rudyvdbrink/CitationDatabase huggingface dataset:
FMRP Control of Ribosome Translocation Promotes Chromatin Modifications and Alternative Splicing of Neuronal Genes Linked to Autism.
Cell reports, 2020

Silencing of FMR1 and loss of its gene product, FMRP, results in fragile X syndrome (FXS). FMRP binds brain mRNAs and inhibits polypeptide elongation. Using ribosome profiling of the hippocampus, we find that ribosome footprint levels in Fmr1-deficient tissue mostly reflect changes in RNA abundance. Profiling over a time course of ribosome runoff in wild-type tissue reveals a wide range of ribosome translocation rates; on many mRNAs, the ribosomes are stalled. Sucrose gradient ultracentrifugation of hippocampal slices after ribosome runoff reveals that FMRP co-sediments with stalled ribosomes, and its loss results in decline of ribosome stalling on specific mRNAs. One such mRNA encodes SETD2, a lysine methyltransferase that catalyzes H3K36me3. Chromatin immunoprecipitation sequencing (ChIP-seq) demonstrates that loss of FMRP alters the deployment of this histone mark. H3K36me3 is associated with alternative pre-RNA processing, which we find occurs in an FMRP-dependent manner on transcripts linked to neural function and autism spectrum disorders.
Structure of Myo7b/USH1C complex suggests a general PDZ domain binding mode by MyTH4-FERM myosins.
Proceedings of the National Academy of Sciences of the United States of America, 2017

Unconventional myosin 7a (Myo7a), myosin 7b (Myo7b), and myosin 15a (Myo15a) all contain MyTH4-FERM domains (myosin tail homology 4-band 4.1, ezrin, radixin, moesin; MF) in their cargo binding tails and are essential for the growth and function of microvilli and stereocilia. Numerous mutations have been identified in the MyTH4-FERM tandems of these myosins in patients suffering visual and hearing impairment. Although a number of MF domain binding partners have been identified, the molecular basis of interactions with the C-terminal MF domain (CMF) of these myosins remains poorly understood. Here we report the high-resolution crystal structure of Myo7b CMF in complex with the extended PDZ3 domain of USH1C (a.k.a., Harmonin), revealing a previously uncharacterized interaction mode both for MyTH4-FERM tandems and for PDZ domains. We predicted, based on the structure of the Myo7b CMF/USH1C PDZ3 complex, and verified that Myo7a CMF also binds to USH1C PDZ3 using a similar mode. The structure of the Myo7b CMF/USH1C PDZ complex provides mechanistic explanations for >20 deafness-causing mutations in Myo7a CMF. Taken together, these findings suggest that binding to PDZ domains, such as those from USH1C, PDZD7, and Whirlin, is a common property of CMFs of Myo7a, Myo7b, and Myo15a.
Single-cell gene expression profiles define self-renewing, pluripotent, and lineage primed states of human pluripotent stem cells.
Stem cell reports, 2014

Pluripotent stem cells display significant heterogeneity in gene expression, but whether this diversity is an inherent feature of the pluripotent state remains unknown. Single-cell gene expression analysis in cell subsets defined by surface antigen expression revealed that human embryonic stem cell cultures exist as a continuum of cell states, even under defined conditions that drive self-renewal. The majority of the population expressed canonical pluripotency transcription factors and could differentiate into derivatives of all three germ layers. A minority subpopulation of cells displayed high self-renewal capacity, consistently high transcripts for all pluripotency-related genes studied, and no lineage priming. This subpopulation was characterized by its expression of a particular set of intercellular signaling molecules whose genes shared common regulatory features. Our data support a model of an inherently metastable self-renewing population that gives rise to a continuum of intermediate pluripotent states, which ultimately become primed for lineage specification.
Age-Related Changes in Topological Degradation of White Matter Networks and Gene Expression in Chronic Schizophrenia.
Brain connectivity, 2017

