rudyvdbrink/CitationDatabase huggingface dataset:
The neurosteroid pregnenolone reverts microtubule derangement induced by the loss of a functional CDKL5-IQGAP1 complex.
Human molecular genetics, 2017

CDKL5 is a protein kinase that plays a key role for neuronal functions as testified by the onset of complex neuronal dysfunctions in patients with genetic lesions in CDKL5. Here we identify a novel interactor of CDKL5, IQGAP1, a fundamental regulator of cell migration and polarity. In accordance with a functional role of this interaction, depletion of CDKL5 impairs cell migration and impedes the localization of IQGAP1 at the leading edge. Moreover, we demonstrate that CDKL5 is required for IQGAP1 to form a functional complex with its effectors, Rac1 and the microtubule plus end tracking protein CLIP170. These defects eventually impact on the microtubule association of CLIP170, thus deranging their dynamics. CLIP170 is a cellular target of the neurosteroid pregnenolone; by blocking CLIP170 in its active conformation, pregnenolone is capable of restoring the microtubule association of CLIP170 in CDKL5 deficient cells and rescuing morphological defects in neurons devoid of CDKL5. These findings provide novel insights into CDKL5 functions and pave the way for target-specific therapeutic strategies for individuals affected with CDKL5-disorder.
Distorted distance perception to reachable points in people with chronic shoulder pain.
Musculoskeletal science & practice, 2019

Perception is not simply a carbon copy of the real world, but is subject to distortions that may reflect protective drive. This study aimed to investigate whether people with chronic shoulder pain show perceptual distortions of space and body that may promote protective behavior. Eighty-four people with shoulder pain and 51 healthy controls participated. Participants estimated (1) distances to points on a cork-board within and outside reaching distance, and (2) the perceived length of their own arms. A novel measure of movement-related pain was also used to determine whether movement-related pain relates to perceptual distortion. Overall, distance and arm length estimates did not differ between groups, nor did participants perceive their arms to be of different length. However, a moderate correlation between movement-related pain and the index of distance perception was found within the pain group, specifically for distance estimates to points within reach. Our results suggest that distorted perception is not a typical consequence of chronic shoulder pain; however, that it may occur in cases where pain is strongly linked to movement. Our findings have implications for understanding avoidance of movement in people with persistent pain.
Comparison of non-invasive MRI measurements of cerebral blood flow in a large multisite cohort.
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 2016

Arterial spin labeling and phase contrast magnetic resonance imaging provide independent non-invasive methods for measuring cerebral blood flow. We compared global cerebral blood flow measurements obtained using pseudo-continuous arterial spin labeling and phase contrast in 436 middle-aged subjects acquired at two sites in the NHLBI CARDIA multisite study. Cerebral blood flow measured by phase contrast (CBFPC: 55.76 ± 12.05 ml/100 g/min) was systematically higher (p < 0.001) and more variable than cerebral blood flow measured by pseudo-continuous arterial spin labeling (CBFPCASL: 47.70 ± 9.75). The correlation between global cerebral blood flow values obtained from the two modalities was 0.59 (p < 0.001), explaining less than half of the observed variance in cerebral blood flow estimates. Well-established correlations of global cerebral blood flow with age and sex were similarly observed in both CBFPCASL and CBFPC CBFPC also demonstrated statistically significant site differences, whereas no such differences were observed in CBFPCASL No consistent velocity-dependent effects on pseudo-continuous arterial spin labeling were observed, suggesting that pseudo-continuous labeling efficiency does not vary substantially across typical adult carotid and vertebral velocities, as has previously been suggested.
Vibration activates the actin/NF-κB axis and upregulates IL-6 and IL-8 expression in human periodontal ligament cells.
Cell biology international, 2020

