rudyvdbrink/CitationDatabase huggingface dataset:
Effects of neuregulin-1 genetic variation and depression symptom severity on longitudinal patterns of psychotic symptoms in primary care attendees.
American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics, 2014

A better understanding of the factors associated with psychotic symptoms could aid early identification and treatment of psychotic disorders. Previous studies have typically utilized cross-sectional study designs and have focused on individuals with psychotic disorders. Thus, examination of promising correlates of psychotic symptoms using longitudinal designs among more broadly defined populations is warranted. Two such correlates are neuregulin-1 (NRG1) genotypic variation and depression symptom severity. Both NRG1 and depression symptom severity have cross-sectional evidence for an association with psychosis but their affect on longitudinal patterns of psychotic symptoms and their potential interaction effects are less clear. Using repeated measures analysis of variance and covariance we modeled the main and interaction effects of NRG1 genotypic variation and depressive symptom severity on longitudinal psychotic symptom patterns in 301 primary care attendees assessed annually over 4 years. One-fifth (19.9%) of the participants reported one or more psychotic symptoms over the 4-year assessment period. We observed a curvilinear (i.e., cubic) association between depression symptom severity at baseline and longitudinal patterns of psychotic symptoms but did not observe a main effect for NRG1 genotypic variation on psychotic symptom patterns. However, NRG1 rs6994992 genotype moderated the curvilinear association between depression symptom severity and psychotic symptom patterns. Specifically, depression symptom severity had less of an effect on longitudinal psychotic symptoms among carriers of the rs6994992 TT genotype compared to CC and CT carriers. Our findings suggest a curvilinear association between depression symptom severity and longitudinal patterns of psychotic symptoms that is moderated by NRG1 genotype.
Generation of Genetically Modified Mice through the Microinjection of Oocytes.
Journal of visualized experiments : JoVE, 2017

The use of genetically modified mice has significantly contributed to studies on both physiological and pathological in vivo processes. The pronuclear injection of DNA expression constructs into fertilized oocytes remains the most commonly used technique to generate transgenic mice for overexpression. With the introduction of CRISPR technology for gene targeting, pronuclear injection into fertilized oocytes has been extended to the generation of both knockout and knockin mice. This work describes the preparation of DNA for injection and the generation of CRISPR guides for gene targeting, with a particular emphasis on quality control. The genotyping procedures required for the identification of potential founders are critical. Innovative genotyping strategies that take advantage of the "multiplexing" capabilities of CRISPR are presented herein. Surgical procedures are also outlined. Together, the steps of the protocol will allow for the generation of genetically modified mice and for the subsequent establishment of mouse colonies for a plethora of research fields, including immunology, neuroscience, cancer, physiology, development, and others.
γ-Hydroxybutyrate and the GABAergic footprint: a metabolomic approach to unpicking the actions of GHB.
Journal of neurochemistry, 2010

Gamma-hydroxybutyrate is found both naturally in the brain and self-administered as a drug of abuse. It has been reported to act at endogenous γ-hydroxybutyrate (GHB) receptors and GABA(B) receptors [GABA(B)R], and may also be metabolized to GABA. Here, the metabolic fingerprints of a range of concentrations of GHB were measured in brain cortical tissue slices and compared with those of ligands active at GHB and GABA-R using principal components analysis (PCA) to identify sites of GHB activity. Low concentrations of GHB (1.0 μM) produced fingerprints similar to those of ligands active at GHB receptors and α4-containing GABA(A)R. A total of 10 μM GHB clustered proximate to mainstream GABAergic synapse ligands, such as 1.0 μM baclofen, a GABA(B)R agonist. Higher concentrations of GHB (30 μM) clustered with GABA(C)R agonists and the metabolic responses induced by blockade of the GABA transporter-1 (GAT1). The metabolic responses induced by 60 and 100 μM GHB were mimicked by simultaneous blockade of GAT1 and GAT3, addition of low concentrations of GABA(C)R antagonists, or increasing cytoplasmic GABA concentrations by incubation with the GABA transaminase inhibitor vigabatrin. These data suggest that at concentrations > 30 μM, GHB may be active via metabolism to GABA, which is then acting upon an unidentified GABAergic master switch receptor (possibly a high-affinity extrasynaptic receptor), or GHB may itself be acting directly on an extrasynaptic GABA-R, capable of turning off large numbers of cells. These results offer an explanation for the steep dose-response curve of GHB seen in vivo, and suggest potential target receptors for further investigation.
Beneficial effects of melatonin on obesity and lipid profile in young Zucker diabetic fatty rats.
Journal of pineal research, 2011

