Biology subjects

Wang, W.-C.

Publications and source records attributed to Wang, W.-C..

7 recordsLinked to original sources

bioRxiv2024

Stabilization of AMPK/PFKL/RPIA in the Glycolytic Bodies Transduces IL6/STAT3 Signal in Hepatocarcinogenesis

Metabolic reprogramming is a pivotal characteristic of cancer, yet the intricate interplay between glycolysis and the pentose phosphate pathway (PPP) remains elusive. This study unveils the pivotal role of 6-phosphofructokinase liver type (PFKL) in glycolysis and ribose 5-phosphate isomerase A (RPIA) in PPP, orchestrating liver tumorigenesis. PFKL, the rate-limiting enzyme in glycolysis, stabilizes RPIA by impeding ubiquitination/proteasome activity. The pro-inflammatory and tumor cytokine interleukin 6 activates pSTAT3 which binds to the promoter region and activates AMPK and PFKL transcription. Furthermore, pAMPK stabilizes PFKL protein by preventing proteasome degradation in hepatoma cells. Inhibiting PFKL, AMPK, and STAT3 genetically or pharmacologically can reduce glycolysis, ATP production, resulting in reduction of hepatoma cell proliferation and migration. Intriguingly, the PFKL, AMPK, RPIA, and PKM2 are co-localized in the Glycolytic body (G-body) which starts forming at chronic hepatitis, dramatically increases during active hepatitis, and the size of G-bodies becomes bigger from cirrhosis to hepatocellular carcinoma. Furthermore, using Bimolecular fluorescence complementation (BiFC) assay, we demonstrated that PFKL and RPIA direct interacts. Targeting AMPK or STAT3 significantly reduced tumor formation and lipid accumulation in zebrafish models, suggesting the STAT3/AMPK/PFKL axis as a potential therapeutic avenue for liver cancer treatment.

cancer biology↗

bioRxiv2023

Hydrogen Sulfide Coordinates Glucose Metabolism Switch through Destabilizing Tetrameric Pyruvate Kinase M2

Cancer cells reprogram their glucose metabolic pathway from oxidative phosphorylation toward aerobic glycolysis. Pyruvate kinase M2 (PKM2), which converts phosphoenolpyruvate (PEP) to pyruvate, is considered the rate-limiting enzyme involved in cancer glucose metabolism. By reducing PKM2 enzyme activity, cancer cells attain a greater fraction of glycolytic metabolites for macromolecule synthesis needed for rapid proliferation. Here we demonstrate that hydrogen sulfide (H2S) destabilizes PKM2 tetramer into dimer/monomer, leading to reduced PKM2 enzyme activity and an increase in the activation of nuclear transcriptional genes mediated by dimeric PKM2. Proteomic profiling of endogenous PKM2 reveals the occurrence of sulfhydration at cysteines, notably at cysteine 326. Blocking PKM2 sulfhydration at cysteine 326 through amino acid mutation stabilizes PKM2 tetramer and crystal structure further indicating that the tetramer organization of PKM2C326S is different from the currently known T or R states, revealing PKM2C326S as a newly identified form. The presence of a PKM2C326S mutant in cancer cells effectively rewires glucose metabolism to mitochondrial respiration, resulting in the significant inhibition of tumor growth. Collectively, PKM2 sulfhydration by H2S serves as a glucose metabolic rewiring mechanism in promoting tumorigenesis, and inhibition of PKM2 sulfhydration may be applied as a new therapeutic approach targeting cancer metabolism. One-Sentence SummaryH2S rewires glucose metabolism by destabilizing PKM2 tetramerization majorly through sulfhydration at cysteine 326 HighlightsO_LIH2S enhances PKM2 dissociation from tetramer to dimer to facilitate dimeric PKM2 nuclear translocation. C_LIO_LIH2S modifies PKM2 sulfhydration, notably at cysteine 326. C_LIO_LIThe crystal structure reveals PKM2C326S as a unique tetramer conformation. C_LIO_LIBlockage of PKM2 sulfhydration at C326 rewires cancer glucose metabolism and significantly inhibits tumor growth. C_LI

cancer biology↗

bioRxiv2020

Hypothalamic dopamine neurons control sensorimotor behavior by modulating brainstem premotor nuclei

Dopamine (DA)-producing neurons are critically involved in the production of motor behaviors in multiple circuits that are conserved from basal vertebrates to mammals. While there is increasing evidence that DA neurons in the hypothalamus play a locomotor role, their precise contributions to behavior and the circuit mechanisms by which they are achieved remain unclear. Here we demonstrate that tyrosine hydroxylase 2-expressing (th2+) DA neurons in the zebrafish hypothalamus fire phasic bursts of activity to acutely promote swimming and modulate audiomotor behaviors on fast timescales. Their anatomy and physiology reveal two distinct functional DA modules within the hypothalamus. The first comprises an interconnected set of cerebrospinal fluid-contacting DA nuclei surrounding the third ventricle, which lack distal projections outside of the hypothalamus and influence locomotion through unknown means. The second includes neurons in the preoptic nucleus, which send long-range projections to targets throughout the brain, including the mid- and hindbrain, where they activate premotor circuits involved in swimming and sensorimotor integration. These data suggest a broad regulation of motor behavior by DA neurons within multiple hypothalamic nuclei and elucidate a novel functional mechanism for the preoptic DA neurons in the initiation of movement.

neuroscience↗

bioRxiv2020

Electrical coupling between chromatophore muscle fibers allows for versatile control of chromatophore expansion in squid.

