Biology subjects

Yao, M.

Publications and source records attributed to Yao, M..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Stretchable, hair-compatible, and long-term stable wearable EEG system

Electroencephalography (EEG) is a cornerstone in both neuroscience research and clinical diagnostics. However, conventional EEG monitoring faces hardware limitations, particularly its adaptability and stability. Headsets either require complicated wiring or do not have enough stretchability and wearability to comply with the diverse head anthropometry and hair conditions of the user population. Additionally, there is an inherent tradeoff between wet and dry electrodes in capturing high-fidelity signals from hair-covered scalp regions while ensuring continuous and long-term recording quality. Here, we present a Mesh-integrated, Stretchable, and Hair-compatible EEG system engineered to overcome these limitations. By incorporating a kirigami-inspired mesh design and stretchable eutectic Gallium-Indium interconnects, MindStretcH adapts to various head sizes and allows for easy wearing and removal. Moreover, its uniquely designed porous, conical, soft 3D-printed mold, embedded with hydrogel electrodes, effectively penetrates hair layers to deliver low impedance and sustained signal integrity with minimal discomfort. We validate MindStretcH through offline and online EEG-based brain-computer interface tasks over a month, demonstrating its exceptional stability in continuous monitoring and dynamic applications. These results mark a promising advance toward non-invasive neural interfaces in both clinical and everyday use.

bioengineering↗

bioRxiv2025

Cell type-specific contributions to impaired blood-brain barrier and cerebral metabolism in presymptomatic 5XFAD mice

Altered cerebral metabolism and blood-brain barrier (BBB) dysfunction are emerging as critical contributors to the preclinical phase of Alzheimers disease (AD), underscoring their role in early pathogenesis. To identify sensitive biomarkers before irreversible neuronal loss and cognitive decline, we examined 5XFAD mice at 3 months of age by applying multiple advanced MRI techniques. Arterial spin tagging based MRI revealed increased BBB permeability and water extraction fraction, indicating compromised BBB integrity at the early stage of pathogenesis in 5xFAD mice. Despite preserved cerebral blood flow, a decreased unit mass cerebral metabolic rate of oxygen (CMRO2) was evident in the same cohorts of 5XFAD mice. Interestingly, a region-specific decrease of tissue pH values was detected in the hippocampus of these 5XFAD mice by creatine chemical exchange saturation transfer MRI. Elevated neuronal H4K12 lactylation in the hippocampus supports the reduced pH values. To further dissect the cellular and molecular mechanisms underlying these MRI-detectable changes in 5XFAD mice, we conducted single-nucleus RNA sequencing (snRNA-Seq) with optimized blood vessel enrichment protocols. Our results revealed cell type-specific transcriptomic changes in the hippocampus of 3-month-old 5XFAD mice, including downregulation of synaptogenesis and synaptic transmission genes in the CA1 and dentate gyrus excitatory neurons, impaired endothelial gene expression linked to brain barrier function and angiogenesis, altered innate immune response genes in astrocytes, as well as upregulation of cholesterol biosynthesis and metabolism genes in the CA1 excitatory neurons. These findings underlie the intricate interplay between BBB disruption and metabolic dysregulation before the onset of cognitive decline in AD. Our study demonstrates that BBB dysfunction and cerebral metabolic alterations preceded brain hypoperfusion and cognitive decline, emphasizing potential molecular pathways for early intervention. These findings, once validated in human studies, could significantly enhance early diagnosis and inform novel therapeutic strategies targeting early AD pathogenesis.

neuroscience↗

bioRxiv2025

Progressively reduced cerebral oxygen metabolism and elevated plasma NfL levels in the zQ175DN mouse model of Huntington disease

