bluuebunny/crossref_metadata_2025 huggingface dataset:
Bone Marrow-Derived, Neural-Like Cells Have the Characteristics of Neurons to Protect the Peripheral Nerve in Microenvironment
Authors: Guo Shi-lei , Zhang Zhi-ying , Xu Yan , Zhi Yun-xia , Han Chang-jie , Zhou Yu-hao , Liu Fang , Lin Hai-yan , Zhang Chuan-sen
Published: March 2015

Effective repair of peripheral nerve defects is difficult because of the slow growth of new axonal growth. We propose that “neural-like cells” may be useful for the protection of peripheral nerve destructions. Such cells should prolong the time for the disintegration of spinal nerves, reduce lesions, and improve recovery. But the mechanism of neural-like cells in the peripheral nerve is still unclear. In this study, bone marrow-derived neural-like cells were used as seed cells. The cells were injected into the distal end of severed rabbit peripheral nerves that were no longer integrated with the central nervous system. Electromyography (EMG), immunohistochemistry, and transmission electron microscopy (TEM) were employed to analyze the development of the cells in the peripheral nerve environment. The CMAP amplitude appeared during the 5th week following surgery, at which time morphological characteristics of myelinated nerve fiber formation were observed. Bone marrow-derived neural-like cells could protect the disintegration and destruction of the injured peripheral nerve.
IFN-CSP Inhibiting Hepatitis B Virus in HepG2.2.15 Cells Involves JAK-STAT Signal Pathway
Authors: Lu Xuemei , Wang Jie , Jin Xiaobao , Huang Yanting , Zeng Wenting , Zhu Jiayong
Published: March 2015

Frequent and high-dose administration of interferon to patients with viral hepatitis results in various side effects. In our previous study, a novel liver-targeting interferon (IFN-CSP) combiningPlasmodiumregion I peptide with IFNα2b was successfully designed and expressed in theEscherichia coliexpression systems. This targeting would target the IFNα2b specifically to the liver, thus reducing the adverse events. In the present study, we further investigated the anti-HBV effects and molecular mechanisms of recombinant IFN-CSP in HepG2.2.15 cell line. Hepatitis B surface antigen (HBsAg) and HBe antigen (HBeAg) in the culture supernatants were analyzed by enzyme-linked immunosorbent assay (ELISA). HBV-DNA was measured by real-time quantitative PCR. HBV core protein was assayed by immunofluorescent and western blot analysis. The expressions of signal transducers and transactivator 1 (STAT1), STAT2, IFN regulatory factor 9 (IRF-9), and 2′-5′-oligoadenylate synthetase 1 (OAS1) were investigated by the reverse transcription PCR and western blot analysis. Results indicate IFN-CSP efficiently inhibited HBsAg and HBeAg secretion, HBV-DNA replication, and HBV core protein expression in HepG2.2.15 cells. The anti-HBV mechanisms involve activation of JAK-STAT signaling and increase of the anti-HBV protein OAS expression. IFN-CSP could be a good substitute for IFNα2b for anti-HBV treatment.
Reduced Sympathetic Response to Head-Up Tilt in Subjects with Mild Cognitive Impairment or Mild Alzheimer's Dementia
Authors: Mellingsæter Marte Rognstad , Wyller Torgeir Bruun , Ranhoff Anette Hylen , Bogdanovic Nenad , Wyller Vegard Bruun
Published: March 2015

Background: Hemodynamic control was compared in patients with mild cognitive impairment (MCI) or mild Alzheimer's dementia (AD) as well as in healthy elderly subjects. Methods: Noninvasive, continuous hemodynamic recordings were obtained from 14 patients and 48 controls during supine rest (tilt of 30 and 70°). Cardiac output, end-diastolic volume, total peripheral resistance, heart rate variability (HRV), systolic blood pressure variability (SBPV), and baroreceptor sensitivity were calculated. Results: At 70° tilt, the HRV indices differed significantly, with higher high-frequency (HF) variability as well as lower low-frequency (LF) variability and LF/HF ratios in the patients. The patients had significantly lower SBPV in the LF range at 30° tilt. Conclusions: The results indicate a poorer sympathetic response to orthostatic stress in MCI and mild AD.
Prevalence of Dementia and Main Subtypes in Rural Northern China
Authors: Ji Yong , Shi Zhihong , Zhang Ying , Liu Shuling , Liu Shuai , Yue Wei , Liu Mengyuan , Huo Ya Ruth , Wang Jinhuan , Wisniewski Thomas
Published: March 2015

Background/Aims: The aim of this article was to estimate the prevalence of and to determine the sociodemographic risk factors for dementia, Alzheimer's disease (AD) and vascular dementia (VaD) among individuals residing in rural northern China. Methods: Between 2011 and 2012, residents aged ≥60 years and residing in rural areas of northern China were clinically assessed for symptoms of dementia, AD and VaD. Diagnoses were made using established criteria and standard procedures. Results: Among 5,578 enrolled study participants aged ≥60 years, the prevalence rates of dementia, AD and VaD were 7.7, 5.4 and 1.7%, respectively. Older age (OR = 1.17; 95% CI: 1.14-1.19) and female gender (OR = 2.13; 95% CI: 1.51-3.00) were identified as independent risk factors for AD. In turn, a higher educational level (OR = 0.36; 95% CI: 0.21-0.60) and engagement in social activities (OR = 0.219; 95% CI: 0.163-0.295) were protective factors. Risk factors associated with VaD were older age (OR = 1.11; 95% CI: 1.1-1.12) and hypertension (OR = 1.83; 95% CI: 1.18-2.86), while a higher educational level (OR = 0.53, 95% CI: 0.44-0.65) and engagement in social activities (OR = 0.34; 95% CI: 0.29-0.41) were protective factors. Conclusion: High rates of dementia (7.7%) and AD (5.4%) were found in the rural areas of northern China. Older age and female gender were identified as risk factors for AD, while older age and hypertension were risk factors for VaD. A higher educational level and engagement in social activities were identified as protective factors against both AD and VaD.
Effectiveness of Natalizumab in Patients with Highly Active Relapsing Remitting Multiple Sclerosis
Authors: Cobo-Calvo Álvaro , Bau Laura , Matas Elisabet , Romero-Pinel Lucía , Mañé Martínez M. Alba , Majós Carles , Martínez Yélamos Sergio
Published: March 2015

