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Abstract Environmental tobacco smoke (ETS) is known to cause lung inflammatory and injurious responses. Smoke exposure is associated with the pathobiology related to lung fibrosis, whereas the mechanism that ETS exposure augments pulmonary fibrogenesis is unclear. We hypothesized that ETS exposure could exacerbate fibrotic responses via collagen dynamic dysregulation and complement activation. C57BL/6J and p16-3MR mice were exposed to ETS followed by bleomycin administration. ETS exposure exacerbated bleomycin-induced collagen and lysyl oxidase overexpression in the fibrotic lesion. ETS exposure also led to augmented bleomycin-induced upregulation of C3 and C3AR, which are pro-fibrotic markers. Moreover, overexpressed collagens and C3 levels were highly significant in males than females. The old mice (17 months old) were exposed to ETS and treated with bleomycin to induce fibrogenesis which is considered as an aging-associated disease. Fewer gene and protein dysregulations trends were identified between ETS exposure with the bleomycin group and the bleomycin alone group in old mice. Based on our findings, we suggested that ETS exposure increases the risk of developing severe lung fibrotic responses via collagen overexpression and lysyl oxidase-mediated collagen stabilization in the fibrotic lesion, and potentially affected the complement system activation induced by bleomycin. Further, male mice were more susceptible than females during fibrogenesis exacerbation. Thus ETS and bleomycin induced lung fibrotic changes via collagen-lysyl oxidase in an age-dependent mechanism.

Abstract Inhaling xenobiotics, such as tobacco smoke is a major risk factor for pulmonary diseases, e.g., COPD/emphysema, interstitial lung disease, and pre‐invasive diseases. Shelterin complex or telosome provides telomeric end protection during replication. Telomere protection protein 1 (TPP1) is one of the main six subunits of the shelterin complex supporting the telomere stability and genomic integrity. Dysfunctional telomeres and shelterin complex are associated as a disease mechanism of tobacco smoke‐induced pulmonary damage and disease processes. The airway epithelium is critical to maintaining respiratory homeostasis and is implicated in lung diseases. Club cells (also known as clara cells) play an essential role in the immune response, surfactant production, and metabolism. Disrupted shelterin complex may lead to dysregulated cellular function, DNA damage, and disease progression. However, it is unknown if the conditional removal of TPP1 from Club cells can induce lung disease pathogenesis caused by tobacco smoke exposure. In this study, conditional knockout of Club‐cell specific TPP1 demonstrated the instability of other shelterin protein subunits, such as TRF1, dysregulation of cell cycle checkpoint proteins, p53 and downstream targets, and dysregulation of telomeric genes. This was associated with age‐dependent senescence‐associated genes, increased DNA damage, and upregulated RANTES/IL13/IL33 mediated lung inflammation and injury network by cigarette smoke (CS). These phenomena are also associated with alterations in cytochrome P450 and glutathione transferases, upregulated molecular pathways promoting lung lesions, bronchial neoplasms, and adenocarcinomas. These findings suggest a pivotal role of TPP1 in maintaining lung homeostasis and injurious responses in response to CS. Thus, these data TPP1 may have therapeutic value in alleviating telomere‐related chronic lung diseases.

Oggetto di questo contributo è un celebre trattato, presumibilmente della seconda metà del V secolo, stipulato dai Lacedemoni con una controparte che figura prima con il nome di Aitoloi, poi con quello di Erxadieise (Osborne - Rhodes, GHI 128). Benché si tratti di un documento ampiamente discusso, rimangono ancora numerosi punti oscuri, quali la definizione del rapporto tra Aitoloi ed Erxadieis, la collocazione geografica dei gruppi umani indicati con questi due etnonimi e la contestualizzazione storica del documento. Alcuni di questi aspetti potevano forse essere chiariti nella sezione iniziale del trattato, giuntaci fortemente mutila. Il contributo tenta così di fare chiarezza sulle principali ambiguità interpretative del documento, attraverso una nuova proposta ricostruttiva delle prime linee di testo.

To evaluate whether there are differences among orthodontists in the clinical management of facemask treatment for early treatment of Class III malocclusion, a survey consisting of 16 questions was conducted among members of the Italian Society of Orthodontics (SIDO). Sixty percent of the respondents were Specialists in Orthodontics (S) whereas 40% were General Dentists practicing Orthodontics (GD). Descriptive statistics were calculated to summarize the collected data. Differences in answers between S and GD were assessed with the Fisher’s exact test for dichotomous variables, chi-square test for qualitative variables, and Mann–Whitney test for ordinal variables. A total of 151 clinicians participated in this survey. As for treatment timing, about 80% of the participants reported treating Class III patients with RPE and facemask between 5 and 8 years of age. Most of the participants requested the patients to wear the facemask in the afternoon and at night for a period of 9 or 12 months with recommended forces of 500 g per side. Comparisons between S and GD showed that S preferred the Petit facemask whereas GD favored the Delaire’s type facemask (Fisher’s Exact test, p = 0.0005). S and GD also differed significantly in their judgment of the most critical time of treatment, which for the majority of GD was the initial period but for the S was the final period (Chi-square test p = 0.0188). This survey showed that the facemask is not well received by the patients who, along with their parents, express concerns regarding its tolerability.

