bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phytochemicals fromDaucus carotahave therapeutic potential against Triple-Negative Breast Cancer PDK1 and PLK1
Authors: Raheem Kayode , Abayomi Modinat , Oluwatosin Maryam , Adewunmi Mary , Ali Ijaz , Muddassar Muhammad 
Published: November 2024

AbstractTriple-negative breast cancer (TNBC) is a deadly form of breast cancer that lacks estrogen, progesterone, and HER2 receptors. The development of drugs for TNBC has been challenging due to the lack of specific therapeutic targets. However, recent studies have shown that targeting the ATP active of the PDK-1 and PLK-1 proteins could be potential drug targets for TNBC treatment. New medications for TNBC have considerable adverse effects, highlighting the need for more targeted and effective therapies.In this study, we employed various computational approaches, including molecular docking, molecular dynamics (MD) simulations, pharmacokinetic studies, binding free energy calculations, principal component analysis (PCA), and alanine scanning analysis, to identify bioactive compounds fromDaucus carota-extracted natural compounds that can bind to these ATP-binding sites and inhibit the activity of PDK1 and PLK1. Our study revealed that eight compounds showed reasonably good docking scores, binding free energies, and ADMET properties against the PDK1 and PLK1 enzymes. Astragalin and scolimoside showed substantial binding affinity and persistent interactions in the pocket region of the two proteins. Further MD simulation studies for 150 ns also suggested that the compounds were stably bound in the active site with very minor fluctuations. We believe that the identified hits for PDK1 and PLK1 fromDaucus carotawill be effective against TNBC in performing the biological assays.
Comparative transcriptomic insights into the evolutionary origin of the tetrapod double cone
Authors: Tommasini Dario , Yoshimatsu Takeshi , Baden Tom , Shekhar Karthik 
Published: November 2024

AbstractThe tetrapod double cone is a pair of tightly associated cones called the “principal” and the “accessory” member. It is found in amphibians, reptiles, and birds, as well as monotreme and marsupial mammals but is absent in fish and eutherian mammals. To explore the potential evolutionary origins of the double cone, we analyzed single-cell and -nucleus transcriptomic atlases of photoreceptors from six vertebrate species: zebrafish, chicken, lizard, opossum, ground squirrel, and human. Computational analyses separated the principal and accessory members in chicken and lizard, identifying molecular signatures distinguishing either member from single cones and rods in the same species. Comparative transcriptomic analyses suggest that both the principal and accessory originated from ancestral red cones. Furthermore, the gene expression variation among cone subtypes mirrors their spectral order (red→green→blue→UV), suggesting a constraint in their order of emergence during evolution. Finally, we find that rods are equally dissimilar to all cone types, suggesting that they emerged before the spectral diversification of cones.
Phospholipid signaling and multivesicular endolysosomes modulate membrane dynamics at the biotrophic interface in Rice Blast
Authors: Selvaraj Poonguzhali , Yang Fan , Zheng Wenhui , Naqvi Naweed I. 
Published: November 2024

