bluuebunny/crossref_metadata_2025 huggingface dataset:
Very Low Density Lipoprotein Metabolism and Plasma Adiponectin as Predictors of High-Density Lipoprotein Apolipoprotein A-I Kinetics in Obese and Nonobese Men
Authors: Chan Dick C. , Barrett P. Hugh R. , Ooi Esther M. M. , Ji Juying , Chan Doris T. , Watts Gerald F.
Published: December 2008

Context: Hypercatabolism of high-density lipoprotein (HDL) apolipoprotein (apo) A-I results in low plasma apoA-I concentration. The mechanisms regulating apoA-I catabolism may relate to alterations in very low density lipoprotein (VLDL) metabolism and plasma adiponectin and serum amyloid A protein (SAA) concentrations.

Objective: We examined the associations between the fractional catabolic rate (FCR) of HDL-apoA-I and VLDL kinetics, plasma adiponectin, and SAA concentrations.

Study Design: The kinetics of HDL-apoA-I and VLDL-apoB were measured in 50 obese and 37 nonobese men using stable isotopic techniques.

Results: In the obese group, HDL-apoA-I FCR was positively correlated with insulin, homeostasis model of assessment for insulin resistance (HOMA-IR) score, triglycerides, VLDL-apoB, and VLDL-apoB production rate (PR). In the nonobese group, HDL-apoA-I FCR was positively correlated with triglycerides, apoC-III, VLDL-apoB, and VLDL-apoB PR and negatively correlated with plasma adiponectin. Plasma SAA was not associated with HDL-apoA-I FCR in either group. In multiple regression analyses, VLDL-apoB PR and HOMA-IR score, and VLDL-apoB PR and adiponectin were independently predictive of HDL-apoA-I FCR in the obese and nonobese groups, respectively. HDL-apoA-I FCR was positively and strongly associated with HDL-apoA-I PR in both groups.

Conclusions: Variation in VLDL-apoB production, and hence plasma triglyceride concentrations, exerts a major effect on the catabolism of HDL-apoA-I. Insulin resistance and adiponectin may also contribute to the variation in HDL-apoA-I catabolism in obese and nonobese subjects, respectively. We also hypothesize that apoA-I PR determines a steady-state, lowered plasma of apoA-I, which may reflect a compensatory response to a primary defect in the catabolism of HDL-apoA-I due to altered VLDL metabolism.
Transcriptional Regulation of the Human Growth Hormone Receptor (hGHR) Gene V2 Promoter by Transcriptional Activators and Repressor
Authors: Wei Yuhong , Puzhko Svetlana , Wabitsch Martin , Goodyer Cynthia Gates
Published: December 2008

The V2 transcript is the major ubiquitously expressed human GH receptor (hGHR) mRNA in all tissues examined to date. In a previous investigation, we defined the V2 promoter as TATA-less and exhibiting many characteristics of a housekeeping gene promoter. We also demonstrated that its basal activity is determined by several different cis-regulatory regions within both the promoter and the V2 exon. In the present study, we used luciferase-reporter, site-directed mutagenesis, gel shift, chromatin immunoprecipitation, and quantitative RT-PCR assays to investigate the ability of certain transcription factors to regulate hGHR V2 transcription through these regions in mammalian cells, including human adipocytes. Ets1 was found to transactivate the V2 proximal promoter through specific Ets sites. Two CCAAT/enhancer-binding protein (C/EBP) family members [C/EBP-homologous protein (CHOP) and C/EBPβ] enhanced V2 transcription via different pathways: indirectly, by association with a V2 exon region (CHOP), and directly, using a V2 proximal promoter noncanonical binding site (C/EBPβ). The Notch signaling mediator, Hes1, potently suppressed V2 promoter activity through interaction with two Hes sites within the V2 exon. We propose that these transcriptional factors regulate hGHR V2 expression by acting as downstream nuclear effectors, linking specific signaling cascades (e.g. MAPK and Notch) triggered by different growth factor-, development-, and nutrition- as well as stress-related stimuli. Our data also suggest that these factors are likely to be important in the differentiation-induced increase in V2 mRNA expression in adipocytes, with Ets1 and CHOP functioning at the preadipocyte stage to prepare the cells for differentiation and increasing C/EBPs and decreasing Hes1 levels contributing during adipocyte maturation.
Integrins and cell-fate determination
Authors: Streuli Charles H.
Published: December 2008

All cellular processes are determined by adhesive interactions between cells and their local microenvironment. Integrins, which constitute one class of cell-adhesion receptor, are multifunctional proteins that link cells to the extracellular matrix and organise integrin adhesion complexes at the cell periphery. Integrin-based adhesions provide anchor points for assembling and organising the cytoskeleton and cell shape, and for orchestrating migration. Integrins also control the fate and function of cells by influencing their proliferation, apoptosis and differentiation. Moreover, new literature demonstrates that integrins control the cell-division axis at mitosis. This extends the influence of integrins over cell-fate decisions, as daughter cells are frequently located in new microenvironments that determine their behaviour following cell division. In this Commentary, I describe how integrins influence cell-fate determination, placing particular emphasis on their role in influencing the direction of cell division and the orientation of the mitotic spindle.
Binding of laminin-1 to monosialoganglioside GM1 in lipid rafts is crucial for neurite outgrowth
Authors: Ichikawa Naoki , Iwabuchi Kazuhisa , Kurihara Hidetake , Ishii Kumiko , Kobayashi Toshihide , Sasaki Takako , Hattori Nobutaka , Mizuno Yoshikuni , Hozumi Kentaro , Yamada Yoshihiko , Arikawa-Hirasawa Eri
Published: December 2008

