bluuebunny/crossref_metadata_2025 huggingface dataset:
In silico evidence for the species-specific conservation of mosquito retroposons: implications as a molecular biomarker
Authors: Byarugaba Wilson , Kajumbula Henry , Wayengera Misaki
Published: July 2009

Background

Mosquitoes are the transmissive vectors for several infectious pathogens that affect man. However, the control of mosquitoes through insecticide and pesticide spraying has proved difficult in the past. We hypothesized that, by virtue of their reported vertical inheritance among mosquitoes, group II introns – a class of small coding ribonucleic acids (scRNAs) – may form a potential species-specific biomarker. Structurally, introns are a six-moiety complex. Depending on the function of the protein encoded within the IV moiety, the highly mobile class of group II introns or retroposons is sub-divided into two: Restriction Endonuclease (REase)-like and Apurinic aPyramydinic Endonuclease (APE)-like. REase-like retroposons are thought to be the ancestors of APE retroposons. Our aim in this study was to find evidence for the highly species-specific conservation of the APE subclass of mosquito retroposons.

Methods and Results

In silico targeted sequence alignments were conducted across a 1,779-organism genome database (1,518 bacterial, 59 archeal, 201 eukaryotic, and the human), using three mosquito retroposon sequence tags (RST) as BLASTN queries [AJ970181 and AJ90201 of Culex pipien origin and AJ970301 of Anoplese sinensis origin]. At a calibration of E = 10, A & D = 100, default filtration and a homology cut-off of >95% identity, no hits were found on any of the 1,518 bacterial genomes. Eleven (100%) and 15 (100%) hits obtained on the 201-eukaryote genome database were homologs (>95% score) of C.pipien quinquefasciatus JHB retroposons, but none of An. sinensis. Twenty and 221 low score (30–43% identity) spurious hits were found at flanking ends of genes and contigs in the human genome with the C.pipien and An. sinensis RSTs respectively. Functional and positional inference revealed these to be possible relatives of human genomic spliceosomes. We advance two models for the application of mosquito RST: as precursors for developing molecular biomarkers for mosquitoes, and as RST-specific monoclonal antibody (MAb)-DDT immunoconjugates to enhance targeted toxicity.

Conclusion

We offer evidence to support the species-specific conservation of mosquito retroposons among lower taxa. Our findings suggest that retroposons may therefore constitute a unique biomarker for mosquito species that may be exploited in molecular entomology. Mosquito RST-specific MAbs may possibly permit synthesis of DDT immunoconjugates that could be used to achieve species-tailored toxicity.
Maternal exposure to nanoparticulate titanium dioxide during the prenatal period alters gene expression related to brain development in the mouse
Authors: Shimizu Midori , Tainaka Hitoshi , Oba Taro , Mizuo Keisuke , Umezawa Masakazu , Takeda Ken
Published: July 2009

Background

Nanotechnology is developing rapidly throughout the world and the production of novel man-made nanoparticles is increasing, it is therefore of concern that nanomaterials have the potential to affect human health. The purpose of this study was to investigate the effects of maternal exposure to nano-sized anatase titanium dioxide (TiO2) on gene expression in the brain during the developmental period using cDNA microarray analysis combined with Gene Ontology (GO) and Medical Subject Headings (MeSH) terms information.

Results

Analysis of gene expression using GO terms indicated that expression levels of genes associated with apoptosis were altered in the brain of newborn pups, and those associated with brain development were altered in early age. The genes associated with response to oxidative stress were changed in the brains of 2 and 3 weeks old mice. Changes of the expression of genes associated with neurotransmitters and psychiatric diseases were found using MeSH terms.

Conclusion

Maternal exposure of mice to TiO2nanoparticles may affect the expression of genes related to the development and function of the central nervous system.
Identification of a crenarchaeal orthologue of Elf1: implications for chromatin and transcription in Archaea
Authors: Daniels Jan-Peter , Kelly Steven , Wickstead Bill , Gull Keith
Published: July 2009

The transcription machineries of Archaea and eukaryotes are similar in many aspects, but little is understood about archaeal chromatin and its role in transcription. Here, we describe the identification in hyperthermophilic Crenarchaeota and a Korarchaeon of an orthologue of the eukaryotic transcription elongation factor Elf1, which has been shown to function in chromatin structure maintenance of actively transcribed templates. Our discovery has implications for the relationship of chromatin and transcription in Archaea and the evolution of these processes in eukaryotes.

Reviewers

This article was reviewed by Chris P. Ponting and Eugene V. Koonin.
A dynamic network of transcription in LPS-treated human subjects
Authors: Seok Junhee , Xiao Wenzhong , Moldawer Lyle L , Davis Ronald W , Covert Markus W
Published: July 2009

Background

Understanding the transcriptional regulatory networks that map out the coordinated dynamic responses of signaling proteins, transcription factors and target genes over time would represent a significant advance in the application of genome wide expression analysis. The primary challenge is monitoring transcription factor activities over time, which is not yet available at the large scale. Instead, there have been several developments to estimate activities computationally. For example, Network Component Analysis (NCA) is an approach that can predict transcription factor activities over time as well as the relative regulatory influence of factors on each target gene.

