bluuebunny/crossref_metadata_2025_split huggingface dataset:
Challenging Backpropagation: Evidence for Target Learning in the Cortex
Authors: Aceituno Pau Vilimelis , de Haan Sander , Loidl Reinhard , Grewe Benjamin F. 
Published: April 2024

1AbstractStudies at the intersection of neuroscience and machine learning have offered new insights to explain hierarchical learning in the neocortex. Two competing hypotheses have emerged: deep learninginspired approximations of the backpropagation algorithm, where neurons adjust synapses to minimize the error, and target learning algorithms, where neurons learn by reducing the feedback needed to achieve a desired activity. Despite decades of research and theoretical arguments supporting either possibility, there is currently no conclusive evidence for either hypothesis. We address this long-standing question by focusing on the relationship between synaptic plasticity and the somatic activity of pyramidal neurons. We first build a pyramidal neuron model integrating subcellular processes including calcium dynamics, backpropagating action potentials, and plateau potentials. Our model predicts that apical synaptic inputs drive basal synaptic plasticity through somatic depolarization caused by plateau potentials. We then test this prediction through in vitro electrophysiology experiments in which we co-stimulate apical and basal synapses to induce basal plasticity. These results allow us to derive distinct predictions for both the target learning and backpropagation hypotheses which we test on in vivo neuronal activity data from the mouse visual cortex. Our findings reveal that cortical learning is consistent with target learning, but not backpropagation, highlighting a critical discrepancy between deep learning and hierarchical learning in the neocortex.
AI reveals a damage signalling hierarchy that coordinates different cell behaviours driving wound re-epithelialisation
Authors: Turley Jake , Robertson Francesca , Chenchiah Isaac V. , Liverpool Tanniemola B. , Weavers Helen , Martin Paul 
Published: April 2024

AbstractOne of the key tissue movements driving closure of a wound is re-epithelialisation. Earlier wound healing studies have described the dynamic cell behaviours that contribute to wound re-epithelialisation, including cell division, cell shape changes and cell migration, as well as the signals that might regulate these cell behaviours. Here, we use a series of deep learning tools to quantify the contributions of each of these cell behaviours from movies of repairing wounds in theDrosophilapupal wing epithelium. We test how each is altered following knockdown of the conserved wound repair signals, Ca2+and JNK, as well as ablation of macrophages which supply growth factor signals believed to orchestrate aspects of the repair process. Our genetic perturbation experiments provide quantifiable insights regarding how these wound signals impact cell behaviours. We find that Ca signalling is a master regulator required for all contributing cell behaviours; JNK signalling primarily drives cell shape changes and divisions, whereas signals from macrophages regulate largely cell migration and proliferation. Our studies show AI to be a valuable tool for unravelling complex signalling hierarchies underlying tissue repair.
A combination of major histocompatibility complex (MHC) I overexpression and type I interferon induce mitochondrial dysfunction in human skeletal myoblasts
Authors: Thoma Anastasia , Bond Holly L , Akter-Miah Tania , Al-Shanti Nasser , Degens Hans , Pekovic-Vaughan Vanja , Lightfoot Adam P 
Published: April 2024

ABSTRACTThe overexpression of major histocompatibility complex (MHC) I on the surface of muscle fibres is a characteristic hallmark of the idiopathic inflammatory myopathies (IIMs), collectively termed myositis. Alongside MHC-I overexpression, sub-types of myositis, display a distinct type I interferon (IFN) signature. This study examined the combinational effects of elevated MHC-I and type I IFNs (IFNα/β) on mitochondrial function, as mitochondrial dysfunction is often seen in IIMs. Human skeletal muscle myoblasts were transfected with an MHC-I isoform using the mammalian HLA-A2/Kbvector. Mitochondrial respiration, mitochondrial membrane potential, and reactive oxygen/nitrogen species generation were assessed with or without IFNα and IFNβ. We show that MHC-I overexpression in human skeletal muscle myoblasts led to decreased basal glycolysis and mitochondrial respiration, cellular spare respiratory capacity, ATP-linked respiration, and an increased proton leak, which were all exaggerated by type I IFNs. Mitochondrial membrane depolarisation was induced by MHC-I overexpression both in absence and presence of type I IFNs. Human myoblasts overexpressing MHC-I showed elevated nitric oxide generation that was abolished when combined with IFN. MHC-I on its own did not result in an increased ROS production, but IFN on their own, or combined with MHC-I overexpression did induce elevated ROS generation. We present new evidence that MHC-I overexpression and type I IFNs aggravate the effects each has on mitochondrial function in human skeletal muscle cells, providing novel insights into their mechanisms of action and suggesting important implications in the further study of myositis pathogenesis.
MCM Double Hexamer Loading Visualised with Human Proteins
Authors: Weissmann Florian , Greiwe Julia F. , Pühringer Thomas , Miller Thomas C. R. , Diffley John F. X. , Costa Alessandro 
Published: April 2024

