bluuebunny/crossref_metadata_2025 huggingface dataset:
Overexpression of hTERT increases stem-like properties and decreases spontaneous differentiation in human mesenchymal stem cell lines
Authors: Tsai Chih-Chien , Chen Chun-Li , Liu Hwa-Chung , Lee Yi-Ting , Wang Hsei-Wei , Hou Lein-Tuan , Hung Shih-Chieh
Published: July 2010

To overcome loss of stem-like properties and spontaneous differentiation those hinder the expansion and application of human mesenchymal stem cells (hMSCs), we have clonally isolated permanent and stable human MSC lines by ectopic overexpression of primary cell cultures of hMSCs with HPV 16 E6E7 and human telomerase reverse transcriptase (hTERT) genes. These cells were found to have a differentiation potential far beyond the ordinary hMSCs. They expressed trophoectoderm and germline specific markers upon differentiation with BMP4 and retinoic acid, respectively. Furthermore, they displayed higher osteogenic and neural differentiation efficiency than primary hMSCs or hMSCs expressed HPV16 E6E7 alone with a decrease in methylation level as proven by a global CpG island methylation profile analysis. Notably, the demethylated CpG islands were highly associated with development and differentiation associated genes. Principal component analysis further pointed out the expression profile of the cells converged toward embryonic stem cells. These data demonstrate these cells not only are a useful tool for the studies of cell differentiation both for the mesenchymal and neurogenic lineages, but also provide a valuable source of cells for cell therapy studies in animal models of skeletal and neurological disorders.
Phylogenetic analysis of ferlin genes reveals ancient eukaryotic origins
Authors: Lek Angela , Lek Monkol , North Kathryn N , Cooper Sandra T
Published: July 2010

Background

The ferlin gene family possesses a rare and identifying feature consisting of multiple tandem C2 domains and a C-terminal transmembrane domain. Much currently remains unknown about the fundamental function of this gene family, however, mutations in its two most well-characterised members, dysferlin and otoferlin, have been implicated in human disease. The availability of genome sequences from a wide range of species makes it possible to explore the evolution of the ferlin family, providing contextual insight into characteristic features that define the ferlin gene family in its present form in humans.

Results

Ferlin genes were detected from all species of representative phyla, with two ferlin subgroups partitioned within the ferlin phylogenetic tree based on the presence or absence of a DysF domain. Invertebrates generally possessed two ferlin genes (one with DysF and one without), with six ferlin genes in most vertebrates (three DysF, three non-DysF). Expansion of the ferlin gene family is evident between the divergence of lamprey (jawless vertebrates) and shark (cartilaginous fish). Common to almost all ferlins is an N-terminal C2-FerI-C2 sandwich, a FerB motif, and two C-terminal C2 domains (C2E and C2F) adjacent to the transmembrane domain. Preservation of these structural elements throughout eukaryotic evolution suggests a fundamental role of these motifs for ferlin function. In contrast, DysF, C2DE, and FerA are optional, giving rise to subtle differences in domain topologies of ferlin genes. Despite conservation of multiple C2 domains in all ferlins, the C-terminal C2 domains (C2E and C2F) displayed higher sequence conservation and greater conservation of putative calcium binding residues across paralogs and orthologs. Interestingly, the two most studied non-mammalian ferlins (Fer-1 and Misfire) in model organisms C. elegans and D. melanogaster, present as outgroups in the phylogenetic analysis, with results suggesting reproduction-related divergence and specialization of species-specific functions within their genus.

Conclusions

Our phylogenetic studies provide evolutionary insight into the ferlin gene family. We highlight the existence of ferlin-like proteins throughout eukaryotic evolution, from unicellular phytoplankton and apicomplexan parasites, through to humans. We characterise the preservation of ferlin structural motifs, not only of C2 domains, but also the more poorly characterised ferlin-specific motifs representing the DysF, FerA and FerB domains. Our data suggest an ancient role of ferlin proteins, with lessons from vertebrate biology and human disease suggesting a role relating to vesicle fusion and plasma membrane specialization.
Genetic and phenotypic diversity in Burkholderia: contributions by prophage and phage-like elements
Authors: Ronning Catherine M , Losada Liliana , Brinkac Lauren , Inman Jason , Ulrich Ricky L , Schell Mark , Nierman William C , DeShazer David
Published: July 2010

Background

Burkholderia species exhibit enormous phenotypic diversity, ranging from the nonpathogenic, soil- and water-inhabiting Burkholderia thailandensis to the virulent, host-adapted mammalian pathogen B. mallei. Genomic diversity is evident within Burkholderia species as well. Individual isolates of Burkholderia pseudomallei and B. thailandensis, for example, carry a variety of strain-specific genomic islands (GIs), including putative pathogenicity and metabolic islands, prophage-like islands, and prophages. These GIs may provide some strains with a competitive advantage in the environment and/or in the host relative to other strains.

Results

Here we present the results of analysis of 37 prophages, putative prophages, and prophage-like elements from six different Burkholderia species. Five of these were spontaneously induced to form bacteriophage particles from B. pseudomallei and B. thailandensis strains and were isolated and fully sequenced; 24 were computationally predicted in sequenced Burkholderia genomes; and eight are previously characterized prophages or prophage-like elements. The results reveal numerous differences in both genome structure and gene content among elements derived from different species as well as from strains within species, due in part to the incorporation of additional DNA, or 'morons' into the prophage genomes. Implications for pathogenicity are also discussed. Lastly, RNAseq analysis of gene expression showed that many of the genes in ϕ1026b that appear to contribute to phage and lysogen fitness were expressed independently of the phage structural and replication genes.

