bluuebunny/crossref_metadata_2025 huggingface dataset:
Social and economic costs and health-related quality of life in stroke survivors in the Canary Islands, Spain
Authors: Lopez-Bastida Julio , Oliva Moreno Juan , Worbes Cerezo Melany , Perestelo Perez Lilisbeth , Serrano-Aguilar Pedro , Montón-Álvarez Fernando
Published: October 2012

Background

Cost-of-illness analysis is the main method of providing an overall vision of the economic impact of a disease. Such studies have been used to set priorities for healthcare policies and inform resource allocation. The aim of this study was to determine the economic burden and health-related quality of life (HRQOL) in the first, second and third years after surviving a stroke in the Canary Islands, Spain.

Methods

Cross-sectional, retrospective study of 448 patients with stroke based on ICD 9 discharge codes, who received outpatient care at five hospitals. The study was approved by the Research Ethics Committee of Nuestra Señora de la Candelaria University Hospital. Data on demographic characteristics, health resource utilization, informal care, labor productivity losses and HRQOL were collected from the hospital admissions databases and questionnaires completed by stroke patients or their caregivers. Labor productivity losses were calculated from physical units and converted into monetary units with a human capital-based method. HRQOL was measured with the EuroQol EQ-5D questionnaire. Healthcare costs, productivity losses and informal care costs were analyzed with log-normal, probit and ordered probit multivariate models.

Results

The average cost for each stroke survivor was €17 618 in the first, €14 453 in the second and €12 924 in the third year after the stroke; the reference year for unit prices was 2004. The largest expenditures in the first year were informal care and hospitalizations; in the second and third years the main costs were for informal care, productivity losses and medication. Mean EQ-5D index scores for stroke survivors were 0.50 for the first, 0.47 for the second and 0.46 for the third year, and mean EQ-5D visual analog scale scores were 56, 52 and 55, respectively.

Conclusions

The main strengths of this study lie in our bottom-up-approach to costing, and in the evaluation of stroke survivors from a broad perspective (societal costs) in the first, second and third years after surviving the stroke. This type of analysis is rare in the Spanish context. We conclude that stroke incurs considerable societal costs among survivors to three years and there is substantial deterioration in HRQOL.
Opsonization of malaria-infected erythrocytes activates the inflammasome and enhances inflammatory cytokine secretion by human macrophages
Authors: Zhou Jingling , Ludlow Louise E , Hasang Wina , Rogerson Stephen J , Jaworowski Anthony
Published: October 2012

Background

Antibody opsonization ofPlasmodium falciparum-infected erythrocytes (IE) plays a crucial role in anti-malarial immunity by promoting clearance of blood-stage infection by monocytes and macrophages. The effects of phagocytosis of opsonized IE on macrophage pro-inflammatory cytokine responses are poorly understood.

Methods

Phagocytic clearance, cytokine response and intracellular signalling were measured using IFN-γ-primed human monocyte-derived macrophages (MDM) incubated with opsonized and unopsonized trophozoite-stage CS2 IE, a chondroitin sulphate-binding malaria strain. Cytokine secretion was measured by bead array or ELISA, mRNA using quantitative PCR, and activation of NF-κB by Western blot and electrophoretic mobility shift assay. Data were analysed using the Mann–Whitney U test or the Wilcoxon signed rank test as appropriate.

Results

Unopsonized CS2 IE were not phagocytosed whereas IE opsonized with pooled patient immune serum (PPS) were (Phagocytic index (PI)=18.4, [SE 0.38] n=3). Unopsonized and opsonized IE induced expression of TNF, IL-1β and IL-6 mRNA by MDM and activated NF-κB to a similar extent. Unopsonized IE induced secretion of IL-6 (median= 622 pg/ml [IQR=1,250-240], n=9) but no IL-1β or TNF, whereas PPS-opsonized IE induced secretion of IL-1β (18.6 pg/mL [34.2-14.4]) and TNF (113 pg/ml [421–17.0]) and increased IL-6 secretion (2,195 pg/ml [4,658-1,095]). Opsonized, but not unopsonized, CS2 IE activated caspase-1 cleavage and enzymatic activity in MDM showing that Fc receptor-mediated phagocytosis activates the inflammasome. MDM attached to IgG-coated surfaces however secreted IL-1β in response to unopsonized IE, suggesting that internalization of IE is not absolutely required to activate the inflammasome and stimulate IL-1β secretion.

Conclusions

It is concluded that IL-6 secretion from MDM in response to CS2 IE does not require phagocytosis, whereas secretion of TNF and IL-1β is dependent on Fcγ receptor-mediated phagocytosis; for IL-1β, this occurs by activation of the inflammasome. The data presented in this paper show that generating antibody responses to blood-stage malaria parasites is potentially beneficial both in reducing parasitaemia via Fcγ receptor-dependent macrophage phagocytosis and in generating a robust pro-inflammatory response.
Valence band offset of β-Ga2O3/wurtzite GaN heterostructure measured by X-ray photoelectron spectroscopy
Authors: Wei Wei , Qin Zhixin , Fan Shunfei , Li Zhiwei , Shi Kai , Zhu Qinsheng , Zhang Guoyi
Published: October 2012

