rudyvdbrink/CitationDatabase huggingface dataset:
Leading RNA Interference Therapeutics Part 2: Silencing Delta-Aminolevulinic Acid Synthase 1, with a Focus on Givosiran.
Molecular diagnosis & therapy, 2020

In November 2019 givosiran became the second small interfering RNA (siRNA)-based drug to receive US Food and Drug Administration (FDA) approval, it has been developed for the treatment of acute intermittent porphyria (AIP), a disorder characterized by life-threatening acute neurovisceral attacks. The porphyrias are a group of disorders in which enzymatic deficiencies in heme production lead to toxic accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen (PBG), which are involved in the neurovisceral attacks. Givosiran acts as a conventional siRNA to trigger RNA interference (RNAi)-mediated gene silencing on delta-ALA synthase 1 (ALAS1), thus returning ALA and PBG metabolites to the physiological level to attenuate further neurotoxicity. Givosiran makes use of a new hepatic-delivery system that conjugates three GalNac (N-acetylgalactosamine) molecules to the siRNA passenger strand. GalNac binds to the liver asialoglycoprotein receptor, favoring the internalization of these GalNac-conjugated siRNAs into the hepatic cells. In a phase I study, subcutaneous monthly administration of givosiran 2.5 mg/kg reduced > 90% of ALA and PBG content. This siRNA is being analyzed in ENVISION (NCT03338816), a phase III, multicenter, placebo-controlled randomized controlled trial. In preliminary results, givosiran achieved clinical endpoints for AIP, reducing urinary ALA levels, and presented a safety profile that enabled further drug development. The clinical performance of givosiran revealed that suppression of ALAS1 by GalNac-decorated siRNAs represents an additional approach for the treatment of patients with AIP that manifests recurrent acute neurovisceral attacks.
Translating protein phosphatase research into treatments for neurodegenerative diseases.
Biochemical Society transactions, 2017

Many of the major neurodegenerative disorders are characterized by the accumulation of intracellular protein aggregates in neurons and other cells in brain, suggesting that errors in protein quality control mechanisms associated with the aging process play a critical role in the onset and progression of disease. The increased understanding of the unfolded protein response (UPR) signaling network and, more specifically, the structure and function of eIF2α phosphatases has enabled the development or discovery of small molecule inhibitors that show great promise in restoring protein homeostasis and ameliorating neuronal damage and death. While this review focuses attention on one or more eIF2α phosphatases, the wide range of UPR proteins that are currently being explored as potential drug targets bodes well for the successful future development of therapies to preserve neuronal function and treat neurodegenerative disease.
Combined assessment of attentional reserve and cognitive-motor effort under various levels of challenge with a dry EEG system.
Psychophysiology, 2018

A novel ERP approach was proposed to index variations in mental workload, particularly in attentional reserve, which is complementary to EEG spectral content thought to reflect mental effort. To our knowledge, no study has assessed mental effort and attentional reserve simultaneously in EEG gel-based and, importantly, dry systems, which are particularly well suited for real-world settings. Therefore, by systematically considering ERP, EEG spectral, and importantly the combination of both, this study examined if a small set of dry EEG electrodes could detect changes in both spectral and ERP metrics to assess the mental workload under various challenges with a similar fidelity to their gel-based counterparts in a laboratory setting. By employing both EEG gel-based and dry systems, the ERP and spectral markers were computed while participants executed a visuomotor task under three levels of challenge. For both EEG systems, more challenging levels of difficulty were associated with concomitant changes in ERP amplitude, and spectral power reflected a reduction of the attentional reserve and an increase in cognitive-motor effort, respectively. Those variations in attentional reserve and cognitive-motor effort collectively indexed mental workload with nearly identical fidelity for both gel-based and dry EEG systems. These findings promise to assess the mental workload in situations where the use of dry EEG systems could be advantageously employed to examine human cognitive-motor performance.
Repeated amphetamine administration and long-term effects on 50-kHz ultrasonic vocalizations: possible relevance to the motivational and dopamine-stimulating properties of the drug.
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 2015