Conclusions

This study provides the first estimate of the relative contribution of prophages to the vast phenotypic diversity found among the Burkholderiae.
Structure-function relationships of wheat flavone O-methyltransferase: Homology modeling and site-directed mutagenesis
Authors: Zhou Jian-Min , Lee Eunjung , Kanapathy-Sinnaiaha Francesca , Park Younghee , Kornblatt Jack A , Lim Yoongho , Ibrahim Ragai K
Published: July 2010

Background

Wheat (Triticum aestivum L.) O-methyltransferase (TaOMT2) catalyzes the sequential methylation of the flavone, tricetin, to its 3'-methyl- (selgin), 3',5'-dimethyl- (tricin) and 3',4',5'-trimethyl ether derivatives. Tricin, a potential multifunctional nutraceutical, is the major enzyme reaction product. These successive methylations raised the question as to whether they take place in one, or different active sites. We constructed a 3-D model of this protein using the crystal structure of the highly homologous Medicago sativa caffeic acid/5-hydroxyferulic acid O-methyltransferase (MsCOMT) as a template with the aim of proposing a mechanism for multiple methyl transfer reactions in wheat.

Results

This model revealed unique structural features of TaOMT2 which permit the stepwise methylation of tricetin. Substrate binding is mediated by an extensive network of H-bonds and van der Waals interactions. Mutational analysis of structurally guided active site residues identified those involved in binding and catalysis. The partly buried tricetin active site, as well as proximity and orientation effects ensured sequential methylation of the substrate within the same pocket. Stepwise methylation of tricetin involves deprotonation of its hydroxyl groups by a His262-Asp263 pair followed by nucleophilic attack of SAM-methyl groups. We also demonstrate that Val309, which is conserved in a number of graminaceous flavone OMTs, defines the preference of TaOMT2 for tricetin as the substrate.

Conclusions

We propose a mechanism for the sequential methylation of tricetin, and discuss the potential application of TaOMT2 to increase the production of tricin as a nutraceutical. The single amino acid residue in TaOMT2, Val309, determines its preference for tricetin as the substrate, and may define the evolutionary differences between the two closely related proteins, COMT and flavone OMT.
Lymphocyte and monocyte flow cytometry immunophenotyping as a diagnostic tool in uncharacteristic inflammatory disorders
Authors: Janols Helena , Bredberg Anders , Thuvesson Irene , Janciauskiene Sabina , Grip Olof , Wullt Marlene
Published: July 2010

Background

Patients with uncharacteristic inflammatory symptoms such as long-standing fatigue or pain, or a prolonged fever, constitute a diagnostic and therapeutic challenge. The aim of the present study was to determine if an extended immunophenotyping of lymphocytes and monocytes including activation markers can define disease-specific patterns, and thus provide valuable diagnostic information for these patients.

Methods

Whole blood from patients with gram-negative bacteraemia, neuroborreliosis, tuberculosis, acute mononucleosis, influenza or a mixed connective tissue disorders, as diagnosed by routine culture and serology techniques was analysed for lymphocyte and monocyte cell surface markers using a no-wash, no-lyse protocol for multi-colour flow cytometry method. The immunophenotyping included the activation markers HLA-DR and CD40. Plasma levels of soluble TNF alpha receptors were analysed by ELISA.

Results

An informative pattern was obtained by combining two of the analysed parameters: (i), the fractions of HLA-DR-expressing CD4+ T cells and CD8+ T cells, respectively, and (ii), the level of CD40 on CD14+ CD16- monocytes. Patients infected with gram-negative bacteria or EBV showed a marked increase in monocyte CD40, while this effect was less pronounced for tuberculosis, borrelia and influenza. The bacterial agents could be distinguished from the viral agents by the T cell result; CD4+ T cells reacting in bacterial infection, and the CD8+ T cells dominating for the viruses. Patients with mixed connective tissue disorders also showed increased activation, but with similar engagement of CD4+ and CD8+ T cells. Analysis of soluble TNF alpha receptors was less informative due to a large inter-individual variation.

Conclusion

Immunophenotyping including the combination of the fractions of HLA-DR expressing T cell subpopulations with the level of CD40 on monocytes produces an informative pattern, differentiating between infections of bacterial and viral origin. Furthermore, a quantitative analysis of these parameters revealed the novel finding of characteristic patterns indicating a subacute bacterial infection, such as borreliosis or tuberculosis, or a mixed connective tissue disorder. The employed flow cytometric method is suitable for clinical diagnostic laboratories, and may help in the assessment of patients with uncharacteristic inflammatory symptoms.
Prevalence, concordance and determinants of human papillomavirus infection among heterosexual partners in a rural region in central Mexico
Authors: Parada Rocio , Morales Rosalba , Giuliano Anna R , Cruz Aurelio , Castellsagué Xavier , Lazcano-Ponce Eduardo
Published: July 2010

Background

Although human papillomavirus (HPV) infection in heterosexual couples has been sparsely studied, it is relevant to understand disease burden and transmission mechanisms. The present study determined the prevalence and concordance of type-specific HPV infection as well as the determinants of infection in heterosexual couples in a rural area of Mexico.