AbstractEukaryotic DNA replication begins with the loading of the MCM replicative DNA helicase as a head-to-head double hexamer (DH) at origins of DNA replication1–3. Our current understanding of how DH is assembled by the Origin Recognition Complex (ORC), CDC6 and CDT1 comes mostly from budding yeast. Here we characterise human DH (hDH) loading using biochemical reconstitution and cryo-electron microscopy with purified proteins. We show that hDH engages DNA differently from yeast (yDH), and generates ∼5 base pairs of unwound DNA at the interface between hexamers, as seen in hDH isolated from cells4. We identify several differences from yeast in the order of factor recruitment and dependencies during hDH assembly. Unlike yeast5–8, the ORC6 subunit of ORC is not essential for initial MCM recruitment or hDH loading, but contributes to an alternative hDH assembly pathway requiring an intrinsically disordered region (IDR) in ORC1, which may work through a novel MCM-ORC (hMO*) intermediate. Our work presents a detailed view of how DHs are assembled in an organism utilising sequence-independent replication origins, it provides further evidence for diversity in eukaryotic DH assembly mechanisms9, and it represents the first step toward reconstitution of DNA replication initiation with purified human proteins.
Evaluating the timecourses of morpho-orthographic, lexical, and grammatical processing following rapid parallel visual presentation: an EEG investigation in English
Authors: Dunagan Donald , Jordan Tyson , Hale John T , Pylkkänen Liina , Chacón Dustin A 
Published: April 2024

AbstractTheories of language processing – and typical experimental methodologies – emphasize the word-by-word processing of sentences. This paradigm is good for approximating speech or careful text reading, but arguably, not for the common, cursory glances used while reading short sentences (e.g., cellphone notifications, social media posts). How can we interpret a sentence in a single glance? In an electroencephalography (EEG) study, brain responses to grammatical sentences (the dogs chase a ball) presented for 200ms diverged from non-lexical consonant strings (thj rjxb zkhtb w lhct) ∼160ms post-sentence onset and from scrambled constructions (a dogs chase ball the) ∼250ms post-sentence onset, demonstrating – at different time points – rapid recognition and cursory analysis of linguistic stimuli. In the grammatical sentences, unigram probability correlated with EEG data ∼150–300ms post-sentence onset, and probability of the word given its context estimated by BERT correlated with EEG data after ∼700–800ms. EEG responses did not diverge between grammatical sentences and their counterparts with ungrammatical agreement (the dogs chases a ball), although EEG responses did diverge for plural vs. singular morphology at ∼200ms. These results suggest that ‘at-a-glance’ reading is possible, based on coactivation of individual lexical items, morphological structures, and constituent structure at ∼200-300ms, but that words are not integrated into a coherent syntactic/semantic analysis, as evidenced by the substantially later responses to BERT probability and the absence of sensitivity to agreement errors.
da_Tracker: Automated workflow for high throughput single cell and single phagosome tracking in infected cells
Authors: Augenstreich Jacques , Poddar Anushka , Belew Ashton T. , El-Sayed Najib M , Briken Volker 
Published: April 2024