Ultrasonic vocalizations (USVs) of 50kHz are thought to indicate positive affective states in rats, and are increasingly being used to investigate the motivational properties of drugs of abuse. However, previous studies have observed that only dopaminergic psychostimulants of abuse, but not other addictive drugs, stimulate 50-kHz USVs immediately after their administration. This would suggest that 50-kHz USVs induced by addictive dopaminergic psychostimulants might reflect rewarding dopaminergic effect, rather than motivational effect. To elucidate this issue, our study compared the effects of the psychostimulant of abuse amphetamine and the dopamine receptor agonist apomorphine on 50-kHz USVs. Rats that received five drug administrations on alternate days in a novel test-cage were first re-exposed to the test-cage 7 days after treatment discontinuation to assess drug-conditioning, and then received a drug challenge. USVs were recorded throughout the experiments together with locomotor activity. To further clarify how amphetamine and apomorphine influenced 50-kHz USVs, rats were subdivided into "low" and "high" vocalizers, and time-dependence of drug effects was assessed. Amphetamine and apomorphine stimulated both 50-kHz USVs and locomotor activity, though they elicited dissimilar changes in these behaviors, depending on drug dose, rats׳ individual predisposition to vocalize, and time. Moreover, only amphetamine-treated rats displayed both sensitized 50-kHz USVs emission and conditioned vocalizations on test-cage re-exposure. These results indicate that the effects of amphetamine on 50-kHz USVs are not mimicked by a dopaminergic agonist with a low abuse potential, and may further support the usefulness of 50-kHz USVs in the study of the motivational properties of psychoactive drugs.
The Contribution of GWAS Loci in Familial Dyslipidemias.
PLoS genetics, 2016

Familial combined hyperlipidemia (FCH) is a complex and common familial dyslipidemia characterized by elevated total cholesterol and/or triglyceride levels with over five-fold risk of coronary heart disease. The genetic architecture and contribution of rare Mendelian and common variants to FCH susceptibility is unknown. In 53 Finnish FCH families, we genotyped and imputed nine million variants in 715 family members with DNA available. We studied the enrichment of variants previously implicated with monogenic dyslipidemias and/or lipid levels in the general population by comparing allele frequencies between the FCH families and population samples. We also constructed weighted polygenic scores using 212 lipid-associated SNPs and estimated the relative contributions of Mendelian variants and polygenic scores to the risk of FCH in the families. We identified, across the whole allele frequency spectrum, an enrichment of variants known to elevate, and a deficiency of variants known to lower LDL-C and/or TG levels among both probands and affected FCH individuals. The score based on TG associated SNPs was particularly high among affected individuals compared to non-affected family members. Out of 234 affected FCH individuals across the families, seven (3%) carried Mendelian variants and 83 (35%) showed high accumulation of either known LDL-C or TG elevating variants by having either polygenic score over the 90th percentile in the population. The positive predictive value of high score was much higher for affected FCH individuals than for similar sporadic cases in the population. FCH is highly polygenic, supporting the hypothesis that variants across the whole allele frequency spectrum contribute to this complex familial trait. Polygenic SNP panels improve identification of individuals affected with FCH, but their clinical utility remains to be defined.
Recommendations for the Study of Vulvar Pain in Women, Part 2: Methodological Challenges.
The journal of sexual medicine, 2020

Chronic vulvar pain is a multidimensional condition with great variability in clinical presentation among affected women. In a companion article, part 1, we reviewed and recommended assessment and measurement tools for vulvar pain and related outcomes with a view toward improving consistency and comparison across studies. Yet methodological challenges to conducting research with this population remain and can further hinder conclusions regarding etiology and treatment.
Filter-probe diffusion imaging improves spinal cord injury outcome prediction.
Annals of neurology, 2018

