bluuebunny/crossref_metadata_2025 huggingface dataset:
Aortic Root Finite Element Modeling From MR Imaging
Authors: Conti Carlo A. , Votta Emiliano , Della Corte Alessandro , Del Viscovo Luca , Cotrufo Maurizio , Redaelli Alberto
Published: March 2014

The aortic root is the portion of the outflow tract of the left ventricle that includes the aortic leaflets, the aortic annulus, the sinuses of Valsalva and the sinotubular junction. The impairment of one or more of these structures can lead not only to dysfunctions of the root, but also to alterations of the adjacent anatomical sites, such as the ascending aorta. The raise and the progress of the alterations are often related to more concomitant factors, whose separated effect can be difficult to assess. At this purpose computational finite element (FE) models can be a useful tool, given their capability the recreate different scenarios by varying one or more parameters of the model in a controlled fashion.
Misinterpretation of Functional Severity of Coronary Stenosis in the Presence of Collateral Flow
Authors: Peelukhana Srikara Viswanath , Banerjee Rupak K. , Effat Mohamed A. , Helmy Tarek
Published: March 2014

Angiography is widely used diagnostic method to find the ischemic severity. However, it is limited in its capacity in determining the functional severity of the stenosis [1]. Hence, a functional diagnostic parameter Fractional Flow Reserve (FFR), defined as the ratio of distal pressure to the proximal pressure at maximum vasodilation [2], at the site of the stenosis, was developed to assess the functional severity of the stenosis. Pijls et al [3], established a threshold value of 0.75 for FFR, based on which coronary intervention decisions are taken. If FFR is below 0.75, a percutaneous coronary intervention is recommended. FFR is calculated during cardiac catheterization by measuring the pressure values across the stenosis. However, the value of FFR measured during cardiac catheterization doesn’t account for the increase in pressure values downstream of stenosis, due to other resistances in coronary circuit, e.g., abnormal microvasculature and functional collaterals, as it cannot delineate the effect of downstream collateral flow or the presence of myocardial diseases.
An Autonomous Cell Type Selective Irreversible Electroporation Microsystem Using Insulator Based Dielectrophoresis (IDEP)
Authors: Shafiee Hadi , Davalos Rafael V.
Published: March 2014

Irreversible electroporation (IRE) is a method to kill cells by exposing the cell to intense electric field pulses[1]. It is postulated that the lipid bilayer rearranges to create permanent defects in the cell membrane which eventually leads to cell death via necrosis[1]. We postulate that the recurrence of cancer for patients treated for the disease would be minimized if their blood was monitored using a microdevice which would destroy existing or new exfoliated cancer cells. Dielectrophoresis (DEP) is the motion of polarizable particles that are suspended in an electrolyte when subjected to a spatially nonuniform electric field [2]. Insulator-based DEP uses insulating structures rather than electrode arrays to produce the nonuniform fields needed to drive DEP. We hypothesize that iDEP can enable the selective IRE of a particular cell type within a microfluidic platform. This manuscript demonstrates through modeling the feasibility of coupling iDEP with IRE using an AC field with a DC offset. Such a platform could be used to selectively destroy isolate cancer cells while not affecting normal cells.
Rough Substratum Surface Facilitates Methicillin-Resistant Staphylococcus aureus Biofilm Formation in the Presence of Antibiotics
Authors: Kostenko Victoria , Boraey Mohammad A. , Salek M. Mehdi , Martinuzzi Robert J.
Published: March 2014

Despite a variety of approaches developed to prevent bacterial colonization and biofilm formation on indwelling medical devices, implant-associated infections remain responsible for about 65% of nosocomial diseases, including MRSA infections [1].
Characterizing the Surface Topography of Viable Cartilage Explants: A Novel Application of the Scanning White Light Interferometer
Authors: Shekhawat Vivek K. , Laurent Michel , Muehleman Carol , Wimmer Markus A.
Published: March 2014

Surface topography is an important parameter that affects friction, lubrication and wear of contacting materials. Articular cartilage has a very distinct topography allowing transport of nutritious fluid under elastohydrodynamic lubrication conditions [1]. Topographical measurements are a prerequisite for ex-vivo explant cultures which have become increasingly popular in the field of mechanobiology. Recently, several laboratories established wear tests [2, 3] to evaluate artificial cartilage repair materials intended to articulate against natural cartilage. Stylus profilometry, originally used in 1986 to establish that surface topography is a valuable indicator of cartilage health [1], remains the dominant technique for determining cartilage topography [4] despite significant shortcomings. Contact-based and slow, it can mar the surface and negatively impact tissue viability. However, to understand the underlying damage mechanism(s) it would be of utmost importance to monitor changes in surface topography during wear testing of viable tissue.
Effect of Degeneration on the Dynamic Viscoelastic Properties of Human Annulus Fibrosus in Tension
Authors: Sen Sounok , Boxberger John I. , Schroeder Yvonne , Espinoza Orias Alejandro , Elliott Dawn M.
Published: March 2014

