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Local active information storage as a tool to understand distributed neural information processing
(2014)
Every act of information processing can in principle be decomposed into the component operations of information storage, transfer, and modification. Yet, while this is easily done for today's digital computers, the application of these concepts to neural information processing was hampered by the lack of proper mathematical definitions of these operations on information. Recently, definitions were given for the dynamics of these information processing operations on a local scale in space and time in a distributed system, and the specific concept of local active information storage was successfully applied to the analysis and optimization of artificial neural systems. However, no attempt to measure the space-time dynamics of local active information storage in neural data has been made to date. Here we measure local active information storage on a local scale in time and space in voltage sensitive dye imaging data from area 18 of the cat. We show that storage reflects neural properties such as stimulus preferences and surprise upon unexpected stimulus change, and in area 18 reflects the abstract concept of an ongoing stimulus despite the locally random nature of this stimulus. We suggest that LAIS will be a useful quantity to test theories of cortical function, such as predictive coding.
Mutations of the isocitrate dehydrogenase-1 (IDH1) and IDH2 genes are among the most frequent alterations in acute myeloid leukemia (AML) and can be found in ∼20% of patients at diagnosis. Among 4930 patients (median age, 56 years; interquartile range, 45-66) with newly diagnosed, intensively treated AML, we identified IDH1 mutations in 423 (8.6%) and IDH2 mutations in 575 (11.7%). Overall, there were no differences in response rates or survival for patients with mutations in IDH1 or IDH2 compared with patients without mutated IDH1/2. However, distinct clinical and comutational phenotypes of the most common subtypes of IDH1/2 mutations could be associated with differences in outcome. IDH1-R132C was associated with increased age, lower white blood cell (WBC) count, less frequent comutation of NPM1 and FLT3 internal tandem mutation (ITD) as well as with lower rate of complete remission and a trend toward reduced overall survival (OS) compared with other IDH1 mutation variants and wild-type (WT) IDH1/2. In our analysis, IDH2-R172K was associated with significantly lower WBC count, more karyotype abnormalities, and less frequent comutations of NPM1 and/or FLT3-ITD. Among patients within the European LeukemiaNet 2017 intermediate- and adverse-risk groups, relapse-free survival and OS were significantly better for those with IDH2-R172K compared with WT IDH, providing evidence that AML with IDH2-R172K could be a distinct entity with a specific comutation pattern and favorable outcome. In summary, the presented data from a large cohort of patients with IDH1/2 mutated AML indicate novel and clinically relevant findings for the most common IDH mutation subtypes.
(1) Background: Patients with locally advanced head and neck squamous cell carcinoma (HNSCC) who are biologically at high risk for the development of loco–regional recurrences after postoperative radiotherapy (PORT) but at intermediate risk according to clinical risk factors may benefit from additional concurrent chemotherapy. In this matched-pair study, we aimed to identify a corresponding predictive gene signature. (2) Methods: Gene expression analysis was performed on a multicenter retrospective cohort of 221 patients that were treated with postoperative radiochemotherapy (PORT-C) and 283 patients who were treated with PORT alone. Propensity score analysis was used to identify matched patient pairs from both cohorts. From differential gene expression analysis and Cox regression, a predictive gene signature was identified. (3) Results: 108 matched patient pairs were selected. We identified a 2-metagene signature that stratified patients into risk groups in both cohorts. The comparison of the high-risk patients between the two types of treatment showed higher loco–regional control (LRC) after treatment with PORT-C (p < 0.001), which was confirmed by a significant interaction term in Cox regression (p = 0.027), i.e., the 2-metagene signature was indicative for the type of treatment. (4) Conclusion: We have identified a novel gene signature that may be helpful to identify patients with high-risk HNSCC amongst those at intermediate clinical risk treated with PORT, who may benefit from additional concurrent chemotherapy.
Background: Advanced liver diseases are associated with profound alterations of the coagulation system increasing the risk not only of bleeding, but also of thromboembolic complications. A recent milestone study has shown that prophylactic anticoagulation in liver cirrhosis patients results in a reduced frequency of hepatic decompensation. Yet, INR measurement, one of the most widely applied tests to assess liver function, only inaccurately predicts the risk of hepatic decompensation related to alterations of the coagulation system. To assess the relationship between selected coagulation factors / natural anticoagulants with INR, MELD score, and hepatic decompensation, we performed the present pilot study. A total number of 92 patients with various stages of liver cirrhosis were included and prospectively followed for at least 6 months. We found that important natural anticoagulants, namely antithrombin and protein C, as well as factor XI (which may also serve as an anticoagulant) decreased earlier and by a larger magnitude than one would expect from classical coagulation test results. The correlation between these factors and INR was only moderate. Importantly, reduced plasma activities of natural anticoagulants but not INR or MELD score were independent predictors of hepatic encephalopathy (P = 0.013 and 0.003 for antithrombin and protein C, respectively).
Conclusion: In patients with liver cirrhosis plasma activities of several natural anticoagulants are earlier and stronger affected than routine coagulation tests. Reduced activities of natural anticoagulants may be predictive for the development of hepatic encephalopathy.
In the colon, a sophisticated balance between immune reaction and tolerance is absolutely required. Dysfunction may lead to pathologic phenotypes ranging from chronic inflammatory processes to cancer development. Two prominent modulators of colon inflammation are represented by the closely related cytokines interleukin (IL)-12 and IL-23, which initiate adaptive Th1 and Th17 immune responses, respectively. In this study, we investigated the impact of the NADPH oxidase protein p47phox, which negatively regulates IL-12 in dendritic cells, on colon cancer development in a colitis-associated colon cancer model. Initially, we found that IL-12−/− mice developed less severe colitis but are highly susceptible to colon cancer. By contrast, p47phox−/− mice showed lower tumor scores and fewer high grade tumors than wild-type (WT) littermates. Treatment with toll-like receptor 9 ligand CpG2216 significantly enhanced colitis in p47phox−/− mice, whereas tumor growth was simultaneously reduced. In tumor tissue of p47phox−/− mice, the IL-23/IL-17 axis was crucially hampered. IL-23p19 protein expression in tumor tissue correlated with tumor stage. Reconstitution of WT mice with IL-23p19−/− bone marrow protected these mice from colon cancer, whereas transplantation of WT hematopoiesis into IL-23p19−/− mice increased the susceptibility to tumor growth. Our study strengthens the divergent role of IL-12 and IL-23 in colon cancer development. With the characterization of p47phox as a novel modulator of both cytokines our investigation introduces a promising new target for antitumor strategies.
Background: Essential Tremor (ET) is a progressive neurological disorder characterized by postural and kinetic tremor most commonly affecting the hands and arms. Medically intractable ET can be treated by deep brain stimulation (DBS) of the ventral intermediate nucleus of thalamus (VIM). We investigated whether the location of the effective contact (most tremor suppression with at least side effects) in VIM-DBS for ET changes over time, indicating a distinct mechanism of loss of efficacy that goes beyond progression of tremor severity, or a mere reduction of DBS efficacy.
Methods: We performed programming sessions in 10 patients who underwent bilateral vim-DBS surgery between 2009 and 2017 at our department. In addition to the intraoperative (T1) and first clinical programming session (T2) a third programming session (T3) was performed to assess the effect- and side effect threshold (minimum voltage at which a tremor suppression or side effects occurred). Additionally, we compared the choice of the effective contact between T1 and T2 which might be affected by a surgical induced “brain shift.”
Discussion: Over a time span of about 4 years VIM-DBS in ET showed continuous efficacy in tremor suppression during stim-ON compared to stim-OFF. Compared to immediate postoperative programming sessions in ET-patients with DBS, long-term evaluationshowednorelevantchangeinthechoiceofcontactwithrespecttosideeffects andefficacy.InthemajorityofthecasestheactivecontactatT2didnotcorrespondtothe most effective intraoperative stimulation site T1, which might be explained by a brain-shift due to cerebral spinal fluid loss after neurosurgical procedure.
Background: In a phase 3 clinical study, patients from Germany with moderate to severe psoriasis who were naïve to systemic treatment and received risankizumab had greater and more rapid disease improvements compared with those who received fumaric acid esters (FAEs).
Objective: To evaluate patient-reported outcomes (PROs) in patients treated with risankizumab compared with FAEs.
