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The spatiotemporal pattern of the spread of pathologically modified tau through brain regions in Alzheimer's disease (AD) can be explained by prion-like cell-to-cell seeding and propagation of misfolded tau aggregates. Hence, to develop targeted therapeutic antibodies, it is important to identify the seeding- and propagation-competent tau species. The hexapeptide [sup.275]VQIIN[K.sup.280] of tau is a critical region for tau aggregation, and K280 is acetylated in various tauopathies, including AD. However, the mechanism that links tau acetylated on lysine 280 (tau-acK280) to subsequent progression to neurodegenerative disease remains unclear. Here, we demonstrate that tau-acK280 is critical for tau propagation processes including secretion, aggregation, and seeding. We developed an antibody, Y01, that specifically targets tau-acK280 and solved the crystal structure of Y01 in complex with an acK280 peptide. The structure confirmed that Y01 directly recognizes acK280 and the surrounding residues. Strikingly, upon interaction with acetylated tau aggregates, Y01 prevented tauopathy progression and increased neuronal viability in neuron cultures and in tau-Tg mice through antibody-mediated neutralization and phagocytosis, respectively. Based on our observations that tau-acK280 is a core species involved in seeding and propagation activities, the Y01 antibody that specifically recognizes acK280 represents a promising therapeutic candidate for AD and other neurodegenerative diseases associated with tauopathy., Introduction Tau, a naturally soluble protein in cells of the central nervous system, promotes microtubule assembly in healthy individuals (1, 2). Hereditary mutations or posttranslational modifications (PTMs) cause soluble tau [...]

In the adult hippocampus, synapses are constantly formed and eliminated.sup.1,2. However, the exact function of synapse elimination in the adult brain, and how it is regulated, are largely unknown. Here we show that astrocytic phagocytosis.sup.3 is important for maintaining proper hippocampal synaptic connectivity and plasticity. By using fluorescent phagocytosis reporters, we find that excitatory and inhibitory synapses are eliminated by glial phagocytosis in the CA1 region of the adult mouse hippocampus. Unexpectedly, we found that astrocytes have a major role in the neuronal activity-dependent elimination of excitatory synapses. Furthermore, mice in which astrocytes lack the phagocytic receptor MEGF10 show a reduction in the elimination of excitatory synapses; as a result, excessive but functionally impaired synapses accumulate. Finally, Megf10-knockout mice show defective long-term synaptic plasticity and impaired formation of hippocampal memories. Together, our data provide strong evidence that astrocytes eliminate unnecessary excitatory synaptic connections in the adult hippocampus through MEGF10, and that this astrocytic function is crucial for maintaining circuit connectivity and thereby supporting cognitive function. In adult mice, astrocytes carry out phagocytosis of excitatory hippocampal synapses through MEGF10 to maintain synaptic and circuit homeostasis., Author(s): Joon-Hyuk Lee [sup.1] , Ji-young Kim [sup.2] [sup.3] , Seulgi Noh [sup.3] [sup.4] , Hyoeun Lee [sup.2] , Se Young Lee [sup.1] , Ji Young Mun [sup.4] , Hyungju [...]

Record-breaking droughts and high temperatures in 2015 across the Pacific Northwest, USA, provide an opportunistic glimpse into potential future thermal regimes of rivers and their implications for freshwater fishes. We applied spatial stream network models to data collected every 30 min for 4 years at 42 sites on the Snoqualmie River (Washington, United States) to compare water temperature patterns, summarized with relevance to particular life stages of native and nonnative fishes, in 2015 with more typical conditions (2012-2014). Although 2015 conditions were drier and warmer than what had been observed since 1960, patterns were neither consistent over the year nor on the network. Some locations showed dramatic increases in air and water temperature, whereas others had temperatures that differed little from typical years; these results contrasted with existing forecasts of future thermal landscapes. If we will observe years like 2015 more frequently in the future, we can expect conditions to be less favorable to native, cool-water fishes such as Chinook salmon (Oncorhynchus tshawytscha) and bull trout (Salvelinus confluentus) but beneficial to warm-water nonnative species such as largemouth bass (Micropterus salmoides). Des secheresses et des temperatures record en 2015 a la grandeur de la region du Pacific Northwest (Etats-Unis) offrent un apercu opportuniste des regimes thermiques futurs potentiels des rivieres et de leurs repercussions sur les poissons d'eau douce. Nous avons applique des modeles spatiaux de reseaux hydrographiques a des donnees recueillies toutes les 30 minutes pendant 4 ans en 42 sites le long de la riviere Snoqualmie (Washington, Etats-Unis) afin de comparer les motifs de temperature de l'eau en 2015, resumes en fonction de differentes etapes des cycles de vie de poissons indigenes et non indigenes, a des conditions plus typiques (2012-2014). Si les conditions de 2015 etaient plus seches et chaudes que ce qui avait ete observe depuis 1960, les motifs n'etaient pas coherents au fil de l'annee ni a l'echelle du reseau. Certains endroits presentaient des augmentations fulgurantes des temperatures de l'air et de l'eau, alors qu'en d'autres endroits, les temperatures differaient peu de celles d'annees typiques; ces resultats different des previsions actuelles concernant les paysages thermiques futurs. Si des annees comme 2015 deviennent plus frequentes a l'avenir, les conditions devraient etre moins favorables aux poissons d'eau froide indigenes comme le saumon chinook (Oncorhynchus tshawytscha) ou l'omble a tete plate (Salvelinus confluentus), mais plus favorables aux especes d'eau chaude non indigenes comme l'achigan a grande bouche (Micropterus salmoides). [Traduit par la Redaction], Introduction Record-breaking droughts and high temperatures observed across the northwestern United States in 2015 provided an opportunistic glimpse into future climates (Marlier et al. 2017). Across the Pacific Northwest, the [...]

