Biology subjects

WANG, Q.

Publications and source records attributed to WANG, Q..

8 recordsLinked to original sources

bioRxiv2026

A brain-tumour axis links chronic stress to gastric cancer progression through NPY signalling

Chronic stress promotes gastric tumour growth, but the central neural pathways remain largely enigmatic. Here, we identify a brain-tumour axis, implicating the central amygdala (CeA) activity in promoting gastric cancer growth through sympathetic neuropeptide Y (NPY) signalling occurring within the tumour. Using clinical datasets, patient samples, pathway tracing, electrophysiology and chemogenetic manipulation, we demonstrate that stress selectively increases NPY Y1 receptor (NPY1R) synthesis in the patients gastric cancer tissue; moreover, the NPY1R density correlates with advanced cancer stage and poor prognosis. In mice, daily constraint chronic stress enhances CeA excitability and promotes sympathetic neurotransmitter norepinephrine release within the tumour microenvironment. Norepinephrine, in turn, increases tumour endogenous NPY/NPY1R production and the activation of downstream MAPK/Erk1/2 signalling pathway, which drives cancer cell proliferation and invasion. Manipulating CeA neuronal activity alone can regulate tumour growth, whereas selectively blocking tumour NPY1R prevents stress-induced tumour progression in vivo and cancer cell migration in vitro. This study identifies a central-to-peripheral circuit linking chronic stress to gastric cancer growth, and highlights NPY1R as a potential therapeutic target.

Cancer Biology↗

bioRxiv2026

Age-Associated Remodeling of neuroglial Connexin43 in the Mouse and Human Brain

Age-dependent changes in the major neuroglial junctional channel Connexin43 (Cx43) are poorly defined. We integrated public multi-organ and single-cell datasets with high-resolution morphological, biochemical, and functional analyses of human and mouse brains. We reveal a non-linear aging trajectory for Cx43, marked by an adaptational midlife elevation followed by a late-life decline. These molecular changes proceed in the absence of significant cell loss but are associated with extensive glial remodeling. Notably, while astrocytic gap junction coupling in the hippocampus remains largely preserved, aging induces a selective increase in hemichannel mediated dye uptake in both microglia and hippocampal astrocytes. In human cortical and hippocampal tissues, we confirm that aging drives a significant reduction in astrocytic Cx43 expression, alongside characteristic morphological simplification of cell structure and domain contraction. Together, our findings redefine the aging brain as a state of active, multi-level glial remodeling rather than a simple decline in connexin-mediated communication.

neuroscience↗

bioRxiv2025

Tryptophan Chemistry Driven by a Widespread Cytochrome P422 Enzyme Family

Tryptophan serves as a versatile biosynthetic precursor across living organisms. While heme-binding proteins (HBPs) mediate key reactions in tryptophan transformation, the full diversity of HBPs remains largely unexplored. Here, we developed the novel Cofactor-Integrative Structural Inspector (CISSspector) to systematically identify HBPs in the extensive extant microbial genomic sequence database, which revealed several uncharacterized HBP families. We experimentally characterized one of the most prominent families, the cytochrome P422 (formerly DUF6875) family, distributed throughout the prokaryotes and eukaryotes. Strikingly, we discovered that this enzyme family orchestrates four chemically distinct and biochemically unprecedented transformations, with regioselectivity, including N1-, C6-, and C7-hydroxylations and intramolecular C-S bond formations. Notably, the discovery of enzymes capable of Trp N1- and C7-hydroxylation addresses a long-standing gap in the natural enzyme arsenal. Structural analysis of the representative cytochrome P422 enzyme Mc170 revealed a structurally unique HBP fold in which conserved residues form a substrate "clamp" that positions the tryptophan indole ring for selective modification. Our work unveils a hidden enzymatic repertoire of HBPs, expands the known landscape of tryptophan metabolism, and establishes an artificial intelligence-augmented framework for discovering cryptic enzymes with broad implications for synthetic biology and natural product discovery.

