bluuebunny/crossref_metadata_2025 huggingface dataset:
The Francisella tularensis LVS ΔpdpCmutant exhibits a unique phenotype during intracellular infection
Authors: Lindgren Marie , Bröms Jeanette E , Meyer Lena , Golovliov Igor , Sjöstedt Anders
Published: January 2013

Background

A prerequisite for the virulence of the facultative intracellular bacterium Francisella tularensis is effective intramacrophage proliferation, which is preceded by phagosomal escape into the cytosol, and ultimately leads to host cell death. Many components essential for the intracellular life cycle are encoded by a gene cluster, the Francisella pathogenicity island (FPI), constituting a type VI secretion system.

Results

We characterized the FPI mutant ΔpdpC of the live vaccine strain (LVS) of F. tularensis and found that it exhibited lack of intracellular replication, incomplete phagosomal escape, and marked attenuation in the mouse model, however, unlike a phagosomally contained FPI mutant, it triggered secretion of IL-1β, albeit lower than LVS, and markedly induced LDH release.

Conclusions

The phenotype of the ΔpdpC mutant appears to be unique compared to previously described F. tularensis FPI mutants.
Is the processing of affective prosody influenced by spatial attention? an ERP study
Authors: Gädeke Julia C , Föcker Julia , Röder Brigitte
Published: January 2013

Background

The present study asked whether the processing of affective prosody is modulated by spatial attention. Pseudo-words with a neutral, happy, threatening, and fearful prosody were presented at two spatial positions. Participants attended to one position in order to detect infrequent targets. Emotional prosody was task irrelevant. The electro-encephalogram (EEG) was recorded to assess processing differences as a function of spatial attention and emotional valence.

Results

Event-related potentials (ERPs) differed as a function of emotional prosody both when attended and when unattended. While emotional prosody effects interacted with effects of spatial attention at early processing levels (< 200 ms), these effects were additive at later processing stages (> 200 ms).

Conclusions

Emotional prosody, therefore, seems to be partially processed outside the focus of spatial attention. Whereas at early sensory processing stages spatial attention modulates the degree of emotional voice processing as a function of emotional valence, emotional prosody is processed outside of the focus of spatial attention at later processing stages.
Introduction of the AmpliChip CYP450 Test to a South African cohort: a platform comparative prospective cohort study
Authors: Dodgen Tyren M , Hochfeld Warren E , Fickl Heidi , Asfaha Sahle M , Durandt Chrisna , Rheeder Paul , Drögemöller Britt I , Wright Galen E B , Warnich Louise , Labuschagne Christiaan DJ , van Schalkwyk Antoinette , Gaedigk Andrea , Pepper Michael S
Published: January 2013

Background

Adverse drug reactions and lack of therapeutic efficacy associated with currently prescribed pharmacotherapeutics may be attributed, in part, to inter-individual variability in drug metabolism. Studies on the pharmacogenetics of Cytochrome P450 (CYP) enzymes offer insight into this variability. The objective of this study was to compare the AmpliChip CYP450 Test® (AmpliChip) to alternative genotyping platforms for phenotype prediction of CYP2C19 and CYP2D6 in a representative cohort of the South African population.

Methods

AmpliChip was used to screen for thirty-three CYP2D6 and three CYP2C19 alleles in two different cohorts. As a comparison cohort 2 was then genotyped using a CYP2D6 specific long range PCR with sequencing (CYP2D6 XL-PCR + Sequencing) platform and a PCR-RFLP platform for seven CYP2C19 alleles.

Results

Even though there was a low success rate for the AmpliChip, allele frequencies for both CYP2D6 and CYP2C19 were very similar between the two different cohorts. The CYP2D6 XL-PCR + Sequencing platform detected CYP2D6*5 more reliably and could correctly distinguish between CYP2D6*2 and *41 in the Black African individuals. Alleles not covered by the AmpliChip were identified and four novel CYP2D6 alleles were also detected. CYP2C19 PCR-RFLP identified CYP2C19*9,*15, *17 and *27 in the Black African individuals, with *2, *17 and *27 being relatively frequent in the cohort. Eliminating mismatches and identifying additional alleles will contribute to improving phenotype prediction for both enzymes. Phenotype prediction differed between platforms for both genes.

Conclusion

Comprehensive genotyping of CYP2D6 and CYP2C19 with the platforms used in this study, would be more appropriate than AmpliChip for phenotypic prediction in the South African population. Pharmacogenetically important novel alleles may remain undiscovered when using assays that are designed according to Caucasian specific variation, unless alternate strategies are utilised.
Chromosomal evolution of Escherichia coli for the efficient production of lycopene
Authors: Chen Yun-Yan , Shen Hong-Jie , Cui Yan-Yan , Chen Shang-Guang , Weng Zhi-Ming , Zhao Ming , Liu Jian-Zhong
Published: January 2013

Background

Plasmid-based overexpression of genes has been the principal strategy for metabolic engineering. However, for biotechnological applications, plasmid-based expression systems are not suitable because of genetic instability, and the requirement for constant selective pressure to ensure plasmid maintenance.

Results

To overcome these drawbacks, we constructed an Escherichia coli lycopene production strain that does not carry a plasmid or an antibiotic marker. This was achieved using triclosan-induced chromosomal evolution, a high gene copy expression system. The engineered strain demonstrated high genetic stability in the absence of the selective agent during fermentation. The replacement of native appY promoter with a T5 promoter, and the deletion of the iclR gene in E. coli CBW 12241 further improved lycopene production. The resulting strain, E. coli CBW 12241(Δ
iclR, PT5-appY), produced lycopene at 33.43 mg per gram of dry cell weight.

