bluuebunny/crossref_metadata_2025_split huggingface dataset:
Minimally and vaguely informative priors to combat practical parameter non-identifiability of hidden Markov models exemplified by ion channel data
Authors: Münch Jan L. , Schmauder Ralf , Paul Fabian , Habeck Michael 
Published: April 2024

AbstractHidden Markov Model (HMM) inference for time-series data from ion channels or other biomolecules is challenging. We argue that inference on partially observed chemical reaction networks (CRNs) suffers from practical parameter non-identifiability (non-PI) that often goes unnoticed in maximum likelihood (ML) inferences. Limitations in the signal bandwidth and a poor signal-to-noise ratio only add to the non-PI problem. We study the role of the prior distribution in the face of non-PI. In particular, we advocate using minimally informative (MI) priors and additional restrictions on the parameter space that can be derived from physical considerations. Using patch clamp (PC) ion-channel measurements as a prototypical time series, we demonstrate Bayesian strategies for alleviating non-PI problems with sharpened prior information.In Bayesian statistics, the prior can substantially modulate the posterior. We demonstrate that non-PI can be severely harmful when using uniform priors on the rate matrix of HMMs, which are implicitly assumed in ML. We show that MI priors enable meaningful HMM inference with data whose quality can be one to two orders of magnitude worse than required to reach the same accuracy with uniform priors. However, we also demonstrate that non-PI pathologies can persist even with a prior MI. In this case, the MI prior alleviates but does not entirely resolve the problem of improper posteriors. For complex HMMs, stronger prior assumptions are needed to render the posterior proper.We propose to confine the parameters to a sampling box whose limits are physically reasonable and derived from theory. This fusion of data and physical information allows for meaningful inferences even for the most complex HMM with data of the lowest quality that we tested. However, hard theoretical limits, such as diffusion-limited binding rates, are rarely available. As an alternative, we test a vague prior on the ratios of each pair of binding rates and additionally unbinding rates, thereby softly linking them. This implicitly assumes finite cooperativity and introduces a bias towards non-cooperativity. However, in contrast to the standard practice of choosing equal chemical rates, which supposes strict non-cooperativity, this additional prior still allows for cooperativity. Despite its vagueness, our prior renders the posterior either proper in a strict sense orsufficientlyproper for all data sets we considered without imposing the assumption of non-cooperativity. Hence, our approach can infer how likely different degrees of cooperativity are. Combining theoretical upper limits and vague finite cooperativity assumptions dramatically improves inferences.
SonoNERFs: Neural Radiance Fields applied to Biological Echolocation Systems allow 3D Scene Reconstruction Through Perceptual Prediction
Authors: Jansen Wouter , Steckel Jan 
Published: April 2024

AbstractIn this paper, we introduce SonoNERFs, a novel approach that adapts Neural Radiance Fields (NeRFs) to model and understand the echolocation process in bats, focusing on the challenges posed by acoustic data interpretation without phase information. Leveraging insights from the field of optical NeRFs, our model, termed SonoNERF, represents the acoustic environment through Neural Reflectivity Fields. This model allows us to reconstruct three-dimensional scenes from echolocation data, obtained by simulating how bats perceive their surroundings through sound. By integrating concepts from biological echolocation and modern computational models, we demonstrate the SonoNERF’s ability to predict echo spectrograms for unseen echolocation poses and effectively reconstruct a mesh-based and energy-based representation of complex scenes. Our work bridges a gap in understanding biological echolocation and proposes a methodological framework that provides a first order model on how scene understanding might arise in echolocating animals. We demonstrate the efficacy of the SonoNERF model on three scenes of increasing complexity, including some biologically relevant prey-predator interactions.
Cellular and molecular changes in the human osteoarthritic and aging hip pulvinar
Authors: Tilouche Bahaeddine , Farhat Stephanie , Short Spencer , Somyk Mariya , Beaulé Paul , Carsen Sasha , Grammatopoulos George , Coutu Daniel L. 
Published: April 2024

