bluuebunny/crossref_metadata_2025 huggingface dataset:
Towards a possible aetiology for depressions?
Authors: Liu Ying , Heiberg Tore , Reichelt Karl-Ludvig
Published: September 2007

Background

Since a genetic disposition for depression is probable, there ought to be biochemical changes. Increased peptide levels with relevant bioactivities have been found in urine in a previous investigation, which may be such changes.

Methods

Urine from patients with severe depression according to ICD 10 have been run on reversed phase High Performance Liquid Chromatography, and off line mass spectrometry was performed on some of these peptides.

Results

We find overlapping patterns of peptide peaks in severe depression, but with considerable individuality. Mass spectrometry shows that some of these peptides are probably of dietary origin, because their sequences are found only in certain dietary proteins. Opioids from casein and gliadin are typical examples.

Conclusion

Our data show that the disposition must be polygenetic because some peptide peaks with the same bioactivity are of different length in different patients, but with the same diagnosis. However, some of the peaks are common Peptide increase in urine is found when break down is deficient, and the data presented agree with reports on peptidase deficiencies in depression. Antidepressant drugs decrease the peptide level after about 3 weeks.
The United States Revised Uniform Anatomical Gift Act (2006): New challenges to balancing patient rights and physician responsibilities
Authors: Verheijde Joseph L , Rady Mohamed Y , McGregor Joan L
Published: September 2007

Advance health care directives and informed consent remain the cornerstones of patients' right to self-determination regarding medical care and preferences at the end-of-life. However, the effectiveness and clinical applicability of advance health care directives to decision-making on the use of life support systems at the end-of-life is questionable. The Uniform Anatomical Gift Act (UAGA) has been revised in 2006 to permit the use of life support systems at or near death for the purpose of maximizing procurement opportunities of organs medically suitable for transplantation. Some states have enacted the Revised UAGA (2006) and a few of those have included amendments while attempting to preserve the uniformity of the revised Act. Other states have introduced the Revised UAGA (2006) for legislation and remaining states are likely to follow soon.

The Revised UAGA (2006) poses challenges to the Patient Self Determination Act (PSDA) embodied in advance health care directives and individual expression about the use of life support systems at the end-of-life. The challenges are predicated on the UAGA revising the default choice to presumption of donation intent and the use of life support systems to ensure medical suitability of organs for transplantation. The default choice trumps the expressed intent in an individual's advance health care directive to withhold and/or withdraw life support systems at the end-of-life. The Revised UAGA (2006) overrides advance directives on utilitarian grounds, which is a serious ethical challenge to society. The subtle progression of the Revised UAGA (2006) towards the presumption about how to dispose of one's organs at death can pave the way for an affirmative "duty to donate". There are at least two steps required to resolve these challenges. First, physicians and hospitals must fulfill their responsibilities to educate patients on the new legislations and document their preferences about the use of life support systems for organ donation at the end-of-life. Second, a broad based societal discussion must be initiated to decide if the Revised UAGA (2006) infringes on the PSDA and the individual's right of autonomy. The discussion should also address other ethical concerns raised by the Revised UAGA (2006), including the moral stance on 1) the interpretation of the refusal of life support systems as not applicable to organ donation and 2) the disregarding of the diversity of cultural beliefs about end-of-life in a pluralistic society.
Aging impacts transcriptomes but not genomes of hormone-dependent breast cancers
Authors: Yau Christina , Fedele Vita , Roydasgupta Ritu , Fridlyand Jane , Hubbard Alan , Gray Joe W , Chew Karen , Dairkee Shanaz H , Moore Dan H , Schittulli Francesco , Tommasi Stefania , Paradiso Angelo , Albertson Donna G , Benz Christopher C
Published: September 2007

Introduction

Age is one of the most important risk factors for human malignancies, including breast cancer; in addition, age at diagnosis has been shown to be an independent indicator of breast cancer prognosis. Except for inherited forms of breast cancer, however, there is little genetic or epigenetic understanding of the biological basis linking aging with sporadic breast cancer incidence and its clinical behavior.

Methods

DNA and RNA samples from matched estrogen receptor (ER)-positive sporadic breast cancers diagnosed in either younger (age ≤ 45 years) or older (age ≥ 70 years) Caucasian women were analyzed by array comparative genomic hybridization and by expression microarrays. Array comparative genomic hybridization data were analyzed using hierarchical clustering and supervised age cohort comparisons. Expression microarray data were analyzed using hierarchical clustering and gene set enrichment analysis; differential gene expression was also determined by conditional permutation, and an age signature was derived using prediction analysis of microarrays.

Results

Hierarchical clustering of genome-wide copy-number changes in 71 ER-positive DNA samples (27 younger women, 44 older women) demonstrated two age-independent genotypes; one with few genomic changes other than 1q gain/16q loss, and another with amplifications and low-level gains/losses. Age cohort comparisons showed no significant differences in total or site-specific genomic breaks and amplicon frequencies. Hierarchical clustering of 5.1 K genes variably expressed in 101 ER-positive RNA samples (53 younger women, 48 older women) identified six transcriptome subtypes with an apparent age bias (P < 0.05). Samples with higher expression of a poor outcome-associated proliferation signature were predominantly (65%) younger cases. Supervised analysis identified cancer-associated genes differentially expressed between the cohorts; with younger cases expressing more cell cycle genes and more than threefold higher levels of the growth factor amphiregulin (AREG), and with older cases expressing higher levels of four different homeobox (HOX) genes in addition to ER (ESR1). An age signature validated against two other independent breast cancer datasets proved to have >80% accuracy in discerning younger from older ER-positive breast cancer cases with characteristic differences in AREG and ESR1 expression.

