Publications by authors named "L Friedrich"

275 Publications

Maternal outcomes and risk factors for COVID-19 severity among pregnant women.

Sci Rep 2021 07 6;11(1):13898. Epub 2021 Jul 6.

Department of Obstetrics & Gynecology, University of Campinas, Campinas, Brazil.

Pregnant women may be at higher risk of severe complications associated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which may lead to obstetrical complications. We performed a case control study comparing pregnant women with severe coronavirus disease 19 (cases) to pregnant women with a milder form (controls) enrolled in the COVI-Preg international registry cohort between March 24 and July 26, 2020. Risk factors for severity, obstetrical and immediate neonatal outcomes were assessed. A total of 926 pregnant women with a positive test for SARS-CoV-2 were included, among which 92 (9.9%) presented with severe COVID-19 disease. Risk factors for severe maternal outcomes were pulmonary comorbidities [aOR 4.3, 95% CI 1.9-9.5], hypertensive disorders [aOR 2.7, 95% CI 1.0-7.0] and diabetes [aOR2.2, 95% CI 1.1-4.5]. Pregnant women with severe maternal outcomes were at higher risk of caesarean section [70.7% (n = 53/75)], preterm delivery [62.7% (n = 32/51)] and newborns requiring admission to the neonatal intensive care unit [41.3% (n = 31/75)]. In this study, several risk factors for developing severe complications of SARS-CoV-2 infection among pregnant women were identified including pulmonary comorbidities, hypertensive disorders and diabetes. Obstetrical and neonatal outcomes appear to be influenced by the severity of maternal disease.
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http://dx.doi.org/10.1038/s41598-021-92357-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260739PMC
July 2021

Learning from Nature: From a Marine Natural Product to Synthetic Cyclooxygenase-1 Inhibitors by Automated De Novo Design.

Adv Sci (Weinh) 2021 Jun 27:e2100832. Epub 2021 Jun 27.

Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 4, Zurich, 8093, Switzerland.

The repertoire of natural products offers tremendous opportunities for chemical biology and drug discovery. Natural product-inspired synthetic molecules represent an ecologically and economically sustainable alternative to the direct utilization of natural products. De novo design with machine intelligence bridges the gap between the worlds of bioactive natural products and synthetic molecules. On employing the compound Marinopyrrole A from marine Streptomyces as a design template, the algorithm constructs innovative small molecules that can be synthesized in three steps, following the computationally suggested synthesis route. Computational activity prediction reveals cyclooxygenase (COX) as a putative target of both Marinopyrrole A and the de novo designs. The molecular designs are experimentally confirmed as selective COX-1 inhibitors with nanomolar potency. X-ray structure analysis reveals the binding of the most selective compound to COX-1. This molecular design approach provides a blueprint for natural product-inspired hit and lead identification for drug discovery with machine intelligence.
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http://dx.doi.org/10.1002/advs.202100832DOI Listing
June 2021

Molecular recognition of structurally disordered Pro/Ala-rich sequences (PAS) by antibodies involves an Ala residue at the hot spot of the epitope.

J Mol Biol 2021 Jun 20;433(18):167113. Epub 2021 Jun 20.

Lehrstuhl für Biologische Chemie, Technische Universität München, Emil-Erlenmeyer-Forum 5, 85354 Freising, Germany; XL-protein GmbH, Lise-Meitner-Strasse 30, 85354 Freising, Germany. Electronic address:

Pro/Ala-rich sequences (PAS) are polypeptides that were developed as a biological alternative to poly-ethylene glycol (PEG) to generate biopharmaceuticals with extended plasma half-life. Like PEG, PAS polypeptides are conformationally disordered and show high solubility in water. Devoid of any charged or prominent hydrophobic side chains, these biosynthetic polymers represent an extreme case of intrinsically disordered proteins. Despite lack of immunogenicity of PAS tags in numerous animal studies we now succeeded in generating monoclonal antibodies (MAbs) against three different PAS versions. To this end, mice were immunized with a PAS#1, P/A#1 or APSA 40mer peptide conjugated to keyhole limpet hemocyanin as highly immunogenic carrier protein. In each case, one MAb with high binding activity and specificity towards a particular PAS motif was obtained. The apparent affinity was strongly dependent on the avidity effect and most pronounced for the bivalent MAb when interacting with a long PAS repeat. X-ray structural analysis of four representative anti-PAS Fab fragments in complex with their cognate PAS epitope peptides revealed interactions dominated by hydrogen bond networks involving the peptide backbone as well as multiple Van der Waals contacts arising from intimate shape complementarity. Surprisingly, Ala, the L-amino acid with the smallest side chain, emerged as a crucial feature for epitope recognition, contributing specific contacts at the center of the paratope in several anti-PAS complexes. Apart from these insights into how antibodies can recognize feature-less peptides without secondary structure, the MAbs characterized in this study offer valuable reagents for the preclinical and clinical development of PASylated biologics.
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http://dx.doi.org/10.1016/j.jmb.2021.167113DOI Listing
June 2021

