bluuebunny/crossref_metadata_2025 huggingface dataset:
Contraception in Late Nineteenth-and Early Twentieth-Century Finland
Authors: Pitkänen Kari J.
Published: December 2003

Finland's fertility decline started in the 1880s among educated people, and in the 1910s among the masses. By the late 1930s, fertility had started to decline even at the most remote areas. Various documents, such as newspapers, magazines, pamphlets, and ethnographic collections, show that although mechanical, quasimodern contraceptives were widely sold and actively marketed in Finland by the early twentieth century, they were mostly used by the upper social segments of the population, and, to some extent, by the working classes of the urban and industrial centers. The primary methods of birth control used by the masses were withdrawal, often in connection with douching and abortion.
Abortion, Birth Control, and Contraception: Fertility Decline in Norway
Authors: Sogner Sølvi
Published: December 2003

Between 1890 and 1930, fertility in Norway was halved; four variables accounted for 63 percent of explained variance. Socioeconomic factors were clearly more important than cultural ones—a finding that does not necessarily contradict results found in other studies: Within a homogenous cultural framework, fertility decline tends to follow socioeconomic development. Qualitative findings corroborate the regression analysis: Districts where women made their earliest and most active use of the right to vote for Parliament—obtained in 1913—also pioneered early fertility decline.
“They Prefer Withdrawal”: The Choice of Birth Control in Britain, 1918–1950
Authors: Fisher Kate , Szreter Simon
Published: December 2003

New findings from an oral-history research project investigating sexuality, marriage, and birth control among working-class couples born in the first quarter of the twentieth century run contrary to the family-planning and marriageguidance manuals of the period, as well to demographers' and historians' assumptions. These couples tended to prefer traditional methods of birth control, notably withdrawal, to more modern, mechanical, ones on the grounds that they were more “natural”. Although many respondents acknowledged that withdrawal compromised sensual pleasure to some extent, most saw equivalent, or worse, drawbacks in the other available means of birth control.
The Fall of Kinship: Towards an Epidemiological Explanation
Authors: Sousa Paulo
Published: December 2003

Kinship used to be described as what anthropologists do. Today, many might well say that it is what anthropologists do not do. One possible explanation is that the notion of kinship fell off anthropology's radar due to the criticisms raised by Needham and Schneider among others, which supposedly demonstrated that kinship is not a sound theoretical concept. Drawing inspiration from epidemiological approaches to cultural phenomena, this article aims to enrich this explanation. Kinship became an unattractive theoretical concept in the subculture of anthropology not simply because of problems with kinship theory per se, but also on account of fundamental changes in the very conception of anthropological knowledge and the impact of these changes on the personal identity of anthropologists.
The “Information Divide” in the Climate Sciences
Authors: Gettelman Andrew
Published: December 2003

The gap between the availability of information in developed and developing countries in climate and meteorology is described and detailed. The description is based on a recent survey of scientists around the world. The information divide results from the high costs of information and lack of resources in many countries and can be compounded by language difficulties and cultural differences. This has led to the breakdown in the flow of weather and forecast data, the flow of journals to developing countries, and the flow of the results of scientific work back to these same journals from developing countries. With the increasing electronic flow of information, many countries are also limited by costly and low-bandwidth access to the Internet. Several ideas for bridging the information divide are also presented, ranging from electronic distribution of journals, to increasing capacity to deal with information, to a commitment to include all users in new strategies for delivering information.
Collaboration between Forecasters and Research Scientists at the NSSL and SPC: The Spring Program
Authors: Kain John S. , Janish Paul R. , Weiss Steven J. , Baldwin Michael E. , Schneider Russell S. , Brooks Harold E.
Published: December 2003

Collaborative activities between operational forecasters and meteorological research scientists have the potential to provide significant benefits to both groups and to society as a whole, yet such collaboration is rare. An exception to this state of affairs is occurring at the National Severe Storms Laboratory (NSSL) and Storm Prediction Center (SPC). Since the SPC moved from Kansas City to the NSSL facility in Norman, Oklahoma in 1997, collaborative efforts between researchers and forecasters at this facility have begun to flourish. This article presents a historical background for this interaction and discusses some of the factors that have helped this collaboration gain momentum. It focuses on the 2001 Spring Program, a collaborative effort focusing on experimental forecasting techniques and numerical model evaluation, as a prototype for organized interactions between researchers and forecasters. In addition, the many tangible and intangible benefits of this unusual working relationship are discussed.
Improvement of Microphysical Parameterization through Observational Verification Experiment
Authors: Stoelinga Mark T. , Hobbs Peter V. , Mass Clifford F. , Locatelli John D. , Colle Brian A. , Houze Robert A. , Rangno Arthur L. , Bond Nicholas A. , Smull Bradley F. , Rasmussen Roy M. , Thompson Gregory , Colman Bradley R.
Published: December 2003

