bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chemoresistance ofTP53mutant AML requires the mevalonate byproduct, GGPP, for regulation of ROS and induction of a mitochondria stress response
Authors: Skuli Sarah J. , Bakayoko A’Ishah , Kruidenier Marisa , Manning Bryan , Pammer Paige , Salimov Akmal , Riley Owen , Brake-Sillá Gisela , Bowman Michael , Martinez-Gutierrez Leslie N. , Buono Roberta , Paul Madhuri , Saland Estelle , Wong Sarah , Xu Jimmy , Nee Eva , Hausler Ryan , Anderson Colin , Reisz Julie A. , D’Alessandro Angelo , Lai Catherine , Maxwell Kara N. , Sarry Jean-Emmanuel , Fruman David A. , Mesaros Clementina , Keith Brian , Simon M. Celeste , Sung Pamela J. , Wertheim Gerald , Skuli Nicolas , Bowman Robert L. , Matthews Andrew , Carroll Martin 
Published: June 2024

AbstractAcute myeloid leukemia (AML) with mutations in the tumor suppressor gene,TP53(TP53mutAML), is fatal with a median survival of only 6 months. RNA sequencing on purified AML patient samples showTP53mutAML has higher expression of mevalonate pathway genes. We retrospectively identified a survival benefit inTP53mutAML patients who received chemotherapy concurrently with a statin, which inhibits the mevalonate pathway. Mechanistically,TP53mutAML resistance to standard AML chemotherapy, cytarabine (AraC), correlates with increased mevalonate pathway activity and a mitochondria stress response with increased mitochondria mass and oxidative phosphorylation. Pretreatment with a statin reverses these effects and chemosensitizesTP53mutAML cell lines and primary samplesin vitroandin vivo. Mitochondria-dependent chemoresistance requires the geranylgeranyl pyrophosphate (GGPP) branch of the mevalonate pathway and novel GGPP-dependent synthesis of glutathione to manage AraC-induced reactive oxygen species (ROS). Overall, we show that the mevalonate pathway is a novel therapeutic target inTP53mutAML.SignificanceChemotherapy-persistingTP53mutAML cells induce a mitochondria stress response that requires mevalonate byproduct, GGPP, through its novel role in glutathione synthesis and regulation of mitochondria metabolism. We provide insight into prior failures of the statin family of mevalonate pathway inhibitors in AML. We identify clinical settings and strategies to successfully target the mevalonate pathway, particularly to address the unmet need ofTP53mutAML.
Polymeric Micellar Nanoparticles Enable Image-guided Drug Delivery in Solid Tumors
Authors: Uddin Jashim , Lo Justin Han-Je , Gupta Mukesh K. , Werfel Thomas A. , Asaduzzaman Abu , Oltman Connor G. , Gbur Eva F. , Mohyuddin Mohammed T. , Nazmin Farhana , Rahman Saidur , Jashim Ahan , Crews Brenda C. , Kingsley Philip J. , Marnett Lawrence J. , Duvall Craig L. , Cook Rebecca S. 
Published: June 2024

ABSTRACTWe report the development of a nanotechnology to co-deliver chemocoxib A with a reactive oxygen species (ROS)-activatable and COX-2 targeted pro-fluorescent probe, fluorocoxib Q (FQ) enabling real time visualization of COX-2 and CA drug delivery into solid cancers, using a di-block PPS135-b-POEGA17copolymer, selected for its intrinsic responsiveness to elevated reactive oxygen species (ROS), a key trait of the tumor microenvironment. FQ and CA were synthesized independently, then co-encapsulated within micellar PPS135-b-POEGA17co-polymeric nanoparticles (FQ-CA-NPs), and were assessed for cargo concentration, hydrodynamic diameter, zeta potential, and ROS-dependent cargo release. The uptake of FQ-CA-NPs in mouse mammary cancer cells and cargo release was assessed by fluorescence microscopy. Intravenous delivery of FQ-CA-NPs to mice harboring orthotopic mammary tumors, followed by vital optimal imaging, was used to assess delivery to tumorsin vivo. The CA-FQ-NPs exhibited a hydrodynamic diameter of 109.2 ± 4.1 nm and a zeta potential (ζ) of –1.59 ± 0.3 mV. Fluorescence microscopy showed ROS-dependent cargo release by FQ-CA-NPs in 4T1 cells, decreasing growth of 4T1 breast cancer cells, but not affecting growth of primary human mammary epithelial cells (HMECs). NP-derived fluorescence was detected in mammary tumors, but not in healthy organs. Tumor LC-MS/MS analysis identified both CA (2.38 nmol/g tumor tissue) and FQ (0.115 nmol/g tumor tissue), confirming the FQ-mediated image guidance of CA delivery in solid tumors. Thus, co-encapsulation of FQ and CA into micellar nanoparticles (FQ-CA-NPs) enabled ROS-sensitive drug release and COX-2-targeted visualization of solid tumors.
Akt2 deficiency impairs Th17 differentiation, augments Th2 differentiation, and alters the peripheral response to immunization
Authors: Banks Lauren B. , Sklarz Tammarah , Gohil Mercy , O’Leary Claire , Behrens Edward M. , Sun Hong , Chen Youhai H. , Koretzky Gary A. , Jordan Martha S. 
Published: June 2024

