bluuebunny/crossref_metadata_2025 huggingface dataset:
DETERMINANTS OF TRANSITIONS TO FIRST SEXUAL INTERCOURSE, MARRIAGE AND PREGNANCY AMONG FEMALE ADOLESCENTS: EVIDENCE FROM SOUTH NYANZA, KENYA
Authors: MAGADI MONICA A. , AGWANDA ALFRED O.
Published: November 2008

The timing of transitions to sexual activity, marriage and childbearing in sub-Saharan Africa is undergoing profound changes. This study investigates the determinants of adolescent transitions in South Nyanza, a socioeconomically deprived setting in Kenya where adolescent reproductive health is a particular concern. The analysis is based on Cox regression of timing of first sexual intercourse, first marriage and first pregnancy, using data from a survey of 1247 females aged 12–19 years. The results show that higher household socioeconomic status and educational attainment are associated with delayed onset of all three transition events. Furthermore, mother’s higher educational attainment is protective for initiation of sexual intercourse while rural residence is protective for pregnancy experience. Other protective factors include communication with parents or with fellow girlfriends. However, discussing sexual matters with boyfriends, high internal locus of control, and gender bias are associated with early onset of the three transition events.
Epidemiological Study Designs to Investigate Gene–Behavior Interactions in the Context of Human Obesity
Authors: Wareham Nicholas J. , Young Elizabeth H. , Loos Ruth J.F.
Published: November 2008

The epidemiology of obesity suggests that, for the majority of individuals, the disorder arises from an interaction between genetic predisposition and lifestyle behaviors such as dietary intake and physical activity. Unravelling the molecular basis of such interactions is complex but is becoming a realistic proposition as evidence emerges from whole genome association studies of genetic variants that are definitively associated with obesity. A range of possible study designs is available for investigating gene–lifestyle interaction, and the strengths and weaknesses of each approach are discussed in this article. Given the likely small main effect of common genetic variants and the difficulties in demonstrating associations of lifestyle factors with future risk of obesity, we would favor an analytical approach based on the clear specification of prior probabilities to reduce the likelihood of false discovery. Mixed approaches combining data from large‐scale observational studies with smaller intervention trials may be ideal. In designing new studies to investigate these issues, a key choice is how precisely to quantify the important, but difficult to measure lifestyle behaviors. It is clear from power calculations that an approach based on enhancing precision of measurement of diet and physical activity is critical.
Implications of Gene–Behavior Interactions: Prevention and Intervention for Obesity
Authors: Bray Molly S.
Published: November 2008

A vast body of research exists to demonstrate that obesity is a complex disorder with a strong genetic basis and a multifactorial etiology. Yet despite the overwhelming evidence that genes play an important role in the development of obesity, many people argue that the increasing prevalence of obesity is simply due to an abundance of palatable food and a dearth of opportunities for physical exercise. While activity and eating behaviors contribute substantially to the development of obesity, considering these to be the only etiologic factors is directly contradictory to what is now known about how eating and energy balance are regulated. Our understanding of the molecular processes controlling eating behavior, in particular, has accelerated exponentially in the last 10 years, and this is one area in which obesity genetics has made great progress. Our challenge is to understand more fully how genetic variation may interact with behavioral factors to influence the regulation of body weight and adiposity. Although exercise and diet strategies are used routinely for obesity treatment, there is a huge variability in how individuals respond to these interventions. There is also a substantial amount of evidence that such responses may also be regulated by genes. Understanding gene–response relationships is the key to developing more efficacious intervention and prevention programs for obesity.
Gene–Environment Interactions in the Etiology of Obesity: Defining the Fundamentals
Authors: Bouchard Claude
Published: November 2008

The concept of gene–environment interaction refers to a situation where the response or the adaptation to an environmental factor, a behavior, or a change in behavior is conditional on the genotype of the individual. Of particular interest for our understanding of the etiology of human obesity is the role played by genotype–nutrition and genotype–physical activity interactions. Evidence for the presence of such interaction effects affecting body mass and body composition comes from experimental studies undertaken with pairs of monozygotic twins and with nuclear families. These studies reveal that there are large individual differences in the responsiveness to well‐defined energy balance manipulations. Overfeeding as well as negative energy balance protocols indicate that the response to these standardized experimental treatments is strongly influenced by one's genetic background. The genes that are responsible for the individual differences in the sensitivity to alterations in energy balance remain to be fully identified. They are likely to be numerous considering the complexity of the biological systems that are involved in body weight regulation. A number of research designs and technologies are available to identify these genes and to delineate the nature and the extent of the genetic polymorphisms involved. It was the purpose of the workshop to define the conditions under which gene–behavior interaction effects of relevance to human obesity could be reliably identified.
Social Class and BMI Among Canadian Adults: A Focus on Occupational Prestige
Authors: McLaren Lindsay , Godley Jenny
Published: November 2008

