bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aluminium alters excitability by inhibiting calcium, sodium and potassium currents in bovine chromaffin cells
Authors: Baraibar Andrés M. , de Pascual Ricardo , Jiménez Carretero Victoria , Hernández Juárez Natalia , Aguirregabiria Alonso Itxaso Edurne , Hernández-Guijo Jesús M. 
Published: January 2023

AbstractAluminium (Al3+) has long been related to neurotoxicity and neurological diseases. This study aims to describe the specific actions of this metal on cellular excitability and neurotransmitter release. Al3+reduced intracellular calcium concentrations around 25% and decreased catecholamine secretion in a dose-dependent manner, with an IC50of 89.1 μM. Al3+blocked calcium currents in a time- and concentration-dependent manner with an IC50of 560 μM. This blockade was irreversible, since it did not recover after wash-out. Moreover, Al3+produced a bigger blockade on N-, P- and Q-type calcium channels subtypes (69.5%) than on L-type channels subtypes (50.5%). Sodium currents were also inhibited by Al3+in a time- and concentration-dependent manner, 24.3% blockade at the closest concentration to the IC50(419 μM). This inhibition was reversible. Voltage-dependent potassium currents were non-significantly affected by Al3+. Nonetheless, calcium/voltage-dependent potassium currents were inhibited in a concentration-dependent manner, with an IC50of 447 μM. This inhibition was related to the depression of calcium influx through voltage-dependent calcium channels subtypes coupled to BK channels. In summary, the blockade of these ionic conductances altered cellular excitability that reduced the action potentials firing and so, the neurotransmitter release and the synaptic transmission. These findings prove that aluminium has neurotoxic properties because it alters neuronal excitability by inhibiting the sodium currents responsible for the generation and propagation of impulse nerve, the potassium current responsible for the termination of action potentials, and the calcium current responsible for the neurotransmitters release.
Ultrasensitive detection of circulating LINE-1 ORF1p as a specific multi-cancer biomarker
Authors: Taylor Martin S. , Wu Connie , Fridy Peter C. , Zhang Stephanie J. , Senussi Yasmeen , Wolters Justina C. , Cheng Wen-Chih , Heaps John , Miller Bryant D. , Mori Kei , Cohen Limor , Jiang Hua , Molloy Kelly R. , Chait Brian T. , Goggins Michael , Bhan Irun , Franses Joseph W. , Yang Xiaoyu , Taplin Mary-Ellen , Wang Xinan , Christiani David C. , Johnson Bruce E. , Meyerson Matthew , Uppaluri Ravindra , Egloff Ann Marie , Denault Elyssa N. , Spring Laura M. , Wang Tian-Li , Shih Ie-Ming , Jung Euihye , Arora Kshitij S. , Zukerberg Lawrence R. , Yilmaz Osman H. , Chi Gary , Norden Bryanna L. , Song Yuhui , Nieman Linda , Parikh Aparna R. , Strickland Matthew , Corcoran Ryan B. , Mustelin Tomas , Eng George , Yilmaz Ömer H. , Matulonis Ursula A. , Skates Steven J. , Rueda Bo R. , Drapkin Ronny , Klempner Samuel J. , Deshpande Vikram , Ting David T. , Rout Michael P. , LaCava John , Walt David R. , Burns Kathleen H. 
Published: January 2023

AbstractImproved biomarkers are needed for early cancer detection, risk stratification, treatment selection, and monitoring treatment response. While proteins can be useful blood-based biomarkers, many have limited sensitivity or specificity for these applications. Long INterspersed Element-1 (LINE-1, L1) open reading frame 1 protein (ORF1p) is a transposable element protein overexpressed in carcinomas and high-risk precursors during carcinogenesis with negligible detectable expression in corresponding normal tissues, suggesting ORF1p could be a highly specific cancer biomarker. To explore the potential of ORF1p as a blood-based biomarker, we engineered ultrasensitive digital immunoassays that detect mid-attomolar (10-17M) ORF1p concentrations in patient plasma samples across multiple cancers with high specificity. Plasma ORF1p shows promise for early detection of ovarian cancer, improves diagnostic performance in a multi-analyte panel, and provides early therapeutic response monitoring in gastric and esophageal cancers. Together, these observations nominate ORF1p as a multi-cancer biomarker with potential utility for disease detection and monitoring.Statement of SignificanceLINE-1 ORF1p transposon protein is pervasively expressed in many cancers and a highly specific biomarker of multiple common, lethal carcinomas and their high-risk precursors in tissue and blood. Ultrasensitive ORF1p assays from as little as 25 μL plasma are novel, rapid, cost-effective tools in cancer detection and monitoring.
Spatiotemporal dynamics of self-generated imagery reveal a reverse cortical hierarchy from cue-induced imagery
Authors: Hu Yiheng , Yu Qing 
Published: January 2023

