bluuebunny/crossref_metadata_2025 huggingface dataset:
Geographical variation in cancer incidence: A clue to causation
Authors: Doll Richard
Published: April 2005

Conclusion

The observations on which our knowledge of the geographical variation in the incidence of cancer is based began to be made by surgeons in the last century who, working first in one country and then in another, realized that the pattern of disease with which they had to deal varied with the society in which they worked. Gross differences were readily accepted, like that reported less than 2 years after Grey Turner's birth between the vale of Kashmir, where Maxwell and Elmslie found that 42 out of 54 epitheliomas (78%) occurred on the skin of the abdomen or thigh, and European countries, where none were reported on these sites in a series of 220 cases [28]; however, smaller differences were not accepted.

The uneven availability of medical services and the disparity in birth and death rates, which produced major differences in the age distribution of different populations, made accurate comparisons impossible and the range of permissible opinion varied from the belief that cancer occurred equally everywhere at the same ages to the belief that the great majority of cases were produced by industrialization. Now, thanks to the development of cancer registries, it has been possible to put the matter beyond doubt and to demonstrate unequivocal differences, some of which are certainly attributable to industrialization, which has sometimes led to the development of the disease and sometimes to its elimination. We know, too, that careful observations, like those made by Denis Burkitt and the hundreds of surgeons and physicians who have collaborated with him throughout Africa, are capable of providing an indication of the relative frequency of different cancers that can provide valuable clues, even in the absence of precise figures for the size of the population served.

If this Congress is able to stimulate the collection of similar figures that will fill in the remaining gaps of the cancer map of the world, it may well make an important contribution to our knowledge of the causes of the disease and the way it can be prevented.
Hemodynamics of arterial stenosis
Authors: Lee Bok Y. , Assadi Cyrus , Madden John L. , Kavner David , Trainor Frieda S. , McCann William J.
Published: April 2005

In order to derive a better understanding of the effect of varying degrees of stenosis on arterial pulsatile waveforms, an in vitro model was constructed and in vivo studies were done in dogs to observe and record the changes in the pulsatile and steady arterial blood flow components. Blood flow measurements were made using the electromagnetic blood flowmeter proximal and distal to the stenosis. The data show that as the degree of stenosis increases, the decreases in the pulsatile components of flow and distal pressure occur earlier and to a much greater degree than changes in mean flow.
Surgical management of papillary muscle rupture due to myocardial infarction
Authors: Gerbode Frank L.A. , Hetzer Roland , Krebber Hans J.
Published: April 2005

Complete or partial rupture of a papillary muscle following myocardial infarction is a severe complication that, without surgical intervention, results in a mortality rate of 95%. Of 41 patients with papillary muscle rupture who were treated surgically, the overall operative mortality rate was 48%, with an 87% mortality rate in 13 patients who entered the hospital in critical condition within 1 month after myocardial infarction. There was an operative mortality rate of 50% in the second month and 33% in the third month following myocardial infarction. Of the patients who underwent operation more than 4 months after infarction, 73% survived. Of 51 patients operated upon for ruptured chordae tendineae of the posterior leaflet of the mitral valve, there were only 2 early and 3 cardiac‐related late deaths. Of these 51 patients, 43 are currently virtually asymptomatic.

Methods to improve the results of surgical therapy in the critically ill patient include drug support for afterload reduction and increased contractility and/or mechanically induced afterload reduction, and diastolic augmentation by intra‐aortic balloon counterpulsation. Because the uninterrupted course of papillary muscle rupture is lethal in almost all cases, attempts should be made to improve the patient's condition in order to allow surgical intervention under optimal conditions. The surgical treatment for ruptured papillary muscle is usually mitral valve replacement. For ruptured chordae of the posterior leaflet, the preferred treatment is plastic repair.
Ecologically based family therapy outcome with substance abusing runaway adolescents
Authors: Slesnick Natasha , Prestopnik Jillian L.
Published: April 2005

Runaway youth report a broader range and higher severity of substance‐related, mental health and family problems relative to non‐runaway youth. Most studies to date have collected self‐report data on the family and social history; virtually no research has examined treatment effectiveness with this population. This study is a treatment development project in which 124 runaway youth were randomly assigned to (1) ecologically based family therapy (EBFT) or (2) service as usual (SAU) through a shelter. Youth completed an intake, posttreatment, 6 and 12 months follow‐up assessment. Youth assigned to EBFT reported greater reductions in overall substance abuse compared to youth assigned to SAU while other problem areas improved in both conditions. Findings suggest that EBFT is an efficacious intervention for this relatively severe population of youth.
Sur une question de H. Brezis, M. Marcus et A.C. Ponce
Authors: Ancona Alano
Published: April 2005

Investigating a question raised in a recent paper of Brezis–Marcus–Ponce [5] we show that if

μ

is a singular continuous Radon measure in the open subset

U

of

\mathbb{R}^{d}

, there is no continuous linear map

f\mapsto (u_{f},g_{f})

from

L^{1}(\mu )

to

H^{1}(U) \times L^{1}(U)

such that

f \cdot \mu = \mathrm{\Delta }u_{f} + g_{f}

in the sense of distributions. A generalization is also described.

