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Excessive accumulation of the extracellular matrix is a hallmark of many inflammatory and fibrotic diseases, including those of the kidney. This study addresses the question whether NO, in addition to inhibiting the expression of MMP-9, a prominent metalloprotease expressed by mesangial cells, additionally modulates expression of its endogenous inhibitor TIMP-1. We demonstrate that exogenous NO has no modulatory effect on the extracellular TIMP-1 content but strongly amplifies the early increase in cytokine-induced TIMP-1 mRNA and protein levels. We examined whether transforming growth factor beta (TGFbeta), a potent profibrotic cytokine, is involved in the regulation of NO-dependent TIMP-1 expression. Experiments utilizing a pan-specific neutralizing TGFbeta antibody demonstrate that the NO-induced amplification of TIMP-1 is mediated by extracellular TGFbeta. Mechanistically, NO causes a rapid increase in Smad-2 phosphorylation, which is abrogated by the addition of neutralizing TGFbeta antisera. Similarly, the NO-dependent increase in Smad-2 phosphorylation is prevented in the presence of an inhibitor of TGFbeta-RI kinase, indicating that the NO-dependent activation of Smad-2 occurs via the TGFbeta-type I receptor. Furthermore, activation of the Smad signaling cascade by NO is corroborated by the NO-dependent increase in nuclear Smad-4 level and is paralleled by increased DNA binding of Smad-2/3 containing complexes to a TIMP-1-specific Smad-binding element (SBE). Reporter gene assays revealed that NO activates a 0.6-kb TIMP-1 gene promoter fragment as well as a TGFbeta-inducible and SBE-driven control promoter. Chromatin immunoprecipitation analysis also demonstrated DNA binding activity of Smad-3 and Smad-4 proteins to the TIMP-1-specific SBE. Finally, by enzyme-linked immunosorbent assay, we demonstrated that NO causes a rapid increase in TGFbeta(1) levels in cell supernatants. Together, these experiments demonstrate that NO by induction of the Smad signaling pathway modulates TIMP-1 expression.
Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families as well as 438 subjects from an independent, sporadic BD case-control cohort were analysed. Polygenic risk scores (PRS) for BD, schizophrenia, and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had significantly higher PRS for all three psychiatric disorders than the independent controls, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and sporadic BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses, therefore, demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. The PRS explained only part of the observed phenotypic variance and rare variants might have also contributed to disease development.
Plants, fungi and algae are important components of global biodiversity and are fundamental to all ecosystems. They are the basis for human well-being, providing food, materials and medicines. Specimens of all three groups of organisms are accommodated in herbaria, where they are commonly referred to as botanical specimens.The large number of specimens in herbaria provides an ample, permanent and continuously improving knowledge base on these organisms and an indispensable source for the analysis of the distribution of species in space and time critical for current and future research relating to global biodiversity. In order to make full use of this resource, a research infrastructure has to be built that grants comprehensive and free access to the information in herbaria and botanical collections in general. This can be achieved through digitization of the botanical objects and associated data.The botanical research community can count on a long-standing tradition of collaboration among institutions and individuals. It agreed on data standards and standard services even before the advent of computerization and information networking, an example being the Index Herbariorum as a global registry of herbaria helping towards the unique identification of specimens cited in the literature.In the spirit of this collaborative history, 51 representatives from 30 institutions advocate to start the digitization of botanical collections with the overall wall-to-wall digitization of the flat objects stored in German herbaria. Germany has 70 herbaria holding almost 23 million specimens according to a national survey carried out in 2019. 