Biology subjects

Ren, J.

Publications and source records attributed to Ren, J..

At least 73 records · Page 4Linked to original sources

bioRxiv2024

Thyroid hormones maintain parvalbumin neuron functions in mouse neocortex

Parvalbumin-expressing GABAergic interneurons play a key role in maintaining the excitation-inhibition balance in the mammalian neocortex. While postnatal maturation of parvalbumin neurons is highly sensitive to thyroid hormone deficiency, the role of these hormones in mature parvalbumin neurons remains poorly understood. Here, we addressed the possibility that thyroid hormones are also required to maintain the function of mature parvalbumin neurons in the mouse neocortex. To this end, Cre/loxP recombination system was used to express a dominant-negative mutated receptor of thyroid hormones to selectively eliminate thyroid hormone signaling in parvalbumin neurons after the onset of parvalbumin expression. We analyzed the neocortical phenotype of these mice by combining genomics, histology, electrophysiology, sleep recordings and behavioral analysis. In the mutant mice, gene expression analysis revealed a decreased expression of key perineuronal net components. parvalbumin neuron excitability was decreased and mice displayed behavioral hyperactivity and increased susceptibility to epileptic seizures. Additionally, sleep analysis revealed that mutant mice spent more time awake, and had a delayed transition to sleep. Electrophysiological recordings further demonstrated altered gamma oscillations in the somatosensory cortex. The findings of this study underscore that thyroid hormones are essential not only for the differentiation of parvalbumin interneurons, but also for the maintenance of their inhibitory function after the onset of parvalbumin expression. As a consequence, alterations in thyroid hormone signaling, during development or in adulthood, may contribute to the occurrence of neurological and psychiatric disorders involving altered cortical oscillations.

neuroscience↗

bioRxiv2024

Leveraging Crosslinker Diffusion to Template Stiffness Gradients in Alginate Hydrogels

Mechanobiology drives many important cell biological behaviors such as stem cell differentiation, cancer drug resistance and cell migration up stiffness gradients, a process called durotaxis. The development of 3D hydrogel systems with tunable 2D mechanical gradient patterns affords the ability to study these mechanosensitive cell behaviors to understand cancer invasion or enhance wound healing through directed migration. In this paper, we developed an approach to spatially imprint within alginate hydrogels, gradients in mechanical properties that can be used to probe mechanobiology. Stencils were easily designed and fabricated using a common craft cutter to control the presentation of a calcium crosslinking solution to alginate gels. Different stencil shapes result in different gradients in opacity that can be imprinted into both thick and thin alginate gels of arbitrary 2D shape. The steepness of the opacity gradient as well as the maximum opacity can be controlled based on reproducible crosslinking kinetics regulated through calcium concentration and gradient developing time. Calcium crosslinking results in both opacity changes as well as increases in elastic modulus in the bulk hydrogel. Opacity correlates with elastic modulus, allowing it to be used as a proxy for local elastic modulus. Functionalized alginate gels with collagen and imprinting stiffness gradients within them resulted in cell invasion that was spatially dependent, where stiffer regions facilitated deeper invasion of breast cancer cells. Consequently, this stenciling approach represents a facile way to control stiffness gradients in alginate gels in order to study mechanosensitive cellular behavior. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=45 SRC="FIGDIR/small/599742v2_ufig1.gif" ALT="Figure 1"> View larger version (14K): org.highwire.dtl.DTLVardef@1182404org.highwire.dtl.DTLVardef@1e4bfb1org.highwire.dtl.DTLVardef@e52778org.highwire.dtl.DTLVardef@8237bd_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2024

Human transcription factor combinations mapped by genome-wide footprinting with deaminase

An individuals somatic cells have the same genome but exhibit cell-type-specific transcriptome regulated by a combination of transcription factors (TFs) for each gene. Mapping of TF sites on the human genome is critically important for understanding functional genomics. Here we report a novel technique to measure human TFs binding sites genome-wide with single-base resolution by footprinting with deaminase (FOODIE). Single-molecule sequencing reads from thousands of cells after in situ deamination yielded site-specific TF binding fractions and the cooperativity among adjacent TFs. In a human lymphoblastoid cell line, we found that genes in a correlated gene module (CGM) share TF(s) in their cis-regulatory elements to participate a particular biological function. Finally, single-cell resolved experiments (scFOODIE) allow cell-type-specific TF footprinting in heterogeneous brain tissues.

