bluuebunny/crossref_metadata_2025 huggingface dataset:
SMAD7 controls iron metabolism as a potent inhibitor of hepcidin expression
Authors: Mleczko-Sanecka Katarzyna , Casanovas Guillem , Ragab Anan , Breitkopf Katja , Müller Alexandra , Boutros Michael , Dooley Steven , Hentze Matthias W. , Muckenthaler Martina U.
Published: December 2009

Hepcidin is the master regulatory hormone of systemic iron metabolism. Hepcidin deficiency causes common iron overload syndromes whereas its overexpression is responsible for microcytic anemias. Hepcidin transcription is activated by the bone morphogenetic protein (BMP) and the inflammatory JAK-STAT pathways, whereas comparatively little is known about how hepcidin expression is inhibited. By using high-throughput siRNA screening we identified SMAD7 as a potent hepcidin suppressor. SMAD7 is an inhibitory SMAD protein that mediates a negative feedback loop to both transforming growth factor-β and BMP signaling and that recently was shown to be coregulated with hepcidin via SMAD4 in response to altered iron availability in vivo. We show that SMAD7 is coregulated with hepcidin by BMPs in primary murine hepatocytes and that SMAD7 overexpression completely abolishes hepcidin activation by BMPs and transforming growth factor-β. We identify a distinct SMAD regulatory motif (GTCAAGAC) within the hepcidin promoter involved in SMAD7-dependent hepcidin suppression, demonstrating that SMAD7 does not simply antagonize the previously reported hemojuvelin/BMP-responsive elements. This work identifies a potent inhibitory factor for hepcidin expression and uncovers a negative feedback pathway for hepcidin regulation, providing insight into a mechanism how hepcidin expression may be limited to avoid iron deficiency.
The neutrophil alloantigen HNA-3a (5b) is located on choline transporter-like protein 2 and appears to be encoded by an R>Q154 amino acid substitution
Authors: Curtis Brian R. , Cox Nancy J. , Sullivan Mia J. , Konkashbaev Anuar , Bowens Krista , Hansen Kirk , Aster Richard H.
Published: December 2009

The molecular basis of the HNA-3a/b (5b/a) leukocyte antigen system has not yet been defined despite evidence that HNA-3a–specific antibodies are particularly prone to cause severe, often fatal, transfusion-related lung injury. We used genome-wide single nucleotide polymorphism scanning and sequencing of DNA from persons of different HNA-3a/b phenotypes to identify a single single nucleotide polymorphism in exon 7 of the CLT2 gene (SLC44A2) that predicts an amino acid substitution in the first extracellular loop of choline transporter-like protein 2, a member of the choline transporter-like protein family of membrane glycoproteins, and correlates perfectly with HNA-3a/b phenotypes (R154 encodes HNA-3a; Q154 encodes HNA-3b). Mass spectrometric analysis of proteins immunoprecipitated from leukocytes by anti–HNA-3a provided direct evidence that anti–HNA-3a recognizes choline transporter-like protein 2. These findings will enable large-scale genotyping for HNA-3a/b to identify blood donors at risk to have HNA-3a–specific antibodies and should facilitate development of practical methods to detect such antibodies and prevent transfusion-related lung injury.
Genetic determinants of hair and eye colours in the Scottish and Danish populations
Authors: Mengel-From Jonas , Wong Terence H , Morling Niels , Rees Jonathan L , Jackson Ian J
Published: December 2009

Background

Eye and hair colour is highly variable in the European population, and is largely genetically determined. Both linkage and association studies have previously been used to identify candidate genes underlying this variation. Many of the genes found were previously known as underlying mutant mouse phenotypes or human genetic disease, but others, previously unsuspected as pigmentation genes, have also been discovered.

Results

We assayed the hair of a population of individuals of Scottish origin using tristimulus colorimetry, in order to produce a quantitative measure of hair colour. Cluster analysis of this data defined two groups, with overlapping borders, which corresponded to visually assessed dark versus red/light hair colour. The Danish population was assigned into categorical hair colour groups. Both cohorts were also assessed for eye colour. DNA from the Scottish group was genotyped at SNPs in 33 candidate genes, using 384 SNPs identified by HapMap as representatives of each gene. Associations found between SNPs and colorimetric hair data and eye colour categories were replicated in a cohort of the Danish population. The Danish population was also genotyped with SNPs in 4 previously described pigmentation genes. We found replicable associations of hair colour with the KITLG and OCA2 genes. MC1R variation correlated, as expected, with the red dimension of colorimetric hair colour in Scots. The Danish analysis excluded those with red hair, and no associations were found with MC1R in this group, emphasising that MC1R regulates the colour rather than the intensity of pigmentation. A previously unreported association with the HPS3 gene was seen in the Scottish population. However, although this replicated in the smaller cohort of the Danish population, no association was seen when the whole study population was analysed.

