Biology subjects

Loh, C.

Publications and source records attributed to Loh, C..

3 recordsLinked to original sources

bioRxiv2023

Towards robust and generalizable representations of extracellular data using contrastive learning

Contrastive learning is quickly becoming an essential tool in neuroscience for extracting robust and meaningful representations of neural activity. Despite numerous applications to neuronal population data, there has been little exploration of how these methods can be adapted to key primary data analysis tasks such as spike sorting or cell-type classification. In this work, we propose a novel contrastive learning framework, CEED (Contrastive Embeddings for Extracellular Data), for high-density extracellular recordings. We demonstrate that through careful design of the network architecture and data augmentations, it is possible to generically extract representations that far outperform current specialized approaches. We validate our method across multiple high-density extracellular recordings. All code used to run CEED can be found at https://github.com/ankitvishnu23/CEED.

neuroscience↗

bioRxiv2023

Single-strand mismatch and damage patterns revealed by single-molecule DNA sequencing

Mutations accumulate in the genome of every cell of the body throughout life, causing cancer and other genetic diseases1-4. Almost all of these mosaic mutations begin as nucleotide mismatches or damage in only one of the two strands of the DNA prior to becoming double-strand mutations if unrepaired or misrepaired5. However, current DNA sequencing technologies cannot resolve these initial single-strand events. Here, we developed a single-molecule, long-read sequencing method that achieves single-molecule fidelity for single-base substitutions when present in either one or both strands of the DNA. It also detects single-strand cytosine deamination events, a common type of DNA damage. We profiled 110 samples from diverse tissues, including from individuals with cancer-predisposition syndromes, and define the first single-strand mismatch and damage signatures. We find correspondences between these single-strand signatures and known double-strand mutational signatures, which resolves the identity of the initiating lesions. Tumors deficient in both mismatch repair and replicative polymerase proofreading show distinct single-strand mismatch patterns compared to samples deficient in only polymerase proofreading. In the mitochondrial genome, our findings support a mutagenic mechanism occurring primarily during replication. Since the double-strand DNA mutations interrogated by prior studies are only the endpoint of the mutation process, our approach to detect the initiating single-strand events at single-molecule resolution will enable new studies of how mutations arise in a variety of contexts, especially in cancer and aging.

genomics↗

bioRxiv2022

Targeting Cblb-Notch1 axis as a novel immunotherapeutic strategy to boost CD8+ T-cells responses

A critical feature of cancer is the ability to induce immunosuppression and evade immune responses. Tumor-induced immunosuppression diminishes the efficacy of endogenous immune responses and decreases the efficacy of cancer immunotherapy. In this study, we describe a new immunosuppressive pathway in which adenosine promotes Cbl-b-mediated Notch1 degradation, causing suppression of CD8+ T-cells effector functions. Genetic KO and pharmacological inhibition of Cbl-b prevents Notch1 degradation in response to adenosine and reactivates its signaling. Reactivation of Notch1 results in enhanced CD8+ T-cell effector functions, anti-cancer response and resistance to immunosuppression. Our work demonstrates that targeting Cbl-b-Notch1 axis is a novel promising strategy for cancer immunotherapy.

cancer biology↗