bluuebunny/crossref_metadata_2025_split huggingface dataset:
Revealing Chloroquine’s Antimalarial Mechanism: The Suppression of Nucleation Events during Heme to Hemozoin Transformation
Authors: Singh Rahul , Singh Rashmi , Srihari Velaga , Makde Ravindra D. 
Published: June 2023

ABSTRACTMalaria parasites generate toxic heme during hemoglobin digestion, which is neutralized by crystallizing into inert hemozoin (β-hematin). Chloroquine blocks this detoxification process, resulting in heme-mediated toxicity in malaria parasites. However, the exact mechanism of chloroquine’s action remains unknown. This study investigates the impact of chloroquine on the transformation of heme into β-hematin. The results show that chloroquine does not completely halt the transformation process but rather slows it down. Additionally, chloroquine complexation with free heme does not affect substrate availability or inhibit β-hematin formation. SEM and XRD studies indicate that the size of β-hematin crystal particles and crystallite increases in the presence of chloroquine, suggesting that chloroquine does not impede crystal growth. These findings suggest that chloroquine delays hemozoin production by perturbing the nucleation events of crystals and/or the stability of crystal nuclei. Thus, contrary to prevailing beliefs, this study provides a new perspective on the working mechanism of chloroquine.
Prolonged exposure to hypergravity increases number and size of cells and enhances lignin deposition in the stem ofArabidopsis thaliana(L.) Heynh
Authors: Shinohara Hironori , Muramoto Masaki , Tamaoki Daisuke , Kamachi Hiroyuki , Inoue Hiroshi , Kume Atsushi , Karahara Ichirou 
Published: June 2023

AbstractWe have performed a lab-based hypergravity cultivation experiment using a centrifuge equipped with a lighting system and examined long-term effects of hypergravity on the development of the main axis (stem) of the Arabidopsis (Arabidopsis thaliana(L.) Heynh.) primary inflorescence. Plants grown under 1 ×g(gravitational acceleration on Earth) conditions for 20-23 days and having the first visible flower bud were exposed to hypergravity at 8 ×gfor 10 days. We analyzed the effect of prolonged hypergravity conditions on growth, lignin deposition, and tissue anatomy of the main axis. As a result, the length of the main axis decreased and cross-sectional area, dry mass per unit length, cell number, lignin content of the main axis significantly increased under hypergravity. Lignin content in the rosette leaves also increased when they were exposed to hypergravity during their development. Except for interfascicular fibers, cross-sectional areas of the tissues composing the internode significantly increased under hypergravity in most type of the tissues in the basal part than the apical part of the main axis, indicating that the effect of hypergravity is more pronounced in the basal part than the apical part. The number of cells in fascicular cambium and xylem significantly increased under hypergravity both in the apical and basal internodes of the main axis, indicating a possibility that hypergravity stimulates procambium activity to produce xylem element more than phloem element. The main axis was suggested to be strengthened through changes in its morphological characteristics as well as lignin deposition under prolonged hypergravity conditions.
Spindle Chirp and other Sleep Oscillatory Features in Young Children with Autism
Authors: Cumming D , Kozhemiako N , Thurm AE , Farmer CA , Purcell SW , Buckley AW 
Published: June 2023

AbstractObjectivesTo determine whether spindle chirp and other sleep oscillatory features differ in young children with and without autism.MethodsAutomated processing software was used to re-assess an extant set of polysomnograms representing 121 children (91 with autism [ASD], 30 typically-developing [TD]), with an age range of 1.35-8.23 years. Spindle metrics, including chirp, and slow oscillation (SO) characteristics were compared between groups. SO and fast and slow spindle (FS, SS) interactions were also investigated. Secondary analyses were performed assessing behavioural data associations, as well as exploratory cohort comparisons to children with non-autism developmental delay (DD).ResultsPosterior FS and SS chirp was significantly more negative in ASD than TD. Both groups had comparable intra-spindle frequency range and variance. Frontal and central SO amplitude were decreased in ASD. In contrast to previous manual findings, no differences were detected in other spindle or SO metrics. The ASD group displayed a higher parietal coupling angle. No differences were observed in phase-frequency coupling. The DD group demonstrated lower FS chirp and higher coupling angle than TD. Parietal SS chirp was positively associated with full developmental quotient.ConclusionsFor the first time spindle chirp was investigated in autism and was found to be significantly more negative than in TD in this large cohort of young children. This finding strengthens previous reports of spindle and SO abnormalities in ASD. Further investigation of spindle chirp in healthy and clinical populations across development will help elucidate the significance of this difference and better understand this novel metric.
The critical role of spatio-temporal control in combinatorial chemo- and magnetic hyperthermia thermo-therapy: ‘the where’, ‘the how’ and ‘the when’
Authors: García-Hevia Lorena , Magalhães Andreia Patrícia , Genicio Nuria , Casafont Íñigo , Costa da Silva Milene , Fanarraga Mónica López , Bañobre-López Manuel , Gallo Juan 
Published: June 2023

