Interleukin (IL)-36α, IL-36β, and IL-36γ are innate mediators of acute epithelial inflammation. We sought to demonstrate that these cytokines are also required for the pathogenesis of plaque ...psoriasis, a common and chronic skin disorder, caused by abnormal T helper 17 (T
17) cell activation. To investigate this possibility, we first defined the genes that are induced by IL-36 cytokines in primary human keratinocytes. This enabled us to demonstrate a significant IL-36 signature among the transcripts that are up-regulated in plaque psoriasis and the susceptibility loci associated with the disease in genome-wide studies. Next, we investigated the impact of in vivo and ex vivo IL-36 receptor blockade using a neutralizing antibody or a recombinant antagonist. Both inhibitors had marked anti-inflammatory effects on psoriatic skin, demonstrated by statistically significant reductions in IL-17 expression, keratinocyte activation, and leukocyte infiltration. Finally, we explored the potential safety profile associated with IL-36 blockade by phenotyping 12 individuals carrying knockout mutations of the IL-36 receptor gene. We found that normal immune function was broadly preserved in these individuals, suggesting that IL-36 signaling inhibition would not substantially compromise host defenses. These observations, which integrate the results of transcriptomics and model system analysis, pave the way for early-stage clinical trials of IL-36 antagonists.
In this paper, we report on the development and first deployment of a distributed optical fiber radiation sensor (DOFRS) for the online monitoring of radiation levels in the high-energy accelerator ...facilities of CERN. The DOFRS is composed of two basic parts: a set of suitably chosen radiation sensitive optical fibers (OFs), to be installed in the machine tunnel, and an optical time domain reflectometer (OTDR), to be installed in a radiation-free area. We carried out a calibration of the radiation response of a P-doped multimode OF under 60 Co <inline-formula> <tex-math notation="LaTeX">\gamma </tex-math></inline-formula>-rays and in the mixed-field radiation environment of the CHARM facility at CERN. By performing OTDR measurements, we are able to probe the radiation-induced attenuation in the OF along its length and calculate the deposited radiation dose with a spatial resolution of 1 m. In this paper, we describe the main features associated with DOFRS implementation in the proton synchrotron booster (PSB) at CERN. We also report the first results obtained from the monitoring of PSB radiation levels since its recommissioning in April 2017. The performances and advantages of the DOFRS system are discussed.
Abstract
Background
To evaluate the adherence to Mediterranean diet (MD) and its major socioeconomic and psychosocial determinants in a large sample of the Italian population, covering three main ...geographical areas of the Country (Southern, Central and Northern).
Methods
Data were obtained from the Italian Nutrition & Health Survey (INHES), including a total of 7, 430 participants (age >20) recruited from all over Italy (2010–13). Dietary information was collected by the European Food Propensity Questionnaire. Adherence to MD was assessed by using the MedDietScore based on 11 food groups. Associations were tested by multivariable logistic regression analysis (Odds ratio OR with 95% CI).
Results
Adherence to MD was higher in Southern Italy as compared with the Northern (OR = 1.34; 95% CI 1.18–1.53), and was closely associated with adult age (OR= 2.40; 1.61–3.58 for those aged > 75 years as compared with 20–34 years) and higher educational level (OR = 1.77; 1.40–2.24 for post-secondary education as opposed to lowest educational attainment). Subjects reporting adverse life events and those with family-related stress were less likely to show an optimal adherence to MD (OR = 0.55; 0.46–0.67 and OR = 0.44; 0.28–0.69, for highest vs. lowest tertile, respectively) as compared with adequate controls. A number of eating behaviours were also inversely associated with MD, such as consuming higher amount of alcohol in the weekend than in week days.
Conclusions
Adherence to MD is strongly determined by age, geographical area and educational level. Psychosocial factors and several eating behaviours are also closely associated.
