bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multistate structures of the MLL1-WRAD complex bound to H2B-ubiquitinated nucleosome
Authors: Hoffmann Niklas A. , Rahman Sanim , Worden Evan J. , Smith Marissa L. , Namitz Kevin E.W. , Knutson Bruce A. , Cosgrove Michael S. , Wolberger Cynthia 
Published: April 2022

AbstractThe human Mixed Lineage Leukemia-1 (MLL1) complex orchestrates methylation of histone H3K4 to promote transcription and is stimulated by monoubiquitination of histone H2B. Recent structures of the MLL1-WRAD core complex, which comprises the MLL1 methyltransferase, WDR5, RbBp5, Ash2L, and DPY-30, have revealed variation in the docking of MLL1-WRAD on nucleosomes and left ambiguous portions of Ash2L and the position of DPY30. We used an integrated approach combining cryo-electron microscopy and mass spectrometry-crosslinking to determine structures of the MLL1-WRAD complex bound to ubiquitinated nucleosomes containing the Ash2L intrinsically disordered region (IDR), SPRY insertion region, Sdc1-DPY30 interacting region (SDI-motif), and the DPY30 dimer. We resolved three additional states of MLL1-WRAD lacking one or more subunits, which may reflect different steps in the assembly of MLL1-WRAD. The subunits in all four states are positioned on the nucleosome in manner that is similar to a previous structure of MLL1-WRAD bound to ubiquitinated nucleosome, but that differs from structures with unmodified nucleosomes, suggesting that H2B-ubiquitin favors assembly of the active complex. Our results provide a more complete picture of MLL1-WRAD and the role of ubiquitin in promoting formation of the active methyltransferase complex.SignificanceThe Mixed Lineage Leukemia-1 (MLL1) complex plays a role in activating transcription by methylating lysine 4 in histone H3, a reaction that is stimulated by the presence of ubiquitin conjugated to histone H2B. Recent structures of the core MLL1 complex, termed MLL1-WRAD, have revealed the existence of multiple docking states and have also left ambiguous portions of the structure. Here we combine mass spectrometry-cross linking with cryo-EM to model additional regions of the MLL1-WRAD complex and identify a series of states that light on complex assembly and the role that ubiquitin plays in orienting MLL1-WRAD on nucleosomes.
Bird community structure in a mixed forest-production landscape in the northern Western Ghats, India
Authors: Munje Avishkar , Kumar Ajith 
Published: April 2022

ABSTRACTProduction landscapes outside protected areas are important for the conservation of wildlife, especially in countries like India with high biodiversity and human densities. Production landscapes like plantations often occur in close proximity to biodiversity-rich areas. Rubber and cashew are lucrative plantation crops in India, which although grown under similar environmental conditions, vary in their management and productivity. These plantation crops are often found along the edges of forests, thereby creating a buffer between forested and urban landscapes. While these areas have the potential to be a refuge for species otherwise restricted to natural forests, they are poorly-studied. To address this knowledge gap, we studied how habitat type (cashew, rubber or forest) and habitat characteristics affect bird diversity and guild structure in the Tillari landscape of Western Ghats, Maharashtra. Additionally, we examined how these effects are mediated by distance of plantations to nearest forest edge. In each habitat type, in 2018, we sampled birds six times each in 30 locations using fixed radius point counts. We found that bird diversity in cashew plantations (14 species) was comparable to that of adjoining forests (15 species). Rubber plantations, on the other hand, had lower bird diversity (9 species) than that in cashew or forests. When bird diversity was analysed based on dietary guilds, rubber plantations had fewer bird species in all guilds and cashew plantations had higher abundance of nectivores and lower richness of insectivores than in forest. Distance from the forest did not affect bird diversity in rubber plantations, whereas cashew plantations had fewer nectivorous birds and higher insectivorous birds away from the forest edge. Our results show that cashew plantations can serve as an important surrogate habitat for forest birds in the northern Western Ghats. The findings indicate the unsuitability of rubber plantations for sustaining bird diversity. While there are many studies available on bird diversity in rubber plantations, this is among the first studies of bird community structure in cashew plantations. At a time when forests are rapidly being cleared for plantations, our findings provide valuable data to examine the differential impacts of plantation type on biodiversity.
Circular RNA’s competing endogenous gene pair as motif in serous ovarian cancer
Authors: Li Haili , Zheng Xubin , Zhang Ning , Gao Jing , Leung Kwong-Sak , Wong Man-Hon , Yang Shu , Liu Yakun , Dong Ming , Bai Huimin , Ye Xiufeng , Cheng Lixin 
Published: April 2022