Methods

A cross-sectional study was conducted in 504 clinically healthy heterosexual couples from four municipalities in the State of Mexico, Mexico. HPV testing was performed using biotinylated L1 consensus primers and reverse line blot in cervical samples from women and in genital samples from men. Thirty-seven HPV types were detected, including high-risk oncogenic types and low-risk types. Multivariate logistic regression models were utilized to evaluate factors associated with HPV.

Results

The prevalence of HPV infection was 20.5% in external male genitals and 13.7% in cervical samples. In 504 sexual couples participating in the study, concordance of HPV status was 79%; 34 partners (6.7%) were concurrently infected, and 21 out of 34 partners where both were HPV positive (61.8%) showed concordance for one or more HPV types. The principal risk factor associated with HPV DNA detection in men as well as women was the presence of HPV DNA in the respective regular sexual partner (OR = 5.15, 95%CI 3.01-8.82). In men, having a history of 10 or more sexual partners over their lifetime (OR 2.5, 95%CI 1.3 - 4.8) and having had sexual relations with prostitutes (OR 1.7, 95%CI 1.01 - 2.8) increased the likelihood of detecting HPV DNA.

Conclusions

In heterosexual couples in rural regions in Mexico, the prevalence of HPV infection and type-specific concordance is high. High-risk sexual behaviors are strong determinants of HPV infection in men.
Gorlin syndrome associated with small bowel carcinoma and mesenchymal proliferation of the gastrointestinal tract: case report and review of literature
Authors: Prodinger Peter M , Sarbia Mario , Maßmann Jörg , Straka Christian , Meyer Günther , Steinlein Ortrud K
Published: July 2010

Background and Case Presentation

A patient with nevoid basal cell carcinoma syndrome (Gorlin syndrome) presented with two unusual clinical features, i.e. adenocarcinoma of the small bowel and extensive mesenchymal proliferation of the lower gastrointestinal tract.

Conclusions

We discuss the possibility that these two features are pathogenetically linked to the formerly undescribed patient's PTCH germ line mutation.
Knowledge, attitudes and practices towards pandemic influenza among cases, close contacts, and healthcare workers in tropical Singapore: a cross-sectional survey
Authors: Yap Jonathan , Lee Vernon J , Yau Teng Yan , Ng Tze Pin , Tor Phern-Chern
Published: July 2010

Background

Effective influenza pandemic management requires understanding of the factors influencing behavioral changes. We aim to determine the differences in knowledge, attitudes and practices in various different cohorts and explore the pertinent factors that influenced behavior in tropical Singapore.

Methods

We performed a cross-sectional knowledge, attitudes and practices survey in the Singapore military from mid-August to early-October 2009, among 3054 personnel in four exposure groups - laboratory-confirmed H1N1-2009 cases, close contacts of cases, healthcare workers, and general personnel.

Results

1063 (34.8%) participants responded. The mean age was 21.4 (SE 0.2) years old. Close contacts had the highest knowledge score (71.7%, p = 0.004) while cases had the highest practice scores (58.8%, p < 0.001). There was a strong correlation between knowledge and practice scores (r = 0.27, p < 0.01) and knowledge and attitudes scores (r = 0.21, p < 0.01). The significant predictors of higher practice scores were higher knowledge scores (p < 0.001), Malay ethnicity (p < 0.001), exposure group (p < 0.05) and lower education level (p < 0.05). The significant predictors for higher attitudes scores were Malay ethnicity (p = 0.014) and higher knowledge scores (p < 0.001). The significant predictor for higher knowledge score was being a contact (p = 0.007).

Conclusion

Knowledge is a significant influence on attitudes and practices in a pandemic, and personal experience influences practice behaviors. Efforts should be targeted at educating the general population to improve practices in the current pandemic, as well as for future epidemics.
Coping flexibility in college students with depressive symptoms
Authors: Zong Ji-Gang , Cao Xiao-Yan , Cao Yuan , Shi Yan-Fang , Wang Yu-Na , Yan Chao , Abela John RZ , Gan Yi-Qun , Gong Qi-Yong , Chan Raymond CK
Published: July 2010

Background

The current study explored the prevalence of depressed mood among Chinese undergraduate students and examined the coping patterns and degree of flexibility of flexibility of such patterns associated with such mood.

Methods

A set of questionnaire assessing coping patterns, coping flexibility, and depressive symptoms were administered to 428 students (234 men and 194 women).

Results

A total of 266 participants both completed the entire set of questionnaires and reported a frequency of two or more stressful life events (the criterion needed to calculate variance in perceived controllability). Findings showed that higher levels of depressive symptoms were significantly associated with higher levels of both event frequency (r = .368, p < .001) and event impact (r = .245, p < .001) and lower levels of perceived controllability (r = -.261, p < .001), coping effectiveness (r = -.375, p < .001), and ratio of strategy to situation fit (r = -.108, p < .05). Depressive symptoms were not significantly associated with cognitive flexibility (variance of perceived controllability; r = .031, p = .527), Gender was not a significant moderator of any of the reported associations.

