bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring the role of glycans in the interaction of SARS-CoV-2 RBD and human receptor ACE2
Authors: Nguyen Kien , Chakraborty Srirupa , Mansbach Rachael A. , Korber Bette , Gnanakaran S.
Published: March 2021

COVID-19 is a highly infectious respiratory disease caused by the novel coronavirus SARS-CoV-2. It has become a global pandemic and its frequent mutations may pose new challenges for vaccine design. During viral infection, the Spike RBD of SARS-CoV-2 binds the human host cell receptor ACE2, enabling the virus to enter the host cell. Both the Spike and ACE2 are densely glycosylated, and it is unclear how distinctive glycan types may modulate the interaction of RBD and ACE2. Detailed understanding of these determinants is key for the development of novel therapeutic strategies. To this end, we perform extensive all-atom simulations of the (i) RBD-ACE2 complex without glycans, (ii) RBD-ACE2 with oligomannose MAN9 glycans in ACE2, and (iii) RBD-ACE2 with complex FA2 glycans in ACE2. These simulations identify the key residues at the RBD-ACE2 interface that form contacts with higher probabilities, thus providing a quantitative evaluation that complements recent structural studies. Notably, we find that this RBD-ACE2 contact signature is not altered by the presence of different glycoforms, suggesting that RBD-ACE2 interaction is robust. Applying our simulated results, we illustrate how the recently prevalent N501Y mutation may alter specific interactions with host ACE2 that facilitate the virus-host binding. Furthermore, our simulations reveal how the glycan on Asn90 of ACE2 can play a distinct role in the binding and unbinding of RBD. Finally, an energetics analysis shows that MAN9 glycans on ACE2 decrease RBD-ACE2 affinity, while FA2 glycans lead to enhanced binding of the complex. Together, our results provide a more comprehensive picture of the detailed interplay between virus and human receptor, which is much needed for the discovery of effective treatments that aim at modulating the physical-chemical properties of this virus.
Ovarian cancers with low CIP2A tumor expression constitute an APR-246 sensitive disease subtype
Authors: Cvrljevic Anna N. , Butt Umar , Huhtinen Kaisa , Grönroos Tove J. , Böckelman Camilla , Lassus Heini , Kaipio Katja , Arsiola Tiina , Laajala Teemu D. , Connolly Denise C. , Ristimäki Ari , Carpen Olli , Pouwels Jeroen , Westermarck Jukka
Published: March 2021

Identification of ovarian cancer (OvCa) patient subpopulations with increased sensitivity to targeted therapies could offer significant clinical benefit. We report that 22% of the high grade OvCa tumors at diagnosis express CIP2A oncoprotein at low levels. CIP2AlowOvCa tumors have significantly lower likelihood of disease relapse after standard chemotherapy, but yet a portion of relapsed tumors retain their CIP2Alowphenotype. We further discover that reactive oxygen species (ROS) inducing compound APR-246 (PRIMA-1Met/Eprenetapopt), currently in clinical development, preferentially kill CIP2AlowOvCa cells across multiple chemotherapy resistant cell lines. Consistent with CIP2AlowOvCa subtype in humans, CIP2A is dispensable for development of MISIIR-TAg-driven mouse OvCa tumors. Nevertheless, CIP2A deficient OvCa tumor cells from MISIIR-TAg mice displayed APR-246 hypersensitivity bothin vitroandin vivo. Mechanistically, the lack of CIP2A expression hypersensitizes the OvCa cells to APR-246 by inhibition of NF-kB activity. Accordingly, combination of APR-246 and Nf-kB inhibitor compounds strongly synergized in killing of CIP2A positive OvCa cells. Collectively, we discover low CIP2A expression as a vulnerability for APR-246 in OvCa. The results warrant consideration of clinical testing of APR-246 for CIP2AlowOvCa tumor subtype patients, and reveal CIP2A as a candidate APR-246 combination therapy target.
Comparison of Type-1 and Type-2 Fuzzy Systems for Mineralization of Bioprinted Bone
Authors: Sedigh Ashkan , Akbarzadeh-T Mohammad-R. , Tomlinson Ryan E.
Published: March 2021

Bioprinting is an emerging tissue engineering method used to generate cell-laden scaffolds with high spatial resolution. Bioprinting parameters, such as pressure, nozzle size, and speed, have a large influence on the quality of the bioprinted construct. Moreover, cell suspension density, cell culture period, and other critical biological parameters directly impact the biological function of the final product. Therefore, an approximation model that can be used to find the values of bioprinting parameters that will result in optimal bioprinted constructs is highly desired. Here, we propose type-1 and type-2 fuzzy systems to handle the uncertainty and imprecision in optimizing the input values. Specifically, we focus on the biological parameters, such as culture period, that can be used to maximize the output value (mineralization volume). To achieve a more accurate approximation, we have compared a type-2 fuzzy system with a type-1 fuzzy system using two levels of uncertainty. We hypothesized that type-2 fuzzy systems may be preferred in biological systems, due to the inherent vagueness and imprecision of the input data. Here, our results demonstrate that the type-2 fuzzy system with a high uncertainty boundary (30%) is superior to type-1 and type-2 with low uncertainty boundary fuzzy systems in the overall output approximation error for bone bioprinting inputs.
Distribution rules of systematic absences and generalized de Wolff figures of merit applied to electron backscatter diffraction ab initio indexing
Authors: Oishi-Tomiyasu Ryoko , Tanaka Tomohito , Nakagawa Jun'ichi
Published: March 2021