ABSTRACTThe non-coding RNA (ncRNA) regulation apprears to be associated to the diagnosis and targeted therapy of complex diseases. Motifs of non-coding RNAs and genes in the competing endogenous RNA (ceRNA) network would probably contribute to the accurate prediction of serous ovarian carcinoma (SOC). Hence, we profiled a whole transcriptome of eight human SOCs and eight controls and constructed a ceRNA network including mRNAs, long ncRNAs, and circular RNAs (circRNAs). We identified the mRNA–ncRNA–mRNA motifs in the ceRNA network named the non-coding RNA’s competing endogenous gene pairs (ceGPs), through the denoised individualized pair analysis of gene expression (deiPAGE) proposed in this study. 18 cricRNA’s ceGPs (cceGPs) were identified from multiple cohorts and were fused as an indicator (SOC index) for SOC discrimination, which carried a high predictive capacity in independent cohorts. It was found that the index was negatively correlated with the CD8+/CD4+ ratio in tumour-infiltration, reflecting the migration and growth of tumour cells in ovarian cancer progression.
One-trial social learning of vervet monkey alarm calling
Authors: Deshpande Adwait , Van Boekholt Bas , Zuberbuhler Klaus 
Published: April 2022

AbstractHow do non-human primates learn to use their alarm calls? Social learning is a promising candidate, but its role in the acquisition of meaning and call usage has not been studied systematically, neither during ontogeny nor in adulthood. To investigate the role of social learning in alarm call comprehension and use, we exposed groups of wild vervet monkeys to two unfamiliar animal models in the presence or absence of conspecific alarm calls. To assess the learning outcome of these experiences, we then presented the models for a second time to the same monkeys, but now without additional alarm call information. In subjects previously exposed in conjunction with alarm calls, we found heightened predator inspection compared to control subjects exposed without alarm calls, indicating one-trial social learning of ‘meaning’. Moreover, some juveniles (but not adults) produced the same alarm calls they heard during the initial exposure whereas the authenticity of the models had an additional effect. We concluded that, in non-human primates, call meaning can be acquired by one-trail social learning but that subject age and core knowledge about predators additionally moderate the acquisition of novel call-referent associations.
Two functionally distinct heme/iron transport systems are virulence determinants of the fish pathogen Flavobacterium psychrophilum
Authors: Zhu Yueying , Lechardeur Delphine , Bernardet Jean-François , Kerouault Brigitte , Guérin Cyprien , Rigaudeau Dimitri , Nicolas Pierre , Duchaud Eric , Rochat Tatiana 
Published: April 2022

AbstractBacterial pathogens have a critical impact on aquaculture, a sector that accounts for half of the human fish consumption. Flavobacterium psychrophilum (phylum Bacteroidetes) is responsible for bacterial cold-water disease in salmonids worldwide. The molecular factors involved in host invasion, colonization and hemorrhagic septicaemia are mostly unknown. In this study, we identified two new TonB-dependent receptors, HfpR and BfpR, that are required for adaptation to iron conditions encountered during infection and for virulence in rainbow trout. Transcriptional analyses revealed that their expression is tightly controlled and upregulated under specific iron sources and concentrations. Characterization of deletion mutants showed that they act without redundancy: BfpR is required for optimal growth in the presence of high hemoglobin level, while HfpR confers the capacity to acquire nutrient iron from heme or hemoglobin under iron scarcity. The gene hfpY, co-transcribed with hfpR, encodes a protein related to the HmuY family. We demonstrated that HfpY binds heme and contributes significantly to host colonization and disease severity. Overall, these results are consistent with a model in which both BfpR and Hfp systems promote heme uptake and respond to distinct signals to adapt iron acquisition to the different stages of pathogenesis. Our findings give insight into the molecular basis of pathogenicity of a serious pathogen belonging to the understudied family Flavobacteriaceae and point to the newly identified heme receptors as promising targets for antibacterial development.
Tumor spheroids accelerate persistently invading cancer cells
Authors: Audoin Melanie , Søgaard Maria Tangen , Jauffred Liselotte 
Published: April 2022

