bluuebunny/crossref_metadata_2025 huggingface dataset:
Rickettsial Actin‐Based Motility
Authors: HEINZEN ROBERT A.
Published: July 2009

Abstract: Actin‐based motility (ABM) is employed by spotted fever group (SFG) rickettsiae, such as Rickettsia rickettsii, to promote cell‐to‐cell spread. Time‐lapse video microscopy revealed that ABM is not strictly confined to SFG rickettsiae as typhus group R. typhi moved at approximately the same rate as R. rickettsii (approximately 4 μm/min), but in a highly erratic fashion. A number of common behaviors were observed between ABM of R. typhi and R. rickettsii, such as entrance into plasma membrane protrusions, formation of new actin tails only on the old surface of newly formed daughter cells, and quick (within 15 sec) reassembly of the actin tail to the opposite pole upon contact with cellular structures that impede forward movement. This last behavior suggests that the rickettsial protein(s) required for ABM is uniformly localized to both poles of the bacterium and possibly throughout the rickettsial surface. Functional roles in rickettsial ABM for neuronal Wiskott‐Aldrich syndrome protein (N‐WASP) and the actin‐related protein (Arp)2/3 complex, critical regulators of ABM of other pathogens, have not been established. Domains of N‐WASP that have characterized inhibitory effects on N‐WASP or Arp2/3 complex function were expressed in HeLa cells infected with R. rickettsii. Shigella flexneri‐infected cells were used as a control. When ectopically expressed, the VCA domain of N‐WASP (VCA) acts as a dominant/negative with respect to Arp2/3 complex function and N‐WASP missing VCA (ΔVCA) acts as a dominant/negative form of N‐WASP. Expression of VCA or ΔVCA severely inhibited S. flexneri ABM (no Shigella motility observed in the majority of expressing cells) while only moderately inhibiting ABM of R. rickettsii (approximately 35% decrease in the rate of ABM). In addition, ectopically expressed full‐length GFP‐N‐WASP was recruited by S. flexneri but not R. rickettsii, and Arp3 was detected by indirect immunofluorescence in S. flexneri actin tails but not within R. rickettsii actin tails. Collectively, these data suggest that rickettsial ABM is independent of N‐WASP and Arp2/3 complex function.
In Vitro Infection of Nonendothelial Cells by Ehrlichia ruminantium
Authors: ZWEYGARTH E. , JOSEMANS A. I.
Published: July 2009

Abstract: The Welgevonden stock of Ehrlichia ruminantium was propagated in eight nonendothelial cell cultures derived from different animal species, both ruminants and nonruminants. The origins of the cells were: bovine fetal testis (BFT), cat ovary (COC), donkey fibroblasts (DFC), sheep fibroblasts (E2), horse testis (HTC), lamb fetal testis (LFT), mouse connective tissue (L), and African green monkey kidney (Vero). Four cell culture types (BFT, E2, LFT and Vero) required supplementation of the medium with cycloheximide for suitable growth of E. ruminantium, whereas the other four (COC, DFC, HTC, and L) did not. Three other stocks of E. ruminantium, Senegal, Ball 3, and Gardel, were also propagated, either in LFT cultures only or in both E2 and LFT cell cultures. The Welgevonden stock was successfully initiated using E2 and LFT cell cultures.
Comparative DNA Microarray Analysis of Host Cell Transcriptional Responses to Infection by Coxiella burnetii or Chlamydia trachomatis
Authors: REN QUN , ROBERTSON SHELLY J. , HOWE DALE , BARROWS LORRAINE F. , HEINZEN ROBERT A.
Published: July 2009

Abstract: DNA microarray analysis was conducted to investigate the transcriptional responses of the human monocytic leukemia cell line THP‐1 to infection by Chlamydia trachomatis or Coxiella burnetii. RNA was isolated from mock infected cells and cells infected for 36 hours using TRIzol reagent. Biotinylated probes synthesized from RNA samples were hybridized to an Affymetrix U133A human genome chip consisting of 18,462 human gene probe sets. A total of 335 and 548 THP‐1 genes were up‐ or downregulated at least twofold in cells infected with C. burnetii or C. trachomatis, respectively, when compared to uninfected cells. There was a high degree of overlap in transcriptional responses to infection with shared responses observed for 39 downregulated and 189 upregulated genes. Numerous pathogen‐specific transcriptional responses were also observed. Quantitative RT‐PCR and immunoblotting confirmed up‐ or down‐regulation of a subset of THP‐1 genes in response to infection by C. burnetii. This study provides insight into the host transcriptional responses to infection by Chlamydia and Coxiella that may affect the infectious cycle of each organism.
Neuroprotection Trek—The Next Generation
Authors: ANDREWS RUSSELL J.
Published: July 2009

Abstract: Neuromodulation denotes controlled electrical stimulation of the central or peripheral nervous system. The three forms of neuromodulation described in this paper—deep brain stimulation, vagus nerve stimulation, and transcranial magnetic stimulation—were chosen primarily for their demonstrated or potential clinical usefulness. Deep brain stimulation is a completely implanted technique for improving movement disorders, such as Parkinson's disease, by very focal electrical stimulation of the brain—a technique that employs well‐established hardware (electrode and pulse generator/battery). Vagus nerve stimulation is similar to deep brain stimulation in being well‐established (for the treatment of refractory epilepsy), completely implanted, and having hardware that can be considered standard at the present time. Vagus nerve stimulation differs from deep brain stimulation, however, in that afferent stimulation of the vagus nerve results in diffuse effects on many regions throughout the brain. Although use of deep brain stimulation for applications beyond movement disorders will no doubt involve placing the stimulating electrode(s) in regions other than the thalamus, subthalamus, or globus pallidus, the use of vagus nerve stimulation for applications beyond epilepsy—for example, depression and eating disorders—is unlikely to require altering the hardware significantly (although stimulation protocols may differ). Transcranial magnetic stimulation is an example of an external or non‐implanted, intermittent (at least given the current state of the hardware) stimulation technique, the clinical value of which for neuromodulation and neuroprotection remains to be determined.
Neuroprotection Trek—The Next Generation
Authors: ANDREWS RUSSELL J.
Published: July 2009

