rudyvdbrink/CitationDatabase huggingface dataset:
A new role for joint mobility in reconstructing vertebrate locomotor evolution.
Proceedings of the National Academy of Sciences of the United States of America, 2021

Reconstructions of movement in extinct animals are critical to our understanding of major transformations in vertebrate locomotor evolution. Estimates of joint range of motion (ROM) have long been used to exclude anatomically impossible joint poses from hypothesized gait cycles. Here we demonstrate how comparative ROM data can be harnessed in a different way to better constrain locomotor reconstructions. As a case study, we measured nearly 600,000 poses from the hindlimb joints of the Helmeted Guineafowl and American alligator, which represent an extant phylogenetic bracket for the archosaurian ancestor and its pseudosuchian (crocodilian line) and ornithodiran (bird line) descendants. We then used joint mobility mapping to search for a consistent relationship between full potential joint mobility and the subset of joint poses used during locomotion. We found that walking and running poses are predictably located within full mobility, revealing additional constraints for reconstructions of extinct archosaurs. The inferential framework that we develop here can be expanded to identify ROM-based constraints for other animals and, in turn, will help to unravel the history of vertebrate locomotor evolution.
COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.
Annals of neurology, 2019

Cytochrome c oxidase (COX) deficiency is a major mitochondrial respiratory chain defect that has vast genetic and phenotypic heterogeneity. This study aims to identify novel causative genes of COX deficiency with only striated muscle-specific symptoms.
Comprehensive Evaluation of Plasma 7-Ketocholesterol and Cholestan-3β,5α,6β-Triol in an Italian Cohort of Patients Affected by Niemann-Pick Disease due to NPC1 and SMPD1 Mutations.
Clinica chimica acta; international journal of clinical chemistry, 2016

Niemann-Pick C disease (NPCD) is a rare autosomal recessive neurovisceral disorder with a heterogeneous clinical presentation. Cholestan-3β,5α,6β-triol and 7-ketocholesterol have been proposed as biomarkers for the screening of NPCD. In this work, we assessed oxysterols levels in a cohort of Italian patients affected by NPCD and analyzed the obtained results in the context of the clinical, biochemical and molecular data. In addition, a group of patients affected by Niemann-Pick B disease (NPBD) were also analyzed. NPC patients presented levels of both oxysterols way above the cut off value, except for 5 siblings presenting the variant biochemical phenotype who displayed levels of 3β,5α,6β-triol below or just above the cut-off value; 2 of them presented also normal levels of 7-KC. Both oxysterols were extremely high in a patient presenting the neonatal systemic lethal phenotype. All NPB patients showed increased oxysterols levels. In conclusion, the reported LC-MS/MS assay provides a robust non-invasive screening tool for NPCD. However, false negative results can be obtained in patients expressing the variant biochemical phenotype. These data strengthen the concept that the results should always be interpreted in the context of the patients' clinical picture and filipin staining and/or genetic studies might still be undertaken in patients with normal levels of oxysterols if symptoms are highly suggestive of NPCD. Both oxysterols are significantly elevated in NPB patients; thus a differential diagnosis should always be performed in patients presenting isolated hepatosplenomegaly, a common clinical sign of both NPCD and NPBD.
A polygenic score for body mass index is associated with depressive symptoms via early life stress: Evidence for gene-environment correlation.
Journal of psychiatric research, 2019