AbstractTime-lapse microscopy has emerged as a crucial tool in cell biology, facilitating a deeper understanding of dynamic cellular processes. While existing tracking tools have proven effective in detecting and monitoring objects over time, the quantification of signals within these tracked objects often faces implementation constraints. In the context of infectious diseases, the quantification of signals at localized compartments within the cell and around intracellular pathogens can provide even deeper insight into the interactions between the pathogen and host cell organelles. Existing quantitative analysis at a single-phagosome level remains limited and dependent on manual tracking methods. We developed a near-fully automated workflow that performs with limited bias, high-throughput cell segmentation and quantitative tracking of both single cell and single bacterium/phagosome within multi-channel, z-stack, time-lapse confocal microscopy videos. We took advantage of the PyImageJ library to bring Fiji functionality into a Python environment and combined deep-learning-based segmentation from Cellpose with tracking algorithms from Trackmate. Our workflow provides a versatile toolkit of functions for measuring relevant signal parameters at the single-cell level (such as velocity or bacterial burden) and at the single-phagosome level (i.e. assessment of phagosome maturation over time). It’s capabilities in both single-cell and single-phagosome quantification, its flexibility and open-source nature should assist studies that aim to decipher for example the pathogenicity of bacteria and the mechanism of virulence factors that could pave the way for the development of innovative therapeutic approaches.
Genome-Wide association study uncovers pea candidate genes and pathways involved in rust resistance
Authors: Osuna-Caballero Salvador , Rubiales Diego , Rispail Nicolas 
Published: April 2024

AbstractPea is an important temperate legume crop providing plant-based proteins for food and feed worldwide. Pea yield can be limited by a number of biotic stresses, among which, rust represents a major limiting factor. Some efforts have been made to assess the natural variation in pea resistance, but its efficient exploitation in breeding is limited since the resistance loci identified so far are scarce and their responsible gene(s) unknown. To overcome this knowledge gap, a comprehensive Genome-Wide Association Study (GWAS) on pea rust, caused byUromyces pisi, has been performed to uncover genetic loci associated with resistance. Utilizing a diverse collection of 320 pea accessions, we evaluated phenotypic responses to two rust isolates using both traditional methods and advanced image-based phenotyping. We detected 95 significant trait-marker associations using a set of 26,045 DArT-seq polymorphic markers. Ourin-silicoanalysis identified 62 candidate genes putatively involved in rust resistance, grouped into different functional categories such as gene expression regulation, vesicle trafficking, cell wall biosynthesis, and hormonal signalling. This research highlights the potential of GWAS to identify resistance sources, molecular markers associated with resistance and candidate genes against pea rust, offering new targets for precision breeding. By integrating our findings with current breeding programs, we can facilitate the development of pea varieties with improved resistance to rust, contributing to sustainable agricultural practices and food security. This study sets the stage for future functional genomic analyses and the application of genomic selection approaches to enhance disease resistance in peas.Key messageCandidate genes and metabolic pathways controlling resistance to rust disease in pea have been proposed through GWAS using 26,045 DArTseq polymorphic markers and phenotypic data from field and controlled conditions.
Postsynaptic BMP signaling regulates myonuclear properties inDrosophilalarval muscles
Authors: von Saucken Victoria E. , Windner Stefanie E. , Baylies Mary K. 
Published: April 2024

AbstractThe syncytial mammalian muscle fiber contains a heterogeneous population of (myo)nuclei. At the neuromuscular junction (NMJ), myonuclei have specialized positioning and gene expression. However, it remains unclear how myonuclei are recruited and what regulates myonuclear output at the NMJ. Here, we identify specific properties of myonuclei located near theDrosophilalarval NMJ. These synaptic myonuclei have increased size in relation to their surrounding cytoplasmic domain (scaling), increased DNA content (ploidy), and increased levels of transcription factor pMad, a readout for BMP signaling activity. Our genetic manipulations show local BMP signaling affects muscle size, nuclear size, ploidy, and NMJ size and function. In support, RNA sequencing analysis reveals that pMad regulates genes involved in muscle growth, ploidy (i.e.,E2f1), and neurotransmission. Our data suggest that muscle BMP signaling instructs synaptic myonuclear output that then positively shapes the NMJ synapse. This study deepens our understanding of how myonuclear heterogeneity supports local signaling demands to fine tune cellular function and NMJ activity.SummaryThe neuromuscular junction (NMJ) is a well characterized synapse, yet the postsynaptic contributions that allow for synapse function are not well understood. This study by von Sauckenet al. uses theDrosophilalarval NMJ to define synaptic muscle (myo)nuclei and their properties and determine how BMP signaling regulates these myonuclear properties.
A human-specific enhancer fine-tunes radial glia potency and corticogenesis
Authors: Liu Jing , Mosti Federica , Zhao Hanzhi T. , Sotelo-Fonseca Jesus E. , Escobar-Tomlienovich Carla F. , Lollis Davoneshia , Musso Camila M. , Mao Yiwei , Massri Abdull J. , Doll Hannah M. , Sousa Andre M. , Wray Gregory A. , Schmidt Ewoud , Silver Debra L. 
Published: April 2024

