bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk Andnegligence In Wills, Estates, and Trusts
Authors: Frost Martyn , Reed Penelope , Baxter Mark
Published: November 2023

In recent years, there has been a dramatic increase in litigation against those who draft wills and trusts. There is significant potential for client dissatisfaction and for claims to arise out of drafting errors; failure to follow instructions; delays and missed critical dates; failure to anticipate risks and to protect the client; errors and omissions in examining and reporting on documentation; incorrect advice as to the law; fraud and dishonesty; and loss of documents. In addition, the book examines how far is it appropriate to ensure that an estate is administered properly. This book offers a detailed examination of the law relating to negligence as it applies to the preparation and administration of wills, trusts, and estates, as well as offering extensive coverage of the relevant taxation issues. This work contains indispensable practical guidance, tailored to meet the demands of contentious solicitors and barristers involved in resolving disputes, and non-contentious solicitors and trust practitioners who want to establish best practice to prevent disputes over wills, trusts, and estates. It includes advice on best practice, explaining how to undertake this work effectively and to maintain an adequate control of risk, in the form of procedures or actions broken down into step by step processes, checklists, and example forms and controls. It contains an overview of the principles and procedure relating to these actions. It also provides appendices of forms, precedents, and checklists. The book expands on Martyn Frost and Penelope Reed's previous book, With the Best Will in the World, (Legalese, January 2002) which was shortlisted for the 2004 High Nets' Private Client Book of the Year.
Other Aspects of The Duty of Care
Authors: Frost Martyn , Reed Penelope , Baxter Mark
Published: November 2023

It is reasonably clear that if there is evidence that the testator̓s intention did not remain fixed and that therefore he cannot be shown with sufficient certainty to wish to benefit the claimant, a claim on a White v Jones basis (for the failure to prepare a will) is going to fail.
The Will Draftsman
Authors: Frost Martyn , Reed Penelope , Baxter Mark
Published: November 2023

Both taking instructions and drafting require a sufficient degree of up-to-date knowledge and training for the complexities of the will in question. To undertake either task with a lack of knowledge, qualification or recent experience, is to accept a level of risk that should normally be regarded as unacceptable by a practice.1 There is, however, no legal restriction on who may prepare a will for profit.
Distributions
Authors: Frost Martyn , Reed Penelope , Baxter Mark
Published: November 2023

The obvious risks in making distributions are that either they are for too great an amount or that they are to the wrong beneficiary. The former can be guarded against by accuracy of the estate or trust accounts and the careful calculation of outstanding liabilities. Comment is made later on the identification of beneficiaries. There are, however, other aspects of policy and planning concerning distributions that should be considered in order to control risk.
What is ‘working time’?
Authors: McLynn Lucy
Published: November 2023

This chapter discusses the various activities that are classified as working time under the Working Time Regulations 1998 (WTR), considers the problems that may arise when a contract makes provision for payment for an hourly rate for working time, summarises the cases on on-call work and the principles which can be drawn from them, and compares the position of working time under the National Minimum Wage (NMW) legislation.
Unfair Dismissal, Detriment And Enforcement
Authors: McLynn Lucy
Published: November 2023

In addition to a worker’s ability to enforce various individual rights under the Working Time Regulations 19981 (WTR) in the employment tribunals, there is specific protection for workers who are treated badly by their employer as a consequence of raising WTR issues. Employees (but not workers) have the protection of automatically unfair dismissal provisions, and workers (including employees) are protected from suffering detriment. This chapter also deals with settling WTR complaints and the regime for enforcement of a number of the WTR protections by the relevant statutory bodies.
Multiple Claimants in Investment Arbitration: Shareholders and Other Stakeholders
Authors: Bishop R Doak
Published: November 2023

This paper will examine the subject of multiple parties in international investment arbitrations, with an emphasis on corporate shareholders or other project owners in arbitrations before the International Centre for Settlement of Investment Disputes (“ICSID”), a specialized institution that administers investment disputes involving governments.
Complex Arbitration: Issues in Enforcement and Annulment Actions of Arbitral Awards Under French Law
Authors: Hascher Dominique T
Published: November 2023

The problems of complex arbitration are notably addressed by French courts in annulment or enforcement proceedings of arbitral awards, pursuant to Article 1502 of the code de procédure civile (Code of Civil Procedure; “NCPC”), on the following grounds: (1) the absence of an arbitration agreement;(2)the irregular constitution of the arbitral tribunal;and (3) the violation of international public policy.
Markets as Networks, Groups, and Communities
Authors: Preda Alex
Published: November 2023

After having discussed passes and dribbles in the previous chapter, I will focus now on the teams entering the Weld of transactions, and engaging in plays of games. Players on a team know each other; very often, they know players on the competing team as well: they meet; they exchange stories; they have a common social life. In short, they have relationships. In the present chapter, I discuss relationships in plays of transactions.
Markets, Information, and Economic Expertise
Authors: Preda Alex
Published: November 2023

