Slowly expanding lesions relate to persisting black-holes and clinical outcomes in relapse-onset multiple sclerosis

Black holes; Chronic active lesions; Volumetric MRIAgujeros negros; Lesiones activas crónicas; Resonancia magnética volumétricaForats negres; Lesions actives cròniques; Ressonància magnètica volumètricaBackground Slowly expanding lesions (SELs) are MRI markers of chronic active lesions in multiple sclerosis (MS). T1-hypointense black holes, and reductions in magnetization transfer ratio (MTR) are pathologically correlated with myelin and axonal loss. While all associated with progressive MS, the relationship between these lesion’s metrics and clinical outcomes in relapse-onset MS has not been widely investigated. Objectives To explore the relationship of SELs with T1-hypointense black holes, and longitudinal T1 intensity contrast ratio and MTR, their correlation to brain volume, and their contribution to MS disability in relapse-onset patients. Methods 135 patients with relapsing-remitting MS (RRMS) were studied with clinical assessments and brain MRI (T2/FLAIR and T1-weighted scans at 1.5/3 T) at baseline and two subsequent follow-ups; a subset of 83 patients also had MTR acquisitions. Early-onset patients were defined when the baseline disease duration was ≤ 5 years (n = 85). SELs were identified using deformation field maps from the manually segmented baseline T2 lesions and differentiated from the non-SELs. Persisting black holes (PBHs) were defined as a subset of T2 lesions with a signal below a patient-specific grey matter T1 intensity in a semi-quantitative manner. SELs, PBH counts, and brain volume were computed, and their associations were assessed through Spearman and Pearson correlation. Clusters of patients according to low (up to 2), intermediate (3 to 10), or high (more than 10) SEL counts were determined with a Gaussian generalised mixture model. Mixed-effects and logistic regression models assessed volumes, T1 and MTR within SELs, and their correlation with Expanded Disability Status Scale (EDSS) and confirmed disability progression (CDP). Results Mean age at study onset was 35.5 years (73% female), disease duration 5.5 years and mean time to last follow-up 6.5 years (range 1 to 12.5); median baseline EDSS 1.5 (range 0 to 5.5) and a mean EDSS change of 0.31 units at final follow-up. Among 4007 T2 lesions, 27% were classified as SELs and 10% as PBHs. Most patients (n = 65) belonged to the cluster with an intermediate SEL count (3 to 10 SELs). The percentage of PBHs was higher in SELs than non-SELs (up to 61% vs 44%, p < 0.001) and within-patient SEL volumes positively correlated with PBH volumes (r = 0.53, p < 0.001). SELs showed a decrease in T1 intensity over time (beta = -0.004, 95%CI −0.005 to −0.003, p < 0.001), accompanied by lower cross-sectional baseline and follow-up MTR. In mixed-effects models, EDSS worsening was predicted by the SEL log-volumes increase over time (beta = 0.11, 95%CI 0.03 to 0.20, p = 0.01), which was confirmed in the sub-cohort of patients with early onset MS (beta = 0.14, 95%CI 0.04 to 0.25, p = 0.008). In logistic regressions, a higher risk for CDP was associated with SEL volumes (OR = 5.15, 95%CI 1.60 to 16.60, p = 0.006). Conclusions SELs are associated with accumulation of more destructive pathology as indicated by an association with PBH volume, longitudinal reduction in T1 intensity and MTR. Higher SEL volumes are associated with clinical progression, while lower ones are associated with stability in relapse-onset MS

Measuring emotional temperatures in Shakespeare’s drama

This paper demonstrates how the computational analysis of Shakespeare’s plays can map the emotional language used across individual plays and across the canon more broadly, affording new insights. It explains how we adapted the “sentiment analysis” tool SentiStrength for use with Early Modern English. Our analyses allow us to test out the long-held critical hypothesis that Shakespeare’s work moved from a comic to a “problem” and tragic period, and thence to a more optimistic redemptive mood in his last plays. The paper will also suggest how computational techniques can further understanding of genre, in particular the relationship between history and tragedy in Shakespeare’s work