SummaryMagnaporthe oryzae, the rice blast pathogen, secretes an arsenal of apoplastic and cytoplasmic effector proteins to suppress host immunity during the biotrophy phase. The proposed non-conventional secretion of cytoplasmic effectors into the Biotrophic Interfacial Complex (BIC), remains uncharted except for the involvement of the exocyst complex therein. Recently, the plant endocytic machinery has been implicated in translocation of cytoplasmic effectors to the host. Here, we used live cell imaging and mutant analyses to provide new insight into late endolysosomal mediators as conduits for establishment of the BIC and/or unconventional secretion across the host interface. Rerouting of the late endocytic GTPase Rab7 occurs at the BIC; and the dominant negative Rab7T22Nled to significant defects in focal interface formation. FYVE biosensor and pharmacological interventions revealed that Rab7 membrane trafficking and establishment/integrity of the biotrophy interface requires the PI3 kinase Vps34 and phosphoinositide PI3(P) function. Additional pharmacological evidence supports endolysosomal trafficking to the host interface follows a distinct non-conventional secretion route too. Finally, we show that the Multi-Vesicular Bodies and lysosomal membranes act as downstream modules of the Rab7 function in precise sorting and specialised traffic of cytoplasmic effectors across theMagnaporthe-Rice interface during blast disease.
Exome-wide analysis of congenital kidney anomalies reveals new genes and shared architecture with developmental disorders
Authors: Milo Rasouly Hila , Krishna Murthy Sarath Babu , Vena Natalie , Povysil Gundula , Beenken Andrew , Verbitsky Miguel , Shril Shirlee , Lekkerkerker Iris , Khan Atlas , Fasel David , Wongboonsin Janewit , Martino Jeremiah , Ke Juntao , Elefant Naama , Tomar Nikita , Harnof Ofek , Yang Sandy , Kisselev Sergey , Bheda Shiraz , Reytan-Miron Sivan , Lim Tze Y , Jamry-Dziurla Anna , Lugani Francesca , Zhang Jun Y , Marasa Maddalena , Kolupaeva Victoria , Groopman Emily E. , Jin Gina , Ghavami Iman , Stevens Kelsey O. , Coughlin Arielle C. , Kil Byum Hee , Chatterjee Debanjana , Bradbury Drew , Zheng Jason , Mehl Karla , Morban Maria , Reingold Rachel , Piva Stacy , Mu Xueru , Mittrori Adele , Szmigielska Agnieszka , Gliwińska Aleksandra , Ranghino Andrea , Bomback Andrew S , Badenski Andrzej , Latos-Bielenska Anna , Materna-Kiryluk Anna , Amoroso Antonio , Izzi Claudia , La Scola Claudio , Cohen David Jonathan , Santoro Domenico , Drozdz Dorota , Fiaccadori Enrico , Lin Fangming , Scolari Francesco , Tondolo Francesco , La Manna Gaetano , Appel Gerald B , Ghiggeri Gian Marco , Zaza Gianluigi , Montini Giovanni , Masnata Giuseppe , Krzemien Grażyna , Pisani Isabella , Radhakrishnan Jai , Zachwieja Katarzyna , Monaco Lauren , Gesualdo Loreto , Biancone Luigi , Murer Luisa , Mizerska-Wasiak Malgorzata , Tkaczyk Marcin , Zaniew Marcin , Borszewska-Kornacka Maria K. , Szczepanska Maria , Saraga Marijan , Rao Maya K , Bodria Monica , Miklaszewska Monika , Uy Natalie S , Baraldi Olga , Bjanid Omar , Esposito Pasquale , Zamboli Pasquale , Marzuillo Pierluigi , Canetta Pietro A , Sikora Przemyslaw , Westland Rik , Crew Russell J , Alam Shumyle , Guarino Stefano , Negrisolo Susanna , Hays Thomas , Grandinetti Valeria , Tasic Velibor , Lozanovski Vladimir J. , Caliskan Yasar , Goldstein David , Lifton Richard P , Ionita-Laza Iuliana , Kiryluk Krzysztof , van Eerde Albertien , Hildebrandt Friedhelm , Sanna-Cherchi Simone , Gharavi Ali G 
Published: November 2024

AbstractKidney anomalies (KA) are developmental disorders that commonly cause pediatric chronic kidney disease and mortality. We examined rare coding variants in 248 KA trios and 1,742 singleton KA cases and compared them to 22,258 controls. Diagnostic and candidate diagnostic variants were detected in 14.1% of cases. We detected a significant enrichment of rare damaging variants in constrained genes expressed during kidney development and in genes associated with other developmental disorders, suggesting phenotype expansion. Consistent with these data, 18% of KA patients with diagnostic variants had neurodevelopmental or cardiac phenotypes. Extrarenal developmental phenotypes were associated with a higher burden of rare variants. Statistical analyses identified 40 novel candidate genes, 2 of which were confirmed as new KA genes:ARID3AandNR6A1.This study suggests that many yet-unidentified syndromes would be discoverable with larger cohorts and cross-phenotype analysis, leading to clarification of the genetic and phenotypic spectrum of developmental disorders.
VirNA: a novel Minimum Spanning Networks algorithm for investigating viral evolution
Authors: Mazzotti G. , Bianco L. , Bado M. , Lavezzo E. , Toppo S. , Fontana P. 
Published: November 2024

