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Ferroptosis is an iron-dependent form of cell death, which is triggered by disturbed membrane integrity due to an overproduction of lipid peroxides. Induction of ferroptosis comprises several alterations, i.e. altered iron metabolism, response to oxidative stress, or lipid peroxide production. At the physiological level transcription, translation, and microRNAs add to the appearance and/or activity of building blocks that negatively or positively balance ferroptosis. Ferroptosis contributes to tissue damage in the case of, e.g., brain and heart injury but may be desirable to overcome chemotherapy resistance. For a more complete picture, it is crucial to also consider the cellular microenvironment, which during inflammation and in the tumor context is dominated by hypoxia. This graphical review visualizes basic mechanisms of ferroptosis, categorizes general inducers and inhibitors of ferroptosis, and puts a focus on microRNAs, iron homeostasis, and hypoxia as regulatory components.
Network graphs have become a popular tool to represent complex systems composed of many interacting subunits; especially in neuroscience, network graphs are increasingly used to represent and analyze functional interactions between multiple neural sources. Interactions are often reconstructed using pairwise bivariate analyses, overlooking the multivariate nature of interactions: it is neglected that investigating the effect of one source on a target necessitates to take all other sources as potential nuisance variables into account; also combinations of sources may act jointly on a given target. Bivariate analyses produce networks that may contain spurious interactions, which reduce the interpretability of the network and its graph metrics. A truly multivariate reconstruction, however, is computationally intractable because of the combinatorial explosion in the number of potential interactions. Thus, we have to resort to approximative methods to handle the intractability of multivariate interaction reconstruction, and thereby enable the use of networks in neuroscience. Here, we suggest such an approximative approach in the form of an algorithm that extends fast bivariate interaction reconstruction by identifying potentially spurious interactions post-hoc: the algorithm uses interaction delays reconstructed for directed bivariate interactions to tag potentially spurious edges on the basis of their timing signatures in the context of the surrounding network. Such tagged interactions may then be pruned, which produces a statistically conservative network approximation that is guaranteed to contain non-spurious interactions only. We describe the algorithm and present a reference implementation in MATLAB to test the algorithm’s performance on simulated networks as well as networks derived from magnetoencephalographic data. We discuss the algorithm in relation to other approximative multivariate methods and highlight suitable application scenarios. Our approach is a tractable and data-efficient way of reconstructing approximative networks of multivariate interactions. It is preferable if available data are limited or if fully multivariate approaches are computationally infeasible.
Hulsik, David Lutje ; Liu, Ying-ying ; Strokappe, Nika M. ; Battella, Simone ; El Khattabi, Mohamed ; McCoy, Laura E. ; Sabin, Charles ; Hinz, Andreas ; Hock, Miriam ; Macheboeuf, Pauline ; Bonvin, Alexandre M. J. J. ; Langedijk, Johannes P. M. ; Davis, David ; Forsman Quigley, Anna ; Aasa-Chapman, Marlén M. I. ; Seaman, Michael S. ; Ramos, Alejandra ; Poignard, Pascal ; Favier, Adrien ; Simorre, Jean-Pierre ; Weiss, Robin A. ; Verrips, C. Theo ; Weissenhorn, Winfried ; Rutten, Lucy
The membrane proximal external region (MPER) of the HIV-1 glycoprotein gp41 is targeted by the broadly neutralizing antibodies 2F5 and 4E10. To date, no immunization regimen in animals or humans has produced HIV-1 neutralizing MPER-specific antibodies. We immunized llamas with gp41-MPER proteoliposomes and selected a MPER-specific single chain antibody (VHH), 2H10, whose epitope overlaps with that of mAb 2F5. Bi-2H10, a bivalent form of 2H10, which displayed an approximately 20-fold increased affinity compared to the monovalent 2H10, neutralized various sensitive and resistant HIV-1 strains, as well as SHIV strains in TZM-bl cells. X-ray and NMR analyses combined with mutagenesis and modeling revealed that 2H10 recognizes its gp41 epitope in a helical conformation. Notably, tryptophan 100 at the tip of the long CDR3 is not required for gp41 interaction but essential for neutralization. Thus bi-2H10 is an anti-MPER antibody generated by immunization that requires hydrophobic CDR3 determinants in addition to epitope recognition for neutralization similar to the mode of neutralization employed by mAbs 2F5 and 4E10.
