bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using flux theory in dynamic omics data sets to identify differentially changing signals using DPoP
Authors: Edwards Harley , Zavorskas Joseph , Huso Walker , Doan Alexander G. , Silbiger Caton , Harris Steven , Srivastava Ranjan , Marten Mark R. 
Published: July 2024

AbstractDerivative profiling (DP) is a novel approach to identify differential signals from dynamic omics data sets. This approach applies variable step-size differentiation to time dynamic omics data. This work assumes that there is a general omics derivative that is a useful and descriptive feature of dynamic omics experiments. We assert that this omics derivative, or omics flux, is a valuable descriptor that can be used instead of, or with, fold change calculations. The results of derivative profiling are compared to established methods such as Multivariate Adaptive Regression Splines (MARS), significance versus fold change analysis (Volcano), and an adjusted ratio over intensity (M/A) analysis to find that there is a statistically significant similarity between the results. This comparison is repeated for transcriptomic and phosphoproteomic expression profiles previously characterized inAspergillus nidulans. This method has been packaged in an open-source, GUI-based MATLAB app, the Derivative Profiling omics Package (DPoP). Gene Ontology (GO) term enrichment has been included in the app so that a user can automatically/programmatically describe the over/under-represented GO terms in the derivative profiling results using domain specific knowledge found in their organism’s specific GO database file. The advantage of the DPoP analysis is that it is computationally inexpensive, it does not require fold change calculations, it describes both instantaneous as well as overall behavior, and it achieves statistical confidence with signal trajectories of a single bio-replicate over four or more points. While we apply this method to time dynamic transcriptomic and phosphoproteomic datasets, it is a numerically generalizable technique that can be applied to any organism and any field interested in time series data analysis. The app described in this work enables omics researchers with no computer science background to apply derivative profiling to their data sets, while also allowing multidisciplined users to build on the nascent idea of profiling derivatives in omics.
The ability of human TIM1 to bind phosphatidylethanolamine enhances viral uptake and efferocytosis compared to rhesus and mouse orthologs
Authors: Zhang Lizhou , Kitzmiller Claire E. , Richard Audrey S. , Popli Sonam , Choe Hyeryun 
Published: July 2024

ABSTRACTT-cell Immunoglobulin and Mucin (TIM)-family proteins facilitate the clearance of apoptotic cells, are involved in immune regulation, and promote infection of enveloped viruses. These processes are frequently studied in experimental animals such as mice or rhesus macaques, but functional differences among the TIM orthologs from these species have not been described. Previously, we reported that while all three human TIM proteins bind phosphatidylserine (PS), only human TIM1 (hTIM1) binds phosphatidylethanolamine (PE), and that this PE-binding ability contributes to both phagocytic clearance of apoptotic cells and virus infection. Here we show that rhesus macaque TIM1 (rhTIM1) and mouse TIM1 (mTIM1) bind PS but not PE and that their inability to bind PE makes them less efficient than hTIM1. We also show that alteration of only two residues of mTIM1 or rhTIM1 enables them to bind both PE and PS, and that these PE-binding variants are more efficient at phagocytosis and mediating viral entry. Further, we demonstrate that the mucin domain also contributes to the binding of the virions and apoptotic cells, although it does not directly bind phospholipid. Interestingly, contribution of the hTIM1 mucin domain is more pronounced in the presence of a PE-binding head domain. These results demonstrate that rhTIM1 and mTIM1 are inherently less functional than hTIM1, owing to their inability to bind PE and their less functional mucin domains. They also imply that mouse and macaque models underestimate the activity of hTIM1.SIGNIFICANCEWe previously reported that human T-cell Immunoglobulin and Mucin protein 1 (TIM1) binds phosphatidylethanolamine (PE) as well as phosphatidylserine (PS) and that PE is exposed on the apoptotic cells and viral envelopes. Moreover, TIM1 recognition of PE contributes to phagocytic clearance of apoptotic cells and virus uptake. Here we report that unlike human TIM1, murine and rhesus TIM1 orthologs bind only PS, and as a result, their ability to clear apoptotic cells or promote virus infection is less efficient. These findings are significant because they imply that the activity of TIM1 in humans is greater than what the studies conducted in common animal models would indicate.
Aneuploidy-induced proteostasis disruption impairs mitochondrial functions and mediates aggregation of mitochondrial precursor proteins through SQSTM1/p62
Authors: Amponsah Prince Saforo , Bökenkamp Jan-Eric , Lenhard Svenja , Behrends Christian , Herrmann Johannes Martin , Räschle Markus , Storchová Zuzana 
Published: July 2024

