bluuebunny/crossref_metadata_2025 huggingface dataset:
Aromatase Deficiency Confers Paradoxical Postischemic Cardioprotection
Authors: Bell James R. , Mellor Kimberley M. , Wollermann Amanda C. , Ip Wendy T. K. , Reichelt Melissa E. , Meachem Sarah J. , Simpson Evan R. , Delbridge Lea M. D.
Published: October 2011

The conventional view is that estrogen confers female cardioprotection. Estrogen synthesis depends on androgen availability, with aromatase regulating conversion of testosterone to estradiol. Extragonadal aromatase expression mediates estrogen production in some tissues, but a role for local steroid conversion has not yet been demonstrated in the heart. This study's goal was to investigate how aromatase deficiency influences myocardial function and ischemic resilience. RT-PCR analysis of C57Bl/6 mouse hearts confirmed cardiac-specific aromatase expression in adult females. Functional performance of isolated hearts from female aromatase knockout (ArKO) and aromatase wild-type mice were compared. Left ventricular developed pressures were similar in aerobic perfusion, but the maximal rate of rise of ventricular pressure was modestly reduced in ArKO hearts (3725 ± 144 vs. 4272 ± 154 mm Hg/sec, P < 0.05). After 25 min of ischemia, the recovery of left ventricular developed pressure was substantially improved in ArKO (percentage of basal at 60 min of reperfusion, 62 ± 8 vs. 30 ± 6%; P < 0.05). Hypercontracture was attenuated (end diastolic pressure, 25 ± 5 vs. 51 ± 1 mm Hg; P < 0.05), and lactate dehydrogenase content of coronary effluent was reduced throughout reperfusion in ArKO hearts. This was associated with a hyperphosphorylation of phospholamban and a reduction in phosphorylated Akt. Immediately after reperfusion, ArKO hearts exhibited increased incidence of ventricular premature beats (194 ± 70 vs. 46 ± 6, P < 0.05). These observations indicate more robust functional recovery, reduced cellular injury, and modified cardiomyocyte Ca2+ handling in aromatase-deficient hearts. Our findings indicate that androgen-to-estrogen conversion may be of pathophysiologic importance to the heart and challenge the notion that estrogen deficiency is deleterious. These studies suggest the possibility that aromatase suppression may offer inotropic benefit in the acute ischemia/reperfusion setting with appropriate arrhythmia management.
Relaxin and Castration in Male Mice Protect from, but Testosterone Exacerbates, Age-Related Cardiac and Renal Fibrosis, Whereas Estrogens Are an Independent Determinant of Organ Size
Authors: Hewitson Tim D. , Zhao Chongxin , Wigg Belinda , Lee Sin Wai , Simpson Evan R. , Boon Wah Chin , Samuel Chrishan S.
Published: October 2011

This study determined the effects of castration and hormone replacement therapy on the age-related cardiac and renal pathology of male relaxin gene-knockout (RlnKO) and age-matched wild-type (RlnWT) mice and that of aged male aromatase knockout (ArKO) mice, which lack estrogens and have 5–10 times the androgen levels of male wild-type mice. One-month-old RlnWT and RlnKO mice were bilaterally gonadectomized or sham operated and maintained until 12 months. Subgroups of castrated animals received testosterone or 17β-estradiol treatment from 9 to 12 months. Male ArKO mice and aromatase wild-type mice were aged to 12 months. Collected heart and kidney tissues were assessed for changes in organ size and fibrosis. Castration reduced body, heart, left ventricle, and kidney weights in both RlnKO and RlnWT mice, and the cardiac/renal fibrosis that was seen in sham RlnKO animals (all P < 0.05 vs. respective sham). Testosterone normalized organ weights and organ weight to body weight ratio of castrated animals and increased cardiac/renal collagen concentration to levels measured in or beyond that of sham RlnKO mice (all P < 0.05 vs. respective castrated mice). Furthermore, expression of TGF-β1, mothers against decapentaplegic homolog 2 (Smad2), and myofibroblast differentiation paralleled the above changes (all P < 0.05 vs. respective castrated mice), whereas matrix metalloproteinase-13 was decreased in testosterone-treated RlnKO mice. Conversely, 17β-estradiol only restored changes in organ size. Consistent with these findings, intact ArKO mice demonstrated increased cardiac/renal fibrosis in the absence of changes in organ size. These findings suggest that relaxin and castration protect, whereas androgens exacerbate, cardiac and renal fibrosis during ageing, whereas estrogens, in synergy with relaxin, regulates age-related changes in organ size.
Endothelial Dysfunction in a Rat Model of PCOS: Evidence of Increased Vasoconstrictor Prostanoid Activity
Authors: Keller Jennifer , Mandala Maurizio , Casson Peter , Osol George
Published: October 2011

