Antidepressant-like effects of pharmacological inhibition of FAAH activity in socially isolated female rats

Pharmacological inhibition of the enzyme fatty acid amide hydrolase (FAAH), which terminates signaling of the endocannabinoid N-arachidonoylethanolamine (or anandamide, AEA), exerts favourable effects in rodent models of stress-related depression. Yet although depression seems to be more common among women than men and in spite of some evidence of sex differences in treatment efficacy, preclinical development of FAAH inhibitors for the pharmacotherapy of stress-related depression has been predominantly conducted in male animals. Here, adult female rats were exposed to six weeks of social isolation and, starting from the second week, treated with the FAAH inhibitor URB694 (0.3 mg/kg/day, i.p.) or vehicle. Compared to pair-housed females, socially isolated female rats treated with vehicle developed behavioral (mild anhedonia, passive stress coping) and physiological (reduced body weight gain, elevated plasma corticosterone levels) alterations. Moreover, prolonged social isolation provoked a reduction in brain-derived neurotrophic factor (BDNF) and AEA levels within the hippocampus. Together, these changes are indicative of an increased risk of developing a depressive-like state. Conversely, pharmacological inhibition of FAAH activity with URB694 restored both AEA and BDNF levels within the hippocampus of socially isolated rats and prevented the development of behavioral and physiological alterations. These results suggest a potential interplay between AEA-mediated signaling and hippocampal BDNF in the pathogenesis of depression-relevant behaviors and physiological alterations and antidepressant action of FAAH inhibition in socially isolated female rats

Nocturnal Heart Rate Variability Might Help in Predicting Severe Obstructive Sleep-Disordered Breathing

Obstructive sleep apnea (OSA) can have long-term cardiovascular and metabolic effects. The identification of OSA-related impairments would provide diagnostic and prognostic value. Heart rate variability (HRV) as a measure of cardiac autonomic regulation is a promising candidate marker of OSA and OSA-related conditions. We took advantage of the Physionet Apnea-ECG database for two purposes. First, we performed time- and frequency-domain analysis of nocturnal HRV on each recording of this database to evaluate the cardiac autonomic regulation in patients with nighttime sleep breathing disorders. Second, we conducted a logistic regression analysis (backward stepwise) to identify the HRV indices able to predict the apnea-hypopnea index (AHI) categories (i.e., "Severe OSA", AHI ≥ 30; "Moderate-Mild OSA", 5 ≥ AHI < 30; and "Normal", AHI < 5). Compared to the "Normal", the "Severe OSA" group showed lower high-frequency power in normalized units (HFnu) and higher low-frequency power in normalized units (LFnu). The standard deviation of normal R-R intervals (SDNN) and the root mean square of successive R-R interval differences (RMSSD) were independently associated with sleep-disordered breathing. Our findings suggest altered cardiac autonomic regulation with a reduced parasympathetic component in OSA patients and suggest a role of nighttime HRV in the characterization and identification of sleep breathing disorders

Hongos formadores de micorrizas arbusculares en el suelo extremadamente contaminado con metales pesados de la cuenca del río Riachuelo