Conclusions

Findings indicate that Chinese university students with depressive symptoms reported experiencing a greater number of negative events than did non-depressed university students. In addition, undergraduates with depressive symptoms were more likely than other undergraduates to utilize maladaptive coping methods. Such findings highlight the potential importance of interventions aimed at helping undergraduate students with a lower coping flexibility develop skills to cope with stressful life events.
Functional expression and intracellular signaling of UTP-sensitive P2Y receptors in theca-interstitial cells
Authors: Vázquez-Cuevas Francisco G , Zárate-Díaz Erika P , Garay Edith , Arellano Rogelio O
Published: July 2010

Background

Purinergic receptors are expressed in the ovary of different species; their physiological roles remain to be elucidated. UTP-sensitive P2Y receptor activity may regulate cell proliferation. The aim of the present work was to study the functional expression of these receptors in theca/interstitial cells (TIC).

Methods

TIC were isolated by centrifugation in a Percoll gradient. P2Y receptors and cellular markers in TIC were detected by RT-PCR and Western blot. Intracellular calcium mobilization induced by purinergic drugs was evaluated by fluorescence microscopy, phosphorylation of MAPK p44/p42 and of cAMP response element binding protein (CREB) was determined by Western blot and proliferation was quantified by [3H]-thymidine incorporation into DNA.

Results

RT-PCR showed expression of p2y2r and p2y6r transcripts, expression of the corresponding proteins was confirmed. UTP and UDP, agonists for P2Y2 and P2Y6 receptors, induced an intracellular calcium increase with a maximum of more than 400% and 200% of basal level, respectively. The response elicited by UTP had an EC50 of 3.5 +/- 1.01 μM, while that for UDP was 3.24 +/- 0.82 μM. To explore components of the pathway activated by these receptors, we evaluated the phosphorylation induced by UTP or UDP of MAPK p44 and p42. It was found that UTP increased MAPK phosphorylation by up to 550% with an EC50 of 3.34 +/- 0.92 and 1.41 +/- 0.67 μM, for p44 and p42, respectively; these increases were blocked by suramin. UDP also induced p44/p42 phosphorylation, but at high concentrations. Phosphorylation of p44/p42 was dependent on PKC and intracellular calcium. To explore possible roles of this pathway in cell physiology, cell proliferation and hCG-induced CREB-phosphorylation assays were performed; results showed that agonists increased cell proliferation and prevented CREB-phosphorylation.

Conclusion

Here, it is shown that UTP-sensitive P2Y receptors are expressed in cultured TIC and that these receptors had the ability to activate mitogenic signaling pathways and to promote cell proliferation, as well as to prevent CREB-phosphorylation by hCG. Regulation of TIC proliferation and steroidogenesis is relevant in ovarian pathophysiology since theca hyperplasia is involved in polycystic ovarian syndrome. Purinergic receptors described might represent an important new set of molecular therapeutic targets.
Development and pilot testing of HEXORR: Hand EXOskeleton Rehabilitation Robot
Authors: Schabowsky Christopher N , Godfrey Sasha B , Holley Rahsaan J , Lum Peter S
Published: July 2010

Background

Following acute therapeutic interventions, the majority of stroke survivors are left with a poorly functioning hemiparetic hand. Rehabilitation robotics has shown promise in providing patients with intensive therapy leading to functional gains. Because of the hand's crucial role in performing activities of daily living, attention to hand therapy has recently increased.

Methods

This paper introduces a newly developed Hand Exoskeleton Rehabilitation Robot (HEXORR). This device has been designed to provide full range of motion (ROM) for all of the hand's digits. The thumb actuator allows for variable thumb plane of motion to incorporate different degrees of extension/flexion and abduction/adduction. Compensation algorithms have been developed to improve the exoskeleton's backdrivability by counteracting gravity, stiction and kinetic friction. We have also designed a force assistance mode that provides extension assistance based on each individual's needs. A pilot study was conducted on 9 unimpaired and 5 chronic stroke subjects to investigate the device's ability to allow physiologically accurate hand movements throughout the full ROM. The study also tested the efficacy of the force assistance mode with the goal of increasing stroke subjects' active ROM while still requiring active extension torque on the part of the subject.

Results

For 12 of the hand digits'15 joints in neurologically normal subjects, there were no significant ROM differences (P > 0.05) between active movements performed inside and outside of HEXORR. Interjoint coordination was examined in the 1stand 3rddigits, and no differences were found between inside and outside of the device (P > 0.05). Stroke subjects were capable of performing free hand movements inside of the exoskeleton and the force assistance mode was successful in increasing active ROM by 43 ± 5% (P < 0.001) and 24 ± 6% (P = 0.041) for the fingers and thumb, respectively.

Conclusions

Our pilot study shows that this device is capable of moving the hand's digits through nearly the entire ROM with physiologically accurate trajectories. Stroke subjects received the device intervention well and device impedance was minimized so that subjects could freely extend and flex their digits inside of HEXORR. Our active force-assisted condition was successful in increasing the subjects' ROM while promoting active participation.
MacroH2A subtypes contribute antagonistically to the transcriptional regulation of the ribosomal cistron during seasonal acclimatization of the carp fish
Authors: Araya I , Nardocci G , Morales JP , Vera MI , Molina A , Alvarez M
Published: July 2010

Background

Incorporation of histone variants into chromatin is one of the epigenetic mechanisms used for regulation of gene expression. Macro (m)H2A is a histone variant that has two different subtypes in vertebrates: mH2A1 and mH2A2. It is known that mH2A is associated with gene silencing, but recent studies indicate that these mH2A subtypes could contribute more widely to transcriptional regulation. We have previously demonstrated that the gene-reprogramming response mediates adaptation of the carp fish to its environment, and that ribosomal gene transcription is seasonally regulated in carp. However, there have been few studies investigating how epigenetic mechanisms contribute to environmental adaptation and, in particular, to ribosomal cistron regulation.

