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Biology subjects

Cain, S.

Publications and source records attributed to Cain, S..

11 recordsLinked to original sources

Verifiable Agentic Science on Public Infrastructure

Autonomous artificial intelligence agents are transforming the practice of science. Across every discipline, researchers are handing data analysis to coding agents that can design and execute complex studies from a single prompt. Yet this revolution carries a threat. When agents improvise in local environments, they leave no verifiable record, ultimately risking a wave of irreproducible science. Solving this crisis requires moving agentic science onto public infrastructure where every action leaves an examinable trail. Here we connect autonomous coding agents to shared computing resources, turning ephemeral prompts into auditable scientific records. After showing that 30 unguided local agents splinter into 18 incompatible pipelines on the same dataset, we conduct an agentic reproduction and discovery study on a large scale---reproducing a large, diverse array of studies with every workflow, history, and intermediate dataset publicly accessible. This complete provenance trail exposes unstated modeling choices, reference mismatches, and subsampled tutorial inputs in published studies, and establishes a new foundation where human scientists can understand, steer, and trust AI-driven discovery.

bioinformatics↗

Apollo 3: Multi-Species Genome Curation

We present Apollo 3, a new manual genome annotation tool that integrates with the JBrowse 2 genome browser. Its functionality is inspired by existing manual genome annotation tools such as Apollo, Artemis, and Otter, but uses an updated and more scalable architecture and technology stack. It allows the simultaneous editing of multiple genomes, including the visualization of synteny to inform those annotations. Apollo 3 can be used as a standalone annotation editor, or it can be installed on a server and used collaboratively. We describe the application's design, features, and use cases.

genomics↗

Standardizing RNA-seq Analysis of Fungal Pathogens Using BRC-Analytics and Agentic AI: A Candidozyma auris Case Study

Candidozyma auris has emerged as a critical global health threat due to multidrug resistance and healthcare-associated transmission. While RNA-seq has become the primary tool for studying C. auris pathogenesis, inconsistent use of reference genomes and bioinformatics tools complicate cross-study comparisons. Here we demonstrate how BRC-Analytics, a platform for pathogen genomics, combined with an agentic AI assistant, enables reproducible RNA-seq analysis. By re-analyzing data from two publications we achieved near-perfect correlation with published results despite annotation version differences. We addressed provenance challenges associated with using AI agents with Galaxy by forcing them to invoke Galaxys native tools rather than manipulating data directly. For custom analyses outside Galaxys toolset, we provide standalone JupyterLite notebooks that reproduce our analysis without AI involvement. This framework--combining AI-assisted automation with rigorous provenance tracking--establishes a template for standardized, reproducible fungal pathogen genomics. To the best of our knowledge, this is the first example of integration between public data repositories, reproducible analysis workflows, and agentic AI tools. Our subsequent efforts will focus on improving the seamlessness of this integration.

genomics↗

From data to publication in a browser with BRC-Analytics: Evolutionary dynamics of coding overlaps in measles virus

The analytical landscape of pathogen research is often fragmented, hindering transparency and reproducibility due to diverse genomic data sources, numerous software tools, and suboptimal integration methods. Here we introduce BRC-analytics, a novel browser-based environment that unifies authoritative sources of genomic data with community-curated best analysis practices on a freely accessible public computational infrastructure. We demonstrate its capabilities by analyzing the evolutionary dynamics within the P/V/C locus of the measles virus, a complex system involving overlapping coding regions and RNA editing. Our analysis, conducted entirely within BRC-analytics, reveals asymmetric evolution of the locuss reading frames under distinct selective pressures. BRC-analytics streamlines the entire research process--from data collection and primary analysis (e.g., variant calling) to interpretation (e.g., using integrated JupyterLite notebooks and LLMs) and publication--into a single web browser session. This eliminates the need for local installations and manual data transfers, implicitly tracking provenance and ensuring reproducibility. The platforms goal is to provide true data-to-publication functionality, making advanced pathogen genomics accessible to a broader research community regardless of their computational expertise or infrastructure access.

genomics↗

Human pluripotent stem cell model of multiple epiphyseal dysplasia with MATN3 mutation identifies altered Matrix organisation and upregulation of the cholesterol biosynthesis pathway

