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We developed three bathochromic, green-light activatable, photolabile protecting groups based on a nitrodibenzofuran (NDBF) core with D-π-A push–pull structures. Variation of donor substituents (D) at the favored ring position enabled us to observe their impact on the photolysis quantum yields. Comparing our new azetidinyl-NDBF (Az-NDBF) photolabile protecting group with our earlier published DMA-NDBF, we obtained insight into its excitation-specific photochemistry. While the “two-photon-only” cage DMA-NDBF was inert against one-photon excitation (1PE) in the visible spectral range, we were able to efficiently release glutamic acid from azetidinyl-NDBF with irradiation at 420 and 530 nm. Thus, a minimal change (a cyclization adding only one carbon atom) resulted in a drastically changed photochemical behavior, which enables photolysis in the green part of the spectrum.
The KASCADE-Grande experiment has significantly contributed to the current knowledge about the energy spectrum and composition of cosmic rays for energies between the knee and the ankle. Meanwhile, post-LHC versions of the hadronic interaction models are available and used to interpret the entire data set of KASCADE-Grande. In addition, a new, combined analysis of both arrays, KASCADE and Grande, was developed significantly increasing the accuracy of the shower observables. First results of the new analysis with the entire data set of the KASCADE-Grande experiment will be the focus of this contribution.
Using CORSIKA for simulating extensive air showers, we study the relation between the shower characteristics and features of hadronic multiparticle production at low energies. We report about investigations of typical energies and phase space regions of secondary particles which are important for muon production in extensive air showers. Possibilities to measure relevant quantities of hadron production in existing and planned accelerator experiments are discussed.
Recent advances in the diagnostic of myeloproliferative neoplasms (MPNs) discovered CALRETICULIN (CALR) mutations as a major driver in these disorders. In contrast to JAK2 mutations being mainly associated with polycythaemia vera, CALR mutations are only associated with primary myelofibrosis (PMF) and essential thrombocythaemia (ET). CALR mutations are present in the majority of PMF and ET patients lacking JAK2 and MPL mutations. As these CALR mutations are absent from reactive bone marrow (BM) lesions their presence indicates ET or PMF. So far these mutations are detectable only by molecular assays. Their molecular detection is cumbersome because of the great CALR mutation heterogeneity. Therefore, the availability of a simple assay would be of great help. All CALR mutations reported lead to a frameshift generating a new 36 amino-acid C-terminus. We generated a monoclonal antibody (CAL2) to this C-neoterminus by immunizing mice with a representative peptide and compared its performance with Sanger sequencing data in 173 MPNs and other BM diseases. There was a 100% correlation between the molecular and the CAL2 immunohistochemical (IHC) assays. Thus, the detection of CALR mutations by the CAL2 IHC is a specific, sensitive, rapid, simple and low-cost method.
Polo-like kinase 1 regulates the stability of the mitotic centromere-associated kinesin in mitosis
(2014)
Proper bi-orientation of chromosomes is critical for the accurate segregation of chromosomes in mitosis. A key regulator of this process is MCAK, the mitotic centromere-associated kinesin. During mitosis the activity and localization of MCAK are regulated by mitotic key kinases including Plk1 and Aurora B. We show here that S621 in the MCAK’s C-terminal domain is the major phosphorylation site for Plk1. This phosphorylation regulates MCAK’s stability and facilitates its recognition by the ubiquitin/proteasome dependent APC/CCdc20 pathway leading to its D-box dependent degradation in mitosis. While phosphorylation of S621 does not directly affect its microtubule depolymerising activity, loss of Plk1 phosphorylation on S621 indirectly enhances its depolymerization activity in vivo by stabilizing MCAK, leading to an increased level of protein. Interfering with phosphorylation at S621 causes spindle formation defects and chromosome misalignments. Therefore, this study suggests a new mechanism by which Plk1 regulates MCAK: by regulating its degradation and hence controlling its turnover in mitosis.
