bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk factors for placenta previa in an Asian population
Authors: Hung Tai‐Ho , Hsieh Ching‐Chang , Hsu Jenn‐Jeih , Chiu Tsung‐Hong , Lo Liang‐Ming , Hsieh T'sang‐T'ang
Published: February 2007

Objective: To identify the risk factors for placenta previa in an Asian population. Methods: This retrospective cohort study involved Taiwanese women delivered between July 1990 and December 2003 at Chang Gung Memorial Hospital, Taipei, Taiwan. Pregnancies complicated by multiple gestation and fetal anomalies were excluded. Results: There were 457 cases of placenta previa (1.2%) among the 37,702 pregnancies analyzed. Risk factors for placenta previa included a prior preterm birth (OR, 6.6; 95% confidence interval [CI], 4.1–10.6); technology‐assisted conception (OR, 4.8; 95% CI, 2.9–7.8); smoking (OR, 3.3; 95% CI, 1.2–9.1) or working (OR, 3.8; 95% CI, 2.8–5.3) during pregnancy; maternal age of, or greater than 35 years (OR, 2.0 to 2.2; 95% CI, 1.3–3.7); and previous induced abortions (OR, 1.3–3.0; 95% CI, 1.1–7.1). Conclusion: The risk factors for placenta previa were found to be the same for Asian women as those previously recorded for American and European women, but additional factors were detected.
Malaria parasite induces tryptophan-related immune suppression in mice
Authors: TETSUTANI K. , TO H. , TORII M. , HISAEDA H. , HIMENO K.
Published: February 2007

Plasmodiumspp. cause the worst parasitic diseases in humans and evade host immunity in complicated ways. Activated catabolism of tryptophan in dendritic cells is thought to suppress immunity, which is mediated by an inducible rate-limiting enzyme of tryptophan catabolism, indoleamine 2,3 dioxygenase (IDO), via both tryptophan depletion and production of toxic metabolites. In various infections, including malaria, IDO is known to be activated but its biological significance is unclear; therefore, we investigated whether malaria parasites induce IDO to suppress host immune responses. We found that enzymatic activity of IDO was elevated systematically in our mouse malaria model, and was abolished byin vivoIDO inhibition with 1-methyl tryptophan. Experimental infection withPlasmodium yoeliishowed that IDO inhibition slightly suppressed parasite density in association with enhanced proliferation and IFN-γ production by CD4+T cells in response to malaria parasites. Our observations suggest that induction of IDO is one of the immune mechanisms of malaria parasites.
Inulin and oligofructose as prebiotics in the prevention of intestinal infections and diseases
Authors: Bosscher D. , Loo J. Van , Franck A.
Published: February 2007

Health and wellbeing are challenged constantly by pathogens. A number of defence mechanisms exist to protect the body from pathogen colonisation and invasion, with an important role to play for the natural intestinal bacterial flora (mainly by bifidobacteria and lactobacilli). The present paper reviews the evidence on the effects of inulin and oligofructose on colonisation and translocation of pathogens and the prevention of intestinal diseases. In vitro experiments have shown that lactic acid-producing bacteria have antagonistic (antibacterial) activity against pathogens partly because of the production of organic acids which are the endproducts of inulin and oligofructose fermentation. In addition, studies with epithelial layers have shown that inulin and oligofructose inhibit pathogen colonisation and that endproducts of their fermentation have the ability to support barrier function. Furthermore, studies in various animal models have shown that inulin and oligofructose accelerate the recovery of beneficial bacteria, slow down pathogen growth, decreasing pathogen colonisation and systemic translocation. Finally, data from human intervention trials either in patients with intestinal disorders or disease, or prone to critical illness, found that inulin and oligofructose restore the balance when the gut microbial community is altered, inhibit the progression of disease or prevent it from relapsing and/or developing. To conclude, the dietary use of inulin and oligofructose offers a promising approach to restore microbial communities and to support barrier function of the epithelia by their prebiotic action. This may offer the host protection against invasion and translocation of pathogens (endogenous and/or exogenous) and in the prevention of gastrointestinal diseases.
The use of proteomic techniques to explore the holistic effects of nutrients in vivo
Authors: Griffiths Helen R. , Grant Melissa M.
Published: February 2007

The availability of ‘omics’ technologies is transforming scientific approaches to physiological problems from a reductionist viewpoint to that of a holistic viewpoint. This is of profound importance in nutrition, since the integration of multiple systems at the level of gene expression on the synthetic side through to metabolic enzyme activity on the degradative side combine to govern nutrient availability to tissues. Protein activity is central to the process of nutrition from the initial absorption of nutrients via uptake carriers in the gut, through to distribution and transport in the blood, metabolism by degradative enzymes in tissues and excretion through renal tubule exchange proteins. Therefore, the global profiling of the proteome, defined as the entire protein complement of the genome expressed in a particular cell or organ, or in plasma or serum at a particular time, offers the potential for identification of important biomarkers of nutritional state that respond to alterations in diet. The present review considers the published evidence of nutritional modulation of the proteome in vivo which has expanded exponentially over the last 3 years. It highlights some of the challenges faced by researchers using proteomic approaches to understand the interactions of diet with genomic and metabolic–phenotypic variables in normal populations.
Regulation of hepatic metabolism by enteral delivery of nutrients
Authors: Dardevet D. , Moore M. C. , Remond D. , Everett-Grueter C. A. , Cherrington A. D.
Published: February 2007

