bluuebunny/crossref_metadata_2025 huggingface dataset:
Sociological Aspects of Poverty: A Conceptual Analysis
Authors: Whyte Donald R.
Published: September 2008

La définition de la pauvreté, comme concept théorlque et comme concept opératlonnel, est passé d'assises s'établissant sur l'analyse des nécessités vitales è la notion de dépossession relative. Cette évolution est apparente à 1'examen des écrits de Malthus, des darwinlstes soclaux et de l'école de sociologie à tendance psycho‐sociale représentée par Cooley. Une redefinition de la pauvreté dans les termes d'une dépossession relative permet de rattacher conceptuellement le phénoméne de la pauvreté à la théorie sociologique contemporalne. II est alors possible de formuler des propositions grace auxquelles on est en mesure de suggerer ce que seraient les causes et les consequences de la pauvrete dans les societes lndustrlelles modemes. En ayant recours a la vaste perspective d'une théorie sociale de l'action, on percoit la manifestation de la pauvreté comme concomitante de la modernisation et dans l'ameélioration des conditions et on doit tenir compte des complexités d'un systéme social caractérisé par la spécialisation poussée et l'interdependance de ses organes.
Sarcasm as Sociation: The Rhetoric of Interaction*
Authors: Ball Donald W.
Published: September 2008

S'inspirant de Simmel, l'auteur voit dans le sarcasme l'une des formes de la sociabilité‐un type de processus social‐que I'on peut soumettre à l'analyse sociologique. Sa discussion préliminaire traite de la forme systématique, cette géométrie simmélienne du monde social, de la fonction et des corrélatifs structuraux de l'activité sociale. Le sarcasme se manifeste surtout dans les relations directes; il résulte plutôt de la définition sociale d'une situation que de l'existence d'un type singulier de communication dont il constituerait une qualité inhérente. Du point de vue formel, le sarcasme est pergu comme une relation tripartite comprenant la personne qui l'emploie, l'objet de la raillerie et l'auditoire. Dans la pratique, l'objet du sarcasme est souvent l'auditoire et moins souvent l'initiateur lui‐même, ce qui reduit à deux les parties. Le sarcasme a la fonction d'un mécanisme de contrôle, d'un échange qui maintient les distances et sauvegarde les llgnes de démarcation, d'un emploi stratégique de la communication et d'une facon de maitriser et de réduire les tensions. Le statut des participants et 1'intimité du groupe sont les corrélatifs structuraux de l'usage du sarcasme. L'auteur suggere de plus qu'une théorie du sarcasme s'allie intimement au schéme conceptuel de Scheler sur le sentiment.
The worker, the workplace, and the need for unemployment insurance*
Authors: BUTLER PETER M. , SMITH RON
Published: September 2008

Le chômage et la dépendance des prestations de l'assurance chômage qui en découle ne peuvent s'expliquer uniquement en termes de compétence naturelle, d'éducation, de formation professionnelle ou d'expérience préalable du travailleur en tant qu'individu. Lorsqu'on analyse ces attributs, on constate que leurs effets sont médiatisés par l'influence du lieu de travail. Pour explorer cette proposition, nous nous servons d'un modèle segmentaire d'établissements identifiés comme étant marginaux ou centraux dans le monde du travail, et fonctionnant selon une analyse des facteurs des caractéristiques de l'établissement. Les données sont tirées d'un échantillon vraisemblable de réclamants de prestations d'assurance chômage de la région canadienne de l'Atlantique. Nous comparons les travailleurs du monde marginal du travail à ceux du monde central en termes de l'usage possible de prestations. La portée théorique et la ligne de conduite de nos conclusions sont soumises à la discussion.

Unemployment and subsequent dependence on unemployment insurance benefits cannot be explained solely in terms of the natural abilities, education, training or previous job experience of individual workers. When these attributes are analyzed, their effects are mediated through the influence of the workplace. To explore this proposition we use a segmentation model where establishments are identified either within the marginal or central work world operationalized through a factor analysis of establishment characteristics. The data are drawn from a probability sample of unemployment insurance claimants in Atlantic Canada. We compare workers in marginal and central work worlds in terms of potential benefit use. We examine through regression analysis the net effect of work world location, its importance in prediction, and its interactive effects with selected personal characteristics on potential benefit use. The theoretical and policy implications of our findings are discussed.
Occupational status attainments of university graduates: individual attributes and labour market effects compared
Authors: HARVEY EDWARD B. , KALWA RICHARD
Published: September 2008

Ce document analyse le processus de realisation d'un statut professionnel pour cinq cohortes de diplômés d'université, hommes et femmes, durant la période s'étendant de 1960 à 1976. Après avoir reçu leurs diplômés, les hommes, comparés à leurs homologues féminins, sont parvenus, en general, à un statut professionnel plus élevé, réparti sur une échelle plus large. Les conséquences des differences socio‐économiques sur la réalisation d'un statut professionnel se sont avèrées minimes ou insignifiantes pour les deux sexes. Les effets des différences de l'enseignement reçu sur le statut professionnel sont plus grands. Les rendements pour l'étudiant avec une moyenne académique élevée sont les mêmes pour les hommes que pour les femmes. Les hommes qui ont poursuivi de hautes études supérieures ont éprouvé un meilleur rendement de méme que les femmes qui se sont spécialisées en sciences. La condition du marché du travail au moment ou ces étudiants ont obtenu leurs diplômes s'est avérée le facteur le plus déterminant dans la réalisation d'un statut professionnel. L'on maintient que la recherche sur la réalisation d'un statut professionnel a largement négligé les facteurs structurels tels que les conséquences du marché du travail, et sa concentration sur le prestige professionnel a entretenu le déguisement des differences entre les sexes dans la réalisation d'un statut professionnel.

