bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Framework for Evaluating Geomagnetic Indices Forecasting Models
Authors: Collado‐Villaverde Armando , Muñoz Pablo , Cid Consuelo 
Published: March 2024

AbstractThe use of Deep Learning models to forecast geomagnetic storms is achieving great results. However, the evaluation of these models is mainly supported on generic regression metrics (such as the Root Mean Squared Error or the Coefficient of Determination), which are not able to properly capture the specific particularities of geomagnetic storms forecasting. Particularly, they do not provide insights during the high activity periods. To overcome this issue, we introduce the Binned Forecasting Error to provide a more accurate assessment of models' performance across the different intensity levels of a geomagnetic storm. This metric facilitates a robust comparison of different forecasting models, presenting a true representation of a model's predictive capabilities while being resilient to different storms duration. In this direction, for enabling fair comparison among models, it is important to standardize the sets of geomagnetic storms for model training, validation and testing. To do this, we have started from the current sets used in the literature for forecasting the SYM‐H, enriching them with newer storms not considered previously, focusing not only on disturbances caused by Coronal Mass Ejections but also addressing High‐Speed Streams. To operationalize the evaluation framework, a comparative study is conducted between a baseline neural network model and a persistence model, showcasing the effectiveness of the new metric in evaluating forecasting performance during intense geomagnetic storms. Finally, we propose the use of preliminary measurements from ACE to evaluate the model performance in settings closer to an operational real‐time scenario, where the forecasting models are expected to operate.
METTL3-dependent m6A modification of PSEN1 mRNA regulates craniofacial development through the Wnt/β-catenin signaling pathway
Authors: Ma Lan , Zhou Xi , Yao Siyue , Zhang Xinyu , Mao Ji , Vona Barbara , Fan Liwen , Lou Shu , Li Dandan , Wang Lin , Pan Yongchu 
Published: March 2024

AbstractCraniofacial malformations, often associated with syndromes, are prevalent birth defects. Emerging evidence underscores the importance of m6A modifications in various bioprocesses such as stem cell differentiation, tissue development, and tumorigenesis. Here, in vivo, experiments with zebrafish models revealed that mettl3-knockdown embryos at 144 h postfertilization exhibited aberrant craniofacial features, including altered mouth opening, jaw dimensions, ethmoid plate, tooth formation and hypoactive behavior. Similarly, low METTL3 expression inhibited the proliferation and migration of BMSCs, HEPM cells, and DPSCs. Loss of METTL3 led to reduced mRNA m6A methylation and PSEN1 expression, impacting craniofacial phenotypes. Co-injection of mettl3 or psen1 mRNA rescued the level of Sox10 fusion protein, promoted voluntary movement, and mitigated abnormal craniofacial phenotypes induced by mettl3 knockdown in zebrafish. Mechanistically, YTHDF1 enhanced the mRNA stability of m6A-modified PSEN1, while decreased METTL3-mediated m6A methylation hindered β-catenin binding to PSEN1, suppressing Wnt/β-catenin signaling. Pharmacological activation of the Wnt/β-catenin pathway partially alleviated the phenotypes of mettl3 morphant and reversed the decreases in cell proliferation and migration induced by METTL3 silencing. This study elucidates the pivotal role of METTL3 in craniofacial development via the METTL3/YTHDF1/PSEN1/β-catenin signaling axis.
Widespread extracellular electron transfer pathways for charging microbial cytochrome OmcS nanowires via periplasmic cytochromes PpcABCDE
Authors: Portela Pilar C. , Shipps Catharine C. , Shen Cong , Srikanth Vishok , Salgueiro Carlos A. , Malvankar Nikhil S. 
Published: March 2024

