The pancreas responds to remote damage and systemic stress by secretion of the pancreatic secretory proteins PSP/regI and PAP/regIII.

In patients with infection and sepsis serum levels of Pancreatic Stone protein/regenerating protein I (PSP) are highly elevated. The origin of PSP during these conditions is presumably the pancreas, however, an intestinal origin cannot be excluded. Similarly, pancreatitis-associated protein (PAP) was identified in the pancreas. These proteins were also localized in intestinal organs. Here we aim to elucidate the bio-distribution of PSP and PAP in animal models of sepsis and in healthy humans. PSP and PAP responded to remote lesions in rats although the pancreatic response was much more pronounced than the intestinal. Tissue distribution of PSP demonstrated a 100-fold higher content in the pancreas compared to any other organ while PAP was most abundant in the small intestine. Both proteins responded to CLP or sham operation in the pancreas. PSP also increased in the intestine during CLP. The distribution of PSP and PAP in human tissue mirrored the distribution in the murine models. Distribution of PSP and PAP was visualized by immunohistochemistry. Rats and mice underwent midline laparotomies followed by mobilization of tissue and incision of the pancreatic duct or duodenum. Standard cecum-ligation-puncture (CLP) procedures or sham laparotomies were performed. Human tissue extracts were analyzed for PSP and PAP. The pancreas reacts to remote lesions and septic insults in mice and rats with increased PSP synthesis, while PAP is selectively responsive to septic events. Furthermore, our results suggest that serum PSP in septic patients is predominantly derived through an acute phase response of the pancreas

Exome-Wide Association Study on Alanine Aminotransferase Identifies Sequence Variants in the GPAM and APOE Associated With Fatty Liver Disease

Background & Aims: Fatty liver disease (FLD) is a growing epidemic that is expected to be the leading cause of end-stage liver disease within the next decade. Both environmental and genetic factors contribute to the susceptibility of FLD. Several genetic variants contributing to FLD have been identified in exome-wide association studies. However, there is still a missing hereditability indicating that other genetic variants are yet to be discovered. Methods: To find genes involved in FLD, we first examined the association of missense and nonsense variants with alanine aminotransferase at an exome-wide level in 425,671 participants from the UK Biobank. We then validated genetic variants with liver fat content in 8930 participants in whom liver fat measurement was available, and replicated 2 genetic variants in 3 independent cohorts comprising 2621 individuals with available liver biopsy. Results: We identified 190 genetic variants independently associated with alanine aminotransferase after correcting for multiple testing with Bonferroni method. The majority of these variants were not previously associated with this trait. Among those associated, there was a striking enrichment of genetic variants influencing lipid metabolism. We identified the variants rs2792751 in GPAM/GPAT1, the gene encoding glycerol-3-phosphate acyltransferase, mitochondrial, and rs429358 in APOE, the gene encoding apolipoprotein E, as robustly associated with liver fat content and liver disease after adjusting for multiple testing. Both genes affect lipid metabolism in the liver. Conclusions: We identified 2 novel genetic variants in GPAM and APOE that are robustly associated with steatosis and liver damage. These findings may help to better elucidate the genetic susceptibility to FLD onset and progression

The TM6SF2 E167K genetic variant induces lipid biosynthesis and reduces apolipoprotein B secretion in human hepatic 3D spheroids

There is a high unmet need for developing treatments for nonalcoholic fatty liver disease (NAFLD), for which there are no approved drugs today. Here, we used a human in vitro disease model to understand mechanisms linked to genetic risk variants associated with NAFLD. The model is based on 3D spheroids from primary human hepatocytes from five different donors. Across these donors, we observed highly reproducible differences in the extent of steatosis induction, demonstrating that inter-donor variability is reflected in the in vitro model. Importantly, our data indicates that the genetic variant TM6SF2 E167K, previously associated with increased risk for NAFLD, induces increased hepatocyte fat content by reducing APOB particle secretion. Finally, differences in gene expression pathways involved in cholesterol, fatty acid and glucose metabolism between wild type and TM6SF2 E167K mutation carriers (N = 125) were confirmed in the in vitro model. Our data suggest that the 3D in vitro spheroids can be used to investigate the mechanisms underlying the association of human genetic variants associated with NAFLD. This model may also be suitable to discover new treatments against NAFLD

Identification, localization and functional in vitro and in vivo activity of oxytocin receptor in the rat penis