Conclusions

We have found novel associations with SNPs in known pigmentation genes and colorimetrically assessed hair colour in a Scottish and a Danish population.
Genome-wide loss-of-function analysis of deubiquitylating enzymes for zebrafish development
Authors: Tse William KF , Eisenhaber Birgit , Ho Steven HK , Ng Qimei , Eisenhaber Frank , Jiang Yun-Jin
Published: December 2009

Background

Deconjugation of ubiquitin and/or ubiquitin-like modified protein substrates is essential to modulate protein-protein interactions and, thus, signaling processes in cells. Although deubiquitylating (deubiquitinating) enzymes (DUBs) play a key role in this process, however, their function and regulation remain insufficiently understood. The "loss-of-function" phenotype studies can provide important information to elucidate the gene function, and zebrafish is an excellent model for this goal.

Results

From an in silico genome-wide search, we found more than 90 putative DUBs encoded in the zebrafish genome belonging to six different subclasses. Out of them, 85 from five classical subclasses have been tested with morpholino (MO) knockdown experiments and 57 of them were found to be important in early development of zebrafish. These DUB morphants resulted in a complex and pleiotropic phenotype that, regardless of gene target, always affected the notochord. Based on the huC neuronal marker expression, we grouped them into five sets (groups I to V). Group I DUBs (otud7b, uchl3 and bap1) appear to be involved in the Notch signaling pathway based on the neuronal hyperplasia, while group IV DUBs (otud4, usp5, usp15 and usp25) play a critical role in dorsoventral patterning through the BMP pathway.

Conclusion

We have identified an exhaustive list of genes in the zebrafish genome belonging to the five established classes of DUBs. Additionally, we performed the corresponding MO knockdown experiments in zebrafish as well as functional studies for a subset of the predicted DUB genes. The screen results in this work will stimulate functional follow-up studies of potential DUB genes using the zebrafish model system.
Polymorphism in the flanking regions of the PbGP43 gene from the human pathogen Paracoccidioides brasiliensis: search for protein binding sequences and poly(A) cleavage sites
Authors: Rocha Antonio A , Morais Flávia V , Puccia Rosana
Published: December 2009

Background

Paracoccidioides brasiliensis is a thermo-dimorphic fungus that causes paracoccidiodomycosis (PCM). Glycoprotein gp43 is the fungal main diagnostic antigen, which can also protect against murine PCM and interact with extracellular matrix proteins. It is structurally related to glucanases, however not active, and whose expression varies considerably. We have presently studied polymorphisms in the PbGP43 flanking regions to help understand such variations.

Results

we tested the protein-binding capacity of oligonucleotides covering the PbGP43 proximal 5' flanking region, including overlap and mutated probes. We used electrophoretic mobility shift assays and found DNA binding regions between positions -134 to -103 and -255 to -215. Only mutation at -230, characteristic of P. brasiliensis phylogenetic species PS2, altered binding affinity. Next, we cloned and sequenced the 5' intergenic region up to position -2,047 from P. brasiliensis Pb339 and observed that it is composed of three tandem repetitive regions of about 500 bp preceded upstream by 442 bp. Correspondent PCR fragments of about 2,000 bp were found in eight out of fourteen isolates; in PS2 samples they were 1,500-bp long due to the absence of one repetitive region, as detected in Pb3. We also compared fifty-six PbGP43 3' UTR sequences from ten isolates and have not observed polymorphisms; however we detected two main poly(A) clusters (1,420 to 1,441 and 1,451 to 1,457) of multiple cleavage sites. In a single isolate we found one to seven sites.

Conclusions

We observed that the amount of PbGP43 transcripts accumulated in P. brasiliensis Pb339 grown in defined medium was about 1,000-fold higher than in Pb18 and 120-fold higher than in Pb3. We have described a series of features in the gene flanking regions and differences among isolates, including DNA-binding sequences, which might impact gene regulation. Little is known about regulatory sequences in thermo-dimorphic fungi. The peculiar structure of tandem repetitive fragments in the 5' intergenic region of PbGP43, their characteristic sequences, besides the presence of multiple poly(A) cleavage sites in the 3' UTR will certainly guide future studies.
Glycosylation-mediated phenylpropanoid partitioning in Populus tremuloides cell cultures
Authors: Payyavula Raja S , Babst Benjamin A , Nelsen Matthew P , Harding Scott A , Tsai Chung-Jui
Published: December 2009

Background

Phenylpropanoid-derived phenolic glycosides (PGs) and condensed tannins (CTs) comprise large, multi-purpose non-structural carbon sinks in Populus. A negative correlation between PG and CT concentrations has been observed in several studies. However, the molecular mechanism underlying the relationship is not known.

