Biology subjects

Keller, S.

Publications and source records attributed to Keller, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Covalent targeting leads to the development of LIMK1 isoform-selective inhibitors

Selectivity for closely related isoforms of protein kinases is a major challenge in the design of drugs and chemical probes. Covalent targeting of unique cysteines is a potential strategy to achieve selectivity for highly conserved binding sites. Here, we used a pan-LIMK inhibitor to selectively probe LIMK1 over LIMK2 by targeting the LIMK1-specific cysteine C349 located in the glycine-rich loop region. Binding kinetics of both non-covalent and covalent LIMK inhibitors were investigated, and the fast on-rate and small size of type-I inhibitors were used in the design of a covalent LIMK1 inhibitor. The developed cell-active, isoform-selective LIMK1 inhibitor showed excellent proteome-wide selectivity in pull-down assays, enabling studies of LIMK1 isoform-selective functions in cellular model systems and providing a versatile chemical tool for studies of the LIMK signalling pathway.

biochemistry↗

bioRxiv2025

Clear Native Gel Electrophoresis for the Purification of Fluorescently Labeled Membrane Proteins in Native Nanodiscs

Native gel electrophoresis techniques, such as blue or clear native gel electrophoresis (BNE or CNE), are widely used to separate and characterize proteins. However, in high-resolution CNE, mild anionic or neutral detergents are often used at concentrations too low to prevent membrane-protein aggregation. Additionally, the identification of proteins is hampered by the lack of suitable molecular-weight markers, like those used in SDS-PAGE. Here, we introduce a novel approach that combines charged polymer-encapsulated nanodiscs and fluorescence correlation spectroscopy (FCS) to address both challenges. Membrane proteins are first extracted using Glyco-DIBMA, a negatively charged amphiphilic copolymer. This enables the spontaneous formation of nanodiscs harboring the fluorescently labeled target protein within a native-like lipid-bilayer environment, which is confirmed by FCS. The nanodiscs are then subjected to detergent-free CNE. As the number of protomers increases, the nanodiscs grow larger resulting in increased migration distances in CNE due to higher charge densities. Crucially, the nanodiscs remain intact throughout CNE, as demonstrated by FCS analysis of resolubilized bands excised from the gels. Moreover, the membrane proteins used in this study: a potassium channel (KvAP), a sodium channel (NavMs), a water channel (GlpF), and a urea channel (HpUreI) do not aggregate, as shown by the fluorescent brightnesses and diffusion times of individual nanodiscs. Moreover, the oligomeric states of membrane proteins can be deduced from the brightness per nanodisc. Since purified membrane proteins remain within a native-like lipid-bilayer environment and avoid detergent exposure, they are immediately suitable for downstream structural and functional studies.

biophysics↗

bioRxiv2025

Vertical RAS-pathway inhibition in pancreatic cancer drives therapeutically exploitable mitochondrial alterations

Background & AimsOncogenic KRAS mutations drive metabolic rewiring in pancreatic ductal adenocarcinoma (PDAC). Src-homology 2 domain-containing phosphatase 2 (SHP2) is essential for full KRAS activity and promising dual SHP2/mitogen-activated protein kinase (MAPK) inhibition is currently being tested in clinical trials. Exploitable metabolic adaptations may contribute to an invariably evolving resistance. MethodsTo understand the metabolic changes induced by dual inhibition, we comprehensively tested cell lines, endogenous tumor models, and patient-derived organoids representing the full spectrum of PDAC molecular subtypes. ResultsWe find that dual SHP2/mitogen-activated protein kinase kinase (MEK1/2) inhibition induces major mitochondrial alterations, elevates reactive oxygen species (ROS) levels and triggers a lipid peroxidase dependency. While anabolic pathways, glycolysis and autophagy were also affected, mitochondrial alterations persisted longterm into a therapy resistant state. ConclusionsThe resulting vulnerability to induction of ferroptotic cell death via combined SHP2/MEK1/2 and glutathione peroxidase (GPX4) inhibition provides a metabolic lever to reinforce RAS-pathway inhibition for targeted PDAC treatment.

