bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epigenetic Modulation of SPCA2 Reverses Epithelial to Mesenchymal Transition in Breast Cancer Cells
Authors: Makena Monish Ram , Ko Myungjun , Dang Donna Kimberly , Rao Rajini 
Published: November 2020

AbstractThe secretory pathway Ca2+-ATPase SPCA2 is a tumor suppressor in triple receptor negative breast cancer (TNBC), a highly aggressive molecular subtype that lacks tailored treatment options. Low expression of SPCA2 in TNBC confers poor survival prognosis in patients. Previous work has established that re-introducing SPCA2 to TNBC cells restores basal Ca2+signaling, represses mesenchymal gene expression, mitigates tumor migrationin vitroand metastasisin vivo. In this study, we examined the effect of histone deacetylase inhibitors (HDACi) in TNBC cell lines. We show that the pan-HDACi vorinostat and the class I HDACi romidepsin induce dose-dependent upregulation of SPCA2 transcript with concurrent downregulation of mesenchymal markers and tumor cell migration characteristic of epithelial phenotype. Silencing SPCA2 abolished the ability of HDACi to reverse epithelial to mesenchymal transition (EMT). Independent of ATPase activity, SPCA2 elevated resting Ca2+levels to activate downstream components of non-canonical Wnt/Ca2+signaling. HDACi treatment led to SPCA2-dependent phosphorylation of CAMKII and β-catenin, turning Wnt signaling off. We conclude that SPCA2 mediates the efficacy of HDACi in reversing EMT in TNBC by a novel mode of non-canonical Wnt/Ca2+signaling. Our findings provide incentive for screening epigenetic modulators that exploit Ca2+signaling pathways to reverse EMT in breast tumors.Simple SummaryThe triple receptor negative breast cancer subtype, or TNBC, currently has no tailored treatment options. TNBC is highly metastatic, associated with high patient mortality, and disproportionately occurs in Black/African American women where it contributes to racial disparities in health outcomes. Therefore, we focused on new therapeutic approaches to TNBC. We discovered that levels of the Calcium-ATPase SPCA2 are abnormally low in TNBC and that these low levels correlate with poor survival prognosis in patients. Previously, we showed that recombinant SPCA2 prevented TNBC cells from acquiring aggressive ‘mesenchymal’ properties associated with metastasis bothin vitroandin vivo. These findings motivated us to search for drugs that turn the SPCA2 gene back on in TNBC cells. In this study, we show that histone deacetylase inhibitors increase SPCA2 levels, activate Ca2+signaling and convert cancer cells to a less aggressive ‘epithelial’ state. These findings could lead to new treatment options for TNBC.Graphical Abstract
Acetylation of L-leucine switches its carrier from the L-amino acid transporter (LAT) to organic anion transporters (OAT)
Authors: Churchill Grant C. , Strupp Michael , Bremova-Ertl Tatiana , Factor Mallory , Patterson Marc C , Platt Frances M. , Galione Antony 
Published: November 2020

