P2X4 Receptor Regulates Alcohol-Induced Responses in Microglia

Mounting evidence indicates that alcohol-induced neuropathology may result from multicellular responses in which microglia cells play a prominent role. Purinergic receptor signaling plays a key role in regulating microglial function and, more importantly, mediates alcohol-induced effects. Our findings demonstrate that alcohol increases expression of P2X4 receptor (P2X4R), which alters the function of microglia, including calcium mobilization, migration and phagocytosis. Our results show a significant up-regulation of P2X4 gene expression as analyzed by real-time qPCR (***p?p?CX3CL1) by 75 % following 48 h of treatment compared to control (***p?CX3CL1-dependent migration was confirmed to be P2X4 receptor-dependent using the antagonist 5-BDBD, which reversed the effects as compared to alcohol alone (***p?p?p?相似文献   

Proteopathic tau seeding predicts tauopathy in vivo

Transcellular propagation of protein aggregates, or proteopathic seeds, may drive the progression of neurodegenerative diseases in a prion-like manner. In tauopathies such as Alzheimer’s disease, this model predicts that tau seeds propagate pathology through the brain via cell–cell transfer in neural networks. The critical role of tau seeding activity is untested, however. It is unknown whether seeding anticipates and correlates with subsequent development of pathology as predicted for a causal agent. One major limitation has been the lack of a robust assay to measure proteopathic seeding activity in biological specimens. We engineered an ultrasensitive, specific, and facile FRET-based flow cytometry biosensor assay based on expression of tau or synuclein fusions to CFP and YFP, and confirmed its sensitivity and specificity to tau (∼300 fM) and synuclein (∼300 pM) fibrils. This assay readily discriminates Alzheimer’s disease vs. Huntington''s disease and aged control brains. We then carried out a detailed time-course study in P301S tauopathy mice, comparing seeding activity versus histological markers of tau pathology, including MC1, AT8, PG5, and Thioflavin S. We detected robust seeding activity at 1.5 mo, >1 mo before the earliest histopathological stain. Proteopathic tau seeding is thus an early and robust marker of tauopathy, suggesting a proximal role for tau seeds in neurodegeneration.Protein aggregation characterizes many neurodegenerative disorders, including Alzheimer’s disease (AD) and the related tauopathies. These disorders feature the accumulation of fibrillar deposits of the microtubule-associated protein tau with progressive deterioration of the central nervous system. Tau pathology and its associated brain atrophy do not appear randomly throughout the brain, but rather progress along distinct neural networks (1–5). This aspect suggests a role for transcellular spread of a pathogenic agent via neural connections. Our laboratory and others have previously hypothesized that tau aggregates—or seeds—serve as this agent of spread, transmitting the aggregated state from cell to cell via prion-like mechanisms (6–15).Mounting fundamental insights support this hypothesis. Tau seeds applied to the outside of cells bind the cell surface by attaching to heparan sulfate proteoglycans, triggering uptake by macropinocytosis (13). Upon internalization, tau seeds nucleate the fibrillization of endogenous tau monomer via templated conformational change, or seeding (8, 10). Tau seeding requires a critical unit of size for activity, as only particular species propagate the aggregated state (16). In vivo studies have described tau protein spreading from local sites to distant regions, presumably via transsynaptic movement (11, 12, 17–19). Finally, our laboratory and another recently demonstrated that tau propagates discrete amyloid conformations through the brains of animals that give rise to unique neuropathologies (18, 20).Despite this evidence, it remains unclear whether the development of proteopathic tau seeding represents a causal process of tauopathy, a downstream consequence of tau fibril accumulation, a coincident trait of neurodegeneration, or even an epiphenomenon. If proteopathic seeds are indeed a causal agent of disease, then their activity should exist in the brains of tauopathy mouse models and human subjects, precede other forms of pathology, and correlate with disease progression.To test these hypotheses, we created a highly sensitive and quantitative assay using a novel FRET-based biosensor cell line that specifically reports tau seeding activity. With this assay, we profiled the temporal evolution of tau seeding activity in the brains of P301S transgenic mice, a model of human tauopathy, and compared it to standard measurements of histopathology taken from the same animals. We find that tau seeding marks incipient tauopathy, occurring far before the onset of several standard histopathological markers. This finding implicates proteopathic tau seeding as a proximal cause of neurodegeneration, and establishes a highly quantitative and sensitive seed detection method.     

Renal bladder ultrasound evaluation in monosymptomatic primary nocturnal enuresis: is it really necessary?

Background

Published guidelines regarding radiographic imaging in the evaluation of monosymptomatic primary nocturnal enuresis (MPNE) are not followed. We aimed to evaluate the prevalence of urological abnormalities on renal/bladder ultrasound (RBUS) in children with MPNE and to compare the RBUS findings in children with and without MPNE.

Methods

Retrospective data collection in all children aged 5–17 years seen for the initial evaluation of MPNE. Control group consisted of age- and sex-matched children who had abdominal ultrasound for other than bladder-/kidney-related causes. RBUS findings were analyzed with regard to the need for intervention and/or follow-up.

Results

While abnormalities on RBUS were seen in 12.54 % of enuretic children and in 5.38 % of controls (p?=?0.004), the majority of these findings were clinically insignificant. Of those with abnormalities, only 4 enuretic children (1.43 %) required intervention and 8 (2.87 %) needed follow-up studies. These rates were not significantly different from the controls. However, enuretic children with RBUS abnormalities appear to be more resistant to treatment than enuretic children with normal RBUS (p?=?0.002).

Conclusions

A small proportion of abnormalities seen on RBUS in children with MPNE require intervention and/or further evaluation. The identification of insignificant RBUS findings could lead to unnecessary additional investigations owing to parental concern. Detailed history and a voiding diary may be sufficient in the initial evaluation of children with MPNE, although RBUS may play an important role in patients who are resistant to treatment.     

