bluuebunny/crossref_metadata_2025 huggingface dataset:
Conjugate Eye Deviation in Acute Intracerebral Hemorrhage
Authors: Sato Shoichiro , Koga Masatoshi , Yamagami Hiroshi , Okuda Satoshi , Okada Yasushi , Kimura Kazumi , Shiokawa Yoshiaki , Nakagawara Jyoji , Furui Eisuke , Hasegawa Yasuhiro , Kario Kazuomi , Arihiro Shoji , Nagatsuka Kazuyuki , Minematsu Kazuo , Toyoda Kazunori
Published: September 2012

Background and Purpose—

Conjugate eye deviation (CED) occurs frequently in patients with acute stroke. The purpose of this study was to elucidate the factors that correlate with CED as well as the relationship between CED and outcomes in patients with acute intracerebral hemorrhage.

Methods—

A total of 211 patients with acute supratentorial intracerebral hemorrhage were recruited in a multicenter, prospective study. CED was assessed with a National Institutes of Health Stroke Scale “best gaze” subscore of ≥1. Hematoma location and volume were assessed on CT.

Results—

Forty-five percent of the patients had CED. On multivariable analysis, right-sided lesion (OR, 2.36; 95% CI, 1.18–4.93), hematoma volume (OR, 1.07; 95% CI, 1.04–1.10 per 1 mL), and baseline Glasgow Coma Scale score (OR, 0.66; 95% CI, 0.53–0.80 per 1 point) were independently associated with CED. After adjusting for sex, age, intraventricular extension of the hematoma, baseline Glasgow Coma Scale score, and hematoma volume, the presence of CED both on admission and 72 hours later was an independent predictor of death or dependency at 3 months poststroke (OR, 5.77; 95% CI, 2.27–16.94). The optimal cutoff volume of hematoma related to CED was ≥13.5 mL for patients with putaminal hemorrhage (sensitivity, 76%; specificity, 72%) and ≥7.7 mL for patients with thalamic hemorrhage (sensitivity, 82%; specificity, 83%).

Conclusions—

The persistence of CED was a significant predictor of death or dependency after acute supratentorial intracerebral hemorrhage even after adjusting for initial severity and hematoma volume. CED can be evoked by a relatively smaller thalamic hematoma than a putaminal hematoma.
Pacific Ocean Contribution to the Asymmetry in Eastern Indian Ocean Variability
Authors: Ummenhofer Caroline C. , Schwarzkopf Franziska U. , Meyers Gary , Behrens Erik , Biastoch Arne , Böning Claus W.
Published: September 2012

Variations in eastern Indian Ocean upper-ocean thermal properties are assessed for the period 1970–2004, with a particular focus on asymmetric features related to opposite phases of Indian Ocean dipole events, using high-resolution ocean model hindcasts. Sensitivity experiments, where interannual atmospheric forcing variability is restricted to the Indian or Pacific Ocean only, support the interpretation of forcing mechanisms for large-scale asymmetric behavior in eastern Indian Ocean variability. Years are classified according to eastern Indian Ocean subsurface heat content (HC) as proxy of thermocline variations. Years characterized by an anomalous low HC feature a zonal gradient in upper-ocean properties near the equator, while high events have a meridional gradient from the tropics into the subtropics. The spatial and temporal characteristics of the seasonal evolution of HC anomalies for the two cases is distinct, as is the relative contribution from Indian Ocean atmospheric forcing versus remote influences from Pacific wind forcing: low events develop rapidly during austral winter/spring in response to Indian Ocean wind forcing associated with an enhanced southeasterly monsoon driving coastal upwelling and a shoaling thermocline in the east; in contrast, formation of an anomalous high eastern Indian Ocean HC is more gradual, with anomalies earlier in the year expanding from the Indonesian Throughflow (ITF) region, initiated by remote Pacific wind forcing, and transmitted through the ITF via coastal wave dynamics. Implications for seasonal predictions arise with high HC events offering extended lead times for predicting thermocline variations and upper-ocean properties across the eastern Indian Ocean.
CMIP3 Subtropical Stratocumulus Cloud Feedback Interpreted through a Mixed-Layer Model
Authors: Caldwell Peter M. , Zhang Yunyan , Klein Stephen A.
Published: September 2012

Large-scale conditions over subtropical marine stratocumulus areas are extracted from global climate models (GCMs) participating in phase 3 of the Coupled Model Intercomparison Project (CMIP3) and used to drive an atmospheric mixed-layer model (MLM) for current and future climate scenarios. Cloud fraction is computed as the fraction of days where GCM forcings produce a cloudy equilibrium MLM state. This model is a good predictor of cloud fraction and its temporal variations on time scales longer than 1 week but overpredicts liquid water path and entrainment.

GCM cloud fraction compares poorly with observations of mean state, variability, and correlation with estimated inversion strength (EIS). MLM cloud fraction driven by these same GCMs, however, agrees well with observations, suggesting that poor GCM low cloud fraction is due to deficiencies in cloud parameterizations rather than large-scale conditions. However, replacing the various GCM cloud parameterizations with a single physics package (the MLM) does not reduce intermodel spread in low-cloud feedback because the MLM is more sensitive than the GCMs to existent intermodel variations in large-scale forcing. This suggests that improving GCM low cloud physics will not by itself reduce intermodel spread in predicted stratocumulus cloud feedback.