biochemistry↗

bioRxiv2024

Chemically Induced Nuclear Pore Complex Protein Degradation via E3 Ligase TRIM21

Despite the exciting progress of the bifunctional degrader molecules, also known as proteolysis-targeting chimeras (PROTACs), the rapidly expanding field is still significantly hampered by the lacking of available E3 ligase ligands. Our research bridges this gap by uncovering a series of small-molecule ligands to the E3 ligase TRIM21 through DNA-Encoded Library (DEL) technology. We confirmed their interaction with TRIM21 using crystallography and demonstrated their anti-proliferative effects across various cancer cell types. Furthermore, proteomic studies identified that the mRNA Export Factor GLE1, and the Nuclear Pore Complex Protein NUP155, were significantly down-regulated upon TRIM21 ligand treatment. This degradation required TRIM21 and was ubiquitin-proteasome-dependent. More specifically, NUP155 was the primary target for the TRIM21 ligands, while GLE1 was considered a passenger target upon the initial degradation of NUP155. Using immunofluorescence techniques, we further demonstrated that the degradation of GLE1 and NUP155 proteins impaired the integrity of the nuclear envelope, leading to cell death. Highlighted by this research, a novel mode of action has been discovered for the TRIM21 E3 ligase ligand, acting as a monovalent degrader that triggers de novo interaction with functional complex proteins and induces their degradation.

cell biology↗

bioRxiv2024

Imaging and quantification of prostate cancer-associated bone by polarization-sensitive optical coherence tomography

Prostate cancer frequently metastasizes to bone, leading to a spectrum of osteosclerotic and osteolytic lesions that cause debilitating symptoms. Accurate differentiation of bone tissue or lesion types can provide opportunity for local pathologic investigation, which is critical for understanding the bone metastasis and remains challenging. Current imaging methods lack the ability to directly differentiate tissues based on collagen organization and may induce invasive effect on bone tissues. We introduce Polarization-Sensitive Optical Coherence Tomography (PS-OCT) to investigate normal, osteosclerotic, and osteolytic bone tissues. High-resolution PS-OCT imaging reveals collagen fiber arrangement, enabling nuanced distinction of degree of collagen alignment among different bone tissue types or regions. We present a novel feature named degree of ordered organization (DOO), derived from the multiple contrasts of PS-OCT that can quantitatively evaluate bone samples from different pathologic groups, including control,osteoblastic and osteolytic tissues. The capacity of PS-OCT to differentiate trabecular/lamellar and irregular (woven bone) regions within the same specimen is tested and validated on ex-vivo samples extracted from 13 subjects. Our study is the first time that PS-OCT is applied to metastatic bone disease with the aim of enhancing the understanding of bone-related pathologies, and potentially impacting clinical practice. This work demonstrates that PS-OCT can provide useful insight into bone microstructures, and thus it has potential applications across diverse bone disorders.

biophysics↗

bioRxiv2023

Reduced PIN1 gene expression in neocortical and limbic brain regions in female Alzheimer's patients correlates with cognitive and neuropathological phenotypes

Women have a higher incidence of Alzheimers disease (AD), even after adjusting for increased longevity. Thus, there is an urgent need to identify the molecular networks that underpin the sex-associated risk of AD. Recent efforts have identified PIN1 as a key regulator of tau phosphorylation signaling pathway. Pin1 is the only gene, to date, that when deleted can cause both tau and A{beta}-related pathologies in an age-dependent manner. We analyzed multiple brain transcriptomic datasets focusing on sex differences in PIN1 mRNA levels, in an aging and AD cohort, which revealed reduced PIN1 levels driven by females. Then, we validated this observation in an independent dataset (ROS/MAP) which also revealed that PIN1 is negatively correlated with multiregional neurofibrillary tangle density and global cognitive function, in females only. Additional analysis revealed a decrease in PIN1 in subjects with mild cognitive impairment (MCI) compared with aged individuals, again, driven predominantly by female subjects. Our results show that while both male and female AD patients show decreased PIN1 expression, changes occur before the onset of clinical symptoms of AD in females and correlate to early events associated with AD risk (e.g., synaptic dysfunction). These changes are specific to neurons, and may be a potential prognostic marker to assess AD risk in the aging population and even more so in AD females with increased risk of AD. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=155 SRC="FIGDIR/small/553279v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@95bd4eorg.highwire.dtl.DTLVardef@bf4e3corg.highwire.dtl.DTLVardef@1a9468corg.highwire.dtl.DTLVardef@56c15e_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