The liver plays a unique role in nutrient homeostasis. Its anatomical location makes it ideally suited to control the systemic supply of absorbed nutrients, and it is the primary organ that can both consume and produce substantial amounts of glucose. Moreover, it is the site of a substantial fraction (about 25 %) of the body's protein synthesis, and the liver and other organs of the splanchnic bed play an important role in sparing dietary N by storing ingested amino acids. This hepatic anabolism is under the control of hormonal and nutritional changes that occur during food intake. In particular, the route of nutrient delivery, i.e. oral (or intraportal)v.peripheral venous, appears to impact upon the disposition of the macronutrients and also to affect both hepatic and whole-body nutrient metabolism. Intraportal glucose delivery significantly enhances net hepatic glucose uptake, compared with glucose infusion via a peripheral vein. On the other hand, concomitant intraportal infusion of both glucose and gluconeogenic amino acids significantly decreases net hepatic glucose uptake, compared with infusion of the same mass of glucose by itself. Delivery of amino acids via the portal vein may enhance their hepatic uptake, however. Elevation of circulating lipids under postprandial conditions appears to impair both hepatic and whole-body glucose disposal. Thus, the liver's role in nutrient disposal and metabolism is highly responsive to the route of nutrient delivery, and this is an important consideration in planning nutrition support and optimising anabolism in vulnerable patients.
Food habits and physical activity patterns among Palestinian adolescents: findings from the national study of Palestinian schoolchildren (HBSC-WBG2004)
Authors: Al Sabbah H , Vereecken C , Kolsteren P , Abdeen Z , Maes L
Published: February 2007

Objective

To describe the food habits and physical (in)activity patterns and to investigate the relationship with sociodemographic factors among Palestinian adolescents.

Design and subjects

The Palestinian Health Behaviour in School-aged Children (HBSC) is a cross-sectional survey of grades 6, 8, 10 and 12. Students completed a modified version of the international HBSC questionnaire. A total of 8885 students were included in this analysis; 53% were from the West Bank and 47% from the Gaza Strip.

Results

Adolescents in the West Bank consume more fruit, meat, chicken, sweets and soft drinks, but less vegetables than adolescents in Gaza (P < 0.01). Girls reported more daily consumption of fruit, vegetables and sweets than boys (P < 0.001), and less consumption of soft drinks, milk, meat and chicken (P < 0.01). Boys were physically more active than girls (P < 0.01), whereas girls reported doing more homework (P < 0.001). Both boys and girls reported less physical activity with increasing age (P < 0.001). Consumption of fruit and milk was positively associated with both parents' education, while consumption of meat, chicken and soft drinks was positively associated with mother's education only. Having breakfast on schooldays was positively associated with the father's education. Physical activity and television viewing were associated with the mother's education (P < 0.01). The parents' level of education had no effect on vegetable consumption and dieting status.

Conclusion

This study indicated that there are problems with Palestinian adolescents' eating, dieting and physical activity. Regional, gender and parental socio-economic status differences should be taken into account in developing interventions. More detailed studies are needed with more elaborate instruments about food habits and physical activity of adolescents.
The impact of body mass index and Western advertising and media on eating style, body image and nutrition transition among Jordanian women
Authors: Madanat Hala N , Brown Ralph B , Hawks Steven R
Published: February 2007

Objectives

To identify the impact of body mass index (BMI) and Western advertising and media on the stage of the nutrition transition among Jordanian women, and to evaluate their impact on eating styles and body image.

Design

A randomised cross-sectional survey that included a variety of culturally measured Likert-type scales and body size images. In addition, BMI was calculated based on measured height and weight.

Setting

In the homes of the participants. The data were collected by female interviewers who worked for the Jordan Department of Statistics.

Subjects

The sample was based on a random and representative selection of 800 mostly urban Jordanian women. A pre-test sample of 100 women was also used to validate the instruments.

Results

Women tended to agree that they ate based on emotional cues. They had high levels of disordered eating attitudes and behaviours and 42.1% were considered restrained eaters. However, these women also had higher than expected body esteem levels and desired a healthy body size. As expected, being obese was associated with a desire to lose weight, being a restrained and emotional eater, and having more disordered eating attitudes and behaviours. Similarly, Western advertising and media were associated with restrained and emotional eating, desired weight loss, and disordered eating attitudes and behaviours.

Conclusions

There is a need to develop health education materials that explain the influence of obesity on health and the negative psychological and physical consequences of restrained and emotional eating, building on the current cultural preferences of healthy body size. Further implications and suggestions for future research are discussed.
Management of close margins in invasive breast cancer
Authors: Bleicher R. J. , Morrow M.
Published: February 2007

Since clinical trials have demonstrated that breast conservation is safe and effective for treatment of invasive breast cancer, there has been considerable disagreement and controversy about what constitutes an acceptable margin in breast cancer. Dogmatic adherence to a set margin for all patients may cause a higher mastectomy rate than necessary, and thus it is important to understand how various clinical and pathologic factors affect local recurrence and outcome. This review discusses that controversy, as well as what factors should be considered when evaluating patients on an individual basis.
Arabidopsis
SNI1 and RAD51D regulate both gene transcription and DNA recombination during the defense response
Authors: Durrant Wendy E. , Wang Shui , Dong Xinnian
Published: February 2007

