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• 1.
Howard Hughes Medical Institute, Kavli Institute for Brain Science, Mortimer B. Zuckerman Mind Brain Behavior Institute, Departments of Neuroscience and Biochemistry and Molecular Biophysics, Columbia University, New York, USA.
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Howard Hughes Medical Institute, Kavli Institute for Brain Science, Mortimer B. Zuckerman Mind Brain Behavior Institute, Departments of Neuroscience and Biochemistry and Molecular Biophysics, Columbia University, New York, USA.
Skilled reaching relies on a V2a propriospinal internal copy circuit2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 508, no 7496, p. 357-363Article in journal (Refereed)

The precision of skilled forelimb movement has long been presumed to rely on rapid feedback corrections triggered by internally directed copies of outgoing motor commands, but the functional relevance of inferred internal copy circuits has remained unclear. One class of spinal interneurons implicated in the control of mammalian forelimb movement, cervical propriospinal neurons (PNs), has the potential to convey an internal copy of premotor signals through dual innervation of forelimb-innervating motor neurons and precerebellar neurons of the lateral reticular nucleus. Here we examine whether the PN internal copy pathway functions in the control of goal-directed reaching. In mice, PNs include a genetically accessible subpopulation of cervical V2a interneurons, and their targeted ablation perturbs reaching while leaving intact other elements of forelimb movement. Moreover, optogenetic activation of the PN internal copy branch recruits a rapid cerebellar feedback loop that modulates forelimb motor neuron activity and severely disrupts reaching kinematics. Our findings implicate V2a PNs as the focus of an internal copy pathway assigned to the rapid updating of motor output during reaching behaviour.

• 2. Bieling, Peter
European Mol Biol Lab, Cell Biol & Biophys Unit, D-69117 Heidelberg, Germany .
Reconstitution of a microtubule plus-end tracking system in vitro2007In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 450, no 7172, p. 1100-1105Article in journal (Refereed)

The microtubule cytoskeleton is essential to cell morphogenesis. Growing microtubule plus ends have emerged as dynamic regulatory sites in which specialized proteins, called plus-end-binding proteins (+TIPs), bind and regulate the proper functioning of microtubules. However, the molecular mechanism of plus-end association by +TIPs and their ability to track the growing end are not well understood. Here we report the in vitro reconstitution of a minimal plus-end tracking system consisting of the three fission yeast proteins Mal3, Tip1 and the kinesin Tea2. Using time-lapse total internal reflection fluorescence microscopy, we show that the EB1 homologue Mal3 has an enhanced affinity for growing microtubule end structures as opposed to the microtubule lattice. This allows it to track growing microtubule ends autonomously by an end recognition mechanism. In addition, Mal3 acts as a factor that mediates loading of the processive motor Tea2 and its cargo, the Clip170 homologue Tip1, onto the microtubule lattice. The interaction of all three proteins is required for the selective tracking of growing microtubule plus ends by both Tea2 and Tip1. Our results dissect the collective interactions of the constituents of this plus-end tracking system and show how these interactions lead to the emergence of its dynamic behaviour. We expect that such in vitro reconstitutions will also be essential for the mechanistic dissection of other plus-end tracking systems.

• 3. Bjorkman, Anne D.
Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
Plant functional trait change across a warming tundra biome2018In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 562, no 7725, p. 57-+Article in journal (Refereed)

The tundra is warming more rapidly than any other biome on Earth, and the potential ramifications are far-reaching because of global feedback effects between vegetation and climate. A better understanding of how environmental factors shape plant structure and function is crucial for predicting the consequences of environmental change for ecosystem functioning. Here we explore the biome-wide relationships between temperature, moisture and seven key plant functional traits both across space and over three decades of warming at 117 tundra locations. Spatial temperature-trait relationships were generally strong but soil moisture had a marked influence on the strength and direction of these relationships, highlighting the potentially important influence of changes in water availability on future trait shifts in tundra plant communities. Community height increased with warming across all sites over the past three decades, but other traits lagged far behind predicted rates of change. Our findings highlight the challenge of using space-for-time substitution to predict the functional consequences of future warming and suggest that functions that are tied closely to plant height will experience the most rapid change. They also reveal the strength with which environmental factors shape biotic communities at the coldest extremes of the planet and will help to improve projections of functional changes in tundra ecosystems with climate warming.

• 4. Boussemart, Lise
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Inserm UMR981, F-94805 Villejuif, France.
eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 513, no 7516, p. 105-109Article in journal (Refereed)

In BRAF(V600)-mutant tumours, most mechanisms of resistance to drugs that target the BRAF and/or MEK kinases rely on reactivation of the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signal transduction pathway, on activation of the alternative, PI(3)K-AKT-mTOR, pathway (which is ERK independent) or on modulation of the caspase-dependent apoptotic cascade. All three pathways converge to regulate the formation of the eIF4F eukaryotic translation initiation complex, which binds to the 7-methylguanylate cap (m(7)G) at the 5' end of messenger RNA, thereby modulating the translation of specific mRNAs. Here we show that the persistent formation of the eIF4F complex, comprising the eIF4E cap-binding protein, the eIF4G scaffolding protein and the eIF4A RNA helicase, is associated with resistance to anti-BRAF, anti-MEK and anti-BRAF plus anti-MEK drug combinations in BRAF(V600)-mutant melanoma, colon and thyroid cancer cell lines. Resistance to treatment and maintenance of eIF4F complex formation is associated with one of three mechanisms: reactivation of MAPK signalling, persistent ERK-independent phosphorylation of the inhibitory eIF4E-binding protein 4EBP1 or increased pro-apoptotic BCL-2-modifying factor (BMF)-dependent degradation of eIF4G. The development of an in situ method to detect the eIF4E-eIF4G interactions shows that eIF4F complex formation is decreased in tumours that respond to anti-BRAF therapy and increased in resistant metastases compared to tumours before treatment. Strikingly, inhibiting the eIF4F complex, either by blocking the eIF4E-eIF4G interaction or by targeting eIF4A, synergizes with inhibiting BRAF(V600) to kill the cancer cells. eIF4F not only appears to be an indicator of both innate and acquired resistance but also is a promising therapeutic target. Combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms arising in BRAF(V600)-mutant cancers.