A sample of the β-Ga2O3/wurtzite GaN heterostructure has been grown by dry thermal oxidation of GaN on a sapphire substrate. X-ray diffraction measurements show that the β-Ga2O3layer was formed epitaxially on GaN. The valence band offset of the β-Ga2O3/wurtzite GaN heterostructure is measured by X-ray photoelectron spectroscopy. It is demonstrated that the valence band of the β-Ga2O3/GaN structure is 1.40 ± 0.08 eV.
Dietary iron intake, body iron stores, and the risk of type 2 diabetes: a systematic review and meta-analysis
Authors: Bao Wei , Rong Ying , Rong Shuang , Liu Liegang
Published: October 2012

Background

Excess iron has been shown to induce diabetes in animal models. However, the results from human epidemiologic studies linking body iron stores and iron intake to the risk of type 2 diabetes mellitus (T2DM) are conflicting. In this study, we aimed to systematically evaluate the available evidence for associations between iron intake, body iron stores, and the risk of T2DM.

Methods

A systematic search of the PubMed/MEDLINE and EMBASE databases to the end of 22 April 2012 was performed, and reference lists of retrieved articles were screened. Two reviewers independently evaluated the eligibility of inclusion and extracted the data. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random-effects models.

Results

We reviewed 449 potentially relevant articles, and 11 prospective studies were included in the analysis. A meta-analysis of five studies gave a pooled RR for T2DM of 1.33 (95% CI 1.19 to 1.48; P<0.001) in individuals with the highest level of heme iron intake, compared with those with the lowest level. The pooled RR for T2DM for a daily increment of 1 mg of heme iron intake was 1.16 (1.09 to 1.23, P<0.001). Body iron stores, as measured by ferritin, soluble transferrin receptor (sTfR) and the sTfR:ferritin ratio, were significantly associated with the risk of T2DM. The pooled RRs for T2DM in individuals with the highest versus the lowest intake of ferritin levels was 1.70 (1.27-2.27, P<0.001) before adjustment for inflammatory markers and 1.63 (1.03-2.56, P = 0.036) after adjustment. We did not find any significant association of dietary intakes of total iron, non-heme, or supplemental iron intake with T2DM risk.

Conclusion

Higher heme iron intake and increased body iron stores were significantly associated with a greater risk of T2DM. Dietary total iron, non-heme iron, or supplemental iron intakes were not significantly associated with T2DM risk.
Genome-wide association studies on HIV susceptibility, pathogenesis and pharmacogenomics
Authors: van Manen Daniëlle , van ‘t Wout Angélique B , Schuitemaker Hanneke
Published: October 2012

Susceptibility to HIV-1 and the clinical course after infection show a substantial heterogeneity between individuals. Part of this variability can be attributed to host genetic variation. Initial candidate gene studies have revealed interesting host factors that influence HIV infection, replication and pathogenesis. Recently, genome-wide association studies (GWAS) were utilized for unbiased searches at a genome-wide level to discover novel genetic factors and pathways involved in HIV-1 infection. This review gives an overview of findings from the GWAS performed on HIV infection, within different cohorts, with variable patient and phenotype selection. Furthermore, novel techniques and strategies in research that might contribute to the complete understanding of virus-host interactions and its role on the pathogenesis of HIV infection are discussed.
Analysis of plant gums and saccharide materials in paint samples: comparison of GC-MS analytical procedures and databases
Authors: Lluveras-Tenorio Anna , Mazurek Joy , Restivo Annalaura , Colombini Maria Perla , Bonaduce Ilaria
Published: October 2012

Background

Saccharide materials have been used for centuries as binding media, to paint, write and illuminate manuscripts and to apply metallic leaf decorations. Although the technical literature often reports on the use of plant gums as binders, actually several other saccharide materials can be encountered in paint samples, not only as major binders, but also as additives. In the literature, there are a variety of analytical procedures that utilize GC-MS to characterize saccharide materials in paint samples, however the chromatographic profiles are often extremely different and it is impossible to compare them and reliably identify the paint binder.

Results

This paper presents a comparison between two different analytical procedures based on GC-MS for the analysis of saccharide materials in works-of-art. The research presented here evaluates the influence of the analytical procedure used, and how it impacts the sugar profiles obtained from the analysis of paint samples that contain saccharide materials. The procedures have been developed, optimised and systematically used to characterise plant gums at the Getty Conservation Institute in Los Angeles, USA (GCI) and the Department of Chemistry and Industrial Chemistry of the University of Pisa, Italy (DCCI). The main steps of the analytical procedures and their optimisation are discussed.

Conclusions

The results presented highlight that the two methods give comparable sugar profiles, whether the samples analysed are simple raw materials, pigmented and unpigmented paint replicas, or paint samples collected from hundreds of centuries old polychrome art objects. A common database of sugar profiles of reference materials commonly found in paint samples was thus compiled. The database presents data also from those materials that only contain a minor saccharide fraction. This database highlights how many sources of saccharides can be found in a paint sample, representing an important step forward in the problem of identifying polysaccharide binders in paint samples.
Inactivation of uptake hydrogenase leads to enhanced and sustained hydrogen production with high nitrogenase activity under high light exposure in the cyanobacterium Anabaena siamensis TISTR 8012
Authors: Khetkorn Wanthanee , Lindblad Peter , Incharoensakdi Aran
Published: October 2012

Background

Biohydrogen from cyanobacteria has attracted public interest due to its potential as a renewable energy carrier produced from solar energy and water. Anabaena siamensis TISTR 8012, a novel strain isolated from rice paddy field in Thailand, has been identified as a promising cyanobacterial strain for use as a high-yield hydrogen producer attributed to the activities of two enzymes, nitrogenase and bidirectional hydrogenase. One main obstacle for high hydrogen production by A. siamensis is a light-driven hydrogen consumption catalyzed by the uptake hydrogenase. To overcome this and in order to enhance the potential for nitrogenase based hydrogen production, we engineered a hydrogen uptake deficient strain by interrupting hupS encoding the small subunit of the uptake hydrogenase.

