bluuebunny/crossref_metadata_2025 huggingface dataset:
High catechin concentrations detected in Withania somnifera (ashwagandha) by high performance liquid chromatography analysis
Authors: Alam Nadia , Hossain Monzur , Khalil Md Ibrahim , Moniruzzaman Mohammed , Sulaiman Siti Amrah , Gan Siew Hua
Published: August 2011

Background

Withania somnifera is an important medicinal plant traditionally used in the treatment of many diseases. The present study was carried out to characterize the phenolic acids, flavonoids and 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) scavenging activities in methanolic extracts of W. somnifera fruits, roots and leaves (WSFEt, WSREt and WSLEt).

Methods

WSFEt, WSREt and WSLEt was prepared by using 80% aqueous methanol and total polyphenols, flavonoids as well as DPPH radical scavenging activities were determined by spectrophotometric methods and phenolic acid profiles were determined by HPLC methods.

Results

High concentrations of both phenolics and flavonoids were detected in all parts of the plant with the former ranging between 17.80 ± 5.80 and 32.58 ± 3.16 mg/g (dry weight) and the latter ranging between 15.49 ± 1.02 and 31.58 ± 5.07 mg/g. All of the three different plant parts showed strong DPPH radical scavenging activities (59.16 ± 1.20 to 91.84 ± 0.38%). Eight polyphenols (gallic, syringic, benzoic, p-coumaric and vanillic acids as well as catechin, kaempferol and naringenin) have been identified by HPLC in parts of the plant as well. Among all the polyphenols, catechin was detected in the highest concentration (13.01 ± 8.93 to 30.61 ± 11.41 mg/g).

Conclusion

The results indicating that W. somnifera is a plant with strong therapeutic properties thus further supporting its traditional claims. All major parts of W. somnifera such as the roots, fruits and leaves provide potential benefits for human health because of its high content of polyphenols and antioxidant activities with the leaves containing the highest amounts of polyphenols specially catechin with strong antioxidant properties.
Real-time PCR detection of Plasmodium directly from whole blood and filter paper samples
Authors: Taylor Brian J , Martin Kimberly A , Arango Eliana , Agudelo Olga M , Maestre Amanda , Yanow Stephanie K
Published: August 2011

Background

Real-time PCR is a sensitive and specific method for the analysis of Plasmodium DNA. However, prior purification of genomic DNA from blood is necessary since PCR inhibitors and quenching of fluorophores from blood prevent efficient amplification and detection of PCR products.

Methods

Reagents designed to specifically overcome PCR inhibition and quenching of fluorescence were evaluated for real-time PCR amplification of Plasmodium DNA directly from blood. Whole blood from clinical samples and dried blood spots collected in the field in Colombia were tested.

Results

Amplification and fluorescence detection by real-time PCR were optimal with 40× SYBR® Green dye and 5% blood volume in the PCR reaction. Plasmodium DNA was detected directly from both whole blood and dried blood spots from clinical samples. The sensitivity and specificity ranged from 93-100% compared with PCR performed on purified Plasmodium DNA.

Conclusions

The methodology described facilitates high-throughput testing of blood samples collected in the field by fluorescence-based real-time PCR. This method can be applied to a broad range of clinical studies with the advantages of immediate sample testing, lower experimental costs and time-savings.
MicroRNA-194 inhibits epithelial to mesenchymal transition of endometrial cancer cells by targeting oncogene BMI-1
Authors: Dong Peixin , Kaneuchi Masanori , Watari Hidemichi , Hamada Junichi , Sudo Satoko , Ju Jingfang , Sakuragi Noriaki
Published: August 2011

Background

Epithelial-mesenchymal transition (EMT) is the key process driving cancer metastasis. Oncogene/self renewal factor BMI-1 has been shown to induce EMT in cancer cells. Recent studies have implied that noncoding microRNAs (miRNAs) act as crucial modulators for EMT. The aims of this study was to determine the roles of BMI-1 in inducing EMT of endometrial cancer (EC) cells and the possible role of miRNA in controlling BMI-1 expression.

Methods and results

We evaluated the expression of BMI-1 gene in a panel of EC cell lines, and detected a strong association with invasive capability. Stable silencing of BMI-1 in invasive mesenchymal-type EC cells up-regulated the epithelial marker E-cadherin, down-regulated mesenchymal marker Vimentin, and significantly reduced cell invasion in vitro. Furthermore, we discovered that the expression of BMI-1 was suppressed by miR-194 via direct binding to the BMI-1 3'-untranslated region 3'-UTR). Ectopic expression of miR-194 in EC cells induced a mesenchymal to epithelial transition (MET) by restoring E-cadherin, reducing Vimentin expression, and inhibiting cell invasion in vitro. Moreover, BMI-1 knockdown inhibited in vitro EC cell proliferation and clone growth, correlated with either increased p16 expression or decreased expression of stem cell and chemoresistance markers (SOX-2, KLF4 and MRP-1).