We previously reported that mechanical vibration-induced proinflammatory cytokines, interleukin-6 (IL-6) and IL-8, expression in human periodontal ligament (hPDL) cells, however, the underlying mechanism remained unclear. Mechanical stimuli are able to activate cellular responses by inducing the activation of several signaling pathways including cytoskeletal changes and inflammation. The actin cytoskeleton is a highly dynamic network and plays many important roles in intracellular events. Here, we aimed to investigate the involvement of a pivotal mediator of inflammatory responses, nuclear factor-κB (NF-κB), and actin polymerization in vibration-induced upregulation of IL-6 and IL-8 expression in hPDL cells. hPDL cells were pretreated with the NF-κB inhibitor BAY 11-7082 or cytochalasin D, respectively, before exposure to vibration. IL-6 and IL-8 messenger RNA (mRNA) and protein expression were quantified by quantitative polymerase chain reaction and enzyme-linked immunosorbent assays, respectively. Subcellular localization of the NF-κB p65 subunit was visualized by immunofluorescent staining. We found an increase in NF-κB nuclear translocation in vibrated cells compared with control cells. Pretreatment with BAY 11-7082 significantly inhibited vibration-induced IL-6 and IL-8 mRNA and protein expression in hPDL cells. Moreover, pretreatment with cytochalasin D inhibited NF-κB nuclear translocation and attenuated upregulation of IL-6 and IL-8 mRNA and protein in vibrated cells. Therefore, modulation of actin cytoskeletal polymerization in response to vibration may activate the NF-κB signaling pathway and subsequently upregulate IL-6 and IL-8 expression in hPDL cells.
How to do health services research in stroke: A focus on performance measurement and quality improvement.
International journal of stroke : official journal of the International Stroke Society, 2018

The objective of this "How to" research series article is to provide guidance on getting started in Health Services Research. The purpose of health services research is to contribute knowledge that can be used to help improve health systems and clinical services through influencing policy and practice. The methods used are broad, have varying levels of rigor, and may require different specialist skills. This paper sets out practical steps for undertaking health services research. Importantly, use of the highlighted techniques can identify solutions to address inadequate knowledge translation or promote greater access to evidence-based stroke care to optimize patient outcomes.
Alarin 6-25Cys antagonizes alarin-specific effects on food intake and luteinizing hormone secretion.
Neuropeptides, 2013

Previous data from our labs and from others have demonstrated that intracerebroventricular (ICV) injection of alarin has orexigenic activity and significantly increases plasma luteinizing hormone (LH) secretion in a gonadotropin-releasing hormone (GnRH) dependent manner. The purpose of the current experiments was to determine if the amino acids at the amino-terminal end of the alarin peptide are critical for alarin's effects on reproductive and feeding systems. First, we injected male mice ICV with full-length alarin (Ala1-25) or peptide fragments missing residues at the amino-terminal end (Ala3-25 or Ala6-25 Cys). Neither peptide fragment alone, significantly increased food intake in male mice compared to controls. Second, ICV injection of Ala1-25, but not Ala3-25, significantly (p < 0.01) increased GnRH-mediated LH secretion. Surprisingly, Ala6-25 Cys significantly (p < 0.05) inhibited plasma LH secretion and inhibited Ala1-25 actions. In conclusion, elimination of the first five amino acids of alarin not only abolishes the biological activity of alarin, but becomes an antagonist to alarin-specific effects. Furthermore, Ala6-25 Cys seems to act as a specific antagonist to putative alarin receptors and therefore may be an important tool in identifying alarin-specific receptors.
Intranasal administration of glial-derived neurotrophic factor (GDNF) rapidly and significantly increases whole-brain GDNF level in rats.
Neuroscience, 2015

Previous studies have shown that glial cell line-derived neurotrophic factor (GDNF) exerts significant neuroprotective effects on substantia nigra (SN) neurons in the rat 6-hydroxydopamine (6-OHDA) model of Parkinson's disease (PD). In this study we used enzyme-linked immunosorbent assay (ELISA) to determine GDNF brain levels and distribution to target regions (i.e. striatum and SN) following intranasal administration of GDNF at different time points after administration. Brain levels increased significantly within 1h following a single 50-μg dose of GDNF in a liposomal formulation, returning to baseline by 24h. In a second study, different doses of GDNF (10-150 μg) in phosphate-buffered saline (PBS) were studied at the 1-h time point. Dose-dependent increases in brain GDNF levels were observed with apparent saturation of uptake at doses above 100 μg. Liposomes delivered 10-fold more GDNF to brain than PBS despite yielding similar neuroprotective efficacy in the 6-OHDA model, suggesting incomplete release of GDNF from liposomes in tissue. In a third study, autoradiography was performed on brain sections taken 1h after intranasal (125)I-labeled GDNF. Radioactivity was detected throughout the brain along the rostral-to-caudal axis, indicating that nasally administered GDNF can reach target areas. Collectively, these results demonstrate that intranasal administration of GDNF in liposomes or PBS achieves significant increases in GDNF in target brain areas, supporting use of intranasal administration as a non-invasive means of delivering GDNF to the brain to protect dopamine neurons and arrest disease progression in PD.
The emergence of digital mental health in low-income and middle-income countries: A review of recent advances and implications for the treatment and prevention of mental disorders.
Journal of psychiatric research, 2021

