Publications by authors named "Thomas Müller"

1,239 Publications

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Thrombosen durch Autoantikörper.

Authors:
Thomas Müller

CME (Berl) 2021 24;18(6):35. Epub 2021 Jun 24.

Springer Medizin, Neu-Isenburg, Germany.

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http://dx.doi.org/10.1007/s11298-021-2047-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190764PMC
June 2021

Rätsel um Ursache von Long-COVID gelüftet?

Authors:
Thomas Müller

CME (Berl) 2021 24;18(6):20-21. Epub 2021 Jun 24.

Springer Medizin, Neu-Isenburg, Germany.

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http://dx.doi.org/10.1007/s11298-021-2051-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190721PMC
June 2021

A germaaluminocene.

Chem Sci 2020 Feb 10;11(11):2982-2986. Epub 2020 Feb 10.

Institute of Chemistry, Carl von Ossietzky University Oldenburg Carl von Ossietzky-Straße 9-11 D-26129 Oldenburg Federal Republic of Germany

The reactions of dipotassium germacyclopentadienediide with two Group 13 dichlorides, Cp*BCl and Cp*AlCl, yield two structurally different products. In the case of boron a borole complex of germanium(ii) is obtained. The aluminium halide gives an unprecedented neutral germaaluminocene. Both compounds were fully characterised by multinuclear NMR spectroscopy supported by DFT computations. The molecular structure of the germaaluminocene was determined by XRD.
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http://dx.doi.org/10.1039/d0sc00401dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157613PMC
February 2020

Microdroplet Mass Spectrometry Enables Extremely Accelerated Pepsin Digestion of Proteins.

J Am Soc Mass Spectrom 2021 Jun 8. Epub 2021 Jun 8.

Institute of Organic Chemistry and Center for Molecular Biosciences (CMBI), Leopold-Franzens University Innsbruck, 6020 Innsbruck, Austria.

In microdroplets, rates of chemical or biomolecular reactions can exceed those in the bulk phase by more than a million times. As electrospray ionization-based mass spectrometry (MS) involves the formation of charged microdroplets, reaction acceleration and online MS monitoring of reaction products can readily be performed at the same time. We investigated accelerated enzymatic reactions in microdroplets and focused on the proteolytic enzyme pepsin. Electrosonic spray ionization (ESSI) was utilized for developing the ultrarapid pepsin in-spray digestion of two different proteins, cytochrome and RocC, at low pH values. The optimization of the protein digestion aimed at achieving maximum sequence coverage for the analyzed proteins. Furthermore, carefully designed control experiments allowed us to unambiguously prove that enzymatic protein cleavage almost exclusively occurs within the spray at a millisecond time scale and not prior to microdroplet generation.
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http://dx.doi.org/10.1021/jasms.1c00126DOI Listing
June 2021

3,9-Disubstituted Bis[1]benzothieno[3,2-;2',3'-][1,4]thiazines with Low Oxidation Potentials and Enhanced Emission.

J Org Chem 2021 Jun 8;86(12):8000-8014. Epub 2021 Jun 8.

Institut für Organische Chemie und Makromolekulare Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstrasse 1, D-40225 Düsseldorf, Germany.

Dibrominated bis[1]benzothieno[3,2-;2',3'-][1,4]thiazines (BBTT) are efficiently synthesized and applied in Suzuki and Buchwald-Hartwig cross-coupling reactions to give access to 3,9-disubstituted BBTT derivatives with extended π-conjugation and enhanced electronic properties. For instance, 3,9-di(hetero)aryl substituted BBTT derivatives surpass their parent congeners phenothiazines with lower oxidation potentials and pronounced yellow to orange-red fluorescence (Φ ≈ 30-45%). In addition, 3,9-bis(di(hetero)arylamino substituted BBTT possess very high lying HOMO energy ( = -4.46 to -4.83 eV), a favorable property of hole transport molecules. A representative X-ray structure analysis reveals that the central BBTT core in these extended π-systems is essentially planarized. Upon protonation of a 3,9-bis(di(hetero)arylamino) substituted BBTT, the absorption color shifts from yellow to deep blue with a concomitant loss of the emission. The optical properties of these novel BBTT derivatives can be plausibly rationalized by time-dependent density functional theory (TD(DFT)) calculations and correlation between experimentally determined oxidation potentials and σ parameters as well as between photophysical data and the specific substituent parameter σ by establishing electronic structure-property relationships.
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http://dx.doi.org/10.1021/acs.joc.1c00397DOI Listing
June 2021

Three-membered cyclic digermylenes stabilised by an N-heterocyclic carbene.

Chem Sci 2021 Mar 22;12(18):6287-6292. Epub 2021 Mar 22.

