Senckenberg German Entomological Institute

Compelling evidence suggests that the transcription factor Foxp3 acts as a master switch governing the development and function of CD4(+) regulatory T cells (Tregs). However, whether transcriptional control of Foxp3 expression itself contributes to the development of a stable Treg lineage has thus far not been investigated. We here identified an evolutionarily conserved region within the foxp3 locus upstream of exon-1 possessing transcriptional activity. Bisulphite sequencing and chromatin immunoprecipitation revealed complete demethylation of CpG motifs as well as histone modifications within the conserved region in ex vivo isolated Foxp3(+)CD25(+)CD4(+) Tregs, but not in naïve CD25(-)CD4(+) T cells. Partial DNA demethylation is already found within developing Foxp3(+) thymocytes; however, Tregs induced by TGF-beta in vitro display only incomplete demethylation despite high Foxp3 expression. In contrast to natural Tregs, these TGF-beta-induced Foxp3(+) Tregs lose both Foxp3 expression and suppressive activity upon restimulation in the absence of TGF-beta. Our data suggest that expression of Foxp3 must be stabilized by epigenetic modification to allow the development of a permanent suppressor cell lineage, a finding of significant importance for therapeutic applications involving induction or transfer of Tregs and for the understanding of long-term cell lineage decisions.

Effective policies to halt biodiversity loss require knowing which anthropogenic drivers are the most important direct causes. Whereas previous knowledge has been limited in scope and rigor, here we statistically synthesize empirical comparisons of recent driver impacts found through a wide-ranging review. We show that land/sea use change has been the dominant direct driver of recent biodiversity loss worldwide. Direct exploitation of natural resources ranks second and pollution third; climate change and invasive alien species have been significantly less important than the top two drivers. The oceans, where direct exploitation and climate change dominate, have a different driver hierarchy from land and fresh water. It also varies among types of biodiversity indicators. For example, climate change is a more important driver of community composition change than of changes in species populations. Stopping global biodiversity loss requires policies and actions to tackle all the major drivers and their interactions, not some of them in isolation.

The ENMTools software package was introduced in 2008 as a platform for making measurements on environmental niche models (ENMs, frequently referred to as species distribution models or SDMs), and for using those measurements in the context of newly developed Monte Carlo tests to evaluate hypotheses regarding niche evolution. Additional functionality was later added for model selection and simulation from ENMs, and the software package has been quite widely used. ENMTools was initially implemented as a Perl script, which was also compiled into an executable file for various platforms. However, the package had a number of significant limitations; it was only designed to fit models using Maxent, it relied on a specific Perl distribution to function, and its internal structure made it difficult to maintain and expand. Subsequently, the R programming language became the platform of choice for most ENM studies, making ENMTools less usable for many practitioners. Here we introduce a new R version of ENMTools that implements much of the functionality of its predecessor as well as numerous additions that simplify the construction, comparison and evaluation of niche models. These additions include new metrics for model fit, methods of measuring ENM overlap, and methods for testing evolutionary hypotheses. The new version of ENMTools is also designed to work within the expanding universe of R tools for ecological biogeography, and as such includes greatly simplified interfaces for analyses from several other R packages.

The first complete World Catalog of sawflies (Hymenoptera, suborder Symphyta) for over 100 years is presented. It contains references to the original descriptions and provides brief distributional data for 803 genera, 8353 species (123 with two or more subspecies) and 161 subspecies in addition to the nominal subspecies. 15245 proposed names are treated, including replacement names, infrasubspecific names and nomina nuda, of which only 22 could not be checked in the original publications. Current taxonomic placement of genera and species and occurrence in zoogeographic regions are indicated. The list of names contains 31245 name combinations, variant spellings and family-group names. The authors attempted to consult all publications with taxonomic content referring to Symphyta that have appeared up to 31.12.2009. The 2960 cited references include all those that are known to contain original descriptions of taxa. Short biographical data and portraits of 168 symphytologists as well as images of representatives of extant sawfly taxa are included.

