bluuebunny/crossref_metadata_2025 huggingface dataset:
14. Interim Applications—Common Types
Authors: Cunningham-Hill Susan , Elder Karen
Published: August 2018

This chapter considers the interim applications that a legal representative may most often come across in practice. It looks at the procedure for the specific interim application. Then it discusses the form of the evidence needed to make or oppose it. The interim applications considered here include an application to set aside default judgment; summary judgment; interim payment; an application for specific disclosure; an application for security for costs; and an application for an injunction.
1. Introduction
Authors: Wright Kathryn , Firth Clare , Crompton Lucy , Fox Helen , Seabridge Frances , Wigglesworth Susan , Smart Elizabeth
Published: August 2018

This chapter begins with a description of how the legal services market has undergone an era of change with the Solicitors Regulation Authority’s (SRA) introduction of a new code of conduct on 6 October 2011, referred to as the outcomes-focused regulation code (OFR Code) and briefly looks at the proposed changes expected to come into force in August 2018. It considers what being a member of the profession and a good solicitor means, the Handbook, and the OFR Code in general. It then looks at the practical application of the OFR Code and the principles, outcomes, and indicative behaviours in the OFR Code which are most relevant to readers at this stage of their legal career as a student and trainee.
3. Money laundering
Authors: Wright Kathryn , Firth Clare , Crompton Lucy , Fox Helen , Seabridge Frances , Wigglesworth Susan , Smart Elizabeth
Published: August 2018

A concerted effort is being made within the EU to crack down on money laundering. This is reflected by both the European Money Laundering Directives, which have led to changes in the UK legislation, in particular the Money Laundering, Terrorist Financing and Transfer of Funds (Information on the Payer) Regulations (MLR). Solicitors are usually unwittingly involved in a money laundering scheme. They can avoid this by being conversant with the requirements of the money laundering legislation and fully complying with it. This chapter explains the process of money laundering; the primary legislation and offences; and the relevance of the legislation to solicitors.
9. Value added tax
Authors: Wright Kathryn , Firth Clare , Crompton Lucy , Fox Helen , Seabridge Frances , Wigglesworth Susan , Smart Elizabeth
Published: August 2018

Value added tax (VAT) is a tax charged on supplies of goods and services made by businesses that have (or should have) registered for VAT. This chapter discusses the circumstances in which VAT is charged; the rates of VAT; when VAT can be reclaimed; accounting for VAT; and doing VAT calculations.
10. Taxation of sole proprietors and partnerships
Authors: Wright Kathryn , Firth Clare , Crompton Lucy , Fox Helen , Seabridge Frances , Wigglesworth Susan , Smart Elizabeth
Published: August 2018

Sole traders and partners are liable to pay income tax on their income in accordance with the Income Tax (Trading and Other Income) Act 2005 (ITTOIA). This chapter discusses income tax liability of sole traders and partners; calculating the trading profits; capital gains and capital losses; trading losses; basis of assessment; capital allowances; and changes in a partnership.
12. Introduction to wills and administration of estates
Authors: Wright Kathryn , Firth Clare , Crompton Lucy , Fox Helen , Seabridge Frances , Wigglesworth Susan , Smart Elizabeth
Published: August 2018

This chapter provides an overview of Chapters 13 to 15. When a person dies, their relatives or friends usually deal with the most pressing matters—registering the death and arranging the funeral—before consulting a solicitor. In simple cases, or where the deceased has left little property, it may well be that a solicitor is not consulted at all. Commonly, however, the advice of a solicitor will be sought as to who is entitled to the deceased ‘sproperty, as to the liability of the estate to tax, and generally as to’ what has to be done’ in order to pass the deceased’s property to those now entitled to it.
14. Application for a grant of representation
Authors: Wright Kathryn , Firth Clare , Crompton Lucy , Fox Helen , Seabridge Frances , Wigglesworth Susan , Smart Elizabeth
Published: August 2018

This chapter discusses the law and procedure relating to the issue of a grant of representation to the personal representatives of someone who has died. It considers the nature, effect, and the principal types of grant; the position of the personal representatives; the responsibilities of solicitors instructed to act in the administration of an estate; obtaining the grant; the court’s requirements; oaths for executors, for administrators with will annexed and for administrators; HM Revenue & Customs (HMRC) requirements; excepted estates; Form IHT 400 and its Schedules; and the calculation of inheritance tax (IHT).
16. Human rights
Authors: Wright Kathryn , Firth Clare , Crompton Lucy , Fox Helen , Seabridge Frances , Wigglesworth Susan , Smart Elizabeth
Published: August 2018

This chapter provides an introduction to the European Convention on Human Rights and the Human Rights Act 1998, taking into account the origins of the Convention and the Human Rights Act 1998 and their incorporation into UK legislation; the general principles of European jurisprudence; the Articles and the Protocols themselves; and areas where potential breaches may occur.
Criminal Litigation 2018-2019
Authors: Hannibal Martin , Mountford Lisa
Published: August 2018

