bluuebunny/crossref_metadata_2025_split huggingface dataset:
Axonal Tau sorting depends on the PRR2 domain and 0N4R-specific interactions hint at distinct roles of Tau isoforms in synaptic plasticity
Authors: Bell-Simons M. , Buchholz S. , Klimek J. , Zempel H. 
Published: July 2024

AbstractTau pathology is a major hallmark of Alzheimer’s disease (AD) and related diseases, called tauopathies. While Tau is normally enriched in axons, somatodendritic missorting of the microtubule-associated protein is a key event in early disease development. Tau missorting promotes synaptic loss and neuronal dysfunction but the mechanisms underlying both normal axonal sorting and pathological missorting remain unclear. Interestingly, the disease-associated Tau brain isoforms show different axodendritic distribution, but the distinct role of these isoforms in health and disease largely unknown. Here, we aimed to identify domains or motifs of Tau and cellular binding partners that are required for efficient axonal Tau sorting, and we studied the differences of the isoform-specific Tau interactome. By using humanMAPT-KO induced pluripotent stem cell (iPSC)-derived glutamatergic neurons, we analyzed the sorting behavior of more than 20 truncated or phosphorylation-mutant Tau constructs, and we used TurboID-based proximity labelling and proteomics to identify sorting- and isoform-specific Tau interactors. We found that efficient axonal Tau sorting was independent of the N-terminal tail, the C-terminal repeat domains, and the general microtubule affinity of Tau. In contrast, the presence of the proline-rich region 2 (PRR2) was necessary for successful sorting. Our interactome data revealed peroxisomal accumulation of the Tau N-terminal half, while axonal Tau interacted with the PP2A activator HSP110. When we compared the interactome of 0N3R- and 0N4R-Tau, we observed specific interactions of 0N4R-Tau with regulators of presynaptic exocytosis and postsynaptic plasticity, which are partially associated with AD pathogenesis, such as members of the CDC42 pathway and the RAB11 proteins, while 0N3R-Tau bound to MAP4 and other cytoskeletal elements. In sum, our study postulates that axonal Tau sorting relies on the PRR2 domain but not on microtubule affinity, and unravels a potential isoform-specific role in synaptic function and AD-related dysfunction.
Drought tolerance as an evolutionary precursor to frost and winter tolerance in grasses
Authors: Schat Laura , Schubert Marian , Fjellheim Siri , Humphreys Aelys M. 
Published: July 2024

AbstractAccumulating evidence is suggesting more frequent tropical-to-temperate transitions than previously thought. This raises the possibility that biome transitions could be facilitated by precursor traits. A wealth of ecological, genetic and physiological evidence suggests overlap between drought and frost stress responses, but the origin of this overlap, i.e. the evolution of these responses relative to each other, is poorly known. Here, we test whether adaptation to frost and/or severe winters in grasses (Poaceae) was facilitated by ancestral adaptation to drought. We used occurrence patterns across Köppen-Geiger climate zones to classify species as drought, frost and/or winter tolerant, followed by comparative analyses. Ancestral state reconstructions revealed different evolutionary trajectories in different clades, suggesting both drought-first and frost-first scenarios. A model of correlated evolution was not supported when transition rate heterogeneity was taken into account or compared to traits simulated under independent evolution. Our findings provide some support for ancestral drought tolerance facilitating transitions to cold, temperate biomes, at least in some clades. Different scenarios in different clades is consistent with present-day grasses being either cold or drought specialists, possibly as a consequence of trade-offs between different stress tolerance responses.
Integrative Imaging of Lung Micro Structure: Amplifying Classical Histology by Paraffin Block μCT and same-slide Scanning Electron Microscopy
Authors: Reiser Johanna , Albers Jonas , Svetlove Angelika , Mertiny Mara , Kommoss Felix K.F. , Schwab Constantin , Schneemann Anna , Tromba Giuliana , Wacker Irene , Curticean Ronald E. , Schroeder Rasmus R. , Kauczor Hans-Ulrich , Wielpütz Mark O. , Dullin Christian , Wagner Willi L. 
Published: July 2024

