bluuebunny/crossref_metadata_2025 huggingface dataset:
Agency
Authors: Munday Roderick
Published: May 2022

Questions of agency regularly arise in the work of commercial practitioners. This book addresses these questions by offering clear and accessible analysis of the main principles and theory of agency law, as well as detailed explanation of the Commercial Agents (Council Directive) Regulations of 1993. Forensic analysis of case law is combined with a practical approach to the law which accurately reflects modern commercial realities, considering the application of agency principles according to particular classes of agents operating in the major commercial sectors. Areas discussed include actual and apparent authority of an agent, agency of necessity, want of authority and ratification looking at the legal relations between principal and agent, and between third party as well as the relations between agent and third party, sub-agency and termination of agency. This fourth edition has been updated to include significant new case law and legislation, while also considering its impact on the principles of agency law. This includes how the European Withdrawal Act (2018) will affect English courts’ interpretation of the Regulations, discussion of an agent’s apparent authority with examination of the disputed decision in East Asia Company Ltd v PT Satria Tirtatama Energindo, agents and contractual undertakings in restraint of trade, as well as the distinction between agents, employees and independent contractors with regards to vicarious liability, as exemplified in three Supreme Court decisions, Various Claimants v Catholic Child Welfare Society, WM Morrison Supermarkets Plc v Various Claimants and Barclays Bank v Various Claimants.
Termination of Agency
Authors: Munday Roderick
Published: May 2022

This chapter considers both how agencies come to be terminated and the effects of termination of agency. It notes ordinary course of events between principal and agent, wherein an agency will come to an end because the parties so wish it. It also refers to parties whose legal relations derive from agreement that are at liberty to release one another from their obligations. The chapter emphasizes how an agency may be terminated by operation of law if the contract between principal and agent is frustrated or if the principal loses legal capacity through death or supervening mental incapacity. It examines the effects of termination, wherein the rules that obtain at common law to reimburse agents apply to commercial agents operating under the Commercial Agents (Council Directive) Regulations 1993.
The Business of Carriage of Goods
Authors: Girvin Stephen
Published: May 2022

This chapter provides an overview of the business of carriage of goods by sea. Cargoes carried by sea include raw materials, such as oil, gas, coal, and iron ore. Agricultural commodities and manufactured goods are also carried by sea, together with industrial materials. The nature of the goods carried and their size determine the contractual relationships between trading parties and counterparties. Bulk goods require different treatment from general cargoes, containerized cargoes, and refrigerated cargoes. The chapter then considers some of the main vessel or ship types and their characteristics as a means to assist in understanding the cargo disputes which may arise. It also looks at the freight market and the charterparty market. Contracts for the international sale of goods typically involve a seller (the shipper) located in one country, and a buyer in a different country; most parties make use of specialized agents, including forwarding agents, loading brokers, and shipbrokers. The responsibilities of sellers and buyers under the contracts of sale will depend upon the terms of the contract entered into. Finally, the chapter explores contracts of affreightment before studying cargo claims.
Paperless Bills of Lading
Authors: Girvin Stephen
Published: May 2022

This chapter reviews paperless bills of lading. Technological advances in the field of maritime commerce has provided strong impetus for the revision of current transport documentation procedures, the use of other carriage documents, renewed interest in the adoption of electronic bills of lading, and the increasing prominence of online web portals. One of the greatest challenges with electronic bills of lading has been mapping the tripartite functions of bills of lading. The chapter then looks at SeaDocs Registry Limited (SeaDocs), which acted as depository and custodian of the paper-based original bill of lading as well as a registry of bill of lading negotiations. It also considers the Comité Maritime International (CMI) Rules for Electronic Bills of Lading; Bolero (Bills of Lading for Europe), essDOCS, and e-titleTM; the Rotterdam Rules and the UNCITRAL Model Law on Electronic Commerce; and blockchain bills of lading.
Reasonable Despatch
Authors: Girvin Stephen
Published: May 2022

This chapter discusses reasonable despatch. The shipowner in all contracts of carriage impliedly undertakes that the vessel is ready to commence the voyage agreed on, to load the cargo to be carried, and shall proceed upon and complete the voyage agreed upon, with all reasonable despatch (or dispatch). As with the implied condition of seaworthiness, the reasonable despatch undertaking is an innominate term of the contract. The claimant’s remedy lies in damages, unless the delay is caused by an excepted peril. The charterer is not able to refuse to load a cargo. Whether the breach is so important as to enable the innocent party to avoid the contract depends on the effects of the breach; the contract may only be repudiated if the delay is such as to frustrate the object of the contract.
Introduction
Authors: Merrett Louise
Published: May 2022

This introductory chapter provides an overview of the private international law issues which arise in connection with international employment contracts. In all cases involving an international employment contract, before the court or tribunal can consider the merits of any dispute, three questions will need to be addressed: (1) Does the court have jurisdiction to hear the case? (2) What law should the court apply to decide the case? (3) Assuming English employment law applies, does the claim or claimant fall within the scope of the relevant provision? Issues of jurisdiction, choice of law, and territorial scope are conceptually distinct. However, this does not mean that common principles do not apply or that parallels cannot be drawn. The chapter then considers the confusion over 'jurisdiction', differentiating between international and domestic jurisdiction and territorial scope.
Conclusions
Authors: Merrett Louise
Published: May 2022