AbstractAkt1 and Akt2, isoforms of the serine threonine kinase Akt, are essential for T cell development. However, their role in peripheral T cell differentiation remains undefined. Using mice with germline deletions of either Akt1 or Akt2, we found that both isoforms are important for Th17 differentiation, although Akt2 loss had a greater impact than loss of Akt1. In contrast to defective IL-17 production, Akt2−/−T cells exhibited enhanced IL-4 productionin vitrounder Th2 polarizing conditions.In vivo, Akt2−/−mice displayed significantly diminished IL-17A and GM-CSF production following immunization with myelin oligodendrocyte glycoprotein (MOG). This dampened response was associated with further alterations in Th cell differentiation including decreased IFNγ production but preserved IL-4 production, and preferential expansion of regulatory T cells compared to non-regulatory CD4 T cells. Taken together, we identify Akt2 as an important signaling molecule in regulating peripheral CD4 T cell responses.
Learning context-aware, distributed gene representations in spatial transcriptomics with SpaCEX
Authors: Sun Xiaobo , Xu Yucheng , Li Wenlin , Huang Mengqian , Wang Ziyi , Chen Jing , Wu Hao 
Published: June 2024

Distributed gene representations are pivotal in data-driven genomic research, offering a structured way to understand the complexities of genomic data and providing foundation for various data analysis tasks. Current gene representation learning methods demand costly pretraining on heterogeneous transcriptomic corpora, making them less approachable and prone to over-generalization. For spatial transcriptomics (ST), there is a plethora of methods for learning spot embeddings but serious lacking method for generating gene embeddings from spatial gene profiles. In response, we present SpaCEX, a pioneer cost-effective self-supervised learning model that generates gene embeddings from ST data through exploiting spatial genomic “context” identified as spatially co-expressed gene groups. SpaCEX-generated gene embeddings (SGE) feature in context-awareness, rich semantics, and robustness to cross-sample technical artifacts. Extensive real data analyses reveal biological relevance of SpaCEX-identified genomic contexts and validate functional and relational semantics of SGEs. We further develop a suite of SGE-based computational methods for a range of key downstream objectives: identifying disease-associated genes and gene-gene interactions, pinpointing genes with designated spatial expression patterns, enhancing transcriptomic coverage of FISH-based ST, detecting spatially variable genes, and improving spatial clustering. Extensive real data results demonstrate these methods’ superior performance, thereby affirming the potential of SGEs in facilitating various analytical task.Significance StatementSpatial transcriptomics enables the identification of spatial gene relationships within tissues, providing semantically rich genomic “contexts” for understanding functional interconnections among genes. SpaCEX marks the first endeavor to effectively harnesses these contexts to yield biologically relevant distributed gene representations. These representations serve as a powerful tool to greatly facilitate the exploration of the genetic mechanisms behind phenotypes and diseases, as exemplified by their utility in key downstream analytical tasks in biomedical research, including identifying disease-associated genes and gene interactions,in silicoexpanding the transcriptomic coverage of low-throughput, high-resolution ST technologies, pinpointing diverse spatial gene expression patterns (co-expression, spatially variable pattern, and patterns with specific expression levels across tissue domains), and enhancing tissue domain discovery.
Genotyping-by-sequencing and DNA array for genomic prediction in soybean oil composition
Authors: Prado Melina , Priolli Regina Helena Geribello , Couto Evellyn Giselly De Oliveira , Sabadin Felipe , Dias Kaio Olimpio das Graças , Pinheiro José Baldin 
Published: June 2024