A soccer match involves not only teams on the Weld, but also commentators; sports journalists and the public observing the play make incessant comments upon what is going on in the Weld, before the play, while this latter unfolds, and after the play. Not only that, the players themselves make comments upon the play while playing and also before and after the play. The play of the game always includes the comments upon the play. Similarly, plays of competitive transactions include comments and judgements upon what is going on, comments which very often are clad in the mantle of expertise.
Technology and Market Information
Authors: Preda Alex
Published: November 2023

In her book on the Chicago Board of Trade (CBOT), Caitlin Zaloom (2006, pp. 54–5, 74) describes how the traders fought over (and resisted) the introduction of computerized trading, only to and themselves later in an environment which didn’t resemble at all the trading pits of the CBOT: impersonal office spaces with rows of computer screens, where the deafening noise of the trading pit had been replaced by computer clicks. Instead of facing each other standing, traders now sat next to each other facing computer screens. While this shift is meant to illustrate the growing role of computers in transactions, it also highlights the fact that markets have technology as an intrinsic component. This has led scholars to argue that markets can be conceived as ‘socio-technical agencements’ (MacKenzie 2009, pp. 20–1; Callon 2007 b, p. 140) or as scopic systems (e.g. Knorr Cetina 2005; Knorr Cetina and Preda 2007). Distinctions such as that between network markets and flow markets (Knorr Cetina 2005, p. 39) are meant to emphasize, among others, the role played by technology, a role which cannot be easily grasped in terms of networks.
Retail Competition: The Use of Ex-Ante and Ex-Post Remedies
Authors: Gorrie* Alastair
Published: November 2023

This chapter looks at remedies in merger cases involving the supermarkets and groceries sectors and goes on to consider other ex-ante remedies (market investigations) and ex-post remedies (Articles 81 and 82). The plan of this chapter is to consider first remedies in merger cases (Section A), then other ex-ante remedies arising out of market investigations (Section B), then remedies in Article 81/Chapter 1 cases (Section C), other ex-post remedies (Section D) and drawing a few conclusions in Section E.
Northern Ireland
Authors: McElrath Karen
Published: November 2023

warring tensions between two factions, ie Protestants and Catholics. This portrayal is limited in two ways. First, it ignores the role of the British state as an active protagonist in the conflict. Second, it suggests that the conflict is ‘tribal’, and one based on religious grounds only.
Finland
Authors: Holmila Marja , Warpenius Katariina
Published: November 2023

On the basis of statistics and official records this chapter examines changing rates of violence in Finnish restaurants, bars, pubs, and nightclubs over a ten-year period. The period in question was characterized by rapid rises in the number of licensed premises and increased use of alcohol. However, data shows that the number of violent assaults in licensed premises did not increase during this period, although rises were recorded in public places and private homes. We argue that one likely reason for this is that, whilst the country’s total consumption of alcohol reached new peaks, the proportion of alcohol sales from on-licensed venues remained static. Another explanation could be that the harm-reduction initiatives targeting on-licensed premises, including campaigns of licensing-law enforcement, proved successful. In the concluding section we discuss the potential for using situational crime-prevention measures as part of an overall strategy for reducing alcohol-related harm.
Italy
Authors: Selmini Rosella , Nobili Gian Guido
Published: November 2023

In contemporary Italian society, ‘nightlife’ is a concept whose importance has increased enormously in many different contexts: as a key element in understanding the changing nature of young people’s lifestyles, a central aspect of urban governance, including crime control and place marketing, and as an issue of public debate. In Italy, as elsewhere, nightlife is also an important issue in two different and conflicting ways: on the one hand, improving access to leisure helps drive and sustain economic development and cultural vibrancy. On the other, nightlife is still associated with feelings of public anxiety and insecurity and with some established and chronic forms of crime and disorder. These different ways of interpreting and attaching meaning to nightlife lie at the core of conflict among different social groups concerning the ways in which nightlife should be regulated.
Can I take Medications for My Pain?
Authors: Lee John , Brook Suzanne , Daniel Clare
Published: November 2023

Medications can have different names and come in different forms. The names often describe something about what they look like or what they do, for example, pills, tablets, patches, creams or pain killers. This chapter will explain more about the different categories of medicine available and how you can use them to maximum benefi t. Quite a few people also want to reduce or stop taking medicines and we will talk about this too. In this chapter, the terms ̒medication̓ or ̒medicine̓ are used interchangeably whereas the term ̒drug̓ normally refers to a chemical compound used as a medicine.
Relaxation
Authors: Lee John , Brook Suzanne , Daniel Clare
Published: November 2023

Many people with back pain feel they need to relax. They may feel that their stress levels are increasing or that their muscles feel tense. Relaxation can help in the following ways: Engaging in relation techniques means your body is doing something that is incompatible with tension and so it reduces tension.
Coping with a New Pain: what can I Expect from Treatments?
Authors: Lee John , Brook Suzanne , Daniel Clare
Published: November 2023

