bluuebunny/crossref_metadata_2025 huggingface dataset:
Physiological CRAC channel activation and pore properties require STIM1 binding to all six Orai1 subunits
Authors: Yen Michelle , Lewis Richard S.
Published: August 2018

The binding of STIM1 to Orai1 controls the opening of store-operated CRAC channels as well as their extremely high Ca2+ selectivity. Although STIM1 dimers are known to bind directly to the cytosolic C termini of the six Orai1 subunits (SUs) that form the channel hexamer, the dependence of channel activation and selectivity on the number of occupied binding sites is not well understood. Here we address these questions using dimeric and hexameric Orai1 concatemers in which L273D mutations were introduced to inhibit STIM1 binding to specific Orai1 SUs. By measuring FRET between fluorescently labeled STIM1 and Orai1, we find that homomeric L273D mutant channels fail to bind STIM1 appreciably; however, the L273D SU does bind STIM1 and contribute to channel activation when located adjacent to a WT SU. These results suggest that STIM1 dimers can interact with pairs of neighboring Orai1 SUs. Surprisingly, a single L273D mutation within the Orai1 hexamer reduces channel open probability by ∼90%, triples the size of the single-channel current, weakens the Ca2+ binding affinity of the selectivity filter, and lowers the selectivity for Na+ over Cs+ in the absence of divalent cations. These findings reveal a surprisingly strong functional coupling between STIM1 binding and CRAC channel gating and pore properties. We conclude that under physiological conditions, all six Orai1 SUs of the native CRAC channel bind STIM1 to effectively open the pore and generate the signature properties of extremely low conductance and high ion selectivity.
Definitions of Resistant and Refractory Cytomegalovirus Infection and Disease in Transplant Recipients for Use in Clinical Trials
Authors: Chemaly Roy F , Chou Sunwen , Einsele Hermann , Griffiths Paul , Avery Robin , Razonable Raymund R , Mullane Kathleen M , Kotton Camille , Lundgren Jens , Komatsu Takashi E , Lischka Peter , Josephson Filip , Douglas Cameron M , Umeh Obi , Miller Veronica , Ljungman Per ,   Resistant Definitions Working Group of the Cytomegalovirus Drug Development Forum
Published: August 2018

Despite advances in preventive strategies, cytomegalovirus (CMV) infection remains a major complication in solid organ and hematopoietic cell transplant recipients. CMV infection may fail to respond to commercially available antiviral therapies, with or without demonstrating genotypic mutation(s) known to be associated with resistance to these therapies. This lack of response has been termed “resistant/refractory CMV” and is a key focus of clinical trials of some investigational antiviral agents. To provide consistent criteria for future clinical trials and outcomes research, the CMV Resistance Working Group of the CMV Drug Development Forum (consisting of scientists, clinicians, regulatory officials, and industry representatives from the United States, Canada, and Europe) has undertaken establishing standardized consensus definitions of “resistant” and “refractory” CMV. These definitions have emerged from the Working Group’s review of the available virologic and clinical literature and will be subject to reassessment and modification based on results of future studies.
1. Introduction
Authors: Cunningham-Hill Susan , Elder Karen
Published: August 2018

This introductory chapter explains the philosophy of the book and its pedagogical features. It assists in broadening research skills and knowledge. Further, it introduces the Civil Procedure Rules. Finally, it highlights professional conduct considerations and how they are dealt with in this book.
13. Interim Applications—General Considerations
Authors: Cunningham-Hill Susan , Elder Karen
Published: August 2018

An interim application is any application made to the court that requires a judicial decision. This is usually in the time between a case being issued and the final trial or determination of the action. This chapter considers the nature of interim applications. It discusses the interim applications made with and without notice, and those made with and without a hearing. It also explains common procedure and time estimates.
15. Part 36 Offers
Authors: Cunningham-Hill Susan , Elder Karen
Published: August 2018

Offers to settle are a common occurrence prior to the resolution dispute or the start of trial. There does not appear to be a limit on the number of offers that can be made, although credibility and common sense would indicate that offers to settle should be made purposefully, but not irrationally. This chapter discusses the main features of Part 36 of the Civil Procedure Rules (CPR) and its Practice Direction in relation to commercial and personal injury claims; practical suggestions on dealing with Part 36 offers; and advising the client. It considers recent cases that demonstrate how the courts apply and interpret CPR Part 36.
16. Disclosure and Inspection
Authors: Cunningham-Hill Susan , Elder Karen
Published: August 2018

This chapter considers the definition of ‘disclosure’, its purpose, its extent, and the process whereby it is implemented. It also looks at other types of disclosure and the times at which such disclosure may take place—some of which may be before litigation has been commenced. The formal provisions for disclosure are contained in the Civil Procedure Rules 31 and the accompanying Practice Direction. The formal disclosure rules apply to cases in the fast track and the multi-track. They do not automatically apply to the small claims track. Disclosure has been much in the legal press recently, and the new draft disclosure rules are discussed.
17. Witness Statements and Documentary Evidence
Authors: Cunningham-Hill Susan , Elder Karen
Published: August 2018