Results

An engineered strain lacking a functional uptake hydrogenase (∆hupS) produced about 4-folds more hydrogen than the wild type strain. Moreover, the ∆hupS strain showed long term, sustained hydrogen production under light exposure with 2–3 folds higher nitrogenase activity compared to the wild type. In addition, HupS inactivation had no major effects on cell growth and heterocyst differentiation. Gene expression analysis using RT-PCR indicates that electrons and ATP molecules required for hydrogen production in the ∆hupS strain may be obtained from the electron transport chain associated with the photosynthetic oxidation of water in the vegetative cells. The ∆hupS strain was found to compete well with the wild type up to 50 h in a mixed culture, thereafter the wild type started to grow on the relative expense of the ∆hupS strain.

Conclusions

Inactivation of hupS is an effective strategy for improving biohydrogen production, in rates and specifically in total yield, in nitrogen-fixing cultures of the cyanobacterium Anabaena siamensis TISTR 8012.
Molecular characterization and ligand binding specificity of the PDZ domain-containing protein GIPC3 from Schistosoma japonicum
Authors: Mu Yi , Huang Haiming , Liu Shuai , Cai Pengfei , Gao Youhe
Published: October 2012

Background

Schistosomiasis is a serious global health problem that afflicts more than 230 million people in 77 countries. Long-term mass treatments with the only available drug, praziquantel, have caused growing concerns about drug resistance. PSD-95/Dlg/ZO-1 (PDZ) domain-containing proteins are recognized as potential targets for the next generation of drug development. However, the PDZ domain-containing protein family in parasites has largely been unexplored.

Methods

We present the molecular characteristics of a PDZ domain-containing protein, GIPC3, from Schistosoma japonicum (SjGIPC3) according to bioinformatics analysis and experimental approaches. The ligand binding specificity of the PDZ domain of SjGIPC3 was confirmed by screening an arbitrary peptide library in yeast two-hybrid (Y2H) assays. The native ligand candidates were predicted by Tailfit software based on the C-terminal binding specificity, and further validated by Y2H assays.

Results

SjGIPC3 is a single PDZ domain-containing protein comprised of 328 amino acid residues. Structural prediction revealed that a conserved PDZ domain was presented in the middle region of the protein. Phylogenetic analysis revealed that SjGIPC3 and other trematode orthologues clustered into a well-defined cluster but were distinguishable from those of other phyla. Transcriptional analysis by quantitative RT-PCR revealed that the SjGIPC3 gene was relatively highly expressed in the stages within the host, especially in male adult worms. By using Y2H assays to screen an arbitrary peptide library, we confirmed the C-terminal binding specificity of the SjGIPC3-PDZ domain, which could be deduced as a consensus sequence, -[SDEC]-[STIL]-[HSNQDE]-[VIL]*. Furthermore, six proteins were predicted to be native ligand candidates of SjGIPC3 based on the C-terminal binding properties and other biological information; four of these were confirmed to be potential ligands using the Y2H system.

Conclusions

In this study, we first characterized a PDZ domain-containing protein GIPC3 in S. japonicum. The SjGIPC3-PDZ domain is able to bind both type I and II ligand C-terminal motifs. The identification of native ligand will help reveal the potential biological function of SjGIPC3. These data will facilitate the identification of novel drug targets against S. japonicum infections.
Can EGFR-TKIs be used in first line treatment for advanced non-small cell lung cancer based on selection according to clinical factors ? -- A literature-based meta-analysis
Authors: Xu Chongrui , Zhou Qing , Wu Yi-long
Published: October 2012

Background

In the first line treatment of non-small cell lung cancer (NSCLC), several clinical trials have shown that not all NSCLC patients can benefit from treatment with tyrosine kinase inhibitors (TKIs) than receiving chemotherapy. Some trials treated patients with TKI according to their clinical characteristics. A few studies only chose patients with an epidermal grouth factor receptor (EGFR) mutation for TKI therapy. We aimed to determine whether patients could be treated with TKIs based on clinical factors in the first-line setting.

Methods

We performed a meta-analysis of randomized trials involving patients with advanced NSCLC treated with chemotherapy or TKIs by different selections. Efficacy outcomes of interest were the objective response rate (ORR), progression-free survival (PFS) and the overall survival (OS) of each treatment arm.

Results

Four trials enrolled unselected patients, and two trials selected East Asian patients using the clinical factors of gender and smoking history. Five trials chose patients with an EGFR mutation who were randomized for treatment with TKI or chemotherapy. For unselected patients, the risk ratio (RR) of the ORR was 3.52, the hazard ratio (HR) of the PFS was 1.29 and the HR of the OS was 1.35. For the clinically selected patients, the RR of the ORR was 0.64. The HRs of the PFS and OS were 0.83 and 0.92, respectively. The ORR and PFS were better for TKIs than for chemotherapy in patients with an EGFR mutation. The ORR was 0.47, and the HRs of the PFS and OS were 0.36 and 1.00, respectively.

