45 results on '"Benjamin Hilton"'
Search Results
2. 17q25.3 copy number changes: association with neurodevelopmental disorders and cardiac malformation
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Nikhil Shri Sahajpal, David H. F. Jeffrey, Barbara R. DuPont, and Benjamin Hilton
- Subjects
Rare copy number variants ,Genotype–phenotype correlation ,17q25 region ,NHEJ ,Neurodevelopmental disorders ,Genetics ,QH426-470 - Abstract
Abstract Copy number variants (CNVs) have been identified as common genomic variants that play a significant role in inter-individual variability. Conversely, rare recurrent CNVs have been found to be causal for many disorders with well-established genotype–phenotype relationships. However, the phenotypic implications of rare non-recurrent CNVs remain poorly understood. Herein, we re-investigated 18,542 cases reported from chromosomal microarray at Greenwood Genetic Center from 2010 to 2022 and identified 15 cases with CNVs involving the 17q25.3 region. We report the detailed clinical features of these subjects, and compare with the cases reported in the literature to determine genotype–phenotype correlations for a subset of genes in this region. The CNVs in the 17q25.3 region were found to be rare events, with a prevalence of 0.08% (15/18542) observed in our cohort. The CNVs were dispersed across the entire 17q25.3 region with variable breakpoints and no smallest region of overlap. The subjects presented with a wide range of clinical features, with neurodevelopmental disorders (autism spectrum disorder, intellectual disability, developmental delay) being the most common features (80%), then expressive language disorder (33%), and finally cardiovascular malformations (26%). The association of CNVs involving the critical gene-rich region of 17q25.3 with neurodevelopmental disorders and cardiac malformation, implicates several genes as plausible drivers for these events.
- Published
- 2023
- Full Text
- View/download PDF
3. P435: Diagnostic yield and copy number findings from 500 clinical genome sequencing cases
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Kameryn Butler, Benjamin Hilton, Timothy Fee, and Barbara DuPont
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Genetics ,QH426-470 ,Medicine - Published
- 2023
- Full Text
- View/download PDF
4. P485: Evaluating novel dosage sensitivity predictors for inclusion in the classification of recurrent copy number variants
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John Herriges, Cassandra Runke, Zoe Lewis, Lucilla Pizzo, Bradley Coe, Laura Conlin, Benjamin Hilton, Brynn Levy, Andrea Vaags, Shulin Zhang, Christa Martin, and Erica Andersen
- Subjects
Genetics ,QH426-470 ,Medicine - Published
- 2023
- Full Text
- View/download PDF
5. P549: Analysis of challenging products of conception cases with optical genome mapping: A preliminary study
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Nikhil Sahajpal, Ashis Mondal, Harmanpreet Singh, Timothy Fee, Fatima Abidi, Benjamin Hilton, Ravindra Kolhe, and Barbara DuPont
- Subjects
Genetics ,QH426-470 ,Medicine - Published
- 2023
- Full Text
- View/download PDF
6. P582: Exon-level copy number variations identified by whole genome sequencing in previously undiagnosed patients with rare hereditary diseases
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Jiyong Wang, Raymond Caylor, Julie Jones, Jennifer Lee, Raymond Louie, Benjamin Hilton, Barbara DuPont, and Kameryn Butler
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Genetics ,QH426-470 ,Medicine - Published
- 2023
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- View/download PDF
7. P657: NSD2 duplication results in distinct phenotype and DNA methylation signature
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Benjamin Hilton, Bekim Sadikovic, Alfredo Brusco, Giovanni Battista Ferrero, Barbara DuPont, Matthew Tedder, Raymond Louie, Nikhil Sahajpal, Erica Andersen, Zoe Lewis, Amanda Openshaw, Jennifer Kerkhof, Haley McConkey, Raissa Relator, Sadegheh Haghshenas, Jack Reilly, and Kathleen Rooney
- Subjects
Genetics ,QH426-470 ,Medicine - Published
- 2023
- Full Text
- View/download PDF
8. Optical Genome Mapping: Integrating Structural Variations for Precise Homologous Recombination Deficiency Score Calculation
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Nikhil Shri Sahajpal, Ashis K. Mondal, Ashutosh Vashisht, Harmanpreet Singh, Andy Wing Chun Pang, Daniel Saul, Omar Nivin, Benjamin Hilton, Barbara R. DuPont, Vamsi Kota, Natasha M. Savage, Alex R. Hastie, Alka Chaubey, and Ravindra Kolhe
- Subjects
optical genome mapping ,homologous recombination deficiency ,HRD scores ,Genetics ,QH426-470 - Abstract
Homologous recombination deficiency (HRD) is characterized by the inability of a cell to repair the double-stranded breaks using the homologous recombination repair (HRR) pathway. The deficiency of the HRR pathway results in defective DNA repair, leading to genomic instability and tumorigenesis. The presence of HRD has been found to make tumors sensitive to ICL-inducing platinum-based therapies and poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibitors (PARPi). However, there are no standardized methods to measure and report HRD phenotypes. Herein, we compare optical genome mapping (OGM), chromosomal microarray (CMA), and a 523-gene NGS panel for HRD score calculations. This retrospective study included the analysis of 196 samples, of which 10 were gliomas, 176 were hematological malignancy samples, and 10 were controls. The 10 gliomas were evaluated with both CMA and OGM, and 30 hematological malignancy samples were evaluated with both the NGS panel and OGM. To verify the scores in a larger cohort, 135 cases were evaluated with the NGS panel and 71 cases with OGM. The HRD scores were calculated using a combination of three HRD signatures that included loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale transitions (LST). In the ten glioma cases analyzed with OGM and CMA using the same DNA (to remove any tumor percentage bias), the HRD scores (mean ± SEM) were 13.2 (±4.2) with OGM compared to 3.7 (±1.4) with CMA. In the 30 hematological malignancy cases analyzed with OGM and the 523-gene NGS panel, the HRD scores were 7.6 (±2.2) with OGM compared to 2.6 (±0.8) with the 523-gene NGS panel. OGM detected 70.8% and 66.8% of additional variants that are considered HRD signatures in gliomas and hematological malignancies, respectively. The higher sensitivity of OGM to capture HRD signature variants might enable a more accurate and precise correlation with response to PARPi and platinum-based drugs. This study reveals HRD signatures that are cryptic to current standard of care (SOC) methods used for assessing the HRD phenotype and presents OGM as an attractive alternative with higher resolution and sensitivity to accurately assess the HRD phenotype.
