bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bayesian parameter inference for epithelial mechanics
Authors: Yan Xin , Ogita Goshi , Ishihara Shuji , Sugimura Kaoru 
Published: April 2024

AbstractCell-based mechanical models, such as the Cell Vertex Model (CVM), have proven useful for studying the mechanical control of epithelial tissue dynamics. We recently developed a statistical method called image-based parameter inference for formulating CVM model functions and estimating their parameters from image data of epithelial tissues. In this study, we employed Bayesian statistics to improve the utility and flexibility of image-based parameter inference. Tests on synthetic data confirmed that both our non-hierarchical and hierarchical Bayesian models provide accurate estimates of model parameters. By applying this method toDrosophilawings, we demonstrated that the reliability of parameter estimation is closely linked to the mechanical anisotropies present in the tissue. Moreover, we revealed that the cortical elasticity term is dispensable for explaining force-shape correlationsin vivo. We anticipate that the flexibility of the Bayesian statistical framework will facilitate the integration of various types of information, thereby contributing to the quantitative dissection of the mechanical control of tissue dynamics.
Disruption of WSB2-mediated NOXA Degradation Induces Synthetic Lethality to Anti-apoptotic BCL-2 Family Protein Inhibitors
Authors: Jiao Dongyue , Chang Kun , Chen Yingji , Jin Jiamin , Mo Ren , Zhang Yucong , Gao Kun , Xu Yaoting , Wang Lixin , Wang Chenji 
Published: April 2024

AbstractAnti-apoptotic BCL-2 family proteins are frequently overexpressed in various cancers, contributing to the initiation and development of cancer, as well as intrinsic or acquired resistance to therapy. Although BCL-2 family protein inhibitors, such as Venetoclax, have demonstrated efficacy in hematological neoplasms, their effectiveness as single agents in solid tumors is limited. Identifying alternative molecular targets that can overcome intrinsic resistance to BCL-2 family protein inhibitors is of great clinical importance. Here, we present evidence of strong synthetic lethal interactions between WSB2, a relatively unexplored substrate-binding receptor of the Cullin 5-RBX2-Elongin B/C (CRL5) E3 ubiquitin ligase complex, and multiple anti-apoptotic BCL-2 family proteins. Mechanistically, an assembled CRL5WSB2E3 ubiquitin ligase complex targets NOXA, a pro-apoptotic BCL-2 family protein, for degradation via the ubiquitin-proteasomal pathway. Ablation of WSB2 leads to a remarkable accumulation of NOXA proteins in cultured cell lines and knockout mouse organs. While WSB2 deficiency alone has a minimal effect on spontaneous apoptosis, it renders cancer cells more susceptible to apoptosis when anti-apoptotic BCL-2 family proteins are genetically depleted or pharmacologically inhibited. These findings establish WSB2 as a critical regulator of mitochondrial apoptosis and highlight the dysregulation of the WSB2-NOXA regulatory axis as a contributing factor to apoptosis resistance in cancer cells. Synergistically targeting WSB2 and anti-apoptotic BCL-2 family proteins holds promising clinical potential in the treatment of human cancers.
CENP-A/CENP-B uncoupling in the evolutionary reshuffling of centromeres
Authors: Cappelletti Eleonora , Piras Francesca M. , Biundo Marialaura , Raimondi Elena , Nergadze Solomon G. , Giulotto Elena 
Published: April 2024