This concluding chapter studies the crucial overlap between jurisdiction, choice of law, and mandatory rules in employment cases. The fact that rules on jurisdiction and choice of law overlap and interrelate means that the rules comprising private international law need to be considered as a whole and cannot be considered in isolation. Moreover, an examination of the detailed private international law rules which apply to employment contracts reveals that there are also common themes, concepts, or rationales which might be drawn from rules in one context and applied in another. In addition, the changes brought about by Brexit have resulted in a number of overlapping regimes which now govern international employment cases. The choice of law rules in the Rome I Regulation and Rome II Regulation remain as part of retained EU law. For cases in the High Court, the common law rules are amended to mirror the provisions which previously applied under the Brussels I Regulation recast. Although in many cases the rules look the same, different principles of interpretation will apply, and, now that the rules are not binding as matter of EU, there will be scope to amend and reform the rules.
Financial Market Infrastructures
Authors: Saguato Paolo , Ferrarini Guido , Pan Eric
Published: May 2022

This chapter analyses the global initiatives for coordination of financial market infrastructure (FMI) regulation that have emerged since the 1990s, reflecting on both the European and the American perspectives. It begins by looking at the different approaches that authorities can take in tackling cross-border phenomena. Finding the right balance between securing national interests and engaging in international relationships is a delicate process: in international financial regulation, authorities can claim extraterritorial application of their domestic regime to keep control of the market and minimize the opportunities of regulatory arbitrage; but they can also try to contain opportunities for regulatory arbitrage by engaging in harmonization and coordination with other countries. The chapter then discusses the dynamics of the European Union and United States relationship and the approaches embraced by the two jurisdictions in regulating and overseeing derivatives central clearinghouses (CCPs) in the aftermath of the global financial crisis. It also examines Brexit and considers the severe challenges that the decision of the United Kingdom to leave the EU will have to the markets, before offering a snapshot of the challenges that financial technology (FinTech) is posing to the existing delicate cross-border regulatory equilibrium.
Central Securities Depositories in the EU
Authors: Ferran Eilís , Hickman Eleanore
Published: May 2022

This chapter discusses the critical role that central securities depositories (CSDs) play in fostering financial stability and operational efficiency in the financial system. CSDs were established for the purpose of reducing risk and increasing efficiency by immobilising securities certificates. They were initially created to serve domestic markets but, in the 1970s, CSDs designed to cater for the international securities markets (ICSDs) began to emerge. The chapter unpacks the 'widely unseen and poorly understood' role CSDs play in the markets, describes the major CSDs operating in the European Union, and analyses the risks associated with CSDs and how CSDs address and mitigate them. It also analyses how the CSDs' governance, business model, and recovery and resolution regimes differ from those of central counterparties (CCPs).
Central Securities Depositories and Participant Default in the EU
Authors: Turing Dermot
Published: May 2022

This chapter explores the legal and regulatory framework of the Central Securities Depositories Regulation (CSDR) and investigates the delicate dynamics of the CSDs' default arrangements to manage a CSD participant's default. CSDs are recognized to be a core component in the smooth functioning of the financial system. CSDR was made law in 2014 and created a new uniform legal and regulatory framework for CSDs in the European Union. One feature of the regulation of CSDs, as with other types of financial market infrastructure, was the requirement for rules and procedure for an orderly management of the default of a CSD participant. The chapter identifies that, while policymakers and CSDs share the same objective of ensuring the safety of securities settlement systems, CSDs' rulebooks and default rules and CSDR itself might have lagged behind the development of new resolution procedures for a participating financial institution which get into difficulties. It critically assesses some of the practices included in CSDs' rulebook on a participant's default management and how they would practically apply vis-à-vis the resolution of a participating firm.
Central Securities Depositories in the United States
Authors: Wice Sam
Published: May 2022

This chapter studies the US central securities depositories (CSDs) landscape, reviewing the market structure and regulatory regime of CSDs. The US financial system has a unique structure for CSDs. The only CSD in the United States, The Depository Trust Company (DTC), is both (i) member-owned and operated and (ii) not directly affiliated with any trading venue. The chapter provides a general overview of the services that DTC offers and the touch points where different practitioners will generally interact with DTC. Particularly, it discusses the process for becoming a member of DTC or making a security eligible in DTC. The chapter also looks at the different transactions DTC provides and why practitioners would want to use those transactions or seek to transact through a stock exchange or similar trading venue. Finally, the chapter examines the general legal framework for CSDs in the United States and how practitioners and members of the public can influence DTC policy.
Intermediated Securities
Authors: Mooney Charles W
Published: May 2022

