rudyvdbrink/CitationDatabase huggingface dataset:
How specific are the conformation-specific α-synuclein antibodies? Characterization and validation of 16 α-synuclein conformation-specific antibodies using well-characterized preparations of α-synuclein monomers, fibrils and oligomers with distinct structures and morphology.
Neurobiology of disease, 2020

Increasing evidence suggests that alpha-synuclein (α-syn) oligomers are obligate intermediates in the pathway involved in α-syn fibrillization and Lewy body (LB) formation, and may also accumulate within LBs in Parkinson's disease (PD) and other synucleinopathies. Therefore, the development of tools and methods to detect and quantify α-syn oligomers has become increasingly crucial for mechanistic studies to understand their role in PD, and to develop new diagnostic methods and therapies for PD and other synucleinopathies. The majority of these tools and methods rely primarily on the use of aggregation state-specific or conformation-specific antibodies. Given the impact of the data and knowledge generated using these antibodies on shaping the foundation and directions of α-syn and PD research, it is crucial that these antibodies are thoroughly characterized, and their specificity or ability to capture diverse α-syn species is tested and validated. Herein, we describe an antibody characterization and validation pipeline that allows a systematic investigation of the specificity of α-syn antibodies using well-defined and well-characterized preparations of various α-syn species, including monomers, fibrils, and different oligomer preparations that are characterized by distinct morphological, chemical and secondary structure properties. This pipeline was used to characterize 18 α-syn antibodies, 16 of which have been reported as conformation- or oligomer-specific antibodies, using an array of techniques, including immunoblot analysis (slot blot and Western blot), a digital ELISA assay using single molecule array technology and surface plasmon resonance. Our results show that i) none of the antibodies tested are specific for one particular type of α-syn species, including monomers, oligomers or fibrils; ii) all antibodies that were reported to be oligomer-specific also recognized fibrillar α-syn; and iii) a few antibodies showed high specificity for oligomers and fibrils but did not bind to monomers. These findings suggest that the great majority of α-syn aggregate-specific antibodies do not differentiate between oligomers and fibrils, thus highlighting the importance of exercising caution when interpreting results obtained using these antibodies. Our results also underscore the critical importance of the characterization and validation of antibodies before their use in mechanistic studies and as diagnostic tools or therapeutic agents. This will not only improve the quality and reproducibility of research and reduce costs but will also reduce the number of therapeutic antibody failures in the clinic.
Two phenotypically and functionally distinct microglial populations in adult zebrafish.
Science advances, 2020

Microglia are the tissue-resident macrophages in the central nervous system and are critically involved in immune defense, neural development and function, and neuroinflammation. The versatility of microglia has long been attributed to heterogeneity. Recent studies have revealed possible heterogeneity in human but not in murine microglia, yet a firm demonstration linking microglial heterogeneity to functional phenotypes remains scarce. Here, we identified two distinct microglial populations in adult zebrafish that differ in morphology, distribution, development, and function. The predominant population, phagocytotic microglia, which expresses
Effects of immunization with heat-killed Mycobacterium vaccae on autism spectrum disorder-like behavior and epileptogenesis in a rat model of comorbid autism and epilepsy.
Brain, behavior, and immunity, 2020

Autism spectrum disorders (ASDs) and epilepsy are often comorbid. The basis for this co-occurrence remains unknown; however, inflammatory stressors during development are a shared risk factor. To explore this association, we tested the effect of repeated immunizations using a heat-killed preparation of the stress-protective immunoregulatory microbe Mycobacterium vaccae NCTC 11,659 (M. vaccae) on the behavioral and epileptogenic consequences of the combined stress-terbutaline (ST) rat model of ASD-like behavior/epilepsy. Repeated immunization of the dam with M. vaccae during pregnancy, followed by immunization of the pups after terbutaline injections, prevented the expression of ASD-like behavior but did not appear to protect against, and may have even enhanced, the spontaneous epileptogenic effects of ST. Maternal M. vaccae injections transferred an anti-inflammatory immunophenotype to offspring, and repeated injections across development prevented ST-induced increases in microglial density at early developmental time points in a region-specific manner. Despite epidemiological comorbidity between ASD/epileptic conditions and shared environmental risk factors, our results suggest that the expression of ASD-like behaviors, but perhaps not epileptogenesis, is sensitive to early anti-inflammatory intervention. These data provide support for the exploration of immunoregulatory strategies to prevent the negative neurodevelopmental behavioral effects of stressors during early critical periods.
Distinct molecular mechanisms control levels of synaptic F-actin.
Cell biology international, 2020