AbstractVisual imagery, the ability to generate visual experience in the absence of direct external stimulation, allows for the construction of rich internal experience in our mental world. Most imagery studies to date have focused on cue-induced imagery, namely the to-be-imagined contents were triggered by external cues. It has remained unclear how internal experience derives volitionally in the absence of any external cues, and whether this kind of self-generated imagery relies on an analogous cortical network as cue-induced imagery. Here, leveraging a novel self-generated imagery paradigm, we systematically examined the spatiotemporal dynamics of self-generated imagery, by having participants volitionally imagining one of the orientations from a learned pool; and of cue-induced imagery, by having participants imagining line orientations based on associative cues acquired previously. Using electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), in combination with multivariate encoding and decoding approaches, our results revealed largely overlapping neural signatures of cue-induced and self-generated imagery in both EEG and fMRI; yet, these neural signatures displayed substantially differential sensitivities to the two types of imagery: self-generated imagery was supported by an enhanced involvement of anterior cortex in generating and maintaining imagined contents, as evidenced by enhanced neural representations of orientations in sustained potentials in central channels in EEG, and in posterior frontal cortex in fMRI. By contrast, cue-induced imagery was supported by enhanced neural representations of orientations in alpha-band activity in posterior channels in EEG, and in early visual cortex in fMRI. These results jointly support a reverse cortical hierarchy in generating and maintaining imagery contents in self-generated versus externally-cued imagery.
Extensive hybridisation between multiple differently adapted species may aid persistence in a changing climate
Authors: Satokangas I , Nouhaud P , Seifert B , Punttila P , Schultz R , Jones MM , Sirén J. , Helanterä H , Kulmuni J 
Published: January 2023

AbstractHybridisation and gene flow can have both deleterious and adaptive consequences for natural populations and species. To better understand the extent and consequences of hybridisation in nature, information on naturally hybridising non-model organisms is required, including characterising the structure and extent of natural hybrid zones. Here we study natural populations of five keystone mound-building wood ant (Formica rufagroup) species across Finland. No genomic studies across the species group exist and the extent of hybridisation and genomic differentiation in sympatry is unknown. Combining genome-wide and morphological data, we show thatFormica rufa,F. aquilonia,F. lugubris, andF. pratensisform distinct gene pools in Finland. We demonstrate more extensive hybridisation than previously thought between all five species and reveal a mosaic hybrid zone betweenF. aquilonia,F. rufaandF. polyctena. We show that hybrids between these climatically differently adapted species occupy warmer habitats than the cold-adapted parentF. aquilonia. This suggests hybrids occupy a different microclimatic niche compared to the locally abundant parent. We propose that wood ant hybridisation may increase with a warming climate, and warm winters, in particular, may provide a competitive advantage for the hybrids overF. aquiloniain the future. In summary, our results demonstrate how extensive hybridisation may help persistence in a changing climate. Additionally, they provide an example on how mosaic hybrid zones can have significant ecological and evolutionary consequences because of their large extent and independent hybrid populations that face both ecological and intrinsic selection pressures.
E2EDA: Protein domain assembly based on end-to-end deep learning
Authors: Zhu Hai-Tao , Xia Yu-Hao , Zhang Guijun 
Published: January 2023

