CDEK: Clinical Drug Experience Knowledgebase

The Clinical Drug Experience Knowledgebase (CDEK) is a database and web platform of active pharmaceutical ingredients with evidence of clinical testing as well as the organizations involved in their research and development. CDEK was curated by disambiguating intervention and organization names from ClinicalTrials.gov and cross-referencing these entries with other prominent drug databases. Approximately 43% of active pharmaceutical ingredients in the CDEK database were sourced from ClinicalTrials.gov and cannot be found in any other prominent compound-oriented database. The contents of CDEK are structured around three pillars: active pharmaceutical ingredients (n = 22 292), clinical trials (n = 127 223) and organizations (n = 24 728). The envisioned use of the CDEK is to support the investigation of many aspects of drug development, including discovery, repurposing opportunities, chemo- and bio-informatics, clinical and translational research and regulatory sciences

Fundamental limits to performance of quantum well infrared detectors

Radiometric, density of states (material), and thermal considerations are used to obtain the figure of merit of the quantum-well GaAs/GaAlAs infrared detectors described by Smith et. al. The results are compared with HgCdTe, the present industry standard, as well as with recent experiments at other laboratories

Rho-stimulated Contractility Contributes to the Fibroblastic Phenotype of Ras-transformed Epithelial Cells

Oncogenic transformation of cells alters their morphology, cytoskeletal organization, and adhesive interactions. When the mammary epithelial cell line MCF10A is transformed by activated H-Ras, the cells display a mesenchymal/fibroblastic morphology with decreased cell–cell junctions but increased focal adhesions and stress fibers. We have investigated whether the transformed phenotype is due to Rho activation. The Ras-transformed MCF10A cells have elevated levels of myosin light chain phosphorylation and are more contractile than their normal counterparts, consistent with the activation of Rho. Furthermore, inhibitors of contractility restore a more normal epithelial phenotype to the Ras-transformed MCF10A cells. However, inhibiting Rho by microinjection of C3 exotransferase or dominant negative RhoA only partially restores the normal phenotype, in that it fails to restore normal junctional organization. This result prompted us to examine the effect that inhibiting Rho would have on the junctions of normal MCF10A cells. We have found that inhibiting Rho by C3 microinjection leads to a disruption of E-cadherin cytoskeletal links in adherens junctions and blocks the assembly of new adherens junctions. The introduction of constitutively active Rho into normal MCF10A cells did not mimic the Ras-transformed phenotype. Thus, these results lead us to conclude that some, but not all, characteristics of Ras-transformed epithelial cells are due to activated Rho. Whereas Rho is needed for the assembly of adherens junctions, high levels of activated Rho in Ras-transformed cells contribute to their altered cytoskeletal organization. However, additional events triggered by Ras must also be required for the disruption of adherens junctions and the full development of the transformed epithelial phenotype

Identification of novel host-oriented targets for Human Immunodeficiency Virus type 1 using Random Homozygous Gene Perturbation

<p>Abstract</p> <p>Background</p> <p>Human Immunodeficiency Virus (HIV) is a global threat to public health. Current therapies that directly target the virus often are rendered ineffective due to the emergence of drug-resistant viral variants. An emerging concept to combat drug resistance is the idea of targeting host mechanisms that are essential for the propagation of the virus, but have a minimal cellular effect.</p> <p>Results</p> <p>Herein, using Random Homozygous Gene Perturbation (RHGP), we have identified cellular targets that allow human MT4 cells to survive otherwise lethal infection by a wild type HIV-1_NL4-3. These gene targets were validated by the reversibility of the RHGP technology, which confirmed that the RHGP itself was responsible for the resistance to HIV-1 infection. We further confirmed by siRNA knockdowns that the RHGP-identified cellular pathways are responsible for resistance to infection by either CXCR4 or CCR5 tropic HIV-1 variants. We also demonstrated that cell clones with these gene targets disrupted by RHGP were not permissible to the replication of a drug resistant HIV-1 mutant.</p> <p>Conclusion</p> <p>These studies demonstrate the power of RHGP to identify novel host targets that are essential for the viral life cycle but which can be safely perturbed without overt cytotoxicity. These findings suggest opportunities for the future development of host-oriented therapeutics with the broad spectrum potential for safe and effective inhibition of HIV infection.</p

