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Handwriting is a component of the complex language that came about late in the history of mankind and which develops late in human beings. Numerous works have raised changes in both the graphic and kinematic characteristics of writing. Although, age does not modify the lexical and syntactic parameters of language, it can however modify its spatial structure, especially pressure and speed. Many neurodegenerative pathologies, especially Alzheimer's disease, are characterized by a progressive disorganization of writing. Depending on the cognitive stage of the dementia, the graphic gesture deteriorates as does the spatial construction. Objective: Our study aims at assessing the characteristics of Arabic writing in a healthy Moroccan population and to compare it to people with mild to moderate Alzheimer's disease. Our objective is to help health professionals detect early cognitive deterioration in neurodegenerative diseases by analyzing the graphic gesture. Handwriting is captured on a graphic tablet (WACOM) and is analyzed "online" as a sequence of acquired signals (position, pressure, speed and pen inclination) in Moroccan patients with mild to moderate Alzheimer's disease and these were compared to those of normal volunteers. We performed a first analysis of the results from 18 Alzheimer's patients compared to 18 control subjects. The results reveal differences between the control and Alzheimer's groups. AD subjects had lower speeds and accelerations compared to the control subjects. The time spent on paper and in the air was significantly greater in the AD subjects. This preliminary analysis of the results allowed us to identify distinguishing characteristics through the analysis of different handwriting parameters in order to identify the two groups studied.
Content available remote Tandemly repeated trinucleotides - comparative analysis
Characteristics of 64 possible tandem trinucleotide repeats (TSSR) from Homo sapiens (hs), Mus musculus (mm) and Rattus norvegicus (rn) genomes are presented. Comparative analysis of TSSR frequency depending on their repetitiveness and similarity of the TSSR length distributions is shown. Comparative analysis of TSSR sequence motifs and association between type of motif and its length (n) using ρ-coefficient method (quantitatively measuring the association between variables in contingency tables) is presented. These analyses were carried out in the context of neurodegenerative diseases based on trinucleotide tandems. The length of these tandems and their relation to other TSSR is estimated. It was found that the higher repetitiveness (n) the lower frequency of trinucleotides tandems. Differences between genomes under consideration, especially in longer than n=9 TSSR were discussed. A significantly higher frequency off A- and T-rich tandems is observed in the human genome (as well as in human mRNA). This observation also applies to mm and rn, although lower abundant in proportion to human genomes was found. The origin of elongation (or shortening) of TSSR seems to be neither frequency nor length dependent. The results of TSSR analysis presented in this work suggest that neurodegenerative disease-related microsatellites do not differ versus the other except the lower frequency versus the other TSSR. CAG occurs with relatively high frequency in human mRNA, although there are other TSSR with higher frequency that do not cause comparable disease disorders. It suggests that the mechanism of TSSR instability is not the only origin of neurodegenerative diseases.
Parkinson’s disease (PD) is the second after Alzheimer’s most popular neurodegenerative disease (ND). Cures for both NDs are currently unavailable. OBJECTIVE: The purpose of our study was to predict the results of different PD patients’ treatments in order to find an optimal one. METHODS: We have compared rough sets (RS) and others, in short, machine learning (ML) models to describe and predict disease progression expressed as UPDRS values (Unified Parkinson’s Disease Rating Scale) in three groups of Parkinson’s patients: 23 BMT (Best Medical Treatment) patients on medication; 24 DBS patients on medication and on DBS therapy (Deep Brain Stimulation) after surgery performed during our study; and 15 POP (Postoperative) patients who had had surgery earlier (before the beginning of our research). Every PD patient had three visits approximately every six months. The first visit for DBS patients was before surgery. On the basis of the following condition attributes: disease duration, saccadic eye movement parameters, and neuropsychological tests: PDQ39 (Parkinson’s Disease Questionnaire - disease-specific health-related quality-of-life questionnaire), and Epworth Sleepiness Scale tests we have estimated UPDRS changes (as the decision attribute). RESULTS: By means of RS rules obtained for the first visit of BMT/DBS/POP patients, we have predicted UPDRS values in the following year (two visits) with global accuracy of 70% for both BMT visits; 56% for DBS, and 67%, 79% for POP second and third visits. The accuracy obtained by ML models was generally in the same range, but it was calculated separately for different sessions (MedOFF/MedON). We have used RS rules obtained in BMT patients to predict UPDRS of DBS patients; for the first session DBSW1: global accuracy was 64%, for the second DBSW2: 85% and the third DBSW3: 74% but only for DBS patients during stimulation-ON. ML models gave better accuracy for DBSW1/W2 session S1(MedOFF): 88%, but inferior results for session S3 (MedON): 58% and 54%. Both RS and ML could not predict UPDRS in DBS patients during stimulation-OFF visits because of differences in UPDRS. By using RS rules from BMT or DBS patients we could not predict UPDRS of POP group, but with certain limitations (only for MedON), we derived such predictions for the POP group from results of DBS patients by using ML models (60%). SIGNIFICANCE: Thanks to our RS and ML methods, we were able to predict Parkinson’s disease (PD) progression in dissimilar groups of patients with different treatments. It might lead, in the future, to the discovery of universal rules of PD progression and optimise the treatment.
