Metabolomics coupled with proteomics advancing drug discovery toward more agile development of targeted combination therapies

To enhance the therapeutic efficacy and reduce the adverse effects of traditional Chinese medicine, practitioners often prescribe combinations of plant species and/or minerals, called formulae. Unfortunately, the working mechanisms of most of these compounds are difficult to determine and thus remain unknown. In an attempt to address the benefits of formulae based on current biomedical approaches, we analyzed the components of Yinchenhao Tang, a classical formula that has been shown to be clinically effective for treating hepatic injury syndrome. The three principal components of Yinchenhao Tang are Artemisia annua L., Gardenia jasminoids Ellis, and Rheum Palmatum L., whose major active ingredients are 6,7-dimethylesculetin (D), geniposide (G), and rhein (R), respectively. To determine the mechanisms underlying the efficacy of this formula, we conducted a systematic analysis of the therapeutic effects of the DGR compound using immunohistochemistry, biochemistry, metabolomics, and proteomics. Here, we report that the DGR combination exerts a more robust therapeutic effect than any one or two of the three individual compounds by hitting multiple targets in a rat model of hepatic injury. Thus, DGR synergistically causes intensified dynamic changes in metabolic biomarkers, regulates molecular networks through target proteins, has a synergistic/additive effect, and activates both intrinsic and extrinsic pathways.

Epistatic effects of potassium channel variation on cardiac repolarization and atrial fibrillation risk

Objectives The aim of this study was to evaluate the role of cardiac K+ channel gene variants in families with atrial fibrillation (AF). Background The K+ channels play a major role in atrial repolarization but single mutations in cardiac K+ channel genes are infrequently present in AF families. The collective effect of background K+ channel variants of varying prevalence and effect size on the atrial substrate for AF is largely unexplored. Methods Genes encoding the major cardiac K+ channels were resequenced in 80 AF probands. Nonsynonymous coding sequence variants identified in AF probands were evaluated in 240 control subjects. Novel variants were characterized using patch-clamp techniques and in silico modeling was performed using the Courtemanche atrial cell model. Results Nineteen nonsynonymous variants in 9 genes were found, including 11 rare variants. Rare variants were more frequent in AF probands (18.8% vs. 4.2%, p < 0.001), and the mean number of variants was greater (0.21 vs. 0.04, p < 0.001). The majority of K+ channel variants individually had modest functional effects. Modeling simulations to evaluate combinations of K+ channel variants of varying population frequency indicated that simultaneous small perturbations of multiple current densities had nonlinear interactions and could result in substantial (>30 ms) shortening or lengthening of action potential duration as well as increased dispersion of repolarization. Conclusions Families with AF show an excess of rare functional K+ channel gene variants of varying phenotypic effect size that may contribute to an atrial arrhythmogenic substrate. Atrial cell modeling is a useful tool to assess epistatic interactions between multiple variants.

Mating compatibility among four pest members of the Bactrocera dorsalis fruit fly species complex (Diptera : Tephritidae)

Bactrocera dorsalis (Hendel), Bactrocera papayae Drew & Hancock, Bactrocera philippinensis Drew & Hancock, and Bactrocera carambolae Drew & Hancock are pest members within the B. dorsalis species complex of tropical fruit flies. The species status of these taxa is unclear and this confounds quarantine, pest management, and general research. Mating studies carried out under uniform experimental conditions are required as part of resolving their species limits. These four taxa were collected from the wild and established as laboratory cultures for which we subsequently determined levels of prezygotic compatibility, assessed by field cage mating trials for all pair-wise combinations. We demonstrate random mating among all pair-wise combinations involving B. dorsalis, B. papayae, and B. philippinensis. B. carambolae was relatively incompatible with each of these species as evidenced by nonrandom mating for all crosses. Reasons for incompatibility involving B. carambolae remain unclear; however, we observed differences in the location of couples in the field cage for some comparisons. Alongside other factors such as pheromone composition or other courtship signals, this may lead to reduced interspecific mating compatibility with B. carambolae. These data add to evidence that B. dorsalis, B. papayae, and B. philippinensis represent the same biological species, while B. carambolae remains sufficiently different to maintain its current taxonomic identity. This poses significant implications for this group's systematics, impacting on pest management, and international trade.

