bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aminoprocalcitonin protects against hippocampal neuronal death via preserving oxidative phosphorylation in refractory status epilepticus
Authors: Song Changgeng , Zhao Jingjing , Hao Jianmin , Mi Dan , Zhang Jiajia , Liu Yingying , Wu Shengxi , Gao Fang , Jiang Wen 
Published: May 2023

AbstractRefractory status epilepticus (RSE) is a neurological emergency where sustaining seizure causes severe neuronal death. Currently, there is no available neuroprotectant effective in RSE. Aminoprocalcitonin (NPCT) is a conserved peptide cleaved from procalcitonin, but its distribution and function in the brain remain enigmatic. Survival of neurons relies on sufficient energy supply. Recently, we found that NPCT was extensively distributed in the brain and had potent modulations on neuronal oxidative phosphorylation (OXPHOS), suggesting that NPCT might be involved in neuronal death by regulating energy status. In the present study, combining biochemical and histological methods, high-throughput RNA-sequence, Seahorse XFe analyser, an array of mitochondria function assays, and behavior-electroencephalogram (EEG) monitoring, we investigated the roles and translational values of NPCT in neuronal death after RSE. We found that NPCT was extensively distributed throughout gray matters in rat brain while RSE triggered NPCT overexpression in hippocampal CA3 pyramidal neurons. High-throughput RNA-sequence demonstrated that the influences of NPCT on primary hippocampal neurons were enriched in OXPHOS. Further function assays verified that NPCT facilitated ATP production, enhanced the activities of mitochondrial respiratory chain complexes I, IV, V, and increased neuronal maximal respiration capacity. NPCT exerted multiple neurotrophic effects including facilitating synaptogenesis, neuritogenesis, spinogenesis, and suppression of caspase-3. A polyclonal NPCT immunoneutralization antibody was developed to antagonize NPCT. In the in vitro 0-Mg2+ seizure model, immunoneutralization of NPCT caused more neuronal death, while exogenous NPCT supplementation, though did not reverse death outcomes, preserved mitochondrial membrane potential. In rat RSE model, both peripheral and intracerebroventricular immunoneutralization of NPCT exacerbated hippocampal neuronal death and peripheral immunoneutralization increased mortality. Intracerebroventricular immunoneutralization of NPCT further led to more serious hippocampal ATP depletion, and significant EEG power exhaustion. We conclude that NPCT is a neuropeptide regulating neuronal OXPHOS. During RSE, NPCT was overexpressed to protect hippocampal neuronal survival via facilitating energy supply.
Disruption of ER ion homeostasis maintained by an ER anion channel CLCC1 contributes to ALS-like pathologies
Authors: Guo Liang , Mao Qionglei , He Ji , Liu Xiaoling , Piao Xuejiao , Luo Li , Hao Xiaoxu , Yu Hanzhi , Song Qiang , Xiao Bailong , Fan Dongsheng , Gao Zhaobing , Jia Yichang 
Published: May 2023

AbstractAlthough anion channel activities have been demonstrated in sarcoplasmic reticulum/endoplasmic reticulum (SR/ER), their molecular identities and functions remain unclear. Here, we link rare variants of Chloride Channel CLIC Like 1 (CLCC1) to amyotrophic lateral sclerosis (ALS)-like pathologies. We demonstrate that CLCC1 is a pore-forming component of an ER anion channel and that ALS-associated mutations impair channel conductance. CLCC1 forms homomultimers and its channel activity is inhibited by luminal Ca2+ but facilitated by phosphatidylinositol 4,5-bisphosphate (PIP2). We identified conserved residues D25 and D181 in CLCC1 N-terminus responsible for Ca2+ binding and luminal Ca2+-mediated inhibition on channel open probability and K298 in CLCC1 intraluminal loop as the critical PIP2-sensing residue. CLCC1 maintains steady-state [Cl–]ER and [K+]ER and ER morphology and regulates ER Ca2+ homeostasis, including internal Ca2+ release and steady-state [Ca2+]ER. ALS-associated mutant forms of CLCC1 increase steady-state [Cl–]ER and impair ER Ca2+ homeostasis, and animals with the ALS-associated mutations are sensitized to stress challenge-induced protein misfolding. Phenotypic comparisons of multiple Clcc1 loss-of-function alleles, including ALS-associated mutations, reveal a CLCC1 dosage dependence in the severity of disease phenotypes in vivo. Similar to CLCC1 rare variations dominant in ALS, 10% of K298A heterozygous mice developed ALS-like symptoms, pointing to a mechanism of channelopathy dominant-negatively induced by a loss-of-function mutation. Conditional knockout of Clcc1 cell-autonomously causes motor neuron loss and ER stress, misfolded protein accumulation, and characteristic ALS pathologies in the spinal cord. Thus, our findings support that disruption of ER ion homeostasis maintained by CLCC1 contributes to ALS-like pathologies.
Seasonal and diurnal variations of Kelvin-Helmholtz Instability at terrestrial magnetopause
Authors: Kavosi S. , Raeder J. , Johnson J. R. , Nykyri K. , Farrugia C. J. 
Published: May 2023