Despite continual increases in numerical model resolution and significant improvements in the forecasting of many meteorological parameters, progress in quantitative precipitation forecasting (QPF) has been slow. This is attributable in part to deficiencies in the bulk microphysical parameterization (BMP) schemes used in mesoscale models to simulate cloud and precipitation processes. These deficiencies have become more apparent as model resolution has increased. To address these problems requires comprehensive data that can be used to isolate errors in QPF due to BMP schemes from those due to other sources. These same data can then be used to evaluate and improve the microphysical processes and hydrometeor fields simulated by BMP schemes. In response to the need for such data, a group of researchers is collaborating on a study titled the Improvement of Microphysical Parameterization through Observational Verification Experiment (IMPROVE). IMPROVE has included two field campaigns carried out in the Pacific Northwest: an offshore frontal precipitation study off the Washington coast in January–February 2001, and an orographic precipitation study in the Oregon Cascade Mountains in November–December 2001. Twenty-eight intensive observation periods yielded a uniquely comprehensive dataset that includes in situ airborne observations of cloud and precipitation microphysical parameters; remotely sensed reflectivity, dual-Doppler, and polarimetric quantities; upper-air wind, temperature, and humidity data; and a wide variety of surface-based meteorological, precipitation, and microphysical data. These data are being used to test mesoscale model simulations of the observed storm systems and, in particular, to evaluate and improve the BMP schemes used in such models. These studies should lead to improved QPF in operational forecast models.
Design and Construction of an Affordable Rotating Table for Classroom Demonstrations of Geophysical Fluid Dynamics Principles
Authors: McNoldy Brian D. , Cheng Anning , Eitzen Zachary A. , Moore Richard W. , Persing John , Schaefer Kevin , Schubert Wayne H.
Published: December 2003

Rotating tables have been in use for many years because of their ability to demonstrate fluid dynamical phenomena, shedding insight on the sometimes complicated or esoteric mathematics used to describe such processes. A small team of students at the Colorado State University (CSU) Department of Atmospheric Science constructed a rotating table, or “spin tank,” assembly that is simple and affordable, yet instructive.

The apparatus is designed to be easy to maintain and operate. The number of moving parts is kept at a minimum, and the electrical components chosen are of high quality. With the aid of a brief instruction manual or tutorial, students and faculty can operate the rotating table and easily perform many demonstrations, with the freedom to vary fluid depth, rotation rate, and acceleration. The entire design and construction process was conducted on a limited budget of $3,000.

A spin tank such as this has practical applications for the qualitative study of fluid dynamics. Fundamental concepts in rotating flow dynamics can be demonstrated to supplement the more rigorous mathematical treatment typically given in oceanography or atmospheric physics graduate-level courses. Topics that have been explored thus far are Ekman pumping, Taylor columns, and barotropic instability, but could be broadened to include subjects such as Rossby waves, baroclinic instability, vortex merger, and thermal convection.
Mature dendritic cells can enhance CD8+ cell noncytotoxic anti-HIV responses: the role of IL-15
Authors: Castelli JoAnn , Thomas Elaine K. , Gilliet Michel , Liu Yong-Jun , Levy Jay A.
Published: December 2003

The CD8+ cell noncytotoxic anti-HIV response (CNAR) is associated with a long-term healthy clinical state in HIV-infected individuals. Over time CNAR is reduced concomitant with progression to disease. In studies to evaluate whether the interaction between CD8+ cells and dendritic cells (DCs) could increase CNAR, CD8+ cells from individuals who showed a decrease in this antiviral activity were cocultured with monocyte-derived dendritic cells matured with CD40 ligand. After coculture with these mature DCs, the CD8+ cells showed an increase in CNAR greater than that observed with CD8+ cells costimulated with CD3/CD28 antibodies. This antiviral response appeared to be mediated primarily by production of interleukin-15 (IL-15) by the mature DCs. Purified IL-15 also enhanced CNAR, whereas IL-12 showed no substantial effect. These studies provide another potential approach by which the immune system in HIV infection could be restored by cytokine therapy, particularly IL-15 administration. (Blood. 2004;103:2699-2704)
Molecular basis for a dominant inactivation of RUNX1/AML1 by the leukemogenic inversion 16 chimera
Authors: Huang Gang , Shigesada Katsuya , Wee Hee-Jun , Liu P. Paul , Osato Motomi , Ito Yoshiaki
Published: December 2003

The Runt domain transcription factor, PEBP2/CBF, is a heterodimer composed of 2 subunits. The DNA-binding α subunit, or RUNX protein, interacts with a partner PEBP2β/CBFβ through the evolutionarily conserved Runt domain. Each of the genes encoding RUNX1 and PEBP2β/CBFβ is frequently involved in acute myeloid leukemia. The chimeric protein, CBFβ(PEBP2β)/SMMHC, is generated as a result of inversion of chromosome 16 in such a way to retain the heterodimerization domain of PEBP2β at the amino-terminal side fused to the C-terminal coiled-coil region of smooth muscle myosin heavy chain (SMMHC). Here we show that, in the chimeric protein, the second heterodimerization domain is created by the fusion junction, enabling the chimeric protein to interact with RUNX1 at far greater affinity than PEBP2β and inactivate the RUNX1/AML1 function. To explain why and how heterozygous CBFB/MYH11 can inactivate homozygous RUNX1 near to completion, we propose a new model for this chimeric protein that consists of a Y-shaped dimer with unpaired N-terminal halves followed by a coiled-coil for the C-terminal region. (Blood. 2004;103:3200-3207)
Uninfected erythrocytes inhibit Plasmodium falciparum–induced cellular immune responses in whole-blood assays
Authors: Struik Siske S. , Omer Fakhreldin M. , Artavanis-Tsakonas Katerina , Riley Eleanor M.
Published: December 2003