Increasing childhood obesity rates are associated with not only adverse physical, but also mental health outcomes, including depression. These negative outcomes may be caused and/or exacerbated by the bullying and shaming overweight individuals experience. As body mass index (BMI) can be highly heritable, we hypothesized that a genetic risk for higher BMI, will predict higher early life stress (ELS), which in turn will predict higher depressive symptoms in adulthood. Such a process will reflect an evocative gene-environment correlation (rGE) wherein an individual's genetically influenced phenotype evokes a reaction from the environment that subsequently shapes the individual's health. We modeled genetic risk using a polygenic score of BMI derived from a recent large GWAS meta-analysis. Self-reports were used for the assessment of ELS and depressive symptoms in adulthood. The discovery sample consisted of 524 non-Hispanic Caucasian university students from the Duke Neurogenetics Study (DNS; 278 women, mean age 19.78 ± 1.23 years) and the independent replication sample consisted of 5930 white British individuals from the UK biobank (UKB; 3128 women, mean age 62.66 ± 7.38 years). A significant mediation effect was found in the DNS (indirect effect = 0.207, bootstrapped SE = .10, bootstrapped 95% CI: 0.014 to 0.421), and then replicated in the UKB (indirect effect = 0.04, bootstrapped SE = .01, bootstrapped 95% CI: 0.018 to 0.066). Higher BMI polygenic scores predicted higher ELS, which in turn predicted higher depressive symptoms. Our findings suggest that evocative rGE may contribute to weight-related mental health problems and stress the need for interventions that aim to reduce weight bias, specifically during childhood.
Inhibitory peptidergic modulation of 
eLife, 2017

Serotonin is an evolutionarily ancient molecule that functions in generating and modulating many behavioral states. Although much is known about how serotonin acts on its cellular targets, how serotonin release is regulated
Atoh1-lineal neurons are required for hearing and for the survival of neurons in the spiral ganglion and brainstem accessory auditory nuclei.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2009

Atoh1 is a basic helix-loop-helix transcription factor necessary for the specification of inner ear hair cells and central auditory system neurons derived from the rhombic lip. We used the Cre-loxP system and two Cre-driver lines (Egr2(Cre) and Hoxb1(Cre)) to delete Atoh1 from different regions of the cochlear nucleus (CN) and accessory auditory nuclei (AAN). Adult Atoh1-conditional knock-out mice (Atoh1(CKO)) are behaviorally deaf, have diminished auditory brainstem evoked responses, and have disrupted CN and AAN morphology and connectivity. In addition, Egr2; Atoh1(CKO) mice lose spiral ganglion neurons in the cochlea and AAN neurons during the first 3 d of life, revealing a novel critical period in the development of these neurons. These new mouse models of predominantly central deafness illuminate the importance of the CN for support of a subset of peripheral and central auditory neurons.
Comparative analysis of spreading depolarizations in brain slices exposed to osmotic or metabolic stress.
BMC neuroscience, 2021

Recurrent spreading depolarizations (SDs) occur in stroke and traumatic brain injury and are considered as a hallmark of injury progression. The complexity of conditions associated with SD in the living brain encouraged researchers to study SD in live brain slice preparations, yet methodological differences among laboratories complicate integrative data interpretation. Here we provide a comparative evaluation of SD evolution in live brain slices, in response to selected SD triggers and in various media, under otherwise standardized experimental conditions.
St. John's Wort seed and feverfew flower extracts relieve painful diabetic neuropathy in a rat model of diabetes.
Fitoterapia, 2014

Painful diabetic peripheral neuropathy (DPN) is a common complication of diabetes and the few approved therapies for the management of pain have limited efficacy and side effects. With the aim to explore and develop new pharmacological treatments, we investigated the antihyperalgesic properties of St. John's Wort (SJW) and feverfew in streptozotocin (STZ)-diabetic rats. Acute administration of a SJW seed extract reversed mechanical hyperalgesia with a prolonged effect. A SJW extract obtained from the aerial portion of the plant and a feverfew flower extract partially relieved neuropathic pain whereas a feverfew leaf extract was ineffective. The antihyperalgesic efficacy of these herbal drugs was comparable to that of clinically used antihyperalgesic drugs (carbamazepine, lamotrigine, l-acetyl-levocarnitine). Further examinations of SJW and feverfew composition revealed that hyperforin and hypericin might be responsible for the antihyperalgesic properties of SJW whereas the efficacy of feverfew seems to be related to the presence of parthenolide. Rats undergoing treatment with SJW and feverfew did not show any behavioral side effect or sign of altered locomotor activity. Our results suggest that SJW and feverfew extracts may become new therapeutic perspectives for painful DPN.
Fluid outflow in the rat spinal cord: the role of perivascular and paravascular pathways.
Fluids and barriers of the CNS, 2018

