Pathological alpha-synuclein impairs adult-born granule cell development and functional integration in the olfactory bulb

Although the role of noxious alpha-synuclein (alpha-SYN) in the degeneration of midbrain dopaminergic neurons and associated motor deficits of Parkinson's disease is recognized, its impact on non-motor brain circuits and related symptoms remains elusive. Through combining in vivo two-photon imaging with time-coded labelling of neurons in the olfactory bulb of A30P alpha-SYN transgenic mice, we show impaired growth and branching of dendrites of adult-born granule cells (GCs),with reduced gain and plasticity of dendritic spines. The spine impairments are especially pronounced during the critical phase of integration of new neurons into existing circuits. Functionally, retarded dendritic expansion translates into reduced electrical capacitance with enhanced intrinsic excitability and responsiveness of GCs to depolarizing inputs, while the spine loss correlates with decreased frequency of AMPA-mediated miniature EPSCs. Changes described here are expected to interfere with the functional integration and survival of new GCs into bulbar networks, contributing towards olfactory deficits and related behavioural impairments

lncRNA Biomarkers of Glioblastoma Multiforme

Long noncoding RNAs (lncRNAs) are RNA molecules of 200 nucleotides or more in length that are not translated into proteins. Their expression is tissue-specific, with the vast majority involved in the regulation of cellular processes and functions. Many human diseases, including cancer, have been shown to be associated with deregulated lncRNAs, rendering them potential therapeutic targets and biomarkers for differential diagnosis. The expression of lncRNAs in the nervous system varies in different cell types, implicated in mechanisms of neurons and glia, with effects on the development and functioning of the brain. Reports have also shown a link between changes in lncRNA molecules and the etiopathogenesis of brain neoplasia, including glioblastoma multiforme (GBM). GBM is an aggressive variant of brain cancer with an unfavourable prognosis and a median survival of 14–16 months. It is considered a brain-specific disease with the highly invasive malignant cells spreading throughout the neural tissue, impeding the complete resection, and leading to post-surgery recurrences, which are the prime cause of mortality. The early diagnosis of GBM could improve the treatment and extend survival, with the lncRNA profiling of biological fluids promising the detection of neoplastic changes at their initial stages and more effective therapeutic interventions. This review presents a systematic overview of GBM-associated deregulation of lncRNAs with a focus on lncRNA fingerprints in patients’ blood

Disruption of Myelin Leads to Ectopic Expression of K(V)1.1 Channels with Abnormal Conductivity of Optic Nerve Axons in a Cuprizone-Induced Model of Demyelination

The molecular determinants of abnormal propagation of action potentials along axons and ectopic conductance in demyelinating diseases of the central nervous system, like multiple sclerosis (MS),are poorly defined. Widespread interruption of myelin occurs in several mouse models of demyelination, rendering them useful for research. Herein, considerable myelin loss is shown in the optic nerves of cuprizone-treated demyelinating mice. Immuno-fluorescence confocal analysis of the expression and distribution of voltage-activated K+ channels (K(V)1.1 and 1.2 alpha subunits) revealed their spread from typical juxta-paranodal (JXP) sites to nodes in demyelinated axons, albeit with a disproportionate increase in the level of K(V)1.1 subunit. Functionally, in contrast to monophasic compound action potentials (CAPs) recorded in controls, responses derived from optic nerves of cuprizone-treated mice displayed initial synchronous waveform followed by a dispersed component. Partial restoration of CAPs by broad spectrum (4-aminopyridine) or K(V)1.1-subunit selective (dendrotoxin K) blockers of K+ currents suggest enhanced K(V)1.1-mediated conductance in the demyelinated optic nerve. Biophysical profiling of K+ currents mediated by recombinant channels comprised of different K(V)1.1 and 1.2 stoichiometries revealed that the enrichment of K(V)1 channels K(V)1.1 subunit endows a decrease in the voltage threshold and accelerates the activation kinetics. Together with the morphometric data, these findings provide important clues to a molecular basis for temporal dispersion of CAPs and reduced excitability of demyelinated optic nerves, which could be of potential relevance to the patho-physiology of MS and related disorders

Pathological alpha-synuclein impairs adult-born granule cell development and functional integration in the olfactory bulb

Although the role of noxious alpha-synuclein (alpha-SYN) in the degeneration of midbrain dopaminergic neurons and associated motor deficits of Parkinson's disease is recognized, its impact on non-motor brain circuits and related symptoms remains elusive. Through combining in vivo two-photon imaging with time-coded labelling of neurons in the olfactory bulb of A30P alpha-SYN transgenic mice, we show impaired growth and branching of dendrites of adult-born granule cells (GCs),with reduced gain and plasticity of dendritic spines. The spine impairments are especially pronounced during the critical phase of integration of new neurons into existing circuits. Functionally, retarded dendritic expansion translates into reduced electrical capacitance with enhanced intrinsic excitability and responsiveness of GCs to depolarizing inputs, while the spine loss correlates with decreased frequency of AMPA-mediated miniature EPSCs. Changes described here are expected to interfere with the functional integration and survival of new GCs into bulbar networks, contributing towards olfactory deficits and related behavioural impairments

All-trans retinoic acid fosters the multifarious U87MG cell line as a model of glioblastoma

