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Phenome-based approach identifies RIC1-linked Mendelian syndrome through zebrafish models, biobank associations and clinical studies.
Unlu G, Qi X, Gamazon ER, Melville DB, Patel N, Rushing AR, Hashem M, Al-Faifi A, Chen R, Li B, Cox NJ, Alkuraya FS, Knapik EW
(2020) Nat Med 26: 98-109
MeSH Terms: Abnormalities, Multiple, Animals, Behavior, Animal, Biological Specimen Banks, Chondrocytes, Disease Models, Animal, Extracellular Matrix, Fibroblasts, Guanine Nucleotide Exchange Factors, Humans, Models, Biological, Musculoskeletal System, Osteogenesis, Phenomics, Phenotype, Procollagen, Protein Transport, Secretory Pathway, Syndrome, Zebrafish, Zebrafish Proteins
Show Abstract · Added January 15, 2020
Discovery of genotype-phenotype relationships remains a major challenge in clinical medicine. Here, we combined three sources of phenotypic data to uncover a new mechanism for rare and common diseases resulting from collagen secretion deficits. Using a zebrafish genetic screen, we identified the ric1 gene as being essential for skeletal biology. Using a gene-based phenome-wide association study (PheWAS) in the EHR-linked BioVU biobank, we show that reduced genetically determined expression of RIC1 is associated with musculoskeletal and dental conditions. Whole-exome sequencing identified individuals homozygous-by-descent for a rare variant in RIC1 and, through a guided clinical re-evaluation, it was discovered that they share signs with the BioVU-associated phenome. We named this new Mendelian syndrome CATIFA (cleft lip, cataract, tooth abnormality, intellectual disability, facial dysmorphism, attention-deficit hyperactivity disorder) and revealed further disease mechanisms. This gene-based, PheWAS-guided approach can accelerate the discovery of clinically relevant disease phenome and associated biological mechanisms.
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21 MeSH Terms
Local, nonlinear effects of cGMP and Ca2+ reduce single photon response variability in retinal rods.
Caruso G, Gurevich VV, Klaus C, Hamm H, Makino CL, DiBenedetto E
(2019) PLoS One 14: e0225948
MeSH Terms: Algorithms, Animals, Biomarkers, Calcium, Cyclic GMP, Mice, Models, Biological, Photons, Retinal Rod Photoreceptor Cells, Rod Cell Outer Segment, Signal Transduction
Show Abstract · Added March 18, 2020
The single photon response (SPR) in vertebrate photoreceptors is inherently variable due to several stochastic events in the phototransduction cascade, the main one being the shutoff of photoactivated rhodopsin. Deactivation is driven by a random number of steps, each of random duration with final quenching occurring after a random delay. Nevertheless, variability of the SPR is relatively low, making the signal highly reliable. Several biophysical and mathematical mechanisms contributing to variability suppression have been examined by the authors. Here we investigate the contribution of local depletion of cGMP by PDE*, the non linear dependence of the photocurrent on cGMP, Ca2+ feedback by making use of a fully space resolved (FSR) mathematical model, applied to two species (mouse and salamander), by varying the cGMP diffusion rate severalfold and rod outer segment diameter by an order of magnitude, and by introducing new, more refined, and time dependent variability functionals. Globally well stirred (GWS) models, and to a lesser extent transversally well stirred models (TWS), underestimate the role of nonlinearities and local cGMP depletion in quenching the variability of the circulating current with respect to fully space resolved models (FSR). These distortions minimize the true extent to which SPR is stabilized by locality in cGMP depletion, nonlinear effects linking cGMP to current, and Ca2+ feedback arising from the physical separation of E* from the ion channels located on the outer shell, and the diffusion of these second messengers in the cytoplasm.
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11 MeSH Terms
Biophysical model-based parameters to classify tumor recurrence from radiation-induced necrosis for brain metastases.
Narasimhan S, Johnson HB, Nickles TM, Miga MI, Rana N, Attia A, Weis JA
(2019) Med Phys 46: 2487-2496
MeSH Terms: Brain Neoplasms, Humans, Magnetic Resonance Imaging, Models, Biological, Necrosis, Patient-Specific Modeling, Radiation Injuries, Radiosurgery, Recurrence, Retrospective Studies
Show Abstract · Added April 2, 2019
PURPOSE - Stereotactic radiosurgery (SRS) is used for local control treatment of patients with intracranial metastases. As a result of SRS, some patients develop radiation-induced necrosis. Radiographically, radiation-induced necrosis can appear similar to tumor recurrence in magnetic resonance (MR) T -weighted contrast-enhanced imaging, T -weighted MR imaging, and Fluid-Attenuated Inversion Recovery (FLAIR) MR imaging. Radiographic ambiguities often necessitate invasive brain biopsies to determine lesion etiology or cause delayed subsequent therapy initiation. We use a biomechanically coupled tumor growth model to estimate patient-specific model parameters and model-derived measures to noninvasively classify etiology of enhancing lesions in this patient population.
