Goethe-Universität Frankfurt am Main
  • Frankfurt am Main, Germany
Recent publications
Temperature-dependent alternative splicing was recently demonstrated for intron 2 of the gene coding for heat shock factor HsfA2 of the tomato plant Solanum lycopersicum, but the molecular mechanism regulating the abundance of such temperature-dependent splice variants is still unknown. We report here on regulatory pre-mRNA structures that could function as regulators by controlling the use of splice sites in a temperature-dependent manner. We investigate pre-mRNA structures at the splice sites of intron 2 of the gene coding for HsfA2 from S. lycopersicum using NMR- and CD-spectroscopy as well as in-line probing. The pre-mRNA undergoes conformational changes between two different secondary structures at the 3' splice site of the intron in a temperature-dependent manner. Previously, it was shown that three single nucleotide polymorphisms (SNPs) in intron 2 of the HsfA2 pre-mRNA affect the splicing efficiency of its pre-mRNA and are linked to the thermotolerance in different tomato species. By comparing pre-mRNA fragments of the tomato species S. lycopersicum and S. peruvianum, we show that these SNPs result in substantial structural differences between the pre-mRNAs of the two species.
Background: The assessment of therapeutic adherence and competence is essential to understand mechanisms that contribute to treatment outcome. Nevertheless, their assessment is often neglected in psychotherapy research. Aims/objective: To develop an adherence and a treatment-specific competence rating scale for Dialectical Behaviour Therapy for Posttraumatic Stress Disorder (DBT-PTSD), and to examine their psychometric properties. Global cognitive behavioural therapeutic competence and disorder-specific therapeutic competence were assessed using already existing scales to confirm their psychometric properties in our sample of patients with PTSD and emotion regulation difficulties. Method: Two rating scales were developed using an inductive procedure. 155 videotaped therapy sessions from a multicenter randomised controlled trial were rated by trained raters using these scales, 40 randomly chosen videotapes involving eleven therapists and fourteen patients were doubly rated by two raters. Results: Both the adherence scale (Patient-level ICC = .98; αs = .65; α p = .75) and the treatment-specific competence scale (Patient-level ICC = .98; αs = .78; α p = .82) for DBT-PTSD showed excellent interrater - and good reliability on the patient level. Content validity, including relevance and appropriateness of all items, was confirmed by experts in DBT-PTSD for the new treatment-specific competence scale. Conclusion: Our results indicate that both scales are reliable instruments. They will be useful to examine possible effects of adherence and treatment-specific competence on DBT-PTSD treatment outcome.
We launched a multinational study to examine changes in substance use during the early phase of the pandemic and to identify factors related to these changes, with a specific focus on the effect of polysubstance use in increasing nicotine, alcohol, and cannabis use. This study was conducted using an online survey in English and seven other languages. The survey included measures focusing on substance use, psychological symptoms, stress, and other health and psychosocial measures. A total sample of 2907 participants was included. The results showed that higher levels of perceived social isolation, depression, and anxiety during the pandemic were associated with increases in nicotine use. Increased alcohol use was associated with feelings of uncertainty and increased depression and anxiety symptoms. Polysubstance use was associated with increases in use of cannabis and alcohol during the pandemic; co-use of cannabis and alcohol increased chances for escalating alcohol use; and increases in cannabis use were influenced by the number rather than the types of substances being used. These results demonstrate a link between COVID-19 related psychological distress and increased substance use during the first wave of the pandemic. They also point-out the contribution of pre-COVID polysubstance use in increases in substance use during COVID-19. © 2022 The Author(s). This open access article is distributed under a Creative Commons Attribution (CC-BY) 4.0 license.