Miss Havent (aged 37) has had low back pain for over twenty years. She has seen many doctors over this time. These have included a surgeon, a rheumatologist and a pain management consultant. No one has ever found a definite cause and at least two doctors have given her different diagnoses. She has had physiotherapy, and acupuncture. Some interventions have helped and some have not. None have helped for a long period of time.
Nights are the Worst Time
Authors: Lee John , Brook Suzanne , Daniel Clare
Published: November 2023

Sleep problems are extremely common in people with pain. The problem maybe finding it hard to get to sleep, waking up through the night or not being able to return to sleep after waking up. Poor sleep can result in feeling slowed mentally and physically, being less able to enjoy things, feeling irritable or low in mood and people often say that their pain is often harder to cope with during these days.
My Pain has got a Whole lot Worse
Authors: Lee John , Brook Suzanne , Daniel Clare
Published: November 2023

Mr Grey is 60 years old and has had back pain for three years. His pain is constant but there are times when it increases in severity. Sometimes he can say why this happens, sometimes he has no idea. During these times Mr Grey feels that he cannot move, his mood is very low and he feels frustrated.
Uk Criminal Cartel Conduct
Authors: O’Kane Michael
Published: November 2023

This chapter focuses primarily on the liability of individuals for the statutory cartel offence set out in section 188 of the Enterprise Act (‘EA’) 2002. The history and development of the law in relation to cartel conduct and the introduction of the cartel offence is analysed in detail in Chapter 1. The main aim of this chapter is to dissect and examine the main elements of the offence and consider the inter- action of the cartel offence with UK and EC civil competition law. The liability of companies and individuals to being prosecuted under the common law offence of conspiracy to defraud is also reviewed (paragraphs 2.121 onwards).
Russian Legal Theory
Authors: Butler William E
Published: November 2023

For nearly three-quarters of a century the fundamentals of Marxism-Leninism comprised the starting point in the former Soviet Union for university and secondary-level studies in every discipline, including law. Courses in political economy, historical materialism, dialectical materialism, history of the Communist Party, and basic principles of Marxism-Leninism were required in the first and second years of higher education to create what the Soviet authorities considered to be the proper ideological and philosophical base for the further acquisition of knowledge. With the demise of the Soviet Union, those ideological foundations were discredited and removed from the curriculum (although not instantaneously).
Constitutional and Administrative Law
Authors: Butler William E
Published: November 2023

The enactment for the first time in Russian history of a genuinely democratic Constitution has given a new dimension to the branch of legal science devoted to State structures.
Civil Law
Authors: Butler William E
Published: November 2023

‘Civil law’ is widely used in several senses. Civil law may refer to Roman law, or to the family of modern legal systems concentrated on the mainland of Europe which has developed on the basis of legal science fashioned after Justinian in the Romano- Germanic universities from the twelfth century, and to the legal systems elsewhere that received the European civilist tradition. In a narrower sense civil law may encompass private law, that is, the branch of law regulating legal relations between natural and juridical persons. In the Soviet legal system civil law was the branch of law regulating ‘property and personal non-property relations’ in a socialist society for the object of creating the material-technical base of communism and in order to satisfy more fully the material and spiritual requirements of citizens. Under a market economy Russian law has dramatically transformed the meaning of civil law to encompass ‘the legal status of the participants of civil turnover, the grounds for the origin and the procedure for the effectuation of the right of ownership and other rights to a thing and exclusive rights in the results of intellectual activity’, the regulation of contractual and other obligations, and also other property and related non-property relations based on equality, autonomy of will, and the property autonomy of the participants thereof (Article 2(1), Civil Code). Anglo-American law, also rooted in the Roman legal tradition, has for historical reasons developed with divisions, concepts, vocabulary, and methods that diverge in many key respects from all the aforementioned notions of civil law.
Making the diagnosis of COPD
Authors: Currie Graeme P
Published: November 2023

Typical symptoms of COPD include breathlessness, chest tightness, wheeze, cough, sputum production (especially in the mornings), reduced exercise capacity, and frequent chest infections. Many other medical conditions have features similar to COPD and need to be excluded. Breathing tests—known as spirometry—are required to diagnose COPD with certainty.
Managing COPD with drugs
Authors: Currie Graeme P
Published: November 2023

All patients with COPD should have a reliever inhaler for use on an ‘as required’ basis; these drugs open up the airway and are called short-acting bronchodilators. Individuals with persistent symptoms should use a preventer inhaler on a daily basis; these drugs also open up the airway and are called long-acting bronchodilators.
Episodes of worsening symptoms (exacerbations)
Authors: Currie Graeme P
Published: November 2023