AbstractWith the development of deep learning, almost all single-domain proteins can be predicted at experimental resolution. However, the structure prediction of multi-domain proteins remains a challenge. Achieving end-to-end protein domain assembly and further improving the accuracy of the full-chain modelling by accurately predicting inter-domain orientation while improving the assembly efficiency will provide significant insights into structure-based drug discovery. In addition, the available GPU memory limits the size of a full-chain protein which can be predicted. Based on the divide-and-conquer strategy, the single-domain structure is predicted by the state-of-the-art prediction method, such as AlphaFold2, and then assembled into a full-chain model through the domain assembly method, which can effectively reduce the demand for hardware resources. In this work, we propose an End-To-End Domain Assembly method based on deep learning, named E2EDA. We first develop an EffificientNetV2-based deep learning model (RMNet), which is specialised for predicting inter-domain orientations. The RMNet uses an attention mechanism to predict inter-domain rigid motion by fusing sequence features, multiple template features and single-domain features. Then, the predicted rigid motions are converted into inter-domain spatial transformations to assemble full-chain models of multi-domain proteins directly without time-consuming simulation processes. Finally, a scoring strategy, RMscore, is designed to select the best model from multiple assembled models to improve assembly accuracy. The experimental results show that the average TM-score of the model assembled by E2EDA on the benchmark set (356) is 0.84, which is better than other domain assembly methods SADA (0.80), DEMO (0.74) and AIDA (0.63). Meanwhile, on our constructed human protein dataset from AlphaFold DB, the model reassembled by E2EDA is 6.8% higher than the full-chain model predicted by AlphaFold2, indicating that E2EDA can capture more accurate inter-domain orientations to improve the quality of the model predicted by AlphaFold2. Furthermore, the average running time of E2EDA on the benchmark is reduced by 74.6% compared with the domain assembly simulation method SADA, which indicates that E2EDA can effectively improve assembly efficiency through an end-to-end manner.The online server is athttp://zhanglab-bioinf.com/E2EDA/.
hb or not hb - when and why accounting for background mortality in toxicological survival models matters?
Authors: Plantade Julie , Baudrot Virgile , Charles Sandrine 
Published: January 2023

AbstractDecisions in Environmental Risk Assessment (ERA) about impacts of chemical compounds on different species are based on critical effect indicators such as the 50% lethal concentration (LC50). Regulatory documents recommend concentration-response (or concentration-effect) model fitting on standard toxicity test data to getLC50values. However, toxicokinetic-toxicodynamic (TKTD) models proved their efficiency to better exploit toxicity test data, at Tier-2 but also at Tier-1, delivering time-independent indicators. In particular,LC50values can be obtained from the reduced General Unified Threshold model of Survival (GUTS-RED) with both variants, Stochastic Death and Individual Tolerance, that include parameterhb, the background mortality. Estimatinghbduring the fitting process or not depends on studies and fitting habits, while it may strongly influence the other GUTS-RED parameters, and consequently theLC50estimate. We hypothesized that estimatinghbfrom all data in all replicates over time should provide more preciseLC50estimates. We then explored how estimatinghbimpacted: (i) GUTS-RED model parameters; (ii) goodness-of-fit criteria (fitting plot, posterior predictive check, parameter correlation); (iii)LC50accuracy and precision. We finally show that estimatinghbdoes not impact theLC50precision while providing more accurate and precise GUTS parameter estimates. Hence, estimatinghbwould lead to a more protective ERA.Graphical abstractSpecifications table
Zinc Alters the Supramolecular Organization of Nucleic Acid Complexes with Full-Length TIA1
Authors: Yang Yizhuo , Fritzsching Keith J. , He Sasha , McDermott Ann E. 
Published: January 2023

ABSTRACTT-Cell Intracellular Antigen-1 (TIA1) is a 43 kDa multi-domain RNA-binding protein involved in stress granule formation during eukaryotic stress response, and has been implicated in neurodegenerative diseases including Welander distal myopathy and amyotrophic lateral sclerosis. TIA1 contains three RNA recognition motifs (RRMs), which are capable of binding nucleic acids and a C-terminal Q/N-rich prion-related domain (PRD) which has been variously described as intrinsically disordered or prion inducing and is believed to play a role in promoting liquid-liquid phase separation connected with the assembly of stress granule formation. Motivated by the fact that our prior work shows RRMs 2 and 3 are well-ordered in an oligomeric full-length form, while RRM1 and the PRD appear to phase separate, the present work addresses whether the oligomeric form is functional and competent for binding, and probes the consequences of nucleic acid binding for oligomerization and protein conformation change. New SSNMR data show that ssDNA binds to full-length oligomeric TIA1 primarily at the RRM2 domain, but also weakly at the RRM3 domain, and Zn2+binds primarily to RRM3. Binding of Zn2+and DNA was reversible for the full-length wild type oligomeric form, and did not lead to formation of amyloid fibrils, despite the presence of the C-terminal prion-related domain. While TIA1:DNA complexes appear as long “daisy chained” structures, the addition of Zn2+caused the structures to collapse. We surmise that this points to a regulatory role for Zn2+. By occupying various “half” binding sites on RRM3 Zn2+may shift the nucleic acid binding off RRM3 and onto RRM2. More importantly, the use of different half sites on different monomers may introduce a mesh of crosslinks in the supramolecular complex rendering it compact and markedly reducing the access to the nucleic acids (including transcripts) from solution.
The characterisation of phytoene synthase-1 and 2, and 1-D-deoxy-xylulose 5-phosphate synthase genes from red chilli pepper (Capsicum annuum)
Authors: Berry Harriet M. , Zhou Nan , Rickett Daniel V. , Baxter Charles J. , Enfissi Eugenia M. A. , Fraser Paul D. 
Published: January 2023