ABSTRACTN-acetyl-DL-leucine is an analogue of the alpha amino acid leucine with a chiral stereocenter. The active L-enantiomer of the racemate is currently under development for rare neurological disorders. Here we present evidence that a selective recognition of N-acetyl-L-leucine versus L-leucine by different uptake transporters significantly contributes to the therapeutic effects of N-acetyl-L-leucine. A previous study of the pharmacokinetics of racemic N-acetyl-DL-leucine and N-acetyl-L-leucine revealed D-L enantiomer competition and saturation kinetics, best explained by carrier-mediated uptake. The strategy we used was to first analyze the physicochemical properties associated with good oral bioavailable drugs and how these are alerted by N-acetylation by comparing N-acetyl-L-leucine with L-leucine. Using in silico computational chemistry we found that N-acetylation has a profound impact on certain physicochemical properties that can rationalize why N-acetyl-L-leucine is drug-like compared to L-leucine. Our calculations show that at physiological pH, L-leucine is a zwitterion, whereas N-acetyl-L-leucine is present as mainly an anion. Specifically, N-acetylation removes a charge from the nitrogen at physiological pH and N-acetyl-L-leucine is an anion that is then a substrate for the organic anion transporters. We examined N-acetyl-L-leucine uptake in human embryonic kidney cells overexpression candidate organic anion transporters (OAT) and pharmacological inhibitors. We found that N-acetyl-L-leucine is a translocated substrate for OAT1 and OAT3 with low affinity (Km ~10 mM). In contrast, L-leucine is known to be transported by the L-type Amino Acid Transporter (LAT) with high affinity (Km ~0.2 mM) and low capacity. The clinical consequence is that L-leucine uptake becomes saturated at 50-fold lower concentration than N-acetyl-L-leucine. These results demonstrate a mechanism of action that explains why N-acetyl-L-leucine is effective as a drug and L-leucine itself is not.
Myelinating Schwann cells and Netrin-1 control intra-nervous vascularization of the developing mouse sciatic nerve
Authors: Taïb Sonia , Lamandé Noël , Martin Sabrina , Topilko Piotr , Brunet Isabelle 
Published: November 2020

AbstractPeripheral nerves are vascularized by a dense network of blood vessels to guarantee their complex function. Despite the crucial role of vascularization to ensure nerve homeostasis and regeneration, the mechanisms governing nerve invasion by blood vessels remain poorly understood. We found that the sciatic nerve invasion by blood vessels begins around embryonic day 16 and continues until birth. Interestingly, intra-nervous blood vessel density significantly decreases during post-natal period, starting from P10. We show that, while the axon guidance molecule Netrin-1 promotes nerve invasion by blood vessels during embryogenesis, myelinated Schwann cells negatively control intra-nervous vascularization during postnatal period.
The receptor-like cytoplasmic kinase MAZZA and CLAVATA-family receptors interactin vivo, together mediating developmental processes inArabidopsis thaliana
Authors: Blümke Patrick , Schlegel Jenia , Becher Sabine , Pinto Karine , Simon Rüdiger 
Published: November 2020

AbstractThe receptor-like kinases (RLKs) CLAVATA1 (CLV1) and BARELY ANY MERISTEMs (BAM1 – 3) form the CLV-family (CLVf), which perceives peptides of the CLV3/EMBRYO SURROUNDING REGION (ESR)-related (CLE) family within various signaling pathways ofArabidopsis thaliana. CLE peptide signaling, which is required for meristem size control, vascular development, or pathogen responses, involves the formation of receptor complexes at the plasma membrane (PM). These complexes comprise RLKs and co-receptors in varying compositions depending on the signaling context and regulate target gene expression, such asWUSCHEL(WUS). How the CLE signal is transmitted intracellularly after perception at the PM is not known.Here, we found that the membrane-associated receptor-like cytoplasmic kinase (RLCK) MAZZA (MAZ) MAZ and additional members of the Pti1-like protein family interactin vivowith CLVf receptors. MAZ, which is widely expressed throughout the plant, localizes to the PM via posttranslational palmitoylation potentially enabling stimulus-triggered protein re-localization. We identified a role for a CLV1/MAZ signaling module during stomatal and root development, and redundancy could potentially mask other phenotypes ofmaz-1mutants. We propose that RLCKs such as MAZ mediate CLVf signaling in a variety of developmental contexts, paving the way towards understanding the intracellular processes after CLE peptide perception.
Epithelial Infection withCandida albicansElicits a Multi-system Response in Planarians
Authors: Maciel Eli Isael , Arevalo Ashley Valle , Ziman Benjamin , Nobile Clarissa J. , Oviedo Néstor J. 
Published: November 2020