Classical histopathology of formalin fixed and paraffin embedded (FFPE) tissue using light microscopy (LM) remains the undisputed gold standard in biomedical microstructural lung tissue analysis. To extend this method, we developed an integrative imaging and processing pipeline which adds 3D context and screening capabilities by micro-CT (μCT) imaging of the entire paraffin block and adds ultrastructural information by correlative same-slide scanning electron microscopy (SEM). The different modalities are integrated by elastic registration to provide hybrid image datasets.Without compromising standard light microscopic readout, we overcome the limitations of conventional histology by combining and integrating several imaging modalities. The biochemical information contained in histological and immunohistological tissue staining is embedded into the 3D tissue configuration and is amplified by adding ultrastructural visualization of features of interest. By combining μCT and conventional histological processing, specimens can be screened, and specifically preselected areas of interest can be targeted in the subsequent sectioning process.While most of the μCT data shown in the manuscript was acquired at a Synchrotron, we further demonstrate that our workflow can also by applied using X-ray microscopy.
The role of LEDGF in transcription is exploited by HIV-1 to position integration
Authors: Pathak Rakesh , Esnault Caroline , Radhakrishnan Rajalingam , Singh Parmit K , Zhang Hongen , Dale Ryan , Anand Abhishek , Bedwell Gregory J , Engelman Alan N , Rabi Ali , Hormoz Sahand , Singh Priyanka , Levin Henry L 
Published: July 2024

AbstractHIV-1 integration occurs across actively transcribed genes due to the interaction of integrase with host chromatin factor LEDGF. Although LEDGF was originally isolated as a co-activator that stimulates promoter activity in purified systems, this role is inconsistent with LEDGF-mediated integration across gene bodies and with data indicating LEDGF is a histone chaperone that promotes transcriptional elongation. We found LEDGF is enriched in pronounced peaks that match the enrichments of H3K4me3 and RNA Pol II at transcription start sites (TSSs) of active promoters. Our genome-wide chromatin mapping revealed that MLL1 had a dominant role in recruiting LEDGF to promoters and the presence of LEDGF recruits RNA Pol II. Enrichment of LEDGF at TSSs correlates strongly with levels of integration across the transcribed sequences, indicating that LEDGF at TSSs contributed to integration across gene bodies. Although the N-terminal Pro-Trp-Trp-Pro (PWWP) domain of LEDGF interacts with nucleosomes containing H3K36me3, a modification thought to recruit LEDGF to chromatin, we found H3K36me3 does not contribute to gene specificity of integration. These data support a dual role model of LEDGF where it is tethered to promoters by MLL1 and recruits RNA Pol II. Subsequently, LEDGF travels across genes to effect HIV-1 integration. Our data also provides a mechanistic context for the contribution made by LEDGF to MLL1-based infant acute leukemia and acute myeloid leukemia in adults.
GeneLLM: A Large cfRNA Language Model for Cancer Screening from Raw Reads
Authors: Deng Siwei , Sha Lei , Jin Yongcheng , Zhou Tianyao , Wang Chengen , Liu Qianpu , Guo Hongjie , Xiong Chengjie , Xue Yangtao , Li Xiaoguang , Li Yuanming , Gao Yaping , Hong Mengyu , Xu Junjie , Chen Shanwen , Wang Pengyuan 
Published: July 2024

AbstractPlasma cell-free RNA (cfRNA) has recently emerged as a promising biomarker for non-invasive early cancer detection and treatment monitoring [8, 28, 31, 32, 38, 40]. Here, we introduce GeneLLM, a novel large language model de-signed to interpret cfRNA sequences directly, bypassing the need for genome annotations. GeneLLM significantly advances the detection accuracy of various cancer types. Our study demonstrates that this method achieves higher accuracy than traditional biomarkers and effectively handles large datasets from different centres, even with low sequencing depth. By avoiding the use of bioinformatics tools to count known genes, GeneLLM also discovered cfRNAs from previously unknown genes, referred to as ‘dark matters’ in the genome, as cancer detec-tion ‘pseudo-biomarkers’. Our results showcase the potential of GeneLLM to revolutionise cancer detection, making it more accessible and cost-effective. By offering a method that does not depend on bioinformatics tools to count known genes, GeneLLM opens new avenues for biomarker discovery and enhances our understanding of intercellular communication through novel RNA molecules.
Combined HDAC and eIF4A inhibition: A novel epigenetic therapy for pancreatic adenocarcinoma
Authors: Safari Maryam , Scotto Luigi , Basseville Agnes , Litman Thomas , Xue Haoran , Petrukhin Luba , Zhou Ping , Morales Diana V. , Damoci Christopher , Zhu Mingzhao , Hull Kenneth , Olive Kenneth P. , Fojo Tito , Romo Daniel , Bates Susan E. 
Published: July 2024