Searching for dark galaxies: the AGES VC2 region

The VC2 strip (part of the AGES blind HI survey) spans 5x1 degrees of the Virgo Cluster, from the outskirts of the cluster to its interior. The strip covers part of subcluster A while avoiding the strong continuum source M87. 40 hours of observations were taken in January-February 2007 using the ALFA instrument on the Arecibo telescope, reaching a noise level as low as 0.5 mJy. For a 200 km/s velocity width, this gives a sensitivity limit of 6*10(6) Msolar at the Virgo distance (16 Mpc). Currently, 36 definite sources have been found, both by eye and with the automatic extractor Polyfind, with an additional 12 requiring follow-up observations, found only by one method

Novel human anti-claudin 1 mAbs inhibit hepatitis C virus infection and may synergize with anti-SRB1 mAb

Hepatitis C virus (HCV) is a major cause of chronic hepatitis and liver carcinoma and new therapies based on novel targets are needed. The tight junction protein claudin 1 (CLDN-1) is essential for HCV cell entry and spread, and anti-CLDN-1 rat and mouse mAbs are safe and effective in preventing and treating HCV infection in a human liver chimeric mouse model. To accelerate translation of these observations into a novel approach to treat HCV infection and disease in humans, we screened a phage display library of human single-chain antibody fragments by using a panel of CLDN-1-positive and -negative cell lines and identified phage specifically binding to CLDN-1. The 12 clones showing the highest levels of binding were converted into human IgG4. Some of these mAbs displayed low-nanomolar affinity, and inhibited infection of human hepatoma Huh7.5 cells by different HCV isolates in a dose-dependent manner. Cross-competition experiments identified six inhibitory mAbs that recognized distinct epitopes. Combination of the human anti-SRB1 mAb C-1671 with these anti-CLDN-1 mAbs could either increase or reduce inhibition of cell culture-derived HCV infection in vitro. These novel human anti-CLDN-1 mAbs are potentially useful to develop a new strategy for anti-HCV therapy and lend support to the combined use of antibodies targeting the HCV receptors CLDN-1 and SRB1, but indicate that care must be taken in selecting the proper combination

TBX21 methylation as a potential regulator of immune suppression in CMS1 subtype colorectal cancer

Cytotoxic T lymphocyte (CTL) infiltration is associated with survival, recurrence, and therapeutic response in colorectal cancer (CRC). Immune checkpoint inhibitor (ICI) therapy, which requires CTLs for response, does not work for most CRC patients. Therefore, it is critical to improve our understanding of immune resistance in this disease. We utilized 2391 CRC patients and 7 omics datasets, integrating clinical and genomic data to determine how DNA methylation may impact survival and CTL function in CRC. Using comprehensive molecular subtype (CMS) 1 patients as reference, we found TBX21 to be the only gene with altered expression and methylation that was associated with CTL infiltration. We found that CMS1 patients with high TBX21 expression and low methylation had a significant survival advantage. To confirm the role of Tbx21 in CTL function, we utilized scRNAseq data, demonstrating the association of TBX21 with markers of enhanced CTL function. Further analysis using pathway enrichment found that the genes TBX21, MX1, and SP140 had altered expression and methylation, suggesting that the TP53/P53 pathway may modify TBX21 methylation to upregulate TBX21 expression. Together, this suggests that targeting epigenetic modification more specifically for therapy and patient stratification may provide improved outcomes in CRC

Slowly expanding lesions relate to persisting black-holes and clinical outcomes in relapse-onset multiple sclerosis

