rudyvdbrink/CitationDatabase huggingface dataset:
Brain-targeted hypoxia-inducible factor stabilization reduces neonatal hypoxic-ischemic brain injury.
Neurobiology of disease, 2021

Hypoxia-inducible factor-1α (HIF1α) is a major regulator of cellular adaptation to hypoxia and oxidative stress, and recent advances of prolyl-4-hydroxylase (P4H) inhibitors have produced powerful tools to stabilize HIF1α for clinical applications. However, whether HIF1α provokes or resists neonatal hypoxic-ischemic (HI) brain injury has not been established in previous studies. We hypothesize that systemic and brain-targeted HIF1α stabilization may have divergent effects. To test this notion, herein we compared the effects of GSK360A, a potent P4H inhibitor, in in-vitro oxygen-glucose deprivation (OGD) and in in-vivo neonatal HI via intracerebroventricular (ICV), intraperitoneal (IP), and intranasal (IN) drug-application routes. We found that GSK360A increased the erythropoietin (EPO), heme oxygenase-1 (HO1) and glucose transporter 1 (Glut1) transcripts, all HIF1α target-genes, and promoted the survival of neurons and oligodendrocytes after OGD. Neonatal HI insult stabilized HIF1α in the ipsilateral hemisphere for up to 24 h, and either ICV or IN delivery of GSK360A after HI increased the HIF1α target-gene transcripts and decreased brain damage. In contrast, IP-injection of GSK360A failed to reduce HI brain damage, but elevated the risk of mortality at high doses, which may relate to an increase of the kidney and plasma EPO, leukocytosis, and abundant vascular endothelial growth factor (VEGF) mRNAs in the brain. These results suggest that brain-targeted HIF1α-stabilization is a potential treatment of neonatal HI brain injury, while systemic P4H-inhibition may provoke unwanted adverse effects.
Elevated protein synthesis in microglia causes autism-like synaptic and behavioral aberrations.
Nature communications, 2020

Mutations that inactivate negative translation regulators cause autism spectrum disorders (ASD), which predominantly affect males and exhibit social interaction and communication deficits and repetitive behaviors. However, the cells that cause ASD through elevated protein synthesis resulting from these mutations remain unknown. Here we employ conditional overexpression of translation initiation factor eIF4E to increase protein synthesis in specific brain cells. We show that exaggerated translation in microglia, but not neurons or astrocytes, leads to autism-like behaviors in male mice. Although microglial eIF4E overexpression elevates translation in both sexes, it only increases microglial density and size in males, accompanied by microglial shift from homeostatic to a functional state with enhanced phagocytic capacity but reduced motility and synapse engulfment. Consequently, cortical neurons in the mice have higher synapse density, neuroligins, and excitation-to-inhibition ratio compared to control mice. We propose that functional perturbation of male microglia is an important cause for sex-biased ASD.
Decompressive craniectomy for massive internal carotid artery infarction after pediatric penetrating neck trauma.
Acta neurochirurgica, 2015

Pediatric penetrating carotid arterial trauma is a rare unreported cause of malignant cerebral infarction. Despite increasing evidence of benefit of decompressive hemicraniectomy (DCH) in pediatric malignant stroke, indications and predictors of outcome remain controversial. We report a 4-year-old boy with penetrating zone II neck trauma with laceration of the right internal carotid artery who developed malignant cerebral infarction requiring DCH. Impressive neurological recovery and excellent functional outcome was observed with good psychomotor development and quality of life. To our knowledge, this is the first reported case of pediatric malignant ICA infarction due to penetrating arterial trauma with good neurologic outcome after DCH.
Integration of Next-Generation Sequencing in Diagnosing and Minimal Residual Disease Detection in Patients With Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia.
Cureus, 2020

