bioRxiv最新文献

{"title":"Waves of transcription drive erythroid differentiation and launch the NRF2-activated antioxidant program","authors":"Ingrid Karppi, Jenny C. Pessa, Adelina Rabenius, Samu V. Himanen, Bina Prajapati, Emilia Barkman Jonsson, Maria K. Vartiainen, Lea Sistonen, Anniina Vihervaara","doi":"10.1101/2024.07.12.603281","DOIUrl":"https://doi.org/10.1101/2024.07.12.603281","url":null,"abstract":"Transcriptional reprogramming drives differentiation and coordinates cellular responses. While mRNA expression in distinct cell types has been extensively analyzed, the mechanisms that control RNA synthesis upon lineage specifications remain unclear. Here, we induce erythroid differentiation in human cells, track transcription and its regulation at nucleotide-resolution, and identify molecular mechanisms that orchestrate gene and enhancer activity during erythroid specification. We uncover waves of transcription and reveal that a brief differentiation signal launches sustained and propagating changes in RNA synthesis and mRNA expression over cell divisions. NRF2, a strong trans-activator upon oxidative stress, drives erythroid differentiation without a detectable increase in reactive oxygen species. In erythroid precursors, NRF2 induces architecturally primed, differentiation-linked enhancers, and genes encoding globin and antioxidant proteins. Projecting signal-induced transcription to DNA accessibility and mRNA expression in single human bone marrow cells, reveals ordered activation of myeloid (GABPA) and erythroid (GATA1, TAL1 and HEMGN) factors in lineage-specification, followed by NRF2-triggered antioxidant response in the late erythroid cells. This study establishes molecular mechanisms that prime, execute, and temporally coordinate RNA synthesis during erythroid differentiation. Furthermore, we show that master regulators of differentiation and stress co-orchestrate erythropoiesis and produce the antioxidant machinery before erythroid cells mature to oxygen transporting enucleated erythrocytes.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":"6 11","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141642243","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":"Ancient tree-topologies and gene-flow processes among human lineages in Africa","authors":"Gwenna Breton, P. Sjödin, Panagiotis I. Zervakis, Romain Laurent, Alain Froment, Agnès E. Sjöstrand, Barry S. Hewlett, Luis B. Barreiro, George H. Perry, H. Soodyall, Evelyne Heyer, Carina M. Schlebusch, M. Jakobsson, P. Verdu","doi":"10.1101/2024.07.15.603519","DOIUrl":"https://doi.org/10.1101/2024.07.15.603519","url":null,"abstract":"The deep history of humans in Africa and the complex divergences and migrations among ancient human genetic lineages remain poorly understood and are the subject of ongoing debate. We produced 73 high-quality whole genome sequences from 14 Central and Southern African populations with diverse, well-documented, languages, subsistence strategies, and socio-cultural practices, and jointly analyze this novel data with 104 African and non-African previously-released whole genomes. We find vast genome-wide diversity and individual pairwise differentiation within and among African populations at continental, regional, and even local geographical scales, often uncorrelated with linguistic affiliations and cultural practices. We combine populations in 54 different ways and, for each population combination separately, we conduct extensive machine-learning Approximate Bayesian Computation inferences relying on genome-wide simulations of 48 competing evolutionary scenarios. We thus reconstruct jointly the tree-topologies and migration processes among ancient and recent lineages best explaining the diversity of extant genomic patterns. Our results show the necessity to explicitly consider the genomic diversity of African populations at a local scale, without merging population samples indiscriminately into larger a priori categories based on geography, subsistence-strategy, and/or linguistics criteria, in order to reconstruct the diverse evolutionary histories of our species. We find that, for all different combinations of Central and Southern African populations, a tree-like evolution with long periods of drift between short periods of unidirectional gene-flow among pairs of ancient or recent lineages best explain observed genomic patterns compared to recurring gene-flow processes among lineages. Moreover, we find that, for 25 combinations of populations, the lineage ancestral to extant Southern African Khoe-San populations diverged around 300,000 years ago from a lineage ancestral to Rainforest Hunter-Gatherers and neighboring agriculturalist populations. We also find that short periods of ancient or recent asymmetrical gene-flow among lineages often coincided with epochs of major cultural and ecological changes previously identified by paleo-climatologists and archaeologists in Sub-Saharan Africa.