Conclusions

Advanced NSCLC patients with an EGFR mutation benefit most from TKIs. EGFR-TKI treatment is justified for patients with unknown EGFR status,and those who cannot tolerate chemotherapy owing to age, poor performance status (PS) or other medical conditions, when selected according to clinical factors in the first-line setting.
Clusterin and FOXL2 Act Concordantly to Regulate Pituitary Gonadotroph Adenoma Growth
Authors: Chesnokova Vera , Zonis Svetlana , Wawrowsky Kolja , Tani Yuji , Ben-Shlomo Anat , Ljubimov Vladimir , Mamelak Adam , Bannykh Serguei , Melmed Shlomo
Published: October 2012

Pituitary tumors grow slowly and despite their high prevalence are invariably benign. We therefore studied mechanisms underlying pituitary tumor growth restraint. Pituitary tumor transforming gene (PTTG), the index human securin, a hallmark of pituitary tumors, triggers pituitary cell proliferation and murine pituitary tumor development. We show that human gonadotroph cell pituitary tumors, unlike other secreting tumor types, express high levels of gonadotroph-specific forkhead transcription factor FOXL2, and both PTTG and Forkhead box protein L2 (FOXL2) stimulate gonadotroph clusterin (Clu) expression. Both Clu RNA isoforms are abundantly expressed in these nonhormone-secreting human tumors, and, when cultured, these tumor cells release highly abundant levels of secreted Clu. FOXL2 directly stimulates the Clu gene promoter, and we show that PTTG triggers ataxia telangiectasia mutated kinase/IGF-I/p38MAPK DNA damage/chromosomal instability signaling, which in turn also induces Clu expression. Consequently, Clu restrains pituitary cell proliferation by inducing cyclin dependent kinase inhibitors p16 and p27, whereas Clu deletion down-regulates p16 and p27 in the Clu−/− mouse pituitary. FOXL2 binds and suppresses the PTTG promoter, and Clu also suppresses PTTG expression, thus neutralizing protumorigenic PTTG gonadotroph tumor cell properties. In vivo, murine gonadotroph LβT2 tumor cell xenografts overexpressing Clu and FOXL2 both grow slower and elicit smaller tumors. Thus, gonadotroph tumor cell proliferation is determined by the interplay between cell-specific FOXL2 with PTTG and Clu.
Geo-Graphs: An Efficient Model for Enforcing Contiguity and Hole Constraints in Planar Graph Partitioning
Authors: King Douglas M. , Jacobson Sheldon H. , Sewell Edward C. , Cho Wendy K. Tam
Published: October 2012

Political districting is an intractable problem with significant ramifications for political representation. Districts often are required to satisfy some legal constraints, but these typically are not very restrictive, allowing decision makers to influence the composition of these districts without violating relevant laws. For example, while districts must often comprise a single contiguous area, a vast collection of acceptable solutions (i.e., sets of districts) remains. Choosing the best set of districts from this collection can be treated as a (planar) graph partitioning problem. When districts must be contiguous, successfully solving this problem requires an efficient computational method for evaluating contiguity constraints; common methods for assessing contiguity can require significant computation as the problem size grows. This paper introduces the geo-graph, a new graph model that ameliorates the computational burdens associated with enforcing contiguity constraints in planar graph partitioning when each vertex corresponds to a particular region of the plane. Through planar graph duality, the geo-graph provides a scale-invariant method for enforcing contiguity constraints in local search. Furthermore, geo-graphs allow district holes (which typically are considered undesirable) to be rigorously and efficiently integrated into the partitioning process.
Process Location and Product Distribution with Uncertain Yields
Authors: Caro Felipe , Rajaram Kumar , Wollenweber Jens
Published: October 2012

We present a framework to analyze the process location and product distribution problem with uncertain yields for a large multinational food processing company. This problem consists of selecting the location of processes, the assignment of products, and the distribution of production quantities to markets in order to minimize total expected costs. It differs from the traditional facility location problem due to characteristics that are inherent to process industry sectors. These include significant economies of scale at high volumes, large switchover times, and production yield uncertainty. We model the problem as a nonlinear mixed-integer program. A challenging aspect of this problem is that the objective function is neither convex nor concave. We develop an exact approach to linearize the objective function. We present heuristics to solve the problem and also construct lower bounds based on a reduction of the constraint set to evaluate the quality of the solutions. This framework has been used to make process choice and product allocation decisions at the food processing company, and the estimated annual cost savings are around 10%, or $50 million. In addition, the insights from the model have had a significant strategic and organizational impact at this company. Our framework and conclusions are relevant to other industrial sectors with similar characteristics, such as pharmaceuticals and specialty chemical manufacturers.
Ranking Games and Gambling: When to Quit When You're Ahead
Authors: Anderson Edward
Published: October 2012