Multiple epiphyseal dysplasia (MED), caused by mutations in MATN3, is a chondrodysplasia affecting the cartilage growth plate and is characterised by delayed epiphyseal ossification, short stature, and early onset osteoarthritis. Here we generated an in vitro human pluripotent stem cell (hPSC) model of cartilage growth-plate development to identify pathogenic mechanisms underlying MED. hPSCs were differentiated to chondrocytes via a mesenchymal intermediate, followed by TGF{beta}3+BMP2 induced chondrogenic pellet culture. MATN3-mutant hPSCs were generated by reprogramming MED patient PBMCs or by CRISPR-Cas9 gene editing to introduce a MATN3 mutation in a hESC line. RNAseq was used to assess chondrogenesis and identify MED pathogenic mechanisms. Transmission electron microscopy (TEM) was used to assess extracellular matrix assembly. The resultant hPSC-derived cartilage pellets displayed a typical cartilage morphology and strongly expressed cartilage matrix markers, e.g., collagen II and matrilin-3. Matrilin-3 protein was detected within both the matrix and cells of heterozygous mutant hPSC-cartilage pellets. RNAseq of mutant hPSC-cartilage pellets revealed significant enrichment for ECM organisation and cholesterol biosynthesis pathway genes as well as sightly increased expression of some unfolded protein response (UPR) marker genes. MATN3 mutant hPSC-derived cartilage pellets displayed abnormal matrix assembly, distended ER, accumulation of lipid droplets, and increased cholesterol content. Our model revealed mutant matrilin-3 induces cholesterol biosynthesis pathway upregulation and abnormal matrix assembly during MED pathogenesis. This study provides new insights into the molecular mechanisms underlying MED and highlights potential therapeutic targets.

cell biology↗

An Information Theory Framework for Movement Path Segmentation and Analysis

Improved animal tracking technologies provide opportunities for novel segmentation of movement tracks/paths into behavioral activity modes (BAMs) critical to understanding the ecology of individuals and the functioning of ecosystems. Current BAM segmentation includes biological change point analyses and hidden Markov models. Here we use an elemental approach to segmenting tracks into {micro}-step-long "base segments" and m-base-segment-long "words." These are respectively clustered into n statistical movement elements (StaMEs) and k "raw" canonical activity modes (CAMs). Once the words are coded using m extracted StaME symbols, those encoded by the same string of symbols, after a rectification processes has been implemented to minimize misassigned words, are identified with particular "rectified" CAM types. The percent of reassignment errors, along with information theory measures, are used to compare the efficiencies of coding both simulated and empirical barn owl data for a selection of parameter values and approaches to clustering.

ecology↗

Low-dimensional representations of genome-scale metabolism

Cellular metabolism is a highly interconnected network with thousands of reactions that convert nutrients into the molecular building blocks of life. Metabolic connectivity varies greatly with cellular context and environmental conditions, and it remains a challenge to compare genome-scale metabolism across cell types because of the high dimensionality of the reaction flux space. Here, we employ self-supervised learning and genome-scale metabolic models to compress the flux space into low-dimensional representations that preserve structure across cell types. We trained variational autoencoders (VAEs) on large fluxomic data (N = 800, 000) sampled from patient-derived models for various cancer cell types. The VAE embeddings have an improved ability to distinguish cell types than the uncompressed fluxomic data, and sufficient predictive power to classify cell types with high accuracy. We tested the ability of these classifiers to assign cell type identities to unlabelled patient-derived metabolic models not employed during VAE training. We further employed the pre-trained VAE to embed another 38 cell types and trained multilabel classifiers that display promising generalization performance. Our approach distils the metabolic space into a semantically rich vector that can be used as a foundation for predictive modelling, clustering or comparing metabolic capabilities across organisms.

