The differentiated cells express both neuronal and glial cell phenotypic markers and exhibit similar functional properties as mouse spiral ganglion primary explants and human sphere-derived spiral ganglion cells. In contrast to other rodent models aiming at sustained production of auditory neurons, no genetic transformation of the progenitors is needed. Phoenix spheres therefore represent an interesting starting point to further investigate self-renewal in the mammalian inner ear, which is still far from any clinical application. In the meantime, phoenix spheres already offer an unlimited source of mammalian auditory neurons for high-throughput screens while substantially reducing the numbers of animals needed.Transthyretin (TTR) amyloidoses are systemic diseases associated with TTR aggregation and extracellular deposition in tissues as amyloid. The most frequent and severe forms of the disease are hereditary and associated with amino acid substitutions in the protein due to single point mutations in the TTR gene (ATTRv amyloidosis). However, the wild type TTR (TTR wt) has an intrinsic amyloidogenic potential that, in particular altered physiologic conditions and aging, leads to TTR aggregation in people over 80 years old being responsible for the non-hereditary ATTRwt amyloidosis. In normal physiologic conditions TTR wt occurs as a tetramer of identical subunits forming a central hydrophobic channel where small molecules can bind as is the case of the natural ligand thyroxine (T4). However, the TTR amyloidogenic variants present decreased stability, and in particular conditions, dissociate into partially misfolded monomers that aggregate and polymerize as amyloid fibrils. Therefore, therapeutic strategies for these amyloidoses may target different steps in the disease process such as decrease of variant TTR (TTRv) in plasma, stabilization of TTR, inhibition of TTR aggregation and polymerization or disruption of the preformed fibrils. While strategies aiming decrease of the mutated TTR involve mainly genetic approaches, either by liver transplant or the more recent technologies using specific oligonucleotides or silencing RNA, the other steps of the amyloidogenic cascade might be impaired by pharmacologic compounds, namely, TTR stabilizers, inhibitors of aggregation and amyloid disruptors. Modulation of different steps involved in the mechanism of ATTR amyloidosis and compounds proposed as pharmacologic agents to treat TTR amyloidosis will be reviewed and discussed.The aim of the present review is to summarize the prevalence of abnormal levels of various metal micronutrients including copper (Cu), iron (Fe), magnesium (Mg), zinc (Zn), and selenium (Se) in Autism Spectrum Disorder (ASD) using hair, nail and serum samples. A correlation of selected abnormal metal ions with known neurodevelopmental processes using Gene Ontology (GO) term was also conducted. Data included in this review are derived from ASD clinical studies performed globally. Metal ion disparity data is also analyzed and discussed based on gender (Male/Female) to establish any gender dependent correlation. Finally, a rational perspective and possible path to better understand the role of metal micronutrients in ASD is suggested.Collagen Q (COLQ) is a specific collagen that anchors acetylcholinesterase (AChE) in the synaptic cleft of the neuromuscular junction. So far, no mutation has been identified in the ACHE human gene but over 50 different mutations in the COLQ gene are causative for a congenital myasthenic syndrome (CMS) with AChE deficiency. Mice deficient for COLQ mimic most of the functional deficit observed in CMS patients. At the molecular level, a striking consequence of the absence of COLQ is an increase in the levels of acetylcholine receptor (AChR) mRNAs and proteins in vivo and in vitro in murine skeletal muscle cells. Here, we decipher the mechanisms that drive AChR mRNA upregulation in cultured muscle cells deficient for COLQ. We show that the levels of AChR β-subunit mRNAs are post-transcriptionally regulated by an increase in their stability. We demonstrate that this process results from an activation of p38 MAPK and the cytoplasmic translocation of the nuclear RNA-binding protein human antigen R (HuR) that interacts with the AU-rich element located within AChR β-subunit transcripts. This HuR/AChR transcript interaction induces AChR β-subunit mRNA stabilization and occurs at a specific stage of myogenic differentiation. In addition, pharmacological drugs that modulate p38 activity cause parallel modifications of HuR protein and AChR β-subunit levels. Thus, our study provides new insights into the signaling pathways that are regulated by ColQ-deficiency and highlights for the first time a role for HuR and p38 in mRNA stability in a model of congenital myasthenic syndrome.Background and Purpose Hearing loss is associated with rising risks of emotional impairments, suggesting emotional processing networks might be involved in the neural plasticity after hearing loss. This study was conducted to explore how functional connectivity of the amygdala reconfigures in the auditory deprived brain and better understand the neural mechanisms underlying hearing loss-related emotional disturbances. Methods In total, 38 chronic sensorineural hearing loss (SNHL) patients and 37 healthy controls were recruited for multimodal magnetic resonance imaging scanning and neuropsychological assessments. Voxel-wise functional connectivity (FC) maps of both the left and right amygdala were conducted and compared between the SNHL patients and healthy controls. The uncinate fasciculus (UF), an association fiber pathway, was reconstructed in both groups. The track number, mean track length, fractional anisotropy (FA) and mean diffusion values of the left and right UF were further quantified, respectively. Besides, Pearson’s correlation analyses were conducted to investigate the relationship between the functional/structural abnormalities and the negative emotional states in SNHL patients. Results The SNHL patients presented higher depressive and anxious levels compared to the healthy controls. Decreased FCs were detected between the amygdala and the auditory cortex, striatum, multimodal processing areas, and frontoparietal control areas in the SNHL patients. The amygdala was found to be structurally connected with several FC decreased regions through the UF. Moreover, the hypo-synchronization and the white matter impairment were both found to be associated with patients’ elevated anxious status. Conclusions These functional and structural findings depicted the reconfiguration of the amygdala in SNHL, which provided a new perspective toward the functional circuit mechanisms targeting the emotional impairments related to hearing loss.Cardiovascular disease (CVD) is the leading cause of death worldwide with mortality rates in women currently exceeding those in men. To date, evidence is widely lacking for unique female determinants of CVD. However, strong associations with psychological stress, obesity or elevated inflammatory biomarkers with adverse cardiovascular outcomes in women have been identified in various studies. Interestingly, amygdalar metabolic activity, a central neural structure involved in emotional stress processing, has proven to be an independent predictor of major adverse cardiovascular events (MACE). Moreover, upregulated amygdalar metabolism was directly linked to myocardial injury in women, but not in men. This newly suggested sex-dependent brain-heart interrelation was further supported by the discovery that bone marrow activity, a surrogate parameter of inflammation, represents a potential bridging link between amygdalar activity and cardiovascular pathology by fueling inflammatory processes that promote atherosclerotic disease. Such malignant cascade of events might account, at least in part, for the excess female mortality seen in women with coronary artery disease and calls for sex-specific research toward pharmacologic or behavioral modulators to improve cardiovascular outcomes, particularly in women. This mini review summarizes recent advances in cardiovascular sex-specific medicine, thereby focusing on the interplay between the limbic system, autonomic regulation and inflammatory biomarkers, which may help to tailor CVD management toward the female cardiovascular phenotype.Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative disorders worldwide, with age being their major risk factor. The increasing worldwide life expectancy, together with the scarcity of available treatment choices, makes it thus pressing to find the molecular basis of AD and PD so that the causing mechanisms can be targeted. To study these mechanisms, gene expression profiles have been compared between diseased and control brain tissues. However, this approach is limited by mRNA expression profiles derived for brain tissues highly reflecting their degeneration in cellular composition but not necessarily disease-related molecular states. We therefore propose to account for cell type composition when comparing transcriptomes of healthy and diseased brain samples, so that the loss of neurons can be decoupled from pathology-associated molecular effects. This approach allowed us to identify genes and pathways putatively altered systemically and in a cell-type-dependent manner in AD and PD brains. Moreover, using chemical perturbagen data, we computationally identified candidate small molecules for specifically targeting the profiled AD/PD-associated molecular alterations. Our approach therefore not only brings new insights into the disease-specific and common molecular etiologies of AD and PD but also, in these realms, foster the discovery of more specific targets for functional and therapeutic exploration.