Physiological cyclic loading of the intervertebral disc generally occurs between 1 and 5 Hz [1]. However, most mechanical assessments of disc AF tissue have relied on uniaxial tensile tests under quasi-static conditions [2]. Furthermore, the few studies that have addressed AF viscoelasticity have reported only static viscoelastic properties such as creep or stress-relaxation [3]. As such, there exists almost no data characterizing the dynamic viscoelastic properties of AF tissue in tension. Such data would be critical for several applications: to elucidate the mechanical progression of intervertebral disc degeneration, to develop and validate structural finite element models, and to provide native tissue benchmarks for regenerative approaches that aim to restore mechanical function to diseased or degenerate tissue. Therefore, the objectives of this study are to: (1) quantify human AF tissue frequency-dependent and strain-dependent viscoelastic properties of human AF tissue in circumferential tension, and (2) determine the effects of disc degeneration on these properties.
Radiofrequency Thermal Ablation of Liver Tumors: Impact of Large Vessels
Authors: Wren J. , Andersson P.
Published: March 2014

Surgical resection is the golden standard for treatment of both primary and metastatic liver tumors, and the method is associated with the highest long-time survival rates [1]. A large number of patients are however not candidates for tumor resection, for example due to un-sufficent hepatic reserve or tumor location relative to large blood vessels. In those cases, an alternative treatment strategy is to heat the tumor(s) to lethal temperatures by means of Radiofrequency (RF) current.
Genipin Protects Engineered Cartilage Against IL-1alpha Induced Degradation
Authors: Tan Andrea R. , Lima Eric G. , Marra Kacey G. , Hung Clark T.
Published: March 2014

Tissue-engineering has great potential for treating cartilage pathologies such as osteoarthritis by replacing degraded tissue with newly developed engineered tissue. However proinflammatory cytokines such as interleukin-1α (IL-1α) are a confounding issue as they are often present in high concentrations as part of the chronic pathology or as a result of the surgical intervention itself(1). The catabolic effects of these mediators may be especially pronounced in engineered tissues whose cells are not yet fully embedded in the potentially chondroprotective enclosure of a cartilaginous extracellular matrix(2). One method to protecting initially fragile constructs from degradation may be through the use of non-toxic cross-linking agents. Genipin is a naturally occurring crosslinking agent that reacts with amino acids or amine groups and leads to the formation of stable crosslinked products that are identifiable by a dark blue pigment (Figure 1). Cartilage cross-linked with genipin has been shown to be more resistant to collagenase digestion(3) and to injection of chondroitinase-ABC(4). In this study, we examined whether engineered constructs pre-treated with genipin would better resist IL-1α induced catabolic degradation.
Modeling the Active Response of Cells to Mechanical Stimulation
Authors: McGarry Patrick , McMeeking Robert M. , Evans Anthony G. , Deshpande Vikram S.
Published: March 2014

The mechanical properties of a cells surrounding environment, or extra cellular matrix (ECM), play a crucial role in cellular behavior. For example, it has been shown that cells tend to spread more on rigid substrates [1, 2] and that motile cells move from regions of low substrate rigidity to regions of high substrate rigidity [3].
The Dynamic Simulation of Flow Through a Tissue Engineered Bileaflet Heart Valve
Authors: Liu Kunlun , Barocas Victor H.
Published: March 2014

Approximately 250,000 patients diagnosed with valvular heart disease undergo valve repair/replacement surgery annually worldwide [1, 2]. Despite being over 50 years old, heart valve replacement technology, with the choice of mechanical or bioprosthetic, remains imperfect. The 10-year mortality rate after replacement is 30–55%, with reoperation rates of 2–4% per year because of mechanical failure, bleeding and thromboembolic complications, and calcification. It is therefore imperative that design and analysis tools be developed for the biosolid and biofluid mechanics of potential replacement valves.
MR Measurement of Pulse Wave Velocity in the Spinal Canal
Authors: Martin Bryn A. , Loth Francis , Kalata Wojciech , Oshinski John N.
Published: March 2014

Non-invasive measurement of pulse wave velocity (PWV) in the cerebrospinal fluid (CSF) system is of interest as a potential indicator of subarachnoid space pressure and compliance, both of which play a role in the development of craniospinal diseases. However, measurement of PWV has eluded researchers primarily due to either a lack of access to CSF velocity measurements or to poor temporal resolution. Here, we present PWV measurements using a novel MR technique that acquires unsteady velocity measurements during the cardiac cycle with a time interval <10 ms. Axial CSF velocity measurements were obtained in the sagittal plane of the cervical spinal region on three patients without cranio-spinal disorders. PWV was estimated by using the time shift identified by the maximum temporal velocity gradient during the cardiac cycle. Based on the maximum velocity gradient, the mean PWV in the three cases was calculated to be 4.6 m/s (stdev 1.7 m/s, p<0.005) during systolic acceleration. The measurements of PWV agree with previously published values.
Hemodynamic Investigation of Flow in the Normal Portal Vein
Authors: George Stephanie M. , Martin Diego R. , Giddens Don P.
Published: March 2014

Cirrhosis is the twelfth leading cause of death in the United States (1). Previous studies have compared portal vein blood flow and velocity in normal subjects and patients with varying results (2–5). In comparing grades of cirrhosis, based on the “Child-Pugh” score, portal flow was significantly affected as the degree of cirrhosis increased (2–4). These previous studies have used a variety of imaging methods; the most common being Doppler Ultrasound (2–5). The use of Magnetic Resonance Imaging (MRI) and phase contrast (PC) – MRI has not been used extensively to study liver hemodynamics. When compared to ultrasound, MRI is often superior in providing anatomical and hemodynamic information. There has also been no in depth study of normal portal vein hemodynamics, an important step for understanding changes due to cirrhosis. This study seeks to preliminarily characterize normal portal venous hemodynamics in a small number of subjects utilizing both MRI and computational fluid dynamics (CFD). The long term clinical objective is to develop non-invasive diagnostic methods to evaluate and monitor the progression of cirrhosis in patients with chronic liver disease.
Analytical Solutions to Axisymmetric Plane Strain Porous Media-Transport Models in Large Arteries
Authors: Vande Geest Jonathan P. , Simon Bruce R.
Published: March 2014