AbstractSoybean oil is intended for various purposes, such as cooking oil and biodiesel. The oil composition changes the shelf life, palatability, and how healthy this oil is for the human diet. Genomic selection jointly uses these traits, phenotypes, and markers from one of the available genotyping platforms to increase genetic gain over time. This study aims to evaluate the impact of different genotyping platforms, DNA arrays, and Genotyping-by-Sequencing (GBS) on genomic selection in relation to the composition of fatty acids in soybean oil and total oil content. We used different quality control parameters, such as heterozygote rate, minor allele frequency, and missing data rate in ten combinations, and two prediction models, BayesB and BRR. To compare the impact of the genotyping approaches, we calculated the principal components analysis from the kinship matrices, the SNP density, and the traits prediction accuracies for each approach. Principal component analysis showed that the DNA array explained better the population genetic architecture.On the other hand, prediction accuracies varied between the different genotyping platforms and only GBS was affected under different quality control parameters. Although the DNA array has important and well-studied polymorphisms for soybeans and is stable, it also has ascertainment bias. GBS, although not stable and requires more robust quality control, can discover alleles specific to the population under study. As soybean oil is used for different functions and the fatty acid profiles are different for each objective, the work constitutes a critical study and direction for improving the composition of soybean oil.
Calibrated prediction of scarce adverse drug reaction labels with conditional neural processes
Authors: Garcia-Ortegon Miguel , Seal Srijit , Singh Shantanu , Bender Andreas , Bacallado Sergio 
Published: June 2024

AbstractAdverse drug reactions (ADRs) are a major source of concern in the development of novel pharmaceuticals. ADRs may be identified in the late stages of development or even after commercialization, which may lead to failure or discontinuation after spending enormous resources on candidate molecules. Thus, predicting ADRs early in the process could help reduce costs by avoiding future failures. However, due to the low number of drugs approved, the amount of historical datapoints on ADRs is limited, which makes their prediction challenging for traditional chemoinformatics methods. Interestingly, each approved drug may have been annotated for hundreds of ADRs, which opens the door to framing ADR prediction as a multi-task or meta-learning problem. In this work, we adopt a meta-learning approach to ADR prediction by applying conditional neural processes (CNPs) to the publicly available Side Effect Resource (SIDER). Our results suggest that CNPs are competitive against single-task baselines even when trained on sparse datasets with missing labels. Furthermore, we find that their predictions are well-calibrated. Finally, we evaluate their performance on ADRs associated to different physiological systems and confirm good predictions across organ classes. Our findings suggest that meta-learning strategies may be beneficial for data-limited clinical endpoints like ADRs.
Clinical Utility of Neurophysiologic Classification (and Declassification) of Myoclonus
Authors: Callister Marcus N. , Klanderman Molly C. , Stockard Alyssa , Van Der Walt Charles , Pena Ashley B. , Caviness John N. 
Published: June 2024

AbstractBackgroundMovement clinical neurophysiology studies can distinguish myoclonus, tremor, and other jerky movements, however there has been limited demonstration of their real-world clinical impact.ObjectiveInvestigate movement study utility in clarifying movement classification and guiding patient management.MethodsRetrospective study of myoclonus-related movement studies.ResultsOf 262 patients referred for consideration of myoclonus, 105 (40%) had myoclonus, 156 (59%) had no myoclonus (the commonest alternative classifications were functional jerks and tremor), and 1 was uncertain. An additional 29 studies identified myoclonus without prior clinical suspicion. 119/134 (89%) myoclonus cases had a specific neurophysiologic subtype identified, most commonly cortical (64, 54%). Diagnostic differential narrowed in 60% of cases, and a new diagnosis was made in 42 (14%) patients. Medication changes were made in 151 patients (52%), with improvement in 35/51 (67%) with follow-up.ConclusionsMovement studies effectively clarified movement classification and identified unsuspected myoclonus, leading to changes in diagnosis and management.
Reproductive Tract Microbial Transitions from Late Gestation to Early Postpartum Using 16S rRNA Metagenetic Profiling in First-Pregnancy Heifers
Authors: Druker Shaked , Sicsic Ron , Ravid Shachar , Scheinin Shani , Raz Tal 
Published: June 2024

