Biology subjects

Small, C.

Publications and source records attributed to Small, C..

11 recordsLinked to original sources

bioRxiv2026

A collaborative submission model for building high-quality data resources at scale through partnership

Community data resources that aggregate datasets across studies are critical infrastructure for modern biomedical research, accelerating discovery as rapidly advancing Artificial Intelligence (AI) models place ever-greater demand on large, well-described data corpora. However, building these resources involves a fundamental tension: comprehensive metadata is imperative for reuse, yet capturing this information systematically requires substantial effort that limits growth. We detail how CZ CELLxGENE Discover has used the collaborative submission model - where data contributors partner with dedicated resource curators - to become a large, widely used single-cell genomics resource for diverse analytical applications including AI model development and integrative analysis. This partnership leverages contributors intimate study knowledge and curators focus on data reuse and expertise in standardization to improve data quality, metadata accuracy, and richness. This is achieved by motivating researcher participation through tangible benefits while minimizing submission burden. We contrast this collaborative model with contributor-driven and resource-driven approaches, highlighting tradeoffs in scalability, consistency across submissions, and quality assurance. The principles and practices we describe provide a framework for building high-quality community data resources across diverse biological data types.

genetics↗

bioRxiv2025

Dorsal forerunner cells transmit epiboly forces to extend the zebrafish notochord

Convergence and extension (C&E) cell movements promote anteroposterior axis extension and narrow both neuroectodermal and mesodermal tissues during gastrulation. Mediolateral cell intercalation is largely responsible for this morphogenetic process in vertebrates, but evidence suggests that additional cell-extrinsic forces generated by surrounding tissues contribute to the shaping of many structures. In zebrafish, for example, mechanical forces generated by the anteriorly migrating prechordal plate cooperate with tissue-autonomous cell intercalations to promote extension of the notochord. Here we propose a novel model for notochord morphogenesis by which mechanical epiboly forces within the enveloping layer are transmitted to the posterior end of the notochord via a cluster of dorsal forerunner cells (DFCs) that physically links the two. We found that scattering or absence of DFCs caused by loss of crb2a or sox32, respectively, reduces notochord C&E and exacerbates axis extension defects in planar cell polarity signaling-deficient embryos. Using an automated image segmentation and cell shape analysis pipeline, we show that cells within the posterior notochord fail to properly elongate when DFCs are scattered or absent. Finally, we demonstrate that loss of crb2a and sox32 fails to disrupt C&E of zebrafish embryonic explants in which no epiboly occurs and all extension is driven by cell-intrinsic behaviors. Together, these findings support a model in which DFCs facilitate mechanical coupling of the enveloping layer to the posterior notochord during epiboly to ensure its robust morphogenesis during gastrulation.

developmental biology↗

bioRxiv2025

Nanobinders for Synaptotagmin 1 enable the analysis of synapticvesicle dynamics in rodent and human models.

Synaptic neurotransmission is a critical hallmark of brain activity and one of the first processes to be affected in neural diseases. Monitoring this process, and in particular synaptic vesicle recycling, in living cells has been instrumental in unraveling mechanisms responsible for neurotransmitter release. However, currently available reporters suffer from major limitations such large probe size or lack of suitability for human neurons, hampering the understanding of human synaptic pathophysiology. Here we describe the NbLumSyt1 toolkit, a panel of nanobody-based affinity probes targeting the luminal domain of the synaptic vesicle protein Synaptotagmin 1 (Syt1). These new tools enable quantitative, non-invasive imaging and functional interrogation of synaptic transmission in human neurons, with unprecedented precision, versatility and cost efficiency, in technologies ranging from fixed-and live-cell super-resolution imaging to electron microscopy and mass spectrometry. Overall, NbLumSyt1 nanobinders provide a valuable platform for human synaptic physiology and pathophysiology, benefiting fundamental neuroscience and translational efforts to study and develop treatments for brain-related disorders.

neuroscience↗

bioRxiv2023

CZ CELLxGENE Discover: A single-cell data platform for scalable exploration, analysis and modeling of aggregated data

Hundreds of millions of single cells have been analyzed to date using high throughput transcriptomic methods, thanks to technological advances driving the increasingly rapid generation of single-cell data. This provides an exciting opportunity for unlocking new insights into health and disease, made possible by meta-analysis that span diverse datasets building on recent advances in large language models and other machine learning approaches. Despite the promise of these and emerging analytical tools for analyzing large amounts of data, a major challenge remains the sheer number of datasets and inconsistent format, data models and accessibility. Many datasets are available via unique portals platforms that often lack interoperability. Here, we present CZ CellxGene Discover (cellxgene.cziscience.com), a data platform that provides curated and interoperable data. This single-cell data resource, available via a free-to-use online data portal, hosts a growing corpus of community contributed data that spans more than 50 million unique cells. Curated, standardized, and associated with consistent cell-level metadata, this collection of interoperable single-cell transcriptomic data is the largest of its kind. A suite of tools and features enables accessibility and reusability of the data via both computational and visual interfaces to allow researchers to rapidly explore individual datasets and perform cross-corpus analysis. This functionality is enabling meta-analyses of tens of millions of cells across studies and tissues and providing global views of human cells at the resolution of single cells.

