bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics and Pharmacogenomics of Once-Daily Raltegravir and Atazanavir in Healthy Volunteers
Authors: Neely Michael , Decosterd Laurent , Fayet Aurélie , Lee Janice Soo Fern , Margol Ashley , Kanani Meera , di Iulio Julia , von Schoen-Angerer Tido , Jelliffe Roger , Calmy Alexandra
Published: September 2010

Atazanavir inhibits UDP-glucuronyl-transferase-1A1 (UGT1A1), which metabolizes raltegravir, but the magnitude of steady-state inhibition and role of the
UGT1A1
genotype are unknown. Sufficient inhibition could lead to reduced-dose and -cost raltegravir regimens. Nineteen healthy volunteers, age 24 to 51 years, took raltegravir 400 mg twice daily (arm A) and 400 mg plus atazanavir 400 mg once daily (arm B), separated by ≥3 days, in a crossover design. After 1 week on each regimen, raltegravir and raltegravir-glucuronide plasma and urine concentrations were measured by liquid chromatography-tandem mass spectrometry in multiple samples obtained over 12 h (arm A) or 24 h (arm B) and analyzed by noncompartmental methods.
UGT1A1
promoter variants were detected with a commercially available kit and published primers. The primary outcome was the ratio of plasma raltegravir
C
tau
, or concentration at the end of the dosing interval, for arm B (24 h) versus arm A (12 h). The arm B-to-arm A geometric mean ratios (95% confidence interval,
P
value) for plasma raltegravir
C
tau
, area under the concentration-time curve from 0 to 12 h (AUC
0-12
), and raltegravir-glucuronide/raltegravir AUC
0-12
were 0.38 (0.22 to 0.65, 0.001), 1.32 (0.62 to 2.81, 0.45), and 0.47 (0.38 to 0.59, <0.001), respectively. Nine volunteers were heterozygous and one was homozygous for a
UGT1A1
reduction-of-function allele, but these were not associated with metabolite formation. Although atazanavir significantly reduced the formation of the glucuronide metabolite, its steady-state boosting of plasma raltegravir did not render the
C
tau
with a once-daily raltegravir dose of 400 mg similar to the
C
tau
with the standard twice-daily dose.
UGT1A1
promoter variants did not significantly influence this interaction.
Preclinical Characterization of BI 201335, a C-Terminal Carboxylic Acid Inhibitor of the Hepatitis C Virus NS3-NS4A Protease
Authors: White Peter W. , Llinàs-Brunet Montse , Amad Ma'an , Bethell Richard C. , Bolger Gordon , Cordingley Michael G. , Duan Jianmin , Garneau Michel , Lagacé Lisette , Thibeault Diane , Kukolj George
Published: September 2010

BI 201335 is a hepatitis C virus (HCV) NS3-NS4A (NS3 coexpressed with NS4A) protease inhibitor that has been shown to have potent clinical antiviral activity. It is a highly optimized noncovalent competitive inhibitor of full-length NS3-NS4A proteases of HCV genotypes 1a and 1b withKivalues of 2.6 and 2.0 nM, respectively.Kivalues of 2 to 230 nM were measured against the NS3-NS4A proteases of HCV genotypes 2 to 6, whereas it was a very weak inhibitor of cathepsin B and showed no measurable inhibition of human leukocyte elastase. BI 201335 was also shown to be a potent inhibitor of HCV RNA replicationin vitrowith 50% effective concentrations (EC50s) of 6.5 and 3.1 nM obtained in genotype 1a and 1b replicon assays. Combinations of BI 201335 with either interferon or ribavirin had additive effects in replicon assays. BI 201335 had good permeability in Caco-2 cell assays and high metabolic stability after incubation with human, rat, monkey, and dog liver microsomes. Its good absorption, distribution, metabolism, and excretion (ADME) profilein vitro, as well as in rat, monkey, and dog, predicted good pharmacokinetics (PK) in humans. Furthermore, drug levels were significantly higher in rat liver than in plasma, suggesting that distribution to the target organ may be especially favorable. BI 201335 is a highly potent and selective NS3-NS4A protease inhibitor with goodin vitroand animal ADME properties, consistent with its good human PK profile, and shows great promise as a treatment for HCV infection.
Emergence of Metallo-β-Lactamase NDM-1-Producing Multidrug-Resistant
Escherichia coli
in Australia
Authors: Poirel Laurent , Lagrutta Emilie , Taylor Peter , Pham Jeanette , Nordmann Patrice
Published: September 2010

A multidrug-resistant
Escherichia coli
isolate recovered in Australia produced a carbapenem-hydrolyzing β-lactamase. Molecular investigations revealed the first identification of the
bla
NDM-1
metallo-β-lactamase gene in that country. In addition, this
E. coli
isolate expressed the extended-spectrum β-lactamase CTX-M-15, together with two 16S rRNA methylases, namely, ArmA and RmtB, conferring a high level of resistance to aminoglycosides.
Inadequate Binding of Immune Regulator Factor H Is Associated with Sensitivity ofBorrelia lusitaniaeto Human Complement
Authors: Dieterich Roswitha , Hammerschmidt Claudia , Richter Dania , Skerka Christine , Wallich Reinhard , Matuschka Franz-Rainer , Zipfel Peter F. , Kraiczy Peter
Published: September 2010

