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The Siren Call of E-Cigarettes

Headlines from MedPage Today® - Mon, 08/25/2014 - 4:29pm
(MedPage Today) -- Video discussants talk about the most important takeaways from the American Heart Association policy statement recommendations on preventing youth access to e-cigarettes.

'Sleep Drunkenness' Common, But Rarely Unexplained (CME/CE)

Headlines from MedPage Today® - Mon, 08/25/2014 - 4:18pm
(MedPage Today) -- So-called confusional arousals were reported in the past year by some 15% of respondents in a population-based survey, with nearly all episodes associated with mental disorders or drugs with known sleep effects.

DRK/DOS/SOS Converge with Crk/Mbc/dCed-12 to Activate Rac1 during Glial Engulfment of Axonal Debris

eScholarship@UMMS - Mon, 08/25/2014 - 3:23pm

Nervous system injury or disease leads to activation of glia, which govern postinjury responses in the nervous system. Axonal injury in Drosophila results in transcriptional up-regulation of the glial engulfment receptor Draper; there is extension of glial membranes to the injury site (termed activation), and then axonal debris is internalized and degraded. Loss of the small GTPase Rac1 from glia completely suppresses glial responses to injury, but upstream activators remain poorly defined. Loss of the Rac guanine nucleotide exchange factor (GEF) Crk/myoblast city (Mbc)/dCed-12has no effect on glial activation, but blocks internalization and degradation of debris. Here we show that the signaling molecules downstream of receptor kinase (DRK) and daughter of sevenless (DOS) (mammalian homologs, Grb2 and Gab2, respectively) and the GEF son of sevenless (SOS) (mammalian homolog, mSOS) are required for efficient activation of glia after axotomy and internalization/degradation of axonal debris. At the earliest steps of glial activation, DRK/DOS/SOS function in a partially redundant manner with Crk/Mbc/dCed-12, with blockade of both complexes strongly suppressing all glial responses, similar to loss of Rac1. This work identifies DRK/DOS/SOS as the upstream Rac GEF complex required for glialresponses to axonal injury, and demonstrates a critical requirement for multiple GEFs in efficient glial activation after injury and internalization/degradation of axonal debris.

More parents nixing anti-bleeding shots for their newborns

news@nature - Mon, 08/25/2014 - 3:21pm

Anti-vax parents are extending their fears into a rejection of all shots — including vitamin K, which can prevent potentially fatal hemorrhaging in infants.

Nature News doi: 10.1038/nature.2014.15749

Phosphatidic acid phospholipase A1 mediates ER-Golgi transit of a family of G protein-coupled receptors

eScholarship@UMMS - Mon, 08/25/2014 - 2:35pm

The coat protein II (COPII)-coated vesicular system transports newly synthesized secretory and membrane proteins from the endoplasmic reticulum (ER) to the Golgi complex. Recruitment of cargo into COPII vesicles requires an interaction of COPII proteins either with the cargo molecules directly or with cargo receptors for anterograde trafficking. We show that cytosolic phosphatidic acid phospholipase A1 (PAPLA1) interacts with COPII protein family members and is required for the transport of Rh1 (rhodopsin 1), an N-glycosylated G protein-coupled receptor (GPCR), from the ER to the Golgi complex. In papla1 mutants, in the absence of transport to the Golgi, Rh1 is aberrantly glycosylated and is mislocalized. These defects lead to decreased levels of the protein and decreased sensitivity of the photoreceptors to light. Several GPCRs, including other rhodopsins and Bride of sevenless, are similarly affected. Our findings show that a cytosolic protein is necessary for transit of selective transmembrane receptor cargo by the COPII coat for anterograde trafficking.

A Large-Scale RNAi-Based Mouse Tumorigenesis Screen Identifies New Lung Cancer Tumor Suppressors that Repress FGFR Signaling

eScholarship@UMMS - Mon, 08/25/2014 - 2:35pm

To discover new tumor suppressor genes (TSGs), we developed a functional genomics approach in which immortalized but non-tumorigenic cells were stably transduced with large-scale short hairpin RNA (shRNA) pools and tested for tumor formation in mice. Identification of shRNAs in resulting tumors revealed candidate TSGs, which were validated experimentally and by analyzing expression in human tumor samples. Using this approach, we identified 24 TSGs that were significantly down-regulated in human lung squamous cell carcinomas (hLSCCs). Amplification of fibroblast growth factor receptor 1 (FGFR1), which aberrantly increases FGFR signaling, is a common genetic alteration in hLSCCs. Remarkably, we found that 17 of the TSGs encode repressors of FGFR signaling. Knockdown of 14 of these TSGs transformed immortalized human bronchial epithelial cells and, in most cases, rendered them sensitive to FGFR inhibitors. Our results indicate that increased FGFR signaling promotes tumorigenesis in many hLSCCs that lack FGFR1 amplification or activating mutations.

