Probing white-matter microstructure with higher-order diffusion tensors and susceptibility tensor MRI.

Diffusion MRI has become an invaluable tool for studying white matter microstructure and brain connectivity. The emergence of quantitative susceptibility mapping and susceptibility tensor imaging (STI) has provided another unique tool for assessing the structure of white matter. In the highly ordered white matter structure, diffusion MRI measures hindered water mobility induced by various tissue and cell membranes, while susceptibility sensitizes to the molecular composition and axonal arrangement. Integrating these two methods may produce new insights into the complex physiology of white matter. In this study, we investigated the relationship between diffusion and magnetic susceptibility in the white matter. Experiments were conducted on phantoms and human brains in vivo. Diffusion properties were quantified with the diffusion tensor model and also with the higher order tensor model based on the cumulant expansion. Frequency shift and susceptibility tensor were measured with quantitative susceptibility mapping and susceptibility tensor imaging. These diffusion and susceptibility quantities were compared and correlated in regions of single fiber bundles and regions of multiple fiber orientations. Relationships were established with similarities and differences identified. It is believed that diffusion MRI and susceptibility MRI provide complementary information of the microstructure of white matter. Together, they allow a more complete assessment of healthy and diseased brains

Concurrent MEK targeted therapy prevents MAPK pathway reactivation during BRAFV600E targeted inhibition in a novel syngeneic murine glioma model.

Inhibitors of BRAFV600E kinase are currently under investigations in preclinical and clinical studies involving BRAFV600E glioma. Studies demonstrated clinical response to such individualized therapy in the majority of patients whereas in some patients tumors continue to grow despite treatment. To study resistance mechanisms, which include feedback activation of mitogen-activated protein kinase (MAPK) signaling in melanoma, we developed a luciferase-modified cell line (2341luc) from a BrafV600E mutant and Cdkn2a- deficient murine high-grade glioma, and analyzed its molecular responses to BRAFV600E- and MAPK kinase (MEK)-targeted inhibition. Immunocompetent, syngeneic FVB/N mice with intracranial grafts of 2341luc were tested for effects of BRAFV600E and MEK inhibitor treatments, with bioluminescence imaging up to 14-days after start of treatment and survival analysis as primary indicators of inhibitor activity. Intracranial injected tumor cells consistently generated high-grade glioma-like tumors in syngeneic mice. Intraperitoneal daily delivery of BRAFV600E inhibitor dabrafenib only transiently suppressed MAPK signaling, and rather increased Akt signaling and failed to extend survival for mice with intracranial 2341luc tumor. MEK inhibitor trametinib delivered by oral gavage daily suppressed MAPK pathway more effectively and had a more durable anti-growth effect than dabrafenib as well as a significant survival benefit. Compared with either agent alone, combined BRAFV600E and MEK inhibitor treatment was more effective in reducing tumor growth and extending animal subject survival, as corresponding to sustained MAPK pathway inhibition. Results derived from the 2341luc engraftment model application have clinical implications for the management of BRAFV600E glioma

An important role for CD4 + T cells in adaptive immunity to Toxoplasma gondii in mice lacking the transcription factor Batf3

Immunity t

A Systematic Review of Minor Phytocannabinoids with Promising Neuroprotective Potential

Embase and Pubmed were systematically searched for articles addressing the neuroprotective properties of phytocannabinoids, aside from cannabidiol and Δ9‐tetrahydrocannabinol, including Δ9‐tetrahydrocannabinolic acid (Δ9‐THCA), Δ9‐tetrahydrocannabivarin (Δ9‐THCV), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabichromene (CBC), cannabichromenic acid (CBCA), cannabichromevarin (CBCV), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabigerivarin (CBGV), cannabigerovarinic acid (CBGVA), cannabichromevarinic acid (CBCVA) cannabidivarinic acid (CBDVA) and cannabinol (CBN). Out of 2,341 studies, 31 articles met inclusion criteria. CBG (range 5 mg.kg‐1 to 20 mg.kg‐1) and CBDV (range 0.2 mg.kg‐1 to 400 mg.kg‐1) displayed efficacy in models of Huntington’s disease and epilepsy. CBC (10‐75 mg.kg‐1), Δ9‐THCA (20 mg.kg‐1) and Δ9‐THCV (range 0.025‐2.5 mg.kg‐1) showed promise in models of seizure and hypomobility, Huntington’s and Parkinson’s disease. Limited mechanistic data showed CBG, VCE.003, VCE.003.2 and Δ9‐THCA mediated some of their effects through PPARy, but no other receptors were probed. Further studies with these phytocannabinoids, and their combinations, are warranted across a range of neurodegenerative disorders

