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Ultrasonic guided waves have been used successfully in structural health monitoring systems to detect damage in isotropic and composite materials with simple and complex geometry. A limitation of current research is given by a lack of freely available benchmark measurements to comparatively evaluate existing methods. This article introduces the extendable online platform Open Guided Waves (http://www.open-guided-waves.de) where high-quality and well-documented datasets for guided wave-based inspections are provided. In this article, we describe quasi-isotropic carbon-fiber-reinforced polymer plates with embedded piezoelectric transducers as a first benchmark structure. Intentionally, this is a structure of medium complexity to enable many researchers to apply their methods. In a first step, ultrasound and X-ray measurements were acquired to verify pristine conditions. Next, mechanical testing was done to determine the stiffness tensor and sample density based on standard test procedures. Guided wave measurements were divided into two parts: first, acoustic wave fields were acquired for a broad range of frequencies by three-dimensional scanning laser Doppler vibrometry. Second, structural health monitoring measurements in the carbon-fiber-reinforced polymer plate were collected at constant temperature using a distributed transducer network and a surface-mounted reversible defect model. Initial results serving as validation are presented and discussed.
Carbon-fiber-reinforced plastics are widely used in lightweight marine structures due to their high strength and superior fatigue behavior. In this article, we will present an innovative methodology for simultaneous load and structural monitoring of a carbon-fiber-reinforced plastic rudder stock as part of a big commercial vessel. Experimental results are presented here from a quasi-static tensile test in which the load monitoring is performed using embedded strain sensors. Structural monitoring is based on high-frequency electromechanical impedance spectroscopy combined with dedicated signal processing and surface-mounted piezoelectric transducers. We have achieved the following results: (1) the demonstration of a hybrid monitoring system including load and structural monitoring, (2) successful embedding of strain gauges during composite manufacturing of the carbon-fiber-reinforced plastic rudder stock, (3) development of instrumentation hardware for multichannel electromechanical impedance measurements, and (4) successful damage detection by means of electromechanical impedance spectroscopy in thick carbon-fiber-reinforced plastic rudder stock samples exploiting strain data.
Hemispherical and cylindrical antenna arrays are widely used in radar-based and tomography-based microwave breast imaging systems. Based on the dielectric contrast between healthy and malignant tissue, a three-dimensional image could be formed to locate the tumor. However, conventional X-ray mammography as the golden standard in breast cancer screening produces two-dimensional breast images so that a comparison between the 3D microwave image and the 2D mammogram could be difficult. In this paper, we present the design and realisation of a UWB breast imaging prototype for the frequency band from 1 to 9 GHz. We present a refined system design in light of the clinical usage by means of a planar scanning and compare microwave images with those obtained by X-ray mammography. Microwave transmission measurements were processed to create a two-dimensional image of the breast that can be compared directly with a two-dimensional mammogram. Preliminary results from a patient study are presented and discussed showing the ability of the proposed system to locate the tumor.
Der Beitrag erkundet die besondere Zeitlichkeit der Psychoanalyse ausgehend von Muße und Müßiggang, Konzepten, die in Nietzsches "Fröhlicher Wissenschaft" eine wichtige Rolle spielen, in Freuds Werk, in dem bekanntlich zahlreiche Arbeitsbegriffe dominieren, jedoch kaum vorkommen. Dennoch lässt sich im Briefwechsel zwischen Freud und Arnold Zweig eine wichtige Spur des Müßiggangs für Freuds eigenes Schreiben aufzeigen. Freud spricht in einer signifikanten Passage, in der es um die existenzielle Bedrohung durch den Nationalsozialismus geht, von einem "Überschuss an Muße". Aus dieser Suspension heraus entsteht sein letztes großes Schreibprojekt: "Der Mann Moses". Muße erweist sich zunehmend als ein Begriff, in dem sich eine andere Zeitlichkeit eröffnet, die etwas mit der Arbeit des Unbewussten in der Psychoanalyse zu tun hat. Der Beitrag schließt, indem die Autorin ihre persönliche Erfahrung dieser anderen Zeitlichkeit schildert. Dabei gerät der Warteraum des Psychoanalytikers als Schwellenraum zwischen der alltäglichen Arbeit und der Arbeit in der Psychoanalyse in den Blick.
