Well-defined Points Research Articles

On-Virus Construction of Polyvalent Glycan Ligands for Cell-Surface Receptors

Glycans arrayed on the exterior of virus particles were used as substrates for glycosyltransferase reactions to build di- and trisaccharides from the virus surface. The resulting particles exhibited tight and specific associations with cognate receptors on beads and cells, in one example defeating in cis cell-surface interactions in a manner characteristic of polyvalent binding. Combined with the ability of viruses to provide structurally well-defined attachment points, the methodology provides a convenient and powerful way to prepare complex carbohydrate ligands for clustered receptors.

Human Reliability Analysis of Cataract Surgery

To evaluate the use of the Human Reliability Analysis of Cataract Surgery tool to identify the frequency and pattern of technical errors observed during phacoemulsification cataract extraction by surgeons with varying levels of experience. Observational cohort study. Thirty-three consecutive phacoemulsification cataract operations were performed by 33 different ophthalmic surgeons with varying levels of operative experience: group 1, fewer than 50 procedures; group 2, between 50 and 250 procedures; and group 3, more than 250 procedures. Face and content validity were surveyed by a panel of senior cataract surgeons. The tool was applied to the 33 randomized and anonymous videos by 2 independent assessors trained in error identification and correct tool use. Task analysis using 10 well-defined end points and error identification using 10 external error modes were performed for each case. The main outcome measures were number of errors performed per task, nature of performed errors (executional or procedural), and surgical experience of operating surgeon. Analysis of 330 constituent steps of 33 operations identified 228 errors, of which 151 (66.2%) were executional and 77 (33.8%) were procedural. The overall highest error probability was associated with sculpting, followed by fragmentation of the nucleus; this was most evident in group 1. Surgeons in group 3 proportionally performed more errors during removal of soft lens matter than those in group 1 or 2. Surgical experience had a significant effect on the number of errors, with a statistically significant difference among the 3 groups (P < .001). The Human Reliability Analysis of Cataract Surgery tool is useful for identifying where technical errors occur during phacoemulsification cataract surgery. The study findings, including the high executional error rate, could be used to enhance and structure resident surgical training and future assessment tools. Face, content, and construct validity of the tool were demonstrated.

Clinical Validation Of Traditional Medicine &amp;Natural Products: Experiences and Suggestions

Traditional systems of medicine [TSM] use poly-herbal or herbo-mineral combinations for preventive health or for curative aspects of illnesses. The rationale applied is of respective TSM's as in Ayurved or Traditional Chinese Medicine or at times it is mix of ingredients claimed to have beneficial effects for an expected clinical outcome [1]. Validation of these products is difficult in view of their functional approaches that are difficult to correlate with present day critical experimental and laboratory parameters. It is not always possible to translate observational clinical predominance in methods of diagnosis, treatment and evaluation into scientific parameters [2]. Principles and significance of composition, issues of standardization, modifications in original forms or manufacturing processes, newer dosage forms and its dose requirements and administration and such several other issues add to the complexities of clinical validation of TSM products [3]. Clinical study designs and phases followed to evaluate conventional medicine do not serve the purpose of scientific objectivity when applied to TSM. Blind adherence to such methods limit clinical studies to derive true benefits of traditional knowledge base [4]. Varied clinical validation experiences by the author in poorly defined group of musculo-skeletal disorders to specific conditions like osteoarthritis and from common cold to a disease entity like Parkinson's disease indicate need to evolve a systematic approach to clinical validation of TSM products [5–14]. There has been a gradual change in approach to clinical studies amongst the experts dealing with these products and treatments. Reviews and efforts are made to understand utility of such studies and develop newer designs [15]. An urgent need is felt to evolve a systematic approach to clinical validations of TSM products and therapies. The solution lies in dealing with multiple factors that contribute to complexities. Clinical outcome being the benchmark of any treatment, need is to evolve an approach to satisfy needs of TSM principles within the frame of scientific objectivity [16]. Basic need is to integrate principles for well-defined end points and to evolve suitable modalities.