À la suite d'une question soulevée dans un travail de Brezis–Marcus–Ponce [5] on montre que si

μ

est une mesure de Radon diffuse et singulière sur l'ouvert

U

de

\mathbb{R}^{d}

, il n'existe pas d'application linéaire continue

f\mapsto (u_{f},g_{f})

de

L^{1}(\mu )

dans

H^{1}(U) \times L^{1}(U)

telle que

f \cdot \mu = \mathrm{\Delta }u_{f} + g_{f}

au sens de

\mathcal{D}^{′}(U)

. On indique ensuite une généralisation.
Depression, anxiety and pain in children with juvenile idiopathic arthritis (JIA)
Authors: Margetić Branimir , Aukst-Margetić Branka , Bilić Ernest , Jelušić Marija , Tambić Bukovac Lana
Published: April 2005

The aim of this study was to assess relations among depression, anxiety and pain in children with juvenile idiopathic arthritis (JIA). Pain was measured with the visual analogue scale (VAS), and depression and anxiety with depression and anxiety subscales from the Trauma Symptom Checklist for Children (TSC-C). Pain perception was significantly correlated with depression scores.
Patient outcomes in schizophrenia I: correlates with sociodemographic variables, psychopathology, and side effects
Authors: Hofer Alex , Baumgartner Susanne , Edlinger Monika , Hummer Martina , Kemmler Georg , Rettenbacher Maria A. , Schweigkofler Hansjoerg , Schwitzer Josef , Fleischhacker W. Wolfgang
Published: April 2005

Objective

The present cross-sectional study examined the relationships of psychopathology, side effects, and sociodemographic factors with treatment outcomes in terms of patients' quality of life (QOL), functioning, and needs for care.

Method

Sixty outpatients with chronic schizophrenia who had been treated with either clozapine or olanzapine for at least 6 months were investigated.

Results

Most psychopathological symptoms as well as psychic side effects, weight gain, and female sex were associated with lower QOL, while cognitive symptoms correlated with better QOL. Female sex, cognitive symptoms, and parkinsonism negatively influenced occupational functioning, and negative symptoms determined a lesser likelihood of living independently. Age, education, depression/anxiety, negative symptoms, and psychic side effects were predictors of patients' needs for care.

Conclusion

Our results highlight the complex nature of patient outcomes in schizophrenia. They reemphasize the need of targeting effectiveness, i.e. both symptomatic improvement as well as drug safety, in such patients.
Sterilization by gamma radiation impairs the tensile fatigue life of cortical bone by two orders of magnitude
Authors: Akkus Ozan , Belaney Ryan M.
Published: April 2005

Cortical bone grafts are utilized frequently for skeletal reconstruction, spinal fusion and tumor surgery. Due to its efficacy and convenience terminal sterilization by gamma radiation is often essential to minimize disease transmission and infection. However. the impairment in the material properties of bone tissue secondary to gamma radiation sterilization is a concern since the mechanical functionality of a bone graft is of primary importance. While the extent of this impairment is well investigated for monotonic loading conditions, there does not seem to exist any information on the effects of gamma radiation sterilization on cortical bone's fatigue properties, the physiologically relevant mode of loading. In this study we investigated the degradation in the high‐cycle and lowcycle tensile fatigue lives of cortical bone tissue secondary to gamma radiation sterilization at a dose of 36.4 kGy which approximately falls in the higher end of the standard dose range used in tissue banking. The high‐cycle and the low‐cycle fatigue tests were conducted under load control at initial strain levels of 0.2% and 0.4%, respectively. Monotonic tensile tests were also conducted to compare the impairment of fatigue properties with the impairment of monotonic properties. Results demonstrated that the impairment in both the high‐cycle and the low‐cycle fatigue lives were two orders of magnitude following sterilization, a change much more pronounced than that observed for monotonic loading. In conclusion, the results suggest that the impairment of the mechanical function of gamma radiation sterilized allografts is even worse in fatigue than monotonically. Therefore, grafts should be designed to minimize functional strains and avoid stress raisers to prevent premature fatigue failures. © 2005 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved.
Reflections
Authors: Beitz Charles R.
Published: April 2005

I am grateful to all five contributors to this Forum for the generosity of their comments about Political Theory and International Relations and their critical interest in the issues taken up in the book. It is a good thing that these issues have attracted the attention of so many talented scholars. This would certainly have occurred even if PTIR had never been written, but I am delighted that the book seems to have been a constructive provocation.
An agent-mediated approach to the support of knowledge sharing in organizations
Authors: DIGNUM VIRGINIA , DIGNUM FRANK , MEYER JOHN-JULES
Published: April 2005

The realization that knowledge management (KM) is primarily a management science and not a computer science implies a different role for technology in KM. This role is concerned with supporting and extending human interaction and learning, and has therefore the need for intelligence-enhanced, integrated and personalized solutions including agent-based approaches. A people-centered view of KM requires support systems that enable the flexible integration of organizational and individual requirements and objectives. This paper introduces the OperA model for organizations that supports individual initiative and collaboration while prescribing a formal structure for organizational processes. The paper introduces the main aspects of the model and describes a case study where OperA is applied to the development of a knowledge-sharing support system.
A Cautionary Note on Incremental Fit Indices Reported by LISREL
Authors: Schmukle Stefan C. , Hardt Jochen
Published: April 2005