• 5.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
Global health estimated over two decades2017In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 545, no 7655, p. 421-422Article in journal (Refereed)
• 6.
Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
Biotechnology: rewriting a genome2013In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 495, no 7439, p. 50-51Article in journal (Other academic)
• 7. Coquel, Flavie
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
SAMHD1 acts at stalled replication forks to prevent interferon induction2018In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 557, no 7703, p. 57-61Article in journal (Refereed)

SAMHD1 was previously characterized as a dNTPase that protects cells from viral infections. Mutations in SAMHD1 are implicated in cancer development and in a severe congenital inflammatory disease known as Aicardi-Goutières syndrome. The mechanism by which SAMHD1 protects against cancer and chronic inflammation is unknown. Here we show that SAMHD1 promotes degradation of nascent DNA at stalled replication forks in human cell lines by stimulating the exonuclease activity of MRE11. This function activates the ATR-CHK1 checkpoint and allows the forks to restart replication. In SAMHD1-depleted cells, single-stranded DNA fragments are released from stalled forks and accumulate in the cytosol, where they activate the cGAS-STING pathway to induce expression of pro-inflammatory type I interferons. SAMHD1 is thus an important player in the replication stress response, which prevents chronic inflammation by limiting the release of single-stranded DNA from stalled replication forks.

• 8. Daumke, Oliver
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Architectural and mechanistic insights into an EHD ATPase involved in membrane remodelling2007In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 449, no 7164, p. 923-927Article in journal (Refereed)

The ability to actively remodel membranes in response to nucleotide hydrolysis has largely been attributed to GTPases of the dynamin superfamily, and these have been extensively studied. Eps15 homology (EH)-domain-containing proteins (EHDs/RME-1/pincher) comprise a less-well-characterized class of highly conserved eukaryotic ATPases implicated in clathrin-independent endocytosis, and recycling from endosomes. Here we show that EHDs share many common features with the dynamin superfamily, such as a low affinity for nucleotides, the ability to tubulate liposomes in vitro, oligomerization around lipid tubules in ring-like structures and stimulated nucleotide hydrolysis in response to lipid binding. We present the structure of EHD2, bound to a non-hydrolysable ATP analogue, and provide evidence consistent with a role for EHDs in nucleotide-dependent membrane remodelling in vivo. The nucleotide-binding domain is involved in dimerization, which creates a highly curved membrane-binding region in the dimer. Oligomerization of dimers occurs on another interface of the nucleotide-binding domain, and this allows us to model the EHD oligomer. We discuss the functional implications of the EHD2 structure for understanding membrane deformation.

• 9. DeLuca, T H
Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
Quantifying nitrogen-fixation in feather moss carpets of boreal forests2002In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 419, no 6910, p. 917-920Article in journal (Refereed)

Biological nitrogen (N) fixation is the primary source of N within natural ecosystems(1), yet the origin of boreal forest N has remained elusive. The boreal forests of Eurasia and North America lack any significant, widespread symbiotic N-fixing plants(1-6). With the exception of scattered stands of alder in early primary successional forests(7), N-fixation in boreal forests is considered to be extremely limited. Nitrogen-fixation in northern European boreal forests has been estimated(2) at only 0.5 kg Nha(-1) yr(-1); however, organic N is accumulated in these ecosystems at a rate of 3 kg N ha(-1) yr(-1) (ref. 8). Our limited understanding of the origin of boreal N is unacceptable given the extent of the boreal forest region, but predictable given our imperfect knowledge of N-fixation(1,9). Herein we report on a N-fixing symbiosis between a cyanobacterium (Nostoc sp.) and the ubiquitous feather moss, Pleurozium schreberi (Bird) Mitt. that alone fixes between 1.5 and 2.0 kg N ha(-1) yr(-1) in mid- to late-successional forests of northern Scandinavia and Finland. Previous efforts have probably underestimated N-fixation potential in boreal forests.

• 10. Dethoff, Elizabeth A
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Visualizing transient low-populated structures of RNA2012In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 491, no 7426, p. 724-728Article in journal (Refereed)

The visualization of RNA conformational changes has provided fundamental insights into how regulatory RNAs carry out their biological functions. The RNA structural transitions that have been characterized so far involve long-lived species that can be captured by structure characterization techniques. Here we report the nuclear magnetic resonance visualization of RNA transitions towards 'invisible' excited states (ESs), which exist in too little abundance (2-13%) and for too short a duration (45-250 μs) to allow structural characterization by conventional techniques. Transitions towards ESs result in localized rearrangements in base-pairing that alter building block elements of RNA architecture, including helix-junction-helix motifs and apical loops. The ES can inhibit function by sequestering residues involved in recognition and signalling or promote ATP-independent strand exchange. Thus, RNAs do not adopt a single conformation, but rather exist in rapid equilibrium with alternative ESs, which can be stabilized by cellular cues to affect functional outcomes.

• 11. Englund, Camilla
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
Jeb signals through the Alk receptor tyrosine kinase to drive visceral muscle fusion2003In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 425, no 6957, p. 512-516Article in journal (Refereed)
• 12.
Queen's University, Kingston, Ontario K7L 3N6.
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
Action plans used in action observation2003In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, ISSN 1476-4687, Vol. 424, no 6950, p. 769-771Article in journal (Refereed)

How do we understand the actions of others? According to the direct matching hypothesis, action understanding results from a mechanism that maps an observed action onto motor representations of that action. Although supported by neurophysiological and brain-imaging studies, direct evidence for this hypothesis is sparse. In visually guided actions, task-specific proactive eye movements are crucial for planning and control. Because the eyes are free to move when observing such actions, the direct matching hypothesis predicts that subjects should produce eye movements similar to those produced when they perform the tasks. If an observer analyses action through purely visual means, however, eye movements will be linked reactively to the observed action. Here we show that when subjects observe a block stacking task, the coordination between their gaze and the actor's hand is predictive, rather than reactive, and is highly similar to the gaze-hand coordination when they perform the task themselves. These results indicate that during action observation subjects implement eye motor programs directed by motor representations of manual actions and thus provide strong evidence for the direct matching hypothesis.

