28 results on '"Neal N."'
Search Results
2. The influence of proline isomerization on potency and stability of anti-HIV antibody 10E8
- Author
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Jian Yu, David D. Ho, Brian D. Weitzner, Neal N. Padte, Yaoxing Huang, Michele Scian, Miklos Guttman, Kelly K. Lee, and Gabriel J. Rocklin
- Subjects
0301 basic medicine ,Proline ,medicine.drug_class ,Stereochemistry ,Kinetics ,lcsh:Medicine ,Monoclonal antibody ,Gp41 ,Biochemical assays ,Epitope ,Article ,Recombinant protein therapy ,03 medical and health sciences ,0302 clinical medicine ,NMR spectroscopy ,Isomerism ,medicine ,lcsh:Science ,Conformational isomerism ,Multidisciplinary ,biology ,Chemistry ,lcsh:R ,Antibodies, Monoclonal ,SAXS ,030104 developmental biology ,biology.protein ,lcsh:Q ,Antibody therapy ,Antibody ,Isomerization ,030217 neurology & neurosurgery - Abstract
Monoclonal antibody (mAb) 10E8 recognizes a highly conserved epitope on HIV and is capable of neutralizing > 95% of circulating viral isolates making it one of the most promising Abs against HIV. Solution instability and biochemical heterogeneity of 10E8 has hampered its development for clinical use. We identify the source of 10E8 heterogeneity being linked to cis/trans isomerization at two prolines within the YPP motif in the CRD3 loop that exists as two predominant conformers that interconvert on a slow timescale. The YtransP conformation conformer can bind the HIV gp41 epitope, while the YcisP is not binding competent and shows a higher aggregation propensity. The high barrier of isomerization and propensity to adopt non-binding competent proline conformers provides novel insight into the slow binding kinetics, low potency, and poor solubility of 10E8. This study highlights how proline isomerization should be considered a critical quality attribute for biotherapeutics with paratopes containing potential cis proline amide bonds.
- Published
- 2020
3. Blending census and paleolimnological data allows for tracking the establishment and growth of a major gannet colony over several centuries.
- Author
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Bosch JL, Álvarez-Manzaneda I, Smol JP, Michelutti N, Robertson GJ, Wilhelm SI, Montevecchi WA, Lang AS, and Hargan KE
- Subjects
- Animals, Newfoundland and Labrador, Censuses, Diatoms growth & development, Population Dynamics, Chlorophyll A analysis, Geologic Sediments analysis, History, 20th Century, Birds
- Abstract
Seabird colonies with long-term monitoring records, i.e., > 50 years, are rare. The population data for northern gannets (Morus bassanus) in Cape St. Mary's (CSM) Ecological Reserve (Newfoundland and Labrador, Canada) is robust, extending back to 1883 when the colony was presumed established. We inferred the colony's historical population shifts by measuring ornithogenic proxies in a dated sediment record collected from a nearby pond. Our record extended to the early eighteenth century, but the proxy data only began to show significant signs of seabird presence between ca. 1832 and 1910, aligning with the period gannets were first observed at CSM. Through the twentieth century, we observed significant increases in δ
15 N, P, Zn, Cd, and chlorophyll a, coeval with a shift in the dominant diatom species, indicating rapid colony growth. The proxies were overall highest in ca. 2005, corresponding to the reported historical maximum of the gannet colony in 2009. Our results validate that paleo-reconstructions using ornithogenic proxies can accurately reflect population trends and provide a stronger understanding of the colony's establishment and growth. This study highlights the value of applying paleolimnological methods in seabird population studies to frame the history of a colony's dynamics and inform conservation efforts., (© 2024. The Author(s).)- Published
- 2024
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4. Intravenous immunoglobulin for patients with unexplained recurrent implantation failure: a 6-year single center retrospective review of clinical outcomes.
- Author
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Peero EK, Banjar S, Khoudja R, Ton-Leclerc S, Beauchamp C, Benoit J, Beltempo M, Dahan MH, Gold P, Kadoch IJ, Jamal W, Laskin C, Mahutte N, Phillips S, Sylvestre C, Reinblatt S, Mazer BD, Buckett W, and Genest G
- Subjects
- Female, Humans, Pregnancy, Birth Rate, Live Birth, Retrospective Studies, Immunoglobulins, Intravenous adverse effects
- Abstract
The effectiveness of intravenous immunoglobulin (IVIg) for patients with unexplained recurrent implantation failure (uRIF) remains debated. We retrospectively analysed outcomes of uRIF patients treated with IVIg compared to a separate control uRIF cohort within our center (01/2014-12/2021). Primary outcomes included live birth, miscarriage, or transfer failure. We documented IVIg side effects and maternal/fetal outcomes. Logistic regression analysis was used to assess for association of IVIg exposure with outcomes and adjust for confounders. The study included 143 patients, with a 2:1 ratio of controls to patients receiving IVIg treatment. Patient characteristics were similar between groups. There was higher live birth rate (LBR) in patients receiving IVIg (32/49; 65.3%) compared to controls (32/94; 34%); p < 0.001). When stratifying patients into moderate and severe uRIF (respectively 3-4 and [Formula: see text] 5 previous good quality blastocyst transfer failures), only patients with severe uRIF benefited from IVIg (LBR (20/29 (69%) versus 5/25 (20%) for controls, p = 0.0004). In the logistic regression analysis, IVIg was associated with higher odds of live birth (OR 3.64; 95% CI 1.78-7.67; p = 0.0004). There were no serious adverse events with IVIg. IVIg can be considered in well selected patients with [Formula: see text] 5 previous unexplained, high quality blastocyst transfer failures. A randomized controlled trial is needed to confirm these findings., (© 2024. Crown.)
