Metabolic Profiling of IDH Mutation and Malignant Progression in Infiltrating Glioma.

Infiltrating low grade gliomas (LGGs) are heterogeneous in their behavior and the strategies used for clinical management are highly variable. A key factor in clinical decision-making is that patients with mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/2) oncogenes are more likely to have a favorable outcome and be sensitive to treatment. Because of their relatively long overall median survival, more aggressive treatments are typically reserved for patients that have undergone malignant progression (MP) to an anaplastic glioma or secondary glioblastoma (GBM). In the current study, ex vivo metabolic profiles of image-guided tissue samples obtained from patients with newly diagnosed and recurrent LGG were investigated using proton high-resolution magic angle spinning spectroscopy (1H HR-MAS). Distinct spectral profiles were observed for lesions with IDH-mutated genotypes, between astrocytoma and oligodendroglioma histologies, as well as for tumors that had undergone MP. Levels of 2-hydroxyglutarate (2HG) were correlated with increased mitotic activity, axonal disruption, vascular neoplasia, and with several brain metabolites including the choline species, glutamate, glutathione, and GABA. The information obtained in this study may be used to develop strategies for in vivo characterization of infiltrative glioma, in order to improve disease stratification and to assist in monitoring response to therapy

Short GRB 130603B: Discovery of a jet break in the optical and radio afterglows, and a mysterious late-time X-ray excess

We present radio, optical/NIR, and X-ray observations of the afterglow of the short-duration 130603B, and uncover a break in the radio and optical bands at 0.5 d after the burst, best explained as a jet break with an inferred jet opening angle of 4-8 deg. GRB 130603B is only the third short GRB with a radio afterglow detection to date, and the first time that a jet break is evident in the radio band. We model the temporal evolution of the spectral energy distribution to determine the burst explosion properties and find an isotropic-equivalent kinetic energy of (0.6-1.7) x 10^51 erg and a circumburst density of 5 x 10^-3-30 cm^-3. From the inferred opening angle of GRB 130603B, we calculate beaming-corrected energies of Egamma (0.5-2) x 10^49 erg and EK (0.1-1.6) x 10^49 erg. Along with previous measurements and lower limits we find a median short GRB opening angle of 10 deg. Using the all-sky observed rate of 10 Gpc^-3 yr^-1, this implies a true short GRB rate of 20 yr^-1 within 200 Mpc, the Advanced LIGO/VIRGO sensitivity range for neutron star binary mergers. Finally, we uncover evidence for significant excess emission in the X-ray afterglow of GRB 130603B at >1 d and conclude that the additional energy component could be due to fall-back accretion or spin-down energy from a magnetar formed following the merger.Comment: Submitted to ApJ; emulateapj style; 10 pages, 1 table, 3 figure

Runaway dynamics in reactor-scale spherical tokamak disruptions

Understanding generation and mitigation of runaway electrons in disruptions is important for the safe operation of future tokamaks. In this paper we investigate the runaway dynamics in reactor-scale spherical tokamaks, focusing on a compact nominal design with a plasma current of 21 megaamperes (MA), 1.8 T magnetic field on axis and major radius of approximately 3 m. We study both the severity of runaway generation during unmitigated disruptions, and the effect that typical mitigation schemes based on massive material injection have on runaway production. The study is conducted using the numerical framework DREAM (Disruption Runaway Electron Analysis Model). We find that, in many cases, mitigation strategies are necessary to prevent the runaway current from reaching multi-MA levels. Our results indicate that, with a suitably chosen deuterium–neon mixture for mitigation, it is possible to achieve a tolerable runaway current and ohmic current evolution. However, this does not account for the runaway source due to wall activation, which has been found to severely limit successful mitigation at conventional aspect ratios, but whose definition requires a more complete wall specification. Furthermore, the majority of the thermal energy loss is found to happen through radial transport rather than radiation, which poses a risk of unacceptable localised heat loads