High-resolution mapping of chromatin packaging in mouse embryonic stem cells and sperm

eScholarship@UMMS - Mon, 08/25/2014 - 2:35pm

Mammalian embryonic stem cells (ESCs) and sperm exhibit unusual chromatin packaging that plays important roles in cellular function. Here, we extend a recently developed technique, based on deep paired-end sequencing of lightly digested chromatin, to assess footprints of nucleosomes and other DNA-binding proteins genome-wide in murine ESCs and sperm. In ESCs, we recover well-characterized features of chromatin such as promoter nucleosome depletion and further identify widespread footprints of sequence-specific DNA-binding proteins such as CTCF, which we validate in knockdown studies. We document global differences in nuclease accessibility between ESCs and sperm, finding that the majority of histone retention in sperm preferentially occurs in large gene-poor genomic regions, with only a small subset of nucleosomes being retained over promoters of developmental regulators. Finally, we describe evidence that CTCF remains associated with the genome in mature sperm, where it could play a role in organizing the sperm genome.

Drosophila Sirt2/mammalian SIRT3 deacetylates ATP synthase beta and regulates complex V activity

eScholarship@UMMS - Mon, 08/25/2014 - 2:35pm

Adenosine triphosphate (ATP) synthase beta, the catalytic subunit of mitochondrial complex V, synthesizes ATP. We show that ATP synthase beta is deacetylated by a human nicotinamide adenine dinucleotide (NAD(+))-dependent protein deacetylase, sirtuin 3, and its Drosophila melanogaster homologue, dSirt2. dsirt2 mutant flies displayed increased acetylation of specific Lys residues in ATP synthase beta and decreased complex V activity. Overexpression of dSirt2 increased complex V activity. Substitution of Lys 259 and Lys 480 with Arg in human ATP synthase beta, mimicking deacetylation, increased complex V activity, whereas substitution with Gln, mimicking acetylation, decreased activity. Mass spectrometry and proteomic experiments from wild-type and dsirt2 mitochondria identified the Drosophila mitochondrial acetylome and revealed dSirt2 as an important regulator of mitochondrial energy metabolism. Additionally, we unravel a ceramide-NAD(+)-sirtuin axis wherein increased ceramide, a sphingolipid known to induce stress responses, resulted in depletion of NAD(+) and consequent decrease in sirtuin activity. These results provide insight into sirtuin-mediated regulation of complex V and reveal a novel link between ceramide and Drosophila acetylome.

A separable domain of the p150 subunit of human Chromatin Assembly Factor-1 promotes protein and chromosome associations with nucleoli

eScholarship@UMMS - Mon, 08/25/2014 - 2:35pm

Chromatin Assembly Factor-1 (CAF-1) is a three-subunit protein complex conserved throughout eukaryotes that deposits histones during DNA synthesis. Here, we present a novel role for the human p150 subunit in regulating nucleolar macromolecular interactions. Acute depletion of p150 causes redistribution of multiple nucleolar proteins and reduces nucleolar association with several repetitive element-containing loci. Notably, a point mutation in a SUMO-interacting motif (SIM) within p150 abolishes nucleolar associations, whereas PCNA or HP1 interaction sites within p150 are not required for these interactions. Additionally, acute depletion of SUMO-2 or the SUMO E2 ligase Ubc9 reduces alpha-satellite DNA association with nucleoli. The nucleolar functions of p150 are separable from its interactions with the other subunits of the CAF-1 complex, because an N-terminal fragment of p150 (p150N) that cannot interact with other CAF-1 subunits is sufficient for maintaining nucleolar chromosome and protein associations. Therefore, these data define novel functions for a separable domain of the p150 protein, regulating protein and DNA interactions at the nucleolus.

