Correction of human nonsense mutation via adenine base editing for Duchenne muscular dystrophy treatment in mouse.

Duchenne muscular dystrophy (DMD) is the most prevalent herediatry disease in men, characterized by dystrophin deficiency, progressive muscle wasting, cardiac insufficiency, and premature mortality, with no effective therapeutic options. Here, we investigated whether adenine base editing can correct pathological nonsense point mutations leading to premature stop codons in the dystrophin gene. We identified 27 causative nonsense mutations in our DMD patient cohort. Treatment with adenine base editor (ABE) could restore dystrophin expression by direct A-to-G editing of pathological nonsense mutations in cardiomyocytes generated from DMD patient-derived induced pluripotent stem cells. We also generated two humanized mouse models of DMD expressing mutation-bearing exons 23 or 30 of human dystrophin gene. Intramuscular administration of ABE, driven by ubiquitous or muscle-specific promoters could correct these nonsense mutations in vivo, albeit with higher efficiency in exon 30, restoring dystrophin expression in skeletal fibers of humanized DMD mice. Moreover, a single systemic delivery of ABE with human single guide RNA (sgRNA) could induce body-wide dystrophin expression and improve muscle function in rotarod tests of humanized DMD mice. These findings demonstrate that ABE with human sgRNAs can confer therapeutic alleviation of DMD in mice, providing a basis for development of adenine base editing therapies in monogenic diseases.

The P286R mutation of DNA polymerase ε activates cancer-cell-intrinsic immunity and suppresses endometrial tumorigenesis via the cGAS-STING pathway.

Endometrial carcinoma (EC) is a prevalent gynecological tumor in women, and its treatment and prevention are significant global health concerns. The mutations in DNA polymerase ε (POLE) are recognized as key features of EC and may confer survival benefits in endometrial cancer patients undergoing anti-PD-1/PD-L1 therapy. However, the anti-tumor mechanism of POLE mutations remains largely elusive. This study demonstrates that the hot POLE P286R mutation impedes endometrial tumorigenesis by inducing DNA breakage and activating the cGAS-STING signaling pathway. The POLE mutations were found to inhibit the proliferation and stemness of primary human EC cells. Mechanistically, the POLE mutants enhance DNA damage and suppress its repair through the interaction with DNA repair proteins, leading to genomic instability and the upregulation of cytoplasmic DNA. Additionally, the POLE P286R mutant also increases cGAS level, promotes TBK1 phosphorylation, and stimulates inflammatory gene expression and anti-tumor immune response. Furthermore, the POLE P286R mutation inhibits tumor growth and facilitates the infiltration of cytotoxic T cells in human endometrial cancers. These findings uncover a novel mechanism of POLE mutations in antagonizing tumorigenesis and provide a promising direction for effective cancer therapy.

Multiple-Input-Multiple-Output Filtered Multitone Time Reversal Acoustic Communications Using Direct Adaptation-Based Turbo Equalization.

This paper proposes using direct adaptation (DA)-based turbo equalization in multiple-input-multiple-output (MIMO) filtered multitone (FMT) time reversal (TR) acoustic communications to jointly suppress noise, residual co-channel interference (CCI) and intersymbol interference (ISI) after the TR process. Soft information-based adaptive decision feedback equalization (ADFE) adjusted according to the recursive expected least squares (RELS) algorithm, including interference cancellation and decoding, is used to construct the DA-based turbo equalization. In the proposed method, soft information is exchanged between soft symbols with soft decisions of decoding iteratively, and interference suppression is proceeded successively and iteratively until the performance is stable. The principle of the proposed method is analyzed, and based on the acoustic channel responses measured in a real experiment, the performance is assessed in relation to that of anther two methods. Compared with the MIMO-FMT TR underwater acoustic communication using interference suppression without error control coding (ECC), the proposed method performs better, benefitting from the ECC included in turbo equalization. Additionally, compared with the MIMO-FMT TR underwater acoustic communication using interference suppression based on hard decision equalization and decoding, the proposed method exhibits superior performance by exploiting soft information.

Protein quality control and aggregation in the endoplasmic reticulum: From basic to bedside.