The Virchow^Robin spaces (VRS), perivascular compartments surrounding small blood vessels as they penetrate the brain parenchyma, are increasingly recognized for their role in leucocyte trafficking as well as for their potential to modulate immune responses. In the present study, we investigated VRS numbers and volumes in different brain regions in 45 multiple sclerosis patients and 30 healthy controls of similar age and gender distribution, applying three different MRI sequence modalities (T 2 -weighted, T 1 -weighted and FLAIR). VRS were detected in comparable numbers in both multiple sclerosis patients and healthy individuals, indicating that perivascular compartments present on MRI are not a unique feature of multiple sclerosis. However, multiple sclerosis patients had significantly larger VRS volumes than healthy controls (P = 0.004).This finding was not explained by a significantly lower brain parenchymal fraction (BPF), resulting from a higher degree of atrophy, in the patient cohort. In a multiple linear regression analysis, age had a significant influence on VRS volumes in the control group but not in multiple sclerosis patients (P = 0.023 and P = 0.263, respectively). A subsequent prospective longitudinal substudy with monthly follow-up MRI over a period of up to 12 months in 18 patients revealed a significant increase in VRS volumes and counts accompanying the occurrence of contrast-enhancing lesions (CEL). At time points when blood^brain barrier (BBB) breakdown was indicated by the appearance of CEL, total VRS volumes and counts were significantly higher compared with preceding time points without CEL (P = 0.011 and P = 0.041, respectively), whereas a decrease thereafter was not statistically significant. Thus, our data points to an association of VRS with CEL as a sign for inflammation rather than with factors such as age, observed in healthy controls, and therefore suggests a role of VRS in inflammatory processes of the brain.

An updated classification of the order Hymenoptera is provided with the current numbers of genera and species described so far specified. The order is composed of 2 suborders, 27 superfamilies, 132 families, 8423 extant genera with an additional 685 extinct genera. Considered one of the most species-rich insects orders a total of 153088 extant species have been described, in addition to 2429 extinct species.

Environmental changes strongly impact the distribution of species and subsequently the composition of species assemblages. Although most community ecology studies represent temporal snap shots, long-term observations are rather rare. However, only such time series allow the identification of species composition shifts over several decades or even centuries. We analyzed changes in the species composition of a southeastern German butterfly and burnet moth community over nearly 2 centuries (1840-2013). We classified all species observed over this period according to their ecological tolerance, thereby assessing their degree of habitat specialisation. This classification was based on traits of the butterfly and burnet moth species and on their larval host plants. We collected data on temperature and precipitation for our study area over the same period. The number of species declined substantially from 1840 (117 species) to 2013 (71 species). The proportion of habitat specialists decreased, and most of these are currently endangered. In contrast, the proportion of habitat generalists increased. Species with restricted dispersal behavior and species in need of areas poor in soil nutrients had severe losses. Furthermore, our data indicated a decrease in species composition similarity between different decades over time. These data on species composition changes and the general trends of modifications may reflect effects from climate change and atmospheric nitrogen loads, as indicated by the ecological characteristics of host plant species and local changes in habitat configuration with increasing fragmentation. Our observation of major declines over time of currently threatened and protected species shows the importance of efficient conservation strategies.

Abstract Severe losses of insects have taken place over major parts of Europe. This negative trend is assumed to be largely the result of agricultural intensification. To analyse potential factors causing this loss of species, we assessed butterfly communities at 21 grassland patches. Seventeen of these were distributed across an agricultural landscape dominated by crop fields; four were embedded in two adjoining managed semi‐natural grassland areas. We assessed environmental parameters such as patch size and habitat quality for each grassland patch. We further incorporated the surrounding land‐cover considering different degrees of land‐use intensity. We classified butterfly species into generalists and specialists according their ecological and behavioural characteristics. As in the managed semi‐natural reference grasslands, species richness and abundance were higher in patches surrounded by extensively used grasslands and unsprayed crop fields, and lower in patches surrounded by sprayed crop fields. Furthermore, blossom density positively affected butterfly occurrence. Our data revealed that specialised butterfly species mainly occur in managed semi‐natural grassland sites, and are largely absent from other grassland plots embedded in the agricultural matrix. Our study underlines the negative impacts of intense conventional agriculture on butterfly species richness and abundance and reveals the urgent need for more nature‐friendly cultivation methods. In situ experiments may help to understand and disentangle single drivers causing this negative trend.

The science of taxonomy, albeit being fundamental for all organismic research, has been underfunded and undervalued for about two generations. We analyze how this could happen, particularly in times of a biodiversity crisis, when we have increased awareness amongst the population and decision makers that knowledge about species we share the planet with is indispensable for finding solutions. We identify five major issues: the habit of holding taxonomy in low esteem; the focus on inappropriate publication metrics in evaluating scientific output; the excessive focus on innovative technology in evaluating scientific relevance; shifting priorities in natural history museums away from their traditional strengths; and changing attitudes towards specimen collecting and increasing legislation regulating collecting and international exchange of specimens. To transform taxonomy into a thriving science again, we urgently suggest significantly increasing baseline funding for permanent positions in taxonomy, particularly in natural history museums; reviving taxonomic research and teaching in universities at the tenured professor level; strongly increasing soft money for integrative taxonomy projects; refraining using journal-based metrics for evaluating individual researchers and scientific output and instead focusing on quality; installing governmental support for open access publishing; focusing digitizing efforts to the most useful parts of collections, freeing resources for improving data quality by improving identifications; requiring natural history museums to focus on collection-based research; and ending the trend of prohibitive legislation towards scientific collecting and international exchange of taxonomic specimens, and instead building legal frameworks supportive of biodiversity research.