Current hypotheses stipulate core symptoms of schizophrenia (SZ) result from the brain's incapacity to integrate neural processes. Converging diffusion magnetic resonance imaging and graph theory studies provide evidence of macrostructural alterations in SZ. However, age-related topological changes within and between white matter (WM) networks and its relationship to gene expression with disease progression remain incompletely understood. This cross-sectional study uses network modeling to investigate changes in WM network organization with disease progression in chronic SZ as well its relationship with gene expression in healthy brains. First, we replicate prior findings demonstrating altered global WM network topology in SZ. Novel results show significantly altered age-related network degradation patterns in patients compared with controls. Specifically, controls show stereotyped, linear global network decline with age. In contrast, patients show nonlinear network decline with age. Further analysis reveals lack of significant topological decline in younger adult patients, which is subsequently followed by stereotyped linear decline in older adult patients. Node-specific analyses show significant topological differences in frontal and limbic regions of younger adult patients compared with age-matched controls, which become less pronounced with age in older adult patients compared with age-matched controls. Lastly, we show several gene expression profiles, including DISC1, are associated with age-related changes in WM disconnectivity. Together, these findings provide novel WM topological and genetic evidence supporting neurodevelopmental models of SZ, suggesting that network remodeling continues throughout the third decade of life before stabilizing.
A Kiss to drive rhythms in reproduction.
The European journal of neuroscience, 2020

Reproduction, like many other biological functions, exhibits marked daily and seasonal rhythms in order to anticipate and adapt breeding activity to environmental challenges. In recent years, studies investigating the neuroendocrine mechanisms driving rhythms in reproduction have unveiled the pivotal role of hypothalamic neurons expressing kisspeptin in integrating and forwarding daily and seasonal cues to the reproductive system. The objective of this review is to summarize the knowledge on the effect and role of this neuropeptide on the mammalian hypothalamo-pituitary-gonadal axis and describe how it is involved in the daily control of ovulation in females and long-term adaptation of reproduction in seasonal breeders.
Determining T2 relaxation time and stroke onset relationship in ischaemic stroke within apparent diffusion coefficient-defined lesions. A user-independent method for quantifying the impact of stroke in the human brain.
Biomedical spectroscopy and imaging, 2019

In hyperacute ischaemic stroke, T2 of cerebral water increases with time. Quantifying this change may be informative of the extent of tissue damage and onset time. Our objective was to develop a user-unbiased method to measure the effect of cerebral ischaemia on T2 to study stroke onset time-dependency in human acute stroke lesions.
Hungry brains: A meta-analytical review of brain activation imaging studies on food perception and appetite in obese individuals.
Neuroscience and biobehavioral reviews, 2018

The dysregulation of food intake in chronic obesity has been explained by different theories. To assess their explanatory power, we meta-analyzed 22 brain-activation imaging studies. We found that obese individuals exhibit hyper-responsivity of the brain regions involved in taste and reward for food-related stimuli. Consistent with a Reward Surfeit Hypothesis, obese individuals exhibit a ventral striatum hyper-responsivity in response to pure tastes, particularly when fasting. Furthermore, we found that obese subjects display more frequent ventral striatal activation for visual food cues when satiated: this continued processing within the reward system, together with the aforementioned evidence, is compatible with the Incentive Sensitization Theory. On the other hand, we did not find univocal evidence in favor of a Reward Deficit Hypothesis nor for a systematic deficit of inhibitory cognitive control. We conclude that the available brain activation data on the dysregulated food intake and food-related behavior in chronic obesity can be best framed within an Incentive Sensitization Theory. Implications of these findings for a brain-based therapy of obesity are briefly discussed.
Transcriptomic profile of the subiculum-projecting VIP GABAergic neurons in the mouse CA1 hippocampus.
Brain structure & function, 2019