Three classical methods of resting-state functional magnetic resonance imaging (rs-fMRI) were employed to explore the local functional abnormalities and their effect on spasm ratings in hemifacial spasm (HFS) patients.

Thirty HFS patients and 30 matched healthy controls (HCs) were recruited. Rs-fMRI data, neurovascular compression (NVC) degree and spasm severity were collected in each subject. Fractional amplitude of low-frequency fluctuation (fALFF), regional homogeneity (ReHo), and degree centrality (DC) were calculated in the whole brain voxels. Two sample

-tests were performed to investigate group differences of fALFF, ReHo, and DC. Correlation analysis was performed to assess the relationships between the regional brain abnormalities and clinical variables in HFS.

Compared with HCs, HFS patients exhibited increased fALFF in the left precuneus and right posterior cingulate cortex (PCC), together with increased ReHo in the bilateral PCC and bilateral precuneus. Decreased ReHo was observed in the right middle occipital gyrus (MOG), right superior occipital gyrus (SOG), right cuneus, and right angular gyrus (AG) in HFS patients. Moreover, ReHo in the right PCC were positively correlated with NVC degree and spasm severity in HFS patients, respectively. Mediation analysis revealed that increased ReHo in the right PCC regulated the neurovascular compression degree, and further resulted in increased spasm ratings.

Our study revealed regional brain dysfunctions from different perspectives and an indirect effect of ReHo in right PCC on spasm ratings predominantly through the alteration of NVC.

Our study revealed regional brain dysfunctions from different perspectives and an indirect effect of ReHo in right PCC on spasm ratings predominantly through the alteration of NVC.