Theoretical and numerical finite element models (FEMs) have been developed for analysis of coupled structural-fluid-species transport in soft tissues [1–3]. Here analytical solutions for coupled diffusive-convective transport of a single, neutral species in soft tissues are presented. Based on experimental observations [4], osmotic pressure and partial Onsager coupling of species transport can be neglected for large mobile species in rabbit carotid arteries. These analytical solutions provide a starting point for development of solutions to more complex problems and allow verification of the associated FEMs under development in our laboratory. The analytical solutions will allow comparison of elastic and poroelastic-species transport for axisymmetric, plane strain in thick-walled arteries including expressions for displacement, strain, stress, pore fluid pressure, and concentration fields. The initial models considered here will be steady state (SS) solutions for compressible, linear, isotropic materials undergoing small strains.
Active and Passive Responses of Myofibroblasts in Response to Mechanical Stretching in 3D Culture
Authors: Nathan Adam C. , Lee Sheng-Lin , Marquez J. Pablo , Ju Tao , Pryse Kenneth M. , Elson Elliot L. , Genin Guy M.
Published: March 2014

The stretch response of myofibroblast cells cultured in a three-dimensional environment was simultaneously measured and observed using a tissue stretching apparatus mounted to a confocal microscope. Optical measurements were used to assess mechanical estimates of cell response obtained through combined mechanical testing and biochemical inhibition. Results show that activated myofibroblasts provide an effective resistance on the order of 100s of kPa. In specific mechanical environments, stretched myofibroblasts release the ECM.
Importance of Calcar Comminution and Screw Length in Proximal Humerus Fractures Treated With Locking Plate Fixation
Authors: Raghava Parthasarathy , Thompson Kevin J. , Ponce Brent A. , Eberhardt Alan W.
Published: March 2014

While proximal humerus fractures are relatively infrequent and the majority are amenable to non-operative treatment, open reduction with internal fixation remains a surgical mainstay [1,2]. With the advent of locking fixation, the majority of proximal humerus fractures requiring surgery are treated with locking plates. Biomechanical studies have demonstrated that locked plating is superior to intramedullary fixation, conventional or blade plating in two and three part proximal humerus fractures [3,4]. Despite the increased stability and use of locking fixation, loss of reduction remains a post-operative problem in osteoporotic bone with comminuted fractures [5]. Presently we hypothesized that: 1) Medial comminution of the calcar region is a determinant of fracture and fixation stability; and 2) Greater stability and increased resistance to varus deformity is gained through use of locking screws that cross the inferior surgical neck and penetrate the humeral head, i.e., the calcar region of the humerus.
Predictions of Vertebral Strength From Quantitative Measures of the Intra-Vertebral Heterogeneity in Density
Authors: Hussein Amira A. , Mason Zachary D. , Morgan Elise F.
Published: March 2014

Current fracture risk estimates for the spine are based on average measures of bone mineral density (BMD) in the vertebral centrum. However, these measures of BMD explain only ∼60% of the variance in vertebral strength [1] and do not discriminate well between fracture and non-fracture cohorts [2]. These limitations of average BMD are likely due to the heterogeneous distribution of bone tissue throughout the vertebra. The density and architecture of vertebral trabecular bone vary as a function of position in the centrum [3]; moreover, these spatial variations have been shown to vary substantially among individuals and with age [3].
The Intrinsic Durability of Aortic Valve ECM in Absence of Cellular Maintenance
Authors: Liao Jun , Joyce Erinn M. , Jones Hugh L. , Tahai Mina , Borazjani Ali , Merryman W. David , Sacks Michael S.
Published: March 2014

In the last two decades, decellularized native aortic valve (AV) has been investigated as tissue engineered heart valve (TEHV) replacements due to their potential to develop into a viable valve.[1] Decellularization removes major immunogenic cellular components. After repopulated with recipient’s cells, TEHV can be readily used because of the necessary functional design.[2] However, several problems with this approach have been identified, such as insufficient cell infiltration, mechanical deterioration, formation of fibrous sheath on implantation, and reduced orifice area after surgery.[3]
Mechanical Properties of TMJ Disc Cells Measured by Atomic Force Microscopy
Authors: Yun Julie X. , Zhang Lixia , Dean Delphine , LaBerge Martine , Yao Hai
Published: March 2014

The temporomandibular joint (TMJ) is a load bearing joint with unique articular structure. The TMJ disc, a fibrocartilaginous tissue, is a major component of jaw function by serving stress distribution and lubrication in the joint. The TMJ disc pathophysiology, such as disc derangement and degeneration, is central to many TMJ disorders affecting a large population. It is generally believed that pathological mechanical loading, such as sustained mechanical loading in jaw clenching and traumatic impact, is the leading cause of TMJ disc derangement [1]. However, the exact mechanism, especially at the cellular level, has not been established. TMJ disc cells, fibrochondrocyte-like cells, respond to chemical and mechanical signals and regulate the physiology and pathology of the disc. However, little is known of the cellular mechanical properties in TMJ disc. The objective of this study is to determine the mechanical properties of a single TMJ disc cell using atomic force microscopy (AFM).
Injury Biomechanics: Evaluating the Evidence to Determine Causation
Authors: Cargill Robert S. , Heller Michelle F.
Published: March 2014

