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Purpose Heritable factors play an important etiologic role in connective tissue disorders (CTD) with vascular involvement, and a genetic diagnosis is getting increasingly important for gene-tailored, personalized patient management. Methods We analyzed 32 disease-associated genes by using targeted next-generation sequencing and exome sequencing in a clinically relevant cohort of 199 individuals. We classified and refined sequence variants according to their likelihood for pathogenicity. Results We identified 1 pathogenic variant (PV; in FBN1 or SMAD3 ) in 15 patients (7.5%) and ≥1 likely pathogenic variant (LPV; in COL3A1 , FBN1 , FBN2 , LOX , MYH11 , SMAD3 , TGFBR1 , or TGFBR2 ) in 19 individuals (9.6%), together resulting in 17.1% diagnostic yield. Thirteen PV/LPV were novel. Of PV/LPV-negative patients 47 (23.6%) showed ≥1 variant of uncertain significance (VUS). Twenty-five patients had concomitant variants. In-depth evaluation of reported/calculated variant classes resulted in reclassification of 19.8% of variants. Conclusion Variant classification and refinement are essential for shaping mutational spectra of disease genes, thereby improving clinical sensitivity. Obligate stringent multigene analysis is a powerful tool for identifying genetic causes of clinically related CTDs. Nonetheless, the relatively high rate of PV/LPV/VUS-negative patients underscores the existence of yet unknown disease loci and/or oligogenic/polygenic inheritance.

On examination the patient was generally fit and well; his pulse was 92 beats per min, blood pressure was 140/90 mm Hg, and his oxygen saturation was 94%. MRI showed a small acute embolic ischaemic lesion in the postcentral gyrus of the right hemisphere (figure 1); doppler and duplex sonography of extracranial and intracranial vessels and multimodal imaging—including magnetic resonance angiography—ruled out any atherosclerotic plaques, dissection, or vasculitis (figure 1). Transoesophageal echocardiography showed a patent foramen ovale (PFO) with spontaneous passage of bubbles and accentuation with Valsalva manoeuvre; no septal aneurysm was seen (figure 2).

Introduction Human speech does not only communicate linguistic information but also paralinguistic features, e.g. information about the identity and the arousal state of the sender. Comparable morphological and physiological constraints on vocal production in mammals suggest the existence of commonalities encoding sender-identity and the arousal state of a sender across mammals. To explore this hypothesis and to investigate whether specific acoustic parameters encode for sender-identity while others encode for arousal, we studied infants of the domestic cat ( Felis silvestris catus ). Kittens are an excellent model for analysing vocal correlates of sender-identity and arousal. They strongly depend on the care of their mother. Thus, the acoustical conveyance of sender-identity and arousal may be important for their survival. Results We recorded calls of 18 kittens in an experimentally-induced separation paradigm, where kittens were spatially separated from their mother and siblings. In the Low arousal condition, infants were just separated without any manipulation. In the High arousal condition infants were handled by the experimenter. Multi-parametric sound analyses revealed that kitten isolation calls are individually distinct and differ between the Low and High arousal conditions. Our results suggested that source- and filter-related parameters are important for encoding sender-identity, whereas time-, source- and tonality-related parameters are important for encoding arousal. Conclusion Comparable findings in other mammalian lineages provide evidence for commonalities in non-verbal cues encoding sender-identity and arousal across mammals comparable to paralinguistic cues in humans. This favours the establishment of general concepts for voice recognition and emotions in humans and animals.