Results

In this study, we analyzed a gene expression data set in blood leukocytes from human subjects administered with lipopolysaccharide (LPS), a prototypical inflammatory challenge, in the context of a reconstructed regulatory network including 10 transcription factors, 99 target genes and 149 regulatory interactions. We found that the computationally estimated activities were well correlated to their coordinated action. Furthermore, we found that clustering the genes in the context of regulatory influences greatly facilitated interpretation of the expression data, as clusters of gene expression corresponded to the activity of specific factors or more interestingly, factor combinations which suggest coordinated regulation of gene expression. The resulting clusters were therefore more biologically meaningful, and also led to identification of additional genes under the same regulation.

Conclusion

Using NCA, we were able to build a network that accounted for between 8–11% genes in the known transcriptional response to LPS in humans. The dynamic network illustrated changes of transcription factor activities and gene expressions as well as interactions of signaling proteins, transcription factors and target genes.
Autophagy activation and enhanced mitophagy characterize the Purkinje cells of pcd mice prior to neuronal death
Authors: Chakrabarti Lisa , Eng Jeremiah , Ivanov Nishi , Garden Gwenn A , La Spada Albert R
Published: July 2009

Purkinje cells are a class of specialized neurons in the cerebellum, and are among the most metabolically active of all neurons, as they receive immense synaptic stimulation, and provide the only efferent output from the cerebellum. Degeneration of Purkinje cells is a common feature of inherited ataxias in humans and mice. To understand Purkinje neuron degeneration, investigators have turned to naturally occurring Purkinje cell degeneration phenotypes in mice to identify key regulatory proteins and cellular pathways. The Purkinje cell degeneration (pcd) mouse is a recessive mutant characterized by complete and dramatic post-natal, cell autonomous Purkinje neuron degeneration and death. As the basis of Purkinje cell death in pcd is unresolved, and contradictory data has emerged for the role of autophagy in Purkinje cell degeneration, we studied the mechanism of Purkinje cell death in pcd mice. BAX null status did not suppress Purkinje neuron death in pcd mice, indicating that classic apoptosis is not responsible for Purkinje cell loss. Interestingly, LC3 Western blot analysis and GFP-LC3 immunostaining of degenerating pcd cerebellum revealed activation of the autophagy pathway. Ultrastructural studies confirmed increased autophagy pathway activity in Purkinje cells, and yielded evidence for mitophagy, in agreement with LC3 immunoblotting of cerebellar fractions. As p62 levels were decreased in pcd cerebellum, our findings suggest that pcd Purkinje cell neurons can execute effective autophagy. However, our results support a role for dysregulated autophagy activation in pcd, and suggest that increased or aberrant mitophagy contributes to the Purkinje cell degeneration in pcd mice.
Influence of the dual ABCB1 and ABCG2 inhibitor tariquidar on the disposition of oral imatinib in mice
Authors: Gardner Erin R , Smith Nicola F , Figg William D , Sparreboom Alex
Published: July 2009

Background

Imatinib, a tyrosine kinase inhibitor currently approved for treatment of several malignancies, has been shown to be a substrate for multiple efflux-transporter proteins, including ABCB1 (P-glycoprotein) and ABCG2 (BCRP). The effect of inhibiting these transporters on tissue exposure to imatinib remains unclear.

Objective

To assess the role of these transporters on drug disposition, 50 mg/kg imatinib was administered to Balb/C mice, 30 minutes after receiving tariquidar (10 mg/kg), an inhibitor of both ABCB1 and ABCG2, or vehicle, via oral gavage.

Methods

Quantitative determination of imatinib in mouse plasma, liver and brain was performed using a newly-developed and validated liquid-chromatography-mass spectrometric method. Results: Exposure to imatinib was 2.2-fold higher in plasma, liver and brain in mice that received tariquidar, as compared to those that received the vehicle (P = 0.001). The peak plasma concentration did not increase substantially, suggesting that tariquidar is affecting the distribution, metabolism and/or excretion of imatinib, rather than absorption. Though tariquidar increased the absolute exposure of imatinib, the brain-to-plasma ratio of imatinib was unaffected.

Conclusion

This study suggests that intentional inhibition of ABCB1 and ABCG2 function at the blood-brain barrier is unlikely to significantly improve clinical outcome of imatinib with currently used dosing regimens.
Factors influencing quality of life of people living with HIV in Estonia: a cross‐sectional survey
Authors: Rüütel Kristi , Pisarev Heti , Loit Helle‐Mai , Uusküla Anneli
Published: July 2009

Background

Identification of factors that determine quality of life is important in order to better tailor health and social care services, and thereby improve the functioning and well being of people living with HIV. The estimated number of people living with HIV in eastern Europe and central Asia is 1.6 million. Little is known about the quality of life of people living with HIV in this region. The main purpose of the present study was to identify the factors influencing quality of life in a sample of HIV‐infected persons in Estonia.

Methods

A convenient sample of 451 patients attending three infectious diseases clinics for routine HIV clinical care visits was recruited for a cross‐sectional survey. The World Health Organization's Quality of Life HIV instrument was used to measure quality of life of the participants and medical data was abstracted from clinical records.

Results

Good overall quality of life was reported by 42.6% (95% CI: 38.0–47.2%) of the study participants (53% men, 60% self‐identify as injecting drug users, 82% <30 years of age, 30% with CD4+ T cell count <300 cells/mm3, and 22% on antiretroviral treatment). We identified the following variables as independent predictors of good overall quality of life: being currently employed or studying (AOR: 2.27, 95% CI: 1.18–4.38); and the absence of HIV‐related symptoms (AOR: 2.31, 95% CI: 1.24–4.29).