The plant immune response known as systemic acquired resistance (SAR) is a general defense mechanism that confers long-lasting resistance against a broad spectrum of pathogens. SAR triggers many molecular changes including accumulation of antimicrobial pathogenesis-related (PR) proteins. Transcription of
PR
genes in
Arabidopsis
is regulated by the coactivator NPR1 and the repressor SNI1. Pathogen infection also triggers an increase in somatic DNA recombination, which results in transmission of changes to the offspring of infected plants. However, it is not known how the induction of homologous recombination during SAR is controlled. Here, we show that SNI1 and RAD51D regulate both gene expression and DNA recombination. In a genetic screen for suppressors of
sni1
, we discovered that RAD51D is required for NPR1-independent
PR
gene expression. As a result, the
rad51d
mutant has enhanced disease susceptibility. Besides altered
PR
gene expression,
rad51d
plants are hypersensitive to DNA-damaging agents and are impaired in homologous recombination. The dual role of RAD51D and SNI1 in
PR
gene transcription and DNA recombination suggests a mechanistic link between the short-term defense response and a long-term survival strategy.
Multigene phylogeny reveals eusociality evolved twice in vespid wasps
Authors: Hines Heather M. , Hunt James H. , O'Connor Timothy K. , Gillespie Joseph J. , Cameron Sydney A.
Published: February 2007

Eusocial wasps of the family Vespidae are thought to have derived their social behavior from a common ancestor that had a rudimentary caste-containing social system. In support of this behavioral scenario, the leading phylogenetic hypothesis of Vespidae places the eusocial wasps (subfamilies Stenogastrinae, Polistinae, and Vespinae) as a derived monophyletic clade, thus implying a single origin of eusocial behavior. This perspective has shaped the investigation and interpretation of vespid social evolution for more than two decades. Here we report a phylogeny of Vespidae based on data from four nuclear gene fragments (18S and 28S ribosomal DNA,
abdominal-A
and
RNA polymerase II
) and representatives from all six extant subfamilies. In contrast to the current phylogenetic perspective, our results indicate two independent origins of vespid eusociality, once in the clade Polistinae+Vespinae and once in the Stenogastrinae. The stenogastrines appear as an early diverging clade distantly related to the vespines and polistines and thus evolved their distinctive form of social behavior from a different ancestor than that of Polistinae+Vespinae. These results support earlier views based on life history and behavior and have important implications for interpreting transitional stages in vespid social evolution.
Defective glycerol metabolism in aquaporin 9 (AQP9) knockout mice
Authors: Rojek Aleksandra M. , Skowronski Mariusz T. , Füchtbauer Ernst-Martin , Füchtbauer Annette C. , Fenton Robert A. , Agre Peter , Frøkiær Jørgen , Nielsen Søren
Published: February 2007

Aquaporin-9 (AQP9) is an aquaglyceroporin membrane channel shown biophysically to conduct water, glycerol, and other small solutes. Because the physiological role/s of AQP9 remain undefined and the expression sites of AQP9 remain incomplete and conflicting, we generated AQP9 knockout mice. In the absence of physiological stress, knockout mice did not display any visible behavioral or severe physical abnormalities. Immunohistochemical analyses using multiple antibodies revealed AQP9 specific labeling in hepatocytes, epididymis, vas deferens, and in epidermis of wild type mice, but a complete absence of labeling in AQP9
−/−
mice. In brain, no detectable labeling was observed. Compared with control mice, plasma levels of glycerol and triglycerides were markedly increased in AQP9
−/−
mice, whereas glucose, urea, free fatty acids, alkaline phosphatase, and cholesterol were not significantly different. Oral administration of glycerol to fasted mice resulted in an acute rise in blood glucose levels in both AQP9
−/−
and AQP9
+/−
mice, revealing no defect in utilization of exogenous glycerol as a gluconeogenic substrate and indicating a high gluconeogenic capacity in nonhepatic organs. Obese

Lepr
db

/

Lepr
db

AQP9
−/−
and obese

Lepr
db

/

Lepr
db

AQP9
+/−
mice showed similar body weight, whereas the glycerol levels in obese

Lepr
db

/

Lepr
db

AQP9
−/−
mice were dramatically increased. Consistent with a role of AQP9 in hepatic uptake of glycerol, blood glucose levels were significantly reduced in

Lepr
db

/

Lepr
db

AQP9
−/−
mice compared with

Lepr
db

/

Lepr
db

AQP9
+/−
in response to 3 h of fasting. Thus, AQP9 is important for hepatic glycerol metabolism and may play a role in glycerol and glucose metabolism in diabetes mellitus.
Host shutoff during productive Epstein–Barr virus infection is mediated by BGLF5 and may contribute to immune evasion
Authors: Rowe Martin , Glaunsinger Britt , van Leeuwen Daphne , Zuo Jianmin , Sweetman David , Ganem Don , Middeldorp Jaap , Wiertz Emmanuel J. H. J. , Ressing Maaike E.
Published: February 2007

Relatively little is known about immune evasion during the productive phase of infection by the γ1-herpesvirus Epstein–Barr virus (EBV). The use of a unique system to isolate cells in lytic cycle allowed us to identify a host shutoff function operating in productively EBV-infected B cells. This impairment of protein synthesis results from mRNA degradation induced upon expression of the early lytic-cycle gene product BGLF5. Recently, a γ2-herpesvirus, Kaposi sarcoma herpesvirus, has also been shown to encode a host shutoff function, indicating that host shutoff appears to be a general feature of γ-herpesviruses. One of the consequences of host shutoff is a block in the synthesis of HLA class I and II molecules, reflected by reduced levels of these antigen-presenting complexes at the surface of cells in EBV lytic cycle. This effect could lead to escape from T cell recognition and elimination of EBV-producing cells, thereby allowing generation of viral progeny in the face of memory T cell responses.
Highly accurate two-gene classifier for differentiating gastrointestinal stromal tumors and leiomyosarcomas
Authors: Price Nathan D. , Trent Jonathan , El-Naggar Adel K. , Cogdell David , Taylor Ellen , Hunt Kelly K. , Pollock Raphael E. , Hood Leroy , Shmulevich Ilya , Zhang Wei
Published: February 2007