This paper analyzes the occupational status attainment process for five cohorts of male and female university graduates spanning the time period 1960 to 1976. When compared to their female counterparts, males on the whole achieve higher occupational status after graduation and experience a wider distribution of status. The effect of socioeconomic variables on occupational attainment are found to be either small or insignificant for both sexes. The effects of educational variables on occupational attainment are greater. The returns to a high undergraduate academic average are similar for males and females; males experience a higher return to graduate study while females experience a larger return to majoring in science. The state of the labour market at time of graduation is found to have the largest effect on occupational status attainment. It is argued that occupational status attainment research has largely neglected such structural factors as labour market effects, and its focus on occupational prestige has tended to mask sex differences in occupational status attainment.
T. H. Robsjohn–Gibbings: Crafting a Modern Home for Postwar America
Authors: Ohad Smith Daniella
Published: September 2008

Terence Harold Robsjohn–Gibbings (1905–1976) was an architect, decorator, furniture designer, tastemaker, and thinker whose innovative ideas on interior design during the postwar era had a formative impact on American domestic culture. Through books, articles, lectures, interior décor, and industrial design, he advanced a singular outlook on the modern home, rooted in Greco–Roman sensibilities, classical principles, and early American domestic culture. By considering his contribution to the emergence of middle–class American style during the formative years of modernism, I propose that although hardly discussed in the literature, Robsjohn–Gibbings had occupied a significant role in steering popular taste away from Art Moderne and from the popular fashion of collecting European antiques and reproductions toward a genuine American modernism. A progressive thinker, he challenged international modernism and the postwar organic language through a scholarly understanding of ancient Greco–Roman furniture and a thorough study of American material culture.
The Architects’ Small House Service Bureau and Interior Design in the 1920s and 1930s
Authors: Tucker Lisa Marie
Published: September 2008

This research examines interior design done under the auspices of the Architects’ Small House Service Bureau (ASHSB) between 1919 and 1934. A group of Minnesota architects created the ASHSB in 1914 to provide a solution to the shortage of affordable middle–class housing in the United States. By 1919, the Bureau had offices throughout the United States and received the endorsement of both the American Institute of Architects (AIA) and the Department of Commerce. During this time, the members of the Bureau produced hundreds of plan sets and monthly bulletins to assist homeowners with their housing choices. The monthly magazine The Small Home, in conjunction with the published plan books— Your Future Home, How to Plan, Finance, and Build Your Home and others—dispensed valuable information to potential home buyers across the nation. To date, only one master's thesis (Lisa Schrenk, University of Virginia, 1990) and a single article (Thomas Harvey, 1991) have been written about the ASHSB. Neither discussed the interior design aspects of these designs and publications or dealt with the broad impact of the interior design done by the ASHSB. This research takes an interpretive–historical approach to the documents and involved extensive archival research at the AIA Headquarters. A content analysis of the publications produced and distributed by the ASHSB reveals a specific design approach to the domestic interior at the beginning of the twentieth century, which was taking place concurrent with developments within the home economics movement and other reformative ideas about the family home. This paper tells the story of the ASHSB and places it within its larger historical context.
Na+,K+‐ATPase is modulated by angiotensin II in diabetic rat kidney – another reason for diabetic nephropathy?
Authors: Fekete Andrea , Rosta Klara , Wagner Laszlo , Prokai Agnes , Degrell Peter , Ruzicska Eva , Vegh Edit , Toth Miklos , Ronai Katalin , Rusai Krisztina , Somogyi Aniko , Tulassay Tivadar , Szabo Attila J , Ver Agota
Published: September 2008

Angiotensin II (ANGII) plays a central role in the enhanced sodium reabsorption in early type 1 diabetes in man and in streptozotocin‐induced (STZ) diabetic rats. This study investigates the effect of untreated STZ‐diabetes leading to diabetic nephropathy in combination with ANGII treatment, on the abundance and localization of the renal Na+,K+‐ATPase (NKA), a major contributor of renal sodium handling. After 7 weeks of STZ‐diabetes (i.v. 65 mg kg−1) a subgroup of control (C) and diabetic (D7) Wistar rats were treated with ANGII (s.c. minipump 33 μg kg−1 h−1 for 24 h; CA and D7A). We measured renal function and mRNA expression, protein level, Serin23 phosphorylation, subcellular distribution, and enzyme activity of NKA α‐1 subunit in the kidney cortex. Diabetes increased serum creatinine and urea nitrogen levels (C versus D7), as did ANGII (C versus CA, D7 versus D7A). Both diabetes (C versus D7) and ANGII increased NKA α‐1 protein level and enzyme activity (C versus CA, D7 versus D7A). Furthermore, the combination led to an additive increase (D7 versus D7A, CA versus D7A). NKA α‐1 Ser23 phosphorylation was higher both in D7 and ANGII‐treated rats in the non‐cytoskeletal fraction, while no signal was detected in the cytoskeletal fraction. Control kidneys showed NKA α‐1 immunopositivity on the basolateral membrane of proximal tubular cells, while both D7 and ANGII broadened NKA immunopositivity towards the cytoplasm. Our study demonstrates that diabetes mellitus (DM) increases the mRNA expression, protein level, Ser23 phosphorylation and enzyme activity of renal NKA, which is further elevated by ANGII. Despite an increase in total NKA quantity in diabetic nephropathy, the redistribution to the cystosol suggests the Na+ pump is no longer functional. ANGII also caused translocation from the basolateral membrane, thus in diabetic states where ANGII level is acutely elevated, the loss of NKA will be exacerbated. This provides another mechanism by which ANGII blockade is likely to be protective.
Induced Pluripotent Stem Cells Generated Without Viral Integration
Authors: Stadtfeld Matthias , Nagaya Masaki , Utikal Jochen , Weir Gordon , Hochedlinger Konrad
Published: September 2008

