Analysis of Compound Synergy in High-Throughput Cellular Screens by Population-Based Lifetime Modeling

Despite the successful introduction of potent anti-cancer therapeutics, most of these drugs lead to only modest tumor-shrinkage or transient responses, followed by re-growth of tumors. Combining different compounds has resulted in enhanced tumor control and prolonged survival. However, methods querying the efficacy of such combinations have been hampered by limited scalability, analytical resolution, statistical feasibility, or a combination thereof. We have developed a theoretical framework modeling cellular viability as a stochastic lifetime process to determine synergistic compound combinations from high-throughput cellular screens. We apply our method to data derived from chemical perturbations of 65 cancer cell lines with two inhibitors. Our analysis revealed synergy for the combination of both compounds in subsets of cell lines. By contrast, in cell lines in which inhibition of one of both targets was sufficient to induce cell death, no synergy was detected, compatible with the topology of the oncogenically activated signaling network. In summary, we provide a tool for the measurement of synergy strength for combination perturbation experiments that might help define pathway topologies and direct clinical trials

NetCoMi: network construction and comparison for microbiome data in R

MOTIVATION Estimating microbial association networks from high-throughput sequencing data is a common exploratory data analysis approach aiming at understanding the complex interplay of microbial communities in their natural habitat. Statistical network estimation workflows comprise several analysis steps, including methods for zero handling, data normalization and computing microbial associations. Since microbial interactions are likely to change between conditions, e.g. between healthy individuals and patients, identifying network differences between groups is often an integral secondary analysis step. Thus far, however, no unifying computational tool is available that facilitates the whole analysis workflow of constructing, analysing and comparing microbial association networks from high-throughput sequencing data. RESULTS Here, we introduce NetCoMi (Network Construction and comparison for Microbiome data), an R package that integrates existing methods for each analysis step in a single reproducible computational workflow. The package offers functionality for constructing and analysing single microbial association networks as well as quantifying network differences. This enables insights into whether single taxa, groups of taxa or the overall network structure change between groups. NetCoMi also contains functionality for constructing differential networks, thus allowing to assess whether single pairs of taxa are differentially associated between two groups. Furthermore, NetCoMi facilitates the construction and analysis of dissimilarity networks of microbiome samples, enabling a high-level graphical summary of the heterogeneity of an entire microbiome sample collection. We illustrate NetCoMi's wide applicability using data sets from the GABRIELA study to compare microbial associations in settled dust from children's rooms between samples from two study centers (Ulm and Munich). AVAILABILITY R scripts used for producing the examples shown in this manuscript are provided as supplementary data. The NetCoMi package, together with a tutorial, is available at https://github.com/stefpeschel/NetCoMi. CONTACT Tel:+49 89 3187 43258; [email protected]. SUPPLEMENTARY INFORMATION Supplementary data are available at Briefings in Bioinformatics online

Solution structure of a bacterial microcompartment targeting peptide and its application in the construction of an ethanol bioreactor

Targeting of proteins to bacterial microcompartments (BMCs) is mediated by an 18-amino-acid peptide sequence. Herein, we report the solution structure of the N-terminal targeting peptide (P18) of PduP, the aldehyde dehydrogenase associated with the 1,2-propanediol utilization metabolosome from Citrobacter freundii. The solution structure reveals the peptide to have a well-defined helical conformation along its whole length. Saturation transfer difference and transferred NOE NMR has highlighted the observed interaction surface on the peptide with its main interacting shell protein, PduK. By tagging both a pyruvate decarboxylase and an alcohol dehydrogenase with targeting peptides, it has been possible to direct these enzymes to empty BMCs in vivo and to generate an ethanol bioreactor. Not only are the purified, redesigned BMCs able to transform pyruvate into ethanol efficiently, but the strains containing the modified BMCs produce elevated levels of alcohol

The Discovery of Infrared Rings in the Planetary Nebula NGC 1514 During the WISE All-Sky Survey

We report the discovery of a pair of infrared, axisymmetric rings in the planetary nebula NGC 1514 during the course of the WISE all-sky mid-infrared survey. Similar structures are seen at visible wavelengths in objects such as the "Engraved Hourglass Nebula" (MyCn 18) and the "Southern Crab Nebula" (Hen 2-104). However, in NGC 1514 we see only a single pair of rings and they are easily observed only in the mid-infrared. These rings are roughly 0.2 pc in diameter, are separated by 0.05 pc, and are dominated by dust emission with a characteristic temperature of 160 K. We compare the morphology and color of the rings to the other nebular structures seen at visible, far-infrared, and radio wavelengths, and close with a discussion of a physical model and formation scenario for NGC 1514.Comment: 16 pages, 10 figures, final version published in 2010 December Astronomical Journa

