bluuebunny/crossref_metadata_2025_split huggingface dataset:
Core Protein-Directed Antivirals and Importin β Can Synergistically Disrupt HBV Capsids
Authors: Kim Christine , Barnes Lauren , Schlicksup Christopher , Patterson Angela , Bothner Brian , Jarrold Martin , Wang Che-Yen Joseph , Zlotnick Adam 
Published: August 2021

ABSTRACTViral structural proteins can have multiple activities. Antivirals that target structural proteins have potential to exhibit multiple antiviral mechanisms. Hepatitis B Virus (HBV) core protein (Cp) is involved in most stages of the viral lifecycle: it assembles into capsids, packages viral RNA, is a metabolic compartment for reverse transcription, interacts with nuclear trafficking machinery, and disassembles to release the viral genome into the nucleus. During nuclear localization, HBV capsids bind to host importins (e.g. Impβ) via Cp’s C-terminal domain (CTD); the CTD is localized to the interior of the capsid and is transiently exposed on the exterior. We used HAP12 as a representative Cp Allosteric Modulators (CpAMs), a class of antivirals that inappropriately stimulates and misdirects HBV assembly and deforms capsids. CpAM impact on other aspects of the HBV lifecycle is poorly understood. We investigated how HAP12 influenced the interactions between empty or RNA-filled capsids with Impβ and trypsin in vitro. We showed that HAP12 can modulate CTD accessibility and capsid stability, depending on the saturation of HAP12-binding sites. We demonstrated that Impβ synergistically contributes to capsid disruption at high levels of HAP12 saturation, using electron microscopy to visualize disruption and rearrangement of Cp dimers into aberrant complexes. However, RNA-filled capsids resisted the destabilizing effects of HAP12 and Impβ. In summary, we show host protein-induced catalysis of capsid disruption, an unexpected additional mechanism of action for CpAMs. Potentially, untimely capsid disassembly can hamper the HBV lifecycle and also cause the virus to become vulnerable to host innate immune responses.IMPORTANCEThe HBV core, an icosahedral complex of 120 copies of the homodimeric core (capsid) protein with or without packaged nucleic acid, is transported to the host nucleus by its interaction with host importin proteins. Importin-core interaction requires the core protein C-terminal domain, which is inside the capsid, to “flip” to the capsid exterior. Core-protein directed drugs that affect capsid assembly and stability have been developed recently. We show that these molecules can, synergistically with importins, disrupt capsids. This mechanism of action, synergism with host protein, has potential to disrupt the virus lifecycle and activate the innate immune system.
Impact of Erg11 amino acid substitutions identified in Candida auris clade III isolates on triazole drug susceptibility
Authors: Williamson Benjamin , Wilk Adam , Guerrero Kevin D. , Mikulski Timothy D. , Elias Tony N. , Sawh Indira , Cancino-Prado Geselle , Gardam Dianne , Heath Christopher H. , Govender Nelesh P. , Perlin David S. , Kordalewska Milena , Healey Kelley R. 
Published: August 2021

AbstractERG11 sequencing of 28 Candida auris clade III isolates revealed the presence of concomitant V125A and F126L substitutions. Heterologous expression of Erg11-V125A/F126L in Saccharomyces cerevisiae led to reduced fluconazole and voriconazole susceptibilities. Generation of single substitution gene variants through site-directed mutagenesis uncovered that F126L primarily contributes to the elevated triazole MICs. A similar, yet diminished pattern of reduced susceptibility was observed with long-tailed triazoles posaconazole and itraconazole for V125A/F126L, F126L, Y132F, and K143R alleles.
Reciprocal regulation of p21 and Chk1 controls the Cyclin D1-RB pathway to mediate senescence onset after DNA damage-induced G2 arrest
Authors: Lossaint Gerald , Horvat Anđela , Gire Véronique , Bacevic Katarina , Mrouj Karim , Charrier-Savournin Fabienne , Georget Virginie , Fisher Daniel , Dulic Vjekoslav 
Published: August 2021

