Mutations in synaptojanin disrupt synaptic vesicle recycling

Journal ArticleSynaptojanin is a polyphosphoinositide phosphatase that is found at synapses and binds to proteins implicated in endocytosis. For these reasons, it has been proposed that synaptojanin is involved in the recycling of synaptic vesicles. Here, we demonstrate that the unc-26 gene encodes the Caenorhabditis elegans ortholog of synaptojanin. unc-26 mutants exhibit defects in vesicle trafficking in several tissues, but most defects are found at synaptic termini

Mutations in Synaptojanin Disrupt Synaptic Vesicle Recycling

Synaptojanin is a polyphosphoinositide phosphatase that is found at synapses and binds to proteins implicated in endocytosis. For these reasons, it has been proposed that synaptojanin is involved in the recycling of synaptic vesicles. Here, we demonstrate that the unc-26 gene encodes the Caenorhabditis elegans ortholog of synaptojanin. unc-26 mutants exhibit defects in vesicle trafficking in several tissues, but most defects are found at synaptic termini. Specifically, we observed defects in the budding of synaptic vesicles from the plasma membrane, in the uncoating of vesicles after fission, in the recovery of vesicles from endosomes, and in the tethering of vesicles to the cytoskeleton. Thus, these results confirm studies of the mouse synaptojanin 1 mutants, which exhibit defects in the uncoating of synaptic vesicles (Cremona, O., G. Di Paolo, M.R. Wenk, A. Luthi, W.T. Kim, K. Takei, L. Daniell, Y. Nemoto, S.B. Shears, R.A. Flavell, D.A. McCormick, and P. De Camilli. 1999. Cell. 99:179–188), and further demonstrate that synaptojanin facilitates multiple steps of synaptic vesicle recycling

Short-term variability in satellite-derived cloud cover and galactic cosmic rays: an update

Previous work by Todd and Kniveton (2001) (TK2001) has indicated a statistically significant association (at the daily timescale) between short-term reductions in galactic cosmic rays, specifically Forbush decrease (FD) events, and reduced cloud cover, mainly over Antarctica (as recorded in International Satellite Cloud Climatology Project (ISCCP) D1 data). This study presents an extension of the previous work using an extended dataset of FD events and ISCCP cloud data over the period 1983-2000, to establish how stable the observed cloud anomalies are. Composite analysis of ISCCP data based on a sample of 32 FD events (excluding those coincident with solar proton events) indicates cloud anomalies with a very similar space/time structure to that previously reported, although of smaller magnitude. Substantial reductions in high level cloud (up to 12% for zonal mean, compared to 18% reported by TK2001) are observed over the high geomagnetic latitudes, especially of the southern hemisphere immediately following FD event onset. Largest anomalies are centred on the Antarctic plateau region during austral winter. However, the largest cloud anomalies occur where the accuracy of the ISCCP cloud retrievals is likely to be lowest, such that the results must be treated with extreme caution. Moreover, significant positive composite mean surface and tropospheric temperature anomalies centred over the same region are also observed for the FD sample from the National Center for Environmental Prediction (NCEP) reanalysis data. Such increased temperatures are inconsistent with the radiative effect of a reduction in high-level cloud during local winter. Overall, the results do not provide strong evidence of a direct galactic cosmic ray/cloud association at short timescales. The results highlight (a) the potential problems of data quality in the high latitude regions (b) the problems inherent in inferring cause and effect relationships from observational data alone (c) the need for further research to test competing hypotheses

On the Joys of Missing Data

We provide conceptual introductions to missingness mechanisms—missing completely at random (MCAR), missing at random (MAR), and missing not at random (MNAR)—and state-of-the-art methods of handling missing data—full-information maximum likelihood (FIML) and multiple imputation (MI)—followed by a discussion of planned missing designs: multiform questionnaire protocols, two-method measurement models, and wave-missing longitudinal designs. We reviewed 80 articles of empirical studies published in the 2012 issues of the Journal of Pediatric Psychology to present a picture of how adequately missing data are currently handled in this field. To illustrate the benefits of utilizing MI or FIML and incorporating planned missingness into study designs, we provide example analyses of empirical data gathered using a three-form planned missing design

Discovery Of Cold, Pristine Gas Possibly Accreting Onto An Overdensity Of Star-Forming Galaxies At Redshift z ~ 1.6

We report the discovery of large amounts of cold (T ~ 10^4 K), chemically young gas in an overdensity of galaxies at redshift z ~ 1.6 in the Great Observatories Origins Deep Survey southern field (GOODS-S). The gas is identified thanks to the ultra-strong Mg II absorption features it imprints in the rest-frame UV spectra of galaxies in the background of the overdensity. There is no evidence that the optically-thick gas is part of any massive galaxy (i.e. M_star > 4x10^9 M_sun), but rather is associated with the overdensity; less massive and fainter galaxies (25.5 < z_850 < 27.5 mag) have too large an impact parameter to be causing ultra-strong absorption systems, based on our knowledge of such systems. The lack of corresponding Fe II absorption features, not detected even in co-added spectra, suggests that the gas is chemically more pristine than the ISM and outflows of star-forming galaxies at similar redshift, including those in the overdensity itself, and comparable to the most metal-poor stars in the Milky Way halo. A crude estimate of the projected covering factor of the high-column density gas (N_H >~ 10^20 cm-2) based on the observed fraction of galaxies with ultra-strong absorbers is C_F ~ 0.04. A broad, continuum absorption profile extending to the red of the interstellar Mg II absorption line by <~ 2000 km/s is possibly detected in two independent co-added spectra of galaxies of the overdensity, consistent with a large-scale infall motion of the gas onto the overdensity and its galaxies. Overall, these findings provides the first tentative evidence of accretion of cold, chemically young gas onto galaxies at high redshift, possibly feeding their star formation activity. The fact that the galaxies are members of a large structure, as opposed to field galaxies, might play a significant role in our ability to detect the accreting gas.Comment: 57 pages, 17 figures, 1 table; accepted for publication by ApJ (Aug 9, 2011); minor modifications to match the accepted versio

