Showing papers by "University of Cologne published in 2014"
Medical University of Vienna1, University of Amsterdam2, Leiden University Medical Center3, Leeds Teaching Hospitals NHS Trust4, Chapel Allerton Hospital5, Humboldt State University6, Oregon Health & Science University7, Utrecht University8, VU University Medical Center9, University of Montpellier10, University of Belgrade11, Erasmus University Rotterdam12, University of Paris-Sud13, Charles University in Prague14, Radboud University Nijmegen Medical Centre15, University of Cologne16, Weston Education Centre17, Tufts University18
TL;DR: These recommendations intend informing rheumatologists, patients, national rheumology societies, hospital officials, social security agencies and regulators about EULAR's most recent consensus on the management of RA, aimed at attaining best outcomes with current therapies.
Abstract: In this article, the 2010 European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA) with synthetic and biological disease-modifying antirheumatic drugs (sDMARDs and bDMARDs, respectively) have been updated. The 2013 update has been developed by an international task force, which based its decisions mostly on evidence from three systematic literature reviews (one each on sDMARDs, including glucocorticoids, bDMARDs and safety aspects of DMARD therapy); treatment strategies were also covered by the searches. The evidence presented was discussed and summarised by the experts in the course of a consensus finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) were determined. Fourteen recommendations were developed (instead of 15 in 2010). Some of the 2010 recommendations were deleted, and others were amended or split. The recommendations cover general aspects, such as attainment of remission or low disease activity using a treat-to-target approach, and the need for shared decision-making between rheumatologists and patients. The more specific items relate to starting DMARD therapy using a conventional sDMARD (csDMARD) strategy in combination with glucocorticoids, followed by the addition of a bDMARD or another csDMARD strategy (after stratification by presence or absence of adverse risk factors) if the treatment target is not reached within 6 months (or improvement not seen at
4,730 citations
Eric A. Collisson1, Joshua D. Campbell2, Angela N. Brooks2, Angela N. Brooks3 +315 more•Institutions (41)
TL;DR: In this paper, the authors report molecular profiling of 230 resected lung adnocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses.
Abstract: Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.
4,104 citations
TL;DR: In this review, emerging concepts in tissue regeneration and repair are highlighted, and some perspectives on how to translate current knowledge into viable clinical approaches for treating patients with wound-healing pathologies are provided.
Abstract: The cellular and molecular mechanisms underpinning tissue repair and its failure to heal are still poorly understood, and current therapies are limited. Poor wound healing after trauma, surgery, acute illness, or chronic disease conditions affects millions of people worldwide each year and is the consequence of poorly regulated elements of the healthy tissue repair response, including inflammation, angiogenesis, matrix deposition, and cell recruitment. Failure of one or several of these cellular processes is generally linked to an underlying clinical condition, such as vascular disease, diabetes, or aging, which are all frequently associated with healing pathologies. The search for clinical strategies that might improve the body’s natural repair mechanisms will need to be based on a thorough understanding of the basic biology of repair and regeneration. In this review, we highlight emerging concepts in tissue regeneration and repair, and provide some perspectives on how to translate current knowledge into viable clinical approaches for treating patients with wound-healing pathologies.
1,947 citations
University of Évry Val d'Essonne1, Crops Research Institute2, Agriculture and Agri-Food Canada3, Fujian Agriculture and Forestry University4, J. Craig Venter Institute5, Plant Genome Mapping Laboratory6, University of Giessen7, French Alternative Energies and Atomic Energy Commission8, Institut national de la recherche agronomique9, National Research Council10, Australian Centre for Plant Functional Genomics11, University of Cologne12, Purdue University13, University of California, Berkeley14, University of British Columbia15, Fondation Jean Dausset Centre d'Etude du Polymorphisme Humain16, Huazhong Agricultural University17, Hunan Agricultural University18, Chungnam National University19, University of Arizona20, University of York21, University of Missouri22, Southern Cross University23, University of Western Australia24, Centre national de la recherche scientifique25
TL;DR: The polyploid genome of Brassica napus, which originated from a recent combination of two distinct genomes approximately 7500 years ago and gave rise to the crops of rape oilseed, is sequenced.
Abstract: Oilseed rape (Brassica napus L.) was formed ~7500 years ago by hybridization between B. rapa and B. oleracea, followed by chromosome doubling, a process known as allopolyploidy. Together with more ancient polyploidizations, this conferred an aggregate 72× genome multiplication since the origin of angiosperms and high gene content. We examined the B. napus genome and the consequences of its recent duplication. The constituent An and Cn subgenomes are engaged in subtle structural, functional, and epigenetic cross-talk, with abundant homeologous exchanges. Incipient gene loss and expression divergence have begun. Selection in B. napus oilseed types has accelerated the loss of glucosinolate genes, while preserving expansion of oil biosynthesis genes. These processes provide insights into allopolyploid evolution and its relationship with crop domestication and improvement.