Conclusion

These findings demonstrate the novel mechanism for BMI-1 in contributing to EC cell invasion and that repression of BMI-1 by miR-194 could have a therapeutic potential to suppress EC metastasis.
Existence and convergence of fixed points for mappings of asymptotically nonexpansive type in uniformly convex W-hyperbolic spaces
Authors: Zhang Jingxin , Cui Yunan
Published: August 2011

Uniformly convex W-hyperbolic spaces with monotone modulus of uniform convexity are a natural generalization of both uniformly convexnormed spaces and CAT(0) spaces. In this article, we discuss the existence of fixed points and demiclosed principle for mappings of asymptotically non-expansive type in uniformly convex W-hyperbolic spaces with monotone modulus of uniform convexity. We also obtain a Δ-convergence theorem of Krasnoselski-Mann iteration for continuous mappings of asymptotically nonexpansive type in CAT(0) spaces.

MSC: 47H09; 47H10; 54E40
Comparative review of three cost-effectiveness models for rotavirus vaccines in national immunization programs; a generic approach applied to various regions in the world
Authors: Postma Maarten J , Jit Mark , Rozenbaum Mark H , Standaert Baudouin , Tu Hong-Anh , Hutubessy Raymond CW
Published: August 2011

Background

This study aims to critically review available cost-effectiveness models for rotavirus vaccination, compare their designs using a standardized approach and compare similarities and differences in cost-effectiveness outcomes using a uniform set of input parameters.

Methods

We identified various models used to estimate the cost-effectiveness of rotavirus vaccination. From these, results using a standardized dataset for four regions in the world could be obtained for three specific applications.

Results

Despite differences in the approaches and individual constituting elements including costs, QALYs Quality Adjusted Life Years and deaths, cost-effectiveness results of the models were quite similar. Differences between the models on the individual components of cost-effectiveness could be related to some specific features of the respective models. Sensitivity analysis revealed that cost-effectiveness of rotavirus vaccination is highly sensitive to vaccine prices, rotavirus-associated mortality and discount rates, in particular that for QALYs.

Conclusions

The comparative approach followed here is helpful in understanding the various models selected and will thus benefit (low-income) countries in designing their own cost-effectiveness analyses using new or adapted existing models. Potential users of the models in low and middle income countries need to consider results from existing studies and reviews. There will be a need for contextualization including the use of country specific data inputs. However, given that the underlying biological and epidemiological mechanisms do not change between countries, users are likely to be able to adapt existing model designs rather than developing completely new approaches. Also, the communication established between the individual researchers involved in the three models is helpful in the further development of these individual models. Therefore, we recommend that this kind of comparative study be extended to other areas of vaccination and even other infectious disease interventions.
G140S/Q148R and N155H mutations render HIV-2 Integrase resistant to Raltegravir whereas Y143C does not
Authors: Ni Xiao-Ju , Delelis Olivier , Charpentier Charlotte , Storto Alexandre , Collin Gilles , Damond Florence , Descamps Diane , Mouscadet Jean-François
Published: August 2011

Background

HIV-2 is endemic in West Africa and has spread throughout Europe. However, the alternatives for HIV-2-infected patients are more limited than for HIV-1. Raltegravir, an integrase inhibitor, is active against wild-type HIV-2, with a susceptibility to this drug similar to that of HIV-1, and is therefore a promising option for use in the treatment of HIV-2-infected patients. Recent studies have shown that HIV-2 resistance to raltegravir involves one of three resistance mutations, N155H, Q148R/H and Y143C, previously identified as resistance determinants in the HIV-1 integrase coding sequence. The resistance of HIV-1 IN has been confirmedin vitrofor mutated enzymes harboring these mutations, but no such confirmation has yet been obtained for HIV-2.

Results

The integrase coding sequence was amplified from plasma samples collected from ten patients infected with HIV-2 viruses, of whom three RAL-naïve and seven on RAL-based treatment at the time of virological failure. The genomes of the resistant strains were cloned and three patterns involving N155H, G140S/Q148R or Y143C mutations were identified. Study of the susceptibility of integrases, either amplified from clinical isolates or obtained by mutagenesis demonstrated that mutations at positions 155 and 148 render the integrase resistant to RAL. The G140S mutation conferred little resistance, but compensated for the catalytic defect due to the Q148R mutation. Conversely, Y143C alone did not confer resistance to RAL unless E92Q is also present. Furthermore, the introduction of the Y143C mutation into the N155H resistant background decreased the resistance level of enzymes containing the N155H mutation.

Conclusion

This study confirms that HIV-2 resistance to RAL is due to the N155H, G140S/Q148R or E92Q/Y143C mutations. The N155H and G140S/Q148R mutations make similar contributions to resistance in both HIV-1 and HIV-2, but Y143C is not sufficient to account for the resistance of HIV-2 genomes harboring this mutation. For Y143C to confer resistancein vitro, it must be accompanied by E92Q, which therefore plays a more important role in the HIV-2 context than in the HIV-1 context. Finally, the Y143C mutation counteracts the resistance conferred by the N155H mutation, probably accounting for the lack of detection of these mutations together in a single genome.
Generation of an infectious clone of HuN4-F112, an attenuated live vaccine strain of porcine reproductive and respiratory syndrome virus
Authors: Zhang Shanrui , Zhou Yanjun , Jiang Yifeng , Li Guoxin , Yan Liping , Yu Hai , Tong Guangzhi
Published: August 2011

Background

Nowadays, PRRS has become one of the most economically important infectious diseases of pig worldwide. To better characterize and understand the molecular basis of PRRSV virulence determinants, it would be important to develop the infectious cDNA clones. In this regard, HuN4-F112, a live-attenuated North-American-type PRRSV vaccine strain, could serve as an excellent model.