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- 2023
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- View/download PDF
9. Clinical Utility of Optical Genome Mapping and 523-Gene Next Generation Sequencing Panel for Comprehensive Evaluation of Myeloid Cancers
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Nikhil Shri Sahajpal, Ashis K. Mondal, Harmanpreet Singh, Ashutosh Vashisht, Sudha Ananth, Daniel Saul, Alex R. Hastie, Benjamin Hilton, Barbara R. DuPont, Natasha M. Savage, Vamsi Kota, Alka Chaubey, Jorge E. Cortes, and Ravindra Kolhe
- Subjects
optical genome mapping ,523-gene NGS panel ,myeloid cancers ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
The standard-of-care (SOC) for genomic testing of myeloid cancers primarily relies on karyotyping/fluorescent in situ hybridization (FISH) (cytogenetic analysis) and targeted gene panels (usually ≤54 genes) that harbor hotspot pathogenic variants (molecular genetic analysis). Despite this combinatorial approach, ~50% of myeloid cancer genomes remain cytogenetically normal, and the limited sequencing variant profiles obtained from targeted panels are unable to resolve the molecular etiology of many myeloid tumors. In this study, we evaluated the performance and clinical utility of combinatorial use of optical genome mapping (OGM) and a 523-gene next-generation sequencing (NGS) panel for comprehensive genomic profiling of 30 myeloid tumors and compared it to SOC cytogenetic methods (karyotyping and FISH) and a 54-gene NGS panel. OGM and the 523-gene NGS panel had an analytical concordance of 100% with karyotyping, FISH, and the 54-gene panel, respectively. Importantly, the IPSS-R cytogenetic risk group changed from very good/good to very poor in 22% of MDS (2/9) cases based on comprehensive profiling (karyotyping, FISH, and 54-gene panel vs. OGM and 523-gene panel), while additionally identifying six compound heterozygous events of potential clinical relevance in six cases (6/30, 20%). This cost-effective approach of using OGM and a 523-gene NGS panel for comprehensive genomic profiling of myeloid cancers demonstrated increased yield of actionable targets that can potentially result in improved clinical outcomes.
- Published
- 2023
- Full Text
- View/download PDF
10. First Principles Calculation of Protein–Protein Dimer Affinities of ALS-Associated SOD1 Mutants
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Shawn C. C. Hsueh, Mark Nijland, Xubiao Peng, Benjamin Hilton, and Steven S. Plotkin
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protein misfolding (conformational) diseases ,amyotrophic lateral sclerosis ,molecular dynamics simulations ,superoxide dismutase (Cu–Zn) ,dimer dissociation ,protein–protein interactions ,Biology (General) ,QH301-705.5 - Abstract
Cu,Zn superoxide dismutase (SOD1) is a 32 kDa homodimer that converts toxic oxygen radicals in neurons to less harmful species. The dimerization of SOD1 is essential to the stability of the protein. Monomerization increases the likelihood of SOD1 misfolding into conformations associated with aggregation, cellular toxicity, and neuronal death in familial amyotrophic lateral sclerosis (fALS). The ubiquity of disease-associated mutations throughout the primary sequence of SOD1 suggests an important role of physicochemical processes, including monomerization of SOD1, in the pathology of the disease. Herein, we use a first-principles statistical mechanics method to systematically calculate the free energy of dimer binding for SOD1 using molecular dynamics, which involves sequentially computing conformational, orientational, and separation distance contributions to the binding free energy. We consider the effects of two ALS-associated mutations in SOD1 protein on dimer stability, A4V and D101N, as well as the role of metal binding and disulfide bond formation. We find that the penalty for dimer formation arising from the conformational entropy of disordered loops in SOD1 is significantly larger than that for other protein–protein interactions previously considered. In the case of the disulfide-reduced protein, this leads to a bound complex whose formation is energetically disfavored. Somewhat surprisingly, the loop free energy penalty upon dimerization is still significant for the holoprotein, despite the increased structural order induced by the bound metal cations. This resulted in a surprisingly modest increase in dimer binding free energy of only about 1.5 kcal/mol upon metalation of the protein, suggesting that the most significant stabilizing effects of metalation are on folding stability rather than dimer binding stability. The mutant A4V has an unstable dimer due to weakened monomer-monomer interactions, which are manifested in the calculation by a separation free energy surface with a lower barrier. The mutant D101N has a stable dimer partially due to an unusually rigid β-barrel in the free monomer. D101N also exhibits anticooperativity in loop folding upon dimerization. These computational calculations are, to our knowledge, the most quantitatively accurate calculations of dimer binding stability in SOD1 to date.
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- 2022
- Full Text
- View/download PDF
11. Oscillatory chiral flows in confined active fluids with obstacles
- Author
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Bo Zhang, Benjamin Hilton, Christopher Short, Anton Souslov, and Alexey Snezhko
- Subjects
Physics ,QC1-999 - Abstract
An active colloidal fluid composed of self-propelled spinning particles injecting energy and angular momentum at the microscale demonstrates spontaneous collective states that range from flocks to coherent vortices. Despite their seeming simplicity, the emergent far-from-equilibrium behavior of these fluids remains poorly understood, presenting a challenge to the design and control of next-generation active materials. When confined in a ring, such so-called polar active fluids acquire chirality once the spontaneous flow chooses a direction. In a perfect ring, this chirality is indefinitely long-lived. Here, we combine experiments on self-propelled colloidal Quincke rollers and mesoscopic simulations of continuum Toner-Tu equations to explore how such chiral states can be controlled and manipulated by obstacles. For different obstacle geometries, three dynamic steady states have been realized: long-lived chiral flow, an apolar state in which the flow breaks up into counter-rotating vortices, and an unconventional collective state with flow having an oscillating chirality. The chirality reversal proceeds through the formation of intermittent vortex chains in the vicinity of an obstacle. We demonstrate that the frequency of collective states with oscillating chirality can be tuned by obstacle parameters. We vary obstacle shapes to design chiral states that are independent of initial conditions. Building on our findings, we realize a system with two triangular obstacles that force the active fluid toward a state with a density imbalance of active particles across the ring. Our results demonstrate how spontaneous polar active flows in combination with size and geometry of scatterers can be used to control dynamic patterns of polar active liquids for materials design.
- Published
- 2020
- Full Text
- View/download PDF
12. Dissociation Dynamics of XPC-RAD23B from Damaged DNA Is a Determining Factor of NER Efficiency.
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Benjamin Hilton, Sathyaraj Gopal, Lifang Xu, Sharmistha Mazumder, Phillip R Musich, Bongsup P Cho, and Yue Zou
- Subjects
Medicine ,Science - Abstract
XPC-RAD23B (XPC) plays a critical role in human nucleotide excision repair (hNER) as this complex recognizes DNA adducts to initiate NER. To determine the mutagenic potential of structurally different bulky DNA damages, various studies have been conducted to define the correlation of XPC-DNA damage equilibrium binding affinity with NER efficiency. However, little is known about the effects of XPC-DNA damage recognition kinetics on hNER. Although association of XPC is important, our current work shows that the XPC-DNA dissociation rate also plays a pivotal role in achieving NER efficiency. We characterized for the first time the binding of XPC to mono- versus di-AAF-modified sequences by using the real time monitoring surface plasmon resonance technique. Strikingly, the half-life (t1/2 or the retention time of XPC in association with damaged DNA) shares an inverse relationship with NER efficiency. This is particularly true when XPC remained bound to clustered adducts for a much longer period of time as compared to mono-adducts. Our results suggest that XPC dissociation from the damage site could become a rate-limiting step in NER of certain types of DNA adducts, leading to repression of NER.
