bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of Clinical Effectiveness and Subjective Satisfaction of a New Toothbrush for Postsurgical Hygiene Care: A Randomized Split‐Mouth Double‐Blind Clinical Trial
Authors: Montevecchi Marco , Moreschi Annalisa , Gatto Maria Rosaria , Checchi Luigi , Checchi Vittorio
Published: March 2015

The aim of this RCT was to evaluate plaque control and gingival health promotion effectiveness of a new toothbrush with extra‐soft filaments in postsurgical sets. Ten consecutive patients with at least two scheduled symmetrical periodontal surgeries were selected. Following the first periodontal surgery, a test (TB1) or control (TB2) toothbrush was randomly assigned. After the second surgery, the remaining toothbrush was given. Patients were asked to gently wipe the surgical area from days 3 to 7 postoperatively and to gently brush using a roll technique from day 7 till the end of the study. Baseline evaluation took place on the day of surgery and follow‐ups were performed at days 7, 14, and 30 postoperatively. A more evident PI reduction was recorded for test toothbrush where a regular decrease was observed till day 14; then, this parameter tended to stabilize, remaining however lower than that recorded for the control toothbrush. There were no statistical differences in the GI between test and control toothbrushes. All patients introduced the test toothbrush at surgical site at third day; the control toothbrush was introduced within a mean of 9 days. The introduction of the test toothbrush 3 days after periodontal surgery may be recommended.
Translational Implications of Tumor Heterogeneity
Authors: Jamal-Hanjani Mariam , Quezada Sergio A. , Larkin James , Swanton Charles
Published: March 2015

Advances in next-generation sequencing and bioinformatics have led to an unprecedented view of the cancer genome and its evolution. Genomic studies have demonstrated the complex and heterogeneous clonal landscape of tumors of different origins and the potential impact of intratumor heterogeneity on treatment response and resistance, cancer progression, and the risk of disease relapse. However, the significance of subclonal mutations, in particular mutations in driver genes, and their evolution through time and their dynamics in response to cancer therapies, is yet to be determined. The necessary tools are now available to prospectively determine whether clonal heterogeneity can be used as a biomarker of clinical outcome and to what extent subclonal somatic alterations might influence clinical outcome. Studies that use longitudinal tissue sampling, integrating both genomic and clinical data, have the potential to reveal the subclonal composition and track the evolution of tumors to address these questions and to begin to define the breadth of genetic diversity in different tumor types and its relevance to patient outcome. Such studies may provide further evidence for drug-resistance mechanisms informing combinatorial, adaptive, and tumor immune therapies placed within the context of tumor evolution. Clin Cancer Res; 21(6); 1258–66. ©2015 AACR.
The Impact of Commercialisation and Genetic Data Sharing Arrangements on Public Trust and the Intention to Participate in Biobank Research
Authors: Critchley Christine , Nicol Dianne , Otlowski Margaret
Published: March 2015

Objectives: The necessity for biobanks to share their resources with third parties poses potential risks to public trust and the intention to participate in genetic research. We explore the effects of data sharing and the type of third-party access (public vs. private) on public trust and, in turn, the intention to participate in biobank research. Methods: An experimental design was used to assess a national sample of 1,701 Australians via a computer-assisted telephone interview. Results: The results revealed that trust and the intention to participate significantly decreased in relation to private compared to public biobanks, and when access to third-party researchers was allowed compared to when it was not. Somewhat surprisingly, no differences were found in relation to the third party being international compared to Australian, but trust and the intention to participate were significantly eroded when private third parties were allowed access. Those with a university education were particularly distrustful of private biobanks and biobanks that allowed access, while those who were more aware of genetic databases appeared more confident with biobanks sharing with private-sector third parties. Conclusion: The pattern of results suggests that public awareness of the need for biobanks to share their resources widely needs to be increased to maintain public trust and support.
Deletion of Myeloid GSK3α Attenuates Atherosclerosis and Promotes an M2 Macrophage Phenotype
Authors: McAlpine Cameron S. , Huang Aric , Emdin Abby , Banko Nicole S. , Beriault Daniel R. , Shi Yuanyuan , Werstuck Geoff H.
Published: March 2015

Objective—

Glycogen synthase kinase (GSK)-3α/β has been implicated in the pathogenesis of diabetes mellitus, cancer, Alzheimer, and atherosclerosis. The tissue- and homolog-specific functions of GSK3α and β in atherosclerosis are unknown. This study examines the effect of hepatocyte or myeloid cell deletion of GSK3α or GSK3β on atherosclerosis in low-density lipoprotein receptor (LDLR)
−/−
mice.

Approach and Results—

We ablated GSK3α or GSK3β expression in hepatic or myeloid cells of LDLR
−/−
mice, and mice were fed a high-fat diet for 10 weeks. GSK3α or GSK3β deficiency in hepatic or myeloid cells did not affect metabolic parameters, including plasma lipid levels. Hepatic deletion of GSK3α or GSK3β did not affect the development of atherosclerosis or hepatic lipid content. Myeloid deletion of GSK3α, but not of GSK3β, reduced atherosclerotic lesion volume and lesion complexity. Mice lacking GSK3α in myeloid cells had a less inflammatory and more anti-inflammatory plasma cytokine profile. Macrophages within atherosclerotic lesions of myeloid GSK3α-deficient mice, but not of GSK3β-deficient mice, displayed reduced expression of markers associated with M1 macrophage polarization and enhanced expression of the M2 markers. Finally, bone marrow–derived macrophages were isolated and differentiated into classical M1 macrophages or alternative M2 macrophages in vitro. GSK3α deletion, but not GSK3β deletion, attenuated the expression of genes associated with M1 polarization while promoting the expression of genes associated with M2 polarization by modulating STAT3 and STAT6 activation.