1,743 citations
TL;DR: Two channelrhodopsins, Chronos and Chrimson, are described, discovered through sequencing and physiological characterization of opsins from over 100 species of alga, that enable two-color activation of neural spiking and downstream synaptic transmission in independent neural populations without detectable cross-talk in mouse brain slice.
Abstract: Optogenetic tools enable examination of how specific cell types contribute to brain circuit functions. A long-standing question is whether it is possible to independently activate two distinct neural populations in mammalian brain tissue. Such a capability would enable the study of how different synapses or pathways interact to encode information in the brain. Here we describe two channelrhodopsins, Chronos and Chrimson, discovered through sequencing and physiological characterization of opsins from over 100 species of alga. Chrimson's excitation spectrum is red shifted by 45 nm relative to previous channelrhodopsins and can enable experiments in which red light is preferred. We show minimal visual system-mediated behavioral interference when using Chrimson in neurobehavioral studies in Drosophila melanogaster. Chronos has faster kinetics than previous channelrhodopsins yet is effectively more light sensitive. Together these two reagents enable two-color activation of neural spiking and downstream synaptic transmission in independent neural populations without detectable cross-talk in mouse brain slice.
1,701 citations
Cornell University1, Stanford University2, Georgetown University3, University of Washington4, St James's University Hospital5, Hofstra University6, Memorial Sloan Kettering Cancer Center7, University of California, San Diego8, Sarah Cannon Research Institute9, Vita-Salute San Raffaele University10, University of California, Los Angeles11, Columbia University12, Claude Bernard University Lyon 113, Royal Liverpool and Broadgreen University Hospital NHS Trust14, Northwestern University15, University of Ulm16, University of Cologne17, University of Texas MD Anderson Cancer Center18
TL;DR: The combination of idelalisib and rituximab, as compared with placebo and r ituximabs, significantly improved progression-free survival, response rate, and overall survival among patients with relapsed CLL who were less able to undergo chemotherapy.
Abstract: BACKGROUND Patients with relapsed chronic lymphocytic leukemia (CLL) who have clinically significant coexisting medical conditions are less able to undergo standard chemotherapy. Effective therapies with acceptable side-effect profiles are needed for this patient population. METHODS In this multicenter, randomized, double-blind, placebo-controlled, phase 3 study, we assessed the efficacy and safety of idelalisib, an oral inhibitor of the delta isoform of phosphatidylinositol 3-kinase, in combination with rituximab versus rituximab plus placebo. We randomly assigned 220 patients with decreased renal function, previous therapy-induced myelosuppression, or major coexisting illnesses to receive rituximab and either idelalisib (at a dose of 150 mg) or placebo twice daily. The primary end point was progression-free survival. At the first prespecified interim analysis, the study was stopped early on the recommendation of the data and safety monitoring board owing to overwhelming efficacy. RESULTS The median progression-free survival was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group, 0.15; P<0.001). Patients receiving idelalisib versus those receiving placebo had improved rates of overall response (81% vs. 13%; odds ratio, 29.92; P<0.001) and overall survival at 12 months (92% vs. 80%; hazard ratio for death, 0.28; P=0.02). Serious adverse events occurred in 40% of the patients receiving idelalisib and rituximab and in 35% of those receiving placebo and rituximab. CONCLUSIONS The combination of idelalisib and rituximab, as compared with placebo and rituximab, significantly improved progression-free survival, response rate, and overall survival among patients with relapsed CLL who were less able to undergo chemotherapy. (Funded by Gilead; ClinicalTrials.gov number, NCT01539512.).
1,538 citations
Harvard University1, Seoul National University2, Fox Chase Cancer Center3, Agency for Science, Technology and Research4, Autonomous University of Barcelona5, University of Washington6, University of Colorado Denver7, Katholieke Universiteit Leuven8, University of Utah9, Memorial Sloan Kettering Cancer Center10, Peter MacCallum Cancer Centre11, University of Cologne12, Heidelberg University13, University of Duisburg-Essen14, German Cancer Research Center15, Princess Margaret Cancer Centre16, Novartis17
TL;DR: Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK.
Abstract: BackgroundNon–small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies. MethodsIn this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib. ResultsA total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of ceritinib was 750 mg once daily; dose-l...
1,297 citations
01 Feb 2014
TL;DR: Chronos and Chrimson as mentioned in this paper have been shown to enable two-color activation of neural spiking and downstream synaptic transmission in independent neural populations without detectable cross-talk in mouse brain slice.
Abstract: Optogenetic tools enable examination of how specific cell types contribute to brain circuit functions. A long-standing question is whether it is possible to independently activate two distinct neural populations in mammalian brain tissue. Such a capability would enable the study of how different synapses or pathways interact to encode information in the brain. Here we describe two channelrhodopsins, Chronos and Chrimson, discovered through sequencing and physiological characterization of opsins from over 100 species of alga. Chrimson's excitation spectrum is red shifted by 45 nm relative to previous channelrhodopsins and can enable experiments in which red light is preferred. We show minimal visual system-mediated behavioral interference when using Chrimson in neurobehavioral studies in Drosophila melanogaster. Chronos has faster kinetics than previous channelrhodopsins yet is effectively more light sensitive. Together these two reagents enable two-color activation of neural spiking and downstream synaptic transmission in independent neural populations without detectable cross-talk in mouse brain slice.