Introduction: We evaluated the effectiveness of natalizumab in patients with highly active, relapsing-remitting multiple sclerosis (HA-RRMS) to identify baseline predictors associated with freedom from disease activity. Methods: We analyzed 70 patients treated with natalizumab and followed for at least 1 year with progression of disability of ≥1 point on the EDSS before starting therapy. We recorded freedom from clinical activity, radiological activity, and disease activity (clinical and radiological). Results: The median (IQR) follow-up was 2.3 (2.0-3.8) years. Of the 52 patients who completed 2 years of treatment, 25 were free of disease activity (48.1%). The ARR decreased from a mean ± SD of 2.49 ± 0.86 at baseline to 0.47 ± 0.83 at the end of the first year (p < 0.001) and 0.34 ± 0.69 at the end of the second year (p < 0.001). The percentage of patients with gadolinium-enhanced lesions decreased from 21 at baseline to 5.7 at the end of the first year (p < 0.001) and to 5.8 during the second year (p < 0.005). Baseline EDSS ≤3.0 was significantly associated with freedom from disease activity (OR, 2.49; 95% CI, 1.24-4.99; p = 0.010). Conclusions: Natalizumab is effective in patients with HA-RRMS. Baseline EDSS ≤3.0 increases the probability of remaining disease-free in HA-RRMS treated with natalizumab.
Targeting DNA Methylation with Green Tea Catechins
Authors: Yiannakopoulou Eugenia C.
Published: March 2015

Aberrant epigenetic alterations in the genome such as DNA methylation play a significant role in cancer development. Green tea catechins have been reported to modulate epigenetic processes. This review aims to synthesize evidence on the modulation of DNA methylation by green tea catechins. Green tea catechins have been reported to reverse DNA methylation of tumor suppressor genes and increase transcription of these genes. Green tea catechins and especially epigallocatechin gallate modulate DNA methylation by attenuating the effect of DNA methyltransferase 1 (DNMT1). However, the exact mechanism of DNMT1 inhibition is not delineated. Suggested mechanisms include direct enzymatic inhibition, indirect enzymatic inhibition, reduced DNMT1 expression and translation. The possible effect of green tea catechins on other pathways of DNA methylation, i.e. methyl-CpG binding domain proteins, has not been investigated. Furthermore, the link between redox properties and epigenetic modulation by green tea catechins has not been defined either. Since green tea catechins are natural compounds with a rather acceptable safety profile, further research on their action as inhibitors of DNA methylation seems worthwhile.
Coagulation Factor XII Gene Mutation in Brazilian Families with Hereditary Angioedema with Normal C1 Inhibitor
Authors: Moreno Adriana S. , Valle Solange O.R. , Levy Soloni , França Alfeu T. , Serpa Faradiba S. , Arcuri Helen A. , Palma Mario S. , Campos Wagner N. , Dias Marina M. , Ponard Denise , Monnier Nicole , Lunardi Joel , Bork Konrad , Silva, Jr. Wilson Araujo , Arruda L. Karla
Published: March 2015

Background: Hereditary angioedema (HAE) with normal C1 inhibitor (C1-INH) is a rare disorder. Mutations of the gene encoding coagulation factor XII have been identified in a subset of patients with this condition. Our aim was to investigate mutations in the F12 gene in patients with HAE with normal C1-INH from Brazil. Methods: We studied 5 Brazilian families with index female patients who presented with recurrent angioedema with normal C1-INH and C4 levels. Genomic DNA was isolated from whole blood and PCR was performed. Mutations were detected by the sequencing of exon 9 of the F12 gene and allelic discrimination. Results: The c.983C>A (p.Thr328Lys) mutation was identified in 16 subjects, from 4 of the 5 families studied, including 8 patients with symptoms of HAE with normal C1-INH (87.5% women) and 8 subjects asymptomatic for HAE (25% women). Mean age at onset of symptoms among the FXII-HAE patients was 13.8 years (range 6-25 years). Recurrent abdominal pain (100%) and subcutaneous angioedema (87.5%) were the most frequent clinical presentations. Two patients presented with associated laryngeal edema. In keeping with previous observations in patients with both C1-INH-HAE and HAE with normal C1-INH, all 7 women with FXII-HAE reported triggering or worsening of symptoms upon intake of estrogen-containing oral contraceptives and/or pregnancy. Conclusions: We report for the first time in Brazil a mutation in the F12 gene as a likely cause of HAE with normal C1-INH in patients with recurrent attacks of angioedema and/or abdominal pain. A higher frequency of abdominal pain attacks and onset of symptoms at a younger age were observed among Brazilian patients when compared to those from other parts of the world.
Inflammatory Morbidity due to Compound Mandibular Body Fractures: Does It Have a Relationship with Treatment Outcome?
Authors: Anyanechi Charles E. , Saheeb Birch D.
Published: March 2015

