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This paper extends the modified Cam-Clay model to describe the behaviour of unsaturated soils by replacing the effective stress with the scaled stress. The scaled stress accounts for the mechanical effect of capillarity by factoring Bishop’s stress with a power function of degree of saturation. The extendedmodified Cam-Clay model postulates the existence of a yield curve in the mean scaled stress 𝑝̅– deviatoric scaled stress 𝑞̅ plane. Coherently with the modified Cam-Clay model, the stress-strain behaviour is predicted by means of an elastic law inside the yield curve. As the scaled stress state evolves onto the yield curve, the behaviour becomes elasto-plastic and this is modelled by a plastic flow rule combined with a volumetric hardening law. The extended modified Cam-Clay model is then validated against experimental data published in the literature. Results show that the proposed approach is capable of well predicting the mechanical behaviour of unsaturated soils during triaxial loading. Future work will be directed at further validating the present formulation along different stress paths as well as accounting for the combined effect of partial saturation and cementation within a critical state framework based on bounding surface plasticity.

Abstract The growth factor Neuregulin-1 (NRG1) has pleiotropic roles in proliferation and differentiation of the stem cell niche in different tissues. It has been implicated in gut, brain and muscle development and repair. Six isoform classes of NRG1 and over 28 protein isoforms have been previously described. Here we report a new class of NRG1, designated NRG1-VII to denote that these NRG1 isoforms arise from a myeloid-specific transcriptional start site (TSS) previously uncharacterized. Long-read sequencing was used to identify eight high-confidence NRG1-VII transcripts. These transcripts presented major structural differences from one another, through the use of cassette exons and alternative stop codons. Expression of NRG1-VII was confirmed in primary human monocytes and tissue resident macrophages and induced pluripotent stem cell-derived macrophages (iPSC-derived macrophages). Isoform switching via cassette exon usage and alternate polyadenylation was apparent during monocyte maturation and macrophage differentiation. NRG1-VII is the major class expressed by the myeloid lineage, including tissue-resident macrophages. Analysis of public gene expression data indicates that monocytes and macrophages are a primary source of NRG1. The size and structure of class VII isoforms suggests that they may be more diffusible through tissues than other NRG1 classes. However, the specific roles of class VII variants in tissue homeostasis and repair have not yet been determined.

Alicerçados na Teoria Histórico-Cultural, objetivamos analisar as contribuições de intervenções em aulas de ciências no ensino de estudantes autistas em processos inclusivos. Em nossa investigação, no período de 1943 até 2022, identificamos 19 trabalhos (oito nacionais e 11 internacionais) que desenvolveram ações pedagógicas na Educação Básica em aulas de ciências com estudantes autistas em escolas comuns. A partir das contribuições dos artigos e referenciais teóricos, defendemos que a organização de atividades de estudos, em aulas de ciências, articuladas em projetos de inclusão escolar que integram o(a) estudante autista em múltiplas experiências sociais, pode se beneficiar de conhecimentos científicos como uma ferramenta importante para promover a ampliação da comunicação, com ou sem fala, e para fomentar o desenvolvimento da consciência do mundo e de si, além de aprimorar a compreensão do que significa ser autista e assumir protagonismos. Convidamos as pesquisas da área a aprofundarem e ampliarem as contribuições.

RESUMO Este ensaio teórico teve por objetivo identificar contribuições da organização do conhecimento científico na sistematização do ensino em ciências, para a constituição humana típica e atípica. Isso foi realizado a partir de ponderações entre textos da área de Ensino de Ciências e pressupostos da Teoria Histórico-Cultural. Assim, apresentamos reflexões acerca de discussões que polarizam a educação de pessoas com deficiência ou autismo no direcionamento curricular, em relação às habilidades funcionais e acadêmicas. A partir da análise de limitações, possibilidades e estratégias educacionais para aulas de ciências, concluímos que as habilidades funcionais, que envolvem conhecimentos cotidianos, não podem configurar critério de exclusão curricular de habilidades acadêmicas, do conhecimento científico, para a educação de pessoas com desenvolvimento atípico. Compreendemos que uma educação científica escolar com vias ao desenvolvimento integral é indissociável das habilidades da vida diária.

Abstract After the introduction of highly active antiretroviral therapies (HAART), an increased incidence of insulin resistance, diabetes mellitus (DM), and cardiovascular diseases has been described. The impact of such conditions on mortality in the post-HAART era has been also assessed in various modes in the literature. In this paper, we report on the death risks for DM, myocardial infarction, and chronic ischemic heart diseases that were investigated among 9662 Italian AIDS cases diagnosed between 1999 and 2005. Death certificates reporting DM, myocardial infarction, and chronic ischemic heart diseases were reviewed to identify the underlying cause of death, and to compare the observed numbers of deaths with the expected ones from the sex- and age-matched, general population of Italy. Person-years at risk of death were computed from date of AIDS diagnosis up to date of death or to December 31, 2006. Standardized mortality ratios (SMR) and their 95% confidence intervals (CI) were computed. DM and cardiovascular diseases were the cause of death for 43 out of 3101 deceased AIDS cases (i.e., 1.4% of all deaths). In comparison with the general population, the risks of death were 6.4-fold higher for DM (95% CI:3.5-10.8), 2.3-fold higher for myocardial infarction (95% CI:1.4-3.7) and 3.0 for chronic ischemic heart diseases (95% CI: 1.5-5.2).

Abstract Background Decentralised clinical trials (DCTs) are clinical trials where all or most trial activities occur in or near participants’ homes instead of hospitals or research sites. While more convenient for participants, DCTs may offer limited opportunities to build trust with investigators and trial teams. This qualitative analysis explored DCT stakeholder views to inform strategies for maximising participant recruitment, retention, and adherence. Methods A secondary analysis of original interview transcripts focused on participant engagement: recruitment, retention, and adherence. Semi-structured interviews were conducted with a purposive sample of stakeholders, including trial managers and administrators, investigators, nurses, vendors, and patient representatives. Interview data were coded using a thematic approach to generate descriptive themes. Results Forty-eight stakeholders were interviewed. Three components of participant engagement in DCTs were identified: identifying and attracting potential participants, retaining participants and encouraging adherence, and involvement of patients and the public. Interviewees believed that a potential participant’s beliefs about research value and their trust in the research team strongly influenced the likelihood of taking part in a DCT. Early involvement of patients was identified as one way to gauge participant priorities. However, perceived burden was seen as a barrier to recruitment. Factors influencing retention and adherence were related to the same underlying motivators that drove recruitment: personal values, circumstances, and burden. Being part of a DCT should not conflict with the original motivations to participate. Conclusion Recruitment, retention, and adherence in DCTs are driven by factors that have previously been found to affect conventional clinical trials. Increasing patient and public involvement can address many of these factors. In contrast to conventional trials, DCTs are perceived as requiring greater emphasis on communication, and contact, to engender trust between participants and researchers despite a relative lack of in-person interaction.