Abstract. Incremental fit indices (IFIs) are regularly used when assessing the fit of structural equation models. IFIs are based on the comparison of the fit of a target model with that of a null model. For maximum-likelihood estimation, IFIs are usually computed by using the χ2 statistics of the maximum-likelihood fitting function (ML-χ2). However, LISREL recently changed the computation of IFIs. Since version 8.52, IFIs reported by LISREL are based on the χ2 statistics of the reweighted least squares fitting function (RLS-χ2). Although both functions lead to the same maximum-likelihood parameter estimates, the two χ2 statistics reach different values. Because these differences are especially large for null models, IFIs are affected in particular. Consequently, RLS-χ2 based IFIs in combination with conventional cut-off values explored for ML-χ2 based IFIs may lead to a wrong acceptance of models. We demonstrate this point by a confirmatory factor analysis in a sample of 2449 subjects.
Magma plumbing processes for persistent activity at Poás volcano, Costa Rica
Authors: Rymer Hazel , Locke Corinne A. , Brenes Jorge , Williams‐Jones Glyn
Published: April 2005

New microgravity data from the active crater of Poás volcano, Costa Rica, collected in 2002–2004 extends the existing dataset to provide a unique 20‐year time series. These data show that gravity has decreased monotonically in the north and east of the crater over the last 5 years, whilst it has increased to the west and remained approximately constant in the south. These changes are interpreted in terms of convective recharge within dendritic intrusions beneath the crater, with overall down‐welling in the north and up‐welling in the west. The data reveal a 5–10 year periodicity in sub‐crater mass movement, but overall, the upper part of the conduit system appears to have maintained a state of mass equilibrium.
Lattice Boltzmann method for gaseous microflows using kinetic theory boundary conditions
Authors: Tang G. H. , Tao W. Q. , He Y. L.
Published: April 2005

The lattice Boltzmann method is developed to study gaseous slip flow in microchannels. An approach relating the Knudsen number with the relaxation time in the lattice Boltzmann evolution equation is proposed by using gas kinetic equation resulting from the Bhatnagar–Gross–Krook collision model. The slip velocity at the solid boundaries is obtained with kinetic theory boundary conditions. The two-dimensional micro-Couette flow, micro-Poiseuille flow, and micro-lid-driven cavity flow are simulated using the present model. It is found that the numerical results agree well with available analytical and benchmark solutions.
Deletion of PPARγ in adipose tissues of mice protects against high fat diet-induced obesity and insulin resistance
Authors: Jones Julie R. , Barrick Cordelia , Kim Kyoung-Ah , Lindner Jill , Blondeau Bertrand , Fujimoto Yuka , Shiota Masakazu , Kesterson Robert A. , Kahn Barbara B. , Magnuson Mark A.
Published: April 2005

Peroxisome proliferator-activated receptor γ (PPARγ) plays a crucial role in adipocyte differentiation, glucose metabolism, and other physiological processes. To further explore the role of PPARγ in adipose tissues, we used a Cre/loxP strategy to generate adipose-specific PPARγ knockout mice. These animals exhibited marked abnormalities in the formation and function of both brown and white adipose tissues. When fed a high-fat diet, adipose-specific PPARγ knockout mice displayed diminished weight gain despite hyperphagia, had diminished serum concentrations of both leptin and adiponectin, and did not develop glucose intolerance or insulin resistance. Characterization of
in vivo
glucose dynamics pointed to improved hepatic glucose metabolism as the basis for preventing high-fat diet-induced insulin resistance. Our findings further illustrate the essential role for PPARγ in the development of adipose tissues and suggest that a compensatory induction of hepatic PPARγ may stimulate an increase in glucose disposal by the liver.
Identification of network-level coding units for real-time representation of episodic experiences in the hippocampus
Authors: Lin Longnian , Osan Remus , Shoham Shy , Jin Wenjun , Zuo Wenqi , Tsien Joe Z.
Published: April 2005

To examine the network-level organizing principles by which the brain achieves its real-time encoding of episodic information, we have developed a 96-channel array to simultaneously record the activity patterns of as many as 260 individual neurons in the mouse hippocampus during various startling episodes. We find that the mnemonic startling episodes triggered firing changes in a set of CA1 neurons in both startle-type and environment-dependent manners. Pattern classification methods reveal that these firing changes form distinct ensemble representations in a low-dimensional encoding subspace. Application of a sliding window technique further enabled us to reliably capture not only the temporal dynamics of real-time network encoding but also postevent processing of newly formed ensemble traces. Our analyses revealed that the network-encoding power is derived from a set of functional coding units, termed neural cliques, in the CA1 network. The individual neurons within neural cliques exhibit “collective cospiking” dynamics that allow the neural clique to overcome the response variability of its members and to achieve real-time encoding robustness. Conversion of activation patterns of these coding unit assemblies into a set of real-time digital codes permits concise and universal representation and categorization of discrete behavioral episodes across different individual brains.
Structural basis for antagonism and resistance of bicalutamide in prostate cancer
Authors: Bohl Casey E. , Gao Wenqing , Miller Duane D. , Bell Charles E. , Dalton James T.
Published: April 2005

Carcinoma of the prostate is the most commonly diagnosed cancer in men. The current pharmacological treatment of choice for progressive androgen-dependent prostate cancer is the nonsteroidal antiandrogen, bicalutamide, either as monotherapy or with adjuvant castration or luteinizing hormone-releasing hormone superagonists to block the synthesis of endogenous testosterone. To date, no nonsteroidal or antagonist-bound androgen receptor (AR) structure is available. We solved the x-ray crystal structure of the mutant W741L AR ligand-binding domain bound to
R
-bicalutamide at 1.8-Å resolution. This mutation confers agonist activity to bicalutamide and is likely involved in bicalutamide withdrawal syndrome. The three-dimensional structure demonstrates that the B ring of
R
-bicalutamide in the W741L mutant is accommodated at the location of the indole ring of Trp-741 in the WT AR bound to dihydrotestosterone. Knowledge of the binding mechanism for
R
-bicalutamide will provide molecular rationale for the development of new antiandrogens and selective AR modulators.
Adaptation without parameter change: Dynamic gain control in motion detection
Authors: Borst Alexander , Flanagin Virginia L. , Sompolinsky Haim
Published: April 2005