Philadelphia-like (Ph-like) acute lymphoblastic leukemia (ALL) is a high-risk subtype of B cell ALL. It accounts for 20% of all B cell ALL cases and is similar to BCR-ABL1 in gene expression profile but lacks BCR-ABL fusion. It is highly heterogeneous and is characterized by genetic alterations that activate kinase and cytokine receptor signaling. Most of these alterations are amenable to tyrosine kinase inhibitors. Ph-like ALL is prevalent in pediatric and young adults, more common in males, and frequently seen in patients with Hispanic ancestry. It is associated with inadequate response to induction therapy, high minimal residual disease (MRD) levels, and increased risk of relapse. Overall survival and event-free survival are also inferior in these patients as compared to non-Ph-like ALL. In the clinical practice, low-density array, real-time quantitative polymerase chain reaction (RQ-PCR), flow cytometry, fluorescence in situ hybridization are used to identify genetic alteration in these patients. With the advent of next-generation sequencing (NGS), our understanding of disease pathogenesis and precision medicine has been improved. In this review, we analyzed data from several studies that used NGS as one of the diagnostic methods to identify genomic lesions in this high-risk subtype of B cell ALL. Studies have shown that NGS is a vital technique to identify various genomic lesions at diagnosis and throughout the treatment that can be missed by the widely used current methods. NGS has improved our understanding of various genomic lesions associated with Ph-like ALL and has helped define disease pathogenesis, MRD evaluation, and stratify therapy to prevent over or under treatment. We are in the era of precision medicine. Therefore unbiased, comprehensive genomic characterization of Ph-like ALL is important to implicate treatment directed against these genomic lesions and improve outcomes in these patients. We also analyzed data from studies that compared NGS with multi-flow cytometry and RQ-PCR for the evaluation of MRD. In the future, more extensive prospective studies are required to confirm the prognostic usefulness of NGS.
Zooming In and Out on One's Life: Autobiographical Representations at Multiple Time Scales.
Journal of cognitive neuroscience, 2020

The ability to decouple from the present environment and explore other times is a central feature of the human mind. Research in cognitive psychology and neuroscience has shown that the personal past and future is represented at multiple timescales and levels of resolution, from broad lifetime periods that span years to short-time slices of experience that span seconds. Here, I review this evidence and propose a theoretical framework for understanding mental time travel as the capacity to flexibly navigate hierarchical layers of autobiographical representations. On this view, past and future thoughts rely on two main systems-event simulation and autobiographical knowledge-that allow us to represent experiential contents that are decoupled from sensory input and to place these on a personal timeline scaffolded from conceptual knowledge of the content and structure of our life. The neural basis of this cognitive architecture is discussed, emphasizing the possible role of the medial pFC in integrating layers of autobiographical representations in the service of mental time travel.
Pandemic Guidance for Stroke Centers Aiding COVID-19 Treatment Teams.
Stroke, 2020

The coronavirus disease 2019 (COVID-19) pandemic has in some regions overwhelmed the capacity and staffing needs of healthcare systems, necessitating the provision of resources and staff from different disciplines to aid COVID treatment teams. Stroke centers have multidisciplinary clinical and procedural expertise to support COVID treatment teams. Staff safety and patient safety are essential, as are open lines of communication between stroke center leaders and hospital leadership in a pandemic where policies and procedures can change or evolve rapidly. Support needs to be allocated in a way that allows for the continued operation of a fully capable stroke center, with the ability to adjust if stroke center volume or staff attrition requires.
Synergistic efficacy and diminished adverse effect profile of composite treatment of several ADHD medications.
Neuropharmacology, 2021

Although attention-deficit/hyperactivity disorder (ADHD) is widely studied, problems regarding the adverse effect risks and non-responder problems still need to be addressed. Combination pharmacotherapy using standard dose regimens of existing medication is currently being practiced mainly to augment the therapeutic efficacy of each drug. The idea of combining different pharmacotherapies with different molecular targets to alleviate the symptoms of ADHD and its comorbidities requires scientific evidence, necessitating the investigation of their therapeutic efficacy and the mechanisms underlying the professed synergistic effects. Here, we injected male ICR mice with MK-801 to induce ADHD behavioral condition. We then modeled a "combined drug" using sub-optimal doses of methylphenidate, atomoxetine, and fluoxetine and investigated the combined treatment effects in MK-801-treated mice. No sub-optimal dose monotherapy alleviated ADHD behavioral condition in MK-801-treated mice. However, treatment with the combined drug attenuated the impaired behavior of MK-801-treated animals. Growth impediment, sleep disturbances, or risk of substance abuse were not observed in mice treated subchronically with the combined drugs. Finally, we observed that the combined ADHD drug rescued alterations in p-AKT and p-ERK1/2 levels in the prefrontal cortex and hippocampus, respectively, of MK-801-treated mice. Our results provide experimental evidence of a possible new pharmacotherapy option in ameliorating the ADHD behavioral condition without the expected adverse effects. The detailed mechanism of action underlying the synergistic therapeutic efficacy and reduced adverse reaction by combinatorial drug treatment should be investigated further in future studies.
Fumarate and oxidative stress synergize to promote stability of C/EBP homologous protein in the adipocyte.
Free radical biology & medicine, 2020

