bluuebunny/crossref_metadata_2025_split huggingface dataset:
BET Inhibitors Target the SCLC-N subtype Small Cell Lung Cancer by Blocking NEUROD1 Transactivation
Authors: Chen Haobin , Gesumaria Lisa , Park Young-Kwon , Oliver Trudy G. , Singer Dinah S. , Ge Kai , Shrump David S. 
Published: October 2021

AbstractSmall cell lung cancer (SCLC) is a recalcitrant malignancy that urgently needs new therapies. Four master transcription factors (ASCL1, NEUROD1, POU2F3, and YAP1) are identified in SCLC, and each defines the transcriptome landscape of one molecular subtype. These master factors have not been directly druggable, and targeting their transcriptional coactivator(s) could provide an alternative approach. Here, we identify that BET bromodomain proteins physically interact with NEUROD1 and function as its transcriptional coactivators. Using CRISPR knockout and ChIP-seq, we demonstrate that NEUROD1 plays a critical role in defining the landscapes of BET bromodomain proteins in the SCLC genome. Targeting BET bromodomain proteins by BET inhibitors leads to broad suppression of the NEUROD1-target genes, especially those associated with superenhancers, and reduces SCLC growth in vitro and in vivo. LSAMP, a membrane protein in the IgLON family, was identified as one of the NEUROD1-target genes mediating BET inhibitor sensitivity in SCLC. Altogether, our study reveals that targeting transcriptional coactivators could be a novel approach to blocking the master transcription factors in SCLC for therapeutic purposes.SignificanceSmall cell lung cancer (SCLC) is the most aggressive form of lung malignancies, and little progress has been made to improve its outcome in the past two decades. It is now recognized that SCLC is not a single disease but has at least four molecular subtypes, and each subtype features the expression of one master transcription factor. Unfortunately, these master transcription factors are not directly druggable. Here, we identified BET bromodomain proteins as the transcriptional coactivators of NEUROD1, one of the master transcription factors in SCLC. Blocking BET bromodomain proteins with inhibitors suppresses NEUROD1-target genes and reduces tumor growth. Our results demonstrate that blocking transcriptional coactivators could be an alternative approach to targeting the master transcription factors in SCLC.
pH dependence of C•A, G•A and A•A mismatches in the stem of precursor microRNA-31
Authors: Kotar Anita , Ma Sicong , Keane Sarah C. 
Published: October 2021

AbstractMicroRNAs (miRNAs) are important regulators of post-transcriptional gene expression. Mature miRNAs are generated from longer transcripts (primary, pri- and precursor, pre-miRNAs) through a series of highly coordinated enzymatic processing steps. The sequence and structure of these pri- and pre-miRNAs play important roles in controlling their processing. Both pri- and pre-miRNAs adopt hairpin structures with imperfect base pairing in the helical stem. Here, we investigated the role of three base pair mismatches (A∙A, G∙A, and C∙A) present in pre-miRNA-31. Using a combination of NMR spectroscopy and thermal denaturation, we found that the three base pair mismatches displayed unique structural properties, including varying dynamics and sensitivity to solution pH. These studies deepen our understanding of how the physical and chemical properties of base pair mismatches influence RNA structural stability.Graphical abstract
OC_Finder: A deep learning-based software for osteoclast segmentation, counting, and classification
Authors: Wang Xiao , Kittaka Mizuho , He Yilin , Zhang Yiwei , Ueki Yasuyoshi , Kihara Daisuke 
Published: October 2021