Biomechanical engineering is a field that encompasses a wide variety of applications including the development and evaluation of medical devices, research regarding sports and sporting equipment, and investigations of how individuals are injured and how those injuries could be prevented. Understanding human tolerance, injury mechanisms, and the facts regarding a given scenario allows the biomechanical engineer to use these data to determine how an individual was injured. As the field of biomechanics is becoming more broadly understood, the biomechanical engineer is being called upon more frequently to contribute to forensic analyses. According to Merriam-Webster, the definition of forensic is as follows: “relating to or dealing with the application of scientific knowledge to legal problems.” For a biomechanical engineer, an increasingly reasonable option is to pursue a career in forensic analysis, where his/her knowledge and skills are employed to help attorneys, judges, juries, and other participants in legal proceedings understand technical concepts key to understanding the case at hand.
Transient Exposure to TGF-B3 Improves Mechanical Properties of MSC-Laden Constructs
Authors: Huang Alice H. , Stein Ashley , Yeger-McKeever Meira , Tuan Rocky S. , Mauck Robert L.
Published: March 2014

Articular cartilage lines the surfaces of joints and functions to absorb shock and distribute load. To date, few strategies exist for restoring damaged articular surfaces; therefore, cartilage tissue engineering (TE) has emerged as a means to generate functional replacement tissues. To optimize growth and maturation of TE constructs, various methodologies have been employed, including 3D culture, coupled with mechanical stimulation [1] and growth factor supplementation [2]. Recently, studies have shown that temporal application of TGF-β3 enhances the compressive properties and GAG content of chondrocyte-laden hydrogels to near-native levels after the removal of this morphogen [3, 4]. However, as chondrocytes may prove impractical for clinical use, mesenchymal stem cells (MSCs) have been increasingly utilized in cartilage TE. While MSCs are able to undergo chondrogenesis and deposit cartilaginous extracellular matrix (ECM), they have not demonstrated functional parity with chondrocytes [5]. One recent study showed MSCs were able to maintain a chondrocytic phenotype after brief exposure of TGF-β3, though mechanical and biochemical properties were not assessed [6]. In this study, we evaluated these properties in chondrocyte- and MSC-laden hydrogels with transient exposure of TGF-β3 in a chemically defined medium. In addition, we explored the effects of varying seeding density in MSC-laden constructs on functional properties. We hypothesized that transient application of TGF-β3 would improve functional properties of MSC-laden constructs in a seeding density-dependent manner, and that these changes would be marked by differences in cartilaginous gene expression, particularly of enzymes involved in proteoglycan synthesis.
The Use of Surface-Based Registration to Facilitate Total Elbow Arthroplasty in the Absence of Key Anatomical Landmarks
Authors: McDonald Colin P. , King Graham J. , Peters Terry M. , Johnson James A.
Published: March 2014

Successful placement of elbow arthroplasty components is dependent on the accurate identification of the flexion-extension (FE) axis, generally defined by the geometric centers of the capitellum and trochlea [1,2]. Brownhill et al. [3] showed that a visual estimation of the FE axis, a technique described by Morrey and Hotchkiss [1], can result in significant errors, even with preserved bone architecture.
Locating Separatrices and Basins of Stability in Biodynamic Systems
Authors: Tanaka Martin L. , Ross Shane D.
Published: March 2014

In biomechanics, a separatrix or recovery envelope exists between standing and falling. Standing with postural sway is a distinctly different type of motion than falling. A comparable problem to standing postural sway is the challenge of maintaining torso stability. In this case, a separatrix exists delineating stable torso sway from unstable and potentially injurious motion. An approach is presented for identifying separatrices in state space generated from noisy time series data sets representative of those generated from experiments. We demonstrate how Lagrangian coherent structures (LCS), ridges in the state space distribution of finite-time Lyapunov exponents (FTLE), can be used to locate these separatrices. As opposed to previous approaches which required an entire vector field, this method can be performed using a single trajectory that evolves over time.
A Theoretical Model of Stretch-Induced Stress Fiber Remodeling
Authors: Kaunas Roland
Published: March 2014

Cyclic stretching of endothelial cells (ECs), such as occurs in arteries during the cardiac cycle, induces ECs and their actin stress fibers to orient perpendicular to the direction of maximum stretch. This perpendicular alignment response is strengthened by increasing the magnitudes of stretch and cell contractility (1). The actin cytoskeleton is a dynamic structure that regulates cell shape changes and mechanical properties. It has been shown that actin stress fibers are ‘prestretched’ under normal, non-perturbed, conditions (2), consistent with the ideas of ‘prestress’ that have motivated tensegrity cell models (3). It has also been shown that ‘tractional forces’ generated by cells at focal adhesions tend to increase proportionately with increasing focal adhesion area, thus suggesting that cells tend to maintain constant the stress borne by a focal adhesion (4). By implication, this suggests that cells try to maintain constant the stress in actin stress fibers. Thus, it seems that cells reorganize or turnover cytoskeletal proteins and adhesion complexes so as to maintain constant a preferred mechanical state. Mizutani et al. (5) referred to this as cellular tensional homeostasis, although they did not suggest a model or theory to account for this dynamic process.
In-Vitro Blood Flow and Wall Shear Stress Measurements in Idealised and Patient Specific Models of the Carotid Artery Bifurcation
Authors: Buchmann Nicolas A. , Jermy Mark C.
Published: March 2014