Over some time, Drosophila melanogaster (Meigen, 1830), commonly called fruit fly, has been used as a model organism in both scientific and medical research. Drosophila in comparison with other mammalian species shares some basic features like physiological, biological, biochemical, and neurological resemblances which make them suitable for use for biomedical research. Fruit fly can be maintained efficiently at a reduced cost in the laboratory, and it is endorsed as an alternative model compared to other vertebrates. It is confirmed and documented that almost 75 % of human disease-causing genes have functional similarities in Drosophila. Nevertheless, the use of D. melanogaster as a model organism was not narrowed to genetic research only, but several experiments. The use of this organism as a model for human diseases has also led to findings like neurodegenerative diseases, Huntington’s disease, spinocerebellar ataxia type 3, cancer, cardiovascular, inflammation and infectious diseases, and metabolic disorders. The fly is used as an ideal model organism for neurodegenerative disease studies such as Alzheimer’s and Parkinson’s, which have become more predominant in today's aging population due to its complex nervous system which conserved neurological function, and the human disease-related loci. In this review, we presented and discussed Drosophila melanogaster as a model to study several human diseases.
Content available remote Genesis of ER Stress in Huntington’s Disease
Recent research has identified ER stress as a major mechanism implicated in cytotoxicity in many neurodegenerative diseases, among them Huntington’s disease. This genetic disorder is of late-onset, progressive and fatal, affecting cognition and movement. There is presently no cure nor any effective therapy for the disease. This review focuses on recent findings that shed light on the mechanisms of the advent and development of ER stress in Huntington’s disease and on its implications, highlighting possible therapeutic avenues that are being or could be explored.
Microglial cells, through the proinflammatory mediators play an important role in host defense and tissue repair in CNS. They contribute to pathomechanisms of Alzheimer’s and other neurodegenerative diseases. The aim of this work was to investigate modifying effects of non-activated migroglia on cholinergic neuronal SN56 cells subjected to common neuroprotective and/or neurotoxic signals. Chronic exposure to Zn or SNP caused loss of viability (30%), inhibition of pyruvate dehydrogenase (PDH) (40%), isocitrate dehydrogenase (60 and 50%) and aconitase activities as well as decrease of acetyl-CoA levels. These alterations in enzyme activities displayed strong direct correlation with depletion of acetylCoA (r=0.86, P<0.0001) and inverse correlation with cell viability (r=0.87, P<0.0001). Resveratrol, free radical scavenger, increased viability of Zn/SNP treated cholinergic cells but did not overcome suppresive effects of SNP and Zn on enzymes activities. Under same neurotoxic conditions, N9 microglial cells cultured on isoporated inserts and added to neuronal culture dishes, also overcame neurotoxic effect Zn and SNP maintaining control levels of acetyl-CoA, enzymes activites and high cell viability. These data sugest that in some specific, pathologic conditions, non-activated microglia may protect neuronal cholinergic neurons against neurotoxic insults by paracrine-like mechanism by protecting their energy metabolism. On the other hand resveratrol neuroprotection may depend on entirely different yet undefined mechanism. Supported by GUMed MN-15, MNiSW NN401029937, IP2010035370, GUMed ST-57 projects.
