bluuebunny/crossref_metadata_2025_split huggingface dataset:
Super-enhancer-drivenCACNA2D2is an EWSR1::WT1 signature gene encoding a diagnostic marker for desmoplastic small round cell tumor (DSRCT)
Authors: Geyer Florian H. , Ritter Alina , Kinn-Gurzo Seneca , Faehling Tobias , Li Jing , Jarosch Armin , Ngo Carine , Vinca Endrit , Aljakouch Karim , Orynbek Azhar , Ohmura Shunya , Kirchner Thomas , Imle Roland , Romero-Pérez Laura , Bertram Stefanie , de Álava Enrique , Postel-Vilnay Sophie , Banito Ana , Sill Martin , Versleijen-Jonkers Yvonne M.H. , Mayer Benjamin F.B. , Ebinger Martin , Sparber-Sauer Monika , Stegmaier Sabine , Baumhoer Daniel , Hartmann Wolfgang , Krijgsveld Jeroen , Horst David , Delattre Olivier , Grohar Patrick J. , Grünewald Thomas G. P. , Cidre-Aranaz Florencia 
Published: July 2024

ABSTRACTDesmoplastic small round cell tumor (DSRCT) is a highly aggressive cancer predominantly occurring in male adolescents and young adults. The lack of a comprehensive understanding on the biology of the disease is paralleled by its dismal survival rates (5–20%). To overcome this challenge, we first identified and prioritized urgently needed resources for clinicians and researchers. Thus, we established genome-wide single-cell RNA-sequencing and bulk proteomic data of in vitro and in vivo-generated knockdown models of the pathognomonic DSRCT fusion oncoprotein (EWSR1::WT1) and combined them with an original systems-biology-based pipeline including patient data and the largest histology collection of DSRCTs and morphological mimics available to date. These novel tools were enriched with curated public datasets including patient- and cell line-derived ChIP-seq, bulk and single-cell RNA-seq studies resulting in a multi-model and multi-omic toolbox for discovery analyses. As a proof of concept, our approach revealed the alpha-2/delta subunit of the voltage-dependent calcium channel complex, CACNA2D2, as a highly overexpressed, super-enhancer driven, direct target of EWSR1::WT1. Single-cell and bulk-level analyses of patient samples and xenografted cell lines highlighted CACNA2D2 as a critical component of our newly established EWSR1::WT1 oncogenic signature, that can be employed to robustly identify DSRCT in reference sets. Finally, we show that CACNA2D2 is a highly sensitive and specific single biomarker for fast, simple, and cost-efficient diagnosis of DSRCT. Collectively, we establish a large-scale multi-omics dataset for this devastating disease and provide a blueprint of how such toolbox can be used to identify new and clinically relevant diagnostic markers, which may significantly reduce misdiagnoses, and thus improve patient care.
MONOPTEROSisoformMP11irrole during somatic embryogenesis inArabidopsis thaliana
Authors: Wójcikowska Barbara , Belaidi Samia , Mironova Victoria , Boisivon Helene Robert 
Published: July 2024

AbstractAuxin is crucial for plant morphogenesis, includingin vivoandin vitroembryo development. Exogenous auxin application is necessary for inducing embryogenic responses inin vitrocultured explants of Arabidopsis and other plants. Thus, components of auxin transport, signaling, and metabolism are key to somatic embryo formation. AUXIN RESPONSE FACTOR (ARF) transcription factors, which bind to auxin response elements to control the auxin-responsive gene expression, are vital in somatic embryo regeneration. ARFs are often repressed by AUXIN/INDOLE-3-ACETIC ACIDs (Aux/IAAs). MONOPTEROS (MP)/ARF5 is especially important in the embryogenic transition, being highly expressed during somatic embryogenesis; its mutant cannot develop somatic embryos. TheMP11irtranscript, an alternatively spliced variant ofMP/ARF5, produces a truncated protein missing the Phox and Bem1p (PB1) domain, crucial for ARF-Aux/IAA dimerization. This makes the MP11ir isoform insensitive to Aux/IAA repression, suggesting auxin-independent regulation. High levels ofMP11irtranscript are observed during auxin- and trichostatin A-dependent induction of somatic embryogenesis. Both MP/ARF5 and MP11ir are essential for embryo regeneration in thempS319mutant. However, overexpressing truncated MP/ARF5 protein (ΔARF5) lacking the PB1 domain inhibits somatic embryogenesis, leading to callus formation instead of somatic embryos. OverexpressingΔARF5, lacking MP/ARF5 protein (mp/arf5mutant), and blocking of MP/ARF5 action with auxin-resistant BODENLOS (BDL) protein affect the expression of genes involved in auxin biosynthesis, likeTRYPTOPHAN AMINOTRANSFERASE OF ARABIDOPSIS 1(TAA1),TAA1-RELATED 1(TAR1),YUCCA3(YUC3),YUC5andYUC8, which may be potential targets of MP11ir and/or MP/ARF5. Consequently,ΔARF5overexpression alters auxin homeostasis and endogenous auxin levels, hindering embryogenic transition.
Genome-wide Identification of the Laccase Gene Family in White Jute (Corchorus capsularis): Potential Targets for Lignin Engineering in Bast Fiber
Authors: Parida Subhadarshini , Jha Deepak Kumar , Kumari Khushbu , Pradhan Seema , Dey Nrisingha , Majumder Shuvobrata 
Published: July 2024