Cases can readily be won or lost on the strength of witness evidence at trial. Important applications may fail if a witness statement does not adequately deal with all of the issues. A legal representative, therefore, must understand both the underlying theory behind the use of witness evidence and documentation during the course of litigation, including the rules on hearsay, and the practical requirements and challenges encountered in the preparation of witness statements. This chapter discusses the use of evidence at trial; the preparation of witness statements for interim applications and at trial; the use of hearsay in civil cases; and evidential tools.
19. Trial, Settlement, and Appeals
Authors: Cunningham-Hill Susan , Elder Karen
Published: August 2018

Although a large percentage of civil cases are settled well in advance of trial, it remains important for legal representatives look to the possibility of running a case to trial. This chapter focuses on fast-track and multi-track cases that proceed to trial. It covers professional conduct issues; procedural and administrative preparation for trial; the day of the trial; judgment and appeals. It also discusses settlement without trial.
Foundations for the LPC 2018-2019
Authors: Firth Clare , Smart Elizabeth , Wright Kathryn , Crompton Lucy , Fox Helen , Seabridge Frances , Wigglesworth Susan
Published: August 2018

Foundations for the LPC covers the compulsory foundation areas of the Legal Practice Course as set out in the LPC Outcomes: Professional Conduct, Tax/Revenue Law, and Wills and Administration of Estates. The volume also features content on human rights law. The volume uses worked examples and scenarios throughout to illustrate key points. To aid understanding and test comprehension of the core material, checkpoints and summaries feature in every chapter. The book covers topics such as professional conduct (including financial services and money laundering), revenue law (including income tax, capital gains tax, VAT, corporation tax, and inheritance tax), wills and administration of estates, and issues related to human rights.
2. Financial services
Authors: Wright Kathryn , Firth Clare , Crompton Lucy , Fox Helen , Seabridge Frances , Wigglesworth Susan , Smart Elizabeth
Published: August 2018

This chapter first introduces the regulation of financial services. It puts the Financial Services and Markets Act 2000 (FSMA 2000) into context and explains the need for authorisation under the Act. It considers what is covered by the general prohibition as well as the meanings of ‘regulated activity’ and ‘specified investment’. The chapter then discusses the position of solicitors, specifically those who are regulated by the Law Society, a designated professional body. The FSMA 2000 has been amended by the Financial Services Act 2012. This introduced changes to the regulation of financial services, including the renaming of the Financial Services Authority as the Financial Conduct Authority.
4. Introduction to revenue law
Authors: Wright Kathryn , Firth Clare , Crompton Lucy , Fox Helen , Seabridge Frances , Wigglesworth Susan , Smart Elizabeth
Published: August 2018

This chapter provides an introduction to some of the essential principles of revenue law and to the main taxes studied on the LPC. It covers the main taxes; the sources of tax law; who pays tax; the administration of the tax system; and appeals against tax decisions.
5. Income tax
Authors: Wright Kathryn , Firth Clare , Crompton Lucy , Fox Helen , Seabridge Frances , Wigglesworth Susan , Smart Elizabeth
Published: August 2018

Income tax is an essential part of a lawyer’s knowledge and professional training. Whilst it is not necessary to have knowledge to the extent that a specialist tax lawyer would have, it is necessary to have knowledge and understanding sufficient to recognise its implications as they arise and affect the client and ourselves. This chapter discusses sources of income tax law; collection and payment of income tax; rates of income tax and allowances; calculation of income tax; sources of taxable income; and charitable giving. This chapter covers the changes introduced by the Autumn 2017 Budget.
6. Capital gains tax
Authors: Wright Kathryn , Firth Clare , Crompton Lucy , Fox Helen , Seabridge Frances , Wigglesworth Susan , Smart Elizabeth
Published: August 2018

Capital gains tax (CGT) is charged on the gain (or increase in value) which is realised when a chargeable asset is disposed of. The statute which sets out all the rules relating to this is the Taxation of Chargeable Gains Tax Act 1992 (TCGA). This chapter discusses the principles of CGT; persons liable for CGT; disposal of assets; chargeable assets; calculation of CGT; the rate of CGT; capital losses; rebasing of assets owned before 31 March 1982; exemptions and reliefs; and death of a taxpayer.
7. Inheritance tax
Authors: Wright Kathryn , Firth Clare , Crompton Lucy , Fox Helen , Seabridge Frances , Wigglesworth Susan , Smart Elizabeth
Published: August 2018

This chapter deals with inheritance tax (IHT). It explains the charge to IHT; potentially exempt transfers (PETs); the transfer of value on death; the occasions to tax; the charge to tax and a lifetime chargeable transfer (LCT); the charge to tax and a LCT where the transferor dies within seven years of the LCT; the charge to tax and a PET; the charge to tax and death; gifts subject to a reservation; liability, burden, and payment of tax; and tax planning.
13. Entitlement to the estate
Authors: Wright Kathryn , Firth Clare , Crompton Lucy , Fox Helen , Seabridge Frances , Wigglesworth Susan , Smart Elizabeth
Published: August 2018

This chapter discusses the law underlying the entitlement to a person’s property on his or her death. It considers the law of ‘testate succession’ where the deceased has left a will; the law of ‘intestate succession’ if there is no will, or if any will left by the deceased is not wholly effective to dispose of their estate; the law governing devolution of property not passing under the terms of the deceased’s will or the operation of the intestacy rules; and the law enabling members of the family or dependants of the deceased to make claims for provision against the estate.
15. Post-grant practice
Authors: Wright Kathryn , Firth Clare , Crompton Lucy , Fox Helen , Seabridge Frances , Wigglesworth Susan , Smart Elizabeth
Published: August 2018

