rudyvdbrink/CitationDatabase huggingface dataset:
SoxC transcription factors are essential for the development of the inner ear.
Proceedings of the National Academy of Sciences of the United States of America, 2015

Hair cells, the mechanosensory receptors of the inner ear, underlie the senses of hearing and balance. Adult mammals cannot adequately replenish lost hair cells, whose loss often results in deafness or balance disorders. To determine the molecular basis of this deficiency, we investigated the development of a murine vestibular organ, the utricle. Here we show that two members of the SoxC family of transcription factors, Sox4 and Sox11, are down-regulated after the epoch of hair cell development. Conditional ablation of SoxC genes in vivo results in stunted sensory organs of the inner ear and loss of hair cells. Enhanced expression of SoxC genes in vitro conversely restores supporting cell proliferation and the production of new hair cells in adult sensory epithelia. These results imply that SoxC genes govern hair cell production and thus advance these genes as targets for the restoration of hearing and balance.
Nuclear magnetic resonance structure revealed that the human polyomavirus JC virus agnoprotein contains an α-helix encompassing the Leu/Ile/Phe-rich domain.
Journal of virology, 2014

Agnoprotein is a small multifunctional regulatory protein required for sustaining the productive replication of JC virus (JCV). It is a mostly cytoplasmic protein localizing in the perinuclear area and forms highly stable dimers/oligomers through a Leu/Ile/Phe-rich domain. There have been no three-dimensional structural data available for agnoprotein due to difficulties associated with the dynamic conversion from monomers to oligomers. Here, we report the first nuclear magnetic resonance (NMR) structure of a synthetic agnoprotein peptide spanning amino acids Thr17 to Glu55 where Lys23 to Phe39 encompassing the Leu/Ile/Phe-rich domain forms an amphipathic α-helix. On the basis of these structural data, a number of Ala substitution mutations were made to investigate the role of the α-helix in the structure and function of agnoprotein. Single L29A and L36A mutations exhibited a significant negative effect on both protein stability and viral replication, whereas the L32A mutation did not. In addition, the L29A mutant displayed a highly nuclear localization pattern, in contrast to the pattern for the wild type (WT). Interestingly, a triple mutant, the L29A+L32A+L36A mutant, yielded no detectable agnoprotein expression, and the replication of this JCV mutant was significantly reduced, suggesting that Leu29 and Leu36 are located at the dimer interface, contributing to the structure and stability of agnoprotein. Two other single mutations, L33A and E34A, did not perturb agnoprotein stability as drastically as that observed with the L29A and L36A mutations, but they negatively affected viral replication, suggesting that the role of these residues is functional rather than structural. Thus, the agnoprotein dimerization domain can be targeted for the development of novel drugs active against JCV infection.
Epithelial-Mesenchymal Transition in Cancer: A Historical Overview.
Translational oncology, 2020

Epithelial-mesenchymal transitions (EMTs), the acquisition of mesenchymal features from epithelial cells, occur during some biological processes and are classified into three types: the first type occurs during embryonic development, the second type is associated with adult tissue regeneration, and the third type occurs in cancer progression. EMT occurring during embryonic development in gastrulation, renal development, and the origin and fate of the neural crest is a highly regulated process, while EMT occurring during tumor progression is highly deregulated. EMT allows the solid tumors to become more malignant, increasing their invasiveness and metastatic activity. Secondary tumors frequently maintain the typical histologic characteristics of the primary tumor. These histologic features connecting the secondary metastatic tumors to the primary is due to a process called mesenchymal-epithelial transition (MET). MET has been demonstrated in different mesenchymal tumors and is the expression of the reversibility of EMT. EMT modulation could constitute an approach to avoid metastasis. Some of the targeted small molecules utilized as antiproliferative agents have revealed to inhibit EMT initiation or maintenance because EMT is regulated through signaling pathways for which these molecules have been designed.
Population description and clinical response assessment for spinal metastases: part 2 of the SPIne response assessment in Neuro-Oncology (SPINO) group report.
Neuro-oncology, 2018