Background Clostridioides difficile infection (CDI) is an infectious nosocomial disease caused by Clostridioides difficile, an opportunistic pathogen that occurs in the intestine after extensive antibiotic regimens. Results Nine C. difficile strains (CBA7201-CBA7209) were isolated from nine patients diagnosed with CDI at the national university hospital in Korea, and the whole genomes of these strains were sequenced to identify their genomic characteristics. Comparative genomic analysis was performed using 51 reference strains and the nine isolated herein. Phylogenetic analysis based on 16S rRNA gene sequences confirmed that all 60 C. difficile strains belong to the genus Clostridioides, while core-genome tree indicated that they were divided into five groups, which was consistent with the results of MLST clade analysis. All strains were confirmed to have a clindamycin antibiotic resistance gene, but the other antibiotic resistance genes differ depending on the MLST clade. Interestingly, the six strains belonging to the sequence type 17 among the nine C. difficile strains isolated here exhibited unique genomic characteristics for PaLoc and CdtLoc, the two toxin gene loci identified in this study, and harbored similar antibiotic resistance genes. Conclusion In this study, we identified the specific genomic characteristics of Korean C. difficile strains, which could serve as basic information for CDI prevention and treatment in Korea. Keywords: Clostridioides difficile, Clostridioides difficile infection, Comparative genomics, Pathogenic features, Toxin A and toxin B, Antibiotic resistance gene, Author(s): Seung Woo Ahn[sup.1], Se Hee Lee[sup.1], Uh Jin Kim[sup.2], Hee-Chang Jang[sup.2], Hak-Jong Choi[sup.1], Hyon E. Choy[sup.3], Seung Ji Kang[sup.2] and Seong Woon Roh[sup.1] Background Clostridioides difficile is a major [...]

Nearly a decade on, the debate around the International Criminal Court's issuance of arrest warrants for the Sudanese President Omar Al Bashir remains heated, and the issue of his head of State immunity remains highly controversial. Recent developments, including Jordan's appeal against the Pre-Trial Chamber's finding of non-compliance with its obligations under the Rome Statute, and Kenya's request to the United Nations to refer the immunity question to the International Court of Justice, suggest a possible conclusion to the Al Bashir case in the near future. This article seeks to contribute to the ongoing debate around head of State immunity by interrogating the assumption that the ICC's removal of Al Bashir's immunity would necessarily benefit the development of international criminal law. It argues that under current state of international law, head of State immunity remains inviolable even before international courts. As a consequence, the article contends that the ICC's removal of Al Bashir's immunity, rather than advancing the fight against impunity, may actually do more harm than good for the future of international criminal law, and especially for the continuing legitimacy of the ICC., I INTRODUCTION The International Criminal Court's ('ICC') decision to issue an arrest warrant for the Sudanese President Omar Al Bashir in March 2009 and again in July 2010 elicited significant [...]

Background Lentibacillus species are gram variable aerobic bacteria that live primarily in halophilic environments. Previous reports have shown that bacteria belonging to this species are primarily isolated from salty environments or food. We isolated a bacterial strain CBA3610, identified as a novel species of the genus Lentibacillus, from a human fecal sample. In this report, the whole genome sequence of Lentibacillus sp. CBA3610 is presented, and genomic analyses are performed. Results Complete genome sequence of strain CBA3610 was obtained through PacBio RSII and Illumina HiSeq platforms. The size of genome is 4,035,571 bp and genes estimated to be 4714 coding DNA sequences and 64 tRNA and 17 rRNA were identified. The phylogenetic analysis confirmed that it belongs to the genus Lentibacillus. In addition, there were genes related to antibiotic resistance and virulence, and genes predicted as CRISPR and prophage were also identified. Genes related to osmotic stress were found according to the characteristics of halophilic bacterium. Genomic differences from other Lentibacillus species were also confirmed through comparative genomic analysis. Conclusions Strain CBA3610 is predicted to be a novel candidate species of Lentibacillus through phylogenetic analysis and comparative genomic analysis with other species in the same genus. This strain has antibiotic resistance gene and pathogenic genes. In future, the information derived from the results of several genomic analyses of this strain is thought to be helpful in identifying the relationship between halophilic bacteria and human gut microbiota. Keywords: Lentibacillus sp. CBA3610, Complete genome sequence, Gut microbiota, Halophile, Author(s): Seung Woo Ahn[sup.1], Se Hee Lee[sup.1], Hong-Seok Son[sup.2], Seong Woon Roh[sup.1] and Yoon-E Choi[sup.3] Background Lentibacillus is a gram-variable, aerobic or facultatively anaerobic, and halophilic bacterial genus of the [...]

Since the discovery of myostatin (MSTN; also known as GDF-8) as a critical regulator of skeletal muscle mass in 1997, there has been an extensive effort directed at understanding the cellular and physiological mechanisms underlying MSTN activity, with the long-term goal of developing strategies and agents capable of blocking MSTN signaling to treat patients with muscle loss. Considerable progress has been made in elucidating key components of this regulatory system, and in parallel with this effort has been the development of numerous biologics that have been tested in clinical trials for a wide range of indications, including muscular dystrophy, sporadic inclusion body myositis, spinal muscular atrophy, cachexia, muscle loss due to aging or following falls, obesity, and type 2 diabetes. Here, I review what is known about the MSTN regulatory system and the current state of efforts to target this pathway for clinical applications., Introduction Myostatin (MSTN; also known as GDF-8) is a secreted signaling molecule that was originally identified in a screen for new members of the TGF-[beta] superfamily (1). MSTN's function was [...]

The master cytokine TGF-[beta] mediates tissue fibrosis associated with inflammation and tissue injury. TGF-[beta] induces fibroblast activation and differentiation into myofibroblasts that secrete extracellular matrix proteins. Canonical TGF-[beta] signaling mobilizes Smad2 and Smad3 transcription factors that control fibrosis by promoting gene expression. However, the importance of TGF-[beta]-Smad2/3 signaling in fibroblast-mediated cardiac fibrosis has not been directly evaluated in vivo. Here, we examined pressure overload-induced cardiac fibrosis in fibroblast- and myofibroblast-specific inducible Creexpressing mouse lines with selective deletion of the TGF-[beta] receptors Tgfbr1/2, Smad2, or Smad3. Fibroblast-specific deletion of Tgfbr1/2 or Smad3, but not Smad2, markedly reduced the pressure overload-induced fibrotic response as well as fibrosis mediated by a heart-specific, latency-resistant TGF-[beta] mutant transgene. Interestingly, cardiac fibroblast-specific deletion of Tgfbr1/2, but not Smad2/3, attenuated the cardiac hypertrophic response to pressure overload stimulation. Mechanistically, loss of Smad2/3 from tissue-resident fibroblasts attenuated injury-induced cellular expansion within the heart and the expression of fibrosis-mediating genes. Deletion of Smad2/3 or Tgfbr1/2 from cardiac fibroblasts similarly inhibited the gene program for fibrosis and extracellular matrix remodeling, although deletion of Tgfbr1/2 uniquely altered expression of an array of regulatory genes involved in cardiomyocyte homeostasis and disease compensation. These findings implicate TGF-[beta]Smad2/3 signaling in activated tissue-resident cardiac fibroblasts as principal mediators of the fibrotic response., Introduction Heart failure is an increasingly prevalent disease characterized by reduced cardiac output resulting from a progressive loss of cardiomyocytes, ventricular chamber remodeling, and accumulation of interstitial fibrosis (1). Excessive [...]

