bioRxiv最新文献

{"title":"High-throughput drug screening for inhibition of influenza A virus infection based on human SIRT1 promoter and Genipin suppressing influenza A virus by activation of AMPK-SIRT1-PGC-1α signaling pathway","authors":"Jinghan Ye, Dekun Liu, Qianwen Wang, Jianping Dai","doi":"10.1101/2024.07.10.602919","DOIUrl":"https://doi.org/10.1101/2024.07.10.602919","url":null,"abstract":"The energy metabolism crisis is considered an important risk factor for severe influenza A virus (IAV) infection. During virus replication, the host cell’s “metabolic reprogramming” is beneficial for increasing the energy demand of the virus. SIRT1 plays a major role in altering metabolic reprogramming, and upregulation of SIRT1 expression can defend against viral infection. This study established a high-throughput drug screening method for human SIRT1 promoter. Nine natural medicines were selected from 134 traditional Chinese medicines. Among them, the activity of Gardenia jasminoides Ellis was relatively high. Further research has found that the plant extract and its active compound Genipin and its derivatives can significantly inhibit IAV replication, improve the survival rate of infected mice, and inhibit pneumonia. In addition, Genipin significantly increased the levels of energy metabolism core regulatory factors SIRT1, PPAR γ, PGC-1 α, and p-AMPK, inhibited IAV induced activation of MAPKs and NF-κB, and alleviated inflammatory response. The pharmacological antagonists of SIRT1 and PGC-1 α, as well as siRNA, significantly counteracted the effects of Genipin on IAV replication and inflammation. In summary, we found that Genipin and its derivatives could significantly inhibit IAV replication and inflammation, possibly by activating the AMPK-SIRT1-PGC-1α signaling pathway and altering metabolic reprogramming.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":"4 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141640971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut-specific H3R signaling orchestrates microglia-dependent resolution of peripheral inflammation","authors":"K. Dürholz, M. Linnerbauer, Eva Schmid, H. Danzer, L. Lößlein, L. Amend, Leona Ehnes, M. Frech, V. Azizov, F. Schälter, A. Gessner, S. Lucas, T. Lesker, R. V. Taudte, Jörg Hofmann, Felix Beyer, H. Bootz-Maoz, Yasmin Reich, Hadar Romano, D. Mauro, R. Beckervordersandforth, Wei Xiang, A. Haghikia, C. Akdis, Francesco Ciccia, T. Bäuerle, K. Sarter, Till Strowig, N. Yissachar, G. Schett, V. Rothhammer, M. Zaiss","doi":"10.1101/2024.07.11.603031","DOIUrl":"https://doi.org/10.1101/2024.07.11.603031","url":null,"abstract":"Chronic inflammatory diseases, like rheumatoid arthritis (RA) have been described to cause central nervous system (CNS) activation. Less is known about environmental factors that enable the CNS to suppress peripheral inflammation in RA. Here, we identified gut microbiota-derived histamine as such factor. We show that low levels of histamine activate the enteric nervous system, increase inhibitory neurotransmitter concentrations in the spinal cord and restore homeostatic microglia, thereby reducing inflammation in the joints. Selective histamine 3 receptor (H3R) signaling in the intestine is critical for this effect, as systemic and intrathecal application did not show effects. Microglia depletion or pharmacological silencing of local nerve fibers impaired oral H3R agonist-induced pro-resolving effects on arthritis. Moreover, therapeutic supplementation of the SCFA propionate identified one way to expand local intestinal histamine concentrations in mice and humans. Thus, we define a gut-CNS-joint axis pathway where microbiota-derived histamine initiates the resolution of arthritis via the CNS. Graphical Abstract Gut microbiota-derived histamine activates enteric neurons via H3R Local intestinal H3R activation induces shift to homeostatic microglia in the spinal cord CNS controlled decrease in endothelial leakiness resolves synovial inflammation","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":"5 11","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141641139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A new alignment-free method: Subsequence Correlation Coefficient Vector(SCCFV) for influenza A comparison using virus genomes","authors":"Lily He, Zhenglong Yu, Xinrui Wu, Yi Zhu","doi":"10.1101/2024.07.12.603253","DOIUrl":"https://doi.org/10.1101/2024.07.12.603253","url":null,"abstract":"Influenza viruses remain a formidable threat to global public health due to their high mutability and infectivity. Accurate prediction of influenza virus subtypes is crucial for clinical treatment and disease prevention. In recent years, machine learning methods have played an important role in studying influenza viruses. This study proposes a new alignment-free method based on the correlation of k-grams called Subsequence Correlation Coefficient Vector (SCCFV) to subtype hemagglutinin (HA) and neuraminidase (NA) of influenza virus. In the method, each influenza virus sequence is converted to four time series and the correlation coefficients of time series are utilized to extract the features of sequences. Then the supervised learning methods are used for the subtype classification of influenza viruses. We compare the effectiveness of the random forest, decision tree and support vector machine classifiers. Experimental results show that the random forest method achieves the best performance with an accuracy of 0.99979, an precision of 0.99996 and a recall of 0.99997. All prediction indicators of our method are significantly higher than traditional methods.