A clone of the continuous human T cell line HUT-102, termed YM 1.2, can spontaneously release alpha-LT in vitro. However, when stimulated with phorbol myristic acetate, these cells release other LT forms. These LT forms were purified to homogeneity by DEAE chromatography, column isoelectric focusing, and polyacrylamide gel electrophoresis. One LT form, termed LT-2, is a 79,000 m.w. component in aqueous solution and composed of 21,000 m.w. subunits. This form is immunologically related to macrophage-derived TNF and has a lytic capacity in vitro on K-562, Molt-4F, and Raji cells similar to that described for cytotoxins derived from NK effector cells, termed NK-CF. A second LT form, termed LT-3, is a single 69,000 m.w. peptide which could not be reduced into the smaller subunits. This form expresses antigens in common with both alpha-LT and TNF, because both anti-LT and anti-TNF were required to completely neutralize cell lytic activity in vitro. Functional testing revealed that the LT-3 form is lytic on all continuous cells tested in vitro, including NK-resistant target cells. The LT-3 component appears similar by immunologic, biochemical, and functional criteria to the LT form derived from primary human cytolytic T cells in vitro. At the levels tested, none of these LT-TNF forms had measurable effects on primary fibroblasts in vitro.

Cytolytic human T cells and the continuous human T cell line YM 1.2 can secrete a lymphotoxin (LT) form, termed LT-3, when stimulated in vitro. LT-3 is immunologically related to, but functionally distinct from, both alpha LT and tumor necrosis factor (TNF). Purified, native LT-3 and recombinant human LT and TNF were tested for their ability to destroy a panel of primary and continuous cell lines in vitro and cause necrosis of 8- to 9-day cutaneous Meth A tumors growing in BALB/c mice. LT-3 is more effective than either LT or TNF in inducing destruction of continuous cell lines in vitro. LT-3 induces destruction of cell lines that are resistant to both TNF and LT, and much less LT-3 is required to destroy cells that are LT and/or TNF sensitive. In contrast, none of these mediators had any measurable negative effects when tested on primary human fibroblasts. Additional studies revealed that LT-3 is also active in vivo and can cause necrosis of cutaneous Meth A tumors when administered intraperitoneally or intratumorally on BALB/c mice. LT-3 induces more rapid, consistent, and complete tumor necrosis than equivalent doses of either LT or TNF.

HIV-1 protease inhibitor (PI), nelfinavir (NFV) induced growth arrest and apoptosis of NCI-H460 and -H520, A549, EBC-1 and ABC-1 non-small-cell lung cancer (NSCLC) cells in association with upregulation of p21waf1, p27kip1 and p53, and downregulation of Bcl-2 and matrix metalloproteinase (MMP)-2 proteins. We found that NFV blocked Akt signalling in these cells as measured by Akt kinase assay with glycogen synthase kinase-3alpha/beta (GSK-3alpha/beta) as a substrate. To explore the role of Akt signalling in NFV-mediated growth inhibition of NSCLC cells, we blocked this signal pathway by transfection of Akt small interfering RNA (siRNA) in these cells; transient transfection of Akt siRNA in NCI-H460 cells decreased the level of Bcl-2 protein and slowed their proliferation compared to the nonspecific siRNA-transfected cells. Conversely, forced-expression of Akt partially reversed NFV-mediated growth inhibition of these cells, suggesting that Akt may be a molecular target of NFV in NSCLC cells. Also, we found that inhibition of Akt signalling by NFV enhanced the ability of docetaxel to inhibit the growth of NCI-H460 and -H520 cells, as measured by MTT assay. Importantly, NFV slowed the proliferation and induced apoptosis of NCI-H460 cells present as tumour xenografts in nude mice without adverse systemic effects. Taken together, this family of compounds might be useful for the treatment of individuals with NSCLC.

The effects of electron-electron correlations on the low-energy electronic structure and their relationship with unconventional superconductivity are central aspects in the research on iron-based pnictide superconductors. Here we use soft x-ray angle-resolved photoemission spectroscopy to study how electronic correlations evolve in different chemically substituted iron pnictides. We find that correlations are intrinsically related to the effective filling of the correlated orbitals, rather than to the filling obtained by valence counting. Combined density functional theory and dynamical mean-field theory calculations capture these effects, reproducing the experimentally observed trend in the correlation strength. The occupation-driven trend in the electronic correlation reported in our paper supports and extends the recently proposed connection between cuprate and pnictide phase diagrams.

