rudyvdbrink/CitationDatabase huggingface dataset:
Counting contacts between neurons in 3D in confocal laser scanning images.
Journal of neuroscience methods, 2008

Study of neuronal networks requires an inventory of the neurons, knowledge of fiber in- and output, and qualitative and quantitative data on the intrinsic connectivity. For this purpose we combined in rat hippocampus fluorescence neuroanatomical tracing and intracellular fluorochrome injection of neurons. Multichannel confocal laser scanning microscopy was followed by computer assisted 3D object- and contact recognition. We describe the factors involved in scanning ('from biological object to voxel') and we compare operator-mediated manual recognition of small 3D objects and contacts with 'objective' processing through software. As in all digital object recognition, thresholding is pivotal. We obtained reproducible, 'objective' thresholds via 3D object-threshold analysis with ImageJ. Objective thresholds were subsequently used in SCIL_Image scripts to identify 3D objects, and to identify and count contacts between labeled fibers and intracellularly injected target neurons. At the extreme magnification necessary to distinguish contacts, Abbe diffraction causes voxels that belong to the pre-contact structure to overlap voxels belonging to the post-contact structure. We call this overlap the 'footprint' and we introduce such footprints and their size as criteria to recognize contacts. Automated contact recognition, applying footprints of 100 voxels (involved structures imaged in their specific channel) gave the highest correlation with findings using the manual approach. We conclude that computer identification and counting of contacts is the method of choice, since it combines reduced human bias with good reproducibility of results and saving of time. Of major importance is that threshold selection is not dependent on the human computer operator.
White matter damage disorganizes brain functional networks in amnestic mild cognitive impairment.
Brain connectivity, 2014

Although progressive functional brain network disruption has been one of the hallmarks of Alzheimer's Disease, little is known about the origin of this functional impairment that underlies cognitive symptoms. We investigated how the loss of white matter (WM) integrity disrupts the organization of the functional networks at different frequency bands. The analyses were performed in a sample of healthy elders and mild cognitive impairment (MCI) subjects. Spontaneous brain magnetic activity (measured with magnetoencephalography) was characterized with phase synchronization analysis, and graph theory was applied to the functional networks. We identified WM areas (using diffusion weighted magnetic resonance imaging) that showed a statistical dependence between the fractional anisotropy and the graph metrics. These regions are part of an episodic memory network and were also related to cognitive functions. Our data support the hypothesis that disruption of the anatomical networks influences the organization at the functional level resulting in the prodromal dementia syndrome of MCI.
Acceleration of biliary cholesterol secretion restores glycemic control and alleviates hypertriglyceridemia in obese db/db mice.
Arteriosclerosis, thrombosis, and vascular biology, 2014

Recent studies support a role for cholesterol in the development of obesity and nonalcoholic fatty liver disease. Mice lacking the ABCG5 ABCG8 (G5G8) sterol transporter have reduced biliary cholesterol secretion and are more susceptible to steatosis, hepatic insulin resistance, and loss of glycemic control when challenged with a high-fat diet. We hypothesized that accelerating G5G8-mediated biliary cholesterol secretion would correct these phenotypes in obese mice.
Stress-induced hyperthermia and infection-induced fever: two of a kind?
Physiology & behavior, 2009

Stress exposure activates the autonomic nervous system and leads to a body temperature increase (stress-induced hyperthermia, SIH). On the other hand, an activation of the immune system in response to an infection leads to fever. Both processes increase body temperature, and the relation between SIH and infection-induced fever has been subject to debate. It is not clear whether SIH is a form of fever, or whether both processes are more or less distinct. We therefore examined the relation between SIH and infection-induced fever by looking at the effects of a GABA(A) receptor agonist (diazepam) and a prostaglandin-synthesis blocking drug (acetylsalicylic acid, aspirin) on both the SIH response and fever in rats and mice. The present study shows that the benzodiazepine diazepam but not the prostaglandin-synthesis blocking drug aspirin dose-dependently attenuated the SIH response in both rats and mice. In contrast, aspirin reduced both LPS- and IL-1beta induced fever, whereas diazepam had little effect on these fever states. Altogether, our findings support the hypothesis that stress-induced hyperthermia and infection-induced fever are two distinct processes mediated largely by different neurobiological mechanisms.
Functional recovery after the systemic administration of mesenchymal stem cells in a rat model of neonatal hypoxia-ischemia.
Journal of neurosurgery. Pediatrics, 2018