The study objective was to investigate the effects of melatonin on obesity and obesity-associated systolic hypertension and dyslipidemia in young male Zucker diabetic fatty (ZDF) rats, an experimental model of the metabolic syndrome. ZDF rats (n=30) and lean littermates (ZL) (n=30) were used. At 6wk of age, both lean and fatty animals were subdivided into three groups (n=10): naive (N), vehicle-treated (V), and melatonin-treated (M) (10mg/kg/day) for 6wk. Vehicle and melatonin were added to the drinking water. Melatonin reduced mean weight gain (51±2/100g BW) versus N-ZDF group (58±3, P<0.05) without food intake differences. M-ZDF rats showed an apparent reduction in systolic hypertension that proved not to be statistically significant, and a significant improvement in dyslipidemia, with a reduction in hypertriglyceridemia from 580±40 to 420.6±40.9mg/dL (P<0.01). Melatonin raised high-density-lipoprotein (HDL) cholesterol in ZDF (from 81.6±4.9 to 103.1±4.5mg/dL, P<0.01) and ZL rats (from 62.8±4.8 to 73.5±4.8mg/dL, P<0.05) and significantly reduced low-density-lipoprotein (LDL) cholesterol in ZDF rats from 5.20±0.4 to 4.14±0.3 mg/dL (P<0.05) but had no effect on total cholesterol levels. To our knowledge, this is the first evidence of a positive effect of melatonin on overweight and lipid pattern of obese Zucker diabetic rats, supporting the proposition that melatonin administration may ameliorate overweight and lipid metabolism in humans. Because these benefits occurred in youth, before advanced metabolic and vascular complications, melatonin might help to prevent cardiovascular disease associated with obesity and dyslipidemia.
Manipulating cognitive reserve: Pre-injury environmental conditions influence the severity of concussion symptomology, gene expression, and response to melatonin treatment in rats.
Experimental neurology, 2017

In an effort to understand the factors that contribute to heterogeneity in outcomes often associated with mTBI in youth, this study examined the role of premorbid differences in cognitive reserve on post-concussive symptoms (PCS), molecular markers, and treatment response. Male and female rats matured in one of three environmental conditions (Stress, Enrichment, Control), received a mTBI in adolescence, and were randomized to melatonin or placebo treatment. All animals underwent a behavioural test battery designed to examine PCS. Using prefrontal cortex and hippocampus tissue, expression of 9 genes was assessed in an effort to determine how the brain's epigenome was influenced by cognitive reserve, mTBI, and melatonin. Enrichment increased cognitive reserve (CR) and prevented lingering symptoms. Conversely, stress was associated with progressive worsening and manifestation of PCS in the longer-term. Melatonin was able to restore baseline function for control and enriched animals, but was ineffective for the stress condition. Epigenetic change in the prefrontal cortex was largely driven by the injury, while gene expression changes in the hippocampus were dependent upon cognitive reserve. The occurrence and severity of PCS is dependent upon a complex and multifaceted array of factors that modify behavioural and epigenetic responses to mTBI and its treatment.
Genetic association study between the detected risk variants based upon type II diabetes GWAS and psychotic disorders in the Japanese population.
Journal of human genetics, 2014

