Biology subjects

Dang, M.

Publications and source records attributed to Dang, M..

12 recordsLinked to original sources

bioRxiv2026

Spatiotemporal coordination of specialized cerebellar networks supports episodic memory in older adults

Episodic memory decline in ageing is typically attributed to the cortico-hippocampal system, yet the cerebellums specific contribution via cerebellar-cerebral circuits remains underexplored. We analysed task-based fMRI data from 821 older adults, including a longitudinal subset of 78 participants followed for four years. Using sparse dictionary learning on task-responsive activity, we identified three non-motor networks: a bilateral lobule VI/Crus I mnemonic-monitoring network, a right lobule Crus I/II default-mode-aligned network, and a right lobule VIIb/VIIIa evidence-evaluation network. While network recruitment varied with task demands and associated with memory performance, phase-specific static cerebellar-cerebral functional connectivity showed stable organization but limited behavioural specificity. In contrast, dynamic functional connectivity patterns effectively distinguished memory-performance groups. Crucially, greater instability in dynamic functional connectivity during encoding predicted longitudinal retrieval slowing. These findings suggest that preserved episodic memory in older adults is supported by the spatiotemporal coordination of specialized cerebellar networks with distributed cerebral networks.

neuroscience↗

bioRxiv2025

A Precisely Controlled Long-Acting Immunosuppression Platform Enables Prolonged Survival of Vascularized Composite Allografts

Vascularized composite allotransplantation (VCA) restores complex tissue defects but demands lifelong systemic immunosuppression. Oral tacrolimus (TAC) is limited by a narrow therapeutic window, pharmacokinetic variability, adherence challenges, and toxicity. Local delivery could mitigate these issues, yet clinical translation has been hindered by burst release, short duration, and the inability to co-deliver agents. We developed PRECISE (Programmable, REtrievable, Controlled ImmunoSuppression Encapsulator), an injectable, in-situ-forming PLGA depot that achieves long-acting, tightly controlled TAC release via structure-guided co-formulation with drug-binding agents (DBAs). GRAS small molecules (e.g., EGCG, maltotriose) identified by in silico docking and in vitro screening suppressed burst and modulated solvent efflux. Notably, rapamycin (RAPA) served dually as an mTOR inhibitor and a TAC-binding excipient, enabling synchronized dual-agent delivery. PRECISE eliminated burst in vitro and produced coordinated TAC+RAPA release with clinically compatible injectability. In rats, monthly intragraft dosing maintained systemic TAC/RAPA within the therapeutic window ([~]5-10 ng/mL) for >300 days, prolonged hindlimb allograft survival, expanded Tregs, and induced donor-specific hyporesponsiveness. Surgical retrieval of the depot triggered rapid TAC decline, demonstrating reversibility. In a stringent, fully MHC-mismatched porcine VCA model, PRECISE maintained on-target drug levels and extended graft survival beyond 90 days with minimal rejection and preserved vascular integrity. PRECISE is, to our knowledge, the first retrievable, injectable platform to deliver long-acting, dual-agent immunosuppression with controlled kinetics, rapid attainment of therapeutic steady state, and sustained graft protection. Its modular, structure-guided design enables clinical translation across VCA and solid-organ transplantation, delivering precise, durable, and safer immunosuppression.

bioengineering↗

bioRxiv2024

A Mechanically Resilient Soft Hydrogel Improves Drug Delivery for Treating Post-Traumatic Osteoarthritis in Physically Active Joints

Intra-articular delivery of disease-modifying osteoarthritis drugs (DMOADs) is likely to be most effective in early post-traumatic osteoarthritis (PTOA) when symptoms are minimal and patients are physically active. DMOAD delivery systems therefore must withstand repeated mechanical loading without affecting the drug release kinetics. Although soft materials are preferred for DMOAD delivery, mechanical loading can compromise their structural integrity and disrupt drug release. Here, we report a mechanically resilient soft hydrogel that rapidly self-heals under conditions resembling human running while maintaining sustained release of the cathepsin-K inhibitor L-006235 used as a proof-of-concept DMOAD. Notably, this hydrogel outperformed a previously reported hydrogel designed for intra-articular drug delivery, used as a control in our study, which neither recovered nor maintained drug release under mechanical loading. Upon injection into mouse knee joints, the hydrogel showed consistent release kinetics of the encapsulated agent in both treadmill-running and non-running mice. In a mouse model of aggressive PTOA exacerbated by treadmill running, L-006235 hydrogel markedly reduced cartilage degeneration. To our knowledge, this is the first hydrogel proven to withstand human running conditions and enable sustained DMOAD delivery in physically active joints, and the first study demonstrating reduced disease progression in a severe PTOA model under rigorous physical activity, highlighting the hydrogels potential for PTOA treatment in active patients.