The authors intravenously infused mesenchymal stem cells (MSCs) into a rat model of neonatal hypoxia-ischemia and found improvements in functional outcome, increased brain volume, and enhanced synaptogenesis. The results of this animal study suggest that the intravenous administration of MSCs should be further explored as a potential treatment for patients suffering from cerebral palsy after hypoxic-ischemic encephalopathy.
Targeting cells with single vectors using multiple-feature Boolean logic.
Nature methods, 2014

Precisely defining the roles of specific cell types is an intriguing frontier in the study of intact biological systems and has stimulated the rapid development of genetically encoded tools for observation and control. However, targeting these tools with adequate specificity remains challenging: most cell types are best defined by the intersection of two or more features such as active promoter elements, location and connectivity. Here we have combined engineered introns with specific recombinases to achieve expression of genetically encoded tools that is conditional upon multiple cell-type features, using Boolean logical operations all governed by a single versatile vector. We used this approach to target intersectionally specified populations of inhibitory interneurons in mammalian hippocampus and neurons of the ventral tegmental area defined by both genetic and wiring properties. This flexible and modular approach may expand the application of genetically encoded interventional and observational tools for intact-systems biology.
Sensing the neuronal glycocalyx by glial sialic acid binding immunoglobulin-like lectins.
Neuroscience, 2014

Sialic acid binding immunoglobulin-like lectins (Siglecs) are cell surface receptors of microglia and oligodendrocytes that recognize the sialic acid cap of healthy neurons and neighboring glial cells. Upon ligand binding, Siglecs typically signal through an immunoreceptor tyrosine-based inhibition motif (ITIM) to keep the cell in a homeostatic status and support healthy neighboring cells. Siglecs can be divided into two groups; the first, being conserved among different species. The conserved Siglec-4/myelin-associated glycoprotein is expressed on oligodendrocytes and Schwann cells. Siglec-4 protects neurons from acute toxicity via interaction with sialic acids bound to neuronal gangliosides. The second group of Siglecs, named CD33-related Siglecs, is almost exclusively expressed on immune cells and is highly variable among different species. Microglial expression of Siglec-11 is human lineage-specific and prevents neurotoxicity via interaction with α2.8-linked sialic acid oligomers exposed on the neuronal glycocalyx. Microglial Siglec-E is a mouse CD33-related Siglec member that prevents microglial phagocytosis and the associated oxidative burst. Mouse Siglec-E of microglia binds to α2.8- and α2.3-linked sialic acid residues of the healthy glycocalyx of neuronal and glial cells. Recently, polymorphisms of the human Siglec-3/CD33 were linked to late onset Alzheimer's disease by genome-wide association studies. Human Siglec-3 is expressed on microglia and produces inhibitory signaling that decreases uptake of particular molecules such as amyloid-β aggregates. Thus, glial ITIM-signaling Siglecs recognize the intact glycocalyx of neurons and are involved in the modulation of neuron-glia interaction in healthy and diseased brain.
Sirtuin (SIRT)-1: At the crossroads of puberty and metabolism.
Current opinion in endocrine and metabolic research, 2020

In the arcuate nucleus (ARC) of the hypothalamus reside two neuronal systems in charge of regulating feeding control and reproductive development. The melanocortin system responds to metabolic fluctuations adjusting food intake, whereas kisspeptin neurons are in charge of the excitatory control of Gonadotropin Hormone Releasing Hormone (GnRH) neurons. While it is known that the melanocortin system regulates GnRH neuronal activity, it was recently demonstrated that kisspeptin neurons not only innervate melanocortin neurons, but also play an active role in the control of metabolism. These two neuronal systems are intricately interconnected forming loops of stimulation and inhibition according to metabolic status. Furthermore, intracellular and epigenetic pathways respond to external environmental signals by changing DNA conformation and gene expression. Here we review the role of Silent mating type Information Regulation 2 homologue 1 (Sirt1), a class III NAD+ dependent protein deacetylase, in the ARC control of pubertal development and feeding behavior.
DJ-1 facilitates the interaction between STAT1 and its phosphatase, SHP-1, in brain microglia and astrocytes: A novel anti-inflammatory function of DJ-1.
Neurobiology of disease, 2013