The Carnegie Supernova Project: Analysis of the First Sample of Low-Redshift Type-Ia Supernovae

We present the analysis of the first set of low-redshift Type Ia supernovae (SNe Ia) by the Carnegie Supernova Project. Well-sampled, high-precision optical (ugriBV) and near-infrared (NIR; YJHKs) light curves obtained in a well-understood photometric system are used to provide light-curve parameters, and ugriBVYJH template light curves. The intrinsic colors at maximum light are calibrated to compute optical--NIR color excesses for the full sample, thus allowing the properties of the reddening law in the host galaxies to be studied. A low value of Rv~1.7, is derived when using the entire sample of SNe. However, when the two highly reddened SNe in the sample are excluded, a value Galactic standard of Rv~3.2 is obtained. The colors of these two events are well matched by a reddening model due to circumstellar dust. The peak luminosities are calibrated using a two-parameter linear fit to the decline rates and the colors, or alternatively, the color excesses. In both cases, dispersions in absolute magnitude of 0.12--0.16 mag are obtained, depending on the filter-color combination. In contrast to the results obtained from color excesses, these fits give Rv~1--2, even when the two highly reddened SNe are excluded. This discrepancy suggests that, beyond the "normal" interstellar reddening produced in the host galaxies, there is an intrinsic dispersion in the colors of SNe Ia which is correlated with luminosity but independent of the decline rate. Finally, a Hubble diagram is produced by combining the results of the fits for each filter. The resulting scatter of 0.12 mag appears to be limited by peculiar velocities as evidenced by the strong correlation between the distance-modulus residuals among the different filters. The implication is that the actual precision of SN Ia distances is 3--4%.Comment: 76 pages, 20 figures, accepted for publication in A

Ultracontinuous single haplotype genome assemblies for the domestic cat (Felis catus) and Asian leopard cat (Prionailurus bengalensis)

In addition to including one of the most popular companion animals, species from the cat family Felidae serve as a powerful system for genetic analysis of inherited and infectious disease, as well as for the study of phenotypic evolution and speciation. Previous diploid-based genome assemblies for the domestic cat have served as the primary reference for genomic studies within the cat family. However, these versions suffered from poor resolution of complex and highly repetitive regions, with substantial amounts of unplaced sequence that is polymorphic or copy number variable. We sequenced the genome of a female F1 Bengal hybrid cat, the offspring of a domestic cat (Felis catus) x Asian leopard cat (Prionailurus bengalensis) cross, with PacBio long sequence reads and used Illumina sequence reads from the parents to phase \u3e99.9% of the reads into the two species’ haplotypes. De novo assembly of the phased reads produced highly continuous haploid genome assemblies for the domestic cat and Asian leopard cat, with contig N50 statistics exceeding 83 Mb for both genomes. Whole genome alignments reveal the Felis and Prionailurus genomes are colinear, and the cytogenetic differences between the homologous F1 and E4 chromosomes represent a case of centromere repositioning in the absence of a chromosomal inversion. Both assemblies offer significant improvements over the previous domestic cat reference genome, with a 100% increase in contiguity and the capture of the vast majority of chromosome arms in one or two large contigs. We further demonstrated that comparably accurate F1 haplotype phasing can be achieved with members of the same species when one or both parents of the trio are not available. These novel genome resources will empower studies of feline precision medicine, adaptation and speciation

A triple nucleus in the Brightest Cluster Galaxy in Abell 193

We present a ground-based near-infrared K-band image and an HST/WFPC2 image of the brightest cluster galaxy in Abell 193 (IC 1695). This object was selected as the central cluster galaxy using X-ray information. Both images reveal a triple nucleus structure. Previously, this galaxy was thought to have only 2 nuclei. We present colours and magnitudes and a colour plot of the three nuclei. The nuclear structure and colours of the nuclei in this galaxy suggest that a merger may have taken place in its recent history.Comment: 5 pages, 3 figures, accepted for publication in MNRA