Background: There is no therapeutic competence and adherence scale for grief-focused cognitive behavioural therapy (grief-focused CBT). However, given the growing body of evidence for the efficacy of grief-focused CBT, such a scale is needed both to ensure the internal validity of clinical trials and to facilitate psychotherapy process research. Objective: To develop and undertake a psychometric evaluation of a therapeutic adherence and competence scale for grief-focused CBT. Method: The scale was developed in two steps. (I) Five experts on the treatment of prolonged grief disorder provided feedback on the relevance and appropriateness of the items. The scale was revised to reflect their feedback. The final therapeutic adherence and competence scale for grief (TACs-G) consisted of 15 adherence and 16 competence items. (II) Psychometric evaluation of the TACs-G was based on the rating of 48 randomly selected PG-CBT sessions by two independent raters. The videos were recorded in the context of a randomized controlled trial (RCT; DRKS00012317.) ICC was used to calculate inter-rater reliability and TACs-G stability over time (re-evaluation of 10 sessions after 12 months). Results: The five experts confirmed the relevance and appropriateness of the items. Interrater reliability was found to be high for the total adherence and competence scores (ICC = 0.889 and 0.782, respectively) and moderate to excellent for individual items (ICC = 0.509-1.00). The TACs-G stability over time was found to be strong for both adherence (ICC = 0.970) and competence total scores (ICC = 0.965). Conclusions: The TACs-G for CBT is a reliable instrument that can be used not only to ensure internal validity but is also suited for psychotherapy process studies. Additionally, it provides a valuable database for targeted feedback in training settings. Highlights: This is the first study to report on the development and psychometrical evaluation of a grief-focused adherence and competence scale.Although an increasing number of clinical trials do report the efficacy of grief-focused cognitive-behavioural therapy, none of these studies used a standardized adherence and competence scale to control internal validity.In the present study, we introduced a therapeutic adherence and competence scale for grief (TACs-G) that can be applied efficiently across different research settings (e.g. manipulation check, dissemination), and report results of good to excellent psychometric properties.The scale itself could prove useful beyond the research setting as it could possibly serve as a basis for feedback in training settings.
Background Although prior reports have evaluated the clinical and cost impacts of cardiovascular magnetic resonance (CMR) for low-to-intermediate-risk patients with suspected significant coronary artery disease (CAD), the cost-effectiveness of CMR compared to relevant comparators remains poorly understood. We aimed to summarize the cost-effectiveness literature on CMR for CAD and create a cost-effectiveness calculator, useable worldwide, to approximate the cost-per-quality-adjusted-life-year (QALY) of CMR and relevant comparators with context-specific patient-level and system-level inputs. Methods We searched the Tufts Cost-Effectiveness Analysis Registry and PubMed for cost-per-QALY or cost-per-life-year-saved studies of CMR to detect significant CAD. We also developed a linear regression meta-model (CMR Cost-Effectiveness Calculator) based on a larger CMR cost-effectiveness simulation model that can approximate CMR lifetime discount cost, QALY, and cost effectiveness compared to relevant comparators [such as single-photon emission computed tomography (SPECT), coronary computed tomography angiography (CCTA)] or invasive coronary angiography. Results CMR was cost-effective for evaluation of significant CAD (either health-improving and cost saving or having a cost-per-QALY or cost-per-life-year result lower than the cost-effectiveness threshold) versus its relevant comparator in 10 out of 15 studies, with 3 studies reporting uncertain cost effectiveness, and 2 studies showing CCTA was optimal. Our cost-effectiveness calculator showed that CCTA was not cost-effective in the US compared to CMR when the most recent publications on imaging performance were included in the model. Conclusions Based on current world-wide evidence in the literature, CMR usually represents a cost-effective option compared to relevant comparators to assess for significant CAD.
Background Hereditary angioedema (HAE) is characterized by potentially severe and life-threatening attacks of localized swelling. Prophylactic therapies are available, including attenuated androgens. Efficacy of attenuated androgens has not been assessed in large, randomized, placebo-controlled trials and can be associated with frequent, and sometimes severe, side effects. As better tolerated targeted therapies become available, attenuated androgen withdrawal is increasingly considered by physicians and their patients with HAE. Attenuated androgens withdrawal has not been systematically studied in HAE, although examination of other disorders indicates that attenuated androgen withdrawal may result in mood disturbances and flu-like symptoms. Standardized protocols for attenuated androgen discontinuation that continue to provide control of attacks while limiting potential attenuated androgen withdrawal symptoms are not established as the outcomes of different withdrawal strategies have not been compared. We aim to describe the challenges of attenuated androgen discontinuation in patients with HAE and how these may continue into the post-androgen period. Case presentation We present a retrospective case series of 10 patients with confirmed type I HAE who have discontinued prophylactic treatment with attenuated androgens. The most common reason for attenuated androgen discontinuation was side effects. Attenuated androgens were either immediately withdrawn, tapered and/or overlapped with another treatment. The major challenge of discontinuation was the management of an increased frequency and severity of HAE attacks in some patients. Conclusions Healthcare teams need to undertake careful planning and monitoring after attenuated androgens discontinuation, and modify treatment strategies if HAE control is destabilized with an increased number of attacks. Discontinuation of attenuated androgens is definitively an option in an evolving HAE treatment landscape, and outcomes can be favourable with additional patient support and education.