In cortical circuits, the vasoactive intestinal peptide (VIP+)-expressing GABAergic cells represent a heterogeneous but unique group of interneurons that is mainly specialized in network disinhibition. While the physiological properties and connectivity patterns have been elucidated in several types of VIP+ interneurons, little is known about the cell type-specific molecular repertoires important for selective targeting of VIP+ cell types and understanding their functions. Using patch-sequencing approach, we analyzed the transcriptomic profile of anatomically identified subiculum-projecting VIP+ GABAergic neurons that reside in the mouse hippocampal CA1 area, express muscarinic receptor 2 and coordinate the hippocampo-subicular interactions via selective innervation of interneurons in the CA1 area and of interneurons and pyramidal cells in subiculum. We explored the VIP+ cell gene expression within major gene families including ion channels, neurotransmitter receptors, neuromodulators, cell adhesion and myelination molecules. Among others, a large variety of genes involved in neuromodulatory signaling, including acetylcholine (Chrna4), norepinephrin (Adrb1), dopamine (Drd1), serotonin (Htr1d), cannabinoid (Cnr1), opioid (Oprd1, Oprl1) and neuropeptide Y (Npy1r) receptors was detected in these cells. Many genes that were enriched in other local VIP+ cell types, including the interneuron-selective interneurons and the cholecystokinin-coexpressing basket cells, were detected in VIP+ subiculum-projecting cells. In addition, the neuronatin (Nnat) and the Purkinje Cell Protein 4 (Pcp4) genes, which were detected previously in long-range projecting GABAergic neurons, were also common for the subiculum-projecting VIP+ cells. The expression of some genes was validated at the protein level, with proenkephalin being identified as an additional molecular marker of this VIP+ cell type. Together, our data indicate that the VIP+ subiculum-projecting cells share molecular identity with other VIP+ and long-range projecting GABAergic neurons, which can be important for specific function of these cells associated with their local and distant projection patterns.
Potential Applications of Digital Technology in Assessment, Treatment, and Self-help for Hallucinations.
Schizophrenia bulletin, 2019

The field of digital mental health is rapidly expanding with digital tools being used in assessment, intervention, and supporting self-help. The application of digital mental health to hallucinations is, however, at a very early stage. This report from a working group of the International Consortium on Hallucinations Research considers particular synergies between the phenomenon of hallucinations and digital tools that are being developed. Highlighted uses include monitoring and managing intermittently occurring hallucinations in daily life; therapeutic applications of audio and video media including virtual and augmented reality; targeting verbal aspects of hallucinations; and using avatars to represent hallucinatory voices. Although there is a well-established Internet-based peer support network, digital resources for hallucinations have yet to be implemented in routine practice. Implementation may benefit from identifying how to market resources to the broad range of populations who experience hallucinations and identifying sustainable funding models. It is envisaged that digital tools will contribute to improved self-management and service provision for people experiencing hallucinations.
Disrupting effect of drug-induced reward on spatial but not cue-guided learning: implication of the striatal protein kinase A/cAMP response element-binding protein pathway.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2011

The multiple memory systems hypothesis posits that different neural circuits function in parallel and may compete for information processing and storage. For example, instrumental conditioning would depend on the striatum, whereas spatial memory may be mediated by a circuit centered on the hippocampus. However, the nature of the task itself is not sufficient to select durably one system over the other. In this study, we investigated the effects of natural and pharmacological rewards on the selection of a particular memory system during learning. We compared the effects of food- or drug-induced activation of the reward system on cue-guided versus spatial learning using a Y-maze discrimination task. Drug-induced reward severely impaired the acquisition of a spatial discrimination task but spared the cued version of the task. Immunohistochemical analysis of the phosphorylated form of the cAMP response element binding (CREB) protein and c-Fos expression induced by behavioral testing revealed that the spatial deficit was associated with a decrease of both markers within the hippocampus and the prefrontal cortex. In contrast, drug reward potentiated the cued learning-induced CREB phosphorylation within the dorsal striatum. Administration of the protein kinase A inhibitor 8-Bromo-adenosine-3',5'-cyclic monophosphorothioate Rp isomer (Rp-cAMPS) into the dorsal striatum before training completely reversed the drug-induced spatial deficit and restored CREB phosphorylation levels within the hippocampus and the prefrontal cortex. Therefore, drug-induced striatal hyperactivity may underlie the declarative memory deficit reported here. This mechanism could represent an important early step toward the development of addictive behaviors by promoting conditioning to the detriment of more flexible forms of memory.
Imaging in the cardiovascular and metabolic disease area.
Drug discovery today, 2013

