bluuebunny/crossref_metadata_2025 huggingface dataset:
Septins enforce morphogenetic events during sexual reproduction and contribute to virulence of Cryptococcus neoformans
Authors: Kozubowski Lukasz , Heitman Joseph
Published: November 2009

Septins are conserved, cytoskeletal GTPases that contribute to cytokinesis, exocytosis, cell surface organization and vesicle fusion by mechanisms that are poorly understood. Roles of septins in morphogenesis and virulence of a human pathogen and basidiomycetous yeast Cryptococcus neoformans were investigated. In contrast to a well‐established paradigm in S. cerevisiae, Cdc3 and Cdc12 septin homologues are dispensable for growth in C. neoformans yeast cells at 24°C but are essential at 37°C. In a bilateral cross between septin mutants, cells fuse but the resulting hyphae exhibit morphological abnormalities, including lack of properly fused specialized clamp cells and failure to produce spores. Interestingly, post‐mating hyphae of the septin mutants have a defect in nuclear distribution. Thus, septins are essential for the development of spores, clamp cell fusion and also play a specific role in nuclear dynamics in hyphae. In the post‐mating hyphae the septins localize to discrete sites in clamp connections, to the septa and the bases of the initial emerging spores. Strains lacking CDC3 or CDC12 exhibit significantly reduced virulence in a Galleria mellonella model of infection. Thus, C. neoformans septins are vital to morphology of the hyphae and contribute to virulence.
Autonomous plasmid‐like replication of a conjugative transposon
Authors: Lee Catherine A. , Babic Ana , Grossman Alan D.
Published: November 2009

Integrative and conjugative elements (ICEs), a.k.a. conjugative transposons, are mobile genetic elements involved in many biological processes, including pathogenesis, symbiosis and the spread of antibiotic resistance. Unlike conjugative plasmids that are extra‐chromosomal and replicate autonomously, ICEs are integrated in the chromosome and replicate passively during chromosomal replication. It is generally thought that ICEs do not replicate autonomously. We found that when induced, Bacillus subtilis ICEBs1 undergoes autonomous plasmid‐like replication. Replication was unidirectional, initiated from the ICEBs1 origin of transfer, oriT, and required the ICEBs1‐encoded relaxase NicK. Replication also required several host proteins needed for chromosomal replication, but did not require the replicative helicase DnaC or the helicase loader protein DnaB. Rather, replication of ICEBs1 required the helicase PcrA that is required for rolling circle replication of many plasmids. Transfer of ICEBs1 from the donor required PcrA, but did not require replication, indicating that PcrA, and not DNA replication, facilitates unwinding of ICEBs1 DNA for horizontal transfer. Although not needed for horizontal transfer, replication of ICEBs1 was needed for stability of the element. We propose that autonomous plasmid‐like replication is a common property of ICEs and contributes to the stability and maintenance of these mobile genetic elements in bacterial populations.
Escherichia coli ribonuclease III activity is downregulated by osmotic stress: consequences for the degradation of bdm mRNA in biofilm formation
Authors: Sim Se‐Hoon , Yeom Ji‐Hyun , Shin Choy , Song Woo‐Seok , Shin Eunkyoung , Kim Hong‐Man , Cha Chang‐Jun , Han Seung Hyun , Ha Nam‐Chul , Kim Si Wouk , Hahn Yoonsoo , Bae Jeehyeon , Lee Kangseok
Published: November 2009

During the course of experiments aimed at identifying genes with ribonuclease III (RNase III)‐dependent expression in Escherichia coli, we found that steady state levels of bdm mRNA were dependent on cellular concentrations of RNase III. The half‐lives of adventitiously overexpressed bdm mRNA and the activities of a transcriptional bdm‘–’cat fusion were observed to be dependent on cellular concentrations of RNase III, indicating the existence of cis‐acting elements in bdm mRNA responsive to RNase III. In vitro and in vivo cleavage analyses of bdm mRNA identified two RNase III cleavage motifs, one in the 5′‐untranslated region and the other in the coding region of bdm mRNA, and indicated that RNase III cleavages in the coding region constitute a rate‐determining step for bdm mRNA degradation. We also discovered that downregulation of the ribonucleolytic activity of RNase III is required for the sustained elevation of RcsB‐induced bdm mRNA levels during osmotic stress and that cells overexpressing bdm form biofilms more efficiently. These findings indicate that the Rcs signalling system has an additional regulatory pathway that functions to modulate bdm expression and consequently, adapt E. coli cells to osmotic stress.
Role of minor determinants of amoxicillin in the diagnosis of immediate allergic reactions to amoxicillin
Authors: Torres M. J. , Ariza A. , Fernández J. , Moreno E. , Laguna J. J. , Montañez M. I. , Ruiz‐Sanchez A. J. , Blanca M.
Published: November 2009

To cite this article: Torres MJ, Ariza A, Fernández J, Moreno E, Laguna JJ, Montañez MI, Ruiz‐Sanchez AJ, Blanca M. Role of minor determinants of amoxicillin in the diagnosis of immediate allergic reactions to amoxicillin. Allergy 2010; 65: 590–596.

Background:  Skin testing of subjects with immediate hypersensitivity to amoxicillin is performed using major and minor determinants of benzylpenicillin plus amoxicillin. However, sensitivity is not optimal, and other determinants need to be considered. We assessed the sensitivity of stable, well‐characterized minor determinants of amoxicillin in subjects with immediate allergic reactions to amoxicillin to improve skin test sensitivity.

Methods:  Amoxicillin, amoxicilloic acid, and diketopiperazine were prepared and characterized by reverse‐phase HPLC, tested in vivo by skin testing and in vitro by basophil activation test and RAST inhibition assay.

