Interaction of hemojuvelin with neogenin results in iron accumulation in human embryonic kidney 293 cells

Type 2 hereditary hemochromatosis (HH) or juvenile hemochromatosis is an early onset, genetically heterogeneous, autosomal recessive disorder of iron overload. Type 2A HH is caused by mutations in the recently cloned hemojuvelin gene (HJV; also called HFE2) (Papanikolaou, G., Samuels, M. E., Ludwig, E. H., MacDonald, M. L., Franchini, P. L., Dube, M. P., Andres, L., MacFarlane, J., Sakellaropoulos, N., Politou, M., Nemeth, E., Thompson, J., Risler, J. K., Zaborowska, C., Babakaiff, R., Radomski, C. C., Pape, T. D., Davidas, O., Christakis, J., Brissot, P., Lockitch, G., Ganz, T., Hayden, M. R., and Goldberg, Y. P. (2004) Nat. Genet. 36, 77–82), whereas Type 2B HH is caused by mutations in hepcidin. HJV is highly expressed in both skeletal muscle and liver. Mutations in HJV are implicated in the majority of diagnosed juvenile hemochromatosis patients. In this study, we stably transfected HJV cDNA into human embryonic kidney 293 cells and characterized the processing of HJV and its effect on iron homeostasis. Our results indicate that HJV is a glycosylphosphatidylinositol-linked protein and undergoes a partial autocatalytic cleavage during its intracellular processing. HJV co-immunoprecipitated with neogenin, a receptor involved in a variety of cellular signaling processes. It did not interact with the closely related receptor DCC (deleted in Colon Cancer). In addition, the HJV G320V mutant implicated in Type 2A HH did not co-immunoprecipitate with neogenin. Immunoblot analysis of ferritin levels and transferrin-55Fe accumulation studies indicated that the HJV-induced increase in intracellular iron levels in human embryonic kidney 293 cells is dependent on the presence of neogenin in the cells, thus linking these two proteins to intracellular iron homeostasis

Antibody to a cryptic, solid phase ClQ antigen in membranoproliferative nephritis

Antibody to a cryptic solid phase Clq antigen in membranoproliferative nephritis. IgG containing material detected in membranoproliferative nephritis (MPGN) serum with a solid phase (sp) Clq ELISA has been presumed to be immune complexes. However, in serum from 13 MPGN patients containing large amounts of spClq-binding material, sucrose density ultracentrifugation and sieve chromatography showed spClq-binding protein to sediment at 7S or cofractionate with IgG. One serum (stored for 12 years) contained, in addition, spClq-binding material sedimenting at more than 19S. Isolated MPGN IgG was shown to bind to spClq SpClq-binding material could be totally removed from MPGN serum by absorption with BSA-anti-BSA immune precipitates, and by acid elution of the precipitates IgG binding to spClq could be recovered. F(ab′)2, isolated from pepsin digested MPGN IgG, continued to bind spClq. Binding of MPGN IgG or F(ab′)2 to spClq was not inhibited by 2 M NaCl. Incubation of MPGN serum with 125I Clq followed by sucrose density ultracentrifugation resulted in a peak of radioactivity at 11S, the sedimentation rate of Clq, giving evidence that material binding fluid phase Clq is not present SpClq-binding IgG was detected in 54% of 68 MPGN patients. These results indicate that the 7S spClq-binding IgG represents antibody to a cryptic antigen revealed only when Clq fixes to a solid surface

Genomic Views of Transcriptional Enhancers: Essential Determinants of Cellular Identity and Activity-Dependent Responses in the CNS.