genomics↗

bioRxiv2024

Signal Antagonists Suppress Pseudomonas syringae Pathogenicity

The bacterial plant pathogen Pseudomonas syringae causes significant damage to economically important crops worldwide. These bacteria coordinate their behavior and virulence through specific signaling compounds, such as the diazeniumdiolate leudiazen. Conventional antibacterial treatments enable the development of resistant strains. A more attractive treatment strategy would involve antagonists that suppress the expression of virulence factors without killing the pathogen, potentially reducing the risk of resistance development. Herein, we present the design and synthesis of analogs of leudiazen, which positively regulates the production of mangotoxin in P. syringae pv. syringae (Pss). Several compounds display inhibitory activity towards mangotoxin production, and a lead compound abolishes necrosis in infected tomato leaves, without significantly affecting bacterial growth. Thus, this study represents a promising advance towards developing effective and sustainable methods for bacterial disease control.

microbiology↗

bioRxiv2024

Engineered bacteria that self-assemble ''bioglass'' polysilicate coatings display enhanced light focusing

Photonic devices are cutting-edge optical materials that produce narrow, intense beams of light, but their synthesis typically requires toxic, complex methodology. Here we employ a synthetic biology approach to produce environmentally-friendly, living microlenses with tunable structural properties. We engineered Escherichia coli bacteria to display the silica biomineralization enzyme silicatein from aquatic sea sponges. Our silicatein-expressing bacteria can self-assemble a shell of polysilicate "bioglass" around themselves. Remarkably, the polysilicate-encapsulated bacteria can focus light into intense nanojets that are nearly an order of magnitude brighter than unmodified bacteria. Polysilicate-encapsulated bacteria are metabolically active for up to four months, potentially allowing them to sense and respond to stimuli over time. Our data demonstrate that engineered bacterial particles have the potential to revolutionize the development of multiple optical and photonic technologies. Significance StatementIn this work, we apply the principles of synthetic biology to create living optical devices. Utilizing the ability of sea sponges to polymerize bioglass from silica precursors in the ocean water using only a single enzyme, silicatein, we have fused this same enzyme to the surface of Escherichia coli bacterial cells. The modified bacteria can polymerize a layer of bioglass at their surface. This bioglass shell allows the bacteria to act as engineered optical devices that are able to scatter high intensity, focused light while also surviving for several months, opening the door to a wide range of sense-and-respond applications. ClassificationBiological Sciences, Applied Biological Sciences

synthetic biology↗

bioRxiv2024

Inducible biosynthesis of bacterial cellulose in recombinant Enterobacter sp. FY-07

Bacterial cellulose (BC) is an extracellular polysaccharide with myriad unique properties, such as high purity, water-holding capacity and biocompatibility, making it attractive in materials science. However, genetic engineering techniques for BC-producing microorganisms are rare. Herein, the electroporation-based gene transformation and the {lambda} Red-mediated gene knockout method with a nearly 100% recombination efficiency were established in the fast-growing and BC hyperproducer Enterobacter sp. FY-07. This genetic manipulation toolkit was validated by inactivating the protein subunit BcsA in the cellulose synthase complex. Subsequently, the inducible BC-producing strains from glycerol were constructed through inducible expression of the key gene fbp in the gluconeogenesis pathway, which recovered more than 80% of the BC production. Finally, the BC properties analysis results indicated that the induced-synthesized BC pellicles were looser, more porous and reduced crystallinity, which could further broaden the application prospects of BC. To our best knowledge, this is the first attempt to construct the completely inducible BC-producing strains. Our work paves the way for increasing BC productivity by metabolic engineering and broadens the available fabrication methods for BC-based advanced functional materials.

synthetic biology↗

bioRxiv2024

CAMSAP3 Forms Dimers via its lapha-helix Domain that Directly Stabilize Non-centrosomal Microtubule Minus Ends