Spirochetes belonging to theBorrelia burgdorferisensu lato complex differ in resistance to complement-mediated killing by human serum. Here, we characterize complement sensitivity of a panel ofB. lusitaniaeisolates derived from ticks collected in Germany and Portugal as well as one patient-derived isolate, PoHL. All isolates are highly susceptible to complement-mediated lysis in human serum and activate complement predominantly by the alternative pathway, leading to an increased deposition of complement components C3, C6, and the terminal complement complex. Interestingly, serum-sensitiveB. lusitaniaeisolates were able to bind immune regulator factor H (CFH), and some strains also bound CFH-related protein 1 (CFHR1) and CFHR2. Moreover, CFH bound to the surface ofB. lusitaniaewas inefficient in mediating C3b conversion. Furthermore, the identification and characterization of a potential CFH-binding protein, OspE, revealed that this molecule possesses a significantly reduced binding capacity for CFH compared to that of CFH-binding OspE paralogs expressed by various serum-resistantBorreliaspecies. This finding suggests that a reduced binding capability of CFH is associated with an increased serum sensitivity ofB. lusitaniaeto human complement.
Epithelial Cell-Derived S100 Calcium-Binding Proteins as Key Mediators in the Hallmark Acute Neutrophil Response duringCandidaVaginitis
Authors: Yano Junko , Lilly Elizabeth , Barousse Melissa , Fidel Paul L.
Published: September 2010

Vulvovaginal candidiasis (VVC), caused byCandidaspecies, is a significant problem in women of childbearing age. Similar to clinical observations, a robust vaginal polymorphonuclear neutrophil (PMN) migration occurs in a subset of mice without affecting vaginal fungal burden. We hypothesize that the vaginal PMN infiltrate and accompanying inflammation are not protective but instead are responsible for the symptoms of infection. The purpose of this study was to identify the signal(s) associated with the PMN response in the established mouse model. Vaginal lavage fluid from inoculated mice were categorized base on PMN counts, evaluated for PMN chemotactic activity and analyzed by SDS-PAGE and mass spectrometry (MS) for unique protein identification. The lavage fluid from inoculated mice with high, but not low, PMN levels showed increased chemotactic activity. Likewise, SDS-PAGE of lavage fluid with high PMN levels showed distinct protein patterns. MS revealed that bands at 6 and 14 kDa matched the PMN chemotactic calcium-binding proteins (CBPs), S100A8 and S100A9, respectively. The presence of the CBPs in lavage fluid was confirmed by Western blots and enzyme-linked immunosorbent assay. Vaginal tissues and epithelial cells from inoculated mice with high PMN levels stained more intensely and exhibited increased mRNA transcripts for both proteins compared to those in mice with low PMN levels. Subsequent antibody neutralization showed significant abrogation of the chemotactic activity when the lavage fluid was treated with anti-S100A8, but not anti-S100A9, antibodies. These results reveal that the PMN chemotactic CBP S100A8 and S100A9 are produced by vaginal epithelial cells following interaction withCandidaand that S100A8 is a strong candidate responsible for the robust PMN migration during experimental VVC.
Development of Two Animal Models To Study the Function of
Vibrio parahaemolyticus
Type III Secretion Systems
Authors: Piñeyro Pablo , Zhou Xiaohui , Orfe Lisa H. , Friel Patrick J. , Lahmers Kevin , Call Douglas R.
Published: September 2010

Vibrio parahaemolyticus
is an emerging food- and waterborne pathogen that encodes two type III secretion systems (T3SSs). Previous studies have linked type III secretion system 1 (T3SS1) to cytotoxicity and T3SS2 to intestinal fluid accumulation, but animal challenge models needed to study these phenomena are limited. In this study we evaluated the roles of the T3SSs during infection using two novel animal models: a model in which piglets were inoculated orogastrically and a model in which mice were inoculated in their lungs (intrapulmonarily). The bacterial strains employed in this study had equivalent growth rates and beta-hemolytic activity based on
in vitro
assays. Inoculation of 48-h-old conventional piglets with 10
11
CFU of the wild-type strain (NY-4) or T3SS1 deletion mutant strains resulted in acute, self-limiting diarrhea, whereas inoculation with a T3SS2 deletion mutant strain failed to produce any clinical symptoms. Intrapulmonary inoculation of C57BL/6 mice with the wild-type strain and T3SS2 deletion mutant strains (5 × 10
5
CFU) induced mortality or a moribund state within 12 h (80 to 100% mortality), whereas inoculation with a T3SS1 deletion mutant or a T3SS1 T3SS2 double deletion mutant produced no mortality. Bacteria were recovered from multiple organs regardless of the strain used in the mouse model, indicating that the mice were capable of clearing the lung infection in the absence of a functional T3SS1. Because all strains had a similar beta-hemolysin phenotype, we surmise that thermostable direct hemolysin (TDH) plays a limited role in these models. The two models introduced herein produce robust results and provide a means to determine how different T3SS1 and T3SS2 effector proteins contribute to pathogenesis of
V. parahaemolyticus
infection.
Branched-Chain Fatty Acids Promote
Listeria monocytogenes
Intracellular Infection and Virulence
Authors: Sun Yvonne , O'Riordan Mary X. D.
Published: September 2010

