bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting Metabolic Dependencies in Acute Myeloid Leukemia: A Dual Strategy using Arsenic Trioxide and Artesunate
Authors: Balasundaram Nithya , Venkatraman Arvind , Augustin Yolanda , Palani Hamenth Kumar , Regnault Clement , Korula Anu , Kulkarni Uday Prakash , Edison Eunice Sindhuvi , Balasubramanian Poonkuzhali , George Biju , Abraham Aby , Krishna Sanjeev , Mathews Vikram 
Published: June 2024

AbstractAcute myeloid leukemia (AML) remains a difficult disease to cure despite recent advances. Off-target side effects of therapy, especially prolonged cytopenia, lead to significant morbidity and mortality. There is an increased recognition that in AML, there is a potentially vulnerable dependence on OXPHOS metabolism, more so in the leukemia stem cell compartment (AML-LSC) that could be exploited. Drug re-purposing screens have suggested the possible role of artesunate (ART) in inhibiting mitochondrial respiration and arsenic trioxide (ATO) in inhibiting glycolysis. Here, we explore the potential of using a combination of ART and ATO to treat AML. Through in-vitro and in-vivo studies, we demonstrate the potential of this combination along with hypo-methylating agents and other mitocans, such as BCL-2 inhibitor venetoclax, to be used in the treatment of AML with minimal off-target effect on normal hematopoietic stem cells (HSC). These observations warrant further exploration of such novel combinations in clinical trials.
Improved BioCyc Operon Prediction: Revisiting the Operon Prediction Problem
Authors: Midford Peter E. , Cadigan John , Karp Peter D. 
Published: June 2024

AbstractIntroductionOperon prediction is a valuable component of microbial-genome annotation because operon organization can yield inferences about gene function, and because knowledge of operon structure can aid the interpretation of gene expression data.MethodsWe present a number of improvements to the existing Pathway Tools operon predictor based mostly on 7 new features that we hypothesized would increase its performance. The new features include shared Gene Ontology biological process terms, similarity of codon usage and GC content, correlated gene expression, and shared protein complex.ResultsWe evaluated the proposed 7 new features and found that the addition of 6 of them improved the performance of the operon predictor from 79.55% to 83.49%, a decrease in error rate of 19.3%. When gene expression data was not included, the accuracy decreased to 82.547, still an improvement of 14.7%. One of the proposed features as well as a previously used feature had no effect and were removed.DiscussionAlthough some of the new features had strong predictive value individually, when combined with the other features they did not have a large impact on predictive accuracy, suggesting that they were not independent from the other features.
Deuterium Metabolic Imaging Phenotypes Mouse Glioblastoma Heterogeneity Through Glucose Turnover Kinetics
Authors: Simões Rui V. , Henriques Rafael N. , Olesen Jonas L , Cardoso Beatriz M. , Fernandes Francisca F. , Monteiro Mariana A.V. , Jespersen Sune N , Carvalho Tânia , Shemesh Noam 
Published: June 2024

AbstractGlioblastomas are aggressive brain tumors with dismal prognosis. One of the main bottlenecks for developing more effective therapies for glioblastoma stems from their histologic and molecular heterogeneity, leading to distinct tumor microenvironments and disease phenotypes. Effectively characterizing these features would improve the clinical management of glioblastoma. Glucose flux rates through glycolysis and mitochondrial oxidation have been recently shown to quantitatively depict glioblastoma proliferation in mouse models (GL261 and CT2A tumors) using dynamic glucose-enhanced (DGE) deuterium spectroscopy. However, the spatial features of tumor microenvironment phenotypes remain hitherto unresolved. Here, we develop a DGE Deuterium Metabolic Imaging (DMI) approach for profiling tumor microenvironments through glucose conversion kinetics. Using a multimodal combination of tumor mouse models, novel strategies for spectroscopic imaging and noise attenuation, and histopathological correlations, we show that tumor lactate turnover mirrors phenotype differences between GL261 and CT2A mouse glioblastoma, whereas recycling of the peritumoral glutamate-glutamine pool is a potential marker of invasion capacity in pooled cohorts, linked to secondary brain lesions. These findings were validated by histopathological characterization of each tumor, including cell density and proliferation, peritumoral invasion and distant migration, and immune cell infiltration. Our study bodes well for precision neuro-oncology, highlighting the importance of mapping glucose flux rates to better understand the metabolic heterogeneity of glioblastoma and its links to disease phenotypes.
Aging limits stemness and tumorigenesis in the lung by reprogramming iron homeostasis
Authors: Zhuang Xueqian , Wang Qing , Joost Simon , Ferrena Alexander , Humphreys David T. , Li Zhuxuan , Blum Melissa , Bastl Klavdija , Ding Selena , Landais Yuna , Zhan Yingqian , Zhao Yang , Chaligne Ronan , Lee Joo-Hyeon , Carrasco Sebastian E. , Bhanot Umeshkumar K. , Koche Richard P. , Bott Matthew J. , Katajisto Pekka , Soto-Feliciano Yadira M. , Pisanic Thomas , Thomas Tiffany , Zheng Deyou , Wong Emily S. , Tammela Tuomas 
Published: June 2024