Conclusions

A lycopene hyper-producer E. coli strain that does not carry a plasmid or antibiotic marker was constructed using triclosan-induced chromosomal evolution. The methods detailed in this study can be used to engineer E. coli to produce other metabolites.
Expression of glioma-associated oncogene 2 (Gli 2) is correlated with poor prognosis in patients with hepatocellular carcinoma undergoing hepatectomy
Authors: Zhang Dawei , Cao Liangqi , Li Yue , Lu Haiwu , Yang Xuewei , Xue Ping
Published: January 2013

Background

Our previous studies showed that glioma-associated oncogene (Gli)2 plays an important role in the proliferation and apoptosis resistance of hepatocellular carcinoma (HCC) cells. The aim of this study was to explore the clinical significance of Gli2 expression in HCC.

Methods

Expression of Gli2 protein was detected in samples from 68 paired HCC samples, the corresponding paraneoplastic liver tissues, and 20 normal liver tissues using immunohistochemistry. Correlation of the immunohistochemistry results with clinicopathologic parameters, prognosis, and the expression of E-cadherin, N-cadherin, and vimentin were analyzed.

Results

Immunohistochemical staining showed high levels of Gli2 protein expression in HCC, compared with paraneoplastic and normal liver tissues (P < 0.05). This high expression level of Gli2 was significantly associated with tumor differentiation, encapsulation, vascular invasion, early recurrence, and intra-hepatic metastasis (P < 0.05). There was a significantly negative correlation between Gli2 and E-cadherin expression (r = −0.302, P < 0.05) and a significantly positive correlation between expression of Gli2 and expression of vimentin (r = −0.468, P < 0.05) and N-cadherin (r = −0.505, P < 0.05). Kaplan-Meier analysis showed that patients with overexpressed Gli2 had significantly shorter overall survival and disease-free survival times (P < 0.05). Multivariate analysis suggested that the level of Gli2 expression was an independent prognostic factor for HCC.

Conclusions

Expression of Gli2 is high in HCC tissue, and is associated with poor prognosis in patients with HCC after hepatectomy.
Berberine protects human renal proximal tubular cells from hypoxia/reoxygenation injury via inhibiting endoplasmic reticulum and mitochondrial stress pathways
Authors: Yu Wenli , Sheng Mingwei , Xu Rubin , Yu Jianjian , Cui Kang , Tong Jingkai , Shi Liying , Ren Hengchang , Du Hongyin
Published: January 2013

Background

Ischemia/reperfusion injury plays a crucial role in renal transplantation, and represents a significant risk factor for acute renal failure and delayed graft function. The pathophysiological contribution of endoplasmic reticulum and mitochondria stress to ischemia/reperfusion injury has also been highlighted. Berberine (BBR) has been showed to attenuate ischemia/reperfusion injury by inhibiting oxidative stress. The study was carried out to investigate whether the pretreatment of BBR could reduce hypoxia/reoxygenation (H/R)-induced injury by inhibiting mitochondria stress and endoplasmic reticulum stress pathways.

Methods

The cultured human renal proximal tubular cell line HK-2 cells were exposed to 24 h hypoxia (5% CO2, 1% O2, 94% N2) followed by 3 h reoxygenation (5% CO2, 21% O2, 74% N2). And BBR was added to the culture medium 2h prior to the treatment. Then the cell viability, oxidative stress level, morphological change of apoptosis and apoptotic rate were determined. In addition, Western blot analysis was performed to identify the expression of apoptotic pathway parameters, including Bcl-2, Bax and cytochrome C involved in mitochondrial-dependent pathway and ER stress hallmarks such as glucose-regulated protein 78 and CCAAT/enhancer binding protein homologous protein.

Results

H/R produced dramatic injuries in HK-2 cells. The cell viability and the oxidative stress level in group H/R was significantly decreased. The classical morphological change of apoptosis was found, while the apoptotic rate and the expression of proteins involved in mitochondrial stress and endoplasmic reticulum stress pathways increased (p<0.05). Administration of BBR significantly inhibited these H/R induced changes (p<0.05).

Conclusion

This study revealed that BBR pretreatment serves a protective role against H/R induced apoptosis of human renal proximal tubular cells, and the mechanism is related to suppression of mitochondrial stress and endoplasmic reticulum stress pathways.
Performance evaluation of reverse osmosis technology for selected antibiotics removal from synthetic pharmaceutical wastewater
Authors: Gholami Mitra , Mirzaei Roya , Kalantary Roshanak Rezaei , Sabzali Ahmad , Gatei Fateme
Published: January 2013

This study addresses the possibility for low pressure reverse osmosis membrane (RE 2521, CSM) process to serve as an alternative to remove selected antibiotics (ampicillin and amoxicillin) from synthetic wastewater by changing operating conditions such as pH = 3, 6.5 and 10; Pressure = 9, 11 and13 (bar); antibiotic concentration = 10, 255 and 500(mg/L), and temperature = 20, 30 and 40°C. The experiment was designed based on Box-benken, which is a Response Surface methodology design (RSM), using Design Expert software. The concentration of antibiotics was measured by applying a UV-spectrophotometer (Cecil), at the wavelength of 254 nm. Results showed a range of rejection percentage from 73.52% to 99.36% and 75.1% to 98.8%, for amoxicillin and ampicillin, respectively. Considering the solute rejections and the membrane porosity show that the prevailing rejection mechanism of the examined antibiotics by the membrane was the size exclusion effect. The permeate flux for both of the antibiotics was 12–18.73 L/m2.h. Although the permeate flux and antibiotic rejection are influenced by operating pressure, pH, and temperature individually, the interaction between operating parameters did not have noticeable effects. According to the results obtained in this study, the application of RO membrane is recommended for the selected antibiotics to be removed to a considerable degree (up to 95%).
HDAC6 as a target for neurodegenerative diseases: what makes it different from the other HDACs?
Authors: Simões-Pires Claudia , Zwick Vincent , Nurisso Alessandra , Schenker Esther , Carrupt Pierre-Alain , Cuendet Muriel
Published: January 2013