Laminin-1, an extracellular matrix molecule, promotes neurite outgrowth through the interaction of integrin and actin. Monosialoganglioside GM1 in the lipid rafts associates with and activates the NGF receptor TrkA, and enhances neurite outgrowth. However, the role of GM1 in laminin-1-induced neurite outgrowth was still unclear. Here, we describe that laminin-1 binds to GM1 through a carbohydrate moiety and a specific conformation of GM1, induces focal formation of large clusters of GM1, and enhances the relocation of TrkA in the membrane of dorsal root ganglion (DRG) and PC12 cells. We found that laminin-1-mediated clustering of GM1 causes the translocation and enrichment of β1 integrin in lipid rafts – where TrkA colocalizes with β1 integrin – and the activation of Lyn, Akt and MAPK to promote the outgrowth of neurites. Our results suggest that the binding of laminin-1 to GM1 facilitates the formation of a focal microdomain in the membrane, and enhances signal transduction that promotes neurite outgrowth by linking NGF-TrkA signaling with the laminin-integrin signaling pathways.
JAM-A promotes neutrophil chemotaxis by controlling integrin internalization and recycling
Authors: Cera Maria Rosaria , Fabbri Monica , Molendini Cinzia , Corada Monica , Orsenigo Fabrizio , Rehberg Markus , Reichel Christoph A. , Krombach Fritz , Pardi Ruggero , Dejana Elisabetta
Published: December 2008

The membrane-associated adhesion molecule JAM-A is required for neutrophil infiltration in inflammatory or ischemic tissues. JAM-A expressed in both endothelial cells and neutrophils has such a role, but the mechanism of action remains elusive. Here we show that JAM-A has a cell-autonomous role in neutrophil chemotaxis both in vivo and in vitro, which is independent of the interaction of neutrophils with endothelial cells. On activated neutrophils, JAM-A concentrates in a polarized fashion at the leading edge and uropod. Surprisingly, a significant amount of this protein is internalized in intracellular endosomal-like vesicles where it codistributes with integrin β1. Clustering of β1 integrin leads to JAM-A co-clustering, whereas clustering of JAM-A does not induce integrin association. Neutrophils derived from JAM-A-null mice are unable to correctly internalize β1 integrins upon chemotactic stimuli and this causes impaired uropod retraction and cell motility. Consistently, inhibition of integrin internalization upon treatment with BAPTA-AM induces a comparable phenotype. These data indicate that JAM-A is required for the correct internalization and recycling of integrins during cell migration and might explain why, in its absence, the directional migration of neutrophils towards an inflammatory stimulus is markedly impaired.
Integrins are required for the differentiation of visceral endoderm
Authors: Liu Jie , He Xiaowen , Corbett Siobhan A. , Lowry Stephen F. , Graham Alan M. , Fässler Reinhard , Li Shaohua
Published: December 2008

Integrins of the β1 subfamily are highly expressed in the early mouse embryo and are essential for the formation of primitive germ layers from the inner cell mass (ICM). We investigated the mechanisms by which αβ1 integrins regulate ICM morphogenesis by using the embryonic-stem-cell-derived embryoid body (EB), a model for peri-implantation development. Ablation of integrin β1 in EBs resulted in endoderm detachment and in maturation defects, which were manifested by the mislocalization of GATA4 in the cytoplasm and the markedly reduced synthesis of basement membrane (BM) components and the lineage marker disabled homolog 2. The mutant endoderm cells failed to spread on BM substrates, but could spread on vitronectin, which induced upregulation of αvβ3 integrin and integrin-dependent GATA4 nuclear translocation. Forced expression of integrin β3 in the mutant EBs completely rescued endoderm morphogenesis, suggesting that integrin β3 can substitute for integrin β1 in the endoderm. Furthermore, the mitogen-activated protein kinases (MAPKs) ERK1 and ERK2 (ERK1/2) and p38 were activated in endoderm in an integrin-dependent fashion. Pharmacological inhibition of ERK1/2 or p38 MAPK blocked vitronectin-induced GATA4 nuclear translocation and endoderm maturation, whereas expression of a constitutively active ERK kinase (MEK1) or p38 MAPK in the mutant cells rescued endoderm maturation in integrin-β1-null endoderm cells. Collectively, these results suggest that integrins are required for both the stable adhesion and maturation of visceral endoderm, the latter being mediated through the activation of ERK1/2 and p38 MAPK.
Mechanisms that regulate adaptor binding to β-integrin cytoplasmic tails
Authors: Legate Kyle R. , Fässler Reinhard
Published: December 2008

Cells recognize and respond to their extracellular environment through transmembrane receptors such as integrins, which physically connect the extracellular matrix to the cytoskeleton. Integrins provide the basis for the assembly of intracellular signaling platforms that link to the cytoskeleton and influence nearly every aspect of cell physiology; however, integrins possess no enzymatic or actin-binding activity of their own and thus rely on adaptor molecules, which bind to the short cytoplasmic tails of integrins, to mediate and regulate these functions. Many adaptors compete for relatively few binding sites on integrin tails, so regulatory mechanisms have evolved to reversibly control the spatial and temporal binding of specific adaptors. This Commentary discusses the adaptor proteins that bind directly to the tails of β integrins and, using talin, tensin, filamin, 14-3-3 and integrin-linked kinase (ILK) as examples, describes the ways in which their binding is regulated.
Education for the Dental Team: Make Your Practice a Centre of Learning Excellence
Authors: Cure Richard
Published: December 2008