ABSTRACTSenescence is an irreversible proliferation withdrawal that can be initiated after DNA damage-induced cell cycle arrest in G2 phase to prevent genomic instability. Senescence onset in G2 is not well understood; it requires p53 and RB family tumour suppressors, but how they are regulated to convert a temporary cell cycle arrest into a permanent one remains unknown. Here, we show that a previously unrecognised balance between the CDK inhibitor p21 and Chk1 controls D-type cyclin-CDK activity during G2 arrest. In non-transformed cells, p21 activates RB in G2 by inhibiting Cyclin D1-CDK2/CDK4. The resulting G2 exit, which precedes appearance of senescence markers, is associated with a mitotic bypass, Chk1 inhibition and DNA damage foci reduction. In p53/RB-proficient cancer cells, compromised G2 exit correlates with sustained Chk1 activity, delayed p21 induction, untimely Cyclin E1 re-expression and genome reduplication. Chk1 depletion promotes cell cycle exit by inducing p21 binding to Cyclin D1 and Cyclin E1-CDK complexes and down-regulating CDK6, whereas Chk2 knockdown promotes RB phosphorylation and delays G2 exit. In conclusion, p21 and Chk2 oppose Chk1 to maintain RB activity, thus controlling DNA damage-induced senescence onset in G2.
The role of visual experience in brain inter-individual variability
Authors: Sen Sriparna , Tong Ningcong , Wang Xiaoying , Bi Yanchao , Striem-Amit Ella 
Published: August 2021

AbstractVisual cortex organization is highly consistent across individuals. But to what degree does this consistency depend on life experience, in particular sensory experience? In this study, we asked whether visual cortex reorganization in congenital blindness results in connectivity patterns that are particularly variable across individuals, focusing on resting-state functional connectivity (RSFC) patterns from primary visual cortex. We show that the absence of shared visual experience results in more-variable RSFC patterns across blind individuals than sighted controls. Increased variability is specifically found in areas that show a group difference between the blind and sighted in their RSFC. These findings reveal a relationship between brain plasticity and individual variability in which reorganization manifests variably across individuals. We further investigated the different patterns of reorganization in the blind, showing that the connectivity to frontal regions, proposed to have a role in reorganization of the visual cortex of the blind towards higher cognitive roles, is highly variable. In a supplementary analysis, we link some of the variability in visual-to-frontal connectivity to another environmental factor – duration of formal education. Together, these findings show a role of sensory and socioeconomic experience in imposing consistency on brain organization. By revealing the idiosyncratic nature of neural reorganization, these findings highlight the importance of considering individual differences in fitting sensory aids and restoration approaches for vision loss.Significance statementThe typical visual system is highly consistent across individuals. What are the origins of this consistency? Comparing the consistency of visual cortex connectivity between people born blind and sighted people, we showed that blindness results in higher variability, suggesting a key impact of individual experience on brain organization. Further, connectivity patterns that changed following blindness were particularly variable, resulting in diverse patterns of brain reorganization. Individual differences in reorganization were also directly affected by non-visual experiences in the blind (years of formal education). Together, these findings show a role of sensory and socioeconomic experiences in creating individual differences in brain organization and endorse the use of individual profiles for rehabilitation and restoration of vision loss.
Identification of INSR protein structural differences in Diabetes Mellitus type 2 subjects from protein sequences
Authors: Carroll Peyton 
Published: August 2021

AbstractIn this paper, we constructed several models of the Insulin Receptor protein(abbreviated INSR) from protein sequences from pathogenic and benign variants of type 2 Diabetes Mellitus patients. Through modeling these variants, we were able to determine which sections of the tertiary structure of the INSR protein were linked to type 2 Diabetes Mellitus. Ultimately, we created a map of the INSR protein and indicated which parts of the protein structure had significant effects on type 2 Diabetes Mellitus. We concluded differences in the charged/polar amino acids on the lower right section of the structure(amino acid numbers 487 and 750) were associated with pathogenic variants, while charged/polar differences on the lower left of the structure(amino acid numbers 669 and 784) had no impact on pathogenicity. We observed several differences in the amino acid chain structure, however they were not unique to the pathogenic variants; they were also seen in the benign variants.
Confined migration promotes cancer metastasis through resistance to anoikis and increased invasiveness
Authors: Fanfone Deborah , Wu Zhi Chong , Mammi Jade , Berthenet Kevin , Neves David , Weber Kathrin , Halaburkova Andrea , Virard François , Bunel Félix , Hernandez-Vargas Hector , Tait Stephen WG , Hennino Anca , Ichim Gabriel 
Published: August 2021

