Niemann-Pick Type C Disease Reveals a Link between Lysosomal Cholesterol and PtdIns(4,5)P2 That Regulates Neuronal Excitability.

There is increasing evidence that the lysosome is involved in the pathogenesis of a variety of neurodegenerative disorders. Thus, mechanisms that link lysosome dysfunction to the disruption of neuronal homeostasis offer opportunities to understand the molecular underpinnings of neurodegeneration and potentially identify specific therapeutic targets. Here, using a monogenic neurodegenerative disorder, NPC1 disease, we demonstrate that reduced cholesterol efflux from lysosomes aberrantly modifies neuronal firing patterns. The molecular mechanism linking alterations in lysosomal cholesterol egress to intrinsic tuning of neuronal excitability is a transcriptionally mediated upregulation of the ABCA1 transporter, whose PtdIns(4,5)P2-floppase activity decreases plasma membrane PtdIns(4,5)P2. The consequence of reduced PtdIns(4,5)P2 is a parallel decrease in a key regulator of neuronal excitability, the voltage-gated KCNQ2/3 potassium channel, which leads to hyperexcitability in NPC1 disease neurons. Thus, cholesterol efflux from lysosomes regulates PtdIns(4,5)P2 to shape the electrical and functional identity of the plasma membrane of neurons in health and disease

The gene–environmental architecture of the development of adolescent substance use

Background: Using a longitudinal twin design and a latent growth curve/autoregressive approach, this study examined the genetic-environmental architecture of substance use across adolescence. Methods: Self-reports of substance use (i.e., alcohol, marijuana) were collected at ages 13, 14, 15 and 17 years from 476 twin pairs (475 boys, 477 girls) living in the Province of Quebec, Canada. Substance use increased linearly across the adolescent years. Results: ACE modeling revealed that genetic, as well as shared and non-shared environmental factors explained the overall level of substance use and that these same factors also partly accounted for growth in substance use from age 13 to age 17. Additional genetic factors predicted the growth in substance use. Finally, autoregressive effects revealed age-specific nonshared environmental influences and, to a lesser degree, age-specific genetic influences, which together accounted for the stability of substance use across adolescence. Conclusions: The results support and expand the notion that genetic and environmental influences on substance use during adolescence are both developmentally stable and developmentally dynamic

Recommendations for the Determination of Nutrients in Seawater to High Levels of Precision and Inter-Comparability using Continuous Flow Analysers

The Global Ocean Ship-based Hydrographic Investigations Program (GO-SHIP) brings together scientists with interests in physical oceanography, the carbon cycle, marine biogeochemistry and ecosystems, and other users and collectors of ocean interior data to develop a sustained global network of hydrographic sections as part of the Global Ocean Climate Observing System. A series of manuals and guidelines are being produced by GO-SHIP which update those developed by the World Ocean Circulation Experiment (WOCE) in the early 1990s. Analysis of the data collected in WOCE suggests that improvements are needed in the collection of nutrient data if they are to be used for determining change within the ocean interior. Production of this manual is timely as it coincides with the development of reference materials for nutrients in seawater (RMNS). These RMNS solutions will be produced in sufficient quantities and be of sufficient quality that they will provide a basis for improving the consistency of nutrient measurements both within and between cruises. This manual is a guide to suggested best practice in performing nutrient measurements at sea. It provides a detailed set of advice on laboratory practice for all the procedures surrounding the use of 1 gas-segmented continuous flow analysers (CFA) for the determination of dissolved nutrients (usually ammonium, nitrate, nitrite, phosphate and silicate) at sea. It does not proscribe the use of a particular instrument or related chemical method as these are well described in other publications. The manual provides a brief introduction to the CFA method, the collection and storage of samples, considerations in the preparation of reagents and the calibrations of the system. It discusses how RMNS solutions can be used to “track” the performance of a system during a cruise and between cruises. It provides a format for the meta-data that need to be reported along side the sample data at the end of a cruise so that the quality of the reported data can be evaluated and set in context relative to other data sets. Most importantly the central manual is accompanied by a set of nutrient standard operating procedures (NSOPs) that provide detailed information on key procedures that are necessary if best quality data are to be achieved consistently. These cover sample collection and storage, an example NSOP for the use of a CFA system at sea, high precision preparation of calibration solutions, assessment of the true calibration blank, checking the linearity of a calibration and the use of internal and externally prepared reference solutions for controlling the precision of data during a cruise and between cruises. An example meta-data report and advice on the assembly of the quality control and statistical data that should form part of the meta-data report are also given

Hydrological and associated biogeochemical consequences of rapid global warming during the Paleocene-Eocene Thermal Maximum