Conclusion

These findings suggest that epigenetic transcriptome changes, more than genotypic variation, account for age-associated differences in sporadic breast cancer incidence and prognosis.
Role of Luteal Glucocorticoid Metabolism during Maternal Recognition of Pregnancy in Women
Authors: Myers Michelle , Lamont M. Christy , van den Driesche Sander , Mary Nirmala , Thong K. Joo , Hillier Stephen G. , Duncan W. Colin
Published: September 2007

The human corpus luteum (hCL) is an active, transient, and dynamic endocrine gland. It will experience extensive tissue and vascular remodeling followed by 1) demise of the whole gland without any apparent scarring or 2) maintenance of structural and functional integrity dependent on conceptus-derived human chorionic gonadotropin (hCG). Because cortisol has well-characterized roles in tissue remodeling and repair, we hypothesized that it may have a role in controlling luteal dissolution during luteolysis and would be locally produced toward the end of the luteal cycle. Glucocorticoid-metabolizing enzymes [11β-hydroxysteroid dehydrogenase (11βHSD) types 1 and 2] and the glucocorticoid receptor (GR) were assessed in hCL and cultures of luteinized granulosa cells (LGC) using immunofluorescence and quantitative RT-PCR. Furthermore, the effect of cortisol on steroidogenic cell survival and fibroblast-like cell activity was explored in vitro. The hCL expressed 11βHSD isoenzymes in LGC and nuclear GR in several cell types. hCG up-regulated the expression and activity of 11βHSD type 1 (P < 0.05) and down-regulated type 2 enzyme (P < 0.05) in vitro and tended to do the same in vivo. Cortisol increased the survival of LGC treated with RU486 (P < 0.05) and suppressed the activity of a proteolytic enzyme associated with luteolysis in fibroblast-like cells (P < 0.05). Our results suggest that, rather than during luteolysis, it is luteal rescue with hCG that is associated with increased local cortisol generation by 11βHSD type 1. Locally generated cortisol may therefore act on the hCL through GR to have a luteotropic role in the regulation of luteal tissue remodeling during maternal recognition of pregnancy.
Compound Heterozygosity for Mutations in LMNA in a Patient with a Myopathic and Lipodystrophic Mandibuloacral Dysplasia Type A Phenotype
Authors: Lombardi Francesca , Gullotta Francesca , Columbaro Marta , Filareto Antonio , D’Adamo Monica , Vielle Anne , Guglielmi Valeria , Nardone Anna Maria , Azzolini Valeria , Grosso Enrico , Lattanzi Giovanna , D’Apice Maria Rosaria , Masala Salvatore , Maraldi Nadir Mario , Sbraccia Paolo , Novelli Giuseppe
Published: September 2007

Context: Mandibuloacral dysplasia type A (MADA; OMIM 248370) is a rare progeroid syndrome characterized by dysmorphic craniofacial and skeletal features, lipodystrophy, and metabolic complications. Most Italian patients carry the same homozygous missense mutation (p.R527H) in the C-terminal tail domain of the LMNA gene, which encodes lamin A/C, an intermediate filament component of the nuclear envelope.

Objective: The objective of the study was to identify novel LMNA mutations in individuals with clinical characteristics (bird-like facies, mandibular and clavicular hypoplasia, acroosteolysis, lipodystrophy, alopecia) observed in other well-known patients.

Design: The LMNA gene was sequenced. Functional properties of the mutant alleles were investigated.

Patient: We report a 27-yr-old Italian woman showing a MADA-like phenotype. Features include a hypoplastic mandible, acroosteolysis, pointed nose, partial loss of sc fat, and a progeric appearance. Due to the absence of clavicular dysplasia and normal metabolic profiles, generally associated with muscle hyposthenia and generalized hypotonia, this phenotype can be considered an atypical laminopathy.

Results: We identified a patient compound heterozygote for the p.R527H and p.V440M alleles. The patient’s cells showed nuclear shape abnormalities, accumulation of pre-lamin A, and irregular lamina thickness. Lamins A and C showed normal expression and localization. The electron microscopy detected heterochromatin defects with a pattern similar to those observed in other laminopathies. However, chromatin analysis showed a normal distribution pattern of the major heterochromatin proteins: heterochromatin protein-1β and histone H3 methylated at lysine 9.