- Published
- 2024
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5. The secure judgment of graphic similarity against malicious adversaries and its applications.
- Author
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Liu X, Xu Y, Luo D, Xu G, Xiong N, and Chen XB
- Abstract
With the advent of the era of big data, privacy computing analyzes and calculates data on the premise of protecting data privacy, to achieve data 'available and invisible'. As an important branch of secure multi-party computation, the geometric problem can solve practical problems in the military, national defense, finance, life, and other fields, and has important research significance. In this paper, we study the similarity problem of geometric graphics. First, this paper proposes the adjacency matrix vector coding method of isomorphic graphics, and use the Paillier variant encryption cryptography to solve the problem of isomorphic graphics confidentiality under the semi-honest model. Using cryptography tools such as elliptic curve cryptosystem, zero-knowledge proof, and cut-choose method, this paper designs a graphic similarity security decision protocol that can resist malicious adversary attacks. The analysis shows that the protocol has high computational efficiency and has wide application value in terrain matching, mechanical parts, biomolecules, face recognition, and other fields., (© 2023. The Author(s).)
- Published
- 2023
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6. Airborne dimethyl sulfide (DMS) cues dimethylsulfoniopropionate (DMSP) increases in the intertidal green alga Ulva fenestrata.
- Author
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Van Alstyne KL, Butler JK, and Smith N
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- Cues, Sulfides chemistry, Ulva metabolism, Sulfonium Compounds metabolism, Chlorophyta metabolism
- Abstract
Although the use of airborne molecules as infochemicals is common in terrestrial plants, it has not been shown to occur in an ecologically relevant context in marine seaweeds. Like terrestrial plants, intertidal plants spend part of their lives emersed at low tide and release volatile organic compounds (VOCs) into the air when they are grazed or physiologically stressed. We hypothesized seaweeds could use airborne VOCs as infochemicals and respond to them by upregulating a keystone defensive metabolite, dimethylsulfoniopropionate (DMSP). We conducted laboratory and field experiments in which Ulva fenestrata was exposed to airborne dimethyl sulfide (DMS), a volatile antiherbivore and antioxidant metabolite released when the seaweed is grazed or physiologically stressed. In the laboratory, U. fenestrata exposed to DMS had 43-48% higher DMSP concentrations, relative to controls, 6-9 days after exposure. In the field, U. fenestrata 1 m downwind of DMS emitters had 19% higher DMSP concentrations than upwind seaweeds after 11 days. To our knowledge, this is the first demonstration of a marine plant using an airborne molecule released when damaged to elicit defensive responses. Our study suggests that the ability to detect airborne compounds has evolved multiple times or before the divergence of terrestrial plants and green algae., (© 2023. The Author(s).)
- Published
- 2023
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7. Identification of large offspring syndrome during pregnancy through ultrasonography and maternal blood transcriptome analyses.
- Author
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Rivera RM, Goldkamp AK, Patel BN, Hagen DE, Soto-Moreno EJ, Li Y, Kim CN, Miller C, Williams F 3rd, Jannaman E, Xiao Y, Tribulo P, Estrada-Cortés E, Brau-Rodríguez AR, Hansen PJ, Wu Z, Spinka CM, Martin N, and Elsik CG
- Subjects
- Animals, Cattle, Female, Fetus, Pregnancy, Ultrasonography, Prenatal, Gene Expression Profiling, Insemination, Artificial veterinary
- Abstract
In vitro production (IVP) of embryos in cattle can result in large/abnormal offspring syndrome (LOS/AOS) which is characterized by macrosomia. LOS can cause dystocia and lead to the death of dam and calf. Currently, no test exists to identify LOS pregnancies. We hypothesized that fetal ultrasonography and/or maternal blood markers are useful to identify LOS. Bovine fetuses were generated by artificial insemination (control) or IVP. Fetal ultrasonographies were taken on gestation D55 (D55) and fetal collections performed on D56 or D105 (gestation in cattle ≈ D280). IVP fetuses weighing ≥ 97 percentile of the control weight were considered LOS. Ultrasonography results show that the product of six D55 measurements can be used to identify extreme cases of LOS. To determine whether maternal blood can be used to identify LOS, leukocyte mRNA from 23 females was sequenced. Unsupervised hierarchical clustering grouped the transcriptomes of the two females carrying the two largest LOS fetuses. Comparison of the leukocyte transcriptomes of these two females to the transcriptome of all other females identified several misregulated transcripts on gestation D55 and D105 with LOC783838 and PCDH1 being misregulated at both time-points. Together our data suggest that LOS is identifiable during pregnancy in cattle., (© 2022. The Author(s).)
- Published
- 2022
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8. Fusion of fully integrated analog machine learning classifier with electronic medical records for real-time prediction of sepsis onset.