ABSTRACTCombinatorial treatments hold the key to the future of cancer treatment as they enhance therapeutic indexes by inducing synergistic effects and reducing resistance processes, while often providing a safer option for patients with fewer off-target effects. However, combinatorial treatments bring extra problems to cancer management not only derived from the actual compatibility of the treatments, but also from their hands-on administration. Operational parameters such as administration order and dosing (dose, spacing) have to be optimized in order to positively impact patient prognosis. Here we present a systematic study on the optimization and the importance of these parameters within the framework of a combinatorial chemo-/thermo-therapy. Parameters like ‘where’, ‘how’ and ‘when’ are investigated in detail. Furthermore, we delve into the underlying biochemical mechanisms driving the observed effects through transcriptome analysis.
Machine learning and phylogenetic models identify predictors of genetic variation in Neotropical amphibians
Authors: Amador Luis , Arroyo-Torres Irvin , Barrow Lisa N. 
Published: June 2023

AbstractAimIntraspecific genetic variation is key for adaptation and survival in changing environments and is known to be influenced by many factors, including population size, migration, and life history traits. We investigated genetic variation within Neotropical amphibian species to provide insights into how natural history traits, phylogeny, climatic, and geographic characteristics influence intraspecific diversity.LocationNeotropics.TaxonAmphibians.MethodsWe assembled datasets using open-access databases for natural history traits, genetic sequences, phylogenetic trees, climatic, and geographic data. For each species, we calculated overall nucleotide diversity (π) and tested for isolation by distance (IBD) and isolation by environment (IBE). We then identified predictors of π, IBD, and IBE using Random Forest (RF) regression or RF classification. To incorporate phylogenetic relationships, we fitted phylogenetic generalized linear mixed models (PGLMMs) to predict π, IBD, and IBE.ResultsWe compiled 4,052 mitochondrial DNA sequences from 256 amphibian species (230 frogs and 26 salamanders), georeferencing 2,477 sequences from 176 species that were not linked to occurrence data. RF regressions and PGLMMs were congruent in identifying range size and precipitation (σ) as the most important predictors of π. RF classification and PGLMMs identified minimum elevation as an important predictor of IBD, and maximum latitude and precipitation (σ) as the best predictors of IBE.Main conclusionsThis study unified machine learning and phylogenetic methods and identified predictors of genetic variation in Neotropical amphibians. This approach was valuable to determine which predictors were congruent between methods. We found that species with small ranges or living in zones with less variable precipitation tended to have low genetic diversity. We also showed that Western Mesoamerica, Andes, and Atlantic Forest biogeographic units harbor high diversity across many species that should be prioritized for protection. These results could play a key role in the development of conservation strategies for Neotropical amphibians.
SoyDNGP: A Web-Accessible Deep Learning Framework for Genomic Prediction in Soybean Breeding
Authors: Gao Pengfei , Zhao Haonan , Luo Zheng , Lin Yifan , Li Yaling , Kong Fanjiang , Fang Chao , Wang Xutong 
Published: June 2023