Conclusion

A comprehensive and competent care system, including health care providers and social workers, is required for an effective response. In addition, social interventions should seek to enhance the economic and employment opportunities for people living with HIV in the region.
Folate rescues lithium-, homocysteine- and Wnt3A-induced vertebrate cardiac anomalies
Authors: Han Mingda , Serrano Maria C. , Lastra-Vicente Rosana , Brinez Pilar , Acharya Ganesh , Huhta James C. , Chen Ren , Linask Kersti K.
Published: July 2009

Elevated plasma homocysteine (HCy), which results from folate (folic acid, FA) deficiency, and the mood-stabilizing drug lithium (Li) are both linked to the induction of human congenital heart and neural tube defects. We demonstrated previously that acute administration of Li to pregnant mice on embryonic day (E)6.75 induced cardiac valve defects by potentiating Wnt–β-catenin signaling. We hypothesized that HCy may similarly induce cardiac defects during gastrulation by targeting the Wnt–β-catenin pathway. Because dietary FA supplementation protects from neural tube defects, we sought to determine whether FA also protects the embryonic heart from Li- or HCy-induced birth defects and whether the protection occurs by impacting Wnt signaling. Maternal elevation of HCy or Li on E6.75 induced defective heart and placental function on E15.5, as identified non-invasively using echocardiography. This functional analysis of HCy-exposed mouse hearts revealed defects in tricuspid and semilunar valves, together with altered myocardial thickness. A smaller embryo and placental size was observed in the treated groups. FA supplementation ameliorates the observed developmental errors in the Li- or HCy-exposed mouse embryos and normalized heart function. Molecular analysis of gene expression within the avian cardiogenic crescent determined that Li, HCy or Wnt3A suppress Wnt-modulated Hex (also known as Hhex) and Islet-1 (also known as Isl1) expression, and that FA protects from the gene misexpression that is induced by all three factors. Furthermore, myoinositol with FA synergistically enhances the protective effect. Although the specific molecular epigenetic control mechanisms remain to be defined, it appears that Li or HCy induction and FA protection of cardiac defects involve intimate control of the canonical Wnt pathway at a crucial time preceding, and during, early heart organogenesis.
β- and γ-cytoplasmic actins display distinct distribution and functional diversity
Authors: Dugina Vera , Zwaenepoel Ingrid , Gabbiani Giulio , Clément Sophie , Chaponnier Christine
Published: July 2009

Using newly generated monoclonal antibodies, we have compared the distribution of β- and γ-cytoplasmic actin in fibroblastic and epithelial cells, in which they play crucial roles during various key cellular processes. Whereas β-actin is preferentially localized in stress fibers, circular bundles and at cell-cell contacts, suggesting a role in cell attachment and contraction, γ-actin displays a more versatile organization, according to cell activities. In moving cells, γ-actin is mainly organized as a meshwork in cortical and lamellipodial structures, suggesting a role in cell motility; in stationary cells, γ-actin is also recruited into stress fibers. β-actin-depleted cells become highly spread, display broad protrusions and reduce their stress-fiber content; by contrast, γ-actin-depleted cells acquire a contractile phenotype with thick actin bundles and shrinked lamellar and lamellipodial structures. Moreover, β- and γ-actin depleted fibroblasts exhibit distinct changes in motility compared with their controls, suggesting a specific role for each isoform in cell locomotion. Our results reveal new aspects of β- and γ-actin organization that support their functional diversity.
Organisation of human ER-exit sites: requirements for the localisation of Sec16 to transitional ER
Authors: Hughes Helen , Budnik Annika , Schmidt Katy , Palmer Krysten J. , Mantell Judith , Noakes Chris , Johnson Andrew , Carter Deborah A. , Verkade Paul , Watson Peter , Stephens David J.
Published: July 2009

The COPII complex mediates the selective incorporation of secretory cargo and relevant machinery into budding vesicles at specialised sites on the endoplasmic reticulum membrane called transitional ER (tER). Here, we show using confocal microscopy, immunogold labelling of ultrathin cryosections and electron tomography that in human cells at steady state, Sec16 localises to cup-like structures of tER that are spatially distinct from the localisation of other COPII coat components. We show that Sec16 defines the tER, whereas Sec23-Sec24 and Sec13-Sec31 define later structures that precede but are distinct from the intermediate compartment. Steady-state localisation of Sec16 is independent of the localisation of downstream COPII components Sec23-Sec24 and Sec13-Sec31. Sec16 cycles on and off the membrane at a slower rate than other COPII components with a greater immobile fraction. We define the region of Sec16A that dictates its robust localisation of tER membranes and find that this requires both a highly charged region as well as a central domain that shows high sequence identity between species. The central conserved domain of Sec16 binds to Sec13 linking tER membrane localisation with COPII vesicle formation. These data are consistent with a model where Sec16 acts as a platform for COPII assembly at ERES.
G2 histone methylation is required for the proper segregation of chromosomes
Authors: Heit Ryan , Rattner Jerome B. , Chan Gordon K. T. , Hendzel Michael J.
Published: July 2009