Diffusion-weighted imaging (DWI) is a powerful tool for investigating spinal cord injury (SCI), but has limited specificity for axonal damage, which is the most predictive feature of long-term functional outcome. In this study, a technique designed to detect acute axonal injury, filter-probe double diffusion encoding (FP-DDE), is compared with standard DWI for predicting long-term functional and cellular outcomes.
Prevalence of spasticity after aneurysmal subarachnoid haemorrhage.
Journal of rehabilitation medicine, 2014

The prevalence of spasticity after stroke is approximately 20%. There is, so far, little information in the literature on the development of spasticity after aneurysmal subarachnoid haemorrhage. The objectives of this study were to estimate the prevalence of spasticity after aneurysmal subarachnoid haemorrhage and to identify possible risk factors in the acute phase.
Cognitive Control Network Contributions to Memory-Guided Visual Attention.
Cerebral cortex (New York, N.Y. : 1991), 2016

Visual attentional capacity is severely limited, but humans excel in familiar visual contexts, in part because long-term memories guide efficient deployment of attention. To investigate the neural substrates that support memory-guided visual attention, we performed a set of functional MRI experiments that contrast long-term, memory-guided visuospatial attention with stimulus-guided visuospatial attention in a change detection task. Whereas the dorsal attention network was activated for both forms of attention, the cognitive control network(CCN) was preferentially activated during memory-guided attention. Three posterior nodes in the CCN, posterior precuneus, posterior callosal sulcus/mid-cingulate, and lateral intraparietal sulcus exhibited the greatest specificity for memory-guided attention. These 3 regions exhibit functional connectivity at rest, and we propose that they form a subnetwork within the broader CCN. Based on the task activation patterns, we conclude that the nodes of this subnetwork are preferentially recruited for long-term memory guidance of visuospatial attention.
A novel mouse model of subcortical infarcts with dementia.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2015

Subcortical white matter (WM) is a frequent target of ischemic injury and extensive WM lesions are important substrates of vascular cognitive impairment (VCI) in humans. However, ischemic stroke rodent models have been shown to mainly induce cerebral infarcts in the gray matter, while cerebral hypoperfusion models show only WM rarefaction without infarcts. The lack of animal models consistently replicating WM infarct damage may partially explain why many neuroprotective drugs for ischemic stroke or VCI have failed clinically, despite earlier success in preclinical experiments. Here, we report a novel animal model of WM infarct damage with cognitive impairment can be generated by surgical implantation of different devices to the right and left common carotid artery (CCA) in C57BL/6J mice. Implantation of an ameroid constrictor to the right CCA resulted in gradual occlusion of the vessel over 28 d, whereas placement of a microcoil to the left CCA induced ∼50% arterial stenosis. Arterial spin labeling showed a gradual reduction of cerebral blood flow over 28 d post operation. Such reductions were more marked in the right, compared with the left, hemisphere and in subcortical, rather than the cortical, areas. Histopathological analysis showed multiple infarct damage in right subcortical regions, including the corpus callosum, internal capsule, hippocampal fimbria, and caudoputamen, in 81% of mice. Mice displaying such damage performed significantly poorer in locomotor and cognitive tests. The current mouse model replicates the phenotypes of human subcortical VCI, including multiple WM infarcts with motor and cognitive impairment.
Disruption of gamma-delta relationship related to working memory deficits in first-episode psychosis.
Journal of neural transmission (Vienna, Austria : 1996), 2020

Working memory (WM) deficits constitute a core symptom of schizophrenia. Inadequacy of WM maintenance in schizophrenia has been reported to reflect abnormalities in the excitation/inhibition (E/I) balance between pyramidal neurons and parvalbumin basket cells, which may explain alterations of the dynamics of gamma and delta oscillations. To address this issue, we assessed event-related gamma (35-45 Hz) and delta (0.5-4 Hz) oscillatory responses in a visual n-back WM task in patients with first-episode psychosis (FEP) and healthy controls (HC). Periodicity analyses of oscillations were computed to explore the relationship between the psychiatric status and the WM load-related processes reflected by each frequency range. The correspondence between nested delta-gamma oscillations was estimated to assess the strength of the frontal E/I balance. In HC, gamma oscillations were synchronized by the stimulus in a 50-150 ms time range for all tasks, and periodicity of the delta cycle was comparable between the tasks. In addition, synchronization of gamma oscillations in HC occurred at the maximal descending phase of the delta cycle half-period, supporting the coexistence of delta-nested gamma oscillations. Compared with controls, FEP patients showed a lack of gamma synchronization independently of the nature of the task, and the period of delta oscillation increased significantly with the difficulty of the WM task. We thus demonstrated in FEP an inability to encode multiple items in short-term memory associated with abnormalities in the relationship between oscillations related to the difficulty of the WM task. These results argue in favor of a dysfunction of the E/I balance in psychosis.
Genome-wide association analysis reveals KCTD12 and miR-383-binding genes in the background of rumination.
Translational psychiatry, 2019