The access to information on the dynamic behaviour of large proteins is usually hindered as spectroscopic methods require the site-specific attachment of biophysical probes. A powerful emerging tool to tackle this issue is amber codon suppression. Till date, its application on large and complex multidomain proteins of MDa size has not been reported. Herein, we systematically investigate the feasibility to introduce different non-canonical amino acids into a 540 kDa homodimeric fatty acid synthase type I by genetic code expansion with subsequent fluorescent labelling. Our approach relies on a microplate-based reporter assay of low complexity using a GFP fusion protein to quickly screen for sufficient suppression conditions. Once identified, these findings were successfully utilized to upscale both the expression scale and the protein size to full-length constructs. These fluorescently labelled samples of fatty acid synthase were subjected to initial biophysical experiments, including HPLC analysis, activity assays and fluorescence spectroscopy. Successful introduction of such probes into a molecular machine such as fatty acid synthases may pave the way to understand the conformational variability, which is a primary intrinsic property required for efficient interplay of all catalytic functionalities, and to engineer them.
The bile acid activated transcription factor farnesoid X receptor (FXR) regulates numerous metabolic processes and is a rising target for the treatment of hepatic and metabolic disorders. FXR agonists have revealed efficacy in treating non-alcoholic steatohepatitis (NASH), diabetes and dyslipidemia. Here we characterize imatinib as first-in-class allosteric FXR modulator and report the development of an optimized descendant that markedly promotes agonist induced FXR activation in a reporter gene assay and FXR target gene expression in HepG2 cells. Differential effects of imatinib on agonist-induced bile salt export protein and small heterodimer partner expression suggest that allosteric FXR modulation could open a new avenue to gene-selective FXR modulators.
Ausgangspunkt der Studie ist die These, dass sprachlich und kulturell heterogene Lerngruppen, an denen Studierende mit und ohne spanischsprachigen Familienhintergrund gemeinsam teilnehmen, als eine günstige Lernsituation betrachtet werden können. Voraussetzung dafür ist, dass die unterschiedlichen sprachlichen und kulturellen Gegebenheiten als Ressourcen für den Unterricht verstanden werden.
Mit dem Fokus auf Sprachveranstaltungen in Spanisch, die von Studierenden an der Johann Wolfgang Goethe-Universität Frankfurt am Main besucht werden, und die im Rahmen ihres Lehramtsstudiums im Fach Spanisch stattfinden, wurden in dieser Studie folgende Forschungsfragen verfolgt:
1. Wie entstehen und entwickeln sich Sprachlernprozesse in sprachlich und kulturell vielfältigen Lernkontexten?
2. Wie zeichnet sich das Lernen in sprachlich und kulturell vielfältigen Lernkontexten aus?
3. Welche sprachlichen und kulturellen Ressourcen können für die sprachliche und kulturelle Förderung genutzt und bewusst eingesetzt werden?
Wichtigste Forschungsergebnisse:
Es wurde festgestellt, dass Sprachlernprozesse bei Studierenden mit und ohne spanischsprachigen Familienhintergrund sowohl im kognitiven als auch im emotionalen Bereich qualitativ unterschiedlich verlaufen und, dass in sprachlich und kulturell vielfältigen Lernkontexten individuelle und überindividuelle Sprachlern-prozesse stattfinden, die einander bedingen.
Was das gemeinsame Lernen angeht, konnte festgestellt werden, dass Studierende ohne spanischsprachigen Familienhintergrund widersprüchliche Erwartungen an die Studierenden mit spanischsprachigem Familienhintergrund haben: Einerseits schätzen sie die Präsenz ihrer Kommilitonen und sehen sie als Mittler zwischen dem Unterricht und der Realität außerhalb des Unterrichts, weil sie die „echte“ Sprache und Kultur in den Klassenraum bringen. Anderseits fühlen sie sich durch ihre Anwesenheit im Unterricht verunsichert, was ihre sprachliche Entwicklung zum Teil hemmt. Bei den Studierenden mit spanischsprachigem Familienhintergrund konnten unterschiedliche Phasen in ihrem Sprachlernprozess beobachtet werden, die ihre Lernattitüde und ihre Haltung zu den Kommilitoninnen und Kommilitonen konditionieren.