AbstractThe industrial bast fibre crop jute (Corchorussp.) is known for its long lignocellulosic multi-utility fibres. Information on jute fibre lignification is limited, and many enzymes in the jute lignin pathway are not well documented. One such enzyme is laccase (EC 1.10.3.2), involved in the final polymerization step of lignification. A whole-genome search of white jute (Corchorus capsularis) revealed 34 putative laccase (CcaLAC) genes. Phylogenetic analysis categorized these genes into six groups, with 17 predominantly expressed in phloem tissue, 9 in leaf, and 4 in xylem and roots. A steady increase in gene expression, from plantlets to crop harvest, was observed for severalCcaLACs. Some were selected for further analysis based on homology withArabidopsislignin pathway-modifying laccases (AtLACs). Transcriptomics data confirmed their expression in phloem tissues, with some showing significantly lower expression indlpf, a low-lignin fibre-containing white jute mutant. Changes inCcaLACexpression were observed under abiotic stresses like ABA hormone and copper heavy metal. Target sites for Ath-miR397a and Ath-miR397b were predicted in 11 and 9CcaLACs, respectively, suggesting possible post-transcriptional modification via microRNA. Subcellular localization showedCcaLACs in multiple plant cell compartments. Protein structure predictions revealed up to 10 motifs in CcaLACs, with 18 containing transmembrane helices. Overall,CcaLAC28andCcaLAC32are likely involved in the lignification process of phloem (bast) in white jute. Modifying these genes could enhance our understanding of lignification and potentially lead to the development of low-lignin jute fibres, meeting high industrial demands globally.HighlightsJute is known for its long lignocellulosic fibres.34 putative laccase genes were identified in white jute.17 laccase genes are mainly expressed in phloem tissue.CcaLAC28andCcaLAC32are key candidates for lignification.Laccase genes showed changes under abiotic stresses.Key MessageIdentified 34 laccase genes in white jute, key for understanding and engineering lignification in fibres.
Ablation of B cell-derived IL-10 increases tuberculosis resistance
Authors: Hertz David , Marwitz Sebastian , Eggers Lars , von Borstel Linda , Parvathy Gishnu Harikumar , Behrends Jochen , Jonigk Danny D. , Manz Rudolf A. , Goldmann Torsten , Schneider Bianca E. 
Published: July 2024

AbstractDue to the historical dogma, that host defense against intracellular pathogens is mediated by cell-mediated immunity, B cells have been considered unimportant in providing protection againstMycobacterium tuberculosis(Mtb) and remained understudied for decades. However, emerging evidence suggests a more complex and multifaceted role for B cells in tuberculosis (TB) immunity. They accumulate at the side of infection in both animal models and human TB patients, suggesting a potential link to protective immunity. Still, the diverse roles of B cells in TB immunity continue to be unraveled. Apart from antibodies, B cells produce a wide range of cytokines, which can influence the local immune response. Here we addressed the relevance of interleukin 10 (IL-10) secreting B cells in long-term control of theMtbBeijing strain HN878. Our research highlights the previously unknown role of B cell-derived IL-10 as a negative regulator of protective immunity in TB. For the first time, we demonstrate that mice lacking B cell-derived IL-10 show increased resistance to aerosolMtbinfection, as evidenced by a delayed onset of clinical symptoms and prolonged survival. Notably, this effect was significantly more pronounced in males compared to females, and was accompanied by male-specific immune alterations, indicating a previously unknown sex-specific regulatory role of B cell-derived IL-10 duringMtbinfection.
The Three Stages of Learning to Master a Sensory Augmentation Device: Activation - Acquisition - Integration
Authors: Mühlinghaus Sascha , Schmidt Vincent , König Peter 
Published: July 2024