Approximately 40% of metastatic cancer patients will develop spinal metastases. The current report provides recommendations for standardization of metrics used for spinal oncology patient population description and outcome assessment beyond local control endpoints on behalf of the SPIne response assessment in Neuro-Oncology (SPINO) group.
Criticality and degeneracy in injury-induced changes in primary afferent excitability and the implications for neuropathic pain.
eLife, 2014

Neuropathic pain remains notoriously difficult to treat despite numerous drug targets. Here, we offer a novel explanation for this intractability. Computer simulations predicted that qualitative changes in primary afferent excitability linked to neuropathic pain arise through a switch in spike initiation dynamics when molecular pathologies reach a tipping point (criticality), and that this tipping point can be reached via several different molecular pathologies (degeneracy). We experimentally tested these predictions by pharmacologically blocking native conductances and/or electrophysiologically inserting virtual conductances. Multiple different manipulations successfully reproduced or reversed neuropathic changes in primary afferents from naïve or nerve-injured rats, respectively, thus confirming the predicted criticality and its degenerate basis. Degeneracy means that several different molecular pathologies are individually sufficient to cause hyperexcitability, and because several such pathologies co-occur after nerve injury, that no single pathology is uniquely necessary. Consequently, single-target-drugs can be circumvented by maladaptive plasticity in any one of several ion channels. DOI: http://dx.doi.org/10.7554/eLife.02370.001.
Reactivation of posttraumatic stress in male disaster survivors: the role of residual symptoms.
Journal of anxiety disorders, 2010

The aim of this study was to establish the relative distribution of resilient, remitted, chronic and reactivated posttraumatic stress disorder (PTSD) in a population of survivors from a major civilian disaster. Residual PTSD symptoms were explored to identify predictors of future reactivation. Symptoms were measured by the Impact of Event Scale (IES) 5.5 months, 14 months and 5 years after the disaster. Forty-eight survivors (79%) were interviewed after 27 years. PTSD status was determined by using the Structural Clinical Interview for DSM-IV axis I Disorders (SCID-I). The distributions were: 58.3% resilient, 14.6% remitted, 8.3% chronic, and 18.8% reactivated PTSD. Number of residual symptoms from intrusion and avoidance 14 months and 5 years past trauma predicted later reactivation. Intrusion symptoms in general, and sleep related intrusions in particular, were the most consistent predictors deserving special attention.
Transcriptional Profiling of a Selective CREB Binding Protein Bromodomain Inhibitor Highlights Therapeutic Opportunities.
Chemistry & biology, 2015

Bromodomains are involved in transcriptional regulation through the recognition of acetyl lysine modifications on diverse proteins. Selective pharmacological modulators of bromodomains are lacking, although the largely hydrophobic nature of the pocket makes these modules attractive targets for small-molecule inhibitors. This work describes the structure-based design of a highly selective inhibitor of the CREB binding protein (CBP) bromodomain and its use in cell-based transcriptional profiling experiments. The inhibitor downregulated a number of inflammatory genes in macrophages that were not affected by a selective BET bromodomain inhibitor. In addition, the CBP bromodomain inhibitor modulated the mRNA level of the regulator of G-protein signaling 4 (RGS4) gene in neurons, suggesting a potential therapeutic opportunity for CBP inhibitors in the treatment of neurological disorders.
Mortality and long-term quality of life after percutaneous tracheotomy in Intensive Care Unit: a prospective observational study.
Minerva anestesiologica, 2018

Quality of life and mortality after percutaneous dilatational tracheotomy (PDT) has been poorly investigated. The aims of this study were to evaluate the independent risk factors for Intensive Care Unit (ICU) mortality and investigate quality of life over the first year after PDT in critically ill patients.
Pharmacological characterization of a novel centrally permeable P2X7 receptor antagonist: JNJ-47965567.
British journal of pharmacology, 2013