SummaryAging is associated with a decline in the number and fitness of adult stem cells1–4. Aging-associated loss of stemness is posited to suppress tumorigenesis5,6, but this hypothesis has not been testedin vivo. Here, using physiologically aged autochthonous genetically engineered mouse models and primary cells7,8, we demonstrate aging suppresses lung cancer initiation and progression by degrading stemness of the alveolar cell of origin. This phenotype is underpinned by aging-associated induction of the transcription factor NUPR1 and its downstream target lipocalin-2 in the cell of origin in mice and humans, leading to a functional iron insufficiency in the aged cells. Genetic inactivation of the NUPR1—lipocalin-2 axis or iron supplementation rescue stemness and promote tumorigenic potential of aged alveolar cells. Conversely, targeting the NUPR1— lipocalin-2 axis is detrimental to young alveolar cells via induction of ferroptosis. We find that aging-associated DNA hypomethylation at specific enhancer sites associates with elevated NUPR1 expression, which is recapitulated in young alveolar cells by inhibition of DNA methylation. We uncover that aging drives a functional iron insufficiency, which leads to loss of stemness and tumorigenesis, but promotes resistance to ferroptosis. These findings have significant implications for the therapeutic modulation of cellular iron homeostasis in regenerative medicine and in cancer prevention. Furthermore, our findings are consistent with a model whereby most human cancers initiate in young individuals, revealing a critical window for such cancer prevention efforts.
MICROBIOME-MODIFIED METABOLITES PREDICT ACUTE BRAIN INJURY OUTCOME
Authors: DeLeon Orlando , Ceccato Hugo D , Sidebottom Ashley , Babtain Nada , Roy Sara , Koval Jason , Roth William H , Beiser David G. , Mansour Ali , Goldenberg Fernando D , Chang Eugene B , Lazaridis Christos 
Published: June 2024

AbstractBACKGROUNDAcute brain injury (ABI)-mediated disruption of the microbiome may potentiate inflammation and secondary brain injury (SBI). However, microbial-specific mediators and mechanisms remain unclear.METHODSThirty-five consecutive patients with ABI admitted to the neuroscience critical care unit at the University of Chicago were prospectively studied. Injury severity at hospital admission was assessed using the Injury Severity Score (ISS) and the Glasgow Coma Scale (GCS). Final neurologic function was assessed via the Glasgow Outcome Score extended (GOSe). Serum, plasma, and stool targeted metabolomics, as well as stool shotgun metagenomics, were performed on longitudinal samples collected during hospitalization.RESULTSMultivariate analysis identified microbiome-modified metabolites that were positively and negatively associated with functional outcomes after ABI. Novel identification of conjugated bile acid (BA) species and vitamin B12 precursors indicative of outcome were detected in the first collected samples (within 48 hours). Network analysis revealed greater integration of negatively associated metabolites across tissues and identified tauro-α/μ-muricholic acid (TMCA) as central to the cross-tissue metabolomes.CONCLUSIONSMicrobiome metabolites may be useful in assessing brain injury outcomes to inform treatment. Bile acid species transformed by the gut microbiome are predictive of ABI outcome.
A machine learning and drug repurposing approach to target ferroptosis in colorectal cancer stratified by sex and KRAS
Authors: Yan Hong , Shen Xinyi , Yao Yisha , Khan Sajid A. , Ma Shuangge , Johnson Caroline H. 
Published: June 2024

