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This article compares the use of discourse markers (DMs) in Italian as a second language (L2) produced by Belgian-Dutch learners, with the DMs produced by Italian native (L1) speakers. The quantitative analysis of the data shows that L1 speakers produce more DMs than L2 speakers, whereas the comparison between the levels of proficiency in L2 reveals an effect of the type of task on the frequency of DMs. From the qualitative analysis, interesting discrepancies emerge between the L1 and the L2 use of DMs, especially those uttered in sentence-internal position. We offer an analysis within the cartographic approach and we demonstrate that the sentence-internal DMs with an epistemic value realize specific syntactic positions dedicated to the expression of modality within the IP layer. We also show that the L2 learners, despite projecting the correct syntactic structure, realize it with pragmatically infelicitous forms as a result of linguistic interference with their L1. Our study brings original evidence on the syntactic status of DMs: given their multifunctionality, more syntactic options are available depending on the markers' discursive and pragmatic import. Furthermore, sentence-internal DMs reveal intriguing properties of the L2 acquisition at the syntax and discourse--pragmatics interface.

This research set out to evaluate video material contained within the English learning coursebook "English M1" which was designed for self-access use. "English M1" is a Brazilian government-sponsored piece of material available for free. It is the first stage of a course that learners would complete independently, unmediated by a teacher. The audiovisual material included a short narrative and two aspects of this were chosen for evaluation: the learners' perception of the language learning affordances of the episodes and how the story appealed to their interest. There is little research carried out on the post use of materials which draws on learners' reports about how they engaged with self-access material. Retrospective evaluations, however, can generate relevant and learner-based criteria for future materials design. This research used semi-structured interviews to gather data about how the learners engaged with the videos, their reasons for doing things in the way they did and their opinion about the plot. Key findings included that self-access materials must provide learners with guidance concerning the affordances of the material and how it could be used as well as optionality in what is delivered for increased chances of relevance and engagement. The article ends with recommendations for the design of video material in self-access materials.

Abstract There are millions of river barriers worldwide, ranging from wooden locks to concrete dams, many of which form associated impoundments to store water in small ponds or large reservoirs. Besides their benefits, there is growing recognition of important environmental and social trade-offs related to these artificial structures. However, global datasets describing their characteristics and geographical distribution are often biased towards particular regions or specific applications, such as hydropower dams affecting fish migration, and are thus not globally consistent. Here, we present a new river barrier and reservoir database developed by the Global Dam Watch (GDW) consortium that integrates, harmonizes, and augments existing global datasets to support large-scale analyses. Data curation involved extensive quality control processes to create a single, globally consistent data repository of instream barriers and reservoirs that are co-registered to a digital river network. Version 1.0 of the GDW database contains 41,145 barrier locations and 35,295 associated reservoir polygons representing a cumulative storage capacity of 7,420 km3 and an artificial terrestrial surface water area of 304,600 km2.

Abstract In cells, signal transduction heavily relies on the intricate regulation of protein kinases, which provide the fundamental framework for modulating most signaling pathways. Dysregulation of kinase activity has been implicated in numerous pathological conditions, particularly in cancer. The druggable nature of most kinases positions them into a focal point during the process of drug development. However, a significant challenge persists, as the role and biological function of nearly one third of human kinases remains largely unknown. Within this diverse landscape, cyclin-dependent kinases (CDKs) emerge as an intriguing molecular subgroup. In human, this kinase family encompasses 21 members, involved in several key biological processes. Remarkably, 13 of these CDKs belong to the category of understudied kinases, and only 5 having undergone broad investigation to date. This knowledge gap underscores the pressing need to delve into the study of these kinases, starting with a comprehensive review of the less-explored ones. Here, we will focus on the PCTAIRE subfamily of CDKs, which includes CDK16, CDK17, and CDK18, arguably among the most understudied CDKs members. To contextualize PCTAIREs within the spectrum of human pathophysiology, we conducted an exhaustive review of the existing literature and examined available databases. This approach resulted in an articulate depiction of these PCTAIREs, encompassing their expression patterns, 3D configurations, mechanisms of activation, and potential functions in normal tissues and in cancer. We propose that this effort offers the possibility of identifying promising areas of future research that extend from basic research to potential clinical and therapeutic applications.

In this study, we investigated whether different morphosyntactic features, i.e. number and gender, play a role during the adult online comprehension of subject relative clauses (SRC) and object relative clauses (ORC), in Italian. This study was inspired by developmental studies showing that children struggle with ORC compared to SRC; yet, ORC comprehension improves if the head and the subject of the RC mismatch in relevant morphosyntactic features (e.g. number but not gender in Italian, based on the featural Relativized Minimality principle, fRM). We found that Italian adults read ORC more slowly than SRC verbs; moreover, ORC verbs were read faster in the head-subject number mismatch condition, while there was no facilitation in the head-subject gender mismatch condition, in line with developmental studies and fRM. We conclude that online parsing is feature-sensitive, that features are not all equally “relevant”, and that current models should be refined to account for these differences.

