A new odorous frog species of Odorrana (Amphibia, Anura, Ranidae) from Guizhou Province, China.

The frog genus Odorrana is distributed across east and southeastern Asia. Based on morphological differences and molecular phylogenetics, a new species of the genus occurring from Leigong Mountain in Guizhou Province, China is described. Phylogenetic analyses based on DNA sequences of the mitochondrial 12S rRNA, 16S rRNA, and ND2 genes supported the new species as an independent lineage. The uncorrected genetic distances between the 12S rRNA, 16S rRNA, and ND2 genes between the new species and its closest congener were 5.0%, 4.9%, and 16.3%, respectively. The new species is distinguished from its congeners by a combination of the following characters: body size moderate (SVL 39.1-49.4 mm in males, 49.7 mm in female); head width larger than head length; tympanum distinctly visible; small rounded granules scattered all over dorsal body and limbs; dorsolateral folds absent; heels overlapping when thighs are positioned at right angles to the body; tibiotarsal articulation reaching the level between eye to nostril when leg stretched forward; vocal sacs absent in male and nuptial pads present on the base of finger I.

DNA origami tubes with reconfigurable cross-sections.

Structural DNA nanotechnology has enabled the design and construction of complex nanoscale structures with precise geometry and programmable dynamic and mechanical properties. Recent efforts have led to major advances in the capacity to actuate shape changes of DNA origami devices and incorporate DNA origami into larger assemblies, which open the prospect of using DNA to design shape-morphing assemblies as components of micro-scale reconfigurable or sensing materials. Indeed, a few studies have constructed higher order assemblies with reconfigurable devices; however, these demonstrations have utilized structures with relatively simple motion, primarily hinges that open and close. To advance the shape changing capabilities of DNA origami assemblies, we developed a multi-component DNA origami 6-bar mechanism that can be reconfigured into various shapes and can be incorporated into larger assemblies while maintaining capabilities for a variety of shape transformations. We demonstrate the folding of the 6-bar mechanism into four different shapes and demonstrate multiple transitions between these shapes. We also studied the shape preferences of the 6-bar mechanism in competitive folding reactions to gain insight into the relative free energies of the shapes. Furthermore, we polymerized the 6-bar mechanism into tubes with various cross-sections, defined by the shape of the individual mechanism, and we demonstrate the ability to change the shape of the tube cross-section. This expansion of current single-device reconfiguration to higher order scales provides a foundation for nano to micron scale DNA nanotechnology applications such as biosensing or materials with tunable properties.

Integrated computer-aided engineering and design for DNA assemblies.

Recently, DNA has been used to make nanodevices for a myriad of applications across fields including medicine, nanomanufacturing, synthetic biology, biosensing and biophysics. However, current DNA nanodevices rely primarily on geometric design, and it remains challenging to rationally design functional properties such as force-response or actuation behaviour. Here we report an iterative design pipeline for DNA assemblies that integrates computer-aided engineering based on coarse-grained molecular dynamics with a versatile computer-aided design approach that combines top-down automation with bottom-up control over geometry. This intuitive framework allows for rapid construction of large, multicomponent assemblies from three-dimensional models with finer control over the geometrical, mechanical and dynamical properties of the DNA structures in an automated manner. This approach expands the scope of structural complexity and enhances mechanical and dynamic design of DNA assemblies.

Stretchable Liquid Metal-Based Conductive Textile for Electromagnetic Interference Shielding.

Conductive textiles (CTs) are promising electromagnetic interference (EMI) shielding materials. Nevertheless, limited stretchability and poor reliability restrict their potential applications in stretchable electronic devices because of the rigid conductive networks. Herein, a highly stretchable and reliable CT is developed for effective EMI shielding by designing a deformable liquid-metal (LM) coating and polydimethylsiloxane (PDMS) protective layer. The resultant PDMS-LM/Textile exhibits an outstanding EMI shielding efficiency (EMI SE) of 72.6 dB at a thickness of only 0.35 mm while maintaining EMI SEs of 66.0 and 52.4 dB under strains of 30 and 50%, respectively. The corresponding EMI SEs hold 91.7 and 80.3% retention after 5000 stretching-releasing cycles, respectively. The superior and durable EMI SE should be ascribed to the perfect connectivity and good deformability of conductive LM networks. Moreover, the LM coating has a robust fastness to the textile substrate, without any obvious decrease in EMI SE after 10 min of ultrasonic treatment and 100 peeling cycles because of the protective effect of the PDMS layer. This work provides a novel route to developing highly stretchable CTs for advanced EMI shielding applications, especially in the field of highly stretchable electronic devices.