Cerebrospinal fluid (CSF) is thought to flow into the brain via perivascular spaces around arteries, where it mixes with interstitial fluid. The precise details concerning fluid outflow remain controversial. Although fluid dynamics have been studied in the brain, little is known about spinal cord fluid inflow and outflow. Understanding the normal fluid physiology of the spinal cord may give insight into the pathogenesis of spinal cord oedema and CSF disorders such as syringomyelia. We therefore aimed to determine the fluid outflow pathways in the rat spinal cord.
Input and output gain modulation by the lateral interhemispheric network in early visual cortex.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2015

Neurons in the cerebral cortex are constantly integrating different types of inputs. Dependent on their origin, these inputs can be modulatory in many ways and, for example, change the neuron's responsiveness, sensitivity, or selectivity. To investigate the modulatory role of lateral input from the same level of cortical hierarchy, we recorded in the primary visual cortex of cats while controlling synaptic input from the corresponding contralateral hemisphere by reversible deactivation. Most neurons showed a pronounced decrease in their response to a visual stimulus of different contrasts and orientations. This indicates that the lateral network acts via an unspecific gain-setting mechanism, scaling the output of a neuron. However, the interhemispheric input also changed the contrast sensitivity of many neurons, thereby acting on the input. Such a contrast gain mechanism has important implications because it extends the role of the lateral network from pure response amplification to the modulation of a specific feature. Interestingly, for many neurons, we found a mixture of input and output gain modulation. Based on these findings and the known physiology of callosal connections in the visual system, we developed a simple model of lateral interhemispheric interactions. We conclude that the lateral network can act directly on its target, leading to a sensitivity change of a specific feature, while at the same time it also can act indirectly, leading to an unspecific gain setting. The relative contribution of these direct and indirect network effects determines the outcome for a particular neuron.
Psychiatry, religion, positive emotions and spirituality.
Asian journal of psychiatry, 2013

This paper proposes that eight positive emotions: awe, love/attachment, trust/faith, compassion, gratitude, forgiveness, joy and hope constitute what we mean by spirituality. These emotions have been grossly ignored by psychiatry. The two sciences that I shall employ to demonstrate this definition of spirituality will be ethology and neuroscience. They are both very new. I will argue that spirituality is not about ideas, sacred texts and theology. Rather, spirituality is all about emotion and social connection that are more dependent on the limbic system than the cortex. Specific religions, for all their limitations, are often the portal through which positive emotions are brought into conscious attention. Neither Freud nor psychiatric textbooks ever mention emotions like joy and gratitude. Hymns and psalms give these emotions pride of place. Our whole concept of psychotherapy might change, if clinicians set about enhancing positive emotions, rather than focusing only on the negative ones.
The effects of stimulus-driven competition and task set on involuntary attention.
Journal of vision, 2014

It is well established that involuntary attention—the exogenous capture of attention by salient but task-irrelevant stimuli—can strongly modulate target detection and discrimination performance. There is an ongoing debate, however, about how involuntary attention affects target performance. Some studies suggest that it results from enhanced perception of the target, whereas others indicate instead that it affects decisional stages of information processing. From a review of these studies, we hypothesized that the presence of distractors and task sets are key factors in determining the effect of involuntary attention on target perception. Consistent with this hypothesis, here we found that noninformative cues summoning involuntary attention affected perceptual identification of a target when distractors were present. This cuing effect could not be attributed to reduced target location uncertainty or decision bias. The only condition under which involuntary attention improved target perception in the absence of distractors occurred when observers did not adopt a task set to focus attention on the target location. We conclude that the perceptual effects of involuntary attention depend on distractor interference and the adoption of a task set to resolve such stimulus competition.
Perspectives of Primary-Care Providers on Heart Failure in Long-Term Care Homes.
Canadian journal on aging = La revue canadienne du vieillissement, 2014

