bluuebunny/crossref_metadata_2025_split huggingface dataset:
The unknown lipids project: harmonized methods improve compound identification and data reproducibility in an inter-laboratory untargeted lipidomics study
Authors: Shen Tong , Conway Ciara , Rempfert Kaitlin R. , Kyle Jennifer E. , Colby Sean M. , Gaul David A. , Habra Hani , Kong Fanzhou , Bloodsworth Kent J. , Allen Douglas , Evans Bradley S. , Du Xiuxia , Fernandez Facundo M. , Metz Thomas O. , Fiehn Oliver , Evans Charles R. 
Published: February 2023

AbstractUntargeted lipidomics allows analysis of a broader range of lipids than targeted methods and permits discovery of unknown compounds. Previous ring trials have evaluated the reproducibility of targeted lipidomics methods, but inter-laboratory comparison of compound identification and unknown feature detection in untargeted lipidomics has not been attempted. To address this gap, five laboratories analyzed a set of mammalian tissue and biofluid reference samples using both their own untargeted lipidomics procedures and a common chromatographic and data analysis method. While both methods yielded informative data, the common method improved chromatographic reproducibility and resulted in detection of more shared features between labs. Spectral search against the LipidBlast in silico library enabled identification of over 2,000 unique lipids. Further examination of LC-MS/MS and ion mobility data, aided by hybrid search and spectral networking analysis, revealed spectral and chromatographic patterns useful for classification of unknown features, a subset of which were highly reproducible between labs. Overall, our method offers enhanced compound identification performance compared to targeted lipidomics, demonstrates the potential of harmonized methods to improve inter-site reproducibility for quantitation and feature alignment, and can serve as a reference to aid future annotation of untargeted lipidomics data.
Cognitive reserve counteracts typical neural activity changes related to ageing
Authors: Cespón Jesús , Chupina Irina , Carreiras Manuel 
Published: February 2023

AbstractStudies have shown that older adults with high Cognitive Reserve (HCR) exhibit better executive functioning than their low CR (LCR) counterparts. However, the neural processes linked to those differences are unclear. This study investigates (1) the neural processes underlying enhanced executive functions in older adults with HCR and (2) how executive control differences are modulated by task difficulty. We recruited 74 participants, who performed two executive control tasks with different difficulty levels while recording the electroencephalogram. The accuracy on both tasks requiring inhibition of irrelevant information was better in the HCR than the LCR group. Also, in the more demanding task, event-related potentials (ERP) latencies related to inhibition and working memory update were faster in HCR than LCR. Moreover, the HCR, but not the LCR, showed larger P300 amplitude in parietal than frontal regions and in the left than right hemisphere, suggesting a posterior to anterior shift of activity and loss of inter-hemispheric asymmetries in LCR participants. These results suggest that high CR counteracts neural activity changes related to ageing. Thus, high levels of CR can be related to maintenance of neural activity patterns typically observed in young adults rather than to deployment of neural compensatory mechanisms.
Near-optimal integration of the magnitude Information of time and numerosity
Authors: Otsuka Taku , Yotsumoto Yuko 
Published: February 2023

AbstractMagnitude information is often correlated in the external world, providing complementary information about the environment. As if to reflect this relationship, the perceptions of different magnitudes (e.g., time and numerosity) are known to influence one another. Recent studies suggest that such magnitude interaction is similar to cue integration, such as multisensory integration. Here, we tested whether human observers could integrate the magnitudes of two quantities with distinct physical units (i.e., time and numerosity) as abstract magnitude information. The participants compared the magnitudes of two visual stimuli based on time, numerosity, or both. Consistent with the predictions of the maximum likelihood estimation (MLE) model, the participants integrated time and numerosity in a near-optimal manner; the weights for numerosity increased as the reliability of the numerosity information increased, and the integrated estimate was more reliable than either the time or numerosity estimate. Furthermore, the integration approached a statistical optimum as the temporal discrepancy of the acquisition of each piece of information became smaller. These results suggest that magnitude interaction arises through a similar computational mechanism to cue integration. They are also consistent with the idea that different magnitudes are processed by a generalized magnitude system.
Corroborating age with oxygen isotope profiles in otoliths: consequences for estimation of growth, productivity and management reference points in northern pike (Esox lucius)in the southern Baltic Sea
Authors: Rittweg Timo D. , Trueman Clive , Ehrlich Elias , Wiedenbeck Michael , Arlinghaus Robert 
Published: February 2023

