Biology subjects

Wang, C.-H.

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

18 recordsLinked to original sources

bioRxiv2026

Specimen-Dependent Sampling and Signal Limitations Govern the Effectiveness of Low-Magnification Super-Resolution in Cryo-EM

Single-particle cryo-EM routinely delivers near-atomic structures; however, optimizing data collection requires a delicate balance among magnification, sampling bandwidth, and particle throughput. Although low-magnification super-resolution imaging can recover information beyond the physical Nyquist limit, its benefit varies substantially among specimens. This variability suggests that the effectiveness of super-resolution may depend on whether reconstruction is limited by detector sampling bandwidth or by the recoverable particle signal. However, the conditions that distinguish these two regimes remain poorly defined. Here, we systematically compared super-resolution and physical-pixel workflows at two magnifications using apoferritin (APO) and malate synthase G (MSG) as representative specimens with contrasting molecular size, symmetry, and image contrast. At low magnification, APO exhibited sampling-limited behavior, with super-resolution processing achieving 1.72 Angstrom compared with 2.74 Angstrom for physical-pixel processing. In contrast, MSG exhibited predominantly signal-limited behavior under the same conditions, yielding comparable resolutions of 3.05 Angstrom and 2.98 Angstrom for super-resolution and physical-pixel processing, respectively, despite the increased sampling bandwidth. These contrasting responses were further supported by particle-number saturation, per-particle motion correction, and Q-score analyses, which provided complementary evidence for the underlying sampling-limited and signal-limited regimes. Together, these results provide a practical framework for assessing whether reconstruction quality is predominantly constrained by sampling bandwidth or recoverable particle signal and offer a rational basis for balancing achievable resolution and particle throughput when selecting acquisition strategies.

biophysics↗

bioRxiv2026

Structural and Functional Principles of Hcp-Mediated Antibacterial Toxin Delivery by the Type VI Secretion System

The type VI secretion system (T6SS) is a bacterial contractile nanomachine that translocates toxic effectors into neighboring cells, helping bacteria to survive and compete in polymicrobial environments. The core T6SS structural protein Hcp forms the inner tube and mediates the loading and delivery of diverse effectors. Yet, how Hcp selectively recruits structurally and functionally distinct effectors in the absence of recognizable secretion signals remains poorly understood. Here, using Pseudomonas aeruginosa H1-T6SS as a model, we combined competition-coupled deep mutational scanning with cryo-EM based structural analysis to determine how Hcp accommodates distinct effectors. The resulting mutational landscape distinguishes structurally constrained residues required for Hcp tube assembly from lumen-facing residues specialized for cargo engagement. Near-atomic-resolution structures of Hcp bound to Tse2 and Tse4, together with a high-confidence Hcp-Tse1 model, revealed that while effector-specific contacts exist, Hcp engages different cargos through largely shared, dispersed interfaces characterized by polar-biased and variation-tolerant interactions. Comparative structural analyses further showed that effector-interacting residues are not governed by conserved primary-sequence motifs, but by conserved lumen-facing geometry and permissive physicochemical properties across distantly related bacteria. Together, our findings support a model in which Hcp acts as a selective yet adaptable scaffold that accommodates diverse antibacterial effectors through conserved structural features and flexible interaction surfaces, providing a mechanistic framework for understanding cargo selection by the T6SS and explaining how a conserved secretion nanomachine can evolve to deliver diverse toxic payloads.

microbiology↗

bioRxiv2025

Peptide-Specific CAR T cells Recognize WT1 Promiscuously Presented by Diverse HLA Class II Alleles

