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At least 109 records · Page 6
All sourcesNASA NTRSDOE OSTI
DOE OSTI2017

USP39, a direct target of microRNA-133a, promotes progression of pancreatic cancer via the AKT pathway

Ubiquitin specific protease 39 (USP39) is one of the deubiquitinating enzymes without ubiquitin protease activity, which has been implicated in the progression of several cancers. However, the role of USP39 in pancreatic cancer (PC) is largely unknown. In present study, we found that USP39 expression was elevated in PC tissues than adjacent non-tumor tissues. Importantly, we demonstrated that overexpression of USP39 is closely correlated with tumor progression and poor survival in PC patients. Furthermore, high USP39 expression was observed in PC cell lines and ectopic expression of USP39 significantly enhanced in vitro cell proliferation and promoted in vivo tumor growth, whereas silencing USP39 suppressed growth of PC cells. Besides, our experimental data revealed that knockdown of USP39 induced cell apoptosis through inhibition of AKT signaling pathway in PC cells. Moreover, USP39 was a direct target of miR-133a, a microRNA that has been reported to be involved in progression of PC. Taken together, our data provide a novel PC regulatory axis that is miR-133a/USP39, the dysfunction of which drives diverse aspects of the progression of PC. - Highlights: • Upregulation of USP39 expression was significantly associated with the progression and poor survival in PC patients. • Overexpression of USP39 promotes PC cell growth in vitro and in vivo. • AKT pathway partly contributed to the oncogenic effects of USP39 in PC cells. • USP39 was found to be a direct target of miR-133a, which has been reported to be involved in progression of PC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Progression of Non-Small-Cell Lung Cancer During the Interval Before Stereotactic Body Radiotherapy

Purpose: To investigate the relationship between waiting time (WT) and disease progression in patients undergoing stereotactic body radiotherapy (SBRT) for lung adenocarcinoma (AD) or squamous cell carcinoma (SQ). Methods and Materials: 201 patients with Stage I AD or SQ undergoing SBRT between January 2004 and June 2010 were analyzed. The WT was defined as the interval between diagnostic computed tomography before referral and computed tomography for treatment planning or positioning before SBRT. Tumor size was measured on the slice of the longest tumor diameter, and tumor volume was calculated from the longest diameter and the diameter perpendicular to it. Changes in tumor volume and TNM stage progression were evaluated, and volume doubling time (VDT) was estimated. Results: The median WT was 42 days (range, 5-323 days). There was a correlation between WT and rate of increase in volume in both AD and SQ. The median VDTs of AD and SQ were 170 and 93 days, respectively. Thirty-six tumors (23%) did not show volume increase during WTs >25 days. In 41 patients waiting for {<=}4 weeks, no patient showed T stage progression, whereas in 25 of 120 (21%) patients waiting for >4 weeks, T stage progressed from T1 to T2 (p = 0.001). In 10 of 110 (9.1%) T1 ADs and 15 of 51 (29%) T1 SQs, T stage progressed (p = 0.002). N stage and M stage progressions were not observed. Conclusion: Generally, a WT of {<=}4 weeks seems to be acceptable. The WT seems to be more important in SQ than in AD.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2014

