bluuebunny/crossref_metadata_2025 huggingface dataset:
Asialoglycoprotein receptor 1 is a novel PCSK9-independent ligand of liver LDLR that is shed by Furin
Authors: Susan-Resiga Delia , Girard Emmanuelle , Essalmani Rachid , Roubtsova Anna , Marcinkiewicz Jadwiga , Derbali Rabeb M. , Evagelidis Alexandra , Byun Jae H. , Lebeau Paul F. , Austin Richard C. , Seidah Nabil G.
Published: April 2021

The hepatic carbohydrate-recognizing asialoglycoprotein receptor (ASGR1) mediates the endocytosis/lysosomal degradation of desialylated glycoproteins following binding to terminal galactose/N-acetylgalactosamine. Human heterozygote-carriers ofASGR1-deletions exhibited ∼34% lower risk of coronary artery disease and ∼10-14% non-HDL-cholesterol reduction. Since PCSK9 is a major degrader of LDLR, the regulation of LDLR and/or PCSK9 by ASGR1 was studied. Thus, we investigated the role of endogenous/overexpressed ASGR1 on LDLR degradation and functionality by Western-blot and immunofluorescence in HepG2 naïve and HepG2-PCSK9-knockout cells. ASGR1, like PCSK9, targets LDLR and both interact with/enhance the degradation of the receptor independently. Such lack of cooperativity between PCSK9 and ASGR1 on LDLR expression was confirmed in livers of wild-type (WT)versus Pcsk9-/-mice. ASGR1-knockdown in HepG2 naïve cells significantly increased total (∼1.2-fold) and cell-surface (∼4-fold) LDLR protein. In HepG2-PCSK9-knockout cells ASGR1-silencing led to ∼2-fold higher levels of LDLR protein and DiI-LDL uptake, associated with ∼9-fold increased cell-surface LDLR. Overexpression of WT-ASGR1/2 reduced primarily the immature non-O-glycosylated LDLR (∼110 kDa), whereas the triple Gln240/Trp244/Glu253Ala-mutant (loss of carbohydrate-binding) reduced the mature form of the LDLR (∼150 kDa), suggesting that ASGR1 binds the LDLR in sugar-dependent and -independent fashion. Furin sheds ASGR1 atRKMK103↓ into a secreted form, likely resulting in a loss-of-function on LDLR. LDLR is the first example of a liver-receptor ligand of ASGR1. Additionally, we demonstrate that lack of ASGR1 enhances LDLR levels and DiI-LDL incorporation, independently of PCSK9. Overall, silencing of ASGR1 and PCSK9 may lead to higher LDL-uptake by hepatocytes, thereby providing a novel approach to further reduce LDL-cholesterol.
Replication of single-cell proteomics data reveals important computational challenges
Authors: Vanderaa Christophe , Gatto Laurent
Published: April 2021

Introduction

Mass spectrometry-based proteomics is actively embracing quantitative, single-cell level analyses. Indeed, recent advances in sample preparation and mass spectrometry (MS) have enabled the emergence of quantitative MS-based single-cell proteomics (SCP). While exciting and promising, SCP still has many rough edges. The current analysis workflows are custom and built from scratch. The field is therefore craving for standardized software that promotes principled and reproducible SCP data analyses.

Areas covered

This special report is the first step toward the formalization and standardization of SCP data analysis. scp, the software that accompanies this work, successfully replicates one of the landmark SCP studies and is applicable to other experiments and designs. We created a repository containing the replicated workflow with comprehensive documentation in order to favor further dissemination and improvements of SCP data analyses.

Expert opinion

Replicating SCP data analyses uncovers important challenges in SCP data analysis. We describe two such challenges in detail: batch correction and data missingness. We provide the current state-of-the-art and illustrate the associated limitations. We also highlight the intimate dependence that exists between batch effects and data missingness and offer avenues for dealing with these exciting challenges.

1

Article highlights

Single-cell proteomics (SCP) is emerging thanks to several recent technological advances, but further progress is still lagging due to the lack of principled and systematic data analysis.

This work offers a standardized solution for the processing of SCP data demonstrated by the replication of a landmark SCP work.

Two important challenges remain: batch effects and data missingness. Furthermore, these challenges are not independent and therefore need to be modeled simultaneously.
Maternal diet-induced obesity during pregnancy alters lipid supply to fetuses and changes the cardiac tissue lipidome in a sex-dependent manner
Authors: Pantaleão Lucas C. , Inzani Isabella , Furse Samuel , Loche Elena , Hufnagel Antonia , Ashmore Thomas , Blackmore Heather L. , Jenkins Benjamin , Carpenter Asha A. M. , Wilczynska Ania , Bushell Martin , Koulman Albert , Fernandez-Twinn Denise S. , Ozanne Susan E.
Published: April 2021

Maternal obesity during pregnancy has immediate and long-term detrimental effects on the offspring heart. In this study, we characterized the cardiac and circulatory lipid profiles in fetuses of diet-induced obese pregnant mice and established the changes in lipid abundance and fetal cardiac transcriptomics. We used untargeted and targeted lipidomics and transcriptomics to define changes in the serum and cardiac lipid composition and fatty acid metabolism in male and female fetuses. From these analyses we observed: (1) maternal obesity affects the maternal and fetal serum lipidome distinctly; (2) female heart lipidomes are more sensitive to maternal obesity than male fetuses; (3) changes in lipid supply might contribute to early expression of lipolytic genes in mouse hearts exposed to maternal obesity. These results highlight the existence of sexually dimorphic responses of the fetal heart to the samein uteroobesogenic environment and identify lipids species that might mediate programming of cardiovascular health.
Transformation paths and influencing factors of tacit knowledge into explicit knowledge in real estate companies: a qualitative study
Authors: Ni Guodong , Zhang Ziyao , Yuan Zhenmin , Huang Haitao , Xu Na , Deng Yongliang
Published: April 2021

Purpose

The purpose of this paper is to figure out the paths about transformation of tacit knowledge into explicit knowledge, i.e. tacit knowledge explicating (TKE) in real estate companies, and determine the influencing factors of TKE in Chinese real estate companies to enable enterprises make better use of their knowledge resources.