Chimeric antigen receptor (CAR) technology has revolutionized B-cell malignancy treatment by enabling T cells to effectively recognize and target cancer-specific surface antigens. However, CAR T cells show limited efficacy against other blood cancers and solid tumors due to challenges in identifying suitable surface targets. Here, we present a novel approach to CAR development, targeting the intracellular Wilms tumor 1 (WT1) oncoprotein, cross-presented by surface HLA-class II (HLA-II) alleles. WT1-CAR T cells, derived from an antibody raised solely against a WT1 peptide, recognized the WT1330-348 peptide promiscuously presented by 18 out of 20 tested HLA-II alleles, overcoming traditional HLA restrictions. WT1-CAR T cells specifically recognized leukemic cells in a WT1 and HLA-II-dependent manner and mediated an antitumor response in vitro and in vivo. This innovative approach to CAR T cell development transcends traditional HLA restrictions and offers a promising therapeutic option to a wide and genetically diverse patient population. Statement of significanceThis study describes a novel CAR T therapy approach leveraging the distinctive and shared characteristic of HLA-II-peptide binding promiscuity, enabling targeting of the intracellular oncoprotein WT1 presented across diverse HLA-II families. Our study demonstrates a viable framework for designing CAR T therapies that benefit genetically diverse patient populations.

immunology↗

bioRxiv2025

Molecular and functional dissection using CaMPARI-seq reveals the neuronal organization for dissociating optic flow-dependent behaviors

Optic flow processing is critical for the visual control of body and eye movements in many animals. Rotational and translational binocular optic flow patterns need to be clearly distinguished to induce different behavior outputs. However, the specific neuron types and their connectivity involved in this computation remain unclear. Here, we developed a method to link the functional labeling using a photoconvertible calcium indicator called CaMPARI2 and single-cell RNA-sequencing (CaMPARI-seq) to investigate the transcriptional profile of the pretectum, a center for processing optic flow in larval zebrafish. Using this technique, we identified a pretectal cluster expressing tcf7l2, which can be further classified into molecularly distinct subclusters. In vivo calcium imaging and cell ablation revealed that nkx1.2lb-positive pretectal neurons are commissural inhibitory neurons required for the optomotor response but not for the optokinetic response. Our genetic and functional dissection using CaMPARI-seq uncovered the neuronal organization essential for dissociating different optic flow-dependent behaviors.

neuroscience↗

bioRxiv2025

Structural Insights into Immature Dengue Virus-Like Particles Revealed by Cryo-EM and Molecular Dynamics Simulations

The lack of efficacious vaccines against dengue (DENV) infections imposes an enormous burden on global health and the economy. Virus-like particles (VLPs), such as mature DENV VLPs (mDVLPs), have been shown to induce broadly neutralizing antibodies, making them promising next-generation vaccine candidates. However, the limited structural details have restricted efforts to engineer VLPs to attain the desired biophysical and immunological properties. In the current work, we present the cryo-electron microscopy (cryo-EM) structure of immature dengue serotype 2 VLP (imD2VLPs), revealing an architecture composed of a glycoprotein layer with prominent spikes in a T=1 arrangement. These spikes, composed of envelope (E) and precursor membrane (prM) protein heterodimers capped by pr domains, closely resemble immature flavivirus particles. Complementing the static structural details, we performed multiscale molecular dynamics (MD) simulations to elucidate the functional dynamics of imD2VLPs in the context of different lipid envelope compositions. Additionally, MD simulations uncovered the transition pathway between our previously solved mature VLP structure and immature VLP from this work. Here we show that VLP maturation involves a simple sliding-rotating motion without any clashes between E proteins. Our results also indicated that lipid composition plays a critical role in VLP stability, with phospholipid-dominant environments providing greater stability than diacylglycerol-rich vesicles. In addition, we demonstrated enhanced production efficiency of VLPs by generating a stable mammalian cell line using CHO-K1 cells. These findings enabled us not only to predict and manipulate the immunogenic properties of dengue VLPs but also underscored the potential of VLPs as a simplified and manageable model for investigating the structural basis of the dengue virus more effectively.