The Paleocene-Eocene Thermal Maximum (PETM) hyperthermal, ~ 56 million years ago (Ma), is the most dramatic example of abrupt Cenozoic global warming. During the PETM surface temperatures increased between 5 and 9 °C and the onset likely took < 20 kyr. The PETM provides a case study of the impacts of rapid global warming on the Earth system, including both hydrological and associated biogeochemical feedbacks, and proxy data from the PETM can provide constraints on changes in warm climate hydrology simulated by general circulation models (GCMs). In this paper, we provide a critical review of biological and geochemical signatures interpreted as direct or indirect indicators of hydrological change at the PETM, explore the importance of adopting multi-proxy approaches, and present a preliminary model-data comparison. Hydrological records complement those of temperature and indicate that the climatic response at the PETM was complex, with significant regional and temporal variability. This is further illustrated by the biogeochemical consequences of inferred changes in hydrology and, in fact, changes in precipitation and the biogeochemical consequences are often conflated in geochemical signatures. There is also strong evidence in many regions for changes in the episodic and/or intra-annual distribution of precipitation that has not widely been considered when comparing proxy data to GCM output. Crucially, GCM simulations indicate that the response of the hydrological cycle to the PETM was heterogeneous – some regions are associated with increased precipitation – evaporation (P – E), whilst others are characterised by a decrease. Interestingly, the majority of proxy data come from the regions where GCMs predict an increase in PETM precipitation. We propose that comparison of hydrological proxies to GCM output can be an important test of model skill, but this will be enhanced by further data from regions of model-simulated aridity and simulation of extreme precipitation events

Persistence of Effects of VLBW/PT Birth Status and Maternal Emotional Availability (EA) on Child EA Trajectories

Few studies have examined the longitudinal impact of birth status on the infant–mother relationship and on children’s socio-emotional development. In the present study we investigated developmental patterns of such relationships [using the Emotional Availability (EA) Scales] in fullterm and VLBW/PT infants from infancy to emerging school age. Our objectives were to: (a) model the developmental trajectories of EA dimensions (maternal sensitivity, structuring, non-hostility; child responsiveness, involvement) in a VLBW/PT and fullterm sample, (b) identify potential effects of VLBW/PT status on these trajectories, and (c) determine whether the effects of VLBW/PT status on children’s socio-emotional development (child EA) remained after accounting for the effect of maternal EA. Child–mother dyads (n = 109) were observed in home-based interactions (face-to-face and free play) when children were 6, 12, 18, and 57-months-old in fullterm (37–41 weeks, &gt;2500 g; n = 48) and healthy VLBW/PT (26–32 weeks gestation, birth weight 800–1500 g, corrected for gestational age; n = 61) children. Developmental trajectories of maternal and child EA were assessed using multilevel growth modeling in Mplus. Results indicated that, even after controlling for maternal EA, there was a persistent negative effect of VLBW/PT birth status on child EA trajectories. Both initially and over time, VLBW/PT infants lagged behind their fullterm counterparts on levels of responsiveness and involvement with mothers. There was also a persistent positive effect of maternal EA (sensitivity and structuring) on child EA trajectories. Higher average levels of maternal sensitivity and structuring across time were also associated with higher and persistent levels of child responsiveness and involvement of their mothers. Importantly, results held after modeling both effects together, and after controlling for maternal education and child gender. Our results have implications for VLBW/PT children’s development, the parent–child relationship, and integrating family level factors and relationship dimensions in early prevention and intervention programs

Whole-genome and long-read sequencing identify a novel mechanism in RFC1 resulting in CANVAS syndrome

OBJECTIVES: Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) results from biallelic intronic pentanucleotide repeats in METHODS: We performed whole-genome sequencing (WGS) on peripheral blood DNA samples from the proband and his unaffected mother. We performed DNA long-read sequencing and synthesized complementary DNA from RNA using peripheral blood from the proband. RESULTS: WGS confirmed the maternally inherited DISCUSSION: We report an adult with CANVAS due to compound heterozygous pathogeni

Progress in Interferometry for LISA at JPL

Recent advances at JPL in experimentation and design for LISA interferometry include the demonstration of Time Delay Interferometry using electronically separated end stations, a new arm-locking design with improved gain and stability, and progress in flight readiness of digital and analog electronics for phase measurements.Comment: 11 pages, 9 figures, LISA 8 Symposium, Stanford University, 201

NPC1 regulates the distribution of phosphatidylinositol 4-kinases at Golgi and lysosomal membranes