AbstractAberrant chromosomal content, or aneuploidy, profoundly affects cellular physiology. Even a gain of a single chromosome disrupts proteostasis due to overexpression of numerous proteins. Consequently, cells accumulate SQSTM1/p62-positive cytosolic bodies and show altered proteasomal and lysosomal activity. To elucidate the p62 interaction network in aneuploid cells, we conducted p62 immunoprecipitation and proximity labeling assays followed by mass spectrometry analysis. Our investigation revealed the enrichment of mitochondrial proteins within the cytosolic p62 interactome and proxitome in aneuploid cells, but not in the proxitome spatially confined to autophagosomes. Immunofluorescence microscopy confirmed increased colocalization of p62 with novel interactors and with mitochondrial proteins in polysomic cells. Moreover, we observed mitochondrial defects characterized by increased perinuclear clustering, reduced oxygen consumption, and reduced mitochondrial DNA abundance in polysomic cells. Furthermore, we demonstrate that polysomic cells exhibit reduced import of mitochondrial proteins and accumulation of mitochondrial precursor proteins in the cytosol. Our data suggest that proteotoxic stress induced by chromosome gains leads to the sequestration of mitochondrial precursor proteins into cytosolic p62-bodies and compromises mitochondrial function.
On the mode of anti-C. albicansactivity of a bis(benzoxaborole) analogue of Tavaborole
Authors: Gadakh Sachin , Szczepińska Teresa , Potoczna Małgorzata , Okitsu-Sakurayama Shiho , Podlasz Piotr , Rogalska Marta , Kaczorowska Ewa , Adamczyk-Woźniak Agnieszka , Staniszewska Monika 
Published: July 2024

AbstractWe presented the pharmacodynamic relationship between benzoxaborole concentrations andCandida albiansblastoconidial population dynamics. Bis(benzoxaborole) analogue (2) andTavaborole(ref.) showed comparable moderate effects againstC. albicans(time-kill kinetic assays). Benzoxaboroles inhibited theC. albicansgrowth during 72 h (fungicidal after 2 h of that time) with metabolic reduction (%R=64). Biofilm-inhibiting concentration (BIC50=2 μg/mL) is the lowest concentration of bezoxaboroles that presented 50% inhibition of biofilm metabolic activity vs non-treated control.2displayed poor ability to inhibit morphogenesis ofC. albicans. Safety and fungicidal activity are still in high demand against biofilm grown on fibroblasts and the zebrafish modelin vivo. This biofilm model was used to study the interactions between theC. albicansmorphogenesis and benzoxaboroles. Benzoxaboroles displayed selectivity in cytotoxic effects.2exhibited significantly lower embryotoxicity vs ref. IC50>128 μg/mL for2. Ref. at 256 μg/mL showed approximately 80% viability of VERO E6 cells. A higher selectivity of the ref—drug to the pathogen than to the mammalian cells was observed. Contrariwise, ref. and2showed IC50=2 μg/mL against PBMCs. Benzoxaborole antifungal development targets ergosterol binding. RNAseq data indicated that efflux pumps (MDR) inC. albicanswere upregulated. Inositol-1-phosphate synthase was repressed under the benzoxaborole treatment.MDR1upregulation by2was accompanied by theIFD6(aldo-keto reductase) increase and the coordination of multiple coactivators (IFD6, TNA1encoding putative nicotinic acid transporter). Benzoxaboroles represent a similar resistance mechanism to azoles due to the subsequent expression ofMDR1andIDF6. Docking studies confirmed the proposed interactions of benzoxaborole adenosinemonophosphate adduct with LeuRS. Moreover,C5_04480C_A(cell wall biogenesis, protein folding, modification, and destination) was negatively regulated in response to the benzoxaborole stress. Benzoxaborole-altering efflux inhibitors are important for the development of combination strategies in candidiasis. Our findings present an innovative concept that can inspire further studies for designing and building new antifungal benzoxaborole.
Explicit description of viral capsid subunit shapes by unfolding dihedrons
Authors: Toyooka Ryuya , Nishimoto Seri , Tendo Tomoya , Horiyama Takashi , Tachi Tomohiro , Matsunaga Yasuhiro 
Published: July 2024