We investigate the magnetism of a previously unexplored distorted spin-1/2 kagome model consisting of three symmetry-inequivalent nearest-neighbor antiferromagnetic Heisenberg couplings J ⬡ , J , and $$J^{\prime}$$ J ′ , and uncover a rich ground state phase diagram even at the classical level. Using analytical arguments and numerical techniques we identify a collinear $$\overrightarrow{Q}=0$$ Q → = 0 magnetic phase, two unusual non-collinear coplanar $$\overrightarrow{Q}=(1/3,1/3)$$ Q → = ( 1 / 3 , 1 / 3 ) phases and a classical spin liquid phase with a degenerate manifold of non-coplanar ground states, resembling the jammed spin liquid phase found in the context of a bond-disordered kagome antiferromagnet. We further show with density functional theory calculations that the recently synthesized Y-kapellasite Y 3 Cu 9 (OH) 19 Cl 8 is a realization of this model and predict its ground state to lie in the region of $$\overrightarrow{Q}=(1/3,1/3)$$ Q → = ( 1 / 3 , 1 / 3 ) order, which remains stable even after the inclusion of quantum fluctuation effects within variational Monte Carlo and pseudofermion functional renormalization group. The presented model opens a new direction in the study of kagome antiferromagnets.
Murine acetaminophen-induced acute liver injury (ALI) serves as paradigmatic model for drug-induced hepatic injury and regeneration. As major cause of ALI, acetaminophen overdosing is a persistent therapeutic challenge with N-acetylcysteine clinically used to ameliorate parenchymal necrosis. To identify further treatment strategies that serve patients with poor N-acetylcysteine responses, hepatic 3′mRNA sequencing was performed in the initial resolution phase at 24 h/48 h after sublethal overdosing. This approach disclosed 45 genes upregulated (≥5-fold) within this time frame. Focusing on C5aR1, we observed in C5aR1-deficient mice disease aggravation during resolution of intoxication as evidenced by increased liver necrosis and serum alanine aminotransferase. Moreover, decreased hepatocyte compensatory proliferation and increased caspase-3 activation at the surroundings of necrotic cores were detectable in C5aR1-deficient mice. Using a non-hypothesis-driven approach, herein pro-regenerative/-resolving effects of C5aR1 were identified during late acetaminophen-induced ALI. Data concur with protection by the C5a/C5aR1-axis during hepatectomy and emphasize the complex role of inflammation during hepatic regeneration and repair.
The chemical pollution crisis severely threatens human and environmental health globally. To tackle this challenge the establishment of an overarching international science–policy body has recently been suggested. We strongly support this initiative based on the awareness that humanity has already likely left the safe operating space within planetary boundaries for novel entities including chemical pollution. Immediate action is essential and needs to be informed by sound scientific knowledge and data compiled and critically evaluated by an overarching science–policy interface body. Major challenges for such a body are (i) to foster global knowledge production on exposure, impacts and governance going beyond data-rich regions (e.g., Europe and North America), (ii) to cover the entirety of hazardous chemicals, mixtures and wastes, (iii) to follow a one-health perspective considering the risks posed by chemicals and waste on ecosystem and human health, and (iv) to strive for solution-oriented assessments based on systems thinking. Based on multiple evidence on urgent action on a global scale, we call scientists and practitioners to mobilize their scientific networks and to intensify science–policy interaction with national governments to support the negotiations on the establishment of an intergovernmental body based on scientific knowledge explaining the anticipated benefit for human and environmental health.