Results

In this paper, we report the occurrence of differential incorporation of mH2A subtypes into chromatin during seasonal adaptation in the carp, an event that concurs with opposing transcriptional states. Moreover, we observed that enrichment of mH2A1 in the ribosomal cistron during winter, and conversely, enrichment of mH2A2 during summer. mH2A1 consistently colocalizes with a heterochromatin marker (H3K27me2; histone H3 trimethylated at lysine 27) and mH2A2 with a euchromatin marker (H3K4me3; histone H3 trimethylated at lysine 4). Similar results were found for the L41gene, with enrichment of mH2A in the promoter region.

Conclusions

We have characterized both mH2A subtypes from carp fish, and evaluated their participation in the regulation of the ribosomal cistron. Our findings indicate that differential incorporation of mH2A subtypes into the ribosome could regulate gene expression during the acclimatization process in carp. Our results reveal differential chromatin incorporation of the mH2A subtypes during the environmental adaptation process, correlating wtih antagonistic transcriptional states in the carp ribosomal cistron.
Early administration of norepinephrine increases cardiac preload and cardiac output in septic patients with life-threatening hypotension
Authors: Hamzaoui Olfa , Georger Jean-François , Monnet Xavier , Ksouri Hatem , Maizel Julien , Richard Christian , Teboul Jean-Louis
Published: July 2010

Introduction

We sought to examine the cardiac consequences of early administration of norepinephrine in severely hypotensive sepsis patients hospitalized in a medical intensive care unit of a university hospital.

Methods

We included 105 septic-shock patients who already had received volume resuscitation. All received norepinephrine early because of life-threatening hypotension and the need to achieve a sufficient perfusion pressure rapidly and to maintain adequate flow. We analyzed the changes in transpulmonary thermodilution variables associated with the increase in mean arterial pressure (MAP) induced by norepinephrine when the achieved MAP was ≥65 mm Hg.

Results

Norepinephrine significantly increased MAP from 54 ± 8 to 76 ± 9 mm Hg, cardiac index (CI) from 3.2 ± 1.0 to 3.6 ± 1.1 L/min/m2, stroke volume index (SVI) from 34 ± 12 to 39 ± 13 ml/m2, global end-diastolic volume index (GEDVI) from 694 ± 148 to 742 ± 168 ml/m2, and cardiac function index (CFI) from 4.7 ± 1.5 to 5.0 ± 1.6 per min. Beneficial hemodynamic effects on CI, SVI, GEDVI, and CFI were observed in the group of 71 patients with a baseline echocardiographic left ventricular ejection fraction (LVEF) >45%, as well as in the group of 34 patients with a baseline LVEF ≤45%. No change in CI, SVI, GEDVI, or CFI was observed in the 17 patients with baseline LVEF ≤45% for whom values of MAP ≥75 mm Hg were achieved with norepinephrine.

Conclusions

Early administration of norepinephrine aimed at rapidly achieving a sufficient perfusion pressure in severely hypotensive septic-shock patients is able to increase cardiac output through an increase in cardiac preload and cardiac contractility. This effect remained in patients with poor cardiac contractility except when values of MAP ≥75 mm Hg were achieved.
A Global Building Inventory for Earthquake Loss Estimation and Risk Management
Authors: Jaiswal Kishor , Wald David , Porter Keith
Published: July 2010

We develop a global database of building inventories using taxonomy of global building types for use in near-real-time post-earthquake loss estimation and pre-earthquake risk analysis, for the U.S. Geological Survey's Prompt Assessment of Global Earthquakes for Response (PAGER) program. The database is available for public use, subject to peer review, scrutiny, and open enhancement. On a country-by-country level, it contains estimates of the distribution of building types categorized by material, lateral force resisting system, and occupancy type (residential or nonresidential, urban or rural). The database draws on and harmonizes numerous sources: (1) UN statistics, (2) UN Habitat's demographic and health survey (DHS) database, (3) national housing censuses, (4) the World Housing Encyclopedia and (5) other literature.
Probabilities of Exceeding Different Limit States for Buildings Subjected to Narrow-Band Ground Motions
Authors: Ruiz Sonia E. , Montiel Marco A. , Arroyo Moisés
Published: July 2010

Non-uniform values of recurrence intervals to seismic failure of structures are shown to occur for different limit states. The median capacity and the capacity and demand factors specified by currently accepted criteria are calculated for a set of 5-, 10-, 15-, and 24-story buildings, built on very soft soil sites and exposed to narrow-band ground motions. Using these values and the demand hazard curves for each structure, the recurrence intervals to failure are obtained for serviceability, life-safety and near-collapse limit states. Based on the results, it is concluded that for the design of structures exposed to the action of narrow-band motions, it may be appropriate to use capacity and demand factors that depend on their fundamental periods of vibration.
The Influence of Geographical Resolution of Urban Exposure Data in an Earthquake Loss Model for Istanbul
Authors: Bal Ihsan Engin , Bommer Julian J. , Stafford Peter J. , Crowley Helen , Pinho Rui
Published: July 2010

