Recognition for an Innate Explorer

On June 5, 2013, Ruslan Medzhitov received the Else Kröner-Fresenius Immunology Award. This recognition goes to an individual who has had such an influence on basic and medical immunology that it is almost difficult to recall a time before his discoveries were made. But in reality, that time was not long ago. To mark this celebratory event, I highlight the conceptual revolution spurred by his work, which continues to inspire excitement today

PRRs are watching you: Localization of innate sensing and signaling regulators

AbstractTo prevent the spread of infection, an invading pathogen must first be recognized by the innate immune system. Host pattern recognition receptors detect distinct pathogen-associated molecules and induce the transcription and release of interferon and inflammatory molecules to resolve infection. Unlike infections with pathogens that replicate autonomously from the host, viral infections blur the boundaries of self and non-self. Differentiation of host from virus is achieved by restricting localization of host nucleic acids and by placing pattern recognition receptors in specific subcellular compartments. Within this review, we discuss how several families of pattern recognition receptors act to provide a comprehensive surveillance network that has the potential to induce interferon expression in response to any viral infection

The tryptophan pathway genes of the Sargasso Sea metagenome: new operon structures and the prevalence of non-operon organization

An analysis of the seven genes of the tryptophan pathway in the Sargasso Sea metagenome shows that the majority of contigs and scaffolds contain whole or split operons that are similar to previously analyzed trp gene organizations

Differentiable Vertex Fitting for Jet Flavour Tagging

We propose a differentiable vertex fitting algorithm that can be used for secondary vertex fitting, and that can be seamlessly integrated into neural networks for jet flavour tagging. Vertex fitting is formulated as an optimization problem where gradients of the optimized solution vertex are defined through implicit differentiation and can be passed to upstream or downstream neural network components for network training. More broadly, this is an application of differentiable programming to integrate physics knowledge into neural network models in high energy physics. We demonstrate how differentiable secondary vertex fitting can be integrated into larger transformer-based models for flavour tagging and improve heavy flavour jet classification.Comment: 11 page

Legionella Subvert the Functions of Rab1 and Sec22b to Create a Replicative Organelle

Legionella pneumophila is a bacterial pathogen that infects eukaryotic host cells and replicates inside a specialized organelle that is morphologically similar to the endoplasmic reticulum (ER). To better understand the molecular mechanisms governing transport of the Legionella-containing vacuole (LCV), we have identified host proteins that participate in the conversion of the LCV into a replicative organelle. Our data show that Rab1 is recruited to the LCV within minutes of uptake. Rab1 recruitment to the LCV precedes remodeling of this compartment by ER-derived vesicles. Genetic inhibition studies demonstrate that Rab1 is important for the recruitment of ER-derived vesicles to the LCV and that inhibiting Rab1 function abrogates intracellular growth of Legionella. Morphological studies indicate that the Sec22b protein is located on ER-derived vesicles recruited to the LCV and that Sec22b is delivered to the LCV membrane. Sec22b function was found to be important for biogenesis of the specialized organelle that supports Legionella replication. These studies demonstrate that Legionella has the ability to subvert Rab1 and Sec22b function to facilitate the transport and fusion of ER-derived vesicles with the LCV, resulting in the formation of a specialized organelle that can support bacterial replication

Bacterial Isolation by Lectin-Modified Microengines

New template-based self-propelled gold/nickel/polyaniline/platinum (Au/Ni/PANI/Pt) microtubular engines, functionalized with the Concanavalin A (ConA) lectin bioreceptor, are shown to be extremely useful for the rapid, real-time isolation of Escherichia coli (E. coli) bacteria from fuel-enhanced environmental, food, and clinical samples. These multifunctional microtube engines combine the selective capture of E. coli with the uptake of polymeric drug-carrier particles to provide an attractive motion-based theranostics strategy. Triggered release of the captured bacteria is demonstrated by movement through a low-pH glycine-based dissociation solution. The smaller size of the new polymer-metal microengines offers convenient, direct, and label-free optical visualization of the captured bacteria and discrimination against nontarget cells

Deep-sea microbes as tools to refine the rules of innate immune pattern recognition.