Whole-blood assays (WBAs) have been successfully used as a simple tool for immuno-epidemiological field studies evaluating cellular immune responses to mycobacterial and viral antigens. Rather unexpectedly, we found very poor cytokine responses to malaria antigens in WBAs in 2 immuno-epidemiological studies carried out in malaria endemic populations in Africa. We have therefore conducted a detailed comparison of cellular immune responses to live (intact) and lysed malaria-infected erythrocytes in WBAs and in peripheral blood mononuclear cell (PBMC) cultures. We observed profound inhibition of both proliferative and interferon-γ responses to malarial antigens in WBAs as compared with PBMC cultures. This inhibition was seen only for malaria antigens and could not be overcome by increasing either antigen concentration or responder cell numbers. Inhibition was mediated by intact erythrocytes and occurred early in the culture period, suggesting that failure of antigen uptake might underlie the lack of T-cell responses. In support of this hypothesis, we have shown that intact uninfected erythrocytes specifically inhibit phagocytosis of infected red blood cells by peripheral blood monocytes. We propose that specific biochemical interactions with uninfected erythrocytes inhibit the phagocytosis of malaria-infected erythrocytes and that this may impede T-cell recognition in vivo. (Blood. 2004; 103:3084-3092)
Gene expression profile of adult T-cell acute lymphocytic leukemia identifies distinct subsets of patients with different response to therapy and survival
Authors: Chiaretti Sabina , Li Xiaochun , Gentleman Robert , Vitale Antonella , Vignetti Marco , Mandelli Franco , Ritz Jerome , Foa Robin
Published: December 2003

Gene expression profiles were examined in 33 adult patients with T-cell acute lymphocytic leukemia (T-ALL). Nonspecific filtering criteria identified 313 genes differentially expressed in the leukemic cells. Hierarchical clustering of samples identified 2 groups that reflected the degree of T-cell differentiation but was not associated with clinical outcome. Comparison between refractory patients and those who responded to induction chemotherapy identified a single gene, interleukin 8 (IL-8), that was highly expressed in refractory T-ALL cells and a set of 30 genes that was highly expressed in leukemic cells from patients who achieved complete remission. We next identified 19 genes that were differentially expressed in T-ALL cells from patients who either had a relapse or remained in continuous complete remission. A model based on the expression of 3 of these genes was predictive of duration of remission. The 3-gene model was validated on a further set of T-ALL samples from 18 additional patients treated on the same clinical protocol. This study demonstrates that gene expression profiling can identify a limited number of genes that are predictive of response to induction therapy and remission duration in adult patients with T-ALL. (Blood. 2004;103:2771-2778)
Are SOCS suppressors, regulators, and degraders?
Authors: Johnston James A
Published: December 2003

Suppressors of cytokine signaling have been identified as inhibitors of cytokine signaling and have been shown to act in a classical feedback loop. The prototype members of this family, cytokine-inducible Src homology 2-containing protein and suppressors of cytokine signaling SOC was cloned as cytokine-inducible immediate early gene that could inhibit the activation of signal transducer and activator of transcription factors and block biological responses to several cytokines. Although steady progress has been made in the identification of SOCS and their physiological importance, precisely how SOCS proteins function has not yet been discovered. Many recent findings indicate that the SOCS act as adaptors that regulate the turnover of certain substrates by interacting with and activating an E3 ubiquitin ligase. Here, I explore recent evidence (presented at the International Cytokine Society meeting in Dublin, Ireland, September 2003) that SOCS molecules may not act simply as regulators of cytokine responses but may also play an essential role in determining cell fate and controlling cell differentiation.
Pathologic Variables and Recurrence Rates As Related to Obesity and Race in Men With Prostate Cancer Undergoing Radical Prostatectomy
Authors: Amling Christopher L. , Riffenburgh Robert H. , Sun Leon , Moul Judd W. , Lance Raymond S. , Kusuda Leo , Sexton Wade J. , Soderdahl Douglas W. , Donahue Timothy F. , Foley John P. , Chung Andrew K. , McLeod David G.
Published: December 2003

Purpose

To determine if obesity is associated with higher prostate specific antigen recurrence rates after radical prostatectomy (RP), and to explore racial differences in body mass index (BMI) as a potential explanation for the disparity in outcome between black and white men.

Patients and Methods

A retrospective, multi-institutional pooled analysis of 3,162 men undergoing RP was conducted at nine US military medical centers between 1987 and 2002. Patients were initially categorized as obese (BMI ≥ 30 kg/m2), overweight (BMI 25 to 30 kg/m2), or normal (BMI ≤ 25 kg/m2). For analysis, normal and overweight groups were combined (BMI < 30 kg/m2) and compared with the obese group (BMI ≥ 30 kg/m2) with regard to biochemical recurrence (prostate-specific antigen ≥ 0.2 ng/mL) after RP.

