bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification and Integration of Key-Metabolic Reactions from Untargeted Metabolomics
Authors: Köhler Nikolai , Würf Vivian , Rose Tim D. , Pauling Josch K. 
Published: May 2023

AbstractMetabolomics has become increasingly popular in biological and biomedical research, especially for multi-omics studies, due to the many associations of metabolism with diseases. This development is driven by improvements in metabolite identification and generating large amounts of data, increasing the need for computational solutions for data interpretation. In particular, only few computational approaches directly generating mechanistic hypotheses exist, making the biochemical interpretation of metabolomics data difficult. We presentmantra, an approach to estimate how metabolic reactions change their activity between biological conditions without requiring absolute quantification of metabolites. Starting with a data-specific metabolic network we utilize linear models between substrates and products of a metabolic reaction to approximate deviations in activity. The obtained estimates can subsequently be used for network enrichment and integration with other omics data. By applyingmantrato untargeted metabolomics measurements of Triple-Negative Breast Cancer biopsies, we show that it can accurately pinpoint biomarkers. On a dataset of stool metabolomics from Inflammatory Bowel Disease patients, we demonstrate that predictions on our proposed reaction metric generalize to an independent validation cohort and that it can be used for multi-omics network integration. By allowing mechanistic interpretation we facilitate knowledge extraction from metabolomics experiments.
In situ Quantification of Biomolecular Concentration of Cytoplasmic Membraneless Organelles in a Living Cell
Authors: Shibuya Ren , Kajimoto Shinji , Yaginuma Hideyuki , Ariyoshi Tetsuro , Okada Yasushi , Nakabayashi Takakazu 
Published: May 2023

ABSTRACTLiquid droplets formed via intracellular Liquid–liquid phase separation (LLPS) are called membraneless organelles and provide enzymatic reaction fields for maintaining cellular homeostasis, while they can be sources of protein aggregates and fibrils, causing neurodegenerative diseases. To understand the nature of intracellular liquid droplets, it is essential to quantify liquid droplets inside a living cell. Here, we performed near-IR fluorescence and Raman imaging to quantify chemical components inside stress granules (SGs) formed via LLPS in living cells under oxidative stress. The Raman images of stressed cells indicate the concentration of nucleic acids in the SGs was 20% higher than surrounding cytoplasm, while the lipid concentration was lower. The intensity of biomolecular C–H bands relative to the water band shows the net concentration of biomolecules was almost the same inside and outside the SGs, indicating intracellular droplets are not highly condensed, but the crowding environments are similar to the surroundings.TOC GRAPHICS
Diffusion Tensor Imaging: Influence of segmentation on fiber tracking in the supraspinatus muscle – an inter-operator reliability analysis
Authors: Vetter Sebastian , Köhler Hans-Peter , Hepp Pierre , Steinke Hanno , Schleifenbaum Stefan , Theopold Jan , Kiem Simon , Witt Maren , Henkelmann Jeanette , Roth Christian 
Published: May 2023

AbstractThe ability of muscle to generate force depends on its architecture and quality. MR-based diffusion tensor imaging of muscle (mDTI) is an innovative approach for showing the fiber arrangement for the whole muscle volume. For accurate calculations of fiber metrics, muscle segmentation prior to tractography seems mandatory. Since segmentation is known to be operator dependent, it is important to understand how segmentation affects tractography. The aim of this study was to compare the results of deterministic fiber tracking based on muscle models generated by two independent operators. In addition, this study compares the results with a segmentation-free approach. Fifteen subjects underwent mDTI of the right shoulder. The results showed that mDTI can be successfully applied to complex joints such as the human shoulder. Furthermore, operators segmentation did not influence the results of fiber tracking and showed excellent intraclass correlation estimates (≥ 0.975). As an exploratory approach, the segmentation-free fiber tracking showed significant differences in terms of mean fascicle length. Based on these findings, we assume that tractography does not require a detailed muscle segmentation. Furthermore, it implies that mDTI and automatic segmentation approaches or even a segmentation-free analysis can be considered for evaluation of muscle changes.
Spectral consistency in sound sequence affects perceptual accuracy in discriminating subdivided rhythmic patterns
Authors: Nitta Jun , Kondoh Sotaro , Okanoya Kazuo , Tachibana Ryosuke O. 
Published: May 2023