AbstractMechanical stress is known to fuel several hallmarks of cancer, ranging from genome instability to uncontrolled proliferation or invasion. Cancer cells are constantly challenged by mechanical stresses not only in the primary tumour but also during metastasis. However, this latter has seldom been studied with regards to mechanobiology, in particular resistance to anoikis, a cell death programme triggered by loss of cell adhesion. Here, we show in vitro that migrating breast cancer cells develop resistance to anoikis following their passage through microporous membranes mimicking confined migration (CM), a mechanical constriction that cancer cells encounter during metastasis. This CM-induced resistance was mediated by Inhibitory of Apoptosis Proteins (IAPs), and sensitivity to anoikis could be restored after their inhibition using SMAC mimetics. Anoikis-resistant mechanically-stressed cancer cells displayed enhanced cell motility and evasion from natural killer cell-mediated immune surveillance, as well as a marked advantage to form lung metastatic lesions in mice. Our findings reveal that CM increases the metastatic potential of breast cancer cells.
ExSTED microscopy reveals contrasting functions of dopamine and somatostatin CSF-c neurons along the central canal
Authors: Jalalvand Elham , Alvelid Jonatan , Coceano Giovanna , Edwards Steven , Robertson Brita , Grillner Sten , Testa Ilaria 
Published: August 2021

AbstractThe spatial location of cerebrospinal fluid contacting (CSF-c) neurons enables important regulatory homeostatic functions regarding pH and motion control. Their intricate organization, facing the central canal and extending across the spinal cord, in relation to specific subtypes is poorly understood. This calls for imaging methods with a high spatial resolution (5-10 nm) to resolve the synaptic and ciliary compartments of each individual cell to elucidate their signalling pathways and enough throughput to dissect the cellular organization. Here, light-sheet and expansion microscopy resolved the persistent ventral and lateral organization of dopamine and somatostatin CSF-c neuronal types.The number of somatostatin-containing dense core vesicles, resolved by STED microscopy, was shown to be markedly reduced upon each exposure to alkaline or acidic pH inhibiting any movement as part of a homeostatic response. Their cilia symmetry was unravelled by ExSTED as sensory in contrast with the motile one found in the dopaminergic ph insensitive neurons. This novel experimental workflow elucidates the functional role of CSF-c neuron subtypes in situ paving the way for further spatial and functional cell type classification.
Circulating microRNAs as noninvasive biomarkers for canine Cushing’s syndrome
Authors: Sanders Karin , Veldhuizen Anouk , Kooistra Hans S. , Slob Adri , Timmermans-Sprang Elpetra P.M. , Riemers Frank M. , Daminet Sylvie , Fracassi Federico , van Nimwegen Sebastiaan A. , Meij Björn P. , Galac Sara 
Published: August 2021

AbstractCanine Cushing’s syndrome (hypercortisolism) can be caused by a pituitary tumor (pituitary-dependent hypercortisolism; PDH) or a cortisol-secreting adrenocortical tumor (csACT). For both cases, noninvasive biomarkers that could pre-operatively predict the risk of recurrence after surgery would greatly impact clinical decision making. The aim of this study was to determine whether circulating microRNAs (miRNAs) can be used as noninvasive biomarkers for canine Cushing’s syndrome.After a pilot study with 40 miRNAs in blood samples of healthy dogs (n = 3), dogs with PDH (n = 3) and dogs with a csACT (n = 4), we selected a total of 20 miRNAs for the definitive study. In the definitive study, these 20 miRNAs were analyzed in blood samples of healthy dogs (n = 6), dogs with PDH (n = 19, pre-and post-operative samples) and dogs with a csACT (n = 26, pre-operative samples).In dogs with PDH, six miRNAs (miR-122-5p, miR-126-5p, miR-141-3p, miR-222-3p, miR-375-3p and miR-483-3p) were differentially expressed compared to healthy dogs. Of one miRNA, miR-122-5p, the expression levels did not overlap between healthy dogs and dogs with PDH (p = 2.9×10−4), significantly decreased after hypophysectomy (p = 0.013), and were significantly higher (p = 0.017) in dogs with recurrence (n = 3) than in dogs without recurrence for at least one year after hypophysectomy (n = 7). In dogs with csACTs, two miRNAs (miR-483-3p and miR-223-3p) were differentially expressed compared to healthy dogs. Additionally, miR-141-3p was expressed significantly lower (p = 0.009) in dogs with csACTs that had a histopathological Utrecht score of ≥ 11 compared to those with a score of < 11.These results indicate that circulating miRNAs have the potential to be noninvasive biomarkers in dogs with Cushing’s syndrome that may contribute to clinical decision-making.
Usutu virus escapes langerin-induced restriction to productively infect human Langerhans cells, unlike West Nile virus
Authors: Martin Marie-France , Maarifi Ghizlane , Abiven Hervé , Seffals Marine , Mouchet Nicolas , Beck Cécile , Bodet Charles , Lévèque Nicolas , Arhel Nathalie J. , Blanchet Fabien P. , Simonin Yannick , Nisole Sébastien 
Published: August 2021

