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OBJECTIVE: The dysregulation of the axon guidance pathway is common in pancreatic ductal adenocarcinoma (PDAC), yet our understanding of its biological relevance is limited. Here, we investigated the functional role of the axon guidance cue SEMA3A in supporting PDAC progression. DESIGN: We integrated bulk and single-cell transcriptomic datasets of human PDAC with in situ hybridisation analyses of patients tissues to evaluate SEMA3A expression in molecular subtypes of PDAC. Gain and loss of function experiments in PDAC cell lines and organoids were performed to dissect how SEMA3A contributes to define a biologically aggressive phenotype. RESULTS: In PDAC tissues, SEMA3A is expressed by stromal elements and selectively enriched in basal-like/squamous epithelial cells. Accordingly, expression of SEMA3A in PDAC cells is induced by both cell-intrinsic and cell-extrinsic determinants of the basal-like phenotype. In vitro, SEMA3A promotes cell migration as well as anoikis resistance. At the molecular level, these phenotypes are associated with increased focal adhesion kinase signalling through canonical SEMA3A-NRP1 axis. SEMA3A provides mouse PDAC cells with greater metastatic competence and favours intratumoural infiltration of tumour-associated macrophages and reduced density of T cells. Mechanistically, SEMA3A functions as chemoattractant for macrophages and skews their polarisation towards an M2-like phenotype. In SEMA3Ahigh tumours, depletion of macrophages results in greater intratumour infiltration by CD8+T cells and better control of the disease from antitumour treatment. CONCLUSIONS: Here, we show that SEMA3A is a stress-sensitive locus that promotes the malignant phenotype of basal-like PDAC through both cell-intrinsic and cell-extrinsic mechanisms.

How RNA-binding proteins (RBPs) convey regulatory instructions to the core effectors of RNA processing is unclear. Here, we document the existence and functions of a multivalent RBP-effector interface. We show that the effector interface of a conserved RBP with an essential role in metazoan development, Unkempt, is mediated by a novel type of dual-purpose peptide motifs that can contact two different surfaces of interacting proteins. Unexpectedly, we find that the multivalent contacts do not merely serve effector recruitment but are required for the accuracy of RNA recognition by Unkempt. Systems analyses reveal that multivalent RBP-effector contacts can repurpose the principal activity of an effector for a different function, as we demonstrate for the reuse of the central eukaryotic mRNA decay factor CCR4-NOT in translational control. Our study establishes the molecular assembly and functional principles of an RBP-effector interface.

Retinitis pigmentosa (RP) is a common form of retinal dystrophy that can be caused by mutations in any one of dozens of rod photoreceptor genes. The genetic heterogeneity of RP represents a significant challenge for the development of effective therapies. Here, we present evidence for a potential gene-independent therapeutic strategy based on targeting Nr2e3, a transcription factor required for the normal differentiation of rod photoreceptors. Nr2e3 knockout results in hybrid rod photoreceptors that express the full complement of rod genes, but also a subset of cone genes. We show that germline deletion of Nr2e3 potently protects rods in three mechanistically diverse mouse models of retinal degeneration caused by bright-light exposure (light damage), structural deficiency (rhodopsin-deficient Rho-/- mice), or abnormal phototransduction (phosphodiesterase-deficient rd10 mice). Nr2e3 knockout confers strong neuroprotective effects on rods without adverse effects on their gene expression, structure, or function. Furthermore, in all three degeneration models, prolongation of rod survival by Nr2e3 knockout leads to lasting preservation of cone morphology and function. These findings raise the possibility that upregulation of one or more cone genes in Nr2e3-deficient rods may be responsible for the neuroprotective effects we observe.