AbstractMusical compositions are distinguished by their unique rhythmic patterns, determined by subtle differences in how regular beats are subdivided. Precise perception of these subdivisions is essential for discerning nuances in rhythmic patterns. While musical rhythm typically comprises sound elements with a variety of timbres or spectral cues, the impact of such spectral variations on the perception of rhythmic patterns remains unclear. Here, we show that consistency in spectral cues affects perceptual accuracy in discriminating subdivided rhythmic patterns. We conducted online experiments using rhythmic sound sequences consisting of band-passed noise bursts to measure discrimination accuracy. Participants were asked to discriminate between a swing-like rhythm sequence, characterized by a 2:1 interval ratio, and its more or less exaggerated version. This task was also performed under two additional rhythm conditions: inversed-swing rhythm (1:2 ratio) and regular subdivision (1:1 ratio). The center frequency of the band noises was either held constant or alternated between two values. Our results revealed a significant decrease in discrimination accuracy when the center frequency was alternated, irrespective of the rhythm ratio condition. This suggests that rhythm perception is not only shaped by temporal structure but also affected by spectral properties.
Sorting receptor SORCS2 facilitates a protective stress response in pancreatic islets
Authors: Kalnytska Oleksandra , Qvist Per , Kunz Séverine , Conrad Thomas , Willnow Thomas E. , Schmidt Vanessa 
Published: May 2023

ABSTRACTObjectiveSORCS2 is an intracellular sorting receptor genetically associated with body mass index (BMI) in humans, yet its mode of action remains unknown. Elucidating the receptor function that defines its role in metabolic health is the objective of this work.MethodsCombiningin vivometabolic studies in SORCS2-deficient mouse models withex vivostructural and functional analyses as well as single-cell transcriptomics of murine pancreatic tissues, we studied the pathophysiological consequences of receptor dysfunction for metabolism.ResultsOur studies identified an important role for SORCS2 in islet stress response essential to sustain glucose-stimulated insulin release. In detail, we show that SORCS2 is predominantly expressed in islet alpha cells. Loss of receptor expression coincides with the inability of these cells to produce osteopontin, a secreted factor that facilitates insulin release from beta cells under stress. In line with diminished osteopontin levels, beta cells in SORCS2- deficient islets show changes in gene expression patterns related to aggravated ER stress, protein misfolding, as well as mitochondrial dysfunction; and they exhibit defects in insulin granule maturation and a blunted response to glucose stimulationin vivoandex vivo. Impaired glucose tolerance in receptor mutant mice coincides with alterations in body weight and composition.ConclusionOur data identified a novel concept in protective islet stress response involving the alpha cell receptor SORCS2 and provide experimental support for association ofSORCS2with metabolic control in humans.
New Curcuphenol Analogues Possess Anti-Metastatic Biological Activity
Authors: Ellis Samantha L.S. , Nohara Lilian L. , Dada Sarah , Saranchova Iryna , Munro Lonna , Choi Kyung Bok , Garrovillas Emmanuel , Pfeifer Cheryl G. , Williams David E. , Cheng Ping , Andersen Raymond J. , Jefferies Wilfred A. 
Published: May 2023