Camouflage color change in cephalopods is generated by the expansion and relaxation of hundreds to thousands of chromatophore pigment organs in the skin. Individual chromatophores display color when the central pigment sac is expanded to several times its original size by a ring of 20-30 radial muscles, which are electrically coupled and are innervated by multiple motoneurons. However, mechanisms for their neuromuscular control are unclear. Here we characterize chromatophore expansion kinematics and perform simultaneous whole-cell recordings on pairs of muscle fibers of a chromatophore in squid hatchlings. We show that activity is highly correlated between muscle fibers of a chromatophore due to a high ratio of electrical coupling between all muscles for slow currents. However, fast currents are filtered and decrease rapidly further away from the muscle receiving the inputs. This low-pass filtering property of electrical coupling allows fast inputs to activate one muscle while persistent inputs spread throughout the chromatophore to synchronously activate all muscles, providing a versatile mode of control for chromatophore expansion.

systems biology↗

bioRxiv2020

Visual and semantic representations predict subsequent memory in perceptual and conceptual memory tests

It is generally assumed that the encoding of a single event generates multiple memory representations, which contribute differently to subsequent episodic memory. We used fMRI and representational similarity analysis (RSA) to examine how visual and semantic representations predicted subsequent memory for single item encoding (e.g., seeing an orange). Three levels of visual representations corresponding to early, middle, and late visual processing stages were based on a deep neural network. Three levels of semantic representations were based on normative Observed ("is round"), Taxonomic ("is a fruit"), and Encyclopedic features ("is sweet"). We identified brain regions where each representation type predicted later Perceptual Memory, Conceptual Memory, or both (General Memory). Participants encoded objects during fMRI, and then completed both a word-based conceptual and picture-based perceptual memory test. Visual representations predicted subsequent Perceptual Memory in visual cortices, but also facilitated Conceptual and General Memory in more anterior regions. Semantic representations, in turn, predicted Perceptual Memory in visual cortex, Conceptual Memory in the perirhinal and inferior prefrontal cortex, and General Memory in the angular gyrus. These results suggest that the contribution of visual and semantic representations to subsequent memory effects depends on a complex interaction between representation, test type, and storage location.

neuroscience↗

bioRxiv2018

The more you know: Investigating why adults get a bigger memory boost from semantic congruency than children

Humans possess the capacity to employ prior knowledge in the service of our ability to remember; thus, memory is oftentimes superior for information that is semantically congruent with our prior knowledge. This congruency benefit grows during development, but little is understood about neurodevelopmental differences that underlie this growth. Here, we sought to explore the brain mechanisms underlying these phenomena. To this end, we examined the neural substrates of semantically congruent vs. incongruent item-context associations in 116 children and 25 young adults who performed encoding and retrieval tasks during functional MRI data collection. Participants encoded item-context pairs by judging whether an item belonged in a scene. Episodic memory was then tested with a source memory task. Consistent with prior work, source memory accuracy improved with age, and was greater for congruent than incongruent pairs; further, this congruency benefit was greater in adults than children. Age-related differences were observed across univariate, functional connectivity, and multivariate analyses, particularly in lateral prefrontal cortex (PFC). In sum, our results revealed two general age differences. First, left ventrolateral/rostrolateral PFC exhibited age-related increases in univariate activity, as well as greater functional connectivity with temporal regions during the processing of congruency. Second, right rostrolateral PFC activation was associated with successfully encoded congruent associations in adults, but not children. Finally, multivariate analyses provided evidence for stronger veridical memory in adults than children in right ventrolateral PFC. These effects in right lateral PFC were significantly correlated with memory performance, implicating them in the process of remembering congruent associations. These results connect brain regions associated with top-down control in the congruency benefit and age-related improvements therein.

neuroscience↗

bioRxiv2018

Excitatory TMS Boosts Memory Representations

Brain stimulation technologies have seen increasing application in basic science investigations, specifically towards the goal of improving memory functioning. However, proposals concerning the neural mechanisms underlying cognitive enhancement often rely on simplified notions of excitation and, most applications examining the effects of transcranial magnetic stimulation (TMS) on functional neuroimaging measures have been limited to univariate analyses of brain activity. We present here analyses using representational similarity analysis (RSA) and encoding-retrieval similarity (ERS) analysis in order to quantify the effect of TMS on memory representations. To test whether an increase in local excitability in PFC can have measurable influences on upstream representations in earlier temporal memory regions, we compared 1Hz and 5Hz stimulation to the left dorsolateral PFC. We found that 10 minutes of 5Hz rTMS, relative to 1Hz, had multiple effects on neural representations: 1) greater RSA during both encoding and retrieval, 2) greater ERS across all items, and, critically, 3) increasing ERS in MTL with increasing univariate activity in DLPFC, and greater functional connectivity for hits than misses between these regions. These results provide the first evidence of rTMS enhancing semantic representations and strengthen the idea that rTMS may affect the reinstatement of previously experienced events in upstream regions.

neuroscience↗