bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic analysis ofMycobacterium brumaesustains its nonpathogenic and immunogenic phenotype
Authors: Renau-Mínguez Chantal , Herrero-Abadía Paula , Sentandreu Vicente , Ruiz-Rodriguez Paula , Torrents Eduard , Chiner-Oms Álvaro , Torres-Puente Manuela , Comas Iñaki , Julián Esther , Coscolla Mireia
Published: December 2022

M. brumaeis a rapid-growing, non-pathogenic Mycobacterium species, originally isolated from environmental and human samples in Barcelona, Spain.M. brumaeis not pathogenic and its in vitro phenotype and immunogenic properties have been well characterized. However, the knowledge of its underlying genetic composition is still incomplete. In this study, we first describe the 4 Mb genome of theM. brumaetype strain ATCC 51384T assembling PacBio reads, and second, we assess the low intraspecies variability by comparing the type strain with Illumina reads from three additional strains.M. brumaegenome is composed of a circular chromosome with a high GC content of 69.2 % and containing 3,791 CDSs, 97 pseudogenes, one prophage and no CRISPR loci.M. brumaehas shown no pathogenic potential in in vivo experiments, and our genomic analysis confirms its phylogenetic position with other non-pathogenic and rapid growing mycobacteria. Accordingly, we determined the absence of virulence related genes, such as ESX-1 locus and most PE/PPE genes, among others. Although immunogenic potential ofM. brumaewas proved to be as high asMycobacterium bovisBCG, the only mycobacteria licensed to treat cancer, the genomic content ofM. tuberculosisT cell and B cell antigens inM. brumaeis considerably lower than those ofM. bovisBCG. Overall, this work provides relevant genomic data on one of the species of the mycobacterial genus with high therapeutic potential.
Genetic estimates of the initial peopling of Polynesian islands actually reflect later inter-island contacts
Authors: Huang Yilei , Carmi Shai , Reich David , Ringbauer Harald
Published: December 2022

The timing of the initial peopling of the Polynesian islands remains highly debated. Suggested dates are primarily based on archaeological evidence and differ by several hundred years. Ioannidis et al. [2021] used genome-wide data from 430 modern individuals from 21 Pacific islands to obtain genetic estimates. Their results supported late settlement dates, e.g. approximately 1200 CE for Rapa Nui. However, when investigating the underlying model we found that the genetic estimator used by Ioannidis et al. [2021] is biased to be about 300 years too old. Correcting for this bias gives genetic settlement dates that are more recent than any dates consistent with archaeological records, as radiocarbon dating of human-modified artifacts shows settlement definitively earlier than the bias-corrected genetic estimates. These too-recent estimates can only be explained by substantial gene flow between islands after their initial settlements. Therefore, contacts attested by archaeological and linguistic evidence [Kirch, 2021] must have been accompanied also by demographically significant movement of people. This gene flow well after the initial settlements was not modelled by Ioannidis et al. [2021] and challenges their interpretation that carving anthropomorphic stone statues was spread during initial settlements of islands. Instead, the distribution of this cultural practice likely reflects later inter-island exchanges, as suggested earlier [Kirch, 2017].
Genetic identification and reiterated captures suggests that theAstyanax mexicanusEl Pachón cavefish population is closed and declining
Authors: Legendre Laurent , Rode Julie , Germon Isabelle , Pavie Marie , Quiviger Carla , Policarpo Maxime , Leclercq Julien , Père Stéphane , Fumey Julien , Hyacinthe Carole , Ornelas-García Patricia , Espinasa Luis , Rétaux Sylvie , Casane Didier
Published: December 2022

The size ofAstyanax mexicanusblind cavefish populations of North-East Mexico is a demographic parameter of great importance for investigating a variety of ecological, evolutionary and conservation issues. However, very few estimates have been obtained. For these mobile animals living in an environment difficult to explore as a whole, methods based on capture-mark-recapture are appropriate, but the feasibility of such approach and the interpretation of the results depend on several assumptions that must be carefully examined. Here, we provide evidence that minimally invasive genetic identification from captures at different time intervals can give insights on cavefish population size dynamics as well as other important demographic parameters of interest. We also provide tools to calibrate sampling and genotyping efforts necessary to reach a given level of precision. Our results suggest that the El Pachón cave population is currently very small, of an order of magnitude of a few hundreds of individuals, and is distributed in a relatively isolated area. The probable decline in population size in the El Pachón cave since the last census in 1971 raises serious conservation issues.
Illuminating protein space with a programmable generative model
Authors: Ingraham John , Baranov Max , Costello Zak , Frappier Vincent , Ismail Ahmed , Tie Shan , Wang Wujie , Xue Vincent , Obermeyer Fritz , Beam Andrew , Grigoryan Gevorg
Published: December 2022

