New measurement of the scattering cross section of slow neutrons on liquid parahydrogen from neutron transmission

Liquid hydrogen is a dense Bose fluid whose equilibrium properties are both calculable from first principles using various theoretical approaches and of interest for the understanding of a wide range of questions in many body physics. Unfortunately, the pair correlation function $g(r)$ inferred from neutron scattering measurements of the differential cross section $d\sigma \over d\Omega$ from different measurements reported in the literature are inconsistent. We have measured the energy dependence of the total cross section and the scattering cross section for slow neutrons with energies between 0.43~meV and 16.1~meV on liquid hydrogen at 15.6~K (which is dominated by the parahydrogen component) using neutron transmission measurements on the hydrogen target of the NPDGamma collaboration at the Spallation Neutron Source at Oak Ridge National Laboratory. The relationship between the neutron transmission measurement we perform and the total cross section is unambiguous, and the energy range accesses length scales where the pair correlation function is rapidly varying. At 1~meV our measurement is a factor of 3 below the data from previous work. We present evidence that these previous measurements of the hydrogen cross section, which assumed that the equilibrium value for the ratio of orthohydrogen and parahydrogen has been reached in the target liquid, were in fact contaminated with an extra non-equilibrium component of orthohydrogen. Liquid parahydrogen is also a widely-used neutron moderator medium, and an accurate knowledge of its slow neutron cross section is essential for the design and optimization of intense slow neutron sources. We describe our measurements and compare them with previous work.Comment: Edited for submission to Physical Review

Zirconium Metal-Organic Polyhedra with Dual Behavior for Organophosphate Poisoning Treatment

Organophosphate nerve agents and pesticides are extremely toxic compounds because they result in acetylcholinesterase (AChE) inhibition and concomitant nerve system damage. Herein, we report the synthesis, structural characterization, and proof-of-concept utility of zirconium metal-organic polyhedra (Zr-MOPs) for organophosphate poisoning treatment. The results show the formation of robust tetrahedral cages [((n-butylCpZr)3(OH)3O)4L6]Cl6(Zr-MOP-1; L = benzene-1,4-dicarboxylate, n-butylCp = n-butylcyclopentadienyl, Zr-MOP-10, and L = 4,4′-biphenyldicarboxylate) decorated with lipophilic alkyl residues and possessing accessible cavities of ∼9.8 and ∼10.7 Å inner diameters, respectively. These systems are able to both capture the organophosphate model compound diisopropylfluorophosphate (DIFP) and host and release the AChE reactivator drug pralidoxime (2-PAM). The resulting 2-PAM@Zr-MOP-1(0) host-guest assemblies feature a sustained delivery of 2-PAM under simulated biological conditions, with a concomitant reactivation of DIFP-inhibited AChE. Finally, 2-PAM@Zr-MOP systems have been incorporated into biocompatible phosphatidylcholine liposomes with the resulting assemblies being non-neurotoxic, as proven using neuroblastoma cell viability assays

Heterologous expression screens in Nicotiana benthamiana identify a candidate effector of the wheat Yellow Rust Pathogen that associates with processing bodies

Rust fungal pathogens of wheat (Triticum spp.) affect crop yields worldwide. The molecular mechanisms underlying the virulence of these pathogens remain elusive, due to the limited availability of suitable molecular genetic research tools. Notably, the inability to perform high-throughput analyses of candidate virulence proteins (also known as effectors) impairs progress. We previously established a pipeline for the fast-forward screens of rust fungal candidate effectors in the model plant Nicotiana benthamiana. This pipeline involves selecting candidate effectors in silico and performing cell biology and protein-protein interaction assays in planta to gain insight into the putative functions of candidate effectors. In this study, we used this pipeline to identify and characterize sixteen candidate effectors from the wheat yellow rust fungal pathogen Puccinia striiformis f sp tritici. Nine candidate effectors targeted a specific plant subcellular compartment or protein complex, providing valuable information on their putative functions in plant cells. One candidate effector, PST02549, accumulated in processing bodies (P-bodies), protein complexes involved in mRNA decapping, degradation, and storage. PST02549 also associates with the P-body-resident ENHANCER OF mRNA DECAPPING PROTEIN 4 (EDC4) from N. benthamiana and wheat. We propose that P-bodies are a novel plant cell compartment targeted by pathogen effectors

Physiological lentiviral vectors for the generation of improved CAR-T cells

Anti-CD19 chimeric antigen receptor (CAR)-T cells have achieved impressive outcomes for the treatment of relapsed and refractory B-lineage neoplasms. However, important limitations still remain due to severe adverse events (i.e., cytokine release syndrome and neuroinflammation) and relapse of 40%-50% of the treated patients. Most CAR-T cells are generated using retroviral vectors with strong promoters that lead to high CAR expression levels, tonic signaling, premature exhaustion, and overstimulation, reducing efficacy and increasing side effects. Here, we show that lentiviral vectors (LVs) expressing the transgene through a WAS gene promoter (AW-LVs) closely mimic the T cell receptor (TCR)/CD3 expression kinetic upon stimulation. These AW-LVs can generate improved CAR-T cells as a consequence of their moderate and TCR-like expression profile. Compared with CAR-T cells generated with human elongation factor alpha (EF1 alpha)-driven-LVs, AW-CAR-T cells exhibited lower tonic signaling, higher proportion of naive and stem cell memory T cells, less exhausted phenotype, and milder secretion of tumor necrosis factor alpha (TNF-alpha) and interferon (IFN)-gamma after efficient destruction of CD19(+) lymphoma cells, both in vitro and in vivo. Moreover, we also showed their improved efficiency using an in vitro CD19(+) pancreatic tumor model. We finally demonstrated the feasibility of large-scale manufacturing of AW-CAR-T cells in guanosine monophosphate (GMP)-like conditions. Based on these data, we propose the use of AWLVs for the generation of improved CAR-T products

Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors

Delta-9-tetrahydrocannabinol (THC), the main psychoactive compound of marijuana, induces numerous undesirable effects, including memory impairments, anxiety, and dependence. Conversely, THC also has potentially therapeutic effects, including analgesia, muscle relaxation, and neuroprotection. However, the mechanisms that dissociate these responses are still not known. Using mice lacking the serotonin receptor 5-HT2A, we revealed that the analgesic and amnesic effects of THC are independent of each other: while amnesia induced by THC disappears in the mutant mice, THC can still promote analgesia in these animals. In subsequent molecular studies, we showed that in specific brain regions involved in memory formation, the receptors for THC and the 5-HT2A receptors work together by physically interacting with each other. Experimentally interfering with this interaction prevented the memory deficits induced by THC, but not its analgesic properties. Our results highlight a novel mechanism by which the beneficial analgesic properties of THC can be dissociated from its cognitive side effects

Physical mixing effects on iron biogeochemical cycling: FeCycle experiment

The effects of physical processes on the distribution, speciation, and sources/sinks for Fe in a high-nutrient low-chlorophyll (HNLC) region were assessed during FeCycle, a mesoscale SF6 tracer release during February 2003 (austral summer) to the SE of New Zealand. Physical mixing processes were prevalent during FeCycle with rapid patch growth (strain rate γ = 0.17–0.20 d−1) from a circular shape (50 km2) into a long filament of ∼400 km2 by day 10. Slippage between layers saw the patch-head overlying noninfused waters while the tail was capped by adjacent surface waters resulting in a SF6 maximum at depth. As the patch developed it entrained adjacent waters containing higher chlorophyll concentrations, but similar dissolved iron (DFe) levels, than the initial infused patch. DFe was low ∼60 pmol L−1 in surface waters during FeCycle and was dominated by organic complexation. Nighttime measurements of Fe(II) ∼20 pmol L−1 suggest the presence of Fe(II) organic complexes in the absence of an identifiable fast Fe(III) reduction process. Combining residence times and phytoplankton uptake fluxes for DFe it is cycled through the biota 140–280 times before leaving the winter mixed layer (WML). This strong Fe demand throughout the euphotic zone coupled with the low Fe:NO3 − (11.9 μmol:mol) below the ferricline suggests that vertical diffusion of Fe is insufficient to relieve chronic iron limitation, indicating the importance of atmospheric inputs of Fe to this region

Future therapeutic targets in rheumatoid arthritis?

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint inflammation. Without adequate treatment, patients with RA will develop joint deformity and progressive functional impairment. With the implementation of treat-to-target strategies and availability of biologic therapies, the outcomes for patients with RA have significantly improved. However, the unmet need in the treatment of RA remains high as some patients do not respond sufficiently to the currently available agents, remission is not always achieved and refractory disease is not uncommon. With better understanding of the pathophysiology of RA, new therapeutic approaches are emerging. Apart from more selective Janus kinase inhibition, there is a great interest in the granulocyte macrophage-colony stimulating factor pathway, Bruton's tyrosine kinase pathway, phosphoinositide-3-kinase pathway, neural stimulation and dendritic cell-based therapeutics. In this review, we will discuss the therapeutic potential of these novel approaches

Multiplicity dependence of jet-like two-particle correlations in p-Pb collisions at sNN\sqrt{s_{NN}} = 5.02 TeV

Two-particle angular correlations between unidentified charged trigger and associated particles are measured by the ALICE detector in p-Pb collisions at a nucleon-nucleon centre-of-mass energy of 5.02 TeV. The transverse-momentum range 0.7 $< p_{\rm{T}, assoc} < p_{\rm{T}, trig} <$ 5.0 GeV/$c$ is examined, to include correlations induced by jets originating from low momen\-tum-transfer scatterings (minijets). The correlations expressed as associated yield per trigger particle are obtained in the pseudorapidity range $|\eta|<0.9$. The near-side long-range pseudorapidity correlations observed in high-multiplicity p-Pb collisions are subtracted from both near-side short-range and away-side correlations in order to remove the non-jet-like components. The yields in the jet-like peaks are found to be invariant with event multiplicity with the exception of events with low multiplicity. This invariance is consistent with the particles being produced via the incoherent fragmentation of multiple parton--parton scatterings, while the yield related to the previously observed ridge structures is not jet-related. The number of uncorrelated sources of particle production is found to increase linearly with multiplicity, suggesting no saturation of the number of multi-parton interactions even in the highest multiplicity p-Pb collisions. Further, the number scales in the intermediate multiplicity region with the number of binary nucleon-nucleon collisions estimated with a Glauber Monte-Carlo simulation.Comment: 23 pages, 6 captioned figures, 1 table, authors from page 17, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/161