Most patients with COPD will experience a worsening of symptoms (called an exacerbation) at some time; these should be treated promptly. Most exacerbations can be successfully managed at home with short courses of steroid tablets and antibiotics, and increased use of reliever inhalers. If admitted to hospital, patients will probably receive oxygen, high-dose inhaled bronchodilators (drugs to open up the airways) and a short course of steroid tablets and antibiotics.
Capacity-building
Authors: Turk Volker
Published: November 2023

In ideal circumstances, the state, in the exercise of its sovereignty, provides a safe, secure and stable environment, guarantees the functioning of basic services, and protects human rights. The effective exercise of state power and corresponding state responsibilities are, along with people and territory, core defining features of statehood. However, this ideal is not met in situations of underdevelopment, poor governance, weak or fragile state structures, or violent conflict-all situations in which the state is either unwilling or unable to exercise effectively power and responsibilities through national structures.
Conflict Economies
Authors: Wennmann Achim
Published: November 2023

Conflict economies are an established concept in the history of warfare and the emergence of the state in Europe. Historically, mobilizing resources for war became one of the major preoccupations of rulers and they consequently devoted the largest share of national revenue to war-making. However, changes in weapons technology increased the cost of warfare and encouraged innovations in fundraising strategies-including the development of state taxation systems, central banking, and the formation of state institutions-that ultimately fostered state¬building in Europe between the 16th and 19th centuries (Tilly, 1992). In terms of guerrilla warfare, conflict economies defined the relationship between guerrillas and local populations. As guerrillas were difficult to distinguish from civilian populations, they provided cover from the relatively stronger state armed forces. However, a tension arose once the economic requirements of the guerrillas went above what local populations were willing to provide, thus jeopardizing the pro¬ vision of protection (Rufin, 1996: 23).
International Crimes
Authors: Doswald-Beck Louise
Published: November 2023

The notion of international crimes became well established in 1945 with the Charter of the International Military Tribunal in Nuremberg. This charter pro¬ vided for the trial of persons not only of war crimes, which existed before this date, but also of crimes against peace and crimes against humanity committed during the Second World War. The same set of crimes was prosecuted by the Tribunal for the Far East, established in 1946.
Mine Action
Authors: Orifici Davide , Damman Suzanne
Published: November 2023

The definition of mine action has evolved over time together with the operational activities in mine-affected countries. The use of the term ‘mine action’ to describe the discipline was formally endorsed by the United Nations in its policy document issued in 1998 (UNMAS, 1998), although it was already used the previous year in a groundbreaking study of indigenous mine action capacities.
Return and Reintegration
Authors: Tennant Vicky
Published: November 2023

The concept of return and reintegration is most commonly used with reference to people and communities who have been forcibly displaced as a result of conflict, war, persecution, or natural disasters. The right to return (and, conversely, the right not to be forced to return to a situation of danger or persecution) developed as a key component of international human rights law and refugee law in the mid-twentieth century. The related concept of reintegration has developed more recently, and encompasses the complex process by which returnees are gradually reincorporated within the social, economic and cultural fabric of their communities, and their rights as citizens restored to them.
Rule of Law
Authors: Gowlland-Debbas Vera , Pergantis Vassilis
Published: November 2023

The rule of law concept was conceived as a constraining force against political power when jus divinum and natural law lost their legitimacy and binding force. It is inextricably linked to the liberal state and the idea of constitutionalism. Despite its frequent use, the term lacks conceptual clarity. While the idea of the rule of law has been characterized as a pleonasm or as an ‘essentially contestable concept’ (Fallon, 1997: 7), others consider it ‘a key element of constitutional democracy’ (Maddex, 2000: 305). Undeniably an open-textured notion, the rule of law can be better characterized as a normative standard, albeit a general, vague, and imprecise one, always to be attained (Salmon, 2001: 1049).
Writing Up Your Research
Authors: Hancké Bob
Published: November 2023

Everyone who teaches graduate students probably recognizes the following scene, if not from our own graduate experience, then definitely from our years as a teacher. Ask any third or fourth-year doctoral student how far they’ve got in their research and there is a big chance that you receive an answer along the lines of ‘I have finished my Weld research and am now beginning to write it up. I hope to finish a draft in the next six months and submit my thesis in about a year.’ Ask the same student again a year later, and you are bound to receive a very similar answer. Has this student truly done nothing in between? Very unlikely. What has probably happened is something else. The student has discovered that producing your research—asking the right question, collecting material, and interpreting it in a way that it sheds new light on the issue—is something very different from reproducing your research on paper. Unfortunately, since the thesis is ultimately what they are judged on, there is no short cut. The student almost certainly also discovered that more empirical research was needed, not in the general, almost ubiquitous sense that students always claim that they need to do more research, but in the practical sense that when they started writing up, they discovered there were holes in their material in light of the argument they were making.
Basics
Authors: Dixon R M W
Published: November 2023

In writing this book I have two aims. To provide an outline characterization of the structure of human language. And to provide a guide for those who wish to pursue the central business of linguistics—describing and analysing natural languages, and then by inductive generalization contributing to the typological theory summarized here.
Analysis, Argumentation, and Explanation
Authors: Dixon R M W
Published: November 2023

