bluuebunny/crossref_metadata_2025_split huggingface dataset:
Insulin docking within the open hemichannel of connexin 43 may reduce risk of amyotrophic lateral sclerosis
Authors: Lehrer Steven , Rheinstein Peter H. 
Published: May 2022

AbstractBackgroundType 2 diabetes (T2D), characterized by hyperinsulinemia, protects motor neurons against amyotrophic lateral sclerosis (ALS). Type 1 diabetes and a total lack of insulin are associated with increased risk of ALS. Connexin 43 (Cx43), an astrocyte protein, operates as an open pore via which toxic substances from the astrocytes reach the motor neurons.MethodsIn the current study we performed molecular docking of insulin with monomeric Cx31, monomeric Cx43, and hexameric Cx31 to assess whether insulin might affect the pore. Hexameric Cx31 and hexameric Cx43 have hemichannels composed of 6 subunits that work as transmembrane channels, binding together to form gap junction intercellular channels that open and close. We used the program AutoDock Vina Extended for the molecular docking study.ResultsCx31 shares amino acid and structural similarity to Cx43 and insulin docks to the same position of the N-terminal domain of monomeric Cx31 and monomeric Cx43. Insulin docks within the open hemichannel of hexameric Cx31, potentially blocking it. The block may be responsible for the protective relationship of T2D to ALS.ConclusionInsulin, especially intranasal insulin, might be a treatment for ALS. An insulin secretogogue such as oral sulfonylurea or glinide might also be of value.
Atomic protein structure refinement using all-atom graph representations and SE(3)-equivariant graph neural networks
Authors: Wu Tianqi , Cheng Jianlin 
Published: May 2022

AbstractThree-dimensional (3D) protein structures reveal the fundamental information about protein function. The state-of-art protein structure prediction methods such as Alphafold are being widely used to predict structures of uncharacterized proteins in biomedical research. There is a significant need to further improve the quality and nativeness of the predicted structures to enhance their usability. Current machine learning methods of refining protein structures focus mostly on improving the backbone quality of predicted structures without effectively leveraging and enhancing the conformation of all atoms including side-chain, while molecular simulation methods are computationally intensive and time-consuming.In this work, we develop ATOMRefine, a deep learning-based, end-to-end, all-atom protein structural model refinement method. It uses a SE(3)-equivariant graph transformer network that is equivariant to the rotation and translation of 3D structures in conjunction with a novel graph representation of all atoms to directly refine protein atomic coordinates of all the atoms in a predicted tertiary structure represented as a molecular graph. The method is first trained and tested on the structural models in AlphafoldDB whose experimental structures are known, and then blindly tested on 69 CASP14 regular targets and 7 CASP14 refinement targets. ATOMRefine improves the quality of both backbone atoms and all-atom conformation of the initial structural models generated by AlphaFold. It also performs better than the state-of-the-art refinement methods in multiple evaluation metrics including an all-atom model quality score – the MolProbity score based on the analysis of all-atom contacts, bond length, atom clashes, torsion angles, and side-chain rotamers. As ATOMRefine can refine a protein structure quickly, it provides a viable, fast solution for improving protein geometry and fixing structural errors of predicted structures through direct coordinate refinement.
New hypotheses of cell type diversity and novelty from comparative single cell and nuclei transcriptomics in echinoderms
Authors: Meyer Anne , Ku Carolyn , Hatleberg William , Telmer Cheryl A. , Hinman Veronica 
Published: May 2022