Conclusions—

Our findings suggest that deletion of myeloid GSK3α attenuates the progression of atherosclerosis by promoting an M2 macrophage phenotype.
Preexisting Serum Autoantibodies Against the NMDAR Subunit NR1 Modulate Evolution of Lesion Size in Acute Ischemic Stroke
Authors: Zerche Maria , Weissenborn Karin , Ott Christoph , Dere Ekrem , Asif Abdul R. , Worthmann Hans , Hassouna Imam , Rentzsch Kristin , Tryc Anita B. , Dahm Liane , Steiner Johann , Binder Lutz , Wiltfang Jens , Sirén Anna-Leena , Stöcker Winfried , Ehrenreich Hannelore
Published: March 2015

Background and Purpose—

Recently, we reported high seroprevalence (age-dependent up to >19%) of
N
-methyl-
d
-aspartate-receptor subunit NR1 (NMDAR1) autoantibodies in both healthy and neuropsychiatrically ill subjects (N=4236). Neuropsychiatric syndrome relevance was restricted to individuals with compromised blood–brain barrier, for example, apolipoprotein E4 (APOE4) carrier status, both clinically and experimentally. We now hypothesized that these autoantibodies may upon stroke be protective in individuals with hitherto intact blood–brain barrier, but harmful for subjects with chronically compromised blood–brain barrier.

Methods—

Of 464 patients admitted with acute ischemic stroke in the middle cerebral artery territory, blood for NMDAR1 autoantibody measurements and APOE4 carrier status as indicator of a preexisting leaky blood–brain barrier was collected within 3 to 5 hours after stroke. Evolution of lesion size (delta day 7–1) in diffusion-weighted magnetic resonance imaging was primary outcome parameter. In subgroups, NMDAR1 autoantibody measurements were repeated on days 2 and 7.

Results—

Of all 464 patients, 21.6% were NMDAR1 autoantibody–positive (immunoglobulin M, A, or G) and 21% were APOE4 carriers. Patients with magnetic resonance imaging data available on days 1 and 7 (N=384) were divided into 4 groups according to NMDAR1 autoantibody and APOE4 status. Groups were comparable in all stroke-relevant presenting characteristics. The autoantibody+/APOE4− group had a smaller mean delta lesion size compared with the autoantibody−/APOE4- group, suggesting a protective effect of circulating NMDAR1 autoantibodies. In contrast, the autoantibody+/APOE4+ group had the largest mean delta lesion area. NMDAR1 autoantibody serum titers dropped on day 2 and remounted by day 7.

Conclusions—

Dependent on blood–brain barrier integrity before an acute ischemic brain injury, preexisting NMDAR1 autoantibodies seem to be beneficial or detrimental.
The Image of the Change: From the I Ching to the Evolution of Chaos
Authors: Zou Yuting
Published: March 2015

This article is dedicated to artistic explorations of change, with the I Ching (The Book of Changes) as a stepping stone. The author uses modern mathematics to identify the basic types of change in the I Ching codes and to build a bottom-up I Ching systemization with an associated aesthetic principle. Moreover, the author introduces other (chaotic) types of change to sparsely fill the gap between the basic I Ching orders and the ultimate Change, allowing artistic speculation reflecting the evolution of many types of change by means of digital simulations, 3D volumetric display, etc.
Lectotypification of the name Polycnemum majus (Amaranthaceae s.str.)
Authors: FREITAG HELMUT , Iamonico Duilio
Published: March 2015

As part of a revision of the genus Polycnemum Linnaeus (1753: 35) in Europe we here present a nomenclatural study of the untypified name Polycnemum majus A. Braun ex Bogenhard (1841: 151–152). This study is also related to a joint nomenclatural investigation of the Linnaean names of Camphorosma Linnaeus (1753: 122), where we detected that most original material of C. acuta Linnaeus (1753: 122) agrees with P. majus. That matter and a corresponding formal proposal to conserve P. majus so as to maintain that name will be published elsewhere.
Objective Diagnostics and the Madden–Julian Oscillation. Part I: Methodology
Authors: Wolding Brandon O. , Maloney Eric D.
Published: March 2015

Diagnostics obtained as an extension of empirical orthogonal function (EOF) analysis are shown to address many disadvantages of using EOF-based indices to assess the state of the Madden–Julian oscillation (MJO). The real-time multivariate MJO (RMM) index and the filtered MJO OLR (FMO) index are used to demonstrate these diagnostics. General characteristics of the indices, such as the geographical regions that most heavily influence each index, are assessed using the diagnostics. The diagnostics also identify how a given field, at various geographical locations, influences the index value at a given time. Termination (as defined by the RMM index) of the October 2011 MJO event that occurred during the Cooperative Indian Ocean Experiment on Intraseasonal Variability in the Year 2011 (CINDY) Dynamics of the MJO (DYNAMO) field campaign is shown to have resulted from changes in zonal wind anomalies at 200 hPa over the eastern Pacific Ocean, despite the onset of enhanced convection in the Indian Ocean and the persistence of favorable lower- and upper-level zonal wind anomalies near this region. The diagnostics objectively identify, for each specific geographical location, the index phase where the largest MJO-related anomalies in a given field are likely to be observed. This allows for the geographical variability of anomalous conditions associated with the MJO to be easily assessed throughout its life cycle. In Part II of this study, unique physical insight into the moist static energy and moisture budgets of the MJO is obtained from the application of diagnostics introduced here.
Examining the Relationships Among Coaching, Trustworthiness, and Role Behaviors
Authors: Kim Sewon , Kuo Min-Hsun
Published: March 2015