Three billion years of evolution have produced a tremendous diversity of protein molecules, and yet the full potential of this molecular class is likely far greater. Accessing this potential has been challenging for computation and experiments because the space of possible protein molecules is much larger than the space of those likely to host function. Here we introduce Chroma, a generative model for proteins and protein complexes that can directly sample novel protein structures and sequences and that can be conditioned to steer the generative process towards desired properties and functions. To enable this, we introduce a diffusion process that respects the conformational statistics of polymer ensembles, an efficient neural architecture for molecular systems based on random graph neural networks that enables long-range reasoning with sub-quadratic scaling, equivariant layers for efficiently synthesizing 3D structures of proteins from predicted inter-residue geometries, and a general low-temperature sampling algorithm for diffusion models. We suggest that Chroma can effectively realize protein design as Bayesian inference under external constraints, which can involve symmetries, substructure, shape, semantics, and even natural language prompts. With this unified approach, we hope to accelerate the prospect of programming protein matter for human health, materials science, and synthetic biology.
The type 1 diabetes-associated lncRNAARGIparticipates in virus-induced pancreatic β cell inflammation
Authors: González-Moro Itziar , Garcia-Etxebarria Koldo , Mendoza Luis Manuel , Fernández-Jiménez Nora , Mentxaka-Salgado Jon , Olazagoitia-Garmendia Ane , Arroyo María Nicol , Sawatani Toshiaki , de Beek Anne Op , Cnop Miriam , Igoillo-Esteve Mariana , Santin Izortze
Published: December 2022

Type 1 diabetes-associated single nucleotide polymorphisms are mainly located in non-coding regions of the human genome. Single nucleotide polymorphisms located in long non-coding RNAs may result in the disruption of their secondary structure, affecting their function.

Here, we functionally characterized the virus-induced type 1 diabetes-associated lncRNAARGI(Antiviral Response Gene Inducer).ARGIupregulation in pancreatic β cells leads to the transcriptional activation of antiviral and pro-inflammatory genes. Upon a viral insult,ARGIis upregulated in the nuclei of pancreatic β cells and binds to CTCF to interact with the regulatory regions ofIFNβand interferon-stimulated genes, promoting their transcriptional activation in an allele-specific manner.

The presence of the risk allele for type 1 diabetes inARGIinduces an hyperactivation of type I IFN response in β cells, an expression signature that is present in the pancreas of diabetic patients. These data shed light on the molecular mechanisms by which type 1 diabetes-related single nucleotide polymorphisms in long non-coding RNAs influence pathogenesis at the pancreatic β cell level.
Integrated genetic and metabolic characterisation of diverse Latin American cassava (Manihot esculentaCrantz) germplasm; implications for future breeding strategies
Authors: Perez-Fons L , Ovalle TM , Drapal M , Ospina MA , Bohorquez-Chaux A , Becerra Lopez-Lavalle LA , Fraser PD
Published: December 2022

Cassava is an important staple crop for food security in Africa and South America. The present study describes an integrated genomic and metabolomic approach to the characterisation of Latin American cassava germplasm. Classification based on genotyping and the leaf metabolome correlates, the key finding being the adaption to specific eco-geographical environments. In contrast the root metabolome does not relate to the genotypic clustering, suggesting different spatial regulation of this tissue’s metabolome. The data has been used to generate pan-metabolomes for specific tissues and the inclusion of phenotypic data has enabled the identification of metabolic sectors underlying traits of interest. For example, tolerance to whiteflies was not linked to cyanide content but to cell wall related phenylpropanoids or apocarotenoids. Collectively, these data advance the communities resources and provides a valuable insight into new parental breeding materials with traits of interest directly related to combating food security.

Significance statement

Cassava is a staple crop in developing countries of sub-tropical regions. Traditionally, cassava has been considered as a subsistence crop. However recently it has become a sustainable solution to fulfil both hunger and malnutrition needs, and drive economic development. Varietal improvement via classic breeding has successfully delivered products into the Asian market by including/exchanging germplasm from original Latin American collections. Conversely, modest progress has been achieved in Sub-Saharan countries since genetic resources are biased towards exploitation of local landraces and uncharacterised parental material. The present work explores the genetic and metabolic diversity of Latin American cassava’s genebank, one of the largest and most complete worldwide. These data provide a robust characterisation of valuable germplasm that can be exploited in breeding programmes.
WASCO: A Wasserstein-based statistical tool to compare conformational ensembles of intrinsically disordered proteins
Authors: González-Delgado Javier , Sagar Amin , Zanon Christophe , Lindorff-Larsen Kresten , Bernadó Pau , Neuvial Pierre , Cortés Juan
Published: December 2022

The structural investigation of intrinsically disordered proteins (IDPs) requires ensemble models describing the diversity of the conformational states of the molecule. Due to their probabilistic nature, there is a need for new paradigms that understand and treat IDPs from a purely statistical point of view, considering their conformational ensembles as well-defined probability distributions. In this work, we define a conformational ensemble as an ordered set of probability distributions and provide a suitable metric to detect differences between two given ensembles at the residue level, both locally and globally. The underlying geometry of the conformational space is properly integrated, being one ensemble characterized by a set of probability distributions supported on the three-dimensional Euclidean space (for global-scale comparisons) and on the two-dimensional flat torus (for local-scale comparisons). The inherent uncertainty of the data is also taken into account to provide finer estimations of the differences between ensembles. Additionally, an overall distance between ensembles is defined from the differences at the residue level. We illustrate the interest of the approach with several examples of applications for the comparison of conformational ensembles: (i) produced from molecular dynamics (MD) simulations using different force fields, and (ii) before and after refinement with experimental data. We also show the usefulness of the method to assess the convergence of MD simulations. The numerical tool has been implemented in Python through easy-to-use Jupyter Notebooks available athttps://gitlab.laas.fr/moma/WASCO.
RNAseq-based gene expression analysis ofMelolontha hippocastanihindgut pockets and the surrounding hindgut wall tissue
Authors: Alonso-Pernas Pol , Boland Wilhelm
Published: December 2022