Criminal Litigation offers a guide to the areas of criminal litigation covered in the Legal Practice Course. Making use of realistic case studies backed up by online documentation, the text combines theory with practical considerations and encourages a focus on putting knowledge into a practical context. The volume covers all procedural and evidential issues that arise in criminal cases. The more complex areas of criminal litigation are examined using diagrams, flowcharts, and examples, while potential changes in the law are highlighted. This edition has been fully revised to reflect the most recent law and practice in all aspects of criminal litigation.
1. Introduction
Authors: Hannibal Martin , Mountford Lisa
Published: August 2018

This introductory chapter briefly sets out the volume’s purpose, which is to explain the legal, procedural and evidential rules governing how cases are dealt with by the criminal justice system. It then explains the philosophy of the text and its unique features; introduces the key personnel and organisations within the criminal justice system; introduces the Criminal Procedure Rules; explains the classification of offences according to their trial venue; summarizes the jurisdiction of the criminal courts; stresses the importance of the pervasive issue of human rights; and highlights professional conduct considerations in the context of criminal litigation.
2. An Introduction to the Law of Criminal Evidence and Advocacy
Authors: Hannibal Martin , Mountford Lisa
Published: August 2018

Both prosecutors and defence lawyers must have a good understanding of the rules of criminal evidence and be able to apply the rules in a highly practical way to the issues in a case. This chapter provides a brief introduction to the main evidential rules which are considered further in later chapters. In particular, it addresses the following: the purpose of rules of evidence; the core concepts of relevance, admissibility, and weight; and the different types of evidence.
3. The Powers to Stop, Search and Arrest
Authors: Hannibal Martin , Mountford Lisa
Published: August 2018

The police have extensive statutory powers to stop and search and to arrest a person in connection with the investigation of a criminal offence under various statutes, including the Police and Criminal Evidence Act 1984 (PACE 1984), the Terrorism Act 2000, the Misuse of Drugs Act 1971, and the Serious Organised Crime and Police Act 2005. This chapter examines the powers of stop and search before arrest; powers of arrest under PACE 1984; powers to search a person and his property after arrest; the power to grant street bail; and the right to liberty under Article 5 European Convention on Human Rights (ECHR 1950).
10. The Law and Practice Relating to Court Bail
Authors: Hannibal Martin , Mountford Lisa
Published: August 2018

This chapter explains the practice and procedure of court bail. It examines the grounds upon which bail might be refused; the factors a court can have regard to when deciding whether bail should be granted; the procedure at a contested bail application; appeals against bail decisions; and bail and Article 5 of the European Convention on Human Rights 1950 (ECHR 1950).
12. Prosecuting Summary Offences
Authors: Hannibal Martin , Mountford Lisa
Published: August 2018

A summary trial will be held where a defendant pleads not guilty to a summary-only offence or pleads not guilty to an either-way offence where the magistrates’ court has accepted jurisdiction to try the offence at the allocation hearing and the defendant has consented to summary trial. This chapter deals with the steps in preparing for a summary trial. It considers pleading guilty by post; the circumstances in which a defendant can be summarily tried in her absence; the rules governing the drafting of a written charge/information; the pre-trial disclosure of evidence in a summary case; case management; the steps when preparing for summary trial; and the procedure at a summary trial on a not guilty plea.
15. The Burden of Proof
Authors: Hannibal Martin , Mountford Lisa
Published: August 2018

This chapter explains the rules governing the legal and evidential burdens of proof that decide which party has the responsibility of proving a fact in issue to the court. It then discusses the degree of persuasiveness the evidence must attain to satisfy the appropriate standard of proof including the test for a successful submission of no case to answer and considers the human rights issues in those exceptional situations where the accused has the legal burden of proof. For both the prosecution and the defence, the rules that allocate the burden of proof and the degree of proof are fundamental to the outcome of a case at trial.
16. Witness Evidence
Authors: Hannibal Martin , Mountford Lisa
Published: August 2018

This chapter explains the law, procedure, and the practical issues associated with witness evidence. It considers the circumstances in which a witness can refresh his memory from an earlier written statement; the test to decide a witness’ competence to give evidence; the compellability of a witness; the assistance available to ‘vulnerable’ or ‘intimidated’ witnesses to give evidence under a special measures direction; a witness taking the oath or affirming; the rules associated with examination-in-chief; and the rules associated with cross-examination including admission of non-defendant bad character and re-examination.
17. Corroboration, the ‘Turnbull Guidelines’ and Opinion Evidence
Authors: Hannibal Martin , Mountford Lisa
Published: August 2018

This chapter considers the nature of corroborative evidence; the situations where corroborative evidence is required as a matter of law; the situations where a corroboration warning might be given as a matter of judicial discretion; and the application of the ‘Turnbull guidelines’ in cases where eye-witness identification is disputed. It also explains the rules relating to opinion evidence and to expert opinion evidence in particular.
18. Hearsay Evidence
Authors: Hannibal Martin , Mountford Lisa
Published: August 2018

Hearsay evidence in criminal cases most often arises in two situations: if a witness testifies about facts of which he has no personal knowledge because the facts were communicated to the witness by another person who is not in court; and where a witness’ written statement is put before the court because the witness is unable to attend court to give oral evidence. This chapter discusses the general rule of hearsay evidence; identifying hearsay evidence; statutory exceptions to the hearsay rule; hearsay evidence under the Criminal Justice Act (CJA) 2003; hearsay admissible under the preserved common law rules; procedure for admitting hearsay evidence; and hearsay evidence and the European Convention on Human Rights (ECHR) 1950.
22. Specific Types of Sentence and the Plea in Mitigation
Authors: Hannibal Martin , Mountford Lisa
Published: August 2018