Abstract Platinum (PT)-resistant Epithelial Ovarian Cancer (EOC) grows as a metastatic disease, disseminating in the abdomen and pelvis. Very few options are available for PT-resistant EOC patients, and little is known about how the acquisition of PT-resistance mediates the increased spreading capabilities of EOC. Here, using isogenic PT-resistant cells, genetic and pharmacological approaches, and patient-derived models, we report that Integrin α6 (ITGA6) is overexpressed by PT-resistant cells and is necessary to sustain EOC metastatic ability and adhesion-dependent PT-resistance. Using in vitro approaches, we showed that PT induces a positive loop that, by stimulating ITGA6 transcription and secretion, contributes to the formation of a pre-metastatic niche enabling EOC cells to disseminate. At molecular level, ITGA6 engagement regulates the production and availability of insulin-like growth factors (IGFs), over-stimulating the IGF1R pathway and upregulating Snail expression. In vitro data were recapitulated using in vivo models in which the targeting of ITGA6 prevents PT-resistant EOC dissemination and improves PT-activity, supporting ITGA6 as a promising druggable target for EOC patients.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, characterized by an intense desmoplastic reaction that compresses blood vessels and limits nutrient supplies. PDAC aggressiveness largely relies on its extraordinary capability to thrive and progress in a challenging tumor microenvironment. Dysregulation of the onco-suppressor miR-15a has been extensively documented in PDAC. Here, we identified the transcription factor Fos-related antigen-2 (Fra-2) as a miR-15a target mediating the adaptive mechanism of PDAC to nutrient deprivation. We report that the IGF1 signaling pathway was enhanced in nutrient deprived PDAC cells and that Fra-2 and IGF1R were significantly overexpressed in miR-15a downmodulated PDAC patients. Mechanistically, we discovered that miR-15a repressed IGF1R expression via Fra-2 targeting. In miR-15a-low context, IGF1R hyperactivated mTOR, modulated the autophagic flux and sustained PDAC growth in nutrient deprivation. In a genetic mouse model, Mir15aKO PDAC showed Fra-2 and Igf1r upregulation and mTOR activation in response to diet restriction. Consistently, nutrient restriction improved the efficacy of IGF1R inhibition in a Fra-2 dependent manner. Overall, our results point to a crucial role of Fra-2 in the cellular stress response due to nutrient restriction typical of pancreatic cancer and support IGF1R as a promising and vulnerable target in miR-15a downmodulated PDAC.

Abstract The extracellular matrix (ECM) is an important component of the tumor microenvironment and undergoes extensive remodeling during both initiation and progression of breast cancer (BC). EMILIN1 is an ECM glycoprotein, whose function has been linked to cancer and metastasis. However, EMILIN1 role during mammary gland and BC development has never been investigated. In silico and molecular analyses of human samples from normal mammary gland and BC showed that EMILIN1 expression was lower in tumors than in healthy mammary tissue and it predicted poor prognosis, particularly in HER2-positive BC. HER2+ BC accounts for 15-20% of all invasive BC and is characterized by high aggressiveness and poor prognosis. The Δ16HER2 isoform, a splice variant with very high oncogenic potential, is frequently expressed in HER2+ BC and correlates with metastatic disease. To elucidate the role of EMILIN1 in BC, we analyzed the phenotype of MMTV-Δ16HER2 transgenic mice, developing spontaneous multifocal mammary adenocarcinomas, crossed with EMILIN1 knock-out (KO) animals. We observed that Δ16HER2/EMILIN1 KO female mice exhibited an accelerated normal mammary gland development and a significantly anticipated appearance of palpable tumors (13.32 vs 15.28 weeks). This accelerated tumor initiation was corroborated by an increased number of tumor foci observed in mammary glands from Δ16HER2/EMILIN1 KO mice compared to the wild-type counterpart. Altogether our results underscore the centrality of ECM in the process of BC initiation and point to a role for EMILIN1 during normal mammary gland development and in protecting from HER2-driven breast tumorigenesis.

Present bladder cancer therapies have relatively limited therapeutic impact and account for one of the highest lifetime treatment costs per patient. Therefore, there is an urgent need to explore novel and optimized treatment strategies. The present study investigated the effects of inhibiting endogenous hydrogen sulfide (H2S) production on bladder cell viability and in vivo tumor progression. We targeted the H2S-producing enzyme, cystathionine γ-lyase, in 5637 cells using propargylglycine (H2S inhibitor) and performed cytofluorimetric analysis to evaluate cell viability. We then tested the efficacy of propargylglycine alone or in combination with gemcitabine (conventional chemotherapy) in an intravesical murine model of bladder cancer. Magnetic resonance imaging and immunohistochemical staining for cell proliferation, apoptosis, immune-cell infiltration, and neovascularization were performed to evaluate tumor response. Compared to control conditions or cohorts, propargylglycine administration significantly attenuated bladder cancer cell viability in vitro (p < 0.0001) and tumor growth (p < 0.002) and invasion in vivo. Furthermore, propargylglycine enhanced the anti-cancer effects of gemcitabine, resulting in tumor regression (p < 0.0001). Moreover, propargylglycine induced cleaved PARP-1-activated apoptosis (p < 0.05), as well as intratumoral CD8+ T cell (p < 0.05) and F4/80+ macrophage (p < 0.002) infiltration. Propargylglycine also reduced intratumoral neovascularization (p < 0.0001) and cell proliferation (p < 0.0002). Importantly, the pro-apoptotic and anti-neovascularization effects of gemcitabine were enhanced by propargylglycine co-administration. Our findings suggest that inhibition of endogenous H2S production can be protective against bladder cancer by enhancing the chemotherapeutic action of gemcitabine and may be a novel pharmacological target and approach for improved bladder cancer diagnosis and treatments in the future.