Investigation between the S377G3 GATA-4 polymorphism and migraine

Migraine is a common and painful neurological disorder, with genetic and environmental components. Several conditions have been shown to be comorbid with migraine, notably a cardiac malformation affecting the interatrial septum and leading to patent foramen ovale (PFO). Mutations in the development regulatory gene GATA-4, located on human chromosome 8p23.1-p22, have been found to be responsible for some cases of congenital heart defects including PFO. To determine whether the GATA-4 gene is involved in migraine, the present study performed an association analysis of a common GATA-4 variant that results in a change of amino acid (S377G), in a large case/control population (275 unrelated Caucasian migraineurs versus 275 control individuals). The results showed that there was no significant association for this polymorphism between migraine and controls (χ² = 0.84, P = 0.66). Thus it appears that the GATA-4 (S377G) mutation does not play a significant role in common migraine susceptibility.

Ultimate load behaviour of box-columns under combined loading of axial compression and torsion

This paper describes a study of the theoretical and experimental behaviour of box-columns of varying b/t ratios under loadings of axial compression and torsion and their combinations. Details of the testing rigs and the testing methods, the results obtained such as the load-deflection curves and the interaction diagrams, and experimental observations regarding the behaviour of box-models and the types of local plastic mechanisms associated with each type of loading are presented. A simplified rigid-plastic analysis is carried out to study the collapse behaviour of box-columns under these loadings, based on the observed plastic mechanisms, and the results are compared with those of experiments.

Bricolage as a path to innovativeness for resource constrained new firms

Evidence suggests that both nascent and young firms (henceforth: “new firms”)—despite typically being small and resource-constrained—are sometimes able to innovate effectively. Such firms are seldom able to invest in lengthy and expensive development processes, which suggests that they may frequently rely instead on other pathways to generate innovativeness within the firm. In this paper, we develop and test arguments that “bricolage,” defined as making do by applying combinations of the resources at hand to new problems and opportunities, provides an important pathway to achieve innovation for new resource-constrained firms. Through bricolage, resource-constrained firms engage in the processes of “recombination” that are core to creating innovative outcomes. Based on a large longitudinal dataset, our results suggest that variations in the degree to which firms engage in bricolage behaviors can provide a broadly applicable explanation of innovativeness under resource constraints by new firms. We find no general support for our competing hypothesis that the positive effects may level off or even turn negative at high levels of bricolage..

Towards a model of spray-canopy interactions : interception, shatter, bounce and retention of droplets on horizontal leaves

Pesticides used in agricultural systems must be applied in economically viable and environmentally sensitive ways, and this often requires expensive field trials on spray deposition and retention by plant foliage. Computational models to describe whether a spray droplet sticks (adheres), bounces or shatters on impact, and if any rebounding parent or shatter daughter droplets are recaptured, would provide an estimate of spray retention and thereby act as a useful guide prior to any field trials. Parameter-driven interactive software has been implemented to enable the end-user to study and visualise droplet interception and impaction on a single, horizontal leaf. Living chenopodium, wheat and cotton leaves have been scanned to capture the surface topography and realistic virtual leaf surface models have been generated. Individual leaf models have then been subjected to virtual spray droplets and predictions made of droplet interception with the virtual plant leaf. Thereafter, the impaction behaviour of the droplets and the subsequent behaviour of any daughter droplets, up until re-capture, are simulated to give the predicted total spray retention by the leaf. A series of critical thresholds for the stick, bounce, and shatter elements in the impaction process have been developed for different combinations of formulation, droplet size and velocity, and leaf surface characteristics to provide this output. The results show that droplet properties, spray formulations and leaf surface characteristics all influence the predicted amount of spray retained on a horizontal leaf surface. Overall the predicted spray retention increases as formulation surface tension, static contact angle, droplet size and velocity decreases. Predicted retention on cotton is much higher than on chenopodium. The average predicted retention on a single horizontal leaf across all droplet size, velocity and formulations scenarios tested, is 18, 30 and 85% for chenopodium, wheat and cotton, respectively.