Results

Of 3,162 patients, 600 (19.0%) were obese and 2,562 (81%) were not obese. BMI was an independent predictor of higher Gleason grade cancer (P < .001) and was associated with a higher risk of biochemical recurrence (P = .027). Blacks had higher BMI (P < .001) and higher recurrence rates (P = .003) than whites. Both BMI (P = .028) and black race (P = .002) predicted higher prostate specific antigen recurrence rates. In multivariate analysis of race, BMI, and pathologic factors, black race (P = .021) remained a significant independent predictor of recurrence.

Conclusion

Obesity is associated with higher grade cancer and higher recurrence rates after RP. Black men have higher recurrence rates and greater BMI than white men. These findings support the hypothesis that obesity is associated with progression of latent to clinically significant prostate cancer (PC) and suggest that BMI may account, in part, for the racial variability in PC risk.
Are Patients Diagnosed With Breast Cancer Before Age 50 Years Ever Cured?
Authors: Brenner Hermann , Hakulinen Timo
Published: December 2003

Purpose

Breast cancer diagnosed before the age of 50 years has become a common disease in many developed countries. Although average remaining life expectancy in the affected age groups is usually several decades, data regarding survival perspectives beyond 10 to 20 years after diagnosis are sparse. The aim of this study was to assess long-term survival in a large population-based sample of patients diagnosed with breast cancer before age 50 years.

Patients and Methods

Relative survival within up to 40 years after diagnosis was assessed for cohorts of women diagnosed with breast cancer before age 50 years and notified to the nationwide Finnish Cancer Registry within various time intervals since 1953. In addition, up-to-date estimates of 40-year relative survival were obtained by exclusively looking at the survival experience of breast cancer patients in recent years (1993 to 1999) using period analysis, a new method of survival analysis.

Results

Prognosis of patients diagnosed with breast cancer before age 50 years has considerably improved during the past decades. According to the latest estimates from period analysis, cumulative 40-year relative survival is now approximately 43% for all cancers combined, 57% for localized cancers, and 24% for cancers with regional tumor spread. Nevertheless, patients diagnosed with breast cancer before age 50 years continue to have increased mortality throughout at least four decades after diagnosis. This applies even if breast cancer is diagnosed in a localized stage and in the absence of a second primary breast cancer.

Conclusion

Despite major improvement in prognosis over time, breast cancer occurring among patients who are younger than 50 years remains a chronic disease that affects prognosis for decades.
Luteinizing Hormone-Induced Connexin 43 Down-Regulation: Inhibition of Translation
Authors: Kalma Yael , Granot Irit , Galiani Dalia , Barash Amihai , Dekel Nava
Published: December 2003

The coordinated function of the different compartments of the follicle, the oocyte and the somatic cumulus/granulosa cells, is enabled by the presence of a network of cell-to-cell communication generated by gap junctions. Connexin 43 (Cx43) is the most abundant gap junction protein expressed by the ovarian follicle. The expression of Cx43 is subjected to the control of gonadotropins as follows: FSH up-regulates, whereas LH down-regulates its levels. The aim of this study was to explore the mechanism by which LH reduces the levels of Cx43 and to identify the signal transduction pathway involved in this process. The effect of LH was studied in vitro using isolated intact ovarian follicles. The possible mediators of LH-induced Cx43 down-regulation were examined by incubating the follicles with LH in the presence or absence of inhibitors of protein kinase A (PKA) and of MAPK signaling pathways. Our experiments revealed a 3-h half-life of Cx43 in both control and LH-treated follicles, suggesting that LH did not affect the rate of Cx43 degradation. We further demonstrated that the level of Cx43 mRNA was not significantly influenced by this gonadotropin. However, upon LH administration, [35S]methionine incorporation into Cx43 protein was remarkably reduced. The LH-induced arrest of Cx43 synthesis was counteracted by inhibitors of both the PKA and the MAPK cascades. We show herein that LH inhibits Cx43 expression by reducing its rate of translation and that this effect is mediated by both PKA and MAPK.
Insulin-Like Growth Factor-Induced Transcriptional Activity of the Skeletal α-Actin Gene Is Regulated by Signaling Mechanisms Linked to Voltage-Gated Calcium Channels during Myoblast Differentiation
Authors: Spangenburg Espen E. , Bowles Douglas K. , Booth Frank W.
Published: December 2003

IGF-I activates signaling pathways that increase the expression of muscle-specific genes in differentiating myoblasts. Induction of skeletal α-actin expression occurs during differentiation through unknown mechanisms. The purpose of this investigation was to examine the mechanisms that IGF-I uses to induce skeletal α-actin gene expression in C2C12 myoblasts. IGF-I increased skeletal α-actin promoter activity by 107% compared with the control condition. Ni+ [T-type voltage-gated Ca2+ channel (VGCC) inhibitor] reduced basal-induced activation of the skeletal α-actin promoter by approximately 84%, and nifedipine (L-type VGCC inhibitor) inhibited IGF-I-induced activation of the skeletal α-actin promoter by 29–48%. IGF-I failed to increase skeletal α-actin promoter activity in differentiating dysgenic (lack functional L-type VGCC) myoblasts; 30 mm K+ and 30 mm K++IGF-I increased skeletal α-actin promoter activity by 162% and 76% compared with non-IGF-I or IGF-I-only conditions, respectively. IGF-I increased calcineurin activity, which was inhibited by cyclosporine A. Further, cyclosporine A inhibited K++IGF-I-induced activation of the skeletal α-actin promoter. Constitutively active calcineurin increased skeletal α-actin promoter activity by 154% and rescued the nifedipine-induced inhibition of L-type VGCC but failed to rescue the Ni+-inhibition of T-type VGCC. IGF-I-induced nuclear factor of activated T-cells transcriptional activity was not inhibited by nifedipine or Ni+. IGF-I failed to increase serum response factor transcriptional activity; however, serum response factor activity was reduced in the presence of Ni+. These data suggest that IGF-I-induced activation of the skeletal α-actin promoter is regulated by the L-type VGCC and calcineurin but independent of nuclear factor of activated T-cell transcriptional activity as C2C12 myoblasts differentiate into myotubes.
Fos and Jun Inhibit Estrogen-Induced Transcription of the Human Progesterone Receptor Gene through an Activator Protein-1 Site
Authors: Petz Larry N. , Ziegler Yvonne S. , Schultz Jennifer R. , Nardulli Ann M.
Published: December 2003