Results

In the study, genomic sequence of HuN4-F112, an attenuated vaccine virus derived from the highly pathogenic porcine reproductive and respiratory syndrome virus (PRRSV) HuN4 strain, was determined and its full-length cDNA was cloned. Capped RNA was transcribed in vitro from the cDNA clone and transfected into BHK-21 cells. The supernatant from transfected monolayers were serially passaged in Marc-145 cells. The rescued virus exhibited a similar growth pattern to its parental virus in Marc-145 cells with peak titers at 48 h post-infection.

Conclusion

In conclusion, we rescued virus from an infectious cDNA clone of attenuated vaccine. It is possible in the future that a new attenuated PRRSV vaccine with broader specificity and good immunogenicity can be designed in vitro via an infectious cDNA clone platform coupled with validated information on virulence determinants.
Mice lacking caspase-2 are protected from behavioral changes, but not pathology, in the YAC128 model of Huntington disease
Authors: Carroll Jeffrey B , Southwell Amber L , Graham Rona K , Lerch Jason P , Ehrnhoefer Dagmar E , Cao Li-Ping , Zhang Wei-Ning , Deng Yu , Bissada Nagat , Henkelman R Mark , Hayden Michael R
Published: August 2011

Background

Huntington Disease (HD) is a neurodegenerative disorder in which caspase activation and cleavage of substrates, including the huntingtin protein, has been invoked as a pathological mechanism. Specific changes in caspase-2 (casp2) activity have been suggested to contribute to the pathogenesis of HD, however unique casp2 cleavage substrates have remained elusive. We thus utilized mice completely lacking casp2 (casp2-/-) to examine the role played by casp2 in the progression of HD. This 'substrate agnostic' approach allows us to query the effect of casp2 on HD progression without pre-defining proteolytic substrates of interest.

Results

YAC128 HD model mice lacking casp2 show protection from well-validated motor and cognitive features of HD, including performance on rotarod, swimming T-maze, pre-pulse inhibition, spontaneous alternation and locomotor tasks. However, the specific pathological features of the YAC128 mice including striatal volume loss and testicular degeneration are unaltered in mice lacking casp2. The application of high-resolution magnetic resonance imaging (MRI) techniques validates specific neuropathology in the YAC128 mice that is not altered by ablation of casp2.

Conclusions

The rescue of behavioral phenotypes in the absence of pathological improvement suggests that different pathways may be operative in the dysfunction of neural circuitry in HD leading to behavioral changes compared to the processes leading to cell death and volume loss. Inhibition of caspase-2 activity may be associated with symptomatic improvement in HD.
Degeneration of penicillin production in ethanol-limited chemostat cultivations of Penicillium chrysogenum: A systems biology approach
Authors: Douma Rutger D , Batista Joana M , Touw Kai M , Kiel Jan AKW , Krikken Arjen M , Zhao Zheng , Veiga Tânia , Klaassen Paul , Bovenberg Roel AL , Daran Jean-Marc , Heijnen Joseph J , van Gulik Walter M
Published: August 2011

Background

In microbial production of non-catabolic products such as antibiotics a loss of production capacity upon long-term cultivation (for example chemostat), a phenomenon called strain degeneration, is often observed. In this study a systems biology approach, monitoring changes from gene to produced flux, was used to study degeneration of penicillin production in a high producing Penicillium chrysogenum strain during prolonged ethanol-limited chemostat cultivations.

Results

During these cultivations, the biomass specific penicillin production rate decreased more than 10-fold in less than 22 generations. No evidence was obtained for a decrease of the copy number of the penicillin gene cluster, nor a significant down regulation of the expression of the penicillin biosynthesis genes. However, a strong down regulation of the biosynthesis pathway of cysteine, one of the precursors of penicillin, was observed. Furthermore the protein levels of the penicillin pathway enzymes L-α-(δ-aminoadipyl)-L-α-cystenyl-D-α-valine synthetase (ACVS) and isopenicillin-N synthase (IPNS), decreased significantly. Re-cultivation of fully degenerated cells in unlimited batch culture and subsequent C-limited chemostats did only result in a slight recovery of penicillin production.

Conclusions

Our findings indicate that the observed degeneration is attributed to a significant decrease of the levels of the first two enzymes of the penicillin biosynthesis pathway, ACVS and IPNS. This decrease is not caused by genetic instability of the penicillin amplicon, neither by down regulation of the penicillin biosynthesis pathway. Furthermore no indications were obtained for degradation of these enzymes as a result of autophagy. Possible causes for the decreased enzyme levels could be a decrease of the translation efficiency of ACVS and IPNS during degeneration, or the presence of a culture variant impaired in the biosynthesis of functional proteins of these enzymes, which outcompeted the high producing part of the population.
Secretory glands in cercaria of the neuropathogenic schistosome Trichobilharzia regenti - ultrastructural characterization, 3-D modelling, volume and pH estimations
Authors: Ligasová Anna , Bulantová Jana , Šebesta Ondřej , Kašný Martin , Koberna Karel , Mikeš Libor
Published: August 2011

Background

Cercariae of schistosomes employ bioactive molecules for penetration into their hosts. These are released from specialized unicellular glands upon stimuli from host skin. The glands were previously well-described in the human pathogen Schistosoma mansoni. As bird schistosomes can also penetrate human skin and cause cercarial dermatitis, our aim was to characterize the architecture and ultrastructure of glands in the neurotropic bird schistosome Trichobilharzia regenti and compare it with S. mansoni. In the context of different histolytic enzymes used by these two species, we focused also on the estimations of gland volumes and pH in T. regenti.