Design/methodology/approach

The study adopted an exploratory design method using thematic analysis and grounded theory, and semi-structured interviews were conducted to collect data. The interviewees consisted of employees in different positions, who come from Chinese real estate companies with different ranking ranges and different knowledge management levels. Data collection was divided into two rounds for the identification of transformation paths and influencing factors.

Findings

This study has shown that 11 paths about TKE divided into solidified organization process and construction of organizational infrastructure go into effect within the real estate companies. Factors influencing TKE in real estate companies concern three main categories: organizational distal factors, contextual proximal factors and individual factors, including 21 subordinates in total. Furthermore, correlation between TKE paths and influencing factors is established.

Research limitations/implications

Research results may lack generalizability due to the method adopted. Therefore, researchers are encouraged to verify the outcomes of this research.

Practical implications

This research provides a new idea and solutions for the tacit knowledge management in real estate companies.

Originality/value

To the best of the authors’ knowledge, this study is the first to systematically identify paths and the influencing factors of TKE in real estate companies, contribute to the incipient but growing understanding of achievement of “tacit to explicit” and enrich the corporate tacit knowledge management literature.
Chanda Kochhar at ICICI bank: lessons in governance
Authors: Bhaskaran Bala
Published: April 2021

Learning outcomes

After a successful discussion and analysis of the case, the participants will be able to distinguish and appreciate the situations of conflict of interest (COI), whistle-blowing, etc. Initiate appropriate methods to avoid/minimize the impact of COI and ensure justice and fair-play to all stake-holders. Identify and appreciate the work-context of each executive-position and initiate standard operating procedures to protect the interests of the enterprise and all its stakeholders. Appreciate the relevance of whistle-blowing and to initiate appropriate methods to ensure justice and fair-play to all stake-holders.

Case overview/synopsis

In the context of the Industrial Credit and Investment Corporation of India (ICICI)-bank, the systemic inadequacies seemed to have failed in preventing the incidences of COI. The organization was too centralized to be able to respond proactively to the allegations. The case lays bare the inadequacy of professionalism among the media in responding promptly to such instances. The case generalizes that, with increasing globalization, such incidences have global ramifications and the organizations face much greater risks than ever. The case concludes that to emerge as a mature and leading organization in the global market, ICICI-bank needed to strengthen various aspects of corporate governance; similarly to emerge as a developed economy, India needed to develop independent watchdogs to monitor the activities of corporations continuously. Media needed to be independent and mature to fulfil its duty of continuous and transparent communication to the public.

Complexity academic level

The case can be understood and analysed by management students in the post-graduate level or by working executives with at least four to five years of experience in the corporate sector.

Supplementary materials

Teaching notes are available for educators only.

Subject code

CSS 11: Strategy.
Defining money laundering under Malawian law: a critical appraisal for compliance with international standards
Authors: Bande Lewis Chezan
Published: April 2021

Purpose

The purpose of this paper is to critically appraise the legal definition of the offence of money laundering under Malawian law. The goal is to evaluate whether the definition meets international standards and best practices on legal definition of money laundering, particularly as contained in the United Nations Convention against Transnational Organized Crime (UNCATOC).

Design/methodology/approach

The paper is a doctrinal analysis of the legal definition of the offence of money laundering under Malawian law. It examines the constituent elements of the offence based on the traditional conception of a criminal offence as constituting the prohibited conduct (or actus reus) and the mental element (or mens rea). The paper comparatively evaluates the offence vis-à-vis international standards and best practices, particularly as contained in the UNCATOC.

Findings

The paper concludes that the definition is compliant with international standards and best practices.

Research limitations/implications

The paper is based on the statutory definition of the offence, but was unable to examine how the offence is interpreted and applied in concrete cases by Malawian courts. The reason is the lack of any case law through which courts have interpreted and applied the offence.

Practical implications

The paper provides the template for future interpretation and application of the offence by courts in the future.

Social implications

Enhancing the clarity and certainty in the law on money laundering in Malawi.

Originality/value

The paper is an elucidation of a statutory provision that was recently adopted in Malawi and for which there is no authoritative clarification. The paper, therefore, makes an invaluable contribution to the fight against money laundering in Malawi by being a guide to law enforcers, lawyers, courts and policy/legislative makers.
Language and discounting future value: language as a moderator of internationalization–innovation performance relationships
Authors: Lim Eunah , Powell K. Skylar
Published: April 2021

Purpose

Research on relationships between firms' degree of internationalization (DOI) and innovation performance has been mixed, and moderators of these relationships need to be explored. We focus on patents granted as an indicator of innovation performance and explore the moderating role of firms' home-country languages on the DOI–innovation performance relationship. We argue that in countries with languages that always require speakers to grammatically mark the future, firms will focus less on the future value of patents, which should moderate DOI–innovation performance relationships.