1,152 citations
TL;DR: In patients with intermediate-risk pulmonary embolism, fibrinolytic therapy prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke.
Abstract: BACKGROUND: The role of fibrinolytic therapy in patients with intermediate-risk pulmonary embolism is controversial. METHODS: In a randomized, double-blind trial, we compared tenecteplase plus heparin with placebo plus heparin in normotensive patients with intermediate-risk pulmonary embolism. Eligible patients had right ventricular dysfunction on echocardiography or computed tomography, as well as myocardial injury as indicated by a positive test for cardiac troponin I or troponin T. The primary outcome was death or hemodynamic decompensation (or collapse) within 7 days after randomization. The main safety outcomes were major extracranial bleeding and ischemic or hemorrhagic stroke within 7 days after randomization. RESULTS: Of 1006 patients who underwent randomization, 1005 were included in the intention-to-treat analysis. Death or hemodynamic decompensation occurred in 13 of 506 patients (2.6%) in the tenecteplase group as compared with 28 of 499 (5.6%) in the placebo group (odds ratio, 0.44; 95% confidence interval, 0.23 to 0.87; P=0.02). Between randomization and day 7, a total of 6 patients (1.2%) in the tenecteplase group and 9 (1.8%) in the placebo group died (P=0.42). Extracranial bleeding occurred in 32 patients (6.3%) in the tenecteplase group and 6 patients (1.2%) in the placebo group (P<0.001). Stroke occurred in 12 patients (2.4%) in the tenecteplase group and was hemorrhagic in 10 patients; 1 patient (0.2%) in the placebo group had a stroke, which was hemorrhagic (P=0.003). By day 30, a total of 12 patients (2.4%) in the tenecteplase group and 16 patients (3.2%) in the placebo group had died (P=0.42). CONCLUSIONS: In patients with intermediate-risk pulmonary embolism, fibrinolytic therapy prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke. (Funded by the Programme Hospitalier de Recherche Clinique in France and others; PEITHO EudraCT number, 2006-005328-18; ClinicalTrials.gov number, NCT00639743.).
1,140 citations
Northwestern University1, University of Texas at Austin2, University of Alberta3, University of Arizona4, University of Georgia5, University of Florida6, Eastern Kentucky University7, American Museum of Natural History8, Pennsylvania State University9, Harvard University10, University of Cologne11, University of British Columbia12, Duke University13, Spanish National Research Council14, New York Botanical Garden15, Ludwig Maximilian University of Munich16, Université de Montréal17, Centre national de la recherche scientifique18, Chinese Academy of Sciences19, University of Michigan20, Donald Danforth Plant Science Center21
TL;DR: Strong and robust support is found for a sister-group relationship between land plants and one group of streptophyte green algae, the Zygnematophyceae, and suggests that phylogenetic hypotheses used to understand the evolution of fundamental plant traits should be reevaluated.
Abstract: Reconstructing the origin and evolution of land plants and their algal relatives is a fundamental problem in plant phylogenetics, and is essential for understanding how critical adaptations arose, including the embryo, vascular tissue, seeds, and flowers. Despite advances in molecular systematics, some hypotheses of relationships remain weakly resolved. Inferring deep phylogenies with bouts of rapid diversification can be problematic; however, genome-scale data should significantly increase the number of informative characters for analyses. Recent phylogenomic reconstructions focused on the major divergences of plants have resulted in promising but inconsistent results. One limitation is sparse taxon sampling, likely resulting from the difficulty and cost of data generation. To address this limitation, transcriptome data for 92 streptophyte taxa were generated and analyzed along with 11 published plant genome sequences. Phylogenetic reconstructions were conducted using up to 852 nuclear genes and 1,701,170 aligned sites. Sixty-nine analyses were performed to test the robustness of phylogenetic inferences to permutations of the data matrix or to phylogenetic method, including supermatrix, supertree, and coalescent-based approaches, maximum-likelihood and Bayesian methods, partitioned and unpartitioned analyses, and amino acid versus DNA alignments. Among other results, we find robust support for a sister-group relationship between land plants and one group of streptophyte green algae, the Zygnematophyceae. Strong and robust support for a clade comprising liverworts and mosses is inconsistent with a widely accepted view of early land plant evolution, and suggests that phylogenetic hypotheses used to understand the evolution of fundamental plant traits should be reevaluated.
1,026 citations
TL;DR: The complete SEQC data sets, comprising >100 billion reads, provide unique resources for evaluating RNA-seq analyses for clinical and regulatory settings, and measurement performance depends on the platform and data analysis pipeline, and variation is large for transcript-level profiling.