cell biology↗

bioRxiv2023

Improvements to the Gulf Pipefish Syngnathus scovelli Genome

The Gulf pipefish Syngnathus scovelli has emerged as an important species in the study of sexual selection, development, and physiology, among other topics. The fish family Syngnathidae, which includes pipefishes, seahorses, and seadragons, has become an increasingly attractive target for comparative research in ecological and evolutionary genomics. These endeavors depend on having a high-quality genome assembly and annotation. However, the first version of the S. scovelli genome assembly was generated by short-read sequencing and annotated using a small set of RNA-sequence data, resulting in limited contiguity and a relatively poor annotation. Here, we present an improved genome assembly and an enhanced annotation, resulting in a new official gene set for S. scovelli. By using PacBio long-read high-fidelity (Hi-Fi) sequences and a proximity ligation (Hi-C) library, we fill small gaps and join the contigs to obtain 22 chromosome-level scaffolds. Compared to the previously published genome, the gaps in our novel genome assembly are smaller, the N75 is much larger (13.3 Mb), and this new genome is around 95% BUSCO complete. The precision of the gene models in the NCBIs eukaryotic annotation pipeline was enhanced by using a large body of RNA-Seq reads from different tissue types, leading to the discovery of 28,162 genes, of which 8,061 were non-coding genes. This new genome assembly and the annotation are tagged as a RefSeq genome by NCBI and thus provide substantially enhanced genomic resources for future research involving S. scovelli.

genomics↗

bioRxiv2022

Surface SV2A-Syt1 nanoclusters act as a sequestration hub that limits dynamin-1 recruitment and targeting to recycling synaptic vesicles

Following exocytosis, the recapture of plasma membrane-stranded vesicular proteins into recycling synaptic vesicles (SVs) is essential for sustaining neurotransmission. Surface clustering of vesicular proteins has been postulated as a pre-assembly mechanism for endocytosis - ensuring high-fidelity retrieval. Here, we used single-molecule imaging to examine the nanoclustering of synaptotagmin-1 (Syt1) and synaptic vesicle protein 2A (SV2A) in hippocampal neurons. Syt1 forms surface nanoclusters through interaction of its C2B domain with SV2A, that are sensitive to mutations in this domain (Syt1K326A/K328A) and knocking down SV2A. SV2A co-cluster with Syt1 and blocking SV2As cognate interaction with Syt1 (SV2AT84A) also decreased SV2A clustering. Surprisingly, impairing SV2A-Syt1 nanoclustering enhanced plasma membrane recruitment of key endocytic protein dynamin-1, leading to accelerated Syt1 endocytosis, altered intracellular sorting and decreased trafficking of Syt1 to Rab5-positive endocytic compartments. SV2A-Syt1 surface nanoclusters therefore negatively regulate the rate of their own re-entry into recycling SVs by controlling the recruitment of the endocytic machinery.

neuroscience↗

bioRxiv2022

Small-spored Alternaria spp. (section Alternaria) are common on wild tomato species

The wild relatives of modern tomato crops are native to South America. These plants occur in habitats as different as the Andes and the Atacama Desert and are to some degree all susceptible to fungal pathogens of the genus Alternaria. Alternaria is a large genus. On tomato, several species cause early blight, leaf spot, and other diseases. We collected Alternaria-like infection lesions from the leaves of eight wild tomato species from Chile and Peru. Using molecular barcoding markers, we characterized the pathogens. The infection lesions were caused predominantly by small-spored species of Alternaria of the section Alternaria, like A. alternata, but also by Stemphylium spp., Alternaria spp. from the section Ulocladioides, and other related species. Morphological observations and an infection assay confirmed this. Comparative genetic diversity analyses show a larger diversity in this wild system than in studies of cultivated Solanum species. As A. alternata has been reported to be an increasing problem on cultivated tomato, investigating the evolutionary potential of this pathogen is not only interesting to scientists studying wild plant-pathosystems. It could also inform crop protection and breeding programs to be aware of potential epidemics caused by species still confined to South America.