In low-income and middle-income countries (LMICs), emerging digital mental health interventions should be accompanied by regular and comprehensive assessment of available scientific evidence. This review aims to support efforts to monitor progress in digital mental health research, ensuring new evidence can guide researchers, clinicians, policymakers and program managers positioned to adopt and implement these digitally-enabled treatments. In accordance with PRISMA guidelines, an electronic database search from 2016 to 2020 yielded 37 digital intervention studies for detection, diagnosis, prevention, treatment, and/or management of a broad range of mental disorders in 13 LMICs. This date range was selected to update previous reviews. Most studies involved online interventions and many reported feasibility and acceptability, reflected by participant satisfaction or program adherence. About half the studies (N = 23) reported clinical benefits based on changes in mental health. For depression and mood disorders, some digital interventions showed improvements in depressive symptoms, quality of life, treatment adherence, and recovery. However, sample sizes were small and studies focused primarily on adults. Further limiting generalizability was the lack of consistency in clinical assessment and measurement tools between studies. No studies reported worsening symptoms, negative acceptability or dissatisfaction with digital interventions, suggesting possible publication bias. While digital interventions show promise, it remains difficult to conclude that digital interventions are effective from these studies, as it is prudent to exercise caution before drawing conclusions about clinical effectiveness. This review reflects continued growth in digital mental health research in LMICs and further highlights the need for rigorous evaluation of effectiveness and cost-effectiveness.
Sperm forward motility is negatively affected by short-term exposure to altitude hypoxia.
Andrologia, 2016

Human exposure to altitude is a model to study the role of oxygen in different areas of physiology and pathophysiology. The aim of this study was to evaluate whether a short exposure to hypoxia (5 days) combined with exercise, at altitude ranging from 900 m above sea level to 5895 m above sea level (Kilimanjaro Expedition) can modify seminal and reproductive hormonal parameter levels in human beings. During the ascent, blood oxygen saturation at 3.848 m above sea level was found to be decreased when compared to sea level (P < 0.02). The sperm forward motility at sea level after the expedition showed a significant reduction ​​(P < 0.02). There were no changes in other seminal parameters among those compared. Determination of the hormonal plasma concentrations showed that baseline values of follicle-stimulating hormone, total testosterone, prolactin and oestradiol were unchanged at sea level after the hypoxic experience, with respect to baseline values at sea level. On the other hand, luteinising hormone levels after altitudes trekking significantly increased compared to levels before the expedition (P < 0.05). Because of the short-term exposure, we can assume that the reduced forward motility described here may result from the effects of the acute altitude hypoxia on spermatozoa during the epididymal transit where they mature acquiring their motility.
Cell type-specific epigenetic links to schizophrenia risk in the brain.
Genome biology, 2019

The importance of cell type-specific epigenetic variation of non-coding regions in neuropsychiatric disorders is increasingly appreciated, yet data from disease brains are conspicuously lacking. We generate cell type-specific whole-genome methylomes (N = 95) and transcriptomes (N = 89) from neurons and oligodendrocytes obtained from brain tissue of patients with schizophrenia and matched controls.
Modeling induced pluripotent stem cells from fibroblasts of Duchenne muscular dystrophy patients.
The International journal of neuroscience, 2014

