TY  - JOUR
A1  - Lu, Yuan
A1  - Boswell, Wiliam
A1  - Boswell, Mikki
A1  - Klotz, Barbara
A1  - Kneitz, Susanne
A1  - Regneri, Janine
A1  - Savage, Markita
A1  - Mendoza, Cristina
A1  - Postlethwait, John
A1  - Warren, Wesley C.
A1  - Schartl, Manfred
A1  - Walter, Ronald B.
T1  - Application of the Transcriptional Disease Signature (TDSs) to Screen Melanoma-Effective Compounds in a Small Fish Model
JF  - Scientific Reports
N2  - Cell culture and protein target-based compound screening strategies, though broadly utilized in selecting candidate compounds, often fail to eliminate candidate compounds with non-target effects and/or safety concerns until late in the drug developmental process. Phenotype screening using intact research animals is attractive because it can help identify small molecule candidate compounds that have a high probability of proceeding to clinical use. Most FDA approved, first-in-class small molecules were identified from phenotypic screening. However, phenotypic screening using rodent models is labor intensive, low-throughput, and very expensive. As a novel alternative for small molecule screening, we have been developing gene expression disease profiles, termed the Transcriptional Disease Signature (TDS), as readout of small molecule screens for therapeutic molecules. In this concept, compounds that can reverse, or otherwise affect known disease-associated gene expression patterns in whole animals may be rapidly identified for more detailed downstream direct testing of their efficacy and mode of action. To establish proof of concept for this screening strategy, we employed a transgenic strain of a small aquarium fish, medaka (Oryzias latipes), that overexpresses the malignant melanoma driver gene xmrk, a mutant egfr gene, that is driven by a pigment cell-specific mitf promoter. In this model, melanoma develops with 100% penetrance. Using the transgenic medaka malignant melanoma model, we established a screening system that employs the NanoString nCounter platform to quantify gene expression within custom sets of TDS gene targets that we had previously shown to exhibit differential transcription among xmrk-transgenic and wild-type medaka. Compound-modulated gene expression was identified using an internet-accessible custom-built data processing pipeline. The effect of a given drug on the entire TDS profile was estimated by comparing compound-modulated genes in the TDS using an activation Z-score and Kolmogorov-Smirnov statistics. TDS gene probes were designed that target common signaling pathways that include proliferation, development, toxicity, immune function, metabolism and detoxification. These pathways may be utilized to evaluate candidate compounds for potential favorable, or unfavorable, effects on melanoma-associated gene expression. Here we present the logistics of using medaka to screen compounds, as well as, the development of a user-friendly NanoString data analysis pipeline to support feasibility of this novel TDS drug-screening strategy.
KW  - bioinformatics
KW  - phenotypic screening
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237322
VL  - 9
ER  - 
TY  - JOUR
A1  - Mercier, Rebecca
A1  - Wolmarans, Annemarie
A1  - Schubert, Jonathan
A1  - Neuweiler, Hannes
A1  - Johnson, Jill L.
A1  - LaPointe, Paul
T1  - The conserved NxNNWHW motif in Aha-type co-chaperones modulates the kinetics of Hsp90 ATPase stimulation
JF  - Nature Communications
N2  - Hsp90 is a dimeric molecular chaperone that is essential for the folding and activation of hundreds of client proteins. Co-chaperone proteins regulate the ATP-driven Hsp90 client activation cycle. Aha-type co-chaperones are the most potent stimulators of the Hsp90 ATPase activity but the relationship between ATPase regulation and in vivo activity is poorly understood. We report here that the most strongly conserved region of Aha-type co-chaperones, the N terminal NxNNWHW motif, modulates the apparent affinity of Hsp90 for nucleotide substrates. The ability of yeast Aha-type co-chaperones to act in vivo is ablated when the N terminal NxNNWHW motif is removed. This work suggests that nucleotide exchange during the Hsp90 functional cycle may be more important than rate of catalysis.