The Riachuelo river basin (RRB) is considered one of the most polluted environments in the world. Knowledge of arbuscular mycorrhizal fungi (AMF) adapted to this extremely polluted environment is important for the establishment of future soil restoration projects. This work aims to make a first list of AMF species present on the RRB. Soil and root samples were randomly taken in an area of approximately 1500 m2, mycorrhization percentages were evaluated. AMF species were detected by molecular and morphological techniques. Sixteen AMF morphological species and 64 molecular species were reported in this work. Dominikia iranica, Funneliformis constrictum, Funneliformis mosseae, Rhizophagus intraradices, Rhizophagus irregularis and Septoglomus viscosum were detected by both techniques while Claroideoglomus sp. was only detected by pyrosequencing. The list of species reported in this work represents the first description of the RRB AMF community.La cuenca del río Riachuelo (CRR) es considerada uno de los ambientes más contaminados del mundo. Conocer los hongos formadores de micorrizas arbusculares (HFMA) adaptados a este ambiente extremadamente contaminado es importante para el establecimiento de futuros proyectos de restauración de suelos. Este trabajo se propuso hacer una primera lista de especies de HFMA presentes en la CRR. Se tomaron muestras de suelo y raíces al azar en un área de aproximadamente 1500 m2 y se evaluaron los porcentajes de micorrización. La identificación de especies de HFMA se basó en técnicas moleculares y morfológicas. Se detectaron 16 especies morfológicas y 64 especies moleculares de HFMA. Dominikia iranica, Funneliformis constrictum, Funneliformis mosseae, Rhizophagus intraradices, Rhizophagus irregularis y Septoglomus viscosum se detectaron mediante ambas técnicas, mientras que Claroideoglomus sp. solo fue detectado por pirosecuenciación. La lista de especies reportada en este trabajo representa la primera descripción de la comunidad de HFMA de la CRR.Fil: Colombo, Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Biodiversidad y Biología Experimental y Aplicada. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biodiversidad y Biología Experimental y Aplicada; ArgentinaFil: Benavidez, Matias Ernesto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Biodiversidad y Biología Experimental y Aplicada. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biodiversidad y Biología Experimental y Aplicada; ArgentinaFil: Fernandez Bidondo, Laura. Universidad Nacional de Quilmes; ArgentinaFil: Silvani, Vanesa Analia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Biodiversidad y Biología Experimental y Aplicada. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biodiversidad y Biología Experimental y Aplicada; ArgentinaFil: Bompadre, María J.. Universidad Nacional de Quilmes; ArgentinaFil: Statello, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Biodiversidad y Biología Experimental y Aplicada. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biodiversidad y Biología Experimental y Aplicada; ArgentinaFil: Scorza, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Biodiversidad y Biología Experimental y Aplicada. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biodiversidad y Biología Experimental y Aplicada; ArgentinaFil: Scotti, Adalgisa. Comisión Nacional de Energía Atómica; ArgentinaFil: Godeas, Alicia Margarita. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Biodiversidad y Biología Experimental y Aplicada. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biodiversidad y Biología Experimental y Aplicada; Argentin

Bionic for Training: Smart Framework Design for Multisensor Mechatronic Platform Validation

: Home monitoring supports the continuous improvement of the therapy by sharing data with healthcare professionals. It is required when life-threatening events can still occur after hospital discharge such as neonatal apnea. However, multiple sources of external noise could affect data quality and/or increase the misdetection rate. In this study, we developed a mechatronic platform for sensor characterizations and a framework to manage data in the context of neonatal apnea. The platform can simulate the movement of the abdomen in different plausible newborn positions by merging data acquired simultaneously from three-axis accelerometers and infrared sensors. We simulated nine apnea conditions combining three different linear displacements and body postures in the presence of self-generated external noise, showing how it is possible to reduce errors near to zero in phenomena detection. Finally, the development of a smart 8Ws-based software and a customizable mobile application were proposed to facilitate data management and interpretation, classifying the alerts to guarantee the correct information sharing without specialized skills

Bionic for training: Smart framework design for multisensor mechatronic platform validation

Home monitoring supports the continuous improvement of the therapy by sharing data with healthcare professionals. It is required when life-threatening events can still occur after hospital discharge such as neonatal apnea. However, multiple sources of external noise could affect data quality and/or increase the misdetection rate. In this study, we developed a mechatronic platform for sensor characterizations and a framework to manage data in the context of neonatal apnea. The platform can simulate the movement of the abdomen in different plausible newborn positions by merging data acquired simultaneously from three-axis accelerometers and infrared sensors. We simulated nine apnea conditions combining three different linear displacements and body postures in the presence of self-generated external noise, showing how it is possible to reduce errors near to zero in phenomena detection. Finally, the development of a smart 8Ws-based software and a customizable mobile application were proposed to facilitate data management and interpretation, classifying the alerts to guarantee the correct information sharing without specialized skills

