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From birth to bite: the evolutionary ecology of India's medically most important snake venoms. 从出生到咬伤:印度医学上最重要蛇毒的进化生态学。
IF 4.4 1区 生物学
BMC Biology Pub Date : 2024-07-29 DOI: 10.1186/s12915-024-01960-8
R R Senji Laxme, Suyog Khochare, Siddharth Bhatia, Gerard Martin, Kartik Sunagar
{"title":"From birth to bite: the evolutionary ecology of India's medically most important snake venoms.","authors":"R R Senji Laxme, Suyog Khochare, Siddharth Bhatia, Gerard Martin, Kartik Sunagar","doi":"10.1186/s12915-024-01960-8","DOIUrl":"10.1186/s12915-024-01960-8","url":null,"abstract":"<p><strong>Background: </strong>Snake venoms can exhibit remarkable inter- and intraspecific variation. While diverse ecological and environmental factors are theorised to explain this variation, only a handful of studies have attempted to unravel their precise roles. This knowledge gap not only impedes our understanding of venom evolution but may also have dire consequences on snakebite treatment. To address this shortcoming, we investigated the evolutionary ecology of venoms of Russell's viper (Daboia russelii) and spectacled cobra (Naja naja), India's two clinically most important snakes responsible for an alarming number of human deaths and disabilities.</p><p><strong>Methodology: </strong>Several individuals (n = 226) of D. russelii and N. naja belonging to multiple clutches (n = 9) and their mothers were maintained in captivity to source ontogenetic stage-specific venoms. Using various in vitro and in vivo assays, we assessed the significance of prey, ontogeny and sex in driving venom composition, function, and potency.</p><p><strong>Results: </strong>Considerable ontogenetic shifts in venom profiles were observed in D. russelii, with the venoms of newborns being many times as potent as juveniles and adults against mammalian (2.3-2.5 ×) and reptilian (2-10 ×) prey. This is the first documentation of the ontogenetic shift in viperine snakes. In stark contrast, N. naja, which shares a biogeographic distribution similar to D. russelii, deployed identical biochemical cocktails across development. Furthermore, the binding kinetics of cobra venom toxins against synthetic target receptors from various prey and predators shed light on the evolutionary arms race.</p><p><strong>Conclusions: </strong>Our findings, therefore, provide fascinating insights into the roles of ecology and life history traits in shaping snake venoms.</p>","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11287890/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141791979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Hierarchical lncRNA regulatory network in early-onset severe preeclampsia. 早发重度子痫前期的分层lncRNA调控网络
IF 4.4 1区 生物学
BMC Biology Pub Date : 2024-07-29 DOI: 10.1186/s12915-024-01959-1
Haihua Liu, Zhijian Wang, Yanjun Li, Qian Chen, Sijia Jiang, Yue Gao, Jing Wang, Yali Chi, Jie Liu, Xiaoli Wu, Qiong Chen, Chaoqun Xiao, Mei Zhong, Chunlin Chen, Xinping Yang
{"title":"Hierarchical lncRNA regulatory network in early-onset severe preeclampsia.","authors":"Haihua Liu, Zhijian Wang, Yanjun Li, Qian Chen, Sijia Jiang, Yue Gao, Jing Wang, Yali Chi, Jie Liu, Xiaoli Wu, Qiong Chen, Chaoqun Xiao, Mei Zhong, Chunlin Chen, Xinping Yang","doi":"10.1186/s12915-024-01959-1","DOIUrl":"10.1186/s12915-024-01959-1","url":null,"abstract":"<p><strong>Background: </strong>Recent studies have shown that several long non-coding RNAs (lncRNAs) in the placenta are associated with preeclampsia (PE). However, the extent to which lncRNAs may contribute to the pathological progression of PE is unclear.</p><p><strong>Results: </strong>Here, we report a hierarchical regulatory network involved in early-onset severe PE (EOSPE). We have carried out transcriptome sequencing on the placentae from patients and normal subjects to identify the differentially expressed genes (DEGs), including some lncRNAs (DElncRNAs). We then constructed a high-quality hierarchical regulatory network of lncRNAs, transcription factors (TFs), and target DEGs, containing 1851 lncRNA-TF interactions and 6901 TF-promoter interactions. The lncRNA-to-target regulatory interactions were further validated by the triplex structures between the DElncRNAs and the promoters of the target DEGs. The DElncRNAs in the regulatory network were clustered into 3 clusters, one containing DElncRNAs correlated with the blood pressure, including FLNB-AS1 with targeting 27.89% (869/3116) DEGs in EOSPE. We further demonstrated that FLNB-AS1 could bind the transcription factor JUNB to regulate a series members of the HIF-1 signaling pathway in trophoblast cells.