bioinformatics↗

bioRxiv2024

The Taiwan Precision Medicine Initiative: A Cohort for Large-Scale Studies

The Taiwan Precision Medicine Initiative (TPMI), a project initiated by the Academia Sinica in collaboration with 16 major medical centers around Taiwan, has recruited 565,390 participants who consented to provide DNA samples for genetic profiling and grant access to their electronic medical records (EMR) for studies to develop precision medicine. Access to the EMR is both retrospective and prospective, allowing researchers to conduct prospective studies over time. Genetic profiling is done with population-optimized SNP arrays for the Han Chinese populations that enable genetic analyses such as genome-wide association, phenome-wide association, and polygenic risk score studies to evaluate common disease risk and pharmacogenetic response. Furthermore, the TPMI participants agree to be contacted for future research opportunities related to their genetic risks and receive personalized genetic risk profiles with health management recommendations. TPMI has established the TPMI Data Access Platform (TDAP), a central database and analysis platform that both safeguards the security of the data and facilitates academic research. The TPMI is the largest non-European cohort that merges genetic profiles with EMR in the world. With a cohort that can be followed over time, it can be utilized to validate genetic risk prediction models, conduct clinical trials to show the efficacy of risk-based health management, and optimize health policies based on genetic risks. In this report, we describe the TPMI study design, the population and genetic characteristics of the TPMI cohort, and the power it provides to conduct crucial studies in developing precision medicine on a population and personal level. As Han Chinese represent almost 20% of the worlds population, the results of TPMI studies will benefit >1.4 billion people around the world and serve as a model for developing population-based precision medicine.

genetics↗

bioRxiv2024

In vitro and in vivo evaluation of Ulva lactuca for wound healing

Ulva lactuca (U. lactuca) is an important seaweed species. Some ingredients in these seaweeds are thought to accelerate wound healing. However, limited data on the use of seaweed for wound healing exists. This study examined whether ethanol or aqueous extracts of U. lactuca promote antioxidant and anti-inflammatory properties in vitro and wound healing in vitro and in vivo. Cell proliferation, antioxidation, and migration were observed in NIH3T3 cells treated with U. lactuca extract in vitro. Both U. lactuca extracts were examined for their ability to inhibit inflammatory cytokine synthesis in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. In vivo experiments involved four groups of albino mice (BALB/c; 10 mice per group). One 1.0 cm2 wound was created via excision of full-thickness skin on the back of all mice. Mice in Group I mice were treated topically with the ethanol extract of U. lactuca (25 mg/mL) for 10 d. group II mice were treated topically with an aqueous extract of U. lactuca (12.5 mg/mL) for 10 d. Group III received topical application of phosphate-buffered saline solution. Group IV wounds were maintained without treatment. Both extracts significantly increased fibroblast proliferation. The antioxidant activity of the U. lactuca extract was determined using a total antioxidant capacity assay. Both extracts inhibited the release of tumor necrosis factor- (TNF-) and interferon-{gamma} (IFN-{gamma}) from LPS-mediated inflammation in RAW 264.7 cells. These extracts also upregulated the expression of Th2 cytokines such as transforming growth factor beta 1 (TGF-{beta}1) and interleukin 10 (IL-10) in RAW 264.7 cells under pro-inflammatory conditions. Both extracts enhanced the migratory ability of NIH3T3 cells. U. lactuca ethanol extract enhances wound healing properties in vivo. These results suggest that bioactive compounds derived from U. lactuca extract are beneficial for wound healing and anti-inflammatory therapies.

pharmacology and toxicology↗

bioRxiv2024

Cryo-EM inspired NMR analysis reveals a pH-induced conformational switching mechanism for imparting dynamics to Betanodavirus protrusions