Polymerization of filamentous (F)-actin at the neuronal synapse plays an important role in neuronal function. However, the regulatory mechanisms controlling the levels of synaptic actin remain incompletely understood. Here, I used established pharmacological blockers to acutely disrupt the function of actin polymerization machinery, then quantified their effect on synaptic F-actin levels. Synaptic F-actin was modestly decreased by inhibition of Arp2/3-dependent actin branching. Blockade of formin-dependent actin elongation resulted in an Arp2/3-dependent increase in synaptic actin that could be mimicked by limited actin depolymerization. Limited actin depolymerization was also sufficient to reverse a decrease in synaptic F-actin caused by prolonged blockade of synaptic NMDA-type glutamate receptors. These results suggest that interplay between different actin polymerization pathways may regulate synaptic actin dynamics.
Time, pattern, and outcome of medulloblastoma relapse and their association with tumour biology at diagnosis and therapy: a multicentre cohort study.
The Lancet. Child & adolescent health, 2020

Disease relapse occurs in around 30% of children with medulloblastoma, and is almost universally fatal. We aimed to establish whether the clinical and molecular characteristics of the disease at diagnosis are associated with the nature of relapse and subsequent disease course, and whether these associations could inform clinical management.
Correction to: inhibition of p38 MAPK activity leads to cell type-specific effects on the molecular circadian clock and time-dependent reduction of glioma cell invasiveness.
BMC cancer, 2019

Following publication of the original article [1], we have been notified that the tagging of one of the author names was done incorrectly in the XML version of the paper. The online and pdf versions of this paper are not affected by the change. Original and corrected tagging can be seen below. The original article has been corrected.
Plasma Lipids as Biomarkers for Alzheimer's Disease: A Systematic Review.
Cureus, 2020

Alzheimer's disease (AD) is caused by several risk factors leading to dementia. It's diagnosis usually depends on clinical presentation and certain biomarkers in the cerebrospinal fluid (CSF). The brain has a high content of cholesterol and the metabolism of cholesterol in the brain can be associated with beta-amyloid plaques formation, which is seen in Alzheimer's disease. Given these implications, we studied if plasma lipid levels can vary in Alzheimer's disease and if these can be used as biomarkers to diagnose and predict the progression of Alzheimer's disease. Certain mutations in the brain cholesterol transport receptors and proteins and their association with Alzheimer's were also studied. This systematic review abides by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched multiple databases, such as Pubmed, Google Scholar, Pubmed central, ScienceDirect, Web of Science, and Medline with the help of keywords like Alzheimer's disease, cognitive impairment, plasma lipid biomarkers, cholesterol, brain cholesterol metabolism separately and in combination with each other. We collected 49 quality appraised articles on the association between plasma lipids and Alzheimer's disease and the genetic mutations in alleles related to cholesterol metabolism and Alzheimer's disease by applying the inclusion and exclusion criteria. Based on the finding of the studies reviewed, we found an association between plasma lipids, polymorphisms in genes associated with cholesterol transport, and Alzheimer's disease. Increased serum low-density lipoprotein (LDL-C), triglycerides (TG), total cholesterol (TC), sphingolipids, 24S hydroxycholesterol (24S-HC), 27O hydroxycholesterol (27O-HC) was associated with Alzheimer's. Decreased high-density lipoprotein (HDL-C) and phospholipids were noticed. Genetic mutations in apolipoprotein E (ApoE), apolipoprotein B (ApoB), apolipoprotein A (ApoA), ATP binding cassette transporter 1 (ABCA1), ATP binding cassette transporter 7 (ABCA7), amyloid precursor protein (APP), cytochrome P450 family 46 subfamilies A member 1 (CYP46A1), presenilin 1 (PSEN1), presenilin 2 (PSEN2) are also associated with increased risk of Alzheimer's disease. This study found an association between plasma lipids and Alzheimer's, proving that plasma lipids can be used as biomarkers for early diagnosis of Alzheimer's disease. It may also help predict the prognosis and stage the disease severity. Further studies are needed to find out the exact mechanism behind these changes.
Cholinergic neural activity directs retinal layer-specific angiogenesis and blood retinal barrier formation.
Nature communications, 2019

