DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières Syndrome astrocytes

Aberrant induction of type I IFN is a hallmark of the inherited encephalopathy Aicardi-Goutières syndrome (AGS), but the mechanisms triggering disease in the human central nervous system (CNS) remain elusive. Here, we generated human models of AGS using genetically modified and patient-derived pluripotent stem cells harboring TREX1 or RNASEH2B loss-of-function alleles. Genome-wide transcriptomic analysis reveals that spontaneous proinflammatory activation in AGS astrocytes initiates signaling cascades impacting multiple CNS cell subsets analyzed at the single-cell level. We identify accumulating DNA damage, with elevated R-loop and micronuclei formation, as a driver of STING- and NLRP3-related inflammatory responses leading to the secretion of neurotoxic mediators. Importantly, pharmacological inhibition of proapoptotic or inflammatory cascades in AGS astrocytes prevents neurotoxicity without apparent impact on their increased type I IFN responses. Together, our work identifies DNA damage as a major driver of neurotoxic inflammation in AGS astrocytes, suggests a role for AGS gene products in R-loop homeostasis, and identifies common denominators of disease that can be targeted to prevent astrocyte-mediated neurotoxicity in AGS

Low in‑hospital mortality rate in patients with COVID‑19 receiving thromboprophylaxis: data from the multicentre observational START‑COVID Register

Abstract COVID-19 infection causes respiratory pathology with severe interstitial pneumonia and extra-pulmonary complications; in particular, it may predispose to thromboembolic disease. The current guidelines recommend the use of thromboprophylaxis in patients with COVID-19, however, the optimal heparin dosage treatment is not well-established. We conducted a multicentre, Italian, retrospective, observational study on COVID-19 patients admitted to ordinary wards, to describe clinical characteristic of patients at admission, bleeding and thrombotic events occurring during hospital stay. The strategies used for thromboprophylaxis and its role on patient outcome were, also, described. 1091 patients hospitalized were included in the START-COVID-19 Register. During hospital stay, 769 (70.7%) patients were treated with antithrombotic drugs: low molecular weight heparin (the great majority enoxaparin), fondaparinux, or unfractioned heparin. These patients were more frequently affected by comorbidities, such as hypertension, atrial fibrillation, previous thromboembolism, neurological disease,and cancer with respect to patients who did not receive thromboprophylaxis. During hospital stay, 1.2% patients had a major bleeding event. All patients were treated with antithrombotic drugs; 5.4%, had venous thromboembolism [30.5% deep vein thrombosis (DVT), 66.1% pulmonary embolism (PE), and 3.4% patients had DVT + PE]. In our cohort the mortality rate was 18.3%. Heparin use was independently associated with survival in patients aged ≥ 59 years at multivariable analysis. We confirmed the high mortality rate of COVID-19 in hospitalized patients in ordinary wards. Treatment with antithrombotic drugs is significantly associated with a reduction of mortality rates especially in patients older than 59 years

Environmental Factors in the Onset of Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is a heterogeneous clinical condition, whose prevalence has grown considerably during the last decade. Genetic factors are thought to underpin the disorder, but common genetic variants and epigenetic mechanisms have been increasingly called into question for the majority of ASD cases. Growing prenatal exposure to new environmental toxicants has been shown to potentially affect brain development, leading to altered cognitive, social, attentive, behavioral and motor performance. Both epidemiological evidence and mechanistic studies assessing oxidative stress, neuroinflammation, epigenetic alterations and impaired signal transduction, all observed following neurotoxicant exposure, indeed lend biological plausibility to Gene x Environment interactions, whereby environmental toxicants interacting additively or synergistically with genetic liability, can push prenatal neurodevelopmental processes over the threshold for postnatal ASD expression. Research on environmental contributions to ASD and on specific Gene x Environment interaction models ultimately aims at defining targeted preventive strategies

Massively parallel solution of large scale network flow problems

Two massively parallel algorithms for large scale linear and convex quadratic network flow problems are proposed and studied. The methods are based on the alternating step method for monotropic programming. The original network flow problem is decomposed in simple subproblems involving only few variables for which solution in closed form exists. Computational results obtained on the CRAY T3D show that the methods hold the promise of solving extremely large size problems