Trimethylation of lysine 9 on histone H3 (H3K9me3) is known both to be necessary for proper chromosome segregation and to increase in late G2. We investigated the role of late G2 methylation, specifically in mitotic progression, by inhibiting methylation for 2 hours prior to mitosis using the general methylation inhibitor adenosine dialdehyde (AdOx). AdOx inhibits all methylation events within the cell but, by shortening the treatment length to 2 hours and studying mitotic cells, the only methylation events that are affected are those that occur in late G2. We discovered that methylation events in this time period are crucial for proper mitosis. Mis-segregation of chromosomes is observed with AdOx treatment. Through studies of histone modifications, we have found that inhibiting late G2 methylation affects trimethylation of H3K9 and H4K20. The mitotic checkpoint is active and many kinetochore proteins localize properly, however, pericentric chromatin in these cells is found to be less compact (dense). The reduced integrity of pericentric heterochromatin might be responsible for a noted loss of tension at the centromere in AdOx-treated cells and activation of the spindle assembly checkpoint. We postulate that late G2 methylation is necessary for proper pericentric heterochromatin formation. The results suggest that a reduction in heterochromatin integrity might interfere both with microtubule attachment to chromosomes and with the proper sensing of tension from correct microtubule-kinetochore connections, either of which will result in activation of the mitotic checkpoint.
Phosphorylation of CLASP2 by GSK-3β regulates its interaction with IQGAP1, EB1 and microtubules
Authors: Watanabe Takashi , Noritake Jun , Kakeno Mai , Matsui Toshinori , Harada Takumi , Wang Shujie , Itoh Norimichi , Sato Kazuhide , Matsuzawa Kenji , Iwamatsu Akihiro , Galjart Niels , Kaibuchi Kozo
Published: July 2009

Polarised cell migration is required for various cell behaviours and functions. Actin and microtubules are coupled structurally and distributed asymmetrically along the front-rear axis of migrating cells. CLIP-associating proteins (CLASPs) accumulate near the ends of microtubules at the front of migrating cells to control microtubule dynamics and cytoskeletal coupling. Regional inhibition of GSK-3β is responsible for this asymmetric distribution of CLASPs. However, it is not known how GSK-3β regulates the activity of CLASPs for linkage between actin and microtubules. Here we identified IQGAP1, an actin-binding protein, as a novel CLASP-binding protein. GSK-3β directly phosphorylates CLASP2 at Ser533 and Ser537 within the region responsible for the IQGAP1 binding. Phosphorylation of CLASP2 results in the dissociation of CLASP2 from IQGAP1, EB1 and microtubules. At the leading edges of migrating fibroblasts, CLASP2 near microtubule ends partially colocalises with IQGAP1. Expression of active GSK-3β abrogates the distribution of CLASP2 on microtubules, but not that of a nonphosphorylatable CLASP2 mutant. The phosphorylated CLASP2 does not accumulate near the ends of microtubules at the leading edges. Thus, phosphorylation of CLASP2 by GSK-3β appears to control the regional linkage of microtubules to actin filaments through IQGAP1 for cell migration.
The dynamic properties of intermediate filaments during organelle transport
Authors: Chang Lynne , Barlan Kari , Chou Ying-Hao , Grin Boris , Lakonishok Margot , Serpinskaya Anna S. , Shumaker Dale K. , Herrmann Harald , Gelfand Vladimir I. , Goldman Robert D.
Published: July 2009

Intermediate filament (IF) dynamics during organelle transport and their role in organelle movement were studied using Xenopus laevis melanophores. In these cells, pigment granules (melanosomes) move along microtubules and microfilaments, toward and away from the cell periphery in response to α-melanocyte stimulating hormone (α-MSH) and melatonin, respectively. In this study we show that melanophores possess a complex network of vimentin IFs which interact with melanosomes. IFs form an intricate, honeycomb-like network that form cages surrounding individual and small clusters of melanosomes, both when they are aggregated and dispersed. Purified melanosome preparations contain a substantial amount of vimentin, suggesting that melanosomes bind to IFs. Analyses of individual melanosome movements in cells with disrupted IF networks show increased movement of granules in both anterograde and retrograde directions, further supporting the notion of a melanosome-IF interaction. Live imaging reveals that IFs, in turn, become highly flexible as melanosomes disperse in response to α-MSH. During the height of dispersion there is a marked increase in the rate of fluorescence recovery after photobleaching of GFP-vimentin IFs and an increase in vimentin solubility. These results reveal a dynamic interaction between membrane bound pigment granules and IFs and suggest a role for IFs as modulators of granule movement.
TheADAMTS12metalloprotease gene is epigenetically silenced in tumor cells and transcriptionally activated in the stroma during progression of colon cancer
Authors: Moncada-Pazos Angela , Obaya Alvaro J. , Fraga Mario F. , Viloria Cristina G. , Capellá Gabriel , Gausachs Mireia , Esteller Manel , López-Otín Carlos , Cal Santiago
Published: July 2009