Objective: The aim of this study was to evaluate the relationship between the degree of preoperative pain and trismus with the development of complications following the repair of isolated unilateral compound mandibular body fractures using a closed reduction technique. Subjects and Methods: This was a 7-year prospective study carried out at the Dental and Maxillofacial Surgery Clinic of the University of Calabar Teaching Hospital, Calabar, Nigeria. Of a total of 97 patients, 83 (85.6%) subjects (66 males, 17 females, ratio 5:1) were preoperatively evaluated for trismus and pain in a blinded manner by a single examiner, and complications were recorded postoperatively. The data obtained were statistically analyzed with EPI Info 2008 software. Results: Of the 83 patients treated, 13 (15.7%) developed complications. The fractures were most common in the age range of 21-40 years (n = 45, 54.2%). The age (p = 0.02) and gender (p = 0.01) distribution of the subjects was significant. The more severe the limitation of mouth opening (p = 0.03) and pain (p = 0.04) before treatment, the more complications developed, and these significantly affected treatment outcome. Impaired mastication and facial asymmetry (n = 17, 41.5%) were the most common complications. Conclusion: This study showed that posttrauma pain and trismus due to unilateral mandibular body fractures may be associated with the development of complications. An adequately powered prospective study treating patients at 5 or 7 days is required in order to make the case for later intervention.
KISS1R: Hallmarks of an Effective Regulator of the Neuroendocrine Axis
Authors: Millar Robert P. , Babwah Andy V.
Published: March 2015

Kisspeptin (KP) is now well recognized as a potent stimulator of gonadotropin-releasing hormone (GnRH) secretion and thereby a major regulator of the neuroendocrine-reproductive axis. KP signals via KISS1R, a G protein-coupled receptor (GPCR) that activates the G proteins Gαq/11. Modulation of the interaction of KP with KISS1R is therefore a potential new therapeutic target for stimulating (in infertility) or inhibiting (in hormone-dependent diseases) the reproductive hormone cascade. Major efforts are underway to target KISS1R in the treatment of sex steroid hormone-dependent disorders and to stimulate endogenous hormonal responses along the neuroendocrine axis as part of in vitro fertilization protocols. The development of analogs modulating KISS1R signaling will be aided by an understanding of the intracellular pathways and dynamics of KISS1R signaling under normal and pathological conditions. This review focuses on KISS1R recruitment of intracellular signaling (Gαq/11- and β-arrestin-dependent) pathways that mediate GnRH secretion and the respective roles of rapid desensitization, internalization, and recycling of resensitized receptors in maintaining an active population of KISS1R at the cell surface to facilitate prolonged KP signaling. Additionally, this review summarizes and discusses the major findings of an array of studies examining the desensitization of KP signaling in man, domestic and laboratory animals. This discussion highlights the major effects of ligand efficacy and concentration and the physiological, developmental, and metabolic status of the organism on KP signaling. Finally, the potential for the utilization of KP and analogs in stimulating and inhibiting the reproductive hormone cascade as an alternative to targeting the downstream GnRH receptor is discussed.
Impact of Thyroid Hormones on Estrogen Receptor α-Dependent Transcriptional Mechanisms in Ventromedial Hypothalamus and Preoptic Area
Authors: Faustino Larissa C. , Gagnidze Khatuna , Ortiga-Carvalho Tania M. , Pfaff Donald W.
Published: March 2015

Elevated levels of thyroid hormones (TH) reduce estradiol (E2)-dependent female sexual behavior. E2 stimulates progesterone receptor (Pgr) and oxytocin receptor (Oxtr) within the ventromedial hypothalamus and preoptic area, critical hypothalamic nuclei for sexual and maternal behavior, respectively. Here, we investigated the impact of TH on E2-dependent transcriptional mechanisms in female mice. First, we observed that triiodothyronine (T3) inhibited the E2 induction of Pgr and Oxtr. We hypothesized that differences in histone modifications and receptor recruitment could explain the influence of TH on E2-responsive Pgr and Oxtr expression. We observed that histone H3 acetylation (H3Ac) and methylation (H3K4me3) was gene and brain-region specific. We then analyzed the recruitment of estrogen receptor α (ERα) and TH receptor α (TRα) on the putative regulatory sequences of Pgr and Oxtr. Interestingly, T3 inhibited E2-induced ERα binding to a specific Pgr enhancer site, whereas TRα binding was not affected, corroborating our theory that the competitive binding of TRα to an ERα binding site can inhibit ERα transactivation and the subsequent E2-responsive gene expression. On the Oxtr promoter, E2 and T3 worked together to modulate ERα and TRα binding. Finally, the E2-dependent induction of cofactors was reduced by hypothyroidism and T3. Thus, we determined that the Pgr and Oxtr promoter regions are responsive to E2 and that T3 interferes with the E2 regulation of Pgr and Oxtr expression by altering the recruitment of receptors to DNA and changing the availability of cofactors. Collectively, our findings provide insights into molecular mechanisms of response to E2 and TH interactions controlling sex behavior in the hypothalamus.
Factors Controlling Movement of Skeletal Muscles
Authors: Grounds Miranda D.
Published: March 2015

The contraction of specialized skeletal muscle cells results in classic movements of bones and other parts of the body that are vital for life. There is exquisite control over the movement of diverse types of muscles. This paper indicates the way in which skeletal muscles (myofibres) are formed; then factors that contribute to generating the movement are outlined: these include the nerve, sarcomeres, cytoskeleton, cell membrane and the extracellular matrix. The factors controlling the movement of mature myofibres in 3-dimensional tissues in vivo are vastly more complex than for tissue cultured immature muscle cells in an artificial in vitro environment.
A new genus and species of false vampire (Chiroptera: Megadermatidae) from peninsular Thailand
Authors: SOISOOK PIPAT , PRAJAKJITR AMORN , KARAPAN SUNATE , FRANCIS CHARLES M. , BATES PAUL J. J.
Published: March 2015