• 13.
Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Helmholtz Centre for Infection Research, Department of Regulation in Infection Biology, Braunschweig 38124, Germany; 3Max Planck Institute for Infection Biology, Department of Regulation in Infection Biology, Berlin 10117, Germany.
Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Helmholtz Centre for Infection Research, Department of Regulation in Infection Biology, Braunschweig 38124, Germany; 3Max Planck Institute for Infection Biology, Department of Regulation in Infection Biology, Berlin 10117, Germany. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Helmholtz Centre for Infection Research, Department of Regulation in Infection Biology, Braunschweig 38124, Germany; 3Max Planck Institute for Infection Biology, Department of Regulation in Infection Biology, Berlin 10117, Germany.
The CRISPR-associated DNA-cleaving enzyme Cpf1 also processes precursor CRISPR RNA2016In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 532, no 7600, p. 517-520Article in journal (Refereed)

CRISPR-Cas systems that provide defence against mobile genetic elements in bacteria and archaea have evolved a variety of mechanisms to target and cleave RNA or DNA(1). The well-studied types I, II and III utilize a set of distinct CRISPR-associated ( Cas) proteins for production of mature CRISPR RNAs (crRNAs) and interference with invading nucleic acids. In types I and III, Cas6 or Cas5d cleaves precursor crRNA (pre-crRNA)(2-5) and the mature crRNAs then guide a complex of Cas proteins ( Cascade-Cas3, type I; Csm or Cmr, type III) to target and cleave invading DNA or RNA(6-12). In type II systems, RNase III cleaves pre-crRNA base-paired with trans-activating crRNA (tracrRNA) in the presence of Cas9 (refs 13, 14). The mature tracrRNA-crRNA duplex then guides Cas9 to cleave target DNA15. Here, we demonstrate a novel mechanism in CRISPR-Cas immunity. We show that type V-A Cpf1 from Francisella novicida is a dual-nuclease that is specific to crRNA biogenesis and target DNA interference. Cpf1 cleaves pre-crRNA upstream of a hairpin structure formed within the CRISPR repeats and thereby generates intermediate crRNAs that are processed further, leading to mature crRNAs. After recognition of a 5'-YTN- 3' protospacer adjacent motif on the non-target DNA strand and subsequent probing for an eight-nucleotide seed sequence, Cpf1, guided by the single mature repeat-spacer crRNA, introduces double-stranded breaks in the target DNA to generate a 5' overhang(16). The RNase and DNase activities of Cpf1 require sequence- and structure-specific binding to the hairpin of crRNA repeats. Cpf1 uses distinct active domains for both nuclease reactions and cleaves nucleic acids in the presence of magnesium or calcium. This study uncovers a new family of enzymes with specific dual endoribonuclease and endonuclease activities, and demonstrates that type V- A constitutes the most minimalistic of the CRISPR- Cas systems so far described.

• 14.
Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
Real-world results2018In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 557, no 7703, p. 130-130Article in journal (Other academic)
• 15. Fuchsberger, Christian
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences, Lund University Diabetes Centre, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
The genetic architecture of type 2 diabetes2016In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 536, no 7614, p. 41-47Article in journal (Refereed)

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.

• 16.
Institut für Physik, Johannes Gutenberg-Universität, 55099 Mainz, Germany.
Institut für Physik, Johannes Gutenberg-Universität, 55099 Mainz, Germany. Institut für Physik, Johannes Gutenberg-Universität, 55099 Mainz, Germany. Institut für Physik, Johannes Gutenberg-Universität, 55099 Mainz, Germany. Umeå University, Faculty of Science and Technology, Physics. Institut für Physik, Johannes Gutenberg-Universität, 55099 Mainz, Germany, Institut für Angewandte Physik, Universität Bonn, 53115 Bonn, Germany. Institut für Physik, Johannes Gutenberg-Universität, 55099 Mainz, Germany, Institute of Quantum Electronics, ETH Zürich, 8093 Zürich, Switzerland. Institut für Physik, Johannes Gutenberg-Universität, 55099 Mainz, Germany.
Direct observation of second-order atom tunnelling2007In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 448, no 7157, p. 1029-1032Article in journal (Refereed)
• 17. Grill, G.
Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
Mapping the world's free-flowing rivers2019In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 569, no 7755, p. 215-221Article in journal (Refereed)

Free-flowing rivers (FFRs) support diverse, complex and dynamic ecosystems globally, providing important societal and economic services. Infrastructure development threatens the ecosystem processes, biodiversity and services that these rivers support. Here we assess the connectivity status of 12 million kilometres of rivers globally and identify those that remain free-flowing in their entire length. Only 37 per cent of rivers longer than 1,000 kilometres remain free-flowing over their entire length and 23 per cent flow uninterrupted to the ocean. Very long FFRs are largely restricted to remote regions of the Arctic and of the Amazon and Congo basins. In densely populated areas only few very long rivers remain free-flowing, such as the Irrawaddy and Salween. Dams and reservoirs and their up- and downstream propagation of fragmentation and flow regulation are the leading contributors to the loss of river connectivity. By applying a new method to quantify riverine connectivity and map FFRs, we provide a foundation for concerted global and national strategies to maintain or restore them.

• 18.
Limnology, Department of Ecology and Evolution, Uppsala University, Norbyvägen 18D, SE-752 36 Uppsala, Sweden.
Temperature-controlled organic carbon mineralization in lake sediments2010In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 466, no 7305, p. 478-481Article in journal (Refereed)

Peatlands, soils and the ocean floor are well-recognized as sites of organic carbon accumulation and represent important global carbon sinks. Although the annual burial of organic carbon in lakes and reservoirs exceeds that of ocean sediments, these inland waters are components of the global carbon cycle that receive only limited attention. Of the organic carbon that is being deposited onto the sediments, a certain proportion will be mineralized and the remainder will be buried over geological timescales. Here we assess the relationship between sediment organic carbon mineralization and temperature in a cross-system survey of boreal lakes in Sweden, and with input from a compilation of published data from a wide range of lakes that differ with respect to climate, productivity and organic carbon source. We find that the mineralization of organic carbon in lake sediments exhibits a strongly positive relationship with temperature, which suggests that warmer water temperatures lead to more mineralization and less organic carbon burial. Assuming that future organic carbon delivery to the lake sediments will be similar to that under present-day conditions, we estimate that temperature increases following the latest scenarios presented by the Intergovernmental Panel on Climate Change could result in a 4-27 per cent (0.9-6.4 Tg C yr(-1)) decrease in annual organic carbon burial in boreal lakes.

