The digital services act: an analysis of its ethical, legal, and social implications

In December 2020, the European Commission issued the Digital Services Act (DSA), a legislative proposal for a single market of digital services, focusing on fundamental rights, data privacy, and the protection of stakeholders. The DSA seeks to promote European digital sovereignty, among other goals. This article reviews the literature and related documents on the DSA to map and evaluate its ethical, legal, and social implications. It examines four macro-areas of interest regarding the digital services offered by online platforms. The analysis concludes that, so far, the DSA has led to contrasting interpretations, ranging from stakeholders expecting it to be more challenging for gatekeepers, to others objecting that the proposed obligations are unjustified. The article contributes to this debate by arguing that a more robust framework for the benefit of all stakeholders should be defined

AI Risk Assessment: A Scenario-Based, Proportional Methodology for the AI Act

The EU Artificial Intelligence Act (AIA) defines four risk categories for AI systems: unacceptable, high, limited, and minimal. However, it lacks a clear methodology for the assessment of these risks in concrete situations. Risks are broadly categorized based on the application areas of AI systems and ambiguous risk factors. This paper suggests a methodology for assessing AI risk magnitudes, focusing on the construction of real-world risk scenarios. To this scope, we propose to integrate the AIA with a framework developed by the Intergovernmental Panel on Climate Change (IPCC) reports and related literature. This approach enables a nuanced analysis of AI risk by exploring the interplay between (a) risk determinants, (b) individual drivers of determinants, and (c) multiple risk types. We further refine the proposed methodology by applying a proportionality test to balance the competing values involved in AI risk assessment. Finally, we present three uses of this approach under the AIA: to implement the Regulation, to assess the significance of risks, and to develop internal risk management systems for AI deployers

Numerical investigation of tearing modes amplitude oscillations

A recently observed phenomenon involving magnetic islands in high-density pulses in the Frascati Tokamak Upgrade is investigated using numerical simulations in slab geometry. This phenomenon was given the name “limit cycles” because of the figure drawn by the trajectory of the system in the amplitude/frequency plane of magnetic islands. In this regime of propagation, the magnetic islands show a quasi-periodic modulation of their amplitude and rotation frequency. The Fourier analysis of the experimental signals shows a large harmonic content, which we ascribed to a significant island deformation in the cycle phase. We performed a series of numerical simulations by integrating a four-field system of equations through a finite difference code to check this hypothesis. The results of the simulations show that a large density gradient causes a significant island deformation in the nonlinear regime, in agreement with our hypothesis. This deformation is caused by the diamagnetic velocity shear resulting from the nonlinear flattening of the density profile inside the island separatrix

Widespread mRNA Association with Cytoskeletal Motor Proteins and Identification and Dynamics of Myosin-Associated mRNAs in S. cerevisiae

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 her e 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

Congenital malformations potentially affecting respiratory function: Multidisciplinary approach and follow-up

Background and aim. Congenital malformations such as oesophageal atresia (OA) and tracheoe-sophageal fistula (TOF), congenital pulmonary airway malformations (CPAMs), congenital diaphragmatic hernia (CDH) and vascular rings (VRs) can affect lung development and respiratory function. This observa-tional study describes our multidisciplinary approach and respiratory follow-up of children with such congenital malformations. Methods. Clinical data of children followed at the Pediatric Respiratory Unit of Parma University Hospital (Italy) between January 2015 and January 2020 were collected. Results. Twenty-three patients with congenital malformation affecting lung development were identified. Almost half of our patients were diagnosed with fetal ultrasound. Children attended the clinic at a mean age of 3 (3.7) years and follow-up visits were scheduled every 6 months average. More than half of our patients were hospitalized for lower respiratory tract infections. Six out of 9 children able to perform spirometry showed anomalies in lung function. Chest physiotherapy was recommended especially in children with OA. Conclusions. Children with congenital malformations affecting lung development are at risk of short and long-term respiratory complications, especially in the first years of life. OA was the malformation more associated to respiratory problems. Multidisciplinary approach and appropriate personalized follow-up are recommended for the best management of these children. (www.actabiomedica.it)

Communication between levels of transcriptional control improves robustness and adaptivity

Regulation of eukaryotic gene expression depends on groups of related proteins acting at the levels of chromatin organization, transcriptional initiation, RNA processing, and nuclear transport. However, a unified understanding of how these different levels of transcriptional control interact has been lacking. Here, we combine genome-wide protein–DNA binding data from multiple sources to infer the connections between functional groups of regulators in Saccharomyces cerevisiae. Our resulting transcriptional network uncovers novel biological relationships; supporting experiments confirm new associations between actively transcribed genes and Sir2 and Esc1, two proteins normally linked to silencing chromatin. Analysis of the regulatory network also reveals an elegant architecture for transcriptional control. Using communication theory, we show that most protein regulators prefer to form modules within their functional class, whereas essential proteins maintain the sparse connections between different classes. Moreover, we provide evidence that communication between different regulatory groups improves the robustness and adaptivity of the cell