Conclusions: The clinical and cellular features of this patient show overlapping laminopathy phenotypes that could be due to the combination of p.R527H and p.V440M alleles.
OTX5 Regulates Pineal Expression of the Zebrafish REV-ERBα through a New DNA Binding Site
Authors: Nishio Shin-ichi , Kakizawa Tomoko , Chatelain Gilles , Triqueneaux Gérard , Brunet Frédéric , Rambaud Juliette , Lamonerie Thomas , Laudet Vincent
Published: September 2007

The pineal gland plays a central role in the photoneuroendocrine system and acts as a photosensory organ in lower vertebrates. The orphan nuclear receptor Rev-erbα (NR1D1) has previously been shown to be expressed in the pineal and to be regulated with a robust circadian rhythm during zebrafish embryogenesis. This early pineal expression is under the control of the transcription factor Orthodenticle homeobox 5 (Otx5). In this paper, we show that Otx5 regulates the second zfRev-erbα promoter, ZfP2. Despite the absence of a classical Otx-binding site within ZfP2, this regulation depends on the integrity of the Otx5 homeodomain. Mapping experiments as well as EMSAs show that this interaction between Otx5 and ZfP2 depends on a noncanonical bipartite Otx-binding site (GANNCTTA and TAAA) that we called pineal expression related element (PERE). We showed that PERE is necessary for pineal expression in vivo by injecting zebrafish embryos with wild type and mutated versions of zfRev-erbα promoter fused to green fluorescent protein. Interestingly, PERE is found upstream of other genes expressed in the pineal gland, suggesting that it may play an important role in governing pineal expression. Our data establish that PERE is a novel cis-acting element contributing to pineal-specific gene expression and to Otx target gene regulation.
Induction of proepicardial marker gene expression by the liver bud
Authors: Ishii Yasuo , Langberg Jonathan D. , Hurtado Romulo , Lee Sharrell , Mikawa Takashi
Published: September 2007

Cells of the coronary vessels arise from a unique extracardiac mesothelial cell population, the proepicardium, which develops posterior to the sinoatrial region of the looping-stage heart. Although contribution of the proepicardial cells to cardiac development has been studied extensively, it remains unresolved how the proepicardium is induced and specified in the mesoderm during embryogenesis. It is known, however, that the proepicardium develops from the mesothelium that overlays the liver bud. Here, we show that the expression of proepicardial marker genes - Wt1, capsulin (epicardin, pod1, Tcf21) and Tbx18, can be induced in naïve mesothelial cells by the liver bud, both in vitro and in vivo. Lateral embryonic explants, when co-cultured with the liver bud, were induced to express these proepicardial marker genes. The same induction of the marker genes was detected in vivo when a quail liver bud was implanted in the posterior-lateral regions of a chick embryo. This ectopic induction of marker gene expression was not evident when other endodermal tissues, such as the lung bud or stomach, were implanted. This inductive response to the liver bud was not detectable in host embryos before stage 12 (16-somite stage). These results suggest that, after a specific developmental stage, a large area of the mesothelium becomes competent to express proepicardial marker genes in response to localized liver-derived signal(s). The developmentally regulated competency of mesothelium and a localized inductive signal might play a role in restricting the induction of the proepicardial marker gene expression to a specific region of the mesothelium. The data might also provide a foundation for future engineering of a coronary vascular progenitor population.
Independent functions and mechanisms for homeobox geneBarx1in patterning mouse stomach and spleen
Authors: Kim Byeong-Moo , Miletich Isabelle , Mao Junhao , McMahon Andrew P. , Sharpe Paul A. , Shivdasani Ramesh A.
Published: September 2007

Homeobox genes convey positional information in embryos and their role in patterning the mammalian gut is a topic of considerable interest. Barx1 is expressed selectively in fetal stomach mesenchyme and directs differentiation of overlying endoderm. Recombinant tissue cultures and study of young mouse embryos previously suggested that Barx1 controls expression of secreted Wnt antagonists, which suppress endodermal Wnt signaling, to enable stomach epithelial differentiation. We overcame mid-gestational lethality of Barx1-/- mouse embryos and report here the spectrum of anomalies in a distinctive and unprecedented model of gastrointestinal homeotic transformation. Using various mouse models, we confirm the importance of attenuated Wnt signaling in stomach development and the role of Barx1 in suppressing endodermal Wnt activity. Absence of Barx1 also results in fully penetrant defects in positioning and expansion of the spleen, an organ that originates within the mesothelial lining of the stomach. Barx1 is absent from the spleen primordium but highly expressed in the mesogastrium, indicating an indirect effect on spleen development. However,our results argue against a role for Wnt antagonism in genesis of the spleen. Mouse spleen development relies on several homeodomain transcriptional regulators that are expressed in the spleen primordium. Loss of Barx1 does not affect expression of any of these genes but notably reduces expression of Wt1,a transcription factor implicated in spleen morphogenesis and expressed in the mesothelium. These observations place Barx1 proximally within a Wt1 pathway of spleen development and reveal how a homeotic regulator employs different molecular mechanisms to mold neighboring organs.
mDia2 regulates actin and focal adhesion dynamics and organization in the lamella for efficient epithelial cell migration
Authors: Gupton Stephanie L. , Eisenmann Kathryn , Alberts Arthur S. , Waterman-Storer Clare M.
Published: September 2007

