ALBERT

Description: Leukocyte adhesion deficiency type II is a hereditary disorder of neutrophil migration caused by mutations in the guanosine diphosphate-fucose transporter gene ( SLC35C1 ). In these patients, inability to generate key fucosylated molecules including sialyl Lewis X leads to leukocytosis and recurrent infections, in addition to short stature and developmental delay. We report two brothers with short stature and developmental delay who are compound heterozygotes for novel mutations in SLC35C1 resulting in partial in vivo defects in fucosylation. Specifically, plasma glycoproteins including immunoglobulin G demonstrated marked changes in glycoform distribution. While neutrophil rolling on endothelial selectins was partially impeded, residual adhesion proved sufficient to avoid leukocytosis or recurrent infection. These findings demonstrate a surprising degree of immune redundancy in the face of substantial alterations in adhesion molecule expression, and show that short stature and developmental delay may be the sole presenting signs in this disorder.

Description: Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P 〈 1 x 10 –6 ), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 ( P = 2.19 x 10 –11 ) and rs4907479 within the MCF2L gene at 13q34 ( P = 3.3 x 10 –10 ). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region—the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs ( r 2 = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case–case P ≤ 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer.

Description: The metabolic differences between B-NHL and primary human B cells are poorly understood. Among human B-cell non-Hodgkin lymphomas (B-NHL), primary effusion lymphoma (PEL) is a unique subset that is linked to infection with Kaposi's sarcoma-associated herpesvirus (KSHV). We report that the metabolic profiles of primary B cells are significantly different from that of PEL. Compared with primary B cells, both aerobic glycolysis and fatty acid synthesis (FAS) are up-regulated in PEL and other types of nonviral B-NHL. We found that aerobic glycolysis and FAS occur in a PI3K-dependent manner and appear to be interdependent. PEL overexpress the fatty acid synthesizing enzyme, FASN, and both PEL and other B-NHL were much more sensitive to the FAS inhibitor, C75, than primary B cells. Our findings suggest that FASN may be a unique candidate for molecular targeted therapy against PEL and other B-NHL.

Description: Mitochondrial dysfunction is commonly observed in degenerative disorders, including Alzheimer's and Parkinson's disease that are characterized by the progressive and selective loss of neuronal subpopulations. It is currently unclear, however, whether mitochondrial dysfunction is primary or secondary to other pathogenic processes that eventually lead to age-related neurodegeneration. Here we establish an in vivo Drosophila model of mitochondrial dysfunction by downregulating the catalytic subunit of mitochondrial DNA (mtDNA) polymerase in cholinergic, serotonergic and dopaminergic neurons. The resulting flies are characterized by lowered respiratory chain activity, premature aging, age-related motor deficits as well as adult onset, progressive and cell-type-specific, dopaminergic neurodegeneration. Using this model, we find that associated lethality can be partially rescued by targeting PINK1/parkin signaling or Drp1, both of which have been implicated in mitochondrial dynamics and Parkinson's disease. Bypassing mitochondrial complex III/IV deficiencies with Alternative oxidase ( AOX ), however, fully restores ATP levels and prevents dopaminergic neurodegeneration. In contrast, ATP levels and neurodegeneration are not rescued when mitochondrial complex I deficiencies are bypassed with NADH-Q oxidoreductase . Our results demonstrate that mtDNA-mediated mitochondrial dysfunction can cause age-related and cell-type-specific neurodegeneration which AOX is able to alleviate and indicate that AOX or its surrogates may prove useful as a therapeutic tool for limiting respiratory chain deficiencies caused by mtDNA decline in healthy aging and neurodegenerative disease.

