bluuebunny/crossref_metadata_2025 huggingface dataset:
Interactive effects of grazing and shrubs on the annual plant community in semi‐arid Mediterranean shrublands
Authors: Osem Yagil , Perevolotsky Avi , Kigel Jaime
Published: February 2009

Question: We studied the interactive effects of grazing and dwarf shrub cover on the structure of a highly diverse annual plant community.

Location: Mediterranean, semi‐arid shrubland in the Northern Negev desert, Israel.

Methods: Variation in the biomass and plant density of annual species in the shrub and open patches was monitored during four years, inside and outside exclosures protected from sheep grazing, in two contrasting topographic sites: north and south‐facing slopes that differed in their dominant dwarf shrubs species: Sarcopoterium spinosus and Corydothymus capitatus, respectively.

Results: Above‐ground biomass, density and richness of annual species were lower under the canopy of both shrub species compared to the adjacent open patches in the absence of grazing. Grazing reduced the biomass of annuals in open patches of both topographic sites, but not in the shrub patches. On the north‐facing slope, grazing also reduced plant density and richness in the open patches, but increased plant density in the shrub patches. At the species level, various response patterns to the combined effects of grazing and patch type were exhibited by different annuals. Protection against the direct impacts of grazing by shrub cover as well as species‐specific interactions between shrubs and annuals were observed. A conceptual mechanistic model explaining these interactions is proposed.

Conclusion: In semi‐arid Mediterranean shrublands grazing and dwarf shrub cover interact in shaping the structure of the annual plant community through (1) direct impacts of grazing restricted to the open patches, (2) species‐specific facilitation/ interference occurring in the shrub patches and (3) subsequent further processes occurring among the interconnected shrub and open patches mediated through variation in seed flows between patches.
Fire disturbance and forest structure in old‐growth mixed conifer forests in the northern Sierra Nevada, California
Authors: Beaty R. Matthew , Taylor Alan H.
Published: February 2009

Question:This study evaluates how fire regimes influence stand structure and dynamics in old‐growth mixed conifer forests across a range of environmental settings.

Location:A 2000‐ha area of mixed conifer forest on the west shore of Lake Tahoe in the northern Sierra Nevada, California.

Methods:We quantified the age, size, and spatial structure of trees in 12 mixed conifer stands distributed across major topographic gradients. Fire history was reconstructed in each stand using fire scar dendrochronology. The influence of fire on stand structure was assessed by comparing the fire history with the age, size, and spatial structure of trees in a stand.

Results:There was significant variation in species composition among stands, but not in the size, age and spatial patterning of trees. Stands had multiple size and age classes with clusters of similar aged trees occurring at scales of 113 ‐ 254 m2. The frequency and severity of fires was also similar, and stands burned with low to moderate severity in the dormant season on average every 9–17 years. Most fires were not synchronized among stands except in very dry years. No fires have burned since ca. 1880.

Conclusions:Fire and forest structure interact to perpetuate similar stand characteristics across a range of environmental settings. Fire occurrence is controlled primarily by spatial variation in fuel mosaics (e.g. patterns of abundance, fuel moisture, forest structure), but regional drought synchronizes fire in some years. Fire exclusion over the last 120 years has caused compositional and structural shifts in these mixed conifer forests.
Quantifying patterns and controls of mire vegetation succession in a southern boreal bog in Finland using partial ordinations
Authors: Tuittila E.‐S. , Väliranta M. , Laine J. , Korhola A.
Published: February 2009

Question: How do we distinguish between concurrent allogenic and autogenic forcings behind changing patterns in plant community structures during mire development?

Location: Lakkasuo raised bog, southern Finland.

Methods: Two radiometrically dated peat profiles were studied using high resolution plant macrofossil analysis. A combination of partial direct and indirect gradient analyses (CCA and DCA) was applied to quantify the role of different drivers of vegetation changes.

Results: Autogenic hydroseral succession explained 16% of the compositional variation in the vegetation. Disturbance successions initiated by fire explained 15% of the variation in the hummock, but only 9% in the wetter lawn. The early post‐disturbance successional stages were characterized by Eriophorum vaginatum. After partialling out the effects of peat depth and time since fire, a moisture gradient explained 29% of variation in the hummock core and 26% in the lawn. The analyses also indicated alternation between species with a similar niche. This interaction gradient explained 26% and 31% of the compositional variation in the hummock and lawn, respectively. The similar order of species replacement from both cores supported the existence of general directional succession in mire vegetation, both during the mire development and after fire events. The autogenic succession was slow and gradual while the disturbance successions were episodic and fast.

Conclusion: Our results support the paradigm of the complex nature of mire vegetation dynamics where several interlinked agents have simultaneous effects. The approach of combining partial ordinations developed here appeared to be a useful tool to assess the role of different environmental factors in controlling the vegetation succession.
Spatial confusion or clarity? Reply to Ricotta & Avena
Authors: Podani János
Published: February 2009

Abstract. This communication is a response to a recent suggestion that ordinal data of the Braun‐Blanquet type (BB) can be directly or, after conversion to ranks, indirectly analysed by metric methods. I show that the proposals on structure in topological spaces made by Ricotta & Avena in a recent contribution to this Forum are confounding because (1) they use the term ‘topological’ in the inappropriate way, and (2) the measure they propose is in fact a metric, rather than merely topological. In addition, I illustrate with a few examples how a truly topological measure functions, so that the reader can appreciate the ideas behind their definitions. By reference to axiomatic measurement theory, I argue that whenever vegetation scientists know exactly at the outset what attributes they wish to express by relevé data, what questions they are asking and whenever they are aware of the basic properties of the BB scale, ordinal data analysis is still the most logical choice.
Functional analysis of mutations in UDP‐galactose‐4‐epimerase (GALE) associated with galactosemia in Korean patients using mammalian GALE‐null cells
Authors: Bang You‐Lim , Nguyen Trang T. T. , Trinh Tram T. B. , Kim Yun J. , Song Junghan , Song Young‐Han
Published: February 2009