Tyrosine phosphorylation regulates the adhesions of ras-transformed breast epithelia

Transformed epithelial cells often are characterized by a fibroblastic or mesenchymal morphology. These cells exhibit altered cell-cell and cell-substrate interactions. Here we have identified changes in the adhesions and cytoskeletal interactions of transformed epithelial cells that contribute to their altered morphology. Using MCF-10A human breast epithelial cells as a model system, we have found that transformation by an activated form of ras is characterized by less developed adherens- type junctions between cells but increased focal adhesions. Contributing to the modified adherens junctions of the transformed cells are decreased interactions among beta-catenin, E-cadherin, and the actin cytoskeleton. The ras-transformed cells reveal elevated phosphotyrosine in many proteins, including beta-catenin and p120 Cas. Whereas in the normal cells beta-catenin is found in association with E- cadherin, p120 Cas is not. In the ras-transformed cells, the situation is reversed; tyrosine-phosphorylated p120 Cas, but not tyrosine- phosphorylated beta-catenin, now is detected in E-cadherin complexes. The tyrosine-phosphorylated beta-catenin also shows increased detergent solubility, suggesting a decreased association with the actin cytoskeleton. p120 Cas, whether tyrosine phosphorylated or not, partitions into the detergent soluble fraction, suggesting that it is not tightly bound to the actin cytoskeleton in either the normal or ras- transformed cells. Inhibitors of tyrosine kinases decrease the level of tyrosine phosphorylation and restore a normal epithelial morphology to the ras-transformed cells. In particular, decreased tyrosine phosphorylation of beta-catenin is accompanied by increased interaction with both E-cadherin and the detergent insoluble cytoskeletal fraction. These results suggest that elevated tyrosine phosphorylation of proteins such as beta-catenin and p120 Cas contribute to the altered adherens junctions of ras-transformed epithelia

Integrin-mediated cell adhesion activates mitogen-activated protein kinases.

Integrins can function as signal-transducing receptors capable of modulating cell growth and gene expression (Juliano, R. L., and Haskill, S. (1993) J. Cell Biol. 120, 577-585; Hynes, R. O. (1992) Cell 69, 11-25). An early event in integrin signaling in fibroblasts and other cells involves activation of pp125FAK, a cytoplasmic tyrosine kinase (Hanks, S. K., Calalb, M. B., Harper, M. C., and Patel, S. K. (1992) Proc. Natl. Acad. Sci. U. S. A. 89, 8487-8491; Schaller, M. D., Borgman, C. A., Cobb, B. S., Vines, R. R., Reynolds, A. B., and Parsons, J. T. (1992) Proc. Natl. Acad. Sci. U. S. A. 89, 5192-5196). Here we report a novel aspect of integrin-mediated signal transduction. We demonstrate that adhesion of cells to substrata coated with extracellular matrix proteins, or with a synthetic peptide containing the RGD sequence, can cause activation of mitogen-activated protein (MAP) kinases in 3T3 or REF52 fibroblasts. Activation of MAP kinases seems to depend on integrin engagement rather than simply on cell attachment. Thus, MAP kinases are activated when cells adhere to substrata coated with the integrin ligands fibronectin or laminin, but not when cells adhere to poly-D-lysine, a nonspecific adhesion-promoting polypeptide. Treatment of cells with cytochalasin D, an inhibitor of actin microfilament assembly, almost completely blocks adhesion-induced MAP kinase activation, indicating a critical role for the cytoskeleton. In REF52 cells, we have observed that activation of MAP kinases is accompanied by redistribution of the protein to the nucleus, suggesting that the activated kinases may impinge on factors regulating gene expression. Thus, integrin-mediated cell adhesion seems a sufficient stimulus to cause activation and nuclear translocation of MAP kinases. This may have important implications for the regulation of cell growth and differentiation by the extracellular matrix

Seasonal melting and the formation of sedimentary rocks on Mars, with predictions for the Gale Crater mound

