Overexpression of Inosine 5′-Monophosphate Dehydrogenase Type II Mediates Chemoresistance to Human Osteosarcoma Cells

overexpression in osteosarcoma patients with poor response to chemotherapy. The aim of this study was to provide evidence for direct involvement of IMPDH2 in the development of chemoresistance..IMPDH2 is directly involved in the development of chemoresistance in osteosarcoma cells, suggesting that targeting of IMPDH2 by RNAi or more effective pharmacological inhibitors in combination with chemotherapy might be a promising means of overcoming chemoresistance in osteosarcomas with high IMPDH2 expression

Multiwavelength Variability of Sagittarius A* in 2019 July

We report timing analysis of near-infrared (NIR), X-ray, and sub-millimeter (submm) data during a three-day coordinated campaign observing Sagittarius A*. Data were collected at 4.5 micron with the Spitzer Space Telescope, 2-8 keV with the Chandra X-ray Observatory, 3-70 keV with NuSTAR, 340 GHz with ALMA, and at 2.2 micron with the GRAVITY instrument on the Very Large Telescope Interferometer. Two dates show moderate variability with no significant lags between the submm and the infrared at 99% confidence. July 18 captured a moderately bright NIR flare (F_K ~ 15 mJy) simultaneous with an X-ray flare (F ~ 0.1 cts/s) that most likely preceded bright submm flux (F ~ 5.5 Jy) by about +34 (+14 -33) minutes at 99% confidence. The uncertainty in this lag is dominated by the fact that we did not observe the peak of the submm emission. A synchrotron source cooled through adiabatic expansion can describe a rise in the submm once the synchrotron-self-Compton NIR and X-ray peaks have faded. This model predicts high GHz and THz fluxes at the time of the NIR/X-ray peak and electron densities well above those implied from average accretion rates for Sgr A*. However, the higher electron density postulated in this scenario would be in agreement with the idea that 2019 was an extraordinary epoch with a heightened accretion rate. Since the NIR and X-ray peaks can also be fit by a non-thermal synchrotron source with lower electron densities, we cannot rule out an unrelated chance coincidence of this bright submm flare with the NIR/X-ray emission.Comment: Accepted for publication in The Astrophysical Journa

First direct detection of an exoplanet by optical interferometry; Astrometry and K-band spectroscopy of HR8799 e

To date, infrared interferometry at best achieved contrast ratios of a few times $10^{-4}$ on bright targets. GRAVITY, with its dual-field mode, is now capable of high contrast observations, enabling the direct observation of exoplanets. We demonstrate the technique on HR8799, a young planetary system composed of four known giant exoplanets. We used the GRAVITY fringe tracker to lock the fringes on the central star, and integrated off-axis on the HR8799e planet situated at 390 mas from the star. Data reduction included post-processing to remove the flux leaking from the central star and to extract the coherent flux of the planet. The inferred K band spectrum of the planet has a spectral resolution of 500. We also derive the astrometric position of the planet relative to the star with a precision on the order of 100$\,\mu$as. The GRAVITY astrometric measurement disfavors perfectly coplanar stable orbital solutions. A small adjustment of a few degrees to the orbital inclination of HR 8799 e can resolve the tension, implying that the orbits are close to, but not strictly coplanar. The spectrum, with a signal-to-noise ratio of $\approx 5$ per spectral channel, is compatible with a late-type L brown dwarf. Using Exo-REM synthetic spectra, we derive a temperature of $1150\pm50$\,K and a surface gravity of $10^{4.3\pm0.3}\,$cm/s$^{2}$. This corresponds to a radius of $1.17^{+0.13}_{-0.11}\,R_{\rm Jup}$ and a mass of $10^{+7}_{-4}\,M_{\rm Jup}$, which is an independent confirmation of mass estimates from evolutionary models. Our results demonstrate the power of interferometry for the direct detection and spectroscopic study of exoplanets at close angular separations from their stars.Comment: published in A&