C/EBP homologous protein (CHOP) is a transcription factor that is elevated in adipose tissue across many models of diabetes and metabolic stress. Although increased CHOP levels are associated with the terminal response to endoplasmic reticulum stress and apoptosis, there is no evidence for CHOP mediated apoptosis in the adipose tissue during diabetes. CHOP protein levels increase in parallel with protein succination, a fumarate derived cysteine modification, in the adipocyte during metabolic stress. We investigated the factors contributing to sustained CHOP proteins levels in the adipocyte, with an emphasis on the regulation of CHOP protein turnover by metabolite-driven modification of Keap1 cysteines. CHOP protein stability was investigated in conditions of nutrient stress due to high glucose or elevated fumarate (fumarase knockdown model); where cysteine succination is specifically elevated. CHOP protein turnover is significantly reduced in models of elevated glucose and fumarate with a ~30% increase in CHOP stability (p > 0.01), in part due to decreased CHOP phosphorylation. Sustained CHOP levels occur in parallel with elevated heme-oxygenase-1, a production of increased Nrf2 transcriptional activity and Keap1 modification. While Keap1 is directly succinated in the presence of excess fumarate derived from genetic knockdown of fumarase (fumarate levels are elevated >20-fold), it is the oxidative modification of Keap1 that predominates in adipocytes matured in high glucose (fumarate increases 4-5 fold). Elevated fumarate indirectly regulates CHOP stability through the induction of oxidative stress. The antioxidant N-acetylcysteine (NAC) reduces fumarate levels, protein succination and CHOP levels in adipocytes matured in high glucose. Elevated CHOP does not contribute elevated apoptosis in adipocytes, but plays a redox-dependent role in decreasing the adipocyte secretion of interleukin-13, an anti-inflammatory chemokine. NAC treatment restores adipocyte IL-13 secretion, confirming the redox-dependent regulation of a potent anti-inflammatory eotaxin. This study demonstrates that physiological increases in the metabolite fumarate during high glucose exposure contributes to the presence of oxidative stress and sustained CHOP levels in the adipocyte during diabetes. The results reveal a novel metabolic link between mitochondrial metabolic stress and reduced anti-inflammatory adipocyte signaling as a consequence of reduced CHOP protein turnover.
Accuracy and precision of small saccades.
Scientific reports, 2020

Despite recent advances on the mechanisms and purposes of fine oculomotor behavior, a rigorous assessment of the precision and accuracy of the smallest saccades is still lacking. Yet knowledge of how effectively these movements shift gaze is necessary for understanding their functions and is helpful in further elucidating their motor underpinnings. Using a combination of high-resolution eye-tracking and gaze-contingent control, here we examined the accuracy and precision of saccades aimed toward targets ranging from [Formula: see text] to [Formula: see text] eccentricity. We show that even small saccades of just 14-[Formula: see text] are very effective in centering the stimulus on the retina. Furthermore, we show that for a target at any given eccentricity, the probability of eliciting a saccade depends on its efficacy in reducing the foveal offset. The pattern of results reported here is consistent with current knowledge on the motor mechanisms of microsaccade production.
Binding of Factor VIII to Lipid Nanodiscs Increases its Clotting Function in a Mouse Model of Hemophilia A.
Journal of blood disorders & transfusion, 2015