This chapter reflects on the operations, impact, and role that financial market infrastructures (FMIs) have in the US securities holding system and more broadly on the society. It identifies the regulatory failures in the regulation of securities holding FMI systems and the costs and risks intermediated securities systems imposed on securities markets (internal cost) and on the economy and the public interest more generally (external costs). While intermediation in the securities holding environment is essential for modern securities markets, it nevertheless imposes externalities onto outside constituencies that need to be addressed. The chapter challenges the status quo of the securities holding infrastructures. It engages their primary regulators to set more ambitious goals for the intermediated securities system and engages with policy options oriented towards increased transparency and direct holding.
Data Reporting in the EU
Authors: Schmies Christian , Sajnovits Alexander
Published: May 2022

This chapter examines the legislative and regulatory initiatives adopted by the European Union to address MiFID I shortcomings, reading the functioning and transparency of financial markets. The new MiFID II/MiFIR regime essentially addresses these identified deficits by means of three regulatory measures. First, it considerably extends the scope and increases the stringency of the obligations with regard to pre- and post-trade transparency with a view to improving the quality of pre- and post-trade transparency data. Second, it instigates a shift towards increased trading on regulated trading venues or on other regulated platforms (more extensive market regulation and trading obligations) and, third, it extends the scope of reporting obligations vis-à-vis the supervisory authorities to enable better monitoring of the financial markets. The already extensive Level 1 requirements have been further specified by numerous pieces of highly detailed Level 2 legal acts. In addition, the European Securities and Markets Authority (ESMA) has already issued several guidelines and Q&As to harmonize supervisory practice. The resulting network of regulations poses immense challenges for legal practice—as is increasingly characteristic of European capital market law today.
Qualitative Capital Requirements and their Relationship with MREL/TLAC
Authors: Tröger Tobias H
Published: May 2022

This chapter investigates the relationship of qualitative capital requirements with total loss absorbing capacity (TLAC)/minimum requirement for own funds and eligible liabilities (MREL). The resulting rather complex, multi-layered structure established under Basel III and further refined under the Basel III Accord’s finalization (commonly referred to as ‘Basel IV’) reflects proportionality considerations and seeks to accommodate banks’ desire to retain sufficient leeway to choose from a mix of capital and (hybrid) debt instruments to fulfil regulatory capital requirements. The chapter begins with a critical review of the functional rationale that underpins capital-reliant banking regulation, which serves as the focal point for a normatively guided interpretation of the regulatory framework. It then identifies the key determinants for the actual loss-absorbing capacity of institutions’ CET1, AT1, and T2 capital, as well as their TLAC/MREL items. Finally, the chapter looks into issues regarding the relationship between the multiple layers of regulatory capital such as the stacking order of capital requirements and the restrictions on double-gearing of capital.
Netting and Capital Markets Driven Transactions as Credit Risk Mitigation
Authors: Haentjens Matthias , Joosen Bart PM
Published: May 2022

This chapter explores funded credit protection in the form of netting and financial collateral. It looks at the relationship between the specific credit risk mitigation (CRM) rules discussed in Chapter Eight and the legal or private law concepts that form the background of the CRM rules for netting and financial collateral. All CRM rules assume that under the relevant private law(s), the ‘credit protection arrangement’ that is envisaged to result in ‘credit risk mitigation’, be ‘legally effective and enforceable’. Where the Capital Requirements Regulation (CRR) requires CRM arrangements to be ‘legally effective and enforceable’, an important issue is whether netting can be effectuated when need be, i.e. in the event of a default by the counterparty of the relevant institution. Especially applicable insolvency laws may limit this ability. The chapter then considers how there is a strong fragmentation of the rules for netting within the CRR framework.
Capital Buffers for Systemically Important Banks and the Systemic Risk Buffer
Authors: Tröger Tobias H
Published: May 2022

This chapter highlights the capital buffer requirements that specifically address systemic risks that either flow from an institution’s indispensable position in the financial system (i.e., globally and other systemically important institutions, G-SIIs and O-SIIs) or from sector-wide risks that potentially afflict all, or a systemically relevant fraction of, banks. It begins by looking at the regulatory rationale that underpins the Basel Committee on Banking Supervision (BCBS) recommendations and their European implementation. The chapter then considers the interrelationship between buffer and other capital requirements. Where a group, on a consolidated basis, is required to maintain both a G-SII buffer and an O-SII buffer, only the higher of the two shall apply. Where an O-SII is the subsidiary of a G-SII or of an institution or of a group headed by an EU parent institution, the O-SII buffer rate that applies to the subsidiary on an individual or sub-consolidated basis is restricted, reflecting the additional loss-absorbing capacity that stems from the entity’s group affiliation.
Liquidity Risk and its Management
Authors: Boonstra Wim , Cleen Bruno De
Published: May 2022