cancer biology↗

bioRxiv2025

Does white matter structure relate to hemispheric language lateralisation? A systematic review

The relationship between functional language lateralisation and diffusion MRI-based white matter metrics remains a subject of considerable interest and complexity. This systematic review aims to synthesise existing diffusion MRI studies examining white matter correlates of functional language dominance. Twenty-five studies were identified through searches of Web of Science, Scopus, and Ovid MEDLINE (search period: inception to 16th March 2023) involving adults with epilepsy, tumours, or healthy controls. The results suggest that while the arcuate fasciculus, particularly its fractional anisotropy (FA), is commonly associated with language lateralisation in clinical populations, the findings in healthy individuals are more variable, often influenced by factors such as handedness. Other white matter tracts, including the corpus callosum and uncinate fasciculus, showed less consistent associations with language dominance across studies. Interestingly, temporal lobe regions, especially those involved in semantic processing, exhibited stronger correlations with diffusion measures compared to areas associated with phonological tasks. Methodological inconsistencies, such as variability in sample selection, task design, and analytical techniques, were identified as significant challenges in comparing findings across studies. Future research should aim for larger, more diverse sample sizes, whole- brain approaches, and a wider range of fMRI tasks to better elucidate the role of white matter in language lateralisation. If regions of interest (ROI)-based studies are utilised, a more standardised approach to tract segmentation should be adopted to ensure consistency and improve comparability across studies.

neuroscience↗

bioRxiv2024

An asymmetric nautilus-like HflK/C assembly controls FtsH proteolysis of membrane proteins

FtsH, a AAA protease, associates with HflK/C subunits to form a megadalton complex that spans the inner membrane and extends into the periplasm of E. coli. How this complex and homologous assemblies in eukaryotic organelles recruit, extract, and degrade membrane-embedded substrates is unclear. Following overproduction of protein components, recent cryo-EM structures reveal symmetric HflK/C cages surrounding FtsH in a manner proposed to inhibit degradation of membrane-embedded substrates. Here, we present structures of native complexes in which HflK/C instead forms an asymmetric nautilus-like assembly with an entryway for membrane-embedded substrates to reach and be engaged by FtsH. Consistent with this nautilus-like structure, proteomic assays suggest that HflK/C enhances FtsH degradation of certain membrane-embedded substrates. The membrane curvature in our FtsH{middle dot}HflK/C complexes is opposite that of surrounding membrane regions, a property that correlates with lipid-scramblase activity and possibly with FtsHs function in the degradation of membrane-embedded proteins.

biochemistry↗

bioRxiv2024

Deep Learning-based Modeling for Preclinical Drug Safety Assessment

In drug development, assessing the toxicity of candidate compounds is crucial for successfully transitioning from preclinical research to early-stage clinical trials. Drug safety is typically assessed using animal models with a manual histopathological examination of tissue sections to characterize the dose-response relationship of the compound - a timeintensive process prone to inter-observer variability and predominantly involving tedious review of cases without abnormalities. Artificial intelligence (AI) methods in pathology hold promise to accelerate this assessment and enhance reproducibility and objectivity. Here, we introduce TRACE, a model designed for toxicologic liver histopathology assessment capable of tackling a range of diagnostic tasks across multiple scales, including situations where labeled data is limited. TRACE was trained on 15 million histopathology images extracted from 46,734 digitized tissue sections from 157 preclinical studies conducted on Rattus norvegicus. We show that TRACE can perform various downstream toxicology tasks spanning histopathological response assessment, lesion severity scoring, morphological retrieval, and automatic dose-response characterization. In an independent reader study, TRACE was evaluated alongside ten board-certified veterinary pathologists and achieved higher concordance with the consensus opinion than the average of the pathologists. Our study represents a substantial leap over existing computational models in toxicology by offering the first framework for accelerating and automating toxicological pathology assessment, promoting significant progress with faster, more consistent, and reliable diagnostic processes. Live Demo: https://mahmoodlab.github.io/tox-foundation-ui/

bioinformatics↗

bioRxiv2024

Capturing G protein-coupled receptors into native lipid-bilayer nanodiscs using new diisobutylene/maleic acid (DIBMA) copolymers