ABSTRACTBackgroundWhile CENP-A is the epigenetic determinant of the centromeric function, the role of CENP-B, the sole centromeric protein binding a specific DNA sequence (CENP-B-box), remains elusive. In the few mammalian species analyzed so far, the CENP-B box is contained in the major satellite repeat that is present at all centromeres. We previously demonstrated that, in the genusEquus, some centromeres lack any satellite repeat.ResultsHere, we show that, in fourEquusspecies, CENP-B is expressed but does not bind the numerous satellite-free and the majority of satellite-based centromeres while it is localized at several ancestral now inactive centromeres. The absence of CENP-B is related to the lack of CENP-B boxes rather than to peculiar features of the protein itself. CENP-B boxes are comprised in a previously undescribed repeat which is not the major satellite bound by CENP-A. Comparative sequence analysis suggests that this satellite was centromeric in the equid ancestor, lost centromeric function during evolution and gave rise to a short CENP-A bound repeat not containing the CENP-B box but being enriched in dyad symmetries. Centromeres lacking CENP-B are functional and recruit normal amounts of the centromeric proteins CENP-A and CENP-C.ConclusionsWe propose that the uncoupling between CENP-B and CENP-A may have played a role in the evolutionary reshuffling of equid centromeres. This study provides new insights into the complexity of centromere organization in a largely biodiverse world where the majority of mammalian species still have to be studied.
Damage explains function in spiking neural networks representing central pattern generator
Authors: Pryyma Yuriy , Yakovenko Sergiy 
Published: April 2024

AbstractComplex biological systems evolved to control dynamics in the presence of noisy and often unpredictable inputs. The staple example is locomotor control, which is vital for survival. Control of locomotion results from interactions between multiple systems--from passive dynamics of inverted pendulum governing body motion to coupled neural oscillators that integrate predictive forward and sensory feedback signals. The neural dynamic computations are expressed in the rhythmogenic spinal network termed the central pattern generator (CPG). While a system of ordinary differential equations or a rate model is typically “good enough” to describe the CPG function, the computations performed by thousands of neurons in vertebrates are poorly understood. To study the distributed computations of a well-defined neural dynamic system, we developed a CPG model for gait expressed with the spiking neural networks (SNN). The SNN-CPG model faithfully recreated the input-output relationship of the rate model, describing the modulation of gait phase characteristics. The degradation of distributed computation within elements of the SNN-CPG model was further studied with “lesion” experiments. We found that lesioning flexor or extensor elements, with otherwise identical structural organization of reciprocal networks, affected differently the overall CPG computation. This result mimics experimental observations. Moreover, the increasing general excitability within the network can compensate for the loss of function after progressive lesions. This observation may explain the response to spinal stimulation and propose a novel theoretical framework for degraded computations and their applications within restorative technologies.
Impact of photobleaching of fluorescent proteins on FRET measurements under two-photon excitation
Authors: Adhikari Dhruba P. , Stoneman Michael R. , Raicu Valerica 
Published: April 2024

ABSTRACTFörster resonance energy transfer (FRET) is a widely used technique for nanoscale molecular distance measurements, which makes FRET ideal for studying protein interactions and quaternary structure of protein complexes. In this work, we were interested in how photobleaching of donor and acceptor molecules affects the FRET results under various excitation conditions. We conducted a systematic study, under two-photon excitation, of the effects of the excitation power and the choice of excitation wavelengths upon the measured FRET efficiencies of multiplex protein constructs, consisting of one donor and either one or two acceptors, using both the kinetic theory of FRET and numerical simulations under given excitation conditions. We found that under low excitation power and properly chosen excitation wavelengths the relationship between the FRET efficiency of a trimeric construct ADA agrees within 2% with the FRET efficiency computed (via the kinetic theory of FRET in the absence of photobleaching) from two dimeric constructs ADN and NDA. By contrast, at higher excitation powers the FRET efficiencies changed significantly, due to the photobleaching of both the donor (through direct excitation) and the acceptor (mostly through FRET-induced excitation). Based on these results and numerical simulations using a simple but powerful algorithm, we also provide guidelines for choosing appropriate experimental conditions for reliable FRET measurements in complexes of associating molecules of biological interest.
A multiplexed and quantitative assay for small-molecule detection via photo-crosslinking of structure switching aptamers
Authors: Newman Sharon S. , Wilson Brandon , Zheng Liwei , Eisenstein Michael , Soh Tom 
Published: April 2024