</p><p><strong>Conclusions: </strong>Our results suggest that the differential expression of lncRNAs may perturb the lncRNA-TF-DEG hierarchical regulatory network, leading to the dysregulation of many genes involved in EOSPE. Our study provides a new strategy and a valuable resource for studying the mechanism underlying gene dysregulation in EOSPE patients.</p>","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11287949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141791980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Keratinocytes drive the epithelial hyperplasia key to sea lice resistance in coho salmon. 角质细胞驱动上皮增生,这是库氏鲑抵抗海虱的关键。
IF 4.4 1区 生物学
BMC Biology Pub Date : 2024-07-29 DOI: 10.1186/s12915-024-01952-8
S J Salisbury, R Ruiz Daniels, S J Monaghan, J E Bron, P R Villamayor, O Gervais, M D Fast, L Sveen, R D Houston, N Robinson, D Robledo
{"title":"Keratinocytes drive the epithelial hyperplasia key to sea lice resistance in coho salmon.","authors":"S J Salisbury, R Ruiz Daniels, S J Monaghan, J E Bron, P R Villamayor, O Gervais, M D Fast, L Sveen, R D Houston, N Robinson, D Robledo","doi":"10.1186/s12915-024-01952-8","DOIUrl":"10.1186/s12915-024-01952-8","url":null,"abstract":"<p><strong>Background: </strong>Salmonid species have followed markedly divergent evolutionary trajectories in their interactions with sea lice. While sea lice parasitism poses significant economic, environmental, and animal welfare challenges for Atlantic salmon (Salmo salar) aquaculture, coho salmon (Oncorhynchus kisutch) exhibit near-complete resistance to sea lice, achieved through a potent epithelial hyperplasia response leading to rapid louse detachment. The molecular mechanisms underlying these divergent responses to sea lice are unknown.</p><p><strong>Results: </strong>We characterized the cellular and molecular responses of Atlantic salmon and coho salmon to sea lice using single-nuclei RNA sequencing. Juvenile fish were exposed to copepodid sea lice (Lepeophtheirus salmonis), and lice-attached pelvic fin and skin samples were collected 12 h, 24 h, 36 h, 48 h, and 60 h after exposure, along with control samples. Comparative analysis of control and treatment samples revealed an immune and wound-healing response that was common to both species, but attenuated in Atlantic salmon, potentially reflecting greater sea louse immunomodulation. Our results revealed unique but complementary roles of three layers of keratinocytes in the epithelial hyperplasia response leading to rapid sea lice rejection in coho salmon. Our results suggest that basal keratinocytes direct the expansion and mobility of intermediate and, especially, superficial keratinocytes, which eventually encapsulate the parasite.</p><p><strong>Conclusions: </strong>Our results highlight the key role of keratinocytes in coho salmon's sea lice resistance and the diverged biological response of the two salmonid host species when interacting with this parasite. This study has identified key pathways and candidate genes that could be manipulated using various biotechnological solutions to improve Atlantic salmon sea lice resistance.</p>","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11287951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141791981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Plancitoxin-1 mediates extracellular trap evasion by the parasitic helminth Trichinella spiralis. Plancitoxin-1 介导寄生蠕虫旋毛虫躲避细胞外捕捉器。
IF 4.4 1区 生物学
BMC Biology Pub Date : 2024-07-29 DOI: 10.1186/s12915-024-01958-2
Jing Ding, Ning Xu, Jing Wang, Yushu He, Xuelin Wang, Mingyuan Liu, Xiaolei Liu