This work presents Particle Image Velocimetry (PIV) measurements in idealised and patient specific human carotid artery bifurcations (CAB) under steady and pulsatile flow. The geometry and corresponding boundary conditions were obtained by Magnetic Resonance Imaging (MRI) and replicated in an in-vitro model. A complex three-dimensional flow structure exists inside the CAB and vorticity and wall shear stress data are used to quantify the differences between the idealised and patient specific geometry.
Hemodynamic Investigation of Normal Developing Aortic Arch in the Chick Embryo
Authors: Wang Yajuan , Dur Onur , Patrick Michael J. , Tinney Joseph P. , Tobita Kimimasa , Pekkan Kerem , Keller Bradley B.
Published: March 2014

Governed by genetic and epigenetic feedback [1], during embryonic cardiac development, the anatomy of aortic arches demonstrates drastic three dimensional (3D) changes that interact with the function of cardiovascular system. Six major pairs of aortic arches appear at different embryonic periods and eventually form the two brachiocephalic arteries (left and right third), an aortic arch (left fourth) and pulmonary arteries and ductus arteriosus (left and right sixth) [2–4], Fig 1. Flow-driven hemodynamic loading plays a major role in this dynamic process. Morphological studies on the embryonic aortic arches began over 100 years ago while the recent remarkable developments include understanding genetic determinants such as the effects of neural crest cells [5,6]. However the relationship between hemodynamic factors and the dynamic 3D geometry changes is still limited requiring an interdisciplinary research effort [7,8].
Effect of Replacement of an Anterior Disc and Total Anatomical Facet System on Biomechanics of Lumbar Spine: A FEM Study
Authors: Kiapour A. , Goel V. K. , Hoy R. W. , Fellenz F. , Stewart D.
Published: March 2014

To address the issue of facet pain, a potential limiting factor with use of the anterior disc alone, 360 dynamic systems are being considered. The advent of facet replacement technology provides an opportunity to asses the combination of anterior disc with artificial facets to address facet pain. The purpose of this study was to explore the impact such a combination has on the tissues and function of the lumbar spine and each other. To this end a validated finite element (FE) model of the lumbar spine was used to evaluate the biomechanics of an anterior disc arthroplasty with a facet arthroplasty system.
Soccer Ball Heading Model
Authors: Paris Anthony J. , Antonini Kyle R. , Chaffin Brandon M.
Published: March 2014

Increasing attention on health and safety has brought attention to the possible cumulative head trauma of soccer ball heading. Attempts to study the correlation of neurocognitive deficits with heading, the acceleration of the head during heading, and the effectiveness of soccer headgear have appeared in the literature [1–7]. Lacking was an analytically based, experimentally verified biomechanics model of the impact between the soccer ball and the head. Such a model was attempted here. Figure 1 shows (a) a drawing of the impact at time t used to develop the theoretical analysis and (b) the solid resin sphere and fixture, soccer ball, and force plate experimental apparatus.
Dlk1 Promotes a Fast Motor Neuron Biophysical Signature Required for Peak Force Execution
Authors: Müller Daniel , Cherukuri Pitchaiah , Henningfeld Kristine , Poh Chor Hoon , Wittler Lars , Grote Phillip , Schlüter Oliver , Schmidt Jennifer , Laborda Jorge , Bauer Steven R. , Brownstone Robert M. , Marquardt Till
Published: March 2014

Quick, Quick, Slow

The slow muscles of postural stability and the fast muscles of running and jumping are driven by motor neurons that are differentiated by fast and slow biophysical properties. By retrograde labeling of mouse and chick muscle fibers,

Müller
et al.

(p.
1264
) characterized the developmental distinctions between fast and slow motor neurons. A transmembrane protein, when over- or underexpressed, was discovered to drive specification of the motor neurons and a downstream effector specified some, but not all, of the biophysical attributes.
Stirring the Simmering “Designer Baby” Pot
Authors: Murray Thomas H.
Published: March 2014

How much discretion should parents be granted in determining what sort of child they have?
Ligand-Controlled C(sp
3
)–H Arylation and Olefination in Synthesis of Unnatural Chiral α–Amino Acids
Authors: He Jian , Li Suhua , Deng Youqian , Fu Haiyan , Laforteza Brian N. , Spangler Jillian E. , Homs Anna , Yu Jin-Quan
Published: March 2014

A Palladium 1–2 Punch

Methods to replace carbon-hydrogen bonds directly with carbon-carbon bonds offer enticing prospects for streamlining the synthesis of organic compounds. The trouble is that it is hard to select any particular C-H bond and to avoid making complex mixtures of products.

He
et al.