A new method for electron backscatter diffraction ab initio indexing is reported that adopts several methods originally invented for powder indexing. Distribution rules of systematic absences and error-stable Bravais lattice determination are used to eliminate the negative influence of non-visible bands and erroneous information from visible bands. In addition, generalized versions of the de Wolff figures of merit are proposed as a new sorting criterion for the obtained unit-cell parameters, which can be used in both orientation determination and ab initio indexing from Kikuchi patterns. Computational results show that the new figures of merit work well, similar to the original de Wolff Mn
. The ambiguity of the indexing solutions is also pointed out, which happens in particular for low-symmetry cells and may generate multiple distinct solutions even if very accurate positions of band centre lines and the projection centre are given. It is supposed that this is the reason why indexing was successful in an orthorhombic case but not in a triclinic cell.
Preliminary results of neutron and X-ray diffraction data collection on a lytic polysaccharide monooxygenase under reduced and acidic conditions
Authors: Schröder Gabriela C. , O'Dell William B. , Swartz Paul D. , Meilleur Flora
Published: March 2021

Lytic polysaccharide monooxygenases (LPMOs) are copper-center enzymes that are involved in the oxidative cleavage of the glycosidic bond in crystalline cellulose and other polysaccharides. The LPMO reaction is initiated by the addition of a reductant and oxygen to ultimately form an unknown activated copper–oxygen species that is responsible for polysaccharide-substrate H-atom abstraction. Given the sensitivity of metalloproteins to radiation damage, neutron protein crystallography provides a nondestructive technique for structural characterization while also informing on the positions of H atoms. Neutron cryo-crystallography permits the trapping of catalytic intermediates, thereby providing insight into the protonation states and chemical nature of otherwise short-lived species in the reaction mechanism. To characterize the reaction-mechanism intermediates of LPMO9D from Neurospora crassa, a cryo-neutron diffraction data set was collected from an ascorbate-reduced crystal. A second neutron diffraction data set was collected at room temperature from an LPMO9D crystal exposed to low-pH conditions to probe the protonation states of ionizable groups involved in catalysis under acidic conditions.
Boundary-spanning search, knowledge integration capability and sustainable competitive advantage
Authors: Yang Miaomiao , Wang Juanru , Yang Jin
Published: March 2021

Purpose

The purpose of this paper is to investigate how boundary-spanning search affects sustainable competitive advantage under the conditions that competitors also search and to test the moderating role of knowledge integration capability.

Design/methodology/approach

This paper classifies boundary-spanning search into proactive search and responsive search by considering competition and develops a theoretical model in which knowledge integration capability moderates the effects of proactive and responsive searches on sustainable competitive advantage. Empirical analyses were conducted on the data of 245 Chinese advanced manufacturing firms.

Findings

The results show that proactive and responsive searches have inverted U-shaped relationships with sustainable competitive advantage. Moreover, the relationships between proactive and responsive searches and sustainable competitive advantage are moderated by knowledge integration capability. Specifically, as knowledge integration capability increases, the inverted U-shaped relationship between proactive search and sustainable competitive advantage becomes flatter, whereas the inverted U-shaped relationship between responsive search and sustainable competitive advantage becomes almost linear.

Originality/value

This paper enriches the research of boundary-spanning search by considering competition and uncovers how boundary-spanning search affects sustainable competitive advantage under the conditions that competitors also search. Furthermore, this paper sheds light on that the effects of proactive and responsive searches on sustainable competitive advantage are even more complex than inverted U-shaped patterns and provides a contingent viewpoint to deeply understand the relationship between boundary-spanning search and sustainable competitive advantage.
Familial altruism and reputation risk: evidence from China
Authors: Fang Hanqing “Chevy” , Shi Yulin , Wu Zhenyu
Published: March 2021

Purpose

The authors study the effects of altruism and intention for succession on family firm's reputation risk-taking behaviors in Chinese publicly listed companies.

Design/methodology/approach

The authors use earnings management as a proxy for reputation risk in family firms, and hand-collected relationship between family members to measure the closeness of incumbent family members and their potential successors as a proxy for the altruistic degree.

Findings

Results show that, in developing countries like China, familial altruism in family firms with succession plans, which does not reduce the practice of earnings management, should be considered by practitioners while detecting it.

Originality/value

The hand collected data are very unique; the authors have focused on the relationship between incumbents and successors and the authors define their closeness by using genes shared between them.
Assessing large-scale digitization using Web analytics
Authors: Lapworth Emily
Published: March 2021

Purpose

The purpose of this study is to assess the use of digital collections created via the large-scale digitization of archival collections. The large-scale digitization method specifically examined is the reuse of archival description from finding aids to create digital collections that consist mainly of compound digital objects, equivalent to a folder of items, minimally described at the aggregate level. This paper compares Web analytics data for two large-scale digital collections and one digital collection with rich, item-level description.