Results:  Patients with immediate hypersensitivity to amoxicillin were selected: Group A (n = 32), skin test positive just to amoxicillin; Group B (n = 19), skin test positive to benzylpenicillin determinants; Group C (n = 10), skin test negative and amoxicillin drug provocation test positive. In Group A, 27 subjects (81.8%) were skin test positive to amoxicillin, ten (30.3%) to amoxicilloic acid, two (6.1%) to diketopiperacine, and six (18.2%) negative. In Group B, nine (50%) were positive to amoxicillin, eight (42.1%) to amoxicilloic acid, none to diketopiperacine, and nine (50%) negative. In Group C, skin tests were negative. BAT was positive to amoxicillin in 26 patients (50.9%), to amoxicilloic acid in 15 (29.1%), and diketopiperazine in four (7.8%). RAST inhibition studies showed > 50% inhibition in all sera, with the highest concentration of amoxicillin and amoxicilloic acid.

Conclusions:  The combination of minor determinants of amoxicillin, amoxicilloic acid, and diketopiperazine seems to be of no greater value than the use of amoxicillin alone. Further efforts are needed to find new structures to improve sensitivity in the diagnosis of immediate hypersensitivity to betalactams.
A pilot study of genetic differentiation between two phenotypes of a Mediterranean population of the bivalve Cerastoderma glaucum and genetic discrimination with other Cerastoderma glaucum and Cerastoderma edule populations outside the Mediterranean
Authors: Ladhar‐Chaabouni Rim , Hamza‐Chaffai Amel , Hardivillier Yann , Chénais Benoît , Denis Françoise
Published: November 2009

The internal transcribed spacer 1 (ITS1) region of 29 individuals of Cerastoderma glaucum (from the Mediterranean Sea, the Atlantic and the North Sea) and 18 individuals of Cerastoderma edule (from the Atlantic and the North Sea) and the cytochrome c oxidase subunit I (COI) region of 43 individuals of C. glaucum (from the Mediterranean Sea, the Atlantic and the North Sea) and 9 individuals of C. edule (from the Atlantic and the North Sea) were PCR amplified and sequenced. The ITS1 sequences led us to describe 27 genetic haplotypes, while 21 genetic haplotypes were determined via the COI sequences. The ITS1 and the COI sequences revealed an important genetic variability within the Mediterranean population of C. glaucum, which contained two different phenotypes: orange foot and yellow foot. A genetic differentiation between the two phenotypes was revealed by the nucleotide diversity index (π) and is strengthened by the AMOVA analysis. This result leads us to suspect the presence of two different groups in the same population of C. glaucum. Nevertheless to be confirmed this hypothesis requires further studies using more locations and a larger number of sample sizes.
Quantitative assessment of gene methylation in neoplastic and non‐neoplastic gastric epithelia using methylation‐specific DNA microarray
Authors: Tamura Gen , So Kanji , Miyoshi Hiroaki , Honda Teiichiro , Nishizuka Satoshi , Motoyama Teiichi
Published: November 2009

A fiber‐type DNA microarray was used to calculate methylation rates (MR) of four tumor suppressor genes, lysyl oxidase (LOX), p16, RUNX3, and tazarotene‐induced gene 1 (TIG1). MR were calculated in 26 primary gastric cancers and corresponding non‐neoplastic gastric epithelia, and the results were compared to those of conventional methylation‐specific polymerase chain reaction (MSP). MR ranged from 0.1% to 69.1% (mean, 18.3%) for LOX, 0.5–74.1% (mean, 15.7%) for p16, 0.2–76.5% (mean, 22.7%) for RUNX3, and 0.6–41.2% (mean, 5.8%) for TIG1 in primary gastric cancers, and from 0.1% to 25.8% (mean, 8.7%) for LOX, 1.0– 23.2% (mean, 10.3%) for p16, 0.7–25.1% (mean, 5.5%) for RUNX3, and 1.8–27.6% (mean, 11.4%) for TIG1 in corresponding non‐neoplastic gastric epithelia. Although MR varied significantly across different samples for both neoplastic and non‐neoplastic gastric epithelia, high‐level methylation (MR >40%) was cancer specific and was observed in 19.2%, 19.2%, 30.8%, and 3.8% of primary gastric cancers for LOX, p16, RUNX3, and TIG1, respectively. All samples with high‐level methylation, as well as some samples with low MR (particularly <10%) were judged to be methylation positive on conventional MSP. Quantitative analysis of gene methylation using methylation‐specific DNA microarray is a promising method for cancer diagnosis.
Clinicocytopathology of breast cancers with a ring‐like appearance on ultrasonography and/or magnetic resonance imaging
Authors: Yamaguchi Rin , Tanaka Maki , Yokoyama Toshiro , Nonaka Hideyuki , Kojima Kazuyuki , Terasaki Hiroshi , Yamaguchi Miki , Fukunaga Mari , Toh Uhi , Nakashima Osamu , Kage Masayoshi , Yano Hirohisa
Published: November 2009