AbstractExtracellular electron transfer (EET) via microbial nanowires drives globally-important environmental processes and biotechnological applications for bioenergy, bioremediation, and bioelectronics. Due to highly-redundant and complex EET pathways, it is unclear how microbes wire electrons rapidly (>106 s−1) from the inner-membrane through outer-surface nanowires directly to an external environment despite a crowded periplasm and slow (<105 s−1) electron diffusion among periplasmic cytochromes. Here, we show that Geobacter sulfurreducens periplasmic cytochromes PpcABCDE inject electrons directly into OmcS nanowires by binding transiently with differing efficiencies, with the least-abundant cytochrome (PpcC) showing the highest efficiency. Remarkably, this defined nanowire-charging pathway is evolutionarily conserved in phylogenetically-diverse bacteria capable of EET. OmcS heme reduction potentials are within 200 mV of each other, with a midpoint 82 mV-higher than reported previously. This could explain efficient EET over micrometres at ultrafast (<200 fs) rates with negligible energy loss. Engineering this minimal nanowire-charging pathway may yield microbial chassis with improved performance.
Epigenetic modulators link mitochondrial redox homeostasis to cardiac function in a sex-dependent manner
Authors: ElBeck Zaher , Hossain Mohammad Bakhtiar , Siga Humam , Oskolkov Nikolay , Karlsson Fredrik , Lindgren Julia , Walentinsson Anna , Koppenhöfer Dominique , Jarvis Rebecca , Bürli Roland , Jamier Tanguy , Franssen Elske , Firth Mike , Degasperi Andrea , Bendtsen Claus , Menzies Robert I. , Streckfuss-Bömeke Katrin , Kohlhaas Michael , Nickel Alexander G. , Lund Lars H. , Maack Christoph , Végvári Ákos , Betsholtz Christer 
Published: March 2024

AbstractWhile excessive production of reactive oxygen species (ROS) is a characteristic hallmark of numerous diseases, clinical approaches that ameliorate oxidative stress have been unsuccessful. Here, utilizing multi-omics, we demonstrate that in cardiomyocytes, mitochondrial isocitrate dehydrogenase (IDH2) constitutes a major antioxidative defense mechanism. Paradoxically reduced expression of IDH2 associated with ventricular eccentric hypertrophy is counterbalanced by an increase in the enzyme activity. We unveil redox-dependent sex dimorphism, and extensive mutual regulation of the antioxidative activities of IDH2 and NRF2 by a feedforward network that involves 2-oxoglutarate and L-2-hydroxyglutarate and mediated in part through unconventional hydroxy-methylation of cytosine residues present in introns. Consequently, conditional targeting of ROS in a murine model of heart failure improves cardiac function in sex- and phenotype-dependent manners. Together, these insights may explain why previous attempts to treat heart failure with antioxidants have been unsuccessful and open new approaches to personalizing and, thereby, improving such treatment.
Mapping human tissues with highly multiplexed RNA in situ hybridization
Authors: Kalhor Kian , Chen Chien-Ju , Lee Ho Suk , Cai Matthew , Nafisi Mahsa , Que Richard , Palmer Carter R. , Yuan Yixu , Zhang Yida , Li Xuwen , Song Jinghui , Knoten Amanda , Lake Blue B. , Gaut Joseph P. , Keene C. Dirk , Lein Ed , Kharchenko Peter V. , Chun Jerold , Jain Sanjay , Fan Jian-Bing , Zhang Kun 
Published: March 2024

AbstractIn situ transcriptomic techniques promise a holistic view of tissue organization and cell-cell interactions. There has been a surge of multiplexed RNA in situ mapping techniques but their application to human tissues has been limited due to their large size, general lower tissue quality and high autofluorescence. Here we report DART-FISH, a padlock probe-based technology capable of profiling hundreds to thousands of genes in centimeter-sized human tissue sections. We introduce an omni-cell type cytoplasmic stain that substantially improves the segmentation of cell bodies. Our enzyme-free isothermal decoding procedure allows us to image 121 genes in large sections from the human neocortex in <10 h. We successfully recapitulated the cytoarchitecture of 20 neuronal and non-neuronal subclasses. We further performed in situ mapping of 300 genes on a diseased human kidney, profiled >20 healthy and pathological cell states, and identified diseased niches enriched in transcriptionally altered epithelial cells and myofibroblasts.
Balancing competing effects of tissue growth and cytoskeletal regulation during Drosophila wing disc development
Authors: Kumar Nilay , Rangel Ambriz Jennifer , Tsai Kevin , Mim Mayesha Sahir , Flores-Flores Marycruz , Chen Weitao , Zartman Jeremiah J. , Alber Mark 
Published: March 2024