An electrochemical biosensor exploiting binding-induced changes in electron transfer of electrode-attached DNA origami to detect hundred nanometer-scale targets.

The specific detection in clinical samples of analytes with dimensions in the tens to hundreds of nanometers, such as viruses and large proteins, would improve disease diagnosis. Detection of these "mesoscale" analytes (as opposed to their nanoscale components), however, is challenging as it requires the simultaneous binding of multiple recognition sites often spaced over tens of nanometers. In response, we have adapted DNA origami, with its unparalleled customizability to precisely display multiple target-binding sites over the relevant length scale, to an electrochemical biosensor platform. Our proof-of-concept employs triangular origami covalently attached to a gold electrode and functionalized with redox reporters. Electrochemical interrogation of this platform successfully monitors mesoscale, target-binding-induced changes in electron transfer in a manner consistent with coarse-grained molecular dynamics simulations. Our approach enables the specific detection of analytes displaying recognition sites that are separated by ∼40 nm, a spacing significantly greater than that achieved in similar sensor architectures employing either antibodies or aptamers.

Uncertainty quantification of a DNA origami mechanism using a coarse-grained model and kinematic variance analysis.

Significant advances have been made towards the design, fabrication, and actuation of dynamic DNA nanorobots including the development of DNA origami mechanisms. These DNA origami mechanisms integrate relatively stiff links made of bundles of double-stranded DNA and relatively flexible joints made of single-stranded DNA to mimic the design of macroscopic machines and robots. Despite reproducing the complex configurations of macroscopic machines, these DNA origami mechanisms exhibit significant deviations from their intended motion behavior since nanoscale mechanisms are subject to significant thermal fluctuations that lead to variations in the geometry of the underlying DNA origami components. Understanding these fluctuations is critical to assess and improve the performance of DNA origami mechanisms and to enable precise nanoscale robotic functions. Here, we report a hybrid computational framework combining coarse-grained modeling with kinematic variance analysis to predict uncertainties in the motion pathway of a multi-component DNA origami mechanism. Coarse-grained modeling was used to evaluate the variation in geometry of individual components due to thermal fluctuations. This variation was incorporated in kinematic analyses to predict the motion pathway uncertainty of the entire mechanism, which agreed well with experimental characterization of motion. We further demonstrated the ability to predict the probability density of DNA origami mechanism conformations based on analysis of mechanical properties of individual joints. This integration of computational analysis, modeling tools, and experimental methods establish the foundation to predict and manage motion uncertainties of general DNA origami mechanisms to guide the design of DNA-based nanoscale machines and robots.

Paper Origami-Inspired Design and Actuation of DNA Nanomachines with Complex Motions.

Significant progress in DNA nanotechnology has accelerated the development of molecular machines with functions like macroscale machines. However, the mobility of DNA self-assembled nanorobots is still dramatically limited due to challenges with designing and controlling nanoscale systems with many degrees of freedom. Here, an origami-inspired method to design transformable DNA nanomachines is presented. This approach integrates stiff panels formed by bundles of double-stranded DNA connected with foldable creases formed by single-stranded DNA. To demonstrate the method, a DNA version of the paper origami mechanism called a waterbomb base (WBB) consisting of six panels connected by six joints is constructed. This nanoscale WBB can follow four distinct motion paths to transform between five distinct configurations including a flat square, two triangles, a rectangle, and a fully compacted trapezoidal shape. To achieve this, the sequence specificity of DNA base-pairing is leveraged for the selective actuation of joints and the ion-sensitivity of base-stacking interactions is employed for the flattening of joints. In addition, higher-order assembly of DNA WBBs into reconfigurable arrays is achieved. This work establishes a foundation for origami-inspired design for next generation synthetic molecular robots and reconfigurable nanomaterials enabling more complex and controllable motion.

Cation-Activated Avidity for Rapid Reconfiguration of DNA Nanodevices.