AbstractOsteoclasts are multinucleated cells that exclusively resorb bone matrix proteins and minerals on the bone surface. They differentiate from monocyte/macrophage-lineage cells in the presence of osteoclastogenic cytokines such as the receptor activator of nuclear factor-κB ligand (RANKL) and are stained positive for tartrate-resistant acid phosphatase (TRAP). In vitro, osteoclast formation assays are commonly used to assess the capacity of osteoclast precursor cells for differentiating into osteoclasts wherein the number of TRAP-positive multinucleated cells are counted as osteoclasts. Osteoclasts are manually identified on cell culture dishes by human eyes, which is a labor-intensive process. Moreover, the manual procedure is not objective and result in lack of reproducibility. To accelerate the process and reduce the workload for counting the number of osteoclasts, we developed OC_Finder, a fully automated system for identifying osteoclasts in microscopic images. OC_Finder consists of segmentation and classification steps. OC_Finder detected osteoclasts differentiated from wild-type and Sh3bp2KI/+ precursor cells at a 99.4% accuracy for segmentation and at a 98.1% accuracy for classification. The number of osteoclasts classified by OC_Finder was at the same accuracy level with manual counting by a human expert. Together, successful development of OC_Finder suggests that deep learning is a useful tool to perform prompt and accurate unbiased classification and detection of specific cell types in microscopic images.
Biophysical Kv channel alterations dampen excitability of cortical PV interneurons and contribute to network hyperexcitability in early Alzheimer’s
Authors: Oláh Viktor Janos , Goettemoeller Annie M , Dimidschstein Jordane , Rowan Matthew JM 
Published: October 2021

SummaryIn Alzheimer’s disease (AD), a multitude of genetic risk factors and early biomarkers are known. Nevertheless, the causal factors responsible for initiating cognitive decline in AD remain controversial. Toxic plaques and tangles correlate with progressive neuropathology, yet disruptions in circuit activity emerge before their deposition in AD models and patients. Parvalbumin (PV) interneurons are potential candidates for dysregulating cortical excitability, as they display altered AP firing before neighboring excitatory neurons in prodromal AD. Here we report a novel mechanism responsible for PV hypoexcitability in young adult familial AD mice. We found that biophysical modulation of K+ channels, but not changes in mRNA expression, are responsible for dampened excitability. These K+ conductances could efficiently regulate near-threshold AP firing, resulting in gamma-frequency specific network hyperexcitability. Our findings suggest that posttranslational modulation of ion channels can reshape cortical network activity prior to changes in their gene expression in early AD.
Dissecting the Roles of the Tuberin Protein in the Subcellular Localization of the G2/M Cyclin, Cyclin B1
Authors: Dare-Shih Jessica , Pillon Adam , Fong Jackie , da Silva Elizabeth Fidalgo , Porter Lisa A. 
Published: October 2021

AbstractTuberin is a major component of the protein regulatory complex known as the Tuberous Sclerosis Complex and plays a crucial role in cell cycle progression and protein synthesis. Mutations in the Tuberin gene, TSC2, lead to the formation of benign tumors in many organ systems and causes the Tuberous Sclerosis Complex disorder. Genotypes ranging from point mutations to large deletions in the TSC2 gene have been clinically characterized with a wide range of phenotypes from skin tumors to large brain tumors. Our current work investigates the molecular mechanisms behind Tuberin and its ability to regulate the cell cycle through its binding to the G2/M cyclin, Cyclin B1. After creating an early stop codon in a critical region of the Tuberin, our results show the in vitro phenotype that occurs from a truncated Tuberin protein. Herein we demonstrate that this clinically relevant truncated form of Tuberin promotes an increased nuclear accumulation of Cyclin B1 and a subsequent increase in cell proliferation supporting the phenotypic data seen in the clinic with Tuberous Sclerosis Complex patients showing deletions within the TSC2 gene. This data provides an insight into some of the functional and molecular consequences of truncated proteins that are seen in clinical patients.
Transcriptomically unique endolysosomal and homeostatic microglia populations in Alzheimer’s disease and aged human brain
Authors: Prater Katherine E. , Green Kevin J. , Mamde Sainath , Sun Wei , Cochoit Alexandra , Smith Carole L. , Chiou Kenneth L. , Heath Laura , Rose Shannon E. , Wiley Jesse , Keene C. Dirk , Kwon Ronald Y. , Snyder-Mackler Noah , Blue Elizabeth E. , Logsdon Benjamin , Young Jessica E. , Shojaie Ali , Garden Gwenn A. , Jayadev Suman 
Published: October 2021