There is little evidence regarding what makes managerial coaching effective. To explore this topic more deeply, we looked at coaching relationship and performance behavior. We examined the associations between managerial coaching and employee in-role performance, organizational citizenship behavior–individual (OCBI), and organizational citizenship behavior–organization (OCBO), with the mediating effect of manager’s trustworthiness as perceived by employees. Using 280 dyad surveys, we found that managerial coaching had a direct impact on employee performance behavior of OCBI and OCBO as well as employee perception of manager’s trustworthiness. Bootstrapping analytic findings revealed that managerial coaching also indirectly influenced employee in-role performance, OCBI, and OCBO through employee perception of manager’s trustworthiness. The current study findings offer an initial endorsement for coaching effectiveness in this largely uncharted topic area and further provide empirical support to the theoretical underpinnings of managerial coaching based on social exchange theory. Limitations are discussed and directions for future studies are suggested.
Refinement of a thermal threshold probe to prevent burns
Authors: Dixon MJ , Taylor PM , Slingsby LC , Murrell JC
Published: March 2015

Thermal threshold testing is commonly used for pain research. The stimulus may cause burning and merits prevention. Thermal probe modifications hypothesized to reduce burning were evaluated for practicality and effect. Studies were conducted on two humans and eight cats. Unmodified probe 0 was tested on two humans and promising modifications were also evaluated on cats. Probe 1 incorporated rapid cooling after threshold was reached: probe 1a used a Peltier system and probe 1b used water cooling. Probe 2 released skin contact immediately after threshold. Probe 3 (developed in the light of evidence of ‘hot spots’ in probe 0) incorporated reduced thermal mass and even heating across the skin contact area. Human skin was heated to 48℃ (6℃ above threshold) and the resulting burn was evaluated using area of injury and a simple descriptive scale (SDS). Probe 1a cooled the skin but required further heat dissipation, excessive power, was not ‘fail-safe’ and was inappropriate for animal mounting. Probe 1b caused less damage than no cooling (27 ± 13 and 38 ± 11 mm2 respectively, P = 0.0266; median SDS 1.5 and 4 respectively, P = 0.0317) but was cumbersome. Probe 2 was unwieldy and was not evaluated further. Probe 3 produced even heating without blistering in humans. With probe 3 in cats, after opioid treatment, thermal threshold reached cut-out (55℃) on 24 occasions, exceeded 50℃ in a further 32 tests and exceeded 48℃ in the remainder. No skin damage was evident immediately after testing and mild hyperaemia in three cats at 2–3 days resolved rapidly. Probe 3 appeared to be suitable for thermal threshold testing.
Do economic conditions influence union activism behaviour?
Authors: Angrave David , Charlwood Andy , Greenwood Ian
Published: March 2015

This article develops and tests the theory that union activism is related to economic conditions using a nationally representative panel of workers from the UK. Results suggest that a fall in real wages of two percentage points and a three percentage point increase in the unemployment rate are both associated with a one-tenth increase in the probability that a ‘benchmark’ worker will become a union activist (albeit from a low base). This relationship is largely explained by the behaviour of workers in highly unionized sectors.
Is Unbleached Cotton Better Than Bleached? Exploring the Limits of Life-Cycle Assessment in the Textile Sector
Authors: Roos Sandra , Posner Stefan , Jönsson Christina , Peters Greg M.
Published: March 2015

The applicability of life-cycle assessment (LCA) for the textile industry is discussed with a special focus on environmental impact from chemicals. Together with issues of water depletion and energy use, the use of chemicals and their emissions are important environmental considerations for textile products. However, accounting for chemicals is a weak point in LCA methodology and practice. Two research questions were investigated in a case study of hospital garments: 1) whether LCA adds value to assessments of the chemical performance of textile products, and 2) whether inclusion of toxicity issues in LCA affects environmental performance rankings for textile products. It is concluded that the quantitative and holistic tool LCA is useful for environmental decision makers in the textile industry, and becomes more effective when chemical impacts are included. A flexible way forward is demonstrated to meet the challenge of accounting for chemicals in LCAs of textile products.
A Content Analysis of Infant and Toddler Food Advertisements in Taiwanese Popular Pregnancy and Early Parenting Magazines
Authors: Chen Yi-Chun , Chang Jung-Su , Gong Yu-Tang
Published: March 2015

Background:

Mothers who are exposed to formula advertisements (ads) are less likely to initiate breastfeeding and more likely to breastfeed for a shorter duration than other mothers.

Objective:

The purpose of this study was to examine infant and toddler food ads in pregnancy and early parenting magazines.

Methods:

A content analysis of infant and toddler food ads printed in 12 issues of 4 magazines published in 2011 was performed. Coding categories of ads included product category, advertisement category, marketing information, and advertising appeal. The target age and health-related message of each product were coded.

Results:

The researchers identified 756 infant and toddler food ads in the magazines. Compared with complementary food ads, formula product ads used more marketing strategies such as antenatal classes and baby contests to influence consumers and promote products. Nutritional quality and child health benefits were the two most frequently used advertising appeals. In addition, this study identified 794 formula products and 400 complementary food products; 42.8% of the complementary food products were intended for 4-month-old infants. Furthermore, 91.9% of the ads for formula products and 81% of the ads for complementary food products contained claims concerning health function or nutrient content.