Replication and Virus-Induced Transcriptome of HAdV-5 in Normal Host Cells versus Cancer Cells - Differences of Relevance for Adenoviral Oncolysis

Adenoviruses (Ads), especially HAdV-5, have been genetically equipped with tumor-restricted replication potential to enable applications in oncolytic cancer therapy. Such oncolytic adenoviruses have been well tolerated in cancer patients, but their anti-tumor efficacy needs to be enhanced. In this regard, it should be considered that cancer cells, dependent on their tissue of origin, can differ substantially from the normal host cells to which Ads are adapted by complex virus-host interactions. Consequently, viral replication efficiency, a key determinant of oncolytic activity, might be suboptimal in cancer cells. Therefore, we have analyzed both the replication kinetics of HAdV-5 and the virus-induced transcriptome in human bronchial epithelial cells (HBEC) in comparison to cancer cells. This is the first report on genome-wide expression profiling of Ads in their native host cells. We found that E1A expression and onset of viral genome replication are most rapid in HBEC and considerably delayed in melanoma cells. In squamous cell lung carcinoma cells, we observed intermediate HAdV-5 replication kinetics. Infectious particle production, viral spread and lytic activity of HAdV-5 were attenuated in melanoma cells versus HBEC. Expression profiling at the onset of viral genome replication revealed that HAdV-5 induced the strongest changes in the cellular transcriptome in HBEC, followed by lung cancer and melanoma cells. We identified prominent regulation of genes involved in cell cycle and DNA metabolism, replication and packaging in HBEC, which is in accord with the necessity to induce S phase for viral replication. Strikingly, in melanoma cells HAdV-5 triggered opposing regulation of said genes and, in contrast to lung cancer cells, no weak S phase induction was detected when using the E2F promoter as reporter. Our results provide a rationale for improving oncolytic adenoviruses either by adaptation of viral infection to target tumor cells or by modulating tumor cell functions to better support viral replication

A Regression-based K nearest neighbor algorithm for gene function prediction from heterogeneous data

BACKGROUND: As a variety of functional genomic and proteomic techniques become available, there is an increasing need for functional analysis methodologies that integrate heterogeneous data sources. METHODS: In this paper, we address this issue by proposing a general framework for gene function prediction based on the k-nearest-neighbor (KNN) algorithm. The choice of KNN is motivated by its simplicity, flexibility to incorporate different data types and adaptability to irregular feature spaces. A weakness of traditional KNN methods, especially when handling heterogeneous data, is that performance is subject to the often ad hoc choice of similarity metric. To address this weakness, we apply regression methods to infer a similarity metric as a weighted combination of a set of base similarity measures, which helps to locate the neighbors that are most likely to be in the same class as the target gene. We also suggest a novel voting scheme to generate confidence scores that estimate the accuracy of predictions. The method gracefully extends to multi-way classification problems. RESULTS: We apply this technique to gene function prediction according to three well-known Escherichia coli classification schemes suggested by biologists, using information derived from microarray and genome sequencing data. We demonstrate that our algorithm dramatically outperforms the naive KNN methods and is competitive with support vector machine (SVM) algorithms for integrating heterogenous data. We also show that by combining different data sources, prediction accuracy can improve significantly. CONCLUSION: Our extension of KNN with automatic feature weighting, multi-class prediction, and probabilistic inference, enhance prediction accuracy significantly while remaining efficient, intuitive and flexible. This general framework can also be applied to similar classification problems involving heterogeneous datasets