KW  - biophysics
KW  - cell growth
KW  - chaperones
KW  - enzymes
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224007
VL  - 10
ER  - 
TY  - JOUR
A1  - Lübcke, Paul M.
A1  - Ebbers, Meinolf N. B.
A1  - Volzke, Johann
A1  - Bull, Jana
A1  - Kneitz, Susanne
A1  - Engelmann, Robby
A1  - Lang, Hermann
A1  - Kreikemeyer, Bernd
A1  - Müller-Hilke, Brigitte
T1  - Periodontal treatment prevents arthritis in mice and methotrexate ameliorates periodontal bone loss
JF  - Scientific Reports
N2  - Recent studies indicate a causal relationship between the periodontal pathogen P. gingivalis and rheumatoid arthritis involving the production of autoantibodies against citrullinated peptides. We therefore postulated that therapeutic eradication P. gingivalis may ameliorate rheumatoid arthritis development and here turned to a mouse model in order to challenge our hypothesis. F1 (DBA/1 x B10.Q) mice were orally inoculated with P. gingivalis before collagen-induced arthritis was provoked. Chlorhexidine or metronidazole were orally administered either before or during the induction phase of arthritis and their effects on arthritis progression and alveolar bone loss were compared to intraperitoneally injected methotrexate. Arthritis incidence and severity were macroscopically scored and alveolar bone loss was evaluated via microcomputed tomography. Serum antibody titres against P. gingivalis were quantified by ELISA and microbial dysbiosis following oral inoculation was monitored in stool samples via microbiome analyses. Both, oral chlorhexidine and metronidazole reduced the incidence and ameliorated the severity of collagen-induced arthritis comparable to methotrexate. Likewise, all three therapies attenuated alveolar bone loss. Relative abundance of Porphyromonadaceae was increased after oral inoculation with P. gingivalis and decreased after treatment. This is the first study to describe beneficial effects of non-surgical periodontal treatment on collagen-induced arthritis in mice and suggests that mouthwash with chlorhexidine or metronidazole may also be beneficial for patients with rheumatoid arthritis and a coexisting periodontitis. Methotrexate ameliorated periodontitis in mice, further raising the possibility that methotrexate may also positively impact on the tooth supporting tissues of patients with rheumatoid arthritis.
KW  - rheumatic diseases
KW  - rheumatology
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237355
VL  - 9
ER  - 
TY  - JOUR
A1  - Seitz, Nicola
A1  - vanEngelsdorp, Dennis
A1  - Leonhardt, Sara D.
T1  - Conserving bees in destroyed landscapes: The potentials of reclaimed sand mines
JF  - Global Ecology and Conservation
N2  - Sand mines represent anthropogenically impacted habitats found worldwide, which bear potential for bee conservation. Although floral resources can be limited at these habitats, vegetation free patches of open sandy soils and embankments may offer good nesting possibilities for sand restricted and other bees. We compared bee communities as found in three reclaimed sand mines and at adjacent roadside meadows in Maryland, USA, over two years. Both sand mines and roadsides hosted diverse bee communities with 111 and 88 bee species, respectively. Bee abundances as well as richness and Shannon diversity of bee species were higher in sand mines than at roadsides and negatively correlated with the percentage of vegetational ground cover. Species composition also differed significantly between habitats. Sand mines hosted a higher proportion of ground nesters, more uncommon and more ‘sand loving’ bees similar to natural sandy areas of Maryland. Despite the destruction of the original pre-mining habitat, sand mines thus appear to represent a unique habitat for wild bees, particularly when natural vegetation and open sand spots are encouraged. Considering habitat loss, the lack of natural disturbance regimes, and ongoing declines of wild bees, sand mines could add promising opportunities for bee conservation which has hitherto mainly focused on agricultural and urban habitats.
KW  - bee conservation
KW  - bee decline
KW  - habitat restoration
KW  - land use
KW  - wild bees
KW  - ground nesters
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235877
VL  - 19
ER  - 
TY  - JOUR
A1  - Hofrichter, Michaela A. H.