Histone deacetylase (HDAC) inhibitors have been demonstrated to be beneficial in animal models of neurodegenerative diseases. Such results were mainly associated with the epigenetic modulation caused by HDACs, especially those from class I, via chromatin deacetylation. However, other mechanisms may contribute to the neuroprotective effect of HDAC inhibitors, since each HDAC may present distinct specific functions within the neurodegenerative cascades. Such an example is HDAC6 for which the role in neurodegeneration has been partially elucidated so far. The strategy to be adopted in promising therapeutics targeting HDAC6 is still controversial. Specific inhibitors exert neuroprotection by increasing the acetylation levels of α-tubulin with subsequent improvement of the axonal transport, which is usually impaired in neurodegenerative disorders. On the other hand, an induction of HDAC6 would theoretically contribute to the degradation of protein aggregates which characterize various neurodegenerative disorders, including Alzheimer’s, Parkinson’s and Hutington’s diseases. This review describes the specific role of HDAC6 compared to the other HDACs in the context of neurodegeneration, by collecting in silico, in vitro and in vivo results regarding the inhibition and/or knockdown of HDAC6 and other HDACs. Moreover, structure, function, subcellular localization, as well as the level of HDAC6 expression within brain regions are reviewed and compared to the other HDAC isoforms. In various neurodegenerative diseases, the mechanisms underlying HDAC6 interaction with other proteins seem to be a promising approach in understanding the modulation of HDAC6 activity.
Experiences with AR plots: design issues and recommendations for augmented reality based mobile games
Authors: Dixon Dan , Kiani Saad Liaquat , Ikram Ahsan
Published: January 2013

Digital games have the potential for changing attitudes towards social issues such as climate change and sustainability. This paper presents the experience of developing a prototype locative game with an augmented reality interface that is designed to fit in with the fractured nature of travel time on public transport. We discuss the technical challenges, usability issues and game design approaches used to work within these constraints.
Gene expression profiling of early intervertebral disc degeneration reveals a down-regulation of canonical Wnt signaling and caveolin-1 expression: implications for development of regenerative strategies
Authors: Smolders Lucas A , Meij Björn P , Onis David , Riemers Frank M , Bergknut Niklas , Wubbolts Richard , Grinwis Guy CM , Houweling Martin , Groot Koerkamp Marian JA , van Leenen Dik , Holstege Frank CP , Hazewinkel Herman AW , Creemers Laura B , Penning Louis C , Tryfonidou Marianna A
Published: January 2013

Introduction

Early degeneration of the intervertebral disc (IVD) involves a change in cellular differentiation from notochordal cells (NCs) in the nucleus pulposus (NP) to chondrocyte-like cells (CLCs). The purpose of this study was to investigate the gene expression profiles involved in this process using NP tissue from non-chondrodystrophic and chondrodystrophic dogs, a species with naturally occurring IVD degeneration.

Methods

Dual channel DNA microarrays were used to compare 1) healthy NP tissue containing only NCs (NC-rich), 2) NP tissue with a mixed population of NCs and CLCs (Mixed), and 3) NP tissue containing solely CLCs (CLC-rich) in both non-chondrodystrophic and chondrodystrophic dogs. Based on previous reports and the findings of the microarray analyses, canonical Wnt signaling was further evaluated using qPCR of relevant Wnt target genes. We hypothesized that caveolin-1, a regulator of Wnt signaling that showed significant changes in gene expression in the microarray analyses, played a significant role in early IVD degeneration. Caveolin-1 expression was investigated in IVD tissue sections and in cultured NCs. To investigate the significance of Caveolin-1 in IVD health and degeneration, the NP of 3-month-old Caveolin-1 knock-out mice was histopathologically evaluated and compared with the NP of wild-type mice of the same age.

Results

Early IVD degeneration involved significant changes in numerous pathways, including Wnt/β-catenin signaling. With regard to Wnt/β-catenin signaling, axin2 gene expression was significantly higher in chondrodystrophic dogs compared with non-chondrodystrophic dogs. IVD degeneration involved significant down-regulation of axin2 gene expression. IVD degeneration involved significant down-regulation in Caveolin-1 gene and protein expression. NCs showed abundant caveolin-1 expression in vivo and in vitro, whereas CLCs did not. The NP of wild-type mice was rich in viable NCs, whereas the NP of Caveolin-1 knock-out mice contained chondroid-like matrix with mainly apoptotic, small, rounded cells.

Conclusions

Early IVD degeneration involves down-regulation of canonical Wnt signaling and Caveolin-1 expression, which appears to be essential to the physiology and preservation of NCs. Therefore, Caveolin-1 may be regarded an exciting target for developing strategies for IVD regeneration.
Mammographic density and risk of breast cancer according to tumor characteristics and mode of detection: a Spanish population-based case-control study
Authors: Pollán Marina , Ascunce Nieves , Ederra María , Murillo Alberto , Erdozáin Nieves , Alés-Martínez Jose Enrique , Pastor-Barriuso Roberto
Published: January 2013

Introduction

It is not clear whether high mammographic density (MD) is equally associated with all subtypes of breast cancer (BC). We investigated the association between MD and subsequent BC, considering invasiveness, means of detection, pathologic subtype, and the time elapsed since mammographic exploration and BC diagnosis.