Design/methodology/approach

This study analyzed one year of Web analytics for three digital collections. The main research question of this study is: Are digital collections of minimally described compound objects used less than digital collections of richly described single objects?

Findings

This study found that the large-scale digital collections analyzed received less use than the traditional item-level collection, when examined at the item level. At the object level, the large-scale collections did not always receive less use than the traditional item-level collection.

Research limitations/implications

This study is limited to three different digital collections from one institution. Web analytics also represent a limited interpretation of “use.”

Practical implications

This study presents a method for other institutions to assess their own large-scale digitization efforts and contributes to the profession’s understanding of the impact of large-scale digitization.

Originality/value

This paper is unique because it uses Web analytics to compare the use of large-scale digital collections to the use of traditional boutique digital collections.
Traditional water knowledge: challenges and opportunities to build resilience to urban floods
Authors: Asad Rumana , Ahmed Iftekhar , Vaughan Josephine , von Meding Jason
Published: March 2021

Purpose

Urban flooding in developing countries of the Global South is growing due to extreme rainfall and sea-level rise induced by climate change, as well as the proliferation of impervious, built-up areas resulting from unplanned urbanisation and development. Continuous loss of traditional knowledge related to local water management practices, and the de-valuing of such knowledge that goes hand-in-hand with globalised aspirations, is inhibiting flood resilience efforts. This paper aims to address the need to include traditional water knowledge (TWK) in urban living and development processes in the Global South.

Design/methodology/approach

This paper commences with a review of existing frameworks that focus on natural resource management, critically assessing two existing frameworks of traditional ecological knowledge (TEK). The assessment of the existing approaches contributes to this paper’s development of a novel framework to promote TWK with regard to resilience and risk reduction, specifically for developing flood adaptive strategies, which is the second stage of this paper. Finally, the paper explains how the framework can contribute to the field of urban design and planning using examples from the literature to demonstrate challenges and opportunities related to the adaptation of such a framework.

Findings

The framework developed in this paper reveals three proposed vertices of TWK, named as place-based landscape knowledge, water use and management and water values. This framework has the potential to produce context-specific knowledge that can contribute to flood-resilient built-environment through urban design and practices.

Research limitations/implications

The framework developed in this paper reveals three proposed vertices of TWK, named place-based landscape knowledge, water use and management and water values. This framework has the potential to produce context-specific knowledge that can contribute to flood-resilient built-environment through urban design and practices.

Originality/value

Within the field of TEK research, very few researchers have explored the field of developing flood resilience in an urban context. The proposed TWK framework presented in this paper will help to fill that gap.
Factors affecting transaction costs in megaprojects: a qualitative comparative analysis
Authors: Wang Dedong , Li Hui , Lu Yongqiang
Published: March 2021

Purpose

The purpose of this study is to examine the factors influencing the transaction costs (TCs) in megaprojects to provide a basis for controlling project costs.

Design/methodology/approach

This study selects six factors influencing the TCs in megaprojects from the perspective of TC theory and relational contract theory (RCT) through literature review. On the basis of crisp-set qualitative comparative analysis (QCA), this study tests combined factors influencing the TCs and the interaction between them.

Findings

Results show that in megaprojects, TCs are affected by combination factors. The combination of asset specificity, uncertainty, transaction frequency and trust and the combination of asset specificity, reputation and trust will control TCs in certain situations. In the configuration leading to high project TCs, the combination of environmental and behavioral uncertainties is a necessary condition.

Originality/value

This paper fills up the research gap in the field of megaproject TCs, and researchers can focus on this field in the future.
Economic development, population and civil war: a Bayesian changepoint model
Authors: Luo Shali , Choi Seung-Whan
Published: March 2021

Purpose

This study proposes a Bayesian approach to analyze structural breaks and examines whether structural changes have occurred, at the onset of civil war, with respect to economic development and population during the period from 1945 to 1999.

Design/methodology/approach

In the Bayesian logit regression changepoint model, parameters of covariates are allowed to shift individually, regime transitions can move back and forth, and the model is applicable to cross-sectional, time-series data.

Findings

Contrary to popular belief that the causal process of civil war changed with the end of the Cold War, the empirical analysis shows that the regression relationships between civil war and economic development, as well as between civil war and population, remain quite stable during the study period.

Originality/value

This is the first to develop a Bayesian logit regression changepoint model and to apply it to studies of economic development and civil war.
An assessment of budgeting and budgetary controls among small and medium-sized enterprises: evidence from a developing economy
Authors: Matsoso Mamorena Lucia , Nyathi Moses , Nakpodia Franklin A.
Published: March 2021

Purpose

The capacity to plan, manage and control small and medium-sized enterprises (SMEs) is critical to realising their organisational goals. This paper assesses the effectiveness and perception of budgeting and budgetary control systems among SMEs.