AbstractKelvin-Helmholtz Instability is ubiquitous at Earth’s magnetopause and plays an important role in plasma entry into the magnetosphere during northward interplanetary magnetic fields. Here, using one solar cycle of data from NASA THEMIS (Time History of Events and Macro scale Interactions during Substorms) and MMS (Magnetospheric Multiscale) missions, we found that KHI occurrence rates show seasonal and diurnal variations with the rate being high near the equinoxes and low near the solstices. The instability depends directly on the Earth’s dipole tilt angle. The tilt toward or away from the Sun explains most of the seasonal and diurnal variations, while the tilt in the plane perpendicular to the Earth‐Sun line explains the difference between the equinoxes. The results reveal the critical role of dipole tilt in modulating KHI across the magnetopause as a function of time, highlighting the importance of Sun-Earth geometry for solar wind-magnetosphere interaction and for space weather.
Privacy risks of whole-slide image sharing in digital pathology
Authors: Holub Petr , Müller Heimo , Bíl Tomáš , Pireddu Luca , Plass Markus , Prasser Fabian , Schlünder Irene , Zatloukal Kurt , Nenutil Rudolf , Brázdil Tomáš 
Published: May 2023

AbstractAccess to large volumes of so-called whole-slide images—high-resolution scans of complete pathological slides—has become a cornerstone of the development of novel artificial intelligence methods in pathology for diagnostic use, education/training of pathologists, and research. Nevertheless, a methodology based on risk analysis for evaluating the privacy risks associated with sharing such imaging data and applying the principle “as open as possible and as closed as necessary” is still lacking. In this article, we develop a model for privacy risk analysis for whole-slide images which focuses primarily on identity disclosure attacks, as these are the most important from a regulatory perspective. We introduce a taxonomy of whole-slide images with respect to privacy risks and mathematical model for risk assessment and design . Based on this risk assessment model and the taxonomy, we conduct a series of experiments to demonstrate the risks using real-world imaging data. Finally, we develop guidelines for risk assessment and recommendations for low-risk sharing of whole-slide image data.
C(alkyl)–C(vinyl) bond cleavage enabled by Retro-Pallada-Diels-Alder reaction
Authors: Zhao Qingyang , Yu Le , Zhang Yao-Du , Guo Yong-Qiang , Chen Ming , Ren Zhi-Hui , Guan Zheng-Hui 
Published: May 2023

AbstractActivation and cleavage of carbon–carbon (C–C) bonds is a fundamental transformation in organic chemistry while inert C–C bonds cleavage remains a long-standing challenge. Retro-Diels-Alder (retro-DA) reaction is a well-known and important tool for C–C bonds cleavage but less been explored in methodology by contrast to other strategies. Herein, we report a selective C(alkyl)–C(vinyl) bond cleavage strategy realized through the transient directing group mediated retro-Diels-Alder reaction of a six-membered palladacycle, which is obtained from an in situ generated hydrazone and palladium hydride species. This unprecedented strategy exhibits good tolerances and thus offers new opportunities for late-stage modifications of complex molecules. DFT calculations revealed that an intriguing retro-Pd(IV)-Diels-Alder process is possibly involved in the catalytic cycle, thus bridging both Retro-Diels-Alder reaction and C–C bond cleavage. We anticipate that this strategy should prove instrumental for potential applications to achieve the modification of functional organic skeletons in synthetic chemistry and other fields involving in molecular editing.
Symport and antiport mechanisms of human glutamate transporters
Authors: Qiu Biao , Boudker Olga 
Published: May 2023