We recently found that the oxytocin receptor (OTR) is expressed in the human and rabbit corpus cavernosum and mediates contractility in vitro. The present study extended our investigations to the rat, and explored whether OTR regulates penile detumescence in vivo. Real-time RT-PCR quantitatively characterized the distribution of OTR mRNA in the male genital tract. Specific transcripts for OTR were expressed in all the tissues investigated. Penile expression of OTR was comparable to that observed in testis and prostate. Western blot analysis detected a single band of the expected molecular mass for OTR in all tissues examined, including rat penis. Expression of OTR protein in rat penile extracts was further confirmed by binding studies, using the OTR selective radiolabeled ligand 125I-OTA (Kd=17 ± 6.5 pM, Bmax=15.7 ± 5 fmoles/mg protein). OTR was immunolocalized to the endothelial and smooth muscle compartments of cavernous spaces and blood vessels. In rat corpus cavernosum strips, oxytocin (OT) and an OTR selective agonist ([Thr4,Gly7]OT) induced identical increases in tension, while different vasopressin agonists were less active. In vivo, OT intra-cavernous injection (ICI) dose-dependently inhibited intracavernous pressure (ICP) increase elicited by either electrical stimulation of the cavernous nerve or ICI of papaverine with similar IC50s (117.7 ± 37 mU). The OTR antagonist, atosiban, counteracted the contractile effect of OT both in vitro and in vivo. Atosiban alone significantly increased ICP at lower stimulation frequencies (2 Hz=P<0.001 and 4 Hz=P<0.05 vs control), but not at the maximal frequency (16 Hz). Our data showed that OTR is present in the rat penis and mediates contractility both in vitro and in vivo, therefore suggesting a role for OT in maintaining penile detumescence

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

Observation and Characterization of a Cosmic Muon Neutrino Flux from the Northern Hemisphere using six years of IceCube data

The IceCube Collaboration has previously discovered a high-energy astrophysical neutrino flux using neutrino events with interaction vertices contained within the instrumented volume of the IceCube detector. We present a complementary measurement using charged current muon neutrino events where the interaction vertex can be outside this volume. As a consequence of the large muon range the effective area is significantly larger but the field of view is restricted to the Northern Hemisphere. IceCube data from 2009 through 2015 have been analyzed using a likelihood approach based on the reconstructed muon energy and zenith angle. At the highest neutrino energies between 191 TeV and 8.3 PeV a significant astrophysical contribution is observed, excluding a purely atmospheric origin of these events at $5.6\,\sigma$ significance. The data are well described by an isotropic, unbroken power law flux with a normalization at 100 TeV neutrino energy of $\left(0.90^{+0.30}_{-0.27}\right)\times10^{-18}\,\mathrm{GeV^{-1}\,cm^{-2}\,s^{-1}\,sr^{-1}}$ and a hard spectral index of $\gamma=2.13\pm0.13$. The observed spectrum is harder in comparison to previous IceCube analyses with lower energy thresholds which may indicate a break in the astrophysical neutrino spectrum of unknown origin. The highest energy event observed has a reconstructed muon energy of $(4.5\pm1.2)\,\mathrm{PeV}$ which implies a probability of less than 0.005% for this event to be of atmospheric origin. Analyzing the arrival directions of all events with reconstructed muon energies above 200 TeV no correlation with known $\gamma$-ray sources was found. Using the high statistics of atmospheric neutrinos we report the currently best constraints on a prompt atmospheric muon neutrino flux originating from charmed meson decays which is below $1.06$ in units of the flux normalization of the model in Enberg et al. (2008).Comment: 20 pages, 21 figure

All-sky search for time-integrated neutrino emission from astrophysical sources with 7 years of IceCube data

Since the recent detection of an astrophysical flux of high energy neutrinos, the question of its origin has not yet fully been answered. Much of what is known about this flux comes from a small event sample of high neutrino purity, good energy resolution, but large angular uncertainties. In searches for point-like sources, on the other hand, the best performance is given by using large statistics and good angular reconstructions. Track-like muon events produced in neutrino interactions satisfy these requirements. We present here the results of searches for point-like sources with neutrinos using data acquired by the IceCube detector over seven years from 2008--2015. The discovery potential of the analysis in the northern sky is now significantly below $E_\nu^2d\phi/dE_\nu=10^{-12}\:\mathrm{TeV\,cm^{-2}\,s^{-1}}$, on average $38\%$ lower than the sensitivity of the previously published analysis of four years exposure. No significant clustering of neutrinos above background expectation was observed, and implications for prominent neutrino source candidates are discussed.Comment: 19 pages, 17 figures, 3 tables; ; submitted to The Astrophysical Journa

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