Point or distributed optical fiber (OF)-based dosimeters can exploit the observed linear dependence of the radiation-induced attenuation (RIA) at 1550 nm in phosphosilicate OFs to monitor the total ...ionizing dose (TID). The temperature dependence of the radiation sensitivity coefficients at 1550 nm (expressed in dB km<inline-formula> <tex-math notation="LaTeX">^{-1} </tex-math></inline-formula> Gy<inline-formula> <tex-math notation="LaTeX">^{-1} </tex-math></inline-formula>) of three phosphorus-doped single-mode OFs has been investigated between −80 °C and 300 °C for TID ranging from 1 Gy to 1 kGy(SiO 2 ). Our measurements reveal the same temperature dependence of the calibration factor for the three fibers at the higher temperatures (>120 °C) where the P1 defects, at the origin of the IR-RIA, are metastable. However, the uncertainties on the TID measurements through the fiber-based dosimeter remain within the 15% for temperatures ranging from −80 °C to 120 °C for the three tested fibers. The independence of the RIA and then of the dose measurements from the dose rate is also maintained in this temperature range.
Nearly half of adolescents experience depressive or aggressive symptoms that impair their functioning at some point in adolescence. Experiencing intense difficult emotions and difficulties regulating ...such emotions may lead to these depressive and aggressive symptoms. However, existing work largely investigates how adolescent emotions at a single time point predict adolescent depressive or aggressive symptoms months or years later. New investigations are needed to capture the dynamic, changing nature of adolescents’ daily experiences of emotions and symptoms of mental distress. Such investigations would further understanding of how emotions affect mental health in adolescents’ everyday lives. Answering this call, the present study investigated how emotion dysregulation moderated and mediated daily associations between sadness and depressive symptoms and between anger and aggression utilizing ecological momentary assessment in a community sample of 103 Italian adolescents (
M
age
= 16.77,
SD
= 0.78, range: 15–18 years old; 47% female). The results revealed that if an adolescent experienced higher-than-usual sadness or anger on a particular day, then they also experienced higher than usual depressive or aggressive symptoms, respectively. Emotion dysregulation mediated and moderated these associations. Adolescents with higher anger had greater difficulties regulating their anger, which led to higher aggressive symptoms (a mediating effect). If adolescents’ sadness was higher than usual on a given day, their depressive symptoms were more severe than usual if they also had higher than usual difficulties regulating sadness (a moderating effect). These findings contribute to our understanding of how emotions impact mental distress on a daily basis for adolescents, emphasize the importance of examining specific adolescent emotions, and shed new light on how emotional regulatory capacities influence emotions and mental health in adolescents’ everyday lives.
Red blood cells (RBCs) are characterized by a remarkable elasticity, which allows them to undergo very large deformation when passing through small vessels and capillaries. This extreme deformability ...is altered in various clinical conditions, suggesting that the analysis of red blood cell (RBC) mechanics has potential applications in the search for non-invasive and cost-effective blood biomarkers. Here, we provide a comparative study of the mechanical response of RBCs in patients with Alzheimer’s disease (AD) and healthy subjects. For this purpose, RBC viscoelastic response was investigated using atomic force microscopy (AFM) in the force spectroscopy mode. Two types of analyses were performed: (i) a conventional analysis of AFM force–distance (FD) curves, which allowed us to retrieve the apparent Young’s modulus, E; and (ii) a more in-depth analysis of time-dependent relaxation curves in the framework of the standard linear solid (SLS) model, which allowed us to estimate cell viscosity and elasticity, independently. Our data demonstrate that, while conventional analysis of AFM FD curves fails in distinguishing the two groups, the mechanical parameters obtained with the SLS model show a very good classification ability. The diagnostic performance of mechanical parameters was assessed using receiving operator characteristic (ROC) curves, showing very large areas under the curves (AUC) for selected biomarkers (AUC > 0.9). Taken all together, the data presented here demonstrate that RBC mechanics are significantly altered in AD, also highlighting the key role played by viscous forces. These RBC abnormalities in AD, which include both a modified elasticity and viscosity, could be considered a potential source of plasmatic biomarkers in the field of liquid biopsy to be used in combination with more established indicators of the pathology.