On breast cancer imaging some cancers have an anechoic or high‐echoic zone in the tumor on ultrasonography and ring‐shaped enhancement on contrast‐enhanced magnetic resonance imaging (MRI) with high intensity in the central area of the tumor on T2‐weighted imaging, necessitating their differentiation from benign disease. Thus, nine breast cancers with a ring‐like appearance on imaging were analyzed on cytopathology. Histologically the cancer cells of these lesions showing a ring‐like appearance were located in the periphery of the tumor, with a central hypocellular zone. Five such lesions with a thick, doughnut‐like appearance were identified as cancers with acellular zones (CAC), and four lesions with a thinner, rim‐like appearance as matrix‐producing carcinomas (MPC). The percentage ratio of the cancer‐zone width to the tumor diameter was 26.4 ± 7.8 and 8.0 ± 3.2 (mean ± SD), respectively (P= 0.003). Cytologically, highly atypical, naked‐nucleus cells were observed in eight of the nine cancers. In two MPC and three CAC, cartilage matrix and amorphous material, respectively, were observed in the background. In summary, the present series of breast cancers having a ring appearance on imaging did not have uniform cytopathological features. They were classified as MPC or CAC, and cytology was useful in their diagnosis and differentiation in some cases.
Thyroid‐like low‐grade nasopharyngeal papillary adenocarcinoma: Report of two cases
Authors: Ohe Chisato , Sakaida Noriko , Tadokoro Chika , Fukui Hideto , Asako Mikiya , Tomoda Koichi , Uemura Yoshiko
Published: November 2009

Thyroid‐like low‐grade nasopharyngeal papillary adenocarcinoma (LGNPPA) is extremely rare; only four cases have been reported. Herein are presented the case reports of two Japanese male patients with thyroid‐like LGNPPA. Macroscopically, these tumors were pedunculated polypoid masses on the roof of the nasopharynx. Microscopically, they were characterized by papillary and glandular epithelial proliferation. The papillae were complex and tightly packed with hyalinized fibrovascular cores and lined by columnar and pseudostratified cells with intervening spindle‐shaped cells. Both cell types had round to oval vesicular nuclei with tiny nucleoli and mildly eosinophilic cytoplasm. Mitotic figures were not evident and necrosis was not observed. Psammoma bodies were seen focally in one of the patients. Transition from normal surface epithelium to tumor cells was identified in both cases. On immunohistochemistry the tumor cells were positive for cytokeratin (CK)7, CK19, thyroid transcription factor‐1 (TTF‐1) and vimentin. They were negative for CK5/6, CK20, thyroglobulin, S‐100 protein and CD15. In situ hybridization for EBV was negative. Nasopharyngeal tumors with similar morphological appearance should be examined for TTF‐1 immunoreactivity, and patients should be clinically followed to determine the course of this unusual disease and the significance of TTF‐1 expression.
Parvalbumin‐containing neurons, perineuronal nets and experience‐dependent plasticity in murine barrel cortex
Authors: Nowicka Dorota , Soulsby Susan , Skangiel‐Kramska Jolanta , Glazewski Stanislaw
Published: November 2009

The ability to undergo experience‐dependent plasticity in the neocortex is often limited to early development, but also to particular cortical loci and specific experience. In layers II–IV of the barrel cortex, plasticity evoked by removing all but one vibrissae (univibrissa rearing) does not have a time limit except for layer IV barrels, where it can only be induced during the first postnatal week. In contrast, deprivation of every second vibrissa (chessboard deprivation) removes time limits for plasticity. The mechanism permitting plasticity in response to chessboard deprivation and halting it in reply to univibrissa rearing is unknown. Condensation of chondroitin sulfate proteoglycans into perineuronal nets and an increase in intracortical inhibition mediated by parvalbumin‐containing interneurons are implicated in closing the critical period for ocular dominance plasticity. These factors could also be involved in setting up the critical period in barrels in a way that depends on a particular sensory experience. We therefore examined changes in density of parvalbumin‐containing cells and perineuronal nets during development of mouse barrel cortex and after brief univibrissa and chessboard experience in adolescence. We observed a progressive increase in the density of the two markers across cortical layers between postnatal day 10 and 20, which was especially pronounced in the barrels. Univibrissa rearing, but not chessboard deprivation, increased the density of perineuronal nets and parvalbumin‐containing cells in the deprived barrels, but only those that immediately neighbour the undeprived barrel. These data suggest the involvement of both tested factors in closing the critical period in barrels in an experience‐dependent manner.
Neural correlates of conflict resolution between automatic and volitional actions by basal ganglia
Authors: Watanabe Masayuki , Munoz Douglas P.
Published: November 2009

A dominant basal ganglia (BG) model consists of two functionally opposite pathways: one facilitates motor output and the other suppresses it. Although this idea was originally proposed to account for motor deficits, it has been extended recently also to explain cognitive deficits. Here, we employed the antisaccade paradigm (look away from a stimulus) to address the role of the caudate nucleus, the main BG input stage where the two pathways diverge, in conflict resolution. Using single neuron recordings in awake monkeys, we identified the following three groups of neurons. The first group of neurons showed activity consistent with sensory‐driven (automatic) saccades toward a contralateral visual stimulus. The second group of neurons showed activity consistent with internally driven (volitional) saccades toward the contralateral side regardless of stimulus locations. The third group of neurons showed similar firing characteristics with the second group of neurons, except that their preferred saccade direction was ipsilateral. The activity of the three groups of neurons was correlated with behavioral outcome. Based on these findings, we suggest the following hypothesis: the first and second groups of neurons encoding automatic and volitional saccades, respectively, might give rise to the facilitation (direct) pathway and promote saccades toward the opposite directions, which creates a response conflict. This conflict could be resolved by the third group of caudate neurons, which might give rise to the suppression (indirect) pathway and attenuate inappropriate saccade commands toward the stimulus.
Dopamine–oxytocin interactions in penile erection
Authors: Baskerville T. A. , Allard J. , Wayman C. , Douglas A. J.
Published: November 2009