Many membrane proteins, including G-protein-coupled receptors (GPCRs), are susceptible to denaturation when extracted from their native membrane by detergents. Therefore, alternative methods have been developed, including amphiphilic copolymers that enable the direct extraction of functional membrane proteins along with their surrounding lipids, leading to the formation of native lipid-bilayer nanodiscs. Among these amphiphilic copolymers, styrene/maleic acid (SMA) and diisobutylene/maleic acid (DIBMA) polymers have been extensively studied and successfully utilized to isolate various types of membrane proteins, including GPCRs. Despite their many benefits, SMA and DIBMA polymers also have significant drawbacks that limit their application. Most notably, both SMA and DIBMA carry high negative charge densities, which can interfere with protein-protein and protein-lipid interactions through unspecific Coulombic attraction or repulsion. Herein, we describe a series of new amphiphilic copolymers derived from DIBMA via partial amidation of the carboxylate pendant groups with various biocompatible amines. The nanodisc-forming properties of the new polymers were assessed using model membranes as well as in the context of extracting the melanocortin 4 receptor (MC4R), a prototypical class A GPCR. While each new DIBMA variant displays distinct features that may be favorable for selected applications, we identified a new PEGylated DIBMA variant called mPEG4-DIBMA as particularly promising for the studied purpose. On the one hand, mPEG4-DIBMA abolishes unspecific interactions with the tested peptide ligand, a prerequisite for reliably characterizing GPCR-ligand interactions. On the other hand, mPEG4-DIBMA outperforms other polymers such as SMA and DIBMA by achieving higher extraction efficiencies of MC4R from Sf9 insect cell membranes. Thus, this new nanodisc-forming polymer combines two key advantages that are crucial for investigating GPCRs in a well-defined but still native lipid-bilayer environment, thus paving the way for manifold future applications.

biochemistry↗

bioRxiv2024

Methane and ethane production rates by methyl-coenzyme M reductase in cell extracts from different methanogens

The enzyme methyl-coenzyme M reductase (Mcr) is responsible for most of the biologically produced methane. Mcr catalyzes the reversible conversion of methyl-coenzyme M and coenzyme B to methane and the corresponding heterodisulfide CoM-S-S-CoB as the last step in all methanogens. In anaerobic methanotrophs, it catalyzes the same reaction to proceed in the reverse direction. While Mcr has been historically considered as an enzyme exclusive to the one-carbon metabolism, recent studies have demonstrated that homologs of Mcr have evolved to catalyze the first step of the archaeal anaerobic oxidation of medium and long-chain alkanes to their corresponding alkyl-coenzyme M thioethers. While ample metagenomic studies and data related to Mcr is available, in vitro experiments are limited, because purifying Mcr in its active nickel-I form is challenging. Fully active enzyme has only been reported for Methanothermobacter marburgensis isoenzyme I, from which most of the enzyme studies have been performed. To get an overview of the substrate scope of different Mcr variants, we tested cell-free lysates from the methanogens Methanosarcina mazei, Methanosarcina acetivorans, Methanococcus maripaludis, Methanothermococcus okinawensis, and M. marburgensis for their rates to convert methyl- and ethyl-coenzyme M to methane and to ethane, respectively. Cell extracts from M. mazei showed an ethane production rate of ca. 8% relative to methane production at 37 {degrees}C, and about 14% at 49 {degrees}C in an assay relying on titanium (III) citrate and cobalamin to regenerate coenzyme B from the CoM-S-S-CoB heterodisulfide. For cell extracts of M. marburgensis, we found an ethane-to-methane production rate of 8%, which is substantially higher than the reported value of ca. 0.3% for the ratio of their maximal catalytic rate for purified isoenzyme I. Since M. marburgensis is known to express two isoenzymes depending on the growth conditions, we hypothesize that isoenzyme II is substantially more promiscuous towards ethane formation than the well-described isoenzyme I. Which it is still challenging to obtain accurate kinetic parameters of the Mcr-catalyzed reaction, our experiments demonstrate that Mcr activity can be quickly and conveniently studied via cell-free lysates, and that substrate promiscuity towards ethane formation is generally larger than anticipated.