AbstractViral capsid assembly and the design of capsid-based nanocontainers critically depend on understanding the shapes and interfaces of constituent protein subunits. However, a comprehensive framework for characterizing these features is still lacking. Here, we introduce a novel approach based on spherical tiling theory that explicitly describes the 2D shapes and interfaces of subunits in icosahedral capsids. Our method unfolds spherical dihedrons defined by icosahedral symmetry axes, enabling systematic characterization of all possible subunit geometries. Applying this framework to realT= 1 capsid structures reveals distinct interface groups within this single classification, with variations in interaction patterns around 3-fold and 5-fold symmetry axes. We validate our classification through molecular docking simulations, demonstrating its consistency with physical subunit interactions. This analysis suggests different assembly pathways for capsid nucleation. Our general framework is applicable to other triangular numbers, paving the way for broader studies in structural virology and nanomaterial design.
Resolving the Structure of a Guanine Quadruplex in TMPRSS2 Messenger RNA by Circular Dichroism and Molecular Modeling
Authors: D’Anna Luisa , Froux Aurane , Rainot Aurianne , Spinello Angelo , Perricone Ugo , Barbault Florent , Grandemange Stéphanie , Barone Giampaolo , Terenzi Alessio , Monari Antonio 
Published: July 2024

AbstractThe presence of a guanine quadruplex in the opening reading frame of the messenger RNA coding for the transmembrane serine protease 2 (TMPRSS2) may pave the way to original anticancer and host-oriented antiviral strategy. Indeed, TMPRSS2 in addition to being overexpressed in different cancer types, is also related to the infection of respiratory viruses, including SARS-CoV-2, by promoting the cellular and viral membrane fusion through its proteolytic activity. The design of selective ligands targeting TMPRSS2 messenger RNA requires a detailed knowledge, at atomic level, of its structure. Therefore, we have used an original experimental-computational protocol to predict the first resolved structure of the parallel guanine quadruplex secondary structure in the RNA of TMPRSS2, which shows a rigid core flanked by a flexible loop. This represents the first atomic scale structure of the guanine quadruplex structure present in TMPRSS2 messenger RNA.
Collective flow of circadian clock information in honeybee colonies
Authors: Mellert Julia , Kłos Weronika , Dormagen David M. , Wild Benjamin , Zachariae Adrian , Smith Michael L. , Galizia C. Giovanni , Landgraf Tim 
Published: July 2024

AbstractHoneybee colonies exhibit a collective circadian rhythm reflecting the periodic dynamics of the environment. Thousands of workers, including those engaged in in-hive tasks, must synchronize in various processes that may be rhythmic, such as nectar inflows, or non-rhythmic, such as brood care but it remains unknown how those different rhythms are integrated into a colony-level circadian rhythm. Using an AI-driven automated tracking system, we obtained uninterrupted long-term tracking of all individuals in two honeybee colonies. We demonstrate that circadian rhythmicity is present across all age groups and that this rhythm is entrained into all individuals, however, with peak activity shifting by up to 2 hours in workers furthest from the entrance. Extensive data analysis and an agent-based model suggest that mechanical interactions between individuals facilitate the transfer of movement speed, and hence Zeitgeber information. Finally, we show that this speed transfer leads to a collective slow wave of activity that initiates at the nest entrance, spreading throughout the nest. This simple mechanism, workers bumping into each other, enables colonies to entrain their rhythm to the daily cycle of the external environment and, because of the spatial organization of the nest, activates different groups of workers sequentially. The speed transfer interactions demonstrate a tightly-tuned mechanism that underlines the elegant self-organization of the superorganism.
Dissecting the Genetic Basis of Superior Traits in Thermosensitive Genic Male Sterile Line 1892S Through Genome-Wide Analysis
Authors: Zhang Wei , Zhang Dewen 
Published: July 2024