This chapter explains the causes of liquidity risk and illustrates how regulators have tried to capture liquidity risk in the supervisory regime of Basel III introduced in 2010 by the Basel Committee of Banking Supervision (BCBS). It begins by looking at two important misunderstandings about banking that often lead to major confusion in the discussion on bank stability: the myth of the risk-free bank and the idea that banks can create ‘their own money’. The chapter then traces the origins and the importance of liquidity risk, before focusing on liquidity risk from both the asset and the liability side of the bank balance. It also provides an outline of how bank supervisors in the past dealt with liquidity risks, before discussing the Liquidity Coverage Ratio (LCR) and the Net Stable Funding Ratio (NSFR) and the effects these ratios have on European banks. Finally, the chapter considers the impact of today’s non-conventional monetary policy.
The SUMO components in rheumatoid arthritis
Authors: Wu Qian , Jiang Yao , You Chongge
Published: May 2022

Small ubiquitin-like modifier (SUMO) proteins can reversibly attach covalently or non-covalently to lysine residues of various substrates. The processes are named SUMOylation and de-SUMOylation, which maintain a dynamic balance in the physiological state, and are regulated by SUMO components. However, the dysregulation of components disturbs the balance and alters the functions of target proteins, which causes the occurrence of diseases. To date, certain SUMO components, including SUMO-1, SUMO-2/3, SAE1/Uba2, Ubc9, PIASs (protein inhibitors of activated signal transducer and activator of transcription) and SENPs (SUMO-specific proteases), have been found to participate in the pathogenesis of RA and their potential value as therapeutic targets also have been highlighted. In addition, single nucleotide polymorphisms (SNPs) in the SUMO components have been reported to be associated with disease susceptibility. Until now, only the SNP site of SUMO-4 has been reported in RA. Here we provided a systematic overview of the general characteristics of SUMO components and highlighted a summary of their impact on RA.
Minimal, Relaxing Membranectomies for the Management of Opacified Hyaloid With Diabetic Tractional Retinal Detachments in Monocular Patients: A Novel Surgical Technique
Authors: Berrocal Maria H. , Acaba-Berrocal Luis
Published: May 2022

Purpose:

Vitrectomy for severe tractional retinal detachments is a high-risk procedure given the surgical complexity and potential for postoperative complications. The risk is compounded when operating on monocular patients. We developed a novel technique using hyaloidal removal and minimal relaxing membranectomies for tractional retinal detachments with an opacified hyaloid over the fovea in monocular, diabetic patients and evaluated complications and outcomes.

Methods:

The technique was performed in nine monocular, diabetic patients with decreased visual acuity from opaque hyaloid with centripetal tractional retinal detachments. Outcomes included postoperative best-corrected visual acuity, retinal reattachment rate, redetachments, and complications.

Results:

Average age was 58 years (range 43–74) and the average follow-up time was 43.6 months (range 36–64). Preoperative best-corrected visual acuity ranged from 1.0 to 2.3 logMAR (20/200 - Hand Motion) with a mean of 1.39 logMAR (20/500). Postoperative best-corrected visual acuity at last follow-up ranged from 0.2 to 1.0 logMAR (20/30–20/200) with a mean of 0.49 logMAR (20/60) (P < 0.001). All eyes had attached posterior poles at last follow-up. Complications were observed in two eyes and included nonclearing hemorrhage and capsular opacity.

Conclusion:

Vitrectomy with minimal, relaxing membranectomies is an option for monocular patients in whom intervention is needed, but are at high risk for complications.
The Menopause Management Vacuum
Authors: Faubion Stephanie S. , Shufelt Chrisandra
Published: May 2022

The burden of untreated menopause symptoms in midlife women is substantial and can result in reduced quality of life as well as lost work productivity, lost opportunities for advancement at work, and increased health care costs. Unfortunately, the health care system is largely unprepared to help women manage these symptoms, which have a mean duration of 7 to 9 years. Hormone therapy usage rates have plummeted following publication of the results of the Women's Health Initiative trials due to safety concerns. In addition, postgraduate medical training programs include minimal to no training on menopause management. These and other factors have contributed to what is essentially a menopause management vacuum. This vacuum created a market opportunity, particularly given the fact that midlife women are potent drivers of the global economy. In this review, we outline the menopause management gaps and discuss a multipronged approach to close these gaps and improve the care of midlife women.
Hormone Replacement Therapy After Breast Cancer
Authors: Bluming Avrum Zvi
Published: May 2022

This article reviews the decades of evidence supporting the reproducible benefits of HRT for menopausal symptom control, improved cardiac health, prevention of hip fracture, reduction in the risk and pace of cognitive decline, and enhanced longevity. It quantifies the increased risk of thromboembolism associated with oral, though not transdermal, HRT. It evaluates the repeated claims that HRT is associated with an increased risk of breast cancer development, and, when administered to breast cancer survivors, an increased risk of breast cancer recurrence. Twenty-five studies of HRT after a breast cancer diagnosis, published between 1980 and 2013, are discussed, as are the 20 reviews of those studies published between 1994 and 2021. Only 1 of the 25 studies, the HABITS trial, demonstrated an increased risk of recurrence, which was limited to local or contralateral, and not distant, recurrence. None of the studies, including HABITS, reported increased breast cancer mortality associated with HRT. Even in the HABITS trial, the absolute increase in the number of women who had a recurrence (localized only) associated with HRT administration was 22. It is on the basis of these 22 patients that HRT, with its demonstrated benefits for so many aspects of women’s health, is being denied to millions of breast cancer survivors around the world.
Mechanistic Effects of Estrogens on Breast Cancer
Authors: Santen Richard J. , Stuenkel Cynthia A. , Yue Wei
Published: May 2022

Purpose

Current concepts regarding estrogen and its mechanistic effects on breast cancer in women are evolving. This article reviews studies that address estrogen-mediated breast cancer development, the prevalence of occult tumors at autopsy, and the natural history of breast cancer as predicted by a newly developed tumor kinetic model.