Clinical research demonstrates an association between polycystic ovary syndrome (PCOS) and endothelial dysfunction, a pathological state widely believed to be a hallmark of vascular disease; the underlying pathways, however, have not been defined. The purpose of this study was to characterize endothelial function in resistance arteries in a novel rat model of PCOS. Female rats were randomized at 3–4 wk to implantation of a 7.5-mg, 90-d dihydrotestosterone (DHT) pellet or a matched placebo. At 15–16 wk, experiments were performed on isolated mesenteric resistance arteries using a pressurized arteriograph. Endothelial function was assessed by the vasodilatory response of preconstricted arteries to acetylcholine (ACh) in the absence and presence of inhibitors for cyclooxygenase (indomethacin) and the thromboxane prostanoid receptor antagonist (SQ29,548). Distensibility was evaluated by measuring vessel diameter from 3–100 mm Hg, and elastin/collagen content was calculated on formalin-fixed vessels. Serum steroid levels were analyzed by sensitive RIA. DHT-induced PCOS rats were heavier, cycled irregularly, and had elevated blood pressure and smaller arterial lumens than controls. Furthermore, DHT vessels showed significantly reduced vasodilatory efficacy to ACh (with no change in sensitivity), reduced distensibility, and increased elastin content compared with controls. Within DHT animals, maximal dilation correlated negatively to DHT levels (r = −0.72) but not to body weight. Preincubation with either indomethacin or SC29,548 abrogated the dysfunction and restored full efficacy to ACh (P < 0.05). This is the first report to demonstrate the presence of endothelial dysfunction in a hyperandrogenic rat model of PCOS and to identify the role of vasoconstrictor prostanoids, allowing for more targeted research regarding the development of disease and potential therapeutic interventions.
Neurotrophins Acting Via TRKB Receptors Activate the JAGGED1-NOTCH2 Cell-Cell Communication Pathway to Facilitate Early Ovarian Development
Authors: Dorfman Mauricio D. , Kerr Bredford , Garcia-Rudaz Cecilia , Paredes Alfonso H. , Dissen Gregory A. , Ojeda Sergio R.
Published: October 2011

Tropomyosin-related kinase (TRK) receptor B (TRKB) mediates the supportive actions of neurotrophin 4/5 and brain-derived neurotrophic factor on early ovarian follicle development. Absence of TRKB receptors reduces granulosa cell (GC) proliferation and delays follicle growth. In the present study, we offer mechanistic insights into this phenomenon. DNA array and quantitative PCR analysis of ovaries from TrkB-null mice revealed that by the end of the first week of postnatal life, Jagged1, Hes1, and Hey2 mRNA abundance is reduced in the absence of TRKB receptors. Although Jagged1 encodes a NOTCH receptor ligand, Hes1 and Hey2 are downstream targets of the JAGGED1-NOTCH2 signaling system. Jagged1 is predominantly expressed in oocytes, and the abundance of JAGGED1 is decreased in TrkB−/− oocytes. Lack of TRKB receptors also resulted in reduced expression of c-Myc, a NOTCH target gene that promotes entry into the cell cycle, but did not alter the expression of genes encoding core regulators of cell-cycle progression. Selective restoration of JAGGED1 synthesis in oocytes of TrkB−/− ovaries via lentiviral-mediated transfer of the Jagged1 gene under the control of the growth differentiation factor 9 (Gdf9) promoter rescued c-Myc expression, GC proliferation, and follicle growth. These results suggest that neurotrophins acting via TRKB receptors facilitate early follicle growth by supporting a JAGGED1-NOTCH2 oocyte-to-GC communication pathway, which promotes GC proliferation via a c-MYC-dependent mechanism.
Neuronal regeneration in a zebrafish model of adult brain injury
Authors: Kishimoto Norihito , Shimizu Kohei , Sawamoto Kazunobu
Published: October 2011

Neural stem cells in the subventricular zone (SVZ) of the adult mammalian forebrain are a potential source of neurons for neural tissue repair after brain insults such as ischemic stroke and traumatic brain injury (TBI). Recent studies show that neurogenesis in the ventricular zone (VZ) of the adult zebrafish telencephalon has features in common with neurogenesis in the adult mammalian SVZ. Here, we established a zebrafish model to study injury-induced neurogenesis in the adult brain. We show that the adult zebrafish brain possesses a remarkable capacity for neuronal regeneration. Telencephalon injury prompted the proliferation of neuronal precursor cells (NPCs) in the VZ of the injured hemisphere, compared with in the contralateral hemisphere. The distribution of NPCs, viewed by BrdU labeling and ngn1-promoter-driven GFP, suggested that they migrated laterally and reached the injury site via the subpallium and pallium. The number of NPCs reaching the injury site significantly decreased when the fish were treated with an inhibitor of γ-secretase, a component of the Notch signaling pathway, suggesting that injury-induced neurogenesis mechanisms are at least partly conserved between fish and mammals. The injury-induced NPCs differentiated into mature neurons in the regions surrounding the injury site within a week after the injury. Most of these cells expressed T-box brain protein (Tbr1), suggesting they had adopted the normal neuronal fate in this region. These results suggest that the telencephalic VZ contributes to neural tissue recovery following telencephalic injury in the adult zebrafish, and that the adult zebrafish is a useful model for regenerative medicine.
Tracing notochord-derived cells using a Noto-cre mouse: implications for intervertebral disc development
Authors: McCann Matthew R. , Tamplin Owen J. , Rossant Janet , Séguin Cheryle A.
Published: October 2011

