bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protein Structure Inspired Drug Discovery
Authors: Qiao Fangfang , Binknowski T. Andrew , Broughan Irene , Chen Weining , Natarajan Amarnath , Schiltz Gary E. , Scheidt Karl A. , Anderson Wayne F. , Bergan Raymond 
Published: May 2024

AbstractDrug discovery starts with known function, either of a compound or a protein, in-turn prompting investigations to probe 3D structure of the compound-protein interface. As protein structure determines function, we hypothesized that unique 3D structural motifs represent primary information denoting unique function that can drive discovery of novel agents. Using a physics-based protein structure analysis platform developed by us, designed to conduct computationally intensive analysis at supercomputing speeds, we probed a high-resolution protein x-ray crystallographic library developed by us. We selected 3D structural motifs whose function was not otherwise established, that offered environments supporting binding of drug-like chemicals and were present on proteins that were not established therapeutic targets. For each of eight potential binding pockets on six different proteins we accessed a 60 million compound library and used our analysis platform to evaluate binding. Using eight-day colony formation assays acquired compounds were screened for efficacy against human breast, prostate, colon and lung cancer cells and toxicity against human bone marrow stem cells. Compounds selectively inhibiting cancer growth segregated to two pockets on separate proteins. The compound, Dxr2-017, exhibited selective activity against human melanoma cells in the NCI-60 cell line screen, had an IC50 of 19 nM against human melanoma M14 cells in our eight-day assay, while over 2100-fold higher concentrations inhibited stem cells by less than 30%. We show that Dxr2-017 induces anoikis, a unique form of programmed cell death in need of targeted therapeutics. The predicted target protein for Dxr2-017 is expressed in bacteria, not in humans. This supports our strategy of focusing on unique 3D structural motifs. It is known that functionally important 3D structures are evolutionarily conserved. Here we demonstrate proof-of-concept that protein structure represents high value primary data to support discovery of novel therapeutics. This approach is widely applicable.Author summaryWe introduce the concept that protein 3D structure represents primary information which can support downstream investigations, in this instance leading to the discovery of novel anticancer therapeutics.
Direct detection of 8-oxo-dG using nanopore sequencing
Authors: Pagès-Gallego Marc , van Soest Daan M. K. , Besselink Nicolle J. M. , Straver Roy , Keijer Janneke P. , Vermeulen Carlo , Marcozzi Alessio , van Roosmalen Markus J. , van Boxtel Ruben , Burgering Boudewijn M. T. , Dansen Tobias B. , de Ridder Jeroen 
Published: May 2024

AbstractGenomic DNA is constantly subjected to oxidative damage, which is thought to be one of the major drivers of cancer and age-dependent decline. The most prominent consequence is the modification of guanine into 8-hydroxyguanine (8-oxo-dG), which has important mutagenic potential and plays a role in methylation-mediated gene regulation. Methods to simultaneously detect and quantify 8-oxo-dG within its genomic context have been lacking; mainly because these methods rely on indirect detection or are based on hydrolysis of the DNA. Nanopore sequencing has been deployed for the direct detection of base-modifications like cytosine methylation during sequencing. However, currently there is no model to detect 8-oxo-dG by nanopore sequencing due to the lack of training data. Here, we developed a strategy based on synthetic oligos to create long DNA molecules with context variability for effective deep learning and nanopore sequencing. Moreover, we showcase a training approach suitable to deal with the extreme scarceness of 8-oxo-dG compared to canonical G to enable specific 8-oxo-dG detection. Applied to an inducible tissue culture system for oxidative DNA damage, our approach reveals variable 8-oxo-dG distribution across the genome, a dissimilar context pattern to C>A mutations, and concurrent 5-mC depletion within a 2-kilobase window surrounding 8-oxo-dG sites. These findings not only underscore the potential of nanopore sequencing in epigenetic research, but also shed light on 8-oxo-dG’s role in genomic regulation. By simultaneously measuring 5-mC and 8-oxo-dG at single molecule resolution, our study provides insights into the functional interplay between these DNA modifications. Moreover, our approach using synthetic oligos to generate a ground truth from machine learning modification calling could be applied to any other DNA modification. Overall, our work contributes to advancing the field of epigenetics and highlights nanopore sequencing as a powerful tool for studying DNA modifications.
EV-Checklist: A fast documentation tool for enhancing transparency and accessibility in extracellular vesicle research
Authors: Poupardin Rodolphe , Wolf Martin , Maeding Nicole , Fuhrmann Gregor , Strunk Dirk 
Published: May 2024