AbstractStudies in recent years indicate that reproductive tract microbial communities are crucial for shaping mammals’ health and reproductive outcomes. Following parturition, uterine bacterial contamination often occurs due to the open cervix, which may lead to postpartum uterine inflammatory diseases, especially in primiparous individuals. However, investigations into spatio-temporal microbial transitions in the reproductive tract of primigravid females remain limited. Our objective was to describe and compare the microbial community compositions in the vagina at late gestation and in the vagina and uterus at early postpartum in first-pregnancy heifers. Three swab samples were collected from 33 first-pregnancy Holstein-Friesian heifers: one vaginal sample at gestation day 258±4, and vaginal and uterine samples at postpartum day 7±2. Each sample underwent 16S rRNA V4 region metagenetic analysis via Illumina MiSeq, with bioinformatics following Mothur MiSeq SOP. The reproductive tract bacterial communities were assigned to 1,255 genus-level OTUs across 30 phyla. Dominant phyla, accounting for approximately 90% of the communities, included Proteobacteria, Firmicutes, Actinobacteria, Bacteroidetes, and Fusobacteria. However, the results revealed distinct shifts in microbial composition between the prepartum vagina (Vag-pre), postpartum vagina (Vag-post), and postpartum uterus (Utr-post). The Vag-pre and Utr-post microbial profiles were the most distinct. The Utr-post group had lower relative abundances of Proteobacteria but higher abundances of Bacteroidetes, Fusobacteria, and Tenericutes compared to Vag-pre, while Vag-post displayed intermediate values for these phyla, suggesting a transitional profile. Additionally, the Utr-post group exhibited lower bacterial richness and diversity compared to both Vag-pre and Vag-post. The unsupervised probabilistic Dirichlet Multinomial Mixtures model identified two distinct community types: most Vag-pre samples clustered into one type and Utr-post samples into another, while Vag-post samples were distributed evenly between the two. LEfSe analysis revealed distinct microbial profiles at the genus level. Overall, specific microbial markers were associated with anatomical and temporal transitions, revealing a dynamic microbial landscape during the first pregnancy and parturition. These differences highlight the complexity of these ecosystems and open new avenues for research in reproductive biology and microbial ecology.
The urban physical exposome and leisure-time physical activity in early midlife: a FinnTwin12 study
Authors: Wang Zhiyang , Aaltonen Sari , Teeuwen Roos , Milias Vasileios , Peuters Carmen , Raimbault Bruno , Palviainen Teemu , Lumpe Erin , Dick Danielle , Salvatore Jessica E. , Foraster Maria , Dadvand Payam , Júlvez Jordi , Psyllidis Achilleas , van Kamp Irene , Kaprio Jaakko 
Published: June 2024

AbstractLeisure-time physical activity is beneficial for health and is associated with various urban characteristics. Using the exposome framework, the totality of the environment, this study investigated how urban physical environments were associated with leisure-time physical activity during early midlife. A total of 394 participants (mean age: 37, range 34-40) were included from the FinnTwin12 cohort residing in five major Finnish cities in 2020. We comprehensively curated 145 urban physical exposures at residential addresses of participants and measured three leisure-time physical activity measures: (1) total leisure-time physical activity (total LTPA) and its sub-domains (2) leisure-time physical activity without commuting activity (LTPA) and (3) commuting activity. Using K-prototypes cluster analysis, we identified three urban clusters: “original city center,” “new city center,” and “suburban”. Results from adjusted linear regression models showed that participants in the “suburban” cluster had lower levels of total LTPA (beta: -0.13, 95% CI: -0.23, -0.03) and LTPA (beta: -0.17, 95% CI: -0.28, -0.05), compared to those in the “original city center” cluster. The eXtreme Gradient Boosting models ranked exposures related to greenspaces, pocket parks, and road junctions as the top important factors influencing outcomes, and their relationships with outcomes were largely non-linear. More road junctions and more pocket parks correlated with higher total LTPA and LTPA. When the all-year normalized difference vegetation index within a 500 m buffer fell below 0.4, it correlated with higher levels of total LTPA, whereas above 0.4, it correlated with lower levels. To conclude, our findings revealed a positive correlation between urbanicity and physical activity in Finnish cities and decomposed this complexity into crucial determinants. Importance rankings and nonlinear patterns offer valuable insights for future policies and projects targeting physical inactivity.
Co-developing a novel intervention to promote wellbeing of family caregivers of individuals with spinal cord injury: Research protocol
Authors: Mohammadi Somayyeh , Erlander Beth , Cathcart Heather , Robillard Julie M. , Whitehurst David GT , Pauly Elena , Pagé Brooke , Sauvageau Sophia , Miller William C. 
Published: June 2024