It is common for rewards to be given on the basis of a rank ordering, so that relative performance amongst a cohort is the criterion. In this paper we formulate an equilibrium model in which an agent makes successive decisions on whether or not to gamble and is rewarded on the basis of a rank ordering of the final position amongst competing players. One application of this model is to the behavior of mutual fund managers who are paid depending on funds under management, which in turn are greatly influenced by annual or quarterly rank orderings. Our model deals with a situation in which fund managers can elect either to pick stocks or to use a market-tracking strategy. In equilibrium the distribution of the final position will have a negative skew. We explore how this distribution depends on the number of players, the probability of success when gambling, the structure of the rewards, and on information regarding the performance of other players.
Reviews Films
Authors: Debono’s John , Regan Patrick
Published: October 2012

Hugo: A 3D Tribute to Cinema’s History Hugo (2011) USA Director Martin Scorsese Runtime 126 minutes

The Skin I Live In (La piel que habito, 2011) Spain Pedro Almodóvar Runtime 117 minutes
Optical components and optical systems for VCSEL diode laser systems
Authors: Gronenborn Stephan , Miller Michael , Heusler Gero , Mönch Holger
Published: October 2012

High power vertical-cavity surface-emitting laser (VCSEL) arrays can be used as a versatile illumination and heating source. They are widely scalable in power and offer a robust and economic solution for many new applications with moderate brightness requirements. The use of VCSEL arrays for high power laser diode applications enables multiple benefits: full wafer level production of VCSELs including combination with micro-optics; assembly technologies allowing large synergy with LED assembly thus profiting from the fast development in solid state lighting; outstanding reliability and a modular approach on all levels. With the use of μ-lenses, the described optical principle of near field imaging and superpositioning of many thousands of VCSELs gives perfect control over intensity distribution and is inherently robust. With a slightly modified approach, lines of any desired length can be built from modules of 1-cm length and are therefore scalable for a wide range of applications.
Development and evaluation of an automated digital image analysis software for obtaining seagrass leaf metrics
Authors: Ramfos Alexis , Gazis Andreas , Katselis George
Published: October 2012

We developed a simple and inexpensive digital image analysis method for measuring leaf area and the length of strapped-shaped seagrass leaves. The method uses specialized software that permits automatic leaf and scale recognition in digital images along with batch image processing. The leaf biometrics of 80 Posidonia oceanica and Cymodocea nodosa leaves were used for the evaluation of the method for accuracy, precision, and speed in comparison to manual measurements. Each leaf was measured 90 times under different combinations of several factors that might affect software estimation. The factors examined included leaf shape, leaf orientation in the image, scale dimensions, image resize, and binary conversion. Estimates of leaf length and leaf area were highly correlated between the new image analysis procedure and manual measurements. Relative error values between the two methods were <10% in 99% of leaf length measures and in 75% of leaf area measures. The factors examined explained <10% of the relative error variance; the remaining variance was mostly attributed to technical issues concerning leaf size and image illumination. The digital method proved to be approximately 2.5 times faster than the manual one.
Satisfier function in Ritz–Galerkin method for the identification of a time-dependent diffusivity
Authors: Yousefi S. A. , Lesnic Daniel , Barikbin Zahra
Published: October 2012

The problem of recovering a
time-dependent coefficient in a parabolic partial differential
equation has attracted considerable attention in the classical
literature on inverse heat conduction problems. In this article, the Ritz–Galerkin method with satisfier
function is utilized to solve the inverse problems of identifying the
temperature and the unknown diffusion coefficient
in the one-dimensional heat equation from various additional information. Numerical examples are presented and discussed.
Inverse problems for second-order differential pencils with Dirichlet boundary conditions
Authors: Buterin Sergey A. , Yurko Vjacheslav A.
Published: October 2012

Inverse spectral problems are studied for second-order differential pencils on a finite interval with
arbitrary behavior of the spectrum. The spectral data introduced generalize the classical discrete spectral data
corresponding to the specification of the spectral function for the selfadjoint Sturm–Liouville operator. The connection
with other types of spectral characteristics is investigated. By the method of spectral mappings a uniqueness theorem is
proved and constructive procedures for solving the inverse problem are obtained.
AMP Kinase Activation Mitigates Dopaminergic Dysfunction and Mitochondrial Abnormalities inDrosophilaModels of Parkinson's Disease
Authors: Ng Chee-Hoe , Guan Melissa S. H. , Koh Cherlyn , Ouyang Xuezhi , Yu Fengwei , Tan Eng-King , O'Neill Sharon Philomena , Zhang Xiaodong , Chung Jongkyeong , Lim Kah-Leong
Published: October 2012

Mutations in parkin and LRRK2 together account for the majority of familial Parkinson's disease (PD) cases. Interestingly, recent evidence implicates the involvement of parkin and LRRK2 in mitochondrial homeostasis. Supporting this, we show here by means of theDrosophilamodel system that, like parkin, LRRK2 mutations induce mitochondrial pathology in flies when expressed in their flight muscles, the toxic effects of which can be rescued by parkin coexpression. When expressed specifically in fly dopaminergic neurons, mutant LRRK2 results in the appearance of significantly enlarged mitochondria, a phenotype that can also be rescued by parkin coexpression. Importantly, we also identified in this study that epigallocatechin gallate (EGCG), a green tea-derived catechin, acts as a potent suppressor of dopaminergic and mitochondrial dysfunction in both mutant LRRK2 and parkin-null flies. Notably, the protective effects of EGCG are abolished when AMP-activated protein kinase (AMPK) is genetically inactivated, suggesting that EGCG-mediated neuroprotection requires AMPK. Consistent with this, direct pharmacological or genetic activation of AMPK reproduces EGCG's protective effects. Conversely, loss of AMPK activity exacerbates neuronal loss and associated phenotypes in parkin and LRRK mutant flies. Together, our results suggest the relevance of mitochondrial-associated pathway in LRRK2 and parkin-related pathogenesis, and that AMPK activation may represent a potential therapeutic strategy for these familial forms of PD.
Molecular Genetic Analysis of Sexual Rejection: Roles of Octopamine and Its Receptor OAMB inDrosophilaCourtship Conditioning
Authors: Zhou Chuan , Huang Hai , Kim Susy M. , Lin Hsuanwen , Meng Xianglan , Han Kyung-An , Chiang Ann-Shyn , Wang Jing W. , Jiao Renjie , Rao Yi
Published: October 2012