Dopamine and oxytocin have established roles in the central regulation of penile erection in rats; however, the neural circuitries involved in a specific erectile context and the interaction between dopamine and oxytocin mechanisms remain to be elucidated. The medial preoptic area (MPOA), supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus may serve as candidate sites because they contain oxytocin cells, receive dopaminergic inputs and have been implicated in mediating masculine sexual behavior. Double immunofluorescence revealed that substantial numbers of oxytocin cells in the MPOA, SON and PVN possess dopamine D2, D3 and D4 receptors. In anaesthetized rats, using intracavernous pressure as a physiological indicator of erection, blockade of lumbosacral oxytocin receptors (UK, 427843) reduced erectile responses to a nonselective dopamine agonist (apomorphine), suggesting that dopamine recruits a paraventriculospinal oxytocin pathway. In conscious males in the absence of a female, penile erection elicited by a D2/D3 (Quinelorane) but not D4 (PD168077) agonist was associated with activation of medial parvocellular PVN oxytocin cells. In another experiment where males were given full access to a receptive female, a D4 (L‐745870) but not D2 or D3 antagonist (L‐741626; nafadotride) inhibited penile erection (intromission), and this was correlated with SON magnocellular oxytocin neuron activation. Together, the data suggest dopamine’s effects on hypothalamic oxytocin cells during penile erection are context‐specific. Dopamine may act via different parvocellular and magnocellular oxytocin subpopulations to elicit erectile responses, depending upon whether intromission is performed. This study demonstrates the potential existence of interaction between central dopamine and oxytocin pathways during penile erection, with the SON and PVN serving as integrative sites.
Long‐term synaptic plasticity is impaired in rats with lesions of the ventrolateral preoptic nucleus
Authors: Arrigoni Elda , Lu Jun , Vetrivelan Ramalingam , Saper Clifford B.
Published: November 2009

Impairment of memory functions has been frequently reported in models of sleep deprivation. Similarly, hippocampal long‐term synaptic plasticity has been shown to be sensitive to sleep loss caused by acute sleep restriction. However, such approaches are limited by the stressful nature of sleep deprivation, and because it is difficult to study long‐term sleep restriction in animals. Here, we report the effects of chronic sleep loss on hippocampal long‐term potentiation (LTP) in a rodent model of chronic partial sleep deprivation. We studied LTP of the Schaffer collateral–CA1 synapses in hippocampal slices prepared from rats with lesions of the ventrolateral preoptic nucleus (VLPO), which suffered reductions in total sleep time for several weeks after lesions. In slices prepared from VLPO‐lesioned rats, LTP was impaired proportionally to the amount of sleep loss, and the decline in LTP followed a single exponential function over the amount of accumulated sleep debt. As compared with sham‐lesioned controls, hippocampal slices from VLPO‐lesioned rats showed a greater response to adenosine antagonists and greater paired‐pulse facilitation (PPF). However, exogenous adenosine depressed evoked synaptic transmission and increased PPF in VLPO‐lesioned and sham‐lesioned rats by equal amounts, suggesting that the greater endogenous adenosine inhibitory tone in the VLPO‐lesioned rats is associated with greater ligand accumulation rather than a change in adenosine receptor sensitivity or adenosine‐mediated neurotransmitter release probability. LTP in VLPO‐lesioned animals was partially restored by adenosine antagonists, suggesting that adenosine accumulation in VLPO‐lesioned animals could account for some of the observed synaptic plasticity deficits.
Extinction of cued fear memory involves a distinct form of depotentiation at cortical input synapses onto the lateral amygdala
Authors: Hong Ingie , Song Beomjong , Lee Sukwon , Kim Jihye , Kim Jeongyeon , Choi Sukwoo
Published: November 2009

The amygdala is known to be a critical storage site of conditioned fear memory. Among the two major pathways to the lateral amygdala (LA), the cortical pathway is known to display a presynaptic long‐term potentiation which is occluded with fear conditioning. Here we show that fear extinction results in a net depression of conditioning‐induced potentiation at cortical input synapses onto the LA (C‐LA synapses). Fear conditioning induced a significant potentiation of excitatory postsynaptic currents at C‐LA synapses compared with naïve and unpaired controls, whereas extinction apparently reversed this potentiation. Paired‐pulse low‐frequency stimulation (pp‐LFS) induced synaptic depression in the C‐LA pathway of fear‐conditioned rats, but not in naïve or unpaired controls, indicating that the pp‐LFS‐induced depression is specific to associative learning‐induced changes (pp‐LFS‐induced depotentiationex vivo). Importantly, extinction occluded pp‐LFS‐induced depotentiationex vivo, suggesting that extinction shares some mechanisms with the depotentiation. pp‐LFS‐induced depotentiationex vivo required NMDA receptor (NMDAR) activity, consistent with a previous finding that blockade of amygdala NMDARs impaired fear extinction. In addition, pp‐LFS‐induced depotentiationex vivo required activity of group II metabotropic glutamate receptors (mGluRs), known to be present at presynaptic terminals, but not AMPAR internalization, consistent with a presynaptic mechanism for pp‐LFS‐induced depotentiationex vivo. This result is in contrast with another form of ex vivo depotentiation in the thalamic pathway that requires both group I mGluR activity and AMPAR internalization. We thus suggest that extinction of conditioned fear involves a distinct form of depotentiation at C‐LA synapses, which depends upon both NMDARs and group II mGluRs.
Embryonic striatal grafts restore bi‐directional synaptic plasticity in a rodent model of Huntington’s disease
Authors: Mazzocchi‐Jones David , Döbrössy Máté , Dunnett Stephen B.
Published: November 2009

