rudyvdbrink/CitationDatabase huggingface dataset:
Systematic Analysis and Biomarker Study for Alzheimer's Disease.
Scientific reports, 2018

Revealing the relationship between dysfunctional genes in blood and brain tissues from patients with Alzheimer's Disease (AD) will help us to understand the pathology of this disease. In this study, we conducted the first such large systematic analysis to identify differentially expressed genes (DEGs) in blood samples from 245 AD cases, 143 mild cognitive impairment (MCI) cases, and 182 healthy control subjects, and then compare these with DEGs in brain samples. We evaluated our findings using two independent AD blood datasets and performed a gene-based genome-wide association study to identify potential novel risk genes. We identified 789 and 998 DEGs common to both blood and brain of AD and MCI subjects respectively, over 77% of which had the same regulation directions across tissues and disease status, including the known ABCA7, and the novel TYK2 and TCIRG1. A machine learning classification model containing NDUFA1, MRPL51, and RPL36AL, implicating mitochondrial and ribosomal function, was discovered which discriminated between AD patients and controls with 85.9% of area under the curve and 78.1% accuracy (sensitivity = 77.6%, specificity = 78.9%). Moreover, our findings strongly suggest that mitochondrial dysfunction, NF-κB signalling and iNOS signalling are important dysregulated pathways in AD pathogenesis.
Structure-function analysis of SAP97, a modular scaffolding protein that drives dendrite growth.
Molecular and cellular neurosciences, 2015

Activation of AMPA receptors assembled with the GluA1 subunit can promote dendrite growth in a manner that depends on its direct binding partner, SAP97. SAP97 is a modular scaffolding protein that has at least seven recognizable protein-protein interaction domains. Several complementary approaches were employed to show that the dendrite branching promoting action of full length SAP97 depends on ligand(s) that bind to the PDZ3 domain. Ligand(s) to PDZ1, PDZ2 and I3 domains also contribute to dendrite growth. The ability of PDZ3 ligand(s) to promote dendrite growth depends on localization at the plasma membrane along with GluA1 and SAP97. These results suggest that the assembly of a multi-protein complex at or near synapses is vital for the translation of AMPA-R activity into dendrite growth.
Pattern of acute induction of Homer1a gene is preserved after chronic treatment with first- and second-generation antipsychotics: effect of short-term drug discontinuation and comparison with Homer1a-interacting genes.
Journal of psychopharmacology (Oxford, England), 2011

Homer1a is a glutamate-related gene whose expression is induced by antipsychotics acutely (i.e. 90 min after treatment). Acute Homer1a expression is preserved after prolonged antipsychotic treatments, while the effects of short-term discontinuation after chronic antipsychotic treatment have not yet been assessed. Here, we studied early and long-term effects on gene expression by antipsychotics for Homer1a and other components of glutamatergic synapses. In the first paradigm, we evaluated Homer1a acute expression by single administration of antipsychotics (haloperidol 0.8 mg/kg, ziprasidone 10 and 4 mg/kg, clozapine 15 mg/kg). Haloperidol and ziprasidone induced Homer1a in the striatum. Induction by ziprasidone was dose-dependent. These results suggest that acute Homer1a expression correlates with dopaminergic affinity and motor side effects of antipsychotics. In the second paradigm, we studied antipsychotic-mediated long-term changes in Homer1a and glutamate-related genes. Rats were treated (21 days) with haloperidol 0.8 mg/kg, ziprasidone 4 mg/kg, or vehicle, and then sacrificed at 90 min (early time-point) or 24 h (delayed time-point) after last injection. Gene expression at these two time-points was compared. Homer1a preserved its pattern of expression at the early but not at the delayed time-point. Significant changes were also observed for PSD-95. The results suggest that Homer1a preserves its expression profile after chronic antipsychotics.
Why STAN might not be dead.
The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians, 2017