bioengineering↗

bioRxiv2023

Tractable and Expressive Generative Models of Genetic Variation Data

Generative models play an important role in population genetics, being used to generate artificial genomes (AGs) that help benchmark methods, test evolutionary hypotheses, and construct reference panels for imputation while working around data-sharing restrictions. Existing generative models of genetic variation, however, struggle to faithfully express dependencies in the data while retaining tractability and preserving privacy. We introduce Genetic Probabilistic Circuits (GPC), a deep generative model for genetic variation data based on hidden Chow-Liu trees represented as probabilistic circuits. GPC generalizes traditional hidden Markov models by allowing arbitrary tree structures over latent variables, enabling it to capture long-range dependencies among SNPs. GPC is tractable, supporting exact computation of marginal and conditional probabilities that enables both AG generation and direct genotype imputation (avoiding the need for simulating AGs). We show that GPC generates AGs that accurately reproduce population structure and linkage disequilibrium patterns across a range of length scales. Compared to other deep generative approaches, GPC consistently improves imputation accuracy, with particularly strong gains for low-frequency variants and in populations that are not well-represented in public reference panels. Finally, we show that GPC better preserves privacy of the training data, thereby providing a practical framework for AG generation in settings with limited data access.

genetics↗

bioRxiv2023

Triggering receptor expressed on myeloid cells 2 (TREM2) regulates phagocytosis in glioblastoma

Glioblastomas (GBMs) are tumors of the central nervous system that remain recalcitrant to both standard of care chemo-radiation and immunotherapies. Emerging approaches to treat GBMs include depletion or re-education of innate immune cells including microglia (MG) and macrophages (MACs). Here we show myeloid cell restricted expression of triggering receptor expressed on myeloid cells 2 (TREM2) across low- and high-grade human gliomas. TREM2 expression did not correlate with immunosuppressive pathways, but rather showed strong positive association with phagocytosis markers such as lysozyme (LYZ) and CD163 in gliomas. In line with these observations in patient tumors, Trem2-/- mice did not exhibit improved survival compared to wildtype (WT) mice when implanted with mouse glioma cell lines, unlike observations previously seen in peripheral tumor models. Gene expression profiling revealed pathways related to inflammation, adaptive immunity, and autophagy that were significantly downregulated in tumors from Trem2-/- mice compared to WT tumors. Using ZsGreen-expressing CT-2A orthotopic implants, we found higher tumor antigen engulfment in Trem2+ MACs, MG, and dendritic cells. Our data uncover TREM2 as an important immunomodulator in gliomas and inducing TREM2 mediated phagocytosis can be a potential immunotherapeutic strategy for brain tumors. Key pointsO_LITREM2 is not associated with immunosuppressive molecules in GBM C_LIO_LITREM2 is associated with phagocytosis in both human and mouse gliomas C_LIO_LIDeletion of Trem2 in mice does not improve survival in glioma models C_LI Importance of the studyTriggering receptor expressed on myeloid cells 2 (TREM2) has been implicated as a major immunoregulator in both neurodegenerative diseases and systemic cancers, yet its functional role in gliomas remains unclear. This study reveals that unlike in other cancers, TREM2 is not associated with immunosuppression in the glioma microenvironment. In fact, TREM2 expression is associated with phagocytosis in both human and mouse gliomas, similar to its role in Alzheimers disease. These findings indicate that TREM2 blockade will not be a viable treatment strategy for gliomas. Instead, TREM2 induction may boost the potential of myeloid cells in the tumor microenvironment to engulf cancer cells.

cancer biology↗

bioRxiv2022

Immune Contexture of Isocitrate Dehydrogenase stratified Human Gliomas

The brain tumor immune microenvironment (TIME) continuously evolves during glioma progression, but only a limited view of a highly complex glioma associated immune contexture across isocitrate dehydrogenase mutation (IDH) classified gliomas is known. Herein, we present an unprecedentedly comprehensive view of myeloid and lymphoid cell type diversity based on our single cell RNA sequencing and spectral cytometry-based interrogation of tumor-associated leukocytes from fifty-five IDH stratified primary and recurrent human gliomas and three non-glioma brains. Our analyses revealed twenty-two myeloid and lymphoid cell types within and across glioma subtypes. Glioma severity correlated with microglial attrition concomitant with a continuum of invading monocyte-derived microglia-like and macrophages amongst other infiltrating conventional T and NK lymphocytes and unconventional mucosa associated invariant T (MAIT) cells. Specifically, certain microglial and monocyte-derived subpopulations were associated with antigen presentation gene modules, akin to cross-presenting dendritic cells (DCs). Furthermore, we identified phagocytosis and antigen presentation gene modules enriched in Triggering receptor expressed on myeloid (TREM)-2+ cells as a putative anti-glioma axis. Accelerated glioma growth was observed in Trem2 deficient mice implanted with CT2A glioma cells affirming the anti-glioma role of TREM2+ myeloid cells. In addition to providing a comprehensive landscape of glioma-specific immune contexture, our investigations discover TREM2 as a novel immunotherapy target for brain malignancies.