ObjectivesTo analyse the influence of geolocation and ethnicity on the clinical presentation of primary Sjögren's syndrome (SjS) at diagnosis.MethodsThe Big Data Sjögren Project Consortium is an international, multicentre registry designed in 2014. By January 2016, 20 centres from five continents were participating. Multivariable logistic regression analyses were performed.ResultsWe included 7748 women (93%) and 562 men (7%), with a mean age at diagnosis of primary SjS of 53 years. Ethnicity data were available for 7884 patients (95%): 6174 patients (78%) were white, 1066 patients (14%) were Asian, 393 patients (5%) were Hispanic, 104 patients (1%) were black/African-American and 147 patients (2%) were of other ethnicities. SjS was diagnosed a mean of 7 years earlier in black/African-American compared with white patients; the female-to-male ratio was highest in Asian patients (27:1) and lowest in black/African-American patients (7:1); the prevalence of sicca symptoms was lowest in Asian patients; a higher frequency of positive salivary biopsy was found in Hispanic and white patients. A north-south gradient was found with respect to a lower frequency of ocular involvement in northern countries for dry eyes and abnormal ocular tests in Europe (OR 0.46 and 0.44, respectively) and Asia (OR 0.18 and 0.49, respectively) compared with southern countries. Higher frequencies of antinuclear antibodies (ANAs) were reported in northern countries in America (OR=1.48) and Asia (OR=3.80) while, in Europe, northern countries had lowest frequencies of ANAs (OR=0.67) and Ro/La (OR=0.69).ConclusionsThis study provides the first evidence of a strong influence of geolocation and ethnicity on the phenotype of primary SjS at diagnosis.

ObjectiveTo develop and validate ClinESSDAI (Clinical European League Against Rheumatism Sjögren's Syndrome Disease Activity Index), ie, ESSDAI without the biological domain.Patients and methodsThe 702 fictive vignettes derived from 96 real cases of primary Sjögren's syndrome of the ESSDAI development study were used. As for ESSDAI development, the physician assessment of disease activity (0–10 scale) was used as the ‘gold standard’ in a multivariate model for weighting domains, after removing the biological domain. The reliability, assessed by intraclass correlation coefficient (ICC) between ClinESSDAI and ESSDAI, explored if ClinESSDAI was equivalent to ESSDAI. Its psychometric (ie, measurement) properties were compared with that of ESSDAI in an independent cohort. Also, its use was evaluated on data of two clinical trials.ResultsIn multivariate modelling, all 11 domains remained significantly associated with disease activity, with slight modifications of some domain weights. Reliability between clinESSDAI and ESSDAI was excellent (ICC=0.98 and 0.99). Psychometric properties of clinESSDAI, disease activity levels and minimal clinically important improvement thresholds and its ability to detect change over time in clinical trials were very close to that of ESSDAI.ConclusionsClinESSDAI appears valid and very close to the original ESSDAI. This score provides an accurate evaluation of disease activity independent of B-cell biomarkers. It could be used in various circumstances: (i) in biological/clinical studies to avoid data collinearity, (ii) in clinical trials, as secondary endpoint, to detect change independent of biological effect of the drug, (iii) in clinical practice to assess disease activity for visits where immunological tests have not been done.