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":"8 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141641615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Persistent activity during working memory maintenance predicts long-term memory formation in the human hippocampus","authors":"Jonathan Daume, Jan Kamiński, Y. Salimpour, W. S. Anderson, T. Valiante, A. Mamelak, Ueli Rutishauser","doi":"10.1101/2024.07.15.603630","DOIUrl":"https://doi.org/10.1101/2024.07.15.603630","url":null,"abstract":"Working Memory (WM) and Long-Term Memory (LTM) are often viewed as separate cognitive systems. Little is known about how these systems interact when forming memories. We recorded single neurons in the human medial temporal lobe while patients maintained novel items in WM and a subsequent recognition memory test for the same items. In the hippocampus but not the amygdala, the level of WM content-selective persist activity during WM maintenance was predictive of whether the item was later recognized with high confidence or forgotten. In contrast, visually evoked activity in the same cells was not predictive of LTM formation. During LTM retrieval, memory-selective neurons responded more strongly to familiar stimuli for which persistent activity was high while they were maintained in WM. Our study suggests that hippocampal persistent activity of the same cell supports both WM maintenance and LTM encoding, thereby revealing a common single-neuron component of these two memory systems.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":"63 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141643699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CELLNET technology: Spatially organized, functional 3D networks at single cell resolution","authors":"Arun Poudel, Puskal Kunwar, Ujjwal Aryal, Anna-Blessing Merife, P. Soman","doi":"10.1101/2024.07.12.603216","DOIUrl":"https://doi.org/10.1101/2024.07.12.603216","url":null,"abstract":"Cells possess the remarkable ability to generate tissue-specific 3D interconnected networks and respond to a wide range of stimuli. Understanding the link between the spatial arrangement of individual cells and their networks’ emergent properties is necessary for the discovery of both fundamental biology as well as applied therapeutics. However, current methods spanning from lithography to 3D photo-patterning to acoustofluidic devices are unable to generate interconnected and organized single cell 3D networks within native extracellular matrix (ECM). To address this challenge, we report a novel technology coined as CELLNET. This involves the generation of crosslinked collagen within multi-chambered microfluidic devices followed by femtosecond laser ablation of 3D microchannel networks and cell seeding. Using model cells, we show that cell migrate within ablated networks within hours, self-organize and form viable, interconnected, 3D networks in custom architectures such as square grid, concentric circle, parallel lines, and spiral patterns. Heterotypic CELLNETs can also be generated by seeding multiple cell types in side-chambers of the devices. The functionality of cell networks can be studied by monitoring the real-time calcium signaling response of individual cells and signal propagation within CELLNETs when subjected to flow stimulus alone or a sequential combination of flow and biochemical stimuli. Furthermore, user-defined disrupted CELLNETs can be generated by lethally injuring target cells within the 3D network and analyzing the changes in their signaling dynamics. As compared to the current self-assembly based methods that exhibit high variability and poor reproducibility, CELLNETs can generate organized 3D single-cell networks and their real-time signaling responses to a range of stimuli can be accurately captured using simple cell seeding and easy-to-handle microfluidic devices. CELLNET, a new technology agnostic of cell types, ECM formulations, 3D cell-connectivity designs, or location and timing of network disruptions, could pave the way to address a range of fundamental and applied bioscience applications. Teaser New technology to generate 3D single cell interconnected and disrupted networks within natural extracellular matrix in custom configurations.