AbstractAccurate and precise age estimates are crucial for assessing the life-history of fish and providing management advice for fisheries, but age validation studies remain rare or absent in many species. Aging from scales is common, as it is non-lethal, but potential for underaging old fish exists. Using 85 northern pike (Esox lucius) collected from the southern Baltic Sea in Germany as a model, we corroborated age readings based on annual cycles of oxygen isotopes (δ18O) in otoliths to infer the timing and validity of growth, so as to compare results with visual age estimations from scales and otoliths. Otoliths were accurate and precise, while age readings from scales systematically underestimated the age of old pike. Fitting population-level von Bertalanffy growth models to the size-at-age data estimated viaδ18O-profiling, otoliths or scales revealed a larger terminal length (L∞) and a lower body growth coefficientkin scale-aged fish compared to otolith and corroborated age data. Populating an age-structured model with structure-specific growth model parameters demonstrated that the maximum sustainable yield (MSY) was estimated to be about 37% lower using scale-informed growth models relative to growth models fitted to corroborated and otolith-based size-at-age data. Thus, pike populations assessed and modeled based on scale age readings might appear less productive than they really are. Using scale-based ages to inform management regulations may therefore result in too conservative management and lost biomass yield, while instilling unrealistic angler expectations as to the trophy potential of the fishery.
Effect of crocin and treadmill exercise on oxidative stress and heart damage in diabetic rats
Authors: Pourmousavi Laleh , Asadi Rasoul Hashemkandi , Zehsaz Farzad , Jadidi Roghayeh Pouzesh 
Published: February 2023

AbstractObjectivein diabetes the production of free radicals and inflammatory agents in the heart tissue is increased and the expression of genes associated with the induction of apoptosis is altered. Considering the importance of common cardiovascular disorders in diabetes, this study investigated the effect of eight weeks of aerobic exercise and kerosene use alone, as well as tissue damage and oxidative stress caused by diabetes in the heart of adult rats.Materials and MethodsTo induce diabetes, streptozotocin 50 mg/kg was injected as a single dose intraperitoneally. After 72 hours, blood glucose levels were monitored by a glucometer, and blood glucose above 250 mg/dl was considered diabetes. Continuous treadmill exercise was performed for eight weeks by placing the animal on the treadmill. Next, the animals were anesthetized, and samples were taken from the hearts and frozen in liquid nitrogen. Then, superoxide dismutase (SOD), glutathione peroxidase (GPx), and malondialdehyde (MDA) were measured in the cardiac tissue. Finally, the hearts of half of the animals were immediately immersed in formalin solution for histological changes.ResultsAccording to our findings, diabetes increased lipid peroxidation, which was characterized by increased MDA levels in the control diabetes group and decreased SOD and GPx levels (P<0.05). It also changes the balance of expression of genes associated with apoptosis control, increased Bcl-2-associated X (Bax) expression, and decreased Bcl-2 expression (P <0.05). Also, we observed the induction of apoptosis in cardiac tissue. Using eight weeks of continuous exercise and administration of crocin significantly reduced blood sugar levels and lipid peroxidation and increased the activity of antioxidant enzymes and Bcl- 2 gene expression compared to the diabetes control group. In addition, continuous exercise and kerosene improved the oxidative stress parameters in the control group.ConclusionsThe results of this study showed that diabetes could cause oxidative stress and heart dysfunction. Moreover, simultaneously and separately, aerobic exercise with treadmill and crocin administration can reduce these disorders and prevent apoptosis in the heart tissue.
Benchmarking algorithms for joint integration of unpaired and paired single-cell RNA-seq and ATAC-seq data
Authors: Lee Michelle Y. Y. , Kaestner Klaus H. , Li Mingyao 
Published: February 2023

