-positive for mycobacteria initially diagnosed as MTB complex infection and later identified as BCG disease by molecular methods.

Objective. Aim of this study was molecular identification in clinical specimens of NonTuberculous Mycobacteria (NTM) with commercial methods and automated sequencing. Materials and methods. Three thousand clinical specimens were analyzed for the isolation of Mycobacteria. Forty strains of NTM were previously analyzed with GenoType Mycobacteria CM/AS kit and then with partial 16S rDNA sequencing. Results. 38/40 NMT strains were identified with GenoType Mycobacteria CM/AS kit as: M. gordonae (15), M. intracellulare (8), M. xenopi (8), M. mucogenicum (2), M. kansasii (2), M. chelonae (1), M. avium (1), M. lentiflavum (1). Two unidentified strains were subjected to 16S rDNA sequencing and were identified as M. kumamotonense. Conclusions. Partial 16SrDNA sequencing is a valid assay to study NTM strains unidentified with commercial assays. This new approach, applied to clinical diagnostic, also permits the recognition of unusual strains or new species.