Methods: Adult patients were randomized 1:1 to receive either risankizumab 150 mg subcutaneous injections at weeks 0, 4 and 16 or FAEs (Fumaderm®) provided according to the prescribing label. PRO secondary endpoints assessed were Psoriasis Symptom Scale (PSS), Dermatology Life Quality Index (DLQI), 36-Item Short Form Health Survey, version 2 (SF-36v2), Patient Benefit Index (PBI), Hospital Anxiety and Depression Scale (HADS), Patient Global Assessment (PtGA) and European Quality of Life 5 Dimensions 5 Level (EQ-5D-5L). PROs were assessed at weeks 0, 16 and 24.
Results: Sixty patients each were randomized to receive risankizumab or FAEs. A significant PSS improvement was observed with risankizumab vs. FAEs at weeks 16 and 24 for total and psoriasis-associated redness, itching and burning scores (P < 0.001). DLQI scores were significantly lower (reflecting better health-related quality of life) with risankizumab vs. FAEs, with least squares (LS) mean differences of −7.4 and −7.6 at weeks 16 and 24, respectively (both P < 0.001). Patients randomized to risankizumab also had larger improvements in SF-36 Physical and Mental Component Summary scores, HADS anxiety and depression scores, PtGA, and EQ-5D-5L index and visual analogue scale scores (all P ≤ 0.002) at weeks 16 and 24 compared with FAEs. PBI was significantly higher, indicating greater benefit, with risankizumab vs. FAEs, with an LS mean difference of 1.1 and 1.3 at weeks 16 and 24, respectively (both P < 0.001).
Conclusions: Risankizumab provides significant benefits over FAEs in improving PROs across several dimensions in patients with moderate to severe psoriasis.
Dual function of the NK cell receptor 2B4 (CD244) in the regulation of HCV-specific CD8+ T cells
(2011)
The outcome of viral infections is dependent on the function of CD8+ T cells which are tightly regulated by costimulatory molecules. The NK cell receptor 2B4 (CD244) is a transmembrane protein belonging to the Ig superfamily which can also be expressed by CD8+ T cells. The aim of this study was to analyze the role of 2B4 as an additional costimulatory receptor regulating CD8+ T cell function and in particular to investigate its implication for exhaustion of hepatitis C virus (HCV)-specific CD8+ T cells during persistent infection. We demonstrate that (i) 2B4 is expressed on virus-specific CD8+ T cells during acute and chronic hepatitis C, (ii) that 2B4 cross-linking can lead to both inhibition and activation of HCV-specific CD8+ T cell function, depending on expression levels of 2B4 and the intracellular adaptor molecule SAP and (iii) that 2B4 stimulation may counteract enhanced proliferation of HCV-specific CD8+ T cells induced by PD1 blockade. We suggest that 2B4 is another important molecule within the network of costimulatory/inhibitory receptors regulating CD8+ T cell function in acute and chronic hepatitis C and that 2B4 expression levels could also be a marker of CD8+ T cell dysfunction. Understanding in more detail how 2B4 exerts its differential effects could have implications for the development of novel immunotherapies of HCV infection aiming to achieve immune control.
Background: Ribavirin (RBV) remains part of several interferon-free treatment strategies even though its mechanisms of action are still not fully understood. One hypothesis is that RBV increases responsiveness to type I interferons. Pegylated Interferon alpha (PEG-IFNa) has recently been shown to alter natural killer (NK) cell function possibly contributing to control of hepatitis C virus (HCV) infection. However, the effects of ribavirin alone or in combination with IFNa on NK cells are unknown.
Methods: Extensive ex vivo phenotyping and functional analysis of NK cells from hepatitis C patients was performed during antiviral therapy. Patients were treated for 6 weeks with RBV monotherapy (n = 11), placebo (n = 13) or PEG-IFNa-2a alone (n = 6) followed by PEG-IFNa/RBV combination therapy. The effects of RBV and PEG-IFNa-2a on NK cells were also studied in vitro after co-culture with K562 or Huh7.5 cells.
Results: Ribavirin monotherapy had no obvious effects on NK cell phenotype or function, neither ex vivo in patients nor in vitro. In contrast, PEG-IFNa-2a therapy was associated with an increase of CD56bright cells and distinct changes in expression profiles leading to an activated NK cell phenotype, increased functionality and decline of terminally differentiated NK cells. Ribavirin combination therapy reduced some of the IFN effects. An activated NK cell phenotype during therapy was inversely correlated with HCV viral load.
Conclusions: PEG-IFNa activates NK cells possibly contributing to virological responses independently of RBV. The role of NK cells during future IFN-free combination therapies including RBV remains to be determined.
Prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing. Resulting fibrosis and portal hypertension, as a possible secondary event, may necessitate treatment. Overexpression of mouse renin in the transgenic rat model, TGR(mREN2)27, leads to spontaneous development of NAFLD. Therefore, we used TGR(mREN2)27 rats as a model of NAFLD where we hypothesized increased susceptibility and investigated fibrosis and portal hypertension and associated pathways. 12-week old TGR(mREN2)27 rats received either cholestatic (BDL) or toxic injury (CCl4 inhalation). Portal and systemic hemodynamic assessments were performed using microsphere technique with and without injection of the Janus-Kinase 2 (JAK2) inhibitor AG490 or the non-peptidic Ang(1-7) agonist, AVE0991. The extent of liver fibrosis was assessed in TGR(mREN2)27 and wild-type rats using standard techniques. Protein and mRNA levels of profibrotic, renin-angiotensin system components were assessed in liver and primary hepatic stellate cells (HSC) and hepatocytes. TGR(mREN2)27 rats developed spontaneous, but mild fibrosis and portal hypertension due to the activation of the JAK2/Arhgef1/ROCK pathway. AG490 decreased migration of HSC and portal pressure in isolated liver perfusions and in vivo. Fibrosis or portal hypertension after cholestatic (BDL) or toxic injury (CCl4) was not aggravated in TGR(mREN2)27 rats, probably due to decreased mouse renin expression in hepatocytes. Interestingly, portal hypertension was even blunted in TGR(mREN2)27 rats (with or without additional injury) by AVE0991. TGR(mREN2)27 rats are a suitable model of spontaneous liver fibrosis and portal hypertension but not with increased susceptibility to liver damage. After additional injury, the animals can be used to evaluate novel therapeutic strategies targeting Mas.
The transcription factor Meis1 drives myeloid leukemogenesis in the context of Hox gene overexpression but is currently considered undruggable. We therefore investigated whether myeloid progenitor cells transformed by Hoxa9 and Meis1 become addicted to targetable signaling pathways. A comprehensive (phospho)proteomic analysis revealed that Meis1 increased Syk protein expression and activity. Syk upregulation occurs through a Meis1-dependent feedback loop. By dissecting this loop, we show that Syk is a direct target of miR-146a, whose expression is indirectly regulated by Meis1 through the transcription factor PU.1. In the context of Hoxa9 overexpression, Syk signaling induces Meis1, recapitulating several leukemogenic features of Hoxa9/Meis1-driven leukemia. Finally, Syk inhibition disrupts the identified regulatory loop, prolonging survival of mice with Hoxa9/Meis1-driven leukemia.