Abstract: Three examples of neuroprotective applications of electrical stimulation—neuromodulation—are considered: (1) the diagnosis and treatment of epilepsy, (2) the augmentation of peripheral nerve regeneration after transection, and (3) the interaction between electrical stimulation and neurotrophins (notably brain derived neurotrophic factor [BDNF]) in various neuroprotective situations. The research cited demonstrates clear benefit from appropriate electrical stimulation in the treatment of (1) certain patients with medication‐refractory epilepsy, and (2) the functional regeneration of peripheral nerves after transection and surgical repair. Furthermore, neuromodulation of peripheral nerve regeneration has been associated with an increase in the neurotrophin BDNF. The roles of BDNF and other neurotrophins in several disorders of the nervous system are discussed in the context of neuromodulation and its augmentation of neurotrophins. Neuromodulation—at least in part through its effect on BDNF and other neurotrophins—will likely play a major role in the treatment (and possibly prevention) of disorders of the nervous system for which neuroproteive pharmacologic agents have traditionally been sought.
Melatonin Ameliorates Neurologic Damage and Neurophysiologic Deficits in Experimental Models of Stroke
Authors: REITER RUSSEL J. , SAINZ ROSA M. , LOPEZ‐BURILLO SILVIA , MAYO JUAN C. , MANCHESTER LUCIEN C. , TAN DUN XIAN
Published: July 2009

Abstract: This review summarizes the numerous reports that have documented the neuroprotective actions of melatonin in experimental models of ischemia/reperfusion injury (stroke). In these investigations, which have used three species (rat, gerbil, and cat), melatonin was universally found to reduce brain damage that normally occurs as a consequence of the temporary interruption of blood flow followed by the reflow of oxygenated blood to the brain. The exogenous administration of melatonin in these experimental stroke models reduced infarct volume, lowered the frequency of apoptosis, increased the number of surviving neurons, reduced reactive gliosis, lowered the oxidation of neural lipids and oxidatively damaged DNA, induced bcl‐2 gene expression (the activity of which improves cell survival), upregulated excision repair cross‐complementing factor 6 (an essential gene for preferential DNA excision repair), restrained poly(ADP ribose) synthetase (which depletes cellular NAD resulting in the loss of ATP) activity, and improved neurophysiologic outcomes. Under no circumstances did melatonin exacerbate the damage associated with ischemia/reperfusion injury. As well as the beneficial pharmacologic actions of melatonin, several studies show that a relative deficiency of endogenous melatonin exaggerates neural damage due to stroke; this suggests that even physiologic concentrations of melatonin normally serve to protect the brain against damage. The primary action to explain melatonin's protective effects may relate to its ubiquitous direct and indirect antioxidative actions, although other beneficial functions of melatonin are not precluded.
Gene Therapy and Hypothermia for Stroke Treatment
Authors: YENARI MIDORI A. , ZHAO HENG , GIFFARD RONA G. , SOBEL RAYMOND A. , SAPOLSKY ROBERT M. , STEINBERG GARY K.
Published: July 2009

Abstract: We have previously reported studies of gene therapy using a neurotropic herpes simplex viral (HSV) vector system containing bipromoter vectors to transfer various protective genes to neurons. Using this system in experimental models of stroke, cardiac arrest, and excitotoxicity, we found that it is possible to enhance neuron survival against such cerebral insults by overexpressing genes that target various facets of injury. Among the genes we studied, the anti‐apoptotic protein BCL‐2 improved neuron survival following various insults, and was protective even when administered after stroke onset. BCL‐2 is thought to protect cells from apoptotic death by preventing cytochrome c release from the mitochondria and subsequent caspase activation. We and others have established that cooling the brain by a few degrees markedly reduces ischemic injury and improves neurologic deficits in models of cerebral ischemia and trauma. This hypothermic neuroprotection is also associated with BCL‐2 upregulation in some instances. Furthermore, hypothermia suppresses many aspects of apoptotic death including cytochrome c release, caspase activation, and DNA fragmentation. Here we show that two different kinds of protective therapies, BCL‐2 overexpression and hypothermia, both inhibit aspects of apoptotic cell death cascades, and that a combination treatment can prolong the temporal therapeutic window for gene therapy.
EEG Deficits in Chronic Marijuana Abusers during Monitored Abstinence
Authors: HERNING RONALD I. , BETTER WARREN , TATE KIMBERLY , CADET JEAN L.
Published: July 2009