Institute of Chemistry, Carl von Ossietzky University of Oldenburg Carl von Ossietzky-Str. 9-11 D-26129 Oldenburg Federal Republic of Germany

Treatment of potassium salts of silole dianions with donor stabilised germanium dichlorides gave the anticipated silagermafulvenylidenes RSi = Ge(Do) (RSi = 1-silacyclopentadiendiyl, Do = N-heterocyclic carbene (NHC)) only as transient intermediates in a side reaction. They were detected by NMR spectroscopy and, in one case, the formal dimer, 2,4-disila-1λ,3λ-digermetane, was isolated. The main products of these reactions are sila-bis-λ-germiranes, directly interconnected digermylenes that are part of a three-membered ring. The structural data, supported by the results of density functional calculations confirm the digermylene nature of these products with a long inner cyclic Ge-Ge bond that decreases the inherent high ring strain in silagermiranes.
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http://dx.doi.org/10.1039/d1sc00956gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115106PMC
March 2021

Omega-3 Fatty Acids and Their Role in Pediatric Cancer.

Nutrients 2021 May 26;13(6). Epub 2021 May 26.

Department of Pediatrics I, Division of Hematology and Oncology, Medical University of Innsbruck, 6020 Innsbruck, Austria.

Background: Malnutrition is common in children with cancer and is associated with adverse clinical outcomes. The need for supportive care is becoming ever more evident and the role of nutrition in oncology is still not sufficiently understood. In particular, the consequences of macro- and micronutrient deficiencies require further research. As epidemiological data suggest anti-tumoral properties of omega-3 (n-3) polyunsaturated fatty acids (PUFAs), we reviewed the role of nutrition and n-3 supplementation in pediatric oncology.

Methods: A comprehensive literature search was conducted on PubMed through 5 February 2021 to select meta-analyses, systematic reviews, observational studies, and individual randomized controlled trials (RCTs) on macro- and micronutrient supplementation in pediatric oncology. The search strategy included the following medical subject headings (MeSH) and keywords: "childhood cancer", "pediatric oncology", "nutritional status", "malnutrition", and "omega-3-fatty-acids". The reference lists of all relevant articles were screened to include potentially pertinent studies.

Results: We summarize evidence about the importance of adequate nutrition in childhood cancer and the role of n-3 PUFAs and critically interpret findings. Possible effects of supplementation on the nutritional status and benefits during chemotherapy are discussed as well as strategies for primary and secondary prevention.

Conclusion: We here describe the obvious benefits of omega-3 supplementation in childhood cancer. Further large scale clinical trials are required to verify potential anti-cancer effects of n-3 fatty acids.
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http://dx.doi.org/10.3390/nu13061800DOI Listing
May 2021

Triazolyl Conjugated (Oligo)Phenothiazines Building Blocks for Hybrid Materials-Synthesis and Electronic Properties.

Molecules 2021 May 15;26(10). Epub 2021 May 15.

Institut für Organische Chemie und Makromolekulare Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstrasse 1, D-40225 Düsseldorf, Germany.

The Cu-catalyzed alkyne-azide 1,3-dipolar cycloaddition variant provides a highly efficient entry to conjugated triazolyl-substituted (oligo)phenothiazine organosilicon derivatives with luminescence and reversible redox characteristics. Furthermore, by in-situ co-condensation synthesis several representative mesoporous MCM-41 type silica hybrid materials with embedded (oligo)phenothiazines are prepared and characterized with respect to their structural and electronic properties. The hybrid materials also can be oxidized to covalently bound embedded radical cations, which are identified by their UV/Vis absorption signature and EPR signals.
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http://dx.doi.org/10.3390/molecules26102950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156644PMC
May 2021

Protective T-cell receptor identification for orthotopic reprogramming of immunity in refractory virus infections.

Mol Ther 2021 May 28. Epub 2021 May 28.

Department of Pediatric Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Germany; German Center for Infection Research (DZIF), partner site Munich.

Viral infections cause life-threatening disease in immunocompromised patients and especially following transplantation. T-cell receptor (TCR) engineering redirects specificity and can bring significant progress to emerging adoptive T-cell transfer (ACT) approaches. T-cell epitopes are well described, whereas knowledge is limited which TCRs mediate protective immunity. Here, refractory adenovirus (AdV) infection after hematopoietic stem cell transplantation (HSCT) was treated with ACT of highly purified Hexon5-specific T cells using pMHC-Streptamers against the immunodominant HLA-A*0101-restricted peptide LTDLGQNLLY. AdV was successfully controlled through this oligoclonal ACT. Novel protective TCRs were isolated ex vivo and preclinically engineered into the TCR locus of allogeneic 3-party primary T cells by CRISPR/Cas9-mediated orthotopic TCR replacement. Both, TCR knock-out and targeted integration of the new TCR in one single engineering step led to physiological expression of the transgenic TCR. Reprogrammed TCR-edited T cells showed strong virus-specific functionality like cytokine release, effector marker upregulation and proliferation capacity, as well as cytotoxicity against LTDLGQNLLY-presenting and AdV-infected targets. In conclusion, ex vivo isolated TCRs with clinical proven protectivity through ACT could be redirected into T cells from naïve 3-party donors. This approach ensures that transgenic TCRs are protective with potential off-the-shelf use and widened applicability of ACT to various refractory emerging viral infections.
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http://dx.doi.org/10.1016/j.ymthe.2021.05.021DOI Listing
May 2021

Biallelic variants in VPS50 cause a neurodevelopmental disorder with neonatal cholestasis.

