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Case report of long-term postural tachycardia syndrome in a patient after messenger RNA coronavirus disease-19 vaccination with mRNA-1273.
Reiner, MF, Schmidt, D, Frischknecht, L, Ruschitzka, F, Duru, F, Saguner, AM
European heart journal. Case reports. 2023;(8):ytad390
Abstract
BACKGROUND Postural tachycardia syndrome (POTS) is characterized by orthostatic intolerance and heart rate increase in an upright position without orthostatic hypotension. It has been described after coronavirus disease-19 (COVID-19) as well as after COVID-19 vaccination. CASE SUMMARY A 54-year-old female patient presented with a 9-months history of severe orthostatic intolerance since COVID-19 vaccination with messenger RNA (mRNA)-1273 (Spikevax, Moderna). Except for diet-controlled coeliac disease, the patient was healthy, had no allergies, and did not take regular medication. Tilt table testing revealed a significant heart rate increase to 168 bpm without orthostatic hypotension accompanied by light-headedness, nausea, and syncope, findings consistent with POTS. Potential underlying causes including anaemia, thyroid dysfunction, adrenal insufficiency, pheochromocytoma, (auto)-immune disease, chronic inflammation as well as neurological causes were ruled out. Echocardiography and cardiac stress magnetic resonance imaging (MRI) did not detect structural or functional heart disease or myocardial ischaemia. Forty-eight-hour-electrocardiogram (ECG) showed no tachycardias other than sinus tachycardia. Finally, genomic analysis did not detect an inherited arrhythmia syndrome. Serologic analysis revealed adequate immune response to mRNA-1273 vaccination without signs of previous severe acute respiratory syndrome-coronavirus-2 infection. While ivabradine was not tolerated and metoprolol extended release only slightly improved symptoms, physical exercise reduced orthostatic intolerance moderately. At a 5-months follow-up, the patient remained dependant on assistance for activities of daily living. DISCUSSION The temporal association of POTS with the COVID-19 vaccination in a previously healthy patient and the lack of evidence of an alternative aetiology suggests COVID-19 vaccination is the potential cause of POTS in this patient. To our knowledge, this is the first case reporting severe, long-term, and treatment-refractory POTS following COVID-19 vaccination with mRNA1273.
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2.
Screening for Primordial RNA-Peptide Interactions Using High-Density Peptide Arrays.
Jenne, F, Berezkin, I, Tempel, F, Schmidt, D, Popov, R, Nesterov-Mueller, A
Life (Basel, Switzerland). 2023;(3)
Abstract
RNA-peptide interactions are an important factor in the origin of the modern mechanism of translation and the genetic code. Despite great progress in the bioinformatics of RNA-peptide interactions due to the rapid growth in the number of known RNA-protein complexes, there is no comprehensive experimental method to take into account the influence of individual amino acids on non-covalent RNA-peptide bonds. First, we designed the combinatorial libraries of primordial peptides according to the combinatorial fusion rules based on Watson-Crick mutations. Next, we used high-density peptide arrays to investigate the interaction of primordial peptides with their cognate homo-oligonucleotides. We calculated the interaction scores of individual peptide fragments and evaluated the influence of the peptide length and its composition on the strength of RNA binding. The analysis shows that the amino acids phenylalanine, tyrosine, and proline contribute significantly to the strong binding between peptides and homo-oligonucleotides, while the sum charge of the peptide does not have a significant effect. We discuss the physicochemical implications of the combinatorial fusion cascade, a hypothesis that follows from the amino acid partition used in the work.
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[Ocular symptoms in cerebellitis caused by COVID-19 : Cerebellitis, a less noticed disease with neuro-ophthalmological findings].