This paper discusses the future educational needs of the changing dental team, the potential for new institutions and teachers to deliver and assess that education, including outreach-based teaching and learning, and interchangeability of educational credits between institutions. The author's opinion is that primary care practices can become ‘centres of learning’ where all members of the dental team can interact to teach and learn together at the same time. The development of a career pathway for dental care professionals (DCPs), a more unified pan-Europe approach to integrated dental education and the development of further roles for senior dental students are proposed. The importance of dentistry acting upon sound, innovative concepts, and of not resisting educational change, is stressed.
A Question of Value: A Qualitative Study of Vocational Dental Practitioners’ Views on Oral Healthcare Systems and Their Future Careers
Authors: Gallagher Jennifer E , Clarke Wendy , Eaton Kenneth A , Wilson Nairn HF
Published: December 2008

Background

New dental graduates in England and Wales spend one year as vocational dental practitioners (VDPs) preparing for independent clinical practice. In recent years, they have entered a state-funded healthcare system undergoing the greatest period of change since the inception of the National Health Service (NHS) and a profession in which there has been a significant shift of care to the private sector. Against this background, the objectives of this study were to investigate VDPs’ vision of their future professional career and the influences that will impact on their choice of state-funded (NHS) and/or private dentistry, and to identify what factors may attract graduates to work for the NHS.

Methods

In 2004/2005, purposive sampling of a range of VDP training schemes across England and Wales was used to select the VDPs from ten schemes to take part in focus groups. To standardise data collection, a topic guide was used. Respondents’ views were recorded on tape and field notes. The data were transcribed and analysed using framework methodology.

Results

Ninety-nine VDPs from all parts of England and Wales participated in ten focus groups. They identified three main categories of future practice: private, state-funded (NHS), and mixed. Private practice was perceived as providing ‘professional independence’, ‘financial reward’, ‘time with patients’ and ‘clinical freedom’. NHS practice was associated with ‘providing access to specialist training’ and ‘gaining clinical experience’, often as preparation for private practice. Providing NHS care was attractive for VDPs who valued the ethos of public service. The VDPs considered that NHS practice could be made more attractive to young dentists by a range of factors, involving the funding, culture and philosophy of the system and the degree of fit with their personal and professional vision. They reported that they would welcome ‘incentives to work in areas of high need’, ‘assistance with debt’ and a ‘culture of valuing NHS dentists’.

Conclusions

The findings suggest that the commitment to healthcare systems of the VDPs who took part in this study was associated with being true to their values and being valued within the system. They perceived a tension between state-funded and private practice, considering the latter more likely to meet personal and professional expectations. However, they remained open to working in an enhanced and supportive state-funded system, should it correspond with their values, and demonstrate that they were valued healthcare professionals.
Can Protein Contamination be Removed from Hand Endodontic Instruments?
Authors: Whitworth Christine L , Davies Karen , Palmer Nikolaus OA
Published: December 2008

Aim

The aim of this study was to quantify total protein adhering to hand endodontic files and to measure and compare the efficacy of ultrasonic cleaning and washer-disinfectors, with and without presoaking, in protein removal from clinically contaminated endodontic files.

Method

Total protein contamination of the endodontic files was quantified using an assay reagent colorimetric method. Twelve general dental practitioners were recruited to collect clinically contaminated files. One hundred and fifty clinically contaminated files were allowed to air-dry in sterile plastic containers and a further 60 files were immersed, working end down, in enzymatic detergent immediately following clinical use. Thirty clinically contaminated files were tested for total protein contamination as a positive control. Sixty files were subjected to ultrasonic cleaning and 30 to processing in each of the washer-disinfectors. The presoaked files were divided into two groups of 30 for processing in the washer-disinfectors. A further group of brand-new, unused files were tested for protein contamination as a negative control.

Results

Protein was present on 29 of the 30 new files tested. The median total mass of protein recovered from clinically contaminated hand endodontic instruments was 2.046 μg. The most effective method of presterilisation cleaning tested was a presoak in Alkazyme™ followed by processing in the Miele G7881 washer-disinfector.

Conclusion

The most effective method of presterilisation cleaning for hand endodontic files is a presoak in Alkazyme™, an alkaline enzymatic detergent, followed by processing in a Miele G7881 washer-disinfector. This study provides up-to-date evidence that newer methods of presterilisation cleaning may fail to remove protein from endodontic hand instruments totally. This may have implications for all reusable dental instruments.
Mentoring. A Quality Assurance Tool for Dentists Part 2: What are Mentoring and Coaching?
Authors: Holt Vernon P , Ladwa Russ
Published: December 2008

In this paper, the traditional model of mentoring is briefly explained. A description of the current technique, which has developed from the traditional model, is then presented and a distinction made between mentoring and coaching, followed by a brief explanation of how mentoring, coaching and counselling make up a triad of helping activities. The authors then provide information on the use and impact of mentoring and coaching in some areas of human activity, other than dentistry, before outlining the application potential of these approaches in general dental practice. The paper concludes that the modern approach to mentoring and counselling offers a person-centred approach that is much more likely than traditional approaches to produce personal change, personal growth and personal development. Further aspects of this important and exciting subject will be explored in subsequent papers in this series.
Factors Affecting the Referral of Potentially Malignant Lesions from Primary Dental Care: A Pilot Study in South Yorkshire
Authors: Brocklehurst Paul R , Baker Sarah R , Speight Paul M
Published: December 2008

Aims

Early diagnosis of oral cancer is an essential element of prevention, yet many patients present late, suggesting that criteria used for referral miss the small or early-stage lesions. The aims of this study were to determine what cues are used by primary care dentists when making the decision to refer a suspicious lesion, and to investigate their recent referral behaviour.