Results

The architecture and 3-D models of two types of acetabular penetration glands, their ducts and of the head gland are shown here. We characterized secretory vesicles in all three gland types by means of TEM and confirmed accuracy of the models obtained by confocal microscopy. The results of two independent approaches showed that the glands occupy ca. one third of cercarial body volume (postacetabular glands ca. 15%, circumacetabular 12% and head gland 6%). The inner environment within the two types of acetabular glands differed significantly as evidenced by dissimilar ability to bind fluorescent markers and by pH value which was higher in circumacetabular (7.44) than in postacetabular (7.08) glands.

Conclusions

As far as we know, this is the first presentation of a 3-D model of cercarial glands and the first exact estimation of the volumes of the three gland types in schistosomes. Our comparisons between T. regenti and S. mansoni implied that the architecture and ultrastructure of the glands is most likely conserved within the family. Only minor variations were found between the two species. It seems that the differences in molecular composition have no effect on general appearance of the secretory cells in TEM. Fluorescent markers employed in this study, distinguishing between secretory vesicles and gland types, can be useful in further studies of mechanisms used by cercariae for host invasion. Results of the first attempts to estimate pH within schistosome glands may help further understanding of regulation of enzymatic activities present within the glands.
Application of Benchtop-magnetic resonance imaging in a nude mouse tumor model
Authors: Caysa Henrike , Metz Hendrik , Mäder Karsten , Mueller Thomas
Published: August 2011

Background

MRI plays a key role in the preclinical development of new drugs, diagnostics and their delivery systems. However, very high installation and running costs of existing superconducting MRI machines limit the spread of MRI. The new method of Benchtop-MRI (BT-MRI) has the potential to overcome this limitation due to much lower installation and almost no running costs. However, due to the low field strength and decreased magnet homogeneity it is questionable, whether BT-MRI can achieve sufficient image quality to provide useful information for preclinical in vivo studies. It was the aim of the current study to explore the potential of BT-MRI on tumor models in mice.

Methods

We used a prototype of an in vivo BT-MRI apparatus to visualise organs and tumors and to analyse tumor progression in nude mouse xenograft models of human testicular germ cell tumor and colon carcinoma.

Results

Subcutaneous xenografts were easily identified as relative hypointense areas in transaxial slices of NMR images. Monitoring of tumor progression evaluated by pixel extension analyses based on NMR images correlated with increasing tumor volume calculated by calliper measurement. Gd-BOPTA contrast agent injection resulted in a better differentiation between parts of the urinary tissues and organs due to fast elimination of the agent via kidneys. In addition, interior structuring of tumors could be observed. A strong contrast enhancement within a tumor was associated with a central necrotic/fibrotic area.

Conclusions

BT-MRI provides satisfactory image quality to visualize organs and tumors and to monitor tumor progression and structure in mouse models.
Love, eye contact and the developmental origins of empathy v. psychopathy
Authors: Dadds Mark R. , Allen Jennifer L. , Oliver Bonamy R. , Faulkner Nathan , Legge Katherine , Moul Caroline , Woolgar Matthew , Scott Stephen
Published: August 2011

Background

A propensity to attend to other people's emotions is a necessary condition for human empathy.

Aims

To test our hypothesis that psychopathic disorder begins as a failure to attend to the eyes of attachment figures, using a ‘love’ scenario in young children.

Method

Children with oppositional defiant disorder, assessed for callous–unemotional traits, and a control group were observed in a love interaction with mothers. Eye contact and affection were measured for each dyad.

Results

There was no group difference in affection and eye contact expressed by the mothers. Compared with controls, children with oppositional defiant disorder expressed lower levels of affection back towards their mothers; those with high levels of callous–unemotional traits showed significantly lower levels of affection than the children lacking these traits. As predicted, the former group showed low levels of eye contact toward their mothers. Low eye contact was not correlated with maternal coercive parenting or feelings toward the child, but was correlated with psychopathic fearlessness in their fathers.

Conclusions

Impairments in eye contact are characteristic of children with callous–unemotional traits, and these impairments are independent of maternal behaviour.
Analysis of Prognostic Factors of Comprehensive Geriatric Assessment and Development of a Clinical Scoring System in Elderly Asian Patients With Cancer
Authors: Kanesvaran Ravindran , Li Huihua , Koo Khai-Nee , Poon Donald
Published: August 2011

Purpose

To determine the impact of each comprehensive geriatric assessment (CGA) domain on overall survival (OS) and develop a prognostic scoring system for elderly patients with cancer.

Patients and Methods

A retrospective analysis of CGA data collected from 249 consecutive patients with cancer who attended the outpatient geriatric oncology clinic at the National Cancer Center Singapore age 70 years or older was performed. Univariate and multivariate analyses were performed using Cox proportional hazards method to identify significant prognostic factors within the CGA. A simple nomogram to predict OS was developed using regression coefficients from the multivariate model. Concordance between predicted and observed response of the individual patient score was evaluated by means of Harrell's c-index. Calibration was performed using simulated data via bootstrap.