Conclusions:

Taiwanese pregnancy and early parenting magazines contain numerous infant and toddler food ads. These ads generally use health-related claims regarding specific nutrient content and health functions to promote infant and toddler foods. Health professionals should provide more information to parents on the differences between breast milk and formula milk, and they should be aware of the potential effect of infant and toddler food ads on parents’ infant feeding decisions.
Bees Algorithm for multimodal function optimisation
Authors: Zhou ZD , Xie YQ , Pham DT , Kamsani S , Castellani M
Published: March 2015

The aim of multimodal optimisation is to find significant optima of a multimodal objective function including its global optimum. Many real-world applications are multimodal optimisation problems requiring multiple optimal solutions. The Bees Algorithm is a global optimisation procedure inspired by the foraging behaviour of honeybees. In this paper, several procedures are introduced to enhance the algorithm’s capability to find multiple optima in multimodal optimisation problems. In the proposed Bees Algorithm for multimodal optimisation, dynamic colony size is permitted to automatically adapt the search effort to different objective functions. A local search approach called balanced search technique is also proposed to speed up the algorithm. In addition, two procedures of radius estimation and optima elitism are added, to respectively enhance the Bees Algorithm’s ability to locate unevenly distributed optima, and eliminate insignificant local optima. The performance of the modified Bees Algorithm is evaluated on well-known benchmark problems, and the results are compared with those obtained by several other state-of-the-art algorithms. The results indicate that the proposed algorithm inherits excellent properties from the standard Bees Algorithm, obtaining notable efficiency for solving multimodal optimisation problems due to the introduced modifications.
Novel Approaches to the Treatment of Hepatitis C Virus Infection
Authors: Dymock Brian W , Jones Philip S , Wilson Francis X
Published: March 2015

Hepatitis C virus (HCV) has infected millions of people worldwide and emerged as a global health crisis. This review reports approaches currently being taken to combat the virus. Viral targets have received the most attention, particularly the NS3 serine protease where potent inhibitors have been described. Crystal structures of key replicative enzymes, NS3 protease, NS3 helicase, NS5B polymerase and now full-length NS3 protease-helicase, are available. More recently, targeting the host system has become of interest, particularly inhibitors of inosine monophosphate dehydrogenase. Research aimed at novel treatments for HCV disease is gathering pace and very recent developments in cell-based assay systems can only hasten the discovery of improved therapies.
Structure-Activity Relationship Studies on Potential Non-Nucleoside DABO-Like Inhibitors of HIV-1 Reverse Transcriptase
Authors: Costi Roberta , Di Santo Roberto , Artico Marino , Massa Silvio , Lavecchia Antonio , Marceddu Tiziana , Sanna Laura , La Colla Paolo , Marongiu Maria Elena
Published: March 2015

Using 2,6-dichloro-4-aminopyrimidine, a number of uracil and cytosine derivatives with both arylthio and alkoxy moieties were prepared. These novel pyrimidines share chemical similarities with DABOs and HEPTs, two classes of nonnucleoside human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitors (NNRTIs), which have been widely studied of late. All new derivatives were tested in MT-4 cells to explore their potential in vivo anti-HIV activity. Like other NNRTIs, they selectively inhibit HIV-1 but not HIV- 2. The majority of test derivatives were found to have low potency and were sometimes more cytotoxic than zidovudine and emivirine (formerly MKC-442), used here as reference drugs. Uracil and cytosine derivatives bearing a sec-butoxy chain and a methyl-substituted benzenesulphonyl moiety were the most potent. Enzyme assays proved that these derivatives target RT. Structure-activity relationship studies established a correlation between the anti-HIV-1 activity and the meta substitution on the phenyl ring; furthermore, oxidation of sulphide to sulphone significantly increased the potency of certain derivatives.
Effect of Intramuscularly Injected Polyprenols on Influenza Virus Infection in Mice
Authors: Safatov AS , Sergeev AN , Shishkina LN , Pyankov OV , Poryvaev VD , Bulychev LE , Petrishchenko VA , Pyankova OG , Zhukov VA , Ryzhikov AB , Boldyrev AN , Buryak GA , Raldugin VA , Kukina TP , Tolstikov GA
Published: March 2015

This study demonstrates the possibility of achieving a prophylactic effect by intramuscular injection of Abies sibirica polyprenols for the control of influenza virus infection in mice. One of the five polyprenol preparations tested, preparation N1, which had the lowest hydrophilic-lipophilic balance (8.6), produced a significant protective effect when injected in a dose of 2000 μg/mouse 2 days before aerosol infection of mice with influenza virus. A moderate protective effect was also observed using a second preparation, designated N2. One day after aerosol infection, animals pre-treated with 2000 μg doses of the polyprenol preparations or Hanks' solution showed no difference in the level of interferon accumulation in the lungs. Three days after injection of preparation N2 and N1, a significant decrease in spleen and thymus weights was observed in the mice. One day after injection of these preparations, the number of lymphocytes in the bronchoalveolar tract of the mice exceeded almost twice that seen in mice treated with placebo. After 3 days, relative and absolute numbers of macrophages decreased, whereas those of lymphocytes increased significantly. Three days after the administration of preparations N1 and N2, macrophages became approximately twice as active in absorbing zymozan granules. Preparation N1 affected the system of superoxide radical anion production to a greater extent than preparation N2. The production of radical anions by the macrophages of the bronchoalveolar tract in the mice, 1 day after intramuscular injection of preparation N1, was significantly higher than that seen on day 3 and that induced by preparation N2 1 and 3 days after injection. These data indicate that emulsions of polyprenols that have relatively low hydrophilic-lipophilic balance, inhibit influenza virus infection in mice through a modulation of the host immune response.
HIV Immunotherapeutic Vaccines
Authors: Peters Barry S
Published: March 2015