Back pain related to intervertebral disc degeneration is the most common musculoskeletal problem, with a lifetime prevalence of 82%. The lack of effective treatment for this widespread problem is directly related to our limited understanding of disc development, maintenance and degeneration. The aim of this study was to determine the developmental origins of nucleus pulposus cells within the intervertebral disc using a novel notochord-specific Cre mouse. To trace the fate of notochordal cells within the intervertebral disc, we derived a notochord-specific Cre mouse line by targeting the homeobox gene Noto. Expression of this gene is restricted to the node and the posterior notochord during gastrulation [embryonic day 7.5 (E7.5)-E12.5]. The Noto-cre mice were crossed with a conditional lacZ reporter for visualization of notochord fate in whole-mount embryos. We performed lineage-tracing experiments to examine the contribution of the notochord to spinal development from E12.5 through to skeletally mature mice (9 months). Fate mapping studies demonstrated that, following elongation and formation of the primitive axial skeleton, the notochord gives rise to the nucleus pulposus in fully formed intervertebral discs. Cellular localization of β-galactosidase (encoded by lacZ) and cytokeratin-8 demonstrated that both notochordal cells and chondrocyte-like nucleus pulposus cells are derived from the embryonic notochord. These studies establish conclusively that notochordal cells act as embryonic precursors to all cells found within the nucleus pulposus of the mature intervertebral disc. This suggests that notochordal cells might serve as tissue-specific progenitor cells within the disc and establishes the Noto-cre mouse as a unique tool to interrogate the contribution of notochordal cells to both intervertebral disc development and disc degeneration.
Migratory navigation in birds: new opportunities in an era of fast-developing tracking technology
Authors: Guilford Tim , Åkesson Susanne , Gagliardo Anna , Holland Richard A. , Mouritsen Henrik , Muheim Rachel , Wiltschko Roswitha , Wiltschko Wolfgang , Bingman Verner P.
Published: October 2011

Birds have remained the dominant model for studying the mechanisms of animal navigation for decades, with much of what has been discovered coming from laboratory studies or model systems. The miniaturisation of tracking technology in recent years now promises opportunities for studying navigation during migration itself (migratory navigation) on an unprecedented scale. Even if migration tracking studies are principally being designed for other purposes, we argue that attention to salient environmental variables during the design or analysis of a study may enable a host of navigational questions to be addressed, greatly enriching the field. We explore candidate variables in the form of a series of contrasts (e.g. land vs ocean or night vs day migration), which may vary naturally between migratory species, populations or even within the life span of a migrating individual. We discuss how these contrasts might help address questions of sensory mechanisms, spatiotemporal representational strategies and adaptive variation in navigational ability. We suggest that this comparative approach may help enrich our knowledge about the natural history of migratory navigation in birds.
Influence of elevated temperature on metabolism during aestivation: implications for muscle disuse atrophy
Authors: Young Karen M. , Cramp Rebecca L. , White Craig R. , Franklin Craig E.
Published: October 2011

Reactive oxygen species (ROS), produced commensurate with aerobic metabolic rate, contribute to muscle disuse atrophy (MDA) in immobilised animals by damaging myoskeletal protein and lipids. Aestivating frogs appear to avoid MDA in part by substantially suppressing metabolic rate. However, as ectotherms, metabolic rate is sensitive to environmental temperature, and the high ambient temperatures that may be experienced by frogs during aestivation could in fact promote MDA. In this study, we investigated the effect of temperature on the metabolic rate of the aestivating frog Cyclorana alboguttata and its skeletal muscles in order to determine their likely susceptibility to MDA. Compared with non-aestivating frogs, a significant decrease in metabolic rate was recorded for aestivating frogs at 20, 24 and 30°C. At 30°C, however, the metabolic rate of aestivating frogs was significantly higher, approximately double that of frogs aestivating at 20 or 24°C, and the magnitude of the metabolic depression was significantly reduced at 30°C compared with that at 20°C. Temperature effects were also observed at the tissue level. At 24 and 30°C the metabolic rate of all muscles from aestivating frogs was significantly depressed compared with that of muscles from non-aestivating frogs. However, during aestivation at 30°C the metabolic rates of gastrocnemius, sartorius and cruralis were significantly elevated compared with those from frogs aestivating at 24°C. Our data show that the metabolism of C. alboguttata and its skeletal muscles is elevated at higher temperatures during aestivation and that the capacity of the whole animal to actively depress metabolism is impaired at 30°C.
Social synchronization of circadian locomotor activity rhythm in the fruit fly Drosophila melanogaster
Authors: Lone Shahnaz Rahman , Sharma Vijay Kumar
Published: October 2011

Circadian clocks regulate the physiology and behaviour of organisms across a wide range of taxa. To keep track of local time, these clocks use a variety of time cues such as light–dark, temperature, food availability and social interaction cycles. This study assessed the role of social cues in modulating circadian clocks of the fruit fly Drosophila melanogaster. Using pair-wise interactions, we first estimated the percentage contribution of each interacting partner on the cumulative rhythmic behaviour of the pairs. Subsequently, we studied the effects of multi-individual (group-wise) interactions on the rhythmic behaviour of the group by estimating phase synchrony between individuals of different strains (having different circadian periods) maintained in both homogeneous and heterogeneous groups. Although it is known that social interactions improve synchrony between interacting individuals, we asked whether such interactions are able to synchronize the circadian rhythms of highly phase-desynchronized flies. We found that, although interactions between fly strains possessing different circadian periods failed to produce synchrony, social interactions among phase-desynchronized flies did enhance the phase synchrony of the interacting individuals. Differently phased individuals living in social groups displayed significantly greater phase synchrony than those living solitarily. Social synchronization is olfaction mediated as group-wise interactions among phase-desynchronized flies possessing compromised olfactory ability (Or83b0) did not improve phase synchrony. These results suggest that social cues synchronize the circadian clocks of Drosophila provided that the interacting individuals have similar clock periods.
Mechanisms of stable lipid loss in a social insect
Authors: Ament Seth A. , Chan Queenie W. , Wheeler Marsha M. , Nixon Scott E. , Johnson S. Peir , Rodriguez-Zas Sandra L. , Foster Leonard J. , Robinson Gene E.
Published: October 2011

