An integrated approach to change the outcome part I: neuromuscular screening methods to identify high ACL injury risk athletes

An important step for treatment of a particular injury etiology is the appropriate application of a treatment targeted to the population at risk. An anterior cruciate ligament (ACL) injury risk algorithm has been defined that employs field-based techniques in lieu of laboratory-based motion analysis systems to identify athletes with high ACL injury risk landing strategies. The resultant field-based assessment techniques, in combination with the developed prediction algorithm, allow for low-cost identification of athletes who may be at increased risk of sustaining ACL injury. The combined simplicity and accuracy of the field-based tool facilitate its use to identify specific factors that may increase risk of injury in female athletes. The purpose of this report is to demonstrate novel algorithmic techniques to accurately capture and analyze measures of knee valgus motion, knee flexion range of motion, body mass, tibia length and quadriceps to hamstrings ratio with video analysis software typically used by coaches, strength and conditioning specialists, and athletic trainers. The field-based measurements and software analyses were used in a prediction algorithm to identify those at potential risk of noncontact ACL injury that may directly benefit from neuromuscular training.     

An integrated approach to epitope analysis II: A system for proteomic-scale prediction of immunological characteristics

Background

Improving our understanding of the immune response is fundamental to developing strategies to combat a wide range of diseases. We describe an integrated epitope analysis system which is based on principal component analysis of sequences of amino acids, using a multilayer perceptron neural net to conduct QSAR regression predictions for peptide binding affinities to 35 MHC-I and 14 MHC-II alleles.

Results

The approach described allows rapid processing of single proteins, entire proteomes or subsets thereof, as well as multiple strains of the same organism. It enables consideration of the interface of diversity of both microorganisms and of host immunogenetics. Patterns of binding affinity are linked to topological features, such as extracellular or intramembrane location, and integrated into a graphical display which facilitates conceptual understanding of the interplay of B-cell and T-cell mediated immunity. Patterns which emerge from application of this approach include the correlations between peptides showing high affinity binding to MHC-I and to MHC-II, and also with predicted B-cell epitopes. These are characterized as coincident epitope groups (CEGs). Also evident are long range patterns across proteins which identify regions of high affinity binding for a permuted population of diverse and heterozygous HLA alleles, as well as subtle differences in reactions with MHCs of individual HLA alleles, which may be important in disease susceptibility, and in vaccine and clinical trial design. Comparisons are shown of predicted epitope mapping derived from application of the QSAR approach with experimentally derived epitope maps from a diverse multi-species dataset, from Staphylococcus aureus, and from vaccinia virus.

Conclusions

A desktop application with interactive graphic capability is shown to be a useful platform for development of prediction and visualization tools for epitope mapping at scales ranging from individual proteins to proteomes from multiple strains of an organism. The possible functional implications of the patterns of peptide epitopes observed are discussed, including their implications for B-cell and T-cell cooperation and cross presentation.     

A dynamic assessment of water scarcity risk in the Lower Brahmaputra River Basin: An integrated approach

Many international river basins are likely to experience increasing water scarcity over the coming decades. This water scarcity is not rooted only in the limitation of resources, i.e. the shortage in the availability of freshwater relative to water demand, but also on social factors (e.g. flawed water planning and management approaches, institutional incapability to provide water services, unsustainable economic policies). Therefore, the assessment of water scarcity risks is not limited to the assessment of physical water supply and demand, but it requires also consideration of several socio-economic factors. In this study, we provide a comprehensive dynamic assessment of water scarcity risks for the Lower Brahmaputra river basin, a region where the hydrological impact of climate change is expected to be particularly strong and population pressure is high. The basin area of Brahmaputra River lies among four different countries: China, India, Bangladesh and Bhutan. For water scarcity assessment, we propose a novel integration of different approaches: (i) the assessment of water scarcity risk, considering complex social-ecological system; (ii) the analysis of dynamic behaviour of the system; (iii) exploration of participatory approach in which limited number of stakeholders identify the most relevant issues with reference to water scarcity risks and provide their preferences for the aggregation of risk assessment indicators. Results show that water scarcity risk is expected to slightly increase and to fluctuate remarkably as a function of the hazard signal. Social indicators show trends that can at least partially compensate the increasing trend of the drought index. The results of this study are intended to be used for contributing to planned adaptation of water resources systems, in Lower Brahmaputra River Basin.     