Many sensory systems adapt their input-output relationship to changes in the statistics of the ambient stimulus. Such adaptive behavior has been measured in a motion detection sensitive neuron of the fly visual system, H1. The rapid adaptation of the velocity response gain has been interpreted as evidence of optimal matching of the H1 response to the dynamic range of the stimulus, thereby maximizing its information transmission. Here, we show that correlation-type motion detectors, which are commonly thought to underlie fly motion vision, intrinsically possess adaptive properties. Increasing the amplitude of the velocity fluctuations leads to a decrease of the effective gain and the time constant of the velocity response without any change in the parameters of these detectors. The seemingly complex property of this adaptation turns out to be a straightforward consequence of the multidimensionality of the stimulus and the nonlinear nature of the system.
The gene expression signatures of melanoma progression
Authors: Haqq Christopher , Nosrati Mehdi , Sudilovsky Daniel , Crothers Julia , Khodabakhsh Daniel , Pulliam Brian L. , Federman Scot , Miller James R. , Allen Robert E. , Singer Mark I. , Leong Stanley P. L. , Ljung Britt-Marie , Sagebiel Richard W. , Kashani-Sabet Mohammed
Published: April 2005

Because of the paucity of available tissue, little information has previously been available regarding the gene expression profiles of primary melanomas. To understand the molecular basis of melanoma progression, we compared the gene expression profiles of a series of nevi, primary melanomas, and melanoma metastases. We found that metastatic melanomas exhibit two dichotomous patterns of gene expression, which unexpectedly reflect gene expression differences already apparent in comparing laser-capture microdissected radial and vertical phases of a large primary melanoma. Unsupervised hierarchical clustering accurately separated nevi and primary melanomas. Multiclass significance analysis of microarrays comparing normal skin, nevi, primary melanomas, and the two types of metastatic melanoma identified 2,602 transcripts that significantly correlated with sample class. These results suggest that melanoma pathogenesis can be understood as a series of distinct molecular events. The gene expression signatures identified here provide the basis for developing new diagnostics and targeting therapies for patients with malignant melanoma.
BCL6b mediates the enhanced magnitude of the secondary response of memory CD8
+
T lymphocytes
Authors: Manders Peter M. , Hunter Patricia J. , Telaranta Aino I. , Carr James M. , Marshall Jennifer L. , Carrasco Marlene , Murakami Yusuke , Palmowski Michael J. , Cerundolo Vincenzo , Kaech Susan M. , Ahmed Rafi , Fearon Douglas T.
Published: April 2005

A characteristic of the secondary response of CD8
+
T cells that distinguishes it from the primary response is the generation of greater numbers of effector cells. Because effector CD8
+
T cells are derived from a pool of less differentiated, replicating cells in secondary lymphoid organs, and because IL-2 mediates effector differentiation, the enhanced secondary response may reflect the enlargement of this generative pool by the transient repression of IL-2-mediated differentiation. We have examined for this function the transcriptional repressor BCL6b, a homologue of BCL6 that represses IL-2-induced B cell differentiation. BCL6b is expressed in a small subset of antigen-experienced CD8
+
T cells. Ectopic expression of BCL6b in CD8
+
T cells diminishes their growth in response to IL-2
in vitro
. Female mice in which the
BCL6b
gene has been interrupted have normal primary responses of CD8
+
T cells to infection with vaccinia expressing the H-Y epitope, Uty, but Uty-specific, BCL6b
–/–
, memory CD8
+
T cells have diminished recall proliferative responses to this epitope
in vitro
. BCL6b
–/–
mice also have normal primary CD8
+
T cell responses to influenza infection, but nucleoprotein peptide-specific, BCL6b
–/–
, memory CD8
+
T cells have a cell autonomous defect in the number of effector cells generated in response to reinfection. Therefore, BCL6b is required for the enhanced magnitude of the secondary response of memory CD8
+
T cells.
Corticotropin-releasing hormone activates ERK1/2 MAPK in specific brain areas
Authors: Refojo Damián , Echenique Carlos , Müller Marianne B. , Reul Johannes M. H. M. , Deussing Jan M. , Wurst Wolfgang , Sillaber Inge , Paez-Pereda Marcelo , Holsboer Florian , Arzt Eduardo
Published: April 2005