Worker honey bees undergo a socially regulated, highly stable lipid loss as part of their behavioral maturation. We used large-scale transcriptomic and proteomic experiments, physiological experiments and RNA interference to explore the mechanistic basis for this lipid loss. Lipid loss was associated with thousands of gene expression changes in abdominal fat bodies. Many of these genes were also regulated in young bees by nutrition during an initial period of lipid gain. Surprisingly, in older bees, which is when maximum lipid loss occurs, diet played less of a role in regulating fat body gene expression for components of evolutionarily conserved nutrition-related endocrine systems involving insulin and juvenile hormone signaling. By contrast, fat body gene expression in older bees was regulated more strongly by evolutionarily novel regulatory factors, queen mandibular pheromone (a honey bee-specific social signal) and vitellogenin (a conserved yolk protein that has evolved novel, maturation-related functions in the bee), independent of nutrition. These results demonstrate that conserved molecular pathways can be manipulated to achieve stable lipid loss through evolutionarily novel regulatory processes.
Dopamine as an anorectic neuromodulator in the cockroachRhyparobia maderae
Authors: Allen Jaclyn M. , Van Kummer Brooke H. , Cohen Randy W.
Published: October 2011

Insects, including cockroaches, self-select a balanced diet when faced with different nutrient choices. For self-selection to be carried out effectively, insects possess neuroregulatory systems to control their food intake. In the present study, we examined the role of the neurotransmitter dopamine (DA) in the feeding regulation of the Madeira cockroach (Rhyparobia maderae). When R. maderae nymphs were injected with 20 μl of 100 mmol l–1 DA, they showed an 83.3% reduction in sucrose intake and a 78.9% reduction in total intake compared with saline-injected controls. The DA agonist, 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN) (100 mmol l–1 in 1 μl), caused a significant reduction in sucrose feeding, reducing feeding by 47.3% compared with saline-injected controls. Protein feeding was also significantly reduced by 6,7-ADTN to 62%. Rhyparobia maderae nymphs injected with the DA antagonist chlorpromazine (100 mmol l–1 in 1 μl) did not differ significantly from control nymphs in their feeding behavior. Interestingly, R. maderae nymphs injected with 2 μl or 5 μl chlorpromazine (100 mmol l–1) showed significantly increased mortality rates of 47.5% or 66.7%, respectively. The DA antagonist, spiperone (100 mmol l–1 in 1 μl), caused a significant feeding response, showing an increase in feeding in both sucrose (310.6%) and total intake (236.3%). Casein feeding in R. maderae nymphs was also elevated (70.8%) but this was not statistically significant. The experiments with DA, the DA agonist 6,7-ADTN and the DA antagonist spiperone strongly suggest that the neurotransmitter DA is involved in regulating feeding in the cockroach R. maderae.
Sound production in the longnose butterflyfishes (genusForcipiger): cranial kinematics, muscle activity and honest signals
Authors: Boyle Kelly S. , Tricas Timothy C.
Published: October 2011

Many teleost fishes produce sounds for social communication with mechanisms that do not involve swim bladder musculature. Such sounds may reflect physical attributes of the sound-production mechanism, be constrained by body size and therefore control signal reliability during agonistic behaviors. We examined kinematics of the cranium, median fins and caudal peduncle during sound production in two territorial chaetodontid butterflyfish sister species: forcepsfish (Forcipiger flavissimus) and longnose butterflyfish (F. longirostris). During intraspecific agonistic encounters, both species emit a single pulse sound that precedes rapid cranial rotation at velocities and accelerations that exceed those of prey strikes by many ram-and suction-feeding fishes. Electromyography showed that onsets of activity for anterior epaxialis, sternohyoideus, A1 and A2 adductor mandibulae muscles and sound emission are coincident but precede cranial elevation. Observations indicate that sound production is driven by epaxial muscle contraction whereas a ventral linkage between the head and pectoral girdle is maintained by simultaneous activity from the adductor mandibulae and sternohyoideus. Thus, the girdle, ribs and rostral swim bladder are pulled anteriorly before the head is released and rotated dorsally. Predictions of the hypothesis that acoustic signals are indicators of body size and kinematic performance were confirmed. Variation in forcepsfish sound duration and sound pressure level is explained partly by cranial elevation velocity and epaxial electromyogram duration. Body size, however, explains most variation in duration and sound pressure level. These observed associations indicate that forcepsfish sounds may be accurate indicators of size and condition that are related to resource holding potential during social encounters.
In-plane Orientation of Fluorescent Molecules in Friction-transferred Films
Authors: Koshiba Yasuko , Misaki Masahiro , Kanda Kotomi , Miyaji Hiroaki , Ishida Kenji , Ueda Yasukiyo
Published: October 2011

Thin films of fluorescent molecules were prepared by friction-transfer and investigated by UV–vis absorption and PL measurements and TEM observation. Molecules with a long skeleton were aligned nearly horizontally and parallel to the friction direction in the film. Such in-plane orientation is advantageous in fabricating OLEDs with respect to light-outcoupling efficiency.
Emission and Quenching of the Pyrenesulfonate Excimer on a Dodecyltrimethylammonium Micellar Surface
Authors: Takezaki Makoto , Tominaga Toshihiro
Published: October 2011