Gastrointestinal stromal tumor (GIST) has emerged as a clinically distinct type of sarcoma with frequent overexpression and mutation of the
c-Kit
oncogene and a favorable response to imatinib mesylate [also known as STI571 (Gleevec)] therapy. However, a significant diagnostic challenge remains in the differentiation of GIST from leiomyosarcomas (LMSs). To improve on the diagnostic evaluation and to complement the immunohistochemical evaluation of these tumors, we performed a whole-genome gene expression study on 68 well characterized tumor samples. Using bioinformatic approaches, we devised a two-gene relative expression classifier that distinguishes between GIST and LMS with an accuracy of 99.3% on the microarray samples and an estimated accuracy of 97.8% on future cases. We validated this classifier by using RT-PCR on 20 samples in the microarray study and on an additional 19 independent samples, with 100% accuracy. Thus, our two-gene relative expression classifier is a highly accurate diagnostic method to distinguish between GIST and LMS and has the potential to be rapidly implemented in a clinical setting. The success of this classifier is likely due to two general traits, namely that the classifier is independent of data normalization and that it uses as simple an approach as possible to achieve this independence to avoid overfitting. We expect that the use of simple marker pairs that exhibit these traits will be of significant clinical use in a variety of contexts.
Male fetal germ cells are targets for androgens that physiologically inhibit their proliferation
Authors: Merlet Jorge , Racine Chrystèle , Moreau Evelyne , Moreno Stéphanie G. , Habert René
Published: February 2007

In adulthood, the action of androgens on seminiferous tubules is essential for full quantitatively normal spermatogenesis and fertility. In contrast, their role in the fetal testis, and particularly in fetal germ cell development, remains largely unknown. Using testicular feminized (Tfm) mice, we investigated the effects of a lack of functional androgen receptor (AR) on fetal germ cells, also named gonocytes. We demonstrated that endogenous androgens/AR physiologically control normal gonocyte proliferation. We observed an increase in the number of gonocytes at 17.5 days postconception resulting from an increase in proliferative activity inTfmmice. In a reciprocal manner, gonocyte proliferation is decreased by the addition of DHT in fetal testis organotypic culture. Furthermore, the AR coregulator Hsp90α (mRNA and protein) specifically expressed in gonocytes was down-regulated inTfmmice at 15.5 days postconception. To investigate whether these effects could result from direct action of androgens on gonocytes, we collected pure gonocyte preparations and detected AR transcripts therein. We used an original model harboring a reporter gene that specifically reflects AR activity by androgens and clearly demonstrated the presence of a functional AR protein in fetal germ cells. These data providein vivoandin vitroevidence of a new control of endogenous androgens on gonocytes identified as direct target cells for androgens. Finally, our results focus on a new pathway in the fetal testis during the embryonic period, which is the most sensitive to antiandrogenic endocrine disruptors.
An Andean origin of
Phytophthora infestans
inferred from mitochondrial and nuclear gene genealogies
Authors: Gómez-Alpizar Luis , Carbone Ignazio , Ristaino Jean Beagle
Published: February 2007

Phytophthora infestans
(Mont.) de Bary caused the 19th century Irish Potato Famine. We assessed the genealogical history of
P. infestans
using sequences from portions of two nuclear genes (β-
tubulin
and
Ras
) and several mitochondrial loci P3, (
rpl
14,
rpl
5, tRNA) and P4 (
Cox1
) from 94 isolates from South, Central, and North America, as well as Ireland. Summary statistics, migration analyses and the genealogy of current populations of
P. infestans
for both nuclear and mitochondrial loci are consistent with an “out of South America” origin for
P. infestans
. Mexican populations of
P. infestans
from the putative center of origin in Toluca Mexico harbored less nucleotide and haplotype diversity than Andean populations. Coalescent-based genealogies of all loci were congruent and demonstrate the existence of two lineages leading to present day haplotypes of
P. infestans
on potatoes. The oldest lineage associated with isolates from the section Anarrhichomenun including
Solanum tetrapetalum
from Ecuador was identified as
Phytophthora andina
and evolved from a common ancestor of
P. infestans
. Nuclear and mitochondrial haplotypes found in Toluca Mexico were derived from only one of the two lineages, whereas haplotypes from Andean populations in Peru and Ecuador were derived from both lineages. Haplotypes found in populations from the U.S. and Ireland was derived from both ancestral lineages that occur in South America suggesting a common ancestry among these populations. The geographic distribution of mutations on the rooted gene genealogies demonstrate that the oldest mutations in
P. infestans
originated in South America and are consistent with a South American origin.
Vascular endothelial tyrosine phosphatase (VE-PTP)-null mice undergo vasculogenesis but die embryonically because of defects in angiogenesis
Authors: Dominguez Melissa G. , Hughes Virginia C. , Pan Li , Simmons Mary , Daly Christopher , Anderson Keith , Noguera-Troise Irene , Murphy Andrew J. , Valenzuela David M. , Davis Samuel , Thurston Gavin , Yancopoulos George D. , Gale Nicholas W.
Published: February 2007