Description: Mitochondrial dysfunction is a significant factor in human disease, ranging from systemic disorders of childhood to cardiomyopathy, ischaemia and neurodegeneration. Cytochrome oxidase, the terminal enzyme of the mitochondrial respiratory chain, is a frequent target. Lower eukaryotes possess alternative respiratory-chain enzymes that provide non-proton-translocating bypasses for respiratory complexes I (single-subunit reduced nicotinamide adenine dinucleotide dehydrogenases, e.g. Ndi1 from yeast) or III + IV [alternative oxidase (AOX)], under conditions of respiratory stress or overload. In previous studies, it was shown that transfer of yeast Ndi1 or Ciona intestinalis AOX to Drosophila was able to overcome the lethality produced by toxins or partial knockdown of complex I or IV. Here, we show that AOX can provide a complete or substantial rescue of a range of phenotypes induced by global or tissue-specific knockdown of different cIV subunits, including integral subunits required for catalysis, as well as peripheral subunits required for multimerization and assembly. AOX was also able to overcome the pupal lethality produced by muscle-specific knockdown of subunit CoVb, although the rescued flies were short lived and had a motility defect. cIV knockdown in neurons was not lethal during development but produced a rapidly progressing locomotor and seizure-sensitivity phenotype, which was substantially alleviated by AOX. Expression of Ndi1 exacerbated the neuronal phenotype produced by cIV knockdown. Ndi1 expressed in place of essential cI subunits produced a distinct residual phenotype of delayed development, bang sensitivity and male sterility. These findings confirm the potential utility of alternative respiratory chain enzymes as tools to combat mitochondrial disease, while indicating important limitations thereof.

Description: Changes in gene dosage are a major driver of cancer, known to be caused by a finite, but increasingly well annotated, repertoire of mutational mechanisms. This can potentially generate correlated copy-number alterations across hundreds of linked genes, as exemplified by the 2% of childhood acute lymphoblastic leukaemia (ALL) with recurrent amplification of megabase regions of chromosome 21 (iAMP21). We used genomic, cytogenetic and transcriptional analysis, coupled with novel bioinformatic approaches, to reconstruct the evolution of iAMP21 ALL. Here we show that individuals born with the rare constitutional Robertsonian translocation between chromosomes 15 and 21, rob(15;21)(q10;q10)c, have approximately 2,700-fold increased risk of developing iAMP21 ALL compared to the general population. In such cases, amplification is initiated by a chromothripsis event involving both sister chromatids of the Robertsonian chromosome, a novel mechanism for cancer predisposition. In sporadic iAMP21, breakage-fusion-bridge cycles are typically the initiating event, often followed by chromothripsis. In both sporadic and rob(15;21)c-associated iAMP21, the final stages frequently involve duplications of the entire abnormal chromosome. The end-product is a derivative of chromosome 21 or the rob(15;21)c chromosome with gene dosage optimized for leukaemic potential, showing constrained copy-number levels over multiple linked genes. Thus, dicentric chromosomes may be an important precipitant of chromothripsis, as we show rob(15;21)c to be constitutionally dicentric and breakage-fusion-bridge cycles generate dicentric chromosomes