Design/methodology/approach

Relying on the goal-setting theory (GST) and a methodology that accommodates questionnaires, data were collected from 170 manufacturing SMEs located in Cape Town, South Africa.

Findings

Research results affirm that the deployment of budgeting benefits from a positive perception of the value of budgeting and budgetary controls by key SME stakeholders. The study also finds that the perception of budgeting mirrors the level of education of SME operators, as educated respondents understand the value of implementing robust budgeting systems. Despite its focus on manufacturing SMEs, this study suggests that the manufacturing budget is the least utilised budgeting system among these organisations.

Practical implications

The study reinforces the communication power of budgeting and budgetary controls as SMEs and economic agents are not only aware of corporate objectives but are equally incentivised to support the attainment of these objectives.

Originality/value

Despite the extensive application of GST among scholars, its use in budgeting and budgetary control literature, particularly among SMEs in developing contexts, is limited. In line with GST, this study indicates that when agents establish and implement a plan, they are motivated to pursue and realise the set expectations while consistently evaluating themselves for improvement opportunities.
The effects of government spending shocks on real exchange rate in Ethiopia
Authors: Gidey Hiluf Techane , Nuru Naser Yenus
Published: March 2021

Purpose

Government spending has inconclusive effect on real exchange rate. From the very beginning neoclassical economists argued that a rise in government spending brings depreciation in real exchange rate while neo-Keynesians claimed that government spending appreciates real exchange rate. Hence, the main purpose of this paper is to examine the effect of government spending shock and its components' shocks, namely government consumption and government investment on real exchange rate over the period 2001Q1–2016Q1 for Ethiopia.

Design/methodology/approach

To examine the effects of government spending shocks on real exchange rate, Jordà's (2005) local projection method is employed in this study. The exogenous shocks, however, are identified recursively in a vector autoregressive model.

Findings

The impulse responses show that government spending shock leads to a statistically significant appreciation of real exchange rate in Ethiopia. This evidence supports the neo-Keynesian school of thought who predicts an appreciation of real exchange rate from a rise in government spending. While government investment shock depreciates real exchange rate on impact insignificantly, government consumption shock appreciates real exchange rate in this small open economy.

Originality/value

This research contributes to the scarce literature on the effect of fiscal policy shock on real exchange rate in small open economies like Ethiopia.
Refining a subsidiary evolution framework: clarifying key concepts
Authors: Jakobsson Johan , Lagerström Katarina , Schweizer Roger
Published: March 2021

Purpose

While the evolution of subsidiaries has received considerable research attention, the framework for understanding it has not evolved much since the late 1990s. The purpose of this paper is to add both clarity and depth to the work on the foundations for – as well as the processes of – capability creation and development as a subsidiary evolves.

Design/methodology/approach

This conceptual paper takes as its point of departure the micro-foundation literature, with a specific emphasis on the capability development literature. To describe capability creation and development, both the resource-based view and the resource management perspective are used here.

Findings

The paper adds a conceptual layer to the drivers of subsidiary evolution. To add further clarity regarding how capabilities are actually formed, the resources for capability creation and development are specified herein as entities, abilities and capacity. Arguments are also presented for why capabilities ought to be viewed as patterned behavior to decrease the terminological ambiguity surrounding the concept of capabilities. The process of capability creation and development with an emphasis on learning is brought forward. Further, capability typologies, in terms of substantive, managerial and dynamic capabilities, are presented to add specificity to the kinds of capabilities that are created and developed within a subsidiary.

Originality/value

Clarifying the concept of capability and how capabilities are formed by using advancements in the literature is important to add precision to the literature on the evolution of subsidiaries.
Effect of 3D printer enabled surface morphology and composition on coral growth in artificial reefs
Authors: Matus Ilse Valenzuela , Lino Alves Jorge , Góis Joaquim , Barata da Rocha Augusto , Neto Rui , Da Silva Mota Carlos
Published: March 2021

Purpose

The purpose of this paper is to prove and qualify the influence of textured surface substrates morphology and chemical composition on the growth and propagation of transplanted corals. Use additive manufacturing and silicone moulds for converting three-dimensional samples into limestone mortar with white Portland cement substrates for coral growth.

Design/methodology/approach

Tiles samples were designed and printed with different geometries and textures inspired by nature marine environment. Commercial coral frag tiles were analysed through scanning electron microscopy (SEM) to identify the main chemical elements. Raw materials and coral species were selected. New base substrates were manufactured and deployed into a closed-circuit aquarium to monitor the coral weekly evolution process and analyse the results obtained.

Findings

Experimental results provided positive statistical parameters for future implementation tests, concluding that the intensity of textured surface, interfered favourably in the coralline algae biofilm growth. The chemical composition and design of the substrates were determinant factors for successful coral propagation. Recesses and cavities mimic the natural rocks aspect and promoted the presence and interaction of other species that favour the richness of the ecosystem.