Results

Populus cell cultures produce CTs but not PGs under normal conditions. Feeding salicyl alcohol resulted in accumulation of salicins, the simplest PG, in the cells, but not higher-order PGs. Salicin accrual reflected the stimulation of a glycosylation response which altered a number of metabolic activities. We utilized this suspension cell feeding system as a model for analyzing the possible role of glycosylation in regulating the metabolic competition between PG formation, CT synthesis and growth. Cells accumulated salicins in a dose-dependent manner following salicyl alcohol feeding. Higher feeding levels led to a decrease in cellular CT concentrations (at 5 or 10 mM), and a negative effect on cell growth (at 10 mM). The competition between salicin and CT formation was reciprocal, and depended on the metabolic status of the cells. We analyzed gene expression changes between controls and cells fed with 5 mM salicyl alcohol for 48 hr, a time point when salicin accumulation was near maximum and CT synthesis was reduced, with no effect on growth. Several stress-responsive genes were up-regulated, suggestive of a general stress response in the fed cells. Salicyl alcohol feeding also induced expression of genes associated with sucrose catabolism, glycolysis and the Krebs cycle. Transcript levels of phenylalanine ammonia lyase and most of the flavonoid pathway genes were reduced, consistent with down-regulated CT synthesis.

Conclusions

Exogenous salicyl alcohol was readily glycosylated in Populus cell cultures, a process that altered sugar utilization and phenolic partitioning in the cells. Using this system, we identified candidate genes for glycosyltransferases that may mediate the glycosylation, and for transporters that mediate the subcellular compartmentalization of sugars and phenolic glycosides. The suspension cells appear to represent a facile system for dissecting the regulation of phenolic carbon partitioning, and in turn, its effects on growth in Populus.
Effects of phone versus mail survey methods on the measurement of health-related quality of life and emotional and behavioural problems in adolescents
Authors: Erhart Michael , Wetzel Ralf M , Krügel André , Ravens-Sieberer Ulrike
Published: December 2009

Background

Telephone interviews have become established as an alternative to traditional mail surveys for collecting epidemiological data in public health research. However, the use of telephone and mail surveys raises the question of to what extent the results of different data collection methods deviate from one another. We therefore set out to study possible differences in using telephone and mail survey methods to measure health-related quality of life and emotional and behavioural problems in children and adolescents.

Methods

A total of 1700 German children aged 8-18 years and their parents were interviewed randomly either by telephone or by mail. Health-related Quality of Life (HRQoL) and mental health problems (MHP) were assessed using the KINDL-R Quality of Life instrument and the Strengths and Difficulties Questionnaire (SDQ) children's self-report and parent proxy report versions. Mean Differences ("d" effect size) and differences in Cronbach alpha were examined across modes of administration. Pearson correlation between children's and parents' scores was calculated within a multi-trait-multi-method (MTMM) analysis and compared across survey modes using Fisher-Z transformation.

Results

Telephone and mail survey methods resulted in similar completion rates and similar socio-demographic and socio-economic makeups of the samples. Telephone methods resulted in more positive self- and parent proxy reports of children's HRQoL (SMD ≤ 0.27) and MHP (SMD ≤ 0.32) on many scales. For the phone administered KINDL, lower Cronbach alpha values (self/proxy Total: 0.79/0.84) were observed (mail survey self/proxy Total: 0.84/0.87). KINDL MTMM results were weaker for the phone surveys: mono-trait-multi-method mean r = 0.31 (mail: r = 0.45); multi-trait-mono-method mean (self/parents) r = 0.29/0.36 (mail: r = 0.34/0.40); multi-trait-multi-method mean r = 0.14 (mail: r = 0.21). Weaker MTMM results were also observed for the phone administered SDQ: mono-trait-multi-method mean r = 0.32 (mail: r = 0.40); multi-trait-mono-method mean (self/parents) r = 0.24/0.30 (mail: r = 0.20/0.32); multi-trait-multi-method mean r = 0.14 (mail = 0.14). The SDQ classification into borderline and abnormal for some scales was affected by the method (OR = 0.36-1.55).

Conclusions

The observed differences between phone and mail surveys are small but should be regarded as relevant in certain settings. Therefore, while both methods are valid, some changes are necessary. The weaker reliability and MTMM validity associated with phone methods necessitates improved phone adaptations of paper and pencil questionnaires. The effects of phone versus mail survey modes are partly different across constructs/measures.
Design and pre-clinical profiling of a Plasmodium falciparum MSP-3 derived component for a multi-valent virosomal malaria vaccine
Authors: Tamborrini Marco , Mueller Markus S , Stoffel Sabine A , Westerfeld Nicole , Vogel Denise , Boato Francesca , Zurbriggen Rinaldo , Robinson John A , Pluschke Gerd
Published: December 2009

Background

Clinical profiling of two components for a synthetic peptide-based virosomal malaria vaccine has yielded promising results, encouraging the search for additional components for inclusion in a final multi-valent vaccine formulation. This report describes the immunological characterization of linear and cyclized synthetic peptides comprising amino acids 211-237 ofPlasmodium falciparummerozoite surface protein (MSP-3).

