bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hormone replacement therapy improves contractile function and myonuclear organization of single muscle fibres from postmenopausal monozygotic female twin pairs
Authors: Qaisar Rizwan , Renaud Guillaume , Hedstrom Yvette , Pöllänen Eija , Ronkainen Paula , Kaprio Jaakko , Alen Markku , Sipilä Sarianna , Artemenko Konstantin , Bergquist Jonas , Kovanen Vuokko , Larsson Lars 
Published: March 2013

Key points
The ageing‐related impairment of muscle function and consequent falls and fall‐related injuries have severe negative effects on morbidity and mortality in old age, with women being more negatively affected than men.
The effects of hormone replacement therapy (HRT) on regulation of muscle contraction and myonuclear organization were investigated in monozygous postmenopausal twin pairs where only one twin was an HRT‐user.
HRT treatment improved single fibre force‐generating capacity (specific force), without affecting fibre size and speed of contraction, due to fibre type‐specific effects on force and number of force‐generating cross‐bridges.
HRT had a significant effect on the myonuclear organization in slow‐twitch muscle fibres, improving the synthetic capacity of the myonuclei and optimizing transport of proteins.
Significant positive effects on regulation of muscle contraction and myonuclear organization were observed at the cellular level in response to HRT with consequences for quality of life in postmenopausal women.
Abstract  Ageing is associated with a decline in muscle mass and strength leading to increased physical dependency in old age. Postmenopausal women experience a greater decline than men of similar age in parallel with the decrease in female sex steroid hormone production. We recruited six monozygous female twin pairs (55–59 years old) where only one twin pair was on hormone replacement therapy (HRT use = 7.8 ± 4.3 years) to investigate the association of HRT with the cytoplasmic volume supported by individual myonuclei (myonuclear domain (MND) size,) together with specific force at the single fibre level. HRT use was associated with a significantly smaller (∼27%; P < 0.05) mean MND size in muscle fibres expressing the type I but not the IIa myosin heavy chain (MyHC) isoform. In comparison to non‐users, higher specific force was recorded in HRT users both in muscle fibres expressing type I (∼27%; P < 0.05) and type IIa (∼23%; P < 0.05) MyHC isoforms. These differences were fibre‐type dependent, i.e. the higher specific force in fast‐twitch muscle fibres was primarily caused by higher force per cross‐bridge while slow‐twitch fibres relied on both a higher number and force per cross‐bridge. HRT use had no effect on fibre cross‐sectional area (CSA), velocity of unloaded shortening (V0) and relative proportion of MyHC isoforms. In conclusion, HRT appears to have significant positive effects on both regulation of muscle contraction and myonuclei organization in postmenopausal women.
Complete blockade of the vasorelaxant effects of angiotensin‐(1–7) and bradykinin in murine microvessels by antagonists of the receptor Mas
Authors: Peiró Concepción , Vallejo Susana , Gembardt Florian , Palacios Erika , Novella Susana , Azcutia Verónica , Rodríguez‐Mañas Leocadio , Hermenegildo Carlos , Sánchez‐Ferrer Carlos F. , Walther Thomas 
Published: March 2013