This work exploits the concept of one-class classifier applied to the problem of anomaly detection in communication networks. The article presents the design of an innovative anomaly detection algorithm based on polynomial interpolation technique and statistical analysis. The innovative method is applied to datasets largely used in the scientific community for bench-marking such as KDD99, UNSW-NB15 and CSE-CIC-IDS-2018, and further evaluated with application to a novel available dataset EDGE-IIOTSET 2022. The paper also reports experimental results showing that the proposed methodology outperforms classic one-class classifiers, such as Extreme Learning Machine and Support Vector Machine models, and rule-based intrusion detection system like SNORT. With respect to binary classifiers, this work has the advantage of not requiring any a-priori knowledge about attacks and is based on the collection of only normal data traffic.

Background: Epidural analgesia (EA) is effective in patients undergoing minimal invasive repair of pectus excavatum (MIRPE) but is associated with major complications such as epidural hematomas. It is recommended to assess coagulation status in patients receiving anticoagulant therapy prior to EA, although no consensus exists in patients without a history of bleeding tendency or anticoagulant therapy. Thus, the aim of this paper was to assess 1) the prevalence of abnormal routine coagulation parameters, i.e., international normalized ratio (INR) and platelet count, and 2) the safety of EA in patients undergoing MIRPE. Methods: In this retrospective study, we identified 1,973 patients undergoing MIRPE at our center between 2001 and 2019. Complications related to EA were registered for all patients. Information on coagulation parameters was present in 929 patients. Patients with spontaneously elevated INR ≥1.5 were referred for assessment of coagulation factor VII in order to assess the cause of the elevated INR. Results: Of 929 patients with coagulation information available, 18 patients had spontaneously elevated INR ≥1.5 (1.9%). In patients with INR ≥1.5, 12 patients underwent further assessment of factor VII, with all patients having a slightly reduced factor VII close to the lower reference range. The majority of the 1,973 patients undergoing MIRPE received EA (99.6%) with very low complication rates (0.2%) and no incidence of epidural hematomas. Conclusion: In patients undergoing MIRPE, coagulation screening prior to EA should not be mandatory as it revealed no clinically relevant consequences. EA is safe with very low complication rates.

Abstract Objective The high co-occurrence of non-suicidal self-injury (NSSI) behaviours and eating disorder (ED) symptoms suggests these conditions share common aetiological processes. We assessed a new integrative model of shared factors for NSSI and ED symptoms, where affect dysregulation, impulsivity, self-esteem, and body dissatisfaction mediated the relationship between insecure attachment and maladaptive schemas and NSSI and ED symptoms. A further aim of the study was to assess whether the model behaved similarly across a clinical eating disorder (ED) and a community sample. Method 123 females with a lifetime ED diagnosis and 531 female individuals from the community completed an online survey, which included measures assessing the variables of interest. A cross-sectional single time point analysis was used. Results Invariance testing indicated that the model was structurally non-invariant (different across groups). The proposed integrative model was a good fit for the ED group, but for the community sample only a revised model reached an acceptable fit. Both attachment and maladaptive schemas, included early in the model, were implicated in the pathways leading to ED and NSSI symptoms in the ED and community groups. In the community group, impulsivity, a mediator, was a shared predictor for NSSI and bulimic symptoms. No other mediating variables were shared by NSSI and ED symptoms in the two groups. Overall, the proposed model explained slightly more variance for the ED group relative to the community group in drive for thinness (R 2 = .57 vs .51) and NSSI (R 2 = .29 vs .24) but less variance in bulimic symptoms (R 2 = .33 vs .39). Conclusion We conclude that the current model provides only limited support for explaining the comorbidity between NSSI and ED symptoms. It is vital to consider both common (e.g., attachment and maladaptive schemas) and specific factors (e.g., impulsivity) to better understand the pathways that lead to the co-occurrence of NSSI and ED symptoms. A new integrative model assessed whether emotion dysregulation, impulsivity, self-esteem, and body dissatisfaction were mediators in the relationship between insecure attachment and maladaptive beliefs about the world and the self and subsequent eating disorder and self-harm symptoms. A further aim was to assess whether the proposed model differed between a clinical eating disorder and a community sample. All participants were female and included 123 patients with a lifetime eating disorder and 531 individuals from the community. Participating individuals completed an online survey at one timepoint, which included measures assessing the variables of interest. The findings of the current study indicated that the proposed model was a good match for the clinical eating disorder sample, but for the community sample only a revised model yielded acceptable statistical fit. Both insecure attachment and maladaptive beliefs about the world and the self, included early in the model, were indirectly related to eating disorder and self-harm symptoms for both the eating disorder and the community groups. Impulsivity, a mediator, was the only shared predictor for self-harm, and bulimic symptoms in the community group. We conclude that the current model provides only limited support for explaining the comorbidity between self-harming behaviours and disordered eating symptoms.