Endoplasmic reticulum (ER) is the largest membrane-bound compartment in all cells and functions as a key regulator in protein biosynthesis, lipid metabolism, and calcium balance. Mammalian endoplasmic reticulum has evolved with an orchestrated protein quality control system to handle defective proteins and ensure endoplasmic reticulum homeostasis. Nevertheless, the accumulation and aggregation of misfolded proteins in the endoplasmic reticulum may occur during pathological conditions. The inability of endoplasmic reticulum quality control system to clear faulty proteins and aggregates from the endoplasmic reticulum results in the development of many human disorders. The efforts to comprehensively understand endoplasmic reticulum quality control network and protein aggregation will benefit the diagnostics and therapeutics of endoplasmic reticulum storage diseases. Herein, we overview recent advances in mammalian endoplasmic reticulum protein quality control system, describe protein phase transition model, and summarize the approaches to monitor protein aggregation. Moreover, we discuss the therapeutic applications of enhancing endoplasmic reticulum protein quality control pathways in endoplasmic reticulum storage diseases.

CRISPR-Based Therapeutic Gene Editing for Duchenne Muscular Dystrophy: Advances, Challenges and Perspectives.

Duchenne muscular dystrophy (DMD) is a severe neuromuscular disease arising from loss-of-function mutations in the dystrophin gene and characterized by progressive muscle degeneration, respiratory insufficiency, cardiac failure, and premature death by the age of thirty. Albeit DMD is one of the most common types of fatal genetic diseases, there is no curative treatment for this devastating disorder. In recent years, gene editing via the clustered regularly interspaced short palindromic repeats (CRISPR) system has paved a new path toward correcting pathological mutations at the genetic source, thus enabling the permanent restoration of dystrophin expression and function throughout the musculature. To date, the therapeutic benefits of CRISPR genome-editing systems have been successfully demonstrated in human cells, rodents, canines, and piglets with diverse DMD mutations. Nevertheless, there remain some nonignorable challenges to be solved before the clinical application of CRISPR-based gene therapy. Herein, we provide an overview of therapeutic CRISPR genome-editing systems, summarize recent advancements in their applications in DMD contexts, and discuss several potential obstacles lying ahead of clinical translation.

Regulation of Embryonic Stem Cell Self-Renewal.

Embryonic stem cells (ESCs) are a type of cells capable of self-renewal and multi-directional differentiation. The self-renewal of ESCs is regulated by factors including signaling pathway proteins, transcription factors, epigenetic regulators, cytokines, and small molecular compounds. Similarly, non-coding RNAs, small RNAs, and microRNAs (miRNAs) also play an important role in the process. Functionally, the core transcription factors interact with helper transcription factors to activate the expression of genes that contribute to maintaining pluripotency, while suppressing the expression of differentiation-related genes. Additionally, cytokines such as leukemia suppressor factor (LIF) stimulate downstream signaling pathways and promote self-renewal of ESCs. Particularly, LIF binds to its receptor (LIFR/gp130) to trigger the downstream Jak-Stat3 signaling pathway. BMP4 activates the downstream pathway and acts in combination with Jak-Stat3 to promote pluripotency of ESCs in the absence of serum. In addition, activation of the Wnt-FDZ signaling pathway has been observed to facilitate the self-renewal of ESCs. Small molecule modulator proteins of the pathway mentioned above are widely used in in vitro culture of stem cells. Multiple epigenetic regulators are involved in the maintenance of ESCs self-renewal, making the epigenetic status of ESCs a crucial factor in this process. Similarly, non-coding RNAs and cellular energetics have been described to promote the maintenance of the ESC's self-renewal. These factors regulate the self-renewal and differentiation of ESCs by forming signaling networks. This review focused on the role of major transcription factors, signaling pathways, small molecular compounds, epigenetic regulators, non-coding RNAs, and cellular energetics in ESC's self-renewal.

Marine Application Evaluation of Monocular SLAM for Underwater Robots.

With the development of artificial intelligence technology, visual simultaneous localization and mapping (SLAM) has become a cheap and efficient localization method for underwater robots. However, there are many problems in underwater visual SLAM, such as more serious underwater imaging distortion, more underwater noise, and unclear details. In this paper, we study these two problems and chooses the ORB-SLAM2 algorithm as the method to obtain the motion trajectory of the underwater robot. The causes of radial distortion and tangential distortion of underwater cameras are analyzed, a distortion correction model is constructed, and five distortion correction coefficients are obtained through pool experiments. Comparing the performances of contrast-limited adaptive histogram equalization (CLAHE), median filtering (MF), and dark channel prior (DCP) image enhancement methods in underwater SLAM, it is found that the DCP method has the best image effect evaluation, the largest number of oriented fast and rotated brief (ORB) feature matching, and the highest localization trajectory accuracy. The results show that the ORB-SLAM2 algorithm can effectively locate the underwater robot, and the correct distortion correction coefficient and DCP improve the stability and accuracy of the ORB-SLAM2 algorithm.