The assumption of near-universal bacterial detection by pattern recognition receptors is a foundation of immunology. The limits of this pattern recognition concept, however, remain undefined. As a test of this hypothesis, we determined whether mammalian cells can recognize bacteria that they have never had the natural opportunity to encounter. These bacteria were cultivated from the deep Pacific Ocean, where the genus Moritella was identified as a common constituent of the culturable microbiota. Most deep-sea bacteria contained cell wall lipopolysaccharide (LPS) structures that were expected to be immunostimulatory, and some deep-sea bacteria activated inflammatory responses from mammalian LPS receptors. However, LPS receptors were unable to detect 80% of deep-sea bacteria examined, with LPS acyl chain length being identified as a potential determinant of immunosilence. The inability of immune receptors to detect most bacteria from a different ecosystem suggests that pattern recognition strategies may be defined locally, not globally.R01 AI093589 - NIAID NIH HHS; P30 DK034854 - NIDDK NIH HHS; U19 AI133524 - NIAID NIH HHS; R01 AI147314 - NIAID NIH HHS; R01 AI116550 - NIAID NIH HHS; R37 AI116550 - NIAID NIH HHS; R01 AI123820 - NIAID NIH HHSAccepted manuscrip

A panel of induced pluripotent stem cells from chimpanzees: A resource for comparative functional genomics

Comparative genomics studies in primates are restricted due to our limited access to samples. In order to gain better insight into the genetic processes that underlie variation in complex phenotypes in primates, we must have access to faithful model systems for a wide range of cell types. To facilitate this, we generated a panel of 7 fully characterized chimpanzee induced pluripotent stem cell (iPSC) lines derived from healthy donors. To demonstrate the utility of comparative iPSC panels, we collected RNA-sequencing and DNA methylation data from the chimpanzee iPSCs and the corresponding fibroblast lines, as well as from 7 human iPSCs and their source lines, which encompass multiple populations and cell types. We observe much less withinspecies variation in iPSCs than in somatic cells, indicating the reprogramming process erases many inter-individual differences. The low within-species regulatory variation in iPSCs allowed us to identify many novel inter-species regulatory differences of small magnitude

Exploration of the Transition from the Hydrodynamiclike to the Strongly Kinetic Regime in Shock-Driven Implosions

Clear evidence of the transition from hydrodynamiclike to strongly kinetic shock-driven implosions is, for the first time, revealed and quantitatively assessed. Implosions with a range of initial equimolar D[superscript 3]He gas densities show that as the density is decreased, hydrodynamic simulations strongly diverge from and increasingly overpredict the observed nuclear yields, from a factor of ∼2 at 3.1  mg/cm[superscript 3] to a factor of 100 at 0.14  mg/cm[superscript 3]. (The corresponding Knudsen number, the ratio of ion mean-free path to minimum shell radius, varied from 0.3 to 9; similarly, the ratio of fusion burn duration to ion diffusion time, another figure of merit of kinetic effects, varied from 0.3 to 14.) This result is shown to be unrelated to the effects of hydrodynamic mix. As a first step to garner insight into this transition, a reduced ion kinetic (RIK) model that includes gradient-diffusion and loss-term approximations to several transport processes was implemented within the framework of a one-dimensional radiation-transport code. After empirical calibration, the RIK simulations reproduce the observed yield trends, largely as a result of ion diffusion and the depletion of the reacting tail ions.United States. Dept. of Energy (Grant DE-NA0001857)United States. Dept. of Energy (Grant DE-FC52-08NA28752)University of Rochester. Fusion Science Center (5-24431)National Laser User’s Facility (DE-NA0002035)University of Rochester. Laboratory for Laser Energetics (415935-G)Lawrence Livermore National Laboratory (B597367

Near-complete backbone resonance assignments of acid-denatured human cytochrome c in dimethylsulfoxide: a prelude to studying interactions with phospholipids

Human cytochrome c plays a central role in the mitochondrial electron transfer chain and in the intrinsic apoptosis pathway. Through the interaction with the phospholipid cardiolipin, cytochrome c triggers release of pro-apoptotic factors, including itself, from the mitochondrion into the cytosol of cells undergoing apoptosis. The cytochrome c/cardiolipin complex has been extensively studied through various spectroscopies, most recently with high-field solution and solid-state NMR spectroscopies, but there is no agreement between the various studies on key structural features of cytochrome c in its complex with cardiolipin. In the present study, we report backbone 1H, 13C, 15N resonance assignments of acid-denatured human cytochrome c in the aprotic solvent dimethylsulfoxide. These have led to the assignment of a reference 2D 1H-15N HSQC spectrum in which out of the 99 non-proline residues 87% of the backbone amides are assigned. These assignments are being used in an interrupted H/D exchange strategy to map the binding site of cardiolipin on human cytochrome c