Background Anemia is the most common and serious cancer-related complication. This study aimed to evaluate the efficacy of administration of ferric carboxymaltose without erythropoiesis-stimulating agents for treating anemia in cancer patients. Moreover, we identified the biomarkers of hemoglobin response to predict the need for iron therapy. Methods and findings We enrolled patients with solid cancers who were treated at a single institute (Samsung Medical Center, South Korea), from April 2015 to July 2017, in this prospective single-arm Phase II clinical trial. Patients received intravenous ferric carboxymaltose (1,000 mg) infusion on the first day (visit 1) of treatment. The primary end point was the number of hemoglobin responders, defined as patients with an increase in hemoglobin level [greater than or equal to] 1.0 g/dL from the baseline, a hemoglobin level [greater than or equal to] 11.0 g/dL, or both, within an 8-week observation period (week 3, 6, or 8). Secondary end points included changes in transferrin saturation and levels of soluble transferrin receptors, hepcidin, erythropoietin, interleukin-6, and C-reactive protein (CRP) at each visit. Of the 103 recruited patients, 92 were eligible for analysis. The mean patient age was 57.3 ± 12.5 years, and 54.3% of the patients were women. The most common diagnoses were breast cancer (n = 23, 25.1%), lung cancer (n = 21, 22.9%), gastrointestinal cancer (n = 20, 20.9%), and lymphoma (n = 16, 17.7%). A hemoglobin response was observed in 36 (39.1%), 53 (57.6%), and 61 (66.3%) patients in the third, fifth, and eighth weeks, respectively. The mean increase in hemoglobin levels from the baseline to the end of treatment was 1.77 ± 1.30 g/dL. Baseline values of hepcidin (p = 0.008), total iron binding capacity (p = 0.014), ferritin (p = 0.048), and CRP (p = 0.044) were significantly different between the responder and nonresponder groups. Multiple logistic regression analysis for baseline anemia-related biochemical variable significantly associated with the hemoglobin response showed that only baseline hepcidin level was a significant factor for hemoglobin response (odds ratio = 0.95, 95% confidence interval 0.90-1.0, p = 0.045). Hemoglobin responders had significantly lower hepcidin levels than nonresponders (mean [±standard deviation], 13.45 [±14.71] versus 35.22 [±40.470 ng/ml]; p = 0.007). However, our analysis had some limitations such as the different patient characteristics in the studies that were included, institutional differences in the measurement of hepcidin level, and missing data on long-term safety. Therefore, our findings need further validation. Conclusions Intravenous ferric carboxymaltose (1,000 mg) monotherapy increases hemoglobin levels without serious adverse events in patients with cancer. Hepcidin is a useful biomarker for predicting iron requirement in cancer patients. Trial registration Clinicaltrials.gov NCT02599012, Author(s): Jun Ho Jang 1, Youjin Kim 1,2,*, Silvia Park 3,4,*, Kihyun Kim 1, Seok Jin Kim 1, Won Seog Kim 1, Chul Won Jung 1, Jeeyun Lee 1, Se-Hoon [...]

Objective Each supraglottic airway requires different anesthetic depth because it has a specific structure and different compressive force in the oropharyngeal cavity. We designed the study to compare the effect-site concentration (Ce) of remifentanil in 50 % of patients (EC50) for successful insertion of the i-gel second-generation supraglottic airway device with that for laryngeal mask airway (LMA) insertion during target-controlled infusion (TCI) of propofol. Methods Forty-one female patients were randomized to the i-gel group (n = 20) or the LMA group (n = 21). Anesthesia was induced with propofol Ce of 5 [mu]g/ml and the predetermined remifentanil Ce, and the i-gel or LMA was inserted 5 min later. The remifentanil Ce was estimated by modified Dixon's up-and-down method (initial concentration: 3.0 ng/ml, step size: 0.5 ng/ml). The patient's response to device insertion was classified as either 'success (no movement)' or 'failure (movement)'. Results Using the Dixon's up-and-down method, EC50 of remifentanil Ce for the i-gel (1.58 ± 0.41 ng/ml) was significantly lower than that for LMA (2.25 ± 0.55 ng/ml) (p = 0.038). Using isotonic regression, EC50 (83 % CI) of remifentanil in the i-gel group [1.50 (1.37-1.80) ng/ml] was statistically lower than that in the LMA group [2.00 (1.82-2.34) ng/ml]. EC95 (95 % CI) of remifentanil in the i-gel group [2.38 (1.48-2.50) ng/ml] was statistically lower than that in the LMA group [3.35 (2.58-3.48) ng/ml]. Conclusions We found that EC50 of remifentanil Ce for i-gel insertion (1.58 ng/ml) was significantly lower than that for LMA insertion (2.25 ng/ml) in female patients during propofol TCI without neuromuscular blockade., Author(s): Jong Bum Choi[sup.1] , Hyun Jeong Kwak[sup.2] , Kyung Cheon Lee[sup.2] , Se Ryeon Lee[sup.3] , Sook Young Lee[sup.3] , Jong Yeop Kim[sup.3] Author Affiliations: (1) Department of Anesthesiology [...]