Towards local progression estimation of pulmonary emphysema using CT

Purpose: Whole lung densitometry on chest CT images is an accepted method for measuring tissue destruction in patients with pulmonary emphysema in clinical trials. Progression measurement is required for evaluation of change in health condition and the effect of drug treatment. Information about the location of emphysema progression within the lung may be important for the correct interpretation of drug efficacy, or for determining a treatment plan. The purpose of this study is therefore to develop and validate methods that enable the local measurement of lung density changes, which requires proper modeling of the effect of respiration on density. Methods: Four methods, all based on registration of baseline and follow-up chest CT scans, are compared. The first naïve method subtracts registered images. The second employs the so-called dry sponge model, where volume correction is performed using the determinant of the Jacobian of the transformation. The third and the fourth introduce a novel adaptation of the dry sponge model that circumvents its constant-mass assumption, which is shown to be invalid. The latter two methods require a third CT scan at a different inspiration level to estimate the patient-specific density-volume slope, where one method employs a global and the other a local slope. The methods were validated on CT scans of a phantom mimicking the lung, where mass and volume could be controlled. In addition, validation was performed on data of 21 patients with pulmonary emphysema. Results: The image registration method was optimized leaving a registration error below half the slice increment (median 1.0 mm). The phantom study showed that the locally adapted slope model most accurately measured local progression. The systematic error in estimating progression, as measured on the phantom data, was below 2 gr/l for a 70 ml (6%) volume difference, and 5 gr/l for a 210 ml (19%) difference, if volume correction was applied. On the patient data an underlying linearity assumption relating lung volume change with density change was shown to hold (fitR{sup 2} = 0.94), and globalized versions of the local models are consistent with global results (R{sup 2} of 0.865 and 0.882 for the two adapted slope models, respectively). Conclusions: In conclusion, image matching and subsequent analysis of differences according to the proposed lung models (i) has good local registration accuracy on patient data, (ii) effectively eliminates a dependency on inspiration level at acquisition time, (iii) accurately predicts progression in phantom data, and (iv) is reasonably consistent with global results in patient data. It is therefore a potential future tool for assessing local emphysema progression in drug evaluation trials and in clinical practice.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

TU-D-207B-01: A Prediction Model for Distinguishing Radiation Necrosis From Tumor Progression After Gamma Knife Radiosurgery Based On Radiomics Features From MR Images

Purpose: To develop and validate a prediction model using radiomics features extracted from MR images to distinguish radiation necrosis from tumor progression for brain metastases treated with Gamma knife radiosurgery. Methods: The images used to develop the model were T1 post-contrast MR scans from 71 patients who had had pathologic confirmation of necrosis or progression; 1 lesion was identified per patient (17 necrosis and 54 progression). Radiomics features were extracted from 2 images at 2 time points per patient, both obtained prior to resection. Each lesion was manually contoured on each image, and 282 radiomics features were calculated for each lesion. The correlation for each radiomics feature between two time points was calculated within each group to identify a subset of features with distinct values between two groups. The delta of this subset of radiomics features, characterizing changes from the earlier time to the later one, was included as a covariate to build a prediction model using support vector machines with a cubic polynomial kernel function. The model was evaluated with a 10-fold cross-validation. Results: Forty radiomics features were selected based on consistent correlation values of approximately 0 for the necrosis group and >0.2 for the progression group. In performing the 10-fold cross-validation, we narrowed this number down to 11 delta radiomics features for the model. This 11-delta-feature model showed an overall prediction accuracy of 83.1%, with a true positive rate of 58.8% in predicting necrosis and 90.7% for predicting tumor progression. The area under the curve for the prediction model was 0.79. Conclusion: These delta radiomics features extracted from MR scans showed potential for distinguishing radiation necrosis from tumor progression. This tool may be a useful, noninvasive means of determining the status of an enlarging lesion after radiosurgery, aiding decision-making regarding surgical resection versus conservative medical management.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Progressive Dynamics for Cloth and Shell Animation

We propose Progressive Dynamics, a coarse-to-fine, level-of-detail simulation method for the physics-based animation of complex frictionally contacting thin shell and cloth dynamics. Progressive Dynamics provides tight-matching consistency and progressive improvement across levels, with comparable quality and realism to high-fidelity, IPC-based shell simulations [Li et al. 2021] at finest resolutions. Together these features enable an efficient animation-design pipeline with predictive coarse-resolution previews providing rapid design iterations for a final, to-be-generated, high-resolution animation. In contrast, previously, to design such scenes with comparable dynamics would require prohibitively slow design iterations via repeated direct simulations on high-resolution meshes. We evaluate and demonstrate Progressive Dynamics's features over a wide range of challenging stress-tests, benchmarks, and animation design tasks. Here Progressive Dynamics efficiently computes consistent previews at costs comparable to coarsest-level direct simulations. Its matching progressive refinements across levels then generate rich, high-resolution animations with high-speed dynamics, impacts, and the complex detailing of the dynamic wrinkling, folding, and sliding of frictionally contacting thin shells and fabrics.

