bluuebunny/crossref_metadata_2025_split huggingface dataset:
Zmiz1 is a novel regulator of lymphatic endothelial cell gene expression and function
Authors: K C Rajan , Patel Nehal R , Shenoy Anoushka , Scallan Joshua P , Chiang Mark Y , Galazo Maria J , Meadows Stryder M 
Published: July 2023

AbstractZinc Finger MIZ-Type Containing 1 (Zmiz1), also known as ZIMP10 or RAI17, is a transcription cofactor and member of the Protein Inhibitor of Activated STAT (PIAS) family of proteins. Zmiz1 is critical for a variety of biological processes including vascular development. However, its role in the lymphatic vasculature is unknown. In this study, we utilized human dermal lymphatic endothelial cells (HDLECs) and an inducible, lymphatic endothelial cell (LEC)-specificZmiz1knockout mouse model to investigate the role of Zmiz1 in LECs. Transcriptional profiling ofZmiz1-deficient HDLECs revealed downregulation of genes crucial for lymphatic vessel development. Additionally, our findings demonstrated that loss of Zmiz1 results in reduced expression of proliferation and migration genes in HDLECs and reduced proliferation and migrationin vitro. We also presented evidence that Zmiz1 regulates Prox1 expressionin vitroandin vivoby modulating chromatin accessibility at Prox1 regulatory regions. Furthermore, we observed that loss ofZmiz1in mesenteric lymphatic vessels significantly reduced valve density. Collectively, our results highlight a novel role of Zmiz1 in LECs and as a transcriptional regulator of Prox1, shedding light on a previously unknown regulatory factor in lymphatic vascular biology.
Large pilin subunits provide distinct structural and mechanical properties for theMyxococcus xanthustype IV pilus
Authors: Treuner-Lange Anke , Zheng Weili , Viljoen Albertus , Lindow Steffi , Herfurth Marco , Dufrêne Yves F. , Søgaard-Andersen Lotte , Egelman Edward H. 
Published: July 2023

SummaryType IV pili (T4P) are ubiquitous bacterial cell surface filaments important for surface motility, adhesion to biotic and abiotic surfaces, DNA uptake, biofilm formation, and virulence. T4P are built from thousands of copies of the major pilin subunit and tipped by a complex composed of minor pilins and in some systems also the PilY1 adhesin. While the major pilins of structurally characterized T4P have lengths of up to 161 residues, the major pilin PilA ofMyxococcus xanthusis unusually large with 208 residues. All major pilins have a highly conserved N-terminal domain and a highly variable C-terminal domain, and the additional residues in theM. xanthusPilA are due to a larger C-terminal domain. We solved the structure of theM. xanthusT4P (T4PMx) at a resolution of 3.0 Å using cryo-electron microscopy (cryo-EM). The T4PMxfollows the structural blueprint observed in other T4P with the pilus core comprised of the extensively interacting N-terminal α1-helices while the globular domains decorate the T4P surface. The atomic model of PilA built into this map shows that the large C-terminal domain has much more extensive intersubunit contacts than major pilins in other T4P. As expected from these greater contacts, the bending and axial stiffness of the T4PMxis significantly higher than that of other T4P and supports T4P-dependent motility on surfaces of different stiffnesses. Notably, T4PMxvariants with interrupted intersubunit interfaces had decreased bending stiffness and strongly reduced motility on all surfaces. These observations support an evolutionary scenario whereby the large major pilin enables the formation of a rigid T4P that expands the environmental conditions in which the T4P system functions.
CTCF/cohesin organize the ground state of chromatin-nuclear speckle association
Authors: Yu Ruofan , Roseman Shelby , Siegenfeld Allison P. , Nguyen Son C. , Joyce Eric F. , Liau Brian B. , Krantz Ian D. , Alexander Katherine A. , Berger Shelley L. 
Published: July 2023