The ability to design and control DNA nanodevices with programmed conformational changes has established a foundation for molecular-scale robotics with applications in nanomanufacturing, drug delivery, and controlling enzymatic reactions. The most commonly used approach for actuating these devices, DNA binding and strand displacement, allows devices to respond to molecules in solution, but this approach is limited to response times of minutes or greater. Recent advances have enabled electrical and magnetic control of DNA structures with sub-second response times, but these methods utilize external components with additional fabrication requirements. Here, we present a simple and broadly applicable actuation method based on the avidity of many weak base-pairing interactions that respond to changes in local ionic conditions to drive large-scale conformational transitions in devices on sub-second time scales. To demonstrate such ion-mediated actuation, we modified a DNA origami hinge with short, weakly complementary single-stranded DNA overhangs, whose hybridization is sensitive to cation concentrations in solution. We triggered conformational changes with several different types of ions including mono-, di-, and trivalent ions and also illustrated the ability to engineer the actuation response with design parameters such as number and length of DNA overhangs and hinge torsional stiffness. We developed a statistical mechanical model that agrees with experimental data, enabling effective interpretation and future design of ion-induced actuation. Single-molecule Förster resonance energy-transfer measurements revealed that closing and opening transitions occur on the millisecond time scale, and these transitions can be repeated with time resolution on the scale of one second. Our results advance capabilities for rapid control of DNA nanodevices, expand the range of triggering mechanisms, and demonstrate DNA nanomachines with tunable analog responses to the local environment.

Three-dimensional structural dynamics of DNA origami Bennett linkages using individual-particle electron tomography.

Scaffolded DNA origami has proven to be a powerful and efficient technique to fabricate functional nanomachines by programming the folding of a single-stranded DNA template strand into three-dimensional (3D) nanostructures, designed to be precisely motion-controlled. Although two-dimensional (2D) imaging of DNA nanomachines using transmission electron microscopy and atomic force microscopy suggested these nanomachines are dynamic in 3D, geometric analysis based on 2D imaging was insufficient to uncover the exact motion in 3D. Here we use the individual-particle electron tomography method and reconstruct 129 density maps from 129 individual DNA origami Bennett linkage mechanisms at ~ 6-14 nm resolution. The statistical analyses of these conformations lead to understanding the 3D structural dynamics of Bennett linkage mechanisms. Moreover, our effort provides experimental verification of a theoretical kinematics model of DNA origami, which can be used as feedback to improve the design and control of motion via optimized DNA sequences and routing.

A practical community-based response strategy to interrupt Ebola transmission in sierra Leone, 2014-2015.

BACKGROUND: The Ebola virus disease spread rapidly in West Africa in 2014, leading to the loss of thousands of lives. Community engagement was one of the key strategies to interrupt Ebola transmission, and practical community level measures needed to be explored in the field and tailored to the specific context of communities. METHODS: First, community-level education on Ebola virus disease (EVD) prevention was launched for the community's social mobilizers in six districts in Sierra Leone beginning in November 2014. Then, from January to May of 2015, in three pilot communities, local trained community members were organized to engage in implementation of EVD prevention and transmission interruption measures, by involving them in alert case report, contact tracing, and social mobilization. The epidemiological indicators of transmission interruption in three study communities were evaluated. RESULTS: A total of 6 016 community social mobilizers from 185 wards were trained by holding 279 workshops in the six districts, and EVD message reached an estimated 631 680 residents. In three pilot communities, 72 EVD alert cases were reported, with 70.8 % of them detected by trained local community members, and 14 EVD cases were finally identified. Contact tracing detected 64.3 % of EVD cases. The median duration of community infectivity for the cases was 1 day. The secondary attack rate was 4.2 %, and no third generation of infection was triggered. No health worker was infected, and no unsafe burial and noncompliance to EVD control measures were recorded. The community-based measures were modeled to reduce 77 EVD cases, and the EVD-free goal was achieved four months earlier in study communities than whole country of Sierra Leone. CONCLUSIONS: The community-based strategy of social mobilization and community engagement was effective in case detection and reducing the extent of Ebola transmission in a country with weak health system. The successfully practical experience to reduce the risk of Ebola transmission in the community with poor resources would potentially be helpful for the global community to fight against the EVD and the other diseases in the future.

Direct design of an energy landscape with bistable DNA origami mechanisms.