Background Microplastic pollution has become a serious global environmental threat. The abundance of microplastics in the air is an order of magnitude higher than that in other media, which means that all living animals breathing with lungs (including humans) cannot escape the fate of inhaling microplastics. However, there is no direct evidence to demonstrate what type and abundance of microplastics exist in lung tissue. In addition, whether the retention of microplastics and the long-term friction between microplastics and lung tissue are related to some respiratory diseases is largely unknown. Ground glass nodules (GGNs) are areas of lesions of homogeneous density and with hazy increase in density in the lung field that do not obscure the bronchovascular structure, which have been increasingly identified in past decades. Although their etiology is broad, the correlation of microplastics with GGNs remains elusive. Results In this study, we identified the presence of 65 microfibers, including 24 microplastics (> 20 μm) in 100 human lung tissues with μ-FTIR. The detection rate of microfibers in tumor was 58%, higher than that in normal tissue (46%), and 2/3 of microplastics were found in tumor. Microfibers seemed to be embedded in lung tissues, which was suggested by the in situ observation via LDIR. Additionally, sub-micron-sized plastic particles were also detected in some lung tissues with Raman. The abundance of microfibers in lung tissue gradually accumulated with the increase of age. Moreover, the detection rate in tumor of patients with higher microfiber exposure risk history was significantly higher than those with a relatively lower one, implying microfiber inhalation could be related to the formation of GGN. Further, serious weared surface of microfibers isolated from lung tissue emphasized a possible link of surface roughness to the disease progression. Conclusions Collectively, the existence of microplastics in human lung tissues was validated, and their correlation with GGN formation was preliminarily explored, which laid a foundation for future research on microplastic exposure in the etiology of lung cancer and other related respiratory diseases. Graphical Abstract
Recent experimental findings have reported the presence of unconventional charge orders in the enlarged (2 × 2) unit-cell of kagome metals AV 3 Sb 5 (A = K, Rb, Cs) and hinted towards specific topological signatures. Motivated by these discoveries, we investigate the types of topological phases that can be realized in such kagome superlattices. In this context, we employ a recently introduced statistical method capable of constructing topological models for any generic lattice. By analyzing large data sets generated from symmetry-guided distributions of randomized tight-binding parameters, and labeled with the corresponding topological index, we extract physically meaningful information. We illustrate the possible real-space manifestations of charge and bond modulations and associated flux patterns for different topological classes, and discuss their relation to present theoretical predictions and experimental signatures for the AV 3 Sb 5 family. Simultaneously, we predict higher-order topological phases that may be realized by appropriately manipulating the currently known systems.
Background Recent pathomolecular studies on the MLL-AF4 fusion protein revealed that the murinized version of MLL-AF4, the MLL-Af4 fusion protein, was able to induce leukemia when expressed in murine or human hematopoietic stem/progenitor cells (Lin et al. in Cancer Cell 30:737–749, 2016). In parallel, a group from Japan demonstrated that the pSer domain of the AF4 protein, as well as the pSer domain of the MLL-AF4 fusion is able to bind the Pol I transcription factor complex SL1 (Okuda et al. in Nat Commun 6:8869, 2015). Here, we investigated the human MLL-AF4 and a pSer-murinized version thereof for their functional properties in mammalian cells. Gene expression profiling studies were complemented by intracellular localization studies and functional experiments concerning their biological activities in the nucleolus. Results Based on our results, we have to conclude that MLL-AF4 is predominantly localizing inside the nucleolus, thereby interfering with Pol I transcription and ribosome biogenesis. The murinized pSer-variant is localizing more to the nucleus, which may suggest a different biological behavior. Of note, AF4-MLL seems to cooperate at the molecular level with MLL-AF4 to steer target gene transcription, but not with the pSer-murinized version of it. Conclusion This study provides new insights and a molecular explanation for the described differences between hMLL-hAF4 (not leukemogenic) and hMLL-mAf4 (leukemogenic). While the human pSer domain is able to efficiently recruit the SL1 transcription factor complex, the murine counterpart seems to be not. This has several consequences for our understanding of t(4;11) leukemia which is the most frequent leukemia in infants, childhood and adults suffering from MLL-r acute leukemia.