Sprinkled throughout the genome are a million regulatory sequences called transcriptional enhancers that activate gene promoters in the right cells, at the right time. Enhancers endow the brain with its incredible diversity of cell types and also translate neural activity into gene induction. Thanks to rapid advances in genomic technologies, it is now possible to identify thousands of enhancers rapidly, test their transcriptional function en masse, and address their neurobiological functions via genome editing. Enhancers also promise to be a great technological opportunity for neuroscience, offering the potential for cell-type-specific genetic labeling and manipulation without the need for transgenesis. The objective of this review and the accompanying 2015 SfN mini-symposium is to highlight the use of new and emerging genomic technologies to probe enhancer function in the nervous system.Significance statementTranscriptional enhancers turn on genes in the right cells, at the right time. Enhancers are also the genomic sequences that encode the incredible diversity of cell types in the brain and enable the brain to turn genes on in response to new experiences. New technology enables enhancers to be found and manipulated. The study of enhancers promises to inform our understanding of brain development and function. The application of enhancer technology holds promise in accelerating basic neuroscience research and enabling gene therapies to be targeted to specific cell types in the brain

Neuroanatomical Correlates of the Income-Achievement Gap

In the United States, the difference in academic achievement between higher- and lower-income students (i.e., the income-achievement gap) is substantial and growing. In the research reported here, we investigated neuroanatomical correlates of this gap in adolescents (N = 58) in whom academic achievement was measured by statewide standardized testing. Cortical gray-matter volume was significantly greater in students from higher-income backgrounds (n = 35) than in students from lower-income backgrounds (n = 23), but cortical white-matter volume and total cortical surface area did not differ significantly between groups. Cortical thickness in all lobes of the brain was greater in students from higher-income than lower-income backgrounds. Greater cortical thickness, particularly in temporal and occipital lobes, was associated with better test performance. These results represent the first evidence that cortical thickness in higher- and lower-income students differs across broad swaths of the brain and that cortical thickness is related to scores on academic-achievement tests.Bill & Melinda Gates FoundationNational Institutes of Health (U.S.) (Grant F32 HD079143-01)National Institutes of Health (U.S.) (Grant F32 MH095354-01

Reply to Fischer et al

We welcome the correspondence from Fischer and colleagues regarding our recent paper on vocal learning in chimpanzee food grunts [1]. Fischer et al. make two challenges to our paper's conclusions, which we address here

Prognostic impact of fractional flow reserve measurements in patients with acute coronary syndromes: a subanalysis of the FLORIDA study

Randomized trials suggest benefits for fractional flow reserve (FFR)-guided vs. angiography-guided treatment strategies in well-defined and selected patient cohorts with acute coronary syndromes (ACS). The long-term prognostic value of FFR measurement in unselected all-comer ACS patients, however, remains unknown. This subanalysis of the Fractional FLOw Reserve In cardiovascular DiseAses (FLORIDA) study sought to investigate the long-term effects of FFR in the management of lesions in patients with acute coronary syndrome (ACS). FLORIDA was an observational all-comer cohort study performed in Germany, that was population-based and unselected. Patients enrolled into the anonymized InGef Research Database presenting with ACS and undergoing coronary angiography between January 2014 and December 2015 were included in the analysis. Patients were stratified into either the FFR-guided or the angiography-guided treatment arm, based on the treatment received. A matched cohort study design was used. The primary endpoint was all-cause mortality. The secondary endpoint was major adverse cardiovascular events (MACE), a composite of death, non-fatal myocardial infarction (MI), and repeat revascularization. Follow-up time was 3 years. Rates of 3-year mortality were 10.2 and 14.0% in the FFR-guided and the angiography-guided treatment arms (p = 0.04), corresponding to a 27% relative risk reduction for FFR in ACS patients. Rates of MACE were similar in both arms (47.7 vs. 51.5%, p = 0.14), including similar rates of non-fatal MI (27.7 vs. 25.4%, p = 0.47) and revascularization (9.9 vs. 12.1%, p = 0.17). In this large, all-comer observational study of ACS patients, FFR-guided revascularization was associated with a lower mortality at 3 years. This finding encourages the routine use of FFR to guide lesion revascularization in patients presenting with ACS