Reducing complication rates and hospital readmissions while revising the enhanced recovery after bariatric surgery (ERABS) protocol

Background: To optimize the postoperative phase following bariatric surgery, the enhanced recovery after bariatric surgery pathway (ERABS) has been developed. The aim of ERABS is to create a care path that is as safe, efficient and patient-friendly as possible. Continuous evaluation and optimization of ERABS are important to ensure a safe treatment path and may result in better outcomes. The objective of this study was to compare the clinical outcomes of patients undergoing bariatric surgery over 2014–2017, during which the ERABS protocol was continuously evaluated and optimized. Methods: This is a retrospective cohort study. Data were collected from patients undergoing a primary Roux-en-Y gastric bypass or sleeve gastrectomy between January 2014 and December 2017. Outcomes were early complications, unplanned hospital revisits, readmissions, duration of surgery and length of hospital stay. Results: 2889 patients underwent a primary bariatric procedure in a single center. There was a significant decrease in minor complications over the years from 7.0 to 1.9% (p < 0.001). Hospital revisit rates decreased after 2015 (p < 0.001). Readmission rates decreased over time (p < 0.001). The mean duration of surgery decreased from 52 (in 2014) to 41 (in 2017) minutes (p < 0.001). Median length of hospital stay decreased from 1.8 to 1.5 days in 2015 (p = 0.002) and remained stable since. Conclusion: An improvement of the ERABS protocol was associated with a decrease in minor complication rates, number of unplanned hospital revisits and readmission rates after primary bariatric procedures

Re-structuring of marine communities exposed to environmental change

Species richness is the most commonly used but controversial biodiversity metric in studies on aspects of community stability such as structural composition or productivity. The apparent ambiguity of theoretical and experimental findings may in part be due to experimental shortcomings and/or heterogeneity of scales and methods in earlier studies. This has led to an urgent call for improved and more realistic experiments. In a series of experiments replicated at a global scale we translocated several hundred marine hard bottom communities to new environments simulating a rapid but moderate environmental change. Subsequently, we measured their rate of compositional change (re-structuring) which in the great majority of cases represented a compositional convergence towards local communities. Re-structuring is driven by mortality of community components (original species) and establishment of new species in the changed environmental context. The rate of this re-structuring was then related to various system properties. We show that availability of free substratum relates negatively while taxon richness relates positively to structural persistence (i.e., no or slow re-structuring). Thus, when faced with environmental change, taxon-rich communities retain their original composition longer than taxon-poor communities. The effect of taxon richness, however, interacts with another aspect of diversity, functional richness. Indeed, taxon richness relates positively to persistence in functionally depauperate communities, but not in functionally diverse communities. The interaction between taxonomic and functional diversity with regard to the behaviour of communities exposed to environmental stress may help understand some of the seemingly contrasting findings of past research

Deep, Wide-field CCD Photometry for the Open Cluster NGC3532

We present the results of a deep, wide-field CCD survey for the open cluster NGC~3532. Our new $BV(RI)_{c}$ photometry effectively covers a one square degree area and reaches an unprecedented depth of $V\sim21$ to reveal that NGC~3532 is a rich open cluster that harbors a large number of faint, low-mass stars. We employ a number of methods to reduce the impact of field star contamination in the cluster color-magnitude diagrams, including supplementing our photometry with $JHK_{s}$ data from the 2MASS catalog. These efforts allow us to define a robust sample of candidate main sequence stars suitable for a purely empirical determination of the cluster's parameters by comparing them to the well-established Hyades main sequence. Our results confirm previous findings that NGC~3532 lies fairly near to the Sun [$(m-M)_0=8.46\pm0.05$; $492^{+12}_{-11}$~pc] and has an extremely low reddening for its location near the Galactic plane [$E(B-V)=0.028\pm0.006$]. Moreover, an age of $\sim300$\,Myr has been derived for the cluster by fitting a set of overshooting isochrones to the well-populated upper main-sequence. This new photometry also extends faint enough to reach the cluster white dwarf sequence, as confirmed by our photometric recovery of eight spectroscopically identified members of the cluster. Using the location of these eight members, along with the latest theoretical cooling tracks, we have identified $\sim30$ additional white dwarf stars in the $[V,~(B-V)]$ color-magnitude diagram that have a high probability of belonging to NGC~3532. The age we derive from fitting white dwarf isochrones to the locus of these stars, $300\pm100$\,Myr, is consistent with the age derived from the turnoff. Our analysis of the photometry also includes an estimation of the binary star fraction, as well as a determination of the cluster's luminosity and mass functions.Comment: Accepted for publication in AJ. 55 pages, 21 figures. High-quality version with complete data tables can be downloaded from http://www.phys.lsu.edu/~jclem/NGC3532