The objective was to examine BMI of working‐age Canadian adults in relation to occupational prestige, adjusting for other aspects of social class including household income and respondent's education. We analyzed data from 49,252 adults (age 25–64) from Cycle 2.1 of the Canadian Community Health Survey, a cross‐sectional self‐report survey conducted in 2003. Multiple linear regression was used to examine the relation between BMI and occupational prestige, adjusting for other sociodemographic variables. For women, higher ranking occupations showed lower average BMI relative to the lowest ranking occupations, but this effect was largely eliminated when adjusting for education. For men, occupation effects endured in adjusted models and we detected some evidence of a pattern whereby men in occupations characterized by management/supervisory responsibilities were heavier than those in the lowest ranking occupations (i.e., elemental sales and service). Results are interpreted in light of the symbolic value of body size in western culture, which differs for men and women. Men in positions of management/supervision may benefit from the physical dominance conveyed by a larger body size, and thus occupational prestige rankings may help us to understand the gender differences in the patterning of BMI by different indicators of social class.
Angiogenic factors and pre-eclampsia: an early marker is needed
Authors: Stepan Holger
Published: November 2008

Pre-eclampsia, a pregnancy complication characterized by hypertension and proteinuria, is still a major cause of neonatal and maternal mortality, and acute and long-term morbidities for both mother and neonate. There is mounting evidence that an imbalance between angiogenic factors, such as VEGF (vascular endothelial growth factor) or PlGF (placental growth factor), and factors inhibiting angiogenesis, such as sFlt1 (soluble fms-like tyrosine kinase 1) and sEng (soluble endoglin), are closely related to the pathogenesis of pre-eclampsia. In the present issue of Clinical Science, Bills and co-workers report that VEGF165b, an alternative splice variant of the VEGF pre-mRNA, is up-regulated in women with normal pregnancy and that this increase was delayed or diminished in women who developed pre-eclampsia. Thus this protein could serve (alone or in combination with other parameters) as a new marker for risk assessment in terms of pre-eclampsia.
A model-based analysis of the dynamics of carbon balance at the whole-plant level in Arabidopsis thaliana
Authors: Christophe Angélique , Letort Véronique , Hummel Irène , Cournède Paul-Henry , de Reffye Philippe , Lecœur Jérémie
Published: November 2008

Arabidopsis thaliana (L.) Heynh. is used as a model plant in many research projects. However, few models simulate its growth at the whole-plant scale. The present study describes the first model of Arabidopsis growth integrating organogenesis, morphogenesis and carbon-partitioning processes for aerial and subterranean parts of the plant throughout its development. The objective was to analyse competition among sinks as they emerge from patterns of plant structural development. The model was adapted from the GreenLab model and was used to estimate organ sink strengths by optimisation against biomass measurements. Dry biomass production was calculated by a radiation use efficiency-based approach. Organogenesis processes were parameterised based on experimental data. The potential of this model for growth analysis was assessed using the Columbia ecotype, which was grown in standard environmental conditions. Three phases were observed in the overall time course of trophic competition within the plant. In the vegetative phase, no competition was observed. In the reproductive phase, competition increased with a strong increase when lateral inflorescences developed. Roots and internodes and structures bearing siliques were strong sinks and had a similar impact on competition. The application of the GreenLab model to the growth analysis of A. thaliana provides new insights into source–sink relationships as functions of phenology and morphogenesis.
Transient shade and drought have divergent impacts on the temperature sensitivity of dark respiration in leaves of Geum urbanum
Authors: Slot Martijn , Zaragoza-Castells Joana , Atkin Owen K.
Published: November 2008

The respiratory response of plants to temperature is a critical biotic feedback in the study of global climate change. Few studies, however, have investigated the effects of environmental stresses on the short-term temperature response of dark respiration (Rdark) at the leaf level. We investigated the effect of shade and transient drought on the temperature sensitivity (Q10; the proportional increase in respiration per 10°C increase in temperature) of Rdark of Geum urbanum L. in controlled experiments. Shade effects were most pronounced following sustained, near-darkness, when rates of leaf Rdark at a set measuring temperature (25°C) and the Q10 of Rdark were both reduced. By contrast, rates of leaf Rdark and the Q10 of Rdark both increased in response to the onset of severe water stress. Water stress was associated with a rapid (but reversible) decline in rates of light-saturated photosynthesis (Psat), stomatal closure (gs) and progressive wilting. Re-watering resulted in a rapid recovery of Psat, gs and a decline in the Q10 of Rdark (due to larger proportional reductions in the rate of Rdark measured at 25°C compared with those measured at 14°C). The concentration of soluble sugars in leaves did not decline during drought (5–7 day cycles) or shading, but during drought the starch concentration dropped, suggesting starch to sugar conversion helped to maintain homeostatic concentrations of soluble sugars. Thus, the drought and shade induced changes in Rdark were unlikely to be due to stress-induced changes in substrate supply. Collectively, the data highlight the dynamic responses of respiratory Q10 values to changes in water supply and sustained reductions in growth irradiance. If widespread, such changes in the Q10 of leaf respiration could have important implications for predicted rates of ecosystem carbon exchange in the future, particularly in areas that experience more frequent droughts.
Telomere length change in European sea bass (Dicentrarchus labrax)
Authors: Horn T. , Gemmell N. J. , Robertson B. C. , Bridges C. R.
Published: November 2008

Telomeres, the repetitive sequences found at the end of chromosomes, are observed to shorten with age in birds and mammals, but to date no investigation on changes of telomere length has been made in long-lived marine fish during ageing. We have measured the telomere length of European sea bass (Dicentrarchus labrax) ranging in age from 12 to 94 months. No overall decrease of telomere length could be detected, but a broad range of intraspecies variation was observed. Telomere length change does not appear to be useful for estimating age in this species, but may prove a useful tool for examining individual fitness and response to stress.
Postperovskite phase equilibria in the MgSiO
3
–Al
2
O
3
system
Authors: Tsuchiya Jun , Tsuchiya Taku
Published: November 2008