ABSTRACTNext Generation Sequencing technologies are essential in public health surveillance for tracking pathogen evolution, spread, and the emergence of new variants. However, the extensive sequencing of viral genomes during recent pandemics has highlighted the limitations of traditional molecular phylogenetic algorithms in capturing fine-grained evolutionary details, emphasizing the urge for more effective approaches to manage these large-scale data. VirNA (Viral Network Analyzer) addresses this challenge by reconstructing detailed mutation patterns and tracing pathogen evolutionary routes in specific regions through Minimum Spanning Networks. It analyzes thousands of sequences, generating networks where nodes represent identical genomic sequences linked to their metadata, while edges represent evolutionary pathways.AUTHOR SUMMARYThe authors present Viral Network Analyzer (VirNA), a new tool designed to help track the spread of viruses during pandemics. During recent outbreaks, researchers faced challenges due to the sheer volume of viral genome data. Traditional tools struggled to process this massive amount of information effectively. VirNA solves this problem by using a powerful method called Minimum Spanning Networks (MSN) with enhanced features to analyze large datasets quickly and accurately. VirNA allows scientists to map how viruses spread in specific areas, providing critical insights that other tools couldn’t achieve. It complements traditional phylogenetic methods, offering a detailed look at viral transmission routes. This makes it a valuable asset for public health surveillance, helping experts understand and respond to pandemics more effectively. Already tested in previous studies, VirNA represents a significant breakthrough for future pandemic preparedness, offering new ways to handle and interpret big data in viral research.
Critical Spacing in Cell-Matrix Mechanical Feedback Controls Tissue Condensation
Authors: Peng Xiangjun , Huang Yuxuan , Elson Elliot L. , Genin Guy M. , Feng Xi-Qiao 
Published: November 2024

ABSTRACTThe mechanical interplay between cells and their extracellular matrix (ECM) presents a fundamental paradox in mechanobiology: while individual cells respond monotonically to increasing mechanical stimulus, collective cellular behaviors exhibit sharp transitions at critical cell densities. This is particularly evident in tissue condensation, where cell-seeded collagen matrices either dramatically contract or remain unchanged depending on whether the initial cell spacing falls below or above a critical threshold. Here we resolve this apparent contradiction through bio-chemo-mechanical modeling of cell-ECM interactions. We show that while increasing ECM stiffness enhances individual cell activation, it simultaneously weakens the mechanical cross-talk between cells, creating a non-monotonic relationship that governs collective behavior. This competition between local activation and neighbor communication establishes a critical spacing threshold below which cells can mechanically polarize their neighbors through ECM remodeling. The predicted critical spacing aligns with experimental observations of the cell density required for tissue condensation, reconciling single-cell and collective responses. Our model reveals how recursive interactions between cellular contractility and ECM mechanics give rise to emergent spatial ordering, demonstrating how complex multicellular behaviors can emerge from simple mechanical principles. These findings provide a physical basis for understanding mechanobiological signaling, with implications for tissue development and disease progression.
An SH3-binding allosteric modulator stabilizes the global conformation of the AML-associated Src-family kinase, Hck
Authors: Selzer Ari M. , Gerlach Gabriella , Gonzalez-Areizaga Giancarlo , Wales Thomas E. , Cui Stephanie Y. , Iyer Prema , Engen John R. , Camacho Carlos , Ishima Rieko , Smithgall Thomas E. 
Published: November 2024