Differences in EIS and EIS change between GCMs are found to be a good predictor of current-climate MLM cloud amount and future cloud change. CMIP3 GCMs predict a robust increase of 0.5–1 K in EIS over the next century, resulting in a 2.3%–4.5% increase in MLM cloudiness. If EIS increases are real, subtropical stratocumulus may damp global warming in a way not captured by the GCMs studied.
Dual-Directional Radar Observation for Preliminary Assessment of the Ku-Band Broadband Radar Network
Authors: Yoshikawa Eiichi , Ushio Tomoo , Kawasaki Zen , Chandrasekar V.
Published: September 2012

A short-baseline weather radar network consisting of Ku-band broadband radars (BBR) for meteorological application is under development. The BBR is a short-range and high-resolution Doppler radar for meteorological application, whose range and temporal resolution are several meters and 1 min per volume scan, respectively and coverage is from 50 m to 15 or 20 km. A radar network consisting of BBRs is useful for rapidly and accurately detecting and analyzing small-scale weather phenomena such as localized scattered thunderstorms, tornadoes, and downbursts in locations with a complex topography such as urban or mountainous area. The BBR network project plans to deploy three BBRs in the north Osaka, Japan, area and to observe and analyzing small-scale weather phenomena in detail. At present, two functioning BBRs have been deployed in the Osaka area. This paper presents a description of the BBR network project and its preliminary assessment. Observations of the two-BBR test bed derive expected properties of the three-BBR network, which efficiently covers troposphere in the overlapped area with a minimum observable altitude of tens of meters and a sensitivity of 10.2 dBZ (spatial average at a 5000-km altitude). Integrated reflectivity and preliminary algorithm for multiradar products in the two-BBR test bed, presenting a promising fine structure of precipitation cells, is also shown.
An Upwind-Biased Transport Scheme Using a Quadratic Reconstruction on Spherical Icosahedral Grids
Authors: Miura Hiroaki , Skamarock William C.
Published: September 2012

Several transport schemes developed for spherical icosahedral grids are based on the piecewise linear approximation. The simplest one among them uses an algorithm where the tracer distribution in the upwind side of a cell face is reconstructed using a linear surface. Recently, it was demonstrated that using second- or fourth-order reconstructions instead of the linear one produces better results. The computational cost of the second-order reconstruction method was not much larger than the linear one, while that of the fourth-order one was significantly larger. In this work, the authors propose another second-order reconstruction scheme on the spherical icosahedral grids, motivated by some ideas from the piecewise parabolic method. The second-order profile of a tracer is reconstructed under two constraints: (i) the area integral of the profile is equal to the cell-averaged value times the cell area and (ii) the profile is the least squares fit to the cell-vertex values. The new scheme [the second upwind-biased quadratic approximation (UQA-2)] is more accurate than the preceding second-order reconstruction scheme [the first upwind-biased quadratic approximation (UQA-1)] in most of the tests in this work. Solutions of UQA-2 are sharper than those of UQA-1, although with slightly larger phase errors. The computational cost of UQA-2 is comparable to UQA-1.
Road Safety Education: A Paradoxical State for Children in a Rural Primary School in South Africa
Authors: Joubert Ina JC , Fraser William J , Sentsho Mpoye L
Published: September 2012

The study explores the response of rural primary school children to road safety education programmes. In this qualitative research project, we employed an interpretivist paradigm to investigate and understand children’s responses to road safety education in one school in the Moloto Village, Mpumalanga Province, South Africa. Drawing on various participatory activities done by the child participants, as well as non-participant observation by the researchers through ‘photo voice’, the researchers posit their findings. The key finding is that the children theoretically know what to do when using the road as pedestrians but that they do not apply road safety rules as the community’s unsafe road use behaviour undermines all road safety skills the children have learnt at school. The paradox between what the literature on road safety education prescribes and what the national curriculum of South Africa promotes regarding road safety, and what the children apply in their daily lives, is apparent and noteworthy.
Commonly altered genomic regions in acute myeloid leukemia are enriched for somatic mutations involved in chromatin remodeling and splicing
Authors: Dolnik Anna , Engelmann Julia C. , Scharfenberger-Schmeer Maren , Mauch Julian , Kelkenberg-Schade Sabine , Haldemann Berit , Fries Tamara , Krönke Jan , Kühn Michael W. M. , Paschka Peter , Kayser Sabine , Wolf Stephan , Gaidzik Verena I. , Schlenk Richard F. , Rücker Frank G. , Döhner Hartmut , Lottaz Claudio , Döhner Konstanze , Bullinger Lars
Published: September 2012

Acute myeloid leukemia (AML) is characterized by molecular heterogeneity. As commonly altered genomic regions point to candidate genes involved in leukemogenesis, we used microarray-based comparative genomic hybridization and single nucleotide polymorphism profiling data of 391 AML cases to further narrow down genomic regions of interest. Targeted resequencing of 1000 genes located in the critical regions was performed in a representative cohort of 50 AML samples comprising all major cytogenetic subgroups. We identified 120 missense/nonsense mutations as well as 60 insertions/deletions affecting 73 different genes (∼ 3.6 tumor-specific aberrations/AML). While most of the newly identified alterations were nonrecurrent, we observed an enrichment of mutations affecting genes involved in epigenetic regulation including known candidates like TET2, TET1, DNMT3A, and DNMT1, as well as mutations in the histone methyltransferases NSD1, EZH2, and MLL3. Furthermore, we found mutations in the splicing factor SFPQ and in the nonclassic regulators of mRNA processing CTCF and RAD21. These splicing-related mutations affected 10% of AML patients in a mutually exclusive manner. In conclusion, we could identify a large number of alterations in genes involved in aberrant splicing and epigenetic regulation in genomic regions commonly altered in AML, highlighting their important role in the molecular pathogenesis of AML.
Loss of kindlin-3 alters the threshold for NK cell activation in human leukocyte adhesion deficiency-III
Authors: Gruda Raizy , Brown Alice C. N. , Grabovsky Valentin , Mizrahi Saar , Gur Chamutal , Feigelson Sara W. , Achdout Hagit , Bar-on Yotam , Alon Ronen , Aker Memet , Davis Daniel M. , Mandelboim Ofer
Published: September 2012