AbstractFor eons, turmeric and curcumin have been used as culinary spices and as traditional medicines and as vogue dietary supplements for a growing list of disorders, including arthritis, digestive disorders, respiratory infections, allergies, liver disease, depression and cancer. The activities of these spices are commonly attributed to curcuminoids; however, the medical applications of this class of compounds has been limited due to the low water solubility, chemical instability, acid lability, poor absorption, rapid catabolism by enzymes of the diverse curcuminoids contained in turmeric and curcumin extracts. Furthermore, identifying the bio-active curcuminoids with unique molecular entities responsible for specific medicinal benefit is at its infancy. To overcome these many issues and substantially advance this area of inquiry, we created a water-soluble achiral curcuphenol analogue and a water-soluble racemic analogue that have enhanced chemical characteristics and biological performance, and we subsequently demonstrated their ability to reverse the immune-escape phenotype, a process that enables tumours to hide from host immune responses and thereby provides tumours a significant growth advantage to metastatic tumours. The discovery that curcuphenols can reverse tumour immune-escape mechanisms and thereby reduce tumour growth, provides a rationale for the development of advanced dissecting nutraceuticals and bioceuticals for unique chemical entities as therapeutic building blocks to synthesize analogues with optimal chemical characteristics capable of harnessing the power of the immune system to extinguish metastatic cancers and beyond.
The transcription factor DksA exerts opposing effects on cell division depending on the presence of ppGpp
Authors: Anderson Sarah E. , Vadia Stephen E. , McKelvy Jane , Levin Petra Anne 
Published: May 2023

AbstractBacterial cell size is a multifactorial trait that is influenced by variables including nutritional availability and the timing of cell division. Prior work revealed a negative correlation between the alarmone (p)ppGpp (ppGpp) and cell length inEscherichia coli, suggesting that ppGpp may promote assembly of the division machinery (divisome) and cytokinesis in this organism. To clarify this counterintuitive connection between a starvation induced stress response effector and cell proliferation, we undertook a systematic analysis of growth and division inE. colicells defective in ppGpp synthesis and/or engineered to overproduce the alarmone. Our data indicate that ppGpp acts indirectly on divisome assembly through its role as a global mediator of transcription. Loss of either ppGpp (ppGpp0) or the ppGpp-associated transcription factor DksA led to increased average length, with ppGpp0mutants also exhibiting a high frequency of extremely long filamentous cells. Using heat-sensitive division mutants and fluorescently labeled division proteins, we confirmed that ppGpp and DksA are cell division activators. We found that ppGpp and DksA regulate division through their effects on transcription, although the lack of known division genes or regulators in available transcriptomics data strongly suggests that this regulation is indirect. Surprisingly, we also found that DksA inhibits division in ppGpp0cells, contrary to its role in a wild-type background. We propose that the ability of ppGpp to switch DksA from a division inhibitor to a division activator helps tune cell length across different concentrations of ppGpp.ImportanceCell division is a key step in the bacterial lifecycle that must be appropriately regulated to ensure survival. This work identifies the alarmone ppGpp as a general regulator of cell division, extending our understanding of the role of ppGpp beyond a signal for starvation and other stress. Even in nutrient replete conditions, basal levels of ppGpp are essential for division to occur appropriately and for cell size to be maintained. This study establishes ppGpp as a “switch” that controls whether the transcription factor DksA behaves as a division activator or inhibitor. This unexpected finding enhances our understanding of the complex regulatory mechanisms employed by bacteria to coordinate division with diverse aspects of cell growth and stress response. Because division is an essential process, a better understanding the mechanisms governing assembly and activation of the division machinery could contribute to the development of novel therapeutics to treat bacterial infections.
Stability Oracle: A Structure-Based Graph-Transformer for Identifying Stabilizing Mutations
Authors: Diaz Daniel J. , Gong Chengyue , Ouyang-Zhang Jeffrey , Loy James M. , Wells Jordan , Yang David , Ellington Andrew D. , Dimakis Alex , Klivans Adam R. 
Published: May 2023