AbstractThere is an unmet need for molecular detection assays that enable the multiplexed, quantification of smallmolecule analytes. We present xPlex, an assay that combines aptamer switches with ultraviolet-crosslinkable complementary strands to record target-binding events. When the aptamer’s small-molecule target is present, the crosslinkable strand is displaced, enabling PCR amplification and detection of the relevant aptamer. In the absence of that target, the aptamer is readily cross-linked to the strand, preventing amplification from happening. The resulting aptamer-specific amplicons can be detected and quantified in a multiplexed fashion using high-throughput sequencing. We demonstrate quantitative performance for a pair of small-molecule analytes, dopamine and glucose, and show that this assay retains good specificity with mixtures of the two molecules at various concentrations. We further show that xPlex can effectively evaluate the specificity of cross-reactive aptamers to a range of different small-molecule analytes. We believe the xPlex assay format could offer a useful strategy for achieving multiplexed analysis of small-molecule targets in a variety of scenarios.
CA1i pyramidal neurons mediate the role of NMDA receptor subunit GluN3A in depressive behavior and D-serine anti-depression
Authors: Zhang Wei , Wang Jiesi , Dai Jiajie , Zhuo Linan , Zhao Mingyue , Ye Haimou , Wang Weiwen 
Published: April 2024

AbstractDepression is a heterogeneous psychiatric disorder characterized by multiple symptom clusters. N-methyl-d-aspartic acid receptors (NMDARs), consisting of various subunit proteins GluN1-3, are known to be critical molecular bases for the occurrence and treatment of depression. However, the involvement of the NMDAR subunit GluN3A in the heterogeneity of depressive symptoms and antidepressant effects remains unclear. Here, we found that chronic social defeat stress (CSDS) induced a range of depression-related behaviors, including decreased social interest, increased helplessness and anxiety-like behavior, and reduced GluN3A mRNA and protein expression in the hippocampal CA1 intermediate (CA1i) region. Additionally, GluN3A knockout (KO) mice exhibited pronounced helplessness behavior. Increasing GluN3A expression in the CA1i in both models specifically reversed the increased helplessness behavior but not social interest and anxiety-like behavior. Furthermore, the lack of CA1i GluN3A expression reduced the activity of CA1i pyramidal neurons in mice during helplessness behavior, a phenomenon also reversed by upregulating CA1i GluN3A expression. Further bidirectional modulation of CA1i pyramidal neuron activity directly mimicked or reversed CSDS-induced helplessness behavior. Finally, injection of D-serine into the CA1i rapidly improved helplessness behavior in CSDS mice while increasing the activity of CA1i pyramidal neurons, whereas knockout of the GluN3A or inhibition of CA1i neuron activity prevented the effect of D-serine. Our study elucidates the critical role of GluN3A subunit in regulating depression-related helplessness behavior and its mechanisms, as well as its role in the rapid antidepressant effect of D-serine, which deepen the understanding of the complex pathophysiology of depression and develop a potential clinical treatment new target.
CaClust: linking genotype to transcriptional heterogeneity of follicular lymphoma using BCR and exomic variants
Authors: Oksza-Orzechowski Kazimierz , Quinten Edwin , Darvish-Shafighi Shadi , Kiełbasa Szymon M. , van Kessel Hugo W. , de Groen Ruben A. L. , Vermaat Joost S. P. , Yáñez Julieta H. Sepúlveda , Navarrete Marcelo A. , Veelken Hendrik , van Bergen Cornelis A. M. , Szczurek Ewa 
Published: April 2024

AbstractTumor tissues exhibit high genotypic and transcriptional heterogeneity, resulting from tumor evolution and affecting cancer progression and treatment. These two types of heterogeneity in follicular lymphoma were so far predominantly studied in separation. To comprehensively investigate the evolution and genotype to phenotype maps in follicular lymphoma, we introduce CaClust, a probabilistic graphical model that integrates deep whole exome, single-cell RNA and B-cell receptor sequencing data to infer clone genotypes, cell-to-clone mapping, and single-cell genotyping. CaClust outperforms a state-of-the-art model on simulated and patient data. In-depth analysis of 22492 single cells and whole exomes from four follicular lymphoma samples using CaClust gives insights into effects of driver mutations, follicular lymphoma evolution, and possible therapeutic targets. CaClust single-cell genotyping agrees with genotypes observed in an independent targeted resequencing experiment. Our approach is the first to evaluate the strength of genotype to phenotype links in follicular lymphoma in the evolutionary context of the disease.
Native Proteomics by Capillary Zone Electrophoresis-Mass Spectrometry
Authors: Wang Qianyi , Wang Qianjie , Qi Zihao , Moeller William , Wysocki Vicki H , Sun Liangliang 
Published: April 2024