Anteiso-branched-chain fatty acids (BCFA) represent the dominant group of membrane fatty acids and have been established as crucial determinants in resistance against environmental stresses in
Listeria monocytogenes
, a facultative intracellular pathogen. Here, we investigate the role of anteiso-BCFA in
L. monocytogenes
virulence by using mutants deficient in branched-chain alpha-keto acid dehydrogenase (BKD), an enzyme complex involved in the synthesis of BCFA. In tissue culture models of infection, anteiso-BCFA contributed to intracellular growth and survival in macrophages and significantly enhanced plaque formation upon prolonged infection in L2 fibroblasts. The intracellular defects observed could be attributed partially to insufficient listeriolysin O (LLO) production, indicating a requirement for anteiso-BCFA in regulating virulence factor production. In a murine model of infection, the BKD-deficient mutant was highly attenuated, further emphasizing the importance of BKD-mediated metabolism in
L. monocytogenes
virulence. This study demonstrates an underappreciated role for BCFA in bacterial pathogenesis, which may provide insight into the development and application of antimicrobial agents.
Enteroaggregative
Escherichia coli
Disrupts Epithelial Cell Tight Junctions
Authors: Strauman Maura C. , Harper Jill M. , Harrington Susan M. , Boll Erik Juncker , Nataro James P.
Published: September 2010

Enteroaggregative
Escherichia coli
(EAEC) is responsible for inflammatory diarrhea in diverse populations, but its mechanisms of pathogenesis have not been fully elucidated. We have used a previously characterized polarized intestinal T84 cell model to investigate the effects of infection with EAEC strain 042 on tight junction integrity. We find that infection with strain 042 induces a decrease in transepithelial electrical resistance (TER) compared to uninfected controls and to cells infected with commensal
E. coli
strain HS. When the infection was limited after 3 h by washing and application of gentamicin, we observed that the TER of EAEC-infected monolayers continued to decline, and they remained low even as long as 48 h after the infection. Cells infected with the afimbrial mutant strain 042
aafA
exhibited TER measurements similar to those seen in uninfected monolayers, implicating the aggregative adherence fimbriae II (AAF/II) as necessary for barrier dysfunction. Infection with wild-type strain 042 induced aberrant localization of the tight junction proteins claudin-1 and, to a lesser degree, occludin. EAEC-infected T84 cells exhibited irregular shapes, and some cells became elongated and/or enlarged; these effects were not observed after infection with commensal
E. coli
strain HS or 042
aafA
. The effects on tight junctions were also observed with AAF/I-producing strain JM221, and an afimbrial mutant was similarly deficient in inducing barrier dysfunction. Our results show that EAEC induces epithelial barrier dysfunction
in vitro
and implicates the AAF adhesins in this phenotype.
Characterization of Toxin Plasmids in
Clostridium perfringens
Type C Isolates
Authors: Gurjar Abhijit , Li Jihong , McClane Bruce A.
Published: September 2010

Clostridium perfringens
type C isolates cause enteritis necroticans in humans or necrotizing enteritis and enterotoxemia in domestic animals. Type C isolates always produce alpha toxin and beta toxin but often produce additional toxins, e.g., beta2 toxin or enterotoxin. Since plasmid carriage of toxin-encoding genes has not been systematically investigated for type C isolates, the current study used Southern blot hybridization of pulsed-field gels to test whether several toxin genes are plasmid borne among a collection of type C isolates. Those analyses revealed that the surveyed type C isolates carry their beta toxin-encoding gene (
cpb
) on plasmids ranging in size from ∼65 to ∼110 kb. When present in these type C isolates, the beta2 toxin gene localized to plasmids distinct from the
cpb
plasmid. However, some enterotoxin-positive type C isolates appeared to carry their enterotoxin-encoding
cpe
gene on a
cpb
plasmid. The
tpeL
gene encoding the large clostridial cytotoxin was localized to the
cpb
plasmids of some
cpe
-negative type C isolates. The
cpb
plasmids in most surveyed isolates were found to carry both IS
1151
sequences and the
tcp
genes, which can mediate conjugative
C. perfringens
plasmid transfer. A
dcm
gene, which is often present near
C. perfringens
plasmid-borne toxin genes, was identified upstream of the
cpb
gene in many type C isolates. Overlapping PCR analyses suggested that the toxin-encoding plasmids of the surveyed type C isolates differ from the
cpe
plasmids of type A isolates. These findings provide new insight into plasmids of proven or potential importance for type C virulence.
In VivoDiscrimination of Type 3 Secretion System-Positive and -NegativePseudomonas aeruginosavia a Caspase-1-Dependent Pathway
Authors: Wangdi Tamding , Mijares Lilia A. , Kazmierczak Barbara I.
Published: September 2010

Microbe-associated molecular patterns are recognized by Toll-like receptors of the innate immune system. This recognition enables a rapid response to potential pathogens but does not clearly provide a way for the innate immune system to discriminate between virulent and avirulent microbes. We find that pulmonary infection of mice with type 3 translocation-competentPseudomonas aeruginosatriggers a rapid inflammatory response, while infection with isogenic translocation-deficient mutants does not. Discrimination between translocon-positive and -negative bacteria requires caspase-1 activity in bone marrow-derived cells and interleukin-1 receptor signaling. Thus, the activation of caspase-1 by bacteria expressing type 3 secretion systems allows for rapid recognition of bacteria expressing conserved functions associated with virulence.
Syntheses and structural characterizations ofcloso and nido 10-vertex metallatricarbanonaboranes
Authors: Perez-Gavilan Ariane , Carroll Patrick J. , Sneddon Larry G.
Published: September 2010