Comparative Analysis of the Therapeutic Effects of Amniotic Membrane and Umbilical Cord Derived Mesenchymal Stem Cells for the Treatment of Type 2 Diabetes.

Type 2 diabetes mellitus (T2DM), one of the most common carbohydrate metabolism disorders, is characterized by chronic hyperglycemia and insulin resistance (IR), and has become an urgent global health challenge. Mesenchymal stem cells (MSCs) originating from perinatal tissues such as umbilical cord (UC) and amniotic membrane (AM) serve as ideal candidates for the treatment of T2DM due to their great advantages in terms of abundant source, proliferation capacity, immunomodulation and plasticity for insulin-producing cell differentiation. However, the optimally perinatal MSC source to treat T2DM remains elusive. This study aims to compare the therapeutic efficacy of MSCs derived from AM and UC (AMMSCs and UCMSCs) of the same donor in the alleviation of T2DM symptoms and explore the underlying mechanisms. Our results showed that AMMSCs and UCMSCs displayed indistinguishable immunophenotype and multi-lineage differentiation potential, but UCMSCs had a much higher expansion capacity than AMMSCs. Moreover, we uncovered that single-dose intravenous injection of either AMMSCs or UCMSCs could comparably reduce hyperglycemia and improve IR in T2DM db/db mice. Mechanistic investigations revealed that either AMMSC or UCMSC infusion could greatly improve glycolipid metabolism in the liver of db/db mice, which was evidenced by decreased liver to body weight ratio, reduced lipid accumulation, upregulated glycogen synthesis, and increased Akt phosphorylation. Taken together, these data indicate that the same donor-derived AMMSCs and UCMSCs possessed comparable effects and shared a similar hepatoprotective mechanism on the alleviation of T2DM symptoms.

Protein Aggregation in the ER: Calm behind the Storm.

As one of the largest organelles in eukaryotic cells, the endoplasmic reticulum (ER) plays a vital role in the synthesis, folding, and assembly of secretory and membrane proteins. To maintain its homeostasis, the ER is equipped with an elaborate network of protein folding chaperones and multiple quality control pathways whose cooperative actions safeguard the fidelity of protein biogenesis. However, due to genetic abnormalities, the error-prone nature of protein folding and assembly, and/or defects or limited capacities of the protein quality control systems, nascent proteins may become misfolded and fail to exit the ER. If not cleared efficiently, the progressive accumulation of misfolded proteins within the ER may result in the formation of toxic protein aggregates, leading to the so-called "ER storage diseases". In this review, we first summarize our current understanding of the protein folding and quality control networks in the ER, including chaperones, unfolded protein response (UPR), ER-associated protein degradation (ERAD), and ER-selective autophagy (ER-phagy). We then survey recent research progress on a few ER storage diseases, with a focus on the role of ER quality control in the disease etiology, followed by a discussion on outstanding questions and emerging concepts in the field.

How does CBCT reconstruction algorithm impact on deformably mapped targets and accumulated dose distributions?

PURPOSE: We performed quantitative analysis of differences in deformable image registration (DIR) and deformable dose accumulation (DDA) computed on CBCT datasets reconstructed using the standard (Feldkamp-Davis-Kress: FDK_CBCT) and a novel iterative (iterative_CBCT) CBCT reconstruction algorithms. METHODS: Both FDK_CBCT and iterative_CBCT images were reconstructed for 323 fractions of treatment for 10 prostate cancer patients. Planning CT images were deformably registered to each CBCT image data set. After daily dose distributions were computed, they were mapped to planning CT to obtain deformed doses. Dosimetric and image registration results based CBCT images reconstructed by two algorithms were compared at three levels: (A) voxel doses over entire dose calculation volume, (B) clinical constraint results on targets and sensitive structures, and (C) contours propagated to CBCT images using DIR results based on three algorithms (SmartAdapt, Velocity, and Elastix) were compared with manually delineated contours as ground truth. RESULTS: (A) Average daily dose differences and average normalized DDA differences between FDK_CBCT and iterative_CBCT were ≤1 cGy. Maximum daily point dose differences increased from 0.22 ± 0.06 Gy (before the deformable dose mapping operation) to 1.33 ± 0.38 Gy after the deformable dose mapping. Maximum differences of normalized DDA per fraction were up to 0.80 Gy (0.42 ± 0.19 Gy). (B) Differences in target minimum doses were up to 8.31 Gy (-0.62 ± 4.60 Gy) and differences in critical structure doses were 0.70 ± 1.49 Gy. (C) For mapped prostate contours based on iterative_CBCT (relative to standard FDK_CBCT), dice similarity coefficient increased by 0.10 ± 0.09 (p < 0.0001), mass center distances decreased by 2.5 ± 3.0 mm (p < 0.00005), and Hausdorff distances decreased by 3.3 ± 4.4 mm (p < 0.00015). CONCLUSIONS: The new iterative CBCT reconstruction algorithm leads to different mapped volumes of interest, deformed and cumulative doses than results based on conventional FDK_CBCT.