Exposure data available to developers of earthquake loss models are often very crudely aggregated spatially, and in such cases very considerable effort can be required to refine the geographical resolution of the building stock inventory. The influence of the geographical resolution of the exposure data for the Sea of Marmara region in Turkey is explored using several different levels of spatial aggregation to estimate the losses due to a single earthquake scenario. The results show that the total damage over an urban area, expressed as a mean damage ratio (MDR), is rather insensitive to the spatial resolution of the exposure data if a sufficiently large number of ground-motion simulations are used. However, the variability of the MDR estimates does reduce as the spatial resolution becomes higher, reducing the number of simulations required, although there appears to be a law of diminishing returns in going to very high exposure data resolution. This is largely due to the inherent and irreducible spatial variability of ground motion, which suggests that if only mean MDR estimates are needed, the effort required to refine the spatial definition of exposure data is not justified.
Cracking an Open Safe: Uncertainty in HAZUS-Based Seismic Vulnerability Functions
Authors: Porter Keith
Published: July 2010

The “cracking an open safe” methodology has been used to tabulate HAZUS-based seismic vulnerability as functions of structure-independent intensity, while avoiding iteration in the structural analysis. The vulnerability functions give mean damage factor (MDF, defined here as mean repair cost as a fraction of replacement cost) versus 5%-damped elastic spectral acceleration response at 0.3-second and 1.0-second periods, for every combination of occupancy type, model building type, design level, magnitude, distance, site soil classification, etc. Like HAZUS-MH, these prior seismic vulnerability functions give no estimate of uncertainty in damage factor. The coefficient of variation (COV) of damage factor is readily calculated by taking advantage of the fact that that at any level of excitation there is a probability mass function of damage state and an implicit distribution of repair cost conditioned on damage state. COV is calculated here for each combination of occupancy type, model building type, etc., tabulated alongside MDF, and the tables presented for public use at www.risk-agora.org . It is found that a HAZUS-based COV generally decreases with increasing MDF (as has been observed using other analytical vulnerability methods), and the standard deviation of damage factor generally increases with increasing MDF.
Modeling Post-Earthquake Functionality of Regional Health Care Facilities
Authors: Yavari Soheil , Chang Stephanie E. , Elwood Kenneth J.
Published: July 2010

This study introduces a methodology for anticipating the post-earthquake functionality of hospitals in a region. Performance levels for interacting systems (structural, nonstructural, lifeline, and personnel) in a hospital are operationally defined, empirically correlated, and probabilistically modeled using damage data from past earthquakes. Separate models are developed for buildings built before and after the 1973 California Hospital Seismic Safety Act. Performance estimates of the systems are used to anticipate overall hospital functionality. Effects of external power and water outage are also included. As a case study, the methodology is utilized to predict the functionality of hospitals in Los Angeles County for two earthquake scenarios. Findings indicate that in a M6.9 Verdugo fault earthquake scenario, nearly half of county hospitals have at least a 50% chance of experiencing significant loss of functionality. Such findings can support emergency response planning as well as seismic retrofit prioritization.
A Ground Motion Scaling Method considering Higher-Mode Effects and Structural Characteristics
Authors: Weng Yuan-Tao , Tsai Keh-Chyuan , Chan Ya-Ran
Published: July 2010

As nonlinear response history analysis (NLRHA) becomes a frequently used procedure for the seismic demand evaluation of multistory buildings, it becomes increasingly important to develop a ground motion scaling method which properly includes the dominating modes in the seismic demand estimates. This paper proposes a multimode ground motion scaling (MMS) method, which applies the square root of the sum of the squares (SRSS) or complete quadratic combination (CQC) rule in computing peak seismic demands. The aim is to minimize the weighted sum of the square differences between the spectral responses of a given ground motion and the design response spectrum for the first few modes. Using four case studies, this paper compares the effectiveness of the MMS method with the other common scaling procedures. It is illustrated that the MMS method is effective in reducing the scatter in the peak seismic demands computed from both the response spectral analysis (RSA) and the NLRHA. Recommendations for selecting the ground motion records for the application of MMS method are also provided.
Developing a Sense of Safety
Authors: SULLIVAN REGINA M.
Published: July 2010

Abstract: Clinical data suggests a strong negative impact of traumatic attachments on adult mental illness, presumably through organizing brain development. To further explore this clinical issue, a mammalian model of imprinting was developed to characterize the neural basis of attachment in both healthy and traumatic attachments. The altricial neonatal rat must learn the mother's odor for nipple attachment, huddling, and orienting to the mother, all of which are required for pup survival. While it appears maladaptive to depend upon learning for attachment, the unique learning system of neonatal pups greatly enhances odor‐preference learning and attachment while pups are confined to the nest. This heightened learning is expressed behaviorally as an enhanced ability to acquire learned odor preferences and a decreased ability to acquire learned odor aversions. Specifically, both odor‐milk and odor‐shock (0.5 mA) conditioning result in odor‐preference acquisition. It appears as though there are at least three brain structures underlying the neonatal rat's sensitive period for heightened odor learning: (1) odor learning is encoded in the olfactory bulb; (2) the hyperfunctioning noradrenergic locus coeruleus (LC) appears to support preference conditioning through release of NE; and (3) the hypofunctioning amygdala appears to underlie pups' difficulty in learning odor aversions. Overall, this suggests that the CNS of altricial infants is specialized for optimizing attachments to their caregiver.
A Mitochondrial Etiology of Neurodegenerative Diseases: Evidence from Parkinson's Disease
Authors: Khusnutdinova Elza , Gilyazova Irina , Ruiz‐Pesini Eduardo , Derbeneva Olga , Khusainova Rita , Khidiyatova Irina , Magzhanov Rim , Wallace Douglas C.
Published: July 2010