Conservation of hypogea and their accessibility by the visitors is a hard question, due to the interaction of different factors such as the intrinsic characteristics of the hypogeal environments and the presence of public. A particular case is represented by the Mithraeum of Marino Laziale, located a few kilometers away from Rome and accidentally discovered in the 1960s. The uniqueness of the discovery was the presence of a well-preserved painting of the Mithraic scene (II century A.D.) probably due to the oblivion of the place of worship over the centuries as well as the isolation from the outdoor environment. Unfortunately, despite a recent complete restoration and recovery of the archaeological area, which ended in 2015, the area was never open to the visitors and only two years after completing the works it was no longer safe to use. Hence, the need for a new planning of interventions starting from the deep knowledge of this cultural heritage and from the analysis of past incorrect actions to arrive at the opening—without any risk for the archaeological findings and visitors—and management of this site, never exposed to the public. Therefore, since 2018 a diagnostic campaign and microclimate monitoring have been started. The data collected during the two years of investigations have been fundamental to assess the conservation state of the hypogeal environment and the potential risks for the preservation of the three paintings (the Mithraic scene and two dadophores). Long-term monitoring of indoor environmental conditions assumes the role of an essential tool for the planning of preventive conservation strategies but also for the control of the site after its opening to the visitors. Furthermore, the characterization of the microclimate is non-invasive, sufficiently economical and accurate. In this paper, the characterization of surfaces in the Mithraic gallery through optical microscopy, UV fluorescence/imaging techniques, FT-IR spectroscopy, XRD and the microclimatic parameters variation in the presence or absence of visitors are used to define the strategies for the opening and fruition of the Mithraeum. The strategies for the sustainable fruition of this unique archaeological site have been defined through a conservation protocol approved by the Italian Ministry of Cultural Heritage and necessary for the site managers and curators of the Municipality of Marino Laziale to finally support its opening.

There is a persistent variation in cancer outcomes among and within European countries suggesting (among other causes) inequalities in access to or delivery of high‐quality cancer care. European policy (EU Cancer Mission and Europe’s Beating Cancer Plan) is currently moving towards a mission‐oriented approach addressing these inequalities. In this study, we used the quantitative and qualitative data of the Organisation of European Cancer Institutes’ Accreditation and Designation Programme, relating to 40 large European cancer centres, to describe their current compliance with quality standards, to identify the hallmarks common to all centres and to show the distinctive features of Comprehensive Cancer Centres. All Comprehensive Cancer Centres and Cancer Centres accredited by the Organisation of European Cancer Institutes show good compliance with quality standards related to care, multidisciplinarity and patient centredness. However, Comprehensive Cancer Centres on average showed significantly better scores on indicators related to the volume, quality and integration of translational research, such as high‐impact publications, clinical trial activity (especially in phase I and phase IIa trials) and filing more patents as early indicators of innovation. However, irrespective of their size, centres show significant variability regarding effective governance when functioning as entities within larger hospitals.

Abstract To examine the acute effects of aerobic exercise (AE), resistance exercise (RE) or combined exercise (CE) on flow-mediated dilation (FMD), progenitor cells (PCs), endothelial progenitor cells (EPCs), oxidative stress markers and endothelial-cell derived microvesicles (EMVs) in patients with hypertension. This is a randomized, parallel-group clinical trial involving an intervention of one session of three different modalities of exercise. Thirty-three males (43 ± 2y) were randomly divided into three groups: a session of AE (n = 11, 40 min, cycle ergometer, 60% HRR); a session of RE (n = 11, 40 min, 4 × 12 lower limb repetitions, 60% 1-RM); or a session of CE (n = 11, 20-min RE + 20-min AE). FMD was assessed 10 min before and 10, 40 and 70 min post-intervention. Blood samples were collected at the same time points (except 40 min). FMD were similar in all groups and from baseline (within each group) after a single exercise bout (AE, RE or CE). At 70 min, RE group showed higher levels of PCs compared to the AE (81%) and CE group (60%). PC levels were reduced from baseline in all groups (AE: 32%, p = 0.037; RE: 15%, p = 0.003; CE: 17%, p = 0.048). The levels of EPCs, EMVs and oxidative stress were unchanged. There were no acute effects of moderate-intensity exercise on FMD, EPCs, EMVs and oxidative stress, but PCs decreased regardless of the exercise modality. Individuals with controlled hypertension do not seem to have impaired vascular function in response to a single exercise bout.

Some of Earth’s earliest continental crust has been previously inferred to have formed from partial melting of hydrated mafic crust at pressures above 1.5 GPa (more than 50 km deep), pressures typically not reached in post-Archean continental crust. Here, the authors show that such high pressure signatures can result from melting of mantle sources rather than melting of crust, and they suggest there is a lack of evidence that Earth’s earliest crust melted at depths significantly below 40 km.

Identifying patients at risk of poor response to neoadjuvant chemoradiotherapy (nCRT) is an emerging clinical need in locally advanced rectal cancer (LARC). SMAD3 is a key player in the chemoradio-resistance phenotype and its expression is both constitutive and locally induced. The aim was to investigate both host (genetic polymorphisms) and tumor SMAD3 profiling to predict response to nCRT. In a group of 76 LARC patients, SMAD3 and phosphorylated-SMAD3 expression was assessed by immunohistochemistry in preoperative tumor tissue. In an expanded study group (n = 378), a set of SMAD3 polymorphisms (rs35874463, rs1065080, rs1061427, rs17228212, rs744910, and rs745103) was analyzed. Association with tumor regression grade (TRG) and patient prognosis (progression-free survival [PFS] and overall survival [OS]) was assessed. Patients with high tumor expression of SMAD3 had a significantly increased risk of poor response (TRG≥2) [cellularity >55% (OR:10.36, p = 0.0004), or moderate/high intensity (OR:5.20, p = 0.0038), or an H-score≥1 (OR:9.84, p = 0.0004)]. Patients carrying the variant SMAD3 rs745103-G allele had a poorer response (OR:0.48, p = 0.0093), a longer OS (HR:0.65, p = 0.0307), and a trend for longer PFS (HR:0.75, p = 0.0944). Patients who carried both high SMAD3 tumor expression and the wild-type rs745103-A allele had an extremely high risk of not achieving a complete response (OR:13.45, p = 0.0005). Host and tumor SMAD3 status might be considered to improve risk stratification of LARC patients to facilitate selection for alternative personalized neoadjuvant strategies including intensified regimens.