There is a widely held belief that the use of non-invasive imaging can reduce the gap between basic science and clinical proof-of-concept, ultimately improving decision-making and therefore the efficiency of the drug development process. Imaging techniques such as positron emission tomography (PET) and magnetic resonance imaging (MRI) are routinely used in oncology and neuroscience drug development. However, less attention has been paid to the systematic use of imaging in the cardiovascular and metabolic disease area. Here, with an emphasis on 'early clinical' development, we discuss the application of imaging in those areas, highlighting opportunities and challenges.
N17 Modifies mutant Huntingtin nuclear pathogenesis and severity of disease in HD BAC transgenic mice.
Neuron, 2015

The nucleus is a critical subcellular compartment for the pathogenesis of polyglutamine disorders, including Huntington's disease (HD). Recent studies suggest the first 17-amino-acid domain (N17) of mutant huntingtin (mHTT) mediates its nuclear exclusion in cultured cells. Here, we test whether N17 could be a molecular determinant of nuclear mHTT pathogenesis in vivo. BAC transgenic mice expressing mHTT lacking the N17 domain (BACHD-ΔN17) show dramatically accelerated mHTT pathology exclusively in the nucleus, which is associated with HD-like transcriptionopathy. Interestingly, BACHD-ΔN17 mice manifest more overt disease-like phenotypes than the original BACHD mice, including body weight loss, movement deficits, robust striatal neuron loss, and neuroinflammation. Mechanistically, N17 is necessary for nuclear exclusion of small mHTT fragments that are part of nuclear pathology in HD. Together, our study suggests that N17 modifies nuclear pathogenesis and disease severity in HD mice by regulating subcellular localization of known nuclear pathogenic mHTT species.
Morphometric analysis of astrocytes in brainstem respiratory regions.
The Journal of comparative neurology, 2018

Astrocytes, the most abundant and structurally complex glial cells of the central nervous system, are proposed to play an important role in modulating the activities of neuronal networks, including respiratory rhythm-generating circuits of the preBötzinger complex (preBötC) located in the ventrolateral medulla of the brainstem. However, structural properties of astrocytes residing within different brainstem regions are unknown. In this study astrocytes in the preBötC, an intermediate reticular formation (IRF) region with respiratory-related function, and a region of the nucleus tractus solitarius (NTS) in adult rats were reconstructed and their morphological features were compared. Detailed morphological analysis revealed that preBötC astrocytes are structurally more complex than those residing within the functionally distinct neighboring IRF region, or the NTS, located at the dorsal aspect of the medulla oblongata. Structural analyses of the brainstem microvasculature indicated no significant regional differences in vascular properties. We hypothesize that high morphological complexity of preBötC astrocytes reflects their functional role in providing structural/metabolic support and modulation of the key neuronal circuits essential for breathing, as well as constraints imposed by arrangements of associated neurons and/or other local structural features of the brainstem parenchyma.
Effects of dietary components on intestinal permeability in health and disease.
American journal of physiology. Gastrointestinal and liver physiology, 2020

Altered intestinal permeability plays a role in many pathological conditions. Intestinal permeability is a component of the intestinal barrier. This barrier is a dynamic interface between the body and the food and pathogens that enter the gastrointestinal tract. Therefore, dietary components can directly affect this interface, and many metabolites produced by the host enzymes or the gut microbiota can act as signaling molecules or exert direct effects on this barrier. Our aim was to examine the effects of diet components on the intestinal barrier in health and disease states. Herein, we conducted an in-depth PubMed search based on specific key words (diet, permeability, barrier, health, disease, and disorder), as well as cross references from those articles. The normal intestinal barrier consists of multiple components in the lumen, epithelial cell layer and the lamina propria. Diverse methods are available to measure intestinal permeability. We focus predominantly on human in vivo studies, and the literature is reviewed to identify dietary factors that decrease (e.g., emulsifiers, surfactants, and alcohol) or increase (e.g., fiber, short-chain fatty acids, glutamine, and vitamin D) barrier integrity. Effects of these dietary items in disease states, such as metabolic syndrome, liver disease, or colitis are documented as examples of barrier dysfunction in the multifactorial diseases. Effects of diet on intestinal barrier function are associated with precise mechanisms in some instances; further research of those mechanisms has potential to clarify the role of dietary interventions in treating diverse pathologic states.
Expression of P2X5 receptors in the mouse CNS.
Neuroscience, 2008