Cell migration requires spatial and temporal regulation of filamentous actin (F-actin) dynamics. This regulation is achieved by distinct actin-associated proteins, which mediate polymerization, depolymerization, severing, contraction, bundling or engagement to the membrane. Mammalian Diaphanous-related (mDia) formins, which nucleate, processively elongate, and in some cases bundle actin filaments, have been extensively studied in vitro, but their function in the cell has been less well characterized. Here we study the role of mDia2 activity in the dynamic organization of F-actin in migrating epithelial cells. We find that mDia2 localizes in the lamella of migrating epithelial cells, where it is involved in the formation of a stable pool of cortical actin and in maintenance of polymerization-competent free filament barbed ends at focal adhesions. Specific inhibition of mDia2 alters focal adhesion turnover and reduces migration velocity. We suggest that the regulation of filament assembly dynamics at focal adhesions may be necessary for the formation of a stable pool of cortical lamella actin and the proper assembly and disassembly dynamics of focal adhesions, making mDia2 an important factor in epithelial cell migration.
RGS19 regulates Wnt–β-catenin signaling through inactivation of Gαo
Authors: Feigin Michael E. , Malbon Craig C.
Published: September 2007

The Wnt–β-catenin pathway controls numerous cellular processes, including differentiation, cell-fate decisions and dorsal-ventral polarity in the developing embryo. Heterotrimeric G-proteins are essential for Wnt signaling, and regulator of G-protein signaling (RGS) proteins are known to act at the level of G-proteins. The functional role of RGS proteins in the Wnt–β-catenin pathway was investigated in mouse F9 embryonic teratocarcinoma cells. RGS protein expression was investigated at the mRNA level, and each RGS protein identified was overexpressed and tested for the ability to regulate the canonical Wnt pathway. Expression of RGS19 specifically was found to attenuate Wnt-responsive gene transcription in a time- and dose-dependent manner, to block cytosolic β-catenin accumulation and Dishevelled3 (Dvl3) phosphorylation in response to Wnt3a and to inhibit Wnt-induced formation of primitive endoderm (PE). Overexpression of a constitutively active mutant of Gαo rescued the inhibition of Lef-Tcf-sensitive gene transcription caused by RGS19. By contrast, expression of RGS19 did not inhibit activation of Lef-Tcf gene transcription when induced in response to Dvl3 expression. However, knockdown of RGS19 by siRNA suppressed canonical Wnt signaling, suggesting a complex role for RGS19 in regulating the ability of Wnt3a to signal to the level of β-catenin and gene transcription.
Muscles do more positive than negative work in human locomotion
Authors: DeVita Paul , Helseth Joseph , Hortobagyi Tibor
Published: September 2007

Muscle work during level walking and ascent and descent ramp and stairway walking was assessed in order to explore the proposition that muscles perform more positive than negative work during these locomotion tasks. Thirty four healthy human adults were tested while maintaining a constant average walking velocity in the five gait conditions. Ground reaction force and sagittal plane kinematic data were obtained during the stance phases of these gaits and used in inverse dynamic analyses to calculate joint torques and powers at the hip,knee and ankle. Muscle work was derived as the area under the joint power vs time curves and was partitioned into positive, negative and net components. Dependent t-tests were used to compare positive and negative work in level walking and net joint work between ascent and descent gaits on the ramp and stairs (P<0.010). Total negative and positive work in level walking was –34 J and 50 J, respectively, with the difference in magnitude being statistically significant(P<0.001). Level walking was therefore performed with 16 J of net positive muscle work per step. The magnitude of the net work in ramp ascent was 25% greater than the magnitude of net work in ramp descent (89 vs–71 J m–1, P<0.010). Similarly, the magnitude of the net work in stair ascent was 43% greater than the magnitude of net work in stair descent (107 vs –75 J step–1, P<0.000). We identified three potential causes for the reduced negative vs positive work in these locomotion tasks: (1) the larger magnitude of the accelerations induced by the larger ground reaction forces in descending compared to ascending gaits elicited greater energy dissipation in non-muscular tissues, (2) the ground reaction force vector was directed closer to the joint centers in ramp and stair descent compared to ascent, which reduced the load on the muscular tissues and their energy dissipating response, and (3) despite the need to produce negative muscle work in descending gaits, both ramp and stair descent also had positive muscle work to propel the lower extremity upward and forward into the swing phase movement trajectory. We used these data to formulate two novel hypotheses about human locomotion. First, level walking requires muscles to generate a net positive amount of work per gait cycle to overcome energy losses by other tissues. Second, skeletal muscles generate more mechanical energy in gait tasks that raise the center of mass compared to the mechanical energy they dissipate in gait tasks that lower the center of mass, despite equivalent changes in total mechanical energy.
The contribution of mineral to the material properties of vertebral cartilage from the smooth-hound shark Mustelus californicus
Authors: Porter Marianne E. , Koob Thomas J. , Summers Adam P.
Published: September 2007

Elasmobranch vertebral cartilage has a substantial mineral fraction(39–55%) and the arrangement of mineral varies among species. We examined vertebrae from one shark species, Mustelus californicus, to determine mineral content, the effect of mineral on material properties and the viscoelastic response of vertebral cartilage. We serially demineralized vertebrae and compressively tested them to failure at varying strain rates. Mineral in vertebral cartilage varies within individuals, intraspecifically and interspecifically; this is in contrast to bone, in which significant variation in mineral content is pathological or an interspecific effect. Within Mustelus, vertebrae with larger mineral fractions were significantly stiffer and stronger; however when variation is assessed across species, the structure has a larger effect. Shark vertebral cartilage did not show a substantial viscoelastic response at biologically relevant strain rates, validating the use of quasistatic testing for this material.
To what extent might N2 limit dive performance in king penguins?
Authors: Fahlman A. , Schmidt A. , Jones D. R. , Bostrom B. L. , Handrich Y.
Published: September 2007