Structural DNA nanotechnology provides a feasible technique for the design and fabrication of complex geometries even exhibiting controllable dynamic behavior. Recently we have demonstrated the possibility of implementing macroscopic engineering design approaches to construct DNA origami mechanisms (DOM) with programmable motion and tunable flexibility. Here, we implement the design of compliant DNA origami mechanisms to extend from prescribing motion to prescribing an energy landscape. Compliant mechanisms facilitate motion via deformation of components with tunable stiffness resulting in well-defined mechanical energy stored in the structure. We design, fabricate, and characterize a DNA origami nanostructure with an energy landscape defined by two stable states (local energy minima) separated by a designed energy barrier. This nanostructure is a four-bar bistable mechanism with two undeformed states. Traversing between those states requires deformation, and hence mechanical energy storage, in a compliant arm of the linkage. The energy barrier for switching between two states was obtained from the conformational distribution based on a Boltzmann probability function and closely follows a predictive mechanical model. Furthermore, we demonstrated the ability to actuate the mechanism into one stable state via additional DNA inputs and then release the actuation via DNA strand displacement. This controllable multistate system establishes a foundation for direct design of energy landscapes that regulate conformational dynamics similar to biomolecular complexes.

Mechanical design of DNA nanostructures.

Structural DNA nanotechnology is a rapidly emerging field that has demonstrated great potential for applications such as single molecule sensing, drug delivery, and templating molecular components. As the applications of DNA nanotechnology expand, a consideration of their mechanical behavior is becoming essential to understand how these structures will respond to physical interactions. This review considers three major avenues of recent progress in this area: (1) measuring and designing mechanical properties of DNA nanostructures, (2) designing complex nanostructures based on imposed mechanical stresses, and (3) designing and controlling structurally dynamic nanostructures. This work has laid the foundation for mechanically active nanomachines that can generate, transmit, and respond to physical cues in molecular systems.

Programmable motion of DNA origami mechanisms.

DNA origami enables the precise fabrication of nanoscale geometries. We demonstrate an approach to engineer complex and reversible motion of nanoscale DNA origami machine elements. We first design, fabricate, and characterize the mechanical behavior of flexible DNA origami rotational and linear joints that integrate stiff double-stranded DNA components and flexible single-stranded DNA components to constrain motion along a single degree of freedom and demonstrate the ability to tune the flexibility and range of motion. Multiple joints with simple 1D motion were then integrated into higher order mechanisms. One mechanism is a crank-slider that couples rotational and linear motion, and the other is a Bennett linkage that moves between a compacted bundle and an expanded frame configuration with a constrained 3D motion path. Finally, we demonstrate distributed actuation of the linkage using DNA input strands to achieve reversible conformational changes of the entire structure on ∼ minute timescales. Our results demonstrate programmable motion of 2D and 3D DNA origami mechanisms constructed following a macroscopic machine design approach.

DNA origami compliant nanostructures with tunable mechanical properties.

DNA origami enables fabrication of precise nanostructures by programming the self-assembly of DNA. While this approach has been used to make a variety of complex 2D and 3D objects, the mechanical functionality of these structures is limited due to their rigid nature. We explore the fabrication of deformable, or compliant, objects to establish a framework for mechanically functional nanostructures. This compliant design approach is used in macroscopic engineering to make devices including sensors, actuators, and robots. We build compliant nanostructures by utilizing the entropic elasticity of single-stranded DNA (ssDNA) to locally bend bundles of double-stranded DNA into bent geometries whose curvature and mechanical properties can be tuned by controlling the length of ssDNA strands. We demonstrate an ability to achieve a wide range of geometries by adjusting a few strands in the nanostructure design. We further developed a mechanical model to predict both geometry and mechanical properties of our compliant nanostructures that agrees well with experiments. Our results provide a basis for the design of mechanically functional DNA origami devices and materials.

A Symbolic Formulation for Analytical Compliance Analysis and Synthesis of Flexure Mechanisms.