Summary: Pathogenic viruses induce metabolic changes in host cells to secure the availability of biomolecules and energy to propagate. Influenza A virus (IAV) and severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) both infect the human airway epithelium and are important human pathogens. The metabolic changes induced by these viruses in a physiologically relevant human model and how this affects innate immune responses to limit viral propagation are not well known. Using an ex vivo model of pseudostratified primary human airway epithelium, we here demonstrate that infection with both IAV and SARS-CoV-2 resulted in distinct metabolic changes including increases in lactate dehydrogenase A (LDHA) expression and LDHA-mediated lactate formation. Interestingly, LDHA regulated both basal and induced mitochondrial anti-viral signaling protein (MAVS)-dependent type I interferon (IFN) responses to promote IAV, but not SARS-CoV-2, replication. Our data demonstrate that LDHA and lactate promote IAV but not SARS-CoV-2 replication by inhibiting MAVS-dependent induction of type I IFN in primary human airway epithelium.

The aim was to study the number of accesses to the Emergency Room (ER) requiring psychiatric evaluation in the four months following the lockdown period for the COVID-19 outbreak (May 4th, 2020-August 31th, 2020). The study is a retrospective longitudinal observational study of the ER admissions of the Hospitals of Cesena and Forlì (Emilia Romagna region) leading to psychiatric assessment. Sociodemographic variables, history for medical comorbidities or psychiatric disorders, reason for ER admission, psychiatric diagnosis at discharge and measures taken by the psychiatrist were collected. An increase of 9.4% of psychiatric assessments was observed. The difference was more pronounced in the first two months after lockdown, with a 21.7% increase of number of ER accesses, while after two months numbers were the same as those of the year before. Admission with anxiety symptoms and history of psychiatric disorder decreased significantly. Moreover, there is an age trend with an increasing age of admission.

Alternative splicing (AS) of RNA is a key mechanism that results in the expression of multiple transcript isoforms from single genes and leads to an increase in the complexity of both the transcriptome and proteome. Regulation of AS is critical for the correct functioning of many biological pathways, while disruption of AS can be directly pathogenic in diseases such as cancer or cause risk for complex disorders. Current short-read sequencing technologies achieve high read depth but are limited in their ability to resolve complex isoforms. In this review we examine how long-read sequencing (LRS) technologies can address this challenge by covering the entire RNA sequence in a single read and thereby distinguish isoform changes that could impact RNA regulation or protein function. Coupling LRS with technologies such as single cell sequencing, targeted sequencing and spatial transcriptomics is producing a rapidly expanding suite of technological approaches to profile alternative splicing at the isoform level with unprecedented detail. In addition, integrating LRS with genotype now allows the impact of genetic variation on isoform expression to be determined. Recent results demonstrate the potential of these techniques to elucidate the landscape of splicing, including in tissues such as the brain where AS is particularly prevalent. Finally, we also discuss how AS can impact protein function, potentially leading to novel therapeutic targets for a range of diseases.

Aiming for a cost-effective and environmentally friendly material, we propose the replacement of glass fiber/poly(acrylonitrile-co-butadiene-co-styrene) (ABS) composites by composites with cellulosic reinforcing agents. Industrial production of these composites is hindered by high cost and/or fiber surface modification methods. We report that 30% in weight (wt. %) of pristine cellulose fibers (CF) are highly adherent to an ABS matrix, as verified by microscopy. This provides an overall enhancement of 20% in tensile and flexural mechanical properties. Fiber/matrix adhesion derives from the oxidation of polybutadiene (PB) segments during extrusion, which generates epoxide groups that react with hydroxyls from CF to form ether bonds. We used additives for testing improvement of fiber/matrix adhesion. The addition of XIBOND™ 160 (maleic anhydride grafted polystyrene) reduces fiber/matrix adhesion due to the competition between the grafting of cellulose fibers onto PS segments of the additive and PB domains of ABS. Lignin catalyzes the epoxide reaction with hydroxyls, which leads to improvements in flexural mechanical properties. Overall, ca. 20 wt. % of ABS can be effectively saved by adding 30 wt. % of CF, with improvement of mechanical properties. The density of the composites is 1.3 g cm−3, similar to glass fiber/ABS composite densities. Therefore, CF is effective as a reinforcing filler for ABS, reducing cost and improving mechanical properties.

Haploidentical hematopoietic stem cell transplantation (h-HSCT) represents an efficient curative approach for patients affected by hematologic malignancies in which the reduced intensity conditioning induces a state of immunologic tolerance between donor and recipient. However, opportunistic viral infections greatly affect h-HSCT clinical outcomes. NK cells are the first lymphocytes that recover after transplant and provide a prompt defense against human cytomegalovirus (HCMV) infection/reactivation. By undertaking a longitudinal single-cell computational profiling of multiparametric flow cytometry, we show that HCMV accelerates NK cell immune reconstitution together with the expansion of CD158b1b2jpos/NKG2Aneg/NKG2Cpos/NKp30lo NK cells. The frequency of this subset correlates with HCMV viremia, further increases in recipients experiencing multiple episodes of viral reactivations, and persists for months after the infection. The transcriptional profile of FACS-sorted CD158b1b2jpos NK cells confirmed the ability of HCMV to deregulate NKG2C, NKG2A, and NKp30 gene expression, thus inducing the expansion of NK cells with adaptive traits. These NK cells are characterized by the downmodulation of several gene pathways associated with cell migration, the cell cycle, and effector-functions, as well as by a state of metabolic/cellular exhaustion. This profile reflects the functional impairments of adaptive NK cells to produce IFN-γ, a phenomenon also due to the viral-induced expression of lymphocyte-activation gene 3 (LAG-3) and programmed cell death protein 1 (PD-1) checkpoint inhibitors.