Proteases have long been associated with tumor progression, given their ability to degrade extracellular matrix components and facilitate invasion and metastasis. However, recent findings indicate that different proteases can also act as tumor-suppressor enzymes. We have recently reported that lung carcinoma cells expressing the ADAMTS-12 metalloprotease show a remarkable impairment of growth in immunodeficient mice as compared with parental cells. Here, we show that ADAMTS12 promoter is hypermethylated in cancer cell lines and tumor tissues. Interestingly, ADAMTS12 expression in the stromal cells surrounding epithelial malignant cells is higher than in the paired normal tissues. Moreover, the expression of this metalloprotease in colon fibroblasts co-cultured with colon cancer cell lines is higher than in those cultured alone. Furthermore, the expression of ADAMTS-12 by these fibroblasts is linked with an anti-proliferative effect on tumor cells. Based on these findings, we hypothesize that ADAMTS-12 is a novel anti-tumor protease that can reduce the proliferative properties of tumor cells. This function is lost by epigenetic silencing in tumor cells, but concurrently induced in stromal cells, probably as part of a response of the normal tissue aimed at controlling the progression of cancer.
Entrepreneurial Optimism in the Market for Technological Inventions
Authors: Dushnitsky Gary
Published: July 2009

How do potentially optimistic entrepreneurs attract prospective investors? We investigate an entrepreneur's decision to pursue either disclosure—where investors inspect the invention—or a contingent payment scheme (CPS) offer (e.g., salary deferral, royalty-based license)—where an invention's value is inferred from the entrepreneur's willingness to make her pay contingent on the invention's success. Using a parsimonious model, we highlight the role of optimism and demonstrate that it only affects CPS ex post. As a result, a novel trade-off unfolds ex ante: In choosing an action that maximizes the valuation of the invention, a moderately wealthy entrepreneur weighs optimism discount (affecting CPS) versus imitation discount (affecting disclosure). More broadly, the paper advances a view of entrepreneurs as optimists, thus departing from the prevailing approach, which characterizes entrepreneurs as opportunistic individuals who consciously pursue self-serving goals.
Investigating the Antecedents of Team-Based Clan Control: Adding Social Capital as a Predictor
Authors: Kirsch Laurie J. , Ko Dong-Gil , Haney Mark H.
Published: July 2009

Organizations are increasingly relying on team-based structures as work becomes more complex, nonroutine, and knowledge intensive. Teams comprised of individuals with diverse skills and expertise may be well suited to perform such work. However, as teams become more prevalent, organizations may struggle with ways to exercise control. Formal controls, with their focus on prespecified rules, performance targets, and hierarchical relationships, may be less effective in a teamwork environment than clan control, in which work-related behavior is motivated by shared norms and values, as well as a common vision, and individuals attempt to be accepted or “regular” members of a team. However, little is known about the antecedents of clan control. Much of the existing empirical research on the antecedents of control has been influenced by Ouchi's (Ouchi, W. G. 1977. The relationship between organizational structure and organizational control. Admin. Sci. Quart. 22 95–113) framework, which posits clan control is used when managers lack knowledge of means–ends relationships and are unable to measure outcomes. This paper adopts the view that clan control is a “people” or social process and argues that social capital, a construct that reflects connections and relationships among individuals, is a missing, key antecedent of clan control. In particular, we posit that the existence of social capital enables team members, as well as project managers, to facilitate clan control within a team, i.e., team-based clan control. A model is developed and hypotheses are tested using survey data collected from 95 information systems project teams. The results suggest that social capital assets are associated with team-based clan control. Recognizing that the project manager typically has a different level of organizational authority than team members, additional hypotheses are developed relating characteristics of the project manager to team-based clan control. The results of these tests suggest that team-based clan control is also dependent on the manager's knowledge of business processes and the application area, coupled with the extent to which he observes the behaviors of the project team. Thus, our results suggest that there are conditions under which team-based clan control is facilitated by the project team as a whole (including team members and project managers), as well as conditions under which team-based clan control is facilitated by project managers in their role as team leaders. Implications and suggestions for future work are discussed.
Liraglutide: A Once-Daily Incretin Mimetic for the Treatment of Type 2 Diabetes Mellitus
Authors: Neumiller Joshua J , Campbell R Keith
Published: July 2009

Objective:

To review the pharmacology, pharmacokinetics, efficacy, and safety of liraglutide, a glucagon-like peptide 1 (GLP-1) analog for the treatment of type 2 diabetes mellitus.

Data Sources:

A MEDLINE search (1966–May 2009) was conducted for English-language articles using the terms glucagon-like peptide 1, incretin mimetic, NN2211, and liraglutide. Abstracts presented at the American Diabetes Association and European Association for the Study of Diabetes annual meetings in 2006, 2007, and 2008 were also searched for relevant data.

Study Selection and Data Extraction:

Articles pertinent to the pharmacology, pharmacokinetics, efficacy, and safety of liraglutide were reviewed.

Data Synthesis:

Liraglutide is a GLP-1 analog with pharmacokinetic properties suitable for once-daily administration. Clinical trial data from large, controlled studies demonstrate the effectiveness of liraglutide in terms of hemoglobin A1c (A1C) reduction, reductions in body weight, and the drug's low risk for hypoglycemic events when used as monotherapy. Data also support benefits of liraglutide therapy on β-cell responsiveness to glucose, with animal and in vitro data indicating potential benefits in β-cell mass and neogenesis with liraglutide treatment. Liraglutide has been studied as monotherapy and in combination with metformin, glimepiride, and rosiglitazone for the treatment of type 2 diabetes. Additionally, comparative data with insulin glargine and exenatide therapy are available from Phase 3 trials providing practitioners valuable clinical data on which to base clinical decision making. Overall, liraglutide is well tolerated with dose-dependent nausea, vomiting, and diarrhea being the most commonly reported adverse events in clinical trials.