(p.
1216
) report that a pair of powerful pyrimidine ligands induces a palladium catalyst to add aryl groups selectively to amino acid derivatives. One ligand promotes addition of a single aryl group to the β-carbon center; the other appends a second, potentially different aryl group to the same carbon—all in the same flask.
Ukraine's Science Reformers Seize the Moment
Authors: Stone Richard
Published: March 2014

Ukraine's parliament is considering legislation that would transform the nation's science and higher education system.
Cancer Genes Help HIV Persist, Complicating Cure Efforts
Authors: Cohen Jon
Published: March 2014

HIV persists by tapping cancer genes.
Talking Back to Madness
Authors: Balter Michael
Published: March 2014

As the search for genes and new drugs for schizophrenia stalls, psychotherapies are getting new attention.
Adenovirus Type 4 and 7 Vaccination or Adenovirus Type 4 Respiratory Infection Elicits Minimal Cross-Reactive Antibody Responses to Nonhuman Adenovirus Vaccine Vectors
Authors: Paris Robert , Kuschner Robert A. , Binn Leonard , Thomas Stephen J. , Colloca Stefano , Nicosia Alfredo , Cortese Riccardo , Bailer Robert T. , Sullivan Nancy , Koup Richard A.
Published: March 2014

Antivector immunity may limit the immunogenicity of adenovirus vector vaccines. We tested sera from individuals immunized with adenovirus type 4 and 7 (Ad4 and Ad7, respectively) vaccine or naturally infected with Ad4 for their ability to neutralize a panel of E1-deleted human and chimpanzee adenoviruses (ChAd). Small statistically significant increases in titers to ChAd63, ChAd3, human Ad35, and human Ad5 were observed. Neutralizing antibodies elicited by Ad4 infection or immunization results in a small amount of adenovirus cross-reactivity.
Mycobacterium avium subsp. paratuberculosis Antibody Response, Fecal Shedding, and Antibody Cross-Reactivity to Mycobacterium bovis in M. avium subsp. paratuberculosis-Infected Cattle Herds Vaccinated against Johne's Disease
Authors: Tewari Deepanker , Hovingh Ernest , Linscott Rick , Martel Edmond , Lawrence John , Wolfgang David , Griswold David
Published: March 2014

Vaccination for Johne's disease with killed inactivated vaccine in cattle herds has shown variable success. The vaccine delays the onset of disease but does not afford complete protection. Johne's disease vaccination has also been reported to interfere with measurements of cell-mediated immune responses for the detection of bovine tuberculosis. Temporal antibody responses and fecal shedding ofMycobacterium aviumsubsp.paratuberculosis, the causative agent of Johne's disease, were measured in 2 dairy cattle herds using Johne's disease vaccine (Mycopar) over a period of 7 years. Vaccination against Johne's disease resulted in positive serumM. aviumsubsp.paratuberculosisantibody responses in both herds, and the responses persisted in vaccinated cattle up to 7 years of age. Some vaccinated animals (29.4% in herd A and 36.2% in herd B) showed no serological reactivity toM. aviumsubsp.paratuberculosis.M. aviumsubsp.paratuberculosis-specific antibody responses were also detected in milk from Johne's disease-vaccinated animals, but fewer animals (39.3% in herd A and 49.4% in herd B) had positive results with milk than with serum samples. With vaccination againstM. aviumsubsp.paratuberculosis, fecal shedding in both dairy herds was reduced significantly (P< 0.001). In addition, when selected Johne's disease-vaccinated and -infected animals were investigated for serological cross-reactivity toMycobacterium bovis, no cross-reactivity was observed.
Comparison of Test Methodologies for Foot-and-Mouth Disease Virus Serotype A Vaccine Matching
Authors: Tekleghiorghis Tesfaalem , Weerdmeester Klaas , van Hemert-Kluitenberg Froukje , Moormann Rob J. M. , Dekker Aldo
Published: March 2014

Vaccination has been one of the most important interventions in disease prevention and control. The impact of vaccination largely depends on the quality and suitability of the chosen vaccine. To determine the suitability of a vaccine strain, antigenic matching is usually studied byin vitroanalysis. In this study, we performed threein vitrotest methods to determine which one gives the lowest variability and the highest discriminatory capacity. Binary ethylenimine inactivated vaccines, prepared from 10 different foot-and-mouth disease (FMD) virus serotype A strains, were used to vaccinate cattle (5 animals for each strain). The antibody titers in blood serum samples 3 weeks postvaccination (w.p.v.) were determined by a virus neutralization test, neutralization index test, and liquid-phase blocking enzyme-linked immunosorbent assay (ELISA). The titers were then used to calculate relationship coefficient (r1) values. Theser1values were compared to the genetic lineage using receiver operating characteristic (ROC) analysis. In the two neutralization test methods, the median titers observed against the test strains differed considerably, and the sera of the vaccinated animals did not always show the highest titers against their respective homologous virus strains. When the titers were corrected for test strain effect (scaling), the variability (standard error of the mean per vaccinated group) increased because the results were on a different scale, but the discriminatory capacity improved. An ROC analysis of ther1value calculated on both observed and scaled titers showed that onlyr1values of the liquid-phase blocking ELISA gave a consistent statistically significant result. Under the conditions of the present study, the liquid-phase blocking ELISA showed less variation and still had a higher discriminatory capacity than the other tests.
Development and Optimization of a High-Throughput Assay To Measure Neutralizing Antibodies against Clostridium difficile Binary Toxin
Authors: Xie Jinfu , Horton Melanie , Zorman Julie , Antonello Joseph M. , Zhang Yuhua , Arnold Beth A. , Secore Susan , Xoconostle Rachel , Miezeiewski Matthew , Wang Su , Price Colleen E. , Thiriot David , Goerke Aaron , Gentile Marie-Pierre , Skinner Julie M. , Heinrichs Jon H.
Published: March 2014

