rudyvdbrink/CitationDatabase huggingface dataset:
Cortical hierarchy, dual counterstream architecture and the importance of top-down generative networks.
NeuroImage, 2021

Hierarchy is a major organizational principle of the cortex and underscores modern computational theories of cortical function. The local microcircuit amplifies long-distance inter-areal input, which show distance-dependent changes in their laminar profiles. Statistical modeling of these changes in laminar profiles demonstrates that inputs from multiple hierarchical levels to their target areas show remarkable consistency, allowing the construction of a cortical hierarchy based on a principle of hierarchical distance. The statistical modeling that is applied to structure can also be applied to laminar differences in the oscillatory coherence between areas thereby determining a functional hierarchy of the cortex. Close examination of the anatomy of inter-areal connectivity reveals a dual counterstream architecture with well-defined distance-dependent feedback and feedforward pathways in both the supra- and infragranular layers, suggesting a multiplicity of feedback pathways with well-defined functional properties. These findings are consistent with feedback connections providing a generative network involved in a wide range of cognitive functions. A dynamical model constrained by connectivity data sheds insight into the experimentally observed signatures of frequency-dependent Granger causality for feedforward versus feedback signaling. Concerted experiments capitalizing on recent technical advances and combining tract-tracing, high-resolution fMRI, optogenetics and mathematical modeling hold the promise of a much improved understanding of lamina-constrained mechanisms of neural computation and cognition. However, because inter-areal interactions involve cortical layers that have been the target of important evolutionary changes in the primate lineage, these investigations will need to include human and non-human primate comparisons.
Conformational dynamics between transmembrane domains and allosteric modulation of a metabotropic glutamate receptor.
eLife, 2019

Metabotropic glutamate receptors (mGluRs) are class C, synaptic G-protein-coupled receptors (GPCRs) that contain large extracellular ligand binding domains (LBDs) and form constitutive dimers. Despite the existence of a detailed picture of inter-LBD conformational dynamics and structural snapshots of both isolated domains and full-length receptors, it remains unclear how mGluR activation proceeds at the level of the transmembrane domains (TMDs) and how TMD-targeting allosteric drugs exert their effects. Here, we use time-resolved functional and conformational assays to dissect the mechanisms by which allosteric drugs activate and modulate mGluR2. Single-molecule subunit counting and inter-TMD fluorescence resonance energy transfer measurements in living cells reveal LBD-independent conformational rearrangements between TMD dimers during receptor modulation. Using these assays along with functional readouts, we uncover heterogeneity in the magnitude, direction, and the timing of the action of both positive and negative allosteric drugs. Together our experiments lead to a three-state model of TMD activation, which provides a framework for understanding how inter-subunit rearrangements drive class C GPCR activation.
The inability of an early post-transplantation intrarenal resistive index to predict renal allograft function at 12 weeks after engraftment in young adults.
Acta radiologica (Stockholm, Sweden : 1987), 2016

Background The intrarenal resistive index (RI) is a promising tool for predicting renal graft outcomes. Due to the complexity of graft function and the presence of diverse contributing factors, however, the available data are inconclusive. Purpose To examine the performance of the RI 1 week after transplant in predicting allograft function at week 12, with an emphasis on the type of intrarenal artery used in the examination. Material and Methods A total of 58 first-time living-donor kidney-allograft-transplantation patients aged less than 50 years underwent Doppler ultrasonography (US) of the intrarenal arteries 1 week after engraftment. The RI was calculated for both the segmental (RI-C) and interlobar-arcuate (RI-P) arteries. Serum creatinine level and the creatinine reduction ratio (CRR) were determined at weeks 1 and 12 post transplantation. Results While the RI did not correlate with serum creatinine level and CRR at week 1, significant correlations were present between the RI and serum creatinine level (r = 0.28, P = 0.03 for both RI-C and RI-P) and CRR (r = -0.25, P = 0.05 for both RI-C and RI-P) at week 12. The sensitivity, specificity, positive predictive value, and negative predictive value of using RI-C in predicting abnormal 12-week serum creatinine level were 51.2%, 52.9%, 72.4%, and 31.3%, respectively; and 53.7%, 47.1%, 70.9%, and 29.6% for RI-P, respectively ( P > 0.99 for all comparisons). Conclusion Early post-transplantation RI correlates significantly with both serum creatinine level and creatinine reduction ratio 12 weeks after engraftment with intermediate predictive accuracy.
A Phase III, Randomized, Placebo-controlled Trial to Assess the Efficacy and Safety of Once-daily SPN-812 (Viloxazine Extended-release) in the Treatment of Attention-deficit/Hyperactivity Disorder in School-age Children.
Clinical therapeutics, 2020

