Virtual communities as an organizational mechanism for embedding knowledge in drug discovery:the case of chemical biology plattform

In this paper, we document the lessons from the development of chemical biology platform in a major pharmaceutical company, and the outcomes of the early phases of this experiment. Although the concept of chemical biology is not new, its evolution and deployment in the drug development process is relatively new. The present experiment thus has to deal with both the scientific novelty of chemical biology, and organizational challenge of embedding it in the ongoing process of drug development. The notion of virtual communities or platforms overlaid on the traditional matrix of drug development served to introduce the approach, with some remarkable outcomes

Dose delivery accuracy on helical tomotherapy for 4-dimensional tumor motion — a phantom study

BACKGROUND: The advances in image guidance and capability of highly conformal dose deliveries made possible the use of helical tomotherapy (HT) for lung cancer treatment. To determine the effect of respiratory motion on the delivered dose in HT, film dosimetry using a dynamic phantom was performed. This was a phantom study to determine the effect of motion on the delivered dose in HT. MATERIALS AND METHODS: 4D computed tomography (4DCT) was acquired for various target motions of CIRS dynamic phantom (CIRS Inc., Norfolk, USA) with 2.5cm diameter spherical target of volume 8.2 cc moving in the COS4 motion pattern. AveIP images and treatment plans were generated in the HT planning system. Target excursions during treatment delivery were changed in the superior-inferior, anteroposterior and lateral directions. The breathing cycle time was varied from 4 to 5 sec. and also the delivery interruptions were introduced. A film was exposed for each delivery and gamma analysis was performed. RESULTS: The gamma pass rate (GPR) with 3%, 2 mm criteria for the target motion in the S-I direction showed a significant reduction from 97.5% to 54.4% as the motion increased from 3 mm to  8 mm (p = 0.03). For the target motion in S-I = 8 mm, L-R = A-P = 3 mm, the percentage decrease in the GPR was 74% (p = 0.001) for three interruptions. CONCLUSION: The ITV based approach in HT is ideal for a shallow breathing situation when the tumor excursions were confined to 5 mm in the S-I and 3 mm in L-R and A-P directions

Flecainide challenge test: Predictors of unmasking of type 1 Brugada ECG pattern among those with non-type 1 Brugada ECG pattern

AbstractBackgroundMany subjects in community have non-type 1 Brugada pattern ECG with atypical symptoms, relevance of which is not clear. Provocative tests to unmask type 1 Brugada pattern in these patients would help in diagnosing Brugada Syndrome. However sensitivity and specificity of provocating drugs are variable.MethodsWe studied 29 patients referred to our institute with clinical presentation suggestive but not diagnostic of Brugada or with non-Type 1 Brugada pattern ECG. Flecainide Challenge Test (FCT) was done in these patients (IV Flecainide test in 4 patients and Oral Flecainide in 25 patients). Resting 12-lead ECG with standard precordial leads and ECG with precordial leads placed 1 Intercostal space above were performed after flecainide administration every 5 min for first 30 min and every 30 min thereafter until ECG became normal or upto 6 h. The positivity was defined as inducible Type 1 Brugada pattern in atleast 2 right sided leads.ResultMedian age was 35(range = 5–65) years. In 16 (55%) patients the Type 1 Brugada pattern was unmasked. There were no episodes of major AV block, atrial or ventricular tachyarrhythmia. Three groups were considered for analysis: Group 1(n = 9) – FCT Positive among patients with non-type 1 Brugada ECG pattern, Group 2(n = 4) – FCT Negative among the patients with non-type 1 Brugada ECG pattern, and Group 3(n = 7) – FCT Positive among patients with no spontaneous Brugada ECG pattern. Binary logistic regression analysis found that family h/o SCD was predictive of FCT positivity in Group 1 (Odd’s ratio 21, 95% Confidence interval 1.04 to 698.83, p = 0.004).ConclusionOral flecainide is useful and safe for unmasking of Type I Brugada pattern. In our study, among the many variables studied, family history of sudden cardiac death was the only predictor of flecainide test positivity among those with non-Type 1 Brugada pattern

Modelling Effects of Tariff Liberalisation on India’s Key Export Sectors: Analysis of the EU–India Free Trade Agreement

Trade agreements are increasingly being negotiated between developed and emerging economy partners. An example is the EU–India Free Trade Agreement (FTA) for which negotiations began in 2007. There has been a debate on the potential effects of the proposed FTA and how this can impact on India’s key export sectors. Our study addresses this aspect from a global computable general equilibrium (CGE) modelling perspective. Using the Global Trade Analysis Project (GTAP) framework, we analyse trade and welfare impacts of the proposed FTA between the EU and India. Two scenarios are modelled: first, complete and immediate elimination of tariff on all goods traded and second, selective tariff elimination on textiles, wearing apparel and leather goods—products in which India has a comparative advantage. Results under both scenarios show that India enjoys positive welfare effects though there is a possibility of trade diversion. Under scenario 1, India loses due to a negative terms of trade (ToT) effect. Under scenario 2, with selective sectoral liberalisation, gains are mainly concentrated in the textiles, wearing apparel and leather sectors. There is a positive output effect from change in demand for factors of production, suggesting that the proposed FTA could lead to relocation of labour-intensive production to India

Separating the Early Universe from the Late Universe: cosmological parameter estimation beyond the black box

