bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chimeric Antigen Receptor T Cells Guided by the Single-Chain Fv of a Broadly Neutralizing Antibody Specifically and Effectively Eradicate Virus Reactivated from Latency in CD4
+
T Lymphocytes Isolated from HIV-1-Infected Individuals Receiving Suppressive Combined Antiretroviral Therapy
Authors: Liu Bingfeng , Zou Fan , Lu Lijuan , Chen Cancan , He Dalian , Zhang Xu , Tang Xiaoping , Liu Chao , Li Linghua , Zhang Hui 
Published: August 2016

ABSTRACT

Despite the advent of combined antiretroviral therapy (cART), the persistence of viral reservoirs remains a major barrier to curing human immunodeficiency virus type 1 (HIV-1) infection. Recently, the shock and kill strategy, by which such reservoirs are eradicated following reactivation of latent HIV-1 by latency-reversing agents (LRAs), has been extensively practiced. It is important to reestablish virus-specific and reliable immune surveillance to eradicate the reactivated virus-harboring cells. In this report, we attempted to reach this goal by using newly developed chimeric antigen receptor (CAR)-T cell technology. To generate anti-HIV-1 CAR-T cells, we connected the single-chain variable fragment of the broadly neutralizing HIV-1-specific antibody VRC01 to a third-generation CAR moiety as the extracellular and intracellular domains and subsequently transduced this into primary CD8
+
T lymphocytes. We demonstrated that the resulting VC-CAR-T cells induced T cell-mediated cytolysis of cells expressing HIV-1 Env proteins and significantly inhibited HIV-1 rebound after removal of antiviral inhibitors in a viral infectivity model in cell culture that mimics the termination of the cART in the clinic. Importantly, the VC-CAR-T cells also effectively induced the cytolysis of LRA-reactivated HIV-1-infected CD4
+
T lymphocytes isolated from infected individuals receiving suppressive cART. Our data demonstrate that the special features of genetically engineered CAR-T cells make them a particularly suitable candidate for therapeutic application in efforts to reach a functional HIV cure.

IMPORTANCE
The presence of latently infected cells remains a key obstacle to the development of a functional HIV-1 cure. Reactivation of dormant viruses is possible with latency-reversing agents, but the effectiveness of these compounds and the subsequent immune response require optimization if the eradication of HIV-1-infected cells is to be achieved. Here, we describe the use of a chimeric antigen receptor, comprised of T cell activation domains and a broadly neutralizing antibody, VRC01, targeting HIV-1 to treat the infected cells. T cells expressing this construct exerted specific cytotoxic activity against wild-type HIV-1-infected cells, resulting in a dramatic reduction in viral rebound
in vitro
, and showed persistent effectiveness against reactivated latently infected T lymphocytes from HIV-1 patients receiving combined antiretroviral therapy. The methods used in this study constitute an improvement over existing CD4-based CAR-T technology and offer a promising approach to HIV-1 immunotherapy.
Human Herpesvirus 6B Downregulates Expression of Activating Ligands during Lytic Infection To Escape Elimination by Natural Killer Cells
Authors: Schmiedel Dominik , Tai Julie , Levi-Schaffer Francesca , Dovrat Sarah , Mandelboim Ofer 
Published: August 2016