Methods

A cross-sectional study using a postal questionnaire was undertaken in a major conurbation in South Yorkshire. The questionnaire was sent to all 95 practices in the area concerned. Primary care dentists were asked to score a range of cues on a five-point scale and list their top ten. Experience of referrals made in the last 12 months was also recorded.

Results

Forty-two questionnaires were returned (44.2%). The cues that primary care dentists ‘agreed’ or ‘strongly agreed’ would initiate a referral were: ‘fixed’, ‘smokes >20 cigarettes/day’, ‘indurated’, ‘ragged borders’ and ‘ulceration’. The most cited top-ten cues were ‘ulcerated’, ‘fixed to underlying tissues’, ‘smoking’ and ‘indurated’. The median number of lesions referred was 0.77 per 1000 adult patients. Twenty-six dentists recorded their experience of 29 lesions. Of these, 17% had been found by the patient whereas 80% had been found at a routine dental examination. Seventy-nine per cent had been present for more than six weeks. Reasons for referral included atypical appearance (38%), ulceration (21%) and location (21%). Fifty-four per cent of primary care dentists described their relationship with secondary care as either ‘good’ or ‘excellent’.

Conclusions

The most cited cues related to established or advanced disease, not to ‘red’ and ‘white’ lesions, which the National Institute for Health and Clinical Excellence (NICE) recommend for early referral. Even allowing for the relatively poor response rate, this suggests that some small lesions of oral cancer are being missed.
Effects of Critical Illness and Organ Failure on Therapeutic Argatroban Dosage Requirements in Patients with Suspected or Confirmed Heparin-Induced Thrombocytopenia
Authors: Keegan Shaun P , Gallagher Erika M , Ernst Neil E , Young Emily J , Mueller Eric W
Published: December 2008

BACKGROUND

Critically ill patients often require therapeutic argatroban dosages lower than those recommended in package labeling. The magnitude of dosage alteration in relation to severity of organ failure is unknown.

OBJECTIVE

To compare therapeutic argatroban dosages between critically ill and noncritically ill patients with confirmed or suspected heparin-induced thrombocytopenia and investigate the relationship between total Sequential Organ Failure Assessment (SOFA) score and therapeutic argatroban dosage.

METHODS

This retrospective cohort study was conducted at an urban academic medical center. Adults without Child-Pugh class C hepatic dysfunction who received argatroban for more than 24 hours over a 3-year period were included. Therapeutic argatroban dosage was that resulting in 2 consecutive activated partial thromboplastin time (aPTT) values 1.5–3 times the patient-specific baseline obtained at least 4 hours apart. Initial argatroban dosages were at the discretion of the managing service.

RESULTS

Fifty-three patients (critically ill, n = 34; noncritically ill, n = 19) were included. Critically ill patients had higher median [interquartile range] Acute Physiology and Chronic Health Evaluation (APACHE II) (17 [12–21] vs 10 [3.25–17.75]; p = 0.007) and SOFA (11 [7–13] vs 2 [0–2.75]; p < 0.001) scores. Critically ill patients required lower mean ± SD therapeutic argatroban dosage (0.6 ± 0.5 vs 1.4 ± 0.9 µg/kg/min; p < 0.001). There was no significant difference in time to therapeutic aPTT or proportion of aPTTs within therapeutic range. Argatroban dosage was inversely related to SOFA score tertiles (<6: 1.34 ± 0.82 µg/kg/min; 6–9: 0.93 ± 0.54; ≥10: 0.40 ± 0.27; p < 0.001). Total SOFA score at the time of argatroban initiation was independently associated with an argatroban dosage less than 0.75 µg/kg/min (OR 1.5, 95% CI 1.2 to 1.8; p < 0.001). Adverse events were similar between groups.

CONCLUSIONS

Critically ill patients with single or multiple organ failure require lower therapeutic argatroban dosages compared with noncritically ill patients. Because of an inverse relationship with SOFA score, initial argatroban dosage in critically ill patients should be based on the presence and magnitude of organ failure.
A Common Single Nucleotide Polymorphism Alters the Synthesis and Secretion of Neuropeptide Y
Authors: Mitchell Gregory C. , Wang Qian , Ramamoorthy Prabhu , Whim Matthew D.
Published: December 2008

A single nucleotide polymorphism (SNP) in the neuropeptide Y gene has been associated with elevated serum lipid levels and cardiovascular disease. The polymorphism (T1128C) changes the seventh amino acid in the prohormone from leucine to proline. It has been speculated this alters neuropeptide Y (NPY) synthesis, trafficking, or secretion. We tested this hypothesis by expressing the mutant and wild-type prohormones in CNS neurons and endocrine cells. Synthesis and trafficking were followed using immunocytochemistry and fluorescent protein-tagged fusion constructs. Mutant prohormone was synthesized and entered the regulated secretory pathway. When expressed in endocrine cells, wild-type and mutant proteins were found in the same large dense core granules. However, the T1128C polymorphism altered the degree of copackaging, and, on average, individual granules contained more mutant prohormone. This was not attributable to codon bias but to the change in prohormone sequence. Global prohormone targeting was normal, because in hippocampal neurons, the polarized distribution of the mutant prohormone was indistinguishable from the wild-type. When secretion was measured from chromaffin cells, brief depolarizations triggered peptide secretion, confirming the entry of the mutant prohormone into the regulated secretory pathway. However, cells that expressed the mutant protein had increased levels of peptide secretion. We conclude that the T1128C polymorphism alters the packaging and secretion of NPY. In contrast to SNPs in other prohormones, we could not find a phenotype until the prohormone was tracked at the single granule level. These results are consistent with studies showing the T1128C polymorphism has pleiotropic effects.
Midbrain Dopamine Receptor Availability Is Inversely Associated with Novelty-Seeking Traits in Humans
Authors: Zald David H. , Cowan Ronald L. , Riccardi Patrizia , Baldwin Ronald M. , Ansari M. Sib , Li Rui , Shelby Evan S. , Smith Clarence E. , McHugo Maureen , Kessler Robert M.
Published: December 2008