Application of a vortex tracking method to the piston-like behaviour in a semi-entrained vertical gap

Near resonance the piston mode amplitude in semi-entrained volumes of fluid such as in moonpools or in between a ship and a terminal may become large relative to the level of excitation. Linear theory is known to over-predict the fluid response in these types of systems significantly, suffering from the lack of damping whose only manifestation is radiated waves. In reality, however, viscous effects may act as damping and nonlinear effects associated with the free surface conditions may cause transfer of energy between the different modes. In the present work, which is within the framework of potential theory, a fully nonlinear numerical wavetank based on Green’s 2nd identity coupled with an inviscid vortex tracking method is applied to the moonpool problem. The paper presents a methodology for perpetual simplification of the free shear layer as the system undergoes near sinusoidal motion in order to reach steady state. This is practically impossible without such simplifications due to the otherwise exceedingly complex wake structures evolving only after the first one or two periods. Also the in- and out-flow of the boundary layers are modelled. The results are compared to experiments. In the investigated cases models of rectangular shape with sharp corners provide well-defined separation points, and such sharp corners are in practice introduced e.g. by bilge keels. It is found that: (1) The damping effect associated with the nonlinear free surface conditions are of minor importance, (2) the effect of the in- and out-flow of the boundary layer is negligible to all practical purposes, whereas (3) the flow separation explains the major part of the discrepancy between the measured response and that estimated by linear theory.

Muscle wasting in intensive care patients: Ultrasound observation of the M. quadriceps femoris muscle layer

Patients in intensive care exhibit a high degree of loss of muscle mass. Appropriate instruments are needed to document muscle wasting in these patients. The aim of this pilot study was to describe muscle wasting in patients in the intensive care unit. Two-fold study setting: prospective longitudinal and cross-sectional single-blind. A total of 118 patients in the intensive care unit (length of stay 1-98 days; male:female ratio 88:30; age 55 +/- 17 years) were included in a two-fold study setting. Muscle layer thickness of the M. quadriceps femoris was documented using ultrasound measurement at well-defined points. Seventeen pilot-patients were measured twice; at baseline and after 28 days. In another group of 101 patients, muscle layer thickness was determined once after a random length of stay. The results of both groups were compared and correlated. In both groups, M. quadriceps femoris thickness showed a significant negative correlation with length of stay in the intensive care unit (p < 0.01). Furthermore, muscle wasting in intensive care patients could be described using a logarithmic function. Loss of muscle mass shows a negative correlation with length of stay, and seems to be higher during the first 2-3 weeks of immobilization/intensive care unit stay. Ultrasound is a valid and practical measurement tool for documenting muscle mass (e.g. muscle layer thickness) as part of the daily routine at an intensive care unit.

Bessel’s Graphical Solution of Three-Point Problem in Plane-Table Surveying—Limitation and Alternative Solutions

The orientation of a plane table at a new station is carried out with the help of three well-defined visible points available on the ground along with their corresponding plot on the plan using Bessel’s graphical solution. There are seven regions (R1–R7) in and around the area bounded by the three well-defined ground points and the plane table may be stationed in any one of them for orientation. While carrying out such field work, a completely opposite orientation was obtained for the plane-table station in reference to the ground points and corresponding plotted plan points for some of the regions, hinting at possible limitation of the method. This paper makes an effort to understand and analyze the limitation of Bessel’s graphical solution. The orientations were carried out on an AutoCAD worksheet and cross checked through field works. It was observed that the position of the plane table station and the third point used to draw the ray in reference to the line joining the first two points used for sight...