The generation of disease-specific induced pluripotent stem cell (iPS cell) lines from patients with incurable diseases is a promising approach for studying disease mechanisms and for drug screening. Such innovation enables us to obtain autologous cell sources for regenerative medicine. Herein, we report the generation and characterization of iPS cells from the fibroblasts of patients with a family history of Duchenne muscular dystrophy (DMD); these fibroblasts were obtained from patients at 22 gestational weeks of age and exhibit exon duplication from exons 16 to 42. The DMD-iPS cells were generated by the ectopic expression of four transcription factors: OCT4, SOX2, KLF4, and c-MYC; the DMD-iPS cells expressed several pluripotency markers and could be differentiated into various somatic cell types both in vitro and in vivo. Furthermore, DMD-iPSCs showed the differentiation potential to neuronal lineage. Thus, DMD-iPS cells are expected to serve as an in vitro disease model system, which will lay a foundation for the production of autologous cell therapies that avoid immune rejection and enable the correction of gene defects prior to tissue reconstitution.
A comprehensive overview of mitochondrial DNA 4977-bp deletion in cancer studies.
Oncology reviews, 2019

Mitochondria are cellular machines essential for energy production. The biogenesis of mitochondria is a highly complex and it depends on the coordination of the nuclear and mitochondrial genome. Mitochondrial DNA (mtDNA) mutations and deletions are suspected to be associated with carcinogenesis. The most described mtDNA deletion in various human cancers is called the 4977-bp common deletion (mDNA
Interactions between intercellular adhesion molecule-5 positive elements and their surroundings in the rodent visual cortex.
Communicative & integrative biology, 2013

The telencephalon-associated intercellular adhesion molecule 5 (Telencephalin; ICAM-5) regulates dendritic maturation, a process dependent on extracellular proteases in the developing brain. Using transmission electron microscopy, we have reported previously that ICAM-5 is localized primarily in dendritic protrusions during a period of robust synaptogenesis (P14 in mouse visual cortex). As dendritic protrusions mature (P28), ICAM-5 immuno-reactivity shifts from dendritic protrusions into dendritic shafts. ICAM-5 immuno-reactivity does not shift in animals lacking the matrix metalloproteinase-9 (MMP-9), a protease shown to regulate ICAM-5 cleavage. Cleaved ICAM-5 (soluble fraction; sICAM-5) has been shown to bind to a number of receptors located in neighboring structures, resulting in a variety of downstream signaling events, including enhanced neurotransmission. Here, we investigated the potential MMP-regulated ICAM-5 signaling by examining the relationship between ICAM-5 immuno-positive elements and the structures that directly neighbor them.
Characterizing Cortex-Wide Dynamics with Wide-Field Calcium Imaging.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2021

The brain functions through coordinated activity among distributed regions. Wide-field calcium imaging, combined with improved genetically encoded calcium indicators, allows sufficient signal-to-noise ratio and spatiotemporal resolution to afford a unique opportunity to capture cortex-wide dynamics on a moment-by-moment basis in behaving animals. Recent applications of this approach have been uncovering cortical dynamics at unprecedented scales during various cognitive processes, ranging from relatively simple sensorimotor integration to more complex decision-making tasks. In this review, we will highlight recent scientific advances enabled by wide-field calcium imaging in behaving mice. We then summarize several technical considerations and future opportunities for wide-field imaging to uncover large-scale circuit dynamics.
Aged chimpanzees exhibit pathologic hallmarks of Alzheimer's disease.
Neurobiology of aging, 2017

Alzheimer's disease (AD) is a uniquely human brain disorder characterized by the accumulation of amyloid-beta protein (Aβ) into extracellular plaques, neurofibrillary tangles (NFT) made from intracellular, abnormally phosphorylated tau, and selective neuronal loss. We analyzed a large group of aged chimpanzees (n = 20, age 37-62 years) for evidence of Aβ and tau lesions in brain regions affected by AD in humans. Aβ was observed in plaques and blood vessels, and tau lesions were found in the form of pretangles, NFT, and tau-immunoreactive neuritic clusters. Aβ deposition was higher in vessels than in plaques and correlated with increases in tau lesions, suggesting that amyloid build-up in the brain's microvasculature precedes plaque formation in chimpanzees. Age was correlated to greater volumes of Aβ plaques and vessels. Tangle pathology was observed in individuals that exhibited plaques and moderate or severe cerebral amyloid angiopathy, a condition in which amyloid accumulates in the brain's vasculature. Amyloid and tau pathology in aged chimpanzees suggests these AD lesions are not specific to the human brain.
p73 regulates ependymal planar cell polarity by modulating actin and microtubule cytoskeleton.
Cell death & disease, 2018