Abstract: Cognitive, cerebrovascular, and psychiatric impairments have been documented with chronic marijuana users. To better understand the nature and duration of these neurocognitive changes in marijuana abusers, we recorded the resting EEG of 29 abstinent chronic marijuana abusers and 21 control subjects. The marijuana abusers were tested twice: the first evaluation occurred within 72 hours of admission to the inpatient research unit; the second evaluation occurred after 28 to 30 days of monitored abstinence. A three‐minute period of EEG was recorded during resting eyes‐closed conditions from eight electrodes (F3, C3, P3, O1, F4, C4, P4, and O2). The artifacted EEG was converted to six frequency bands (δ, θ, α1, α2, β1, and β2) using a fast Fourier transform. During early abstinence, absolute power was significantly lower (p < 0.05) for the marijuana abusers than for the control subjects for the θ and α1 bands. These reductions in θ and α1 power persisted for 28 days of monitored abstinence. These EEG changes, together with cerebral blood flow deficits, might underlie the cognitive alterations observed in marijuana abusers. Additional research is needed to determine how long these deficits persist during abstinence and if treatment with neuroprotective agents may reverse them.
Chronic Exposure to NMDA Receptor and Sodium Channel Blockers during Development in Monkeys and Rats
Authors: PAULE MERLE G. , FOGLE C. MATTHEW , ALLEN RICHARD R. , PEARSON EDWIN C. , HAMMOND TIMOTHY G. , POPKE E. JON
Published: July 2009

Abstract:The effects of chronic administration of MK‐801 (NMDA‐receptor antagonist) and remacemide (sodium channel blocker) on monkey learning of several brain function tasks was assessed in juveniles (nine months old). Low (LO) and high (HI) doses of both drugs were given orally each day for 18 months. There were no adverse effects of any treatment on tests of short‐term memory or motivation. HI doses of both MK‐801 and remacemide delayed acquisition of a visual discrimination task (the remacemide effect was much greater). HI doses of remacemide alone severely disrupted learning task acquisition and this effect lasted for several months after dosing. Thus, in monkeys, chronic blockade of NMDA receptors is relatively well tolerated, whereas blockade of sodium channels (perhaps in conjunction with NMDA receptor blockade) has long‐term—perhaps permanent—consequences. To further explore the roles of NMDA receptors and sodium channels in these effects, MK‐801, phenytoin (sodium channel blocker), or both were administered to rats and the acquisition of tasks similar to those used in the monkey study were assessed. Dosing began at weaning and continued for nine months. Throughout the study, HI MK‐801 subjects exhibited impaired performance in all tasks. Some effects of MK‐801 were blocked completely by phenytoin. In the rat, blockade of sodium channels was well tolerated but blockade of NMDA receptors had significant and long‐term (permanent?) adverse consequences. These data contrast markedly with those obtained for the monkey and suggest, at least for some drug classes, that the rat might not be a good predictor of effects in primates.
N‐Methyl‐d‐aspartate and TrkB Receptor Activation in Cerebellar Granule Cells
Authors: JIANG XUEYING , ZHU DAMING , OKAGAKI PETER , LIPSKY ROBERT , WU XUAN , BANAUDHA KRISHNA , MEAROW KAREN , STRAUSS KENNETH I. , MARINI ANN M.
Published: July 2009

Abstract:Delineating the mechanisms of survival pathways that exist in neurons will provide important insight into how neurons utilize intracellular proteins as neuroprotectants against the causes of acute neurodegeneration. We have employed cultured rat cerebellar granule cells as a model for determining the mechanisms of these intraneuronal survival pathways. Glutamate has long been known to kill neurons by anN‐methyl‐d‐aspartate (NMDA) receptor‐mediated mechanism. Paradoxically, subtoxic concentrations of NMDA protect neurons against glutamate‐mediated excitotoxicity. Because NMDA protects neurons in physiologic concentrations of glucose and oxygen, we refer to this phenomenon as physiologic preconditioning. One of the major mechanisms of NMDA neuroprotection involves the activation of NMDA receptors leading to the rapid release of brain‐derived neurotrophic factor (BDNF). BDNF then binds to and activates its cognate receptor, receptor tyrosine kinase B (TrkB). The efficient utilization of these two receptors confers remarkable resistance against millimolar concentrations of glutamate that kill more than eighty percent of the neurons in the absence of preconditioning the neurons with a subtoxic concentration of NMDA. Exactly how the neurons mediate neuroprotection by activation of both receptors is just beginning to be understood. Both NMDA and TrkB receptors activate nuclear factor kappaB (NF‐κB), a transcription factor known to be involved in protecting neurons against many different kinds of toxic insults. By converging on survival transcription factors, such as NF‐κB, NMDA and TrkB receptors protect neurons. Thus, crosstalk between these very different receptors provides a rapid means of neuronal communication to upregulate survival proteins through release and transcriptional activation of messenger RNA.
Multiple Sclerosis and Glutamate
Authors: GROOM ANTHONY J. , SMITH TERENCE , TURSKI LECHOSLAW
Published: July 2009

Abstract:Experimental autoimmune encephalomyelitis reproduces in rodents the features of multiple sclerosis, an immune‐mediated, disabling disorder of the human nervous system. No adequate therapy is available for multiple sclerosis, despite anti‐inflammatory, immunosuppressive, and immunomodulatory measures. Increasingly glutamate is implicated in the pathogenesis of neurodegenerative diseases. Here we (1) review changes in the glutamatergic system in multiple sclerosis and (2) reveal the effects of glutamate AMPA antagonists in acute and chronic rodent models of multiple sclerosis. Administration of structurally diverse competitive and non‐competitive AMPA antagonists reduces neurologic disability in rodents subjected to acute experimental autoimmune encephalomyelitis. In addition, AMPA antagonists are active in both the adoptive transfer and in chronic models of experimental autoimmune encephalomyelitis in rats and mice and affect both the acute and chronic relapsing phases. Moreover, short‐term therapy with AMPA antagonists leads to sustained benefit well into the progressive phases. These results imply that therapeutic strategies for multiple sclerosis should be complemented by glutamate AMPA antagonists to reduce neurologic disability.
Neuroprotective Effects of l‐Carnitine in Induced Mitochondrial Dysfunction
Authors: BINIENDA ZBIGNIEW K.
Published: July 2009