AfterDrosophilamales are rejected by mated females, their subsequent courtship is inhibited even when encountering virgin females. Molecular mechanisms underlying courtship conditioning in the CNS are unclear. In this study, we find that tyramine β hydroxylase (TβH) mutant males unable to synthesize octopamine (OA) showed impaired courtship conditioning, which could be rescued by transgenic TβH expression in the CNS. Inactivation of octopaminergic neurons mimicked the TβH mutant phenotype. Transient activation of octopaminergic neurons in males not only decreased their courtship of virgin females, but also produced courtship conditioning. Single cell analysis revealed projection of octopaminergic neurons to the mushroom bodies. Deletion of the OAMB gene encoding an OA receptor expressed in the mushroom bodies disrupted courtship conditioning. Inactivation of neurons expressing OAMB also eliminated courtship conditioning. OAMB neurons responded robustly to male-specific pheromonecis-vaccenyl acetate in a dose-dependent manner. Our results indicate that OA plays an important role in courtship conditioning through its OAMB receptor expressed in a specific neuronal subset of the mushroom bodies.
Dissociating the Detection of Intentionality from Animacy in the Right Posterior Superior Temporal Sulcus
Authors: Gao Tao , Scholl Brian J. , McCarthy Gregory
Published: October 2012

Certain motion patterns can cause even simple geometric shapes to be perceived as animate. Viewing such displays evokes strong activation in temporoparietal cortex, including areas in and near the (predominantly right) posterior superior temporal sulcus (pSTS). These brain regions are sensitive to socially relevant information, but the nature of the social information represented in pSTS is unclear. For example, previous studies have been unable to explore the perception of shifting intentions beyond animacy. This is due in part to the ubiquitous use of complex displays that combine several types of social information, with little ability to control lower-level visual cues. Here we address this challenge by manipulating intentionality with parametric precision while holding cues to animacy constant. Human subjects were exposed to a “wavering wolf” display, in which one item (the wolf) chased continuously, but its goal (i.e., the sheep) frequently switched among other shapes. By contrasting this with three other control displays, we find that the wolf's changing intentions gave rise to strong selective activation in the right pSTS, compared with (1) a wolf that chases with a single unchanging intention, (2) very similar patterns of motion (and motion change) that are not perceived as goal-directed, and (3) abrupt onsets and offsets of moving objects. These results demonstrate in an especially well controlled manner that right pSTS is involved in social perception beyond physical properties such as motion energy and salience. More importantly, these results demonstrate for the first time that this region represents perceived intentions beyond animacy.
Spike Phase Locking in CA1 Pyramidal Neurons Depends on Background Conductance and Firing Rate
Authors: Broicher Tilman , Malerba Paola , Dorval Alan D. , Borisyuk Alla , Fernandez Fernando R. , White John A.
Published: October 2012

Oscillatory activity in neuronal networks correlates with different behavioral states throughout the nervous system, and the frequency–response characteristics of individual neurons are believed to be critical for network oscillations. Recentin vivostudies suggest that neurons experience periods of high membrane conductance, and that action potentials are often driven by membrane potential fluctuations in the living animal. To investigate the frequency–response characteristics of CA1 pyramidal neurons in the presence of high conductance and voltage fluctuations, we performed dynamic-clamp experiments in rat hippocampal brain slices. We drove neurons with noisy stimuli that included a sinusoidal component ranging, in different trials, from 0.1 to 500 Hz. In subsequent data analysis, we determined action potential phase-locking profiles with respect to background conductance, average firing rate, and frequency of the sinusoidal component. We found that background conductance and firing rate qualitatively change the phase-locking profiles of CA1 pyramidal neurons versus frequency. In particular, higher average spiking rates promoted bandpass profiles, and the high-conductance state promoted phase-locking at frequencies well above what would be predicted from changes in the membrane time constant. Mechanistically, spike rate adaptation and frequency resonance in the spike-generating mechanism are implicated in shaping the different phase-locking profiles. Our results demonstrate that CA1 pyramidal cells can actively change their synchronization properties in response to global changes in activity associated with different behavioral states.
Processing of Natural Sounds in Human Auditory Cortex: Tonotopy, Spectral Tuning, and Relation to Voice Sensitivity
Authors: Moerel Michelle , De Martino Federico , Formisano Elia
Published: October 2012