A mathematical model was used to explore if elevated levels of N2, and risk of decompression sickness (DCS), could limit dive performance (duration and depth) in king penguins (Aptenodytes patagonicus). The model allowed prediction of blood and tissue (central circulation, muscle, brain and fat) N2 tensions(PN2) based on different cardiac outputs and blood flow distributions. Estimated mixed venous PN2 agreed with values observed during forced dives in a compression chamber used to validate the assumptions of the model. During bouts of foraging dives, estimated mixed venous and tissue PN2 increased as the bout progressed. Estimated mean maximum mixed venous PN2 upon return to the surface after a dive was 4.56±0.18 atmospheres absolute (ATA;range: 4.37–4.78 ATA). This is equivalent to N2 levels causing a 50% DCS incidence in terrestrial animals of similar mass. Bout termination events were not associated with extreme mixed venous N2levels. Fat PN2 was positively correlated with bout duration and the highest estimated fat PN2occurred at the end of a dive bout. The model suggested that short and shallow dives occurring between dive bouts help to reduce supersaturation and thereby DCS risk. Furthermore, adipose tissue could also help reduce DCS risk during the first few dives in a bout by functioning as a sink to buffer extreme levels of N2.
Interdependence of Ca2+ and proton movements in trout hepatocytes
Authors: Ahmed Khaled H. , Pelster Bernd
Published: September 2007

This study was undertaken to investigate possible interrelationships between Ca2+ homeostasis and pH regulation in trout hepatocytes. Exposure of cells to Ca2+ mobilizing agents ionomycin (0.5 μmol l–1) and thapsigargin (0.1 μmol l–1)induced an increase in intracellular pH (pHi) that was dependent on Ca2+ influx from the extracellular medium as well as Ca2+ release from intracellular pools. Surprisingly, this increase in pHi and intracellular Ca2+ concentration,[Ca2+]i, was not accompanied by any change in proton secretion. By contrast, removal of extracellular Ca2+(Ca2+e) using EGTA (0.5 mmol l–1)briefly increased proton secretion rate with no apparent effect on pHi, while chelation of Ca2+i using BAPTA-AM (25 μmol l–1) resulted in a drop in pHi and a sustained increase in proton secretion rate. [Ca2+]i therefore affected intracellular proton distribution and/or proton production and also affected the distribution of protons across the cell membrane. Accordingly, changes in pHi were not always compensated for by proton secretion across the cell membrane.

Alteration in pHe below and above normal values induced a slow,continuous increase in [Ca2+]i with a tendency to stabilize upon exposure to high pHe values. Rapid pHi increase induced by NH4Cl was accompanied by an elevation in[Ca2+]i from both extracellular and intracellular compartments. Ca2+e appeared to be involved in pHi regulation following NH4Cl-induced alkalinization whereas neither removal of Ca2+e nor chelation of Ca2+i affected pHi recovery following Na-propionate exposure. Similarly, [Ca2+]i increase induced by hypertonicity appeared to be a consequence of the changes in pHi as Na-free medium as well as cariporide diminished the hypertonicity-induced increase in[Ca2+]i. These results imply that a compensatory relationship between changes in pHi and proton secretion across cell plasma membrane is not always present. Consequently, calculating proton extrusion from buffering capacity and rate of pHi change cannot be taken as an absolute alternative for measuring proton secretion rate, at least in response to Ca2+ mobilizing agents.
Reference-Dependent Risk Attitudes
Authors: Kőszegi Botond , Rabin Matthew
Published: September 2007

We use Kőszegi and Rabin's (2006) model of reference-dependent utility, and an extension of it that applies to decisions with delayed consequences, to study preferences over monetary risk. Because our theory equates the reference point with recent probabilistic beliefs about outcomes, it predicts specific ways in which the environment influences attitudes toward modest-scale risk. It replicates “classical” prospect theory—including the prediction of distaste for insuring losses—when exposure to risk is a surprise, but implies first-order risk aversion when a risk, and the possibility of insuring it, are anticipated. A prior expectation to take on risk decreases aversion to both the anticipated and additional risk. For large-scale risk, the model allows for standard “consumption utility” to dominate reference-dependent “gain-loss utility,” generating nearly identical risk aversion across situations. (JEL D81)
Mismatch
Authors: Shimer Robert
Published: September 2007

This paper develops a dynamic model of mismatch. Workers and jobs are randomly allocated to labor markets. Each market clears, but some have excess (unemployed) workers and some have excess (vacant) jobs. As workers and jobs switch markets, unemployed workers find vacancies and employed workers become unemployed. The model is quantitatively consistent with the business cycle frequency comovement of unemployment, vacancies, and the job finding rate and explains much of these variables' volatility. It can also address cyclicality in the separation rate into unemployment and duration dependence in the job finding rate. The results are robust to some nonrandom mobility. (JEL E24, J41, J63, J64)
On the Cyclicality of Research and Development
Authors: Barlevy Gadi
Published: September 2007