- Author
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Sadasivuni S, Saha M, Bhatia N, Banerjee I, and Sanyal A
- Subjects
- Electronic Health Records, Humans, Machine Learning, Vital Signs, Artificial Intelligence, Sepsis diagnosis
- Abstract
The objective of this work is to develop a fusion artificial intelligence (AI) model that combines patient electronic medical record (EMR) and physiological sensor data to accurately predict early risk of sepsis. The fusion AI model has two components-an on-chip AI model that continuously analyzes patient electrocardiogram (ECG) data and a cloud AI model that combines EMR and prediction scores from on-chip AI model to predict fusion sepsis onset score. The on-chip AI model is designed using analog circuits for sepsis prediction with high energy efficiency for integration with resource constrained wearable device. Combination of EMR and sensor physiological data improves prediction performance compared to EMR or physiological data alone, and the late fusion model has an accuracy of 93% in predicting sepsis 4 h before onset. The key differentiation of this work over existing sepsis prediction literature is the use of single modality patient vital (ECG) and simple demographic information, instead of comprehensive laboratory test results and multiple vital signs. Such simple configuration and high accuracy makes our solution favorable for real-time, at-home use for self-monitoring., (© 2022. The Author(s).)
- Published
- 2022
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9. Characterization of mitochondrial health from human peripheral blood mononuclear cells to cerebral organoids derived from induced pluripotent stem cells.
- Author
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Duong A, Evstratova A, Sivitilli A, Hernandez JJ, Gosio J, Wahedi A, Sondheimer N, Wrana JL, Beaulieu JM, Attisano L, and Andreazza AC
- Subjects
- Biomarkers, Cell Culture Techniques, Cellular Reprogramming genetics, Electrophysiological Phenomena, Fluorescent Antibody Technique, Mitochondria genetics, Mitochondria ultrastructure, Organoids, Synapses physiology, Synaptic Transmission, Cell Differentiation, Induced Pluripotent Stem Cells cytology, Induced Pluripotent Stem Cells metabolism, Leukocytes, Mononuclear cytology, Leukocytes, Mononuclear metabolism, Mitochondria metabolism, Neurogenesis
- Abstract
Mitochondrial health plays a crucial role in human brain development and diseases. However, the evaluation of mitochondrial health in the brain is not incorporated into clinical practice due to ethical and logistical concerns. As a result, the development of targeted mitochondrial therapeutics remains a significant challenge due to the lack of appropriate patient-derived brain tissues. To address these unmet needs, we developed cerebral organoids (COs) from induced pluripotent stem cells (iPSCs) derived from human peripheral blood mononuclear cells (PBMCs) and monitored mitochondrial health from the primary, reprogrammed and differentiated stages. Our results show preserved mitochondrial genetics, function and treatment responses across PBMCs to iPSCs to COs, and measurable neuronal activity in the COs. We expect our approach will serve as a model for more widespread evaluation of mitochondrial health relevant to a wide range of human diseases using readily accessible patient peripheral (PBMCs) and stem-cell derived brain tissue samples.
- Published
- 2021
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10. Author Correction: A pre-Inca pot from underwater ruins discovered in an Andean lake provides a sedimentary record of marked hydrological change.
- Author
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Michelutti N, Sowell P, Tapia PM, Grooms C, Polo M, Gambetta A, Ausejo C, and Smol JP
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2020
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11. Bitumen from the Dead Sea in Early Iron Age Nubia.
- Author
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Fulcher K, Stacey R, and Spencer N
- Abstract
Bitumen has been identified for the first time in Egyptian occupied Nubia, from within the town of Amara West, occupied from around 1300 to 1050 BC. The bitumen can be sourced to the Dead Sea using biomarkers, evidencing a trade in this material from the eastern Mediterranean to Nubia in the New Kingdom or its immediate aftermath. Two different end uses for bitumen were determined at the site. Ground bitumen was identified in several paint palettes, and in one case can be shown to have been mixed with plant gum, which indicates the use of bitumen as a ground pigment. Bitumen was also identified as a component of a friable black solid excavated from a tomb, and a black substance applied to the surface of a painted and plastered coffin fragment. Both contained plant resin, indicating that this substance was probably applied as a ritual funerary liquid, a practice identified from this time period in Egypt. The use of this ritual, at a far remove from the royal Egyptian burial sites at Thebes, indicates the importance of this ritual as a component of the funeral, and the value attributed to the material components of the black liquid.
- Published
- 2020
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12. Comparative Proteomics Reveal Me31B's Interactome Dynamics, Expression Regulation, and Assembly Mechanism into Germ Granules during Drosophila Germline Development.
- Author
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McCambridge A, Solanki D, Olchawa N, Govani N, Trinidad JC, and Gao M
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- Animals, Arabidopsis Proteins metabolism, Drosophila melanogaster metabolism, Embryo, Nonmammalian metabolism, Female, Gene Expression Regulation, Developmental, Membrane Transport Proteins metabolism, Oocytes metabolism, Peptide Initiation Factors metabolism, Protein Interaction Maps, Ribonucleoproteins metabolism, DEAD-box RNA Helicases metabolism, Drosophila Proteins metabolism, Drosophila melanogaster growth & development, Oocytes growth & development, Proteomics methods
- Abstract
Me31B is a protein component of Drosophila germ granules and plays an important role in germline development by interacting with other proteins and RNAs. To understand the dynamic changes that the Me31B interactome undergoes from oogenesis to early embryogenesis, we characterized the early embryo Me31B interactome and compared it to the known ovary interactome. The two interactomes shared RNA regulation proteins, glycolytic enzymes, and cytoskeleton/motor proteins, but the core germ plasm proteins Vas, Tud, and Aub were significantly decreased in the embryo interactome. Our follow-up on two RNA regulations proteins present in both interactomes, Tral and Cup, revealed that they colocalize with Me31B in nuage granules, P-bodies/sponge bodies, and possibly in germ plasm granules. We further show that Tral and Cup are both needed for maintaining Me31B protein level and mRNA stability, with Tral's effect being more specific. In addition, we provide evidence that Me31B likely colocalizes and interacts with germ plasm marker Vas in the ovaries and early embryo germ granules. Finally, we show that Me31B's localization in germ plasm is likely independent of the Osk-Vas-Tud-Aub germ plasm assembly pathway although its proper enrichment in the germ plasm may still rely on certain conserved germ plasm proteins.