AbstractMicroglia contribute to Alzheimer’s Disease (AD) progression and are candidate therapeutic targets. Human microglia exhibit an array of transcriptional phenotypes implying that accurate manipulation of microglial function will require clarity of their molecular states and context dependent regulation. To increase the number of microglia analyzed per subject we employed fluorescence activated nuclei sorting prior to single-nucleus RNA-seq on human prefrontal cortices. We observed microglia phenotypes previously unrecognized in human brain gene expression studies and mapped their transcriptomic relationships by trajectory inference. Three clusters were enriched for endolysosomal pathways, one of which showed differential expression of AD GWAS genes in addition to genes implicated in nucleic acid detection and interferon signaling. Analysis of the “homeostatic” microglia cluster revealed a uniquely AD subcluster. Our study demonstrates the value of deeply profiling microglia to explore the biological implications of microglia transcriptomic diversity.
Structural Dynamics of Real and Modeled Solanum Stamens: Implications for Pollen Ejection by Buzzing Bees
Authors: Jankauski Mark , Ferguson Riggs , Russell Avery , Buchmann Stephen 
Published: October 2021

AbstractAn estimated 10% of flowering plant species conceal their pollen within tube-like anthers that dehisce through small apical pores (poricidal anthers). Bees extract pollen from poricidal anthers through a complex motor routine called floral buzzing, whereby the bee applies vibratory forces to the flower stamen by rapidly contracting its flight muscles. The resulting deformation depend on the stamen’s natural frequencies and vibration mode shapes, yet for most poricidal species these properties have not been sufficiently characterized. We performed experimental modal analysis on Solanum elaeagnifolium stamens to quantify their natural frequencies and vibration modes. Based on morphometric and dynamic measurements, we developed a finite element model of the stamen to identify how variable material properties, geometry and bee weight could affect its dynamics. In general, stamen natural frequencies fell outside the reported floral buzzing range, and variations in stamen geometry and material properties were unlikely to bring natural frequencies within this range. However, inclusion of bee mass reduced natural frequencies to within the floral buzzing frequency range and gave rise to an axial-bending vibration mode. We hypothesize that floral buzzing bees exploit the large vibration amplification factor of this mode to increase anther deformation, which may facilitate pollen ejection.
Riemannian Geometries of Visual Space: Variable Curvature and Horizon
Authors: Turski Jacek 
Published: October 2021

AbstractThis is a study of the phenomenal geometries constructed in the Riemannian geometry framework from simulated iso-disparity conics in the horizontal visual plane of the binocular system with the asymmetric eyes (AEs). For the eyes’ resting vergence posture, which depends on parameters of the AE, the iso-disparity conics are frontal straight lines in physical space. For all other fixations, the simulated iso-disparity conics consist of families of the ellipses or hyperbolas depending on both the AE’s parameters and the bifoveal fixation. However, the iso-disparity conic’s arcs are perceived in the gaze direction as the frontal lines. Thus, geometries of physical and visual spaces are different. An assumption underlying the relevant architecture of the human visual system is combined with results from simulated iso-disparity straight lines, giving the relative depth as a function of the AE’s parameters and the distance. This establishes the metric tensor in binocular space of fixations for the eyes’ resting vergence posture. The resulting geodesics in the gaze direction, give the distance to the horizon and zero curvature. For all other fixations, only the sign of the curvature may be inferred from the global behavior of the simulated iso-disparity conics.
Structural snapshots of V/A-ATPase reveal a new paradigm for rotary catalysis
Authors: Kishikawa J. , Nakanishi A. , Nakano A. , Saeki S. , Furuta A. , Kato T. , Mistuoka K. , Yokoyama K. 
Published: October 2021

AbstractV/A-ATPase is a motor protein that shares a common rotary catalytic mechanism with FoF1 ATP synthase. When powered by ATP hydrolysis, the V1 moiety rotates the central rotor against the A3B3 hexamer, composed of three catalytic AB dimers adopting different conformations (ABopen, ABsemi, and ABclosed). Here we have determined the atomic models of 18 catalytic intermediates of the V1 moiety of V/A-ATPase under different reaction conditions by single particle Cryo-EM, which revealed that the rotor does not rotate immediately after binding of ATP to the V1. Instead, three events proceed simultaneously with the 120° rotation of the shaft: hydrolysis of ATP in ABsemi, zipper movement in ABopen by the binding ATP, and unzipper movement in ABclosed with release of both ADP and Pi. This indicates the unidirectional rotation of V/A-ATPase by a ratchet-like mechanism owing to ATP hydrolysis in ABsemi, rather than the power stroke model proposed previously for F1-ATPase.
In silico analyses of maleidride biosynthetic gene clusters
Authors: Williams Katherine , de Mattos-Shipley Kate M. J. , Willis Christine L. , Bailey Andrew M. 
Published: October 2021