Brain 2021 May 26. Epub 2021 May 26.

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.

Golgi-associated retrograde protein (GARP) and endosome-associated recycling protein (EARP) complexes are membrane-tethering heterotetramers located at the trans-Golgi network and recycling endosomes, respectively. GARP and EARP share the three subunits VPS51, VPS52, and VPS53, while VPS50 is unique to EARP and VPS54 to GARP. Retrograde transport of endosomal cargos to the TGN is mediated by GARP and endocytic recycling by EARP. Here we report two unrelated individuals with homozygous variants in VPS50, a splice variant (c.1978-1G>T) and an in-frame deletion (p.Thr608del). Both patients had severe developmental delay, postnatal microcephaly, corpus callosum hypoplasia, seizures and irritability, transient neonatal cholestasis, and failure to thrive. Light and transmission electron microscopy of liver from one revealed absence of gamma-glutamyltransferase at bile canaliculi, with mislocalization to basolateral membranes, and abnormal tight junctions. Using patient-derived fibroblasts, we identified reduced VPS50 protein accompanied by reduced levels of VPS52 and VPS53. While transferrin-receptor internalization rate was normal in cells of both patients, recycling of the receptor to the plasma membrane was significantly delayed. These data underscore the importance of VPS50 and/or the EARP complex in endocytic recycling and suggest an additional function in establishing cell polarity and trafficking between basolateral and apical membranes in hepatocytes. Individuals with biallelic hypomorphic variants in VPS50, VPS51 or VPS53 show an overarching neurodegenerative disorder with severe developmental delay, intellectual disability, microcephaly, early-onset epilepsy, and variable atrophy of the cerebellum, cerebrum, and/or brainstem. The term "GARP/EARP deficiency" designates disorders in such individuals.
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http://dx.doi.org/10.1093/brain/awab206DOI Listing
May 2021

Beim Kolonkarzinom ist auf Geschlechterunterschiede zu achten.

Authors:
Thomas Müller

MMW Fortschr Med 2021 May;163(10):14-15

Springer Medizin, Neu-Isenburg, Germany.

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http://dx.doi.org/10.1007/s15006-021-9981-9DOI Listing
May 2021

Honeybee communication during collective defence is shaped by predation.

BMC Biol 2021 May 25;19(1):106. Epub 2021 May 25.

Institute for Theoretical Physics, Universität Innsbruck, Innsbruck, 6020, Austria.

Background: Social insect colonies routinely face large vertebrate predators, against which they need to mount a collective defence. To do so, honeybees use an alarm pheromone that recruits nearby bees into mass stinging of the perceived threat. This alarm pheromone is carried directly on the stinger; hence, its concentration builds up during the course of the attack. We investigate how bees react to different alarm pheromone concentrations and how this evolved response pattern leads to better coordination at the group level.

Results: We first present a dose-response curve to the alarm pheromone, obtained experimentally. This data reveals two phases in the bees' response: initially, bees become more likely to sting as the alarm pheromone concentration increases, but aggressiveness drops back when very high concentrations are reached. Second, we apply Projective Simulation to model each bee as an artificial learning agent that relies on the pheromone concentration to decide whether to sting or not. Individuals are rewarded based on the collective performance, thus emulating natural selection in these complex societies. By also modelling predators in a detailed way, we are able to identify the main selection pressures that shaped the response pattern observed experimentally. In particular, the likelihood to sting in the absence of alarm pheromone (starting point of the dose-response curve) is inversely related to the rate of false alarms, such that bees in environments with low predator density are less likely to waste efforts responding to irrelevant stimuli. This is compensated for by a steep increase in aggressiveness when the alarm pheromone concentration starts rising. The later decay in aggressiveness may be explained as a curbing mechanism preventing worker loss.

Conclusions: Our work provides a detailed understanding of alarm pheromone responses in honeybees and sheds light on the selection pressures that brought them about. In addition, it establishes our approach as a powerful tool to explore how selection based on a collective outcome shapes individual responses, which remains a challenging issue in the field of evolutionary biology.
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http://dx.doi.org/10.1186/s12915-021-01028-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147350PMC
May 2021

Radicals and Anions of Siloles and Germoles.

Chemistry 2021 May 12. Epub 2021 May 12.

Institute of Chemistry, Carl von Ossietzky University Oldenburg, Carl von Ossietzky-Str. 9-11, 26129, Oldenburg, Germany, European Union.