AbstractExtracellular vesicle (EV) research has experienced rapid growth in the past decade. While community-driven efforts, such as the MISEV guidelines (2014, 2018, 2023), have aimed to standardize reporting and enhance experimental rigor, these have not yet been universally adopted in daily EV research practices. The complexity and time commitment required by existing reporting tools can deter researchers from fully embracing them, leading to incomplete or inconsistent documentation in EV studies. Therefore, we created EV-checklist, a complementary digital tool to streamline documentation during manuscript submission and increase transparency for the reviewers, editors and readers. Our tool guides researchers through a straightforward checklist covering nomenclature, source, isolation, characterization, and functional studies of EVs. It generates a concise two-page PDF formatted table for easy integration into manuscripts and provides editors, reviewers, and readers with a clear overview of the conducted studies. EV-Checklist intends to complement existing comprehensive registries as a ‘fast-and-easy’ tool to enhance clarity and accessibility of methodological and functional insights. It may also promote higher adherence to documentation standards and in EV studies. Our tool is available onhttps://ev-zone.org.
LncCE: Landscape of Cellular-Elevated LncRNAs in Single Cells Across Normal and Cancer Tissues
Authors: Xu Kang , Liu Yujie , Lv Chongwen , Luo Ya , Shi Jingyi , Zou Haozhe , Zhou Weiwei , Lv Dezhong , Yang Changbo , Li Yongsheng , Xu Juan 
Published: May 2024

AbstractLong non-coding RNAs (lncRNAs) have emerged as significant players for maintaining the morphology and function of tissues or cells. The precise regulatory effectiveness of lncRNA is closely associated with the spatial expression patterns across tissues and cells. Here, we proposed the Cellular-Elevated LncRNA (LncCE) database to systematically explore cellular-elevated (CE) lncRNAs across normal and cancer tissues in single cells. LncCE encompasses 87,946 CE lncRNAs of 149 cell types by analyzing 181 single-cell RNA sequencing (scRNA-seq) datasets, involved in 20 fetal normal tissues, 59 adult normal tissues, as well as 32 adult and 5 pediatric cancer tissues.Two main search options were provided via a given lncRNA name or a cell type. The output results emphasize both qualitative and quantitative expression features of lncRNAs across different cell types, co-expression with protein-coding genes as well as their involved in biological functions. For cancers, LncCE particularly provided quantitative figures for exhibiting their expression changes compared to control samples and clinical associations with patient overall survivals. Together, LncCE offers an extensive, quantitative and user-friendly interface to investigate cellular-elevated expression atlas for lncRNAs across normal and cancers tissues at single-cell level. The LncCE database is available athttp://bio-bigdata.hrbmu.edu.cn/LncCE.
The role of ADAR editing and nonsense-mediated decay in Parkinson’s Disease
Authors: Mercer Heather Milliken , Nair Aiswarya Mukundan , Tariq Ayesha , Piontkivska Helen 
Published: May 2024

AbstractParkinson’s Disease (PD) is a multifactorial disease with heterogenous phenotypes that vary across individuals, as well as by age and sex. Therefore, it is likely that multiple interacting factors, such as environmental influences and aging, as well as genetic factors, including dynamic RNA (ADAR, Adenosine Deaminases Acting on RNA) editing, may play a role in PD pathology. In this analysis of 317 transcriptomes of healthy controls, PD and prodromal patients aged 65 years or older, from Parkinson’s Project Markers Initiative dataset, we observe differences in ADAR expression, number of putative ADAR edits, editing index, and the number of high and moderate impact edits between control groups and diseased samples, particularly when ADAR editing is associated with nonsense-mediated decay (NMD). Likewise, differentially expressed genes between comparison groups were linked to NMD-related pathways. NMD is an important process in detecting deleterious nonsense sequences in mRNA transcripts and eliminating them from the cell. Thus, NMD regulation serves an important role in neurodevelopment, neural differentiation, and neural maturation. RNA misprocessing, which includes dysregulation of NMD, is known to play an important role in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia. Our results suggest that NMD may also be an important factor in PD physiology.
Emergence of potato virus Y outbreaks in tomatoes in Brazil, the disease and spread
Authors: Lucena Vivian S. , Nakasu Erich Y. T. , Pereira José L. , Rêgo-Machado Camila M. , Rodrigues Cristiano S. , Ueno Bernardo , Morais Ivair J. , Inoue-Nagata Alice K. 
Published: May 2024