Results

Median age of the patients was 77 years (range, 70 to 94 years). In our model, age (hazard ratio [HR], 1.04; 95% CI, 1.01 to 1.07), abnormal albumin level (HR, 1.97; 95% CI, 1.23 to 3.15), poor Eastern Cooperative Oncology Group performance status (≥ 2 v < 2: HR, 1.77; 95% CI, 1.15 to 2.72), abnormal geriatric depression scale status (HR, 1.81; 95% CI, 1.29 to 2.56), high malnutrition risk (high v low risk: HR, 1.84; 95% CI, 1.17 to 2.87), and advanced disease stage (late v early: HR, 1.71; 95% CI, 0.98 to 2.95) were independent predictors of survival.

Conclusion

Results confirm the importance of the CGA in assessment of elderly patients with cancer. The development of this nomogram incorporating these prognostic factors helps predict OS of patients, for further intervention.
Early Modern “Neoliberalisms”: England and the English Caribbean
Authors: Forman Valerie
Published: August 2011

By viewing economic, political, and literary developments through the anachronistic lens of neoliberalism, this essay calls attention to largely overlooked interrelations between the market and seventeenth-century arguments for political freedom. The essay tracks the trope of the neo-Roman political slave to tyranny as it collides with the institution of African slavery in early modern political debates over property and in pamphlets protesting injustices in the trades in sugar, slaves, and indentured servants. Using narrative digressions to stage a struggle for primacy between background and foreground and between text and New World context, Aphra Behn's Oroonoko: A Royal Slave exploits these tensions between the economic and political domains to reveal the market not only as an ethical framework for political freedom but also as a tyrant ruling over those it dispossesses. Taken together, the essay's texts tell a story about economic and political entanglements that intensify even as the economic realm attempts to establish itself as an independent domain. This story develops alongside another: if freedom was initially conceived out of a relationship between subject and ruler, by the end of the seventeenth century the possibilities for political freedom depended on a set of global relations that included not only the citizen and the government but also its colonies and the markets they produce.
Imaginary Value and the Value of the Imaginary: J. G. Schlosser, E. T. A. Hoffmann, and the Convergence of Aesthetics and Economics in German Romanticism
Authors: Gray Richard T.
Published: August 2011

Economics and aesthetics emerged in the mid-eighteenth century as scientific enterprises concerned fundamentally with questions of value. But whereas economics sought to jettison imaginary and subjective investments from its theory of value and to insist on principles of quantification (culminating in Karl Marx's famous critique of commodity fetishism), aesthetics founded its theory of value on the cornerstone of subjective and imaginative value attribution. This essay examines two German Romantic thinkers, the economist Johann Georg Schlosser and the writer E. T. A. Hoffmann, who turn to aesthetic idealism and a theory of productive imagination to heal this rift between economics and aesthetics. Both Schlosser's economic theories and Hoffmann's literary practice (as exemplified by his short story “Des Vetters Eckfenster” [“My Cousin's Corner Window”]) represent the view that economic and aesthetic values emerge at the intersection between the material attributes of the (economic or aesthetic) object and the imaginative fantasies projected onto it by prospective consumers.
With Plato in Italy: The Value of Literary Fiction in Napoleonic Italy
Authors: Dainotto Roberto M.
Published: August 2011

It is often assumed that a special function of imaginative and fictional writing and a special aesthetic value as a distinctive feature of literary prose are the fruits of what has been called the “invention of literature” between the eighteenth and nineteenth centuries: the transformation of writing, that is, from rhetoric or belles lettres to art. However, while much has been written and said about the French, German, and Scottish Enlightenments, little is known about the Italian one. Engaged in a reevaluation of this lesser-known, peripheral Enlightenment, this essay discusses Vincenzo Cuoco's novel Plato in Italy in the local context of the transformation of the publishing industry in Italy and in the European context of Bonapartism. Fiction acquires here a special kind of value: that of reimagining a radical democracy betrayed by Napoleonic restoration.
HNF4A is essential for specification of hepatic progenitors from human pluripotent stem cells
Authors: DeLaForest Ann , Nagaoka Masato , Si-Tayeb Karim , Noto Fallon K. , Konopka Genevieve , Battle Michele A. , Duncan Stephen A.
Published: August 2011

The availability of pluripotent stem cells offers the possibility of using such cells to model hepatic disease and development. With this in mind, we previously established a protocol that facilitates the differentiation of both human embryonic stem cells and induced pluripotent stem cells into cells that share many characteristics with hepatocytes. The use of highly defined culture conditions and the avoidance of feeder cells or embryoid bodies allowed synchronous and reproducible differentiation to occur. The differentiation towards a hepatocyte-like fate appeared to recapitulate many of the developmental stages normally associated with the formation of hepatocytes in vivo. In the current study, we addressed the feasibility of using human pluripotent stem cells to probe the molecular mechanisms underlying human hepatocyte differentiation. We demonstrate (1) that human embryonic stem cells express a number of mRNAs that characterize each stage in the differentiation process, (2) that gene expression can be efficiently depleted throughout the differentiation time course using shRNAs expressed from lentiviruses and (3) that the nuclear hormone receptor HNF4A is essential for specification of human hepatic progenitor cells by establishing the expression of the network of transcription factors that controls the onset of hepatocyte cell fate.
LGN-dependent orientation of cell divisions in the dermomyotome controls lineage segregation into muscle and dermis
Authors: Ben-Yair Raz , Kahane Nitza , Kalcheim Chaya
Published: August 2011