In this study, the metatranscriptome of newly-discovered structures attached at the distal end of the hindgut of the larvae of a coleopteran (Melolontha hippocastani), is compared with that of the surrounding hindgut wall. Larvae were collected in their natural habitat, RNA was extracted using a commercial kit and sequenced in a Illumina HiSeq2500 platform. 250 bp paired-end reads were used to de novo assemble the transcriptomes. Contig annotation was carried out with BLASTx and Blast2GO PRO and differential expression analysis was performed in edgeR. Contigs aligned mainly toAchromobactersp. in the pockets and to the Firmicutes phylum in hindgut wall. Host RNAs were expressed in the pockets in higher amounts than in hindgut wall. Gene expression suggest that pocket bacteria undergo aerobic metabolism and are exposed to higher levels of oxidative stress than the population of the hindgut wall. Hypothetical functions for the pocket might be immune-stimulation and regulation of host development, while the hindgut wall appears to be devoted to degradation of dietary polysaccharides and host nitrogenous wastes. Further research is necessary to experimentally prove these suggested roles.
DYNATE: Localizing Rare-Variant Association Regions via Multiple Testing Embedded in an Aggregation Tree
Authors: Li Xuechan , Pura John , Allen Andrew , Owzar Kouros , Lu Jianfeng , Harms Matthew , Xie Jichun
Published: December 2022

Rare variants (RVs) genetic association studies enable researchers to uncover the variation in phenotypic traits left unexplained by common variation. Traditional single-variant analysis lacks power; thus, researchers have developed various methods to aggregate the effects of RVs across genomic regions to study their collective impact. Some existing methods utilize a static delineation of genomic regions, often resulting in suboptimal effect aggregation, as neutral subregions within the test region will result in an attenuation of signal. Other methods use varying windows to search for signals but often result in long regions containing many neutral RVs. To pinpoint short genomic regions enriched for disease-associated RVs, we developed a novel method, DYNATE (DYNamic Aggregation TEsting). DYNATE dynamically and hierarchically aggregates smaller genomic regions into larger ones and performs multiple testing for disease associations with controlled weighted false discovery rate. Extensive numerical simulations demonstrate the superior performance of DYNATE under various scenarios compared to existing methods. Importantly, DYNATE-identified regions have higher enrichment levels of disease-associated RVs. We applied DYNATE to an amyotrophic lateral sclerosis (ALS) study and identified a new gene,EPG5, harboringpossibly pathogenic mutations.
Partition complex structure can arise from sliding and bridging of ParB dimers
Authors: Connolley Lara , Schnabel Lucas , Thanbichler Martin , Murray Seán M.
Published: December 2022

Chromosome segregation is vital for cell replication and in many bacteria is controlled by the ParABSsystem. A key part of this machinery is the association of ParB proteins to theparS-containing centromeric region to form the partition complex. Despite much work, the formation and structure of this nucleoprotein complex has remained unclear. However, it was recently discovered that CTP binding allows ParB dimers to entrap and slide along the DNA, as well as leading to more efficient condensation through ParB-mediated DNA bridging. Here, we use semi-flexible polymer simulations to show how these properties of sliding and bridging can explain partition complex formation. We find that transient ParB bridges can organise the DNA into either a globular state or into hairpins and helical structures, depending on the bridge lifetime. In separate stochastic simulations, we show that ParB sliding reproduces the experimentally measured multi-peaked binding profile ofCaulobacter crescentus, indicating that bridging and other potential roadblocks are sufficiently short-lived that they do not hinder ParB spreading. Indeed, upon coupling the two simulation frameworks into a unified sliding and bridging model, we find that short-lived ParB bridges do not hinder ParB sliding and the model can reproduce both the ParB binding profile as well as the condensation of the nucleoprotein complex. Overall, our model clarifies the mechanism of partition complex formation and predicts its fine structure. We speculate that the DNA hairpins produced by ParB bridging underlie the secondary function of ParB to load the Structural Maintenance of Chromosome (SMC) complex onto the DNA.
Myofibroblast Ccn3 is regulated by Yap and Wwtr1 and contributes to adverse cardiac outcomes
Authors: Flinn Michael A. , Alvarez-Argote Santiago , Knas Makenna C. , Almeida Victor Alencar , Paddock Samantha J. , Zhou Xiaoxu , Buddell Tyler , Jamal Ayana , Liu Pengyuan , Drnevich Jenny , Patterson Michaela , Link Brian A. , O’Meara Caitlin C.
Published: December 2022