Expression of H3K4me3 and H3K9ac in breast cancer

PURPOSE Breast cancer is the leading cause of cancer death in females. Histone modifications have been shown to have an influence on the gene expression. This study focusses on the histone modifications H3K9ac and H3K4me3 in breast cancer and their impact on survival METHODS: H3K4me3 and H3K9ac expression was immunohistochemically examined in 235 tissue samples. RESULTS Positive estrogen receptor status was correlated with a higher IRS of the nuclear (p = 0.033), and of the cytoplasmic H3K4me3 staining (p = 0.009). H3K9ac intensity was associated to the Her2 status (p = 0.045) and to poor prognosis in cells with positive Ki67 status (p = 0.013). A high intensity of nuclear H3K4me3 staining was found to be correlated with a lower 10-year-survival (p = 0.026) and with lower breast cancer-specific survival (p = 0.004). High percentage score (> 190) of H3K9ac expression was correlated to worse breast cancer-specific survival (p = 0.005). Shorter progression-free survival was found in patients with nuclear (p = 0.013) and cytoplasmic H3K4me3expression (p = 0.024) and H3K9ac expression (p = 0.023). CONCLUSION This analysis provides new evidence of histone modifications in breast cancer. High H3K4me3 and H3K9ac expression was correlated with survival rates. Further investigation of histone modifications in breast cancer could lead to a more profound understanding of the molecular mechanisms of cancer development and could result in new therapeutic strategies

Caseworker-Perceived Caregiver Substance Abuse and Child Protective Services Outcomes

The authors used data from the National Survey of Child and Adolescent Well-Being to examine associations of child protective services (CPS) caseworkers' perceptions of caregiver substance abuse with their perceptions of the severity of risk and harm a child experienced as a result of alleged maltreatment, as well as with whether a family experienced a range of CPS outcomes. The outcomes included whether the family received services from CPS, was substantiated for maltreatment, experienced child removal, and was subject to a termination of parental rights (TPR) petition. The authors also compared the magnitude of the association between caseworker-perceived caregiver substance abuse and each outcome to that of the association between other maltreatment-related risk factors and each outcome. Findings suggest that, all else equal, caseworker-perceived caregiver substance abuse is associated with increased caseworker perceptions that children have experienced severe risk and harm and also with an increased probability of each of the CPS outcomes except TPR. Moreover, these associations are equal in magnitude or larger than those between the other risk factors and the outcomes. These findings imply that CPS decisions are heavily influenced by caseworker perceptions of caregiver substance abuse, regardless of the presence of other risk factors for child maltreatment

Inhibitory NKG2A⁺ and absent activating NKG2C⁺ NK cell responses are associated with the development of EBV⁺ lymphomas

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus, which infects over 90% of the adult human population worldwide. After primary infections, EBV is recurrently reactivating in most adult individuals. It is, however, unclear, why these EBV reactivations progress to EBV+ Hodgkin (EBV+HL) or non-Hodgkin lymphomas (EBV+nHL) only in a minority of EBV-infected individuals. The EBV LMP-1 protein encodes for a highly polymorphic peptide, which upregulates the immunomodulatory HLA-E in EBV-infected cells, thereby stimulating the inhibitory NKG2A-, but also the activating NKG2C-receptor on natural killer (NK) cells. Using a genetic-association approach and functional NK cell analyses, we now investigated, whether these HLA-E-restricted immune responses impact the development of EBV+HL and EBV+nHL. Therefore, we recruited a study cohort of 63 EBV+HL and EBV+nHL patients and 192 controls with confirmed EBV reactivations, but without lymphomas. Here, we demonstrate that in EBV+ lymphoma patients exclusively the high-affine LMP-1 GGDPHLPTL peptide variant-encoding EBV-strains reactivate. In EBV+HL and EBV+nHL patients, the high-expressing HLA-E*0103/0103 genetic variant was significantly overrepresented. Combined, the LMP-1 GGDPHLPTL and HLA-E*0103/0103 variants efficiently inhibited NKG2A+ NK cells, thereby facilitating the in vitro spread of EBV-infected tumor cells. In addition, EBV+HL and EBV+nHL patients, showed impaired pro-inflammatory NKG2C+ NK cell responses, which accelerated the in vitro EBV-infected tumor cells spread. In contrast, the blocking of NKG2A by monoclonal antibodies (Monalizumab) resulted in efficient control of EBV-infected tumor cell growth, especially by NKG2A+NKG2C+ NK cells. Thus, the HLA-E/LMP-1/NKG2A pathway and individual NKG2C+ NK cell responses are associated with the progression toward EBV+ lymphomas.</p