The plane of cell divisions is pivotal for differential fate acquisition. Dermomyotome development provides an excellent system with which to investigate the link between these processes. In the central sheet of the early dermomyotome, single epithelial cells divide with a planar orientation. Here, we report that in the avian embryo, in addition to self-renewing, a subset of progenitors translocates into the myotome where they generate differentiated myocytes. By contrast, in the late epithelium, individual progenitors divide perpendicularly to produce both mitotic myoblasts and dermis. To examine whether spindle orientations influence fate segregation, early planar divisions were randomized and/or shifted to a perpendicular orientation by interfering with LGN function or by overexpressing inscuteable. Clones derived from single transfected cells exhibited an enhanced proportion of mixed dermomyotome/myotome progeny at the expense of `like' daughter cells in either domain. Loss of LGN or Gαi1 function in the late epithelium randomized otherwise perpendicular mitoses and favored muscle development at the expense of dermis. Hence, LGN-dependent early planar divisions are required for the proper allocation of progenitors into either dermomyotome or myotome, whereas late perpendicular divisions are necessary for the normal balance between muscle and dermis production.
Cell cycle-regulated multi-site phosphorylation of Neurogenin 2 coordinates cell cycling with differentiation during neurogenesis
Authors: Ali Fahad , Hindley Chris , McDowell Gary , Deibler Richard , Jones Alison , Kirschner Marc , Guillemot Francois , Philpott Anna
Published: August 2011

During development of the central nervous system, the transition from progenitor maintenance to differentiation is directly triggered by a lengthening of the cell cycle that occurs as development progresses. However, the mechanistic basis of this regulation is unknown. The proneural transcription factor Neurogenin 2 (Ngn2) acts as a master regulator of neuronal differentiation. Here, we demonstrate that Ngn2 is phosphorylated on multiple serine-proline sites in response to rising cyclin-dependent kinase (cdk) levels. This multi-site phosphorylation results in quantitative inhibition of the ability of Ngn2 to induce neurogenesis in vivo and in vitro. Mechanistically, multi-site phosphorylation inhibits binding of Ngn2 to E box DNA, and inhibition of DNA binding depends on the number of phosphorylation sites available, quantitatively controlling promoter occupancy in a rheostat-like manner. Neuronal differentiation driven by a mutant of Ngn2 that cannot be phosphorylated by cdks is no longer inhibited by elevated cdk kinase levels. Additionally, phosphomutant Ngn2-driven neuronal differentiation shows a reduced requirement for the presence of cdk inhibitors. From these results, we propose a model whereby multi-site cdk-dependent phosphorylation of Ngn2 interprets cdk levels to control neuronal differentiation in response to cell cycle lengthening during development.
Distinct and mutually inhibitory binding by two divergent β-catenins coordinates TCF levels and activity inC. elegans
Authors: Yang Xiao-Dong , Huang Shuyi , Lo Miao-Chia , Mizumoto Kota , Sawa Hitoshi , Xu Wenqing , Robertson Scott , Lin Rueyling
Published: August 2011

Wnt target gene activation in C. elegans requires simultaneous elevation of β-catenin/SYS-1 and reduction of TCF/POP-1 nuclear levels within the same signal-responsive cell. SYS-1 binds to the conserved N-terminal β-catenin-binding domain (CBD) of POP-1 and functions as a transcriptional co-activator. Phosphorylation of POP-1 by LIT-1, the C. elegans Nemo-like kinase homolog, promotes POP-1 nuclear export and is the main mechanism by which POP-1 nuclear levels are lowered. We present a mechanism whereby SYS-1 and POP-1 nuclear levels are regulated in opposite directions, despite the fact that the two proteins physically interact. We show that the C terminus of POP-1 is essential for LIT-1 phosphorylation and is specifically bound by the diverged β-catenin WRM-1. WRM-1 does not bind to the CBD of POP-1, nor does SYS-1 bind to the C-terminal domain. Furthermore, binding of WRM-1 to the POP-1 C terminus is mutually inhibitory with SYS-1 binding at the CBD. Computer modeling provides a structural explanation for the specificity in WRM-1 and SYS-1 binding to POP-1. Finally, WRM-1 exhibits two independent and distinct molecular functions that are novel for β-catenins: WRM-1 serves both as the substrate-binding subunit and an obligate regulatory subunit for the LIT-1 kinase. Mutual inhibitory binding would result in two populations of POP-1: one bound by WRM-1 that is LIT-1 phosphorylated and exported from the nucleus, and another, bound by SYS-1, that remains in the nucleus and transcriptionally activates Wnt target genes. These studies could provide novel insights into cancers arising from aberrant Wnt activation.
The cytoplasmic domain of neuropilin 1 is dispensable for angiogenesis, but promotes the spatial separation of retinal arteries and veins
Authors: Fantin Alessandro , Schwarz Quenten , Davidson Kathryn , Normando Eduardo M. , Denti Laura , Ruhrberg Christiana
Published: August 2011