ABSTRACTTheHerpesviridaefamily consists of eight viruses, most of which infect a majority of the human population. One of the less-studied members is human herpesvirus 6 (HHV-6) (Roseolovirus), which causes a mild, well-characterized childhood disease. Primary HHV-6 infection is followed by lifelong latency. Reactivation frequently occurs in immunocompromised patients, such as those suffering from HIV infection or cancer or following transplantation, and causes potentially life-threatening complications. In this study, we investigated the mechanisms that HHV-6 utilizes to remain undetected by natural killer (NK) cells, which are key participants in the innate immune response to infections. We revealed viral mechanisms which downregulate ligands for two powerful activating NK cell receptors: ULBP1, ULBP3, and MICB, which trigger NKG2D, and B7-H6, which activates NKp30. Accordingly, this downregulation impaired the ability of NK cells to recognize HHV-6-infected cells. Thus, we describe for the first time immune evasion mechanisms of HHV-6 that protect lytically infected cells from NK elimination.IMPORTANCEHuman herpesvirus 6 (HHV-6) latently infects a large portion of the human population and can reactivate in humans lacking a functional immune system, such as cancer or AIDS patients. Under these conditions, it can cause life-threatening diseases. To date, the actions and interplay of immune cells, and particularly cells of the innate immune system, during HHV-6 infection are poorly defined. In this study, we aimed to understand how cells undergoing lytic HHV-6 infection interact with natural killer (NK) cells, innate lymphocytes constituting the first line of defense against viral intruders. We show that HHV-6 suppresses the expression of surface proteins that alert the immune cells by triggering two major receptors on NK cells, NKG2D and NKp30. As a consequence, HHV-6 can replicate undetected by the innate immune system and potentially spread infection throughout the body. This study advances the understanding of HHV-6 biology and the measures it uses to successfully escape immune elimination.
Stimulation of the Replication of ICP0-Null Mutant Herpes Simplex Virus 1 and pp71-Deficient Human Cytomegalovirus by Epstein-Barr Virus Tegument Protein BNRF1
Authors: Lu Yongxu , Orr Anne , Everett Roger D. 
Published: August 2016

ABSTRACT
It is now well established that several cellular proteins that are components of promyelocytic leukemia nuclear bodies (PML NBs, also known as ND10) have restrictive effects on herpesvirus infections that are countered by viral proteins that are either present in the virion particle or are expressed during the earliest stages of infection. For example, herpes simplex virus 1 (HSV-1) immediate early (IE) protein ICP0 overcomes the restrictive effects of PML-NB components PML, Sp100, hDaxx, and ATRX while human cytomegalovirus (HCMV) IE protein IE1 targets PML and Sp100, and its tegument protein pp71 targets hDaxx and ATRX. The functions of these viral regulatory proteins are in part interchangeable; thus, both IE1 and pp71 stimulate the replication of ICP0-null mutant HSV-1, while ICP0 increases plaque formation by pp71-deficient HCMV. Here, we extend these studies by examining proteins that are expressed by Epstein-Barr virus (EBV). We report that EBV tegument protein BNRF1, discovered by other investigators to target the hDaxx/ATRX complex, increases the replication of both ICP0-null mutant HSV-1 and pp71-deficient HCMV. In addition, EBV protein EBNA-LP, which targets Sp100, also augments ICP0-null mutant HSV-1 replication. The combination of these two EBV regulatory proteins had a greater effect than each one individually. These findings reinforce the concept that disruption of the functions of PML-NB proteins is important for efficient herpesvirus infections.

IMPORTANCE
Whether a herpesvirus initiates a lytic infection in a host cell or establishes quiescence or latency is influenced by events that occur soon after the viral genome has entered the host cell nucleus. Certain cellular proteins respond in a restrictive manner to the invading pathogen's DNA, while viral functions are expressed that counteract the cell-mediated repression. One aspect of cellular restriction of herpesvirus infections is mediated by components of nuclear structures known as PML nuclear bodies (PML NBs), or ND10. Members of the alpha-, beta-, and gammaherpesvirus families all express proteins that interact with, degrade, or otherwise counteract the inhibitory effects of various PML NB components. Previous work has shown that there is the potential for a functional interchange between the viral proteins expressed by alpha- and betaherpesviruses, despite a lack of obvious sequence similarity. Here, this concept is extended to include a member of the gammaherpesviruses.
The Antiviral Alkaloid Berberine Reduces Chikungunya Virus-Induced Mitogen-Activated Protein Kinase Signaling
Authors: Varghese Finny S. , Thaa Bastian , Amrun Siti Naqiah , Simarmata Diane , Rausalu Kai , Nyman Tuula A. , Merits Andres , McInerney Gerald M. , Ng Lisa F. P. , Ahola Tero 
Published: August 2016