Entscheidend für die Konstruktion gemeinsamer Sprachlernprozessen ist, dass die Studierenden ihre Positionierung als peer ihrer Kommilitoninnen und Kommilitonen bewusst wahrnehmen, was nicht immer der Fall ist. Auch die Bewusstwerdung der eigenen Funktion als Mittler zwischen Sprachen und Kulturen insbesondere (aber nicht nur) bei Studierenden mit spanischsprachigem Familienhintergrund soll im Unterricht durch die Reflexion über die eigene sprachliche und kulturelle Identität gefördert werden.
Im Umgang mit solchen Lerngruppen haben Dozentinnen und Dozenten unterschiedliche Erwartungen. In der Regel werden aber Lerninhalte vermittelt, die die sprachliche und kulturelle Vielfalt im Unterricht nicht berücksichtigen. Für die Leistungsbewertung beider Studierendengruppen werden oft unterschiedliche Kriterien angewendet, woraus Konflikte zwischen den Veranstaltungsteilnehmerinnen und -teilnehmern entstehen.
Die Rolle der Dozentinnen und Dozenten selbst ist in der Gestaltung gemeinsamer Lernkontexte, in denen die Interaktion der Studierenden gefördert werden, grundlegend. Damit dies gelingt, sollen sie einerseits für Mehrsprachigkeit als Phänomen der Gesellschaft, das den Sprachunterricht im besonderen Maße betrifft, sensibilisiert sein. Andererseits soll ihnen bewusst werden, dass das Sprachenlernen aus einer kognitiven und einer emotionalen Seite besteht, die in engem Zusammenhang mit mehrsprachigen und mehrkulturellen Identitätskonstruktionen stehen. Beide Seiten sollen im Unterricht gefördert werden.
Objective: To evaluate the efficacy and tolerability of brivaracetam (BRV) in a severely drug refractory cohort of patients with epileptic encephalopathies (EE).
Method: A multicenter, retrospective cohort study recruiting all patients treated with EE who began treatment with BRV in an enrolling epilepsy center between 2016 and 2017.
Results: Forty-four patients (27 male [61%], mean age 29 years, range 6 to 62) were treated with BRV. The retention rate was 65% at 3 months, 52% at 6 months and 41% at 12 months. A mean retention time of 5 months resulted in a cumulative exposure to BRV of 310 months. Three patients were seizure free during the baseline. At 3 months, 20 (45%, 20/44 as per intention-to-treat analysis considering all patients that started BRV including three who were seizure free during baseline) were either seizure free (n = 4; 9%, three of them already seizure-free at baseline) or reported at least 25% (n = 4; 9%) or 50% (n = 12; 27%) reduction in seizures. An increase in seizure frequency was reported in two (5%) patients, while there was no change in the seizure frequency of the other patients. A 50% long-term responder rate was apparent in 19 patients (43%), with two (5%) free from seizures for more than six months and in nine patients (20%, with one [2 %] free from seizures) for more than 12 months. Treatment-emergent adverse events were predominantly of psychobehavioural nature and were observed in 16%.
Significance: In this retrospective analysis the rate of patients with a 50% seizure reduction under BRV proofed to be similar to those seen in regulatory trials for focal epilepsies. BRV appears to be safe and relatively well tolerated in EE and might be considered in patients with psychobehavioral adverse events while on levetiracetam.
Background: The combination of intermediate-dose cytarabine plus mitoxantrone (IMA) can induce high complete remission rates with acceptable toxicity in elderly patients with acute myeloid leukemia (AML). We present the final results of a randomized-controlled trial comparing IMA with the standard 7 + 3 induction regimen consisting of continuous infusion cytarabine plus daunorubicin (DA).
Patients and methods: Patients with newly diagnosed AML >60 years were randomized to receive either intermediate-dose cytarabine (1000 mg/m2 twice daily on days 1, 3, 5, 7) plus mitoxantrone (10 mg/m2 days 1–3) (IMA) or standard induction therapy with cytarabine (100 mg/m2 continuously days 1–7) plus daunorubicin (45 mg/m2 days 3–5) (DA). Patients in complete remission after DA received intermediate-dose cytarabine plus amsacrine as consolidation treatment, whereas patients after IMA were consolidated with standard-dose cytarabine plus mitoxantrone.