AbstractThe red colouration of ripe chilli pepper fruit is due to the presence of the carotenoid capsanthin. 1-D-deoxy-xylulose 5-phosphate synthase (DXS) and phytoene synthase(s) (PSY) are influential biosynthetic steps in the carotenoid pathway. A panel of chilli accessions for varying fruit colour intensity revealed the correlation of carotenoid content withPSYandDXStranscript levels. ThePSYandDXSgenes were sequenced from high and low carotenoid genotypes to deduce potential allelic variation.PSY-1 and -2 showed tissue specific expression, withPSY-1and 2 expressed in chromoplast and chloroplast containing tissues, respectively. Protein modelling, phylogenetic analysis and transcription factor analysis was conducted to understand how the allelic variation identified could affect carotenoid biosynthesis and regulation, and subsequently colour intensity phenotype. A candidate mutation located in the transit peptide of the PSY-1 protein sequence was identified in the low colour intensity genotype. Within the promoter region of theDXSgene present in the high colour intensity genotype sequence variation was determined in the glyceraldehyde 3-phosphate binding motif (GAPF) of the promoter region. These data can be exploited to develop tools and resources for the breeding of high colour intensity chilli pepper fruit.Key policy highlightsUsing the molecular findings disclosed in this article the potential exists to develop molecular markers for the breeding varieties of chilli peppers with improved aesthetic consumer preference and nutritional attributes.
Resting-state fMRI signals contain spectral signatures of local hemodynamic response timing
Authors: Bailes Sydney M. , Gomez Daniel E. P. , Setzer Beverly , Lewis Laura D. 
Published: January 2023

AbstractFunctional magnetic resonance imaging (fMRI) has proven to be a powerful tool for noninvasively measuring human brain activity; yet, thus far, fMRI has been relatively limited in its temporal resolution. A key challenge is understanding the relationship between neural activity and the blood-oxygenation-level-dependent (BOLD) signal obtained from fMRI, generally modeled by the hemodynamic response function (HRF). The timing of the HRF varies across the brain and individuals, confounding our ability to make inferences about the timing of the underlying neural processes. Here we show that resting-state fMRI signals contain information about HRF temporal dynamics that can be leveraged to understand and characterize variations in HRF timing across both cortical and subcortical regions. We found that the frequency spectrum of resting-state fMRI signals significantly differs between voxels with fast versus slow HRFs in human visual cortex. These spectral differences extended to subcortex as well, revealing significantly faster hemodynamic timing in the lateral geniculate nucleus of the thalamus. Ultimately, our results demonstrate that the temporal properties of the HRF impact the spectral content of resting-state fMRI signals and enable voxel-wise characterization of relative hemodynamic response timing. Furthermore, our results show that caution should be used in studies of resting-state fMRI spectral properties, as differences can arise from purely vascular origins. This finding provides new insight into the temporal properties of fMRI signals across voxels, which is crucial for accurate fMRI analyses, and enhances the ability of fast fMRI to identify and track fast neural dynamics.
PI(3,5)P2Controls the Signaling Activity of Class I PI3K
Authors: Sun Jiachen , Zalejski Julian , Song Seohyeon , Sharma Ashutosh , Wang Wei , Hu Yusi , Lo Wen-Ting , Koch Philipp Alexander , Singh Jagriti , Singaram Indira , An Baoshu , Zhao Jean J. , Gong Liang-Wei , Haucke Volker , Gao Ruixuan , Cho Wonhwa 
Published: January 2023