AbstractThe interchromatin space in the cell nucleus contains various membrane-less nuclear bodies. Recent findings indicate that nuclear speckles, comprising a distinct nuclear body, exhibit interactions with certain chromatin regions in a ground state. Key questions are how this ground state of chromatin-nuclear speckle association is established and what are the gene regulatory roles of this layer of nuclear organization. We report here that chromatin structural factors CTCF and cohesin are required for full ground state association between DNA and nuclear speckles. Disruption of ground state DNA-speckle contacts via either CTCF depletion or cohesin depletion had minor effects on basal level expression of speckle-associated genes, however we show strong negative effects on stimulus-dependent induction of speckle-associated genes. We identified a putative speckle targeting motif (STM) within cohesin subunit RAD21 and demonstrated that the STM is required for chromatin-nuclear speckle association. In contrast to reduction of CTCF or RAD21, depletion of the cohesin releasing factor WAPL stabilized cohesin on chromatin and DNA-speckle contacts, resulting in enhanced inducibility of speckle-associated genes. In addition, we observed disruption of chromatin-nuclear speckle association in patient derived cells with Cornelia de Lange syndrome (CdLS), a congenital neurodevelopmental diagnosis involving defective cohesin pathways, thus revealing nuclear speckles as an avenue for therapeutic inquiry. In summary, our findings reveal a mechanism to establish the ground organizational state of chromatin-speckle association, to promote gene inducibility, and with relevance to human disease.
CuticleTrace: A toolkit for capturing cell outlines of leaf cuticle with implications for paleoecology and paleoclimatology
Authors: Lloyd Benjamin A. , Barclay Richard S. , Dunn Regan E. , Currano Ellen D. , Mohamaad Ayuni I. , Skersies Kymbre , Punyasena Surangi W. 
Published: July 2023

ABSTRACTPremiseLeaf epidermal cell morphology is closely tied to plants’ evolutionary histories and growth environments, and is therefore of interest to many plant biologists. However, cell measurement can be time-consuming and restrictive with current methods. CuticleTrace is a suite of FIJI and R-based functions that streamlines and automates the segmentation and measurement of epidermal pavement cells across a wide range of cell morphologies and image qualities.Methods and ResultsWe evaluated CuticleTrace-generated measurements against those from alternate automated methods and expert and undergraduate hand-tracings across a taxonomically diverse 50-image dataset of variable image qualities. We observed ∼93% statistical agreement between CuticleTrace and expert hand-traced measurements, outperforming alternate methods.ConclusionsCuticleTrace is broadly applicable, modular, and customizable, and integrates data visualization and cell shape measurement with image segmentation, lowering the barrier to high-throughput studies of epidermal morphology by vastly decreasing the labor investment required to generate high-quality cell shape datasets.
Autoencoder-transformed transcriptome improves genotype-phenotype association studies
Authors: Li Qing , Bian Jiayi , Weeraman Janith , Leung Albert , Yang Guotao , Chekouo Thierry , Yan Jun , Wu Jingjing , Long Quan 
Published: July 2023

AbstractTranscriptome-wide association study (TWAS) is an emerging model leveraging gene expressions to direct genotype-phenotype association mapping. A key component in TWAS is the prediction of gene expressions; and many statistical approaches have been developed along this line. However, a problem is that many genes have low expression heritability, limiting the performance of any predictive model. In this work, hypothesizing that appropriate denoising may improve the quality of expression data (including heritability), we propose AE-TWAS, which adds a transformation step before conducting standard TWAS. The transformation is composed of two steps by first splitting the whole transcriptome into co-expression networks (modules) and then using autoencoder (AE) to reconstruct the transcriptome data within each module. This transformation removes noise (including nonlinear ones) from the transcriptome data, paving the path for downstream TWAS. We showed two inspiring properties of AE-TWAS: (1) After transformation, the transcriptome data enjoy higher expression heritability at the low-heritability spectrum and possess higher connectivity within the modules. (2) The transferred transcriptome indeed enables better performance of TWAS; and moreover, the newly formed highly connected genes (i.e., hub genes) are more functionally relevant to diseases, evidenced by their functional annotations and overlap with TWAS hits.
Improving PD-1 blockade plus chemotherapy for complete remission of lung cancer by nanoPDLIM2
Authors: Sun Fan , Yan Pengrong , Xiao Yadong , Zhang Hongqiao , Shapiro Steven D. , Xiao Gutian , Qu Zhaoxia 
Published: July 2023