Design and Experiments of a Portable Seabed Integrated Detection Sonar.

The integrated observation of seabed topography, sediment geomorphology and sub-bottom profile information is very important for seabed remote sensing and mapping. To improve the efficiency of seabed detection and meet the needs of portable development of detection equipment, we developed a portable seabed feature integrated detection sonar (PSIDS) with whcih a single sonar device can simultaneously detect the above three types of seabed information. The underwater transducer is mainly composed of the following three components: a parametric emission array as the sound source, a high frequency receiving linear array for multibeam echo signal collection, and a two-dimensional vector hydrophone for receiving the low-frequency sediment echo signal. Field experiments were conducted to validate the performance of the PSIDS on 11-17 January 2018 in Jiaozhou Bay, China. (1) PSIDS could perform the functions of both multibeam sonar and sub-bottom profiler; (2) The synchronously and integrated measurement of various seabed information was achieved by alternately emitting multibeam echo-sounding and sub-bottom profiling signal using parametric source. The detection results proved the feasibility and practicability of PSIDS to achieve multiple seafloor characteristics. PSIDS provides a new idea for developing integrated seabed detection sonar. In terms of convenience and data fusion, it is a good option to use this equipment for integrated seabed detection.

Mesenchymal Stem Cell-Based Therapy for Diabetes Mellitus: Enhancement Strategies and Future Perspectives.

Diabetes mellitus (DM), a chronic disorder of carbohydrate metabolism, is characterized by the unbridled hyperglycemia resulted from the impaired ability of the body to either produce or respond to insulin. As a cell-based regenerative therapy, mesenchymal stem cells (MSCs) hold immense potency for curing DM duo to their easy isolation, multi-differentiation potential, and immunomodulatory property. However, despite the promising efficacy in pre-clinical animal models, naive MSC administration fails to exhibit clinically satisfactory therapeutic outcomes, which varies greatly among individuals with DM. Recently, numbers of innovative strategies have been applied to improve MSC-based therapy. Preconditioning, genetic modification, combination therapy and exosome application are representative strategies to maximize the therapeutic benefits of MSCs. Therefore, in this review, we summarize recent advancements in mechanistic studies of MSCs-based treatment for DM, and mainly focus on the novel approaches aiming to improve the anti-diabetic potentials of naive MSCs. Additionally, the potential directions of MSCs-based therapy for DM are also proposed at a glance.

Time-delayed interactions on acoustically driven bubbly screens.

The influence of the compressibility effects is discussed, including the time delays on the dynamics of acoustically excited bubbly screens. In the linear regime, it is shown that the proposed model for the infinite bubbly screen recovers the results predicted by the effective medium theory (EMT) up to the second order without introducing any fitting parameter when the wavelength is large compared to the inter-bubble distance. However, the effect of boundaries on the finite bubbly screens is shown to lead to the appearance of multiple local resonances and characteristic periodic structures, which limit the applicability of the EMT. In addition, a local resonance phenomenon in the liquid spacings between the bubbles is observed for both the infinite and finite bubbly screens with crystal structures, and these effects vanish as the crystal structure is perturbed. In the nonlinear regime, the current model is treated with time-delay effects as a delay differential equation, which is directly solved numerically. The appearance of an optimal distance for the subharmonic emission for the crystal structures is shown, and the accuracy of the EMT in the strong nonlinear regime is discussed.

Optimal subharmonic emission of stable bubble oscillations in a tube.