The excimer formation and decay dynamics of pyrenesulfonate on a cationic micellar surface have been studied by measuring the decay of monomer fluorescence as well as the rise and decay of the excimer emission. The excimer formation rate constant, lifetime, and quenching rate constant by the monomer were found to be 2.1 × 107 s−1, 46.2 ns, and 2.6 × 106 s−1, respectively.
pH and Sugar Responsive Host Polymer Hydrogels Designed Based on Sugar and Boronic Acid Interaction
Authors: Tamesue Shingo , Numata Munenori , Shinkai Seiji
Published: October 2011

By mixing boronic acid-modified poly(acrylic acid) (pAA-BA) and β-1,3-glucan Schizophyllan (SPG) in water at pH 9.9, hydrogel was readily formed with the aid of the sugar and boronic acid interaction. This hydrogel showed the reversible transformation between sol and gel depending on the medium pH. Moreover, this hydrogel stability was sensitive to fructose concentration. As one potential output, we prepared the hydrogel including single-walled carbon nanotubes, utilizing the nanotube-wrapping property inherent to SPG.
Quantitative Analysis of Trace Heavy Elements in Geological Samples Utilizing High-energy (116 keV) Synchrotron Radiation X-ray Fluorescence Analysis for Forensic Investigation
Authors: Bong Willy Shun Kai , Nakai Izumi , Furuya Shunsuke , Suzuki Hiroko , Abe Yoshinari , Osaka Keiichi , Matsumoto Takuya , Itou Masayoshi , Imai Noboru , Ninomiya Toshio
Published: October 2011

High-energy (116 keV) synchrotron radiation X-ray fluorescence analysis has for the first time been applied to the quantitative analysis of trace heavy elements of geological samples. Calibration curves for the determination of trace heavy elements were obtained by measuring 7 reference rock samples and showed good linearity because of the high penetrating power of the high-energy X-rays. It is found that this method is suitable for rapid and nondestructive quantitative characterization of trace heavy elements in trace amount of soil samples for forensic investigation.
Rational Design of a New IMP Aptamer Based on a TPP Riboswitch and a Hypoxanthine Aptamer
Authors: Tokui Misato , Yamauchi Takahiro , Miyoshi Daisuke , Kamiya Hisaya , Nishimura Akira , Sugimoto Naoki
Published: October 2011

We rationally designed a new inosine monophosphate (IMP) aptamer based on structural information from the natural thiamine pyrophosphate (TPP) riboswitch and an in vitro-selected hypoxanthine aptamer. The value of the binding affinity (Ka) for the newly designed IMP aptamer for IMP was (2.6 ± 3.2) × 107 M−1, which was 10-times larger than that for TPP. These results demonstrated that structure-based design of aptamers can be a useful scheme to develop artificial aptamers.
Apolipoproteins: metabolic role and clinical biochemistry applications
Authors: Dominiczak Marek H , Caslake Muriel J
Published: October 2011

Lipoprotein metabolism is dependent on apolipoproteins, multifunctional proteins that serve as templates for the assembly of lipoprotein particles, maintain their structure and direct their metabolism through binding to membrane receptors and regulation of enzyme activity. The three principal functions of lipoproteins are contribution to interorgan fuel (triglyceride) distribution (by means of the fuel transport pathway), to the maintenance of the extracellular cholesterol pool (by means of the overflow pathway) and reverse cholesterol transport. The most important clinical application of apolipoprotein measurements in the plasma is in the assessment of cardiovascular risk. Concentrations of apolipoprotein B and apolipoprotein AI (and their ratio) seem to be better markers of cardiovascular risk than conventional markers such as total cholesterol and LDL-cholesterol. Apolipoprotein measurements are also better standardized than the conventional tests. We suggest that measurements of apolipoprotein AI and apolipoprotein B are included as a part of the specialist lipid profile. We also suggest that lipoprotein (a) should be measured as part of the initial assessment of dyslipidaemias because of its consistent association with cardiovascular risk. Genotyping of apolipoprotein E isoforms remains useful in the investigation of mixed dyslipidaemias. Lastly, the role of postprandial metabolism is increasingly recognized in the context of atherogenesis, obesity and diabetes. This requires better markers of chylomicrons, very-low-density lipoproteins and remnant particles. Measurements of apolipoprotein B48 and remnant lipoprotein cholesterol are currently the key tests in this emerging field.
Immune thrombocytopenia and pregnancy
Authors: Sankaran Srividhya , Robinson Susan E
Published: October 2011