A role for the V0 sector of the V-ATPase in neuroexocytosis: exogenous V0d blocks complexin and SNARE interactions with V0c

V-ATPase is an important factor in synaptic vesicle acidification and is implicated in synaptic transmission. Rotation of the extra-membranous V1 sector drives proton transfer through the membrane-embedded multi-subunit V0 sector of the V-ATPase. Intra-vesicular protons are then used to drive neurotransmitter uptake by synaptic vesicles. V0a and V0c, two membrane subunits of the V0 sector have been shown to interact with SNARE proteins and their photo-inactivation rapidly impairs synaptic transmission. V0d, a soluble subunit of the V0 sector strongly interacts with its membrane embedded subunits and is crucial for the canonic proton transfer activity of the V-ATPase. Our investigations show that the loop 1.2 of V0c interacts with complexin, a major partner of the SNARE machinery and that V0d1 binding to V0c inhibits this interaction, as well as V0c association with SNARE complex. Injection of recombinant V0d1 in rat superior cervical ganglion neurons rapidly reduced neurotransmission. In chromaffin cells, V0d1 overexpression and V0c silencing modified in a comparable manner several parameters of unitary exocytotic events. Our data suggest that V0c subunit promotes exocytosis via interactions with complexin and SNAREs and that this activity can be antagonized by exogenous V0d.

cell biology↗

bioRxiv2020

Inter-subject pattern analysis for multivariate group analysis of functional neuroimaging. A unifying formalization.

Background and objectiveIn medical imaging, population studies have to overcome the differences that exist between individuals to identify invariant image features that can be used for diagnosis purposes. In functional neuroimaging, an appealing solution to identify neural coding principles that hold at the population level is inter-subject pattern analysis, i.e. to learn a predictive model on data from multiple subjects and evaluate its generalization performance on new subjects. Although it has gained popularity in recent years, its widespread adoption is still hampered by the blatant lack of a formal definition in the literature. In this paper, we precisely introduce the first principled formalization of inter-subject pattern analysis targeted at multivariate group analysis of functional neuroimaging. MethodsWe propose to frame inter-subject pattern analysis as a multi-source transductive transfer question, thus grounding it within several well defined machine learning settings and broadening the spectrum of usable algorithms. We describe two sets of inter-subject brain decoding experiments that use several open datasets: a magnetoencephalography study with 16 subjects and a functional magnetic resonance imaging paradigm with 100 subjects. We assess the relevance of our framework by performing model comparisons, where one brain decoding model exploits our formalization while others do not. ResultsThe first set of experiments demonstrates the superiority of a brain decoder that uses subject-by-subject standardization compared to state of the art models that use other standardization schemes, making the case for the interest of the transductive and the multi-source components of our formalization The second set of experiments quantitatively shows that, even after such transformation, it is more difficult for a brain decoder to generalize to new participants rather than to new data from participants available in the training phase, thus highlighting the transfer gap that needs to be overcome. ConclusionThis paper describes the first formalization of inter-subject pattern analysis as a multi-source transductive transfer learning problem. We demonstrate the added value of this formalization using proof-of-concept experiments on several complementary functional neuroimaging datasets. This work should contribute to popularize inter-subject pattern analysis for functional neuroimaging population studies and pave the road for future methodological innovations.

neuroscience↗