Neuropilin 1 (NRP1) is a transmembrane glycoprotein that is essential for blood vessel development in vertebrates. Best known for its ability to bind members of the vascular endothelial growth factor (VEGF) and class 3 semaphorin families through its extracellular domain, it also has a highly conserved cytoplasmic domain, which terminates in a SEA motif that binds the PDZ protein synectin/GIPC1/NIP. Previous studies in zebrafish embryos and tissue culture models raised the possibility that the SEA motif of NRP1 is essential for angiogenesis. Here, we describe the generation of mice that express a form of NRP1 that lacks the cytoplasmic domain and, therefore, the SEA motif (Nrp1cytoΔ/Δ mice). Our analysis of pre- and perinatal vascular development revealed that vasculogenesis and angiogenesis proceed normally in these mutants, demonstrating that the membrane-anchored extracellular domain is sufficient for vessel growth. By contrast, the NRP1 cytoplasmic domain is required for normal arteriovenous patterning, because arteries and veins crossed each other at an abnormally high frequency in the Nrp1cytoΔ/Δ retina, as previously reported for mice with haploinsufficient expression of VEGF in neural progenitors. At crossing sites, the artery was positioned anteriorly to the vein, and both vessels were embedded in a shared collagen sleeve. In human eyes, similar arteriovenous crossings are risk factors for branch retinal vein occlusion (BRVO), an eye disease in which compression of the vein by the artery disrupts retinal blood flow, causing local tissue hypoxia and impairing vision. Nrp1cytoΔ/Δ mice may therefore provide a suitable genetic model to study the aetiology of BRVO.
Notch pathway activation can replace the requirement for Wnt4 and Wnt9b in mesenchymal-to-epithelial transition of nephron stem cells
Authors: Boyle Scott C. , Kim Mijin , Valerius M. Todd , McMahon Andrew P. , Kopan Raphael
Published: August 2011

The primary excretory organ in vertebrates is the kidney, which is responsible for blood filtration, solute homeostasis and pH balance. These functions are carried out by specialized epithelial cells organized into tubules called nephrons. Each of these cell types arise during embryonic development from a mesenchymal stem cell pool through a process of mesenchymal-to-epithelial transition (MET) that requires sequential action of specific Wnt signals. Induction by Wnt9b directs cells to exit the stem cell niche and express Wnt4, which is both necessary and sufficient for the formation of epithelia. Without either factor, MET fails, nephrons do not form and newborn mice die owing to kidney failure. Ectopic Notch activation in stem cells induces mass differentiation and exhaustion of the stem cell pool. To investigate whether this reflected an interaction between Notch and Wnt, we employed a novel gene manipulation strategy in cultured embryonic kidneys. We show that Notch activation is capable of inducing MET in the absence of both Wnt4 and Wnt9b. Following MET, the presence of Notch directs cells primarily to the proximal tubule fate. Only nephron stem cells have the ability to undergo MET in response to Wnt or Notch, as activation in the closely related stromal mesenchyme has no inductive effect. These data demonstrate that stem cells for renal epithelia are uniquely poised to undergo MET, and that Notch activation can replace key inductive Wnt signals in this process. After MET, Notch provides an instructive signal directing cells towards the proximal tubule lineage at the expense of other renal epithelial fates.
Fluorido Complex Formation of Element 104, Rutherfordium (Rf)
Authors: Ishii Yasuo , Toyoshima Atsushi , Tsukada Kazuaki , Asai Masato , Li Zijie , Nagame Yuichiro , Miyashita Sunao , Mori Tomotaka , Suganuma Hideo , Haba Hiromitsu , Goto Shin-ichi , Kudo Hisaaki , Akiyama Kazuhiko , Oura Yasuji , Shinohara Atsushi , Schädel Matthias , Pershina Valeria , Kratz Jens V
Published: August 2011

We have investigated the cation-exchange behavior of element 104, rutherfordium (Rf), together with its lighter group-4 homologs Zr and Hf, and the tetravalent pseudo-homolog Th in HF/HNO3 mixed solution. The results, obtained on a one-atom-at-a-time scale, demonstrate that distribution coefficients (Kd) of Rf in HF/0.10 M HNO3 decrease with increasing concentration of the fluoride ion [F−]. This resembles the behavior of the homologs, indicating the consecutive formation of fluorido complexes of Rf. We also measured the Kd values of Rf and the homologs as a function of the hydrogen ion concentration [H+] in the range of [F−] = 5.29 × 10−7–3.17 × 10−6 M. The log Kd values decrease linearly with an increase of log[H+] with slopes between −2.1 and −2.5. This indicates that these elements are likely to form the same chemical compounds: mixture of [MF]3+ and [MF2]2+ (M = Rf, Zr, Hf, and Th) in the studied solution. It is also ascertained that the fluorido complex formation of Rf is significantly weaker than that of Zr and Hf, but it is stronger than that of Th.
Explaining Bargaining Impasse: The Role of Self-Serving Biases
Authors: Babcock Linda , Loewenstein George
Published: August 2011

The authors review studies conducted by themselves and coauthors that document a 'self-serving' bias in judgments of fairness and demonstrate that the bias is an important cause of impasse in negotiations. They discuss experimental evidence showing that (1) the bias causes impasse; (2) it is possible to reduce impasses by debiasing bargainers; and (3) the bias results from selective evaluation of information. The authors also review results from a field study of negotiations between teachers' unions and school boards in Pennsylvania that both document the fairness bias in a naturalistic setting and demonstrates its impact on strikes.
The Time-Varying NAIRU and its Implications for Economic Policy
Authors: Gordon Robert J
Published: August 2011