Synergistic tumor suppression by combined inhibition of telomerase and CDKN1A

eScholarship@UMMS - Mon, 08/25/2014 - 2:35pm

Tumor suppressor p53 plays an important role in mediating growth inhibition upon telomere dysfunction. Here, we show that loss of the p53 target gene cyclin-dependent kinase inhibitor 1A (CDKN1A, also known as p21WAF1/CIP1) increases apoptosis induction following telomerase inhibition in a variety of cancer cell lines and mouse xenografts. This effect is highly specific to p21, as loss of other checkpoint proteins and CDK inhibitors did not affect apoptosis. In telomerase, inhibited cell loss of p21 leads to E2F1- and p53-mediated transcriptional activation of p53-upregulated modulator of apoptosis, resulting in increased apoptosis. Combined genetic or pharmacological inhibition of telomerase and p21 synergistically suppresses tumor growth. Furthermore, we demonstrate that simultaneous inhibition of telomerase and p21 also suppresses growth of tumors containing mutant p53 following pharmacological restoration of p53 activity. Collectively, our results establish that inactivation of p21 leads to increased apoptosis upon telomerase inhibition and thus identify a genetic vulnerability that can be exploited to treat many human cancers containing either wild-type or mutant p53.

Quantitative proteomic analysis reveals posttranslational responses to aneuploidy in yeast

eScholarship@UMMS - Mon, 08/25/2014 - 2:34pm

Aneuploidy causes severe developmental defects and is a near universal feature of tumor cells. Despite its profound effects, the cellular processes affected by aneuploidy are not well characterized. Here, we examined the consequences of aneuploidy on the proteome of aneuploid budding yeast strains. We show that although protein levels largely scale with gene copy number, subunits of multi-protein complexes are notable exceptions. Posttranslational mechanisms attenuate their expression when their encoding genes are in excess. Our proteomic analyses further revealed a novel aneuploidy-associated protein expression signature characteristic of altered metabolism and redox homeostasis. Indeed aneuploid cells harbor increased levels of reactive oxygen species (ROS). Interestingly, increased protein turnover attenuates ROS levels and this novel aneuploidy-associated signature and improves the fitness of most aneuploid strains. Our results show that aneuploidy causes alterations in metabolism and redox homeostasis. Cells respond to these alterations through both transcriptional and posttranscriptional mechanisms.

OncoBriefs: Low-Nicotine Cigs, Prostate Bx and UTI, Myeloma Drug (CME/CE)

Headlines from MedPage Today® - Mon, 08/25/2014 - 1:30pm
(MedPage Today) -- Use of reduced-nicotine cigarettes did not increase smoking intensity or exposure to tobacco toxins among smokers who did not intend to quit, a prospective clinical study showed.

Physician Recruiters Chasing Primary Care Clinicians

Headlines from MedPage Today® - Mon, 08/25/2014 - 12:30pm
(MedPage Today) -- Primary care continues to be in high demand with in-house physician recruiter jobs, and primary care job placements were up in 2013 over 2012, physician recruiters reported.

Zorvolex for OA Approved by FDA

Headlines from MedPage Today® - Mon, 08/25/2014 - 11:09am
(MedPage Today) -- The FDA today approved a new low-dose formulation of diclofenac (Zorvolex) for the treatment of osteoarthritis pain, manufacturer Iroko Pharmaceuticals announced.

EndoType: A New Bar for T1D Antibody Tests?

Headlines from MedPage Today® - Mon, 08/25/2014 - 10:34am
(MedPage Today) -- Endocrinologists have been using antibody tests to distinguish type 1 diabetes in tough cases for a long time, so it's no wonder the FDA's approval earlier this week of the ZnT8 antibody test as the "first" raised eyebrows.

Morning Break: Money Talks at One Cardio Journal

Headlines from MedPage Today® - Mon, 08/25/2014 - 9:45am
(MedPage Today) -- Health news and commentary from around the Web, gathered by the MedPage Today staff.

Increase E-Cig Regulation, Says AHA (CME/CE)

Headlines from MedPage Today® - Mon, 08/25/2014 - 6:10am
(MedPage Today) -- In a policy statement issued by the American Heart Association, researchers recommend stricter regulations on e-cigarette use, manufacturing, marketing, and distribution.

The Week Ahead: Teen Mental Health, Vaping, ESC Preview

Headlines from MedPage Today® - Sun, 08/24/2014 - 4:52pm
(MedPage Today) -- New federal survey data are to be released on teen mental health, and there's more news on the e-cigarette industry -- brought to you by MedPage Today.

Double threat for Tibet

news@nature - Sun, 08/24/2014 - 1:21pm

Climate change and human development are jeopardizing the plateau’s fragile environment.

Nature 512 240 doi: 10.1038/512240a

Need Funding for Orgasm Research? Have We Got a Match.com for You!

Headlines from MedPage Today® - Sun, 08/24/2014 - 11:00am
(MedPage Today) -- A preview of what comes next for sexuality studies.
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