{"title":"Plancitoxin-1 mediates extracellular trap evasion by the parasitic helminth Trichinella spiralis.","authors":"Jing Ding, Ning Xu, Jing Wang, Yushu He, Xuelin Wang, Mingyuan Liu, Xiaolei Liu","doi":"10.1186/s12915-024-01958-2","DOIUrl":"10.1186/s12915-024-01958-2","url":null,"abstract":"<p><strong>Background: </strong>Trichinella spiralis (T. spiralis) is a parasitic helminth that causes a globally prevalent neglected zoonotic disease, and worms at different developmental stages (muscle larvae, adult worms, newborn larvae) induce immune attack at different infection sites, causing serious harm to host health. Several innate immune cells release extracellular traps (ETs) to entrap and kill most pathogens that invade the body. In response, some unicellular pathogens have evolved a strategy to escape capture by ETs through the secretion of nucleases, but few related studies have investigated multicellular helminths.</p><p><strong>Results: </strong>In the present study, we observed that ETs from neutrophils capture adult worms of T. spiralis, while ETs from macrophages trap muscle larvae and newborn larvae, and ETs had a killing effect on parasites in vitro. To defend against this immune attack, T. spiralis secretes plancitoxin-1, a DNase II-like protein, to degrade ETs and escape capture, which is essential for the survival of T. spiralis in the host.</p><p><strong>Conclusions: </strong>In summary, these findings demonstrate that T. spiralis escapes ET-mediated capture by secreting deoxyribonuclease as a potential conserved immune evasion mechanism, and plancitoxin-1 could be used as a potential vaccine candidate.</p>","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11287892/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141791982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Diversely evolved xibalbin variants from remipede venom inhibit potassium channels and activate PKA-II and Erk1/2 signaling. 从remipede毒液中演化出的不同xibalbin变体可抑制钾通道并激活PKA-II和Erk1/2信号传导。
IF 4.4 1区 生物学
BMC Biology Pub Date : 2024-07-29 DOI: 10.1186/s12915-024-01955-5
Ernesto Lopes Pinheiro-Junior, Ehsan Alirahimi, Steve Peigneur, Jörg Isensee, Susanne Schiffmann, Pelin Erkoc, Robert Fürst, Andreas Vilcinskas, Tobias Sennoner, Ivan Koludarov, Benjamin-Florian Hempel, Jan Tytgat, Tim Hucho, Björn M von Reumont
{"title":"Diversely evolved xibalbin variants from remipede venom inhibit potassium channels and activate PKA-II and Erk1/2 signaling.","authors":"Ernesto Lopes Pinheiro-Junior, Ehsan Alirahimi, Steve Peigneur, Jörg Isensee, Susanne Schiffmann, Pelin Erkoc, Robert Fürst, Andreas Vilcinskas, Tobias Sennoner, Ivan Koludarov, Benjamin-Florian Hempel, Jan Tytgat, Tim Hucho, Björn M von Reumont","doi":"10.1186/s12915-024-01955-5","DOIUrl":"10.1186/s12915-024-01955-5","url":null,"abstract":"<p><strong>Background: </strong>The identification of novel toxins from overlooked and taxonomically exceptional species bears potential for various pharmacological applications. The remipede Xibalbanus tulumensis, an underwater cave-dwelling crustacean, is the only crustacean for which a venom system has been described. Its venom contains several xibalbin peptides that have an inhibitor cysteine knot (ICK) scaffold.</p><p><strong>Results: </strong>Our screenings revealed that all tested xibalbin variants particularly inhibit potassium channels. Xib<sub>1</sub> and xib<sub>13</sub> with their eight-cysteine domain similar to spider knottins also inhibit voltage-gated sodium channels. No activity was noted on calcium channels. Expanding the functional testing, we demonstrate that xib<sub>1</sub> and xib<sub>13</sub> increase PKA-II and Erk1/2 sensitization signaling in nociceptive neurons, which may initiate pain sensitization. Our phylogenetic analysis suggests that xib<sub>13</sub> either originates from the common ancestor of pancrustaceans or earlier while xib<sub>1</sub> is more restricted to remipedes. The ten-cysteine scaffolded xib<sub>2</sub> emerged from xib<sub>1</sub>, a result that is supported by our phylogenetic and machine learning-based analyses.</p><p><strong>Conclusions: </strong>Our functional characterization of synthesized variants of xib<sub>1</sub>, xib<sub>2</sub>, and xib<sub>13</sub> elucidates their potential as inhibitors of potassium channels in mammalian systems. The specific interaction of xib<sub>2</sub> with Kv1.6 channels, which are relevant to treating variants of epilepsy, shows potential for further studies. At higher concentrations, xib<sub>1</sub> and xib<sub>13</sub> activate the kinases PKA-II and ERK1/2 in mammalian sensory neurons, suggesting pain sensitization and potential applications related to pain research and therapy. While tested insect channels suggest that all probably act as neurotoxins, the biological function of xib<sub>1</sub>, xib<sub>2,</sub> and xib<sub>13</sub> requires further elucidation. A novel finding on their evolutionary origin is the apparent emergence of X. tulumensis-specific xib<sub>2</sub> from xib<sub>1</sub>. Our study is an important cornerstone for future studies to untangle the origin and function of these enigmatic proteins as important components of remipede but also other pancrustacean and arthropod venoms.</p>","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11288129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141791978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Single-mitochondrion sequencing uncovers distinct mutational patterns and heteroplasmy landscape in mouse astrocytes and neurons. 单线粒体测序揭示了小鼠星形胶质细胞和神经元中不同的突变模式和异质结构。