SummaryHumans evolved an extraordinarily expanded and complex cerebral cortex, associated with developmental and gene regulatory modifications1–3. Human accelerated regions (HARs) are highly conserved genomic sequences with human-specific nucleotide substitutions. Although there are thousands of annotated HARs, their functional contribution to human-specific cortical development is largely unknown4,5.HARE5is a HAR transcriptional enhancer of the WNT signaling receptorFrizzled8 (FZD8)active during brain development6. Here, using genome-edited mouse and primate models, we demonstrate that human(Hs) HARE5fine-tunes cortical development and connectivity by controlling the proliferative and neurogenic capacity of neural progenitor cells (NPCs).Hs-HARE5knock-in mice have significantly enlarged neocortices containing more neurons. By measuring neural dynamicsin vivowe show these anatomical features correlate with increased functional independence between cortical regions. To understand the underlying developmental mechanisms, we assess progenitor fate using live imaging, lineage analysis, and single-cell RNA sequencing. This revealsHs-HARE5modifies radial glial progenitor behavior, with increased self-renewal at early developmental stages followed by expanded neurogenic potential. We use genome-edited human and chimpanzee (Pt) NPCs and cortical organoids to assess the relative enhancer activity and function ofHs-HARE5andPt-HARE5.Using these orthogonal strategies we show four human-specific variants inHARE5drive increased enhancer activity which promotes progenitor proliferation. These findings illustrate how small changes in regulatory DNA can directly impact critical signaling pathways and brain development. Our study uncovers new functions for HARs as key regulatory elements crucial for the expansion and complexity of the human cerebral cortex.
Centromeric localization of KNL2 and CENP-C proteins in plants depends on their centromere-targeting domain and DNA-binding regions
Authors: Yalagapati Surya Prakash , Ahmadli Ulkar , Sinha Aditya , Kalidass Manikandan , Dabravolski Siarhei , Zuo Sheng , Yadala Ramakrishna , Rutten Twan , Berr Alexandre , Talbert Paul , Lermontova Inna 
Published: April 2024

AbstractIn eukaryotic organisms, proper chromosome segregation during cell division depends on the centromeric histone H3 (CENH3) variant. Our previous studies identified a plant CENH3 assembly factor, Kinetochore Null2 (αKNL2), that possesses a centromere-targeting motif, CENPC-k, similar to the CENPC motif in CENP-C. Additionally, we have demonstrated that αKNL2 can bind DNAin vitro,independent of its CENPC-k motif. Thus, the mechanism underlying the binding of αKNL2 to centromeric DNA remains elusive.Our study shows that the CENPC-k and CENPC motifs alone are not sufficient to target the centromere inN. benthamianaandA. thaliana.In-silicoanalysis revealed flanking DNA-binding regions near the CENPC-k and CENPC motifs, suggesting their importance in interacting with centromeric DNA. Fusion of protein fragments containing these motifs to EYFP facilitated targeting to the centromere. Deletion of DNA-binding domains reduced the centromeric localization of αKNL2-C, whereas fusion of CENPC-k to the H-NS protein from E. coli targeted it to centromeres.We conclude that targeting of αKNL2 and CENP-C proteins to centromeres is dependent on the CENPC-k/CENPC motifs, and their sequence-independent DNA-binding promotes anchoring at the centromere. Understanding the targeting mechanisms of KNL2 and CENP-C may help to engineer kinetochore structure by targeting chromatin modifying proteins to centromeres.
Extracellular vesicles adhere to cells primarily by interactions of integrins and GM1 with laminin
Authors: Isogai Tatsuki , Hirosawa Koichiro M. , Kanno Miki , Sho Ayano , Kasai Rinshi S. , Komura Naoko , Ando Hiromune , Furukawa Keiko , Ohmi Yuhsuke , Furukawa Koichi , Yokota Yasunari , Suzuki Kenichi G. N. 
Published: April 2024