Economists have recently argued recessions play a useful role in fostering growth. Yet a major source of growth, R&D, is procyclical. This paper argues one reason for procyclical R&D is a dynamic externality inherent in R&D that makes entrepreneurs short-sighted and concentrate their innovation in booms, even when it is optimal to concentrate it in recessions. Additional forces may imply that procyclical R&D is desirable, but equilibrium R&D is likely to be too procyclical, and macroeconomic shocks are likely to have overly persistent effects on output and make growth more costly than in the absence of such shocks.
Markets in China and Europe on the Eve of the Industrial Revolution
Authors: Shiue Carol H , Keller Wolfgang
Published: September 2007

Why did Western Europe industrialize first? An influential view holds that its exceptionally well-functioning markets supported with a certain set of institutions provided the incentives to make investments needed to industrialize. This paper examines this hypothesis by comparing the actual performance of markets in terms of market integration in Western Europe and China, two regions that were relatively advanced in the preindustrial period, but would start to industrialize about 150 years apart. We find that the performance of markets in China and Western Europe overall was comparable in the late eighteenth century. Market performance in England was higher than in the Yangzi Delta, and markets in England also performed better than those in continental Western Europe. This suggests strong market performance may be necessary, but it is not sufficient for industrialization. Rather than being a key condition for subsequent growth, improvements in market performance and growth occurred simultaneously. (JEL N13, N15, O47)
Do Markets Reduce Costs? Assessing the Impact of Regulatory Restructuring on US Electric Generation Efficiency
Authors: Fabrizio Kira R , Rose Nancy L , Wolfram Catherine D
Published: September 2007

While neoclassical models assume static cost-minimization by firms, agency models suggest that firms may not minimize costs in less-competitive or regulated environments. We test this using a transition from cost-of-service regulation to market-oriented environments for many US electric generating plants. Our estimates of input demand suggest that publicly owned plants, whose owners were largely insulated from these reforms, experienced the smallest efficiency gains, while investor-owned plants in states that restructured their wholesale electricity markets improved the most. The results suggest modest medium-term efficiency benefits from replacing regulated monopoly with a market-based industry structure. (JEL D24, L11, L51, L94, L98)
Selection Bias, Demographic Effects, and Ability Effects in Common Value Auction Experiments
Authors: Casari Marco , Ham John C , Kagel John H
Published: September 2007

Inexperienced women, along with economics and business majors, are much more susceptible to the winner's curse, as are subjects with lower SAT/ACT scores. There are strong selection effects in bid function estimates for inexperienced and experienced subjects due to bankruptcies and bidders who have lower earnings returning less frequently as experienced subjects. These selection effects are not identified using standard econometric techniques but are identified through experimental treatment effects. Ignoring these selection effects leads to misleading estimates of learning. (JEL D44, D83, J16)
Do Vertical Mergers Facilitate Upstream Collusion?
Authors: Nocke Volker , White Lucy
Published: September 2007

We investigate the impact of vertical mergers on upstream firms' ability to collude when selling to downstream firms in a repeated game. We show that vertical mergers give rise to an outlets effect: the deviation profits of cheating unintegrated firms are reduced as these firms can no longer profitably sell to the downstream affiliates of their integrated rivals. Vertical mergers also result in an opposing punishment effect: integrated firms typically make more profit in the punishment phase than unintegrated upstream firms. The net result of these effects in an unintegrated industry is to facilitate upstream collusion. We provide conditions under which further vertical integration also facilitates collusion. (JEL D43, G34, L12, L13)
Auctions with Anticipated Regret: Theory and Experiment
Authors: Filiz-Ozbay Emel , Ozbay Erkut Y
Published: September 2007

This paper demonstrates theoretically and experimentally that in first-price auctions overbidding with respect to the risk neutral Nash equilibrium might be driven from anticipated loser regret (felt when bidders lose at an affordable price). Different information structures are created to elicit regret: bidders know they will learn the winning bid if they lose (loser regret condition); or the second-highest bid if they win (winner regret condition); or they will receive no feedback regarding the other bids. Bidders in loser regret condition anticipated regret and significantly overbid. However, bidders in the winner regret condition did not anticipate regret. (JEL D44)
Contracting with Repeated Moral Hazard and Private Evaluations
Authors: Fuchs William
Published: September 2007

A repeated moral hazard setting in which the Principal privately observes the Agent's output is studied. The optimal contract for a finite horizon is characterized, and shown to require burning of resources. These are only burnt after the worst possible realization sequence and the amount is independent of both the length of the horizon and the discount factor. For the infinite horizon. it is shown that there is no loss from restricting the analysis to contracts in which the Agent receives a constant efficiency wage and no feedback until he is fired. Furthermore, optimal contracts cannot be replicated by short-term contracts. A family of fixed interval review contracts is characterized. Longer review intervals are preferable but harder to implement. Comparative statics on the review length are carried out. Finally, these contracts are shown approximate first best if players are very patient. (JEL D82, D86)
Exchange Asymmetries Incorrectly Interpreted as Evidence of Endowment Effect Theory and Prospect Theory?
Authors: Plott Charles R , Zeiler Kathryn
Published: September 2007

Systematic asymmetries in exchange behavior have been widely interpreted as support for “endowment effect theory,” an application of prospect theory positing that loss aversion and utility function kinks set by entitlements explain observed asymmetries. We experimentally test an alternative explanation, namely, that asymmetries are explained by classical preference theories finding influence through the experimental procedures typically used. Contrary to the predictions of endowment effect theory, we observe no asymmetries when we modify procedures to remove the influence of classical preference theories. When we return to traditional-type procedures, however, the asymmetries reappear. The results support explanations based in classical preference theories and reject endowment effect theory. (JEL D01)
Surviving Andersonville: The Benefits of Social Networks in POW Camps
Authors: Costa Dora L , Kahn Matthew E
Published: September 2007