Immune thrombocytopenia (ITP) is not infrequently encountered during reproductive years with an estimated incidence of 0.1–1 per 1000 pregnancies. An international consensus group recently re-defined ITP and outlined standardized response criteria and up-to-date investigation and management. The pathogenesis encompasses autoantibody platelet destruction and immune-mediated decreased platelet production. Maternal antibodies may cross the placenta and have the potential to cause fetal and/or neonatal thrombocytopenia. The diagnosis and subsequent management of ITP in pregnancy requires a multidisciplinary approach involving the midwife, obstetrician, haematologist and anaesthetist. Women with ITP diagnosed prior to pregnancy should receive preconception counselling to outline potential treatments and provide information regarding expected maternal and neonatal outcome. Management prior to 36 weeks aims to avoid treatment in the absence of bleeding and ensure an acceptable platelet count for planned procedures. At 34–36 weeks, women are generally reviewed to consider whether a tailored course of treatment is required in preparation for delivery. Further research is required to determine a suitable platelet count for neuraxial anaesthesia. The mode of delivery should be guided by obstetric indication. It is pertinent to consider both the risk of maternal bleeding and thrombosis in maternal ITP. The risk of neonatal intracranial haemorrhage in association with ITP is less than 1%. Postpartum a cord blood platelet count should be checked. Additional management is dependent upon the neonatal platelet count. Data collection using the new standardized terminology should provide robust comparable epidemiological data regarding ITP in pregnancy.
Ribosomal RNA processing in Candida albicans
Authors: Pendrak Michael L. , Roberts David D.
Published: October 2011

Ribosome assembly begins with conversion of a polycistronic precursor into 18S, 5.8S, and 25S rRNAs. In the ascomycete fungus Candida albicans, rRNA transcription starts 604 nt upstream of the 18S rRNA junction (site A1). One major internal processing site in the 5′ external transcribed spacer (A0) occurs 108 nt from site A1. The A0–A1 fragment persists as a stable species during log phase growth and can be used to assess proliferation rates. Separation of the small and large subunit pre-rRNAs occurs at sites A2 and A3 in internal transcribed spacer-1 Saccharomyces cerevisiae pre-rRNA. However, the 5′ end of the 5.8S rRNA is represented by only a 5.8S (S) form, and a 7S rRNA precursor of the 5.8S rRNA extends into internal transcribed spacer 1 to site A2, which differs from S. cerevisiae. External transcribed spacer 1 and internal transcribed spacers 1 and 2 show remarkable structural similarity with S. cerevisiae despite low sequence identity. Maturation of C. albicans rRNA resembles other eukaryotes in that processing can occur cotranscriptionally or post-transcriptionally. During rapid proliferation, U3 snoRNA-dependent processing occurs before large and small subunit rRNA separation, consistent with cotranscriptional processing. As cells pass the diauxic transition, the 18S pre-rRNA accumulates into stationary phase as a 23S species, possessing an intact 5′ external transcribed spacer extending to site A3. Nutrient addition to starved cells results in the disappearance of the 23S rRNA, indicating a potential role in normal physiology. Therefore, C. albicans reveals new mechanisms that regulate post- versus cotranscriptional rRNA processing.
Cotranscriptional effect of a premature termination codon revealed by live-cell imaging
Authors: de Turris Valeria , Nicholson Pamela , Orozco Rodolfo Zamudio , Singer Robert H. , Mühlemann Oliver
Published: October 2011

Aberrant mRNAs with premature translation termination codons (PTCs) are recognized and eliminated by the nonsense-mediated mRNA decay (NMD) pathway in eukaryotes. We employed a novel live-cell imaging approach to investigate the kinetics of mRNA synthesis and release at the transcription site of PTC-containing (PTC+) and PTC-free (PTC−) immunoglobulin-μ reporter genes. Fluorescence recovery after photobleaching (FRAP) and photoconversion analyses revealed that PTC+ transcripts are specifically retained at the transcription site. Remarkably, the retained PTC+ transcripts are mainly unspliced, and this RNA retention is dependent upon two important NMD factors, UPF1 and SMG6, since their depletion led to the release of the PTC+ transcripts. Finally, ChIP analysis showed a physical association of UPF1 and SMG6 with both the PTC+ and the PTC− reporter genes in vivo. Collectively, our data support a mechanism for regulation of PTC+ transcripts at the transcription site.
Nucleotide modifications and tRNA anticodon–mRNA codon interactions on the ribosome
Authors: Allnér Olof , Nilsson Lennart
Published: October 2011

We have carried out molecular dynamics simulations of the tRNA anticodon and mRNA codon, inside the ribosome, to study the effect of the common tRNA modifications cmo5U34 and m6A37. In tRNAVal, these modifications allow all four nucleotides to be successfully read at the wobble position in a codon. Previous data suggest that entropic effects are mainly responsible for the extended reading capabilities, but detailed mechanisms have remained unknown. We have performed a wide range of simulations to elucidate the details of these mechanisms at the atomic level and quantify their effects: extensive free energy perturbation coupled with umbrella sampling, entropy calculations of tRNA (free and bound to the ribosome), and thorough structural analysis of the ribosomal decoding center. No prestructuring effect on the tRNA anticodon stem–loop from the two modifications could be observed, but we identified two mechanisms that may contribute to the expanded decoding capability by the modifications: The further reach of the cmo5U34 allows an alternative outer conformation to be formed for the noncognate base pairs, and the modification results in increased contacts between tRNA, mRNA, and the ribosome.
Long noncoding RNAs are generated from the mitochondrial genome and regulated by nuclear-encoded proteins
Authors: Rackham Oliver , Shearwood Anne-Marie J. , Mercer Tim R. , Davies Stefan M.K. , Mattick John S. , Filipovska Aleksandra
Published: October 2011