ABSTRACTPancreatic ductal adenocarcinoma-(PDAC) needs innovative approaches due to its 12% 5-year survival despite current therapies. We show marked sensitivity of pancreatic cancer cells to the combination of a novel eIF4A inhibitor, des-methyl pateamine A (DMPatA), and a histone deacetylase inhibitor, romidepsin, inducing epigenetic reprogramming as an innovative therapeutic strategy. Exploring the mechanistic activity of this combination showed that with a short duration of romidepsin at low doses, robust acetylation persisted up to 48h with the combination, while histone acetylation rapidly faded with monotherapy. This represents an unexpected mechanism of action against PDAC cells that triggers transcriptional overload, metabolic stress, and augmented DNA damage. Structurally different class I HDAC inhibitors exhibit the same hyperacetylation patterns when co-administered with DMPatA, suggesting a class effect. We show efficacy of this combination regimen against tumor growth in a MIA PaCa-2 xenograft model of PDAC with persistent hyperacetylation confirmed in tumor samples.STATEMENT OF SIGNIFICANCEPancreatic ductal adenocarcinoma, a significant clinical challenge, could benefit from the latent potential of epigenetic therapies like HDAC inhibitors-(HDIs), typically limited to hematological malignancies. Our study shows that a synergistic low dose combination of HDIs with an eIF4A-inhibitor in pancreatic cancer models results in marked pre-clinical efficacy, offering a promising new treatment strategy.
Hierarchical population genetic structure and signatures of adaptation inLates calcarifer
Authors: Campbell Matthew A. , Becker Joy A. 
Published: July 2024

AbstractContextLates calcariferis a widespread Indo-Pacific fish that is important in aquaculture, recreational and commercial fisheries. Genetic divergences from different data sources and sampling schemes have been reported.AimsTo conduct phylogenetic and population genetic analyses from a geographically and phylogenetically representative data set to identify hierarchical divisions withinL. calcarifer. We further test the evolutionary significance of genetic units in terms of signatures of adaptation.MethodsUsing a whole-genome sequence data set of 61 fish including an outgroup, we conducted phylogenetic and population genetic analyes. We also generated measures of Fst, nucleotide diversity (π) and Tajima’s D (D).Key ResultsWe identify three main lineages ofL. calcarifercorresponding to the Indian subcontinent, Southeast Asia and Australasia. Subdivision within each of the three main lineages is also identified and characterized. Adaptively significant differences are indicated within and between the three main lineages.ConclusionsL. calcariferexhibits genetic divergences at different levels that originate before and during the Pleistocene. These divergences are associated with adaptive divergence but unclear phenotypic changes.ImplicationsThis study highlights the need for comprehensive sampling and integrative study of genotypes and phenotypes across the range ofL. calcarifer.
Exploring individual codon influence on protein expression: a predictive approach
Authors: Zaytsev Konstantin , Bogatyreva Natalya , Fedorov Alexey 
Published: July 2024

ABSTRACTAn important role of a particular synonymous codon composition of a gene on its expression level is well-known. There are a number of algorithms optimising codon usage of recombinant genes to maximise their expression in host cells. Nevertheless, the problem has not been solved yet and remains relevant. In the realm of modern biotechnology, directing protein production to a specific level is crucial for metabolic engineering, genome rewriting, and a growing number of other applications. In this study, we propose two new simple statistical and empirical methods for predicting the protein expression level from the nucleotide sequence of the corresponding gene: Codon Expression Index Score (CEIS) and Codon Productivity Score (CPS). Both of these methods are based on the influence of each individual codon in the gene on the overall expression level of the encoded protein and the frequencies of isoacceptors in the species. Our predictions achieve a correlation with experimentally measured quantitative proteome data ofEscherichia coliup to a level of r=0.7, which is superior to any previously proposed methods. Our work helps to understand how codons determine translation rates; based on our methods, it is possible to design proteins optimised for expression in a particular organism.
Myelin-informed forward models for M/EEG source reconstruction
Authors: Helbling S , Meyer SS , Weiskopf N 
Published: July 2024