ABSTRACTCandida albicansis one of the most common fungal pathogens of humans. Prior work introduced the planarianSchmidtea mediterraneaas a new model system to study the host response to fungal infection at the organismal level. In the current study, we analyzed host-pathogen changes that occurredin situduring early infection withC. albicans. We found that the transcription factor Bcr1 and its downstream adhesin Als3 are required forC. albicansto adhere to and colonize the planarian epithelial surface, and that adherence ofC. albicanstriggers a multi-system host response that is mediated by the Dectin signaling pathway. This infection response is characterized by two peaks of stem cell divisions and transcriptional changes in differentiated tissues including the nervous and the excretory systems. This response bears some resemblance to a wound-like response to physical injury; however, it takes place without visible tissue damage and it engages a distinct set of progenitor cells. Overall, we identified twoC. albicansproteins that mediate epithelial infection of planarians and a comprehensive host response facilitated by diverse tissues to effectively clear the infection.
Bioinformatic and computational analysis reveals the prevalence and nature of PY motif-mediated protein-protein interactions in the Nedd4 family of ubiquitin ligases
Authors: Hatstat A. Katherine , Pupi Michael D. , McCafferty Dewey G. 
Published: November 2020

AbstractThe Nedd4 family contains several structurally related but functionally distinct HECT-type ubiquitin ligases. The members of the Nedd4 family are known to recognize substrates through their multiple WW domains, which recognize PY motifs (PPxY, LPxY) or phospho-threonine or phospho-serine residues. To better understand substrate specificity across the Nedd4 family, we report the development and implementation of a python-based tool, PxYFinder, to identify PY motifs in the primary sequences of previously identified interactors of Nedd4 and related ligases. Using PxYFinder, we find that, on average, half of Nedd4 family interactions are PY-motif mediated. Further, we find that PPxY motifs are more prevalent than LPxY motifs and are more likely to occur in proline-rich regions. Further, PPxY regions are more disordered on average relative to LPxY-containing regions. Informed by consensus sequences for PY motifs across the Nedd4 interactome, we rationally designed a peptide library and employed a computational screen, revealing sequence- and biomolecular interaction-dependent determinants of WW-domain/PY-motif interactions. Cumulatively, our efforts provide a new bioinformatic tool and expand our understanding of sequence and structural factors that contribute to PY-motif mediated substrate recognition across the Nedd4 family.
SAM homeostasis is regulated by CFIm-mediated splicing of MAT2A
Authors: Scarborough Anna M. , Flaherty Juliana N. , Hunter Olga V. , Liu Kuanqing , Kumar Ashwani , Xing Chao , Tu Benjamin P. , Conrad Nicholas K. 
Published: November 2020

SUMMARYS-adenosylmethionine (SAM) is the methyl donor for nearly all cellular methylation events. Cells regulate intracellular SAM levels through intron detention of the MAT2A RNA, which encodes only SAM synthetase expressed in most cells. The N6-adenosine methyltransferase METTL16 promotes splicing of the MAT2A detained intron by an unknown mechanism. Using an unbiased CRISPR knock-out screen, we identified CFIm25 (NUDT21) to be a regulator of MAT2A intron detention and intracellular SAM levels. CFIm25 is a component of the cleavage factor Im(CFIm) complex that regulates poly(A) site selection, but we show it promotes MAT2A splicing, independent of poly(A) site selection. CFIm25-mediated MAT2A splicing induction requires the RS domains of its binding partners, CFIm68 and CFIm59 as well as binding sites in detained intron and 3′ UTR. These studies uncover mechanisms that regulate MAT2A intron detention and reveal previously undescribed roles for CFImin splicing and SAM metabolism.
The small GTPase Arf6 functions as a membrane tether in a chemically-defined reconstitution system
Authors: Fujibayashi Kana , Mima Joji 
Published: November 2020