Abstract: We present primary results from the Sequencing Quality Control (SEQC) project, coordinated by the US Food and Drug Administration. Examining Illumina HiSeq, Life Technologies SOLiD and Roche 454 platforms at multiple laboratory sites using reference RNA samples with built-in controls, we assess RNA sequencing (RNA-seq) performance for junction discovery and differential expression profiling and compare it to microarray and quantitative PCR (qPCR) data using complementary metrics. At all sequencing depths, we discover unannotated exon-exon junctions, with >80% validated by qPCR. We find that measurements of relative expression are accurate and reproducible across sites and platforms if specific filters are used. In contrast, RNA-seq and microarrays do not provide accurate absolute measurements, and gene-specific biases are observed for all examined platforms, including qPCR. Measurement performance depends on the platform and data analysis pipeline, and variation is large for transcript-level profiling. The complete SEQC data sets, comprising >100 billion reads (10Tb), provide unique resources for evaluating RNA-seq analyses for clinical and regulatory settings.
University of Cologne1, Hacettepe University2, Boston Children's Hospital3, Katholieke Universiteit Leuven4, Post Graduate Institute of Medical Education and Research5, Necker-Enfants Malades Hospital6, Pasteur Institute7, Catholic University of the Sacred Heart8, National and Kapodistrian University of Athens9, Statens Serum Institut10, Second Military Medical University11, University Medical Center Utrecht12, University of Delhi13, Carlos III Health Institute14, Central European Institute of Technology15, Hospital General Universitario Gregorio Marañón16, University of Liverpool17, Innsbruck Medical University18, Radboud University Nijmegen Medical Centre19, Manchester Academic Health Science Centre20, University of Milan21, University of Würzburg22
TL;DR: These European Society for Clinical Microbiology and Infectious Diseases and European Confederation of Medical Mycology Joint Clinical Guidelines focus on the diagnosis and management of mucormycosis and strongly recommend continuing treatment until complete response demonstrated on imaging and permanent reversal of predisposing factors.
TL;DR: It is demonstrated that renal tubules do not undergo sensitization to necroptosis upon genetic ablation of either FADD or caspase-8 and that the RIPK1 inhibitor necrostatin-1 (Nec-1) does not protect freshly isolated tubules from hypoxic injury, and ferroptosis mediates postischemic and toxic renal necrosis.
Abstract: Receptor-interacting protein kinase 3 (RIPK3)-mediated necroptosis is thought to be the pathophysiologically predominant pathway that leads to regulated necrosis of parenchymal cells in ischemia-reperfusion injury (IRI), and loss of either Fas-associated protein with death domain (FADD) or caspase-8 is known to sensitize tissues to undergo spontaneous necroptosis. Here, we demonstrate that renal tubules do not undergo sensitization to necroptosis upon genetic ablation of either FADD or caspase-8 and that the RIPK1 inhibitor necrostatin-1 (Nec-1) does not protect freshly isolated tubules from hypoxic injury. In contrast, iron-dependent ferroptosis directly causes synchronized necrosis of renal tubules, as demonstrated by intravital microscopy in models of IRI and oxalate crystal-induced acute kidney injury. To suppress ferroptosis in vivo, we generated a novel third-generation ferrostatin (termed 16-86), which we demonstrate to be more stable, to metabolism and plasma, and more potent, compared with the first-in-class compound ferrostatin-1 (Fer-1). Even in conditions with extraordinarily severe IRI, 16-86 exerts strong protection to an extent which has not previously allowed survival in any murine setting. In addition, 16-86 further potentiates the strong protective effect on IRI mediated by combination therapy with necrostatins and compounds that inhibit mitochondrial permeability transition. Renal tubules thus represent a tissue that is not sensitized to necroptosis by loss of FADD or caspase-8. Finally, ferroptosis mediates postischemic and toxic renal necrosis, which may be therapeutically targeted by ferrostatins and by combination therapy.
TL;DR: In this article, the authors argue that the production of mantle-derived or juvenile continental crust during the accretionary history of the Central Asian Orogenic Belt (CAOB) has been grossly overestimated.
TL;DR: Five miRNA binding site SNPs associated significantly with breast cancer risk are located in the 3′ UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively, which belongs to miRNA machinery genes and has a central role in initial miRNA processing.
Abstract: Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88-0.96), rs1052532 (OR 0.97; 95% CI: 0.95-0.99), rs10719 (OR 0.97; 95% CI: 0.94-0.99), rs4687554 (OR 0.97; 95% CI: 0.95-0.99, and rs3134615 (OR 1.03; 95% CI: 1.01-1.05) located in the 3' UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects.
TL;DR: It is proposed that phosphorylation of Parkin at Ser65 serves to prime the E3 ligase enzyme for activation by ubiquitinPhospho−Ser65, suggesting that small molecules that mimic ubiquitins could hold promise as novel therapies for Parkinson's disease.