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":"14 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141642359","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":"Tempo-dependent selective enhancement of neural responses at the beat frequency can be explained by both an oscillator and an evoked model","authors":"Atser Damsma, Mitchell de Roo, Keith Doelling, Pierre-Louis Bazin, F. L. Bouwer","doi":"10.1101/2024.07.11.603023","DOIUrl":"https://doi.org/10.1101/2024.07.11.603023","url":null,"abstract":"The synchronization of neural oscillations with an external regularity such as a musical beat has been regarded as an important mechanism for the brain to make sense of our auditory environment. Such synchronization is often quantified as phase locking of neural oscillations to a stimulus, but this method has been criticized for not differentiating between entrainment – the rate-dependent adjustment of an ongoing endogenous oscillation to an external regularity – and evoked neural responses to the rhythmic stimulus. Here, we aimed to differentiate between these two accounts by measuring EEG responses to non-isochronous rhythmic sequences played at five different rates. Behaviorally, participants shifted the perceived level of regularity depending on the tempo, towards the preferred beat rate (∼2 Hz). We found a similar shift in the EEG data, with strongest neural phase locking at the level of the note rate for slow tempi, and at the level of a hierarchical beat for faster tempi, independent of active attention to the sounds. While this pattern of results is in line with entrainment accounts of beat perception and could indeed be mimicked by an oscillator model, it was explained equally well using a model simulating evoked responses. An additional phase concentration metric of the EEG data fell in between the predictions of these two models. In conclusion, we show that neural responses to rhythm are selectively enhanced at the beat rate in a tempo-dependent manner, but that this selective neural enhancement can be explained by successive evoked responses as well as by assuming the presence of oscillatory entrainment.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":"3 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141642685","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":"Climate adaptation in P. trichocarpa: key adaptive loci identified for stomata and leaf traits","authors":"Marie C Klein, Zi Meng, Jack H. Bailey‐Bale, Suzanne Milner, Peicai Shi, W. Muchero, Jin-Gui Chen, T. Tschaplinski, Daniel Jacobson, John Lagergren, Matthew Lane, Chris O’Brien, H. B. Chhetri, Mengjun Shu, Peter Freer-Smith, Thomas N. Buckley, T. S. Magney, J. G. Monroe, G. Tuskan, Gail Taylor","doi":"10.1101/2024.07.11.603099","DOIUrl":"https://doi.org/10.1101/2024.07.11.603099","url":null,"abstract":"Identifying the genetic basis of traits underlying climate adaptation remains a key goal for predicting species responses to climate change, enabling the elucidation of gene targets for future climate-resilient crops. Here, we measured 14 leaf and stomatal traits under control (well-watered) and drought conditions, subsampling a diversity collection of over 1,300 Populus trichocarpa genotypes, a potential biofuel feedstock crop. Stomatal traits were correlated with the climate of origin for genotypes, such that those originating from environments subject to water deficit tended to have smaller stomata, but with higher density. Stomatal traits were also correlated with leaf morphology, with larger leaves having larger stomata and lower stomatal density mirrored in correlations to climate of origin. The direction of plastic responses - reduced stomatal size under drought - mirrors the correlations seen among genotypes with respect to the aridity of environmental origin. Genome-Wide Association Studies (GWAS) identified loci underlying trait diversity, including candidates contributing to stomatal size. We used climate of origin to predict stomatal size in genotypes with unknown trait values and found that these predicted phenotypes confirmed empirically measured allele effects. Finally, we found evidence that future climates may select for alleles contributing to decreased stomatal size, with the strength of selection depending on the availability of moisture. These findings reveal adaptive variation in stomatal and physiological traits along with underlying genetic loci, with implications for future selection and breeding - providing insights into the responses to future climate change. Highlight Research on Populus trichocarpa reveals adaptation of physiological and stomatal traits linked to drought tolerance, with genotypes from arid regions exhibiting smaller stomata, offering insights for climate change adaptation and sustainable biofuel production.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":"88 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141642596","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":"Drug-repurposing screen identifies thiostrepton as a novel regulator of the tumor suppressor DAB2IP","authors":"Rossella De Florian Fania, S. Maiocchi, Raffaella Klima, Valeria Pellegrini, Sabrina Ghetti, Davide Selvestrel, Luca L. Fava, Luca Braga, Licio Collavin","doi":"10.1101/2024.07.12.603185","DOIUrl":"https://doi.org/10.1101/2024.07.12.603185","url":null,"abstract":"The tumor suppressor DAB2IP, a RasGAP and cytoplasmic adaptor protein, modulates signal transduction in response to several extracellular stimuli, negatively regulating multiple oncogenic pathways. Accordingly, the loss of DAB2IP in tumor cells fosters metastasis and enhances chemo- and radio-resistance. DAB2IP is rarely mutated in cancer but is frequently downregulated or inactivated by multiple mechanisms. Solid experimental evidence show that DAB2IP reactivation can reduce cancer aggressiveness in tumors driven by multiple different oncogenic mutations, making this protein an interesting target for anti-cancer therapy. Based on these premises, we screened a library of FDA-approved drugs to search for molecules that can increase DAB2IP protein levels. We exploited CRISPR/Cas9 gene editing to generate two prostate cancer cell models in which endogenous DAB2IP is fused to HiBiT, a peptide tag that enables luminescence-based detection of protein levels in a sensitive and quantitative manner. Using this approach, we identified drugs able to increase DAB2IP levels. We focus our attention on thiostrepton, a natural cyclic oligopeptide antibiotic that has been reported to inhibit survival of various cancer cell lines. Functional experiments revealed that the cancer inhibitory effect of thiostrepton is reduced in the absence of DAB2IP, suggesting that the observed upregulation contributes to its action. These findings encourage the further development of thiostrepton for the treatment of solid cancers, and unveil a novel molecular mechanism underlying its anti-tumoral action.