Computer Science↗
DOE OSTI2025

HP-MDR: High-performance and Portable Data Refactoring and Progressive Retrieval with Advanced GPUs

Scientific applications produce vast amounts of data, posing grand challenges in the underlying data management and analytic tasks. Progressive compression is a promising way to address this problem, as it allows for on-demand data retrieval with significantly reduced data movement cost. However, most existing progressive methods are designed for CPUs, leaving a gap for them to unleash the power of today’s heterogeneous computing systems with GPUs.In this work, we propose HP-MDR, a high-performance and portable data refactoring and progressive retrieval framework for GPUs. Our contributions are four-fold: (1) We carefully optimize the bitplane encoding and lossless encoding, two key stages in progressive methods, to achieve high performance on GPUs; (2) We propose pipeline optimization and incorporate it with data refactoring and progressive retrieval workflows to further enhance the performance for large data process; (3) We leverage our framework to enable high-performance data retrieval with guaranteed error control for common Quantities of Interest; (4) We evaluate HP-MDR and compare it with state of the arts using five real-world datasets. Experimental results demonstrate that HP-MDR delivers an average 13.68 × and 6.31 × throughput in data refactoring and progressive retrieval tasks, respectively. It also leads to 11.22 × throughput for recomposing required data representations under Quantity-of-Interest error control and 6.04 × performance for the corresponding end-to-end data retrieval, when compared with state-of-the-art solutions.

Li, Yanliang [University of Oregon]↗
DOE OSTI2019

Progress Update on Iterative Reconstruction of Neutron Tomographic Images, 2019

The fiscal year (FY) 2019 update of this report satisfies the technical deliverable “Simultaneous reconstruction of simultaneous observables” for project OR16-ML-3DTomography-PD3Jb, “3D Tomography and Image Processing Using Fast Neutrons.” At its inception, this project had two overall goals. The first of these goals was to extend associated-particle fast neutron transmission and, particularly, induced-reaction tomographic imaging algorithms to three dimensions. The second of these goals was to automatically segment the resultant tomographic images into constituent parts and then extract information about the parts, such as the class of shape and potentially shape parameters. This report addresses the component of the project concerned with three-dimensional (3D) image reconstruction and represents the cumulative progress to date. In particular, it addresses the ability to decompose neutrons arriving at times consistent with transmission into transmission and small-angle scattering. Because incremental progress in each year builds on the previous year’s progress and end-ofyear status, progress is most usefully recorded in a cumulative document where incremental progress is reported on a year-by-year basis. Consequently, this report constitutes an update of the last 3 years’ reports [1, 2, 14]. The present year’s progress is detailed in Section 7.

47 OTHER INSTRUMENTATION↗
DOE OSTI2023

Probing Fundamental Mechanisms of Plastic Deformation with High Energy X-rays (Final Progress Report)

