IL-15 sustains IL-7R-independent ILC2 and ILC3 development

The signals that maintain tissue-resident innate lymphoid cells (ILC) in different microenvironments are incompletely understood. Here we show that IL-7 receptor (IL-7R) is not strictly required for the development of any ILC subset, as residual cells persist in the small intestinal lamina propria (siLP) of adult and neonatal Il7ra(−/−) mice. Il7ra(−/−) ILC2 primarily express an ST2(−) phenotype, but are not inflammatory ILC2. CCR6(+) ILC3, which express higher Bcl-2 than other ILC3, are the most abundant subset in Il7ra(−/−) siLP. All ILC subsets are functionally competent in vitro, and are sufficient to provide enhanced protection to infection with C. rodentium. IL-15 equally sustains wild-type and Il7ra(−/−) ILC survival in vitro and compensates for IL-7R deficiency, as residual ILCs are depleted in mice lacking both molecules. Collectively, these data demonstrate that siLP ILCs are not completely IL-7R dependent, but can persist partially through IL-15 signalling

Regulation and Function of TREM2-dependent Pathways in Neurodegeneration

Carriers of the R47H allele of the microglia-specific lipid receptor TREM2 have a greatly increased risk of developing Alzheimerճ disease. The objective of this dissertation is to develop further mechanistic knowledge about how TREM2 is regulated and how TREM2 mutations affect microglia and neurodegeneration. Using an in vitro reporter assay, we find that several AD risk-associated TREM2 mutations decrease ligand-dependent activation. Using humanized TREM2 mice, we find that in vivo, the R47H mutation leads to reduced microglia activation and response to A_, as well as decreased shedding of soluble TREM2. These results suggest that TREM2 is protective during disease. We find that TREM2-deficient macrophages in vitro are more susceptible to stress-induced loss of mTOR signaling, increased autophagy, and low-energy status. In vivo, microglia similarly fail to maintain mTOR signaling and increase autophagy in an A_ mouse model, which could be rescued by enhancing energy utilization with long-term cyclocreatine supplementation. These results suggest that TREM2 is playing a fundamental role in maintaining microglia health and survival rather than triggering a specific activation signature. Finally, we perform an unbiased CRISPR-Cas9 knockout screen to identify and characterize pathways that regulate TREM2 surface expression, identifying TMEM131 as a suppressor of TREM2 surface expression. We further demonstrate that TMEM131 regulation of TREM2 does not involve cleavage or degradation of TREM2 from the cell surface or require the unique intramembranous charge of TREM2. These results provide a stepping stone for identifying novel therapeutic targets related to TREM2

Comparing Grounded Theory and Topic Modeling: Extreme Divergence or Unlikely Convergence?

Researchers in information science and related areas have developed various methods for analyzing textual data, such as survey responses. This article describes the application of analysis methods from two distinct fields, one method from interpretive social science and one method from statistical machine learning, to the same survey data. The results show that the two analyses produce some similar and some complementary insights about the phenomenon of interest, in this case, nonuse of social media. We compare both the processes of conducting these analyses and the results they produce to derive insights about each method\u27s unique advantages and drawbacks, as well as the broader roles that these methods play in the respective fields where they are often used. These insights allow us to make more informed decisions about the tradeoffs in choosing different methods for analyzing textual data. Furthermore, this comparison suggests ways that such methods might be combined in novel and compelling ways

Observation of Exclusive Gamma Gamma Production in p pbar Collisions at sqrt{s}=1.96 TeV

We have observed exclusive \gamma\gamma production in proton-antiproton collisions at \sqrt{s}=1.96 TeV, using data from 1.11 \pm 0.07 fb^{-1} integrated luminosity taken by the Run II Collider Detector at Fermilab. We selected events with two electromagnetic showers, each with transverse energy E_T > 2.5 GeV and pseudorapidity |\eta| < 1.0, with no other particles detected in -7.4 < \eta < +7.4. The two showers have similar E_T and azimuthal angle separation \Delta\phi \sim \pi; 34 events have two charged particle tracks, consistent with the QED process p \bar{p} to p + e^+e^- + \bar{p} by two-photon exchange, while 43 events have no charged tracks. The number of these events that are exclusive \pi^0\pi^0 is consistent with zero and is < 15 at 95% C.L. The cross section for p\bar{p} to p+\gamma\gamma+\bar{p} with |\eta(\gamma)| < 1.0 and E_T(\gamma) > 2.5$ GeV is 2.48^{+0.40}_{-0.35}(stat)^{+0.40}_{-0.51}(syst) pb.Comment: 7 pages, 4 figure

Combined search for the standard model Higgs boson decaying to a bb pair using the full CDF data set

We combine the results of searches for the standard model Higgs boson based on the full CDF Run II data set obtained from sqrt(s) = 1.96 TeV p-pbar collisions at the Fermilab Tevatron corresponding to an integrated luminosity of 9.45/fb. The searches are conducted for Higgs bosons that are produced in association with a W or Z boson, have masses in the range 90-150 GeV/c^2, and decay into bb pairs. An excess of data is present that is inconsistent with the background prediction at the level of 2.5 standard deviations (the most significant local excess is 2.7 standard deviations).Comment: To be published in Phys. Rev. Lett (v2 contains minor updates based on comments from PRL

Shrinking a large dataset to identify variables associated with increased risk of Plasmodium falciparum infection in Western Kenya

Large datasets are often not amenable to analysis using traditional single-step approaches. Here, our general objective was to apply imputation techniques, principal component analysis (PCA), elastic net and generalized linear models to a large dataset in a systematic approach to extract the most meaningful predictors for a health outcome. We extracted predictors for Plasmodium falciparum infection, from a large covariate dataset while facing limited numbers of observations, using data from the People, Animals, and their Zoonoses (PAZ) project to demonstrate these techniques: data collected from 415 homesteads in western Kenya, contained over 1500 variables that describe the health, environment, and social factors of the humans, livestock, and the homesteads in which they reside. The wide, sparse dataset was simplified to 42 predictors of P. falciparum malaria infection and wealth rankings were produced for all homesteads. The 42 predictors make biological sense and are supported by previous studies. This systematic data-mining approach we used would make many large datasets more manageable and informative for decision-making processes and health policy prioritization

Measurement of the WZWZ Cross Section and Triple Gauge Couplings in ppˉp \bar p Collisions at s=1.96\sqrt{s} = 1.96 TeV

This Letter describes the current most precise measurement of the $WZ$ production cross section as well as limits on anomalous $WWZ$ couplings at a center-of-mass energy of 1.96 TeV in proton-antiproton collisions for the Collider Detector at Fermilab (CDF). $WZ$ candidates are reconstructed from decays containing three charged leptons and missing energy from a neutrino, where the charged leptons are either electrons or muons. Using data collected by the CDF II detector (7.1 fb$^{-1}$ of integrated luminosity), 63 candidate events are observed with the expected background contributing $8 \pm 1$ events. The measured total cross section $\sigma (p \bar p \to WZ) = 3.93_{-0.53}^{+0.60}(\text{stat})_{-0.46}^{+0.59}(\text{syst})$ pb is in good agreement with the standard model prediction of $3.50\pm 0.21$. The same sample is used to set limits on anomalous $WWZ$ couplings.Comment: Resubmission to PRD-RC after acceptance (27 July 2012