- Published
- 2016
- Full Text
- View/download PDF
13. Clinical Validation and Diagnostic Utility of Optical Genome Mapping in Prenatal Diagnostic Testing
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Nikhil S. Sahajpal, Ashis K. Mondal, Timothy Fee, Benjamin Hilton, Lawrence Layman, Alex R. Hastie, Alka Chaubey, Barbara R. DuPont, and Ravindra Kolhe
- Subjects
Molecular Medicine ,Pathology and Forensic Medicine - Abstract
The standard-of-care (SOC) diagnostic prenatal testing includes a combination of cytogenetic methods such as karyotyping, fluorescence in situ hybridization (FISH), and chromosomal microarray (CMA) using either direct or cultured amniocytes or chorionic villi sampling (CVS). However, each technology has its limitations: karyotyping has a low resolution (>5Mb), FISH is targeted, and CMA does not detect balanced structural variants (SVs) or decipher complex rearrangements in the genome. These limitations necessitate the use of multiple tests, either simultaneously or sequentially to reach a genetic diagnosis. This long-standing prenatal testing workflow demonstrates the need for an alternative technology that can provide high-resolution results in a cost and time-effective manner. Optical genome mapping (OGM) is an emerging technology that has demonstrated its ability to detect all classes of SVs, including copy number variations (CNVs) and balanced abnormalities in a single assay, but has not been evaluated in the prenatal setting. This retrospective validation study analyzed 114 samples (including replicates), representing 94 unique and well-characterized samples that were received in our laboratory for traditional cytogenetic analysis with karyotyping, FISH, and/or CMA. Samples comprised 84 cultured amniocytes, and 10 phenotypically normal and cytogenetically negative controls. Six samples were run in triplicate to evaluate intra-run, inter-run, and inter-instrument reproducibility. Clinically relevant SVs and CNVs were reported using the Bionano Access software with standardized and built-in filtration criteria and phenotype-specific analysis. OGM was 100% concordant in identifying the 101 aberrations that included 29 interstitial/terminal deletions, 28 duplications, 26 aneuploidies, 6 absence of heterozygosity (AOH), 3 triploid genomes, 4 Isochromosomes, 1 translocation, and revealed the identity of 3 marker chromosomes, and 1 chromosome with additional material not determined by karyotyping. Additionally, OGM detected 64 additional clinically reportable SVs in 43 samples. OGM demonstrated high technical and analytical robustness and a limit of detection of 5% allele fraction for interstitial deletions and duplications, and 10% allele fraction for translocation and aneuploidy. This study demonstrates that OGM has the potential to identify unique genomic abnormalities such as CNVs, AOHs, and several classes of SVs including complex structural rearrangements. OGM has a standardized laboratory workflow and reporting solution that can be adopted in routine clinical laboratories and demonstrates the potential to replace the current SOC methods for prenatal diagnostic testing. We recommend its use as a first-tier genetic diagnostic test in a prenatal setting.
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- 2023
14. Clinical Utility of Optical Genome Mapping and 523-Gene Next Generation Sequencing Panel for Comprehensive Evaluation of Myeloid Cancers
- Author
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Kolhe, Nikhil Shri Sahajpal, Ashis K. Mondal, Harmanpreet Singh, Ashutosh Vashisht, Sudha Ananth, Daniel Saul, Alex R. Hastie, Benjamin Hilton, Barbara R. DuPont, Natasha M. Savage, Vamsi Kota, Alka Chaubey, Jorge E. Cortes, and Ravindra
- Subjects
optical genome mapping ,523-gene NGS panel ,myeloid cancers - Abstract
The standard-of-care (SOC) for genomic testing of myeloid cancers primarily relies on karyotyping/fluorescent in situ hybridization (FISH) (cytogenetic analysis) and targeted gene panels (usually ≤54 genes) that harbor hotspot pathogenic variants (molecular genetic analysis). Despite this combinatorial approach, ~50% of myeloid cancer genomes remain cytogenetically normal, and the limited sequencing variant profiles obtained from targeted panels are unable to resolve the molecular etiology of many myeloid tumors. In this study, we evaluated the performance and clinical utility of combinatorial use of optical genome mapping (OGM) and a 523-gene next-generation sequencing (NGS) panel for comprehensive genomic profiling of 30 myeloid tumors and compared it to SOC cytogenetic methods (karyotyping and FISH) and a 54-gene NGS panel. OGM and the 523-gene NGS panel had an analytical concordance of 100% with karyotyping, FISH, and the 54-gene panel, respectively. Importantly, the IPSS-R cytogenetic risk group changed from very good/good to very poor in 22% of MDS (2/9) cases based on comprehensive profiling (karyotyping, FISH, and 54-gene panel vs. OGM and 523-gene panel), while additionally identifying six compound heterozygous events of potential clinical relevance in six cases (6/30, 20%). This cost-effective approach of using OGM and a 523-gene NGS panel for comprehensive genomic profiling of myeloid cancers demonstrated increased yield of actionable targets that can potentially result in improved clinical outcomes.
- Published
- 2023
- Full Text
- View/download PDF
15. Driftfusion: an open source code for simulating ordered semiconductor devices with mixed ionic-electronic conducting materials in one dimension
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Philip Calado, Ilario Gelmetti, Benjamin Hilton, Mohammed Azzouzi, Jenny Nelson, and Piers R. F. Barnes
- Subjects
Condensed Matter - Mesoscale and Nanoscale Physics ,Modeling and Simulation ,Mesoscale and Nanoscale Physics (cond-mat.mes-hall) ,FOS: Physical sciences ,Physics - Applied Physics ,Applied Physics (physics.app-ph) ,Computational Physics (physics.comp-ph) ,Electrical and Electronic Engineering ,Physics - Computational Physics ,Atomic and Molecular Physics, and Optics ,Electronic, Optical and Magnetic Materials - Abstract
The recent emergence of lead-halide perovskites as active layer materials for thin film semiconductor devices including solar cells, light emitting diodes, and memristors has motivated the development of several new drift-diffusion models that include the effects of both mobile electronic and ionic charge carriers. The aim of this work is to provide a comprehensive guide to Driftfusion, a versatile simulation tool built for simulating one-dimensional ordered semiconductor devices with mixed ionic-electronic conducting layers. Driftfusion enables users to model devices with multiple, distinct, material layers and up to four charge carrier species: electrons and holes by default plus up to two ionic species. The time-dependent carrier continuity equations are fully-coupled to Poisson's equation enabling transient optoelectronic device measurement protocols to be simulated. In addition to material and device-wide properties, users have direct access to adapt the physical models for carrier transport, generation and recombination. Furthermore, a graded-interface approach circumvents the requirement for boundary conditions at material interfaces and enables interface-specific properties, such as high rates of interfacial recombination, to be introduced., Comment: Main text: 30 pages, 17 figures, Supplemental information: 29 pages, 20 figures
