Developmental regulation of GABAergic signalling in the hippocampus of neuroligin 3 R451C knock-in mice: an animal model of Autism

Autism Spectrum Disorders (ASDs) comprise an heterogeneous group of neuro-developmental abnormalities, mainly of genetic origin, characterized by impaired social interactions, communications deficits and stereotyped behaviors. In a small percentage of cases, ASDs have been found to be associated with single mutations in genes involved in synaptic function. One of these involves the postsynaptic cell adhesion molecule neuroligin (NL) 3. NLs interact with presynaptic neurexins (Nrxs) to ensure a correct cross talk between post and presynaptic specializations. Here, transgenic mice carrying the human R451C mutation of Nlgn3, were used to study GABAergic signaling in the hippocampus early in postnatal life. Whole cell recordings from CA3 pyramidal neurons in slices from NL3 R451C knock-in mice revealed an enhanced frequency of Giant Depolarizing Potentials, as compared to controls. This effect was probably dependent on an increased GABAergic drive to principal cells as demonstrated by the enhanced frequency of miniature GABAA-mediated (GPSCs), but not AMPA-mediated postsynaptic currents (EPSCs). Changes in frequency of mGPSCs were associated with an acceleration of their decay kinetics, in the absence of any change in unitary synaptic conductance or in the number of GABAA receptor channels, as assessed by peak scaled non-stationary fluctuation analysis. The enhanced GABAergic but not glutamatergic transmission early in postnatal life may change the excitatory/inhibitory balance known to play a key role in the construction and refinement of neuronal circuits during postnatal development. This may lead to behavioral deficits reminiscent of those observed in ASDs patients. \ua9 2013 Pizzarelli and Cherubini

SRGAP2 and Its Human-Specific Paralog Co-Regulate the Development of Excitatory and Inhibitory Synapses.

The proper function of neural circuits requires spatially and temporally balanced development of excitatory and inhibitory synapses. However, the molecular mechanisms coordinating excitatory and inhibitory synaptogenesis remain unknown. Here we demonstrate that SRGAP2A and its human-specific paralog SRGAP2C co-regulate the development of excitatory and inhibitory synapses in cortical pyramidal neurons in vivo. SRGAP2A promotes synaptic maturation, and ultimately the synaptic accumulation of AMPA and GABAA receptors, by interacting with key components of both excitatory and inhibitory postsynaptic scaffolds, Homer and Gephyrin. Furthermore, SRGAP2A limits the density of both types of synapses via its Rac1-GAP activity. SRGAP2C inhibits all identified functions of SRGAP2A, protracting the maturation and increasing the density of excitatory and inhibitory synapses. Our results uncover a molecular mechanism coordinating critical features of synaptic development and suggest that human-specific duplication of SRGAP2 might have contributed to the emergence of unique traits of human neurons while preserving the excitation/inhibition balance

Neuroinflammatory processes, A1 astrocyte activation and protein aggregation in the retina of Alzheimer’s disease patients, possible biomarkers for early diagnosis

Alzheimer's disease (AD), a primary cause of dementia in the aging population, is characterized by extracellular amyloid-beta peptides aggregation, intracellular deposits of hyperphosphorylated tau, neurodegeneration and glial activation in the brain. It is commonly thought that the lack of early diagnostic criteria is among the main causes of pharmacological therapy and clinical trials failure; therefore, the actual challenge is to define new biomarkers and non-invasive technologies to measure neuropathological changes in vivo at pre-symptomatic stages. Recent evidences obtained from human samples and mouse models indicate the possibility to detect protein aggregates and other pathological features in the retina, paving the road for non-invasive rapid detection of AD biomarkers. Here, we report the presence of amyloid beta plaques, tau tangles, neurodegeneration and detrimental astrocyte and microglia activation according to a disease associated microglia phenotype (DAM). Thus, we propose the human retina as a useful site for the detection of cellular and molecular changes associated with Alzheimer's disease

Ecological and environmental factors affecting the risk of tick-borne encephalitis in Europe, 2017 to 2021

Background: Tick-borne encephalitis (TBE) is a disease which can lead to severe neurological symptoms, caused by the TBE virus (TBEV). The natural transmission cycle occurs in foci and involves ticks as vectors and several key hosts that act as reservoirs and amplifiers of the infection spread. Recently, the incidence of TBE in Europe has been rising in both endemic and new regions. Aim: In this study we want to provide comprehensive understanding of the main ecological and environmental factors that affect TBE spread across Europe. Methods: We searched available literature on covariates linked with the circulation of TBEV in Europe. We then assessed the best predictors for TBE incidence in 11 European countries by means of statistical regression, using data on human infections provided by the European Surveillance System (TESSy), averaged between 2017 and 2021. Results: We retrieved data from 62 full-text articles and identified 31 different covariates associated with TBE occurrence. Finally, we selected eight variables from the best model, including factors linked to vegetation cover, climate, and the presence of tick hosts. Discussion: The existing literature is heterogeneous, both in study design and covariate types. Here, we summarised and statistically validated the covariates affecting the variability of TBEV across Europe. The analysis of the factors enhancing disease emergence is a fundamental step towards the identification of potential hotspots of viral circulation. Hence, our results can support modelling efforts to estimate the risk of TBEV infections and help decision-makers implement surveillance and prevention campaigns