Huntingtons disease (HD) is a progressive neurodegenerative disorder caused by a CAG-repeat expansion in exon-1 of the huntingtin gene. Currently, no disease-modifying therapies are available, with a significant challenge in evaluating therapeutic efficacy before clinical symptoms emerge. This highlights the need for early biomarkers and intervention strategies. Therefore, it is essential to develop and characterize accurate mouse models and identify early biomarkers for preclinical therapeutic development. In this study, we characterized the pathological progression of the heterozygous zQ175 neo-deleted knock in (zQ175DN) mouse model across four age groups: 3, 6, 10, and 16 months to identify human translatable outcome measures. T2-relaxation-under-spin-tagging (TRUST) MRI was used to assess global CMRO2, while T2-weighted MRI was used to analyze brain volumes. Significant brain volume loss was detected as early as 6 months of age, worsening progressively with age in the zQ175 DN mice, resembling HD brain volumetric changes. A decline in CMRO2 was observed in 6-month-old zQ175 DN mice, with significant and progressive reductions in 10- and 16-months old HD mice. Additionally, PHP1-positive mutant huntingtin (mHTT) aggregates were present in the striatum of zQ175 DN mice at all four age groups, with intranuclear localization prior to 6 months, transitioning to both intranuclear and neuropil aggregates in older zQ175 DN mice, suggesting that the localization of mHTT aggregates may reflect the severity of HD pathogenesis. Interestingly, plasma neurofilament light chain (NfL) protein concentrations were significantly elevated at 6 months of age and older zQ175DN mice. These findings provide valuable insights for selecting outcome measures in preclinical evaluations of HD therapies using the zQ175 DN mouse model.

neuroscience↗

bioRxiv2025

Tumor Treating Fields inhibit cell proliferation and promote immunogenic cell death in biliary tract cancer cells

Tumor Treating Fields (TTFields) are low-intensity, intermediate-frequency alternating electric fields that exert antimitotic effects on cancer cells. This study evaluated the in vitro efficacy of TTFields on biliary tract cancer (BTC) cell lines HCCC-9810 and RBE, investigating their sensitivity to TTFields across varying frequencies and electric field intensities. The results demonstrated that a frequency of 150 kHz induced the most pronounced cytotoxic effects, significantly impairing clonogenicity and migratory capacity while inducing abnormal mitotic processes. Furthermore, TTFields treatment triggered a marked upregulation of immunogenic cell death (ICD) biomarkers, including enhanced surface exposure of calreticulin (CRT) and increased extracellular release of high mobility group box 1 (HMGB1) and ATP. These findings indicate that TTFields represent a promising therapeutic approach for BTC, not only by suppressing tumor proliferation but also by enhancing ICD.

cancer biology↗

bioRxiv2025

The spinal premotor network driving scratching flexor and extensor alternation

Rhythmic motor behaviors are generated by neural networks termed central pattern generators (CPGs). Although locomotor CPGs have been extensively characterized, it remains unknown how the neuronal populations composing them interact to generate adaptive rhythms. We explored the non-linear cooperation dynamics among the three main populations of ipsilaterally projecting spinal CPG neurons - V1, V2a, V2b neurons - in scratch reflex rhythmogenesis. Ablation of all three neuronal subtypes reduced the oscillation frequency. Activation of excitatory V2a neurons enhanced the oscillation frequency, while activating inhibitory V1 neurons caused atonia. These findings required the development of a novel neuromechanical model that consists of flexor and extensor modules coupled via inhibition, in which rhythm in each module is generated by self-bursting excitatory populations and accelerated by intra-module inhibition. Inter-module inhibition coordinates the phases of flexor and extensor activity and slows the oscillations, while facilitation mechanisms in excitatory neurons explain the V2a activation-driven increase in frequency.

neuroscience↗

bioRxiv2024

Afadin Sorts Different Retinal Neuron Types into Accurate Cellular Layers

Neurons use cell-adhesion molecules (CAMs) to interact with other neurons and the extracellular environment: the combination of CAMs specifies migration patterns, neuronal morphologies, and synaptic connections across diverse neuron types. Yet little is known regarding the intracellular signaling cascade mediating the CAM recognitions at the cell surface across different neuron types. In this study, we investigated the neural developmental role of Afadin1-4, a cytosolic adapter protein that connects multiple CAM families to intracellular F-actin. We introduced the conditional Afadin mutant5 to an embryonic retinal Cre, Six3-Cre6-8. We reported that the mutants lead to the scrambled retinal neuron distribution, including Bipolar Cells (BCs), Amacrine Cells (ACs), and retinal ganglion cells (RGCs), across three cellular layers of the retina. This scrambled pattern was first reported here at neuron-type resolution. Importantly, the mutants do not display deficits for BCs, ACs, or RGCs in terms of neural fate specifications or survival. Additionally, the displayed RGC types still maintain synaptic partners with putative AC types, indicating that other molecular determinants instruct synaptic choices independent of Afadin. Lastly, there is a significant decline in visual function and mis-targeting of RGC axons to incorrect zones of the superior colliculus, one of the major retinorecipient areas. Collectively, our study uncovers a unique cellular role of Afadin in sorting retinal neuron types into proper cellular layers as the structural basis for orderly visual processing.