- Published
- 2020
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13. A pre-Inca pot from underwater ruins discovered in an Andean lake provides a sedimentary record of marked hydrological change.
- Author
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Michelutti N, Sowell P, Tapia PM, Grooms C, Polo M, Gambetta A, Ausejo C, and Smol JP
- Abstract
Pre-Hispanic artifacts and sacred architecture were recently discovered submerged in a large lake (Laguna Sibinacocha) in the Peruvian Andes. The underwater ruins indicate a dramatic shift in the region's hydrology but the timing and triggers of this shift remain unknown. In a novel approach blending archaeology and paleoecology, we analyzed a sediment sequence from within one of the recovered artifacts, specifically a pot from the Late Intermediate Period (~1000-1400 CE). Radioisotopic dating of discrete sediment intervals sampled from the pot show a stratigraphically intact profile that preserves a history of change at this site. The pot's basal sediment age places the timing of lake-level rise at ~1600 CE, which post-dates the end of the Inca Empire (1400-1532 CE) by several decades. The ubiquity of planktonic algae throughout the sediment profile suggests water levels remained high above the pot since its submergence. Paleoclimate data from the nearby Quelccaya ice core records indicate lake flooding followed a pronounced wet period beginning ~1520 CE. These data show the permanence of mean state changes in climate on the region's hydrology, with clear implications for the study site (an important water resource for ~500,000 people) and other lakes in the rapidly warming Andes.
- Published
- 2019
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14. The browning and re-browning of lakes: Divergent lake-water organic carbon trends linked to acid deposition and climate change.
- Author
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Meyer-Jacob C, Michelutti N, Paterson AM, Cumming BF, Keller WB, and Smol JP
- Abstract
Dissolved organic carbon (DOC) concentrations and water colour are increasing in many inland waters across northern Europe and northeastern North America. This inland-water "browning" has profound physical, chemical and biological repercussions for aquatic ecosystems affecting water quality, biological community structures and aquatic productivity. Potential drivers of this "browning" trend are complex and include reductions in atmospheric acid deposition, changes in land use/cover, increased nitrogen deposition and climate change. However, because of the overlapping impacts of these stressors, their relative contributions to DOC dynamics remain unclear, and without appropriate long-term monitoring data, it has not been possible to determine whether the ongoing "browning" is unprecedented or simply a "re-browning" to pre-industrial DOC levels. Here, we demonstrate the long-term impacts of acid deposition and climate change on lake-water DOC concentrations in low and high acid-deposition areas using infrared spectroscopic techniques on ~200-year-long lake-sediment records from central Canada. We show that acid deposition suppressed naturally higher DOC concentrations during the 20th century, but that a "re-browning" of lakes is now occurring with emissions reductions in formerly high deposition areas. In contrast, in low deposition areas, climate change is forcing lakes towards new ecological states, as lake-water DOC concentrations now often exceed pre-industrial levels.
- Published
- 2019
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15. Reversal of Surfactant Protein B Deficiency in Patient Specific Human Induced Pluripotent Stem Cell Derived Lung Organoids by Gene Therapy.
- Author
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Leibel SL, Winquist A, Tseu I, Wang J, Luo D, Shojaie S, Nathan N, Snyder E, and Post M
- Subjects
- Cell Differentiation, Epithelial Cells physiology, Fibroblasts cytology, Genetic Markers, Green Fluorescent Proteins genetics, Humans, Induced Pluripotent Stem Cells transplantation, Lentivirus genetics, Organoids, Pulmonary Alveolar Proteinosis genetics, Pulmonary Alveolar Proteinosis therapy, Pulmonary Alveoli cytology, Pulmonary Surfactant-Associated Protein B genetics, Genetic Therapy methods, Induced Pluripotent Stem Cells cytology, Lung cytology, Pulmonary Alveolar Proteinosis congenital, Pulmonary Surfactant-Associated Protein B deficiency
- Abstract
Surfactant protein B (SFTPB) deficiency is a fatal disease affecting newborn infants. Surfactant is produced by alveolar type II cells which can be differentiated in vitro from patient specific induced pluripotent stem cell (iPSC)-derived lung organoids. Here we show the differentiation of patient specific iPSCs derived from a patient with SFTPB deficiency into lung organoids with mesenchymal and epithelial cell populations from both the proximal and distal portions of the human lung. We alter the deficiency by infecting the SFTPB deficient iPSCs with a lentivirus carrying the wild type SFTPB gene. After differentiating the mutant and corrected cells into lung organoids, we show expression of SFTPB mRNA during endodermal and organoid differentiation but the protein product only after organoid differentiation. We also show the presence of normal lamellar bodies and the secretion of surfactant into the cell culture medium in the organoids of lentiviral infected cells. These findings suggest that a lethal lung disease can be targeted and corrected in a human lung organoid model in vitro.
- Published
- 2019
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16. Global view of the RAF-MEK-ERK module and its immediate downstream effectors.