AbstractArf-family small GTPases are essential protein components for membrane trafficking in all eukaryotic endomembrane systems, particularly during the formation of membrane-bound, coat protein complex-coated transport carriers. In addition to their roles in the transport carrier formation, a number of Arf-family GTPases have been reported to physically associate with coiled-coil tethering proteins and multisubunit tethering complexes, which are responsible for membrane tethering, a process of the initial contact between transport carriers and their target subcellular compartments. Nevertheless, whether and how indeed Arf GTPases are involved in the tethering process remain unclear. Here, using a chemically-defined reconstitution approach with purified proteins of two representative Arf isoforms in humans (Arf1, Arf6) and synthetic liposomes for model membranes, we discovered that Arf6 can function as a bona fide membrane tether, directly and physically linking two distinct lipid bilayers even in the absence of any other tethering factors, whereas Arf1 retained little potency to trigger membrane tethering under the current experimental conditions. Arf6-mediated membrane tethering reactions requiretrans-assembly of membrane-anchored Arf6 proteins and can be reversibly controlled by the membrane attachment and detachment cycle of Arf6. The intrinsic membrane tethering activity of Arf6 was further found to be significantly inhibited by the presence of membrane-anchored Arf1, suggesting that the tethering-competent Arf6-Arf6 assembly intranscan be prevented by the heterotypic Arf1-Arf6 association in acisconfiguration. Taken together, these findings lead us to postulate that self-assemblies of Arf-family small GTPases on lipid bilayers contribute to driving and regulating the tethering events of intracellular membrane trafficking.
The road ahead: should Hong Kong develop five pillars of old age protection?
Authors: Lam Gigi 
Published: November 2020

PurposeThis paper demonstrates that Hong Kong currently provides four pillars of old-age protection: a publicly managed and noncontributory social security system (zero pillar), a funded contribution scheme (the second pillar), voluntary personal savings (the third pillar) and informal support, formal social programs and other individual financial assets (the fourth pillar). This paper aims at evaluating current four pillars of old-age protection and unraveling the deep-seated causes underlying the current old-age protection model by tracing a short history from 1965 onward. This paper aims at making recommendations about the current old-age protection model.Design/methodology/approachThe paper analyzes the current four pillars of old age protection. A comprehensive literature review was conducted covering relevant government reports, academics' journal papers and nongovernmental organizations' reports concerning the development of old age protection system from 1965 to the present.FindingsThe poverty rate of elderly residents was approximately 44.5% between 2009 and 2018, indicating that the four pillars of old-age protection had been unable to alleviate poverty in the aging population. The development of the current four pillars is attributed to a residual welfare system, the effectiveness of which is further dependent on familial dependence or welfare financialization. However, the reliability of familial dependence is affected by the declining coresidence rate and low fertility rate, whereas welfare financialization not only predominately favors financial institutions but also exacerbates income polarization. Therefore, the University of Hong Kong (2014) introduced an additional pillar of noncontributory social pension and assistance, which generated a contentious debate. The Hong Kong Special Administrative Region (HKSAR) government initiated a public engagement exercise on retirement protection in 2015 to assess public opinion on old-age protection. These consultation exercises were met with broad public disappointment because of the explicit reservations imposed by the government on the proposals.Practical implicationsAlthough the government's resistant attitude can be attributed to the residual welfare system, pension reform needs to be urgently implemented at three levels, namely strengthening of each pillar, emphasis on the pillar's interrelatedness and introduction of the first pillar.Originality/valueThe poverty of the elderly population is serious in Hong Kong. It is important to solve the deep-seated problems faced by the current old-age protection model. Hence, it comes a critical time to design a sustainable old-age protection model despite the heated discussion on the establishment of a central provident fund and pension system among officials since 1960s.
Family business in tourism: an international systematic review of literature with an emphasis on Latin America
Authors: López-Chávez Beatriz Adriana , Maldonado-Alcudia César , Larrañaga Núñez Ana María 
Published: November 2020