The NAIRU, the unemployment rate consistent with a constant rate of inflation, is estimated, in this paper, as a parameter allowed to vary over time. Value is determined in an econometric model where the inflation rate depends on its past values, demand and supply shocks. The NAIRU estimated for the GDP deflator varies over the past forty years within 5.4 to 6.5 percent; its estimated value for the most recent quarter (1996:Q2) is 5.6 percent. The NAIRU has declined in recent years in response to global competition, immigration, other factors weakening labor's bargaining position, and the rapidly declining prices of computers and other electronics.
Capacity Utilization
Authors: Corrado Carol , Mattey Joe
Published: August 2011

This article reviews how the Federal Reserve measures capacity utilization and explains why capacity utilization has been, and likely will remain, a useful indicator of inflationary pressures and business cycle fluctuations. The authors also explain why economic developments, such as the pace of technological change, increased international trade, and a shift in the share of the workforce to service-producing industries, have not substantially affected the indicator value of capacity utilization. A microtheoretic description of the concept of capacity utilization is offered. Evidence on the plausibility of microeconomic structural interpretations of the relation between capacity utilization and price changes is reviewed.
Retrospectives: Classical Family Values: Ending the Poor Laws as They Knew Them
Authors: Persky Joseph
Published: August 2011

Poor law reform in the early 1830s provides a key example of the deep conflicts between classical liberal principles of self-reliance and the realities of dependency. Eminent economists, such as Nassau Senior and Thomas Malthus, argued that the dependency of women and children calls forth and motivates its own support from the altruism of husbands and fathers. Like modern welfare reformers, the classical economists asserted the natural necessity and sufficiency of such dependency and ignored its powerful implications for the intergenerational perpetuation of a highly illiberal inequality of opportunity.
Theory Ahead of Language in the Economics of Unemployment
Authors: Rogerson Richard
Published: August 2011

This paper discusses, from the perspective of modern theories of unemployment, several unemployment concepts that have been used over the years. It argues that many of these concepts are of limited value and are dominated by a few simple concepts that are basic in the analysis of stochastic general equilibrium models.
Time to Ditch the NAIRU
Authors: Galbraith James K
Published: August 2011

The concept of a natural rate of unemployment, or nonaccelerating inflation rate of unemployment (NAIRU), remains controversial after twenty-five years. This essay presents a brief for no-confidence, in four parts. First, the theoretical case for the natural rate is not compelling. Second, the evidence for a vertical Phillips curve and the associated accelerationist hypothesis that lowering unemployment past the NAIRU leads to unacceptable acceleration of inflation is weak. Third, economists have failed to reach professional consensus on estimating the NAIRU. Fourth, adherence to the concept as a guide to policy has major social costs but negligible benefits.
The Growth of Temporary Services Work
Authors: Segal Lewis M , Sullivan Daniel G
Published: August 2011

Temporary services employment grew rapidly over the past several decades and now accounts for a sizable fraction of aggregate employment. The authors use Current Population Survey data to examine the changing nature of temporary work and discuss explanations for its growth. Temps are no longer overwhelmingly female or limited to clerical occupations. They have less labor market security than permanent workers, being prone to more unemployment and more underemployment. Few, however, are in temp positions a year later and the majority transition to permanent employment. Temp wages are approximately 20 percent below permanent workers, but individual and job characteristics explain approximately two-thirds of the gap.
In Honor of David Card: Winner of the John Bates Clark Medal
Authors: Freeman Richard B
Published: August 2011

This paper describes the contribution of David Card, winner of the John Bates Clark Medal, to economics and the new empiricism that has become such an important part of the profession. Card's forte is creative and careful empirical scholarship that exploits modern computerized data sets with thousands or hundreds of thousands of observations and that uses plausible sources of exogenous change in key variables to determine behavioral responses. The work has the flavor of a laboratory scientist reporting an experiment. It has illuminated virtually all areas of labor economics and has implications for the understanding of the economy writ large.
Institutional Changes and Rising Wage Inequality: Is There a Linkage?
Authors: Fortin Nicole M , Lemieux Thomas
Published: August 2011

In this paper, the authors analyze the role of three institutional changes--the decline in the real value of the minimum wage, deunionization, and economic deregulation--on the rise in wage inequality in the United States during the 1980s. They argue that about a third of the increase in male and female wage inequality can be traced to these institutional changes. Deunionization had a significant effect on the rise in inequality for men, while the minimum wage is what matters most for women. The authors find the direct impact of economic deregulation to be comparatively small.
The Future Information Infrastructure in Economics
Authors: Goffe William L , Parks Robert P
Published: August 2011

This paper is a first look at how the information infrastructure for economists will change with the arrival of the Internet. While paper has long been used for the flow of information in the profession, computer networks are starting to supplement it and, in the not-to-distant future, will replace paper. The authors examine the myriad ways in which a networked world will benefit the profession. The most exciting is the easy access to the material that lies at the heart of their profession: journals, working papers, data, and teaching.
The AEA's Electronic Publishing Plans: A Progress Report
Authors: Varian Hal R
Published: August 2011

This paper describes the American Economic Association's electronic publishing plans. Special attention is given to the JSTOR project and to pricing issues. There is also some speculation about how journals and publication will evolve in this new medium.