New combinations of antiretrovirals have improved the quality of life and length of survival of patients with HIV infection and AIDS, but they have significant disadvantages. These include considerable toxicity, the development of drug resistance and expense. Successful immunotherapeutic vaccination against HIV would overcome these problems. None of the approaches that have been tried so far have shown a sufficient effect on HIV replication or on immunorestoration to merit their introduction to clinical practice. The most developed agent thus far is Remune, a gp120 depleted whole killed HIV-1 vaccine that has shown marked cytotoxic T lymphocyte responses when administered to man. CD4 count and HIV-1 viral load responses have occurred, but have so far been disappointing in their magnitude. Remune is entering Phase III trials in North America, Europe and the Far East, to determine clinical efficacy. Immunization using recombinant HIV envelope proteins, such as rgp160, for example with VaxSyn, have failed to produce a therapeutic response. Similarly, agents using HIV core antigens, such as p24VLP, have also failed to work. Hence, newer strategies have been tried. Recombinant canarypox vaccines like ALVAC 1452 and highly attenuated vaccinia virus vaccines, such as NYVAC, have been used in combination with HIV genes and peptides. Preliminary results suggest that they might reduce the HIV replication rate, but this needs confirming in larger clinical trials. DNA vaccination has produced encouraging results in monkeys, but the success has not yet been repeated in humans. Other strategies at an early stage include the exploitation of the protective alloimmune response in man. Outside the immunotherapeutic area, other promising new strategies that are being developed in parallel, include the fusion inhibitors, such as T-20. The potential benefits from a successful immunotherapeutic vaccine dictate that this area should, and will receive priority.
Differential Susceptibility of Retroviruses to Nucleoside Analogues
Authors: Rosenblum Lisa L , Patton Gillian , Grigg Andrew R , Frater Alexander J , Cain Dionne , Erlwein Otto , Hill Claire L , Clarke John R , McClure Myra O
Published: March 2015

Retroviruses may cause diseases in their vertebrate hosts. They are distinguished by their common means of replication involving reverse transcription, a process inhibited by nucleoside reverse transcriptase inhibitors (NRTIs) and other compounds used in antiretroviral chemotherapy. Previous work on NRTIs has been limited to their effect on human immunodeficiency virus (HIV) (for review see Ho & Hitchcock, 1989; Weller, 1999) and little information exists regarding the efficacy and therapeutic potential of these drugs against other retroviruses. We have tested all six NRTIs licensed for HIV treatment [didanosine (ddI), zalcitabine (ddC), lamivudine (3TC), stavudine (d4T), zidovudine (AZT) and abacavir (ABC)] against seven retroviruses representative of the traditional subfamilies: Spumavirinae, Lentivirinae and the Oncovirinae. As expected, each drug showed a range of activities against the panel of retroviruses, some drugs inhibiting other viruses at concentrations well below those required for HIV. Overall, AZT was the most active inhibitor (IC50 range, 0.032–1.0 μM), being most active against the Spuma (foamy) viruses. Abacavir was inhibitory for HIV-1, MN strain (HIV-1 MN), amphotrophic murine leukemia virus (MLV-A) and simian foamy virus type 6 (SFV-6). The least effective inhibitor, 3TC (IC50 range, 0.32–>100 μM), was most potent against simian retrovirus types 1 and 2 (SRV-1, SRV-2) and HIV-1, but did not inhibit foamy viruses and MLV-A. Additionally, there were differences in the concentration of drug required to inhibit closely related viruses. Taken together, these data suggest that NRTIs have a wide spectrum of antiretroviral activity and the activity of compounds, even against closely related retroviruses, cannot be predicted.
5′-Nor Carbocyclic 5′-Deoxy-5′-(Isobutylthio)Adenosine and a 2′,3′-Dideoxy-2′,3′-Didehydro Derivative
Authors: Das Subha R , Schneller Stewart W , Balzarini Jan , De Clercq Erik
Published: March 2015

The inhibition of biochemical processes requiring S-adenosylmethionine as a co-factor have led to many nucleoside-based medicinal agents. Included in this group are 5′-deoxy-5′-(isobutylthio)adenosine (SIBA), a nucleoside with antiparasitic, antiviral and antiproliferative effects, and 5′-noraristeromycin, a carbocyclic-derived nucleoside with potent antiviral properties. This report brings together the structural components of these two compounds by describing both enantiomers of carbocyclic 5′-nor SIBA (3 and 4). Owing to the recent interest in 2′,3′-dideoxy-2′,3′-didehydro nucleosides as antiviral agents, this derivative of 3 (5) is also described. All three compounds were screened against a variety of viruses and were found to be inactive at high concentrations or at limiting concentrations for the screening methods. The viruses subjected to 3–5 were herpes simplex virus types 1 and 2, human cytomegalovirus, vaccinia virus, vesicular stomatitis virus, respiratory syncytial virus, varicella zoster virus, coxsackie virus, parainfluenza-3 virus, sindbis virus, punta toro virus, reovirus-1, human immunodeficiency virus, influenza virus types A and B, adenovirus type 1 and measles virus. These results suggest that the C-5′ methylene of the C-5′ thio-based carbocyclic nucleosides is important for their antiviral properties.
Stereochemistry as a Major Determinant of the Anti-HIV Activity of Chiral Naphthyl Thiourea Compounds
Authors: Venkatachalam TK , Mao C , Uckun FM
Published: March 2015

Eleven chiral naphthyl thiourea (CNT) compounds were synthesized as non-nucleoside inhibitors (NNI) of the reverse transcriptase (RT) enzyme of HIV-1. Molecular modelling studies indicated that, because of the asymmetric geometry of the NNI binding pocket, the ‘R” stereoisomers would fit the NNI binding pocket of the HIV-1 RT much better than the corresponding ‘S” stereoisomers, as reflected by their 104-fold lower Ki values. The ‘R” stereoisomers of all 11 compounds inhibited the recombinant RT in vitro with lower IC50 values than their enantiomers. Of seven CNT compounds whose ‘R” stereoisomers exhibited nanomolar IC50 values against recombinant RT, five were further evaluated for their ability to inhibit HIV-1 replication in human peripheral blood mononuclear cells (PBMC). All five ‘R” stereoisomers were active anti-HIV agents and inhibited the replication of the HIV-1 strains HTLV-IIIB (NNI-sensitive), A17 (NNI- resistant, Y181C mutant RT) and A17Var (NNI- resistant, Y181C plus K103N mutant RT), as well as primary HIV-1 isolates from AIDS patients in human PBMC at nanomolar concentrations, whereas their enantiomers were inactive. The lead compounds, 1R and 5R, were 3 log more potent than the standard NNI drug nevirapine against the NNI-resistant HIV-1 strains. Our data establish the stereochemistry as a major determinant of the potency of this new class of NNI.
Peptidyl Diazomethyl Ketones Inhibit the Human Rhinovirus 3C Protease: Effect on Virus Yield by Partial Block of P3 Polyprotein Processing
Authors: Murray Michael A , Janc James W , Venkatraman Shankar , Babé Lilia M
Published: March 2015