Auditory cortical processing of complex meaningful sounds entails the transformation of sensory (tonotopic) representations of incoming acoustic waveforms into higher-level sound representations (e.g., their category). However, the precise neural mechanisms enabling such transformations remain largely unknown. In the present study, we use functional magnetic resonance imaging (fMRI) and natural sounds stimulation to examine these two levels of sound representation (and their relation) in the human auditory cortex. In a first experiment, we derive cortical maps of frequency preference (tonotopy) and selectivity (tuning width) by mathematical modeling of fMRI responses to natural sounds. The tuning width maps highlight a region of narrow tuning that follows the main axis of Heschl's gyrus and is flanked by regions of broader tuning. The narrowly tuned portion on Heschl's gyrus contains two mirror-symmetric frequency gradients, presumably defining two distinct primary auditory areas. In addition, our analysis indicates that spectral preference and selectivity (and their topographical organization) extend well beyond the primary regions and also cover higher-order and category-selective auditory regions. In particular, regions with preferential responses to human voice and speech occupy the low-frequency portions of the tonotopic map. We confirm this observation in a second experiment, where we find that speech/voice selective regions exhibit a response bias toward the low frequencies characteristic of human voice and speech, even when responding to simple tones. We propose that this frequency bias reflects the selective amplification of relevant and category-characteristic spectral bands, a useful processing step for transforming a sensory (tonotopic) sound image into higher level neural representations.
Central Amygdala Metabotropic Glutamate Receptor 5 in the Modulation of Visceral Pain
Authors: Crock Lara W. , Kolber Benedict J. , Morgan Clinton D. , Sadler Katelyn E. , Vogt Sherri K. , Bruchas Michael R. , Gereau Robert W.
Published: October 2012

Painful bladder syndrome is a debilitating condition that affects 3–6% of women in the United States. Multiple lines of evidence suggest that changes in CNS processing are key to the development of chronic bladder pain conditions but little is known regarding the underlying cellular, molecular, and neuronal mechanisms. Using a mouse model of distention-induced bladder pain, we found that the central nucleus of the amygdala (CeA) is a critical site of neuromodulation for processing of bladder nociception. Furthermore, we demonstrate that metabotropic glutamate receptor 5 (mGluR5) activation in the CeA induces bladder pain sensitization by increasing CeA output. Thus, pharmacological activation of mGluR5 in the CeA is sufficient to increase the response to bladder distention. Additionally, pharmacological blockade or virally mediated conditional deletion of mGluR5 in the CeA reduced responses to bladder distention suggesting that mGluR5 in the CeA is also necessary for these responses. Finally, we used optogenetic activation of the CeA and demonstrated that this caused a robust increase in the visceral pain response. The CeA-localized effects on responses to bladder distention are associated with changes in extracellular signal-regulated kinases 1/2 (ERK1/2) phosphorylation in the spinal cord. Overall, these data demonstrate that mGluR5 activation leads to increased CeA output that drives bladder pain sensitization.
Phosphorylation of MeCP2 at Ser421 Contributes to Chronic Antidepressant Action
Authors: Hutchinson Ashley N. , Deng Jay V. , Cohen Sonia , West Anne E.
Published: October 2012

Although tricyclic antidepressants rapidly activate monoaminergic neurotransmission, these drugs must be administered chronically to alleviate symptoms of depression. This observation suggests that molecular mechanisms downstream of monoamine receptor activation, which include the induction of gene transcription, underlie chronic antidepressant-induced changes in behavior. Here we show that methyl-CpG-binding protein 2 (MeCP2) regulates behavioral responses to chronic antidepressant treatment. Imipramine administration induces phosphorylation of MeCP2 at Ser421 (pMeCP2) selectively in the nucleus accumbens and the lateral habenula, two brain regions important for depressive-like behaviors. To test the role of pMeCP2 in depressive-like behaviors, we used male mice that bear a germ-line mutation knocked into the X-linkedMecp2locus that changes Ser421 to a nonphosphorylatable Ala residue (S421A). MeCP2 S421A knock-in (KI) mice showed increased immobility in forced-swim and tail-suspension tests compared with their wild-type (WT) littermates. However, immobility of both MeCP2 WT and KI mice in forced swim was reduced by acute administration of imipramine, demonstrating that loss of pMeCP2 does not impair acute pharmacological sensitivity to this drug. After chronic social defeat stress, chronic administration of imipramine significantly improved social interaction in the MeCP2 WT mice. In contrast, the MeCP2 KI mice did not respond to chronic imipramine administration. These data suggest novel roles for pMeCP2 in the sensitivity to stressful stimuli and demonstrate that pMeCP2 is required for the effects of chronic imipramine on depressive-like behaviors induced by chronic social defeat stress.
Aging Affects Neural Precision of Speech Encoding
Authors: Anderson Samira , Parbery-Clark Alexandra , White-Schwoch Travis , Kraus Nina
Published: October 2012