ABSTRACTGlioblastoma brain tumors form in brains’ white matter and remains one of the most lethal cancers despite intensive therapy and surgery. The complex morphology of these tumors includes infiltrative growth and gain of cell motility. Therefore, various brain-mimetic model systems have been developed to investigate invasion dynamics. Despite this, exactly how gradients of cell density, chemical signals and metabolites influence individual cells’ migratory behavior remains elusive. Here we show that the gradient field – induced by the spheroid – accelerates cells’ invasion of the extracellular matrix. We show that cells are pushed away from the spheroid along a radial gradient, as predicted by a biased persistent random walk (BPRW). Thus, our results grasp in a simple model the complex behavior of metastasizing cells. We anticipate that this well-defined and quantitative assay could be instrumental in the development of new anti-cancer strategies.
Application of light-sheet mesoscopy to image host-pathogen interactions in intact organs
Authors: Battistella Eliana , Quintana Juan F. , McConnell Gail 
Published: April 2022

AbstractHuman African Trypanosomiasis (HAT) is a disease caused by the extracellular parasite Trypanosoma brucei that affects the central nervous system (CNS) during the chronic stage of the infection, inducing neuroinflammation, coma, and death if left untreated. However, little is known about the structural change happening in the brain as result of the infection. So far, infection-induced neuroinflammation has been observed with conventional methods, such as immunohistochemistry, electron microscopy, and 2-photon microscopy only in small portions of the brain, which may not be representative of the disease. In this paper, we have used a newly-developed light-sheet illuminator to image the level of neuroinflammation in chronically infected mice and we use analyse these data to compare the infection in naïve controls. This system was developed for imaging in combination with the Mesolens objective lens, providing sub-cellular resolution for imaging volumes exceeding 39 mm3 in an acquisition time of only 8 hours. The mouse brain specimens were cleared using CUBIC+, followed by antibody staining to locate Glial Fibrillary Acid Protein (GFAP) expressing cells, primarily astrocytes and ependymocytes, used here as a proxy for cell reactivity and gliosis. The large capture volume allowed us to detect GFAP+ cells and spatially resolve the innate responses to T. brucei infection. Based on morphometric analyses and spatial distribution of GFAP+ cells, our data demonstrates a significant increase in cell dendrite branching around the lateral ventricle, as well as dorsal and ventral third ventricles, that are negatively correlated with the branch extension in distal sites from the circumventricular spaces. To our knowledge, this is the first report highlighting the potential of light-sheet mesoscopy to characterise the inflammatory responses of the mouse brain to parasitic infection at the cellular level in intact cleared organs, opening new avenues for the development of new mesoscale imaging techniques for the study of host-pathogen interactions.
Talin-drug interaction reveals a key molecular determinant for biphasic mechanical effect: studied under single-molecule resolution
Authors: Chakraborty Soham , Bhatt Madhu , Chowdhury Debojyoti , Chaudhuri Deep , Haldar Shubhasis 
Published: April 2022