Wetlands such as bogs, swamps, or freshwater marshes are hotspots of biodiversity. For 5.1 million km2 of inland wetlands, the dynamics of area and water storage, which strongly impact biodiversity and ecosystem services, were simulated using the global hydrological model WaterGAP. For the first time, the impacts of both human water use and man‐made reservoirs (WUR) and future climate change (CC) on wetlands around the globe were quantified. WUR impacts are concentrated in arid/semiarid regions, where WUR decreased mean wetland water storage by more than 5% on 8.2% of the mean wetland area during 1986–2005 (Am), with highest decreases in groundwater depletion area. Using output of three climate models, CC impacts on wetlands were quantified, distinguishing unavoidable impacts [i.e., at 2 °C global warming (GW)] from avoidable impacts (difference between 3 °C and 2 °C impacts). Even unavoidable CC impacts are projected to be much larger than WUR impacts, also in arid/semiarid regions. On most wetland area with reliable estimates, avoidable CC impacts are more than twice as large as unavoidable impacts. In case of 2 °C GW, half of Am is estimated to be unaffected by mean storage changes of more than 5%, but only one third in case of 3 °C GW. Temporal variability of water storage will increase for most wetlands. Wetlands in dry regions will be affected the most, particularly by water storage decreases in the dry season. Different from wealthier countries, low‐income countries will dominantly suffer from a decrease in wetland water storage due to CC.
Siebert, Stefan ; Kummu, Matti ; Porkka, Miina ; Döll, Petra ; Ramankutty, Navin ; Scanlon, Bridget R.
Irrigation intensifies land use by increasing crop yield but also impacts water resources. It affects water and energy balances and consequently the microclimate in irrigated regions. Therefore, knowledge of the extent of irrigated land is important for hydrological and crop modelling, global change research, and assessments of resource use and management. Information on the historical evolution of irrigated lands is limited. The new global Historical Irrigation Dataset (HID) provides estimates of the temporal development of the area equipped for irrigation (AEI) between 1900 and 2005 at 5 arc-minute resolution. We collected subnational irrigation statistics from various sources and found that the global extent of AEI increased from 63 million ha (Mha) in 1900 to 112 Mha in 1950 and 306 Mha in 2005. We developed eight gridded versions of time series of AEI by combining subnational irrigation statistics with different data sets on the historical extent of cropland and pasture. Different rules were applied to maximize consistency of the gridded products to subnational irrigation statistics or to historical cropland and pasture data sets. The HID reflects very well the spatial patterns of irrigated land in the western United States as shown on historical maps. Mean aridity on irrigated land increased and river discharge decreased from 1900–1950 whereas aridity decreased from 1950–2005. The dataset and its documentation are made available in an open data repository at https://mygeohub.org/publications/8 (doi:10.13019/M2MW2G).
Siebert, Stefan ; Kummu, Matti ; Porkka, Miina ; Döll, Petra ; Ramankutty, Navin ; Scanlon, Bridget R.
Irrigation intensifies land use by increasing crop yield but also impacts water resources. It affects water and energy balances and consequently the microclimate in irrigated regions. Therefore, knowledge of the extent of irrigated land is important for hydrological and crop modelling, global change research, and assessments of resource use and management. Information on the historical evolution of irrigated lands is limited. The new global historical irrigation data set (HID) provides estimates of the temporal development of the area equipped for irrigation (AEI) between 1900 and 2005 at 5 arcmin resolution. We collected sub-national irrigation statistics from various sources and found that the global extent of AEI increased from 63 million ha (Mha) in 1900 to 111 Mha in 1950 and 306 Mha in 2005. We developed eight gridded versions of time series of AEI by combining sub-national irrigation statistics with different data sets on the historical extent of cropland and pasture. Different rules were applied to maximize consistency of the gridded products to sub-national irrigation statistics or to historical cropland and pasture data sets. The HID reflects very well the spatial patterns of irrigated land as shown on historical maps for the western United States (around year 1900) and on a global map (around year 1960). Mean aridity on irrigated land increased and mean natural river discharge on irrigated land decreased from 1900 to 1950 whereas aridity decreased and river discharge remained approximately constant from 1950 to 2005. The data set and its documentation are made available in an open-data repository at https://mygeohub.org/publications/8 (doi:10.13019/M20599).
Ovseiko, Pavel V. ; Greenhalgh, Trisha ; Adam, Paula ; Grant, Jonathan ; Hinrichs-Krapels, Saba ; Graham, Kathryn E. ; Valentine, Pamela A. ; Sued, Omar ; Boukhris, Omar F. ; Al Olaqi, Nada M. ; Al Rahbi, Idrees S. ; Dowd, Anne-Maree ; Bice, Sara ; Heiden, Tamika L. ; Fischer, Michael D. ; Dopson, Sue ; Norton, Robyn ; Pollitt, Alexandra ; Wooding, Steven ; Balling, Gert V. ; Jakobsen, Ulla ; Kuhlmann, Ellen ; Klinge, Ineke ; Pololi, Linda H. ; Jagsi, Reshma ; Lawton Smith, Helen ; Etzkowitz, Henry ; Nielsen, Mathias W. ; Carrion, Carme ; Solans‐Domènech, Maite ; Vizcaino, Esther ; Naing, Lin ; Cheok, Quentin H. N. ; Eckelmann, Baerbel ; Simuyemba, Moses C. ; Msiska, Temwa ; Declich, Giovanna ; Edmunds, Laurel D. ; Kiparoglou, Vasiliki ; Buchan, Alison M. J. ; Williamson, Catherine ; Lord, Graham M. ; Channon, Keith M. ; Surender, Rebecca ; Buchan, Alastair M.