We investigate high-
P
,
T
phase equilibria of the MgSiO
3
–Al
2
O
3
system by means of the density functional ab initio computation methods with multiconfiguration sampling. Being different from earlier studies based on the static substitution properties with no consideration of Rh
2
O
3
(II) phase, present calculations demonstrate that (
i
) dissolving Al
2
O
3
tends to decrease the postperovskite transition pressure of MgSiO
3
but the effect is not significant (≈-0.2 GPa/mol% Al
2
O
3
); (
ii
) Al
2
O
3
produces the narrow perovskite+postperovskite coexisting
P
,
T
area (≈1 GPa) for the pyrolitic concentration (
x
Al2O3
≈6 mol%), which is sufficiently responsible to the deep-mantle D″ seismic discontinuity; (
iii
) the transition would be smeared (≈4 GPa) for the basaltic Al-rich composition (
x
Al2O3
≈20 mol%), which is still seismically visible unless iron has significant effects; and last (
iv
) the perovskite structure spontaneously changes to the Rh
2
O
3
(II) with increasing the Al concentration involving small displacements of the Mg-site cations.
L1 recombination-associated deletions generate human genomic variation
Authors: Han Kyudong , Lee Jungnam , Meyer Thomas J. , Remedios Paul , Goodwin Lindsey , Batzer Mark A.
Published: November 2008

Mobile elements have created structural variation in the human genome through their
de novo
insertions and post-insertional genomic rearrangements. L1 elements are a type of long interspersed element (LINE) that is dispersed at high copy numbers within most mammalian genomes. To determine the magnitude of L1 recombination-associated deletions (L1RADs), we computationally extracted L1RAD candidates by comparing the human and chimpanzee genomes and verified each of the L1RAD events by using wet-bench analyses. Through these analyses, we identified 73 human-specific L1RAD events that occurred subsequent to the divergence of the human and chimpanzee lineages. Despite their low frequency, the L1RAD events deleted ≈450 kb of the human genome. One L1RAD event generated a large deletion of ≈64 kb. Multiple alignments of prerecombination and postrecombination L1 elements suggested that two different deletion mechanisms generated the L1RADs: nonallelic homologous recombination (55 events) and nonhomologous end joining between two L1s (18 events). In addition, the position of L1RADs throughout the genome does not correlate with local chromosomal recombination rates. This process may be implicated in the partial regulation of L1 copy numbers by the finding that ≈60% of the DNA sequences deleted by the L1RADs consist of L1 sequences that were either directly involved in the recombination events or located in the intervening sequence between recombining L1s. Overall, there is increasing evidence that L1RADs have played an important role in creating structural variation.
Molecular and cellular components of the mating machinery in
Anopheles gambiae
females
Authors: Rogers David W. , Whitten Miranda M. A. , Thailayil Janis , Soichot Julien , Levashina Elena A. , Catteruccia Flaminia
Published: November 2008

Anopheles gambiae
mosquitoes are the principal vectors of malaria. A major determinant of the capacity of these mosquitoes as disease vectors is their high reproductive rate. Reproduction depends on a single insemination, which profoundly changes the behavior and physiology of females. To identify factors and mechanisms relevant to the fertility of
A. gambiae
, we performed a comprehensive analysis of the molecular and cellular machinery associated with copulation in females. Initial whole-body microarray experiments comparing virgins with females at 2 h, 6 h, and 24 h after mating detected large transcriptional changes. Analysis of tissue localization identified a subset of genes whose expression was strikingly regulated by mating in the lower reproductive tract and, surprisingly, the gut. In the atrium of virgin females, where the male seminal fluid is received, our studies revealed a “mating machinery” consisting of molecular and structural components that are turned off or collapse after copulation, suggesting that this tissue loses its competence for further insemination. In the sperm storage organ, we detected a number of mating-responsive genes likely to have a role in the maintenance and function of stored sperm. These results identify genes and mechanisms regulating the reproductive biology of
A. gambiae
females, highlighting considerable differences with
Drosophila melanogaster
. Our data inform vector control strategies and reveal promising targets for the manipulation of fertility in field populations of these important disease vectors.
CD4 cell-secreted, posttranslationally modified cytokine GIF suppresses Th2 responses by inhibiting the initiation of IL-4 production
Authors: Kim-Saijo Misa , Janssen Edith M. , Sugie Katsuji
Published: November 2008

T helper 2 (Th2) cells are critical to the induction of IgE antibody and allergic inflammation, but how the pathological pathways are controlled in nonallergic individuals remains unclear. Here we report that glycosylation-inhibiting factor (GIF) suppresses Th2 effector generation. GIF is a cytokine encoded by the same gene that codes for macrophage migration inhibitory factor (MIF). GIF-deficient mice demonstrated enhanced T-dependent antibody formation especially of IgE isotype and allergic airway inflammation with the generation of regulatory T cells unaffected. GIF-deficient macrophages and dendritic cells revealed normal responsiveness to toll-like receptor (TLR) ligands. GIF undergoes a unique posttranslational modification, cysteinylation. The modified GIF, mainly secreted by activated T cells derived from CD4+CD25−cells, inhibited IL-4 production by the same cells whereas the unmodified GIF showed no effect. Bone marrow chimera experiment demonstrated that T cell-derived GIF suppressed the generation of Th effectors that secrete IL-4. During the first 24 h of CD3/CD28 stimulationin vitro, GIF secreted from naïve CD4 cells acted on the same cells, maintained nuclear factor of activated T cells (NFAT)c2 in the nucleus, and repressed IL-4 mRNA levels. Thus, GIF represents a self-regulatory mechanism of Th2 cell generation from naïve CD4 cells, in which the posttranslational modification plays a crucial role.
Stress-driven buckling patterns in spheroidal core/shell structures
Authors: Yin Jie , Cao Zexian , Li Chaorong , Sheinman Izhak , Chen Xi
Published: November 2008