Methods

This article reviews previously published studies from the authors and articles pertinent to the data presented.

Results

We discuss the concepts of adaptive hypersensitivity that develops in response to long-term deprivation of estrogen and results in both increased cell proliferation and apoptosis. The effects of menopausal hormonal therapy on breast cancer in postmenopausal women are interpreted based on the tumor kinetic model. Studies of the administration of a tissue selective estrogen complex in vitro, in vivo, and in patients are described. We review the various clinical studies of breast cancer prevention with selective estrogen receptor modulators and aromatase inhibitors. Finally, the effects of the underlying risk of breast cancer on the effects of menopausal hormone therapy are outlined.

Discussion

The overall intent of this review is to present data supporting recent concepts, discuss pertinent literature, and critically examine areas of controversy.
Estrogen for the Treatment and Prevention of Breast Cancer
Authors: Abderrahman Balkees , Jordan V. Craig
Published: May 2022

In 1971, Sir Alexander Haddow et al. delivered the inaugural David A. Karnofsky lecture at the American Society for Clinical Oncology. This award was designated American Society for Clinical Oncology’s highest, as he had used translational research to identify the first clinical therapy, that is, synthetic estrogens to treat breast cancer. His lecture was entitled “Thoughts on Chemical Therapy.” For 40 years, high-dose synthetic estrogens were used as palliative therapy, for some advanced breast cancer patients 5 years following menopause. Mechanisms were unknown. Tamoxifen, a failed “morning-after pill,” is an antiestrogen in estrogen receptor–positive breast cancer, which was subsequently used to treat all stages of breast cancer and to prevent breast cancer. In 2008, Jordan was selected to present the 38th Karnofsky lecture entitled: “The Paradoxical Action of Estrogen in Breast Cancer—Survival or Death?” Unexpectedly, through a study of acquired resistance to long-term tamoxifen therapy, estrogen-induced apoptosis in long-term estrogen-deprived breast cancer was deciphered in Jordan’s laboratory. These data and the biological rules established under laboratory conditions provided molecular mechanisms to aid in the interpretation of the Women's Health initiative in the United States and the Million Women Study in the United Kingdom. In addition, by establishing laboratory models to understand mechanisms of estrogen-induced apoptosis, new estrogen derivatives were successfully evaluated in the laboratory and tested as candidates for women after the therapeutic failure of antiestrogenic strategies to treat breast cancer. For the future, the knowledge obtained about estrogen-induced apoptosis in cancer holds the promise of discovering new therapies to control or cure cancer in general.
Decreased spontaneous brain activity in the dorsal visual pathway in age-related macular degeneration patients revealed by fractional amplitude of low-frequency fluctuation
Authors: Lai Ping-Hong , Cai Yue-Hong , Zhong Yu-Lin , Huang Xin
Published: May 2022

Background

Age-related macular degeneration (AMD) is the leading cause of visual loss in the developed world and damages the central retina. Growing evidences demonstrated that AMD patients were associated with brain structure changes in visual pathway. However, it remains unknown whether alterations of spontaneous brain activity changes occur in AMD patients.

Purpose

The purpose of this study was to investigate the effect of central vision loss on spontaneous brain activity in AMD patients.

Material and methods

Seventeen AMD patients and 17 healthy controls (HCs) underwent resting-state MRI scans. The fractional amplitude of low-frequency fluctuations (fALFFs) was applied to investigate the spontaneous brain activity changes in AMD patients.

Results

Compared with HC group, AMD patients showed significant decreased fALFF values in the right calcarine/cuneus (brodmann area 17,8) and right superior parietal lobule (brodmann area 7).

Conclusion

Our results showed that AMD patients had decreased brain activities in the dorsal visual pathway, which offer important insights into the neural mechanisms of central visual field defect in AMD patients.
Shape driven confluent rigidity transition in curved biological tissues
Authors: Thomas Evan , Hopyan Sevan
Published: May 2022