AbstractThe emergence of ’Mexican Fire’ disease in Brazilian tomato fields, attributed to potato virus Y (PVY), has raised concerns. Characterized by severe necrosis on median leaves, the definitive etiological agent of this disease remained unverified despite PVY detection in symptomatic plants. Our study aimed to elucidate the causal agent, occurrence, spread, and symptomatology of Mexican Fire. Deep sequencing of tomato leaves with typical necrotic symptoms confirmed the association with PVY, reinforcing its role as the causal agent. Serological tests with a PVY-specific polyclonal antibody consistently correlated symptoms with virus presence in a fresh market tomato field, with higher PVY incidence near older tomato and maize plants. Necrotic leaf distribution analysis revealed a predominant occurrence in median leaves, progressing upwards. Deep sequencing of symptomatic field samples exclusively detected PVY, reaffirming its role in symptom induction. Importantly, PVY inoculation under field and greenhouse conditions fulfilled Koch’s Postulates, triggering leaf necrosis. Our findings unequivocally establish PVY as the causal agent of Mexican Fire disease, shedding light on its etiology, incidence, spread, and symptom expression, crucial for effective disease management strategies.
The dynamic climate adaptation of indicator warbler species complex in the Pacific Rainforest
Authors: Wang Silu 
Published: May 2024

AbstractUnderstanding the functional responses of ecosystems to climate change is critical to predict and conserve global biodiversity. The evolution of indicator species provides an efficient avenue towards the functional biome response to climate change. Leveraging decades of citizen science data coupled with high-resolution spatiotemporal climate data, I dissected the climate change response of hybridizingSetophagawarblers, indicator species breeding in the mysterious canopy of the Pacific Rainforest. Breeding habitat temperature and precipitation powerfully predicted the breeding occupancy of the northern (S. townsendi) and the southern species (S. occidentalis). Both species showed positive climatic responses in the recent decade when the recent breeding occupancy was greater than the expected contingency. This implies the potential climate adaptation or life history plasticity in the breeding warbler populations. However, theS. occidentalisshowed a compromised climate response in 2000-10, when the predicted breeding occupancy was significantly lower than the expected contingency. The compromised response might be due to rampant decline of July precipitation in 2000-10, compared to previous decades. Although the July precipitation continued to decline in 2010-20,S. occidentalisshowed signs of recovery, after generations of climate adaptation. I further evaluated their breeding niche competition, reflected by the overlap of breeding occupancy between species. I found that the competition potential was the lowest in 2000-10 when both species were at the trough of breeding occupancy, which recovered in 2010-20. This study shed light on eco-evo feedback in the indicating species complex and illuminated the functional response of the rainforest ecosystem to climate change.
lme4breeding: enabling genetic evaluation in the era of genomic data
Authors: Covarrubias-Pazaran Giovanny 
Published: May 2024

AbstractMixed models are a cornerstone in quantitative genetics to study the genetics of complex traits. A standard quantitative genetic model assumes that the effects of some random effects (e.g., individuals) are correlated based on their identity by descent and state. In addition, other relationships arise in the genotype by environment interactions (i.e., covariance structures). Open-source mixed model routines are available but do not account for complex covariance structures and are able to fit big genomic models. The lme4breeding R package was developed as an extension of the lme4 package and allows correlated random effects and complex covariance structures to be fitted for Gaussian, binary, and count responses. The correlation between levels of the random effect (e.g., individuals) is accounted for by post-multiplying the incidence matrix of the levels of this random factor by the Cholesky factor of the corresponding (co)variance matrix (e.g., the genomic relationship matrix). To enable big genomic models the eigen decomposition of relationship matrices is enabled. Maximum likelihood and REML estimation are available in lme4breeding. This note describes the type of models that can be fitted using lme4breeding and presents some examples.
Cardioprotection by Poloxamer 188 is Mediated through Increased Endothelial Nitric Oxide Production
Authors: Chen Gaoxian , Douglas Hunter F. , Li Zhu , Cleveland William J. , Balzer Claudius , Yannopolous Demetris , Chen Ian Ying-Li , Obal Detlef , Riess Matthias L. 
Published: May 2024

