rudyvdbrink/CitationDatabase huggingface dataset:
Evaluation of safety and efficacy as an adjuvant for the chitosan-based vaccine delivery vehicle ViscoGel in a single-blind randomised Phase I/IIa clinical trial.
Vaccine, 2014

ViscoGel, a chitosan-based hydrogel, has earlier been shown to improve humoral and cell-mediated immune responses in mice. In this study, a Phase I/IIa clinical trial was conducted to primarily evaluate safety and secondarily to study the effects of ViscoGel in combination with a model vaccine, Act-HIB to Haemophilus influenzae type b, administered as a single intramuscular injection. Healthy volunteers of both sexes, ages 22-50 and not previously vaccinated to HIB, were recruited. The trial had two phases. In Phase A, three ascending dose levels of ViscoGel (25, 50 and 75mg) were evaluated for safety in 3×10 subjects. Phase B had a single-blind, randomised, parallel-group design evaluating safety and efficacy in five groups, 20 subjects/group, comparing vaccination with 0.2μg or 2μg Act-HIB alone or combined with ViscoGel (50mg) and one group receiving the standard Act-HIB dose (10μg). No safety or tolerability concerns were identified. Local, transient reactions at the injection site were the most common adverse events. These were more frequent in groups receiving Act-HIB+ViscoGel, while other AEs were recorded at similar frequency in Act-HIB and Act-HIB+ViscoGel groups. Efficacy was evaluated by measuring serum anti-HIB antibodies and cellular responses in peripheral blood mononuclear cells (PBMC). There was a large variation in baseline anti-HIB antibody titres and no adjuvant effect was observed on the anti-HIB antibody production in groups vaccinated with Act-HIB+ViscoGel. ELISpot analyses revealed increased interferon-γ (IFN-γ) responses to Act-HIB in PBMCs from subjects vaccinated with Act-HIB in combination with ViscoGel, compared to groups receiving Act-HIB alone. Moreover, ViscoGel counteracted an inhibitory effect of Act-HIB vaccination on the IFN-γ response to both the vaccine itself and an irrelevant influenza antigen. In summary, ViscoGel was found to be safe and well-tolerated, supporting further examination of ViscoGel as a new innovative vehicle for vaccine development.
Retinoic acid catabolizing enzyme CYP26C1 is a genetic modifier in SHOX deficiency.
EMBO molecular medicine, 2016

Mutations in the homeobox gene SHOX cause SHOX deficiency, a condition with clinical manifestations ranging from short stature without dysmorphic signs to severe mesomelic skeletal dysplasia. In rare cases, individuals with SHOX deficiency are asymptomatic. To elucidate the factors that modify disease severity/penetrance, we studied a three-generation family with SHOX deficiency. The variant p.Phe508Cys of the retinoic acid catabolizing enzyme CYP26C1 co-segregated with the SHOX variant p.Val161Ala in the affected individuals, while the SHOX mutant alone was present in asymptomatic individuals. Two further cases with SHOX deficiency and damaging CYP26C1 variants were identified in a cohort of 68 individuals with LWD The identified CYP26C1 variants affected its catabolic activity, leading to an increased level of retinoic acid. High levels of retinoic acid significantly decrease SHOX expression in human primary chondrocytes and zebrafish embryos. Individual morpholino knockdown of either gene shortens the pectoral fins, whereas depletion of both genes leads to a more severe phenotype. Together, our findings describe CYP26C1 as the first genetic modifier for SHOX deficiency.
Hepatic protein tyrosine phosphatase receptor gamma links obesity-induced inflammation to insulin resistance.
Nature communications, 2017