To investigate the evolutionary diversification and morphological evolution of grass supertribe Poodae (subfam. Pooideae, Poaceae) we conducted a comprehensive molecular phylogenetic analysis including representatives from most of its accepted genera. We focused on generating a DNA sequence dataset of plastid matK gene–3′trnK exon and trnL-trnF regions and nuclear ribosomal (nr) ITS1–5.8S gene–ITS2 and ETS that was taxonomically overlapping as completely as possible (altogether 257 species). The idea was to infer whether phylogenetic trees or certain clades based on plastid and nrDNA data correspond with each other or discord, revealing signatures of past hybridization. The datasets were analysed separately, in combination, by excluding taxa with discordant placements in the individual gene trees and with duplication of these taxa in away that each duplicate has only one data partition (plastid or nrDNA). We used maximum likelihood, maximum parsimony and Bayesian approaches. Instances of severe conflicts between the phylogenetic trees derived from both datasets, some of which have been noted earlier, point to hybrid origin of several lineages such as the ABCV clade encompassing several subtribes and subordinate clades, subtribes Airinae, Anthoxanthinae, Antinoriinae, subtr. nov., Aristaveninae, Avenulinae, subtr. nov., Helictochloinae, subtr. nov., Holcinae, Phalaridinae, Scolochloinae, Sesleriinae, Torreyochloinae and genera Arctopoa, Castellia, Graphephorum, Hyalopodium, Lagurus, Macrobriza, Puccinellia plus Sclerochloa, Sesleria, Tricholemma, Tzveleviochloa, etc. 'Calamagrostis' flavens appears to be an intergeneric hybrid between Agrostis and Calamagrostis. Analyses excluding all lineages with demonstrably cytonuclear discordance revealed three supported main clades within Poodae that were present in both the plastid and nrDNA trees. They fully corresponded in their delineation but were phylogenetically differently arranged, pointing to hybrid origin of one of them. We propose to consider these main clades in classification as separate tribes Aveneae, Poeae s.str. and Festuceae with a phylogenetic arrangement of Aveneae (Poeae, Festuceae) in plastid versus Festuceae (Aveneae, Poeae) in nrDNA trees. Phylogenetic incongruence of the plastid and nuclear markers extends across all hierarchical taxonomic levels of Poodae, ranging from species (not studied here) to genera, subtribes and tribes, therefore the deepest taxonomic levels, emphasizing the enormous significance of reticulate evolution in this large group of grasses. A partly revised classification is presented, including the introduction of a new tribe Festuceae and a re-instatement of tribe Aveneae. Following a comparatively narrow delineation of preferably monophyletic subtribes, Antinoriinae, Avenulinae, Brizochloinae, Helictochloinae and Hypseochloinae are described as new. New genera are Arctohyalopoa and Hyalopodium. New combinations are Anthoxanthum glabrum subsp. sibiricum, A. nitens subsp. kolymense, Arctohyalopoa ivanovae, A. jurtzevii, A. lanatiflora, A. momica, Colpodium biebersteinianum, C. kochii, C. pisidicum, C. trichopodum, C. verticillatum, Dupontia fulva, Festuca masafuerana, F. robinsoniana, Graphephorum canescens, G. cernuum, Hyalopodium araraticum, Paracolpodium baltistanicum, Parapholis cylindrica, P. ×pauneroi. Festuca dolichathera and F. masatierrae are new names.

The grass subfamily Pooideae was studied using DNA sequence information from the chloroplast (cp) matK gene–3′trnK exon and the nuclear ribosomal (nr) ITS1–5.8S gene–ITS2 in a sample of 67 taxa covering all of its tribes. Branches with strong bootstrap support are consistently resolved in both datasets, whereas discrepancy is confined to low-support or unsupported nodes in one of the datasets. The results do not reveal a significant role of past hybridisation, plastid lineage sorting or reticulation in the evolutionary diversification of the major lineages of the subfamily. The combined analysis of the plastid and nuclear datasets results in a largely well-supported pattern of divergence for the major lineages of the subfamily. Some re-alignments of tribes and subtribes are proposed and discussed with reference to relevant morphological and structural characters. We propose the recognition of broader tribes Nardeae with subtribes Nardinae and Lygeinae, Meliceae with subtribes Brylkiniinae and Melicinae, Stipeae with subtribes Ampelodesminae and Stipinae, and Triticeae with subtribes Littledaleinae, Brominae and Hordeinae. For the tribe complex of Aveneae and Poeae, the clear-cut split into two major clades and further resolution into some high-support lineages depicted by cpDNA is not contradicted by nuclear ITS and their taxonomic treatment as separate tribes or a single tribe remains an unanswered question.

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.

100 species representing 48 genera from the grass tribes Aveneae and Poeae, 30 genera from other tribes of Pooideae and outgroups were studied using matK chloroplast sequence data to address systematic questions. Data were evaluated using maximum parsimony and Bayesian methods. The results support a broadly delineated subfamily Pooideae with Brachyelytrum and Nardus/Lygeum as basal lineages. Aveneae/Poeae + Bromeae/Triticeae + Brachypodium are sister to a polytomy that contains the strongly supported lineages Meliceae and Stipeae, including Ampelodesmos. A further, but less well supported, assemblage within this polytomy consists of Aveneae subtribe Duthieinae + Anisopogon + Phaenosperma. Brachypodium is sister to a well-supported lineage that includes Aveneae/Poeae and Bromeae/Triticeae. Within Aveneae/Poeae, two clades are apparent, which do not completely correspond to the traditional tribes Aveneae and Poeae. We argue that Aveneae and Poeae should be maintained as separate tribes rather than being merged under Poeae. The position of several genera and minor lineages within both clades is examined with reference to morphology, biogeography, ecology, and current taxonomic treatments. On the basis of a number of synapomorphies from morphological and molecular data, the monotypic genera Lygeum (Lygeeae) and Nardus (Nardeae) are lumped under the Nardeae. Brachypodium is supported as a separate tribe, Brachypodieae.