AbstractWhile ATP-site inhibitors for protein-tyrosine kinases are often effective drugs, their clinical utility can be limited by off-target activity and acquired resistance mutations due to the conserved nature of the ATP-binding site. However, combining ATP-site and allosteric kinase inhibitors can overcome these shortcomings in a double-drugging framework. Here we explored the allosteric effects of two pyrimidine diamines, PDA1 and PDA2, on the conformational dynamics and activity of the Src-family tyrosine kinase Hck, a promising drug target for acute myeloid leukemia. Using1H-15N HSQC NMR, we mapped the binding site for both analogs to the SH3 domain. Despite the shared binding site, PDA1 and PDA2 had opposing effects on near-full-length Hck dynamics by hydrogen-deuterium exchange mass spectrometry, with PDA1 stabilizing and PDA2 disrupting the overall kinase conformation. Kinase activity assays were consistent with these observations, with PDA2 enhancing kinase activity while PDA1 was without effect. Molecular dynamics simulations predicted selective bridging of the kinase domain N-lobe and SH3 domain by PDA1, a mechanism of allosteric stabilization supported by site-directed mutagenesis of N-lobe contact sites. Cellular thermal shift assays confirmed SH3 domaindependent interaction of PDA1 with wild-type Hck in myeloid leukemia cells and with a kinase domain gatekeeper mutant (T338M). These results identify PDA1 as a starting point for Src-family kinase allosteric inhibitor development that may work in concert with ATP-site inhibitors to suppress the evolution of resistance.
Oral exposure to PET microplastics alters the pancreatic transcriptome – implications for the pathogenesis of type 1 diabetes
Authors: Mierzejewski Karol , Kurzyńska Aleksandra , Golubska Monika , Gałęcka Ismena , Całka Jarosław , Bogacka Iwona 
Published: November 2024

AbstractType 1 diabetes is a chronic autoimmune disease, the incidence of which has been steadily increasing in recent years, particularly among adolescents. The disease results from a combination of genetic and environmental factors that lead to the destruction of insulin-producing beta cells in the pancreas. Recently, the potential role of microplastics in the pathogenesis of various diseases has gained attention. Therefore, the aim of this study was to investigate the impact of PET microplastics on the pancreas using immature pigs as a model organism. The global transcriptomic profile of the pancreas was analyzed in piglets treated with either a low (0.1 g/day) or high dose (1 g/day) of PET microplastics for 4 weeks using RNA-Seq. The analysis revealed a dose-dependent effect of PET microplastics on gene expression. A low dose affected the expression of one gene, while a high dose impacted the expression of 86 genes. The differentially expressed genes, including immune cell markers, cytokines and chemokines, may activate the immune system in the pancreas in a way that is characteristic of the pathogenesis of type 1 diabetes. It suggests that oral exposure to PET microplastics may be a new risk factor for the development of this disease.
Evolution of vocal production learning in parrots
Authors: Krasheninnikova A , Smeele SQ , Snijders M , Haldar E , Carpenter J , Zamora R , Naguib M , Wolf JBW , Gahr M , von Bayern AMP 
Published: November 2024

AbstractVocal production learning (VPL), the capacity to imitate sounds, is a crucial, but not exclusive component of human language. VPL is rare in animals but common in birds, where it evolved independently in songbirds, hummingbirds, and parrots. Parrots (Psittaciformes) learn new vocalizations throughout their lives and exhibit astonishing vocal flexibility and imitation capacity. They can copy allospecific sounds, e.g., human words and learn their associated meanings. Parrots, therefore, present an intriguing model to shed light on how VPL evolved and how it may relate to other language-relevant traits. How widely VPL is distributed across Psittaciformes and to what extent (qualitative) species differences exist, remains unknown. Here, we provide the first comprehensive overview of the phylogenetic distribution of (allospecific) VPL in this clade by conducting surveys of publicly available video footage. Out of the 398 currently recognized extant species, we found videos for 163, of which 136 showed evidence of VPL. Phylogenetic analyses suggest secondary losses and reacquisitions of VPL covarying with socioecological parameters (gregariousness), life-history (longevity), and morphological (body size) traits. This study provides the first insights into interspecific variation in vocal learning across all parrot species and reveals potential socio-ecological drivers of its evolution.SignificanceLittle is known about the selective forces that favor the evolution of vocal production learning (VPL), a rare trait in animals and a prerequisite for the evolution of human language. We provide the first insights into interspecific variation in VPL in the evolutionary history of parrots and uncover candidate evolutionary drivers. The current data suggest that the evolution of VPL within parrots has been highly dynamic, with multiple secondary losses and reacquisitions. Our model showed that VPL most likely was the ancestral state. Sociality, longevity and body size explain variation in VPL together with a highly uncertain effect of brain size. The findings may motivate comparative work in other taxa and contribute to research into the evolutionary origins of human language.
Metapredict enables accurate disorder prediction across the Tree of Life
Authors: Lotthammer Jeffrey M. , Hernández-García Jorge , Griffith Daniel , Weijers Dolf , Holehouse Alex S. , Emenecker Ryan J. 
Published: November 2024