AbstractExcitatory amino acid transporters (EAATs) uptake glutamate into glial cells and neurons. EAATs achieve million-fold transmitter gradients by symporting it with three sodium ions and a proton, and countertransporting a potassium ion via an elevator mechanism. Despite the availability of structures, the symport and antiport mechanisms still need to be clarified. We report high-resolution cryo-EM structures of human EAAT3 bound to the neurotransmitter glutamate with symported ions, potassium ions, sodium ions alone, or without ligands. We show that an evolutionarily conserved occluded translocation intermediate has a dramatically higher affinity for the neurotransmitter and the countertransported potassium ion than outward- or inward-facing transporters and plays a crucial role in ion coupling. We propose a comprehensive ion coupling mechanism involving a choreographed interplay between bound solutes, conformations of conserved amino acid motifs, and movements of the gating hairpin and the substrate-binding domain.
Global green hydrogen-based steel opportunities surrounding high quality renewable energy and iron ore deposits
Authors: Devlin Alexandra , Kossen Jannik , Goldie-Jones Haulwen , Yang Aidong 
Published: May 2023

AbstractThe steel sector currently accounts for 7% of global energy-related CO2 emissions and requires deep reform to disconnect from fossil fuels. Here, we investigate the market competitiveness of one of the widely considered decarbonisation routes for primary steel production: green hydrogen-based direct reduction of iron ore followed by electric arc furnace steelmaking. Through analysing over 300 locations by combined use of optimisation and machine learning, we show that competitive renewables-based steel production is located nearby the tropic of Capricorn and Cancer, characterised by superior solar with supplementary onshore wind, in addition to high-quality iron ore and low steelworker wages. If coking coal prices remain high, fossil-free steel could attain competitiveness in favourable locations from 2030, further improving towards 2050. Large-scale implementation requires attention to the abundance of suitable iron ore and other resources such as land and water, technical challenges associated with direct reduction, and future supply chain configuration.
Chemical imaging reveals diverse functions of tricarboxylic acid metabolites in root growth and development
Authors: Zhang Tao , Noll Sarah E. , Peng Jesus T. , Klair Amman , Tripka Abigail , Stutzman Nathan , Cheng Casey , Zare Richard N. , Dickinson Alexandra J. 
Published: May 2023

AbstractUnderstanding how plants grow is critical for agriculture and fundamental for illuminating principles of multicellular development. Here, we apply desorption electrospray ionization mass spectrometry imaging (DESI-MSI) to the chemical mapping of the developing maize root. This technique reveals a range of small molecule distribution patterns across the gradient of stem cell differentiation in the root. To understand the developmental logic of these patterns, we examine tricarboxylic acid (TCA) cycle metabolites. In both Arabidopsis and maize, we find evidence that elements of the TCA cycle are enriched in developmentally opposing regions. We find that these metabolites, particularly succinate, aconitate, citrate, and α-ketoglutarate, control root development in diverse and distinct ways. Critically, the developmental effects of certain TCA metabolites on stem cell behavior do not correlate with changes in ATP production. These results present insights into development and suggest practical means for controlling plant growth.
Re-convolving the compositional landscape of primary and recurrent glioblastoma reveals prognostic and targetable tissue states
Authors: Al-Dalahmah Osama , Argenziano Michael G. , Kannan Adithya , Mahajan Aayushi , Furnari Julia , Paryani Fahad , Boyett Deborah , Save Akshay , Humala Nelson , Khan Fatima , Li Juncheng , Lu Hong , Sun Yu , Tuddenham John F. , Goldberg Alexander R. , Dovas Athanassios , Banu Matei A. , Sudhakar Tejaswi , Bush Erin , Lassman Andrew B. , McKhann Guy M. , Gill Brian J. A. , Youngerman Brett , Sisti Michael B. , Bruce Jeffrey N. , Sims Peter A. , Menon Vilas , Canoll Peter 
Published: May 2023

AbstractGlioblastoma (GBM) diffusely infiltrates the brain and intermingles with non-neoplastic brain cells, including astrocytes, neurons and microglia/myeloid cells. This complex mixture of cell types forms the biological context for therapeutic response and tumor recurrence. We used single-nucleus RNA sequencing and spatial transcriptomics to determine the cellular composition and transcriptional states in primary and recurrent glioma and identified three compositional ‘tissue-states’ defined by cohabitation patterns between specific subpopulations of neoplastic and non-neoplastic brain cells. These tissue-states correlated with radiographic, histopathologic, and prognostic features and were enriched in distinct metabolic pathways. Fatty acid biosynthesis was enriched in the tissue-state defined by the cohabitation of astrocyte-like/mesenchymal glioma cells, reactive astrocytes, and macrophages, and was associated with recurrent GBM and shorter survival. Treating acute slices of GBM with a fatty acid synthesis inhibitor depleted the transcriptional signature of this pernicious tissue-state. These findings point to therapies that target interdependencies in the GBM microenvironment.
Regional and global impact of CO2 uptake in the Benguela Upwelling System through preformed nutrients
Authors: Siddiqui Claire , Rixen Tim , Lahajnar Niko , Van der Plas Anja K. , Louw Deon C. , Lamont Tarron , Pillay Keshnee 
Published: May 2023

