1,720,957 research outputs found
Kidney in a box: sviluppo di un modello renale in vitro per lo studio delle ciliopatie
No full textLe cellule epiteliali renali possiedono un'innata capacità di percepire e rispondere a segnali meccanici e chimici presenti nell'ambiente tubulare, una funzione essenziale per il mantenimento dell'omeostasi dei fluidi e degli elettroliti. Sebbene tradizionalmente attribuita a proteine di membrana plasmatica, come canali ionici e trasportatori, evidenze recenti evidenziano il ruolo fondamentale degli organelli intracellulari come centri di segnalazione in questo processo. Questa tesi indaga i meccanismi di segnalazione specifici degli organelli nelle cellule epiteliali renali, con particolare attenzione al segnale calcio-mediato dai lisosomi e alla segnalazione β-adrenergica mediata dalle ciglia primarie.
I nostri risultati mostrano che il rilascio di Ca2+ dai lisosomi tramite TRPML1 induce oscillazioni prolungate del Ca2+ citosolico attraverso i recettori inositolo 1,4,5-trifosfato (Ins3PRs) situati sul reticolo endoplasmatico. Questa cascata di segnalazione modula l'organizzazione del citoscheletro, attiva la segnalazione calcineurina/NFAT e promuove l’accumulo apicale del canale dell'acqua AQP2, essenziale per il riassorbimento dell'acqua nel dotto collettore. Inoltre, dimostriamo che le ciglia primarie fungono da hub di segnalazione β-adrenergica, con i recettori β2-adrenergici (β2ARs) localizzati sulla cilia che giocano un ruolo predominante nella regolazione dei livelli di cAMP citosolico. Tuttavia, i nostri risultati indicano che la segnalazione β-adrenergica ciliare dipende principalmente dal pool di cAMP citosolico, piuttosto che dalla generazione diretta di segnali all'interno della cilia stessa. Una delle principali difficoltà nello studio di questi complessi percorsi di segnalazione è l'assenza di modelli in vitro fisiologicamente rilevanti che riproducano il microambiente dinamico del rene. Per superare questo ostacolo, abbiamo utilizzato il bioreattore LiveBox2, in grado di simulare le condizioni di stress da flusso di fluidi che le cellule sperimentano in vivo. I nostri risultati dimostrano che la coltura dinamica all'interno di questo sistema migliora l'integrità epiteliale, modula la composizione delle proteine delle giunzioni strette e riorganizza il citoscheletro di actina, facilitando così il traffico di AQP2 verso la membrana apicale. Integrando tecniche avanzate di biologia molecolare con tecnologie innovative basate su bioreattori, questo lavoro fornisce nuove intuizioni sul ruolo degli organelli intracellulari nella segnalazione epiteliale renale. Questi risultati ampliano la nostra comprensione della fisiologia renale e aprono nuove prospettive per lo sviluppo di strategie terapeutiche mirate alle patologie renali.Kidney epithelial cells possess an intrinsic ability to sense and respond to mechanical and chemical cues within the tubular environment, a function essential for maintaining fluid and electrolyte homeostasis. While traditionally attributed to plasma membrane proteins such as ion channels and transporters, recent evidence highlights the pivotal role of intracellular organelles as key signaling hubs in this process. This thesis investigates organelle-specific signaling mechanisms in renal epithelial cells, with a focus on lysosomal calcium signaling and primary cilia-mediated β-adrenergic signaling.
Our findings reveal that lysosomal Ca2+ release via TRPML1 induces sustained cytosolic Ca2+ oscillations through inositol 1,4,5-trisphosphate receptors (Ins3PRs) on the endoplasmic reticulum. This signaling cascade modulates cytoskeletal organization, activates calcineurin/NFAT signaling, and promotes the apical accumulation of the water channel AQP2—critical for water reabsorption in the collecting duct. Additionally, we demonstrate that primary cilia serve as mechanosensors in β-adrenergic signaling, with β2-adrenergic receptors (β2ARs) localized to the cilium playing a predominant role in regulating cytosolic cAMP levels. However, our results indicate that ciliary β-adrenergic signaling is primarily dependent on cytosolic cAMP rather than direct signal generation within the cilium itself.
A key challenge in studying these intricate signaling pathways is the absence of physiologically relevant in vitro models that replicate the kidney’s dynamic microenvironment. To address this, we employed the LiveBox2 bioreactor, which simulates fluid shear stress conditions experienced in vivo. Our results show that dynamic culture within this system enhances epithelial integrity, modulates tight junction protein composition, and reorganizes the actin cytoskeleton, thereby facilitating AQP2 trafficking to the apical membrane.
By integrating advanced molecular biology techniques with innovative bioreactor technology, this work provides new insights into the role of intracellular organelles in renal epithelial signaling. These findings advance our understanding of kidney function and open new avenues for therapeutic strategies targeting kidney disease
Targeting the Ca2+ signaling toolkit as an alternative strategy to mitigate SARS-CoV-2-induced cardiovascular adverse events
No full textCa2+ signaling events are essential for maintaining cardiovascular health, regulating critical functions in both endothelial and cardiac cells. SARS-CoV-2 infection impinges this delicate balance, leading to severe cardiovascular complications. SARS-CoV-2 binds to the ACE2 receptor on endothelial and cardiomyocyte surfaces, triggering abnormal increases in intracellular Ca2+ levels that promote endothelial dysfunction, inflammation, and hypercoagulation. In endothelial cells, this dysregulation activates a pro-inflammatory state and compromises vascular integrity. In cardiomyocytes, SARS-CoV-2-induced Ca2+ imbalances contribute to arrhythmias and heart failure by promoting abnormal Ca2+ cycling and energy metabolism disruptions. Additionally, the cytokine storm associated with COVID-19 amplifies these effects by further altering Ca2+ handling, enhancing inflammatory responses, and promoting thrombosis. Targeting Ca2+ channels, particularly endolysosomal two-pore channels, represents a promising therapeutic approach to counteract SARS-CoV-2’s effects on Ca2+ dynamics. Several FDA-approved drugs that modulate Ca2+ signaling could be repurposed to prevent viral entry and mitigate cardiovascular damage. Understanding these Ca2+-related mechanisms offers valuable insights for developing treatments to reduce cardiovascular risk in COVID-19 and potentially future viral infections impacting the cardiovascular system
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Profilassi con vitamina D nel lattante: l’importanza di capirsi bene
No full textThe paper describes a case of intoxication from vitamin D in a 35-day infant of exclusive breastfeeding life who was administered 8000 IU of vitamin D per day over 4 weeks. There was an important linguistic barrier with her mother. The clinical picture was exclusively characterized by constipation, with adequate growth. Laboratory investigations showed calcemia at upper limits (11.1 mg/dl), elevated levels of 25-OH vitamin D3 (25-OH), equal to 375 μg/l, and renal ultrasound finding compatible with microlithiasis. The clinical picture was resolved with an intravenous hydration and suspension of vitamin supplementation. The case shows that in a situation in which there is a condition of family vulnerability it is necessary to make sure that any prescription has been correctly understood
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