Embryonic striatal grafts integrate with the host striatal circuitry, forming anatomically appropriate connections capable of influencing host behaviour. In addition, striatal grafts can influence host behaviour via a variety of non‐specific, trophic and pharmacological mechanisms; however, direct evidence that recovery is dependent on circuit reconstruction is lacking. Recent studies suggest that striatal grafts alleviate simple motor deficits, and also that learning of complex motor skills and habits can also be restored. However, although the data suggest that such ‘re‐learning’ requires integration of the graft into the host striatal circuitry, little evidence exists to demonstrate that such integration includes functional synaptic connections. Here we demonstrate that embryonic striatal grafts form functional connections with the host striatal circuitry, capable of restoring stable synaptic transmission, within an excitotoxic lesion model of Huntington’s disease. Furthermore, such ‘functional integration’ of the striatal graft enables the expression of host–graft bi‐directional synaptic plasticity, similar to the normal cortico‐striatal circuit. These results indicate that striatal grafts express synaptic correlates of learning, and thereby provide direct evidence of functional neuronal circuit repair, an essential component of ‘functional integration’.
Activity‐driven mobilization of post‐synaptic proteins
Authors: Gutiérrez R. Carolina , Flynn Robyn , Hung Johanna , Kertesz Audrey C. , Sullivan Andrea , Zamponi Gerald W. , El‐Husseini Alaa , Colicos Michael A.
Published: November 2009

Synapses established during central nervous system development can be modified through synapse elimination and formation. These processes are, in part, activity dependent and require regulated trafficking of post‐synaptic components. Here, we investigate the activity‐driven remodeling of cultured rat hippocampal neurons at 14 days in vitro, focusing on the post‐synaptic proteins PSD‐95, Shank, neuroligin (NL)1 and actin. Using live imaging and photoconductive stimulation, we found that high‐frequency activity altered the trajectory, but not velocity, of PSD‐95‐GFP and Shank‐YFP clusters, whereas it reduced the speed and increased the number of NL1 clusters. Actin‐CFP reorganized into puncta following activity and ∼50% of new puncta colocalized with NL1 clusters. Actin reorganization was enhanced by the overexpression of NL1 and decreased by the expression of an NL1 mutant, NL1‐R473C. These results demonstrate activity‐dependent changes that may result in the formation of new post‐synaptic sites and suggest that NL1 modulates actin reorganization. The results also suggest that a common mechanism underlies both the developmental and activity‐dependent remodeling of excitatory synapses.
The relation of ventromedial prefrontal cortex activity and heart rate fluctuations at rest
Authors: Ziegler Gabriel , Dahnke Robert , Yeragani Vikram K. , Bär Karl‐Jürgen
Published: November 2009

Recent studies applying functional magnetic resonance imaging have focused on the description of cerebral substrates of changes in cardiac function during diverse autonomic maneuvers or stressful cognitive tasks. These studies might be limited by the indistinguishable neuronal activity due to cognitive processes, which are known to influence autonomic function, and the ‘baseline’ activity in the central autonomic network. We therefore investigated 26 healthy volunteers in the magnetic resonance scanner to simultaneously obtain functional brain images and RR intervals (intervals between ventricular depolarizations) of the high‐resolution electrocardiogram. The mean RR interval length within each functional scan was computed, which was finally convolved with the canonical hemodynamic response function to obtain a regressor for the functional time series. The resulting individual contrast image indicated a positive covariation of the blood oxygen level‐dependent signal and RR interval length in the ventromedial prefrontal cortex (vmPFC). Furthermore, a reduced mean cross‐approximate entropy value was shown for the interaction between the vmPFC and individual RR intervals. This suggests reduced asynchrony between the heart rate and vmPFC activity in contrast to other brain areas. Our findings confirm data obtained in animals describing the vmPFC as an important forebrain structure of the central autonomic network and an influence of the vmPFC in the cortical generation of efferent vagal activity. This finding needs to be investigated in diseases with known suppression of efferent vagal modulation.
Engineering neuronal nicotinic acetylcholine receptors with functional sensitivity to α‐bungarotoxin: a novel α3‐knock‐in mouse
Authors: Caffery Philip M. , Krishnaswamy Arjun , Sanders Tanya , Liu Jing , Hartlaub Hilary , Klysik Jan , Cooper Ellis , Hawrot Edward
Published: November 2009

We report here the construction of a novel knock‐in mouse expressing chimeric α3 nicotinic acetylcholine receptor (nAChR) subunits with pharmacological sensitivity to α‐bungarotoxin (αBTX). Sensitivity was generated by substituting five amino acids in the loop C (β9–β10) region of the mouse α3 subunit with the corresponding residues from the α1 subunit of the muscle type receptor from Torpedo californica. To demonstrate the utility of the underlying concept, expressed α3[5] subunits were characterized in the superior cervical ganglia (SCG) of homozygous knock‐in mice, where the synaptic architecture of postsynaptic α3‐containing nAChR clusters could now, for the first time, be directly visualized and interrogated by live‐staining with rhodamine‐conjugated αBTX. Consistent with the postsynaptic localization of ganglionic nAChRs, the αBTX‐labeled puncta colocalized with a marker for synaptic varicosities. Following in vivo deafferentation, these puncta persisted but with significant changes in intensity and distribution that varied with the length of the recovery period. Compound action potentials and excitatory postsynaptic potentials recorded from SCG of mice homozygous for α3[5] were abolished by 100 nmαBTX, even in an α7 null background, demonstrating that synaptic throughput in the SCG is completely dependent on the α3‐subunit. In addition, we observed that the genetic background of various inbred and outbred mouse lines greatly affects the functional expression of α3[5]‐nAChRs, suggesting a powerful new approach for exploring the molecular mechanisms underlying receptor assembly and trafficking. As αBTX‐sensitive sequences can be readily introduced into other nicotinic receptor subunits normally insensitive to αBTX, the findings described here should be applicable to many other receptors.
Efficacy and safety of monotherapy of sitagliptin compared with metformin in patients with type 2 diabetes
Authors: Aschner P. , Katzeff H. L. , Guo H. , Sunga S. , Williams‐Herman D. , Kaufman K. D. , Goldstein B. J. ,   for the Sitagliptin Study 049 Group
Published: November 2009

Aim: To compare the efficacy and safety of monotherapy with sitagliptin and metformin in treatment‐naïve patients with type 2 diabetes.