Older adults frequently report they can hear what is said but cannot understand the meaning, especially in noise. This difficulty may arise from the inability to process rapidly changing elements of speech. Aging is accompanied by a general slowing of neural processing and decreased neural inhibition, both of which likely interfere with temporal processing in auditory and other sensory domains. Age-related reductions in inhibitory neurotransmitter levels and delayed neural recovery can contribute to decreases in the temporal precision of the auditory system. Decreased precision may lead to neural timing delays, reductions in neural response magnitude, and a disadvantage in processing the rapid acoustic changes in speech. The auditory brainstem response (ABR), a scalp-recorded electrical potential, is known for its ability to capture precise neural synchrony within subcortical auditory nuclei; therefore, we hypothesized that a loss of temporal precision results in subcortical timing delays and decreases in response consistency and magnitude. To assess this hypothesis, we recorded ABRs to the speech syllable /da/ in normal hearing younger (18–30 years old) and older (60–67 years old) adult humans. Older adults had delayed ABRs, especially in response to the rapidly changing formant transition, and greater response variability. We also found that older adults had decreased phase locking and smaller response magnitudes than younger adults. Together, our results support the theory that older adults have a loss of temporal precision in the subcortical encoding of sound, which may account, at least in part, for their difficulties with speech perception.
Temporal Tuning Properties along the Human Ventral Visual Stream
Authors: Gauthier Baptiste , Eger Evelyn , Hesselmann Guido , Giraud Anne-Lise , Kleinschmidt Andreas
Published: October 2012

Both our environment and our behavior contain many spatiotemporal regularities. Preferential and differential tuning of neural populations to these regularities can be demonstrated by assessing rate dependence of neural responses evoked during continuous periodic stimulation. Here, we used functional magnetic resonance imaging to measure regional variations of temporal sensitivity along the human ventral visual stream. By alternating one face and one house stimulus, we combined sufficient low-level signal modulation with changes in semantic meaning and could therefore drive all tiers of visual cortex strongly enough to assess rate dependence. We found several dissociations between early visual cortex and middle- and higher-tier regions. First, there was a progressive slowing down of stimulation rates yielding peak responses along the ventral visual stream. This finding shows the width of temporal integration windows to increase at higher hierarchical levels. Next, for fixed rates, early but not higher visual cortex responses additionally depended on the length of stimulus exposure, which may indicate increased persistence of responses to short stimuli at higher hierarchical levels. Finally, attention, which was recruited by an incidental task, interacted with stimulation rate and shifted tuning peaks toward lower frequencies. Together, these findings quantify neural response properties that are likely to be operational during natural vision and that provide putative neurofunctional substrates of mechanisms that are relevant in several psychophysical phenomena as masking and the attentional blink. Moreover, they illustrate temporal constraints for translating the deployment of attention into enhanced neural responses and thereby account for lower limits of attentional dwell time.
Ectopic Expression of Select Innexins in Individual Central Neurons Couples Them to Pre-Existing Neuronal or Glial Networks That Express the Same Innexin
Authors: Firme Constantine P. , Natan Ryan G. , Yazdani Neema , Macagno Eduardo R. , Baker Michael W.
Published: October 2012

Fifteen of the 21 innexin (Inx) genes (Hve-inx) found in the genome of the medicinal leech,Hirudo verbana, are expressed in the CNS (Kandarian et al., 2012). Two are expressed pan-neuronally, while the others are restricted in their expression to small numbers of cells, in some cases reflecting the membership of known networks of electrically coupled and dye-coupled neurons or glial cells. We report here that whenHve-inxgenes characteristic of discrete coupled networks were expressed ectopically in neurons known not to express them, the experimental cells were found to become dye coupled with the other cells in that network.Hve-inx6is normally expressed by only three neurons in each ganglion, which form strongly dye-coupled electrical connections with each other [Shortening-Coupling interneuron (S-CI) network] (Muller and Scott, 1981; Dykes and Macagno, 2006). But whenHve-inx6was ectopically expressed in a variety of central embryonic neurons, those cells became dye coupled with the S-CI network. Similarly,Hve-inx2is normally uniquely expressed by the ganglion's large glial cells, but when it was ectopically expressed in different central neurons, they became dye coupled to the glial cells. In contrast, overexpression of the pan-neuronal Inx genesHve-inx1andHve-inx14did not yield any novel instances of dye coupling to pre-existent neuronal networks. These results reveal that expression of certain innexins is sufficient to couple individual neurons to pre-existing networks in the CNS. We propose that a primary determinant of selective neuronal connectivity and circuit formation in the leech is the surface expression of unique subsets of gap junctional proteins.
Stochastic Facilitation of Artificial Tactile Sensation in Primates
Authors: Medina Leonel E. , Lebedev Mikhail A. , O'Doherty Joseph E. , Nicolelis Miguel A. L.
Published: October 2012

Artificial sensation via electrical or optical stimulation of brain sensory areas offers a promising treatment for sensory deficits. For a brain–machine–brain interface, such artificial sensation conveys feedback signals from a sensorized prosthetic limb. The ways neural tissue can be stimulated to evoke artificial sensation and the parameter space of such stimulation, however, remain largely unexplored. Here we investigated whether stochastic facilitation (SF) could enhance an artificial tactile sensation produced by intracortical microstimulation (ICMS). Two rhesus monkeys learned to use a virtual hand, which they moved with a joystick, to explore virtual objects on a computer screen. They sought an object associated with a particular artificial texture (AT) signaled by a periodic ICMS pattern delivered to the primary somatosensory cortex (S1) through a pair of implanted electrodes. During each behavioral trial, aperiodic ICMS (i.e., noise) of randomly chosen amplitude was delivered to S1 through another electrode pair implanted 1 mm away from the site of AT delivery. Whereas high-amplitude noise worsened AT detection, moderate noise clearly improved the detection of weak signals, significantly raising the proportion of correct trials. These findings suggest that SF could be used to enhance prosthetic sensation.