Abstract: We have previously reported that the Parkinson's disease-associated kinase PINK1 (PTEN-induced putative kinase 1) is activated by mitochondrial depolarization and stimulates the Parkin E3 ligase by phosphorylating Ser65 within its Ubl (ubiquitin-like) domain. Using phosphoproteomic analysis, we identified a novel ubiquitin phosphopeptide phosphorylated at Ser65 that was enriched 14-fold in HEK (human embryonic kidney)-293 cells overexpressing wild-type PINK1 stimulated with the mitochondrial uncoupling agent CCCP (carbonyl cyanide m-chlorophenylhydrazone), to activate PINK1, compared with cells expressing kinase-inactive PINK1. Ser65 in ubiquitin lies in a similar motif to Ser65 in the Ubl domain of Parkin. Remarkably, PINK1 directly phosphorylates Ser65 of ubiquitin in vitro. We undertook a series of experiments that provide striking evidence that Ser65-phosphorylated ubiquitin (ubiquitinPhospho−Ser65) functions as a critical activator of Parkin. First, we demonstrate that a fragment of Parkin lacking the Ubl domain encompassing Ser65 (ΔUbl-Parkin) is robustly activated by ubiquitinPhospho−Ser65, but not by non-phosphorylated ubiquitin. Secondly, we find that the isolated Parkin Ubl domain phosphorylated at Ser65 (UblPhospho−Ser65) can also activate ΔUbl-Parkin similarly to ubiquitinPhospho−Ser65. Thirdly, we establish that ubiquitinPhospho−Ser65, but not non-phosphorylated ubiquitin or UblPhospho−Ser65, activates full-length wild-type Parkin as well as the non-phosphorylatable S65A Parkin mutant. Fourthly, we provide evidence that optimal activation of full-length Parkin E3 ligase is dependent on PINK1-mediated phosphorylation of both Parkin at Ser65 and ubiquitin at Ser65, since only mutation of both proteins at Ser65 completely abolishes Parkin activation. In conclusion, the findings of the present study reveal that PINK1 controls Parkin E3 ligase activity not only by phosphorylating Parkin at Ser65, but also by phosphorylating ubiquitin at Ser65. We propose that phosphorylation of Parkin at Ser65 serves to prime the E3 ligase enzyme for activation by ubiquitinPhospho−Ser65, suggesting that small molecules that mimic ubiquitinPhospho−Ser65 could hold promise as novel therapies for Parkinson's disease.
TL;DR: In this article, a coexpression vector, Optopatch, enabled cross-talk-free genetically targeted all-optical electrophysiology without the use of conventional electrodes.
Abstract: All-optical electrophysiology-spatially resolved simultaneous optical perturbation and measurement of membrane voltage-would open new vistas in neuroscience research. We evolved two archaerhodopsin-based voltage indicators, QuasAr1 and QuasAr2, which show improved brightness and voltage sensitivity, have microsecond response times and produce no photocurrent. We engineered a channelrhodopsin actuator, CheRiff, which shows high light sensitivity and rapid kinetics and is spectrally orthogonal to the QuasArs. A coexpression vector, Optopatch, enabled cross-talk-free genetically targeted all-optical electrophysiology. In cultured rat neurons, we combined Optopatch with patterned optical excitation to probe back-propagating action potentials (APs) in dendritic spines, synaptic transmission, subcellular microsecond-timescale details of AP propagation, and simultaneous firing of many neurons in a network. Optopatch measurements revealed homeostatic tuning of intrinsic excitability in human stem cell-derived neurons. In rat brain slices, Optopatch induced and reported APs and subthreshold events with high signal-to-noise ratios. The Optopatch platform enables high-throughput, spatially resolved electrophysiology without the use of conventional electrodes.
TL;DR: Recent findings that highlight the complex regulatory networks that control skin immunity are discussed, and new paradigms for the mechanisms that regulate skin immune responses in host defence and in chronic inflammation are provided.
Abstract: Immune responses in the skin are important for host defence against pathogenic microorganisms However, dysregulated immune reactions can cause chronic inflammatory skin diseases Extensive crosstalk between the different cellular and microbial components of the skin regulates local immune responses to ensure efficient host defence, to maintain and restore homeostasis, and to prevent chronic disease In this Review, we discuss recent findings that highlight the complex regulatory networks that control skin immunity, and we provide new paradigms for the mechanisms that regulate skin immune responses in host defence and in chronic inflammation
TL;DR: This work reviews recent empirical and theoretical developments of the genotype–fitness map, identifies methodological issues and organizing principles, and discusses possibilities to develop more realistic fitness landscape models.
Abstract: A central topic in biology concerns how genotypes determine phenotypes and functions of organisms that affect their evolutionary fitness. This Review discusses recent advances in the development of empirical fitness landscapes and their contribution to theoretical analyses of the predictability of evolution. The genotype–fitness map (that is, the fitness landscape) is a key determinant of evolution, yet it has mostly been used as a superficial metaphor because we know little about its structure. This is now changing, as real fitness landscapes are being analysed by constructing genotypes with all possible combinations of small sets of mutations observed in phylogenies or in evolution experiments. In turn, these first glimpses of empirical fitness landscapes inspire theoretical analyses of the predictability of evolution. Here, we review these recent empirical and theoretical developments, identify methodological issues and organizing principles, and discuss possibilities to develop more realistic fitness landscape models.