Corticotropin-releasing hormone (CRH) coordinates hormonal and behavioral responses to stress. The mitogen-activated protein kinase extracellular signal-related kinase 1/2 (ERK1/2) mediates several functions in different forebrain structures and recently has been implicated in CRH signaling in cultured cells. To study
in vivo
CRH-mediated activation of central ERK1/2, we investigated the expression pattern of the phosphorylated ERK1/2(
p
-ERK1/2) in the mouse brain after intracerebroventricular CRH injections. As shown by immunohistochemistry and confocal microscopy analysis, CRH administration increased
p
-ERK1/2 levels specifically in the CA3 and CA1 hippocampal subfields and basolateral complex of the amygdala, both structures related to external environmental information processing and behavioral aspects of stress. Other regions such as hypothalamic nuclei and the central nucleus of the amygdala, also related to central CRH system but involved in the processing of the ascending visceral information and neuroendocrine-autonomic response to stress, did not show CRH-mediated ERK1/2 activation. To dissect the involvement of CRH receptor 1 (CRHR1) and CRHR2, we used conditional knockout mice in which
Crhr1
is inactivated in the anterior forebrain and limbic structures. The conditional genetic ablation of
Crhr1
inhibited the
p
-ERK1/2 increase, underlining the involvement of CRHR1 in the CRH-mediated activation. These findings underscore the fact that CRH activates
p
-ERK1/2 through CRHR1 only in selected brain regions, pointing to a specific role of this pathway in mediating behavioral adaptation to stress.
Time-limited modulation of appetitive Pavlovian memory by D1 and NMDA receptors in the nucleus accumbens
Authors: Dalley Jeffrey W. , Lääne Kristjan , Theobald David E. H. , Armstrong Hannah C. , Corlett Philip R. , Chudasama Yogita , Robbins Trevor W.
Published: April 2005

Recent research has implicated the nucleus accumbens (NAc) in consolidating recently acquired goal-directed appetitive memories, including spatial learning and other instrumental processes. However, an important but unresolved issue is whether this forebrain structure also contributes to the consolidation of fundamental forms of appetitive learning acquired by Pavlovian associative processes. In addition, although dopaminergic and glutamatergic influences in the NAc have been implicated in instrumental learning, it is unclear whether similar mechanisms operate during Pavlovian conditioning. To evaluate these issues, the effects of posttraining intra-NAc infusions of D1, D2, and NMDA receptor antagonists, as well as
d
-amphetamine, were determined on Pavlovian autoshaping in rats, which assesses learning by discriminated approach behavior to a visual conditioned stimulus predictive of food reward. Intracerebral infusions were given either immediately after each conditioning session to disrupt early memory consolidation or after a delay of 24 h. Findings indicate that immediate, but not delayed, infusions of both D1 (SCH 23390) and NMDA (AP-5) receptor antagonists significantly impair learning on this task. By contrast, amphetamine and the D2 receptor antagonist sulpiride were without significant effect. These findings provide the most direct demonstration to date that D1 and NMDA receptors in the NAc contribute to, and are necessary for, the early consolidation of appetitive Pavlovian learning.
Revelation, Tradition, and Scripture
Authors: O'Collins SJ Gerald , Farrugia SJ Mario
Published: April 2005

This chapter offers a Catholic view of divine revelation, the response of human faith, the tradition that hands on belief in God, and the scriptures that are inspired by the Holy Spirit. The saving self-revelation of God comes through an interplay of deeds and words, is centred on Christ, and is a past, present, and future reality. Tradition should be understood both as a process (the act of tradition) and as a living heritage (tradition as content). Being an inspired, written record, the Bible is not to be simply identified with revelation. Biblical truth is progressive, personal, and salvific. The canon of scriptures, the closed list of inspired books, arose through their subsequent recognition by the Church.
Basic Characteristics of Catholicism
Authors: O'Collins SJ Gerald , Farrugia SJ Mario
Published: April 2005

Any list of the basic distinctive characteristics of Catholic Christianity should include the following features: it is centred on Jesus, along with his mother Mary; it takes up material objects into its sacramental and devotional life; it practises the principle of ‘both\and’ (e.g. both grace and freedom; both faith and reason; both worldwide unity and new religious movements).
Hypoxia‐inducible factor‐1α (HIF‐1α) escapes O2‐driven proteasomal degradation irrespective of its subcellular localization: nucleus or cytoplasm
Authors: Berra Edurne , Roux Danièle , Richard Darren E , Pouysségur Jacques
Published: April 2005

Eukaryotic cells sense oxygen and adapt to hypoxia by regulating a number of genes. Hypoxia‐inducible factor 1 (HIF‐1) is the ‘master’ in this pleiotypic response. HIF‐1 comprises two members of the basic helix–loop–helix transcription factor family, HIF‐1α and HIF‐1β. The HIF‐1α protein is subject to drastic O2‐dependent proteasomal control. However, the signalling components regulating the ‘switch’ for ‘escaping’ proteasomal degradation under hypoxia are still largely unknown. The rapid nuclear translocation of HIF‐1α could represent an efficient way to escape from this degradation. We therefore asked, where in the cell is HIF‐1α degraded? To address this question, we trapped HIF‐1α either in the cytoplasm, by fusing HIF‐1α to the cytoplasmic domain of the Na+‐H+ exchanger (NHE‐1), or in the nucleus, by treatment with leptomycin B. Surprisingly, we found that HIF‐1α is stabilized by hypoxia and undergoes O2‐dependent proteasomal degradation with an identical half‐life (5–8 min) in both cellular compartments. Therefore, HIF‐1α entry into the nucleus is not, as proposed, a key event that controls its stability. This result markedly contrasts with the mechanism that controls p53 degradation via MDM2.
Unique coexpression in osteoblasts of broadly expressed genes accounts for the spatial restriction of ECM mineralization to bone
Authors: Murshed Monzur , Harmey Dympna , Millán José Luis , McKee Marc D. , Karsenty Gerard
Published: April 2005