ABSTRACTMaleidrides are a family of structurally related fungal natural products, many of which possess diverse, potent bioactivities. Previous identification of several maleidride biosynthetic gene clusters, and subsequent experimental work, has determined the ‘core’ set of genes required to construct the characteristic medium-sized alicyclic ring with maleic anhydride moieties. Through genome mining, this work has used these core genes to discover ten entirely novel maleidride biosynthetic gene clusters, amongst both publicly available genomes, and encoded within the genome of the previously un-sequenced epiheveadride producer Wicklowia aquatica CBS125634. We have undertaken phylogenetic analyses and comparative bioinformatics on all known and putative maleidride biosynthetic gene clusters to gain further insights regarding these unique biosynthetic pathways.
The influence of the quality criteria on the quality cost of suppliers in SMEs
Authors: Masoudi Ehsan , Shahin Arash 
Published: October 2021

PurposeAfter quality costing, most companies do not know how to invest in supplier quality improvement. This study aims to develop a comprehensive model for the effect of supplier quality criteria on supplier quality costs.Design/methodology/approachThe independent variable of supplier quality criteria and the dependent variable of supplier quality costs have been identified based on a literature review. Then a model has been developed for the effect of the variables. A questionnaire has been designed and distributed to 158 small and medium enterprises (SMEs) in Jey Industrial Town located in the Isfahan Province. Structural equation modeling and partial least square structural equation modeling (PLS-SEM) have been used for data analysis.FindingsSupplier quality criteria influenced supplier quality costs (with a value of 0.711). The results also implied that organizational quality had the highest impact. The appraisal costs and the internal failure costs of purchasing received most of the influence. Also, process quality and consequential costs of failure purchasing had the lowest influencing and influenced values.Practical implicationsThe findings of this research encourage the managers of SMEs to evaluate and rank the most appropriate quality criteria related to quality costs for selecting a supplier as one of the most fundamental decisions in supply chain management.Social implicationsAppropriate selection of quality criteria influencing quality costs results in reduced quality cost. Quality cost reduction also results in decreased products' fixed prices. Ultimately, the company will have more competitive pricing, and consumers will benefit from such a significant advantage.Originality/valueStudying the influence of supplier quality criteria on supplier quality costs is relatively new in the manufacturing industry. The comprehensiveness of the investigated variables is also another advantage of the proposed model.
Learning processes and knowledge transfer in the upward spiral model: an empirical assessment of springboard multinational enterprises
Authors: Torrecillas Celia , Brandão Fischer Bruno 
Published: October 2021

Purpose
The springboard theory for multinational enterprises and the upward spiral model address the expansion of emerging countries’ multinational enterprises (MNEs) abroad as a set of resource-building stages. This paper aims to analyze this model by qualifying knowledge flows in three domains: learning effects, transfer flows and global connections.

Design/methodology/approach
The authors use 2018 data from the ORBIS database to identify evidence concerning the springboard MNE (SMNE) phenomenon. The authors select MNE firms from 93 emerging economies with presence in 71 developed and 93 developing countries. In addition, the authors differentiate between the levels of technological intensity of emerging market MNEs’ sectors.

Findings
The results highlight the existence of learning processes taking place in subsidiaries and feeding back into parent firms, as well as the existence of capability transfer from home to host units.