neuroscience↗

bioRxiv2024

An endogenous cluster of target-directed microRNA degradation sites induces decay of distinct microRNA families

While much is known about miRNA biogenesis and canonical miRNA targeting, relatively less is understood about miRNA decay. The major miRNA decay pathway in metazoans is mediated through target-directed miRNA degradation (TDMD), in which certain RNAs can "trigger" miRNA decay. All known triggers for TDMD base pair with the miRNA seed, and extensively base pair on the miRNA 3' end, a pattern that supposedly induces a TDMD-competent conformational change of Argonaute (Ago), allowing for miRNA turnover. Here, we utilized Ago1-CLASH to find that the Drosophila transcript Kah contains at least two triggers, a "trigger cluster", against miR-9b and the miR-279 family. One of these triggers contains minimal/non-canonical 3' end base pairing but is still sufficient to induce TDMD of the entire miR-279 family. We found that these clustered triggers likely lack cooperativity, the minimal 3' pairing is required for miR-279 family turnover, and probed the in-cell RNA structure of the Kah trigger cluster. Overall, this study expands the list of endogenous triggers and the unexpectedly complex regulatory network governing miRNA degradation.

molecular biology↗

bioRxiv2024

PTTG1-Mediated Pericyte Dysfunction Drives Diabetes-Induced Microvascular Dysfunction

BackgroundPericytes are crucial for the development, stabilization, and functional regulation of microvasculature, especially in the retina. In diabetic retinopathy (DR), early loss of pericytes is a key event that drives microvascular dysfunction. Despite their critical role, the mechanisms underlying the functional heterogeneity of pericytes in DR remain poorly understood, impeding the development of effective therapeutic strategies. MethodsWe employed single-cell RNA sequencing to construct a comprehensive single- cell atlas of non-diabetic and diabetic retinas. Using bioinformatic clustering and subcluster analysis, we identified a specific pericyte subcluster associated with diabetic microvascular complications. Differential gene expression analysis and immunofluorescence validation highlighted PTTG1 as a potential key regulator of pericyte dysfunction. To investigate its functional role, we emplyed CRISPR/Cas9 and adenoviral vectors to modulate PTTG1 expression in vitro and in vivo. Combined transcriptomic and metabolomic approaches were used to explore the mechanistic pathways through which PTTG1 influences pericyte biology and vascular function. ResultsWe identified a novel pericyte subcluster characterized by elevated expression of PTTG1, which was strongly correlated with diabetic microvascular dysfunction. Silencing PTTG1 using CRISPR/Cas9 and siRNA in vitro mitigated pericyte dysfunction under high- glucose conditions. Targeted knockdown of PTTG1 using viral vectors improved retinal vascular integrity and reduced neovascularization in diabetic mice. Transcriptomic and untargeted metabolomic analyses revealed that PTTG1 knockdown reprogrammed pericyte energy metabolism by modulating glycolysis pathway genes, reducing oxidative stress, and restoring pericyte function, ultimately alleviating microvascular dysfunction in DR. ConclusionsPTTG1 plays a critical role in regulating pericyte dysfunction and maintaining vascular homeostasis in diabetic retinopathy. By modulating key metabolic pathways and pericyte phenotypes, PTTG1 represents a promising therapeutic target for treating diabetic microvascular complications. These insights offer a novel molecular framework for developing targeted therapies aimed at restoring retinal vascular health in diabetic patients.

molecular biology↗

bioRxiv2024

Quantitative Resolving Cell Fate in the Early Embryogenesis of Caenorhabditis elegans