A1  - Doll, Julia
A1  - Habibi, Haleh
A1  - Enayati, Samaneh
A1  - Mehrjardi, Mohammad Yahya Vahidi
A1  - Müller, Tobias
A1  - Dittrich, Marcus
A1  - Haaf, Thomas
A1  - Vona, Barbara
T1  - Exome-wide copy number variation analysis identifies a COL9A1 in frame deletion that is associated with hearing loss
JF  - European Journal of Medical Genetics
N2  - Pathogenic variants in COL9A1 are primarily associated with autosomal recessive Stickler syndrome. Patients with COL9A1-associated Stickler syndrome (STL) present hearing loss (HL), ophthalmic manifestations and skeletal abnormalities. However, the clinical spectrum of patients with COL9A1 variants can also include multiple epiphyseal dysplasia, as well as non-syndromic HL that was observed in one previously reported proband. Exome sequencing was performed on the genomic DNA of an Iranian patient and his affected brother who both report non-syndromic HL. A 44.6 kb homozygous in-frame deletion spanning exons 6 to 33 of COL9A1 was detected via exome-based copy number variation analysis. The deleted exons were confirmed by PCR in the patient and his affected brother, who both have non-syndromic HL. Segregation analysis via qPCR confirmed the parents as heterozygous deletion carriers. Breakpoint analysis mapped the homozygous deletion spanning introns 5 to 33 (g.70,948,188_70,997,277del, NM_001851.4(COL9A1):c.697–3754_2112+769del, p.(Phe233_Ser704del), with an additional 67 bp of inserted intronic sequence that may have originated due to a fork stalling and template switching/microhomology-mediated break-induced replication (FoSTeS/MMBIR) mechanism. This mechanism has not been previously implicated in HL or STL. This is also the first reported copy number variation in COL9A1 that was identified through an exome data set in an Iranian family with apparent non-syndromic HL. The present study emphasizes the importance of exome-wide copy number variation analysis in molecular diagnosis and provides supporting evidence to associate COL9A1 with autosomal recessive non-syndromic HL.
KW  - COL9A1
KW  - copy number variation
KW  - FoSTeS/MMBIR mechanism
KW  - non-syndromic hearing loss
KW  - Stickler syndrome
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-322008
VL  - 62
ER  - 
TY  - JOUR
A1  - Baluapuri, Apoorva
A1  - Hofstetter, Julia
A1  - Dudvarski Stankovic, Nevenka
A1  - Endres, Theresa
A1  - Bhandare, Pranjali
A1  - Vos, Seychelle Monique
A1  - Adhikari, Bikash
A1  - Schwarz, Jessica Denise
A1  - Narain, Ashwin
A1  - Vogt, Markus
A1  - Wang, Shuang-Yan
A1  - Düster, Robert
A1  - Jung, Lisa Anna
A1  - Vanselow, Jens Thorsten
A1  - Wiegering, Armin
A1  - Geyer, Matthias
A1  - Maric, Hans Michael
A1  - Gallant, Peter
A1  - Walz, Susanne
A1  - Schlosser, Andreas
A1  - Cramer, Patrick
A1  - Eilers, Martin
A1  - Wolf, Elmar
T1  - MYC Recruits SPT5 to RNA Polymerase II to Promote Processive Transcription Elongation
JF  - Molecular Cell
N2  - The MYC oncoprotein binds to promoter-proximal regions of virtually all transcribed genes and enhances RNA polymerase II (Pol II) function, but its precise mode of action is poorly understood. Using mass spectrometry of both MYC and Pol II complexes, we show here that MYC controls the assembly of Pol II with a small set of transcription elongation factors that includes SPT5, a subunit of the elongation factor DSIF. MYC directly binds SPT5, recruits SPT5 to promoters, and enables the CDK7-dependent transfer of SPT5 onto Pol II. Consistent with known functions of SPT5, MYC is required for fast and processive transcription elongation. Intriguingly, the high levels of MYC that are expressed in tumors sequester SPT5 into non-functional complexes, thereby decreasing the expression of growth-suppressive genes. Altogether, these results argue that MYC controls the productive assembly of processive Pol II elongation complexes and provide insight into how oncogenic levels of MYC permit uncontrolled cellular growth.