Key points
Two distinct angiotensin‐(1–7) [Ang‐(1–7)] receptor blockers, A779 and d‐Pro‐Ang‐(1–7), can completely prevent Ang‐(1–7)‐induced vasorelaxation.
Genetic deficiency of Mas completely prevents vascular responses to Ang‐(1–7).
Genetic deficiency of Mas completely prevents vascular responses to other NO‐dependent vasorelaxants (bradykinin).
Mas plays a key role in NO‐mediated vasodilatation by modulating vasorelaxant‐mediated phosphorylation of endothelial nitric oxide synthase in endothelial cells.
Abstract  The heptapeptide angiotensin‐(1–7) is a biologically active metabolite of angiotensin II, the predominant peptide of the renin–angiotensin system. Recently, we have shown that the receptor Mas is associated with angiotensin‐(1–7)‐induced signalling and mediates, at least in part, the vasodilatory properties of angiotensin‐(1–7). However, it remained controversial whether an additional receptor could account for angiotensin‐(1–7)‐induced vasorelaxation. Here, we used two different angiotensin‐(1–7) antagonists, A779 and d‐Pro‐angiotensin‐(1–7), to address this question and also to study their influence on the vasodilatation induced by bradykinin. Isolated mesenteric microvessels from both wild‐type and Mas‐deficient C57Bl/6 mice were precontracted with noradrenaline, and vascular reactivity to angiotensin‐(1–7) and bradykinin was subsequently studied using a small‐vessel myograph. Furthermore, mechanisms for Mas effects were investigated in primary human umbilical vein endothelial cells. Both angiotensin‐(1–7) and bradykinin triggered a concentration‐dependent vasodilatation in wild‐type microvessels, which was absent in the presence of a nitric oxide synthase inhibitor. In these vessels, the pre‐incubation with the Mas antagonists A779 or d‐Pro‐angiotensin‐(1–7) totally abolished the vasodilatory capacity of both angiotensin‐(1–7) and bradykinin, which was nitric oxide mediated. Accordingly, Mas‐deficient microvessels lacked the capacity to relax in response to either angiotensin‐(1–7) or bradykinin. Pre‐incubation of human umbilical vein endothelial cells with A779 prevented bradykinin‐mediated NO generation and NO synthase phosphorylation at serine 1177. The angiotensin‐(1–7) antagonists A779 and d‐Pro‐angiotensin‐(1–7) equally block Mas, which completely controls the angiotensin‐(1–7)‐induced vasodilatation in mesenteric microvessels. Importantly, Mas also appears to be a critical player in NO‐mediated vasodilatation induced by renin–angiotensin system‐independent agonists by altering phosphorylation of NO synthase.
Weight Drives Caspofungin Pharmacokinetic Variability in Overweight and Obese People: Fractal Power Signatures beyond Two-Thirds or Three-Fourths
Authors: Hall Ronald G. , Swancutt Mark A. , Meek Claudia , Leff Richard , Gumbo Tawanda 
Published: March 2013

ABSTRACT

Echinocandins, such as caspofungin, are commonly used to treat candidemia and aspergilllosis. Success rates for candidemia treatment are approximately 70%. Dose optimization may further help improve these success rates, given that the microbial effect of these agents is concentration dependent. There are conflicting data as regards the effect of weight and/or obesity on caspofungin drug concentrations. We designed a prospective study to evaluate the population pharmacokinetics of caspofungin in adults with a weight difference range of 100 kg. Caspofungin pharmacokinetics were best described using a two-compartment pharmacokinetic model. There were 18 subjects studied, of whom half were women. The central volume was typically 4.2 liters but increased by a factor of (weight/53.6)
3/4
. The peripheral compartment volume was typically 2.53 liters but increased by a factor of (weight/53.6)
3/2
, an unusual power law signature. Similarly, the 3/4 power law best described the relationship between weight and systemic clearance for persons weighing >66.3 kg, whereas intercompartmental clearance was best described by the 3/2 power signature. There are two implications of our findings. First, lower caspofungin area-under-the-concentration-time curves are achieved in obese persons than thinner ones. This suggests that dose optimization in heavier patients may improve clinical success rates. Second, the 3/2 exponent is unusual in fractal geometry-based scaling and warrants further study. Moreover, this suggests that use of a “floating” instead of a fixed exponent may be more useful in studies where weight is under investigation as a potential cause of pharmacokinetic variability within adult patients. (This study protocol was registered at
www.clinicaltrials.gov
under registration number NCT01062165.)
Effect of Oseltamivir Carboxylate Consumption on Emergence of Drug-Resistant H5N2 Avian Influenza Virus in Mallard Ducks
Authors: Achenbach Jenna E. , Bowen Richard A. 
Published: March 2013