Sequential decision fusion of multibiometrics applied to text-dependent speaker verification for controlled errors

Reliability of the performance of biometric identity verification systems remains a significant challenge. Individual biometric samples of the same person (identity class) are not identical at each presentation and performance degradation arises from intra-class variability and inter-class similarity. These limitations lead to false accepts and false rejects that are dependent. It is therefore difficult to reduce the rate of one type of error without increasing the other. The focus of this dissertation is to investigate a method based on classifier fusion techniques to better control the trade-off between the verification errors using text-dependent speaker verification as the test platform. A sequential classifier fusion architecture that integrates multi-instance and multisample fusion schemes is proposed. This fusion method enables a controlled trade-off between false alarms and false rejects. For statistically independent classifier decisions, analytical expressions for each type of verification error are derived using base classifier performances. As this assumption may not be always valid, these expressions are modified to incorporate the correlation between statistically dependent decisions from clients and impostors. The architecture is empirically evaluated by applying the proposed architecture for text dependent speaker verification using the Hidden Markov Model based digit dependent speaker models in each stage with multiple attempts for each digit utterance. The trade-off between the verification errors is controlled using the parameters, number of decision stages (instances) and the number of attempts at each decision stage (samples), fine-tuned on evaluation/tune set. The statistical validation of the derived expressions for error estimates is evaluated on test data. The performance of the sequential method is further demonstrated to depend on the order of the combination of digits (instances) and the nature of repetitive attempts (samples). The false rejection and false acceptance rates for proposed fusion are estimated using the base classifier performances, the variance in correlation between classifier decisions and the sequence of classifiers with favourable dependence selected using the 'Sequential Error Ratio' criteria. The error rates are better estimated by incorporating user-dependent (such as speaker-dependent thresholds and speaker-specific digit combinations) and class-dependent (such as clientimpostor dependent favourable combinations and class-error based threshold estimation) information. The proposed architecture is desirable in most of the speaker verification applications such as remote authentication, telephone and internet shopping applications. The tuning of parameters - the number of instances and samples - serve both the security and user convenience requirements of speaker-specific verification. The architecture investigated here is applicable to verification using other biometric modalities such as handwriting, fingerprints and key strokes.

Bridging the biology of the ovine TRALI model – human inflammatory cell responses to TRALI inducing supernatants

Background Transfusion-related acute lung injury (TRALI) is a serious and potentially fatal consequence of transfusion. A two-event TRALI model demonstrated date-of-expiry - day (D) 5 platelet (PLT) and D42 packed red blood cell (PRBC) supernatants (SN) induced TRALI in LPS-treated sheep. We have adapted a whole blood transfusion culture model as an investigative bridge between the ovine TRALI model human responses to transfusion. Methods A whole blood transfusion model was adapted to replicate the ovine model - specifically +/- 0.23μg/mL LPS as the first event and 10% SN volume (transfusion) as the second event. Four pooled SN from blood products, previously used in the TRALI ovine model, were investigated: D1-PLT, D5-PLT, D1-PRBC, and D42-PRBC. Fresh human whole blood (recipient) was mixed with combinations of LPS and BP-SN stimuli and incubated in vitro for 6 hrs. Addition of golgi plug enabled measurement of monocyte cytokine production (IL-6, IL-8, IL-10, IL-12, TNF-α, IL-1α, CXCL-5, IP-10, MIP-1α, MCP-1) using multi-colour flow cytometry. Responses for 6 recipients were assessed. Results In the presence of LPS, D42-PRBC-SN significantly increased monocyte IL-6 (P=0.031), IL-8 (P=0.016) and IL-1α (P=0.008) production compared to D1-PRBC-SN. This response to D42-PRBC-SN was LPS-dependent, and was not evident in non-LPSstimulated controls. This response was also specific to D42-PRBC-SN, as similar changes were not evident for the D5-PLT-SN, compared to the D1-PLT-SN, regardless of the presence of LPS. D5-PLT-SN significantly increased IL-12 production (P=0.024) compared to D1-PLT-SN. This response was again LPS-dependent. Conclusions These data demonstrate a novel two-event mechanism of monocyte inflammatory response that was dependent upon both the presence of date-of-expiry blood product SN and LPS. Further, these results demonstrate different cytokines responses induced by date-of-expiry PLT-SN and PRBC-SN. These data are consistent with the evidence from the ovine TRALI model, and enhancing its relevance to transfusion related changes in humans.