Nervous necrosis virus (NNV), a non-enveloped betanodavirus, causes neuropathies and retinopathies in farmed fish, damaging aquaculture worldwide. NNV has 60 conspicuous surface protrusions comprising the protrusion domain (P-domain) of its capsid protein. Although NNV protrusions play critical roles in infectivity, the underlying dynamics remain unclear. Our cryogenic electron microscopy (cryo-EM)-derived structures of Dragon grouper (Epinephelus lanceolatus) NNV reveal that the protrusions undergo low-pH-induced compaction and movement. We show that the P-domain is monomeric in solution at a pH germane to infection (7.0). Moreover, nuclear magnetic resonance (NMR) structures reveal a peptide (amino acids 311-330) that adopts a flexible loop to form an open pocket. NMR spectral analysis at pH 5.0 aided by molecular dynamics (MD) simulations show that this loop switches to a {beta}-strand under acidic conditions, eliciting pocket closure and P-domain trimerization, highlighting a unique pH-sensing feature. Our docking analysis revealed the N-terminal moiety of sialic acid inserted into and interacting with conserved residues in the pocket. Additionally, a low-pH-induced conformational change in the linker region via peptide bond isomerization conferred malleability on the protrusions. Our work uncovers the protrusion dynamics of a betanodavirus governing its infectivity through a pH-dependent conformational switching mechanism, providing insights into complex virus-host interactions.

biochemistry↗

bioRxiv2023

Use of phase plate cryo-EM reveals conformation diversity of therapeutic IgG with 50 kDa Fab fragment resolved below 6 angstrom

While cryogenic electron microscopy (cryo-EM) is fruitfully used for harvesting high-resolution structures of sizable macromolecules, its application to small or flexible proteins composed of domains like immunoglobulin (IgG) remain challenging. Here, we applied single particle cryo-EM to Rituximab, a therapeutic IgG mediating cancer cell toxicity, to explore its solution conformations. We found Rituximab molecules exhibited aggregates in cryo-EM specimens contrary to its solution behavior, and utilized a non-ionic detergent to successfully disperse them as isolated particles amenable to single particle analysis. As the detergent adversely reduced the protein-to-solvent contrast, we employed phase plate contrast to mitigate the impaired protein visibility. Assisted by phase plate imaging, we obtained a canonical three-arm IgG structure with other structures displaying variable arm densities co-existing in solution, affirming high flexibility of arm-connecting linkers. Furthermore, we showed phase plate imaging enables reliable structure determination of Fab to sub-nanometer resolution from ab initio, yielding a characteristic two-lobe structure that could be unambiguously docked with crystal structure. Our findings revealed conformation diversity of IgG and demonstrated phase plate was viable for cryo-EM analysis of small proteins without symmetry. This work helps extend cryo-EM boundaries, providing a valuable imaging and structural analysis framework for macromolecules with similar challenging features.

biochemistry↗

bioRxiv2023

Tight junctions regulate lumen morphology via hydrostatic pressure and junctional tension

Formation of fluid filled lumen by epithelial tissues is a fundamental process for organ development. How epithelial cells regulate the hydraulic and cortical forces to control lumen morphology is not completely understood. Here, we quantified the mechanical role of tight junctions in lumen formation using genetically modified MDCKII cysts. We found that the paracellular ion barrier formed by claudin receptors is not required for hydraulic inflation of lumen. However, depletion of the zonula occludens scaffold resulted in lumen collapse and folding of apical membranes. Combining quantitative measurements and perturbations of hydrostatic lumen pressure and junctional tension with modelling, we were able to predict lumen morphologies from the pressure-tension force balance. We found that in MDCK tissue the tight junction promotes formation of spherical lumen by decreasing cortical tension via inhibition of myosin. In addition, we found that the apical surface area of cells is largely uncoupled from lumen volume changes, suggesting that excess apical area contributes to lumen opening in the low-pressure regime. Overall, our findings provide a mechanical understanding of how epithelial cells use tight junctions to modulate tissue and lumen shape.

cell biology↗

bioRxiv2023

Simple Causal Relationships in Gene Expression Discovered through Deep Learned Collective Variables