An integrated approach to taphonomy and faunal change in the Shungura formation (Ethiopia) and its implication for hominid evolution

Environmental and faunal changes through time have been recorded for many African Plio-Pleistocene sites. Fossil evidence suggests that there is a continuous, if not uniform, transformation of the fauna and flora from the Pliocene through the end of Pleistocene. However, discerning major biotic turnovers and linking them to global and regional climatic changes have been complicated by many factors, notably taphonomy and discontinuity of the fossil evidence, notwithstanding the considerable work of some researchers (e.g., Vrba, E.S., 1988. Late Pliocene climatic events and hominid evolution, in: Grine, F. (Ed.), Evolutionary History of the "Robust" Australopithecines. De Gruyter, New York, pp. 405-426, Vrba, E.S., 1995. The fossil record of African (Mammalia, Bovidae) in relation to human evolution and paleoclimate, in: Vrba, E.S., Denton, G.H., Partridge, T.C., Burkle, L.H. (Eds.), Paleoclimate and Evolution, with Emphasis on Human Origins. Yale University Press, New Haven, pp. 385-424). A sample of over 22,000 fossils collected by the French Omo Expedition, from the Shungura Formation of Ethiopia, was analyzed using an integrated approach to investigate taphonomic and faunal change patterns. The following results are obtained: (1) Univariate and multivariate studies support continuous faunal change from Member A through Member G of the Shungura sequence; (2) Correspondence analysis (CA) on extant bovids in African game parks shows that bovid tribes and genera are generally characterized by habitat specificity; (3) Taphonomic studies demonstrate that the relative abundance of different skeletal elements varies according to depositional environment; (4) CA on 73 localities of the Shungura Formation and 19 mammalian taxa points to a major faunal change around the base of Member G dated to ca. 2.3 Ma. This transformation is characterized by a change to open and edaphic grassland as a dominant type of environment; (5) This major faunal change correlates in time with the appearance of A. boisei. It is tentatively suggested that this major biome change is associated with an anagenetic speciation from A. aethiopicus to A. boisei.     

An integrated risk assessment for climate change: analysing the vulnerability of sharks and rays on Australia's Great Barrier Reef

An Integrated Risk Assessment for Climate Change (IRACC) is developed and applied to assess the vulnerability of sharks and rays on Australia's Great Barrier Reef (GBR) to climate change. The IRACC merges a traditional climate change vulnerability framework with approaches from fisheries ecological risk assessments. This semi‐quantitative assessment accommodates uncertainty and can be applied at different spatial and temporal scales to identify exposure factors, at‐risk species and their key biological and ecological attributes, critical habitats a`nd ecological processes, and major knowledge gaps. Consequently, the IRACC can provide a foundation upon which to develop climate change response strategies. Here, we describe the assessment process, demonstrate its application to GBR shark and ray species, and explore the issues affecting their vulnerability to climate change. The assessment indicates that for the GBR, freshwater/estuarine and reef associated sharks and rays are most vulnerable to climate change, and that vulnerability is driven by case‐specific interactions of multiple factors and species attributes. Changes in temperature, freshwater input and ocean circulation will have the most widespread effects on these species. Although relatively few GBR sharks and rays were assessed as highly vulnerable, their vulnerability increases when synergies with other factors are considered. This is especially true for freshwater/estuarine and coastal/inshore sharks and rays. Reducing the impacts of climate change on the GBR's sharks and rays requires a range of approaches including mitigating climate change and addressing habitat degradation and sustainability issues. Species‐specific conservation actions may be required for higher risk species (e.g. the freshwater whipray, porcupine ray, speartooth shark and sawfishes) including reducing mortality, preserving coastal catchments and estuarine habitats, and addressing fisheries sustainability. The assessment identified many knowledge gaps concerning GBR habitats and processes, and highlights the need for improved understanding of the biology and ecology of the sharks and rays of the GBR.     

Cellular assay optimization: part II: the use of a simple integrated robotic work cell to allow the multiplexed batching of cellular assays

This report describes the implementation of an automated work cell with commercially available hardware and software, capable of handling up to 15 separate reagents for performing 96-well or 384-well assays but with a small footprint and only a single liquid dispenser and two plate washers. Extremely flexible software was used to enable this simple work cell to perform processes that would traditionally require a much larger, more expensive automation platform. With the development of the C-Myc assays for the targets DYRK, BMX, PERK, and FAK, the authors describe a software solution to multibatch assays to run simultaneously, reducing reagent dead volume and increasing the efficiency of running multiple assays such that the time to generate data across multiple targets was significantly shortened. Although a larger automated system with multiple robotic arms and extensive equipment would also be able to process multiple assays simultaneously, the work cell we have described represents an inexpensive and flexible, easily upgradable option suitable for a wider range of labs.     