Recently, a meta-analysis, including 26 526 laboring vertex singletons at term, summarized all available level-1 data from six high-quality randomized clinical trials (RCTs) on the use of ST analysis (STAN) during labor as an adjunct to conventional intrapartum fetal heart rate monitoring. The meta-analysis showed that STAN did not improve perinatal outcomes or decrease cesarean deliveries. Nonetheless, there are still reasons to believe STAN may have a role in the future research on intrapartum fetal monitoring. Out of six trials included in the meta-analysis, two included all cephalic singletons in labor, and four enrolled only high-risk pregnant women. This combination of both low- and high-risk populations may have distorted the potential impact of STAN. The test for heterogeneity between both subgroups was found to be statistically significant, indicating that the effect of STAN was different in high-risk women compared to a combination of both low- and high-risk women. Furthermore, the classifications of the fetal heart rate patterns used in the included randomized trials were different. Last but not least, despite >26 000 women with singleton gestations were included in the meta-analysis, the evidence still suffers from a lack of power, especially for subgroup analyses. In summary, while the level-1 data so far indicate overall no perinatal benefit of adding STAN to conventional intrapartum fetal heart rate monitoring for the outcomes most of interest, several issues point to the fact that more research is needed before the STAN technology can be deemed of no value for fetal monitoring in labor.
Pomegranate juice and specific components inhibit cell and molecular processes critical for metastasis of breast cancer.
Breast cancer research and treatment, 2012

Breast cancer is the most common cancer and the second leading cause of cancer death and morbidity among women in the western world. Pomegranate juice (PJ) and three of its specific components have been shown to inhibit processes involved in prostate cancer metastasis. If this also proves to be true for breast cancer, these natural treatments will be promising agents against breast cancer that can serve as potentially effective and nontoxic alternatives or adjuncts to the use of conventional selective estrogen receptor modulators for breast cancer prevention and treatment. To test this possibility, we have used two breast cancer cell lines, MDA-MB-231 cells (ER(-)) and MCF7 (ER(+)), and the non-neoplastic cell line MCF10A. We show that, in addition to inhibiting growth of the breast cancer cells, PJ or a combination of its components luteolin (L) + ellagic acid (E) + punicic acid (P) increase cancer cell adhesion and decrease cancer cell migration but do not affect normal cells. These treatments also inhibit chemotaxis of the cancer cells to SDF1α, a chemokine that attracts breast cancer cells to the bone. We hypothesized that PJ and L + E + P stimulate expression of genes that increase adhesion and inhibit genes that stimulate cell migration and inhibit chemotaxis to SDF1α. Using qPCR, we confirmed these proposed effects on gene expression and in addition we found that a gene important in epithelial-to-meshenchymal transitions is decreased. We also found that pro-inflammatory cytokines/chemokines are significantly reduced by these treatments, thereby having the potential to decrease inflammation and its impact on cancer progression. Discovery that PJ and L + E + P are inhibitory of metastatic processes in breast cancer cells in addition to prostate cancer cells indicate that they are potentially a very effective treatment to prevent cancer progression in general.
Clinically useful brain imaging for neuropsychiatry: How can we get there?
Depression and anxiety, 2017

Despite decades of research, visions of transforming neuropsychiatry through the development of brain imaging-based "growth charts" or "lab tests" have remained out of reach. In recent years, there is renewed enthusiasm about the prospect of achieving clinically useful tools capable of aiding the diagnosis and management of neuropsychiatric disorders. The present work explores the basis for this enthusiasm. We assert that there is no single advance that currently has the potential to drive the field of clinical brain imaging forward. Instead, there has been a constellation of advances that, if combined, could lead to the identification of objective brain imaging-based markers of illness. In particular, we focus on advances that are helping to (1) elucidate the research agenda for biological psychiatry (e.g., neuroscience focus, precision medicine), (2) shift research models for clinical brain imaging (e.g., big data exploration, standardization), (3) break down research silos (e.g., open science, calls for reproducibility and transparency), and (4) improve imaging technologies and methods. Although an arduous road remains ahead, these advances are repositioning the brain imaging community for long-term success.
Inflammatory, apoptotic, and survival gene signaling in Alzheimer's disease. A review on the bioactivity of neuroprotectin D1 and apoptosis.
Molecular neurobiology, 2010