Several epidemiological and genetic studies have suggested that the risk of type II diabetes (T2D) is likely to overlap with the susceptibility to psychotic disorders such as schizophrenia (SCZ) and bipolar disorder (BD). In this study, we aimed to examine the association of single-nucleotide polymorphisms (SNPs) detected in previous T2D genome-wide association studies (GWAS) with SCZ, BD and psychosis (SCZ plus BD). A total of 37 SNPs were selected from the literature. A two-stage analysis was conducted using a first set of screening samples (total N=3037) and a second set of replication samples (N=4950). None of the SNPs showed a significant association to the screening samples after correction for multiple testing. To avoid type II error, we genotyped the top three SNPs in BCL11A, HMG20A and HNF4A showing associations with any of the phenotypes (Puncorrected <0.01) using independent samples to replicate the nominal associations. However, we were unable to find any significant associations based on the screening results (Puncorrected>0.05). Our findings did not support the shared genetic risk between T2D and psychotic disorders in the Japanese population. However, further replication using a larger sample size is required.
Using Sox2 to alleviate the hallmarks of age-related hearing loss.
Ageing research reviews, 2020

Age-related hearing loss (ARHL) is the most prevalent sensory deficit. ARHL reduces the quality of life of the growing population, setting seniors up for the enhanced mental decline. The size of the needy population, the structural deficit, and a likely research strategy for effective treatment of chronic neurosensory hearing in the elderly are needed. Although there has been profound advancement in auditory regenerative research, there remain multiple challenges to restore hearing loss. Thus, additional investigations are required, using novel tools. We propose how the (1) flat epithelium, remaining after the organ of Corti has deteriorated, can be converted to the repaired-sensory epithelium, using Sox2. This will include (2) developing an artificial gene regulatory network transmitted by (3) large viral vectors to the flat epithelium to stimulate remnants of the organ of Corti to restore hair cells. We hope to unite with our proposal toward the common goal, eventually restoring a functional human hearing organ by transforming the flat epithelial cells left after the organ of Corti loss.
Canonical transient receptor potential channel subtype 3-mediated hair cell Ca(2+) entry regulates sound transduction and auditory neurotransmission.
The European journal of neuroscience, 2013

The physiological significance of canonical transient receptor potential (TRPC) ion channels in sensory systems is rapidly emerging. Heterologous expression studies show that TRPC3 is a significant Ca(2+) entry pathway, with dual activation via G protein-coupled receptor (GPCR)-phospholipase C-diacylglycerol second messenger signaling, and through negative feedback, whereby a fall in cytosolic Ca(2+) releases Ca(2+) -calmodulin channel block. We hypothesised that the latter process contributes to cochlear hair cell cytosolic Ca(2+) homeostasis. Confocal microfluorimetry with the Ca(2+) indicator Fluo-4 acetoxymethylester showed that, when cytosolic Ca(2+) was depleted, Ca(2+) re-entry was significantly impaired in mature TRPC3(-/-) inner and outer hair cells. The impact of this disrupted Ca(2+) homeostasis on sound transduction was assessed with the use of distortion product otoacoustic emissions (DPOAEs), which constitute a direct measure of the outer hair cell transduction that underlies hearing sensitivity and frequency selectivity. TRPC3(-/-) mice showed significantly stronger DPOAE (2f1  - f2 ) growth functions than wild-type (WT) littermates within the frequency range of best hearing acuity. This translated to hyperacusis (decreased threshold) measured by the auditory brainstem response (ABR). TRPC3(-/-) and WT mice did not differ in the levels of temporary and permanent threshold shift arising from noise exposure, indicating that potential GPCR signaling via TRPC3 is not pronounced. Overall, these data suggest that the Ca(2+) set-point in the hair cell, and hence membrane conductance, is modulated by TRPC3s through their function as a negative feedback-regulated Ca(2+) entry pathway. This TPRC3-regulated Ca(2+) homeostasis shapes the sound transduction input-output function and auditory neurotransmission.
Automated analysis of NeuronJ tracing data.
Cytometry. Part A : the journal of the International Society for Analytical Cytology, 2009

