Biology subjects

Fischer, J.

Publications and source records attributed to Fischer, J..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Organoid-based modeling of platinum resistance identifies KRT17 as both a response mediator and biomarker for targeted therapy in ovarian cancer

Variable platinum responses drive high mortality in high-grade serous ovarian cancer (HGSOC), but to date, there is no molecular approach to define resistance levels for clinical decision-making. Here, we developed the organoid drug resistance assay (ODR-test) with patient-derived organoids from our ovarian cancer biobank and found that all HGSOC patients develop molecular resistance under exposure to carboplatin, although with varying clinical implications. Sustained phenotypic reprogramming and cellular plasticity under carboplatin pressure emerged as a conserved mechanism irrespective of the basal resistance level. Transcriptional and proteomic analyses revealed changes in cell adhesion and differentiation in post-platinum lines as adaptive responses that drive the increase in resistance. We identified Keratin 17 (KRT17) as a mediator of developing platinum resistance and validated its function by CRISPR/Cas9 and overexpression. Additionally, we found that KRT17 expression status (K-score) is a significant negative prognostic histopathological biomarker in a large cohort (N=384) of advanced HGSOC patients. In organoids, increased KRT17 levels enhanced sensitivity to PI3K/Akt inhibitors Alpelisib and Afuresertib, highlighting the potential of KRT17 as a stratification biomarker for targeted therapies.

cancer biology↗

bioRxiv2025

Robust and Adaptive Non-Parametric Tests for Detecting General Distributional Shifts in Gene Expression

Differential expression analysis is crucial in genomics, yet existing methods primarily focus on detecting mean shifts. Variance shifts in gene expression are well-documented in studies of cellular signaling pathways, and more recently they have characterized aging, thus motivating the need for flexible detection approaches that include tests of expression variance changes. In this work, we present QRscore (Quantile Rank Score), a general method for detecting distributional shifts in gene expression by extending the Mann-Whitney test into a flexible family of rank-based tests. Here, we focus on implementing QRscore to detect shifts in mean and variance in gene expression, using weights designed from negative binomial (NB) and zero-inflated negative binomial (ZINB) models to combine the strengths of parametric and non-parametric approaches. We show through simulations that QRscore not only achieves high statistical power while controlling the false discovery rate (FDR), but also outperforms existing methods in detecting variance shifts and mean shifts. Applying QRscore to bulk RNA-seq data from the Genotype-Tissue Expression (GTEx) project, we identified numerous differentially dispersed genes and differentially expressed genes across 33 tissues. Notably, many genes have significant variance shifts but non-significant mean shifts. QRscore augments the genome bioinformatics toolkit by offering a powerful and flexible approach for differential expression analysis. QRscore is available in R, at https://github.com/songlab-cal/QRscore.

bioinformatics↗

bioRxiv2025

Tonkean macaques do not prefer the helper or the hinderer in the hill paradigm

Evaluating others prosocial tendencies can benefit individuals by allowing them to interact with prosocial individuals and avoid antisocial ones. The ontogeny of humans strong prosocial preference has been widely investigated using the hill paradigm. Childrens preference for helper over hinderer agents was measured after they watched a scene in which the helper agent pushed a climber up a hill while the hinderer agent pushed the climber down the hill. Bonobos tested with the hill paradigm preferred the hinderer over the helper, contrasting previous findings for other nonhuman primates. We tested Tonkean macaques (Macaca tonkeana) using the same procedure as the one used with bonobos to see whether they would also exhibit a hinderer preference. Subjects did not prefer the helper over the hinderer (or vice versa). The low attentional level observed in our subjects suggests a lack of interest in the video stimuli. This finding relates to more general questions regarding how animals perceive abstract animated onscreen stimuli and the relevance of the hill paradigm in investigating prosocial preferences. Studies using various experimental paradigms with conspecifics or human actors as social agents are needed to investigate further the social evaluation of prosocial behaviours in Tonkean macaques, bonobos, and other primates.

