Biology subjects

Lee, B.

Publications and source records attributed to Lee, B..

At least 19 recordsLinked to original sources

bioRxiv2018

Unraveling the polygenic architecture of complex traits using blood eQTL meta-analysis

SummaryWhile many disease-associated variants have been identified through genome-wide association studies, their downstream molecular consequences remain unclear.\n\nTo identify these effects, we performed cis- and trans-expression quantitative trait locus (eQTL) analysis in blood from 31,684 individuals through the eQTLGen Consortium.\n\nWe observed that cis-eQTLs can be detected for 88% of the studied genes, but that they have a different genetic architecture compared to disease-associated variants, limiting our ability to use cis-eQTLs to pinpoint causal genes within susceptibility loci.\n\nIn contrast, trans-eQTLs (detected for 37% of 10,317 studied trait-associated variants) were more informative. Multiple unlinked variants, associated to the same complex trait, often converged on trans-genes that are known to play central roles in disease etiology.\n\nWe observed the same when ascertaining the effect of polygenic scores calculated for 1,263 genome-wide association study (GWAS) traits. Expression levels of 13% of the studied genes correlated with polygenic scores, and many resulting genes are known to drive these traits.

genomics↗

bioRxiv2018

Caries Prevalence and Experience in Individuals with Osteogenesis Imperfecta

ObjectiveDentinogenesis Imperfecta (DI) forms a group of dental abnormalities frequently found associated with Osteogenesis Imperfecta (OI), a hereditary disease characterized by bone fragility. The objectives of this study was to quantify the caries experience among different OI-types and quantify how these values change due to DI. MethodsTo determine which clinical characteristics were associated with increased CPE in patients with OI, the adjusted DFT scores were used to account for frequent hypodontia, impacted teeth and retained teeth in OI population. ResultsThe stepwise regression analysis while controlling for all other variables demonstrated the presence of DI (OR 2.43; CI 1.37 to 4.32; p=0.002) as the significant independent predictor of CPE in the final model. ConclusionThis study found no evidence that CPE of OI subjects differs between the types of OI. The presence of DI when controlled for other factors was found to be the significant predictor of CPE.

epidemiology↗

bioRxiv2018

Oral Health-Related Quality of Life in Children and Adolescents with Osteogenesis Imperfecta: cross-sectional study

BackgroundOsteogenesis imperfecta (OI) affects dental and craniofacial development and may therefore impair Oral Health-Related Quality of Life (OHRQoL). However, little is known about OHRQoL in children and adolescents with OI. The aim of this study was to explore the influence of OI severity on oral health-related quality of life in children and adolescents.\n\nMethodsChildren and adolescents aged 8-14 years were recruited in the context of a multicenter longitudinal study (Brittle Bone Disease Consortium) that enrolls individuals with OI in 10 centers across North America. OHRQoL was assessed using the Child Perceptions Questionnaire (CPQ) versions for 8 to 10-year-olds (CPQ8-10) and for 11 to 14-year-olds (CPQ11-14).\n\nResultsA total of 138 children and adolescents (62% girls) diagnosed with OI types I, III, IV, V and VI (n=65, 30, 37, 4 and 2, respectively) participated in the study. CPQ8-10 scores were similar between OI types in children aged 8 to 10 years. In the 11 to 14-year-old group, CPQ11-14-scores were significantly higher (i.e. worse) for OI types III (24.7 [SD 12.5]) and IV (23.1 [SD 14.8]) than for OI type I (16.5 [SD 12.8]) (P<0.05). The difference between OI types was due to the association between OI types and the functional limitations domain, as OI types III and IV were associated with significantly higher grade of functional limitations compared to OI type I.\n\nConclusionThe severity of OI impacts OHRQoL in adolescents aged 11 to 14 years, but not in children age 8 to 10 years.

