Biology subjects

Chien, J.

Publications and source records attributed to Chien, J..

9 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

Interferon signaling underlies radiotherapy responses in malignant peripheral nerve sheath tumors (MPNSTs)

Malignant peripheral nerve sheath tumors (MPNSTs) have poor outcomes despite multimodal treatment with surgery, radiation, and systemic therapy. Here, we combine bulk and single cell transcriptomics, genome wide CRISPRi screens, and multiplatform molecular analysis across MPNST cells, mouse allograft models, and human patient samples to understand the mediators of radiation response. Our data reveal MPNSTs induce a type I interferon signature that functionally underlies radiation response. Moreover, irradiation of immunocompetent mouse MPNST allografts leads to interferon mediated T-cell recruitment and activation. Analysis of human MPNST resection specimens demonstrates increased microenvironmental and CD8+ T-cell infiltration are associated with improved local control following radiotherapy while chromosome 9p loss, which harbors an interferon gene cluster, is associated with poor radiotherapy response and decreased CD8+ T-cell infiltration. Taken together, these results provide preclinical rationale for combining immunomodulatory agents targeting interferon signaling to improve radiation responses in MPNSTs, which may be broadly applicable to other soft tissue sarcomas.

cancer biology↗

bioRxiv2025

Role of drug induced nuclear CTSL (nCTSL) in DNA damage response in cancer- therapeutic implications

ABSTRACT Background: Despite treatment advances, ovarian cancer (OC) remains the deadliest gynecological cancer, with a ~70% mortality rate. OCs initially respond to platinum chemotherapy but often develop resistance. While PARP inhibitors improve relapse-free survival in responsive cases, they do not extend overall survival. This underscores the need for effective combination therapies beyond BRCA status. The lysosomal protein cathepsin L (CTSL) can traffic to the nucleus, where it can regulate DNA repair and serve as a chromatin modifier. Here, we tested the hypothesis that nucleoside analog clofarabine (CLF) induced nuclear CTSL (nCTSL) serves as a biomarker of sensitivity to DNA-damaging agents in ovarian cancer. Methods: Role of nuclear CTSL in DNA damage, synergy with PARPis and CRM1 inhibitor, tumor regression was analyzed by 3D-spheroid culture, colony forming assay, subcellular fractions, comet assay, and IFC/ western-blotting using PARP inhibitor-sensitive and -resistant OC cell lines, ex vivo cultures of patient-derived OC ascites cells (OVA), primary OCs, and patient-derived xenografts (PDXs). Results: In OC cell lines, treatment with CLF induced nCTSL in a subset of models-designated CLF-responsive (CLF-r)-and sensitized them to the PARP inhibitors olaparib and rucaparib. In CLF-non-responsive (CLF-nr) models, nCTSL trafficking and drug synergy were achieved with the CLF+olaparib combination. Synergy was observed in 47% of CLF-r and 24% of CLF-nr OVA samples. Mechanistically, CLF monotherapy induced nuclear import of CTSL via KPNB1 in CLF-r cells, while combination treatment with CLF+olaparib was required in CLF-nr cells. CLF also downregulated the nuclear export protein CRM1 in both CLF-r and CLF-nr models. CTSL knockdown conferred resistance to CLF+olaparib in both cohorts, supporting a functional role for nCTSL in therapeutic response. Notably, in a subset of OVAs (29%) classified as CLF-resistant (CLF-Res), CLF failed to downregulate CRM1; however, pharmacological inhibition of CRM1 with KPT8602 restored sensitivity to CLF+PARP inhibitor treatment. In vivo, CLF+olaparib treatment in CLF-r and CLF-nr PDX models led to enhanced DNA damage, reduced tumor burden, and prolonged survival. Conclusion: Collectively, these findings identify nCTSL as a predictive marker of response to DNA-damaging therapies and support the CLF+olaparib combination as a promising strategy for overcoming drug resistance in OC via CTSL-mediated DNA damage.

cancer biology↗

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

Neural dynamics in the limbic system during male social behaviors

Sexual and aggressive behaviors are two evolutionarily conserved social behaviors vital for an animals survival and reproductive success. While an increasing number of brain regions in the limbic system have been identified as functionally relevant for these two types of behaviors, an understanding of how social cues are represented across brain regions and how social behaviors are generated via this network activity remains elusive. To gain a holistic view of the neural responses during social behaviors, we utilized multi-fiber photometry to simultaneously record Ca2+ signals of estrogen receptor alpha (Esr1)-expressing cells from 13 limbic brain regions in male mice during sexual and aggressive behaviors and compare the response magnitude and temporal patterns across regions. We find that conspecific sensory information, as well as social action initiation signals, are widely distributed in the limbic system and can be decoded from the network activity. Cross-region correlation analysis reveals striking increases in functional connectivity in the network during the action initiation phase of social behaviors whereas advanced copulation is accompanied by a "dissociated" network state. Based on the response patterns, we propose a mating-biased network (MBN) and an aggression-biased network (ABN) for mediating male sexual and aggressive behaviors, respectively.

neuroscience↗

bioRxiv2022

Abstraction of reward context facilitates relative reward coding in dorsal and ventral anterior cingulate cortex