Novelty-seeking personality traits are a major risk factor for the development of drug abuse and other unsafe behaviors. Rodent models of temperament indicate that high novelty responding is associated with decreased inhibitory autoreceptor control of midbrain dopamine neurons. It has been speculated that individual differences in dopamine functioning also underlie the personality trait of novelty seeking in humans. However, differences in the dopamine system of rodents and humans, as well as the methods for assessing novelty responding/seeking across species leave unclear to what extent the animal models inform our understanding of human personality. In the present study we examined the correlation between novelty-seeking traits in humans and D2-like (D2/D3) receptor availability in the substantia nigra/ventral tegmental area. Based on the rodent literature we predicted that novelty seeking would be characterized by lowered levels of D2-like (auto)receptor availability in the midbrain. Thirty-four healthy adults (18 men, 16 women) completed the Tridimensional Personality Questionnaire-Novelty-Seeking Scale and PET scanning with the D2/D3ligand [18F]fallypride. Novelty-Seeking personality traits were inversely associated with D2-like receptor availability in the ventral midbrain, an effect that remained significant after controlling for age. We speculate that the lower midbrain (auto)receptor availability seen in high novelty seekers leads to accentuated dopaminergic responses to novelty and other conditions that induce dopamine release.
Bursicon Functions within theDrosophilaCNS to Modulate Wing Expansion Behavior, Hormone Secretion, and Cell Death
Authors: Peabody Nathan C. , Diao Fengqiu , Luan Haojiang , Wang Howard , Dewey Elizabeth M. , Honegger Hans-Willi , White Benjamin H.
Published: December 2008

Hormones are often responsible for synchronizing somatic physiological changes with changes in behavior. Ecdysis (i.e., the shedding of the exoskeleton) in insects has served as a useful model for elucidating the molecular and cellular mechanisms of this synchronization, and has provided numerous insights into the hormonal coordination of body and behavior. An example in which the mechanisms have remained enigmatic is the neurohormone bursicon, which, after the final molt, coordinates the plasticization and tanning of the initially folded wings with behaviors that drive wing expansion. The somatic effects of the hormone are governed by bursicon that is released into the blood from neurons in the abdominal ganglion (the BAG), which die after wing expansion. How bursicon induces the behavioral programs required for wing expansion, however, has remained unknown. Here we show by targeted suppression of excitability that a pair of bursicon-immunoreactive neurons distinct from the BAGand located within the subesophageal ganglion inDrosophila(the BSEG) is involved in controlling wing expansion behaviors. Unlike the BAG, the BSEGarborize widely in the nervous system, including within the abdominal neuromeres, suggesting that, in addition to governing behavior, they also may modulate the BAG.Indeed, we show that animals lacking bursicon receptor function have deficits both in the humoral release of bursicon and in posteclosion apoptosis of the BAG. Our results reveal novel neuromodulatory functions for bursicon and support the hypothesis that the BSEGare essential for orchestrating both the behavioral and somatic processes underlying wing expansion.
Preso, A Novel PSD-95-Interacting FERM and PDZ Domain Protein That Regulates Dendritic Spine Morphogenesis
Authors: Lee Hyun Woo , Choi Jeonghoon , Shin Hyewon , Kim Karam , Yang Jinhee , Na Moonseok , Choi So Yoen , Kang Gil Bu , Eom Soo Hyun , Kim Hyun , Kim Eunjoon
Published: December 2008

PSD-95 is an abundant postsynaptic density (PSD) protein involved in the formation and regulation of excitatory synapses and dendritic spines, but the underlying mechanisms are not comprehensively understood. Here we report a novel PSD-95-interacting protein Preso that regulates spine morphogenesis. Preso is mainly expressed in the brain and contains WW (domain with two conserved Trp residues), PDZ (PSD-95/Dlg/ZO-1), FERM (4.1, ezrin, radixin, and moesin), and C-terminal PDZ-binding domains. These domains associate with actin filaments, the Rac1/Cdc42 guanine nucleotide exchange factor βPix, phosphatidylinositol-4,5-bisphosphate, and the postsynaptic scaffolding protein PSD-95, respectively. Preso overexpression increases the density of dendritic spines in a manner requiring WW, PDZ, FERM, and PDZ-binding domains. Conversely, knockdown or dominant-negative inhibition of Preso decreases spine density, excitatory synaptic transmission, and the spine level of filamentous actin. These results suggest that Preso positively regulates spine density through its interaction with the synaptic plasma membrane, actin filaments, PSD-95, and the βPix-based Rac1 signaling pathway.
Encoding Human Sexual Chemosensory Cues in the Orbitofrontal and Fusiform Cortices
Authors: Zhou Wen , Chen Denise
Published: December 2008