This chapter discusses the law and practice relating to the administration and winding up of an estate once the court has issued the grant. It considers the duties and powers of personal representatives; administering the estate; and distributing the estate.
5. The Right to Silence at the Police Station
Authors: Hannibal Martin , Mountford Lisa
Published: August 2018

This chapter explains the substantive law governing a defendant’s silence at the police station under ss. 34, 36, and 37 Criminal Justice and Public Order Act (CJPOA) 1994. It covers the risks associated with s. 34 CJPOA 1994; drawing inferences from a failure to account under ss. 36 and 37 CJPOA 1994; and the practical aspects associated with remaining silent.
6. Challenging Unlawfully and Unfairly Obtained Evidence
Authors: Hannibal Martin , Mountford Lisa
Published: August 2018

This chapter examines the court’s powers to exclude unlawfully or unfairly obtained prosecution evidence by examining the position in relation to confession evidence excluded under ss. 76 and 78 Police and Criminal Evidence Act (PACE) 1984; and other prosecution evidence excluded at common law, under s. 78 PACE 1984, and as an abuse of process.
7. Obtaining Identification Evidence
Authors: Hannibal Martin , Mountford Lisa
Published: August 2018

This chapter considers the following: the dangers of eye-witness identification; how identification evidence is obtained by the police during the police investigation; the pre-trial safeguards contained in the identification procedures under Code D of the Police and Criminal Evidence Act 1984 (PACE); the admissibility of eye-witness evidence obtained in breach of Code D; obtaining fingerprints, intimate and non-intimate samples at the police station; DNA evidence and identification evidence given by expert witnesses.
8. The Decision to Prosecute and the Prosecution’s Duties of Disclosure of Evidence
Authors: Hannibal Martin , Mountford Lisa
Published: August 2018

This chapter first explains the role of the Crown Prosecution Service (CPS) and the factors that are taken into account when deciding to charge a suspect or to divert him from prosecution. It then examines the important obligations which are placed upon the CPS both at common law and under statute to serve pre-trial disclosure of evidence upon the defendant and their importance to the right to a fair trial. Defence disclosure obligations are also considered.
9. Funding of Criminal Defence Services and First Appearance Process
Authors: Hannibal Martin , Mountford Lisa
Published: August 2018

This chapter considers the public funding of criminal proceedings and the early stages of the criminal litigation process. Topics discussed include legal aid as a human right; pre-charge advice and assistance; funded representation in court; representation orders; the interests of justice test; means testing and its application to cases tried in the magistrates’ court; the means test as applied to cases triable on indictment; work that can be done under a representation order; acquitted defendants and Defendants’ Costs Order; the future of public funding; and preparing for the first appearance before the magistrates’ court.
11. Prosecuting an Either-Way Offence
Authors: Hannibal Martin , Mountford Lisa
Published: August 2018

Either-way offences include assault occasioning actual bodily harm, theft, and burglary. These offences can be committed with varying degrees of seriousness depending on the aggravating or mitigating features in the particular case. The more aggravating features, the more serious the offence will be regarded. This chapter examines the procedure for deciding where an either-way offence should be tried which includes the plea before venue and allocation procedure; the relative merits of summary trial and trial on indictment; and for those either-way offences that are to be tried in the Crown Court, the next stage of the proceedings.
13. Crown Court Proceedings Pre-Trial
Authors: Hannibal Martin , Mountford Lisa
Published: August 2018

This chapter deals with pre-trial practices and procedures of indictable-only offences. It covers sending indictable-only cases to the Crown Court under s. 51 Crime and Disorder Act 1998 (CDA 1998); preparing for the preliminary hearing in the Crown Court; preparing for trial on indictment; pre-trial disclosure issues and defence statements; instructing counsel; and pre-trial hearings including the Plea and Trial Preparation Hearing (PTPH).
19. Character Evidence and the Accused as a Witness at Trial
Authors: Hannibal Martin , Mountford Lisa
Published: August 2018

This chapter examines the evidential rules that apply to the defendant at trial. These include the defendant’s competence and compellability; the course of the defendant’s evidence; drawing an adverse inference under s. 35 Criminal Justice and Public Order Act 1994 from the defendant’s silence at trial; the admissibility of a defendant’s past bad character; admissibility of defendant’s good character; and arguments for and against the defendant giving evidence.
1. Introduction
Authors: Abbey Robert , Richards Mark
Published: August 2018

Property Law and Practice (PLP) covers all aspects of the process that is otherwise called conveyancing. It is how practitioners arrange the transmission of property ownership from seller to buyer. This introductory chapter provides an overview of PLP. Specifically, it explains the three foundations upon which PLP rests: land law, contract law, and trusts.
4. Taking instructions and other initial matters
Authors: Abbey Robert , Richards Mark
Published: August 2018

This chapter discusses initial activities in the conveyancing process including advising joint buyers on co-ownership; advising buyers to have a survey of the property carried out before exchange of contracts; estate agents; capital gains tax; stamp duty land tax; client care and advice on costs; professional conduct; the Law Society’s National Conveyancing Protocol; and advising on finance.
6. Pre-contract searches and enquiries
Authors: Abbey Robert , Richards Mark
Published: August 2018