Microtubules are vital components of the cytoskeleton. Their plus ends are dynamic and respond to changes in cell morphology, while the minus ends are stable and serve a crucial role in microtubule seeding and maintaining spatial organization. In mammalian cells, the calmodulin-regulated spectrin-associated proteins (CAMSAPs), play a key role in directly regulating the dynamics of non-centrosomal microtubules minus ends. However, the molecular mechanisms are not yet fully understood. Our study reveals that CAMSAP3 forms dimers through its C-terminal -helix; this dimerization not only enhances the microtubule-binding affinity of the CKK domain but also enables the CKK domain to regulate the dynamics of microtubules. Furthermore, CAMSAP3 also specializes in decorating at the minus end of microtubules through the combined action of the microtubule-binding domain (MBD) and the C-terminal -helix, thereby achieving dynamic regulation of the minus ends of microtubules. These findings are crucial for advancing our understanding and treatment of diseases associated with non-centrosomal microtubules. SignificanceOur study reveals the molecular mechanism of how CAMSAP3, a key regulator of non-centrosomal microtubule dynamics, directly regulates the dynamics of non-centrosomal microtubule minus ends through CKK domain. CAMSAP3 forms dimers through its C-terminal -helix, which enhances the CKK domain of CAMSAP3 binding to microtubule minus ends and confers stability of them. This finding is not limited to CAMSAP3, but can also be applied to the understanding of the regulation of non-centrosomal microtubule minus end stability by CAMSAP family proteins. Our findings deepen our comprehension of cellular structure and function, offering insights into the role of microtubules in cellular integrity and disease. This study fills a significant knowledge gap and lays the foundation for future research into the complex balance of microtubule dynamics required for cellular health and disease prevention.

cell biology↗

bioRxiv2024

Methyltransferase DNMT3B promotes colorectal cancer cell proliferation by inhibiting PLCG2

BackgroundAberrant DNA methylation patterns in the promoter region of PLCG2 have been associated with dysregulated signaling pathways and cellular functions. Its role in colorectal cancer cells is still unknown. MethodsqRT-PCR was used to examine DNMT3B expression in colorectal cancer. Western blot and immunohistochemistry were used to analyze DNMT3B and PLCG2 protein levels in colorectal tissues and cell lines. The cell counting kit-8 and colony experiments were used to identify the proliferation of colorectal cancer cells. Methylation-specific PCR (MSP) and bisulfite-sequencing PCR (BSP) was used to measure DNA methylation levels. ResultsDNMT3B is overexpressed in colorectal cell in TCGA datasets and Kaplan-Meier plots. DNMT3B is significantly overexpressed in tumor tissues compared to adjacent non-tumor tissues. Western blotting results demonstrated high expression of DNMT3B in tumor tissues. Compared to normal colonic epithelial cells, colorectal cancer cell lines exhibited elevated levels of PLCG2 methylation. oePLCG2 effectively prevented the in vivo xenograft tumor growth of colorectal cancer. ConclusionsPLCG2 is identified as a key downstream regulatory protein of DNMT3B in colorectal cancer. DNMT3B Inhibits PLCG2 transcription through methylation of the PLCG2 promoter region. DNMT3B controls colorectal cancer cell proliferation through the PLCG2, which is useful for creating therapeutic approaches that target PLCG2 expression for the treatment of colorectal cancer.

cancer biology↗

bioRxiv2024

Functional Biosynthetic Stereodivergence in a Gene Cluster via a Dihydrosydnone N-oxide