Aging is associated with an enhanced susceptibility to brain dysfunction, loss of memory, and cognitive decline and significantly influences the quality of life for the affected individual. Recent molecular-genetic approaches have provided powerful insights into common age-related diseases that are both progressive and multifactorial, such as Alzheimer's disease (AD), and in vitro in AD models. These investigations have uncovered consistent deficits in brain gene signaling mechanisms and neurotrophic substances known to contribute to normal brain function. Inflammatory signaling pathways involving up-regulation of cytosolic phospholipase A(2) and the arachidonic acid cycle, the depletion of the brain-essential fatty acid docosahexaenoic acid (DHA) and DHA-derived neuroprotectin D1, and changes in the expression of key proapoptotic and antiapoptotic members of the Bcl-2 gene family are thought to be major contributors to pathogenic processes in degenerating brain tissue. This review will focus on the roles of stress genes, apoptosis-related genes, and inflammation in the molecular genetics of AD with emphasis on the interactive nature of inflammatory, neurotrophic, and apoptotic signaling and will highlight areas of rapid progress in the characterization of action of DHA and neuroprotectin D1 and address important research challenges. We also attempt to integrate these molecular, genetic, and neurochemical changes with cellular pathways involved in brain aging to formulate an integrated understanding of multifactorial age-related neurologic disease and pharmacotherapeutic strategies that may be useful in the restoration of homeostatic brain function.
Categorial compositionality II: universal constructions and a general theory of (quasi-)systematicity in human cognition.
PLoS computational biology, 2011

A complete theory of cognitive architecture (i.e., the basic processes and modes of composition that together constitute cognitive behaviour) must explain the systematicity property--why our cognitive capacities are organized into particular groups of capacities, rather than some other, arbitrary collection. The classical account supposes: (1) syntactically compositional representations; and (2) processes that are sensitive to--compatible with--their structure. Classical compositionality, however, does not explain why these two components must be compatible; they are only compatible by the ad hoc assumption (convention) of employing the same mode of (concatenative) compositionality (e.g., prefix/postfix, where a relation symbol is always prepended/appended to the symbols for the related entities). Architectures employing mixed modes do not support systematicity. Recently, we proposed an alternative explanation without ad hoc assumptions, using category theory. Here, we extend our explanation to domains that are quasi-systematic (e.g., aspects of most languages), where the domain includes some but not all possible combinations of constituents. The central category-theoretic construct is an adjunction involving pullbacks, where the primary focus is on the relationship between processes modelled as functors, rather than the representations. A functor is a structure-preserving map (or construction, for our purposes). An adjunction guarantees that the only pairings of functors are the systematic ones. Thus, (quasi-)systematicity is a necessary consequence of a categorial cognitive architecture whose basic processes are functors that participate in adjunctions.
Resveratrol corrects aberrant splicing of 
Neural regeneration research, 2020

Myotonic dystrophy type 1 (DM1) is a spliceopathy related to the mis-splicing of several genes caused by sequestration of nuclear transcriptional RNA-binding factors from non-coding CUG repeats of DMPK pre-mRNAs. Dysregulation of ryanodine receptor 1 (RYR1), sarcoplasmatic/endoplasmatic Ca
A Subpopulation of Striatal Neurons Mediates Levodopa-Induced Dyskinesia.
Neuron, 2018