AbstractUsutu virus (USUV) and West Nile virus (WNV) are phylogenetically close emerging arboviruses transmitted by mosquitoes, and constitute a global public health threat. Since USUV and WNV enter the body through the skin, the first immune cells they encounter are skin-resident dendritic cells, the most peripheral outpost of immune defense. This unique network is composed of Langerhans cells (LCs) and dermal DCs, which reside in the epidermis and the dermis, respectively.Using human skin explants, we show that while both viruses can replicate in keratinocytes, they can also infect resident DCs with distinct tropism, since WNV preferentially infects DCs in the dermis, whereas USUV has a greater propensity to infect LCs. Using both purified human epidermal LCs (eLCs) and monocyte derived LCs (MoLCs), we confirm that LCs sustain a faster and more efficient replication of USUV compared with WNV and that this correlates with a more intense innate immune response to USUV compared with WNV. Next, we show that ectopic expression of the LC-specific C-type lectin receptor (CLR), langerin, in HEK293T cells allows WNV and USUV to bind and enter, but supports the subsequent replication of USUV only. Conversely, blocking or silencing langerin in MoLCs or eLCs made them resistant to USUV infection, thus demonstrating that USUV uses langerin to enter and replicate in LCs. Altogether, our results demonstrate that LCs constitute privileged target cells for USUV in human skin, because langerin favors its entry and replication. Intriguingly, this suggests that USUV efficiently escapes the antiviral functions of langerin, which normally safeguards LCs from most viral infections.
“We are different, that’s a fact, but they treat us like we’re different-er”: understandings of autism and adolescent identity development
Authors: Mesa Sue , Hamilton Lorna G. 
Published: August 2021

PurposeA key development in early adolescence is the active construction of individual identity; for autistic young people, integrating the idea of “being autistic” forms part of this process. The purpose of this paper is to explore identity development from a contextualist perspective, foregrounding young people’s experiences within mainstream educational settings.Design/methodology/approachA longitudinal, qualitative methodology was used: semi-structured interviews were conducted annually with 14 autistic young people, their parents and teachers between school years 6 and 9.FindingsYoung people felt different from their neurotypical peers and their acceptance of their diagnosis changed over time as they managed their developing personal and public identities. In pursuit of being treated “normally,” many camouflaged their differences at school, which sometimes involved opting out of school-based support. Adults described their own understandings of autism and discussed the responses of others in the school environment to autistic differences.Originality/valueThe influence of sociocultural discourses of autism on young people’s identity development is discussed and implications for both school based and post-diagnostic support for young people and their families explored.
Do firms adjust board gender diversity in response to economic policy uncertainty?
Authors: Jumreornvong Seksak , Treepong karuna Sirimon , Tong Shenghui , Jiraporn Pornsit 
Published: August 2021

Purpose
This paper aims to explore the effect of economic policy uncertainty (EPU) on board gender diversity. Prior research shows that female directors play a beneficial role. The advantage of board gender diversity should be particularly helpful when firms have to navigate an uncertain environment. So the authors hypothesize that firms adjust their board gender diversity in response to EPU.