Schmidt, D
Die Ophthalmologie. 2023;(1):2-6
Abstract
The disease pattern of acute cerebellitis has been increasingly noticed in recent years. Two different courses had been observed. A mild form with slight ataxic disorders (as a postinfectious self-limiting disease) and a fulminant course of cerebellitis with cerebellar swelling, which compresses Sylvius' aqueduct, leading to an increased intracranial pressure with an obstructive hydrocephalus, and downward herniation of the cerebellar tonsils in the foramen magnum. In this case the course can be fatal if neurosurgical emergency treatment comes too late. Cerebellitis has been observed as a sequela to a virus infection and by autoimmune-mediated inflammation. Numerous publications were concerned with childhood cerebellitis but less commonly in adults. Neuro-ophthalmological findings were frequently described as nystagmus (horizontal gaze-evoked nystagmus, vertical nystagmus, downbeat nystagmus, periodic alternating nystagmus), papilledema, more rarely paresis of the abducens or facial nerve, photophobia and very rarely an opsoclonous-myoclonous syndrome. Cerebellitis with neuro-ophthalmological findings has repeatedly been described in adults during the coronavirus disease 2019 (COVID-19) pandemic.
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Investigating the interaction between dietary polyphenols, the SARS CoV-2 spike protein and the ACE-2 receptor.
Schmidt, D, Hakeem Said, I, Ohl, N, Sharifii, M, Cotrell, P, Kuhnert, N
Food & function. 2022;(15):8038-8046
Abstract
The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has called for an urgent need for the identification of compounds able to control, prevent or slow down the global pandemic. Several dietary polyphenols were assayed against binding to the SARS CoV-2 S1 spike protein and the human ACE-2 receptor, the target of the SARS CoV-2 virus using nano differential scanning fluorimetry, suggesting interaction of dietary polyphenols with both proteins. Following this initial screening the two dietary polyphenols with the strongest affinity were evaluated in a second functional binding assay. The assay was based on the thermophoresis of a fluorescently labelled spike protein and the ACE-2 receptor in the presence of dietary concentrations of the polyphenol in question. It could be experimentally shown that 5-caffeoyl quinic acid and epicatechin reduce the binding constant between SARS CoV-2 spike protein of the alpha variant and the ACE-2 receptor by a factor of ten. The finding could as well be applied to black tea and a coffee beverage with dietary 5-CQA concentrations for the alpha variant Spike protein. Hence it can be speculated that a cup of coffee reduces binding of the virus to its human target, therefore reducing the likelihood of infection with SARS CoV-2, acting as a virus entry-inhibitor.
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5.
Endophytic Fungi: Biological Control and Induced Resistance to Phytopathogens and Abiotic Stresses.
Fontana, DC, de Paula, S, Torres, AG, de Souza, VHM, Pascholati, SF, Schmidt, D, Dourado Neto, D
Pathogens (Basel, Switzerland). 2021;(5)
Abstract
Plant diseases cause losses of approximately 16% globally. Thus, management measures must be implemented to mitigate losses and guarantee food production. In addition to traditional management measures, induced resistance and biological control have gained ground in agriculture due to their enormous potential. Endophytic fungi internally colonize plant tissues and have the potential to act as control agents, such as biological agents or elicitors in the process of induced resistance and in attenuating abiotic stresses. In this review, we list the mode of action of this group of microorganisms which can act in controlling plant diseases and describe several examples in which endophytes were able to reduce the damage caused by pathogens and adverse conditions. This is due to their arsenal of molecules generated during the interaction by which they form a kind of biological shield in the plant. Furthermore, considering that endophytic fungi can be an important tool in managing for biotic and abiotic stresses due to the large amount of biologically active substances produced, bioprospecting this class of microorganisms is tending to increase and generate valuable products for agriculture.
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6.
Photoswitchable Azo- and Diazocine-Functionalized Derivatives of the VEGFR-2 Inhibitor Axitinib.