Deboronation of the 11-vertex metallatricarbadecaboranes 1-(η5-C5H5)-2-Ph-closo-1,2,3,4-M-C3B7H9 [M = Ru, Fe] and 1,1,1-(CO)3-2-Ph-closo-1,2,3,4-M-C3B7H9 [M = Re] with tetrabutylammonium fluoride (TBAF) produced the first examples of the 10-vertex families of closo and nido metallatricarbanonaborane complexes, 2-(η5-C5H5)-10-Ph-closo-2,1,6,10-M-C3B6H8 [M = Ru (1), Fe (2)] and 5,5,5-(CO)3-10-Ph-nido-5,6,9,10-Re-C3B6H9– (3). Crystallographic characterizations of 1 and 3 confirmed geometries, based on a bicapped square antiprism for 1 and a bicapped square antiprism with one missing vertex for 3, that are consistent with their respective 22 (closo) and 24 (nido) skeletal-electron counts.
SMOOTHING IMPRECISE 1.5D TERRAINS
Authors: GRAY CHRIS , LÖFFLER MAARTEN , SILVEIRA RODRIGO I.
Published: September 2010

We study optimization problems for polyhedral terrains in the presence of data imprecision. An imprecise terrain is given by a triangulated point set where the height component of the vertices is specified by an interval of possible values. We restrict ourselves to terrains with a one-dimensional projection, usually referred to as 1.5-dimensional terrains, where an imprecise terrain is given by an x-monotone polyline, and the y-coordinate of each vertex is not fixed but only constrained to a given interval. Motivated mainly by applications in terrain analysis, in this paper we study five different optimization measures related to obtaining smooth terrains, for the 1.5-dimensional case. In particular, we present exact algorithms to minimize and maximize the total turning angle, as well as to minimize the maximum slope change. Furthermore, we also give approximation algorithms to minimize the largest turning angle and to maximize the smallest turning angle.
ALMOST OPTIMAL SOLUTIONS TO k-CLUSTERING PROBLEMS
Authors: KUMAR PANKAJ , KUMAR PIYUSH
Published: September 2010

We implement an algorithm for k-clustering for small k in fixed dimensions and report experimental results here. Although the theoretical bounds on the running time are hopeless for 1 + ∊ approximating k-clusters, we note that for dimensions 2 and 3, k-clustering is practical for small k (k ≤ 4) and simple enough shapes. For the purposes of this paper, k is a small fixed constant.
FINDING MANY OPTIMAL PATHS WITHOUT GROWING ANY OPTIMAL PATH TREES
Authors: CHEN DANNY Z. , MISIOŁEK EWA
Published: September 2010

Many algorithms for applications such as pattern recognition, computer vision, and computer graphics seek to compute actual optimal paths in weighted directed graphs. The standard approach for reporting an actual optimal path is based on building a single-source optimal path tree. A technique by Chen et al.2 was given for a class of problems such that a single actual optimal path can be reported without maintaining any single-source optimal path tree, thus significantly reducing the space bound of those problems with no or little increase in their running time. In this paper, we extend the technique by Chen et al.2 to the generalized problem of reporting many actual optimal paths with different starting and ending vertices in certain directed graphs, and show how this new technique yields improved results on several application problems, such as reconstructing a 3-D surface band bounded by two simple closed curves, finding various constrained segmentation of 2-D medical images, and circular string-to-string correction. We also correct an error in the time/space complexity for the well-cited circular string-to-string correction algorithm12 and give an improved result for this problem. Although the generalized many-path problem seems more difficult than the single-path cases, our algorithms have nearly the same space and time bounds as those of the single-path cases. Our technique is likely to help improve many other optimal paths or dynamic programming algorithms.
VORONOI DIAGRAM OF POLYGONAL CHAINS UNDER THE DISCRETE FRÉCHET DISTANCE
Authors: BEREG SERGEY , BUCHIN KEVIN , BUCHIN MAIKE , GAVRILOVA MARINA , ZHU BINHAI
Published: September 2010

Polygonal chains are fundamental objects in many applications like pattern recognition and protein structure alignment. A well-known measure to characterize the similarity of two polygonal chains is the (continuous/discrete) Fréchet distance. In this paper, for the first time, we consider the Voronoi diagram of polygonal chains in d-dimension under the discrete Fréchet distance. Given a set [Formula: see text] of n polygonal chains in d-dimension, each with at most k vertices, we prove fundamental properties of such a Voronoi diagram [Formula: see text]. Our main results are summarized as follows.

• The combinatorial complexity of [Formula: see text] is at most O(ndk+∊).

• The combinatorial complexity of [Formula: see text] is at least Ω(ndk) for dimension d = 1, 2; and Ω(nd(k-1)+2) for dimension d > 2.
ACCURACY CHARACTERIZATION OF AN INTEGRATED OPTICAL-BASED METHOD FOR LOADS MEASUREMENT IN COMPUTER AIDED SURGERY
Authors: CAMMARATA SERGIO , CAMMARATA MARCO , LOPOMO NICOLA , BIGNOZZI SIMONE , CERVERI PIETRO , FERRIGNO GIANCARLO , ZAFFAGNINI STEFANO , VISANI ANDREA
Published: September 2010