animal behavior and cognition↗

bioRxiv2025

Differences in cell-associated and cell-free microbial DNA in blood

In the absence of infection, blood has previously been understood to be free of microbes. However, with advances in sequencing technology this notion has been challenged, prompting new investigations into microbial DNA within the blood of both healthy and diseased individuals. To comprehensively survey microbial DNA in blood, we separated blood into fractions (plasma, red blood cells, and buffy coat) and assessed if the microbial-DNA is cell-free by the addition of DNase to a subset of each fraction. We measured 16S rRNA gene copy number with digital droplet PCR and identified the taxonomic origin of the microbial DNA with synthetic full-length 16S rRNA gene sequencing. As a use case, we examine microbial DNA from the blood of 5 men without prostate cancer (PC), 5 men with low-grade PC, and 5 men with high-grade PC. Our study demonstrates that the majority of microbial DNA is cell-free, indicating that it is not representative of proliferating microbes. Our analyses also revealed buffy coat had the lowest number of 16S rRNA gene copies yet highest number of genera of the fractions (median 23.3 copies/{micro}L and 10 genera) and thus may be a useful fraction to study moving forward. Additionally, microbial DNA in blood may have utility as a biomarker, as we detected disease-associated compositional differences in the plasma and buffy coat fractions. This study lays the groundwork for rigorously studying microbial DNA in blood, however larger studies are needed to confirm our disease-association findings. ImportanceThe concept of a "blood microbiome" has sparked debate in recent years, with questions about whether microbes truly exist in circulation. This study provides a crucial evaluation of the fractions of blood and their capacity to harbor microbial DNA, offering important context for prior and future research. By using DNase to differentiate between cell-associated and cell-free microbial DNA, we show that while microbial DNA is present in blood, it is sparse and heterogenous. These findings highlight the need for rigorous study design that carefully considers both positive and negative controls, as well as the specific blood fractions being examined.

systems biology↗

bioRxiv2025

Identifying Sex Differences in Lung Adenocarcinoma Using Multi-Omics Integrative Protein Signaling Networks

Lung adenocarcinoma (LUAD) exhibits differences between the sexes in incidence, prognosis, and therapy, suggesting underexplored molecular mechanisms. We conducted an integrative multi-omics analysis using the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and The Cancer Genome Atlas (TCGA) datasets to contrast transcriptomes and proteomes between sexes. We used TIGER to analyze TCGA-LUAD expression data and found sex-biased activity of transcription factors (TFs); we used PTM-SEA with CPTAC-LUAD proteomics data and found sex-biased kinase activity. We combined these to construct a kinase-TF signaling network and discovered druggable pathways linked to cancer-related processes. We also found significant sex biases in clinically relevant TFs and kinases, including NR3C1, AR, and AURKA. Using the PRISM drug screening database, we identified potential sex-specific drugs, such as glucocorticoid receptor agonists and aurora kinase inhibitors. Our findings emphasize the importance of considering sex and using multi-omics network methods to discover personalized cancer therapies.

cancer biology↗

bioRxiv2024

Reproducible processing of TCGA regulatory networks

BackgroundTechnological advances in sequencing and computation have allowed deep exploration of the molecular basis of diseases. Biological networks have proven to be a useful framework for interrogating omics data and modeling regulatory gene and protein interactions. Large collaborative projects, such as The Cancer Genome Atlas (TCGA), have provided a rich resource for building and validating new computational methods resulting in a plethora of open-source software for downloading, pre-processing, and analyzing those data. However, for an end-to-end analysis of regulatory networks a coherent and reusable workflow is essential to integrate all relevant packages into a robust pipeline. FindingsWe developed tcga-data-nf, a Nextflow workflow that allows users to reproducibly infer regulatory networks from the thousands of samples in TCGA using a single command. The workflow can be divided into three main steps: multi-omics data, such as RNA-seq and methylation, are downloaded, preprocessed, and lastly used to infer regulatory network models with the netZoo software tools. The workflow is powered by the NetworkDataCompanion R package, a standalone collection of functions for managing, mapping, and filtering TCGA data. Here we show how the pipeline can be used to study the differences between colon cancer subtypes that could be explained by epigenetic mechanisms. Lastly, we provide pre-generated networks for the 10 most common cancer types that can be readily accessed. Conclusionstcga-data-nf is a complete yet flexible and extensible framework that enables the reproducible inference and analysis of cancer regulatory networks, bridging a gap in the current universe of software tools.