Overall, substantial progress was made on developing BCDI techniques in the direction of imaging defects in multi-crystal samples. Section 2.1 describes a new method to reconstruct the 3D atomic displacement field within a grain from multiple coherently resolved diffraction peaks. The key development is the ability to recover a best fit to the grain shape at the same time as the internal displacement (strain) variation with no prior knowledge of the microstructure. This is complemented by the development of a method, Sec. 2.2, to separate out sets of Laue reflections that belong to a single grain (and thus be able to index its orientation) in the commonly encountered situation in which the beam illuminates several grains in a given location. This is essential for enabling collection of coherent diffraction data (at APS 34-ID-C) from neighboring grains. All experiments depend on the quality of samples used. Although good progress has been made with thin film samples, we are working with a broader range of geometries. A new sample design uses a high-Z metal (e.g., Pt) deposited in a sub-micron trench in a low-Z metal (e.g., Al) so that the grain size is prevented from exceeding the current limit for BCDI. We also report in section 3.1 on successfully applying NF-HEDM to a fine-grain Mg sample that would normally be considered out of scope for the method. This represents progress towards being able to map out polycrystalline samples in 3D before performing BCDI on individual grains. We further report in section 3.2 on preliminary NF-HEDM characterization of a sample of UO2 that has sub-micron grains; the data imply the capability of mapping fine-grain polycrystals at 1-ID-E, again for the purposes of BCDI in the bulk. Lastly, our plan is to load grains in polycrystalline samples by inducing thermal stress. We also report the experimental measurements of the Ti- 6Al-4V alloy obtained at the European Synchrotron Radiation Facility (ESRF), which had been indexed and mapped via HEDM at APS in section 9. As discussed below, however, technique development pre-occupied the team throughout the project which meant that we did not make any significant progress towards answering the original hypotheses as stated in the proposal. In summary, we assert that we have made good progress in methods and samples and future work taking advantage of this progress is likely to obtain and analyze BCDI data from multiple adjacent grains in 3D polycrystals. Obtaining such data depends on re-gaining access to the Advanced Photon Source, which is anticipated in late summer or the Fall. In all cases, work has involved close collaboration with faculty, staff, postdocs and students from Brigham Young University (BYU), the Los Alamos National Laboratory and APS beamlines 1-ID and 34-ID.

36 MATERIALS SCIENCE↗
DOE OSTI2023

Image-based time series analysis to establish differential disease progression for two Fusarium head blight pathogens in oat spikelets with variable resistance

Oat-based value-added products have increased their value as healthy foodstuff. Fusarium head blight (FHB) infections and the mycotoxins accumulated to the oat seeds, however, pose a challenge to oat production. The FHB infections are predicted to become more prevalent in the future changing climates and under more limited use of fungicides. Both these factors increase the pressure for breeding new resistant cultivars. Until now, however, genetic links in oats against FHB infection have been difficult to identify. Therefore, there is a great need for more effective breeding efforts, including improved phenotyping methods allowing time series analysis and the identification of molecular markers during disease progression. To these ends, dissected spikelets of several oat genotypes with different resistance profiles were studied by image-based methods during disease progression by Fusarium culmorum or F. langsethiae species. The chlorophyll fluorescence of each pixel in the spikelets was recorded after inoculation by the two Fusarium spp., and the progression of the infections was analyzed by calculating the mean maximum quantum yield of PSII (F v /F m ) values for each spikelet. The recorded values were (i) the change in the photosynthetically active area of the spikelet as percentage of its initial size, and (ii) the mean of F v /F m values of all fluorescent pixels per spikelet post inoculation, both indicative of the progression of the FHB disease. The disease progression was successfully monitored, and different stages of the infection could be defined along the time series. The data also confirmed the differential rate of disease progression by the two FHB causal agents. In addition, oat varieties with variable responses to the infections were indicated.

oats↗
NASA NTRS1962

Studies in the Fields of Space Flight and Guidance Theory: Progress Report - No. 2

Compiled in this paper are 11 progress papers from 7 of the agencies working under contract to MSFC in the areas of guidance theory and space flight theory. This is the second paper of the "Progress Reports" and covers the period from December 1, 1961 to June 15, 1962. Extensive references are made to "Progress Report No. 1." This second progress report is referred to as "report" and "Progress Report No. 1" will be referred to as the "first report" in this introduction. Information given in the first report is not repeated herein. The reports of the various contractors will be referred to by index number as papers. There are two parallel series of publications covering the over-all activities at MSFC in the areas of guidance theory and space flight theory. One is the series of progress reports of which this paper is the second in the series. The other is the series of "Status Reports on Theory of Space Flight and Adaptive Guidance." These series along with a few other special reports, give a complete picture of the immediate objectives, accomplishments, and final goals of Aeroballistics Division and associated contr

FLIGHT OPTIMIZATION↗
NASA NTRS1994

Characterization of Damage Progression in SCS-6/timetal 21S (0)4 Under Thermomechanical Fatigue Loadings