biochemistry↗

bioRxiv2022

Training the next generation of researchers in the Organ-on-Chip field

Organ-on-chip (OoC) technology bridges the principles of biology and engineering to create a new generation of in vitro models and involves highly interdisciplinary collaboration across STEM disciplines. Training the next generation of scientists, technicians and policy makers is a challenge that requires a tailored effort. To promote the qualification, usability, uptake and long-term development of OoC technology, we designed a questionnaire to evaluate the key aspects for training, identify the major stakeholders to be trained, their professional level and specific skillset. The 151 respondents unanimously agreed on the need to train the next generation of OoC researchers and that the training should be provided early, in interdisciplinary subjects and throughout the researchers career. We identified two key training priorities: (i) training scientists with a biology background in microfabrication and microfluidics principles and (ii) training OoC developers in pharmacology/toxicology. This makes training in OoC a transdisciplinary challenge rather than an interdisciplinary one. The data acquired and analyzed here serves to guide training initiatives for preparing competent and transdisciplinary researchers, capable of assuring the successful development and application of OoC technologies in academic research, pharmaceutical/chemical/cosmetic industries, personalized medicine and clinical trials on chip.

scientific communication and education↗

bioRxiv2021

MetaProFi: A protein-based Bloom filter for storing and querying sequence data for accurate identification of functionally relevant genetic variants

Technological advances of next-generation sequencing present new computational challenges to develop methods to store and query these data in time- and memory-efficient ways. We present MetaProFi (https://github.com/kalininalab/metaprofi), a Bloom filter-based tool that, in addition to supporting nucleotide sequences, can for the first time directly store and query amino acid sequences and translated nucleotide sequences, thus bringing sequence comparison to a more biologically relevant protein level. Owing to the properties of Bloom filters, it has a zero false-negative rate, allows for exact and inexact searches, and leverages disk storage and Zstandard compression to achieve high time and space efficiency. We demonstrate the utility of MetaProFi by indexing UniProtKB datasets at organism- and at sequence-level in addition to the indexing of Tara Oceans dataset and the 2585 human RNA-seq experiments, showing that MetaProFi consumes far less disk space than state-of-the-art-tools while also improving performance.

bioinformatics↗

bioRxiv2021

Protein abundance and folding rather than the redox state of Kelch13 determine the artemisinin susceptibility of Plasmodium falciparum

Decreased susceptibilities of Plasmodium falciparum towards the endoperoxide antimalarial artemisinin are linked to mutations of residue C580 of Kelch13, which is the homologue of the redox sensor Keap1 in vertebrates. Here, we addressed whether mutations alter the artemisinin susceptibility by modifying the redox properties of Kelch13 or by compromising its native fold or abundance. Using selection-linked integration and the glmS ribozyme, efficient down-regulation of Kelch13 resulted in ring-stage survival rates around 40%. While the loss of a potential disulfide bond between residues C580 and C532 had no effect on the artemisinin suceptibility, the thiol group of C473 could not be replaced. We also established a protocol for the production of recombinant Kelch13. In contrast to cysteine-to-serine replacements, common field mutations resulted in misfolded and insoluble protein. In summary, not the redox properties but impaired folding of Kelch13, resulting in a decreased Kelch13 abundance, is the central parameter for mutant selection.

biochemistry↗

bioRxiv2021

A Bioinspired Glycopolymer for Capturing Membrane Proteins in Native-Like Lipid-Bilayer Nanodiscs