systems biology↗

The Statistical Building Blocks of Animal Movement Simulations

Animal movement plays a key role in many ecological processes and has a direct influence on an individuals fitness at several scales of analysis (i.e., next-step, subdiel, day-by-day, seasonal). This high-lights the need to dissect movement behavior at different spatio-temporal scales and develop hierarchical movement tools for generating realistic tracks to supplement existing single-temporal-scale simulators. In reality, animal movement paths are a concatenation of fundamental movement elements (FuMEs: e.g., a step or wing flap), but these are not generally extractable from a relocation time-series track (e.g., sequential GPS fixes) from which step-length (SL, aka velocity) and turning-angle (TA) time series can be extracted. For short, fixed-length segments of track, we generate their SL and TA statistics (e.g., means, standard deviations, correlations) to obtain segment-specific vectors that can be cluster into different types. We use the centroids of these clusters to obtain a set of statistical movement elements (StaMEs; e.g. directed fast movement versus random slow movement elements) that we use as a basis for analyzing and simulating movement tracks. Our novel concept is that sequences of StaMEs provide a basis for constructing and fitting step-selection kernels at the scale of fixed-length canonical activity modes: short fixed-length sequences of interpretable activity such as dithering, ambling, directed walking, or running. Beyond this, variable length pure or characteristic mixtures of CAMs can be interpreted as behavioral activity modes (BAMs), such as gathering resources (a sequence of dithering and walking StaMEs) or beelining (a sequence of fast directed-walk StaMEs interspersed with vigilance and navigation stops). Here we formulate a multi-modal, step-selection kernel simulation framework, and construct a 2-mode movement simulator (Numerus ANIMOVER_1), using Numerus RAMP technology. We also illustrate methods for extracting StaMEs from both simulated and real data from two barn owls (Tyto alba) in the Harod Valley, Israel. Overall, our new bottom-up approach to path segmentation allows us to both dissect real movement tracks and generate realistic synthetic ones, thereby providing a general tool for testing hypothesis in movement ecology and simulating animal movement in diverse contexts such as evaluating an individuals response to landscape changes, release of an individual into a novel environment, or identifying when individuals are sick or unusually stressed.

ecology↗

FAIR Header Reference genome: A TRUSTworthy standard

The lack of interoperable data standards among reference genome data-sharing platforms inhibits cross-platform analysis while increasing the risk of data provenance loss. Here, we describe the FAIR-bioHeaders Reference genome (FHR), a metadata standard guided by the principles of Findability, Accessibility, Interoperability, and Reuse (FAIR) in addition to the principles of Transparency, Responsibility, User focus, Sustainability, and Technology (TRUST). The objective of FHR is to provide an extensive set of data serialisation methods and minimum data field requirements while still maintaining extensibility, flexibility, and expressivity in an increasingly decentralised genomic data ecosystem. The effort needed to implement FHR is low; FHRs design philosophy ensures easy implementation while retaining the benefits gained from recording both machine and human-readable provenance.

bioinformatics↗

JBrowse 2: A modular genome browser with views of synteny and structural variation

We present JBrowse 2, a general-purpose genome annotation browser offering enhanced visualization of complex structural variation and evolutionary relationships. JBrowse 2 retains the core features of the open-source JavaScript genome browser JBrowse while adding new views for synteny, dotplots, breakpoints, gene fusions, and whole-genome overviews. The software readily allows users to share sessions, open multiple genomes or views, and navigate quickly between these views. It can be embedded in a web page, used as a standalone desktop application, or run from Jupyter notebooks or R sessions. Using a plugin framework, developers can create new data adapters, track types, and visualizations. These improvements are enabled by a ground-up redesign of the JBrowse architecture using modern web technology. We describe application functionality, use cases, performance benchmarks, and implementation notes for web administrators and developers.

bioinformatics↗

JBrowse Jupyter: A Python interface to JBrowse 2

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSMotivationC_ST_ABSJBrowse Jupyter is a package that aims to close the gap between Python programming and genomic visualization. Web-based genome browsers are routinely used for publishing and inspecting genome annotations. Historically they have been deployed at the end of bioinformatics pipelines, typically decoupled from the analysis itself. However, emerging technologies such as Jupyter notebooks enable a more rapid iterative cycle of development, analysis and visualization. ResultsWe have developed a package that provides a python interface to JBrowse 2s suite of embeddable components, including the primary Linear Genome View. The package enables users to quickly set up, launch and customize JBrowse views from Jupyter notebooks. In addition, users can share their data via Googles Colab notebooks, providing reproducible interactive views. AvailabilityJBrowse Jupyter is released under the Apache License and is available for download on PyPI. Source code and demos are available on GitHub at https://github.com/GMOD/jbrowse-jupyter. Contactihh@berkeley.edu

bioinformatics↗