Recent evidence suggests that kindlin-3 is a major coactivator, required for most, if not all, integrin activities. Here we studied the function of kindlin-3 in regulating NK cell activation by studying a patient with kindlin-3 deficiency (leukocyte adhesion deficiency-III). We found that kindlin-3 is required for NK cell migration and adhesion under shear force. Surprisingly, we also found that kindlin-3 lowers the threshold for NK cell activation. Loss of kindlin-3 has a pronounced effect on NK cell–mediated cytotoxicity triggered by single activating receptors. In contrast, for activation through multiple receptors, kindlin-3 deficiency is overcome and target cells killed. The realization that NK cell activity is impaired, but not absent in leukocyte adhesion deficiency, may lead to the development of more efficient therapy for this rare disease.
Cytokine activation induces human memory-like NK cells
Authors: Romee Rizwan , Schneider Stephanie E. , Leong Jeffrey W. , Chase Julie M. , Keppel Catherine R. , Sullivan Ryan P. , Cooper Megan A. , Fehniger Todd A.
Published: September 2012

Natural killer (NK) cells are lymphocytes that play an important role in the immune response to infection and malignancy. Recent studies in mice have shown that stimulation of NK cells with cytokines or in the context of a viral infection results in memory-like properties. We hypothesized that human NK cells exhibit such memory-like properties with an enhanced recall response after cytokine preactivation. In the present study, we show that human NK cells preactivated briefly with cytokine combinations including IL-12, IL-15, and IL-18 followed by a 7- to 21-day rest have enhanced IFN-γ production after restimulation with IL-12 + IL-15, IL-12 + IL-18, or K562 leukemia cells. This memory-like phenotype was retained in proliferating NK cells. In CD56dim NK cells, the memory-like IFN-γ response was correlated with the expression of CD94, NKG2A, NKG2C, and CD69 and a lack of CD57 and KIR. Therefore, human NK cells have functional memory-like properties after cytokine activation, which provides a novel rationale for integrating preactivation with combinations of IL-12, IL-15, and IL-18 into NK cell immunotherapy strategies.
IS-seq: a novel high throughput survey of in vivo IS6110 transposition in multiple Mycobacterium tuberculosis genomes
Authors: Reyes Alejandro , Sandoval Andrea , Cubillos-Ruiz Andrés , Varley Katherine E , Hernández-Neuta Ivan , Samper Sofía , Martín Carlos , García María Jesús , Ritacco Viviana , López Lucelly , Robledo Jaime , Zambrano María Mercedes , Mitra Robi D , Del Portillo Patricia
Published: September 2012

Background

The insertion element IS6110 is one of the main sources of genomic variability in Mycobacterium tuberculosis, the etiological agent of human tuberculosis. Although IS 6110 has been used extensively as an epidemiological marker, the identification of the precise chromosomal insertion sites has been limited by technical challenges. Here, we present IS-seq, a novel method that combines high-throughput sequencing using Illumina technology with efficient combinatorial sample multiplexing to simultaneously probe 519 clinical isolates, identifying almost all the flanking regions of the element in a single experiment.

Results

We identified a total of 6,976 IS6110 flanking regions on the different isolates. When validated using reference strains, the method had 100% specificity and 98% positive predictive value. The insertions mapped to both coding and non-coding regions, and in some cases interrupted genes thought to be essential for virulence or in vitro growth. Strains were classified into families using insertion sites, and high agreement with previous studies was observed.

Conclusions

This high-throughput IS-seq method, which can also be used to map insertions in other organisms, extends previous surveys of in vivo interrupted loci and provides a baseline for probing the consequences of disruptions in M. tuberculosis strains.
Genetic variation in hippocampal microRNA expression differences in C57BL/6 J X DBA/2 J (BXD) recombinant inbred mouse strains
Authors: Parsons Michael J , Grimm Christina , Paya-Cano Jose L , Fernandes Cathy , Liu Lin , Philip Vivek M , Chesler Elissa J , Nietfeld Wilfried , Lehrach Hans , Schalkwyk Leonard C
Published: September 2012

Background

miRNAs are short single-stranded non-coding RNAs involved in post-transcriptional gene regulation that play a major role in normal biological functions and diseases. Little is currently known about how expression of miRNAs is regulated. We surveyed variation in miRNA abundance in the hippocampus of mouse inbred strains, allowing us to take a genetic approach to the study of miRNA regulation, which is novel for miRNAs. The BXD recombinant inbred panel is a very well characterized genetic reference panel which allows quantitative trait locus (QTL) analysis of miRNA abundance and detection of correlates in a large store of brain and behavioural phenotypes.

Results

We found five suggestivetransQTLs for the regulation of miRNAs investigated. Further analysis of these QTLs revealed two genes,TnikandPhf17,under themiR-212regulatory QTLs, whose expression levels were significantly correlated with miR-212 expression. We found that miR-212 expression is correlated with cocaine-related behaviour, consistent with a reported role for this miRNA in the control of cocaine consumption. miR-31 is correlated with anxiety and alcohol related behaviours. KEGG pathway analysis of each miRNA’s expression correlates revealed enrichment of pathways including MAP kinase, cancer, long-term potentiation, axonal guidance and WNT signalling.