A new genus and associated species of false vampire, family Megadermatidae, are described based on three specimens from Bala Forest, Narathiwat Province, peninsular Thailand. The new taxon is characterised by a unique combination of distinctive dental, cranial, and external characters, some of which are shared with exclusively African genera and some with Asian genera. These characters are comparable to, or exceed in number, those differentiating currently recognised genera in the family Megadermatidae. They include the absence of a first upper premolar; greatly enlarged upper canine without an anterolingual cingular cusp but with a robust posterolingual cusp; unmodified upper first molar with the preparacrista subequal in length to the postmetacrista, the metastyle not reduced and situated labially; robust lower canine without an anterolingual cusp; the first lower premolar enlarged, equal to or larger than the second lower premolar. In the skull, there is a pronounced rostral depression but no well developed frontal shield with preorbital and/or postorbital processes; the coronoid process is greatly enlarged in each half mandible. Externally, the body size is relatively large and the posterior noseleaf is rounded. The baculum has a robust shaft and two short prongs—the bacula of all five other species of megadermatid are illustrated for the first time; extraordinarily, those of Macroderma gigas and Megaderma lyra comprise two separate bones. DNA barcoding indicate a genetic divergence of about 20 percent (sequence divergence in the mitochondrial gene CO1) between the new genus and species of Megaderma and Cardioderma. Currently, despite numerous bat surveys in peninsular Thailand, the new genus is only known from Bala Forest. The small area of this forest and the very low capture rate suggest that the new species may be extremely rare. Its natural history is little known, although its robust dental and cranial features when coupled with chance observations of its feeding behaviour, suggest it may specialise in eating large beetles. Its conservation status is considered to be at risk owing to the rapid loss of forest habitat in much of the Thai-Malay peninsula.
Redescription of Astyanax guianensis Eigenmann 1909 (Characiformes: Characidae), a poorly known and widespread fish from the Amazon, Orinoco and Guiana Shield drainages
Authors: MARINHO MANOELA M. F. , CAMELIER PRISCILA , BIRINDELLI JOSÉ L. O.
Published: March 2015

Astyanax guianensis is redescribed based on the holotype, paratypes, and additional specimens from the rio Essequibo in Guyana, rio Orinoco in Venezuela and from several localities in the Amazon river basin in Brazil, Colombia and Bolivia. Astyanax guianensis is diagnosed by having five to 10 maxillary teeth, 31 to 35 pored lateral-line scales, 21 to 25 branched anal-fin rays, and a dark vertical humeral blotch followed by a clear area and then by a dark longitudinal stripe, ending before the caudal-fin rays. In addition, comments on the importance of revisionary studies on the species of the Characidae are provided.
A new species of Alterosa Blahnik (Trichoptera: Philopotamidae: Philopotaminae) from Espírito Santo State, southeastern Brazil
Authors: BARCELOS-SILVA PATRIK , DUMAS LEANDRO LOURENÇO , PES ANA MARIA
Published: March 2015

The genus Alterosa was erected by Blahnik (2005) to include 20 new species, as well as two previously described species, Dolophilodes (Sortosa) sanctipauli Flint 1971 and Dolophilodes (Sortosa) marinonii Almeida & Duarte 2003 that Blahnik transferred into it. Currently the genus contains 38 species, all of them endemic to the Brazilian Atlantic Forest (Jardim & Dumas 2012; Dumas & Nessimian 2013; Dumas et al. 2013). The rapid increase in the number of species reflects a likelihood that much of the total diversity within Alterosa is unknown. Adults are usually encountered in pristine headwaters, rapids of streams, or small rivers, and are rarely collected near large rivers (Dumas et al. 2013). The immature stages are unknown. Although there are superficial similarities among the species within the genus, they can be easily identified by male genital features (Jardim & Dumas 2012). Recently, Dumas et al. (2013) provide an identification key based on characters of male genitalia.
Response of Southern Ocean Convection and Abyssal Overturning to Surface Buoyancy Perturbations
Authors: Morrison Adele K. , England Matthew H. , Hogg Andrew McC.
Published: March 2015

This study explores how buoyancy-driven modulations in the abyssal overturning circulation affect Southern Ocean temperature and salinity in an eddy-permitting ocean model. Consistent with previous studies, the modeled surface ocean south of 50°S cools and freshens in response to enhanced surface freshwater fluxes. Paradoxically, upper-ocean cooling also occurs for small increases in the surface relaxation temperature. In both cases, the surface cooling and freshening trends are linked to reduced convection and a slowing of the abyssal overturning circulation, with associated changes in oceanic transport of heat and salt. For small perturbations, convective shutdown does not begin immediately, but instead develops via a slow feedback between the weakened overturning circulation and buoyancy anomalies. Two distinct phases of surface cooling are found: an initial smaller trend associated with the advective (overturning) adjustment of up to ~60 yr, followed by more rapid surface cooling during the convective shutdown period. The duration of the first advective phase decreases for larger forcing perturbations. As may be expected during the convective shutdown phase, the deep ocean warms and salinifies for both types of buoyancy perturbation. However, during the advective phase, the deep ocean freshens in response to freshwater perturbations but salinifies in the surface warming perturbations. The magnitudes of the modeled surface and abyssal trends during the advective phase are comparable to the recent observed multidecadal Southern Ocean temperature and salinity changes.
Atmospheric Circulation Characteristics Favoring Dust Outbreaks over the Solar Village, Central Saudi Arabia*
Authors: Houssos E. E. , Chronis T. , Fotiadi A. , Hossain F.
Published: March 2015