ABSTRACT

Oseltamivir carboxylate (OC) has been detected in environmental waters at various levels during recent influenza seasons in humans, reflecting levels of usage and stability of this drug. In consideration of the role of waterfowl as hosts for influenza viruses that may contribute to human infections, we evaluated the effect of consumption of low doses of OC on development of oseltamivir-resistant influenza virus mutants in mallard ducks (
Anas platyrhynchos
) infected with two different low-pathogenic (LP) H5N2 avian influenza viruses (AIV). We detected development of virus variants carrying a known molecular marker of oseltamivir resistance (neuraminidase E119V) in 4 out of 6 mallards infected with A/Mallard/Minnesota/182742/1998 (H5N2) and exposed to 1,000 ng/liter OC. The mutation first appeared as a minor population on days 5 to 6 and was the dominant genotype on days 6 to 8. Oseltamivir-resistant mutations were not detected in virus from ducks not exposed to the drug or in ducks infected with a second strain of virus and similarly exposed to OC. Virus isolates carrying the E119V mutation displayed
in vitro
replication kinetics similar to those of the wild-type virus, but
in vivo
, the E119V virus rapidly reverted back to wild type in the absence of OC, and only the wild-type parental strain was transmitted to contact ducks. These results indicate that consumption by wild waterfowl of OC in drinking water may promote selection of the E119V resistance mutation in some strains of H5N2 AIV that could contribute to viruses infecting human populations.
Pharmacokinetics of Phase I Nevirapine Metabolites following a Single Dose and at Steady State
Authors: Fan-Havard Patty , Liu Zhongfa , Chou Monidarin , Ling Yonghua , Barrail-Tran Aurélie , Haas David W. , Taburet Anne-Marie ,   the ANRS12154 Study Group
Published: March 2013

ABSTRACT

Nevirapine is one of the most extensively prescribed antiretrovirals worldwide. The present analyses used data and specimens from two prior studies to characterize and compare plasma nevirapine phase I metabolite profiles following a single 200-mg oral dose of nevirapine in 10 HIV-negative African Americans and a steady-state 200-mg twice-daily dose in 10 HIV-infected Cambodians. Nevirapine was assayed by high-performance liquid chromatography (HPLC). The 2-, 3-, 8- and 12-hydroxy and 4-carboxy metabolites of nevirapine were assayed by liquid chromatography-tandem mass spectrometry (LC/MS/MS). Pharmacokinetic parameters were calculated by noncompartmental analysis. The metabolic index for each metabolite was defined as the ratio of the metabolite area under the concentration-time curve (AUC) to the nevirapine AUC. Every metabolite concentration was much less than the corresponding nevirapine concentration. The predominant metabolite after single dose and at steady state was 12-hydroxynevirapine. From single dose to steady state, the metabolic index increased for 3-hydroxynevirapine (
P
< 0.01) but decreased for 2-hydroxynevirapine (
P
< 0.001). The 3-hydroxynevirapine metabolic index was correlated with nevirapine apparent clearance (
P
< 0.001). These findings are consistent with induction of CYP2B6 (3-hydroxy metabolite) and a possible inhibition of CYP3A (2-hydroxy metabolite), although these are preliminary data. There were no such changes in metabolic indexes for 12-hydroxynevirapine or 4-carboxynevirapine. Two subjects with the CYP2B6 *6*6 genetic polymorphism had metabolic indexes in the same range as other subjects. These results suggest that nevirapine metabolite profiles change over time under the influence of enzyme induction, enzyme inhibition, and host genetics. Further work is warranted to elucidate nevirapine biotransformation pathways and implications for drug efficacy and toxicity.
Structure-Based Discovery of the Novel Antiviral Properties of Naproxen against the Nucleoprotein of Influenza A Virus
Authors: Lejal Nathalie , Tarus Bogdan , Bouguyon Edwige , Chenavas Sylvie , Bertho Nicolas , Delmas Bernard , Ruigrok Rob W. H. , Di Primo Carmelo , Slama-Schwok Anny 
Published: March 2013