Extracellular matrix (ECM) mineralization is a physiological process in bone and a pathological one in soft tissues. The mechanisms determining the spatial restriction of ECM mineralization to bone physiologically are poorly understood. Here we show that a normal extracellular phosphate concentration is required for bone mineralization, while lowering this concentration prevents mineralization of any ECM. However, simply raising extracellular phosphate concentration is not sufficient to induce pathological mineralization, this is because of the presence in all ECMs of pyrophosphate, an inhibitor of mineralization. ECM mineralization occurs only in bone because of the exclusive coexpression in osteoblasts ofType I collagenandTnap, an enzyme that cleaves pyrophosphate. This dual requirement explains whyTnapectopic expression in cells producing fibrillar collagen is sufficient to induce pathological mineralization. This study reveals that coexpression in osteoblasts of otherwise broadly expressed genes is necessary and sufficient to induce bone mineralization and provides evidence that pathological mineralization can be prevented by modulating extracellular phosphate concentration.
Pervasive regulation of Drosophila Notch target genes by GY-box-, Brd-box-, and K-box-class microRNAs
Authors: Lai Eric C. , Tam Bergin , Rubin Gerald M.
Published: April 2005

Although hundreds of distinct animal microRNAs (miRNAs) are known, the specific biological functions of only a handful are understood at present. Here, we demonstrate that three different families of Drosophila miRNAs directly regulate two large families of Notch target genes, including basic helix–loop–helix (bHLH) repressor and Bearded family genes. These miRNAs regulate Notch target gene activity via GY-box (GUCUUCC), Brd-box (AGCUUUA), and K-box (cUGUGAUa) motifs. These are conserved sites in target 3′-untranslated regions (3′-UTRs) that are complementary to the 5′-ends of miRNAs, or “seed” regions. Collectively, these motifs represent >40 miRNA-binding sites in Notch target genes, and we show all three classes of motif to be necessary and sufficient for miRNA-mediated regulation in vivo. Importantly, many of the validated miRNA-binding sites have limited pairing to miRNAs outside of the “box:seed” region. Consistent with this, we find that seed-related miRNAs that are otherwise quite divergent can regulate the same target sequences. Finally, we demonstrate that ectopic expression of several Notch-regulating miRNAs induces mutant phenotypes that are characteristic of Notch pathway loss of function, including loss of wing margin, thickened wing veins, increased bristle density, and tufted bristles. Collectively, these data establish insights into miRNA target recognition and demonstrate that the Notch signaling pathway is a major target of miRNA-mediated regulation in Drosophila.
Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint
Authors: Byun Tony S. , Pacek Marcin , Yee Muh-ching , Walter Johannes C. , Cimprich Karlene A.
Published: April 2005

The ATR-dependent DNA damage response pathway can respond to a diverse group of lesions as well as inhibitors of DNA replication. Using the Xenopus egg extract system, we show that lesions induced by UV irradiation and cis-platinum cause the functional uncoupling of MCM helicase and DNA polymerase activities, an event previously shown for aphidicolin. Inhibition of uncoupling during elongation with inhibitors of MCM7 or Cdc45, a putative helicase cofactor, results in abrogation of Chk1 phosphorylation, indicating that uncoupling is necessary for activation of the checkpoint. However, uncoupling is not sufficient for checkpoint activation, and DNA synthesis by Polα is also required. Finally, using plasmids of varying size, we demonstrate that all of the unwound DNA generated at a stalled replication fork can contribute to the level of Chk1 phosphorylation, suggesting that uncoupling amplifies checkpoint signaling at each individual replication fork. Taken together, these observations indicate that functional uncoupling of MCM helicase and DNA polymerase activities occurs in response to multiple forms of DNA damage and that there is a general mechanism for generation of the checkpoint-activating signal following DNA damage.
Systems Rebalancing of Metabolism in Response to Sulfur Deprivation, as Revealed by Metabolome Analysis of Arabidopsis Plants
Authors: Nikiforova Victoria J. , Kopka Joachim , Tolstikov Vladimir , Fiehn Oliver , Hopkins Laura , Hawkesford Malcolm J. , Hesse Holger , Hoefgen Rainer
Published: April 2005

Sulfur is an essential macroelement in plant and animal nutrition. Plants assimilate inorganic sulfate into two sulfur-containing amino acids, cysteine and methionine. Low supply of sulfate leads to decreased sulfur pools within plant tissues. As sulfur-related metabolites represent an integral part of plant metabolism with multiple interactions, sulfur deficiency stress induces a number of adaptive responses, which must be coordinated. To reveal the coordinating network of adaptations to sulfur deficiency, metabolite profiling of Arabidopsis has been undertaken. Gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry techniques revealed the response patterns of 6,023 peaks of nonredundant ion traces and relative concentration levels of 134 nonredundant compounds of known chemical structure. Here, we provide a catalogue of the detected metabolic changes and reconstruct the coordinating network of their mutual influences. The observed decrease in biomass, as well as in levels of proteins, chlorophylls, and total RNA, gives evidence for a general reduction of metabolic activity under conditions of depleted sulfur supply. This is achieved by a systemic adjustment of metabolism involving the major metabolic pathways. Sulfur/carbon/nitrogen are partitioned by accumulation of metabolites along the pathway O-acetylserine to serine to glycine, and are further channeled together with the nitrogen-rich compound glutamine into allantoin. Mutual influences between sulfur assimilation, nitrogen imbalance, lipid breakdown, purine metabolism, and enhanced photorespiration associated with sulfur-deficiency stress are revealed in this study. These responses may be assembled into a global scheme of metabolic regulation induced by sulfur nutritional stress, which optimizes resources for seed production.
Characterization of Arsenate Reductase in the Extract of Roots and Fronds of Chinese Brake Fern, an Arsenic Hyperaccumulator
Authors: Duan Gui-Lan , Zhu Yong-Guan , Tong Yi-Ping , Cai Chao , Kneer Ralf
Published: April 2005