Chemosensory communication of affect and motivation is ubiquitous among animals. In humans, emotional expressions are naturally associated with faces and voices. Whether chemical signals play a role as well has hardly been addressed. Here, we use functional magnetic resonance imaging to show that the right orbitofrontal cortex, right fusiform cortex, and right hypothalamus respond to airborne natural human sexual sweat, indicating that this particular chemosensory compound is encoded holistically in the brain. Our findings provide neural evidence that socioemotional meanings, including the sexual ones, are conveyed in the human sweat.
Spatial Learning Impairment, Enhanced CDK5/p35 Activity, and Downregulation of NMDA Receptor Expression in Transgenic Mice Expressing Tau-Tubulin Kinase 1
Authors: Sato Shinji , Xu Jiqing , Okuyama Satoshi , Martinez Lindsey B. , Walsh Shannon M. , Jacobsen Michael T. , Swan Russell J. , Schlautman Joshua D. , Ciborowski Pawel , Ikezu Tsuneya
Published: December 2008

Tau-tubulin kinase-1 (TTBK1) is involved in phosphorylation of tau protein at specific Serine/Threonine residues found in paired helical filaments, suggesting its role in tauopathy pathogenesis. We found that TTBK1 levels were upregulated in brains of human Alzheimer' disease (AD) patients compared with age-matched non-AD controls. To understand the effects of TTBK1 activationin vivo, we developed transgenic mice harboring human full-length TTBK1 genomic DNA (TTBK1-Tg). Transgenic TTBK1 is highly expressed in subiculum and cortical pyramidal layers, and induces phosphorylated neurofilament aggregation. TTBK1-Tg mice show significant age-dependent memory impairment as determined by radial arm water maze test, which is associated with enhancement of tau and neurofilament phosphorylation, increased levels of p25 and p35, both activators of cyclin-dependent protein kinase 5 (CDK5), enhanced calpain I activity, and reduced levels of hippocampal NMDA receptor types 2B (NR2B) and D. Enhanced CDK5/p35 complex formation is strongly correlated with dissociation of F-actin from p35, suggesting the inhibitory mechanism of CDK5/p35 complex formation by F-actin. Expression of recombinant TTBK1 in primary mouse cortical neurons significantly downregulated NR2B in a CDK5- and calpain-dependent manner. These data suggest that TTBK1 in AD brain may be one of the underlying mechanisms inducing CDK5 and calpain activation, NR2B downregulation, and subsequent memory dysfunction.
Stimulus-Induced Changes in Blood Flow and 2-Deoxyglucose Uptake Dissociate in Ipsilateral Somatosensory Cortex
Authors: Devor Anna , Hillman Elizabeth M. C. , Tian Peifang , Waeber Christian , Teng Ivan C. , Ruvinskaya Lana , Shalinsky Mark H. , Zhu Haihao , Haslinger Robert H. , Narayanan Suresh N. , Ulbert Istvan , Dunn Andrew K. , Lo Eng H. , Rosen Bruce R. , Dale Anders M. , Kleinfeld David , Boas David A.
Published: December 2008

The present study addresses the relationship between blood flow and glucose consumption in rat primary somatosensory cortex (SI)in vivo. We examined bilateral neuronal and hemodynamic changes and 2-deoxyglucose (2DG) uptake, as measured by autoradiography, in response to unilateral forepaw stimulation. In contrast to the contralateral forepaw area, where neuronal activity, blood oxygenation/flow and 2DG uptake increased in unison, we observed, in the ipsilateral SI, a blood oxygenation/flow decrease and arteriolar vasoconstriction in the presence of increased 2DG uptake. Laminar electrophysiological recordings revealed an increase in ipsilateral spiking consistent with the observed increase in 2DG uptake. The vasoconstriction and the decrease in blood flow in the presence of an increase in 2DG uptake in the ipsilateral SI contradict the prominent metabolic hypothesis regarding the regulation of cerebral blood flow, which postulates that the state of neuroglial energy consumption determines the regional blood flow through the production of vasoactive metabolites. We propose that other factors, such as neuronal (and glial) release of messenger molecules, might play a dominant role in the regulation of blood flowin vivoin response to a physiological stimulus.
Ongoing Activity Fluctuations in hMT+ Bias the Perception of Coherent Visual Motion
Authors: Hesselmann Guido , Kell Christian A. , Kleinschmidt Andreas
Published: December 2008

We have recently shown that intrinsic fluctuations of ongoing activity during baseline have an impact on perceptual decisions reported for an ambiguous visual stimulus (Hesselmann et al., 2008). To test whether this result generalizes from the visual object domain to other perceptual and neural systems, the current study investigated the effect of ongoing signal fluctuations in motion-sensitive brain regions on the perception of coherent visual motion. We determined motion coherence thresholds individually for each subject using a dynamic random dot display. During functional magnetic resonance imaging (fMRI), brief events of subliminal, supraliminal, and periliminal coherent motion were presented with long and variable interstimulus intervals between them. On each trial, subjects reported whether they had perceived “coherent” or “random” motion, and fMRI signal time courses were analyzed separately as a function of stimulus and percept type. In the right motion-sensitive occipito-temporal cortex (hMT+), coherent percepts of periliminal stimuli yielded a larger stimulus-evoked response than random percepts. Prestimulus baseline activity in this region was also significantly higher in these coherent trials than in random trials. As in our previous study, however, the relation between ongoing and evoked activity was not additive but interacted with perceptual outcome. Our data thus suggest that endogenous fluctuations in baseline activity have a generic effect on subsequent perceptual decisions. Although mainstream analytical techniques used in functional neuroimaging do not capture this nonadditive effect of baseline on evoked response, it is in accord with postulates from theoretical frameworks as, for instance, predictive coding.
Spred1Is Required for Synaptic Plasticity and Hippocampus-Dependent Learning
Authors: Denayer Ellen , Ahmed Tariq , Brems Hilde , Van Woerden Geeske , Borgesius Nils Zuiderveen , Callaerts-Vegh Zsuzsanna , Yoshimura Akihiko , Hartmann Dieter , Elgersma Ype , D'Hooge Rudi , Legius Eric , Balschun Detlef
Published: December 2008