somatically. Furthermore, our data illustrate that several cancer-specific mutational processes, applied sequentially, can coordinate to fashion copy-number profiles over large genomic scales, incrementally refining the fitness benefits of aggregated gene dosage changes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3976272/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3976272/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Yilong -- Schwab, Claire -- Ryan, Sarra L -- Papaemmanuil, Elli -- Robinson, Hazel M -- Jacobs, Patricia -- Moorman, Anthony V -- Dyer, Sara -- Borrow, Julian -- Griffiths, Mike -- Heerema, Nyla A -- Carroll, Andrew J -- Talley, Polly -- Bown, Nick -- Telford, Nick -- Ross, Fiona M -- Gaunt, Lorraine -- McNally, Richard J Q -- Young, Bryan D -- Sinclair, Paul -- Rand, Vikki -- Teixeira, Manuel R -- Joseph, Olivia -- Robinson, Ben -- Maddison, Mark -- Dastugue, Nicole -- Vandenberghe, Peter -- Haferlach, Claudia -- Stephens, Philip J -- Cheng, Jiqiu -- Van Loo, Peter -- Stratton, Michael R -- Campbell, Peter J -- Harrison, Christine J -- 077012/Z/05/Z/Wellcome Trust/United Kingdom -- 088340/Wellcome Trust/United Kingdom -- 093867/Wellcome Trust/United Kingdom -- U10 CA098543/CA/NCI NIH HHS/ -- U10 CA180886/CA/NCI NIH HHS/ -- WT088340MA/Wellcome Trust/United Kingdom -- England -- Nature. 2014 Apr 3;508(7494):98-102. doi: 10.1038/nature13115. Epub 2014 Mar 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2]. ; 1] Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK [2]. ; Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK. ; West Midlands Regional Genetics Laboratory, Birmingham Women's NHS Foundation Trust, Birmingham B15 2TG, UK. ; Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury SP2 8BJ, UK. ; Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. ; 1] West Midlands Regional Genetics Laboratory, Birmingham Women's NHS Foundation Trust, Birmingham B15 2TG, UK [2] School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, UK. ; Department of Pathology, The Ohio State University, Columbus, Ohio 43210, USA. ; Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama 35233, USA. ; Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield S10 2TH, UK. ; Cytogenetics Laboratory, Northern Genetics Service, Newcastle upon Tyne NE7 7DN, UK. ; Oncology Cytogenetics, The Christie NHS Foundation Trust, Manchester M20 4BX, UK. ; Regional Cytogenetics Unit, Genetic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Saint Mary's Hospital, Manchester M13 9WL, UK. ; Institute of Health and Society, Newcastle University, Newcastle upon Tyne NE2 4AX, UK. ; 1] Genetics Department, Portuguese Oncology Institute, Porto University, 4200-072 Porto, Portugal [2] Biomedical Sciences Institute (ICBAS), Porto University, 4200-072 Porto, Portugal. ; Laboratoire d'Hematologie, Genetique des Hemopathies, Hopital Purpan, 31059 Toulouse, France. ; 1] Center for Human Genetics, University Hospital Leuven, 3000 Leuven, Belgium [2] KU Leuven, 3000 Leuven, Belgium. ; MLL Munich Leukemia Laboratory, Munich 81377, Germany. ; 1] Center for Human Genetics, University Hospital Leuven, 3000 Leuven, Belgium [2] KU Leuven, 3000 Leuven, Belgium [3] Department of Electrical Engineering - ESAT, University of Leuven, 3000 Leuven, Belgium. ; 1] Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] Center for Human Genetics, University Hospital Leuven, 3000 Leuven, Belgium [3] KU Leuven, 3000 Leuven, Belgium. ; 1] Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] Department of Haematology, University of Cambridge, Cambridge CB2 2XY, UK [3].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670643" target="_blank"〉PubMed〈/a〉