87% of these specimens are not yet digitized. Experiences from other countries like France, the Netherlands, Finland, the US and Australia show that herbaria can be comprehensively and cost-efficiently digitized in a relatively short time due to established workflows and protocols for the high-throughput digitization of flat objects.Most of the herbaria are part of a university (34), fewer belong to municipal museums (10) or state museums (8), six herbaria belong to institutions also supported by federal funds such as Leibniz institutes, and four belong to non-governmental organizations. A common data infrastructure must therefore integrate different kinds of institutions.Making full use of the data gained by digitization requires the set-up of a digital infrastructure for storage, archiving, content indexing and networking as well as standardized access for the scientific use of digital objects. A standards-based portfolio of technical components has already been developed and successfully tested by the Biodiversity Informatics Community over the last two decades, comprising among others access protocols, collection databases, portals, tools for semantic enrichment and annotation, international networking, storage and archiving in accordance with international standards. This was achieved through the funding by national and international programs and initiatives, which also paved the road for the German contribution to the Global Biodiversity Information Facility (GBIF).Herbaria constitute a large part of the German botanical collections that also comprise living collections in botanical gardens and seed banks, DNA- and tissue samples, specimens preserved in fluids or on microscope slides and more. Once the herbaria are digitized, these resources can be integrated, adding to the value of the overall research infrastructure. The community has agreed on tasks that are shared between the herbaria, as the German GBIF model already successfully demonstrates.We have compiled nine scientific use cases of immediate societal relevance for an integrated infrastructure of botanical collections. They address accelerated biodiversity discovery and research, biomonitoring and conservation planning, biodiversity modelling, the generation of trait information, automated image recognition by artificial intelligence, automated pathogen detection, contextualization by interlinking objects, enabling provenance research, as well as education, outreach and citizen science.We propose to start this initiative now in order to valorize German botanical collections as a vital part of a worldwide biodiversity data pool.
Major mood disorders, which primarily include bipolar disorder and major depressive disorder, are the leading cause of disability worldwide and pose a major challenge in identifying robust risk genes. Here, we present data from independent large-scale clinical data sets (including 29 557 cases and 32 056 controls) revealing brain expressed protocadherin 17 (PCDH17) as a susceptibility gene for major mood disorders. Single-nucleotide polymorphisms (SNPs) spanning the PCDH17 region are significantly associated with major mood disorders; subjects carrying the risk allele showed impaired cognitive abilities, increased vulnerable personality features, decreased amygdala volume and altered amygdala function as compared with non-carriers. The risk allele predicted higher transcriptional levels of PCDH17 mRNA in postmortem brain samples, which is consistent with increased gene expression in patients with bipolar disorder compared with healthy subjects. Further, overexpression of PCDH17 in primary cortical neurons revealed significantly decreased spine density and abnormal dendritic morphology compared with control groups, which again is consistent with the clinical observations of reduced numbers of dendritic spines in the brains of patients with major mood disorders. Given that synaptic spines are dynamic structures which regulate neuronal plasticity and have crucial roles in myriad brain functions, this study reveals a potential underlying biological mechanism of a novel risk gene for major mood disorders involved in synaptic function and related intermediate phenotypes.
Ziel: Wiederansiedlungen und anderen Formen der gezielten Einbürgerung kommen im Naturschutz eine wachsende Bedeutung zu, nicht zuletzt vor dem Hintergrund zukünftiger Klimaveränderungen. Besonders in fragmentierten Habitaten können Wiederansiedlungen ein geeignetes Mittel sein, um eine hohe Artenvielfalt zu erhalten bzw. wieder herzustellen. In dieser Untersuchung wurden Informationen zu bisherigen Wiederansiedlungsversuchen von Pflanzenarten in Deutschland zusammengetragen, um folgende Fragen zu beantworten: (1) Wie verteilen sich die in Wiederansiedlungsprojekten berücksichtigten Arten auf verschiedene Pflanzenfamilien, Standorttypen, Habitattypen und ökologische Strategietypen, und sind gefährdete Arten bestimmter Eigenschaften und Ansprüche, verglichen mit der Gesamtzahl gefährdeter Arten, in Wiederansiedlungsprojekten adäquat repräsentiert? (2) Werden Arten, für die national oder regional eine besonders große Verantwortlichkeit besteht, in Wiederansiedlungsprojekten hinreichend berücksichtigt? (3) Beeinflusst die Auswahl der wiedereinzubringenden Arten die Chancen für einen Erfolg oder Misserfolg der Projekte?