Originality/value

Additive manufacturing provided an innovative method of production for ecology restoration areas, allowing rapid prototyping of substrates with high complexity morphologies, a critical and fundamental attribute to guarantee coral growth and Crustose Coralline Algae. The result of this study showed the feasibility of this approach using three-dimensional printing technologies.
Does lesbian and gay friendliness pay off? A new look at LGBT policies and firm performance
Authors: Fatmy Veda , Kihn John , Sihvonen Jukka , Vähämaa Sami
Published: March 2021

This paper examines the association between LGBT‐friendly corporate policies and firm performance. Using data on US firms from 2003 to 2016, we document that LGBT friendliness is positively associated with firm performance. Specifically, we find strong evidence that more LGBT‐friendly firms have higher profitability and higher stock market valuations. Our results further demonstrate that the positive effect of progressive LGBT policies on firm performance is more pronounced for firms located in more liberal states. Overall, our empirical findings provide support for the view that socially progressive corporate policies and diversity management may create value for the firm.
The effect of needle and syringe program and opioid agonist therapy on the risk of HIV, hepatitis B and C virus infection for people who inject drugs in Amsterdam, the Netherlands: findings from an emulated target trial
Authors: van Santen Daniela K. , Boyd Anders , Matser Amy , Maher Lisa , Hickman Matthew , Lodi Sara , Prins Maria
Published: March 2021

Background and aims

Major declines in HIV and hepatitis C and B virus (HCV/HBV) incidence among people who inject drugs (PWID) have been attributed to early implementation of harm‐reduction programs (HRP) in the Netherlands, but alternative factors such as selective mortality and demographic and drug market shifts over time probably contributed to observed incidence declines. We quantified and tested the effect of HRP participation on risk of these infections among PWID in Amsterdam, the Netherlands.

Design

We emulated the design of a hypothetical, ideal randomized trial using observational data from the Amsterdam Cohort Studies (1985–2014).

Setting

Amsterdam, the Netherlands.

Participants

We included PWID who ever used opioids, had a recent history of injecting drug use (IDU) and tested negative for HIV, HCV or HBV. Of 983 participants, 640, 137 and 308 were included for the HIV, HCV and HBV analyses and 59, 45 and 49 seroconversions were observed, respectively.

Interventions

Intervention arms were: complete HRP participation [≥ 60 mg/day methadone and 100% needle and syringe program (NSP) coverage, or any methadone dose if no recent injection drug use] versus no HRP and partial HRP participation combined (< 60 methadone mg/day and/or < 100% NSP coverage).

Conclusions

Complete participation in harm reduction programs appears to have led to substantial decreases in HIV and hepatitis C and B virus acquisition risk among people who inject drugs in the Netherlands.

Measurements

Separately for each infection, we estimated the hazard ratios (HR) comparing HRP arms using marginal structural models.

Findings

Compared with no/partial HRP participation, complete HRP participation led to lower risk of HIV [HR = 0.54, 95% confidence interval (CI) = 0.27–1.08], HCV (HR = 0.16, 95% CI = 0.06–0.40) and HBV (HR = 0.28, 95% CI = 0.13–0.61) acquisition.
How Institutional Identity Shapes College Student Recruitment: The Relationship Between Religious Distinctiveness and Market Demand
Authors: Rine P. Jesse , Brown Joshua T. , Hunter James M.
Published: March 2021

Institutional diversity has long been recognized as a signature strength of the American system of higher education, yet the sector contributing most to this remarkable feature—small and midsized private colleges—currently finds itself under significant financial pressure as a result of recent social and economic disruptions. To overcome such challenges, campus leaders must understand the market positioning of the institutions they serve. This article investigates the relationship between market demand and organizational distinctiveness within one segment of the diverse private sector—religiously affiliated colleges. It draws upon longitudinal data from the membership of one national professional association, the Council for Christian Colleges & Universities, to develop an empirical typology of institutional religious distinctiveness and examine patterns of market demand over time. Results suggest that religious distinctiveness has a medium effect on student demand at both the application and matriculation phases of the admissions process. The article concludes by considering appropriate recruitment strategies for faith‐based colleges and universities depending on their degree of religious distinctiveness.
Choosing Transformation Over Tradition: The Changing Perception of Online Education
Authors: Ronkowitz Kenneth , Ronkowitz Lynnette Condro
Published: March 2021

Despite advancements in online education, misperceptions persist that create obstacles to the integration of online classes in higher education. This essay refutes misconceptions about online education and highlights key components of a strong online course. As a result of the pandemic, it became apparent that there is a conflation between “school” and “education” that has prompted contradistinction. This discussion provides insight into some of the social and economic implications of the culture of our education system.
Intention without action? Differences between whistleblowing intention and behavior on corruption and fraud
Authors: Oelrich Sebastian
Published: March 2021