Abstract: The neuroprotective action of l‐carnitine (LC) in the rat model of 3‐nitropropionic acid (3‐NPA)‐induced mitochondrial dysfunction was examined. 3‐NPA is known to produce decreases in neuronal ATP levels via inhibition of the succinate dehydrogenase (SDH) at complex II of the mitochondrial electron transport chain. SDH is involved in reactions of the Krebs cycle and oxidative phosphorylation, and its inhibition leads to both necrosis and apoptosis. LC enhances mitochondrial metabolism and, together with its acetylated form, acetyl‐l‐carnitine (ALC), via the LC‐ALC‐mediated transfer of acetyl groups, plays an important modulatory role in neurotransmitter signal transduction pathways and gene expression in neuronal cells. In the study described here, adult male Sprague‐Dawley rats were injected with 3‐NPA alone or treated with LC prior to 3‐NPA administration. Pretreatment with LC totally prevented the 3‐NPA‐induced decrease in brain temperature measured using temperature probes implanted intracranially. It appears that the protective effects of LC against 3‐NPA‐induced neurotoxicity are achieved via compensatory enhancement of several pathways of mitochondrial energy metabolism. The results of this and previous studies conducted by our division in the 3‐NPA model of mitochondrial dysfunction demonstrate that 3‐NPA may be employed in vivo to evaluate enhancers of mitochondrial function that might exert neuroprotective effects.
3‐Nitropropionic Acid Inhibition of Succinate Dehydrogenase (Complex II) Activity in Cultured Chinese Hamster Ovary Cells
Authors: SCALLET ANDREW C. , HALEY RANEY L. , SCALLET DORI M. , DUHART HELEN M. , BINIENDA ZBIGNIEW K.
Published: July 2009

Abstract:3‐Nitropropionic acid (3‐NPA) is an inhibitor of the mitochondrial enzyme succinate dehydrogenase (SDH, a part of complex II) that links the tricarboxylic acid (TCA) cycle to the respiratory electron transport chain. 3‐NPA inactivates SDH by covalently and irreversibly binding to its active site. We previously examined the effects of 3‐NPA on the histochemical activity of SDHin vivo,by using the reduction of a yellow tetrazolium dye (nitro blue tetrazolium) to a blue formazan as an indicator. In studies of cultured cells, the related dye methylthiazoletetrazolium (MTT) has commonly been used as an indicator of the presence and number of viable cells; that is cells that are capable of producing energy via the TCA cycle. Here we observed that doses of 3‐NPA as low as 10−8M inhibited formazan production in anin vitromodel system using CHO cells. This effect was antagonized by l‐carnitine, which greatly increased the production of formazan, indicating a considerable improvement in energy production by the cultured cells. CHO cells appear to be a convenient model for the evaluation of therapeutic compounds that may modulate cellular bioenergetics.
Mitochondria as a Target for Neurotoxins and Neuroprotective Agents
Authors: BACHURIN SERGEY O. , SHEVTSOVA ELENA P. , KIREEVA ELENA G. , OXENKRUG GREGORY F. , SABLIN SERGEY O.
Published: July 2009

Abstract:Mitochondrial permeability transition pores represent a multiprotein complex that includes components of both inner and outer membrane. The pores regulate transport of ions and peptides in and out of mitochondria, and their regulation is associated with a general mechanism for maintaining Ca2+homeostasis in the cell and apoptosis. Various pathologic factors may induce a pathologic activation of the permeability transition and an irreversible opening of mitochondria pores. This event is a major step in the development of neurotoxicity and neurodegeneration. This paper explores the effect of MPP+and β‐amyloid fragment 25‐35, neurotoxins that are known to generate Parkinson's‐like syndrome and Alzheimer's disease, on the regulation of the mitochondrial pores. Both neurotoxins induce opening of mitochondrial pores, which is prevented by cyclosporin A, a specific inhibitor of the permeability transition. The effect of MPP+and β‐amyloid may be also prevented by an endogenous precursor of melatonin,N‐acetylserotonin, by an anti‐Alzheimer's medication tacrine, and by dimebon, which is in development as an agent for the therapy of Alzheimer's disease and other types of dementia. The paper illustrates that the effect on mitochondrial pores is an important aspect of the mechanism of neurotoxicity. Substances that may prevent opening of mitochondrial pores induced by neurotoxins may preserve the mitochondrial function and, thus, may have potential as neuroprotective agents.
Quasi-Steady-State Displacement Response of Whole Human Cadaveric Knees in a MRI Scanner
Authors: Martin K. J. , Neu C. P. , Hull M. L.
Published: July 2009