The synthesis of persistent sila- and germacyclopentadienyl (silolyl- and germolyl-) radicals by careful stoichiometric reduction of the corresponding halides with potassium is reported. The radicals were characterized by EPR spectroscopy and trapping reactions. The reduction of tris(trimethylsilyl)silyl-substituted halides was successful while smaller substituents (i. e., t-Butyl, Ph) gave the corresponding dimers. The EPR spectroscopic parameter of the synthesized tetrolyl radicals indicate only small spin delocalization to the butadiene unit due to cross-hyperconjugation. Silolyl- and germolyl anions are unavoidable byproducts and are isolated in the form of their potassium salts and characterized by X-ray crystallography. The comparison of the molecular structures of two closely related potassium silolides provided an example for different coordination of the potassium cation to the silolyl anion (η vs. η coordination) that triggers the switch between delocalized and localized states.
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http://dx.doi.org/10.1002/chem.202101415DOI Listing
May 2021

Pathogenic STX3 variants affecting the retinal and intestinal transcripts cause an early-onset severe retinal dystrophy in microvillus inclusion disease subjects.

Hum Genet 2021 May 11. Epub 2021 May 11.

Department of Neurobiology and Anatomy, MSB 7.046, McGovern Medical School at the University of Texas HSC (UTHealth), 6431 Fannin Street, Houston, TX, 77030, USA.

Biallelic STX3 variants were previously reported in five individuals with the severe congenital enteropathy, microvillus inclusion disease (MVID). Here, we provide a significant extension of the phenotypic spectrum caused by STX3 variants. We report ten individuals of diverse geographic origin with biallelic STX3 loss-of-function variants, identified through exome sequencing, single-nucleotide polymorphism array-based homozygosity mapping, and international collaboration. The evaluated individuals all presented with MVID. Eight individuals also displayed early-onset severe retinal dystrophy, i.e., syndromic-intestinal and retinal-disease. These individuals harbored STX3 variants that affected both the retinal and intestinal STX3 transcripts, whereas STX3 variants affected only the intestinal transcript in individuals with solitary MVID. That STX3 is essential for retinal photoreceptor survival was confirmed by the creation of a rod photoreceptor-specific STX3 knockout mouse model which revealed a time-dependent reduction in the number of rod photoreceptors, thinning of the outer nuclear layer, and the eventual loss of both rod and cone photoreceptors. Together, our results provide a link between STX3 loss-of-function variants and a human retinal dystrophy. Depending on the genomic site of a human loss-of-function STX3 variant, it can cause MVID, the novel intestinal-retinal syndrome reported here or, hypothetically, an isolated retinal dystrophy.
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http://dx.doi.org/10.1007/s00439-021-02284-1DOI Listing
May 2021

Verdoppelte Mortalität bei Demenz-Psychose.

Authors:
Thomas Müller

MMW Fortschr Med 2021 05;163(9):19

Springer Medizin, Neu-Isenburg, Germany.

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http://dx.doi.org/10.1007/s15006-021-9925-4DOI Listing
May 2021

Depressionen über drei Generationen.

Authors:
Thomas Müller

MMW Fortschr Med 2021 05;163(9):18

Springer Medizin, Neu-Isenburg, Germany.

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http://dx.doi.org/10.1007/s15006-021-9926-3DOI Listing
May 2021

Infectious complications and graft outcome following treatment of acute antibody-mediated rejection after kidney transplantation: A nationwide cohort study.

PLoS One 2021 30;16(4):e0250829. Epub 2021 Apr 30.

Transplantation Center, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland.

Acute antibody-mediated rejection (AMR) remains a challenge after kidney transplantation (KT). As there is no clear-cut treatment recommendation, accurate information on current therapeutic strategies in real-life practice is needed. KT recipients from the multicenter Swiss Transplant Cohort Study treated for acute AMR during the first post-transplant year were included retrospectively. We aimed at describing the anti-rejection protocols used routinely, as well as patient and graft outcomes, with focus on infectious complications. Overall, 65/1669 (3.9%) KT recipients were treated for 75 episodes of acute AMR. In addition to corticosteroid boluses, most common therapies included plasmapheresis (56.0%), intravenous immunoglobulins (IVIg) (38.7%), rituximab (25.3%), and antithymocyte globulin (22.7%). At least one infectious complication occurred within 6 months from AMR treatment in 63.6% of patients. Plasmapheresis increased the risk of overall (hazard ratio [HR]: 2.89; P-value = 0.002) and opportunistic infection (HR: 5.32; P-value = 0.033). IVIg exerted a protective effect for bacterial infection (HR: 0.29; P-value = 0.053). The recovery of renal function was complete at 3 months after AMR treatment in 67% of episodes. One-year death-censored graft survival was 90.9%. Four patients (6.2%) died during the first year (two due to severe infection). In this nationwide cohort we found significant heterogeneity in therapeutic approaches for acute AMR. Infectious complications were common, particularly among KT recipients receiving plasmapheresis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250829PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087104PMC
April 2021

Advanced Microscopy for Liver and Gut Ultrastructural Pathology in Patients with MVID and PFIC Caused by MYO5B Mutations.

