rudyvdbrink/CitationDatabase huggingface dataset:
Spatio-temporal models of mental processes from fMRI.
NeuroImage, 2011

Understanding the highly complex, spatially distributed and temporally organized phenomena entailed by mental processes using functional MRI is an important research problem in cognitive and clinical neuroscience. Conventional analysis methods focus on the spatial dimension of the data discarding the information about brain function contained in the temporal dimension. This paper presents a fully spatio-temporal multivariate analysis method using a state-space model (SSM) for brain function that yields not only spatial maps of activity but also its temporal structure along with spatially varying estimates of the hemodynamic response. Efficient algorithms for estimating the parameters along with quantitative validations are given. A novel low-dimensional feature-space for representing the data, based on a formal definition of functional similarity, is derived. Quantitative validation of the model and the estimation algorithms is provided with a simulation study. Using a real fMRI study for mental arithmetic, the ability of this neurophysiologically inspired model to represent the spatio-temporal information corresponding to mental processes is demonstrated. Moreover, by comparing the models across multiple subjects, natural patterns in mental processes organized according to different mental abilities are revealed.
Effect of social interactions on hippocampal protein expression in animal dominant and submissive model of behavioral disorders.
Proteomics. Clinical applications, 2017

Psychiatric conditions, in many cases, arise from social interactions necessary for optimal mental functioning. Dominance and submissiveness are two opposite poles of behavior, stemming from processes of social interactions between members inside one group or species. Extreme dominance and submissiveness expressions in humans is accompanied by mental impairments, including mania and depression. Here, taking advantage of animals bred selectively for traits of dominance and submissiveness, we assess protein expression profiles in dominant and submissive mice in the context of social interaction.
Neurodevelopmental mechanisms of schizophrenia: understanding disturbed postnatal brain maturation through neuregulin-1-ErbB4 and DISC1.
Trends in neurosciences, 2009

Schizophrenia (SZ) is primarily an adult psychiatric disorder in which disturbances caused by susceptibility genes and environmental insults during early neurodevelopment initiate neurophysiological changes over a long time course, culminating in the onset of full-blown disease nearly two decades later. Aberrant postnatal brain maturation is an essential mechanism underlying the disease. Currently, symptoms of SZ are treated with anti-psychotic medications that have variable efficacy and severe side effects. There has been much interest in the prodromal phase and the possibility of preventing SZ by interfering with the aberrant postnatal brain maturation associated with this disorder. Thus, it is crucial to understand the mechanisms that underlie the long-term progression to full disease manifestation to identify the best targets and approaches towards this goal. We believe that studies of certain SZ genetic susceptibility factors with neurodevelopmental implications will be key tools in this task. Accumulating evidence suggests that neuregulin-1 (NRG1) and disrupted-in-schizophrenia-1 (DISC1) are probably functionally convergent and play key roles in brain development. We provide an update on the role of these emerging concepts in understanding the complex time course of SZ from early neurodevelopmental disturbances to later onset and suggest ways of testing these in the future.
Oxytocin-augmented social cognitive skills training in schizophrenia.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2014

Impairments in social cognition are common in schizophrenia and predict poor functional outcome. The purpose of this proof-of-concept randomized, parallel group clinical trial was to assess whether intranasal oxytocin (OT), given before social cognitive training, enhances learning of social cognitive skills. Twenty seven male outpatients with schizophrenia participated in a 6-week (12 session) training on social cognitive skills. Training focused on three domains: facial affect recognition, social perception, and empathy. Subjects were randomly assigned (double blind) to receive either intranasal OTor placebo 30 min before each session. Participants did not receive OT between sessions or on the day of assessments. We evaluated scores on social-cognition measures, as well as clinical symptoms and neurocognition, at baseline, 1 week following the final training session, and 1 month later. Our prespecified primary outcome measure was a social-cognition composite score comprised of five individual measures. There were main effects of time (indicating improvement across the combined-treatment groups) on the social-cognition composite score at both 1 week and 1 month following completion of training. Subjects receiving OT demonstrated significantly greater improvements in empathic accuracy than those receiving placebo at both posttreatment and 1 month follow up. There were no OT-related effects for the other social cognitive tests, clinical symptoms, or neurocognition. This study provides initial support for the idea that OT enhances the effectiveness of training when administered shortly before social cognitive training sessions. The effects were most pronounced on empathic accuracy, a high-level social cognitive process that is not easily improved in current social cognitive remediation programs.
Mapping brain metabolic connectivity in awake rats with μPET and optogenetic stimulation.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013