- Published
- 2022
16. SmartShelter: A Sustainable power system design using energy harvesting techniques.
- Author
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Leticia Ibarra, Benjamin Hilton, Mehna Nawal, Salvador Carreon-Bautista, Mohamed Abouzied, Xiaosen Liu, Roland Ribeiro, Judy Amanor-Badu, Ethan Miller, Jorge Vanegas, and Edgar Sánchez-Sinencio
- Published
- 2014
- Full Text
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17. Correction to: Driftfusion: an open source code for simulating ordered semiconductor devices with mixed ionic-electronic conducting materials in one dimension
- Author
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Philip Calado, Ilario Gelmetti, Benjamin Hilton, Mohammed Azzouzi, Jenny Nelson, and Piers R. F. Barnes
- Subjects
Modeling and Simulation ,Electrical and Electronic Engineering ,Atomic and Molecular Physics, and Optics ,Electronic, Optical and Magnetic Materials - Published
- 2022
18. Quasilinear dynamics of KdV-type equations
- Author
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Harrop-Griffiths, Benjamin Hilton
- Subjects
Mathematics - Abstract
We consider the behavior of nonlinear KdV-type equations that admit quasilinear dynamics in the sense that the nonlinear flow cannot be simply treated as a perturbation of the linear flow, even for small initial data.We treat two problems in particular. First we study the local dynamics of KdV-type equations with nonlinearities involving two spatial derivatives. A key obstruction to well-posedness arises from to the Mizohata condition. This leads to an additional integrability requirement for the solution in the absence of a suitable null structure. In this case we prove local well-posedness for large, low-regularity data in translation-invariant spaces.Second we explore the global dynamics of the modified Korteweg de-Vries equation. We establish modified asymptotic behavior without relying on the integrable structure of the equation. This approach has the advantage that it can be used for a wide class of short-range perturbations of the mKdV. To give a thorough description of the asymptotic behavior we prove an asymptotic completeness result that relates mKdV solutions to the 1-parameter family of solutions to the Painlevé II equation.
- Published
- 2015
19. ATR prevents Ca2+ overload‐induced necrotic cell death through phosphorylation‐mediated inactivation of PARP1 without DNA damage signaling
- Author
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Xiaochun Yu, Yue Zou, Yetunde Makinwa, Hui Wang-Heaton, Phillip R. Musich, Brian M. Cartwright, Nikolozi Shkriabai, Mamuka Kvaratskhelia, Zhengke Li, Benjamin Hilton, Qian Chen, and Shengheng Guan
- Subjects
0301 basic medicine ,Programmed cell death ,DNA damage ,Poly (ADP-Ribose) Polymerase-1 ,Apoptosis ,Ataxia Telangiectasia Mutated Proteins ,Mitochondrion ,Biochemistry ,PARP1 ,necrosis ,03 medical and health sciences ,chemistry.chemical_compound ,Neuroblastoma ,0302 clinical medicine ,Genetics ,Tumor Cells, Cultured ,Humans ,Kinase activity ,Phosphorylation ,Molecular Biology ,Research Articles ,Kinase ,Chemistry ,Ca2+ overload ,PARP1 phosphorylation ,Cell biology ,Oxidative Stress ,030104 developmental biology ,ATR ,Ionomycin ,Calcium ,Reactive Oxygen Species ,030217 neurology & neurosurgery ,Biotechnology ,Research Article ,DNA Damage ,Signal Transduction - Abstract
Hyperactivation of PARP1 is known to be a major cause of necrotic cell death by depleting NAD+/ATP pools during Ca2+ overload which is associated with many ischemic diseases. However, little is known about how PARP1 hyperactivity is regulated during calcium overload. In this study we show that ATR kinase, well known for its role in DNA damage responses, suppresses ionomycin, glutamate, or quinolinic acid‐induced necrotic death of cells including SH‐SY5Y neuronal cells. We found that the inhibition of necrosis requires the kinase activity of ATR. Specifically, ATR binds to and phosphorylates PARP1 at Ser179 after the ionophore treatments. This site‐specific phosphorylation inactivates PARP1, inhibiting ionophore‐induced necrosis. Strikingly, all of this occurs in the absence of detectable DNA damage and signaling up to 8 hours after ionophore treatment. Furthermore, little AIF was released from mitochondria/cytoplasm for nuclear import, supporting the necrotic type of cell death in the early period of the treatments. Our results reveal a novel ATR‐mediated anti‐necrotic mechanism in the cellular stress response to calcium influx without DNA damage signaling.
- Published
- 2021
20. 21. A case of supernumerary ring chromosome 20 involving the gene ASXL1 resulting in brain abnormalities
- Author
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Benjamin Hilton, Barbara DuPont, and Kameryn Butler
- Subjects
Cancer Research ,Genetics ,Molecular Biology - Published
- 2022
21. 17. Chromosome 2p duplication associated mechanisms and clinical presentations
- Author
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Xiaolan Fang, Benjamin Hilton, and Barbara DuPont
- Subjects
Cancer Research ,Genetics ,Molecular Biology - Published
- 2022
22. Oscillatory chiral flows in confined active fluids with obstacles
- Author
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Anton Souslov, Bo Zhang, Alexey Snezhko, Benjamin Hilton, and Christopher Short
- Subjects
Physics ,Physics::Fluid Dynamics ,Chemical physics ,Polar ,Soft Condensed Matter (cond-mat.soft) ,FOS: Physical sciences ,Condensed Matter - Soft Condensed Matter - Abstract
An active colloidal fluid comprised of self-propelled spinning particles injecting energy and angular momentum at the microscale demonstrates spontaneous collective states that range from flocks to coherent vortices. Despite their seeming simplicity, the emergent far-from-equilibrium behavior of these fluids remains poorly understood, presenting a challenge to the design and control of next-generation active materials. When confined in a ring, such so-called polar active fluids acquire chirality once the spontaneous flow chooses a direction. In a perfect ring, this chirality is indefinitely long-lived. Here, we combine experiments on self-propelled colloidal Quincke rollers and mesoscopic simulations of continuum Toner-Tu equations to explore how such chiral states can be controlled and manipulated by obstacles. For different obstacle geometries three dynamic steady states have been realized: long-lived chiral flow, an apolar state in which the flow breaks up into counter-rotating vortices and an unconventional collective state with flow having an oscillating chirality. The chirality reversal proceeds through the formation of intermittent vortex chains in the vicinity of an obstacle. We demonstrate that the frequency of collective states with oscillating chirality can be tuned by obstacle parameters. We vary obstacle shapes to design chiral states that are independent of initial conditions. Building on our findings, we realize a system with two triangular obstacles that force the active fluid towards a state with a density imbalance of active particles across the ring. Our results demonstrate how spontaneous polar active flows in combination with size and geometry of scatterers can be used to control dynamic patterns of polar active liquids for materials design., 13 pages, 5 figures
- Published
- 2020
23. eP413: Type II cat eye syndrome in a newborn with intrauterine growth retardation and echogenic intracardiac focus during pregnancy
- Author
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Jiyong Wang, Marsha Waters, Loretta Witt, Sarah Miller, Mary Alice Moore, Camerun Washington, Curtis Rogers, Kameryn Butler, Benjamin Hilton, and Barbara DuPont
- Subjects
Genetics (clinical) - Published
- 2022
24. 3. Standardizing recurrent copy number variant classification – From benign to reduced and high penetrance regions
- Author
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John Herriges, Benjamin Hilton, Shulin Zhang, Laura K. Conlin, Bradley P. Coe, Erica F. Andersen, Erin Rooney Riggs, Justin Schleede, Brynn Levy, Erik C. Thorland, Vaidehi Jobanputra, Marsha Speevak, McKinsey L. Goodenberger, Prabakaran Paulraj, Cassandra K. Runke, and Christa Lese Martin
- Subjects
Genetics ,Cancer Research ,Copy-number variation ,Biology ,Molecular Biology ,High penetrance - Published
- 2021
25. Physiological Demands of Common Occupational Tasks among Australian Police Officers: A Descriptive Analysis
- Author
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Amy Decker, Benjamin Hilton, Jay Dawes, Robert Lockie, and Robin M Orr
- Subjects
Adult ,Heart Rate ,Stress, Physiological ,Occupational Exposure ,Public Health, Environmental and Occupational Health ,Australia ,Humans ,Police - Abstract
Objectives The aim of this study was to investigate the physiological demands placed on Australian police officers carrying out common operational tasks. Methods Forty participants (n = 40) from an Australian police force (mean age = 33.58 ± 7.78 years, mean height = 177.70 ± 7.28 cm, mean weight = 85.68 ± 14.52 kg, mean years of service: 6.74 ± 6.29 years) were recruited through preidentified local area commands. Spanning nine police stations from the same Australian state, volunteers wore monitoring devices to collect physiological measures (heart rate, respiratory rate, and skin temperature) throughout the course of four consecutive shifts (two day shifts and two night shifts). Descriptive data were recorded and analyzed by task and changes in physiological measures. Results Of the 345 duty calls attended by participants, the four most commonly reported tasks were as follows: ‘check bona fides’ (n = 76; 22%), ‘driving urgently’ (n = 45; 13%), ‘attending a domestic incident’ (n = 37; 10%), and ‘attending a concern for welfare’ (n = 30; 8%). Mean percentages of maximum heart rates (%HRmax) were considered of very light exercise intensity and ranged from 47.11 (± 7.18) to 50.15 (± 9.35) % for checking bona fides through to driving urgently respectively. Fifteen percent of tasks attended had officers exceed 100 %HRmax (near maximal to maximal exercise intensity). Mean skin temperatures varied little (36.02–36.27°C) between tasks, while mean respiratory rates were lowest when attending a domestic incident and highest when driving urgently (22.56 ± 3.83 and 24.72 ± 6.12 breaths/min, respectively). Conclusion Police officers experienced numerous physiological challenges ranging from an intensity of very light exercise through to near maximal and maximal exercise throughout their working day with occasions where their heart rates exceeded 100 %HRmax. These findings highlight the physiological stress associated with common occupational policing tasks, highlighting the importance of cardiovascular health in police officers and the need for cardiovascular monitoring and conditioning.