Conclusions

The BXD reference panel allowed us to establish genetic regulation and characterize biological function of specific miRNAs. QTL analysis enabled detection of genetic loci that regulate the expression of these miRNAs. eQTLs that regulate miRNA abundance are a new mechanism by which genetic variation influences brain and behaviour. Analysis of one of these QTLs revealed a gene,Tnik,which may regulate the expression of a miRNA, a molecular pathway and a behavioural phenotype. Evidence of genetic covariation of miR-212 abundance and cocaine related behaviours is strongly supported by previous functional studies, demonstrating the value of this approach for discovery of new functional roles and downstream processes regulated by miRNA.
Whole transcriptome analysis of a reversible neurodegenerative process in Drosophila reveals potential neuroprotective genes
Authors: Ferreiro María José , Rodríguez-Ezpeleta Naiara , Pérez Coralia , Hackenberg Michael , Aransay Ana María , Barrio Rosa , Cantera Rafael
Published: September 2012

Background

Neurodegenerative diseases are progressive and irreversible and they can be initiated by mutations in specific genes. Spalt-like genes (Sall) encode transcription factors expressed in the central nervous system. In humans, SALL mutations are associated with hereditary syndromes characterized by mental retardation, sensorineural deafness and motoneuron problems, among others. Drosophila sall mutants exhibit severe neurodegeneration of the central nervous system at embryonic stage 16, which surprisingly reverts later in development at embryonic stage 17, suggesting a potential to recover from neurodegeneration. We hypothesize that this recovery is mediated by a reorganization of the transcriptome counteracting SALL lost. To identify genes associated to neurodegeneration and neuroprotection, we used mRNA-Seq to compare the transcriptome of Drosophila sall mutant and wild type embryos from neurodegeneration and reversal stages.

Results

Neurodegeneration stage is associated with transcriptional changes in 220 genes, of which only 5% were already described as relevant for neurodegeneration. Genes related to the groups of Redox, Lifespan/Aging and Mitochondrial diseases are significantly represented at this stage. By contrast, neurodegeneration reversal stage is associated with significant changes in 480 genes, including 424 not previously associated with neuroprotection. Immune response and Salt stress are the most represented groups at this stage.

Conclusions

We identify new genes associated to neurodegeneration and neuroprotection by using an mRNA-Seq approach. The strong homology between Drosophila and human genes raises the possibility to unveil novel genes involved in neurodegeneration and neuroprotection also in humans.
An atypical case of neuronal ceroid lipofuscinosis with co-inheritance of a variably penetrant POLG1mutation
Authors: Staropoli John F , Xin Winnie , Barone Rosemary , Cotman Susan L , Sims Katherine B
Published: September 2012

Background

The neuronal ceroid lipofuscinoses (NCLs, or Batten disease) comprise the most common Mendelian form of childhood-onset neurodegeneration, but the functions of the known underlying gene products remain poorly understood. The clinical heterogeneity of these disorders may shed light on genetic interactors that modify disease onset and progression.

Case presentation

We describe a proband with congenital hypotonia and an atypical form of infantile-onset, biopsy-proven NCL. Pathologic and molecular work-up of this patient identified CLN5 mutations as well as a mutation―previously described as incompletely penetrant or a variant of unknown significance―in POLG1, a nuclear gene essential for maintenance of mitochondrial DNA (mtDNA) copy number. The congenital presentation of this patient is far earlier than that described for either CLN5 patients or affected carriers of the POLG1 variant (c.1550 G > T, p.Gly517Val). Assessment of relative mtDNA copy number and mitochondrial membrane potential in the proband and control subjects suggested a pathogenic effect of the POLG1 change as well as a possible functional interaction with CLN5 mutations.

Conclusions

These findings suggest that an incompletely penetrant variant in POLG1 may modify the clinical phenotype in a case of CLN5 and are consistent with emerging evidence of interactions between NCL-related genes and mitochondrial physiology.
Simultaneous modulation of the intrinsic and extrinsic pathways by simvastatin in mediating prostate cancer cell apoptosis
Authors: Goc Anna , Kochuparambil Samith T , Al-Husein Belal , Al-Azayzih Ahmad , Mohammad Shuaib , Somanath Payaningal R
Published: September 2012

Background

Recent studies suggest the potential benefits of statins as anti-cancer agents. Mechanisms by which statins induce apoptosis in cancer cells are not clear. We previously showed that simvastatin inhibit prostate cancer cell functions and tumor growth. Molecular mechanisms by which simvastatin induce apoptosis in prostate cancer cells is not completely understood.

Methods

Effect of simvastatin on PC3 cell apoptosis was compared with docetaxel using apoptosis, TUNEL and trypan blue viability assays. Protein expression of major candidates of the intrinsic pathway downstream of simvastatin-mediated Akt inactivation was analyzed. Gene arrays and western analysis of PC3 cells and tumor lysates were performed to identify the candidate genes mediating extrinsic apoptosis pathway by simvastatin.

Results

Data indicated that simvastatin inhibited intrinsic cell survival pathway in PC3 cells by enhancing phosphorylation of Bad, reducing the protein expression of Bcl-2, Bcl-xL and cleaved caspases 9/3. Over-expression of PC3 cells with Bcl-2 or DN-caspase 9 did not rescue the simvastatin-induced apoptosis. Simvastatin treatment resulted in increased mRNA and protein expression of molecules such as TNF, Fas-L, Traf1 and cleaved caspase 8, major mediators of intrinsic apoptosis pathway and reduced protein levels of pro-survival genes Lhx4 and Nme5.