AbstractBackgroundImmune checkpoint inhibitors (ICIs) and their combination with other therapies such as chemotherapy, fail in most cancer patients. We previously identified the PDZ-LIM domain-containing protein 2 (PDLIM2) as abona fidetumor suppressor that is repressed in lung cancer to drive cancer and its chemo and immunotherapy resistance, suggesting a new target for lung cancer therapy improvement.MethodsHuman clinical samples and data were used to investigatePDLIM2genetic and epigenetic changes in lung cancer. Using an endogenous mouse lung cancer model faithfully recapitulating refractory human lung cancer and a clinically feasible nano-delivery system, we investigated the therapeutic efficacy, action mechanism, and safety of systemically administrated PDLIM2 expression plasmids encapsulated in nanoparticles (nanoPDLIM2) and its combination with PD-1 antibody and chemotherapeutic drugs.ResultsPDLIM2 repression in human lung cancer involves both genetic deletion and epigenetic alteration. NanoPDLIM2 showed low toxicity, high tumor specificity, antitumor activity, and greatly improved the efficacy of anti-PD-1 and chemotherapeutic drugs, with complete tumor remission in most mice and substantial tumor reduction in the remaining mice by their triple combination. Mechanistically, nanoPDLIM2 increased major histocompatibility complex class I (MHC-I) expression, suppressed multi-drug resistance 1 (MDR1) induction and survival genes and other tumor-related genes expression in tumor cells, and enhanced lymphocyte tumor infiltration, turning the cold tumors hot and sensitive to ICIs and rendering them vulnerable to chemotherapeutic drugs and activated tumor-infiltrating lymphocytes (TILs) including those unleashed by ICIs.ConclusionsThese studies established a clinically applicable PDLIM2-based combination therapy with great efficacy for lung cancer and possibly other cold cancers.
Identification of Low-Complexity Domains by Compositional Signatures Reveals Class-Specific Frequencies and Functions Across Reference Proteomes
Authors: Cascarina Sean M. , Ross Eric D. 
Published: July 2023

AbstractLow-complexity domains (LCDs) in proteins are typically enriched in one or two predominant amino acids. As a result, LCDs often exhibit unusual structural/biophysical tendencies and can occupy functional niches. However, for each organism, protein sequences must be compatible with intracellular biomolecules and physicochemical environment, both of which vary from organism to organism. This raises the possibility that LCDs may occupy sequence spaces in select organisms that are otherwise prohibited in most organisms. Here, we report a comprehensive survey of LCDs in all known reference proteomes (>21k organisms), with added focus on rare and unusual types of LCDs. LCDs were sorted into a rich hierarchical database according to both the primary amino acid and secondary amino acid in each LCD sequence, facilitating detailed comparisons of LCD class frequencies across organisms. Examination of LCD classes at different depths (i.e., domain of life, organism, protein, and per- residue levels) reveals unique facets of LCD frequencies and functions. To our surprise, all 400 LCD classes occur in nature, although some are exceptionally rare. A number of rare classes can be defined for each domain of life, with many LCD classes appearing to be eukaryote- specific. Multiple eukaryote-specific LCD classes could be linked to consistent sets of functions across organisms. Our analysis methods enable simultaneous, direct comparison of all LCD classes between individual organisms, resulting in a proteome-scale view of differences in LCD frequencies and functions. Together, these results highlight the remarkable diversity and functional specificity of LCDs across all known life forms.
Unraveling the Potential of Epicatechin Gallate fromCrataegus oxyacanthain Targeting Aberrant Cardiac Ca2+ Signalling Proteins: An in-depthIn-SilicoInvestigation for Heart Failure Therapy
Authors: Praveen J , Anusuyadevi M , Jayachandra KS 
Published: July 2023