- Published
- 2020
26. 10. New evidence for triplosensitivity of TBL1XR1
- Author
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Barbara R. DuPont, Kameryn M. Butler, Shannon Bell, Benjamin Hilton, and Katie Clarkson
- Subjects
Cancer Research ,Evolutionary biology ,Genetics ,Biology ,Molecular Biology - Published
- 2021
27. 23. Incidental findings on XON array: Our experience over the last two years
- Author
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Benjamin Hilton, Timothy Fee, Alka Chaubey, and Barbara R. DuPont
- Subjects
Cancer Research ,Genetics ,Biology ,Molecular Biology ,Developmental psychology - Published
- 2021
28. 19. De novo homozygous variant due to uniparental isodisomy results in a recessive disorder
- Author
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Allie Merrihew, Barbara R. DuPont, Jennifer M. Gass, Raymond J. Louie, Michael J. Lyons, and Benjamin Hilton
- Subjects
Genetics ,Cancer Research ,Uniparental Isodisomy ,Biology ,Molecular Biology - Published
- 2021
29. 16. Copy number variants at Chr16p11.2 and relevant clinical presentations
- Author
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Xiaolan Fang, Barbara R. DuPont, and Benjamin Hilton
- Subjects
Cancer Research ,Genetics ,Computational biology ,Copy-number variation ,Biology ,Molecular Biology - Published
- 2021
30. 17. In silico SNP array for aiding in interpretation of genomic microarray results: Application to case of mosaic trisomy 9
- Author
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Barbara R. DuPont, Benjamin Hilton, Timothy Fee, and David B. Everman
- Subjects
Cancer Research ,Microarray ,In silico ,Genetics ,medicine ,Mosaic (geodemography) ,Computational biology ,Biology ,medicine.disease ,Molecular Biology ,Trisomy 9 ,SNP array ,Interpretation (model theory) - Published
- 2021
31. Standardizing the classification of recurrent copy number variants–incorporation of sub-clinical phenotype data for CNVs with reduced penetrance
- Author
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Christa Lese Martin, Shulin Zhang, Justin Schleede, Bradley P. Coe, John Herriges, Erica F. Andersen, Prabakaran Paulraj, Benjamin Hilton, Brynn Levy, Laura K. Conlin, Vaidehi Jobanputra, and Cassandra K. Runke
- Subjects
Genetics ,Endocrinology ,Endocrinology, Diabetes and Metabolism ,Sub clinical ,Copy-number variation ,Biology ,Molecular Biology ,Biochemistry ,Penetrance ,Phenotype - Published
- 2021
32. Chronic myelomonocytic leukemia with ETV6-ABL1 rearrangement and SMC1A mutation
- Author
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Reha M. Toydemir, Alice Cluff, Benjamin Hilton, Daanish Hoda, Prabakaran Paulraj, Philippe Szankasi, Jay Patel, Kianoush Sadre-Bazzaz, and Melissa H. Cessna
- Subjects
Male ,Cancer Research ,Myeloid ,Lineage (genetic) ,Oncogene Proteins, Fusion ,Chromosomal Proteins, Non-Histone ,Mutation, Missense ,Chronic myelomonocytic leukemia ,Chromosomal translocation ,Cell Cycle Proteins ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Monocytosis ,hemic and lymphatic diseases ,Genetics ,medicine ,Missense mutation ,Humans ,Molecular Biology ,Gene Rearrangement ,ABL ,Leukemia, Myelomonocytic, Chronic ,Middle Aged ,Protein-Tyrosine Kinases ,medicine.disease ,ETV6 ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Karyotyping ,Cancer research - Abstract
Chronic myelomonocytic leukemia (CMML) is a rare malignant neoplasm of the blood-forming cells in bone marrow characterized by persistent monocytosis. Although most patients with CMML show clonal genetic aberrations, there is no known cytogenetic or molecular genetic finding that is specific to CMML. We report a patient who had a clinical and morphological presentation consistent with CMML. The genetic work-up showed an ETV6-ABL1 fusion consequent to a 9;12 translocation, and a missense mutation in SMC1A (c.1757G>A, p.Arg586Gln). The SMC1A mutations are recurrent, albeit rare, in myeloid malignancies, without an established clinical significance in CMML. ETV6-ABL1 fusion is a rare but recurrent genetic aberration found in various hematologic malignancies involving both the lymphoid and myeloid lineage, but to the best of our knowledge, CMML is an exceptionally rare presentation of ETV6-ABL1 rearranged neoplasm. ETV6-ABL1 fusion is often formed through complex rearrangements, and usually cryptic by routine G-banded chromosome analysis. The diseases associated with this rearrangement generally have an aggressive course, hence detecting or excluding this rearrangement during diagnostic work-up is critical for treatment planning.
