Biology subjects

Mueller, L.

Publications and source records attributed to Mueller, L..

25 records · Page 2Linked to original sources

bioRxiv2021

Design of D-amino acids SARS-CoV-2 Main protease inhibitors using the cationic peptide from rattlesnake venom as a scaffold

The C30 Endopeptidase (3C-like protease; 3CLpro) is essential for the life cycle of SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) since it plays a pivotal role in viral replication and transcription and is hence a promising drug target. Molecules isolated from animals, insects, plants or microorganisms can serve as a scaffold for the design of novel biopharmaceutical products. Crotamine, a small cationic peptide from the venom of the rattlesnake Crotalus durissus terrificus has been the focus of many studies since it exhibits activities such as analgesic, in vitro antibacterial and hemolytic activities. The crotamine derivative L-peptides (L-CDP) that inhibit the 3CL protease in the low {micro}M range were examined since they are susceptible to proteolytic degradation; we explored the utility of their D-enantiomers form. Comparative uptake inhibition analysis showed D-CDP as a promising prototype for a D-peptide-based drug. We also found that the D-peptides can impair SARS-CoV-2 replication in vivo, probably targeting the viral protease 3CLpro.

biochemistry↗

bioRxiv2020

Genome of Solanum pimpinellifolium provides insights into structural variants during tomato breeding

Solanum pimpinellifolium (SP) is the wild progenitor of cultivated tomato. Because of its remarkable stress tolerance and intense flavor, SP has been used as an important germplasm donor in modern breeding of tomato. Here we present a high-quality chromosome-scale genome sequence of SP LA2093. Genome comparison identifies more than 92,000 high-confidence structural variants (SVs) between LA2093 and the modern cultivar, Heinz 1706. Genotyping these SVs in ~600 representative tomato accessions unravels alleles under selection during tomato domestication, improvement and modern breeding, and discovers numerous novel SVs underlying genes known to regulate important breeding traits such as fruit weight and lycopene content. Expression quantitative trait locus (eQTL) analysis detects hotspots harboring master regulators controlling important fruit quality traits, including cuticular wax accumulation and flavonoid biosynthesis, and novel SVs contributing to these complex regulatory networks. The LA2093 genome sequence and the identified SVs provide rich resources for future research and biodiversity-based breeding.

genomics↗

bioRxiv2020

SARS-CoV-2 targets cortical neurons of 3D human brain organoids and shows neurodegeneration-like effects

COVID-19 pandemic caused by SARS-CoV-2 infection is a public health emergency. COVID-19 typically exhibits respiratory illness. Unexpectedly, emerging clinical reports indicate that neurological symptoms continue to rise, suggesting detrimental effects of SARS-CoV-2 on the central nervous system (CNS). Here, we show that a Dusseldorf isolate of SARS-CoV-2 enters 3D human brain organoids within two days of exposure. Using COVID-19 convalescent serum, we identified that SARS-CoV-2 preferably targets soma of cortical neurons but not neural stem cells, the target cell type of ZIKA virus. Imaging cortical neurons of organoids reveal that SARS-CoV-2 exposure is associated with missorted Tau from axons to soma, hyperphosphorylation, and apparent neuronal death. Surprisingly, SARS-CoV-2 co-localizes specifically with Tau phosphorylated at Threonine-231 in the soma, indicative of early neurodegeneration-like effects. Our studies, therefore, provide initial insights into the impact of SARS-CoV-2 as a neurotropic virus and emphasize that brain organoids could model CNS pathologies of COVID-19. One sentence summaryCOVID-19 modeling in human brain organoids

cell biology↗

bioRxiv2019

Chromosomal length reference assembly for Diaphorina citri using single-molecule sequencing and Hi-C proximity ligation with manually curated genes in developmental, structural and immune pathways

BackgroundDiaphorina citri is a vector of "Candidatus Liberibacter asiaticus" (CLas), the gram-negative bacterial pathogen associated with citrus greening disease. Control measures rely on pesticides with negative impacts on the environment, natural ecosystems and human and animal health. In contrast, gene-targeting methods have the potential to specifically target the vector species and/or reduce pathogen transmission. ResultsTo improve the genomic resources needed for targeted pest control, we assembled a D. citri genome based on PacBio long reads followed by proximity ligation-based scaffolding. The 474 Mb genome has 13 chromosomal-length scaffolds. 1,036 genes were manually curated as part of a community annotation project, composed primarily of undergraduate students. We also computationally identified a total of 1,015 putative transcription factors (TFs) and were able to infer motifs for 337 TFs (33 %). In addition, we produced a genome-independent transcriptome and genomes for D. citri endosymbionts. ConclusionsManual annotation provided more accurate gene models for use by researchers and also provided an excellent training opportunity for students from multiple institutions. All resources are available on CitrusGreening.org and NCBI. The chromosomal-length D. citri genome assembly serves as a blueprint for the development of collaborative genomics projects for other medically and agriculturally significant insect vectors.