A detailed experimental investigation was performed at a single maximum cyclic stress (sigma max) level to physically characterize the progression of thermomechanical fatigue (lW) damage in continuously reinforced (0 deg) SCS-6/Timetal 21S, a titanium matrix composite. In-phase (IP) and out of-phase (OP) loadings were investigated at sigma max = 1000 MPa with a temperature cycle from 150 to 6500 C. Damage progression, in terms of macroscopic property degradation, was experimentally quantified through an advanced TMF test methodology which incorporates explicit measurements of the isothermal static moduli at the TMF temperature extremes and the coefficient of thermal expansion (CTE) as functions of the TMF cycles. Detailed characterization of the physical damage progression at the microstructural level was performed by interrupting multiple TMF tests at various stages of mechanical property degradation and analyzing the microstructure through extensive destructive metallography. Further, the extent of damage was also quantified through residual static strength measurements. Results indicated that damage initiation occurred very early in cyclic life (N less than 0.1Nf) for both the IP and OP TMF loadings. IP TMF damage was found to be dominated by fiber breakage with a physical damage progression in the microstructure which was difficult to quantify. OP TMF loadings produced matrix cracking exclusively associated with surface initiations. Here, damage progression was easily distinguished in terms of both the number of cracks and their relative inward progressions toward the outer fiber rows with increased cycling. The point at which the leading cracks reached the outer fiber rows (when localized fiber/matrix de-bonding and matrix crack bridging occurred) appeared to be reflected in the macroscopic property degradation curves.

Castelli, Michael G.↗
NASA NTRS2008

Factors Influencing Progressive Failure Analysis Predictions for Laminated Composite Structure

Progressive failure material modeling methods used for structural analysis including failure initiation and material degradation are presented. Different failure initiation criteria and material degradation models are described that define progressive failure formulations. These progressive failure formulations are implemented in a user-defined material model for use with a nonlinear finite element analysis tool. The failure initiation criteria include the maximum stress criteria, maximum strain criteria, the Tsai-Wu failure polynomial, and the Hashin criteria. The material degradation model is based on the ply-discounting approach where the local material constitutive coefficients are degraded. Applications and extensions of the progressive failure analysis material model address two-dimensional plate and shell finite elements and three-dimensional solid finite elements. Implementation details are described in the present paper. Parametric studies for laminated composite structures are discussed to illustrate the features of the progressive failure modeling methods that have been implemented and to demonstrate their influence on progressive failure analysis predictions.

Knight, Norman F., Jr.↗
DOE OSTI2023

Effects of unburnt reaction progress on stretch flame dynamics under elevated temperatures

Flames in practical combustors and engines are inevitably subject to the effects of upstream chemical reaction progress and stretch, induced by elevated thermodynamic conditions and flow non-uniformities, respectively. Recent shock tube experiments and simulation studies on flame propagation have shown that flame speed under engine-relevant conditions can be enhanced with non-negligible upstream chemical reaction progress, especially when low-temperature heat release is involved in the unburnt mixture. On the other hand, depending on the mixture equivalence ratio and diluents, nonequidiffusion (including the non-unity Lewis number effect and the preferential diffusion effect) can couple with the flame stretch to fundamentally affect the flame propagation, which can manifest as either facilitation or suppression. Depending on the transport property of a reacting mixture, there hence can be either inhibition or promotion from unburnt reaction progress and stretch effects on flame propagation. In the current work, through one-dimensional numerical simulations of transient planar and spherical flames of n-heptane/air under elevated thermodynamic conditions, the combined effects of upstream chemical reaction progress and stretch on flame propagation are investigated. Results show that for both lean and rich n-heptane/air mixtures, flame speed can be substantially promoted with reaction progress, while the rich mixtures can exhibit opposite stretch dependence after first-stage ignition. Different definitions of effective Lewis number are adopted to explain the change in Markstein length for spherical flame in lean and rich mixtures reformed by the low temperature chemistry. Further, this work fills an important gap in laminar premixed flame research relevant to practical combustion systems and can provide useful insight into local turbulent flame behaviors and phi-sensitivity in engine combustion.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2018