This paper presents a symbolic formulation for analytical compliance analysis and synthesis of flexure mechanisms with serial, parallel, or hybrid topologies. Our approach is based on the screw theory that characterizes flexure deformations with motion twists and loadings with force wrenches. In this work, we first derive a symbolic formulation of the compliance and stiffness matrices for commonly used flexure elements, flexure joints, and simple chains. Elements of these matrices are all explicit functions of flexure parameters. To analyze a general flexure mechanism, we subdivide it into multiple structural modules, which we identify as serial, parallel, or hybrid chains. We then analyze each module with the known flexure structures in the library. At last, we use a bottom-up approach to obtain the compliance/stiffness matrix for the overall mechanism. This is done by taking appropriate coordinate transformation of twists and wrenches in space. Four practical examples are provided to demonstrate the approach. A numerical example is employed to compare analytical compliance models against a finite element model. The results show that the errors are sufficiently small (2%, compared with finite element (FE) model), if the range of motion is limited to linear deformations. This work provides a systematical approach for compliance analysis and synthesis of general flexure mechanisms. The symbolic formulation enables subsequent design tasks, such as compliance synthesis or sensitivity analysis.

Intravascular ultrasound area strain imaging used to characterize tissue components and assess vulnerability of atherosclerotic plaques in a rabbit model.

The purpose of this study was to investigate the association of area strain and tissue components and vulnerability of atherosclerotic plaques in a rabbit model. Forty purebred New Zealand rabbits underwent balloon-induced abdominal aorta endothelium injury, then a high-cholesterol diet for 24 weeks. Intravascular ultrasound (IVUS) images of abdominal aortas were acquired in situ and two consecutive frames near the end-diastole were used to construct an IVUS elastogram. Histologic slices matched with corresponding IVUS images were stained for fatty and collagen components, smooth muscle cells (SMCs) and macrophages. Regions-of-interest (ROIs) in plaques were classified as fibrous, fibro-fatty or fatty according to histologic study. Vulnerability indexes of ROIs were calculated as (fat + macrophage)/(collagen + SMCs). The area strain of these ROIs was calculated by use of an in-house-designed software system with a block-matching-based algorithm. Area strain was significantly higher in fatty ROIs (0.056 ± 0.003) than in fibrous (0.019 ± 0.002, p < 0.001) or fibro-fatty ROIs (0.033 ± 0.003, p < 0.001). The sensitivity and specificity of area strain for fatty ROIs characterization was 75.0% and 80.2% (area under the curve [AUC] 0.858, 95% confidence interval [CI] = 0.800-0.916, p < 0.001) and 75.0% and 75.3% (AUC 0.859, 95% CI = 0.801-0.917, p < 0.001) for fibrous ROIs, as demonstrated by receiver operating characteristic curve analysis. Area strain was positively correlated with vulnerability index (r(2) = 0.495, p < 0.001), fatty components (r(2) = 0.332, p < 0.001) and macrophage infiltration (r(2) = 0.406, p < 0.001); and negatively correlated with collagen and SMC composition (r(2) = 0.115 and r(2) = 0.169, p < 0.001, respectively). Area strain calculation with IVUS elastography based on digital B-mode analysis is feasible and can be useful for tissue characterization and plaque vulnerability assessment.

Atherosclerotic plaque components characterization and macrophage infiltration identification by intravascular ultrasound elastography based on b-mode analysis: validation in vivo.

Intravascular ultrasound elastography (IVUSE) is a promising imaging technique for early investigation of vulnerable plaques. Compared to radiofrequency signal processing, digital B-mode analysis is simple and of higher portability. However, rare studies have been reported validating the latter technique in vivo. In this study, we developed an IVUSE computer software system involving semi-automatic border delineation and block-matching algorithm and validated the system in vivo. Seven minipigs were fed with atherogenic diet for 40 weeks. For each pig, the endothelium of one side of the renal arteries was denuded at the fifth week. With cross-correlation analysis, Lagrangian strain was calculated from two intravascular ultrasound images acquired in situ. Sixty regions of interests were selected from 35 elastograms matched well with the corresponding histological slices. Plaque types within these regions were classified as fibrous, fibro-fatty or fatty on Masson's trichrome and Oil-red O staining. Macrophage infiltration was also evaluated with immunohistology. Comparison between the mean strain value of the region of interest and the histological results revealed significant differences in strain values among different plaque types and non-diseased artery walls. The extent of macrophage infiltration was found to be correlated positively with strain values. For identification of fibro-fatty and fibrous plaques and macrophage infiltration, the system showed high sensitivity (93, 96 and 92%, respectively) and specificity (89, 76 and 66%, respectively), as revealed by receiver operating characteristic analysis. Our IVUSE system based on B-mode analysis is capable of characterizing fibrous and fibro-fatty plaques and macrophage intensity, thus holds potential for identifying vulnerable plaque.