AbstractHow a developing organ robustly coordinates the cellular mechanics and growth to reach a final size and shape remains poorly understood. Through iterations between experiments and model simulations that include a mechanistic description of interkinetic nuclear migration, we show that the local curvature, height, and nuclear positioning of cells in the Drosophila wing imaginal disc are defined by the concurrent patterning of actomyosin contractility, cell-ECM adhesion, ECM stiffness, and interfacial membrane tension. We show that increasing cell proliferation via different growth-promoting pathways results in two distinct phenotypes. Triggering proliferation through insulin signaling increases basal curvature, but an increase in growth through Dpp signaling and Myc causes tissue flattening. These distinct phenotypic outcomes arise from differences in how each growth pathway regulates the cellular cytoskeleton, including contractility and cell-ECM adhesion. The coupled regulation of proliferation and cytoskeletal regulators is a general strategy to meet the multiple context-dependent criteria defining tissue morphogenesis.
Extended stop codon context predicts nonsense codon readthrough efficiency in human cells
Authors: Mangkalaphiban Kotchaphorn , Fu Lianwu , Du Ming , Thrasher Kari , Keeling Kim M. , Bedwell David M. , Jacobson Allan 
Published: March 2024

AbstractProtein synthesis terminates when a stop codon enters the ribosome’s A-site. Although termination is efficient, stop codon readthrough can occur when a near-cognate tRNA outcompetes release factors during decoding. Seeking to understand readthrough regulation we used a machine learning approach to analyze readthrough efficiency data from published HEK293T ribosome profiling experiments and compared it to comparable yeast experiments. We obtained evidence for the conservation of identities of the stop codon, its context, and 3’-UTR length (when termination is compromised), but not the P-site codon, suggesting a P-site tRNA role in readthrough regulation. Models trained on data from cells treated with the readthrough-promoting drug, G418, accurately predicted readthrough of premature termination codons arising from CFTR nonsense alleles that cause cystic fibrosis. This predictive ability has the potential to aid development of nonsense suppression therapies by predicting a patient’s likelihood of improvement in response to drugs given their nonsense mutation sequence context.
Structure of an open KATP channel reveals tandem PIP2 binding sites mediating the Kir6.2 and SUR1 regulatory interface
Authors: Driggers Camden M. , Kuo Yi-Ying , Zhu Phillip , ElSheikh Assmaa , Shyng Show-Ling 
Published: March 2024

AbstractATP-sensitive potassium (KATP) channels, composed of four pore-lining Kir6.2 subunits and four regulatory sulfonylurea receptor 1 (SUR1) subunits, control insulin secretion in pancreatic β-cells. KATP channel opening is stimulated by PIP2 and inhibited by ATP. Mutations that increase channel opening by PIP2 reduce ATP inhibition and cause neonatal diabetes. Although considerable evidence has implicated a role for PIP2 in KATP channel function, previously solved open-channel structures have lacked bound PIP2, and mechanisms by which PIP2 regulates KATP channels remain unresolved. Here, we report the cryoEM structure of a KATP channel harboring the neonatal diabetes mutation Kir6.2-Q52R, in the open conformation, bound to amphipathic molecules consistent with natural C18:0/C20:4 long-chain PI(4,5)P2 at two adjacent binding sites between SUR1 and Kir6.2. The canonical PIP2 binding site is conserved among PIP2-gated Kir channels. The non-canonical PIP2 binding site forms at the interface of Kir6.2 and SUR1. Functional studies demonstrate both binding sites determine channel activity. Kir6.2 pore opening is associated with a twist of the Kir6.2 cytoplasmic domain and a rotation of the N-terminal transmembrane domain of SUR1, which widens the inhibitory ATP binding pocket to disfavor ATP binding. The open conformation is particularly stabilized by the Kir6.2-Q52R residue through cation-π bonding with SUR1-W51. Together, these results uncover the cooperation between SUR1 and Kir6.2 in PIP2 binding and gating, explain the antagonistic regulation of KATP channels by PIP2 and ATP, and provide a putative mechanism by which Kir6.2-Q52R stabilizes an open channel to cause neonatal diabetes.
One-Tip enables comprehensive proteome coverage in minimal cells and single zygotes
Authors: Ye Zilu , Sabatier Pierre , Martin-Gonzalez Javier , Eguchi Akihiro , Lechner Maico , Østergaard Ole , Xie Jingsheng , Guo Yuan , Schultz Lesley , Truffer Rafaela , Bekker-Jensen Dorte B. , Bache Nicolai , Olsen Jesper V. 
Published: March 2024