Mapping protein cysteine sulfonic acid modifications with specific enrichment and mass spectrometry: An integrated approach to explore the cysteine oxidation

Oxidation of thiol proteins, which results in conversion of cysteine residues to cysteine sulfenic, sulfinic or sulfonic acids, is an important posttranslational control of protein function in cells. To facilitate the analysis of this process with MALDI‐MS, we have developed a method for selective enrichment and identification of peptides containing cysteine sulfonic acid (sulfopeptides) in tryptic digests of proteins based on ionic affinity capture using polyarginine‐coated nanodiamonds as high‐affinity probes. The method was applied to selectively concentrate sulfopeptides from either a highly dilute solution or a complex peptide mixture in which the abundance of the sulfonated analyte is as low as 0.02%. The polyarginine‐coated probes exhibit a higher affinity for peptides containing multiple sulfonic acids than peptides containing single sulfonic acid. The limit of the detection is in the femtomole range, with the MALDI‐TOF mass spectrometer operating in the negative ion mode. The results show that the new approach has good specificity even in the presence of phosphopeptides. An application of this method for selective enrichment and structural identification of sulfopeptides is demonstrated with the tryptic digests of performic‐acid‐oxidized BSA.     

An approach to the modeling of the tolerance mechanism in the drug effect. II: On the implications of compensatory regulation

In the previous paper (Peper et al., 1987: J. theor. Biol. 127, 413), a model of drug tolerance was developed based on the assumption that the decrease of drug effect after repeated administration of a drug is caused by the involved regulations in the organism adapting themselves to the presence of the drug. In the present paper, the behaviour of the model is studied with respect to the dose-response relation, the drug effect in dependent and non-dependent subjects and withdrawal symptoms. Computer simulations demonstrate the model to be highly sensitive to sudden changes of drug dose. Dependent on the open loop gain of the adaptive mechanism, a sudden decrease of drug dose might result in an effect opposite to the common drug effect. In the model, the rate of decrease of drug dose necessary for optimal drug withdrawal appears to be determined by the same mechanism as the rate of increase of dose necessary for a constant effect at the commencement of treatment. The behaviour of the model suggests the degree of drug dependence in an addicted subject to depend on the extent to which non-somatic factors are involved in the process of initiation of the adaptive mechanisms.     

An integrated approach to diagnosis and management of severe haemoptysis in patients admitted to the intensive care unit: a case series from a referral centre

Background

Limited data are available concerning patients admitted to the intensive care unit (ICU) for severe haemoptysis. We reviewed a large series of patients managed in a uniform way to describe the clinical spectrum and outcome of haemoptysis in this setting, and better define the indications for bronchial artery embolisation (BAE).

Methods

A retrospective chart review of 196 patients referred for severe haemoptysis to a respiratory intermediate care ward and ICU between January 1999 and December 2001. A follow-up by telephone interview or a visit.

Results

Patients (148 males) were aged 51 (± sd, 16) years, with a median cumulated amount of bleeding averaging 200 ml on admission. Bronchiectasis, lung cancer, tuberculosis and mycetoma were the main underlying causes. In 21 patients (11%), no cause was identified. A first-line bronchial arteriography was attempted in 147 patients (75%), whereas 46 (23%) received conservative treatment. Patients who underwent BAE had a higher respiratory rate, greater amount of bleeding, persistent bloody sputum and/or evidence of active bleeding on fiberoptic bronchoscopy. When completed (n = 131/147), BAE controlled haemoptysis in 80% of patients, both in the short and long (> 30 days) terms. Surgery was mostly performed when bronchial arteriography had failed and/or bleeding recurred early after completed BAE. Bleeding was controlled by conservative measures alone in 44 patients. The ICU mortality rate was low (4%).

Conclusion

Patients with evidence of more severe or persistent haemoptysis were more likely to receive BAE rather than conservative management. The procedure was effective and safe in most patients with severe haemoptysis, and surgery was mostly reserved to failure of arteriography and/or early recurrences after BAE.     

Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy: part II: the early evidence linking hypercholesterolemia to coronary disease in humans

The first in this series of historical reviews dealt with the pioneering animal model work of Anitschkow, implicating blood cholesterol in the pathogenesis of atherosclerosis, and the pivotally important work of Gofman, providing evidence that lipoprotein-bound cholesterol was a major factor in the human disease. This second installment reviews the early lines of evidence linking hypercholesterolemia in humans to the progression of atherosclerosis and the risk of coronary heart disease. The argument is made that by 1970, the evidence was already strong enough to justify intervention to lower blood cholesterol levels if all the available lines of evidence had been taken into account. Yet, it would be almost two decades before lowering blood cholesterol levels became a national public health goal. Some of the reasons the "cholesterol controversy" continued in the face of powerful evidence supporting intervention are discussed.     

An integrated approach to the analysis and modeling of protein sequences and structures. II. On the relationship between sequence and structural similarity for proteins that are not obviously related in sequence

Here, we discuss the relationship between protein sequence and protein structural similarity. It is established that a protein structural distance (PSD) of 2.0 is a threshold above which two proteins are unlikely to have a detectable pairwise sequence relationship. A precise correlation is established between the level of sequence similarity, defined by a normalized Smith-Waterman score, and the probability that two proteins will have a similar structure (defined by pairwise PSD<2). This correlation can be used in evaluating the likelihood for success in a comparative modeling procedure. We establish the existence of a correlation between sequence and structural similarity for pairs of proteins that are related in structure but whose sequence relationship is not detectable using standard pairwise sequence alignments. Although it is well known that there is a close relationship between sequence and structural similarity for pairwise sequence identities greater than about 30 %, there has been little discussion as to the possible existence of such a relationship for pairs of proteins in or below the twilight zone of sequence similarity (<25 % pairwise sequence identity). Possible implications of our results for the evolution of protein structure are discussed.     

An integrated metabolic modeling approach to describe the energy efficiency of Escherichia coli fermentations under oxygen-limited conditions: Cellular energetics, carbon flux, and acetate production

An integrated metabolic model for the production of acetate by growing Escherichia coli on glucose under aerobic conditions is presented. The model is based on parameters which are easily determined by experiments. Forming the basis for this integrated metabolic model are the 12 principal precursor metabolites for biosynthetic pathways, the Embden-Meyerhof-Parnas pathway, the pentose phosphate cycle, the tricarboxylic acid cycle and the anapleurotic reactions, the Crabtree effect, the Pasteur effect, and the details of bacterial respiration. The result can be used to explain phenomena often observed in industrial fermentations, i.e., increased acetate production which follows from high glucose uptake rate, a low oxygen concentration, a high specific growth rate, or a combination of these conditions. (c) 1993 John Wiley & Sons, Inc.     

Morphology of cell injury: An approach to the EDIT programme by the use of tobacco pollen tubes. Evaluation-guided Development of New In Vitro Test Batteries

Tobacco pollen tubes were used as a standard in vitro system to investigate cell growth aberrations caused by some of the Multicentre Evaluation of In Vitro Cytotoxicity (MEIC) programme chemicals and other toxic compounds. Changes in cytoskeletal pattern were observed in the tube cells by using tubulin immunofluorescence and rhodamin-phalloidin fluorescence for the localisation of microtubules and actin filaments, respectively. Four different types of cell malformation were found: screw-like growth, isodiametric tip swelling, hook formation, and pollen grain enlargement. We suggest that these malformations resulted from an interference by the chemicals with the cytosolic calcium gradient which controls tip growth and the orientation of the pollen tube. The results may contribute to a general understanding of toxicity-based cell malformations.     

An integrated morphological and molecular approach to a new species description in the Trypanosomatidae: the case of Leptomonas podlipaevi n. sp., a parasite of Boisea rubrolineata (Hemiptera: Rhopalidae)

Leptomonas podlipaevi n. sp., a new trypanosomatid species, is described herein based on light microscopic, ultrastructural, and molecular phylogenetic data. The organism is pleomorphic both in host and culture, with two predominant forms-a typical promastigote with a long flagellum and a shorter promastigote with a small or barely extending flagellum. Several spliced leader RNA repeat sequences obtained from the original cultures and the clonal lines representing two types of cells were all nearly identical. These sequences formed a tight cluster in the neighbor-joining tree well separated from other trypanosomatid species. Glyceraldehyde phosphate dehydrogenase gene sequences were determined for L. podlipaevi and 10 previously described trypanosomatid species. Molecular phylogenetic analysis has demonstrated that the new species is most closely related to Leptomonas seymouri and Leptomonas pyrrhocoris. The analysis has also highlighted the polyphyly of the genus Leptomonas.