Protein glycation is initiated by a nucleophilic addition reaction between the free amino group from a protein, lipid or nucleic acid and the carbonyl group of a reducing sugar. This reaction forms a reversible Schiff base, which rearranges over a period of days to produce ketoamine or Amadori products. The Amadori products undergo dehydration and rearrangements and develop a cross-link between adjacent proteins, giving rise to protein aggregation or advanced glycation end products (AGEs). A number of studies have shown that glycation induces the formation of the β-sheet structure in β-amyloid protein, α-synuclein, transthyretin (TTR), copper-zinc superoxide dismutase 1 (Cu, Zn-SOD-1), and prion protein. Aggregation of the β-sheet structure in each case creates fibrillar structures, respectively causing Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, familial amyloid polyneuropathy, and prion disease. It has been suggested that oligomeric species of glycated α-synuclein and prion are more toxic than fibrils. This review focuses on the pathway of AGE formation, the synthesis of different types of AGE, and the molecular mechanisms by which glycation causes various types of neurodegenerative disease. It discusses several new therapeutic approaches that have been applied to treat these devastating disorders, including the use of various synthetic and naturally occurring inhibitors. Modulation of the AGE-RAGE axis is now considered promising in the prevention of neurodegenerative diseases. Additionally, the review covers several defense enzymes and proteins in the human body that are important anti-glycating systems acting to prevent the development of neurodegenerative diseases.
Oxidative stress is one of the possible mechanisms of neurodegeneration. One of the elements of this mechanism are altered iron homeostasis and changes concerning of iron metabolism regulatory proteins. The primary iron storage protein in cells is ferritin, composed of heavy (H) and light (L) chains. In brain tissue neurons contain mainly ferritin H-chains, whereas glial cells are rich in L-chains. To the best of our knowledge, this is the first study that compares structure of ferritin and histopathological hallmarks in hippocampal tissue affected by the pathological process of Alzheimer’s disease (AD). Our data indicate a statistically significant correlation between the concentration of L chains of ferritin, the H/L ratio and the amount of senile plaques in the subiculum, CA1 and CA4 sectors of the hippocampus (p<0.001, p=0.025, p=0.029). A significant correlation was also found between the concentration of L-ferritin and neuronal loss (p=0.0026). These findings indicate an important role of ferritin light chains in neurodegeneration, that is linked to chronic inflammation processes and the associated activation of the microglia rich of L chains.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease leading to degeneration and loss of motoneurons in the spinal cord anterior horns. Although etiology of the disease is unknown there is a hypothesis assuming that survival motor neuron protein (SMN) may save motoneurons from degeneration not only in spinal muscular atrophy (SMA) but also in ALS. In animal models of ALS the neuroprotective role of SMN was observed but it is not known whether the phenomenon is present in humans. Therefore we decided to examine immunoexpression of SMN and functionally associated with it gemin 2, 3 and 4 in the anterior horn neurons of patients with sporadic form of ALS (sALS). Material and methods: The material was composed of 10 spinal cords of patients with sALS who died at the age of 52–87 years 1–8 years after the onset of the disease. On formalin-fixed and paraffin-embedded spinal cords immunohistochemistry was applied. The immunohistochemical reactions were performed with antibodies against SMN and gemin 2, 3 and 4 according to the avidin-biotin-peroxidase method. Results: In all the examined cases expression of SMN and gemin 3 in spinal cord neurons was found although intensity of the immune reactions was diverse. The immunolabel were the most intense in patients with acute course of sALS and gradually decreased with longevity of the disease. Not only motoneurons but also interneurons and sensory neurons revealed immunoexpression of SMN and gemin 3. The immune reaction to gemin 2 was negative. The immunoreactivity for gemin 4 was also negative or very weak. Conclusions: (1) In humans, expression of SMN and gemin 3 in neurons is present through the whole lifespan. (2) In sALS, expression of gemin 2 and 4 is abnormal: absent or diminished respectively. (3) Presence of all components of the SMN-gemin complex is probably necessary for its normal functioning. (4) Since the immunoreactivity for SMN, and gemin 2, 3 and 4 was similar in all the examined cases and 6 from the 10 cases were at the age of 65–87 years it seems that advanced age has no influence on expression of the investigated proteins. This study was supported by the Ministry of Science and Higher Education grant NN 401 014640