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder caused by the death of dopaminergic neurons in the substantia nigra. Importantly, altered astrocyte and microglial functions could contribute to neuronal death in PD. In this study, we demonstrate a novel mechanism by which DJ-1 (PARK7), an early onset autosomal-recessive PD gene, negatively regulates inflammatory responses of astrocytes and microglia by facilitating the interaction between STAT1 and its phosphatase, SHP-1 (Src-homology 2-domain containing protein tyrosine phosphatase-1). Astrocytes and microglia cultured from DJ-1-knockout (KO) mice exhibited increased expression of inflammatory mediators and phosphorylation levels of STAT1 (p-STAT1) in response to interferon-gamma (IFN-γ) compared to cells from wild-type (WT) mice. DJ-1 deficiency also attenuated IFN-γ-induced interactions of SHP-1 with p-STAT1 and STAT1, measured 1 and 12h after IFN-γ treatment, respectively. Subsequent experiments showed that DJ-1 directly interacts with SHP-1, p-STAT1, and STAT1. Notably, DJ-1 bound to SHP-1 independently of IFN-γ, whereas the interactions of DJ-1 with p-STAT1 and STAT1 were dependent on IFN-γ. Similar results were obtained in brain slice cultures, where IFN-γ induced much stronger STAT1 phosphorylation and inflammatory responses in KO slices than in WT slices. Moreover, IFN-γ treatment induced neuronal damage in KO slices. Collectively, these findings suggest that DJ-1 may function as a scaffold protein that facilitates SHP-1 interactions with p-STAT1 and STAT1, thereby preventing extensive and prolonged STAT1 activation. Thus, the loss of DJ-1 function may increase the risk of PD by enhancing brain inflammation.
Combination of pharmacotherapy and lidocaine analgesic block of the peripheral trigeminal branches for trigeminal neuralgia: a pilot study.
Arquivos de neuro-psiquiatria, 2015

Classical trigeminal neuralgia (CTN) is treated predominantly by pharmacotherapy but side effects and unsuccessful occurs. The current study was carried out to evaluate the therapeutic effect of combination of pharmacotherapy and lidocaine block. Thirteen patients with CTN managed with pharmacotherapy were recruited and assigned either to no additional treatment (Group I) or to additional analgesic block (Group II). The primary endpoint was the reduction in the frequency of pain episodes in a month assessed at 30 and 90 days. Comparisons of measurements of pain, general health and depression scales were secondary endpoints. The results from the follow-up visits at 30 and 90 days showed the Group II to have larger reduction in the frequency of pain and exhibited a bigger improvement in the scores of the pain, general health and depression scales. The results from this preliminary study suggest a clinical benefit of the combination of pharmacotherapy and lidocaine block.
Mechanisms of gene targeting in higher eukaryotes.
Cellular and molecular life sciences : CMLS, 2016

Targeted genome modifications using techniques that alter the genomic information of interest have contributed to multiple studies in both basic and applied biology. Traditionally, in gene targeting, the target-site integration of a targeting vector by homologous recombination is used. However, this strategy has several technical problems. The first problem is the extremely low frequency of gene targeting, which makes obtaining recombinant clones an extremely labor intensive task. The second issue is the limited number of biomaterials to which gene targeting can be applied. Traditional gene targeting hardly occurs in most of the human adherent cell lines. However, a new approach using designer nucleases that can introduce site-specific double-strand breaks in genomic DNAs has increased the efficiency of gene targeting. This new method has also expanded the number of biomaterials to which gene targeting could be applied. Here, we summarize various strategies for target gene modification, including a comparison of traditional gene targeting with designer nucleases.
Delirium prevalence and prevention in patients with acute brain injury: A prospective before-and-after intervention study.
Intensive & critical care nursing, 2020

Knowledge regarding delirium prevention in patients with acute brain injury remains limited. We tested the hypothesis that an intervention bundle which targeted sedation, sleep, pain, and mobilisation would reduce delirium in patients with acute brain injury.
Exome sequencing of Finnish isolates enhances rare-variant association power.
Nature, 2019

Exome-sequencing studies have generally been underpowered to identify deleterious alleles with a large effect on complex traits as such alleles are mostly rare. Because the population of northern and eastern Finland has expanded considerably and in isolation following a series of bottlenecks, individuals of these populations have numerous deleterious alleles at a relatively high frequency. Here, using exome sequencing of nearly 20,000 individuals from these regions, we investigate the role of rare coding variants in clinically relevant quantitative cardiometabolic traits. Exome-wide association studies for 64 quantitative traits identified 26 newly associated deleterious alleles. Of these 26 alleles, 19 are either unique to or more than 20 times more frequent in Finnish individuals than in other Europeans and show geographical clustering comparable to Mendelian disease mutations that are characteristic of the Finnish population. We estimate that sequencing studies of populations without this unique history would require hundreds of thousands to millions of participants to achieve comparable association power.
Comparison of neuropathogenicity of poliovirus in two transgenic mouse strains expressing human poliovirus receptor with different distribution patterns.
The Journal of general virology, 2002