AbstractCell types are the fundamental building blocks of metazoan biodiversity and offer a powerful perspective for inferring evolutionary phenomena. With the development of single-cell transcriptomic techniques, new definitions of cell types are emerging. This allows a conceptual reassessment of traditional definitions of novel cell types and their evolution. Research in echinoderms, particularly sea star and sea urchin embryos have contributed significantly to understanding the evolution of novel cell types, in particular the primary mesenchyme cells (PMCs) and pigment cells that are found in sea urchin but not sea star embryos. This paper outlines the development of a gene expression atlas for the bat star, Patiria miniata, using single nuclear RNA sequencing (snRNA-seq) of embryonic stages. The atlas revealed 22 cell clusters covering all expected cell types from the endoderm, mesoderm and ectoderm germ layers. In particular, four distinct neural clusters, an immune cluster, and distinct right and left coelom clusters were revealed as distinct cell states. A comparison with Strongylocentrotus purpuratus embryo single cell transcriptomes was performed using 1:1 orthologs to anchor and then compare gene expression patterns. S. purpuratus primordial germ cell equivalents were not detected in P. minata, while the left coelom of P. miniata has no equivalent cell cluster in S. purpuratus. Pigment cells of S. purpuratus map to clusters containing immune mesenchyme and neural cells of P. miniata, while the PMCs of S. purpuratus are revealed as orthologous to the right coelom cluster of P. miniata. These results suggest a new interpretation of the evolution of these well-studied cell types and a reflection on the definition of novel cell types.
Effects of anti-fibrotic standard of care drugs on senescent human lung fibroblasts
Authors: Garcia Stephanie B. , Hohmann Miriam S. , Coelho Ana Lucia , Verri Waldiceu A. , Hogaboam Cory M. 
Published: May 2022

AbstractRationaleCellular senescence is crucial in the progression of idiopathic pulmonary fibrosis (IPF), but it is yet unclear whether the standard-of-care (SOC) drugs nintedanib and pirfenidone have senolytic properties.ObjectivesWe attempted to illuminate the effects of SOC drugs on senescent normal and IPF lung fibroblasts in vitro.MethodsColorimetric/fluorimetric assays, qRT-PCR, and western blotting were used to evaluate the effect of SOC drugs on senescent normal and IPF lung fibroblasts.ResultsSOC drugs did not induce apoptosis in the absence of death ligands in either normal or IPF senescent cells. Nintedanib increased caspase-3 activity in the presence of Fas Ligand (FasL) in normal but not in IPF senescent fibroblasts. Conversely, nintedanib enhanced B cell lymphoma (Bcl)-2 expression in senescent IPF lung fibroblasts. Moreover, in senescent IPF cells, pirfenidone alone induced mixed lineage kinase domain-like pseudokinase (MLKL) phosphorylation, provoking necroptosis. However, fragmented gasdermin D, indicating pyroptosis, was not detected under any condition. In addition, SOC drugs increased transcript levels of fibrotic and senescence markers in senescent IPF fibroblasts, whereas D+Q inhibited all these markers. Finally, D+Q enhanced growth differentiation factor 15 (GDF15) transcript and protein levels in both normal and IPF senescent fibroblasts.ConclusionsIn the presence and absence of the extrinsic pro-apoptotic ligands, SOC drugs failed to trigger apoptosis in senescent fibroblasts, possibly due to enhanced Bcl-2 levels and the activation of the necroptosis pathway. SOC drugs elevated fibrotic and senescence markers in IPF lung fibroblasts. Together, these data demonstrated the inefficacy of SOC in targeting senescent cells. Further investigation is required to fully elucidate the therapeutic implications of SOC drugs on other senescent cell types in IPF.
Heterologous expression of a lycophyte protein enhances angiosperm seedling vigor
Authors: Koh Samuel W.H. , Bascom Carlisle S. , Berenguer Eduardo , Ingram Gwyneth , Estelle Mark , Hardtke Christian S. 
Published: May 2022