The subharmonic acoustic emission of a stable oscillating bubble inside a rigid tube is investigated by direct numerical simulation. The mechanisms of bubble-tube interaction on the acoustic wave emitted by the bubble are clarified. When the bubble is small compared to the tube diameter, a critical threshold for the pressure amplitude appears beyond the point which nonspherical effects become important and bubble breaks. For a finite tube diameter, the scattered wave by the bubble is shown to generate a plane wave where the intensity of the subharmonic component becomes maximum for an optimal distance between the bubble and the tube wall. This effect seems to be directly related to the appearance of local resonance phenomena and a bubble resonance shift where liquid's compressibility plays a major role.

A simple model of bubble cluster dynamics in an acoustic field.

The dynamics of bubble clouds induced by ultrasound field are investigated in a regime where the cloud size is much smaller than the ultrasound wavelength. Two frequently used models describing the dynamics of individual bubbles inside a bubble cluster in an acoustic field are studied, one based on the homogeneity assumption, and the other based on the simultaneous motion assumption. A modified formula of the homogenization-based model is presented, and an inherent distinction in bubble-bubble interaction term is found in comparison to the simultaneous motion model. To gain insight into the mechanisms of such distinction, a reduced model unifying these two models is presented, and such distinction is explained by the spatial dependence of the bubble-bubble interaction in a bubble cluster accordingly. To validate the reduced model, the normalized distance γbb and the cloud interaction parameter B0 are used as two scaling parameters, and the comparison between the present model and the coupled Rayleigh-Plesset type equations is made. A conclusion is that, in the weak bubble-bubble interaction case (γbb>10), the reduced model can well reproduce the radial motion of bubbles in the cluster during the growth stage and the collapse stage in each acoustic cycle; in the strong bubble-bubble interaction case (γbb<10), the growth phase of bubbles in the cluster can be accurately predicted by the reduced model only if B0 or the amplitude of driving field is small.

Joint Time-Reversal Space-Time Block Coding and Adaptive Equalization for Filtered Multitone Underwater Acoustic Communications.

Underwater acoustic (UWA) sensor networks demand high-rate communications with high reliability between sensor nodes for massive data transmission. Filtered multitone (FMT) is an attractive multicarrier technique used in high-rate UWA communications, and can obviously shorten the span of intersymbol interference (ISI) with high spectral efficiency and low frequency offset sensitivity by dividing the communication band into several separated wide sub-bands without guard bands. The joint receive diversity and adaptive equalization scheme is often used as a general ISI suppression technique in FMT-UWA communications, but large receive array for high diversity gain has an adverse effect on the miniaturization of UWA sensor nodes. A time-reversal space-time block coding (TR-STBC) technique specially designed for frequency-selective fading channels can replace receive diversity with transmit diversity for high diversity gain, and therefore is helpful for ISI suppression with simple receive configuration. Moreover, the spatio-temporal matched filtering (MF) in TR-STBC decoding can mitigate ISI obviously, and therefore is of benefit to lessen the complexion of adaptive equalization for post-processing. In this paper, joint TR-STBC and adaptive equalization FMT-UWA communication method is proposed based on the merit of TR-STBC. The proposed method is analyzed in theory, and its performance is assessed using simulation analysis and real experimental data collected from an indoor pool communication trial. The validity of the proposed method is proved through comparing the proposed method with the joint single-input-single-output (SISO) and adaptive equalization method and the joint single-input-multiple-output (SIMO) and adaptive equalization method. The results show that the proposed method can achieve better communication performance than the joint SISO and adaptive equalization method, and can achieve similar performance with more simpler receive configuration as the joint SIMO and adaptive equalization method.

Filtered Multitone Modulation Underwater Acoustic Communications Using Low-Complexity Channel-Estimation-Based MMSE Turbo Equalization.

Filtered multitone (FMT) modulation divides the communication band into several subbands to shorten the span of symbols affected by multipath in underwater acoustic (UWA) communications. However, there is still intersymbol interference (ISI) in each subband of FMT modulation degrading communication performance. Therefore, ISI suppression techniques must be applied to FMT modulation UWA communications. The suppression performance of traditional adaptive equalization methods often exploited in FMT modulation UWA communications is limited when the effect of ISI spans tens of symbols or large constellation sizes are used. Turbo equalization consisting of adaptive equalization and channel decoding can improve equalization performance through information exchanging and iterative processes. To overcome the shortcoming of traditional minimum mean square error (MMSE) equalization and effectively suppress the ISI with relatively low computation complexity, an FMT modulation UWA communication using low-complexity channel-estimation-based (CE-based) MMSE turbo equalization is proposed in this paper. In the proposed method, turbo equalization is first exploited to suppress the ISI in FMT modulation UWA communications, and the equalizer coefficients of turbo equalization are adjusted using the low-complexity CE-based MMSE algorithm. The proposed method is analyzed in theory and verified by simulation analysis and real data collected in the experiment carried out in a pool with multipath propagation. The results demonstrate that the proposed method can achieve better communication performance with a higher bit rate than the FMT modulation UWA communication using traditional MMSE adaptive equalization.

