Harnessing Unresolved Lensed Quasars: The Mathematical Foundation of the Fluctuation Curves

Strong gravitational lensed quasars (QSOs) have emerged as powerful and novel cosmic probes as they can deliver crucial cosmological information, such as a measurement of the Hubble constant, independent of other probes. Although the upcoming LSST survey is expected to discover $10^3-10^4$ lensed QSOs, a large fraction will remain unresolved due to seeing. The stochastic nature of the quasar intrinsic flux makes it challenging to identify lensed ones and measure the time delays using unresolved light curve data only. In this regard, Bag et al (2022) introduced a data-driven technique based on the minimization of the fluctuation in the reconstructed image light curves. In this article, we delve deeper into the mathematical foundation of this approach. We show that the lensing signal in the fluctuation curve is dominated by the auto-correlation function (ACF) of the derivative of the joint light curve. This explains why the fluctuation curve enables the detection of the lensed QSOs only using the joint light curve, without making assumptions about QSO flux variability, nor requiring any additional information. We show that the ACF of the derivative of the joint light curve is more reliable than the ACF of the joint light curve itself because intrinsic quasar flux variability shows significant auto-correlation up to a few hundred days (as they follow a red power spectrum). In addition, we show that the minimization of fluctuation approach provides even better precision and recall as compared to the ACF of the derivative of the joint light curve when the data have significant observational noise.Comment: 20 pages, 8 figures, 1 tabl

Antifungal defense of probiotic Lactobacillus rhamnosus GG is mediated by blocking adhesion and nutrient depletion

Data Availability: All relevant data are available from the Gene Expression Omnibus at the following accession number: GSE97755. Funding: This work was funded by the German Research Council (DFG) Graduation College 685, Dr. Jekyll and Mr. Hyde: A systems approach to the therapy of nosocomial infections caused by Candida albicans: a commensal organism switches to a deadly pathogen/ PTJ (FKZ: 0315409BBMBF), the Dr. Manfred Plempel-foundation, the Dr. Siegried Stettendorf-Foundation, the InfectERA Program (FunComPath; BMBF FKZ 031L0001A), the Integrated Research and Treatment Center for Sepsis Control and Care (CSCC) project CanBac (BMBF, FKZ: 01EO1002), and the German Research Council (DFG) GZ:HE7565/1-1. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Transcriptome-proteome compendium of the Antarctic krill (Euphausia superba): Metabolic potential and repertoire of hydrolytic enzymes

The Antarctic krill (Euphausia superba Dana) is a keystone species in the Southern Ocean that uses an arsenal of hydrolases for biomacromolecule decomposition to effectively digest its omnivorous diet. The present study builds on a hybrid-assembled transcriptome (13,671 ORFs) combined with comprehensive proteome profiling. The analysis of individual krill compartments allowed detection of significantly more different proteins compared to that of the entire animal (1,464 vs. 294 proteins). The nearby krill sampling stations in the Bransfield Strait (Antarctic Peninsula) yielded rather uniform proteome datasets. Proteins related to energy production and lipid degradation were particularly abundant in the abdomen, agreeing with the high energy demand of muscle tissue. A total of 378 different biomacromolecule hydrolysing enzymes were detected, including 250 proteases, 99 CAZymes, 14 nucleases and 15 lipases. The large repertoire in proteases is in accord with the protein-rich diet affiliated with E. superba’s omnivorous lifestyle and complex biology. The richness in chitin-degrading enzymes allows not only digestion of zooplankton diet, but also the utilization of the discharged exoskeleton after moulting

Scalable production of iPSC-derived human neurons to identify tau-lowering compounds by high-content screening

Lowering total tau levels is an attractive therapeutic strategy for Alzheimer's disease and other tauopathies. High-throughput screening in neurons derived from human induced pluripotent stem cells (iPSCs) is a powerful tool to identify tau-targeted therapeutics. However, such screens have been hampered by heterogeneous neuronal production, high cost and low yield, and multi-step differentiation procedures. We engineered an isogenic iPSC line that harbors an inducible neurogenin 2 transgene, a transcription factor that rapidly converts iPSCs to neurons, integrated at the AAVS1 locus. Using a simplified two-step protocol, we differentiated these iPSCs into cortical glutamatergic neurons with minimal well-to-well variability. We developed a robust high-content screening assay to identify tau-lowering compounds in LOPAC and identified adrenergic receptors agonists as a class of compounds that reduce endogenous human tau. These techniques enable the use of human neurons for high-throughput screening of drugs to treat neurodegenerative disease

KDEL Receptor (Erd2p)-mediated Retrograde Transport of the Cholera Toxin A Subunit from the Golgi Involves COPI, p23, and the COOH Terminus of Erd2p