Design/methodology/approach

We use an unbalanced panel consisting of 567 firm-year observations of 64 different large automotive suppliers from the year 2007 through 2019. This database was analyzed using negative binomial models with a 3-years lag structure and firm controls.

Findings

Results show a U-shaped DOI–innovation performance relationship, but only for firms from countries that do not always require speakers to grammatically mark the future. Additionally, a firm's status as being from a country where dominate languages always require speakers to grammatically mark the future has a direct negative relationship with innovation performance.

Research limitations/implications

Limitations are that the sample included a large number of firms from one country (i.e. Japan) and focused on a single industry. Additionally, we used a narrow operational definition of innovation performance (i.e. patents) and relied upon a single methodology. In terms of implications, we identify one moderator that helps explain mixed results of past DOI–innovation performance research, and we identify a direct relationship between language and innovation performance. Hence, future research in this area should control for the dominant language type of firms' home countries.

Originality/value

To our knowledge, this is the first study to examine how language moderates DOI–innovation performance relationships and also relates to innovation performance directly.
Mammalian herbivore movement into drought refugia has cascading effects on savanna insect communities
Authors: Trisos Matthew O. , Parr Catherine L. , Davies Andrew B. , Leitner Monica , February Edmund C.
Published: April 2021

Global climate change is predicted to increase the frequency of droughts, with major impacts on tropical savannas. It has been suggested that during drought, increased soil moisture and nutrients on termite mounds could benefit plants but it is unclear how such benefits could cascade to affect insect communities.

Here, we describe the effects of drought on vegetation structure, the cascading implications for invertebrates and how termite mounds influence such effects. We compared how changes in grass biomass affected grasshopper and ant diversity on and off Macrotermes mounds before (2012) and during a drought (2016) at two locations that experienced large variation in drought severity (Skukuza and Pretoriuskop) in the Kruger National Park, South Africa.

The 2013–2016 drought was not ubiquitous across the study site, with rainfall decreasing at Skukuza and being above average at Pretoriuskop. However, grass biomass declined at both locations. Grasshopper abundance decreased at droughted Skukuza both on and off mounds but decreased on mounds and increased off mounds at non‐droughted Pretoriuskop. Ant abundance and species richness increased at Skukuza but remained the same on mounds and decreased off mounds at Pretoriuskop.

Our results demonstrate the spatially extensive effects of drought. Despite above average rainfall in 2016 at Pretoriuskop, grass biomass decreased, likely due to an influx of large mammalian herbivores from drought‐affected areas. This decrease in grass biomass cascaded to affect grasshoppers and ants, further illustrating the effects of drought on invertebrates in adjoining areas with higher rainfall. Our grasshopper results also suggest that increased drought in savannas will contribute to overall declines in insect abundance. Moreover, our recorded increase in ant abundance was primarily in the form of increases in dominant species, illustrating how drought‐induced shifts in relative abundance will likely influence ecosystem structure and function.

Our study highlights the phenomenon of spill‐over drought effects and suggests rather than mitigating drought, termite mounds can instead become the focus for more intense grazing, with important consequences for insect communities.
Eiders, nutrients and eagles: Bottom‐up and top‐down population dynamics in a marine bird
Authors: Morelli Federico , Laursen Karsten , Svitok Marek , Benedetti Yanina , Møller Anders Pape
Published: April 2021

The main objective of this long‐term study (1978–2016) was to find the underlying factors behind the declining trends of eiderSomateria mollissimain the Baltic/Wadden Sea.

Specifically, we aimed at quantifying the bottom‐up effect of nutrients, through mussel stocks, on reproduction and abundance of eider, and the top‐down effects caused by white‐tailed eagleHaliaeetus albicillapredation.

Bottom‐up effects increase marine primary productivity with subsequent effects on food availability for a major mussel predator. Top‐down effects may also regulate eider populations because during incubation female eiders are vulnerable to predation by eagles.

Our structural equation modelling explained a large percentage of the variance in eider abundance. We conclude that the Baltic/Wadden Sea eider population was regulated directly by white‐tailed sea eagle predation on incubating females and indirectly by the amount of nutrients in seawater affecting both mussel stocks and the breeding success of eiders, reflecting density dependence.

These findings may explain the decreasing trend in the Baltic/Wadden Sea eider population during the last decades as an additive effect of top‐down and bottom‐up factors, and likely as an interaction between them.
Rapid evolution of a floral trait following acquisition of novel pollinators
Authors: Mackin Christopher R. , Peña Julián F. , Blanco Mario A. , Balfour Nicholas J. , Castellanos Maria Clara
Published: April 2021

Changes in the pollinator assemblage visiting a plant can have consequences for reproductive success and floral evolution. We studied a recent plant trans‐continental range expansion to test whether the acquisition of new pollinator functional groups can lead to rapid adaptive evolution of flowers.

InDigitalis purpurea,we compared flower visitors, floral traits and natural selection between native European populations and those in two Neotropical regions, naturalised after independent introductions. Bumblebees are the main pollinators in native populations while both bumblebees and hummingbirds are important visitors in the new range. We confirmed that the birds are effective pollinators and deposit more pollen grains on stigmas than bumblebees.