Dynamic Adaptable Asynchronous Progress Model for MPI RMA Multiphase Applications

Casper is a process-based asynchronous progress model for MPI one-sided communication on multi-and many-core architectures. The one-sided communication is not truly one-sided in most MPI implementations: the target process still relies on software progress to complete incoming operations. Casper allows the user to specify an arbitrary number of cores dedicated to background ghost processes and transparently redirects the RMA operations to ghost processes by utilizing the PMPI redirection and MPI-3 shared-memory technologies. Although Casper benefits applications that suffer from lack of asynchronous progress, the operation redirection design might not support complex multiphase applications effectively, which often involve dynamically changing communication density and computing workloads. In this paper, we present an adaptive mechanism in Casper to address the limitation of static asynchronous progress in multiphase applications. For this we exploit two adaptive strategies, a user-guided strategy and a fully transparent and automatic strategy based on self-profiling and prediction, to dynamically reconfigure the asynchronous progress in Casper according to real-time performance characteristics during multiphase execution. We evaluate the adaptive approaches in both microbenchmarks and a real quantum chemistry application suite, NWChem, on the Cray XC30 supercomputer and an Intel Omni-Path cluster.

97 MATHEMATICS AND COMPUTING↗
DOE OSTI2023

A General Framework for Progressive Data Compression and Retrieval

In scientific simulations, observations, and experiments, the transfer of data to and from disk and across networks has become a major bottleneck for data analysis and visualization. Compression techniques have been employed to tackle this challenge, but traditional lossy methods often demand conservative error tolerances to meet the numerical accuracy requirements of both anticipated and unknown data analysis tasks. Progressive data compression and retrieval has emerged as a promising solution, where each analysis task dictates its own accuracy needs. However, few analysis algorithms inherently support progressive data processing, and adapting compression techniques, file formats, client/server frameworks, and APIs to support progressivity can be challenging. Here, this paper presents a framework that enables progressive-precision data queries for any data compressor or numerical representation. Our strategy hinges on a multi-component representation that successively reduces the error between the original and compressed field, allowing each field in the progressive sequence to be expressed as a partial sum of components. We have implemented this approach with four established scientific data compressors and assessed its effectiveness using real-world data sets from the SDRBench collection. The results show that our framework competes in accuracy with the standalone compressors it is based upon. Additionally, (de)compression time is proportional to the number of components requested by the user. Finally, our framework allows for fully lossless compression using lossy compressors when a sufficient number of components are employed.

97 MATHEMATICS AND COMPUTING↗
DOE OSTI2014

Relationship of computed tomography perfusion and positron emission tomography to tumour progression in malignant glioma

Introduction: This study aimed to explore the potential for computed tomography (CT) perfusion and 18-Fluorodeoxyglucose positron emission tomography (FDG-PET) in predicting sites of future progressive tumour on a voxel-by-voxel basis after radiotherapy and chemotherapy. Methods: Ten patients underwent pre-radiotherapy magnetic resonance (MR), FDG-PET and CT perfusion near the end of radiotherapy and repeated post-radiotherapy follow-up MR scans. The relationships between these images and tumour progression were assessed using logistic regression. Cross-validation with receiver operating characteristic (ROC) analysis was used to assess the value of these images in predicting sites of tumour progression. Results: Pre-radiotherapy MR-defined gross tumour; near-end-of-radiotherapy CT-defined enhancing lesion; CT perfusion blood flow (BF), blood volume (BV) and permeability-surface area (PS) product; FDG-PET standard uptake value (SUV); and SUV:BF showed significant associations with tumour progression on follow-up MR imaging (P < 0.0001). The mean sensitivity (±standard deviation), specificity and area under the ROC curve (AUC) of PS were 0.64 ± 0.15, 0.74 ± 0.07 and 0.72 ± 0.12 respectively. This mean AUC was higher than that of the pre-radiotherapy MR-defined gross tumour and near-end-of-radiotherapy CT-defined enhancing lesion (both AUCs = 0.6 ± 0.1, P ≤ 0.03). The multivariate model using BF, BV, PS and SUV had a mean AUC of 0.8 ± 0.1, but this was not significantly higher than the PS only model. Conclusion: PS is the single best predictor of tumour progression when compared to other parameters, but voxel-based prediction based on logistic regression had modest sensitivity and specificity.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2015