Results: Between February 2005 and October 2009, 485 patients were randomized; 241 for treatment arm DA and 244 for IMA; 76% of patients were >65 years. The complete response rate after DA was 39% [95% confidence interval (95% CI): 33–45] versus 55% (95% CI: 49–61) after IMA (odds ratio 1.89, P = 0.001). The 6-week early-death rate was 14% in both arms. Relapse-free survival curves were superimposable in the first year, but separated afterwards, resulting in 3-year relapse-free survival rates of 29% versus 14% in the DA versus IMA arms, respectively (P = 0.042). The median overall survival was 10 months in both arms (P = 0.513).
Conclusion: The dose escalation of cytarabine in induction therapy lead to improved remission rates in the elderly AML patients. This did not translate into a survival advantage, most likely due to differences in consolidation treatment. Thus, effective consolidation strategies need to be further explored. In combination with an effective consolidation strategy, the use of intermediate-dose cytarabine in induction may improve curative treatment for elderly AML patients.
Dreams and psychosis share several important features regarding symptoms and underlying neurobiology, which is helpful in constructing a testable model of, for example, schizophrenia and delirium. The purpose of the present communication is to discuss two major concepts in dreaming and psychosis that have received much attention in the recent literature: insight and dissociation. Both phenomena are considered functions of higher order consciousness because they involve metacognition in the form of reflective thought and attempted control of negative emotional impact. Insight in dreams is a core criterion for lucid dreams. Lucid dreams are usually accompanied by attempts to control the dream plot and dissociative elements akin to depersonalization and derealization. These concepts are also relevant in psychotic illness. Whereas insightfulness can be considered innocuous in lucid dreaming and even advantageous in psychosis, the concept of dissociation is still unresolved. The present review compares correlates and functions of insight and dissociation in lucid dreaming and psychosis. This is helpful in understanding the two concepts with regard to psychological function as well as neurophysiology.
Chemotherapy and diffuse low-grade gliomas : a survey within the European Low-Grade Glioma Network
(2018)
Background: Diffuse low-grade gliomas (DLGGs) are rare and incurable tumors. Whereas maximal safe, functional-based surgical resection is the first-line treatment, the timing and choice of further treatments (chemotherapy, radiation therapy, or combined treatments) remain controversial.
Methods: An online survey on the management of DLGG patients was sent to 28 expert centers from the European Low-Grade Glioma Network (ELGGN) in May 2015. It contained 40 specific questions addressing the modalities of use of chemotherapy in these patients.
Results: The survey demonstrated a significant heterogeneity in practice regarding the initial management of DLGG patients and the use of chemotherapy. Interestingly, radiation therapy combined with the procarbazine, CCNU (lomustine), and vincristine regimen has not imposed itself as the gold-standard treatment after surgery, despite the results of the Radiation Therapy Oncology Group 9802 study. Temozolomide is largely used as first-line treatment after surgical resection for high-risk DLGG patients, or at progression.
Conclusions: The heterogeneity in the management of patients with DLGG demonstrates that many questions regarding the postoperative strategy and the use of chemotherapy remain unanswered. Our survey reveals a high recruitment potential within the ELGGN for retrospective or prospective studies to generate new data regarding these issues.
Cancer metabolism is characterized by extensive glucose consumption through aerobic glycolysis. No effective therapy exploiting this cancer trait has emerged so far, in part, due to the substantial side effects of the investigated drugs. In this study, we examined the side effects of a combination of isocaloric ketogenic diet (KD) with the glycolysis inhibitor 2-deoxyglucose (2-DG). Two groups of eight athymic nude mice were either fed a standard diet (SD) or a caloric unrestricted KD with a ratio of 4 g fat to 1 g protein/carbohydrate. 2-DG was investigated in commonly employed doses of 0.5 to 4 g/kg and up to 8 g/kg. Ketosis was achieved under KD (ketone bodies: SD 0.5 ± 0.14 mmol/L, KD 1.38 ± 0.28 mmol/L, p < 0.01). The intraperitoneal application of 4 g/kg of 2-DG caused a significant increase in blood glucose, which was not prevented by KD. Sedation after the 2-DG treatment was observed and a behavioral test of spontaneous motion showed that KD reduced the sedation by 2-DG (p < 0.001). A 2-DG dose escalation to 8 g/kg was lethal for 50% of the mice in the SD and for 0% of the mice in the KD group (p < 0.01). A long-term combination of KD and an oral 1 or 2 g 2-DG/kg was well-tolerated. In conclusion, KD reduces the sedative effects of 2-DG and dramatically increases the maximum tolerated dose of 2-DG. A continued combination of KD and anti-glycolytic therapy is feasible. This is, to our knowledge, the first demonstration of increased tolerance to glycolysis inhibition by KD.