This study examines the atmospheric circulation characteristics of dust outbreaks (DOs) over the central Arabian Peninsula. Based on a 12-yr (1999–2011) Aerosol Robotic Network (AERONET) database over the Solar Village in Saudi Arabia and criteria pertinent to the aerosol optical depth at 500 nm and the Ångström exponent, 177 DOs have been identified. Factor and cluster analysis are further applied on the 1000- and 700-hPa geopotential height daily patterns of the days preceding the onset of the DOs and the days of the DOs’ initiation, revealing four main types (clusters) of the atmospheric circulation evolution leading to DOs. During the winter season, the anticyclonic circulation intensifies over the Middle East causing the strengthening of the pressure gradient over the Arabian Peninsula, inducing northerly winds over the study region, thereby favoring dust entrainment in the atmosphere (cluster 1, 16 DOs, 9%). The passage of midlatitude cyclones over the northern or central Arabian Peninsula is frequently accompanied by postfrontal northerly winds also promoting the presence of DOs in the region (cluster 2, 41 DOs, 23%). The DOs during spring are likely favored by the enhancement of convective activity, as the thermal low over the Arabian Peninsula further influences the dynamics of the upper troposphere (cluster 3, 73 DOs, 41%). During summer the pressure gradient over the study region is greatly enhanced due to the extension of the subtropical Azores anticyclone over the Mediterranean. The latter is the main driver triggering the DOs in this cluster category (cluster 4, 46 DOs, 27%).
Improved Tropical Storm Forecasts with GOES-13/15 Imager Radiance Assimilation and Asymmetric Vortex Initialization in HWRF
Authors: Zou X. , Qin Z. , Zheng Y.
Published: March 2015

The Geostationary Operational Environmental Satellite (GOES) imagers provide high temporal- and spatial-resolution data for many applications, such as monitoring severe weather events. In this study, radiance observations of four infrared channels from GOES-13 and GOES-15 imagers are directly assimilated using the National Centers for Environmental Prediction (NCEP) gridpoint statistical interpolation (GSI) analysis system to produce the initial conditions for the Hurricane Weather Research and Forecasting Model (HWRF). Impacts of GOES imager data assimilation on track and intensity forecasts are demonstrated for a landfalling tropical storm that moved across the Gulf of Mexico—Debby (2012). With a higher model top and a warm start, an asymmetric component is also added to the original HWRF symmetric vortex initialization. Two pairs of data assimilation and forecasting experiments are carried out for assessing the impacts of the GOES imager data assimilation on tropical storm forecasts. The first pair employs a symmetric vortex initialization and the second pair includes an asymmetric vortex initialization. Numerical forecast results from these experiments are compared against each other. It is shown that a direct assimilation of GOES-13 and GOES-15 imager radiance observations, which are available at all analysis times, in HWRF results in a consistently positive impact on the track and intensity forecasts of Tropical Storm Debby in the Gulf of Mexico. The largest positive impact on the track and intensity forecasts comes from a combined effect of GOES imager radiance assimilation and an asymmetric vortex initialization.
Human Lives at Risk because of Eustatic Sea Level Rise and Extreme Coastal Flooding in the Twenty-First Century
Authors: Adachi Yosuke
Published: March 2015

Sea level rise (SLR) is a topic of increasing importance, as global warming continues to drive it at the global level and other factors such as land subsidence also affect it at the local level. Economic and human-based approaches have been taken to assess its impact on society. However, quantifications of the effect of SLR on mortality have not been extensive. Therefore, the objective of this study is to quantify the relative impact of SLR on mortality due to extreme coastal flooding for 2011–2100. First, an empirical relationship between annual storm surges caused by tropical cyclones (TCs) and associated fatalities is established. Next, a conceptual framework is introduced to measure rises in sea level due to gradual SLR and temporary storm surges on a common scale called cumulatively raised sea level. An analysis applying SLR projections to this framework shows that, in addition to the deaths that occur because of coastal flooding due to TCs, at least 84–139 deaths due to extra coastal flooding caused by SLR may occur in the United States by 2100, in the absence of coastal population changes, adaptation, and protection failure. Higher-than-expected rates of SLR due to increased discharge from polar glaciers will raise this estimate to 277. Protection failure will also result in more fatalities. Conversely, adaptation, even when combined with coastal population increases, may lead to fewer fatalities.
Synthesis and Anti-HIV Activity of Prodrugs Derived from Saquinavir and Indinavir
Authors: Giorgio Audrey Farèse-Di , Rouquayrol Marielle , Greiner Jacques , Aubertin Anne-Marie , Vierling Pierre , Guedj Roger
Published: March 2015