Obesity-induced inflammation engenders insulin resistance and type 2 diabetes mellitus (T2DM) but the inflammatory effectors linking obesity to insulin resistance are incompletely understood. Here, we show that hepatic expression of Protein Tyrosine Phosphatase Receptor Gamma (PTPR-γ) is stimulated by inflammation in obese/T2DM mice and positively correlates with indices of inflammation and insulin resistance in humans. NF-κB binds to the promoter of Ptprg and is required for inflammation-induced PTPR-γ expression. PTPR-γ loss-of-function lowers glycemia and insulinemia by enhancing insulin-stimulated suppression of endogenous glucose production. These phenotypes are rescued by re-expression of Ptprg only in liver of mice lacking Ptprg globally. Hepatic PTPR-γ overexpression that mimics levels found in obesity is sufficient to cause severe hepatic and systemic insulin resistance. We propose hepatic PTPR-γ as a link between obesity-induced inflammation and insulin resistance and as potential target for treatment of T2DM.
Piloting cognitive-behavioral therapy for insomnia integrated with prolonged exposure.
Psychological trauma : theory, research, practice and policy, 2019

Approximately 35-61% of individuals with posttraumatic stress disorder (PTSD) report insomnia. Further, upward of 70% report clinically significant insomnia following PTSD treatment. There are converging lines of evidence suggesting that insomnia not only independently affects daytime functioning and worsens PTSD symptoms but also may compromise response to PTSD treatment, such as prolonged exposure (PE). Taken together, integrated insomnia and PTSD treatment may increase client-centered care and treatment outcomes.
Reliable Next-Generation Sequencing of Formalin-Fixed, Paraffin-Embedded Tissue Using Single Molecule Tags.
The Journal of molecular diagnostics : JMD, 2016

Sequencing of tumor DNA to detect genetic aberrations is becoming increasingly important, not only to refine cancer diagnoses but also to predict response to targeted treatments. Next-generation sequencing is widely adopted in diagnostics for the analyses of DNA extracted from routinely processed formalin-fixed, paraffin-embedded tissue, fine-needle aspirates, or cytologic smears. PCR-based enrichment strategies are usually required to obtain sufficient read depth for reliable detection of genetic aberrations. However, although the read depth relates to sensitivity and specificity, PCR duplicates generated during target enrichment may result in overestimation of library complexity, which may result in false-negative results. Here, we report the validation of a 23-gene panel covering 41 hotspot regions using single-molecule tagging of DNA molecules by single-molecule molecular inversion probes (smMIPs), allowing assessment of library complexity. The smMIP approach outperforms Sanger and Ampliseq-Personal Genome Machine-based sequencing in our clinical diagnostic setting. Furthermore, single-molecule tags allow consensus sequence read formation, allowing detection to 1% allele frequency and reliable exclusion of variants to 3%. The number of false-positive calls is also markedly reduced (>10-fold), and our panel design allows for distinction between true mutations and deamination artifacts. Not only is this technique superior, smMIP-based library preparation is also scalable, easy to automate, and flexible. We have thus implemented this approach for sequence analysis of clinical samples in our routine diagnostic workflow.
Slc26a6 functions as an electrogenic Cl-/HCO3- exchanger in cardiac myocytes.
Cardiovascular research, 2013

Alterations in cardiac acid-base balance can produce profound impact on excitation-contraction coupling and precipitate cardiac dysfunction and arrhythmias. A member of the solute carrier (SLC) family, Slc26a6, has been shown to be a chloride-hydroxyl exchanger and the predominant chloride-bicarbonate exchanger in the mouse heart. However, the exact isoforms and functional characteristics of cardiac Slc26a6 remain unknown. The objective of the present study is to determine the molecular identity of cardiac Slc26a6 isoforms, to examine their cellular expressions in the heart, and to test the function of Slc26a6 in cardiomyocytes.
Autonomic regulation of hepatic glucose production.
Comprehensive Physiology, 2015

Glucose produced by the liver is a major energy source for the brain. Considering its critical dependence on glucose, it seems only natural that the brain is capable of monitoring and controlling glucose homeostasis. In addition to neuroendocrine pathways, the brain uses the autonomic nervous system to communicate with peripheral organs. Within the brain, the hypothalamus is the key region to integrate signals on energy status, including signals from lipid, glucose, and hormone sensing cells, with afferent neural signals from the internal and external milieu. In turn, the hypothalamus regulates metabolism in peripheral organs, including the liver, not only via the anterior pituitary gland but also via multiple neuropeptidergic pathways in the hypothalamus that have been identified as regulators of hepatic glucose metabolism. These pathways comprise preautonomic neurons projecting to nuclei in the brain stem and spinal cord, which relay signals from the hypothalamus to the liver via the autonomic nervous system. The neuroendocrine and neuronal outputs of the hypothalamus are not separate entities. They appear to act as a single integrated regulatory system, far more subtle, and complex than when each is viewed in isolation. Consequently, hypothalamic regulation should be viewed as a summation of both neuroendocrine and neural influences. As a result, our endocrine-based understanding of diseases such as diabetes and obesity should be expanded by integration of neural inputs into our concept of the pathophysiological process.
Neuroscience, lie-detection, and the law: contrary to the prevailing view, the suitability of brain-based lie-detection for courtroom or forensic use should be determined according to legal and not scientific standards.
Trends in cognitive sciences, 2010