This chapter examines pre-contract searches and enquiries. Searches are requests for information about the subject property made by conveyancers that are sent to various agencies that hold that information, like local authorities. Enquiries are questions about the subject property that are sent to a seller to answer. These are interesting and important subjects within the conveyancing process and cover a lot of points that can be of considerable consequence to a buyer.
12. Pre-completion procedures
Authors: Abbey Robert , Richards Mark
Published: August 2018

Pre-completion searches are a critical part of any property transaction and conveyancing practitioners must be fully acquainted with all aspects of pre-completion searches. This chapter discusses pre-completion procedures; pre-completion when acting for the buyer; pre-completion when acting for the seller; pre-completion searches; acting for the lender; buying from a company; physical inspection of the subject property; and completion statements.
15. Delays and remedies
Authors: Abbey Robert , Richards Mark
Published: August 2018

This chapter considers what can be done if a conveyancing contract is delayed, disputed or denied. A practitioner must be able to advise a client when a transaction goes wrong and remedies are sought to correct that wrong. The discussions cover late completion; conditions when time is of the essence for a conveyancing contract; consequences of delay; notices to complete; and remedies.
1. Characteristics of partnerships
Authors: Slorach J. Scott , Ellis Jason
Published: August 2018

This chapter discusses the rules for determining whether a partnership has come into existence as well as the formalities with which businesses which will be run through partnerships must comply. It looks at the Partnership Act 1890. It then provides a definition of partnership. Next it considers the nature of partnership and terminology; the number of partners; the capacity to form a partnership; the duration of partnership; and partnership name and the publicity of information.
2. Partnership management and finance
Authors: Slorach J. Scott , Ellis Jason
Published: August 2018

This chapter first discusses the legal relationship between the partners under section 24 of the Partnership Act 1890. It then explains the duty of good faith; the partnership’s finances; the distinction between a partner and a lender; division of profits and sharing of losses between partners; payment of interest; and partnership property.
3. Liability of partners to outsiders
Authors: Slorach J. Scott , Ellis Jason
Published: August 2018

Partners will incur debts and other obligations in the course of carrying on the partnership’s business. This chapter examines the nature of the partners’ liabilities in these circumstances and the extent to which an individual partner can bind the partnership as a whole. It then considers whether it is possible for individuals who are not partners at the time the debt or obligation was incurred to be liable for that debt or obligation.
6. The partnership agreement
Authors: Slorach J. Scott , Ellis Jason
Published: August 2018

This chapter focuses on provisions that may be included in a partnership agreement. It first considers whether a formal, written agreement is necessary at all. It then discusses the clauses of the partnership agreement and the issues which a prospective new partner might wish to consider before putting his signature to a partnership agreement.
8. Formation of a limited company
Authors: Slorach J. Scott , Ellis Jason
Published: August 2018

This chapter considers the process by which a limited company is formed and the steps required both for and following its formation. It also looks at shelf companies, as an alternative means of providing a company to a client, and the related changes which can be made to a company’s main features. The process of registering a company is governed by the Companies Act 2006.
9. Directors and secretary
Authors: Slorach J. Scott , Ellis Jason
Published: August 2018

This chapter considers the law relating to company officers. This is a combination of statute, common law, and regulations under a company’s articles of association. The discussions cover the division of powers within a company; appointment of directors, managing directors, alternate directors, and shadow directors; retirement of directors; removal of directors from office; powers of directors; directors’ duties; statutory controls on directors; the directors and protection of outsiders; and the company secretary.
12. Disposal of shares
Authors: Slorach J. Scott , Ellis Jason
Published: August 2018

This chapter considers the various ways in which a shareholder in a company may dispose of his interest in the company either during his lifetime or on death. It discusses the transfer of shares; transmission by operation of law; buy-back and redemption by a company; and financial assistance.
15. Disclosure obligations of companies and company accounts
Authors: Slorach J. Scott , Ellis Jason
Published: August 2018

This chapter considers the information about companies which is publicly available, paying particular attention to the rules with which the company must comply in relation to its accounts. It also provides some guidance on how to interpret the published accounts of a company.
16. Public companies
Authors: Slorach J. Scott , Ellis Jason
Published: August 2018

This chapter first discusses the distinguishing features of a public company. It then considers the advantages and disadvantages of obtaining a listing with the United Kingdom Listing Authority (UKLA) and the requirements for seeking and maintaining that listing.
23. Value Added Tax
Authors: Slorach J. Scott , Ellis Jason
Published: August 2018

This chapter discusses value added tax (VAT) in the UK. VAT is charged on supplies of goods and services made in the UK. Where a person makes taxable supplies in excess of a set limit in any one-year period, he must register with Her Majesty’s Revenue and Customs (HMRC). He must then account to HMRC for VAT on all taxable supplies made. The total amount payable may be reduced by the amount of VAT which he has paid on certain taxable supplies made to him. The liability to pay VAT to HMRC rests on suppliers of goods and services. However, the cost of the tax is actually borne by suppliers’ customers who are charged VAT on the goods and services they purchase. VAT is charged in the UK under the Value Added Tax Act (VATA) 1994.
26. Liabilities arising from insolvency
Authors: Slorach J. Scott , Ellis Jason
Published: August 2018