Many natural fruits and vegetables adopt an approximately spheroidal shape and are characterized by their distinct undulating topologies. We demonstrate that various global pattern features can be reproduced by anisotropic stress-driven buckles on spheroidal core/shell systems, which implies that the relevant mechanical forces might provide a template underpinning the topological conformation in some fruits and plants. Three dimensionless parameters, the ratio of effective size/thickness, the ratio of equatorial/polar radii, and the ratio of core/shell moduli, primarily govern the initiation and formation of the patterns. A distinct morphological feature occurs only when these parameters fall within certain ranges: In a prolate spheroid, reticular buckles take over longitudinal ridged patterns when one or more parameters become large. Our results demonstrate that some universal features of fruit/vegetable patterns (e.g., those observed in Korean melons, silk gourds, ribbed pumpkins, striped cavern tomatoes, and cantaloupes, etc.) may be related to the spontaneous buckling from mechanical perspectives, although the more complex biological or biochemical processes are involved at deep levels.
Hormesis Predicts Low-Dose Responses Better Than Threshold Models
Authors: Calabrese Edward J. , Stanek Edward J. , Nascarella Marc A. , Hoffmann George R.
Published: November 2008

This study evaluated characteristics of the concentration-response relationships of chemicals from the U.S. National Cancer Institute (NCI) Yeast Anticancer Drug Screen database with respect to the threshold and the hormetic dose-response models. The database reported concentration-response studies of 2189 chemicals from a broad range of chemical classes. The biological end point was growth in 13 strains of yeast ( Saccharomyces cerevisiae), most of which contain genetic alterations affecting DNA repair or cell cycle control. The analysis was limited to studies that satisfied a priori entry criteria for evaluation, including having two or more concentrations in the nontoxic zone (below a Benchmark Dose). The mean growth response compared to untreated controls of these doses was significantly greater than 100% in all 13 yeast strains, ranging from ~105% to ~111%. Under a threshold model, one would expect values more closely approximating 100%. Moreover, the distribution of responses below the BMD5 for chemicals was shifted upwardly from the expectations of a threshold model for all strains. These results indicate that for the chemicals and yeast strains studied, the responses are more consistent with a hormetic model than a threshold model, and they strengthen previous results presented by Calabrese et al. (2006 , Toxicol. Sci. 94:368–378). Taken together, the analyses provide strong evidence for hormesis, a phenomenon with a broad range of biomedical and toxicological implications.
Mannose 6-Phosphate/Insulin-like Growth Factor 2 Receptor Limits Cell Invasion by Controlling αVβ3 Integrin Expression and Proteolytic Processing of Urokinase-type Plasminogen Activator Receptor
Authors: Schiller Herbert B. , Szekeres Andreas , Binder Bernd R. , Stockinger Hannes , Leksa Vladimir
Published: November 2008

The multifunctional mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) is considered a tumor suppressor. We report here that RNA interference with M6P/IGF2R expression in urokinase-type plasminogen activator (uPA)/urokinase-type plasminogen activator receptor (uPAR) expressing human cancer and endothelial cells resulted in increased pericellular plasminogen activation, cell adhesion, and higher invasive potential through matrigel. M6P/IGF2R silencing led also to the cell surface accumulation of urokinase and plasminogen and enhanced expression of αV integrins. Genetic rescue experiments and inhibitor studies revealed that the enhanced plasminogen activation was due to a direct effect of M6P/IGF2R on uPAR, whereas increased cell adhesion to vitronectin was dependent on αV integrin expression and not uPAR. Increased cell invasion of M6P/IGF2R knockdown cells was rescued by cosilencing both uPAR and αV integrin. Furthermore, we found that M6P/IGF2R expression accelerates the cleavage of uPAR. M6P/IGF2R silencing resulted in an increased ratio of full-length uPAR to the truncated D2D3 fragment, incapable of binding most uPAR ligands. We conclude that M6P/IGF2R controls cell invasion by regulating αV integrin expression and by accelerating uPAR cleavage, leading to the loss of the urokinase/vitronectin/integrin-binding site on uPAR.
SIRT2 Suppresses Adipocyte Differentiation by Deacetylating FOXO1 and Enhancing FOXO1's Repressive Interaction with PPARγ
Authors: Wang Fei , Tong Qiang
Published: November 2008