AbstractSingle-cell RNA-sequencing (scRNA-seq) measures gene expression in single cells, while single-nucleus ATAC-sequencing (snATAC-seq) enables the quantification of chromatin accessibility in single nuclei. These two data types provide complementary information for deciphering cell types/states. However, when analyzed individually, scRNA-seq and snATAC-seq data often produce conflicting results regarding cell type/state assignment. In addition, there is a loss of power as the two modalities reflect the same underlying cell types/states. Recently, it has become possible to measure both gene expression and chromatin accessibility from the same nucleus. Such paired data make it possible to directly model the relationships between the two modalities. However, given the availability of the vast amount of single-modality data, it is desirable to integrate the paired and unpaired single-modality data to gain a comprehensive view of the cellular complexity. Here, we benchmarked the performance of seven existing single-cell multi-omic data integration methods. Specifically, we evaluated whether these methods are able to uncover peak-gene associations from single-modality data, and to what extent the multiome data can provide additional guidance for the analysis of the existing single-modality data. Our results indicate that multiome data are helpful for annotating single-modality data, but the number of cells in the multiome data is critical to ensure a good cell type annotation. Additionally, when generating a multiome dataset, the number of cells is more important than sequencing depth for cell type annotation. Lastly, Seurat v4 is the best at integrating scRNA-seq, snATAC-seq, and multiome data even in the presence of complex batch effects.
Aryl hydrocarbon receptor knockout accelerates PanIN formation and fibro-inflammation in a mutantKras-driven pancreatic cancer model
Authors: Walcheck Morgan T. , Schwartz Patrick B. , Carrillo Noah D. , Matkowsky Kristina A. , Nukaya Manabu , Bradfield Christopher A. , Ronnekleiv-Kelly Sean M. 
Published: February 2023

ABSTRACTObjectivesThe pathogenesis of pancreas cancer (PDAC) remains poorly understood, hindering efforts to develop a more effective therapy for PDAC. Recent discoveries show the aryl hydrocarbon receptor (AHR) plays a crucial role in the pathogenesis of several cancers, and can be targeted for therapeutic effect. However, its involvement in PDAC remains unclear. Therefore, we evaluated the role of AHR in the development of PDACin vivo.MethodsWe created a global AHR-null, mutantKras-driven PDAC mouse model (A-/-KC) and evaluated the changes in PDAC precursor lesion formation (Pan-IN 1, 2, and 3) and associated fibro-inflammation between KC and A-/-KC at 5 months of age. We then examined the changes in the immune microenvironment followed by single-cell RNA-sequencing analysis to evaluate concomitant transcriptomic changes.ResultsWe found a significant increase in PanIN-1 lesion formation and PanIN-1 associated fibro-inflammatory infiltrate in A-/-KC vs KC mice. This was associated with significant changes in the adaptive immune system, particularly a decrease in the CD4+/CD8+ T-cell ratio, as well as a decrease in the T-regulatory/Th17 T-cell ratio suggesting unregulated inflammation.ConclusionThese findings show the loss of AHR results in heightenedKras-induced PanIN formation, through modulation of immune cells within the pancreatic tumor microenvironment.
Systematic comparison of temporal transcriptional responses to hepatotoxicants in primary human hepatocytes and HepaRG cells using concentration-response modelling of gene co-expression networks
Authors: Kunnen Steven J. , Arnesdotter Emma , Willenbockel Christian Tobias , Vinken Mathieu , van de Water Bob 
Published: February 2023

