bluuebunny/crossref_metadata_2025 huggingface dataset:
15. Track allocation and case management
Authors: Sime Stuart
Published: August 2017

Judicial case management of civil litigation is one of the central planks of the Civil Procedure Rules 1998 (CPR). In exercising their powers to manage cases, the courts will be seeking to secure the overriding objective of the CPR of ensuring that cases are dealt with justly and at proportionate cost. This chapter discusses procedural judges; docketing; provisional track allocation; filing directions questionnaires; track allocation rules; notice of allocation; allocation directions; ADR and stays to allow for settlement; transfer to appropriate court; trial in the Royal Courts of Justice; changing tracks; and subsequent case management.
28. Fast track
Authors: Sime Stuart
Published: August 2017

The fast track provides a ‘no-frills’ procedure for medium-sized cases that do not justify the detailed and meticulous preparation appropriate for complex and important cases. Instead, cases allocated to this track will be progressed to trial within a short timescale after the filing of a defence. The fast track covers the majority of defended claims within the £10,000 to £25,000 monetary band. It also deals with non-monetary claims such as injunctions, declarations, and claims for specific performance which are unsuitable for the small claims track and do not require the more complex treatment of the multi-track. This chapter provides directions for cases allocated to the fast track; standard fast track timetable; agreed directions; varying the directions timetable; listing for trial; fast track trial; and costs in fast track cases.
31. Disclosure
Authors: Sime Stuart
Published: August 2017

The Civil Procedure Rules 1998 (CPR) require the parties to give advance notice to their opponents of all the material documentation in their control. This is done in two stages. At the first stage the parties send each other lists of documents, a process called ‘disclosure’. The second stage is ‘inspection’, which is the process by which the other side can request copies of documents appearing in the list of documents, typically with photocopies being provided by the disclosing party. This chapter discusses these processes. It covers lawyers’ and clients’ responsibilities; the stage when disclosure takes place; disclosure orders; standard disclosure; menu option disclosure; duty to search; list of documents; privilege; inspection; orders in support of disclosure; documents referred to in statements of case, etc.; admission of authenticity; and collateral use.
37. Sanctions
Authors: Sime Stuart
Published: August 2017

A court can impose sanctions to ensure that its case management directions and orders are complied with, and to retain control over the conduct of litigation. These range from adverse interim costs orders through to striking out the whole or part of the defaulting party’s statement of case. This chapter discusses sanctions for non-compliance with pre-action protocols, with the Civil Procedure Rules 1998 (CPR), and with directions; application for sanctions; non-compliance with an unless order; striking out; less serious immediate sanctions; extending time and correcting errors; and relief from sanctions and setting aside.
41. Judgments and orders
Authors: Sime Stuart
Published: August 2017

This chapter discusses the rules on judgments and orders. Although there is likely to be a delay between judgment being pronounced and the judgment being sealed and served, r 40.7(1) of the Civil Procedure Rules 1998 (CPR) provides that judgment in fact takes effect from the day it was given. After a judgment or order has been pronounced by the court, the next step is to have it drawn up. This chapter discusses settlements; orders made at hearings; form of judgments and orders; general rules relating to drawing up orders and judgments; and register of judgments.
43. Freezing injunctions
Authors: Sime Stuart
Published: August 2017

This chapter discusses the rules on freezing injunctions. A freezing injunction is an interim order restraining a party from removing assets located within the jurisdiction out of the country, or from dealing with assets whether they are located within the jurisdiction or not. The order is usually restricted to assets not exceeding the value of the claim. The main purpose of a freezing injunction is to prevent the injustice of a defendant’s assets being salted away so as to deprive the claimant of the fruits of any judgment that may be obtained.
14. Post-completion procedures
Authors: Abbey Robert , Richards Mark
Published: August 2017

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.
Civil Litigation 2017-2018
Authors: Cunningham-Hill Susan , Elder Karen
Published: August 2017

Civil Litigation introduces the processes and procedures involved in making and defending civil litigation claims. Following the chronological progression of a civil litigation claim, the volume offers practical guidance on advising clients whilst ensuring that the principles of the SRA Handbook and Code of Conduct 2011 are maintained. Diagrams at the beginning of chapters make clear the way in which the litigation procedure works and help with the understanding of the nature of the process as a whole. Examples provide a realistic context for learning, while issues of cost, best practice, and professional conduct are clearly highlighted. Alternative dispute resolution is given appropriate practical emphasis, and references to the Civil Procedure Rules throughout make sure that students are ready for life in practice. This edition has been revised to reflect the most up to date law and practice in all aspects of litigation practice. It also contains a new chapter on assessment of cost proceedings. An additional chapter on the Online Resource Centre provides a practical guide to court hearings.
5. Alternative dispute resolution
Authors: Cunningham-Hill Susan , Elder Karen
Published: August 2017