AbstractMagnetoencephalography (MEG) and Electroencephalography (EEG) provide direct electrophysiological measures at an excellent temporal resolution, but the spatial resolution of source-reconstructed current activity is limited to several millimetres. Here we show, using simulations of MEG signals and Bayesian model comparison, that non-invasive myelin estimates from high-resolution quantitative magnetic resonance imaging (MRI) can enhance MEG/EEG source reconstruction. Our approach assumes that MEG/EEG signals primarily arise from the synchronised activity of pyramidal cells, and since most of the myelin in the cortical sheet originates from these cells, myelin density can predict the strength of cortical sources measured by MEG/EEG. Leveraging recent advances in quantitative MRI, we exploit this structure-function relationship and scale the leadfields of the forward model according to the local myelin density estimates from in vivo quantitative MRI to inform MEG/EEG source reconstruction. Using Bayesian model comparison and dipole localisation errors (DLEs), we demonstrate that adapting local forward fields to reflect increased local myelination at the site of a simulated source explains the simulated data better than models without such leadfield scaling. Our model comparison framework proves sensitive to myelin changes in simulations with exact coregistration and moderate-to-high sensor-level signal-to-noise ratios (≥10 dB) for the multiple sparse priors (MSP) and empirical Bayesian beamformer (EBB) approaches. Furthermore, we sought to infer the microstructure giving rise to specific functional activation patterns by comparing the myelin-informed model which was used to generate the activation with a set of test forward models incorporating different myelination patterns. We found that the direction of myelin changes, however not their magnitude, can be inferred by Bayesian model comparison. Finally, we apply myelin-informed forward models to MEG data from a visuo-motor experiment. We demonstrate improved source reconstruction accuracy using myelin estimates from a quantitative longitudinal relaxation (R1) map and discuss the limitations of our approach.HighlightsWe use quantitative MRI to implement myelin-informed forward models for M/EEGLocal myelin density was modelled by adapting the local leadfieldsMyelin-informed forward models can improve source reconstruction accuracyWe can infer the directionality of myelination patterns, but not their strengthWe apply our approach to MEG data from a visuo-motor experiment
Functional monocentricity with holocentric characteristics and chromosome-specific centromeres in a stick insect
Authors: Toubiana William , Dumas Zoé , Van Patrick Tran , Parker Darren J. , Mérel Vincent , Schubert Veit , Aury Jean-Marc , Bournonville Lorène , Cruaud Corinne , Houben Andreas , Istace Benjamin , Labadie Karine , Noel Benjamin , Schwander Tanja 
Published: July 2024

ABSTRACTCentromeres are specialized genomic regions that are critical for chromosome segregation in eukaryotes. However, how the diversity of centromeres evolved, ranging from localized centromeres in monocentric species to complex chromosome-wide distributed centromere regions in holocentric species, remains elusive. Our cellular and genomic analyses inTimemastick insects reveal that within cell variation of the major centromere protein CenH3 recapitulates the variation typically observed across species. While CenH3-containing nucleosomes are distributed in a monocentric fashion on autosomes and bind tandem repeat sequences specific to individual or small groups of chromosomes, they exhibit a holocentric-like distribution on the sex chromosome and bind to more complex intergenic regions. Despite this contrasting distribution, all chromosomes, including the sex chromosome, attach to spindle microtubules at a single location, marking the first instance of a functionally monocentric species with holocentric-like attributes. Together, our findings highlight the potential for gradual transitions towards holocentricity or CenH3-independent centromere determination, and help to understand the rapid centromere sequence divergence between species.
Rod-shaped microglia interact with neuronal dendrites to regulate cortical excitability in TDP-43 related neurodegeneration
Authors: Xie Manling , Miller Alessandra S. , Pallegar Praveen N. , Umpierre Anthony , Liang Yue , Wang Na , Zhang Shuwen , Nagaraj Nagaswaroop Kengunte , Fogarty Zachary C. , Ghayal Nikhil B. , Oskarsson Björn , Zhao Shunyi , Zheng Jiaying , Qi Fangfang , Nguyen Aivi , Dickson Dennis W. , Wu Long-Jun 
Published: July 2024

