Ablation of neuropilin 1 from glioma-associated microglia and macrophages slows tumor progression

Gliomas are the most commonly diagnosed primary tumors of the central nervous system (CNS). Median times of survival are dismal regardless of the treatment approach, underlying the need to develop more effective therapies. Modulation of the immune system is a promising strategy as innate and adaptive immunity play important roles in cancer progression. Glioma associated microglia and macrophages (GAMs) can comprise over 30% of the cells in glioma biopsies. Gliomas secrete cytokines that suppress the anti-tumorigenic properties of GAMs, causing them to secrete factors that support the tumor's spread and growth. Neuropilin 1 (Nrp1) is a transmembrane receptor that in mice both amplifies pro-angiogenic signaling in the tumor microenvironment and affects behavior of innate immune cells. Using a Cre-lox system, we generated mice that lack expression of Nrp1 in GAMs. We demonstrate, using an in vivo orthotopic glioma model, that tumors in mice with Nrp1-deficient GAMs exhibit less vascularity, grow at a slower pace, and are populated by increased numbers of anti-tumorigenic GAMs. Moreover, glioma survival times in mice with Nrp1-deficient GAMs were significantly longer. Treating wild-type mice with a small molecule inhibitor of Nrp1's b1 domain, EG00229, which we show here is selective for Nrp1 over Nrp2, yielded an identical outcome. Nrp1-deficient or EG00229-treated wild-type microglia exhibited a shift towards anti-tumorigenicity as evident by altered inflammatory marker profiles in vivo and decreased SMAD2/3 activation when conditioned in the presence of glioma-derived factors. These results provide support for the proposal that pharmacological inhibition of Nrp1 constitutes a potential strategy for suppressing glioma progression

Retraction Note: Identification of a novel Na+-coupled Fe3+-citrate transport system, distinct from mammalian INDY, for uptake of citrate in mammalian cells.

This paper has been retracted at the request of the authors

Performance of the Charge Injection Capability of Suzaku XIS

A charge injection technique is applied to the X-ray CCD camera, XIS (X-ray Imaging Spectrometer) onboard Suzaku. The charge transfer inefficiency (CTI) in each CCD column (vertical transfer channel) is measured by the injection of charge packets into a transfer channel and subsequent readout. This paper reports the performances of the charge injection capability based on the ground experiments using a radiation damaged device, and in-orbit measurements of the XIS. The ground experiments show that charges are stably injected with the dispersion of 91eV in FWHM in a specific column for the charges equivalent to the X-ray energy of 5.1keV. This dispersion width is significantly smaller than that of the X-ray events of 113eV (FWHM) at approximately the same energy. The amount of charge loss during transfer in a specific column, which is measured with the charge injection capability, is consistent with that measured with the calibration source. These results indicate that the charge injection technique can accurately measure column-dependent charge losses rather than the calibration sources. The column-to-column CTI correction to the calibration source spectra significantly reduces the line widths compared to those with a column-averaged CTI correction (from 193eV to 173eV in FWHM on an average at the time of one year after the launch). In addition, this method significantly reduces the low energy tail in the line profile of the calibration source spectrum.Comment: Paper contains 18 figures and 15 tables. Accepted for publication in PAS

Itinerant ferromagnetism in half-metallic CoS_2

We have investigated electronic and magnetic properties of the pyrite-type CoS_2 using the linearized muffin-tin orbital (LMTO) band method. We have obtained the ferromagnetic ground state with nearly half-metallic nature. The half-metallic stability is studied by using the fixed spin moment method. The non-negligible orbital magnetic moment of Co 3d electrons is obtained as $\mu_L = 0.06 \mu_B$ in the local spin density approximation (LSDA). The calculated ratio of the orbital to spin angular momenta / = 0.15 is consistent with experiment. The effect of the Coulomb correlation between Co 3d electrons is also explored with the LSDA + U method. The Coulomb correlation at Co sites is not so large, $U \lesssim 1$ eV, and so CoS_2 is possibly categorized as an itinerant ferromagnet. It is found that the observed electronic and magnetic behaviors of CoS_2 can be described better by the LSDA than by the LSDA + U.Comment: 4 pages, 3 postscript figure