Positron emission tomography (PET) with [(18)F]2-fluoro-2-deoxy-D-glucose was used to measure changes in regional brain glucose metabolism (BGluM) in response to optogenetic stimulation (using the excitatory channelrhodopsin-2) of the nucleus accumbens (NAc) in awake rats. We demonstrated not only increases in BGluM that correlated with c-Fos expression in the region of stimulation, but also BGluM increases in the ipsilateral striatum, periaqueductal gray, and somatosensory cortex, and in contralateral amygdala, ventral pallidum, globus pallidus, and hippocampus, as well as decreases in BGluM in regions of the default mode network (retrosplenial cortex and cingulate gyrus) and secondary motor cortex. Additional exploration of c-Fos expression in regions found to be activated by PET results found corroborating evidence, with increased c-Fos expression in the ipsilateral somatosensory cortex, contralateral amygdala and globus pallidus, and bilateral periaqueductal gray. These findings are consistent with optogenetic excitation of the area of stimulation (NAc), as well as with stimulatory and inhibitory effects on downstream regions. They also confirm the utility of PET imaging to monitor connectivity in the awake rodent brain.
Lupus autoantibodies act as positive allosteric modulators at GluN2A-containing NMDA receptors and impair spatial memory.
Nature communications, 2020

Patients with Systemic lupus erythematosus (SLE) experience various peripheral and central nervous system manifestations including spatial memory impairment. A subset of autoantibodies (DNRAbs) cross-react with the GluN2A and GluN2B subunits of the NMDA receptor (NMDAR). We find that these DNRAbs act as positive allosteric modulators on NMDARs with GluN2A-containing NMDARs, even those containing a single GluN2A subunit, exhibiting a much greater sensitivity to DNRAbs than those with exclusively GluN2B. Accordingly, GluN2A-specific antagonists provide greater protection from DNRAb-mediated neuronal cell death than GluN2B antagonists. Using transgenic mice to perturb expression of either GluN2A or GluN2B in vivo, we find that DNRAb-mediated disruption of spatial memory characterized by early neuronal cell death and subsequent microglia-dependent pathologies requires GluN2A-containing NMDARs. Our results indicate that GluN2A-specific antagonists or negative allosteric modulators are strong candidates to treat SLE patients with nervous system dysfunction.
Genome-Wide Meta-Analyses of FTND and TTFC Phenotypes.
Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco, 2020

FTND (Fagerstrӧm test for nicotine dependence) and TTFC (time to smoke first cigarette in the morning) are common measures of nicotine dependence (ND). However, genome-wide meta-analysis for these phenotypes has not been reported.
Isolation of Adult Human Astrocyte Populations from Fresh-frozen Cortex using Fluorescence-Activated Nuclei Sorting.
Journal of visualized experiments : JoVE, 2021

The complexity of human astrocytes remains poorly defined in primary human tissue, requiring better tools for their isolation and molecular characterization. Fluorescence-activated nuclei sorting (FANS) can be used to successfully isolate and study human neuronal nuclei (NeuN+) populations from frozen archival tissue, thereby avoiding problems associated with handling fresh tissue. However, efforts to similarly isolate astroglia from the non-neuronal (NeuN-) element are lacking. A recently developed and validated immunotagging strategy uses three transcription factor antibodies to simultaneously isolate enriched neuronal (NeuN+), astrocyte (paired box protein 6 (PAX6)+NeuN-), and oligodendrocyte progenitor (OLIG2+NeuN-) nuclei populations from non-diseased, fresh (unfixed) snap-frozen postmortem human temporal neocortex tissue. This technique was shown to be useful for the characterization of cell type-specific transcriptome alterations in primary pathological epilepsy neocortex. Transcriptomic analyses confirmed that PAX6+NeuN- sorted populations are robustly enriched for pan-astrocyte markers and capture astrocytes in both resting and reactive conditions. This paper describes the FANS methodology for the isolation of astrocyte-enriched nuclei populations from fresh-frozen human cortex, including tissue dissociation into single-nucleus (sn) suspension; immunotagging of nuclei with anti-NeuN and anti-PAX6 fluorescently conjugated antibodies; FANS gating strategies and quality control metrics for optimizing sensitivity and specificity during sorting and for confirming astrocyte enrichment; and recommended procurement for downstream transcriptome and chromatin accessibility sequencing at bulk or sn resolution. This protocol is applicable for non-necrotic, fresh-frozen, human cortical specimens with various pathologies and recommended postmortem tissue collection within 24 h.
Metabolomic Profiling of Bile Acids in Clinical and Experimental Samples of Alzheimer's Disease.
Metabolites, 2017