Background: The Corpus callosum (Cc) in the cerebral cortex is a bundle of neural fibers that facilitates inter-hemispheric communication. The Cc area and area of its sub-regions (also known as parcels) have been examined as a biomarker for cortical pathology and differential diagnosis in neurodegenerative diseases such as Autism, Alzheimer’s disease (AD), and more. Manual segmentation and parcellation of Cc are laborious and time-consuming. The present work proposes a novel work of automated parcellated Cc (PCc) segmentation that will serve as a potential biomarker to study and diagnose neurological disorders in brain MRI images. Method: In this perspective, the present work aims to develop an automated PCc segmentation from mid-sagittal T1- weighted (w) 2D brain MRI images using a deep learning-based fully convolutional network, a modified residual attention U-Net, referred to as PCcS-RAU-Net. The model has been modified to use a multi-class segmentation configuration with five target classes (parcels): rostrum, genu, mid-body, isthmus and splenium. Results: The experimental research uses two benchmark MRI datasets, ABIDE and OASIS. The proposed PCcS-RAU-Net outperformed existing methods on the ABIDE dataset with a DSC of 97.10% and MIoU of 94.43%. Furthermore, the model’s performance is validated on the OASIS and Real clinical image (RCI) data and hence verifies the model’s generalization capability. Conclusion: The proposed PCcS-RAU-Net model extracts essential characteristics such as the total area of the Cc (TCcA) to categorize MRI slices into healthy controls (HC) and disease groups. Also, sub-regional areas, Cc1A to Cc5A, help study atrophy progression for early diagnosis.
Introduction. Despite the growing interest in the consequences of caring for patients with Huntington disease (pHD), little is known about the family caregivers of such patients in Poland. Identification of their needs can improve caregivers’ wellbeing, the quality of care and condition of pHD. The aim of this study was to understand the social functioning of family caregivers of pHD and their perception of the caregiving role. Materials and methods. Data was collected from 55 family caregivers of pHD. A structured questionnaire was used consisting of 86 questions subsumed into five domains: ‘Problems’ and ‘Feelings related to caregiving’, ‘Attitude toward caregiving’, ‘Satisfaction with life’ and ‘Perception of healthcare services’. Correlations between the different scales and other characteristics were measured as potential predictors of the burden. Non-parametric statistical methods were used in the analysis. Results. Most respondents experienced a high (50.9%) or moderate (30.95%) feeling of burden. Although 70.9% of caregivers perceived caregiving positively, for many it was a source of negative feelings. Only 10.9% of respondents declared that caregiving decreased their QoL. Carers’ perception of caregiving was mostly influenced by their negative experiences with the healthcare system. Respondents’ domicile, religious practices, age, income, marital status, time of diagnosis and of caregiving, patient’s age and stage of disease also influenced their experiences. Conclusions. Health professionals and policy planners should focus on monitoring caregivers’ health, identifying their needs, sources of distress, and supporting caregivers’ coping strategies. They should also be better educated about the clinical and practical aspects of HD.