Plaque volume compression ratio, a novel biomechanical index, is independently associated with ischemic cerebrovascular events.

OBJECTIVE: The purpose of this study was to develop a new biomechanical index for assessing the elastic characteristics of carotid plaques and to test the association between carotid plaque elasticity and ischemic cerebrovascular events (ICEs). METHODS: One hundred and eighteen carotid plaques were detected with real-time three-dimensional ultrasonography in 104 patients. All patients received MRI and were divided into two groups according to the history of ICEs: patients with ICEs (n=58, including 20 patients with transient ischemic attack and 38 with ischemic stroke) and patients without ICEs (n=46). The carotid plaque volume at end diastole (Vd) and end systole (Vs) was measured by use of a TomTec (Munich, Germany) workstation. Plaque volume compression ratio (VCR) was calculated as (Vd-Vs)/Vd x 100 and the reproducibility of VCR measurement was analyzed. The carotid intima-media thickness, plaque area and plaque acoustic density were also measured. Multivariate logistic regression was used to test the association between ICEs and plaque ultrasonic parameters or traditional risk factors including age, sex, smoking, blood pressure, history of coronary heart disease, levels of serum low-density lipoprotein, triglyceride and glucose. RESULTS: Satisfactory images of carotid plaques were obtained in all patients by real-time three-dimensional ultrasonography. Patients with ICEs and patients without ICEs differed significantly in VCR (22.19+/-8.42 vs. 13.95+/-7.86, P<0.01). Regression analysis revealed that systolic blood pressure, [odds ratio (OR)=1.054, 95% confidence interval (CI)=1.028-1.081, P<0.001] and VCR (OR=1.074, 95% CI=1.022-1.128, P<0.001) were associated with ICEs independently. Plaque volume had only a marginal association with ICEs (OR=1.007, 95% CI=1.000-1.013, P=0.05). CONCLUSION: Measurement of VCR provides a noninvasive approach to the evaluation of the elasticity of carotid plaques, which is associated independently with ICEs. Thus, real-time three-dimensional ultrasonography-derived VCR holds a great potential in identifying patients with high risk of ICEs.

[A correlation study of serum inflammatory factors and intravascular ultrasound features of atherosclerotic plaques in patients with angina pectoris].

OBJECTIVE: To elucidate the relationship between serum inflammatory factors and intravascular ultrasound (IVUS) findings of atherosclerotic plaques in patients with stable and unstable angina. METHODS: Thirteen patients with stable angina (SA) in group A and nineteen patients with unstable angina (UA) in group B underwent study. Concentrations of hsCRP, sVCAM-1 and sICAM-1 were measured by means of Enzyme-Linked-Immunosorbent Assay (ELISA) and IVUS was used to analysis the coronary lesions. Their results were analyzed by correlate analysis. RESULTS: Concentration of hsCRP, sVCAM-1 and sICAM-1 were significantly higher in group B (4.7 mg/L +/- 2.6 mg/L, 789 micro g/L +/- 65 micro g/L and 365 micro g/L +/- 63 micro g/L) than in group A (2.4 mg/L +/- 1.8 mg/L, 544 micro g/L +/- 70 micro g/L and 264 micro g/L +/- 53 micro g/L, P < 0.01, respectively). IVUS found that 69.2% (18/26) patients in group B had soft lipid plaques, while patients in group A mainly had fibrous and mixed plaques, only 13.3% (2/15) had soft plaques. There were more eccentric plaques and EEMA in group B than in group A (P < 0.05, respectively), and PA and lumen area stenosis ratio (LAS) in group B were larger than those of group A (P < 0.01, respectively). Positive remodeling pattern was observed in 65.4% (17/26) lesions in group B while 66.6% (10/15) lesions in group A showed negative remodeling. sICAM-1 correlated well with RI (r = 0.475, P < 0.05) and C-RP with EEMA (r = 0.448, P < 0.05). CONCLUSION: High levels of hsCRP, sVCAM-1 and sICAM-1 are sensitive predictors of unstable angina. The features of unstable atherosclerotic plaques are eccentric, soft plaques, with large plaque areas. The vessel at the lesion shows positive remodeling. Inflammatory reaction correlated well with vascular enlargement and remodeling.