With a view to improving the pharmacological properties, safety and pharmacokinetic profiles of current protease inhibitors, the synthesis of various acyl-substituted saquinavir and indinavir prodrugs, their in vitro stability with respect to hydrolysis and their anti-HIV (LAI and HTLV IIIB) activity and cytotoxicity in CEM-SS and MT4 cells have been investigated. Hydrolysis of the ester bond and liberation of the active free drug was found to be crucial for HIV inhibition: the faster the hydrolysis, the closer the anti-HIV activity was to that of the respective parent drug. This is the case for most of the C-14-substituted indinavir and saquinavir derivatives (IC50 from 10 to 360 nM for ester half-lives of 90 min to 40 h). Concomitantly, the level of HIV inhibition is very low for the prodrugs for which hydrolysis is very slow. This is the case with the myristoyl or oleyl saquinavir esters, owing to the stable masking of the hydroxyl that is part of the peptidomimetic non-cleavable transition state isostere responsible for the inhibitory potency of saquinavir (and indinavir). In contrast, the anti-HIV activity of the monosubstituted C-8 indinavir prodrugs seems not to be correlated with their resistance to hydrolysis, as expected (the C-8 hydroxyl of indinavir is not involved in the transition state isostere). No cytotoxicity was detected for the indinavir and saquinavir prodrugs for concentrations as high as 10 or even 100 μM, thus indicating promising therapeutic potential.
The Enantioselectivity of Enzymes Involved in Current Antiviral Therapy Using Nucleoside Analogues: A New Strategy?
Authors: Maury Georges
Published: March 2015

This review is primarily intended for synthetic bio-organic chemists and enzymologists who are interested in new strategies in the design of virus inhibitors. It is an attempt to assess the importance of the enzymatic properties of L-nucleosides and their analogues, particularly those that are active against viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), herpes simplex virus (HSV), etc. Only data obtained with purified enzymes have been considered and discussed. The examined enzymes include nucleoside- or nucleotide-phosphorylating enzymes, catabolic enzymes, viral target enzymes and cellular polymerases. The enantioselectivities of these enzymes were determined from existing data and are significant only when a sufficient number of enantiomeric pairs of substrates could be examined. The reported data emphasize the weak enantioselectivities of cellular or viral nucleoside kinases and some viral DNA polymerases. Thus, cellular deoxycytidine kinase has a considerably relaxed enantioselectivity with respect to a large number of nucleosides or their analogues, and it occupies a strategic position in the intracellular activation of the compounds. Similarly, HIV-1 reverse transcriptase often has a relatively weak enantioselectivity and can be inhibited by the 5-triphosphates of a large series of L-nucleosides and analogues. In contrast, degradation enzymes, such as adenosine or cytidine deaminases, generally demonstrate strict enantioselectivities favouring D-enantiomers and are used by chemists in asymmetric syntheses. The weak enantioselectivities of some enzymes involved in nucleoside metabolism are more or less pronounced, and one enantiomer or the other is favoured depending on the substrate. This suggests that the low enantioselectivity is fortuitous and does not result from evolutionary pressure, since these enzymes do not create or modify asymmetric centres in substrates. The combined enantioselectivities of the enzymes examined in this review strongly suggest that the field of L-nucleosides and their analogues should be systematically explored in the search for new virus inhibitors.
Differences in DNA Packaging Genes and Sensitivity to Benzimidazole Ribonucleosides between Human Cytomegalovirus Strains AD169 and Towne
Authors: Krosky Paula M , Ptak Roger G , Underwood Mark R , Biron Karen K , Townsend Leroy B , Drach John C
Published: March 2015

The AD169 strain of human cytomegalovirus was approximately twofold more sensitive to poly-halogenated benzimidazole ribonucleosides than Towne strain. Sequence differences between the two strains have been identified in genes UL51, UL52, UL56, UL77, UL89 and UL104. Because these genes are involved in cleavage and packaging of viral DNA and the benzimidazole ribonucleosides inhibit this process, these sequence differences may be involved in the difference in drug sensitivity.
Synthesis and Anti-Varicella-Zoster Virus Activity of Some Novel Bicyclic Nucleoside Inhibitors: Effect of Enhanced Aqueous Solubility
Authors: Brancale A , Srinivasan S , McGuigan C , Andrei G , Snoeck R , De Clercq E , Balzarini J
Published: March 2015

We have recently reported the discovery of an entirely new category of potent anti-varicella-zoster virus agents based on novel deoxynucleoside analogues bearing unusual fluorescent bicyclic furo base moieties. Initial studies revealed an absolute requirement of a long alkyl side-chain, with an optimal length of C8–C10, for antiviral activity. However, the impact of this requirement on the physical properties of these compounds is high: inherent lipophilicity and extremely poor aqueous solubility, which may limit the use of these nucleosides as drugs. In order to address this issue, we have now prepared a new series of analogues, bearing ether and glycol type side-chains, designed to improve the aqueous solubility of the compounds. Synthesis of target nucleosides involved Pd-catalysed coupling of terminal alkynes with 5-iodo-2′-deoxyuridine. The 5-alkynyl nucleosides thus obtained were then treated with copper (I) iodide to produce the desired bicyclic analogues. As anticipated, the new compounds exhibited a dramatic increase in aqueous solubility, although antiviral activity was significantly reduced. A possible correlation between antiviral activity and overall compound lipophilicity is discussed.
Anti-HIV-1 Activity in Vitro of Ceftazidime Degradation Products
Authors: Hobi Reinhard , Hübscher Ulrich , Neftel Klaus , Alteri Enrica , Poncioni Bernard , Walker Maja R , Woods-Cook Kathie , Schneider Peter , Lazdins Janis K
Published: March 2015