AbstractThe landscape of sex differences in Colorectal Cancer (CRC) has not been well characterized with respect to the mechanisms of action for oncogenes such as KRAS. However, our recent study showed that tumors from male patients with KRAS mutations have decreased iron-dependent cell death called ferroptosis. Building on these findings, we further examined ferroptosis in CRC, considering both sex of the patient and KRAS mutations, using public databases and our in-house CRC tumor cohort.Through subsampling inference and variable importance analysis (VIMP), we identified significant differences in gene expression between KRAS mutant and wild type tumors from male patients. These genes suppress (e.g.,SLC7A11) or drive (e.g.,SLC1A5) ferroptosis, and these findings were further validated with Gaussian mixed models. Furthermore, we explored the prognostic value of ferroptosis regulating genes and discovered sex- and KRAS-specific differences at both the transcriptional and metabolic levels by random survival forest with backward elimination algorithm (RSF-BE). Of note, genes and metabolites involved in arginine synthesis and glutathione metabolism were uniquely associated with prognosis in tumors from males with KRAS mutations.Additionally, drug repurposing is becoming popular due to the high costs, attrition rates, and slow pace of new drug development, offering a way to treat common and rare diseases more efficiently. Furthermore, increasing evidence has shown that ferroptosis inhibition or induction can improve drug sensitivity or overcome chemotherapy drug resistance. Therefore, we investigated the correlation between gene expression, metabolite levels, and drug sensitivity across all CRC primary tumor cell lines using data from the Genomics of Drug Sensitivity in Cancer (GDSC) resource. We observed that ferroptosis suppressor genes such asDHODH,GCH1, andAIFM2in KRAS mutant CRC cell lines were resistant to cisplatin and paclitaxel, underscoring why these drugs are not effective for these patients. The comprehensive map generated here provides valuable biological insights for future investigations, and the findings are supported by rigorous analysis of large-scale publicly available data and our in-house cohort. The study also emphasizes the potential application of VIMP, Gaussian mixed models, and RSF-BE models in the multi-omics research community. In conclusion, this comprehensive approach opens doors for leveraging precision molecular feature analysis and drug repurposing possibilities in KRAS mutant CRC.
scCancerExplorer: a comprehensive database for interactively exploring single-cell multi-omics data of human pan-cancer
Authors: Huang Changzhi , Liu Zekai , Guo Yunlei , Wang Wanchu , Yuan Zhen , Guan Yusheng , Pan Deng , Hu Zhibin , Sun Linhua , Fu Zan , Bian Shuhui 
Published: June 2024

ABSTRACTGenomic, epigenomic, and transcriptomic alterations are hallmarks of cancer cells, and are closely connected. Especially, epigenetic regulation plays a critical role in tumorigenesis and progression. The growing single-cell epigenome data in cancer research provide new opportunities for data mining from a more comprehensive perspective. However, there is still a lack of databases designed for interactively exploring the single-cell multi-omics data of human pan-cancer, especially for the single-cell epigenome data. To fill in the gap, we developed scCancerExplorer, a comprehensive and user-friendly database to facilitate the exploration of the single-cell genome, epigenome (chromatin accessibility and DNA methylation), and transcriptome data of 50 cancer types. Five major modules were provided to explore those data interactively, including “integrated multi-omics analysis”, “single-cell transcriptome”, “single-cell epigenome”, “single-cell genome”, and “TCGA analysis”. By simple clicking, users can easily investigate gene expression features, chromatin accessibility patterns, transcription factor activities, DNA methylation states, copy number variations, and TCGA survival analysis results. Taken together, scCancerExplorer is distinguished from previous databases with rich and interactive functions for exploring the single-cell multi-omics data of human pan-cancer. It bridges the gap between single-cell multi-omics data and the end-users, and will facilitate progress in the field of cancer research. scCancerExplorer is freely accessible viahttps://bianlab.cn/scCancerExplorer.
N2 Sleep Inspires Insight
Authors: Löwe Anika T. , Petzka Marit , Tzegka Maria , Schuck Nicolas W. 
Published: June 2024