Bifidobacterial transfer from mother to child as examined by an animal model

Bifidobacteria commonly constitute the most abundant group of microorganisms in the healthy infant gut. Their intestinal establishment is believed to be maternally driven, and their acquisition has even been postulated to occur during pregnancy. In the current study, we evaluated bifidobacterial mother-to infant transmission events in a rat model by means of quantitative PCR (qPCR), as well as by Internally Transcribed Spacer (ITS) bifidobacterial profiling. The occurrence of strains supplied by mothers during pregnancy to their corresponding newborns was observed and identified by analysis immediately following C-section delivery. These findings provide intriguing support for the existence of an unknown route to facilitate bifidobacterial transfer during the very early stages of life

RNA delivery by extracellular vesicles in mammalian cells and its applications.

The term 'extracellular vesicles' refers to a heterogeneous population of vesicular bodies of cellular origin that derive either from the endosomal compartment (exosomes) or as a result of shedding from the plasma membrane (microvesicles, oncosomes and apoptotic bodies). Extracellular vesicles carry a variety of cargo, including RNAs, proteins, lipids and DNA, which can be taken up by other cells, both in the direct vicinity of the source cell and at distant sites in the body via biofluids, and elicit a variety of phenotypic responses. Owing to their unique biology and roles in cell-cell communication, extracellular vesicles have attracted strong interest, which is further enhanced by their potential clinical utility. Because extracellular vesicles derive their cargo from the contents of the cells that produce them, they are attractive sources of biomarkers for a variety of diseases. Furthermore, studies demonstrating phenotypic effects of specific extracellular vesicle-associated cargo on target cells have stoked interest in extracellular vesicles as therapeutic vehicles. There is particularly strong evidence that the RNA cargo of extracellular vesicles can alter recipient cell gene expression and function. During the past decade, extracellular vesicles and their RNA cargo have become better defined, but many aspects of extracellular vesicle biology remain to be elucidated. These include selective cargo loading resulting in substantial differences between the composition of extracellular vesicles and source cells; heterogeneity in extracellular vesicle size and composition; and undefined mechanisms for the uptake of extracellular vesicles into recipient cells and the fates of their cargo. Further progress in unravelling the basic mechanisms of extracellular vesicle biogenesis, transport, and cargo delivery and function is needed for successful clinical implementation. This Review focuses on the current state of knowledge pertaining to packaging, transport and function of RNAs in extracellular vesicles and outlines the progress made thus far towards their clinical applications

Valutazione della regolazione neurovegetativa cardiaca mediante analisi della variabilità della frequenza cardiaca: studi preclinici e clinici