A cholera toxin mutant (CTX–K63) unable to raise cAMP levels was used to study in Vero cells the retrograde transport of the toxin A subunit (CTX-A–K63), which possesses a COOH-terminal KDEL retrieval signal. Microinjected GTP-γ-S inhibits the internalization as well as Golgi–ER transport of CTX-A–K63. The appearance of CTX-A–K63 in the Golgi induces a marked dispersion of Erd2p and p53 but not of the Golgi marker giantin. Erd2p is translocated under these conditions most likely to the intermediate compartment as indicated by an increased colocalization of Erd2p with mSEC13, a member of the mammalian coat protein II complex. IgGs as well as Fab fragments directed against Erd2p, β-COP, or p23, a new member of the p24 protein family, inhibit or block retrograde transport of CTX-A–K63 from the Golgi without affecting its internalization or its transport to the Golgi. Anti-Erd2p antibodies do not affect the binding of CTX-A to Erd2p, but inhibit the CTX-K63–induced translocation of Erd2p and p53

Localization and functional characterization of the pathogenesis-related proteins Rbe1p and Rbt4p in Candida albicans

Members of the Cysteine-rich secretory protein, Antigen 5 and Pathogenesis-related 1 (CAP) protein superfamily are important virulence factors in fungi but remain poorly characterized on molecular level. Here, we investigate the cellular localization and molecular function of Rbe1p and Rbt4p, two CAP family members from the human pathogen Candida albicans. We unexpectedly found that Rbe1p localizes to budding sites of yeast cells in a disulfide bond-dependent manner. Furthermore, we show that Rbe1p and Rbt4p bind free cholesterol in vitro and export cholesteryl acetate in vivo. These findings suggest a previously undescribed role for Rbe1p in cell wall- associated processes and a possible connection between the virulence attributes of fungal CAP proteins and sterol binding

The Infrared Imaging Spectrograph (IRIS) for TMT: Instrument Overview

We present an overview of the design of IRIS, an infrared (0.84 - 2.4 micron) integral field spectrograph and imaging camera for the Thirty Meter Telescope (TMT). With extremely low wavefront error (<30 nm) and on-board wavefront sensors, IRIS will take advantage of the high angular resolution of the narrow field infrared adaptive optics system (NFIRAOS) to dissect the sky at the diffraction limit of the 30-meter aperture. With a primary spectral resolution of 4000 and spatial sampling starting at 4 milliarcseconds, the instrument will create an unparalleled ability to explore high redshift galaxies, the Galactic center, star forming regions and virtually any astrophysical object. This paper summarizes the entire design and basic capabilities. Among the design innovations is the combination of lenslet and slicer integral field units, new 4Kx4k detectors, extremely precise atmospheric dispersion correction, infrared wavefront sensors, and a very large vacuum cryogenic system.Comment: Proceedings of the SPIE, 9147-76 (2014

Next-generation sequencing diagnostics of bacteremia in septic patients

Background: Bloodstream infections remain one of the major challenges in intensive care units, leading to sepsis or even septic shock in many cases. Due to the lack of timely diagnostic approaches with sufficient sensitivity, mortality rates of sepsis are still unacceptably high. However a prompt diagnosis of the causative microorganism is critical to significantly improve outcome of bloodstream infections. Although various targeted molecular tests for blood samples are available, time-consuming blood culture-based approaches still represent the standard of care for the identification of bacteria. Methods: Here we describe the establishment of a complete diagnostic workflow for the identification of infectious microorganisms from seven septic patients based on unbiased sequence analyses of free circulating DNA from plasma by next-generation sequencing. Results: We found significant levels of DNA fragments derived from pathogenic bacteria in samples from septic patients. Quantitative evaluation of normalized read counts and introduction of a sepsis indicating quantifier (SIQ) score allowed for an unambiguous identification of Gram-positive as well as Gram-negative bacteria that exactly matched with blood cultures from corresponding patient samples. In addition, we also identified species from samples where blood cultures were negative. Reads of non-human origin also comprised fragments derived from antimicrobial resistance genes, showing that, in principle, prediction of specific types of resistance might be possible. Conclusions: The complete workflow from sample preparation to species identification report could be accomplished in roughly 30 h, thus making this approach a promising diagnostic platform for critically ill patients suffering from bloodstream infections

The ID1-CULLIN3 Axis Regulates Intracellular SHH and WNT Signaling in Glioblastoma Stem Cells

SummaryInhibitor of differentiation 1 (ID1) is highly expressed in glioblastoma stem cells (GSCs). However, the regulatory mechanism responsible for its role in GSCs is poorly understood. Here, we report that ID1 activates GSC proliferation, self-renewal, and tumorigenicity by suppressing CULLIN3 ubiquitin ligase. ID1 induces cell proliferation through increase of CYCLIN E, a target molecule of CULLIN3. ID1 overexpression or CULLIN3 knockdown confers GSC features and tumorigenicity to murine Ink4a/Arf-deficient astrocytes. Proteomics analysis revealed that CULLIN3 interacts with GLI2 and DVL2 and induces their degradation via ubiquitination. Consistent with ID1 knockdown or CULLIN3 overexpression in human GSCs, pharmacologically combined control of GLI2 and β-CATENIN effectively diminishes GSC properties. A ID1-high/CULLIN3-low expression signature correlates with a poor patient prognosis, supporting the clinical relevance of this signaling axis. Taken together, a loss of CULLIN3 represents a common signaling node for controlling the activity of intracellular WNT and SHH signaling pathways mediated by ID1