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":"14 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141644053","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":"Beyond Static Models: The Dynamic Interplay of Facial Emotions and Attentional Scope","authors":"Kesong Hu, Shuchang He, Qi Li, Chiang-Shan R. Li","doi":"10.1101/2024.07.15.603432","DOIUrl":"https://doi.org/10.1101/2024.07.15.603432","url":null,"abstract":"The interplay between emotion and attention has long been intensely scrutinized, with competing theories proposing divergent mechanisms. Building on our previous work, here we present evidence that refines these perspectives, revealing a nuanced, temporally dynamic relationship between emotional stimuli and attentional focus. Using a modified Flanker task with facial emotion cues, we demonstrate that the effects of emotional stimuli on attention evolve over time, contrary to traditional fixed-effect assumptions. Our results show distinct temporal patterns: Neutral faces elicited typical flanker effects initially, but only interference persisted later. Early-stage happy faces amplified flanker facilitation but not interference, while threat faces augmented flanker interference but not facilitation. In the late stage, flanker facilitation disappeared across all emotion conditions, and interference patterns converged, mirroring the neutral face condition. These findings indicate emotion’s influence on attention is more complex and dynamic than previously recognized, potentially reflecting learning or habituation processes. We propose a new framework for understanding emotion-attention interactions that transcends traditional dichotomies of attention focus and approach-avoidance, offering a more nuanced perspective on this critical cognitive interface.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":"11 23","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141640570","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":"Widespread parasite infections in living resident killer whales in the Northeast Pacific Ocean","authors":"Natalie C. Mastick, A.M. Van Cise, K. Parsons, E. Ashe, R. Williams, J.N. Childress, A. Nguyen, H. Fearnbach, J. Durban, C. Emmons, B. Hanson, D. Olsen, C.L. Wood","doi":"10.1101/2024.07.10.602791","DOIUrl":"https://doi.org/10.1101/2024.07.10.602791","url":null,"abstract":"Multiple populations of resident ecotype killer whales (Orcinus orca ater) inhabit the Northeast Pacific, but the southern resident killer whale (SRKW) population is the most at-risk. SRKWs were listed as endangered in the United States in 2005 and have since shown little sign of recovery. Several factors have been identified as key threats to this population, and previously published studies suggest the population may be energetically stressed. Underlying health risks, such as parasitism, may be contributing to this population’s failure to recover, but little is known about parasite infections in living individuals from natural killer whale populations. To assess the prevalence of internal parasite infections in Northeastern Pacific killer whales, we examined scat from endangered SRKW (n = 25) compared to two conspecific populations of resident killer whales that are not in decline: northern resident (NRKW, n = 2) and southern Alaska resident killer whales (SARKW, n = 7), and one offshore killer whale (OKW, n = 1). We analyzed 35 fecal samples collected from 27 wild killer whales using both microscopic identification of parasite eggs and genetic detection of parasites through DNA metabarcoding. We used body condition indices derived from concurrent aerial photogrammetry to evaluate whether parasite infection status was associated with individual body condition. We found that most individuals sampled (94%) were positive for Anisakis spp. – a parasitic nematode known to inhabit the intestines of cetaceans. These infections were detected across populations, and were not correlated with body condition, based on limited paired data. These results suggest that Anisakis infection is widespread among resident killer whales of the Northeast Pacific. The widespread detections of Anisakis among the samples examined here emphasizes the need for further work to understand the potential health impacts of parasitic infections on individual killer whales, and potential synergistic effects with other environmental stressors.