Warm intervals within the Pliocene epoch (5.33-2.58 million years ago) were characterized by global temperatures comparable to those predicted for the end of this century and atmospheric CO 2 concentrations similar to today. Estimates for global sea level highstands during these times imply possible retreat of the East Antarctic ice sheet, but ice-proximal evidence from the Antarctic margin is scarce. Here we present new data from Pliocene marine sediments recovered offshore of Adélie Land, East Antarctica, that reveal dynamic behaviour of the East Antarctic ice sheet in the vicinity of the low-lying Wilkes Subglacial Basin during times of past climatic warmth. Sedimentary sequences deposited between 5.3 and 3.3 million years ago indicate increases in Southern Ocean surface water productivity, associated with elevated circum-Antarctic temperatures. The geochemical provenance of detrital material deposited during these warm intervals suggests active erosion of continental bedrock from within the Wilkes Subglacial Basin, an area today buried beneath the East Antarctic ice sheet. We interpret this erosion to be associated with retreat of the ice sheet margin several hundreds of kilometres inland and conclude that the East Antarctic ice sheet was sensitive to climatic warmth during the Pliocene. © 2013 Macmillan Publishers Limited. All rights reserved.

The mission of HL-2A is to explore the key physical topics relevant to ITER and to the advanced tokamak operation (e.g. the operation of future HL-2M), such as the access of H-mode, energetic particle physics, edge-localized mode (ELM) mitigation/suppression and disruption mitigation. Since the 2016 Fusion Energy Conference, the HL-2A team has focused on the investigations on the following areas: (i) pedestal dynamics and L-H transition, (ii) techniques of ELM control, (iii) turbulence and transport, (iv) energetic particle physics. The HL-2A results demonstrated that the increase of mean shear flow plays a key role in triggering L-I and I-H transitions, while the change of flow is mainly induced by the ion pressure gradient. Both mitigation and suppression of ELMs were realized by laser blow-off seeded impurity (Al, Fe, W). The 30% Ne mixture supersonic molecular beam injection seeding also robustly induced ELM mitigation. The ELMs were mitigated by low-hybrid current drive. The stabilization of m/n = 1/1 ion fishbone activities by electron cyclotron resonance heating was found on the HL-2A. A new m/n = 2/1 ion fishbone activity was observed recently, and the modelling indicated that passing fast ions dominantly contribute to the driving of 2/1 fishbone. The non-linear coupling between the toroidal Alfven eigenmode and tearing mode (TM) led to the generation of a high frequency mode with the toroidal mode number n = 0. The turbulence was modulated by TM when the island width exceeds a threshold and the modulation is localized merely in the inner area of the islands. Meanwhile, turbulence radial spread took place across the island region.

The multi-staged XENON program at INFN Laboratori Nazionali del Gran Sasso aims to detect dark matter with two-phase liquid xenon time projection chambers of increasing size and sensitivity. The XENONnT experiment is the latest detector in the program, planned to be an upgrade of its predecessor XENON1T. It features an active target of 5.9 tonnes of cryogenic liquid xenon (8.5 tonnes total mass in cryostat). The experiment is expected to extend the sensitivity to WIMP dark matter by more than an order of magnitude compared to XENON1T, thanks to the larger active mass and the significantly reduced background, improved by novel systems such as a radon removal plant and a neutron veto. This article describes the XENONnT experiment and its sub-systems in detail and reports on the detector performance during the first science run.

Preceding a core-collapse supernova (CCSN), various processes produce an increasing amount of neutrinos of all flavors characterized by mounting energies from the interior of massive stars. Among them, the electron antineutrinos are potentially detectable by terrestrial neutrino experiments such as KamLAND and Super-Kamiokande (SK) via inverse beta decay interactions. Once these pre-supernova (pre-SN) neutrinos are observed, an early warning of the upcoming CCSN can be provided. In light of this, KamLAND and SK, both located in the Kamioka mine in Japan, have been monitoring pre-SN neutrinos since 2015 and 2021, respectively. Recently, we performed a joint study between KamLAND and SK on pre-SN neutrino detection. A pre-SN alert system combining the KamLAND detector and the SK detector was developed and put into operation, which can provide a supernova alert to the astrophysics community. Fully leveraging the complementary properties of these two detectors, the combined alert is expected to resolve a pre-SN neutrino signal from a 15 M ⊙ star within 510 pc of the Earth at a significance level corresponding to a false alarm rate of no more than 1 per century. For a Betelgeuse-like model with optimistic parameters, it can provide early warnings up to 12 hr in advance.

The nature of dark matter and properties of neutrinos are among the most pressing issues in contemporary particle physics. The dual-phase xenon time-projection chamber is the leading technology to cover the available parameter space for Weakly Interacting Massive Particles (WIMPs), while featuring extensive sensitivity to many alternative dark matter candidates. These detectors can also study neutrinos through neutrinoless double-beta decay and through a variety of astrophysical sources. A next-generation xenon-based detector will therefore be a true multi-purpose observatory to significantly advance particle physics, nuclear physics, astrophysics, solar physics, and cosmology. This review article presents the science cases for such a detector.