Germline mutations inSPRED1, a negative regulator of Ras, have been described in a neurofibromatosis type 1 (NF1)-like syndrome (NFLS) that included learning difficulties in some affected individuals. NFLS belongs to the group of phenotypically overlapping neuro-cardio-facial-cutaneous syndromes that are all caused by germ line mutations in genes of the Ras/mitogen-activated protein kinase extracellular signal-regulated kinase (ERK) pathway and that present with some degree of learning difficulties or mental retardation. We investigated hippocampus-dependent learning and memory as well as synaptic plasticity inSpred1−/−mice, an animal model of this newly discovered human syndrome.Spred1−/−mice show decreased learning and memory performance in the Morris water maze and visual-discrimination T-maze, but normal basic neuromotor and sensory abilities. Electrophysiological recordings on brain slices from these animals identified defects in short- and long-term synaptic hippocampal plasticity, including a disequilibrium between long-term potentiation (LTP) and long-term depression in CA1 region. Biochemical analysis, 4 h after LTP induction, demonstrated increased ERK-phosphorylation inSpred1−/−slices compared with those of wild-type littermates. This indicates that deficits in hippocampus-dependent learning and synaptic plasticity induced bySPRED1deficiency are related to hyperactivation of the Ras/ERK pathway.
Transcranial Magnetic Stimulation to the Frontal Operculum and Supramarginal Gyrus Disrupts Planning of Outcome-Based Hand–Object Interactions
Authors: Tunik Eugene , Lo On-Yee , Adamovich Sergei V.
Published: December 2008

Behavioral data suggest that goals inform the selection of motor commands during planning. We investigated the neural correlates that mediate planning of goal-oriented actions by asking 10 healthy subjects to prepare either a goal-specific movement toward a common object (a cup), with the intent of grasping-to-pour (liquid into it) or grasping-to-move (to another location) the object, or performing a non-object-oriented stimulus-response task (move a finger). Single-pulse transcranial magnetic stimulation was administered on 50% of trials to the supramarginal gyrus (SMG), anterior intraparietal sulcus, inferior frontal gyrus opercularis (IFGo), and triangularis during motor planning. Stimulation to SMG and IFGo caused a significant delay in planning goal-oriented actions but not responses to an arbitrary stimulus. Despite the delay, movement execution was not affected, suggesting that the motor plan remained intact. Our data implicate the SMG and IFGo in planning goal-oriented hand–object interactions.
Cell-Type-Dependent Molecular Composition of the Axon Initial Segment
Authors: Lorincz Andrea , Nusser Zoltan
Published: December 2008

The exact site of initiation and shape of action potentials vary among different neuronal types. The reason for this variability is largely unknown, but the subunit composition, density and distribution of voltage-gated sodium (Nav) and potassium (Kv) channels within the axon initial segment (AIS) are likely to play a key role. Here, we asked how heterogeneous are the density and distribution of Nav and Kv channels within the AISs of a variety of excitatory and inhibitory neurons. Most of the studied cell types expressed a high density of Nav1.6, Kv1.1, and Kv1.2 subunits in their AIS, but the Nav1.1 subunit could only be detected in GABAergic interneurons. A proximo-distal gradient in the density of these subunits was observed within the AIS of certain nerve cells but not in others. For example, a gradual increase of the Nav1.6 subunit was observed in cortical layer 2/3 and hippocampal CA1 pyramidal cell (PC) AISs, whereas its density was rather uniform in layer 5 PC AISs. The Nav1.1 subunit was distributed evenly along the AIS of short-axon cells of the main olfactory bulb but was restricted to the proximal part of the AIS in cortical and cerebellar interneurons. Our results reveal a cell type-dependent expression of sodium and potassium channel subunits with varying densities along the proximo-distal axis of the AISs. This precise arrangement is likely to contribute to the diversity of firing properties observed among central neurons.
Differential cAMP Signaling at Hippocampal Output Synapses
Authors: Wozny Christian , Maier Nikolaus , Fidzinski Pawel , Breustedt Jörg , Behr Joachim , Schmitz Dietmar
Published: December 2008

cAMP is a critical second messenger involved in synaptic transmission and synaptic plasticity. Here, we show that activation of the adenylyl cyclase by forskolin and application of the cAMP-analog Sp-5,6-DCl-cBIMPS both mimicked and occluded tetanus-induced long-term potentiation (LTP) in subicular bursting neurons, but not in subicular regular firing cells. Furthermore, LTP in bursting cells was inhibited by protein kinase A (PKA) inhibitors Rp-8-CPT-cAMP and H-89. Variations in the degree of EPSC blockade by the low-affinity competitive AMPA receptor-antagonist γ-d-glutamyl-glycine (γ-DGG), analysis of the coefficient of variance as well as changes in short-term potentiation suggest an increase of glutamate concentration in the synaptic cleft after expression of LTP. We conclude that presynaptic LTP in bursting cells requires activation of PKA by a calcium-dependent adenylyl cyclase while LTP in regular firing cells is independent of elevated cAMP levels. Our results provide evidence for a differential role of cAMP in LTP at hippocampal output synapses.
NMDA- and β-Amyloid1–42-Induced Neurotoxicity Is Attenuated in Serine Racemase Knock-Out Mice
Authors: Inoue Ran , Hashimoto Kenji , Harai Tomomi , Mori Hisashi
Published: December 2008