This study presents an early-stage design exploration of NRG-Foam, an innovative insulation material composed of cementitious foam doped with microencapsulated phase change materials (MPCMs). The study comprises the static part that utilizes life cycle assessment and life cycle costing assessment for getting insight into the impacts of the NRG-Foam production process and the dynamic part that identifies the trade-offs between performance characteristics of NRG-Foam using multi-objective optimization. The production of MPCMs was found to be a major contributor to environmental impacts while the addition of small amounts of reduced graphene oxide amplifies the impacts even further. The hot spot analysis pinpointed high electricity consumption as the main driver of environmental impacts. A multi-objective optimization analysis revealed trade-offs between performance characteristics, emphasizing the necessity of compromises during material development. The selection of the MPCM type was shown to be determinative of the final properties of NRG-Foam.

Ischemic cardiovascular and venous thromboembolic events are a frequent cause of death in severe COVID-19 patients. Platelet activation plays a key role in these complications, however platelet lipidomics have not been studied yet. The aim of our pilot investigation was to perform a preliminary study of platelet lipidomics in COVID-19 patients compared to healthy subjects. Lipid extraction and identification of ultrapurified platelets from eight hospitalized COVID-19 patients and eight age- and sex-matched healthy controls showed a lipidomic pattern almost completely separating COVID-19 patients from healthy controls. In particular, a significant decrease of ether phospholipids and increased levels of ganglioside GM3 were observed in platelets from COVID-19 patients. In conclusion, our study shows for the first time that platelets from COVID-19 patients display a different lipidomics signature distinguishing them from healthy controls, and suggests that altered platelet lipid metabolism may play a role in viral spreading and in the thrombotic complications of COVID-19.

Objective: Bipolar disorder is a heritable chronic mental disorder that causes psychosocial impairment through depressive/manic episodes. Familial transmission of bipolar disorder does not follow simple Mendelian patterns of inheritance. The aim of this study was to describe a large family with 12 members affected by bipolar disorder. Whole-exome sequencing was performed for eight members, three of whom were diagnosed with bipolar disorder, and another reported as “borderline.” Methods: Whole-exome sequencing data allowed us to select variants that the affected members had in common, including and excluding the “borderline” individual with moderate anxiety and obsessive-compulsive traits. Results: The results favored designating certain genes as predispositional to bipolar disorder: a heterozygous missense variant in CLN6 resulted in a “borderline” phenotype that, if combined with a heterozygous missense variant in ZNF92, is responsible for the more severe bipolar disorder phenotype. Both rare missense changes are predicted to disrupt protein function. Conclusions: Loss of both alleles in CLN6 causes neuronal ceroid lipofuscinosis, a severe progressive childhood neurological disorder. Our results indicate that heterozygous CLN6 carriers, previously reported as healthy, may be susceptible to bipolar disorder later in life if associated with additional variants in ZNF92.

The objective of this study was to review the scientific evidence currently available on 3D printable materials and 3D printing technologies used for the fabrication of permanent restorations, focusing on material properties that are clinically relevant. A literature search was performed on four databases (MEDLINE/PubMed, Scopus, Cochrane Library, Web of Science) for articles published from January 2013 until November 2023, using a combination of free words: (restorative dentistry OR prosthetic dentistry) AND (3D printing OR additive manufacturing OR rapid prototyping) AND materials. Two reviewers screened titles and/or abstracts of 2.468 unique studies. In total, 83 studies were selected for full-text reading, from which 36 were included in the review. The assessed variables were mechanical properties, reporting in most of the cases positive results, dimensional accuracy and fit, reporting conflicting results with a predominance of positive, aesthetic properties, with positive reports but scarcely addressed, and biological properties, almost unexplored in independent studies. Despite numerous studies with positive results in favor, papers with negative outcomes were also retrieved. Aesthetic and biological properties are conversely still mostly unexplored. There remains a lack of conclusive evidence for viable 3D printable restorative and prosthodontic materials for permanent restorations. Research should be strengthened by defining international standards for laboratory testing and, where pre-clinical data are promising, conducting clinical trials.