Conclusions

Our study provides the first report that simvastatin simultaneously modulates intrinsic and extrinsic pathways in the regulation of prostate cancer cell apoptosis in vitro and in vivo, and render reasonable optimism that statins could become an attractive anti-cancer agent.
Neck/shoulder pain and low back pain among school teachers in China, prevalence and risk factors
Authors: Yue Pengying , Liu Fengying , Li Liping
Published: September 2012

Background

School teachers represent an occupational group among which there appears to be a high prevalence of neck and/or shoulder pain (NSP) and low back pain (LBP). Epidemiological data on NSP and LBP in Chinese teachers are limited. The aim of this study was to investigate the prevalence of and risk factors for NSP and LBP among primary, secondary and high school teachers.

Methods

In a cross-sectional study of teachers from 7 schools, information on participant demographics, work characteristics, occupational factors and musculoskeletal symptoms and pain were collected.

Results

Among 893 teachers, the prevalence of NSP and LBP was 48.7% and 45.6% respectively. There was significant association between the level and prevalence of NSP and LBP among teachers in different schools. The prevalence of NSP among female teachers was much higher than that for males. Self-reported NSP was associated with physical exercise (OR 0.55, 95% CI 0.35 to 0.86), prolonged standing (1.74, 1.03 to 2.95), sitting (1.76, 1.23 to 2.52) and static posture (2.25, 1.56 to 3.24), and uncomfortable back support (1.77, 1.23 to 2.55). LBP was more consistently associated with twisting posture (1.93, 1.30 to 2.87), uncomfortable back support (1.62, 1.13 to 2.32) and prolonged sitting (1.42, 1.00 to 2.02) and static posture (1.60, 1.11 to 2.31).

Conclusions

NSP and LBP are common among teachers. There were strong associations with different individual, ergonomic, and occupational factors.
Quality of life predicts survival in patients with non-small cell lung cancer
Authors: Li Tsai-Chung , Li Chia-Ing , Tseng Chun-Hua , Lin Kuan-Shin , Yang Sing-Yu , Chen Chih-Yi , Hsia Te-Chun , Lee Yih-Dar , Lin Cheng-Chieh
Published: September 2012

Background

Patients with non-small cell lung cancer (NSCLC) have a poor prognosis. The objective of this study was to examine the relationship of EORTC QLQ-C30 and QLQ-LC13 and survival in patients with NSCLC undergoing different treatments.

Methods

Investigators conducted a health-related quality of life (HRQOL) survey of 488 patients with NSCLC: 162 patients undergoing surgery, 312 patients without surgery, and their survival status was prospectively followed up. EORTC QLQ-C30 and QLQ-LC13 scores and clinical variables at baseline were analyzed using Cox’s proportional hazard regression to identify factors that influenced survival.

Results

Median survival of these 474 patients was 9.82 months. After adjustment, emotional functioning scale, and symptom scales of pain and nausea/vomiting are associated with survival in NSCLC patients with surgery whereas social functioning scale, and symptom scales for fatigue, appetite loss, and financial problems had a significant impact on survival in NSCLC patients without surgery. The results of multivariate analysis showed that none of QLQ-LC13 scales are significant predictors of survival. After simultaneously considering these scales, we found significant independent predictors of survival were nausea/vomiting (HR = 0.11, 95% CI = 0.02-0.63 for score >0 compared with =0) in NSCLC patients with surgery and appetite loss (HR = 1.77, 95% CI = 1.26-2.49 for score >0 compared with =0) in NSCLC patients without surgery.

Conclusions

HRQOL provides additional predictive information that supplements traditional clinical factors, and is a new prognostic indicator for survival of NSCLC patients under different treatments.
Production of copolyesters of 3-hydroxybutyrate and medium-chain-length 3-hydroxyalkanoates by E. coli containing an optimized PHA synthase gene
Authors: Gao Xue , Yuan Xiao-Xi , Shi Zhen-Yu , Guo Ying-Ying , Shen Xiao-Wen , Chen Jin-Chun , Wu Qiong , Chen Guo-Qiang
Published: September 2012

Background

Microbial polyhydroxyalkanoates (PHA) are biopolyesters consisting of diverse monomers. PHA synthase PhaC2Ps cloned from Pseudomonas stutzeri 1317 is able to polymerize short-chain-length (scl) 3-hydroxybutyrate (3HB) monomers and medium-chain-length (mcl) 3-hydroxyalkanoates (3HA) with carbon chain lengths ranging from C6 to C12. However, the scl and mcl PHA production in Escherichia coli expressing PhaC2Ps is limited with very low PHA yield.

Results

To improve the production of PHA with a wide range of monomer compositions in E. coli, a series of optimization strategies were applied on the PHA synthase PhaC2Ps. Codon optimization of the gene and mRNA stabilization with a hairpin structure were conducted and the function of the optimized PHA synthase was tested in E. coli. The transcript was more stable after the hairpin structure was introduced, and western blot analysis showed that both codon optimization and hairpin introduction increased the protein expression level. Compared with the wild type PhaC2Ps, the optimized PhaC2Ps increased poly-3-hydroxybutyrate (PHB) production by approximately 16-fold to 30% of the cell dry weight. When grown on dodecanoate, the recombinant E. coli harboring the optimized gene phaC2

Ps

O with a hairpin structure in the 5’ untranslated region was able to synthesize 4-fold more PHA consisting of 3HB and medium-chain-length 3HA compared to the recombinant harboring the wild type phaC2

Ps
.