IF 4.4 1区 生物学
BMC Biology Pub Date : 2024-07-29 DOI: 10.1186/s12915-024-01953-7
Parnika S Kadam, Zijian Yang, Youtao Lu, Hua Zhu, Yasemin Atiyas, Nishal Shah, Stephen Fisher, Erik Nordgren, Junhyong Kim, David Issadore, James Eberwine
{"title":"Single-mitochondrion sequencing uncovers distinct mutational patterns and heteroplasmy landscape in mouse astrocytes and neurons.","authors":"Parnika S Kadam, Zijian Yang, Youtao Lu, Hua Zhu, Yasemin Atiyas, Nishal Shah, Stephen Fisher, Erik Nordgren, Junhyong Kim, David Issadore, James Eberwine","doi":"10.1186/s12915-024-01953-7","DOIUrl":"10.1186/s12915-024-01953-7","url":null,"abstract":"<p><strong>Background: </strong>Mitochondrial (mt) heteroplasmy can cause adverse biological consequences when deleterious mtDNA mutations accumulate disrupting \"normal\" mt-driven processes and cellular functions. To investigate the heteroplasmy of such mtDNA changes, we developed a moderate throughput mt isolation procedure to quantify the mt single-nucleotide variant (SNV) landscape in individual mouse neurons and astrocytes. In this study, we amplified mt-genomes from 1645 single mitochondria isolated from mouse single astrocytes and neurons to (1) determine the distribution and proportion of mt-SNVs as well as mutation pattern in specific target regions across the mt-genome, (2) assess differences in mtDNA SNVs between neurons and astrocytes, and (3) study co-segregation of variants in the mouse mtDNA.</p><p><strong>Results: </strong>(1) The data show that specific sites of the mt-genome are permissive to SNV presentation while others appear to be under stringent purifying selection. Nested hierarchical analysis at the levels of mitochondrion, cell, and mouse reveals distinct patterns of inter- and intra-cellular variation for mt-SNVs at different sites. (2) Further, differences in the SNV incidence were observed between mouse neurons and astrocytes for two mt-SNV 9027:G > A and 9419:C > T showing variation in the mutational propensity between these cell types. Purifying selection was observed in neurons as shown by the Ka/Ks statistic, suggesting that neurons are under stronger evolutionary constraint as compared to astrocytes. (3) Intriguingly, these data show strong linkage between the SNV sites at nucleotide positions 9027 and 9461.</p><p><strong>Conclusions: </strong>This study suggests that segregation as well as clonal expansion of mt-SNVs is specific to individual genomic loci, which is important foundational data in understanding of heteroplasmy and disease thresholds for mutation of pathogenic variants.</p>","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11287894/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141791983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Somatostatin signalling coordinates energy metabolism allocation to reproduction in zebrafish. 体生长抑素信号协调斑马鱼的能量代谢和繁殖。
IF 4.4 1区 生物学
BMC Biology Pub Date : 2024-07-29 DOI: 10.1186/s12915-024-01961-7
Jie Chen, Wenting Zhao, Lei Cao, Rute S T Martins, Adelino V M Canário
{"title":"Somatostatin signalling coordinates energy metabolism allocation to reproduction in zebrafish.","authors":"Jie Chen, Wenting Zhao, Lei Cao, Rute S T Martins, Adelino V M Canário","doi":"10.1186/s12915-024-01961-7","DOIUrl":"10.1186/s12915-024-01961-7","url":null,"abstract":"<p><strong>Background: </strong>Energy allocation between growth and reproduction determines puberty onset and fertility. In mammals, peripheral hormones such as leptin, insulin and ghrelin signal metabolic information to the higher centres controlling gonadotrophin-releasing hormone neurone activity. However, these observations could not be confirmed in lower vertebrates, suggesting that other factors may mediate the energetic trade-off between growth and reproduction. A bioinformatic and experimental study suggested co-regulation of the circadian clock, reproductive axis and growth-regulating genes in zebrafish. While loss-of-function of most of the identified co-regulated genes had no effect or only had mild effects on reproduction, no such information existed about the co-regulated somatostatin, well-known for its actions on growth and metabolism.