A role for cytochrome c and cytochrome c peroxidase in electron shuttling from Erv1

Erv1 is a flavin-dependent sulfhydryl oxidase in the mitochondrial intermembrane space (IMS) that functions in the import of cysteine-rich proteins. Redox titrations of recombinant Erv1 showed that it contains three distinct couples with midpoint potentials of -320, -215, and -150 mV. Like all redox-active enzymes, Erv1 requires one or more electron acceptors. We have generated strains with erv1 conditional alleles and employed biochemical and genetic strategies to facilitate identifying redox pathways involving Erv1. Here, we report that Erv1 forms a 1:1 complex with cytochrome c and a reduced Erv1 can transfer electrons directly to the ferric form of the cytochrome. Erv1 also utilized molecular oxygen as an electron acceptor to generate hydrogen peroxide, which is subsequently reduced to water by cytochrome c peroxidase (Ccp1). Oxidized Ccp1 was in turn reduced by the Erv1-reduced cytochrome c. By coupling these pathways, cytochrome c and Ccp1 function efficiently as Erv1-dependent electron acceptors. Thus, we propose that Erv1 utilizes diverse pathways for electron shuttling in the IMS.

Application of inertia-induced excitation theory for nonlinear acoustic modes in colloidal plasma equilibrium flow

Application of inertia-induced acoustic excitation theory offers a new resonant excitation source channel of acoustic turbulence in the transonic domain of plasma flow. In bi-ion plasmas like colloidal plasma, two well-defined transonic points exist corresponding to the parent ion and the dust grain-associated acoustic modes. As usual, the modified ion acoustic mode (also known as dust ion-acoustic (DIA) wave) dynamics associated with parent ion inertia is excitable for both nanoscale-and micronscale-sized dust grains. It is found that the so-called (ion) acoustic mode (also known as dust-acoustic (DA) wave) associated with nanoscale dust grain inertia is indeed resonantly excitable through the active role of weak but finite parent ion inertia. It is interestingly conjectured that the same excitation physics, as in the case of normal plasma sound mode, operates through the active inertial role of plasma thermal species. Details of the nonlinear acoustic mode analyses of current interest in transonic domains of such impure plasmas in hydrodynamic flow are presented.

Sampling small-scale and large-scale conformational changes in proteins and molecular complexes

Sampling of small-scale and large-scale motions is important in various computational tasks, such as protein-protein docking and ligand binding. Here, we report further development and applications of the activation-relaxation technique for internal coordinate space trajectories (ARTIST). This method generates conformational moves of any complexity and size by identifying and crossing well-defined saddle points connecting energy minima. Simulations on two all-atom proteins and three protein complexes containing between 70 and 300 amino acids indicate that ARTIST opens the door to the full treatment of all degrees of freedom in dense systems such as protein-protein complexes.

The influence of structure on the behaviour of London Clay

An intensive investigation is described into the London Clay units from Heathrow Terminal 5. Intrinsic properties and composition were established, and relating the behaviour of intact and reconstituted samples allowed the effects of the clay's natural structure to be identified at all depths. Structure varied between units, but some general features emerged that have not been seen in other stiff clays. In particular, intact samples follow paths under isotropic or K0 compression that fail to provide well-defined gross yield points, or converge with the unit's intrinsic compression lines. Structure contributes to the enhanced shear strength of intact unfissured clay and affects the initial stiffness relationships. Some identifiable features of the intact units’ fabric correlated directly with their behaviour. Natural fissures within the clay, the most important mesofabric feature, had an important impact on shear strength and led to an unusual pattern of directional dependence, and particle orientation trends identified by scanning electron microscopy governed the strong elastic stiffness anisotropy. The potential for destructuration through swelling to low effective stresses was also studied and found significant for subsequent volumetric compression behaviour, but not for shearing. Hight et al. synthesise the data from this and companion papers presented by the authors, and discuss the practical consequences of the results obtained.