Parkinson's disease is characterized by the progressive loss of midbrain dopamine neurons. Dopamine replacement therapy with levodopa alleviates parkinsonian motor symptoms but is complicated by the development of involuntary movements, termed levodopa-induced dyskinesia (LID). Aberrant activity in the striatum has been hypothesized to cause LID. Here, to establish a direct link between striatal activity and dyskinesia, we combine optogenetics and a method to manipulate dyskinesia-associated neurons, targeted recombination in active populations (TRAP). We find that TRAPed cells are a stable subset of sensorimotor striatal neurons, predominantly from the direct pathway, and that reactivation of TRAPed striatal neurons causes dyskinesia in the absence of levodopa. Inhibition of TRAPed cells, but not a nonspecific subset of direct pathway neurons, ameliorates LID. These results establish that a distinct subset of striatal neurons is causally involved in LID and indicate that successful therapeutic strategies for treating LID may require targeting functionally selective neuronal subtypes.
Common Data Elements for Unruptured Intracranial Aneurysms and Subarachnoid Hemorrhage Clinical Research: A National Institute for Neurological Disorders and Stroke and National Library of Medicine Project.
Neurocritical care, 2019

The goal for this project was to develop a comprehensive set of common data elements (CDEs), data definitions, case report forms and guidelines for use in unruptured intracranial aneurysm (UIA) and subarachnoid hemorrhage (SAH) clinical research, as part of a new joint effort between the National Institute of Neurological Disorders and Stroke (NINDS) and the National Library of Medicine of the US National Institutes of Health. These UIA and SAH CDEs will join several other neurological disease-specific CDEs that have already been developed and are available for use by research investigators.
Object parsing in the left lateral occipitotemporal cortex: Whole shape, part shape, and graspability.
Neuropsychologia, 2020

Small and manipulable objects (tools) preferentially evoke a network of brain regions relative to other objects, including the lateral occipitotemporal cortex (LOTC), which is assumed to process tool shape information. Given the correlation between various object properties, the exact type of information being represented in the LOTC remains debated. In three fMRI experiments, we examined the effects of multiple levels of shape (whole vs. object parts) and motor-related (grasping; manipulation) information. Combining representational similarity analysis and commonality analysis allowed us to partition the unique and shared effects of correlated dimensions. We found that grasping manner (for pickup), not the overall object shape or manner of manipulation, uniquely explained the LOTC neural activity pattern (Experiments 1 and 2). Experiment 3 tested tools composed of two parts to understand better how grasping manner was computed from object visual inputs. Support vector machine analysis revealed that the LOTC activity could decode different shapes of the tools' handle parts but not the tools' head parts. Together, these results suggest that the LOTC parses tool shapes by how it maps onto grasping programs; such parsing is not fully based on the whole-object shape but rather an interaction between the whole (where to grasp) and its parts (distinguishing the shape for the grasping part for specific grasping manners).
The SCN1A mutation database: updating information and analysis of the relationships among genotype, functional alteration, and phenotype.
Human mutation, 2015

Mutations in the SCN1A gene have been identified in epilepsy patients with widely variable phenotypes and modes of inheritance and in asymptomatic carriers. This raises challenges in evaluating the pathogenicity of SCN1A mutations. We systematically reviewed all SCN1A mutations and established a database containing information on functional alterations. In total, 1,257 mutations have been identified, of which 81.8% were not recurrent. There was a negative correlation between phenotype severity and missense mutation frequency. Further analyses suggested close relationships among genotype, functional alteration, and phenotype. Missense mutations located in different sodium channel regions were associated with distinct functional changes. Missense mutations in the pore region were characterized by the complete loss of function, similar to haploinsufficiency. Mutations with severe phenotypes were more frequently located in the pore region, suggesting that functional alterations are critical in evaluating pathogenicity and can be applied to patient management. A negative correlation was found between phenotype severity and familial incidence, and incomplete penetrance was associated with missense and splice site mutations, but not truncations or genomic rearrangements, suggesting clinical genetic counseling applications. Mosaic mutations with a load of 12.5-25.0% were potentially pathogenic with low penetrance, suggesting the need for future studies on less pathogenic genomic variations.
RNA metabolism: putting the brake on the UPR.
EMBO reports, 2015