Basic linguistic theory provides a flexible, analytic framework in terms of which the grammar of each individual language can be formulated. It furnishes an array of grammatical categories and construction types—together with varieties of interrelations between them—from which appropriate choices are made.
Doing Typology
Authors: Dixon R M W
Published: November 2023

Linguistic typology is ‘the classification of languages according to their general structure rather than according to their historical or geographical relationship’ (Bazell 1958: 3). It aims at putting forward hypotheses concerning universal characteristics of underlying grammatical categories and structures, and interrelations between them. Some of the earliest endeavours were the classifications of languages into isolating, agglutinating, and fusional (or inflectional) types, or along the continuum from analytic to synthetic (to which the label ‘polysynthetic’ has been unnecessarily added), as described in §5.5. (However, the actual term ‘linguistic typology’ did not come into circulation until relatively recently.)
Transitivity
Authors: Dixon R M W
Published: November 2023

Each clause has a transitivity value, which determines the number of core arguments it requires. §13.1 discusses clausal transitivity, the functional roles which define arguments, and the ways in which they are identified in surface structure.
Copula Clauses and Verbless Clauses
Authors: Dixon R M W
Published: November 2023

Each language has intransitive and transitive clause types. There is frequently a further minor—but still important—type: copula clause. This has as predicate a copula verb, taking two core arguments, Copula Subject (CS) and Copula Complement (CC).The predicate in an intransitive or transitive clause has reference. A copula verb as predicate is different in that it has relational rather than referential meaning.
Possession
Authors: Dixon R M W
Published: November 2023

The term ‘possession’ is used to cover a wide range of relationships. Every language has—in its grammar—a ‘possessive construction’ within an NP; for example the surgeon’s knife or the trunk of the tree in English. There is cross- linguistic variation concerning what kind of person, animal, or thing may be the possessor, what may be the possessed, and what kind of possessive relationship is involved. Also, as to whether there is some formal marking on the possessor, or on the possessed, or on both, or on neither (possessor and possessed then being simply apposed).
Reason and Judgment
Authors: Sachs Justice Albie
Published: November 2023

When I had been in solitary confinement I had wondered why it had been so difficult to be brave. Now as a judge I found myself puzzled by how difficult it was to be logical. Surely, I had thought, judgments wrote themselves: connect the principles with the facts, and the solution will ?ow like water from a rock struck by Moses. Yet in reality I laboured mightily, changed my arguments frequently, felt I was always on the verge of wrapping it all up and yet never quite able to achieve the certainty I craved. Neither life experiences nor application of dogmatic rules provided obvious answers. My secretary once informed me that her computer showed that I was proposing corrections to the twenty-sixth version of a draft, and that she and my law clerks sometimes conspired to hide my judgments in case I felt the urge to make yet one more change.
The Beginning and the End
Authors: Sachs Justice Albie
Published: November 2023

In the beginning and in the end is the word, at least as far as the life of a judge is concerned. We pronounce. We work with words, and become amongst the most influential story-tellers of our age. How we tell the story is often as important as what we say. The voice we use cannot be that of a depersonalized and divine oracle that declares solutions to the problems of human life through the enunciation of pure and detached wisdom. Nor dare we seek to imitate the artificial sound of a computer that has been programmed to produce inexorable outcomes. We speak with the living voices of real protagonists who are immersed in and affected by the very processes we deal with. If law is a machine we are the ghosts that inhabit it and give it life. We are animated by consciences that will have been shaped not only by our learning but by our varied engagements with life, by experiences both inside and outside the law. And we continue to live in the very world on which we pronounce. Indeed, being a judge and participating in the work of the courts is nothing less than a rich and ongoing life experience in itself.
A Latent Activated Olfactory Stem Cell State Revealed by Single Cell Transcriptomic and Epigenomic Profiling
Authors: Van den Berge Koen , Chou Hsin-Jung , Kunda Divya , Risso Davide , Street Kelly , Purdom Elizabeth , Dudoit Sandrine , Ngai John , Heavner Whitney
Published: November 2023

The olfactory epithelium is one of the few regions of the nervous system that sustains neurogenesis throughout life. Its experimental accessibility makes it especially tractable for studying molecular mechanisms that drive neural regeneration after injury-induced cell death. In this study, we used single cell sequencing to identify major regulatory players in determining olfactory epithelial stem cell fate after acute injury. We combined gene expression and accessible chromatin profiles of individual lineage traced olfactory stem cells to predict transcription factor activity specific to different lineages and stages of recovery. We further identified a discrete stem cell state that appears poised for activation, characterized by accessible chromatin around wound response and lineage specific genes prior to their later expression in response to injury. Together these results provide evidence that a subset of quiescent olfactory epithelial stem cells are epigenetically primed to support injury-induced regeneration.
Intrinsic dynamics of randomly clustered networks generate place fields and preplay of novel environments
Authors: Breffle Jordan , Germaine Hannah , Shin Justin D. , Jadhav Shantanu P. , Miller Paul
Published: November 2023

