Chemokines in the balance: Maintenance of homeostasis and protection at CNS barriers

In the adult central nervous system (CNS), chemokines and their receptors are involved in developmental, physiological and pathological processes. Although most lines of investigation focus on their ability to induce the migration of cells, recent studies indicate that chemokines also promote cellular interactions and activate signaling pathways that maintain CNS homeostatic functions. Many homeostatic chemokines are expressed on the vasculature of the blood brain barrier including CXCL12, CCL19, CCL20, and CCL21. While endothelial cell expression of these chemokines is known to regulate the entry of leukocytes into the CNS during immunosurveillance, new data indicate that CXCL12 is also involved in diverse cellular activities including adult neurogenesis and neuronal survival, having an opposing role to the homeostatic chemokine, CXCL14, which appears to regulate synaptic inputs to neural precursors. Neuronal expression of CX3CL1, yet another homeostatic chemokine that promotes neuronal survival and communication with microglia, is partly regulated by CXCL12. Regulation of CXCL12 is unique in that it may regulate its own expression levels via binding to its scavenger receptor CXCR7/ACKR3. In this review, we explore the diverse roles of these and other homeostatic chemokines expressed within the CNS, including the possible implications of their dysfunction as a cause of neurologic disease

Novel Roles for Selected Genes in Meiotic DNA Processing

High-throughput studies of the 6,200 genes of Saccharomyces cerevisiae have provided valuable data resources. However, these resources require a return to experimental analysis to test predictions. An in-silico screen, mining existing interaction, expression, localization, and phenotype datasets was developed with the aim of selecting minimally characterized genes involved in meiotic DNA processing. Based on our selection procedure, 81 deletion mutants were constructed and tested for phenotypic abnormalities. Eleven (13.6%) genes were identified to have novel roles in meiotic DNA processes including DNA replication, recombination, and chromosome segregation. In particular, this analysis showed that Def1, a protein that facilitates ubiquitination of RNA polymerase II as a response to DNA damage, is required for efficient synapsis between homologues and normal levels of crossover recombination during meiosis. These characteristics are shared by a group of proteins required for Zip1 loading (ZMM proteins). Additionally, Soh1/Med31, a subunit of the RNA pol II mediator complex, Bre5, a ubiquitin protease cofactor and an uncharacterized protein, Rmr1/Ygl250w, are required for normal levels of gene conversion events during meiosis. We show how existing datasets may be used to define gene sets enriched for specific roles and how these can be evaluated by experimental analysis

LIFE-SHARE Project: Developing a Digitisation Strategy Toolkit

This poster will outline the Digitisation Strategy Toolkit created as part of the LIFE-SHARE project. The toolkit is based on the lifecycle model created by the LIFE project and explores the creation, acquisition, ingest, preservation (bit-stream and content) and access requirements for a digitisation strategy. This covers the policies and infrastructure required in libraries to establish successful practices. The toolkit also provides both internal and external resources to support the service. This poster will illustrate how the toolkit works effectively to support digitisation with examples from three case studies at the Universities of Leeds, Sheffield and York

Timelike Killing Fields and Relativistic Statistical Mechanics

For spacetimes with timelike Killing fields, we introduce a "Fermi-Walker-Killing" coordinate system and use it to prove a Liouville Theorem for an appropriate volume element of phase space for a statistical mechanical system of particles. We derive an exact relativistic formula for the Helmholtz free energy of an ideal gas and compare it, for a class of spacetimes, to its Newtonian analog, derived both independently and as the Newtonian limit of our formula. We also find the relativistic thermodynamic equation of state. Specific examples are given in Kerr spacetime.Comment: This version contains minor corrections, additional discussion, and will appear in Classical and Quantum Gravit

A Statistical Mechanical Problem in Schwarzschild Spacetime

We use Fermi coordinates to calculate the canonical partition function for an ideal gas in a circular geodesic orbit in Schwarzschild spacetime. To test the validity of the results we prove theorems for limiting cases. We recover the Newtonian gas law subject only to tidal forces in the Newtonian limit. Additionally we recover the special relativistic gas law as the radius of the orbit increases to infinity. We also discuss how the method can be extended to the non ideal gas case.Comment: Corrected an equation misprint, added four references, and brief comments on the system's center of mass and the thermodynamic limi