The unfolded protein response (UPR) is a major signaling cascade that determines cell fate under conditions of endoplasmic reticulum (ER) stress. The kinetics and amplitude of UPR responses are tightly controlled by several feedback loops and the expression of positive and negative regulators. In this issue of EMBO Reports, the Wilkinson lab uncovers a novel function of nonsense-mediated RNA decay (NMD) in fine-tuning the UPR. NMD is an mRNA quality control mechanism known to destabilize aberrant mRNAs that contain premature termination codons. In this work, NMD was shown to determine the threshold of stress necessary to activate the UPR, in addition to adjusting the amplitude of downstream responses and the termination phase. These effects were mapped to the control of the mRNA stability of IRE1, a major ER stress transducer. This study highlights the dynamic crosstalk between mRNA metabolism and the proteostasis network demonstrating the physiological relevance of normal mRNA regulation by the NMD pathway.
An insight of sleep disorders in Africa.
eNeurologicalSci, 2016

Sleep is a recurrent physiologic and fundamental process in every human being, regardless of ethnicity, gender, birthplace, or occupation; however, the features of sleep are swayed by genetic background and environmental influences. All these factors have an intricate relationship, and arise from a complex and assorted genetic repertoire in the alleles that promote a higher genetic variation in human populations. Sleep disorders have become an uprising public health problem in the modern society; in addition, the correlation between sleep disorders and the development of late chronic diseases has been extensively studied, finding an important causality between them. Therefore, an adequate evaluation of the current situation in a developing continent such as Africa is essential to develop satisfactory health policies. In this review, we will reprise several aspects that influence the sleep-wake cycle in individuals with African heritage (including African Americans and sub-Saharan Africans), such as genetic background, HIV infection, tropical diseases, immunological markers, cultural aspects, and place them into Africa's context in order to have a better comprehension of its situation.
Chronic opioid induced constipation in patients with nonmalignant pain: challenges and opportunities.
Therapeutic advances in gastroenterology, 2015

With the recent introduction and approval of medications directed at the treatment of opioid induced constipation (OIC) in patients with nonmalignant pain, there is increased interest and understanding of the unmet need and opportunities to enhance patient management. The high incidence of OIC is associated with rapid increase of narcotic analgesic prescriptions for nonmalignant chronic pain. This review addresses briefly the mechanisms of action of opioids that lead to OIC, the differential tolerance of gastrointestinal organs to the effects of opioids, the size and scope of the problem, the definition and outcome measures for OIC, current differential diagnosis and management algorithms, and the pharmacology and efficacy of treatments for OIC in patients with nonmalignant pain.
Presynaptic CLC-3 determines quantal size of inhibitory transmission in the hippocampus.
Nature neuroscience, 2011

The absence of the chloride channel CLC-3 in Clcn3(-/-) mice results in hippocampal degeneration with a distinct temporal-spatial sequence that resembles neuronal loss in temporal lobe epilepsy. We examined how the loss of CLC-3 might affect GABAergic synaptic transmission in the hippocampus. An electrophysiological study of synaptic function in hippocampal slices taken from Clcn3(-/-) mice before the onset of neurodegeneration revealed a substantial decrease in the amplitude and frequency of miniature inhibitory postsynaptic currents compared with those in wild-type slices. We found that CLC-3 colocalized with the vesicular GABA transporter VGAT in the CA1 region of the hippocampus. Acidification of inhibitory synaptic vesicles induced by Cl(-) showed a marked dependence on CLC-3 expression. The decrease in inhibitory transmission in Clcn3(-/-) mice suggests that the neurotransmitter loading of synaptic vesicles was reduced, which we attribute to defective vesicular acidification. Our observations extend the role of Cl(-) in inhibitory transmission from that of a postsynaptic permeant species to a presynaptic regulatory element.