Development of the vascular system depends on the highly coordinated actions of a variety of angiogenic regulators. Several of these regulators are members of the tyrosine kinase superfamily, including VEGF receptors and angiopoietin receptors, Tie1 and Tie2. Tyrosine kinase signaling is counter-regulated by the activity of tyrosine phosphatases, including vascular endothelial protein tyrosine phosphatase (VE-PTP), which has previously been shown to modulate Tie2 activity. We generated mice in which VE-PTP is replaced with a reporter gene. We confirm that VE-PTP is expressed in endothelium and also show that VE-PTP is highly expressed in the developing outflow tract of the heart and later is expressed in developing heart valves. Vasculogenesis occurs normally in mice lacking VE-PTP; however, angiogenesis is abnormal. Angiogenic defects in VE-PTP-null mice were most pronounced in the yolk sac and include a complete failure to elaborate the primitive vascular scaffold into higher-order branched arteries, veins, and capillaries. VE-PTP continues to be expressed into adulthood in the vasculature and heart valves, suggesting later roles in vascular development or homeostasis. VE-PTP is also expressed in the vasculature of growing tumors, suggesting that VE-PTP may be a new potential target for angiogenic therapies.
Regulation of brefeldin A-inhibited guanine nucleotide-exchange protein 1 (BIG1) and BIG2 activity via PKA and protein phosphatase 1γ
Authors: Kuroda Fuminobu , Moss Joel , Vaughan Martha
Published: February 2007

Brefeldin A-inhibited guanine nucleotide-exchange proteins (GEPs) BIG1 and BIG2 activate ADP-ribosylation factor (ARF) GTPases, which are required for vesicular trafficking. Both molecules contain one or more sites for binding protein kinase A, i.e., A kinase-anchoring protein (AKAP) sequences. Elevation of cell cAMP caused PKA-catalyzed phosphorylation and nuclear accumulation of BIG1 but not BIG2. We then asked whether BIG1 phosphorylation altered its GEP activity. Incubation of BIG1 or BIG2 with PKA catalytic subunits and ATP resulted in retardation of their electrophoretic migration, consistent with PKA phosphorylation. Okadaic acid inhibits many protein phosphatases, including protein phosphatase 1 (PP1) and PP2A, that can reverse PKA-catalyzed phosphorylation. Incubation of HepG2 cells with okadaic acid caused concentration-dependent accumulation of presumably phosphorylated BIG1 and BIG2 with decreased mobility, which was increased by subsequent incubation
in vitro
with specific recombinant phosphatases, PP1γ > PP2A ≫ PP1α. For assays of GEP activity, BIG1 and BIG2 were immunoprecipitated from cells that had been depleted, respectively, of BIG2 and BIG1 by using specific siRNA. GEP activity of each was significantly decreased after incubation with recombinant PKA plus ATP and restored by incubation with PP1γ. In agreement with a role for PP1γ in regulation of BIG, endogenous PP1γ, but not PP1α or β, was immunoprecipitated with BIG1 or BIG2 from microsomal fractions. All observations are consistent with the effects of BIG1 and BIG2 phosphorylation on vesicular trafficking, via alterations in ARF activation and regulatory roles for cAMP, PKA, and PP1γ in ARF activation by BIG1 and BIG2.
Revealing Early Steps of α2β1Integrin-mediated Adhesion to Collagen Type I by Using Single-Cell Force Spectroscopy
Authors: Taubenberger Anna , Cisneros David A. , Friedrichs Jens , Puech Pierre-Henri , Muller Daniel J. , Franz Clemens M.
Published: February 2007

We have characterized early steps of α2β1integrin-mediated cell adhesion to a collagen type I matrix by using single-cell force spectroscopy. In agreement with the role of α2β1as a collagen type I receptor, α2β1-expressing Chinese hamster ovary (CHO)-A2 cells spread rapidly on the matrix, whereas α2β1-negative CHO wild-type cells adhered poorly. Probing CHO-A2 cell detachment forces over a contact time range of 600 s revealed a nonlinear adhesion response. During the first 60 s, cell adhesion increased slowly, and forces associated with the smallest rupture events were consistent with the breakage of individual integrin–collagen bonds. Above 60 s, a fraction of cells rapidly switched into an activated adhesion state marked by up to 10-fold increased detachment forces. Elevated overall cell adhesion coincided with a rise of the smallest rupture forces above the value required to break a single-integrin–collagen bond, suggesting a change from single to cooperative receptor binding. Transition into the activated adhesion mode and the increase of the smallest rupture forces were both blocked by inhibitors of actomyosin contractility. We therefore propose a two-step mechanism for the establishment of α2β1-mediated adhesion as weak initial, single-integrin–mediated binding events are superseded by strong adhesive interactions involving receptor cooperativity and actomyosin contractility.
Nascent Transcription ofMCM2-7Is Important for Nuclear Localization of the Minichromosome Maintenance Complex in G1
Authors: Braun Katherine A. , Breeden Linda L.
Published: February 2007