This chapter deals with the methods by which the Civil Procedure Rules (CPR) encourage parties to settle their disputes at an early stage and, ultimately, without proceeding trial. It also looks at the methods of dispute resolution that may be available, including a more detailed look at the most common ones. It covers the different types of alternative dispute resolution (ADR); the integration of ADR into the CPR; the philosophy of ADR; and a detailed look at mediation.
11. Drafting statements of case
Authors: Cunningham-Hill Susan , Elder Karen
Published: August 2017

Legal representatives will draft many statements of case in order to produce accurate, relevant, and compelling formal court documents. This chapter provides key formulae to help those new to practice produce competent statements of case. It explains the purpose of a statement of case; the standard requirements of a statement of case; the particulars of claim; the defence; additional claims; the reply; the Part 18 request for further information; and amendments to statements of case.
3. Money laundering
Authors: Wright Kathryn , Firth Clare , Crompton Lucy , Fox Helen , Seabridge Frances , Wigglesworth Susan , Smart Elizabeth
Published: August 2017

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 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.
11. Taxation of trusts and settlements
Authors: Wright Kathryn , Firth Clare , Crompton Lucy , Fox Helen , Seabridge Frances , Wigglesworth Susan , Smart Elizabeth
Published: August 2017

Settlements may be created by settlors in their lifetime, or by will, or they may arise under the intestacy rules. This chapter considers the tax implications of such settlements from the perspective of both the trustees and the beneficiaries. It considers each of the three main taxes separately: inheritance tax, capital gains tax, and income tax.
Criminal Litigation 2017-2018
Authors: Hannibal Martin , Mountford Lisa
Published: August 2017

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 2017

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 2017

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.
6. Challenging Unlawfully and Unfairly Obtained Evidence
Authors: Hannibal Martin , Mountford Lisa
Published: August 2017

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.
11. Prosecuting an Either-Way Offence
Authors: Hannibal Martin , Mountford Lisa
Published: August 2017

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; 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.
24. Youth Justice—Introduction
Authors: Hannibal Martin , Mountford Lisa
Published: August 2017

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.
26. Sentencing Young Offenders
Authors: Hannibal Martin , Mountford Lisa
Published: August 2017

This chapter considers the range of disposals available where a young offender admits the offence(s) or a finding of guilt is recorded against him. It discusses the principles which guide the sentencing of youths; the youth court’s sentencing powers; the adult magistrates’ court sentencing powers; the Crown Court’s sentencing powers; and sentencing a ‘dangerous’ young offender.
8. Formation of a limited company
Authors: Slorach J. Scott , Ellis Jason
Published: August 2017

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 2017

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.
10. Shareholders
Authors: Slorach J. Scott , Ellis Jason
Published: August 2017

This chapter focuses on the position of shareholders in relation to a company. It considers the following issues: registration of membership; the powers of shareholders in relation to their company; the legal protection given to shareholders by the rules of equity and by the Companies Act 2006; and the payment of dividends to shareholders.
11. Company finance
Authors: Slorach J. Scott , Ellis Jason
Published: August 2017

This chapter considers how companies raise money through a combination of equity and debt finance. It discusses the issuance of shares; share capital; financial assistance by company for purchase of shares; classes of shares; finance through borrowing; secured loans; registration of charges; priority of charges; remedies of debenture-holders; receivers; position of lenders and debenture-holders; and steps to be taken by a lender to a company.
15. Disclosure obligations of companies and company accounts
Authors: Slorach J. Scott , Ellis Jason
Published: August 2017

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.
18. The corporation tax system
Authors: Slorach J. Scott , Ellis Jason
Published: August 2017

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.
20. Taxation of distributions and debenture interest
Authors: Slorach J. Scott , Ellis Jason
Published: August 2017

This chapter deals with the taxation of distributions by way of dividend and of debenture interest. Both dividends and debenture interest are income returns on investments made in companies and, therefore, subject to income tax.
28. Limited liability partnerships
Authors: Slorach J. Scott , Ellis Jason
Published: August 2017

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.
Lawyers' Skills
Authors: Webb Julian , Maughan Caroline , Maughan Mike , Keppel-Palmer Marcus , Boon Andrew
Published: August 2017