Abstract Background Metabolic syndrome represents a pancreatic ductal adenocarcinoma (PDAC) risk factor. Metabolic alterations favor PDAC onset, which occurs early upon dysmetabolism. Pancreatic neoplastic lesions evolve within a dense desmoplastic stroma, consisting in abundant extracellular matrix settled by cancer associated fibroblasts (CAFs). Hereby, dysmetabolism and PDAC association was analyzed focusing on CAF functions. Methods PDAC development upon dysmetabolic conditions was investigated in: 1) high fat diet fed wild type immunocompetent syngeneic mice by orthotopic transplantation of pancreatic intraepithelial neoplasia (PanIN) organoids; and 2) primary pancreatic CAFs isolated from chemotherapy naïve PDAC patients with/without an history of metabolic syndrome. Results The dysmetabolic-associated higher PDAC aggressiveness was paralleled by collagen fibril enrichment due to prolyl 4-hydroxylase subunit alpha 1 (P4HA1) increased function. Upon dysmetabolism, P4HA1 boosts collagen proline hydroxylation, intensifies collagen contraction strength, precluding PDAC infiltration. Noteworthy, semaglutide, an incretin agonist, prevents the higher dysmetabolism-dependent PDAC stromal deposition and allows T lymphocyte infiltration, reducing tumor development. Conclusions These results shed light on novel therapeutic options for PDAC patients with metabolic syndrome aimed at PDAC stroma reshape.

Abstract Neuronal population activity in sensory cortices is the substrate for perceptual decisions. Yet, we still do not understand how neuronal information content in sensory cortices relates to behavioral reports. To reconcile neurometric and psychometric performance, we recorded the activity of V1 neurons in mice performing a Go/NoGo orientation discrimination task. We found that, around the discrimination threshold, V1 does not represent the orientation of the stimuli as canonically expected. Instead, it forms categorical representations characterized by a relocation of activity at task-relevant domains of the orientation representational space. The relative neuronal activity at those discrete domains accurately predicted the probabilities of the animals’ decisions. Our results thus suggest that the categorical integration of discretized feature representations from sensory cortices explains perceptual decisions.

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadly type of cancer, with an extremely low five-year overall survival rate. To date, current treatment options primarily involve various chemotherapies, which often prove ineffective and are associated with substantial toxicity. Furthermore, immunotherapies utilizing checkpoint inhibitors have shown limited efficacy in this context, highlighting an urgent need for novel therapeutic strategies. This study investigates the preclinical efficacy of an innovative targeted therapy based on antibody-cytokine fusion proteins, specifically interleukin-2 (IL-2), a pivotal driver of cell-mediated immunity, fused to L19 antibody, which selectively binds to extra domain B of fibronectin (EDB-FN1) expressed in the tumor microenvironment. Methods We tested the effectiveness of different immunocytokines through in vivo characterization in syngeneic C57BL/6J orthotopic mouse models of PDAC. Based on these results, we decided to focus on L19-IL2. To assess the efficacy of this immunocytokine we developed an ex-vivo immune-spheroid interaction platform derived from murine 3D pancreatic cultures, and telomerase reverse transcriptase (TERT) specific T-lymphocytes. Moreover, we evaluated the anti-cancer effect of L19-IL2 in combination with standard therapy in vivo experiments in PDAC mouse models. Tumor samples collected after the treatments were characterized for tumor infiltrating immune cell components by bulk RNA sequencing (RNA-seq) and spatial transcriptomics (Stereo-seq) analysis. Results The tumor-targeted L19-IL2 fusion protein demonstrated potent, dose-dependent anti-tumor activity in mice with pancreatic tumors resistant to standard chemotherapy. Spatial Transcriptomics (ST) and RNA-seq analyses indicated that L19-IL2 treatment induced a significant influx of immune cells into the tumor microenvironment, with these cells expressing activation markers like granzymes, perforins, and the IL-2 receptors. Conclusions Our results demonstrated that L19-IL2 enhances immune infiltration and cytotoxicity, remodeling the “cold” tumor microenvironment (TME) in PDAC. This innovative antibody-cytokine fusion protein improves therapeutic outcomes, paving the way for novel targeted treatment strategies in PDAC.