This chapter explains specific types of sentence and provide guidance on how a defence solicitor might prepare and deliver a plea in mitigation. It discusses when discretionary custodial sentence can be imposed; custody between the ages 18 and 21; length of custodial sentence; suspended sentence of imprisonment; concluding remarks on discretionary custodial sentences; fixed length sentences; sentencing dangerous offenders; community sentences; community sentences under the Criminal Justice Act (CJA) 2003; guilty plea credit and community orders; enforcement of community orders under the CJA 2003 in the event of breach; deferring sentence; fines; compensation orders; conditional discharge; absolute discharge; bind over; ancillary orders; structuring a plea in mitigation; advocacy and the plea in mitigation; and professional conduct.
23. Appeals
Authors: Hannibal Martin , Mountford Lisa
Published: August 2018

This chapter explains the practice and procedure involved in appealing against a decision of the magistrates’ court or the Crown Court. The discussions include the reopening of a case; appeal to the Crown Court; appeal by way of case stated; judicial review; appeal against sentence from the Crown Court; appeal to the Supreme Court; the Criminal Cases Review Commission; and whether the prosecution enjoys a right to appeal.
24. Youth Justice—Introduction
Authors: Hannibal Martin , Mountford Lisa
Published: August 2018

This chapter discusses the following issues: the terminology of youth justice; the youth justice organisations; the meaning of parental responsibility; the principal aims of the youth justice system; the early diversion procedures to prevent further offending; the juvenile at the police station; the alternatives to prosecution; and the decision to charge.
25. Prosecuting Young Offenders
Authors: Hannibal Martin , Mountford Lisa
Published: August 2018

Where a prosecution is commenced against a child aged 10 to 13 years or against a young person aged 14 to 17 years, the general rule is that he will be tried and sentenced in the youth court. The youth court adopts more informal and less adversarial procedures to deal with the needs and vulnerabilities of young defendants. However, there are exceptional situations (grave offences and dangerous offenders) where they will be tried in the Crown Court or when jointly charged with an adult sometimes in the adult magistrates’ court. This chapter discusses the rules for deciding where a young person is to be tried; the rules for trying a young person in the Crown Court; the rules for trying a young person in the adult magistrates’ court; the young defendant’s right to court bail; and the procedure in the youth court.
Property Law 2018-2019
Authors: Abbey Robert , Richards Mark
Published: August 2018

Property Law is a companion that guides through the intricacies of the conveyancing process. Drawing on practical experience of legal practice, with a residential and a commercial conveyancing focus, the volume offers explanations of often complex processes. The title contains practical guidance on how to approach each stage of a conveyancing transaction in practice. This edition has been fully updated with recent developments in the law, including discussion of ‘Help to buy’ shared ownership schemes, coverage of the Land Transaction Tax, and updated tax rates and chargeable amounts for enveloped dwellings.
3. An outline of a conveyancing transaction
Authors: Abbey Robert , Richards Mark
Published: August 2018

This chapter explains the process of conveyancing as a whole through an outline of a typical conveyancing transaction. It describes a transaction in outline; energy performance certificates; the Land Registry Portal; and the Law Society’s Conveyancing Quality Scheme; and the future of conveyancing.
5. The draft contract
Authors: Abbey Robert , Richards Mark
Published: August 2018

This chapter considers issues relating to the drafting the contract for the seller. These include occupiers and tenancies; seller’s duty of disclosure; formalities; contents of the contract; deposit; completion; title guarantee; indemnity covenants; sales of part; option agreements; and conditional contracts.
7. Town and country planning
Authors: Abbey Robert , Richards Mark
Published: August 2018

Town and country planning legislation aims to control the development of land and buildings. Section 57(1) of the Town and Country Planning Act 1990 stipulates that ‘planning permission is required for the carrying out of any development of land’. This chapter first discusses the two main elements of town and country planning: (1) obtaining planning permission for new developments; and (2) the change of use of existing properties. It then explains breaches of planning control and enforcement; building regulations; and typical planning enquiries. A town and country planning decision tree is also presented.
8. Deducing and investigating title
Authors: Abbey Robert , Richards Mark
Published: August 2018

Deducing title is the process by which the seller demonstrates to the buyer that the seller owns the property and can convey it. In a modern conveyancing transaction the parties will deduce and investigate title before contracts are exchanged. This chapter explains the process of deducing title; investigating title; and some special title situations.
9. Mortgages
Authors: Abbey Robert , Richards Mark
Published: August 2018

This chapter deals with important issues arising in relation to a mortgage taken out by a client to assist in financing the purchase of a property. It looks at the most popular types of mortgage, the impact of the Financial Services and Markets Act 2000, and other matters, including important professional conduct issues. It also considers mortgages of leasehold property and mortgages of commercial property.
10. Exchange of contracts
Authors: Abbey Robert , Richards Mark
Published: August 2018