Collective cell motions underlie structure formation during embryonic development. Tissues exhibit emergent multicellular characteristics such as jamming, rigidity transitions, and glassy dynamics, but there remain questions about how those tissue scale dynamics derive from local cell level properties. Specifically, there has been little consideration of the interplay between local tissue geometry and cellular properties influencing larger scale tissue behaviours. Here we consider a simple two dimensional computational vertex model for confluent tissue monolayers, which exhibits a rigidity phase transition controlled by the shape index (ratio of perimeter to square root area) of cells, on surfaces of constant curvature. We show that the critical point for the rigidity transition is a function of curvature such that positively curved systems are likely to be in a less rigid, more fluid, phase. Likewise, negatively curved systems (saddles) are likely to be in a more rigid, less fluid, phase. A phase diagram we generate for the curvature and shape index constitutes a testable prediction from the model. The curvature dependence is interesting because it suggests a natural explanation for more dynamic tissue remodelling and facile growth in regions of higher surface curvature, without invoking the need for biochemical or other physical differences. This has potential ramifications for our understanding of morphogenesis of budding and branching structures.
Anti-SARS-Cov-2 S-RBD IgG formed after BNT162b2 vaccination can bind C1q and activate complement
Authors: Abu-Humaidan Anas H. A. , Ahmad Fatima M. , Awajan Dima , Jarrar Raba’a F. , Alaridah Nader
Published: May 2022

Introduction

Activation of the classical complement pathway through C1q binding to immunoglobulins (Ig) contributes to pathogen neutralization, thus, the ability of Ig produced after vaccination to bind C1q could affect vaccine efficacy. In this study, we investigated C1q binding and subsequent complement activation by anti-spike (S) protein receptor-binding domain (RBD) specific antibodies produced following vaccination with either the mRNA vaccine BNT162b2 or the inactivated vaccine BBIBP-CorV.

Methods

Serum samples were collected in the period July 2021-March 2022. Participants’ demographic data, type of vaccine, date of vaccination, as well as adverse effects of the vaccine were recorded. The serum samples were incubated with S protein RBD-coated plates. Levels of human IgG, IgM, and C1q, that were bound to the plate, as well as formed C5b-9, were compared between different groups of participants.

Results

A total of 151 samples were collected from vaccinated (n=116) and non-vaccinated (n=35) participants. Participants who received either one or two doses of BNT162b2 formed higher levels of anti-RBD IgG than participants who received BBIBP-CorV. The anti-RBD IgG formed following either vaccine bound C1q, but significantly more C1q binding was observed in participants who received BNT162b2. Subsequently, C5b-9 formation was significantly higher in participants who received BNT162b2, while no significant difference in C5b-9 formation was found between the non-vaccinated and BBIBP-CorV groups. Formation of C5b-9 was strongly correlated to C1q binding, additionally, the ratio of formed C5b-9/ bound C1q was significantly higher in the BNT162b2 group.

Conclusion

Anti-RBD IgG formed following vaccination can bind C1q with subsequent complement activation, the degree of terminal complement pathway activation differed between vaccines, which could play a role in in the protection offered by COVID-19 vaccines. Further investigation into the correlation between vaccine protection and the ability of vaccine generated antibodies to activate complement is required.
Spatial Transcriptomics Prediction from Histology jointly through Transformer and Graph Neural Networks
Authors: Zeng Yuansong , Wei Zhuoyi , Yu Weijiang , Yin Rui , Li Bingling , Tang Zhonghui , Lu Yutong , Yang Yuedong
Published: May 2022

The rapid development of spatial transcriptomics allows for the measurement of RNA abundance at a high spatial resolution, making it possible to simultaneously profile gene expression, spatial locations, and the corresponding hematoxylin and eosin-stained histology images. Since histology images are relatively easy and cheap to obtain, it is promising to leverage histology images for predicting gene expression. Though several methods have been devised to predict gene expression using histology images, they don’t simultaneously include the 2D vision features and the spatial dependency, limiting their performances. Here, we have developed Hist2ST, a deep learning-based model using histology images to predict RNA-seq expression. At each sequenced spot, the corresponding histology image is cropped into an image patch, from which 2D vision features are learned through convolutional operations. Meanwhile, the spatial relations with the whole image and neighbored patches are captured through Transformer and graph neural network modules, respectively. These learned features are then used to predict the gene expression by following the zero-inflated negative binomial (ZINB) distribution. To alleviate the impact by the small spatial transcriptomics data, a self-distillation mechanism is employed for efficient learning of the model. Hist2ST was tested on the HER2-positive breast cancer and the cutaneous squamous cell carcinoma datasets, and shown to outperform existing methods in terms of both gene expression prediction and following spatial region identification. Further pathway analyses indicated that our model could reserve biological information. Thus, Hist2ST enables generating spatial transcriptomics data from histology images for elucidating molecular signatures of tissues.
Sex-limited diversification of the eye in Heliconius butterflies
Authors: Buerkle Nathan P. , VanKuren Nicholas W. , Westerman Erica L. , Kronforst Marcus R. , Palmer Stephanie E.
Published: May 2022