The limitations of current US Food and Drug Administration (FDA)-approved medications for the treatment of attention-deficit/hyperactivity disorder (ADHD) set the need for the development of novel, effective, and tolerable medications to treat this disorder. The purpose of this study was to evaluate whether treatment with SPN-812 (viloxazine extended-release) significantly reduces symptoms of ADHD in children.
Abundance and localization of human UBE3A protein isoforms.
Human molecular genetics, 2020

Loss of UBE3A expression, a gene regulated by genomic imprinting, causes Angelman syndrome (AS), a rare neurodevelopmental disorder. The UBE3A gene encodes an E3 ubiquitin ligase with three known protein isoforms in humans. Studies in mouse suggest that the human isoforms may have differences in localization and neuronal function. A recent case study reported mild AS phenotypes in individuals lacking one specific isoform. Here we have used CRISPR/Cas9 to generate isogenic human embryonic stem cells (hESCs) that lack the individual protein isoforms. We demonstrate that isoform 1 accounts for the majority of UBE3A protein in hESCs and neurons. We also show that UBE3A predominantly localizes to the cytoplasm in both wild type and isoform-null cells. Finally, we show that neurons lacking isoform 1 display a less severe electrophysiological AS phenotype.
A physical model for dementia.
Physica A, 2017

Aging associated brain decline often result in some kind of dementia. Even when this is a complex brain disorder a physical model can be used in order to describe its general behavior. A probabilistic model for the development of dementia is obtained and fitted to some experimental data obtained from the Alzheimer's Disease Neuroimaging Initiative. It is explained how dementia appears as a consequence of aging and why it is irreversible.
Organizing principles underlying microorganism's growth-robustness trade-off.
Free radical biology & medicine, 2014

Growth Robustness Reciprocity (GRR) is an intriguing microbial manifestation: the impairment of microorganism's growth enhances their ability to resist acute stresses, and vice-versa. This is caused by regulatory interactions that determine higher expression of protection mechanisms in response to low growth rates. But because such regulatory mechanisms are species-specific, GRR must result from convergent evolution. Why does natural selection favor such an outcome? We used mathematical models of optimal cellular resource allocation to identify the general principles underlying GRR. Non-linear optimization allowed to predict allocation patterns of biosynthetic resources (ribosomes devoted to the synthesis of each cell component) that maximize growth. These models predict the down-regulation of stress defenses under high substrate availabilities and low stress levels. Under these conditions, stress tolerance ensues from growth-related damage dilution: the higher the substrate availability, the fastest the dilution of damaged proteins by newly synthesized proteins, the lower the accumulation of damaged components into the cell. In turn, under low substrate availability growth is too slow for effective damage dilution, and the expression of the defenses up to some optimal level then increases growth. As a consequence, slow-growing cells are pre-adapted to withstand acute stresses. Therefore, the observed negative correlation between growth and stress tolerance can be explained as a consequence of optimal resource allocation for maximal growth. We acknowledge fellowship SFRH/BPD/90065/2012 and grants PEst-C/SAU/LA0001/2013-2014 and FCOMP-01-0124-FEDER-020978 financed by FEDER through the "Programa Operacional Factores de Competitividade, COMPETE" and by national funds through "FCT, Fundação para a Ciência e a Tecnologia" (project PTDC/QUI-BIQ/119657/2010).
Dysregulation of Decision Making Related to Metabotropic Glutamate 5, but Not Midbrain D
Biological psychiatry, 2020