AbstractStabilizing proteins is a fundamental challenge in protein engineering and is almost always a prerequisite for the development of industrial and pharmaceutical biotechnologies. Here we present Stability Oracle: a structure-based graph-transformer framework that achieves state-of-the-art performance on predicting the effect of a point mutation on a protein’s thermodynamic stability (ΔΔG). A strength of our model is its ability to identifystabilizingmutations, which often make up a small fraction of a protein’s mutational landscape. Our framework introduces several data and machine learning innovations to overcome well-known challenges in data scarcity and bias, generalization, and computation time. Stability Oracle is first pretrained on over 2M masked microenvironments and then fine-tuned using a novel data augmentation technique, Thermodynamic Permutations (TP), applied to a ∼120K curated subset of the mega-scale cDNA display proteolysis dataset. This technique increases the original 120K mutations to over 2M thermodynamically valid ΔΔG measurements to generate the first structure training set that samples and balances all 380 mutation types. By using the masked microenvironment paradigm, Stability Oracle does not require a second mutant structure and instead uses amino acid structural embeddings to represent a mutation. This architectural design accelerates training and inference times: we can both train on 2M instances with just 119 structures and generate deep mutational scan (DMS) predictions from only the wildtype structure. We benchmark Stability Oracle with both experimental and AlphaFold structures of all proteins on T2837, a test set that aggregates the common test sets (SSym, S669, p53, and Myoglobin) with all additional experimental data from proteins with over a 30% sequence similarity overlap. We used TP augmented T2837 to evaluate performance for engineering protein stability: Stability Oracle correctly identifies 48% of stabilizing mutations (ΔΔG < −0.5 kcal/mol) and 74% of its stabilizing predictions are indeed stabilizing (18% and 8% of predictions were neutral and destabilizing, respectively). For a fair comparison between sequence and structure-based fine-tuned deep learning models, we build on the Prostata framework and fine-tune the sequence embeddings of ESM2 on our training set (Prostata-IFML). A head-to-head comparison demonstrates that Stability Oracle outperforms Prostata-IFML on regression and classification even though the model is 548 times smaller and is pretrained with 4000 times fewer proteins, highlighting the advantages of learning from structures.
The p97/VCP adapter UBXD1 drives AAA+ remodeling and ring opening through multi-domain tethered interactions
Authors: Braxton Julian R. , Altobelli Chad R. , Tucker Maxwell R. , Tse Eric , Thwin Aye C. , Arkin Michelle R. , Southworth Daniel R. 
Published: May 2023

ABSTRACTp97/VCP is an essential cytosolic AAA+ ATPase hexamer that extracts and unfolds substrate polypeptides during protein homeostasis and degradation. Distinct sets of p97 adapters guide cellular functions but their roles in direct control of the hexamer are unclear. The UBXD1 adapter localizes with p97 in critical mitochondria and lysosome clearance pathways and contains multiple p97-interacting domains. We identify UBXD1 as a potent p97 ATPase inhibitor and report structures of intact p97:UBXD1 complexes that reveal extensive UBXD1 contacts across p97 and an asymmetric remodeling of the hexamer. Conserved VIM, UBX, and PUB domains tether adjacent protomers while a connecting strand forms an N-terminal domain lariat with a helix wedged at the interprotomer interface. An additional VIM-connecting helix binds along the second AAA+ domain. Together these contacts split the hexamer into a ring-open conformation. Structures, mutagenesis, and comparisons to other adapters further reveal how adapters containing conserved p97-remodeling motifs regulate p97 ATPase activity and structure.
Developing and testing a social media-based intervention for improving business skills and income levels of young smallholder farmers
Authors: Gever Verlumun Celestine , Abdullah Nabaz Nawzad , Onakpa Mohammed Shaibu , Onah Ogochukwu Gabriella , Onyia Chukwuemeka Chiebonam , Iwundu Ifeanyi E. , Gever Esther Rita 
Published: May 2023