During both sleep and awake immobility, hippocampal place cells reactivate time-compressed versions of sequences representing recently experienced trajectories in a phenomenon known as replay. Intriguingly, spontaneous sequences can also correspond to forthcoming trajectories in novel environments experienced later, in a phenomenon known as preplay. Here, we present a model showing that sequences of spikes correlated with the place fields underlying spatial trajectories in both previously experienced and future novel environments can arise spontaneously in neural circuits with random, clustered connectivity rather than pre-configured spatial maps. Moreover, the realistic place fields themselves arise in the circuit from minimal, landmark-based inputs. We find that preplay quality depends on the network’s balance of cluster isolation and overlap, with optimal preplay occurring in small-world regimes of high clustering yet short path lengths. We validate the results of our model by applying the same place field and preplay analyses to previously published rat hippocampal place cell data. Our results show that clustered recurrent connectivity can generate spontaneous preplay and immediate replay of novel environments. These findings support a framework whereby novel sensory experiences become associated with preexisting “pluripotent” internal neural activity patterns.
Graph attention-based fusion of pathology images and gene expression for prediction of cancer survival
Authors: Zheng Yi , Conrad Regan D. , Green Emily J. , Burks Eric J. , Betke Margrit , Beane Jennifer E. , Kolachalama Vijaya B.
Published: November 2023

Multimodal machine learning models are being developed to analyze pathology images and other modalities, such as gene expression, to gain clinical and biological in-sights. However, most frameworks for multimodal data fusion do not fully account for the interactions between different modalities. Here, we present an attention-based fusion architecture that integrates a graph representation of pathology images with gene expression data and concomitantly learns from the fused information to predict patient-specific survival. In our approach, pathology images are represented as undirected graphs, and their embeddings are combined with embeddings of gene expression signatures using an attention mechanism to stratify tumors by patient survival. We show that our framework improves the survival prediction of human non-small cell lung cancers, out-performing existing state-of-the-art approaches that lever-age multimodal data. Our framework can facilitate spatial molecular profiling to identify tumor heterogeneity using pathology images and gene expression data, complementing results obtained from more expensive spatial transcriptomic and proteomic technologies.
Linked-Pair Long-Read Sequencing Strategy for Targeted Resequencing and Enrichment
Authors: Uppuluri Lahari , Shi Christina Huan , Varapula Dharma , Young Eleanor , Ehrlich Rachel L. , Wang Yilin , Piazza Danielle , Mell Joshua Chang , Yip Kevin Y. , Xiao Ming
Published: November 2023

In this report, we present linked-pair sequencing, a novel strategy to construct a long-read sequencing library such that adjacent fragments are linked with end-terminal duplications. We use the CRISPR-Cas9 nickase enzyme and a pool of multiple sgRNAs to perform non-random fragmentation of targeted long DNA molecules (>300kb) into smaller library-sized fragments (about 20 kbp) in a manner so as to retain physical linkage information (up to 1000 bp) between adjacent fragments. DNA molecules targeted for fragmentation are preferentially ligated with adaptors for sequencing, so this method can enrich targeted regions while taking advantage of the long-read sequencing platforms. This enables the sequencing of target regions with significantly lower total coverage, and the genome sequence within linker regions provides information for assembly and phasing. We demonstrated the validity and efficacy of the method first using phage and then by sequencing a panel of 100 full-length cancer-related genes (including both exons and introns) in the human genome. When the designed linkers contained heterozygous genetic variants, long haplotypes could be established. This sequencing strategy can be readily applied in both PacBio and Oxford Nanopore platforms. This economically viable approach is useful for targeted enrichment of hundreds of target genomic regions and where long no-gap contigs need deep sequencing.
Automated machine learning and explainable AI (AutoML-XAI) for metabolomics: improving cancer diagnostics
Authors: Bifarin Olatomiwa O. , Fernández Facundo M.
Published: November 2023

Motivation

Metabolomics generates complex data necessitating advanced computational methods for generating biological insight. While machine learning (ML) is promising, the challenges of selecting the best algorithms and tuning hyperparameters, particularly for nonexperts, remain. Automated machine learning (AutoML) can streamline this process; however, the issue of interpretability could persist. This research introduces a unified pipeline that combines AutoML with explainable AI (XAI) techniques to optimize metabolomics analysis.