Exchange of contracts is the most critical stage in the conveyancing process as it represents the point at which the parties become legally bound to proceed. This chapter examines pre-exchange matters; the process by which contracts are actually exchanged; and matters that should be attended to immediately after exchange has taken place. It also considers the risk and responsibility for buildings insurance, and the consequences of the buyer occupying the property before completion.
11. The purchase deed
Authors: Abbey Robert , Richards Mark
Published: August 2018

The purchase deed transfers the legal estate in the property from the seller to the buyer. Whereas the contract sets out what the parties have agreed, the purchase deed actually puts those agreed terms into effect. This chapter discusses drafting and approving the deed; forms of purchase deed; the plan in a purchase; execution of purchase deed; and advising the client.
13. Completion
Authors: Abbey Robert , Richards Mark
Published: August 2018

Completion is the moment in time when the buyer pays over the balance of the purchase price to the seller in exchange for the deeds (if any), executed purchase deed, keys, and, if the contract so provides, vacant possession. This chapter discusses the how, where, and when for completion; deeds and unregistered land; postal completions; dealing with the discharge of the seller’s mortgage; the Land Registry’s electronic discharge (e-DS1) scheme; and the outcome of completion.
14. Post-completion procedures
Authors: Abbey Robert , Richards Mark
Published: August 2018

Conveyancing practitioners, whether they are acting for the seller or the buyer, still have much to do once completion has taken place. However, the buyer’s solicitor will have more work to do, as in most transactions acting on behalf of the buyer means after completion dealing with the possible payment of stamp duty land tax and then registration of the title and/or transfer. So far as the seller is concerned, if there is a mortgage, paying off any lender is required, as well as accounting to the client for the net proceeds of sale. This chapter considers all these post-completion procedures.
16. Leaseholds
Authors: Abbey Robert , Richards Mark
Published: August 2018

This chapter first examines some of the more commonly encountered elements or clauses in most leases. Essentially, it sets out what one might expect to see in a lease of either residential or commercial property. The discussions then turn to the Council of Mortgage Lenders’ Handbook for Solicitors and Licensed Conveyancers England and Wales; defective leases; liability on covenants in leases: enforcement; granting new leases; existing leases; and enfranchisement.
17. New properties
Authors: Abbey Robert , Richards Mark
Published: August 2018

This chapter discusses issues relating to the sale of new properties. It covers acting for a developer or buyer, road and sewer agreements, structural defects insurance, and synchronizing completion of a related sale when acting for the buyer of new property.
18. Commercial conveyancing
Authors: Abbey Robert , Richards Mark
Published: August 2018

Commercial conveyancing services support the market in and for commercial property. This chapter focuses on several different topics that relate to commercial property and involve specialist knowledge of commercial conveyancing. These include commercial leases; buying and selling commercial freeholds; and commercial property and some elements of revenue law.
19. Landlord and Tenant Act 1954, Part II
Authors: Abbey Robert , Richards Mark
Published: August 2018

This chapter considers the provisions of the Landlord and Tenant Act 1954, Part II, which provides security of tenure for the majority of business tenants by giving them a statutory right to renew their lease or tenancy. It explains the need for ‘tenancy’; need for ‘occupation’; need for ‘the purposes of a business’; key methods of termination under the Act; section 40 notices; interim rent applications; landlord’s statutory grounds of opposition; tenant’s right to compensation; and the terms of the new tenancy.
Business Law 2018-2019
Authors: Slorach J. Scott , Ellis Jason
Published: August 2018

Business Law provides practical, up-to-date coverage of company, partnership, taxation, and insolvency law, plus all relevant aspects of EU law. The title provides all of the relevant material needed to understand the latest legal developments affecting business law transactions. Coverage of the Companies Act 2006 is fully integrated and given prominence, mirroring the emphasis that business law courses place on this central piece of legislation. Additional emphasis has been placed on taxation and business accounts. Examples are used throughout the volume which helps readers to contextualise their learning effectively. Updated statutory references allow for the cross-referencing to appropriate primary sources, and the interpretation of such sources. The volume looks at partnerships, companies, taxation, insolvency, and other topics such as choice of business medium, limited liability partnerships, sale of a business, and shareholder agreements.
4. Partnership disputes
Authors: Slorach J. Scott , Ellis Jason
Published: August 2018

A decision of the majority of the partners on an ‘ordinary matter’ is binding on the minority. The wishes of the majority prevail over those of the minority who object. However, partnership law provides some machinery for protecting the partner who is aggrieved by what the other partners have done. This chapter considers the remedies available to a partner. These include dissolution of the partnership, appointment of a receiver, arbitration, and expulsion of the partner.
5. Termination of and retirement from a partnership
Authors: Slorach J. Scott , Ellis Jason
Published: August 2018

An individual may cease to be a partner on the happening of one of the following events: the dissolution of the partnership; his retirement; or expulsion from the partnership. If the partnership is dissolved, the partnership will come to an end and its assets and business dealt with accordingly. The situation is different on the retirement or expulsion of a partner. Here, the former partners can carry on the business, albeit through the medium of a newly constituted partnership. This chapter considers the legal consequences of the occurrence of these events.
7. Limited companies—an introduction
Authors: Slorach J. Scott , Ellis Jason
Published: August 2018