Description: Nuclear collisions recreate conditions in the universe microseconds after the Big Bang. Only a very small fraction of the emitted fragments are light nuclei, but these states are of fundamental interest. We report the observation of antihypertritons--comprising an antiproton, an antineutron, and an antilambda hyperon--produced by colliding gold nuclei at high energy. Our analysis yields 70 +/- 17 antihypertritons ((Lambda)(3)-H) and 157 +/- 30 hypertritons (Lambda3H). The measured yields of Lambda3H ((Lambda)(3)-H) and 3He (3He) are similar, suggesting an equilibrium in coordinate and momentum space populations of up, down, and strange quarks and antiquarks, unlike the pattern observed at lower collision energies. The production and properties of antinuclei, and of nuclei containing strange quarks, have implications spanning nuclear and particle physics, astrophysics, and cosmology.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉STAR Collaboration -- Abelev, B I -- Aggarwal, M M -- Ahammed, Z -- Alakhverdyants, A V -- Alekseev, I -- Anderson, B D -- Arkhipkin, D -- Averichev, G S -- Balewski, J -- Barnby, L S -- Baumgart, S -- Beavis, D R -- Bellwied, R -- Betancourt, M J -- Betts, R R -- Bhasin, A -- Bhati, A K -- Bichsel, H -- Bielcik, J -- Bielcikova, J -- Biritz, B -- Bland, L C -- Bonner, B E -- Bouchet, J -- Braidot, E -- Brandin, A V -- Bridgeman, A -- Bruna, E -- Bueltmann, S -- Bunzarov, I -- Burton, T P -- Cai, X Z -- Caines, H -- Calderon, M -- Catu, O -- Cebra, D -- Cendejas, R -- Cervantes, M C -- Chajecki, Z -- Chaloupka, P -- Chattopadhyay, S -- Chen, H F -- Chen, J H -- Chen, J Y -- Cheng, J -- Cherney, M -- Chikanian, A -- Choi, K E -- Christie, W -- Chung, P -- Clarke, R F -- Codrington, M J M -- Corliss, R -- Cramer, J G -- Crawford, H J -- Das, D -- Dash, S -- Davila Leyva, A -- De Silva, L C -- Debbe, R R -- Dedovich, T G -- DePhillips, M -- Derevschikov, A A -- Derradi de Souza, R -- Didenko, L -- Djawotho, P -- Dogra, S M -- Dong, X -- Drachenberg, J L -- Draper, J E -- Dunlop, J C -- Dutta Mazumdar, M R -- Efimov, L G -- Elhalhuli, E -- Elnimr, M -- Engelage, J -- Eppley, G -- Erazmus, B -- Estienne, M -- Eun, L -- Evdokimov, O -- Fachini, P -- Fatemi, R -- Fedorisin, J -- Fersch, R G -- Filip, P -- Finch, E -- Fine, V -- Fisyak, Y -- Gagliardi, C A -- Gangadharan, D R -- Ganti, M S -- Garcia-Solis, E J -- Geromitsos, A -- Geurts, F -- Ghazikhanian, V -- Ghosh, P -- Gorbunov, Y N -- Gordon, A -- Grebenyuk, O -- Grosnick, D -- Grube, B -- Guertin, S M -- Gupta, A -- Gupta, N -- Guryn, W -- Haag, B -- Hamed, A -- Han, L-X -- Harris, J W -- Hays-Wehle, J P -- Heinz, M -- Heppelmann, S -- Hirsch, A -- Hjort, E -- Hoffman, A M -- Hoffmann, G W -- Hofman, D J -- Hollis, R S -- Huang, B -- Huang, H Z -- Humanic, T J -- Huo, L -- Igo, G -- Iordanova, A -- Jacobs, P -- Jacobs, W W -- Jakl, P -- Jena, C -- Jin, F -- Jones, C L -- Jones, P G -- Joseph, J -- Judd, E G -- Kabana, S -- Kajimoto, K -- Kang, K -- Kapitan, J -- Kauder, K -- Keane, D -- Kechechyan, A -- Kettler, D -- Kikola, D P -- Kiryluk, J -- Kisiel, A -- Klein, S R -- Knospe, A G -- Kocoloski, A -- Koetke, D D -- Kollegger, T -- Konzer, J -- Kopytine, M -- Koralt, I -- Koroleva, L -- Korsch, W -- Kotchenda, L -- Kouchpil, V -- Kravtsov, P -- Krueger, K -- Krus, M -- Kumar, L -- Kurnadi, P -- Lamont, M A C -- Landgraf, J M -- LaPointe, S -- Lauret, J -- Lebedev, A -- Lednicky, R -- Lee, C-H -- Lee, J H -- Leight, W -- Levine, M J -- Li, C -- Li, L -- Li, N -- Li, W -- Li, X -- Li, Y -- Li, Z -- Lin, G -- Lindenbaum, S J -- Lisa, M A -- Liu, F -- Liu, H -- Liu, J -- Ljubicic, T -- Llope, W J -- Longacre, R S -- Love, W A -- Lu, Y -- Luo, X -- Ma, G L -- Ma, Y G -- Mahapatra, D P -- Majka, R -- Mal, O I -- Mangotra, L K -- Manweiler, R -- Margetis, S -- Markert, C -- Masui, H -- Matis, H S -- Matulenko, Yu A -- McDonald, D -- McShane, T S -- Meschanin, A -- Milner, R -- Minaev, N G -- Mioduszewski, S -- Mischke, A -- Mitrovski, M K -- Mohanty, B -- Mondal, M M -- Morozov, B -- Morozov, D A -- Munhoz, M G -- Nandi, B K -- Nattrass, C -- Nayak, T K -- Nelson, J M -- Netrakanti, P K -- Ng, M J -- Nogach, L V -- Nurushev, S B -- Odyniec, G -- Ogawa, A -- Okada, H -- Okorokov, V -- Olson, D -- Pachr, M -- Page, B S -- Pal, S K -- Pandit, Y -- Panebratsev, Y -- Pawlak, T -- Peitzmann, T -- Perevoztchikov, V -- Perkins, C -- Peryt, W -- Phatak, S C -- Pile, P -- Planinic, M -- Ploskon, M A -- Pluta, J -- Plyku, D -- Poljak, N -- Poskanzer, A M -- Potukuchi, B V K S -- Powell, C B -- Prindle, D -- Pruneau, C -- Pruthi, N K -- Pujahari, P R -- Putschke, J -- Qiu, H -- Raniwala, R -- Raniwala, S -- Ray, R L -- Redwine, R -- Reed, R -- Ritter, H G -- Roberts, J B -- Rogachevskiy, O V -- Romero, J L -- Rose, A -- Roy, C -- Ruan, L -- Sahoo, R -- Sakai, S -- Sakrejda, I -- Sakuma, T -- Salur, S -- Sandweiss, J -- Sangaline, E -- Schambach, J -- Scharenberg, R P -- Schmitz, N -- Schuster, T R -- Seele, J -- Seger, J -- Selyuzhenkov, I -- Seyboth, P -- Shahaliev, E -- Shao, M -- Sharma, M -- Shi, S S -- Sichtermann, E P -- Simon, F -- Singaraju, R N -- Skoby, M J -- Smirnov, N -- Sorensen, P -- Sowinski, J -- Spinka, H M -- Srivastava, B -- Stanislaus, T D S -- Staszak, D -- Stevens, J R -- Stock, R -- Strikhanov, M -- Stringfellow, B -- Suaide, A A P -- Suarez, M C -- Subba, N L -- Sumbera, M -- Sun, X M -- Sun, Y -- Sun, Z -- Surrow, B -- Svirida, D N -- Symons, T J M -- Szanto de Toledo, A -- Takahashi, J -- Tang, A H -- Tang, Z -- Tarini, L H -- Tarnowsky, T -- Thein, D -- Thomas, J H -- Tian, J -- Timmins, A R -- Timoshenko, S -- Tlusty, D -- Tokarev, M -- Trainor, T A -- Tram, V N -- Trentalange, S -- Tribble, R E -- Tsai, O D -- Ulery, J -- Ullrich, T -- Underwood, D G -- Van Buren, G -- van Leeuwen, M -- van Nieuwenhuizen, G -- Vanfossen, J A Jr -- Varma, R -- Vasconcelos, G M S -- Vasiliev, A N -- Videbaek, F -- Viyogi, Y P -- Vokal, S -- Voloshin, S A -- Wada, M -- Walker, M -- Wang, F -- Wang, G -- Wang, H -- Wang, J S -- Wang, Q -- Wang, X L -- Wang, Y -- Webb, G -- Webb, J C -- Westfall, G D -- Whitten, C Jr -- Wieman, H -- Wingfield, E -- Wissink, S W -- Witt, R -- Wu, Y -- Xie, W -- Xu, H -- Xu, N -- Xu, Q H -- Xu, W -- Xu, Y -- Xu, Z -- Xue, L -- Yang, Y -- Yepes, P -- Yip, K -- Yoo, I-K -- Yue, Q -- Zawisza, M -- Zbroszczyk, H -- Zhan, W -- Zhang, J -- Zhang, S -- Zhang, W M -- Zhang, X P -- Zhang, Y -- Zhang, Z P -- Zhao, J -- Zhong, C -- Zhou, J -- Zhou, W -- Zhu, X -- Zhu, Y H -- Zoulkarneev, R -- Zoulkarneeva, Y -- New York, N.Y. -- Science. 2010 Apr 2;328(5974):58-62. doi: 10.1126/science.1183980. Epub 2010 Mar 4.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20203011" target="_blank"〉PubMed〈/a〉

Description: Journal of the American Chemical Society DOI: 10.1021/jacs.7b06960