In order to determine the influence of poliovirus receptor (PVR) expression on poliovirus cell tropism and neuropathogenesis, two transgenic (tg) mouse models were produced in which PVR was expressed under the transcriptional control of the human PVR gene promoter (hg-PVR mice) and the CAG promoter (CAG-PVR mice). Then the pathogenicity of poliovirus after intracerebral inoculation of the type 1 Mahoney strain was compared. These showed completely different clinical and pathological changes. In the former, the expression of PVR in neurons in the central nervous system (CNS) conferred susceptibility to poliovirus, and a paralytic disease that resembled the human poliomyelitis occurred. In the latter, PVR expression was detected in glial and ependymal cells in addition to the neurons. Paralysis of the limbs and death were rarely observed and mice survived without showing substantial clinical abnormality. Histopathological examination revealed that glial and ependymal cells also became susceptible to poliovirus infection. Poliovirus antigens were mainly detected in ependymal and glial cells and hippocampal neurons near the lateral ventricles in the brain, but were not frequently detected in neurons in the brainstem unlike in the hg-PVR mice. The levels of viral antigens and virus recovered from the CNS of CAG-PVR mice began to decrease as early as 2 days after inoculation, which suggested induction of a fast immune response. These results suggest that the neuropathogenicity of poliovirus changes markedly depending on the specific expression of the PVR molecule in the CNS.
Positron emission tomography imaging demonstrates correlation between behavioral recovery and correction of dopamine neurotransmission after gene therapy.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2009

In vivo gene transfer using viral vectors is an emerging therapy for neurodegenerative diseases with a clinical impact recently demonstrated in Parkinson's disease patients. Recombinant adeno-associated viral (rAAV) vectors, in particular, provide an excellent tool for long-term expression of therapeutic genes in the brain. Here we used the [(11)C]raclopride [(S)-(-)-3,5-dichloro-N-((1-ethyl-2-pyrrolidinyl)methyl)-2-hydroxy-6-methoxybenzamide] micro-positron emission tomography (PET) technique to demonstrate that delivery of the tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1) enzymes using an rAAV5 vector normalizes the increased [(11)C]raclopride binding in hemiparkinsonian rats. Importantly, we show in vivo by microPET imaging and postmortem by classical binding assays performed in the very same animals that the changes in [(11)C]raclopride after viral vector-based enzyme replacement therapy is attributable to a decrease in the affinity of the tracer binding to the D(2) receptors, providing evidence for reconstitution of a functional pool of endogenous dopamine in the striatum. Moreover, the extent of the normalization in this non-invasive imaging measure was highly correlated with the functional recovery in motor behavior. The PET imaging protocol used in this study is fully adaptable to humans and thus can serve as an in vivo imaging technique to follow TH + GCH1 gene therapy in PD patients and provide an additional objective measure to a potential clinical trial using rAAV vectors to deliver l-3,4-dihydroxyphenylanaline in the brain.
Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder.
Molecular psychiatry, 2014

Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency ≤1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10(-4) after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10(-3) after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10(-2)). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.
Aberrant differentiation of glutamatergic cells in neocortex of mouse model for fragile X syndrome.
Neurobiology of disease, 2009

The lack of fragile X mental retardation protein (FMRP) causes fragile X syndrome, a common form of inherited mental retardation. Our previous studies revealed alterations in the differentiation of FMRP-deficient neural progenitors. Here, we show abnormalities in neurogenesis in the mouse and human embryonic FMRP-deficient brain as well as after in utero transfection of I304N mutated FMRP, which acts in a dominant negative manner in the wild-type mouse brain. Progenitors accumulated abnormally in the subventricular zone of the embryonic Fmr1-knockout (Fmr1-KO) mouse neocortex. An increased density of cells expressing sequentially an intermediate progenitor marker, T-box transcription factor (Tbr2), and a postmitotic neuron marker, T-brain 1 (Tbr1), indicated that the differentiation to glutamatergic cell lineages was particularly disturbed. These abnormalities were associated with an increased density of pyramidal cells of the layer V in the early postnatal neocortex suggesting a role for FMRP in the regulation of the differentiation of neocortical glutamatergic neurons.