The possibility of using neuroimaging to detect deception in legal settings has generated widespread resistance. Many neuroscientists insist the research is flawed science, containing weaknesses of reliability (the degree of accuracy), external validity (do laboratory results predict real-world outcomes), and construct validity (do studies test what they purport to test). These flaws are real, but although using neural lie-detection in non-experimental legal settings is premature, the critics are mistaken in believing that scientific standards should determine when these methods are ready for legal use. Law's goals differ from science's, and the legal suitability of neural lie-detection depends on legal standards and not those determining what good science is.
A Role for the Left Angular Gyrus in Episodic Simulation and Memory.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2017

Functional magnetic resonance imaging (fMRI) studies indicate that episodic simulation (i.e., imagining specific future experiences) and episodic memory (i.e., remembering specific past experiences) are associated with enhanced activity in a common set of neural regions referred to as the core network. This network comprises the hippocampus, medial prefrontal cortex, and left angular gyrus, among other regions. Because fMRI data are correlational, it is unknown whether activity increases in core network regions are critical for episodic simulation and episodic memory. In the current study, we used MRI-guided transcranial magnetic stimulation (TMS) to assess whether temporary disruption of the left angular gyrus would impair both episodic simulation and memory (16 participants, 10 females). Relative to TMS to a control site (vertex), disruption of the left angular gyrus significantly reduced the number of internal (i.e., episodic) details produced during the simulation and memory tasks, with a concomitant increase in external detail production (i.e., semantic, repetitive, or off-topic information), reflected by a significant detail by TMS site interaction. Difficulty in the simulation and memory tasks also increased after TMS to the left angular gyrus relative to the vertex. In contrast, performance in a nonepisodic control task did not differ statistically as a function of TMS site (i.e., number of free associates produced or difficulty in performing the free associate task). Together, these results are the first to demonstrate that the left angular gyrus is critical for both episodic simulation and episodic memory.
Voxel-based meta-analysis via permutation of subject images (PSI): Theory and implementation for SDM.
NeuroImage, 2019

Coordinate-based meta-analyses (CBMA) are very useful for summarizing the large number of voxel-based neuroimaging studies of normal brain functions and brain abnormalities in neuropsychiatric disorders. However, current CBMA methods do not conduct common voxelwise tests, but rather a test of convergence, which relies on some spatial assumptions that data may seldom meet, and has lower statistical power when there are multiple effects. Here we present a new algorithm that can use standard voxelwise tests and, importantly, conducts a standard permutation of subject images (PSI). Its main steps are: a) multiple imputation of study images; b) imputation of subject images; and c) subject-based permutation test to control the familywise error rate (FWER). The PSI algorithm is general and we believe that developers might implement it for several CBMA methods. We present here an implementation of PSI for seed-based d mapping (SDM) method, which additionally benefits from the use of effect sizes, random-effects models, Freedman-Lane-based permutations and threshold-free cluster enhancement (TFCE) statistics, among others. Finally, we also provide an empirical validation of the control of the FWER in SDM-PSI, which showed that it might be too conservative. We hope that the neuroimaging meta-analytic community will welcome this new algorithm and method.
Stress-dependent opioid and adrenergic modulation of newly retrieved fear memory.
Neurobiology of learning and memory, 2014