• 19. Handa, I. Tanya
Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
Consequences of biodiversity loss for litter decomposition across biomes2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 509, no 7499, p. 218-221Article in journal (Refereed)

The decomposition of dead organic matter is a major determinant of carbon and nutrient cycling in ecosystems, and of carbon fluxes between the biosphere and the atmosphere(1-3). Decomposition is driven by a vast diversity of organisms that are structured in complex food webs(2,4). Identifying the mechanisms underlying the effects of biodiversity on decomposition is critical(4-6) given the rapid loss of species worldwide and the effects of this loss on human well-being(7-9). Yet despite comprehensive syntheses of studies on how biodiversity affects litter decomposition(4-6,10), key questions remain, including when, where and how biodiversity has a role and whether general patterns and mechanisms occur across ecosystems and different functional types of organism(4,9-12). Here, in field experiments across five terrestrial and aquatic locations, ranging from the subarctic to the tropics, we show that reducing the functional diversity of decomposer organisms and plant litter types slowed the cycling of litter carbon and nitrogen. Moreover, we found evidence of nitrogen transfer from the litter of nitrogen-fixing plants to that of rapidly decomposing plants, but not between other plant functional types, highlighting that specific interactions in litter mixtures control carbon and nitrogen cycling during decomposition. The emergence of this general mechanism and the coherence of patterns across contrasting terrestrial and aquatic ecosystems suggest that biodiversity loss has consistent consequences for litter decomposition and the cycling of major elements on broad spatial scales.

• 20. Hibar, Derrek P.
Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
Common genetic variants influence human subcortical brain structures2015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 520, no 7546, p. 224-U216Article in journal (Refereed)

The highly complex structure of the human brain is strongly shaped by genetic influences(1). Subcortical brain regions form circuits with cortical areas to coordinate movement(2), learning, memory(3) and motivation(4), and altered circuits can lead to abnormal behaviour and disease(5). To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume(5) and intracranial volume(6). These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 X 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

• 21. Ho, Joshua W. K.
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Comparative analysis of metazoan chromatin organization2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 512, no 7515, p. 449-U507Article in journal (Refereed)

Genome function is dynamically regulated in part by chromatin, which consists of the histones, non-histone proteins and RNA molecules that package DNA. Studies in Caenorhabditis elegans and Drosophila melanogaster have contributed substantially to our understanding of molecular mechanisms of genome function in humans, and have revealed conservation of chromatin components and mechanisms(1-3). Nevertheless, the three organisms have markedly different genome sizes, chromosome architecture and gene organization. On human and fly chromosomes, for example, pericentric heterochromatin flanks single centromeres, whereas worm chromosomes have dispersed heterochromatin-like regions enriched in the distal chromosomal 'arms', and centromeres distributed along their lengths(4,5). To systematically investigate chromatin organization and associated gene regulation across species, we generated and analysed a large collection of genome-wide chromatin data sets from cell lines and developmental stages in worm, fly and human. Here we present over 800 new data sets from our ENCODE and modENCODE consortia, bringing the total to over 1,400. Comparison of combinatorial patterns of histone modifications, nuclear lamina-associated domains, organization of large-scale topological domains, chromatin environment at promoters and enhancers, nucleosome positioning, and DNA replication patterns reveals many conserved features of chromatin organization among the three organisms. We also find notable differences in the composition and locations of repressive chromatin. These data sets and analyses provide a rich resource for comparative and species-specific investigations of chromatin composition, organization and function.

• 22. Holmström, Mats
Institutet för rymdfysik (IRF).
Energetic neutral atoms as the explanation for the high-velocity hydrogen around HD 209458b2008In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 451, p. 970-972Article in journal (Refereed)

Absorption in the stellar Lyman- $\alpha$(Ly$\alpha$) line observed during the transit of the extrasolar planet HD 209458b in front of its host star reveals high-velocity atomic hydrogen at great distances from the planet1, 2. This has been interpreted as hydrogen atoms escaping from the planet's exosphere1, 3, possibly undergoing hydrodynamic blow-off4, and being accelerated by stellar radiation pressure. Energetic neutral atoms around Solar System planets have been observed to form from charge exchange between solar wind protons and neutral hydrogen from the planetary exospheres5, 6, 7, however, and this process also should occur around extrasolar planets. Here we show that the measured transit-associated Ly$\alpha$ absorption can be explained by the interaction between the exosphere of HD 209458b and the stellar wind, and that radiation pressure alone cannot explain the observations. As the stellar wind protons are the source of the observed energetic neutral atoms, this provides a way of probing stellar wind conditions, and our model suggests a slow and hot stellar wind near HD 209458b at the time of the observations. line observed during the transit of the extrasolar planet HD 209458b in front of its host star reveals high-velocity atomic hydrogen at great distances from the planet1, 2. This has been interpreted as hydrogen atoms escaping from the planet's exosphere1, 3, possibly undergoing hydrodynamic blow-off4, and being accelerated by stellar radiation pressure. Energetic neutral atoms around Solar System planets have been observed to form from charge exchange between solar wind protons and neutral hydrogen from the planetary exospheres5, 6, 7, however, and this process also should occur around extrasolar planets. Here we show that the measured transit-associated Ly$\alpha$ absorption can be explained by the interaction between the exosphere of HD 209458b and the stellar wind, and that radiation pressure alone cannot explain the observations. As the stellar wind protons are the source of the observed energetic neutral atoms, this provides a way of probing stellar wind conditions, and our model suggests a slow and hot stellar wind near HD 209458b at the time of the observations.

• 23. Hung, Rayjean J
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q252008In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 452, no 7187, p. 633-637Article in journal (Refereed)

Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 x 10(-10)). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 x 10(-20) overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N'-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.