Bloodstream infections (BSI) are a frequent complication in patients with hematological and oncological diseases. However, the impact of different bacterial species causing BSI and of multiple BSI remains incompletely understood. We performed a retrospective study profiling 637 bacterial BSI episodes in hematological and oncological patients. Based on the 30-day (30d) overall survival (OS), we analyzed different types of multiple BSI and grouped BSI-associated bacteria into clusters followed by further assessment of clinical and infection-related characteristics. We discovered that polymicrobial BSI (different organisms on the first day of a BSI episode) and sequential BSI (another BSI before the respective BSI episode) were associated with a worse 30d OS. Different bacterial groups could be classified into three BSI outcome clusters based on 30d OS: favorable (FAV) including mainly common skin contaminants, Escherichia spp. and Streptococcus spp.; intermediate (INT) including mainly Enterococcus spp., vancomycin-resistant Enterococcus spp., and multidrug-resistant gram-negative bacteria (MDRGN); and adverse (ADV) including MDRGN with an additional carbapenem-resistance (MDRGN+CR). A polymicrobial or sequential BSI especially influenced the outcome in the combination of two INT cluster BSI. The presence of a polymicrobial BSI and the assignment into the BSI outcome clusters were identified as independent risk factors for 30d mortality in a Cox multivariate regression analysis. The assignment to a BSI outcome cluster and the differentiated perspective of multiple BSI open new insights into the prognosis of patients with BSI and should be further validated in other patient cohorts.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers potential cure to acute myeloid leukemia (AML) patients. However, infections with commensal bacteria are an important cause for non-relapse mortality (NRM). We have previously described the impact of multidrug-resistant organism (MDRO) colonization on the survival of allo-HSCT patients. In the aforementioned publication, according to consensus, we there did not consider the opportunistic gram-negative bacterium Stenotrophomonas maltophilia (S. maltophilia) to be an MDRO. Since rate of S. maltophilia colonization is increasing, and it is not known whether this poses a risk for allo-HSCT patients, we here analyzed here its effect on the previously described and now extended patient cohort. We report on 291 AML patients undergoing allo-HSCT. Twenty of 291 patients (6.9%) were colonized with S. maltophilia. Colonized patients did not differ from non-colonized patients with respect to their age, remission status before allo-HSCT, donor type and HSCT-comorbidity index. S. maltophilia colonized patients had a worse overall survival (OS) from 6 months up to 60 months (85% vs. 88.1% and 24.7% vs. 59.7%; p = 0.007) due to a higher NRM after allo-HSCT (6 months: 15% vs. 4.8% and 60 months: 40.1% vs. 16.2% p = 0.003). The main cause of mortality in colonized patients was infection (46.2% of all deaths) and in non-colonized patients relapse (58.8% of all deaths). 5/20 colonized patients developed an invasive infection with S. maltophilia. The worse OS after allo-HSCT due to higher infection related mortality might implicate the screening of allo-HSCT patients for S. maltophilia and a closer observation of colonized patients as outpatients.
Background: Preclinical studies demonstrate synergism between cancer immunotherapy and local radiation, enhancing anti-tumor effects and promoting immune responses. BI1361849 (CV9202) is an active cancer immunotherapeutic comprising protamine-formulated, sequence-optimized mRNA encoding six non-small cell lung cancer (NSCLC)-associated antigens (NY-ESO-1, MAGE-C1, MAGE-C2, survivin, 5T4, and MUC-1), intended to induce targeted immune responses.
Methods: We describe a phase Ib clinical trial evaluating treatment with BI1361849 combined with local radiation in 26 stage IV NSCLC patients with partial response (PR)/stable disease (SD) after standard first-line therapy. Patients were stratified into three strata (1: non-squamous NSCLC, no epidermal growth factor receptor (EGFR) mutation, PR/SD after ≥4 cycles of platinum- and pemetrexed-based treatment [n = 16]; 2: squamous NSCLC, PR/SD after ≥4 cycles of platinum-based and non-platinum compound treatment [n = 8]; 3: non-squamous NSCLC, EGFR mutation, PR/SD after ≥3 and ≤ 6 months EGFR-tyrosine kinase inhibitor (TKI) treatment [n = 2]). Patients received intradermal BI1361849, local radiation (4 × 5 Gy), then BI1361849 until disease progression. Strata 1 and 3 also had maintenance pemetrexed or continued EGFR-TKI therapy, respectively. The primary endpoint was evaluation of safety; secondary objectives included assessment of clinical efficacy (every 6 weeks during treatment) and of immune response (on Days 1 [baseline], 19 and 61).
Results: Study treatment was well tolerated; injection site reactions and flu-like symptoms were the most common BI1361849-related adverse events. Three patients had grade 3 BI1361849-related adverse events (fatigue, pyrexia); there was one grade 3 radiation-related event (dysphagia). In comparison to baseline, immunomonitoring revealed increased BI1361849 antigen-specific immune responses in the majority of patients (84%), whereby antigen-specific antibody levels were increased in 80% and functional T cells in 40% of patients, and involvement of multiple antigen specificities was evident in 52% of patients. One patient had a partial response in combination with pemetrexed maintenance, and 46.2% achieved stable disease as best overall response. Best overall response was SD in 57.7% for target lesions.
Conclusion: The results support further investigation of mRNA-based immunotherapy in NSCLC including combinations with immune checkpoint inhibitors.
Trial registration: ClinicalTrials.gov identifier: NCT01915524.
Background: Patients with locally advanced bladder cancer (cT3/4 cN0/N+ cM0) have a poor prognosis despite radical surgical therapy and perioperative chemotherapy. Preliminary data suggest that the combination of radiation and immunotherapy does not lead to excess toxicity and may have synergistic (abscopal) anti-tumor effects. We hypothesize that the combined preoperative application of the PD-1 checkpoint-inhibitor Nivolumab with concomitant radiation therapy of the bladder and pelvic region followed by radical cystectomy with standardized lymphadenectomy is safe and feasible and might improve outcome for patients with locally advanced bladder cancer.
Methods: Study design: “RACE IT” (AUO AB 65/18) is an investigator initiated, prospective, multicenter, open, single arm phase II trial sponsored by Technical University Munich. Study drug and funding are provided by the company Bristol-Myers Squibb.
Study treatment: Patients will receive Nivolumab 240 mg i.v. every 2 weeks for 4 cycles preoperatively with concomitant radiation therapy of bladder and pelvic region (max. 50.4 Gy). Radical cystectomy with standardized bilateral pelvic lymphadenectomy will be performed between week 11–15.
Primary endpoint: Rate of patients with completed treatment consisting of radio-immunotherapy and radical cystectomy at the end of week 15.
Secondary endpoints: Acute and late toxicity, therapy response and survival (1 year follow up).
Main inclusion criteria: Patients with histologically confirmed, locally advanced bladder cancer (cT3/4, cN0/N+), who are ineligible for neoadjuvant, cisplatin-based chemotherapy or who refuse neoadjuvant chemotherapy.
Main exclusion criteria: Patients with metastatic disease (lymph node metastasis outside pelvis or distant metastasis) or previous chemo-, immune- or radiation therapy.
Planned sample size: 33 patients, interim analysis after 11 patients.
Several clinically used drugs are derived from microorganisms that often produce them via non-ribosomal peptide synthetases (NRPS), giant megasynthases that activate and connect individual amino acids in an assembly line fashion. Since NRPS are not restricted to the incorporation of the 20 proteinogenic amino acids, their efficient manipulation would allow the biotechnological generation of several different peptides including linear, cyclic and further modified derivatives. Here we describe a detailed phylogenetic analysis of several bacterial NRPS that led to the identification of a new recombination breakpoint within the thiolation (T) domain important in natural NRPS evolution. From this an evolutionary-inspired eXchange Unit between T domains (XUT) approach was developed, which allows the assembly of NRPS fragments over a broad range of GC contents, protein similarities, and extender unit specificities, as was shown for the specific production of a proteasome inhibitor, designed and assembled from five different NRPS fragments.
The nuclear exosome and its essential co-factor, the RNA helicase MTR4, play crucial roles in several RNA degradation pathways. Besides unwinding RNA substrates for exosome-mediated degradation, MTR4 associates with RNA-binding proteins that function as adaptors in different RNA processing and decay pathways. Here, we identify and characterize the interactions of human MTR4 with a ribosome processing adaptor, NVL, and with ZCCHC8, an adaptor involved in the decay of small nuclear RNAs. We show that the unstructured regions of NVL and ZCCHC8 contain short linear motifs that bind the MTR4 arch domain in a mutually exclusive manner. These short sequences diverged from the arch-interacting motif (AIM) of yeast rRNA processing factors. Our results suggest that nuclear exosome adaptors have evolved canonical and non-canonical AIM sequences to target human MTR4 and demonstrate the versatility and specificity with which the MTR4 arch domain can recruit a repertoire of different RNA-binding proteins.