While Yap and Wwtr1 regulate resident cardiac fibroblast to myofibroblast differentiation following cardiac injury, their role specifically in activated myofibroblasts remains unexplored. Here we assess the pathophysiological and cellular consequence of genetic depletion of Yap alone (Yapfl/fl;PostnMCM) or Yap and Wwtr1 (Yapfl/fl;Wwtr1fl/+;PostnMCM) in adult mouse myofibroblasts following myocardial infarction and identify and validate novel downstream factors specifically in cardiac myofibroblasts that mediate pathological remodeling. Following myocardial infarction, depletion of Yap in myofibroblasts had minimal effect on heart function while depletion of Yap/Wwtr1 resulted in smaller scars, reduced interstitial fibrosis, and improved ejection fraction and fractional shortening. Single cell RNA sequencing of interstitial cardiac cells 7 days post infarction showed suppression of pro-fibrotic genes in fibroblasts derived fromYapfl/fl,Wwtr1fl/+;PostnMCMhearts. In vivo myofibroblast depletion of Yap/Wwtr1 as well in vitro knockdown of Yap/Wwtr1 dramatically decreased RNA and protein expression of the matricellular factor Ccn3. Administration of recombinant CCN3 to adult mice following myocardial infarction remarkably aggravated cardiac function and scarring. CCN3 administration drove myocardial gene expression of pro-fibrotic genes in infarcted left ventricles implicating CCN3 as a novel driver of cardiac fibrotic processes following myocardial infarction.
Visualization & Quality Control Tools for Large-scale Multiplex Tissue Analysis in TissUUmaps 3
Authors: Behanova Andrea , Avenel Christophe , Andersson Axel , Chelebian Eduard , Klemm Anna , Wik Lina , Östman Arne , Wählby Carolina
Published: December 2022

Large-scale multiplex tissue analysis aims to understand processes such as development and tumor formation by studying the occurrence and interaction of cells in local environments in e.g. tissue samples from patient cohorts. A typical procedure in the analysis is to delineate individual cells, classify them into cell types, and analyze their spatial relationships. All steps come with a number of challenges, and to address them and identify the bottlenecks of the analysis, it is necessary to include quality control tools in the analysis workflow. This makes it possible to optimize the steps and adjust settings in order to get better and more precise results. Additionally, the development of automated approaches for tissue analysis requires visual verification to reduce skepticism with regard to the accuracy of the results. Quality control tools could be used to build users’ trust in automated approaches. In this paper, we present three plugins for visualization and quality control in large-scale multiplex tissue analysis of microscopy images. The first plugin focuses on the quality of cell staining, the second one was made for interactive evaluation and comparison of different cell classification results, and the third one serves for reviewing interactions of different cell types.
Network topology in brain tumor patients with and without structural epilepsy- a prospective MEG-study
Authors: Ladisich Barbara , Rampp Stefan , Trinka Eugen , Weisz Nathan , Schwartz Christoph , Kraus Theo , Sherif Camillo , Marhold Franz , Demarchi Gianpaolo
Published: December 2022

It has been proposed that functional connectivity (FC) and network topology (NT) are altered in patients with glial brain tumors. So far there is no consensus on the pattern of these changes, furthermore data on FC in patients with brain metastases (BMs) as well as on the presence and absence of tumor-related epilepsy is lacking.

We aimed to analyze preoperative NT of newly diagnosed, singular, supratentorial glial brain tumors (GBTs) and BMs with and without structural epilepsy.

FC and NT derived from resting state magnetoencephalography (MEG) were compared between patients (PAs) and matched healthy controls (HCs), between GBTs and BMs as well as between patients with and without structural epilepsy. We investigated all patients, who met our inclusion criteria from February 2019 to March 2021. Clinical data was collected from patients’ electronic medical charts. We analyzed whole brain (wb) connectivity in six frequency bands, calculated three different network topological parameters (node degree (ND), shortest path length (L), clustering coefficient (CC)) and performed a stratification, where differences in the power were to be found. For data analysis we used Fieldtrip, Brain Connectivity Matlab toolboxes and in-house built scripts.

We consecutively included 41 patients (21 men), mean age 60.1ys (range 23-82), who were operated on at our institution. Tumor histology included high-grade gliomas (n=18), low-grade gliomas (n=4), dysembryoplastic neuroepithelial tumor (DNET, n=1), BMs (n=14) and others (n=4). Statistical analysis revealed a significant decrease for wb ND in patients compared to healthy controls in every frequency range analyzed at the descriptive and corrected level (p1-30Hz=0.002, pγ=0.002, pβ=0.002, pα=0.002, pθ=0.024, pδ=0.002). Furthermore, at the descriptive level, we found a significant augmentation for wb CC (p1-30Hz=0.031, pδ=0.013) in PAs compared to HCs, which did not persist the false discovery rate (FDR) correction. There were no differences in the networks of glial brain tumors and metastases identified. However, we found a significant increase in wb CC in patients with structural epilepsy (pθ= 0.048), and significantly lower wb ND (pα= 0.039) at the uncorrected level.