Twenty-seven percent of the Union Army prisoners captured July 1863 or later died in captivity. At Andersonville, the death rate may have been as high as 40 percent. How did men survive such horrific conditions? Using two independent datasets, we find that friends had a statistically significant positive effect on survival probabilities and that the closer the ties between friends as measured by such identifiers as ethnicity, kinship, and the same hometown, the bigger was the impact of friends on survival probabilities. (JEL N41, Z13)
Individual Consumption Risk and the Welfare Cost of Business Cycles
Authors: De Santis Massimiliano
Published: September 2007

We measure the welfare gain from removing aggregate consumption fluctuations in a model where each individual faces incomplete consumption insurance. We show that, because this welfare gain is a convex function of the overall consumption risk—aggregate plus idiosyncratic—each individual faces, to gauge the magnitude of the gain, it is important to match individuals' overall risk prior to any policy. In an economy calibrated to match individuals' overall risk, even removing 10 percent of aggregate fluctuations can result in a large welfare gain. Further, large gains do not necessarily depend on the countercyclical nature of idiosyncratic risk. (JEL E21, E32)
Substitution of the use of radioactivity by fluorescence for biochemical studies of RNA
Authors: Ying Bei-Wen , Fourmy Dominique , Yoshizawa Satoko
Published: September 2007

We present here the use of fluorescent methodologies for structural and functional studies of RNA in place of radioactivity. The methods are highly sensitive and quantitative with the use of an infrared fluorescence imaging system. IRD-700 and IRD-800 labels are used for fluorescence detection. Chemical probing methods are largely used for mapping RNA secondary structure and to monitor ligand interactions and conformational changes involving individual bases of RNA. The new fluorescent primer extension methodology allows simple and fast chemical probing of RNA with high sensitivity. IRD-700 and IRD-800 labeled primers can also be used to monitor protein–RNA interactions by fluorescent mobility shift assays. The speed and ease of these approaches are advantages over prior methods that used hazardous radioisotopes. Structural and biochemical investigations of RNA should benefit from the use of these fluorescent methodologies.
ISIS 301012 Gene Therapy for Hypercholesterolemia: Sense, Antisense, or Nonsense?
Authors: Ito Matthew K
Published: September 2007

Objective:

To present an overview of antisense technology and to review and assess available literature on the chemistry, pharmacology, pharmacokinetics, drug interactions, preclinical and clinical studies, dosing, and adverse events of ISIS 301012 in the treatment of hyperlipidemia.

Data Sources:

PubMed database searches were conducted from 1966 to May 2007 using the search terms ISIS 301012. antisense, oligonucleotide, hypercholesterolemia. hyperlipidemia, and apolipoprotein B. Bibliographies of relevant review articles and information from the manufacturer were reviewed for additional references.

Study Selection and Data Extraction:

Available English-language literature, including abstracts, preclinical, and clinical trials, review articles, and scientific presentations were examined.

Data Synthesis:

Apolipoprotein B is an important structural protein on the surface of atherogenic lipoproteins such as remnant very-low-density lipoprotein and low-density lipoprotein and facilitates the clearance of these particles from the circulation by binding to the low-density lipoprotein receptor. Overproduction of apolipoprotein B or reduced receptor-mediated clearance of lipoproteins leads to elevaled serum cholesterol levels and premature atherosclerosis. ISIS 301012 is an antisense oligonucleotide that inhibits apolipoprotein B production by binding directly to and reducing the expression of apolipoprotein B messenger RNA. In a clinical trial, ISIS 301012 50–400 mg administered weekly via subcutaneous injection (or 4 weeks reduced apolipoprotein B by 14.3–47.4% and low-density lipoprotein cholesterol by 5.9–40% al 55 days. The most frequent adverse event was injection-site erythema that resotved spontaneously. Studies are ongoing to further define the safety, efficacy, and pharmacokinetics of ISIS 301012 as add-on therapy in patients with heterozygous and homozygous familial hypercholesterolemia. No pharmacokinetic interactions have been demonstrated with ezetimibe and simvastatin.

Conclusions:

ISIS 301012 is the first agent to enter clinical trials utilizing an antisense mechanism for reducing the production of apolipoprotein B. Further studies are needed to verify its safety, efficacy, and position of therapy in the dyslipidemic patient.
Molecular evidence forChondrophycus poiteauivar.gemmiferuscomb. etstat. nov. (Ceramiales, Rhodophyta) from the Mexican Caribbean Sea: implications for the taxonomy of theLaurenciacomplex
Authors: Díaz-Larrea Jhoana , Sentíes Abel , Fujii Mutue T. , Pedroche Francisco F. , Oliveira Mariana C.
Published: September 2007