Global investment in biomedical research has grown significantly over the last decades, reaching approximately a quarter of a trillion US dollars in 2010. However, not all of this investment is distributed evenly by gender. It follows, arguably, that scarce research resources may not be optimally invested (by either not supporting the best science or by failing to investigate topics that benefit women and men equitably). Women across the world tend to be significantly underrepresented in research both as researchers and research participants, receive less research funding, and appear less frequently than men as authors on research publications. There is also some evidence that women are relatively disadvantaged as the beneficiaries of research, in terms of its health, societal and economic impacts. Historical gender biases may have created a path dependency that means that the research system and the impacts of research are biased towards male researchers and male beneficiaries, making it inherently difficult (though not impossible) to eliminate gender bias. In this commentary, we – a group of scholars and practitioners from Africa, America, Asia and Europe – argue that gender-sensitive research impact assessment could become a force for good in moving science policy and practice towards gender equity. Research impact assessment is the multidisciplinary field of scientific inquiry that examines the research process to maximise scientific, societal and economic returns on investment in research. It encompasses many theoretical and methodological approaches that can be used to investigate gender bias and recommend actions for change to maximise research impact. We offer a set of recommendations to research funders, research institutions and research evaluators who conduct impact assessment on how to include and strengthen analysis of gender equity in research impact assessment and issue a global call for action.
Recent phylogenomic studies have failed to conclusively resolve certain branches of the placental mammalian tree, despite the evolutionary analysis of genomic data from 32 species. Previous analyses of single genes and retroposon insertion data yielded support for different phylogenetic scenarios for the most basal divergences. The results indicated that some mammalian divergences were best interpreted not as a single bifurcating tree, but as an evolutionary network. In these studies the relationships among some orders of the super-clade Laurasiatheria were poorly supported, albeit not studied in detail. Therefore, 4775 protein-coding genes (6,196,263 nucleotides) were collected and aligned in order to analyze the evolution of this clade. Additionally, over 200,000 introns were screened in silico, resulting in 32 phylogenetically informative long interspersed nuclear elements (LINE) insertion events.
The present study shows that the genome evolution of Laurasiatheria may best be understood as an evolutionary network. Thus, contrary to the common expectation to resolve major evolutionary events as a bifurcating tree, genome analyses unveil complex speciation processes even in deep mammalian divergences. We exemplify this on a subset of 1159 suitable genes that have individual histories, most likely due to incomplete lineage sorting or introgression, processes that can make the genealogy of mammalian genomes complex.
These unexpected results have major implications for the understanding of evolution in general, because the evolution of even some higher level taxa such as mammalian orders may sometimes not be interpreted as a simple bifurcating pattern.