epidemiology↗

bioRxiv2018

Dental and facial characteristics of osteogenesis imperfecta type V

Osteogenesis imperfecta (OI) type V is an ultrarare heritable bone disorder caused by the heterozygous c.-14C>T mutation in IFITM5. The dental and craniofacial phenotype has not been described in detail. In the present multicenter study (Brittle Bone Disease Consortium) 14 individuals with OI type V (age 3 to 50 years; 10 females, 4 males) underwent dental and craniofacial assessment. None of the individuals had dentinogenesis imperfecta. Six of the 9 study participants (66%) for whom panoramic radiographs were obtained had at least one missing tooth (range 1 to 9). Class II molar occlusion was present in 8 (57%) of the 14 study participants. The facial profile was retrusive and lower face height was decreased in 8 (57%) individuals. Cephalometry, performed in three study participants, revealed a severely retrusive maxilla and mandible, and poorly angulated incisors in a 14-year old girl, a protrusive maxilla and a retrusive mandible in a 14-year old boy. Cone beam computed tomograpy scans were obtained from two study participants and demonstrated intervertebral disc calcification at the C2-C3 level in one individual. Our study observed that OI type V is associated with missing permanent teeth, especially permanent premolar, but not with dentinogenesis imperfecta. The pattern of craniofacial abnormalities in OI type V thus differs from that in other severe OI types, such as OI type III and IV, and could be described as a bimaxillary retrusive malocclusion with reduced lower face height and multiple missing teeth.

genetics↗

bioRxiv2018

Implantable electrical stimulation bioreactor with liquid crystal polymer based electrodes for enhanced bone regeneration at mandibular large defects in rabbit

The osseous regeneration of large bone defects is still a major clinical challenge in maxillofacial and orthopedic surgery. Our previous studies demonstrated that electrical stimulation (ES) with biphasic current pulse showed proliferative effects on bone cells and enhanced secretion of bone-forming growth factors. This study presents an implantable electrical stimulation bioreactor with electrodes based on liquid crystal polymer (LCP), which has excellent bone-binding property. The bioreactor was implanted into a critical sized bone defect and subjected to ES for one week, where bone regeneration was evaluated four weeks after surgery using micro-CT. The effect of ES via bioreactor was compared with a sham control group and positive control group that received recombinant human bone morphogenetic protein (rhBMP)-2 (20 g). New bone volume per tissue volume (BV/TV) in the ES and rhBMP-2 groups increased to 171% (p < 0.001) and 210% (p < 0.001), respectively, compared to that in the sham control group. In the histological evaluation, there was no inflammation within bone defects and adjacent to LCP in all groups. This study showed that the ES bioreactor with LCP electrodes could enhance bone regeneration at large bone defects, where LCP can act as a mechanically resistant outer box without inflammation.

bioengineering↗

bioRxiv2018

Real-time non-invasive intracranial state estimation using unscented Kalman filter

Intracranial pressure (ICP) monitoring is desirable as a first-line measure to assist decision-making in cases of increased ICP. Clinically, non-invasive ICP monitoring is also required to avoid infection and hemorrhage in patients. The relationships among the arterial blood pressure (Pa), ICP, cerebral blood flow, and its velocity (QCBFv) measured by transcranial Doppler ultrasound measurement have been reported. However, real-time non-invasive ICP estimation using these modalities is less well documented. Here, we present a novel algorithm for real-time and non-invasive ICP monitoring with QCBFv and Pa, called direct-current (DC)-ICP. This technique is compared with invasive ICP for 11 traumatic-brain-injury patients admitted to Cheju Halla Hospital and Gangnam Severance Hospital from July 2017 to June 2018. The inter-subject correlation coefficient between true and estimate was 0.70. The AUCs of the ROCs for prediction of increased ICP for the DC-ICP methods are 0.816. Thus, QCBFv monitoring can facilitate reliable real-time ICP tracking with our novel DC-ICP algorithm, which can provide valuable information under clinical conditions.