Biological engineering of microorganisms to produce value-added chemicals is a promising route to sustainable manufacturing. However, overproduction of metabolic intermediates at high titer, rate, and yield from inexpensive substrates is challenging in non-model systems where limited information is available regarding metabolic flux and its control in production conditions. Integrated multi-omic analyses of engineered strains offers an in-depth look at metabolites and proteins directly involved in growth and production of target and non-target bioproducts. Here we applied multi-omic analyses to overproduction of the polymer precursor 3-hydroxypropionic acid (3HP) in the filamentous fungus Aspergillus pseudoterreus. A synthetic pathway consisting of aspartate decarboxylase, beta-alanine pyruvate transaminase, and 3HP dehydrogenase was designed and built for A. pseudoterreus. Strains with single- and multi-copy integration events were isolated and multi-omics analysis consisting of intracellular and extracellular metabolomics and targeted and global proteomics was used to interrogate the strains in shake-flask and bioreactor conditions. Production of a variety of co-products (organic acids and glycerol) and oxidative degradation of 3HP were identified as metabolic pathways competing with 3HP production. Intracellular accumulation of nitrogen as 2,4-diaminobutanoate was identified as an off-target nitrogen sink that may also limit flux through the engineered 3HP pathway. Elimination of the high-expression oxidative 3HP degradation pathway by deletion of a putative malonate semialdehyde dehydrogenase improved the yield of 3HP by 3.4 × after 10 days in shake-flask culture. This is the first report of 3HP production in a filamentous fungus amenable to industrial scale biomanufacturing of organic acids at high titer and low pH.

The main purpose of this paper is to show in general lines how divination is a key element in the construction of dramatic strategies in Aeschylus’ seven surviving plays, due to the fact that divination informs and defines both the singularity of the Aeschylean poetry and his worldview. Therefore, first, I will show how the most well-known features of Aeschylean tragedy come as a result of how the poet uses divination in his work. Then I will briefly discuss the presence of divination elements in the seven plays.

Personas have become an important tool for Human-Computer Interaction professionals. However, they are not immune to limits and critique, including stereotyping. We suggest that while some of the criticisms to personas are important, the use of personas is open to them in part because of an unquestioned focus on explicating user needs and goals. Traditionally indeed, personas and the associated scenarios are created by focusing on needs and goals of the target users. This focus, while helping designers, also obscures some other potentially relevant aspects. In particular, when the goal of the product or software being designed is associated with social and political goals rather than with bringing a product to the market, it may be relevant to focus personas on political aspirations, social values and the will of personas to take action. We argue that it would be possible when producing personas (and associated scenarios too) to partially move away from representing needs and embrace personas which more explicitly represent political or social beliefs. We suggest that drawing on phenomenography will allow to achieve this. We provide empirical evidence for our position from two large-scale European projects, the first one in the area of Social Innovation and the second in the area of eParticipation.

The cytogenetic hallmark of Chronic Myeloid Leukemia (CML) is the presence of Philadelphia (Ph) chromosome, which results from a reciprocal translocation t(9;22)(q34;q11). In this report, we describe a CML patient with no evidence of Ph chromosome but trisomy of chromosome 8 as single cytogenetic abnormality and a typical e14a2 (b3a2) BCR-ABL1 fusion transcript. Fluorescence In Situ Hybridization (FISH) analysis revealed an uncommon signal pattern: the fusion signals were located on both copies of chromosome 22. During the course of the disease the appearance of the p.(Tyr315Ile) mutation was recorded. To the best of our knowledge this is the first Ph chromosome-negative CML case with e14a2 (b3a2) BCR-ABL1 transcript and p.(Tyr315Ile) mutation.

PurposeTo explore the feasibility and efficacy of a dose intensification with Intensity Modulated Radiation Therapy and Simultaneous Integrated Boost (IMRT-SIB) in locally advanced esophageal and gastroesophageal cancer (GEJ).Methods and MaterialsWe retrospectively analyzed a series of 69 patients with esophageal or GEJ cancer treated at our Institute, between 2016 and 2019, with preoperative IMRT and SIB up to 52.5–54 Gy in 25 fractions in 5 weeks and concurrent carboplatin (AUC2) and paclitaxel (50 mg/m2), as in the CROSS regimen.ResultsAll patients completed the planned IMRT–SIB program with a median of four (range 1–5) cycles of concurrent paclitaxel/carboplatin. Compliance to IMRT–SIB was 93%, whereas 54% of patients received four to five cycles and 87% at least three cycles of concurrent carboplatin/paclitaxel. Grade 3 toxicity was reported in 19% of patients. Complete clinical response (cCR) was achieved in 48%, and 13% had disease progression after chemoradiation (CRT). Overall, 49% of patients underwent surgery; reasons for non-operation included cCR in cervical tumor location (10%) or cCR and patient decision (13%). A pathologic complete response (pCR) was achieved in 44% of resected patients. Postoperative complications and mortality rates were 21 and 6%, respectively. At a median follow-up of 12 months (6–25), 2-year overall and progression-free (PFS) survival rates were 81 and 54%, respectively. No difference in PFS by histologic type in operated patients was reported. Non-operated cCR patients had higher PFS, including cervical locations and selected cCR patients who decided for non-operation (75 vs 30%, p < 0.01).ConclusionThe study reported favorable results in safety and feasibility of the IMRT–SIB dose intensification in our preoperative CRT program. The toxicity was acceptable, allowing a high compliance to intensified radiation doses with dose reduction of concurrent paclitaxel/carboplatin in some patients. The high rate of cCR and pCR suggested this intensified program is effective in the preoperative CRT and, for selected responsive patients, in the non-operative approach to esophageal and GEJ cancer. The 2-year survival rates were promising. A prospective study is being planned to confirm these observations.

Tourism is capable of distributing wealth and participating substantially in the economic development of many countries. However, to ensure these benefits, the planning, management, and monitoring of a sustainable offer become crucial. Despite the increasingly widespread attention to sustainability in this sector, however, the concept of sustainable tourism still appears fragmented and fuzzy. The theoretical frameworks used in many studies often reduce sustainability to its environmental or social aspects and consider such pillars as separate issues. Furthermore, although most studies acknowledge that a potentially wide number of stakeholders play a role in sustainable tourism production, they have so far focused on host communities, tourism producers, or tourists themselves independently. Fewer explorations have addressed simultaneously different stakeholders, their perceptions of sustainable tourism experience, and the various concerns and tensions that may arise. This study aims to investigate sustainability issues in tourism by considering the voices of two relevant stakeholders involved in “co-producing” the tourism experience: tourists and tour operators. Based on a qualitative study conducted in Italy, the article critically discusses how travelers and tour operators craft the sustainability idea, the implicit assumptions that rely on their different perspectives, and their practical implications. The results highlight four different narratives on sustainable tourism, which are related to different assumptions on sustainability and actions legitimated to generate sustainable value. Finally, the article offers insights into how to develop a more holistic and critical approach to sustainable tourism through education and communication.