RITA, the RBP‐J interacting and tubulin‐associated protein, has been reported to be related to tumor development, but the underlying mechanisms are not understood. Since RITA interacts with tubulin and coats microtubules of the cytoskeleton, we hypothesized that it is involved in cell motility. We show here that depletion of RITA reduces cell migration and invasion of diverse cancer cell lines and mouse embryonic fibroblasts. Cells depleted of RITA display stable focal adhesions (FA) with elevated active integrin, phosphorylated focal adhesion kinase, and paxillin. This is accompanied by enlarged size and disturbed turnover of FA. These cells also demonstrate increased polymerized tubulin. Interestingly, RITA is precipitated with the lipoma‐preferred partner (LPP), which is critical in actin cytoskeleton remodeling and cell migration. Suppression of RITA results in reduced LPP and α‐actinin at FA leading to compromised focal adhesion turnover and actin dynamics. This study identifies RITA as a novel crucial player in cell migration and invasion by affecting the turnover of FA through its interference with the dynamics of actin filaments and microtubules. Its deregulation may contribute to malignant progression.
Adipose-derived mesenchymal stem cells (ASCs) are considered to be a useful tool for regenerative medicine, owing to their capabilities in differentiation, self-renewal, and immunomodulation. These cells have become a focus in the clinical setting due to their abundance and easy isolation. However, ASCs from different depots are not well characterized. Here, we analyzed the functional similarities and differences of subcutaneous and visceral ASCs. Subcutaneous ASCs have an extraordinarily directed mode of motility and a highly dynamic focal adhesion turnover, even though they share similar surface markers, whereas visceral ASCs move in an undirected random pattern with more stable focal adhesions. Visceral ASCs have a higher potential to differentiate into adipogenic and osteogenic cells when compared to subcutaneous ASCs. In line with these observations, visceral ASCs demonstrate a more active sonic hedgehog pathway that is linked to a high expression of cilia/differentiation related genes. Moreover, visceral ASCs secrete higher levels of inflammatory cytokines interleukin-6, interleukin-8, and tumor necrosis factor α relative to subcutaneous ASCs. These findings highlight, that both ASC subpopulations share multiple cellular features, but significantly differ in their functions. The functional diversity of ASCs depends on their origin, cellular context and surrounding microenvironment within adipose tissues. The data provide important insight into the biology of ASCs, which might be useful in choosing the adequate ASC subpopulation for regenerative therapies.
Function of p21 (Cip1/Waf1/CDKN1A) in migration and invasion of cancer and trophoblastic cells
(2019)
Tumor progression and pregnancy have several features in common. Tumor cells and placental trophoblasts share many signaling pathways involved in migration and invasion. Preeclampsia, associated with impaired differentiation and migration of trophoblastic cells, is an unpredictable and unpreventable disease leading to maternal and perinatal mortality and morbidity. Like in tumor cells, most pathways, in which p21 is involved, are deregulated in trophoblasts of preeclamptic placentas. The aim of the present study was to enlighten p21’s role in tumorigenic choriocarcinoma and trophoblastic cell lines. We show that knockdown of p21 induces defects in chromosome movement during mitosis, though hardly affecting proliferation and cell cycle distribution. Moreover, suppression of p21 compromises the migration and invasion capability of various trophoblastic and cancer cell lines mediated by, at least partially, a reduction of the extracellular signal-regulated kinase 3, identified using transcriptome-wide profiling, real-time PCR, and Western blot. Further analyses show that downregulation of p21 is associated with reduced matrix metalloproteinase 2 and tissue inhibitor of metalloproteinases 2. This work evinces that p21 is involved in chromosome movement during mitosis as well as in the motility and invasion capacity of trophoblastic and cancer cell lines.
Adipose-derived mesenchymal stem cells (ASCs) have crucial functions, but their roles in obesity are not well defined. We show here that ASCs from obese individuals have defective primary cilia, which are shortened and unable to properly respond to stimuli. Impaired cilia compromise ASC functionalities. Exposure to obesity-related hypoxia and cytokines shortens cilia of lean ASCs. Like obese ASCs, lean ASCs treated with interleukin-6 are deficient in the Hedgehog pathway, and their differentiation capability is associated with increased ciliary disassembly genes like AURKA. Interestingly, inhibition of Aurora A or its downstream target the histone deacetylase 6 rescues the cilium length and function of obese ASCs. This work highlights a mechanism whereby defective cilia render ASCs dysfunctional, resulting in diseased adipose tissue. Impaired cilia in ASCs may be a key event in the pathogenesis of obesity, and its correction might provide an alternative strategy for combating obesity and its associated diseases.