AbstractNext generation risk assessment of chemicals revolves around the use of mechanistic information without animal experimentation. In this regard, toxicogenomics has proven to be a useful tool to elucidate the underlying mechanisms of adverse effects of xenobiotics. In the present study, two widely used humanin vitrohepatocyte culture systems, namely primary human hepatocytes (PHH) and human hepatoma HepaRG cells, were exposed to liver toxicants known to induce liver cholestasis, steatosis or necrosis. Benchmark concentration-response modelling was applied to transcriptomics gene co-expression networks (modules) in order to derive benchmark concentrations (BMCs) and to gain mechanistic insight into the hepatotoxic effects. BMCs derived by concentration-response modelling of gene co-expression modules recapitulated concentration-response modelling of individual genes. Although PHH and HepaRG cells showed overlap in deregulated genes and modules by the liver toxicants, PHH demonstrated a higher responsiveness, based on the lower BMCs of co-regulated gene modules. Such BMCs can be used as point of departure (PoD) for assessing module-associated cellular (stress) pathways/processes. This approach identified clear PoDs of around Cmaxlevels for the tested drugs, while for cosmetics ingredients the BMCs were 10-100 fold higher than the estimated plasma concentrations. This approach could serve next generation risk assessment practice to identify early responsive modules at low BMCs, that could be linked to key events in liver adverse outcome pathways. In turn, this can assist in delineating potential hazards of new test chemicals usingin vitrosystems and used in a risk assessment when BMCs are paired with chemical exposure assessment.
A chemoproteomic platform for reactive fragment profiling against the deubiquitinases
Authors: Cookson Rosa , Vuorinen Aini , Pettinger Jonathan , Kennedy Cassandra R. , Kirkpatrick Joanna M. , Peltier-Heap Rachel E. , Powell Andrew , Snijders Ambrosius P. , Skehel Mark , House David , Rittinger Katrin , Bush Jacob T. 
Published: February 2023

SummaryChemoproteomics is a powerful method capable of detecting interactions between small molecules and the proteome, however its use as a high-throughput screening method for chemical libraries has so far been limited. To address this need, we have further developed a chemoproteomics workflow to screen cysteine reactive covalent fragments in cell lysates against the deubiquitinating (DUB) enzymes using activity-based protein profiling. By using targeted ubiquitin probes, we have addressed sensitivity and affinity limitations, enabling target identification and covalent fragment library profiling in a 96-well plate format. The use of data independent acquisition (DIA) methods for MS analysis combined with automated Evosep liquid chromatography (LC) reduced instrument runtimes to 21 minutes per sample and simplified the workflow. In this proof-of-concept study, we have profiled 138 covalent fragments against 57 DUB proteins and validated four hit fragments against OTUD7B and UCHL3 through site identification experiments and orthogonal biochemical activity assays.Graphical abstract
Environment Modulates Protein Heterogeneity Through Transcriptional and Translational Stop Codon Miscoding
Authors: Romero Romero Maria Luisa , Kirilenko Anastasiia , Poehls Jonas , Richter Doris , Jumel Tobias , Shevchenko Anna , Toth-Petroczy Agnes 
Published: February 2023

ABSTRACTStop codon miscoding events give rise to longer proteins, which may alter the protein’s function and thereby generate short-lasting phenotypic variability from a single gene.In order to systematically assess the frequency and origin of stop codon miscoding events, we designed a library of reporters. We introduced premature stop codons into mScarlet that enabled high-throughput quantification of protein synthesis termination errors inE.coliusing fluorescent microscopy. We found that under stress conditions, stop codon miscoding may occur with a rate as high as 80%, depending on the nucleotide context, suggesting that evolution frequently samples stop codon miscoding events. The analysis of selected reporters by mass spectrometry and RNA-seq showed that not only translation but also transcription errors contribute to stop codon miscoding. The RNA polymerase is more likely to misincorporate a nucleotide at premature stop codons. Proteome-wide detection of stop codon miscoding by mass spectrometry revealed that temperature regulates the expression of cryptic sequences generated by stop codon miscoding inE.coli.Overall, our findings suggest that the environment influences the accuracy of protein production, which increases protein heterogeneity when the organisms need to adapt to new conditions.
Unraveling the causal genes and transcriptomic determinants of human telomere length
Authors: Chang Ying , Zhou Yao , Zhou Junrui , Li Wen , Cao Jiasong , Shen Yongmei , Fan Xutong , Yang Hongxi , Dong Xiaobao , Zhang Shijie , Yi Xianfu , Shuai Ling , Shi Lei , Liu Zhe , Yang Jie , Hao Jihui , Chen Kexin , Huang Dandan , Wang Feng , Li Mulin Jun 
Published: February 2023