Chirality features a critical role in the biochemistry of life and often only one enantiomeric series is observed (homochirality). Only few natural products have been obtained as racemates, e.g. the quorum-sensing signal valdiazen produced by Burkholderia cenocepacia H111. In this study, we investigated its biosynthetic gene cluster and discovered that both the enantiomerically pure (R)-fragin and the racemic valdiazen are obtained from the same pathway. This stereodivergence is based on the unusual heterocycle dihydrosydnone N-oxide intermediate, as evident from gene knockout, stable isotope feeding experiments, and mass spectrometry experiments. Both non-enzymatic racemisation via keto-enol tautomerisation and enzyme-mediated dynamic kinetic resolution were found to be crucial to this stereodivergent pathway. This novel mechanism underpins the production of configurationally and biologically distinct metabolites from a single gene cluster. Our findings highlight the intricate design of an intertwined biosynthesis pathway, providing a deeper understanding of microbial secondary metabolism related to microbial communication. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/591611v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@11b63corg.highwire.dtl.DTLVardef@d339e6org.highwire.dtl.DTLVardef@17e34b1org.highwire.dtl.DTLVardef@b58692_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2024

Matrix Vesicles from Osteoblasts Promote Atherosclerotic Calcification

BackgroundsVascular calcification often occurs with osteoporosis, a contradictory association known as "the calcification paradox". Osteoblast-derived matrix vesicles (Ost-MVs) have been implicated in bone mineralization, and also have a potential role in ectopic vascular calcification. Herein, we aim to investigate the contributions that Ost-MVs make to the bone-vascular calcification paradox and the underlying mechanisms. Methods and ResultsHyperlipidemia-induced atherosclerotic calcification in mice was accompanied with bone mineral loss, as evidenced by reduced deposition of Ost-MVs in the bone matrix and increased release of Ost-MVs into the circulation. Intravenous injection of fluorescent DiI-labeled Ost-MVs revealed a marked fluorescence accumulation in the aorta of atherogenic mice, whereas no fluorescence signals were observed in normal controls. Using proteomics to analyze proteins in non-matrix bound Ost-MVs and mineralized SMC-derived MVs (SMC-MVs), we found Lamp1 was specifically expressed in SMC-MVs, and Nid2 was exclusively expressed in Ost-MVs. We further demonstrated that both Lamp1 and Nid2 were co-localized with Collagen I within calcific plaques, indicating the involvement of both Ost-MVs and SMC-MVs in atherosclerotic calcification. Mechanistically, LPS-induced vascular injury facilitated the transendothelial transport of Ost-MVs. The recruitment of circulating Ost-MVs was regulated by remodeled Collagen I during calcification progression. Furthermore, the phenotypic transition of SMCs determined the endocytosis of Ost-MVs. Finally, we demonstrated that either recruited Ost-MVs or resident SMC-MVs accelerated atherosclerotic calcification, depending on the Ras-Raf-ERK signaling. ConclusionAtherosclerotic calcification-induced Ost-MVs are released into circulation, facilitating the transport from bone to plaque lesions and exacerbating artery calcification progression. The mechanisms of Ost-MVs recruitment include vascular injury allowing transendothelial transport of Ost-MVs, collagen I remodeling promoting Ost-MVs aggregation, and SMC phenotypic switch to facilitate Ost-MVs uptake. Our results further revealed that both recruited Ost-MVs and calcifying SMC-MVs aggravate calcification through the Ras-Raf-ERK pathway.

cell biology↗

bioRxiv2024

Structural plasticity of 2A proteins in the Parechovirus family

Parechoviruses, including Parechovirus A that infects humans as well as Parechovirus B (formerly Ljungan virus) and Parechovirus C (formerly Sebokele virus) that infect rodents, belong to a group of picornaviruses whose 2A proteins, instead of being proteases, contain a conserved H-box and NC-motif and are homologous to a small cellular lipid-modifying enzyme (PLAAT3) that acts as a host factor, enabling the picornavirus life cycle. Despite the common evolutionary origin, 2AH/NC proteins and PLAAT3 have no conserved function, as the active site of the viral proteins cannot support catalysis. Here, we set out to find if all Parechovirus species share the structural rearrangement that destroys the active site configuration of the cellular enzyme. This has revealed a remarkable structural plasticity of these 2AH/NC proteins that arises not only from sequence differences between species, but also from differences in the length of the recombinantly expressed proteins, resulting in large structural rearrangements. These include rerouting of a large internal loop and repositioning of the C-terminal helix with respect to the central {beta}-sheet, and these in turn influence the oligomeric state of the protein. We discuss how this structural plasticity could correlate with the function of these proteins in the viral life cycle and how this could recapitulate the possible evolution of this protein from host factor to viral 2AH/NC protein, with new independent functions in RNA replication.