Hemophilia A is a congenital bleeding disorder caused by defective or deficient factor VIII (FVIII). The active form of FVIII is the co-factor for the serine protease factor IXa (FIXa) in the membrane-bound intrinsic tenase (FVIIIa-FIXa) complex. The assembly of the FVIIIa-FIXa complex on the activated platelet surface is critical for successful blood clotting.
Endovascular coil embolization of unruptured posterior communicating artery aneurysm.
Neurosurgical focus, 2014

The patient is a 60-year-old woman who presented to her primary care physician with new onset of headache. She was neurologically intact without cranial nerve deficit. An outpatient CT angiogram (CTA) revealed no subarachnoid hemorrhage, but showed a right-sided posterior communicating artery aneurysm measuring 11 mm by 10 mm. Digitally subtracted cerebral angiography confirmed these measurements and showed that the aneurysm was amenable to endovascular coil embolization. The patient underwent aneurysm coiling without complication and was discharged to home on postoperative Day 1. The video can be found here: http://youtu.be/MjOc3Zpv2K8 .
The quality of visual information about the lower extremities influences visuomotor coordination during virtual obstacle negotiation.
Journal of neurophysiology, 2018

Successful negotiation of obstacles during walking relies on the integration of visual information about the environment with ongoing locomotor commands. When information about the body and the environment is removed through occlusion of the lower visual field, individuals increase downward head pitch angle, reduce foot placement precision, and increase safety margins during crossing. However, whether these effects are mediated by loss of visual information about the lower extremities, the obstacle, or both remains to be seen. Here we used a fully immersive, virtual obstacle negotiation task to investigate how visual information about the lower extremities is integrated with information about the environment to facilitate skillful obstacle negotiation. Participants stepped over virtual obstacles while walking on a treadmill with one of three types of visual feedback about the lower extremities: no feedback, end-point feedback, and a link-segment model. We found that absence of visual information about the lower extremities led to an increase in the variability of leading foot placement after crossing. The presence of a visual representation of the lower extremities promoted greater downward head pitch angle during the approach to and subsequent crossing of an obstacle. In addition, having greater downward head pitch was associated with closer placement of the trailing foot to the obstacle, further placement of the leading foot after the obstacle, and higher trailing foot clearance. These results demonstrate that the fidelity of visual information about the lower extremities influences both feedforward and feedback aspects of visuomotor coordination during obstacle negotiation. NEW & NOTEWORTHY Here we demonstrate that visual information about the lower extremities is utilized for precise foot placement and control of safety margins during obstacle negotiation. We also found that when a visual representation of the lower extremities is present, this information is used in the online control of foot trajectory. Together, our results highlight how visual information about the body and the environment is integrated with motor commands for planning and online control of obstacle negotiation.
The effects of acute and repeated methylenedioxypyrovalerone (MDPV) administration on striatal transcriptome networks in male long evans rats.
Neuroscience letters, 2019

The psychoactive drug methylenedioxypyrovalerone (MDPV) elicits feelings of euphoria and hyperexcitability, but can also result in paranoia, agitation, and depression by unknown mechanisms. We identified molecular networks in the rat striatum that were affected by single or repeated exposure to MDPV. Male Long Evans rats were injected with either saline or MDPV (1 mg/kg) (single or repeated MDPV) over 5 days. To distinguish the effects of repeated MDPV from a single exposure, an additional group received saline over 4 days and then MDPV on the 5th day. Twenty-four hours after the final injection, the left dorsal striatum was processed for transcriptomics. The transcriptome response was subtle after 24 h, and a single gene passed an FDR correction (LOC103691845) following repeated MDPV treatment. Gene set and subnetwork enrichment analyses were conducted to improve data interpretation from a network perspective. Consistent with the mode of action of MDPV, networks related to the nigrostriatal dopaminergic system were altered in the rat striatum. Transcriptional networks related to cognition, short and long-term memory, and synaptic transmission were over-represented in the striatum of rats repeatedly injected with MDPV. This study identifies potential transcriptional networks altered by single or repeated MDPV exposure, which can be interrogated further to elucidate molecular mechanisms underlying cathinone abuse.
Antidepressant treatment is associated with epigenetic alterations of Homer1 promoter in a mouse model of chronic depression.
Journal of affective disorders, 2021