Resenha de: GONÇALVES, Guilherme Leite; COSTA, Sérgio. Um porto no capitalismo global: desvendando a acumulação entrelaçada no Rio de Janeiro. São Paulo: Boitempo, 2020. 152p.

This research aimed to evaluate the ideal proportion of two stabilizers in elastomeric compositions indicated for tire sidewall. The stabilizers applied in different proportions were N-1,3-dimethyl-butyl-N'-phenyl-p-phenylenediamine (6PPD) and oligomerized 2,2,4-trimethyl-quinoline (TMQ). Nine compositions were prepared with 0.5, 1.5 and 2.5 phr of 6PPD combined with 0.5, 1.0 and 1.5 phr of TMQ. The compounds were exposed to accelerated aging processes, including thermo-oxidative, photochemical and ozone chamber. Also, the samples were aged in the environment for 440 days. At regular intervals, the samples were evaluated. Gas chromatography was used to quantify the content of 6PPD. Overall, the samples exposed to thermo-oxidative aging showed the greatest loss of mechanical properties (tear and tensile strength) as well as the 6PPD content. From the mechanical strength results, it was possible to conclude that the best combination of stabilizers was 2.5 phr of 6PPD and 1.0 of TMQ.

BACKGROUND Calpains are present in almost all organisms and comprise a family of calcium-dependent cysteine peptidases implicated in crucial cellular functions. Trypanosoma cruzi, the causative agent of Chagas disease, presents an expansion on this gene family with unexplored biological properties. OBJECTIVES Here, we searched for calpains in the T. cruzi genome, evaluated the mRNA levels, calpain activity and the protein expression and determined the cellular localisation in all three parasite life cycle forms. METHODS/FINDINGS Sixty-three calpain sequences were identified in T. cruzi CL Brener genome, with fourteen domain arrangements. The comparison of calpain mRNA abundance by quantitative polymerase chain reaction (qPCR) revealed seven up-regulated sequences in amastigotes and/or bloodstream trypomastigotes and five in epimastigotes. Western Blotting analysis revealed seven different molecules in the three parasite forms, and one amastigote-specific, while no proteolytic activity could be detected. Flow cytometry assays revealed a higher amount of intracellular calpains in amastigotes and/or trypomastigotes in comparison to epimastigotes. Finally, ultrastructural analysis revealed the presence of calpains in the cytoplasm, vesicular and plasma membranes of the three parasite forms, and in the paraflagellar rod in trypomastigotes. CONCLUSION Calpains are differentially expressed and localised in the T. cruzi life cycle forms. This study adds data on the calpain occurrence and expression pattern in T. cruzi.

Ozonide antimalarials, OZ277 (arterolane) and OZ439 (artefenomel), are synthetic peroxide-based antimalarials with potent activity against the deadliest malaria parasite, Plasmodium falciparum. Here we used a "multi-omics" workflow, in combination with activity-based protein profiling (ABPP), to demonstrate that peroxide antimalarials initially target the haemoglobin (Hb) digestion pathway to kill malaria parasites. Time-dependent metabolomic profiling of ozonide-treated P. falciparum infected red blood cells revealed a rapid depletion of short Hb-derived peptides followed by subsequent alterations in lipid and nucleotide metabolism, while untargeted peptidomics showed accumulation of longer Hb-derived peptides. Quantitative proteomics and ABPP assays demonstrated that Hb-digesting proteases were increased in abundance and activity following treatment, respectively. Ozonide-induced depletion of short Hb-derived peptides was less extensive in a drug-treated K13-mutant artemisinin resistant parasite line (Cam3.IIR539T) than in the drug-treated isogenic sensitive strain (Cam3.IIrev), further confirming the association between ozonide activity and Hb catabolism. To demonstrate that compromised Hb catabolism may be a primary mechanism involved in ozonide antimalarial activity, we showed that parasites forced to rely solely on Hb digestion for amino acids became hypersensitive to short ozonide exposures. Quantitative proteomics analysis also revealed parasite proteins involved in translation and the ubiquitin-proteasome system were enriched following drug treatment, suggestive of the parasite engaging a stress response to mitigate ozonide-induced damage. Taken together, these data point to a mechanism of action involving initial impairment of Hb catabolism, and indicate that the parasite regulates protein turnover to manage ozonide-induced damage.

Human life intimately depends on plants for food, biomaterials, health, energy, and a sustainable environment. Various plants have been genetically improved mostly through breeding, along with limited modification via genetic engineering, yet they are still not able to meet the ever-increasing needs, in terms of both quantity and quality, resulting from the rapid increase in world population and expected standards of living. A step change that may address these challenges would be to expand the potential of plants using biosystems design approaches. This represents a shift in plant science research from relatively simple trial-and-error approaches to innovative strategies based on predictive models of biological systems. Plant biosystems design seeks to accelerate plant genetic improvement using genome editing and genetic circuit engineering or create novel plant systems through de novo synthesis of plant genomes. From this perspective, we present a comprehensive roadmap of plant biosystems design covering theories, principles, and technical methods, along with potential applications in basic and applied plant biology research. We highlight current challenges, future opportunities, and research priorities, along with a framework for international collaboration, towards rapid advancement of this emerging interdisciplinary area of research. Finally, we discuss the importance of social responsibility in utilizing plant biosystems design and suggest strategies for improving public perception, trust, and acceptance.

Understanding how regulators of inflammation affect nucleic acid sensing is important for targeting research against inflammatory diseases and conditions. Here, the authors identify Nrf2 as an important negative regulator of STING and suggest a link between metabolic reprogramming and antiviral cytosolic DNA sensing in human cells.

Acute pulmonary injury, or acute respiratory distress syndrome, has a high incidence in elderly individuals and high mortality in its most severe degree, becoming a challenge to public health due to pathophysiological complications and increased economic burden. Acute pulmonary injury can develop from sepsis, septic shock, and pancreatitis causing reduction of alveolar airspace due to hyperinflammatory response. Oxidative stress acts directly on the maintenance of inflammation, resulting in tissue injury, as well as inducing DNA damages. Once the DNA is damaged, enzymatic DNA repair mechanisms act on lesions in order to maintain genomic stability and, consequently, contribute to cell viability and homeostasis. Although palliative treatment based on mechanical ventilation and antibiotic using have a kind of efficacy, therapies based on modulation of DNA repair and genomic stability could be effective for improving repair and recovery of lung tissue in patients with acute pulmonary injury.