Summaries of plenary, symposia, and oral sessions at the XXII World Congress of Psychiatric Genetics, Copenhagen, Denmark, 12-16 October 2014

The XXII World Congress of Psychiatric Genetics, sponsored by the International Society of Psychiatric Genetics, took place in Copenhagen, Denmark, on 12-16 October 2014. A total of 883 participants gathered to discuss the latest findings in the field. The following report was written by student and postdoctoral attendees. Each was assigned one or more sessions as a rapporteur. This manuscript represents topics covered in most, but not all of the oral presentations during the conference, and contains some of the major notable new findings reported

T cell derived IL-10 is dispensable for tolerance induction in a murine model of allergic airway inflammation

Regulatory mechanisms initiated by allergen specific immunotherapy are mainly attributed to T cell-derived IL-10. However, it has not been shown that T cell-derived IL-10 is required for successful tolerance induction. Here, we analyze cellular sources and the functional relevance of cell type specific IL-10 during tolerance induction in a murine model of allergic airway inflammation. While tolerance induction was effective in IL-10 competent mice, neutralizing IL-10 prior to tolerogenic treatment completely abrogated the beneficial effects. Cellular sources of IL-10 during tolerance induction were identified by using transcriptional reporter mice as T cells, B cells and to a lesser extent DCs. Interestingly, tolerance induction was still effective in mice with T cell-, B cell-, B and T cell- or DC-specific IL-10 deficiency. In contrast, tolerance induction was not possible in mice lacking IL-10 in all hematopoetic cells, while it was effective in bone marrow chimera that lacked IL-10 only in non-hematopoetic cells. Taken together, allergen specific tolerance depends on IL-10 from hematopoetic sources. The beneficial effects of allergen specific immunotherapy cannot solely be attributed to IL-10 from T cells, B cells or even DCs, suggesting a high degree of cellular redundancy in IL-10 mediated tolerance

The outburst of the changing-look AGN IRAS23226-3843 in 2019

IRAS23226-3843 has previously been classified as a changing-look AGN based on X-ray and optical spectral variations. In 2019, Swift observations revealed a strong rebrightening in X-ray and UV fluxes in comparison to observations in 2017. We took follow-up Swift, XMM-Newton, and NuSTAR observations together with optical spectra (SALT and SAAO 1.9m telescope) from 2019 until 2021. IRAS23226-3843 showed a strong X-ray and optical outburst in 2019. It varied in the X-ray and optical continuum by a factor of 5 and 1.6, respectively, within two months. This corresponds to a factor of 3 in the optical after correction for the host galaxy contribution. The Balmer and FeII emission-line intensities showed comparable variability amplitudes. The Halpha profiles changed from a blue-peaked profile in the years 1997 and 1999 to a broad double-peaked profile in 2017 and 2019. However, there were no major profile variations in the extremely broad double-peaked profiles despite the strong intensity variations in 2019. One year after the outburst, the optical spectral type changed and became a Seyfert type 2 in 2020. Blue outflow components are present in the Balmer lines and in the Fe band in the X-rays. A deep broadband XMM-Newton/NuSTAR spectrum was taken during the maximum state in 2019. This spectrum is qualitatively very similar to a spectrum taken in 2017, but by a factor of 10 higher. The soft X-ray band appears featureless. The soft excess is well modeled with a Comptonization model. A broadband fit with a power-law continuum, Comptonized soft excess, and Galactic absorption gives a good fit to the combined EPIC-pn and NuSTAR spectrum. In addition, we see a complex and broadened Fe K emission-line profile in the X-rays. The changing-look character in IRAS23226-3843 is most probably caused by changes in the accretion rate -- based on the short-term variations on timescales of weeks to months.Comment: 21 pages, 14 figures, Astronomy & Astrophysics in pres