This chapter considers the rules which enable insolvency practitioners to claim assets which are not held by the insolvent company itself. It discusses wrongful trading; transactions at an undervalue and preferences; transactions defrauding creditors; and floating charges.
27. Choice of business medium
Authors: Slorach J. Scott , Ellis Jason
Published: August 2018

This chapter makes a comparison between companies, on the one hand, and partnerships or sole traders, on the other, in order to explain the various factors which should be taken into account when choosing the two business media. It considers factors such as risk of capital, expense, publicity, taxation, interest relief, capital gains, inheritance tax, pensions and social security Due to the range of variables, the desirability of limited liability means that incorporation may be the only viable option, although this can also be achieved by setting up a limited liability partnership. Where limited liability is not of great importance, the tax factors will be more significant and these would have to be examined from a number of perspectives, including the size of anticipated profits, the particular financial circumstances of the promoters of the business, and any particular expectations they had about their stake in the business.
29. Sale of a business to a company
Authors: Slorach J. Scott , Ellis Jason
Published: August 2018

A sole trader or partnership may decide, for a variety of reasons, to incorporate the business. Incorporation will give rise to a number of tax and other problems. This chapter considers these problems and how they can be avoided, or at least mitigated. It shows that the tax rules are the most important in this area, since if they are not appreciated the payment of an unexpected tax bill can cause very serious cash flow problems. These include rules on income tax, capital gains tax, VAT, and stamp duty/stamp duty land tax.
The Dynamical Mordell–Lang Conjecture for Skew-Linear Self-Maps. Appendix by Michael Wibmer
Authors: Ghioca Dragos , Xie Junyi
Published: August 2018

Let $k$ be an algebraically closed field of characteristic $0$, let $N\in{\mathbb{N}}$, let $g:{\mathbb{P}}^1{\longrightarrow } {\mathbb{P}}^1$ be a nonconstant morphism, and let $A:{\mathbb{A}}^N{\longrightarrow } {\mathbb{A}}^N$ be a linear transformation defined over $k({\mathbb{P}}^1)$, that is, for a Zariski-open dense subset $U\subset{\mathbb{P}}^1$, we have that for $x\in U(k)$, the specialization $A(x)$ is an $N$-by-$N$ matrix with entries in $k$. We let $f:{\mathbb{P}}^1\times{\mathbb{A}}^N{\dashrightarrow } {\mathbb{P}}^1\times{\mathbb{A}}^N$ be the rational endomorphism given by $(x,y)\mapsto (\,g(x), A(x)y)$. We prove that if $g$ induces an automorphism of ${\mathbb{A}}^1\subset{\mathbb{P}}^1$, then each irreducible curve $C\subset{\mathbb{A}}^1\times{\mathbb{A}}^N$ that intersects some orbit $\mathcal{O}_f(z)$ in infinitely many points must be periodic under the action of $f$. Furthermore, in the case $g:{\mathbb{P}}^1{\longrightarrow } {\mathbb{P}}^1$ is an endomorphism of degree greater than $1$, then we prove that each irreducible subvariety $Y\subset{\mathbb{P}}^1\times{\mathbb{A}}^N$ intersecting an orbit $\mathcal{O}_f(z)$ in a Zariski dense set of points must be periodic. Our results provide the desired conclusion in the Dynamical Mordell–Lang Conjecture in a couple new instances. Moreover, our results have interesting consequences toward a conjecture of Rubel and toward a generalized Skolem–Mahler–Lech problem proposed by Wibmer in the context of difference equations. In the appendix it is shown that the results can also be used to construct Picard–Vessiot extensions in the ring of sequences.
Evidence-based medicine and precision medicine: Complementary approaches to clinical decision-making
Authors: Chow Ngai , Gallo Lucas , Busse Jason W
Published: August 2018

Evidence-based medicine is widely promoted for decision-making in health care and is associated with improved patient outcomes. Critics have suggested that evidence-based medicine focuses primarily on groups of patients rather than individuals, but often fail to consider subgroup analyses, N-of-1 trials, and the incorporation of patient values and preferences. Precision medicine has been promoted as an approach to individualize diagnosis and treatment of diseases through genetic, biomarker, phenotypic, and psychosocial characteristics. However, there are often high costs associated with personalized medicine, and high-quality evidence is lacking for effectiveness in many applications. For the potential of personalized medicine to be realized, it must adhere to the principles of evidence-based medicine: (1) evidence in isolation is not sufficient to make clinical decisions—patient’s values and preferences as well as resource implications must be considered, and (2) there is a hierarchy of evidence to guide clinical decision-making and studies at lower risk of bias are likely to provide more trustworthy findings.
Poor Control of Cucurbit Powdery Mildew Associated with First Detection of Resistance to Cyflufenamid in the Causal Agent, Podosphaera xanthii, in the United States
Authors: McGrath Margaret T. , Sexton Zachary F.
Published: August 2018

This report is about the first known occurrence of resistance to cyflufenamid, a Fungicide Resistance Action Committee (FRAC) code U6 fungicide, in Podosphaera xanthii in the United States. This fungus causes powdery mildew in cucurbit crops, the most common disease of this important crop group. Knowledge about resistance is important for guiding fungicide programs. Mobile, targeted fungicides, which have moderate or high resistance risk, are the most effective management tool for this disease. The pathogen is a documented high resistance risk organism having already developed resistance to fungicides in FRAC groups 1, 3, 7, 11, and 13.
Calcinosis in scleroderma
Authors: Valenzuela Antonia , Song Paula , Chung Lorinda
Published: August 2018

Purpose of review

To provide an update on the available literature regarding the epidemiology, pathophysiology, diagnosis, and treatment of calcinosis cutis in patients with systemic sclerosis (SSc).