J Clin Med 2021 Apr 28;10(9). Epub 2021 Apr 28.

Institute of Cell Biology, Medical University of Innsbruck, A-6020 Innsbruck, Austria.

Mutations in the actin motor protein myosinVb (myo5b) cause aberrant apical cargo transport and the congenital enteropathy microvillus inclusion disease (MVID). Recently, missense mutations in myo5b were also associated with progressive familial intrahepatic cholestasis (MYO5B-PFIC). Here, we thoroughly characterized the ultrastructural and immuno-cytochemical phenotype of hepatocytes and duodenal enterocytes from a unique case of an adult MYO5B-PFIC patient who showed constant hepatopathy but only periodic enteric symptoms. Selected data from two other patients supported the findings. Advanced methods such as cryo-fixation, freeze-substitution, immuno-gold labeling, electron tomography and immuno-fluorescence microscopy complemented the standard procedures. Liver biopsies showed mislocalization of Rab11 and bile canalicular membrane proteins. Rab11-positive vesicles clustered around bile canaliculi and resembled subapical clusters of aberrant recycling endosomes in enterocytes from MVID patients. The adult patient studied in detail showed a severe, MVID-specific enterocyte phenotype, despite only a mild clinical intestinal presentation. This included mislocalization of numerous proteins essential for apical cargo transport and morphological alterations. We characterized the heterogeneous population of large catabolic organelles regarding their complex ultrastructure and differential distribution of autophagic and lysosomal marker proteins. Finally, we generated duodenal organoids/enteroids from biopsies that recapitulated all MVID hallmarks, demonstrating the potential of this disease model for personalized medicine.
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http://dx.doi.org/10.3390/jcm10091901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125609PMC
April 2021

Perspective: Treatment for Disease Modification in Chronic Neurodegeneration.

Cells 2021 Apr 12;10(4). Epub 2021 Apr 12.

Center of Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Margarete-Höppel-Platz 1, 97080 Würzburg, Germany.

Symptomatic treatments are available for Parkinson's disease and Alzheimer's disease. An unmet need is cure or disease modification. This review discusses possible reasons for negative clinical study outcomes on disease modification following promising positive findings from experimental research. It scrutinizes current research paradigms for disease modification with antibodies against pathological protein enrichment, such as α-synuclein, amyloid or tau, based on post mortem findings. Instead a more uniform regenerative and reparative therapeutic approach for chronic neurodegenerative disease entities is proposed with stimulation of an endogenously existing repair system, which acts independent of specific disease mechanisms. The repulsive guidance molecule A pathway is involved in the regulation of peripheral and central neuronal restoration. Therapeutic antagonism of repulsive guidance molecule A reverses neurodegeneration according to experimental outcomes in numerous disease models in rodents and monkeys. Antibodies against repulsive guidance molecule A exist. First clinical studies in neurological conditions with an acute onset are under way. Future clinical trials with these antibodies should initially focus on well characterized uniform cohorts of patients. The efficiency of repulsive guidance molecule A antagonism and associated stimulation of neurogenesis should be demonstrated with objective assessment tools to counteract dilution of therapeutic effects by subjectivity and heterogeneity of chronic disease entities. Such a research concept will hopefully enhance clinical test strategies and improve the future therapeutic armamentarium for chronic neurodegeneration.
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http://dx.doi.org/10.3390/cells10040873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069143PMC
April 2021

Full-Genome Sequences and Phylogenetic Analysis of Archived Danish European Bat Lyssavirus 1 (EBLV-1) Emphasize a Higher Genetic Resolution and Spatial Segregation for Sublineage 1a.

Viruses 2021 04 7;13(4). Epub 2021 Apr 7.

Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut (FLI), WHO Collaborating Centre for Rabies Surveillance and Research, OIE Reference Laboratory for Rabies, 17493 Greifswald-Insel Riems, Germany.

European bat lyssavirus type 1 (EBLV-1) is the causative agent for almost all reported rabies cases found in European bats. In recent years, increasing numbers of available EBLV-1 full genomes and their phylogenetic analyses helped to further elucidate the distribution and genetic characteristics of EBLV-1 and its two subtypes, namely EBLV-1a and EBLV-1b. Nonetheless, the absence of full-genome sequences from regions with known detections of EBLV-1 still limit the understanding of the phylogeographic relations between viruses from different European regions. In this study, a set of 21 archived Danish EBLV-1 samples from the years 1985 to 2009 was processed for the acquisition of full-genome sequences using a high-throughput sequencing approach. Subsequent phylogenetic analysis encompassing all available EBLV-1 full genomes from databases revealed the Danish sequences belong to the EBLV-1a subtype and further highlighted the distinct, close phylogenetic relationship of Danish, Dutch and German isolates in this region. In addition, the formation of five putative groups nearly exclusively formed by Danish isolates and the overall increased resolution of the EBLV-1a branch indicate a higher genetic diversity and spatial segregation for this sublineage than was previously known. These results emphasize the importance of phylogenetic analyses of full-genome sequences of lyssaviruses for genetic geography.
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http://dx.doi.org/10.3390/v13040634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067844PMC
April 2021

Argatroban versus heparin in patients without heparin-induced thrombocytopenia during venovenous extracorporeal membrane oxygenation: a propensity-score matched study.