Myosin Phosphatase Regulatory Pathways

In many ways, the smooth muscle cell (SMC) has been at the forefront in defining cellular signaling pathways. For example, the initial description of agonist-dependent intracellular calcium ([Ca2+]i) transients was made on vertebrate vascular SMC using aqueorin as the indicator.1 Delineation of nitric oxide (NO) and cGMP signaling was first accomplished in smooth muscle.2,3 And more recently, insights into the general mechanisms of gene transcription that dictate phenotypic traits of cells are being defined by smooth muscle specific gene expression.4,5 It should come as no surprise then that the interactions among many signaling pathways in cells should be explained first in the SMC. Perhaps the reason for the central position of the SMC in defining paradigms in cellular biology is that there are well-defined physiologic end points amenable to measurement (ie, contractile force) and even better described and easily quantified biochemical pathways that underlie said physiologic end points (ie, myosin regulatory light chain phosphorylation). From a historical perspective, the role of protein phosphorylation in smooth muscle contraction as a paradigm for cell signaling follows only that for the control of glycogen metabolism (see 6,7 for reviews). Increases in the levels of cytosolic [Ca2+]i initiate smooth muscle contraction by binding to the universal intracellular Ca2+ receptor protein, calmodulin (CaM), which in turn binds to and activates smooth muscle myosin light chain kinase (MLCK). Activated MLCK catalyzes the phosphorylation serine-19 of the regulatory myosin light chain (MLC) thereby increasing cross-bridge cycling and the rate of tension development. Dephosphorylation of MLC is catalyzed by smooth muscle specific myosin light chain phosphatase (MLCP). Decreases in cytosolic [Ca2+]i and MLC dephosphorylation are considered salient events in smooth muscle relaxation. What has become apparent only within the last decade is the fact that …

Metabolic Syndrome and Early Death

This editorial appraises an article in the current issue of Hypertension that examines the prospective relationships between features of the metabolic syndrome (MetS) and early death in a population-based cohort form Northern Italy.1 We also discuss, in light of that study’s findings, how relevant conventional definitions of the MetS are for identifying individuals at high risk of early death. The MetS describes a constellation of metabolic and cardiovascular disease risk factors. Although varying definitions of the MetS exist, all of the commonly used definitions include a measure of obesity, hyperglycemia, hypertension, and dyslipidemia.2–4 These definitions are based on “expert” opinion and not on evidence derived from prospective studies, which would be preferable. Thus, it remains uncertain whether the component features of the MetS or the thresholds at which each component is defined as present or absent are informative and optimal for predicting risk of disease or early death. It is also undetermined whether MetS represents a distinct pathophysiological entity. Notwithstanding these issues, the syndrome is extensively used in research studies, and many advocate its use in clinical practice5 to identify people at high risk of cardiovascular disease and early death. The idea that cardiovascular risk factors with a common etiology cluster in certain individuals at high risk of cardiovascular disease was first popularized by Reaven6 in the 1980s, although the origins of the MetS date back much earlier.7 Reaven’s6 emphasis was on elucidating the underlying pathophysiology of cardiovascular disease, for which he postulated that insulin resistance plays a pivotal role, and not on developing a diagnosis of MetS, which could be used in clinical practice. Superficially, at least, MetS relates strongly with cardiovascular morbidity and early death8; this is perhaps unsurprising, because so too do each of the component features of the …

Fingerprints of Delocalized Transition States in Quantum Dynamics

Reactions with delocalized transition states (plateau reactions) can be characterized statically by their energy profile along the reaction path, where they exhibit a broad, flat region instead of one or several well-defined saddle points on the potential energy surface. Employing our new, highly flexible quantum dynamics code to perform two-dimensional and effective four-dimensional quantum wave packet propagations on ab initio based model potentials, we show that plateau reactions can also be discerned from the other standard reaction types by their dynamics.