Current anti-epileptic drugs (AEDs) act on a limited set of neuronal targets, are ineffective in a third of patients with epilepsy, and do not show disease-modifying properties. MicroRNAs are small noncoding RNAs that regulate levels of proteins by post-transcriptional control of mRNA stability and translation. MicroRNA-134 is involved in controlling neuronal microstructure and brain excitability and previous studies showed that intracerebroventricular injections of locked nucleic acid (LNA), cholesterol-tagged antagomirs targeting microRNA-134 (Ant-134) reduced evoked and spontaneous seizures in mouse models of status epilepticus. Translation of these findings would benefit from evidence of efficacy in non-status epilepticus models and validation in another species. Here, we report that electrographic seizures and convulsive behavior are strongly reduced in adult mice pre-treated with Ant-134 in the pentylenetetrazol model. Pre-treatment with Ant-134 did not affect the severity of status epilepticus induced by perforant pathway stimulation in adult rats, a toxin-free model of acquired epilepsy. Nevertheless, Ant-134 post-treatment reduced the number of rats developing spontaneous seizures by 86% in the perforant pathway stimulation model and Ant-134 delayed epileptiform activity in a rat ex vivo hippocampal slice model. The potent anticonvulsant effects of Ant-134 in multiple models may encourage pre-clinical development of this approach to epilepsy therapy.
Hygroscopicity of nanoparticles produced from homogeneous nucleation in the CLOUD experiments
(2015)
Sulfuric acid, amines and oxidized organics have been found to be important compounds in the nucleation and initial growth of atmospheric particles. Because of the challenges involved in determining the chemical composition of objects with very small mass, however, the properties of the freshly nucleated particles and the detailed pathways of their formation processes are still not clear. In this study, we focus on a challenging size range, i.e. particles that have grown to diameters of 10 and 15nm following nucleation, and measure their water uptake. Water uptake constrains their chemical composition. We use a nanometer-hygroscopicity tandem differential mobility analyzer (nano-HTDMA) at subsaturated conditions (ca. 90% relative humidity at 293 K) to measure the hygroscopicity of particles during the seventh Cosmics Leaving OUtdoor Droplets (CLOUD7) experiments performed at CERN in 2012. In CLOUD7, the hygroscopicity of nucleated nanoparticles was measured in the presence of sulfuric acid, sulfuric acid-dimethylamine, and sulfuric acid-organics derived from α-pinene oxidation. The hygroscopicity parameter Κ decreased with increasing particle size indicating decreasing acidity of particles. No clear effect of the sulfuric acid monomer concentrations on the hygroscopicities of 10nm particles produced from sulfuric acid and dimethylamine was observed, whereas the hygroscopicity of 15nm particles sharply decreased with decreasing sulfuric acid monomer concentrations. In 20 particular, when the concentrations of sulfuric acid was 5.1 x 106 molecules cm exp -3 in the gas phase, and the dimethylamine mixing ratio was 11.8 ppt, the measured Κ of 15nm particles was 0.3 ± 0.01 close to the value reported for dimethylamine sulfate (DMAS) (Κ DMAS ~ 0.28). Furthermore, the difference in Κ between sulfuric acid and sulfuric acid-dimethylamine experiments increased with increasing particle size. The Κ values of particles in the presence of sulfuric acid and organics were much smaller than those of particles in the presence of sulfuric acid and dimethylamine. This suggests that the organics produced from α-pinene ozonolysis play a significant role in particle growth already at 10nm sizes.
Hygroscopicity of nanoparticles produced from homogeneous
nucleation in the CLOUD experiments
(2016)
Sulfuric acid, amines and oxidized organics have been found to be important compounds in the nucleation and initial growth of atmospheric particles. Because of the challenges involved in determining the chemical composition of objects with very small mass, however, the properties of the freshly nucleated particles and the detailed pathways of their formation processes are still not clear. In this study, we focus on a challenging size range, i.e., particles that have grown to diameters of 10 and 15 nm following nucleation, and measure their water uptake. Water uptake is useful information for indirectly obtaining chemical composition of aerosol particles. We use a nanometer-hygroscopicity tandem differential mobility analyzer (nano-HTDMA) at subsaturated conditions (ca. 90 % relative humidity at 293 K) to measure the hygroscopicity of particles during the seventh Cosmics Leaving OUtdoor Droplets (CLOUD7) campaign performed at CERN in 2012. In CLOUD7, the hygroscopicity of nucleated nanoparticles was measured in the presence of sulfuric acid, sulfuric acid–dimethylamine, and sulfuric acid–organics derived from α-pinene oxidation. The hygroscopicity parameter κ decreased with increasing particle size, indicating decreasing acidity of particles. No clear effect of the sulfuric acid concentration on the hygroscopicity of 10 nm particles produced from sulfuric acid and dimethylamine was observed, whereas the hygroscopicity of 15 nm particles sharply decreased with decreasing sulfuric acid concentrations. In particular, when the concentration of sulfuric acid was 5.1 × 106 molecules cm−3 in the gas phase, and the dimethylamine mixing ratio was 11.8 ppt, the measured κ of 15 nm particles was 0.31 ± 0.01: close to the value reported for dimethylaminium sulfate (DMAS) (κDMAS ∼ 0.28). Furthermore, the difference in κ between sulfuric acid and sulfuric acid–imethylamine experiments increased with increasing particle size. The κ values of particles in the presence of sulfuric acid and organics were much smaller than those of particles in the presence of sulfuric acid and dimethylamine. This suggests that the organics produced from α-pinene ozonolysis play a significant role in particle growth even at 10 nm sizes.
Spatial and temporal processes shaping microbial communities are inseparably linked but rarely studied together. By Illumina 16S rRNA sequencing, we monitored soil bacteria in 360 stations on a 100 square meter plot distributed across six intra-annual samplings in a rarely managed, temperate grassland. Using a multi-tiered approach, we tested the extent to which stochastic or deterministic processes influenced the composition of local communities. A combination of phylogenetic turnover analysis and null modeling demonstrated that either homogenization by unlimited stochastic dispersal or scenarios, in which neither stochastic processes nor deterministic forces dominated, explained local assembly processes. Thus, the majority of all sampled communities (82%) was rather homogeneous with no significant changes in abundance-weighted composition. However, we detected strong and uniform taxonomic shifts within just nine samples in early summer. Thus, community snapshots sampled from single points in time or space do not necessarily reflect a representative community state. The potential for change despite the overall homogeneity was further demonstrated when the focus shifted to the rare biosphere. Rare OTU turnover, rather than nestedness, characterized abundance-independent β-diversity. Accordingly, boosted generalized additive models encompassing spatial, temporal and environmental variables revealed strong and highly diverse effects of space on OTU abundance, even within the same genus. This pure spatial effect increased with decreasing OTU abundance and frequency, whereas soil moisture – the most important environmental variable – had an opposite effect by impacting abundant OTUs more than the rare ones. These results indicate that – despite considerable oscillation in space and time – the abundant and resident OTUs provide a community backbone that supports much higher β-diversity of a dynamic rare biosphere. Our findings reveal complex interactions among space, time, and environmental filters within bacterial communities in a long-established temperate grassland.
Correlative microscopy incorporates the specificity of fluorescent protein labeling into high-resolution electron micrographs. Several approaches exist for correlative microscopy, most of which have used the green fluorescent protein (GFP) as the label for light microscopy. Here we use chemical tagging and synthetic fluorophores instead, in order to achieve protein-specific labeling, and to perform multicolor imaging. We show that synthetic fluorophores preserve their post-embedding fluorescence in the presence of uranyl acetate. Post-embedding fluorescence is of such quality that the specimen can be prepared with identical protocols for scanning electron microscopy (SEM) and transmission electron microscopy (TEM); this is particularly valuable when singular or otherwise difficult samples are examined. We show that synthetic fluorophores give bright, well-resolved signals in super-resolution light microscopy, enabling us to superimpose light microscopic images with a precision of up to 25 nm in the x-y plane on electron micrographs. To exemplify the preservation quality of our new method we visualize the molecular arrangement of cadherins in adherens junctions of mouse epithelial cells.
We present a study of the influence of disorder on the Mott metal-insulator transition for the organic charge-transfer salt κ -(BEDT-TTF) 2 Cu[N(CN) 2 ]Cl. To this end, disorder was introduced into the system in a controlled way by exposing the single crystals to X-ray irradiation. The crystals were then fine-tuned across the Mott transition by the application of continuously controllable He-gas pressure at low temperatures. Measurements of the thermal expansion and resistance show that the first-order character of the Mott transition prevails for low irradiation doses achieved by irradiation times up to 100 h. For these crystals with a moderate degree of disorder, we find a first-order transition line which ends in a second-order critical endpoint, akin to the pristine crystals. Compared to the latter, however, we observe a significant reduction of both, the critical pressure pc and the critical temperature Tc . This result is consistent with the theoretically-predicted formation of a soft Coulomb gap in the presence of strong correlations and small disorder. Furthermore, we demonstrate, similar to the observation for the pristine sample, that the Mott transition after 50 h of irradiation is accompanied by sizable lattice effects, the critical behavior of which can be well described by mean-field theory. Our results demonstrate that the character of the Mott transition remains essentially unchanged at a low disorder level. However, after an irradiation time of 150 h, no clear signatures of a discontinuous metal-insulator transition could be revealed anymore. These results suggest that, above a certain disorder level, the metal-insulator transition becomes a smeared first-order transition with some residual hysteresis.