Certain endogenous bile acids have been proposed as potential therapies for ameliorating Alzheimer's disease (AD) but their role, if any, in the pathophysiology of this disease is not currently known. Given recent evidence of bile acids having protective and anti-inflammatory effects on the brain, it is important to establish how AD affects levels of endogenous bile acids. Using LC-MS/MS, this study profiled 22 bile acids in brain extracts and blood plasma from AD patients (n = 10) and age-matched control subjects (n = 10). In addition, we also profiled brain/plasma samples from APP/PS1 and WT mice (aged 6 and 12 months). In human plasma, we detected significantly lower cholic acid (CA, p = 0.03) in AD patients than age-matched control subjects. In APP/PS1 mouse plasma we detected higher CA (p = 0.05, 6 months) and lower hyodeoxycholic acid (p = 0.04, 12 months) than WT. In human brain with AD pathology (Braak stages V-VI) taurocholic acid (TCA) were significantly lower (p = 0.01) than age-matched control subjects. In APP/PS1 mice we detected higher brain lithocholic acid (p = 0.05) and lower tauromuricholic acid (TMCA; p = 0.05, 6 months). TMCA was also decreased (p = 0.002) in 12-month-old APP/PS1 mice along with 5 other acids: CA (p = 0.02), β-muricholic acid (p = 0.02), Ω-muricholic acid (p = 0.05), TCA (p = 0.04), and tauroursodeoxycholic acid (p = 0.02). The levels of bile acids are clearly disturbed during the development of AD pathology and, since some bile acids are being proposed as potential AD therapeutics, we demonstrate a method that can be used to support work to advance bile acid therapeutics.
GPR55 controls functional differentiation of self-renewing epithelial progenitors for salivation.
JCI insight, 2019

GPR55, a lipid-sensing receptor, is implicated in cell cycle control, malignant cell mobilization, and tissue invasion in cancer. However, a physiological role for GPR55 is virtually unknown for any tissue type. Here, we localize GPR55 to self-renewing ductal epithelial cells and their terminally differentiated progeny in both human and mouse salivary glands. Moreover, we find GPR55 expression downregulated in salivary gland mucoepidermoid carcinomas and GPR55 reinstatement by antitumor irradiation, suggesting that GPR55 controls renegade proliferation. Indeed, GPR55 antagonism increases cell proliferation and function determination in quasiphysiological systems. In addition, Gpr55-/- mice present ~50% enlarged submandibular glands with many more granulated ducts, as well as disordered endoplasmic reticuli and with glycoprotein content. Next, we hypothesized that GPR55 could also modulate salivation and glycoprotein content by entraining differentiated excretory progeny. Accordingly, GPR55 activation facilitated glycoprotein release by itself, inducing low-amplitude Ca2+ oscillations, as well as enhancing acetylcholine-induced Ca2+ responses. Topical application of GPR55 agonists, which are ineffective in Gpr55-/- mice, into adult rodent submandibular glands increased salivation and saliva glycoprotein content. Overall, we propose that GPR55 signaling in epithelial cells ensures both the life-long renewal of ductal cells and the continuous availability of saliva and glycoproteins for oral health and food intake.
Object size determines the spatial spread of visual time.
Proceedings. Biological sciences, 2016