Climate change impacts biodiversity and is driving range shifts of species and populations across the globe. To understand the effects of climate warming on biota, long-term observations of the occurrence of species and detailed knowledge on their ecology and life-history is crucial. Mountain species particularly suffer under climate warming and often respond to environmental changes by altitudinal range shifts. We assessed long-term distribution trends of mountain butterflies across the eastern Alps and calculated species' specific annual range shifts based on field observations and species distribution models, counterbalancing the potential drawbacks of both approaches. We also compiled details on the ecology, behaviour and life-history, and the climate niche of each species assessed. We found that the highest altitudinal maxima were observed recently in the majority of cases, while the lowest altitudes of observations were recorded before 1980. Mobile and generalist species with a broad ecological amplitude tended to move uphill more than specialist and sedentary species. As main drivers we identified climatic conditions and topographic variables, such as insolation and solar irradiation. This study provides important evidence for responses of high mountain taxa to rapid climate change. Our study underlines the advantage of combining historical surveys and museum collection data with cutting-edge analyses.

Abstract Current studies have shown a severe general decline in insect species diversity, their abundance, and a biomass reduction of flying insects. Most of previous studies have been performed at single sites, or were spatially restricted at the landscape level. In this study, we analyse trends of species richness and shifts in species composition of butterflies and burnet moth species across the federal state of Baden-Württemberg in south-western Germany, covering an area of 35,750 km 2 . The data set consists of 233,474 records and covers a period from 1750 until today. We grouped species according to their species´ specific functional traits and analyse how species with different habitat requirements and behaviour respond to land-use changes over time. Our data document a significant loss of relative abundance for most species, especially since the 1950s until today. Species demanding specific habitat requirements are more seriously suffering under this trend than generalists. This in particular affects taxa adapted to extensively used xerothermic grasslands, bogs or other habitats maintained by traditional low-productivity agricultural practices of the past. Our data indicate large-scale decline in relative abundance of many butterfly and burnet moth species, which happened in particular during the past few decades.

Trait-based analyses explaining the different responses of species and communities to environmental changes are increasing in frequency. European butterflies are an indicator group that responds rapidly to environmental changes with extensive citizen science contributions to documenting changes of abundance and distribution. Species traits have been used to explain long- and short-term responses to climate, land-use and vegetation changes. Studies are often characterised by limited trait sets being used, with risks that the relative roles of different traits are not fully explored. Butterfly trait information is dispersed amongst various sources and descriptions sometimes differ between sources. We have therefore drawn together multiple information sets to provide a comprehensive trait database covering 542 taxa and 25 traits described by 217 variables and sub-states of the butterflies of Europe and Maghreb (northwest Africa) which should serve for improved trait-based ecological, conservation-related, phylogeographic and evolutionary studies of this group of insects. We provide this data in two forms; the basic data and as processed continuous and multinomial data, to enhance its potential usage.

With the aim of supporting ecological analyses in butterflies, the third most species-rich superfamily of Lepidoptera, this paper presents the first time-calibrated phylogeny of all 496 extant butterfly species in Europe, including 18 very localised endemics for which no public DNA sequences had been available previously. It is based on a concatenated alignment of the mitochondrial gene COI and up to eleven nuclear gene fragments, using Bayesian inferences of phylogeny. To avoid analytical biases that could result from our region-focussed sampling, our European tree was grafted upon a global genus-level backbone butterfly phylogeny for analyses. In addition to a consensus tree, the posterior distribution of trees and the fully concatenated alignment are provided for future analyses. Altogether a complete phylogenetic framework of European butterflies for use by the ecological and evolutionary communities is presented.