Galactosemia is caused by defects in the galactose metabolic pathway, which consists of three enzymes, including UDP‐galactose‐4‐epimerase (GALE). We previously reported nine mutations in Korean patients with epimerase‐deficiency galactosemia. In order to determine the functional consequences of these mutations, we expressed wild‐type and mutant GALE proteins in 293T cells. GALEE165K and GALEW336X proteins were unstable, had reduced half‐life, formed aggregates and were partly degraded by the proteasome complex. When expressed in GALE‐null ldlD cells GALEE165K, GALER239W, GALEG302D and GALEW336X had no detectable enzyme activity, although substantial amounts of protein were detected in western blots. The relative activities of other mutants were lower than that of wild‐type. In addition, unlike wild‐type, GALER239W and GALEG302D were not able to rescue galactose‐sensitive cell proliferation when stably expressed in ldlD cells. The four inactive mutant proteins did not show defects in dimerization or affect the activity of other mutant alleles identified in patients. Our observations show that altered protein stability is due to misfolding and that loss or reduction of enzyme activity is responsible for the molecular defects underlying GALE‐deficiency galactosemia.
17β‐Hydroxysteroid Dehydrogenases in Human Breast Cancer
Authors: Nagasaki Shuji , Miki Yasuhiro , Akahira Jun‐ichi , Suzuki Takashi , Sasano Hironobu
Published: February 2009

Estrogen plays a pivotal role in development and progression of human breast carcinoma. Before menopause the main source of estrogen in women is circulating estrogen secreted from the ovary, but following menopause the source changes to the hormone that is converted from circulating adrenal androgens in peripheral tissues. Therefore, adrenal androgens have to be converted to estrogen to stimulate breast carcinoma cells. In these steps, several enzymes such as aromatase, steroid sulfatase, and 17β‐hydroxysteroid dehydrogenases (17β‐HSDs) are involved in the production of estrogens.

The reaction related to 17β‐HSDs activity is one of the last steps of estradiol biosynthesis, and 14 isozymes of 17β‐HSD have been identified at this juncture. The balance of the relative expression levels of 17β‐HSD isozymes in human breast carcinomas is thought to play a pivotal role in supply of estradiol to estrogen receptor positive carcinoma cells. Understanding the character of 17β‐HSD isozymes in human breast carcinoma thus provides important information on the mechanisms of biosynthesis of estradiol in breast carcinoma and for development of a therapeutic agent targeted for inhibition of local estradiol synthesis in breast carcinoma cells. In the present review we summarize the roles played by 17β‐HSDs in human breast carcinoma to obtain a better understanding of the properties of 17β‐HSDs in human breast carcinoma.
Genetic Determined Downregulation of Both Type 1 and Type 2 Cytokine Pathways Might Be Protective against Pancreatic Cancer
Authors: Scola Letizia , Giacalone Antonio , Marasà Lorenzo , Mirabile Monica , Vaccarino Loredana , Forte Giusi Irma , Giannitrapani Lydia , Caruso Calogero , Montalto Giuseppe , Lio Domenico
Published: February 2009

Many cytokine polymorphisms have been studied for associations with susceptibility to breast, gastric, liver, lung, prostate, and ovarian cancer without conclusive results. The cytokine network, indeed, is characterized by complex interactions, and the final biological effect of a single genetic variation depends on the balance among different molecular signals. As is well known, Th1/Th2 cytokine unbalanced production might predispose to different pathologies, cancer included. In general, a prolonged type 1 inflammatory response might allow that cells accumulating enough “genetic hits” are promoted to neoplastic transformation. On the other hand, IL‐13‐producing cells through the IL‐13/IL‐4 receptor‐alpha (R‐α) pathway might facilitate escape from tumor immunosurveillance. Here are reported data on the evaluation of the influence of some type 2 and type 1 cytokine genetic polymorphisms as risk factors for pancreatic cancer. There was no overall association between pancreatic cancer risk and single cytokine SNPs. On the other hand, in evaluating the influence of combined cytokine genotypes we found that the combined IL‐10‐1082GA heterozygous and IL‐4 Rα‐1902AA homozygous genotype is underrepresented in the pancreatic cancer subject group. As is well known, the IL‐10‐1082GA genotype is associated with an intermediate production of this regulatory cytokine, whereas the IL‐10‐1902AA genotype of the IL‐4Rα gene is associated with a reduced efficiency in signal transduction when the receptor is engaged by IL‐13 or IL‐4. These results strongly suggest that a genetic background associated to a mild downregulation of type 1 and type 2 inflammatory signals might be protective against pancreatic cancer.
Aromatase Inhibitors and Breast Cancer
Authors: Macedo Luciana Furtado , Sabnis Gauri , Brodie Angela
Published: February 2009

