miRNAs as Influencers of Cell-Cell Communication in Tumor Microenvironment

microRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the posttranscriptional level, inducing the degradation of the target mRNA or translational repression. MiRNAs are involved in the control of a multiplicity of biological processes, and their absence or altered expression has been associated with a variety of human diseases, including cancer. Recently, extracellular miRNAs (ECmiRNAs) have been described as mediators of intercellular communication in multiple contexts, including tumor microenvironment. Cancer cells cooperate with stromal cells and elements of the extracellular matrix (ECM) to establish a comfortable niche to grow, to evade the immune system, and to expand. Within the tumor microenvironment, cells release ECmiRNAs and other factors in order to influence and hijack the physiological processes of surrounding cells, fostering tumor progression. Here, we discuss the role of miRNAs in the pathogenesis of multicomplex diseases, such as Alzheimer's disease, obesity, and cancer, focusing on the contribution of both intracellular miRNAs, and of released ECmiRNAs in the establishment and development of cancer niche. We also review growing evidence suggesting the use of miRNAs as novel targets or potential tools for therapeutic applications

Pneumo- and neurotropism of avian origin Italian highly pathogenic avian influenza H7N1 isolates in experimentally infected mice

AbstractAn experimental infection of mice was performed in order to investigate the potential for interspecies transmission in mammals of Italian HPAI viruses of the H7N1 subtype. Three avian origin isolates were selected, two strains obtained from ostrich (one of which contained a PB2-627 Lysine residue) and one from a chicken. Following intranasal infection of mice, clinical signs and mortality were recorded in the experimental groups challenged with the two ostrich isolates, while only weight loss was observed in those receiving the chicken strain. Viruses were recovered to a varying extent from respiratory and nervous tissues of infected animals. These results suggest that HPAI viruses, other than H5N1 and H7N7, may have zoonotic implications, and support the consensus that AI infections in poultry are to be eradicated rather than contained

Hyperspectral imaging with deformable gratings fabricated with metal-elastomer nanocomposites

We report the fabrication and characterization of a simple and compact hyperspectral imaging setup based on a stretchable diffraction grating made with a metal-polymer nanocomposite. The nanocomposite is produced by implanting Ag clusters in a poly(dimethylsiloxane) film by supersonic cluster beam implantation. The deformable grating has curved grooves and is imposed on a concave cylindrical surface, thus obtaining optical power in two orthogonal directions. Both diffractive and optical powers are obtained by reflection, thus realizing a diffractive-catoptric optical device. This makes it easier to minimize aberrations. We prove that, despite the extended spectral range and the simplified optical scheme, it is actually possible to work with a traditional CCD sensor and achieve a good spectral and spatial resolution

La qualità dell’assistenza infermieristica in ambito oncologico: protocollo di validazione dello strumento Quality of Oncology Nursing Care Scale (QONCS)

BACKGROUND: Nurses play a key role in the care of people with cancer. Providing quality nursing care means responding appropriately to the physical and psychosocial needs of the patient. The Quality of Oncology Nursing Care Scale (QONCS) tool is the first tool to be developed on a consolidated conceptual model that includes the main themes emerging from previous studies concerning the quality of oncology nursing care. To date, in Italy, there is no tool capable of measuring the quality of nursing care perceived by patients suffering from oncological pathology. OBJECTIVES: The general purpose of the study is to adapt the QONCS tool in the Italian context in order to investigate the quality of nursing care perceived by cancer patients and its related factors. METHODS: The study will be developed into four phases: (a) the cultural adaptation of the instrument to the Italian context; (b) the assessment of the face and content validity of the instrument; (c) the evaluation of construct validity and reliability, and (d) the description of the quality of nursing care as perceived by the patients including factors/items confirmed in the validation process. EXPECTED OUTCOMES: We intend to validate the tool on more than 400 people affected by oncological pathology. The construct that the tool intends to measure will be confirmed through exploratory and confirmatory factor analysis and will report high internal consistency and test-retest reliability.BACKGROUND: Gli infermieri hanno un ruolo fondamentale nella cura delle persone affette da patologia oncologica. Fornire un’assistenza infermieristica di qualità significa provvedere a rispondere in modo pertinente ai bisogni fisici e psicosociali dell’assistito. Lo strumento Quality of Oncology Nursing Care Scale (QONCS) è il primo strumento ad essere costruito su un modello concettuale consolidato che include i principali temi emersi da studi precedenti aventi per oggetto la qualità dell’assistenza infermieristica in ambito oncologico. Non esiste ad oggi in Italia uno strumento capace di misurare la qualità dell’assistenza infermieristica percepita dalla persona affetta da patologia oncologica. OBIETTIVI: Finalità generale dello studio è adattare nel contesto italiano lo strumento QONCS al fine di indagare la qualità dell’assistenza infermieristica percepita dagli assistiti oncologici e i fattori che influiscono su di essa. METODI: Lo studio è articolato in quattro fasi: (a) l’adattamento culturale dello strumento al contesto italiano; (b) la valutazione della validità di facciata e contenuto dello strumento; (c) la valutazione della validità di costrutto e affidabilità dello strumento e (d) la descrizione della qualità dell’assistenza infermieristica come percepita dagli assistiti includendo fattori/item confermati nel processo di validazione. ESITI ATTESI: Si intende validare lo strumento su più di 400 persone affette da patologia oncologica. Il costrutto che lo strumento intende misurare sarà confermato attraverso analisi fattoriale esplorativa e confermativa e riporterà una elevata consistenza interna e affidabilità test-retest