Methoden: Informationen zu Wiederansiedlungsprojekten in Deutschland wurden aus publizierten und Internet-Quellen sowie unveröffentlichten Berichten zusammengetragen. Berücksichtigt wurden dabei Versuche, die auf einzelne Arten ausgerichtet waren und im Rahmen wissenschaftlicher oder Naturschutz-bezogener Projekte durchgeführt wurden. Für alle Arten wurden Daten zur Systematik, Lebensform, zu ökologischen Merkmalen und Habitatansprüchen zusammengestellt. Eine Liste aller national oder regional gefährdeten, für Wiederansiedlungen berücksichtigten und nicht-berücksichtigten Arten diente als Referenz für die statistischen Auswertungen.
Ergebnisse: Die Liste aller wiedereingebürgerten Gefäßpflanzen umfasste 196 Arten. Im Vergleich zur Gesamtheit aller gefährdeten Taxa in Deutschland waren Arten aus Familien mit großen und auffälligen, oft insektenbestäubten Blüten (zum Beispiel Orchidaceae) überrepräsentiert. Häufiger als statistisch erwartet wurden Arten aus halb-natürlichen Habitattypen, wie Trockenrasen und Heiden, wiederangesiedelt. Besonders viele Projekte betrafen Arten in Kalkmagerrasen auf trockenen, basenreichen und nährstoffarmen Standorten. Im Gegensatz dazu waren Taxa naturnaher Pflanzengemeinschaften (alpine und Stein-Formationen, Wälder) unterrepräsentiert. Etwa 25 % aller wiederangesiedelten Arten gelten regional als gefährdet, deutschlandweit aber als ungefährdet. Von den 150 Arten, für die Deutschland eine besonders große Verantwortlichkeit trägt, wurden nur 14 (9,3 %) in Wiedereinbürgerungsprojekten berücksichtigt. Der Erfolg der Wiederansiedlungen war nur in einem Drittel der Fälle dokumentiert, in denen sich zeigte, dass Wiedereinbürgerungen in nährstoffarmen Lebensräumen relativ oft erfolglos bleiben, Versuche mit nährstoffbedürftigen und konkurrenzstarken Arten dagegen häufiger gelingen.
Schlussfolgerungen: Wiederansiedlungen gefährdeter Arten sollten stärker auf die gefährdeten Arten fokussieren, für die national oder regional eine besonders große Verantwortlichkeit besteht. Die unterschiedlichen Erfolgschancen von Wiederansiedlungen in verschiedenen Habitaten sollten stärker als bisher bei der Auswahl der Arten berücksichtigt werden.
Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. BD shows substantial clinical and genetic overlap with other psychiatric disorders, in particular schizophrenia (SCZ). The genes underlying this etiological overlap remain largely unknown. A recent SCZ genome wide association study (GWAS) by the Psychiatric Genomics Consortium identified 128 independent genome-wide significant single nucleotide polymorphisms (SNPs). The present study investigated whether these SCZ-associated SNPs also contribute to BD development through the performance of association testing in a large BD GWAS dataset (9747 patients, 14278 controls). After re-imputation and correction for sample overlap, 22 of 107 investigated SCZ SNPs showed nominal association with BD. The number of shared SCZ-BD SNPs was significantly higher than expected (p = 1.46x10-8). This provides further evidence that SCZ-associated loci contribute to the development of BD. Two SNPs remained significant after Bonferroni correction. The most strongly associated SNP was located near TRANK1, which is a reported genome-wide significant risk gene for BD. Pathway analyses for all shared SCZ-BD SNPs revealed 25 nominally enriched gene-sets, which showed partial overlap in terms of the underlying genes. The enriched gene-sets included calcium- and glutamate signaling, neuropathic pain signaling in dorsal horn neurons, and calmodulin binding. The present data provide further insights into shared risk loci and disease-associated pathways for BD and SCZ. This may suggest new research directions for the treatment and prevention of these two major psychiatric disorders.