Abstract Purpose: Vanucizumab is an investigational antiangiogenic, first-in-class, bispecific mAb targeting VEGF-A and angiopoietin-2 (Ang-2). This first-in-human study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of vanucizumab in adults with advanced solid tumors refractory to standard therapies. Experimental Design: Patients received escalating biweekly (3–30 mg/kg) or weekly (10–30 mg/kg) intravenous doses guided by a Bayesian logistic regression model with overdose control. Results: Forty-two patients were treated. One dose-limiting toxicity, a fatal pulmonary hemorrhage from a large centrally located mediastinal mass judged possibly related to vanucizumab, occurred with the 19 mg/kg biweekly dose. Arterial hypertension (59.5%), asthenia (42.9%), and headache (31%) were the most common toxicities. Seventeen (41%) patients experienced treatment-related grade ≥3 toxicities. Toxicity was generally higher with weekly than biweekly dosing. A MTD of vanucizumab was not reached in either schedule. Pharmacokinetics were dose-linear with an elimination half-life of 6–9 days. All patients had reduced plasma levels of free VEGF-A and Ang-2; most had reductions in KTRANS (measured by dynamic contrast-enhanced MRI). Two patients (renal cell and colon cancer) treated with 30 mg/kg achieved confirmed partial responses. Ten patients were without disease progression for ≥6 months. A flat-fixed 2,000 mg biweekly dose (phamacokinetically equivalent to 30 mg/kg biweekly) was recommended for further investigation. Conclusions: Biweekly vanucizumab had an acceptable safety and tolerability profile consistent with single-agent use of selective inhibitors of the VEGF-A and Ang/Tie2 pathway. Vanucizumab modulated its angiogenic targets, impacted tumor vascularity, and demonstrated encouraging antitumor activity in this heterogeneous population. Clin Cancer Res; 24(7); 1536–45. ©2017 AACR.

With efficient sequencing techniques, full mitochondrial genomes are rapidly replacing other widely used markers, such as the nuclear rRNA genes, for phylogenetic analysis but their power to resolve deep levels of the tree remains controversial. We studied phylogenetic relationships of leaf beetles (Chrysomelidae) in the tribes Galerucini and Alticini (root worms and flea beetles) based on full mitochondrial genomes (103 newly sequenced), and compared their performance to the widely sequenced nuclear rRNA genes (full 18S, partial 28S). Our results show that: (i) the mitogenome is phylogenetically informative from subtribe to family level, and the per-nucleotide contribution to nodal support is higher than that of rRNA genes, (ii) the Galerucini and Alticini are reciprocally monophyletic sister groups, if the classification is adjusted to accommodate several 'problematic genera' that do not fit the dichotomy of lineages based on the presence (Alticini) or absence (Galerucini) of the jumping apparatus, and (iii) the phylogenetic results suggest a new classification system of Galerucini with eight subtribes: Oidina, Galerucina, Hylaspina, Metacyclina, Luperina, Aulacophorina, Diabroticina and Monoleptina.

Abstract Understanding the dynamics of biodiversity, including the spatial distribution of genetic diversity, is critical for predicting responses to environmental changes, as well as for effective conservation measures. This task requires tracking changes in biodiversity at large spatial scales and correlating with species functional traits. We provide three comprehensive resources to understand the determinants for mitochondrial DNA differentiation represented by (a) 15,609 COI sequences and (b) 14 traits belonging to 307 butterfly species occurring in Western‐Central Europe and (c) the first multi‐locus phylogenetic tree of all European butterfly species. By applying phylogenetic regressions we show that mitochondrial DNA spatial differentiation (as measured with G ST , G ′ ST , D and D ST ) is negatively correlated with species traits determining dispersal capability and colonization ability. Thanks to the high spatial resolution of the COI data, we also provide the first zoogeographic regionalization maps based on intraspecific genetic variation. The overall pattern obtained by averaging the spatial differentiation of all Western‐Central European butterflies shows that the paradigm of long‐term glacial isolation followed by rapid pulses of post‐glacial expansion has been a pervasive phenomenon in European butterflies. The results and the extensive data sets we provide here constitute the basis for genetically‐informed conservation plans for a charismatic group in a continent where flying insects are under alarming decline.