AbstractThe cardiovascular sarcoplasmic reticulum (SR) calcium (Ca2+) ATPase is an imperative determinant of cardiac functionality. In addition, anomalies in Ca2+ handling protein and atypical energy metabolism are inherent in heart failure (HF). Moreover, Ca2+ overload in SR leads to mitochondrial matrix Ca2+ overload, which can trigger the generation of Reactive Oxygen Species (ROS), culminating in the triggering of the Permeability Transition Pore (PTP) and Cytochrome C release, resulting in apoptosis that leads to arrhythmias and numerous disorders. Although proteins involved in the molecular mechanism of Ca2+ dysfunction regarding mitochondrial dysfunction remains elusive, this study aims to assess the major Ca2+ handling proteins which may be involved in the Ca2+ malfunction that causes mitochondrial dysfunction and predicting the most effective drug by targeting the analyzed Ca2+ handling proteins through variousinsilicoanalyses.Thirteen proteins absorbed from interaction analysis were docked with four optimal phytochemicals fromCrataegus oxyacantha(COC) to identify the potential agonist/antagonist against those anomalies causing Ca2+ handling signaling proteins. Furthermore,The ADMET profile of tyramine, vitexin, epicatechin, and epicatechin gallate was acclimated to evaluate potential drugability utilizing QikProp by Schrodinger.Keeping this in view, critical molecular docking evaluations were performed using Glide (Maestro), autodock, and autodock vina.Based on the results of 156 dockings by Maestro, auto-dock, and auto-dock vina, PKA Cα with epicatechin gallate exhibits good interaction. Therefore, a 2000ns molecular dynamics (MD) simulation was utilized to assess the feasible phytochemical epicatechin gallate - PKA Cα complex binding stability utilizing Desmond. As a result, the molecular dynamics simulation study confirmed that epicatechin gallate from COC has high possibilities to inhibit the aberrant cardiac Ca2+ signaling proteins due to its conformational rigidity.
Combined representation of visual features in the scene-selective cortex
Authors: Kang Jisu , Park Soojin 
Published: July 2023

ABSTRACTVisual features of separable dimensions like color and shape conjoin to represent an integrated entity. We investigated how visual features bind to form a complex visual scene. Specifically, we focused on features important for visually guided navigation: direction and distance. Previously, separate works have shown that directions and distances of navigable paths are coded in the occipital place area (OPA). Using functional magnetic resonance imaging (fMRI), we tested how separate features are concurrently represented in the OPA. Participants saw eight different types of scenes, in which four of them had one path and the other four had two paths. In single-path scenes, path direction was either to the left or to the right. In double-path scenes, both directions were present. Each path contained a glass wall located either near or far, changing the navigational distance. To test how the OPA represents paths in terms of direction and distance features, we took three approaches. First, the independent-features approach examined whether the OPA codes directions and distances independently in single-path scenes. Second, the integrated-features approach explored how directions and distances are integrated into path units, as compared to pooled features, using double-path scenes. Finally, the integrated-paths approach asked how separate paths are combined into a scene. Using multi-voxel pattern similarity analysis, we found that the OPA’s representations of single-path scenes were similar to other single-path scenes of either the same direction or the same distance. Representations of double-path scenes were similar to the combination of two constituent single-paths, as a combined unit of direction and distance rather than pooled representation of all features. These results show that the OPA combines the two features to form path units, which are then used to build multiple-path scenes. Altogether, these results suggest that visually guided navigation may be supported by the OPA that automatically and efficiently combines multiple features relevant for navigation and represent anavigation file.
Patterns of speciation in a parapatric pair ofSaturniamoths as revealed by Target Capture
Authors: Khan Maria , Joshi Mukta , Espeland Marianne , Huemer Peter , Vaamonde Carlos Lopez , Mutanen Marko 
Published: July 2023

AbstractThe focus of this study is to understand the evolutionary relationships and taxonomy of widely distributed parapatric species pair of wild silk moths,Saturnia pavoniaandSaturnia pavoniella(Lepidoptera: Saturniidae) in Europe. To address species delimitation challenges associated with many parapatric taxa, target enrichment and mtDNA sequencing was employed alongside phylogenetic, species delimitation, admixture and introgression analyses. The dataset included individuals from both species, two hybrids generated in the lab, as well as individuals from outside the contact zone. Nuclear markers strongly supported bothS. pavoniaandS. pavoniellaas two distinct species, with the hybrids grouping together as intermediate and separate from both species. However, the maximum likelihood (ML) tree generated from mtDNA sequencing data presented a different picture, showing both taxa to be phylogenetically intermixed. This inconsistency may be attributed to mitonuclear discordance, which can arise from biological factors (e.g., introgressive hybridization or incomplete lineage sorting) or alternatively operational factors (e.g., incorrect species delimitation). We further provide the evidence of past introgression to have taken place, but no evidence of current admixture between the two species. Finally, we discuss our results from evolutionary point of view taking into consideration the past climatic oscillations that has likely shaped the present dynamics between the species. Overall, this study demonstrated the effectiveness of the target enrichment approach in resolving the phylogenetic relationships between closely related parapatric species and providing insights into their taxonomic delimitation.
A heterozygousCEBPAmutation disrupting the bZIP domain causes MDS disease progression
Authors: Almaghrabi Ruba , Alyayhawi Yara , Keane Peter , Ward Carl , Bayley Rachel , Sargas Claudia , Menendez Pablo , Murphy George J. , Sobahy Turki , Baghdadi Mohammed A. , Flemban Arwa F , Kabrah Saeed , Akerman Ildem , Raghavan Manoj , Barragan Eva , Bonifer Constanze , Garcia Paloma 
Published: July 2023