Developments in high-content phenotypic screening with single-cell read-out hold the promise of revealing interactions and functional relationships between genes at the genomic scale scale. However, the high-dimensionality and noisiness of gene expression makes this endeavor highly challenging when treated as a conventional problem in causal machine learning, both because of the statistical power required and because of the limits on computational tractability. Here we take different tack, and propose a deep-learning approach that finds low-dimensional representations of gene expression in which the response to genetic perturbation is highly predictable. We demonstrate that the interactions between genes that are cooperative in these representations are highly consistent with known ground-truth in terms of causal ordering, functional relatedness, and synergistic impact on cell growth and death. Our novel, statistical physics-inspired approach provides a tractable means through which to examine the response the living cell to perturbation, employing coarse graining that reduces data requirements and focuses on identifying simple relationships between groups of genes. Author summaryUnderstanding the causal relationships between genes and the functions of a cells molecular components has long been a challenge in biology and biomedicine. With recent advancements in technologies that manipulate and measure the activity of thousands of genes at once at the single-cell level, scientists are now afforded with the opportunity to interrogate such relationships at scale. However, extracting useful information from the vast readouts of these technologies is non-trivial, in part due to their many-dimensional and noisy nature. Here we develop a machine learning model that allows for the interpretation of complex genetic perturbations in terms of a simple set of causal relations. By analyzing cooperative groups of genes identified by our model, we demonstrate the model can group genes accurately based on their biological function, their relative ordering up- or downstream in the flow of causation, and how their activities combine to affect cell growth and death. Our approach complements existing machine learning methods in providing a simple way to interpret causal mechanism governing genetic interactions and functional states of cells.

genomics↗

bioRxiv2022

Reconstructing human Brown Fat developmental trajectory in vitro

Brown adipocytes represent a specialized type of mammalian adipocytes able to uncouple nutrient catabolism from ATP generation to dissipate energy as heat. They play an important role in mammals, allowing non-shivering thermogenesis to regulate body temperature in response to cold exposure. In humans, the brown fat tissue is composed of small discrete depots found mostly throughout the neck and trunk region. Increasing brown fat activity either with drug treatment or cell therapy is considered a potential approach for the treatment of metabolic syndrome and obesity. The recent development of in vitro differentiation strategies relying on human pluripotent stem cells (hPSCs) offers the possibility to produce unlimited amounts of brown adipocytes. A strategy efficiently applied to several tissues is to recapitulate step by step the development of the tissue of interest by exposing hPSCs to the signaling cues used during normal embryonic development. However, this strategy has proven difficult to implement for brown fat as the development of this tissue is poorly understood. Here, we first used single cell RNA sequencing to characterize the development of interscapular brown fat in mouse. Our analysis identified a previously unrecognized population of brown adipocytes precursors characterized by expression of the transcription factor GATA6. We show that this precursor population can be efficiently generated from paraxial mesoderm precursors differentiated in vitro from hPSCs by modulating the signaling pathways identified in our transcriptomic analysis. These precursors can in turn be efficiently converted into functional brown adipocytes which can respond to adrenergic stimuli by increasing their metabolism resulting in heat production.

developmental biology↗

bioRxiv2021

TNF Blockade Reduces Prostatic Hyperplasia and Inflammation while Limiting BPH Diagnosis in Patients with Autoimmune Disease

Benign prostatic hyperplasia (BPH) is ostensibly linked to autoimmune (AI) diseases, but whether the prostate is a target of systemic inflammation associated with AI conditions is unknown. Prostatic inflammation is linked to fibrosis, hyperplasia, and reduced responses to BPH-related medical therapies. This study was conducted to determine if AI disease correlates with BPH diagnosis and whether systemic targeting of an inflammatory mediator limits prostatic inflammation and hyperplasia. Patient medical records (n=112,152) were evaluated to determine BPH prevalence among different AI diseases. Inflammatory cells from human BPH tissues were analyzed by single-cell (sc)RNA-seq and the tumor necrosis factor (TNF)-antagonist etanercept was tested in two murine models of prostatic enlargement. BPH prevalence was significantly higher among patients with AI disease compared to unaffected individuals. However, AI patients treated with TNF-antagonists had a significantly reduced incidence of BPH. Data from scRNA- seq identified macrophages as a dominant source of TNF and in vitro assays confirmed that TNF stimulates BPH-derived fibroblast proliferation. In the AI patient cohort and murine models, systemic treatment with TNF-antagonists decreased prostatic epithelial proliferation, macrophage infiltration, and epithelial NF{kappa}B activation compared to control tissues. These studies are the first to show that patients with AI diseases have a heightened susceptibility to BPH and that the TNF-signaling axis is important for BPH pathogenesis. Macrophage-secreted TNF may mechanistically drive BPH via chronic activation of the signaling axis and NF{kappa}B. TNF blockade appears to be a promising new pharmacological approach to target inflammation and suppress BPH. One sentence summaryPatient data and mouse models suggest that repurposing tumor necrosis factor alpha blockade reduces inflammation-mediated prostatic hyperplasia.