To investigate the evolutionary diversification and morphological evolution of grass supertribe Poodae (subfam. Pooideae, Poaceae) we conducted a comprehensive molecular phylogenetic analysis including representatives from most of their accepted genera. We focused on generating a DNA sequence dataset of plastid matK gene-3′trnK exon and trnL-trnF regions and nuclear ribosomal ITS1-5.8S gene-ITS2 and ETS that was taxonomically overlapping as completely as possible (altogether 257 species). The idea was to infer whether phylogenetic trees or certain clades based on plastid and nuclear DNA data correspond with each other or discord, revealing signatures of past hybridization. The datasets were analysed using maximum parsimony, maximum likelihood and Bayesian approaches. Instances of severe conflicts between the phylogenetic trees derived from both datasets, some of which have been noted earlier, unambiguously point to hybrid origin of several lineages (subtribes, groups of genera, sometimes genera) such as Phalaridinae, Scolochloinae, Sesleriinae, Torreyochloinae; Arctopoa, Castellia, Graphephorum, Hyalopodium, Lagurus, Macrobriza, Puccinellia plus Sclerochloa, Sesleria, Tricholemma, American Trisetum, etc. and presumably Airinae, Holcinae and Phleinae. ‘Calamagrostis’ flavens appears to be an intergeneric hybrid between Agrostis and Calamagrostis. Most frequently there is good agreement of other regions of the trees, apart from intrinsic different phylogenetic resolution of the respective DNA markers. To explore the to date rather unclear morphological evolution of our study group a data matrix encompassing finally 188 characters was analysed for ancestral state reconstructions (ASR) using the tree from the combined molecular dataset as presumably best approximation to the species phylogeny. For 74 characters ASRs were feasible and yielded partly surprising results for the study group as a whole but also for some of their subdivisions. Considering taxonomy and classification it became evident, that many morphological characters show a very high degree of homoplasy and are seemingly able to change within comparatively short timespans in the evolution of our grasses. Most of the taxonomic units distinguished within our study group, e.g. as subtribes, are defined less by consistent morphological characters or character combinations and should be rather understood as clades revealed by molecular phylogenetic analysis. One reason for this extreme homoplasy concerning traditionally highly rated characters of inflorescences or spikelets and their components might be that they have little to do with pollination (always wind) or adaptation to pollinators as in other angiosperms but rather with dispersal and diaspores. Easily changing structure of spikelet disarticulation, of glume, lemma or awn characters might be advantageous in the rapid adaptation to different habitats and micro-habitats, which was evidently most successfully accomplished by these grasses. A partly revised classification of Poodae is presented, including a re-instatement of tribes Aveneae and Poeae s.str. Following a comparatively narrow delineation of preferably monophyletic subtribes, Antinoriinae, Avenulinae, Brizochloinae, Helictochloinae, Hypseochloinae are described as new. New genera are Arctohyalopoa and Hyalopodium. New combinations are Arctohyalopoa lanatiflora, A. lanatiflora subsp. ivanoviae, A. lanatiflora subsp. momica, Colpodium biebersteinianum, C. kochii, C. trichopodum, C. verticillatum, Deschampsia micrathera, Dupontia fulva, Festuca masafuerana, Hyalopodium araraticum, Paracolpodium baltistanicum, Parapholis cylindrica, P. xpauneroi. Festuca masatierrae is a new name.