AbstractSeedling vigor is a key agronomic trait that determines juvenile plant performance. Angiosperm seeds develop inside fruits and are connected to the mother plant through vascular tissues. Their formation requires plant-specific genes, such as BREVIS RADIX (BRX) in Arabidopsis thaliana roots. BRX family proteins are found throughout the angiosperms but also occur in non-vascular bryophytes and non-seed lycophytes. They consist of four conserved domains, including the tandem “BRX-domains”. We found that bryophyte or lycophyte BRX homologs can only partially substitute for Arabidopsis BRX (AtBRX) because they miss key features in the linker between the BRX-domains. Intriguingly however, expression of a BRX homolog from the lycophyte Selaginella moellendorffii (SmBRX) in A. thaliana wildtype background confers robustly enhanced root growth vigor that persists throughout the life cycle. This effect can be traced back to a substantial increase in seed and embryo size, and can be reproduced with a modified, “SmBRX-like” variant of AtBRX. Our results thus suggest that BRX variants could serve as biotechnological tools to boost seedling vigor and shed light on the activity of ancient, non-angiosperm BRX family proteins.
Replicative Instability Drives Cancer Progression
Authors: Morris Benjamin B. , Smith Jason P. , Zhang Qi , Jiang Zhijie , Hampton Oliver A. , Churchman Michelle L. , Arnold Susanne M. , Owen Dwight H. , Gray Jhanelle E. , Dillon Patrick M. , Soliman Hatem H. , Stover Daniel G. , Colman Howard , Chakravarti Arnab , Shain Kenneth H. , Silva Ariosto S. , Villano John L. , Vogelbaum Michael A. , Borges Virginia F. , Akerley Wallace L. , Gentzler Ryan D. , Hall Richard D. , Matsen Cindy B. , Ulrich C. M. , Post Andrew R. , Nix David A. , Singer Eric A. , Larner James M. , Stukenberg P. Todd , Jones David R. , Mayo Marty W. 
Published: May 2022

AbstractIn the past decade, defective DNA repair has been increasingly linked with cancer progression. Human tumors with markers of defective DNA repair and increased replication stress have been shown to exhibit genomic instability and poor survival rates across tumor types. Here we utilize-omics data from two independent consortia to identify the genetic underpinnings of replication stress, therapy resistance, and primary carcinoma to brain metastasis in BRCA wildtype tumors. In doing so, we have defined a new pan-cancer class of tumors characterized by replicative instability (RIN). RIN is defined by genomic evolution secondary to replicative challenge. Our data supports a model whereby defective single-strand break repair, translesion synthesis, and non-homologous end joining effectors drive RIN. Collectively, we find that RIN accelerates cancer progression by driving copy number alterations and transcriptional program rewiring that promote tumor evolution.Statement of SignificanceDefining the genetic basis of genomic instability with wildtype BRCA repair effectors is a significant unmet need in cancer research. Here we identify and characterize a pan-cancer cohort of tumors driven by replicative instability (RIN). We find that RIN drives therapy resistance and distant metastases across multiple tumor types.
Messenger-RNA Modification Standards and Machine Learning Models Facilitate Absolute Site-Specific Pseudouridine Quantification
Authors: Makhamreh Amr , Tavakoli Sepideh , Gamper Howard , Nabizadehmashhadtoroghi Mohammad , Fallahi Ali , Hou Ya-Ming , Rouhanifard Sara H. , Wanunu Meni 
Published: May 2022

AbstractEnzyme-mediated chemical modifications to mRNA are important for fine-tuning gene expression, but they are challenging to quantify due to low copy number and limited tools for accurate detection. Existing studies have typically focused on the identification and impact of adenine modifications on mRNA (m6A and inosine) due to the availability of analytical methods. The pseudouridine (Ψ) mRNA modification is also highly abundant but difficult to detect and quantify because there is no available antibody, it is mass silent, and maintains canonical basepairing with adenine. Nanopores may be used to directly identify Ψ sites in RNAs using a systematically miscalled base, however, this approach is not quantitative and highly sequence dependent. In this work, we apply supervised machine learning models that are trained on sequence-specific, synthetic controls to endogenous transcriptome data and achieve the first quantitative Ψ occupancy measurement in human mRNAs. Our supervised machine learning models reveal that for every site studied, different signal parameters are required to maximize Ψ classification accuracy. We show that applying our model is critical for quantification, especially in low-abundance mRNAs. Our engine can be used to profile Ψ-occupancy across cell types and cell states, thus providing critical insights about physiological relevance of Ψ modification to mRNAs.
Independent regulation of mtDNA quantity and quality resets the mitochondrial genome in C. elegans primordial germ cells
Authors: Schwartz Aaron Z.A. , Tsyba Nikita , Abdu Yusuff , Patel Maulik R. , Nance Jeremy 
Published: May 2022