TL;DR: OPA1 processing by YEM1L and OMA1 is dispensable for mitochondrial fusion and instead drives mitochondrial fragmentation, which is crucial for mitochondrial integrity and quality control.
Abstract: Mitochondrial fusion and structure depend on the dynamin-like GTPase OPA1, whose activity is regulated by proteolytic processing. Constitutive OPA1 cleavage by YME1L and OMA1 at two distinct sites leads to the accumulation of both long and short forms of OPA1 and maintains mitochondrial fusion. Stress-induced OPA1 processing by OMA1 converts OPA1 completely into short isoforms, inhibits fusion, and triggers mitochondrial fragmentation. Here, we have analyzed the function of different OPA1 forms in cells lacking YME1L, OMA1, or both. Unexpectedly, deletion of Oma1 restored mitochondrial tubulation, cristae morphogenesis, and apoptotic resistance in cells lacking YME1L. Long OPA1 forms were sufficient to mediate mitochondrial fusion in these cells. Expression of short OPA1 forms promoted mitochondrial fragmentation, which indicates that they are associated with fission. Consistently, GTPase-inactive, short OPA1 forms partially colocalize with ER–mitochondria contact sites and the mitochondrial fission machinery. Thus, OPA1 processing is dispensable for fusion but coordinates the dynamic behavior of mitochondria and is crucial for mitochondrial integrity and quality control.
TL;DR: The results identify signaling via IL-6 as an important determinant of the alternative activation of macrophages and assign an unexpected homeostatic role to IL- 6 in limiting inflammation.
Abstract: Obesity and resistance to insulin are closely associated with the development of low-grade inflammation. Interleukin 6 (IL-6) is linked to obesity-associated inflammation; however, its role in this context remains controversial. Here we found that mice with an inactivated gene encoding the IL-6Rα chain of the receptor for IL-6 in myeloid cells (Il6ra(Δmyel) mice) developed exaggerated deterioration of glucose homeostasis during diet-induced obesity, due to enhanced resistance to insulin. Tissues targeted by insulin showed increased inflammation and a shift in macrophage polarization. IL-6 induced expression of the receptor for IL-4 and augmented the response to IL-4 in macrophages in a cell-autonomous manner. Il6ra(Δmyel) mice were resistant to IL-4-mediated alternative polarization of macrophages and exhibited enhanced susceptibility to lipopolysaccharide (LPS)-induced endotoxemia. Our results identify signaling via IL-6 as an important determinant of the alternative activation of macrophages and assign an unexpected homeostatic role to IL-6 in limiting inflammation.
TL;DR: In this paper, a new scaling model based on analytical approximations to modeled fluxes of the main atmospheric cosmic-ray particles responsible for in situ cosmogenic nuclide production is proposed.
TL;DR: It is concluded that life expectancy in morphologically defined ET is significantly reduced but remains superior to that of PV, regardless of mutational status, and in PMF, JAK2/CALR/MPLmutational status is prognostically informative.
TL;DR: Modulation of either proteasome activity or autophagic-lysosomal potential extends lifespan and protects organisms from symptoms associated with proteostasis disorders, suggesting that protein clearance mechanisms are directly linked to ageing and age-associated diseases.
Abstract: The ability to maintain a functional proteome, or proteostasis, declines during the ageing process. Damaged and misfolded proteins accumulate with age, impairing cell function and tissue homeostasis. The accumulation of damaged proteins contributes to multiple age-related diseases such as Alzheimer's, Parkinson's or Huntington's disease. Damaged proteins are degraded by the ubiquitin-proteasome system or through autophagy-lysosome, key components of the proteostasis network. Modulation of either proteasome activity or autophagic-lysosomal potential extends lifespan and protects organisms from symptoms associated with proteostasis disorders, suggesting that protein clearance mechanisms are directly linked to ageing and age-associated diseases.
TL;DR: It is reported that repetitive UV exposure of primary cutaneous melanomas in a genetically engineered mouse model promotes metastatic progression, independent of its tumour-initiating effects, and that ulcerated primary human melanomas with abundant neutrophils and reactive angiogenesis frequently show angiotropism and a high risk for metastases.