The efficacy of a series of diazomethyl ketones (DMKs) was measured in rhinovirus-infected cultures and against the HRV14 3C protease. Their specificity and potency were confirmed against purified recombinant enzyme expressed in a yeast secretion system. An internally quenched fluorescent peptide substrate was used to assess the potency against the enzyme, obtaining a 50% inhibitory concentration (IC50) of 1 μM for both Z-L-F-Q-CHN2 and Z-V-L-F-Q-CHN2, while a lower affinity was observed for Z-F-Q-CHN2. The tripeptide Z-L-F-Q-CHN2 blocked viral replication with an IC50 value of 30 μM as judged by the reduction in viral induced cytopathy of HeLa-H1 cells, as well as a marked reduction in viral plaque formation (50% effective concentration=20 μM). Western blot analysis of viral proteins from infected cells indicates that this inhibitor works specifically by blocking viral polyprotein maturation, displaying a reduction of detectable 3C protease and an accumulation of the 3CD polypeptide. These results indicate that DMK inhibitors of the 3C protease have antiviral potency. Furthermore, the pattern of viral protein processing observed suggests that reducing the concentration of mature HRV 3C protease even in the presence of increased 3CD protein is sufficient to block proper viral processing and significantly reduce virus yield.
Synthesis and Antiherpesvirus Activities of 5-Alkyl-2-Thiopyrimidine Nucleoside Analogues
Authors: Shigeta S , Mori S , Watanabe F , Takahashi K , Nagata T , Koike N , Wakayama T , Saneyoshi M
Published: March 2015

Twenty 5-alkyl-2-thiopyrimidine nucleosides were newly synthesized and examined for antiviral activities against herpes simplex virus (HSV), varicella-zoster virus (VZV) and human cytomegalovirus (HCMV). In this study, 2′-deoxy-5- alkyl-2-thiocytidine analogues had lower 50% effective concentration (EC50) values against HSV- 1, and 2/-deoxy-5-alkyl-2-thiouridine analogues showed lower EC50 against VZV than their congeners of arabinoside form. Among the compounds examined, 2′-deoxy-5-ethyl and 5-propyl- 2-thiocytidine (TN-53 and TN-54) were most potent and selective anti-HSV compounds. Their EC50s were 0.04 and 0.15 μM, and selectivity indexes were more than 7215 and 1849, respectively. On the other hand, 2′-deoxy-5-propyl-2-thiouridine (TN-51), 5-bromovinyl-2-thiouracil arabinoside (TN-65) and 5-styryl-2-thiouracil arabinoside (TN-67) were most potent and selective anti-VZV compounds. Their EC50s were 3.1, 3.8 and 2.6 μM for CaQu strain of VZV, respectively, and 2.1 to 3.0 times lower than that of acyclovir. All 2-thiopyrimidine nucleoside analogues did not show antiviral activities against thymidine kinase (TK) negative strains of HSV-1 and VZV. Only three 2-thiocytosine arabinoside compounds showed marginal anti-CMV activities (EC50s were 57–159 μM). All of the five alkyl-2-thio-pyrimidine nucleoside analogues examined were not cytotoxic to human lymphoblastoid cells (RPMI8226) and human embryonic fibroblast cells (MRC-5) at 240 μM (100 pg/ml) or more. Regarding the structure-activity relationship of 5-alkyl-2-thiopyrimidine nucleoside analogues, the following remarks will be noted. Elongation of 5-alkyl chain (methyl to ethyl) of 2-thiocytosine in both deoxyribosyl and arabinosyl nucleosides increased anti-HSV-1 activity but not anti-VZV activity. Furthermore, elongation of the same chain (ethyl to propyl) of 2-thiodeoxyuridine increased anti-VZV activity whereas it did not in the case of 2-thiouracil arabinosides.
A Sulphated Fucan from the Laminaria Abyssalis Inhibits the Human T Cell Lymphotropic Virus Type 1-Induced Syncytium Formation in HeLa Cells
Authors: Romanos MTV , Andrada-Serpa MJ , Mourão PAS , Yoneshigue-Valentin Y , Costa SS , Pereira MS , Miranda MMFS , Gonçalves JLS , Wigg MD
Published: March 2015

This work evaluated the effect of a sulphated fucan extracted from the Laminaria abyssalis marine algae on the human T cell lymphotropic virus type 1 (HTLV-1)-induced syncytium formation. The experiments were carried out in HeLa cells cocultured with a HTLV-1-infected T cell line (C91/PL cells) in the presence of the sulphated polysaccharide at concentration below that corresponding to the ED50. The sulphated fucan inhibited almost 100% of the syncytium formation at concentration of 100 μg/ml and was still active (>95%) at a concentration of 25 μg/ml. It was also observed that the best inhibition occurred when the compound was added in the first 2 h of the cell-to-cell contact. This is the first report showing that a purified sulphated polysaccharide, extracted from marine algae, is able to inhibit the cell-to-cell contact essential for the spreading of the HTLV-1.
Synthesis, Solution Conformation and Anti-HIV Activity of Novel 3-Substituted-2′,3′-Dideoxy-5-Hydroxymethyl-Uridines and Their 4,5-Substituted Analogues
Authors: Poznanski Jaroslaw , Bretner Maria , Kulikowski Tadeusz , Balzarini Jan , Van Aerschot Arthur , De Clercq Erik
Published: March 2015