Understanding the neurobiology of depression and the mechanism of action of therapeutic measures is currently a research priority. We have shown that the expression of the synaptic protein Homer1a correlates with depression-like behavior and its induction is a common mechanism of action of different antidepressant treatments. However, the mechanism of Homer1a regulation is still unknown.
Down-regulation of Aquaporin-1 mediates a microglial phenotype switch affecting glioma growth.
Experimental cell research, 2020

Aquaporin 1 (AQP1), a transmembrane protein that forms water channels, has previously been shown to facilitate growth and progression of many types of tumors by modulating tumor cell migration, proliferation and angiogenesis. Here, we determined the impact of AQP1 expression in the tumor environment on the progression of brain tumors. Primary microglia from wild type(WT) and AQP1 knockout(KO) mice were used to test AQP1 effect on microglia function by using Western blot, quantative PCR, in an experimental in vivo mouse glioma model and organotypic brain slice culture. Deletion of AQP1 in the host tissue significantly reduced the survival of the mice implanted with GL261 glioma cells. The density of glioma-associated microglia/macrophages was almost doubled in AQP1KO mice. We found that factors secreted from GL261 cells decrease microglial AQP1 expression via the MEK/ERK pathway, and that inhibition of this pathway with Trametinib reduced tumor growth and prolonged the survival of tumor bearing mice, an effect which required the presence of microglia. Deletion of AQP1 in cultured microglia resulted in an increase in migratory activity and a decrease in TLR4-dependent innate immune responses. Our study demonstrates a functional relevance of AQP1 expression in microglia and hints to AQP1 as a potential novel target for glioma therapy.
Sleep characteristics across the lifespan in 1.1 million people from the Netherlands, United Kingdom and United States: a systematic review and meta-analysis.
Nature human behaviour, 2021

We aimed to obtain reliable reference charts for sleep duration, estimate the prevalence of sleep complaints across the lifespan and identify risk indicators of poor sleep. Studies were identified through systematic literature search in Embase, Medline and Web of Science (9 August 2019) and through personal contacts. Eligible studies had to be published between 2000 and 2017 with data on sleep assessed with questionnaires including ≥100 participants from the general population. We assembled individual participant data from 200,358 people (aged 1-100 years, 55% female) from 36 studies from the Netherlands, 471,759 people (40-69 years, 55.5% female) from the United Kingdom and 409,617 people (≥18 years, 55.8% female) from the United States. One in four people slept less than age-specific recommendations, but only 5.8% slept outside of the 'acceptable' sleep duration. Among teenagers, 51.5% reported total sleep times (TST) of less than the recommended 8-10 h and 18% report daytime sleepiness. In adults (≥18 years), poor sleep quality (13.3%) and insomnia symptoms (9.6-19.4%) were more prevalent than short sleep duration (6.5% with TST < 6 h). Insomnia symptoms were most frequent in people spending ≥9 h in bed, whereas poor sleep quality was more frequent in those spending <6 h in bed. TST was similar across countries, but insomnia symptoms were 1.5-2.9 times higher in the United States. Women (≥41 years) reported sleeping shorter times or slightly less efficiently than men, whereas with actigraphy they were estimated to sleep longer and more efficiently than man. This study provides age- and sex-specific population reference charts for sleep duration and efficiency which can help guide personalized advice on sleep length and preventive practices.
Increasing the reproducibility of fluid biomarker studies in neurodegenerative studies.
Nature communications, 2020

Biomarkers have revolutionized scientific research on neurodegenerative diseases, in particular Alzheimer's disease, transformed drug trial design, and are also increasingly improving patient management in clinical practice. A few key cerebrospinal fluid biomarkers have been robustly associated with neurodegenerative diseases. Several novel biomarkers are very promising, especially blood-based markers. However, many biomarker findings have had low reproducibility despite initial promising results. In this perspective, we identify possible sources for low reproducibility of studies on fluid biomarkers for neurodegenerative diseases, with a focus on Alzheimer's disease. We suggest guidelines for researchers and journal editors, with the aim to improve reproducibility of findings.