Compulsive patterns of drug use are thought to be the consequence of drug-induced adaptations in the neural mechanisms that enable behavior to be flexible. Neuroimaging studies have found evidence of robust alterations in glutamate and dopamine receptors within brain regions that are known to be critical for decision-making processes in cocaine-dependent individuals, and these changes have been argued to be the consequence of persistent drug use. The causal relationships among drug-induced alterations, cocaine taking, and maladaptive decision-making processes, however, are difficult to establish in humans.
Interventional Procedures in Episodic Migraine.
Current pain and headache reports, 2020

Migraine is a common disorder which in many cases can be adequately treated with medications. However, there are some patients who may either not respond to medications or have contraindications to their use. In this review, we will evaluate the available literature on the interventional procedures available to treat patients with episodic migraine. We will review the technical details of performing the procedures, the potential mechanisms of action, and available data on their effectiveness.
In search of common developmental and evolutionary origin of the claustrum and subplate.
The Journal of comparative neurology, 2020

The human claustrum, a major hub of widespread neocortical connections, is a thin, bilateral sheet of gray matter located between the insular cortex and the striatum. The subplate is a largely transient cortical structure that contains some of the earliest generated neurons of the cerebral cortex and has important developmental functions to establish intra- and extracortical connections. In human and macaque some subplate cells undergo regulated cell death, but some remain as interstitial white matter cells. In mouse and rat brains a compact layer is formed, Layer 6b, and it remains underneath the cortex, adjacent to the white matter. Whether Layer 6b in rodents is homologous to primate subplate or interstitial white matter cells is still debated. Gene expression patterns, such as those of Nurr1/Nr4a2, have suggested that the rodent subplate and the persistent subplate cells in Layer 6b and the claustrum might have similar origins. Moreover, the birthdates of the claustrum and Layer 6b are similarly precocious in mice. These observations prompted our speculations on the common developmental and evolutionary origin of the claustrum and the subplate. Here we systematically compare the currently available data on cytoarchitecture, evolutionary origin, gene expression, cell types, birthdates, neurogenesis, lineage and migration, circuit connectivity, and cell death of the neurons that contribute to the claustrum and subplate. Based on their similarities and differences we propose a partially common early evolutionary origin of the cells that become claustrum and subplate, a likely scenario that is shared in these cell populations across all amniotes.
TFEB/Mitf links impaired nuclear import to autophagolysosomal dysfunction in C9-ALS.
eLife, 2020

Disrupted nucleocytoplasmic transport (NCT) has been implicated in neurodegenerative disease pathogenesis; however, the mechanisms by which disrupted NCT causes neurodegeneration remain unclear. In a
rAAV8 and rAAV9-Mediated Long-Term Muscle Transduction with Tacrolimus (FK506) in Non-Human Primates.
Molecular therapy. Methods & clinical development, 2020

To establish an efficient, safe immunosuppressive regimen of adeno-associated vector (AAV)-mediated gene therapy for Duchenne muscular dystrophy (DMD), we evaluated the effect of tacrolimus (FK506) on skeletal muscle transduction with AAV8 and AAV9 vectors expressing the
Kinematic but not clinical measures predict falls in Parkinson-related orthostatic hypotension.
Journal of neurology, 2021

We sought to test the hypothesis that technology could predict the risk of falls in Parkinson's disease (PD) patients with orthostatic hypotension (OH) with greater accuracy than in-clinic assessment.
Role of vitamin B12 deficiency in ischemic stroke risk and outcome.
Neural regeneration research, 2021

Currently, ischemic stroke is the most prevalent form of stroke compared to hemorrhagic and there is a high incidence in older adults. Nutrition is a modifiable risk factor for stroke. B-vitamins are part of a metabolic network that integrates nutritional signals with biosynthesis, redox homeostasis, and epigenetics. These vitamins play an essential role in the regulation of cell proliferation, stress resistance, and embryo development. A deficiency in vitamin B12 is common in older adults and has been reported to be implicated in ischemic stroke. The aim of this review was to investigate whether vitamin B12 deficiencies impact the risk and outcome of ischemic stroke. Clinical data from our literature review strongly suggest that a deficiency in vitamin B12 is a risk factor for ischemic stroke and possible outcome. Our survey of the literature has identified that there is a gap in the understanding of the mechanisms through which a vitamin B12 deficiency leads to an increased risk of stroke and outcome. A vitamin B12 deficiency can increase homocysteine levels, which are a well-established risk factor for ischemic stroke. Another potential mechanism through which vitamin B12 deficient may impact neurological function and increase risk of stroke, is changes in myelination, however this link requires further investigation. Further studies are required in model systems to understand how a vitamin B12 deficiency changes the brain.
Childhood maltreatment, prefrontal-paralimbic gray matter volume, and substance use in young adults and interactions with risk for bipolar disorder.
Scientific reports, 2021