AbstractIschemia/reperfusion (I/R) injury significantly contributes to the morbidity and mortality associated with cardiac events. Poloxamer 188 (P188), a nonionic triblock copolymer, has been proposed to mitigate I/R injury by stabilizing cell membranes. However, the underlying mechanisms remain incompletely understood, particularly concerning endothelial cell function and nitric oxide (NO) production.We employed human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) and endothelial cells (ECs) to elucidate the effects of P188 on cellular survival, function, and NO secretion under simulated I/R conditions. iPSC-CMs contractility and iPSC-ECs’ NO production were assessed following exposure to P188. Further, an isolated heart model using Brown Norway rats subjected to I/R injury was utilized to evaluate the ex-vivo cardioprotective effects of P188, examining cardiac function and NO production, with and without the administration of a NO inhibitor.In iPSC-derived models, P188 significantly preserved CM contractile function and enhanced cell viability after hypoxia/reoxygenation. Remarkably, P188 treatment led to a pronounced increase in NO secretion in iPSC-ECs, a novel finding demonstrating endothelial protective effects beyond membrane stabilization. In the rat isolated heart model, administration of P188 during reperfusion notably improved cardiac function and reduced I/R injury markers. This cardioprotective effect was abrogated by NO inhibition, underscoring the pivotal role of NO. Additionally, a dose-dependent increase in NO production was observed in non-ischemic rat hearts treated with P188, further establishing the critical function of NO in P188 induced cardioprotection.In conclusion, our comprehensive study unveils a novel role of NO in mediating the protective effects of P188 against I/R injury. This mechanism is evident in both cellular models and intact rat hearts, highlighting the potential of P188 as a therapeutic agent against I/R injury. Our findings pave the way for further investigation into P188’s therapeutic mechanisms and its potential application in clinical settings to mitigate I/R-related cardiac dysfunction.
WEDAP: A Python Package for Streamlined Plotting of Molecular Simulation Data
Authors: Yang Darian T. , Chong Lillian T. 
Published: May 2024

AbstractGiven the growing interest in path sampling methods for extending the timescales of molecular dynamics (MD) simulations, there has been great interest in software tools that streamline the generation of plots for monitoring the progress of large-scale simulations. Here, we present the WEDAP Python package for simplifying the analysis of data generated from either conventional MD simulations or the weighted ensemble (WE) path sampling method, as implemented in the widely used WESTPA software package. WEDAP facilitates (i) the parsing of WE simulation data stored in highly compressed, hierarchical HDF5 files, and (ii) incorporates trajectory weights from WE simulations into all generated plots. Our Python package consists of multiple user-friendly interfaces: a command-line interface, a graphical user interface, and a Python application programming interface. We demonstrate the plotting features of WEDAP through a series of examples using data from WE and conventional MD simulations that focus on the HIV-1 capsid protein C-terminal domain dimer as a showcase system. The source code for WEDAP is freely available on GitHub athttps://github.com/chonglab-pitt/wedap.
Sex-specific expression of the human NAFLD-NASH transcriptional signatures in the liver of medaka with a history of ancestral bisphenol A exposure
Authors: Chakraborty Sourav , Anand Santosh , Bhandari Ramji Kumar 
Published: May 2024