Root extracts from the arsenic (As) hyperaccumulating Chinese brake fern (Pteris vittata) were shown to be able to reduce arsenate to arsenite. An arsenate reductase (AR) in the fern showed a reaction mechanism similar to the previously reported Acr2p, an AR from yeast (Saccharomyces cerevisiae), using glutathione as the electron donor. Substrate specificity as well as sensitivity toward inhibitors for the fern AR (phosphate as a competitive inhibitor, arsenite as a noncompetitive inhibitor) was also similar to Acr2p. Kinetic analysis showed that the fern AR had a Michaelis constant value of 2.33 mm for arsenate, 15-fold lower than the purified Acr2p. The AR-specific activity of the fern roots treated with 2 mm arsenate for 9 d was at least 7 times higher than those of roots and shoots of plant species that are known not to tolerate arsenate. A T-DNA knockout mutant of Arabidopsis (Arabidopsis thaliana) with disruption in the putative Acr2 gene had no AR activity. We could not detect AR activity in shoots of the fern. These results indicate that (1) arsenite, the previously reported main storage form of As in the fern fronds, may come mainly from the reduction of arsenate in roots; and (2) AR plays an important role in the detoxification of As in the As hyperaccumulating fern.
Ethylene Insensitivity Conferred by theGreen-ripeandNever-ripe 2Ripening Mutants of Tomato
Authors: Barry Cornelius S. , McQuinn Ryan P. , Thompson Andrew J. , Seymour Graham B. , Grierson Donald , Giovannoni James J.
Published: April 2005

The ripening of a fleshy fruit represents the summation of an array of biochemical processes that are regulated by interactions between developmental programs and environmental inputs. Analysis of tomato (Solanum lycopersicum) mutants and inhibitor studies indicate that ethylene is necessary for full development of the ripening program of climacteric fruit such as tomato, yet ethylene alone is not sufficient. This suggests that an interaction between ethylene and nonethylene (or developmental) pathways mediates ripening. In this study, we have examined the physiological basis for ripening inhibition of the dominant Green-ripe (Gr) and Never-ripe 2 (Nr-2) mutants of tomato. Our data suggest that this inhibition is due to ethylene insensitivity in mutant fruit. Further investigation of ethylene responses in Gr and Nr-2 plants also revealed weak ethylene insensitivity during floral senescence and abscission and, during inhibition of root elongation, a phenotype associated with the triple response. However, ethylene-induced inhibition of hypocotyl elongation and petiole epinasty are normal in Gr and Nr-2, suggesting that these loci regulate a subset of ethylene responses. We have mapped both dominant mutations to a 2-cM overlapping region of the long arm of chromosome 1 of tomato, a region not previously linked to any known ethylene signaling loci. The phenotypic similarity and overlapping map location of these mutations suggest Gr and Nr-2 may be allelic and may possibly encode a novel component of the ethylene response pathway.
Citrate Secretion Coupled with the Modulation of Soybean Root Tip under Aluminum Stress. Up-Regulation of Transcription, Translation, and Threonine-Oriented Phosphorylation of Plasma Membrane H+-ATPase
Authors: Shen Hong , He Long Fei , Sasaki Takayuki , Yamamoto Yoko , Zheng Shao Jian , Ligaba Ayalew , Yan Xiao Long , Ahn Sung Ju , Yamaguchi Mineo , Sasakawa Hideo , Matsumoto Hideaki
Published: April 2005

The aluminum (Al)-induced secretion of citrate has been regarded as an important mechanism for Al resistance in soybean (Glycine max). However, the mechanism of how Al induces citrate secretion remains unclear. In this study, we investigated the regulatory role of plasma membrane H+-ATPase on the Al-induced secretion of citrate from soybean roots. Experiments performed with plants grown in full nutrient solution showed that Al-induced activity of plasma membrane H+-ATPase paralleled secretion of citrate. Vanadate and fusicoccin, an inhibitor and an activator, respectively, of plasma membrane H+-ATPase, exerted inhibitory and stimulatory effects on the Al-induced secretion of citrate. Higher activity of plasma membrane H+-ATPase coincided with more citrate secretion in Al-resistant than Al-sensitive soybean cultivars. These results suggested that the effects of Al stress on citrate secretion were mediated via modulation of the activity of plasma membrane H+-ATPase. The relationship between the Al-induced secretion of citrate and the activity of plasma membrane H+-ATPase was further demonstrated by analysis of plasma membrane H+-ATPase transgenic Arabidopsis (Arabidopsis thaliana). When plants were grown on Murashige and Skoog medium containing 30 μ  m Al (9.1 μ  m Al3+ activity), transgenic plants exuded more citrate compared with wild-type Arabidopsis. Results from real-time reverse transcription-PCR and immunodetection analysis indicated that the increase of plasma membrane H+-ATPase activity by Al is caused by transcriptional and translational regulation. Furthermore, plasma membrane H+-ATPase activity and expression were higher in an Al-resistant cultivar than in an Al-sensitive cultivar. Al activated the threonine-oriented phosphorylation of plasma membrane H+-ATPase in a dose- and time-dependent manner. Taken together, our results demonstrated that up-regulation of plasma membrane H+-ATPase activity was associated with the secretion of citrate from soybean roots.
Arabidopsis CBF3/DREB1A and ABF3 in Transgenic Rice Increased Tolerance to Abiotic Stress without Stunting Growth
Authors: Oh Se-Jun , Song Sang Ik , Kim Youn Shic , Jang Hyun-Jun , Kim Soo Young , Kim Minjeong , Kim Yeon-Ki , Nahm Baek Hie , Kim Ju-Kon
Published: April 2005