Coupled Heat Transfer Analysis in Regeneratively Cooled Thrust Chambers

A computational procedure able to describe the coupled hot-gas/wall/coolant environment that occurs in most liquid rocket engines and to provide a quick and reliable prediction of thrust-chamber wall temperature and heat flux as well as coolant-flow characteristics, like pressure drop and temperature gain in the regenerative circuit is presented and demonstrated. The coupled analysis is performed by means of an accurate CFD solver of the Reynolds-Averaged Navier-Stokes equations for the hot-gas flow and a simplified quasi-2D approach, which widely relies on semi-empirical relations, to study the problem of coolant flow and wall structure heat transfer in the cooling channels. Coupled computations of the Space Shuttle Main Engine Main Combustion Chamber are performed and compared with available literature data. Results show a reasonable agreement in terms of coolant pressure drop and temperature gain with nominal data, whereas the computed wall temperature peak is quite closer to hot-firing data than to the nominal value. © 2012 by B. Betti, M. Pizzarelli, F. Nasuti

Admission levels of asymmetric and symmetric dimethylarginine predict long-term outcome in patients with community-acquired pneumonia

During infection, there is an activation of the L-arginine-nitric-oxide pathway, with a shift from nitric oxide synthesis to a degradation of L-arginine to its metabolites, asymmetric and symmetric dimethylarginine (ADMA and SDMA). However, the prognostic implications for short-term or long-term survival remains unclear. We investigated the association of L-arginine, ADMA, and SDMA with adverse clinical outcomes in a well-defined cohort of patients with community-acquired pneumonia (CAP).; We measured L-arginine, ADMA, and SDMA in 268 CAP patients from a Swiss multicenter trial by mass spectrometry and used Cox regression models to investigate associations between blood marker levels and disease severity as well as mortality over a period of 6 years.; Six-year mortality was 44.8%. Admission levels of ADMA and SDMA (μmol/L) were correlated with CAP severity as assessed by the pneumonia severity index (r = 0.32, p < 0.001 and r = 0.56, p < 0.001 for ADMA and SDMA, respectively) and higher in 6-year non-survivors versus survivors (median 0.62 vs. 0.48; p < 0.001 and 1.01 vs. 0.85; p < 0.001 for ADMA and SDMA, respectively). Both ADMA and SDMA were significantly associated with long-term mortality (hazard ratios [HR] 4.44 [95% confidence intervals (CI) 1.84 to 10.74] and 2.81 [95% CI 1.45 to 5.48], respectively). The effects were no longer significant after multivariate adjustment for age and comorbidities. No association of L-arginine with severity and outcome was found.; Both ADMA and SDMA show a severity-dependent increase in patients with CAP and are strongly associated with mortality. This association is mainly explained by age and comorbidities.; ISRCTN95122877 . Registered 31 July 2006

Clinical and patient-reported trajectories at end-of-life in older patients with advanced CKD

Background We explore longitudinal trajectories of clinical indicators, patient-reported outcomes, and hospitalizations, in the years preceding death in a population of older patients with advanced chronic kidney disease (CKD). Methods The EQUAL study is a European observational prospective cohort study with an incident eGFR Results We included 661 decedents with a median time to death of 2.0 years (IQR 0.9-3.2). During the years preceding death, eGFR, Subjective Global Assessment score, and blood pressure declined, with accelerations seen at 6 months preceding death. Serum hemoglobin, hematocrit, cholesterol, calcium, albumin, and sodium values declined slowly during follow-up, with accelerations observed between 6 and 12 months preceding death. Physical and mental quality of life declined linearly throughout follow-up. The number of reported symptoms was stable up to 2 years prior to death, with an acceleration observed at 1 year prior to death. The rate of hospitalization was stable at around one hospitalization per person year, increasing exponentially at 6 months preceding death. Conclusions We identified clinically relevant physiological accelerations in patient trajectories that began similar to 6 to 12 months prior to death, which are likely multifactorial in nature, but correlate with a surge in hospitalizations. Further research should focus on how to effectively use this knowledge to inform patient and family expectations, to benefit the planning of (end-of-life) care, and to establish clinical alert systems.Clinical epidemiolog

GABA is essential for the construction of neuronal circuits early in development: dysfunction in Autism Spectrum Disorders

Complementary and alternative medicine in treating autism: myths and realit