We found convergent changes in the two new regions towards larger proximal corolla tubes, a floral trait that restricts access to nectar to visitors with long mouthparts. There was a strong positive linear selection for this trait in the introduced populations, particularly on the length of the proximal corolla tube, consistent with the addition of hummingbirds as pollinators.

Synthesis. The addition of new pollinators is likely to happen often as humans influence the ranges of plants and pollinators but it is also a common feature in the long‐term evolution of the angiosperms. We show how novel selection followed by very rapid evolutionary change can be an important force behind the extraordinary diversity of flowers.
Shoulder dystocia, umbilical cord blood gases and neonatal encephalopathy
Authors: Battin Malcolm R. , van den Boom Jutta , Oben Glenda , McDonald Gabrielle
Published: April 2021

The interpretation of umbilical cord gases may not be straightforward following shoulder dystocia. We reviewed Perinatal and Maternal Mortality Review Committee data from New Zealand infants with moderate and severe neonatal encephalopathy (NE) for 2010–2017 inclusive. If one or more of: pH of ≤7.1; base excess of ≤–12 mmol/L; or lactate of ≥6 mmol/L were present it was considered an abnormal result. One‐third (12/36) of infants born following shoulder dystocia had documented umbilical cord gases within the normal range. It is important for clinicians to be aware of this possibility when assessing newborn infants with NE.
Direct assessment of individual skin barrier components by electrical impedance spectroscopy
Authors: Mannweiler Roman , Bergmann Sophia , Vidal‐y‐Sy Sabine , Brandner Johanna M. , Günzel Dorothee
Published: April 2021

Background

Expression of the tight junction proteins Cldn1 and 4 is altered in skin diseases such as atopic dermatitis, and Cldn1 deficiency affects skin barrier formation. Impedance spectroscopy (IS) has been proven to allow detection of alterations in the skin barrier but is currently unable to separate effects on viable epidermis (VE) and stratum corneum (SC).

Methods

Effects of siRNA‐mediated Cldn1 and 4 knockdown in reconstructed human epidermis (RHE) on VE and SC barrier function were investigated with Ussing chamber‐based IS. Barrier components were sequentially altered, employing iron oxide nanoparticles and EGTA, to identify their contribution to the impedance spectrum. Resistance changes due to apically applied hyperosmolar electrolyte were used to identify barrier defects non‐invasively.

Results

IS of RHE yielded two relaxation frequencies, representing the barrier properties of the SC (~1000 Hz) and VE (~100 Hz). As proof of concept, it was shown that the Cldn1 knockdown‐induced resistance drop arises from the impairment of both SC and VE, indicated by a shift of both relaxation frequencies. Hyperosmolar electrolyte penetration allowed non‐invasive detection of Cldn1 knockdown via time‐dependent frequency shifts. The absence of Cldn4 knockdown‐induced changes revealed the weaknesses of transepithelial electrical resistance analysis.

Conclusion

In conclusion, the present technique allows to separately measure the barrier properties of SC and VE and further evaluate the Cldn1 and 4 knockdown impact on the skin barrier. As the measurement with agarose‐embedded electrolyte allowed non‐invasive identification of the Cldn1 knockdown, this opens the way to detailed in vivo skin barrier assessment.
Eczema herpeticum in atopic dermatitis
Authors: Traidl Stephan , Roesner Lennart , Zeitvogel Jana , Werfel Thomas
Published: April 2021

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases leading to pruritic skin lesions. A subset of AD patients exhibits a disseminated severe HSV infection called eczema herpeticum (EH) that can cause life‐threatening complications. This review gives an overview of the clinical picture, and characteristics of the patients as well as the diagnosis and therapy of EH. A special focus lies on the pathophysiological hallmarks identified so far that predispose for EH. This aspect covers genetic aberrations, immunological changes, and environmental influences displaying a complex multifactorial situation, which is not completely understood. Type 2 skewing of virus‐specific T cells in ADEH+ patients has been implicated in immune profile abnormalities, along with impaired functions of dendritic cells and natural killer cells. Furthermore, aberrations in interferon pathway‐related genes such as IFNG and IFNGR1 have been identified to increase the risk of EH. IL‐4, IL‐25, and thymic stromal lymphopoietin (TSLP) are overexpressed in EH, whereas antimicrobial peptides like human β‐defensins and LL‐37 are reduced. Concerning the epidermal barrier, single nucleotide polymorphisms (SNPs) in skin barrier proteins such as filaggrin were identified in ADEH+ patients. A dysbalance of the skin microbiome also contributes to EH due to an increase of Staphylococcus aureus, which provides a supporting role to the viral infection via secreted toxins such as α‐toxin. The risk of EH is reduced in AD patients treated with dupilumab. Further research is needed to identify and specifically target risk factors for EH in AD patients.
Complication profile of augmentation cystoplasty in contemporary paediatric urology: a 20‐year review
Authors: Taghavi Kiarash , O'Hagan Lomani A , Bortagaray Juan , Bouty Aurore , M Hutson John , O'Brien Mike
Published: April 2021

Background

The aim of this study was to describe the complication profile of augmentation cystoplasty in contemporary paediatric urology as well as its effect on bladder metrics.

Methods

Consecutive operative cases were retrospectively reviewed at a single institution over 20 years (1999–2019). Short‐ and long‐term outcomes and complications following augmentation cystoplasty were defined.