Lawyers’ Skills helps students develop the legal skills required for successful practice in the modern solicitors’ firm. The book equips students with a solid understanding of the theory and concepts underpinning the key skills areas of legal writing and drafting, interviewing and advising, practical legal research, and advocacy, enabling students to develop, practise, and refine the legal skills they will depend on throughout their professional career. It goes beyond coverage of the assessed skills, providing guidance on a range of professional skills that should be mastered before going into practice, including effective time management, negotiation, and email etiquette. The inclusion of realistic examples from practice, tasks, and reflective exercises reflects the interactive nature of skills as a subject and encourages students to develop, practice, and refine their legal skills. Chapter summaries, diagrams, and self-test questions are also featured throughout and provide additional learning support to students. The text is essential reading for all LPC students and is also a useful source of reference for practitioners wishing to refresh their legal skills. After an introduction, the book covers: interviewing and advising; legal writing; drafting legal documents; legal research; practical problem-solving; negotiation; advocacy and the solicitor; managing your workload; and continuing your learning.
26. Immigration and asylum
Authors: Peers Steve
Published: August 2017

This chapter explores EU law on immigration and asylum. It first describes the basic legal framework for the adoption of EU rules on immigration and asylum. It then discusses the rules for visas and border control; irregular migration; legal migration; and asylum legislation.
From Classical Toxicology to Tox21: Some Critical Conceptual and Technological Advances in the Molecular Understanding of the Toxic Response Beginning From the Last Quarter of the 20th Century
Authors: Choudhuri Supratim , Patton Geoffrey W , Chanderbhan Ronald F , Mattia Antonia , Klaassen Curtis D
Published: August 2017

Toxicology has made steady advances over the last 60+ years in understanding the mechanisms of toxicity at an increasingly finer level of cellular organization. Traditionally, toxicological studies have used animal models. However, the general adoption of the principles of 3R (Replace, Reduce, Refine) provided the impetus for the development of in vitro models in toxicity testing. The present commentary is an attempt to briefly discuss the transformation in toxicology that began around 1980. Many genes important in cellular protection and metabolism of toxicants were cloned and characterized in the 80s, and gene expression studies became feasible, too. The development of transgenic and knockout mice provided valuable animal models to investigate the role of specific genes in producing toxic effects of chemicals or protecting the organism from the toxic effects of chemicals. Further developments in toxicology came from the incorporation of the tools of “omics” (genomics, proteomics, metabolomics, interactomics), epigenetics, systems biology, computational biology, and in vitro biology. Collectively, the advances in toxicology made during the last 30–40 years are expected to provide more innovative and efficient approaches to risk assessment. A goal of experimental toxicology going forward is to reduce animal use and yet be able to conduct appropriate risk assessments and make sound regulatory decisions using alternative methods of toxicity testing. In that respect, Tox21 has provided a big picture framework for the future. Currently, regulatory decisions involving drugs, biologics, food additives, and similar compounds still utilize data from animal testing and human clinical trials. In contrast, the prioritization of environmental chemicals for further study can be made using in vitro screening and computational tools.
Plant-Herbivore Interactions: A Case of an Extreme Generalist, the Two-Spotted Spider Mite Tetranychus urticae
Authors: Rioja Cristina , Zhurov Vladimir , Bruinsma Kristie , Grbic Miodrag , Grbic Vojislava
Published: August 2017

Plant-herbivore interactions evolved over long periods of time, resulting in an elaborate arms race between interacting species. While specialist herbivores evolved specific strategies to cope with the defenses of a limited number of hosts, our understanding of how generalist herbivores deal with the defenses of a plethora of diverse host plants is largely unknown. Understanding the interaction between a plant host and a generalist herbivore requires an understanding of the plant’s mechanisms aimed at defending itself and the herbivore’s mechanisms intended to counteract diverse defenses. In this review, we use the two-spotted spider mite (TSSM), Tetranychus urticae (Koch) as an example of a generalist herbivore, as this chelicerate pest has a staggering number of plant hosts. We first establish that the ability of TSSM to adapt to marginal hosts underlies its polyphagy and agricultural pest status. We then highlight our understanding of direct plant defenses against spider mite herbivory and review recent advances in uncovering mechanisms of spider mite adaptations to them. Finally, we discuss the adaptation process itself, as it allows TSSM to overcome initially effective plant defenses. A high-quality genome sequence and developing genetic tools, coupled with an ease of mite experimental selection to new hosts, make TSSM an outstanding system to study the evolution of host range, mechanisms of pest xenobiotic resistance and plant-herbivore interactions. In addition, knowledge of plant defense mechanisms that affect mite fitness are of practical importance, as it can lead to development of new control strategies against this important agricultural pest. In parallel, understanding mechanisms of mite counter adaptations to these defenses is required to maintain the efficacy of these control strategies in agricultural practices.
Characterization ofBotrytis cinereaIsolates From Grape Vineyards in China
Authors: Zhang Yanjie , Li Xinghong , Shen Fengying , Xu Huanping , Li Yaning , Liu Daqun
Published: August 2017