Selection due to nonretention mortality in gillnet fisheries for salmon

Fisheries often exert selective pressures through elevated mortality on a nonrandom component of exploited stocks. Selective removal of individuals will alter the composition of a given population, with potential consequences for its size structure, stability and evolution. Gillnets are known to harvest fish according to size. It is not known, however, whether delayed mortality due to disentanglement from gillnets exerts selective pressures that reinforce or counteract harvest selection. We examined gillnet disentanglement in exploited populations of sockeye salmon (Oncorhynchus nerka) in Bristol Bay, Alaska, to characterize the length distribution of fish that disentangle from gillnets and determine whether nonretention mortality reinforces harvest selection and exerts common pressures according to sex and age. We also evaluated discrete spawning populations to determine whether nonretention affects populations with different morphologies in distinct ways. In aggregate, nonretention mortality in fish that disentangle from gillnets counters harvest selection but with different effects by sex and age. At the level of individual spawning populations, nonretention mortality may exert stabilizing, disruptive, or directional selection depending on the size distribution of a given population. Our analyses suggest nonretention mortality exerts significant selective pressures and should be explicitly included in analyses of fishery-induced selection

Preventive drugs in the last year of life of older adults with cancer: Is there room for deprescribing?

BACKGROUND: The continuation of preventive drugs among older patients with advanced cancer has come under scrutiny because these drugs are unlikely to achieve their clinical benefit during the patients' remaining lifespan. METHODS: A nationwide cohort study of older adults (those aged ≥65 years) with solid tumors who died between 2007 and 2013 was performed in Sweden, using routinely collected data with record linkage. The authors calculated the monthly use and cost of preventive drugs throughout the last year before the patients' death. RESULTS: Among 151,201 older persons who died with cancer (mean age, 81.3 years [standard deviation, 8.1 years]), the average number of drugs increased from 6.9 to 10.1 over the course of the last year before death. Preventive drugs frequently were continued until the final month of life, including antihypertensives, platelet aggregation inhibitors, anticoagulants, statins, and oral antidiabetics. Median drug costs amounted to $1482 (interquartile range [IQR],$700-$2896]) per person, including$213 (IQR, $77-$490) for preventive therapies. Compared with older adults who died with lung cancer (median drug cost, $205; IQR,$61-$523), costs for preventive drugs were higher among older adults who died with pancreatic cancer (adjusted median difference,$13; 95% confidence interval, $5-$22) or gynecological cancers (adjusted median difference, $27; 95$18-$36). There was no decrease noted with regard to the cost of preventive drugs throughout the last year of life. CONCLUSIONS: Preventive drugs commonly are prescribed during the last year of life among older adults with cancer, and often are continued until the final weeks before death. Adequate deprescribing strategies are warranted to reduce the burden of drugs with limited clinical benefit near the end of life

The Transcriptional Repressor TupA in Aspergillus niger Is Involved in Controlling Gene Expression Related to Cell Wall Biosynthesis, Development, and Nitrogen Source Availability.

The Tup1-Cyc8 (Ssn6) complex is a well characterized and conserved general transcriptional repressor complex in eukaryotic cells. Here, we report the identification of the Tup1 (TupA) homolog in the filamentous fungus Aspergillus niger in a genetic screen for mutants with a constitutive expression of the agsA gene. The agsA gene encodes a putative alpha-glucan synthase, which is induced in response to cell wall stress in A. niger. Apart from the constitutive expression of agsA, the selected mutant was also found to produce an unknown pigment at high temperatures. Complementation analysis with a genomic library showed that the tupA gene could complement the phenotypes of the mutant. Screening of a collection of 240 mutants with constitutive expression of agsA identified sixteen additional pigment-secreting mutants, which were all mutated in the tupA gene. The phenotypes of the tupA mutants were very similar to the phenotypes of a tupA deletion strain. Further analysis of the tupA-17 mutant and the DeltatupA mutant revealed that TupA is also required for normal growth and morphogenesis. The production of the pigment at 37 degrees C is nitrogen source-dependent and repressed by ammonium. Genome-wide expression analysis of the tupA mutant during exponential growth revealed derepression of a large group of diverse genes, including genes related to development and cell wall biosynthesis, and also protease-encoding genes that are normally repressed by ammonium. Comparison of the transcriptome of up-regulated genes in the tupA mutant showed limited overlap with the transcriptome of caspofungin-induced cell wall stress-related genes, suggesting that TupA is not a general suppressor of cell wall stress-induced genes. We propose that TupA is an important repressor of genes related to development and nitrogen metabolism