Butterflies have evolved an immense diversity in eye organization to support a range of vision-based behaviors including courtship, oviposition, and foraging. This diversity has been surveyed extensively across the butterfly phylogeny, and here we take a complementary approach to characterize the eye within a group of closely related Heliconius butterflies. Using a combination of immunostaining for different opsins and eyeshine for determining the distribution of light-filtering screening pigments, we identified several sexually dimorphic features of eye organization where male eyes varied and female eyes did not. Ultraviolet (UV) sensitive photoreceptors varied in which of two UV opsins were expressed, including co-expression of both within single photoreceptors, and these differences were consistent with a role in courtship and conspecific identification. Additional differences across species and sex included the distribution of three ommatidial types defined by the expression pattern of UV and blue opsins, the distribution of a red screening pigment, and which ommatidial types expressed the red screening pigment. We hypothesize that female eyes are optimized for a dimorphic behavior such as oviposition, while male eyes adapt to other selective pressures such as the local light environment.
Real-time feeding behavior monitoring by electrical penetration graph rapidly reveals host plant susceptibility to crapemyrtle bark scale (Hemiptera: Eriococcidae)
Authors: Wu Bin , Chun Elizabeth , Xie Runshi , Knox Gary W. , Gu Mengmeng , Qin Hongmin
Published: May 2022

Host range confirmation of invasive hemipterans relies on the evaluation of plant susceptibility though greenhouse or field trials, which are inefficient and time-consuming. When the green industry faces the fast-spreading threat of invasive pests such as crapemyrtle bark scale (Acanthococcus lagerstroemiae), it is imperative to timely identify potential host plants and evaluate plant resistance/susceptibility to pest infestation. In this study, we developed an alternative technology to complement the conventional host confirmation methods. We used electrical penetration graph (EPG) based technology to monitor the A. lagerstroemiae stylet-tip position when it was feeding on different plant tissues in real-time. The frequency and relative amplitude of insect feeding waveforms (recorded by EPG) were extracted by an R programming-based software written to generate eleven feeding parameters for comparative analysis between plant species. The results demonstrated that the occurrences of phloem phase and xylem phase offered conclusive evidence for host plant evaluation. Furthermore, parameters including the percentage of insects capable of accessing phloem tissue, time duration spent on initiating phloem phase and ingesting phloem sap, provided insight into why host plant susceptibility differs among similar plant species. In summary, this study developed a novel real-time diagnostic tool for quick A. lagerstroemiae host confirmation, which laid the essential foundation for effective pest management.

Simple Summary

Crapemyrtle bark scale (CMBS; Acanthococcus lagerstroemiae), an invasive polyphagous sap feeder in the United States, has spread across 16 U.S. states in less than two decades, posing potential risks to the Green Industry. Confirming the host range is crucial for effective pest management of invasive insects. However, host range confirmation relying on greenhouse or field trials is often inefficient and time-consuming. In this study, we used the electrical penetration graph (EPG) to monitor the stylet penetration of CMBS in plant tissue in real-time. An R programming-based application was developed to better characterize the insect feeding waveforms recorded by EPG. By analyzing EPG-based feeding parameters, we demonstrated that CMBS have difficulty accessing the phloem tissue (salivation and ingestion) of a resistant plant compared to a susceptible plant. Importantly, we hereby present CMBS typical feeding behaviors on susceptible and non-susceptible plants comparatively, which provides direct evidence for revealing unknown hosts rapidly.
The metabolite-controlled ubiquitin conjugase Ubc8 promotes mitochondrial protein import by enhancing assembly of the TOM complex
Authors: Rödl Saskia , Brave Fabian den , Räschle Markus , Lenhard Svenja , Groh Carina , Becker Hanna , Zimmermann Jannik , Morgan Bruce , Richling Elke , Becker Thomas , Herrmann Johannes M.
Published: May 2022

Mitochondria are essential organelles that play a key role in cellular energy metabolism. Transitions between glycolytic and respiratory conditions induce considerable adaptations of the cellular proteome. These metabolism-dependent changes are particularly pronounced for the protein composition of mitochondria. Here we show that the yeast cytosolic ubiquitin conjugase Ubc8 plays a crucial role in the remodeling process when cells transition from respiratory to fermentative conditions. Ubc8 is a conserved and well-studied component of the catabolite control system that is known to regulate the stability of gluconeogenesis enzymes. Unexpectedly, we found that Ubc8 also promotes the assembly of the translocase of the outer membrane of mitochondria (TOM) and stabilizes its cytosol-exposed receptor subunit Tom22. Ubc8 deficiency results in a compromised protein import into mitochondria and a subsequent accumulation of mitochondrial precursor proteins in the cytosol. Our observations show that Ubc8, which is controlled by the prevailing metabolic conditions, promotes the switch from glucose synthesis to glucose usage in the cytosol and induces the biogenesis of the mitochondrial TOM machinery in order to improve mitochondrial protein import during phases of metabolic transition.
Mycobacterium tuberculosis transcriptional regulator Rv1019 is upregulated in hypoxia and negatively regulates Rv3230c-Rv3229c operon encoding enzymes in the oleic acid biosynthetic pathway
Authors: Pushparajan Akhil Raj , Edison Lekshmi K , Kumar Ramakrishnan Ajay
Published: May 2022