Results

Of the 71 operative cases; the most common underlying diagnoses were neurogenic bladder (34%), exstrophy‐epispadias complex (30%) and posterior urethral valves (23%). The most common tissue‐type utilized was ileal (58%) and ureteric (30%). Peri‐operative urine leak affected nine (13%) children but reservoir perforations were less common (4%). Mean end‐of‐study detrusor pressure improved significantly following bladder augmentation (38–17 cmH2O, P < 0.001). Bladder capacity improved significantly (67–89%, P = 0.041). The median follow‐up was 4.5 years (interquartile range: 1.9–10 years). Bladder urolithiasis affected 13 (18%) patients, and symptomatic urinary tract infections 36 (51%) patients. Formation of a continent catheterisable channel contributed a number of complications relating predominantly to stenosis (50%). Repeat augmentation cystoplasty was necessary in three (4%) cases.

Conclusion

Augmentation cystoplasty is a surgical intervention that improves bladder metrics. Given the potential complications, careful patient selection and appropriate pre‐operative counselling are essential. Furthermore, pro‐active post‐operative management and transitional care are vital in the surgical care of children following augmentation cystoplasty.
Evolution of surgical management for phaeochromocytoma over a 17‐year period: an Australian perspective
Authors: Cherry Tiffany J. , Gorelik Alexandra , Miller Julie A.
Published: April 2021

Background

Minimally invasive adrenalectomy and advances in anaesthetic techniques have transformed surgery for phaeochromocytoma. This 17‐year review describes the evolution of phaeochromocytoma care in our unit.

Methods

We performed a retrospective cohort review of all patients who underwent adrenalectomy for phaeochromocytoma from 2000 to 2016. Patients were divided into three time periods, early: 2000–2005 (n = 17), middle: 2006–2010 (n = 15) and late: 2011–2016 (n = 24). The posterior retroperitoneoscopic adrenalectomy was introduced in 2011. Demographics and clinicopathological details were extracted. Median values for nominal data were compared using Mann–Whitney U‐test. A chi‐squared test was used to compare categorical data.

Results

Sixty‐one adrenalectomies were performed on 56 patients: 19 open, 17 laparoscopic and 20 posterior retroperitoneoscopic adrenalectomies. The median length of operation decreased from 135 to 90 min from the early to the late time period (P > 0.05). Length of stay decreased from a median of 5 days in the early group to 1 day in the late group (P = 0.01). A total of 94.1% of the early period patients were admitted to the intensive care unit compared to 30.4% of the late group (P = <0.01). Need for post‐operative vasopressors and blood transfusions was significantly reduced.

Conclusion

Over the 17‐year period, the choice of operative technique has transitioned towards posterior retroperitoneoscopic adrenalectomy. Operative time, rate of intensive care unit admission, and admission length have all decreased without any increase in rates of complications.
β‐Arrestin1 and GPCR kinase2 play permissive roles in Src‐mediated endocytosis of α4β2 nicotinic ACh receptors
Authors: Acharya Srijan , Kundu Dooti , Kim Kyeong‐Man
Published: April 2021

Background and Purpose

The α4β2 nicotinic ACh receptor (nAChR), a subtype of the ligand‐gated ion channel, is abundantly expressed in the brain and is implicated in several neurological disorders. The endocytosis of nAChRs plays important roles in the pathogenesis of neurological diseases, but the underlying molecular mechanisms remain poorly understood.

Experimental Approach

Loss‐of‐function approaches and mutants of α4β2 nAChRs that display different endocytic properties were used to identify the cellular components and processes responsible for endocytosis. The signalling cascade that leads to endocytosis was deduced via protein interactions in predicted cellular components. The endocytosis of α4β2 nAChRs was determined and crosschecked using an ELISA and radioligand assay.

Key Results

Endocytosis of α4β2 nAChRs occurred through clathrin‐mediated endocytosis in a dynamin‐dependent manner. 14‐3‐3η‐dependent Src‐mediated phosphorylation of the nAChR α4 subunit at Y575 was required for nAChR endocytosis, and this occurred with the assistance of β‐arrestin1 and GPCR kinase 2 (GRK2) without the need for kinase activity. Endocytosis triggered the mouse double minute 2 homologue‐mediated ubiquitination and subsequent down‐regulation of α4β2 nAChRs.

Conclusions and Implications

α4β2 nAChR, an ionophore receptor, employs the metabotropic signalling pathway required for endocytosis, which leads to ubiquitination and down‐regulation. Further, GRK2 and β‐arrestin1, usually associated with GPCR signalling, are involved in the endocytosis of α4β2 nAChRs via different mechanisms. Considering the functional and pathological implications of nAChR endocytosis, results obtained in this study are crucial for the progression of basic research and clinical investigations.
Two‐minute tidal breathing methacholine bronchial challenge: Comparison of two jet nebulisers
Authors: Zhu Zheng , Wang Hongyu , Xie Yanqing , An Jiaying , Li Jing , Zheng Jinping
Published: April 2021

Background

The American Thoracic Society (ATS) guideline for methacholine challenge testing (MCT) recommended using the English Wright (EW) nebuliser. However, other brands of nebulisers are also indicated to be acceptable for this technique, but further validation of nebuliser performance is recommended.

Objective

To compare the methacholine provocation concentration causing a 20% fall in forced expiratory volume in 1 second (PC20‐FEV1) measured by using EW nebuliser and DV 646 nebuliser.