Prevalence, trends and associated socio-economic factors of obesity in South Asia

Aim Worldwide obesity levels have increased unprecedentedly over the past couple of decades. Although the prevalence, trends and associated socio-economic factors of the condition have been extensively reported in Western populations, less is known regarding South Asian populations. Methods A review of articles using Medline with combinations of the MeSH terms: 'Obesity', 'Overweight' and 'Abdominal Obesity' limiting to epidemiology and South Asian countries. Results Despite methodological heterogeneity and variation according to country, area of residence and gender , the most recent nationally representative and large regional data demonstrates that without any doubt there is a epidemic of obesity, overweight and abdominal obesity in South Asian countries. Prevalence estimates of overweight and obesity (based on Asian cut-offs: overweight ≥ 23 kg/m(2), obesity ≥ 25 kg/m(2)) ranged from 3.5% in rural Bangladesh to over 65% in the Maldives. Abdominal obesity was more prevalent than general obesity in both sexes in this ethnic group. Countries with the lowest prevalence had the highest upward trend of obesity. Socio-economic factors associated with greater obesity in the region included female gender, middle age, urban residence, higher educational and economic status. Conclusion South Asia is significantly affected by the obesity epidemic. Collaborative public health interventions to reverse these trends need to be mindful of many socio-economic constraints in order to provide long-term solutions.

From science to management : using Bayesian networks to learn about Lyngbya

Toxic blooms of Lyngbya majuscula occur in coastal areas worldwide and have major ecological, health and economic consequences. The exact causes and combinations of factors which lead to these blooms are not clearly understood. Lyngbya experts and stakeholders are a particularly diverse group, including ecologists, scientists, state and local government representatives, community organisations, catchment industry groups and local fishermen. An integrated Bayesian Network approach was developed to better understand and model this complex environmental problem, identify knowledge gaps, prioritise future research and evaluate management options.

Traffic safety risks trends and patterns analysis on motorways

Crashes that occur on motorways contribute to a significant proportion (40-50%) of non-recurrent motorway congestion. Hence, reducing the frequency of crashes assist in addressing congestion issues (Meyer, 2008). Analysing traffic conditions and discovering risky traffic trends and patterns are essential basics in crash likelihood estimations studies and still require more attention and investigation. In this paper we will show, through data mining techniques, that there is a relationship between pre-crash traffic flow patterns and crash occurrence on motorways, compare them with normal traffic trends, and that this knowledge has the potentiality to improve the accuracy of existing crash likelihood estimation models, and opens the path for new development approaches. The data for the analysis was extracted from records collected between 2007 and 2009 on the Shibuya and Shinjuku lines of the Tokyo Metropolitan Expressway in Japan. The dataset includes a total of 824 rear-end and sideswipe crashes that have been matched with crashes corresponding traffic flow data using an incident detection algorithm. Traffic trends (traffic speed time series) revealed that crashes can be clustered with regards to the dominant traffic patterns prior to the crash occurrence. K-Means clustering algorithm applied to determine dominant pre-crash traffic patterns. In the first phase of this research, traffic regimes identified by analysing crashes and normal traffic situations using half an hour speed in upstream locations of crashes. Then, the second phase investigated the different combination of speed risk indicators to distinguish crashes from normal traffic situations more precisely. Five major trends have been found in the first phase of this paper for both high risk and normal conditions. The study discovered traffic regimes had differences in the speed trends. Moreover, the second phase explains that spatiotemporal difference of speed is a better risk indicator among different combinations of speed related risk indicators. Based on these findings, crash likelihood estimation models can be fine-tuned to increase accuracy of estimations and minimize false alarms.