Rice (Oryza sativa), a monocotyledonous plant that does not cold acclimate, has evolved differently from Arabidopsis (Arabidopsis thaliana), which cold acclimates. To understand the stress response of rice in comparison with that of Arabidopsis, we developed transgenic rice plants that constitutively expressed CBF3/DREB1A (CBF3) and ABF3, Arabidopsis genes that function in abscisic acid-independent and abscisic acid-dependent stress-response pathways, respectively. CBF3 in transgenic rice elevated tolerance to drought and high salinity, and produced relatively low levels of tolerance to low-temperature exposure. These data were in direct contrast to CBF3 in Arabidopsis, which is known to function primarily to enhance freezing tolerance. ABF3 in transgenic rice increased tolerance to drought stress alone. By using the 60 K Rice Whole Genome Microarray and RNA gel-blot analyses, we identified 12 and 7 target genes that were activated in transgenic rice plants by CBF3 and ABF3, respectively, which appear to render the corresponding plants acclimated for stress conditions. The target genes together with 13 and 27 additional genes are induced further upon exposure to drought stress, consequently making the transgenic plants more tolerant to stress conditions. Interestingly, our transgenic plants exhibited neither growth inhibition nor visible phenotypic alterations despite constitutive expression of the CBF3 or ABF3, unlike the results previously obtained from Arabidopsis where transgenic plants were stunted.
Unique Translation Initiation at the Second AUG Codon Determines Mitochondrial Localization of the Phage-Type RNA Polymerases in the Moss Physcomitrella patens
Authors: Kabeya Yukihiro , Sato Naoki
Published: April 2005

The nuclear genome of the moss Physcomitrella patens contains two genes encoding phage-type RNA polymerases (PpRPOT1 and PpRPOT2). Each of the PpRPOT1 and PpRPOT2 transcripts possesses two in-frame AUG codons at the 5′ terminus that could act as a translational initiation site. Observation of transient and stable Physcomitrella transformants expressing the 5′ terminus of each PpRPOT cDNA fused with the green fluorescent protein gene suggested that both PpRPOT1 and PpRPOT2 are not translated from the first (upstream) AUG codon in the natural context but translated from the second (downstream) one, and that these enzymes are targeted only to mitochondria, although they are potentially targeted to plastids when translation is forced to start from the first AUG codon. The influence of the 5′-upstream sequence on the translation efficiency of the two AUG codons in PpRPOT1 and PpRPOT2 was quantitatively assessed using a β-glucuronidase reporter. The results further supported that the second AUG codon is the sole translation initiation site in Physcomitrella cells. An Arabidopsis (Arabidopsis thaliana) RPOT homolog AtRpoT;2 that possesses two initiation AUG codons in its transcripts, as do the RPOTs of P. patens, has been regarded as a dually targeted protein. When the localization of AtRpoT;2 was tested using green fluorescent protein in a similar way, AtRpoT;2 was also observed only in mitochondria in many Arabidopsis tissues. These results suggest that, despite the presence of two in-frame AUGs at the 5′ termini of RPOTs in Physcomitrella and Arabidopsis, the second AUG is specifically recognized as the initiation site in these organisms, resulting in expression of a protein that is targeted to mitochondria. This finding may change the current framework of thinking about the transcription machinery of plastids in land plants.
A review of the efficacy and safety of key ingredients of over‐the‐counter products for weight management
Authors: Ruxton C.H.S. , Gardner E.J.
Published: April 2005

Purpose

Over‐the‐counter (OTC) weight management products are popular with the public. Manufacturers frequently claim beneficial effects of these products, however current legislation does not compel them to support these claims with research. This paper identifies the key ingredients of OTC weight management products and evaluates evidence for their safety and efficacy.

Design/methodology/approach

Using Medline, published evidence on key ingredients and formulations was gathered. Contact was also made with manufacturers to ascertain whether unpublished data were available. All studies were assessed for quality. The efficacy and safety of the ingredients and formulations were then reviewed.

Findings

The results showed little evidence for most weight loss claims, with the exception of a formulation containing Yerba maté, Guarana and Damiana. In addition, studies on pyruvate, conjugated linoleic acid, and Citrus aurantium demonstrated positive effects on weight loss, suggesting that they may be useful in future formulations. Safety implications were noted for ephedrine.

Practical implications

Better labelling and supporting literature should be introduced by reputable manufacturers and retailers to help the public assess the efficacy of weight loss aids.

Research limitations/implications

Given the popularity of self‐treatment, there is a need for more manufacturers to submit their products to impartial clinical trials. OTC weight management products could be useful in addressing obesity, but most still need scientific evidence to demonstrate safety and effectiveness.

Originality/value

This review reviews the available evidence on ingredients of OTC weight management products, providing a unique guide to what works, and what doesn't.