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Biology subjects

Schenk, L.

Publications and source records attributed to Schenk, L..

5 recordsLinked to original sources

Bridging Bibliometrics and Biology: A Framework for the Relevance Scoring and Biological Stratification of Scalable MeSH Co-occurrence Networks

Systematic literature review is often limited by the rigidity of search strings, which often miss non-obvious but highly relevant topics. Controlled vocabularies such as Medical Subject Headings (MeSH) facilitate the review process, but relationships between terms, and their relevance to a hypothesis of interest, are rarely stated explicitly. Presented here is a MeSH term extraction and networking technique, seeded by a single query for Allergic Contact Dermatitis, forming a "themed" network of terms. The resulting co-occurrence network is pruned by an unsupervised consensus of Metropolis-criterion likelihood search strategies, isolating a significant core subgraph and filtering out incidental co-indexing. Symmetrically normalized Article Relevancy Scores (ARS) then evaluate each article against the network's weighted terms across the annotated MEDLINE corpus, correcting for publication volume bias; Mean Relevancy Scoring (MRS) inverts these scores back onto the terms, scoring each MeSH term by the mean ARS of the articles carrying it to measure its specificity to the query. Benchmarked against the expert-curated Adverse Outcome Pathway (AOP) for Allergic Contact Dermatitis, the network recovered key event terminology and identified highly specific literature that standard retrieval methods overlooked. This data-driven approach quantitatively assesses associated MeSH terminology, extracting biologically relevant concepts and key relationships directly from the underlying structure of the literature. By automating the discovery of these latent connections, the framework provides a reproducible, scalable foundation for understanding the biomedical literary space surrounding a given search string, assisting systematic review creation, mechanistic pathway mapping, and hypothesis generation across biomedical disciplines.

bioinformatics↗

No effects of APOE ε4 on spatial navigation and broader cognition in young adults genetically at risk for Alzheimer's disease

Alzheimers disease (AD) causes progressive memory loss and disorientation. It is preceded by a prolonged preclinical phase marked by pathological changes in medial temporal lobe regions involved in spatial navigation. Spatial navigation tasks have been proposed for early AD detection, and altered navigation performance was reported in older carriers of the apolipoprotein E (APOE) {varepsilon}4 allele, the major genetic risk factor for sporadic AD. However, whether spatial navigation or other cognitive abilities are affected in younger {varepsilon}4 carriers remains unclear. Here, we genotyped 1000 healthy young adults (18-35 years) who completed the app-based navigation game "Sea Hero Quest" and several tasks assessing working memory, processing speed, executive functioning, and face recognition. {varepsilon}4 carriers ({varepsilon}3{varepsilon}4, N = 88) showed no significant differences from non-carriers ({varepsilon}3{varepsilon}3, N = 327) in spatial navigation or other cognitive abilities, supported by equivalence testing and Bayesian analyses. Exploratory findings suggested altered spatial navigation in {varepsilon}2 carriers ({varepsilon}2{varepsilon}2/{varepsilon}2{varepsilon}3/{varepsilon}2{varepsilon}4, Ns = 7/51/7) versus {varepsilon}3{varepsilon}3 controls, who stayed closer to environmental borders and showed better memory updating, face recognition, and processing speed. Therefore, APOE-related behavioural differences in young adults appear small at best, highlighting the need for paradigms sensitive to very subtle changes decades before potential dementia onset.

neuroscience↗

Split-Indigoidine synthetase as optical reporter for benchmarking protein-protein interactions

Indigoidine is a blue pigment biosynthesized by a single-module Non-Ribosomal Peptide Synthetase (NRPS) using L-glutamine as substrate. Despite its potential as a colorimetric reporter, no such system has been established from it to date. We used a recently characterized interdomain fusion site located between its adenylation (A) and thiolation (T) domains to develop the Indi2GO system, which provides a naked-eye detectable and quantitative optical readout of transient and covalent protein-protein-interaction (PPI) in living cells. Indi2GO enables high-throughput benchmarking and optimization of PPI tools in a standard 96-well plate reader format, without requiring exogenous substrates, specialized equipment or complex analytical workflows. We demonstrate its broad applicability with three widely used protein-protein interaction tools: SYNZIPS, inteins, and the SpyTag:SpyCatcher system. We used Indi2GO to validate novel SYNZIP pairs, which we used in NRPS engineering, highlighting its applicability for the development of novel PPI-mediating tools in the context of NRPS engineering and synthetic biology.

synthetic biology↗

Structure of zebrafish NLRP3 reveals a novel mode of inflammasome activation

NLRP3 is an innate immune sensor of a broad range of stimuli, which upon activation forms a multiprotein inflammasome complex triggering caspase-1 activation, IL-1{beta} and IL-18 maturation, and inflammatory cell death. The canonical NLRP3 activation pathway has been well characterized from a structural perspective. It involves the association of NLRP3 with membranes in the form of inactive oligomeric "cage" complexes, which, upon activation, convert to an active oligomeric NLRP3 disc. NLRP3 structural rearrangements during non-classical NLRP3 activation pathways, however, remain unknown. Here, we report a novel mode of NLRP3 activation utilized by the NLRP3 homolog from zebrafish. The cryo-EM structure of zebrafish NLRP3 shows that, unlike human NLRP3, it forms disc-shaped heptamers that undergo further trimerization, resulting in a 21-mer oligomeric arrangement. Surprisingly, a single zebrafish NLRP3 heptamer cannot arrange its PYD domains into a PYD helix and therefore requires a trimer of heptamers to form a PYD filament that enables ASC oligomerization. Furthermore, zebrafish NLRP3 does not associate with the Golgi network, nor does it form inactive "cage" oligomers or interact with NEK7. Thus, our data demonstrate an ancestral non-canonical structural mechanism of NLRP3 activation, which may shed light on alternative NLRP3 activation pathways present in humans.

immunology↗

Evolutionary Inspired Engineering of Megasynthetases

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.

synthetic biology↗