Effects of omega-3 supplementation on muscle damage after resistance exercise in young women: a randomized placebo-controlled trial.

Nutr Health 2021 Jun 16:2601060211022266. Epub 2021 Jun 16.

Graduate Program on Rehabilitation Sciences, 117303Federal University of Health Sciences of Porto Alegre, Brazil.

Background: Omega-3 is a nutritional strategie that have been used to recover muscles from exercise-induced muscle damage in a preventive perspective.

Aim: To verify whether omega-3 (ω-3) supplementation after a session of resistance exercise facilitates muscle recovery in women undergoing a balanced diet.

Methods: This clinical trial was registered under the number NCT02839525. Thirty healthy women (22.2 ± 3.3 years) participated in this double-blinded, placebo-controlled trial. They were randomly distributed into ω-3 (=15) and placebo (=15) groups. They ingested ω-3 fish oil (3200 mg/day) or placebo (olive oil) at the dinner after the exercise bout (10 sets of 10 unilateral eccentric contractions in a knee extension chair), as well as at lunch for the three subsequent days. In addition, both groups followed a balanced diet along the four days. Muscle soreness and maximal isometric and isokinetic voluntary contractions were assessed immediately before, and 24, 48, and 72 hours after the resistance exercise.

Main Findings: There was no significant group-time interaction for any outcome. Participants presented increased levels of muscle soreness and reduced muscle strength capacity along the three days after exercise. There was no difference between placebo and ω-3 groups.

Conclusion: Supplementation of ω-3 fish oil for three days after resistance exercise provided no additional benefits compared to placebo supplementation on recovery of healthy young women following a balanced diet.
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http://dx.doi.org/10.1177/02601060211022266DOI Listing
June 2021

GABAergic signaling in human and murine NK cells upon challenge with Toxoplasma gondii.

J Leukoc Biol 2021 May 24. Epub 2021 May 24.

Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.

Protective cytotoxic and proinflammatory cytokine responses by NK cells impact the outcome of infections by Toxoplasma gondii, a common parasite in humans and other vertebrates. However, T. gondii can also sequester within NK cells and downmodulate their effector functions. Recently, the implication of GABA signaling in infection and inflammation-related responses of mononuclear phagocytes and T cells has become evident. Yet, the role of GABAergic signaling in NK cells has remained unknown. Here, we report that human and murine NK cells synthesize and secrete GABA in response to infection challenge. Parasitized NK cells secreted GABA, whereas activation stimuli, such as IL-12/IL-18 or parasite lysates, failed to induce GABA secretion. GABA secretion by NK cells was associated to a transcriptional up-regulation of GABA synthesis enzymes (glutamate decarboxylases [GAD65/67]) and was abrogated by GAD inhibition. Further, NK cells expressed GABA-A receptor subunits and GABA signaling regulators, with transcriptional modulations taking place upon challenge with T. gondii. Exogenous GABA and GABA-containing supernatants from parasitized dendritic cells (DCs) impacted NK cell function by reducing the degranulation and cytotoxicity of NK cells. Conversely, GABA-containing supernatants from NK cells enhanced the migratory responses of parasitized DCs. This enhanced DC migration was abolished by GABA-A receptor antagonism or GAD inhibition and was reconstituted by exogenous GABA. Jointly, the data show that NK cells are GABAergic cells and that GABA hampers NK cell cytotoxicity in vitro. We hypothesize that GABA secreted by parasitized immune cells modulates the immune responses to T. gondii infection.
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http://dx.doi.org/10.1002/JLB.3HI0720-431RDOI Listing
May 2021
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