Reliability of programmed death ligand 1 (PD-L1) tumor proportion score (TPS) on cytological smears in advanced non-small cell lung cancer: a prospective validation study

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 (<1%, 1–49% and ⩾50%; <50%, ⩾50%). Results: The overall agreement between histological samples and cytological smears was moderate (kappa = 0.537). However, when the cyto-histological concordance was calculated using the cut-off of 50%, the agreement was good (kappa = 0.740). With the same cut-off, and assuming as gold-standard the results on formalin-fixed paraffin-embedded materials, PD-L1 evaluation on smears showed specificity and negative predictive values of 98.1% and 93.9%, respectively. Conclusion: Cytological smears can be used in routine clinical practice for PD-L1 assessment with a cut-off of 50%, expanding the potential pool of NSCLC patients as candidates for first-line single agent pembrolizumab therapy

Phospho-p38 MAPK expression in COPD patients and asthmatics and in challenged bronchial epithelium

Background: The role of mitogen-activated protein kinases (MAPK) in regulating the inflammatory response in the airways of patients with chronic obstructive pulmonary disease (COPD) and asthmatic patients is unclear. Objectives: To investigate the expression of activated MAPK in lungs of COPD patients and in bronchial biopsies of asthmatic patients and to study MAPK expression in bronchial epithelial cells in response to oxidative and inflammatory stimuli. Methods: Immunohistochemical expression of phospho (p)-p38 MAPK, p-JNK1 and p-ERK1/2 was measured in bronchial mucosa in patients with mild/moderate (n = 17), severe/very severe (n = 16) stable COPD, control smokers (n = 16), control non-smokers (n = 9), in mild asthma (n = 9) and in peripheral airways from COPD patients (n = 15) and control smokers (n = 15). Interleukin (IL)-8 and MAPK mRNA was measured in stimulated 16HBE cells. Results: No significant differences in p-p38 MAPK, p-JNK or p-ERK1/2 expression were seen in bronchial biopsies and peripheral airways between COPD and control subjects. Asthmatics showed increased submucosal p-p38 MAPK expression compared to COPD patients (p 2O2), cytomix (tumour necrosis factor-\u3b1 + IL-1\u3b2 + interferon-\u3b3) and lipopolysaccharide (LPS) upregulated IL-8 mRNA at 1 or 2 h. p38 MAPK\u3b1 mRNA was significantly increased after H2O2 and LPS treatment. JNK1 and ERK1 mRNA were unchanged after H2O2, cytomix or LPS treatments. Conclusion: p-p38 MAPK expression is similar in stable COPD and control subjects but increased in the bronchi of mild asthmatics compared to stable COPD patients. p38 MAPK mRNA is increased after bronchial epithelial challenges in vitro. These data together suggest a potential role for this MAPK in Th2 inflammation and possibly during COPD exacerbations

Innate immunity but not NLRP3 inflammasome activation correlates with severity of stable COPD

Background In models of COPD, environmental stressors induce innate immune responses, inflammasome activation and inflammation. However, the interaction between these responses and their role in driving pulmonary inflammation in stable COPD is unknown. Objectives To investigate the activation of innate immunity and inflammasome pathways in the bronchial mucosa and bronchoalveolar lavage (BAL) of patients with stable COPD of different severity and control healthy smokers and non-smokers. Methods Innate immune mediators (interleukin (IL)-6, IL-7, IL-10, IL-27, IL-37, thymic stromal lymphopoietin (TSLP), interferon γ and their receptors, STAT1 and pSTAT1) and inflammasome components (NLRP3, NALP7, caspase 1, IL-1β and its receptors, IL-18, IL-33, ST2) were measured in the bronchial mucosa using immunohistochemistry. IL-6, soluble IL-6R, sgp130, IL-7, IL-27, HMGB1, IL-33, IL-37 and soluble ST2 were measured in BAL using ELISA. Results In bronchial biopsies IL-27+ and pSTAT1+ cells are increased in patients with severe COPD compared with control healthy smokers. IL-7+ cells are increased in patients with COPD and control smokers compared with control non-smokers. In severe stable COPD IL-7R+, IL-27R+ and TSLPR+ cells are increased in comparison with both control groups. The NALP3 inflammasome is not activated in patients with stable COPD compared with control subjects. The inflammasome inhibitory molecules NALP7 and IL-37 are increased in patients with COPD compared with control smokers. IL-6 levels are increased in BAL from patients with stable COPD compared with control smokers with normal lung function whereas IL-1β and IL-18 were similar across all groups. Conclusions Increased expression of IL-27, IL-37 and NALP7 in the bronchial mucosa may be involved in progression of stable COPD