Intrinsically chiral ferronematic liquid crystals : An inversion of the helical twist sense at the chiral nematic – Chiral ferronematic phase transition

Funding Information: The research was supported by the National Science Centre (Poland) under the grant no. 2016/22/A/ST5/00319. C.T.I. and J.M.D.S. acknowledge the financial support of the Engineering and Physical Sciences Research Council [EP/V048775/1].Peer reviewedPostprin

Ferroelectric Nematic-Isotropic Liquid Critical End Point

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NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Hepatocellular carcinoma (HCC) can have viral or non-viral causes(1-5). Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need(6,7). Here we report the progressive accumulation of exhausted, unconventionally activated CD8(+)PD1(+) T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8(+)PD1(+) T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8(+)PD1(+)CXCR6(+), TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8(+) T cells or TNF neutralization, suggesting that CD8(+) T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8(+)PD1(+) T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment

The P2 Receptor Antagonist PPADS Supports Recovery from Experimental Stroke In Vivo

BACKGROUND: After ischemia of the CNS, extracellular adenosine 5'-triphosphate (ATP) can reach high concentrations due to cell damage and subsequent increase of membrane permeability. ATP may cause cellular degeneration and death, mediated by P2X and P2Y receptors. METHODOLOGY/PRINCIPAL FINDINGS: The effects of inhibition of P2 receptors by pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) on electrophysiological, functional and morphological alterations in an ischemia model with permanent middle cerebral artery occlusion (MCAO) were investigated up to day 28. Spontaneously hypertensive rats received PPADS or vehicle intracerebroventricularly 15 minutes prior MCAO for up to 7 days. The functional recovery monitored by qEEG was improved by PPADS indicated by an accelerated recovery of ischemia-induced qEEG changes in the delta and alpha frequency bands along with a faster and sustained recovery of motor impairments. Whereas the functional improvements by PPADS were persistent at day 28, the infarct volume measured by magnetic resonance imaging and the amount of TUNEL-positive cells were significantly reduced by PPADS only until day 7. Further, by immunohistochemistry and confocal laser scanning microscopy, we identified both neurons and astrocytes as TUNEL-positive after MCAO. CONCLUSION: The persistent beneficial effect of PPADS on the functional parameters without differences in the late (day 28) infarct size and apoptosis suggests that the early inhibition of P2 receptors might be favourable for the maintenance or early reconstruction of neuronal connectivity in the periinfarct area after ischemic incidents

PEGylated Liposomes as Carriers of Hydrophobic Porphyrins

Sterically stabilized liposomes (SSLs) (PEGylated liposomes) are applied as e ff ective drug delivery vehicles. Under- standing the interactions between hydrophobic compounds and PEGylated membranes is therefore important to determine the e ff ectiveness of PEGylated liposomes for delivery of drugs or other bioactive substances. In this study, we have combined fl uorescence quenching analysis (FQA) experiments and all-atom molecular dynamics (MD) simulations to study the e ff ect of membrane PEGylation on the location and orientation of 5,10,15,20-tetrakis(4- hydroxyphenyl)porphyrin (p-THPP) that has been used in our study as a model hydrophobic compound. First, we consider the properties of p-THPP in the presence of di ff erent fl uid phosphatidylcholine bilayers that we use as model systems for protein-free cell membranes. Next, we studied the interaction between PEGylated membranes and p-THPP. Our MD simulation results indicated that the arrangement of p-THPP within zwitterionic membranes is dependent on their free volume, and p-THPP solubilized in PEGylated liposomes is localized in two preferred positions: deep within the membrane (close to the center of the bilayer) and in the outer PEG corona (p-THPP molecules being wrapped with the polymer chains). Fluorescence quenching methods con fi rmed the results of atomistic MD simulations and showed two populations of p-THPP molecules as in MD simulations. Our results provide both an explanation for the experimental observation that PEGylation improves the drug-loading e ffi ciency of membranes and also a more detailed molecular-level description of the interactions between porphyrins and lipid membranes

Magnetized plasma implosion in a snail target driven by a moderateintensity laser pulse

Optical generation of compact magnetized plasma structures is studied in the moderate intensity domain. A sub-ns laser beam irradiated snail-shaped targets with the intensity of about 10(16) W/cm(2). With a neat optical diagnostics, a sub-megagauss magnetized plasmoid is traced inside the target. On the observed hydrodynamic time scale, the hot plasma formation achieves a theta-pinch-like density and magnetic field distribution, which implodes into the target interior. This simple and elegant plasma magnetization scheme in the moderate-intensity domain is of particular interest for fundamental astrophysical-related studies and for development of future technologies © The Author(s) 201