AbstractEastern Boundary Upwelling Systems (EBUS) are highly productive ecosystems. However, being poorly sampled and represented in global models, their role as atmospheric CO2 sources and sinks remains elusive. In this work, we present a compilation of shipboard measurements over the past two decades from the Benguela Upwelling System (BUS) in the southeast Atlantic Ocean. Here, the warming effect of upwelled waters increases CO2 partial pressure (pCO2) and outgassing in the entire system, but is exceeded in the south through biologically-mediated CO2 uptake through biologically unused, so-called preformed nutrients supplied from the Southern Ocean. Vice versa, inefficient nutrient utilization leads to preformed nutrient formation, increasing pCO2 and counteracting human-induced CO2 invasion in the Southern Ocean. However, preformed nutrient utilization in the BUS compensates with ~22–75 Tg C year−1 for 20–68% of estimated natural CO2 outgassing in the Southern Ocean’s Atlantic sector (~ 110 Tg C year−1), implying the need to better resolve global change impacts on the BUS to understand the ocean’s role as future sink for anthropogenic CO2.
Direct nucleophilic and electrophilic activation of alcohols using a unified boron-based organocatalyst scaffold
Authors: Rygus Jason P. G. , Hall Dennis G. 
Published: May 2023

AbstractOrganocatalytic strategies for the direct activation of hydroxy-containing compounds have paled in comparison to those applicable to carbonyl compounds. To this end, boronic acids have emerged as valuable catalysts for the functionalization of hydroxy groups in a mild and selective fashion. Distinct modes of activation in boronic acid-catalyzed transformations are often accomplished by vastly different catalytic species, complicating the design of broadly applicable catalyst classes. Herein, we report the use of benzoxazaborine as a general scaffold for the development of structurally related yet mechanistically divergent catalysts for the direct nucleophilic and electrophilic activation of alcohols under ambient conditions. The utility of these catalysts is demonstrated in the monophosphorylation of vicinal diols and the reductive deoxygenation of benzylic alcohols and ketones respectively. Mechanistic studies of both processes reveal the contrasting nature of key tetravalent boron intermediates in the two catalytic manifolds.
Distinguishing artificial spin ice states using magnetoresistance effect for neuromorphic computing
Authors: Hu Wenjie , Zhang Zefeng , Liao Yanghui , Li Qiang , Shi Yang , Zhang Huanyu , Zhang Xumeng , Niu Chang , Wu Yu , Yu Weichao , Zhou Xiaodong , Guo Hangwen , Wang Wenbin , Xiao Jiang , Yin Lifeng , Liu Qi , Shen Jian 
Published: May 2023

AbstractArtificial spin ice (ASI) consisting patterned array of nano-magnets with frustrated dipolar interactions offers an excellent platform to study frustrated physics using direct imaging methods. Moreover, ASI often hosts a large number of nearly degenerated and non-volatile spin states that can be used for multi-bit data storage and neuromorphic computing. The realization of the device potential of ASI, however, critically relies on the capability of transport characterization of ASI, which has not been demonstrated so far. Using a tri-axial ASI system as the model system, we demonstrate that transport measurements can be used to distinguish the different spin states of the ASI system. Specifically, by fabricating a tri-layer structure consisting a permalloy base layer, a Cu spacer layer and the tri-axial ASI layer, we clearly resolve different spin states in the tri-axial ASI system using lateral transport measurements. We have further demonstrated that the tri-axial ASI system has all necessary required properties for reservoir computing, including rich spin configurations to store input signals, nonlinear response to input signals, and fading memory effect. The successful transport characterization of ASI opens up the prospect for novel device applications of ASI in multi-bit data storage and neuromorphic computing.
Southern Tibetan rifting since late Miocene enabled by basal shear of the underthrusting Indian lithosphere
Authors: Zhang Bingfeng , Bao Xuewei , Wu Yingkai , Xu Yixian , Yang Wencai 
Published: May 2023