The progesterone receptor (PR) gene is activated by estrogen in normal reproductive tissues and in MCF-7 human breast cancer cells. Although it is typically thought that estrogen responsiveness is mediated through estrogen response elements (EREs), the human PR gene lacks a palindromic ERE sequence. We have identified an activating protein-1 (AP-1) site at +745 in the human PR gene that bound purified Fos and Jun and formed a complex with Fos/Jun heterodimers present in MCF-7 nuclear extracts. Surprisingly, mutating the +745 AP-1 site in the context of a 1.5-kb region of the PR gene significantly enhanced estrogen receptor (ER) α-mediated transactivation, suggesting that the wild-type +745 AP-1 site plays a role in inhibiting PR gene expression in the presence of hormone. In support of this idea, transient transfection assays demonstrated that increasing levels of Fos and Jun repressed transcription of a reporter plasmid containing the +745 AP-1 site. Fos levels were transiently increased, ERα levels were decreased, and Jun was dephosphorylated after MCF-7 cells were treated with estrogen. Chromatin immunoprecipitation assays demonstrated that Jun was associated with the +745 AP-1 site in the endogenous PR gene in the presence and in the absence of estrogen, but that ERα and Fos were only associated with the +745 AP-1 site after estrogen treatment of MCF-7 cells. Our studies suggest that the human PR gene is regulated by multiple transcription factors and that the differential binding of these dynamically regulated trans-acting factors influences gene expression.
The EZC-Prostate Model: Noninvasive Prostate Imaging in Living Mice
Authors: Xie Xiaoming , Luo Zheng , Slawin Kevin M. , Spencer David M.
Published: December 2003

Recently, progress in the development of prostate-specific promoters and high resolution imaging techniques has made real-time monitoring of transgenic expression possible, opening a vista of potentially important in vivo models of prostate disease. Herein, we describe a novel prostate reporter model, called the EZC-prostate model that permits both ex vivo and in vivo imaging of the prostate using a sensitive charge-coupled device. Firefly luciferase and enhanced green fluorescent protein were targeted to the prostate epithelium using the composite human kallikrein 2 (hK2)-based promoter, hK2-E3/P. In EZC-prostate mice, the ventral and dorsal/lateral prostate lobes were brilliant green under fluorescence microscopy, with expression localized to the secretory epithelium. In contrast, enhanced green fluorescent protein was undetectable in the anterior lobes of prostate, seminal vesicles, testes, liver, lung, and brain. The kinetics of luciferase activity in intact and castrated living mice monitored with the IVIS charge-coupled device-based imaging system confirmed that firefly luciferase expression was largely prostate restricted, increased with age up to 24 wk, and was androgen dependent. Decreases in reporter expression after 24 wk may reflect well known, age-related decreases in androgen signaling with age in humans. Ex vivo imaging of microdissected animals further confirmed that the luminescence detected in living mice emanated predominately from the prostate, with minor signals originating from the testes and cecum. These data demonstrate that the hK2-E3/P promoter directs strong prostate-specific expression in a transgenic mouse model. Multigenic models, generated by crosses with various hyperplastic and neoplastic prostate disease models, could potentially provide powerful new tools in longitudinal monitoring of changes in prostate size, androgen signaling, metastases, or response to novel therapies without sacrificing large cohorts of animals.
Partial loss-of-function alleles reveal a role forGNOMin auxin transport-related, post-embryonic development ofArabidopsis
Authors: Geldner Niko , Richter Sandra , Vieten Anne , Marquardt Sebastian , Torres-Ruiz Ramon A. , Mayer Ulrike , Jürgens Gerd
Published: December 2003

The Arabidopsis GNOM gene encodes an ARF GDP/GTP exchange factor involved in embryonic axis formation and polar localisation of the auxin efflux regulator PIN1. To examine whether GNOM also plays a role in post-embryonic development and to clarify its involvement in auxin transport,we have characterised newly isolated weak gnom alleles as well as trans-heterozygotes of complementing strong alleles. These genotypes form a phenotypic series of GNOM activity in post-embryonic development,with auxin-related defects, especially in the maintenance of primary root meristem activity and in the initiation and organisation of lateral root primordia. Our results suggest a model for GNOM action mediating auxin transport in both embryogenesis and post-embryonic organ development.
The planar cell polarity protein Strabismus promotes Pins anterior localization during asymmetric division of sensory organ precursor cells inDrosophila
Authors: Bellaïche Yohanns , Beaudoin-Massiani Olivia , Stüttem Isabella , Schweisguth François
Published: December 2003