P2X receptors are ATP-gated cationic channels composed of seven known subunits (P2X1-7) which are involved in different functions in neural tissue. The present study investigates the P2X5 receptor expression pattern in the mouse CNS using immunohistochemistry and in situ hybridization histochemistry. The specificity of the immunostaining has been verified by pre-absorption, Western blot and in situ hybridization methods. Heavy P2X5 receptor immunostaining was observed in the mitral cells of the olfactory bulb; cerebral cortex; globus pallidum, anterior cortical amygdaloid nucleus, amygdalohippocampal area of subcortical telencephalon; anterior nuclei, anteroventral nucleus, ventrolateral nucleus of thalamus; supraoptic nucleus, ventromedial nucleus, arcuate nucleus of hypothalamus; substantia nigra of midbrain; pontine nuclei, mesencephalic trigeminal nucleus, motor trigeminal nucleus, ambiguous nucleus, inferior olive, hypoglossal nucleus, dorsal motor vagus nucleus, area postrema of hindbrain; Purkinje cells of cerebellum; and spinal cord. The identification of extensive P2X5 receptor immunoreactivity and mRNA distribution within the CNS of the mouse demonstrated here is consistent with a role for extracellular ATP acting as a fast neurotransmitter.
Novel therapeutics based on tau/microtubule dynamics: WO2008084483.
Expert opinion on therapeutic patents, 2009

The present patent deals with the generation of peptides derived from the activity-dependent peptide and tau mimetic to study its effect on microtubule stability, its ability to bind to tubulin and MAPs, as well as promoting cell survival.
Soft Polydimethylsiloxane-Supported Lipid Bilayers for Studying T Cell Interactions.
Biophysical journal, 2021

Much of what we know about the early stages of T cell activation has been obtained from studies of T cells interacting with glass-supported lipid bilayers that favor imaging but are orders of magnitude stiffer than typical cells. We developed a method for attaching lipid bilayers to polydimethylsiloxane polymer supports, producing "soft bilayers" with physiological levels of mechanical resistance (Young's modulus of 4 kPa). Comparisons of T cell behavior on soft and glass-supported bilayers revealed that whereas late stages of T cell activation are thought to be substrate-stiffness dependent, early calcium signaling was unaffected by substrate rigidity, implying that early steps in T cell receptor triggering are not mechanosensitive. The exclusion of large receptor-type phosphatases was observed on the soft bilayers, however, even though it is yet to be demonstrated at authentic cell-cell contacts. This work sets the stage for an imaging-based exploration of receptor signaling under conditions closely mimicking physiological cell-cell contact.
Advanced glycation end products (AGEs), protein aggregation and their cross talk: new insight in tumorigenesis.
Glycobiology, 2019

Protein glycation and protein aggregation are two distinct phenomena being observed in cancer cells as factors promoting cancer cell viability. Protein aggregation is an abnormal interaction between proteins caused as a result of structural changes in them after any mutation or environmental assault. Protein aggregation is usually associated with neurodegenerative diseases like Alzheimer's and Parkinson's, but of late, research findings have shown its association with the development of different cancers like lung, breast and ovarian cancer. On the contrary, protein glycation is a cascade of irreversible nonenzymatic reaction of reducing sugar with the amino group of the protein resulting in the modification of protein structure and formation of advanced glycation end products (AGEs). These AGEs are reported to obstruct the normal function of proteins. Lately, it has been reported that protein aggregation occurs as a result of AGEs. This aggregation of protein promotes the transformation of healthy cells to neoplasia leading to tumorigenesis. In this review, we underline the current knowledge of protein aggregation and glycation along with the cross talk between the two, which may eventually lead to the development of cancer.