Background As a large-scale study of Koreans, we evaluated the association between BRCA mutation and the prevalence of non-breast and ovary cancers in first- and second-degree relatives of high-risk breast cancer patients. Methods We organized familial pedigrees of 2555 patients with breast cancer who underwent genetic screening for BRCA1/2 in Samsung Medical Center between January 2002 and May 2018. Families with a member that had a history of cancer other than of the breast or ovary were regarded positive for other primary cancer. Results The median age of the population was 40 years (range, 19 to 82 years). BRCA mutation was detected in 377 (14.8%) of the patients. The BRCA-positive group had a higher frequency of family history of breast or ovarian cancer (p < 0.001), bilateral breast cancer (p = 0.021), and the male gender (p = 0.038). There were 103 (27.3%) patients who had multiple risk factors in the BRCA-positive group, while there were 165 (7.6%) patients who had multiple risk factors in the BRCA-negative group (p < 0.001). BRCA mutation was detected in 215 (11.7%) of the 1841 families without history of other primary cancers. Among the 714 families with histories of other primary cancers, 162 (22.7%) had BRCA mutation, and this was significantly more frequent (p < 0.001) than in those without a history. The occurrence of other primary cancers in families of high-risk patients was associated with a younger age at diagnosis (p = 0.044), bilateral breast cancer (p = 0.006), and BRCA mutations (p < 0.001). The most common site for the occurrence of another type of primary cancer was the stomach. In the BRCA-positive group, the proportional incidences of stomach, pancreas, colorectal, lung, and uterine cancer were 13.8, 4.0, 7.7, 8.8, and 5.0%, respectively; these were all relatively higher than those in the BRCA-negative group. Conclusions We confirmed that BRCA mutation was associated with having multiple risk factors and an increased prevalence of non-breast and ovary cancers in first- and second-degree relatives of high-risk breast cancer patients. Due to the possibility of inherited cancer risk, genetic counseling with options for risk assessment and management should be provided to both patients and families of BRCA mutation carriers. Keywords: Breast cancer, BRCA mutation, Family history, Genetic counseling, Author(s): Hakyoung Kim[sup.1] , Doo Ho Choi[sup.1] , Won Park[sup.1] , Young-Hyuck Im[sup.2] , Jin Seok Ahn[sup.2] , Yeon Hee Park[sup.2] , Seok Jin Nam[sup.3] , Seok Won Kim[sup.3] , [...]

A complete finite-element analysis method for corona discharge process, which is governed and coupled by charge transport equation and electric field equation, was presented. The charge transport equation of first order was transformed into second order by utilizing the artificial diffusion scheme. The two second-order equations were analyzed by the finite-element formulation which is well-developed for second-order equations. The Fowler-Nordheim injection boundary condition was adopted for charge transport equation. After verifying the numerical results by comparing to the analytic solutions using parallel plane electrodes with one carrier system, we extended the result to blade-plane electrodes in 2-D xy geometry with three carriers system. Radius of the sharp tip was taken to be 50 [micro]m. When this sharp geometry was solved by utilizing the space discretizing methods, the very sharp tip was found to cause a singularity in electric field and space charge distribution around the tip. To avoid these numerical difficulties in the finite-element method, finer meshes, a higher-order shape function, and artificial diffusion scheme were employed. Index Terms--Artificial diffusion, corona discharge, Fowler-Nordheim field emission, hydrodynamic diffusion-drift model, space charge propagation.

Background Recently, urinary exosomal WT1 has been proposed as a novel biomarker for simple podocyte injury. We investigated urinary exosomal WT1 to confirm its role as a non-invasive biomarker for predicting steroid responsiveness or renal pathological conditions in patients with idiopathic nephrotic syndrome (NS). Case Diagnosis Forty children with active NS were recruited. Twenty-eight (70%) were steroid-sensitive, including 3 with minimal change NS (MCNS) and 1 with focal segmental glomerulosclerosis (FSGS). The remaining 12 (30%) were steroid-resistant, including 8 with FSGS and 4 with MCNS. Urinary exosomes were isolated by a differential centrifugation method, and WT1 was measured by Western blot analysis. Results WT1 was detected in 25 patients (62.5%). There was no significant difference in the proportion of the patients with a detectable amount of WT1 according to steroid responsiveness or renal pathological condition, the amount of WT1 showed no significant difference according to steroid responsiveness or renal pathological condition, and there was no significant difference in the amount of proteinuria between patients with or without detectable WT1. Conclusions Urinary exosomal WT1 was detected in some patients with NS. However, its role as an appropriate biomarker in childhood NS was not verified in this study. Keywords Urinary exosome * WT1 * Idiopathic nephrotic syndrome * Biomaker, Introduction Idiopathic nephrotic syndrome (NS) is one of the most common glomerular diseases in children. While NS can be clinically classified as steroid-sensitive (SSNS) and steroid-resistant (SRNS), it can be [...]

ABSTRACT TPA is a potent regulator of cell growth, including cell proliferation and differentiation. In this study, we determined the effect of silibinin on TPA-induced growth arrest in breast cancer [...]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2010.08.022 Byline: Young Jae Lee, Alexandra McPherron, Susan Choe, Yasuo Sakai, Roshantha A. Chandraratna, Se-Jin Lee, S. Paul Oh Keywords: GDF11; ACVR2; CYP26A1; Retinoic acid; Vertebral patterning; RAR inhibitor Abstract: Mice deficient in growth differentiation factor 11 (GDF11) signaling display anterior transformation of axial vertebrae and truncation of caudal vertebrae. However, the in vivo molecular mechanisms by which GDF11 signaling regulates the development of the vertebral column have yet to be determined. We found that Gdf11 and Acvr2b mutants are sensitive to exogenous RA treatment on vertebral specification and caudal vertebral development. We show that diminished expression of Cyp26a1, a retinoic acid inactivating enzyme, and concomitant elevation of retinoic acid activity in the caudal region of Gdf11.sup.-/- embryos may account for this phenomenon. Reduced expression or function of Cyp26a1 enhanced anterior transformation of axial vertebrae in wild-type and Acvr2b mutants. Furthermore, a pan retinoic acid receptor antagonist (AGN193109) could lessen the anterior transformation phenotype and rescue the tail truncation phenotype of Gdf11.sup.-/- mice. Taken together, these results suggest that GDF11 signaling regulates development of caudal vertebrae and is involved in specification of axial vertebrae in part by maintaining Cyp26a1 expression, which represses retinoic acid activity in the caudal region of embryos during the somitogenesis stage. Article History: Received 20 March 2010; Revised 20 August 2010; Accepted 20 August 2010