Our data suggests that network topology is altered in brain tumor patients, which is in line with previous studies. Tumor histology per se might not influence the brain’s functional network, however, tumor-related epilepsy seems to do so. Longitudinal studies and in-depth analysis of possible factors and confounders might be helpful to further substantiate these findings.
MLcps: Machine Learning Cumulative Performance Score for classification problems
Authors: Akshay Akshay , Abedi Masoud , Shekarchizadeh Navid , Burkhard Fiona C. , Katoch Mitali , Bigger-Allen Alex , Adam Rosalyn M. , Monastyrskaya Katia , Gheinani Ali Hashemi
Published: December 2022

Motivation

A performance metric is a tool to measure the correctness of a trained Machine Learning (ML) model. Numerous performance metrics have been developed for classification problems making it overwhelming to select the appropriate one since each of them represents a particular aspect of the model. Furthermore, selection of a performance metric becomes harder for problems with imbalanced and/or small datasets. Therefore, in clinical studies where datasets are frequently imbalanced and, in situations when the prevalence of a disease is low or the collection of patient samples is difficult, deciding on a suitable metric for performance evaluation of an ML model becomes quite challenging. The most common approach to address this problem is measuring multiple metrics and compare them to identify the best-performing ML model. However, comparison of multiple metrics is laborious and prone to user preference bias. Furthermore, evaluation metrics are also required by ML model optimization techniques such as hyperparameter tuning, where we train many models, each with different parameters, and compare their performances to identify the best-performing parameters. In such situations, it becomes almost impossible to assess different models by comparing multiple metrics.

Results

Here, we propose a new metric called Machine Learning Cumulative Performance Score (MLcps) as a Python package for classification problems. MLcps combines multiple pre-computed performance metrics into one metric that conserves the essence of all pre-computed metrics for a particular model. We tested MLcps on 4 different publicly available biological datasets and the results reveal that it provides a comprehensive picture of overall model robustness.

Availability

MLcps is available athttps://pypi.org/project/MLcps/and cases of use are available athttps://mybinder.org/v2/gh/FunctionalUrology/MLcps.git/main.

Supplementary information

Supplementary data are available at Bioinformatics online.
Heterochromatin and RNAi act independently to ensure genome stability in Mucorales human fungal pathogens
Authors: Navarro-Mendoza María Isabel , Pérez-Arques Carlos , Heitman Joseph
Published: December 2022

Chromatin modifications play a fundamental role in controlling transcription and genome stability and yet despite their importance, are poorly understood in early-diverging fungi. We present the first comprehensive study of histone-lysine and DNA methyltransferases across the Mucoromycota, emphasizing heterochromatin formation pathways that rely on the Clr4 complex involved in H3K9-methylation, the Polycomb-repressive complex 2 driving H3K27-methylation, or DNMT1-like methyl-transferases that catalyze 5mC DNA methylation. Our analysis uncovered H3K9-methylated heterochromatin as the major chromatin modification repressing transcription in these fungi, which lack both Polycomb silencing and cytosine methylation. Although small RNAs generated by RNAi pathways facilitate the formation of heterochromatin in many eukaryotic organisms, we show that RNAi is not required to maintain either genomic or centromeric heterochromatin inMucor. H3K9-methylation and RNAi act independently to control centromeric regions, suggesting a functional sub-specialization. Whereas the H3K9 methyltransferase Clr4 and heterochromatin formation are essential for cell viability, RNAi is dispensable for viability yet acts as the main epigenetic, regulatory force repressing transposition of centromeric GremLINE1 elements. Mutations inactivating canonical RNAi lead to rampant transposition and insertional inactivation of targets resulting in antimicrobial drug resistance. This fine-tuned, Rdrp2-dependent RNAi activity is critical for genome stability, restricting GremLINE1 retroelements to the centromeres where they occupy long heterochromatic islands. Taken together, our results suggest that RNAi and heterochromatin formation are independent genome defense and regulatory mechanisms in the Mucorales, contributing to a paradigm shift from the co-transcriptional gene silencing observed in fission yeasts to models in which heterochromatin and RNAi operate independently in early-diverging fungi.
A generalized adaptive harvesting model exhibits cusp bifurcation, noise, and rate-associated tipping pathways
Authors: Tekwa E.W. , Junquera Victoria
Published: December 2022

The sustainability of renewable resource harvesting may be threatened by environmental and socioeconomic changes that induce tipping points. Here, we propose a synthetic harvesting model with a comprehensive set of socioecological factors that have not been explored together, including market price and stock value, effort and processing costs, labour and natural capital elasticities, societal risk aversion, maximum sustainable yield (MSY), and population growth shape. We solve for harvest rate and stock biomass solutions by applying a timescale-separation between fast ecological dynamics and slow institutional adaptation that responds myopically to short-term net profit. The result is a cusp bifurcation with two composite bifurcation parameters: 1. consumptive scarcityλcor the ratio of market price-to-processing cost divided byMSY(leading to a pitchfork), and 2. non-consumptive scarcityλnor the stock value minus a scaled effort cost (leading to saddle-nodes or folds). Together, consumptive and non-consumptive scarcities create a cusp catastrophe. We further identify four tipping phenomena: 1. process (harvest rate) noise-induced tipping; 2. exogenous (λc) rate+process noise-induced tipping; 3. exogenous noise-induced reduction in tipping; and 4. exogenous cycle-induced reduction in tipping. Case 2 represents the first mechanistically motivated example of rate-associated tipping in socioecological systems, while cases 3 and 4 resemble noise-induced stability. We discuss the empirical relevance of catastrophe and tipping in natural resource management. Our work shows that human institutional behaviour coupled with changing socioecological conditions can cause counterintuitive sustainability and resilience outcomes.
Shifting effects of host physiological condition following pathogen establishment
Authors: Langwig Kate E. , Kilpatrick A. Marm , Kailing Macy J. , Laggan Nichole , White J. Paul , Kaarakka Heather M. , Redell Jennifer A. , DePue John E. , Parise Katy L. , Foster Jeffrey T. , Hoyt Joseph R.
Published: December 2022