We have developed a breast cancer intratumoral aromatase model to simulate the postmenopausal breast cancer patient in order to compare the antitumor efficacy of aromatase inhibitors (AIs) and antiestrogens (AEs). The AI letrozole sustained growth inhibition longer than the AE tamoxifen. Nevertheless, eventually tumors began to grow despite continued treatment. Estrogen receptor‐α (ER‐α) levels decreased below control levels concomitant with increased phosphorylation of ER‐α and unaltered progesterone receptor (PgR) levels. Expression of Her‐2, p‐Shc, Grb‐2, p‐Raf, p‐Mekl/2, and p‐MAPK was increased in the letrozole‐resistant tumors. When cells isolated from letrozole‐resistant tumors (LTLTCa cells) were treated with inhibitors of the Her‐2 signaling pathway, such as trastuzumab (herceptin), ER‐α was restored. Furthermore, sensitivity of LTLTCa cells to AIs and AEs was regained. These findings suggest cross‐talk between ER and Her‐2 signaling. To prevent activation of the Her‐2 pathway and resistance to AIs, mice were treated with a combination of an AI anastrozole and the ER downregulator fulvestrant. This resulted in no increase in Her‐2 and p‐MAPK levels, and tumor growth was significantly inhibited. Thus, blocking both ER and Her‐2 signaling delayed development of resistance to AIs. This hypothesis was supported by the finding that growth of letrozole‐resistant tumors was reduced when xenografts were treated with trastuzumab combined with letrozole. In addition, resistance to letrozole could be reversed by discontinuing letrozole. Our findings indicate that after letrozole treatment is stopped, the antitumor effect of letrozole can be restored when the AI treatment is resumed.
CCR5 Proinflammatory Allele in Prostate Cancer Risk
Authors: Balistreri Carmela Rita , Carruba Giuseppe , Calabrò Maurizio , Campisi Ildegarda , Carlo Daniele Di , Lio Domenico , Colonna‐Romano Giuseppina , Candore Giuseppina , Caruso Calogero
Published: February 2009

Prostate cancer (PCa) is the most common malignant neoplasm in older men in Western countries. The number of affected older men is increasing. Therefore, strategies for prevention of prostate cancer are crucial. To this purpose it is essential to know the mechanisms involved in development and progression of this malignancy. Recently, an increasing body of genetic and epidemiological studies proposed new hypotheses for prostate carcinogenesis. It has been suggested that genetic factors as well as exposure to environmental factors such as infectious agents, dietary carcinogens, and hormonal imbalances participate in PCa development. Besides, chronic inflammation plays a key role in PCa. Taking into consideration this complex scenario, in the present study we evaluated whether CCR5Δ32 deletion of CCR5 gene might be associated with PCa susceptibility. For the control group we used centenarians, since they represent a disease‐free human model. These preliminary results suggest that the CCR5Δ32 anti‐inflammatory variant might be a resistance factor for the development of PCa.
Application of a New Classification to a Breast Tumor Series from a Population‐Based Cancer Registry
Authors: Zarcone Maurizio , Amodio Rosalba , Campisi Ildegarda , Cusimano Rosanna , Dolcemascolo Cecilia , Miceli Vitale , Traina Adele , Macaluso Maurizio
Published: February 2009

A new classification based on gene expression profiling or immunohistochemical (IHC) characteristics may replace current histopathological classifications and predict better clinical outcomes. We used IHC markers to classify incident cases ascertained by the Palermo Breast Cancer Registry (2002–2004) into four subtypes: luminal‐A (ER+ or PgR+ and HER2/neu−); luminal‐B (ER+ or PgR+, HER2/neu+); basal‐like (ER−, PgR−, HER2/neu−); and HER2+/ER− (HER2/neu+, ER−, PgR−). We evaluated HER2/neu, ER and PgR in 1300/1985 (65%) cases. The most common IHC‐subtype was luminal‐A (68%), whereas luminal‐B, basal‐like, and HER2+/ER− accounted for 14%, 13%, and 5%, respectively. IHC‐subtypes were not associated with tumor size, geographic location within the province, or menopause, but differed by NPI (P < 0.0001), grading (P < 0.0001), lymph‐node involvement (P= 0.04), metastases (P= 0.04), and TNM stage (P= 0.04). Endocrine therapy was administered to 81% of 519 postmenopausal, luminal‐A, and luminal‐B cases and to 32% of 114 postmenopausal, basal‐like, and HER2+/ER− cases.
16α‐Hydroxyestrone Inhibits Estrogen Sulfotransferase Activity in Human Liver Cancer Cells
Authors: Campisi Ildegarda , Granata Orazia M. , Cocciadiferro Letizia , Calabrò Maurizio , Polito Lucia M. , Carruba Giuseppe
Published: February 2009

In this study we investigated the impact of estrogen antagonists and of 16α‐OHE1 (an estrogen derivative that binds to and induces transactivation of estrogen receptors) on estrogen metabolism in malignant HepG2 human liver cells featured by high estrogen sulfotransferase (EST); our aim was to clarify the potential correlation of EST and ER. As expected, the HepG2 cells exhibited a very high EST activity, with the majority of estrogen metabolites (over 86%) being detected as sulfates by 24 h. The coincubation of E2 and the antiestrogen tamoxifen induced a weak inhibition of EST activity (from 85.4% to 81.5%), while the coincubation with the pure antagonist ICI‐182 and with 16α‐OHE1 produced a 50% and 90% decrease of EST, respectively. Interestingly, both selective estrogen receptor modulators (SERMs) TAM and ICI‐182, along with the same 16α‐OHE1, gave rise respectively to a 2.8%, 3.2%, and 4.6% ofde novo16α‐OHE1 formation. The inhibition of EST and the increase of 16α‐OHE1 formation were both time‐ and dose‐dependent. Our results suggest that EST activity is tightly associated with ER transactivation and can be regulated by selective estrogen receptor modulators (SERMs), including antiestrogens and 16α‐OHE1. In this framework, 16α‐OHE1 may have a potential role in human liver carcinogenesis, also through the inhibition of EST and the production of unconjugated, bioavailable estrogens.
Curcumin as a Possible Lead Compound against Hormone‐Independent, Multidrug‐Resistant Breast Cancer
Authors: Labbozzetta Manuela , Notarbartolo Monica , Poma Paola , Maurici Annamaria , Inguglia Luigi , Marchetti Paolo , Rizzi Michele , Baruchello Riccardo , Simoni Daniele , D'Alessandro Natale
Published: February 2009