It is important to determine the three-dimensional nonuniform deformation of articular cartilage in its native environment. A new magnetic resonance imaging (MRI)-based technique (cartilage deformation by tag registration (CDTR)) has been developed, which can determine such deformations provided that the compressive load-displacement response of the knee reaches a quasi-steady state during cyclic loading. The objectives of this study were (1) to design and construct an apparatus to cyclically compress human cadaveric knees to physiological loads in a MRI scanner, (2) to determine the number of load cycles required to reach a quasi-steady-state load-displacement response for cyclic loading of human cadaveric knees, and (3) to collect sample MR images of undeformed and deformed states of tibiofemoral cartilage free of artifact while using the apparatus within a MRI scanner. An electropneumatic MRI-compatible apparatus was constructed to fit in a clinical MRI scanner, and a slope criterion was defined to indicate the point at which a quasi-steady-state load-displacement response, which would allow the use of CDTR, occurred during cyclic loading of a human knee. The average number of cycles required to reach a quasi-steady-state load-displacement response according to the slope criterion defined herein for three cadaveric knee joints was 356±69. This indicates that human knee joint specimens can be cyclically loaded such that deformation is repeatable according to MRI requirements of CDTR. Sample images of tibiofemoral cartilage were obtained for a single knee joint. These images demonstrate the usefulness of the apparatus in a MRI scanner. Thus the results of this study are a crucial step toward developing a MRI-based method to determine the deformations of articular cartilage in whole human cadaveric knees.
Ballistic Resistant Body Armor: Contemporary and Prospective Materials and Related Protection Mechanisms
Authors: David N. V. , Gao X.-L. , Zheng J. Q.
Published: July 2009

Modern military operations, technology-driven war tactics, and current on-street weapons and ammunition necessitate the development of advanced ballistic protection body armor systems that are damage-resistant, flexible, lightweight, and of great energy absorbing capacity. A number of studies related to new concepts and designs of body armor materials (including those derived from or inspired by nature) have been conducted in the past two decades to meet the new demands. Ballistic fabrics, ceramics, and laminated composites are among the leading materials used in modern body armor designs, and nano-particle and natural fiber filled composites are candidate materials for new-generation body armor systems. Properties and ballistic resistance mechanisms of such materials have been extensively investigated. Based on a comprehensive and critical review of the advances and findings resulting from these investigations, a comparative study on design, protection mechanisms, and performance evaluation of various types of anti-ballistic body armor is presented in this paper. Body armor systems made from different materials and exhibiting distinct ballistic energy absorption mechanisms are discussed, and key factors that influence the ballistic performance and energy absorbing mechanisms of the body armor systems are identified.
Multi-Axial Mechanical Stimulation of HUVECs Demonstrates That Combined Loading is not Equivalent to the Superposition of Individual Wall Shear Stress and Tensile Hoop Stress Components
Authors: Breen Liam T. , McHugh Peter E. , Murphy Bruce P.
Published: July 2009

Over the past 25 years, many laboratory based bioreactors have been used to study the cellular response to hemodynamic forces. The vast majority of these studies have focused on the effect of a single isolated hemodynamic force, generally consisting of a wall shear stress (WSS) or a tensile hoop strain (THS). However, investigating the cellular response to a single isolated force does not accurately represent the true in vivo situation, where a number of forces are acting simultaneously. This study used a novel bioreactor to investigate the cellular response of human umbilical vein endothelial cells (HUVECs) exposed to a combination of steady WSS and a range of cyclic THS. HUVECs exposed to a range of cyclic THS (0–12%), over a 12 h testing period, expressed an upregulation of both ICAM-1 and VCAM-1. HUVECs exposed to a steady WSS (0 dynes/cm2 and 25 dynes/cm2), over a 12 h testing period, also exhibited an ICAM-1 upregulation but a VCAM-1 downregulation, where the greatest level of WSS stimulus resulted in the largest upregulation and downregulation of ICAM-1 and VCAM-1, respectively. A number of HUVEC samples were exposed to a high steady WSS (25 dynes/cm2) combined with a range of cyclic THS (0–4%, 0–8%, and 0–12%) for a 12 h testing period. The initial ICAM-1 upregulation, due to the WSS alone, was downregulated with the addition of a cyclic THS. It was observed that the largest THS (0–12%) had the greatest reducing effect on the ICAM-1 upregulation. Similarly, the initial VCAM-1 downregulation, due to the high steady WSS alone, was further downregulated with the addition of a cyclic THS. A similar outcome was observed when HUVEC samples were exposed to a low steady WSS combined with a range of cyclic THS. However, the addition of a THS to the low WSS did not result in an expected ICAM-1 downregulation. In fact, it resulted in a trend of unexpected ICAM-1 upregulation. The unexpected cellular response to the combination of a steady WSS and a cyclic THS demonstrates that such a response could not be determined by simply superimposing the cellular responses exhibited by ECs exposed to a steady WSS and a cyclic THS that were applied in isolation.
Poro-Viscoelastic Behavior of Gelatin Hydrogels Under Compression-Implications for Bioelasticity Imaging
Authors: Kalyanam Sureshkumar , Yapp Rebecca D. , Insana Michael F.
Published: July 2009

Ultrasonic elasticity imaging enables visualization of soft tissue deformation for medical diagnosis. Our aim is to understand the role of flow-dependent and flow-independent viscoelastic mechanisms in the response of biphasic polymeric media, including biological tissues and hydrogels, to low-frequency forces. Combining the results of confined and unconfined compression experiments on gelatin hydrogels with finite element analysis (FEA) simulations of the experiments, we explore the role of polymer structure, loading, and boundary conditions in generating contrast for viscoelastic features. Feature estimation is based on comparisons between the biphasic poro-elastic and biphasic poro-viscoelastic (BPVE) material models, where the latter adds the viscoelastic response of the solid polymer matrix. The approach is to develop a consistent FEA material model (BPVE) from confined compression-stress relaxation measurements to extract the strain dependent hydraulic permeability variation and cone-plate rheometer measurements to obtain the flow-independent viscoelastic constants for the solid-matrix phase. The model is then applied to simulate the unconfined compression experiment to explore the mechanics of hydropolymers under conditions of quasi-static elasticity imaging. The spatiotemporal distributions of fluid and solid-matrix behavior within the hydrogel are studied to propose explanations for strain patterns that arise during the elasticity imaging of heterogeneous media.
Tension and Combined Tension-Extension Structural Response and Tolerance Properties of the Human Male Ligamentous Cervical Spine
Authors: Dibb Alan T. , Nightingale Roger W. , Luck Jason F. , Chancey V. Carol , Fronheiser Lucy E. , Myers Barry S.
Published: July 2009