KW  - MYC
KW  - SPT5
KW  - SUPT5H
KW  - SPT6
KW  - RNA polymerase II
KW  - transcription
KW  - elongation rate
KW  - processivity
KW  - directionality
KW  - tumorigenesis
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221438
VL  - 74
ER  - 
TY  - JOUR
A1  - Mooij, Wolf M
A1  - van Wijk, Dianneke
A1  - Beusen, Arthur HW
A1  - Brederveld, Robert J
A1  - Chang, Manqi
A1  - Cobben, Marleen MP
A1  - DeAngelis, Don L
A1  - Downing, Andrea S
A1  - Green, Pamela
A1  - Gsell, Alena S
A1  - Huttunen, Inese
A1  - Janse, Jan H
A1  - Janssen, Annette BG
A1  - Hengeveld, Geerten M
A1  - Kong, Xiangzhen
A1  - Kramer, Lilith
A1  - Kuiper, Jan J
A1  - Langan, Simon J
A1  - Nolet, Bart A
A1  - Nuijten, Rascha JM
A1  - Strokal, Maryna
A1  - Troost, Tineke A
A1  - van Dam, Anne A
A1  - Teurlincx, Sven
T1  - Modeling water quality in the Anthropocene: directions for the next-generation aquatic ecosystem models
JF  - Current Opinion in Environmental Sustainability
N2  - “Everything changes and nothing stands still” (Heraclitus). Here we review three major improvements to freshwater aquatic ecosystem models — and ecological models in general — as water quality scenario analysis tools towards a sustainable future. To tackle the rapid and deeply connected dynamics characteristic of the Anthropocene, we argue for the inclusion of eco-evolutionary, novel ecosystem and social-ecological dynamics. These dynamics arise from adaptive responses in organisms and ecosystems to global environmental change and act at different integration levels and different time scales. We provide reasons and means to incorporate each improvement into aquatic ecosystem models. Throughout this study we refer to Lake Victoria as a microcosm of the evolving novel social-ecological systems of the Anthropocene. The Lake Victoria case clearly shows how interlinked eco-evolutionary, novel ecosystem and social-ecological dynamics are, and demonstrates the need for transdisciplinary research approaches towards global sustainability.
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224173
VL  - 36
ER  - 
TY  - JOUR
A1  - Hartke, Juliane
A1  - Sprenger, Philipp P.
A1  - Sahm, Jacqueline
A1  - Winterberg, Helena
A1  - Orivel, Jérôme
A1  - Baur, Hannes
A1  - Beuerle, Till
A1  - Schmitt, Thomas
A1  - Feldmeyer, Barbara
A1  - Menzel, Florian
T1  - Cuticular hydrocarbons as potential mediators of cryptic species divergence in a mutualistic ant association
JF  - Ecology and Evolution
N2  - Upon advances in sequencing techniques, more and more morphologically identical organisms are identified as cryptic species. Often, mutualistic interactions are proposed as drivers of diversification. Species of the neotropical parabiotic ant association between Crematogaster levior and Camponotus femoratus are known for highly diverse cuticular hydrocarbon (CHC) profiles, which in insects serve as desiccation barrier but also as communication cues. In the present study, we investigated the association of the ants’ CHC profiles with genotypes and morphological traits, and discovered cryptic species pairs in both genera. To assess putative niche differentiation between the cryptic species, we conducted an environmental association study that included various climate variables, canopy cover, and mutualistic plant species. Although mostly sympatric, the two Camponotus species seem to prefer different climate niches. However in the two Crematogaster species, we could not detect any differences in niche preference. The strong differentiation in the CHC profiles may thus suggest a possible role during speciation itself either by inducing assortative mating or by reinforcing sexual selection after the speciation event. We did not detect any further niche differences in the environmental parameters tested. Thus, it remains open how the cryptic species avoid competitive exclusion, with scope for further investigations.