AbstractMass spectrometry (MS)-based proteomics workflows typically involve complex, multi-step processes, presenting challenges with sample losses, reproducibility, requiring substantial time and financial investments, and specialized skills. Here we introduce One-Tip, a proteomics methodology that seamlessly integrates efficient, one-pot sample preparation with precise, narrow-window data-independent acquisition (nDIA) analysis. One-Tip substantially simplifies sample processing, enabling the reproducible identification of >9000 proteins from ~1000 HeLa cells. The versatility of One-Tip is highlighted by nDIA identification of ~6000 proteins in single cells from early mouse embryos. Additionally, the study incorporates the Uno Single Cell Dispenser™, demonstrating the capability of One-Tip in single-cell proteomics with >3000 proteins identified per HeLa cell. We also extend One-Tip workflow to analysis of extracellular vesicles (EVs) extracted from blood plasma, demonstrating its high sensitivity by identifying >3000 proteins from 16 ng EV preparation. One-Tip expands capabilities of proteomics, offering greater depth and throughput across a range of sample types.
Combined KRAS-MAPK pathway inhibitors and HER2-directed drug conjugate is efficacious in pancreatic cancer
Authors: Bulle Ashenafi , Liu Peng , Seehra Kuljeet , Bansod Sapana , Chen Yali , Zahra Kiran , Somani Vikas , Khawar Iftikhar Ali , Chen Hung-Po , Dodhiawala Paarth B. , Li Lin , Geng Yutong , Mo Chia-Kuei , Mahsl Jay , Ding Li , Govindan Ramaswamy , Davies Sherri , Mudd Jacqueline , Hawkins William G. , Fields Ryan C. , DeNardo David G. , Knoerzer Deborah , Held Jason M. , Grierson Patrick M. , Wang-Gillam Andrea , Ruzinova Marianna B. , Lim Kian-Huat 
Published: March 2024

AbstractTargeting the mitogen-activated protein kinase (MAPK) cascade in pancreatic ductal adenocarcinoma (PDAC) remains clinically unsuccessful. We aim to develop a MAPK inhibitor-based therapeutic combination with strong preclinical efficacy. Utilizing a reverse-phase protein array, we observe rapid phospho-activation of human epidermal growth factor receptor 2 (HER2) in PDAC cells upon pharmacological MAPK inhibition. Mechanistically, MAPK inhibitors lead to swift proteasomal degradation of dual-specificity phosphatase 6 (DUSP6). The carboxy terminus of HER2, containing a TEY motif also present in extracellular signal-regulated kinase 1/2 (ERK1/2), facilitates binding with DUSP6, enhancing its phosphatase activity to dephosphorylate HER2. In the presence of MAPK inhibitors, DUSP6 dissociates from the protective effect of the RING E3 ligase tripartite motif containing 21, resulting in its degradation. In PDAC patient-derived xenograft (PDX) models, combining ERK and HER inhibitors slows tumour growth and requires cytotoxic chemotherapy to achieve tumour regression. Alternatively, MAPK inhibitors with trastuzumab deruxtecan, an anti-HER2 antibody conjugated with cytotoxic chemotherapy, lead to sustained tumour regression in most tested PDXs without causing noticeable toxicity. Additionally, KRAS inhibitors also activate HER2, supporting testing the combination of KRAS inhibitors and trastuzumab deruxtecan in PDAC. This study identifies a rational and promising therapeutic combination for clinical testing in PDAC patients.
The evolutionary origin of naturally occurring intermolecular Diels-Alderases from Morus alba
Authors: Ding Qi , Guo Nianxin , Gao Lei , McKee Michelle , Wu Dongshan , Yang Jun , Fan Junping , Weng Jing-Ke , Lei Xiaoguang 
Published: March 2024

AbstractBiosynthetic enzymes evolutionarily gain novel functions, thereby expanding the structural diversity of natural products to the benefit of host organisms. Diels-Alderases (DAs), functionally unique enzymes catalysing [4 + 2] cycloaddition reactions, have received considerable research interest. However, their evolutionary mechanisms remain obscure. Here, we investigate the evolutionary origins of the intermolecular DAs in the biosynthesis of Moraceae plant-derived Diels-Alder-type secondary metabolites. Our findings suggest that these DAs have evolved from an ancestor functioning as a flavin adenine dinucleotide (FAD)-dependent oxidocyclase (OC), which catalyses the oxidative cyclisation reactions of isoprenoid-substituted phenolic compounds. Through crystal structure determination, computational calculations, and site-directed mutagenesis experiments, we identified several critical substitutions, including S348L, A357L, D389E and H418R that alter the substrate-binding mode and enable the OCs to gain intermolecular DA activity during evolution. This work provides mechanistic insights into the evolutionary rationale of DAs and paves the way for mining and engineering new DAs from other protein families.
Higher-order Granger reservoir computing: simultaneously achieving scalable complex structures inference and accurate dynamics prediction
Authors: Li Xin , Zhu Qunxi , Zhao Chengli , Duan Xiaojun , Zhao Bolin , Zhang Xue , Ma Huanfei , Sun Jie , Lin Wei 
Published: March 2024