Critical role of ribavirin for the achievement of early virological response to HCV therapy in HCV/HIV‐coinfected patients

The response to hepatitis C virus (HCV) therapy seems to be lower in HCV/HIV-coinfected patients than in HCV-monoinfected individuals. Given that most pivotal trials conducted in coinfected patients have used the combination of pegylated interferon (pegIFN) along with fixed low doses (800 mg/day) of ribavirin (RBV), it is unclear whether HIV itself and/or suboptimal RBV exposure could explain this poorer outcome. Two well-defined end points of early virological response were evaluated in Peginterferon Ribavirina España Coinfección (PRESCO), a multicentre trial in which the combination of pegIFN plus RBV (1000 mg if body weight <75 kg and 1200 mg if >75 kg) was prescribed to coinfected patients. For comparisons, we used unpublished data from early kinetics in two other large trials, one performed in HIV-negative patients [Pegasys International Study Group (PISG)] in which RBV 1000-1200 mg/day was used and another [AIDS Pegasys Ribavirin Coinfection Trial (APRICOT)] in which HIV-positive patients received fixed low RBV doses (800 mg/day). A total of 348 HCV/HIV-coinfected patients from the PRESCO trial were analysed as well as all patients treated with pegIFN plus RBV, who completed 12 weeks of therapy in the comparative studies (435 in PISG and 268 in APRICOT). Negative serum HCV-RNA at week 4 (which has the highest positive predictive value of sustained virological response, SVR) was attained in 33.3%, 31.2% and 13% of treated patients with HCV genotype 1, respectively, in PRESCO, PISG and APRICOT. For HCV genotypes 2/3, responses were 83.7%, 84.2% and 37%, respectively. A decline lower than 2 log(10) at week 12 (which has the highest negative predictive value of SVR) was seen in 25.5%, 19.5% and 37% of HCV genotype-1-infected patients, and in 2.1%, 2.9% and 12% of genotypes-2/3-infected patients, respectively. Prescription of high RBV doses enhances the early virological response to HCV therapy in HCV/HIV-coinfected patients, with results approaching those seen in HCV-monoinfected patients.

Development of a static and dynamic simulator for osteosyntheses of the mandible

The development of new methods and materials for osteosynthesis requires in vitro testing prior to clinical use to exclude major problems or difficulties. In the field of oral and maxillofacial surgery no standardized testing procedures have so far been established. From a biomechanical point of view the lower jaw can be described as a lever that during the chewing cycle various forces at various points of the bone act upon. Standardized solid foam polyurethane mandibles (Sawbones, Malmö, Sweden) were used for the testing of various types of screws and different types of fractures. Via linkages that were connected to hydraulic cylinders defined forces were exerted on the polyurethane mandibles and the deformation was registered depending on the force. Monitoring was carried out contactless and therefore without back coupling by the use of a video system that recorded well-defined points on both sides of the fracture line. The photographs were then evaluated by special software (SIMI MOTION CAPTURE). The control of the cylinders was performed through a processor that besides static forces also allowed dynamic testing (e.g. sinusoid oscillation with defined amplitude and number of cycles). For the standardized and realistic three-dimensional static or dynamic testing of new methods and materials for osteosynthesis of the lower jaw this test stand has proved to be optimally suitable. Independent on the type of fracture and the material used the field of application for our test stand is the complete lower jaw. Therefore an ethically correct and economically reasonable testing of industrial products and clinical methods of osteosynthesis can be performed with this simulator.

Future of ToxicologyPredictive Toxicology: An Expanded View of “Chemical Toxicity”

A chemistry approach to predictive toxicology relies on structure-activity relationship (SAR) modeling to predict biological activity from chemical structure. Such approaches have proven capabilities when applied to well-defined toxicity end points or regions of chemical space. These approaches are less well-suited, however, to the challenges of global toxicity prediction, i.e., to predicting the potential toxicity of structurally diverse chemicals across a wide range of end points of regulatory and pharmaceutical concern. New approaches that have the potential to significantly improve capabilities in predictive toxicology are elaborating the "activity" portion of the SAR paradigm. Recent advances in two areas of endeavor are particularly promising. Toxicity data informatics relies on standardized data schema, developed for particular areas of toxicological study, to facilitate data integration and enable relational exploration and mining of data across both historical and new areas of toxicological investigation. Bioassay profiling refers to large-scale high-throughput screening approaches that use chemicals as probes to broadly characterize biological response space, extending the concept of chemical "properties" to the biological activity domain. The effective capture and representation of legacy and new toxicity data into mineable form and the large-scale generation of new bioassay data in relation to chemical toxicity, both employing chemical structure information to inform and integrate diverse biological data, are opening exciting new horizons in predictive toxicology.