- Author
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Santini CC, Longden J, Schoof EM, Simpson CD, Jeschke GR, Creixell P, Kim J, Wu X, Turk BE, Rosen N, Poulikakos PI, and Linding R
- Subjects
- Apoptosis drug effects, Cell Line, Tumor, Drug Resistance, Neoplasm drug effects, Extracellular Signal-Regulated MAP Kinases metabolism, Humans, MAP Kinase Signaling System drug effects, Melanoma pathology, Mitogen-Activated Protein Kinase Kinases metabolism, Phosphorylation drug effects, Proteome, Proteomics methods, Proto-Oncogene Proteins B-raf metabolism, Skin Neoplasms pathology, Extracellular Signal-Regulated MAP Kinases antagonists & inhibitors, Imidazoles pharmacology, Indazoles pharmacology, Melanoma metabolism, Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors, Oximes pharmacology, Piperazines pharmacology, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Pyridones pharmacology, Pyrimidinones pharmacology, Skin Neoplasms metabolism
- Abstract
Small molecule inhibitors of BRAF and MEK have proven effective at inhibiting tumor growth in melanoma patients, however this efficacy is limited due to the almost universal development of drug resistance. To provide advanced insight into the signaling responses that occur following kinase inhibition we have performed quantitative (phospho)-proteomics of human melanoma cells treated with either dabrafenib, a BRAF inhibitor; trametinib, a MEK inhibitor or SCH772984, an ERK inhibitor. Over nine experiments we identified 7827 class I phosphorylation sites on 4960 proteins. This included 54 phosphorylation sites that were significantly down-modulated after exposure to all three inhibitors, 34 of which have not been previously reported. Functional analysis of these novel ERK targets identified roles for them in GTPase activity and regulation, apoptosis and cell-cell adhesion. Comparison of the results presented here with previously reported phosphorylation sites downstream of ERK showed a limited degree of overlap suggesting that ERK signaling responses may be highly cell line and cue specific. In addition we identified 26 phosphorylation sites that were only responsive to dabrafenib. We provide further orthogonal experimental evidence for 3 of these sites in human embryonic kidney cells over-expressing BRAF as well as further computational insights using KinomeXplorer. The validated phosphorylation sites were found to be involved in actin regulation, which has been proposed as a novel mechanism for inhibiting resistance development. These results would suggest that the linearity of the BRAF-MEK-ERK module is at least context dependent.
- Published
- 2019
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17. Hybrid 3D ranging and velocity tracking system combining multi-view cameras and simple LiDAR.
- Author
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Radwell N, Selyem A, Mertens L, Edgar MP, and Padgett MJ
- Abstract
Scanning our surroundings has become one of the key challenges in automation. Effective and efficient position, distance and velocity sensing is key to accurate decision making in automated applications from robotics to driverless cars. Light detection and ranging (LiDAR) has become a key tool in these 3D sensing applications, where the time-of-flight (TOF) of photons is used to recover distance information. These systems typically rely on scanning of a laser spot to recover position information. Here we demonstrate a hybrid LiDAR approach which combines a multi-view camera system for position and distance information, and a simple (scanless) LiDAR system for velocity tracking and depth accuracy. We show that we are able to combine data from the two component systems to provide a compound image of a scene with position, depth and velocity data at more than 1 frame per second with depth accuracy of 2.5 cm or better. This hybrid approach avoids the bulk and expense of scanning systems while adding velocity information. We hope that this approach will offer a simpler, more robust alternative to 3D scanning systems for autonomous vehicles.
- Published
- 2019
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18. Utility of 15(S)-HETE as a Serological Marker for Eosinophilic Esophagitis.
- Author
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Lu S, Herzlinger M, Cao W, Noble L, Yang D, Shapiro J, Kurtis J, LeLeiko N, and Resnick M
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- Area Under Curve, Biomarkers blood, Biopsy, Cell Count, Child, Cytokines blood, Diagnosis, Differential, Eosinophilic Esophagitis diagnosis, Eosinophils pathology, Esophageal Diseases blood, Esophageal Diseases diagnosis, Esophagoscopy, Female, Humans, Male, Sensitivity and Specificity, Eosinophilic Esophagitis blood, Hydroxyeicosatetraenoic Acids blood
- Abstract
The pathogenesis of eosinophilic esophagitis (EoE) involves Th2-mediated eosinophil recruitment and degranulation into the esophagus. However, measuring serum Th2 cytokines, eosinophils, and eosinophil-derived products does not reliably distinguish EoE from control populations. Non-invasive methods to diagnose EoE are lacking. We evaluated the diagnostic value of a novel candidate biomarker of EoE: 15(S)-hydroxyeicosatetraenoic acid (HETE). We used immunoassay to measure 15(S)-HETE and cytokine profiles in patients undergoing endoscopy with known or suspected EoE. 31 subjects were enrolled, 16 with EoE, and 15 with an alternate diagnosis. 15(S)-HETE was elevated in the EoE group compared to non-EoE group. The sensitivity and specificity of 15(S)-HETE to be used as a non-invasive marker is 50% and 80%, respectively. 15(S)-HETE may aid in the diagnosis of EoE.
- Published
- 2018
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19. Cerium oxide nanoparticles with antioxidant capabilities and gadolinium integration for MRI contrast enhancement.