- Published
- 2019
33. Progerin sequestration of PCNA promotes replication fork collapse and mislocalization of XPA in laminopathy-related progeroid syndromes
- Author
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Brian M. Cartwright, Hui Tang, Ji Liu, Antonio E. Rusiñol, Benjamin Hilton, Phillip R. Musich, Youjie Wang, Rowdy Jones, Yiyong Liu, Yue Zou, and Maya Breitman
- Subjects
0301 basic medicine ,Genome instability ,endocrine system ,DNA Repair ,DNA damage ,DNA repair ,Apoptosis ,Biochemistry ,Progeroid syndromes ,Histones ,03 medical and health sciences ,0302 clinical medicine ,Progeria ,Proliferating Cell Nuclear Antigen ,Genetics ,medicine ,Humans ,DNA Breaks, Double-Stranded ,RNA, Small Interfering ,Molecular Biology ,Cells, Cultured ,biology ,integumentary system ,Point mutation ,Research ,Fibroblasts ,Progerin ,medicine.disease ,Lamin Type A ,Proliferating cell nuclear antigen ,Cell biology ,Xeroderma Pigmentosum Group A Protein ,Protein Subunits ,Protein Transport ,030104 developmental biology ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,Mutation ,biology.protein ,Biotechnology - Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder that is caused by a point mutation in the LMNA gene, resulting in production of a truncated farnesylated-prelamin A protein (progerin). We previously reported that XPA mislocalized to the progerin-induced DNA double-strand break (DSB) sites, blocking DSB repair, which led to DSB accumulation, DNA damage responses, and early replication arrest in HGPS. In this study, the XPA mislocalization to DSBs occurred at stalled or collapsed replication forks, concurrent with a significant loss of PCNA at the forks, whereas PCNA efficiently bound to progerin. This PCNA sequestration likely exposed ds-ssDNA junctions at replication forks for XPA binding. Depletion of XPA or progerin each significantly restored PCNA at replication forks. Our results suggest that although PCNA is much more competitive than XPA in binding replication forks, PCNA sequestration by progerin may shift the equilibrium to favor XPA binding. Furthermore, we demonstrated that progerin-induced apoptosis could be rescued by XPA, suggesting that XPA-replication fork binding may prevent apoptosis in HGPS cells. Our results propose a mechanism for progerin-induced genome instability and accelerated replicative senescence in HGPS.-Hilton, B. A., Liu, J., Cartwright, B. M., Liu, Y., Breitman, M., Wang, Y., Jones, R., Tang, H., Rusinol, A., Musich, P. R., Zou, Y. Progerin sequestration of PCNA promotes replication fork collapse and mislocalization of XPA in laminopathy-related progeroid syndromes.
- Published
- 2017
34. Unusual sequence effects on nucleotide excision repair of arylamine lesions: DNA bending/distortion as a primary recognition factor
- Author
-
Fengting Liang, Yue Zou, Satyakam Patnaik, Alexander D. MacKerell, Benjamin Hilton, Bin Lin, Eva Darian, Bongsup P. Cho, and Vipin Jain
- Subjects
Models, Molecular ,DNA Repair ,DNA repair ,DNA damage ,Electrophoretic Mobility Shift Assay ,Context (language use) ,Molecular Dynamics Simulation ,Genome Integrity, Repair and Replication ,Biology ,010402 general chemistry ,01 natural sciences ,DNA Adducts ,03 medical and health sciences ,chemistry.chemical_compound ,Escherichia coli ,Genetics ,Aminobiphenyl Compounds ,Electrophoretic mobility shift assay ,Nuclear Magnetic Resonance, Biomolecular ,030304 developmental biology ,Fluorenes ,0303 health sciences ,Endodeoxyribonucleases ,Base Sequence ,Transition (genetics) ,Circular Dichroism ,Escherichia coli Proteins ,Deoxyguanosine ,2-Acetylaminofluorene ,Molecular biology ,0104 chemical sciences ,chemistry ,Biochemistry ,Nucleic Acid Conformation ,Thermodynamics ,DNA ,DNA Damage ,Nucleotide excision repair - Abstract
The environmental arylamine mutagens are implicated in the etiology of various sporadic human cancers. Arylamine-modified dG lesions were studied in two fully paired 11-mer duplexes with a -G*CN- sequence context, in which G* is a C8-substituted dG adduct derived from fluorinated analogs of 4-aminobiphenyl (FABP), 2-aminofluorene (FAF) or 2-acetylaminofluorene (FAAF), and N is either dA or dT. The FABP and FAF lesions exist in a simple mixture of ‘stacked’ (S) and ‘B-type’ (B) conformers, whereas the N-acetylated FAAF also samples a ‘wedge’ (W) conformer. FAAF is repaired three to four times more efficiently than FABP and FAF. A simple A- to -T polarity swap in the G*CA/G*CT transition produced a dramatic increase in syn-conformation and resulted in 2- to 3-fold lower nucleotide excision repair (NER) efficiencies in Escherichia coli. These results indicate that lesion-induced DNA bending/thermodynamic destabilization is an important DNA damage recognition factor, more so than the local S/B-conformational heterogeneity that was observed previously for FAF and FAAF in certain sequence contexts. This work represents a novel 3′-next flanking sequence effect as a unique NER factor for bulky arylamine lesions in E. coli.
- Published
- 2012
35. ATR Plays a Direct Antiapoptotic Role at Mitochondria, which Is Regulated by Prolyl Isomerase Pin1
- Author
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Xiao Zhen Zhou, Brian M. Cartwright, Kun Ping Lu, Hui Wang, Moises A. Serrano, Phillip R. Musich, Benjamin Hilton, Yue Zou, and Zhengke Li
- Subjects
Protein Conformation ,DNA damage ,Cell ,Apoptosis ,Ataxia Telangiectasia Mutated Proteins ,Mitochondrion ,Article ,03 medical and health sciences ,0302 clinical medicine ,Bcl-2-associated X protein ,stomatognathic system ,Cell Line, Tumor ,medicine ,Prolyl isomerase ,Humans ,Kinase activity ,Protein kinase A ,Molecular Biology ,030304 developmental biology ,bcl-2-Associated X Protein ,Peptidylprolyl isomerase ,0303 health sciences ,Binding Sites ,biology ,Kinase ,Cytochromes c ,Cell Biology ,Peptidylprolyl Isomerase ,HCT116 Cells ,Cell biology ,Mitochondria ,NIMA-Interacting Peptidylprolyl Isomerase ,medicine.anatomical_structure ,HEK293 Cells ,Gene Expression Regulation ,Biochemistry ,030220 oncology & carcinogenesis ,biology.protein ,PIN1 ,biological phenomena, cell phenomena, and immunity ,DNA Damage ,BH3 Interacting Domain Death Agonist Protein - Abstract
ATR, a PI3K-like protein kinase, plays a key role in regulating DNA damage responses. Its nuclear checkpoint kinase function is well documented, but little is known about its function outside the nucleus. Here we report that ATR has an antiapoptotic activity at mitochondria in response to UV damage, and this activity is independent of its hallmark checkpoint/kinase activity and partner ATRIP. ATR contains a BH3-like domain that allows ATR-tBid interaction at mitochondria, suppressing cytochrome c release and apoptosis. This mitochondrial activity of ATR is downregulated by Pin1 that isomerizes ATR from cis-isomer to trans-isomer at the phosphorylated Ser428-Pro429 motif. However, UV inactivates Pin1 via DAPK1, stabilizing the pro-survival cis-isomeric ATR. In contrast, nuclear ATR remains in the trans-isoform disregarding UV. This cytoplasmic response of ATR may provide a mechanism for the observed antiapoptotic role of ATR in suppressing carcinogenesis and its inhibition in sensitizing anticancer agents for killing of cancer cells.