AbstractBy augmenting sensory perception through technology, researchers study how humans use and perceive the novel sensory input provided. Nevertheless, little is known about how learning unfolds over time. To this end, 27 participants trained with an augmentation device (feelSpace belt), which provides tactile feedback about the direction of the cardinal north, over the course of six weeks. During the training phase, we tracked participants’ progress using two different self-report questionnaires containing Likert-scale and open questions. Experts quantified responses to open questions using a previously established category system. As human raters are known to be susceptible to biases, we later reproduced the expert categorization using ChatGPT-4, finding a high congruence between the two classification approaches. The results suggest a three-stage model that best describes the process of acquiring an augmented sense. During the early activation stage, processing the augmented signal requires effort, induces fatigue, and a heightened awareness of the environment. In the knowledge acquisition phase, participants develop a more detailed cognitive spatial representation containing information about objects and places in relation to their current location. The deep integration stage is marked by participants seamlessly integrating the augmented information into existing perceptual processes and automatic use. The results support the supervised use of large language models (LLMs) for the analysis of qualitative data.
Pre-stimulus Activity Mediates Event-Related Theta Synchronization and Alpha Desynchronization During Memory Formation in Healthy Aging
Authors: Strzelczyk Dawid , Langer Nicolas 
Published: July 2024

AbstractThe capacity to learn is a key determinant for the quality of life but is known to decline to varying degrees with age. However, despite mounting evidence of memory deficits in older age, the neural mechanisms contributing to successful or impeded memory remain unclear. Previous research has primarily focused on memory formation through remembered versus forgotten comparisons, lacking the ability to capture the incremental nature of learning. Moreover, previous EEG studies have primarily examined oscillatory brain activity during the encoding phase, such as event-related synchronization (ERS) of mid-frontal theta and desynchronisation (ERD) of parietal alpha, while neglecting the potential influence of pre-stimulus activity. To address these limitations, we employed a sequence learning paradigm, where 113 young and 117 older participants learned a fixed sequence of visual locations through repeated observations (6423 sequence repetitions, 55 ’944 stimuli). This paradigm enabled us to investigate mid-frontal theta ERS, parietal alpha ERD, and how they are affected by pre-stimulus activity during the incremental learning process. Behavioral results revealed that young subjects learned significantly faster than older subjects, in line with expected age-related cognitive decline. Successful incremental learning was directly linked to decreases of mid-frontal theta ERS and increases of parietal alpha ERD. Notably, these neurophysiological changes were less pronounced in older individuals, reflecting a slower rate of learning. Importantly, the mediation analysis revealed that in both age groups, mid-frontal pre-stimulus theta partially mediated the relationship between learning and mid-frontal theta ERS. Furthermore, the overall impact of learning on parietal alpha ERD was primarily driven by its positive influence on pre-stimulus alpha activity. Our findings offer new insights into the age-related differences in memory formation and highlight the importance of pre-stimulus activity in explaining post-stimulus responses during learning.
In-SilicoAnalyses of Molecular Force Sensors for Mechanical Characterization of Biological Systems
Authors: Lopez Diana M. , Castro Carlos E. , Sotomayor Marcos 
Published: July 2024