A model for the formation and distribution of sedimentary rocks on Mars is proposed. The rate-limiting step is supply of liquid water from seasonal melting of snow or ice. The model is run for a O(10^2) mbar pure CO2 atmosphere, dusty snow, and solar luminosity reduced by 23%. For these conditions snow only melts near the equator, and only when obliquity >40 degrees, eccentricity >0.12, and perihelion occurs near equinox. These requirements for melting are satisfied by 0.01-20% of the probability distribution of Mars' past spin-orbit parameters. Total melt production is sufficient to account for aqueous alteration of the sedimentary rocks. The pattern of seasonal snowmelt is integrated over all spin-orbit parameters and compared to the observed distribution of sedimentary rocks. The global distribution of snowmelt has maxima in Valles Marineris, Meridiani Planum and Gale Crater. These correspond to maxima in the sedimentary-rock distribution. Higher pressures and especially higher temperatures lead to melting over a broader range of spin-orbit parameters. The pattern of sedimentary rocks on Mars is most consistent with a Mars paleoclimate that only rarely produced enough meltwater to precipitate aqueous cements and indurate sediment. The results suggest intermittency of snowmelt and long globally-dry intervals, unfavorable for past life on Mars. This model makes testable predictions for the Mars Science Laboratory rover at Gale Crater. Gale Crater is predicted to be a hemispheric maximum for snowmelt on Mars.Comment: Submitted to Icarus. Minor changes from submitted versio

Mastcam-Z multispectral database from the Perseverance rover’s traverse in the Jezero crater floor, Mars (sols 0-380)

NASA’s Mars-2020 Perseverance rover spent its first year in Jezero crater studying the mafic lava flows of the Máaz formation and the ultramafic cumulates of the Séítah formation. Perseverance’s Mastcam-Z instrument, a pair of multispectral, stereoscopic zoom-lens cameras, provides broadband red/green/blue (RGB), narrowband visible to near-infrared color (VNIR, 440-1020 nm wavelength range). We compiled Mastcam-Z spectra from Perseverance’s exploration of the Jezero crater floor in the first 380 sols of its mission. Here, we provide a database of ~2400 representative spectra with extensive metadata, and the locations of the regions of interest (ROIs) from which the spectra were extracted. We also include “natural color” red, green, blue (RGB) images for context, “enhanced color images” derived by stretching narrowband images, and “decorrelation stretch” (DCS) images. This dataset can serve as a baseline to interpret future observations from Perseverance’s ongoing exploration of Jezero crater, Mars

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials

Background Patients with chronic obstructive pulmonary disease (COPD) have few options for treatment. The efficacy and safety of the phosphodiesterase-4 inhibitor roflumilast have been investigated in studies of patients with moderate-to-severe COPD, but not in those concomitantly treated with longacting inhaled bronchodilators. The effect of roflumilast on lung function in patients with COPD that is moderate to severe who are already being treated with salmeterol or tiotropium was investigated. Methods In two double-blind, multicentre studies done in an outpatient setting, after a 4-week run-in, patients older than 40 years with moderate-to-severe COPD were randomly assigned to oral roflumilast 500 mu g or placebo once a day for 24 weeks, in addition to salmeterol (M2-127 study) or tiotropium (M2-128 study). The primary endpoint was change in prebronchodilator forced expiratory volume in 1s (FEV(1)). Analysis was by intention to treat. The studies are registered with ClinicalTrials.gov, number NCT00313209 for M2-127, and NCT00424268 for M2-128. Findings In the salmeterol plus roflumilast trial, 466 patients were assigned to and treated with roflumilast and 467 with placebo; in the tiotropium plus roflumilast trial, 371 patients were assigned to and treated with roflumilast and 372 with placebo. Compared with placebo, roflumilast consistently improved mean prebronchodilator FEV(1) by 49 mL (p<0.0001) in patients treated with salmeterol, and 80 mL (p<0.0001) in those treated with tiotropium. Similar improvement in postbronchodilator FEV(1) was noted in both groups. Furthermore, roflumilast had beneficial effects on other lung function measurements and on selected patient-reported outcomes in both groups. Nausea, diarrhoea, weight loss, and, to a lesser extent, headache were more frequent in patients in the roflumilast groups. These adverse events were associated with increased patient withdrawal. Interpretation Roflumilast improves lung function in patients with COPD treated with salmeterol or tiotropium, and could become an important treatment for these patients