Childhood maltreatment is associated with adverse effects on the brain, and an increased risk for psychopathology, including mood and substance use disorders. Individuals vary on the degree to which they exhibit neurobiological and clinical differences following maltreatment. Individuals with bipolar disorder exhibit greater magnitude of maltreatment-related prefrontal-paralimbic gray matter volume (GMV) deficits compared to typically developing individuals. It is unclear if greater structural differences stem from greater neural vulnerability to maltreatment in bipolar disorder, or if they relate to presence of other clinical features associated with childhood maltreatment, e.g., elevated prevalence of comorbid substance use disorders. To investigate this, we compared young adults with a family history of bipolar disorder (n = 21), but who did not fulfill diagnostic criteria for bipolar disorder, with typically developing young adults without a family history of bipolar disorder (n = 26). Participants completed structural neuroimaging, clinical and family history interviews, and assessment of childhood maltreatment and recent alcohol and cannabis use patterns. We examined relations between childhood maltreatment and prefrontal-paralimbic GMV by modeling main effects of maltreatment and family history group by maltreatment interactions on prefrontal-paralimbic GMV. We also examined relations between maltreatment and associated GMV changes with recent alcohol and cannabis use. Childhood maltreatment correlated with lower ventral, rostral and dorsolateral prefrontal and insular cortical GMV across all participants regardless of the presence or absence of familial history of bipolar disorder. However, exploratory analyses did reveal greater maltreatment-related GMV differences in individuals with prodromal symptoms of depression. Lower insula GMV was associated with greater frequency of cannabis use across all participants and greater quantity of alcohol use only in those with familial risk for bipolar disorder. Results suggest familial risk for bipolar disorder, and presumably genetic risk, may relate to outcomes following childhood maltreatment and should be considered in prevention/early intervention strategies.
Minimally invasive oblique interbody fusion for correction of iatrogenic lumbar deformity.
Neurosurgical focus: Video, 2020

Spinal instability may arise as a consequence of decompressive lumbar surgery. An oblique lumbar interbody fusion combined with pedicle screw fixation can provide indirect decompression on neural elements, stabilization of mobile spondylolisthesis, and restoration of segmental lordosis. Minimally invasive techniques may facilitate a shorter hospitalization and faster recovery than a traditional open revision operation. The authors describe the use of an anterior interbody fusion via an oblique retroperitoneal approach and posterior pedicle screw fixation to treat a 67-year-old woman who developed L3-4 and L4-5 unstable spondylolisthesis after a lumbar laminectomy. The video can be found here: https://youtu.be/KWwGMIoDrmU.
Exon-Skipping Oligonucleotides Restore Functional Collagen VI by Correcting a Common COL6A1 Mutation in Ullrich CMD.
Molecular therapy. Nucleic acids, 2020

Collagen VI-related congenital muscular dystrophies (COL6-CMDs) are the second most common form of congenital muscular dystrophy. Currently, there is no effective treatment available. COL6-CMDs are caused by recessive or dominant mutations in one of the three genes encoding for the α chains of collagen type VI (COL6A1, COL6A2, and COL6A3). One of the most common mutations in COL6-CMD patients is a de novo deep intronic c.930+189C > T mutation in COL6A1 gene. This mutation creates a cryptic donor splice site and induces incorporation of a novel in-frame pseudo-exon in the mature transcripts. In this study, we systematically evaluated the splice switching approach using antisense oligonucleotides (ASOs) to correct this mutation. Fifteen ASOs were designed using the RNA-tiling approach to target the misspliced pseudo-exon and its flanking sequences. The efficiency of ASOs was evaluated at RNA, protein, and structural levels in skin fibroblasts established from four patients carrying the c.930+189C > T mutation. We identified two additional lead ASO candidates that efficiently induce pseudo-exon exclusion from the mature transcripts, thus allowing for the restoration of a functional collagen VI microfibrillar matrix. Our findings provide further evidence for ASO exon skipping as a therapeutic approach for COL6-CMD patients carrying this common intronic mutation.
Switching to fingolimod in PREFERMS: Effect of treatment history and naïvety on clinical, MRI and treatment satisfaction outcomes
Multiple sclerosis and related disorders, 2020

