Biology subjects

Lim, S.

Publications and source records attributed to Lim, S..

8 recordsLinked to original sources

bioRxiv2026

AnnFlux: object-conditioned neural stochastic differential equations for single-cell perturbation dynamics

Single-cell perturbation profiling measures responses to genetic and chemical interventions, yet most models learn a static map, ignoring how populations move over time and how perturbations combine. AnnFlux, an object-conditioned stochastic differential equation, learns a drift field in latent cell-state space. Conditioning on the perturbing object makes the field queryable one object at a time, yielding per-object drifts comparable across genes and drugs. By learning a drift field tailored to each perturbation context, it interpolates a held-out timepoint in an epithelial-mesenchymal transition time course and predicts unseen perturbations. Beyond point estimates, AnnFlux improves distributional fidelity and predicts responses to held-out perturbation combinations. An IFN-response signature predicted by AnnFlux was associated with TLS proximity in an independent pan-cancer spatial atlas. This framework maps perturbation-driven cell-state evolution as continuous trajectories and represents unseen perturbations using prior-knowledge embeddings.

bioinformatics↗

bioRxiv2018

Meteorin-like (Metrnl) adipomyokine improves glucose tolerance in type 2 diabetes via AMPK pathway

Meteorin-like (metrnl) is a recently identified adipomyokine that has beneficial effects on glucose metabolism. However, its underlying mechanism of action is not completely understood. In this study, we have shown that a level of metrnl increase in vitro under electrical-pulse-stimulation (EPS) and in vivo in exercise mice, suggesting that metrnl is an exercise-induced myokine. In addition, metrnl increases glucose uptake through the calcium-dependent AMPK pathway. Metrnl also increases the phosphorylation of HDAC5, a transcriptional repressor of GLUT4, in an AMPK-dependent manner. Phosphorylated HDAC5 interacts with 14-3-3 proteins and sequesters them in the cytoplasm, resulting in the activation of GLUT4 transcription. The intraperitoneal injection of recombinant metrnl improves glucose tolerance in mice with high fat-induced obesity or type 2 diabetes (db/db), but this is not seen in AMPK {beta}1{beta}2 muscle-specific null mice (AMPK {beta}1{beta}2 MKO). In conclusion, we have demonstrated that metrnl induces beneficial effects on glucose metabolism via AMPK and is a promising therapeutic candidate for glucose-related diseases such as type 2 diabetes.

biochemistry↗

bioRxiv2018

Identification of STK25 as a direct activator of LATS signaling

The Hippo pathway maintains tissue homeostasis by negatively regulating the oncogenic transcriptional co-activators YAP and TAZ. Though functional inactivation of the Hippo pathway is common in tumors, mutations in core pathway components are rare. Thus, understanding how tumor cells inactivate Hippo signaling remains a key unresolved question. Here, we identify the kinase STK25 as a novel activator of Hippo signaling. We demonstrate that loss of STK25 promotes YAP/TAZ activation and enhanced cellular proliferation, even under normally growth-suppressive conditions. We reveal that STK25 activates LATS via a previously unobserved mechanism, in which STK25 directly phosphorylates the LATS activation loop. This represents a new paradigm in Hippo activation and distinguishes STK25 from all other identified kinase activators of LATS. STK25 is significantly focally deleted across a wide spectrum of human cancers, suggesting STK25 loss may represent a common mechanism by which tumor cells functionally impair the Hippo tumor suppressor pathway.

cell biology↗

bioRxiv2018

Chemotaxis model for human breast cancer cells based on signal-to-noise ratio

Chemotaxis, a biased migration of cells under a chemical gradient, plays a significant role in diverse biological phenomena including cancer metastasis. Stromal cells release signaling proteins to induce chemotaxis, which further causes organ-specific metastasis. Epidermal growth factor (EGF) is an example of the chemical attractants, and its gradient stimulates metastasis of breast cancer cells. Hence, the interactions between EGF and breast cancer cells have long been a subject of interest for oncologists and clinicians. However, most current approaches do not systematically separate the effects of gradient and absolute concentration of EGF on chemotaxis of breast cancer cells. In this work, we develop a theoretical model based on signal-to-noise ratio to represent stochastic properties and report our microfluidic experiments to verify the analytical predictions from the model. The results demonstrate that even under the same EGF concentration gradients, breast cancer cells can reveal distinct chemotaxis patterns at different absolute concentrations. Moreover, we found that addition of EGF receptor antibody can promote chemotaxis at a low EGF level. This apparently counterintuitive finding suggests that EGF receptor-targeted therapy may stimulate metastasis of breast cancer at a particular condition, which should be considered in anticancer drug design.

biophysics↗

bioRxiv2018

Discordant attributes of structural and functional connectivity in a two-layer multiplex network