Heintze, L, Schmidt, D, Rodat, T, Witt, L, Ewert, J, Kriegs, M, Herges, R, Peifer, C
International journal of molecular sciences. 2020;(23)
Abstract
In this study, we aimed at the application of the concept of photopharmacology to the approved vascular endothelial growth factor receptor (VEGFR)-2 kinase inhibitor axitinib. In a previous study, we found out that the photoisomerization of axitinib's stilbene-like double bond is unidirectional in aqueous solution due to a competing irreversible [2+2]-cycloaddition. Therefore, we next set out to azologize axitinib by means of incorporating azobenzenes as well as diazocine moieties as photoresponsive elements. Conceptually, diazocines (bridged azobenzenes) show favorable photoswitching properties compared to standard azobenzenes because the thermodynamically stable Z-isomer usually is bioinactive, and back isomerization from the bioactive E-isomer occurs thermally. Here, we report on the development of different sulfur-diazocines and carbon-diazocines attached to the axitinib pharmacophore that allow switching the VEGFR-2 activity reversibly. For the best sulfur-diazocine, we could verify in a VEGFR-2 kinase assay that the Z-isomer is biologically inactive (IC50 >> 10,000 nM), while significant VEGFR-2 inhibition can be observed after irradiation with blue light (405 nm), resulting in an IC50 value of 214 nM. In summary, we could successfully develop reversibly photoswitchable kinase inhibitors that exhibit more than 40-fold differences in biological activities upon irradiation. Moreover, we demonstrate the potential advantage of diazocine photoswitches over standard azobenzenes.
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7.
Is There a Role for Environmental and Metabolic Factors Predisposing to Severe COVID-19?
Bornstein, SR, Voit-Bak, K, Schmidt, D, Morawietz, H, Bornstein, AB, Balanzew, W, Julius, U, Rodionov, RN, Biener, AM, Wang, J, et al
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2020;(7):540-546
Abstract
The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic affects people around the world. However, there have been striking differences in the number of infected individuals and deaths in different countries. Particularly, within Central Europe in countries that are similar in ethnicity, age, and medical standards and have performed similar steps of containment, such differences in mortality rates remain inexplicable. We suggest to consider and explore environmental factors to explain these intriguing variations. Countries like Northern Italy, France, Spain, and UK have suffered from 5 times more deaths from the corona virus infection than neighboring countries like Germany, Switzerland, Austria, and Denmark related to the size of their respective populations. There is a striking correlation between the level of environmental pollutants including pesticides, dioxins, and air pollution such as NO2 known to affect immune function and healthy metabolism with the rate of mortality in COVID-19 pandemic in these European countries. There is also a correlation with the use of chlorination of drinking water in these regions. In addition to the improvement of environmental protective programs, there are possibilities to lower the blood levels of these pollutants by therapeutic apheresis. Furthermore, therapeutic apheresis might be an effective method to improve metabolic inflammation, altered vascular perfusion, and neurodegeneration observed as long-term complications of COVID-19 disease.
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8.
Targeted insertional mutagenesis libraries for deep domain insertion profiling.
Coyote-Maestas, W, Nedrud, D, Okorafor, S, He, Y, Schmidt, D
Nucleic acids research. 2020;(2):e11
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Abstract
Domain recombination is a key principle in protein evolution and protein engineering, but inserting a donor domain into every position of a target protein is not easily experimentally accessible. Most contemporary domain insertion profiling approaches rely on DNA transposons, which are constrained by sequence bias. Here, we establish Saturated Programmable Insertion Engineering (SPINE), an unbiased, comprehensive, and targeted domain insertion library generation technique using oligo library synthesis and multi-step Golden Gate cloning. Through benchmarking to MuA transposon-mediated library generation on four ion channel genes, we demonstrate that SPINE-generated libraries are enriched for in-frame insertions, have drastically reduced sequence bias as well as near-complete and highly-redundant coverage. Unlike transposon-mediated domain insertion that was severely biased and sparse for some genes, SPINE generated high-quality libraries for all genes tested. Using the Inward Rectifier K+ channel Kir2.1, we validate the practical utility of SPINE by constructing and comparing domain insertion permissibility maps. SPINE is the first technology to enable saturated domain insertion profiling. SPINE could help explore the relationship between domain insertions and protein function, and how this relationship is shaped by evolutionary forces and can be engineered for biomedical applications.