Byline: Alan F. Hamlet (1,2), Se-Yeun Lee (1), Kristian E. B. Mickelson (3), Marketa M. Elsner (1,2) Abstract: Climate strongly affects energy supply and demand in the Pacific Northwest (PNW) and Washington State (WA). We evaluate potential effects of climate change on the seasonality and annual amount of PNW hydropower production, and on heating and cooling energy demand. Changes in hydropower production are estimated by linking simulated streamflow scenarios produced by a hydrology model to a simulation model of the Columbia River hydro system. Changes in energy demand are assessed using gridded estimates of heating degree days (HDD) and cooling degree days (CDD) which are then combined with population projections to create energy demand indices that respond both to climate, future population, and changes in residential air conditioning market penetration. We find that substantial changes in the amount and seasonality of energy supply and demand in the PNW are likely to occur over the next century in response to warming, precipitation changes, and population growth. By the 2040s hydropower production is projected to increase by 4.7--5.0% in winter, decrease by about 12.1--15.4% in summer, with annual reductions of 2.0--3.4%. Larger decreases of 17.1--20.8% in summer hydropower production are projected for the 2080s. Although the combined effects of population growth and warming are projected to increase heating energy demand overall (22--23% for the 2020s, 35--42% for the 2040s, and 56--74% for the 2080s), warming results in reduced per capita heating demand. Residential cooling energy demand (currently less than one percent of residential demand) increases rapidly (both overall and per capita) to 4.8--9.1% of the total demand by the 2080s due to increasing population, cooling degree days, and air conditioning penetration. Author Affiliation: (1) Department of Civil and Environmental Engineering, University of Washington, Seattle, WA, 98195, USA (2) Center for Science in the Earth System, Climate Impacts Group, University of Washington, Seattle, WA, 98195, USA (3) US Army Corps of Engineers, Seattle District, 4735 E. Marginal Way, Seattle, WA, 98134, USA Article History: Registration Date: 29/03/2010 Received Date: 04/06/2009 Accepted Date: 23/03/2010 Online Date: 05/05/2010

Byline: Marketa M. Elsner (1), Lan Cuo (2), Nathalie Voisin (3), Jeffrey S. Deems (4), Alan F. Hamlet (1,3), Julie A. Vano (3), Kristian E. B. Mickelson (5), Se-Yeun Lee (3), Dennis P. Lettenmaier (1,3) Abstract: Pacific Northwest (PNW) hydrology is particularly sensitive to changes in climate because snowmelt dominates seasonal runoff, and temperature changes impact the rain/snow balance. Based on results from the Fourth Assessment Report of the Intergovernmental Panel on Climate Change (IPCC AR4), we updated previous studies of implications of climate change on PNW hydrology. PNW 21st century hydrology was simulated using 20 Global Climate Models (GCMs) and 2 greenhouse gas emissions scenarios over Washington and the greater Columbia River watershed, with additional focus on the Yakima River watershed and the Puget Sound which are particularly sensitive to climate change. We evaluated projected changes in snow water equivalent (SWE), soil moisture, runoff, and streamflow for A1B and B1 emissions scenarios for the 2020s, 2040s, and 2080s. April 1 SWE is projected to decrease by approximately 38--46% by the 2040s (compared with the mean over water years 1917--2006), based on composite scenarios of B1 and A1B, respectively, which represent average effects of all climate models. In three relatively warm transient watersheds west of the Cascade crest, April 1 SWE is projected to almost completely disappear by the 2080s. By the 2080s, seasonal streamflow timing will shift significantly in both snowmelt dominant and rain--snow mixed watersheds. Annual runoff across the State is projected to increase by 2--3% by the 2040s these changes are mainly driven by projected increases in winter precipitation. Author Affiliation: (1) Center for Science in the Earth System, Climate Impacts Group, University of Washington, Box 355672, Seattle, WA, 98195-5672, USA (2) Australia Commonwealth Scientific and Industrial Research Organization (CSIRO), 37 Graham Road, Highett, VIC, 3190, Australia (3) Department of Civil and Environmental Engineering, University of Washington, Box 352700, Seattle, WA, 98195-2700, USA (4) National Snow and Ice Data Center, 449 UCB University of Colorado, Boulder, CO, 80309-0449, USA (5) US Army Corps of Engineers, Seattle District, P.O. Box 3755, Seattle, WA, 98124-3755, USA Article History: Registration Date: 29/03/2010 Received Date: 04/06/2009 Accepted Date: 23/03/2010 Online Date: 04/05/2010

Anticipated future temperature changes in the mountainous U.S. Pacific Northwest will cause reduced spring snow pack, earlier melt, earlier spring peak flow and lower summer flow in transient rain-snow and snowmelt dominant river basins. In the context of managed flood control, these systematic changes are likely to disrupt the balance between flood control and reservoir refill in existing reservoir systems. To adapt to these hydrologic changes, refill timing and evacuation requirements for flood control need to be modified. This work poses a significant systems engineering problem, especially for large, multiobjective water systems. An existing optimization/ simulation procedure is refined for rebalancing flood control and refill objectives for the Columbia River Basin for anticipated global warming. To calibrate the optimization model for the 20th century flow, the objective function is tuned to reproduce the current reliability of reservoir refill, while providing comparable levels of flood control to those produced by current flood control practices. After the optimization model is calibrated using the 20th century flow the same objective function is used to develop flood control curves for a global warming scenario which assumes an approximately 2[degrees]C increase in air temperature. Robust decreases in system storage deficits are simulated for the climate change scenario when optimized flood rule curves replace the current flood control curves, without increasing monthly flood risks. DOI: 10.1061/(ASCE)0733-9496(2009)135:6(440) CE Database subject headings: Climate changes: Floods: Reservoir operation: Columbia River: Optimization: Simulation: Hydrologic models; Global warming.

Abstract Matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) expression are pivotal steps in cancer metastasis. Herein, we investigated the effect of silibinin, a major constituent (flavanolignan) of the [...]