Wet grasslands once covered a large area in the lowlands of northern Germany, but have declined since several decades as a result of land use intensification. Permanent plot data from such grasslands in the region that would allow to assess the extent of changes in species composition and richness are still rare. Here, we present a re-visitation study of 52 quasi-permanent plots from the Stedinger Land area in the basin of the river Weser near Bremen, comparing quadrat data between 1948 and 2015. In 1948, the grasslands were characterized by species typical of wet, moderately fertile grasslands belonging to the Bromo-Senecionetum aquatici (Bromion racemosi), including 15 species currently classified as threatened. Until 2015, the vegetation had changed strongly: almost all indicators of wet grasslands had either declined or completely vanished, whereas more nutrient-demanding species of less wet soils had increased, especially grasses. The cumulative number of species had declined by 50%, while mean plot species richness had decreased by 64.6%, mainly resulting from the pronounced loss of many herbs. A comparison of mean Ellenberg indicator values suggested that the plots had become drier, but also more base- and nutrient-rich, most likely triggered by the intensification of land use with drainage and fertilization as well as more frequent and earlier cutting. Our study reflects the dramatic loss of plant species diversity in wet grasslands over the past 60−70 years in areas not preserved and properly managed, and it documents the need for protecting remnants of these grasslands and for restoring wet grassland areas by re-wetting, nutrient removal and the transition to a less intensive land use.
Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).
Mammalian retinae have rod photoreceptors for night vision and cone photoreceptors for daylight and colour vision. For colour discrimination, most mammals possess two cone populations with two visual pigments (opsins) that have absorption maxima at short wavelengths (blue or ultraviolet light) and long wavelengths (green or red light). Microchiropteran bats, which use echolocation to navigate and forage in complete darkness, have long been considered to have pure rod retinae. Here we use opsin immunohistochemistry to show that two phyllostomid microbats, Glossophaga soricina and Carollia perspicillata, possess a significant population of cones and express two cone opsins, a shortwave-sensitive (S) opsin and a longwave-sensitive (L) opsin. A substantial population of cones expresses S opsin exclusively, whereas the other cones mostly coexpress L and S opsin. S opsin gene analysis suggests ultraviolet (UV, wavelengths <400 nm) sensitivity, and corneal electroretinogram recordings reveal an elevated sensitivity to UV light which is mediated by an S cone visual pigment. Therefore bats have retained the ancestral UV tuning of the S cone pigment. We conclude that bats have the prerequisite for daylight vision, dichromatic colour vision, and UV vision. For bats, the UV-sensitive cones may be advantageous for visual orientation at twilight, predator avoidance, and detection of UV-reflecting flowers for those that feed on nectar.
Nach Nutzungsaufgabe ehemals artenreicher Feuchtwiesen (Senecioni-Brometum racemosi) der Talauen entwickelten sich artenarme Hochstaudenfluren. Das qualitative Ausmaß der Veränderungen konnte am Beispiel des mittleren Ostetals durch den Vergleich genauer Vegetationskarten und Dauerquadrataufnahmen analysiert werden. Der drastische Artenzahlrückgang ist verbunden mit der Dominanz weniger, hochwüchsiger Arten. Phalaridetum, Glycerietum, Filipendula- und Convolvuletalia-Gesellschaften sind auch noch nach 30 Jahren Brache Folgegesellschaften des Senecioni-Brometum. Aufgrund ihrer Konstitutionsmerkmale (Nährstoffakkumulation, Phytomasseproduktion und Fähigkeit, mit kräftigen Rhizomausläufern hohe Streuauflagen zu durchwachsen) sind Filipendula, Glyceria oder Phalaris in der Lage, in allen Ausbildungen der Sumpfdotterblumen-Wassergreiskrautwiesen schnell die Vorherrschaft zu gewinnen. Standorttypische Gehölze benachbarter Alno-Ulmion-Gesellschaften konnten sich infolge starker Beschattung noch nicht etablieren. Nach Wiederaufnahme der Nutzung ist bereits in den ersten 3 Jahren ein gravierender Ertragsrückgang festzustellen. In den nicht gedüngten Mädesüß-, Wasserschwaden- und Rohrglanzgras-Brachen wird bei zweimaliger Mahd bereits nach 3 Jahren eine erfolgsversprechende Restitution artenreicher Sumpfdotterblumenwiesen eingeleitet: viele Kennarten charakterisieren den rapiden Anstieg der Artenzahl. Die Reversibilität der Bracheentwicklung kann mit einer schnellen "biologischen Auslagerung" der naturnahen (nicht meliorierten) Brachestandorte erklärt werden.