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Anti-HLA antibodies with complementary and synergistic interaction geometries promote classical complement activation on platelets.
Rijkers, M, Schmidt, D, Lu, N, Kramer, CSM, Heidt, S, Mulder, A, Porcelijn, L, Claas, FHJ, Leebeek, FWG, Jansen, AJG, et al
Haematologica. 2019;(2):403-416
Abstract
High titers of HLA antibodies are associated with platelet refractoriness, causing poor platelet increments after transfusions in a subset of patients with HLA antibodies. Currently, we do not know the biological mechanisms that explain the variability in clinical responses in HLA alloimmunized patients receiving platelet transfusions. Previously we showed that a subset of anti-HLA IgG-antibodies induces FcγRIIa-dependent platelet activation and enhanced phagocytosis. Here, we investigated whether anti-HLA IgG can induce complement activation on platelets. We found that a subset of anti-HLA IgG induced complement activation via the classical pathway, causing C4b and C3b deposition and formation of the membrane-attack complex. This resulted in permeabilization of platelet membranes and increased calcium influx. Complement activation also caused enhanced α-granule release, as measured by CD62P surface exposure. Blocking studies revealed that platelet activation was caused by FcγRIIa-dependent signaling as well as HLA antibody induced complement activation. Synergistic complement activation employing combinations of monoclonal IgGs suggested that assembly of oligomeric IgG complexes strongly promoted complement activation through binding of IgGs to different antigenic determinants on HLA. In agreement with this, we observed that preventing anti-HLA-IgG hexamer formation using an IgG-Fc:Fc blocking peptide, completely inhibited C3b and C4b deposition. Our results show that HLA antibodies can induce complement activation on platelets including membrane attack complex formation, pore formation and calcium influx. We propose that these events can contribute to fast platelet clearance in vivo in patients refractory to platelet transfusions with HLA alloantibodies, who may benefit from functional-platelet matching and treatment with complement inhibitors.
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Repeating of local therapy of distant metastases increases overall survival in patients with synchronous metastasized rectal cancer-a monocentric analysis.
Haderlein, M, Lettmaier, S, Langheinrich, M, Schmid, A, Semrau, S, Hecht, M, Beck, M, Schmidt, D, Grützmann, R, Fietkau, R, et al
International journal of colorectal disease. 2018;(11):1533-1541
Abstract
PURPOSE The aim was to evaluate the outcome of treatment-naive patients with synchronous metastatic rectal cancer after chemotherapy with FOLFOXIRI followed by local therapeutic procedures of all tumor lesions as complete as possible. METHODS We reviewed data of 30 patients with synchronous distant metastatic rectal cancer who underwent chemotherapy with FOLFOXIRI and subsequent local therapy in our institution. RESULTS Median follow-up was 28 months (range: 8; 74). Cumulative overall survival (OS) and progression-free survival (PFS) was 93.3, 76.9, 55.6% and 46.2, 29.7, 29.7% after 1, 2, 4 years. Non-response to chemotherapy with FOLFOXIRI was associated with a highly significant decreased OS (p < 0.0001). The consistent use of local ablative procedures led to a statistically significant increase in OS (p < 0.0001), but not in PFS (p = 0.635). Patients with ≤ 4 distant metastases showed a better OS (p = 0.033). CONCLUSIONS Response to intensified first-line chemotherapy with FOLFOXIRI, treatment of the primary rectal tumor, and repeated thorough local ablative procedures in patients with synchronous metastasized rectal cancer may lead to long-term survival, even in a subset of patients with unresectable disease at initial diagnosis.