We examine the possible evidence that the phytochemical curcumin may overcome resistance to hormonal and cytotoxic agents in breast cancer. We present our observations on MCF‐7R, a multidrug‐resistant (MDR) variant of the MCF‐7 breast cancer cell line. In contrast to MCF‐7, MCF‐7R lacks aromatase and estrogen receptor α (ERα) and overexpresses the multidrug transporter ABCB1 and the products of different genes implicated in cell proliferation and survival, like c‐IAP‐1, NAIP, survivin, and COX‐2. Nevertheless, in cytotoxicity and cell death induction assays, we found that the antitumor activity of curcumin is substantial both in MCF‐7 and in MCF‐7R. We elaborated the diketone system of curcumin into different analogues; the benzyloxime and the isoxazole and pyrazole heterocycles showed remarkable increases in the antitumor potency both in the parental and in the MDR MCF‐7 cells. Furthermore, curcumin or, more potently, the isoxazole analogue, produced early reductions in the amounts of relevant gene transcripts that were diverse (i.e., they were relative to Bcl‐2 and Bcl‐XL in MCF‐7 and the inhibitory of apoptosis proteins and COX‐2 in MCF‐7R) in the two cell lines. Thus, the two compounds exhibited the remarkable property of being able to modify their molecular activities according to the distinct characteristics of the parental and MDR cells. We discuss also how curcumin may (1) exert antitumor effects in breast cancer through ER‐dependent and ER‐independent mechanisms; and (2) act as a drug transporter‐mediated MDR reversal agent. Overall, the structure of curcumin may represent the basis for the development of new, effective anticancer agents in hormone‐independent MDR breast cancer.
Perspectives in Understanding the Role of Human 17β‐Hydroxysteroid Dehydrogenases in Health and Disease
Authors: Meier Marc , Möller Gabriele , Adamski Jerzy
Published: February 2009

Steroid signaling involves specific receptors that mediate genomic effects and many further proteins responsible for fast nongenomic activities. Metabolism at the position 17 of the steroid scaffold plays a pivotal role in the final regulation of the biological potency of steroid hormones. Enzymes responsible for that, the 17β‐hydroxysteroid dehydrogenases (17β‐HSD), act as carbonyl reductases and require cofactors for their catalytic activity. There is a substantial amount of evidence that human 17β‐HSDs are as well involved in the metabolic pathways of retinoids and fatty acid beyond that which has so far been anticipated. At present fourteen 17β‐HSDs have been annotated and characterized, and more might follow. Many of 17β‐HSDs have been shown to be involved in the pathogenesis of human disorders and are targets for therapeutic intervention. Strategies on deciphering the physiological role of the 17β‐HSD and the genetic predisposition for associated diseases will be presented involving analyses of animal models.
Molecular Characterization of Aromatase
Authors: Hong Yanyan , Li Hongzhi , Yuan Yate‐Ching , Chen Shiuan
Published: February 2009

Aromatase is an estrogen synthetase. Estrogens are female sex hormones involved in the development and growth of breast tumors. Elucidation of the structure‐function relationship of aromatase has been of significant interest since its inhibitors have shown great promise in fighting breast cancer. Aromatase belongs to the cytochrome P450 family and forms an electron‐transfer complex with its partner, NADPH‐cytochrome P450 reductase. Because of the membrane‐bound character and heme‐binding instability, no crystal structure of aromatase has been reported so far. Much remains to be investigated, including the 3‐dimensional structure of aromatase, interaction between aromatase and reductase, catalytic mechanism of estrogen synthesis by aromatase, and the binding mechanism of aromatase inhibitors. This review presents current knowledge about structural and functional characteristics of aromatase to address unsolved mysteries about this enzyme.
Aromatase in Nontumoral and Malignant Human Liver Tissues and Cells
Authors: Carruba Giuseppe
Published: February 2009

We have investigated activity and expression of key steroids enzymes, including aromatase, in nontumoral, cirrhotic, and malignant human liver tissues and cells. Following 24 and 72 h incubation of malignant human liver cell lines HepG2, HuH7, and HA22T cells with testosterone (T) used as androgen precursor, we observed an increasingly high proportion of T oxidation to androstenedione, with aromatase being the prevalent enzyme activity in HepG2 and HuH7 cells at 72 h, while no aromatase could be detected in HA22T cells. On the other hand, balance of 5α‐ and 5β‐pathways was largely in favor of the 5α‐pathway in HA22T cells and in favor of the 5β‐pathways in HuH7 cells. In in vivo studies conducted in nontumoral, cirrhotic, and malignant human liver tissue samples, aromatase activity was, respectively, undetectable, moderate, and elevated. RT‐PCR analysis revealed high, intermediate, and very low levels of aromatase expression in HepG2, HuH7, and HA22T cells, respectively. Interestingly, both amphiregulin, a member of the EGF family of EGFR ligands, and an estrogen receptor (ER)‐α, the hERα46, exhibited a corresponding figure of expression, being very high in HepG2 cells and markedly lower in HA22T and HuH7 cells. We propose here that locally elevated estrogen formation, brought about by high aromatase expression and activity, may result in the promotion of liver tumor cell growth through the induction of AREG via an ER‐mediated mechanism.
Estrogen Sulfotransferases in Breast and Endometrial Cancers
Authors: Pasqualini Jorge Raul
Published: February 2009