Cell fate diversity is generated in part by the unequal segregation of cell-fate determinants during asymmetric cell division. In the Drosophila bristle lineage, the sensory organ precursor (pI) cell is polarized along the anteroposterior (AP) axis by Frizzled (Fz) receptor signaling. We show here that Fz localizes at the posterior apical cortex of the pI cell prior to mitosis, whereas Strabismus (Stbm) and Prickle (Pk),which are also required for AP polarization of the pI cell, co-localize at the anterior apical cortex. Thus, asymmetric localization of Fz, Stbm and Pk define two opposite cortical domains prior to mitosis of the pI cell. At mitosis, Stbm forms an anterior crescent that overlaps with the distribution of Partner of Inscuteable (Pins) and Discs-large (Dlg), two components of the anterior Dlg-Pins-Gαi complex that regulates the localization of cell-fate determinants. At prophase, Stbm promotes the anterior localization of Pins. By contrast, Dishevelled (Dsh) acts antagonistically to Stbm by excluding Pins from the posterior cortex. We propose that the Stbm-dependent recruitment of Pins at the anterior cortex of the pI cell is a novel read-out of planar cell polarity.
Multiple signaling pathways and a selector protein sequentially regulateDrosophilawing development
Authors: Yan Shian-Jang , Gu Yi , Li Willis X. , Fleming Robert J.
Published: December 2003

Drosophila wing development is a useful model to study organogenesis, which requires the input of selector genes that specify the identity of various morphogenetic fields (Weatherbee, S. D. and Carroll, S. B.(1999) Cell 97, 283-286) and cell signaling molecules. In order to understand how the integration of multiple signaling pathways and selector proteins can be achieved during wing development, we studied the regulatory network that controls the expression of Serrate (Ser), a ligand for the Notch(N) signaling pathway, which is essential for the development of the Drosophila wing, as well as vertebrate limbs. Here, we show that a 794 bp cis-regulatory element located in the 3′ region of the Ser gene can recapitulate the dynamic patterns of endogenous Ser expression during wing development. Using this enhancer element,we demonstrate that Apterous (Ap, a selector protein), and the Notch and Wingless (Wg) signaling pathways, can sequentially control wing development through direct regulation of Ser expression in early, mid and late third instar stages, respectively. In addition, we show that later Ser expression in the presumptive vein cells is controlled by the Egfr pathway. Thus, a cis-regulatory element is sequentially regulated by multiple signaling pathways and a selector protein during Drosophila wing development. Such a mechanism is possibly conserved in the appendage outgrowth of other arthropods and vertebrates.
Characterization of a novel ZP3-independent sperm-binding ligand that facilitates sperm adhesion to the egg coat
Authors: Rodeheffer Carey , Shur Barry D.
Published: December 2003

During mammalian fertilization, sperm adhere to the extracellular coat of the egg, or zona pellucida, in a species-specific manner. In mouse, evidence suggests that sperm recognize and bind to specific oligosaccharide ligands within the zona pellucida glycoprotein, ZP3, viaβ1,4-galactosyltransferase I (GalT I), a lectin-like receptor on the sperm surface. Although in vitro experiments using isolated gametes lend support to this model, recent in vivo studies of genetically altered mice question whether ZP3 and/or GalT I are solely responsible for sperm-egg binding. In this regard, sperm from GalT I-null mice bind poorly to ZP3 and fail to undergo a zona-induced acrosome reaction; however, they still bind to the ovulated egg coat in vitro.

In this report, we characterize a novel ZP3- and GalT I-independent mechanism for sperm adhesion to the egg coat. Results show that the ovulated zona pellucida contains at least two distinct ligands for sperm binding: a ZP3-independent ligand that is peripherally associated with the egg coat and facilitates gamete adhesion; and a ZP3-dependent ligand that is present in the insoluble zona matrix and is recognized by sperm GalT I to facilitate acrosomal exocytosis. The ZP3-independent ligand is not a result of contamination by egg cortical granules, nor is it the mouse homolog of oviduct-specific glycoprotein. It behaves as a 250 kDa, WGA-reactive glycoprotein with a basic isoelectric point, distinguishing it from the acidic glycoproteins that form the insoluble matrix of the egg coat. When eluted from isoelectric focusing gels, the acidic matrix glycoproteins possess sperm-binding activity for wild-type sperm, but not for GalT I-null sperm,whereas the basic glycoprotein retains sperm-binding activity for both wild-type and GalT I-null sperm. Thus, GalT I-null sperm are able to resolve gamete recognition into at least two distinct binding events, leading to the characterization of a novel, peripherally associated, sperm-binding ligand on the ovulated zona pellucida.
Inactivation of mouse Twisted gastrulation reveals its role in promoting Bmp4 activity during forebrain development
Authors: Zakin Lise , De Robertis E. M.
Published: December 2003