The anterior cingulate cortex (ACC) is believed to be involved in many cognitive processes, including linking goals to actions and tracking decision-relevant contextual information. ACC neurons robustly encode expected outcomes, but how this relates to putative functions of ACC remains unknown. Here, we approach this question from the perspective of population codes by analyzing neural spiking data in the ventral and dorsal banks of the ACC in monkeys trained to perform a stimulus-motor mapping task. We found that neural populations favor a representational geometry that emphasizes contextual information, while facilitating the independent, abstract representation of multiple task-relevant variables. In addition, trial outcomes were primarily encoded relative to task context, suggesting that the population structures we observe could be a mechanism allowing feedback to be interpreted in a context-dependent manner. Together, our results point to a prominent role for ACC in context-setting and relative interpretation of outcomes, facilitated by abstract, or "untangled," representations of task variables. Author SummaryThe ability to interpret events in light of the current context is a critical facet of higher-order cognition. The anterior cingulate cortex is suggested to be important for tracking information about current contexts, while alternate views hold that its function is more related to the motor system and linking goals to appropriate motor responses. Here, we evaluated these two possibilities by recording anterior cingulate neurons from monkeys performing a stimulus-motor mapping task in which compound cues both defined the current reward context and instructed appropriate motor responses. By analyzing geometric properties of neural population activity, we found that the ACC prioritized context information, representing it as a dominant, abstract concept. Ensuing trial outcomes were then coded relative to these contexts, suggesting an important role for these representations in context-dependent evaluation. Such mechanisms may be critical for the abstract reasoning and generalization characteristic of biological intelligence.

neuroscience↗

bioRxiv2020

ConsHMM Atlas: conservation state annotations for major genomes and human genetic variation

ConsHMM is a method recently introduced to annotate genomes into conservation states, which are defined based on the combinatorial and spatial patterns of which species align to and match a reference genome in a multi-species DNA sequence alignment. Previously, ConsHMM was only applied to a single genome for one multi-species sequence alignment. Here we apply ConsHMM to produce 22 additional genome annotations covering human and seven other organisms for a variety of multi-species alignments. Additionally, we have extended ConsHMM to generate allele specific annotations, which we used to produce conservation state annotations for every possible single nucleotide mutation in the human genome. Finally, we provide a web interface to interactively visualize parameters and annotation enrichments for ConsHMM models. These annotations and visualizations comprise the ConsHMM Atlas, which we expect will be a valuable resource for analyzing a variety of major genomes and genetic variation.

bioinformatics↗

bioRxiv2019

A Canal-Associated Neuron cAMP signalling pathway that regulates C. elegans larval development

Caenorhabditis elegans larval development requires the function of the two Canal-Associated Neurons (CANs): killing the CANs by laser microsurgery or disrupting their development by mutating the gene ceh-10 results in early larval arrest. How these cells promote larval development, however, remains a mystery. In screens for mutations that bypass CAN function, we identified the gene kin-29, which encodes a member of the Salt-Inducible Kinase (SIK) family and a component of a conserved pathway that regulates various C. elegans phenotypes. Like kin-29 loss, gain-of-function mutations in genes that may act upstream of kin-29 or growth in cyclic-AMP analogs bypassed ceh-10 larval arrest, suggesting that a conserved adenylyl cyclase/PKA pathway inhibits KIN-29 to promote larval development and that loss of CAN function results in dysregulation of KIN-29 and larval arrest. The adenylyl cyclase ACY-2 mediates CAN-dependent larval development: acy-2 mutant larvae arrested development with a similar phenotype to ceh-10 mutants, and the arrest phenotype was suppressed by mutations in kin-29. ACY-2 is predominantly expressed in the CANs, and we provide evidence that the acy-2 functions in the CANs to promote larval development. By contrast, cell-specific expression experiments suggest that kin-29 acts in both the hypodermis and neurons, but not in the CANs. Based on our findings, we propose that cAMP produced by ACY-2 in the CANs acts in neighboring neurons and hypodermal cells where it activates PKA and inhibits KIN-29 to promote larval development. We discuss how this conserved pathway could be partitioned between two cells.

developmental biology↗

bioRxiv2018

Heterozygous mutations in p97 and resistance to p97 inhibitors

In recent years, multiple studies including ours have reported on the mechanism of resistance towards p97 inhibitors. While all these studies outline target alteration via mutations in p97 as the primary mechanism of resistance, discrepancies persist in the current literature due to the occurrence of both heterozygous and homozygous mutations when using HCT116 cells. Here, we report a pre-existing heterozygous frameshift mutation at codon 616 (N616fs*) in one of the p97 alleles in HCT116 cells and show that this mutant allele is subjected to nonsense-mediated decay. Furthermore, we independently generated p97 inhibitor (CB-5083) resistant HCT116 cells, and we observed a single heterozygous mutation at codon 526 (L526S) in genomic DNA sequencing but a homozygous L526S mutation in complementary DNA sequencing, indicating that the missense mutation (L526S) occurs in the allele that does not harbor the frameshift N616fs* mutation. Our results underscore the importance of performing simultaneous genomic and complementary DNA sequencing when confirming mutations in p97.

cancer biology↗