neuroscience↗

bioRxiv2018

Dynamic Regulation of RNA Structure in Mammalian Cells

RNA structure is intimately connected to each step of gene expression. Recent advances have enabled transcriptome-wide maps of RNA secondary structure, termed RNA structuromes. However, previous whole-cell analyses lacked the resolution to unravel the dynamic regulation of RNA structure across subcellular states. Here we reveal the RNA structuromes in three compartments -- chromatin, nucleoplasm and cytoplasm. The cytotopic structuromes substantially expand RNA structural information, and enable detailed investigation of the central role of RNA structure in linking transcription, translation, and RNA decay. Through comparative structure analysis, we develop a resource to visualize the interplay of RNA-protein interactions, RNA chemical modifications, and RNA structure, and predict both direct and indirect reader proteins of RNA modifications. We validate the novel role of the RNA binding protein LIN28A as an N6-methyladenosine (m6A) modification \"anti-reader\". Our results highlight the dynamic nature of RNA structures and its functional significance in gene regulation.

molecular biology↗

bioRxiv2018

40 Hz acoustic stimulation decreases amyloid beta and modulates brain rhythms in a mouse model of Alzheimers disease

IntroductionThe accumulation of amyloid-beta (A{beta}) is one of the neuropathologic hallmarks of Alzheimers disease (AD) and abnormal gamma band oscillations and brain connectivity have been observed. Recently, a therapeutic potential of gamma entrainment of the brain was reported by Iaccarino et al. However, the affected areas were limited to hippocampus and visual cortex. Therefore, we sought to test the effects of acoustic stimulation in a mouse model of AD.\n\nMethodsFreely moving 6-month-old 5XFAD mice with electroencephalogram (EEG) electrodes were treated with daily two-hour acoustic stimulation at 40Hz for 2 weeks. A{beta} and microglia were evaluated by immunohistochemistry and ELISA. Evoked and spontaneous gamma power were analyzed by wavelet analysis. Coherence, phase locking value (PLV), and cross-frequency coupling were analyzed.\n\nResultsThe number of A{beta} plaques decreased in the pre-and infralimbic (PIL) and hippocampus regions and soluble A{beta}-40 and A{beta}-42 peptides in PIL in the acoustic stimulation group. We also found that the number of microglia increased in PIL and hippocampus. In EEG analysis, evoked gamma power was decreased and spontaneous gamma power was increased. Gamma coherence and phase locking value did not show significant changes. Cross-frequency coupling was shifted from gamma-delta to gamma-theta rhythm.\n\nConclusionIn summary, we found that acoustic stimulation at 40Hz can reduce A{beta} in the brain and restore the gamma band oscillations and the frontoparietal connectivity. Our data suggest that acoustic stimulation might alter the natural deterioration processes of AD and have a therapeutic potential in AD.

neuroscience↗

bioRxiv2018

Mobility in Osteogenesis Imperfecta: A Multicenter North American Study

BackgroundOsteogenesis imperfecta (OI) is a genetic connective tissue disorder characterized by increased bone fragility and recurrent fractures. The phenotypic severity of OI has a significant influence on the ability to walk but little is known about the ambulatory characteristics, strength, or functional abilities in individuals with OI, especially in the more severe forms. To advance clinical research in OI, the Linked Clinical Research Centers, network of clinical centers in North America with significant experience in treating patients with OI, was established in 2009. The purpose of this work was to characterize mobility in OI using standard clinical assessment tools. and determine if any patient characteristics could be used to predict mobility outcomes.\n\nMethodsData were collected at five clinical sites and included age, gender, ethnicity, height, weight, use of assistive device, and bisphosphonate use and mobility metrics (age at first walk, Gillette Functional Assessment Questionnaire, Functional Mobility Scale, and distance walked in the 6 minute walk test). Linear mixed models were developed to explore the relationships between subject demographics and mobility metrics.\n\nResultsThe study identified 491 individuals age 3 and older. In general, the results showed minor limitations in the type I group while the more severe types showed more significant limitations in all mobility metrics analyzed. Height and weight were shown to be the most significant predictors of mobility metrics. Relationships with mobility and bisphosphonates varied with OI type and whether oral or IV was used.\n\nConclusionThis paper is the most comprehensive report of mobility in individuals with OI to date. These results are vital to understanding the mobility limitations of specific types of OI and beneficial when developing rehabilitation protocols for this population. It is important for physicians, patients, and caregivers to gain insight into severity and classification of the disease and the influence of disease-related characteristics on the prognosis for mobility.

bioengineering↗

bioRxiv2018

TORC1 modulation in adipose tissue is required for organismal adaptation to hypoxia in Drosophila.