Pluripotent stem cells have been generated from mouse and human somatic cells by viral expression of the transcription factors Oct4, Sox2, Klf4, and c-Myc. A major limitation of this technology is the use of potentially harmful genome-integrating viruses. We generated mouse induced pluripotent stem (iPS) cells from fibroblasts and liver cells by using nonintegrating adenoviruses transiently expressing Oct4, Sox2, Klf4, and c-Myc. These adenoviral iPS (adeno-iPS) cells show DNA demethylation characteristic of reprogrammed cells, express endogenous pluripotency genes, form teratomas, and contribute to multiple tissues, including the germ line, in chimeric mice. Our results provide strong evidence that insertional mutagenesis is not required for in vitro reprogramming. Adenoviral reprogramming may provide an improved method for generating and studying patient-specific stem cells and for comparing embryonic stem cells and iPS cells.
For Equality, Education Matters
Authors: Lemieux Thomas
Published: September 2008

The Race Between Education and Technology
.
By Claudia Goldin and Lawrence F. Katz
. Belknap Press (Harvard University Press), Cambridge, MA, 2008. 496 pp. $39.95, £25.95, €28. ISBN 9780674028678.

The authors lay out an economic framework for thinking about how technological change and human capital accumulation interact to affect pay and inequality, which, they argue, provides a crucial perspective for understanding the evolution of the U.S. economy.
Structural Basis of CXCR4 Sulfotyrosine Recognition by the Chemokine SDF-1/CXCL12
Authors: Veldkamp Christopher T. , Seibert Christoph , Peterson Francis C. , De la Cruz Norberto B. , Haugner John C. , Basnet Harihar , Sakmar Thomas P. , Volkman Brian F.
Published: September 2008

Solving the structure of the chemokine SDF-1 bound to an extracellular domain of its receptor CXCR4 has illustrated the basis of receptor sulfotyrosine recognition by chemokines and led to the discovery of an inhibitor of leukocyte chemotaxis.
Phosphoinositide 3-Kinase p110β Activity: Key Role in Metabolism and Mammary Gland Cancer but Not Development
Authors: Ciraolo Elisa , Iezzi Manuela , Marone Romina , Marengo Stefano , Curcio Claudia , Costa Carlotta , Azzolino Ornella , Gonella Cristiano , Rubinetto Cristina , Wu Haiyan , Dastrù Walter , Martin Erica L. , Silengo Lorenzo , Altruda Fiorella , Turco Emilia , Lanzetti Letizia , Musiani Piero , Rückle Thomas , Rommel Christian , Backer Jonathan M. , Forni Guido , Wymann Matthias P. , Hirsch Emilio
Published: September 2008

The phosphoinositide 3-kinase p110β subunit has noncatalytic functions; its catalytic activity is pertinent to both diabetes and cancer.
β3 Integrin as a Coreceptor for TLR2
Authors: Gough Nancy R.
Published: September 2008

Toll-like receptor 2 (TLR2) is one of a family of TLRs involved in recognition of pathogenic molecular motifs. TLR2 signaling is specifically activated by bacterial lipoproteins, such as LTA (lipoteichoic acid) and zymosan, and can be activated by synthetic bacterial lipopeptides (BLPs) consisting of tri- or di-palmitoyl-
S
-glycerylcysteine and a short peptide, but not mono-acylated peptides. Gerold
et al
. found that human monocytes (THP-1 cells) produced more inflammatory cytokine in response to the triacylated BLP(SK4) in the presence of serum than in the absence, and, with a version of BLP(SK4) modified with a crosslinker and affinity tags, identified vitronectin as the serum protein responsible for this enhanced response. Priming THP-1 cells with a phorbol ester increased the transcription and abundance of the β3 integrin subunit, which is the receptor for vitronectin, and primed cells plated on vitronectin, but not other extracellular matrix proteins, showed enhanced cytokine production in response to BLP(SK4), as well as to the TLR2 ligands LTA and zymosan, and the TLR4 ligand LPS. Blocking β3 integrin with either function-blocking antibodies or with a snake venom protein inhibited BLP(SK4)-mediated stimulation of cytokine production. When β3 integrin was knocked down with shRNA, the cells produced much less cytokine in response to BLP(SK4); however, the response to LPS, which activates TLR4, was not affected. Cells from patients with Glanzmann thrombasthenia, which have mutations in the ITGA2B gene encoding the integrin α2b or ITGB3 encoding the β3 integrin, lacked β3 on the surface and did not produce cytokines in response to BLP(SK4), suggesting that integrin β3 is essential for TLR2 signaling. β3 was coimmunoprecipitated with TLR2 from THP-1 cells, and BLP(SK4) disrupted this interaction and appeared to destabilize β3, as it became undetectable shortly after stimulation. The authors suggest that vitronectin presents pathogen lipopeptides to a complex of β3 integrin and TLR2, which activates TLR2 and disrupts the complex.

G. Gerold, K. A. Ajaj, M. Bienert, H.-J. Laws, A. Zychlinsky, J. L. de Diego, A Toll-like receptor 2-integrin β
3
complex senses bacterial lipopeptides via vitronectin.
Nat. Immunol.
9
, 761-768 (2008).
[PubMed]
Sometimes Less Is More
Authors: VanHook Annalisa M.
Published: September 2008

The 3′ untranslated regions (3′UTRs) of mRNAs contain sequences that influence the stability, subcellular localization, and translation of the mRNAs. Transcript isoforms that encode the same protein but differ in their 3′UTRs, therefore, often result in differences in protein production. Sandberg
et al
. examined the changes in expression of mRNA isoforms that accompany activation of T lymphocytes. Activation resulted in the increased abundance of isoforms with shorter 3′UTRs relative to those with longer 3′UTRs as measured 48 hours after activation. These shorter 3′UTRs lacked regulatory elements, such as microRNA (miRNA) target sites, through which translation is inhibited. Luciferase reporter assays confirmed that more protein is produced from constructs that contained shorter rather than longer 3′UTRs, presumably because the longer UTRs contained inhibitory regulatory elements. In the case of
Hip2
, deleting miRNA target sites from a long 3′UTR resulted in the production of protein that was similar in abundance to that produced from the short isoform 3′UTR transcripts. Thus, producing mRNAs with shorter 3′UTRs in response to activation may serve as a global cellular mechanism to increase protein abundance as the cells begin to proliferate. This phenomenon was observed in immune cell activation in both humans and mice and correlated with proliferation in many different cell types.