Studies of neuronal differentiation in vitro often involve tracing and analysis of neurites. NeuronJ (Meijering et al., Cytometry Part A 2004;58A:167-176; http://www.imagescience.org/meijering/software/neuronj/) is a program that can be used for semiautomated tracing of individual neurons; when tracing is completed, a text file containing neurite length measurements is generated. Using cultured hippocampal neurons, we have found that to reach statistical significance it is generally necessary to trace about 100 neurons in each treatment group. Posttracing data analysis requires importing each text file into a statistics program. Analysis of distinct parameters, such as effects of a treatment on axonal versus dendritic branching, requires a great deal of time consuming posttracing data manipulation. We have developed XL_Calculations, a Java-based program that performs batch analysis on NeuronJ measurement files and automatically makes multiple calculations, including the number, length, and total output (sum length) of primary, secondary, and tertiary neurites on axons and dendrites, and writes the calculations into an Excel worksheet. Batch processing of NeuronJ measurement files dramatically reduces the time required to analyze neuronal morphology. In addition, our program performs more than 45 distinct calculations, enabling detailed determination of treatment effects on neuronal differentiation. Using this program to analyze NeuronJ tracing data, we demonstrate that continuous exposure of differentiating hippocampal neurons to Netrin 1 increases the number of secondary branches on both axons and dendrites, without significantly altering the length of the axon, dendrites, or branches. Similar results were obtained when neurons were grown on poly-D-lysine or laminin.
Temperature Accelerated Molecular Dynamics with Soft-Ratcheting Criterion Orients Enhanced Sampling by Low-Resolution Information.
Journal of chemical theory and computation, 2015

Many proteins exhibit an equilibrium between multiple conformations, some of them being characterized only by low-resolution information. Visiting all conformations is a demanding task for computational techniques performing enhanced but unfocused exploration of collective variable (CV) space. Otherwise, pulling a structure toward a target condition biases the exploration in a way difficult to assess. To address this problem, we introduce here the soft-ratcheting temperature-accelerated molecular dynamics (sr-TAMD), where the exploration of CV space by TAMD is coupled to a soft-ratcheting algorithm that filters the evolving CV values according to a predefined criterion. Any low resolution or even qualitative information can be used to orient the exploration. We validate this technique by exploring the conformational space of the inactive state of the catalytic domain of the adenyl cyclase AC from Bordetella pertussis. The domain AC gets activated by association with calmodulin (CaM), and the available crystal structure shows that in the complex the protein has an elongated shape. High-resolution data are not available for the inactive, CaM-free protein state, but hydrodynamic measurements have shown that the inactive AC displays a more globular conformation. Here, using as CVs several geometric centers, we use sr-TAMD to enhance CV space sampling while filtering for CV values that correspond to centers moving close to each other, and we thus rapidly visit regions of conformational space that correspond to globular structures. The set of conformations sampled using sr-TAMD provides the most extensive description of the inactive state of AC up to now, consistent with available experimental information.
Scanning the horizon: towards transparent and reproducible neuroimaging research.
Nature reviews. Neuroscience, 2017

Functional neuroimaging techniques have transformed our ability to probe the neurobiological basis of behaviour and are increasingly being applied by the wider neuroscience community. However, concerns have recently been raised that the conclusions that are drawn from some human neuroimaging studies are either spurious or not generalizable. Problems such as low statistical power, flexibility in data analysis, software errors and a lack of direct replication apply to many fields, but perhaps particularly to functional MRI. Here, we discuss these problems, outline current and suggested best practices, and describe how we think the field should evolve to produce the most meaningful and reliable answers to neuroscientific questions.
Directional Trans-Synaptic Labeling of Specific Neuronal Connections in Live Animals.
Genetics, 2015