PurposeThis study aimed to develop and test the impact of a social media-based intervention for improving the business skills and income of young smallholder farmers.Design/methodology/approachFirst, the researchers used an exploratory approach to develop a social media-based intervention for acquiring business skills and improving income. Second, the researchers tested the effectiveness of the developed programme on a sample of 506 young smallholder farmers. Finally, the intervention and data collection took place over five years (2017–2021).FindingsThe result showed steady improvements in business skills and income from 2017 to 2021 for the treatment group, unlike the control group. Also, improvements in business skills led to a reduction in expenses and an increase in profit from 2017 to 2021. A further evaluation of the result showed that an addition of 5.1 mean scores in business skills led to the addition of $91 income between 2017 and 2018; for 2018–2019, 2.6 improvements in business skills increased income by $123. For 2019–2020, a 2.7 improvement increased income by $209, whilst for 2020–2021, a 1.6 improvement increased income by $320.Originality/valueThe results of this study could help explore ways of using social media to change behaviour aimed at improving income amongst young smallholder farmers.
Is critical thinking a future skill for business success: science mapping and literature review
Authors: Skrzek-Lubasińska Małgorzata , Malik Radosław 
Published: May 2023

PurposeThis article aims to review critical thinking (CT) as a future skill in business.Design/methodology/approachThe study employed two research methods: science mapping analysis based on bibliometric keyword co-occurrence data and systematic literature review following PRISMA guidelines. The application of two distinctive research methods meant that we could obtain a broad picture thematic overview as well as a detailed, fine-grained insight into the content of CT business research.FindingsResearch in CT in business studies is dominated by themes related to education, university and learning that far outweigh CT business application, which focuses on three research axes. These are specific business functions (e.g. accounting, marketing, human resources and identifying business opportunities), certain skills used in business (e.g. decision-making and creativity) and other business-related topics (including ethics, stakeholder relations and individual employee performance).Practical implicationsThe article identifies new research gaps related to the link between CT and business performance, a firm’s ability to innovate and company characteristics. Moreover, the article highlights that CT positively influences business decision-making under the influence of cognitive biases and heuristics.Originality/valueThe article provides the first literature review on CT in business research. It uses a novel method of science mapping analysis to show unbiased algorithmic-based insight into the structure of the research, followed by a systematic literature review.
The importance of being … transnational
Authors: Ietto-Gillies Grazia 
Published: May 2023

Purpose
The paper takes the lead from Forsgren and Yamin (2022), “The MNE as the ‘crown of creation’?: A commentary on mainstream theories of multi-national enterprises”, and accepts that the MNE can, indeed, be seen as the “crown of creation” in the world of business. The purpose of the paper is to show that this is due to advantages of multi/transnationality that must be sought outside rather than within the firm itself.

Design/methodology/approach
The paper argues that the advantages of multi-nationality derive from the differences in regulatory regimes between nation-states and, specifically, from laws and regulations regarding the following: labour and social security, industrial policy, taxation and environmental regulations. Some examples are given.

Findings
It is claimed that the transnational company (TNC) has the ability to operate as a unified centre of strategic decision-making, and this gives it an advantage compared to operators it bargains with who do not possess such ability. Three such operators are discussed: labour, governments of nation-states and suppliers. In TNCs’ operations with foreign countries, a distinction is made between the spatial dimension and the regulatory regimes dimension. The interaction between these two dimensions leads to discussions on: regions within nation-states and their regulatory regimes, global value chains (GVCs) and free/investment zones (F/IZs). The conclusions draw policy implications and research agenda implications touching also on issues of TNCs as creator/destructors of social values.

Research limitations/implications
The paper refers to other published work by the author – solo or as co-author – where the arguments are further developed, including the finding of a detailed case study. There are policy implications regarding labour and its trade unions (TUs) as well governments and their taxation and industrial policies. Details of such policies need further development.

Practical implications
There are implications for theory development, policies and for research agendas.

Social implications
Governments of nation-states and institutions within them – such as TUs – should try to co-ordinate rather than compete with each other in their bargaining with transnational companies. The breakaway of regions within nation-states further increases the power of TNCs.

Originality/value
In the development of theories of the TNC, this work shifts the focus from internal characteristics within the firm and its markets to external ones: to the nation-states as jurisdictional loci. The distinction between spatial and regulatory regimes dimensions in dealing with transnational activities allows a novel viewpoint on: regions, GVCs and IZs. A novel viewpoint is also given in relation to the role of TNCs in social value.