Abstract. To reconstruct the phylogeny of the Sericini and their systematic position among the scarabaeid beetles, cladistic analyses were performed using 107 morphological characters from the adults and larvae of forty‐nine extant scarabaeid genera. Taxa represent most ‘traditional’ subfamilies of coprophagous and phytophagous Scarabaeidae, with emphasis on the Sericini and other melolonthine lineages. Several poorly studied exoskeletal features have been examined, including the elytral base, posterior wing venation, mouth parts, endosternites, coxal articulation, and genitalia. The results of the analysis strongly support the monophyly of the ‘orphnine group’ + ‘melolonthine group’ including phytophagous scarabs such as Dynastinae, Hopliinae, Melolonthinae, Rutelinae, and Cetoniinae. This clade was identified as the sister group to the ‘dung beetle line’ represented by Aphodius + Copris . The ‘melolonthine group’ is comprised in the strict consensus tree by two major clades and two minor lineages, with the included taxa of Euchirinae, Rutelinae, and Dynastinae nested together in one of the major clades (‘melolonthine group I’). Melolonthini, Cetoniinae, and Rutelinae are strongly supported, whereas Melolonthinae and Pachydemini appear to be paraphyletic. Sericini + Ablaberini were identified to be sister taxa nested within the second major melolonthine clade (‘melolonthine group II’). As this clade is distributed primarily in the southern continents, one could assume that Sericini + Ablaberini are derived from a southern lineage. Plausibly, ancestors of Sericini + Ablaberini and Athlia were separated by a vicariance event, such as the separation of the African plate from the rest of Gondwana, whereas Sericini and Ablaberini probably diversified during the early Tertiary, with dispersal of some basal Sericini to South America.

Morocco is a well known hot-spot of biodiversity in the Mediterranean basin. While some taxa like vascular plants are relatively well recorded, important groups of pollinators like bees are still understudied. This article presents an updated checklist of the bee species of Morocco and includes a summary of global and regional distribution of each species. A total of 961 species belonging to six bee families and 68 genera are recorded: Andrenidae (8 genera, 217 species); Apidae (15 genera, 241 species); Colletidae (2 genera, 74 species), Halictidae (12 genera, 144 species), Megachilidae (28 genera, 271 species) and Melittidae (3 genera, 14 species). Among them, 67 species are recorded for the first time in Morocco. Around 70% of the bee fauna of Morocco consists of widespread Palaearctic species. Only 18% of Moroccan species recorded are restricted to North Africa and 8% are Moroccan single-country endemics (81 species). Afrotropical elements in the Moroccan fauna are few, with only 3% of Morocco species co-occuring in that region. This checklist is intended to stimulate new regional research on bees including their taxonomy and biogeography. As many groups of bees have been understudied, discovery of new species for science and new records for the country can be expected. Additional research including inventorying, monitoring, and integrative taxonomic studies are needed to develop a comprehensive strategy for bee conservation in Morocco.

The first records for Brazil of two sciarid species, Bradysia difformisFrey, 1948 [= paupera(Tuomikoski, 1960)] and Bradysia ocellaris(Comstock, 1882) [= tritici(Coquillett, 1895)] (Diptera, Sciaridae) are presented. These are the first records of these species for the Neotropical region. Males and females of both species are fully described and illustrated. Information is given about synonymy and the location of the type material. Bradysia agrestisSasakawa, 1978 is a new synonym of Bradysia difformis. Information about the zoogeographic distribution and habitats, of Bradysia difformis and Bradysia ocellaris is provided.

Immunotoxins (ITs) consisting of a cell-binding component and a potent toxin were developed as a new class of biological anti-tumor agents to improve adjuvant therapy. Hodgkin's lymphoma (HL) has been demonstrated to be an excellent target for ITs because high concentrations of lymphocyte activation markers such as CD25 and CD30 are expressed on Hodgkin and Reed-Sternberg (H-RS). Several ITs against these antigens have shown potent antitumor effects against H-RS cells in vitro and in different HL animal models. On the basis of its superiority in preclinical models, the anti-CD25 IT RFT5-SMPT-dgA was subsequently evaluated in a phase I study in patients with refractory Hodgkin's lymphoma. The IT was constructed by linking the monoclonal antibody (Moab) RFT5 via a sterically hindered disulfide linker (SMPT) to deglycosylated ricin A-chain (dgA). All 15 patients enrolled in this trial were heavily pretreated with a mean of five different prior therapies. The IT was administered intravenously over four hours on days 1-3-5-7 for total doses per cycle of 5, 10, 15, or 20 mg/m2. Side effects were reversible and related to the vascular leak syndrome (VLS), i.e. decrease in serum albumin, edema, weight gain, hypotension, tachycardia, myalgia, and weakness. In all three patients receiving 20 mg/m2 NCI toxicity grade III was observed. Thus, 15 mg/m2 is the maximal tolerated dose (MTD) of RFT5-SMPT-dgA. 50% of the patients developed human anti-ricin A-chain antibodies (HARA) and/or human anti-mouse antibodies (HAMA). Clinical results included two partial remissions (PR), one minor response (MR), three stable disease (SD) and nine progressive disease (PD). In an extension of the phase I trial, five additional patients have been treated at the MTD.