Results

We tested our approach on two datasets: renal cell carcinoma (RCC) urine metabolomics and ovarian cancer (OC) serum metabolomics. AutoML, using auto-sklearn, surpassed standalone ML algorithms such as SVM and random forest in differentiating between RCC and healthy controls, as well as OC patients and those with other gynecological cancers (Non-OC). Autosklearn employed a mix of algorithms and ensemble techniques, yielding a superior performance (AUC of 0.97 for RCC and 0.85 for OC). Shapley Additive Explanations (SHAP) provided a global ranking of feature importance, identifying dibutylamine and ganglioside GM(d34:1) as the top discriminative metabolites for RCC and OC, respectively. Waterfall plots offered local explanations by illustrating the influence of each metabolite on individual predictions. Dependence plots spotlighted metabolite interactions, such as the connection between hippuric acid and one of its derivatives in RCC, and between GM3(d34:1) and GM3(18:1_16:0) in OC, hinting at potential mechanistic relationships. Through decision plots, a detailed error analysis was conducted, contrasting feature importance for correctly versus incorrectly classified samples. In essence, our pipeline emphasizes the importance of harmonizing AutoML and XAI, facilitating both simplified ML application and improved interpretability in metabolomics data science.

Availability

https://github.com/obifarin/automl-xai-metabolomics

Contact:facundo.fernandez@chemistry.gatech.edu
Reproductive character displacement explains strengthening of mechanical barriers in damselflies
Authors: Ballen-Guapacha Andrea Viviana , Ospina-Garces Sandra M. , Sanchez-Guillen Rosa Ana
Published: November 2023

Reinforcing natural selection against maladaptive hybrids can favor the strengthening of premating reproductive isolation driving a pattern of Reproductive Character Displacement (RCD). In a recent study conducted in North-West (NW) (older) Spanish hybrid zone, was detected an asymmetric reinforcement of the mechanical isolation in the reciprocal cross direction betweenI. graellsiimales andI. elegansfemales. Furthermore, in the North-Central and Mediterranean (NCM) (younger) hybrid zone was also detected a similar strengthening of the mechanical isolation, consistent with a pattern of asymmetric reinforcement in this hybrid zone as well. In this study, we did geometric morphometrics analyses, shape, and Centroid Size (CS), on male and female secondary sexual traits to investigate whether reinforcement has generated a pattern of RCD of these traits in both hybrid zones. We detected, in the NW hybrid zone, unidirectional RCD (CS) of the male caudal appendages ofI. graellsii, and bidirectional RCD (shape) of the female prothorax. Consistently with the prediction that the signal of reinforcement may diminish rapidly once reinforcement ceases to operate, a stronger signal of RCD was detected in the NCM than in the NW hybrid region. In this region, was detected unidirectional RCD (CS) of the male caudal appendages which was consistent with the lock-and-key mechanism of genital coevolution, as well as RCD (shape) of the female prothorax ofI. elegans.Interestingly, our study highlights the importance of using geometric morphometrics to deal with the complexity of reproductive structures and controlling for environmental and geographic factors to investigate RCD.
Deep-Learning-Enabled Differentiation between Intraprostatic Gold Fiducial Markers and Calcification in Quantitative Susceptibility Mapping
Authors: Stewart Ashley Wilton , Goodwin Jonathan , Richardson Matthew , Robinson Simon Daniel , O’Brien Kieran , Jin Jin , Barth Markus , Bollmann Steffen
Published: November 2023

Purpose

Interest is growing in MR-only radiotherapy (RT) planning for prostate cancer (PCa) due to the potential reductions in cost and patient exposure to radiation, and a more streamlined work-flow and patient imaging pathway. However, in MRI, the gold fiducial markers (FMs) used for target localization appear as signal voids, complicating differentiation from other void sources such as calcifications and bleeds. This work investigates using Quantitative Susceptibility Mapping (QSM), an MRI phase post-processing technique, to aid in the differentiation task. It also presents deep learning models that capture nuanced information and automate the segmentation task, facilitating a streamlined approach to MR-only RT.

Methods

CT and MRI, including GRE and T1-weighted imaging, were acquired from 26 PCa patients, each with three implanted gold FMs. GRE data were post-processed into QSM,T2*, andR2*maps using QSMxT’s body imaging pipeline. Statistical analyses were conducted to investigate the quantitative differentiation of FMs and calcification in each contrast. 3D U-Nets were developed using fastMONAI to automate the segmentation task using various combinations of MR-derived contrasts, with a model trained on CT used as a baseline. Models were evaluated using precision and recall calculated using a leave-one-out cross-validation scheme.

Results

Significant differences were observed between FM and calcification regions in CT, QSM andT2*, though overlap was observed in QSM andT2*. The baseline CT U-Net achieved an FM-level precision of ≈ 98% and perfect recall. The best-performing QSM-based model achieved precision and recall of 80% and 90%, respectively, while conventional MRI had values below 70% and 80%, respectively. The QSM-based model produced segmentations with good agreement with the ground truth, including a challenging FM that coincided with a bleed.