Conclusions

The levels of both PHB and scl-mcl PHA in E. coli were significantly increased by series of optimization strategies applied on PHA synthase PhaC2Ps. These results indicate that strategies including codon optimization and mRNA stabilization are useful for heterologous PHA synthase expression and therefore enhance PHA production.
An internal deletion in MTH1 enables growth on glucose of pyruvate-decarboxylase negative, non-fermentative Saccharomyces cerevisiae
Authors: Oud Bart , Flores Carmen-Lisset , Gancedo Carlos , Zhang Xiuying , Trueheart Joshua , Daran Jean-Marc , Pronk Jack T , van Maris Antonius JA
Published: September 2012

Background

Pyruvate-decarboxylase negative (Pdc-) strains of Saccharomyces cerevisiae combine the robustness and high glycolytic capacity of this yeast with the absence of alcoholic fermentation. This makes Pdc-
S. cerevisiae an interesting platform for efficient conversion of glucose towards pyruvate-derived products without formation of ethanol as a by-product. However, Pdc- strains cannot grow on high glucose concentrations and require C2-compounds (ethanol or acetate) for growth under conditions with low glucose concentrations, which hitherto has limited application in industry.

Results

Genetic analysis of a Pdc- strain previously evolved to overcome these deficiencies revealed a 225bp in-frame internal deletion in MTH1, encoding a transcriptional regulator involved in glucose sensing. This internal deletion contains a phosphorylation site required for degradation, thereby hypothetically resulting in increased stability of the protein. Reverse engineering of this alternative MTH1 allele into a non-evolved Pdc- strain enabled growth on 20 g l-1 glucose and 0.3% (v/v) ethanol at a maximum specific growth rate (0.24 h-1) similar to that of the evolved Pdc- strain (0.23 h-1). Furthermore, the reverse engineered Pdc- strain grew on glucose as sole carbon source, albeit at a lower specific growth rate (0.10 h-1) than the evolved strain (0.20 h-1). The observation that overexpression of the wild-type MTH1 allele also restored growth of Pdc-
S. cerevisiae on glucose is consistent with the hypothesis that the internal deletion results in decreased degradation of Mth1. Reduced degradation of Mth1 has been shown to result in deregulation of hexose transport. In Pdc- strains, reduced glucose uptake may prevent intracellular accumulation of pyruvate and/or redox problems, while release of glucose repression due to the MTH1 internal deletion may contribute to alleviation of the C2-compound auxotrophy.

Conclusions

In this study we have discovered and characterised a mutation in MTH1 enabling Pdc- strains to grow on glucose as the sole carbon source. This successful example of reverse engineering not only increases the understanding of the glucose tolerance of evolved Pdc-
S. cerevisiae, but also allows introduction of this portable genetic element into various industrial yeast strains, thereby simplifying metabolic engineering strategies.
Coronin 3 promotes gastric cancer metastasis via the up-regulation of MMP-9 and cathepsin K
Authors: Ren Gui , Tian Qifei , An Yanxin , Feng Bin , Lu Yuanyuan , Liang Jie , Li Kai , Shang Yulong , Nie Yongzhan , Wang Xin , Fan Daiming
Published: September 2012

Background

Coronins are a family of highly evolutionary conserved proteins reportedly involved in the regulation of actin cytoskeletal dynamics, although only coronin 3 has been shown to be related to cancer cell migration. In glioblastoma cells, the knockdown of coronin 3 inhibits cell proliferation and invasion. Coronin 3 is also associated with the aggression and metastasis of hepatocellular carcinoma. In this paper, we analyze the migration, invasion and metastasis abilities of gastric cancer cells after up- or down-regulation of coronin 3, and explore the mechanism of coronin 3 in the process of gastric cancer metastasis.

Results

The expression of coronin 3 was higher in the highly metastatic sub-cell line MKN28-M, which we established in our laboratory. We also demonstrated that the expression of coronin 3 was remarkably higher in lymph lode metastases than in primary gastric cancer tissues, and over-expression of coronin 3 was correlated with the increased clinical stage and lymph lode metastasis. Recombinant lentiviral vectors encoding shRNAs were designed to down-regulate coronin 3 expression in gastric cancer cell lines. Stable knockdown of coronin 3 by this lentiviral vector could efficiently inhibit the migration and invasion of MKN45 gastric cancer cells. In contrast, up-regulation of coronin 3 significantly enhanced migration and invasion of MKN28-NM cells. In addition, knockdown of coronin 3 significantly reduced liver metastasis in mice after tail vein injection of gastric cancer cells. The Human Tumor Metastasis PCR Array was used to screen the metastasis-associated genes identified by the down-regulation of coronin 3, and the results suggested that, following the knockdown of coronin 3, the tumor cell migration and invasion were inhibited by the reduced expression of MMP-9 and cathepsin K.

Conclusion

Coronin 3 is highly expressed in gastric cancer metastases and can promote the metastatic behaviors of gastric cancer cells, including their migration and invasion.
Development of a new humanized mouse model to study acute inflammatory arthritis
Authors: Misharin Alexander V , Haines G Kenneth , Rose Shawn , Gierut Angelical K , Hotchkiss Richard S , Perlman Harris
Published: September 2012

Background

Substantial advances have been generated in understanding the pathogenesis of rheumatoid arthritis (RA). Current murine models of RA-like disease have provided great insights into the molecular mechanism of inflammatory arthritis due to the use of genetically deficient or transgenic mice. However, these studies are limited by differences that exist between human and murine immune systems. Thus, the development of an animal model that utilizes human immune cells, will afford the opportunity to study their function in the initiation and propagation of inflammatory arthritis.