Heart failure (HF) is common among long-term care (LTC) residents, and may account for 40 per cent of acute-care transfers. Canadian Cardiovascular Society HF guidelines endorse standard therapies; yet LTC residents are less likely to receive treatment. This qualitative study employed focus groups to explore perceptions, from 18 physicians and nurse practitioners in three Ontario homes, on HF care practices and challenges. For example, participants reported challenges with HF diagnostic skills and procedural knowledge. They also identified the need for interprofessional collaboration and role clarification to improve HF care and outcomes. To address these challenges, multimodal interventions and bedside teaching are required. Leadership was viewed as essential to improve HF care. Several concerns arose regarding knowledge gaps and clinical deficits among primary-care providers who manage heart failure in LTC residents. Multimodal, clinically focused educational and interprofessional solutions are needed to improve HF care in long-term care.
Anti-MOG antibodies are under polygenic regulation with the most significant control coming from the C-type lectin-like gene locus.
Genes and immunity, 2013

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that is genetically complex. There is evidence supporting a role of myelin oligodendrocyte glycoprotein (MOG) humoral immunity in MS. We aimed to determine the genetic regulation of anti-MOG antibodies and their involvement in disease, by using MOG-induced experimental autoimmune encephalomyelitis (EAE) in rat, an animal model that closely mimics human MS. We show polygenic regulation of anti-MOG antibodies in two backcross populations, including a major genetic determinant for antibody expression on chromosome 4, Amig3. We fine-mapped the region to 539 kilobases (kb) consisting of a complex of seven C-type lectin receptor genes (Dcir4, Dcir3, Dcir2, Dcir1, Dcar1, Mcl and Mincle) that was captured in the APLEC congenic strain. We confirmed that Amig3 regulates anti-MOG antibody levels in MOG-EAE, and further showed that immune reactions during initiation of EAE were skewed toward increased numbers of B cells in the EAE-protected APLEC strain, together with higher anti-MOG IgG1 and lower IgG2b levels. Taken together, our data demonstrated complex regulation of the antibody response during EAE and that skewing the antibody response toward Th2 contributed to protection from EAE.
Taste familiarity is inversely correlated with Arc/Arg3.1 hemispheric lateralization.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013

Biochemical, electrophysiological, and imaging studies suggest that the anterior part of the insular cortex (IC) serves as primary taste cortex, whereas fMRI studies in human propose that the anterior IC is also involved in processing of general novelty or saliency information. Here, we compared activity regulated cytoskeleton associated protein (Arc)/Arg3.1 protein levels in the rat IC following administration of familiar versus novel tastes. Surprisingly, there was no correlation between novel taste and Arc/Arg3.1 levels when measured as the sum of both left and right insular cortices. However, when left and right IC were examined separately, Arc/Arg3.1 level was lateralized following novel taste learning. Moreover, Arc/Arg3.1 lateralization was inversely correlated with taste familiarity, whereas the high lateralization of Arc/Arg3.1 expression observed following novel taste learning is reduced proportionally to the increment in taste familiarity. In addition, unilateral inhibition of protein synthesis in the IC had asymmetrical effect on memory, inducing strong memory impairment similarly to bilateral inhibition or memory preservation, indicating that hemispheric lateralization is central for processing taste saliency information. These results provide indications, at the gene level of expression, for the role of IC lateralization in processing novel taste information and for the asymmetrical contribution of protein synthesis in each hemisphere during memory consolidation.
Making Drosophila lineage-restricted drivers via patterned recombination in neuroblasts.
Nature neuroscience, 2014