Methods

Subjects were randomly assigned to undergo 2‐min tidal breathing methacholine challenge with either EW or DV 646 nebuliser on two separate days, which were at least 24 hours but not more than 7 days apart. The above procedure was repeated for each subject in 1 month, but the nebulisers were selected in a reverse order.

Results

The study includes 15 mild and stable asthmatic patients. The geometric means (SD) of methacholine PC20 measured with using EW and DV 646 nebulisers were 1.82 (6.38) mg/mL versus 0.83 (1.82) mg/mL, respectively in the initial two visits and 2.56 (6.29) mg/mL versus 0.78 (1.40) mg/mL in the following two visits (both P < 0.05). There are well correlations between PC20‐EW1 and PC20‐EW2 (r = 0.99, P < 0.01), PC20‐DV1 and PC20‐DV2 (r = 0.88, P < 0.01), and between PC20‐EW1 and PC20‐DV1 (r = 0.91, P < 0.01), PC20‐EW2 and PC20‐DV2 (r = 0.78, P < 0.01).

Conclusions

PC20‐FEV1 measured by using the two conventional jet nebulisers was both repeatable and the results were highly correlated.
Underpricing in a developing capital market: Australian equity issuances, 1920–39†
Authors: Fleming Grant , Liu Zhangxin (Frank) , Merrett David , Ville Simon
Published: April 2021

Developing capital markets generally lack the regulatory safeguards and rich informational sources that assist investors in judging new equity issues in modern markets. Focusing on the early stage capital market in interwar Australia, we calculate the success (underpricing and percentage raised) of 786 new equity issues, comparing initial public offerings, seasoned equity offerings, and rights issues. We examine whether the use of underwriters and the choice of security (ordinary or preference shares) affected the success of the equity issue. We find that certification by underwriters had no effect on capital‐raising success once we controlled for firm‐specific factors in the multivariate regressions, while underpricing and percentage raised varied by type of shares offered to investors.
Kant on limits, boundaries, and the positive function of ideas
Authors: Howard Stephen
Published: April 2021

It is commonly claimed that Kant's critical philosophy aims to limit reason's speculative use and its metaphysical pretensions. This paper argues that such claims should be amended in light of a technical distinction between negative limits and positive boundaries that Kant held throughout his career. Kant's only extended discussion of this distinction appears in §§57–60 of the Prolegomena, a division entitled “On pure reason's boundary‐determination”. I examine these sections in detail in order to elucidate the account of the limits and boundaries of the activity of different cognitive faculties in the Critique of Pure Reason. I argue that once we understand a key ambition of the Critique to be the positive determination of the boundary between objects of experience and things in themselves, we gain insight into the essential contribution that Kant's theory of the positive utility of ideas of reason makes to the critical philosophy.
A game of thrones—Dynamics of internal CEO succession and outcome
Authors: Blank Brian , Hadley Brandy , Minnick Kristina , Rivolta Mia L.
Published: April 2021

We examine the implications of chief executive officer (CEO) succession methods for firm outcomes and executive incentives. Focusing on internal CEO successions, we find that the largest U.S. firms typically rely on two types of succession methods, namely, heir apparent and horse race successions. Although heir apparent and horse race CEO candidates have similar qualifications, the consequences of these two succession methods differ significantly. We find that horse race successions induce conflict and are detrimental to firm performance but not necessarily to the newly appointed CEOs. Our findings suggest succession method influences firm performance, executive incentives and CEO labour markets.
Outcomes after cervical vertebral interbody fusion using an interbody fusion device and polyaxial pedicle screw and rod construct in 10 horses (2015‐2019)
Authors: Pezzanite Lynn M. , Easley Jeremiah T. , Bayless Rosemary , Aldrich Ellison , Nelson Brad B. , Seim Howard B. , Nout‐Lomas Yvette S.
Published: April 2021

Background

Further development of surgical techniques for equine cervical stabilisation is necessary to make the procedure less technically demanding, reduce complications and improve outcomes.

Objective

To describe clinical outcomes and owner reports in horses undergoing placement of an interbody fusion device and polyaxial pedicle screw and rod construct for cervical vertebral fusion in horses with cervical vertebral compressive myelopathy.

Study design

Retrospective case series.

Methods

Data were retrieved from medical records of 10 horses undergoing cervical vertebral fusion (2015‐2019). Records were evaluated for signalment, duration of clinical signs, number and location of compression sites, grade of ataxia, duration of hospitalisation and complications. Long‐term follow‐up was obtained through clinical re‐evaluation, postoperative radiographs and owner contact.

Results

Breeds were mixed. Median age was 24 (range 12‐168) months. There were 2/10 mares, 4/10 geldings and 4/10 stallions. Preoperative grade of ataxia ranged from 1‐3/5. Fusion was performed at one (n = 3) or two (n = 7) sites. Two horses were euthanised within the first year. In 6 of 8 horses with ≥1‐year follow‐up, ataxia improved by 1‐3 grades, with an average improvement of 1.25 grades. In four horses, ataxia improved to grade 0‐1. In two horses the gait was unaffected, but neck comfort improved. Complications included seroma formation (n = 9), pain (n = 5), fever (n = 4), upper respiratory tract obstruction (n = 2), azotemia (n = 2), screw breakage (n = 2), progression of neurological signs (n = 1), Horner's Syndrome (n = 1), dysphagia (n = 1), hives (n = 1), implant infection (n = 1) and nondisplaced fracture (n = 1).

Main limitations

Small case series, heterogeneous patient population.