KW  - environmental association
KW  - integrative taxonomy
KW  - niche differentiation
KW  - population structure
KW  - sexual selection
KW  - speciation
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227857
VL  - 9
ER  - 
TY  - JOUR
A1  - König, Kerstin
A1  - Zundel, Petra
A1  - Krimmer, Elena
A1  - König, Christian
A1  - Pollmann, Marie
A1  - Gottlieb, Yuval
A1  - Steidle, Johannes L. M.
T1  - Reproductive isolation due to prezygotic isolation and postzygotic cytoplasmic incompatibility in parasitoid wasps
JF  - Ecology and Evolution
N2  - The reproductive barriers that prevent gene flow between closely related species are a major topic in evolutionary research. Insect clades with parasitoid lifestyle are among the most species-rich insects and new species are constantly described, indicating that speciation occurs frequently in this group. However, there are only very few studies on speciation in parasitoids. We studied reproductive barriers in two lineages of Lariophagus distinguendus (Chalcidoidea: Hymenoptera), a parasitoid wasp of pest beetle larvae that occur in human environments. One of the two lineages occurs in households preferably attacking larvae of the drugstore beetle Stegobium paniceum (“DB-lineage”), the other in grain stores with larvae of the granary weevil Sitophilus granarius as main host (“GW-lineage”). Between two populations of the DB-lineage, we identified slight sexual isolation as intraspecific barrier. Between populations from both lineages, we found almost complete sexual isolation caused by female mate choice, and postzygotic isolation, which is partially caused by cytoplasmic incompatibility induced by so far undescribed endosymbionts which are not Wolbachia or Cardinium. Because separation between the two lineages is almost complete, they should be considered as separate species according to the biological species concept. This demonstrates that cryptic species within parasitoid Hymenoptera also occur in Central Europe in close contact to humans.
KW  - cytoplasmic incompatibility
KW  - endosymbiotic bacteria
KW  - Lariophagus distinguendus
KW  - parasitoid wasps
KW  - sexual isolation
KW  - speciation
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222796
VL  - 9
ER  - 
TY  - JOUR
A1  - Kendall, Liam K.
A1  - Rader, Romina
A1  - Gagic, Vesna
A1  - Cariveau, Daniel P.
A1  - Albrecht, Matthias
A1  - Baldock, Katherine C. R.
A1  - Freitas, Breno M.
A1  - Hall, Mark
A1  - Holzschuh, Andrea
A1  - Molina, Francisco P.
A1  - Morten, Joanne M.
A1  - Pereira, Janaely S.
A1  - Portman, Zachary M.
A1  - Roberts, Stuart P. M.
A1  - Rodriguez, Juanita
A1  - Russo, Laura
A1  - Sutter, Louis
A1  - Vereecken, Nicolas J.