Cervello e cuore sono intimamente interconnessi, tuttavia, solo nelle ultime decadi crescente attenzione è stata dedicata alla regolazione nervosa dell’attività cardiaca e a come essa si modifica ed adatta alle diverse esigenze ambientali e in risposta a stimoli di varia natura. L’analisi della variabilità della frequenza cardiaca (HRV) come strumento di indagine dell’input neurovegetativo al cuore ed espressione della funzione e dello stato del cosiddetto “Brain-Heart axis” è al centro della trattazione della presente tesi, nell’ambito della quale sono presentati quattro studi sperimentali. La possibile presenza di disfunzioni autonomiche è stata infatti indagata in modelli animali di stress ed in una condizione clinica neonatale. Il primo studio ha previsto l’uso di un modello di topo Knockout (KO) condizionale per il recettore Y1 del neuropeptide Y, nel quale, grazie alla combinazione del sistema Cre-loxP e di quello tet-off, la delezione post-natale del gene Npy1r risultava ristretta a livello limbico. Tale approccio è stato usato per indagare il ruolo del recettore Y1 a livello ippocampale nella regolazione neurovegetativa dell’attività cardiaca a riposo, durante un challenge farmacologico di manipolazione del sistema nervoso autonomo ed in risposta ad uno stress sociale acuto e cronico. I topi KO mostravano una diminuita modulazione vagale e ridotta HRV in condizioni basali. Inoltre una ridotta espressione del gene Npy1r portava ad una diminuita reattività ad uno stress acuto ma non sembrava modificare la risposta al protocollo di stress psicosociale cronico attuato in questo studio. Nel secondo studio ratti, selezionati sulla base del loro tempo di latenza all’attacco verso un conspecifico estraneo nell’ambito del “resident-intruder” test, sono stati selezionati e classificati per aggressività come “High-aggressive” (HA) e “Non-aggressive” (NA). Tali animali sono successivamente stati sottoposti ad un challenge immunitario (somministrazione intraperitoneale di lipopolisaccaride, LPS). Sonno, temperatura corticale (risposta febbrile) e regolazione autonomica dell’attività cardiaca sono quindi stati valutati in entrambi i gruppi. In risposta all’LPS, solo i ratti HA mostravano un prolungato aumento del tempo speso nella fase di sonno NREM, accompagnato da una prolungata febbre. Mentre entrambi i gruppi mostravano inibizione del sonno REM ed una riduzione della HRV e della modulazione parasimpatica. Il terzo studio è stato disegnato per valutare l’insorgenza di segni fisiologici e comportamentali caratterizzanti uno stato simil-depressivo in seguito ad isolamento sociale cronico in femmine di ratto e determinare se tali sintomi siano associati o meno ad alterazioni cardiovascolari e della regolazione autonomica della frequenza cardiaca. Inoltre, è stato valutato il coinvolgimento della segnalazione endocannabinoide anche in prospettiva della successiva valutazione degli effetti del potenziamento farmacologico della stessa mediante l’inibizione dell’attività dell’enzima FAAH. Femmine di ratto wild type dopo 6 settimane di isolamento sociale sviluppavano vari segni fisiologici e comportamentali riconducibili all’instaurarsi di una condizione simil-depressiva (aumentata immobilità nel test di nuoto forzato; lieve stato anedonico; riduzione dell’attività motoria durante la fase attiva del ciclo luce/buio; iperattività dell’asse ipotalamo-ipofisi-surrene (HPA); ridotta espressione di BDNF ippocampale). Inoltre l’isolamento produceva alterazioni del ritmo circadiano della frequenza cardiaca ed ipertrofia cardiaca. Tuttavia, non sono state ritrovate drammatiche alterazioni nei parametri della HRV. L’osservata riduzione dell’endocannabinoide anandamide (AEA) nello striato e nell’ippocampo suggeriva un possibile ruolo per il sistema di neuromodulazione in questione che incentiva l’esecuzione della fase successiva (valutazione effetti dell’inibitore FAAH, URB694). Nell’ultimo studio è stata valutata la regolazione autonomica cardiaca in neonati (pre-termine e termine) presentanti convulsioni per valutare la possibile utilità dell’analisi della HRV per rilevamento/predizione e gestione delle convulsioni neonatali. I risultati suggerivano alterazioni della regolazione neurovegetativa della funzione cardiaca a riposo nei pazienti presentanti convulsioni. Un aumento della HRV è stato invece osservato durante gli episodi convulsivi soltanto tra i nati a termine, suggerendo un possibile meccanismo protettivo di natura vagale. Tuttavia la validazione dell’uso degli indici della HRV per l’identificazione/predizione delle convulsioni neonatali necessita di ulteriori studi. In conclusione, oltre ai singoli obiettivi perseguiti da ciascuno studio e all’importanza dell’utilizzo di modelli animali nella ricerca preclinica, dalla presente trattazione emergono l’importanza e la necessità di utilizzare un efficace strumento, come l’analisi della HRV, per valutare attività, adattamenti e possibili disfunzioni del sistema nervoso autonomo in diverse condizioni sia fisiologiche che patologiche in ambito preclinico e clinico