Abstract: Intermittent intense ultraviolet (UV) exposure represents an important aetiological factor in the development of malignant melanoma. The ability of UV radiation to cause tumour-initiating DNA mutations in melanocytes is now firmly established, but how the microenvironmental effects of UV radiation influence melanoma pathogenesis is not fully understood. Here we report that repetitive UV exposure of primary cutaneous melanomas in a genetically engineered mouse model promotes metastatic progression, independent of its tumour-initiating effects. UV irradiation enhanced the expansion of tumour cells along abluminal blood vessel surfaces and increased the number of lung metastases. This effect depended on the recruitment and activation of neutrophils, initiated by the release of high mobility group box 1 (HMGB1) from UV-damaged epidermal keratinocytes and driven by Toll-like receptor 4 (TLR4). The UV-induced neutrophilic inflammatory response stimulated angiogenesis and promoted the ability of melanoma cells to migrate towards endothelial cells and use selective motility cues on their surfaces. Our results not only reveal how UV irradiation of epidermal keratinocytes is sensed by the innate immune system, but also show that the resulting inflammatory response catalyses reciprocal melanoma-endothelial cell interactions leading to perivascular invasion, a phenomenon originally described as angiotropism in human melanomas by histopathologists. Angiotropism represents a hitherto underappreciated mechanism of metastasis that also increases the likelihood of intravasation and haematogenous dissemination. Consistent with our findings, ulcerated primary human melanomas with abundant neutrophils and reactive angiogenesis frequently show angiotropism and a high risk for metastases. Our work indicates that targeting the inflammation-induced phenotypic plasticity of melanoma cells and their association with endothelial cells represent rational strategies to specifically interfere with metastatic progression.
University of Arizona1, University of Washington2, Beijing Institute of Genomics3, University of Alberta4, Northwestern University5, University of Texas at Austin6, University of Georgia7, University of Florida8, Pennsylvania State University9, Université de Montréal10, Centre national de la recherche scientifique11, Eastern Kentucky University12, University of British Columbia13, Harvard University14, University of Cologne15, Duke University16, Spanish National Research Council17, New York Botanical Garden18, Ludwig Maximilian University of Munich19, Chinese Academy of Sciences20, Donald Danforth Plant Science Center21, University of Michigan22
TL;DR: How to access the data used in a phylogenomics analysis of the first 85 species, and how to visualize the gene and species trees of the 1KP project.
Abstract: The 1,000 plants (1KP) project is an international multi-disciplinary consortium that has generated transcriptome data from over 1,000 plant species, with exemplars for all of the major lineages across the Viridiplantae (green plants) clade. Here, we describe how to access the data used in a phylogenomics analysis of the first 85 species, and how to visualize our gene and species trees. Users can develop computational pipelines to analyse these data, in conjunction with data of their own that they can upload. Computationally estimated protein-protein interactions and biochemical pathways can be visualized at another site. Finally, we comment on our future plans and how they fit within this scalable system for the dissemination, visualization, and analysis of large multi-species data sets.
TL;DR: This study estimated fresh and dry biomass on a summer barley test site with 18 cultivars and two nitrogen (N)-treatments using the plant height (PH) from crop surface models (CSMs), which has potential for future application by non-professionals.
Abstract: Crop monitoring is important in precision agriculture. Estimating above-ground biomass helps to monitor crop vitality and to predict yield. In this study, we estimated fresh and dry biomass on a summer barley test site with 18 cultivars and two nitrogen (N)-treatments using the plant height (PH) from crop surface models (CSMs). The super-high resolution, multi-temporal (1 cm/pixel) CSMs were derived from red, green, blue (RGB) images captured from a small unmanned aerial vehicle (UAV). Comparison with PH reference measurements yielded an R2 of 0.92. The test site with different cultivars and treatments was monitored during “Biologische Bundesanstalt, Bundessortenamt und CHemische Industrie” (BBCH) Stages 24–89. A high correlation was found between PH from CSMs and fresh biomass (R2 = 0.81) and dry biomass (R2 = 0.82). Five models for above-ground fresh and dry biomass estimation were tested by cross-validation. Modelling biomass between different N-treatments for fresh biomass produced the best results (R2 = 0.71). The main limitation was the influence of lodging cultivars in the later growth stages, producing irregular plant heights. The method has potential for future application by non-professionals, i.e., farmers.