Conclusions

This technique resulted in ≥1 grade gait improvement in 6/10 cases operated and 6/8 cases for which ≥1‐year follow‐up was available, similar to other methods. Fatal complications related to implant placement did not occur. This technique may represent a safer alternative to current techniques of ventral interbody fusion with similar outcomes.
Structural basis for substrate specificity of the peroxisomal acyl‐CoA hydrolase MpaH’ involved in mycophenolic acid biosynthesis
Authors: You Cai , Li Fengwei , Zhang Xingwang , Ma Li , Zhang Yu‐Zhong , Zhang Wei , Li Shengying
Published: April 2021

Mycophenolic acid (MPA) is a fungal natural product and first‐line immunosuppressive drug for organ transplantations and autoimmune diseases. In the compartmentalized biosynthesis of MPA, the acyl‐coenzyme A (CoA) hydrolase MpaH' located in peroxisomes catalyzes the highly specific hydrolysis of MPA‐CoA to produce the final product MPA. The strict substrate specificity of MpaH' not only averts undesired hydrolysis of various cellular acyl‐CoAs, but also prevents MPA‐CoA from further peroxisomal β‐oxidation catabolism. To elucidate the structural basis for this important property, in this study, we solve the crystal structures of the substrate‐free form of MpaH' and the MpaH'S139A mutant in complex with the product MPA. The MpaH' structure reveals a canonical α/β‐hydrolase fold with an unusually large cap domain and a rare location of the acidic residue D163 of catalytic triad after strand β6. MpaH' also forms an atypical dimer with the unique C‐terminal helices α13 and α14 arming the cap domain of the other protomer and indirectly participating in the substrate binding. With these characteristics, we propose that MpaH' and its homologs form a new subfamily of α/β hydrolase fold protein. The crystal structure of MpaH'S139A/MPA complex and the modeled structure of MpaH'/MPA‐CoA, together with the structure‐guided mutagenesis analysis and isothermal titration calorimetry (ITC) measurements, provide important mechanistic insights into the high substrate specificity of MpaH'.
High‐performance photocatalyst containing noble metals selectively deposited inside mesopore
Authors: Ishikawa Toshihiro
Published: April 2021

We describe a general photoelectrical deposition process for the priority deposition of noble metals inside surface mesopores, which are selectively formed in the interstitial regions between crystal arrays composed of sintered photoactive nanocrystals. The basis of our approach is to prepare continuous coherent bonds between photoactive nanocrystals aligned toward the surface accompanied by the formation of interstices (2–20 nm) filled with a heterogeneous insulator phase between the crystal arrays; the subsequent removal of part of the heterogeneous phase creates surface mesopores. The coherent crystalline structure causes a smooth electron flow from the outside to the inside of the array through the coherent boundaries of the nanocrystals during photodeposition using an ultraviolet lamp, accompanied by outside‐hole consumption and noble metal deposition in the recesses of the surface mesopores. The size and morphology of the deposited noble metals are restricted to the shape of the formed mesopores, which can be easily controlled. This approach is applicable to a wide range of functional materials and is expected to be applicable to the preparation of excellent photocatalysts, redox catalysts, and photochromic materials. Using our new process, we also achieved a remarkable increase in the photocatalytic activity of the obtained Pd‐deposited TiO2/SiO2 photocatalytic fiber.
On God’s Practical Knowledge of Creation
Authors: Errington Andrew
Published: April 2021

This article explores a question that exercised Thomas Aquinas, the nature of God’s knowledge of creation, and more particularly, its practical character. It first sets out the logic of Aquinas’s position, articulated especially in Summa Theologiae I, q. 14, a. 16, that God does have practical knowledge of creation, but that this is contained within God’s speculative self‐knowledge. It suggests that this position raises questions about the adequacy of its treatment of practical knowledge, particularly to do with the central analogy of an artisan’s knowledge of what is made. The article explores these questions, first, by drawing on contemporary philosophical discussions of practical knowledge, and second, by considering a biblical text in which both a form of practical knowledge and of the artisan analogy are prominent: the book of Proverbs.
Asset classification under the IFRS 9 framework for the construction of a banking investment portfolio
Authors: Brito Rui Pedro , Júdice Pedro
Published: April 2021

Under the International Financial Reporting Standard 9 framework, we analyze the trade‐off of classifying a financial asset at amortized cost versus at fair value. Defining an impairment model and based on historical (2003–2019) data for the 10‐year Portuguese Government bonds, we analyze the annual performance (income/comprehensive income) of different investment allocations. Setting as objectives the maximization of the income and the minimization of the semivariance of the comprehensive income, we suggest a biobjective model in order to find efficient allocations. Given the nonsmoothness of the semivariance function, we compute the solution of the suggested model by means of a multiobjective derivative‐free algorithm. Assuming that the yields and funding rates follow a correlated mean‐reverting process and that the bonds' rating dynamics are described by an ordinal response model, we show a possible approach to mitigate the estimation error ingrained in the proposed biobjective stochastic model. Finally, we assess the out‐of‐sample performance of some of the suggested efficient allocations.
Focal impulse and rotor modulation guided ablation versus pulmonary vein isolation for atrial fibrillation: A meta‐analysis of head‐to‐head comparative studies
Authors: Romero Jorge , Gabr Mohamed , Alviz Isabella , Briceno David , Diaz Juan Carlos , Rodriguez Daniel , Patel Kavisha , Polanco Dalvert , Trivedi Chintan , Mohanty Sanghamitra , Della Rocca Domenico , Lakkireddy Dhanunjaya , Natale Andrea , Di Biase Luigi
Published: April 2021

Introduction

Empirical pulmonary vein isolation (PVI) remains the cornerstone for catheter ablation of atrial fibrillation (AF). Various ablation strategies and modalities are continually tested with the aim of improving ablation outcomes. Although focal impulse and rotor modulation (FIRM)‐guided ablation is currently used as an adjunct to PVI, evidence supporting this strategy is conflicting. We sought to examine whether the utilization of FIRM‐guided ablation with or without PVI is associated with a decrease in all‐atrial arrhythmia recurrence as compared to PVI alone.