- Author
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Eriksson P, Tal AA, Skallberg A, Brommesson C, Hu Z, Boyd RD, Olovsson W, Fairley N, Abrikosov IA, Zhang X, and Uvdal K
- Abstract
The chelating gadolinium-complex is routinely used as magnetic resonance imaging (MRI) -contrast enhancer. However, several safety issues have recently been reported by FDA and PRAC. There is an urgent need for the next generation of safer MRI-contrast enhancers, with improved local contrast and targeting capabilities. Cerium oxide nanoparticles (CeNPs) are designed with fractions of up to 50% gadolinium to utilize the superior MRI-contrast properties of gadolinium. CeNPs are well-tolerated in vivo and have redox properties making them suitable for biomedical applications, for example scavenging purposes on the tissue- and cellular level and during tumor treatment to reduce in vivo inflammatory processes. Our near edge X-ray absorption fine structure (NEXAFS) studies show that implementation of gadolinium changes the initial co-existence of oxidation states Ce
3+ and Ce4+ of cerium, thereby affecting the scavenging properties of the nanoparticles. Based on ab initio electronic structure calculations, we describe the most prominent spectral features for the respective oxidation states. The as-prepared gadolinium-implemented CeNPs are 3-5 nm in size, have r1 -relaxivities between 7-13 mM-1 s-1 and show clear antioxidative properties, all of which means they are promising theranostic agents for use in future biomedical applications.- Published
- 2018
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20. Optimization of ClpXP activity and protein synthesis in an E. coli extract-based cell-free expression system.
- Author
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Shi X, Wu T, M Cole C, K Devaraj N, and Joseph S
- Subjects
- Adenosine Triphosphate chemistry, Adenosine Triphosphate genetics, Endopeptidase Clp chemistry, Escherichia coli chemistry, Escherichia coli metabolism, Escherichia coli Proteins chemistry, Promoter Regions, Genetic, Protein Biosynthesis genetics, Synthetic Biology, Cell-Free System, Endopeptidase Clp genetics, Escherichia coli genetics, Escherichia coli Proteins genetics, Transcription, Genetic
- Abstract
Protein degradation is a fundamental process in all living cells and is essential to remove both damaged proteins and intact proteins that are no longer needed by the cell. We are interested in creating synthetic genetic circuits that function in a cell-free expression system. This will require not only an efficient protein expression platform but also a robust protein degradation system in cell extract. Therefore, we purified and tested the activity of E. coli ClpXP protease in cell-free transcription-translation (TX-TL) systems that used E. coli S30 cell extract. Surprisingly, our studies showed that purified ClpXP added to the TX-TL system has very low proteolytic activity. The low activity of ClpXP was correlated with the rapid consumption of adenosine triphosphate (ATP) in cell extract. We improved the activity of ClpXP in cell extract by adding exogenous ATP and an energy regeneration system. We then established conditions for both protein synthesis, and protein degradation by ClpXP to occur simultaneously in the TX-TL systems. The optimized conditions for ClpXP activity will be useful for creating tunable synthetic genetic circuits and in vitro synthetic biology.
- Published
- 2018
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21. Peptide Sequencing Directly on Solid Surfaces Using MALDI Mass Spectrometry.
- Author
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Zhao ZG, Cordovez LA, Johnston SA, and Woodbury N
- Subjects
- Amino Acids chemistry, Sequence Analysis methods, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization methods, Peptides chemistry
- Abstract
There are an increasing variety of applications in which peptides are both synthesized and used attached to solid surfaces. This has created a need for high throughput sequence analysis directly on surfaces. However, common sequencing approaches that can be adapted to surface bound peptides lack the throughput often needed in library-based applications. Here we describe a simple approach for sequence analysis directly on solid surfaces that is both high speed and high throughput, utilizing equipment available in most protein analysis facilities. In this approach, surface bound peptides, selectively labeled at their N-termini with a positive charge-bearing group, are subjected to controlled degradation in ammonia gas, resulting in a set of fragments differing by a single amino acid that remain spatially confined on the surface they were bound to. These fragments can then be analyzed by MALDI mass spectrometry, and the peptide sequences read directly from the resulting spectra.
- Published
- 2017
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22. Neuroprotective Effects of Trigeminal Nerve Stimulation in Severe Traumatic Brain Injury.
- Author
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Chiluwal A, Narayan RK, Chaung W, Mehan N, Wang P, Bouton CE, Golanov EV, and Li C
- Subjects
- Animals, Cerebrovascular Circulation, Interleukin-6 metabolism, Male, Oxygen Consumption, Rats, Rats, Sprague-Dawley, Tumor Necrosis Factor-alpha metabolism, Brain Injuries, Traumatic therapy, Electric Stimulation Therapy methods, Trigeminal Nerve physiology
- Abstract
Following traumatic brain injury (TBI), ischemia and hypoxia play a major role in further worsening of the damage, a process referred to as 'secondary injury'. Protecting neurons from causative factors of secondary injury has been the guiding principle of modern TBI management. Stimulation of trigeminal nerve induces pressor response and improves cerebral blood flow (CBF) by activating the rostral ventrolateral medulla. Moreover, it causes cerebrovasodilation through the trigemino-cerebrovascular system and trigemino-parasympathetic reflex. These effects are capable of increasing cerebral perfusion, making trigeminal nerve stimulation (TNS) a promising strategy for TBI management. Here, we investigated the use of electrical TNS for improving CBF and brain oxygen tension (PbrO
2 ), with the goal of decreasing secondary injury. Severe TBI was produced using controlled cortical impact (CCI) in a rat model, and TNS treatment was delivered for the first hour after CCI. In comparison to TBI group, TBI animals with TNS treatment demonstrated significantly increased systemic blood pressure, CBF and PbrO2 at the hyperacute phase of TBI. Furthermore, rats in TNS-treatment group showed significantly reduced brain edema, blood-brain barrier disruption, lesion volume, and brain cortical levels of TNF-α and IL-6. These data provide strong early evidence that TNS could be an effective neuroprotective strategy.- Published