Methods

BC cases occurring in the population of women who attended screening from 1997 through 2004 in Navarre, a Spanish region with a fully consolidated screening program, were identified via record linkage with the Navarre Cancer Registry (n = 1,172). Information was extracted from the records of their first attendance at screening in that period. For each case, we randomly selected four controls, matched by screening round, year of birth, and place of residence. Cases were classified according to invasiveness (ductal carcinoma in situ (DCIS) versus invasive tumors), pathologic subtype (considering hormonal receptors and HER2), and type of diagnosis (screen-detected versus interval cases). MD was evaluated by a single, experienced radiologist by using a semiquantitative scale. Data on BC risk factors were obtained by the screening program in the corresponding round. The association between MD and tumor subtype was assessed by using conditional logistic regression.

Results

MD was clearly associated with subsequent BC. The odds ratio (OR) for the highest MD category (MD >75%) compared with the reference category (MD <10%) was similar for DCIS (OR = 3.47; 95% CI = 1.46 to 8.27) and invasive tumors (OR = 2.95; 95% CI = 2.01 to 4.35). The excess risk was particularly high for interval cases (OR = 7.72; 95% CI = 4.02 to 14.81) in comparison with screened detected tumors (OR = 2.17; 95% CI = 1.40 to 3.36). Sensitivity analyses excluding interval cases diagnosed in the first year after MD assessment or immediately after an early recall to screening yielded similar results. No differences were seen regarding pathologic subtypes. The excess risk associated with MD persisted for at least 7 to 8 years after mammographic exploration.

Conclusions

Our results confirm that MD is an important risk factor for all types of breast cancer. High breast density strongly increases the risk of developing an interval tumor, and this excess risk is not completely explained by a possible masking effect.
Plasma thioredoxin levels during post-cardiac arrest syndrome: relationship with severity and outcome
Authors: Mongardon Nicolas , Lemiale Virginie , Borderie Didier , Burke-Gaffney Anne , Perbet Sébastien , Marin Nathalie , Charpentier Julien , Pène Frédéric , Chiche Jean-Daniel , Mira Jean-Paul , Cariou Alain
Published: January 2013

Introduction

Despite experimental evidence, clinical demonstration of acute state of oxidative stress and inflammation during post-cardiac arrest syndrome is lacking. Plasma level of thioredoxin (TRX), a redox-active protein induced under conditions of oxidative stress and inflammation, is increased in various critical care conditions. We determined plasma TRX concentrations after cardiac arrest and assessed relationships with severity and outcome.

Methods

Retrospective study of consecutive patients admitted to a single academic intensive care unit (ICU) for out-of-hospital cardiac arrest (between July 2006 and March 2008). Plasma levels of TRX were measured at admission, day (D) 1, 2 and 3.

Results

Of 176 patients included, median TRX values measured in ICU survivors and non-survivors were, respectively: 22 ng/mL (7.8 to 77) vs. 72.4 (21.9 to 117.9) at admission (P < 0.001); 5.9 (3.5 to 25.5) vs. 23.2 (5.8 to 81.4) at D1 (P = 0.003); 10.8 (3.6 to 50.8) vs. 11.7 (4.5 to 66.4) at D2 (P = 0.22); and 16.7 (5.3 to 68.3) vs. 17 (4.3 to 62.9) at D3 (P = 0.96). Patients dying within 24 hours had significantly (P < 0.001) higher TRX levels (118.6 ng/mL (94.8 to 280)) than those who died after 24 hours or survived (50.8 (13.9 to 95.7) and 22 (7.8 to 77)). The area under the ROC curve to predict early death was 0.84 (0.76 to 0.91).

TRX levels on admission were significantly correlated with 'low-flow' duration (P = 0.003), sequential organ failure assessment (SOFA) score (P < 0.001), and blood lactate concentration (P < 0.001), but not with 'no-flow' duration or simplified acute physiology score (SAPS) II score. TRX levels and admission arterial pO2 correlated negatively (r = -0.17, P = 0.03). Finally, cardiac arrest with cardiac etiology exhibited lower levels of TRX than in cases of extra-cardiac cause (46 ng/mL (11 to 104) vs. 68 (42 to 137), P = 0.01).

Conclusions

Our data show for the first time that TRX levels were elevated early following cardiac arrest, suggestive of oxidative stress and inflammation occurring with this condition. Highest values were found in the most severe patients. TRX could be a useful tool for further exploration and comprehension of post-cardiac arrest syndrome.
Cyclic arginine-glycine-aspartate attenuates acute lung injury in mice after intestinal ischemia/reperfusion
Authors: Matsuo Shingo , Yang Weng-Lang , Aziz Monowar , Jacob Asha , Wang Ping
Published: January 2013

Introduction

Intestinal ischemia is a critical problem resulting in multiple organ failure and high mortality of 60 to 80%. Acute lung injury (ALI) is a common complication after intestinal ischemia/reperfusion (I/R) injuries and contributes to the high mortality rate. Moreover, activated neutrophil infiltration into the lungs is known to play a significant role in the progression of ALI. Integrin-mediated interaction is involved in neutrophil transmigration. Synthetic peptides containing an arginine-glycine-aspartate sequence compete with adhesive proteins and inhibit integrin-mediated interaction and signaling. Thus, we hypothesized that the administration of a cyclic arginine-glycine-aspartate peptide (cRGD) inhibited neutrophil infiltration and provided protection against ALI induced by intestinal I/R.