Amphiphilic copolymers that directly extract membrane proteins and lipids from cellular membranes to form nanodiscs combine the advantages of harsher membrane mimics with those of a native-like membrane environment. Among the few commercial polymers that are capable of forming nanodiscs, alternating diisobutylene/maleic acid (DIBMA) copolymers have gained considerable popularity as gentle and UV-transparent alternatives to aromatic polymers. However, their moderate hydrophobicities and high electric charge densities render all existing aliphatic copolymers rather inefficient under near-physiological conditions. Here, we introduce Glyco-DIBMA, a bioinspired glycopolymer that possesses increased hydrophobicity and reduced charge density but nevertheless retains excellent solubility in aqueous solutions. Glyco-DIBMA outperforms established aliphatic copolymers in that it solubilizes lipid vesicles of various compositions much more efficiently, thereby furnishing smaller, more narrowly distributed nanodiscs that preserve a bilayer architecture and exhibit rapid lipid exchange. We demonstrate the superior performance of Glyco-DIBMA in preparative and analytical applications by extracting a broad range of integral membrane proteins from cellular membranes and further by purifying a membrane-embedded voltage-gated K+ channel, which was fluorescently labeled and analyzed with the aid of microfluidic diffusional sizing (MDS) directly within native-like lipid-bilayer nano-discs.

biochemistry↗

bioRxiv2020

The secreted hypersensitive response inducing protein 1 from Botrytis cinerea displays non-canonical PAMP-activity

According to their lifestyle, plant pathogens are divided into biotrophic and necrotrophic organisms. While biotrophic pathogens establish a relationship with living host cells, necrotrophic pathogens rapidly kill host cells and feed on the cell debris. To this end, the necrotrophic ascomycete fungus Botrytis cinerea secretes large amounts of phytotoxic proteins and cell wall degrading enzymes. However, the precise role of these proteins during the infection process is unknown. Here we report on the identification and characterization of the previously unknown toxic protein hypersensitive response inducing protein 1 (Hip1), which induces plant cell death. We found the adoption of a folded protein structure to be a prerequisite for Hip1 to exert its necrosis-inducing activity in Nicotiana benthamiana. Localization and the induction of specific plant responses by Hip1 indicate recognition as pathogen-associated molecular pattern at the plant plasma membrane. Our results demonstrate that recognition of Hip1, even in the absence of obvious enzymatic or poreforming activity, induces strong plant defense reactions eventually leading to plant cell death.

plant biology↗

bioRxiv2020

Experimental Reptarenavirus Infection of Boa constrictor and Python regius

Boid inclusion body disease (BIBD) causes losses in captive constrictor snake populations globally. BIBD associates with formation of cytoplasmic inclusion bodies (IB) which mainly comprise reptarenavirus nucleoprotein (NP). In 2017, BIBD was reproduced by cardiac injection of boas and pythons with reptarenaviruses, thus demonstrating a causative link between reptarenavirus infection and the disease. Herein, we report experimental infections of pythons (N=16) and boas (N=16) with three reptarenavirus isolates. First, we used pythons (N=8) to test two virus delivery routes: intraperitoneal injection and tracheal instillation. Independent of the delivery route, we detected viral RNA but no IBs in tissues two weeks post inoculation. Next, we inoculated pythons (N=8) via the trachea. During the four month following the infection snakes showed transient central nervous system (CNS) signs but lacked detectable IB at the time of euthanasia. One of the snakes developed severe CNS signs and we succeeded in re-isolating the virus from the brain of this individual, and could demonstrate viral antigen in neurons. In a third attempt, we tested co-housing, vaccination, and sequential infection with multiple reptarenavirus isolates on boas (N=16). At 10 months post inoculation all except one snake tested positive for viral RNA but none exhibited the characteristic IB. Analysis of the antibody responses demonstrated lower neutralizing but higher anti-reptarenavirus NP titers in experimentally versus naturally reptarenavirus infected boas. Our findings suggest that in addition to reptarenavirus infection, other factors, e.g. the antibody response, contribute to BIBD pathogenesis. IMPORTANCEA 2017 study demonstrated cardiac reptarenavirus injection to induce boid inclusion body disease (BIBD) in pythons and boas. In the present study, we experimentally infected pythons and boas with reptarenavirus via either intraperitoneal injection or tracheal instillation. We found both virus delivery routes to result in infection; though the latter could reflect the natural route of infection. In the experimentally infected snakes, we did not find evidence of inclusion body (IB) formation, characteristic to BIBD, in pythons or in boas. Most of the snakes (11/12) studied were reptarenavirus infected after ten-month follow up, which suggests that they could eventually have developed BIBD. We further found differences between the antibody responses of experimentally and naturally reptarenavirus infected snakes, which could indicate that the pathogenesis of BIBD involves factors additional to reptarenavirus infection. As snakes are poikilotherm, also the housing conditions could have an effect.