The nematode Caenorhabditis elegans exhibits an invariant cell lineage during its development where the gene-molecular network that regulates the development is crucial for the biological process. While there are many molecular cell atlases describing the phenomena and key molecules involved in cell transformation, the underlying mechanisms from a systems biology perspective have received less attention. Based on an endogenous molecular-cellular theory that relates the molecular mechanisms to biological phenotypes, we constructed a model of core endogenous network to describe the early stages of embryonic development of the nematode. Different cell types and intermediate cell states during development from zygotes to founder cells correspond to the steady states of the network as a nonlinear stochastic dynamical system. Connections between steady states form a topological landscape that encompasses known developmental lineage trajectories. By regulating the expression of agents in the network, we quantitatively simulated the effects of the Wnt and Notch signaling pathway on cell fate transitions and predicted the possible trajectories of transdifferentiation of the AB cell across the lineage. The success of the current study may help advance our understanding of the fundamental principles of developmental biology and cell fate determination, offering an effective tool for quantitative analysis of cellular processes.

developmental biology↗

bioRxiv2024

Discovery of novel 1,4-dicarbonylthiosemicarbazides as DNA gyrase inhibitors for the treatment of MRSA infection

Antibiotic resistance has become a serious threat to public health, thus novel antibiotics are urgently needed to combat drug-resistant bacteria including MRSA (methicillin-resistant S. aureus). The 1,4-dicarbonylthiosemicarbazide is an interesting chemotype that could exhibit antibacterial activity. However, the currently available compounds are not as potent as clinical antibiotics. Herein, we adopted the computer-aided drug design strategy, substructure search, to retrieve antibacterial 1,4-dicarbonylthiosemicarbazide derivatives, and identified compound B5 (Specs ID: AG-690/15432331) from the Specs chemical library that exhibited moderate activity (minimum inhibitory concentration (MIC): 6.25 {micro}g/mL) against S. aureus (ATCC 29213). Based on that compound, we further designed and synthesized 45 derivatives, and evaluated their antibacterial activity. Eight derivatives were more potent than or equivalent to vancomycin (MIC: 1.56 {micro}g/mL). We compared the three most potent ones for their cytotoxicity to HepG2 and HUVEC cells and selected compound 1b as our lead compound for comprehensive biological evaluation. As a result, compound 1b exhibited a bacteriostatic mode, and was active against a panel of gram-positive bacteria strains, metabolically stable, and effective to protect the mice from MRSA infection. More importantly, we applied 2D similarity calculation and reverse docking to predict potential targets of compound 1b. Through experimental validation and molecular dynamics simulation, we were able to confirm that compound 1b inhibited S. aureus DNA gyrase (IC50: 1.81 {micro}M) and DNA supercoiling, potentially by binding to the ATPase domain, where ASP81, GLU58 and GLN91 formed key hydrogen bonds. Taken together, we have discovered a new class of DNA gyrase inhibitors represented by compound 1b for the treatment of MRSA infection, through the design, synthesis, and biological evaluation of novel 1,4-dicarbonylthiosemicarbazides. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/611349v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@549dadorg.highwire.dtl.DTLVardef@13bff64org.highwire.dtl.DTLVardef@1fc2c00org.highwire.dtl.DTLVardef@acee76_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIAn interesting 1,4-dicarbonylthiosemicarbazide derivative B5 with moderate antibacterial activity for S. aureus was discovered by substructure search. C_LIO_LIBased on B5, 45 new 1,4-dicarbonylthiosemicarbazides were designed, synthesized and biologically evaluated, which led to the discovery of a promising lead compound 1b. C_LIO_LICompound 1b exhibited good antibacterial activity for a panel of gram-positive bacteria strains, and was effective to protect mice from MRSA infection. C_LIO_LIThe 1,4-dicarbonylthiosemicarbazides represented by compound 1b were discovered as a new class of DNA gyrase inhibitors, by target prediction and experimental validation. C_LI

pharmacology and toxicology↗

bioRxiv2024

Structural and functional insights into Cdc45 recruitment by Sld7-Sld3 for CMG complex formation

DNA replication requires recruitment of Cdc45 and GINS into the MCM double hexamer by initiation factors to form an active helicase, the Cdc45-MCM-GINS (CMG) complex, at the replication origins. The initiation factor Sld3 is a central regulator of Cdc45 and GINS recruitment, working with Sld7 together. However, the mechanism through which Sld3 regulates CMG complex formation remains unclear. Here, we present the structure of the Sld3 Cdc45-binding domain in complex with Cdc45 (Sld3CBD-Cdc45), showing detailed interactions and conformational changes required for binding to each other. The mutant analysis indicated that the binding between Sld3CBD and Cdc45 could be broken easily. We also revealed that Sld3CBD, GINS, and MCM bind to different sites on Cdc45 in the Sld3CBD-CMG model, indicating that after recruitment of Cdc45, Sld7-Sld3 could remain in Cdc45-MCM until CMG formation. The consistency between the particle size of Sld7-Sld3-Cdc45 and the distance between Sld3CBDs in the Cdc45-MCM dimer indicated the binding manner of the Cdc45-Sld3-[Sld7]2-Sld3-Cdc45 off/on MCM double hexamer. A DNA-binding assay of Sld3 and its complexes with single-stranded ARS1 fragments revealed a relationship between the dissociation of Sld7-Sld3 from CMG and the unwound single-stranded DNA. These findings help to further our understanding of the molecular basis of the regulation of CMG complex formation by Sld3.