Prediction of Children\u27s Early Academic Adjustment from Their Temperament: The Moderating Role of Peer Temperament

The goal of the study was to examine whether target children’s temperamental negative emotional expressivity (NEE) and effortful control in the fall of kindergarten predicted academic adjustment in the spring and whether a classmate’s NEE and effortful control moderated these relations. Target children’s NEE and effortful control were measured in the fall via multiple methods, academic adjustment was measured via reading and math standardized tests in the spring, and observations of engagement in the classroom were conducted throughout the year. In the fall, teachers nominated a peer with whom each target child spent the most time and rated that peer’s temperament. Target children with high effortful control had high reading and math achievement (ps = .04 and \u3c .001, respectively), and children with low NEE increased in engagement during the year (p \u3c .001). Peers’ temperament did not have a direct relation to target children’s academic adjustment. Peers’ NEE, however, moderated the relation between target children’s effortful control, as well as NEE, and changes in engagement (ps = .03 and .05, respectively). Further, peers’ effortful control moderated the relations between target children’s NEE and reading and changes in engagement (ps = .02 and .04, respectively). In each case, target children’s temperament predicted the outcome in expected directions more strongly when peers had low NEE or high effortful control. Results are discussed in terms of how children’s temperamental qualities relate to academic adjustment, and how the relation between NEE and changes in engagement, in particular, depends on peers’ temperament

The Histone Variant H2A.W Defines Heterochromatin and Promotes Chromatin Condensation in Arabidopsis

SummaryHistone variants play crucial roles in gene expression, genome integrity, and chromosome segregation. We report that the four H2A variants in Arabidopsis define different genomic features, contributing to overall genomic organization. The histone variant H2A.W marks heterochromatin specifically and acts in synergy with heterochromatic marks H3K9me2 and DNA methylation to maintain transposon silencing. In vitro, H2A.W enhances chromatin condensation by promoting fiber-to-fiber interactions via its conserved C-terminal motif. In vivo, H2A.W is required for heterochromatin condensation, demonstrating that H2A.W plays critical roles in heterochromatin organization. Similarities in conserved motifs between H2A.W and another H2A variant in metazoans suggest that plants and animals share common mechanisms for heterochromatin condensation

Wearable devices can predict the outcome of standardized 6-minute walk tests in heart disease

Wrist-worn devices with heart rate monitoring have become increasingly popular. Although current guidelines advise to consider clinical symptoms and exercise tolerance during decision-making in heart disease, it remains unknown to which extent wearables can help to determine such functional capacity measures. In clinical settings, the 6-minute walk test has become a standardized diagnostic and prognostic marker. We aimed to explore, whether 6-minute walk distances can be predicted by wrist-worn devices in patients with different stages of mitral and aortic valve disease. A total of n = 107 sensor datasets with 1,019,748 min of recordings were analysed. Based on heart rate recordings and literature information, activity levels were determined and compared to results from a 6-minute walk test. The percentage of time spent in moderate activity was a predictor for the achievement of gender, age and body mass index-specific 6-minute walk distances (p < 0.001; R2 = 0.48). The uncertainty of these predictions is demonstrated