The minichromosome maintenance genes (MCM2-7) are transcribed at M/G1just as the Mcm complex is imported into the nucleus to be assembled into prereplication complexes, during a period of low cyclin-dependent kinase (CDK) activity. The CDKs trigger DNA replication and prevent rereplication in part by exporting Mcm2-7 from the nucleus during S phase. We have found that repression of MCM2-7 transcription in a single cell cycle interferes with the nuclear import of Mcms in the subsequent M/G1phase. This suggests that nascent Mcm proteins are preferentially imported into the nucleus. Consistent with this, we find that loss of CDK activity in G2/M is not sufficient for nuclear import, there is also a requirement for new protein synthesis. This requirement is not met by constitutive production of Cdc6 and does not involve synthesis of new transport machinery. The Mcm proteins generated in the previous cell cycle, which are unable to reaccumulate in the nucleus, are predominantly turned over by ubiquitin-mediated proteolysis in late mitosis/early G1. Therefore, the nuclear localization of Mcm2-7 is dependent on nascent transcription and translation of Mcm2-7 and the elimination of CDK activity which occurs simultaneously as cells enter G1.
Sensory Ciliogenesis inCaenorhabditis elegans: Assignment of IFT Components into Distinct Modules Based on Transport and Phenotypic Profiles
Authors: Ou Guangshuo , Koga Makato , Blacque Oliver E. , Murayama Takashi , Ohshima Yasumi , Schafer Jenny C. , Li Chunmei , Yoder Bradley K. , Leroux Michel R. , Scholey Jonathan M.
Published: February 2007

Sensory cilium biogenesis within Caenorhabditis elegans neurons depends on the kinesin-2–dependent intraflagellar transport (IFT) of ciliary precursors associated with IFT particles to the axoneme tip. Here we analyzed the molecular organization of the IFT machinery by comparing the in vivo transport and phenotypic profiles of multiple proteins involved in IFT and ciliogenesis. Based on their motility in wild-type and bbs (Bardet-Biedl syndrome) mutants, IFT proteins were classified into groups with similar transport profiles that we refer to as “modules.” We also analyzed the distribution and transport of fluorescent IFT particles in multiple known ciliary mutants and 49 new ciliary mutants. Most of the latter mutants were snip-SNP mapped and one, namely dyf-14(ks69), was cloned and found to encode a conserved protein essential for ciliogenesis. The products of these ciliogenesis genes could also be assigned to the aforementioned set of modules or to specific aspects of ciliogenesis, based on IFT particle dynamics and ciliary mutant phenotypes. Although binding assays would be required to confirm direct physical interactions, the results are consistent with the hypothesis that the C. elegans IFT machinery has a modular design, consisting of modules IFT-subcomplex A, IFT-subcomplex B, and a BBS protein complex, in addition to motor and cargo modules, with each module contributing to distinct functional aspects of IFT or ciliogenesis.
Liver Progenitor Cells Develop Cholangiocyte-Type Epithelial Polarity in Three-dimensional Culture
Authors: Tanimizu Naoki , Miyajima Atsushi , Mostov Keith E.
Published: February 2007

Cholangiocytes are cellular components of the bile duct system of the liver, which originate from hepatoblasts during embryonic liver development. Although several transcription factors and signaling molecules have been implicated in bile duct development, its molecular mechanism has not been studied in detail. Here, we applied a three-dimensional (3D) culture technique to a liver progenitor cell line, HPPL, to establish an in vitro culture system in which HPPL acquire differentiated cholangiocyte characteristics. When HPPL were grown in a gel containing Matrigel, which contains extracellular matrix components of basement membrane, HPPL developed apicobasal polarity and formed cysts, which had luminal space inside. In the cysts, F-actin bundles and atypical protein kinase C were at the apical membrane, E-cadherin was localized at the lateral membrane, and β-catenin and integrin α6 were located at the basolateral membrane. HPPL in cysts expressed cholangiocyte markers, including cytokeratin 19, integrin β4, and aquaporin-1, but not a hepatocyte marker, albumin. Furthermore, HPPL transported rhodamine 123, a substrate for multidrug resistance gene products, from the basal side to the central lumen. These data indicate that HPPL develop cholangiocyte-type epithelial polarity in 3D culture. Phosphatidylinositol 3-kinase signaling was essential for proliferation and survival of HPPL in culture, whereas laminin-1 was a crucial component of Matrigel for inducing epithelial polarization of HPPL. Because HPPL cysts display structural and functional similarities with bile ducts, the 3D culture of HPPL recapitulates in vivo cholangiocyte differentiation and is useful to study the molecular mechanism of bile duct development in vitro.
Menstrual Blood-derived Cells Confer Human Dystrophin Expression in the Murine Model of Duchenne Muscular Dystrophy via Cell Fusion and Myogenic Transdifferentiation
Authors: Cui Chang-Hao , Uyama Taro , Miyado Kenji , Terai Masanori , Kyo Satoru , Kiyono Tohru , Umezawa Akihiro
Published: February 2007