AbstractThe progression of fatty liver disease to non-alcoholic steatohepatitis (NASH) is a leading cause of death in humans. Lifestyles and environmental chemical exposures can increase the susceptibility of humans to NASH. In humans, the presence of bisphenol A (BPA) in urine is associated with fatty liver disease, but whether ancestral BPA exposure leads to the activation of human NAFLD-NASH-associated genes in the unexposed descendants is unclear. In this study, using medaka fish as an animal model for human NAFLD, we investigated the transcriptional signatures of human NAFLD-NASH and their associated roles in the pathogenesis of the liver of fish who were not directly exposed but their ancestors were exposed to BPA during embryonic and perinatal development three generations prior. Comparison of bulk RNA-Seq data of the liver in BPA lineage male and female medaka with publicly available human NAFLD-NASH patient data revealed transgenerational alterations in the transcriptional signature of human NAFLD-NASH in medaka liver. Twenty percent of differentially expressed genes (DEGs) were upregulated in both human NAFLD patients and medaka. Specifically in females, among the total shared DEGs in the liver of BPA lineage fish and NAFLD patient groups, 27.69% DEGs were downregulated and 20% DEGs were upregulated. Off all DEGs, 52.31% DEGs were found in ancestral BPA-lineage females, suggesting that NAFLD in females shared majority of human NAFLD gene networks. Pathway analysis revealed beta-oxidation, lipoprotein metabolism, and HDL/LDL-mediated transport processes linked to downregulated DEGs in BPA lineage males and females. In contrast, the expression of genes encoding lipogenesis-related proteins was significantly elevated in the liver of BPA lineage females only. BPA lineage females exhibiting activationof myc, atf4, xbp1,stat4, and cancerous pathways, as well as inactivation ofigf1, suggest their possible association with an advanced NAFLD phenotype. The present results suggest that gene networks involved in the progression of human NAFLD and the transgenerational NAFLD in medaka are conserved and that medaka can be an excellent animal model to understand the development and progression of liver disease and environmental influences in the liver.
Vesicle-Mediated Regulation of Pollen tube Growth inTorenia fournieri
Authors: Jin Xingyue , Mizukami Akane G. , Okuda Satohiro , Higashiyama Tetsuya 
Published: May 2024

AbstractIn flowering plants, the growth of pollen tubes carrying sperm cells to the female gametophyte is necessary for double fertilization and seed development. The rate of growth of the pollen tube tip determines the fertility of many artificially cultivated plants and depends on the vesicle-mediated transport of cell membrane and cell wall components. However, the investigation of vesicle transport is hampered by the lack of transgenic methods for economically important plants. Here, we developed a method to transiently inhibit vesicle activity using brefeldin A (BFA) and antisense oligodeoxynucleotides (AS-ODNs) targeting key genes in the wishbone flower (Torenia fournieri), which has been used in studies of sexual reproduction in plants. BFA disrupted vesicle gradient homeostasis, thereby altering cell wall deposition and pollen tube morphology. The AS-ODN targetingTorenia fournieri ANXUR(TfANX), which is implicated in maintaining pollen tube growth and is used as a marker to assess inhibition by AS-ODNs, penetrated cell membranes and inhibited the expression of target genes. The treatment of pollen tubes with AS-ODN againstTfRABA4D, which is specifically expressed in pollen and involved in regulating vesicle targeting, resulted in pollen tubes with a bulging phenotype and disrupted pectin deposition, effects similar to those of BFA. In summary, vesicle-mediated mechanisms regulate the patterning of the pollen tube cell wall inT.fournieriand our findings could facilitate the genetic manipulation of horticultural crops.
PowerCHORD: constructing optimal experimental designs for biological rhythm discovery
Authors: Silverthorne Turner , Carlucci Matthew , Petronis Arturas , Stinchcombe Adam R 
Published: May 2024

AbstractEqually spaced temporal sampling is the standard protocol for the study of biological rhythms. These equispaced designs perform well when calibrated to an oscillator’s period yet can have systematic detection biases when applied to rhythms of unknown periodicity. Here, we present a broadly-applicable set of computational methods for seeking optimal measurement schedules for rhythm detection. Our PowerCHORD methods generate experimental designs by maximizing a closed-form expression for the statistical power of the cosinor model using a black-box optimization method (differential evolution), a brute-force search, or mixed-integer conic programming. Application of these three methods showed numerically that they improve upon equispaced designs under many experimental contexts. Our numerical results also revealed an intuitive approach for achieving optimal power for simultaneous investigation of circadian, circalunar, and circannual rhythms. Our findings suggest that timing optimization is an effective yet under-explored tool for improving biological rhythm discovery.