ABSTRACTMechanical forces play key roles in biological processes such as cell migration and sensory perception. In recent years molecular force sensors have been developed as tools forin situforce measurements. Here we use all-atom steered molecular dynamics simulations to predict and study the relationship between design parameters and mechanical properties for three types of molecular force sensors commonly used in cellular biological research: two peptide-and one DNA-based. The peptide-based sensors consist of a pair of fluorescent proteins, which can undergo Förster resonance energy transfer (FRET), linked by spider silk (GPGGA)nor synthetic (GGSGGS)ndisordered regions. The DNA-based sensor consists of two fluorophore-labeled strands of DNA that can be unzipped or sheared upon force application with a FRET signal as readout of dissociation. We simulated nine sensors, three of each kind. After equilibration, flexible peptide linkers of three different lengths were stretched by applying forces to their N-and C-terminal Cα atoms in opposite directions. Similarly, we equilibrated a DNA-based sensor and pulled on the phosphate atom of the terminal guanine of one strand and a selected phosphate atom on the other strand in the opposite direction. These simulations were performed at constant velocity (0.01 nm/ns – 10 nm/ns) and constant force (10 pN – 500 pN) for all versions of the sensors. Our results show how the force response of these sensors depends on their length, sequence, configuration and loading rate. Mechanistic insights gained from simulations analyses indicate that interpretation of experimental results should consider the influence of transient formation of secondary structure in peptide-based sensors and of overstretching in DNA-based sensors. These predictions can guide optimal fluorophore choice and facilitate the rational design of new sensors for use in protein, DNA, hybrid systems, and molecular devices.STATEMENT OF SIGNIFICANCEBiomolecular structures involved in various biological processes, including muscle function and sensory perception, generate, convey, and respond to mechanical forces.In-vivoaccurate measurement of these forces is challenging but needed to understand biological function. Here we present a comprehensive computational analysis of three different types of molecular force sensors used to report pico-Newton level forces in biomolecular systems. Our atom-level simulation predictions provide mechanistic insight that can facilitate experimental data interpretation, selection of sensor design parameters, and the development of new force sensors tailored to specific applications and environments.
An enhancer-AAV toolbox to target and manipulate distinct interneuron subtypes
Authors: Furlanis Elisabetta , Dai Min , Leyva Garcia Brenda , Vergara Josselyn , Pereira Ana , Pelkey Kenneth , Tran Thien , Gorissen Bram L. , Vlachos Anna , Hairston Ariel , Huang Shuhan , Dwivedi Deepanjali , Du Sarah , Wills Sara , McMahon Justin , Lee Anthony T. , Chang Edward F. , Razzaq Taha , Qazi Ahmed , Vargish Geoffrey , Yuan Xiaoqing , Caccavano Adam , Hunt Steven , Chittajallu Ramesh , McLean Nadiya , Hewit Lauren , Paranzino Emily , Rice Haley , Cummins Alex C. , Plotnikova Anya , Mohanty Arya , Tangen Anne Claire , Shin Jung Hoon , Azadi Reza , Eldridge Mark A.G. , Alvarez Veronica A. , Averbeck Bruno B. , Alyahyay Mansour , Reyes Vallejo Tania , Soheib Mohammed , Vattino Lucas G. , MacGregor Cathryn P. , Banks Emmie , Olah Viktor Janos , Naskar Shovan , Hill Sophie , Liebergall Sophie , Badiani Rohan , Hyde Lili , Xu Qing , Allaway Kathryn C. , Goldberg Ethan M. , Nowakowski Tomasz J. , Lee Soohyun , Takesian Anne E. , Ibrahim Leena A. , Iqbal Asim , McBain Chris J. , Dimidschstein Jordane , Fishell Gord , Wang Yating 
Published: July 2024

SUMMARYIn recent years, we and others have identified a number of enhancers that, when incorporated into rAAV vectors, can restrict the transgene expression to particular neuronal populations. Yet, viral tools to access and manipulate fine neuronal subtypes are still limited. Here, we performed systematic analysis of single cell genomic data to identify enhancer candidates for each of the cortical interneuron subtypes. We established a set of enhancer-AAV tools that are highly specific for distinct cortical interneuron populations and striatal cholinergic neurons. These enhancers, when used in the context of different effectors, can target (fluorescent proteins), observe activity (GCaMP) and manipulate (opto- or chemo-genetics) specific neuronal subtypes. We also validated our enhancer-AAV tools across species. Thus, we provide the field with a powerful set of tools to study neural circuits and functions and to develop precise and targeted therapy.
Synergistic Biophysics and Machine Learning Modeling to Rapidly Predict Cardiac Growth Probability
Authors: Jones Clara E. , Oomen Pim J.A. 
Published: July 2024

AbstractComputational models that can predict growth and remodeling of the heart could have important clinical applications. However, the time it takes to calibrate and run current models while considering data uncertainty and variability makes them impractical for routine clinical use. This study aims to address this need by creating a computational framework to efficiently predict cardiac growth probability. We utilized a biophysics model to rapidly simulate cardiac growth following mitral valve regurgitation (MVR). Here we developed a two-tiered Bayesian History Matching approach augmented with Gaussian process emulators for efficient calibration of model parameters to align with growth outcomes within a 95%confidence interval. We first generated a synthetic data set to assess the accuracy of our framework, and the effect of changes in data uncertainty on growth predictions. We then calibrated our model to match baseline and chronic canine MVR data and used an independent data set to successfully validate the ability of our calibrated model to accurately predict cardiac growth probability. The combined biophysics and machine learning modeling framework we proposed in this study can be easily translated to predict patient-specific cardiac growth.
Epigenomic manipulation reveals the relationship between locus specific chromatin dynamics and gene expression
Authors: Venu Vrinda , Small Eric M. , Roth Cullen , Adikari Samantha H. , Cornelia Vlot Anna Hendrika , Sullivan Kyle A. , Abeyratne Chanaka Roshan , Jacobson Daniel , Starkenburg Shawn R. , Sanbonmatsu Karissa Y. , Steadman Christina R. 
Published: July 2024