METHODS - In this initial, preliminary retrospective study, we evaluated five patients with tumor recurrence and five with radiation-induced necrosis. Longitudinal patient-specific MR imaging data were used in conjunction with the model to parameterize tumor cell proliferation rate and tumor cell diffusion coefficient, and Dice correlation coefficients were used to quantify degree of correlation between model-estimated mechanical stress fields and edema visualized from MR imaging.
RESULTS - Results found four statistically relevant parameters which can differentiate tumor recurrence and radiation-induced necrosis.
CONCLUSIONS - This preliminary investigation suggests potential of this framework to noninvasively determine the etiology of enhancing lesions in patients who previously underwent SRS for intracranial metastases.
© 2019 American Association of Physicists in Medicine.
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10 MeSH Terms
Spatiotemporal control and modeling of morphogen delivery to induce gradient patterning of stem cell differentiation using fluidic channels.
O'Grady B, Balikov DA, Wang JX, Neal EK, Ou YC, Bardhan R, Lippmann ES, Bellan LM
(2019) Biomater Sci 7: 1358-1371
MeSH Terms: Cell Differentiation, Cells, Cultured, Humans, Microfluidic Analytical Techniques, Models, Biological, Morphogenesis, Stem Cells
Show Abstract · Added March 18, 2020
The process of cell differentiation in a developing embryo is influenced by numerous factors, including various biological molecules whose presentation varies dramatically over space and time. These morphogens regulate cell fate based on concentration profiles, thus creating discrete populations of cells and ultimately generating large, complex tissues and organs. Recently, several in vitro platforms have attempted to recapitulate the complex presentation of extrinsic signals found in nature. However, it has been a challenge to design versatile platforms that can dynamically control morphogen gradients over extended periods of time. To address some of these issues, we introduce a platform using channels patterned in hydrogels to deliver multiple morphogens to cells in a 3D scaffold, thus creating a spectrum of cell phenotypes based on the resultant morphogen gradients. The diffusion coefficient of a common small molecule morphogen, retinoic acid (RA), was measured within our hydrogel platform using Raman spectroscopy and its diffusion in our platform's geometry was modeled using finite element analysis. The predictive model of spatial gradients was validated in a cell-free hydrogel, and temporal control of morphogen gradients was then demonstrated using a reporter cell line that expresses green fluorescent protein in the presence of RA. Finally, the utility of this approach for regulating cell phenotype was demonstrated by generating opposing morphogen gradients to create a spectrum of mesenchymal stem cell differentiation states.
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MeSH Terms
Merging Orthovoltage X-Ray Minibeams spare the proximal tissues while producing a solid beam at the target.
Dilmanian FA, Krishnan S, McLaughlin WE, Lukaniec B, Baker JT, Ailawadi S, Hirsch KN, Cattell RF, Roy R, Helfer J, Kruger K, Spuhler K, He Y, Tailor R, Vassantachart A, Heaney DC, Zanzonico P, Gobbert MK, Graf JS, Nassimi JR, Fatemi NN, Schweitzer ME, Bangiyev L, Eley JG
(2019) Sci Rep 9: 1198
MeSH Terms: Brain Neoplasms, Computer Simulation, Gold, Humans, Metal Nanoparticles, Models, Biological, Monte Carlo Method, Radiography, Radiometry, Radiosurgery, Radiotherapy, Radiotherapy Dosage, X-Ray Therapy, X-Rays
Show Abstract · Added March 30, 2020
Conventional radiation therapy of brain tumors often produces cognitive deficits, particularly in children. We investigated the potential efficacy of merging Orthovoltage X-ray Minibeams (OXM). It segments the beam into an array of parallel, thin (~0.3 mm), planar beams, called minibeams, which are known from synchrotron x-ray experiments to spare tissues. Furthermore, the slight divergence of the OXM array make the individual minibeams gradually broaden, thus merging with their neighbors at a given tissue depth to produce a solid beam. In this way the proximal tissues, including the cerebral cortex, can be spared. Here we present experimental results with radiochromic films to characterize the method's dosimetry. Furthermore, we present our Monte Carlo simulation results for physical absorbed dose, and a first-order biologic model to predict tissue tolerance. In particular, a 220-kVp orthovoltage beam provides a 5-fold sharper lateral penumbra than a 6-MV x-ray beam. The method can be implemented in arc-scan, which may include volumetric-modulated arc therapy (VMAT). Finally, OXM's low beam energy makes it ideal for tumor-dose enhancement with contrast agents such as iodine or gold nanoparticles, and its low cost, portability, and small room-shielding requirements make it ideal for use in the low-and-middle-income countries.