Recent findings

We identified observational studies that describe the frequency of calcinosis in SSc and associated clinical features; molecular studies exploring potential pathogenic mechanisms; and case reports and case series describing new diagnostic approaches and treatments.

Calcinosis cutis is the deposition of insoluble calcium in the skin and subcutaneous tissues. It represents a major clinical problem in patients with SSc affecting at least one quarter of patients. It is associated with longer disease duration, digital ulcers, acro-osteolysis, positive anticentromere antibody, and positive anti-PM/Scl antibody. Although pathogenesis is unknown, there is evidence supporting local trauma, chronic inflammation, vascular hypoxia, and dysregulation of bone matrix proteins as potential mechanisms. Diagnosis can be made clinically or with plain radiography. Several pharmacologic therapies have been tried for calcinosis with variable and modest results, but surgical excision of calcium deposits remains the mainstay of treatment.
Liposuction Gives Complete Reduction of Arm Lymphedema following Breast Cancer Treatment—A 5-year Prospective Study in 105 Patients without Recurrence
Authors: Hoffner Mattias , Ohlin Karin , Svensson Barbro , Manjer Jonas , Hansson Emma , Troëng Thomas , Brorson Håkan
Published: August 2018

Background:

Arm lymphedema is a well-recognized complication after breast cancer surgery that negatively impacts patients’ quality of life, both physiologically and psychologically. Lymph stasis and inflammation result in excess formation of adipose tissue, which makes removal of the deposited subcutaneous fat necessary to eliminate the excess volume. Liposuction, combined with postoperative controlled compression therapy (CCT), is the only treatment that gives complete reduction of the excess volume. The aim of this study was to evaluate the 5-year results after liposuction in combination with CCT.

Methods:

Patients consecutively operated on between 1993 and 2012 were identified from the lymphedema registry, comprising all patients with nonpitting lymphedema treated with liposuction and CCT in our department. Standardized forms were used to collect pre-, peri-, and postoperative data.

Results:

One hundred five women with nonpitting edema were treated. The mean interval between the breast cancer operation and lymphedema start was 2.9 ± 5.0 years, the mean duration of lymphedema was 10 ± 7.4 years, and the preoperative mean excess volume was 1,573 ± 645 ml. The mean volume aspirated was 1,831 ± 599 ml. Postoperative mean reduction 5 years postoperatively was 117% ± 26% as compared with the healthy arm.

Conclusion:

Liposuction is an effective method for the treatment of chronic, nonpitting, arm lymphedema resistant to conservative treatment. The volume reduction remains complete after 5 years.
Is It Time to Give Athletes a Voice in the Dissemination Strategies of Concussion-Related Information? Exploratory Examination of 2444 Adolescent Athletes
Authors: Beakey Mark , Keenan Brian , Tiernan Stephen , Collins Kieran
Published: August 2018

Objective:

The objective of the research was to screen male and female adolescent athletes on their concussion educational histories and preferred future methods of education in terms of educational messenger, modality, and concussion-related areas of interest.

Design:

Cross-sectional survey.

Setting:

Examination setting within the classroom.

Participants:

Adolescent male (n = 1854) and female (n = 590) athletes aged 12 to 18 years.

Main Outcome Measures:

To explore the concussion educational histories and preferred future methods of education in Irish male and female adolescent athletes.

Results:

19.7% (n = 482) of the sample received education in the past 12 months. Male athletes had a significantly higher rate of previous education than female athletes (41% vs 17%). The methods used in previous educational interventions are failing to match the interests of the athletes. Sex played a significant role in the preferred educational methods, as male and female athletes had significant differences in their choice of educational messenger, modality, and concussion-related areas of interest.

Conclusions:

The current disparity in previous concussion education rates between male and female adolescent athletes should be addressed. Forthcoming research should explore the efficacy of tailoring knowledge translation strategies to match the specific needs of the recipient.
Temporal Trends and Risk Factors for Postcolonoscopy Colorectal Cancer
Authors: Uche-Anya Eugenia N. , DeCuir Nicole , Lebwohl Benjamin
Published: August 2018

Background:

Colonoscopy is effective for colorectal cancer (CRC) prevention, yet patients may develop CRC despite adhering to screening/surveillance intervals. There are limited data on predictive factors associated with these postcolonoscopy CRCs (PCCRCs). We aimed to measure PCCRC rates and identify risk factors for PCCRC.

Methods:

We performed a case-control study, comparing patients with PCCRCs to spontaneous CRCs diagnosed during a 12.5-year period at an academic medical center. PCCRCs were defined as CRCs diagnosed in between guideline-recommended screening/surveillance intervals.