A novel technique was proposed for evaluating a local heat source in film power capacitors by adopting a minimized analysis model. It is impossible to analyze directly the distributions of heat source in a capacitor element because of tiny scale of aluminum foil and polypropylene film compared to the length of capacitor element. To overcome such a multi-scale problem, here, we proposed a local heat source approximation technique (LHSA) by adopting the time-harmonic analysis of electroquasistatic (EQS) conduction law. To evaluate the dielectric losses in polypropylene film, the complex permittivity was introduced for calculating the effective conductivity subjected to the sinusoidal electric field. These numerical results show that the main heat source originated from the dielectric materials not the metal electrodes in film power capacitors. Finally, the computational fluid dynamic (CFD) solver was adopted by considering the conduction, natural convection, and thermal radiation effects. The results from the proposed method were compared to and were in good agreement with those from the experiments with five sample capacitors of 6600/3800 V, 60 Hz, and 100 kvar. Index Terms--Complex permittivity, computational fluid dynamics (CFD), electroquasistatics (EQS), film power capacitors, local heat source, loss tangent, multi-scale problems, polypropylene films, power dissipation.

In this paper, we present an efficient modeling scheme based on a level set approach for electromagnetic systems including moving parts. The combination of finite elements and the level-set technique allows us to trace the interface variation on a fixed mesh of finite element. It does not require remeshing for the evolving geometry. The material data of moving objects is easily set using the Heaviside function obtained from the level set equation. For the driving force of dynamics equation, the total force on dielectric object is obtained by integrating the body force density of electric charge method. The numerical results of the test model show usefulness of the proposed scheme. Index Terms--Dynamics, finite element modeling, level set method, moving object.

A Compton camera is usually composed of a scatterer detector and an absorber detector. The interaction position resolution of the absorber detector is the critical or limiting detector parameter that most seriously affects the imaging resolution of the table-top Compton camera currently under development in our group. Currently, it is assumed that all interactions occur at the centers of the detector segments of the absorber detector (25-segmented germanium detector), which is a simple but obviously not the best practice, considering that the interaction depths of the photons in the absorber detector, especially of low-energy photons, are not distributed uniformly. More photons have interaction in the front region of the detector due to the limited penetrating depth of the photons. Therefore, the present study developed a novel, 'average interaction depth (AID)' method, which improves the imaging resolution of Compton camera by additionally considering the average interaction depth of the incident photon in the absorber detector. Simulations with Geant4 showed that the imaging resolution of the Compton camera can be significantly improved by using the AID method. For example, the resolution for a 511 keV point source was improved from 9.9 mm to 7.6 mm in full width at half maximum (FWHM). For a 364 keV [gamma] point source, the improvement was even more significant from 11.4 mm to 7.2 mm. Index Terms--Absorber, Compton camera, Geant4, interaction depth.

In this paper, an implementation of virtual work principle in virtual air gap is proposed for the calculation of contact and body forces. To calculate the proper values of the magnetic field at virtual air-gap, we exploit the generalized magnetic source methods. It is shown that appropriately sized virtual elements can be allocated in the virtual air-gap by one-dimensionally extending the virtual gap while keeping the previously calculated field intensity. Both an element's and total forces can be obtained by virtual distortion of the concerned virtual elements. The proposed method provides a good accuracy even when the two contacting objects have the different permeability. As a validation, numerical examples are presented for the force distribution and total force. Index Terms--Body force distribution, force calculation, virtual air gap, virtual element, virtual work principle.

A fully packed capillary electrochromatographic (CEC) microchip showing improved solution and chip handling was developed. Microchannels for the CEC microchip were patterned on a cyclic olefin copolymer substrate by injection molding and packed fully with 0.8-[micro]m monodisperse colloidal silica beads utilizing a self-assembly packing technique. The silica packed chip substrate was covered and thermally press-bonded. After fabrication, the chip was filled with buffer solution by self-priming caprilary action. The self-assembly packing at each channel served as a built-in nanofilter allowing quick loading of samples and running buffer solution without filtration. Because of a large surface area-to-volume ratio of the silica packing, reproducible control of electroosmotic flow was possible without leveling of the solutions in the reservoirs resulting 1.3% rsd in migration rate. The capillary electrophoretic separation characteristics of the chip were studied using fluorescein isothiocyanate (FITC)-derivatized amino acids as probe molecules. A mixture of FITC and four FITC-derivatized amino acids was successfully separated with 2-mm separation channel length.

Three different Kelvin force expressions were expanded by incorporating the virtual air-gap scheme to calculate the total force and the distributions of force density. Conventionally, the Kelvin force density can be expressed by using two different fields such as an external applied field and total field acting on a dipole. Until now, the Kelvin force density with total field (KV) has been used for calculating the total force and force density. Since there is no single well-accepted manipulating technique, it has been difficult to directly compute the Kelvin force by adopting the external field approach; however, using the virtual air-gap scheme, the direct calculation of both Kelvin force density with external applied field (KVE), and with total field (KVT) as the local distributions of body force density was able to be evaluated. We tested three numerical analysis models to verify our proposed method. First, the nonlinear magnetic material was considered and compared the total force with different gap distances to contact position. Second, the distributions of force density were compared to each other. An irregularity aroused in the distributions of force density by the KVE and KVT. Finally, to remove the irregularity, one possible approach, forming sliced-tube regions aligned with the field direction, was suggested and examined. Index Terms--External field, force field, Kelvin force density, total field, virtual air-gap scheme.

Predicting the motion of superparamagnetic iron oxide nanoparticles (SPION) in biological systems is one of the most relevant parameters for the biomedical application of SPION. Recently, magnetic nanoparticles such as SPION have been utilized as the MR image contrast agent, targeted drug delivery, magnetic separation, biosensor, etc. Because the size of SPION is in the nanometer scale, it is difficult to test their dynamics under an external magnetic field experimentally. Moreover, when the SPION moves in a viscous fluid such as blood, the situation can be more complicated. To overcome these difficulties, we proposed a fast-solving technique combined with the finite-element method for analyzing the dynamic characteristics of SPION in a viscous fluid under an external magnetic field. Using this numerical modeling, the effective system dimension, external magnetic field, particle size, and trajectory of SPION can be estimated. To verify the proposed method, three magnetic systems with permanent magnet and micro capillary were tested. Index Terms--Superparamagnetic iron oxide nanoparticles (SPION), targeted drug delivery, trajectory, viscous fluid.