Centre national de la recherche scientifique1, Chalmers University of Technology2, Spanish National Research Council3, INAF4, Max Planck Society5, Rutgers University6, University of Toulouse7, University of Cologne8, King Abdulaziz University9, ETH Zurich10, University of La Laguna11, Kapteyn Astronomical Institute12, Leiden University13
TL;DR: In this paper, the authors used the Atacama Large Millimeter Array (ALMA) to map the emission of a set of dense molecular gas (n(H2)'1056 cm3) tracers (CO(3-2), CO(6-5), HCN(4-3), HCO+CS(7-6)) and their underlying continuum emission in the central r ∼ 2 kpc of NGC 1068 with spatial resolutions ∼0:3000:500 (∼20-35 pc for the assumed distance of D = 14 Mpc
Abstract: Aims. We investigate the fueling and the feedback of star formation and nuclear activity in NGC 1068, a nearby (D = 14 Mpc) Seyfert 2 barred galaxy, by analyzing the distribution and kinematics of the molecular gas in the disk. We aim to understand if and how gas accretion can self-regulate.Methods. We have used the Atacama Large Millimeter Array (ALMA) to map the emission of a set of dense molecular gas (n(H2) ' 1056 cm3) tracers (CO(3-2), CO(6-5), HCN(4-3), HCO+(4-3), and CS(7-6)) and their underlying continuum emission in the central r ∼ 2 kpc of NGC 1068 with spatial resolutions ∼0:3000:500 (∼20-35 pc for the assumed distance of D = 14 Mpc). Results. The sensitivity and spatial resolution of ALMA give an unprecedented detailed view of the distribution and kinematics of the dense molecular gas (n(H2) ≈ 1056cm3) in NGC 1068. Molecular line and dust continuum emissions are detected from a r ∼ 200 pc off-centered circumnuclear disk (CND), from the 2.6 kpc-diameter bar region, and from the r ∼ 1:3 kpc starburst (SB) ring. Most of the emission in HCO+, HCN, and CS stems from the CND. Molecular line ratios show dramatic order-of-magnitude changes inside the CND that are correlated with the UV/X-ray illumination by the active galactic nucleus (AGN), betraying ongoing feedback. We used the dust continuum fluxes measured by ALMA together with NIR/MIR data to constrain the properties of the putative torus using CLUMPY models and found a torus radius of 20+6 10 pc. The Fourier decomposition of the gas velocity field indicates that rotation is perturbed by an inward radial flow in the SB ring and the bar region. However, the gas kinematics from r ∼ 50 pc out to r ∼ 400 pc reveal a massive (Mmol ∼ 2:7+0:9 1:2 × 107 M) outflow in all molecular tracers. The tight correlation between the ionized gas outflow, the radio jet, and the occurrence of outward motions in the disk suggests that the outflow is AGN driven. Conclusions. The molecular outflow is likely launched when the ionization cone of the narrow line region sweeps the nuclear disk. The outflow rate estimated in the CND, dM=dt ∼ 63+21 37 M yr1, is an order of magnitude higher than the star formation rate at these radii, confirming that the outflow is AGN driven. The power of the AGN is able to account for the estimated momentum and kinetic luminosity of the outflow. The CND mass load rate of the CND outflow implies a very short gas depletion timescale of ≤1 Myr. The CND gas reservoir is likely replenished on longer timescales by efficient gas inflow from the outer disk. © ESO 2014.
TL;DR: Europa's Plumes Jupiter's moon Europa has a subsurface ocean and a relatively young icy surface, and spectral images taken by the Hubble Space Telescope show ultraviolet emissions from the moon's atmosphere that are consistent with two 200-km-high plumes of water vapor.
Abstract: In November and December 2012 the Hubble Space Telescope (HST) imaged Europa’s ultraviolet emissions in the search for vapor plume activity. We report statistically significant coincident surpluses of hydrogen Lyman-α and oxygen OI130.4 nm emissions above the southern hemisphere in December 2012. These emissions are persistently found in the same area over ~7 hours, suggesting atmospheric inhomogeneity; they are consistent with two 200-km-high plumes of water vapor with line-of-sight column densities of about 1020 m−2. Nondetection in November and in previous HST images from 1999 suggests varying plume activity that might depend on changing surface stresses based on Europa’s orbital phases. The plume was present when Europa was near apocenter and not detected close to its pericenter, in agreement with tidal modeling predictions.
TL;DR: It is shown that kinase-independent scaffolding RIPK1 functions regulate homeostasis and prevent inflammation in barrier tissues by inhibiting epithelial cell apoptosis and necroptosis, and is identified as a more potent trigger of inflammation compared with apoptosis.
Abstract: Necroptosis has emerged as an important pathway of programmed cell death in embryonic development, tissue homeostasis, immunity and inflammation. RIPK1 is implicated in inflammatory and cell death signalling and its kinase activity is believed to drive RIPK3-mediated necroptosis. Here we show that kinase-independent scaffolding RIPK1 functions regulate homeostasis and prevent inflammation in barrier tissues by inhibiting epithelial cell apoptosis and necroptosis. Intestinal epithelial cell (IEC)-specific RIPK1 knockout caused IEC apoptosis, villus atrophy, loss of goblet and Paneth cells and premature death in mice. This pathology developed independently of the microbiota and of MyD88 signalling but was partly rescued by TNFR1 (also known as TNFRSF1A) deficiency. Epithelial FADD ablation inhibited IEC apoptosis and prevented the premature death of mice with IEC-specific RIPK1 knockout. However, mice lacking both RIPK1 and FADD in IECs displayed RIPK3-dependent IEC necroptosis, Paneth cell loss and focal erosive inflammatory lesions in the colon. Moreover, a RIPK1 kinase inactive knock-in delayed but did not prevent inflammation caused by FADD deficiency in IECs or keratinocytes, showing that RIPK3-dependent necroptosis of FADD-deficient epithelial cells only partly requires RIPK1 kinase activity. Epidermis-specific RIPK1 knockout triggered keratinocyte apoptosis and necroptosis and caused severe skin inflammation that was prevented by RIPK3 but not FADD deficiency. These findings revealed that RIPK1 inhibits RIPK3-mediated necroptosis in keratinocytes in vivo and identified necroptosis as a more potent trigger of inflammation compared with apoptosis. Therefore, RIPK1 is a master regulator of epithelial cell survival, homeostasis and inflammation in the intestine and the skin.