Duchenne muscular dystrophy (DMD), the most common lethal genetic disorder in children, is an X-linked recessive muscle disease characterized by the absence of dystrophin at the sarcolemma of muscle fibers. We examined a putative endometrial progenitor obtained from endometrial tissue samples to determine whether these cells repair muscular degeneration in a murine mdx model of DMD. Implanted cells conferred human dystrophin in degenerated muscle of immunodeficient mdx mice. We then examined menstrual blood–derived cells to determine whether primarily cultured nontransformed cells also repair dystrophied muscle. In vivo transfer of menstrual blood–derived cells into dystrophic muscles of immunodeficient mdx mice restored sarcolemmal expression of dystrophin. Labeling of implanted cells with enhanced green fluorescent protein and differential staining of human and murine nuclei suggest that human dystrophin expression is due to cell fusion between host myocytes and implanted cells. In vitro analysis revealed that endometrial progenitor cells and menstrual blood–derived cells can efficiently transdifferentiate into myoblasts/myocytes, fuse to C2C12 murine myoblasts by in vitro coculturing, and start to express dystrophin after fusion. These results demonstrate that the endometrial progenitor cells and menstrual blood–derived cells can transfer dystrophin into dystrophied myocytes through cell fusion and transdifferentiation in vitro and in vivo.
Impaired Fertility and Spermiogenetic Disorders with Loss of Cell Adhesion in Male Mice Expressing an Interfering Rap1 Mutant
Authors: Aivatiadou Evanthia , Mattei Elisabetta , Ceriani Michela , Tilia Leila , Berruti Giovanna
Published: February 2007

The guanosine trisphosphatase Rap1 serves as a critical player in signal transduction, somatic cell proliferation and differentiation, and cell–cell adhesion by acting through distinct mechanisms. During mouse spermiogenesis, Rap1 is activated and forms a signaling complex with its effector, the serine-threonine kinase B-Raf. To investigate the functional role of Rap1 in male germ cell differentiation, we generated transgenic mice expressing an inactive Rap1 mutant selectively in differentiating spermatids. This expression resulted in a derailment of spermiogenesis due to an anomalous release of immature round spermatids from the seminiferous epithelium within the tubule lumen and in low sperm counts. These spermiogenetic disorders correlated with impaired fertility, with the transgenic males being severely subfertile. Because mutant testis exhibited perturbations in ectoplasmic specializations (ESs), a Sertoli–germ cell-specific adherens junction, we searched for expression of vascular endothelial cadherin (VE-cadherin), an adhesion molecule regulated by Rap1, in spermatogenic cells of wild-type and mutant mice. We found that germ cells express VE-cadherin with a timing strictly related to apical ES formation and function; immature, VE-cadherin–positive spermatids were, however, prematurely released in the transgenic testis. In conclusion, interfering with Rap1 function during spermiogenesis leads to reduced fertility by impairment of germ–Sertoli cell contacts; our transgenic mouse provides an in vivo model to study the regulation of ES dynamics.
Chromosome Malorientations after Meiosis II Arrest Cause Nondisjunction
Authors: Janicke Marie A. , Lasko Loren , Oldenbourg Rudolf , LaFountain James R.
Published: February 2007

This study investigated the basis of meiosis II nondisjunction. Cold arrest induced a fraction of meiosis II crane fly spermatocytes to form (n + 1) and (n − 1) daughters during recovery. Live-cell liquid crystal polarized light microscope imaging showed nondisjunction was caused by chromosome malorientation. Whereas amphitely (sister kinetochore fibers to opposite poles) is normal, cold recovery induced anaphase syntely (sister fibers to the same pole) and merotely (fibers to both poles from 1 kinetochore). Maloriented chromosomes had stable metaphase positions near the equator or between the equator and a pole. Syntelics were at the spindle periphery at metaphase; their sisters disconnected at anaphase and moved all the way to a centrosome, as their strongly birefringent kinetochore fibers shortened. The kinetochore fibers of merotelics shortened little if any during anaphase, making anaphase lag common. If one fiber of a merotelic was more birefringent than the other, the less birefringent fiber lengthened with anaphase spindle elongation, often permitting inclusion of merotelics in a daughter nucleus. Meroamphitely (near amphitely but with some merotely) caused sisters to move in opposite directions. In contrast, syntely and merosyntely (near syntely but with some merotely) resulted in nondisjunction. Anaphase malorientations were more frequent after longer arrests, with particularly long arrests required to induce syntely and merosyntely.
Activation of Microglia Acidifies Lysosomes and Leads to Degradation of Alzheimer Amyloid Fibrils
Authors: Majumdar Amitabha , Cruz Dana , Asamoah Nikiya , Buxbaum Adina , Sohar Istvan , Lobel Peter , Maxfield Frederick R.
Published: February 2007

Microglia are the main immune cells of the brain, and under some circumstances they can play an important role in removal of fibrillar Alzheimer amyloid β peptide (fAβ). Primary mouse microglia can internalize fAβ, but they do not degrade it efficiently. We compared the level of lysosomal proteases in microglia and J774 macrophages, which can degrade fAβ efficiently, and we found that microglia actually contain higher levels of many lysosomal proteases than macrophages. However, the microglial lysosomes are less acidic (average pH of ∼6), reducing the activity of lysosomal enzymes in the cells. Proinflammatory treatments with macrophage colony-stimulating factor (MCSF) or interleukin-6 acidify the lysosomes of microglia and enable them to degrade fAβ. After treatment with MCSF, the pH of microglial lysosomes is similar to J774 macrophages (pH of ∼5), and the MCSF-induced acidification can be partially reversed upon treatment with an inhibitor of protein kinase A or with an anion transport inhibitor. Microglia also degrade fAβ if lysosomes are acidified by an ammonia pulse-wash or by treatment with forskolin, which activates protein kinase A. Our results indicate that regulated lysosomal acidification can potentiate fAβ degradation by microglia.
A Phenomics Approach in Yeast Links Proton and Calcium Pump Function in the Golgi
Authors: Yadav Jyoti , Muend Sabina , Zhang Yongqiang , Rao Rajini
Published: February 2007