R. Sandberg, J. R. Neilson, A. Sarma, P. A. Sharp, C. B. Burge, Proliferating cells express mRNAs with shortened 3′ untranslated regions and fewer microRNA target sites.
Science
320
, 1643-1647 (2008).
[Abstract]
[Full Text]
An Alternative Mechanism of Eukaryotic Translation Initiation
Authors: Morley Simon J. , Coldwell Mark J.
Published: September 2008

Cell stress activates signaling pathways, allowing cells to choose between survival and apoptosis. Translation plays a critical role in balancing this choice by allowing for rapid and physiologically responsive changes in de novo gene expression. The steady-state abundance of cellular inhibitor of apoptosis 2 (cIAP2) is increased in response to various cell stresses. This modular protein contains baculoviral IAP repeat (BIR) motifs and ubiquitin protein ligase (E3) activity, which allows it to bind directly to caspases and to modulate activation of the transcription factor, nuclear factor κB (NF-κB). The messenger RNA (mRNA) encoding cIAP2 is a large 5.5-kb transcript, with a highly structured 5′ untranslated region (5′UTR) also containing 64 upstream initiation codons ahead of the true start codon.
cIAP2
employs an unusual cap-dependent mechanism of ribosome shunting to bypass the majority of the inhibitory elements in the 5′UTR, a mechanism first described for plant pararetroviruses. Furthermore, in mammalian cells, this poorly understood mechanism of translation for
cIAP2
is enhanced during mild stress in the absence of pararetrovirus-encoded proteins known to be essential for this process in plant cells. Here, we discuss how
cIAP2
might utilize the stress-mediated shunt process in the absence of viral proteins, which suggests a more widespread role for canonical initiation factors, internal ribosome entry sequence–specific trans-acting factors, and mRNA structure in translational control during stress.
Dissociation of Heterotrimeric G Proteins in Cells
Authors: Lambert Nevin A.
Published: September 2008

Heterotrimeric G proteins dissociate into their component Gα and Gβγ subunits when these proteins are activated in solution. Until recently, it has not been known if subunit dissociation also occurs in cells. The development of optical methods to study G protein activation in live cells has made it possible to demonstrate heterotrimer dissociation at the plasma membrane. However, subunit dissociation is far from complete, and many active [guanosine triphosphate (GTP)–bound] heterotrimers are intact in a steady state. This unexpectedly reluctant dissociation calls for inclusion of a GTP-bound heterotrimeric state in models of the G protein cycle and places renewed emphasis on the relation between subunit dissociation and effector activation.
Polarity Proteins Get Excluded
Authors: VanHook Annalisa M.
Published: September 2008

Early embryonic morphogenetic events such as gastrulation and cell fate specification often rely on radial polarization of the embryo. In the nematode
Caenorhabditis elegans
, several polarity proteins, including the PDZ-containing PAR-6, are localized to the uncontacted outer surface of each of the early embryonic somatic (EES) cells from the four-cell stage through gastrulation. The "outer surface" here is defined as that part of an EES cell’s membrane that does not contact other EES cells and corresponds to the outside surface of the embryo. These polarity proteins act as landmarks that enable the cells to undergo the asymmetric shape changes that direct gastrulating cells inward. Anderson
et al
. identified
PAR-6-at-contacts
(
pac-1
) in a screen for mutations that affect the localization of PAR-6 in EES cells. PAC-1 was required for the localization of PAR-6, PAR-3, and atypical protein kinase C (PKC-3) to the outer cortex of the early embryo, as all three proteins were distributed uniformly over the EES cell surfaces in
pac-1
mutants. The accumulation of activated (phosphorylated) myosin regulatory light chain (p-rMLC) on the outer surfaces of EES cells decreased in
pac-1
mutants as compared with wild type. This cortical myosin contractile network drives the cell ingressions that define gastrulation; thus, gastrulation slowed in
pac-1
mutants. A transgenically expressed green fluorescent protein (GFP)-tagged version of PAC-1 rescued the
pac-1
mutant phenotype and localized to the inner surfaces of EES cells, where cells contacted one another. PAC-1 contained a pleckstrin homology (PH) domain and a Rho GTPase-activating protein (RhoGAP) domain. Genetic experiments demonstrated that the RhoGAP domain of PAC-1 was required to both establish and maintain the asymmetric distribution of PAR-6 in EES cells. The Rho GTPase CDC42, which is required for PAR-6 localization, was identified as the most likely PAC-1 substrate on the basis of genetic and expression data. The authors propose a model in which PAC-1 inhibits CDC42 where cells contact one another, thereby restricting active CDC42 to the cell’s outer cortex, where it mediates the assembly of the polarity complex composed of PAR-6, PAR-3, and PKC-3.