cell biology↗

bioRxiv2020

Discovery of isoplumbagin as a novel NQO1 substrate and anti-cancer quinone

Isoplumbagin (5-hydroxy-3-methyl-1,4-naphthoquinone), a naturally occurring quinone from Lawsonia inermis and Plumbago europaea, that has been reported to have anti-inflammatory and anti-microbial activity. Inflammation has long been implicated in cancer progression. In this study, we examined the anti-cancer effect of chemically-synthesized isoplumbagin. Our results revealed that isoplumbagin treatment suppressed cell viability and invasion of highly invasive oral squamous cell carcinoma (OSCC) OC3-IV2 cells, glioblastoma U87 cells, non-small cell lung carcinoma H1299 cells, prostate cancer PC3 cells, and cervical cancer Hela cells by using MTT and Boyden chamber assays. In vivo studies demonstrate the inhibitory effect of 2 mg/kg isoplumbagin on the growth of orthotopic xenograft tumors derived from OSCC cells. Mechanistically, isoplumbagin exerts its cytotoxic effect through acting as a substrate of NAD(P)H quinone dehydrogenase 1 (NQO1) to generate hydroquinone, which reverses mitochondrial fission phenotype, reduces mitochondrial complex IV activity and thus compromises mitochondrial function. Collectively, this work reveals an anti-cancer activity of isoplumbagin mainly through modulating mitochondrial dynamics and function. Chemical compounds: Isoplumbagin (PubChem CID: 375105)

pharmacology and toxicology↗

bioRxiv2019

Hippocampal place cells encode local surface texture boundaries

The cognitive map is often assumed to be a Euclidean map that isometrically represents the real world (i.e. the Euclidean distance between any two locations in the physical world should be preserved on the cognitive map). However, accumulating evidence suggests that environmental boundaries can distort the mental representations of a physical space. For example, the distance between two locations can be remembered as longer than the true physical distance if the locations are separated by a boundary. While this overestimation is observed under different experimental conditions, even when the boundary is formed by flat surface cues, its physiological basis is not well understood. We examined the neural representation of flat surface cue boundaries, and of the space segregated by these boundaries, by recording place cell activity from dorsal CA1 and CA3 while rats foraged on a circular track or square platform with inhomogeneous surface textures. About 40% of the place field edges concentrated near the surface cue boundaries on the circular track (significantly above the chance level 33%). Similarly, the place field edges were more prevalent near the boundaries on the platforms than expected by chance. In both 1-dimensional and 2-dimensional environments, the population vectors of place cell activity changed more abruptly with distance between locations that crossed cue boundaries than between locations within a bounded region. These results show that the locations of surface boundaries were evident as enhanced decorrelations of the neural representations of locations to either side of the boundaries. This enhancement might underlie the cognitive phenomenon of overestimation of distances across boundaries.

neuroscience↗

bioRxiv2018

The strength of protein-protein interactions controls the information capacity and dynamical response of signaling networks