This chapter considers the legal position of limited companies. Many businesses are run by limited companies. These range from international conglomerates to companies owned by one person running a small business. The discussions cover the concept of the company; sources of company law; registration; types of registered company; the company as a separate legal personality; and lifting the veil of incorporation.
13. Company meetings and resolutions
Authors: Slorach J. Scott , Ellis Jason
Published: August 2018

This chapter describes the meetings of shareholders and the resolutions passed during such meetings. It covers the types of general meeting; resolutions; calling a general meeting; notice of meetings; proceedings at meetings; minutes and returns; and written resolutions.
17. Income tax: sole traders and partnerships
Authors: Slorach J. Scott , Ellis Jason
Published: August 2018

This chapter considers the taxation of income earned from a trade or profession. It covers the basic system of taxation; taxable profits for business; the basis of assessment; losses under the income tax system; and income tax liability of partnerships.
18. The corporation tax system
Authors: Slorach J. Scott , Ellis Jason
Published: August 2018

This chapter deals with the corporation tax system, which determines the tax liability of companies. It discusses the calculation of profits; tax assessment; relief for trade losses; and taxation of close companies.
22. Capital gains tax and inheritance tax on business assets
Authors: Slorach J. Scott , Ellis Jason
Published: August 2018

This chapter examines the capital gains tax (CGT) and inheritance tax regimes which apply to individuals in relation to businesses and business assets. Under the provisions of the Taxation of Chargeable Gains Act (TCGA) 1992, CGT is payable when a taxable person makes a disposal of chargeable assets giving rise to a chargeable gain unless an exemption or relief applies. The chapter first discusses the various rules which need to be considered to establish a taxpayer’s CGT liability on any given disposal. It then covers CGT in the business context; disposals of partnership property; disposals of shares; disposals of business assets owned by those involved in the business; the purchase by a company of its own shares; and inheritance tax.
24. Personal bankruptcy
Authors: Slorach J. Scott , Ellis Jason
Published: August 2018

The partner or sole trader may be made bankrupt if his liabilities exceed his assets or if he has insufficient liquid assets to pay his current liabilities even if the value of his total assets exceeds the value of his total liabilities. The law of bankruptcy is mostly contained in the Enterprise Act (EA) 2002. This chapter discusses the bankruptcy procedure; the trustee in bankruptcy; effect of the bankruptcy order on the bankrupt personally; assets in the bankrupt’s estate; distribution of the bankrupt’s assets; duration of the bankruptcy and discharge of the bankrupt; fast track voluntary arrangement scheme; and individual voluntary arrangement.
28. Limited liability partnerships
Authors: Slorach J. Scott , Ellis Jason
Published: August 2018

This chapter first discusses the key elements of limited liability partnerships (LLPs). It then considers the factors influencing choice of LLP. There are two instances where the question of choosing an LLP arises: as part of a business start-up or existing partnerships considering conversion. When considering LLPs, it should always be remembered that their resemblance to traditional partnerships is an exception rather than a rule, and that it is better to think of them as corporate structures.
30. Shareholders’ agreements
Authors: Slorach J. Scott , Ellis Jason
Published: August 2018

This chapter considers shareholders’ agreements. It discusses the advantages of a shareholders’ agreement; drafting a shareholders’ agreement; legal limits on the use of shareholders’ agreements; and enforcing the agreement.
Uniqueness of multipliers in optimal control: the missing piece
Authors: Becerril Jorge A , Cortez Karla L , Rosenblueth Javier F
Published: August 2018

In a well-known paper by Kyparisis it is proved that, in nonlinear programming, the uniqueness of Lagrange multipliers is equivalent to a strict version of the Mangasarian–Fromovitz constraint qualification which, in turn, implies the satisfaction of second-order necessary optimality conditions. This is no longer the case in optimal control where, as shown in a recent paper, the corresponding strict constraint qualification is only sufficient for the uniqueness of multipliers. In this paper we exhibit the missing piece: a new, simple condition, implied by the strict constraint qualification, which is necessary and sufficient for the uniqueness of multipliers in optimal control.
Mechanistic machine learning: how data assimilation leverages physiologic knowledge using Bayesian inference to forecast the future, infer the present, and phenotype
Authors: Albers David J , Levine Matthew E , Stuart Andrew , Mamykina Lena , Gluckman Bruce , Hripcsak George
Published: August 2018

We introduce data assimilation as a computational method that uses machine learning to combine data with human knowledge in the form of mechanistic models in order to forecast future states, to impute missing data from the past by smoothing, and to infer measurable and unmeasurable quantities that represent clinically and scientifically important phenotypes. We demonstrate the advantages it affords in the context of type 2 diabetes by showing how data assimilation can be used to forecast future glucose values, to impute previously missing glucose values, and to infer type 2 diabetes phenotypes. At the heart of data assimilation is the mechanistic model, here an endocrine model. Such models can vary in complexity, contain testable hypotheses about important mechanics that govern the system (eg, nutrition’s effect on glucose), and, as such, constrain the model space, allowing for accurate estimation using very little data.
The impact of p53 function on the metabolic activation of the carcinogenic air pollutant 3-nitrobenzanthrone and its metabolites 3-aminobenzanthrone and N-hydroxy-3-aminobenzanthrone in human cells
Authors: Wohak Laura E , Baranski Ann-Christin , Krais Annette M , Schmeiser Heinz H , Phillips David H , Arlt Volker M
Published: August 2018