Neurobiological underpinnings of cyberbullying: A pilot functional magnetic resonance imaging study

There is a dearth of research that has investigated the neural correlates of cyberbullying, using task‐based functional magnetic resonance imaging (fMRI) and, specifically, in a real‐time context such as observing cyberbullying scenarios. This article presents pilot data from a novel protocol designed to undertake such research with the overall aim being to elucidate the neurobiological underpinnings of cyberbullying via task‐based fMRI (tb‐fMRI)) in passive cyberbystanders. Young adults (N = 32, 18 to 25 years old) viewed six negative (cyberbullying) and six neutral stimuli from the Cyberbullying Picture Series (CyPicS) while undergoing tb‐fMRI. Our results revealed 12 clusters of significantly greater blood‐oxygenation‐level‐dependent (BOLD) responses (family wise error corrected p _FWE < .05) in participants when viewing cyberbullying stimuli compared to neutral stimuli, across a distributed network of regions including left and right middle temporal gyrus, default mode network hubs, left and right posterior cerebellum/vermis, and putamen. Further analysis also revealed greater BOLD response in females compared to males, as well as in those with no prior experience of cyberbullying compared to those with prior experience (despite gender), when viewing the cyberbullying stimuli compared to the neutral stimuli. These results bring us closer to understanding the neurobiological underpinnings that may be associated with cybervictim/bully status and outcomes.     

One stop shop approach for the diagnosis of liver hemangioma

Hepatic hemangioma is usually detected on a routine ultrasound examination because of silent clinical behaviour. The typical ultrasound appearance of hemangioma is easily recognizable and quickly guides the diagnosis without the need for further investigation. But there is also an entire spectrum of atypical and uncommon ultrasound features and our review comes to detail these particular aspects. An atypical aspect in standard ultrasound leads to the continuation of explorations with an imaging investigation with contrast substance [ultrasound/ computed tomography/or magnetic resonance imaging (MRI)]. For a clinician who practices ultrasound and has an ultrasound system in the room, the easiest, fastest, non-invasive and cost-effective method is contrast enhanced ultrasound (CEUS). Approximately 85% of patients are correctly diagnosed with this method and the patient has the correct diagnosis in about 30 min without fear of malignancy and without waiting for a computer tomography (CT)/MRI appointment. In less than 15% of patients CEUS does not provide a conclusive appearance; thus, CT scan or MRI becomes mandatory and liver biopsy is rarely required. The aim of this updated review is to synthesize the typical and atypical ultrasound aspects of hepatic hemangioma in the adult patient and to propose a fast, non-invasive and cost-effective clinical-ultrasound algorithm for the diagnosis of hepatic hemangioma.     

Immunogenicity Following Administration of BNT162b2 and Ad26.COV2.S COVID-19 Vaccines in the Pregnant Population during the Third Trimester

Globally, COVID-19 vaccines are currently being used to prevent transmission and to reduce morbidity and death associated with SARS-CoV-2 infection. Current research reveals that vaccines such as BNT162b2 and Ad26.COV2.S are highly immunogenic and have high short-term effectiveness for most of the known viral variants. Clinical trials showed satisfying results in the general population, but the reluctance in testing and vaccinating pregnant women left this category with little evidence regarding the safety, efficacy, and immunogenicity following COVID-19 vaccination. With the worldwide incidence of COVID-19 remaining high and the possibility of new transmissible SARS-CoV-2 mutations, data on vaccination effectiveness and antibody dynamics in pregnant patients are critical for determining the need for special care or further booster doses. An observational study was developed to evaluate pregnant women receiving the complete COVID-19 vaccination scheme using the BNT162b2 and Ad26.COV2.S, and determine pregnancy-related outcomes in the mothers and their newborns, as well as determining adverse events after vaccination and immunogenicity of vaccines during four months. There were no abnormal findings in pregnancy and newborn characteristics comparing vaccinated versus unvaccinated pregnant women. COVID-19 seropositive pregnant women had significantly higher spike antibody titers than seronegative patients with similar characteristics, although they were more likely to develop fever and lymphadenopathy following vaccination. The same group of pregnant women showed no statistically significant differences in antibody titers during a 4-month period when compared with case-matched non-pregnant women. The BNT162b2 and Ad26.COV2.S vaccines are safe to administer during the third trimester of pregnancy, while their safety, efficacy, and immunogenicity remain similar to those of the general population.     

The Influence of the Elemental Composition,Crystal Structure,and Grain Structure of the Ferro-Piezoceramics of Various Degrees of the Ferro-Hardness on the Stability of the Polarized State

Ferro-piezoceramic materials (FPCM) with different degrees of ferrohardness were fabricated by double solid-phase synthesis followed by the sintering technique using hot pressing method. The X-ray studies carried out in a wide temperature range showed that with increasing temperature, each of the studied FPCM undergoes a series of phase transformations, accompanied by a change in the symmetry of the unit cell. In this case, near the phase transition to the nonpolar cubic phase, in each of the FPCM, the formation of a fuzzy symmetry region is observed, which is characterized by weak distortions and temperature–time instability of the crystal structure. The study of the piezoelectric modulus d₃₃ in the quasi-static regime as a function of temperature made it possible to reveal the different nature of its behavior in materials of various degrees of ferrohardness. It was shown that the conservation of the state in ferrosoft materials above the Curie temperature is associated with the relaxation nature of the change in their properties, the existence of a region of fuzzy symmetry (noncubic phase) in them above the Curie temperature, and increased inertia of the system. The expediency of taking into account the presented results in the development of electromechanical converters based on FPCM of various degrees of ferrohardness, operated under temperature effects, including cyclic ones, was shown.