Understanding animal behavior and development requires visualization and analysis of their synaptic connectivity, but existing methods are laborious or may not depend on trans-synaptic interactions. Here we describe a transgenic approach for in vivo labeling of specific connections in Caenorhabditis elegans, which we term iBLINC. The method is based on BLINC (Biotin Labeling of INtercellular Contacts) and involves trans-synaptic enzymatic transfer of biotin by the Escherichia coli biotin ligase BirA onto an acceptor peptide. A BirA fusion with the presynaptic cell adhesion molecule NRX-1/neurexin is expressed presynaptically, whereas a fusion between the acceptor peptide and the postsynaptic protein NLG-1/neuroligin is expressed postsynaptically. The biotinylated acceptor peptide::NLG-1/neuroligin fusion is detected by a monomeric streptavidin::fluorescent protein fusion transgenically secreted into the extracellular space. Physical contact between neurons is insufficient to create a fluorescent signal, suggesting that synapse formation is required. The labeling approach appears to capture the directionality of synaptic connections, and quantitative analyses of synapse patterns display excellent concordance with electron micrograph reconstructions. Experiments using photoconvertible fluorescent proteins suggest that the method can be utilized for studies of protein dynamics at the synapse. Applying this technique, we find connectivity patterns of defined connections to vary across a population of wild-type animals. In aging animals, specific segments of synaptic connections are more susceptible to decline than others, consistent with dedicated mechanisms of synaptic maintenance. Collectively, we have developed an enzyme-based, trans-synaptic labeling method that allows high-resolution analyses of synaptic connectivity as well as protein dynamics at specific synapses of live animals.
Taking the pulse of aging: mapping pulse pressure and elasticity in cerebral arteries with optical methods.
Psychophysiology, 2014

Cerebrovascular support is crucial for healthy cognitive and brain aging. Arterial stiffening is a cause of reduced brain blood flow, a predictor of cognitive decline, and a risk factor for cerebrovascular accidents and Alzheimer's disease. Arterial health is influenced by lifestyle factors, such as cardiorespiratory fitness (CRF). We investigated new noninvasive optical measures of cerebrovascular health, which provide estimates of arterial pulse parameters (pulse pressure, transit time, and compliance/elasticity) within specific cerebral arteries and cortical regions, and low-resolution maps of large superficial cerebral arteries. We studied naturally occurring variability in these parameters in adults (aged 55-87), and found that these indices of cerebrovascular health are negatively correlated with age and positively with CRF and gray and white matter volumes. Further, regional pulse transit time predicts specific neuropsychological performance.
Repair of traumatic plasmalemmal damage to neurons and other eukaryotic cells.
Neural regeneration research, 2016

The repair (sealing) of plasmalemmal damage, consisting of small holes to complete transections, is critical for cell survival, especially for neurons that rarely regenerate cell bodies. We first describe and evaluate different measures of cell sealing. Some measures, including morphological/ultra-structural observations, membrane potential, and input resistance, provide very ambiguous assessments of plasmalemmal sealing. In contrast, measures of ionic current flow and dye barriers can, if appropriately used, provide more accurate assessments. We describe the effects of various substances (calcium, calpains, cytoskeletal proteins, ESCRT proteins, mUNC-13, NSF, PEG) and biochemical pathways (PKA, PKC, PLC, Epac, cytosolic oxidation) on plasmalemmal sealing probability, and suggest that substances, pathways, and cellular events associated with plasmalemmal sealing have undergone a very conservative evolution. During sealing, calcium ion influx mobilizes vesicles and other membranous structures (lysosomes, mitochondria, etc.) in a continuous fashion to form a vesicular plug that gradually restricts diffusion of increasingly smaller molecules and ions over a period of seconds to minutes. Furthermore, we find no direct evidence that sealing occurs through the collapse and fusion of severed plasmalemmal leaflets, or in a single step involving the fusion of one large wound vesicle with the nearby, undamaged plasmalemma. We describe how increases in perikaryal calcium levels following axonal transection account for observations that cell body survival decreases the closer an axon is transected to the perikaryon. Finally, we speculate on relationships between plasmalemmal sealing, Wallerian degeneration, and the ability of polyethylene glycol (PEG) to seal cell membranes and rejoin severed axonal ends - an important consideration for the future treatment of trauma to peripheral nerves. A better knowledge of biochemical pathways and cytoplasmic structures involved in plasmalemmal sealing might provide insights to develop treatments for traumatic nerve injuries, stroke, muscular dystrophy, and other pathologies.