Estrogen sulfotransferase is significantly more active in the normal breast cell (e.g., Human 7) than in the cancer cell (e.g., MCF‐7). The data suggest that in breast cancer sulfoconjugated activity is carried out by another enzyme, the SULT1A, which acts at high concentration of the substrates. In breast cancer cells sulfotransferase (SULT) activity can be stimulated by various progestins: medrogestone, promegestone, and nomegestrol acetate, as well as by tibolone and its metabolites. SULT activities can also be controlled by other substances including phytoestrogens, celecoxib, flavonoids (e.g., quercetin, resveratrol), and isoflavones. SULT expression was localized in breast cancer cells, which can be stimulated by promegestone and correlated with the increase of the enzyme activity. The estrogen sulfotransferase (SULT1E1), which acts at nanomolar concentration of estradiol, can inactivate most of this hormone present in the normal breast; however, in the breast cancer cells, the sulfotransferase denoted as SULT1A1 is mainly present, and this acts at micromolar concentrations of E2. A correlation was postulated among breast cancer cell proliferation, the effect of various progestins, and sulfotransferase stimulation. In conclusion, it is suggested that factors involved in the stimulation of the estrogen sulfotransferases could provide new possibilities for the treatment of patients with hormone‐dependent breast and endometrial cancers.
5α‐Reductase Isozymes and Androgen Actions in the Prostate
Authors: Zhu Yuan‐Shan , Imperato‐McGinley Julianne L.
Published: February 2009

Androgens acting via the androgen receptor play critical roles in prostate development, growth, and pathogenesis. There are two potent androgens, testosterone and dihydrotestosterone (DHT), in humans and mammals. DHT is converted from testosterone by 5α‐reductase isozymes. Two 5α‐reductase isozymes have been identified. Although both isozymes are expressed, 5α‐reductase‐2 is the predominant isozyme in the human prostate. Mutations in 5α‐reductase‐2 gene cause the 5α‐reductase‐2 deficiency syndrome. Affected 46, XY individuals have a small, nonpalpable, and rudimentary prostate in adulthood. Neither benign prostate hyperplasia (BPH) nor prostate cancer has been reported in these patients. The prostate is small in animals with 5α‐reductase‐2 gene knockout or treated with specific 5α‐reductase inhibitors. 5α‐reductase isozymes are molecular targets for the prevention and treatment of BPH and prostate cancer. Moreover, androgen actions on prostate gene expression and cell growth are directly modulated by estrogen receptor ligands via protein−protein interactions. The studies of 5α‐reductases and androgen actions highlight the importance of 5α‐reductase isozymes in male sexual differentiation and prostate physiology and pathophysiology.
The Dual, Opposing Roles of Estrogen in the Prostate
Authors: Ellem Stuart J. , Risbridger Gail P.
Published: February 2009

Both androgens and estrogens play a significant role in the prostate and are critical for normal prostate growth and development. The role of androgens in the prostate and in prostate disease is well known, however, the role for estrogens in the prostate and in prostate disease is complex and is still only just beginning to be appreciated. Our understanding of the role and action of estrogens in the prostate has advanced significantly recently due to important discoveries, including the discovery of a second estrogen receptor subtype (ER‐β), the detection of aromatase in the prostate, and the identification of rapid nongenomic estrogen signaling. We now know that estrogens are essential for normal tissue homeostasis within the prostate and that too little or too much leads to perturbation of the glands growth and the emergence of disease. We are also beginning to recognize the importance and differential roles of the estrogen receptors ER‐α and ER‐β. Specifically, the activation of ER‐α leads to aberrant proliferation, inflammation, and the development of premalignant lesions, while, in contrast, the activation of ER‐β is critical in prostatic stromal−epithelial cell signaling and mediating antiproliferative effects that balance the proliferative action of androgens on the epithelia. These data have established the importance and complexity of estrogen action. We now know that estrogens have the capacity to exert both beneficial and adverse effects in the prostate via ER‐β and ER‐α, respectively. Based on this, the selective targeting of estrogen action may form the basis of new therapies for prostate disease.
From North‐South to ‘Global’ South? An Investigation of a Changing ‘South’ Using Airline Flows between Cities, 1970–2005
Authors: Taylor Peter J. , Derudder Ben , García Cándida Gago , Witlox Frank
Published: February 2009

Using a city‐centred approach to development issues, this article critiques the recent concept of ‘Global South’. With its provenance from the ‘South’ half of the 1970s ‘North‐South divide’, the concept recognizes the transformations of the world economy since the 1970s, latterly known as globalization, by adding the adjective ‘global’ but leaves the geography undisturbed: the map of ‘South’ in ‘Global South’ is the same as in the North‐South divide. The limitation of this static geography in dynamic times is explored using relational geographies based upon airline flights and passengers between cities. Flight patterns for 1970, 1991 and 2005 are used to show the prime finding that contrasts a dense Pacific Asian network with airline patterns in the rest of the ‘South’. In addition, there appears to be bifurcation of the ‘South’ with Latin America having less inter‐regional South‐South links than other regions. Specific origin/destination data for 2001 provide a cross‐sectional depiction of the details of this South geography and confirm the very large flows into, through and out of Pacific Asia. These results are interpreted using Jacobs’ work on economic change and moral syndromes. We conclude that ‘Global South’ is a geographical chaotic conception, which has possible implications for its major sponsor, the United Nations Development Programme, wedded to an old political geography while ‘real, existing’ economic development proceeds regardless.
Spaces and Networks of Musical Creativity in the City
Authors: Watson Allan , Hoyler Michael , Mager Christoph
Published: February 2009