One hundred thirty-five single-spore isolates were collected from grape vineyards from 15 provinces or autonomous regions belonging to five viticulture climatic zones in China. All the isolates were identified as Botrytis cinerea based on their morphological and molecular characters. The 135 isolates were all heterothallic isolates. Seventy-one isolates belonged to the MAT1-1 type and 64 were characterized to MAT1-2 type. All the isolates studied belonged to Group II based on PCR-RFLP of the Bc-hch locus. The four TE genotypes, transposa, Boty-only, Flipper-only, and vacuma, comprised 51.9%, 33.3%, 10.4%, and 4.5%, respectively, of the total population. The frequency of transposa was highest in the total population and the most of any subpopulation (each viticulture climatic zone), and Boty-only was highest in warm areas (46.2%). Vacuma was mainly distributed in northern China, although in small amounts, and Flipper-only was mainly was distributed in humid tropical areas (42.9%). A microsatellite analysis of B. cinerea populations was performed to assess the genetic population structure. A total of 127 different MLGs were identified among 135 B. cinerea isolates, with a genotypic diversity of 0.9991. The transposa population isolates showed higher genetic diversity than other populations. Pairwise tests of genetic differentiation among four TE-type populations yielded generally low to high Gst values. All isolates belonged to two genetic clusters. The population microsatellite diversity and genetic structure had a certain correlation with the TE type and geographic origin. This is the first report of the genotypic diversity of B. cinerea isolates from grape vineyards across China.
Effect of Family-Based Education on the Quality of Life of Persons With Type 2 Diabetes: A Randomized Clinical Trial
Authors: Ebrahimi Hossein , Ashrafi Zahra , Rudsari Daryadokht Masroor , Parsayekta Zohreh , Haghani Hamid
Published: August 2017

Background:

Diabetes, a disease with increasing prevalence, requires comprehensive support from family members to ensure that sufferers are able to perform daily activities. The chronic nature of diabetes and its potential side effects impose high financial costs on patients and families, reduce their quality of life (QOL), and change the lifestyle of both patients and their families.

Purpose:

The aim of this study was to investigate the effects of a family-based training program on QOL in persons with Type 2 diabetes.

Methods:

A randomized clinical trial was used to assess the effects of an educational program on QOL both before and after 12 weeks of training for the experimental group (40 patients and families) and of standard care for the control group (40 patients) at an endocrinology clinic in a hospital in Iran. A demographic and social questionnaire and the QOL questionnaire for patients with Type 2 diabetes were used for data collection. The study groups were selected using block randomization sampling, and results were analyzed using descriptive and inferential statistics.

Results:

Both the experimental and control groups were homogeneousin terms of demographic characteristics and QOL before the intervention. The results of the mean score of patient QOL after the 12-week training program showed a significant difference between the scores for the two groups of patients in the physical, mental, social, economic, disease, and treatment dimensions. Moreover, the total score and QOL of the experimental group improved significantly after the patients’ families had attended the training program.

Conclusions/Implications for Practice:

Educating the families of patients was shown in this study to improve the QOL of the patient. The design of educational programs for nursing students must emphasize the role of the family in the care of chronic patients.
Antiviral Therapy in Patients With Chronic Hepatitis C-related Hepatocellular Carcinoma Responding to Palliative Treatment
Authors: Yu Jung-Hwan , Kim Ja Kyung , Lee Kwan Sik , Lee Jung Il
Published: August 2017

Background/Aim:

Advances in hepatitis C virus (HCV) treatment offer high sustained virologic response rates with minimal side-effects. However, benefits of eradicating HCV in hepatocellular carcinoma (HCC) patients whose life expectancies are hard to be determined after palliative therapy still needs to be assessed. This study sought to evaluate prognostic factors for survival in HCV-related HCC patients that responded to the palliative HCC treatment to speculate whether treating HCV would be beneficial in these patients.