bioinformatics↗

bioRxiv2024

Patterns of landscape partitioning indicate low levels of resource competition among neighbouring Guinea baboon(Papio papio) parties

BackgroundAccess to critical resources, including food, water, or shelter, significantly determines individual fitness. As these resources are limited in most habitats, animals may employ strategies of landscape partitioning to mitigate the impact of direct resource competition. Territoriality may be regarded as an aggressive form of landscape partitioning but in non-territorial species, other forms exist. Animals living in groups with greater flexibility in their association patterns, such as multilevel societies with fission-fusion dynamics, may adjust their grouping and space use patterns to short-term variations in ecological conditions such as food availability, predation pressure, or the presence of conspecific groups. This flexibility may allow them to balance the costs of competition while reaping the benefits of better predator detection and defence. MethodsWe explored patterns of landscape partitioning among neighbouring Guinea baboon (Papio papio) parties in the Niokolo-Koba National Park, Senegal. Guinea baboons live in a multilevel society in which parties predictably form higher-level associations ("gangs"). We used four years of locational data from individuals equipped with GPS collars to estimate annual home ranges, home range overlap, and minimum distances between parties. We examined whether food availability and predator presence levels affected the cohesion between parties in 2022. ResultsWe found substantial home range and core area overlap among parties (33 to 100%). We found no effect of food availability or predator presence on the distance to the closest neighbouring party; the minimum distance between parties was less than 100 m on average. ConclusionsOur results suggest a low level of feeding competition between our study parties. Whether this is a general feature of Guinea baboons or particular to the situation in the Niokolo-Koba National Park remains to be investigated.

ecology↗

bioRxiv2024

Selective loss of Y chromosomes in lung adenocarcinoma modulates the tumor immune environment through cancer/testis antigens

There is increasing recognition that the allosomes, X and Y, play an important role in health and disease beyond the determination of biological sex. A loss of the Y chromosome (LOY) occurs in most solid tumors in males and is often associated with worse survival, suggesting that LOY may give tumor cells a growth or survival advantage. We here use an expression-based continuous measure of LOY that allows us to investigate LOY in lung adenocarcinoma (LUAD) using both bulk and single-cell expression data. We find evidence suggesting that LOY affects the tumor immune environment by altering cancer/testis antigen expression and consequently facilitating tumor immune evasion, also reflected in inferred gene regulatory networks. In immunotherapy data, we further show that LOY and changes in expression of particular cancer/testis antigens are associated with response to pembrolizumab treatment and outcome. This computational study provides new insights into the mechanisms behind LOY in LUAD and a powerful biomarker for predicting immunotherapy response in LUAD tumors in males.

cancer biology↗

bioRxiv2024

Pipeline Olympics: continuable benchmarking of computational workflows for DNA methylation sequencing data against an experimental gold-standard

DNA methylation is a widely studied epigenetic mark and a powerful biomarker of cell type, age, environmental exposures, and disease. Whole-genome sequencing following selective conversion of unmethylated cytosines into thymines via bisulfite treatment or enzymatic methods remains the reference method for DNA methylation profiling genome-wide. While numerous software tools facilitate processing of DNA methylation sequencing reads, a comprehensive benchmarking study has been lacking thus far. In this study, we systematically compared complete computational workflows for processing DNA methylation sequencing data using a dedicated benchmarking dataset generated with five genome-wide profiling protocols. As an evaluation reference, we employed highly quantitative locus-specific measurements from our preceding benchmark of targeted DNA methylation assays. Based on this experimental gold-standard assessment and several comprehensive metrics, we identified workflows that consistently demonstrated superior performance and revealed major workflow development trends. To facilitate the sustainability of our benchmark, we implemented an interactive workflow execution and data presentation platform, adaptable to user-defined criteria and seamlessly expandable to future software.