ABSTRACTThe nucleoprotein (NP) binds the viral RNA genome and associates with the polymerase in a ribonucleoprotein complex (RNP) required for transcription and replication of influenza A virus. NP has no cellular counterpart, and the NP sequence is highly conserved, which led to considering NP a hot target in the search for antivirals. We report here that monomeric nucleoprotein can be inhibited by a small molecule binding in its RNA binding groove, resulting in a novel antiviral against influenza A virus. We identified naproxen, an anti-inflammatory drug that targeted the nucleoprotein to inhibit NP-RNA association required for NP function, by virtual screening. Further docking and molecular dynamics (MD) simulations identified in the RNA groove two NP-naproxen complexes of similar levels of interaction energy. The predicted naproxen binding sites were tested using the Y148A, R152A, R355A, and R361A proteins carrying single-point mutations. Surface plasmon resonance, fluorescence, and otherin vitroexperiments supported the notion that naproxen binds at a site identified by MD simulations and showed that naproxen competed with RNA binding to wild-type (WT) NP and protected active monomers of the nucleoprotein against proteolytic cleavage. Naproxen protected Madin-Darby canine kidney (MDCK) cells against viral challenges with the H1N1 and H3N2 viral strains and was much more effective than other cyclooxygenase inhibitors in decreasing viral titers of MDCK cells. In a mouse model of intranasal infection, naproxen treatment decreased the viral titers in mice lungs. In conclusion, naproxen is a promising lead compound for novel antivirals against influenza A virus that targets the nucleoprotein in its RNA binding groove.
Comparative
In Vitro
Activities of GSK2251052, a Novel Boron-Containing Leucyl-tRNA Synthetase Inhibitor, against 916 Anaerobic Organisms
Authors: Goldstein Ellie J. C. , Citron Diane M. , Tyrrell Kerin L. , Merriam C. Vreni 
Published: March 2013

ABSTRACT

We studied the comparative
in vitro
activity of GSK2251052, a novel boron leucyl-tRNA synthetase inhibitor, against 916 clinical anaerobic isolates using CLSI methods. The GSK MIC
50
/MIC
90
for all isolates tested were 2 and 4 μg/ml, and the MIC
90
s against 302
Bacteroides fragilis
and
Bacteroides thetaiotaomicron
strains were 4 and 8 μg/ml, respectively. All
Clostridium perfringens
strains had GSK2251052 MICs of >32 μg/ml. There was no relationship between increased MICs for any other antibiotics and that of GSK2251052.
Gain-of-Function Mutations in
PDR1
, a Regulator of Antifungal Drug Resistance in Candida glabrata, Control Adherence to Host Cells
Authors: Vale-Silva Luís , Ischer Françoise , Leibundgut-Landmann Salomé , Sanglard Dominique 
Published: March 2013