An increasing body of evidence suggests that the purinergic receptor P2X, ligand-gated ion channel, 7 (P2X7) in the CNS may play a key role in neuropsychiatry, neurodegeneration and chronic pain. In this study, we characterized JNJ-47965567, a centrally permeable, high-affinity, selective P2X7 antagonist.
Maternal psychopathology and offspring clinical outcome: a four-year follow-up of boys with ADHD.
European child & adolescent psychiatry, 2017

Previous cross-sectional research has shown that parents of children with attention deficit hyperactivity disorder (ADHD) have high rates of psychopathology, especially ADHD and depression. However, it is not clear whether different types of parent psychopathology contribute to the course and persistence of ADHD in the child over time. The aim of this two wave study was to investigate if mother self-reported ADHD and depression influence persistence of offspring ADHD and conduct disorder symptom severity in adolescents diagnosed with ADHD in childhood. A sample of 143 males with a confirmed diagnosis of ADHD participated in this study. ADHD and conduct disorder symptoms were assessed at baseline and reassessed 4 years later. The boys in this sample had a mean age of 10.7 years at Time 1 (SD 2.14, range 6-15 years) and 13.73 years at Time 2 (SD 1.74, range 10-17 years). Questionnaire measures were used to assess ADHD and depression symptoms in mothers at Time 1. Mother self-reported ADHD was not associated with a change in child ADHD or conduct symptom severity over time. Mother self-reported depression was found to predict an increase in child conduct disorder symptoms, but did not contribute to ADHD symptom levels. This study provides the first evidence that concurrent depression in mothers may be a predictor of worsening conduct disorder symptoms in adolescents with ADHD. It may, therefore, be important to screen for depression in mothers of children with ADHD in clinical practice to tailor interventions accordingly.
Posterior cortical atrophy: a single case cognitive and radiological follow-up.
Neurocase, 2018

Posterior cortical atrophy (PCA) is a rare neurodegenerative syndrome characterized by initial predominant visuoperceptual deficits followed by a progressive decline in other cognitive functions. This syndrome has not been as thoroughly described as other dementias, particularly from a neuropsychological evolution perspective with only a few studies describing the evolution of its cognitive progression. In this investigation we review the literature on this rare condition and we perform a 7-year neuropsychological and neuroradiological follow-up of a 64-year-old man with PCA. The subject's deficits initially appeared in his visuoperceptual skills with later affectation appearing in language and other cognitive functions, this being coherent with the patient's parieto-temporal atrophy evolution.
Effects of environmental enrichment and social isolation on sucrose consumption and preference: associations with depressive-like behavior and ventral striatum dopamine.
Neuroscience letters, 2008

Little attention has been directed towards environmental control of sensitivity to natural reward and its possible relationship with other motivated behaviors, besides the well-known effects of environmental enrichment and social isolation on drug self-administration and locomotor sensitization to psychostimulants. Here, we investigate the effects of these rearing conditions on sucrose consumption and preference, and tissue levels of striatal dopamine. The possible relationship among sucrose intake, immobility behavior in the forced swimming test, and dopamine concentration was explored through correlation and regression analyses. Even though all animals preferred sucrose over water, we found, that during postnatal period, isolated rats consumed more sucrose than control or enriched littermates. In isolated rats sucrose intake correlated positively with ventral but not with dorsal striatum dopamine, even when striatal dopamine did not differ among groups. Especially in isolated animals immobility behavior was positively predicted by differences in sucrose intake. The dopamine concentration did not correlate with immobility behavior. Taken together, the present data support previous findings regarding the effects of early life events upon reward-sensitivity and depressive-like behavior, and also provide further evidence about the relationship between these motivated behaviors and the likely role of ventral striatum dopamine in regulating them.
Post-stroke deficit prediction from lesion and indirect structural and functional disconnection.
Brain : a journal of neurology, 2020