SUMMARYIntrinsically disordered proteins and protein regions (collectively IDRs) are critical in numerous cellular processes. To understand how IDRs facilitate function, we need tools to accurately and rapidly identify them from sequence. While many methods for disorder prediction exist, we are currently limited by throughput and accuracy for evolutionary scale analyses. To bridge this gap, we developed metapredict V3, an updated version of our disorder predictor that enables evolutionary-scale disorder prediction. Metapredict V3 enables proteome-scale prediction with state-of-the-art accuracy in seconds and was developed with a focus on usability. It is distributed as a web server, Python software package, command-line interface, and Google Colab notebook. Here, we leverage the accuracy and throughput of metapredict V3 to predict disorder for over 20,000 proteomes to evaluate the prevalence of disorder across the kingdoms of life.
Early Life Predictors of Child Development at Kindergarten: A Structural Equation Model using a Longitudinal Cohort
Authors: Turner Sarah E. , Goguen Stephanie , Dufault Brenden , Mayer Teresa , Mandhane Piushkumar J. , Moraes Theo J. , Turvey Stuart E. , Simons Elinor , Subbarao Padmaja , Azad Meghan B. 
Published: November 2024

AbstractIntroductionEarly child development sets the stage for lifelong health. Identifying early life factors related to child development can help guide programs and policies to bolster child health and wellbeing. The objective of this research was to examine how a broad range of predictors, measured prenatally to the third year of life, are related to child development at kindergarten.MethodsWe linked survey data from the Manitoba site of the CHILD Cohort Study with data from the Early Development Instrument (EDI) assessment, completed in kindergarten by the Manitoba public school system (n=442 children). The EDI measures five domains of development (ex. language, physical), scored to indicate the bottom 10% (i.e. ‘vulnerable’) of the population on one or more domains. Using structural equation modelling, we grouped 23 predictors of child development into six latent factors including prenatal exposures, child health and lifestyle, family stress, and socioeconomic status. We examined the associations between each latent factor and EDI vulnerability.ResultsOverall, 20.1% of children were vulnerable on one or more EDI domains. Higher family stress at 1 year and 3 years was related to a 0.20 (p-value ≤ 0.001) and 0.33 (p-value ≤ 0.001) standardized increase of EDI vulnerability. Higher socioeconomic status was related to a - 0.26 (p-value =0.01) standardized increase of EDI vulnerability, and this link was partially mediated through family stress at three years (10.6% mediated). Prenatal exposures (e.g. maternal diet quality), as well as child health and lifestyle factors (e.g. weekday sleep) were not related to EDI vulnerability.ConclusionsSupporting parental mental health throughout early life, universal screening for early life stress, as well as targeting programs and supports for those living with low SES appear to be priority areas that could help to improve early child development.
ENCODE guided WGS analysis can identify trait associated regulatory regions driven by rare-variants
Authors: Flanagan Jack Thomas , Nam Kisung , Lee Seunggeun 
Published: November 2024

AbstractLarge-scale whole-genome sequencing (WGS) data provides unprecedented opportunity to explore the role of rare variants in non-coding regions on complex traits. However, unlike gene-based exome analysis, non-coding regions lack a well-defined unit for rare-variant testing. Here, we utilized 1,036,913 candidate Cis-Regulatory Elements (cCREs) from ENCODE as analysis units and conducted rare-variant association analysis for 100 traits with SAIGE-GENE+. In a discovery set of 150K White-British samples we identified 1,987 significant associations and replicated 88% of them in a validation set of 250K White-British samples. Associations were enriched in promoter-like signals (PLS) and proximal enhancer- like signals (pELS). Conditional analyses of 230 cCREs across five traits on GWAS variants identified 68 independent cCRE associations. A leukemia case study highlighted key loci, including a PLS for SRSF2 and a pELS for BCL6, demonstrating the effectiveness of cCRE- based analysis.