Results:

During the 12.5-year period, of 1266 CRCs diagnosed, 122 (10%) were PCCRCs. 70% of PCCRCs were diagnosed within 5 years of a prior colonoscopy. There was an increasing trend for PCCRC rates in recent years [odds ratio (OR), 2.78; 95% confidence interval (CI), 1.51-5.09], with PCCRCs comprising 13.6% of cancers diagnosed in 2016 as compared with 5.7% of cancers diagnosed in 2005. Older age (OR per year, 1.02; 95% CI, 1.01-1.04), proximal colonic location (OR, 1.99; 95% CI, 1.20-3.33) and early stage (OR, 2.57; 95% CI, 1.34-4.95) were associated with PCCRCs. In total, 41% of PCCRCs were diagnosed by a different physician from the physician who did the prior colonoscopy, and 42% of physicians did not diagnose any of their PCCRC cases.

Conclusions:

PCCRC rates are rising in recent years, likely reflecting the widespread adoption of colonoscopy as a primary screening tool, and are more common in older patients and those with proximal, early-stage tumors. The finding that a large proportion of PCCRCs are diagnosed by a different physician raises the concern that physicians are unaware of their own patients’ PCCRCs.
Probiotics and Evidence-based Medicine
Authors: Koch Maurizio
Published: August 2018

The methods used to discern the structure (anatomy) and function (physiology) of the indigenous microbiota can be divided according to which aspect of the microbiota they can interrogate and are positioned accordingly. At the most basic level, methods can simply describe the community structure of the microbiota, that is, which taxa are present and in what relative amounts. Methods that investigate functional potential generally catalog the coding potential of individual members of the microbiota or the entire community (the metagenome). To measure function directly a catalog of the expressed microbial genes (the metatranscriptome) or the proteins or metabolites present in the microbiome environment must be generated. So, complexity in understanding the role of microbiota is quite rejecting the interested clinician. Evidence-based medicine can offer an answer suggesting strict definition of populations, measurement techniques, and external validity.
sierra-local: A lightweight standalone application for secure HIV-1 drug resistance prediction
Authors: Ho Jasper C , Ng Garway T , Renaud Mathias , Poon Art FY
Published: August 2018

Genotypic resistance interpretation systems for the prediction and interpretation of HIV-1 antiretroviral resistance are an important part of the clinical management of HIV-1 infection. Current interpretation systems are generally hosted on remote webservers that enable clinical laboratories to generate resistance predictions easily and quickly from patient HIV-1 sequences encoding the primary targets of modern antiretroviral therapy. However they also potentially compromise a health provider’s ethical, professional, and legal obligations to data security, patient information confidentiality, and data provenance. Furthermore, reliance on web-based algorithms makes the clinical management of HIV-1 dependent on a network connection. Here, we describe the development and validation ofsierra-local, an open-source implementation of the Stanford HIVdb genotypic resistance interpretation system for local execution, which aims to resolve the ethical, legal, and infrastructure issues associated with remote computing. This package reproduces the HIV-1 resistance scoring by the web-based Stanford HIVdb algorithm with a high degree of concordance (99.997%) and a higher level of performance than current methods of accessing HIVdb programmatically.
Balancing dynamic tradeoffs drives cellular reprogramming
Authors: Babos Kimberley N. , Galloway Kate E. , Kisler Kassandra , Zitting Madison , Li Yichen , Quintino Brooke , Chow Robert H. , Zlokovic Berislav V. , Ichida Justin K.
Published: August 2018

Although cellular reprogramming continues to generate new cell types, reprogramming remains a rare cellular event. The molecular mechanisms that limit reprogramming, particularly to somatic lineages, remain unclear. By examining fibroblast-to-motor neuron conversion, we identify a previously unappreciated dynamic between transcription and replication that determines reprogramming competency. Transcription factor overexpression forces most cells into states that are refractory to reprogramming and are characterized by either hypertranscription with little cell division, or hyperproliferation with low transcription. We identify genetic and chemical factors that dramatically increase the number of cells capable of both hypertranscription and hyperproliferation. Hypertranscribing, hyperproliferating cells reprogram at 100-fold higher, near-deterministic rates. We demonstrate that elevated topoisomerase expression endows cells with privileged reprogramming capacity, suggesting that biophysical constraints limit cellular reprogramming to rare events.
A feedback loop between miRNA-155, Programmed cell death 4 and Activation Protein-1 modulates the expression of miR-155 and tumorigenesis in tongue cancer
Authors: Zargar Shabir , Tomar Vivek , Shyamsundar Vidyarani , Vijayalakshmi Ramshankar , Somasundaram Kumaravel , Karunagaran Devarajan
Published: August 2018