Generally in the anterior cruciate ligament (ACL) injury assessment specific laxity tests (i.e., Lachman, drawer tests) are clinically performed to evaluate the presence of ligamentous lesion. At present these tests are qualitatively evaluated by the surgeon and some quantitative measurements can be performed only for Lachman/drawer tests by means of dedicated devices. This study aimed to characterize the accuracy of a novel integrated optical-based method that can be used both in intra-operative and in office assessment of ACL injuries; in particular this technology was addressed to measure the loads/torques applied during clinical laxity tests, extending the current possible quantitative evaluations. The system, based on a commercial optical localizer and common springs, was spatially characterized in order to verify displacement/rotation and corresponding applied load/torque measurements. Evaluated limits of agreement between measured and applied loads were from –0.541 to 1.781 N, with a bias of 0.621 N (P = 0.05) in a dedicated clinical-like setup. This approach reported an excellent accuracy in load measurements, showing its possible integration in computer-aided surgery (CAS).
BIOMECHANICAL EFFECTS OF FOAM INSERTS ON FOREFOOT LOAD DURING THE HIGH-HEELED GAIT: A PILOT STUDY
Authors: LI J. S. , GU Y. D. , REN X. J. , LAKE M. J. , ZENG Y. J.
Published: September 2010

This pilot study analyzed the loading on the medial forefoot (MF) region during walking in high-heel shoes. Eight healthy female volunteers have participated in this study with the heel height varied from 0 cm (flat), 4.5 cm (low), and 8.5 cm (high). The results showed that the load on MF increased with the heel height and the magnitude of the load could be effectively reduced by using foam inserts. Comparative studies of foams with different hardness and thicknesses showed that thicker soft foams had a significant advantage over thiner hard foams (P < 0.05) in reducing the peak pressures. An optimum condition with a thick soft insert could reduce MF pressure by 26%, impact force by 27%, and force time integral by 20% when compared to the condition without insert.
TENDON REFLEX AND STRATEGIES FOR QUANTIFICATION, WITH NOVEL METHODS INCORPORATING WIRELESS ACCELEROMETER REFLEX QUANTIFICATION DEVICES, A PERSPECTIVE REVIEW
Authors: LEMOYNE ROBERT , MASTROIANNI TIMOTHY , COROIAN CRISTIAN , GRUNDFEST WARREN
Published: September 2010

The deep tendon reflex is a fundamental aspect of a neurological examination. The two major parameters of the tendon reflex are response and latency, which are presently evaluated qualitatively during a neurological examination. The reflex loop is capable of providing insight into the status and therapy response of both upper and lower motor neuron syndromes. Attempts have been made to ascertain reflex response and latency; however, these systems are relatively complex, resource intensive, with issues of consistent and reliable accuracy. The solution presented is a wireless quantified reflex device using tandem three-dimensional (3D) wireless accelerometers to obtain response based on acceleration waveform amplitude and latency derived from temporal acceleration waveform disparity. Three specific aims have been established for the proposed wireless quantified reflex device:

(1) Demonstrate the wireless quantified reflex device is reliably capable of ascertaining quantified reflex response and latency using a quantified input.

(2) Evaluate the precision of the device using an artificial reflex system.

(3) Conduct a longitudinal study respective of subjects with healthy patellar tendon reflexes, using the wireless quantified reflex evaluation device to obtain quantified reflex response and latency.

Aim 1 has led to a steady evolution of the wireless quantified reflex device from a singular 2D wireless accelerometer capable of measuring reflex response to a tandem 3D wireless accelerometer capable of reliably measuring reflex response and latency. The hypothesis for aim 1 is that a reflex quantification device can be established for reliably measuring reflex response and latency for the patellar tendon reflex, comprised of an integrated system of wireless 3D MEMS accelerometers. Aim 2 further emphasized the reliability of the wireless quantified reflex device by evaluating an artificial reflex system. The hypothesis for aim 2 is that the wireless quantified reflex device can obtain reliable reflex parameters (response and latency) from an artificial reflex device. Aim 3 synthesizes the findings relevant to aim 1 and 2, while applying the wireless accelerometer reflex quantification device to a longitudinal study of healthy patellar tendon reflexes. The hypothesis for aim 3 is that during a longitudinal evaluation of the deep tendon reflex the parameters for reflex response and latency can be measured with a considerable degree of accuracy, reliability, and reproducibility. Enclosed is a detailed description of a wireless quantified reflex device with research findings and potential utility of the system, inclusive of a comprehensive description of tendon reflexes, prior reflex quantification systems, and correlated applications.
TENDON SLACK LENGTH AND ITS EFFECT ON MUSCLE FORCE-GENERATION CHARACTERISTICS
Authors: NAM YOONSU , UHM HYUN WOO
Published: September 2010

Based on the force transfer relationship from muscle to tendon, a chart determining a normalized tendon force is developed. A sensitivity analysis verifies that the tendon slack length is the most critical parameter affecting the tendon force. Therefore, it may be claimed that the variation of this parameter from Delp's reference data will noticeably change the musculotendon characteristics of a subject. The effect of tendon slack length change on this characteristic was analyzed theoretically and checked by numerical results. An optimization algorithm was introduced, which searches the tendon slack lengths of quadriceps by minimizing the differences of calculated knee extension moment from experimental data.
Hydrogeothermal studies in the United Kingdom
Authors: Barker J. A. , Downing R. A. , Gray D. A. , Findlay J. , Kellaway G. A. , Parker R. H. , Rollin K. E.
Published: September 2010