AbstractSoybean is a globally significant crop, playing a vital role in human nutrition and agriculture. Its complex genetic structure and wide trait variation, however, pose challenges for breeders and researchers aiming to optimize its yield and quality. Addressing this biological complexity requires innovative and accurate tools for trait prediction. In response to this challenge, we have developed SoyDNGP, a Convolutional Neural Networks (CNN)-based model that offers significant advancements in the field of soybean trait prediction. Compared to existing methods, such as DeepGS and DNNGP, SoyDNGP boasts a distinct advantage due to its lower parameter volume and superior predictive accuracy. Through rigorous performance comparison, including prediction accuracy and model complexity, SoyDNGP consistently outperformed its counterparts. Furthermore, it effectively predicted complex traits with remarkable precision, demonstrating robust performance across different sample sizes and trait complexities. We also tested the versatility of SoyDNGP across multiple crop species, including Cotton, Maize, Rice, and Tomato. Our results showed its consistent and comparable performance, emphasizing SoyDNGP’s potential as a versatile tool for genomic prediction across a broad range of crops. To enhance its accessibility to users without extensive programming experience, we have designed a user-friendly web server, available athttp://xtlab.hzau.edu.cn/SoyDNGP. The server provides two primary features: ‘Trait Lookup’, offering users the ability to access pre-existing trait predictions for over 500 soybean accessions, and ‘Trait Prediction’, allowing for the upload of VCF files for trait estimation. By providing a high-performing, accessible tool for trait prediction and genomic analysis, SoyDNGP opens up new possibilities in the quest for efficient and optimized soybean breeding.
Herpes-like viral elements and universal subtelomeric ribosomal RNA genes in a chromosome-scale thraustochytrid genome assembly
Authors: Collier Jackie L. , Rest Joshua S. , Gallot-Lavallée Lucie , Lavington Erik , Kuo Alan , Jenkins Jerry , Plott Chris , Pangilinan Jasmyn , Daum Chris , Grigoriev Igor V. , Filloramo Gina V. , Novák Vanclová Anna M. G. , Archibald John M. 
Published: June 2023

ABSTRACTWe used long-read sequencing to produce a telomere-to-telomere genome assembly for the heterotrophic stramenopile protistAurantiochytrium limacinumMYA-1381. Its ∼62 Mbp nuclear genome comprises 26 linear chromosomes with a novel configuration: subtelomeric rDNAs are interspersed with long repeated sequence elements denoted as LOng REpeated - TElomere And Rdna Spacers (LORE-TEARS). These repeats may play a role in chromosome end maintenance. A ∼300 Kbp circular herpesvirus-like genomic element is present at a high copy number. A 269 Kbp related virus-like element was found to reside between two complete sets of rRNA and LORE-TEAR sequences on one end of chromosome 15, indicating recent recombination between the viral and nuclear genome. Our data reveal new types of giant endogenous viral elements originating from herpes-like viruses and existing as either ‘stand-alone’ or integrated elements.
Modelling Human Post-Implantation Development via Extra-Embryonic Niche Engineering
Authors: Hislop Joshua , Alavi Amir , Song Qi , Schoenberger Rayna , Keshavarz F. Kamyar , LeGraw Ryan , Velazquez Jeremy , Mokhtari Tahere , Taheri Mohammad Nasser , Rytel Matthew , de Sousa Lopes Susana M Chuva , Watkins Simon , Stolz Donna , Kiani Samira , Sozen Berna , Bar-Joseph Ziv , Ebrahimkhani Mo R. 
Published: June 2023

AbstractImplantation of the human embryo commences a critical developmental stage that comprises profound morphogenetic alteration of embryonic and extra-embryonic tissues, axis formation, and gastrulation events. Our mechanistic knowledge of this window of human life remains limited due to restricted access toin vivosamples for both technical and ethical reasons. Additionally, human stem cell models of early post-implantation development with both embryonic and extra-embryonic tissue morphogenesis are lacking. Here, we present iDiscoid, produced from human induced pluripotent stem cells via an engineered a synthetic gene circuit. iDiscoids exhibit reciprocal co-development of human embryonic tissue and engineered extra-embryonic niche in a model of human post-implantation. They exhibit unanticipated self-organization and tissue boundary formation that recapitulates yolk sac-like tissue specification with extra-embryonic mesoderm and hematopoietic characteristics, the formation of bilaminar disc-like embryonic morphology, the development of an amniotic-like cavity, and acquisition of an anterior-like hypoblast pole and posterior-like axis. iDiscoids offer an easy-to-use, high-throughput, reproducible, and scalable platform to probe multifaceted aspects of human early post-implantation development. Thus, they have the potential to provide a tractable human model for drug testing, developmental toxicology, and disease modeling.
Local, Quantitative Morphometry of Fibroproliferative Lung Injury using Laminin
Authors: Cox Brendan P. , Hannan Riley T. , Batrash Noora , Sturek Jeffrey M. 
Published: June 2023