Materials and Methods:

In this retrospective cohort study, the medical records of 97 patients that showed complete or partial response to the initial HCC treatment were included.

Results:

Receiving HCV treatment [hazard ratio (HR), 0.244; 95% confidence interval (CI), 0.075-0.788; P=0.018] increased the survival, whereas partial response to the initial HCC treatment (HR, 1.795; 95% CI, 1.071-3.008; P=0.026) and increased Child-Turcotte-Pugh score (HR, 2.017; 95% CI, 1.196-3.403; P=0.009) reduced the survival. From 97 patients, 16 patients were eventually treated for HCV. The mean time from the last HCC therapy to HCV treatment was 16.9±13.9 months. The median time of follow-up after HCV treatment was 10.0 months (range, 3 to 47 mo). Among the HCV-treated patients 3 patients had HCC recurred. The time to progression in HCV-treated patients were significantly longer than those untreated for HCV (P=0.032).

Conclusions:

Although treating HCV in HCC patient that undergo noncurative HCC treatment is still debatable, this study results carefully suggest that HCV-related HCC patients that responded to the initial HCC palliative treatment might benefit from HCV treatment.
Undifferentiated Endometrial Carcinomas Show Frequent Loss of Core Switch/Sucrose Nonfermentable Complex Proteins
Authors: Köbel Martin , Hoang Lien N. , Tessier-Cloutier Basile , Meng Bo , Soslow Robert A. , Stewart Colin J.R. , Lee Cheng-Han
Published: August 2017

Undifferentiated endometrial carcinoma is an aggressive type of endometrial carcinoma that typically presents with advanced stage disease and rapid clinical progression. In contrast to dedifferentiated endometrial carcinoma, undifferentiated carcinoma lacks a concurrent differentiated (typically low-grade endometrioid) carcinoma component, though the undifferentiated component of dedifferentiated carcinoma is similar histologically and immunophenotypically to pure undifferentiated carcinoma. We recently identified 3 mutually exclusive mechanisms of switch/sucrose nonfermentable (SWI/SNF) complex inactivation (BRG1 inactivation, INI1 inactivation or ARID1A/ARID1B co-inactivation) that are associated with histologic dedifferentiation in the majority of dedifferentiated endometrial carcinoma. In the current study, we aimed to determine by immunohistochemistry whether these patterns of SWI/SNF inactivation also occur in undifferentiated endometrial carcinomas. Of the 34 undifferentiated carcinomas examined, 17 (50%) exhibited SWI/SNF complex inactivation, with 11 tumors showing complete loss of both ARID1A and ARID1B, 5 showing complete loss of BRG1 and 1 showing complete loss of INI1. Ten of the remaining 17 undifferentiated carcinomas showed the following alterations: 5 tumors (15%) showed loss of ARID1A only with intact ARID1B, BRG1, and INI1 expression, 4 tumors (12%) showed mutated patterns of p53 staining with intact SWI/SNF protein expression, and 1 tumor (3%) harbored a POLE exonuclease domain mutation (P286R). SWI/SNF complex-inactivated tumors presented more frequently with extrauterine disease spread than those with intact expression (88% vs. 41%, respectively). In addition, patients with SWI/SNF complex-inactivated tumors had a significantly worse disease-specific survival (P=0.02). The findings here demonstrate frequent SWI/SNF complex inactivation in undifferentiated endometrial carcinomas, which has future implications regarding therapies that target chromatin remodelling and epigenetic control.
Inflammatory Stroma of Lymphoepithelioma-like Carcinoma of the Cervix: Immunohistochemical Study of 3 Cases and Review of the Literature
Authors: Philippe Amandine , Rassy Marc , Craciun Ligia , Naveaux Céline , Willard-Gallo Karen , Larsimont Denis , Veys Isabelle
Published: August 2017