Methods: In a double‐blind study, 1050 treatment‐naïve patients (i.e. not taking an antihyperglycaemic agent for ≥16 weeks prior to study entry) with type 2 diabetes and an HbA1c 6.5–9% were randomized (1:1) to treatment with once‐daily sitagliptin 100 mg (N = 528) or twice‐daily metformin 1000 mg (N = 522) for 24 weeks. Metformin was up‐titrated from 500 to 2000 mg per day (or maximum tolerated daily dose ≥1000 mg) over a period of 5 weeks. The primary analysis used a per‐protocol (PP) approach to assess whether sitagliptin was non‐inferior to metformin based on HbA1c change from baseline at week 24. Non‐inferiority was to be declared if the upper boundary of the 95% confidence interval (CI) for the between‐group difference in this endpoint was <0.40%.

Results: From a mean baseline HbA1c of 7.2% in the PP population, HbA1c change from baseline was −0.43% with sitagliptin (n = 455) and −0.57% with metformin (n = 439). The between‐group difference (95% CI) was 0.14% (0.06, 0.21), thus confirming non‐inferiority. Baseline HbA1c influenced treatment response, with larger reductions in HbA1c observed in patients with baseline HbA1c≥8% in the sitagliptin (–1.13%; n = 74) and metformin (–1.24%; n = 73) groups. The proportions of patients at week 24 with HbA1c values at the goals of <7 or <6.5% were 69 and 34% with sitagliptin and 76 and 39% with metformin, respectively. Fasting plasma glucose changes from baseline were −11.5 mg/dL (–0.6 mmol/l) and −19.4 mg/dl (–1.1 mmol/l) with sitagliptin and metformin, respectively (difference in LS mean change from baseline [95% CI] = 8.0 mg /dl [4.5,11.4]). Both treatments led to similar improvements from baseline in measures of homeostasis model assessment‐β cell function (HOMA‐β) and insulin resistance (HOMA‐IR). The incidence of hypoglycaemia was 1.7% with sitagliptin and 3.3% with metformin (p = 0.116). The incidence of gastrointestinal‐related adverse experiences was substantially lower with sitagliptin (11.6%) compared with metformin (20.7%) (difference in incidence [95% CI] = −9.1% [−13.6,−4.7]), primarily because of significantly decreased incidences of diarrhoea (3.6 vs. 10.9%; p < 0.001) and nausea (1.1 vs. 3.1%; p = 0.032). Body weight was reduced from baseline with both sitagliptin (LS mean change [95% CI] = −0.6 kg [−0.9,−0.4]) and metformin (–1.9 kg [–2.2, −1.7]) (p < 0.001 for sitagliptin vs. metformin).

Conclusions: In this 24‐week monotherapy study, sitagliptin was non‐inferior to metformin in improving HbA1c in treatment‐naïve patients with type 2 diabetes. Although both treatments were generally well tolerated, a lower incidence of gastrointestinal‐related adverse experiences was observed with sitagliptin.
A one‐year study to assess the safety and efficacy of the CB1R inverse agonist taranabant in overweight and obese patients with type 2 diabetes
Authors: Kipnes M. S. , Hollander P. , Fujioka K. , Gantz I. , Seck T. , Erondu N. , Shentu Y. , Lu K. , Suryawanshi S. , Chou M. , Johnson‐Levonas A. O. , Heymsfield S. B. , Shapiro D. , Kaufman K. D. , Amatruda J. M.
Published: November 2009

Aim: To evaluate the efficacy and safety of taranabant in overweight and obese patients with type 2 diabetes mellitus (T2DM).

Methods: This was a multicenter, double‐blind, randomized, placebo‐controlled study in overweight and obese patients with T2DM (ages ≥ 18 and ≤ 75 years) with a BMI ≥ 27 kg/m2 and ≤ 43 kg/m2 and HbA1c ≥7.0 and ≤ 10.0%, who were either not on an antihyperglycaemic agent or on a stable dose of metformin (≥ 1500 mg/day). After a 2‐week placebo run‐in, patients were randomized to placebo (N = 156) or taranabant 0.5‐mg (N = 155), 1‐mg (N = 157), or 2‐mg (N = 155) once daily for 52 weeks. Primary efficacy endpoints were changes from baseline in body weight (BW) and HbA1c at Week 36, with results at Week 52 being key secondary endpoints.