Crit Care 2021 04 29;25(1):160. Epub 2021 Apr 29.

Department of Internal Medicine II, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany.

Background: During venovenous extracorporeal membrane oxygenation (vvECMO), direct thrombin inhibitors are considered by some potentially advantageous over unfractionated heparin (UFH). We tested the hypothesis that Argatroban is non-inferior to UFH regarding thrombosis and bleeding during vvECMO.

Methods: We conducted a propensity-score matched observational non-inferiority study of consecutive patients without heparin-induced-thrombocytopenia (HIT) on vvECMO, treated between January 2006 and March 2019 in the medical intensive care unit at the University Hospital Regensburg. Anticoagulation was realized with UFH until August 2017 and with Argatroban from September 2017 onwards. Target activated partial thromboplastin time was 50 ± 5seconds in both groups. Primary composite endpoint was major thrombosis and/or major bleeding. Major bleeding was defined as a drop in hemoglobin of ≥ 2 g/dl/day or in transfusion of ≥ 2 packed red cells/24 h, or retroperitoneal, cerebral, or pulmonary bleeding. Major thrombosis was defined as obstruction of > 50% of the vessel lumen diameter by means of duplex sonography. We also assessed technical complications such as oxygenator defects or pump head thrombosis, the time-course of platelets, and the cost of anticoagulation (including HIT-testing).

Results: Out of 465 patients receiving UFH, 78 were matched to 39 patients receiving Argatroban. The primary endpoint occurred in 79% of patients in the Argatroban group and in 83% in the UFH group (non-inferiority for Argatroban, p = 0.026). The occurrence of technical complications was equally distributed (Argatroban 49% vs. UFH 42%, p = 0.511). The number of platelets was similar in both groups before ECMO therapy but lower in the UFH group after end of ECMO support (median [IQR]: 141 [104;198]/nl vs. 107 [54;171]/nl, p = 0.010). Anticoagulation costs per day of ECMO were higher in the Argatroban group (€26 [13.8;53.0] vs. €0.9 [0.5;1.5], p < 0.001) but not after accounting for blood products and HIT-testing (€63 [42;171) vs. €40 [17;158], p = 0.074).

Conclusion: In patients without HIT on vvECMO, Argatroban was non-inferior to UFH regarding bleeding and thrombosis. The occurrence of technical complications was similarly distributed. Argatroban may have less impact on platelet decrease during ECMO, but this finding needs further evaluation. Direct drug costs were higher for Argatroban but comparable to UFH after accounting for HIT-testing and transfusions.
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http://dx.doi.org/10.1186/s13054-021-03581-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081564PMC
April 2021

Expanding controlled donation after the circulatory determination of death: stronger emphasis on different cultural, religious and legal backgrounds is needed.

Intensive Care Med 2021 Jun 27;47(6):724-725. Epub 2021 Apr 27.

Department of Clinical Engineering and Department of Intensive Care Medicine, Tokyo Women's Medical University Hospital, Tokyo, Japan.

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http://dx.doi.org/10.1007/s00134-021-06405-2DOI Listing
June 2021

Fluorescent Indolo[3,2-a]phenazines against Toxoplasma gondii: Concise Synthesis by Gold-Catalyzed Cycloisomerization with 1,2-Silyl Migration and ipso-Iodination Suzuki Sequence.

Chemistry 2021 Apr 21. Epub 2021 Apr 21.

Institut für Organische Chemie und Makromolekulare Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany.

A gold-catalyzed cycloisomerization of 2-indolyl-3-[(trimethylsilyl)ethynyl)]quinoxalines with concomitant 1,2-silyl shift forms 6-(trimethylsilyl)indolo[3,2-a]phenazines in moderate to excellent yield. These silylated heterocycles are readily transformed into 6-aryl-indolo[3,2-a]phenazines in moderate to good yield by one-pot ipso-iodination Suzuki coupling. The title compounds represent a novel type of tunable luminophore. Structure-property relationships for 6-aryl-indolo[3,2-a]phenazines obtained from Hammett correlations with σ substituent parameters indicate that emission maxima, Stokes shifts, and fluorescence quantum yields can be fine-tuned by the remote para-aryl substituent. Furthermore, indolo[3,2-a]phenazines were found to exhibit interesting activities against medically relevant pathogens such as the Apicomplexa parasite Toxoplasma gondii with an IC of up to 0.67±0.13 μM. Thus, these compounds are promising candidates for novel anti-parasitic therapies.
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http://dx.doi.org/10.1002/chem.202101391DOI Listing
April 2021

Silylium Ions: From Elusive Reactive Intermediates to Potent Catalysts.