ABSTRACT

Candida glabrata
is an emerging opportunistic pathogen that is known to develop resistance to azole drugs due to increased drug efflux. The mechanism consists of
CgPDR1
-mediated upregulation of ATP-binding cassette transporters. A range of gain-of-function (GOF) mutations in
CgPDR1
have been found to lead not only to azole resistance but also to enhanced virulence. This implicates
CgPDR1
in the regulation of the interaction of
C. glabrata
with the host. To identify specific
CgPDR1
-regulated steps of the host-pathogen interaction, we investigated in this work the interaction of selected
CgPDR1
GOF mutants with murine bone marrow-derived macrophages and human acute monocytic leukemia cell line (THP-1)-derived macrophages, as well as different epithelial cell lines. GOF mutations in
CgPDR1
did not influence survival and replication within macrophages following phagocytosis but led to decreased adherence to and uptake by macrophages. This may allow evasion from the host's innate cellular immune response. The interaction with epithelial cells revealed an opposite trend, suggesting that GOF mutations in
CgPDR1
may favor epithelial colonization of the host by
C. glabrata
through increased adherence to epithelial cell layers. These data reveal that GOF mutations in
CgPDR1
modulate the interaction with host cells in ways that may contribute to increased virulence.
Nanogel-Based PspA Intranasal Vaccine Prevents Invasive Disease and Nasal Colonization by Streptococcus pneumoniae
Authors: Kong Il Gyu , Sato Ayuko , Yuki Yoshikazu , Nochi Tomonori , Takahashi Haruko , Sawada Shinichi , Mejima Mio , Kurokawa Shiho , Okada Kazunari , Sato Shintaro , Briles David E. , Kunisawa Jun , Inoue Yusuke , Yamamoto Masafumi , Akiyoshi Kazunari , Kiyono Hiroshi 
Published: March 2013

ABSTRACTTo establish a safer and more effective vaccine against pneumococcal respiratory infections, current knowledge regarding the antigens common among pneumococcal strains and improvements to the system for delivering these antigens across the mucosal barrier must be integrated. We developed a pneumococcal vaccine that combines the advantages of pneumococcal surface protein A (PspA) with a nontoxic intranasal vaccine delivery system based on a nanometer-sized hydrogel (nanogel) consisting of a cationic cholesteryl group-bearing pullulan (cCHP). The efficacy of the nanogel-based PspA nasal vaccine (cCHP-PspA) was tested in murine pneumococcal airway infection models. Intranasal vaccination with cCHP-PspA provided protective immunity against lethal challenge withStreptococcus pneumoniaeXen10, reduced colonization and invasion by bacteria in the upper and lower respiratory tracts, and induced systemic and nasal mucosal Th17 responses, high levels of PspA-specific serum immunoglobulin G (IgG), and nasal and bronchial IgA antibody responses. Moreover, there was no sign of PspA delivery by nanogel to either the olfactory bulbs or the central nervous system after intranasal administration. These results demonstrate the effectiveness and safety of the nanogel-based PspA nasal vaccine system as a universal mucosal vaccine against pneumococcal respiratory infection.
The Plasmodium vivax Merozoite Surface Protein 1 Paralog Is a Novel Erythrocyte-Binding Ligand of P. vivax
Authors: Cheng Yang , Wang Yue , Ito Daisuke , Kong Deok-Hoon , Ha Kwon-Soo , Chen Jun-Hu , Lu Feng , Li Jian , Wang Bo , Takashima Eizo , Sattabongkot Jetsumon , Tsuboi Takafumi , Han Eun-Taek 
Published: March 2013