AbstractTumor-derived extracellular vesicles (EVs) have attracted significant attention, yet the molecular mechanisms that govern their specific binding to recipient cells remain elusive. Our in vitro study utilizing single-particle tracking demonstrated that integrin heterodimers comprising α6β4 and α6β1 and ganglioside, GM1 are responsible for the binding of small-EV (sEV) subtypes to laminin. EVs derived from four distinct tumor cell lines, regardless of size, exhibited high binding affinities for laminin but not for fibronectin, although fibronectin receptors are abundant in EVs and have functional roles in EV-secreting cells. Our findings revealed that integrins in EVs bind to laminin via the conventional molecular interface, facilitated by CD151 rather than by inside-out signaling of talin-1 and kindlin-2. Super-resolution movie observation revealed that sEV integrins bind only to laminin on living recipient cells. Furthermore, sEVs bound to HUVEC and induced cell branching morphogenesis in a laminin-dependent manner. Thus, we demonstrated that EVs predominantly bind to laminin on recipient cells, which is indispensable for cell responses.SummaryQuantitative assessments using single-molecule imaging and super-resolution microscopy revealed that all extracellular vesicle subtypes derived from four distinct tumor cell lines, regardless of size, bind to laminin predominantly via CD151-facilitated integrin heterodimers and GM1, leading to response of recipient cells.
Limits on dark matter annihilation in prompt cusps from the isotropic gamma-ray background
Authors: Delos M. Sten , Korsmeier Michael , Widmark Axel , Blanco Carlos , Linden Tim , White Simon D. M. 
Published: April 2024

Recent studies indicate that thermally produced dark matter will form highly concentrated, low-mass cusps in the early universe that often survive until the present. While these cusps contain a small fraction of the dark matter, their high density significantly increases the expected γ-ray flux from dark matter annihilation, particularly in searches of large angular regions. We utilize 14 years of Fermi-LAT data to set strong constraints on dark matter annihilation through a detailed study of the isotropic γ-ray background, excluding with 95% confidence dark matter annihilation to bb¯ final states for dark matter masses below 120 GeV.

Published by the American Physical Society
2024
Mechanical and radar absorption properties of sheep wool/epoxy composites
Authors: Saracoglu Goksel , Kiriş Serap , Çoban Sezer , Karaaslan Muharrem , Depci Tolga , Bayraktar Emin 
Published: April 2024

Purpose
The aim of this study is to determine the fracture behavior of wool felt and fabric based epoxy composites and their responses to electromagnetic waves.

Design/methodology/approach
Notched and unnotched tensile tests of composites made of wool only and hybridized with a glass fiber layer were carried out, and fracture behavior and toughness at macro scale were determined. They were exposed to electromagnetic waves between 8 and 18 GHz frequencies using two horn antennas.

Findings
The keratin and lignin layer on the surface of the wool felt caused lower values to be obtained compared to the mechanical values given by pure epoxy. However, the use of wool felt in the symmetry layer of the laminated composite material provided higher mechanical values than the composite with glass fiber in the symmetry layer due to the mechanical interlocking it created. The use of wool in fabric form resulted in an increase in the modulus of elasticity, but no change in fracture toughness was observed. As a result of the electromagnetic analysis, it was also seen in the electromagnetic analysis that the transmittance of the materials was high, and the reflectance was low throughout the applied frequency range. Hence, it was concluded that all of the manufactured materials could be used as radome material over a wide band.

Practical implications
Sheep wool is an easy-to-supply and low-cost material. In this paper, it is presented that sheep wool can be evaluated as a biocomposite material and used for radome applications.

Originality/value
The combined evaluation of felt and fabric forms of a natural and inexpensive reinforcing element such as sheep wool and the combined evaluation of fracture mechanics and electromagnetic absorption properties will contribute to the evaluation of biocomposites in aviation.