Methods

Ischemia in adult male C57BL/6 mice was induced by fastening the superior mesenteric artery with 4-0 suture. Forty-five minutes later, the vascular suture was released to allow reperfusion. cRGD (5 mg/kg body weight) or normal saline (vehicle) was administered by intraperitoneal injection 1 hour prior to ischemia. Blood, gut, and lung tissues were collected 4 hours after reperfusion for various measurements.

Results

Intestinal I/R caused severe widespread injury to the gut and lungs. Treatment with cRGD improved the integrity of microscopic structures in the gut and lungs, as judged by histological examination. Intestinal I/R induced the expression of β1, β2 and β3 integrins, intercellular adhesion molecule-1, and fibronectin. cRGD significantly inhibited myeloperoxidase activity in the gut and lungs, as well as neutrophils and macrophages infiltrating the lungs. cRGD reduced the levels of TNF-α and IL-6 in serum, in addition to IL-6 and macrophage inflammatory protein-2 in the gut and lungs. Furthermore, the number of TUNEL-staining cells and levels of cleaved caspase-3 in the lungs were significantly lowered in the cRGD-treated mice in comparison with the vehicle mice.

Conclusions

Treatment with cRGD effectively protected ALI and gut injury, lowered neutrophil infiltration, suppressed inflammation, and inhibited lung apoptosis after intestinal I/R. Thus, there is potential for developing cRGD as a treatment for patients suffering from ALI caused by intestinal I/R.
Reciprocal interactions of mouse bone marrow-derived mesenchymal stem cells and BV2 microglia after lipopolysaccharide stimulation
Authors: Rahmat Zul'atfi , Jose Shinsmon , Ramasamy Rajesh , Vidyadaran Sharmili
Published: January 2013

Introduction

Mesenchymal stem cells (MSCs) are immunosuppressive, but we lack an understanding of how these adult stem cells are in turn affected by immune cells and the surrounding tissue environment. As MSCs have stromal functions and exhibit great plasticity, the influence of an inflamed microenvironment on their responses is important to determine. MSCs downregulate microglial inflammatory responses, and here we describe the mutual effects of coculturing mouse bone marrow MSCs with BV2 microglia in a lipopolysaccharide (LPS) inflammatory paradigm.

Methods

Mouse MSCs were cultured from femoral and tibial bone marrow aspirates and characterized. MSCs were cocultured with BV2 microglia at four seeding-density ratios (1:0.2, 1:0.1, 1:0.02, and 1:0.01 (BV2/MSC)), and stimulated with 1 μg/ml LPS. In certain assays, MSCs were separated from BV2 cells with a cell-culture insert to determine the influence of soluble factors on downstream responses. Inflammatory mediators including nitric oxide (NO), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and chemokine (C-C motif) ligand 2 (CCL2) were measured in cocultures, and MSC and BV2 chemotactic ability determined by migration assays.

Results

We demonstrated MSCs to increase expression of NO and IL-6 and decrease TNF-α in LPS-treated cocultures. These effects are differentially mediated by soluble factors and cell-to-cell contact. In response to an LPS stimulus, MSCs display distinct behaviors, including expressing IL-6 and very high levels of the chemokine CCL2. Microglia increase their migration almost fourfold in the presence of LPS, and interestingly, MSCs provide an equal impetus for microglia locomotion. MSCs do not migrate toward LPS but migrate toward microglia, with their chemotaxis increasing when microglia are activated. Similarly, MSCs do not produce NO when exposed to LPS, but secrete large amounts when exposed to soluble factors from activated microglia. This demonstrates that certain phenotypic changes of MSCs are governed by inflammatory microglia, and not by the inflammatory stimulus. Nonetheless, LPS appears to "prime" the NO-secretory effects of MSCs, as prior treatment with LPS triggers a bigger NO response from MSCs after exposure to microglial soluble factors.

Conclusions

These effects demonstrate the multifaceted and reciprocal interactions of MSCs and microglia within an inflammatory milieu.
Comparison of the therapeutic effects of human and mouse adipose-derived stem cells in a murine model of lipopolysaccharide-induced acute lung injury
Authors: Zhang Shijia , Danchuk Svitlana D , Imhof Kathleen MP , Semon Julie A , Scruggs Brittni A , Bonvillain Ryan W , Strong Amy L , Gimble Jeffrey M , Betancourt Aline M , Sullivan Deborah E , Bunnell Bruce A
Published: January 2013

Introduction

Adipose-derived stem cells (ASCs) have emerged as important regulators of inflammatory/immune responses in vitro and in vivo and represent attractive candidates for cell-based therapies for diseases that involve excessive inflammation. Acute lung injury (ALI) is an inflammatory condition for which treatment is mainly supportive due to lack of effective therapies. In this study, the therapeutic effects of ASC-based therapy were assessed in vivo by comparison of the anti-inflammatory properties of both human and murine ASCs in a mouse model of lipopolysaccharide (LPS)-induced ALI.

Methods

Human ASCs (hASCs) or mouse ASCs (mASCs) were delivered to C57Bl/6 mice (7.5 × 105 total cells/mouse) by oropharyngeal aspiration (OA) four hours after the animals were challenged with lipopolysaccharide (15 mg/kg). Mice were sacrificed 24 and 72 hours after LPS exposure, and lung histology examined for evaluation of inflammation and injury. Bronchoalveolar lavage fluid (BALF) was analyzed to determine total and differential cell counts, total protein and albumin concentrations, and myeloperoxidase (MPO) activity. Cytokine expression in the injured lungs was measured at the steady-state mRNA levels and protein levels for assessment of the degree of lung inflammation.