Animals often develop in conditions where environmental conditions such as food, oxygen and temperature fluctuate. The ability to adapt their metabolism to these fluctuations is important to ensure normal development and viability. In most animals, low oxygen (hypoxia) is deleterious, however some animals can alter their physiology to thrive under hypoxia. Here we show that TORC1 modulation in adipose tissue is required for organismal adaptation to hypoxia in Drosophila. We find that hypoxia rapidly suppresses TORC1 kinase signalling in Drosophila larvae via TSC-mediated inhibition of Rheb. We show that this hypoxia-mediated inhibition of TORC1 specifically in the larval fat body is essential for viable development to adulthood. Moreover, we find that these effects of TORC1 inhibition on hypoxia tolerance are mediated through remodeling of fat body lipid droplets and lipid storage. These studies identify the larval adipose tissue as a key hypoxia sensing tissue that coordinates whole-body development and survival to changes in environmental oxygen by modulating TORC1 and lipid storage.

developmental biology↗

bioRxiv2018

ATRAID, a genetic factor that regulates the clinical action of nitrogen-containing bisphosphonates on bone.

Nitrogen-containing bisphosphonates (N-BPs), such as alendronate, are the most widely prescribed medications for diseases involving bone, with nearly 200 million prescriptions written annually. Recently, widespread use of N-BPs has been challenged due to the risk of rare but traumatic side effects such as atypical femoral fracture (AFFs) and osteonecrosis of the jaw (ONJ). N-BPs bind to and inhibit farnesyl diphosphate synthase (FDPS), resulting in defects in protein prenylation. Yet it remains poorly understood what other cellular factors might allow N-BPs to exert their pharmacological effects. Here, we performed genome-wide studies in cells and patients to identify the poorly characterized gene, ATRAID. Loss of ATRAID function results in selective resistance to N-BP-mediated loss of cell viability and the prevention of alendronate-mediated inhibition of prenylation. ATRAID is required for alendronate inhibition of osteoclast function, and ATRAID-deficient mice have impaired therapeutic responses to alendronate in both postmenopausal and senile (old age) osteoporosis models. Lastly, we performed exome sequencing on patients taking N-BPs that suffered ONJ or an AFF. ATRAID is one of three genes that contain rare non-synonymous coding variants in patients with ONJ or AFF that is also differentially expressed in poor outcome groups of patients treated with N-BPs. We functionally validated this patient variation in ATRAID as conferring cellular hypersensitivity to N-BPs. Our work adds key insight into the mechanistic action of N-BPs and the processes that might underlie differential responsiveness to N-BPs in people. One Sentence SummaryATRAID is essential for responses to the commonly prescribed osteoporosis drugs nitrogen-containing bisphosphonates. OverlineBONE

genomics↗

bioRxiv2018

Loss-of-function in IRF2BPL is associated with neurological phenotypes

The Interferon Regulatory Factor 2 Binding Protein Like (IRF2BPL) gene encodes a member of the IRF2BP family of transcriptional regulators. Currently the biological function of this gene is obscure, and the gene has not been associated with a Mendelian disease. Here we describe seven individuals affected with neurological symptoms who carry damaging heterozygous variants in IRF2BPL. Five cases carrying nonsense variants in IRF2BPL resulting in a premature stop codon display severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and a lack of coordination. Two additional individuals, both with missense variants, display global developmental delay and seizures and a relatively milder phenotype than those with nonsense alleles. The bioinformatics signature for IRF2BPL based on population genomics is consistent with a gene that is intolerant to variation. We show that the IRF2BPL ortholog in the fruit fly, called pits (protein interacting with Ttk69 and Sin3A), is broadly expressed including the nervous system. Complete loss of pits is lethal early in development, whereas partial knock-down with RNA interference in neurons leads to neurodegeneration, revealing requirement for this gene in proper neuronal function and maintenance. The nonsense variants in IRF2BPL identified in patients behave as severe loss-of-function alleles in this model organism, while ectopic expression of the missense variants leads to a range of phenotypes. Taken together, IRF2BPL and pits are required in the nervous system in humans and flies, and their loss leads to a range of neurological phenotypes in both species.