Urban geography, both material and imagined, is a crucial mediating factor in the production and consumption of music. The city provides the concrete places which offer spaces for musical creativity. While certain spaces such as recording studios are specifically organised for this purpose, music is produced in many spaces, from the bedroom, garage or home studio, to community and youth centres, to street corners and clubs. Cities also sustain networks that foster and support musical creativity. These networks come together in locales of creativity and production to find fixity in the concrete spaces of the city. At the same time the networks are fluid, with musical knowledge moving within and between cities through the mobility of skilled creatives and new technologies. A growing body of geographical literature is attempting to foreground the spatial in music studies by focusing on local scenes, musical production, and the particularity of certain places. This article aims to provide an overview of current geographical research and debates on music, with an explicit focus on the role of urban space in musical creativity, and on the musically creative networks at work within and between cities. We argue that there is a need to situate creativity more squarely in its material and embodied contexts of production and to consider the ways in which creative individuals interact in complex ways with urban physical form, technology, and other actors in networks of creativity and production.
International Council for Standardization in Haematology – the first 40 years
Authors: LEWIS S. M.
Published: February 2009

This brief history of the origin and development of ICSH must, inevitably, be selective as it has been extracted from the many pages of the records of the meetings of the ICSH board and its secretariat, the annual assembly and the reports of the various expert panels and working groups. It is hoped that it will give a picture of the way in which ICSH functioned and the many experts around the world who have contributed to its activities – but with an apology and appreciation, to other colleagues who have not been named in this annotation, but who made significant contributions to the activities that are described.
The enigma of cytosolic two‐component systems: a hypothesis
Authors: Krell Tino , Busch Andreas , Lacal Jesús , Silva‐Jiménez Hortencia , Ramos Juan‐Luis
Published: February 2009

One‐component systems (OCSs) and cytosolic two‐component regulatory systems (TCSs) appear to share the same biological function, which consists in the transcriptional control in response to the cellular concentration of signal molecules. However, cytosolic TCSs as compared with OCSs represent a genetic and metabolic burden to the cell: the genetic information encoding a TCS is significantly larger than that of an OCS, two or more proteins instead of one need to be synthesized for a TCS and operation of the latter system requires the expense of ATP which is not the case for most OCSs. The evolutionary advantages of cytosolic TCSs over OCSs are thus not obvious. We hypothesize here that the increased capacity of cytosolic TCSs to respond to multiple signals is a major advantage over OCSs. Different mechanisms for the incorporation of additional signals into the regulatory circuit are discussed. The inclusion of several signals into the definition of the final regulatory response is proposed to result in a better adaptation of the host to given environmental conditions.
Synopsis ofLeymusHochst. (Triticeae: Poaceae)
Authors: YEN Chi , YANG Jun‐Liang , BAUM Bernard R.
Published: February 2009

Leymusis a genus in the Triticeae tribe, Poaceae. The taxa of this genus are allopolyploid species which possess theNsandXmgenomes. According to cytological, cytogenetic and molecular genetic analyses, some species ofHystrixandElymusought to be transferred to this genus. A world revision of the genusLeymusis needed. In this paper we summarize experimental results, provide a key to sections, species and varieties, and list all the taxa we recognize inLeymuswith their synonyms. This synopsis is a new taxonomic system to be used for the revision ofLeymus.
Musa chunii Häkkinen, a new species (Musaceae) from Yunnan, China and taxonomic identity of Musa rubra
Authors: HÄKKINEN Markku
Published: February 2009

The center of diversity of the genus Musa (Musaceae) is in Southeast Asia, a region not studied in detail and where new species and varieties continue to be reported. A new wild banana species, M. chunii Häkkinen from Yunnan, China is described and illustrated based on observed morphological characteristics in the field. This extremely rare new species was only found in Tongbiguan Nature Reserve, Dehong District, West Yunnan. A key to M. chunii and related taxa is provided. In addition, critical notes regarding M. rubra Kurz identity are given.
Regulatory T cells and liver pathology in a murine graft versus host response model
Authors: Miyazaki Teruo , Doy Mikio , Ikegami Tadashi , Honda Akira , Unno Rie , Itoh Shinichi , Bouscarel Bernard , Matsuzaki Yasushi
Published: February 2009

Aim:  We have previously reported in mice the hepatic inflammatory in graft versus host response (GVHR) model due to the disparity of major histocompatibility complex class‐II. The regulatory T (Treg) cells have been reported to control excessive immune response and prevent immune‐related diseases. This study aimed to investigate the pathogenesis profiles of chronic GVHR progression, focusing on the Treg cells.

Methods:  GVHR mice induced by parental spleen CD4+ T cell injection were sacrificed after 0, 2, 4, and 8 weeks (G0, G2, G4, G8). Further, one GVHR group received anti‐IL‐10 antibody in advance and were maintained for 2 weeks. Pathologic profiles of hepatic infiltrating inflammatory cells were evaluated by haematoxylin and eosin and immunohistochemistry staining with surface markers including Treg cell markers.