Clostridium difficilestrains producing binary toxin, in addition to toxin A (TcdA) and toxin B (TcdB), have been associated with more severe disease and increased recurrence ofC. difficileinfection in recent outbreaks. Binary toxin comprises two subunits (CDTa and CDTb) and catalyzes the ADP-ribosylation of globular actin (G-actin), which leads to the depolymerization of filamentous actin (F-actin) filaments. A robust assay is highly desirable for detecting the cytotoxic effect of the toxin and the presence of neutralizing antibodies in animal and human sera to evaluate vaccine efficacy. We describe here the optimization, using design-of-experiment (DOE) methodology, of a high-throughput assay to measure the toxin potency and neutralizing antibodies (NAb) against binary toxin. Vero cells were chosen from a panel of cells screened for sensitivity and specificity. We have successfully optimized the CDTa-to-CDTb molar ratio, toxin concentration, cell-seeding density, and sera-toxin preincubation time in the NAb assay using DOE methodology. This assay is robust, produces linear results across serial dilutions of hyperimmune serum, and can be used to quantify neutralizing antibodies in sera from hamsters and monkeys immunized withC. difficilebinary toxin-containing vaccines. The assay will be useful forC. difficilediagnosis, for epidemiology studies, and for selecting and optimizing vaccine candidates.
Evaluation of the Architect Epstein-Barr Virus (EBV) Viral Capsid Antigen (VCA) IgG, VCA IgM, and EBV Nuclear Antigen 1 IgG Chemiluminescent Immunoassays for Detection of EBV Antibodies and Categorization of EBV Infection Status Using Immunofluorescence Assays as the Reference Method
Authors: Corrales Isabel , Giménez Estela , Navarro David
Published: March 2014

Commercial immunoassays for detecting IgG and IgM antibodies against Epstein-Barr virus (EBV), viral capsid antigens (VCA), and IgGs toward EBV nuclear antigen-1 (EBNA-1) are routinely used in combination to categorize EBV infection status. In this study, we evaluated the performances of the Architect EBV VCA IgG, VCA IgM, and EBNA-1 IgG chemiluminescent microparticle assays (CMIAs) in EBV serological analyses using indirect immunofluorescence assays and anticomplement immunofluorescence assays as the reference methods for VCA IgG, VCA IgM, and EBNA-1 IgG antibody detection, respectively. A total of 365 serum samples representing different EBV serological profiles were included in this study. The κ values (concordances between the results) obtained in the Architect CMIA and those in the reference assays were 0.905 (P< 0.0001) for VCA IgM, 0.889 (P< 0.0001) for VCA IgG, and 0.961 (P< 0.0001) for EBNA-1 IgG. The sensitivities and specificities were, respectively, 91.08% and 99.48% for VCA IgM, 99.23% and 86.27% for VCA IgG, and 96.77% and 99.16% for EBNA-1 IgG. The sensitivities and specificities of the Architect CMIA panel were, respectively, 99.15% and 98.6% for diagnosing a primary infection, 97.62% and 93.39% for diagnosing a past EBV infection, and 92.42% and 97.82% for diagnosing the absence of an EBV infection. In summary, we demonstrated that the Architect EBV antibody panel performs very well for EBV antibody detection and correctly categorizes clinically relevant EBV infection states.
Epidemiology of Candida kefyr in Patients with Hematologic Malignancies
Authors: Dufresne Simon F. , Marr Kieren A. , Sydnor Emily , Staab Janet F. , Karp Judith E. , Lu Kit , Zhang Sean X. , Lavallée Christian , Perl Trish M. , Neofytos Dionysios
Published: March 2014

Candida kefyr
is an emerging pathogen among patients with hematologic malignancies (HM). We performed a retrospective study at Johns Hopkins Hospital to evaluate the epidemiology of
C. kefyr
colonization and infection in HM patients between 2004 and 2010. Eighty-three patients were colonized and/or infected with
C. kefyr
, with 8 (9.6%) having invasive candidiasis (IC). The yearly incidence of
C. kefyr
colonization and candidemia increased over the study period (
P
< 0.01), particularly after 2009. In 2010,
C. kefyr
caused 16.7% of candidemia episodes. The monthly incidence of
C. kefyr
was higher during the summer throughout the study. In a cohort of patients with acute myelogenic leukemia receiving induction chemotherapy, risks for
C. kefyr
colonization included the summer season (odds ratio [OR], 3.1;
P
= 0.03); administration of an azole (OR, 0.06;
P
< 0.001) or amphotericin B (OR, 0.35;
P
= 0.05) was protective. Fingerprinting of 16 isolates by repetitive sequence-based PCR showed that all were different genotypes. The epidemiology of
C. kefyr
candidemia was evaluated in another hospital in Montreal, Canada; data confirmed higher rates of
C. kefyr
infection in the summer.
C. kefyr
appears to be increasing in HM patients, with prominent summer seasonality. These findings raise questions about the effect of antifungal agents and health care exposures (e.g., yogurt) on the epidemiology of this yeast.
Characterization of Multidrug-Resistant Group B Streptococci with Reduced Penicillin Susceptibility Forming Small Non-Beta-Hemolytic Colonies on Sheep Blood Agar Plates
Authors: Banno Hirotsugu , Kimura Kouji , Tanaka Yosuke , Kitanaka Hiromitsu , Jin Wanchun , Wachino Jun-ichi , Yamada Keiko , Shibayama Keigo , Arakawa Yoshichika
Published: March 2014