molecular biology↗

bioRxiv2024

Evolution of the Spatial transcriptomic landscape during the progression of high-grade pancreatic intraductal papillary mucinous neoplasms to invasive cancer

Intraductal papillary mucinous neoplasms (IPMN) is one of the known precancerous lesions. Patients prognosis is aggravated as IPMN transforms into invasive Pancreatic Ductal Adenocarcinoma (PDAC). The molecular mechanisms underlying this progression lack effective experimental models and urgently need to be elaborated. We performed spatial transcriptomics (ST) on fresh tissue samples from the same patient including normal pancreas, high-grade IPMN, and invasive PDAC, and described the step-by-step development of transcriptional landscape including clone evolution and adjacent TME feature variation. Our findings identified the master transcript factors and critical signaling pathways promoting IPMN progression to invasive PDAC. Additionally, both IPMN and PDAC harbored the ELF3, MYC, and KLF4 amplification. The Spatial CNV profile demonstrated significant heterogeneity among PDAC in their spatial distribution compared to IPMN, with seven distinct subclones showing diverse functions, such as hypoxia, oxidative phosphorylation, and epithelial-mesenchymal Transition. We observed a marked shift in the immune landscape, with the depletion of CD4+ T-cells and dendritic cells and an increase in immune-suppressive M2 macrophages in invasive PDAC, indicating a transition to an immune-evasive microenvironment. Additionally, cancer-associated fibroblasts (CAFs), particularly myofibroblastic CAFs, were enriched adjacent to invasive PDAC, suggesting their active role in tumor progression. By leveraging spatial transcriptomic analysis, our study provides comprehensive insights into the intricate molecular landscape that underlies the progression of IPMNs to invasive PDAC. These findings not only enhance our understanding of this complex process but also offer valuable knowledge for early diagnosis and intervention. HighlightsO_LISpatial CNV analysis reveals clonal evolution and distinct subclones in PDAC. C_LIO_LIKey drivers like ELF3, MYC, and KLF4 are amplified in both IPMN and invasive PDAC. C_LIO_LIImmune landscape shifts from pro-inflammatory in IPMN to immune-evasive in PDAC. C_LIO_LIEnrichment of myofibroblastic CAFs suggests their role in tumor progression C_LI

cancer biology↗

bioRxiv2024

Bioadhesive Hydrogel-Coupled and Miniaturized Ultrasound Transducer System for Long-Term, Wearable Neuromodulation

Transcranial focused ultrasound has become a promising non-invasive approach for neuromodulation applications, particularly for neurodegenerative diseases and psychiatric illnesses. However, its implementation in wearable neuromodulation has thus far been limited due to the devices large size, which needs external supporting systems for the neuromodulation process. Furthermore, the need for ultrasound gel for acoustic coupling between the device and skin limits the viability for long-term use, due to its inherent susceptibility to dehydration and lack of adhesiveness to form a stable interface. Here, we report a wearable miniaturized ultrasound device with size comparable to standard EEG/ECG electrodes integrated with bioadhesive hydrogel to achieve efficient acoustic intensity upon ultrasound stimulation for long-term, wearable primary somatosensory cortical stimulation. Specifically, air-cavity Fresnel lens (ACFAL) based self-focusing acoustic transducer (SFAT) was fabricated using a lithography-free microfabrication process. Our transducer was able to achieve an acoustic intensity of up to 30.7 W/cm2 (1.92 MPa) in free-field with a focal depth of 10 mm. Bioadhesive hydrogel was developed to address the need for long-term stability of acoustic couplant for ultrasound application. The hydrogel demonstrated less than 13% attenuation in acoustic intensity and stable adhesion force of 0.961 N/cm over 35 days. Leveraging our bioadhesive hydrogel-integrated wearable ultrasound transducer, we were able to suppress somatosensory evoked potentials elicited by median nerve stimulation via functional electrical stimulation over 28 days, demonstrating the efficacy of our transducer for long-term, wearable neuromodulation in the brain.