D. C. Anderson, J. S. Gill, R. M. Cinalli, J. Nance, Polarization of the
C. elegans
embryo by RhoGAP-mediated exclusion of PAR-6 from cell contacts.
Science
320
, 1771-1774 (2008).
[Abstract]
[Full Text]
Starved into Action
Authors: Foley John F.
Published: September 2008

Stimulation of cell growth by growth hormone (GH) involves the phosphorylation and activation of the signal transducer and activator of transcription (STAT) proteins STAT5A and STAT5B. These proteins translocate to the nucleus and activate the transcription of target genes, including that encoding insulin-like growth factor 1 (IGF-1), the main mediator of the effects of GH. Under fasting conditions, GH signaling is inhibited by an unknown mechanism. Production of the hormone fibroblast growth factor 21 (FGF21) is stimulated during fasting, which led Inagaki
et
al
. to investigate its role in inhibiting GH signaling. The authors generated
FGF21
-transgenic mice, which had constitutively higher serum concentrations of FGF21 than did wild-type mice. The
FGF21
-transgenic mice were smaller and lighter than wild-type mice even though they did not eat any less. The serum concentration of IGF-1 and the abundance of IGF-1 mRNA in the liver were lower in
FGF21
-transgenic mice than in wild-type mice. This was also true for acid-labile subunit (ALS), which binds to and stabilizes IGF-1 in the circulation. In contrast, the abundance of mRNA of IGF-1 binding protein (IGFBP-1), an inhibitor of IGF-1 signaling, was higher in the liver of
FGF21
-transgenic mice compared to that in wild-type mice. The abundance of phosphorylated, but not total, STAT5A and STAT5B was lower in
FGF21
-transgenic mice than in wild-type mice. In addition, the mRNA of suppressor of cytokine signaling 2 (SOCS2), an inhibitor of GH receptor signaling, was more abundant in the
FGF21
-transgenic animals. Finally, administration of recombinant FGF21 to wild-type mice reduced the abundance of phosphorylated STAT5 in the liver and the serum concentration of IGF-1, suggesting an important role for FGF21 in inhibiting GH signaling during fasting.

T. Inagaki, V. Y. Lin, R. Goetz, M. Mohammadi, D. J. Mangelsdorf, S. A. Kliewer, Inhibition of growth hormone signaling by the fasting-induced hormone FGF21.
Cell
Metab
.
8
, 77-83 (2008).
[PubMed]
Spreading the Word
Authors: Hurtley Stella M.
Published: September 2008

Individual dendritic spines, the receiving ends of synapses, compartmentalize small diffusible molecules. In particular, Ca
2+
signals in spines are synapse-specific. However, synapses interact in subtle ways through diffusible postsynaptic factors, which suggests the existence of molecular signals that are activated at individual synapses but that can spread to other synapses. Harvey
et al.
used 2-photon glutamate uncaging to induce long-term potentiation (LTP)--the electrophysiological correlate of memory--at single spines while imaging Ras activity using 2-photon fluorescence lifetime imaging. Ca
2+
-dependent Ras activation spread over ~10 micrometers of dendritic length and invaded nearby spines by diffusion. Neighboring synapses along a short stretch of dendrite may thus be coregulated due to this spread of signals downstream.

C. D. Harvey, R. Yasuda, H. Zhong, K. Svoboda, The spread of Ras activity triggered by activation of a single dendritic spine.
Science
321
, 136-140 (2008).
[Abstract]
[Full Text]
Positive Repression
Authors: Foley John F.
Published: September 2008

Although the transmembrane protein CD44 does not itself signal, its association with tumor cell growth and metastasis is probably due to its ability to costimulate growth factor receptor signaling. Noticing a correlation between the abundance of CD44 and that of mutant forms of the tumor suppressor protein p53 in various carcinomas, Godar
et al
. investigated the relationship between p53 and CD44 in human breast primary epithelial cells (BPECs). Immunofluorescent staining and Western blotting analyses revealed the mutually exclusive presence of p53 and CD44 in immortalized BPEC (BPEC-T) cells. The abundance of CD44 protein was higher in BPEC-T cells treated with p53-specific short hairpin RNA (shRNA) than in control cells, which, together with semiquantitative reverse transcription polymerase chain reaction assays, suggested the repression of
CD44
expression by p53. Indeed, CD44 was more abundant in the mammary glands of
p53
–/–
mice than in those of wild-type mice. Reporter assays and gel-shift analysis showed that p53 directly repressed
CD44
expression, and this direct interaction was confirmed by chromatin immunoprecipitation assays. Stimulation of cell proliferation by epidermal growth factor was greater in cells that overexpressed CD44 than in wild-type cells, which was also true for cells in which p53 was knocked down with shRNA. Cells overexpressing CD44 were more resistant to drug-induced, p53-dependent apoptosis than were control cells. Although transformed (p53-inactivated) BPEC-T cells formed tumors when transferred to susceptible mice, those treated with CD44-specific shRNA formed fewer and smaller tumors. Together, these data suggest that the basal abundance of p53 in mammary epithelial cells is sufficient to repress
CD44
expression and thus prevent growth and tumor initiation.

S. Godar, T. A. Ince, G. W. Bell, D. Feldser, J. L. Donaher, J. Bergh, A. Liu, K. Miu, R. S. Watnick, F. Reinhardt, S. S. McAllister, T. Jacks, R. A. Weinberg, Growth-inhibitory and tumor-suppressive functions of p53 depend on its repression of
CD44
expression.
Cell
134
, 62-73 (2008).
[PubMed]
Regulating Estrogen Receptor’s Cytoplasmic Partners
Authors: Ray L. Bryan
Published: September 2008