Ruminative response style is a passive and repetitive way of responding to stress, associated with several disorders. Although twin and candidate gene studies have proven the genetic underpinnings of rumination, no genome-wide association study (GWAS) has been conducted yet. We performed a GWAS on ruminative response style and its two subtypes, brooding and reflection, among 1758 European adults recruited in the general population of Budapest, Hungary, and Manchester, United Kingdom. We evaluated single-nucleotide polymorphism (SNP)-based, gene-based and gene set-based tests, together with inferences on genes regulated by our most significant SNPs. While no genome-wide significant hit emerged at the SNP level, the association of rumination survived correction for multiple testing with KCTD12 at the gene level, and with the set of genes binding miR-383 at the gene set level. SNP-level results were concordant between the Budapest and Manchester subsamples for all three rumination phenotypes. SNP-level results and their links to brain expression levels based on external databases supported the role of KCTD12, SRGAP3, and SETD5 in rumination, CDH12 in brooding, and DPYSL5, MAPRE3, KCNK3, ATXN7L3B, and TPH2 in reflection, among others. The relatively low sample size is a limitation of our study. Results of the first GWAS on rumination identified genes previously implicated in psychiatric disorders underscoring the transdiagnostic nature of rumination, and pointed to the possible role of the dorsolateral prefrontal cortex, hippocampus, and cerebellum in this cognitive process.
SOX2 expression is upregulated in adult spinal cord after contusion injury in both oligodendrocyte lineage and ependymal cells.
Journal of neuroscience research, 2013

The upregulation of genes normally associated with development may occur in the adult after spinal cord injury (SCI). To test this, we performed real-time RT-PCR array analysis of mouse spinal cord mRNAs comparing embryonic day (E)14.5 spinal cord with intact adult and adult cord 1 week after a clinically relevant standardized contusion SCI. We found significantly increased expression of a large number of neural development- and stem cell-associated genes after SCI. These included Sox2 (sex determining region Y-box 2), a transcription factor that regulates self-renewal and potency of embryonic neural stem cells and is one of only a few key factors needed to induce pluripotency. In adult spinal cord of Sox2-EGFP mice, Sox2-EGFP was found mainly in the ependymal cells of the central canal. After SCI, both mRNA and protein levels of Sox2 were significantly increased at and near the injury site. By 1 day, Sox2 was upregulated in NG2(+) oligodendrocyte progenitor cells (OPC) in the spared white matter. By 3 days, Sox2-EGFP ependymal cells had increased proliferation and begun to form multiple layers and clusters of cells in the central lesion zone of the cord. Expression of Sox2 by NG2(+) cells had declined by 1 week, but increased numbers of other Sox2-expressing cells persisted for at least 4 weeks after SCI in both mouse and rat models. Thus, SCI upregulates many genes associated with development and neural stem cells, including the key transcription factor Sox2, which is expressed in a pool of cells that persists for weeks after SCI.
Precision in the development of neocortical architecture: From progenitors to cortical networks.
Progress in neurobiology, 2019