AbstractOsteoarthritis (OA) represents a multifaceted pathology characterized by intricate signaling across various joint tissues, where the sub-synovial adipose tissue (ssAT) has been suggested to play diverse roles, from serving as a stem cell reservoir, mechanosensing, serving as a neuroendocrine organ, to modulating inflammation. In this study, we aimed to uncouple the cellular and molecular alterations within the human hip ssAT (the pulvinar) linked to OA and aging, elucidating the distinct contributions of disease onset and progression versus normal aging. Our findings show a pronounced increase in mesenchymal stem/progenitor cells (MSPCs) in the osteoarthritic pulvinar, associated with the upregulation of putative MSPC markers (DPP4, and THY1), indicating an adaptive repair response. Concurrently, in OA patients we observed an altered immune landscape featuring reduced innate immune cells and elevated exhausted CD8+ cells, along with upregulation of genes critical for inflammation and fibroblast activation. Our findings reveal a nuanced picture of OA, where increased stem cell numbers and vascularization, combined with specific gene expression patterns differentiate OA from normal aging. This study not only delineates the roles of inflammation, immune regulation, and stem cell activity in the OA pulvinar but also identifies potential therapeutic targets to modulate these pathways, offering novel insights into OA as a complex interplay of degenerative and intrinsic tissue repair.
Variability of Auditory Brainstem Responses in Diversity Outbred Mice
Authors: Taszus Roxana , Rio Joaquin del , Stoessel Alexander , Nowotny Manuela 
Published: April 2024

AbstractInbred mouse strains are mainly used in hearing research as animal models. Most of these lab mice strains consist of genetically identical individuals and natural variability as it is found in wild populations is not represented. Jackson Laboratories generated a new mice strain by an outbred of different mice strains to create mice with different pheno- and genotype, the Diversity Outbred strain (J:DO). By using 20 J:DO mice at the age of eight to nine weeks, we aimed to test the hearing variability in auditory thresholds and measured auditory brainstem responses at 15 different frequencies and sound pressure level from 0 to 80 dB SPL. Our measurements revealed a wide hearing bandwidth in J:DO mice that span over about 4.5 octaves. The high-frequency cut-off of the hearing threshold varied from 21 to 80 kHz and was on median at 64 kHz. Whereas the low frequency cut-off was at 3 kHz with low variation. The median characteristic frequency was found at 15 kHz and showed not a high variation in the sound level to induce an ABR threshold (20 dB SPL). We found not differences in hearing between male and female J:DOs. Future studies on hearing impairments in mice that aim to base on a genetically variable population could benefit from this new mouse strain and use our dataset on the hearing threshold in J:DO mice is a basis.
Connectomic Analysis of Mitochondria in the Central Brain ofDrosophila
Authors: Rivlin Patricia K , Januszewski Michal , Longden Kit D , Neace Erika , Scheffer Louis K , Ordish Christopher , Clements Jody , Phillips Elliott , Smith Natalie , Takemura Satoko , Umayam Lowell , Walsh Claire , Yakal Emily A , Plaza Stephen M , Berg Stuart 
Published: April 2024

AbstractMitochondria are an integral part of the metabolism of a neuron. EM images of fly brain volumes, taken for connectomics, contain mitochondria as well as the cells and synapses that have already been reported. Here, from theDrosophilahemibrain dataset, we extract, classify, and measure approximately 6 million mitochondria among roughly 21 thousand neurons of more than 5500 cell types. Each mitochondrion is classified by its appearance - dark and dense, light and sparse, or intermediate - and the location, orientation, and size (in voxels) are annotated. These mitochondria are added to our publicly available data portal, and each synapse is linked to its closest mitochondrion. Using this data, we show quantitative evidence that mitochodrial trafficing extends to the smallest dimensions in neurons. The most basic characteristics of mitochondria - volume, distance from synapses, and color - vary considerably between cell types, and between neurons with different neurotransmitters. We find that polyadic synapses with more post-synaptic densities (PSDs) have closer and larger mitochondria on the pre-synaptic side, but smaller and more distant mitochondria on the PSD side. We note that this relationship breaks down for synapses with only one PSD, suggesting a different role for such synapses.
ADrosophilamodel for mechanistic investigation of tau protein spread
Authors: Bankapalli Kondalarao , Thomas Ruth E. , Vincow Evelyn S. , Milstein Gillian , Fisher Laura V. , Pallanck Leo J. 
Published: April 2024