Following the increase in oil prices in the mid‐1970s, Britain assessed its geothermal resources. Low‐temperature, hot‐water resources, in the range 40°C to 100°C, occur in Permo‐Triassic sandstones in several deep sedimentary basins. In total these resources are estimated at 69.1 × 10
18
joules (J) (2576 million tonnes coal equivalent). Resources also occur in Upper Palaeozoic aquifers but, as the permeability of these aquifers depends upon fissures, exploitation is difficult. The only surface manifestations of hot water at depth are the warm springs at Bath and Bristol and in the Peak District and Taff Valley, which issue from the Carboniferous Limestone. The potential of radiothermal granites for Hot Dry Rock (HDR) development has also been investigated, particularly in the Carnmenellis granite in Cornwall. Three boreholes drilled in the granite to depths of over 2 km have been connected by developing natural fractures. Water circulation between the boreholes and through the fractured rock has been successful.
The Third Glossop Lecture
Authors: Chandler R. J.
Published: September 2010

The cycle of events and natural processes that affect the geotechnical properties of clay sediments in a depositional basin (the ‘Geotechnical Cycle’) includes: deposition, consolidation/compaction, diagenesis, tectonic disturbance, weathering and erosion. Some of these processes can occur in parallel; their combined effects control the mechanical behaviour of clay sediments. Processes involved in the Geotechnical Cycle are reviewed, using case studies chosen where possible from the London Basin; examples from other depositional basins emphasize the many common elements that control the behaviour of clay sediments.

A simple soil behaviour model (based on the ‘sensitivity framework’) is described that combines the consolidation (geological compaction) and strength behaviour of natural clays, both during loading (deposition) and unloading (erosion). This model enables the mechanical consequences of soil structure (including the effects of diagenesis) to be quantified. Its merits are that it describes real soils, thus aiding ground characterization, and also allows an assessment of such factors as sample disturbance, while providing a realistic and straightforward geotechnical framework.

The effects of tectonic events on the geotechnical behaviour of clays are reviewed in the particular context of flexural slip, and its influence on stability problems.

Uplift, then erosion, results in basin sediments becoming overconsolidated; the history of the London Basin is used to emphasize both what is known and, in particular, what is not known, of these phases of basin history. Following erosion, weathering processes further modify the mechanical properties of clays. The most obvious indicator of weathering is oxidation, with its associated colour changes. The depth of oxidation in the London Clay Formation is reviewed, and shown to relate to topographic position and former groundwater conditions. Finally, the sensitivity framework is used to examine the effects of weathering on the mechanical behaviour of clay, particularly the reduction of yield stress in one‐dimensional compression.
Tension pile tests in chalk
Authors: Matthews M. C. , Clayton C. R. I. , Bica A. V. D.
Published: September 2010

This paper reports the results of a series of pull-out tests performed on mini-piles in chalk. Also reported are load–displacement data for similar piles when used in a group, for anchoring large-diameter plate loading test equipment. A comparison is made with the limited data reported in the literature. The observed uplift resistance of these piles is compared with that predicted by existing design methods, based upon SPT, and vertical effective stress.
Auditing the Groundwater Yield Reassessments
Authors: Besien T. J. , Perkins M. A.
Published: September 2010

Throughout 1997 the 28 water companies of England and Wales prepared reassessments of the reliable yields of their groundwater sources using the United Kingdom Water Industry Research (UKWIR) methodology, as required by the Environment Agency (the Agency). An audit of these reassessments was carried out by the Halcrow Group Ltd. The work involved the strategic audit of approximately 5% of the total number of groundwater sources. The purpose of this strategic audit was to ensure that the approach of the water companies to the yield calculations was consistent and followed the UKWIR methodology; quality assurance systems were in place; and all assumptions or deviations from the methodology were justified, and where necessary, were reported to the Agency. The overall level of water company compliance was good. There were several technical issues regarding the methodology, which meant that in places it was not fully followed. General audit observations, implementation issues and technical issues are discussed, and potential improvements to the methodology are suggested.
Estimation of the mean and reproducibility of aggregate compositions based on constituent mass data
Authors: Howarth R. J.
Published: September 2010

Given a set of representative samples of aggregate source material (e.g. from a stockpile or production line), it is shown that if only percentaged data is reported, the mean composition of the percentaged data is best calculated using a robust estimate of the logratio mean. However, if raw mass data is also available (as will generally be the case), then it is best to first calculate the average of the constituent masses, and then to convert these into a percentage. The difference between confidence, prediction and tolerance intervals is reviewed and it is shown that the repeatability of aggregate samples and an effective long-term ‘detection limit’ for constituents can be reliably estimated using duplicates of run-of-the-mill samples; an upper boundary can be placed on the detection limit by application of, say, a two-sided {95%, 99%} tolerance interval. Numerical approximations are given to enable a variety of normal two-sided tolerance factors to be computed.
Debris flow defences at Aoraki Mount Cook Village, New Zealand
Authors: Skermer N.A. , Rawlings G.E. , Hurley A.J.
Published: September 2010