Methods

One to two-day old irradiated NOD-scid IL2rγ

null
(NSG) mice were reconstituted with human CD34+ cord blood stem cells. Leukocytes were analyzed by flow cytometry and circulating antibodies were determined by ELISA. Arthritis was induced by injecting complete Freund’s adjuvant into knee or ankle joints. Mice were also treated with the TNF inhibitor, Etanercept, or PBS and joints were analyzed histologically.

Results

Humanized mice were established with high reconstitution rates and were able to spontaneously produce human immunoglobulins as well as specific IgG in response to immunization. Intraperitoneal injection of thioglycolate or injection of complete Freund’s adjuvant into joints resulted in migration of human immune cells to the injected sites. Arthritic humanized mice treated with Etanercept had markedly less inflammation, which was associated with decreased total numbers of human CD45+ cells, including human lymphocytes and neutrophils.

Conclusions

The humanized mouse model is a new model to study inflammatory arthritis disease using human leukocytes without rejection of engrafted tissue. Future studies may adapt this system to incorporate RA patient cord blood and develop a chimeric animal model of inflammatory arthritis using genetically predisposed immune cells.
Anomalous luminescence phenomena of indium-doped ZnO nanostructures grown on Si substrates by the hydrothermal method
Authors: Wang Jen-Cheng , Cheng Fang-Ching , Liang Yu-Ting , Chen Hung-Ing , Tsai Chung-Yuan , Fang Chia-Hui , Nee Tzer-En
Published: September 2012

In recent years, zinc oxide (ZnO) has become one of the most popular research materials due to its unique properties and various applications. ZnO is an intrinsic semiconductor, with a wide bandgap (3.37 eV) and large exciton binding energy (60 meV) making it suitable for many optical applications. In this experiment, the simple hydrothermal method is used to grow indium-doped ZnO nanostructures on a silicon wafer, which are then annealed at different temperatures (400°C to 1,000°C) in an abundant oxygen atmosphere. This study discusses the surface structure and optical characteristic of ZnO nanomaterials. The structure of the ZnO nanostructures is analyzed by X-ray diffraction, the superficial state by scanning electron microscopy, and the optical measurements which are carried out using the temperature-dependent photoluminescence (PL) spectra. In this study, we discuss the broad peak energy of the yellow-orange emission which shows tendency towards a blueshift with the temperature increase in the PL spectra. This differs from other common semiconductors which have an increase in their peak energy of deep-level emission along with measurement temperature.
Development of the excretory system in a polyplacophoran mollusc: stages in metanephridial system development
Authors: Baeumler Natalie , Haszprunar Gerhard , Ruthensteiner Bernhard
Published: September 2012

Background

Two types of excretory systems, protonephridia and metanephridial systems are common among bilaterians. The homology of protonephridia of lophotrochozoan taxa has been widely accepted. In contrast, the homology of metanephridial systems – including coelomic cavities as functional units – among taxa as well as the homology between the two excretory systems is a matter of ongoing discussion. This particularly concerns the molluscan kidneys, which are mostly regarded as being derived convergently to the metanephridia of e.g. annelids because of different ontogenetic origin. A reinvestigation of nephrogenesis in polyplacophorans, which carry many primitive traits within molluscs, could shed light on these questions.

Results

The metanephridial system of Lepidochitona corrugata develops rapidly in the early juvenile phase. It is formed from a coelomic anlage that soon achieves endothelial organization. The pericardium and heart are formed from the central portion of the anlage. The nephridial components are formed by outgrowth from lateral differentiations of the anlage. Simultaneously with formation of the heart, podocytes appear in the atrial wall of the pericardium. In addition, renopericardial ducts, kidneys and efferent nephroducts, all showing downstream ciliation towards the internal lumen, become differentiated (specimen length: 0.62 mm). Further development consists of elongation of the kidney and reinforcement of filtration and reabsorptive structures.

Conclusions

During development and in fully formed condition the metanephridial system of Lepidochitona corrugata shares many detailed traits (cellular and overall organization) with the protonephridia of the same species. Accordingly, we suggest a serial homology of various cell types and between the two excretory systems and the organs as a whole. The formation of the metanephridial system varies significantly within Mollusca, thus the mode of formation cannot be used as a homology criterion. Because of similarities in overall organization, we conclude that the molluscan metanephridial system is homologous with that of the annelids not only at the cellular but also at the organ level.
Sulforaphane prevention of diabetes-induced aortic damage was associated with the up-regulation of Nrf2 and its down-stream antioxidants
Authors: Miao Xiao , Bai Yang , Sun Weixia , Cui Wenpeng , Xin Ying , Wang Yuehui , Tan Yi , Miao Lining , Fu Yaowen , Su Guanfang , Cai Lu
Published: September 2012

Background

Oxidative stress plays an important role in diabetes-induced vascular inflammation and pathogenesis. Nuclear factor E2-related factor-2 (Nrf2) is a transcription factor orchestrating antioxidant and cyto-protective responses to oxidative stress. In the present study, we tested whether sulforaphane (SFN) can protect the aorta from diabetes and, if so, whether the aortic protection is associated with up-regulation of Nrf2 and its down-stream antioxidants.