Sirtuin family of proteins possesses NAD-dependent deacetylase and ADP ribosyltransferase activities. They are found to respond to nutrient deprivation and profoundly regulate metabolic functions. We have previously reported that caloric restriction increases the expression of one of the seven mammalian sirtuins, SIRT2, in tissues such as white adipose tissue. Because adipose tissue is a key metabolic organ playing a critical role in whole body energy homeostasis, we went on to explore the function of SIRT2 in adipose tissue. We found short-term food deprivation for 24 h, already induces SIRT2 expression in white and brown adipose tissues. Additionally, cold exposure elevates SIRT2 expression in brown adipose tissue but not in white adipose tissue. Intraperitoneal injection of a β-adrenergic agonist (isoproterenol) enhances SIRT2 expression in white adipose tissue. Retroviral expression of SIRT2 in 3T3-L1 adipocytes promotes lipolysis. SIRT2 inhibits 3T3-L1 adipocyte differentiation in low-glucose (1 g/l) or low-insulin (100 nM) condition. Mechanistically, SIRT2 suppresses adipogenesis by deacetylating FOXO1 to promote FOXO1's binding to PPARγ and subsequent repression on PPARγ transcriptional activity. Overall, our results indicate that SIRT2 responds to nutrient deprivation and energy expenditure to maintain energy homeostasis by promoting lipolysis and inhibiting adipocyte differentiation.
The Rho1p Exchange Factor Rgf1p Signals Upstream from the Pmk1 Mitogen-activated Protein Kinase Pathway in Fission Yeast
Authors: Garcia Patricia , Tajadura Virginia , Sanchez Yolanda
Published: November 2008

The Schizosaccharomyces pombe exchange factor Rgf1p specifically regulates Rho1p during polarized growth. Rgf1p activates the β-glucan synthase (GS) complex containing the catalytic subunit Bgs4p and is involved in the activation of growth at the second end, a transition that requires actin reorganization. In this work, we investigated Rgf1p signaling and observed that Rgf1p acted upstream from the Pck2p-Pmk1p MAPK signaling pathway. We noted that Rgf1p and calcineurin play antagonistic roles in Cl−homeostasis; rgf1Δ cells showed the vic phenotype (viable in the presence of immunosuppressant and chlorine ion) and were unable to grow in the presence of high salt concentrations, both phenotypes being characteristic of knockouts of the MAPK components. In addition, mutations that perturb signaling through the MAPK pathway resulted in defective cell integrity (hypersensitivity to caspofungin and β-glucanase). Rgf1p acts by positively regulating a subset of stimuli toward the Pmk1p-cell integrity pathway. After osmotic shock and cell wall damage HA-tagged Pmk1p was phosphorylated in wild-type cells but not in rgf1Δ cells. Finally, we provide evidence to show that Rgf1p regulates Pmk1p activation in a process that involves the activation of Rho1p and Pck2p, and we demonstrate that Rgf1p is unique in this signaling process, because Pmk1p activation was largely independent of the other two Rho1p-specific GEFs, Rgf2p and Rgf3p.
Mitochondria Are Linked to Calcium Stores in Striated Muscle by Developmentally Regulated Tethering Structures
Authors: Boncompagni Simona , Rossi Ann E. , Micaroni Massimo , Beznoussenko Galina V. , Polishchuk Roman S. , Dirksen Robert T. , Protasi Feliciano
Published: November 2008

Bi-directional calcium (Ca2+) signaling between mitochondria and intracellular stores (endoplasmic/sarcoplasmic reticulum) underlies important cellular functions, including oxidative ATP production. In striated muscle, this coupling is achieved by mitochondria being located adjacent to Ca2+ stores (sarcoplasmic reticulum [SR]) and in proximity of release sites (Ca2+ release units [CRUs]). However, limited information is available with regard to the mechanisms of mitochondrial-SR coupling. Using electron microscopy and electron tomography, we identified small bridges, or tethers, that link the outer mitochondrial membrane to the intracellular Ca2+ stores of muscle. This association is sufficiently strong that treatment with hypotonic solution results in stretching of the SR membrane in correspondence of tethers. We also show that the association of mitochondria to the SR is 1) developmentally regulated, 2) involves a progressive shift from a longitudinal clustering at birth to a specific CRU-coupled transversal orientation in adult, and 3) results in a change in the mitochondrial polarization state, as shown by confocal imaging after JC1 staining. Our results suggest that tethers 1) establish and maintain SR–mitochondrial association during postnatal maturation and in adult muscle and 2) likely provide a structural framework for bi-directional signaling between the two organelles in striated muscle.
Mus81, Rhp51(Rad51), and Rqh1 Form an Epistatic Pathway Required for the S-Phase DNA Damage Checkpoint
Authors: Willis Nicholas , Rhind Nicholas
Published: November 2008

The S-phase DNA damage checkpoint slows the rate of DNA synthesis in response to damage during replication. In the fission yeast Schizosaccharomyces pombe, Cds1, the S-phase-specific checkpoint effector kinase, is required for checkpoint signaling and replication slowing; upon treatment with the alkylating agent methyl methane sulfonate, cds1Δ mutants display a complete checkpoint defect. We have identified proteins downstream of Cds1 required for checkpoint-dependant slowing, including the structure-specific endonuclease Mus81 and the helicase Rqh1, which are implicated in replication fork stability and the negative regulation of recombination. Removing Rhp51, the Rad51 recombinase homologue, suppresses the slowing defect of rqh1Δ mutants, but not that of mus81Δ mutant, defining an epistatic pathway in which mus81 is epistatic to rhp51 and rhp51 is epistatic to rqh1. We propose that restraining recombination is required for the slowing of replication in response to DNA damage.
Fas Death Receptor Enhances Endocytic Membrane Traffic Converging into the Golgi Region
Authors: Degli Esposti Mauro , Tour Julien , Ouasti Sihem , Ivanova Saska , Matarrese Paola , Malorni Walter , Khosravi-Far Roya
Published: November 2008