Hub-Centered Gene Network Reconstruction Using Automatic Relevance Determination

Network inference deals with the reconstruction of biological networks from experimental data. A variety of different reverse engineering techniques are available; they differ in the underlying assumptions and mathematical models used. One common problem for all approaches stems from the complexity of the task, due to the combinatorial explosion of different network topologies for increasing network size. To handle this problem, constraints are frequently used, for example on the node degree, number of edges, or constraints on regulation functions between network components. We propose to exploit topological considerations in the inference of gene regulatory networks. Such systems are often controlled by a small number of hub genes, while most other genes have only limited influence on the network's dynamic. We model gene regulation using a Bayesian network with discrete, Boolean nodes. A hierarchical prior is employed to identify hub genes. The first layer of the prior is used to regularize weights on edges emanating from one specific node. A second prior on hyperparameters controls the magnitude of the former regularization for different nodes. The net effect is that central nodes tend to form in reconstructed networks. Network reconstruction is then performed by maximization of or sampling from the posterior distribution. We evaluate our approach on simulated and real experimental data, indicating that we can reconstruct main regulatory interactions from the data. We furthermore compare our approach to other state-of-the art methods, showing superior performance in identifying hubs. Using a large publicly available dataset of over 800 cell cycle regulated genes, we are able to identify several main hub genes. Our method may thus provide a valuable tool to identify interesting candidate genes for further study. Furthermore, the approach presented may stimulate further developments in regularization methods for network reconstruction from data

Sarcoidosis activates diverse transcriptional programs in bronchoalveolar lavage cells

Abstract Background Sarcoidosis is a multisystem immuno-inflammatory disorder of unknown etiology that most commonly involves the lungs. We hypothesized that an unbiased approach to identify pathways activated in bronchoalveolar lavage (BAL) cells can shed light on the pathogenesis of this complex disease. Methods We recruited 15 patients with various stages of sarcoidosis and 12 healthy controls. All subjects underwent bronchoscopy with lavage. For each subject, total RNA was extracted from BAL cells and hybridized to an Affymetrix U133A microarray. Rigorous statistical methods were applied to identify differential gene expression between subjects with sarcoidosis vs. controls. To better elucidate pathways differentially activated between these groups, we integrated network and gene set enrichment analyses of BAL cell transcriptional profiles. Results Sarcoidosis patients were either non-smokers or former smokers, all had lung involvement and only two were on systemic prednisone. Healthy controls were all non-smokers. Comparison of BAL cell gene expression between sarcoidosis and healthy subjects revealed over 1500 differentially expressed genes. Several previously described immune mediators, such as interferon gamma, were upregulated in the sarcoidosis subjects. Using an integrative computational approach we constructed a modular network of over 80 gene sets that were highly enriched in patients with sarcoidosis. Many of these pathways mapped to inflammatory and immune-related processes including adaptive immunity, T-cell signaling, graft vs. host disease, interleukin 12, 23 and 17 signaling. Additionally, we uncovered a close association between the proteasome machinery and adaptive immunity, highlighting a potentially important and targetable relationship in the pathobiology of sarcoidosis. Conclusions BAL cells in sarcoidosis are characterized by enrichment of distinct transcriptional programs involved in immunity and proteasomal processes. Our findings add to the growing evidence implicating alveolar resident immune effector cells in the pathogenesis of sarcoidosis and identify specific pathways whose activation may modulate disease progression

Differential modulation of the TRAIL receptors and the CD95 receptor in colon carcinoma cell lines