ABSTRACTBrain protein aggregates are a hallmark of neurodegenerative disease. Previous work indicates that specific protein components of these aggregates are toxic, including tau in Alzheimer’s disease and related tauopathies. Increasing evidence also indicates that these toxic proteins traffic between cells in a prion-like fashion, thereby spreading pathology from one brain region to another. However, the mechanisms involved in trafficking are poorly understood. We therefore developed a transgenicDrosophilamodel to facilitate rapid evaluation of candidate tau trafficking modifiers. Our model uses the bipartite Q system to drive co-expression of tau and GFP in the fly eye. We find age-dependent tau spread into the brain, represented by detection of tau, but not GFP in the brain. We also found that tau trafficking was attenuated upon inhibition of the endocytic factordynaminor the kinaseglycogen synthase kinase-3β(GSK-3β). Further work revealed that dynamin promotes tau uptake in recipient tissues, whereas GSK-3β appears to promote tau spread via direct phosphorylation of tau. Our robust and flexible system will promote the identification of tau trafficking components involved in the pathogenesis of neurodegenerative diseases.SUMMARY STATEMENTThe trafficking of toxic proteins in neurodegenerative disease is well-known but poorly understood. Our model will allow rapid and new insight into molecular mechanisms underlying this process.
Resolving and Quantifying Viral-Like Particles via Blind Deconvolution
Authors: Figueroa Jose L , Bellanger Madeline , Fulghum Bryan , Visscher Pieter T , White Richard Allen 
Published: April 2024

AbstractViruses represent the most numerous ‘biological entities’ on Earth; but the direct quantification of viruses within ecosystems reminds an ongoing challenge. The classical method of epifluorescence microscopy (EFM) reminds the gold standard measurement of viral-like particles (VLPs) within ecosystems. Quantifying VLPs in epifluorescence microscopy is burdened by ongoing challenges that include manual human counting, an absence of accurate morphological sizing, and the a range of viral sizes (20-300 nm) falling below the diffraction limit of light microscopy. Here, a proof-of-concept computer vision framework for the automated enumeration and sizing of viral-like particles is presented, known as EpiVirQuant. A novel tunable pointspread function is introduced which allows for a dynamic blind deconvolution. Final enumeration by EpiVirQuant was directly compared to manual human counting which yielded 18% more VLPs identified. EpiVirQuant quantified average VLP size of 179.5 nm, which is consistent with median size of VLPs in nature of of _160 nm. Runtime ranged from 60-80 seconds-perimage depending on parameter selection. This provides a viable proof-of-concept cost-effective solution for the enumeration and large-scale morphological analysis of VLPs.
Bi-level Graph Learning Unveils Prognosis-Relevant Tumor Microenvironment Patterns in Breast Multiplexed Digital Pathology
Authors: Wang Zhenzhen , Santa-Maria Cesar A. , Popel Aleksander S. , Sulam Jeremias 
Published: April 2024