Die vorliegende Arbeit befasst sich mit der Entwicklung einer spektroskopischen Methode für die medizinische Diagnostik und zielt auf die Einführung neuer analytischer Methoden in die klinische Praxis, die eine höhere Qualität bei der Behandlung von Patienten sowie eine Kostensenkung versprechen. Es wird eine reagenzienfreie infrarotspektroskopische Messmethode vorgestellt, mit der die Konzentrationen bestimmter Inhaltsstoffe von Körper- und anderen Flüssigkeiten quantitativ bestimmt werden können. Dabei kommt das kommerzielle FTIR- (Fourier-Transform Infrarot-) Spektrometer ALPHA der Firma Bruker zum Einsatz, für das eine spezielle ATR- (Abgeschwächte Totalreflexion) Messzelle konstruiert wurde. Diese eignet sich sowohl für Durchflussmessungen bei Volumenströmen von bis zu 1 l/min als auch für diskrete Proben mit einem minimalen Volumen von 10 µl. Die Kombination aus Spektrometer und Messzelle stellt somit ein kompaktes Messgerät dar, das zur Steuerung und Auswertung lediglich einen Computer benötigt und dessen Stabilität ebenfalls Langzeitmessungen erlaubt. Es stellt damit eine Basis für ein neuartiges Medizingerät dar, das auch außerhalb der Laborumgebung und insbesondere in der klinischen Routine von ungeschultem Personal eingesetzt werden kann.
Die quantitative Auswertung der Spektren erfolgt mittels multivariater Kalibrierung und PLS (Partial Least Squares) Regression. Dabei werden für die unterschiedlichen Inhaltsstoffe entsprechende Kalibriermodelle verwendet, die aus einer Reihe sorgfältig ausgewählter Proben erstellt wurden. Die Auswahl bezieht sich dabei vor allem auf einen breiten Konzentrationsbereich und auf möglichst unabhängig voneinander schwankende Konzentrationswerte der Inhaltsstoffe. Es wurden daher sowohl Proben im physiologischen als auch im pathologischen Bereich verwendet. Da die Konzentrationswerte der Kalibrierproben bekannt sein müssen, wurden die Proben mittels konventioneller klinischer Methoden analysiert. Die Genauigkeit dieser Referenzanalytik begrenzt dabei die maximale Genauigkeit der vorgestellten Methode.
Im Rahmen dieser Arbeit wurden Kalibriermodelle für die Inhaltsstoffe Glucose, Harnstoff, Creatinin und Lactat in der Waschlösung bei der Hämodialyse (Dialysat) sowie für die Inhaltsstoffe Glucose, Harnstoff, Cholesterol, Triacylglyceride, Albumin und Gesamtprotein in Vollblut und ebenso für Hämoglobin und Immunglobulin G in hämolysiertem Vollblut erstellt. Im Fall von Dialysat wurden hierfür sowohl künstlich erstellte sowie auch bei realen Dialysebehandlungen von Patienten entnommene Proben verwendet. Für Vollblut wurden bestehende Spektren an das neue Messgerät angepasst und durch Spektren neuer Blutproben erweitert. Die hiermit erreichte Genauigkeit und Präzision genügt in den meisten Fällen bereits klinischen Ansprüchen.
Für Dialysat wird gezeigt, dass mit dem vorgestellten Aufbau bereits kontinuierliche inline-Messungen direkt am Patienten möglich sind und gute Ergebnisse liefern. Dabei wurde sowohl auf eine einfache Anwendbarkeit während der Dialysebehandlung als auch auf eine einfache Bedienung mittels der vorgestellten Software geachtet. Das Gerät lässt sich somit problemlos in den klinischen Alltag integrieren und bietet aufgrund der Reagenzienfreiheit eine kostengünstige Methode zur kontinuierlichen und regelmäßigen Überwachung der Behandlungsverläufe.
Im Fall von Vollblut wird gezeigt, dass Messungen mit einer Probenmenge von 10 µl beispielsweise aus der Fingerbeere prinzipiell möglich sind und ebenfalls reproduzierbare Ergebnisse liefern. Damit steht eine präzise, einfache, kompakte und betriebskostengünstige Methode zur Verfügung, um in kurzer Zeit wichtige Blutparameter quantitativ bestimmen zu können.