bioengineering↗

bioRxiv2024

Distinguishing microgliosis and tau deposition in the mouse brain using paramagnetic and diamagnetic susceptibility source separation

Tauopathies, including Alzheimers disease (AD), are neurodegenerative disorders characterized by hyperphosphorylated tau protein aggregates in the brain. In addition to protein aggregates, microglia-mediated inflammation and iron dyshomeostasis are other pathological features observed in AD and other tauopathies. It is known that these alterations at the subcellular level occur much before the onset of macroscopic tissue atrophy or cognitive deficits. The ability to detect these microstructural changes with MRI therefore has substantive importance for improved characterization of disease pathogenesis. In this study, we demonstrate that quantitative susceptibility mapping (QSM) with paramagnetic and diamagnetic susceptibility source separation has the potential to distinguish neuropathological alterations in a transgenic mouse model of tauopathy. 3D multi-echo gradient echo data were acquired from fixed brains of PS19 (Tau) transgenic mice and age-matched wild-type (WT) mice (n = 5 each) at 11.7 T. The multi-echo data were fit to a 3-pool complex signal model to derive maps of paramagnetic component susceptibility (PCS) and diamagnetic component susceptibility (DCS). Group-averaged signal fraction and composite susceptibility maps showed significant region-specific differences between the WT and Tau mouse brains. Significant bilateral increases in PCS and |DCS| were observed in specific hippocampal and cortical sub-regions of the Tau mice relative to WT controls. Comparison with immunohistological staining for microglia (Iba1) and phosphorylated-tau (AT8) further indicated that the PCS and DCS differences corresponded to regional microgliosis and tau deposition in the PS19 mouse brains, respectively. The results demonstrate that quantitative susceptibility source separation may provide sensitive imaging markers to detect distinct pathological alterations in tauopathies.

neuroscience↗

bioRxiv2024

Senolytic therapy preserves blood-brain barrier integrity and promotes microglia homeostasis in a tauopathy model

Cellular senescence, characterized by expressing the cell cycle inhibitory proteins, is evident in driving age-related diseases. Senescent cells play a crucial role in the initiation and progression of tau-mediated pathology, suggesting that targeting cell senescence offers a therapeutic potential for treating tauopathy associated diseases. This study focuses on identifying non-invasive biomarkers and validating their responses to a well-characterized senolytic therapy combining dasatinib and quercetin (D+Q), in a widely used tauopathy mouse model, PS19. We employed human-translatable MRI measures, including water extraction with phase-contrast arterial spin tagging (WEPCAST) MRI, T2 relaxation under spin tagging (TRUST), longitudinally assessed brain physiology and high-resolution structural MRI evaluated the brain regional volumes in PS19 mice. Our data reveal increased BBB permeability, decreased oxygen extraction fraction, and brain atrophy in 9-month-old PS19 mice compared to their littermate controls. (D+Q) treatment effectively preserves BBB integrity, rescues cerebral oxygen hypometabolism, attenuates brain atrophy, and alleviates tau hyperphosphorylation in PS19 mice. Mechanistically, D+Q treatment induces a shift of microglia from a disease-associated to a homeostatic state, reducing a senescence-like microglial phenotype marked by increased p16/INK4a. D+Q-treated PS19 mice exhibit enhanced cue-associated cognitive performance in the tracing fear conditioning test compared to the vehicle-treated littermates, implying improved cognitive function by D+Q treatment. Our results pave the way for application of senolytic treatment as well as these noninvasive MRI biomarkers in clinical trials in tauopathy associated neurological disorders.

neuroscience↗

bioRxiv2024

Integrated Analyses of Multi-omic Data Derived from Paired Primary Lung Cancer and Brain Metastasis Reveals the Metabolic Vulnerability as a Novel Therapeutic Target