Background: Slowly expanding lesions (SELs) are MRI markers of chronic active lesions in multiple sclerosis (MS). T1-hypointense black holes, and reductions in magnetization transfer ratio (MTR) are pathologically correlated with myelin and axonal loss. While all associated with progressive MS, the relationship between these lesion's metrics and clinical outcomes in relapse-onset MS has not been widely investigated. Objectives: To explore the relationship of SELs with T1-hypointense black holes, and longitudinal T1 intensity contrast ratio and MTR, their correlation to brain volume, and their contribution to MS disability in relapse-onset patients. Methods: 135 patients with relapsing-remitting MS (RRMS) were studied with clinical assessments and brain MRI (T2/FLAIR and T1-weighted scans at 1.5/3 T) at baseline and two subsequent follow-ups; a subset of 83 patients also had MTR acquisitions. Early-onset patients were defined when the baseline disease duration was &amp; LE; 5 years (n = 85). SELs were identified using deformation field maps from the manually segmented baseline T2 lesions and differentiated from the non-SELs. Persisting black holes (PBHs) were defined as a subset of T2 lesions with a signal below a patient-specific grey matter T1 intensity in a semi-quantitative manner. SELs, PBH counts, and brain volume were computed, and their associations were assessed through Spearman and Pearson correlation. Clusters of patients according to low (up to 2), intermediate (3 to 10), or high (more than 10) SEL counts were determined with a Gaussian generalised mixture model. Mixed-effects and logistic regression models assessed volumes, T1 and MTR within SELs, and their correlation with Expanded Disability Status Scale (EDSS) and confirmed disability progression (CDP). Results: Mean age at study onset was 35.5 years (73% female), disease duration 5.5 years and mean time to last follow-up 6.5 years (range 1 to 12.5); median baseline EDSS 1.5 (range 0 to 5.5) and a mean EDSS change of 0.31 units at final follow-up. Among 4007 T2 lesions, 27% were classified as SELs and 10% as PBHs. Most patients (n = 65) belonged to the cluster with an intermediate SEL count (3 to 10 SELs). The percentage of PBHs was higher in SELs than non-SELs (up to 61% vs 44%, p &lt; 0.001) and within-patient SEL volumes positively correlated with PBH volumes (r = 0.53, p &lt; 0.001). SELs showed a decrease in T1 intensity over time (beta = -0.004, 95%CI -0.005 to -0.003, p &lt; 0.001), accompanied by lower cross-sectional baseline and follow-up MTR. In mixed effects models, EDSS worsening was predicted by the SEL log-volumes increase over time (beta = 0.11, 95% CI 0.03 to 0.20, p = 0.01), which was confirmed in the sub-cohort of patients with early onset MS (beta = 0.14, 95%CI 0.04 to 0.25, p = 0.008). In logistic regressions, a higher risk for CDP was associated with SEL volumes (OR = 5.15, 95%CI 1.60 to 16.60, p = 0.006). Conclusions: SELs are associated with accumulation of more destructive pathology as indicated by an association with PBH volume, longitudinal reduction in T1 intensity , MTR. Higher SEL volumes are associated with clinical progression, while lower ones are associated with stability in relapse-onset MS

The SAMI Pilot Survey: stellar kinematics of galaxies in Abell 85, 168 and 2399

We present the SAMI Pilot Survey, consisting of integral field spectroscopy of 106 galaxies across three galaxy clusters, Abell 85, Abell 168 and Abell 2399. The galaxies were selected by absolute magnitude to have Mr < -20.25 mag. The survey, using the Sydney-AAO Multi-object Integral field spectrograph (SAMI), comprises observations of galaxies of all morphological types with 75 per cent of the sample being early-type galaxies (ETGs) and 25 per cent being late-type galaxies (LTGs). Stellar velocity and velocity dispersion maps are derived for all 106 galaxies in the sample. The lambdaR parameter, a proxy for the specific stellar angular momentum, is calculated for each galaxy in the sample. We find a trend between lambdaR and galaxy concentration such that LTGs are less concentrated higher angular momentum systems, with the fast-rotating ETGs (FRs) more concentrated and lower in angular momentum. This suggests that some dynamical processes are involved in transforming LTGs to FRs, though a significant overlap between the lambdaR distributions of these classes of galaxies implies that this is just one piece of a more complicated picture. We measure the kinematic misalignment angle, Psi, for the ETGs in the sample, to probe the intrinsic shapes of the galaxies. We find the majority of FRs (83 per cent) to be aligned, consistent with them being oblate spheroids (i.e. discs). The slow rotating ETGs (SRs), on the other hand, are significantly more likely to show kinematic misalignment (only 38 per cent are aligned). This confirms previous results that SRs are likely to be mildly triaxial systems