Recent studies on the effect of stress on modulation of fear memory in our laboratory have uncovered endogenous opioid and adrenergic based modulation systems, working in concert, that limit the strengthening or weakening of newly acquired fear memory during consolidation under conditions of mild or intense stress, respectively. The present study sought to determine if similar stress-dependent modulation, mediated by endogenous opioid and adrenergic systems, occurs during reconsolidation of newly retrieved fear memory. Rats underwent contextual fear conditioning followed 24h later by reactivation of fear memory; a retention test was administered the next day. Stress was manipulated by varying duration of recall of fear memory during reactivation. In the first experiment, vehicle or the opioid-receptor blocker naloxone was administered immediately after varied durations (30 or 120 s) of reactivation. The results indicate that (1) reactivation, in the absence of drug, has a marked effect on freezing behavior-as duration of reactivation increases from 30 to 120 s, freezing behavior and presumably fear-induced stress increases and (2) naloxone, administered immediately after 30 s (mild stress) or 120 s (intense stress) of reactivation, enhances or impairs retention, respectively, the next day. In the second experiment, naloxone and the ß-adrenergic blocker propranolol were administered either separately or in combination immediately after 120 s (intense stress) reactivation. The results indicate that separate administration of propranolol and naloxone impairs retention, while the combined administration fails to do so. Taken together the results of the two experiments are consistent with a protective mechanism, mediated by endogenous opioid and adrenergic systems working in concert, that limits enhancement and impairment of newly retrieved fear memory during reactivation in a stress-dependent manner.
In vitro exposure to the organochlorine p,p'-DDE affects functional human sperm parameters.
Chemosphere, 2015

Although no information exists regarding the levels of p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) on reproductive fluids of heavily exposed populations, they are possibly quite high given the serum levels reported so far. In these populations altered semen quality has been reported, although the direct effects of this DDT metabolite on crucial sperm parameters remain largely unexplored. With this in mind, a long-term in vitro incubation that better mimics the putative continuous exposure of spermatozoa to p,p'-DDE in the female reproductive tract in vivo was used. Before compromising sperm viability, continuous p,p'-DDE exposure remarkably decreased sperm motility, possibly due to the combined reduction in the proportion of sperm with high mitochondrial membrane potential and cellular ATP levels, all of which were clearly more affected at 50 and 100 μM p,p'-DDE. Moreover, 25 μM p,p'-DDE was also able to promote a decline in sperm with high MMP, however without significantly affecting motility. On the other hand, p,p'-DDE at the highest concentration strongly inhibited the process of capacitation following 24h of incubation. In conclusion, human sperm function is affected by continuous high p,p'-DDE exposure which may ultimately compromise male fertility. Given our previously findings that showed a non-regulated Ca(2+) entry in the presence of p,p'-DDE, we suggest that this organochlorine may promote mitochondrial Ca(2+) overload which may culminate in a general mitochondrial dysfunction and cellular ATP depletion, thus affecting sperm fertilizing potential. Our findings suggest a broader understanding of the non-genomic mechanism of p,p'-DDE action in human sperm.
Disrupting the clustering of GABAA receptor α2 subunits in the frontal cortex leads to reduced γ-power and cognitive deficits.
Proceedings of the National Academy of Sciences of the United States of America, 2013

In schizophrenia, cognitive dysfunction is highly predictive of poor patient outcomes and is not responsive to current medications. Postmortem studies have suggested that cognitive deficits in schizophrenia are correlated with modifications in the number and size of inhibitory synapses. To test if these modifications lead to cognitive deficits, we have created a dominant-negative virus [adeno-associated (AAV)-DN1] that disrupts the clustering of γ-aminobutyric acid type A receptors (GABA(A)Rs) at postsynaptic inhibitory specializations. When injected into the frontal cortex of mice, AAV-DN1 impairs GABA(A)R α2 subunit and GABA transporter 1 (GAT-1) clustering, but increases GABA(A)R α1 subunit clustering on the perisomatic region, with no influence on axon-initial segment clustering. Mice expressing AAV-DN1 have prepulse inhibition deficits and impairments in working memory. Significantly, these behavioral deficits are paralleled by a reduction in electroencephalography γ-power. Collectively, our study provides functional evidence revealing that GABAergic synapses in the prefrontal cortex directly contribute to cognition and γ-power.
Polymeric alkylpyridinium salts permit intracellular delivery of human Tau in rat hippocampal neurons: requirement of Tau phosphorylation for functional deficits.
Cellular and molecular life sciences : CMLS, 2015