bioinformatics↗

bioRxiv2024

Meat transfers follow social ties in the multi-level society of Guinea baboons but are not related to male reproductive success

In human foraging societies, hunting skill is often interpreted as a signal of male quality linked to his reproductive success through his ability to provision his family and community. Similarly, in some bird and insect species, males offer their mates food to indicate their quality as a provider. Among non-human primates, however, the relationship between meat sharing and reproductive success is underexplored, leaving the evolutionary origins of this phenomenon unresolved. Guinea baboons (Papio papio) are a promising model to investigate whether meat sharing signals male quality, since females choose their mates, have been shown to rely on males to catch and share prey, and are responsive to male foraging skill. We combined records of 109 meat-eating events with nine years of behavioural data to test whether males who more frequently acquired and shared meat with females had more females in their social units for longer. Contrary to our predictions, we found no evidence that females preferred males who acquired or shared meat more frequently, suggesting that meat acquisition does not function as a signal of male quality in Guinea baboons. One explanation may be the relatively low frequency of meat-eating events. Another is that females are less dependent on males for meat than previously reported. Our results revealed that nearly half (41%) of female meat intake originated from sources other than her unit male, including the first documented cases of female prey capture (11% of events). Thus, females likely apply other, more pertinent, criteria in mate choice.

animal behavior and cognition↗

bioRxiv2024

Idiosyncrasy in gestural communication: a case study of hand-clapping in a Barbary macaque (Macaca sylvanus)

While it is well established that apes invent or individually learn new gestures, cases of development and use of novel gestures in monkeys are more rarely described. We report a case of a novel, idiosyncratic gesture in a Barbary macaque (Macaca sylvanus) at La Foret des Singes, Rocamadour, France. One adult male, Jomanix, was observed hand-clapping. To our knowledge, hand-clapping has never been described before in this species. To hand-clap, the male briefly shifted his weight onto his legs, lifted his upper body, and clapped both hands together. We recorded 30 instances of hand-clapping. Twenty-five of these hand-claps occurred in combination with other agonistic signals, such as lunges and open mouth threats. Recipients either responded with counter-aggression (N = 9) or a submissive response (N = 16). In five of the 30 events, the context was unclear. These observations suggest that the gesture constitutes an agonistic signal. According to the staff at La Foret des Singes, the hand-clapping may have been copied from staff members who occasionally hand-clap to shoo the animals away from areas where they were not supposed to be, but that notion remains speculative. In the meantime, another subject from the same group reportedly started to hand-clap, but the subject had passed away before we could document the behaviour. The observations show that Jomanix can flexibly combine a novel gesture with other established communicative signals. The hand-clap is goal-directed and fulfils the criteria for first-order intentional communication. This case, as well as anecdotal reports from a Tonkean macaque (Macaca tonkeana) hand-clapping to get attention, reveals greater flexibility in the gestural communication of this genus than previously assumed but also underscores that social learning of the production of communicative gestures occurs rarely in this taxon.

animal behavior and cognition↗

bioRxiv2024

SNAP-tag2: faster and brighter protein labeling

SNAP-tag is a powerful tool for labeling proteins with synthetic fluorophores in bioimaging. However, its utility in live-cell applications can be constrained by its relatively slow labeling kinetics and the limited cell permeability of its substrates. Here we introduce new labeling substrates and an engineered SNAP-tag for faster labeling in vitro and in live cells. SNAP-tag2 presents a second-order rate constant with rhodamine substrates that approaches 107 s-1 M-1, a 100-fold improvement over the corresponding SNAP-tag-substrate pairs. When labeled with highly fluorogenic dyes, SNAP-tag2 also shows a 5-fold increase in fluorescence brightness relative to currently used SNAP-tag. The increased labeling kinetics and brightness of SNAP-tag2 translates into a greatly improved performance in various live-cell (super-resolution) imaging applications.

biochemistry↗

bioRxiv2024

Comparing efficiencies of population control methods for responding to foreign animal disease threats in wild pigs