Human mitochondrial long noncoding RNAs (lncRNAs) have not been described to date. By analysis of deep-sequencing data we have identified three lncRNAs generated from the mitochondrial genome and confirmed their expression by Northern blotting and strand-specific qRT–PCR. We show that the abundance of these lncRNAs is comparable to their complementary mRNAs and that nuclear-encoded mitochondrial proteins involved in RNA processing regulate their expression. We also identify the 5′ and 3′ transcript ends of the three lncRNAs and show that mitochondrial RNase P protein 1 (MRPP1) is important for the processing of these transcripts. Finally, we show that mitochondrial lncRNAs form intermolecular duplexes and that their abundance is cell- and tissue-specific, suggesting a functional role in the regulation of mitochondrial gene expression.
Dimerization of oskar 3′ UTRs promotes hitchhiking for RNA localization in the Drosophila oocyte
Authors: Jambor Helena , Brunel Christine , Ephrussi Anne
Published: October 2011

mRNA localization coupled with translational control is a highly conserved and widespread mechanism for restricting protein expression to specific sites within eukaryotic cells. In Drosophila, patterning of the embryo requires oskar mRNA transport to the posterior pole of the oocyte and translational repression prior to localization. oskar RNA splicing and the 3′ untranslated region (UTR) are required for posterior enrichment of the mRNA. However, reporter RNAs harboring the oskar 3′ UTR can localize by hitchhiking with endogenous oskar transcripts. Here we show that the oskar 3′ UTR contains a stem–loop structure that promotes RNA dimerization in vitro and hitchhiking in vivo. Mutations in the loop that abolish in vitro dimerization interfere with reporter RNA localization, and restoring loop complementarity restores hitchhiking. Our analysis provides insight into the molecular basis of RNA hitchhiking, whereby localization-incompetent RNA molecules can become locally enriched in the cytoplasm, by virtue of their association with transport-competent RNAs.
Book Reviews
Authors: Rand Graham K.
Published: October 2011

In Book Reviews, we review an extensive and diverse range of books. They cover theory and applications in operations research, statistics, management science, econometrics, mathematics, computers, and information systems. In addition, we include books in other fields that emphasize technical applications. The editor will be pleased to receive an e-mail from those willing to review a book, with an indication of specific areas of interest. If you are aware of a specific book that you would like to review, or that you think should be reviewed, please contact the editor.
Marketing Optimization in Retail Banking
Authors: Sundararajan Ramasubramanian , Bhaskar Tarun , Sarkar Abhinanda , Dasaratha Sridhar , Bal Debasis , Marasanapalle Jayanth K. , Zmudzka Beata , Bak Karolina
Published: October 2011

In this paper, we address the problem of making optimal product offers to customers of a retail bank by using techniques including Markov chains, genetic algorithms, mathematical programming, and design of experiments. Our challenges were large problem size, uncertainty about estimates of customer responses to product offers, and practical issues in training and implementation. The solution had an estimated financial impact of around $20 million; it also provided other intangible benefits, including structured decision making, the capability of performing what-if analysis, and portability to other markets and portfolios.
Randomized Controlled Trial Evaluating Pictogram Augmentation of HIV Medication Information
Authors: Wilby Kyle , Marra Carlo A , da Silva Jack H , Grubisic Maja , Harvard Stephanie , Lynd Larry D
Published: October 2011

Background::

Antiretroviral therapy for the management of HIV typically requires the chronic use of 3 or more medications. As such, patients with HIV are required to manage complex dosing schedules and are at risk of multiple potential adverse effects. The use of pictograms on medication vials as a means of improving patients' understanding of medication information has been shown to positively influence understanding and adherence compared to those using text atone.

Objective:

To determine whether pictograms (Pharmaglyph) increase patient recall of targeted information associated with HIV medications and whether patients can interpret the intended meaning of pictograms that they had not seen previously.

Methods:

A randomized, controlled trial was conducted in HIV-positive patients aged 19 years or older who were receiving a new prescription for an antiretroviral medication from the ambulatory pharmacy at St. Paul's Hospital in Vancouver, British Columbia, Canada. Participants were randomized to receive either pictogram-enhanced medication information or standard counseling. At the first follow-up visit, each patient's recall of the medication information was evaluated, and differences between groups were compared.

Results:

Eighty-two subjects were randomized, 40 to the intervention group and 42 to the control arm. The mean (SD) number of HIV medications was nearly equal between the intervention and control groups: 3.0 (1.5) and 3.1 (1.4), respectively. After a mean of 34 days, 33 patients in the intervention arm and 39 in the control arm completed the study. The majority (88%) of the targeted pieces of information in the intervention group were correctly identified at follow-up, compared to only 2% in the control group (Fisher exact test; p < 0.0001).

Conclusions:

Pictograms improve the recall of targeted medication information among patients receiving antiretroviral therapy for HIV management; however, this appears to be dependent on the fact that these patients received a verbal explanation of each pictogram prior to use.
Vemurafenib (PLX4032): An Orally Available Inhibitor of Mutated BRAF for the Treatment of Metastatic Melanoma
Authors: Heakal Yasser , Kester Mark , Savage Scott
Published: October 2011

Objective:

To summarize the preclinical and clinical data on vemurafenib, approved by the Food and Drug Administration (FDA) on August 17, 2011, and discuss the drug's clinical advantages and limitations.

Data Sources:

An English-language literature search of MEDLINE/PubMed (1966-August 2011), using the terms PLX4032, RG7204, R05185426, vemurafenib, and metastatic melanoma, was conducted. In addition, information and data were obtained from meeting abstracts, clinical trial registries, and news releases from the FDA.

Study Selection and Data Extraction:

All relevant published articles and abstracts on vemurafenib were included. Clinical trial registries and meeting abstracts were used to obtain information regarding ongoing trials. All peer-reviewed articles containing information regarding the clinical safety and efficacy of vemurafenib were evaluated for inclusion.