Planar cell polarity (PCP) and intercellular junctional complexes establish tissue structure and coordinated behaviors across epithelial sheets. In multiciliated ependymal cells, rotational and translational PCP coordinate cilia beating and direct cerebrospinal fluid circulation. Thus, PCP disruption results in ciliopathies and hydrocephalus. PCP establishment depends on the polarization of cytoskeleton and requires the asymmetric localization of core and global regulatory modules, including membrane proteins like Vangl1/2 or Frizzled. We analyzed the subcellular localization of select proteins that make up these modules in ependymal cells and the effect of Trp73 loss on their localization. We identify a novel function of the Trp73 tumor suppressor gene, the TAp73 isoform in particular, as an essential regulator of PCP through the modulation of actin and microtubule cytoskeleton dynamics, demonstrating that Trp73 is a key player in the organization of ependymal ciliated epithelia. Mechanistically, we show that p73 regulates translational PCP and actin dynamics through TAp73-dependent modulation of non-musclemyosin-II activity. In addition, TAp73 is required for the asymmetric localization of PCP-core and global signaling modules and regulates polarized microtubule dynamics, which in turn set up the rotational PCP. Therefore, TAp73 modulates, directly and/or indirectly, transcriptional programs regulating actin and microtubules dynamics and Golgi organization signaling pathways. These results shed light into the mechanism of ependymal cell planar polarization and reveal p73 as an epithelial architect during development regulating the cellular cytoskeleton.
Individual differences in laughter perception reveal roles for mentalizing and sensorimotor systems in the evaluation of emotional authenticity.
Cerebral cortex (New York, N.Y. : 1991), 2015

Humans express laughter differently depending on the context: polite titters of agreement are very different from explosions of mirth. Using functional MRI, we explored the neural responses during passive listening to authentic amusement laughter and controlled, voluntary laughter. We found greater activity in anterior medial prefrontal cortex (amPFC) to the deliberate, Emitted Laughs, suggesting an obligatory attempt to determine others' mental states when laughter is perceived as less genuine. In contrast, passive perception of authentic Evoked Laughs was associated with greater activity in bilateral superior temporal gyri. An individual differences analysis found that greater accuracy on a post hoc test of authenticity judgments of laughter predicted the magnitude of passive listening responses to laughter in amPFC, as well as several regions in sensorimotor cortex (in line with simulation accounts of emotion perception). These medial prefrontal and sensorimotor sites showed enhanced positive connectivity with cortical and subcortical regions during listening to involuntary laughter, indicating a complex set of interacting systems supporting the automatic emotional evaluation of heard vocalizations.
Retinal processing: global players like it local.
Current biology : CB, 2010

A recent study of a specific type of retinal amacrine cell shows how a single interneuron can implement a large number of parallel feedback circuits, illustrating how highly complex circuits can be generated by a small number of neurons.
Orbital frontal cortex updates state-induced value change for decision-making.
eLife, 2018

Recent hypotheses have posited that orbital frontal cortex (OFC) is important for using inferred consequences to guide behavior. Less clear is OFC's contribution to goal-directed or model-based behavior, where the decision to act is controlled by previous experience with the consequence or outcome. Investigating OFC's role in learning about changed outcomes separate from decision-making is not trivial and often the two are confounded. Here we adapted an incentive learning task to mice, where we investigated processes controlling experience-based outcome updating independent from inferred action control. We found chemogenetic OFC attenuation did not alter the ability to perceive motivational state-induced changes in outcome value but did prevent the experience-based updating of this change. Optogenetic inhibition of OFC excitatory neuron activity selectively when experiencing an outcome change disrupted the ability to update, leaving mice unable to infer the appropriate behavior. Our findings support a role for OFC in learning that controls decision-making.