d-Serine is detected in the brain and acts as a coagonist at the “glycine-site” of the NMDA-type glutamate receptor. Althoughd-serine can be directly produced froml-serine by serine racemase (SR), the relative contribution of SR ind-serine formationin vivois not known. Pathological roles of braind-serine mediating NMDA receptor overactivation are suggested in studies usingin vitroculture systems. However, we have recently demonstrated the differential SR protein expressionin vivoand in culture. Here, we reported an ∼90% decrease in forebraind-serine content in SR knock-out (KO) mice. We also found a reduced neurotoxicity induced by NMDA- and Aβ1–42- peptide injections into the forebrain in SR KO mice. These results suggest that SR is the major enzyme ford-serine production in the brain,d-serine is the predominant endogenous coagonist of the NMDA receptor in the forebrain, andd-serine may be involved in controlling the extent of NMDA receptor-mediated neurotoxic insults observed in disorders including Alzheimer's disease. The control of SR activity andd-serine level in the brain may lead to a novel strategy for neuroprotection against various neurodegenerative diseases.
Neural Dissociation of Delay and Uncertainty in Intertemporal Choice
Authors: Luhmann Christian C. , Chun Marvin M. , Yi Do-Joon , Lee Daeyeol , Wang Xiao-Jing
Published: December 2008

Decision makers often face choices whose consequences unfold over time. To explore the neural basis of such intertemporal choice behavior, we devised a novel two-alternative choice task with probabilistic reward delivery and contrasted two conditions that differed only in whether the outcome was revealed immediately or after some delay. In the immediate condition, we simply varied the reward probability of each option and the outcome was revealed immediately. In the delay condition, the outcome was revealed after a delay during which the reward probability was governed by a constant hazard rate. Functional imaging revealed a set of brain regions, such as the posterior cingulate cortex, parahippocampal gyri, and frontal pole, that exhibited activity uniquely associated with the temporal aspects of the task. This engagement of the so-called “default network” suggests that during intertemporal choice, decision makers simulate the impending delay via a process of prospection.
Inhibition of ovulation by a lipoxygenase inhibitor involves reduced cyclooxygenase-2 expression and prostaglandin E2 production in gonadotropin-primed immature rats
Authors: Kurusu Shiro , Jinno Masako , Ehara Hirosato , Yonezawa Tomohiro , Kawaminami Mitsumori
Published: December 2008

Potential roles of cyclooxygenase (COX) pathway of arachidonic acid (AA) metabolism are established in a murine model of induced ovulation. Pharmacological inhibition of an alternative lipoxygenase (LOX) pathway has been shown to cause defective ovulation, but the mechanism is still undefined. This study investigated the effects of two LOX inhibitors and their time dependency on ovulation and COX activity in gonadotropins (eCG and human chorionic gonadotropin (hCG))-primed immature rats. Intra-ovarian bursal treatment with a general LOX inhibitor nordihydroguaiaretic acid (NDGA) at 0 h post-hCG (hCG0h) dose dependently inhibited ovulation rate. The drug was still but less effective when treated at hCG6h. A more specific inhibitor, 3,4-dihydroxyphenyl ethanol (DPE) was also inhibitory when treated at hCG0h but not at hCG6h. Interestingly, treatment with DPE at hCG0h resulted in attenuated expression of immunoreactive PTGS2 in granulosa layers and concomitant decrease in ovarian prostaglandin E2(PGE2) content at hCG8h. NDGA treatment reduced immunoreactive PTGS2. Ovulatory impairment by both inhibitors was prevented by systemic administration of PGE2at hCG6h. Immunohistochemistry revealed the expression of ALOX5 and ALOX12 in both thecal and granulosa layers of preovulatory follicles and, notably, the augmented immunoreactivities during 8 h after hCG treatment. Our results indicate the probable presence of multiple LOX isoforms and that specific inhibition of LOX at an early stage of hCG-signaling led to reduced PTGS2 activity and thus defective ovulation. They reveal a probable relationship between two pathways of AA metabolism and account at least partly for the mechanism by which the LOX inhibitor causes impaired ovulation.
International Perspectives
Authors: Vidyasagar Dharmapuri
Published: December 2008

Transfer of technology from developed to developing countries can improve health care worldwide. Several approaches have been used with varying success, including self-sponsored models, government- or institution-sponsored models, planned program development, and single or multinational/multi-institutional collaboration. Although technology transfer and training of individuals are highly important, sustainable programs may provide the most lasting effects. Successful partnerships require fiscal commitments, cooperation, strategic planning, and thoughtful human interrelationships.
Folic Acid
Authors: Johnston Richard B.
Published: December 2008

Based on evidence that folic acid (FA) therapy could reduce the occurrence and recurrence of neural tube defects (NTDs) in pregnant women, the United States Food and Drug Administration mandated the addition of FA to all “enriched” cereal-grain products. Further, women of childbearing potential should consume a supplement containing 400 mcg of FA daily. Rates of births affected by NTDs have decreased since the advent of FA fortification. FA fortification also may have a benefit on the development of vascular disease, other birth defects, and cognitive decline. Concerns have been raised that FA fortification might mask or exacerbate the consequences of vitamin B12 deficiency, promote cancer through epigenetic hypermethylation, or interfere with antifolate treatment. However, there is no evidence to date that foods fortified with FA cause harm. More research is required to examine the safety of FA fortification more thoroughly, but clinicians should exert every effort to communicate the need for women of childbearing age to consume at least 400 mcg/day of FA.