• 24.
Umeå University, Faculty of Science and Technology, Ecology and Environmental Science.
Umeå University, Faculty of Science and Technology, Ecology and Environmental Science. Umeå University, Faculty of Science and Technology, Ecology and Environmental Science. Umeå University, Faculty of Science and Technology, Ecology and Environmental Science. Umeå University, Faculty of Science and Technology, Ecology and Environmental Science. Umeå University, Faculty of Science and Technology, Ecology and Environmental Science.
Light limitation of nutrient-poor lake ecosystems2009In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 460, p. 506-509Article in journal (Refereed)

Productivity denotes the rate of biomass synthesis in ecosystems and is a fundamental characteristic that frames ecosystem function and management. Limitation of productivity by nutrient availability is an established paradigm for lake ecosystems1, 2, 3. Here, we assess the relevance of this paradigm for a majority of the world's small, nutrient-poor lakes, with different concentrations of coloured organic matter4, 5. By comparing small unproductive lakes along a water colour gradient, we show that coloured terrestrial organic matter controls the key process for new biomass synthesis (the benthic primary production) through its effects on light attenuation. We also show that this translates into effects on production and biomass of higher trophic levels (benthic invertebrates and fish). These results are inconsistent with the idea that nutrient supply primarily controls lake productivity, and we propose that a large share of the world's unproductive lakes, within natural variations of organic carbon and nutrient input, are limited by light and not by nutrients. We anticipate that our result will have implications for understanding lake ecosystem function and responses to environmental change. Catchment export of coloured organic matter is sensitive to short-term natural variability and long-term, large-scale changes, driven by climate and different anthropogenic influences6, 7. Consequently, changes in terrestrial carbon cycling will have pronounced effects on most lake ecosystems by mediating changes in light climate and productivity of lakes.

• 25. Kern, Jan
Umeå University, Faculty of Science and Technology, Department of Chemistry. Department of Chemistry—Ångström, Molecular Biomimetics, Uppsala University, Uppsala, Sweden. Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Science and Technology, Department of Chemistry.
Structures of the intermediates of Kok’s photosynthetic water oxidation clock2018In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 563, p. 421-425Article in journal (Refereed)

Inspired by the period-four oscillation in flash-induced oxygen evolution of photosystem II discovered by Joliot in 1969, Kok performed additional experiments and proposed a five-state kinetic model for photosynthetic oxygen evolution, known as Kok’s S-state clock or cycle1,2. The model comprises four (meta)stable intermediates (S0, S1, S2 and S3) and one transient S4 state, which precedes dioxygen formation occurring in a concerted reaction from two water-derived oxygens bound at an oxo-bridged tetra manganese calcium (Mn4CaO5) cluster in the oxygen-evolving complex3–7. This reaction is coupled to the two-step reduction and protonation of the mobile plastoquinone QB at the acceptor side of PSII. Here, using serial femtosecond X-ray crystallography and simultaneous X-ray emission spectroscopy with multi-flash visible laser excitation at room temperature, we visualize all (meta)stable states of Kok’s cycle as high-resolution structures (2.04–2.08 Å). In addition, we report structures of two transient states at 150 and 400 µs, revealing notable structural changes including the binding of one additional ‘water’, Ox, during the S2→S3 state transition. Our results suggest that one water ligand to calcium (W3) is directly involved in substrate delivery. The binding of the additional oxygen Ox in the S3 state between Ca and Mn1 supports O–O bond formation mechanisms involving O5 as one substrate, where Ox is either the other substrate oxygen or is perfectly positioned to refill the O5 position during O2 release. Thus, our results exclude peroxo-bond formation in the S3 state, and the nucleophilic attack of W3 onto W2 is unlikely.

• 26.
Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Division of Genetics, Department of Medicine, Brigham & Women’s Hospital, Boston, Massachusetts 02115, USA. Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Molecular and Cell Biology, University of California at Berkeley, and Department of Genome Dynamics, Lawrence Berkeley National Lab, Berkeley, California 94720, USA. Department of Biology, Washington University in St Louis, St Louis, Missouri 63130, USA. MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, Massachusetts 02139, USA. Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA. Division of Genetics, Department of Medicine, Brigham & Women’s Hospital, Boston, Massachusetts 02115, USA. Division of Genetics, Department of Medicine, Brigham & Women’s Hospital, Boston, Massachusetts 02115, USA. Department of Biology, Washington University in St Louis, St Louis, Missouri 63130, USA. Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey 08854, USA. Division of Genetics, Department of Medicine, Brigham & Women’s Hospital, Boston, Massachusetts 02115, USA. Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey 08854, USA. Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA. Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA. Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA. Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA. Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA. Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA. Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA. Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA. Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA. Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA. MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, Massachusetts 02139, USA. Department of Biology, Washington University in St Louis, St Louis, Missouri 63130, USA. Division of Genetics, Department of Medicine, Brigham & Women’s Hospital, Boston, Massachusetts 02115, USA. Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey 08854, USA. Department of Molecular and Cell Biology, University of California at Berkeley, and Department of Genome Dynamics, Lawrence Berkeley National Lab, Berkeley, California 94720, USA. Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Comprehensive analysis of the chromatin landscape in Drosophila melanogaster2011In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Nature, ISSN 1476-4687 EISSN, Vol. 471, no 7339, p. 480-485Article in journal (Refereed)

Chromatin is composed of DNA and a variety of modified histones and non-histone proteins, which have an impact on cell differentiation, gene regulation and other key cellular processes. Here we present a genome-wide chromatin landscape for Drosophila melanogaster based on eighteen histone modifications, summarized by nine prevalent combinatorial patterns. Integrative analysis with other data (non-histone chromatin proteins, DNase I hypersensitivity, GRO-Seq reads produced by engaged polymerase, short/long RNA products) reveals discrete characteristics of chromosomes, genes, regulatory elements and other functional domains. We find that active genes display distinct chromatin signatures that are correlated with disparate gene lengths, exon patterns, regulatory functions and genomic contexts. We also demonstrate a diversity of signatures among Polycomb targets that include a subset with paused polymerase. This systematic profiling and integrative analysis of chromatin signatures provides insights into how genomic elements are regulated, and will serve as a resource for future experimental investigations of genome structure and function.