Background Despite advances in treatment of patients with non-small cell lung cancer, carriers of certain genetic alterations are prone to failure. One such factor frequently mutated, is the tumor suppressor PTEN. These tumors are supposed to be more resistant to radiation, chemo- and immunotherapy. Results We demonstrate that loss of PTEN led to altered expression of transcriptional programs which directly regulate therapy resistance, resulting in establishment of radiation resistance. While PTEN-deficient tumor cells were not dependent on DNA-PK for IR resistance nor activated ATR during IR, they showed a significant dependence for the DNA damage kinase ATM. Pharmacologic inhibition of ATM, via KU-60019 and AZD1390 at non-toxic doses, restored and even synergized with IR in PTEN-deficient human and murine NSCLC cells as well in a multicellular organotypic ex vivo tumor model. Conclusion PTEN tumors are addicted to ATM to detect and repair radiation induced DNA damage. This creates an exploitable bottleneck. At least in cellulo and ex vivo we show that low concentration of ATM inhibitor is able to synergise with IR to treat PTEN-deficient tumors in genetically well-defined IR resistant lung cancer models.
Background The extramuscular connective tissue (ECT) has been shown to play a significant role in mechanical force transmission between musculoskeletal structures. Due to this and owing to its tight connection with the underlying muscle, the ECT may be vulnerable to excessive loading. The present study aimed to investigate the effect of eccentric elbow flexor exercise on the morphology of the biceps brachii ECT. In view of the high nociceptive capacity of the ECT, an additional objective was to elucidate the potential relationship between ECT damage and the occurrence of delayed onset muscle soreness (DOMS). Methods Eleven healthy participants (♂ = 7; 24 ± 2 years) performed fatiguing dumbbell elbow flexor eccentric exercise (EE) for one arm and concentric exercise (CE) for the other arm in random order and with random arm allocation. Before, immediately after and 24–96 h post-exercise, maximal voluntary isometric contraction torque of the elbow flexors (dynamometer), pressure pain (algometer), palpation pain (100 mm visual analog scale), biceps brachii ECT thickness and ECT/muscle mobility during passive movement (both high-resolution ultrasound) were examined. Results Palpation pain, suggestive of DOMS, was greater after EE than CE, and maximal voluntary isometric contraction torque decreased greater after EE than CE (p < .05). Relative to CE, EE increased ECT thickness at 48 (+ 17%), 72 (+ 14%) and 96 (+ 15%) hours post-exercise (p < .05). At 96 h post-EE, the increase in ECT thickness correlated with palpation pain (r = .68; p < .05). ECT mobility was not different between conditions, but compared to CE, muscle displacement increased at 24 (+ 31%), 72 (+ 31%) and 96 (+ 41%) hours post-EE (p < .05). Conclusion Collectively, these results suggest an involvement of the ECT changes in delayed onset muscle soreness.
Tilletia caries and T. laevis , which are the causal agents of common bunt, as well as T. controversa, which causes dwarf bunt of wheat, threaten especially organic wheat farming. The three closely related fungal species differ in their teliospore morphology and partially in their physiology and infection biology. The gene content as well as intraspecies variation in these species and the genetic basis of their separation is unknown. We sequenced the genome of four T. caries , five T. controversa , and two T. laevis and extended this dataset with five publicly available ones. The genomes of the three species displayed microsynteny with up to 94.3% pairwise aligned regions excluding repetitive regions. The majority of functionally characterized genes involved in pathogenicity, life cycle, and infection of corn smut, Ustilago maydis, were found to be absent or poorly conserved in the draft genomes and the biosynthetic pathway for trimethylamine in Tilletia spp. could be different from bacteria. Overall, 75% of the identified protein-coding genes comprising 84% of the total predicted carbohydrate utilizing enzymes, 72.5% putatively secreted proteins, and 47.4% of effector-like proteins were conserved and shared across all 16 isolates. We predicted nine highly identical secondary metabolite biosynthesis gene clusters comprising in total 62 genes in all species and none were species-specific. Less than 0.1% of the protein-coding genes were species-specific and their function remained mostly unknown. Tilletia controversa had the highest intraspecies genetic variation, followed by T. caries and the lowest in T. laevis. Although the genomes of the three species are very similar, employing 241 single copy genes T. controversa was phylogenetically distinct from T. caries and T. laevis , however these two could not be resolved as individual monophyletic groups. This was in line with the genome-wide number of single nucleotide polymorphisms and small insertions and deletions. Despite the conspicuously different teliospore ornamentation of T. caries and T. laevis , a high degree of genomic identity and scarcity of species-specific genes indicate that the two species could be conspecific.