The Golgi-localized Ca2+- and Mn2+-transporting ATPase Pmr1 is important for secretory pathway functions. Yeast mutants lacking Pmr1 show growth sensitivity to multiple drugs (amiodarone, wortmannin, sulfometuron methyl, and tunicamycin) and ions (Mn2+and Ca2+). To find components that function within the same or parallel cellular pathways as Pmr1, we identified genes that shared multiple pmr1 phenotypes. These genes were enriched in functional categories of cellular transport and interaction with cellular environment, and predominantly localize to the endomembrane system. The vacuolar-type H+-transporting ATPase (V-ATPase), rather than other Ca2+transporters, was found to most closely phenocopy pmr1Δ, including a shared sensitivity to Zn2+and calcofluor white. However, we show that pmr1Δ mutants maintain normal vacuolar and prevacuolar pH and that the two transporters do not directly influence each other's activity. Together with a synthetic fitness defect of pmr1ΔvmaΔ double mutants, this suggests that Pmr1 and V-ATPase work in parallel toward a common function. Overlaying data sets of growth sensitivities with functional screens (carboxypeptidase secretion and Alcian Blue binding) revealed a common set of genes relating to Golgi function. We conclude that overlapping phenotypes with Pmr1 reveal Golgi-localized functions of the V-ATPase and emphasize the importance of calcium and proton transport in secretory/prevacuolar traffic.
Gene symbol disambiguation using knowledge-based profiles
Authors: Xu Hua , Fan Jung-Wei , Hripcsak George , Mendonça Eneida A. , Markatou Marianthi , Friedman Carol
Published: February 2007

Motivation: The ambiguity of biomedical entities, particularly of gene symbols, is a big challenge for text-mining systems in the biomedical domain. Existing knowledge sources, such as Entrez Gene and the MEDLINE database, contain information concerning the characteristics of a particular gene that could be used to disambiguate gene symbols.

Results: For each gene, we create a profile with different types of information automatically extracted from related MEDLINE abstracts and readily available annotated knowledge sources. We apply the gene profiles to the disambiguation task via an information retrieval method, which ranks the similarity scores between the context where the ambiguous gene is mentioned, and candidate gene profiles. The gene profile with the highest similarity score is then chosen as the correct sense. We evaluated the method on three automatically generated testing sets of mouse, fly and yeast organisms, respectively. The method achieved the highest precision of 93.9% for the mouse, 77.8% for the fly and 89.5% for the yeast.

Availability: The testing data sets and disambiguation programs are available at http://www.dbmi.columbia.edu/~hux7002/gsd2006

Contact:  friedman@dbmi.columbia.edu
Clustering by common friends finds locally significant proteins mediating modules
Authors: Andreopoulos Bill , An Aijun , Wang Xiaogang , Faloutsos Michalis , Schroeder Michael
Published: February 2007

Motivation: Much research has been dedicated to large-scale protein interaction networks including the analysis of scale-free topologies, network modules and the relation of domain–domain to protein–protein interaction networks. Identifying locally significant proteins that mediate the function of modules is still an open problem.

Method: We use a layered clustering algorithm for interaction networks, which groups proteins by the similarity of their direct neighborhoods. We identify locally significant proteins, called mediators, which link different clusters. We apply the algorithm to a yeast network.

Results: Clusters and mediators are organized in hierarchies, where clusters are mediated by and act as mediators for other clusters. We compare the clusters and mediators to known yeast complexes and find agreement with precision of 71% and recall of 61%. We analyzed the functions, processes and locations of mediators and clusters. We found that 55% of mediators to a cluster are enriched with a set of diverse processes and locations, often related to translocation of biomolecules. Additionally, 82% of clusters are enriched with one or more functions. The important role of mediators is further corroborated by a comparatively higher degree of conservation across genomes. We illustrate the above findings with an example of membrane protein translocation from the cytoplasm to the inner nuclear membrane.

Availability: All software is freely available under Supplementary information.

Contact:  williama@biotec.tu-dresden.de

Supplementary information:  http://www.cse.yorku.ca/billa/MODULARPIN/
Psychosocial Issues in Patients With Congestive Heart Failure
Authors: Richardson Luann G.
Published: February 2007

Psychosocial issues are important variables that need to be addressed in patients with congestive heart failure (CHF). Unfortunately, these issues are often overlooked. Depression and lack of social support have been shown to have a negative impact on patients with CHF. Patients with CHF who are depressed or who lack social support have been shown to have increased morbidity and hospital readmission rates, to be less adherent to their medical regimen, and to have an overall increase in cost of care. The variables are often interrelated, as high levels of social support may lessen the impact of depression on mortality. In addition, certain biologic factors may influence the impact of psychosocial factors in patients with CHF. This review addresses the effects of depression, treatment adherence, and social support in patients with CHF and suggests interventions targeted to these problems. Health care professionals must assess these issues in all patients with CHF, address their specific needs, and intervene appropriately when warranted.
Understanding the Essentials of Blood Lipid Metabolism
Authors: Kingsbury Kori J. , Bondy Greg
Published: February 2007

The authors present an introduction to the basics of lipid metabolism including an overview of the structure and function of lipoproteins and a description of the pathways of lipid metabolism. Dyslipidemia is an important risk factor in the context of cardiovascular disease, and appropriate intervention can have a significant impact on clinical outcomes. The information presented herein will help to provide a foundation of knowledge on which to base the assessment and treatment of dyslipidemic patients. A better understanding of lipid metabolism will help health care professionals to provide better care in the realm of dyslipidemia management.