Conclusions:

Once-daily administration may provide a therapeutic advantage for liraglutide over twice-daily exenatide, with similar improvements in A1C and body weight observed when liraglutide was compared with exenatide. The glucose-dependent mechanism of insulin release with GLP-1 agonist therapy holds potential clinical significance in the management of postprandial hyperglycemic excursions, with minimal risk of hypoglycemia.
Consolidation of an Extinction Memory Depends on the Unconditioned Stimulus Magnitude Previously Experienced during Training
Authors: Stollhoff Nicola , Eisenhardt Dorothea
Published: July 2009

Here, we examine the role of the magnitude of the unconditioned stimulus (US) during classical conditioning in consolidation processes after memory retrieval. We varied the US durations during training and we test the impact of these variations on consolidation after memory retrieval with one or two conditioned stimulus-only trials. We found that the consolidation of an extinction memory depends on US duration during training and ruled out the possibility that this effect is attributable to differences in satiation after conditioning. We conclude that consolidation of an extinction memory is triggered only when the duration of the US reaches a critical threshold. This demonstrates that memory consolidation cannot be regarded as an isolated process depending solely on training conditions. Instead, it depends on the animal's previous experience as well.
Mesencephalic Astrocyte-Derived Neurotrophic Factor Is Neurorestorative in Rat Model of Parkinson's Disease
Authors: Voutilainen Merja H. , Bäck Susanne , Pörsti Eeva , Toppinen Liisa , Lindgren Lauri , Lindholm Päivi , Peränen Johan , Saarma Mart , Tuominen Raimo K.
Published: July 2009

Neurotrophic factors are promising candidates for the treatment of Parkinson's disease (PD). Mesencephalic astrocyte-derived neurotrophic factor (MANF) belongs to a novel evolutionarily conserved family of neurotrophic factors. We examined whether MANF has neuroprotective and neurorestorative effect in an experimental model of PD in rats. We also studied the distribution and transportation of intrastriatally injected MANF in the brain and compared it with glial cell line-derived neurotrophic factor (GDNF). Unilateral lesion of nigrostriatal dopaminergic system was induced by intrastriatal injection of 6-hydroxydopamine (6-OHDA). Amphetamine-induced turning behavior was monitored up to 12 weeks after the unilateral lesion. The local diffusion at the injection site and transportation profiles of intrastriatally injected MANF and GDNF were studied by immunohistochemical detection of the unlabeled growth factors as well as by autoradiographic and gamma counting detection of125I-labeled trophic factors. Intrastriatally injected MANF protected nigrostriatal dopaminergic nerves from 6-OHDA-induced degeneration as evaluated by counting tyrosine hydroxylase (TH)-positive cell bodies in the substantia nigra (SN) and TH-positive fibers in the striatum. More importantly, MANF also restored the function of the nigrostriatal dopaminergic system when administered either 6 h before or 4 weeks after 6-OHDA administration in the striatum. MANF was distributed throughout the striatum more readily than GDNF. The mechanism of MANF action differs from that of GDNF because intrastriatally injected125I-MANF was transported to the frontal cortex, whereas125I-GDNF was transported to the SN. Our results suggest that MANF is readily distributed throughout the striatum and has significant therapeutic potential for the treatment of PD.
Encoding of Marginal Utility across Time in the Human Brain
Authors: Pine Alex , Seymour Ben , Roiser Jonathan P. , Bossaerts Peter , Friston Karl J. , Curran H. Valerie , Dolan Raymond J.
Published: July 2009

Marginal utility theory prescribes the relationship between the objective property of the magnitude of rewards and their subjective value. Despite its pervasive influence, however, there is remarkably little direct empirical evidence for such a theory of value, let alone of its neurobiological basis. We show that human preferences in an intertemporal choice task are best described by a model that integrates marginally diminishing utility with temporal discounting. Using functional magnetic resonance imaging, we show that activity in the dorsal striatum encodes both the marginal utility of rewards, over and above that which can be described by their magnitude alone, and the discounting associated with increasing time. In addition, our data show that dorsal striatum may be involved in integrating subjective valuation systems inherent to time and magnitude, thereby providing an overall metric of value used to guide choice behavior. Furthermore, during choice, we show that anterior cingulate activity correlates with the degree of difficulty associated with dissonance between value and time. Our data support an integrative architecture for decision making, revealing the neural representation of distinct subcomponents of value that may contribute to impulsivity and decisiveness.
Increased Synthesis of Spermidine as a Result of Upregulation of Arginase I Promotes Axonal Regeneration in Culture andIn Vivo
Authors: Deng Kangwen , He Huifang , Qiu Jin , Lorber Barbara , Bryson J. Barney , Filbin Marie T.
Published: July 2009