Background Bacterial burden as well as duration of bacteremia influence the outcome of patients with bloodstream infections. Promptly decreasing bacterial load in the blood by using extracorporeal devices in addition to anti-infective therapy has recently been explored. Preclinical studies with the Seraph® 100 Microbind® Affinity Blood Filter (Seraph® 100), which consists of heparin that is covalently bound to polymer beads, have demonstrated an effective binding of bacteria and viruses. Pathogens adhere to the heparin coated polymer beads in the adsorber as they would normally do to heparan sulfate on cell surfaces. Using this biomimetic principle, the Seraph® 100 could help to decrease bacterial burden in vivo. Methods This first in human, prospective, multicenter, non-randomized interventional study included patients with blood culture positive bloodstream infection and the need for kidney replacement therapy as an adjunctive treatment for bloodstream infections. We performed a single four-hour hemoperfusion treatment with the Seraph® 100 in conjunction with a dialysis procedure. Post procedure follow up was 14 days. Results Fifteen hemodialysis patients (3F/12 M, age 74.0 [68.0–78.5] years, dialysis vintage 28.0 [11.0–45.0] months) were enrolled. Seraph® 100 treatment started 66.4 [45.7–80.6] hours after the initial positive blood culture was drawn. During the treatment with the Seraph® 100 with a median blood flow of 285 [225–300] ml/min no device or treatment related adverse events were reported. Blood pressure and heart rate remained stable while peripheral oxygen saturation improved during the treatment from 98.0 [92.5–98.0] to 99.0 [98.0–99.5] %; p = 0.0184. Four patients still had positive blood culture at the start of Seraph® 100 treatment. In one patient blood cultures turned negative during treatment. The time to positivity (TTP) was increased between inflow and outflow blood cultures by 36 [− 7.2 to 96.3] minutes. However, overall TTP increase was not statistical significant. Conclusions Seraph® 100 treatment was well tolerated. Adding Seraph® 100 to antibiotics early in the course of bacteremia might result in a faster resolution of bloodstream infections, which has to be evaluated in further studies . Trail registration : ClinicalTrials.gov Identifier: NCT02914132 , first posted September 26, 2016.
Alterations of RNA editing that affect the secondary structure of RNAs can cause human diseases. We therefore studied RNA editing in failing human hearts. Transcriptome sequencing showed that adenosine-to-inosine (A-to-I) RNA editing was responsible for 80% of the editing events in the myocardium. Failing human hearts were characterized by reduced RNA editing. This was primarily attributable to Alu elements in introns of protein-coding genes. In the failing left ventricle, 166 circRNAs were upregulated and 7 circRNAs were downregulated compared to non-failing controls. Most of the upregulated circRNAs were associated with reduced RNA editing in the host gene. ADAR2, which binds to RNA regions that are edited from A-to-I, was decreased in failing human hearts. In vitro, reduction of ADAR2 increased circRNA levels suggesting a causal effect of reduced ADAR2 levels on increased circRNAs in the failing human heart. To gain mechanistic insight, one of the identified upregulated circRNAs with a high reduction of editing in heart failure, AKAP13, was further characterized. ADAR2 reduced the formation of double-stranded structures in AKAP13 pre-mRNA, thereby reducing the stability of Alu elements and the circularization of the resulting circRNA. Overexpression of circAKAP13 impaired the sarcomere regularity of human induced pluripotent stem cell-derived cardiomyocytes. These data show that ADAR2 mediates A-to-I RNA editing in the human heart. A-to-I RNA editing represses the formation of dsRNA structures of Alu elements favoring canonical linear mRNA splicing and inhibiting the formation of circRNAs. The findings are relevant to diseases with reduced RNA editing and increased circRNA levels and provide insights into the human-specific regulation of circRNA formation.
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