Understanding host persistence with emerging pathogens is essential for conserving populations. Hosts may initially survive pathogen invasions through pre-adaptive mechanisms. However, whether pre-adaptive traits are directionally selected to increase in frequency depends on the heritability and environmental dependence of the trait and the costs of trait maintenance. Body condition is likely an important pre-adaptive mechanism aiding in host survival, although can be seasonally variable in wildlife hosts. We used data collected over seven years on bat body mass, infection, and survival to determine the role of host body condition during the invasion and establishment of the emerging disease, white-nose syndrome. We found that when the pathogen first invaded, bats with higher body mass were more likely to survive, but this effect dissipated following the initial epizootic. We also found that heavier bats lost more weight overwinter, but fat budgeting depended on infection severity. Lastly, we found little support that bat mass increased in the population after pathogen arrival, and there was high annual plasticity in individual bat masses. Overall, our results suggest that factors that contribute to host survival during pathogen invasion may diminish over time, and are potentially replaced by other host adaptations.
Weakly electric fish use self-generated motion to discriminate object shape
Authors: Skeels Sarah , von der Emde Gerhard , de Perera Theresa Burt
Published: December 2022

Body movements are known to play an active role in sensing. However, it is not fully understood what information is provided by these movements. The Peter’s elephantnose fish,Gnathonemus petersiisense their environment through active electrolocation during which they use epidermal electroreceptors to perceive object-induced distortions of a self-produced electric field. The analysis of electric images projected on their skin enables them to discriminate between three-dimensional objects. While we know the electric image parameters used to encode numerous object properties, we don’t understand how these images encode object shape. We hypothesise that ‘movement-induced modulations’ (MIMs) evoked by body movements might be involved in shape discrimination during active electrolocation. To test this, we trained fish to complete a shape discrimination task in a two-alternative forced-choice setup, and then manipulated the space available to individuals for scanning movements to see if this led to a change in their discrimination performance. We found that if enough space was available, fish were very good at discriminating objects of different shapes. However, performance decreased strongly when the space was reduced so that scanning movements were impaired. Our study demonstrates the importance of body movements for gaining complex environmental information such as object shape through active electrolocation. Movement can enhance perception by allowing the extraction of certain kinds of information. Similar observations have been made in other animals using different senses, suggesting that the core principles of sensory-motor integration might be valid for various sensory modalities.
The python-derived 16α-hydroxylated bile acid, pythocholic acid decreases food intake and increases jejunal fatty acid ethanolamides in mice
Authors: Higuchi Sei , Wood Courtney , DiPatrizio Nicholas V. , Kawamura Akira , Haeusler Rebecca A.
Published: December 2022

Objective

Modulation of bile acid (BA) structure is a potential strategy for obesity and metabolic disease treatment. BAs act not only as signaling molecules involved in energy expenditure and glucose homeostasis, but also as regulators of food intake. The structure of BAs, particularly the position of the hydroxyl groups of BAs impacts food intake partly by intestinal effects: (1) modulating the activity of N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD), which produces the anorexigenic bioactive lipid oleoylethanolamide (OEA), or (2) regulating lipid absorption and the gastric emptying-satiation pathway. We hypothesized that 16α-hydroxylated BAs uniquely regulate food intake, because of the long intermeal intervals in snake species in which these BAs are abundant. However, the effects of 16α-hydroxylated BAs in mammals are completely unknown, because 16α-hydroxylated BAs are not naturally found in mammals. To test the effect of 16α-hydroxylated BAs on food intake, we isolated the 16α-hydroxylated BA pythocholic acid from ball pythons (Python regius).

Methods

Pythocholic acid or deoxycholic acid (DCA) were given by oral gavage in mice. DCA is known to increase NAPE-PLD activity better than other mammalian BAs. We evaluated food intake, OEA levels and gastric emptying in mice.

Results

We successfully isolated pythocholic acid from ball pythons for experimental use. Pythocholic treatment significantly decreased food intake compared with DCA treatment, and this was associated with increased jejunal OEA, but no change in gastric emptying or lipid absorption.

Conclusion

The exogenous bile acid pythocholic acid is a novel regulator of food intake and the satiety signal OEA in the mouse intestine.

Highlights

Pythocholic acid decreases food intake.

Pythocholic acid increases intestinal OEA and other fatty acid ethanolamides.

The effects of pythocholic acid on OEA and hypophagia are greater than the effects of DCA.