Whistleblowing is an effective tool against fraud and corruption in organizations. However, as researchers have struggled to acquire data on actual whistleblowers, research relies on hypothetical intention data and student samples, which is seen as a major limitation. Using a field study of 1,416 employees from China, Germany, and Russia, the purpose of this article is to identify differences and similarities between intention and actual whistleblowing decisions, thus aiding research and interpretation of prior and future studies. I also contribute by analyzing whether findings can be generalized across different cultures and whether status and power influence the whistleblowing process. My results reveal that the key difference between hypothetical and real decisions is not in variables that affect the process, but in effect sizes: Employees underestimate the effect of situational (retaliation) and organizational (compliance measures) variables in hypothetical compared to actual whistleblowing. Thus, reliance on intention research is not inherently problematic, when effect sizes are interpreted with caution. I also find that results are similar across countries and that status and power may not be decisive factors in whistleblowing. My findings should also be of interest to practitioners and policymakers, as they assist in designing effective whistleblowing systems and environments in organizations.
Upregulation of the pathogenic transcription factor SPI1/PU.1 in tuberous sclerosis complex and focal cortical dysplasia by oxidative stress
Authors: Zimmer Till S. , Korotkov Anatoly , Zwakenberg Susan , Jansen Floor E. , Zwartkruis Fried J. T. , Rensing Nicholas R. , Wong Michael , Mühlebner Angelika , van Vliet Erwin A. , Aronica Eleonora , Mills James D.
Published: March 2021

Tuberous sclerosis complex (TSC) is a congenital disorder characterized by cortical malformations and concomitant epilepsy caused by loss‐of‐function mutations in the mTOR suppressorsTSC1orTSC2. While the underlying molecular changes caused by mTOR activation in TSC have previously been investigated, the drivers of these transcriptional change have not been fully elucidated. A better understanding of the perturbed transcriptional regulation could lead to the identification of novel pathways for therapeutic intervention not only in TSC, but other genetic epilepsies in which mTOR activation plays a key role, such as focal cortical dysplasia 2b (FCD). Here, we analyzed RNA sequencing data from cortical tubers and a tsc2−/−zebrafish. We identified differential expression of the transcription factors (TFs) SPI1/PU.1, IRF8, GBX2, and IKZF1 of which SPI1/PU.1 and IRF8 targets were enriched among the differentially expressed genes. Furthermore, for SPI1/PU.1 these findings were conserved in TSC zebrafish model. Next, we confirmed overexpression of SPI1/PU.1 on the RNA and protein level in a separate cohort of surgically resected TSC tubers and FCD tissue, in fetal TSC tissue, and aTsc1GFAP−/−mouse model of TSC. Subsequently, we validated the expression of SPI1/PU.1 in dysmorphic cells with mTOR activation in TSC tubers. In fetal TSC, we detected SPI1/PU.1 expression prenatally and elevated RNA Spi1 expression inTsc1GFAP−/−mice before the development of seizures. Finally,in vitro, we identified that in astrocytes and neuronsSPI1transcription was driven by H2O2‐induced oxidative stress, independent of mTOR. We identified SPI1/PU.1 as a novel TF involved in the pro‐inflammatory gene expression of malformed cells in TSC and FCD 2b. This transcriptional program is activated in response to oxidative stress and already present prenatally. Importantly, SPI1/PU.1 protein appears to be strictly limited to malformed cells, as we did not find SPI1/PU.1 protein expression in mice nor in ourin vitromodels.
Mechanisms of endocannabinoid transport in the brain
Authors: Kaczocha Martin , Haj‐Dahmane Samir
Published: March 2021

The endocannabinoids 2‐arachidonoylglycerol (2‐AG) and anandamide are among the best studied lipid messengers in the brain. By activating cannabinoid receptors in the CNS, endocannabinoids tune synaptic function, thereby influencing a variety of physiological and behavioural processes. Extensive research conducted over the last few decades has considerably enhanced our understanding of the molecular mechanisms and physiological functions of the endocannabinoid system. It is now well‐established that endocannabinoids are synthesized by postsynaptic neurons and serve as retrograde messengers that suppress neurotransmitter release at central synapses. While the detailed mechanisms by which endocannabinoids gate synaptic function and behavioural processes are relatively well characterized, the mechanisms governing endocannabinoid transport at central synapses remain ill defined. Recently, several studies have begun to unravel the mechanisms governing intracellular and intercellular endocannabinoid transport. In this review, we will focus on new advances in the mechanisms of intracellular and synaptic endocannabinoid transport in the CNS.

LINKED ARTICLES

This article is part of a themed issue on New discoveries and perspectives in mental and pain disorders. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.17/issuetoc
Order and Atmospheric Memory: Cleaning Up the Past, Designing the Future
Authors: Schwabe Siri
Published: March 2021

This article is concerned with the relationship between atmosphere and memory in the context of rapid urban development. I explore this relationship by looking to the northeastern fringes of central Stockholm, where a new neighborhood is being constructed in extension of industrial and residential areas long established as integral albeit peripheral parts of the city. Known by its official English‐language moniker as Stockholm Royal Seaport, this neighborhood‐in‐the‐works occupies a unique location within the growing city. Meanwhile, the local environment is currently undergoing a process of cleaning up that allows for a multisensorial and imaginative engagement with both past and future. In interrogating this case, I argue that designing for the future has come to entail a curation of the past that obfuscates difference and creates order throughatmospheric memory: memory that shapes and is shaped by atmospheres.
Board reforms around the world: The effect on corporate social responsibility
Authors: Liao Chih‐Hsien , San Ziyao , Tsang Albert , Yu Li
Published: March 2021

Research Question/Issue

This study examines the effects of major board reforms on firms' corporate social responsibility (CSR) performance in countries around the world.