• 27.
National Institute for Physiological Sciences, Myodaiji, Okazaki .
Kyoto University. Fukushima Medical University School of Medicine, Fukushima. Kyoto University. Kyoto University. National Institute for Physiological Sciences, Myodaiji, Okazaki . National Institute for Basic Biology, Okazaki, he Graduate University for Advanced Studies (Sokendai), Hayama, Kanagawa. National Institute for Basic Biology, Okazaki, he Graduate University for Advanced Studies (Sokendai), Hayama, Kanagawa. National Institute for Physiological Sciences, Myodaiji, Okazaki . Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Kyoto University. Fukushima Medical University School of Medicine, Fukushima. National Institute for Physiological Sciences, Myodaiji, Okazaki , he Graduate University for Advanced Studies (Sokendai), Hayama, Kanagawa.
Genetic dissection of the circuit for hand dexterity in primates2012In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 487, no 7406, p. 235-U1510Article in journal (Refereed)

It is generally accepted that the direct connection from the motor cortex to spinal motor neurons is responsible for dexterous hand movements in primates(1-3). However, the role of the 'phylogenetically older' indirect pathways from the motor cortex to motor neurons, mediated by spinal interneurons, remains elusive. Here we used a novel double-infection technique to interrupt the transmission through the propriospinal neurons (PNs)(4-6), which act as a relay of the indirect pathway in macaque monkeys (Macaca fuscata and Macaca mulatta). The PNs were double infected by injection of a highly efficient retrograde gene-transfer vector into their target area and subsequent injection of adeno-associated viral vector at the location of cell somata. This method enabled reversible expression of green fluorescent protein (GFP)-tagged tetanus neurotoxin, thereby permitting the selective and temporal blockade of the motor cortex-PN-motor neuron pathway. This treatment impaired reach and grasp movements, revealing a critical role for the PN-mediated pathway in the control of hand dexterity. Anti-GFP immunohistochemistry visualized the cell bodies and axonal trajectories of the blocked PNs, which confirmed their anatomical connection to motor neurons. This pathway-selective and reversible technique for blocking neural transmission does not depend on cell-specific promoters or transgenic techniques, and is a new and powerful tool for functional dissection in system-level neuroscience studies.

• 28. Lamichhaney, Sangeet
Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
Evolution of Darwin's finches and their beaks revealed by genome sequencing2015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 518, no 7539Article in journal (Refereed)

Darwin's finches, inhabiting the Galapagos archipelago and Cocos Island, constitute an iconic model for studies of speciation and adaptive evolution. Here we report the results of whole-genome re-sequencing of 120 individuals representing all of the Darwin's finch species and two close relatives' Phylogenetic analysis reveals important discrepancies with the phenotype-based taxonomy. We find extensive evidence for interspecific gene flow throughout the radiation. Hybridization has given rise to species of mixed ancestry. A 240 kilobase haplotype encompassing the ALX1 gene that encodes a transcription factor affecting craniofacial. development is strongly associated with beak shape diversity across Darwin's finch species as well as within the medium ground finch (Geospiza fortis) a species that has undergone rapid evolution of beak shape in response to environmental changes. The ALX1 haplotype has contributed to diversification of beak shapes among the Darwin's finches and thereby, to an expanded utilization of food resources.

• 29. Li, X P
Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
A pigment-binding protein essential for regulation of photosynthetic light harvesting2000In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 403, no 6768, p. 391-395Article in journal (Refereed)

Photosynthetic light harvesting in plants is regulated in response to changes in incident light intensity. Absorption of light that exceeds a plant's capacity for fixation of CO2 results in thermal dissipation of excitation energy in the pigment antenna of photosystem II by a poorly understood mechanism. This regulatory process, termed nonphotochemical quenching, maintains the balance between dissipation and utilization of light energy to minimize generation of oxidizing molecules, thereby protecting the plant against photo-oxidative damage. To identify specific proteins that are involved in nonphotochemical quenching, we have isolated mutants of Arabidopsis thaliana that cannot dissipate excess absorbed light energy. Here we show that the gene encoding PsbS, an intrinsic chlorophyll-binding protein of photosystem II, is necessary for nonphotochemical quenching but not for efficient light harvesting and photosynthesis, These results indicate that PsbS may be the site for nonphotochemical quenching, a finding that has implications for the functional evolution of pigment-binding proteins.

• 30. Lien, Sigbjorn
Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
The Atlantic salmon genome provides insights into rediploidization2016In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 533, no 7602, p. 200-205Article in journal (Refereed)

The whole-genome duplication 80 million years ago of the common ancestor of salmonids (salmonid-specific fourth vertebrate whole-genome duplication, Ss4R) provides unique opportunities to learn about the evolutionary fate of a duplicated vertebrate genome in 70 extant lineages. Here we present a high-quality genome assembly for Atlantic salmon (Salmo salar), and show that large genomic reorganizations, coinciding with bursts of transposon-mediated repeat expansions, were crucial for the post-Ss4R rediploidization process. Comparisons of duplicate gene expression patterns across a wide range of tissues with orthologous genes from a pre-Ss4R outgroup unexpectedly demonstrate far more instances of neofunctionalization than subfunctionalization. Surprisingly, we find that genes that were retained as duplicates after the teleost-specific whole-genome duplication 320 million years ago were not more likely to be retained after the Ss4R, and that the duplicate retention was not influenced to a great extent by the nature of the predicted protein interactions of the gene products. Finally, we demonstrate that the Atlantic salmon assembly can serve as a reference sequence for the study of other salmonids for a range of purposes.

• 31. Lloyd-Price, Jason
Umeå University, Faculty of Medicine, Department of Odontology. Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases2019In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 569, no 7758, p. 655-661Article in journal (Refereed)

Inflammatory bowel diseases, which include Crohn's disease and ulcerative colitis, affect several million individuals worldwide. Crohn's disease and ulcerative colitis are complex diseases that are heterogeneous at the clinical, immunological, molecular, genetic, and microbial levels. Individual contributing factors have been the focus of extensive research. As part of the Integrative Human Microbiome Project (HMP2 or iHMP), we followed 132 subjects for one year each to generate integrated longitudinal molecular profiles of host and microbial activity during disease (up to 24 time points each; in total 2,965 stool, biopsy, and blood specimens). Here we present the results, which provide a comprehensive view of functional dysbiosis in the gut microbiome during inflammatory bowel disease activity. We demonstrate a characteristic increase in facultative anaerobes at the expense of obligate anaerobes, as well as molecular disruptions in microbial transcription (for example, among clostridia), metabolite pools (acylcarnitines, bile acids, and short-chain fatty acids), and levels of antibodies in host serum. Periods of disease activity were also marked by increases in temporal variability, with characteristic taxonomic, functional, and biochemical shifts. Finally, integrative analysis identified microbial, biochemical, and host factors central to this dysregulation. The study's infrastructure resources, results, and data, which are available through the Inflammatory Bowel Disease Multi'omics Database (http://ibdmdb.org), provide the most comprehensive description to date of host and microbial activities in inflammatory bowel diseases.

Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
Genetic studies of body mass index yield new insights for obesity biology2015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 518, no 7538, p. 197-U401Article in journal (Refereed)

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in upto 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 x 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for similar to 2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous systemin obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

• 33.
Umeå University, Faculty of Science and Technology, Physics.
Umeå University, Faculty of Science and Technology, Physics.
Magnetic Carbon2001In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 413, no 6857, p. 716-718Article in journal (Refereed)

Paper retracted.

• 34. Marouli, Eirini
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
Rare and low-frequency coding variants alter human adult height2017In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 542, no 7640, p. 186-190Article in journal (Refereed)

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

• 35. Mayor, Jordan R.
Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Center for Macroecology, Evolution and Climate, The Natural History Museum of Denmark, University of Copenhagen DK-2100, Copenhagen Ø, Denmark.
Elevation alters ecosystem properties across temperate treelines globally2017In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 542, no 7639, p. 91-95Article in journal (Refereed)

Temperature is a primary driver of the distribution of biodiversity as well as of ecosystem boundaries(1,2). Declining temperature with increasing elevation in montane systems has long been recognized as a major factor shaping plant community biodiversity, metabolic processes, and ecosystem dynamics(3,4). Elevational gradients, as thermoclines, also enable prediction of long-term ecological responses to climate warming(5-7). One of the most striking manifestations of increasing elevation is the abrupt transitions from forest to treeless alpine tundra(8). However, whether there are globally consistent above-and belowground responses to these transitions remains an open question(4). To disentangle the direct and indirect effects of temperature on ecosystem properties, here we evaluate replicate treeline ecotones in seven temperate regions of the world. We find that declining temperatures with increasing elevation did not affect tree leaf nutrient concentrations, but did reduce ground-layer community-weighted plant nitrogen, leading to the strong stoichiometric convergence of ground-layer plant community nitrogen to phosphorus ratios across all regions. Further, elevation-driven changes in plant nutrients were associated with changes in soil organic matter content and quality (carbon to nitrogen ratios) and microbial properties. Combined, our identification of direct and indirect temperature controls over plant communities and soil properties in seven contrasting regions suggests that future warming may disrupt the functional properties of montane ecosystems, particularly where plant community reorganization outpaces treeline advance.

• 36. McElreath, Richard
Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
Evolution of animal personalities2007In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 450, p. E5-Article in journal (Refereed)
• 37. NCD Risk Factor Collaboration (NCD-RisC),
Forsner, Maria (Contributor)
Umeå University, Faculty of Medicine, Department of Nursing.
Söderberg, Stefan (Contributor)
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
Rising rural body-mass index is the main driver of the global obesity epidemic in adults2019In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 569, no 7755, p. 260-264Article in journal (Refereed)

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities1,2. This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity3,4,5,6. Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017—and more than 80% in some low- and middle-income regions—was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing—and in some countries reversal—of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.

• 38.
Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
Flood warnings: [review of "The future of large dams" by T. Scudder]2005In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 435, no 7045, p. 1031-1031Article, book review (Other academic)
• 39. Novak, R
Emergence of vancomycin tolerance in Streptococcus pneumoniae.1999In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 399, no 6736, p. 590-593Article in journal (Refereed)

Streptococcus pneumoniae, the pneumococcus, is the most common cause of sepsis and meningitis. Multiple-antibiotic-resistant strains are widespread, and vancomycin is the antibiotic of last resort. Emergence of vancomycin resistance in this community-acquired bacterium would be catastrophic. Antibiotic tolerance, the ability of bacteria to survive but not grow in the presence of antibiotics, is a precursor phenotype to resistance. Here we show that loss of function of the VncS histidine kinase of a two-component sensor-regulator system in S. pneumoniae produced tolerance to vancomycin and other classes of antibiotic. Bacterial two-component systems monitor environmental parameters through a sensor histidine-kinase/phosphatase, which phosphorylates/dephosphorylates a response regulator that in turn mediates changes in gene expression. These results indicate that signal transduction is critical for the bactericidal activity of antibiotics. Experimental meningitis caused by the vncS mutant failed to respond to vancomycin. Clinical isolates tolerant to vancomycin were identified and DNA sequencing revealed nucleotide alterations in vncS. We conclude that broad antibiotic tolerance of S. pneumoniae has emerged in the community by a molecular mechanism that eliminates sensitivity to the current cornerstone of therapy, vancomycin.

• 40. Nystedt, Björn
Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
The Norway spruce genome sequence and conifer genome evolution2013In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 497, no 7451, p. 579-584Article in journal (Refereed)

Conifers have dominated forests for more than 200 million years and are of huge ecological and economic importance. Here we present the draft assembly of the 20-gigabase genome of Norway spruce (Picea abies), the first available for any gymnosperm. The number of well-supported genes (28,354) is similar to the >100 times smaller genome of Arabidopsis thaliana, and there is no evidence of a recent whole-genome duplication in the gymnosperm lineage. Instead, the large genome size seems to result from the slow and steady accumulation of a diverse set of long-terminal repeat transposable elements, possibly owing to the lack of an efficient elimination mechanism. Comparative sequencing of Pinus sylvestris, Abies sibirica, Juniperus communis, Taxus baccata and Gnetum gnemon reveals that the transposable element diversity is shared among extant conifers. Expression of 24-nucleotide small RNAs, previously implicated in transposable element silencing, is tissue-specific and much lower than in other plants. We further identify numerous long (>10,000 base pairs) introns, gene-like fragments, uncharacterized long non-coding RNAs and short RNAs. This opens up new genomic avenues for conifer forestry and breeding.

Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
Genetics of rheumatoid arthritis contributes to biology and drug discovery2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 506, no 7488, p. 376-381Article in journal (Refereed)

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)(1). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating similar to 10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2-4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation(5), cis-acting expression quantitative trait loci(6) and pathway analyses(7-9)-as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes-to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

• 42.
Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
Fibronectin binding mediated by a novel class of surface organelles on Escherichia coli1989In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 338, no 6217, p. 652-5Article in journal (Refereed)

Gram-negative bacteria are known to produce two types of surface organelles: flagella, which are required for motility and chemotaxis, and pili (fimbriae), which play a part in the interaction of bacteria with other bacteria and with eukaryotic host cells. Here we report a third class of E. coli surface organelles for which we propose the name curli. Curli are coiled surface structures composed of a single type of subunit, the curlin, which differs from all known pilin proteins and is synthesized in the absence of a cleavable signal peptide. Although the gene encoding this structural subunit, crl, is present and transcribed in most natural isolates of E. coli, only certain strains are able to assemble the subunit protein into curli. This assembly process occurs preferentially at growth temperatures below 37 degrees C. The ability of curli to mediate binding to fibronectin may be a virulence-associated property for wound colonization and for the colonization of fibronectin-coated surfaces.