In this paper, the virtual air-gap formulae for electromagnetic forces are derived from the generalized forms of equivalent source methods, such as magnetic charge and magnetizing current. The virtual air-gap approach is based on the idea that insertion of infinitesimally thin air gap causes no real variation of electromagnetic field system. For total force calculation of a magnetic body in contact with other ones of ferromagnetic or permanent magnets, the virtual air-gap formulae can employ the conventional force methods, such as Maxwell stress, magnetic charge, and magnetizing current. The virtual air-gap approach is validated by numerical test results. Index Terms--Force calculation, generalized magnetic charge method, generalized magnetizing current method, virtual air gap.

In this paper, a new, general form of the equivalent magnetizing current method is proposed for calculating the total force of magnetized bodies in contact, including ferromagnetic and permanent magnet. This method is formulated in way similar to the generalized equivalent magnetic charge method. It provides consistent numerical results of force calculation, whether or not one magnetized body is in contact with the other one. The validity of this evaluation method for magnetic forces is shown by close observation of the formulae and numerical test results. Index Terms--Magnetic force, magnetized material, magnetizing current method.

Myostatin is a secreted protein that normally functions as a negative regulator of muscle growth. Agents capable of blocking the myostatin signaling pathway could have important applications for treating human muscle degenerative diseases as well as for enhancing livestock production. Here we describe a potent myostatin inhibitor, a soluble form of the activin type IIB receptor (ACVR2B), which can cause dramatic increases in muscle mass (up to 60% in 2 weeks) when injected into wild-type mice. Furthermore, we show that the effect of the soluble receptor is attenuated but not eliminated in [Mstn.sup.-/-] mice, suggesting that at least one other ligand in addition to myostatin normally functions to limit muscle growth. Finally, we provide genetic evidence that these ligands signal through both activin type II receptors, ACVR2 and ACVR2B, to regulate muscle growth in vivo. myostatin | TGF-[beta]

Increasing complexity of a system-on-chip design demands efficient on-chip interconnection architecture such as on-chip network to overcome limitations of bus architecture. In this brief, we propose a packet-switched on-chip interconnection network architecture, through which multiple processing units of different clock frequencies can communicate with each other without global synchronization. The architecture is analyzed in terms of area and energy consumption, and implementation issues on building blocks are addressed for cost-effective design. A test chip is implemented using 0.38-[micro]m CMOS technology, and measured its operation at 800 MHz to demonstrate its feasibility. Index Terms--Communication architecture, interconnection network, network on chip (NoC), on-chip network (OCN), system on chip (SoC).

To analyze the mechanical dynamic characteristics of electromechanical system, we present a new and fast method using the reduced modeling technique for the levitated conductor. As of now, to solve this electromechanical system, the finite element method (FEM) or the boundary element method (BEM) employing the finite difference time-stepping scheme is used. These approaches, however, need too much solving time because the system matrix equation should be solved at each time step. Additionally, when the operation condition is changed or it needs more incremental steps, the system should be solved from the beginning again. To reduce the solving time, we use the circuit parameters of self- and mutual inductances which are evaluated using the FEM and the conductor segmentation. The formulated ordinary differential equations are solved using the fourth-order Runge--Kutta method. To show validity and usefulness of this proposed method, the TEAM Workshop Problem 28 model is tested, and the results of the experiment and time-stepping FEM are compared to this new method. Index Terms--Eddy current levitation, electromagnetic motional system, extracted circuit parameter, finite element method (FEM), Runge--Kutta method.

The conventional force calculation methods can be applied only for the total force of the objects surrounded by air or vacuum. In this paper, a new general form of equivalent magnetic charge method is proposed for calculating force density and total forces of materials in contact including ferromagnetic and permanent magnet. It provides surface force density on the interface of different materials. The validity of this method is shown by direct observation of the formulas and numerical tests. Index Terms--Force density, magnetic charge method, total force.

Muscle wasting and weakness are the most common disorders found among the children. Myostatin plays an important role in regulating muscle mass in them. Muscle bulk and strength could be therapeutically increased by inactivation of myostatin.

It is demonstrated that split-flow thin (SPLITT) fractionation, a continuous separation technique for sorting particles or macromolecules, can be utilized for the fractionation of environmental particles to study a size-dependent analysis of pollutants. In this study, focuses are made on the use of a pinched inlet gravitational SPLITT fractionation, a modified form of SPLITT channel formed by reducing the sample inlet thickness of the channel to improve separation efficiency, to separate marine sediments into five different sizes (< 1.0, ~1.0 to 2.5, ~2.5 to 5.0, ~5.0 to 10, and ~10 to 53/[micro]m). The resulting size fractions are examined with high resolution gas chromatography/high resolution mass spectrometry to determine the size-dependent distribution of polychlorinated dibenzo-p-dioxins and dibenzofurans along with a statistical data treatment and are analyzed with inductively coupled plasma-atomic emission spectrometry and graphite furnace atomic absorption spectrometry to ascertain its major and trace metals. It is shown that the combined analytical methods detailed in this study can be powerfully utilized in such a way as to analyze pollutant distribution and its concentration with regard to particle sizes for an environmental assessment.

The magnetic charge method is described to determine the magnetic force density due to mechanical deformation for nonlinear magnetic materials. To exhibit validity and usefulness of the proposed method, an axisymmetric actuator and an electromagnet with highly saturated cantilever plate is examined.

A new method of fast solving technique for electro-mechanical motional systems is presented and by using various numerical analysis methods the dynamic characteristics of electro-mechanical systems are analyzed. The results show that the proposed method dramatically reduces the time usually taken to solve the problem using the time stepping method.

A new approach to the finite element open boundary problems using high order boundary sensitivity is presented in order to overcome the shortcomings of Finite Element Method (FEM) boundary truncation error in the open boundary problems. The method is applied to the finite element analysis of air-core magnet to validate the proposed method.

Recently, various micro-or nanometer-scale electromagnetic systems have been being developed. For analysis and design of those systems, precise calculation of electromagnetic field distribution is required especially on some minute local region. When the interesting parts in the system are extremely small compared to the whole region, its geometrical modeling and physical evaluation become a serious problem. In this paper, to resolve this problem, we present a numerical technique of electromagnetic field analysis for minute and fine structures. That is a sequential sub-window technique for closing up local electric field in the small region. The sub-window technique is on the basis of the finite element method and the outer boundary condition. To show the usefulness of the proposed algorithm, we tested it through two numerical models with exact analytic solutions. Their results showed the validity of the sub-window zooming-in technique. It was also applied to a real model of ferroelectric thin film recording by scanning probe microscopy. Index Terms--Finite element method, nanometer-scale, sub-window, zooming-in.