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141641047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MYC Binding Near Transcriptional End Sites Regulates Basal Gene Expression, Read-Through Transcription and Intragenic Contacts","authors":"Huabo Wang, Bingwei Ma, Taylor Stevens, Jessica Knapp, Jie Lu, E. Prochownik","doi":"10.1101/2024.07.11.603118","DOIUrl":"https://doi.org/10.1101/2024.07.11.603118","url":null,"abstract":"The MYC oncoprotein regulates numerous genes involved in cellular processes such as cell cycle and mitochondrial and ribosomal structure and function. This requires heterodimerization with its partner, MAX, and binding to specific promoter and enhancer elements. Here, we show that MYC and MAX also bind near transcriptional end sites (TESs) of over one-sixth of all annotated genes. These interactions are dose-dependent, evolutionarily conserved, stabilize the normally short-lived MYC protein and regulate expression both in concert with and independent of MYC’s binding elsewhere. MYC’s TES binding occurs in association with other transcription factors, alters the chromatin landscape, increases nuclease susceptibility and can alter transcriptional read-through, particularly in response to certain stresses. MYC-bound TESs can directly contact promoters and may fine-tune gene expression in response to both physiologic and pathologic stimuli. Collectively, these findings support a previously unrecognized role for MYC in regulating transcription and its read-through via direct intragenic contacts between TESs and promoters.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":"77 19","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141642964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Consistent and scalable monitoring of birds and habitats along a coffee production intensity gradient","authors":"Marius Somveille, Joe Grainger-Hull, Nicole Ferguson, Sarab S. Sethi, Fernando González-García, Valentine Chassagnon, Cansu Oktem, Mathias Disney, G. Bautista, John Vandermeer, Ivette Perfecto","doi":"10.1101/2024.07.12.603271","DOIUrl":"https://doi.org/10.1101/2024.07.12.603271","url":null,"abstract":"Land use change associated with agricultural intensification is a leading driver of biodiversity loss in the tropics. To evaluate the habitat-biodiversity relationship in production systems of tropical agricultural commodities, which is critical for certifying and examining the success of biodiversity-friendly agricultural practices, birds are commonly used as indicators. However, consistently and reliably monitoring how bird communities are affected by land use change throughout the annual cycle in a way that can be scalable is challenging using traditional survey methods. In this study, we examined whether the automated analysis of audio data collected by passive acoustic monitoring, together with the analysis of remote sensing data, can be used to efficiently monitor avian biodiversity along the gradient of habitat degradation associated with the intensification of coffee production. Coffee is an important crop produced in tropical forested regions, whose production is expanding and intensifying, and coffee production systems form a gradient of ecological complexity ranging from forest-like shaded polyculture to dense sun-exposed monoculture. We used LiDAR technology to survey the habitat, in combination with autonomous recording units and a vocalisation classification algorithm to assess bird community composition in a coffee landscape comprising a shade-grown coffee farm, a sun coffee farm, and a forest remnant, located in southern Mexico. We found that combining LiDAR with the automated analysis of continuously collected bioacoustics data can capture the expected functional signatures of avian communities as a function of habitat quality in the coffee landscape. Thus, we show that this approach can be a robust way to monitor how biodiversity responds to land use intensification in the tropics. A major advantage of this approach is that it has the potential to be deployed cost-effectively at large scales to help design and certify biodiversity-friendly productive landscapes.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":"8 23","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141640428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of clinically relevant radionuclides on the activation of a type I interferon response by radiopharmaceuticals in syngeneic murine tumor models","authors":"Caroline P. Kerr, Julia Sheehan-Klenk, J. Grudzinski, D. Adam, Thanh Phuong T. Nguyen, Carolina A. Ferreira, A. Bates, Won Jong Jin, O-Seo Kwon, Aeli P. Olson, Wilson Lin, Meredith Hyun, J. Jagodinsky, Maria Powers, R. Sriramaneni, Paul A. Clark, Amanda G. Shea, Hansel Comas Rojas, Cynthia Choi, Christopher F. Massey, L. Zangl, A. Pinchuk, E. Aluicio‐Sarduy, KyungMann Kim, J. Engle, Reinier Hernandez, Bryan P Bednarz, J. Weichert, Zachary S Morris","doi":"10.1101/2024.07.10.602990","DOIUrl":"https://doi.org/10.1101/2024.07.10.602990","url":null,"abstract":"Radiopharmaceutical therapies (RPT) activate a type I interferon (IFN1) response in tumor cells. We hypothesized that the timing and amplitude of this response varies by isotope. We compared equal doses delivered by 90Y, 177Lu, and 225Ac in vitro as unbound radionuclides and in vivo when chelated to NM600, a tumor-selective alkylphosphocholine. Response in murine MOC2 head and neck carcinoma and B78 melanoma was evaluated by qPCR and flow cytometry. Therapeutic response to 225Ac-NM600+anti-CTLA4+anti-PD-L1 immune checkpoint inhibition (ICI) was evaluated in wild-type and stimulator of interferon genes knockout (STING KO) B78. The timing and magnitude of IFN1 response correlated with radionuclide half-life and linear energy transfer. CD8+/Treg ratios increased in tumors 7 days after 90Y- and 177Lu-NM600 and day 21 after 225Ac-NM600. 