AbstractTalin as an adhesion protein, exhibits a strong force-dependent structure-function dynamics. Being a mechanosensitive focal adhesion (FA) protein, talin might interact to several FA targeting drugs; however, the molecular mechanism of talin-drug interactions remains elusive. Here we combined magnetic tweezers and molecular dynamics (MD) simulation to explore mechanical stability of talin with three drugs based on their talin specificity. Interestingly, our study revealed that talin displays a bimodal force distribution with a low and high unfolding force population. We observed that talin nonspecific drugs (tamoxifen and letrozole) display biphasic effect: increase talin mechanical stability upto optimum concentration, followed by a decrease in stability with further concentration increase. By contrast, talin-specific cyanidin 3-O-glucoside promotes a steady increase to talin mechanical stability with its concentration. We reconciled our observation from the simulation study: tamoxifen enters into talin hydrophobic core, eventually destabilizing the protein; whereas cyanidin 3-O-glucoside stabilizes the protein core by maintaining the inter-helix distance. Finally, we observed a strong correlation among hydrophobicity and cavity analysis, illustrating a detailed mechanistic analysis of drug effect on the mechanosensitive protein. Overall this study presents a novel perspective for drug designing against mechanosensitive proteins and studying off-target effects of already known drugs.
mRNAid, an Open-Source Platform for Therapeutic mRNA Design and Optimization Strategies
Authors: Vostrosablin Nikita , Lim Shuhui , Gopal Pooja , Brazdilova Kveta , Parajuli Sushmita , Wei Xiaona , Gromek Anna , Spale Martin , Muzdalo Anja , Yeo Constance , Wardyn Joanna , Mejzlik Petr , Henry Brian , Partridge Anthony W. , Bitton Danny A. 
Published: April 2022

AbstractRecent COVID-19 vaccines unleashed the potential of mRNA-based therapeutics. mRNA optimization is indispensable for reducing immunogenicity, ensuring stability, and maximizing protein output. We present mRNAid, an experimentally validated software for mRNA optimization and visualization that generates mRNA sequences with comparable if not superior characteristics to commercially optimized sequences. To encompass all aspects of mRNA design, we also interrogated the impact of uridine content, nucleoside analogs and UTRs on expression and immunogenicity.
Protein evidence of unannotated ORFs inDrosophilareveals unappreciated diversity in the evolution of young proteins
Authors: Zheng Eric B , Zhao Li 
Published: April 2022

AbstractDe novogene origination, where a previously non-genic genomic sequence becomes genic through evolution, has been increasingly recognized as an important source of evolutionary novelty across diverse taxa. Manyde novogenes have been proposed to be protein-coding, and in several cases have been experimentally shown to yield protein products. However, the systematic study ofde novoproteins has been hampered by doubts regarding the translation of their transcripts without the experimental observation of protein products. Using a systematic, ORF-focused mass-spectrometry-first computational approach, we identify almost 1000 unannotated open reading frames with evidence of translation (utORFs) in the model organismDrosophila melanogaster, 371 of which have canonical start codons. To quantify the comparative genomic similarity of these utORFs acrossDrosophilaand to infer phylostratigraphic age, we further develop a synteny-based protein similarity approach. Combining these results with reference datasets on tissue- and life-stage-specific transcription and conservation, we identify different properties amongst these utORFs. Contrary to expectations, the fastest-evolving utORFs are not the youngest evolutionarily. We observed more utORFs in the brain than in the testis. Most of the identified utORFs may be ofde novoorigin, even accounting for the possibility of false-negative similarity detection. Finally, sequence divergence after an inferredde novoorigin event remains substantial, raising the possibility thatde novoproteins turn over frequently. Our results suggest that there is substantial unappreciated diversity inde novoprotein evolution: many more may exist than have been previously appreciated; there may be divergent evolutionary trajectories; andde novoproteins may be gained and lost frequently. All in all, there may not exist a single characteristic model ofde novoprotein evolution, but rather complex origins and evolutionary trajectories forde novoproteins.Impact statementThe analysis of mass-spectrometry data for all possible open reading frames reveals protein evidence for evolutionarily young, unannotated proteins with distinct characters.
Downregulation of dystrophin expression occurs across diverse tumors, correlates with the age of onset, staging and reduced survival of patients
Authors: Alnassar Nancy , Borczyk Malgorzata , Tsagkogeorga Georgia , Korostynski Michal , Han Namshik , Górecki Dariusz C 
Published: April 2022