The tumour suppressor p53, encoded by TP53, is a key player in a wide network of signalling pathways. We investigated its role in the bioactivation of the environmental carcinogen 3-nitrobenzanthrone (3-NBA)found in diesel exhaust and its metabolites 3-aminobenzanthrone (3-ABA) and N-hydroxy-3-aminobenzanthrone (N-OH-3-ABA) in a panel of isogenic human colorectal HCT116 cells differing only with respect to their TP53 status [i.e. TP53(+/+), TP53(+/−), TP53(−/−), TP53(R248W/+) or TP53(R248W/−)]. As a measure of metabolic competence, DNA adduct formation was determined using 32P-postlabelling. Wild-type (WT) p53 did not affect the bioactivation of 3-NBA; no difference in DNA adduct formation was observed in TP53(+/+), TP53(+/−) and TP53(−/−) cells. Bioactivation of both metabolites 3-ABA and N-OH-3-ABA on the other hand was WT-TP53 dependent. Lower 3-ABA- and N-OH-3-ABA-DNA adduct levels were found in TP53(+/−) and TP53(−/−) cells compared to TP53(+/+) cells, and p53’s impact was attributed to differences in cytochrome P450 (CYP) 1A1 expression for 3-ABA whereas for N-OH-3-ABA, an impact of this tumour suppressor on sulphotransferase (SULT) 1A1/3 expression was detected. Mutant R248W-p53 protein function was similar to or exceeded the ability of WT-p53 in activating 3-NBA and its metabolites, measured as DNA adducts. However, identification of the xenobiotic-metabolising enzyme(s) (XMEs), through which mutant-p53 regulates these responses, proved difficult to decipher. For example, although both mutant cell lines exhibited higher CYP1A1 induction after 3-NBA treatment compared to TP53(+/+) cells, 3-NBA-derived DNA adduct levels were only higher in TP53(R248W/−) cells but not in TP53(R248W/+) cells. Our results show that p53’s influence on carcinogen activation depends on the agent studied and thereby on the XMEs that mediate the bioactivation of that particular compound. The phenomenon of p53 regulating CYP1A1 expression in human cells is consistent with other recent findings; however, this is the first study highlighting the impact of p53 on sulphotransferase-mediated (i.e. SULT1A1) carcinogen metabolism in human cells.
Computer-Assisted Navigation for Real Time Planning of Pedicle Subtraction Osteotomy in Cervico-Thoracic Deformity Correction
Authors: Shin John H , Yanamadala Vijay , Cha Thomas D
Published: August 2018

BACKGROUND

Pedicle subtraction osteotomy (PSO) at the cervicothoracic junction (CTJ) is a powerful technique to correct severe kyphosis and sagittal malalignment. Reported techniques have demonstrated the safety and efficacy of the PSO, however limited visualization of surrounding tissues increases the potential for complications with this advanced technique.

OBJECTIVE

To describe the application of computed tomographic (CT)-based image guidance to the planning and execution of PSO at the CTJ.

METHODS

Intraoperative registration and verification of anatomic landmarks are performed with the intraoperative O-arm CT across the CTJ. With the navigation probe, the targeted pedicle is identified and the intended trajectories are rehearsed and saved on the navigational computer. As the PSO is performed, the navigation probe is used to check the depth, accuracy, and trajectory through each side. The extent of soft tissue dissection around the lateral aspect of the vertebral body through which the PSO is performed is also verified in real time. This technique was performed in 12 consecutive patients from 2013-2016. An IRB approved, retrospective analysis was performed from a prospective spinal deformity outcomes database. Patient consent is not required for publication as this report does not describe a specific case but rather a surgical technique used in practice.

RESULTS

There were no vascular, esophageal, or soft tissue injuries in 12 consecutive patients. There were no cases of paralysis. Two patients developed hand weakness days after surgery. Intraoperative O-arm CT performed after closure of the osteotomy confirmed the accuracy of the osteotomy planning with no breach of the anterior cortical wall of the osteotomized vertebral body.

CONCLUSION

CT-guided navigation allows for 3-dimensional visualization of the CTJ and minimizes complications associated with inadequate surgical visualization of vascular and deep organ structures.
The Effects of a Life Stress Emotional Awareness and Expression Interview for Women with Chronic Urogenital Pain: A Randomized Controlled Trial
Authors: Carty Jennifer N , Ziadni Maisa S , Holmes Hannah J , Tomakowsky Janice , Peters Kenneth , Schubiner Howard , Lumley Mark A
Published: August 2018

Objective

Women with chronic urogenital pain (CUP) conditions have elevated rates of lifetime trauma, relational stress, and emotional conflicts, but directly assessing and treating psychological stress is rarely done in women’s health care settings. We developed and tested the effects on patients’ somatic and psychological symptoms of a life stress interview that encourages disclosure about stressors and uses experiential techniques to increase awareness of links between stress, emotions, and symptoms.