Conclusion

The model performance highlights the value of using QSM over indirect measures in MRI, such as signal voids in magnitude-based contrasts. The results also indicate that a U-Net can capture more information about the presentation of FMs and other sources than would be possible using susceptibility quantification alone, which may be less reliable due to the diverse presentation of sources across a patient population. In our study, QSM was a reliable discriminator of FMs and other sources in the prostate, facilitating an accurate and streamlined approach to MR-only RT.
Increasing spectral DCM flexibility and speed by leveraging Julia’s ModelingToolkit and automated differentiation
Authors: Hofmann David , Chesebro Anthony G. , Rackauckas Chris , Mujica-Parodi Lilianne R. , Friston Karl J. , Edelman Alan , Strey Helmut H.
Published: November 2023

Using neuroimaging and electrophysiological data to infer neural parameter estimations from theoretical circuits requires solving the inverse problem. Here, we provide a new Julia language package designed to i) compose complex dynamical models in a simple and modular way with ModelingToolkit.jl, ii) implement parameter fitting based on spectral dynamic causal modeling (sDCM) using the Laplace approximation, analogous to MATLAB implementation in SPM12, and iii) leverage Julia’s unique strengths to increase accuracy and speed by employing Automatic Differentiation during the fitting procedure. To illustrate the utility of our flexible modular approach, we provide a method to improve correction for fMRI scanner field strengths (1.5T, 3T, 7T) when fitting models to real data.
Multi-echo Acquisition and Thermal Denoising Advances Precision Functional Imaging
Authors: Moser Julia , Nelson Steven M. , Koirala Sanju , Madison Thomas J. , Labonte Alyssa K. , Morales Carrasco Cristian , Feczko Eric , Moore Lucille A. , Lundquist Jacob T. , Weldon Kimberly B. , Grimsrud Gracie , Hufnagle Kristina , Ahmed Weli , Myers Michael J. , Adeyemo Babatunde , Snyder Abraham Z. , Gordon Evan M. , Dosenbach Nico U. F. , Tervo-Clemmens Brenden , Larsen Bart , Moeller Steen , Yacoub Essa , Vizioli Luca , Uğurbil Kamil , Laumann Timothy O. , Sylvester Chad M. , Fair Damien A.
Published: November 2023

The characterization of individual functional brain organization with Precision Functional Mapping has provided important insights in recent years in adults. However, little is known about the ontogeny of inter-individual differences in brain functional organization during human development. Precise characterization of systems organization during periods of high plasticity is likely to be essential for discoveries promoting lifelong health. Obtaining precision fMRI data during development has unique challenges that highlight the importance of establishing new methods to improve data acquisition, processing, and analysis. Here, we investigate two methods that can facilitate attaining this goal: multi-echo (ME) data acquisition and thermal noise removal with Noise Reduction with Distribution Corrected (NORDIC) principal component analysis. We applied these methods to precision fMRI data from adults, children, and newborn infants. In adults, both ME acquisitions and NORDIC increased temporal signal to noise ratio (tSNR) as well as the split-half reliability of functional connectivity matrices, with the combination helping more than either technique alone. The benefits of NORDIC denoising replicated in both our developmental samples. ME acquisitions revealed longer and more variable T2* relaxation times across the brain in infants relative to older children and adults, leading to major differences in the echo weighting for optimally combining ME data. This result suggests ME acquisitions may be a promising tool for optimizing developmental fMRI, albeit application in infants needs further investigation. The present work showcases methodological advances that improve Precision Functional Mapping in adults and developmental populations and, at the same time, highlights the need for further improvements in infant specific fMRI.
3D-printed, Citrate-based Bioresorbable Vascular Scaffolds for Coronary Artery Angioplasty
Authors: Ding Yonghui , Warlick Liam , Chen Mian , Taddese Eden , Collins Caralyn , Fu Rao , Duan Chongwen , Wang Xinlong , Ware Henry , Sun Cheng , Ameer Guillermo
Published: November 2023

Fully bioresorbable vascular scaffolds (BVSs) were designed to overcome the limitations of metallic drug-eluting stents (DESs). However, current polymer-based BVSs, such as Abbott’s Absorb, the only US FDA-approved BVS, struggle with increased strut thickness (150 μm for Absorb) and exacerbated tissue inflammation, leading to inferior clinical performance compared to metallic DESs. Here we develop a drug-eluting BVS (DE-BVS) through the innovative use of photopolymerizable, citrate-based materials and high-precision additive manufacturing process. Bare BVS with a clinically relevant strut thickness of 62 μm can be produced in a high-throughput manner, i.e. one BVS per minute. By modulating the coating polymer and structure, we achieve a controlled release of anti-restenosis drug of everolimus from DE-BVSs. We show the mechanical competence of DE-BVS and the successful deployment in swine coronary arteries using a custom-built balloon catheter delivery system. We further demonstrate that BVS and DE-BVS remain safe and effective to keep the vessel patency, induce limited inflammation, and facilitate the recovery of smooth muscle and endothelial tissues over 28 days implantation in swine coronary arteries. All these evaluated pre-clinical performances are largely comparable to the commercial XIENCE™ DES (Abbott Vascular).