Results:  Remarkable hepatic inflammatory in G2 significantly and gradually improved over time up to G8. In immunohistochemical staining, the increased IL‐10 receptor β+ Tr1 cells in G2 were maintained through to G8; although other inflammatory cells decreased from G2 to G8. By contrast, in the anti‐IL‐10 antibody received‐GVHR mice, the Tr1 cells were not detectable with significant inflammatory aggravation, while FoxP3+ Treg cells significantly enhanced.

Conclusions:  These findings in the GVHR mice suggest that the expression and activity of Treg cells, especially the Tr1 cells, might be key factors for pathologic alteration in immune‐related liver disease.
Adult progressive intrahepatic cholestasis associated with genetic variations in ATP8B1 and ABCB11
Authors: Hsu Yao‐Chun , Chen Huey‐Ling , Wu Mu‐Zon , Liu Yu‐Jung , Lee Po‐Huang , Sheu Jin‐Chuan , Chen Chien‐Hung
Published: February 2009

Severe intrahepatic cholestasis with low serum γ‐glutamyltranspeptidase (γ‐GT) activity is exceptionally rare in adult patients, and its association with multi‐genetic alterations of bile salt transporters has not been reported. We investigated a 25‐year‐old man presenting with a four‐year history of jaundice. Laboratory and radiographic examinations revealed clinical pictures of progressive intrahepatic cholestasis with low γ‐GT. Serial liver histopathology demonstrated cirrhosis resulting from progressive persistent cholestatic injury. Genetic sequencing studies for the entire coding exons of ATP8B1 and ABCB11 uncovered a heterozygous missense mutation 1798 C‐>T (R600W) in ATP8B1, and a homozygous nucleotide substitution 1331 T‐>C (V444A) in ABCB11. In conclusion, this is a rare case of adult onset progressive intrahepatic cholestasis with low γ‐GT associated with heterozygous ATP8B1 mutation and homozygous ABCB11 polymorphism. Further studies are necessary to investigate the impact of heterozygous R600W mutation and whether other cholestatic disorders are multi‐genetic.
The deacetylase enzyme SIRT1 is not associated with oxidative capacity in rat heart and skeletal muscle and its overexpression reduces mitochondrial biogenesis
Authors: Gurd Brendon J. , Yoshida Yuko , Lally James , Holloway Graham P. , Bonen Arend
Published: February 2009

Deacetylation of PGC‐1α by SIRT1 is thought to be an important step in increasing PGC‐1α transcriptional activity, since in muscle cell lines SIRT1 induces PGC‐1α protein expression and mitochondrial biogenesis. We examined the relationship between SIRT1 protein and activity, PGC‐1α and markers of mitochondrial density, (a) across a range of metabolically heterogeneous skeletal muscles and the heart, and when mitochondrial biogenesis was stimulated by (b) chronic muscle stimulation (7 days) and (c) AICAR administration (5 days), and finally, (d) we also examined the effects of SIRT1 overexpression on mitochondrial biogenesis and PGC‐1α. SIRT1 protein and activity were correlated (r= 0.97). There were negative correlations between SIRT1 protein and PGC‐1α (r=−0.95), COX IV (r=−0.94) and citrate synthase (r=−0.97). Chronic muscle stimulation and AICAR upregulated PGC‐1α protein (22–159%) and oxidative capacity (COX IV, 20–69%); in each instance SIRT1 protein was downregulated by 20–40%, while SIRT1 intrinsic activity was increased. SIRT1 overexpression in rodent muscle increased SIRT1 protein (+240%) and doubled SIRT1 activity, but PGC‐1α (−25%), mtTFA (−14%) and COX IV (−10%) proteins were downregulated. Taken altogether these experiments are not consistent with the notion that SIRT1 protein plays an obligatory regulatory role in the process of PGC‐1α‐mediated mitochondrial biogenesis in mammalian muscle.
A Transposon-Based Genetic Screen in Mice Identifies Genes Altered in Colorectal Cancer
Authors: Starr Timothy K. , Allaei Raha , Silverstein Kevin A. T. , Staggs Rodney A. , Sarver Aaron L. , Bergemann Tracy L. , Gupta Mihir , O'Sullivan M. Gerard , Matise Ilze , Dupuy Adam J. , Collier Lara S. , Powers Scott , Oberg Ann L. , Asmann Yan W. , Thibodeau Stephen N. , Tessarollo Lino , Copeland Neal G. , Jenkins Nancy A. , Cormier Robert T. , Largaespada David A.
Published: February 2009

Human colorectal cancers (CRCs) display a large number of genetic and epigenetic alterations, some of which are causally involved in tumorigenesis (drivers) and others that have little functional impact (passengers). To help distinguish between these two classes of alterations, we used a transposon-based genetic screen in mice to identify candidate genes for CRC. Mice harboring mutagenic Sleeping Beauty (SB) transposons were crossed with mice expressing SB transposase in gastrointestinal tract epithelium. Most of the offspring developed intestinal lesions, including intraepithelial neoplasia, adenomas, and adenocarcinomas. Analysis of over 16,000 transposon insertions identified 77 candidate CRC genes, 60 of which are mutated and/or dysregulated in human CRC and thus are most likely to drive tumorigenesis. These genes include
APC, PTEN
, and
SMAD4
. The screen also identified 17 candidate genes that had not previously been implicated in CRC, including
POLI, PTPRK
, and
RSPO2
.
Antibacterial Activity of Ultrashort Cationic Lipo-β-Peptides
Authors: Serrano Griselda N. , Zhanel George G. , Schweizer Frank
Published: February 2009

