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Changing nutrient cycling in Lake Baikal, the world’s oldest lake 期刊论文
Proceedings of the National Academy of Sciences, 2020
作者:  George E. A. Swann;  Virginia N. Panizzo;  Sebastiano Piccolroaz;  Vanessa Pashley;  Matthew S. A. Horstwood;  Sarah Roberts;  Elena Vologina;  Natalia Piotrowska;  Michael Sturm;  Andre Zhdanov;  Nikolay Granin;  Charlotte Norman;  Suzanne McGowan;  Anson W. Mackay
收藏  |  浏览/下载:28/0  |  提交时间:2020/10/26
Ensuring meiotic DNA break formation in the mouse pseudoautosomal region 期刊论文
NATURE, 2020
作者:  Schuessler, R. X.;  Bekker, H.;  Brass, M.;  Cakir, H.;  Crespo Lopez-Urrutia, J. R.;  Door, M.;  Filianin, P.;  Harman, Z.;  Haverkort, M. W.;  Huang, W. J.;  Indelicato, P.;  Keitel, C. H.;  Koenig, C. M.;  Kromer, K.;  Mueller, M.;  Novikov, Y. N.;  Rischka, A.;  Schweiger, C.;  Sturm, S.;  Ulmer, S.;  Eliseev, S.;  Blaum, K.
收藏  |  浏览/下载:50/0  |  提交时间:2020/07/03

In mice, the pseudoautosomal region of the sex chromosomes undergoes a dynamic structural rearrangement to promote a high rate of DNA double-strand breaks and to ensure X-Y recombination.


Sex chromosomes in males of most eutherian mammals share only a small homologous segment, the pseudoautosomal region (PAR), in which the formation of double-strand breaks (DSBs), pairing and crossing over must occur for correct meiotic segregation(1,2). How cells ensure that recombination occurs in the PAR is unknown. Here we present a dynamic ultrastructure of the PAR and identify controlling cis- and trans-acting factors that make the PAR the hottest segment for DSB formation in the male mouse genome. Before break formation, multiple DSB-promoting factors hyperaccumulate in the PAR, its chromosome axes elongate and the sister chromatids separate. These processes are linked to heterochromatic mo-2 minisatellite arrays, and require MEI4 and ANKRD31 proteins but not the axis components REC8 or HORMAD1. We propose that the repetitive DNA sequence of the PAR confers unique chromatin and higher-order structures that are crucial for recombination. Chromosome synapsis triggers collapse of the elongated PAR structure and, notably, oocytes can be reprogrammed to exhibit spermatocyte-like levels of DSBs in the PAR simply by delaying or preventing synapsis. Thus, the sexually dimorphic behaviour of the PAR is in part a result of kinetic differences between the sexes in a race between the maturation of the PAR structure, formation of DSBs and completion of pairing and synapsis. Our findings establish a mechanistic paradigm for the recombination of sex chromosomes during meiosis.


  
Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I 期刊论文
NATURE, 2020, 581 (7806) : 100-+
作者:  Waszak, Sebastian M.;  Robinson, Giles W.;  Gudenas, Brian L.;  Smith, Kyle S.;  Forget, Antoine;  Kojic, Marija;  Garcia-Lopez, Jesus;  Hadley, Jennifer;  Hamilton, Kayla V.;  Indersie, Emilie;  Buchhalter, Ivo;  Kerssemakers, Jules;  Jager, Natalie;  Sharma, Tanvi;  Rausch, Tobias;  Kool, Marcel;  Sturm, Dominik;  Jones, David T. W.;  Vasilyeva, Aksana;  Tatevossian, Ruth G.;  Neale, Geoffrey;  Lombard, Berangere;  Loew, Damarys;  Nakitandwe, Joy;  Rusch, Michael;  Bowers, Daniel C.;  Bendel, Anne;  Partap, Sonia;  Chintagumpala, Murali;  Crawford, John;  Gottardo, Nicholas G.;  Smith, Amy;  Dufour, Christelle;  Rutkowski, Stefan;  Eggen, Tone;  Wesenberg, Finn;  Kjaerheim, Kristina;  Feychting, Maria;  Lannering, Birgitta;  Schuz, Joachim;  Johansen, Christoffer;  Andersen, Tina V.;  Roosli, Martin;  Kuehni, Claudia E.;  Grotzer, Michael;  Remke, Marc;  Puget, Stephanie;  Pajtler, Kristian W.;  Milde, Till;  Witt, Olaf;  Ryzhova, Marina;  Korshunov, Andrey;  Orr, Brent A.;  Ellison, David W.;  Brugieres, Laurence;  Lichter, Peter;  Nichols, Kim E.;  Gajjar, Amar;  Wainwright, Brandon J.;  Ayrault, Olivier;  Korbel, Jan O.;  Northcott, Paul A.;  Pfister, Stefan M.
收藏  |  浏览/下载:66/0  |  提交时间:2020/07/03

Immune evasion is a major obstacle for cancer treatment. Common mechanisms of evasion include impaired antigen presentation caused by mutations or loss of heterozygosity of the major histocompatibility complex class I (MHC-I), which has been implicated in resistance to immune checkpoint blockade (ICB) therapy(1-3). However, in pancreatic ductal adenocarcinoma (PDAC), which is resistant to most therapies including ICB4, mutations that cause loss of MHC-I are rarely found(5) despite the frequent downregulation of MHC-I expression(6-8). Here we show that, in PDAC, MHC-I molecules are selectively targeted for lysosomal degradation by an autophagy-dependent mechanism that involves the autophagy cargo receptor NBR1. PDAC cells display reduced expression of MHC-I at the cell surface and instead demonstrate predominant localization within autophagosomes and lysosomes. Notably, inhibition of autophagy restores surface levels of MHC-I and leads to improved antigen presentation, enhanced anti-tumour T cell responses and reduced tumour growth in syngeneic host mice. Accordingly, the anti-tumour effects of autophagy inhibition are reversed by depleting CD8(+) T cells or reducing surface expression of MHC-I. Inhibition of autophagy, either genetically or pharmacologically with chloroquine, synergizes with dual ICB therapy (anti-PD1 and anti-CTLA4 antibodies), and leads to an enhanced anti-tumour immune response. Our findings demonstrate a role for enhanced autophagy or lysosome function in immune evasion by selective targeting of MHC-I molecules for degradation, and provide a rationale for the combination of autophagy inhibition and dual ICB therapy as a therapeutic strategy against PDAC.


Inhibition of the autophagy-lysosome system upregulates surface expression of MHC class I proteins and enhances antigen presentation, and evokes a potent anti-tumour immune response that is mediated by CD8(+) T cells.


  
Star formation inside a galactic outflow 期刊论文
NATURE, 2017, 544 (7649) : 202-+
作者:  Maiolino, R.;  Russell, H. R.;  Fabian, A. C.;  Carniani, S.;  Gallagher, R.;  Cazzoli, S.;  Arribas, S.;  Belfiore, F.;  Bellocchi, E.;  Colina, L.;  Cresci, G.;  Ishibashi, W.;  Marconi, A.;  Mannucci, F.;  Oliva, E.;  Sturm, E.
收藏  |  浏览/下载:20/0  |  提交时间:2019/04/09