The single crystal growth of 19 different intermetallic compounds within the LnT2X2 family (with Ln = lanthanides, T = Co, Ru, Rh, Ir, and X = Si, P) is presented, by employing a high-temperature metal-flux technique. The habitus of the obtained crystals is platelet-like with the crystallographic c direction perpendicular to the surface and with individual masses between 1 and 100 mg. The magnetic properties of these crystals are characterized by magnetization, heat-capacity, and resistivity measurements. These crystals form the materials basis for a thorough study of exciting surface properties by angle-resolved photoemission spectroscopy.
Many clinically used drugs are derived from or inspired by bacterial natural products that often are biosynthesised via non-ribosomal peptide synthetases (NRPS), giant megasynthases that activate and join individual amino acids in an assembly line fashion. Since NRPS are not limited to the incorporation of the 20 proteinogenic amino acids, their efficient manipulation would allow the biotechnological generation of complex peptides including linear, cyclic and further modified natural product analogues, e.g. to optimise natural product leads. Here we describe a detailed phylogenetic analysis of several bacterial NRPS that led to the identification of a new recombination breakpoint within the thiolation (T) domain that is important for natural NRPS evolution. From this, an evolution-inspired eXchange Unit between T domains (XUT) approach was developed which allows the assembly of NRPS fragments over a broad range of GC contents, protein similarities, and extender unit specificities, as demonstrated for the specific production of a proteasome inhibitor designed and assembled from five different NRPS fragments.
The study of neutron-induced reactions is of high relevance in a wide variety of fields, ranging from stellar nucleosynthesis and fundamental nuclear physics to applications of nuclear technology. In nuclear energy, high accuracy neutron data are needed for the development of Generation IV fast reactors and accelerator driven systems, these last aimed specifically at nuclear waste incineration, as well as for research on innovative fuel cycles. In this context, a high luminosity Neutron Time Of Flight facility, n_TOF, is operating at CERN since more than a decade, with the aim of providing new, high accuracy and high resolution neutron cross-sections. Thanks to the features of the neutron beam, a rich experimental program relevant to nuclear technology has been carried out so far. The program will be further expanded in the near future, thanks in particular to a new high-flux experimental area, now under construction.
The n_TOF facility operates at CERN with the aim of addressing the request of high accuracy nuclear data for advanced nuclear energy systems as well as for nuclear astrophysics. Thanks to the features of the neutron beam, important results have been obtained on neutron induced fission and capture cross sections of U, Pu and minor actinides. Recently the construction of another beam line has started; the new line will be complementary to the first one, allowing to further extend the experimental program foreseen for next measurement campaigns.
The COVID-19 pandemic has caused strains on health systems worldwide disrupting routine hospital services for all non-COVID patients. Within this retrospective study, we analyzed inpatient hospital admissions across 18 German university hospitals during the 2020 lockdown period compared to 2018. Patients admitted to hospital between January 1 and May 31, 2020 and the corresponding periods in 2018 and 2019 were included in this study. Data derived from electronic health records were collected and analyzed using the data integration center infrastructure implemented in the university hospitals that are part of the four consortia funded by the German Medical Informatics Initiative. Admissions were grouped and counted by ICD 10 chapters and specific reasons for treatment at each site. Pooled aggregated data were centrally analyzed with descriptive statistics to compare absolute and relative differences between time periods of different years. The results illustrate how care process adoptions depended on the COVID-19 epidemiological situation and the criticality of the disease. Overall inpatient hospital admissions decreased by 35% in weeks 1 to 4 and by 30.3% in weeks 5 to 8 after the lockdown announcement compared to 2018. Even hospital admissions for critical care conditions such as malignant cancer treatments were reduced. We also noted a high reduction of emergency admissions such as myocardial infarction (38.7%), whereas the reduction in stroke admissions was smaller (19.6%). In contrast, we observed a considerable reduction in admissions for non-critical clinical situations, such as hysterectomies for benign tumors (78.8%) and hip replacements due to arthrosis (82.4%). In summary, our study shows that the university hospital admission rates in Germany were substantially reduced following the national COVID-19 lockdown. These included critical care or emergency conditions in which deferral is expected to impair clinical outcomes. Future studies are needed to delineate how appropriate medical care of critically ill patients can be maintained during a pandemic.
About half of present-day cloud condensation nuclei originate from atmospheric nucleation, frequently appearing as a burst of new particles near midday1. Atmospheric observations show that the growth rate of new particles often accelerates when the diameter of the particles is between one and ten nanometres2,3. In this critical size range, new particles are most likely to be lost by coagulation with pre-existing particles4, thereby failing to form new cloud condensation nuclei that are typically 50 to 100 nanometres across. Sulfuric acid vapour is often involved in nucleation but is too scarce to explain most subsequent growth5,6, leaving organic vapours as the most plausible alternative, at least in the planetary boundary layer7,8,9,10. Although recent studies11,12,13 predict that low-volatility organic vapours contribute during initial growth, direct evidence has been lacking. The accelerating growth may result from increased photolytic production of condensable organic species in the afternoon2, and the presence of a possible Kelvin (curvature) effect, which inhibits organic vapour condensation on the smallest particles (the nano-Köhler theory)2,14, has so far remained ambiguous. Here we present experiments performed in a large chamber under atmospheric conditions that investigate the role of organic vapours in the initial growth of nucleated organic particles in the absence of inorganic acids and bases such as sulfuric acid or ammonia and amines, respectively. Using data from the same set of experiments, it has been shown15 that organic vapours alone can drive nucleation. We focus on the growth of nucleated particles and find that the organic vapours that drive initial growth have extremely low volatilities (saturation concentration less than 10−4.5 micrograms per cubic metre). As the particles increase in size and the Kelvin barrier falls, subsequent growth is primarily due to more abundant organic vapours of slightly higher volatility (saturation concentrations of 10−4.5 to 10−0.5 micrograms per cubic metre). We present a particle growth model that quantitatively reproduces our measurements. Furthermore, we implement a parameterization of the first steps of growth in a global aerosol model and find that concentrations of atmospheric cloud concentration nuclei can change substantially in response, that is, by up to 50 per cent in comparison with previously assumed growth rate parameterizations.
The growth of freshly formed aerosol particles can be the bottleneck in their survival to cloud condensation nuclei. It is therefore crucial to understand how particles grow in the atmosphere. Insufficient experimental data has impeded a profound understanding of nano-particle growth under atmospheric conditions. Here we study nano-particle growth in the CLOUD (Cosmics Leaving OUtdoors Droplets) chamber, starting from the formation of molecular clusters. We present measured growth rates at sub-3 nm sizes with different atmospherically relevant concentrations of sulphuric acid, water, ammonia and dimethylamine. We find that atmospheric ions and small acid-base clusters, which are not generally accounted for in the measurement of sulphuric acid vapour, can participate in the growth process, leading to enhanced growth rates. The availability of compounds capable of stabilizing sulphuric acid clusters governs the magnitude of these effects and thus the exact growth mechanism. We bring these observations into a coherent framework and discuss their significance in the atmosphere.
The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.
The design, construction, and commissioning of the ALICE Time-Projection Chamber (TPC) is described. It is the main device for pattern recognition, tracking, and identification of charged particles in the ALICE experiment at the CERN LHC. The TPC is cylindrical in shape with a volume close to 90 m3 and is operated in a 0.5 T solenoidal magnetic field parallel to its axis.
In this paper we describe in detail the design considerations for this detector for operation in the extreme multiplicity environment of central Pb–Pb collisions at LHC energy. The implementation of the resulting requirements into hardware (field cage, read-out chambers, electronics), infrastructure (gas and cooling system, laser-calibration system), and software led to many technical innovations which are described along with a presentation of all the major components of the detector, as currently realized. We also report on the performance achieved after completion of the first round of stand-alone calibration runs and demonstrate results close to those specified in the TPC Technical Design Report.