</p><p><strong>Results: </strong>We show that somatostatin signalling is pivotal in regulating fecundity and metabolism. Knock-out of zebrafish somatostatin 1.1 (sst1.1) and somatostatin 1.2 (sst1.2) caused a 20-30% increase in embryonic primordial germ cells, and sst1.2<sup>-/-</sup> adults laid 40% more eggs than their wild-type siblings. The sst1.1<sup>-/-</sup> and sst1.2<sup>-/-</sup> mutants had divergent metabolic phenotypes: the former had 25% more pancreatic α-cells, were hyperglycaemic and glucose intolerant, and had increased adipocyte mass; the latter had 25% more pancreatic β-cells, improved glucose clearance and reduced adipocyte mass.</p><p><strong>Conclusions: </strong>We conclude that somatostatin signalling regulates energy metabolism and fecundity through anti-proliferative and modulatory actions on primordial germ cells, pancreatic insulin and glucagon cells and the hypothalamus. The ancient origin of the somatostatin system suggests it could act as a switch linking metabolism and reproduction across vertebrates. The results raise the possibility of applications in human and animal fertility.</p>","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11288053/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
GSRF-DTI: a framework for drug-target interaction prediction based on a drug-target pair network and representation learning on a large graph. GSRF-DTI:基于药物-靶标配对网络和大型图谱表征学习的药物-靶标相互作用预测框架。
IF 4.4 1区 生物学
BMC Biology Pub Date : 2024-07-18 DOI: 10.1186/s12915-024-01949-3
Yongdi Zhu, Chunhui Ning, Naiqian Zhang, Mingyi Wang, Yusen Zhang
{"title":"GSRF-DTI: a framework for drug-target interaction prediction based on a drug-target pair network and representation learning on a large graph.","authors":"Yongdi Zhu, Chunhui Ning, Naiqian Zhang, Mingyi Wang, Yusen Zhang","doi":"10.1186/s12915-024-01949-3","DOIUrl":"10.1186/s12915-024-01949-3","url":null,"abstract":"<p><strong>Background: </strong>Identification of potential drug-target interactions (DTIs) with high accuracy is a key step in drug discovery and repositioning, especially concerning specific drug targets. Traditional experimental methods for identifying the DTIs are arduous, time-intensive, and financially burdensome. In addition, robust computational methods have been developed for predicting the DTIs and are widely applied in drug discovery research. However, advancing more precise algorithms for predicting DTIs is essential to meet the stringent standards demanded by drug discovery.</p><p><strong>Results: </strong>We proposed a novel method called GSRF-DTI, which integrates networks with a deep learning algorithm to identify DTIs. Firstly, GSRF-DTI learned the embedding representation of drugs and targets by integrating multiple drug association information and target association information, respectively. Then, GSRF-DTI considered the influence of drug-target pair (DTP) association on DTI prediction to construct a drug-target pair network (DTP-NET). Next, we utilized GraphSAGE on DTP-NET to learn the potential features of the network and applied random forest (RF) to predict the DTIs. Furthermore, we conducted ablation experiments to validate the necessity of integrating different types of network features for identifying DTIs. It is worth noting that GSRF-DTI proposed three novel DTIs.</p><p><strong>Conclusions: </strong>GSRF-DTI not only considered the influence of the interaction relationship between drug and target but also considered the impact of DTP association relationship on DTI prediction. We initially use GraphSAGE to aggregate the neighbor information of nodes for better identification. Experimental analysis on Luo's dataset and the newly constructed dataset revealed that the GSRF-DTI framework outperformed several state-of-the-art methods significantly.</p>","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11256582/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141632684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Endosomal protein DENND10/FAM45A integrates extracellular vesicle release with cancer cell migration 内体蛋白DENND10/FAM45A将细胞外囊泡释放与癌细胞迁移结合在一起