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14 MeSH Terms
Arrestin mutations: Some cause diseases, others promise cure.
Gurevich VV, Gurevich EV
(2019) Prog Mol Biol Transl Sci 161: 29-45
MeSH Terms: Animals, Arrestin, Disease, Eye, Humans, Mammals, Models, Biological, Mutation
Show Abstract · Added March 18, 2020
Arrestins play a key role in homologous desensitization of G protein-coupled receptors (GPCRs) and regulate several other vital signaling pathways in cells. Considering the critical roles of these proteins in cellular signaling, surprisingly few disease-causing mutations in human arrestins were described. Most of these are loss-of-function mutations of visual arrestin-1 that cause excessive rhodopsin signaling and hence night blindness. Only one dominant arrestin-1 mutation was discovered so far. It reduces the thermal stability of the protein, which likely results in photoreceptor death via unfolded protein response. In case of the two nonvisual arrestins, only polymorphisms were described, some of which appear to be associated with neurological disorders and altered response to certain treatments. Structure-function studies revealed several ways of enhancing arrestins' ability to quench GPCR signaling. These enhanced arrestins have potential as tools for gene therapy of disorders associated with excessive signaling of mutant GPCRs.
© 2019 Elsevier Inc. All rights reserved.
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MeSH Terms
Low-rank plus sparse compressed sensing for accelerated proton resonance frequency shift MR temperature imaging.
Cao Z, Gore JC, Grissom WA
(2019) Magn Reson Med 81: 3555-3566
MeSH Terms: Ablation Techniques, Animals, Brain, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Magnetic Resonance Imaging, Interventional, Models, Biological, Phantoms, Imaging, Thalamus, Thermography
Show Abstract · Added March 26, 2019
PURPOSE - To improve multichannel compressed sensing (CS) reconstruction for MR proton resonance frequency (PRF) shift thermography, with application to MRI-induced RF heating evaluation and MR guided high intensity focused ultrasound (MRgFUS) temperature monitoring.
METHODS - A new compressed sensing reconstruction is proposed that enforces joint low rank and sparsity of complex difference domain PRF data between post heating and baseline images. Validations were performed on 4 retrospectively undersampled dynamic data sets in PRF applications, by comparing the proposed method to a previously described L and total variation- (TV-) based CS approach that also operates on complex difference domain data, and to a conventional low rank plus sparse (L+S) separation-based CS reconstruction applied to the original domain data.
RESULTS - In all 4 retrospective validations, the proposed reconstruction method outperformed the conventional L+S and L +TV CS reconstruction methods with a 3.6× acceleration ratio in terms of temperature accuracy with respect to fully sampled data. For RF heating evaluation, the proposed method achieved RMS error of 12%, compared to 19% for the L+S method and 17% for the L +TV method. For in vivo MRgFUS thalamotomy, the peak temperature reconstruction errors were 19%, 31%, and 35%, respectively.
CONCLUSION - The complex difference-based low rank and sparse model enhances compressibility for dynamic PRF temperature imaging applications. The proposed multichannel CS reconstruction method enables high acceleration factors for PRF applications including RF heating evaluation and MRgFUS sonication.
© 2019 International Society for Magnetic Resonance in Medicine.
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11 MeSH Terms
Hypoxia, angiogenesis, and metabolism in the hereditary kidney cancers.