microbiology↗

bioRxiv2020

Frequent subgraph mining for biologically meaningful structural motifs

Identification of biologically relevant motifs in proteins is a long-standing problem in bioinformatics, especially when considering distantly related proteins where sequence analysis alone becomes increasingly difficult. Here we present a novel approach to identify such motifs in protein three-dimensional structures without depending on sequence alignment by representing structures as graphs in the form of residue interaction networks and employing a modified frequent subgraph mining algorithm. These networks represent residues as vertices while contacts between residues are denoted by edges labeled with Euclidean distances. We use frequent subgraph mining to determine all subgraphs that are subgraph isomorphic to, i.e. are contained in, at least a given number of such networks generated from structures in the same protein family. For this we introduce two extensions of the classical frequent subgraph mining: approximate matching of distance-based labels to account for small variations between protein structures and scoring as well as score-based filtering of subgraphs in order to identify structurally conserved motifs and to counteract the expanding size of the search space. This approach was then validated by demonstrating that it can rediscover previously characterized functionally important structural motifs in selected protein families. For further validation we show that it is also able to identify motifs that correspond to patterns in the PROSITE database. We then applied our approach to all superfamilies in the SCOP database and found an enrichment of residues in the ligand binding site in the discovered motifs evidencing their functional importance. Finally we use the approach to discover a novel structural motif in jelly-roll capsid proteins found in members of the picornavirus-like superfamily. This is presented together with an efficient open source implementation of the algorithm called RINminer. Author summaryAs the evolutionary distance between proteins increases, their sequence identity drops rapidly, whereas functionally important sequence motifs and three-dimensional (3D) structural scaffold, in which they are embedded, are more conserved. We developed an approach that automatically identifies such motifs by converting protein 3D structures into a set of graphs and then employing the frequent subgraph mining framework. In these graphs, residues are represented as vertices, and if two residues interact in the corresponding protein 3D structure, they are connected by an edge labeled with the Euclidean distance between the residues. In the classical setting of frequent subgraph mining, all subgraphs from a database of graphs are enumerated and the ones that are exactly found, i.e. are subgraph isomorphic, in more than a certain number of graphs are listed as supported. Our approach introduces two new concepts: approximately isomorphic subgraphs and an efficient scoring scheme that allows to retain only biologically relevant subgraph in the enumeration step. Approximate isomorphism allows edge labels not to match exactly, and thus account for natural deviations between 3D structures of related proteins. With our approach, we were able to automatically rediscover known motifs from PROSITE, as well as in three well-studied extremely diverse protein families. We predicted functionally important residues in SCOP superfamilies and demonstrated that they tend to lie in structurally meaningful regions: ligand-binding sites and protein core. Additionally, we present a previously unreported structural motif in jelly-roll viral capsids.