ABSTRACT

Chikungunya virus (CHIKV) has infected millions of people in the tropical and subtropical regions since its reemergence in the last decade. We recently identified the nontoxic plant alkaloid berberine as an antiviral substance against CHIKV in a high-throughput screen. Here, we show that berberine is effective in multiple cell types against a variety of CHIKV strains, also at a high multiplicity of infection, consolidating the potential of berberine as an antiviral drug. We excluded any effect of this compound on virus entry or on the activity of the viral replicase. A human phosphokinase array revealed that CHIKV infection specifically activated the major mitogen-activated protein kinase (MAPK) signaling pathways extracellular signal-related kinase (ERK), p38 and c-Jun NH
2
-terminal kinase (JNK). Upon treatment with berberine, this virus-induced MAPK activation was markedly reduced. Subsequent analyses with specific inhibitors of these kinases indicated that the ERK and JNK signaling cascades are important for the generation of progeny virions. In contrast to specific MAPK inhibitors, berberine lowered virus-induced activation of all major MAPK pathways and resulted in a stronger reduction in viral titers. Further, we assessed the
in vivo
efficacy of berberine in a mouse model and measured a significant reduction of CHIKV-induced inflammatory disease. In summary, we demonstrate the efficacy of berberine as a drug against CHIKV and highlight the importance of the MAPK signaling pathways in the alphavirus infectious cycle.

IMPORTANCE
Chikungunya virus (CHIKV) is a mosquito-borne virus that causes severe and persistent muscle and joint pain and has recently spread to the Americas. No licensed drug exists to counter this virus. In this study, we report that the alkaloid berberine is antiviral against different CHIKV strains and in multiple human cell lines. We demonstrate that berberine collectively reduced the virus-induced activation of cellular mitogen-activated protein kinase signaling. The relevance of these signaling cascades in the viral life cycle was emphasized by specific inhibitors of these kinase pathways, which decreased the production of progeny virions. Berberine significantly reduced CHIKV-induced inflammatory disease in a mouse model, demonstrating efficacy of the drug
in vivo
. Overall, this work makes a strong case for pursuing berberine as a potential anti-CHIKV therapeutic compound and for exploring the MAPK signaling pathways as antiviral targets against alphavirus infections.
Tectonic settings of continental crust formation: Insights from Pb isotopes in feldspar inclusions in zircon
Authors: Delavault Hélène , Dhuime Bruno , Hawkesworth Chris J. , Cawood Peter A. , Marschall Horst ,   and the Edinburgh Ion Microprobe Facility
Published: August 2016

Abstract
Most crustal rocks derive from preexisting crust, and so the composition of newly generated (juvenile) continental crust, and hence the tectonic settings of its formation, have remained difficult to determine, especially for the first billion years of Earth’s evolution. Modern primitive mantle–derived magmas have distinct U/Pb ratios, depending on whether they are generated in intraplate (mean U/Pb = 0.37) or in subduction settings (mean U/Pb = 0.10). The U/Pb ratio can therefore be used as a proxy for the tectonic settings in which juvenile continental crust is generated. This paper presents a new way to see back to the U/Pb ratios of juvenile continental crust that formed hundreds to thousands of millions of years ago, based on ion probe analysis of Pb isotopes in alkali feldspar and plagioclase inclusions within well-dated zircons. Pb isotope data are used to calculate the time-integrated U/Pb ratios (i.e., 238U/204Pb = µ) for the period between the Hf model age and the U-Pb crystallization age of the zircons. These time-integrated ratios reflect the composition of the juvenile continental crust at the time it was extracted from the mantle, and so they can be used as a proxy for the tectonic setting of formation of that crust. Two test samples with Proterozoic Hf model ages and Paleozoic crystallization ages have feldspar inclusions with measured Pb isotope ratios that overlap within analytical error for each sample. Sample Z7.3.1 from Antarctica has Pb isotope ratios (mean 206Pb/204Pb = 16.88 ± 0.08, 1σ) that indicate it was derived from source rocks with low U/Pb ratios (∼0.11), similar to those found in subduction-related settings. Sample Temora 2 from Australia has more radiogenic Pb isotope ratios (mean 206Pb/204Pb = 19.11 ± 0.23, 1σ) indicative of a source with higher U/Pb ratios (∼0.36), similar to magmas generated in intraplate settings. Analysis of detrital populations with a range of Hf model ages (e.g., Hadean to Phanerozoic), and for which zircons and their inclusions represent the only archive of their parent magmas, should ultimately open new avenues to our understanding of the formation and the evolution of the continental crust through time.
The outcome of antenatal ultrasound diagnosed anomalies of the kidney and urinary tract in a large Danish birth cohort
Authors: Andrés-Jensen Liv , Jørgensen Finn Stener , Thorup Jorgen , Flachs Julie , Madsen Jan Lysgaard , Maroun Lisa Leth , Nørgaard Pernille , Vinicoff Pablo Gustavo , Olsen Beth Härstedt , Cortes Dina 
Published: August 2016