AbstractTelomere length (TL) shortening is a pivotal indicator of biological aging and is associated with many human diseases. The genetic determinates of human TL have been widely investigated, however, most existing studies were conducted based on adult tissues which are heavily influenced by lifetime exposure. Based on the analyses of terminal restriction fragment (TRF) length of telomere, individual genotypes, and gene expressions on 166 healthy placental tissues, we systematically interrogated TL-modulated genes and their potential functions. We found that placental TL is relatively longer across human tissues and which maintenance is mostly connected to genes responsible for alternative lengthening of telomeres. Trans-ancestral TL genome-wide association studies (GWASs) on 644,553 individuals identified 20 novel genetic associations and provided increased polygenic determination of human TL. Next, we integrated the powerful TL GWAS with placental expression quantitative trait locus (eQTL) mapping to prioritize 31 likely causal genes, among which 4 were functionally validated, includingMMUT, RRM1, KIAA1429, andYWHAZ. Finally, modeling transcriptomic signatures and TRF-based TL improved the prediction performance of human TL. This study deepened our understanding of causal genes and transcriptomic determinants of human TL, promoting the mechanistic research on fine-grained TL regulation.
The role of cuticular hydrocarbons in intraspecific aggression in the invasive antCardiocondyla obscurior
Authors: Drakula Maja , Buellesbach Jan , Schrader Lukas 
Published: February 2023

AbstractCuticular hydrocarbons (CHCs) are important cues for nestmate discrimination and intraspecific aggression in ants. In invasive ants, diminished CHC profile diversity is suspected to contribute to the ecological and evolutionary success of populations by reducing intraspecific aggression between colonies. The antCardiocondyla obscuriorhas successfully colonized habitats around the world, reaching high local population densities. However, despite being invasive, colonies still react aggressively against each other, especially in interactions with non-nestmate alate queens. Here, we study whether CHCs are relevant for antagonistic interactions in this species, by combining behavioral experiments with gas-chromatography coupled with mass spectrometry (GC-MS). We show that queen and worker CHC profiles show pronounced quantitative as well as qualitative differences, that queens with depleted CHC profiles receive virtually no aggression from non-nestmates, and that aggression levels are positively correlated with the naturally occurring CHC profile differences between colonies. These findings provide first empirical evidence for a role of CHCs and chemical diversity in antagonistic behaviors against foreign queens in this species. They further suggest that invasive populations ofC. obscuriorare multicolonial and polydomous.
Role of Complementarity-Determining Regions 1 and 3 in Pathologic Amyloid Formation by Human Immunoglobulin κ1 Light Chains
Authors: Klimtchuk Elena S. , Peterle Daniele , Bullitt Esther A. , Connors Lawreen H. , Engen John R. , Gursky Olga 
Published: February 2023

AbstractImmunoglobulin light chain (LC) amyloidosis is a life-threatening disease whose understanding and treatment is complicated by vast numbers of patient-specific mutations. To address molecular origins of the disease, we explored 14 patient-derived and engineered proteins related to κ1-family germline genes IGKVLD-33*01 and IGKVLD-39*01. Hydrogen-deuterium exchange mass spectrometry analysis of local conformational dynamics in full-length recombinant LCs and their fragments was integrated with studies of thermal stability, proteolytic susceptibility, amyloid formation, and amyloidogenic sequence propensities using spectroscopic, electron microscopic and bioinformatics tools. The results were mapped on the atomic structures of native and fibrillary proteins. Proteins from two κ1 subfamilies showed unexpected differences. Compared to their germline counterparts, amyloid LC related to IGKVLD-33*01 was less stable and formed amyloid faster, whereas amyloid LC related to IGKVLD-39*01 had similar stability and formed amyloid slower. These and other differences suggest different major factors influencing amyloid formation. In 33*01-related amyloid LC, these factors involved mutation-induced destabilization of the native structure and probable stabilization of amyloid. The atypical behaviour of 39*01-related amyloid LC tracked back to increased dynamics/exposure of amyloidogenic segments in βC’Vand βEVthat could initiate aggregation, combined with decreased dynamics/exposure near the Cys23-Cys88 disulfide whose rearrangement is rate-limiting to amyloidogenesis. The results suggest distinct amyloidogenic pathways for closely related LCs and point to the antigen-binding, complementarity-determining regions CDR1 and CDR3, which are linked via the conserved internal disulfide, as key factors in amyloid formation by various LCs.