PurposeThe purpose of this study is to analyze the current state of knowledge of family businesses in tourism through a systematic review of international academic literature with an emphasis on Latin America.Design/methodology/approachThe paper opted for a systematic review involving analyzing international academic documents, articles, dissertations and papers that presented both theoretical and empirical research results. The search was conducted from January to April 2019 on online databases and search engines.FindingsStudies are concentrated in strategic planning and competitiveness. Most of them are published since 2014 by Ibero-American countries. Some features are coincident among the varied geographical contexts, as the importance of generational succession planning; search for family welfare throughout the business; and the existence of own capacities and resources. Besides, the owner's objectives and gender involvement differ in the research results of developed countries and emerging economies; some implications for Latin America are analyzed.Originality/valueThe family business has international economic relevance, especially in tourism. Still, the studies in this field are few, even when tourism implies processes and interactions that can influence the development of the companies that integrate their industry. In this way, a compilation of the recent works is carried out, in order to identify how the complex family dynamics with tourism are integrated into the studies, main contributions to the field and knowledge gaps.
Humanistic leadership in a Chinese context
Authors: Yang Bo , Fu Pingping , Beveridge ‘Alim J. , Qu Qing 
Published: November 2020

PurposeThrough three case studies, the authors aim to examine how Confucian humanistic philosophy can be applied to leadership practices and show how it is possible to practice humanistic leadership in the Chinese context.Design/methodology/approachThe authors use case studies of three exemplary humanistic leaders and the companies they lead to describe their leadership practices and influence on others and their companies.FindingsThe authors identify three common elements that connect their observations to an emerging scholarly conceptualization of humanistic leadership and develop a framework of Confucian humanistic leadership consisting of five attributes. The cases the authors studied suggest that the five attributes should be understood as being mutually reinforcing and acting in concert, rather than each acting independently of the others. The authors found that there is inherent consistency and connection between the core values of Confucianism and humanistic leadership.Originality/valueThe research contributes to the leadership literature, specifically the emerging literature on humanistic leadership, by introducing a framework for Confucian humanistic leadership. While much of the extant literature on humanistic leadership has been conceptual, the study shows how it is possible to practice humanistic leadership in the Chinese context by drawing on the foundation provided by Confucian humanistic philosophy. The findings also contribute to humanistic leadership research by providing important insights into specific capabilities that can help put the principles of humanistic leadership into practice, but that have not been considered to date.
Does the market for corporate control influence executive risk-taking incentives? Evidence from takeover vulnerability
Authors: Ongsakul Viput , Chatjuthamard Pattanaporn , Jiraporn Napatsorn , Jiraporn Pornsit 
Published: November 2020

Purpose
This study aims to investigate the role of the market for corporate control as an external governance mechanism and its effect on executive risk-taking incentives. Managers tend to be risk-averse as they are more exposed to idiosyncratic risk, resulting in sub-optimal risk-taking that does not maximize shareholders’ wealth. The takeover market alleviates this problem, inducing managers to take more risk. Therefore, risk-taking incentives inside the firm are less powerful when the outside takeover market is more active.

Design/methodology/approach
Exploiting a novel measure of takeover vulnerability recently constructed by Cain et al. (2017), the authors explore how takeover vulnerability influences executive risk-taking incentives. Using a large sample of US firms, the authors use fixed-effects regressions, propensity score matching and instrumental variable analysis.

Findings
Consistent with this study’s hypothesis, a more active takeover market results in less powerful risk-taking incentives. Specifically, a rise in takeover vulnerability by one standard deviation diminishes executive risk-taking incentives by 22.39%, which is an economically meaningful magnitude.

Originality/value
To the best of the authors’ knowledge, this study is the first to explore the effect of the takeover market on managerial risk-taking incentives, using a novel measure of takeover susceptibility. The authors’ measure of takeover vulnerability is considerably less susceptible to endogeneity, enabling the authors to draw causal inferences with more confidence.