To decrease the toxicity of potent anti-HIV nucleosides 3-azido-2′,3′-dideoxythymidine (AZT) and 2,3′-dideoxy-3′-fluorothymidine (3-FddThd, FLT), their new analogues, 3-azido-2′,3′-dideoxy-5-hydroxymethyluridine (3-Az5HmddUrd) and 2,3′-dideoxy-3′-fluoro-5-hydroxymethyluridine (3′-F5HmddUrd), were synthesized. The reaction of 3′-azido-2′,3′-dideoxyuridine (3′-AzddUrd) and 2,3′-dideoxy-3′-fluorouridine (3′-FddUrd) with formaldehyde, under strongly alkaline conditions and at elevated temperature, proceeded after 4 days to completion to afford the corresponding 5-hydroxymethyl derivatives 3′-Az5HmddUrd and 3′-F5HmddUrd in good yield. These compounds were also prepared by oxidation of AZT and FLT with the use of K2S2O8. 1H NMR analyses were subjected to the series of 3′,4 and 5-substituted pyrimidine 2′-deoxy- and 2′,3′-dideoxynucleosides involving 3′-Az5HmddUrd and 3′-F5HmddUrd. Analysis of the sugar furanose ring puckering demonstrated that all 3′-fluorine derivatives exhibited strong domination of the S conformation (∼100%) while 3-substitution by electron-donating groups, such as NH2, increased population of the N conformation. Experimentally observed substituent effect on the furanose ring puckering equilibrium was reconstructed in the 100 ps molecular dynamic trajectories obtained for AZT, FLT, dThd, 2′,3′-ddThd and 3′-amino-2′,3′-ddThd. It may be concluded that anti-HIV activity is linked to a direct interaction of the 3′-sub-stituent with reverse transcriptase (RT) binding site. Anti-HIV activities of 3′-Az5HmddUrd and 3′-F5HmddUrd are lower than activity of AZT and FLT; however, 3′-Az5HmddUrd and 3′-F5HmddUrd are less toxic than AZT and FLT.
Synthesis and Antiviral Activities of 3-Aralkyl-Thiomethylimidazo[1,2-b]Pyridazine Derivatives
Authors: Galtier Christophe , Mavel Sylvie , Snoeck Robert , Andreï Graciela , Pannecouque Christophe , Witvrouw Myriam , Balzarini Jan , De Clercq Erik , Gueiffier Alain
Published: March 2015

The synthesis of novel substituted 3-aralkylth-iomethylimidazo[1,2- b]pyridazines is reported. All of the synthesized compounds are devoid of antiviral activity against the replication of human immunodeficiency virus. However, compounds 6-chloro-8-methyl-3-phenethylthioimidazo[1,2- b]pyridazine and 6-chloro-2-methyl-3-phenethyl-thioimidazo[1,2- b]pyridazine are potent inhibitors of the replication of human cytomegalovirus in vitro, while compounds 6-chloro-2-methyl-3-benzylthiomethylimidazo[1,2- b]pyridazine and 6-chloro-2-methyl-3-phenethyl-thioimidazo[1,2- b]pyridazineare inhibitors of the replication of varicella-zoster virus. The results presented here suggest that compound 10 should be considered as a new lead in the development of antiviral agents.
Structure-Activity Relationship Studies on a Novel Family of Specific HIV-1 Reverse Transcriptase Inhibitors
Authors: Bonache María-Cruz , Chamorro Cristina , Lobatón Esther , De Clercq Erik , Balzarini Jan , Velázquez Sonsoles , Camarasa María-José , San-Félix Ana
Published: March 2015

We have previously reported the discovery and preliminary structure-activity relationships of a new class of specific HIV-1 reverse transcriptase (RT) inhibitors whose prototype compound is the 1-[2′,5′-bis- O-( tert-butyldimethylsilyl)-β-D-ribofuranosyl]-3- N-[(carboxy) methyl]-thymine. In an attempt to increase the inhibitory efficacy against HIV-1 RT of this new class of nucleosides, and to further explore the structural features required for anti-HIV-1 activity, different types of modifications have been carried out on the prototype compound. These include substitution of the tert-butyldimethylsilyl groups by other liphophilic groups, replacement of the carboxy group at the N-3 position of the nucleobase by other functional groups, change in the length of the spacer between the thymine and the carboxylic acid residue and substitution of the thymine moiety by other pyrimidine (uracil, 5-ethyluracil) or purine (hypoxanthine) nucleobases. In addition, the most salient structural features of this new class of HIV-1-specific nucleosides have been incorporated into classical HIV RT nucleoside inhibitors such as ddI, AZT, d4T. Our studies demonstrate that both the carboxymethyl moiety at the nucleobase and tert-butyldimethylsilyl groups at the sugar are important structural components since deletion of either of them is detrimental to the antiviral activity.
Pharmacokinetic Evaluation of 3′-Azido-2′, 3′-Dideoxyuridine-5′-O-Valinate-Hydrochloride as a Prodrug of the Anti-HIV Nucleoside 3′-Azido-2′, 3′-Dideoxyuridine
Authors: Kong Linghui , Cooperwood John S , Huang Shu-Hui Christine , Chu Chung K , Boudinot F Douglas
Published: March 2015

