Phosphatidylinositol-(4,5)-bisphosphate regulates sorting signal recognition by the clathrin-associated adaptor complex AP2

The alpha,beta2,mu2,sigma2 heterotetrameric AP2 complex is recruited exclusively to the phosphatidylinositol-4,5-bisphosphate (PtdIns4,5P(2))-rich plasma membrane where, amongst other roles, it selects motif-containing cargo proteins for incorporation into clathrin-coated vesicles. Unphosphorylated and mu2Thr156-monophosphorylated AP2 mutated in their alphaPtdIns4,5P(2), mu2PtdIns4,5P(2), and mu2Yxxvarphi binding sites were produced, and their interactions with membranes of different phospholipid and cargo composition were measured by surface plasmon resonance. We demonstrate that recognition of Yxxvarphi and acidic dileucine motifs is dependent on corecognition with PtdIns4,5P(2), explaining the selective recruitment of AP2 to the plasma membrane. The interaction of AP2 with PtdIns4,5P(2)/Yxxvarphi-containing membranes is two step: initial recruitment via the alphaPtdIns4,5P(2) site and then stabilization through the binding of mu2Yxxvarphi and mu2PtdIns4,5P(2) sites to their ligands. The second step is facilitated by a conformational change favored by mu2Thr156 phosphorylation. The binding of AP2 to acidic-dileucine motifs occurs at a different site from Yxxvarphi binding and is not enhanced by mu2Thr156 phosphorylation

Selenoprotein P Influences Colitis-Induced Tumorigenesis by Mediating Stemness and Oxidative Damage.

Patients with inflammatory bowel disease are at increased risk for colon cancer due to augmented oxidative stress. These patients also have compromised antioxidant defenses as the result of nutritional deficiencies. The micronutrient selenium is essential for selenoprotein production and is transported from the liver to target tissues via selenoprotein P (SEPP1). Target tissues also produce SEPP1, which is thought to possess an endogenous antioxidant function. Here, we have shown that mice with Sepp1 haploinsufficiency or mutations that disrupt either the selenium transport or the enzymatic domain of SEPP1 exhibit increased colitis-associated carcinogenesis as the result of increased genomic instability and promotion of a protumorigenic microenvironment. Reduced SEPP1 function markedly increased M2-polarized macrophages, indicating a role for SEPP1 in macrophage polarization and immune function. Furthermore, compared with partial loss, complete loss of SEPP1 substantially reduced tumor burden, in part due to increased apoptosis. Using intestinal organoid cultures, we found that, compared with those from WT animals, Sepp1-null cultures display increased stem cell characteristics that are coupled with increased ROS production, DNA damage, proliferation, decreased cell survival, and modulation of WNT signaling in response to H2O2-mediated oxidative stress. Together, these data demonstrate that SEPP1 influences inflammatory tumorigenesis by affecting genomic stability, the inflammatory microenvironment, and epithelial stem cell functions

Mutation in Mouse Hei10, an E3 Ubiquitin Ligase, Disrupts Meiotic Crossing Over

Crossing over during meiotic prophase I is required for sexual reproduction in mice and contributes to genome-wide genetic diversity. Here we report on the characterization of an N-ethyl-N-nitrosourea-induced, recessive allele called mei4, which causes sterility in both sexes owing to meiotic defects. In mutant spermatocytes, chromosomes fail to congress properly at the metaphase plate, leading to arrest and apoptosis before the first meiotic division. Mutant oocytes have a similar chromosomal phenotype but in vitro can undergo meiotic divisions and fertilization before arresting. During late meiotic prophase in mei4 mutant males, absence of cyclin dependent kinase 2 and mismatch repair protein association from chromosome cores is correlated with the premature separation of bivalents at diplonema owing to lack of chiasmata. We have identified the causative mutation, a transversion in the 5′ splice donor site of exon 1 in the mouse ortholog of Human Enhancer of Invasion 10 (Hei10; also known as Gm288 in mouse and CCNB1IP1 in human), a putative B-type cyclin E3 ubiquitin ligase. Importantly, orthologs of Hei10 are found exclusively in deuterostomes and not in more ancestral protostomes such as yeast, worms, or flies. The cloning and characterization of the mei4 allele of Hei10 demonstrates a novel link between cell cycle regulation and mismatch repair during prophase I