AbstractMitochondria contain an independent genome, called mtDNA, which contains essential metabolic genes. Although mtDNA mutations occur at high frequency, they are inherited infrequently, indicating that germline mechanisms limit their accumulation. To determine how germline mtDNA is regulated, we examined the control of mtDNA quantity and quality in C. elegans primordial germ cells (PGCs). We show that PGCs generate a bottleneck in mtDNA number by segregating mitochondria into lobe-like protrusions that are cannibalized by adjacent cells, reducing mtDNA content two-fold. As PGCs exit quiescence and divide, mtDNAs replicate to maintain a set point of ∼200 mtDNAs per germline stem cell. Whereas PGC lobe cannibalism eliminates mtDNAs stochastically, we show that the kinase PINK1, operating independently of Parkin and autophagy, preferentially reduces the fraction of mutant mtDNAs. Thus, PGCs employ parallel mechanisms to control both the quantity and quality of the founding population of germline mtDNAs.
Draft genome of six Cuban Anolis lizards and insights into genetic changes during the diversification
Authors: Kanamori Shunsuke , Díaz Luis M. , Cádiz Antonio , Yamaguchi Katsushi , Shigenobu Shuji , Kawata Masakado 
Published: May 2022

AbstractThe detection of various type of genomic variants and their accumulation processes during species diversification and adaptive radiation is important for understanding the molecular and genetic basis of evolution. Anolis lizards in the West Indies are good models for studying the mechanism of the evolution because of the repeated evolution of their morphology and the ecology. In this study, we performed de novo genome assembly of six Cuban Anolis lizards with different ecomorphs and thermal habitats (Anolis isolepis, Anolis allisoni, Anolis porcatus, Anolis allogus, Anolis homolechis, and Anolis sagrei). As a result, we obtained six novel draft genomes with relatively long and high gene completeness, with scaffold N50 ranging from 5.56–39.79 Mb, and vertebrate Benchmarking Universal Single-Copy Orthologs completeness ranging from 77.5% to 86.9%. Subsequently, we performed comparative analysis of genomic contents including those of mainland Anolis lizards to estimate genetic variations that had emerged and accumulated during the diversification of Anolis lizards. Comparing the repeat element compositions and repeat landscapes revealed differences in the accumulation process between Cuban trunk-crown and trunk-ground species, LTR accumulation observed only in A. carolinensis, and separate expansions of several families of LINE in each of Cuban trunk-ground species. The analysis of duplicated genes suggested that the proportional difference of duplicated gene number among Cuban Anolis lizards may be associated to the difference of their habitat range. Furthermore, Pairwise Sequentially Markovian Coalescent analysis proposed that the effective population sizes of each species might have been affected by Cuba’s geohistory. Hence, these six novel draft genome assemblies and detected genetic variations can be a springboard for the further genetic elucidation of the Anolis lizard’s diversification.SignificanceAnolis lizard in the West Indies is excellent model for studying the mechanisms of speciation and adaptive evolution. Still, due to a lack of genome assemblies, genetic variations and accumulation process of them involved in the diversification remain largely unexplored. In this study, we reported the novel genome assemblies of six Cuban Anolis lizards and analyzed evolution of genome contents. From comparative genomic analysis and inferences of genetic variation accumulation process, we detected species- and lineage-specific transposon accumulation processes and gene copy number evolution, considered to be associated with the adaptation to their habitats. Additionally, we estimated past effective population sizes and the results suggested its relationship to Cuba’s geohistory.
Impact valuations in social finance: emic and polyvocal stakeholder accounts
Authors: Ruff Kate , Nappert Pier-Luc , Graham Cameron 
Published: May 2022

PurposeThis paper aims to understand how social finance and impact measurement experts include stakeholders' voices in valuations of social and environmental impact.Design/methodology/approachThe paper used the content analysis of an online discussion forum where experts discussed impact valuation approaches.FindingsMany experts seek impact valuations that take into account the experiences of those whose lives are most affected. Ideally, these accounts need to be emic to (in the language of) those stakeholders, and polyvocal (representing many different stakeholders' voices). However, these experts also seek to effect systemic change by encouraging mainstream financial markets to use social and environmental valuations in their decision-making. These experts consider full plurality too complex to be useable by financial markets, so the experts argue in favor of etic valuations (stated in the language of investors), to appeal to mainstream finance, while endeavoring nonetheless to represent multiple stakeholders' voices. The authors identify two discursive strategies used to resolve this tension: effacing of differences between diverse stakeholders, and overstating the universality of money as a common language.Social implicationsThe terms emic and polyvocal provide experts with nuanced ways to understand “stakeholder voice.” The authors hope these nuances inspire new insights and strategies and help the community with their goal of bridging to mainstream finance.Originality/valueThe paper presents a theoretical framework for describing plurality in impact valuations and examines the challenges of bridging from social finance, which seeks to give voice and representation to those whose lives are most affected, to mainstream finance.
Centers of data appropriation: evidence from a Nordic hotel chain
Authors: Knudsen Dan-Richard , Bourmistrov Anatoli , Kaarbøe Katarina 
Published: May 2022