AbstractHybrid rice has revolutionized food security by leveraging heterosis, a phenomenon where offspring outperform their parents. Sterile lines, crucial for controlled cross-pollination in hybrid breeding, have played a central role in this success. This study delves into the superior alleles of 1892S, a two-line sterile rice line widely used as a female parent in central China. By integrating extensive hybridization data, high-throughput genome sequencing, and bioinformatic analysis (RiceNavi), we elucidate the genetic underpinnings of 1892S’s exceptional adaptability. The results reveal its remarkable compatibility as a female parent in over 114 hybrid varieties, potentially due to the influence of Japonica characteristics contributing to strong hybrid vigor. Furthermore, some favorable alleles were identified that were associated with lodging resistance, high yield potential, and improved nitrogen use efficiency etc. The comprehensive characterization of 1892S provides valuable insights for future hybrid rice breeding programs, ultimately facilitating the development of superior rice varieties.
Genetic Manipulation of Caveolin-1 in the Mouse Model of Marfan Syndrome Associated Aortic Root Aneurysm: Effects on Endothelial and Smooth Muscle Function
Authors: Curry Tala , Gusek Brikena , Potter Ross M. , Bucky Jones T. , Dickman Raechel , Johnson Nathan , Vallejo-Elias Johana , Esfandiarei Mitra 
Published: July 2024

ABSTRACTMarfan Syndrome (MFS) is a systemic connective tissue disorder caused by mutations in the gene encoding for the large glycoprotein Fibrillin-1 (Fbn1), leading to wide-spectrum clinical manifestations, with the most life-threatening being aortic root aneurysm. MFS aortic aneurysm is known to be associated with reduced endothelial nitric oxide synthase (eNOS)-mediated nitric oxide (NO) production. Previous studies have shown that caveolin-1 (Cav1), a coat protein of caveolae structure on the plasma membrane, acts as a negative regulator of eNOS activity. This suggests that Cav1 may play a role in the development of aortic root aneurysm in MFS by modulating eNOS activity. In this study, we investigated the role of Cav1 in regulating aortic smooth muscle and endothelial function, aortic wall elasticity, and wall strength by generating MFS mice (FBN1+/Cys1041Gly) lackingCav1gene expression (MFS/Cav1KO). Our data show that ablation of theCav1gene results in a significant decrease in aortic smooth muscle contraction in response to the vasoconstricting agent phenylephrine seemingly due to a marked increase in NO production within the aortic wall. We also showed that acetylcholine-induced vasorelaxation was increased in MFS/Cav1KO mice potentially through the endothelial nitric oxide-dependent mechanism, further confirming inhibitory role of Cav1 on endothelial NO production. In addition, aortic wall elastin fiber structure and strength were markedly improved in male MFS/Cav1KO mice. This study demonstrates the regulatory role of Cav1 during the development of aortic root aneurysm in MFS mice through its effects on smooth muscle and endothelial functions in an NO-dependent manner.
Three Dimensional Multiscalar Neurovascular Nephron Connectivity Map of the Human Kidney Across the Lifespan
Authors: McLaughlin Liam , Zhang Bo , Sharma Siddharth , Knoten Amanda L. , Kaushal Madhurima , Purkerson Jeffrey M. , Huyck Heidy , Pryhuber Gloria S. , Gaut Joseph P. , Jain Sanjay 
Published: July 2024

AbstractThe human kidney is a vital organ with a remarkable ability to coordinate the activity of up to a million nephrons, its main functional tissue unit (FTU), and maintain homeostasis. We developed tissue processing and analytical methods to construct a 3D map of neurovascular nephron connectivity of the human kidney and glean insights into how this structural organization enables coordination of various functions of the nephron, such as glomerular filtration, solute and water absorption, secretion by the tubules, and regulation of blood flow and pressure by the juxtaglomerular apparatus, in addition to how these functions change across disease and lifespans. Using light sheet fluorescence microscopy (LSFM) and morphometric analysis we discovered changes in anatomical orientation of the vascular pole, glomerular density, volume, and innervation through postnatal development and ageing. The extensive nerve network exists from cortex FTUs to medullary loop of Henle, providing connectivity within segments of the same nephron, and between separate nephrons. The nerves organize glomeruli into discreet communities (in the same network of nerves). Adjacent glomerular communities are connected to intercommunal “mother glomeruli” by nerves, a pattern repeating throughout the cortex. These neuro-nephron networks are not developed in postnatal kidneys and are disrupted in diseased kidneys (diabetic or hydronephrosis). This structural organization likely poises the entire glomerular and juxtaglomerular FTUs to synchronize responses to perturbations in fluid homeostasis, utilizing mother glomeruli as network control centers.
Genome structural variants shape adaptive success of an invasive urban malaria vectorAnopheles stephensi
Authors: Samano Alejandra , Kumar Naveen , Liao Yi , Ishtiaq Farah , Chakraborty Mahul 
Published: July 2024