Abstract We identify a symplectic potential for general relativity in tetrad and connection variables that is fully gauge-invariant, using the freedom to add surface terms. When torsion vanishes, it does not lead to surface charges associated with the internal Lorentz transformations, and reduces exactly to the symplectic potential given by the Einstein-Hilbert action. In particular, it reproduces the Komar form when the variation is a Li derivative, and the geometric expression in terms of extrinsic curvature and 2d corner data for a general variation. The additional surface term vanishes at spatial infinity for asymptotically flat spacetimes, thus the usual Poincaré charges are obtained. We prove that the first law of black hole mechanics follows from the Noether identity associated with the covariant Lie derivative, and that it is independent of the ambiguities in the symplectic potential provided one takes into account the presence of non-trivial Lorentz charges that these ambiguities can introduce.

Jose Antonio Alves Torrano, or, as he is better known, JAA Torrano, abbreviation with which he has always signed his academic production, is a professor of Greek language and literature in the Department of Classical and Vernacular Letters of the Faculty of Philosophy, Letters and Sciences of the Universidade de São Paulo (FFLCH-USP).

Purpose: The aim of this study is to evaluate the long term survival of the addition of gefitinib to chemoradiotherapy (CRT) in locally advanced rectal cancer (LARC). Methods and materials: This previously published multicentre, open-label, phase I-II study, enrolled patients (pts) with LARC to receive CRT with concurrent 5-fluorouracil continuous intravenous infusion and a dose escalation of orally administered gefitinib, followed 6–8 weeks later by surgery. An intra-operative radiotherapy boost of 10 Gy was planned. Adjuvant chemotherapy was administrated in ypN1-2 pts. After a median f/u of >10 years, we analyzed Local Control (LC), Metastasis Free Survival (MFS), Disease Free Survival (DFS), Disease Specific Survival (DSS) and Overall Survival (OS). Predictive endpoints of clinical outcomes were tested by univariate and multivariate analysis. Variables analyzed included: age, gefitinib dose and interruptions, adjuvant CT, surgery type, ypT, ypN, and TRG grade. We have also analyzed late toxicity according to CTCAEv4. Results: Of the 41 initially enrolled pts, 39 were evaluable (27M, 12F). With a median f/u of 133 months, LC, MFS, DFS, OS and DSS at 5 years were 84%; 71%; 64%; 87% and 92%, respectively. The OS and DSS at 10 years were 61,5% and 76%, respectively. Grade 3-4 late toxicity occurred in 38% of pts: sexual (28,2%) and gastrointestinal toxicities (10,2%). Conclusion: Long term outcomes and late toxicity were similar to previously reported series. The addition of gefitinib did not improve outcomes in LARC. Gefitinib is not recommended for rectal cancer patients who received 5-FU based preoperative CRT. Further studies may identify if gefitinib is beneficial in selected group of patients. Keywords: Rectal cancer, Gefitinib, Log term follow-up, Chemoradiotherapy

Crassulacean acid metabolism (CAM) is a metabolic adaptation of photosynthesis that enhances water use efficiency. Here, via genomic analysis of Kalanchoë, the authors provide evidence for convergent evolution of protein sequence and temporal gene expression underpinning the multiple independent emergences of CAM.

Ibrutinib represents extraordinary progress in the treatment of chronic lymphocytic leukemia (CLL). However, treatment-related adverse events limit the benefit of this agent. This observational, multicenter study focused on the incidence, risk factors, and prognostic impact of infections in 494 patients with CLL treated with an ibrutinib-based treatment. Ibrutinib was given to 89 (18%) previously untreated patients (combined with rituximab, 24) and 405 (82%) relapsed/refractory patients. Pneumonia (PN), grade ≥3 non-opportunistic infections (NOI), and opportunistic infections (OI) were recorded in 32% of patients with an overall incidence rate per 100 person-year of 15.3% (PN, 10%; NOI, 3.3%; OI, 2%). Infections were the reason for the permanent discontinuation of ibrutinib in 9% of patients. Patients who experienced pneumonia or a severe infection showed a significantly inferior survival than those who were infection-free (p < 0.0001). A scoring system based on the three factors associated with a significant and independent impact on infections—PN or severe infection in the year before starting ibrutinib, chronic obstructive pulmonary disease, ≥2 prior treatments—identified patients with a two- to threefold increase in the rate of infections. In conclusion, the results of this study highlight the adverse impact of infectious events on the outcomes of CLL patients treated with ibrutinib.

Background: Type 1 Diabetes Mellitus (T1DM) is a widespread chronic disease in industrialized countries. Preventing blood glucose levels from exceeding the euglycaemic range would reduce the incidence of diabetes-related complications and improve the quality of life of subjects with T1DM. As a consequence, in the last decade, many Machine Learning algorithms aiming to forecast future blood glucose levels have been proposed. Despite the excellent performance they obtained, the prediction of abrupt changes in blood glucose values produced during physical activity (PA) is still one of the main challenges. Methods: A Jump Neural Network was developed in order to overcome the issue of predicting blood glucose values during PA. Three learning configurations were developed and tested: offline training, online training, and online training with reinforcement. All configurations were tested on six subjects suffering from T1DM that held regular PA (three aerobic and three anaerobic) and exploited Continuous Glucose Monitoring (CGM). Results: The forecasting performance was evaluated in terms of the Root-Mean-Squared-Error (RMSE), according to a paradigm of Precision Medicine. Conclusions: The online learning configurations performed better than the offline configuration in total days but not on the only CGM associated with the PA; thus, the results do not justify the increased computational burden because the improvement was not significant.