Methods

In this randomized trial, women with CUP recruited at a multidisciplinary women’s urology center received either a single 90-minute life stress interview (N = 37) or no interview (treatment-as-usual control; N = 25). Self-report measures of pain severity (primary outcome), pain interference, pelvic floor symptoms, and psychological symptoms (anxiety and depression) were completed at baseline and six-week follow-up.

Results

Differences between the life stress interview and control conditions at follow-up were tested with analyses of covariance, controlling for baseline level of the outcome and baseline depression. Compared with the control condition, the interview resulted in significantly lower pain severity and pelvic floor symptoms, but the interview had no effect on pain interference or psychological symptoms.

Conclusions

An intensive life stress emotional awareness expression interview improved physical but not psychological symptoms among women with CUP seen in a tertiary care clinic. This study suggests that targeting stress and avoided emotions and linking them to symptoms may be beneficial for this complex group of patients.
Sterilization procedures for CO2 incubators
Authors: Knegendorf Leonard , Brill Holger , Steinmann Joerg , Pahl Steffen , Steinmann Eike , Brill Florian H.H.
Published: August 2018

Cell culture methods are utilized ubiquitously in science and pharmaceutical and biotech industries. Sterility is one crucial factor for maintenance of cells and creation of valid data from experiments. As cells are usually cultured in CO2 incubators, those are one bottleneck in terms of sterility in a cell culture lab. This review gives an overview on the different sterilization procedures for CO2 incubators on the market with emphasize to considerations from a practical point of view. It compares sterilization by dry heat, steam, gas and ultraviolet radiation in terms of validity and practicability in accordance with international standards and regulations and transfers literature consensus about these methods to CO2 incubators. As conclusion, the authors give recommendations for a sterile working environment in line with good cell culture practice.
Added Value of Whole-Exome and Transcriptome Sequencing for Clinical Molecular Screenings of Advanced Cancer Patients With Solid Tumors
Authors: Koeppel Florence , Bobard Alexandre , Lefebvre Céline , Pedrero Marion , Deloger Marc , Boursin Yannick , Richon Catherine , Chen-Min-Tao Romy , Robert Guillaume , Meurice Guillaume , Rouleau Etienne , Michiels Stefan , Massard Christophe , Scoazec Jean-Yves , Solary Eric , Soria Jean-Charles , André Fabrice , Lacroix Ludovic
Published: August 2018

Comprehensive genomic profiling using high-throughput sequencing brings a wealth of information, and its place in the clinical setting has been increasingly prominent. This review emphasizes the utility of whole-exome sequencing (WES) and transcriptome sequencing (RNAseq) in patient care and clinical research, based on published reports as well as our experience with the MOSCATO-01 (MOlecular Screening for CAncer Treatment Optimization) molecular triage trial at Gustave Roussy Cancer Center. In this trial, all contributive samples of patients with advanced solid tumors were analyzed prospectively with targeted gene sequencing (TGS) and comparative genomic hybridization. In addition, 92 consecutive metastatic patients with contributive biopsies were sequenced for WES and RNAseq and compared with TGS and comparative genomic hybridization. Whole-exome sequencing allowed the reporting of additional variants in relevant genes in 38% of patients. Mutation detection sensitivity of WES was 95% compared with TGS. Additional information derived from WES and RNAseq could influence clinical decision, including fusion transcripts, expression levels, allele-specific expression, alternate transcripts, RNA-based pathogen diagnostic, tumor mutation load, mutational signatures, expression signatures, HLA genotyping, and neoepitope prediction. The current challenge is to be able to process the large-scale data from these comprehensive genome-wide technologies in an efficient way.
A Reassessment of the Taxonomic Position of Mesosaurs Based on Two Data Matrices
Authors: Laurin Michel , Piñeiro Graciela
Published: August 2018

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The Early Permian mesosaurs are the oldest known primarily aquatic amniotes. Despite the interest that they have generated over time, their affinities remain controversial. Recently, two hypotheses have been supported, in which mesosaurs are either the sister-group of all other sauropsids, or the sister-group of other parareptiles. We recently upheld the former hypothesis, but in the latest study on mesosaur affinities, MacDougall et al. published a study highly critical of our work, while upholding the hypothesis that mesosaurs are basal parareptiles. We expect that the debate about mesosaur affinities will continue in the foreseeable future, but we wish to respond to the two central comments published by MacDougall et al. in 2018, who argue that variability in the temporal fenestration of early sauropsids, combined with the omission of several recently-described parareptile taxa, explain the differences in topologies between their study and ours. Reanalyzing our data matrix and theirs without characters linked with temporal fenestration, and removing from their matrix the parareptile taxa that they added (and that we omitted) does not alter the resulting topologies. Thus, their main conclusions are false; the differences in taxonomic position of mesosaurs must result from character choice and scoring differences.
Bradycardic mice undergo effective heart rate improvement after specific homing to the sino-atrial node and differentiation of adult muscle derived stem cells
Authors: Mesirca Pietro , Mamaeva Daria , Bidaud Isabelle , Baudot Matthias , Davaze Romain , DiFrancesco Mattia L. , Mitutsova Violeta , Torrente Angelo G. , Arsic Nikola , Nargeot Joël , Striessnig Jörg , Lee Amy , Lamb Ned J. , Mangoni Matteo E. , Fernandez Anne
Published: August 2018