Electrospun nanosized cellulose fibers using ionic liquids at room temperature

Aiming at replacing the noxious solvents commonly employed, ionic-liquid-based solvents have been recently explored as novel non-volatile and non-flammable media for the electrospinning of polymers. In this work, nanosized and biodegradable cellulose fibers were obtained by electrospinning at room temperature using a pure ionic liquid or a binary mixture of two selected ionic liquids. The electrospinning of 8 wt% cellulose in 1-ethyl-3-methylimidazolium acetate medium (a low viscosity and room temperature ionic liquid capable of efficiently dissolving cellulose) showed to produce electrospun fibers with average diameters within (470 ± 110) nm. With the goal of tailoring the surface tension of the spinning dope, a surface active ionic liquid was further added in a 0.10 : 0.90 mole fraction ratio. Electrospun cellulose fibers from the binary mixture composed of 1-ethyl-3-methylimidazolium acetate and 1-decyl-3-methylimidazolium chloride ionic liquids presented average diameters within (120 ± 55) nm. Scanning electron microscopy, X-ray diffraction analysis, nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy, and thermogravimetric assays were used as core methods to evaluate the structural integrity, morphology and crystallinity of the raw, electrospun, and regenerated samples of cellulose. Moreover, the photoluminescence spectra of both raw and electrospun fibers were acquired, and compared, indicating that the cellulose emitting centers are not affected by the dissolution of cellulose in ionic liquids. Finally, the use of non-volatile solvents in electrospinning coupled to a water coagulation bath allows the recovery of the ionic fluid, and represents a step forward into the search of environmentally friendly alternatives to the conventional approaches

A Compensatory Mutation Provides Resistance to Disparate HIV Fusion Inhibitor Peptides and Enhances Membrane Fusion

Fusion inhibitors are a class of antiretroviral drugs used to prevent entry of HIV into host cells. Many of the fusion inhibitors being developed, including the drug enfuvirtide, are peptides designed to competitively inhibit the viral fusion protein gp41. With the emergence of drug resistance, there is an increased need for effective and unique alternatives within this class of antivirals. One such alternative is a class of cyclic, cationic, antimicrobial peptides known as θ-defensins, which are produced by many non-human primates and exhibit broad-spectrum antiviral and antibacterial activity. Currently, the θ-defensin analog RC-101 is being developed as a microbicide due to its specific antiviral activity, lack of toxicity to cells and tissues, and safety in animals. Understanding potential RC-101 resistance, and how resistance to other fusion inhibitors affects RC-101 susceptibility, is critical for future development. In previous studies, we identified a mutant, R5-tropic virus that had evolved partial resistance to RC-101 during in vitro selection. Here, we report that a secondary mutation in gp41 was found to restore replicative fitness, membrane fusion, and the rate of viral entry, which were compromised by an initial mutation providing partial RC-101 resistance. Interestingly, we show that RC-101 is effective against two enfuvirtide-resistant mutants, demonstrating the clinical importance of RC-101 as a unique fusion inhibitor. These findings both expand our understanding of HIV drug-resistance to diverse peptide fusion inhibitors and emphasize the significance of compensatory gp41 mutations. © 2013 Wood et al

Lenticular nucleus correlates of general self-efficacy in young adults

General self-efficacy (GSE) is an important factor in education, social participation, and medical treatment. However, the only study that has investigated the direct association between GSE and a neural correlate did not identify specific brain regions, rather only assessed brain structures, and included older adult subjects. GSE is related to motivation, physical activity, learning, the willingness to initiate behaviour and expend effort, and adjustment. Thus, it was hypothesized in the present study that the neural correlates of GSE might be related to changes in the basal ganglia, which is a region related to the abovementioned self-efficacy factors. This study aimed to identify the brain structures associated with GSE in healthy young adults (n = 1204, 691 males and 513 females, age 20.7 ± 1.8 years) using regional grey matter density and volume (rGMD and rGMV), fractional anisotropy (FA) and mean diffusivity (MD) analyses of magnetic resonance imaging (MRI) data. The findings showed that scores on the GSE Scale (GSES) were associated with a lower MD value in regions from the right putamen to the globus pallidum; however, there were no significant association between GSES scores and regional brain structures using the other analyses (rGMD, rGMV, and FA). Thus, the present findings indicated that the lenticular nucleus is a neural correlate of GSE

Originality of divergent thinking is associated with working memory–related brain activity: evidence from a large sample study

The originality of creativity measured by divergent thinking (CMDT) is a unique variable that is positively correlated with psychometric intelligence and other psychological measures. Here, we aimed to determine the associations of CMDT originality/fluency scores and brain activity associated with working memory (WM) and simple cognitive processes during the N-back paradigm in a cohort of 1221 young adults. We observed that originality/fluency scores were associated with greater brain activity during the 0-back simple cognitive task and 2-back WM task in key nodes of the ventral attention system in the right hemisphere. Further, subjects with higher originality/fluency scores showed lower task-induced deactivations in areas of the default mode network, especially during the 2-back task. Psychological analyses revealed the associations of originality/fluency scores with both psychometric intelligence and systemizing. We also observed the effects of interaction between sex and originality/fluency scores on functional activity during the 0-back task in posterior parts of the default mode network together with other areas as well as simple processing speed. These results indicate that the originality of CMDT is associated with (a) greater activation of the ventral attention system, which is involved in reorienting attention and (b) reduced task-induced deactivation of the default mode network, which is indicative of alterations in attentional reallocation, and (c) cognitive correlates of originality of CMDT and revealed sex differences in these associations