We present a method for measuring the cosmic matter budget without assumptions about speculative Early Universe physics, and for measuring the primordial power spectrum P*(k) non-parametrically, either by combining CMB and LSS information or by using CMB polarization. Our method complements currently fashionable ``black box'' cosmological parameter analysis, constraining cosmological models in a more physically intuitive fashion by mapping measurements of CMB, weak lensing and cluster abundance into k-space, where they can be directly compared with each other and with galaxy and Lyman alpha forest clustering. Including the new CBI results, we find that CMB measurements of P(k) overlap with those from 2dF galaxy clustering by over an order of magnitude in scale, and even overlap with weak lensing measurements. We describe how our approach can be used to raise the ambition level beyond cosmological parameter fitting as data improves, testing rather than assuming the underlying physics.Comment: Replaced to match accepted PRD version. Refs added. Combined CMB data and window functions at http://www.hep.upenn.edu/~max/pwindows.html or from [email protected]. 18 figs, 19 journal page

Measuring the metric: a parametrized post-Friedmanian approach to the cosmic dark energy problem

We argue for a ``parametrized post-Friedmanian'' approach to linear cosmology, where the history of expansion and perturbation growth is measured without assuming that the Einstein Field Equations hold. As an illustration, a model-independent analysis of 92 type Ia supernovae demonstrates that the curve giving the expansion history has the wrong shape to be explained without some form of dark energy or modified gravity. We discuss how upcoming lensing, galaxy clustering, cosmic microwave background and Lyman alpha forest observations can be combined to pursue this program, which generalizes the quest for a dark energy equation of state, and forecast the accuracy that the proposed SNAP satellite can attain.Comment: Replaced to match accepted PRD version. References and another example added, section III omitted since superceded by astro-ph/0207047. 11 PRD pages, 7 figs. Color figs and links at http://www.hep.upenn.edu/~max/gravity.html or from [email protected]

Clustering of dark matter tracers: generalizing bias for the coming era of precision LSS

On very large scales, density fluctuations in the Universe are small, suggesting a perturbative model for large-scale clustering of galaxies (or other dark matter tracers), in which the galaxy density is written as a Taylor series in the local mass density, delta, with the unknown coefficients in the series treated as free "bias" parameters. We extend this model to include dependence of the galaxy density on the local values of nabla_i nabla_j phi and nabla_i v_j, where phi is the potential and v is the peculiar velocity. We show that only two new free parameters are needed to model the power spectrum and bispectrum up to 4th order in the initial density perturbations, once symmetry considerations and equivalences between possible terms are accounted for. One of the new parameters is a bias multiplying s_ij s_ji, where s_ij=[nabla_i nabla_j \nabla^-2 - 1/3 delta^K_ij] delta. The other multiplies s_ij t_ji, where t_ij=[nabla_i nabla_j nabla^-2 - 1/3 delta^K_ij](theta-delta), with theta=-(a H dlnD/dlna)^-1 nabla_i v_i. (There are other, observationally equivalent, ways to write the two terms, e.g., using theta-delta instead of s_ij s_ji.) We show how short-range (non-gravitational) non-locality can be included through a controlled series of higher derivative terms, starting with R^2 nabla^2 delta, where R is the scale of non-locality (this term will be a small correction as long as k^2 R^2 is small, where k is the observed wavenumber). We suggest that there will be much more information in future huge redshift surveys in the range of scales where beyond-linear perturbation theory is both necessary and sufficient than in the fully linear regime.Comment: 24 pg., 5 fi

LiDAR-based reference aboveground biomass maps for tropical forests of South Asia and Central Africa

Accurate mapping and monitoring of tropical forests aboveground biomass (AGB) is crucial to design effective carbon emission reduction strategies and improving our understanding of Earth’s carbon cycle. However, existing large-scale maps of tropical forest AGB generated through combinations of Earth Observation (EO) and forest inventory data show markedly divergent estimates, even after accounting for reported uncertainties. To address this, a network of high-quality reference data is needed to calibrate and validate mapping algorithms. This study aims to generate reference AGB datasets using field inventory plots and airborne LiDAR data for eight sites in Central Africa and five sites in South Asia, two regions largely underrepresented in global reference AGB datasets. The study provides access to these reference AGB maps, including uncertainty maps, at 100 m and 40 m spatial resolutions covering a total LiDAR footprint of 1,11,650 ha [ranging from 150 to 40,000 ha at site level]. These maps serve as calibration/validation datasets to improve the accuracy and reliability of AGB mapping for current and upcoming EO missions (viz., GEDI, BIOMASS, and NISAR)

Measurement of the azimuthal anisotropy of Y(1S) and Y(2S) mesons in PbPb collisions at √S^{S}NN = 5.02 TeV

The second-order Fourier coefficients (υ$_{2}$) characterizing the azimuthal distributions of Υ(1S) and Υ(2S) mesons produced in PbPb collisions at $\sqrt{s_{NN}}$ = 5.02 TeV are studied. The Υmesons are reconstructed in their dimuon decay channel, as measured by the CMS detector. The collected data set corresponds to an integrated luminosity of 1.7 nb$^{-1}$. The scalar product method is used to extract the υ$_{2}$ coefficients of the azimuthal distributions. Results are reported for the rapidity range |y| < 2.4, in the transverse momentum interval 0 < p$_{T}$ < 50 GeV/c, and in three centrality ranges of 10–30%, 30–50% and 50–90%. In contrast to the J/ψ mesons, the measured υ$_{2}$ values for the Υ mesons are found to be consistent with zero