Farmers’ Markets (FMs) have gained relevance in recent years as increasingly acknowledged to be critical to turn to more equitable food systems, easing agroecological transition, and preserving biocultural heritage. However, the issue of the forms of social and institutional coordination needed to create, organize, manage and promote FMs is a recent topic in the literature, and their governance is still poorly considered. Based on a set of case studies in Tuscany, Italy, this paper intends to contribute to filling this gap by analysing the forms of governance and the role of different stakeholders. The hypothesis is that FMs are social constructions that respond to processes of social and institutional innovation through direct exchanges between producers, consumers and other stakeholders, articulated at both local and non-local level. The aim of the paper is to explore the interactions between stakeholders and the corresponding forms of multi-level governance that emerge. The method for testing the hypotheses is qualitative, through semi-structured interviews to FMs managers and conversations with producers and other stakeholders, conducted between May and August 2022 in Tuscany. The research was complemented by consultation of indirect sources, such as FMs websites and social networks. The results are summarized in the elaboration of a three-dimensional and territorially embedded governance model. The first dimension refers to the management of internal relations between stakeholders within the FM. The second corresponds to the activation of dialogue, negotiation, and agreement with the municipality and other local authorities, and with local farmers’ unions. The third type corresponds to vertical flows between the FMs and extraterritorial bodies, i.e., regional government, regional and national farmers’ unions and other stakeholder associations. It is important to note that at FMs level, processes of hybridization between the different types of governance are established. The article contributes to the analysis of FMs as economic and social constructions and may be useful for establishing comparative frameworks around institutional and collective action dimensions, multi-actor and multilevel studies of governance.

Introduction: Growing evidence supports extracorporeal cardiopulmonary resuscitation (ECPR) for refractory out-of-hospital cardiac arrest (OHCA) patients, especially in experienced centres. We present characteristics, treatments, and outcomes of patients treated with ECPR in a high-volume cardiac arrest centre in the metropolitan area of Milan, Italy and determine prognostic factors. Methods: Refractory OHCA patients treated with ECPR between 2013 and 2022 at IRCCS San Raffaele Scientific Institute in Milan had survival and neurological outcome assessed at hospital discharge. Results: Out of 307 consecutive OHCA patients treated with ECPR (95% witnessed, 66% shockable, low-flow 70 [IQR 58–81] minutes), 17% survived and 9.4% had favourable neurological outcome. Survival and favourable neurological outcome increased to 51% (OR = 8.7; 95% CI, 4.3–18) and 28% (OR = 6.3; 95% CI, 2.8–14) when initial rhythm was shockable and low-flow (time between CPR initiation and ROSC or ECMO flow) ≤60 minutes and decreased to 9.5% and 6.3% when low-flow exceeded 60 minutes (72% of patients). At multivariable analysis, shockable rhythm (aOR for survival = 2.39; 95% CI, 1.04–5.48), shorter low-flow (aOR = 0.95; 95% CI, 0.94–0.97), intermittent ROSC (aOR = 2.5; 95% CI, 1.2–5.6), and signs of life (aOR = 3.7; 95% CI, 1.5–8.7) were associated with better outcomes. Survival reached 10% after treating 104 patients (p for trend

Abstract Reprogramming of amino acid metabolism, sustained by oncogenic signaling, is crucial for cancer cell survival under nutrient limitation. Here we discovered that missense mutant p53 oncoproteins stimulate de novo serine/glycine synthesis and essential amino acids intake, promoting breast cancer growth. Mechanistically, mutant p53, unlike the wild-type counterpart, induces the expression of serine-synthesis-pathway enzymes and L-type amino acid transporter 1 (LAT1)/CD98 heavy chain heterodimer. This effect is exacerbated by amino acid shortage, representing a mutant p53-dependent metabolic adaptive response. When cells suffer amino acids scarcity, mutant p53 protein is stabilized and induces metabolic alterations and an amino acid transcriptional program that sustain cancer cell proliferation. In patient-derived tumor organoids, pharmacological targeting of either serine-synthesis-pathway and LAT1-mediated transport synergizes with amino acid shortage in blunting mutant p53-dependent growth. These findings reveal vulnerabilities potentially exploitable for tackling breast tumors bearing missense TP53 mutations.