Das kompakte und reagenzienfreie Messsystem erlaubt eine Vielzahl von Anwendungen, die insbesondere von den schnellen Analyseergebnissen und den geringen Verbrauchskosten profitieren. Beispielsweise beim Blutspendedienst, beim Hausarzt oder in Seniorenheimen kann die schnelle und einfache Ermittlung der hier untersuchten Blutparameter zur ersten Beurteilung des Patienten dienen und damit die Diagnose erleichtern. Der hohe Probendurchsatz und die vernachlässigbaren Betriebskosten führen in diesem Fall zu einer schnellen Amortisierung der Anschaffungskosten. Auch in Apotheken kann mit einem derartigen System ein erweiterter Service für Kunden angeboten werden.
Aufgrund des geringen Probenvolumens kommt das Messsystem ebenfalls für Anwendungen im Versuchstierbereich in Frage, beispielsweise für die Untersuchung von Mäuseblut in der German Mouse Clinic am Helmholtz Zentrum München. Die der Maus zu entnehmende Blutmenge und damit die Belastung des Tieres kann hierdurch erheblich reduziert werden.
Die Kompaktheit dieses universellen Systems erlaubt es weiterhin, eine Vielzahl anderer Flüssigkeiten zu untersuchen, die bereits erfolgreich infrarotspektroskopisch analysiert wurden. Dazu gehört unter anderem Urin, Bier und Wein.
In der Arbeit wird abschließend ebenfalls gezeigt, dass der Einsatz abstimmbarer Quantenkaskadenlaser zusammen mit der ATR-Technik prinzipiell die Möglichkeit eröffnet, die aufwändigen und teuren FTIR-Spektrometer zu ersetzen. Langfristig ist sowohl mit einer Verkleinerung des Aufbaus als auch mit einem Sinken des derzeit noch sehr hohen Anschaffungspreises zu rechnen. Der bereits verfügbare Abstimmbereich genügt zur Bestimmung der Glucosekonzentration. Eine Erweiterung, beispielsweise durch die Verwendung mehrerer Quantenkaskadenlaser mit unterschiedlichem Abstimmbereich, ermöglicht die Untersuchung weiterer Parameter.
The microtubule (MT) cytoskeleton is crucial for cell motility and migration by regulating multiple cellular activities such as transport and endocytosis of key components of focal adhesions (FA). The kinesin-13 family is important in the regulation of MT dynamics and the best characterized member of this family is the mitotic centromere-associated kinesin (MCAK/KIF2C). Interestingly, its overexpression has been reported to be related to increased metastasis in various tumor entities. Moreover, MCAK is involved in the migration and invasion behavior of various cell types. However, the precise molecular mechanisms were not completely clarified. To address these issues, we generated CRISPR/dCas9 HeLa and retinal pigment epithelium (RPE) cell lines overexpressing or downregulating MCAK. Both up- or downregulation of MCAK led to reduced cell motility and poor migration in malignant as well as benign cells. Specifically, it’s up- or downregulation impaired FA protein composition and phosphorylation status, interfered with a proper spindle and chromosome segregation, disturbed the assembly and disassembly rate of FA, delayed cell adhesion, and compromised the plus-tip dynamics of MTs. In conclusion, our data suggest MCAK act as an important regulator for cell motility and migration by affecting the actin-MT cytoskeleton dynamics and the FA turnover, providing molecular mechanisms by which deregulated MCAK could promote malignant progression and metastasis of tumor cells.
Background: Lipedema is a chronic disorder of the adipose tissue that affects mainly women, characterised by symmetrical, excessive fatty tissue on the legs and pain. Standard conservative treatment is long-term comprehensive decongestive therapy (CDT) to alleviate lipedema-related pain and to improve psychosocial well-being, mobility and physical activity. Patients may benefit from surgical removal of abnormally propagated adipose tissue by liposuction. The LIPLEG trial evaluates the efficacy and safety of liposuction compared to standard CDT.
Methods/design: LIPLEG is a randomised controlled multicentre investigator-blinded trial. Women with lipedema (n=405) without previous liposuction will be allocated 2:1 to liposuction or CDT. The primary outcome of the trial is leg pain reduction by ≥2 points on a visual analogue scale ranging 0–10 at 12 months on CDT or post-completion of liposuction. Secondary outcomes include changes in leg pain severity, health-related quality of life, depression tendency, haematoma tendency, prevalence of oedema, modification physical therapy scope, body fat percentage, leg circumference and movement restriction.