Abstract
With the foreseen upgrades in HL-LHC, the Versatile Link Plus project was launched to develop the optical fibre links between the experiments and the counting room, in order to reach higher ...data rates. New fibre cabling plants have been designed in this framework for tight integration in experiment front ends and operation at higher radiation doses. Those cabling plants make use of novel multi-fibre assemblies that are tailored to the specific experiment requirements and conditions. This paper describes the design decisions that have led to the final production-ready prototypes and the related implementation of a large-scale procurement framework.
Cancer genetic heterogeneity offers a wide repertoire of molecular determinants to be screened as therapeutic targets. Here, we identify potential anticancer targets by exploiting negative genetic ...interactions between genes with driver loss-of-function mutations (recessive cancer genes) and their functionally redundant paralogs. We identify recessive genes with additional copies and experimentally test our predictions on three paralogous pairs. We confirm digenic negative interactions between two cancer genes (SMARCA4 and CDH1) and their corresponding paralogs (SMARCA2 and CDH3). Furthermore, we identify a trigenic negative interaction between the cancer gene DNMT3A, its functional paralog DNMT3B, and a third gene, DNMT1, which encodes the only other human DNA-methylase domain. Although our study does not exclude other causes of synthetic lethality, it suggests that functionally redundant paralogs of cancer genes could be targets in anticancer therapy.
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•Compensatory negative interactions occur between cancer genes and their paralogs•These negative interactions suggest potential anticancer therapy targets•SMARCA4 and CDH1 genetically interact with their paralogs•The three human DNA methyltransferases have negative genetic interactions
Ciccarelli and colleagues now test for negative epistasis between cancer genes and their functionally redundant paralogs. They experimentally confirm genetic interactions between two cancer genes (SMARCA4 and CHD1) and their paralogs. They also show that the simultaneous silencing of the tumor suppressor DNMT3A and two other genes reduces cell proliferation. If these interactions are maintained in real tumors, then functionally redundant paralogs of cancer genes might be exploited as cancer-specific therapeutic targets.
The radiation response of a phosphorus-doped multimode optical fiber is investigated under both transient (pulsed X-rays) and steady-state (γ- and X-rays) irradiations. The influence of a H 2 ...preloading on the fiber radiation-induced attenuation (RIA) in the 300-2000-nm wavelength range has been characterized. To better understand the impact of this treatment, online behaviors of fiber samples containing different amounts of gas are compared from glass saturation (100%) to less than 1%. In addition to these in situ experiments, additional postirradiation spectroscopic techniques have been performed such as electron paramagnetic resonance or luminescence measurements to identify the different point defects responsible for the induced losses and their H 2 dependence. All our data at room temperature (RT) highlight a strong positive impact of H 2 , even at very low concentrations, on the RIA. Hydrogen quickly passivates (t <; 1 s) most of the defects responsible for the visible-near-IR RIA, mainly phosphorus oxygen hole centers (POHC) and P1 defects. However, 1 year after the H 2 loading at RT or when operating at liquid nitrogen temperature, the RIA levels of the not-treated and H 2 -loaded fiber become comparable. The obtained results provide a better understanding of the potential and limitations of H 2 -loading treatment to design radiation-hardened fiber links.
We investigate the potential of innovative optical fiber bulk materials made by the sol-gel technique for realtime proton beam monitoring. Those types of glass are made of amorphous silica (a-SiO 2 ) ...doped with either Copper (Cu) or Cerium (Ce) ions. These optimized materials possess very interesting light emission properties when exposed to protons. For both types of glasses, online monitoring of the strong radiationinduced luminescence (RIL) allows to monitor the time evolution of the proton flux with ms resolution and the cumulated proton fluence can be precisely deduced by integrating the RIL signal. Furthermore, we showed that both samples present opticallystimulated luminescence (OSL) that could be exploited shortly after the end of the irradiation to reconstruct the cumulated fluence too. Preliminary tests presented in this paper have been performed at TRIUMF facility with high energy (30 - 63 MeV) protons at flux and fluences representative of proton therapy treatments. Obtained results demonstrate the potential of the developed optical materials for proton beam monitoring and permits to identify the needs for future experiments on microstructured fibers elaborated from these optical materials.
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