PRR11 regulates late-S to G2/M phase progression and induces premature chromatin condensation (PCC)

Recently, we have demonstrated that proline-rich protein 11 (PRR11) is a novel tumor-related gene product likely implicated in the regulation of cell cycle progression as well as lung cancer development. However, its precise role in cell cycle progression remains unclear. In the present study, we have further investigated the expression pattern and functional implication of PRR11 during cell cycle in detail in human lung carcinoma-derived H1299 cells. According to our immunofluorescence study, PRR11 was expressed largely in cytoplasm, the amount of PRR11 started to increase in the late S phase, and was retained until just before mitotic telophase. Consistent with those observations, siRNA-mediated knockdown of PRR11 caused a significant cell cycle arrest in the late S phase. Intriguingly, the treatment with dNTPs further augmented PRR11 silencing-mediated S phase arrest. Moreover, knockdown of PRR11 also resulted in a remarkable retardation of G2/M progression, and PRR11-knockdown cells subsequently underwent G2 phase cell cycle arrest accompanied by obvious mitotic defects such as multipolar spindles and multiple nuclei. In addition, forced expression of PRR11 promoted the premature Chromatin condensation (PCC), and then proliferation of PRR11-expressing cells was massively attenuated and induced apoptosis. Taken together, our current observations strongly suggest that PRR11, which is strictly regulated during cell cycle progression, plays a pivotal role in the regulation of accurate cell cycle progression through the late S phase to mitosis. - Highlights: • PRR11 started to increase in the late S phase and was retained until just before mitotic telophase. • PRR11-knockdown caused a significant cell cycle arrest in the late S phase and G2 phase. • The treatment with dNTPs further augmented PRR11 silencing-mediated S phase arrest. • PRR11-knockdown led to multipolar spindles and multiple nuclei. • Forced expression of PRR11 promoted the PCC and inhibited cell proliferation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Progressive hearing loss and degeneration of hair cell stereocilia in taperin gene knockout mice

The TPRN gene encodes taperin, which is prominently present at the taper region of hair cell stereocilia. Mutations in TPRN have been reported to cause autosomal recessive nonsyndromic deafness 79(DFNB 79). To investigate the role of taperin in pathogenesis of hearing loss, we generated TPRN knockout mice using TALEN technique. Sanger sequencing confirmed an 11 bp deletion at nucleotide 177–187 in exon 1 of TPRN, which results in a truncated form of taperin protein. Heterozygous TPRN{sup +/−} mice showed apparently normal auditory phenotypes to their wide-type (WT) littermates. Homozygous TPRN{sup −/−} mice exhibited progressive sensorineural hearing loss as reflected by auditory brainstem response to both click and tone burst stimuli at postnatal days 15 (P15), 30 (P30), and 60 (P60). Alex Fluor-594 phalloidin labeling showed no obvious difference in hair cell numbers in the cochlea between TPRN{sup −/−} mice and WT mice under light microscope. However, scanning electronic microscopy revealed progressive degeneration of inner hair cell stereocilia, from apparently normal at postnatal days 3 (P3) to scattered absence at P15 and further to substantial loss at P30. The outer hair cell stereocilia also showed progressive degeneration, though much less severe, Collectively, we conclude that taperin plays an important role in maintenance of hair cell stereocilia. Establishment of TPRN knockout mice enables further investigation into the function of this gene. - Highlights: • TPRN{sup −/−} mice were generated using TALEN technique. • TPRN{sup −/−} mice presented progressive hearing loss. • WT and TPRN{sup −/−} mice showed no difference in hair cell numbers. • TPRN{sup −/−} mice showed progressive degeneration of hair cell stereocilia.

60 APPLIED LIFE SCIENCES↗