genomics↗

bioRxiv2019

Network Topology Dynamics of Circulating Biomarkers and Cognitive Performance in Older Cytomegalovirus-seropositive or -seronegative Men and Women

BackgroundCytokines are signaling molecules operating within complex cascade patterns and having exceptional modulatory functions. They impact various physiological processes such as neuroendocrine and metabolic interactions, neurotrophins metabolism, neuroplasticity, and may affect behavior and cognition. In our previous study, we found that sex and Cytomegalovirus (CMV)-serostatus may modulate levels of circulating pro- and anti-inflammatory cytokines, metabolic factors, immune cells, and cognitive performance, as well as associations between them.\n\nResultsIn the present study, we used a graph-theoretical approach to investigate the network topology dynamics of 22 circulating biomarkers and 11 measures of cognitive performance in 161 older participants recruited to undergo a six-months training intervention. For network construction, we applied coefficient of determination (R2) that was calculated for all possible pairs of variables (N = 33) in four groups (CMV- men and women; CMV+ men and women). Network topology has been evaluated by clustering coefficient (CC) and characteristic path length (CPL) as well as local (Elocal) and global (Eglobal) efficiency, showing the degree of network segregation (CC and Elocal) and integration (CPL and Eglobal). We found that networks under consideration showed small-world networks properties with more random characteristics. Mean CC, as well as local and global efficiency were highest and CPL shortest in CMV- males (having lowest inflammatory status and highest cognitive performance). CMV- and CMV+ females did not show any significant differences. Modularity analyses showed that the networks exhibit in all cases highly differentiated modular organization (with Q-value ranged between 0.397 and 0.453).\n\nConclusionsIn this work, we found that segregation and integration properties of the network were notably stronger in the group with balanced inflammatory status. We were also able to confirm our previous findings that CMV-infection and sex modulate multiple circulating biomarkers and cognitive performance and that balanced inflammatory and metabolic status in elderly contributes to better cognitive functioning. Thus, network analyses provide a useful strategy for visualization and quantitative description of multiple interactions between various circulating pro- and anti-inflammatory biomarkers, hormones, neurotrophic and metabolic factors, immune cells, and measures of cognitive performance and can be in general applied for analyzing interactions between different physiological systems.

immunology↗

bioRxiv2017

De-novo assembly of zucchini genome reveals a whole genome duplication associated with the origin of the Cucurbita genus

The Cucurbita genus (squashes, pumpkins, gourds) includes important domesticated species such as C. pepo, C. maxima and C. moschata. In this study, we present a high-quality draft of the zucchini (C. pepo) genome. The assembly has a size of 263 Mb, a scaffold N50 of 1.8 Mb, 34,240 gene models, includes 92% of the conserved BUSCO core gene set, and it is estimated to cover 93.0% of the genome. The genome is organized in 20 pseudomolecules, that represent 81.4% of the assembly, and it is integrated with a genetic map of 7,718 SNPs. Despite its small genome size three independent evidences support that the C. pepo genome is the result of a Whole Genome Duplication: the topology of the gene family phylogenies, the karyotype organization, and the distribution of 4DTv distances. Additionally, 40 transcriptomes of 12 species of the genus were assembled and analyzed together with all the other published genomes of the Cucurbitaceae family. The duplication was detected in all the Cucurbita species analyzed, including C. maxima and C. moschata, but not in the more distant cucurbits belonging to the Cucumis and Citrullus genera, and it is likely to have happened 30 {+/-} 4 Mya in the ancestral species that gave rise to the genus.

genomics↗

bioRxiv2016

Design Specifications for Cellular Regulation

A critical feature of all cellular processes is the ability to control the rate of gene or protein expression and metabolic flux in changing environments through regulatory feedback. We review the many ways that regulation is represented through causal, logical and dynamical components. Formalizing the nature of these components promotes effective comparison among distinct regulatory networks and provides a common framework for the potential design and control of regulatory systems in synthetic biology.

systems biology↗