Results: In the all‐patients‐treated population, using a last‐observation‐carried‐forward analysis, reductions in BW were −2.5, −3.7, −4.5 and −5.1 kg at Week 36 and −2.4, −4.0, −4.6 and −5.3 kg at Week 52 in the placebo, 0.5‐, 1‐ and 2‐mg groups, respectively (all doses significant vs. placebo at both time points). The proportion of patients who lost ≥ 5 and ≥ 10% of their baseline BW was significantly greater in the 1‐ and 2‐mg groups vs. placebo at Week 36 and all taranabant groups vs. placebo at Week 52. Reductions in HbA1c were −0.40, −0.47, −0.68 and −0.71% at Week 36 and −0.30, −0.43, −0.65 and −0.64% at Week 52, in the placebo, 0.5‐, 1‐ and 2‐mg groups, respectively (1‐ and 2‐mg doses significant vs. placebo at both time points). After 52 weeks, the incidences of adverse experiences classified in the gastrointestinal (diarrhoea, nausea, vomiting), nervous system‐related (dizziness, sensory‐related), and psychiatric (irritability, depression‐related) organ systems were numerically higher or statistically significantly higher in all taranabant groups compared with the placebo group.

Conclusions: After 36 and 52 weeks, treatment with taranabant at the 1‐ and 2‐mg doses led to clinically significant weight loss and improvement in glycaemic parameters in overweight and obese patients with T2DM that was associated with dose‐related increases in adverse experiences. Based on these data and data from other Phase III clinical studies, it was determined that the overall safety and efficacy profile of taranabant did not support further development for the treatment of obesity.
Low density lipoprotein‐cholesterol variability in patients with type 2 diabetes taking atorvastatin compared to simvastatin: justification for direct measurement?
Authors: Sathyapalan T. , Atkin S. L. , Kilpatrick E. S.
Published: November 2009

Aim: The benefit of direct, as opposed to calculated, low density lipoprotein ‐cholesterol (LDL‐C) measurement remains unclear. This study compared the biological variability of direct LDL in patients with type 2 diabetes (T2DM) on equivalent doses of the short half‐life statin, simvastatin or the longer half‐life statin, atorvastatin.

Methods: A cross‐over study of biological variation of lipids in 26 patients with T2DM taking either simvastatin 40 mg (n = 10) or atorvastatin 10 mg. After 3 months on one statin, fasting lipids were measured on 10 occasions over a 5‐week period. The same procedure was then followed on the other statin. The variability of LDL‐C was established using a Beckman direct assay.

Results: As a group, mean LDL was no different between statins (mean ± s.d.) (1.69 ± 0.60 mmol/l simvastatin vs. 1.67 ± 0.60 mmol/l atorvastatin, p = 0.19). However, in all patients, the intraindividual biological variability of LDL while taking simvastatin was markedly higher than with atorvastatin (average s.d. = 0.17 mmol /l simvastatin vs. 0.01 mmol/l, p < 0.0001). Friedewald calculated LDL variability was no different between statins (average s.d. = 0.34 mmol /l simvastatin vs. 0.21 mmol/l atorvastatin, p = 0.19).

Conclusions: In contrast to calculated values, direct measurement revealed LDL to be much more stable (the s.d. being an order of magnitude) in T2DM patients taking atorvastatin rather than simvastatin. This means LDL targets can be consistently met with less lipid monitoring using atorvastatin rather than simvastatin. Direct LDL measurement may therefore have a particular role in monitoring patients on statin treatment.
The diversity field of New World leaf‐nosed bats (Phyllostomidae)
Authors: Villalobos Fabricio , Arita Héctor T.
Published: November 2009

Aim  To analyse how the patterns of species richness for the whole family Phyllostomidae determine the structure of diversity fields (sets of species‐richness values) within the ranges of individual bat species.

Location  The range of the family Phyllostomidae in North and South America.

Methods  We generated a database of the occurrence of 143 phyllostomid bat species in 6794 quadrats, analysing the species‐richness frequency distribution for all sites, and for subsets of sites defined by the geographic ranges of species. Range–diversity plots, depicting simultaneously the size and the mean species richness of ranges, were built to explore the patterns of co‐occurrence in widespread and restricted species. We compared the empirical patterns against two null models: (1) with scattered (non‐cohesive) ranges, and (2) with cohesive ranges modelled with the spreading‐dye algorithm. Diversity fields were analysed with richness maps for individual species and with comparisons of species‐richness frequency distributions.

Results  Overall richness frequency distribution showed a multimodal pattern, whereas simulated distributions showed lower values of variance, and were unimodal (for model 1) and bimodal (for model 2). Range–diversity plots for the empirical data and for the cohesive‐ranges simulation showed a strong tendency of species to co‐occur in high‐diversity sites. The scattered‐ranges simulation showed no such tendency. Diversity fields varied according to idiosyncratic features of species generating particular geographic patterns and richness frequency distributions.

Main conclusions  Phyllostomid bats show a higher level of co‐occurrence than expected from null models. That tendency in turn implies a higher variance in species richness among sites, generating a wider species‐richness frequency distribution. The diversity field of individual species results from the size, shape and location of ranges, but also depends on the general pattern of richness for the whole family.
Morphological skin colour changes in teleosts
Authors: Leclercq Eric , Taylor John F , Migaud Hervé
Published: November 2009

Morphological skin colour change in fish is often referred to in the sole context of background adaptation. It is becoming increasingly apparent that it is a broad phenomenon elicited by a variety of factors. To date, no review has attempted to integrate the different types of morphological colour changes occurring in teleosts, their ecological origins and the regulatory mechanisms involved, often restricting the view on the subject. First, the origin of skin colour is addressed in teleosts including chromatophore type and distribution, pigment biosynthetic pathways and their interactions to one‐another. Second, the different types of morphological colour changes occurring in teleosts are categorized and a key distinction is made between proximate and ultimate morphological colour changes. These are defined respectively as the change of phenotype during an established life‐stage in response to environmental interactions and during the transition between two developmental‐stages phenotypically pre‐adapted to their ancestral ecosystems. Nutrition and UV‐light are primary factors of proximate morphological colour changes beyond the control of the organism. By contrast, background light conditions and social interactions are secondary proximate factors acting through the control of the organism. Highly diversified among teleosts, ultimate morphological skin colour changes are presented in term of alterations in skin structure and pigment deposition during metamorphosis in different species. Finally, the physiological and endocrine mechanisms regulating both proximate and ultimate morphological colour changes are reviewed.
NOMINAL AND REAL WAGE RIGIDITIES IN NEW KEYNESIAN MODELS: A CRITICAL SURVEY
Authors: Riggi Marianna
Published: November 2009