AbstractFamily caregivers of individuals with spinal cord injury (fcSCI) are responsible for providing assistance with activities of daily living for individuals with spinal cord injury (SCI), which can include emotional support and physical assistance. Over time, providing daily support can put fcSCI at risk of experiencing caregiver burden. Burden and distress can have a substantial impact on fcSCI’s wellbeing as well as their ability to respond to the needs of the individual with SCI. A direct predictor of fcSCI burden is their appraisal of their ability to cope with the individual with SCI’s illness. Therefore, supporting fcSCI’s access to education relevant to their role and the health and wellbeing of the individual with SCI can help decrease levels of burden. The purpose of this study is to evaluate the fidelity of the intervention named COMPANION and the study protocol for an eHealth approach designed to improve outcomes for fcSCI. COMPANION, co-created with caregiver partners, is an online education program designed to provide accessible education and support for fcSCI. A concurrent mixed methods study including a feasibility randomized controlled trial will be conducted to (i) assess the process, resource, management and treatment indicators; (ii) estimate the parameters needed for a full-scale, multi-site randomized controlled trial and (iii) evaluate the effect that COMPANION has on caregiver clinical outcomes compared to a control group. The primary outcome measured will be fcSCI’s burden in addition to secondary outcomes measuring depression, anxiety, relationship satisfaction, and quality of life. The fcSCI in the intervention group will be given access to COMPANION (at T1) and data will be collected again after three months (T2) and six months (T3) to capture the impact of COMPANION on fcSCI’s psychological wellbeing. Study results will evaluate whether the full study can and should be conducted and will lead to refinement of COMPANION.
Inter-individual differences in cerebrovascular reactivity are synchronized within functional networks and tissue layers: evidence from healthy older adults and patients with hypertension
Authors: Nanayakkara Nuwan D. , Meusel Liesel-Ann , Anderson Nicole D. , Chen J. Jean 
Published: June 2024

AbstractFunctional-connectivity mapping has primarily relied resting-state functional MRI (rs-fMRI), and resting-state functional networks (RSNs) have been used widely to represent interactions within brain circuits. However, recent work demonstrated that resting-state functional networks (RSNs) may co-exist with vascular networks. In this work, we clarify the nature of these vascular networks by assessing the spatial covariation structure in breath-holding-based CVR amplitude and lag in a group of healthy older adults. We demonstrate a spatial synchrony in CVR amplitude and lag co-variations across participants confined to RSNs. Such a network structure is not seen when looking at the time-variate BOLD signal response to the breathhold. a network structure is also maintained in older adults with clinical hypertension, demonstrating its robustness against vascular pathologies. CVR amplitude is also found to vary with tissue layer in the grey matter and white matter, being most variable in deep WM and least variable in superficial cortex. Conversely, CVR lag appears to be organized by fibre tracts. This work demonstrates the use of cross-participant covariation patterns in CVR as an informative way of mapping the vascular routes in the GM and WM, and also raises questions about the nature and interpretation of RSNs.
Axon length-dependent synapse loss is mediated by neuronal cytokine-induced glial phagocytosis
Authors: Tenedini Federico , Yin Chang , Huang Jessica , Dhiman Neena , Soba Peter , Parrish Jay Z. 
Published: June 2024

AbstractMany neurodegenerative disorders (NDDs) preferentially affect neurons with long or complex axonal arbors, but our understanding of this specific vulnerability is limited. UsingDrosophilalarval class IV dendrite arborization (C4da) neurons, we found that neuronal activation of the integrated stress response (ISR) induces axon length-dependent degeneration (LDD). We identified the Interleukin-6 homologue unpaired 3 (upd3) as both necessary and sufficient for LDD in C4da neurons. Upd3 recruits glial cells to phagocytose presynapses preferentially on neurons with long axons, revealing an intrinsic axon length-dependent vulnerability to glia-mediated presynapse removal. Finally, we found that axon length-dependent presynapse loss in fly models of human NDDs utilized this pathway. Altogether, our studies identify inflammatory cytokine signaling from neurons to glia as a key determinant in axon length-dependent vulnerability.One-Sentence SummarySensory neurons exhibit intrinsic length-dependent vulnerability to presynapse removal driven by cytokine activation of glia.