Targeting a host-cell entry factor barricades antiviral-resistant HCV variants from on-therapy breakthrough in human-liver mice

Objective: Direct-acting antivirals (DAAs) inhibit hepatitis C virus (HCV) infection by targeting viral proteins that play essential roles in the replication process. However, selection of resistance-associated variants (RAVs) during DAA therapy has been a cause of therapeutic failure. In this study, we wished to address whether such RAVs could be controlled by the co-administration of host-targeting entry inhibitors that prevent intrahepatic viral spread. Design: We investigated the effect of adding an entry inhibitor (the anti-scavenger receptor class B type I mAb1671) to a DAA monotherapy (the protease inhibitor ciluprevir) in human-liver mice chronically infected with HCV of genotype 1b. Clinically relevant non-laboratory strains were used to achieve viraemia consisting of a cloud of related viral variants (quasispecies) and the emergence of RAVs was monitored at high resolution using next-generation sequencing. Results: HCV-infected human-liver mice receiving DAA monotherapy rapidly experienced on-therapy viral breakthrough. Deep sequencing of the HCV protease domain confirmed the manifestation of drug-resistant mutants upon viral rebound. In contrast, none of the mice treated with a combination of the DAA and the entry inhibitor experienced on-therapy viral breakthrough, despite detection of RAV emergence in some animals. Conclusions: This study provides preclinical in vivo evidence that addition of an entry inhibitor to an anti-HCV DAA regimen restricts the breakthrough of DAA-resistant viruses. Our approach is an excellent strategy to prevent therapeutic failure caused by on-therapy rebound of DAA-RAVs. Inclusion of an entry inhibitor to the newest DAA combination therapies may further increase response rates, especially in difficult-to-treat patient populations

The SAMI Galaxy Survey: A Range in S0 Properties Indicating Multiple Formation Pathways

It has been proposed that S0 galaxies are either fading spirals or the result of galaxy mergers. The relative contribution of each pathway, and the environments in which they occur remains unknown. Here we investigate stellar and gas kinematics of 219 S0s in the SAMI Survey to look for signs of multiple formation pathways occurring across the full range of environments. We identify a large range of rotational support in their stellar kinematics, which correspond to ranges in their physical structure. We find that pressure-supported S0s with $v/{\sigma}$ below 0.5 tend to be more compact and feature misaligned stellar and gas components, suggesting an external origin for their gas. We postulate that these S0s are consistent with being formed through a merger process. Meanwhile, comparisons of ellipticity, stellar mass and S\'ersic index distributions with spiral galaxies shows that the rotationally supported S0s with $v/{\sigma}$ above 0.5 are more consistent with a faded spiral origin. In addition, a simulated merger pathway involving a compact elliptical and gas-rich satellite results in an S0 that lies within the pressure-supported group. We conclude that two S0 formation pathways are active, with mergers dominating in isolated galaxies and small groups, and the faded spiral pathway being most prominent in large groups ($10^{13} < M_{halo} < 10^{14}$).Comment: 14 pages, 12 figures, accepted for publication in MNRA

The SAMI galaxy survey: Can we trust aperture corrections to predict star formation?

In the low-redshift Universe (z < 0.3), our view of galaxy evolution is primarily based on fibre optic spectroscopy surveys. Elaborate methods have been developed to address aperture effects when fixed aperture sizes only probe the inner regions for galaxies of ever decreasing redshift or increasing physical size. These aperture corrections rely on assumptions about the physical properties of galaxies. The adequacy of these aperture corrections can be tested with integral-field spectroscopic data. We use integral-field spectra drawn from 1212 galaxies observed as part of the SAMI Galaxy Survey to investigate the validity of two aperture correction methods that attempt to estimate a galaxy's total instantaneous star formation rate. We show that biases arise when assuming that instantaneous star formation is traced by broad-band imaging, and when the aperture correction is built only from spectra of the nuclear region of galaxies. These biases may be significant depending on the selection criteria of a survey sample. Understanding the sensitivities of these aperture corrections is essential for correct handling of systematic errors in galaxy evolution studies