The estrogen (E
2
) receptor is best known for its actions as a transcriptional activator, but evidence continues to accumulate for rapid nongenomic effects of estrogen receptors outside the nucleus as well. Le Romancer
et al
. provide evidence that interaction of estrogen receptor alpha (Erα) with phosphoinositide 3-kinase (PI3K) and the tyrosine kinase Src depends on covalent modification of ERα by arginine methylation. The arginine methyltransferase PRMT1 (protein arginine methyltransferase 1) is known to associate with Erα and to regulate its transcriptional activity. Le Romancer
et al
. developed an antibody that appears to specifically recognize ERα that is dimethylated on R260. Immunoprecipitation of ERα from the human breast cancer cell line MCF-7 with this antibody showed that methylation of the receptor was increased within 5 min of treatment of cells with E
2
and that the methylated form of the receptor was found exclusively in the cytoplasm (although the bulk of ERα was localized in the nucleus). Methylation of ERα was correlated with its association with Src and the p85 subunit of PI3K. Depletion of PRMT1 from cells by treating them with siRNA inhibited the formation of the protein complex. Examination of tyrosine phosphorylated proteins associated with the activated receptor identified focal adhesion kinase as a new component in the complex. In mouse NIH 3T3 cells transfected with wild-type ERα, phosphorylation of the kinase Akt was evident within 5 min of E
2
treatment, but such regulation of Akt was diminished in cells expressing a mutant form of ERα in which the site of methylation was modified to prevent methylation. About half of the invasive human breast cancer samples tested showed abnormally high amounts of ERα methylation, but it remains to be determined how this relates to tumor phenotypes and dependence of tumor growth on E
2
.

M. Le Romancer, I. Treilleux, N. Leconte, Y. Robin-Lespinasse, S. Sentis, K. Bouchekioua-Bouzaghou, S. Goddard, S. Gobert-Gosse, L. Corbo, Regulation of estrogen rapid signaling through arginine methylation by PRMT1.
Mol
.
Cell
31
, 212-221 (2008).
[PubMed]
Finding a Target or Settling Down with One
Authors: Adler Elizabeth M.
Published: September 2008

Natural killer (NK) cells navigate to transformed or virus-infected cells and bind to them through integrins and NK receptors to form a "lytic synapse." Both navigation and formation of the lytic synapse depend on the actin cytoskeleton, leading Butler
et al
. to investigate the role of HS1 (a homolog of the actin-binding protein cortactin) in NK cell-mediated cell cytolysis. When NK cells (or a leukemia-derived NK cell line) were exposed to target cells, or beads coated with the β2 integrin LFA-1 ligand ICAM-1 and the NK receptor ligand ULBP, HS1 localized to the contact site and became tyrosine phosphorylated. Moreover, HS1 knockdown with short hairpin RNA decreased cytolysis of target cells. Experiments in which HS1 was knocked down and cells were transfected with HS1 mutants in which one or both of two tyrosine residues were substituted with phenylalanine (Y378F, Y397F, and Y378FY397F) implicated HS1 phosphorylation in NK cell cytolytic activity and revealed distinct roles for phosphorylation of these two residues. Adhesion to ICAM-1 stimulated HS1 phosphorylation on Tyr
397
; further, Tyr
397
was required for cell adhesion to ICAM-1. Tyr
397
was required for chemokine-dependent conversion--through "inside-out" signaling--of LFA-1 to a high-affinity state and for signals downstream of LFA-1 involved in recruitment of actin, LFA-1, the actin regulator WASp, and the guanine nucleotide exchange factor Vav1 to the lytic synapse. Although HS1 Tyr
397
was not required for recruitment of the adaptor DAP10 to the NKG2D receptor, it was implicated in downstream signaling. In contrast, phosphorylation of HS1 Tyr
378
was required for chemotaxis. Thus, HS1 appears to be critical to NK cell chemotaxis, formation of the lytic synapse, and cytolysis, with distinct functions depending on phosphorylation of Tyr
397
and Tyr
378
. Beemiller and Krummel provide thoughtful commentary, noting that HS1 may act as a switch to enable NK cells to convert from a migratory mode to one in which they form a stable contact with a target cell.

B. Butler, D. H. Kastendieck, J. A. Cooper, Differently phosphorylated forms of the cortactin homolog HS1 mediate distinct functions in natural killer cells.
Nat. Immunol.
9
, 887-897 (2008).
[PubMed]

P. Beemiller, M. F. Krummel, Distinct functions for HS1 in chemosensory versus adhesive signaling.
Nat. Immunol.
9
, 833-834 (2008).
[PubMed]
A New TRADDition in Intracellular Antiviral Signaling
Authors: Pietras Eric M. , Cheng Genhong
Published: September 2008

To effectively defeat viral infection, a mammalian host must detect the presence of viruses and activate a robust antiviral response, which is mediated by cytokines known as type I interferons (IFNs). Much excitement has been generated by the discovery of the retinoic acid–induced gene 1–like helicase (RLH) pathway, which detects RNA-containing viruses in the cytoplasm and activates the type I IFN response. A study now describes a role for the tumor necrosis factor receptor (TNFR)–associated death domain (TRADD) in the antiviral response and sheds new light on how the RLH signaling complex is organized upon viral infection.
Signaling in Time and Place
Authors: Ray L. Bryan
Published: September 2008

Proteins that participate in biological regulatory mechanisms are often assembled into large complexes within which various signaling molecules interact to propagate a biochemical signal. Matsuzawa
et al.
characterize such a complex of proteins assembled at the activated receptor CD40 (a member of the tumor necrosis factor receptor family) on the cell surface. The complex formed at the cell surface within a few minutes after binding of ligand to the receptor but after 30 minutes had moved to the cytoplasm. Surprisingly, activation of mitogen-activated protein kinases (MAPKs) JNK and p38 and of the MAPK kinase MEKK1 was only detected once the complex left the receptor and moved into the cytosol. Degradation of the adaptor protein TRAF3 was required to initiate release of the complex from CD40. Other receptors may also use such a mechanism to specify the time and place at which signaling proteins are activated in response to receptor stimulation.