Myostatin is a transforming growth factor [beta] family member that acts as a negative regulator of skeletal muscle growth. Myostatin circulates in the blood of adult mice in a noncovalently held complex with other proteins, including its propeptide, which maintain the C-terminal dimer in a latent, inactive state. This latent form of myostatin can be activated in vitro by treatment with acid; however, the mechanisms by which latent myostatin is activated in vivo are unknown. Here, we show that members of the bone morphogenetic protein-1/tolloid (BMP-1/TLD) family of metal-loproteinases can cleave the myostatin propeptide in this complex and can thereby activate latent myostatin. Furthermore, we show that a mutant form of the propeptide resistant to cleavage by BMP-1/TLD proteinases can cause significant increases in muscle mass when injected into adult mice. These findings raise the possibility that members of the BMP-1/TLD family may be involved in activating latent myostatin in vivo and that molecules capable of inhibiting these proteinases may be effective agents for increasing muscle mass for both human therapeutic and agricultural applications.

Laterally driven microresonators were used to estimate the temperature-dependent elastic modulus of single-crystalline Si for microelectromechanical systems (MEMS). The resonators were fabricated through surface micromachining from silicon-on-glass wafers. They were moved laterally by alternating electrostatic force at a series of frequencies, and then a resonance frequency was determined, under temperature cycling in the range of 25 [degrees]C to 600 [degrees]C, by detecting the maximum displacement. The elastic modulus was obtained at the temperature range by Rayleigh's energy method from the detected resonance frequency. At this time, the temperature dependency of elastic modulus was affected by surface oxidation as well as its intrinsic variation: a temperature cycle permanently reduces the resonance frequency. The effect of Si oxidation was analyzed for thermal cycling by applying a simple composite model to the measured frequency data; here the oxide thickness was estimated from the difference in the resonance frequency before and after the temperature cycle, and was confirmed by field-emission scanning electron microscopy. Finally, the temperature coefficient of the elastic modulus of Si in the direction was determined as -64 x [10.sup.-6][[degrees]C.sup.-1]]. This value was quite comparable to those reported in previous literatures, and much more so if the specimen temperature is calibrated more exactly. [892] Index Terms--Elastic modulus, microelectromechanical system (MEMS), oxidation, resonance frequency, single-crystalline Si, temperature effect.

Growth/differentiation factor 11 (Gdf11) is a transforming growth factor [beta] family member previously shown to control anterior/posterior patterning of the axial skeleton. We now report that Gdf11 also regulates kidney organogenesis. Mice carrying a targeted deletion of Gdf11 possess a spectrum of renal abnormalities with the majority of mutant animals lacking both kidneys. Histological analysis revealed a failure in ureteric bud formation at the initial stage of metanephric development in most Gdfll mutant embryos examined. The metanephric mesenchyme of mutant embryos lacking a ureteric bud was found to be defective in the expression of glial cell line-derived neurotrophic factor (Gdnf), a gene known to direct ureteric bud outgrowth. The addition of Gdnf protein to urogenital tracts taken from Gdfll null embryos induced ectopic ureteric bud formation along the Wolffian duct. Our studies suggest that Gdf11 may be important in directing the initial outgrowth of the ureteric bud from the Wolffian duct by controlling the expression of Gdnf in the metanephric mesenchyme. Keywords: Gdf11' Gdnf; Kidney organogenesis; Metanephric development; Ureteric bud

A design technique is described for dealing with magnetic force distributions in 2-D linear magnetic systems.

This paper presents a generalized sensitivity formula that is applicable to any objective function of the optimization problems in two-dimensional (2-D) linear magnetostatic systems. For the objective function defined on an interface boundary as well as in a region, the shape design sensitivity expression is derived in a closed form from the augmented Lagrangian method, the material derivative concept and the adjoint variable method. The resultant sensitivity formula is expressed as a line integral along the interface boundary undergoing shape modification. Three shape design problems, whose objective functions are defined on an interface boundary or in a region, are tested to validate the derived sensitivity formula. Index Terms--Adjoint variable method, augmented Lagrangian method, continuum approach, design sensitivity analysis, magnetostatic system, shape optimization.

A number of electromagnetic devices periodically driven by solid-state switches have been analyzed with time-stepping finite element method, which requires much time to reach a steady state. The sensitivity analysis which have been used for the shape design is employed for an efficient analysis of linear magnetodynamics with nonsinusoidal driving sources. The high-order frequency sensitivity from the time-harmonic finite element formulation is used along with Fourier transform and Taylor series expansion. The algorithm is validated through two numerical examples of a single-phase transformer and an induction heating system driven by a trapezoidal voltage source. Index terms - Nonsinusoidal steady state analysis, time-harmonic FEM, high-order frequency sensitivity, linear magnetodynamics, Fourier transform, Taylor series

Myostatin (GDF-8) is a member of the transforming growth factor [Beta] superfamily of secreted growth and differentiation factors that is essential for proper regulation of skeletal muscle mass in mice. Here we report the myostatin sequences of nine other vertebrate species and the identification of mutations in the coding sequence of bovine myostatin in two breeds of double-muscled cattle, Belgian Blue and Piedmontese, which are known to have an increase in muscle mass relative to conventional cattle. The Belgian Blue myostatin sequence contains an 11-nucleotide deletion in the third exon which causes a frameshift that eliminates virtually all of the mature, active region of the molecule. The Piedmontese myostatin sequence contains a missense mutation in exon 3, resulting in a substitution of tyrosine for an invariant cysteine in the mature region of the protein. The similarity in phenotypes of double-muscled cattle and myostatin null mice suggests that myostatin performs the same biological function in these two species and is a potentially useful target for genetic manipulation in other farm animals.

Growth/differentiation factor-8 (GDF-8), a new murine TGF-beta family member, has been identified by using degenerate polymerase chain reaction. This is expressed only in developing and adult skeletal muscle. Research based on gene targeting in mice indicates that GDF-8 acts specifically as a negative regulator of skeletal muscle growth. In particular, loss of GDF-8 function produces a significant increase in skeletal muscle mass.