IF 5.4 1区 生物学
BMC Biology Pub Date : 2024-07-10 DOI: 10.1186/s12915-024-01948-4
Shenqing Sun, Qian Li, Ganggang Liu, Xiaoheng Huang, Aiqing Li, Haoran Guo, Lijuan Qi, Jie Zhang, Jianrui Song, Xiong Su, Yanling Zhang
{"title":"Endosomal protein DENND10/FAM45A integrates extracellular vesicle release with cancer cell migration","authors":"Shenqing Sun, Qian Li, Ganggang Liu, Xiaoheng Huang, Aiqing Li, Haoran Guo, Lijuan Qi, Jie Zhang, Jianrui Song, Xiong Su, Yanling Zhang","doi":"10.1186/s12915-024-01948-4","DOIUrl":"https://doi.org/10.1186/s12915-024-01948-4","url":null,"abstract":"Mounting evidence shows that tumor-derived extracellular vesicles (EVs) are critical constituents in the tumor microenvironment. The composition and function of EVs often change during cancer progression. However, it remains less clear how cancer cells modulate their own EV biogenesis to promote tumor development. The release of EVs is closely linked to the endolysosome system residing within the cell. The current study aims to decipher the role of endosomal protein DENND10 in cancer development. Bioinformatics data mining showed that DENND10 expression is significantly associated with poor prognosis in multiple cancer types and up-regulated in metastatic breast cancer cell lines. DENND10 knockout (DENND10-KO) in breast cancer cells led to defective EV biogenesis due to impaired endolysosomal trafficking. Intriguingly, DENND10-KO cells exhibited reductions in cell spreading, migration, invasion, and metastatic potential in vivo. These deficiencies in cell motility were associated with compromised cytoskeleton organization. Importantly, wild-type conditioned medium or EVs restored the migratory ability and cytoskeletal organization of DENND10-KO cells. Global proteomic profiling revealed that DENND10 depletion led to a distinct EV compositional landscape with remodeled profiles of extracellular matrix (ECM) and adhesion molecules. Consistently, exogenous application of ECM molecules rescued the spreading and migration of DENND10-KO cells. In summary, our study unveiled DENND10 as an intrinsic regulator of cell migration that modifies the tumor microenvironment through autocrine EV release, which could be exploited for developing targeted therapies for tumor metastasis.","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141575226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
AtSNU13 modulates pre-mRNA splicing of RBOHD and ALD1 to regulate plant immunity. AtSNU13 可调节 RBOHD 和 ALD1 的前核糖核酸剪接,从而调控植物免疫。
IF 4.4 1区 生物学
BMC Biology Pub Date : 2024-07-10 DOI: 10.1186/s12915-024-01951-9
Yanke Jiang, Yingzhe Yue, Chongchong Lu, Muhammad Zunair Latif, Haifeng Liu, Zhaoxu Wang, Ziyi Yin, Yang Li, Xinhua Ding
{"title":"AtSNU13 modulates pre-mRNA splicing of RBOHD and ALD1 to regulate plant immunity.","authors":"Yanke Jiang, Yingzhe Yue, Chongchong Lu, Muhammad Zunair Latif, Haifeng Liu, Zhaoxu Wang, Ziyi Yin, Yang Li, Xinhua Ding","doi":"10.1186/s12915-024-01951-9","DOIUrl":"10.1186/s12915-024-01951-9","url":null,"abstract":"<p><p>Pre-mRNA splicing is a significant step for post-transcriptional modifications and functions in a wide range of physiological processes in plants. Human NHP2L binds to U4 snRNA during spliceosome assembly; it is involved in RNA splicing and mediates the development of human tumors. However, no ortholog has yet been identified in plants. Therefore, we report At4g12600 encoding the ortholog NHP2L protein, and AtSNU13 associates with the component of the spliceosome complex; the atsnu13 mutant showed compromised resistance in disease resistance, indicating that AtSNU13 is a positive regulator of plant immunity. Compared to wild-type plants, the atsnu13 mutation resulted in altered splicing patterns for defense-related genes and decreased expression of defense-related genes, such as RBOHD and ALD1. Further investigation shows that AtSNU13 promotes the interaction between U4/U6.U5 tri-snRNP-specific 27 K and the motif in target mRNAs to regulate the RNA splicing. Our study highlights the role of AtSNU13 in regulating plant immunity by affecting the pre-mRNA splicing of defense-related genes.</p>","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11234627/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141562734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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