genetics↗

bioRxiv2018

Visual physiology of the Layer 4 cortical circuit in silico

Despite advances in experimental techniques and accumulation of large datasets concerning the composition and properties of the cortex, quantitative modeling of cortical circuits under in-vivo-like conditions remains challenging. Here we report and publicly release a biophysically detailed circuit model of layer 4 in the mouse primary visual cortex, receiving thalamo-cortical visual inputs. The 45,000-neuron model was subjected to a battery of visual stimuli, and results were compared to published work and new in vivo experiments. Simulations reproduced a variety of observations, including effects of optogenetic perturbations. Critical to the agreement between responses in silico and in vivo were the rules of functional synaptic connectivity between neurons. Interestingly, after extreme simplification the model still performed satisfactorily on many measurements, although quantitative agreement with experiments suffered. These results emphasize the importance of functional rules of cortical wiring and enable a next generation of data-driven models of in vivo neural activity and computations.\n\nAUTHOR SUMMARYHow can we capture the incredible complexity of brain circuits in quantitative models, and what can such models teach us about mechanisms underlying brain activity? To answer these questions, we set out to build extensive, bio-realistic models of brain circuitry employing systematic datasets on brain structure and function. Here we report the first modeling results of this project, focusing on the layer 4 of the primary visual cortex (V1) of the mouse. Our simulations reproduced a variety of experimental observations in a large battery of visual stimuli. The results elucidated circuit mechanisms determining patters of neuronal activity in layer 4 - in particular, the roles of feedforward thalamic inputs and specific patterns of intracortical connectivity in producing tuning of neuronal responses to the orientation of motion. Simplification of neuronal models led to specific deficiencies in reproducing experimental data, giving insights into how biological details contribute to various aspects of brain activity. To enable future development of more sophisticated models, we make the software code, the model, and simulation results publicly available.

neuroscience↗

bioRxiv2018

Microdeletions excluding YWHAE and PAFAH1B1 cause a unique leukoencephalopathy and hypermobility syndrome: Further delineation of the 17p13.3 microdeletion spectrum

PurposeBrain malformations are caused by 17p13.3 deletions: lissencephaly with deletions of the larger Miller-Dieker syndrome region or smaller deletions of only PAFAH1B1, as well as various abnormalities, including white matter changes, in the distinct syndrome due to deletions including YWHAE and CRK but sparing PAFAH1B1. We sought to understand the significance of 17p13.3 deletions between the YWHAE/CRK and PAFAH1B1 loci.\n\nMethodsWe analyzed the clinical features of five individuals from four families with 17p13.3 deletions between and not including YWHAE/CRK and PAFAH1B1 identified among individuals undergoing clinical chromosomal microarray testing.\n\nResultsFour individuals from three families have multi-focal white matter lesions and hypermobile joints, while a fifth had a normal MRI. A combination of our patients and a review of those in the literature with white matter changes and deletions in this chromosomal region narrows the overlapping region for this brain phenotype to [~]345 kb, including 11 RefSeq genes, with RTN4RL1 haploinsufficiency as the best candidate for causing this.\n\nConclusionWhile previous literature has hypothesized dysmorphic features and white matter changes related to YWHAE, our cohort contributes evidence to the presence of additional genes within 17p13.3 required for proper brain development.

genetics↗

bioRxiv2018

Phenotypic expansion in DDX3X -- a common cause of intellectual disability in females