Glencoe Stream is a small watershed draining slopes of the Sealy Range in the Southern Alps, New Zealand. It flows alongside the Hermitage Hotel at Aoraki Mount Cook Village which is a world heritage site with spectacular views towards Mount Cook. The stream is very active and poses a debris flow threat to the hotel as shown by the serious event which occurred in December, 1957. It has developed a debris and alluvial fan in post glacial time which has spread out over the recent glacial deposits in the Hooker valley, to which Glencoe Stream is a tributary. In 1996 the authors studied the geotechnical hazards in the watershed and designed engineering works to protect the hotel complex. An approximate relationship was developed between the magnitude and frequency of flood and debris flow events. The size of events and estimated return periods, together with the assessment of severity or consequences, allowed the level of risk to be addressed. Mitigative measures to protect against the hazards to provide a level of protection comparable to those in other jurisdictions in mountainous terrain were addressed. Design parameters were taken to be a debris flow with a 1:200 return period, a pure water flood of 25 cumecs, and a required debris storage volume of 100 000 m
3
. Active mitigative measures considered included engineered structures to channel the events into a developed storage area and passive measures included land use zoning and planning restrictions. The engineered measures do not provide protection against extreme events and a residual risk always remains to developments on the fan. The engineered measures were completed in 1999 at a cost of NZ $1.3 M and the zoning to allow controlled development has also been put in place.
Block movements in the Pennines and South Wales and their association with landslides
Authors: Donnelly L.J. , Northmore K.J, , Siddle H.J.
Published: September 2010

Fault scarps and graben features indicative of slope deformation have been observed adjacent to the rear scarps of landslides and on moorland plateaux in the Pennines. The scarps are distinct, up to 2 m high and can be traced for a maximum distance of approximately 400 m. These severely reduce the strength of the rock mass, enable groundwater to be channelled onto the upper valley slopes and may have played an important role in the initiation of first-time slope failures, and in the reactivation of older landslides. These features are similar to those recently described on the interfluves of the South Wales Coalfield valleys, and are consistent with those described as ‘block movements’ elsewhere in the world. Those in South Wales have been interpreted, by some previous investigators, as being generated during mining subsidence. However, in the Pennines, the slope and plateaux movements occur in the Namurian (Upper Carboniferous) sedimentary sequences where there has been no mining and it is therefore evident that other mechanisms are involved. In both South Wales and the Pennines steep-sided valleys have incised the moorland plateaux which in both cases are capped by strong, well-jointed cap rocks. These have exposed the underlying, much weaker, fissile mudstones which form the middle and lower slopes. These block movements in the Pennines are documented, discussed and compared with those in South Wales.
Influence of heterogeneity on undrained clay slope stability
Authors: Hicks Michael A. , Samy Kristinah
Published: September 2010

This paper concentrates on the fact that natural materials are variable, and that representation of this variability appears crucial to getting a realistic understanding of certain geotechnical problems. In this case, finite elements have been used to assess the influence of heterogeneity on the stability of a clay slope, characterized by a spatially varying undrained shear strength
c

u

. For low to intermediate values of the coefficient of variation (e.g. 0.1–0.3), as are often observed in practice, pointwize variability can be approximated by a normal distribution. Data on spatial variability are more scarce, although vertical scales of fluctuation are usually much smaller than horizontal scales of fluctuation, and will often be small relative to the height of a slope. The results show that, for a given factor of safety, reliability is greatest for
c

u

constant with depth. For
c

u

increasing linearly with depth, reliability decreases due to the greater range of possible rupture surfaces: hence, in conventional (deterministic) design, higher factors of safety (or lower characteristic values) would be needed. In this study, horizontal anisotropy (of the heterogeneity) causes modest changes in reliability. However, problems are identified in which anisotropy is likely to have a significant influence.
Admixture Mapping Comes of Age
Authors: Winkler Cheryl A. , Nelson George W. , Smith Michael W.
Published: September 2010

Admixture mapping is based on the hypothesis that differences in disease rates between populations are due in part to frequency differences in disease-causing genetic variants. In admixed populations, these genetic variants occur more often on chromosome segments inherited from the ancestral population with the higher disease variant frequency. A genome scan for disease association requires only enough markers to identify the ancestral chromosome segments; for recently admixed populations, such as African Americans, 1,500–2,500 ancestry-informative markers (AIMs) are sufficient. The method was proposed over 50 years ago, but the AIM panels and statistical methods required have only recently become available. Since the first admixture scan in 2005, the genetic bases for a range of diseases/traits have been identified by admixture mapping. Here, we provide a historical perspective, review AIM panels and software packages, and discuss recent successes and unexpected insights into human diseases that exhibit disparate rates across human populations.
Genetics of Coronary Artery Disease
Authors: Musunuru Kiran , Kathiresan Sekar
Published: September 2010

Coronary artery disease and its clinical manifestations, including myocardial infarction, are heritable traits, consistent with a role for inherited DNA sequence variation in conferring risk for disease. Knowledge of the new sequence variations in the genome that confer risk has the potential to illuminate new causal biologic pathways in humans and to thereby further improve diagnosis and treatment. Here, we review recent progress in mapping genetic loci related to coronary disease and risk factor phenotypes, including plasma lipoprotein concentrations. Genome-wide linkage (in families) and association (in populations) studies have identified more than a dozen genetic loci related to coronary disease. A key challenge now is to move from mapping loci to pinpointing causal genes and variants, and to develop a molecular understanding of how these genes lead to coronary disease.
Genomics of Long-Range Regulatory Elements
Authors: Noonan James P. , McCallion Andrew S.
Published: September 2010