The death receptor Fas/CD95 initiates apoptosis by engaging diverse cellular organelles including endosomes. The link between Fas signaling and membrane traffic has remained unclear, in part because it may differ in diverse cell types. After a systematic investigation of all known pathways of endocytosis, we have clarified that Fas activation opens clathrin-independent portals in mature T cells. These portals drive rapid internalization of surface proteins such as CD59 and depend upon actin-regulating Rho GTPases, especially CDC42. Fas-enhanced membrane traffic invariably produces an accumulation of endocytic membranes around the Golgi apparatus, in which recycling endosomes concentrate. This peri-Golgi polarization has been documented by colocalization analysis of various membrane markers and applies also to active caspases associated with internalized receptor complexes. Hence, T lymphocytes show a diversion in the traffic of endocytic membranes after Fas stimulation that seems to resemble the polarization of membrane traffic after their activation.
Kinesin-8 from Fission Yeast: A Heterodimeric, Plus-End–directed Motor that Can Couple Microtubule Depolymerization to Cargo Movement
Authors: Grissom Paula M. , Fiedler Thomas , Grishchuk Ekaterina L. , Nicastro Daniela , West Robert R. , Richard McIntosh J.
Published: November 2008

Fission yeast expresses two kinesin-8s, previously identified and characterized as products of the klp5+and klp6+genes. These polypeptides colocalize throughout the vegetative cell cycle as they bind cytoplasmic microtubules during interphase, spindle microtubules, and/or kinetochores during early mitosis, and the interpolar spindle as it elongates in anaphase B. Here, we describe in vitro properties of these motor proteins and some truncated versions expressed in either bacteria or Sf9 cells. The motor-plus-neck domain of Klp6p formed soluble dimers that cross-linked microtubules and showed both microtubule-activated ATPase and plus-end–directed motor activities. Full-length Klp5p and Klp6p, coexpressed in Sf9 cells, formed soluble heterodimers with the same activities. The latter recombinant protein could also couple microbeads to the ends of shortening microtubules and use energy from tubulin depolymerization to pull a load in the minus end direction. These results, together with the spindle localizations of these proteins in vivo and their requirement for cell viability in the absence of the Dam1/DASH kinetochore complex, support the hypothesis that fission yeast kinesin-8 contributes both to chromosome congression to the metaphase plate and to the coupling of spindle microtubules to kinetochores during anaphase A.
Human BRE1 Is an E3 Ubiquitin Ligase for Ebp1 Tumor Suppressor
Authors: Liu Zhixue , Oh Sang-Muk , Okada Masashi , Liu Xia , Cheng Dongmei , Peng Junmin , Brat Daniel J. , Sun Shi-yong , Zhou Wei , Gu Wei , Ye Keqiang
Published: November 2008

Human Bre1, an E3 ligase for H2B monoubiquitination, binds p53 and enhances activator-dependent transcription. Ebp1, an ErbB3 receptor-binding protein, inhibits cell proliferation and acts as a tumor suppressor. Here, we show that hBre1 acts as an E3 ubiquitin ligase for Ebp1 tumor suppressor and promotes its polyubiquitination and degradation. Ebp1 is polyubiquitinated in cancer cells, which is regulated by its phosphorylation. We identified hBre1 acting as an E3 ligase for Ebp1 and increasing its polyubiquitination. Depletion of hBre1 blocks Ebp1's polyubiquitination and elevates its protein level, preventing cancer proliferation. hBre1 binds Ebp1 and suppresses its repressive effect on E2F-1. Moreover, Ebp1 protein level is substantially diminished in human cancers. It is robustly phosphorylated and localized in the nucleus of primary gliomas, correlating with hBre1 subcellular residency. Thus, hBre1 inhibits Ebp1's tumor suppressive activity through mediating its polyubiquitination and degradation.
Clustering in a network of non-identical and mutually interacting agents
Authors: De Smet Filip , Aeyels Dirk
Published: November 2008

Clustering is a phenomenon that may emerge in multi-agent systems through self-organization: groups arise consisting of agents with similar dynamic behaviour. It is observed in fields ranging from the exact sciences to social and life sciences; consider, for example, swarm behaviour of animals or social insects, the dynamics of opinion formation or the synchronization (which corresponds to cluster formation in the phase space) of coupled oscillators modelling brain or heart cells. We consider a clustering model with a general network structure and saturating interaction functions. We derive both necessary and sufficient conditions for clustering behaviour of the model and we investigate the cluster structure for varying coupling strength. Generically, each cluster asymptotically reaches a (relative) equilibrium state. We discuss the relationship of the model to swarming, and we explain how the model equations naturally arise in a system of interconnected water basins. We also indicate how the model applies to opinion formation dynamics.
Multiple origins of deep-sea Asellota (Crustacea: Isopoda) from shallow waters revealed by molecular data
Authors: Raupach Michael J , Mayer Christoph , Malyutina Marina , Wägele Johann-Wolfgang
Published: November 2008