AbstractNative proteomics measures endogenous proteoforms and protein complexes under a near physiological condition using native mass spectrometry (nMS) coupled with liquid-phase separations. Native proteomics should provide the most accurate bird’s-eye view of proteome dynamics within cells, which is fundamental for understanding almost all biological processes. nMS has been widely employed to characterize well-purified protein complexes. However, there are only very few trials of utilizing nMS to measure proteoforms and protein complexes in a complex sample (i.e., a whole cell lysate). Here, we pioneer the native proteomics measurement of large proteoforms or protein complexes up to 400 kDa from a complex proteome via online coupling of native capillary zone electrophoresis (nCZE) to an ultra-high mass range (UHMR) Orbitrap mass spectrometer. The nCZE-MS technique enabled the measurement of a 115-kDa standard protein complex while consuming only about 0.1 ng of protein material. nCZE-MS analysis of anE.colicell lysate detected 72 proteoforms or protein complexes in a mass range of 30-400 kDa in a single run while consuming only 50-ng protein material. The mass distribution of detected proteoforms or protein complexes agreed well with that from mass photometry measurement. This work represents a technical breakthrough in native proteomics for measuring complex proteomes.
Pear (Pyrus communisL. cv. Conference) has shade-tolerant features allowing for consistent agrivoltaic crop yield
Authors: Reher Thomas , Willockx Brecht , Schenk Ann , Bisschop Jolien , Huyghe Yasmin , Nicolaï Bart M. , Martens Johan A. , Diels Jan , Cappelle Jan , Van de Poel Bram 
Published: April 2024

AbstractTransitioning to a fossil fuel free society requires an increase in solar energy production. However, expanding solar power to farmland competes with food production. Additionally, climate change threatens food security and leads increasingly to yield losses.Agrivoltaics (AV) systems produce solar energy and food on the same field, while sheltering crops. In AV systems, crops grow in a modified environment with reduced solar irradiance, a tempered microclimate and a potential physical cover protecting against hail damage.This research describes pear production under an AV pilot with 24% light reduction for 3 consecutive seasons. AV pear trees yielded 14% less than the reference. Flowering and fruit set was unchanged while AV reduced leaf flavonoid levels. The leaf photosynthetic light response was identical, yet a delayed leaf senescence under AV suggests an adaptation to the modified environment. AV impacted fruit shape, as there was an increase in the number of bottle shaped pears and a reduction in caliber. Other fruit quality traits were broadly unaffected, yet postharvest ethylene production was higher for AV fruit in 2022 than for the control.This study demonstrates that AV systems hold potential for pear production under temperate climates and highlights plant adaptations that make this possible.HighlightPear cultivation in agrivoltaic systems integrates renewable energy and sustainable fruit production. This study provides insights into crop yield, fruit quality, and plant adaptation towards an agrivoltaic environment.
Imaging demyelinated axons after spinal cord injuries with PET tracer [18F]3F4AP
Authors: Ramos-Torres Karla M. , Conti Sara , Zhou Yu-Peng , Tiss Amal , Caravagna Celine , Takahashi Kazue , He Zhigang , Wilks Moses Q. , Eckl Sophie , Sun Yang , Biundo Jason , Gong Kuang , He Zhigang , Linnman Clas , Brugarolas Pedro 
Published: April 2024