Deep neural networks for unsupervised damage detection on the Z24 bridge

During their life-cycle, civil infrastructures are continuously prone to significant functionality losses, primarily due to material's degradation and exposure to several natural hazards. Following these concerns, many researchers have attempted to develop reliable monitoring strategies, as integration to visual inspections, to efficiently ensure bridge maintenance and early-stage damage detection. In this framework, recent improvements in sensor technologies and data science have stimulated the use of Machine Learning (ML) algorithms for Structural Health Monitoring (SHM). Among unsupervised learning techniques, the potential of autoencoder networks has been attracting notable interest in the context of anomaly detection. In this light, the present paper proposes two different autoencoder-based damage detection techniques, focused on the Multi-Layer Perceptron (MLP) and the Convolutional Autoencoder (CAE) networks, respectively. During the training, the selected ML models learn how reconstructing raw acceleration sequences acquired from sound conditions. Unknown data, including both healthy and damaged bridge responses, are afterwards used to test the implemented networks and to detect damage occurrence. To this aim, a specific index of reconstruction loss is selected as a damage sensitive feature with the aim to quantify the errors between the original and reconstructed sequences. The performance exhibited by the two approaches is compared and evaluated by application to the Z24 benchmark bridge. Results demonstrate the effectiveness of the proposed methodology to perform feature classification and real time damage detection at the level of macro-sequences as new sensor data is collected, resulting suitable for continuous assessment of full-scale monitored bridges

Frataxin deficiency shifts metabolism to promote reactive microglia via glucose catabolism

Immunometabolism investigates the intricate relationship between the immune system and cellular metabolism. This study delves into the consequences of mitochondrial frataxin (FXN) depletion, the primary cause of Friedreich's ataxia (FRDA), a debilitating neurodegenerative condition characterized by impaired coordination and muscle control. By using single-cell RNA sequencing, we have identified distinct cellular clusters within the cerebellum of an FRDA mouse model, emphasizing a significant loss in the homeostatic response of microglial cells lacking FXN. Remarkably, these microglia deficient in FXN display heightened reactive responses to inflammatory stimuli. Furthermore, our metabolomic analyses reveal a shift towards glycolysis and itaconate production in these cells. Remarkably, treatment with butyrate counteracts these immunometabolic changes, triggering an antioxidant response via the itaconate-Nrf2-GSH pathways and suppressing the expression of inflammatory genes. Furthermore, we identify Hcar2 (GPR109A) as a mediator involved in restoring the homeostasis of microglia without FXN. Motor function tests conducted on FRDA mice underscore the neuroprotective attributes of butyrate supplementation, enhancing neuromotor performance. In conclusion, our findings elucidate the role of disrupted homeostatic function in cerebellar microglia in the pathogenesis of FRDA. Moreover, they underscore the potential of butyrate to mitigate inflammatory gene expression, correct metabolic imbalances, and improve neuromotor capabilities in FRDA

Liver-directed lentiviral gene therapy corrects hemophilia A mice and achieves normal-range factor VIII activity in non-human primates

: Liver gene therapy with adeno-associated viral (AAV) vectors delivering clotting factor transgenes into hepatocytes has shown multiyear therapeutic benefit in adults with hemophilia. However, the mostly episomal nature of AAV vectors challenges their application to young pediatric patients. We developed lentiviral vectors, which integrate in the host cell genome, that achieve efficient liver gene transfer in mice, dogs and non-human primates, by intravenous delivery. Here we first compare engineered coagulation factor VIII transgenes and show that codon-usage optimization improved expression 10-20-fold in hemophilia A mice and that inclusion of an unstructured XTEN peptide, known to increase the half-life of the payload protein, provided an additional >10-fold increase in overall factor VIII output in mice and non-human primates. Stable nearly life-long normal and above-normal factor VIII activity was achieved in hemophilia A mouse models. Overall, we show long-term factor VIII activity and restoration of hemostasis, by lentiviral gene therapy to hemophilia A mice and normal-range factor VIII activity in non-human primate, paving the way for potential clinical application