Adult spinal axons do not spontaneously regenerate after injury. However, if the peripheral branch of dorsal root ganglion neurons is lesioned before lesioning the central branch of the same neurons in the dorsal column, these central axons will regenerate and, if cultured, are not inhibited from extending neurites by myelin-associated inhibitors of regeneration such as myelin-associated glycoprotein (MAG). This effect can be mimicked by elevating cAMP and is transcription dependent. The ability of cAMP to overcome inhibition by MAG in culture involves the upregulation of the enzyme arginase I (Arg I) and subsequent increase in synthesis of polyamines such as putrescine. Now we show that a peripheral lesion also induces an increase in Arg I expression and synthesis of polyamines. We also show that the conditioning lesion effect in overcoming inhibition by MAG is initially dependent on ongoing polyamine synthesis but, with time after lesion, becomes independent of ongoing synthesis. However, if synthesis of polyamines is blockedin vivothe early phase of good growth after a conditioning lesion is completely blocked and the later phase of growth, when ongoing polyamine synthesis is not required during culture, is attenuated. We also show that putrescine must be converted to spermidine both in culture andin vivoto overcome inhibition by MAG and that spermidine can promote optic nerve regenerationin vivo. These results suggest that spermidine could be a useful tool in promoting CNS axon regeneration after injury.
Early Postnatal Development of Spontaneous and Acoustically Evoked Discharge Activity of Principal Cells of the Medial Nucleus of the Trapezoid Body: AnIn VivoStudy in Mice
Authors: Sonntag Mandy , Englitz Bernhard , Kopp-Scheinpflug Cornelia , Rübsamen Rudolf
Published: July 2009

The calyx of Held synapse in the medial nucleus of the trapezoid body of the auditory brainstem has become an establishedin vitromodel to study the development of fast glutamatergic transmission in the mammalian brain. However, we still lackin vivodata at this synapse on the maturation of spontaneous and sound-evoked discharge activity before and during the early phase of acoustically evoked signal processing (i.e., before and after hearing onset). Here we reportin vivosingle-unit recordings in mice from postnatal day 8 (P8) to P28 with a specific focus on developmental changes around hearing onset (P12). Data were obtained from two mouse strains commonly used in brain slice recordings: CBA/J and C57BL/6J. Spontaneous discharge rates progressively increased from P8 to P13, initially showing bursting patterns and large coefficients of variation (CVs), which changed to more continuous and random discharge activity accompanied by gradual decrease of CV around hearing onset. From P12 on, sound-evoked activity yielded phasic-tonic discharge patterns with discharge rates increasing up to P28. Response thresholds and shapes of tuning curves were adult-like by P14. A gradual shortening in response latencies was observed up to P18. The three-dimensional tonotopic organization of the medial nucleus of the trapezoid body yielded a high-to-low frequency gradient along the mediolateral and dorsoventral but not in the rostrocaudal axes. These data emphasize that models of signal transmission at the calyx of Held based onin vitrodata have to take developmental changes in firing rates and response latencies up to the fourth postnatal week into account.
Distinct Firing Patterns of Identified Basket and Dendrite-Targeting Interneurons in the Prefrontal Cortex during Hippocampal Theta and Local Spindle Oscillations
Authors: Hartwich Katja , Pollak Thomas , Klausberger Thomas
Published: July 2009

The medial prefrontal cortex is involved in working memory and executive control. However, the collective spatiotemporal organization of the cellular network has not been possible to explain during different brain states. We show that pyramidal cells in the prelimbic cortex fire synchronized to hippocampal theta and local spindle oscillations in anesthetized rats. To identify which types of interneurons contribute to the synchronized activity, we recorded and juxtacellularly labeled parvalbumin- and calbindin-expressing (PV+/CB+) basket cells and CB-expressing, PV-negative (CB+/PV−) dendrite-targeting interneurons during both network oscillations. All CB+/PV− dendrite-targeting cells strongly decreased their firing rate during hippocampal theta oscillations. Most PV+/CB+ basket cells fired at the peak of dorsal CA1 theta cycles, similar to prefrontal pyramidal cells. We show that pyramidal cells in the ventral hippocampus also fire around the peak of dorsal CA1 theta cycles, in contrast to previously reported dorsal hippocampal pyramidal cells. Therefore, prefrontal neurons might be driven by monosynaptic connections from the ventral hippocampus during theta oscillations. During prefrontal spindle oscillations, the majority of pyramidal cells and PV+/CB+ basket cells fired preferentially at the trough and early ascending phase, but CB+/PV− dendrite-targeting cells fired uniformly at all phases. We conclude that PV+/CB+ basket cells contribute to rhythmic responses of prefrontal pyramidal cells in relation to hippocampal and thalamic inputs and CB+/PV− dendrite-targeting cells modulate the excitability of dendrites and spines regardless of these field rhythms. Distinct classes of GABAergic interneuron in the prefrontal cortex contribute differentially to the synchronization of pyramidal cells during network oscillations.
Dynein Light Chain LC8 Regulates Syntaphilin-Mediated Mitochondrial Docking in Axons
Authors: Chen Yan-Min , Gerwin Claudia , Sheng Zu-Hang
Published: July 2009