Theoretical and experimental study on multibeam synthetic aperture sonar.

High-resolution imaging method is one of the researching focuses of underwater acoustic detection. Underwater small-target detection also requires detailed imaging technology. Multibeam echo sounders (MBESs) and synthetic aperture sonar (SAS) are the effective instruments widely researched to obtain underwater acoustic images. Constrained by the theory, the along-track resolution of MBES decreases with distance and the gaps problem of SAS always exists and both inevitably limit the quality of acoustic imaging. In this paper, a two dimensional multibeam synthetic aperture sonar (MBSAS) model is designed to overcome the shortcomings of conventional underwater imaging instruments. MBSAS can provide a three dimensional (3D) high-resolution acoustic image without a gap problem. An echo model and transducer array manifold are designed to meet the requirements of engineering applications. Imaging theory and target simulations prove the feasibility of the MBSAS model. The performance of the proposed model is demonstrated with a tank experiment. A detailed image is obtained through an experiment that can indicate the shapes of targets and has the ability to separate adjacent targets. The simulations and experimental results indicate that MBSAS can obtain a more detailed 3D full-scan image than conventional MBES and SAS system with a better energy focusing ability.

Influence of bubble distributions on the propagation of linear waves in polydisperse bubbly liquids.

The influence of the spatial distributions of bubbles on the propagation of linear acoustic waves in polydisperse bubbly liquids is studied. Using the diagrammatic approach, the effective wavenumber, which includes both spatial information and higher orders of multiple scattering, is presented. The phase speed and attenuation coefficient of acoustic waves in bubbly liquids are calculated from the effective wavenumber. A three-dimensional random model, the Generalized Matérn's hard-core point process, is used to close the model. Numerical simulations reveal that as the bubble volume fraction becomes larger so does the effect of the bubble distributions on the attenuation and phase speed. The irregular discrepancy between previously reported experimental results and the classical theory is attributed to the influence of bubble clustering on the propagation of linear waves. The comparison between the present model and the experimental measurements [Leroy, Strybulevych, Page, and Scanlon. (2011). Phys. Rev. E 83, 046605] reveals that the proposed correction term significantly improves the theoretical predictions.

On the improvement of CBCT image quality for soft tissue-based SRS localization.

PURPOSE: We explore the optimal cone-beam CT (CBCT) acquisition parameters to improve CBCT image quality to enhance intracranial stereotactic radiosurgery (SRS) localization and also assess the imaging dose levels associated with each imaging protocol. METHODS: Twenty-six CBCT acquisition protocols were generated on an Edge® linear accelerator (Varian Medical Systems, Palo Alto, CA) with different x-ray tube current and potential settings, gantry rotation trajectories, and gantry rotation speeds. To assess image quality, images of the Catphan 504 phantom were analyzed to evaluate the following image quality metrics: uniformity, HU constancy, spatial resolution, low contrast detection, noise level, and contrast-to-noise ratio (CNR). To evaluate the imaging dose for each protocol, the cone-beam dose index (CBDI) was measured. To validate the phantom results, further analysis was performed with an anthropomorphic head phantom as well as image data acquired for a clinical SRS patient. RESULTS: The Catphan data indicates that adjusting acquisition parameters had direct effects on the image noise level, low contrast detection, and CNR, but had minimal effects on uniformity, HU constancy, and spatial resolution. The noise level was reduced from 34.5 ± 0.3 to 18.5 ± 0.2 HU with a four-fold reduction in gantry speed, and to 18.7 ± 0.2 HU with a four-fold increase in tube current. Overall, the noise level was found to be proportional to inverse square root of imaging dose, and imaging dose was proportional to the product of total tube current-time product and the cube of the x-ray potential. Analysis of the anthropomorphic head phantom data and clinical SRS imaging data also indicates that noise is reduced with imaging dose increase. CONCLUSIONS: Our results indicate that optimization of the imaging protocol, and thereby an increase in the imaging dose, is warranted for improved soft-tissue visualization for intracranial SRS.