Conduit integrity is compromised during acute lymph node expansion

Lymph nodes (LNs) work as filtering organs, constantly sampling peripheral cues. This is facilitated by the conduit network, a parenchymal tubular-like structure formed of bundles of aligned extracellular matrix (ECM) fibrils ensheathed by fibroblastic reticular cells (FRCs). LNs undergo 5-fold expansion with every adaptive immune response and yet these ECM-rich structures are not permanently damaged. Whether conduit integrity and filtering functions are affected during cycles of LN expansion and resolution is not known. Here we show that the conduit structure is disrupted during acute LN expansion but FRC-FRC contacts remain intact. In homeostasis, polarised FRCs adhere to the underlying substrate to deposit ECM ba-solaterally. ECM production by FRCs is regulated by the C-type lectin CLEC-2, expressed by dendritic cells (DCs), at transcriptional and secretory levels. Inflamed LNs maintain conduit size-exclusion, but flow becomes leaky, which allows soluble antigens to reach more antigen-presenting cells. We show how dynamic communication between peripheral tissues and LNs changes during immune responses, and describe a mechanism that enables LNs to prevent inflammation-induced fibrosis

Expression of MK-1 and RegⅣ and its clinicopathological significances in the benign and malignant lesions of gallbladder

<p>Abstract</p> <p>Background</p> <p>To study the expression of MK-1 and RegⅣ and to detect their pathological significances in benign and malignant lesions of gallbladder.</p> <p>Methods</p> <p>The expression of MK-1 and RegⅣ was detected by immunohistochemical method in paraffin-embedded sections of surgical resected specimens from gallbladder adenocarcinoma (n = 108), peritumoral tissues (n = 46), adenomatous polyp (n = 15), and chronic cholecystitis (n = 35).</p> <p>Results</p> <p>The positive rate of MK-1 or RegⅣ expression was significantly higher in gallbladder adenocarcinoma than that in peritumoral tissues (χ²_MK-1= 18.76, <it>P </it>< 0.01; χ²_RegⅣ= 9.92, <it>P </it>< 0.01), denomatous polyp (χ²_MK-1= 9.49, <it>P </it>< 0.01; χ²_RegⅣ= 8.59, <it>P </it>< 0.01) and chronic cholecystitis (χ²_MK-1= 24.11, <it>P </it>< 0.01; χ²_RegⅣ= 19.24, <it>P </it>< 0.01). The positive cases of MK-1 and/or RegⅣ in the benign lesions showed moderately- or severe-atypical hyperplasia of gallbladder epitheli. The positive rates of MK-1 were significantly higher in the cases of well-differentiated adenocarcinoma, no-metastasis of lymph node, and no-invasiveness of regional tissues than those in the ones of differentiated adenocarcinoma, metastasis of lymph node, and invasiveness of regional tissues in gallbladder adenocarcinoma (<it>P </it>< 0.05 or <it>P </it>< 0.01). On the contrary, the positive rates of RegⅣ were significantly lower in the cases of well-differentiated adenocarcinoma, no-metastasis of lymph node, and no-invasiveness of regional tissues than those in the ones of differentiated adenocarcinoma, metastasis of lymph node, and invasiveness of regional tissues in gallbladder adenocarcinoma (<it>P </it>< 0.05 or <it>P </it>< 0.01). Univariate Kaplan-Meier analysis showed that decreased expression of MK-1 (<it>P </it>= 0.09) or increased expression of RegⅣ (<it>P </it>= 0.003) was associated with decreased overall survival. Multivariate Cox regression analysis showed that decreased expression of MK-1 (<it>P </it>= 0.033) and increased expression of RegⅣ (<it>P </it>= 0.008) was an independent prognostic predictor in gallbladder adenocarcinoma.</p> <p>Conclusions</p> <p>The expression of MK-1 and/or RegⅣ might be closely related to the carcinogenesis, clinical biological behaviors, and prognosis of gallbladder adenocarcinoma.</p

An All-Sky Search for Three Flavors of Neutrinos from Gamma-Ray Bursts with the IceCube Neutrino Observatory

We present the results and methodology of a search for neutrinos produced in the decay of charged pions created in interactions between protons and gamma-rays during the prompt emission of 807 gamma-ray bursts (GRBs) over the entire sky. This three-year search is the first in IceCube for shower-like Cherenkov light patterns from electron, muon, and tau neutrinos correlated with GRBs. We detect five low-significance events correlated with five GRBs. These events are consistent with the background expectation from atmospheric muons and neutrinos. The results of this search in combination with those of IceCube's four years of searches for track-like Cherenkov light patterns from muon neutrinos correlated with Northern-Hemisphere GRBs produce limits that tightly constrain current models of neutrino and ultra high energy cosmic ray production in GRB fireballs.Comment: 33 pages, 14 figures; minor changes made to match published version in the Astrophysical Journal, 2016 June 2