Patients suffering from tauopathies including frontotemporal dementia (FTD) and Alzheimer's disease (AD) present with intra-neuronal aggregation of microtubule-associated protein Tau. During the disease process, Tau undergoes excessive phosphorylation, dissociates from microtubules and aggregates into insoluble neurofibrillary tangles (NFTs), accumulating in the soma. While many aspects of the disease pathology have been replicated in transgenic mouse models, a region-specific non-transgenic expression model is missing. Complementing existing models, we here report a novel region-specific approach to modelling Tau pathology. Local co-administration of the pore-former polymeric 1,3-alkylpyridinium salts (Poly-APS) extracted from marine sponges, and synthetic full-length 4R recombinant human Tau (hTau) was performed in vitro and in vivo. At low doses, Poly-APS was non-toxic and cultured cells exposed to Poly-APS (0.5 µg/ml) and hTau (1 µg/ml; ~22 µM) had normal input resistance, resting-state membrane potentials and Ca(2+) transients induced either by glutamate or KCl, as did cells exposed to a low concentration of the phosphatase inhibitor Okadaic acid (OA; 1 nM, 24 h). Combined hTau loading and phosphatase inhibition resulted in a collapse of the membrane potential, suppressed excitation and diminished glutamate and KCl-stimulated Ca(2+) transients. Stereotaxic infusions of Poly-APS (0.005 µg/ml) and hTau (1 µg/ml) bilaterally into the dorsal hippocampus at multiple sites resulted in hTau loading of neurons in rats. A separate cohort received an additional 7-day minipump infusion of OA (1.2 nM) intrahippocampally. When tested 2 weeks after surgery, rats treated with Poly-APS+hTau+OA presented with subtle learning deficits, but were also impaired in cognitive flexibility and recall. Hippocampal plasticity recorded from slices ex vivo was diminished in Poly-APS+hTau+OA subjects, but not in other treatment groups. Histological sections confirmed the intracellular accumulation of hTau in CA1 pyramidal cells and along their processes; phosphorylated Tau was present only within somata. This study demonstrates that cognitive, physiological and pathological symptoms reminiscent of tauopathies can be induced following non-mutant hTau delivery into CA1 in rats, but functional consequences hinge on increased Tau phosphorylation. Collectively, these data validate a novel model of locally infused recombinant hTau protein as an inducer of Tau pathology in the hippocampus of normal rats; future studies will provide insights into the pathological spread and maturation of Tau pathology.
Naloxone-precipitated withdrawal ameliorates impairment of cost-benefit decision making in morphine-treated rats: Involvement of BDNF, p-GSK3-β, and p-CREB in the amygdala.
Neurobiology of learning and memory, 2020

Several studies indicated that morphine administration impairs cognitive brain functions. Therefore, in the current study, we investigated the effect of subchronic exposure to morphine and its withdrawal on effort- and/or delay-based forms of cost-benefit decision making and alterations in p-CREB/CREB ratio, p-GSK3β/GSK3β ratio, and BDNF level during decision making in the amygdala. Our data displayed an impairment of both forms of cost-benefit decision making following subchronic exposure to morphine. However, preference of high reward/high effort and/or high delay reward increased after naloxone injection. In molecular section, levels of BDNF and p-CREB/CREB ratio increased during cost-benefit decision making while p-GSK3β/GSK3β ratio decreased in both forms of decision making. In morphine-treated rats, level of BDNF and p-CREB/CREB ratio reduced during both forms of decision making while p-GSK3β/GSK3β ratio increased during delay-based and did not have a significant difference with the control group during effort-based decision making. On the withdrawal day, BDNF level raised while p-GSK3β/GSK3β ratio attenuated compared to morphine-treated group in both form of decision making. In addition, p-CREB/CREB ratio increased only during delay-based decision making on the withdrawal day. In conclusion, our data revealed that subchronic exposure to morphine interferes with the cost-benefit decision making may be via changes in level of BDNF, p-CREB/CREB and p-GSK3β/GSK3β ratio in the amygdala.