Previously reported
d
,
l
-lipo-α-peptides and their lipo-β-peptide counterparts (C16-KGGK, C16-KAAK, C16-KKKK, and C12-KLLK) were studied, and the lipo-β-peptides were found to retain antimicrobial activity. Likewise, no significant changes in antimicrobial activity were found upon activity comparisons with
d
,
l
-amino acid-based lipopeptides or any
l
-amino acid lipopeptides. As a defined amphipathic structure is unlikely to form with such short molecules and as similar activities were obtained from all lipopeptides, we suspect that the action of membrane permeation is retained.
Combination Therapy of Advanced Invasive Pulmonary Aspergillosis in Transiently Neutropenic Rats Using Human Pharmacokinetic Equivalent Doses of Voriconazole and Anidulafungin
Authors: van de Sande Wendy W. J. , Mathot Ron A. A. , ten Kate Marian T. , van Vianen Wim , Tavakol Mehri , Rijnders Bart J. A. , Bakker-Woudenberg Irma A. J. M.
Published: February 2009

At present, voriconazole (VOR) is the drug of first choice for treating invasive pulmonary aspergillosis (IPA). However, particularly in advanced stages of disease and in the severely immunocompromised host, the mortality remains substantial. The combination of VOR with an echinocandin may improve the therapeutic outcome. We investigate here whether combining VOR and anidulafungin (ANI) in advanced IPA in transiently neutropenic rats results in a higher therapeutic efficacy. Since VOR is metabolized more rapidly in rodents than in humans, dosage adjustment for VOR is necessary to obtain an area under the plasma concentration-time curve (AUC) in rodents that is equivalent to that of humans. In this study, the pharmacokinetics of VOR and ANI in rats were elucidated, and dosage schedules were applied that produced AUCs similar to those of humans. The developed dose schedules were well tolerated by the rats, without effects on renal and hepatic functions. VOR showed excellent efficacy in early IPA (100% rat survival). In advanced IPA, VOR was less efficacious (50% rat survival), whereas a significant decrease in galactomannan concentrations in lungs and sera was found in surviving rats. ANI administered in advanced IPA resulted in 22% rat survival, and the serum concentrations of fungal galactomannan were slightly but not significantly decreased. The addition of ANI to VOR did not result in significantly increased therapeutic efficacy in advanced IPA, resulting in 67% rat survival and a significant decrease in galactomannan concentration in serum. In conclusion, VOR monotherapy is therapeutically effective in the treatment of advanced-stage IPA and superior to the use of ANI. Combining both agents does not significantly improve the therapeutic outcome.
Polymeric Linear Peptide Chimeric Vaccine-Induced Antimalaria Immunity Is Associated with Enhanced In Vitro Antigen Loading
Authors: Silva-Flannery Luciana M. , Cabrera-Mora Monica , Dickherber Megan , Moreno Alberto
Published: February 2009

Immunization of mice withPlasmodium bergheiorPlasmodium yoeliisynthetic linear peptide chimeras (LPCs) based on the circumsporozoite protein protects against experimental challenge with viable sporozoites. The immunogenicity of LPCs is significantly enhanced by spontaneous polymerization. To better understand the antigenic properties of polymeric antimalarial peptides, we studied the immune responses elicited in mice immunized with a polymer or a monomer of a linear peptide construct specific forP. yoeliiand compared the responses of antigen-presenting cells following incubation with both peptide species. Efficient uptake of the polymeric peptide in vitro resulted in higher expression of the coactivation markers CD80, CD40, and CD70 on dendritic cells and higher proinflammatory cytokine production than with the monomeric peptide. Macropinocytosis seems to be the main route used by polymeric peptides internalized by antigen-presenting cells. Spontaneous polymerization of synthetic antimalarial-peptide constructs to target professional antigen-presenting cells shows promise for simple delivery of subunit malaria vaccines.
Variant-Specific Immunity to
Plasmodium berghei
in Pregnant Mice
Authors: Megnekou Rosette , Hviid Lars , Staalsoe Trine
Published: February 2009

We have investigated the immunological basis of pregnancy-related
Plasmodium berghei
recrudescence in immune mice with substantial preexisting immunity. Specifically, we examined the relevance of this experimental model to the study of pregnancy-associated malaria (PAM) caused by
P. falciparum
in women with substantial preexisting protective immunity. We used mice with immunity induced prior to pregnancy and employed flow cytometry to assess their levels of immunoglobulin G (IgG) recognizing antigens on the surfaces of infected erythrocytes (IEs) in plasma. After immunization, the mice did not possess IgG specific for antigens on IEs obtained during pregnancy-related recrudescence but they acquired recrudescence-specific IgG over the course of several pregnancies and recrudescences. In contrast, levels of antibodies recognizing IEs from nonpregnant mice did not increase with increasing parity. Furthermore, maternal hemoglobin levels increased and pregnancy-related parasitemia decreased with increasing parity. Finally, parasitemic mice produced smaller litters and pups with lower weights than nonparasitemic mice. Taken together, these observations suggest that levels of antibodies specific for recrudescence-type IEs are related to the protection of pregnant mice from maternal anemia, low birth weight, and decreased litter size. We conclude that the model replicates many of the key parasitological and immunological features of PAM, although the
P. berghei
genome does not encode proteins homologous to the
P. falciparum
erythrocyte membrane protein 1 adhesins, which are of key importance in
P. falciparum
malaria. The study of
P. berghei
malaria in pregnant, immune mice can be used to gain significant new insights regarding malaria pathogenesis and immunity in general and regarding PAM in particular.