AbstractThe tumor microenvironment is widely recognized for its central role in driving cancer progression and influencing prognostic outcomes. There have been increasing efforts dedicated to characterizing this complex and heterogeneous environment, including developing potential prognostic tools by leveraging modern deep learning methods. However, the identification of generalizable data-driven biomarkers has been limited, in part due to the inability to interpret the complex, black-box predictions made by these models. In this study, we introduce a data-driven yet interpretable approach for identifying patterns of cell organizations in the tumor microenvironment that are associated with patient prognoses. Our methodology relies on the construction of a bi-level graph model: (i) a cellular graph, which models the intricate tumor microenvironment, and (ii) a population graph that captures inter-patient similarities, given their respective cellular graphs, by means of a soft Weisfeiler-Lehman subtree kernel. This systematic integration of information across different scales enables us to identify patient subgroups exhibiting unique prognoses while unveiling tumor microenvironment patterns that characterize them. We demonstrate our approach in a cohort of breast cancer patients and show that the identified tumor microenvironment patterns result in a risk stratification system that provides new complementary information with respect to standard stratification systems. Our results, which are validated in two independent cohorts, allow for new insights into the prognostic implications of the breast tumor microenvironment. This methodology could be applied to other cancer types more generally, providing insights into the cellular patterns of organization associated with different outcomes.
Forces directing the systemic correlations of cell migration
Authors: De la Fuente Ildefonso M. , Carrasco-Pujante Jose , Camino-Pontes Borja , Fedetz Maria , Bringas Carlos , Pérez-Samartín Alberto , Pérez-Yarza Gorka , López José I. , Malaina Iker , Cortes Jesus M 
Published: April 2024

AbstractDirectional motility is an essential property of cells. Despite its enormous relevance in many fundamental physiological and pathological processes, how cells control their locomotion movements remains an unresolved question. Here we have addressed the systemic processes driving the directed locomotion of cells. Specifically, we have performed an exhaustive study analyzing the trajectories of 700 individual cells belonging to three different species (Amoeba proteus,Metamoeba leningradensisandAmoeba borokensis) in four different scenarios: in absence of stimuli, under an electric field (galvanotaxis), in a chemotactic gradient (chemotaxis), and under simultaneous galvanotactic and chemotactic stimuli. All movements were analyzed using advanced quantitative tools. The results show that the trajectories are mainly characterized by coherent integrative responses that operate at the global cellular scale. These systemic migratory movements depend on the cooperative non-linear interaction of most, if not all, molecular components of cells.SignificanceCellular migration is a cornerstone issue in many human physiological and pathological processes. For years, the scientific attention has been focused on the individualized study of the diverse molecular parts involved in directional motility; however, locomotion movements have never been regarded as a systemic process that operates at a global cellular scale. In our quantitative experimental analysis essentialsystemicproperties underlying locomotion movements were detected. Such emergent systemic properties are not found specifically in any of the molecular parts, partial mechanisms, or individual processes of the cell. Cellular displacements seem to be regulated by integrative processes operating atsystemiclevel.
Mutant TP53 switches therapeutic vulnerability during gastric cancer progression within Interleukin-6 family cytokines
Authors: Huber Anne , Allam Amr H. , Dijkstra Christine , Thiem Stefan , Huynh Jennifer , Poh Ashleigh R. , Konecnik Joshua , Jacob Saumya P. , Busuttil Rita , Liao Yang , Chisanga David , Shi Wei , Alorro Mariah G. , Forrow Stephen , Tauriello Daniele V.F. , Batlle Eduard , Boussioutas Alex , Williams David S. , Buchert Michael , Ernst Matthias , Eissmann Moritz F. 
Published: April 2024