The Asellota are a highly variable group of Isopoda with many species in freshwater and marine shallow-water environments. However, in the deep sea, they show their most impressive radiation with a broad range of astonishing morphological adaptations and bizarre body forms. Nevertheless, the evolution and phylogeny of the deep-sea Asellota are poorly known because of difficulties in scoring morphological characters. In this study, the molecular phylogeny of the Asellota is evaluated for 15 marine shallow-water species and 101 deep-sea species, using complete 18S and partial 28S rDNA gene sequences. Our molecular data support the monophyly of most deep-sea families and give evidence for a multiple colonization of the deep sea by at least four major lineages of asellote isopods. According to our molecular data, one of these lineages indicates an impressive radiation in the deep sea. Furthermore, the present study rejects the monophyly of the family Janiridae, a group of plesiomorphic shallow-water Asellota, and several shallow-water and deep-sea genera (Acanthaspidia,Ianthopsis,Haploniscus,Echinozone,Eurycope,MunnopsurusandSyneurycope).
Haemoglobin polymorphisms affect the oxygen-binding properties in Atlantic cod populations
Authors: Andersen Øivind , Wetten Ola Frang , De Rosa Maria Cristina , Andre Carl , Carelli Alinovi Cristiana , Colafranceschi Mauro , Brix Ole , Colosimo Alfredo
Published: November 2008

A major challenge in evolutionary biology is to identify the genes underlying adaptation. The oxygen-transporting haemoglobins directly link external conditions with metabolic needs and therefore represent a unique system for studying environmental effects on molecular evolution. We have discovered two haemoglobin polymorphisms in Atlantic cod populations inhabiting varying temperature and oxygen regimes in the North Atlantic. Three-dimensional modelling of the tetrameric haemoglobin structure demonstrated that the two amino acid replacements Met55β1Val and Lys62β1Ala are located at crucial positions of the α1β1subunit interface and haem pocket, respectively. The replacements are proposed to affect the oxygen-binding properties by modifying the haemoglobin quaternary structure and electrostatic feature. Intriguingly, the same molecular mechanism for facilitating oxygen binding is found in avian species adapted to high altitudes, illustrating convergent evolution in water- and air-breathing vertebrates to reduction in environmental oxygen availability. Cod populations inhabiting the cold Arctic waters and the low-oxygen Baltic Sea seem well adapted to these conditions by possessing the high oxygen affinity Val55–Ala62 haplotype, while the temperature-insensitive Met55–Lys62 haplotype predominates in the southern populations. The distinct distributions of the functionally different haemoglobin variants indicate that the present biogeography of this ecologically and economically important species might be seriously affected by global warming.
Identification of miniature inverted-repeat transposable elements (MITEs) and biogenesis of their siRNAs in the Solanaceae: New functional implications for MITEs
Authors: Kuang Hanhui , Padmanabhan Chellappan , Li Feng , Kamei Ayako , Bhaskar Pudota B. , Ouyang Shu , Jiang Jiming , Buell C. Robin , Baker Barbara
Published: November 2008

Small RNAs regulate the genome by guiding transcriptional and post-transcriptional silencing machinery to specific target sequences, including genes and transposable elements (TEs). Although miniature inverted-repeat transposable elements (MITEs) are closely associated with euchromatic genes, the broader functional impact of these short TE insertions in genes is largely unknown. We identified 22 families of MITEs in the Solanaceae (MiS1–MiS22) and found abundant MiS insertions in Solanaceae genomic DNA and expressed sequence tags (EST). Several Solanaceae MITEs generate genome changes that potentially affect gene function and regulation, most notably, a MiS insertion that provides a functionally indispensable alternative exon in the tobacco mosaic virus N resistance gene. We show that MITEs generate small RNAs that are primarily 24 nt in length, as detected by Northern blot hybridization and by sequencing small RNAs of Solanum demissum, Nicotiana glutinosa, and Nicotiana benthamiana. Additionally, we show that stable RNAi lines silencing DICER-LIKE3 (DCL3) in tobacco and RNA-dependent RNA polymerase 2 (RDR2) in potato cause a reduction in 24-nt MITE siRNAs, suggesting that, as in Arabidopsis, TE-derived siRNA biogenesis is DCL3 and RDR2 dependent. We provide evidence that DICER-LIKE4 (DCL4) may also play a role in MITE siRNA generation in the Solanaceae.
Dissecting the effects of mtDNA variations on complex traits using mouse conplastic strains
Authors: Yu Xinhua , Gimsa Ulrike , Wester-Rosenlöf Lena , Kanitz Ellen , Otten Winfried , Kunz Manfred , Ibrahim Saleh M.
Published: November 2008

Previous reports have demonstrated that the mtDNA of mouse common inbred strains (CIS) originated from a single female ancestor and that mtDNA mutations occurred during CIS establishment. This situation provides a unique opportunity to investigate the impact of individual mtDNA variations on complex traits in mammals. In this study, we compiled the complete mtDNA sequences of 52 mouse CIS. Phylogenetic analysis demonstrated that 50 of the 52 CIS descended from a single female Mus musculus domesticus mouse, and mtDNA mutations have accumulated in 26 of the CIS. We then generated conplastic strains on the C57BL/6J background for 12 mtDNA variants with one to three functional mtDNA mutations. We also generated conplastic strains for mtDNA variants of the four M. musculus subspecies, each of which contains hundreds of mtDNA variations. In total, a panel of conplastic strains was generated for 16 mtDNA variants. Phenotypic analysis of the conplastic strains demonstrated that mtDNA variations affect susceptibility to experimental autoimmune encephalomyelitis and anxiety-related behavior, which confirms that mtDNA variations affect complex traits. Thus, we have developed a unique genetic resource that will facilitate exploration of the biochemical and physiological roles of mitochondria in complex traits.
AtHMA3, a P1B-ATPase Allowing Cd/Zn/Co/Pb Vacuolar Storage in Arabidopsis
Authors: Morel Mélanie , Crouzet Jérôme , Gravot Antoine , Auroy Pascaline , Leonhardt Nathalie , Vavasseur Alain , Richaud Pierre
Published: November 2008