Twisted gastrulation (Tsg) is a secreted protein that regulates Bmp signaling in the extracellular space through its direct interaction with Bmp/Dpp and Chordin (Chd)/Short gastrulation (Sog). The ternary complex of Tsg/Chd/Bmp is cleaved by the metalloprotease Tolloid (Tld)/Xolloid (Xld). Studies in Drosophila, Xenopus and zebrafish suggest that Tsg can act both as an anti-Bmp and as a pro-Bmp. We have analyzed Tsgloss-of-function in the mouse. Tsg homozygous mutants are viable but of smaller size and display mild vertebral abnormalities and osteoporosis. We provide evidence that Tsg interacts genetically with Bmp4. When only one copy of Bmp4 is present, a requirement of Tsgfor embryonic development is revealed. Tsg-/-;Bmp4+/- compound mutants die at birth and display holoprosencephaly, first branchial arch and eye defects. The results show that Tsg functions to promote Bmp4 signaling during mouse head development.
Reciprocal regulation of urokinase receptor (CD87)-mediated cell adhesion by plasminogen activator inhibitor-1 and protease nexin-1
Authors: Kanse Sandip M. , Chavakis Triantafyllos , Al-Fakhri Nadia , Hersemeyer Karin , Monard Denis , Preissner Klaus T.
Published: December 2003

Protease nexin-1 (PN-1) and plasminogen activator inhibitor-1 (PAI-1) are serine protease inhibitors that bind to the extracellular matrix protein vitronectin (VN) with high affinity. PAI-1 is known to inhibit cell adhesion and migration by binding to VN and inhibiting the interaction with integrins or the urokinase receptor (uPAR). Unexpectedly, PN-1 was found to increase the association between VN and uPAR in the presence of enzymatically active uPA. Through this mechanism PN-1 also stimulated uPAR-dependent cell adhesion to immobilized VN. In contrast to PAI-1, PN-1 did not influence VN binding to integrins or integrin-mediated cell adhesion. Upon adhesion of monocytes to VN there was an accumulation of uPAR and PN-1 at the interface between the cell and the matrix, whereas on fibronectin (FN) both components were distributed evenly over the whole cell as visualized by confocal microscopy. Immunohistochemistry of atherosclerotic vessels indicated that PN-1 was found associated with smooth muscle cells, macrophages and platelets. In some regions of the diseased vessels PN-1 was in close proximity to VN and uPAR, but no PN-1 was present in normal vessels. These results indicate a novel function of PN-1 linked to complex formation with uPA that leads to the regulation of VN-dependent adhesion of leukocytes.
Meltzer's History of the Federal Reserve
Authors: Laidler David
Published: December 2003

This review argues that Allan Meltzer's account of the Federal Reserve between 1913 and 1951 complements Friedman and Schwartz's in their Monetary History. Meltzer emphasizes policy making within the system, rather than the evolution of the money supply and its effects on the economy. He stresses the uncertainty of the Fed's independence before the 1951 Accord, and the effects of economic ideas, notably the real bills and Riefler-Burgess doctrines, on policy. Many virtues in the book are noted, and one weakness, namely a failure to explain why inadequate ideas became dominant within the Fed when sounder alternatives were available in contemporary monetary thought.
Predecisional Distortion of Information by Auditors and Salespersons
Authors: Russo J. Edward , Meloy Margaret G. , Wilks T. Jeffrey
Published: December 2003

As people are deciding between two alternatives, they may distort new information to support whichever alternative is tentatively preferred. The presence of such predecisional distortion of information was tested in decisions made by two groups of professionals, auditors and salespersons. Both groups exhibited substantial distortion of information, with little reduction for professional decisions compared to nonprofessional ones. However, auditors' distortion was significantly smaller than that of salespersons. In addition, holding professionals accountable for their decisions, akin to a supervisory review, lowered distortion somewhat for salespersons but not at all for auditors. The latter seemed to act as if they were always being held accountable. Because people seem unaware that they are distorting information, at least at the moment this bias is occurring, they are fully convinced of the soundness of their choices. This may make it difficult for distortion to be detected by decision makers themselves or even by supervisors who cannot completely duplicate their subordinate's knowledge.
What's Experience Got to Do With It? Sources of Cost Reduction in a Large Specialty Chemicals Producer
Authors: Sinclair Gavin , Klepper Steven , Cohen Wesley
Published: December 2003

Conventional learning curves relating unit cost to measures of production experience are estimated for 221 specialty chemicals produced by a Fortune 500 company. Detailed records on cost and R…D coupled with insights from company personnel are used to explain the variation across products in the rate of cost reduction. Products that exhibited the strongest relationship between unit cost and measures of production experience were subject to specific initiatives, particularly process R…D. The R…D was not, however, generally motivated or informed, by production experience. However, cumulative past output, the most commonly used measure of production experience, was related to expected future output, which conditioned the expected future returns from R…D and the choice of R…D projects. Thus, cumulative output was connected to unit costs through its role in conditioning incentives to undertake process R…D rather than as a proxy for production experience. This suggests that the strong relationship commonly found between unit cost and measures of production experience may reflect incentives to reduce cost as much as learning from production experience.
Stock Rationing in an M/Ek/1 Make-to-Stock Queue
Authors: Ha Albert Y.
Published: December 2003