Direct detection of Rydberg–Rydberg millimeter-wave transitions in a buffer gas cooled molecular beam

Millimeter-wave transitions between molecular Rydberg states (n ∼ 35) of barium monofluoride are directly detected via Free Induction Decay (FID). Two powerful technologies are used in combination: Chirped-Pulse millimeter-Wave (CPmmW) spectroscopy and a buffer gas cooled molecular beam photoablation source. Hundreds of Rydberg–Rydberg transitions are recorded in 1 h with >10:1 signal:noise ratio and ∼150 kHz resolution. This high resolution, high spectral velocity experiment promises new strategies for rapid measurements of structural and dynamical information, such as the electric structure (multipole moments and polarizabilities) of the molecular ion-core and the strengths and mechanisms of resonances between Rydberg electron and ion-core motions. Direct measurements of Rydberg–Rydberg transitions with kilo-Debye dipole moments support efficient and definitive spectral analysis techniques, such as the Stark demolition and polarization diagnostics, which enable semi-automatic assignments of core-nonpenetrating Rydberg states. In addition, extremely strong radiation-mediated collective effects (superradiance) in a dense Rydberg gas of barium atoms are observed.National Science Foundation (U.S.) (Grant No. CHE-1361865)United States. Department of Defense (National Defence Science & Engineering Graduate Fellowship (NDSEG) Program

Gene Essentiality Profiling Reveals Gene Networks and Synthetic Lethal Interactions with Oncogenic Ras

The genetic dependencies of human cancers widely vary. Here, we catalog this heterogeneity and use it to identify functional gene interactions and genotype-dependent liabilities in cancer. By using genome-wide CRISPR-based screens, we generate a gene essentiality dataset across 14 human acute myeloid leukemia (AML) cell lines. Sets of genes with correlated patterns of essentiality across the lines reveal new gene relationships, the essential substrates of enzymes, and the molecular functions of uncharacterized proteins. Comparisons of differentially essential genes between Ras-dependent and -independent lines uncover synthetic lethal partners of oncogenic Ras. Screens in both human AML and engineered mouse pro-B cells converge on a surprisingly small number of genes in the Ras processing and MAPK pathways and pinpoint PREX1 as an AML-specific activator of MAPK signaling. Our findings suggest general strategies for defining mammalian gene networks and synthetic lethal interactions by exploiting the natural genetic and epigenetic diversity of human cancer cells. Keywords: CRISPR; AML; synthetic lethality; gene networks; RAS; genetic screensNational Institutes of Health (U.S.) (Grant CA103866)National Institutes of Health (U.S.) (Grant F31CA189437

β Cell function after Roux-en-Y gastric bypass surgery or reduced energy intake alone in people with obesity

BackgroundThe effects of diet-induced weight loss (WL) and WL after Roux-en-Y gastric bypass (RYGB) surgery on β cell function (BCF) are unclear because of conflicting results from different studies, presumably because of differences in the methods used to measure BCF, the amount of WL between treatment groups, and baseline BCF. We evaluated the effect of WL after RYGB surgery or reduced energy intake alone on BCF in people with obesity with and without type 2 diabetes.MethodsBCF (insulin secretion in relationship to plasma glucose) was assessed before and after glucose or mixed-meal ingestion before and after (a) progressive amounts (6%, 11%, 16%) of WL induced by a low-calorie diet (LCD) in people with obesity without diabetes, (b) ~20% WL after RYGB surgery or laparoscopic adjustable gastric banding (LAGB) in people with obesity without diabetes, and (c) ~20% WL after RYGB surgery or LCD alone in people with obesity and diabetes.ResultsDiet-induced progressive WL in people without diabetes progressively decreased BCF. Marked WL after LAGB or RYGB in people without diabetes did not alter BCF. Marked WL after LCD or RYGB in people with diabetes markedly increased BCF, without a difference between groups.ConclusionMarked WL increases BCF in people with obesity and diabetes but not in people with obesity without diabetes. The effect of RYGB-induced WL on BCF is not different from the effect of matched WL after LAGB or LCD alone.trial registrationNCT00981500, NCT02207777, NCT01299519.FundingNIH grants R01 DK037948, P30 DK056341, P30 DK020579, UL1 TR002345