bioinformatics↗

bioRxiv2020

Abundance and localization of human UBE3A protein isoforms

Loss of UBE3A expression, a gene regulated by genomic imprinting, causes Angelman Syndrome (AS), a rare neurodevelopmental disorder. The UBE3A gene encodes an E3 ubiquitin ligase with three known protein isoforms in humans. Studies in mouse suggest that the human isoforms may have differences in localization and neuronal function. A recent case study reported mild AS phenotypes in individuals lacking one specific isoform. Here we have used CRISPR/Cas9 to generate isogenic human embryonic stem cells (hESCs) that lack the individual protein isoforms. We demonstrate that isoform 1 accounts for the majority of UBE3A protein in hESCs and neurons. We also show that UBE3A predominantly localizes to the cytoplasm in both wild type and isoform-null cells. Finally, we show that neurons lacking isoform 1 display a less severe electrophysiological AS phenotype.

genetics↗

bioRxiv2019

Model-based analysis of response and resistance factors of cetuximab treatment in gastric cancer cell lines

Targeted cancer therapies are powerful alternatives to chemotherapies or can be used complementary to these. Yet, the response to targeted treatments depends on a variety of factors, including mutations and expression levels, and therefore their outcome is difficult to predict. Here, we develop a mechanistic model of gastric cancer to study response and resistance factors for cetuximab treatment. The model captures the EGFR, ERK and AKT signaling pathways in two gastric cancer cell lines with different mutation patterns. We train the model using a comprehensive selection of time and dose response measurements, and provide an assessment of parameter and prediction uncertainties. We demonstrate that the proposed model facilitates the identification of causal differences between the cell lines. Furthermore, our study shows that the model provides accurate predictions for the responses to different perturbations, such as knockdown and knockout experiments. Among other results, the model predicted the effect of MET mutations on cetuximab sensitivity. These predictive capabilities render the model a powerful basis for the assessment of gastric cancer signaling and for the development and discovery of predictive biomarkers.\n\nAuthor SummaryUnraveling the causal differences between drug responders and non-responders is an important challenge. The information can help to understand molecular mechanisms and to guide the selection and design of targeted therapies. Here, we approach this problem for cetuximab treatment for gastric cancer using mechanistic mathematical modeling. The proposed model describes multiple gastric cancer cell lines and can accurately predict the response in several validation experiments. Our analysis provides a differentiated view on mutations and explains, for instance, the relevance of MET mutations and the insignificance of PIK3CA mutation in the considered cell lines. The model might provide the basis for understanding the recent failure of several clinical studies.

systems biology↗

bioRxiv2018

Enemy release mitigates inbreeding depression in native and invasive Silene latifolia populations: experimental insight into the role of inbreeding x environment interactions in invasion success

Inbreeding and enemy infestation are common in plants and can synergistically reduce their performance. This inbreeding x environment (IxE) interaction may be of particular importance for the success of plant invasions if introduced populations experience a release from attack by natural enemies relative to their native conspecifics. Using native and invasive plant populations, we investigate whether inbreeding affects infestation damage, whether inbreeding depression in performance is mitigated by enemy release and whether genetic differentiation among native and invasive plants modifies these IxE interactions. We used the plant invader Silene latifolia and its natural enemies as a study system. We performed two generations of experimental out- and inbreeding within eight native (European) and eight invasive (North American) S. latifolia populations under controlled conditions using field-collected seeds. Subsequently, we exposed the offspring to an enemy exclusion and inclusion treatment in a common garden in the species native range to assess the interactive effects of population origin (range), breeding treatment and enemy treatment on infestation damage as well as plant performance. Inbreeding increased flower and leaf infestation damage in plants from both ranges, but had opposing effects on fruit damage in native versus invasive plants. Both inbreeding and enemy infestation had negative effects on plant performance, whereby inbreeding depression in fruit number was higher in enemy inclusions than exclusions in plants from both ranges. Moreover, the magnitude of inbreeding depression in fruit number was lower in invasive than native populations. Our results support that inbreeding increases enemy susceptibility of S. latifolia, which magnifies inbreeding depression in the presence of enemies. Enemy release in the invaded habitat may thus increase the persistence of inbred founder populations and thereby contribute to successful invasion. Moreover, our findings emphasize that genetic differentiation among native and invasive plants can shape the magnitude and even the direction of inbreeding effects.

evolutionary biology↗