AbstractHumans sometimes have an insight that leads to a sudden and drastic performance im-provement on the task they are working on. The precise origins of such insights are unknown. Some evidence has shown that sleep facilitates insights, while other work has not found such a relationship. One recent suggestion that could explain this mixed evidence is that different sleep stages have differential effects on insight. In addition, computational work has suggested that neural variability and regularisation play a role in increasing the likelihood of insight. To investigate the link between insight and different sleep stages as well as regularisation, we conducted a preregistered study in which N=90 participants performed a perceptual insight task before and after a 20 minute daytime. Sleep EEG data showed that N2 sleep, but not N1 sleep, increases the likelihood of insight after a nap, suggesting a specific role of deeper sleep. Exploratory analyses of EEG power spectra showed that spectral slopes could predict insight beyond sleep stages, which is broadly in line with theoretical suggestions of a link between insight and regularisation. In combination, our findings point towards a role of N2 sleep and aperiodic, but not oscillatory, neural activity for insight.
Dust storm-driven dispersal of potential pathogens and antibiotic resistance genes in the Eastern Mediterranean
Authors: Erkorkmaz Burak Adnan , Zeevi David , Rudich Yinon 
Published: June 2024

AbstractThe atmosphere hosts a microbiome that connects distant ecosystems yet remains relatively unexplored. In this study, we tested the hypothesis that dust storms enhance the spread of pathogenic microorganisms and whether these microorganisms carry antibiotic resistance and virulence-related genes in the Eastern Mediterranean. We collected air samples during a seasonal transition period, capturing data from 13 dusty days originating from Middle Eastern sources and 32 clear days, with temperatures ranging from 16.5 to 27.1 °C. Using metagenomic analysis, we identified several facultative pathogens likeKlebsiella pneumoniae,Stenotrophomonas maltophilia, andAspergillus fumigatus, which are linked to human respiratory diseases, and others likeZymoseptoria tritici,Fusarium poae, andPuccinia striiformis, which are harmful to wheat. The abundance of these pathogens increased during dust storms and with rising temperatures. Although we did not find strong evidence that these species harbored antibiotic resistance or virulence-related genes, which could be linked to their pathogenic potential, dust storms transported up to 125 times more total antibiotic resistance genes, as measured by RPKM abundance, compared to clear conditions. These levels during dust storms far exceeded those found in other ecosystems. While further research is needed to determine whether dust storms and temperature variations pose an immediate threat to public health and the environment, our findings underscore the importance of continuous monitoring of atmospheric microbiomes. This surveillance is crucial for assessing potential risks to human health and ecosystem stability, particularly in the face of accelerating global climate change.
Role of Stem-Like Cells in Chemotherapy Resistance and Relapse in pediatric T Cell Acute Lymphoblastic Leukemia
Authors: Costea Julia , Rauwolf Kerstin K. , Zafferani Pietro , Rausch Tobias , Mathioudaki Anna , Zaugg Judith , Schrappe Martin , Eckert Cornelia , Escherich Gabriele , Bourquin Jean P. , Bornhauser Beat , Kulozik Andreas E. , Korbel Jan O. 
Published: June 2024

AbstractT cell acute lymphoblastic leukemia (T-ALL) is an aggressive leukemia predominantly affecting adolescents and young adults. T-ALL relapses are characterized by chemotherapy resistance, cellular heterogeneity and dismal outcome. To gain a deeper understanding of the cellular heterogeneity and mechanisms driving relapse, we conducted single-cell full-length RNA sequencing of 13 matched pediatric T-ALL patient-derived xenografts (PDX) samples obtained at initial diagnosis and relapse, generating the to date most comprehensive longitudinal single cell study in paired T-ALL samples, along with 5 non-relapsing PDX samples collected at initial diagnosis. This dataset identifies considerable transcriptomic diversity among individual T-ALL cell populations. Notably however, 11 of the 18 patients exhibit a small T-ALL cell subpopulation with a shared set of gene regulatory networks characterized by a common set of active regulons, expression patterns and splice isoforms. This profile involves the upregulation of a stem-like cell signature with enrichment of cell adhesion, and inhibition of the cell cycle and metabolic activity. Comprehensive investigations of these networks identify transcripts enforcing drug resistance through NF-κB expression and TGF-β signaling and of anti-apoptotic T cell signaling. Longitudinal monitoring of these stem-like cells demonstrates this subpopulation to account for only a small proportion of leukemia cells initially with a substantial expansion at relapse suggesting resistance to first line therapy. Chemotherapy resistance is functionally corroborated throughin vitroandin vivodrug testing. We thus report the discovery of inherently treatment-resistant stem-like T-ALL cell populations underscoring the potential for devising future therapeutic strategies aimed at targeting stemness pathways in pediatric T-ALL.Key PointsSingle-cell full-length RNA sequencing reveals dormant, treatment-resistant cells expanding upon T cell acute lymphoblastic leukemia relapse.Stem-like T-ALL cells exhibit a shared gene regulatory network conferring chemotherapy resistance and relapse.
Distinct attentional profile and functional connectivity of neurons with visual feature coding in the primate brain
Authors: Zhang Jie , Cao Runnan , Zhu Xiaocang , Zhou Huihui , Wang Shuo 
Published: June 2024