Mitochondria in the cell bodies of neurons are transported down neuronal processes in response to changes in local energy and metabolic states. Because of their extreme polarity, neurons require specialized mechanisms to regulate mitochondrial transport and retention in axons. Our previous studies usingsyntaphilin(snph) knock-out mice provided evidence that SNPH targets to axonal mitochondria and controls their mobility through its static interaction with microtubules (MTs). However, the mechanisms regulating SNPH-mediated mitochondrial docking remain elusive. Here, we report an unexpected role for dynein light chain LC8. Using proteomic biochemical and cell biological assays combined with time-lapse imaging in livesnphwild-type and mutant neurons, we reveal that LC8 regulates axonal mitochondrial mobility by binding to SNPH, thus enhancing the SNPH-MT docking interaction. Using mutagenesis assays, we mapped a seven-residue LC8-binding motif. Through this specific interaction, SNPH recruits LC8 to axonal mitochondria; such colocalization is abolished when neurons express SNPH mutants lacking the LC8-binding motif. Transient LC8 expression reduces mitochondrial mobility insnph(+/+) but not (−/−) neurons, suggesting that the observed effect of LC8 depends on the SNPH-mediated docking mechanism. In contrast, deleting the LC8-binding motif impairs the ability of SNPH to immobilize axonal mitochondria. Furthermore, circular dichroism spectrum analysis shows that LC8 stabilizes an α-helical coiled-coil within the MT-binding domain of SNPH against thermal unfolding. Thus, our study provides new mechanistic insights into controlling mitochondrial mobility through a dynamic interaction between the mitochondrial docking receptor and axonal cytoskeleton.
Interoceptive Effects of Alcohol Require mGlu5 Receptor Activity in the Nucleus Accumbens
Authors: Besheer Joyce , Grondin Julie J. M. , Salling Michael C. , Spanos Marina , Stevenson Rebekah A. , Hodge Clyde W.
Published: July 2009

The interoceptive effects of alcohol are major determinants of addiction liability. Metabotropic glutamate (mGlu) receptors are widely expressed in striatal circuits known to modulate drug-seeking. Given that the interoceptive effects of drugs can be important determinants of abuse liability, we hypothesized that striatal mGlu receptors modulate the interoceptive effects of alcohol. Using drug discrimination learning, rats were trained to discriminate alcohol (1 g/kg, i.g.) versus water. We found that systemic antagonism of metabotropic glutamate subtype 5 (mGlu5) receptors [10 mg/kg 2-methyl-6-(phenylethynyl)pyridine (MPEP) and 3 mg/kg 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine], but not mGlu1 receptors ([0.3–3 mg/kg JNJ16259685) (3,4-dihydro-2H-pyrano[2,3]β-quinolin-7-yl)(cis-4-methoxycyclohexyl) methanone)], inhibited the discriminative stimulus effects of alcohol. Furthermore, mGlu5 receptor antagonism (10 mg/kg MPEP) significantly inhibited neuronal activity in the nucleus accumbens core as levels of the transcription factor c-Fos were significantly reduced. Accordingly, targeted inhibition of mGlu5 receptors (20 μg of MPEP) in the nucleus accumbens core blunted the discriminative stimulus effects of alcohol (1 g/kg). Anatomical specificity was confirmed by the lack of effect of inhibition of mGlu5 receptors (10–30 μg of MPEP) in the dorsomedial caudate–putamen and the similar cytological expression patterns and relative density of mGlu5 receptors between the brain regions. Functional involvement of intra-accumbens mGlu5 receptors was confirmed as activation of mGlu5 receptors [10 μg of (RS)-2-amino-2-(2-chloro-5-hydroxyphenyl)acetic acid sodium salt] enhanced the discriminative stimulus effects of a low alcohol dose (0.5 g/kg), and mGlu5 receptor inhibition (20 μg of MPEP) prevented the agonist-induced enhancement. These results show that mGlu5 receptor activity in the nucleus accumbens is required for the expression of the interoceptive effects of alcohol.
Neuronal 3′,3,5-Triiodothyronine (T3) Uptake and Behavioral Phenotype of Mice Deficient inMct8, the Neuronal T3Transporter Mutated in Allan–Herndon–Dudley Syndrome
Authors: Wirth Eva K. , Roth Stephan , Blechschmidt Cristiane , Hölter Sabine M. , Becker Lore , Racz Ildiko , Zimmer Andreas , Klopstock Thomas , Gailus-Durner Valerie , Fuchs Helmut , Wurst Wolfgang , Naumann Thomas , Bräuer Anja , Hrabé de Angelis Martin , Köhrle Josef , Grüters Annette , Schweizer Ulrich
Published: July 2009

Thyroid hormone transport into cells requires plasma membrane transport proteins. Mutations in one of these, monocarboxylate transporter 8 (MCT8), have been identified as underlying cause for the Allan–Herndon–Dudley syndrome, an X-linked mental retardation in which the patients also present with abnormally high 3′,3,5-triiodothyronine (T3) plasma levels. Mice deficient inMct8replicate the thyroid hormone abnormalities observed in the human condition. However, no neurological deficits have been described in mice lackingMct8. Therefore, we subjectedMct8-deficient mice to a comprehensive immunohistochemical, neurological, and behavioral screen. Several behavioral abnormalities were found in the mutants. Interestingly, some of these behavioral changes are compatible with hypothyroidism, whereas others rather indicate hyperthyroidism. We thus hypothesized that neurons exclusively dependent onMct8are in a hypothyroid state, whereas neurons expressing other T3transporters become hyperthyroid, if they are exposed directly to the high plasma T3. The majority of T3uptake in primary cortical neurons is mediated by Mct8, but pharmacological inhibition suggested functional expression of additional T3transporter classes. mRNAs encoding six T3transporters, including L-type amino acid transporters (LATs), were coexpressed withMct8in isolated neurons. We then demonstratedLat2expression in cultured neurons and throughout murine brain development. In contrast,LAT2is expressed in microglia in the developing human brain during gestation, but not in neurons. We suggest that lack of functional complementation by alternative thyroid hormone transporters in developing human neurons precipitates the devastating neurodevelopmental phenotype inMCT8-deficient patients, whereasMct8-deficient mouse neurons are functionally complemented by other transporters, for possiblyLat2.