The Tarim River Basin, located in Xinjiang, NW China, is the largest endorheic river basin of China and one of the largest in whole Central Asia. Due to the extremely arid climate with an annual precipitation of less than 100 mm, the water supply along the Aksu and Tarim River solely depends on river water. This applies for anthropogenic activities (e.g. agriculture) as well as for the natural ecosystems so that both compete for water. The on-going increase of water consumption by agriculture and other human activities in this region has been enhancing the competition for water between human needs and nature. Against this background, 11 German and 6 Chinese universities and research institutes formed the consortium SuMaRiO (www.sumario.de), which aims at gaining a holistic picture of the availability of water resources in the Tarim River Basin and the impacts on anthropogenic activities and natural ecosystems caused by the water distribution within the Tarim River Basin. The discharge of the Aksu River, which is the major tributary to the Tarim, has been increasing over the past 6 decades due to enhanced glacier melt. Alone from 1989 to 2011, the area under agriculture more than doubled. Thereby, cotton became the major crop and there was a shift from small-scale farming to large-scale intensive farming. The major natural ecosystems along the Aksu and Tarim River are riparian ecosystems: Riparian (Tugai) forests, shrub vegetation, reed beds, and other grassland. Within the SuMaRiO Cluster the focus was laid on the Tugai forests, with Populus euphratica as dominant tree, because the most productive and species-rich natural ecosystems can be found among those forests. On sites with groundwater distance of less than 7.5 m the annual increments correlated with river runoffs of the previous year. But, the further downstream along the Tarim River, the more the natural river dynamics ceased, which impacts on the recruitment of Populus euphratica. Household surveys revealed that there is a considerable willingness to pay for conservation of those riparian forests with the mitigation of dust and sandstorms considered as the most important ecosystem service. This interdisciplinary project will result in a decision support tool (DST), build on the participation of regional stakeholders and models based on results and field experiments. This DST finally shall assist stakeholders in balancing the water competition acknowledging the major external effects of any water allocation.
Biological invasions are frequently studied topics in ecological research. Unfortunately, within invasion ecology parasite-associated aspects such as parasite impacts on new environments and on local host populations are less well-studied. Round gobies migrating from the Ponto-Caspian region into the Rhine River system are heavily infested with the Ponto-Caspian acanthocephalan parasite Pomphorhynchus laevis. As shown by experimental infestations the acanthocephalans occur as pre-adults in host-encapsulated cysts within the internal organs of the migrating gobies, but remain infective for their definitive host chub. Recently, we described the occurrence of larvae of another parasite, the invasive eel swim bladder nematode Anguillicola crassus, in these Pomphorhynchus cysts. In the present study, we could prove the infectivity of the nematode larvae for European eels for the first time. After experimental inoculation of Pomphorhynchus cysts occasionally infested with A. crassus larvae, the nematodes grow to maturity and reproduce whereas all P. laevis were unviable. We therefore postulate that the nematode larvae behave like immunological hitchhikers that follow a “Trojan horse strategy” in order to avoid the paratenic host’s immune response. Accordingly, the interaction between both invasive parasites gives first evidence that the invasional meltdown hypothesis may also apply to parasites.
Atmospheric new particle formation is a general phenomenon observed over coniferous forests. So far nucleation is described as a function of gaseous sulfuric acid concentration only, which is unable to explain the observed seasonality of nucleation events at different measurement sites. Here we introduce a new nucleation parameter including ozone and water vapor concentrations as well as UV-B radiation as a proxy for OH radical formation. Applying this new parameter to field studies conducted at Finnish and German measurement sites it is found capable to predict the occurrence of nucleation events and their seasonal and annual variation indicating a significant role of organics. Extrapolation to possible future conditions of ozone, water vapor and organic concentrations leads to a significant potential increase in nucleation event number.
While interleukin (IL)-1β is a potent pro-inflammatory cytokine involved in host defense, high levels can cause life-threatening sterile inflammation including systemic inflammatory response syndrome. Hence, the control of IL-1β secretion is of outstanding biomedical importance. In response to a first inflammatory stimulus such as lipopolysaccharide, pro-IL-1β is synthesized as a cytoplasmic inactive pro-form. Extracellular ATP originating from injured cells is a prototypical second signal for inflammasome-dependent maturation and release of IL-1β. The human anti-protease alpha-1 antitrypsin (AAT) and IL-1β regulate each other via mechanisms that are only partially understood. Here, we demonstrate that physiological concentrations of AAT efficiently inhibit ATP-induced release of IL-1β from primary human blood mononuclear cells, monocytic U937 cells, and rat lung tissue, whereas ATP-independent IL-1β release is not impaired. Both, native and oxidized AAT are active, suggesting that the inhibition of IL-1β release is independent of the anti-elastase activity of AAT. Signaling of AAT in monocytic cells involves the lipid scavenger receptor CD36, calcium-independent phospholipase A2β, and the release of a small soluble mediator. This mediator leads to the activation of nicotinic acetylcholine receptors, which efficiently inhibit ATP-induced P2X7 receptor activation and inflammasome assembly. We suggest that AAT controls ATP-induced IL-1β release from human mononuclear blood cells by a novel triple-membrane-passing signaling pathway. This pathway may have clinical implications for the prevention of sterile pulmonary and systemic inflammation.
Plants, fungi and algae are important components of global biodiversity and are fundamental to all ecosystems. They are the basis for human well-being, providing food, materials and medicines. Specimens of all three groups of organisms are accommodated in herbaria, where they are commonly referred to as botanical specimens.The large number of specimens in herbaria provides an ample, permanent and continuously improving knowledge base on these organisms and an indispensable source for the analysis of the distribution of species in space and time critical for current and future research relating to global biodiversity. In order to make full use of this resource, a research infrastructure has to be built that grants comprehensive and free access to the information in herbaria and botanical collections in general. This can be achieved through digitization of the botanical objects and associated data.The botanical research community can count on a long-standing tradition of collaboration among institutions and individuals. It agreed on data standards and standard services even before the advent of computerization and information networking, an example being the Index Herbariorum as a global registry of herbaria helping towards the unique identification of specimens cited in the literature.In the spirit of this collaborative history, 51 representatives from 30 institutions advocate to start the digitization of botanical collections with the overall wall-to-wall digitization of the flat objects stored in German herbaria. Germany has 70 herbaria holding almost 23 million specimens according to a national survey carried out in 2019. 87% of these specimens are not yet digitized. Experiences from other countries like France, the Netherlands, Finland, the US and Australia show that herbaria can be comprehensively and cost-efficiently digitized in a relatively short time due to established workflows and protocols for the high-throughput digitization of flat objects.Most of the herbaria are part of a university (34), fewer belong to municipal museums (10) or state museums (8), six herbaria belong to institutions also supported by federal funds such as Leibniz institutes, and four belong to non-governmental organizations. A common data infrastructure must therefore integrate different kinds of institutions.Making full use of the data gained by digitization requires the set-up of a digital infrastructure for storage, archiving, content indexing and networking as well as standardized access for the scientific use of digital objects. A standards-based portfolio of technical components has already been developed and successfully tested by the Biodiversity Informatics Community over the last two decades, comprising among others access protocols, collection databases, portals, tools for semantic enrichment and annotation, international networking, storage and archiving in accordance with international standards. This was achieved through the funding by national and international programs and initiatives, which also paved the road for the German contribution to the Global Biodiversity Information Facility (GBIF).Herbaria constitute a large part of the German botanical collections that also comprise living collections in botanical gardens and seed banks, DNA- and tissue samples, specimens preserved in fluids or on microscope slides and more. Once the herbaria are digitized, these resources can be integrated, adding to the value of the overall research infrastructure. The community has agreed on tasks that are shared between the herbaria, as the German GBIF model already successfully demonstrates.We have compiled nine scientific use cases of immediate societal relevance for an integrated infrastructure of botanical collections. They address accelerated biodiversity discovery and research, biomonitoring and conservation planning, biodiversity modelling, the generation of trait information, automated image recognition by artificial intelligence, automated pathogen detection, contextualization by interlinking objects, enabling provenance research, as well as education, outreach and citizen science.We propose to start this initiative now in order to valorize German botanical collections as a vital part of a worldwide biodiversity data pool.