Blood vessels in the central nervous system (CNS) develop unique features, but the contribution of CNS neurons to regulating those features is not fully understood. We report that inhibiting spontaneous cholinergic activity or reducing starburst amacrine cell numbers prevents invasion of endothelial cells into the deep layers of the retina and causes blood-retinal-barrier (BRB) dysfunction in mice. Vascular endothelial growth factor (VEGF), which drives angiogenesis, and Norrin, a Wnt ligand that induces BRB properties, are decreased after activity blockade. Exogenous VEGF restores vessel growth but not BRB function, whereas stabilizing beta-catenin in endothelial cells rescues BRB dysfunction but not vessel formation. We further identify that inhibiting cholinergic activity reduces angiogenesis during oxygen-induced retinopathy. Our findings demonstrate that neural activity lies upstream of VEGF and Norrin, coordinating angiogenesis and BRB formation. Neural activity originating from specific neural circuits may be a general mechanism for driving regional angiogenesis and barrier formation across CNS development.
Additional sampling directions improve detection range of wireless radiofrequency probes.
Magnetic resonance in medicine, 2016

While MRI is enhancing our knowledge about the structure and function of the human brain, subject motion remains a problem in many clinical applications. Recently, the use of wireless radiofrequency markers with three one-dimensional (1D) navigators for prospective correction was demonstrated. This method is restricted in the range of motion that can be corrected, however, because of limited information in the 1D readouts.
Psychosis: a synthesis of motivational and defect perspectives.
American journal of psychoanalysis, 2012

Based on the evolution of human intelligence and the tremendous cognitive capacities arising from it, we have an innate tendency for the extreme thought content, thought form, and sensory perceptions of psychosis. During the conscious and awake state, cognitive regulatory control processes block these more extreme variants to facilitate reality congruency necessary for adaptive functioning. While asleep there is no need for reality congruency and the cognitive regulatory control processes are deactivated allowing psychotic equivalents to be expressed in dreams. This paper helps synthesize the two dominant perspectives regarding the etiology of psychosis: the neuroscience defect perspective and the psychoanalytic motivational perspective. Regarding the former, defective cognitive regulation arising from certain conditions, such as the deficit state of schizophrenia, allows extreme cognitive distortions, thought form variants, and sensory perceptual experiences to intrude into the conscious and awake state, thereby producing psychosis. Consistent with the psychoanalytic motivational perspective, defensive processes can motivate extreme cognitive distortions, thought form variants and sensory perceptual experiences, and also facilitate their expression by deactivating the relevant cognitive regulatory control processes.
Neuroimmune pharmacology as a sub-discipline of immunology in the medical school curriculum.
Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 2011