- 2017
- Full Text
- View/download PDF
23. A Russian Dolls ordering of the Hadamard basis for compressive single-pixel imaging.
- Author
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Sun MJ, Meng LT, Edgar MP, Padgett MJ, and Radwell N
- Abstract
Single-pixel imaging is an alternate imaging technique particularly well-suited to imaging modalities such as hyper-spectral imaging, depth mapping, 3D profiling. However, the single-pixel technique requires sequential measurements resulting in a trade-off between spatial resolution and acquisition time, limiting real-time video applications to relatively low resolutions. Compressed sensing techniques can be used to improve this trade-off. However, in this low resolution regime, conventional compressed sensing techniques have limited impact due to lack of sparsity in the datasets. Here we present an alternative compressed sensing method in which we optimize the measurement order of the Hadamard basis, such that at discretized increments we obtain complete sampling for different spatial resolutions. In addition, this method uses deterministic acquisition, rather than the randomized sampling used in conventional compressed sensing. This so-called 'Russian Dolls' ordering also benefits from minimal computational overhead for image reconstruction. We find that this compressive approach performs as well as other compressive sensing techniques with greatly simplified post processing, resulting in significantly faster image reconstruction. Therefore, the proposed method may be useful for single-pixel imaging in the low resolution, high-frame rate regime, or video-rate acquisition.
- Published
- 2017
- Full Text
- View/download PDF
24. A Formulated TLR7/8 Agonist is a Flexible, Highly Potent and Effective Adjuvant for Pandemic Influenza Vaccines.
- Author
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Van Hoeven N, Fox CB, Granger B, Evers T, Joshi SW, Nana GI, Evans SC, Lin S, Liang H, Liang L, Nakajima R, Felgner PL, Bowen RA, Marlenee N, Hartwig A, Baldwin SL, Coler RN, Tomai M, Elvecrog J, Reed SG, and Carter D
- Subjects
- Humans, Adjuvants, Immunologic, Influenza A Virus, H5N1 Subtype immunology, Influenza Vaccines, Influenza, Human prevention & control, Toll-Like Receptor 7 agonists, Toll-Like Receptor 8 agonists
- Abstract
Since 1997, highly pathogenic avian influenza viruses of the H5N1 subtype have been transmitted from avian hosts to humans. The severity of H5N1 infection in humans, as well as the sporadic nature of H5N1 outbreaks, both geographically and temporally, make generation of an effective vaccine a global public health priority. An effective H5N1 vaccine must ultimately provide protection against viruses from diverse clades. Toll-like receptor (TLR) agonist adjuvant formulations have a demonstrated ability to broaden H5N1 vaccine responses in pre-clinical models. However, many of these agonist molecules have proven difficult to develop clinically. Here, we describe comprehensive adjuvant formulation development of the imidazoquinoline TLR-7/8 agonist 3M-052, in combination with H5N1 hemagglutinin (HA) based antigens. We find that 3M-052 in multiple formulations protects both mice and ferrets from lethal H5N1 homologous virus challenge. Furthermore, we conclusively demonstrate the ability of 3M-052 adjuvant formulations to broaden responses to H5N1 HA based antigens, and show that this broadening is functional using a heterologous lethal virus challenge in ferrets. Given the extensive clinical use of imidazoquinoline TLR agonists for other indications, these studies identify multiple adjuvant formulations which may be rapidly advanced into clinical trials in an H5N1 vaccine.
- Published
- 2017
- Full Text
- View/download PDF
25. Early exposure to thirdhand cigarette smoke affects body mass and the development of immunity in mice.
- Author
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Hang B, Snijders AM, Huang Y, Schick SF, Wang P, Xia Y, Havel C, Jacob P 3rd, Benowitz N, Destaillats H, Gundel LA, and Mao JH
- Subjects
- Animals, Blood Cell Count, Female, Male, Mice, Mice, Inbred C57BL, Body Weight, Hematopoiesis, Tobacco Smoke Pollution adverse effects
- Abstract
Thirdhand smoke (THS) is the fraction of cigarette smoke that persists in indoor environments after smoking. We investigated the effects of neonatal and adult THS exposure on bodyweight and blood cell populations in C57BL/6 J mice. At the end of neonatal exposure, THS-treated male and female mice had significantly lower bodyweight than their respective control mice. However, five weeks after neonatal exposure ended, THS-treated mice weighed the same as controls. In contrast, adult THS exposure did not change bodyweight of mice. On the other hand, both neonatal and adult THS exposure had profound effects on the hematopoietic system. Fourteen weeks after neonatal THS exposure ended, eosinophil number and platelet volume were significantly higher, while hematocrit, mean cell volume, and platelet counts were significantly lower compared to control. Similarly, adult THS exposure also decreased platelet counts and increased neutrophil counts. Moreover, both neonatal and adult THS exposure caused a significant increase in percentage of B-cells and significantly decreased percentage of myeloid cells. Our results demonstrate that neonatal THS exposure decreases bodyweight and that THS exposure induces persistent changes in the hematopoietic system independent of age at exposure. These results also suggest that THS exposure may have adverse effects on human health., Competing Interests: The authors declare no competing financial interests.