Atmospheric new particle formation is a general phenomenon observed over coniferous forests. So far nucleation is either parameterised as a function of gaseous sulphuric acid concentration only, which is unable to explain the observed seasonality of nucleation events at different measurement sites, or as a function of sulphuric acid and organic molecules. Here we introduce different nucleation parameters based on the interaction of sulphuric acid and terpene oxidation products and elucidate the individual importance. They include basic trace gas and meteorological measurements such as ozone and water vapour concentrations, temperature (for terpene emission) and UV B radiation as a proxy for OH radical formation. We apply these new parameters to field studies conducted at conducted at Finnish and German measurement sites and compare these to nucleation observations on a daily and annual scale. General agreement was found, although the specific compounds responsible for the nucleation process remain speculative. This can be interpreted as follows: During cooler seasons the emission of biogenic terpenes and the OH availability limits the new particle formation while towards warmer seasons the ratio of ozone and water vapour concentration seems to dominate the general behaviour. Therefore, organics seem to support ambient nucleation besides sulphuric acid or an OH-related compound. Using these nucleation parameters to extrapolate the current conditions to prognosed future concentrations of ozone, water vapour and organic concentrations leads to a significant potential increase in the nucleation event number.
Background: Targeted therapies have improved therapeutic options of treating renal cell carcinoma (RCC). However, drug response is temporary due to resistance development.
Methods: Functional and molecular changes in RCC Caki-1 cells, after acquired resistance to the mammalian target of rapamycin (mTOR)-inhibitor everolimus (Cakires), were investigated with and without additional application of the histone deacetylase (HDAC)-inhibitor valproic acid (VPA). Cell growth was evaluated by MTT assay, cell cycle progression and apoptosis by flow cytometry. Target molecules of everolimus and VPA, apoptotic and cell cycle regulating proteins were investigated by western blotting. siRNA blockade was performed to evaluate the functional relevance of the proteins.
Results: Everolimus resistance was accompanied by significant increases in the percentage of G2/M-phase cells and in the IC50. Akt and p70S6K, targets of everolimus, were activated in Cakires compared to drug sensitive cells. The most prominent change in Cakires cells was an increase in the cell cycle activating proteins cdk2 and cyclin A. Knock-down of cdk2 and cyclin A caused significant growth inhibition in the Cakires cells. The HDAC-inhibitor, VPA, counteracted everolimus resistance in Cakires, evidenced by a significant decrease in tumor growth and cdk2/cyclin A.
Conclusion: It is concluded that non-response to everolimus is characterized by increased cdk2/cyclin A, driving RCC cells into the G2/M-phase. VPA hinders everolimus non-response by diminishing cdk2/cyclin A. Therefore, treatment with HDAC-inhibitors might be an option for patients with advanced renal cell carcinoma and acquired everolimus resistance.
Background: In many species males face a higher predation risk than females because males display elaborate traits that evolved under sexual selection, which may attract not only females but also predators. Females are, therefore, predicted to avoid such conspicuous males under predation risk. The present study was designed to investigate predator-induced changes of female mating preferences in Atlantic mollies (Poecilia mexicana). Males of this species show a pronounced polymorphism in body size and coloration, and females prefer large, colorful males in the absence of predators. Results: In dichotomous choice tests predator-naïve (lab-reared) females altered their initial preference for larger males in the presence of the cichlid Cichlasoma salvini, a natural predator of P. mexicana, and preferred small males instead. This effect was considerably weaker when females were confronted visually with the non-piscivorous cichlid Vieja bifasciata or the introduced non-piscivorous Nile tilapia (Oreochromis niloticus). In contrast, predator experienced (wild-caught) females did not respond to the same extent to the presence of a predator, most likely due to a learned ability to evaluate their predators' motivation to prey. Conclusions: Our study highlights that (a) predatory fish can have a profound influence on the expression of mating preferences of their prey (thus potentially affecting the strength of sexual selection), and females may alter their mate choice behavior strategically to reduce their own exposure to predators. (b) Prey species can evolve visual predator recognition mechanisms and alter their mate choice only when a natural predator is present. (c) Finally, experiential effects can play an important role, and prey species may learn to evaluate the motivational state of their predators. Keywords: Sexual selection; female choice; non-independent mate choice; predator recognition; Poecilia mexicana
Brain metastases are a common finding upon initial diagnosis of otherwise locally limited non-small cell lung cancer. We present a retrospective case series describing three cases of patients with symptomatic, synchronous brain metastases and resectable lung tumors. The patients received local ablative treatment of the brain metastases followed by neoadjuvant immunochemotherapy with pemetrexed, cisplatin, and pembrolizumab. Afterwards, resection of the pulmonary lesion with curative intent was performed. One patient showed progressive disease 12 months after initial diagnosis, and passed away 31 months after initial diagnosis. Two of the patients are still alive and maintain a good quality of life with a progression-free survival and overall survival of 28 and 35 months, respectively, illustrating the potential of novel combinatorial treatment approaches.
Aims: Somatic mutations in haematopoietic stem cells can lead to the clonal expansion of mutated blood cells, known as clonal haematopoiesis (CH). Mutations in the most prevalent driver genes DNMT3A and TET2 with a variant allele frequency (VAF) ≥ 2% have been associated with atherosclerosis and chronic heart failure of ischemic origin (CHF). However, the effects of mutations in other driver genes for CH with low VAF (<2%) on CHF are still unknown.
Methods and results: Therefore, we analysed mononuclear bone marrow and blood cells from 399 CHF patients by deep error-corrected targeted sequencing of 56 genes and associated mutations with the long-term mortality in these patients (3.95 years median follow-up). We detected 1113 mutations with a VAF ≥ 0.5% in 347 of 399 patients, and only 13% had no detectable CH. Despite a high prevalence of mutations in the most frequently mutated genes DNMT3A (165 patients) and TET2 (107 patients), mutations in CBL, CEBPA, EZH2, GNB1, PHF6, SMC1A, and SRSF2 were associated with increased death compared with the average death rate of all patients. To avoid confounding effects, we excluded patients with DNMT3A-related, TET2-related, and other clonal haematopoiesis of indeterminate potential (CHIP)-related mutations with a VAF ≥ 2% for further analyses. Kaplan–Meier survival analyses revealed a significantly higher mortality in patients with mutations in either of the seven genes (53 patients), combined as the CH-risk gene set for CHF. Baseline patient characteristics showed no significant differences in any parameter including patient age, confounding diseases, severity of CHF, or blood cell parameters except for a reduced number of platelets in patients with mutations in the risk gene set in comparison with patients without. However, carrying a mutation in any of the risk genes remained significant after multivariate cox regression analysis (hazard ratio, 3.1; 95% confidence interval, 1.8–5.4; P < 0.001), whereas platelet numbers did not.
Conclusions: Somatic mutations with low VAF in a distinct set of genes, namely, in CBL, CEBPA, EZH2, GNB1, PHF6, SMC1A, and SRSF2, are significantly associated with mortality in CHF, independently of the most prevalent CHIP-mutations in DNMT3A and TET2. Mutations in these genes are prevalent in young CHF patients and comprise an independent risk factor for the outcome of CHF, potentially providing a novel tool for risk assessment in CHF.
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is an indolent lymphoma, but can transform into diffuse large B cell lymphoma (DLBCL), showing a more aggressive clinical behavior. Little is known about these cases on the molecular level. Therefore, the aim of the present study was to characterize DLBCL transformed from NLPHL (LP-DLBCL) by gene expression profiling (GEP). GEP revealed an inflammatory signature pinpointing to a specific host response. In a coculture model resembling this host response, DEV tumor cells showed an impaired growth behavior. Mechanisms involved in the reduced tumor cell proliferation included a downregulation of MYC and its target genes. Lack of MYC expression was also confirmed in 12/16 LP-DLBCL by immunohistochemistry. Furthermore, CD274/PD-L1 was upregulated in DEV tumor cells after coculture with T cells or monocytes and its expression was validated in 12/19 cases of LP-DLBCL. Thereby, our data provide new insights into the pathogenesis of LP-DLBCL and an explanation for the relatively low tumor cell content. Moreover, the findings suggest that treatment of these patients with immune checkpoint inhibitors may enhance an already ongoing host response in these patients.
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.