Inducible gene expression is an important tool in molecular biology research to study protein function. Most frequently, the antibiotic doxycycline is used for regulation of so-called tetracycline (Tet)-inducible systems. In contrast to stable gene overexpression, these systems allow investigation of acute and reversible effects of cellular protein induction. Recent reports have already called for caution when using Tet-inducible systems as the employed antibiotics can disturb mitochondrial function and alter cellular metabolism by interfering with mitochondrial translation. Reprogramming of energy metabolism has lately been recognized as an important emerging hallmark of cancer and is a central focus of cancer research. Therefore, the scope of this study was to systematically analyze dose-dependent metabolic effects of doxycycline on a panel of glioma cell lines with concomitant monitoring of gene expression from Tet-inducible systems. We report that doxycycline doses commonly used with inducible expression systems (0.01–1 µg/mL) substantially alter cellular metabolism: Mitochondrial protein synthesis was inhibited accompanied by reduced oxygen and increased glucose consumption. Furthermore, doxycycline protected human glioma cells from hypoxia-induced cell death. An impairment of cell growth was only detectable with higher doxycycline doses (10 µg/mL). Our findings describe settings where doxycycline exerts effects on eukaryotic cellular metabolism, limiting the employment of Tet-inducible systems.
Weiträumige Kontaktnetzwerke sorgen für Verbreitung und Transfer von Wissen und Gütern sowie von kulturellen Werten. Der Transport von Lasten und Menschen kann als einer der wichtigsten Eckpfeiler solcher Austauschsysteme gesehen werden. Daher dürften die Suche nach Transportmöglichkeiten und die Entwicklung geeigneter Vehikel in der menschlichen Gedankenwelt seit jeher fest verankert sein. Die hier vorliegenden Beiträge basieren auf den Vorträgen der Tagung „Transporte, Transportwege und Transportstrukturen“ der Arbeitsgemeinschaft Bronzezeit und des Sonderforschungsbereiches 1070 RessourcenKulturen. Sie fassen im archäologischen Befund der Bronzezeit vorhandene Evidenzen zu Transportwegen und -fahrzeugen sowie Aussagen zu Infrastruktur nicht nur zusammen, sondern ergänzen diese um zahlreiche wissenswerte Aspekte. Was können diese Befunde über die Transportvehikel und ihre Bedeutung aussagen? Welche Eigenschaften wiesen diese auf? Handelt es sich bei den Fundstücken um abgenutzte oder mutwillig zerstörte Fahrzeuge bzw. Teile von solchen? Welche Implikationen auf technologischer und sozialer Ebene lassen sich mit den Befunden verbinden? Wie muss man sich die bronzezeitliche Infrastruktur in unterschiedlichen Regionen vorstellen? Inwiefern bildeten Verkehrswege und Austausch eine Ressource? Der detaillierten Beantwortung dieser Fragen ist dieser Band gewidmet, woraus eine übergreifende Zusammenschau von Funden, Befunden und Theorien entstanden ist.