Tensile loading of the human cervical spine results from noncontact inertial loading of the head as well as mandibular and craniofacial impacts. Current vehicle safety standards include a neck injury criterion based on beam theory that uses a linear combination of the normalized upper cervical axial force and sagittal plane moment. This study examines this criterion by imposing combined axial tension and bending to postmortem human subject (PMHS) ligamentous cervical spines. Tests were conducted on 20 unembalmed PMHSs. Nondestructive whole cervical spine tensile tests with varying cranial end condition and anteroposterior loading location were used to generate response corridors for computational model development and validation. The cervical spines were sectioned into three functional spinal segments (Occiput-C2, C4-C5, and C6-C7) for measurement of tensile structural response and failure testing. The upper cervical spine (Occiput-C2) was found to be significantly less stiff, absorb less strain energy, and fail at higher loads than the lower cervical spine (C4-C5 and C6-C7). Increasing the moment arm of the applied tensile load resulted in larger head rotations, larger moments, and significantly higher tensile ultimate strengths in the upper cervical spine. The strength of the upper cervical spine when loaded through the head center of gravity (2417±215 N) was greater than when loaded over the occipital condyles (2032±250 N), which is not predicted by beam theory. Beam theory predicts that increased tensile loading eccentricity results in decreased axial failure loads. Analyses of the force-deflection histories suggest that ligament loading in the upper cervical spine depends on the amount of head rotation orientation, which may explain why the neck is stronger in combined tension and extension.
Combination of CFD and DOE to Analyze and Improve the Mass Flow Rate in Urinary Catheters
Authors: Frawley Patrick , Geron Marco
Published: July 2009

The urinary catheter is a thin plastic tube that has been designed to empty the bladder artificially, effortlessly, and with minimum discomfort. The current CH14 male catheter design was examined with a view to optimizing the mass flow rate. The literature imposed constraints to the analysis of the urinary catheter to ensure that a compromise between optimal flow, patient comfort, and everyday practicality from manufacture to use was achieved in the new design. As a result a total of six design characteristics were examined. The input variables in question were the length and width of eyelets 1 and 2 (four variables), the distance between the eyelets, and the angle of rotation between the eyelets. Due to the high number of possible input combinations a structured approach to the analysis of data was necessary. A combination of computational fluid dynamics (CFD) and design of experiments (DOE) has been used to evaluate the “optimal configuration.” The use of CFD couple with DOE is a novel concept, which harnesses the computational power of CFD in the most efficient manner for prediction of the mass flow rate in the catheter.
Planar Biaxial Mechanical Behavior of Bioartificial Tissues Possessing Prescribed Fiber Alignment
Authors: Jhun Choon-Sik , Evans Michael C. , Barocas Victor H. , Tranquillo Robert T.
Published: July 2009

Though it is widely accepted that fiber alignment has a great influence on the mechanical anisotropy of tissues, a systematic study of the influence of fiber alignment on the macroscopic mechanical behavior by native tissues is precluded due to their predefined microstructure and heterogeneity. Such a study is possible using collagen-based bioartificial tissues that allow for alignment to be prescribed during their fabrication. To generate a systemic variation of strength of fiber alignment, we made cruciform tissue constructs in Teflon molds that had arms of different aspect ratios. We implemented our anisotropic biphasic theory of tissue-equivalent mechanics to simulate the compaction by finite element analysis. Prior to tensile testing, the construct geometry was standardized by cutting test samples with a 1:1 cruciform punch after releasing constructs from the molds. Planar biaxial testing was performed on these samples, after stretching them to their in-mold dimensions to recover in-mold alignment, to observe the macroscopic mechanical response with simultaneous fiber alignment imaging using a polarimetry system. We found that the strength of fiber alignment of the samples prior to release from the molds linearly increased with anisotropy of the mold. In testing after release, modulus ratio (modulus in fiber direction/modulus in normal direction) was greater as the initial strength of fiber alignment increased, that is, as the aspect ratio increased. We also found that the fiber alignment strength and modulus ratio increased in a hyperbolic fashion with stretching for a sample of given aspect ratio.
On the Stiffness Matrix of the Intervertebral Joint: Application to Total Disk Replacement
Authors: O’Reilly Oliver M. , Metzger Melodie F. , Buckley Jenni M. , Moody David A. , Lotz Jeffrey C.
Published: July 2009