TRI-VADO: Tre Velocità per un Percorso di Riqualificazione

Our proposal, a project to give new life to an abandoned segment of the highway, was focused on the creation of a lane not used as bypass for Vado, equipped with sports facilities for those who in recent years had already been spontaneously using this area, extending and closing it as a ring. The project profits from what already exists, with a linearity and affordability that make it feasible. We thought of a promenade with custom speed for each type of user: from the hare to the tortoise ... everyone has their own pace! The portal points out the presence of access to the planned path. It is an “invitation”, with a shrinkage followed by an opening element inredcolor. Eventhebenchesinparkingareashavethesame profile and color, which all characterize the entire project. The same material and formal concept is designed for the totem, a book-shaped structure that marks the kilometers covered, and for the street lights.La nostra proposta di progetto per dare nuova vita al tratto di autostrada abbandonato è stata creare, sulla corsia non destinata alla tangenziale di Vado, un percorso sportivo attrezzato fruibile a quanti, in questi anni, si erano già appropriati dell’area spontaneamente, prolungandolo e chiudendolo ad anello. Il progetto sfrutta ciò che già c’è, presentando una linearità e un’economicità che lo rendono fattibile. E’ stato pensato ad una passeggiata con velocità personalizzate per ogni tipologia di fruitore: dalla lepre alla tartaruga... ognuno ha il suo passo! Il portale indica la presenza dell’accesso al percorso attrezzato. Si tratta di un invito che presenta un restringimento seguito da un’apertura, di colore rosso. Anche le panchine nelle aree di sosta presentano la medesima rastrematura ed il colore caratterizzanti l’intero progetto. Lo stesso concept materico e formale è stato proposto nel totem, un arredo a libro che scandisce i kilometri percorsi e nei lampioni per l’illuminazione

Durable and efficient gene silencing in vivo by hit-and-run epigenome editing

Permanent epigenetic silencing using programmable editors equipped with transcriptional repressors holds great promise for the treatment of human diseases1-3. However, to unlock its full therapeutic potential, an experimental confirmation of durable epigenetic silencing after the delivery of transient delivery of editors in vivo is needed. To this end, here we targeted Pcsk9, a gene expressed in hepatocytes that is involved in cholesterol homeostasis. In vitro screening of different editor designs indicated that zinc-finger proteins were the best-performing DNA-binding platform for efficient silencing of mouse Pcsk9. A single administration of lipid nanoparticles loaded with the editors' mRNAs almost halved the circulating levels of PCSK9 for nearly one year in mice. Notably, Pcsk9 silencing and accompanying epigenetic repressive marks also persisted after forced liver regeneration, further corroborating the heritability of the newly installed epigenetic state. Improvements in construct design resulted in the development of an all-in-one configuration that we term evolved engineered transcriptional repressor (EvoETR). This design, which is characterized by a high specificity profile, further reduced the circulating levels of PCSK9 in mice with an efficiency comparable with that obtained through conventional gene editing, but without causing DNA breaks. Our study lays the foundation for the development of in vivo therapeutics that are based on epigenetic silencing.Experiments in mice show that designed epigenome editors that contain domains of transcriptional repressors can enable stable epigenetic silencing of Pcsk9, a gene with a role in cholesterol homeostasis, without inducing DNA breaks

Parkerings- och mobilitetstjänster för en hållbar stad - Slutrapport i projektet Sampark – metoder, möjligheter och potential att samutnyttja parkeringsytor och mobilitetstjänster med Framtiden-koncernens fastighetsbestånd som fallstudieobjekt

Under åren 2018 till 2021 har IVL Svenska Miljöinstitutet drivit ett samfinansierat forskningsprojekt tillsammans med fastighetsbolaget Framtiden. Projektets mål har varit att bidra med kunskap till ett miljöanpassat byggande med effektiv markanvändning, låg resursanvändning och strukturer som stödjer ett hållbart resande. Parkeringskostnaden mellan olika bolag i Framtiden-koncernen skiljer sig åt och en harmonisering av avgifterna bör därför ske. Dagens avgiftsnivå är generellt låg i jämförelse med både marknadsvärde för parkering i aktuella områden och för att kunna styra och påverka bilresande och bilinnehav. Samband mellan exempelvis prissättning och bilinnehav kan inte bekräftas generellt i bostadsbolagens bestånd, vilket anses bero på avsaknad av tillgängliga data på bilinnehav på fastighetsnivå. Resultat från ett nybyggnadsprojekt visar dock att flexibla och sänkta parkeringstal tillsammans med en marknadsmässig prissättning kan ge effekter på bilinnehav men att det har betydelse hur attraktiva mobilitetstjänsterna är. Omvandling från fasta platser till tillståndsplatser kan ha en stor potential att effektivisera parkeringsbeståndet och därigenom frigöra mark för andra ändamål. Framtiden-koncernen har inte själv full rådighet över parkerings-och mobilitetsfrågorna, men tillsammans med stadsbyggnadskontoret, trafikkontoret, fastighetskontoret samt Göteborg Stads Parkering finns goda möjligheter att minska efterfrågan på bilresor i Göteborgsområdet. Exempelvis innebär förtätning och nybyggnation av bostäder innebär att man behöver bygga på befintliga parkeringsplatser. Krav på Framtiden från andra förvaltningar på att ersätta befintliga markparkeringar med förhållandevis låga avgifter, behöver då vara väl avvägda och ligga i linje med efterfrågan för nyproducerade dyrare parkeringsplatser. Plan-och bygglagens regler behöver också förändras med syfte att premiera och underlätta ett arbete mot ett mer bilsnålt eller transporteffektivt samhälle.I många städer förtätas bostadsbebyggelsen. Samtidigt satsar kommuner och regioner mer på gång, cykel och kollektivtrafik. Marknaden för mobilitetstjänster växer, liksom e-handeln och efterfrågan på elbilsladdning. Kommuners policyer för stadsbyggnad och riktlinjer för parkering inriktas också alltmer på att stödja ett miljömässigt hållbart livsmönster och hållbar mobilitet. För en fastighetsaktör gäller det att förhålla sig till dessa trender samtidigt som man arbetar för att tillhandahålla och skapa hållbara och trygga bostäder och miljöer. Detta projekt har haft som syfte att för fastighetsaktörer som Framtiden öka kunskapen och ge vägledning inom parkering- och mobilitetsområdet