Chem Rev 2021 May 16;121(10):5889-5985. Epub 2021 Apr 16.

Institut für Chemie, Technische Universität Berlin, Strasse des 17 Juni 115, 10623 Berlin, Germany.

The history of silyl cations has all the makings of a drama but with a happy ending. Being considered reactive intermediates impossible to isolate in the condensed phase for decades, their actual characterization in solution and later in solid state did only fuel the discussion about their existence and initially created a lot of controversy. This perception has completely changed today, and silyl cations and their donor-stabilized congeners are now widely accepted compounds with promising use in synthetic chemistry. This review provides a comprehensive summary of the fundamental facts and principles of the chemistry of silyl cations, including reliable ways of their preparation as well as their physical and chemical properties. The striking features of silyl cations are their enormous electrophilicity and as such reactivity as super Lewis acids as well as fluorophilicity. Known applications rely on silyl cations as reactants, stoichiometric reagents, and promoters where the reaction success is based on their steady regeneration over the course of the reaction. Silyl cations can even be discrete catalysts, thereby opening the next chapter of their way into the toolbox of synthetic methodology.
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http://dx.doi.org/10.1021/acs.chemrev.0c00855DOI Listing
May 2021

Experimental Dopamine Reuptake Inhibitors in Parkinson's Disease: A Review of the Evidence.

Authors:
Thomas Müller

J Exp Pharmacol 2021 29;13:397-408. Epub 2021 Mar 29.

Department of Neurology, St. Joseph Hospital Berlin-Weissensee, Berlin, 13088, Germany.

Parkinson's disease (PD) is the second most chronic neurodegenerative disorder worldwide. Deficit of monoamines, particularly dopamine, causes an individually varying compilation of motor and non-motor features. Constraint of presynaptic uptake extends monoamine stay in the synaptic cleft. This review discusses possible benefits of dopamine reuptake inhibition for the treatment of PD. Translation of this pharmacologic principle into positive clinical study results failed to date. Past clinical trial designs did not consider a mandatory, concomitant stable inhibition of glial monoamine turnover, i.e. with monoamine oxidase B inhibitors. These studies focused on improvement of motor behavior and levodopa associated motor complications, which are fluctuations of motor and non-motor behavior. Future clinical investigations in early, levodopa- and dopamine agonist naïve patients shall also aim on alleviation of non-motor symptoms, like fatigue, apathy or cognitive slowing. Oral levodopa/dopa decarboxylase inhibitor application is inevitably necessary with advance of PD. Monoamine reuptake (MRT) inhibition improves the efficacy of levodopa, the blood brain barrier crossing metabolic precursor of dopamine. The pulsatile brain delivery pattern of orally administered levodopa containing formulations results in synaptic dopamine variability. Ups and downs of dopamine counteract the physiologic principle of continuous neurotransmission, particularly in nigrostriatal, respectively mesocorticolimbic pathways, both of which regulate motor respectively non-motor behavior. Thus synaptic dopamine pulsatility overwhelms the existing buffering capacity. Onset of motor and non-motor complications occurs. Future MRT inhibitor studies shall focus on a stabilizing and preventive effect on levodopa related fluctuations of motor and non-motor behavior. Their long-term study designs in advanced levodopa treated patients shall allow a cautious adaptation of oral l-dopa therapy combined with a mandatory inhibition of glial monoamine turnover. Then the evidence for a preventive and beneficial, symptomatic effect of MRT inhibition on motor and non-motor complications will become more likely.
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http://dx.doi.org/10.2147/JEP.S267032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018398PMC
March 2021

Negligible risk of rabies importation in dogs thirty days after demonstration of adequate serum antibody titer.

Vaccine 2021 04 4;39(18):2496-2499. Epub 2021 Apr 4.

Poxvirus and Rabies Branch, Division of High-consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, Center for Disease Control and Prevention, 1600 Clifton Rd NE, Atlanta, GA 30333, USA; World Organisation for Animal Health (OIE) Reference Expert and Laboratory for Rabies.

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http://dx.doi.org/10.1016/j.vaccine.2021.03.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115987PMC
April 2021

[Training module extracorporeal life support (ECLS): consensus statement of the DIVI, DGTHG, DGfK, DGAI, DGIIN, DGF, GRC and DGK].

Anaesthesist 2021 Apr 1. Epub 2021 Apr 1.

Klinik für Akut- und Notfallmedizin, St.-Antonius-Hospital gGmbH, Akademisches Lehrkrankenhaus der RWTH Aachen, Dechant-Deckers-Str. 8, 52249, Eschweiler, Deutschland.