W niniejszej pracy przedstawione zostały wyniki badań meteorytów i próbek biologicznych, przeprowadzonych w ostatnim czasie w kierowanym przeze mnie Laboratorium Spektroskopii Mössbauerowskiej. Badania te dotyczyły między innymi opracowania nowej metody pozwalającej na dokonywanie wstępnej klasyfikacji chondrytów zwyczajnych. Równolegle do badań dotyczących meteorytów zostało zaproponowane użycie spektroskopii mössbauerowskiej do badania próbek biologicznych. Widma mössbauerowskie chondrytów zwyczajnych składają się z dwóch dubletów ze względu na obecność żelaza paramagnetycznego w oliwinach i piroksenach oraz dwóch sekstetów pochodzących od magnetycznie uporządkowanego żelaza obecnego w fazach metalicznych i troilicie. Powierzchnie spektralne różnych faz mineralogicznych w meteorytach, określone przez zastosowanie spektroskopii mössbauerowskiej, są proporcjonalne do liczby atomów żelaza w danej fazie mineralogicznej. Ta właściwość widm mössbauerowskich stanowiła podstawę do skonstruowania metody klasyfikacji chondrytów zwyczajnych. Metoda ta wykorzystuje pola powierzchni spektralnych widm mössbauerowskich, które analizowane są za pomocą wielowymiarowej analizy dyskryminacyjnej i odległości Mahalanobis. Metoda ta nosi nazwę 4M i pozwala określić prawdopodobieństwo przynależności chondrytu zwyczajnego do danego typu - H, L lub LL. Spektroskopia mössbauerowska nie jest rutynowo stosowana do oznaczania stężenia żelaza. Ponieważ jednak ta metoda nie wymaga wstępnej obróbki próbek przed pomiarem, może mieć ona ogromne znaczenie dla oceny stężenia żelaza w próbkach, które można następnie wykorzystać do dalszych badań. Próbki biologiczne są tego dobrym przykładem. Uważa się, że żelazo może odgrywać ważną rolę w neurodegeneracji. W pracy przedstawione zostały wyniki badań porównawczych obszarów ludzkiego mózgu (kontrolnych i patologicznych), przeprowadzonych za pomocą technik spektroskopii mössbauerowskiej i obrazowania metodą rezonansu magnetycznego. Spektroskopia mössbauerowska wykazała wyższe stężenie żelaza w atypowym parkinsonizmie (nazywanym postępującym porażeniem nadjądrowym) w obszarach mózgu takich jak istota czarna (substantia nigra) oraz gałka blada (globus pallidus) w stosunku do próbek stanowiących grupę kontrolną. W pozostałych chorobach neurodegeneracyjnych nie zarejestrowano wzrostu stężenia żelaza w tkankach mózgowych. Ze względu na fakt, że określenie roli żelaza może wnieść bardzo wiele w zrozumienie mechanizmów powstawania i rozwoju chorób neurodegeneracyjnych, badania mössbauerowskie próbek mózgowych stanowią ciekawy i perspektywiczny kierunek badań, który wymaga przeprowadzenia dalszych pomiarów i analiz.
This work presents the recent research results related to meteorites and biological samples conducted in the Mössbauer Spectroscopy Laboratory led by the Author. These studies concerned, among others, the development of a new method allowing for the preliminary classification of ordinary chondrites. Parallel to the research on meteorites, it was proposed to use Mössbauer spectroscopy to study biological samples. The Mössbauer spectra of ordinary chondrites consist of two doublets due to the presence of paramagnetic iron in olivines and pyroxenes and two sextets derived from magnetically ordered iron present in metallic and troilite phases. The spectral areas of various mineralogical phases in meteorites; determined by the use of Mössbauer spectroscopy; are proportional to the number of iron atoms in this mineralogical phase. This property of the Mössbauer spectra formed the basis for constructing a method for classifying ordinary chondrites. This method uses the spectral surface areas of the Mössbauer spectra, which are analysed using multidimensional discriminant analysis and Mahalanobis distances. This method is called 4M and allows one to determine the probability of belonging to one of the types of ordinary chondrites - H, L or LL. Mössbauer spectroscopy in not routinely used to determine iron concentration. However, as this method does not require pre-treatment of samples prior to measurements, it can be of great importance for assessing iron in samples that can then be used for further testing. Here, biological samples are a good example. It is believed that iron can play an important role in neurodegeneration. Thus, the work presents the results of comparative studies of areas of the human brain (control and pathological) carried out using Mössbauer spectroscopy techniques and magnetic resonance imaging. Mössbauer spectroscopy showed a higher concentration of iron in atypical parkinsonism (called progressive supranuclear palsy) in areas of the brain such as substantia nigra and globus pallidus compared to control group samples. In other neurodegenerative diseases, no increase in iron concentration in brain tissues was recorded. Due to the fact that determining the role of iron can contribute a lot to understanding the mechanisms of the formation and development of neurodegenerative diseases, Mössbauer studies of brain samples are an interesting direction of research that requires further measurements and analyses.