AbstractSyncontractional extension is prominent in present-day Tibet, but its origin remains vigorously debated. Several deep-seated geodynamic processes (e.g., Indian underthrusting, horizontal flow, and mantle upwelling) have been linked to Tibetan rifting. Indian underthrusting is a good candidate because it can well explain why surface rifts are more prominent south of the Bangong–Nujiang suture; however, how Indian underthrusting causes extension is not well understood and lacks observational constraints. Seismic anisotropy, measured by exploiting the birefringence effect of shear waves, can be indicative of the deformation styles within the crust. Here, we unveil the dominant convergence-parallel alignment of anisotropic fabrics in the deep crust of the southern Tibetan rifts using seismic recordings collected from our recently deployed and existing seismic stations. This finding suggests that the strong north-directed shearing exerted by the underthrusting Indian plate is key to enabling present-day extension in southern Tibet.
Engineered repeat proteins as scaffolds to assemble multi-enzyme systems for efficient cell-free biosynthesis
Authors: Ledesma-Fernandez Alba , Velasco-Lozano Susana , Santiago-Arcos Javier , López-Gallego Fernando , Cortajarena Aitziber L. 
Published: May 2023

AbstractMulti-enzymatic cascades with enzymes arranged in close-proximity through a protein scaffold can trigger a substrate channeling effect, allowing for efficient cofactor reuse with industrial potential. However, precise nanometric organization of enzymes challenges the design of scaffolds. In this study, we create a nanometrically organized multi-enzymatic system exploiting engineered Tetrapeptide Repeat Affinity Proteins (TRAPs) as scaffolding for biocatalysis. We genetically fuse TRAP domains and program them to selectively and orthogonally recognize peptide-tags fused to enzymes, which upon binding form spatially organized metabolomes. In addition, the scaffold encodes binding sites to selectively and reversibly sequester reaction intermediates like cofactors via electrostatic interactions, increasing their local concentration and, consequently, the catalytic efficiency. This concept is demonstrated for the biosynthesis of amino acids and amines using up to three enzymes. Scaffolded multi-enzyme systems present up to 5-fold higher specific productivity than the non-scaffolded ones. In-depth analysis suggests that channeling of NADH cofactor between the assembled enzymes enhances the overall cascade throughput and the product yield. Moreover, we immobilize this biomolecular scaffold on solid supports, creating reusable heterogeneous multi-functional biocatalysts for consecutive operational batch cycles. Our results demonstrate the potential of TRAP-scaffolding systems as spatial-organizing tools to increase the efficiency of cell-free biosynthetic pathways.
NetBID2 provides comprehensive hidden driver analysis
Authors: Dong Xinran , Ding Liang , Thrasher Andrew , Wang Xinge , Liu Jingjing , Pan Qingfei , Rash Jordan , Dhungana Yogesh , Yang Xu , Risch Isabel , Li Yuxin , Yan Lei , Rusch Michael , McLeod Clay , Yan Koon-Kiu , Peng Junmin , Chi Hongbo , Zhang Jinghui , Yu Jiyang 
Published: May 2023

AbstractMany signaling and other genes known as “hidden” drivers may not be genetically or epigenetically altered or differentially expressed at the mRNA or protein levels, but, rather, drive a phenotype such as tumorigenesis via post-translational modification or other mechanisms. However, conventional approaches based on genomics or differential expression are limited in exposing such hidden drivers. Here, we present a comprehensive algorithm and toolkit NetBID2 (data-driven network-based Bayesian inference of drivers, version 2), which reverse-engineers context-specific interactomes and integrates network activity inferred from large-scale multi-omics data, empowering the identification of hidden drivers that could not be detected by traditional analyses. NetBID2 has substantially re-engineered the previous prototype version by providing versatile data visualization and sophisticated statistical analyses, which strongly facilitate researchers for result interpretation through end-to-end multi-omics data analysis. We demonstrate the power of NetBID2 using three hidden driver examples. We deploy NetBID2 Viewer, Runner, and Cloud apps with 145 context-specific gene regulatory and signaling networks across normal tissues and paediatric and adult cancers to facilitate end-to-end analysis, real-time interactive visualization and cloud-based data sharing. NetBID2 is freely available at https://jyyulab.github.io/NetBID.