The aim of this study was to characterize the inflammatory infiltrate of the lymphoepithelioma-like carcinoma, a variant of squamous cell carcinoma clinically associated with a good prognosis. Immunohistochemistry was used to characterize 3 cases of lymphoepithelioma-like carcinoma in the uterine cervix, diagnosed over a period of 3 yr. The patients were between 30 and 50 yr old. Their cervical smears had shown atypical squamous cells of unknown significance or high-grade squamous intraepithelial lesions, and the initial cervical biopsy showed high-grade cervical intraepithelial neoplasia (CIN3) or squamous cell carcinoma. All patients underwent a Wertheim operation, 2 of which were preceded by a cervicectomy. Microscopically, all tumors were characterized by poorly defined sheets of undifferentiated squamous cells with a syncytial pattern and a dense background of infiltrating lymphocytes. Immunohistochemical analysis revealed that the lymphocytes were predominantly CD3+ and CD8+ T cells. The tumor lobules contained isolated CD8+ T cells, whereas CD4+ T cells and CD20+ B cells surrounded the tumor lobules. CD56+ NK cells and CD79+ B cells were scattered in the tumor tissue. An in situ hybridization staining for Epstein-Barr encoding region was negative but all cases were immunohistochemically positive for P16. Follow-up varied between 2 mo and 2.7 yr. All 3 patients were disease free. Lymphoepithelioma-like carcinoma of the uterine cervix is a variant of squamous cell carcinoma, known for its better prognosis. The good prognosis of this tumor is potentially explained by the high levels of infiltrating CD8+ T cells.
Serial quantification of brain oxygenation in acute stroke using streamlined-qBOLD
Authors: Stone Alan J , Harston George WJ , Carone Davide , Okell Thomas W , Kennedy James , Blockley Nicholas P
Published: August 2017

It has been proposed that metabolic markers of baseline brain oxygenation have a role to play in the early identification of the ischemic penumbra. Streamlined-qBOLD is a magnetic resonance imaging technique that does not require exogenous contrast. It is a refinement of the quantitative BOLD methodology that provides a simplified approach to mapping and quantifying baseline brain oxygenation related parameters (reversible transverse relaxation rate (R2′), deoxygenated blood volume (DBV) and deoxyhaemoglobin concentration ([dHb])) in a clinically relevant manner. Streamlined-qBOLD was applied to an exploratory cohort of acute stroke patients in a serial imaging study. Detailed voxel-level analysis was used to quantify the metabolic profile of ischaemic tissue on presentation and investigate these metrics in relation to tissue outcome. Individual patient examples illustrate the appropriate interpretation of R2′, DBV and [dHb] in acute stroke and demonstrate the ability of this method to deliver regional information related to oxygen metabolism in the ischaemic tissue. Regional analysis confirms that R2′, DBV and [dHb] vary between regions of ischaemia with different tissue outcomes.
Imaging specific cellular glycan structures using glycosyltransferases via click chemistry
Authors: Wu Zhengliang L , Person Anthony , Anderson Matthew , Burroughs Barbara , Tatge Timothy , Zou Yonglong , Wang Liangchun , Geders Todd , Sackstein Robert
Published: August 2017

Heparan sulfate (HS) is a polysaccharide fundamentally important for biologically activities. T/Tn antigens are universal carbohydrate cancer markers. Here, we report the specific imaging of these carbohydrates using a mesenchymal stem cell line and human umbilical vein endothelial cells (HUVEC). The staining specificities were demonstrated by comparing imaging of different glycans and validated by either removal of target glycans, which results in loss of signal, or installation of target glycans, which results in gain of signal. As controls, representative key glycans including O-GlcNAc, lactosaminyl glycans and hyaluronan were also imaged. HS staining revealed novel architectural features of the extracellular matrix (ECM) of HUVEC cells. Results from T/Tn antigen staining suggest that O-GalNAcylation is a rate-limiting step for O-glycan synthesis. Overall, these highly specific approaches for HS and T/Tn antigen imaging should greatly facilitate the detection and functional characterization of these biologically important glycans.
Neurons in primate entorhinal cortex represent gaze position in multiple spatial reference frames
Authors: Meister Miriam L. R. , Buffalo Elizabeth A.
Published: August 2017

Primates predominantly rely on vision to gather information from the environment, and neurons representing visual space and gaze position are found in many brain areas. Within the medial temporal lobe, a brain region critical for memory, neurons in the entorhinal cortex of macaque monkeys exhibit spatial selectivity for gaze position. Specifically, the firing rate of single neurons reflects fixation location within a visual image (Killian et al., 2012). In the rodents, entorhinal cells such as grid cells, border cells, and head direction cells show spatial representations aligned to visual environmental features instead of the body (Hafting et al., 2005, Solstad et al. 2008, Sargolini et al., 2006, Diehl et al., 2017). However, it is not known whether similar allocentric representations exist in primate entorhinal cortex. Here, we recorded neural activity in the entorhinal cortex in two male rhesus monkeys during a naturalistic, free-viewing task. Our data reveal that a majority of entorhinal neurons represent gaze position, and that simultaneously recorded neurons exhibit distinct spatial reference frames, with some neurons aligning to the visual image and others aligning to the monkey’s head position. Our results also show that entorhinal neural activity can be used to predict gaze position with a high degree of accuracy. These findings demonstrate that visuospatial representation is a fundamental property of entorhinal neurons in primates, and suggest that entorhinal cortex may support relational memory and motor planning by coding attentional locus in distinct, behaviorally relevant frames of reference.