Crystal structure and specific heat of GdCuGe

A single crystal study of GdCuGe revealed full copper–germanium ordering: NdPtSb type, space group P6 3 mc, a = 423.2 ( 1 ) , c = 753.7 ( 2 ) pm , w R 2 = 0.0443 , 414 F 2 values and 10 variables. The copper and germanium atoms build up two-dimensional networks of ordered [Cu 3Ge 3] hexagons with Cu–Ge distances of 244 pm. Consecutive [Cu 3Ge 3] layers are rotated by 60° around the perpendicular c-axis with respect to each other. The [Cu 3Ge 3] hexagons show a weak puckering. Heat capacity measurements on the polycrystalline sample of GdCuGe establishes antiferromagnetic ordering around 14 K in agreement with reports in the literature. The curves of heat capacity measured in different applied fields crosses each other at two well-defined points exhibiting a behavior usually associated with heavy fermion compounds. The results of the structural analysis and heat capacity measurements are discussed in the light of these interesting observations for a gadolinium intermetallic.

Remission in depression: definition and initial treatment approaches

Although remission is recognized as the optimal outcome of treatment for depression, remission lacks a universally accepted definition. This is partly due to the lack of objective biologic markers or tests that confirm a response to treatment and no well-defined end points of treatment. Significant symptoms may still exist even though patients may have a full response as measured by currently available standardized psychiatric rating scales. In addition, many patients may experience marked improvement in depressive symptoms but still have impaired psychosocial and work function. Wellness should be determined by evaluating a combination of three key domains: symptoms, functional status and pathophysiologic changes. In choosing an initial medication for depression, physicians are often guided by a mix of evidence-based medicine and unvalidated or even inaccurate clinical lore. In general, most available agents have comparable effectiveness; however, the subtype of depression and age of the patient should be considered.

Principles and Evaluation of Autostereoscopic Photogrammetric Measurement

Stereoscopic perception is a basic requirement for photogrammetric 3D measurement and accurate geospatial data collection. Ordinary stereoscopic techniques require operators wearing glasses or using eyepieces for interpretation and measurement. However, the recent emerging autostereoscopic technology makes it possible to eliminate this requirement. This paper studies the principles and implementation of autostereoscopic photogrammetric measurement and evaluates its performance. We first describe the principles and properties of the parallax barrier-based autostereoscopic display used in this study. As an important metric property, we quantitatively present the autostereoscopic geometry, including viewing zones and the boundary of a viewer’s movement for autostereoscopic measurement. A toolkit AUTO3D is developed that has common photogrammetric functions. The implementation principles are described by addressing the differences compared to the ordinary stereoscopic technology. To evaluate the performance of the autostereoscopic measurement, images at a resolution of 25 � m and 50 � m are measured by a group of seven (7) operators, who are asked to digitize 18 well-defined roof points and 18 ground points. These results are evaluated by comparing the same measurements obtained from a popular stereoscopic photogrammetric workstation. It is shown that the precision of autostereoscopic measurement is about 16 percent to 25 percent lower than the conventional stereo workstation.

ARTIST: An activated method in internal coordinate space for sampling protein energy landscapes

We present the first applications of an activated method in internal coordinate space for sampling all-atom protein conformations, the activation-relaxation technique for internal coordinate space trajectories (ARTIST). This method differs from all previous internal coordinate-based studies aimed at folding or refining protein structures in that conformational changes result from identifying and crossing well-defined saddle points connecting energy minima. Our simulations of four model proteins containing between 4 and 47 amino acids indicate that this method is efficient for exploring conformational space in both sparsely and densely packed environments, and offers new perspectives for applications ranging from computer-aided drug design to supramolecular assembly.