Originality/value
The main contribution is the addition of empirical evidence on the SMNE and specifically the upward spiral model, considering the micro-level and the productivity differences between parent firm and subsidiaries.
Abduction and entrepreneurial learning
Authors: Davidsen Helle Munkholm , Højlund Christina 
Published: October 2021

PurposeThe purpose of this article is to describe the similarities between abductive reasoning and entrepreneurial learning processes in order to contribute to the conceptual understanding of learning as an entrepreneurial process in itself.Design/methodology/approachThe research is theoretically rooted in a conceptual development of the understanding of entrepreneurial learning processes as abductive reasoning inspired by the philosopher Charles Sanders Peirce. The theoretical explication of the connection between entrepreneurial learning processes and abductive reasoning is additionally illustrated by a hypotheses-based didactic model, developed by the authors to scaffold abducting reasoning into learning processes.FindingsThe authors found in the theoretical investigation of abductive reasoning a conceptualisation of entrepreneurial learning processes that connects entrepreneurial learning processes to basic cognitive human competences, and the authors found that key concepts in entrepreneurship, such as hunches and experiments, can be understood in a broader philosophical framework as basic cognitive competences.Practical implicationsThe authors exemplify how abductive reasoning can be used in practice through a hypothesis-based didactic approach designed as a loop model.Originality/valueThe authors have discovered that abduction is closely related to entrepreneurship and can be a central conceptual link in understanding the relationship between entrepreneurship and learning. The athors also believe that Peirce's concept of abduction can contribute to the philosophical understanding of entrepreneurship as another name for a constant rethinking of the world.
Do controlling shareholders share pledging affect goodwill impairment? Evidence from China
Authors: Li Yanxi , Ouyang Shanshan 
Published: October 2021

Purpose
The purpose of this study is to examine the impact of controlling shareholders’ share pledging on goodwill impairment.

Design/methodology/approach
This study empirically investigates the effect of controlling shareholders’ share pledging on both the decision and amount of goodwill impairment for Chinese listed firms from 2007 to 2017.

Findings
This study finds that the proportion of controlling shareholders’ share pledging is negatively related to both impairment decisions and amounts; these negative relationships are intensified when firms face high stock price crash risks. In addition, the empirical results show that firms with larger share pledging are less likely to recognize goodwill impairment or are likely to record relatively smaller impairment amounts when they are followed by fewer financial analysts.

Originality/value
Most of the relevant literature has focused on managers’ behaviors toward goodwill impairments, while less attention has been given to goodwill impairments from the perspective of controlling shareholders. In fact, controlling shareholders may have strong incentives to protect their control rights when they exercise disproportionate control rights, especially in China. Given the high ownership concentration, prior studies may not have adequately explained the agency problem of controlling shareholders in goodwill impairment. This study uses share pledging as a case to fill this gap. Specifically, it investigates whether both goodwill impairment decisions and amounts are affected by controlling shareholders’ share pledging.
Cybersecurity and the new firm: surviving online threats
Authors: Chandna Vallari , Tiwari Praneet 
Published: October 2021

Purpose
Nascent firms and startups are often subject to challenges that their more mature counterparts can avoid. While cybersecurity is an issue that all firms contend with, it is especially challenging for new entrepreneurial ventures who lack the resources and capabilities of established firms. The purpose of this paper is to seek to delve deeper into the cybersecurity and risk management needs of small firms and startups.

Design/methodology/approach
Extant literature and available tools are explored to develop a usable framework applicable to small firms and new entrepreneurial ventures.

Findings
The liabilities of newness and smallness make entrepreneurial ventures a unique context in which to study the significance of cybersecurity and data privacy risk management. The authors offer an overview of issues and potential solutions relevant to entrepreneurial ventures.

Research limitations/implications
While offering practical insights, the work is a theoretical framework. The framework will enable researchers to develop more nuanced theory when it comes to cybersecurity and data privacy risk management.

Practical implications
The framework illustrates four distinct contexts for cybersecurity and risk management when it comes to the needs of small firms and startups. Adoption levels are explained, and small business operators and entrepreneurs can thus use the framework to determine the most appropriate approach for their enterprise.

Originality/value
The authors develop a framework illustrating adoption of different security and risk management practices by entrepreneurial ventures based on their specific needs and context. The authors thus offer practical solutions for startups and nascent firms regarding cybersecurity and privacy management.