Qualitative assessment of Tongue Drive System by people with high-level spinal cord injury

The Tongue Drive System (TDS) is a minimally invasive, wireless, and wearable assistive technology (AT) that enables people with severe disabilities to control their environments using tongue motion. TDS translates specific tongue gestures into commands by sensing the magnetic field created by a small magnetic tracer applied to the user’s tongue. We have previously quantitatively evaluated the TDS for accessing computers and powered wheelchairs, demonstrating its usability. In this study, we focused on its qualitative evaluation by people with high-level spinal cord injury who each received a magnetic tongue piercing and used the TDS for 6 wk. We used two questionnaires, an after-scenario and a poststudy, designed to evaluate the tongue-piercing experience and the TDS usability compared with that of the sip-and-puff and the users’ current ATs. After study completion, 73% of the participants were positive about keeping the magnetic tongue-barbell in order to use the TDS. All were satisfied with the TDS performance and most said that they were able to do more things using TDS than their current ATs (4.22/5)

Parkinson's disease biomarkers: perspective from the NINDS Parkinson's Disease Biomarkers Program

Biomarkers for Parkinson's disease (PD) diagnosis, prognostication and clinical trial cohort selection are an urgent need. While many promising markers have been discovered through the National Institute of Neurological Disorders and Stroke Parkinson's Disease Biomarker Program (PDBP) and other mechanisms, no single PD marker or set of markers are ready for clinical use. Here we discuss the current state of biomarker discovery for platforms relevant to PDBP. We discuss the role of the PDBP in PD biomarker identification and present guidelines to facilitate their development. These guidelines include: harmonizing procedures for biofluid acquisition and clinical assessments, replication of the most promising biomarkers, support and encouragement of publications that report negative findings, longitudinal follow-up of current cohorts including the PDBP, testing of wearable technologies to capture readouts between study visits and development of recently diagnosed (de novo) cohorts to foster identification of the earliest markers of disease onset

Do schools differ in suicide risk? the influence of school and neighbourhood on attempted suicide, suicidal ideation and self-harm among secondary school pupils

<br>Background: Rates of suicide and poor mental health are high in environments (neighbourhoods and institutions) where individuals have only weak social ties, feel socially disconnected and experience anomie - a mismatch between individual and community norms and values. Young people spend much of their time within the school environment, but the influence of school context (school connectedness, ethos and contextual factors such as school size or denomination) on suicide-risk is understudied. Our aim is to explore if school context is associated with rates of attempted suicide and suicide-risk at age 15 and self-harm at age 19, adjusting for confounders.</br> <br>Methods: A longitudinal school-based survey of 1698 young people surveyed when aged 11, (primary school), 15 (secondary school) and in early adulthood (age 19). Participants provided data about attempted suicide and suicide-risk at age 15 and deliberate self-harm at 19. In addition, data were collected about mental health at age 11, social background (gender, religion, etc.), and at age 15, perception of local area (e.g. neighbourhood cohesion, safety/civility and facilities), school connectedness (school engagement, involvement, etc.) and school context (size, denomination, etc.). A dummy variable was created indicating a religious 'mismatch', where pupils held a different faith from their school denomination. Data were analysed using multilevel logistic regression.</br> <br>Results: After adjustment for confounders, pupils attempted suicide, suicide-risk and self-harm were all more likely among pupils with low school engagement (15-18% increase in odds for each SD change in engagement). While holding Catholic religious beliefs was protective, attending a Catholic school was a risk factor for suicidal behaviours. This pattern was explained by religious 'mismatch': pupils of a different religion from their school were approximately 2-4 times more likely to attempt suicide, be a suicide-risk or self-harm.</br> <br>Conclusions: With several caveats, we found support for the importance of school context for suicidality and self-harm. School policies promoting school connectedness are uncontroversial. Devising a policy to reduce risks to pupils holding a different faith from that of their school may be more problematic.</br&gt