Results

Both human and mouse ASC treatments provided protective anti-inflammatory responses. There were decreased levels of leukocyte (for example neutrophil) migration into the alveoli, total protein and albumin concentrations in BALF, and MPO activity after the induction of ALI following both therapies. Additionally, cell therapy with both cell types effectively suppressed the expression of proinflammatory cytokines and increased the anti-inflammatory cytokine interleukin 10 (IL-10). Overall, the syngeneic mASC therapy had a more potent therapeutic effect than the xenogeneic hASC therapy in this model.

Conclusions

Treatment with hASCs or mASCs significantly attenuated LPS-induced acute lung injury in mice. These results suggest a potential benefit for using an ASC-based therapy to treat clinical ALI and may possibly prevent the development of acute respiratory distress syndrome (ARDS).
Fluorouracil, Leucovorin, and Irinotecan Plus Either Sunitinib or Placebo in Metastatic Colorectal Cancer: A Randomized, Phase III Trial
Authors: Carrato Alfredo , Swieboda-Sadlej Anna , Staszewska-Skurczynska Marzanna , Lim Robert , Roman Laslo , Shparyk Yaroslav , Bondarenko Igor , Jonker Derek J. , Sun Yan , De la Cruz Jhony A. , Williams J. Andrew , Korytowsky Beata , Christensen James G. , Lin Xun , Tursi Jennifer M. , Lechuga Maria J. , Van Cutsem Eric
Published: January 2013

Purpose

This double-blind, phase III study aimed to demonstrate that sunitinib plus FOLFIRI (fluorouracil, leucovorin, and irinotecan) was superior to placebo plus FOLFIRI in previously untreated metastatic colorectal cancer (mCRC).

Patients and Methods

Patients were randomly assigned to receive FOLFIRI and either sunitinib (37.5 mg per day) or placebo (4 weeks on treatment, followed by 2 weeks off [schedule 4/2]) until disease progression. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, safety, and patient-reported outcomes. The correlation between genotype and clinical outcomes was also analyzed.

Results

In all, 768 patients were randomly assigned to sunitinib plus FOLFIRI (n = 386) or placebo plus FOLFIRI (n = 382). Following a second prespecified interim analysis, the study was stopped because of potential futility of sunitinib plus FOLFIRI. Final results are reported. The PFS hazard ratio was 1.095 (95% CI, 0.892 to 1.344; one-sided stratified log-rank P = .807), indicating a lack of superiority for sunitinib plus FOLFIRI. Median PFS for the sunitinib arm was 7.8 months (95% CI, 7.1 to 8.4 months) versus 8.4 months (95% CI, 7.6 to 9.2 months) for the placebo arm. Sunitinib plus FOLFIRI was associated with more grade ≥ 3 adverse events and laboratory abnormalities than placebo (especially diarrhea, stomatitis/oral syndromes, fatigue, hand-foot syndrome, neutropenia, thrombocytopenia, anemia, and febrile neutropenia). More deaths as a result of toxicity (12 v four) and significantly more dose delays, dose reductions, and treatment discontinuations occurred in the sunitinib arm.

Conclusion

Sunitinib 37.5 mg per day (schedule 4/2) plus FOLFIRI is not superior to FOLFIRI alone and has a poorer safety profile. This combination regimen is not recommended for previously untreated mCRC.
Oral Antibiotics for Fever in Low-Risk Neutropenic Patients With Cancer: A Double-Blind, Randomized, Multicenter Trial Comparing Single Daily Moxifloxacin With Twice Daily Ciprofloxacin Plus Amoxicillin/Clavulanic Acid Combination Therapy—EORTC Infectious Diseases Group Trial XV
Authors: Kern Winfried V. , Marchetti Oscar , Drgona Lubos , Akan Hamdi , Aoun Mickel , Akova Murat , de Bock Robrecht , Paesmans Marianne , Viscoli Claudio , Calandra Thierry
Published: January 2013

Purpose

This double-blind, multicenter trial compared the efficacy and safety of a single daily oral dose of moxifloxacin with oral combination therapy in low-risk febrile neutropenic patients with cancer.

Patients and Methods

Inclusion criteria were cancer, febrile neutropenia, low risk of complications as predicted by a Multinational Association for Supportive Care in Cancer (MASCC) score > 20, ability to swallow, and ≤ one single intravenous dose of empiric antibiotic therapy before study drug treatment initiation. Early discharge was encouraged when a set of predefined criteria was met. Patients received either moxifloxacin (400 mg once daily) monotherapy or oral ciprofloxacin (750 mg twice daily) plus amoxicillin/clavulanic acid (1,000 mg twice daily). The trial was designed to show equivalence of the two drug regimens in terms of therapy success, defined as defervescence and improvement in clinical status during study drug treatment (< 10% difference).

Results

Among the 333 patients evaluated in an intention-to-treat analysis, therapy success was observed in 80% of the patients administered moxifloxacin and in 82% of the patients administered combination therapy (95% CI for the difference, −10% to 8%, consistent with equivalence). Minor differences in tolerability, safety, and reasons for failure were observed. More than 50% of the patients in the two arms were discharged on protocol therapy, with 5% readmissions among those in either arm. Survival was similar (99%) in both arms.