Effects of initial-state dynamics on collective flow within a coupled transport and viscous hydrodynamic approach

We evaluate the effects of preequilibrium dynamics on observables in ultrarelativistic heavy-ion collisions. We simulate the initial nonequilibrium phase within A MultiPhase Transport (AMPT) model, while the subsequent near-equilibrium evolution is modeled using (2+1)-dimensional relativistic viscous hydrodynamics. We match the two stages of evolution carefully by calculating the full energy-momentum tensor from AMPT and using it as input for the hydrodynamic evolution. We find that when the preequilibrium evolution is taken into account, final-state observables are insensitive to the switching time from AMPT to hydrodynamics. Unlike some earlier treatments of preequilibrium dynamics, we do not find the initial shear viscous tensor to be large. With a shear viscosity to entropy density ratio of $0.12$, our model describes quantitatively a large set of experimental data on Pb+Pb collisions at the Large Hadron Collider(LHC) over a wide range of centrality: differential anisotropic flow $v_n(p_T) ~(n=2-6)$, event-plane correlations, correlation between $v_2$ and $v_3$, and cumulant ratio $v_2\{4\}/v_2\{2\}$.Comment: 10 pages, v2: minor revisio

Sialylation regulates migration in chronic lymphocytic leukemia

Sialylation is the terminal addition of sialic acid to underlying glycans. It plays a prominent role in cell adhesion and immune regulation. Sialylated structures found on adhesion molecules, such as CD49d, mediate the interactions between cancer cells and the microenvironment, facilitating metastatic seeding in target organs. Chronic lymphocytic leukemia (CLL) is a clonal B-cell malignancy characterized by the accumulation of CD5-positive B cells in the peripheral blood, bone marrow and lymph nodes. CLL cells proliferate mainly in the lymph node “proliferation centers”, where the microenvironment provides pro-survival signals. Thus, migration and homing into these protective niches play a crucial role in CLL biology. In recent years, therapeutic strategies aimed at inducing the egress of CLL cells from the lymph nodes and bone marrow into the circulation have been highly successful. In this study, the sialylation status of 79 untreated and 24 ibrutinib-treated CLL patients was characterized by flow cytometry. Moreover, the effect of sialic acid removal on migration was tested by a transwell assay. Finally, we examined the sialylation status of CD49d by Western blot analysis. We found that CLL cells are highly sialylated, particularly those characterized by an “activated” immune phenotype. Notably, sialylation regulates CLL migration through the post-translational modification of CD49d. Finally, we showed that therapeutic agents that induce CLL mobilization from their protective niches, such as ibrutinib, modulate sialic acid levels. We propose that sialylation is an important regulator of CLL trafficking and may represent a novel target to further improve CLL therapy

SARS-CoV-2-related bronchiolitis: a multicentre international study

Background: Bronchiolitis is the main acute lower respiratory tract infection in infants. Data regarding SARS-CoV-2-related bronchiolitis are limited. Objective: To describe the main clinical characteristics of infants with SARS-CoV-2-related bronchiolitis in comparison with infants with bronchiolitis associated with other viruses. Setting, patients, interventions: A multicentre retrospective study was conducted in 22 paediatric emergency departments (PED) in Europe and Israel. Infants diagnosed with bronchiolitis, who had a test for SARS-CoV-2 and were kept in clinical observation in the PED or admitted to hospital from 1 May 2021 to 28 February 2022 were considered eligible for participation. Demographic and clinical data, diagnostic tests, treatments and outcomes were collected. Main outcome measures: The main outcome was the need for respiratory support in infants testing positive for SARS-CoV-2 compared with infants testing negative. Results: 2004 infants with bronchiolitis were enrolled. Of these, 95 (4.7%) tested positive for SARS-CoV-2. Median age, gender, weight, history of prematurity and presence of comorbidities did not differ between the SARS-CoV-2-positive and SARS-CoV-2-negative infants. Human metapneumovirus and respiratory syncytial virus were the viruses most frequently detected in the group of infants negative for SARS-CoV-2.Infants testing positive for SARS-CoV-2 received oxygen supplementation less frequently compared with SARS-CoV-2-negative patients, 37 (39%) vs 1076 (56.4%), p=0.001, OR 0.49 (95% CI 0.32 to 0.75). They received less ventilatory support: 12 (12.6%) high flow nasal cannulae vs 468 (24.5%), p=0.01; 1 (1.0%) continuous positive airway pressure vs 125 (6.6%), p=0.03, OR 0.48 (95% CI 0.27 to 0.85). Conclusions: SARS-CoV-2 rarely causes bronchiolitis in infants. SARS-CoV-2-related bronchiolitis mostly has a mild clinical course