Chappell JC, Payne LB, Rathmell WK
(2019) J Clin Invest 129: 442-451
MeSH Terms: Carcinoma, Renal Cell, Cell Hypoxia, Genetic Diseases, Inborn, Humans, Kidney Neoplasms, Leiomyomatosis, Models, Biological, Mutation, Neoplastic Syndromes, Hereditary, Neovascularization, Pathologic, Von Hippel-Lindau Tumor Suppressor Protein
Show Abstract · Added October 30, 2019
The field of hereditary kidney cancer has begun to mature following the identification of several germline syndromes that define genetic and molecular features of this cancer. Molecular defects within these hereditary syndromes demonstrate consistent deficits in angiogenesis and metabolic signaling, largely driven by altered hypoxia signaling. The classical mutation, loss of function of the von Hippel-Lindau (VHL) tumor suppressor, provides a human pathogenesis model for critical aspects of pseudohypoxia. These features are mimicked in a less common hereditary renal tumor syndrome, known as hereditary leiomyomatosis and renal cell carcinoma. Here, we review renal tumor angiogenesis and metabolism from a HIF-centric perspective, considering alterations in the hypoxic landscape, and molecular deviations resulting from high levels of HIF family members. Mutations underlying HIF deregulation drive multifactorial aberrations in angiogenic signals and metabolism. The mechanisms by which these defects drive tumor growth are still emerging. However, the distinctive patterns of angiogenesis and glycolysis-/glutamine-dependent bioenergetics provide insight into the cellular environment of these cancers. The result is a scenario permissive for aggressive tumorigenesis especially within the proximal renal tubule. These features of tumorigenesis have been highly actionable in kidney cancer treatments, and will likely continue as central tenets of kidney cancer therapeutics.
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11 MeSH Terms
Arrestin-3 scaffolding of the JNK3 cascade suggests a mechanism for signal amplification.
Perry NA, Kaoud TS, Ortega OO, Kaya AI, Marcus DJ, Pleinis JM, Berndt S, Chen Q, Zhan X, Dalby KN, Lopez CF, Iverson TM, Gurevich VV
(2019) Proc Natl Acad Sci U S A 116: 810-815
MeSH Terms: MAP Kinase Kinase 4, MAP Kinase Kinase 7, MAP Kinase Signaling System, Mitogen-Activated Protein Kinase 10, Models, Biological, Phosphorylation, Software, beta-Arrestin 2
Show Abstract · Added April 1, 2019
Scaffold proteins tether and orient components of a signaling cascade to facilitate signaling. Although much is known about how scaffolds colocalize signaling proteins, it is unclear whether scaffolds promote signal amplification. Here, we used arrestin-3, a scaffold of the ASK1-MKK4/7-JNK3 cascade, as a model to understand signal amplification by a scaffold protein. We found that arrestin-3 exhibited >15-fold higher affinity for inactive JNK3 than for active JNK3, and this change involved a shift in the binding site following JNK3 activation. We used systems biochemistry modeling and Bayesian inference to evaluate how the activation of upstream kinases contributed to JNK3 phosphorylation. Our combined experimental and computational approach suggested that the catalytic phosphorylation rate of JNK3 at Thr-221 by MKK7 is two orders of magnitude faster than the corresponding phosphorylation of Tyr-223 by MKK4 with or without arrestin-3. Finally, we showed that the release of activated JNK3 was critical for signal amplification. Collectively, our data suggest a "conveyor belt" mechanism for signal amplification by scaffold proteins. This mechanism informs on a long-standing mystery for how few upstream kinase molecules activate numerous downstream kinases to amplify signaling.
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Poly(Thioketal Urethane) Autograft Extenders in an Intertransverse Process Model of Bone Formation.
McGough MAP, Shiels SM, Boller LA, Zienkiewicz KJ, Duvall CL, Wenke JC, Guelcher SA
(2019) Tissue Eng Part A 25: 949-963
MeSH Terms: Animals, Autografts, Bone Transplantation, Calcium Phosphates, Catalysis, Cell Line, Mice, Models, Biological, Osteogenesis, Polyurethanes, Rabbits, Rats, Nude, Sheep, X-Ray Microtomography
Show Abstract · Added April 10, 2019
IMPACT STATEMENT - The development of autograft extenders is a significant clinical need in bone tissue engineering. We report new settable poly(thioketal urethane)-based autograft extenders that have bone-like mechanical properties and handling properties comparable to calcium phosphate bone cements. These settable autograft extenders remodeled to form new bone in a biologically stringent intertransverse process model of bone formation that does not heal when treated with calcium phosphate bone void fillers or cements alone. This is the first study to report settable autograft extenders with bone-like strength and handling properties comparable to ceramic bone cements, which have the potential to improve treatment of bone fractures and other orthopedic conditions.
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14 MeSH Terms