Eukaryotic cells transmit information by signaling through complex networks of interacting proteins. Here we develop a theoretical and computational framework that relates the biophysics of protein-protein interactions (PPIs) within a signaling network to its information processing properties. To do so, we generalize statistical physics-inspired models for protein binding to account for interactions that depend on post-translational state (e.g. phosphorylation). By combining these models with information-theoretic methods, we find that PPIs are a key determinant of information transmission within a signaling network, with weak interactions giving rise to \"noise\" that diminishes information transmission. While noise can be mitigated by increasing interaction strength, the accompanying increase in transmission comes at the expense of a slower dynamical response. This suggests that the biophysics of signaling protein interactions give rise to a fundamental \"speed-information\" trade-off. Surprisingly, we find that cross-talk between pathways in complex signaling networks do not significantly alter information capacity-an observation that may partially explain the promiscuity and ubiquity of weak PPIs in heavily interconnected networks. We conclude by showing how our framework can be used to design synthetic biochemical networks that maximize information transmission, a procedure we dub \"InfoMax\" design.

systems biology↗

bioRxiv2018

A GYS2/p53 negative feedback loop restricts tumor growth in HBV-related hepatocellular carcinoma

Hepatocarcinogenesis is attributed to the reprogramming of cellular metabolism as consequence of the alteration in metabolite-related gene regulation. Identifying the mechanism of aberrant metabolism is of great potential to provide novel targets for the treatment of hepatocellular carcinoma (HCC). Here, we demonstrated that glycogen synthase 2 (GYS2) restricted tumor growth in HBV-related HCC via a negative feedback loop with p53. Expression of GYS2 was significantly downregulated in HCC and correlated with decreased glycogen content and unfavorable patient outcomes. GYS2 overexpression suppressed, whereas GYS2 knockdown facilitated cell proliferation in vitro and tumor growth in vivo via modulating p53 expression. GYS2 competitively bound to MDM2 to prevent p53 from MDM2-mediated ubiquitination and degradation. Furthermore, GYS2 enhanced the p300-induced acetylation of p53 at K373/382, which in turn inhibited the transcription of GYS2 in the support of HBx/HDAC1 complex. In summary, our findings suggest that GYS2 serves as a prognostic factor and functions as a tumor suppressor in HCC. The newly identified HBx/GYS2/p53 axis is responsible for the deregulation of glycogen metabolism and represents a promising therapeutic target for the clinical management of HCC.\n\nSynopsisThis study elucidate the role of GYS2 in glycogen metabolism and the progression of HCC. The newly identified HBx/GYS2/p53 axis is responsible for the deregulation of glycogen metabolism and represents a promising therapeutic target for the clinical management of HCC.\n\nO_LIDecrease of GYS2 was significantly correlated with decreased glycogen content and unfavorable patient outcomes in a large cohort containing 768 patients with HCC.\nC_LIO_LIGYS2 overexpression suppressed, whereas GYS2 knockdown facilitated cell proliferation in vitro and tumor growth in vivo via modulating p53 signaling pathway.\nC_LIO_LIGYS2 competitively bound to MDM2 to prevent p53 from MDM2-mediated ubiquitination and degradation.\nC_LIO_LIGYS2 enhanced the p300-induced acetylation of p53 at Lys373/382, which in turn inhibited the transcription of GYS2 in the support of HBx/HDAC1 complex.\nC_LI

pathology↗

bioRxiv2018

Pinned, locked, pushed, and pulled traveling waves in structured environments

Traveling fronts describe the transition between two alternative states in a great number of physical and biological systems. Examples include the spread of beneficial mutations, chemical reactions, and the invasions by foreign species. In homogeneous environments, the alternative states are separated by a smooth front moving at a constant velocity. This simple picture can break down in structured environments such as tissues, patchy landscapes, and microfluidic devices. Habitat fragmentation can pin the front at a particular location or lock invasion velocities into specific values. Locked velocities are not sensitive to moderate changes in dispersal or growth and are determined by the spatial and temporal periodicity of the environment. The synchronization with the environment results in discontinuous fronts that propagate as periodic pulses. We characterize the transition from continuous to locked invasions and show that it is controlled by positive density-dependence in dispersal or growth. We also demonstrate that velocity locking is robust to demographic and environmental fluctuations and examine stochastic dynamics and evolution in locked invasions.

ecology↗