Introductions of foreign animal diseases (FADs) into free-ranging wildlife can be difficult to control and devastating for domestic livestock trade. Combating a new FAD introduction in wildlife with an emergency response requires quickly limiting spread of the disease by intensely removing wild animals and recovering their carcasses for proper disposal. In the case of African swine fever virus (ASFv) in wild pigs (Sus scrofa), which has been spreading in many regions of the world, there is little information on the time- and cost-efficiency of methods for intensively and consistently removing wild pigs and recovering carcasses in an emergency response scenario. We compared the efficiencies of aerial operations, trapping, an experimental toxic bait, and ground shooting in northcentral Texas, USA during two months in 2023. Removing and recovering carcasses of wild pigs averaged a rate of 0.15 wild pigs/person hour and cost an average of $233.04/wild pig ($USD 2023) across all four methods. Aerial operations required the greatest initial investment but subsequently was the most time- and cost-efficient, costing an average of $7,266 to incrementally reduce the population by 10% including recovering carcasses. Aerial operations required a ground crew of [~]7 people/helicopter to recover carcasses. Costs for reducing the population of wild pigs using trapping were similar, although took 13.5 times longer to accomplish. A benefit of trapping was carcass recovery was incorporated. Toxic baiting was less efficient because carcass recovery required substantial time, and we removed very few wild pigs with ground shooting in this landscape. We recommend combining aerial and trapping methodologies to remove wild pigs and their carcasses efficiently and effectively during a FAD response. Overall, our findings can inform the preparation of resources, personnel needs, and deployment readiness for FAD responses involving wild pigs.

ecology↗

bioRxiv2024

Choose your partner: Social evaluation of skilfulness at cooperative co-action tasks in Tonkean macaques (Macaca tonkeana)

Social evaluation - inferring individual characteristics of others from their past behaviours - is an adaptive strategy that helps to inform social decisions. However, how nonhuman primates form and use impressions about others to select their social partners strategically is still unclear. In this study, we investigated whether Tonkean macaques, Macaca tonkeana, can spontaneously use information, acquired by observation, to choose the optimal partners for cooperation in two co-action tasks from the same domain. The subjects (N=5) did not prefer to cooperate with the skilful partner compared to the unskilled partner, irrespective of the task or how much attention they paid to the partners actions solving a solo version of one task prior to the test. The probability of optimal choices did not increase through trials either, indicating no learning by experience with the partners across the 16 test trials. Our results contradict findings of previous studies that tested monkeys in different domains of competence and contexts, and thus encourage further investigation on monkeys social evaluation abilities. Our experimental design presents a promising way to investigate different contexts, the inter-individual differences, the different types of social information involved, and the cognitive mechanisms underlying social evaluation and partner selectivity in nonhuman primates.

animal behavior and cognition↗

bioRxiv2024

Ecological risk-taking across age in Barbary macaques

When foraging, animals face decisions regarding unpredictable resources and varying predation risk, in which the cost-benefit trade-off must be assessed. Life-history theory focuses on resource allocation with regard to development and suggests there should be a variation in risk-taking propensity across age, manifested by a shift in goals from gain acquisition to loss aversion over time. Consequently, we aimed to assess age-related variation in decision-making strategies under risk in Barbary macaques (Macaca sylvanus) living at "La Foret des Singes" in Rocamadour, France. We experimentally varied the perceived risk and potential gains in a 2x2 design. The high-risk stimulus was a rubber snake; the low-risk stimulus a cube with a snakeskin pattern. The high-value food reward was a peanut; the low-value food reward a popcorn. In 2022, we presented 83 subjects with one of the four possible factor combinations, and in 2023, we presented 70 individuals with the inverted combination (e.g. snake-popcorn in 2022, cube-peanut in 2023). We took each monkeys propensity to retrieve the reward as a measure of risk-taking, and the latency to retrieve the reward as motivation to engage in the risky choice. Regardless of age, subjects generally retrieved the reward when placed next to the cube, whether peanut or popcorn, but were less likely to retrieve the reward placed next to the snake when this was popcorn rather than peanut. However, older individuals were faster than younger conspecifics to retrieve the reward when it was popcorn, whether paired with the cube or snake. Our results do not comply with the notion that risk-taking propensity declines with age, but rather suggest that in this paradigm, the animals assess the costs and benefits of a risky situation across age, and that the subjective value of a resource may change with age.