SUMMARYMyelodysplastic syndrome disease (MDS) has a variable risk for progression to AML. Mutations inCEBPAare associated with a high risk of disease progression, but whether this mutation is causative for AML development is unclear. To answer this question, we generated patient-derived, MDS-specific iPSCs recapitulating the patient disease phenotype upon differentiation to blood, with hematopoietic progenitor cells showing erythroid and myeloid-dysplasia. Introduction of a frameshift mutation affecting the C/EBPα bZIP domain led to disease progression, with a reduction in clonogenic potential, block in granulocyte development and increased self-renewal capacity of erythroid progenitors. ATAC-seq revealed that the acquisition of this mutation reshaped the chromatin landscape at distal cis-regulatory regions, promoting changes in clonal composition as observed by single cell RNAseq. Our work identifies mutantCEBPAas causative for MDS disease progression, providing a new isogenic MDS experimental model for drug screening to improve diagnostic and therapeutic strategies.HighlightsDevelopment of isogenic iPSC model of clonal evolution of MDSMonoallelic disruption of CEBPA bZIP domain is causative for MDS disease progressionMonoallelic disruption of CEBPA bZIP reshapes chromatin landscapePatient derived iPSCs recapitulate drug responsiveness
Collective dynamics of formin and microtubule and its crosstalk mediated by FHDC1
Authors: Tong Chee San , Su Maohan , Sun He , Chua Xiang Le , Guo Su , Ramaraj Ravinraj S/O , Nicole Wen Pei Ong , Lee Ann Gie , Miao Yansong , Wu Min 
Published: July 2023

AbstractThe coordination between actin and microtubule network is crucial, yet our understanding of the underlying mechanisms remains limited. In this study, we used travelling waves in the cell cortex to characterize the collective dynamics of cytoskeletal networks. Our findings show that Cdc42 and F-BAR-dependent actin waves in mast cells are mainly driven by formin-mediated actin polymerization, with the microtubule-binding formin FH2 domain-containing protein 1 (FHDC1) identified as an early regulator. The depolymerization of microtubules coincides with the nucleation of actin waves, and the concurrent release of FHDC1 from microtubule is required for actin waves. Lastly, we show the importance of the actin-microtubule linkage mediated by FHDC1 in crucial cellular processes such as cell division and migration. Our data provided molecular insights into the nucleation mechanisms of actin waves and uncover an antagonistic interplay between microtubule and actin polymerization in their collective dynamics.
Leishmania major-induced alteration of host cellular and systemic copper homeostasis drives the fate of infection
Authors: Paul Rupam , Chakrabarty Adrija , Samanta Suman , Dey Swastika , Pandey Raviranjan , Maji Saptarshi , Pezacki Aidan T. , Chang Christopher J. , Datta Rupak , Gupta Arnab 
Published: July 2023

AbstractCopper plays a key role in host-pathogen interaction. We found that duringLeishmania majorinfection, the parasite-harboring macrophage regulates its copper homeostasis pathway in a way to facilitate copper-mediated neutralization of the pathogen. Copper-ATPase ATP7A transports copper to amastigote-harboring phagolysosomes to induce stress on parasites.Leishmaniain order to evade the copper stress, utilizes a variety of manipulative measures to lower the host-induced copper stress. It induces deglycosylation and degradation of host-ATP7A and downregulation of copper importer, CTR1 by cysteine oxidation. Additionally,Leishmaniainduces CTR1 endocytosis that arrests copper uptake. In mouse model of infection, we report an increase in systemic bioavailable copper in infected animals. Heart acts as the major organ for diverting its copper reserves to systemic circulation to fight-off infection by downregulating its CTR1. Our study explores reciprocal mechanism of manipulation of host copper homeostasis pathway by macrophage andLeishmaniato gain respective advantages in host-pathogen interaction.