This article provides a description of a proposed sub-module and attendant syllabus for inclusion of neuroimmune pharmacology as a sub-discipline of an immunology course that is offered to medical students during the first year of medical school. Neuroimmune pharmacology is an area of study that integrates fundamental concepts in pharmacology, immunology, neuroscience, and infectious disease. This convergent disciplinary area is of increasing importance to the foundational training of medical students, especially in view of the recognition that a variety of neuropathological processes such as demyelinating disease, drug abuse, and viral encephalitis has an immunological component. A lecture sub-module that addresses this convergent topic is proposed for inclusion as a sub-discipline of an immunology course offered as a component of a Scientific Foundations curriculum that takes place during the first 6 months of medical school. It is proposed to revisit the neuroimmune pharmacology topic area in a more clinical setting during the subsequent 14 months of study when medical students would be presented with an organ system-based curriculum. In this instructional model, basic science teaching faculty would interface with clinical faculty in presenting the topical block material in the context of different organ systems. Discussion of clinical cases related to neuroimmune pharmacology would be integrated into the organ system-based curriculum in order to highlight a translational relevance to medical practice.
Chemogenetic Manipulation of Dopamine Neurons Dictates Cocaine Potency at Distal Dopamine Transporters.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2020

The reinforcing efficacy of cocaine is largely determined by its capacity to inhibit the dopamine transporter (DAT), and emerging evidence suggests that differences in cocaine potency are linked to several symptoms of cocaine use disorder. Despite this evidence, the neural processes that govern cocaine potency
Can Stem Cells Improve Left Ventricular Ejection Fraction in Heart Failure? A Literature Review of Skeletal Myoblasts and Bone Marrow-Derived Cells.
Cureus, 2020

Heart failure is a life-threatening condition that affects millions worldwide and is only expected to get worse with an ageing population. Current treatment regimens rely on medical therapy and heart transplantation as a last resort. Stem cells have been undergoing clinical trials worldwide as a hope for a new and safe clinical treatment. Skeletal myoblasts and bone marrow-derived stem cells are two types of stem cells being tested. The objective is to evaluate the efficacy of these two types of stem cells for heart failure therapy. Data were searched in PubMed using both regular and Medical Subject Heading (MeSH) keywords (stem cells, therapy, heart failure) and then filtered using inclusion/exclusion criteria (language, species, publication date, and age). In total, 31 research articles were reviewed (14 clinical trials, four randomized control trials, nine review articles, one case report, one comparative study, one systematic review, and one categorized as a systematic review and meta-analysis). Both skeletal myoblasts and bone marrow-derived stem cells showed mixed results in improving left ventricular ejection fraction in heart failure patients in the majority of studies. Larger studies need to be done to further investigate the efficacy of stem cells as a therapy for heart failure.
Stability of motor cortex network states during learning-associated neural reorganizations.
Journal of neurophysiology, 2020

A substantial reorganization of neural activity and neuron-to-movement relationship in motor cortical circuits accompanies the emergence of reproducible movement patterns during motor learning. Little is known about how this tempest of neural activity restructuring impacts the stability of network states in recurrent cortical circuits. To investigate this issue, we reanalyzed data in which we recorded for 14 days via population calcium imaging the activity of the same neural populations of pyramidal neurons in layer 2/3 and layer 5 of forelimb motor and premotor cortex in mice during the daily learning of a lever-press task. We found that motor cortex network states remained stable with respect to the critical network state during the extensive reorganization of both neural population activity and its relation to lever movement throughout learning. Specifically, layer 2/3 cortical circuits unceasingly displayed robust evidence for operating at the critical network state, a regime that maximizes information capacity and transmission and provides a balance between network robustness and flexibility. In contrast, layer 5 circuits operated away from the critical network state for all 14 days of recording and learning. In conclusion, this result indicates that the wide-ranging malleability of synapses, neurons, and neural connectivity during learning operates within the constraint of a stable and layer-specific network state regarding dynamic criticality, and suggests that different cortical layers operate under distinct constraints because of their specialized goals.
Daily physical activity in patients on chronic haemodialysis and its relation with fatigue and depressive symptoms.
International urology and nephrology, 2020

Fatigue and depressed mood are considered main impediments to physical activity in haemodialysis (HD) patients. A better understanding of their interrelationships is crucial to develop effective therapies. Moreover, measurement of daily physical activity (DPA) in HD patients is tricky, as it is usually assessed by subjective self-report questionnaires. Therefore, we aimed to objectively measure sponteanous DPA with motion sensors and to explore its relation with fatigue and depressive symptoms.
Alcohol exposure alters pre-mRNA splicing of antiapoptotic Mcl-1L isoform and induces apoptosis in neural progenitors and immature neurons.
Cell death & disease, 2019