Improved limits on dark matter annihilation in the Sun with the 79-string IceCube detector and implications for supersymmetry

We present an improved event-level likelihood formalism for including neutrino telescope data in global fits to new physics. We derive limits on spin-dependent dark matter-proton scattering by employing the new formalism in a re-analysis of data from the 79-string IceCube search for dark matter annihilation in the Sun, including explicit energy information for each event. The new analysis excludes a number of models in the weak-scale minimal supersymmetric standard model (MSSM) for the first time. This work is accompanied by the public release of the 79-string IceCube data, as well as an associated computer code for applying the new likelihood to arbitrary dark matter models.Comment: 24 pages, 8 figs, 1 table. Contact authors: Pat Scott & Matthias Danninger. Likelihood tool available at http://nulike.hepforge.org. v2: small updates to address JCAP referee repor

The IceCube Neutrino Observatory: Instrumentation and Online Systems

The IceCube Neutrino Observatory is a cubic-kilometer-scale high-energy neutrino detector built into the ice at the South Pole. Construction of IceCube, the largest neutrino detector built to date, was completed in 2011 and enabled the discovery of high-energy astrophysical neutrinos. We describe here the design, production, and calibration of the IceCube digital optical module (DOM), the cable systems, computing hardware, and our methodology for drilling and deployment. We also describe the online triggering and data filtering systems that select candidate neutrino and cosmic ray events for analysis. Due to a rigorous pre-deployment protocol, 98.4% of the DOMs in the deep ice are operating and collecting data. IceCube routinely achieves a detector uptime of 99% by emphasizing software stability and monitoring. Detector operations have been stable since construction was completed, and the detector is expected to operate at least until the end of the next decade.Comment: 83 pages, 50 figures; updated with minor changes from journal review and proofin

Lowering IceCube’s energy threshold for point source searches in the southern sky

Observation of a point source of astrophysical neutrinos would be a "smoking gun" signature of a cosmic-ray accelerator. While IceCube has recently discovered a diffuse flux of astrophysical neutrinos, no localized point source has been observed. Previous IceCube searches for point sources in the southern sky were restricted by either an energy threshold above a few hundred TeV or poor neutrino angular resolution. Here we present a search for southern sky point sources with greatly improved sensitivities to neutrinos with energies below 100 TeV. By selecting charged-current nu(mu) interacting inside the detector, we reduce the atmospheric background while retaining efficiency for astrophysical neutrino-induced events reconstructed with sub-degree angular resolution. The new event sample covers three years of detector data and leads to a factor of 10 improvement in sensitivity to point sources emitting below 100 TeV in the southern sky. No statistically significant evidence of point sources was found, and upper limits are set on neutrino emission from individual sources. A posteriori analysis of the highest-energy (similar to 100 TeV) starting event in the sample found that this event alone represents a 2.8 sigma deviation from the hypothesis that the data consists only of atmospheric background

The search for transient astrophysical neutrino emission with IceCube-DeepCore

We present the results of a search for astrophysical sources of brief transient neutrino emission using IceCube and DeepCore data acquired between 2012 May 15 and 2013 April 30. While the search methods employed in this analysis are similar to those used in previous IceCube point source searches, the data set being examined consists of a sample of predominantly sub-TeV muon-neutrinos from the Northern Sky (-5 degrees < delta < 90 degrees) obtained through a novel event selection method. This search represents a first attempt by IceCube to identify astrophysical neutrino sources in this relatively unexplored energy range. The reconstructed direction and time of arrival of neutrino events are used to search for any significant self-correlation in the data set. The data revealed no significant source of transient neutrino emission. This result has been used to construct limits at timescales ranging from roughly 1 s to 10 days for generic soft-spectra transients. We also present limits on a specific model of neutrino emission from soft jets in core-collapse supernovae

Searches for sterile neutrinos with the IceCube detector

The IceCube neutrino telescope at the South Pole has measured the atmospheric muon neutrino spectrum as a function of zenith angle and energy in the approximate 320 GeV to 20 TeV range, to search for the oscillation signatures of light sterile neutrinos. No evidence for anomalous nu(mu) or (nu) over bar (mu) disappearance is observed in either of two independently developed analyses, each using one year of atmospheric neutrino data. New exclusion limits are placed on the parameter space of the 3 + 1 model, in which muon antineutrinos experience a strong Mikheyev-Smirnov-Wolfenstein-resonant oscillation. The exclusion limits extend to sin(2)2 theta(24) <= 0.02 at Delta m(2) similar to 0.3 eV(2) at the 90% confidence level. The allowed region from global analysis of appearance experiments, including LSND and MiniBooNE, is excluded at approximately the 99% confidence level for the global best-fit value of vertical bar U-e4 vertical bar(2)