microbiology↗

bioRxiv2022

Synaptotagmin 1 mediates toxicity of botulinum neurotoxin type A

The extreme neurotoxicity of botulinum neurotoxins (BoNTs), broadly used as a therapeutics, is mediated by their direct binding to two plasma membrane receptors: polysialogangliosides (PSGs) and serotype-dependently either synaptotagmin 1/2 (Syt1/2) or synaptic vesicle glycoprotein 2 (SV2). Here, we demonstrate that although BoNT/A serotype binds directly to PSG and SV2, its neurotoxicity depends on Syt1. Using single-molecule superresolution microscopy of pathological concentrations of BoNT/A holotoxins, we demonstrate that the toxin binds to a preassembled PSG-Syt1 complex that forms nanoclusters with SV2 on the plasma membrane of hippocampal neurons. This coincidental interaction controls the selective endocytic targeting of BoNT/A into synaptic vesicles, leading to incapacitation of neuronal communication. Our results suggest that Syt1-SV2 plasma membrane nanoclusters may acts as a common target for various BoNT serotypes. One-Sentence SummaryBoNT/A hijacks an intrinsic tripartite PSG-Syt1-SV2 endocytic sorting mechanism to incapacitate neuronal communication

neuroscience↗

bioRxiv2021

SV2A-Syt1 interaction controls surface nanoclustering and access to recycling synaptic vesicles

Following exocytosis, the recapture of vesicular proteins stranded at the plasma membrane in recycling synaptic vesicles (SVs) is essential to sustain neurotransmission. Nanoclustering is emerging as a mechanism through which proteins may be pre-assembled prior to endocytosis, to ensure high fidelity of retrieval for subsequent rounds of vesicle fusion. Here, we used single molecule imaging to examine the nanoclustering of synaptotagmin-1 (Syt1) and synaptic vesicle protein 2A (SV2A). Syt1 forms surface nanoclusters through interaction of its C2B domain (K326/K328) with SV2A, as demonstrated by mutating Syt1 (K326A/K328A) and knocking down endogenous SV2A. Blocking cognate interaction with Syt1 (SV2AT84A) also decreased SV2A clustering. Impaired nanoclustering of Syt1 and SV2A leads to accelerated endocytosis of Syt1, altered intracellular sorting and decreased trafficking of Syt1 to a Rab5-positive endocytic pathway. We conclude that the interaction between SV2A and Syt1 locks both molecules into surface nanoclusters, controlling their entry into recycling SVs.

neuroscience↗

bioRxiv2021

AB12PHYLO: an integrated pipeline for Maximum Likelihood phylogenetic inference from ABI trace data

Multi-gene phylogenies constructed from multiplexed and Sanger sequencing data are regularly used in mycology and other disciplines as a cost-effective way of species identification and as a first means to investigate genetic diversity samples. Today, a number of tools exist for each of the steps in this analysis, including quality control and trimming, the generation of a multiple sequence alignment (MSA), extraction of informative sites, and the construction of the final phylogenetic tree. A BLAST search in a reference database is often performed to identify sequences of type specimens to compare the samples with in the phylogeny. Made over the past decades, these tools are all independent from and often not perfectly adapted to one another. We present AB12PHYLO, an integrated pipeline that can perform all necessary steps from reading in raw Sanger sequencing data through visualizing and editing phylogenies. In addition, AB12PHYLO can calculate basic summary statistics for each gene in the phylogeny. AB12PHYLO is designed as a wrapper of several open access and commonly used tools for each of the intermediate stages, and intended to simplify the phylogenetic pipeline while still allowing a high degree of access. It comes as a command-line version for the highest reproducibility and an intuitive graphical user interface (GUI) for easy adoption by IT-agnostic end-users. The use of AB12PHYLO significantly reduces the hands-on working time for these analyses.

evolutionary biology↗

bioRxiv2020

Frontotemporal dementia mutant tau (P301L) locks Fyn in an open, active conformation conducive to nanoclustering

Fyn is a Src kinase that controls critical signalling cascades and its postsynaptic enrichment underpins synaptotoxicity in Alzheimers disease (AD) and frontotemporal dementia (FTLD-tau). Previously, we found that pathogenic FTLD tau mutant (P301L) expression promotes aberrant trapping of Fyn in nanoclusters within hippocampal dendrites via an unknown mechanism (Padmanabhan et al., 2019). Here, we imaged Fyn-mEos2 using single particle tracking photoactivated localization microscopy (sptPALM) to demonstrate that nanoclustering of Fyn in hippocampal dendrites is promoted by Fyns open, primed conformation. Disrupting the auto-inhibitory, closed conformation of Fyn through phospho-inhibition, and perturbation of Fyns SH3 domain increases, Fyns nanoscale trapping. However, inhibition of Fyns catalytic domain has no impact on its mobility. Tau-P301L promotes Fyn lateral trapping via Fyn opening and ensuing increased catalytic activation. Pathogenic tau may therefore drive synaptotoxicity by locking Fyn in an open, catalytically active conformation, leading to postsynaptic entrapment and aberrant signalling cascades.

neuroscience↗