Mechanical circulatory support using extracorporeal life support systems (ECLS) has significantly increased in recent years. These critically ill patients pose special challenges to the multiprofessional treatment team and require comprehensive, interdisciplinary and interprofessional concepts. For this reason, to ensure the best possible patient care a standardized ECLS training module has been created at national specialist society level, taking emergency and intensive care management into account.
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http://dx.doi.org/10.1007/s00101-021-00956-1DOI Listing
April 2021

[Training module extracorporeal life support (ECLS): consensus statement of the DIVI, DGTHG, DGfK, DGAI, DGIIN, DGF, GRC and DGK].

Med Klin Intensivmed Notfmed 2021 Apr 1. Epub 2021 Apr 1.

Klinik für Akut- und Notfallmedizin, St.-Antonius-Hospital gGmbH, Akademisches Lehrkrankenhaus der RWTH Aachen, Dechant-Deckers-Str. 8, 52249, Eschweiler, Deutschland.

Mechanical circulatory support using extracorporeal life support systems (ECLS) has significantly increased in recent years. These critically ill patients pose special challenges to the multiprofessional treatment team and require comprehensive, interdisciplinary and interprofessional concepts. For this reason, to ensure the best possible patient care a standardized ECLS training module has been created at national specialist society level, taking emergency and intensive care management into account.
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http://dx.doi.org/10.1007/s00063-021-00815-2DOI Listing
April 2021

Population genomics and haplotype analysis in spelt and bread wheat identifies a gene regulating glume color.

Commun Biol 2021 Mar 19;4(1):375. Epub 2021 Mar 19.

Center for Desert Agriculture, Biological and Environmental Science and Engineering Division (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.

The cloning of agriculturally important genes is often complicated by haplotype variation across crop cultivars. Access to pan-genome information greatly facilitates the assessment of structural variations and rapid candidate gene identification. Here, we identified the red glume 1 (Rg-B1) gene using association genetics and haplotype analyses in ten reference grade wheat genomes. Glume color is an important trait to characterize wheat cultivars. Red glumes are frequent among Central European spelt, a dominant wheat subspecies in Europe before the 20 century. We used genotyping-by-sequencing to characterize a global diversity panel of 267 spelt accessions, which provided evidence for two independent introductions of spelt into Europe. A single region at the Rg-B1 locus on chromosome 1BS was associated with glume color in the diversity panel. Haplotype comparisons across ten high-quality wheat genomes revealed a MYB transcription factor as candidate gene. We found extensive haplotype variation across the ten cultivars, with a particular group of MYB alleles that was conserved in red glume wheat cultivars. Genetic mapping and transient infiltration experiments allowed us to validate this particular MYB transcription factor variants. Our study demonstrates the value of multiple high-quality genomes to rapidly resolve copy number and haplotype variations in regions controlling agriculturally important traits.
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http://dx.doi.org/10.1038/s42003-021-01908-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979816PMC
March 2021

Different mechanisms of oxygenator failure and high plasma von Willebrand factor antigen influence success and survival of venovenous extracorporeal membrane oxygenation.

PLoS One 2021 18;16(3):e0248645. Epub 2021 Mar 18.

Department of Cardiothoracic Surgery, University Hospital Regensburg, Regensburg, Germany.

Objective: Failure of membrane oxygenator (MO) function of venovenous extracorporeal membrane oxygenators (VV ECMO) remains problematic. The development of device-induced coagulation disorder (COD) or worsened gas transfer (WGT) necessitates a system exchange. The aim was to correlate von Willebrand factor antigen (vWF:Ag) with the predisposition to MO failure and mortality.

Methods: Laboratory parameters (inflammation, coagulation) and ECMO-related data from 31 VV ECMO patients were analyzed before and after the first MO exchange. Study groups were identified according to the exchange reasons (COD, WGT) and the extent of vWF:Ag (low, ≤425%; high, >425%).

Results: vWF:Ag remained unchanged after system exchange. High vWF:Ag was associated with systemic endothelial activation of older and obese patients with elevated SOFA score, increased norepinephrine and higher requirement of continuous renal replacement therapy without an effect on MO runtime and mortality. Including the mechanism of MO failure (COD, WGT), various patient group emerged. COD/low vWF:Ag summarized younger and less critically ill patients that benefit mainly from ECMO by a significant improvement of their inflammatory and coagulation status (CRP, D-dimers, fibrinogen) and highest survival rate (91%). Instead, WGT/high vWF:Ag presented older and more obese patients with a two-digit SOFA score, highest norepinephrine, and aggravated gas transfer. They benefited temporarily from system exchange but with worst survival (33%).

Conclusions: vWF:Ag levels alone cannot predict early MO failure and outcome in VV ECMO patients. Probably, the mechanism of clotting disorder in combination with the vWF:Ag level seems to be essential for clot formation within the MO. In addition, vWF:Ag levels allows the identification different patient populations In particular, WGT/high vWF:Ag represented a critically ill population with higher ECMO-associated mortality.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248645PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971568PMC
March 2021