Research Findings/Insights

Using a difference‐in‐differences design, we find robust evidence that worldwide board reforms can have significant effects on various stakeholders, resulting in increased firm CSR performance in both the environmental and social dimensions. Relative to countries that have implemented comply‐or‐explain reforms, countries with rule‐based reforms tend to drive the increase in CSR performance post‐reform. Our results hold for both first board reforms and major reforms, across different types of reforms, and across various dimensions of CSR performance. In addition, the effect of reforms on CSR performance is more pronounced for firms with higher levels of institutional ownership or lower levels of insider ownership and in countries with weaker CSR awareness and more stringent legal and regulatory environments. Further analyses show that reforms strengthen the relationship between CSR performance and future financial performance. Finally, we explore the possible mechanism through which board reforms could have a significant effect on firms' CSR performance. We find that board reforms increase a firm's likelihood of integrating CSR criteria in executive compensation.

Theoretical/Academic Implications

The findings of this study suggest that worldwide board reforms that aim to increase shareholders' value can also have significant effects on various stakeholders, resulting in increased firm CSR performance in both the environmental and social dimensions, a non‐financial dimension of firm performance.

Practitioner/Policy Implications

Our evidence suggests that increases in CSR performance are an important channel through which board reforms can increase shareholder value. In addition, our findings suggest that the effectiveness of reforms on CSR varies with both firm‐ and country‐level characteristics related to the relative influence of external shareholders. Thus, this study offers insights to policy makers interested in enhancing CSR performance in their country.
Adverse drug event risk assessment by the virtual addition of COVID‐19 repurposed drugs to Medicare and commercially insured patients’ drug regimens: A drug safety simulation study
Authors: Smith Matt K. , Bikmetov Ravil , Al Rihani Sweilem B. , Deodhar Malavika , Hafermann Matthew , Dow Pamela , Turgeon Jacques , Michaud Veronique
Published: March 2021

Drug safety is generally established from clinical trials, by pharmacovigilance programs and during observational phase IV safety studies according to drug intended or approved indications. The objective of this study was to estimate the risk of potential adverse drug events (ADEs) associated with drugs repurposed for coronavirus disease 2019 (COVID‐19) treatment in a large‐scale population. Drug claims were used to calculate a baseline medication risk score (MRS) indicative of ADE risk level. Fictitious claims of repurposed drugs were added, one at a time, to patients’ drug regimens to calculate a new MRS and compute a level of risk. Drug claims data from enrollees with Regence health insurance were used and sub‐payer analyses were performed with Medicare and commercial insured groups. Simulated interventions were conducted with hydroxychloroquine and chloroquine, alone or combined with azithromycin, and lopinavir/ritonavir, along with terfenadine and fexofenadine as positive and negative controls for drug‐induced Long QT Syndrome (LQTS). There were 527,471 subjects (56.6% women; mean [SD] age, 47 years [21]) were studied. The simulated addition of each repurposed drug caused an increased risk of ADEs (median MRS increased by two‐to‐seven points, p < 0.001). The increase in ADE risk was mainly driven by an increase in CYP450 drug interaction risk score and by drug‐induced LQTS risk score. The Medicare group presented a greater risk overall compared to the commercial group. All repurposed drugs were associated with an increased risk of ADEs. Our simulation strategy could be used as a blueprint to preemptively assess safety associated with future repurposed or new drugs.
Macrophage migration inhibitory factor predicts an unfavorable outcome after transarterial chemoembolization for hepatic malignancies
Authors: Wirtz Theresa H. , Loosen Sven H. , Schulze‐Hagen Max , Gorgulho Joao , Kandler Jennis , Joerdens Markus , Demir Münevver , Mohr Raphael , Bruners Philipp , Kuhl Christiane , Trautwein Christian , Berres Marie‐Luise , Tacke Frank , Luedde Tom , Roderburg Christoph
Published: March 2021

Transarterial chemoembolization (TACE) is a therapeutic option for patients with intermediate‐stage hepatocellular carcinoma (HCC) or metastatic liver cancers. Identifying those patients who particularly benefit from TACE remains challenging. Macrophage migration inhibitory factor (MIF) represents is an inflammatory protein described in patients with liver cancer, but no data on its prognostic relevance in patients undergoing TACE exist. Here, we evaluate MIF serum concentrations as a potential biomarker in patients undergoing TACE for primary and secondary hepatic malignancies. MIF serum concentrations were measured by multiplex immunoassay in 50 patients (HCC: n = 39, liver metastases: n = 11) before and 1 day after TACE as well as in 51 healthy controls. Serum concentrations of MIF did not differ between patients and healthy controls. Interestingly, in the subgroup of patients with larger tumor size, significantly more patients had increased MIF concentrations. Patients with an objective tumor response to TACE therapy showed comparable concentrations of serum MIF compared to patients who did not respond. MIF concentrations at day 1 after TACE were significantly higher compared to baseline concentrations. Importantly, baseline MIF concentrations above the optimal cutoff value (0.625 ng/ml) turned out as a significant and independent prognostic marker for a reduced overall survival (OS) following TACE: patients with elevated MIF concentrations showed a significantly reduced median OS of only 719 days compared to patients below the cutoff value (median OS: 1430 days, p = 0.021). Baseline MIF serum concentrations are associated with tumor size of intrahepatic malignancies and predict outcome of patients with liver cancer receiving TACE.
Successful induction of lactation, foal grafting and maintenance of pregnancy in a nonparturient Thoroughbred mare
Authors: Podico G. , Migliorisi A. C. , Wilkins P. A. , Canisso I. F.
Published: March 2021