A1  - Bartomeus, Ignasi
T1  - Pollinator size and its consequences: Robust estimates of body size in pollinating insects
JF  - Ecology and Evolution
N2  - Body size is an integral functional trait that underlies pollination-related ecological processes, yet it is often impractical to measure directly. Allometric scaling laws have been used to overcome this problem. However, most existing models rely upon small sample sizes, geographically restricted sampling and have limited applicability for non-bee taxa. Allometric models that consider biogeography, phylogenetic relatedness, and intraspecific variation are urgently required to ensure greater accuracy. We measured body size as dry weight and intertegular distance (ITD) of 391 bee species (4,035 specimens) and 103 hoverfly species (399 specimens) across four biogeographic regions: Australia, Europe, North America, and South America. We updated existing models within a Bayesian mixed-model framework to test the power of ITD to predict interspecific variation in pollinator dry weight in interaction with different co-variates: phylogeny or taxonomy, sexual dimorphism, and biogeographic region. In addition, we used ordinary least squares regression to assess intraspecific dry weight ~ ITD relationships for ten bees and five hoverfly species. Including co-variates led to more robust interspecific body size predictions for both bees and hoverflies relative to models with the ITD alone. In contrast, at the intraspecific level, our results demonstrate that the ITD is an inconsistent predictor of body size for bees and hoverflies. The use of allometric scaling laws to estimate body size is more suitable for interspecific comparative analyses than assessing intraspecific variation. Collectively, these models form the basis of the dynamic R package, “pollimetry,” which provides a comprehensive resource for allometric pollination research worldwide.
KW  - Apoidea
KW  - biogeography
KW  - body size
KW  - dry weight
KW  - pollimetry
KW  - pollination
KW  - predictive models
KW  - R package
KW  - Syrphidae
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325705
VL  - 9
ER  - 
TY  - JOUR
A1  - Bahram, Mohammad
A1  - Anslan, Sten
A1  - Hildebrand, Falk
A1  - Bork, Peer
A1  - Tedersoo, Leho
T1  - Newly designed 16S rRNA metabarcoding primers amplify diverse and novel archaeal taxa from the environment
JF  - Environmental Microbiology Reports
N2  - High-throughput studies of microbial communities suggest that Archaea are a widespread component of microbial diversity in various ecosystems. However, proper quantification of archaeal diversity and community ecology remains limited, as sequence coverage of Archaea is usually low owing to the inability of available prokaryotic primers to efficiently amplify archaeal compared to bacterial rRNA genes. To improve identification and quantification of Archaea, we designed and validated the utility of several primer pairs to efficiently amplify archaeal 16S rRNA genes based on up-to-date reference genes. We demonstrate that several of these primer pairs amplify phylogenetically diverse Archaea with high sequencing coverage, outperforming commonly used primers. Based on comparing the resulting long 16S rRNA gene fragments with public databases from all habitats, we found several novel family- to phylum-level archaeal taxa from topsoil and surface water. Our results suggest that archaeal diversity has been largely overlooked due to the limitations of available primers, and that improved primer pairs enable to estimate archaeal diversity more accurately.
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221380
VL  - 11
ER  - 
TY  - JOUR
A1  - Müller, Jörg
A1  - Noss, Reed F.
A1  - Thorn, Simon
A1  - Bässler, Claus
A1  - Leverkus, Alexandro B.
A1  - Lindenmayer, David
T1  - Increasing disturbance demands new policies to conserve intact forest
JF  - Conservation Letters
N2  - Ongoing controversy over logging the ancient Białowieża Forest in Poland symbolizes a global problem for policies and management of the increasing proportion of the earth's intact forest that is subject to postdisturbance logging. We review the extent of, and motivations for, postdisturbance logging in protected and unprotected forests globally. An unprecedented level of logging in protected areas and other places where green-tree harvest would not normally occur is driven by economic interests and a desire for pest control. To avoid failure of global initiatives dedicated to reducing the loss of species, five key policy reforms are necessary: (1) salvage logging must be banned from protected areas; (2) forest planning should address altered disturbance regimes for all intact forests to ensure that significant areas remain undisturbed by logging; (3) new kinds of integrated analyses are needed to assess the potential economic benefits of salvage logging against its ecological, economic, and social costs; (4) global and regional maps of natural disturbance regimes should be created to guide better spatiotemporal planning of protected areas and undisturbed forests outside reserves; and (5) improved education and communication programs are needed to correct widely held misconceptions about natural disturbances.
KW  - anthropogenic disturbance
KW  - forestry
KW  - FSC
KW  - natural disturbance
KW  - protected area management
KW  - sanitary logging
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224256
VL  - 12
ER  -