AbstractMutations of theDMDgene, encoding dystrophins, cause Duchenne muscular dystrophy (DMD). Some tumors also display altered dystrophin expression and recent studies identified a developmental onset of DMD. Given that embryogenesis and carcinogenesis share many mechanisms, we analyzed a broad spectrum of tumors to establish whether dystrophin loss evokes related outcomes. Transcriptomic, proteomic, and mutation datasets from fifty tumor tissues and matching controls (10,894 samples) and 140 corresponding tumor cell lines were analyzed. Interestingly,DMDexpression was widespread across healthy tissues at levels comparable to housekeeping genes. In 80% of tumors,DMDexpression was reduced due to transcriptional downregulation and not somatic mutations. The full-length transcript encoding Dp427 was decreased in 68% of tumors, while Dp71 variants showed variability of expression. Hierarchical clustering analysis ofDMDtranscripts distinguished malignant from control tissues. Transcriptomes of primary tumors and tumor cell lines with lowDMDexpression showed enrichment of specific pathways in the differentially expressed genes. Pathways consistently identified: ECM-receptor interaction, calcium signaling and PI3K-Akt, are also altered in DMD muscle. Notably, lowDMDexpression was associated with a more advanced stage, older age of onset, and reduced survival across different tumors. Thus,DMDtranscription occurs throughout a spectrum of normal tissues. The molecular signature associated with its frequent downregulation in malignancies is concordant with changes found in Duchenne muscles, even though these malignancies originate from tissues never previously associated with dystrophin expression or function. Therefore, the importance of this largest known gene extends beyond its roles identified in DMD, certainly into oncology.
Centriolar satellites expedite mother centriole remodeling to promote ciliogenesis
Authors: Hall Emma A. , Kumar Dhivya , Prosser Suzanna L. , Yeyati Patricia L. , Pérez Vicente Herranz , García Verdugo Jose Manuel , Rose Lorraine , McKie Lisa , Dodd Daniel O. , Tennant Peter A. , Megaw Roly , Murphy Laura C. , Ferreira Marissa , Grimes Graeme , Williams Lucy , Quidwai Tooba , Pelletier Laurence , Reiter Jeremy F. , Mill Pleasantine 
Published: April 2022

AbstractCentrosomes are orbited by centriolar satellites, dynamic multiprotein assemblies nucleated by PCM1. To study the requirement for centriolar satellites, we generated mice lacking PCM1. Pcm1−/− mice display partially penetrant perinatal lethality with survivors exhibiting hydrocephalus, oligospermia and cerebellar hypoplasia, as well as variable expressivity of other ciliopathy features including cystic kidneys. Pcm1−/− multiciliated ependymal cells and PCM1−/− retinal pigmented epithelial 1 (RPE1) cells showed reduced ciliogenesis. PCM1−/− RPE1 cells displayed reduced docking of the mother centriole to the ciliary vesicle and removal of CP110 and CEP97 from the distal mother centriole, indicating compromized early ciliogenesis. We show these molecular cascades are maintained in vivo, and we suggest that the cellular threshold to trigger ciliogenesis varies between cell types. We propose that PCM1 and centriolar satellites facilitate efficient trafficking of proteins to and from centrioles, inducing the departure of CP110 and CEP97 to initiate ciliogenesis.
A Deep Learning Method for MiRNA/IsomiR Target Detection
Authors: Talukder Amlan , Zhang Wencai , Li Xiaoman , Hu Haiyan 
Published: April 2022

AbstractMotivationAccurate identification of microRNA (miRNA) targets at base-pair resolution has been an open problem for over a decade. The recent discovery of miRNA isoforms (isomiRs) adds more complexity to this problem. Despite the existence of many methods, none considers isomiRs, and their performance is still suboptimal. We hypothesize that by taking the isomiR-mRNA interaction into account and applying a deep learning model to study miRNA-mRNA interaction features, we may improve the accuracy of miRNA target predictions.ResultsWe developed a deep learning tool called DMISO to capture the intricate features of miRNA/isomiR-mRNA interactions. Based on 10-fold cross-validation, DMISO showed high precision (95%) and recall (90%). Evaluated on three independent datasets, DMISO had superior performance to five tools, including three popular conventional tools and two recently developed deep learning-based tools. By applying two popular feature interpretation strategies, we demonstrated the importance of the miRNA regions other than their seeds and the potential contribution of the RNA-binding motifs within miRNAs/isomiRs and mRNAs to the miRNA/isomiR-mRNA interactions.AvailabilityThe source code and tool are available athttp://hulab.ucf.edu/research/projects/DMISO.Contacthaihu@cs.ucf.edu,xiaoman@mail.ucf.eduSupplementary informationSupplementary data are available online.