This paper considers the stock rationing problem of a single-item, make-to-stock production system with several demand classes and lost sales. When demand is Poisson and processing time has an Erlang distribution, we show that a single-state variable called work storage level can be employed to completely capture the information regarding inventory level and the status of current production. The optimal rationing policy can be characterized by a sequence of monotone critical work storage levels. For each demand class, there exists a work storage level at or below which it is optimal to start rejecting the demand of this class in anticipation of future arrival of higher-priority demands. The optimal production policy can also be characterized by a critical work storage level. Our numerical examples indicate that a critical stock level policy, which ignores information on the status of current production, performs very well.
Management of Antiretroviral Therapy for HIV Infection: Analyzing When to Change Therapy
Authors: D'Amato Rebecca M. , D'Aquila Richard T. , Wein Lawrence M.
Published: December 2003

We analyze two joint decisions in the management of HIV-infected patients on antiretroviral therapy: how frequently to measure a patient's virus level, and when to switch therapy. The underlying stochastic model captures the initial suppression and eventual rebound of the virus level in the blood of a typical HIV-infected patient undergoing treatment. We consider two classes of policies: a viral load policy, which triggers a change in therapy when the current virus level divided by the smallest level achieved thus far exceeds a prespecified threshold, and a proactive policy, which is similar to the viral load policy but also switches drugs at a prespecified time if no evidence of viral rebound has been seen. We find approximate analytical expressions for the probability of switching before the virus reaches its nadir (minimum value) and the mean delay in detection of viral rebound (i.e., the time interval from when the viral nadir occurs until the switch in therapy). Numerical results show that the proactive policy outperforms (i.e., a smaller detection delay for a given probability of prenadir switching) the viral load policy and recent recommendations by an expert AIDS panel, and may delay the onset of multidrug resistance in a significant proportion of patients who experience drug failure.
Product Development Decisions: A Review of the Literature
Authors: Krishnan V. , Ulrich Karl T.
Published: December 2003

This paper is a review of research in product development, which we define as the transformation of a market opportunity into a product available for sale. Our review is broad, encompassing work in the academic fields of marketing, operations management, and engineering design. The value of this breadth is in conveying the shape of the entire research landscape. We focus on product development projects within a single firm. We also devote our attention to the development of physical goods, although much of the work we describe applies to products of all kinds. We look inside the “black box” of product development at the fundamental decisions that are made by intention or default. In doing so, we adopt the perspective of product development as a deliberate business process involving hundreds of decisions, many of which can be usefully supported by knowledge and tools. We contrast this approach to prior reviews of the literature, which tend to examine the importance of environmental and contextual variables, such as market growth rate, the competitive environment, or the level of top-management support.
Recombinant Uncertainty in Technological Search
Authors: Fleming Lee
Published: December 2003

While the course of technological change is widely accepted to be highly uncertain and unpredictable, little work has identified or studied the ultimate sources and causes of that uncertainty. This paper proposes that purely technological uncertainty derives from inventors' search processes with unfamiliar components and component combinations. Experimentation with new components and new combinations leads to less useful inventions on average, but it also implies an increase in the variability that can result in both failure and breakthrough. Negative binomial count and dispersion models with patent citation data demonstrate that new combinations are indeed more variable. In contrast to predictions, however, the reuse of components has a nonmonotonic and eventually positive effect on variability.
The Idea Itself and the Circumstances of Its Emergence as Predictors of New Product Success
Authors: Goldenberg Jacob , Lehmann Donald R. , Mazursky David
Published: December 2003

In view of the distressingly low rate of success in new product introduction, it is important to identify predictive guidelines early in the new product development process so that better choices can be made and unnecessary costs avoided. In this paper, we propose a framework for early analysis based on the success potential embodied in the product-idea itself and the circumstances of its emergence. Based on two studies reporting actual introductions, we identified several determinants (such as how the ideas originated, their specific configurations, and the level of technology required for their implementation) that significantly distinguish successful from unsuccessful new products in the marketplace. We suggest that these factors, together with already known factors of success/failure, may aid in the estimation of the potential of a concept early in its development.
Project Management Under Risk: Using the Real Options Approach to Evaluate Flexibility in R…D
Authors: Huchzermeier Arnd , Loch Christoph H.
Published: December 2003

Managerial flexibility has value in the context of uncertain R…D projects, as management can repeatedly gather information about uncertain project and market characteristics and, based on this information, change its course of action. This value is now well accepted and referred to as “real option value.” We introduce, in addition to the familiar real option of abandonment, the option of corrective action that management can take during the project. The intuition from options pricing theory is that higher uncertainty in project payoffs increases the real option value of managerial decision flexibility. However, R…D managers face uncertainty not only in payoffs, but also from many other sources. We identify five example types of R…D uncertainty, in market payoffs, project budgets, product performance, market requirements, and project schedules. How do they influence the value from managerial flexibility? We find that if uncertainty is resolved or costs/revenues occur after all decisions have been made, more variability may “smear out” contingencies and thus reduce the value of flexibility. In addition, variability may reduce the probability of flexibility ever being exercised, which also reduces its value. This result runs counter to established option pricing theory intuition and contributes to a better risk management in R…D projects. Our model builds intuition for R…D managers as to when it is and when it is not worthwhile to delay commitments—for example, by postponing a design freeze, thus maintaining flexibility in R…D projects.