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":"21 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141641661","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":"The state-of-the-art machine learning model for Plasma Protein Binding Prediction: computational modeling with OCHEM and experimental validation","authors":"Zunsheng Han, Zhonghua Xia, Jie Xia, Igor V Tetko, Song Wu","doi":"10.1101/2024.07.12.603170","DOIUrl":"https://doi.org/10.1101/2024.07.12.603170","url":null,"abstract":"Plasma protein binding (PPB) is closely related to pharmacokinetics, pharmacodynamics and drug toxicity. Prediction of PPB is an alternative to experimental approaches that are known to be time-consuming and costly. Although there are various models and web servers for PPB prediction already available, they suffer from low prediction accuracy and poor interpretability, in particular for molecules with high values, and are most often not properly validated in prospective studies. Here, we carried out strict data curation, and applied consensus modeling to obtain a model with a coefficient of determination of 0.90 and 0.91 on the training set and the test set, respectively. This model was further validated in a prospective study to predict 63 poly-fluorinated and another 25 highly diverse compounds, and its performance for both these sets was superior to that of other previously reported models. To identify structural features related to PPB, we analyzed a model based on Morgan2 fingerprints and identified that features such as aromatic rings, halogen atoms, heterocyclic rings can discriminate high- and low-PPB molecules. In conclusion, we have established a PPB prediction model that showed state-of-the-art performance in prospective screening, which we have made publicly available in the OCHEM platform (https://ochem.eu/article/29). Graphic Abstract","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":"21 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141641662","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":"Cerebellar output shapes cortical preparatory activity during motor adaptation","authors":"Sharon Israely, Hugo Ninou, Ori Rajchert, Lee Elmaleh, R. Harel, Firas Mawase, Jonathan Kadmon, Y. Prut","doi":"10.1101/2024.07.12.603354","DOIUrl":"https://doi.org/10.1101/2024.07.12.603354","url":null,"abstract":"The cerebellum plays a key role in motor adaptation by driving trial-to-trial recalibration of movements based on previous errors. In primates, this adaptive response is achieved by cerebellar modulation of motor cortical signals, but the nature and timing of this process are unknown. Specifically, cortical correlates of adaptation are encoded already in the pre-movement motor plan, but these early cortical signals could be driven by a cerebellar-to-cortical information flow or evolve independently through intracortical mechanisms. To address this question, we trained monkeys to reach against a viscous force field while blocking cerebellar outflow. During the force field trials, the cerebellar block led to impaired adaptation and a compensatory, re-aiming-like shift in motor cortical preparatory activity. In the null-field conditions, the cerebellar block altered neural preparatory activity by increasing task-representation dimensionality and impeding generalization. A computational model indicated that low-dimensional (cerebellar-like) feedback is sufficient to replicate these findings. We conclude that cerebellar signals carry task structure information that constrains the dimensionality of the cortical preparatory manifold and promotes generalization. In the absence of these signals, cortical mechanisms are harnessed to partially restore adaptation.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":"3 12","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141641722","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":"Long-term population dynamics of an endangered butterfly are influenced by hurricane-mediated disturbance","authors":"Sarah R. Steele Cabrera, M. Belitz, Thomas C. Emmel, Emily S. Khazan, Matthew J. Standridge, Kristin A Rossetti, Jaret C. Daniels","doi":"10.1101/2024.07.12.603220","DOIUrl":"https://doi.org/10.1101/2024.07.12.603220","url":null,"abstract":"Effective species conservation requires understanding an organism’s population dynamics and natural history, but long-term data are challenging to collect and maintain. As a result, conservation management decisions are frequently made using short-term data, which are insufficient to accurately assess population trends in most species. For less-studied taxa, including most invertebrates, inadequate understanding of life and natural history also impedes conservation efforts. Long-term studies are highly valuable for improving conservation decisions for target species as they serve as a model for other understudied species. We use mark-recapture data collected over 35 years to examine weather drivers of population patterns for an endangered butterfly, Schaus’ swallowtail (Heraclides ponceana), and to enhance our understanding of its natural history. We show that the population size of Schaus’ swallowtail butterfly was highly variable, ranging from under 100 to over 10,000 individuals. Population size is influenced by weather events and population size in the previous year. Population size was lower immediately following high wind events but was positively influenced by high wind events four years prior, with notable population increases following tropical cyclone events. Precipitation during the dry season preceding the adult flight period was also associated with higher population sizes. This study reveals the potentially beneficial role of hurricane-mediated disturbance on Schaus’ swallowtail populations potentially due to increased treefall gaps and the resulting shifts in plant communities. This remarkable data set represents one of the longest-term studies on a tropical insect.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141643489","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}