Abstract:The coherent elastic scattering of neutrinos off nuclei has eluded detection for four decades, even though its predicted cross-section is the largest by far of all low-energy neutrino couplings. This mode of interaction provides new opportunities to study neutrino properties, and leads to a miniaturization of detector size, with potential technological applications. We observe this process at a 6.7-sigma confidence level, using a low-background, 14.6-kg CsI [Na] scintillator exposed to the neutrino emissions from the Spallation Neutron Source (SNS) at Oak Ridge National Laboratory. Characteristic signatures in energy and time, predicted by the Standard Model for this process, are observed in high signal-to-background conditions. Improved constraints on non-standard neutrino interactions with quarks are derived from this initial dataset.The characteristic most often associated with neutrinos is a very small probability of interaction with other forms of matter, allowing them to traverse astronomical objects while undergoing no energy loss. As a result, large targets (tons to tens of kilotons) are used for their detection. The discovery of a weak neutral current in neutrino interactions (1) implied that neutrinos were capable of coupling to quarks through the exchange of neutral Z bosons. Soon thereafter it was suggested that this mechanism should also lead to coherent interactions between neutrinos and all nucleons present in an atomic nucleus (2). This possibility would exist only as long as the momentum exchanged remained significantly smaller than the inverse of the nuclear size ( Fig. 1A), effectively restricting the process to neutrino energies below a few tens of MeV.The enhancement to the probability of interaction (scattering cross-section) would however be very large when compared to interactions with isolated nucleons, approximately scaling with the square of the number of neutrons in the nucleus (2, 3). For heavy nuclei and sufficiently intense neutrino sources, this can lead to a dramatic reduction in detector mass, down to a few kilograms.Coherent elastic neutrino-nucleus scattering (CEnNS) has evaded experimental demonstration for forty-three years following its first theoretical description. This is somewhat surprising, in view of the magnitude of its expected cross-section relative to other tried-andtested neutrino couplings (Fig. 1B), and of the availability of suitable neutrino sources: solar, atmospheric and terrestrial, supernova bursts, nuclear reactors, spallation facilities, and certain radioisotopes (3). This delay stems from the difficulty in detecting the low-energy (few keV) nuclear recoil produced as the single outcome of the interaction. Compared to a minimum ionizing particle of the same energy, a recoiling nucleus has a diminished ability to generate measurable scintillation or ionization in common radiation detector materials. This is exacerbated by a trade-off between the enhancement to the CEnNS cross-section brought about by a large nuclear mass, and the smaller maxi...

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Kupffer cells and liver sinusoidal endothelial cells (LSEC) clear portal venous blood from gut-derived bacterial degradation products such as lipopolysaccharide (LPS) without inducing a local inflammatory reaction. LPS tolerance was reported for Kupffer cells, but little is known whether sensitivity of LSEC toward LPS is dynamically regulated. Here, we demonstrate that LSEC react to LPS directly as a function of constitutive Toll-like receptor 4 (TLR4)/CD14 expression but gain a LPS-refractory state upon repetitive stimulation without loss of scavenger activity. LPS tolerance in LSEC is characterized by reduced nuclear localization of nuclear factor-kappaB upon LPS rechallenge. In contrast to monocytes, however, TLR4 surface expression of LSEC is not altered by LPS stimulation and thus does not account for LPS tolerance. Mechanistically, LPS tolerance in LSEC is linked to prostanoid production and may account for cross-tolerance of LPS-treated LSEC to interferon-gamma stimulation. Functionally, LPS tolerance in LSEC results in reduced leukocyte adhesion following LPS rechallenge as a consequence of decreased CD54 surface expression. Furthermore, LPS tolerance is operative in vivo, as we observed by intravital microscopy-reduced leukocyte adhesion to LSEC and improved sinusoidal microcirculation in the liver after repetitive LPS challenges. Our results support the notion that LPS tolerance in organ-resident scavenger LSEC contributes to local hepatic control of inflammation.

Background Hepatosteatosis is associated with increased expression of tumor necrosis factor alpha (TNFα) and interleukin (IL)-12, major T helper (Th) 1 cytokines, and reduced hepatic NKT cell numbers. The relationship between lipid accumulation, cytokine expression, and hepatic NKT cells is not known. This study was conducted to assess the role of IL-12 in the development of hepatic steatosis and its potential impact on liver NKT cells. Methods Male C57Bl/6 wild type (Wt) and IL-12-deficient (IL12−/−) mice were fed a choline deficient diet (CDD) for 0, 10 or 20 weeks. Findings CDD led to marked hepatosteatosis, reduced hepatic but not splenic NKT cell numbers and function and increased hepatic expression of the Th1-type cytokines IL-12, interferon gamma (IFNγ) and TNFα in wt mice. Absence of IL-12 resulted in similar CDD-induced hepatosteatosis, but preserved hepatic NKT cells and significantly reduced hepatic IFNγ and TNFα expression. Treatment of CDD fed mice with lipopolysaccharide led to a significant increase in hepatic IL12 expression and Kupffer cell (KC)_depletion reduced liver IL-12 expression and restored NKT cells in CDD-induced fatty liver. Interestingly, KCs from CDD fed mice failed to produce increased quantities of IL12 upon activation in vitro when compared to similarly treated KCs from control fed mice suggesting that secondary factors in vivo promote heightened IL-12 production. Finally, human livers with severe steatosis showed a substantial decrease in NKT and NK cells. Conclusions Hepatosteatosis reduces the numbers of hepatic NKT cells in a KC and IL-12-dependent manner. Our results suggest a pivotal and multi-functional role of KC-derived IL-12 in the altered immune response in steatotic liver, a process which is likely active within human non-alcoholic fatty liver disease.