AbstractInvestigations into the mechanisms of injury and repair in pulmonary fibrosis require consideration of the spatial heterogeneity inherent in the disease. Most scoring of fibrotic remodeling in preclinical animal models rely on the modified Ashcroft score, which is a semi-quantitative scoring rubric of macroscopic resolution. The obvious limitations inherent in manual pathohistological grading have generated an unmet need for unbiased, repeatable scoring of fibroproliferative burden in tissue. Using computer vision approaches on immunofluorescent imaging of the extracellular matrix (ECM) component laminin, we generate a robust and repeatable quantitative remodeling scorer (QRS). In the bleomycin lung injury model, QRS shows significant agreement with modified Ashcroft scoring with a significant Spearman coefficient r=0.768. This antibody-based approach is easily integrated into larger multiplex immunofluorescent experiments, which we demonstrate by testing the spatial apposition of tertiary lymphoid structures (TLS) to fibroproliferative tissue. The tool reported in this manuscript is available as a standalone application which is usable without programming knowledge.
MEK1/2-Targeting PROTACs Promote the Collateral Degradation of CRAF in KRAS Mutant Cells
Authors: Herrera-Montávez Carlos , Kurimchak Alison M. , Hu Xiaoping , Hu Jianping , Jin Jian , Duncan James S. 
Published: June 2023

SUMMARYActivation of the RAS/MAPK pathway is one of the most frequent alterations in cancer; yet therapies targeting this pathway have shown limited benefit due to drug resistance. For example, resistance to MEK inhibitors in KRAS mutant cancer cells occurs due to relief of a negative feedback that promotes CRAF activation and CRAF-MEK protein interactions, bypassing MEK inhibition. Consequently, combining CRAF and MEK inhibitors for KRAS mutant cancer is an area of intense research. Here, we discovered that the MEK1/2 PROTAC (Proteolysis-Targeting Chimeras) degrader, MS934, caused collateral degradation of CRAF in KRAS mutant cells via a PROTAC-mechanism, offering a new strategy to simultaneously degrade both CRAF and MEK1/2. Importantly, CRAF has been shown to have essential kinase-independent growth and survival functions outside the MEK-ERK pathway in KRAS mutant cells, making CRAF degradation an attractive therapeutic avenue. Despite this, to the best of our knowledge, no CRAF PROTACs have been published. Importantly, our discovery of MS934 as a first-in-class dual CRAF/MEK degrader provides a newfound approach to overcome MEK inhibitor resistance due to relief of negative feedback, as well as block CRAF kinase-independent functions in KRAS mutant cells.
Expanding the list of sequence-agnostic enzymes for chromatin conformation capture assays with S1 nuclease
Authors: Gridina Maria , Popov Andrey , Shadskiy Artem , Torgunakov Nikita , Kechin Andrey , Khrapov Evgeny , Ryzhkova Oxana , Filipenko Maxim , Fishman Veniamin 
Published: June 2023

AbstractThis study presents a novel approach for mapping global chromatin interactions using S1 nuclease, a sequence-agnostic enzyme. We develop and outline a protocol that leverages S1 nuclease’s ability to effectively introduce breaks into both open and closed chromatin regions, allowing for comprehensive profiling of chromatin properties. Our S1 Hi-C method enables the preparation of high-quality Hi-C libraries, marking a significant advancement over previously established DNase I Hi-C protocols. Moreover, S1 nuclease’s capability to fragment chromatin to mono-nucleosomes suggests the potential for mapping the three-dimensional organization of the genome at high resolution. This methodology holds promise for an improved understanding of chromatin state-dependent activities and may facilitate the development of new genomic methods.
Disentangling the cascading effects of Grapevine Red Blotch Virus infection on vine physiology
Authors: Copp Cody R. , DeShields Joseph B. , Kar Suraj , Kirk Claire , Clark Ricky , Stowasser Marianna , KC Achala N. , Levin Alexander D. 
Published: June 2023