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and CD95 ligand (CD95L) are potent inducers of apoptosis in various tumour cell types. Death receptors DR4 and DR5 can induce and decoy receptors DcR1 and DcR2 can inhibit TRAIL-mediated apoptosis. The study aim was to investigate whether anticancer agents can modulate similarly TRAIL-receptor and CD95 membrane expression and TRAIL and CD95L sensitivity.Three colon carcinoma cell lines (Caco-2, Colo320 and SW948) were treated with 5-fluorouracil (5-FU), cisplatin or interferon-γ. TRAIL-receptor and CD95 membrane expression was determined flow cytometrically. Sensitivity to TRAIL or CD95L agonistic anti-CD95 antibody was determined with cytotoxicity and apoptosis assays. SW948 showed highest TRAIL sensitivity. The protein synthesis inhibitor cycloheximide decreased FLICE-like inhibitory protein levels in all cell lines, and the TRAIL-resistant cell lines Caco-2 and Colo320 became sensitive for TRAIL. Exposure of the cell lines to 5-FU, cisplatin and interferon-γ left TRAIL-receptor membrane expression and TRAIL sensitivity unaffected. CD95 membrane expression and anti-CD95 sensitivity was, however, modulated by the same drugs in all lines. Cisplatin and interferon-γ raised CD95 membrane levels 6–8-fold, interferon-γ also increased anti-CD95 sensitivity. These results indicate that the CD95 and TRAIL pathways use different mechanisms to respond to various anticancer agents. Induced CD95 membrane upregulation was associated with increased anti-CD95 sensitivity, whereas no upregulation of TRAIL-receptor membrane expression or TRAIL sensitisation could be established. For optimal use of TRAIL-mediated apoptosis for cancer therapy in certain tumours, downregulation of intracellular inhibiting factors may be required

Biosynthesis of Unusual Moth Pheromone Components Involves Two Different Pathways in the Navel Orangeworm, Amyelois transitella

The sex pheromone of the navel orangeworm, Amyelois transitella (Walker) (Lepidoptera: Pyralidae), consists of two different types of components, one type including (11Z,13Z)-11,13-hexadecadienal (11Z,13Z-16:Ald) with a terminal functional group containing oxygen, similar to the majority of moth pheromones reported, and another type including the unusual long-chain pentaenes, (3Z,6Z,9Z,12Z,15Z)-3,6,9,12,15-tricosapentaene (3Z,6Z,9Z,12Z,15Z-23:H) and (3Z,6Z,9Z,12Z,15Z)- 3,6,9,12,15-pentacosapentaene (3Z,6Z,9Z,12Z,15Z-25:H). After decapitation of females, the titer of 11Z,13Z-16:Ald in the pheromone gland decreased significantly, whereas the titer of the pentaenes remained unchanged. Injection of a pheromone biosynthesis activating peptide (PBAN) into the abdomens of decapitated females restored the titer of 11Z,13Z-16:Ald and even increased it above that in intact females, whereas the titer of the pentaenes in the pheromone gland was not affected by PBAN injection. In addition to common fatty acids, two likely precursors of 11Z,13Z-16:Ald, i.e., (Z)-11-hexadecenoic and (11Z,13Z)-11,13-hexadecadienoic acid, as well as traces of (Z)-6-hexadecenoic acid, were found in gland extracts. In addition, pheromone gland lipids contained (5Z,8Z,11Z,14Z,17Z)-5,8,11,14,17-icosapentaenoic acid, which also was found in extracts of the rest of the abdomen. Deuterium-labeled fatty acids, (16,16,16-D3)-hexadecanoic acid and (Z)-[13,13,14,14,15,15,16,16,16-D9]-11-hexadecenoic acid, were incorporated into 11Z,13Z-16:Ald after topical application to the sex pheromone gland coupled with abdominal injection of PBAN. Deuterium label was incorporated into the C23 and C25 pentaenes after injection of (9Z,12Z,15Z)- [17,17,18,18,18-D5]-9,12,15-octadecatrienoic acid into 1–2 d old female pupae. These labeling results, in conjunction with the composition of fatty acid intermediates found in pheromone gland extracts, support different pathways leading to the two pheromone components. 11Z,13Z-16:Ald is probably produced in the pheromone gland by Δ11 desaturation of palmitic acid to 11Z-16:Acid followed by a second desaturation to form 11Z,13Z-16:Acid and subsequent reduction and oxidation. The production of 3Z,6Z,9Z,12Z,15Z-23:H and 3Z,6Z,9Z,12Z,15Z-25:H may take place outside the pheromone gland, and appears to start from linolenic acid, which is elongated and desaturated to form (5Z,8Z,11Z,14Z,17Z)-5,8,11,14,17-icosapentaenoic acid, followed by two or three further elongation steps and finally reductive decarboxylation