In the 'Golden Age of Antibiotics', between 1940 and 1970, the global pharmaceutical companies discovered many antibiotics, such as cephalosporins, tetracyclines, aminoglycosides, glycopeptides, etc., as well as antifungal and antiparisitic agents. Due to several reasons, e.g. the steady re-discovery of already known NPs and the associated high costs, many pharmaceutical companies have significantly scaled back or totally abandoned their NP discovery programs since the late 20th century. Instead those companies started to focus on drug discovery based on combinatorial synthesis and thereby on the creation of enormous synthetic libraries containing small molecules. Unfortunately, this synthetic approach dealing with the optimization of existing NP or antibiotic has its limitations. As a result, leading pharmaceutical companies are re-conducting NPs research to discover new antimicrobials for the upcoming antimicrobial resistance threat. The Natural Product Center of Excellence, a collaboration between Sanofi-Aventis and Fraunhofer IME, is advancing in this context the discovery and development of novel antimicrobial agents for the treatment of infectious diseases through the testing of Sanofi's microbial extract library and strain collection. The aim of the present PhD thesis was the discovery and isolation of novel antimicrobial compounds with improved activities and/or novel MOAs as potential lead compound for a further drug discovery.
Cardiac trabeculation is one of the essential processes required for the formation of a competent ventricular wall, whereby clusters of ventricular cardiomyocytes (CMs) from a single layer delaminate and expand into the cardiac jelly to form sheet-like projections in the developing heart (Samsa et al., 2013). Several congenital heart diseases are associated with defects in the formation of these trabeculae and lead to embryonic lethality (Jenni et al., 1999; Zhang et al., 2013, Jenni et al., 2001; Towbin 2010). It has been experimentally shown that lack of Nrg1/ErbB2/ErbB4, Angipoetin1/Tie2, EphrinB2/B4, BMP10, or any component of the Notch signaling pathway can cause defective trabeculation. Moreover, changes in blood flow and/or contractility can also affect trabeculation (Samsa et al., 2013). Together, these observations demonstrate that cardiac trabeculation is a highly dynamic and regulated process.
Trabeculation is a morphogenetic process that requires control over cell shape changes and rearrangements, similar to those observed during EMT. Epithelial cells within an epithelium are polarized and establish cell-cell junctions with the neighboring cells (Ikenouchi et al., 2003; Ferrer-vaquer et al., 2010), thus epithelial cell polarity is an important feature to maintain cell shape and tissue structure. During developmental processes such as cell migration and cell division or in disease states epithelial polarity might be disrupted. As a consequence of this alteration, cells lose their tight cell-cell adhesions, undergo cytoskeletal rearrangements, change their shape and gain migratory properties becoming mesenchymal cells (Micalizzi et al., 2010). In epithelial cells, apicobasal polarity is regulated by a conserved set of core complexes, including the PAR, Scribble and Crumbs complexes (Kemphues et al., 1988; Bilder and Perrimon, 2000; Teppas et al., 1984). The polarity proteins composing these complexes interact in a well organized and coordinated-manner creating molecular asymmetry along the apicobasal axis of the cell. In turn, this crosstalk regulates the maturation and stabilization of the junctions between cells and cytoskeleton in order to strengthen cell polarization (Roignot et al., 2013). Amongst the different polarity complex, Crumbs has been shown to be a key regulator of apicobasal polarity during development in both vertebrates and invertebrates (Tepass et al., 1990; Fan et al., 2004).
Here, taking advantage of zebrafish as a model organism, I study in vivo at single cell resolution changes in CM apicobasal polarity during cardiac trabeculation. Moreover, I show which factors regulate CM apicobasal polarity during this process. In addition, I dissect the role of the polarity complex Crumbs in regulating CM junctional rearrangements and the formation of the trabecular network.
Knowledge about the biogeographic affinities of the world’s tropical forests helps to better understand regional differences in forest structure, diversity, composition, and dynamics. Such understanding will enable anticipation of region-specific responses to global environmental change. Modern phylogenies, in combination with broad coverage of species inventory data, now allow for global biogeographic analyses that take species evolutionary distance into account. Here we present a classification of the world’s tropical forests based on their phylogenetic similarity. We identify five principal floristic regions and their floristic relationships: (i) Indo-Pacific, (ii) Subtropical, (iii) African, (iv) American, and (v) Dry forests. Our results do not support the traditional neo- versus paleotropical forest division but instead separate the combined American and African forests from their Indo-Pacific counterparts. We also find indications for the existence of a global dry forest region, with representatives in America, Africa, Madagascar, and India. Additionally, a northern-hemisphere Subtropical forest region was identified with representatives in Asia and America, providing support for a link between Asian and American northern-hemisphere forests.