• 43. Pennekamp, Frank
Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Department of Evolutionary Biology and Environmental Studies, University of Zurich, Zurich, Switzerland.
Biodiversity increases and decreases ecosystem stability2018In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 563, no 7729, p. 109-+Article in journal (Refereed)

Losses and gains in species diversity affect ecological stability(1-7) and the sustainability of ecosystem functions and services(8-13). Experiments and models have revealed positive, negative and no effects of diversity on individual components of stability, such as temporal variability, resistance and resilience(2,3,6,11,12,14). How these stability components covary remains poorly understood(15). Similarly, the effects of diversity on overall ecosystem stability(16), which is conceptually akin to ecosystem multifunctionality(17,18), remain unknown. Here we studied communities of aquatic ciliates to understand how temporal variability, resistance and overall ecosystem stability responded to diversity (that is, species richness) in a large experiment involving 690 micro-ecosystems sampled 19 times over 40 days, resulting in 12,939 samplings. Species richness increased temporal stability but decreased resistance to warming. Thus, two stability components covaried negatively along the diversity gradient. Previous biodiversity manipulation studies rarely reported such negative covariation despite general predictions of the negative effects of diversity on individual stability components(3). Integrating our findings with the ecosystem multifunctionality concept revealed hump- and U-shaped effects of diversity on overall ecosystem stability. That is, biodiversity can increase overall ecosystem stability when biodiversity is low, and decrease it when biodiversity is high, or the opposite with a U-shaped relationship. The effects of diversity on ecosystem multifunctionality would also be hump- or U-shaped if diversity had positive effects on some functions and negative effects on others. Linking the ecosystem multifunctionality concept and ecosystem stability can transform the perceived effects of diversity on ecological stability and may help to translate this science into policy-relevant information.

• 44. Pose, David
Max Planck Institute for Developmental Biology, Department of Molecular Biology, Spemannstrasse 35, 72076 Tübingen, Germany.
Temperature-dependent regulation of flowering by antagonistic FLM variants2013In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 503, no 7476, p. 414-+Article in journal (Refereed)
• 45.
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Queen’s University, Kingston, Ontario.
New York College of Osteopathic Medicine, Queen’s University, Kingston, Ontario, New York College of Osteopathic Medicine, Old Westbury, New York. Queen’s University, Kingston, Ontario. Queen’s University, Kingston, Ontario. Queen’s University, Kingston, Ontario. Queen’s University, Kingston, Ontario.
Primary motor cortex underlies multi-joint integration for fast feedback control2011In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 478, no 7369, p. 387-390Article in journal (Refereed)

A basic difficulty for the nervous system is integrating locally ambiguous sensory information to form accurate perceptions about the outside world(1-4). This local-to-global problem is also fundamental to motor control of the arm, because complex mechanical interactions between shoulder and elbow allow a particular amount of motion at one joint to arise from an infinite combination of shoulder and elbow torques(5). Here we show, in humans and rhesus monkeys, that a transcortical pathway through primary motor cortex (M1) resolves this ambiguity during fast feedback control. We demonstrate that single M1 neurons of behaving monkeys can integrate shoulder and elbow motion information into motor commands that appropriately counter the underlying torque within about 50 milliseconds of a mechanical perturbation. Moreover, we reveal a causal link between M1 processing and multi-joint integration in humans by showing that shoulder muscle responses occurring 50 milliseconds after pure elbow displacement can be potentiated by transcranial magnetic stimulation. Taken together, our results show that transcortical processing through M1 permits feedback responses to express a level of sophistication that rivals voluntary control; this provides neurophysiological support for influential theories positing that voluntary movement is generated by the intelligent manipulation of sensory feedback(6,7).

• 46. Ripke, Stephan
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
Biological insights from 108 schizophrenia-associated genetic loci2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 511, no 7510, p. 421-427Article in journal (Refereed)

Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.

• 47.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
Misconceptions of global catastrophe2016In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 532, no 7599, p. 317-318Article in journal (Other academic)
• 48. Ruban, A. V.
Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
Plants lacking the main light harvesting complex retain photosystem II macro-organization2003In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 421, p. 648-652Article in journal (Refereed)
• 49. Russell, Alistair B.
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
Diverse type VI secretion phospholipases are functionally plastic antibacterial effectors2013In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 496, no 7446, p. 508-512Article in journal (Refereed)

Membranes allow the compartmentalization of biochemical processes and are therefore fundamental to life. The conservation of the cellular membrane, combined with its accessibility to secreted proteins, has made it a common target of factors mediating antagonistic interactions between diverse organisms. Here we report the discovery of a diverse superfamily of bacterial phospholipase enzymes. Within this superfamily, we defined enzymes with phospholipase A(1) and A(2) activity, which are common in host-cell-targeting bacterial toxins and the venoms of certain insects and reptiles(1,2). However, we find that the fundamental role of the superfamily is to mediate antagonistic bacterial interactions as effectors of the type VI secretion system (T6SS) translocation apparatus; accordingly, we name these proteins type VI lipase effectors. Our analyses indicate that PldA of Pseudomonas aeruginosa, a eukaryotic-like phospholipase D-3, is a member of the type VI lipase effector superfamily and the founding substrate of the haemolysin co-regulated protein secretion island II T6SS (H2-T6SS). Although previous studies have specifically implicated PldA and the H2-T6SS in pathogenesis(3-5), we uncovered a specific role for the effector and its secretory machinery in intra-and interspecies bacterial interactions. Furthermore, we find that this effector achieves its antibacterial activity by degrading phosphatidylethanolamine, the major component of bacterial membranes. The surprising finding that virulence-associated phospholipases can serve as specific antibacterial effectors suggests that interbacterial interactions are a relevant factor driving the continuing evolution of pathogenesis.

• 50. Sauter, Nicholas K.
Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Science and Technology, Department of Chemistry.
No observable conformational changes in PSII2016In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 533, no 7603, p. E1-E2Article in journal (Refereed)
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