AbstractGlobal changes are associated with the emergence of several invasive species. However, the genomic determinants of the adaptive success of an invasive species in a new environment remain poorly understood. Genomic structural variants (SVs), consisting of copy number variants, play an important role in adaptation. SVs often cause large adaptive shifts in ecologically important traits, which makes SVs compelling candidates for driving rapid adaptations to environmental changes, which is critical to invasive success. To address this problem, we investigated the role SVs play in the adaptive success ofAnopheles stephensi, a primary vector of urban malaria in South Asia and an invasive malaria vector in several South Asian islands and Africa. We collected whole genome sequencing data from 115 mosquitoes from invasive island populations and four locations from mainland India, an ancestral range for the species. We identified 2,988 duplication copy number variants and 16,038 deletions in these strains, with ∼50% overlapping genes. SVs are enriched in genomic regions with signatures of selective sweeps in the mainland and invasive island populations, implying a putative adaptive role of SVs. Nearly all high-frequency SVs, including the candidate adaptive variants, in the invasive island populations are present on the mainland, suggesting a major contribution of existing variation to the success of the island populations. Among the candidate adaptive SVs, three duplications involving toxin-resistance genes evolved, likely due to the widespread application of insecticides in India since the 1950s. We also identify two SVs associated with the adaptation ofAn. stephensilarvae to brackish water in the island and two coastal mainland populations, where the mutations likely originated. Our results suggest that existing SVs play a vital role in the evolutionary success ofAn. stephensiin new environmental conditions.
A structural and mechanistic model for BSEP dysfunction in PFIC2 cholestatic disease
Authors: Gruget Clémence , Reddy Bharat , Moore Jonathan 
Published: July 2024

AbstractBSEP (ABCB11) transports bile salts across the canalicular membrane of hepatocytes, where they are incorporated into bile. Biallelic mutations in BSEP can cause Progressive Familial Intrahepatic Cholestasis Type 2 (PFIC2), a rare pediatric disease characterized by hepatic bile acid accumulation leading to hepatotoxicity and, ultimately, liver failure. The most frequently occurring PFIC2 disease-causing mutations are missense mutations, which often display a phenotype with decreased protein expression and impaired maturation and trafficking to the canalicular membrane. To characterize the mutational effects on protein thermodynamic stability, we carried out biophysical characterization of 13 distinct PFIC2-associated variants using in-cell thermal shift (CETSA) measurements. These experiments reveal a cluster of residues localized to the NBD2-ICL2 interface, which exhibit severe destabilization relative to wild-type BSEP. A high-resolution (2.8 Å) cryo-EM structure provides a framework for rationalizing the CETSA results, revealing a novel, NBD2-localized mechanism through which the most severe missense patient mutations drive cholestatic disease.
Pulsed blue light and phage therapy: A novel synergistic bactericide
Authors: Rimon Amit , Belin Jonathan , Yerushalmy Ortal , Alkalay-Oren Sivan , Eavri Yonatan , Shapochnikov Anatoly , Coppenhagen-Glazer Shunit , Hazan Ronen , Gavish Lilach 
Published: July 2024

AbstractAntibiotic-resistantPseudomonas aeruginosa(PA) is a critical health threat. Novel treatment approaches are urgently required in this post-antibiotic era. In the current study, we investigated the bactericidal combinatorial potential of two non-antibiotic alternative approaches: phage therapy and pulsed blue light (PBL). Bacteriophages (phages), are viruses that specifically infect and lyse bacteria without harming eukaryotic cells. Pulsed blue light (PBL) alters bacterial membranes and was clinically shown to be innocuous to the skin in low doses. Here, using a low dose 457nm, 33KHz PBL combined with specific PA targeting phages, we demonstrated a synergistic effect that achieved complete inhibition of planktonic bacteria and a 40% reduction in formed biofilms. As part of this study, we also developed a user-friendly python-based tool for extraction of growth curve outcomes.In vivostudies are warranted for further validation of this combinatorial treatment. This approach may lead to a novel, antibiotic complementary modality to help patients suffering from difficult-to-treat antibiotic-resistant infections.One Sentence SummaryLow-dose pulsed blue light and phage therapy have a synergistic bactericidal effect onPseudomonas aeruginosaplanktonic cultures and formed biofilm