Behavioural deficits in stroke reflect both structural damage at the site of injury, and widespread network dysfunction caused by structural, functional, and metabolic disconnection. Two recent methods allow for the estimation of structural and functional disconnection from clinical structural imaging. This is achieved by embedding a patient's lesion into an atlas of functional and structural connections in healthy subjects, and deriving the ensemble of structural and functional connections that pass through the lesion, thus indirectly estimating its impact on the whole brain connectome. This indirect assessment of network dysfunction is more readily available than direct measures of functional and structural connectivity obtained with functional and diffusion MRI, respectively, and it is in theory applicable to a wide variety of disorders. To validate the clinical relevance of these methods, we quantified the prediction of behavioural deficits in a prospective cohort of 132 first-time stroke patients studied at 2 weeks post-injury (mean age 52.8 years, range 22-77; 63 females; 64 right hemispheres). Specifically, we used multivariate ridge regression to relate deficits in multiple functional domains (left and right visual, left and right motor, language, spatial attention, spatial and verbal memory) with the pattern of lesion and indirect structural or functional disconnection. In a subgroup of patients, we also measured direct alterations of functional connectivity with resting-state functional MRI. Both lesion and indirect structural disconnection maps were predictive of behavioural impairment in all domains (0.16 < R2 < 0.58) except for verbal memory (0.05 < R2 < 0.06). Prediction from indirect functional disconnection was scarce or negligible (0.01 < R2 < 0.18) except for the right visual field deficits (R2 = 0.38), even though multivariate maps were anatomically plausible in all domains. Prediction from direct measures of functional MRI functional connectivity in a subset of patients was clearly superior to indirect functional disconnection. In conclusion, the indirect estimation of structural connectivity damage successfully predicted behavioural deficits post-stroke to a level comparable to lesion information. However, indirect estimation of functional disconnection did not predict behavioural deficits, nor was a substitute for direct functional connectivity measurements, especially for cognitive disorders.
Bilateral versus ipsilesional cortico-subcortical activity patterns in stroke show hemispheric dependence.
International journal of stroke : official journal of the International Stroke Society, 2017

Background Understanding of interhemispheric interactions in stroke patients during motor control is an important clinical neuroscience quest that may provide important clues for neurorehabilitation. In stroke patients, bilateral overactivation in both hemispheres has been interpreted as a poor prognostic indicator of functional recovery. In contrast, ipsilesional patterns have been linked with better motor outcomes. Aim We investigated the pathophysiology of hemispheric interactions during limb movement without and with contralateral restraint, to mimic the effects of constraint-induced movement therapy. We used neuroimaging to probe brain activity with such a movement-dependent interhemispheric modulation paradigm. Methods We used an fMRI block design during which the plegic/paretic upper limb was recruited/mobilized to perform unilateral arm elevation, as a function of presence versus absence of contralateral limb restriction ( n = 20, with balanced left/right lesion sites). Results Analysis of 10 right-hemispheric stroke participants yielded bilateral sensorimotor cortex activation in all movement phases in contrast with the unilateral dominance seen in the 10 left-hemispheric stroke participants. Superimposition of contralateral restriction led to a prominent shift from activation to deactivation response patterns, in particular in cortical and basal ganglia motor areas in right-hemispheric stroke. Left-hemispheric stroke was in general characterized by reduced activation patterns, even in the absence of restriction, which induced additional cortical silencing. Conclusion The observed hemispheric-dependent activation/deactivation shifts are novel and these pathophysiological observations suggest short-term neuroplasticity that may be useful for hemisphere-tailored neurorehabilitation.
Imaging structural covariance in the development of intelligence.
NeuroImage, 2017