Lung cancer brain metastases (LC-BrMs) are frequently associated with dismal mortality rates in patients with lung cancer; however, standard of care therapies for LC-BrMs are still limited in their efficacy. A deep understanding of molecular mechanisms and tumor microenvironment of LC-BrMs will provide us with new insights into developing novel therapeutics for treating patients with LC-BrMs. Here, we performed integrated analyses of genomic, transcriptomic, proteomic and metabolomic data which were derived from a total number of 174 patients with paired and unpaired primary lung cancer and LC-BrM, spanning four published and two newly generated patient cohorts on both bulk and single cell levels. We uncovered that LC-BrMs exhibited significantly higher intra-tumor heterogeneity. We also observed that mutations in a subset of genes were almost always shared by both primary lung cancers and LC-BrM lesions, including TTN, TP53, MUC16, LRP1B, RYR2, and EGFR. In addition, the genome-wide landscape of somatic copy number alterations was similar between primary lung cancers and LC-BrM lesions. Nevertheless, several regions of focal amplification were significantly enriched in LC-BrMs, including 5p15.33 and 20q13.33. Intriguingly, integrated analyses of transcriptomic, proteomic and metabolomic data revealed mitochondrial-specific metabolism was activated but tumor immune microenvironment was suppressed in LC-BrMs. Subsequently, we validated our results by conducting real-time quantitative reverse transcription PCR experiments, immunohistochemistry and multiplexed immunofluorescence staining of patients paired tumor specimens. Patients with a higher expression of mitochondrial metabolism genes but a lower expression of immune genes in their LC-BrM lesions tended to have a worse survival outcome. Therapeutically, targeting oxidative phosphorylation with gamitrinib in patient-derived organoids specific to LC-BrMs induced apoptosis and inhibited cell proliferation. The combination of gamitrinib plus anti-PD-1 immunotherapy significantly improved survival of mice bearing LC-BrMs. In conclusion, our findings not only provide comprehensive and integrated perspectives of molecular underpinnings of LC-BrMs but also contribute to the development of a potential, rationale-based combinatorial therapeutic strategy with the goal of translating it into clinical trials for patients with LC-BrMs.

cancer biology↗

bioRxiv2023

Energy Landscape near Glioma Decipher the Role of Glioma Stem Cell within Glioma Hierarchy

Glioma stem cells (GSCs) have been recognized as key players in glioma recurrence and therapeutic resistance, presenting a promising target for novel treatments. However, the limited understanding of the role GSCs play in the glioma hierarchy has drawn controversy and hindered research translation into therapies. Despite significant advances in our understanding of gene regulatory networks, the dynamics of these networks and their implications for glioma remain elusive. This study employs a systemic theoretical perspective to integrate empirical knowledge into a core endogenous network model for glioma, thereby elucidating its energy landscape through network dynamics computation. The model identifies two stable states corresponding to astrocytoma and oligodendroglioma, connected by a transitional state associated with GSCs, indicating the instability of GSCs in vivo and providing negative proof of their role as the cellular origin for glioma. We also obtained various stable states further indicative of gliomas multicellular origins and uncovered a group of transition states that could potentially induce tumor heterogeneity and therapeutic resistance. This research proposes that the transitional states linking both glioma stable states are central to glioma heterogeneity and therapy resistance, suggesting a combination of apoptosis-inducing and differentiation-promoting therapies as a potential strategy. Our approach holds promise for advancing glioma therapy by providing a new lens through which to view the complex landscape of glioma biology.

systems biology↗

bioRxiv2023

CEP44 is required for maintaining centriole duplication and spindle integrity

In animal cells, the centrosome, consisting of two centrioles, duplicates only once per cell cycle for bipolar spindle formation. Defective centriole duplication results in abnormal spindle formation and chromosome missegregation, which is closely linked to tumor growth. However, the molecular mechanisms licensing only one centriole duplication cycle within a cell cycle are less well known. Here we found that CEP44 is negatively correlated with breast carcinoma. CEP44, jointly with CEP57 and CEP57L1, maintains centriole engagement in the interphase to ensure centriole duplication once per cell cycle. Depletion of CEP44 leads to centriole overduplication because of premature centriole disengagement, and multipolar spindle formation. Additionally, CEP44 is phosphorylated by Aurora A at the G2/M phase to facilitate spindle localization and maintain spindle integrity. Collectively, our results show the function of CEP44 in spindle formation by preventing centriole overduplication and maintaining spindle integrity, and CEP44 may serve as a potential marker for breast carcinoma prognosis.

cell biology↗