animal behavior and cognition↗

bioRxiv2024

Anti-snake behavior and snake discrimination in vervet monkeys

Anti-predator behavior allows to investigate how animals classify potential threats in their environment and which cognitive mechanisms might be involved in risk assessment. Snakes are common predators for many primate species, yet most of our knowledge on primate anti-snake behavior stems from predator model experiments. Few studies have investigated natural predator-prey interactions. Here, we combine an observational study on anti-snake behavior in free-ranging vervet monkeys, Chlorocebus pygerythrus, with an experimental study of snake classification, to achieve an integrated understanding of the monkeys responses to and classification of snakes. Over 25 months, we gathered data from over 200 individuals in five groups and recorded natural encounters between vervet monkeys and five different species of snakes. We assessed whether the time that monkeys spent inspecting snakes from close by varied with the encountered species. We further examined whether age and sex classes differed in their propensity to inspect snakes or alarm call. Pythons were associated with higher average inspection durations and were more likely to elicit inspection responses. While adult males were less likely to approach and inspect snakes, we found no effect of age or sex on alarm calling probability. Alarm calling appeared to be restricted to individuals in close proximity to snakes, suggesting that recruitment of nearby group members is an essential function of this call type. In the experiments, we tested whether vervet monkeys discriminated snake models by length and/or diameter, but found no effect of model size on the intensity of anti-snake behavior. While the experimental data showed the same trends as data from natural encounters, responses towards model pythons were much stronger than responses towards real pythons. These results point to a potential sampling bias in predator model experiments that needs to be taken into account when assessing data from experiments alone.

animal behavior and cognition↗

bioRxiv2024

Increased female competition for males with enhanced foraging skills in Guinea baboons

Recognizing skillful group members is crucial for making optimal social choices. Whether and how nonhuman animals attribute skill to others is still debated. Using a lever-operated food box, we enhanced the foraging skill of a single male (the specialist) in one zoo housed and two wild groups of Guinea baboon (Papio papio). We measured group members behav-ioral responses before, during, and after our manipulation to reveal whether they focused on the outcome of the males actions or changed their assessment of his long-term value. During the manipulation, females in the specialists unit, but not the wider group, competed over ac-cess to the specialist - increasing their grooming of him tenfold and aggression near him four-fold. Both behaviors were predicted by the amount each female ate from the food box and re-turned to baseline within two weeks of its removal. This behavioral pattern supports an out-come-based assessment where females responded to male-provided benefits (utility) rather than attributing competence (value). TeaserGuinea baboon females monopolize males in relation to their current perceived utility.

animal behavior and cognition↗

bioRxiv2024

node2vec2rank: Large Scale and Stable Graph Differential Analysis via Multi-Layer Node Embeddings and Ranking

1Advances in computational biology now enable the inference of increasingly accurate, genome-wide molecular interaction networks from multi-omic data collected across large cohorts. Comparing such networks across distinct biological states can identify biologically informative and potentially actionable higher-order interactions that differentiate these states. However, developing methods for effective graph differential analysis remains challenging as it requires capturing subtle structural changes within the context of complex, high-dimensional networks shaped by heterogeneous biological processes. We introduce node2vec2rank (n2v2r), a multi-layer spectral embedding algorithm that, in contrast to conventional feature-based approaches, compares graphs by inferring node representations that summarize network structure in a data-driven manner. Node2vec2rank is computationally efficient, stable, and provably recovers the correct ranking of differences between weighted graphs. We used n2v2r to compare networks from breast cancer subtypes, to analyze networks capturing single-cell dynamics, and to investigate sex differences in lung adenocarcinoma. The results of these analyses show that n2v2r is a versatile and powerful tool that can uncover biologically relevant insights from complex biological networks, distinguishing between states of health and disease.

bioinformatics↗