Abstract Smith-Magenis syndrome (SMS) is a neurodevelopmental disorder characterized by cognitive and behavioral symptoms, obesity, and sleep disturbance, and no therapy has been developed to alleviate its symptoms or delay disease onset. SMS occurs due to haploinsufficiency of the retinoic acid-induced-1 (RAI1) gene caused by either chromosomal deletion (SMS-del) or RAI1 missense/nonsense mutation. The molecular mechanisms underlying SMS are unknown. Here, we generated and characterized primary cells derived from four SMS patients (two with SMS-del and two carrying RAI1 point mutations) and four control subjects to investigate the pathogenetic processes underlying SMS. By combining transcriptomic and lipidomic analyses, we found altered expression of lipid and lysosomal genes, deregulation of lipid metabolism, accumulation of lipid droplets, and blocked autophagic flux. We also found that SMS cells exhibited increased cell death associated with the mitochondrial pathology and the production of reactive oxygen species. Treatment with N-acetylcysteine reduced cell death and lipid accumulation, which suggests a causative link between metabolic dyshomeostasis and cell viability. Our results highlight the pathological processes in human SMS cells involving lipid metabolism, autophagy defects and mitochondrial dysfunction and suggest new potential therapeutic targets for patient treatment.

Oxidized lipids are prominent bioactive agents, and yet their molecular repertoire remains largely unknown. Here, the authors apply bioinformatics and LC-MS/MS to uncover the diversity and specificity of modified lipids in human blood plasma of lean and obese individuals.

Abstract Objectives Treatment persistence refers to the act of continuing a treatment as prescribed and reflects the patient's or doctor's judgment about efficacy, tolerability, and acceptability. In patients with schizophrenia, antipsychotic persistence is often poor, because of issues such as lack or loss of efficacy, side effects, and poor adherence, which is often related to the degree to which patients find the medication and overall intervention to be helpful, tolerable, fair, reasonable, appropriate, and consistent with expectations of treatment. Despite the poor antipsychotic persistence that has been reported to date in patients with schizophrenia, we previously observed a relatively high (86%) 6 months persistence with aripiprazole once-monthly (AOM) in a group of patients with schizophrenia, treated in the real world Italian clinical practice. The present study explores the longer term persistence with AOM, over a mean follow-up period of 48 months. Methods This was a multicenter, retrospective, non-interventional follow-up study, aimed at evaluating the longer term persistence with AOM in a group of patients with schizophrenia who had already shown persistence over a period of at least 6 months. The study included 161 individuals who had participated in our previous study, where 86% of participating individuals had shown persistence with AOM for at least 6 months. Non-persistence was defined as discontinuing the medication for any reason. Baseline demographic and clinical characteristics of patients who continued AOM were then compared to those of patients who discontinued the medication. Results Study subjects were predominantly male (64.4%) and their mean age was 39.7 (SD: 12.24). Treatment persistence with AOM was 69.6% and 112 out of 161 patients were still receiving AOM treatment at the last follow-up visit. The mean duration of AOM treatment until the last recorded observation was 55.87 months (median 56.17, SD6.23) for the 112 persistent patients and 32.23 (median 28.68.SD 15.09) months for the 49 non-persistent individuals. The mean observation period for all patients (persistent and non-persistent) was 48.78 months (median 52.54, SD 14.64). For non-persistent subjects, the observation period ended with the discontinuation of AOM. Subjects treated with AOM at 400 mg presented a 69.6% lower risk of all-cause treatment discontinuation when compared with patients treated with 300 mg (HR: 0.314; 95% confidence interval [CI] 0.162–0.608; P = 0.001). The main reasons for discontinuation were lack of efficacy (30.6%), patient/caregiver choice (18.4%), physician’s choice (16.3%), non-adherence (12.2%) and inconvenience (6.1%). Only 3 patients (6.1%) discontinued AOM for tolerability issues. Conclusions In subjects with schizophrenia, who had already shown a 6 months persistence with AOM, a high number of patients (69.6%) continued to be persistent over a 4-year follow-up period. This may reflect a favourable profile of efficacy, tolerability, and acceptability. Larger and prospective studies are warranted to confirm our observations.

Abstract Methacrylic acid‐co‐poly(ethylene glycol methacrylate) (MAA‐co‐PEGMA) copolymers (MPEG‐type polycarboxylate ether (PCE) superplasticizers) are characterized by a comb‐like structure. Although they have been used for years as dispersants in cementitious formulations, their structure–property relationship is still not fully understood. In this work, PCEs with uniform composition and different charge‐density (N) or different side chain lengths (P) are synthesized by free‐radical copolymerization varying the MAA/PEGMA ratios and ethylene oxide units in the PEGMA macromonomers. The effect of these copolymers on the hydration kinetics of an Ordinary Portland Cement (OPC) is analyzed, and it is observed that by increasing the PCE concentration the hydration is delayed. For a given PCE concentration, the delay is longer as the MAA/PEGMA ratio increases or the side chain length of the PEGMA decreases. The hydration delay is proportional to the carboxylate dosage and all PCEs fit in a master curve proving that the microstructure of the PCEs synthesized by free‐radical copolymerization can be correlated with the hydration delay of a commercial OPC.