immunology↗

bioRxiv2021

Myricetin allosterically inhibits Dengue NS2B-NS3 protease as studied by NMR and MD simulations

Dengue NS2B-NS3 protease existing in equilibrium between the active and inactive forms is essential for virus replication, thus representing a key drug target. Here Myricetin, a plant flavonoid, was characterized to non-competitively inhibit Dengue protease. Further NMR study identified the protease residues perturbed by binding to Myricetin, which were utilized to construct the Myricetin-protease complexes. Strikingly, in the active form Myricetin binds a new allosteric site (AS2) far away from the active site pocket and allosteric site (AS1) for binding Curcumin, while in the inactive form it binds both AS1 and AS2. To decipher the mechanism for the allosteric inhibition by Myricetin, we conducted molecular dynamics (MD) simulations on different forms of Dengue NS2B-NS3 protease. Unexpectedly, the binding of Myricetin to AS2 is sufficient to disrupt the active conformation by displacing the characteristic NS2B C-terminal {beta}- hairpin from the active site pocket. By contrast, the binding of Myricetin to AS1 and AS2 results in locking the inactive conformation. Therefore Myricetin represents the first small molecule which allosterically inhibits Dengue protease by both disrupting the active conformation and locking the inactive conformation. The results enforce the notion that a global allosteric network exists in Dengue NS2B-NS3 protease, which is susceptible to allosteric inhibition by small molecules such as Myricetin and Curcumin. As Myricetin has been extensively used as a food additive, it might be directly utilized to fight the Dengue infections and as a promising starting for further design of potent allosteric inhibitors. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/472523v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@ec52d1org.highwire.dtl.DTLVardef@1313dc4org.highwire.dtl.DTLVardef@1ce40b5org.highwire.dtl.DTLVardef@1fa6051_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2021

No Correlation Between Pollen Fertility and Viability: Differential Measures of Male Gametophytic Fitness in Cannabis sativa L.

Pollen grains are male gametophytes, an ephemeral haploid generation of plants, commonly engaging in competition for a limited supply of ovules. Since differential male fertility may influence the direction and pace of population evolution, the relative fitness of pollen is regularly estimated as either pollen viability, the proportion of pollen containing intact cytoplasms and regenerative nuclei, or pollen fertility, the frequency of pollen germinating under standardized conditions. Here, we estimated the relative fitness of pollen in a dioecious, wind-pollinated model system, Cannabis sativa, by characterizing pollen fertility and viability from multiple sires. Pollen fertility quickly declined within two weeks of anther dehiscence, and pollen stored under freezer conditions did not germinate regardless of storage time. In contrast, pollen viability declined slowly and persisted longer than the lifetime of a sporophyte plant under both room temperature and freezer conditions. Pollen samples that underwent both fertility and viability analysis displayed no significant correlation, implying researchers cannot predict pollen fertility from pollen viability, nor infer male gametophytic fitness from a single measure. Our work demonstrates two approaches to measure proxies of male fitness in C. sativa, and identifies new questions around what are valuable estimates of male fitness in plants.

plant biology↗

bioRxiv2021

Immune microenvironment subtypes and association with tumor cell mutations and antigen expression in follicular lymphoma.

Follicular lymphoma (FL) is a B-cell lymphoma with a complex tumor microenvironment that is rich in non-malignant immune cells. We applied single-cell RNA-sequencing to characterize the diverse tumor and immune cell populations of FL and identified major phenotypic subsets of FL T-cells including a novel cytotoxic CD4 T-cell population. Their relative proportions of T-cells defined four major FL subtypes, characterized by differential representation or relative depletion of distinct T-cell subsets. By integrating exome sequencing, we observed that somatic mutations are associated with, but not definitive for, reduced antigen presentation on FL cells. In turn, expression of MHC class II genes by FL cells was associated with significant differences in the proportions and targetable immunophenotypic characteristics. This provides a classification framework of the FL microenvironment, their association with FL genotypes and antigen presentation, and informs different potential immunotherapeutic strategies based upon tumor cell MHC class II expression. Statement of significanceWe have characterized the FL-infiltrating T-cells, identified cytotoxic CD4 T-cells as an important component, showed that the abundance of these T-cell populations is associated with tumor-cell-intrinsic characteristics, and identified sets of targetable immune checkpoints on T-cells that differed between FLs with normal versus low antigen presentation.