Significance Statement

The entorhinal cortex, a brain area important for memory, shows striking spatial activity in rodents through grid cells, border cells, head direction cells, and nongrid spatial cells. The majority of entorhinal neurons signal the location of a rodent relative to visual environmental cues, representing the location of the animal relative to space in the world instead of the body. Recently, our laboratory found that entorhinal neurons can signal location of gaze while a monkey visually explores images. Here, we report that spatial entorhinal neurons are widespread in the monkey, and these neurons are capable of showing a world-based spatial reference frame locked to the bounds of explored images. These results help connect the extensive findings in rodents to the primate.
Parallel Factor ChIP Provides Essential Internal Control for Quantitative Differential ChIP-Seq
Authors: Guertin Michael J , Cullen Amy E , Markowetz Florian , Holding Andrew N
Published: August 2017

A key challenge in quantitative ChIP-seq is the normalisation of data in the presence of genome-wide changes in occupancy. Analysis-based normalisation methods were developed for transcriptomic data and these are dependent on the underlying assumption that total transcription does not change between conditions. For genome-wide changes in transcription factor binding, these assumptions do not hold true. The challenges in normalisation are confounded by experimental variability during sample preparation, processing, and recovery.

We present a novel normalisation strategy utilising an internal standard of unchanged peaks for reference. Our method can be readily applied to monitor genome-wide changes by ChIP-seq that are otherwise lost or misrepresented through analytical normalisation. We compare our approach to normalisation by total read depth and two alternative methods that utilise external experimental controls to study transcription factor binding. We successfully resolve the key challenges in quantitative ChIP-seq analysis and demonstrate its application by monitoring the loss of Estrogen Receptor-alpha (ER) binding upon fulvestrant treatment, ER binding in response to estrodiol, ER mediated change in H4K12 acetylation and profiling ER binding in Patient-Derived Xenographs. This is supported by an adaptable pipeline to normalise and quantify differential transcription factor binding genome-wide and generate metrics for differential binding at individual sites.

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GRAPHICAL ABSTRACT
Generation, selection and transcriptomic profiling of human neuromesodermal and spinal cord progenitors in vitro
Authors: Verrier Laure , Davidson Lindsay , Gierliński Marek , Storey Kate G.
Published: August 2017

Robust protocols for directed differentiation of human pluripotent cells are needed to establish the extent to which mechanisms operating in model organisms are relevant to our own development. Recent work in vertebrate embryos has identified neuromesodermal progenitors as a bipotent cell population that contributes to paraxial mesoderm and spinal cord. However, precise protocols forin vitrodifferentiation of human neuromesodermal progenitors are lacking. Informed by signalling activities during spinal cord generation in amniote embryos, we show here that transient dual-SMAD inhibition, together with retinoic acid (dSMADi-RA), provides rapid and reproducible induction of human spinal cord progenitors from neuromesodermal progenitors. We use CRISPR-Cas9 to engineer a GFP-reporter for a neuromesodermal progenitor-associated transcription factorNkx1.2in human embryonic stem cells, to facilitate selection of this cell population. RNA-sequencing (RNA-Seq) was then used to identify human and conserved neuromesodermal progenitor transcriptional signatures, validate this differentiation protocol and implicate new pathways and processes in human neural differentiation. This optimised protocol, novel reporter line and transcriptomic data are useful resources with which to dissect cellular and molecular mechanisms regulating the generation of human spinal cord, allow scale-up of distinct cell populations for global analyses, including proteomic, biochemical and chromatin interrogation and open up translational opportunities.
HPeV-3 predominated amongParechovirus Apositive infants in the summer of 2013-2014 in Queensland, Australia
Authors: McNeale Donna , Wang Claire Y.T. , Arden Katherine E. , Mackay Ian M.
Published: August 2017

Parechoviruses (HPeV) are not new viruses and are found in the respiratory tract and central nervous system of children and adults in conjunction with a range of acute illnesses. During an Australian outbreak of HPeV in the summer of 2013, we performed PCR-based screening and genotyping to determine whether ill Queensland infants were infected by HPeV. HPeVs were detected among 25/62 samples, identified as HPeV-3 from 23 that could be genotyped. These variants closely matched those occurring during and after the 2013 HPeV season. The inclusion of HPeV screening should be considered among acutely ill young infants during summer.