Anney, Richard ; Klei, Lambertus ; Pinto, Dalila ; Regan, Regina ; Conroy, Judith ; Magalhães, Tiago R. ; Correia, Catarina ; Abrahams, Brett S. ; Sykes, Nuala ; Pagnamenta, Alistair T. ; Almeida, Joana ; Bacchelli, Elena ; Bailey, Anthony J. ; Baird, Gillian ; Battaglia, Agatino ; Berney, Tom ; Bolshakova, Nadia ; Bölte, Sven ; Bolton, Patrick F. ; Bourgeron, Thomas ; Brennan, Sean ; Brian, Jessica ; Carson, Andrew R. ; Casallo, Guillermo ; Casey, Jillian ; Chu, Su H. ; Cochrane, Lynne ; Corsello, Christina ; Crawford, Emily L. ; Crossett, Andrew ; Dawson, Geraldine ; Jonge, Maretha de ; Delorme, Richard ; Drmic, Irene ; Duketis, Eftichia ; Duque, Frederico ; Estes, Annette ; Farrar, Penny ; Fernandez, Bridget A. ; Folstein, Susan E. ; Fombonne, Eric ; Freitag, Christine M. ; Gilbert, John ; Gillberg, Christopher ; Glessner, Joseph T. ; Goldberg, Jeremy ; Green, Jonathan ; Guter, Stephen J. ; Hakonarson, Hakon ; Heron, Elizabeth A. ; Hill, Matthew ; Holt, Richard ; Howe, Jennifer L. ; Hughes, Gillian ; Hus, Vanessa ; Igliozzi, Roberta ; Kim, Cecilia ; Klauck, Sabine M. ; Kolevzon, Alexander ; Korvatska, Olena ; Kustanovich, Vlad ; Lajonchere, Clara M. ; Lamb, Janine A. ; Laskawiec, Magdalena ; Leboyer, Marion ; Le Couteur, Ann ; Leventhal, Bennett L. ; Lionel, Anath C. ; Liu, Xiao-Qing ; Lord, Catherine ; Lotspeich, Linda ; Lund, Sabata C. ; Maestrini, Elena ; Mahoney, William ; Mantoulan, Carine ; Marshall, Christian R. ; McConachie, Helen ; McDougle, Christopher J. ; McGrath, Jane ; McMahon, William M. ; Melhem, Nadine M. ; Merikangas, Alison ; Migita, Ohsuke ; Minshew, Nancy J. ; Mirza, Ghazala K. ; Munson, Jeff ; Nelson, Stanley F. ; Noakes, Carolyn ; Noor, Abdul ; Nygren, Gudrun ; Oliveira, Guiomar ; Papanikolaou, Katerina ; Parr, Jeremy R. ; Parrini, Barbara ; Paton, Tara ; Pickles, Andrew ; Piven, Joseph ; Posey, David J. ; Poustka, Annemarie ; Poustka, Fritz ; Prasad, Aparna ; Ragoussis, Jiannis ; Renshaw, Katy ; Rickaby, Jessica ; Roberts, Wendy ; Roeder, Kathryn ; Roge, Bernadette ; Rutter, Michael L. ; Bierut, Laura Jean ; Rice, John P. ; Salt, Jeff ; Sansom, Katherine ; Sato, Daisuke ; Segurado, Ricardo ; Senman, Lili ; Shah, Naisha ; Sheffield, Val C. ; Soorya, Latha ; Sousa, Inês ; Stoppioni, Vera ; Strawbridge, Christina ; Tancredi, Raffaella ; Tansey, Katherine ; Thiruvahindrapduram, Bhooma ; Thompson, Ann P. ; Thomson, Susanne ; Tryfon, Ana ; Tsiantis, John ; Engeland, Herman van ; Vincent, John B. ; Volkmar, Fred ; Wallace, Simon ; Wang, Kai ; Wang, Zhouzhi ; Wassink, Thomas H. ; Wing, Kirsty ; Wittemeyer, Kerstin ; Wood, Shawn ; Yaspan, Brian L. ; Zurawiecki, Danielle ; Zwaigenbaum, Lonnie ; Betancur, Catalina ; Buxbaum, Joseph D. ; Cantor, Rita M. ; Cook, Edwin H. ; Coon, Hilary ; Cuccaro, Michael L. ; Gallagher, Louise ; Geschwind, Daniel H. ; Gill, Michael ; Haines, Jonathan L. ; Miller, Judith ; Monaco, Anthony P. ; Nurnberger, John I. ; Paterson, Andrew D. ; Pericak-Vance, Margaret Ann ; Schellenberg, Gerard D. ; Scherer, Stephen W. ; Sutcliffe, James S. ; Szatmari, Peter ; Vicente, Astrid M. ; Vieland, Veronica J. ; Wijsman, Ellen M. ; Devlin, Bernie ; Ennis, Sean ; Hallmayer, Joachim
Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10−8. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10−8 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.
Philipp, Oliver ; Hamann, Andrea ; Servos, Jörg ; Werner, Alexandra ; Koch, Ina ; Osiewacz, Heinz D.
Aging of biological systems is controlled by various processes which have a potential impact on gene expression. Here we report a genome-wide transcriptome analysis of the fungal aging model Podospora anserina. Total RNA of three individuals of defined age were pooled and analyzed by SuperSAGE (serial analysis of gene expression). A bioinformatics analysis identified different molecular pathways to be affected during aging. While the abundance of transcripts linked to ribosomes and to the proteasome quality control system were found to decrease during aging, those associated with autophagy increase, suggesting that autophagy may act as a compensatory quality control pathway. Transcript profiles associated with the energy metabolism including mitochondrial functions were identified to fluctuate during aging. Comparison of wild-type transcripts, which are continuously down-regulated during aging, with those down-regulated in the long-lived, copper-uptake mutant grisea, validated the relevance of age-related changes in cellular copper metabolism. Overall, we (i) present a unique age-related data set of a longitudinal study of the experimental aging model P. anserina which represents a reference resource for future investigations in a variety of organisms, (ii) suggest autophagy to be a key quality control pathway that becomes active once other pathways fail, and (iii) present testable predictions for subsequent experimental investigations.