3′-Azido-2′, 3′-dideoxyuridine (AZDU, AzddU, CS-87) has been shown to have potent anti-HIV activity in vitro. However, the compound exhibits a relatively short half-life and incomplete oral bioavailability in humans. In an effort to improve the pharmacokinetic properties of AZDU, prodrug 3′-azido-2′,3′-dideoxyuridine-5′- O-valinate hydrochloride (AZDU-VAL) was synthesized by the esterification of 5′-OH function in AZDU. The objective of this study was to investigate the biotransformation and pharmacokinetics of AZDU-VAL along with its antiviral parent compound AZDU following intravenous and oral administration to rats. Adult male Sprague-Dawley rats were administered AZDU or AZDU-VAL by intravenous injection or oral gavage. Concentrations of AZDU-VAL and AZDU were determined by HPLC. Pharmacokinetic parameters were generated by area-moment analysis. The bioavailability of AZDU after oral administration was approximately 53%. The terminal phase half-life of the nucleoside analogue ranged between 0.6 h after intravenous administration and 1 h following oral administration. In vivo the prodrug was rapidly and efficiently biotransformed to yield AZDU following intravenous and oral administration. The apparent availability of AZDU was virtually complete following oral administration of prodrug AZDU-VAL averaging 101%. The bioavailability of AZDU following intravenous administration of AZDU-VAL averaged 106%. In summary, the disposition of AZDU was dose dependent over the dose range of 25–100 mg/kg. Renal clearance and steady state volume of distribution were lower at the higher dose level. Prodrug AZDU-VAL demonstrated improved oral bioavailability as evidenced by complete absorption and efficient bioconversion to AZDU. The results suggest that AZDU-VAL may be a promising prodrug for the delivery of AZDU.
Mechanism of Antiviral Activities of 3′-Substituted L-Nucleosides against 3Tc-Resistant HBV Polymerase: A Molecular Modelling Approach
Authors: Chong Youhoon , Stuyver Lieven , Otto Michael J , Schinazi Raymond F , Chu Chung K
Published: March 2015

Comparison of the active sites of the human HIV-1 reverse transcriptase (RT) and the homology-modelled hepatitis B virus (HBV) polymerase shows that the active sites of both enzymes are open to L-nucleosides, but the position where the 3′-substituent of the L-ribose projects in HBV polymerase is wider and deeper than HIV-1 RT, which enables the HBV polymerase to accommodate various 3′-substituted L-nucleosides. However, the space is not sufficient to accommodate a bulky 3′-substituent such as the 3′-azido group of L-3′-azido-3′-deoxythymidine. Analysis of the minimized structure of rtM204V HBV polymerase/ 3TCTP complex shows that, instead of the steric stress produced by rtV204, a loss of the van der Waals contact around the oxathiolane sugar moiety of 3TCTP caused by the mutation results in the disruption of the active site. Therefore, nucleosides, which are stabilized by additional specific interaction with the enzyme residues, can have more opportunities to circumvent the destabilization by the loss of hydrophobic interaction conferred by mutation. Specifically, the substitution at the 3′-position would be beneficial as the HBV polymerase has wide open space composed of the highly conserved motif (YMDD) where the 3′-substituents of the L-nucleosides project. As an example, our study shows that the 3′-fluorine atom contributes to the antiviral activity of L-3′-Fd4CTP against rtM204V HBV polymerase by readily compensating for the loss of the van der Waals interaction around the 2′,3′-double bond through a formation of a hydrogen bond to the amide backbone of rtD205.
Action of Celgosivir (6 O-Butanoyl Castanospermine) against the Pestivirus BVDV: Implications for the Treatment of Hepatitis C
Authors: Whitby Kevin , Taylor Debra , Patel Dipa , Ahmed Parvin , Tyms A Stanley
Published: March 2015

α-Glucosidase I inhibitors have been shown to inhibit the replication of a broad range of enveloped viruses by preventing the correct folding of their envelope glycoproteins. This study assesses the potential of 6 O-butanoyl castanospermine (cel-gosivir) as a treatment for hepatitis C virus (HCV). In the absence of an adequate culture system for HCV, the closely related virus, bovine viral diarrhoea virus (BVDV), was used as a surrogate model. Using both a plaque assay and a cytopathic effect assay, celgosivir (IC50 16 and 47 μM respectively) was shown to be more potent than N-nonyl DNJ (105 and 74 μM), castanospermine (110 and 367 μM) and N-butyl DNJ (>250 and 550 μM). Of the α-glucosi-dase inhibitors tested, only N-nonyl DNJ showed evidence of toxicity (CC50 ≥120 μM). Two-way combinations of interferon-α, ribavirin and either celgosivir or castanospermine demonstrated that each could enhance the antiviral efficacy of the others, either additively or synergistically. The observation that the number of viral genomes released from BVDV-infected cells was inhibited by either castanospermine or celgosivir in parallel with the number of infectious units was taken as confirmation that these α-glucosidase I inhibitors block the production or release of flavivirus particles.
Inhibitory Effect of Medicinal Herbs against RNA and DNA Viruses
Authors: Ruffa María Julieta , Wagner Marcelo Luis , Suriano Mónica , Vicente Carlos , Nadinic Jelena , Pampuro Sandra , Salomón Horacio , Campos Rodolfo Héctor , Cavallaro Lucía
Published: March 2015

Fifteen Argentine medicinal plants were tested for their antiviral activity in vitro against herpes simplex viruses types 1 and 2 (HSV-1 and 2), bovine viral diarrhoea virus type 1 (BVDV-1), influenza virus type A (Inf A) and human immunodeficiency virus type 1 (HIV-1). Antiviral activity was evaluated by a reduction in cytopathic effect, plaque-forming units and p24 HIV-1 antigen. The Selective Index of the active extract (SIextract =CC50 extract/EC50 extract) of Coronopus didymus (SIextract=110.7), Juglans australis (SIextract=8.1) and Lippia alba (SIextract=19.2) against BVDV-1, HSV-1 and influenza A virus, respectively, justify a further analysis. None of the seven plants assayed against HIV-1 displayed any antiviral activity. The results of this study justify the continuing isolation and characterization of the antiviral components present.