We isolated and characterized three multidrug-resistant clinical isolates of group B streptococci with reduced penicillin susceptibility (PRGBS) that formed small non-beta-hemolytic colonies on sheep blood agar plates but grew well on chocolate agar plates. They can be overlooked in the bacterial identification step, leading to clinical misdiagnosis and treatment failure.
Anaplasma platys in Bone Marrow Megakaryocytes of Young Dogs
Authors: De Tommasi A. Sara , Baneth Gad , Breitschwerdt Edward B. , Stanneck Dorothee , Dantas-Torres Filipe , Otranto Domenico , de Caprariis Donato
Published: March 2014

Anaplasma platysis an obligate intracellular rickettsial pathogen that infects platelets of dogs, forming basophilic intracellular morulae. In the present report, cellular inclusions were documented in bone marrow thrombocyte precursors of two young naturally infected dogs, indicating thatA. platyscan infect megakaryocytes and promegakaryocytes.
Coronavirus Replicase-Reporter Fusions Provide Quantitative Analysis of Replication and Replication Complex Formation
Authors: Freeman Megan Culler , Graham Rachel L. , Lu Xiaotao , Peek Christopher T. , Denison Mark R.
Published: March 2014

The replication of coronaviruses occurs in association with multiple virus-induced membrane structures that evolve during the course of infection; however, the dynamics of this process remain poorly understood. Previous studies of coronavirus replication complex organization and protein interactions have utilized protein overexpression studies and immunofluorescence of fixed cells. Additionally, live-imaging studies of coronavirus replicase proteins have used fluorescent reporter molecules fused to replicase proteins, but expressed from nonnative locations, mostly late-transcribed subgenomic mRNAs, in the presence or absence of the native protein. Thus, the timing and targeting of native replicase proteins expressed in real time from native locations in the genome remain unknown. In this study, we tested whether reporter molecules could be expressed from the replicase polyprotein of murine hepatitis virus as fusions with nonstructural protein 2 or 3 and whether such reporters could define the targeting and activity of replicase proteins during infection. We demonstrate that the fusion of green fluorescent protein and firefly luciferase with either nonstructural protein 2 or 3 is tolerated and that these reporter-replicase fusions can be used to quantitate replication complex formation and virus replication. The results show that the replicase gene has flexibility to accommodate a foreign gene addition and can be used directly to study replicase complex formation and evolution during infection as well as to provide highly sensitive and specific markers for protein translation and genome replication.

IMPORTANCE
Coronaviruses are a family of enveloped, positive-sense RNA viruses that are important agents of disease, including severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus. Replication is associated with multiple virus-induced membrane structures that evolve during infection; however, the dynamics of this process remain poorly understood. In this study, we tested whether reporter molecules expressed from native locations within the replicase polyprotein of murine hepatitis virus as fusions with nonstructural proteins could define the expression and targeting of replicase proteins during infection in live cells. We demonstrate that the replicase gene tolerates the introduction of green fluorescent protein or firefly luciferase as fusions with replicase proteins. These viruses allow early quantitation of virus replication as well as real-time measurement of replication complexes.
Identification of Cellular Proteins Interacting with the Retroviral Restriction Factor SAMHD1
Authors: St. Gelais Corine , de Silva Suresh , Hach Jocelyn C. , White Tommy E. , Diaz-Griffero Felipe , Yount Jacob S. , Wu Li
Published: March 2014

Human and mouse SAMHD1 proteins block human immunodeficiency virus type 1 (HIV-1) infection in noncycling human monocytic cells by reducing the intracellular deoxynucleoside triphosphate (dNTP) concentrations. Phosphorylation of human SAMHD1 at threonine 592 (T592) by cyclin-dependent kinase 1 (CDK1) and cyclin A2 impairs its HIV-1 restriction activity, but not the dNTP hydrolase activity, suggesting that dNTP depletion is not the sole mechanism of SAMHD1-mediated HIV-1 restriction. Using coimmunoprecipitation and mass spectrometry, we identified and validated two additional host proteins interacting with human SAMHD1, namely, cyclin-dependent kinase 2 (CDK2) and S-phase kinase-associated protein 2 (SKP2). We observed that mouse SAMHD1 specifically interacted with cyclin A2, cyclin B1, CDK1, and CDK2. Given the role of these SAMHD1-interacting proteins in cell cycle progression, we investigated the regulation of these host proteins by monocyte differentiation and activation of CD4
+
T cells and examined their effect on the phosphorylation of human SAMHD1 at T592. Our results indicate that primary monocyte differentiation and CD4
+
T-cell activation regulate the expression of these SAMHD1-interacting proteins. Furthermore, our results suggest that, in addition to CDK1 and cyclin A2, CDK2 phosphorylates T592 of human SAMHD1 and thereby regulates its HIV-1 restriction function.

IMPORTANCE
SAMHD1 is the first dNTP triphosphohydrolase found in mammalian cells. Human and mouse SAMHD1 proteins block HIV-1 infection in noncycling cells. Previous studies suggested that phosphorylation of human SAMHD1 at threonine 592 by CDK1 and cyclin A2 negatively regulates its HIV-1 restriction activity. However, it is unclear whether human SAMHD1 interacts with other host proteins in the cyclin A2 and CDK1 complex and whether mouse SAMHD1 shares similar cellular interacting partners. Here, we identify five cell cycle-related host proteins that interact with human and mouse SAMHD1, including three previously unknown cellular proteins (CDK2, cyclin B1, and SKP2). Our results demonstrate that several SAMHD1-interacting cellular proteins regulate phosphorylation of SAMHD1 and play an important role in HIV-1 restriction function. Our findings help define the role of these cellular interacting partners of SAMHD1 that regulate its HIV-1 restriction function.