ABSTRACT

Merozoite surface protein 1 of
Plasmodium vivax
(PvMSP1), a glycosylphosphatidylinositol-anchored protein (GPI-AP), is a malaria vaccine candidate for
P. vivax
. The paralog of PvMSP1, named
P. vivax
merozoite surface protein 1 paralog (PvMSP1P; PlasmoDB PVX_099975), was recently identified and predicted as a GPI-AP. The similarities in genetic structural characteristics between PvMSP1 and PvMSP1P (e.g., size of open reading frames, two epidermal growth factor-like domains, and GPI anchor motif in the C terminus) led us to study this protein. In the present study, different regions of the PvMSP1P protein, demarcated based on the processed forms of PvMSP1, were expressed successfully as recombinant proteins [i.e., 83 (A, B, and C), 30, 38, 42, 33, and 19 fragments]. We studied the naturally acquired immune response against each fragment of recombinant PvMSP1P and the potential ability of each fragment to bind erythrocytes. The N-terminal fragment (83A) and two C-terminal fragments (33 and 19) reacted strongly with sera from
P. vivax
-infected patients, with 50 to 68% sensitivity and 95 to 96% specificity, respectively. Due to colocalization of PvMSP1P with PvMSP1, we supposed that PvMSP1P plays a similar role as PvMSP1 during erythrocyte invasion. An
in vitro
cytoadherence assay showed that PvMSP1P, especially the 19-kDa C-terminal region, could bind to erythrocytes. We also found that human sera from populations naturally exposed to vivax malaria and antisera obtained by immunization using the recombinant molecule PvMSP1P-19 inhibited
in vitro
binding of human erythrocytes to PvMSP1P-19. These results provide further evidence that the PvMSP1P might be an essential parasite adhesion molecule in the
P. vivax
merozoite and is a potential vaccine candidate against
P. vivax
.
Volcanic hotspots of the central and southern Andes as seen from space by ASTER and MODVOLC between the years 2000 and 2010
Authors: Jay J. A. , Welch M. , Pritchard M. E. , Mares P. J. , Mnich M. E. , Melkonian A. K. , Aguilera F. , Naranjo J. A. , Sunagua M. , Clavero J. 
Published: March 2013

Abstract

We examine 150 volcanoes and geothermal areas in the central, southern and austral Andes for thermal anomalies between the years 2000 and 2010 from two different spaceborne sensors: (1) those automatically detected by the MODVOLC algorithm from MODIS; and (2) manually identified hotspots in night-time images from ASTER (Advanced Spaceborne Thermal Emission and Reflection Radiometer). Based on previous work, we expected to find eight volcanoes displaying thermal anomalies (Ubinas, Villarrica, Copahue, Láscar, Llaima, Chaitén, Lonquimay and Chiliques). We document 35 volcanic areas with pixel-integrated temperatures of 4 up to more than 100 K above background in at least two images, and another 16 areas that have questionable hotspots with either smaller anomalies or a hotspot identified in only one image. Most of the thermal anomalies are related to known activity (i.e. lava and pyroclastic flows, growing lava domes, fumaroles, and lakes) while others are of unknown origin or reflect activity at volcanoes that were not thought to have surface activity. A handful of volcanoes exhibit temporal variations in the magnitude and location of their temperature anomalies that can be related to both documented and undocumented pulses of activity. Our survey reveals that low-amplitude volcanic hotspots detectable from space are more common than expected, based on lower spatial resolution data, and that these features could be more widely used to monitor changes in the activity of remote volcanoes. We find no evidence from ASTER or MODVOLC that the thermal anomalies were affected by six earthquakes with
M
w
above 7 in our study area from 2000 to 2010, although the observations may not have been optimal to detect such anomalies.

Supplementary material:

Supplementary tables of data and figures for the volcanoes studied are available at
http://www.geolsoc.org.uk/SUP18581
.
Magma pathway and its structural controls of Asama Volcano, Japan
Authors: Aoki Yosuke , Takeo Minoru , Ohminato Takao , Nagaoka Yutaka , Nishida Kiwamu 
Published: March 2013

Abstract
Asama Volcano, Japan, is one of the most active volcanoes in the Japanese islands. Recent development of geophysical monitoring in Asama Volcano allows us to infer the magma pathway and its structural controls beneath the volcano. Combining geodetic data and precise earthquake locations during recent eruptions suggests that the magma intrudes several kilometres to the west of the summit to a depth of about 1 km below sea level as a nearly east–west-trending dyke. The vertically intruded magma then moves horizontally by several kilometres to beneath the summit before it ascends vertically to make the surface. Combining the P-wave velocity and the resistivity structure shows that the intrusions are under structural controls. Frozen and fractureless magma associated with volcanic activity until 24 000 years ago impedes the ascent of rising magma on its way to the surface. The S-wave velocity structure inferred from ambient noise tomography reveals a low-velocity body beneath the modelled dyke. From independent information, we have inferred that this low-velocity body is likely to be a magma chamber.