A. Matsuzawa, P.-H. Tseng, S. Vallabhapurapu, J.-L. Luo, W. Zhang, H. Wang, D. A. A. Vignali, E. Gallagher, M. Karin, Essential cytoplasmic translocation of a cytokine receptor–assembled signaling complex.
Science
321
, 663-668 (2008).
[Abstract]
[Full Text]

A. G. Eliopoulos, "Make and brake" in signaling.
Science
321
, 648-649 (2008).
[Summary]
[Full Text]
Two Pathways Are Better Than One
Authors: Foley John F.
Published: September 2008

Glutamate is an excitatory neurotransmitter that activates ionotropic and metabotropic glutamate receptors (mGluRs) on neurons and glia to mediate such functions as synaptic plasticity, proliferation, and survival. mGluR5 activates the transcription factor nuclear factor κB (NF-κB), but the mechanisms involved are unclear. Sitcheran
et al
. performed gel shift assays to demonstrate that glutamate induced the binding of the p65 and p50 NF-κB subunits to DNA in the human glioma cell line, H4. The authors also examined the signaling of the epidermal growth factor receptor (EGFR), which is found on astrocytes and is also known to activate NF-κB. Reporter assays showed that glutamate-induced activation of NF-κB was comparable to that induced by EGF. Western blotting analyses demonstrated that glutamate induced the phosphorylation and activation of inhibitor of κB kinase α and β (IKKα and IKKβ) and of p65. Knockdown of both IKKα and IKKβ in H4 cells by small inhibitory RNA (siRNA) suppressed glutamate-induced phosphorylation of p65. In canonical NF-κB signaling, IKKβ phosphorylates IκBα, which leads to its degradation and the release of active NF-κB subunits. In this study, however, the authors found no evidence of glutamate-induced (or EGF-induced) phosphorylation or degradation of IκBα, although coimmunoprecipitation assays showed that glutamate substantially reduced the interaction between IκBα and p65 compared with that in control cells. Knockdown of EGFR blocked mGluR5-stimulated phosphorylation of p65. The authors found that mGluR5 stimulation led to the phosphorylation of specific tyrosine residues in EGFR and to its physical association with mGluR5. A cell-permeable Ca
2+
chelator blocked mGluR5-mediated NF-κB activation, and an inhibitor of EGFR activity reduced mGluR5-stimulated Ca
2+
signaling. Together, these data suggest that EGFR signaling is critical for the noncanonical activation of NF-κB by glutamate and that this crosstalk may have implications for the treatment of glioblastoma, in which EGFR abundance is increased.

R. Sitcheran, W. C. Comb, P. C. Cogswell, A. S. Baldwin, Essential role for epidermal growth factor receptor in glutamate receptor signaling to NF-κB.
Mol. Cell. Biol.
28
, 5061-5070 (2008).
[Abstract]
[Full Text]
Splice Factor
Authors: Kelner Katrina L.
Published: September 2008

Alternative splicing of transcripts generates significant functional diversity within genomes. This is particularly well illustrated by the CD45 gene, which undergoes regulated activation-dependent alternative splicing in lymphocytes to generate several functionally distinct isoforms. Oberdoerffer
et al.
(see the Perspective by Holmes) identify a specific factor, heterogeneous ribonucleoprotein L-like (hnRNPLL), as a principal regulator of CD45 splicing. Evidence for direct interaction of hnRNPLL with its target transcript was uncovered, although further work will be needed to reveal the precise mechanism by which it binds its target sequences and cooperates with spliceosome components to promote exon excision.

S. Oberdoerffer, L. F. Moita, D. Neems, R. P. Freitas, N. Hacohen, A. Rao, Regulation of CD45 alternative splicing by heterogeneous ribonucleoprotein, hnRNPLL.
Science
321
, 686-691 (2008).
[Abstract]
[Full Text]

N. Holmes, A splicing switch for T cells.
Science
321
, 646-647 (2008).
[Summary]
[Full Text]
T Cells Set Bone Response
Authors: Gough Nancy R.
Published: September 2008

Continuous exposure to parathyroid hormone (PTH), such as occurs in hyperparathyroidism, causes bone loss, whereas intermittent exposure to PTH, which is a treatment for osteoporosis, increases bone volume. Gao
et al
. sought to understand the role of T cells in the bone response to PTH. T cells provide survival cues to bone-building osteoblasts, as well as to bone marrow stromal cells, which are the precursors of the osteoblasts. T cells also stimulate stromal cells and osteoblasts to produce cytokines that trigger differentiation of osteoclasts, the bone-resorbing cells. Thus, T cells and bone cells have a complex relationship. Gao
et al
. found that continuous PTH infusion into mice lacking T cells resulted in less bone loss and less bone resorption. Bone marrow cells cultured from T cell-deficient mice had fewer stromal cells than those from wild-type mice and failed to produce osteoclasts in response to PTH. However, osteoclastogenesis was dose-dependently restored by the addition of T cells, but only if the T cells were added at the time of plating. Stromal cells isolated from wild-type mice that had been exposed to PTH exhibited increased mRNA for RANKL, a cytokine that stimulates osteoclastogenesis, and decreased the mRNA for osteoprotegern (OPG), a decoy ligand of the RANKL receptor. This PTH-stimulated change in cytokine production was absent in cells from the T cell-deficient mice. CD40 is a receptor, which is present on the stromal cells, and responds to CD40L, which is present on the T cells. If the T cells lacked CD40L or the stromal cells lacked CD40, then PTH failed to stimulate osteoclastogenesis of cultured bone marrow cells. Furthermore, continuous PTH exposure in CD40L-deficient mice failed to cause bone loss. Thus, T cells appear to provide signals through CD40L to bone precursors that allow them to survive, alter their cytokine production profile, and increase their responsiveness to the osteoclastogenic activity of PTH.