PurposeResearch suggests that centers of calculation, empowered by accounting inscriptions, are similar to maps: they provide a useful, albeit simplified, version of reality. The purposes of this paper are to examine whether and how digital platforms change the nature of centers of calculation, and to improve the understanding of the relationship between digital platforms and accounting.Design/methodology/approachAn in-depth, single case-study design is used to empirically investigate how a Nordic hotel chain competed with global online travel agencies (OTAs) in the quest for the “new oil”—customer data.FindingsThe paper demonstrates how the case organization created a local alternative to global digital platforms with the aim of acquiring customer data, thereby moving from a center of calculation (CoC) to what authors label a “center of data appropriation” (CDA). While CoCs are guided by accounting inscriptions that enable “mapping”, CDAs are constructed around accounting inscriptions with other properties that enable digital “mirrors” of the economic domain. The authors find that this has two governing effects. First, multiple centers emerge that compete for access to the periphery. Second, future forms of competition can follow dynamic trajectories, where mutual dependence between CDAs may lead to coopetition.Originality/valueScholars have suggested that surveillance capitalism creates market-power imbalances. This study indicates that the transformation of local organizations into CDAs enables them to challenge global digital-platform organizations. Therefore, authors argue that local organizations may retain some market power by establishing local CDAs.
Role of monetary policy in economic growth and development: from theory to empirical evidence
Authors: Mehar Muhammad Ayub 
Published: May 2022

PurposeThis article examines the effects of credit to private sector on the business and trade activities. The effectiveness of rapid expansion in public and private borrowing through state's intervention after COVID-19 pandemic has been assessed in this study.Design/methodology/approachThe model to determine the role of credit expansion is based on four equations estimated through panel least square technique on 18 years data of 186 countries.FindingsIt is concluded that credit to private sector and external debt improve the investment in infrastructure, which is a significant determinant of gross domestic product growth. Empirical evidences corroborate that higher number of firms using banks to finance their investment and the volume of broad money determine the magnitude of credit to private sector.Originality/valueThis study explores some new evidences and aspects of the credit financing which have not been discussed in this way before.
Mapping the landscape of organizational theories for future research themes in supply chain risk management
Authors: Yildiz Çankaya Sibel , Can Saglam Yesim , Sezen Bülent 
Published: May 2022

PurposeThe aim of this conceptual study is to analyze the effects of state-of-the-art research streams on supply chain risk management (SCRM) based on organizational theoretical background and direct future research toward the use of other related organizational theories. This paper seeks to provide a framework for understanding various organizational theories that can impact the understanding of SCRM.Design/methodology/approachA systematic literature review on articles published from 1998 to 2020 was conducted manually in the following databases: Emerald, Science Direct, Taylor & Francis Online, and Wiley online library. Among these articles, the paper by Smeltzer and Siferd (1998) is the first article published on the topic. Therefore, that serves as a starting point for the papers' analysis. A total of 109 articles have been selected and reviewed in detail.FindingsThe results of the study indicate that the articles which utilize theories in SCRM research have been mostly published in the last three years. The quantitative and case studies have been prevalently applied methods in the articles. In total, 34 theories are listed from the investigated articles. The four commonly studied theories among these are the information processing theory, transaction cost theory, contingency theory, and resource-based view.Originality/valueThis paper is the pioneer in the sense that the paper specifically and directly reviews the SCRM literature in terms of organizational theory usage. For future research, this study offers a diffusion of innovation (DOI) theory that explains the factors which can affect the adoption or diffusion of SCRM practices.