Effect of a parenting intervention on decreasing adolescents’ behavioral problems via reduction in attachment insecurity: A longitudinal, multicenter, randomized controlled trial

Introduction: Secure attachment in adolescence, related to caregiving quality, is a robust predictor of positive behavioral adjustment in early adulthood and beyond. Nevertheless, few attempts have been made to develop treatments to promote parent–adolescent attachment security. Methods: Using a longitudinal, multicenter, randomized controlled trial design, two questionnaire-based studies were run in Italy (Study 1: n = 100 mothers of adolescents, 60% boys, Mage = 14.89, SD = 1.58; Study 2: n = 40 mothers and 40 adolescents, 60% boys, Mage = 14.90, SD = 1.91) to test the effectiveness of an attachment-based parenting intervention (i.e., Connect) in reducing adolescents’ behavioral problems and attachment insecurity 2 weeks post-intervention (t2) and at a 4-month follow-up (t3). It was further investigated whether a decrease in avoidant and anxious attachment at t2 would account for changes in externalizing and internalizing problems, respectively, at t3. All adolescents belonged to two-parent intact families. Results: Mothers who completed Connect reported significantly fewer adolescent behavioral problems and lower adolescent attachment insecurity, compared to mothers in the waitlist group, at both t2 and t3 (Study 1). These findings were confirmed in a second subsample (Study 2), considering both mothers’ and adolescents’ reports. Controlling for pre-intervention behavioral problems, reductions in internalizing and externalizing problems were observed in both studies at t3 via a decrease in anxious and avoidant attachment, respectively, at t2. Conclusions: The findings point to the malleability of attachment security in adolescence and highlight the importance of targeting parenting quality to promote adolescent behavioral adjustment

The Italian version of the Reflective Functioning Questionnaire: Validity data for adults and its association with severity of borderline personality disorder.

INTRODUCTION:Impairments in the ability to understand others and the self in terms of internal mental states (reflective functioning [RF] or mentalizing) are thought to play a key role in the development of borderline personality disorder (BPD). The first aim of this study was to validate the Italian version of the Reflective Functioning Questionnaire (RFQ), a brief self-report measure of RF, by examining its factor structure with Principal Component Analyses (PCA), and correlations with constructs that should be theoretically related to RF. In addition, we investigated whether the RFQ could empirically distinguish between healthy controls and carefully diagnosed BPD patients using Research Operating Curve methods, and was related to severity of borderline pathology as measured with the Shedler-Westen Assessment Procedure (SWAP), an observer-rated measure of BPD pathology. METHODS:An Italian translation of the RFQ was administered to a sample of 154 healthy controls and a clinical sample of 59 BPD patients diagnosed with the Structured Clinical Interview for DSM-IV Axis II disorders. Clinical severity of BPD was assessed with the SWAP. Normal controls completed self-report inventories of constructs related to RF (mindfulness, empathy, Theory of Mind, alexithymia, and autistic traits). RESULTS:PCA confirmed the a priori factor structure in the Italian translation of the RFQ, showing two subscales that measure certainty and uncertainty about mental states, with satisfactory reliability and construct validity. These dimensions also distinguished BPD patients from healthy controls (p < 0.05). ROC analyses showed that the uncertainty subscale discriminated BPD patients from healthy individuals (area under the curve = 78%, cut of 4.5 points, sensitivity = 73%, specificity = 68%). Within the patient group, regression analyses showed uncertainty about mental states to have a significant unique contribution in predicting BPD severity (p < 0.05), explaining 12% of the variance. CONCLUSIONS:Results largely supported the reliability and validity of the Italian version of the RFQ. These findings also provide further evidence for the role of impairments in mentalizing and reinforce the rationale for offering mentalization-based interventions to individuals with this disorder