Conclusion

Monotherapy with once daily oral moxifloxacin is efficacious and safe in low-risk febrile neutropenic patients identified with the help of the MASCC scoring system, discharged early, and observed as outpatients.
Shadows of Mashantucket: William Apess and the Representation of Pequot Place
Authors: Rifkin Mark
Published: January 2013

Rifkin’s essay argues that previous considerations of Apess’s work, particularly A Son of the Forest, have mentioned the existence of the Mashantucket reservation and Apess’s relation to it but have not addressed its role as a framing feature of his writing. Through a reading of A Son of the Forest, the essay illustrates how Mashantucket provides a shadow referent for much of the plot of the narrative, and in this way, the essay demonstrates how Apess develops strategies for signifying Native sovereignty in the absence of treaty-like relations that could signal the presence of “political” matters and of Native geopolitical claims.
Comparative Racialization, Immigration Law, and James Williams’s Life and Adventures
Authors: Wong Edlie
Published: January 2013

Wong’s essay investigates James Williams’s largely forgotten postbellum slave narrative, The Life and Adventures of James Williams, A Fugitive Slave (1873) to chart the various constellations of racial formations emerging from the politics and cultures of early black westward migration. Williams’s once-popular autobiography chronicling his experiences as a fugitive slave and California gold miner knits together stories from the Underground Railroad with firsthand observations on Chinese labor migration and Indian resettlement in the West. This essay reads Williams’s narrative alongside the key legal and political contexts that gave its narrative shape (and to which Williams addressed his text), including California Governor John Bigler’s anti-coolieism campaign (1852), the California Supreme Court ruling in People v. Hall (1854), and the widely publicized Modoc War (1872–73). It builds upon the analytics for articulating racial difference honed in US race and ethnic studies to help illuminate Williams’s literary efforts to formulate an early politics of comparative racialization.
HNF1B controls proximal-intermediate nephron segment identity in vertebrates by regulating Notch signalling components and Irx1/2
Authors: Heliot Claire , Desgrange Audrey , Buisson Isabelle , Prunskaite-Hyyryläinen Renata , Shan Jingdong , Vainio Seppo , Umbhauer Muriel , Cereghini Silvia
Published: January 2013

The nephron is a highly specialised segmented structure that provides essential filtration and resorption renal functions. It arises by formation of a polarised renal vesicle that differentiates into a comma-shaped body and then a regionalised S-shaped body (SSB), with the main prospective segments mapped to discrete domains. The regulatory circuits involved in initial nephron patterning are poorly understood. We report here that HNF1B, a transcription factor known to be involved in ureteric bud branching and initiation of nephrogenesis, has an additional role in segment fate acquisition. Hnf1b conditional inactivation in murine nephron progenitors results in rudimentary nephrons comprising a glomerulus connected to the collecting system by a short tubule displaying distal fates. Renal vesicles develop and polarise normally but fail to progress to correctly patterned SSBs. Major defects are evident at late SSBs, with altered morphology, reduction of a proximo-medial subdomain and increased apoptosis. This is preceded by strong downregulation of the Notch pathway components Lfng, Dll1 and Jag1 and the Irx1/2 factors, which are potential regulators of proximal and Henle's loop segment fates. Moreover, HNF1B is recruited to the regulatory sequences of most of these genes. Overexpression of a HNF1B dominant-negative construct in Xenopus embryos causes downregulation specifically of proximal and intermediate pronephric segment markers. These results show that HNF1B is required for the acquisition of a proximo-intermediate segment fate in vertebrates, thus uncovering a previously unappreciated function of a novel SSB subcompartment in global nephron segmentation and further differentiation.
Hepatocyte nuclear factor 1β controls nephron tubular development
Authors: Massa Filippo , Garbay Serge , Bouvier Raymonde , Sugitani Yoshinobu , Noda Tetsuo , Gubler Marie-Claire , Heidet Laurence , Pontoglio Marco , Fischer Evelyne
Published: January 2013

Nephron morphogenesis is a complex process that generates blood-filtration units (glomeruli) connected to extremely long and patterned tubular structures. Hepatocyte nuclear factor 1β (HNF1β) is a divergent homeobox transcription factor that is expressed in kidney from the first steps of nephrogenesis. Mutations in HNF1B (OMIM #137920) are frequently found in patients with developmental renal pathologies, the mechanisms of which have not been completely elucidated. Here we show that inactivation of Hnf1b in the murine metanephric mesenchyme leads to a drastic tubular defect characterized by the absence of proximal, distal and Henle's loop segments. Nephrons were eventually characterized by glomeruli, with a dilated urinary space, directly connected to collecting ducts via a primitive and short tubule. In the absence of HNF1β early nephron precursors gave rise to deformed S-shaped bodies characterized by the absence of the typical bulge of epithelial cells at the bend between the mid and lower segments. The lack of this bulge eventually led to the absence of proximal tubules and Henle's loops. The expression of several genes, including Irx1, Osr2 and Pou3f3, was downregulated in the S-shaped bodies. We also observed decreased expression of Dll1 and the consequent defective activation of Notch in the prospective tubular compartment of comma- and S-shaped bodies. Our results reveal a novel hierarchical relationship between HNF1β and key genes involved in renal development. In addition, these studies define a novel structural and functional component of S-shaped bodies at the origin of tubule formation.
Auxin-associated initiation of vascular cell differentiation by LONESOME HIGHWAY
Authors: Ohashi-Ito Kyoko , Oguchi Mio , Kojima Mikiko , Sakakibara Hitoshi , Fukuda Hiroo
Published: January 2013