Abstract The labour market is receiving increasing attention in the New Keynesian literature. In this paper, I critically survey this literature in order to highlight the role played by wage rigidities in the explanation of fluctuations caused by technology shocks. To this aim, I present a dynamic stochastic general equilibrium model with sticky prices, nominal wage rigidities and hiring costs. The comparison between this model and that of Blanchard and Gali highlights the non‐trivial differences which exist in the way nominal wage and real wage rigidities drive the economy's dynamics. My conclusion is that models incorporating nominal wage rigidities and some degree of price stickiness provide a better account of macroeconomic dynamics than models with real wage rigidities.
The Dynamic Influence of Social Capital on the International Growth of New Ventures
Authors: Prashantham Shameen , Dhanaraj Charles
Published: November 2009

abstract

This paper explores the origin, evolution, and appropriation of social capital by new ventures seeking international growth. Using longitudinal case studies in the software industry, we model the dynamic influence of social capital on new venture internationalization. We theorize that new ventures of founders from a globally‐connected environment, such as with return migration or MNC experience, have higher stocks of initial social capital than others. We provide a nuanced analysis of the dynamic processes involved in the evolution of social capital, and highlight the mechanisms of decay and replenishment over time. Network learning plays a critical role in new ventures' ability to realize the potential contribution of social capital to international growth.
Do Small Farmers Borrow Less When the Lending Rate Increases? Interest Rate Elasticity of Rice Farmers in the Philippines*
Authors: Briones Roehlano M.
Published: November 2009

The new generation of credit programs directed at small borrowers emphasizes financial sustainability. Based on anecdotal information, proponents of cost recovery claim that raising formal lending rates would have a minimal impact on borrowing. However, rigorous evidence for this conjecture is sparse. The present study conducts an econometric test of this conjecture using data from a survey of small rice farmers from the Philippines. Alternative regression techniques tend to reject the conjecture; in particular, a regression that controls for selection effects shows a unitary elastic response of formal borrowing to the lending rate.
Integrity and Fragmentation
Authors: COTTINGHAM JOHN
Published: November 2009

The virtue of integrity does not appear explicitly in either the Aristotelian or the Judaeo‐Christian list of virtues, but elements of both ethical systems implicitly acknowledge the importance of a unified and integrated life. This paper argues that integrity is indispensible for a good human life; the fragmented or compartmentalized life is always subject to instability, in so far as unresolved psychological conflicts and tensions may threaten to derail our ethical plans and projects. Achieving a stable and integrated life requires self‐awareness; and (drawing on insights from the psychoanalytic tradition) it is suggested that self‐awareness is not a simple matter, but requires a complex process of self‐discovery. The paper's final section argues that although vitally necessary for the good life, integrity cannot be sufficient. Against the view of influential writers such as Bernard Williams and Harry Frankfurt, our commitment to our chosen projects, however authentic and integrated, cannot in itself give our lives meaning and value. The good and meaningful life cannot be a matter of authenticity alone, but requires us, whether we like it or not, to bring our projects into line with enduring objective values that we did not create, and which we cannot alter.
Sooner or Later: An Analysis of the Delays in Insider Trading Reporting
Authors: Betzer André , Theissen Erik
Published: November 2009

Abstract:  Until October 2004, corporate insiders in Germany were required to report trades in the shares of their firm ‘without delay’. Yet in practice, substantial reporting delays were common. We show that the delays are related systematically to the characteristics of the firm. Delays are longer in firms with dispersed ownership and in firms using German accounting standards. This suggests that managers of these firms are less responsive to the informational requirements of the capital market. We further find that abnormal returns after the reporting date of an insider trade are independent of the reporting delay. This implies that prices are distorted in the period between the insider trading and the reporting date. This is a strong point in favour of regulations that require and enforce the immediate disclosure of insider trades.
Children at risk for developmental delay can be recognised by stunting, being underweight, ill health, little maternal schooling or high gravidity
Authors: Abubakar Amina , Holding Penny , Van de Vijver Fons J.R. , Newton Charles , Van Baar Anneloes
Published: November 2009

Aims: To investigate markers of risk status that can be easily monitored in resource‐limited settings for the identification of children in need of early developmental intervention.

Methods: Eighty‐five children in Kilifi, Kenya, aged between 2 and 10 months at recruitment, were involved in a 10‐month follow‐up. Data on developmental outcome were collected through parental report using a locally developed checklist. We tested for the unique and combined influence of little maternal schooling and higher gravidity, anthropometric status (being underweight and stunting) and poor health on the level of developmental achievement and the rate of acquisition of developmental milestones.

Results: A model with all five predictors showed a good fit to the data (χ2(21,N = 85) = 23.00,p = .33). Maternal schooling and gravidity and child’s stunting were found to predict the rate of developmental achievements (β = .24, β = .31, and β = .41, respectively). Being underweight, ill‐health, stunting and gravidity predicted initial developmental status (β = −.26, β = −.27, β = −.43, and β = −.27).

Conclusions: Slow rates of developmental achievement can be predicted using these easy‐to‐administer measures and the strongest relationship with risk was based on a combination of all measures.