Introduction: Amyotrophic lateral sclerosis (ALS) is a major neurodegenerative disease to afflict the adult human population. ALS causes a progressive motoneuron degeneration within anterior horns of the spinal cord. Recent data indicate the presence of mutations in the SMN (Survival Motor Neuron) gene that cause a deficits in the level of the functional SMN protein and may be an exacerbating factor in the disease development of rat model of fALS. SMN forms the multiprotein complex with selected gemins (i.a. gemin 2, 3 and 4). It is known, that the complex is important for motoneuron development in ontogenesis as well as in the proper functioning of mature motoneuron. However, the level of the SMN and individual gemin expression during the life both in humans and rats still become uncovered. The aim of our study was to determine the immunoreactivities of SMN and gemins 2, 3 and 4 in rat model of fALS during all life span. Material and method: Male rats mutated in SOD-1 were subjected to experiments. Animals at age of 60 days (group 1), 90 days (group 2), 120 days (group 3) were asymptomatic. The last group involving symptomatic rats was created from animals older than 120 days. Rats were perfused in deep anaesthesia. The spinal cords were removed and processed in routine histological staining techniques as well as in immunohistochemical methods (to detect SMN and selected gemins proteins). Labelling sections of spinal cords were analyzed with light and fluorescent microscope. Result: SMN and all investigated gemins were present in spinal cord motoneurons in rats from all experimental groups. However, the level of staining was weaker in the paretic rats. In the opposition to other examined proteins the immunoreaction of gemin 2 was weaker starting from 90 day of life. Conclusion: The SMN protein complex is present in motoneurons within the spinal cord during all animal lifespan in the rat model of familiar ALS. This study was supported by the Ministry of Science and Higher Education grant NN 401 014640
Given the urgent need for a disease modifying treatment of Alzheimer’s disease (AD), there is increasing interest in tau‑based therapeutics. In a comparative study, methylthioninium chloride (MTC) and leucomethylthioninium salts (LMTX®) (5‑75 mg/kg; oral administration for 3-8 weeks) were assessed preclinically in two novel transgenic tau mouse lines (Line 1, Line 66). Behavioural and histopathological proxies were evaluated. Both MTC and LMTX® dose-dependently rescued the learning impairment and restored behavioural flexibility in a spatial problem‑solving water maze task in Line1 and corrected motor‑learning in Line 66. Simultaneously, both drugs reduced the number of tau-reactive neurons, particularly in the hippocampus and entorhinal cortex in Line 1 and had more widespread effects in Line 66. The data establish that diaminophenothiazine compounds like MTC can reverse both spatial and motor learning deficits and reduce the underlying tau pathology and therefore offer potential for the treatment of tauopathies. In the clinic, symptomatic treatments with cholinesterase inhibitors and/or memantine are relatively ineffective and the need for new treatments targeting the underlying pathology of AD is generally recognised. In most of the failed disease-modifying trials conducted over the last 16 years, patients have been allowed to continue taking symptomatic treatments at stable doses, under the assumption that they do not impair efficacy because the modes of action are different. In recently completed Phase 3 trials testing the tau aggregation inhibitor leuco-methylthioninium bis (hydromethanesulfonate) (LMTM), we found highly significant differences in treatment response according to whether patients were taking LMTM as monotherapy (benefit) or as add‑on to symptomatic treatments (no effect). A large body of preclinical research has then been undertaken in wild-type mice and in our tau transgenic mouse model (Line 1) expressing the core tau unit of the AD paired helical filament with the aim of understanding the mechanisms responsible for the reduced efficacy of LMTM as an add‑on to symptomatic treatments. A range of experimental paradigms were used to measure the effects of chronic pretreatment with the cholinesterase inhibitor rivastigmine given for 2-5 weeks prior to adding LMTM treatment for a further 2‑6 weeks. In tau transgenic mice, LMTM given alone was found to increase hippocampal acetylcholine (ACh) levels, glutamate release from synaptosomal preparations, synaptophysin levels in multiple brain regions, mitochondrial complex IV activity, reduce tau pathology, restore choline acetyl transferase (ChAT) immunoreactivity in basal forebrain, and reverse deficits in spatial learning. Chronic pretreatment with rivastigmine was found to reduce or eliminate almost all LMTM treatment effects, apart from reduction in tau aggregation pathology and restoration of ChAT immunoreactivity in the basal forebrain. LMTM effects on hippocampal ACh and levels of synaptophysin were also reversed in wild‑type mice. Collectively, targeting tangles consisting of MAPT protein tau is a viable strategy in preclinical models and was forward translated to AD patients receiving monotherapy. In the clinic, however, prior symptomatic treatment with a cholinesterase inhibitor prohibited the efficacy of LMTM. Back translation to our tau mouse model reproduced this negative interaction and revealed a mechanistic action across different transmitter systems and at multiple compartmental levels of neural function.
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