Biology subjects

Ozen, A.

Publications and source records attributed to Ozen, A..

5 recordsLinked to original sources

bioRxiv2024

Multi-site Ultrashort Echo Time 3D Phosphorous MRSI repeatability using novel Rosette Trajectory (PETALUTE)

PurposeThis study aims 1) to implement an operator-independent acquisition, reconstruction, and processing pipeline using a novel rosette k-space pattern for UTE 31P 3D MRSI and 2) to evaluate the clinical applicability and replicability at different experimental setups. MethodsA multicenter repeatability study was conducted for the novel UTE 31P 3D Rosette MRSI at three institutions with different experimental setups. Non-localized 31P MRSI data of 5 healthy subjects at each site were acquired with an acquisition delay of 65 s and a final resolution of 10 x 10 x 10 mm3 in 9 min. Spectra were quantified using the LCModel package. The potential acceleration was achieved using compressed sensing on retrospectively undersampled data. Reproducibility at each site was evaluated using the inter-subject coefficient of variance. ResultsThis novel acquisition and advanced processing techniques yielded high-quality spectra and enabled the detection of the critical brain metabolites at three different sites with different hardware specifications. In vivo, feasibility with an acceleration factor of 4 in 6.75 min resulted in a mean Cramer-Rao lower bounds below 20% for PCr, ATPs, PME, and the mean CoV of ATP/PCr resulted in below %20. ConclusionWe demonstrated that UTE 31P 3D Rosette MRSI acquisition, combined with compressed sensing and LCModel analysis, allows patient-friendly, operator-independent, high-resolution 31P MRSI to be acquired at clinical setups.

neuroscience↗

bioRxiv2022

Mechanisms of mRNA processing defects in inherited THOC6 intellectual disability syndrome

THOC6 is the genetic basis of autosomal recessive THOC6 Intellectual Disability Syndrome (TIDS). THOC6 facilitates the formation of the Transcription Export complex (TREX) tetramer, composed of four THO monomers. The TREX tetramer supports mammalian mRNA processing that is distinct from yeast TREX dimer functions. Human and mouse TIDS model systems allow novel THOC6-dependent TREX tetramer functions to be investigated. Biallelic loss-of-function (LOF) THOC6 variants do not influence the expression and localization of TREX members in human cells, but our data suggests reduced binding affinity of ALYREF. Impairment of TREX nuclear export functions were not detected in cells with biallelic THOC6 LOF. Instead, mRNA mis-splicing was observed in human and mouse neural tissue, revealing novel insights into THOC6-mediated TREX coordination of mRNA processing. We demonstrate that THOC6 is required for regulation of key signaling pathways in human corticogenesis that dictate the transition from proliferative to neurogenic divisions that may inform TIDS neuropathology.

molecular biology↗

bioRxiv2021

Myelin Imaging Using 3D Dual-echo Ultra-short Echo Time MRI with Rosette k-Space Pattern

PurposeThis study aimed to develop a new 3D dual-echo rosette k-space trajectory, specifically for ultra-short echo time (UTE) magnetic resonance imaging (MRI) applications. The direct imaging of the myelin bilayer, which has ultra-short transverse relaxation time (uT2), was acquired to test the performance of the proposed UTE sequence. Theory and MethodsThe rosette trajectory was developed based on rotations of a petal-like pattern in the kx-ky plane, with oscillated extensions in kz-direction for 3D coverage. Five healthy volunteers were recruited and underwent ten dual-echo 3D rosette UTE scans with various echo times (TEs). Dual-exponential complex model fitting was performed on the magnitude data to separate uT2 signals, with the output of uT2 fraction, uT2 value, and long T2 value. ResultsThe reconstructed images signal contrast between whiate matter (WM) and grey matter (GM) increased with longer TEs. The WM regions had higher uT2 fraction values than GM (10.9%{+/-}1.9% vs. 5.7%{+/-}2.4%). The uT2 value was approximately 0.15 milliseconds in WM. ConclusionThe higher uT2 fraction value in WM compared to GM demonstrated the ability of the proposed sequence to capture rapidly decaying signals.

neuroscience↗

bioRxiv2021

Human immunodeficiency reveals GIMAP5 as lymphocyte-specific regulator of senescence

Elucidating the molecular basis of immunodeficiency diseases is a powerful approach to discovering new immunoregulatory pathways in humans. Here we report 10 affected individuals from 4 families with a new immunodeficiency disease comprising of severe progressive lymphopenia, autoimmunity, immunodeficiency, and liver disease due to recessive loss of function variants in "GTPase of immunity-associated proteins" protein 5 (GIMAP5). We show that the disease involves the progressive loss of naive T lymphocytes and a corresponding increase in antigen-experienced, but poorly functional and replicatively senescent T cells. In vivo treatment of Gimap5-deficient mice with rapamycin (an inhibitor of mTORC1) significantly restores the fraction of naive T lymphocytes. Furthermore, a GIMAP5-deficient human patient who was treated with rapamycin (sirolimus) showed a remarkable reduction in spleen/lymph node size. Together, these observations reveal that GIMAP5 plays a critical role in lymphocyte metabolism which is essential for senescence prevention and immune competence, suggesting that an inhibitor of mTORC1 could be a valuable clinical intervention in treating patients deficient for GIMAP5.

immunology↗

bioRxiv2018

Resistance from Afar: Distal Mutation V36M Allosterically Modulates the Active Site to Accentuate Drug Resistance in HCV NS3/4A Protease

Hepatitis C virus rapidly evolves, conferring resistance to direct acting antivirals. While resistance via active site mutations in the viral NS3/4A protease has been well characterized, the mechanism for resistance of non-active site mutations is unclear. R155K and V36M often co-evolve and while R155K alters the electrostatic network at the binding site, V36M is more than 13 [A] away. In this study the mechanism by which V36M confers resistance, in the context of R155K, is elucidated with drug susceptibility assays, crystal structures, and molecular dynamics (MD) simulations for three protease inhibitors: telaprevir, boceprevir and danoprevir. The R155K and R155K/V36M crystal structures differ in the -2 helix and E2 strand near the active site, with alternative conformations at M36 and side chains of active site residues D168 and R123, revealing an allosteric coupling, which persists dynamically in MD simulations, between the distal mutation and the active site. This allosteric modulation validates the network hypothesis and elucidates how distal mutations confer resistance through propagation of conformational changes to the active site.

molecular biology↗