Los Entornos Virtuales de Aprendizaje son cada vez más empleados en el diseño de estrategias de capacitación a especialistas interesados en promocionar, socializar y divulgar los resultados científicos de sus investigaciones. Por tal razón el objetivo de la investigación fue diseñar una estrategia de capacitación en Entornos Virtuales de Aprendizaje para la divulgación científica en la Autoridad Nacional Reguladora. Para dar cumplimiento a lo anteriormente expuesto, se emplearon diferentes métodos teóricos, empíricos y estadísticos-matemáticos que permitieron determinar los fundamentos teórico-metodológicos de la investigación, el análisis de los indicadores y la estructura de la estrategia. La estrategia propuesta estuvo estructurada por un sistema de acciones, divididas en cuatro etapas: Diagnóstico, Planificación, Ejecución y Evaluación. El diagnóstico permitió identificar las necesidades de aprendizaje de los especialistas. Luego se planificaron los programas de capacitación para la divulgación de resultados científicos. Se desarrolló un curso virtual de redacción y publicación científica y talleres de publicación en la Revista de Regulación Sanitaria. Se comprobó la efectividad de las acciones a través del monitoreo continuo de las etapas y la valoración de los resultados de la capacitación de los especialistas en la divulgación científica. La estrategia diseñada fue flexible, integradora y se ajustó a las necesidades propias de los especialistas de la institución.

The present study investigated spatial dynamic functional network connectivity (dFNC) in patients with functional hemiparesis (i.e., functional stroke mimics, FSM). The aim of this work was to assess static functional connectivity (large-scale) networks and dynamic brain states, which represent distinct dFNC patterns that reoccur in time and across subjects. Resting-state fMRI data were collected from 15 patients with FSM (mean age = 42.3 ± 9.4, female = 80 %) and 52 age-matched healthy controls (HC, mean age = 42.1 ± 8.6, female = 73 %).Each patient underwent a resting-state functional MRI scan for spatial dFNC evaluation and transcranial magnetic stimulation protocols for indirect assessment of GABAergic and glutamatergic transmission. We considered three dynamic brain networks, i.e., the somatomotor network (SMN), the default mode network (DMN) and the salience network (SN), each summarized into four distinct recurring spatial configurations. Compared to HC, patients with FSM showed significant decreased dwell time, e.g. the time each individual spends in each spatial state of each network, in state 2 of the SMN (HC vs. FSM, 13.5 ± 27.1 vs. 1.9 ± 4.1, p = 0.044). Conversely, as compared to HC, FSM spent more time in state 1 of the DMN (10.8 ± 14.9 vs. 27.3 ± 38.9, p = 0.037) and in state 3 of the SN (23.1 ± 23.0 vs. 38.8 ± 38.2, p = 0.002). We found a significant correlation between the dwell time of impaired functional state of the SMN and measures of GABAergic neurotransmission (r = 0.581, p = 0.037). Specifically, longer impaired dwell time was associated with greater GABAergic inhibition. These findings demonstrate that FSM present altered functional brain network dynamics, which correlate with measures of GABAergic neurotransmission. Both dFNC and GABAergic neurotransmission may serve as potential targets for future intervention strategies.

Background Treatment with immunotherapy can elicit varying responses across cancer types, and the mechanistic underpinnings that contribute to response vrsus progression remain poorly understood. However, to date there are few preclinical models that accurately represent these disparate disease scenarios.Methods Using combinatorial radio-immunotherapy consisting of PD-1 blockade, IL2Rβγ biased signaling, and OX40 agonism we were able to generate preclinical tumor models with conflicting responses, where head and neck squamous cell carcinoma (HNSCC) models respond and pancreatic ductal adenocarcinoma (PDAC) progresses.Results By modeling these disparate states, we find that regulatory T cells (Tregs) are expanded in PDAC tumors undergoing treatment, constraining tumor reactive CD8 T cell activity. Consequently, the depletion of Tregs restores the therapeutic efficacy of our treatment and abrogates the disparity between models. Moreover, we show that through heterotopic implantations the site of tumor development defines the response to therapy, as implantation of HNSCC tumors into the pancreas resulted in comparable levels of tumor progression.Conclusions This work highlights the complexity of combining immunotherapies within the tumor microenvironment (TME) and further defines the immune and non-immune components of the TME as an intrinsic feature of immune suppression.