ObjectiveAntenatal ultrasound diagnosed anomalies of the kidney and urinary tract (AUDAKUT) are reported in 0.3%–5% on prenatal ultrasound (US) and 0.3%–4.5% on postnatal US. The anterior-posterior diameter of the renal pelvis (APD) is an essential measurement. Series with low threshold values of APD prenatally and postnatally will include healthy infants. It is important to avoid follow-up of such infants.InterventionsIn 2006, new Danish guidelines for AUDAKUT were introduced.Aim of studyInvestigations of incidences and type of AUDAKUT based on Danish guidelines, including long-term follow-up.DesignCohort study.SettingCopenhagen University Hospital Hvidovre and Copenhagen University Hospital Rigshospitalet, Denmark.PatientsConsecutive cases with AUDAKUT in the second and third trimesters, which were either terminated before 22 completed weeks of gestation or born in the 8-year period January 2006–December 2013. Patients were followed until June 2014.Results50 193 live born children and 24 terminated fetuses (0.05%) were included. The prevalence of AUDAKUT was only 0.39% prenatally, 0.29% at first postnatal US and 0.22% at the end of follow-up, including terminated cases. The greater the prenatal and postnatal APD, the higher risk of febrile urinary tract infection (fUTI) and surgical intervention, and lower probability of resolution. 25% of the identified patients had fUTI and/or surgery.ConclusionsWe recommend threshold values of APD at least 10 mm in the third trimester and in general at least 12 mm at first postnatal US for intensive follow-up. In this largest to date unselected birth cohort of AUDAKUT, the incidences of clinically significant AUDAKUT were in the lowest range of those previously published.
AN AUDIT OF PAEDIATRIC VANCOMYCIN DOSING
Authors: Mohsin-Shaikh Soomal , Lumb Poonam 
Published: August 2016

AimTo audit whether a new paediatric vancomycin guideline is being adhered to and if therapeutic levels are being achieved.MethodData on doses, age, weight, vancomycin levels, time taken and renal function were collected prospectively by reviewing drug charts of paediatric patients on vancomycin. The patients were followed for their whole vancomycin journey in order to observe if the guidelines were followed throughout. Data were collected between 7th and 30th January 2015. The data were analysed using an excel spreadsheet.Standards▸ 100% of patients <1 month without renal failure should be prescribed an initial dose of 15 mg/kg three times a day▸ 100% of patients ≥1 month without renal failure should be prescribed an initial dose of 20 mg/kg three times a day▸ 100% of patients of all ages with renal impairment (defined as Glomerular filtration rate <50 ml/min) should be prescribed a single dose of 10 mg/kg▸ 90% of patients should have their vancomycin levels taken at the correct time (pre-third dose)▸ 80% of the third dose trough levels should be in range (10–15 mg/L)▸ In 90% of patients with levels out of range, appropriate action should be taken to correct their levels.ResultsData from 15 patients were collected resulting in 62 vancomycin levels.Three of six standards were met. Standards 1 and 3 could not be assessed as no patients were under the age of 1 month or had renal impairment. 100% patients were initiated on the correct staring dose meeting standard 2. One patient excluded from this standard as a clinical decision was made to start the patient on a lower starting dose of 15 mg/kg three times a day due to previous high levels. 90% of vancomycin levels had been taken at the correct time (pre-third dose) thus standard 4 was achieved. However there were 6 occasions when the levels were taken post-third dose or taken pre-maturely. These levels were not in range. Only 33% of patients had the initial level within range for standard 5; after a dose change a further 31% were in range.For standard 6, 93% of actions taken by doctors when the vancomycin levels came back out of range were correct. This standard was achieved.ConclusionThis audit has shown that the guidelines are being followed but the paediatric dosing of vancomycin requires modification to achieve therapeutic levels. Limitations of the audit included low patient numbers, standard 1 and 3 could not be assessed and an assumption was made that all the levels documented were taken at the correct time, unless stated. Not enough data were collected to make suggestions based on different ages. An option would be to follow recommendation that frequency of dosing is changed from three to four times a day.1 A continuous infusion of vancomycin could also be considered.
THE ROLE OF THE PHARMACIST IN PAEDIATRIC PALLIATIVE CARE
Authors: Khan Jumana , Gaze Sian , Tomlin Stephen 
Published: August 2016