Pythocholic acid does not affect lipid absorption or gastric emptying.
Assessing risks and mechanisms of idiosyncratic drug toxicity by fingerprints of cell signaling responses
Authors: Medvedev Alexander V. , Makarov Sergei , Medvedeva Lyubov A. , Martsen Elena , Gorman Kristen L. , Lin Benjamin , Makarov Sergei S.
Published: December 2022

Idiosyncratic drug-induced liver injury (DILI) is the leading cause of post-marketing drug withdrawal. Here, we describe a straightforward DILI liability assessment approach based on fingerprinting cell signaling responses. The readout is the activity of transcription factors (TF) that link signaling pathways to genes. Using a multiplex reporter assay for 45 TFs in hepatocytic cells, we assessed TF activity profiles (TFAP) for 13 pharmacological classes. The TFAP signatures were consistent with primary drug activity but transformed into different, ‘off-target’ signatures at certain concentrations (COFF). We show that the off-target signatures pertained to DILI-relevant mechanisms, including mitochondria malfunction, proteotoxicity, and lipid peroxidation. Based on reported plasma concentrations in humans (CMAX), drugs do not reach the off-target thresholds in vivo, consistent with the lack of overt toxicity in the population. However, DILI liability drugs were dangerously close to the off-target thresholds. We characterized this closeness by the COFF/CMAXratio termed the ‘safety margin’ (SM). Most-DILI-concern drugs invariably showed smaller safety margins than their less-concern counterparts in each pharmacological class and across classes (median SM values of 6.4 and 212.7, respectively (P<0.00015)). Therefore, the TFAP approach helps to explain idiosyncratic drug toxicity and provides clear quantitative metrics for its probability and the underlying mechanisms.
Multisite Thalamic Recordings to Characterize Seizure Propagation in the Human Brain
Authors: Wu Teresa Q. , Kaboodvand Neda , Veit Mike , McGinn Ryan J. , Davey Zachary , Datta Anjali , Graber Kevin D. , Meador Kimford J. , Fisher Robert , Buch Vivek , Parvizi Josef
Published: December 2022

Neuromodulation of the anterior nuclei of the thalamus (ANT) has shown to be efficacious in patients with refractory focal epilepsy, but it is not uniformly effective. One important uncertainty is to what extent thalamic subregions other than the ANT are recruited earlier and more prominently in the propagation of seizures in patients with presumed temporal lobe epilepsy (TLE). To address this unknown, we studied 11 patients with clinical manifestations of TLE planned to undergo invasive stereo-encephalography (sEEG) monitoring. We extended cortical electrodes to reach thalamic nuclear subdivisions in the anterior (ANT), middle (mediodorsal) and or posterior (pulvinar) sites. This multisite thalamic sampling was without any adverse events. Intracranial EEG (iEEG) recordings confirmed seizure-onset in medial temporal lobe, insula, orbitofrontal and temporal neocortical sites – highlighting the importance of iEEG for more accurate localization of seizure foci. Visual review of EEGs documented early and prominent involvement of specific thalamic sites. Seizures originating from the same brain origin produced a stereotyped thalamic EEG signature. Visual review of EEGs, validated with singlepulse corticothalamic evoked potentials, documented early and prominent involvement of thalamic sites that would have not been predicted given the anatomy of seizure onset zones. Pulvinar was involved earlier and more prominently than other sampled nuclear subgroups in 60% of patients, even though all patients had a presumed diagnosis of TLE prior to invasive monitoring. Our findings document the feasibility and safety of multisite sampling from the human thalamus and suggest that the anatomy of thalamic involvement may not be entirely predictable on the basis of clinical information or lobar localization of seizures. Future clinical trials can establish whether offering more personalized targets for thalamic neuromodulation will lead to greater meaningful improvements in outcome.
The interplay of uncertainty, relevance and learning influences auditory categorization
Authors: Sheth Janaki , Collina Jared S. , Piasini Eugenio , Kording Konrad P. , Cohen Yale E. , Geffen Maria N.
Published: December 2022

Auditory perception requires categorizing sound sequences, such as speech or music, into classes, such as syllables or notes. Auditory categorization depends not only on the acoustic waveform, but also on variability and uncertainty in how the listener perceives the sound – including sensory and stimulus uncertainty, the listener’s estimated relevance of the particular sound to the task, and their ability to learn the past statistics of the acoustic environment. Whereas these factors have been studied in isolation, whether and how these factorsinteractto shape categorization remains unknown. Here, we measured human participants’ performance on a multi-tone categorization task and modeled each participant’s behavior using a Bayesian framework. Task-relevant tones contributed more to category choice than task-irrelevant tones, confirming that participants combined information about sensory features with task relevance. Conversely, participants’ poor estimates of task-relevant tones or high-sensory uncertainty adversely impacted category choice. Learning the statistics of sound category over both short and long timescales also affected decisions, biasing the decisions toward the overrepresented category. The magnitude of this effect correlated inversely with participants’ relevance estimates. Our results demonstrate that individual participants idiosyncratically weigh sensory uncertainty, task relevance, and statistics over both short and long timescales, providing a novel understanding of and a computational framework for how sensory decisions are made under several simultaneous behavioral demands.
Anemonefish have finer color discrimination in the ultraviolet
Authors: Mitchell Laurie J. , Phelan Amelia , Cortesi Fabio , Marshall N. Justin , Chung Wen-sung , Osorio Daniel C. , Cheney Karen L.
Published: December 2022