A key question for temporal processing research is how the nervous system extracts event duration, despite a notable lack of neural structures dedicated to duration encoding. This is in stark contrast with the orderly arrangement of neurons tasked with spatial processing. In this study, we examine the linkage between the spatial and temporal domains. We use sensory adaptation techniques to generate after-effects where perceived duration is either compressed or expanded in the opposite direction to the adapting stimulus' duration. Our results indicate that these after-effects are broadly tuned, extending over an area approximately five times the size of the stimulus. This region is directly related to the size of the adapting stimulus-the larger the adapting stimulus the greater the spatial spread of the after-effect. We construct a simple model to test predictions based on overlapping adapted versus non-adapted neuronal populations and show that our effects cannot be explained by any single, fixed-scale neural filtering. Rather, our effects are best explained by a self-scaled mechanism underpinned by duration selective neurons that also pool spatial information across earlier stages of visual processing.
Knowledge and Attitude Regarding Telemedicine Among Doctors in Karachi.
Cureus, 2020

Background Telemedicine is an affordable use of information and communication technology (ICT) to enable long-distance patient care and health care services. While the developed world continues to take advantage of this technology, its concept remains new to Pakistan. This study aims to assess the knowledge and perceptions regarding telemedicine among health care professionals in Karachi, Pakistan. Methods  This cross-sectional study was carried out among doctors employed in the public health sector in Karachi from June 2018 to August 2018. Data were collected using a self-designed well-structured questionnaire using a five-point Likert scale, built after an extensive literature review. Statistical analysis was carried out using SPSS version 22. Categorical data were reported as frequencies and percentages. Results A total of 224 doctors, working in the Department of Internal Medicine (27.6%), Pediatrics (9.8%), Cardiology (6.6%), Gynecology (5.35%), Neurology (5.8%), and other specialties (44.6%), participated in the study. A total of 80.7 % of the doctors were aware of the definition of telemedicine. A total of 28.1% of them believed telemedicine to be effective in providing faster medical care while 23.2% thought of it as a means of reducing the white coat syndrome. A total of 42.9% believed that telemedicine disrupts the doctor-patient relationship and causes a breach of patient privacy. A total of 34.8% of the doctors favored the idea of introducing national standards for practicing telemedicine while 33.5% of doctors also agreed that providing a legal explanation of telemedicine to patients was of paramount importance. Poverty and lack of education (90.6%) was thought to be the biggest barrier to the practice of telemedicine in the developing world. Conclusions The knowledge regarding telemedicine among doctors in Karachi was found to be average. However, the perceptions about and attitude towards the introduction and implementation of this new technology were welcomed by the majority of participants with an emphasis on increasing awareness. Conferences and workshops are needed to increase knowledge about telemedicine in Pakistan.
Cellular and circuit mechanisms of olfactory associative learning in 
Journal of neurogenetics, 2020

Recent years have witnessed significant progress in understanding how memories are encoded, from the molecular to the cellular and the circuit/systems levels. With a good compromise between brain complexity and behavioral sophistication, the fruit fly
Cathepsin D in Podocytes Is Important in the Pathogenesis of Proteinuria and CKD.
Journal of the American Society of Nephrology : JASN, 2016

Studies have revealed many analogies between podocytes and neurons, and these analogies may be key to elucidating the pathogenesis of podocyte injury. Cathepsin D (CD) is a representative aspartic proteinase in lysosomes. Central nervous system neurons in CD-deficient mice exhibit a form of lysosomal storage disease with a phenotype resembling neuronal ceroid lipofuscinoses. In the kidney, the role of CD in podocytes has not been fully explored. Herein, we generated podocyte-specific CD-knockout mice that developed proteinuria at 5 months of age and ESRD by 20-22 months of age. Immunohistochemical analysis of these mice showed apoptotic podocyte death followed by proteinuria and glomerulosclerosis with aging. Using electron microscopy, we identified, in podocytes, granular osmiophilic deposits (GRODs), autophagosome/autolysosome-like bodies, and fingerprint profiles, typical hallmarks of CD-deficient neurons. CD deficiency in podocytes also led to the cessation of autolysosomal degradation and accumulation of proteins indicative of autophagy impairment and the mitochondrial ATP synthase subunit c accumulation in the GRODs, again similar to changes reported in CD-deficient neurons. Furthermore, both podocin and nephrin, two essential components of the slit diaphragm, translocated to Rab7- and lysosome-associated membrane glycoprotein 1-positive amphisomes/autolysosomes that accumulated in podocyte cell bodies in podocyte-specific CD-knockout mice. We hypothesize that defective lysosomal activity resulting in foot process effacement caused this accumulation of podocin and nephrin. Overall, our results suggest that loss of CD in podocytes causes autophagy impairment, triggering the accumulation of toxic subunit c-positive lipofuscins as well as slit diaphragm proteins followed by apoptotic cell death.
Accumulated quiescent neural stem cells in adult hippocampus of the mouse model for the MECP2 duplication syndrome.
Scientific reports, 2017