Cholesterol and phosphoinositides (PI) are two critically important lipids that are found in cellular membranes and dysregulated in many disorders. Therefore, uncovering molecular pathways connecting these essential lipids may offer new therapeutic insights. We report that loss of function of lysosomal Niemann-Pick Type C1 (NPC1) cholesterol transporter, which leads to neurodegenerative NPC disease, initiates a signaling cascade that alters the cholesterol/phosphatidylinositol 4-phosphate (PtdIns4P) countertransport cycle between Golgi-endoplasmic reticulum (ER), as well as lysosome-ER membrane contact sites (MCS). Central to these disruptions is increased recruitment of phosphatidylinositol 4-kinases-PI4KIIα and PI4KIIIβ-which boosts PtdIns4P metabolism at Golgi and lysosomal membranes. Aberrantly increased PtdIns4P levels elevate constitutive anterograde secretion from the Golgi complex, and mTORC1 recruitment to lysosomes. NPC1 disease mutations phenocopy the transporter loss of function and can be rescued by inhibition or knockdown of either key phosphoinositide enzymes or their recruiting partners. In summary, we show that the lysosomal NPC1 cholesterol transporter tunes the molecular content of Golgi and lysosome MCS to regulate intracellular trafficking and growth signaling in health and disease

The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy.

Chronic traumatic encephalopathy (CTE) is a neurodegeneration characterized by the abnormal accumulation of hyperphosphorylated tau protein within the brain. Like many other neurodegenerative conditions, at present, CTE can only be definitively diagnosed by post-mortem examination of brain tissue. As the first part of a series of consensus panels funded by the NINDS/NIBIB to define the neuropathological criteria for CTE, preliminary neuropathological criteria were used by 7 neuropathologists to blindly evaluate 25 cases of various tauopathies, including CTE, Alzheimer's disease, progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, primary age-related tauopathy, and parkinsonism dementia complex of Guam. The results demonstrated that there was good agreement among the neuropathologists who reviewed the cases (Cohen's kappa, 0.67) and even better agreement between reviewers and the diagnosis of CTE (Cohen's kappa, 0.78). Based on these results, the panel defined the pathognomonic lesion of CTE as an accumulation of abnormal hyperphosphorylated tau (p-tau) in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern. The group also defined supportive but non-specific p-tau-immunoreactive features of CTE as: pretangles and NFTs affecting superficial layers (layers II-III) of cerebral cortex; pretangles, NFTs or extracellular tangles in CA2 and pretangles and proximal dendritic swellings in CA4 of the hippocampus; neuronal and astrocytic aggregates in subcortical nuclei; thorn-shaped astrocytes at the glial limitans of the subpial and periventricular regions; and large grain-like and dot-like structures. Supportive non-p-tau pathologies include TDP-43 immunoreactive neuronal cytoplasmic inclusions and dot-like structures in the hippocampus, anteromedial temporal cortex and amygdala. The panel also recommended a minimum blocking and staining scheme for pathological evaluation and made recommendations for future study. This study provides the first step towards the development of validated neuropathological criteria for CTE and will pave the way towards future clinical and mechanistic studies

Optical and Near-IR Imaging of Ultra Steep Spectrum Radio Sources - The K-z diagram of radio and optically selected galaxies

We present optical and/or near-IR images of 128 ultra steep spectrum (USS) radio sources. Roughly half of the objects are identified in the optical images (R 94% are detected at K<~ 22. The mean K-magnitude is K=19.26 within a 2" diameter aperture. The distribution of R-K colors indicates that at least 1/3 of the objects observed have very red colors (R-K>5). The major axes of the identifications in K-band are preferentially oriented along the radio axes, with half of them having compact morphologies. The 22 sources with spectroscopic redshifts and K-band magnitudes follow the K-z relation found from previous radio samples, but with a larger scatter. We argue that this may be due to a dependence of K-magnitude on the radio power, with the highest radio power sources inhabiting the most massive host galaxies. We present a composite K-z diagram of radio-loud and radio-quiet galaxies, selected from the HDF-North and the Hawaii surveys. Out to z <~ 1, the radio-loud galaxies trace the bright envelope of the radio quiet galaxies, while at z >~ 1, the radio-loud galaxies are >~ 2 magnitudes brighter. We argue that this is not due to a contribution from the AGN or emission lines. This difference strongly suggests that radio galaxies pinpoint the most massive systems out to the highest known redshifts, probably due to the mutual correlation of the mass of the galaxy and the radio power on the mass of the central black hole.Comment: 39 Pages, including 10 PostScript figures. Accepted for publication in the January 2002 Astronomical Journal. Figures 2 and 12 are available from http://www.strw.leidenuniv.nl/~debreuck/paper