Evidence continues to accrue implicating mitochondrial dysfunction in the etiology of a number of neurodegenerative diseases. For example, Parkinson's disease (PD) can be induced by mitochondrial toxins, and nuclear DNA (nDNA) loci linked to PD have been associated with mitochondrial dysfunction. Although conclusions about the role of mitochondrial DNA (mtDNA) variants in PD vary, we argue here that this is attributable to the novel genetics of the mtDNA and the fact that clinically relevant mtDNA variation encompasses ancient adaptive polymorphisms, recent deleterious mutations, and somatic mutations. An mtDNA association with PD is supported by an analysis of the Russian Tatar population which revealed that polymorphisms associated with haplogroup H mtDNAs increased PD risk (odds ratio [OR]= 2.58, P= 0.0001), whereas those associated with haplogroup UK cluster mtDNAs were protective (OR = 0.38, P= 0.003). Moreover, mtDNA sequencing revealed that PD patients with either haplogroup H or UK cluster mtDNAs can harbor additional recent variants that might further modulate PD risk. Therefore, the complexity of PD genetics may reflect the complex mitochondrial genetics.
Oxidative Stress and Energy Crises in Neuronal Dysfunction
Authors: Nicholls David G.
Published: July 2010

Mitochondrial dysfunction is implicated in many forms of cell death, particularly in the central nervous system. The mitochondria are required at the same time to generate adenosine 5′‐triphosphate (ATP) for the cell, sequester excess cytoplasmic Ca2+, and both produce and detoxify superoxide free radicals. The electron transport chain and proton circuit are central in keeping these three balls in the air at the same time. We have investigated the bioenergetics of thein situmitochondria in cultured neurons exposed to pathological glutamate concentrations to model glutamate excitotoxicity and have revised the conventional view that mitochondrial calcium loading results in increased oxidative stress that damages the mitochondrion and ultimately the cell. Instead, a central role is played under these conditions by limitations in mitochondrial and cellular ATP generating capacity. Sodium and calcium entering via theN‐methyl‐d‐aspartate receptor impose a large energetic load on cells and can use the entire respiratory capacity of thein situmitochondria. As a result, even modest restrictions in mitochondrial capacity—caused by low concentrations of electron transport chain inhibitors such as rotenone, as in models of Parkinson's disease; low concentrations of uncouplers, to test the so‐called neuroprotective mild uncoupling hypothesis; or preexisting oxidative stress—greatly potentiate glutamate excitotoxicity. Our findings may lead to a reevaluation of the potential for mild uncoupling to provide a neuroprotective role in aging‐related neurodegenerative disorders because the deleterious consequences of restricting ATP generating capacity greatly outweigh the negligible effects on the levels of mitochondrial superoxide radicals in intact neurons.
Nuclear Control of Respiratory Chain Expression by Nuclear Respiratory Factors and PGC‐1‐Related Coactivator
Authors: Scarpulla Richard C.
Published: July 2010

Expression of the respiratory apparatus depends on both nuclear and mitochondrial genes. Although these genes are sequestered in distinct cellular organelles, their transcription relies on nucleus‐encoded factors. Certain of these factors are directed to the mitochondria, where they sponsor the bi‐directional transcription of mitochondrial DNA. Others act on nuclear genes that encode the majority of the respiratory subunits and many other gene products required for the assembly and function of the respiratory chain. The nuclear respiratory factors, NRF‐1 and NRF‐2, contribute to the expression of respiratory subunits and mitochondrial transcription factors and thus have been implicated in nucleo‐mitochondrial interactions. In addition, coactivators of the PGC‐1 family serve as mediators between the environment and the transcriptional machinery governing mitochondrial biogenesis. One family member, peroxisome proliferator‐activated receptor γ coactivator PGC‐1‐related coactivator (PRC), is an immediate early gene product that is rapidly induced by mitogenic signals in the absence of de novo protein synthesis. Like other PGC‐1 family members, PRC binds NRF‐1 and activates NRF‐1 target genes. In addition, PRC complexes with NRF‐2 and HCF‐1 (host cell factor‐1) in the activation of NRF‐2‐dependent promoters. HCF‐1 functions in cell‐cycle progression and has been identified as an NRF‐2 coactivator. The association of these factors with PRC is suggestive of a role for the complex in cell growth. Finally, shRNA‐mediated knock down of PRC expression results in a complex phenotype that includes the inhibition of respiratory growth on galactose and the loss of respiratory complexes. Thus, PRC may help integrate the expression of the respiratory apparatus with the cell proliferative program.
Brain Glucose Hypometabolism and Oxidative Stress in Preclinical Alzheimer's Disease
Authors: Mosconi Lisa , Pupi Alberto , De Leon Mony J.
Published: July 2010