El desarrollo del campo historiográfico en Uruguay, aunque se consolidó tardíamente en comparación con Argentina, experimentó un crecimiento significativo hacia mediados del siglo XX. Juan Antonio Oddone desempeñó un papel crucial en este proceso. El objetivo de este artículo es examinar su contribución a la emergencia y consolidación de la "Nueva Historia". Se analiza su trayectoria desde 1947, cuando ingresó como estudiante en la Facultad de Humanidades y Ciencias de la Universidad de la República, hasta 1985, con su retorno del exilio. Para ello, se recurre a sus memorias póstumas, tituladas Mirando atrás. Historia y Memoria, y a su epistolario, conservado en el Archivo General de la Universidad de la República. Esta comunicación constituye un avance de una investigación en curso. Aunque el enfoque se centra en Uruguay, es importante reconocer que su contexto es inherentemente rioplatense, sugiriendo que el alcance de sus conclusiones puede extenderse más allá de las fronteras nacionales.

Este dosier pretende contribuir al conocimiento sobre la escritura de la historia en Argentina, Uruguay y Paraguay a partir de la experiencia investigadora en archivos personales y el estudio de algunos tipos de escritos autobiográficos de historiadores.

The search for a sustainable food system represents a major scientific challenge, as the food products and especially the waste/residues generated, in the various stages of the food chain, continue to grow. Almonds are appreciated worldwide for their sensory, nutritional and functional properties, but also for their great versatility. The expanding market for almonds and almond products (almond oil, almond milk, almond butter etc.) has led to generation of tons of by-products along the processing chain (hull, shell, skin, blanched water etc.). Various scientific papers proved that almond by-products contain an interesting amount of bioactive compounds, thus increasing the scientific interest in their potential reuse. Almond by-products have been examined mainly for their phytochemical composition, for bioethanol production, and for animal feed. Therefore, this review seeks to complete the knowledge dedicated to the valorization of such by-products especially for the food sector, suggesting further applications for reformulating traditional food products or to develop the new ones.

This study assessed healthcare workers’ (HCWs) knowledge and adherence to hand hygiene principles in a large Italian university hospital, focusing on identifying knowledge gaps and evaluating training effectiveness. A specifically designed 17-item questionnaire, based on the World Health Organization (WHO) Hand Hygiene Knowledge Questionnaire, was used to measure theoretical knowledge, the role of training, and the impact of experience. The survey had an 8% participation rate (542 responses from a total of 6,749 HCWs), with higher responses among nurses and doctors. Results showed moderate knowledge of hand hygiene protocols, averaging 74%, but revealed gaps in comprehension, particularly in the correct use of hand rub and post-contact sanitation. Logistic regression analysis identified significant predictors of knowledge and adherence, with professional characteristics such as professional qualifications and length of service influencing outcomes (p

Elderly individuals affected by neurodegenerative diseases or cerebrovascular disorders commonly exhibit a progressive decline in cognitive function, accompanied by psychiatric and neurobehavioral symptoms that may be ameliorated through the utilisation of non-pharmacological interventions. The primary aim of this study was to assess the effectiveness of novel intervention approaches with technological tools for cognitive stimulation in a geriatric population experiencing cognitive impairment. Interactive cognitive stimulation activities, integrating a robust musical element, were employed not only to enhance cognitive functions but also to promote social interaction among participants. Eight Italian long-term care homes (LTCHs) and day centres, along with two facilities in Switzerland, participated in the study. Each facility was provided with an interactive table featuring serious games, available for approximately one month. Subjects voluntarily engaged in group-based stimulation sessions comprising two to four individuals. A total of 25 health assistants and 110 subjects with cognitive impairment took part in the study. Overall, there was a significant improvement in participants’ QUALID scores upon completion of the study (t = 2.9191; df = 99; p < 0.005). Interestingly, individuals who attended a greater number of sessions exhibited more pronounced psychiatric and behavioural symptoms, as well as lower quality of life scores at both the beginning (T0) and end (T1) of the trial. It is important to note that this study was not a randomized controlled trial (RCT) and participant recruitment was based on voluntary participation without strict inclusion criteria for ensuring proper randomization. This pioneering approach demonstrates the capacity to synergistically enhance conventional methods of cognitive stimulation and socialization for elderly individuals with cognitive impairment.