- Published
- 2017
- Full Text
- View/download PDF
26. Rapid fusion between mesenchymal stem cells and cardiomyocytes yields electrically active, non-contractile hybrid cells.
- Author
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Shadrin IY, Yoon W, Li L, Shepherd N, and Bursac N
- Subjects
- Actinin genetics, Actinin metabolism, Action Potentials drug effects, Animals, Caffeine pharmacology, Calcium chemistry, Calcium metabolism, Calcium Channels, L-Type metabolism, Cell Movement, Cells, Cultured, Coculture Techniques, Connexin 43 genetics, Connexin 43 metabolism, Humans, Ions chemistry, Ions metabolism, Mesenchymal Stem Cells metabolism, Microscopy, Video, Myocytes, Cardiac metabolism, Myosin Type II chemistry, Myosin Type II metabolism, Rats, Rats, Sprague-Dawley, Real-Time Polymerase Chain Reaction, Time-Lapse Imaging, Troponin T genetics, Troponin T metabolism, Cell Fusion, Mesenchymal Stem Cells cytology, Myocytes, Cardiac cytology
- Abstract
Cardiac cell therapies involving bone marrow-derived human mesenchymal stem cells (hMSCs) have shown promising results, although their mechanisms of action are still poorly understood. Here, we investigated direct interactions between hMSCs and cardiomyocytes in vitro. Using a genetic Ca(2+) indicator gCaMP3 to efficiently label hMSCs in co-cultures with neonatal rat ventricular myocytes (NRVMs), we determined that 25-40% of hMSCs (from 4 independent donors) acquired periodic Ca(2+) transients and cardiac markers through spontaneous fusion with NRVMs. Sharp electrode and voltage-clamp recordings in fused cells showed action potential properties and Ca(2+) current amplitudes in between those of non-fused hMSCs and NRVMs. Time-lapse video-microscopy revealed the first direct evidence of active fusion between hMSCs and NRVMs within several hours of co-culture. Application of blebbistatin, nifedipine or verapamil caused complete and reversible inhibition of fusion, suggesting potential roles for actomyosin bridging and Ca(2+) channels in the fusion process. Immunostaining for Cx43, Ki67, and sarcomeric α-actinin showed that fused cells remain strongly coupled to surrounding NRVMs, but downregulate sarcomeric structures over time, acquiring a non-proliferative and non-contractile phenotype. Overall, these results describe the phenotype and mechanisms of hybrid cell formation via fusion of hMSCs and cardiomyocytes with potential implications for cardiac cell therapy.
- Published
- 2015
- Full Text
- View/download PDF
27. Residual force depression in single sarcomeres is abolished by MgADP-induced activation.
- Author
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Trecarten N, Minozzo FC, Leite FS, and Rassier DE
- Subjects
- Adenosine Diphosphate pharmacology, Animals, Calcium metabolism, Muscle Contraction physiology, Muscle, Skeletal drug effects, Rabbits, Sarcomeres drug effects, Adenosine Diphosphate metabolism, Muscle, Skeletal physiology, Sarcomeres physiology
- Abstract
The mechanisms behind the shortening-induced force depression commonly observed in skeletal muscles remain unclear, but have been associated with sarcomere length non-uniformity and/or crossbridge inhibition. The purpose of this study was twofold: (i) to evaluate if force depression is present in isolated single sarcomeres, a preparation that eliminates sarcomere length non-uniformities and (ii) to evaluate if force depression is inhibited when single sarcomeres are activated with MgADP, which biases crossbridges into a strongly-bound state. Single sarcomeres (n = 16) were isolated from rabbit psoas myofibrils using two micro-needles (one compliant, one rigid), piercing the sarcomere externally adjacent to the Z-lines. The sarcomeres were contracted isometrically and subsequently shortened, in both Ca(2+)- and MgADP-activating solutions. Shortening in Ca(2+)-activated samples resulted in a 27.44 ± 9.04% force depression when compared to isometric contractions produced at similar final sarcomere lengths (P < 0.001). There was no force depression in MgADP-activated sarcomeres (force depression = -1.79 ± 9.69%, P = 0.435). These results suggest that force depression is a sarcomeric property, and that is associated with an inhibition of myosin-actin interactions.
- Published
- 2015
- Full Text
- View/download PDF
28. Simultaneous real-time visible and infrared video with single-pixel detectors.
- Author
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Edgar MP, Gibson GM, Bowman RW, Sun B, Radwell N, Mitchell KJ, Welsh SS, and Padgett MJ
- Abstract
Conventional cameras rely upon a pixelated sensor to provide spatial resolution. An alternative approach replaces the sensor with a pixelated transmission mask encoded with a series of binary patterns. Combining knowledge of the series of patterns and the associated filtered intensities, measured by single-pixel detectors, allows an image to be deduced through data inversion. In this work we extend the concept of a 'single-pixel camera' to provide continuous real-time video at 10 Hz , simultaneously in the visible and short-wave infrared, using an efficient computer algorithm. We demonstrate our camera for imaging through smoke, through a tinted screen, whilst performing compressive sampling and recovering high-resolution detail by arbitrarily controlling the pixel-binning of the masks. We anticipate real-time single-pixel video cameras to have considerable importance where pixelated sensors are limited, allowing for low-cost, non-visible imaging systems in applications such as night-vision, gas sensing and medical diagnostics.
- Published
- 2015
- Full Text
- View/download PDF
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