Highlights

HPeV-3 was the most commonParechovirus Agenotype in Queensland summer of 2013/14

HPeV testing should be routine among testing of infants with acute CNS - related symptoms

HPeV is a seasonal virus

Subgenomic phylogenetic analysis of HPeVs can be confounded by the presence of recombination
Selection-like biases emerge in population models with recurrent jackpot events
Authors: Hallatschek Oskar
Published: August 2017

Evolutionary dynamics driven out of equilibrium by growth, expansion or adaptation often generate a characteristically skewed distribution of descendant numbers: The earliest, the most advanced or the fittest ancestors have exceptionally large number of descendants, which Luria and Delbrueck called "jackpot" events. Here, we show that recurrent jackpot events generate a deterministic bias favoring majority alleles, which is equivalent to an effective frequency-dependent selection (proportional to the log ratio of the frequencies of mutant and wild-type alleles). This "fictitious" selection force results from the fact that majority alleles tend to sample deeper into the tail of the descendant distribution. The flipside of this sampling effect is the rare occurrence of large frequency hikes in favor of minority alleles, which ensures that the allele frequency dynamics remains neutral overall unless genuine selection is present. The limiting allele frequency process is dual to the Bolthausen-Sznitman coalescent and has a particularly simple representation in terms of the logarithm of the mutant frequency. The resulting picture of a selection-like bias compensated by rare big jumps allows for an intuitive understanding of allele frequency trajectories and enables the exact calculation of transition densities for a range of important scenarios, including population size changes and different forms of selection. The fixation of unconditionally beneficial mutations is shown to be exponentially suppressed and balancing selection can maintain diversity only if the population size is large enough. We briefly discuss analogous effects in disordered complex systems, where sampling-induced biases can be viewed as ergodicity breaking driving forces.
Resolution of Reprogramming Transition States by Single Cell RNA-Sequencing
Authors: Guo Lin , Wang Xiaoshan , Gao Mingwei , Lin Lihui , Kuang Junqi , Mai Yuanbang , Wu Fang , Liu He , Yang Jiaqi , Chu Shilong , Song Hong , Liu Yujian , Liu Jiadong , Wang Jinyong , Pan Guangjin , Hutchins Andrew P. , Liu Jing , Chen Jiekai , Pei Duanqing
Published: August 2017

The Yamanaka factors convert mouse embryonic fibroblasts (MEFs) into induced pluripotent stem cells (iPSCs) through a highly heterogeneous process. Here we profile single cells undergoing an optimized 7-day reprogramming process and show that cells start reprogramming relatively in sync, but diverge into two branches around day 2. The first branch of cells expressingCd34/Fxyd5/Pscabecome nonpluripotent. The second one contains cells that are firstOct4+, thenDppa5a+ and pluripotent. We show that IFN-γ blocks this late transition. Our results reveal the heterogeneous nature of somatic cell reprogramming, identifyDppa5aas a marker for pluripotent and innate immunity as a potential barrier for reprogramming.

One Sentence Summary

Single cell RNA sequencing reveals a continuum of cell fates from somatic to pluripotent andDppa5aas a marker for chimera-competent iPSCs.
Synergy of Quorum Quenching Enzyme and Quorum Sensing Inhibitor in InhibitingP.aeruginosaQuorum Sensing
Authors: Fong July , Zhang Chaodong , Yang Renliang , Boo Zhao Zhi , Tan Soon Keat , Nielsen Thomas E. , Givskov Michael , Wu Bin , Su Haibin , Yang Liang
Published: August 2017

The threat of antibiotic resistant bacteria has called for alternative antimicrobial strategies that would mitigate the increase of classical resistance mechanism. Many bacteria employ quorum sensing (QS) to govern the production of virulence genes and formation of drug-resistance biofilms. Blocking QS mechanisms have proven to be a functional alternative to conventional antibiotic control of infections. The concepts of quorum sensing inhibitors (QSI) and quorum quenching enzymes (QQ) have been investigated separately. In this study however, we simulated the synergistic effect of QQ and QSI in blocking bacterial QS. This effect was validated by experiments using AiiA and G1 as QQ and QSI respectively onPseudomonas aeruginosaLasR/I and RhlR/I QS circuits. The combination of a QQ and a QSI almost completely blocked theP. aeruginosaQSlasandrhlsystem. Our findings provided a potential application strategy for bacterial QS disruption.