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Background: The Prognostic Nutritional Index (PNI) is a parameter of nutritional and inflammation status related to toxicity in cancer treatment. Since data for head and neck cancer are scanty, this study aims to investigate the association between PNI and acute and late toxicity for this malignancy. Methods: A retrospective cohort of 179 head and neck cancer patients treated with definitive radiotherapy with induction/concurrent chemotherapy was followed-up (median follow-up: 38 months) for toxicity and vital status between 2010 and 2017. PNI was calculated according to Onodera formula and low/high PNI levels were defined according to median value. Odds ratio (OR) for acute toxicity were calculated through logistic regression model; hazard ratios (HR) for late toxicity and survival were calculated through the Cox proportional hazards model. Results: median PNI was 50.0 (interquartile range: 45.5–53.5). Low PNI was associated with higher risk of weight loss > 10% during treatment (OR = 4.84, 95% CI: 1.73–13.53 for PNI < 50 versus PNI ≥ 50), which was in turn significantly associated with worse overall survival, and higher risk of late mucositis (HR = 1.84; 95% CI:1.09–3.12). PNI predicts acute weight loss >10% and late mucositis. Conclusions: PNI could help clinicians to identify patients undergoing radiotherapy who are at high risk of acute and late toxicity.

Background: To retrospectively evaluate the difference in terms of pathologic complete response (pCR) according to time elapsed between chemoradiation (CRT) and total mesorectal excision (TME) on a large unselected real-life dataset of locally advanced rectal cancer (LARC) patients. Methods: A multicentre retrospective cohort study of LARC patients from 21 Italian Radiotherapy Institutions was performed. Patients were stratified into 3 different time intervals from CRT. The 1st group included 300 patients who underwent TME within 6 weeks, the 2nd 1598 patients (TME within 7–12 weeks) and the 3rd 196 patients (TME within 13 or more weeks after CRT), respectively. Results: Data on 2094 LARC patients treated between 1997 and 2016 were considered suitable for analysis. Overall, 578 patients had stage II while 1516 had stage III histological proven invasive rectal adenocarcinoma. A CRT schedule of one agent (N = 1585) or 2-drugs (N = 509) was administered. Overall, pCR was 22.3% (N = 468 patients). The proportion of patients achieving pCR with respect to time interval was, as follows: 12.6% (1st group), 23% (2nd group) and 31.1% (3rd group) (p 5040 cGy (p = 0.002) and longer interval (p 13 weeks) from CRT to surgery improves the pathological response (pCR and pathologic partial response; pPR) in comparison to historic data. Furthermore, radiotherapy dose >5040 cGy and two drugs chemotherapy correlated with pPR rate.

Abstract During symbiosis, organisms use a range of metabolic and protein-based signals to communicate. Of these protein signals, one class is defined as ‘effectors’, i.e., small secreted proteins (SSPs) that cause phenotypical and physiological changes in another organism. To date, protein-based effectors have been described in aphids, nematodes, fungi and bacteria. Using RNA sequencing of Populus trichocarpa roots in mutualistic symbiosis with the ectomycorrhizal fungus Laccaria bicolor, we sought to determine if host plants also contain genes encoding effector-like proteins. We identified 417 plant-encoded putative SSPs that were significantly regulated during this interaction, including 161 SSPs specific to P. trichocarpa and 15 SSPs exhibiting expansion in Populus and closely related lineages. We demonstrate that a subset of these SSPs can enter L. bicolor hyphae, localize to the nucleus and affect hyphal growth and morphology. We conclude that plants encode proteins that appear to function as effector proteins that may regulate symbiotic associations.

Background: Sparse population-based data are available on the prevalence and etiology of chronic liver disease (CLD) in Italy. The study aims to assess the role of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection in CLD according to age, gender and ethnicity. Methods: Clinically diagnosed CLD in the general population aged 20–59 years in the Veneto Region (North-Eastern Italy) were identified through the Adjusted Clinical Groups System, by record linkage of the archive of subjects enrolled in the Regional Health System with Hospital Discharge Records, Emergency Room visits, Chronic disease registry for copayment exemptions, and the Home care database. Age-standardized prevalence rates (PR) were computed in Italians and immigrants, based on country of citizenship. Results: Overall 22,934 subjects affected by CLD in 2016 were retrieved, 21% related to HBV and 43% to HCV infection. The prevalence of HCV-related CLD was higher in males, peaking at 50–54 years (males = 11/1000; females = 4/1000). The PR of HBV-related CLD was almost negligible in the Italian population (1/1000), and higher among immigrants, especially from East Asia (males = 17/1000; females = 11/1000) and Sub-Saharan Africa (males = 13/1000; females = 10/1000). Conclusion: Specific population sub-groups identified by age, gender, and ethnicity, were demonstrated to be at increased risk, and these trends are in line with global epidemiological patterns of viral hepatitis.

The Grapevine Pinot Gris disease (GPG-d) is a novel disease characterized by symptoms such as leaf mottling and deformation, which has been recently reported in grapevines, and mostly in Pinot gris. Plants show obvious symptoms at the beginning of the growing season, while during summer symptom recovery frequently occurs, manifesting as symptomless leaves. A new Trichovirus, named Grapevine Pinot gris virus (GPGV), which belongs to the family Betaflexiviridae was found in association with infected plants. The detection of the virus in asymptomatic grapevines raised doubts about disease aetiology. Therefore, the primary target of this work was to set up a reliable system for the study of the disease in controlled conditions, avoiding interfering factor(s) that could affect symptom development. To this end, two clones of the virus, pRI::GPGV-vir and pRI::GPGV-lat, were generated from total RNA collected from one symptomatic and one asymptomatic Pinot gris grapevine, respectively. The clones, which encompassed the entire genome of the virus, were used in Agrobacterium-mediated inoculation of Vitis vinifera and Nicotiana benthamiana plants. All inoculated plants developed symptoms regardless of their inoculum source, demonstrating a correlation between the presence of GPGV and symptomatic manifestations. Four months post inoculum, the grapevines inoculated with the pRI::GPGV-lat clone developed asymptomatic leaves that were still positive to GPGV detection. Three to four weeks later (i.e. ca. 5 months post inoculum), the same phenomenon was observed in the grapevines inoculated with pRI::GPGV-vir. This observation perfectly matches symptom progression in infected field-grown grapevines, suggesting a possible role for plant antiviral mechanisms, such as RNA silencing, in the recovery process.