Duplications of Methyl CpG binding protein 2 (MECP2) -containing segments lead to the MECP2 duplication syndrome, in which severe autistic symptoms were identified. Whether adult neurogenesis may play a role in pathogenesis of autism and the role of MECP2 on state determination of adult neural stem cells (NSCs) remain largely unclear. Using a MECP2 transgenic (TG) mouse model for the MECP2 duplication syndrome, we found that adult hippocampal quiescent NSCs were significantly accumulated in TG mice comparing to wild type (WT) mice, the neural progenitor cells (NPCs) were reduced and the neuroblasts were increased in adult hippocampi of MECP2 TG mice. Interestingly, we found that parvalbumin (PV) positive interneurons were significantly decreased in MECP2 TG mice, which were critical for determining fates of adult hippocampal NSCs between the quiescence and activation. In summary, we found that MeCP2 plays a critical role in regulating fate determination of adult NSCs. These evidences further suggest that abnormal development of NSCs may play a role in the pathogenesis of the MECP2 duplication syndrome.
The cone-dominant retina and the inner ear of zebrafish express the ortholog of CLRN1, the causative gene of human Usher syndrome type 3A.
Gene expression patterns : GEP, 2013

Clarin-1 (CLRN1) is the causative gene in Usher syndrome type 3A, an autosomal recessive disorder characterized by progressive vision and hearing loss. CLRN1 encodes Clarin-1, a glycoprotein with homology to the tetraspanin family of proteins. Previous cell culture studies suggest that Clarin-1 localizes to the plasma membrane and interacts with the cytoskeleton. Mouse models demonstrate a role for the protein in mechanosensory hair bundle integrity, but the function of Clarin-1 in hearing remains unclear. Even less is known of its role in vision, because the Clrn1 knockout mouse does not exhibit a retinal phenotype and expression studies in murine retinas have provided conflicting results. Here, we describe cloning and expression analysis of the zebrafish clrn1 gene, and report protein localization of Clarin-1 in auditory and visual cells from embryonic through adult stages. We detect clrn1 transcripts as early as 24h post-fertilization, and expression is maintained through adulthood. In situ hybridization experiments show clrn1 transcripts enriched in mechanosensory hair cells and supporting cells of the inner ear and lateral line organ, photoreceptors, and cells of the inner retina. In mechanosensory hair cells, Clarin-1 is polarized to the apical cell body and the synapses. In the retina, Clarin-1 localizes to lateral cell contacts between photoreceptors and is associated with the outer limiting membrane and subapical processes emanating from Müller glial cells. We also find Clarin-1 protein in the outer plexiform, inner nuclear and ganglion cell layers of the retina. Given the importance of Clarin-1 function in the human retina, it is imperative to find an animal model with a comparable requirement. Our data provide a foundation for exploring the role of Clarin-1 in retinal cell function and survival in a diurnal, cone-dominant species.
Neurogenetics: sex and the female brain.
Current biology : CB, 2014

Male flies put on a multimedia show during courtship involving dance, song, perfume and even vibrations; if a female likes it, she pauses to let him know. Recent studies shed new light on how development and experience contribute to neural mechanisms of female sexual receptivity.
De novo and secondary anaplastic meningiomas: a study of clinical and histomolecular prognostic factors.
Neuro-oncology, 2018

Following recent studies underlining the differences between de novo and secondary anaplastic meningiomas and the prognostic value of telomerase reverse transcriptase (TERT) promoter mutation, we decided to conduct a multicenter retrospective study to address these questions and determine specific prognostic factors in each of these 2 anaplastic meningioma subgroups.