Of all brain regions, the 6-layered neocortex has undergone the most dramatic changes in size and complexity during mammalian brain evolution. These changes, occurring in the context of a conserved set of organizational features that emerge through stereotypical developmental processes, are considered responsible for the cognitive capacities and sensory specializations represented within the mammalian clade. The modern experimental era of developmental neurobiology, spanning 6 decades, has deciphered a number of mechanisms responsible for producing the diversity of cortical neuron types, their precise connectivity and the role of gene by environment interactions. Here, experiments providing insight into the development of cortical projection neuron differentiation and connectivity are reviewed. This current perspective integrates discussion of classic studies and new findings, based on recent technical advances, to highlight an improved understanding of the neuronal complexity and precise connectivity of cortical circuitry. These descriptive advances bring new opportunities for studies related to the developmental origins of cortical circuits that will, in turn, improve the prospects of identifying pathogenic targets of neurodevelopmental disorders.
Adult neurogenesis in mammals--a theme with many variations.
The European journal of neuroscience, 2011

Investigations of adult neurogenesis in recent years have revealed numerous differences among mammalian species, reflecting the remarkable diversity in brain anatomy and function of mammals. As a mechanism of brain plasticity, adult neurogenesis might also differ due to behavioural specialization or adaptation to specific ecological niches. Because most research has focused on rodents and only limited data are available on other mammalian orders, it is hotly debated whether, in some species, adult neurogenesis also takes place outside of the well-characterized subventricular zone of the lateral ventricle and subgranular zone of the dentate gyrus. In particular, evidence for the functional integration of new neurons born in 'non-neurogenic' zones is controversial. Considering the promise of adult neurogenesis for regenerative medicine, we posit that differences in the extent, regional occurrence and completion of adult neurogenesis need to be considered from a species-specific perspective. In this review, we provide examples underscoring that the mechanisms of adult neurogenesis cannot simply be generalized to all mammalian species. Despite numerous similarities, there are distinct differences, notably in neuronal maturation, survival and functional integration in existing synaptic circuits, as well as in the nature and localization of neural precursor cells. We also propose a more appropriate use of terminology to better describe these differences and their relevance for brain plasticity under physiological and pathophysiological conditions. In conclusion, we emphasize the need for further analysis of adult neurogenesis in diverse mammalian species to fully grasp the spectrum of variation of this adaptative mechanism in the adult CNS.
Connectivity strength of dissociable striatal tracts predict individual differences in temporal discounting.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2014

Large individual differences exist in the ability to delay gratification for the sake of satisfying longer-term goals. These individual differences are commonly assayed by studying intertemporal preferences, as revealed by choices between immediate and delayed rewards. In the brain, reward-based and goal-oriented decisions are believed to rely on the striatum and its interactions with other cortical and subcortical networks. However, it remains unknown which specific cortical-striatal tracts are involved in intertemporal decision making. We use connectivity analyses in both structural and functional MRI to further our understanding of the relationship between distinct corticostriatal networks and intertemporal preferences in humans. Our results revealed distinct striatal pathways that are differentially related to delay discounting. Structural and functional connectivity between striatum and lateral prefrontal cortex was associated with increased patience, whereas connectivity between subcortical areas and striatum was associated with increased impulsivity. These findings provide novel insights into how the anatomy and functioning of striatal circuits mediate individual differences in intertemporal choice.
Utility of plasma Neurofilament light as a diagnostic and prognostic biomarker of the postural instability gait disorder motor subtype in early Parkinson's disease.
Molecular neurodegeneration, 2020

The main motor subtypes of Parkinson's disease (PD) include tremor-dominant (TD) and postural instability gait disorder (PIGD), with varying disease course that warrant the development of biomarkers capable of predicting progression according to motor subtype. The PIGD subtype is associated with a poorer prognosis, hence identification of a biomarker associated with PIGD is clinically relevant. Neurofilament light (NfL) chain is a potential biomarker of disease severity in neurological disorders including PD. However, no study has investigated NfL and PD motor subtypes. Here, we aimed to investigate the diagnostic and prognostic utility of plasma NfL for PD motor subtypes in early Parkinson's disease. Given the higher risk for cognitive and motor decline in PIGD, we hypothesized that plasma NfL is a potential biomarker for PIGD.