Current treatments for heart automaticity disorders still lack a safe and efficient source of stem cells to restore normal biological pacemaking. Since adult Muscle-Derived Stem Cells (MDSC) show multi-lineage differentiation in vitro including into spontaneously beating cardiomyocytes, we questioned whether they could effectively differentiate into cardiac pacemakers, a specific population of cardiomyocytes producing electrical impulses in the sino-atrial node (SAN) of adult heart. We show here that beating cardiomyocytes, differentiated from MDSC in vitro, exhibit typical characteristics of cardiac pacemakers: expression of markers of the SAN lineage Hcn4, Tbx3 and Islet1, as well as spontaneous calcium transients and hyperpolarization-activated “funny” current and L-type Cav1.3 channels. Pacemaker-like myocytes differentiated in vitro from Cav1.3-deficient mouse stem cells produced slower rate of spontaneous Ca2+ transients, consistent with the reduced activity of native pacemakers in mutant mice. In vivo, undifferentiated wild type MDSC migrated and homed with increased engraftment to the SAN of bradycardic mutant Cav1.3-/- within 2-3 days after systemic I.P. injection. The increased homing of MDSCs corresponded to increased levels of the chemokine SDF1 and its receptor CXCR4 in mutant SAN tissue and was ensued by differentiation of MDSCs into Cav1.3-expressing pacemaker-like myocytes within 10 days and a significant improvement of the heart rate maintained for up to 40 days. Optical mapping and immunofluorescence analyses performed after 40 days on SAN tissue from transplanted wild type and mutant mice showed MDSCs integrated as pacemaking cells both electrically and functionally within recipient mouse SAN. These findings identify MDSCs as directly transplantable stem cells that efficiently home, differentiate and improve heart rhythm in mouse models of congenital bradycardia.
Morphogenesis of neurons and glia within an epithelium
Authors: Low Isabel I. C. , Williams Claire R. , Chong Megan K. , McLachlan Ian G. , Wierbowski Bradley M. , Kolotuev Irina , Heiman Maxwell G.
Published: August 2018

To sense the outside world, some neurons protrude across epithelia, the cellular barriers that line every surface of our bodies. To study the morphogenesis of such neurons, we examined theC. elegansamphid, in which dendrites protrude through a glial channel at the nose. During development, amphid dendrites extend by attaching to the nose via DYF-7, a type of protein typically found in epithelial apical ECM. Here, we show that amphid neurons and glia exhibit epithelial properties, including tight junctions and apical-basal polarity, and develop in a manner resembling other epithelia. We find that DYF-7 is a fibril-forming apical ECM component that prevents rupture of the tube-shaped glial channel, reminiscent of roles for apical ECM in other narrow epithelial tubes. We also identify a role for FRM-2, a homolog of EPBL15/moe/Yurt which promote epithelial integrity in other systems. Finally, we show that other environmentally-exposed neurons share a requirement for DYF-7. Together, our results suggest that these neurons and glia can be viewed as part of an epithelium continuous with the skin, and are shaped by mechanisms shared with other epithelia.
Ultra-fast and accurate motif finding in large ChIP-seq datasets reveals transcription factor binding patterns
Authors: Li Yang , Ni Pengyu , Zhang Shaoqiang , Li Guojun , Su Zhengchang
Published: August 2018

The availability of a large volume of chromatin immunoprecipitation followed by sequencing (ChIP-seq) datasets for various transcription factors (TF) has provided an unprecedented opportunity to identify all functional TF binding motifs clustered in the enhancers in genomes. However, the progress has been largely hindered by the lack of a highly efficient and accurate tool that is fast enough to find not only the target motifs, but also cooperative motifs contained in very large ChIP-seq datasets with a binding peak length of typical enhancers (∼ 1,000 bp). To circumvent this hurdle, we herein present an ultra-fast and highly accurate motif-finding algorithm, ProSampler, with automatic motif length detection. ProSampler first identifies significant k-mers in the dataset and combines highly similar significant k-mers to form preliminary motifs. ProSampler then merges preliminary motifs with subtle similarity using a novel graph-based Gibbs sampler to find core motifs. Finally, ProSampler extends the core motifs by applying a two-proportion z-test to the flanking positions to identify motifs longer than k. As the number of preliminary motifs is much smaller than that of k-mers in a dataset, we greatly reduce the search space of the Gibbs sampler compared with conventional ones. By storing flanking sequences in a hash table, we avoid extensive IO and the necessity of examining all lengths of motifs in an interval. When evaluated on both synthetic and real ChIP-seq datasets, ProSampler runs orders of magnitude faster than the fastest existing tools while more accurately discovering primary motifs as well as cooperative motifs than do the best existing tools. Using ProSampler, we revealed previously unknown complex motif occurrence patterns in large ChIP-seq datasets, thereby providing insights into the mechanisms of cooperative TF binding for gene transcriptional regulation. Therefore, by allowing fast and accurate mining of the entire ChIP-seq datasets, ProSampler can greatly facilitate the efforts to identify the entire cis-regulatory code in genomes.