AbstractRecently, machine learning methods, including reservoir computing (RC), have been tremendously successful in predicting complex dynamics in many fields. However, a present challenge lies in pushing for the limit of prediction accuracy while maintaining the low complexity of the model. Here, we design a data-driven, model-free framework named higher-order Granger reservoir computing (HoGRC), which owns two major missions: The first is to infer the higher-order structures incorporating the idea of Granger causality with the RC, and, simultaneously, the second is to realize multi-step prediction by feeding the time series and the inferred higher-order information into HoGRC. We demonstrate the efficacy and robustness of the HoGRC using several representative systems, including the classical chaotic systems, the network dynamical systems, and the UK power grid system. In the era of machine learning and complex systems, we anticipate a broad application of the HoGRC framework in structure inference and dynamics prediction.
Dynamics of accessible chromatin regions and subgenome dominance in octoploid strawberry
Authors: Fang Chao , Jiang Ning , Teresi Scott J. , Platts Adrian E. , Agarwal Gaurav , Niederhuth Chad , Edger Patrick P. , Jiang Jiming 
Published: March 2024

AbstractSubgenome dominance has been reported in diverse allopolyploid species, where genes from one subgenome are preferentially retained and are more highly expressed than those from other subgenome(s). However, the molecular mechanisms responsible for subgenome dominance remain poorly understood. Here, we develop genome-wide map of accessible chromatin regions (ACRs) in cultivated strawberry (2n = 8x = 56, with A, B, C, D subgenomes). Each ACR is identified as an MNase hypersensitive site (MHS). We discover that the dominant subgenome A contains a greater number of total MHSs and MHS per gene than the submissive B/C/D subgenomes. Subgenome A suffers fewer losses of MHS-related DNA sequences and fewer MHS fragmentations caused by insertions of transposable elements. We also discover that genes and MHSs related to stress response have been preferentially retained in subgenome A. We conclude that preservation of genes and their cognate ACRs, especially those related to stress responses, play a major role in the establishment of subgenome dominance in octoploid strawberry.
Tgfbr1 controls developmental plasticity between the hindlimb and external genitalia by remodeling their regulatory landscape
Authors: Lozovska Anastasiia , Korovesi Artemis G. , Dias André , Lopes Alexandre , Fowler Donald A. , Martins Gabriel G. , Nóvoa Ana , Mallo Moisés 
Published: March 2024

AbstractThe hindlimb and external genitalia of present-day tetrapods are thought to derive from an ancestral common primordium that evolved to generate a wide diversity of structures adapted for efficient locomotion and mating in the ecological niche occupied by the species. We show that despite long evolutionary distance from the ancestral condition, the early primordium of the mouse external genitalia preserved the capacity to take hindlimb fates. In the absence of Tgfbr1, the pericloacal mesoderm generates an extra pair of hindlimbs at the expense of the external genitalia. It has been shown that the hindlimb and the genital primordia share many of their key regulatory factors. Tgfbr1 controls the response to those factors by modulating the accessibility status of regulatory elements that control the gene regulatory networks leading to the formation of genital or hindlimb structures. Our work uncovers a remarkable tissue plasticity with potential implications in the evolution of the hindlimb/genital area of tetrapods, and identifies an additional mechanism for Tgfbr1 activity that might also contribute to the control of other physiological or pathological processes.
Micro-consolidation occurs when learning an implicit motor sequence, but is not influenced by HIIT exercise
Authors: Brooks Emily , Wallis Sarah , Hendrikse Joshua , Coxon James 
Published: March 2024

AbstractWe investigated if micro-consolidation, a phenomenon recently discovered during the brief rest periods between practice when learning an explicit motor sequence, generalises to learning an implicit motor sequence task. We demonstrate micro-consolidation occurs in the absence of explicit sequence awareness. We also investigated the effect of a preceding bout of high-intensity exercise, as exercise is known to augment the consolidation of new motor skills. Micro-consolidation was not modified by exercise.