De novo variants in DDX3X account for 1-3% of unexplained intellectual disability (ID), one of the most common causes of ID, in females. Forty-seven patients (44 females, 3 males) have been described. We identified 29 additional individuals carrying 27 unique DDX3X variants in the setting of complex clinical presentations including developmental delay or ID. In addition to previously reported manifestations, rare or novel phenotypes were identified including respiratory problems, congenital heart disease, skeletal muscle mitochondrial DNA depletion, and late-onset neurologic decline. Our findings expand the spectrum of DNA variants and phenotypes associated with DDX3X disorders.

genetics↗

bioRxiv2018

MicroRNAs as potential therapeutics to enhance chemosensitivity in advancedprostate cancer

Docetaxel and cabazitaxel are taxane chemotherapy treatments for metastatic castration-resistant prostate cancer (CRPC). However, therapeutic resistance remains a major issue. MicroRNAs are short non-coding RNAs that can silence multiple genes, regulating several signalling pathways simultaneously. Therefore, synthetic microRNAs may have therapeutic potential in CRPC by regulating genes involved in taxane response and minimise compensatory mechanisms that cause taxane resistance. To identify microRNAs that can improve the efficacy of taxanes in CRPC, we performed a genome-wide screen of 1280 microRNAs in the CRPC cell lines PC3 and DU145 in combination with docetaxel or cabazitaxel treatment. Mimics of miR-217 and miR-181b-5p enhanced apoptosis significantly in PC3 cells in the presence of these taxanes. These mimics downregulated at least a thousand different transcripts, which were enriched for genes with cell proliferation and focal adhesion functions. Individual knockdown of a selection of 46 genes representing these transcripts resulted in toxic or taxane sensitisation effects, indicating that these genes may be mediating the effects of the microRNA mimics. A range of these genes are expressed in CRPC metastases, suggesting that these microRNA mimics may be functional in CRPC. With further development, these microRNA mimics may have therapeutic potential to improve taxane response in CRPC patients.

cancer biology↗

bioRxiv2018

Multiplex Chromatin Interaction Analysis with Single-Molecule Precision

We describe a microfluidics-based strategy for genome-wide analysis of multiplex chromatin interactions with single-molecule precision. In multiplex chromatin interaction analysis (multi-ChIA), individual chromatin complexes are partitioned into droplets that contain a gel bead with unique DNA barcode, in which tethered chromatin DNA fragments are barcoded and amplified for sequencing and mapping to demarcate chromatin contacts. Thus, multi-ChIA has the unprecedented ability to uncover multiplex chromatin interactions at single-molecule level, which has been impossible using previous methods that rely on analyzing pairwise contacts via proximity ligation. We demonstrate that multiplex chromatin interactions predominantly contribute to topologically associated domains, and clusters of gene promoters and enhancers provide a fundamental topological framework for co-transcriptional regulation.

genomics↗

bioRxiv2017

LARGE, an AMPA receptor interactor, plays a large role in long-term memory formation by driving homeostatic scaling-down

Dynamic trafficking of AMPA-type glutamate receptor (AMPA-R) in neuronal cells is a key cellular mechanism for learning and memory in the brain, which is regulated by AMPA-R interacting proteins. LARGE, a protein associated with intellectual disability, was found to be a novel component of the AMPA-R protein complex in our proteomic study. Here, our functional study of LARGE showed that during homeostatic scaling-down, increased LARGE expression at the Golgi apparatus (Golgi) negatively controlled AMPA-R trafficking from the Golgi to the plasma membrane, leading to downregulated surface and synaptic AMPA-R targeting. In LARGE knockdown mice, long-term potentiation (LTP) was occluded by synaptic AMPA-R overloading, resulting in impaired long-term memory formation. These findings indicate that the fine-tuning of AMPA-R trafficking by LARGE at the Golgi is critical for memory stability in the brain. Our study thus provides novel insights into the pathophysiology of brain disorders associated with intellectual disability.

neuroscience↗