Transcriptional regulation of gene expression plays a significant role in establishing the diversity of human cell types and biological functions from a common set of genes. The components of regulatory control in the human genome include cis-acting elements that act across immense genomic distances to influence the spatial and temporal distribution of gene expression. Here we review the established categories of distant-acting regulatory elements, discussing the classical and contemporary evidence of their regulatory potential and clinical importance. Current efforts to identify regulatory sequences throughout the genome and elucidate their biological significance depend heavily on advances in sequence conservation–based analyses and on increasingly large-scale efforts applying transgenic technologies in model organisms. We discuss the advantages and limitations of sequence conservation as a predictor of regulatory function and present complementary emerging technologies now being applied to annotate regulatory elements in vertebrate genomes.
Informed Consent in Genomics and Genetic Research
Authors: McGuire Amy L. , Beskow Laura M.
Published: September 2010

There are several features of genetic and genomic research that challenge established norms of informed consent. In this paper, we discuss these challenges, explore specific elements of informed consent for genetic and genomic research conducted in the United States, and consider alternative consent models that have been proposed. All of these models attempt to balance the obligation to respect and protect research participants with the larger social interest in advancing beneficial research as quickly as possible.
Public Attitudes and Beliefs About Genetics
Authors: Condit Celeste M.
Published: September 2010

The existing research base on public attitudes about genetics shows that people's attitudes vary according to the specific technologies and purposes to which genetic knowledge is applied. Genetic testing is viewed highly favorably, genetically modified food is viewed with ambivalence, and cloning is viewed negatively. Attitudes are favorable for uses that maintain a perceived natural order and unfavorable for uses that are perceived to change it. Public concerns about control of genetic information and eugenics are evident, but their strength and relevance to policy preference are unclear. The pattern of attitudes can be explained by theories of attitude formation, and the existing base of information can be deepened and given more explanatory and predictive power by integrating future research into the various traditions that theorize attitude formation.
Dispatches from the Evolution Wars: Shifting Tactics and Expanding Battlefields
Authors: Branch Glenn , Scott Eugenie C. , Rosenau Joshua
Published: September 2010

Creationism continues to present a challenge to the teaching of evolution in the United States. With attempts to ban evolution education and to “balance” the teaching of evolution with creationism unavailing, creationists are increasingly favoring the approach of misrepresenting evolution as scientifically controversial. To understand the ongoing challenges facing evolution education in the United States, it is necessary to appreciate creationist actions at the different levels of educational governance—state legislatures, state boards of education, local boards of education, and finally the individual classroom—that serve as the battlegrounds for the evolution education wars. Scientists are in a unique position to defend the teaching of evolution, both by resisting creationist incursions as they occur and by helping to improve the teaching of evolution at both the precollege and college levels.
The Neutral Theory of Molecular Evolution in the Genomic Era
Authors: Nei Masatoshi , Suzuki Yoshiyuki , Nozawa Masafumi
Published: September 2010

The neutral theory of molecular evolution has been widely accepted and is the guiding principle for studying evolutionary genomics and the molecular basis of phenotypic evolution. Recent data on genomic evolution are generally consistent with the neutral theory. However, many recently published papers claim the detection of positive Darwinian selection via the use of new statistical methods. Examination of these methods has shown that their theoretical bases are not well established and often result in high rates of false-positive and false-negative results. When the deficiencies of these statistical methods are rectified, the results become largely consistent with the neutral theory. At present, genome-wide analyses of natural selection consist of collections of single-locus analyses. However, because phenotypic evolution is controlled by the interaction of many genes, the study of natural selection ought to take such interactions into account. Experimental studies of evolution will also be crucial.
Signaling Pathways in Human Skeletal Dysplasias
Authors: Baldridge Dustin , Shchelochkov Oleg , Kelley, Brian , Lee Brendan
Published: September 2010

Human skeletal dysplasias are disorders that result from errors in bone, cartilage, and joint development. A complex series of signaling pathways, including the FGF, TGFβ, BMP, WNT, Notch, and Hedgehog pathways, are essential for proper skeletogenesis, and human skeletal dysplasias are often a consequence of primary or secondary dysregulation of these pathways. Although these pathways interact to regulate bone, cartilage, and joint formation, human genetic phenotypes point to the predominant action of specific components of these pathways. Mutations in the genes with a role in metabolic processing within the cell, the extracellular matrix, and transcriptional regulation can lead to dysregulation of cell–cell and cell–matrix signaling that alters tissue patterning, cell differentiation, proliferation, and apoptosis. We propose a morphogen rheostat model to conceptualize how mutations in different metabolic processes can lead to the integration of differential signaling inputs within a temporal and spatial context to generate apparently divergent skeletal phenotypes.
When t-tests or Wilcoxon-Mann-Whitney tests won't do
Authors: McElduff Fiona , Cortina-Borja Mario , Chan Shun-Kai , Wade Angie
Published: September 2010

t-Tests are widely used by researchers to compare the average values of a numeric outcome between two groups. If there are doubts about the suitability of the data for the requirements of a t-test, most notably the distribution being non-normal, the Wilcoxon-Mann-Whitney test may be used instead. However, although often applied, both tests may be invalid when discrete and/or extremely skew data are analyzed. In medicine, extremely skewed data having an excess of zeroes are often observed, representing a numeric outcome that does not occur for a large percentage of cases (so is often zero) but which also sometimes takes relatively large values. For data such as this, application of the t-test or Wilcoxon-Mann-Whitney test could lead researchers to draw incorrect conclusions. A valid alternative is regression modeling to quantify the characteristics of the data. The increased availability of software has simplified the application of these more complex statistical analyses and hence facilitates researchers to use them. In this article, we illustrate the methodology applied to a comparison of cyst counts taken from control and steroid-treated fetal mouse kidneys.