225Ac-NM600+ICI improved survival in mice with WT but not with STING KO tumors, relative to monotherapies. Immunomodulatory effects of RPT vary with radioisotope and promote STING-dependent enhanced response to ICIs in murine models. Teaser This study describes the time course and nature of tumor immunomodulation by radiopharmaceuticals with differing physical properties.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":"4 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141641561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Actin dynamics sustains spatial gradients of membrane tension in adherent cells","authors":"J. M. García-Arcos, Amine Mehidi, Julissa Sánchez Velázquez, Pau Guillamat, C. Tomba, Laura Houzet, L. Capolupo, Giovanni D’Angelo, Adai Colom, Elizabeth Hinde, Charlotte Aumeier, Aurélien Roux","doi":"10.1101/2024.07.15.603517","DOIUrl":"https://doi.org/10.1101/2024.07.15.603517","url":null,"abstract":"Tension propagates extremely fast in lipid bilayers, precluding the formation of tension gradients. Nevertheless, plasma membrane tension gradients have been evidenced in migrating cells and along axons. Here, using a fluorescent membrane tension probe, we show that membrane tension gradients exist in all adherent cells, whether they migrate or not. Non-adhering cells do not display tension gradients. We further show that branched actin increases tension, while membrane-to-cortex attachments facilitate its propagation. Tension is the lowest at the edge of adhesion sites and highest at protrusions, setting the boundaries of the tension gradients. By providing a quantitative and mechanistic basis behind the organization of membrane tension gradients, our work explains how they are actively sustained in adherent cells.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":"60 18","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141643404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping the genetic landscape establishing a tumor immune microenvironment favorable for anti-PD-1 response in mice and humans","authors":"Daniel A. Skelly, John P Graham, Mingshan Cheng, Mayuko Furuta, Andrew Walter, Thomas A. Stoklasek, Hongyuan Yang, Timothy M. Stearns, Olivier Poirion, Ji-Gang Zhang, J. Grassmann, D. Luo, William F. Flynn, Elise T. Courtois, Chih-Hao Chang, D. Serreze, F. Menghi, L. Reinholdt, Edison T. Liu","doi":"10.1101/2024.07.11.603136","DOIUrl":"https://doi.org/10.1101/2024.07.11.603136","url":null,"abstract":"Identifying host genetic factors modulating immune checkpoint inhibitor (ICI) efficacy has been experimentally challenging because of variations in both host and tumor genomes, differences in the microbiome, and patient life exposures. Utilizing the Collaborative Cross (CC) multi-parent mouse genetic resource population, we developed an approach that fixes the tumor genomic configuration while varying host genetics. With this approach, we discovered that response to anti-PD-1 (aPD1) immunotherapy was significantly heritable in four distinct murine tumor models (H2 between 0.18-0.40). For the MC38 colorectal carcinoma system (H2 = 0.40), we mapped four significant ICI response quantitative trait loci (QTL) localized to mouse chromosomes (mChr) 5, 9, 15 and 17, and identified significant epistatic interactions between specific QTL pairs. Differentially expressed genes within these QTL were highly enriched for immune genes and pathways mediating allograft rejection and graft vs host disease. Using a cross species analytical approach, we found a core network of 48 genes within the four QTLs that showed significant prognostic value for overall survival in aPD1 treated human cohorts that outperformed all other existing validated immunotherapy biomarkers, especially in human tumors of the previously defined immune subtype 4. Functional blockade of two top candidate immune targets within the 48 gene network, GM-CSF and high affinity IL-2/IL-15 signaling, completely abrogated the MC38 tumor transcriptional response to aPD1 therapy in vivo. Thus, we have established a powerful cross species in vivo platform capable of uncovering host genetic factors that establish the tumor immune microenvironment configuration propitious for ICI response.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":"13 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141642025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}