Molecular studies were carried out onChondrophycus gemmiferusandC. poiteaui(Rhodomelaceae) from the Mexican Caribbean Sea. These species are morphologically related, but differ mainly in the presence of the apiculate projection of epidermal cells near the apices of branches. Both species belong toChondrophycus,as indicated by the presence of two periaxial cells per axial segment and a 90° arrangement of tetrasporangia, but share characteristics withLaurenciaspecies (e.g., presence of secondary pit connections between adjacent epidermal cells). The phylogenetic position of these species was inferred by an analysis of chloroplast-encodedrbcL gene sequences of 21 taxa, using two members of the Rhodomelaceae and two of the Ceramiaceae as outgroups. The results corroborate the taxonomy of theLaurenciacomplex, which comprises the generaLaurencia, ChondrophycusandOsmundea, and indicate thatrbcL provides an adequate phylogenetic signal to study the intergeneric and interspecific relationships within the complex. In spite of this, relationships within the clade formed byC. gemmiferusandC. poiteauiwere not resolved by any analysis because of the low level of genetic variation between theirrbcL sequences (0.01–0.02%). On the basis of both molecular data and morphological similarities, we concluded thatC. gemmiferusshould be considered as a variety ofC. poiteauiand the following new combination is proposed:Chondrophycus poiteauivar.gemmiferus(Harvey) comb. etstat. nov.
PIASx Is a MEF2 SUMO E3 Ligase That Promotes Postsynaptic Dendritic Morphogenesis
Authors: Shalizi Aryaman , Bilimoria Parizad M. , Stegmüller Judith , Gaudillière Brice , Yang Yue , Shuai Ke , Bonni Azad
Published: September 2007

Postsynaptic morphogenesis of dendrites is essential for the establishment of neural connectivity in the brain, but the mechanisms that govern postsynaptic dendritic differentiation remain poorly understood. Sumoylation of the transcription factor myocyte enhancer factor 2A (MEF2A) promotes the differentiation of postsynaptic granule neuron dendritic claws in the cerebellar cortex. Here, we identify the protein PIASx as a MEF2 SUMO E3 ligase that represses MEF2-dependent transcription in neurons. Gain-of-function and genetic knockdown experiments in rat cerebellar slices and in the postnatal cerebellumin vivoreveal that PIASx drives the differentiation of granule neuron dendritic claws in the cerebellar cortex. MEF2A knockdown suppresses PIASx-induced dendritic claw differentiation, and expression of sumoylated MEF2A reverses PIASx knockdown-induced loss of dendritic claws. These findings define the PIASx-MEF2 sumoylation signaling link as a key mechanism that orchestrates postsynaptic dendritic claw morphogenesis in the cerebellar cortex and suggest novel functions for SUMO E3 ligases in brain development and plasticity.
Swimming against the Tide: Mobility of the Microtubule-Associated Protein Tau in Neurons
Authors: Konzack Sven , Thies Edda , Marx Alexander , Mandelkow Eva-Maria , Mandelkow Eckhard
Published: September 2007

Long-haul transport along microtubules is crucial for neuronal polarity, and transport defects cause neurodegeneration. Tau protein stabilizes microtubule tracks, but in Alzheimer's disease it aggregates and becomes missorted into the somatodendritic compartment. Tau can inhibit axonal transport by obstructing motors on microtubules, yet tau itself can still move into axons. We therefore investigated tau movement by live-cell fluorescence microscopy, FRAP (fluorescence recovery after photobleaching), and FSM (fluorescence speckle microscopy). Tau is highly dynamic, with diffusion coefficients of ∼3 μm2/s and microtubule dwell times of ∼4 s. This facilitates the entry of tau into axons over distances of millimeters and periods of days. For longer distances and times, two mechanisms of tau transport are observed. At low near-physiological levels, tau is cotransported with microtubule fragments from cell bodies into axons, moving at instantaneous velocities ∼1 μm/s. At high concentrations, tau forms local accumulations moving bidirectionally at ∼0.3 μm/s. These clusters first appear at distal endings of axons and may indicate an early stage of neurite degeneration.
Synaptic Integration of Adult-Generated Olfactory Bulb Granule Cells: Basal Axodendritic Centrifugal Input Precedes Apical Dendrodendritic Local Circuits
Authors: Whitman Mary C. , Greer Charles A.
Published: September 2007

The adult mammalian olfactory bulb (OB) receives a continuing influx of new interneurons. Neuroblasts from the subventricular zone (SVZ) migrate into the OB and differentiate into granule cells and periglomerular cells that are presumed to integrate into the synaptic circuits of the OB. We have used retroviral infection into the SVZ of mice to label adult-generated granule cells and follow their differentiation and integration into OB circuitry. Using synaptic markers and electron microscopy, we show new granule cells integrating into the reciprocal circuitry of the external plexiform layer (EPL), beginning at 21 d postinfection (dpi). We further show that synapses are formed earlier, beginning at 10 dpi, on the somata and basal dendrites of new cells in the granule cell layer (GCL), before dendritic elaboration in the EPL. In the EPL, elaborate dendritic arbors with spines are first evident at 14 dpi. The density of spines increases from 14 to 28 dpi, and then decreases by 56 dpi. Despite the initial appearance of dendritic spines at 14 dpi in the EPL, no expression of presynaptic or postsynaptic markers is seen until 21 dpi. These data suggest that adult-generated granule cells are first innervated by centrifugal or mitral/tufted cell axon collaterals in the GCL and that these inputs may contribute to their differentiation, maturation, and synaptic integration into the dendrodendritic local circuits found in the EPL.