The primary analysis bases on intention-to-treat. Success proportions are compared using the Mantel-Haenszel test stratified by lipedema stage at a 5% two-sided significance level. If this test is statistically significant, the equality of the response proportions in the separate strata is evaluated by Fisher’s exact test in a hierarchical test strategy.
Discussion: LIPLEG assesses whether surgical treatment of lipedema is safe and effective to reduce pain and other lipedema-related health issues. The findings of this trial have the potential to change the standard of care in lipedema.
Trial registration: ClinicalTrials.gov NCT04272827. Registered on February 14, 2020.
Trial status: Protocol version is 02_0, December 17, 2019
Background: The development of the human placenta is tightly coordinated by a multitude of placental cell types, including human chorionic villi mesenchymal stromal cells (hCV-MSCs). Defective hCV-MSCs have been reported in preeclampsia (PE), a gestational hypertensive disease characterized by maternal endothelial dysfunction and systemic inflammation. Our goal was to determine whether hCV-MSCs are ciliated and whether altered ciliation is responsible for defective hCV-MSCs in preeclamptic placentas, as the primary cilium is a hub for signal transduction, which is important for various cellular activities.
Methods: In the present work, we collected placental tissues from different gestational stages and we isolated hCV-MSCs from 1st trimester, term control, and preeclamptic placentas. We studied their ciliation, functionality, and impact on trophoblastic cell lines and organoids formed from human trophoblast stem cells (hTSCs) and from the trophoblastic cell line JEG-3 with various cellular and molecular methods, including immunofluorescence staining, gene analysis, spheroid/organoid formation, motility, and cellular network formation assay. The statistical evaluation was performed using a Student’s t test (two-tailed and paired or homoscedastic) or an unpaired Mann–Whitney U test (two-tailed).
Results: The results show that primary cilia appeared abundantly in normal hCV-MSCs, especially in the early development of the placenta. Compared to control hCV-MSCs, the primary cilia were truncated, and there were fewer ciliated hCV-MSCs derived from preeclamptic placentas with impaired hedgehog signaling. Primary cilia are necessary for hCV-MSCs’ proper signal transduction, motility, homing, and differentiation, which are impaired in preeclamptic hCV-MSCs. Moreover, hCV-MSCs derived from preeclamptic placentas are significantly less capable of promoting growth and differentiation of placental organoids, as well as cellular network formation.
Conclusions: These data suggest that the primary cilium is required for the functionality of hCV-MSCs and primary cilia are impaired in hCV-MSCs from preeclamptic placentas.
Human placentation is a highly invasive process. Deficiency in the invasiveness of trophoblasts is associated with a spectrum of gestational diseases, such as preeclampsia (PE). The oncogene B-cell lymphoma 6 (BCL6) is involved in the migration and invasion of various malignant cells. Intriguingly, its expression is deregulated in preeclamptic placentas. We have reported that BCL6 is required for the proliferation, survival, fusion, and syncytialization of trophoblasts. In the present work, we show that the inhibition of BCL6, either by its gene silencing or by using specific small molecule inhibitors, impairs the migration and invasion of trophoblastic cells, by reducing cell adhesion and compromising the dynamics of the actin cytoskeleton. Moreover, the suppression of BCL6 weakens the signals of the phosphorylated focal adhesion kinase, Akt/protein kinase B, and extracellular regulated kinase 1/2, accompanied by more stationary, but less migratory, cells. Interestingly, transcriptomic analyses reveal that a small interfering RNA-induced reduction of BCL6 decreases the levels of numerous genes, such as p21 activated kinase 1, myosin light chain kinase, and gamma actin related to cell adhesion, actin dynamics, and cell migration. These data suggest BCL6 as a crucial player in the migration and invasion of trophoblasts in the early stages of placental development through the regulation of various genes associated with the migratory machinery.