Plant vascular tissues are essential for the existence of land plants. Many studies of transcriptional regulation and cell-cell communication have revealed the process underlying the development of vascular tissues from vascular initial cells. However, the initiation of vascular cell differentiation is still a mystery. Here, we report that LONESOME HIGHWAY (LHW), which encodes a bHLH transcription factor, is expressed in pericycle-vascular mother cells at the globular embryo stage and is required for proper asymmetric cell division to generate vascular initial cells. In addition, ectopic expression of LHW elicits an ectopic auxin response. Moreover, LHW is required for the correct expression patterns of components related to auxin flow, such as PIN-FORMED 1 (PIN1), MONOPTEROS (MP) and ATHB-8, and ATHB-8 partially rescues the vascular defects of lhw. These results suggest that LHW functions as a key regulator to initiate vascular cell differentiation in association with auxin regulation.
Genetic lineage labeling in zebrafish uncovers novel neural crest contributions to the head, including gill pillar cells
Authors: Mongera Alessandro , Singh Ajeet P. , Levesque Mitchell P. , Chen Yi-Yen , Konstantinidis Peter , Nüsslein-Volhard Christiane
Published: January 2013

At the protochordate-vertebrate transition, a new predatory lifestyle and increased body size coincided with the appearance of a true head. Characteristic innovations of this head are a skull protecting and accommodating a centralized nervous system, a jaw for prey capture and gills as respiratory organs. The neural crest (NC) is a major ontogenetic source for the ‘new head’ of vertebrates and its contribution to the cranial skeleton has been intensively studied in different model organisms. However, the role of NC in the expansion of the respiratory surface of the gills has been neglected. Here, we use genetic lineage labeling to address the contribution of NC to specific head structures, in particular to the gills of adult zebrafish. We generated a sox10:ERT2-Cre line and labeled NC cells by inducing Cre/loxP recombination with tamoxifen at embryonic stages. In juvenile and adult fish, we identified numerous established NC derivatives and, in the cranium, we precisely defined the crest/mesoderm interface of the skull roof. We show the NC origin of the opercular bones and of multiple cell types contributing to the barbels, chemosensory organs located in the mouth region. In the gills, we observed labeled primary and secondary lamellae. Clonal analysis reveals that pillar cells, a craniate innovation that mechanically supports the filaments and forms gill-specific capillaries, have a NC origin. Our data point to a crucial role for the NC in enabling more efficient gas exchange, thus uncovering a novel, direct involvement of this embryonic tissue in the evolution of respiratory systems at the protochordate-vertebrate transition.
An Axiomatic Approach to Systemic Risk
Authors: Chen Chen , Iyengar Garud , Moallemi Ciamac C.
Published: January 2013

Systemic risk refers to the risk of collapse of an entire complex system as a result of the actions taken by the individual component entities or agents that comprise the system. Systemic risk is an issue of great concern in modern financial markets as well as, more broadly, in the management of complex business and engineering systems. We propose an axiomatic framework for the measurement and management of systemic risk based on the simultaneous analysis of outcomes across agents in the system and over scenarios of nature. Our framework defines a broad class of systemic risk measures that accomodate a rich set of regulatory preferences. This general class of systemic risk measures captures many specific measures of systemic risk that have recently been proposed as special cases and highlights their implicit assumptions. Moreover, the systemic risk measures that satisfy our conditions yield decentralized decompositions; i.e., the systemic risk can be decomposed into risk due to individual agents. Furthermore, one can associate a shadow price for systemic risk to each agent that correctly accounts for the externalities of the agent's individual decision making on the entire system.

This paper was accepted by Gérard P. Cachon, stochastic models and simulation.
Product Market Competition, Managerial Compensation, and Firm Size in Market Equilibrium
Authors: Subramanian Ajay
Published: January 2013

We develop a tractable equilibrium model of competing firms in an industry to show how the distribution of firm qualities, moral hazard, and product market characteristics interact to affect firm size, managerial compensation, and market structure. Different determinants of product market competition have contrasting effects on firm size and managerial compensation. Although both firm size and managerial compensation increase with the entry cost, they increase with the elasticity of substitution if and only if firm size exceeds a high threshold but decrease if it is below a low threshold. Aggregate shocks to the firm productivity distribution affect incentives in our equilibrium framework. We show statistically and economically significant empirical support for several hypotheses derived from the theory that relates product market characteristics to managerial compensation, firm size, and the number of firms in the industry. Different determinants of competition indeed have contrasting effects, as predicted by the theory.

This paper was accepted by Brad Barber, finance.
Salesforce Contracting Under Demand Censorship
Authors: Chu Leon Yang , Lai Guoming
Published: January 2013

We study salesforce contracting in an environment where excess demand results in lost sales and the demand information is censored by the inventory level. In our model, a firm contracts with a risk-neutral sales agent with limited liability whose effort increases the demand stochastically. The firm designs the incentive contract and invests in inventory; the agent decides the sales effort. We find that the sales-quota-based bonus contract is optimal in such an environment, and the quota should be set equal to the inventory level when the first-best solution is not attainable. We further reveal that demand censorship can introduce peculiar effects on the optimal sales effort and service level that the firm implements. From our analysis of the additive and multiplicative effort cases, we find that in the additive effort case, it can be optimal, under demand censorship, for the firm to induce an effort and maintain a service level both greater than those under the first-best solution. Scenarios also exist where the firm should induce zero effort. For the multiplicative effort case, the optimal sales effort under demand censorship is lower than the first-best effort, whereas the optimal service level is higher than the first-best service level. The agent earns zero rent in the additive effort case but may earn a positive rent in the multiplicative effort case. Finally, our numerical analysis shows that demand censorship can have a significant negative impact on the value of contracting with the sales agent, especially when the sales margin is low and the market uncertainty is high.