Cephalosporins in aqueous solutions generate degradation products that inhibit in vitro HIV-1 replication in cell lines, as well as in primary cells (lymphocytes and macrophages). This effect is observed at concentrations that do not interfere with the normal functions of these cells. Upon chromatographic fractionation of an aqueous solution of hydrolysed ceftazidime, a high molecular weight fraction (MW 8000) with antiviral activity was isolated. The exact chemical nature of the active component responsible for the anti-HIV activity in vitro appears to be complex and is currently unknown. Inhibition of HIV-1 reverse transcriptase and RNase H activity was observed, however, higher concentrations than those needed to inhibit HIV replication were required. The inhibitory action of the hydrolysed ceftazidime was manifested during the early phase of the HIV-1 life-cycle. Despite a lack of a direct effect of the CD4/gp120 interaction, HIV-1 mediated cell fusion was inhibited by the hydrolysed ceftazidime, suggesting that the active principle acts in a very early stage of the viral life-cycle.
Three-Drug Combinations of Emivirine and Nucleoside Reverse Transcriptase Inhibitors in Vitro: Long-Term Culture of HIV-1-Infected Cells and Breakthrough Viruses
Authors: Nitanda T , Wang X , Somekawa K , Yuasa S , Baba M
Published: March 2015

Emivirine (EMV) is a non-nucleoside reverse transcriptase inhibitor currently undergoing Phase III clinical trials in HIV-1-infected patients. In this study, the anti-HIV-1 activity of EMV in combination with two nucleoside reverse transcriptase inhibitors was examined in cell cultures. The combinations EMV plus stavudine (d4T) plus lamivudine (3TC) and EMV plus d4T plus didanosine (ddl) synergistically inhibited HIV-1 replication in MT-4 cells. Although not statistically significant, EMV plus d4T plus 3TC appeared to be more synergistic than EMV plus d4T plus ddl. Synergism was also observed with any two-drug combinations, such as EMV plus d4T, EMV plus 3TC, EMV plus ddl, d4T plus 3TC, or d4T plus ddl. The three-drug combinations completely suppressed HIV-1 replication for at least 40 days after virus infection. Except for d4T, virus emerged in the presence of every compound alone or some combinations at lower concentrations. Susceptibility tests of the breakthrough viruses to each compound showed that the viruses obtained in the presence of EMV alone and 3TC alone were significantly less susceptible to EMV and 3TC, respectively. These viruses had specific amino acid mutations in their reverse transcriptase.
Intracellular Phosphorylation of Carbocyclic 3-Deazaadenosine, an Anti-Ebola Virus Agent
Authors: Smee Donald F , Bray Mike , Huggins John W
Published: March 2015

Carbocyclic 3-deazaadenosine (C-c3Ado) is a potent inhibitor of Ebola virus in mice by infrequent dosing, even though its half life in plasma is only 23–28 min. This prompted studies to determine whether C-c3Ado undergoes intracellular metabolism to derivatives that may promote in vivo activity. In cells, radiolabelled compound readily underwent metabolism to monophosphate, diphosphate and triphosphate (C-c3ATP) forms, with C-c3ATP being the major metabolite detected. A non-polar metabolite was also detected both inside and outside treated cells. The retention time of C-c3ATP was similar but not identical to ATP on a strong anion exchange high performance liquid chromatography (HPLC) column or on a DEAE-Sephadex open column. C-c3ATP and ATP were susceptible to degradation to their respective nucleosides by bovine alkaline phosphatase. Intracellular formation of C-c3ATP reached a plateau by about 4 h after treatment of monkey (vero 76) and mouse (Balb/3T3 clone A31) cells with 10 or 100 μM extracellular compound. Phosphorylation was linearly dose responsive at 1, 3 and 10 μM. However, the extent of phosphorylation decreased with increasingly higher concentrations (30, 100 and 300 μM). When compound was removed from the medium, the nucleoside cleared the cells within 1 min, whereas C-c3ATP had a half life of decay of 2–3 h in five cell lines. Phosphorylation of C-c3Ado to C-c3ATP was not inhibited by cotreatment of cells (at a 20:1 ratio) with adenosine, guanosine, inosine, xanthosine, cytidine or uridine. There was no evidence of incorporation of C-c3Ado (10 μM) into macromolecules of cells over 72 h, whereas adenosine was readily incorporated. C-c3ATP may represent a form of C-c3Ado that might contribute to extending its intracellular half life or otherwise exhibit antiviral activity and/or toxicity.
Antiviral Activity of Cyclosaligenyl Prodrugs of Acyclovir, Carbovir and Abacavir
Authors: Balzarini Jan , Haller-Meier Friederike , De Clercq Erik , Meier Chris
Published: March 2015

The cyclosaligenyl ( cycloSal) derivatives of the monophosphates of three acyclic or carbocyclic guanosine analogues, for example, acyclovir (ACV), carbovir (CBV) and abacavir (ABC), were investigated for their activity against retrovirus (HIV, Moloney sarcoma virus) and herpes simplex virus (HSV) activity in cell culture. The extent of the antiviral potency of the prodrugs depended on the nature of the nucleoside, the substituent on the cycloSal moiety and the virus investigated. Most notably, and unlike the parent compound ACV, cycloSal-ACV monophosphate (MP) prodrugs retained pronounced activity against ACV-resistant (thymidine kinase-deficient) HSV-1 and also gained anti-HIV activity. While the cycloSal-CBVMP prodrugs did not show enhanced activity compared with the parent compound CBV, the cycloSal-ABCMP prodrugs afforded markedly increased potency against both HSV and HIV. Our data indicate that the cycloSal prodrug approach can be useful to deliver directly the MP derivatives of nucleoside analogues into the intact, virus-infected cells, thus improving and extending the antiviral potency and spectrum of the drugs against retro- and herpesvirus strains.
Anti-HIV-1 Activity of Benzothiadiazine Dioxide
Authors: Martinez Ana , Gil Carmen , Castro Ana , Perez Concepciön , Witvrouw Myriam , Pannecouque Christophe , Balzarini Jan , De Clercq Erik
Published: March 2015