In many animals, ultraviolet (UV) vision guides navigation, foraging, and communication, but few studies have addressed the contribution of UV vision to color discrimination, or behaviorally assessed UV discrimination thresholds. Here, we tested UV-color vision in an anemonefish (Amphiprion ocellaris) using a novel five-channel (RGB-V-UV) LED display designed to test UV perception. We first determined that the maximal sensitivity of theA. ocellarisUV cone was at ∼386 nm using microspectrophotometry. Three additional cone spectral sensitivities had maxima at ∼497, 515, and ∼535 nm, which together informed the modelling of the fish’s color vision. Anemonefish behavioral discrimination thresholds for nine sets of colors were determined from their ability to distinguish a colored target pixel from grey distractor pixels of varying intensity. We found thatA. ocellarisused all four cones to process color information and is therefore tetrachromatic, and fish were better at discriminating colors (i.e., color discrimination thresholds were lower, or more acute) when targets had UV chromatic contrast elicited by greater stimulation of the UV cone relative to other cone types. These findings imply that a UV component of color signals and cues improves their detectability, that likely increases the salience of anemonefish body patterns used in communication and the silhouette of zooplankton prey.
Using TCR and BCR sequencing to unravel the role of T and B cells in abdominal aortic aneurysm
Authors: Elster Christin , Ommer-Bläsius Miriam , Lang Alexander , Vajen Tanja , Pfeiler Susanne , Feige Milena , Quý Khang Lê , Chernigovskaya Maria , Kelm Malte , Winkels Holger , Schmidt Susanne , Greiff Victor , Gerdes Norbert
Published: December 2022

Background

Abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disease, and the pathogenesis is still poorly understood. Recent evidence suggests that AAA displays characteristics of an autoimmune disease and it gained increasing prominence that specific antigen-driven T cells in the aortic tissue may contribute to the initial immune response. Single-cell RNA T- and B cell receptor (TCR and BCR) sequencing is a powerful tool to investigate TCR and BCR clonality and thus to further test this hypothesis. However, difficulties such as very limited numbers of isolated cells must be considered during implementation and data analysis making biological interpretation of the data challenging. Here, we perform a representative analysis of scRNA TCR and BCR sequencing data of experimental murine AAA and show a reliable and streamlined bioinformatic processing pipeline highlighting opportunities and limitations of this approach.

Methods

We performed single-cell RNA TCR and BCR sequencing of isolated lymphocytes from the infrarenal aortic segment of male C57BL/6J mice 3, 7, 14, and 28 days after AAA induction via elastase perfusion of the aorta. Sham operated mice at day 3 and 28 as well as non-operated mice served as controls.

Results

Comparison of complementarity-determining region (CDR3) length distribution of 179 B cells and 796 T cells revealed no differences between AAA and control nor between the disease stages. We found no clonal expansion of B cells in AAA. For T cells, we identified multiple clones in 11 of 16 AAA samples and in 1 of 8 control samples. Comparison of the immune receptor repertoires indicated that only few clones were shared between the individual AAA samples. The most frequently used V-genes in the TCR beta chain in AAA were TRBV3, TRBV19, and TRBV12-2+TRBV13-2.

Conclusion

In summary, we found no clonal expansion of TCRs or BCRs in elastase-induced AAA in mice. Our findings imply that a more precise characterization of TCR and BCR distribution requires a more extensive amount of T and B cells to prevent undersampling and to enable detection of potential rare clones. Using this current scSeq-based approach we did not identify clonal enrichment of T or B cells in experimental AAA.
Color and Spatial Frequency Provide Functional Signatures of Retinotopic Visual Areas
Authors: Loggia Spencer R. , Duffield Stuart J. , Braunlich Kurt , Conway Bevil R.
Published: December 2022

Primate vision relies on retinotopically organized cortex defined by representations of hemifield (upper versus lower visual field), eccentricity (fovea versus periphery), and area (V1, V2, V3, V4). To test for the functional signatures of these organizing principles, we used fMRI to measure responses to colored gratings with varying spatial frequency, color, and saturation across rentinotopically defined parcels in macaque monkeys. Using an approach we call Sparse Supervised Embedding (SSE), we identified stimulus features that differed most across the cortical parcels. Constraining the model according to each voxel’s eccentricity revealed the expected variation of spatial frequency and S-cone modulation with eccentricity. Constraining according to voxel dorsal-ventral location and retinotopic area, revealed two additional components which together provide unexpected functional signatures. First earlier visual areas were more sensitive to contrast and saturation compared to later areas. Second, ventral parcels responded less to luminance contrast and more to color, particularly along the orange-blue intermediate axis in cone-opponent color space. This dorsal-ventral asymmetry resembles differences between candidate dorsal and ventral subdivisions of human V4 but extends to include all retinotopic visual areas, with a magnitude that increased from V1 to V4. Overall, our study demonstrates SSE as a data-driven tool for generating hypotheses about cortical function and behavior, and provides insight into the functional roles of different retinotopic areas.

Significance Statement

This study explores the functional roles of visual areas (V1, V2, V3, V4, V3a, MT) parceled by eccentricity preference and visual hemifield. We employ a new approach called Sparse Supervised Embedding (SSE), a promising technique for visualizing and understanding complex neuroimaging datasets. Analyzing fMRI responses to different color grating stimuli, we uncover a functional organization across these parcels, shedding light on their roles in visual computation. This study enhances our knowledge of processing in early visual cortex and how it varies across the retinotopic map. It also aids in resolving apparent differences between prior human and macaque studies.