The traditional method of establishing the stiffness matrix associated with an intervertebral joint is valid only for infinitesimal rotations, whereas the rotations featured in spinal motion are often finite. In the present paper, a new formulation of this stiffness matrix is presented, which is valid for finite rotations. This formulation uses Euler angles to parametrize the rotation, an associated basis, which is known as the dual Euler basis, to describe the moments, and it enables a characterization of the nonconservative nature of the joint caused by energy loss in the poroviscoelastic disk and ligamentous support structure. As an application of the formulation, the stiffness matrix of a motion segment is experimentally determined for the case of an intact intervertebral disk and compared with the matrices associated with the same segment after the insertion of a total disk replacement system. In this manner, the matrix is used to quantify the changes in the intervertebral kinetics associated with total disk replacements. As a result, this paper presents the first such characterization of the kinetics of a total disk replacement.
Carpal Tunnel Expansion by Palmarly Directed Forces to the Transverse Carpal Ligament
Authors: Li Zong-Ming , Tang Jie , Chakan Matthew , Kaz Rodrigo
Published: July 2009

This study investigated the expansion of the carpal tunnel resulting from the application of palmarly directed forces to the transverse carpal ligament (TCL) from inside the carpal tunnel. Ten fresh-frozen cadaveric hands were dissected to evacuate the carpal tunnel, and thus to expose the TCL. A custom lever device was built to apply forces, ranging from 10 N to 200 N, to the TCL. Without force application, the carpal tunnel area was 148.4±36.8 mm2. The force application caused the TCL to form arches with an increase in cross-sectional areas of 33.3±5.6 mm2 at 10 N and 48.7±11.4 mm2 at 200 N, representing respective increases of 22.4% and 32.8% relative to the initial carpal tunnel area. The TCL length remained constant under the applied forces. It was found that the TCL arch formation was due to the narrowing of the arch width, which resulted from the migration of the bony insertion sites of the TCL. A geometrical model of the carpal tunnel was then developed to elucidate the relationships among the arch width, TCL length, arch height, and arch area. The model illustrated the effectiveness of carpal tunnel expansion by TCL elongation or arch width narrowing.
In Vivo Model for Evaluating the Effects of Mechanical Stimulation on Tissue-Engineered Bone Repair
Authors: Boerckel Joel D. , Dupont Kenneth M. , Kolambkar Yash M. , Lin Angela S. P. , Guldberg Robert E.
Published: July 2009

It has long been known that the bone adapts according to the local mechanical environment. To date, however, a model for studying the effects of functional mechanical loading on tissue-engineered bone repair in vivo has not yet been established. We have developed a rat femoral defect model, in which ambulatory loads are transduced through the implanted tissue-engineered construct to elucidate the role of the mechanical environment in functional restoration of a large bone defect. This model uses compliant fixation plates with integrated elastomeric segments, which allow transduction of ambulatory loads. Multiaxially and uniaxially compliant plates were characterized by mechanical testing and evaluated using in vivo pilot studies. In the first study, experimental limbs were implanted with multiaxial plates, which have a low stiffness in multiple loading modes. In the second study, experimental limbs were stabilized by a uniaxial plate, which allowed only axial deformation of the defect. X-ray scans and mechanical testing revealed that the multiaxial plates were insufficient to stabilize the defect and prevent fracture under ambulatory loads as a result of low flexural and torsional stiffness. The uniaxial plates, however, maintained integrity of the defect when implanted over a 12 week period. Postmortem microCT scans revealed a 19% increase in bone volume in the axially loaded limb compared with the contralateral standard control, and postmortem mechanical testing indicated that torsional strength and stiffness were increased 25.6- and 3.9-fold, respectively, compared with the control. Finite element modeling revealed high strain gradients in the soft tissue adjacent to the newly formed bone within the implanted construct. This study introduces an in vivo model for studying the effects of physiological mechanical loading on tissue-engineered bone repair. Preliminary results using this new in vivo model with the uniaxially compliant plate showed positive effects of load-bearing on functional defect repair.
Design and Validation of a Knee Brace With Feedback to Reduce the Rate of Loading
Authors: Riskowski J. L. , Mikesky A. E. , Bahamonde R. E. , Burr D. B.
Published: July 2009

The repetitive nature of walking can lead to repetitive stress and associated complications due to the rate of loading (ROL) experienced by the body at the initial contact of the foot with the ground. An individual’s gait kinematics at initial contact has been suggested to give rise to the ROL, and a repetitive, high ROL may lead to several disorders, including osteoarthritis. We present the design, development, and validation of a knee brace that provides feedback to the user during gait. The feedback consists of an auditory signal when the specific parameters of knee angle or tibial acceleration 50 ms prior to contact are exceeded. Nine women were recruited for the gait analysis, and the gait characteristics with and without the brace and feedback are analyzed. Our results indicate that using a knee brace with feedback can effectively change the gait kinematics used during walking, leading to a reduced ROL experienced at initial contact. Using a knee brace with feedback is a novel approach to gait retraining. Al-though the kinetics of how the subjects change in gait pattern is unknown, the reduced ROL experienced is significant and warrants further investigation.
Drug Discovery and Natural Products: End of an Era or an Endless Frontier?
Authors: Li Jesse W.-H. , Vederas John C.
Published: July 2009

Toward Drug Development

The vast majority of pharmaceuticals on the market are based on natural product molecules originally derived from living organisms. When it comes to newly approved drugs, however, the situation looks rather different. Difficulties with high-throughput screening and laboratory synthesis of natural products have led drug companies to focus on libraries of synthetic compounds, despite their providing a much lower “hit rate.”
Li and Vederas
(p.
161
) review methodologies that facilitate the screening, analysis, and synthesis of natural product molecules and their derivatives. Given these advances and the vast numbers of organisms and environments that remain to be explored for potential drug candidates, the current lull in newly approved drugs based on natural products will likely be temporary.
Hematopoietic Cytokines Can Instruct Lineage Choice
Authors: Rieger Michael A. , Hoppe Philipp S. , Smejkal Benjamin M. , Eitelhuber Andrea C. , Schroeder Timm
Published: July 2009

Making the Choice

The importance of cytokine signals for the generation of specific blood lineages is well known. However, whether cytokines only influence survival and proliferation of cells that have already committed to one lineage, or if they also influence the lineage choice is unclear. For decades, researchers disputed whether lineage choice of hematopoietic progenitor cells be influenced by cell extrinsic cytokines. Using bioimaging approaches that allow long-term observation of all cells in progenitor cell cultures,

Rieger
et al.