SummaryDysregulation of epigenetic processes leads to a plethora of abnormalities including disease states such as cancer. Therapies focused on epigenetic modulation alter gene expression to correct dysfunction, though the mechanisms and perpetuation of these states is unknown. Here, we use integrated epigenomics and three-dimensional chromatin structure-function analyses after acute histone deacetylase inhibitor cancer drug treatment (suberoylanilide hydroxamic acid in lung cancer cells). Treatment induced substantial (13%) genomic rearrangement that rebounds despite persistent gene expression changes and spreading of acetylation. The chromatin functional landscape (accessibility, active transcription modification, and gene expression) is controlled and locus-specific, while chromatin contacts are globally altered resulting in a moderate weakening of topologically associating domains. Chromatin states are more dynamic at transcriptionally active loci while genes with reduced expression are epigenetically stable suggesting chromatin architectural turnover and nucleosome remodeling is locus-specific and underlies the bidirectional expression changes. Thus, local 3D chromatin and genome structural dynamics is integral for loci regulation in response to epigenomic perturbation. The partial persistence of these altered features may have larger implications for efficacy of epigenetic drugs in amelioration of disease states.
Advancing the Indian Cattle Pangenome: Characterizing Non-Reference Sequences inBos indicus
Authors: Azam Sarwar , Sahu Abhisek , Pandey Naveen Kumar , Neupane Mahesh , Van Tassel Curtis P , Rosen Benjamin D , Gandham Ravi Kumar , Rath Subha Narayan , Majumdar Subeer S 
Published: July 2024

AbstractBackgroundIndia, with the world’s largest cattle population and more than 50 registered breeds ofBos indicus, stands as a vital reservoir of genetic diversity. However, the abundant diversity among Indian cattle breeds highlights the inadequacy of a single reference sequence to represent the entire genomic content of desi cattle. We recognize the need to capture the genomic differences within theBos indicuspopulation as a whole, and specifically within the dairy cattle subset by identifying non-reference sequences and constructing a pangenome.FindingFive representative genomes of prominent dairy breeds, including Gir, Kankrej, Tharparkar, Sahiwal, and Red Sindhi, were sequenced using 10X Genomics ’Linked-Read’ technology. Assemblies generated from these linked-reads ranged from 2.70 Gb to 2.77 Gb,comparable to theBos indicusBrahman reference genome. A pangenome ofBos indicuscattle was constructed by comparing the newly assembled genomes with the reference using alignment and graph-based methods, revealing 8 Mb and 17.7 Mb of novel sequence respectively. A confident set of 6,844 Non-Reference Unique Insertions (NUIs) spanning 7.57 Mbs was identified through both methods, representing the pangenome of IndianBos indicusbreeds. Comparative analysis with previously published pangenomes unveiled 2.8 Mb (37%) commonality with the Chinese indicine pangenome and only 1% commonality with theBos tauruspangenome. Among these, 2,312 NUIs - encompassing ∼2 Mb, were commonly found in 98 samples of the 5 breeds and designated asBos indicusCommon Insertions (BICIs) in the population. Furthermore, 926 BICIs were identified within 682 protein-coding genes, 54 long non-coding RNAs (LncRNA), and 18 pseudogenes. These protein-coding genes were enriched for functions such as chemical synaptic transmission, cell junction organization, cell-cell adhesion, and cell morphogenesis. The protein-coding genes were found in various prominent Quantitative Trait Loci (QTL) regions, suggesting potential roles of BICIs in traits related to milk production, reproduction, exterior, health, meat, and carcass. Notably, 63.21% of the bases within the BICIs call set contained interspersed repeats, predominantly LINEs. Additionally,70.28% of BICIs are shared with other domesticated and wild species, highlighting their evolutionary significance.ConclusionThis is the first report unveiling a robust set of NUIs defining the pangenome ofBos indicusbreeds of India. The analyses contribute valuable insights into the genomic landscape of desi cattle breeds.