biochemistry↗

bioRxiv2024

MGPfactXMBD: A Model-Based Factorization Method for scRNA Data Unveils Bifurcating Transcriptional Modules Underlying Cell Fate Determination

Manifold-learning is particularly useful to resolve the complex cellular state space from single-cell RNA sequences. While current manifold-learning methods provide insights into cell fate by inferring graph-based trajectory at cell level, challenges remain to retrieve interpretable biology underlying the diverse cellular states. Here, we described MGPfactXMBD, a model-based manifold-learning framework and capable to factorize complex development trajectories into independent bifurcation processes of gene sets, and thus enables trajectory inference based on relevant features. MGPfactXMBD offers more nuanced understanding of the biological processes underlying cellular trajectories with potential determinants. When bench-tested across 239 datasets, MGPfactXMBD showed advantages in major quantity-control metrics, such as branch division accuracy and trajectory topology, outperforming most established methods. In real datasets, MGPfactXMBD recovered the critical pathways and cell types in microglia development with experimentally valid regulons and markers. Furthermore, MGPfactXMBD discovered evolutionary trajectories of tumor-associated CD8+ T cells and yielded new subtypes of CD8+ T cells with gene expression signatures significantly predictive of the responses to immune checkpoint inhibitor in independent cohorts. In summary, MGPfactXMBD offers a manifold-learning framework in scRNA-seq data which enables feature selection for specific biological processes and contributing to advance our understanding of biological determination of cell fate.

bioinformatics↗

bioRxiv2024

FTO-mediated m6A demethylation of ULK1 mRNA promotes autophagy and activation of hepatic stellate cells in liver fibrosis

The activation of hepatic stellate cells (HSCs) is the central link in the occurrence and development of liver fibrosis. Our previous studies showed that autophagy promotes HSCs activation and ultimately accelerates liver fibrosis. Unc-51-like autophagy activating kinase 1 (ULK1) is an autophagic initiator in mammals and N6-methyladenosine (m6A) modification is closely related to autophagy. In this study, we find that m6A demethylase fat mass and obesity-associated protein (FTO) is upregulated during HSCs activation and bile duct ligation (BDL)-induced hepatic fibrosis, which is the m6A methylase with the most significant difference in expression. Importantly, we identify that FTO overexpression aggravates HSCs activation and hepatic fibrosis via autophagy. Mechanistically, compared with other autophagy-related genes, ULK1 is the target of FTO due to FTO mainly mediates the m6A demethylation of ULK1 and upregulates its expression, thereby enhancing autophagy and activation of HSCs. Noteworthy, m6A reader YTH domain-containing protein 2 (YTHDC2) decreases ULK1 mRNA level via recognizing the m6A binding site and ultimately inhibits autophagy and activation of HSCs. Taken together, our findings highlight m6A-dependent ULK1 as an essential regulator of HSCs autophagy and reveal ULK1 as a novel potential therapeutic target for hepatic fibrosis treatment. Graphical Abstractm6A demethylases FTO promoted autophagy via recognizing the ULK1 m6A binding site, thus triggering HSCs activation, and eventually leading to liver fibrosis. In this process, YTHDC2 participated in the translation of ULK1. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/584975v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@4fdd01org.highwire.dtl.DTLVardef@136791forg.highwire.dtl.DTLVardef@149f448org.highwire.dtl.DTLVardef@44ca9c_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2024

DeepPrep: An accelerated, scalable, and robust pipeline for neuroimaging preprocessing empowered by deep learning

Neuroimaging has entered the era of big data. However, the advancement of preprocessing pipelines falls behind the rapid expansion of data volume, causing significant computational challenges. Here, we present DeepPrep, a pipeline empowered by deep learning and workflow manager. Evaluated on over 55,000 scans, DeepPrep demonstrates a 11-fold acceleration, exceptional scalability, and robustness compared to the current state-of-the-art pipeline, providing a promising solution to meet the scalability requirements of neuroimaging.