Alternative splicing and expression of splice variants of genes in the brain may lead to the modulation of protein functions, which may ultimately influence behaviors associated with alcohol dependence and neurotoxicity. We recently showed that ethanol exposure can lead to pre-mRNA missplicing of Mcl-1, a pro-survival member of the Bcl-2 family, by downregulating the expression levels of serine/arginine rich splicing factor 1 (SRSF1). Little is known about the physiological expression of these isoforms in neuronal cells and their role in toxicity induced by alcohol exposure during the developmental period. In order to investigate the impact of alcohol exposure on alternative splicing of Mcl-1 pre-mRNA and its role in neurotoxicity, we developed a unique primary human neuronal culture model where neurospheres (hNSPs), neural progenitors (hNPCs), immature neurons, and mature neurons were cultured from the matching donor fetal brain tissues. Our data suggest that neural progenitors and immature neurons are highly sensitive to the toxic effects of ethanol, while mature neuron cultures showed resistance to ethanol exposure. Further analysis of Mcl-1 pre-mRNA alternative splicing by semi-quantitative and quantitative analysis revealed that ethanol exposure causes a significant decrease in Mcl-1L/Mcl-1S ratio in a dose and time dependent manner in neural progenitors. Interestingly, ectopic expression of Mcl-1L isoform in neural progenitors was able to recover the viability loss and apoptosis induced by alcohol exposure. Altogether, these observations suggest that alternative splicing of Mcl-1 may play a crucial role in neurotoxicity associated with alcohol exposure in the developing fetal brain.
Introducing students to neural communication: an embodied-learning classroom demonstration.
NPJ science of learning, 2020

Learning about neural communication can be a dry and challenging undertaking, particularly for students without a background in biology. To enhance learning of this and other STEM material, there has been a call for science educators to embrace the use of active learning techniques. The aim of this Brief Communication is to encourage the use of embodied metaphors in the university classroom by sharing an active learning method for introducing students to a number of key concepts in neural communication. The students work in pairs or small groups, using foam projectiles such as Nerf guns to work through several metaphors for electrical and chemical processes including action potentials, neurotransmission and receptor action, excitatory and inhibitory post-synaptic potentials and neurotransmitter inactivation. The activities are easy to stage and lend themselves well to customisation based on available class size, classroom space, and resources. Student feedback showed that the activities improved self-reported impressions of understanding and ability to convey key concepts to others. The activities thus can serve as a useful method of student engagement and help develop understanding of complex material in a neuroscience classroom.
Modeling flexible behavior in childhood to adulthood shows age-dependent learning mechanisms and less optimal learning in autism in each age group.
PLoS biology, 2020

Flexible behavior is critical for everyday decision-making and has been implicated in restricted, repetitive behaviors (RRB) in autism spectrum disorder (ASD). However, how flexible behavior changes developmentally in ASD remains largely unknown. Here, we used a developmental approach and examined flexible behavior on a probabilistic reversal learning task in 572 children, adolescents, and adults (ASD N = 321; typical development [TD] N = 251). Using computational modeling, we quantified latent variables that index mechanisms underlying perseveration and feedback sensitivity. We then assessed these variables in relation to diagnosis, developmental stage, core autism symptomatology, and associated psychiatric symptoms. Autistic individuals showed on average more perseveration and less feedback sensitivity than TD individuals, and, across cases and controls, older age groups showed more feedback sensitivity than younger age groups. Computational modeling revealed that dominant learning mechanisms underpinning flexible behavior differed across developmental stages and reduced flexible behavior in ASD was driven by less optimal learning on average within each age group. In autistic children, perseverative errors were positively related to anxiety symptoms, and in autistic adults, perseveration (indexed by both task errors and model parameter estimates) was positively related to RRB. These findings provide novel insights into reduced flexible behavior in relation to clinical symptoms in ASD.