Methods

A systematic review of PubMed, Cochrane, and Embase was performed for head‐to‐head study designs comparing outcomes of patients who underwent FIRM‐guided ablation with or without PVI to those who underwent PVI alone. The primary efficacy endpoint was all‐atrial arrhythmia recurrence. The secondary endpoints were complications rates and procedural characteristics.

Results

Overall, six studies comprising 674 patients undergoing either FIRM‐guided ablation ± PVI versus PVI were included (mean age 63.4 ± 9.2, male 74%, 9% paroxysmal AF, 91% nonparoxysmal AF). After a mean follow‐up of 18.8 months, FIRM‐guided ablation with or without PVI was not associated with improvement in all‐atrial arrhythmia recurrence rate compared to PVI alone (43.4% vs. 45.9%, risk ratio [RR]: 1.06; 95% confidence interval [CI]: 0.77–1.47; p = .70). No statistically significant difference was noted in complication rates between the two groups (RR: 1.66; 95% CI: 0.08–34.54; p = .74).

Conclusion

In this meta‐analysis of head‐to‐head comparison studies, FIRM‐guided ablation with or without PVI did not provide any benefit in improving all‐atrial arrhythmia recurrence at follow‐up when compared to PVI alone.
Clinical predictors of heart block during atrioventricular nodal reentrant tachycardia ablation: A multicenter 18‐year experience
Authors: Makker Parth , Saleh Moussa , Vaishnav Aditi S. , Coleman Kristie M. , Beldner Stuart , Ismail Haisam , Sharma Nikhil , Jadonath Ram , Goldner Bruce , Mitra Raman , Epstein Laurence , John Roy , Mountantonakis Stavros E.
Published: April 2021

Background

Catheter ablation is considered the first‐line treatment of symptomatic atrioventricular nodal reentrant tachycardia (AVNRT). It has been associated with a risk of heart block (HB) requiring a pacemaker. This study aims to determine potential clinical predictors of complete heart block as a result AVNRT ablation.

Methods

Consecutive patients undergoing catheter ablation for AVNRT from January 2001 to June 2019 at two tertiary hospitals were included. We defined ablation‐related HB as the unscheduled implantation of pacemaker within a month of the index procedure. Use of electroanatomic mapping (EAM), operator experience, inpatient status, age, sex, fluoroscopy time, baseline PR interval, and baseline HV interval was included in univariate and multivariate models to predict HB post ablation.

Results

In 1708 patients (56.4 ± 17.0 years, 61% females), acute procedural success was 97.1%. The overall incidence of HB was 1.3%. Multivariate analysis showed that age more than 70 (odds ratio [OR] 7.907, p ≤ .001, confidence interval [CI] 2.759–22.666), baseline PR ≥ 190 ms (OR 2.867, p = .026, CI 1.135–7.239) and no use of EAM (OR 0.306, p = .037, CI 0.101–0.032) were independent predictors of HB.

Conclusion

Although the incidence of HB post AVNRT ablation is generally low, patients can be further stratified using three simple predictors.
Histopathology of laboratory‐reared Nothobranchius fishes: Mycobacterial infections versus neoplastic lesions
Authors: Dyková Iva , Žák Jakub , Reichard Martin , Součková Kamila , Slabý Ondřej , Bystrý Vojtěch , Blažek Radim
Published: April 2021

Short‐lived killifishes of the genus Nothobranchius Peters, 1868 (Cyprinodontiformes) are considered promising model organisms for biomedical research on ageing and tumorigenesis. We conducted histopathological analysis of 411 adult individuals from three Nothobranchius species to study details on spontaneous age‐related neoplastic lesions. Light microscopy based on H&E and toluidine blue‐stained sections revealed (a) non‐proliferative liver changes with pronounced vacuolation of hepatocytes; (b) proliferation of kidney haemopoietic tissue contributing to excretory system damage; (c) proliferation of splenic mononuclear haemoblasts accompanied by reduced erythropoiesis; (d) proliferation of mononuclear cell aggregates in the liver parenchyma; and (e) rare occurrence of hepatocellular adenomas. Ziehl–Neelsen (ZN) staining revealed that the proliferative lesions are a host defence response to mycobacterial infections manifested by activation of the mononuclear phagocytic system and atypical granulomatous inflammatory reaction. 16S rRNA analysis identified three species of Mycobacterium in our samples. Our findings turn attention to lesions which mimic neoplasms by their gross appearance and question the light microscopic interpretation of lesions unless differential ZN staining is included. Beyond the limitations of our morphological approach, the intensity of mycobacterial infections is a challenging opportunity for research into the molecular‐genetic background of the mononuclear phagocytic system reaction in Nothobranchius killifish.