An 8‐year‐old mare was presented for induction of lactation and adoption of a 30‐day‐old twin filly. In each of the two seasons prior to presentation, the mare had delivered a foal that died shortly after birth. The mare had been bred by live cover ˜25 days prior to presentation to the Illinois Veterinary Teaching Hospital, but no pregnancy diagnosis was yet performed. Upon arrival at the hospital, pregnancy diagnosis confirmed a viable singleton gestational vesicle. Lactation was induced with dopamine D2 agonists. Immediately before grafting, the mare was started on altrenogest to provide exogenous hormonal support for the pregnancy. After two consecutive days of PGF2αadministration on Day 30 of gestation, the mare began to accept the foal, but by the next day, the mare had insufficient milk production and began to show signs of foal rejection. The mare was treated with acepromazine for sedation and stimulation of lactation, with concurrent analgesic support provided by flunixin meglumine and butorphanol. One ovulation was confirmed on Day 40, and a second ovulation was confirmed on Day 45 of gestation. On Day 47 of gestation, 11 days after adoption, serum progesterone concentration was 13.2 ng/mL. As this value was above the minimum level (≥4 ng/mL) deemed necessary to maintain pregnancy in the mare, altrenogest administration was tapered and ultimately discontinued on Day 50 of gestation. The pair remained at the hospital for treatment of leucopenia in the filly. On Day 61 of gestation, 25 days after adoption, continued maintenance of pregnancy was confirmed in the mare, full lactation had been achieved, and strong bonding between mare and foal was apparent. The pair was discharged from the hospital to the care of the owner.
Development of fly ash cenosphere‐based composite for thermal insulation application
Authors: Nithyanandam Anitha , Deivarajan Thenmuhil
Published: March 2021

Cenosphere‐based composite was developed with addition of clay and other additives, by dry processing route. The performance of cenosphere as high‐temperature insulating material was studied. Cenosphere stands unique among the constituents found in fly ash due to its hollow spherical structure. Cenosphere is utilized in numerous modern applications due to its unique properties such as lightness, high compressive strength, enhanced flow characteristics, less water absorption, chemical inertness, and good thermal resistance. Keeping cenosphere as major component, three different mix recipes for insulating brick were made. The recipes were blended and shaped by pressing, followed by drying and sintering at 1000°C. The prepared samples were analyzed for their physical, mechanical, and thermal properties. The surface and pore distribution are analyzed by scanning electron microscope. Results from the analysis shows that cenosphere can be used as high temperature insulating material.
Screening, confirmation, and treatment rates of hepatitis C virus infection in a tertiary academic medical center in South Korea
Authors: Lee Jae Seung , Choi Hong Jun , Lee Hye Won , Kim Beom Kyung , Park Jun Yong , Kim Do Young , Ahn Sang Hoon , Kim Seung Up
Published: March 2021

Background and Aim

Several barriers prevent the proper screening, diagnosis, and treatment of hepatitis C virus (HCV) infection. We aimed to evaluate the status of HCV screening, confirmation, and treatment rates in a tertiary academic medical center in Korea.

Methods

Patients who visited Severance Hospital between 2015 and 2019 were eligible in this retrospective study. The testing and positivity rates for anti‐HCV antibodies and HCV RNA were sequentially analyzed.

Results

Between 2015 and 2019, 252 057 patients (117 131 men, 46.5%) who underwent anti‐HCV antibody testing were retrospectively reviewed. The median age of the study population was 51.0 years. Patients with positive anti‐HCV antibody test results (n = 2623, 1.0%) showed a higher proportion of liver cirrhosis (17.6% vs 2.0%) and unfavorable laboratory test results (all P < 0.05). The positivity rates were 1.3% and 0.8% in the medical and surgical departments, respectively. HCV RNA was tested in 1628 (62.1%) patients, with a 57.4% (n = 928) positivity rate. The medical department had a higher HCV RNA testing rate than the surgical department (75.4% vs 40.8%). Among the 928 patients who showed positivity for HCV RNA, 847 (90.7%) underwent genotype testing (mostly 1 and 2 [95.4%]). The treatment rate was 66.9% (n = 567); it was higher in the gastroenterology department (70.8%) than in the non‐gastroenterology departments (62.3%).

Conclusions

A considerable proportion of patients testing positive for anti‐HCV antibodies were not referred for proper management. Systematic and automated screening and referral systems, which may help identify patients requiring treatment for HCV infection, are necessary even in tertiary academic medical centers.