- Published
- 2016
- Full Text
- View/download PDF
36. 18. Identification of a cryptic PAX7-FOXO1 rearrangement and characterization of subsequent amplification using genomic microarray in a case of alveolar rhabdomyosarcoma
- Author
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Maria Longhurst, Bo Hong, Kathryn O'Brien, Suying Xu, Benjamin Hilton, and David Scharnhorst
- Subjects
Cancer Research ,Microarray ,Genetics ,Alveolar rhabdomyosarcoma ,medicine ,Identification (biology) ,FOXO1 ,Computational biology ,PAX7 ,Biology ,medicine.disease ,Molecular Biology - Published
- 2018
37. 28. Dosage sensitivity curation of recurrent copy number variant regions
- Author
-
Vaidehi Jobanputra, Christa Lese Martin, Ted Higginbotham, John Herriges, Erik C. Thorland, Prabakaran Paulraj, Hutton M. Kearney, Laura K. Conlin, Erica F. Andersen, Lei Zhang, Bradley P. Coe, Benjamin Hilton, Karen Ouyang, Marsha Speevak, Ross A. Rowsey, Erin Rooney Riggs, and Rachel D. Burnside
- Subjects
Cancer Research ,Genetics ,Copy-number variation ,Sensitivity (control systems) ,Computational biology ,Biology ,Molecular Biology - Published
- 2018
38. Effects of Antidepressants on DSP4/CPT-Induced DNA Damage Response in Neuroblastoma SH-SY5Y Cells
- Author
-
Benjamin Hilton, Meng-Yang Zhu, Kui Cui, and Yan Wang
- Subjects
Programmed cell death ,Benzylamines ,Cell cycle checkpoint ,SH-SY5Y ,DNA damage ,Cell Survival ,Blotting, Western ,Pharmacology ,Biology ,Toxicology ,Article ,Neuroblastoma ,Cell Line, Tumor ,medicine ,Humans ,Viability assay ,Cell Death ,Dose-Response Relationship, Drug ,General Neuroscience ,Cell Cycle Checkpoints ,medicine.disease ,Flow Cytometry ,Antidepressive Agents ,Neuroprotective Agents ,Cell culture ,Autoradiography ,Camptothecin ,medicine.drug ,DNA Damage - Abstract
DNA damage is a form of cell stress and injury. Increased systemic DNA damage is related to the pathogenic development of neurodegenerative diseases. Depression occurs in a relatively high percentage of patients suffering from degenerative diseases, for whom antidepressants are often used to relieve depressive symptoms. However, few studies have attempted to elucidate why different groups of antidepressants have similar effects on relieving symptoms of depression. Previously, we demonstrated that neurotoxins N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4)- and camptothecin (CPT) induced the DNA damage response in SH-SY5Y cells, and DSP4 caused cell cycle arrest which was predominately in the S-phase. The present study shows that CPT treatment also resulted in similar cell cycle arrest. Some classic antidepressants could reduce the DNA damage response induced by DSP4 or CPT in SH-SY5Y cells. Cell viability examination demonstrated that both DSP4 and CPT caused cell death, which was prevented by spontaneous administration of some tested antidepressants. Flow cytometric analysis demonstrated that a majority of the tested antidepressants protect cells from being arrested in S-phase. These results suggest that blocking the DNA damage response may be an important pharmacologic characteristic of antidepressants. Exploring the underlying mechanisms may allow for advances in the effort to improve therapeutic strategies for depression appearing in degenerative and psychiatric diseases.
- Published
- 2015
39. A new structural insight into XPA-DNA interactions
- Author
-
Benjamin Hilton, Steven M. Shell, Nick Shkriabai, Mamuka Kvaratskhelia, Phillip R. Musich, and Yue Zou
- Subjects
Models, Molecular ,lcsh:Life ,lcsh:QR1-502 ,NHS-biotin, N-hydroxysuccinimidobiotin ,Biochemistry ,lcsh:Microbiology ,chemistry.chemical_compound ,ds/ssDNA, double-strand/single-strand DNA ,DNA junction ,0303 health sciences ,Protein footprinting ,030302 biochemistry & molecular biology ,Xeroderma Pigmentosum Group A Protein ,DNA-Binding Proteins ,GGR, global genome repair ,Protein Binding ,endocrine system ,Xeroderma pigmentosum ,HMG-box ,DNA damage ,XPA ,Molecular Sequence Data ,Biophysics ,HGPS, Hutchinson–Gilford progeria syndrome ,Biology ,DNA-binding protein ,S2 ,TCR, transcription-coupled repair ,03 medical and health sciences ,RPA, replication protein A ,NER, nucleotide excision repair ,medicine ,Humans ,Binding site ,DNA-binding domain ,Molecular Biology ,030304 developmental biology ,Original Paper ,Binding Sites ,Base Sequence ,Lysine ,Cell Biology ,DNA ,Q-TOF, quadrupole time-of-flight ,medicine.disease ,nucleotide excision repair ,XPA, Xeroderma pigmentosum group A ,Protein Structure, Tertiary ,lcsh:QH501-531 ,chemistry ,XPA–DNA binding ,DBD, DNA-binding domain ,DTT, dithiothreitol ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,MALDI-TOF, matrix-assisted laser desorption time-of-flight ,Proteolysis ,Nucleic Acid Conformation ,Nucleotide excision repair - Abstract
XPA (xeroderma pigmentosum group A) protein is an essential factor for NER (nucleotide excision repair) which is believed to be involved in DNA damage recognition/verification, NER factor recruiting and stabilization of repair intermediates. Past studies on the structure of XPA have focused primarily on XPA interaction with damaged DNA. However, how XPA interacts with other DNA structures remains unknown though recent evidence suggest that these structures could be important for its roles in both NER and non-NER activities. Previously, we reported that XPA recognizes undamaged DNA ds/ssDNA (double-strand/single-strandDNA) junctions with a binding affinity much higher than its ability to bind bulky DNA damage. To understand how this interaction occurs biochemically we implemented a structural determination of the interaction using a MS-based protein footprinting method and limited proteolysis. By monitoring surface accessibility of XPA lysines to NHS-biotin modification in the free protein and the DNA junction-bound complex we show that XPA physically interacts with the DNA junctions via two lysines, K168 and K179, located in the previously known XPA(98–219) DBD (DNA-binding domain). Importantly, we also uncovered new lysine residues, outside of the known DBD, involved in the binding. We found that residues K221, K222, K224 and K236 in the C-terminal domain are involved in DNA binding. Limited proteolysis analysis of XPA–DNA interactions further confirmed this observation. Structural modelling with these data suggests a clamp-like DBD for the XPA binding to ds/ssDNA junctions. Our results provide a novel structure-function view of XPA–DNA junction interactions.