Verbal and non-verbal intelligence in children is highly correlated, and thus, it has been difficult to differentiate their neural substrates. Nevertheless, recent studies have shown that verbal and non-verbal intelligence can be dissociated and focal cortical regions corresponding to each have been demonstrated. However, the pattern of structural covariance corresponding to verbal and non-verbal intelligence remains unexplored. In this study, we used 586 longitudinal anatomical MRI scans of subjects aged 6-18 years, who had concurrent intelligence quotient (IQ) testing on the Wechsler Abbreviated Scale of Intelligence. Structural covariance networks (SCNs) were constructed using interregional correlations in cortical thickness for low-IQ (Performance IQ=100±8, Verbal IQ=100±7) and high-IQ (PIQ=121±8, VIQ=120±9) groups. From low- to high-VIQ group, we observed constrained patterns of anatomical coupling among cortical regions, complemented by observations of higher global efficiency and modularity, and lower local efficiency in high-VIQ group, suggesting a shift towards a more optimal topological organization. Analysis of nodal topological properties (regional efficiency and participation coefficient) revealed greater involvement of left-hemispheric language related regions including inferior frontal and superior temporal gyri for high-VIQ group. From low- to high-PIQ group, we did not observe significant differences in anatomical coupling patterns, global and nodal topological properties. Our findings indicate that people with higher verbal intelligence have structural brain differences from people with lower verbal intelligence - not only in localized cortical regions, but also in the patterns of anatomical coupling among widely distributed cortical regions, possibly resulting to a system-level reorganization that might lead to a more efficient organization in high-VIQ group.
The efficacy of shock wave therapy in patients with knee osteoarthritis and popliteal cyamella.
The Kaohsiung journal of medical sciences, 2014

This randomized, controlled study was performed to compare the effects of extracorporeal shockwave therapy (ESWT) and ultrasound on the rehabilitation of knee osteoarthritis with popliteal cyamella. One hundred and twenty patients with bilateral moderate knee osteoarthritis (Altman III) and popliteal cyamella were selected and randomly assigned to four groups (GI-GIV). Patients in Groups I-III received isokinetic muscular strengthening exercises three times weekly for 8 weeks. Group II received pulse ultrasound treatment for popliteal cyamella three times weekly for 8 weeks, Group III received weekly shock wave therapy for popliteal cyamella for the first 6 weeks, and Group IV acted as controls. The therapeutic effects were evaluated by changes in the arthritic knees range of motion (ROM), visual analogue scale, Lequesne's index, and muscle peak torques after treatment and at follow-up 6 months later. Each treated group exhibited increased muscle peak torques and significantly reduced pain and disability after treatment and at follow-ups. However, only patients in Groups II and III showed significant improvements in ROM after treatment, and only participants in Group III showed immediate improvement in ROM after each treatment. Patients in Group III also showed the greatest increase in muscular strength and the greatest decrease in disability after treatment and at the follow-ups. ESWT is better than pulse ultrasound in rehabilitation of patients with knee osteoarthritis and popliteal cyamella results in more functional improvements.
The role of fatty acid binding protein 7 in spinal cord astrocytes in a mouse model of experimental autoimmune encephalomyelitis.
Neuroscience, 2019

Fatty acid binding protein 7 (FABP7) is expressed in astrocytes of the developing and mature central nervous system, and modulates astrocyte function by controlling intracellular fatty acid homeostasis. Astrocytes in the spinal cord have an important role in the process of myelin degeneration and regeneration. In the present study, the authors examined the role of FABP7 in astrocytes in a mouse model of experimental autoimmune encephalomyelitis (EAE), which is an established model of multiple sclerosis (MS). FABP7 was expressed in the white matter astrocytes and increased after EAE onset; particularly strong expression was observed in demyelinating regions. In FABP7-knockout (KO) mice, the onset of EAE symptoms occurred earlier than in wild type (WT) mice, and mRNA expression levels of inflammatory cytokines (IL-17 and TNF-α) were higher in FABP7-KO lumbar spinal cord than in WT lumbar spinal cord at early stage of EAE. Interestingly, however, the clinical score was significantly reduced in FABP7-KO mice compared with WT mice in the late phase of EAE. Moreover, the area exhibiting expression of fibronectin, which is an extracellular matrix protein mainly produced by astrocytes and inhibits remyelination of oligodendrocytes, was significantly decreased in FABP7-KO compared with WT mice. Collectively, FABP7 in astrocyte may have a role to protect from the induction of inflammation leading to demyelination in CNS at early phase of EAE. Moreover, FABP7 may be involved in the regulation of fibronectin production through the modification of astrocyte activation at late phase of EAE.