(p.
217
) now demonstrate that certain cytokines can indeed instruct blood lineage choice.
Discovery of Swine as a Host for the
Reston ebolavirus
Authors: Barrette Roger W. , Metwally Samia A. , Rowland Jessica M. , Xu Lizhe , Zaki Sherif R. , Nichol Stuart T. , Rollin Pierre E. , Towner Jonathan S. , Shieh Wun-Ju , Batten Brigid , Sealy Tara K. , Carrillo Consuelo , Moran Karen E. , Bracht Alexa J. , Mayr Gregory A. , Sirios-Cruz Magdalena , Catbagan Davinio P. , Lautner Elizabeth A. , Ksiazek Thomas G. , White William R. , McIntosh Michael T.
Published: July 2009

Not Reston at All

Reston ebolavirus
is named, mistakenly perhaps, for Reston, Virginia, where it was discovered in the 1970s in imported macaques. After some alarm it was found not to be virulent in humans, uniquely among the ebola viruses, which are characteristically fatal causing a horrific spectrum of symptoms. Using a panviral detection assay,
Reston ebolavirus
has been rediscovered by

Barrette
et al.

(p.
204
) in domesticated pigs in the Philippines in association with other viruses that cause respiratory illness. The strains involved are closely related to the original macaque strain and, given how little variance there is among the viruses, it appears that it is freely circulating between these species possibly, like several other zoonotic viruses, having a reservoir in bats. Serological assays indicated that farm workers have become infected, although no obvious symptoms of human disease have been reported.
A Functional Role for Adult Hippocampal Neurogenesis in Spatial Pattern Separation
Authors: Clelland C. D. , Choi M. , Romberg C. , Clemenson G. D. , Fragniere A. , Tyers P. , Jessberger S. , Saksida L. M. , Barker R. A. , Gage F. H. , Bussey T. J.
Published: July 2009

Neurogenesis and Spatial Memory

The dentate gyrus of the hippocampus is one of two sites in the brain where new neurons are produced throughout life. Adult-born neurons integrate into the dentate gyrus circuitry and are thought to play a role in learning and memory. However, their contribution to hippocampal function remains unclear.

Clelland
et al.

(p.
210
) disrupted neurogenesis in mice and used two behavioral tasks to test for impairment in the formation of uncorrelated episodic memory representations. In one task, two arms were presented and the mice were rewarded for choosing the most recently visited arm in an earlier sequence; in the second task, animals were rewarded for choosing a certain location on a touch screen. Ablation of neurogenesis affected discrimination performance in both tasks but only when the arms or screen locations were close to one another. Neurogenesis is thus necessary for spatial pattern separation in the dentate gyrus.
Evolution of the Turtle Body Plan by the Folding and Creation of New Muscle Connections
Authors: Nagashima Hiroshi , Sugahara Fumiaki , Takechi Masaki , Ericsson Rolf , Kawashima-Ohya Yoshie , Narita Yuichi , Kuratani Shigeru
Published: July 2009

Shelling Turtles

In almost all vertebrates, the shoulder girdle (scapula) lies outside the ribs. The turtle is unique in that the carapace, the dorsal part of the shell, which is formed from the ribs, encapsulates the scapula. To understand the origin of the turtle-specific body plan,

Nagashima
et al.

(p.
193
; see the cover; see the Perspective by

Rieppel

) compared chicken, mouse, and the Chinese soft shelled-turtle,
Pelodiscus sinensis
. Modern embryos were studied via whole-mount immunostaining, three-dimensional reconstructions, and with markers for early skeletal precursors and compared with previously reported fossils. Initially, embryos of the three animals share a common developmental pattern, one that is likely to have been shared with their last common ancestor. This pattern, however, is modified in the turtle by a specific folding of its body wall during embryogenesis. This folding preserves some of the connectivity between skeletal and muscle elements but also produces new connections.
Cell Growth and Size Homeostasis in Proliferating Animal Cells
Authors: Tzur Amit , Kafri Ran , LeBleu Valerie S. , Lahav Galit , Kirschner Marc W.
Published: July 2009

Size Matters

Cells of different types come in different sizes. Size is established by a trade-off of growth and division; as a result, the distribution of cell size in a population is held stable over time. A classic question in cell physiology is whether the growth rate of cells is constant over time or whether, as cells grow bigger during the cell cycle, they grow faster and faster. Using experimental and mathematical approaches,

Tzur
et al.

(p.
167
; see the Perspective by

Edgar and Kim

) show that the growth rate of mouse lymphoblastoid cells in culture is slow in the G
1
phase and then increases to reach a constant exponential rate. Thus, there is an active size-control mechanism that limits size variation in animal cells.
Nuclear Waste Management in the United States—Starting Over
Authors: Ewing Rodney C. , von Hippel Frank N.
Published: July 2009

The debate has begun again over the disposition of nuclear fuel and waste.