Design/methodology/approach
The authors execute a regression analysis. To minimize endogeneity, the authors execute firm-fixed effects regressions, an instrumental variable (IV) analysis and propensity score matching.

Findings
Consistent with their hypothesis, the authors find that firms significantly raise board gender diversity in response to EPU. To draw a causal inference, the authors exploit the 9/11 terrorist attack as an exogenous shock that elevated EPU unexpectedly. The authors’ IV analysis corroborates the results. Finally, the authors show that board gender diversity substantially mitigates the adverse effect on shareholder wealth brought about by an unanticipated negative shock attributed to the 9/11 attack.

Originality/value
According to the authors’ knowledge, this study is the first to investigate the effect of EPU on board gender diversity. This research contributes to two important areas of the literature, i.e. board gender diversity and EPU. The authors show that board gender diversity is beneficial and firms act accordingly when facing more economic uncertainty.
“Bookmysurprise”: navigating through the predicament of a start-up
Authors: Bansal Shagun , Kapur Inakshi , Singh Anjani Kumar , Verma Piyush 
Published: August 2021

Learning outcomes
The learning outcomes of this paper are as follows: to identify the pros and cons of waged employment and entrepreneurship, to identify the contextual factors influencing entrepreneurship, to set up a new venture, namely, steps, challenges involved and decision-making process, to scale up a small business; when, how and where? And to tradeoff required for scaling up a small business.

Case overview/synopsis
Pooja, a young management graduate from Varanasi, decided to overcome all challenges and barriers faced by a women entrepreneur and chase her lifelong dream of creating her own event management startup. After having achieved phenomenal success in a short period of time within the city, she began to receive interest from neighbouring cities as well. The decision to scale up operations was particularly difficult for Pooja, as she had funded the venture through her personal funds and personally nurtured the business and her team based on the values of quality and creativity. Like any small business, she had to decide what level of trade-off was required between scaling and dilution of control over the operations.

Complexity academic level
The case study is applicable for students of management. The learnings from the case can be applied by an individual who is looking to start a business or expand one.

Supplementary materials
Teaching Notes are available for educators only.

Subject code
CSS 3: Entrepreneurship.
Knowledge mapping of skills mismatch phenomenon: a scientometric analysis
Authors: Draissi Zineb , Zhanyong Qi , Raguindin Princess Zarla Jurado 
Published: August 2021

PurposeThis paper aims to understand the development track of skills mismatch research and discover the hidden internal connections between literature.Design/methodology/approachThe authors gathered data through scientometric quantitative analysis using CiteSpace. Specifically, this article applied basic analysis, journal cocitation analysis (JCA), author cocitation analysis (ACA) and document cocitation analysis (DCA), cluster analysis, citation burstness detection, scientific research cooperation analysis and coconcurrence analysis of keywords of 3,125 documents from Web of Science core collections for the period 2000–2020.FindingsThrough the document cocitation analysis and the keywords' co-occurrence, this article identifies influential scholars, documents, research institutions, journals and research hotspots in research on the skills mismatch phenomenon. The results showed that the publications had ballooned, and the phenomenon has become an interdisciplinary research subject. The USA and Finland remain the main contributors, which is attributed to their high-yield institutions such as the University of Helsinki, the University of Witwatersrand, the University of Washington and so on. While the African continent lacks research on skills mismatch even with the continent’s effort to overcome such a crucial issue. The paper presents an in-depth analysis of skills and educational mismatch issues to better understand the evolutionary trajectory of the collective knowledge over the past 20 years and highlight the areas of active pursuit.Research limitations/implicationsThe authors only used Web of Science core collection to collect data; however, they can added Scopus indexed database as well to extend the research trends and explore more new research hot topics to solve the skills mismatch phenomenon.Originality/valueThe scientometric analysis is of great significance for identifying the potential relationship between the literature and investigating the knowledge evolution of skills mismatch research. Organisation for Economic Co-operation and Development, the International Labor Organization and the World Health Organization are the giants who are mostly concerned of the mismatch skills phenomenon. Researchers can refer to this study to understand the status quo, gaps and research trends to deal with the skills mismatch issue.