Glioblastoma multiforme (GBM) is a primary brain cancer of poor prognosis, with existing treatments remaining essentially palliative. Current GBM therapy fails due to rapid reappearance of the heterogeneous neoplasm, with models suggesting that the recurrent growth is from treatment-resistant glioblastoma stem-like cells (GSCs). Whether GSCs depend on survival/proliferative cues from their surrounding microenvironmental niche, particularly surrounding the leading edge after treatment remains unknown. Simulating human GBM in the laboratory relies on representative cell lines and xenograft models for translational medicine. Due to U87MG source discrepancy and differential proliferation responses to retinoic acid treatment, this study highlights the challenges faced by laboratory scientists working with this representative GBM cell line. Investigating the response to all trans-retinoic acid (ATRA) revealed its sequestering of the prominin-1 stem cell marker. ICAM-1 universally present throughout U87MG was enhanced by ATRA, of interest for chemotherapy targeting studies. ATRA triggered diverse expression patterns of long non-coding RNAs PARTICLE and GAS5 in the leading edge and established monolayer growth zone microenvironment. Karyotyping confirmed the female origin of U87MG sourced from Europe. Passaging U87MG revealed the presence of chromosomal anomalies reflective of structural genomic alterations in this glioblastoma cell line. All evidence considered, this study exposes further phenotypic nuances of U87MG which may belie researchers seeking data contributing towards the elusive cure for GBM

Exosomes in the diagnosis and treatment of renal cell cancer

Renal cell carcinoma (RCC) is the most prevalent type of kidney cancer originating from renal tubular epithelial cells, with clear cell RCC comprising approximately 80% of cases. The primary treatment modalities for RCC are surgery and targeted therapy, albeit with suboptimal efficacies. Despite progress in RCC research, significant challenges persist, including advanced distant metastasis, delayed diagnosis, and drug resistance. Growing evidence suggests that extracellular vesicles (EVs) play a pivotal role in multiple aspects of RCC, including tumorigenesis, metastasis, immune evasion, and drug response. These membrane-bound vesicles are released into the extracellular environment by nearly all cell types and are capable of transferring various bioactive molecules, including RNA, DNA, proteins, and lipids, aiding intercellular communication. The molecular cargo carried by EVs renders them an attractive resource for biomarker identification, while their multifarious role in the RCC offers opportunities for diagnosis and targeted interventions, including EV-based therapies. As the most versatile type of EVs, exosomes have attracted much attention as nanocarriers of biologicals, with multi-range signaling effects. Despite the growing interest in exosomes, there is currently no widely accepted consensus on their subtypes and properties. The emerging heterogeneity of exosomes presents both methodological challenges and exciting opportunities for diagnostic and clinical interventions. This article reviews the characteristics and functions of exosomes, with a particular reference to the recent advances in their application to the diagnosis and treatment of RCC

Cholinergic neurons—keeping check on amyloid β in the cerebral cortex

The physiological relevance of the uptake of ligands with no apparent trophic functions via the p75 neurotrophin receptor (p75NTR) remains unclear. Herein, we propose a homeostatic role for this in clearance of amyloid β (Aβ) in the brain. We hypothesize that uptake of Aβ in conjunction with p75NTR followed by its degradation in lysosomes endows cholinergic basalo-cortical projections enriched in this receptor a facility for maintaining physiological levels of Aβ in target areas. Thus, in addition to the diffuse modulator influence and channeling of extra-thalamic signals, cholinergic innervations could supply the cerebral cortex with an elaborate system for Aβ drainage. Interpreting the emerging relationship of new molecular data with established role of cholinergic modulator system in regulating cortical network dynamics should provide new insights into the brain physiology and mechanisms of neuro-degenerative diseases

Extended Near-Infrared Optoacoustic Spectrometry for Sensing Physiological Concentrations of Glucose

Glucose sensing is pursued extensively in biomedical research and clinical practice for assessment of the carbohydrate and fat metabolism as well as in the context of an array of disorders, including diabetes, morbid obesity, and cancer. Currently used methods for real-time glucose measurements are invasive and require access to body fluids, with novel tools and methods for non-invasive sensing of the glucose levels highly desired. In this study, we introduce a near-infrared (NIR) optoacoustic spectrometer for sensing physiological concentrations of glucose within aqueous media and describe the glucose spectra within 850–1,900 nm and various concentration ranges. We apply the ratiometric and dictionary learning methods with a training set of data and validate their utility for glucose concentration measurements with optoacoustics in the probe dataset. We demonstrate the superior signal-to-noise ratio (factor of ~3.9) achieved with dictionary learning over the ratiometric approach across the wide glucose concentration range. Our data show a linear relationship between the optoacoustic signal intensity and physiological glucose concentration, in line with the results of optical spectroscopy. Thus, the feasibility of detecting physiological glucose concentrations using NIR optoacoustic spectroscopy is demonstrated, enabling the sensing glucose with ±10 mg/dl precision

Dendritic spine remodeling and plasticity under general anaesthesia

Ever since its first use in surgery, general anesthesia has been regarded as a medical miracle enabling countless life-saving diagnostic and therapeutic interventions without pain sensation and traumatic memories. Despite several decades of research, there is a lack of understanding of how general anesthetics induce a reversible coma-like state. Emerging evidence suggests that even brief exposure to general anesthesia may have a lasting impact on mature and especially developing brains. Commonly used anesthetics have been shown to destabilize dendritic spines and induce an enhanced plasticity state, with effects on cognition, motor functions, mood, and social behavior. Herein, we review the effects of the most widely used general anesthetics on dendritic spine dynamics and discuss functional and molecular correlates with action mechanisms. We consider the impact of neurodevelopment, anatomical location of neurons, and their neurochemical profile on neuroplasticity induction, and review the putative signaling pathways. It emerges that in addition to possible adverse effects, the stimulation of synaptic remodeling with the formation of new connections by general anesthetics may present tremendous opportunities for translational research and neurorehabilitation