Antiviral assays carried out on the potent benzothiadiazine dioxide (BTD) human cytomegalovirus (HCMV) inhibitors have led us to find marginal but selective anti-HIV-1 activity. Specific pharmacological studies, such as time of addition experiments and assays on specific viral strains with mutations on its reverse transcriptase, have indicated that BTD compounds act as non-nucleoside reverse transcriptase inhibitors. Theoretical calculations showed a butterfly conformation for the active derivatives that are compatible with their mechanism of action. Therefore, BTD derivatives can be considered as potential lead compounds for the treatment of opportunistic HCMV infections in immunocompromised individuals such as AIDS patients.
Antiviral Activity of Brassinosteroids Derivatives against Measles Virus in Cell Cultures
Authors: Wachsman Mónica B , Ramirez Javier A , Galagovsky Lydia R , Coto Celia E
Published: March 2015

Twenty-seven brassinosteroid derivatives were tested for antiviral activity against measles virus (MV) via a virus-yield reduction assay. Compounds 6b [(22S,23S)-3β-bromo-5α,22,23-trihydroxystigmastan-6-one], 1d [(22R,23R)-2α,3α,22,23-tetrahydroxy-β-Homo-7-oxa-stigmastan-6-one], 8a [(22R,23R)-3β-fluoro-22,23-dihydroxystigmastan-6-one], 9b [(22S,23S)-3β-fluoro- 5α,22,23-trihydroxystigmastan-6-one] and 10b [(22S,23S)-5α-fluor-3β,22,23-trihydroxystigmastan-6-one], with selectivity indexes (SI) of 40, 57, 31, 37 and 53, are the derivatives with good antiviral activity against MV. These SI values are higher than those obtained with ribavirin (used as reference drug). A comparative analysis of 50% cytotoxic concentration (CC50) values, using confluent non-growing cells, gives and indication of structure—activity relationship. According to their degree of cytotoxicity the compounds were divided in three groups: low, intermediate and high cytotoxicity. By observing the chemical structures of compounds belonging to the first group we can see that less cytotoxic activities are related to the presence of a 3β-hydroxy group on C-3 (ring A) and a double bond between C-22 and C-23 (side chain). The replacement of a 5α-hydroxy group by a 5α-fluoro group enhances cytotoxicity. Halogenated brassinosteroid derivatives in C-3 position are more cytotoxic than those with an acetoxy group in the same position. For compounds 1d, 6b, 10b and ribavirin, cytotoxicity measurements were also done with replicating cells; CC50 values were low, but they still competed favourably with ribavirin against MV.
New Millennium Antivirals against Pandemic and Epidemic Influenza: The Neuraminidase Inhibitors
Authors: Oxford John S , Novelli Patricia , Sefton Armine , Lambkin Robert
Published: March 2015

The mushroom shaped outer spike protein of influenza, neuraminidase, was first discovered nearly 60 years ago. Its importance in viral replication was soon recognised both at the point of viral release from the cell and also enabling passage of virus through nasal fluid to reach the cell. The enzyme active site was identified by x-ray crystallography, allowing an atomic study of interaction of enzyme with the sialic acid substrate. Analogues could then be identified and synthesized and became a focused target for antivirals. With the current threat of bioterrorism and the potential for the emergence of a new pandemic strain in the near future, efforts are underway to develop more potent second-generation anti-neuraminidase inhibitors with enhanced protective and therapeutic effects. Here we review older and newer neuraminidase inhibitors and the role that they will play in the fight against influenza in its epidemic and pandemic face.
Imino Sugars That are Less Toxic but More Potent as Antivirals, In Vitro, Compared with N-n-Nonyl DNJ
Authors: Mehta Anand , Ouzounov Serguey , Jordan Robert , Simsek Ender , Lu Xuanyong , Moriarty Robert M , Jacob Gary , Dwek Raymond A , Block Timothy M
Published: March 2015

Imino sugar glucosidase inhibitors have selective antiviral activity against certain enveloped, mammalian viruses. Deoxynojirimycins (DNJs) modified by N-alkylation to contain a nine carbon atom side chain (N-n-nonyl-deoxynojirimycin; N-nonyl-DNJ, NN-DNJ) were shown to be, for example, at least 20 times more potent in inhibiting hepatitis B virus (HBV) and bovine viral diarrhoea virus (BVDV) in cell based assays than the non-alkylated DNJ. These data suggested that modification of the alkyl side chain could influence antiviral activity. Previous work has focused on varying side chain length. In this report, the influence of side chain branching and cyclization upon toxicity and antiviral activity was explored. Briefly, using a virus secretion assay for HBV and a single step growth (yield reduction) assay for BVDV, 14 different DNJ-based sugars, possessing various N-alkyl substitutions, were tested for antiviral activity. Of the series, N-methoxy-nonyl-DNJ and N-butyl-cyclohexyl DNJ were determined to have the best selectivity index against BVDV and HBV, with the N-methoxy analogue being the most potent with micromolar antiviral activity. The results of this antiviral survey and the implications for the mechanism of action and ultimate therapeutic potential of the DNJ-based imino sugars is provided and discussed.
Synthesis and Antiviral Activity of a Series of New Cyclohexenyl Nucleosides
Authors: Gu Ping , Morral Jordi , Wang Jing , Rozenski Jef , Busson Roger , Van Aerschot Arthur , De Clercq Erik , Herdewijn Piet
Published: March 2015

A series of new cyclohexenyl nucleosides is synthesized by coupling the heterocyclic bases with a protected cyclohexenyl precursor under Mitsunobu conditions. The compounds were evaluated for their antiviral and cytostatic activity. Pronounced activity against herpes simplex virus type 1 and type 2 was observed for the 2,6-diaminopurine analogue.