- Published
- 2014
40. Replication factor C1, the large subunit of replication factor C, is proteolytically truncated in Hutchinson-Gilford progeria syndrome
- Author
-
Hui Tang, Ding Zhi Fang, Yue Zou, Benjamin Hilton, and Phillip R. Musich
- Subjects
Premature aging ,congenital, hereditary, and neonatal diseases and abnormalities ,Aging ,Progeria ,integumentary system ,DNA replication ,nutritional and metabolic diseases ,Cell Biology ,Biology ,RFC1 ,medicine.disease ,Progerin ,Molecular biology ,LMNA ,Replication factor C ,medicine ,Lamin - Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder because of a LMNA gene mutation that produces a mutant lamin A protein (progerin). Progerin also has been correlated to physiological aging and related diseases. However, how progerin causes the progeria remains unknown. Here, we report that the large subunit (RFC1) of replication factor C is cleaved in HGPS cells, leading to the production of a truncated RFC1 of ~ 75 kDa, which appears to be defective in loading proliferating cell nuclear antigen (PCNA) and pol δ onto DNA for replication. Interestingly, the cleavage can be inhibited by a serine protease inhibitor, suggesting that RFC1 is cleaved by a serine protease. Because of the crucial role of RFC in DNA replication, our findings provide a mechanistic interpretation for the observed early replicative arrest and premature aging phenotypes of HPGS and may lead to novel strategies in HGPS treatment. Furthermore, this unique truncated form of RFC1 may serve as a potential marker for HGPS.
- Published
- 2012
41. SmartShelter: A Sustainable power system design using energy harvesting techniques
- Author
-
Edgar Sanchez-Sinencio, Roland Ribeiro, Salvador Carreon-Bautista, Mehna Nawal, Judy Amanor-Badu, Benjamin Hilton, Leticia Ibarra, Mohamed Abouzied, Xiaosen Liu, Ethan Miller, and Jorge A. Vanegas
- Subjects
Stand-alone power system ,Architectural engineering ,Engineering ,Sustainable power ,business.industry ,Systems design ,business ,Energy harvesting ,Construction engineering - Published
- 2014
42. Structural and thermodynamic insight into E. coli UvrABC mediated incision of cluster di-acetylaminofluorene adducts on the NarI sequence
- Author
-
Benjamin Hilton, Anshu Jain, Bin Lin, Yue Zou, Bongsup P. Cho, Vipin Jain, and Alexander D. MacKerell
- Subjects
Circular dichroism ,DNA Repair ,Base pair ,DNA repair ,Stereochemistry ,DNA damage ,Molecular Dynamics Simulation ,Toxicology ,Article ,chemistry.chemical_compound ,DNA Adducts ,Escherichia coli ,Cluster Analysis ,Nucleotide ,Deoxyribonucleases, Type II Site-Specific ,Base Pairing ,chemistry.chemical_classification ,Endodeoxyribonucleases ,Base Sequence ,Escherichia coli Proteins ,General Medicine ,2-Acetylaminofluorene ,chemistry ,Biochemistry ,Oligodeoxyribonucleotides ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,Mutation ,Nucleic acid ,Thermodynamics ,DNA ,Nucleotide excision repair - Abstract
Cluster DNA damage refers to two or more lesions in a single turn of the DNA helix. Such clustering may occur with bulky DNA lesions, which may be responsible for their sequence-dependent repair and mutational outcomes. Here we prepared three 16-mer cluster duplexes in which two fluoroacetylaminofluorene adducts (dG-FAAF) are separated by zero, one, and two nucleotides in the Escherichia coli NarI mutational hot spot (5'-CTCTCG1G2CG3CCATCAC-3'): 5'-CG1*G2*CG3CC-3', 5'-CG1G2*CG3*CC-3', and 5'-CG1*G2CG3*CC-3' (G* = dG-FAAF), respectively. We conducted spectroscopic, thermodynamic, and molecular dynamics studies of these di-FAAF duplexes, and the results were compared with those of the corresponding mono-FAAF adducts in the same NarI sequence [Jain, V., et al. (2012) Nucleic Acids Res. 40, 3939-3951]. Our nucleotide excision repair results showed the diadducts were more reparable than the corresponding monoadducts. Moreover, we observed dramatic flanking base sequence effects on their repair efficiency in the following order: NarI-G2G3 > NarI-G1G3 > NarI-G1G2. The nuclear magnetic resonance, circular dichroism, ultraviolet melting, and molecular dynamics simulation results revealed that in contrast to the monoadducts, diadducts produced a synergistic effect on duplex destabilization. In addition, dG-FAAF at G2G3 and G1G3 destacks the neighboring bases, with greater destabilization occurring with the former. Overall, the results indicate the importance of base stacking and related thermal and thermodynamic destabilization in the repair of bulky cluster arylamine DNA adducts.
- Published
- 2013
43. (5'S)-8,5'-cyclo-2'-deoxyguanosine is a strong block to replication, a potent pol V-dependent mutagenic lesion, and is inefficiently repaired in Escherichia coli
- Author
-
Benjamin Hilton, Rajat S. Das, Yue Zou, Ashis K. Basu, Vijay P. Jasti, and Savithri Weerasooriya
- Subjects
DNA Replication ,congenital, hereditary, and neonatal diseases and abnormalities ,DNA Repair ,DNA polymerase ,DNA repair ,Biochemistry ,DNA polymerase delta ,Cockayne syndrome ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Escherichia coli ,Deoxyguanosine ,skin and connective tissue diseases ,SOS Response, Genetics ,030304 developmental biology ,0303 health sciences ,biology ,Rapid Report ,DNA replication ,nutritional and metabolic diseases ,Base excision repair ,DNA-Directed RNA Polymerases ,medicine.disease ,Molecular biology ,3. Good health ,chemistry ,Mutagenesis ,030220 oncology & carcinogenesis ,biology.protein ,Nucleotide excision repair - Abstract
8,5′-Cyclopurines, making up an important class of ionizing radiation-induced tandem DNA damage, are repaired only by nucleotide excision repair (NER). They accumulate in NER-impaired cells, as in Cockayne syndrome group B and certain Xeroderma Pigmentosum patients. A plasmid containing (5′S)-8,5′-cyclo-2′-deoxyguanosine (S-cdG) was replicated in Escherichia coli with specific DNA polymerase knockouts. Viability was S-cdA > S-cdG. In summary, S-cdG is a major block to DNA replication, highly mutagenic, and repaired slowly in E. coli.
- Published
- 2011
44. Samuel Alderman Lomas (1838-1901) the man with two gravestones, his brother Muscot Atkin Lomas (1840-1907) and their lives in Victorian asylums
- Author
-
Benjamin Hilton and Claire Hilton
- Subjects
Hospitals, Psychiatric ,Male ,History ,Persons with Mental Disabilities ,Medicine (miscellaneous) ,Historical Article ,History, 19th Century ,Ancient history ,History, 20th Century ,Brother ,History and Philosophy of Science ,England ,Intellectual Disability ,Humans ,Cemeteries ,Life history ,Prejudice (legal term) ,Prejudice - Abstract
Samuel Alderman Lomas died in the Hertfordshire County Asylum, Hill End, St Albans in 1901. He was buried in the asylum cemetery where two gravestones bear his name. This paper traces his life history and that of his brother Muscot Atkin Lomas. Both were classed as idiots in Victorian society and spent most of their lives – from childhood until death – in asylums.
- Published
- 2009
45. Beamed Energy Propulsion by Means of Target Ablation
- Author
-
Rosenberg, Benjamin [Hilton Head High School, Hilton Head Island, SC 29926 (United States)]
- Published
- 2004
- Full Text
- View/download PDF
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