cancer biology↗

bioRxiv2021

Structural basis of anti-SARS-CoV-2 activity of hydroxychloroquine: specific binding to NTD/CTD and disruption of LLPS of N protein

Great efforts have led to successfully developing the spike-based vaccines but challenges still exist to completely terminate the SARS-CoV-2 pandemic. SARS-CoV-2 nucleocapsid (N) protein plays the essential roles in almost all key steps of the viral life cycle, thus representing a top drug target. Almost all key functions of N protein including liquid-liquid phase separation (LLPS) depend on its capacity in interacting with nucleic acids. Therefore, only the variants with their N proteins functional in binding nucleic acids might survive and spread in evolution and indeed, the residues critical for binding nucleic acids are highly conserved. Very recently, hydroxychloroquine (HCQ) was shown to prevent the transmission in a large-scale clinical study in Singapore but so far, no specific SARS-CoV-2 protein was experimentally identified to be targeted by HCQ. Here by NMR, we unambiguously decode that HCQ specifically binds NTD and CTD of SARS-CoV-2 N protein with Kd of 112.1 and 57.1 M respectively to inhibit their interaction with nucleic acid, as well as to disrupt LLPS essential for the viral life cycle. Most importantly, HCQ-binding residues are identical in SARS-CoV-2 variants and therefore HCQ is likely effective to them all. The results not only provide a structural basis for the anti-SARS-CoV-2 activity of HCQ, but also renders HCQ to be the first known drug capable of targeting LLPS. Furthermore, the unique structure of the HCQ-CTD complex decodes a promising strategy for further design of better anti-SARS-CoV-2 drugs from HCQ. Therefore, HCQ is a promising candidate to help terminate the pandemic.

biophysics↗

bioRxiv2020

SATB2 induction of a neural crest mesenchyme-like program drives invasion and drug resistance in melanoma

Recent genomic and scRNA-seq analyses of melanoma identified common transcriptional states correlating with invasion or drug resistance, but failed to find recurrent drivers of metastasis. To test whether transcriptional adaptation can drive melanoma progression, we made use of a zebrafish mitfa:BRAFV600E;tp53-/- model, in which malignant progression is characterized by minimal genetic evolution. We undertook an overexpression-screen of 80 epigenetic/transcriptional regulators and found neural crest-mesenchyme developmental regulator SATB2 to accelerate aggressive melanoma development. Its overexpression induces invadopodia formation and invasion in zebrafish tumors and human melanoma cell lines. SATB2 binds and activates neural crest-regulators, including pdgfab and snai2. The transcriptional program induced by SATB2 overlaps with known MITFlowAXLhlgh and AQP1+NGFR1high drug resistant states and functionally drives enhanced tumor propagation and resistance to Vemurafenib in vivo. Here we show that melanoma transcriptional rewiring by SATB2 to a neural crest mesenchyme-like program can drive invasion and drug resistance in endogenous tumors.

cancer biology↗

bioRxiv2020

Resolving the spatial and cellular architecture of lung adenocarcinoma by multi-region single-cell sequencing

Little is known of the geospatial architecture of individual cell populations in lung adenocarcinoma (LUAD) evolution. Here, we perform single-cell RNA sequencing of 186,916 cells from 5 early-stage LUADs and 14 multi-region normal lung tissues of defined spatial proximities from the tumors. We show that cellular lineages, states, and transcriptomic features geospatially evolve across normal regions to LUADs. LUADs also exhibit pronounced intratumor cell heterogeneity within single sites and transcriptional lineage-plasticity programs. T regulatory cell phenotypes are increased in normal tissues with proximity to LUAD, in contrast to diminished signatures and fractions of cytotoxic CD8+ T cells, antigen-presenting macrophages and inflammatory dendritic cells. We further find that the LUAD ligand-receptor interactome harbors increased expression of epithelial CD24 which mediates pro-tumor phenotypes. These data provide a spatial atlas of LUAD evolution, and a resource for identification of targets for its treatment. Statement of significanceThe geospatial ecosystem of the peripheral lung and early-stage LUAD is not known. Our multi-region single-cell sequencing analyses unravel cell populations, states, and phenotypes in the spatial and ecological evolution of LUAD from the lung that comprise high-potential targets for early interception.

cancer biology↗