AbstractAlthough aberrant activation of the KRAS and PI3K pathway alongside TP53 mutations account for frequent aberrations in human gastric cancers, neither the sequence nor the individual contributions of these mutations have been clarified. Here, we establish an allelic series of mice to afford conditional expression in glandular epithelium ofKrasG12D;Pik3caH1047RorTrp53R172Hand/or ablation ofPtenorTrp53. We find thatKrasG12D;Pik3caH1047Ris sufficient to induce adenomas, and that lesions progress to carcinoma when also harboringPten-deletions. Additional challenge with eitherTrp53loss- or gain-of-function alleles further accelerated tumor progression and triggered metastatic disease. While tumor-intrinsic STAT3 signaling in response to gp130 family cytokines remained as a gatekeeper for all stages of tumor development, metastatic progression required a mutantTrp53-induced interleukin (IL)-11 to IL-6 dependency switch. Consistent with poorer survival of patients with high IL6 expression, we identify IL6/STAT3 signaling as a therapeutic vulnerability for TP53-mutant gastric cancer.
Figeno: multi-region genomic figures with long-read support
Authors: Sollier Etienne , Heilmann Jessica , Gerhäuser Clarissa , Scherer Michael , Plass Christoph , Lutsik Pavlo 
Published: April 2024

AbstractSummaryThe vast amount of publicly available genomic data requires analysis and visualization tools. Here, we present figeno, an application for generating publication-quality FIgures for GENOmics. Figeno particularly focuses on multi-region views across genomic breakpoints and on long reads with base modifications. Additionally, we support epigenomic data including ATAC-seq, ChIP-seq or HiC, as well as whole genome sequencing data with copy numbers and structural variants.Availability and ImplementationFigeno is available as a python package with both a command line and graphical user interface. It can be installed via PyPI and the source code is available athttps://github.com/CompEpigen/figeno.Supplementary informationSupplementary data is provided.
Inbreeding and gallbladder cancer risk: Homozygosity associations adjusted for indigenous American ancestry, BMI and genetic risk of gallstone disease
Authors: Ceballos Francisco , Boekstegers Felix , Scherer Dominique , Ponce Carol Barahona , Marcelain Katherine , Gárate-Calderón Valentina , Waldenberger Melanie , Morales Erik , Rojas Armando , Munoz César , Retamales Javier , de Toro Gonzalo , Kortmann Allan Vera , Barajas Olga , Teresa Rivera María , Cortés Analía , Loader Denisse , Saavedra Javiera , Gutiérrez Lorena , Ortega Alejandro , Bertrán Maria Enriqueta , Bartolotti Leonardo , Gabler Fernando , Campos Mónica , Alvarado Juan , Moisán Fabricio , Spencer Loreto , Nervi Bruno , Carvajal-Hausdorf Daniel , Losada Héctor , Almau Mauricio , Fernández Plinio , Olloquequi Jordi , Rothhammer Francisco , Bermejo Justo Lorenzo 
Published: April 2024

AbstractLatin Americans have a rich genetic make-up that translates into heterogeneous fractions of the autosomal genome in runs of homozygosity (FROH), and heterogeneous types and proportions of indigenous American ancestry. While autozygosity has been linked to several human diseases, very little is known about the relationship between inbreeding, genetic ancestry and cancer risk in Latin Americans.Chile has one of the highest incidences of gallbladder cancer (GBC) in the world, and here we investigated the association between inbreeding, GBC, gallstone disease (GSD) and body mass index (BMI) in 4029 genetically admixed Chileans. We calculated individual FROHabove 1.5 Mb and weighted polygenic risk scores for GSD, and applied multiple logistic regression to assess the association between homozygosity and GBC risk.We found that homozygosity was due to a heterogeneous mixture of genetic drift and consanguinity in the study population. Although we found no association between homozygosity and overall GBC risk, we detected interactions between FROHand sex, age, and genetic risk of GSD on GBC risk. Specifically, the increase in GBC risk per 1% FROHwas 19% in men (P-value = 0.002), 30% in those under 60 years of age (P-value = 0.001), and 12% in those with a genetic risk of GSD above the median (P-value = 0.01).The present study highlights the complex interplay between inbreeding, genetic ancestry and genetic risk of GSD in the development of GBC. The applied methodology and our findings underscore the importance of considering the population-specific genetic architecture, along with sex- and age specific-effects, when investigating the genetic basis of complex traits in Latin Americans.