AimTo explore what involvement pharmacists in the UK have in paediatric palliative careObjectives1. To determine the current roles and services provided by pharmacists to paediatric palliative care patients.2. To establish how other members of the multidisciplinary team perceive the pharmacist's role and the extent to which they value the pharmacist's contributions.3. To identify the references used by the multidisciplinary team to make clinical decisions about medication use in paediatric palliative care patients.MethodsAn online questionnaire was designed and emailed to members of the Neonatal and Paediatric Pharmacist's Group and the Association of Paediatric Palliative Medicine. The questionnaire was also sent by post to selected community pharmacists as palliative care is often provided to children in a community setting. Results were analysed using Microsoft Excel and SPSS version 22.ResultsA response rate of 27% (114/430) was achieved. Pharmacists reported supporting children receiving palliative care by supplying medicines, dealing with medication related enquiries and providing advice to nursing and medical staff on the compatibility and stability of drugs. The pharmacist's contributions were highly valued by other members of the paediatric palliative care team as a median rating of 9 (out of 10) was obtained. The results also showed that differences existed in the references used by pharmacists and other healthcare professionals–the Children's British National Formulary was the most commonly used reference across all disciplnes when caring for children requiring palliative care.ConclusionThis is one of the first studies to outline the roles of pharmacists working in paediatric palliative care and has highlighted that pharmacists have an important input in the care of these patients.
INHALER COUNSELLING, THE REAL DEAL OR JUST FRESH AIR?
Authors: Goodwin Richard , Chander Tiranvir , Shah Neha , Tomlin Steve 
Published: August 2016

AimTo evaluate whether healthcare professionals within the local community are able to counsel paediatric patients on the essential steps required for drug delivery with multi-dose inhalers (MDI), MDIs with a spacer and turbohalers.MethodAn expert panel produced and piloted checklists for essential and good practice counselling steps. Eligible participants included healthcare professionals regularly counselling children on inhaler devices, including doctors, nurses and pharmacy team members. Participants were recruited through purposive sampling on a general paediatric ward in a major children's hospital over 2 months and local community pharmacies. Participants counselled on each technique through simulated paediatric scenarios and were assessed by a trained researcher.ResultsThe audit captured 92 healthcare professionals, comprising 43 nurses, 9 doctors, 13 hospital pharmacy staff and 27 community pharmacies team members.Overall 13% (12/92) of participants counselled on all the essential criteria for an MDI inhaler. Pharmacy teams within the hospital and community saw the highest competency levels with 31% (4/13) and 30% (8/27) of staff able to discuss the essential steps respectively, no doctors or nurses were able to indentify all steps.10% (9/92) of participants were able to counsel on all essential steps for a MDI with a spacer device, with no nurse nor doctor achieving all steps. Hospital pharmacy staff were most likely to discuss all the essential steps with 6/13 staff competent and 3/27 community pharmacy team members counselled on the required steps. Commonly omitted steps included shaking the inhaler and leaving sufficient time between doses.Competency levels for turbohaler counselling were low, only 5 participants were able to counsel on the essential steps required. Commonly omitted or incorrect descriptions surrounded the priming of the device and incorrect inhalation technique.ConclusionOur findings mirror those of previously published studies with an adult focused counselling set,these concluded that less than 10% of healthcare professionals were competent with an MDI.1 Though respiratory conditions represent a large proportion of paediatric consultants, healthcare staff are failing to equip patients and carers with the knowledge and skills to utilise even the most common inhaler devices. With the NHS spending £900 million on inhalers2 and hospital admissions increasing dramatically3 more needs to be done to improve inhaler literacy within the local healthcare community.A comprehensive review of training methods needs to be undertaken to ensure these meet the requirements of the local healthcare community. A renewed emphasis on asthma care is required including standard methods for counselling on inhalers.A competency document should be created to assess and validate healthcare professionals to ensure the delivery of accurate and high quality inhaler counselling.