Background: Fumaric acid esters (FAEs; Fumaderm®) are the most frequently prescribed first-line systemic treatment for moderate-to-severe plaque psoriasis in Germany. Risankizumab (Skyrizi®) is a humanized IgG1 monoclonal antibody that specifically binds to the p19 subunit of interleukin 23. Objectives: To compare risankizumab treatment to FAEs in patients with psoriasis. Methods: This phase III randomized, active-controlled, open-label study with blinded assessment of efficacy was conducted in Germany. Patients were randomized (1 : 1) to subcutaneous risankizumab 150 mg (weeks 0, 4 and 16) or oral FAEs at increasing doses from 30 mg daily (week 0) up to 720 mg daily (weeks 8–24). Enrolled patients were adults naïve to and candidates for systemic therapy, with chronic moderate-to-severe plaque psoriasis. Phototherapy was not allowed within 14 days before or during the study. Results: Key efficacy endpoints were met at week 24 for risankizumab (n = 60) vs. FAEs (n = 60) (P < 0·001): achievement of a ≥ 90% improvement in Psoriasis Area and Severity Index (PASI; primary endpoint 83·3% vs. 10·0%), ≥ 100% improvement in PASI (50·0% vs. 5·0%), ≥ 75% improvement in PASI (98·3% vs. 33·3%), ≥ 50% improvement in PASI (100% vs. 53·3%) and a Static Physician’s Global Assessment of clear/almost clear (93·3% vs. 38·3%). The rates of gastrointestinal disorders, flushing, lymphopenia and headache were higher in the FAE group. One patient receiving risankizumab reported a serious infection (influenza, which required hospitalization). There were no malignancies, tuberculosis or opportunistic infections in either treatment arm. Conclusions: Risankizumab was found to be superior to FAEs, providing earlier and greater improvement in psoriasis outcomes that persisted with continued treatment, and more favourable safety results, which is consistent with the known safety profile. No new safety signals for risankizumab or FAEs were observed.
There is a need for diagnostic biomarkers of epilepsy and status epilepticus to support clinical examination, electroencephalography and neuroimaging. Extracellular microRNAs may be potentially ideal biomarkers since some are expressed uniquely within specific brain regions and cell types. Cerebrospinal fluid offers a source of microRNA biomarkers with the advantage of being in close contact with the target tissue and sites of pathology. Here we profiled microRNA levels in cerebrospinal fluid from patients with temporal lobe epilepsy or status epilepticus, and compared findings to matched controls. Differential expression of 20 microRNAs was detected between patient groups and controls. A validation phase included an expanded cohort and samples from patients with other neurological diseases. This identified lower levels of miR-19b in temporal lobe epilepsy compared to controls, status epilepticus and other neurological diseases. Levels of miR-451a were higher in status epilepticus compared to other groups whereas miR-21-5p differed in status epilepticus compared to temporal lobe epilepsy but not to other neurological diseases. Targets of these microRNAs include proteins regulating neuronal death, tissue remodelling, gliosis and inflammation. The present study indicates cerebrospinal fluid contains microRNAs that can support differential diagnosis of temporal lobe epilepsy and status epilepticus from other neurological and non-neurological diseases.
Effects of BPA in snails
(2006)
It is an ethical requirement that new findings be presented in light of and in conjunction with a balanced evaluation of the current knowledge and published literature. We believe that Oehlmann et al. (2006) violated this general principle in several ways. For example, the authors inferred that prosobranch snails have a functional estrogen receptor and therefore a much higher sensitivity to estrogens and endocrine-disrupting compounds (EDCs) than other species previously reported in the literature. We found several other problems in their article...
Background: The inclusion of immune checkpoint inhibitors (ICIs) in therapeutic algorithms has led to significant survival benefits in patients with various metastatic cancers. Concurrently, an increasing number of neurological immune related adverse events (IRAE) has been observed. In this retrospective analysis, we examine the ICI-induced incidence of cerebral pseudoprogression and propose a classification system.
Methods: We screened our hospital information system to identify patients with any in-house ICI treatment for any tumor disease during the years 2007-2019. All patients with cerebral MR imaging (cMRI) of sufficient diagnostic quality were included. cMRIs were retrospectively analyzed according to immunotherapy response assessment for neuro-oncology (iRANO) criteria.
Results: We identified 12 cases of cerebral pseudoprogression in 123 patients treated with ICIs and sufficient MRI. These patients were receiving ICI therapy for lung cancer (n=5), malignant melanoma (n=4), glioblastoma (n=1), hepatocellular carcinoma (n=1) or lymphoma (n=1) when cerebral pseudoprogression was detected. Median time from the start of ICI treatment to pseudoprogression was 5 months. All but one patient developed neurological symptoms. Three different patterns of cerebral pseudoprogression could be distinguished: new or increasing contrast-enhancing lesions, new or increasing T2 predominant lesions and cerebral vasculitis type pattern.
Conclusion: Cerebral pseudoprogression followed three distinct patterns and was detectable in 3.2% of all patients during ICI treatment and in 9.75% of the patients with sufficient brain imaging follow up. The fact that all but one of the affected patients developed neurological symptoms, which would be classified as progressive disease according to iRANO criteria, mandates vigilance in the diagnosis and treatment of ICI-induced cerebral lesions.
Background: Epileptic seizures are common clinical features in patients with acute subdural hematoma (aSDH); however, diagnostic feasibility and therapeutic monitoring remain limited. Surface electroencephalography (EEG) is the major diagnostic tool for the detection of seizures but it might be not sensitive enough to detect all subclinical or nonconvulsive seizures or status epilepticus. Therefore, we have planned a clinical trial to evaluate a novel treatment modality by perioperatively implanting subdural EEG electrodes to diagnose seizures; we will then treat the seizures under therapeutic monitoring and analyze the clinical benefit.
Methods: In a prospective nonrandomized trial, we aim to include 110 patients with aSDH. Only patients undergoing surgical removal of aSDH will be included; one arm will be treated according to the guidelines of the Brain Trauma Foundation, while the other arm will additionally receive a subdural grid electrode. The study's primary outcome is the comparison of incidence of seizures and time-to-seizure between the interventional and control arms. Invasive therapeutic monitoring will guide treatment with antiseizure drugs (ASDs). The secondary outcome will be the functional outcome for both groups as assessed via the Glasgow Outcome Scale and modified Rankin Scale both at discharge and during 6 months of follow-up. The tertiary outcome will be the evaluation of chronic epilepsy within 2-4 years of follow-up.
Discussion: The implantation of a subdural EEG grid electrode in patients with aSDH is expected to be effective in diagnosing seizures in a timely manner, facilitating treatment with ASDs and monitoring of treatment success. Moreover, the occurrence of epileptiform discharges prior to the manifestation of seizure patterns could be evaluated in order to identify high-risk patients who might benefit from prophylactic treatment with ASDs.
Trial registration: ClinicalTrials.gov identifier no. NCT04211233.
Background: In September 2018, Burkholderia cepacia complex (BCC) infections in 3 patients associated with exposure to a mouthwash solution (MWS) were reported to the Robert Koch Institute (RKI). As the product was still on the market and the scale of the outbreak was unclear, a nation-wide investigation was initiated.
Methods: We aimed to investigate BCC infections/colonizations associated with MWS. Hospitals, laboratories, and public health services were informed that BCC isolates should be sent to the RKI. These isolates were typed by pulsed-field gel electrophoresis (PFGE) and whole-genome sequencing (WGS) including development of an ad hoc core genome MLST (cgMLST) scheme.
Results: In total, 36 patients from 6 hospitals met the case definition, the last patient in November 2018. Twenty-nine isolates from 26 of these patients were available for typing. WGS analysis revealed 2 distinct cgMLST clusters. Cluster 1 (Burkholderia arboris) contained isolates from patients and MWS obtained from 4 hospitals and isolates provided by the manufacturer. Patient and MWS isolates from another hospital were assigned to cluster 2 (B. cepacia).
Conclusions: The combined clinical, epidemiological, and microbiological investigation, including whole-genome analysis, allowed for uncovering a supraregional BCC outbreak in health care settings. Strains of B. arboris and B. cepacia were identified as contaminating species of MWS bottles and subsequent colonization and putative infection of patients in several hospitals. Despite a recall of the product by the manufacturer in August 2018, the outbreak lasted until December 2018. Reporting of contaminated medical products and recalls should be optimized to protect patients.