Preeclampsia (PE) remains a leading cause of maternal and perinatal mortality and morbidity worldwide. Its pathogenesis has not been fully elucidated and no causal therapy is currently available. It is of clinical relevance to decipher novel molecular biomarkers. RITA (RBP-J (recombination signal binding protein J)-interacting and tubulin-associated protein) has been identified as a negative modulator of the Notch pathway and as a microtubule-associated protein important for cell migration and invasion. In the present work, we have systematically studied RITA’s expression in primary placental tissues from patients with early- and late-onset PE as well as in various trophoblastic cell lines. RITA is expressed in primary placental tissues throughout gestation, especially in proliferative villous cytotrophoblasts, in the terminally differentiated syncytiotrophoblast, and in migrating extravillous trophoblasts. RITA’s messenger RNA (mRNA) level is decreased in primary tissue samples from early-onset PE patients. The deficiency of RITA impairs the motility and invasion capacity of trophoblastic cell lines, and compromises the fusion ability of trophoblast-derived choriocarcinoma cells. These data suggest that RITA may play important roles in the development of the placenta and possibly in the pathogenesis of PE.
This study provides a graphic overview on core legislation in the area of economic and financial services. The presentation essentially covers the areas within the responsibility of the Economic and Monetary Affairs Committee (ECON); hence it starts with core ECON areas but also displays neighbouring areas of other Committees' competences which are closely connected to and impacting on ECON's work. It shows legislation in force, proposals and other relevant provisions on banking, securities markets and investment firms, market infrastructure, insurance and occupational pensions, payment services, consumer protection in financial services, the European System of Financial Supervision, European Monetary Union, euro bills and coins and statistics, competition, taxation, commerce and company law, accounting and auditing. Moreover, it notes selected provisions that might become relevant in the upcoming Article 50 TEU negotiations.
Introduction: Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin's lymphoma in a real-life clinical setting.
Methods: Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators.
Results: A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician's visual analogue scale; mean improvement from baseline of 12.1 mm).
Conclusions: Data from this registry indicate that rituximab is a commonly employed, well-tolerated therapy with potential beneficial effects in standard of care-refractory autoimmune diseases, and support the results from other open-label, uncontrolled studies.
Infrared spectroscopy in combination with a specially developed attenuated total reflection (ATR) flow cell and multivariate analysis was used for the quantitative analysis of beer and other beverages. IR spectra of samples were obtained in the range from below 1000 cm-1 to 4000 cm-1 and subjected to a multivariate analysis based on calibration sets with laboratory reference standards. In the case of beer, this calibration set included 240 beer samples spanning the entire range of ethanol content, extract and CO2. Based on this calibration, an infrared and UV/Vis spectroscopy-based sensor for the quick and quantitative quality control of beer was developed and subjected to extensive tests in breweries. This sensor meets and exceeds all requirements from brewers for the routine control in the production and bottling. Its use for other beverages, for example wine, juices or apple wine, requires only another set of calibration data for the specific beverage.
Attention-Deficit/Hyperactivity Disorder (ADHD) is frequently comorbid with other psychiatric disorders and also with somatic conditions, such as obesity. In addition to the clinical overlap, significant genetic correlations have been found between ADHD and obesity as well as body mass index (BMI). The biological mechanisms driving this association are largely unknown, but some candidate systems, like dopaminergic neurotransmission and circadian rhythm, have been suggested. Our aim was to identify the biological mechanisms underpinning the link between ADHD and obesity measures. Using the largest GWAS summary statistics currently available for ADHD (N=53,293), BMI (N=681,275), and obesity (N=98,697), we first tested the association of dopaminergic and circadian rhythm gene sets with each phenotype. This hypothesis-driven approach showed that the dopaminergic gene set was associated with both ADHD (P=5.81×10−3) and BMI (P=1.63×10−5), while the circadian rhythm gene set was associated with BMI only (P=1.28×10−3). We then took a data-driven approach by conducting genome-wide ADHD-BMI and ADHD-obesity gene-based meta-analyses, followed by pathway enrichment analyses. This approach further supported the implication of dopaminergic signaling in the link between ADHD and obesity measures, as the Dopamine-DARPP32 Feedback in cAMP Signaling pathway was significantly enriched in both the ADHD-BMI and ADHD-obesity gene-based meta-analysis results. Our findings suggest that dopaminergic neurotransmission, partially through DARPP-32-dependent signaling, is a key player underlying the genetic overlap between ADHD and obesity measures. Uncovering the shared etiological factors underlying the frequently observed ADHD-obesity comorbidity may have important implications in terms of preventive interventions and/or efficient treatment of these conditions.