Y. Gao, X. Wu, M. Terauchi, J.-Y. Li, F. Grassi, S. Galley, X. Yang, M. N. Weitzmann, R. Pacifici, T cells potentiate PTH-induced cortical bone loss through CD40L signaling.
Cell Metab.
8
, 132-145 (2008).
[PubMed]
Back from the Dead
Authors: Foley John F.
Published: September 2008

Autism comprises a complex spectrum of neurodevelopmental disorders, likely caused by a number of different factors, most of which are unknown. The receptors for γ-aminobutyric acid (GABA) and glutamate are implicated in the development of autism, but the study of these and other neurotransmitter receptors in brain tissue is technically challenging. Limon
et al
. used two techniques to investigate proteins derived from postmortem brain tissue from age-matched normal and autistic subjects. First, the authors isolated poly(A
+
) RNA from small quantities of brain tissue and microinjected these samples into
Xenopus
oocytes. Samples were taken from the cerebellum and the temporal cortex because these areas show abnormal neuronal organization in autistic patients. Even though the brains had been in storage for 2 to 5 years, they still contained intact mRNAs that gave rise to a number of different neurotransmitter receptors and voltage-operated ion channels in the injected oocytes, as assessed by electrophysiology experiments. In a second strategy, called microtransplantation, the authors made membrane preparations from the brain tissues, microinjected them into oocytes, and allowed the brain-derived membranes to fuse with the oocyte plasma membrane in a process similar to exocytosis. Electrophysiology experiments showed that the native receptors from the postmortem tissue were functional. Although some trends were observed, no significant molecular differences were found between autistic subjects and the controls. However, as Spitzer discusses, the real strengths of this study are the demonstration that native membrane proteins can still be assayed after long postmortem intervals and the adaptability of this experimental system to the study of other disease states.

A. Limon, J. M. Reyes-Ruiz, R. Miledi, Microtransplantation of neurotransmitter receptors from postmortem autistic brains to
Xenopus
oocytes.
Proc
.
Natl
.
Acad
.
Sci
.
U
.
S
.
A
.
105
, 10973-10977 (2008).
[Abstract]
[Full Text]

N. C. Spitzer, A Rosetta stone for analysis of human membrane protein function.
Proc
.
Natl
.
Acad
.
Sci
.
U
S
A
.
105
, 10641-10642 (2008).
[Full Text]
Fatty Acid-Regulated Diapause
Authors: VanHook Annalisa M.
Published: September 2008

In response to starvation during the first larval (L1) stage,
Caenorhabditis elegans
may undergo developmental arrest to enter a state of diapause. Initiation and maintenance of starvation-induced diapause are mediated by signaling through the insulin pathway and can be reversed by food. Kniazeva
et al.
report that L1 arrest can also be induced by deficiency of the monomethyl branched-chain fatty acid C17ISO, a leucine catabolite. Animals without C17ISO were generated through RNA interference (RNAi) with
edo-5
, which encodes an elongation factor required for C17ISO biosynthesis. C17ISO-deficient animals entered an L1 diapause that was phenotypically similar to that induced by starvation and that could be reversed by dietary supplementation with C17ISO. Starvation-induced and C17ISO deficiency-induced diapause states were initiated and maintained independently: C17ISO supplements did not prevent or reverse starvation-induced arrest, and food did not prevent or reverse C17ISO deficiency-induced arrest. Genetic interaction experiments indicated that C17ISO deficiency-induced arrest, unlike starvation-induced arrest, did not require signaling through the insulin receptor DAF-2. Loss-of-function mutations in genes encoding
daf-16
, which encodes the FOXO transcription factor repressed by DAF-2, or
daf-18
, which encodes the DAF-2 antagonist Pten, did not suppress C17ISO deficiency-induced developmental arrest. Although not mediated by the same signaling pathway, both starvation-induced and C17ISO deficiency-induced arrest were associated with decreased expression of
cki-1
, which encodes a cyclin-dependent kinase that promotes cell cycle exit. Genetic interaction experiments coupled with reporter assays indicated that C17ISO biosynthesis was regulated by both lipid metabolism and dietary protein uptake. It is not surprising that metabolic information and nutritional information are integrated to influence developmental decisions, but it is unexpected that a type of metabolism- or nutrient-induced developmental arrest in
C. elegans
does not depend on insulin signaling.

M. Kniazeva, T. Euler, M. Han, A branched-chain fatty acid is involved in post-embryonic growth control in parallel to the insulin receptor pathway and its biosynthesis is feedback-regulated in
C. elegans
.
Genes & Dev.
22
, 2102-2110 (2008).
[Abstract]
[Full Text]
Axonal Pathfinding in Sight
Authors: Kiberstis Paula A.
Published: September 2008

About 1 in 1000 people are afflicted with Duane’s retraction syndrome (DRS), a complex congenital eye disorder characterized by a restricted ability to move the eye(s) outward or inward. The condition is thought to arise from faulty innervation of extraocular muscles by cranial motor neurons, which probably occurs early in embryogenesis. Miyake
et al.
now provide genetic evidence that strongly supports this hypothesis. Studying families with a variant form of DRS, the authors discovered that the mutations responsible for the disorder fall within a gene on chromosome 2 encoding α2-chimaerin, a RacGAP signaling protein previously implicated in axonal pathfinding of corticospinal nerves in mice. The human mutations cause α2-chimaerin to become overactive, and expression of the mutant protein in a chick embryo model did indeed disrupt oculomotor axon development.

N. Miyake, J. Chilton, M. Psatha, L. Cheng, C. Andrews, W.-M. Chan, K. Law, M. Crosier, S. Lindsay, M. Cheung, J. Allen, N. J. Gutowski, S. Ellard, E. Young, A. Iannaccone, B. Appukuttan, J. T. Stout, S. Christiansen, M. L. Ciccarelli, A. Baldi, M. Campioni, J. C. Zenteno, D. Davenport, L. E. Mariani, M. Sahin, S. Guthrie, E. C. Engle, Human
CHN1
mutations hyperactivate α2-chimaerin and cause Duane's retraction syndrome.
Science
321
, 839-843 (2008).
[Abstract]
[Full Text]