The Arabidopsis (Arabidopsis thaliana) Heavy Metal Associated3 (AtHMA3) protein belongs to the P1B-2 subgroup of the P-type ATPase family, which is involved in heavy metal transport. In a previous study, we have shown, using heterologous expression in the yeast Saccharomyces cerevisiae, that in the presence of toxic metals, AtHMA3 was able to phenotypically complement the cadmium/lead (Cd/Pb)-hypersensitive strain ycf1 but not the zinc (Zn)-hypersensitive strain zrc1. In this study, we demonstrate that AtHMA3 in planta is located in the vacuolar membrane, with a high expression level in guard cells, hydathodes, vascular tissues, and the root apex. Confocal imaging in the presence of the Zn/Cd fluorescent probe BTC-5N revealed that AtHMA3 participates in the vacuolar storage of Cd. A T-DNA insertional mutant was found more sensitive to Zn and Cd. Conversely, ectopic overexpression of AtHMA3 improved plant tolerance to Cd, cobalt, Pb, and Zn; Cd accumulation increased by about 2- to 3-fold in plants overexpressing AtHMA3 compared with wild-type plants. Thus, AtHMA3 likely plays a role in the detoxification of biological (Zn) and nonbiological (Cd, cobalt, and Pb) heavy metals by participating in their vacuolar sequestration, an original function for a P1B-2 ATPase in a multicellular eukaryote.
Five cases of necrotizing fasciitis: Lack of skin inflammatory signs as a clinical clue for the fulminant type
Authors: IWATA Yohei , SATO Shinichi , MURASE Yumi , IIJIMA Ayuko , HAYASHI Kaori , MURAKAMI Sakae , USUDA Toshikazu
Published: November 2008

Herein, we describe five patients with necrotizing fasciitis (NF) who had variable outcomes and clinical manifestations. At the onset, all patients exhibited purpura with or without blister and ulceration accompanied by severe pain and tenderness in the affected skin. Out of five patients, three lacked inflammatory signs such as redness and heat, and two of the three patients showed fulminant progression and died despite intensive treatments including surgical debridement, antimicrobial therapy, close monitoring and physiological support. Tissue specimens from the patients without skin inflammatory signs showed mild neutrophil infiltration in addition to necrosis from the epidermis to subcutaneous fat, and variable amounts of thrombi. Furthermore, numerous bacteria were detected by Gram stain. By contrast, the remaining two patients with skin inflammatory signs revealed slower progression, and tissue specimens from both patients showed heavy neutrophil infiltration, but bacteria were hardly detected. Therefore, these cases suggest the possibility that the paucity of skin inflammatory signs, such as redness and heat, in NF may be a clinical clue to predict the fulminant type.
Case of cystic schwannoma
Authors: CHOI Yu Sung , SHIN Mi Seon , PARK Mi Youn , PARK Hyang Joon
Published: November 2008

Schwannoma is a well‐defined tumor arising from the nerve sheath. It may present as a solitary mass in any part of the body, but is more commonly seen in the head, neck and extremities. We describe a 32‐year‐old female patient with a small dermal nodule on the forehead, which was 2 cm in diameter, round and of a cystic nature. Microscopic examination revealed that it consisted of compact spindle cells arranged partly in short bundles or a fascicular pattern with outstanding cystic degeneration manifested as a large, unilocular cavity in the center of the tumor tissue. The tumor cells were positive for S‐100 protein and negative for epithelial membrane antigen (EMA), while the tumor capsule was positive for EMA. There was no S‐100‐positive membrane‐like structure lining the cyst wall.
Human bronchial intraepithelial T cells produce interferon-γ and stimulate epithelial cells
Authors: Hirosako S , Goto E , Fujii K , Tsumori K , Hirata N , Tsumura S , Kamohara H , Kohrogi H
Published: November 2008

Intraepithelial lymphocytes (IELs) can be identified among epithelial cells in systemic mucosal tissues. Although intestinal IELs play a crucial role in mucosal immunity, their bronchial counterparts have not been well studied. The purpose of this study was to determine the immunological functions of human bronchial IELs, which interact directly with epithelial cells, unlike lamina propria lymphocytes (LPLs). We isolated successfully bronchial IELs and LPLs using a magnetic cell separation system from the T cell suspensions extracted from bronchial specimens far from the tumours of resected lungs. Human bronchial IELs showed an apparent type 1 cytokine profile and proliferated more actively in response to CD2 signalling than did bronchial LPLs. CD8+ IELs were identified as the most significant sources of interferon (IFN)-γ. Human bronchial epithelial cells constitutively produced the T cell growth factors interleukin (IL)-7 and IL-15, and levels of those factors increased when cells were stimulated by IFN-γ. Bronchial epithelial cells expressed cell surface proteins CD58 and E-cadherin, possibly enabling adhesion to IELs. In summary, human bronchial IELs have immunological functions distinct from bronchial LPLs and may interact with epithelial cells to maintain mucosal homeostasis.