Methods

Type 1 diabetes was induced in FVB mice by multiple low-dose streptozotocin. Diabetic and age-matched control mice were treated with or without SFN at 0.5 mg/kg daily in five days of each week for three months. At the end of 3 months treatment of SFN one set of mice were sacrificed to perform the experimental measurements. The second set of both diabetic and control mice were aged for additional 3 months without further SFN treatment and then sacrificed to perform the experimental measurements. Aortas from these mice were assessed for fibrosis, inflammation, oxidative damage, and Nrf2 expression and transcription by immunohistochemical staining and real-time PCR method, respectively.

Results

Diabetes induced significant increases in oxidative stress and inflammation in the aorta at both 3 and 6 months, and fibrotic response at 6 months. SFN completely prevented these diabetic pathogenic changes and also significantly up-regulated the expression of Nrf2 and its down-stream antioxidants.

Conclusions

These results suggest that diabetes-induced aortic fibrosis, inflammation, and oxidative damage can be prevented by SFN. The aortic protection from diabetes by SFN was associated with the up-regulation of Nrf2 and its downstream antioxidants.
Impact of different exercise training modalities on the coronary collateral circulation and plaque composition in patients with significant coronary artery disease (EXCITE trial): study protocol for a randomized controlled trial
Authors: Uhlemann Madlen , Adams Volker , Lenk Karsten , Linke Axel , Erbs Sandra , Adam Jennifer , Thiele Holger , Hilberg Thomas , Gutberlet Matthias , Grunze Martin , Schuler Gerhard C , Möbius-Winkler Sven
Published: September 2012

Background

Exercise training (ET) in addition to optimal medical therapy (OMT) in patients with stable coronary artery disease (CAD) has been demonstrated to be superior to percutaneous coronary interventions (PCI) with respect to the composite endpoint of death, myocardial infarction, stroke, revascularization and hospitalization due to worsening of angina. One mechanism leading to this superiority discussed in the literature is the increase in coronary collateral blood flow due to ET. Until now, data demonstrating the positive effect of ET on the collateral blood flow and the functional capacity of the coronary collateral circulation are still lacking.

Methods/design

The EXCITE trial is a three-armed randomized, prospective, single-center, open-label, controlled study enrolling 60 patients with stable CAD and at least one significant coronary stenosis (fractional flow reserve ≤0.75). The study is designed to compare the influence and efficacy of two different 4-week ET programs [high-intensity interval trainings (IT) versus moderate-intensity exercise training (MT) in addition to OMT] versus OMT only on collateral blood flow (CBF). The primary efficacy endpoint is the change of the CBF of the target vessel after 4 weeks as assessed by coronary catheterization with a pressure wire during interruption of the antegrade flow of the target vessel by balloon occlusion. Secondary endpoints include the change in plaque composition as assessed by intravascular ultrasound (IVUS) after 4 weeks, myocardial perfusion as analyzed in MRI after 4 weeks and 12 months, peak oxygen uptake (V02 peak), change in endothelial function and biomarkers after 4 weeks, 3, 6 and 12 months. The safety endpoint addresses major adverse cardiovascular events (death from cardiovascular cause, myocardial infarction, stroke, TIA, target vessel revascularization or hospitalization) after 12 months.

Discussion

The trial investigates whether ET for 4 weeks increases the CBF in patients with significant CAD compared to a sedentary control group. It also examines the impact of two intensities of ET on the CBF as well as the histological plaque composition. The trial started recruitment in June 2009 and will complete recruitment until June 2012. First results are expected in December 2012 (4-week follow-up), final results (12-month long-term secondary endpoint) in December 2013.

Trial registration

Clinical trial registration information-URL: http://www.clinicaltrials.gov.

Unique identifier: NCT01209637
Damage Assessment and Seismic Intensity Analysis of the 2010 (Mw 8.8) Maule Earthquake
Authors: Astroza Maximiliano , Ruiz Sergio , Astroza Rodrigo
Published: September 2012

The MSK-64 seismic intensities inside the damage area of the 2010 Maule earthquake are estimated. With this purpose, field surveys of damage to typical single-family buildings located in 111 cities of the affected area were used. Cities located close to the north part of the earthquake rupture suffered higher damage, but most of this damage concerned adobe and unreinforced masonry houses. Minor and moderate damage was noted in modern low-rise engineered and nonengineered constructions, especially in confined masonry buildings. Despite the large length of the rupture, which reached more than 450 km, only one intensity value equal to IX was determined, and 21% of the values were greater than VII. The attenuation of seismic intensity was controlled by the distance to the main asperity more than to the hypocenter, which would be an important characteristic of the megathrust earthquakes, and it should therefore be considered in the seismic risk of large subduction environments.
Factors that Exacerbated or Reduced Impacts of the 27 February 2010 Chile Tsunami
Authors: Dengler Lori , Araya Sebastian , Graehl Nicholas , Luna Francisco , Nicolini Troy
Published: September 2012

The 27 February 2010 Maule earthquake produced a significant tsunami that caused damage along over 600 kilometers of the Chilean coast. At least 124 of the confirmed 525 deaths were attributed to the tsunami. We examine factors that influenced losses from the tsunami. Chile's Servicio Hidrográfico y Oceanográ–fico de la Armada (SHOA) issued a tsunami warning about 11 minutes after the earthquake that was canceled shortly afterwards. Few coastal residents heard the warning or the cancelation due to widespread power outages, and the official warning had little impact on survival. Interviews with coastal residents showed a high level of awareness of natural tsunami warning signs. Coastal residents cited the importance of school and government education programs, tsunami evacuation drills, signs, the media, and informed local officials in their decision to evacuate. There were two notable failures: the vulnerability of transient populations and people in areas with no access to high ground.