The main obstacle in eradicating tuberculosis is the ability of Mycobacterium tuberculosis to remain dormant in the host, and then to get reactivated even years later under immuno-compromised conditions. Transcriptional regulation in intracellular pathogens plays an important role in adapting to the challenging environment inside the host cells. Previously, we demonstrated that Rv1019, a putative transcriptional regulator of M. tuberculosis H37Rv, is an autorepressor. We showed that, Rv1019 is cotranscribed with Rv1020 (mfd) and Rv1021 (mazG) encoding DNA repair proteins and negatively regulates the expression of these genes. In the present study, we show that Rv1019 also regulates the expression of the genes Rv3230c and Rv3229c (desA3) which form a two-gene operon in M. tuberculosis. Constitutive expression of Rv1019 in M. tuberculosis significantly downregulated the expression of these genes. Employing Wayne’s hypoxia-induced dormancy model of M. tuberculosis, we show that Rv1019 is upregulated (3-fold) under hypoxia. Finally, by reporter assay, using M. smegmatis as a model, we validate that Rv1019 is recruited to the promoter of Rv3230c-Rv3229c during hypoxia and negatively regulates this operon which is involved in the biosynthesis of oleic acid.
The Drosophila Fab-7 boundary element modulates Abd-B gene activity in the genital disc by guiding an inversion of collinear chromatin organization and alternative promoter use
Authors: Moniot-Perron Laura , Moindrot Benoit , Manceau Line , Edouard Joanne , Jaszczyszyn Yan , Gilardi-Hebenstreit Pascale , Hernandez Céline , Bloyer Sébastien , Noordermeer Daan
Published: May 2022

Hox genes encode transcription factors that specify segmental identities along the Antero-Posterior body axis. These genes are organized in clusters, where their order corresponds to their activity along the body axis, an evolutionary conserved feature known as collinearity. In Drosophila, the BX-C cluster contains the three most posterior Hox genes, where their collinear activation incorporates progressive replacement of histone modifications, reorganization of 3D chromatin architecture and sequential activation of boundary elements and cis-regulatory regions. To dissect functional hierarchies, we compared chromatin organization in larvae and in cell lines, with a focus on the Abd-B gene. Our work establishes the importance of the Fab-7 boundary element for insulation between 3D domains marked by different histone modifications. Interestingly, we detected a non-canonical inversion of collinear chromatin dynamics at the Abd-B gene, with the active histone domain decreasing in size. This chromatin organization differentially instructed alternative Abd-B promoter use, thereby expanding the possibilities to regulate transcriptional output.
Structural basis of human LRRK2 membrane recruitment and activation
Authors: Zhu Hanwen , Tonelli Francesca , Alessi Dario R. , Sun Ji
Published: May 2022

Mutations in LRRK2 are the most common genetic cause of late-onset Parkinson’s disease (PD). LRRK2 encodes the leucine-rich repeat kinase 2 (LRRK2), whose kinase activity is regulated by Rab29, a membrane-anchored GTPase. However, molecular mechanisms underlying Rab29-dependent recruitment and activation of LRRK2 remain unclear. Here we report cryo-EM structures of LRRK2–Rab29 complexes in three oligomeric states, illustrating snapshots of key steps during LRRK2 membrane recruitment and activation. Rab29 binds to the ARM domain of LRRK2, and disruption at the interface abrogates LRRK2 kinase activity. Activation of LRRK2 is underpinned by the formation of an unexpected Rab29-induced super-assembly containing two central kinase-active and two peripheral kinase-inactive LRRK2 protomers. Central protomers undergo pronounced oligomerization-associated rearrangements and adopt an active conformation. Our work reveals the structural mechanism for LRRK2’s spatial regulation controlled by Rab GTPases, provides mechanistic insights into pathogenic mutations and identifies new opportunities to design LRRK2 inhibitors for PD treatment.
Reinstatement of Pavlovian responses to alcohol cues by stress
Authors: Armstrong Anne , Rosenthal Hailey , Stout Nakura , Richard Jocelyn M.
Published: May 2022

Rationale

Stress may contribute to relapse to alcohol use in part by enhancing reactivity to cues previously paired with alcohol. Yet, standard models of stress-induced reinstatement generally use contingent presentations of alcohol-paired cues to reinforce instrumental behaviors, making it difficult to isolate the ability of cues to invigorate alcohol-seeking.

Objective

Here we sought to test the impact of stress on behavioral responses to alcohol-paired cues, using a model of stress-induced reinstatement of Pavlovian conditioned approach, inspired by Nadia Chaudhri’s work on context-induced reinstatement.

Methods

Long Evans rats were trained to associate one auditory cue with delivery of alcohol or sucrose and an alternative auditory cue with no reward. Following extinction training, rats were exposed to a stressor prior to being re-exposed to the cues under extinction conditions. We assessed the effects of yohimbine, intermittent footshock and olfactory cues paired with social defeat on responses to alcohol-paired cues, and the effects of yohimbine on responses to sucrose-paired cues.

Results

The pharmacological stressor, yohimbine, enhanced Pavlovian responses to both alcohol and sucrose cues, but intermittent footshock and social defeat cues did not.

Conclusions

While yohimbine elicited reinstatement of Pavlovian conditioned responses, these effects may be unrelated to activation of stress systems.