A20, a modulator of smooth muscle cell proliferation and apoptosis, prevents and induces regression of neointimal hyperplasia

A20 is a NF‐κB‐dependent gene that has dual anti‐inflammatory and antiapoptotic functions in endothelial cells (EC). The function of A20 in smooth muscle cells (SMC) is unknown. We demonstrate that A20 is induced in SMC in response to inflammatory stimuli and serves an anti‐inflammatory function via blockade of NF‐κB and NF‐κB‐dependent proteins ICAM‐1 and MCP‐1. A20 inhibits SMC proliferation via increased expression of cyclin‐dependent kinase inhibitors p21waf1 and p27kip1. Surprisingly, A20 sensitizes SMC to cytokine‐ and Fas‐mediated apoptosis through a novel NO‐dependent mechanism. In vivo, adenoviral delivery of A20 to medial rat carotid artery SMC after balloon angioplasty prevents neointimal hyperplasia by blocking SMC proliferation and accelerating re‐endothelialization, without causing apoptosis. However, expression of A20 in established neointimal lesions leads to their regression through increased apoptosis. This is the first demonstration that A20 exerts two levels of control of vascular remodeling and healing. A20 prevents neointimal hyperplasia through combined anti‐inflammatory and antiproliferative functions in medial SMC. If SMC evade this first barrier and neointima is formed, A20 has a therapeutic potential by uniquely sensitizing neointimal SMC to apoptosis. A20‐based therapies hold promise for the prevention and treatment of neointimal disease.—Patel, V. I., Daniel, S., Longo, C. R., Shrikhande, G. V., Scali, S. T., Czismadia, E., Groft, C. M., Shukri, T., Motley‐Dore, C., Ramsey, H. E., Fisher, M. D., Grey, S. T., Arvelo, M. B., Ferran, C. A20, a modulator of smooth muscle cell proliferation and apoptosis, prevents and induces regression of neointimal hyperplasia. FASEB J. 20, 1418–1430 (2006)Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154452/1/fsb2fj054981com.pd

Postural stability in older adults with a distal radial fracture

BACKGROUND: The physical risk factors leading to distal radial fractures are poorly understood. The goal of this study was to compare postural stability between older adults with and without a prior distal radial fragility fracture. METHODS: This case-control evaluation was performed at a single tertiary institution. The fracture cohort comprised 23 patients treated for a low-energy distal radial fracture within 6 to 24 months prior to this study. Twenty-three age and sex-matched control participants, without a prior fragility fracture, were selected from an outpatient clinic population. All participants completed a balance assessment with a computerized balance platform device. Dynamic motion analysis (DMA) scores ranging from 0 to 1,440 points are produced, with lower scores indicating better postural stability. Participants also completed validated questionnaires for general health quality (EuroQol-5D-3L [EQ-5D-3L]) and physical activity (Physical Activity Scale for the Elderly [PASE]) and comprehensive health and demographic information including treatment for compromised balance or osteoporosis. Statistical analysis compared data between cases and controls using either the Student t test or the Mann-Whitney U test. RESULTS: There were no significant differences (p > 0.05) in age, sex, body mass index, physical activity score, or EQ-5D-3L general health visual analog scale score between participants with or without prior distal radial fracture. The fracture cohort demonstrated poorer balance, with higher DMA scores at 933 points compared with 790 points for the control cohort (p = 0.008). Nineteen patients (83%) in the fracture cohort reported having dual x-ray absorptiometry (DXA) scans within 5 years prior to this study, but only 2 patients (9%) had ever been referred for balance training with physical therapy. CONCLUSIONS: Older adults who sustain low-energy distal radial fractures demonstrate impaired postural stability compared with individuals of a similar age who have not sustained such fractures. Following a distal radial fracture, these patients may benefit from interventions to improve postural stability. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence

The Vehicle, 1963, Vol. 5

Vol. 5 Table of Contents Milepostspage 3 Rhyme Conceived At DawnDaun Alan Leggpage 4 NightRoss Kokospage 4 UncrownedOra Blanche T. Kingpage 4 SunfishingL.J.G.page 5 The Man Who Went To New YorkEric Crookspage 7 The DreamPauline B. Smithpage 18 Open WindowsDavid Helmpage 19 SalvationChristine McCollpage 19 The Chess GamePierre Hooverpage 20 CataclysmRaymond Kapraunpage 20 A Microscopic ViewKenneth L. Vadovskypage 21 See How Love ComesLiz Puckettpage 21 A Can Of Beer For AndyKenneth L. Vadovskypage 22 A MonsterDixie Lee Motleypage 28 InconstancyJanice Brookspage 29 DreamerDaun Alan Leggpage 29 The Third WishGlenda Vursellpage 30 The MiracleJanice Brookspage 32 What Lives Where Love Once Dwelt?Vernell Vyvialpage 33 The Most Unforgettable Person I Have Ever KnownJames Flingpage 34 Winter ThoughtsPauline B. Smithpage 35 A Winter NightPeggy Lambertpage 35 The Silver WhaleL.J.G.page 36 RaindropsDixie Lee Motleypage 40 Conflict Of Soul IJean Konzelmanpage 40 JudyChristine McCollpage 41 Sadness No. 3 (Vergessen)Sherry Sue Frypage 41 Lost GoldLarry Pricepage 42 EchoesCharles Cooleypage 48 TruthDaun Alan Leggpage 48 SunsetCarol Bennettpage 48 Cover designTom Windsor Illustration for winning storyJoel E. Hendrickshttps://thekeep.eiu.edu/vehicle/1011/thumbnail.jp

The making of a mammalian peroxisome, version 2.0: mitochondria get into the mix

This is the author accepted manuscript. The final version is available from Nature Publishing Group via the DOI in this record.A recent report from the laboratory of Heidi McBride (McGill University) presents a role for mitochondria in the de novo biogenesis of peroxisomes in mammalian cells (1). Peroxisomes are essential organelles responsible for a wide variety of biochemical functions, from the generation of bile, to plasmalogen synthesis, reduction of peroxides, and the oxidation of very long chain fatty acids (2). Like mitochondria, peroxisomes proliferate primarily through growth and division of pre-existing peroxisomes (3-6). However, unlike mitochondria, peroxisomes do not fuse (5,7); further, and perhaps most importantly, they can also be born de novo, a process thought to occur through the generation of pre-peroxisomal vesicles that originate from the endoplasmic reticulum (reviewed in (8,9). De novo peroxisome biogenesis has been extensively studies in yeast, with a major focus on the role of the ER in this process. Comprehensive studies in mammalian cells are, however, scarce (5,10-12). By exploiting patient cells lacking mature peroxisomes, Sugiura et al. (1) now assign a role to ER and mitochondria in de novo mammalian peroxisome biogenesis by showing that the formation of immature preperoxisomes occurs through the fusion of Pex3- / Pex14-containing mitochondriaderived vesicles with Pex16-containing ER-derived vesicles

Novel mutation in the NHLRC1 gene in a Malian family with a severe phenotype of Lafora disease

We studied a Malian family with parental consanguinity and two of eight siblings affected with late-childhood-onset progressive myoclonus epilepsy and cognitive decline, consistent with the diagnosis of Lafora disease. Genetic analysis showed a novel homozygous single-nucleotide variant in the NHLRC1 gene, c.560A>C, producing the missense change H187P. The changed amino acid is highly conserved, and the mutation impairs malin's ability to degrade laforin in vitro. Pathological evaluation showed manifestations of Lafora disease in the entire brain, with particularly severe involvement of the pallidum, thalamus, and cerebellum. Our findings document Lafora disease with severe manifestations in the West African population