Several studies have suggested that functional connectivity (FC) is constrained by the underlying structural connectivity (SC) and mutually correlated. However, not many studies have focused on differences in the network organization of SC and FC, and on how these differences may inform us about their mutual interaction. To explore this issue, we adopt a multi-layer framework, with SC and FC, constructed using Magnetic Resonance Imaging (MRI) data from the Human Connectome Project, forming a two-layer multiplex network. In particular, we examine whether node strength assortativity within and between the SC and FC layer may confer increased robustness against structural failure. We find that, in general, SC is organized assortatively, indicating brain regions are on average connected to other brain regions with similar node strengths. On the other hand, FC shows disassortative mixing. This discrepancy is apparent also among individual resting-state networks within SC and FC. In addition, these patterns show lateralization, with disassortative mixing within FC subnetworks mainly driven from the left hemisphere. We discuss our findings in the context of robustness to structural failure, and we suggest that discordant and lateralized patterns of associativity in SC and FC may explain laterality of some neurological dysfunctions and recovery.

neuroscience↗

bioRxiv2018

A genome-wide miRNA screen identifies regulators of tetraploid cell proliferation

Tetraploid cells, which are most commonly generated by errors in cell division, are genomically unstable and have been shown to promote tumorigenesis. Recent genomic studies have estimated that [~]40% of all solid tumors have undergone a genome-doubling event during their evolution, suggesting a significant role for tetraploidy in driving the development of human cancers. To safeguard against the deleterious effects of tetraploidy, non-transformed cells that fail mitosis and become tetraploid activate both the Hippo and p53 tumor suppressor pathways to restrain further proliferation. Tetraploid cells must therefore overcome these anti-proliferative barriers to ultimately drive tumor development. However, the genetic routes through which spontaneously arising tetraploid cells adapt to regain proliferative capacity remain poorly characterized. Here, we conducted a comprehensive, gain-of-function genome-wide screen to identify miRNAs that are sufficient to promote the proliferation of tetraploid cells. Our screen identified 23 miRNAs whose overexpression significantly promotes tetraploid proliferation. The vast majority of these miRNAs facilitate tetraploid growth by enhancing mitogenic signaling pathways (e.g. miR-191-3p); however, we also identified several miRNAs that impair the p53/p21 pathway (e.g. miR-523-3p), and a single miRNA (miR-24-3p) that potently inactivates the Hippo pathway via downregulation of the tumor suppressor gene NF2. Collectively, our data reveal several avenues through which tetraploid cells may regain the proliferative capacity necessary to drive tumorigenesis.

cancer biology↗

bioRxiv2017

Population-scale organization of cerebellar granule neuron signaling during a visuomotor behavior

Granule cells at the input layer of the cerebellum comprise over half the neurons in the human brain and are thought to be critical for learning. However, little is known about granule neuron signaling at the population scale during behavior. We used calcium imaging in awake zebrafish during optokinetic behavior to record transgenically identified granule neurons throughout a cerebellar population. A significant fraction of the population was responsive at any given time. In contrast to core precerebellar populations, granule neuron responses were relatively heterogeneous, with variation in the degree of rectification and the balance of excitation versus inhibition. Functional correlations were strongest for nearby cells, with weak spatial gradients in the degree of rectification and excitation. These data open a new window upon cerebellar function and suggest granule layer signals represent elementary building blocks underrepresented in core sensorimotor pathways, thereby enabling the construction of novel patterns of activity for learning.\n\nSIGNIFICANCE STATEMENTCerebellar processing is important for a variety of fine motor tasks and sensorimotor adaptations, and a growing body of evidence indicates a prominent role in cognitive control. However, it has been challenging to understand cerebellar function during behavior because of difficulties in recording from cerebellar granule neurons, the most populous neuron type in the brain. We use population-scale optical imaging in the larval zebrafish to compare precerebellar activity to granule cell signaling. Our results suggest a behaviorally relevant expansion of precerebellar signaling representations at the granule layer of the cerebellum.

neuroscience↗

bioRxiv2017

Heartfelt Face Perception via the Interoceptive Pathway - a MEG study

The somatic marker hypothesis proposes that the cortical representation of visceral signals is a crucial component of emotion processing. No previous study has investigated the causal relationships among brain regions that process visceral information during emotional perception. In this magnetoencephalography study of 32 healthy subjects, heartbeat-evoked potentials (HEPs), which reflect the cortical processing of heartbeats, were modulated by the perception of a sad face. The modulation effect was localized to the prefrontal cortices, the globus pallidus, and an interoceptive network including the right anterior insula (RAI) and anterior cingulate cortex (RACC). Importantly, our Granger causality analysis provides the first evidence for increased causal flow of heartbeat information from the RAI to the RACC during sad face perception. Moreover, this HEP modulation effect was neither an artefact nor an effect of visual-evoked potentials. These findings provide important progress in the understanding of brain-body interactions during emotion processing.

neuroscience↗