Data Synthesis:

Before the recent approval (March 2011) of ipilimumab, there was no first-line standard-of-care therapy, with proven overall survival benefit, for the treatment of malignant metastatic melanoma. Unlike ipilimumab, which acts through immune-modulation, vemurafenib is a novel, molecularly targeted therapeutic with preferential efficacy toward a specific mutated oncogenic BRAF-signaling mediator. In recently published results of a Phase 3 clinical trial comparing dacarbazine with vemurafenib, vemurafenib prolonged progression-free and overall survival, with confirmed objective response rate of 48% (95% CI 42 to 55) versus 5% (95% CI 3 to 9) for patients who received dacarbazine (p < 0,001)

Conclusions:

Vemurafenib offers a novel, first-line, personalized therapy for patients who have mutated BRAF, Clinical trials of vemurafenib in combination with ipilimumab or other targeted or cytotoxic chemotherapeutic agents may provide more effective regimens with long-term clinical benefit.
Prefrontal Transcranial Direct Current Stimulation Changes Connectivity of Resting-State Networks during fMRI
Authors: Keeser Daniel , Meindl Thomas , Bor Julie , Palm Ulrich , Pogarell Oliver , Mulert Christoph , Brunelin Jerome , Möller Hans-Jürgen , Reiser Maximilian , Padberg Frank
Published: October 2011

Transcranial direct current stimulation (tDCS) has been proposed for experimental and therapeutic modulation of regional brain function. Specifically, anodal tDCS of the dorsolateral prefrontal cortex (DLPFC) together with cathodal tDCS of the supraorbital region have been associated with improvement of cognition and mood, and have been suggested for the treatment of several neurological and psychiatric disorders. Although modeled mathematically, the distribution, direction, and extent of tDCS-mediated effects on brain physiology are not well understood. The current study investigates whether tDCS of the human prefrontal cortex modulates resting-state network (RSN) connectivity measured by functional magnetic resonance imaging (fMRI). Thirteen healthy subjects underwent real and sham tDCS in random order on separate days. tDCS was applied for 20 min at 2 mA with the anode positioned over the left DLPFC and the cathode over the right supraorbital region. Patterns of resting-state brain connectivity were assessed before and after tDCS with 3 T fMRI, and changes were analyzed for relevant networks related to the stimulation–electrode localizations. At baseline, four RSNs were detected, corresponding to the default mode network (DMN), the left and right frontal-parietal networks (FPNs) and the self-referential network. After real tDCS and compared with sham tDCS, significant changes of regional brain connectivity were found for the DMN and the FPNs both close to the primary stimulation site and in connected brain regions. These findings show that prefrontal tDCS modulates resting-state functional connectivity in distinct functional networks of the human brain.
Random Noise Stimulation Improves Neuroplasticity in Perceptual Learning
Authors: Fertonani Anna , Pirulli Cornelia , Miniussi Carlo
Published: October 2011

Perceptual learning is considered a manifestation of neural plasticity in the human brain. We investigated brain plasticity mechanisms in a learning task using noninvasive transcranial electrical stimulation (tES). We hypothesized that different types of tES would have varying actions on the nervous system, which would result in different efficacies of neural plasticity modulation. Thus, the principal goal of the present study was to verify the possibility of inducing differential plasticity effects using two tES approaches [i.e., direct current stimulation (tDCS) and random noise stimulation (tRNS)] during the execution of a visual perceptual learning task.
State-Dependent and Timing-Dependent Bidirectional Associative Plasticity in the Human SMA-M1 Network
Authors: Arai Noritoshi , Müller-Dahlhaus Florian , Murakami Takenobu , Bliem Barbara , Lu Ming-Kuei , Ugawa Yoshikazu , Ziemann Ulf
Published: October 2011

The supplementary motor area (SMA-proper) plays a key role in the preparation and execution of voluntary movements. Anatomically, SMA-proper is densely reciprocally connected to primary motor cortex (M1), but neuronal coordination within the SMA-M1 network and its modification by external perturbation are not well understood. Here we modulated the SMA-M1 network using MR-navigated multicoil associative transcranial magnetic stimulation in healthy subjects. Changes in corticospinal excitability were assessed by recording motor evoked potential (MEP) amplitude bilaterally in a hand muscle. We found timing-dependent bidirectional Hebbian-like MEP changes during and for at least 30 min after paired associative SMA-M1 stimulation. MEP amplitude increased if SMA stimulation preceded M1 stimulation by 6 ms, but decreased if SMA stimulation lagged M1 stimulation by 15 ms. This associative plasticity in the SMA-M1 network was highly topographically specific because paired associative stimulation of pre-SMA and M1 did not result in any significant MEP change. Furthermore, associative plasticity in the SMA-M1 network was strongly state-dependent because it required priming by near-simultaneous M1 stimulation to occur. We conclude that timing-dependent bidirectional associative plasticity is demonstrated for the first time at the systems level of a human corticocortical neuronal network. The properties of this form of plasticity are fully compatible with spike-timing-dependent plasticity as defined at the cellular level. The necessity of priming may reflect the strong interhemispheric connectivity of the SMA-M1 network. Findings are relevant for better understanding reorganization and potentially therapeutic modification of neuronal coordination in the SMA-M1 network after cerebral lesions such as stroke.