AbstractVisual attention and object recognition are two critical cognitive functions that significantly influence our perception of the world. While these neural processes converge on the temporal cortex, the exact nature of their interactions remains largely unclear. Here, we systematically investigated the interplay between visual attention and object feature coding by training macaques to perform a free-gaze visual search task using natural face and object stimuli. With a large number of units recorded from multiple brain areas, we discovered that units exhibiting visual feature coding displayed a distinct attentional response profile and functional connectivity compared to units not exhibiting feature coding. Attention directed towards search targets enhanced the pattern separation of stimuli across brain areas, and this enhancement was more pronounced for units encoding visual features. Our findings suggest two stages of neural processing, with the early stage primarily focused on processing visual features and the late stage dedicated to processing attention. Importantly, feature coding in the early stage could predict the attentional effect in the late stage. Together, our results suggest an intricate interplay between visual feature and attention coding in the primate brain, which can be attributed to the differential functional connectivity and neural networks engaged in these processes.
CREEPING STEM1 Regulates Directional Auxin Transport for Lodging Resistance in Soybean
Authors: Xu Zhiyong , Zhang Liya , Kong Keke , Kong Jiejie , Ji Ronghuan , Liu Jun , Li Hongyu , Ren Yulong , Zhou Wenbin , Zhao Tao , Zhao Tuanjie , Liu Bin 
Published: June 2024

ABSTRACTSoybean, a staple crop on a global scale, frequently encounters challenges due to lodging under high planting densities, which results in significant yield losses. Despite extensive research, the fundamental genetic mechanisms governing lodging resistance in soybeans remain elusive. In this study, we identify and characterize theCreeping Stem 1(CS1) gene, which plays a crucial role in conferring lodging resistance in soybeans. TheCS1gene encodes a HEAT-repeat protein that modulates hypocotyl gravitropism by regulating amyloplast sedimentation. Functional analysis reveals that the loss ofCS1activity disrupts polar auxin transport, vascular bundle development, and the biosynthesis of cellulose and lignin, ultimately leading to premature lodging and aberrant root development. Conversely, increasingCS1expression significantly enhances lodging resistance and improves yield under conditions of high planting density. Our findings shed light on the genetic mechanisms that underlie lodging resistance in soybeans and highlight the potential ofCS1as a valuable target for genetic engineering to improve crop lodging resistance and yield.
The STAT3-VDAC1 Axis Modulates Mitochondrial Function and Plays a Critical Role in the Survival of Acute Myeloid Leukemia Cells
Authors: Gil Kellen B. , Borg Jamie , Moreira Pereira Rosana , Inguva-Sheth Anagha , Araujo Geovana , Rahkola Jeremy , Showers William , Grier Abby , D’Alessandro Angelo , Smith Clayton , McMahon Christine , Pollyea Daniel A. , Gillen Austin E. , Amaya Maria L. 
Published: June 2024

AbstractSignal transducer and activator of transcription 3 (STAT3) is a well-described transcription factor that mediates oxidative phosphorylation and glutamine uptake in bulk acute myeloid leukemia (AML) cells and leukemic stem cells (LSCs). STAT3 has also been shown to translocate to the mitochondria in AML cells, particularly when phosphorylated at the serine 727 (pSTAT3 S727) residue. Inhibition of STAT3 results in impaired mitochondrial function and decreased leukemia cell viability. We discovered a novel interaction of STAT3 with voltage-dependent anion channel 1 (VDAC1) in the mitochondria that provides a mechanism through which STAT3 modulates mitochondrial function and cell survival. Through VDAC1, STAT3 regulates calcium and oxidative phosphorylation in the mitochondria. STAT3 and VDAC1 inhibition also results in significantly reduced engraftment potential of LSCs, including primary samples resistant to venetoclax. These results implicate STAT3 as a therapeutic target in AML.