One of the main features of Alzheimer's disease (AD) is the severe reduction of the cerebral metabolic rate for glucose (CMRglc). In vivo imaging using positron emission tomography with 2‐[18F]fluoro‐2‐deoxy‐D‐glucose (FDG–PET) demonstrates consistent and progressive CMRglc reductions in AD patients, the extent and topography of which correlate with symptom severity. Increasing evidence suggests that CMRglc reductions occur at the preclinical stages of AD. CMRglc reductions were observed on FDG–PET before the onset of disease in several groups of at‐risk individuals, including patients with mild cognitive impairment (MCI), often a prodrome to AD; presymptomatic individuals carrying mutations responsible for early‐onset familial AD; cognitively normal elderly individuals followed for several years until they declined to MCI and eventually to AD; normal, middle‐aged individuals who expressed subjective memory complaints and were carriers of the apolipoprotein E epsilon‐4 allele, a strong genetic risk factor for late‐onset AD. However, the causes of the early metabolic dysfunction forerunning the onset of AD are not known. An increasing body of evidence indicates a deficient or altered energy metabolism that could change the overall oxidative microenvironment for neurons during the pathogenesis and progression of AD, leading to alterations in mitochondrial enzymes and in glucose metabolism in AD brain tissue. The present paper reviews findings that implicate hypometabolism and oxidative stress as crucial players in the initiation and progression of synaptic pathology in AD.
Evidence of Oxidant Damage in Huntington's Disease: Translational Strategies Using Antioxidants
Authors: Stack Edward C. , Matson Wayne R. , Ferrante Robert J.
Published: July 2010

Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder characterized by progressive motor dysfunction, emotional disturbances, dementia, and weight loss. It is caused by an expanded trinucleotide CAG repeat in the gene coding for the protein, huntingtin. Although no one specific interaction of mutant huntingtin has been suggested to be the pathologic trigger, a large body of evidence suggests that, in both the human condition and in HD mice, oxidative stress may play a role in the pathogenesis of HD. Increased levels of oxidative damage products, including protein nitration, lipid peroxidation, DNA oxidation, and exacerbated lipofuscin accumulation, occur in HD. Strong evidence exists for early oxidative stress in HD, coupled with mitochondrial dysfunction, each exacerbating the other and leading to an energy deficit. If oxidative damage plays a role in HD, then therapeutic strategies that reduce reactive oxygen species may ameliorate the neurodegenerative process. Two such strategies, using coenzyme Q10and creatine, have been proposed. Although each agent has had limited efficacy in HD patients, the optimal therapeutic dose may have been underestimated. High‐dose coenzyme Q10and creatine are safe and tolerable in HD patients and are currently under investigation. In addition, there are parallels in reducing markers of oxidative stress in both HD mice and HD patients after treatment. It is likely that high‐dose coenzyme Q10, creatine, or both agents, will represent a cornerstone defense in ameliorating the progression of HD.
Role of the Ubiquitin Conjugation System in the Maintenance of Mitochondrial Homeostasis
Authors: Neutzner Albert , Benard Giovanni , Youle Richard J. , Karbowski Mariusz
Published: July 2010

Mitochondria are essential for a variety of cellular functions, including ATP production, lipid biosynthesis, and calcium homeostasis. Moreover, a number of major cell signaling pathways, including apoptosis, require mitochondria. Consistent with a major role of mitochondria in the control of cell function, defects of these organelles are thought to induce a variety of pathologies ranging from diabetic neuropathies to Parkinson's and Alzheimer's diseases. Here we discuss the role of ubiquitin (Ub) conjugation in the maintenance of mitochondrial function. We found that at least four putative RING finger E3 Ub ligases, the main determinants of substrate specificity in the ubiquitination system, localize to mitochondria. Our data also demonstrate that mitochondrial membrane dynamics is under the regulatory control of the Ub‐conjugation system. These and data recently published by others indicate that the Ub‐conjugation system and proteasomal degradation of mitochondrial proteins might be vital for the maintenance of mitochondrial homeostasis and lead to cell demise when dysfunctional.
Development of Mitochondria‐targeted Aromatic‐cationic Peptides for Neurodegenerative Diseases
Authors: Szeto Hazel H.
Published: July 2010

Mitochondrial impairment and oxidative damage are intimately involved in the pathogenesis of neurodegenerative diseases. Which is the initiating event is probably irrelevant because each can set into motion a self‐sustaining and amplifying feed‐forward cycle between reactive oxygen species (ROS) generation and mitochondrial impairment. Recent approaches to the development of neuroprotective agents have therefore targeted mitochondria protection and/or reduction of oxidative stress. There are several hurdles in the quest for neuroprotective drugs. The difficulties include penetration of the blood–brain barrier and delivery of drugs to mitochondria. Here we describe a novel class of mitochondria‐targeted peptides that can promote mitochondrial function, reduce mitochondrial ROS generation, inhibit mitochondrial permeability transition, and prevent apoptosis and necrosis. These peptides can readily penetrate the blood–brain barrier and have demonstrated efficacy in animal models of Parkinson's disease and amyotrophic lateral sclerosis.