ABSTRACT3-Phosphoinositides are ubiquitous cellular lipids that play pivotal regulatory roles in health and disease. Among 3-phosphoinositides, phosphatidylinositol-3,5-bisphosphate (PI(3,5)P2) remains the least understood species in terms of its spatiotemporal dynamics and physiological function due to the lack of a specific sensor that allows spatiotemporally resolved quantitative imaging of PI(3,5)P2. Using a newly developed ratiometric PI(3,5)P2sensor engineered from the C-terminal SH2 domain of Class I phosphoinositide 3-kinases (PI3K)-p85α subunit we demonstrate that a unique pool of PI(3,5)P2is generated on lysosomes and late endosomes in response to growth factor stimulation. This PI(3,5)P2, the formation of which is mediated sequentially by Class II PI3KC2β and PIKfyve, plays a crucial role in terminating the activity of growth factor-stimulated Class I PI3K, one of the most frequently mutated proteins in cancer, via specific interaction with its regulatory p85 subunit. A small molecule inhibitor of p85α-PI(3,5)P2binding specifically blocks the feedback inhibition of Class I PI3K by PI(3,5)P2and thus serves as a PI3K activator that promotes neurite growth. Furthermore, cancer-causing mutations of the Class I PI3K-p85 subunit inhibit p85-PI(3,5)P2interaction and thereby induce sustained activation of Class I PI3K. Our results unravel a hitherto unknown spatiotemporally specific regulatory function of PI(3,5)P2that links Class I and II PI3Ks and modulates the magnitude of PI3K-mediated growth factor signaling. These results also suggest new therapeutic possibilities for treating cancer patients with p85 mutations and promoting wound healing and tissue regeneration.
Structural asymmetry in biotic interactions as a tool to understand and predict ecological persistence
Authors: Allen-Perkins Alfonso , García-Callejas David , Bartomeus Ignasi , Godoy Oscar 
Published: January 2023

AbstractA universal feature of ecological systems is that species do not interact with others with the same sign and strength. Yet, the consequences of this asymmetry in biotic interactions for the short- and long-term persistence of individual species and entire communities remains unclear. Here, we develop a set of metrics to evaluate how asymmetric interactions among species translate to asymmetries in their individual vulnerability to extinction under changing environmental conditions. These metrics, which solve previous limitations of how to independently quantify the size from the shape of the so-called feasibility domain, provide rigorous advances to understand simultaneously why some species and communities present more opportunities to persist than others. We further demonstrate that our shape-related metrics are useful to predict short-term changes in species’ relative abundances during seven years in a Mediterranean grassland. Our approach is designed to be applied to any ecological system regardless of the number of species and type of interactions. With it, we show that is possible to obtain both mechanistic and predictive information on ecological persistence for individual species and entire communities, paving the way for a stronger integration of theoretical and empirical research.
Reticulocytes in donor RBC units enhance RBC alloimmunization
Authors: Thomas Tiffany A. , Qiu Annie , Kim Christopher Y. , Gordy Dominique E. , Miller Anabel , Tredicine Maria , Dzieciatkowska Monika , Zotti Flavia Dei , Hod Eldad A. , D’Alessandro Angelo , Zimring James C. , Spitalnik Steven L. , Hudson Krystalyn E. 
Published: January 2023

AbstractAlthough red blood cell (RBC) transfusions save lives, some patients develop clinically-significant alloantibodies against donor blood group antigens, which then have adverse effects in multiple clinical settings. Few effective measures exist to prevent RBC alloimmunization and/or eliminate alloantibodies in sensitized patients. Donor-related factors may influence alloimmunization; thus, there is an unmet clinical need to identify which RBC units are immunogenic. Repeat volunteer blood donors and donors on iron supplements have elevated reticulocyte counts compared to healthy non-donors. Early reticulocytes retain mitochondria and other components, which may act as danger signals in immune responses. Herein, we tested whether reticulocytes in donor RBC units could enhance RBC alloimmunization. Using a murine model, we demonstrate that transfusing donor RBC units with increased reticulocyte frequencies dose-dependently increase RBC alloimmunization rates and alloantibody levels. Transfusing reticulocyte-rich RBC units was associated with increased RBC clearance from the circulation and a robust proinflammatory cytokine response. As compared to previously reported post-transfusion RBC consumption patterns, erythrophagocytosis from reticulocyte-rich units was increasingly performed by splenic B cells. These data suggest that reticulocytes in a donated RBC unit impact the quality of blood transfused, are targeted to a distinct compartment, and may be an underappreciated risk factor for RBC alloimmunization.