AbstractMotor cortical hyperexcitability is well-documented in the presymptomatic stage of amyotrophic lateral sclerosis (ALS). However, the mechanisms underlying this early dysregulation are not fully understood. Microglia, as the principal immune cells of the central nervous system, have emerged as important players in sensing and regulating neuronal activity. Here we investigated the role of microglia in the motor cortical circuits in a mouse model of TDP-43 neurodegeneration (rNLS8). Utilizing multichannel probe recording and longitudinalin vivocalcium imaging in awake mice, we observed neuronal hyperactivity at the initial stage of disease progression. Spatial and single-cell RNA sequencing revealed that microglia are the primary responders to motor cortical hyperactivity. We further identified a unique subpopulation of microglia, rod-shaped microglia, which are characterized by a distinct morphology and transcriptional profile. Notably, rod-shaped microglia predominantly interact with neuronal dendrites and excitatory synaptic inputs to attenuate motor cortical hyperactivity. The elimination of rod-shaped microglia through TREM2 deficiency increased neuronal hyperactivity, exacerbated motor deficits, and further decreased survival rates of rNLS8 mice. Together, our results suggest that rod-shaped microglia play a neuroprotective role by attenuating cortical hyperexcitability in the mouse model of TDP-43 related neurodegeneration.
The Mammalian KU70 C-terminus SAP Domain Is Required to Repair Exogenous DNA Damage
Authors: Wang Yuan , Czap Michael S. , Kim Hailey , Lu Huimei , Liu Jingmei , Chang Yokechen , Romanienko Peter J. , Montagna Cristina , Shen Zhiyuan 
Published: July 2024

AbstractThe mammalian non-homologous end joining (NHEJ) is required for V(D)J recombination as well as coping with exogenously induced DNA double strand breaks (DSBs). Initiated by the binding of KU70/KU80 (KU) dimer to DNA ends and the subsequent recruitment of the DNA- dependent protein kinase catalytic subunit (DNA-PKcs), NHEJ plays a key role in DNA repair. While there has been significant structural understandings of how KU70 participates in NHEJ, the specific function of its highly conserved C-terminal SAP domain remains elusive. In this study, we developed a novel mouse model by deleting the SAP domain but preserving the KU70 nuclear localization and its dimerization ability with KU80. We found that the KU70 SAP deletion did not affect the V(D)J recombination or animal development but significantly impaired the animals and cells in repairing exogenously induced DSBs. We further showed an inability of KU70-ΔSAP cells to retain the DNA Ligase IV (LIG4) and other NHEJ co-factors on chromatin, and a spreading pattern of DSB marker γH2AX in KU70-ΔSAP cells after DNA damage. Our findings suggest that a specific inhibition of the SAP function may offer an opportunity to modulate cell sensitivity to therapeutic DSB-inducing agents without interfering with the developmental function of KU70.KeyPointsGeneration of a novel transgenic mouse line lacking the C-terminal conserved KU70-SAP domainKU70-SAP defends against exogenous DSBs, but unessential for development and V(D)J recombinationKU70-SAP aids in recruiting and retaining NHEJ components, such as LIG4, to DSB sites
Temporal Image Sandwiches Enable Link between Functional Data Analysis and Deep Learning for Single-Plant Cotton Senescence
Authors: DeSalvio Aaron J. , Adak Alper , Arik Mustafa A. , Shepard Nicholas R. , DeSalvio Serina M. , Murray Seth C. , García-Ramos Oriana , Badavath Himabindhu , Stelly David M. 
Published: July 2024

SummarySenescence is a highly ordered degenerative biological process that affects yield and quality in annuals and perennials. Images from 14 unoccupied aerial system (UAS, UAV, drone) flights captured the senescence window across two experiments while functional principal component analysis (FPCA) effectively reduced the dimensionality of temporal visual senescence ratings (VSRs) and two vegetation indices: RCC and TNDGR.Convolutional neural networks (CNNs) trained on temporally concatenated, or “sandwiched,” UAS images of individual cotton plants (Gossypium hirsutumL.), allowed single-plant analysis (SPA). The first functional principal component scores (FPC1) served as the regression target across six CNN models (M1-M6).Model performance was strongest for FPC1 scores from VSR (R2= 0.857 and 0.886 for M1 and M4), strong for TNDGR (R2= 0.743 and 0.745 for M3 and M6), and strong-to- moderate for RCC (R2= 0.619 and 0.435 for M2 and M5), with deep learning attention of each model confirmed by activation of plant pixels within saliency maps.Single-plant UAS image analysis across time enabled translatable implementations of high-throughput phenotyping by linking deep learning with functional data analysis (FDA). This has applications for fundamental plant biology, monitoring orchards or other spaced plantings, plant breeding, and genetic research.