neuroscience↗

bioRxiv2024

Individualized functional connectivity markers associated with motor and mood symptoms of Parkinson's disease

Parkinsons disease (PD) is a complex neurological disorder characterized by many motor and non-motor symptoms. While most studies focus on the motor symptoms of the disease, it is important to identify markers that underlie different facets of the disease. In this case-control study, we sought to discover reliable, individualized functional connectivity markers associated with both motor and mood symptoms of PD. Using functional MRI, we extensively sampled 166 patients with PD (64 women, 102 men; mean age=61.8 years, SD=7.81) and 51 healthy control participants (32 women, 19 men; mean age=55.68 years, SD=7.62). We found that a model consisting of 44 functional connections predicted both motor (UPDRS-III: Pearson r=0.21, FDR-adjusted p=0.006) and mood symptoms (HAMD: Pearson r=0.23, FDR-adjusted p=0.006; HAMA: Pearson r=0.21, FDR-adjusted p=0.006). Two sets of connections contributed differentially to these predictions. Between-network connections, mainly connecting the sensorimotor and visual large-scale functional networks, substantially contributed to the prediction of motor measures, while within-network connections in the insula and sensorimotor network contributed more so to mood prediction. The middle to posterior insula region played a particularly important role in predicting depression and anxiety scores. We successfully replicated and generalized our findings in two independent PD datasets. Taken together, our findings indicate that sensorimotor and visual network markers are indicative of PD brain pathology, and that distinct subsets of markers are associated with motor and mood symptoms of PD.

neuroscience↗

bioRxiv2024

Individual connectivity-based parcellations reflect functional properties of human auditory cortex

Neuroimaging studies of the functional organization of human auditory cortex have focused on group-level analyses to identify tendencies that represent the typical brain. Here, we mapped auditory areas of the human superior temporal cortex (STC) in 30 participants by combining functional network analysis and 1-mm isotropic resolution 7T functional magnetic resonance imaging (fMRI). Two resting-state fMRI sessions, and one or two auditory and audiovisual speech localizer sessions, were collected on 3-4 separate days. We generated a set of functional network-based parcellations from these data. Solutions with 4, 6, and 11 networks were selected for closer examination based on local maxima of Dice and Silhouette values. The resulting parcellation of auditory cortices showed high intraindividual reproducibility both between resting state sessions (Dice coefficient: 69-78%) and between resting state and task sessions (Dice coefficient: 62-73%). This demonstrates that auditory areas in STC can be reliably segmented into functional subareas. The interindividual variability was significantly larger than intraindividual variability (Dice coefficient: 57%-68%, p<0.001), indicating that the parcellations also captured meaningful interindividual variability. The individual-specific parcellations yielded the highest alignment with task response topographies, suggesting that individual variability in parcellations reflects individual variability in auditory function. Connectional homogeneity within networks was also highest for the individual-specific parcellations. Furthermore, the similarity in the functional parcellations was not explainable by the similarity of macroanatomical properties of auditory cortex. Our findings suggest that individual-level parcellations capture meaningful idiosyncrasies in auditory cortex organization.

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

The somato-cognitive action network links diverse neuromodulatory targets for Parkinson's disease

The newly-recognized somato-cognitive action network (SCAN) is posited to be important in movement coordination. Functional disruptions in Parkinsons disease (PD) correspond with complex, non-effector-specific motor symptoms, indicating that SCAN dysfunction may underlie these symptoms. Along the same lines, the SCAN may link multiple neuromodulatory targets used for PD treatment. To investigate the role of the SCAN in PD, we leveraged resting-state precision functional mapping, analyzing data from 673 individuals across 6 independent datasets and 5 types of neuromodulation. Our findings revealed functional abnormalities within the SCAN in PD patients and the selective involvement of the SCAN in diverse neuromodulatory targets. Moreover, our data suggests causal links between SCAN connectivity changes and motor symptom alleviation following both invasive and non-invasive neuromodulation. Collectively, these findings underscore the critical role of the SCAN in the pathophysiology of PD and its brain stimulation treatments, and suggest the SCAN as a promising candidate target for neuromodulation.

neuroscience↗