AbstractSpinal cord injuries (SCI) often lead to lifelong disability. Among the various types of injuries, incomplete and discomplete injuries, where some axons remain intact, offer potential for recovery. However, demyelination of these spared axons can worsen disability. Demyelination is a reversible phenomenon, and drugs like 4-aminopyridine (4AP), which target K+channels in demyelinated axons, show that conduction can be restored. Yet, accurately assessing and monitoring demyelination post-SCI remains challenging due to the lack of suitable imaging methods. In this study, we introduce a novel approach utilizing the positron emission tomography (PET) tracer, [18F]3F4AP, specifically targeting K+channels in demyelinated axons for SCI imaging. Rats with incomplete contusion injuries were imaged up to one month post-injury, revealing [18F]3F4AP’s exceptional sensitivity to injury and its ability to detect temporal changes. Further validation through autoradiography and immunohistochemistry confirmed [18F]3F4AP’s targeting of demyelinated axons. In a proof-of-concept study involving human subjects, [18F]3F4AP differentiated between a severe and a largely recovered incomplete injury, indicating axonal loss and demyelination, respectively. Moreover, alterations in tracer delivery were evident on dynamic PET images, suggestive of differences in spinal cord blood flow between the injuries. In conclusion, [18F]3F4AP demonstrates efficacy in detecting incomplete SCI in both animal models and humans. The potential for monitoring post-SCI demyelination changes and response to therapy underscores the utility of [18F]3F4AP in advancing our understanding and management of spinal cord injuries.
The Genome Explorer Genome Browser
Authors: Herson James , Krummenacker Markus , Spaulding Aaron , O’Maille Paul , Karp Peter D. 
Published: April 2024

AbstractAre two adjacent genes in the same operon? What is the order and spacing between several transcription-factor binding sites? Genome browsers are software data-visualization and exploration tools that enable biologists to answer questions such as these. In this paper we report on a major update to our browser, Genome Explorer, that provides nearly instantaneous scaling and traversing of a genome, enabling users to quickly and easily zoom into an area of interest. The user can rapidly move between scales that depict the entire genome, individual genes, and the sequence; Genome Explorer presents the most relevant detail and context for each scale. By downloading the data for the entire genome to the user’s web browser and dynamically generating visualizations locally, we enable fine control of zoom and pan functions and real-time redrawing of the visualization, resulting in smoother and more intuitive exploration of a genome than is possible with other browsers. Further, genome features are presented together, in-line, using familiar graphical depictions. In contrast, many other browsers depict genome features using data tracks, which have low information density and can visually obscure the relative positions of features. Genome Explorer diagrams have high information density that provides larger amounts of genome context and sequence information to be presented in a given sized monitor than for tracks-based browsers. Genome Explorer provides optional data tracks for analysis of large-scale datasets and a unique comparative mode that aligns genomes at orthologous genes with synchronized zooming.
Establishing comprehensive quaternary structural proteomes from genome sequence
Authors: Catoiu Edward Alexander , Mih Nathan , Lu Maxwell , Palsson Bernhard 
Published: April 2024

AbstractA critical body of knowledge has developed through advances in protein microscopy, protein-fold modeling, structural biology software, availability of sequenced bacterial genomes, large-scale mutation databases, and genome-scale models. Based on these recent advances, we develop a computational framework that; i) identifies the oligomeric structural proteome encoded by an organism’s genome from available structural resources; ii) maps multi-strain alleleomic variation, resulting in the structural proteome for a species; and iii) calculates the 3D orientation of proteins across subcellular compartments with residue-level precision. Using the platform, we; iv) compute the quaternaryE. coliK-12 MG1655 structural proteome; v) use a dataset of 12,000 mutations to build Random Forest classifiers that can predict the severity of mutations; and, in combination with a genome-scale model that computes proteome allocation, vi) obtain the spatial allocation of theE. coliproteome. Thus, in conjunction with relevant datasets and increasingly accurate computational models, we can now annotate quaternary structural proteomes, at genome-scale, to obtain a molecular-level understanding of whole-cell functions.SignificanceAdvancements in experimental and computational methods have revealed the shapes of multi-subunit proteins. The absence of a unified platform that maps actionable datatypes onto these increasingly accurate structures creates a barrier to structural analyses, especially at the genome-scale. Here, we describe QSPACE, a computational annotation platform that evaluates existing resources to identify the best-available structure for each protein in a user’s query, maps the 3D location of actionable datatypes (e.g., active sites, published mutations) onto the selected structures, and uses third-party APIs to determine the subcellular compartment of all amino acids of a protein. As proof-of-concept, we deployed QSPACE to generate the quaternary structural proteome ofE. coliMG1655 and demonstrate two use-cases involving large-scale mutant analysis and genome-scale modelling.