Indirect message injection for MAC generation

This paper presents a model for the generation of a MAC tag using a stream cipher. The input message is used indirectly to control segments of the keystream that form the MAC tag. Several recent proposals can be considered as instances of this general model, as they all perform message accumulation in this way. However, they use slightly different processes in the message preparation and finalisation phases. We examine the security of this model for different options and against different types of attack, and conclude that the indirect injection model can be used to generate MAC tags securely for certain combinations of options. Careful consideration is required at the design stage to avoid combinations of options that result in susceptibility to forgery attacks. Additionally, some implementations may be vulnerable to side-channel attacks if used in Authenticated Encryption (AE) algorithms. We give design recommendations to provide resistance to these attacks for proposals following this model.

Through-focus performance with multifocal contact lenses : effect of binocularity, pupil diameter and inherent ocular aberrations

Purpose to evaluate the effects of the wearer’s pupil size and spherical aberration on visual performance with centre-near, aspheric multifocal contact lenses (MFCLs). The advantage of binocular over monocular vision was also investigated. Methods Twelve young volunteers, with an average age of 27±5 years, participated in the study. LogMAR Visual Acuity (VA) was measured under cycloplegia for a range of defocus levels (from +3.0 to -3.0D, in 0.5D steps) with no correction and with three aspheric MFCLs (Air Optix Aqua Multifocal, Ciba Vision, Duluth, GA, US) with a centre-near design, providing correction for “Low”, “Med” and “High” near demands. Measurements were performed for all combinations of the following conditions: i) artificial pupils of 6mm and 3mm diameter, ii) binocular and monocular (dominant eye) vision. Depth-of-focus (DOF) was calculated from the VA vs. defocus curves. Ocular aberrations under cycloplegia were measured using iTrace. Results VA at -3.0D defocus (simulating near performance) was statistically higher for the 3mm than for the 6mm pupil (p=0.006), and for binocular rather than for monocular vision (p<0.001). Similarly, DOF was better for the 3mm pupil (p=0.002) and for binocular viewing conditions (p<0.001, ANOVA). Both VA at –3.0D defocus and DOF increased as the “addition” of the MFCL correction increased. Finally, with the centre-near MFCLs a linear correlation was found between VA at –3.0D defocus and the wearer’s ocular spherical aberration (R2=0.20 p<0.001 for 6mm data), with the eyes exhibiting the higher positive spherical aberration experiencing lower VAs. By contrast, no correlation was found between VA and spherical aberration at 0.00D defocus (distance vision). Conclusions Both near VA and depth-of-focus improve with these MFCLs, with the effects being more pronounced for small pupils and binocular than for monocular vision. Coupling of the wearer’s ocular spherical aberration with the aberration profiles provided by MFCLs affects their functionality.

Platinum-based chemotherapy in metastatic breast cancer : current status

Cisplatin and carboplatin are active in previously untreated patients with metastatic breast cancer (MBC) with mean response rates (RRs) of 50 and 32%, respectively. In pretreated patients the RR to cisplatin/carboplatin monotherapy declines markedly to <10%. Cisplatin and carboplatin have been combined with many other cytotoxics. In first-line setting high activity has been observed in combination with taxanes or vinorelbine (RRs consistently ∼60%). It appears that these newer combinations are superior to older regimens with etoposide (RRs 30 to 50%) or 5-fluorouracil (RRs 40 to 60%). Cisplatin-/carboplatin-based regimens with infusional 5-FU and epirubicin/paclitaxel/vinorelbine achieve high RRs of around 60 to 80%. However these regimens are difficult to administer in all patients because they require central venous access for continuous 5-FU infusion. In pretreated MBC the combinations of cisplatin-taxane/vinorelbine/gemcitabine or carboplatin-docetaxel/vinorelbine yield RRs of 40 to 50%, which are higher than those achieved with platinum-etoposide/5-FU. In locally advanced disease cisplatin-based regimens achieve very high RRs (>80%). This would suggest that in chemotherapy-naïve patients platinum-based therapy might have an important role to play. Additionally the synergy demonstrated between platinum compounds, taxanes and herceptin, in preclinical and clinical studies is of immense importance and the results of the two ongoing Breast Cancer International Research Group randomized phase III studies are eagerly awaited. These studies may help clarify the role of platinum compounds in the treatment of metastatic and possibly early breast cancer. © 2003 Elsevier Ltd. All rights reserved.