miR-155 is an oncomir, generated as a non-coding RNA from BIC gene whose promoter activity is mainly controlled via AP-1 and NF-κB transcription factors. We found that the expression levels of miR-155 and Pdcd4 exhibit inverse relationship in tongue cancer cells (SAS and AWL) and tumor tissues compared to normal FBM cells and normal tongue tissues, respectively. Insilco and In-vitro studies with 3’UTR of Pdcd4 via luciferase reporter assays, qPCR and western blots show that miR-155 directly targets Pdcd4 mRNA and blocks its expression. Ectopic expression of Pdcd4 or knockdown of miR-155 in tongue cancer cells predominantly reduces AP-1 dependent transcriptional activity of BIC promoter and decreases miR-155 expression. In this study, we demonstrate that miR-155 expression is modulated by a feedback loop between Pdcd4, AP-1 and miR-155 which results in enhanced expression of miR-155 with a consequent progression of tongue tumorigenesis. Further, miR-155 knockdown increases apoptosis, arrests cell cycle, regresses tumor size in xenograft nude mice and reduces cell viability and colony formation in soft agar and clonogenic assays. Thus, the restoration of Pdcd4 levels by the use of molecular manipulation such as using miR-155 sponge have important role in the therapeutic intervention of cancers, including tongue cancer.
CEACAM1 regulates the IL-6 mediated fever response to LPS through the RP105 receptor in murine monocytes
Authors: Zhang Zhifang , Placa Deirdre La , Nguyen Tung , Kujawski Maciej , Le Keith , Li Lin , Shively John E.
Published: August 2018

Systemic inflammation and the fever response to pathogens are coordinately regulated by IL-6 and IL-1β. We previously showed that CEACAM1 regulates the LPS driven expression of IL-1β in murine neutrophils through its ITIM receptor. We now show that the prompt secretion of IL-6 in response to LPS is regulated by CEACAM1 expression on bone marrow monocytes.Ceacam1-/-mice over-produce IL-6 in response to an i.p. LPS challenge, resulting in prolonged surface temperature depression and overt diarrhea compared to their wild type counterparts. Intraperitoneal injection of a64Cu-labeled LPS, PET imaging agent shows confined localization to the peritoneal cavity, and fluorescent labeled LPS is taken up by myeloid splenocytes and muscle endothelial cells. While bone marrow monocytes and their progenitors (CD11b+Ly6G-) express IL-6 in the early response (<2 hours) to LPS in vitro, these cells are not detected in the bone marrow after in vivo LPS treatment due to their rapid and complete mobilization to the periphery. Notably, tissue macrophages are not involved in the early IL-6 response to LPS. In contrast to human monocytes, TLR4 is not expressed on murine bone marrow monocytes. Instead, the alternative LPS receptor RP105 is expressed and recruits MD1, CD14, Src, VAV1 and β-actin in response to LPS to produce IL-6. CEACAM1 negatively regulates RP105 signaling in monocytes by recruitment of SHP-1, resulting in the sequestration of pVAV1 and β-actin from RP105. This novel pathway and regulation of IL-6 producing by CEACAM1 defines a novel role for monocytes in the fever of mice to LPS.

AUTHOR SUMMARY

Fever is one of the most common signs of the immune response to pathogens. The fever response to LPS or endotoxin of gram-negative bacteria is mediated by the combined action of two cytokines, IL-1β and IL-6. Regulation of their production in response to LPS is an important area of investigation. While we previously showed that the regulation of IL-1β production in neutrophils is through the lymphocyte receptor CEACAM1, we were interested if a similar mechanism operated for IL-6. Using a mouse model in which the CEACAM1 gene was knocked out, we show that IL-6 is over-produced compared to normal mice, and that monocytes, rather than neutrophils were the principal IL-6 producing cells. Surprisingly, murine monocytes do not express TLR4, the most commonly studied receptor for LPS, but instead express the low affinity LPS receptor, RP105, a receptor common expressed on B-cells. Furthermore, we show that bone marrow monocytes are rapidly released into the blood and home to tissues throughout the body in response to LPS. These findings explain much of the confusion in the literature concerning the immediate source of IL-6 and the distinct differences between murine and human monocytes in their in responses to LPS.
Gut microbiota composition explains more variance in the host cardiometabolic risk than genetic ancestry
Authors: Guzmán-Castañeda Sandra J. , Ortega-Vega Esteban L. , Cuesta-Zuluaga Jacobo de la , Velásquez-Mejía Eliana P. , Rojas Winston , Bedoya Gabriel , Escobar Juan S.
Published: August 2018

Background

Cardiometabolic affections greatly contribute to the global burden of disease. The susceptibility to these conditions associates with the ancestral genetic composition and gut microbiota. However, studies explicitly testing associations between genetic ancestry and gut microbes are rare. We examined whether the ancestral genetic composition was associated with gut microbiota, and split apart the effects of genetic and non-genetic factors on host health.

Results

We performed a cross-sectional study of 441 community-dwelling Colombian mestizos from five cities. We characterized the host genetic ancestry using 40 ancestry informative markers and gut microbiota through 16S rRNA gene sequencing. We measured variables related to cardiometabolic health (adiposity, blood chemistry and blood pressure), diet (calories, macronutrients and fiber) and lifestyle (physical activity, smoking and medicament consumption). The ancestral genetic composition of the studied population was 67±6% European, 21±5% Native American and 12±5% African. While we found limited evidence of associations between genetic ancestry and gut microbiota or disease risk, we observed a strong link between gut microbes and cardiometabolic health. Multivariable-adjusted linear models indicated that gut microbiota was more likely to explain variance in host health than genetic ancestry. Further, we identified 9 OTUs associated with increased disease risk and 11 with decreased risk.

Conclusions

Gut microbiota seems to be more meaningful to explain cardiometabolic disease risk than genetic ancestry in this mestizo population. Our study suggests that novel ways to control cardiometabolic disease risk, through modulation of the gut microbial community, could be applied regardless of the genetic ancestry of the intervened population.