Injectable disease-modifying therapies (iDMTs) are often used as first-line treatments for relapsing multiple sclerosis. Fingolimod is frequently used following treatment with iDMTs. Whether prior iDMT treatment impacts the effectiveness of subsequent fingolimod therapy is unclear. Here, we assessed switching from iDMTs to fingolimod, and the impact of treatment history on fingolimod escalation using data from the 12-month 'Prospective, Randomized, active-controlled, open-label study to Evaluate patient retention on Fingolimod versus approved first-line disease-modifying thErapies in adults with Relapsing-remitting Multiple Sclerosis' (PREFERMS). The study design and results at the end of randomized treatment (EoRT) in PREFERMS have been published.
Spatial arrangement of testicular cells disrupted by transient scrotal hyperthermia and subsequent impairment of spermatogenesis.
Andrologia, 2020

The spermatogenesis is temperature-dependent and heat stress have destructive effects on spermatogenesis and reduces sperm quality. Sixteen adult mice were allocated to two groups: hyperthermia and control groups. Scrotal hyperthermia was induced by water bath with 43°C for 30 min. Then, the spermatozoon was isolated through the tail region of epididymis for sperm parameters analysis. The testicular tissues were taken for stereological studies, hormonal assay, TUNEL assay and molecular studies. We found a marked decrease in sperm parameters and serum testosterone level in mice induced by scrotal hyperthermia as well as stereological analysis indicated a significant reduction in testicular cells and changes in the spatial arrangement of testicular cells in the scrotal hyperthermia groups compared to the control groups. Moreover, the TUNEL assay results showed that apoptotic cells were enhanced significantly in the group of scrotal hyperthermia compared to the control groups. Furthermore, scrotal hyperthermia caused a reduction in the expression of retinoic acid 8 (STRA8), c-kit and proliferating cell nuclear antigen (PCNA) genes in the scrotal hyperthermia groups compared to the control. According to results, induction of transient scrotal hyperthermia leads to a fluctuation in the spatial arrangement of testicular cells, which finally influences the normal function of spermatogenesis.
[How Treatable is Vascular Dementia?].
Brain and nerve = Shinkei kenkyu no shinpo, 2016

Vascular dementia is an umbrella term, encompassing the pathological changes in the brain due to cerebrovascular disease that result in dementia. Vascular dementia is the second most common form of dementia, after Alzheimer's disease. In this paper, I outline the concept of vascular dementia, the key aspects of the disease that are yet to be clarified, and the current status of clinical trials. Assessing these factors, I discuss how treatable vascular dementia presently is. Use of the term'vascular dementia'is riddled with uncertainties regarding disease classification, and non-standardized diagnostic criteria. There are difficulties in determining the exact relationship between cerebrovascular pathology and cognitive impairment. The comorbid effects of Alzheimer's pathology in some individuals also present an obstacle to reliable clinical diagnosis, and hinder research into effective management approaches. Vascular dementia is preventable and treatable, as there are established primary and secondary prevention measures for the causative cerebrovascular diseases, such as vascular risk factor intervention, antiplatelet therapy, and anticoagulation, amongst others. However, unlike Alzheimer's disease, there are no established symptomatic treatments for vascular dementia. Clinical trials of cholinesterase inhibitors and memantine indicate that they produce small cognitive benefits in patients with vascular dementia, though the exact clinical significance of these is uncertain. Data are insufficient to support the widespread use of these drugs in vascular dementia. Rehabilitation and physical and cognitive exercise may be beneficial, but evidence of cognitive benefit and relief of neuropsychiatric symptoms due to exercise is lacking.