The Drosophila cerebrum originates from about 100 neuroblasts per hemisphere, with each neuroblast producing a characteristic set of neurons. Neurons from a neuroblast are often so diverse that many neuron types remain unexplored. We developed new genetic tools that target neuroblasts and their diverse descendants, increasing our ability to study fly brain structure and development. Common enhancer-based drivers label neurons on the basis of terminal identities rather than origins, which provides limited labeling in the heterogeneous neuronal lineages. We successfully converted conventional drivers that are temporarily expressed in neuroblasts, into drivers expressed in all subsequent neuroblast progeny. One technique involves immortalizing GAL4 expression in neuroblasts and their descendants. Another depends on loss of the GAL4 repressor, GAL80, from neuroblasts during early neurogenesis. Furthermore, we expanded the diversity of MARCM-based reagents and established another site-specific mitotic recombination system. Our transgenic tools can be combined to map individual neurons in specific lineages of various genotypes.
A novel MEIS2 mutation explains the complex phenotype in a boy with a typical NF1 microdeletion syndrome.
European journal of medical genetics, 2021

Concurrence of distinct genetic conditions in the same patient is not rare. Several cases involving neurofibromatosis type 1 (NF1) have recently been reported, indicating the need for more extensive molecular analysis when phenotypic features cannot be explained by a single gene mutation. Here, we describe the clinical presentation of a boy with a typical NF1 microdeletion syndrome complicated by cleft palate and other dysmorphic features, hypoplasia of corpus callosum, and partial bicoronal craniosynostosis caused by a novel 2bp deletion in exon 2 of Meis homeobox 2 gene (MEIS2) inherited from the mildly affected father. This is only the second case of an inherited MEIS2 intragenic mutation reported to date. MEIS2 is known to be associated with cleft palate, intellectual disability, heart defects, and dysmorphic features. Our clinical report suggests that this gene may also have a role in cranial morphogenesis in humans, as previously observed in animal models.
Fingolimod hydrochloride for the treatment of relapsing remitting multiple sclerosis.
Expert opinion on pharmacotherapy, 2017

Fingolimod was the first oral and the first in class disease modifying treatment in multiple sclerosis that acts as sphingosine-1-phospathe receptor agonist. Since approval in 2010 there is a growing experience with fingolimod use in clinical practice, but also next-generation sphingosin-1-receptor agonists in ongoing clinical trials. Growing evidence demonstrates additional effects beyond impact on lymphocyte circulation, highlighting further promising targets in multiple sclerosis therapy. Areas covered: Here we present a systematic review using PubMed database searching and expert opinion on fingolimod use in clinical practice. Long-term data of initial clinical trials and post-marketing evaluations including long-term efficacy, safety, tolerability and management especially within growing disease modifying treatment options and pre-treatment constellation in multiple sclerosis patients are critically discussed. Furthermore novel findings in mechanism of actions and prospective on additional use in progressive forms in multiple sclerosis are presented. Expert opinion: There is an extensive long-term experience on fingolimod use in clinical practice demonstrating the favorable benefit-risk of this drug. Using a defined risk management approach experienced MS clinicians should apply fingolimod after critical choice of patients and review of clinical aspects. Further studies are essential to discuss additional benefit in progressive forms in multiple sclerosis.
Skilled reaching relies on a V2a propriospinal internal copy circuit.
Nature, 2014

The precision of skilled forelimb movement has long been presumed to rely on rapid feedback corrections triggered by internally directed copies of outgoing motor commands, but the functional relevance of inferred internal copy circuits has remained unclear. One class of spinal interneurons implicated in the control of mammalian forelimb movement, cervical propriospinal neurons (PNs), has the potential to convey an internal copy of premotor signals through dual innervation of forelimb-innervating motor neurons and precerebellar neurons of the lateral reticular nucleus. Here we examine whether the PN internal copy pathway functions in the control of goal-directed reaching. In mice, PNs include a genetically accessible subpopulation of cervical V2a interneurons, and their targeted ablation perturbs reaching while leaving intact other elements of forelimb movement. Moreover, optogenetic activation of the PN internal copy branch recruits a rapid cerebellar feedback loop that modulates forelimb motor neuron activity and severely disrupts reaching kinematics. Our findings implicate V2a PNs as the focus of an internal copy pathway assigned to the rapid updating of motor output during reaching behaviour.