AbstractGrapevine Red Blotch Virus is a major grapevine pathogen and is associated with reduced carbon assimilation and delayed berry ripening inVitis viniferaL. Recent work suggests that the virus alters leaf carbon metabolism prior to emergence of visible symptoms. Therefore, diurnal and seasonal measurements were conducted to quantify changes in leaf carbon balance and to elucidate the chronology of symptom progression in leaves and fruit. Healthy and infected vines were assayed in a commercial vineyard during which leaf water relations, photosynthesis, and nonstructural carbohydrates were measured. Additionally, sugar and anthocyanin accumulation in the fruit were monitored at the end of the season to characterize the impact of the virus on ripening. Virus infection significantly reduced carbon assimilation pre- and postveraison, but the impact was more pronounced postveraison and during the afternoon when vine water status was the lowest. Similarly, virus infection significantly increased leaf starch concentration pre- and postveraison, but increased leaf starch in infected vines was detected two weeks prior to veraison. Virus infection had the greatest impact on obstructing leaf carbon export postveraison, especially during the afternoon. The virus had no impact on chlorophyll fluorescence, indicating there was no sustained photosystem impairment and suggesting that changes in chlorophyll fluorescence were a transient response to reduced carbon assimilation and export. This study provides evidence that reduced carbon export constitutes a feedback inhibition response to accumulation of leaf starch prior to the appearance of visible symptoms or impacts to ripening, which may aid earlier detection of the virus.
Characterization of genetic and molecular tools for studying the endogenous expression ofLactate dehydrogenaseinDrosophila melanogaster
Authors: Rai Madhulika , Carter Sarah M. , Shefali Shefali A. , Chawla Geetanjali , Tennessen Jason M. 
Published: June 2023

ABSTRACTDrosophila melanogasterlarval development relies on a specialized metabolic state that utilizes carbohydrates and other dietary nutrients to promote rapid growth. One unique feature of the larval metabolic program is that Lactate Dehydrogenase (Ldh) activity is highly elevated during this growth phase when compared to other stages of the fly life cycle, indicating that Ldh serves a key role in promoting juvenile development. Previous studies of larval Ldh activity have largely focused on the function of this enzyme at the whole animal level, however,Ldhexpression varies significantly among larval tissues, raising the question of how this enzyme promotes tissue-specific growth programs. Here we characterize two transgene reporters and an antibody that can be used to studyLdhexpressionin vivo. We find that all three tools produce similarLdhexpression patterns. Moreover, these reagents demonstrate that the larvalLdhexpression pattern is complex, suggesting the purpose of this enzyme varies across cell types. Overall, our studies validate a series of genetic and molecular reagents that can be used to study glycolytic metabolism in the fly.
Evaluating power to detect recurrent selective sweeps under increasingly realistic evolutionary null models
Authors: Soni Vivak , Johri Parul , Jensen Jeffrey D. 
Published: June 2023

AbstractThe detection of selective sweeps from population genomic data often relies on the premise that the beneficial mutations in question have fixed very near the sampling time. As it has been previously shown that the power to detect a selective sweep is strongly dependent on the time since fixation as well as the strength of selection, it is naturally the case that strong, recent sweeps leave the strongest signatures. However, the biological reality is that beneficial mutations enter populations at a rate, one that partially determines the mean wait time between sweep events and hence their age distribution. An important question thus remains about the power to detect recurrent selective sweeps when they are modelled by a realistic mutation rate and as part of a realistic distribution of fitness effects (DFE), as opposed to a single, recent, isolated event on a purely neutral background as is more commonly modelled. Here we use forward-in-time simulations to study the performance of commonly used sweep statistics, within the context of more realistic evolutionary baseline models incorporating purifying and background selection, population size change, and mutation and recombination rate heterogeneity. Results demonstrate the important interplay of these processes, necessitating caution when interpreting selection scans; specifically, false positive rates are in excess of true positive across much of the evaluated parameter space, and selective sweeps are often undetectable unless the strength of selection is exceptionally strong.Teaser TextOutlier-based genomic scans have proven a popular approach for identifying loci that have potentially experienced recent positive selection. However, it has previously been shown that an evolutionarily appropriate baseline model that incorporates non-equilibrium population histories, purifying and background selection, and variation in mutation and recombination rates is necessary to reduce often extreme false positive rates when performing genomic scans. Here we evaluate the power to detect recurrent selective sweeps using common SFS-based and haplotype-based methods under these increasingly realistic models. We find that while these appropriate evolutionary baselines are essential to reduce false positive rates, the power to accurately detect recurrent selective sweeps is generally low across much of the biologically relevant parameter space.