Methods

These peptides were coupled to phosphatidylethanolamine (PE); the conjugates were intercalated into immunopotentiating reconstituted influenza virosomes (IRIVs) and then used for immunizations in mice to evaluate their capacity to elicitP. falciparumcross-reactive antibodies.

Results

While all MSP-3-derived peptides were able to elicit parasite-binding antibodies, stabilization of turn structures by cyclization had no immune-enhancing effect. Therefore, further pre-clinical profiling was focused on FB-12, a PE conjugate of the linear peptide. Consistent with the immunological results obtained in mice, all FB-12 immunized rabbits tested seroconverted and consistently elicited antibodies that interacted with blood stage parasites. It was observed that a dose of 50 μg was superior to a dose of 10 μg and that influenza pre-existing immunity improved the immunogenicity of FB-12 in rabbits. FB-12 production was successfully up-scaled and the immunogenicity of a vaccine formulation, produced according to the rules of Good Manufacturing Practice (GMP), was tested in mice and rabbits. All animals tested developed parasite-binding antibodies. Comparison of ELISA and IFA titers as well as the characterization of a panel of anti-FB-12 monoclonal antibodies indicated that at least the majority of antibodies specific for the virosomally formulated synthetic peptide were parasite cross-reactive.

Conclusion

These results reconfirm the suitability of IRIVs as a carrier/adjuvant system for the induction of strong humoral immune responses against a wide range of synthetic peptide antigens. The virosomal formulation of the FB-12 peptidomimetic is suitable for use in humans and represents a candidate component for a virosomal multi-valent malaria subunit vaccine.
Effect of hyperlipidemia on the expression of circadian genes in apolipoprotein E knock-out atherosclerotic mice
Authors: Hou Likun , Lu Chao , Huang Yang , Chen Sifeng , Hua Luchun , Qian Ruizhe
Published: December 2009

Background

Circadian patterns of cardiovascular vulnerability were well characterized, with a peak incidence of acute myocardial infarction and stroke secondary to atherosclerosis in the morning, which showed the circadian clock may take part in the pathological process of atherosclerosis induced by hyperlipidemia. Hence, the effect of hyperlipidemia on the expression of circadian genes was investigated in atherosclerotic mouse model.

Results

In apoE-/-mice on regular chow or high-fat diet, an atherosclerotic mouse model induced by heperlipidemia, we found that the peak concentration of serum lipids was showed four or eight hours later in apoE-/- mice, compared to C57BL/6J mice. During the artificial light period, a reduce in circulating level of serum lipids corresponded with the observed increase of the expression levels of some the transcription factors involved in lipid metabolism, such as PPARα and RXRα. Meanwhile, the expression of circadian genes was changed following with amplitude reduced or the peak mRNA level delayed.

Conclusions

Our studies indicated that heperlipidemia altered both the rhythmicity and expression of circadian genes. Diet-induced circadian disruption may affect the process of atherosclerosis and some acute cardiovascular disease.
Methylation associated inactivation of RASSF1A and its synergistic effect with activated K-Ras in nasopharyngeal carcinoma
Authors: Wang Tao , Liu Hongli , Chen Yeshan , Liu Wei , Yu Jing , Wu Gang
Published: December 2009

Background

Epigenetic silencing of tumor suppressor genes associated with promoter methylation is considered to be a hallmark of oncogenesis. RASSF1A is a candidate tumor suppressor gene which was found to be inactivated in many human cancers. Although we have had a prelimilary cognition about the function of RASSF1A, the exact mechanisms about how RASSF1A functions in human cancers were largely unknown. Moreover, the effect of mutated K-Ras gene on the function of RASSF1A is lacking. The aim of this study was to investigate the expression profile and methylation status of RASSF1A gene, and to explore its concrete mechanisms as a tumor suppressor gene in Nasopharyngeal Carcinoma.

Methods

We examined the expression profile and methylation status of RASSF1A in two NPC cell lines, 38 primary nasopharyngeal carcinoma and 14 normal nasopharyngeal epithelia using RT-PCR and methylated specific PCR(MSP) respectively. 5-aza-dC was then added to confirm the correlation between hypermethylation status and inactivation of RASSF1A. The NPC cell line CNE-2 was transfected with exogenous pcDNA3.1(+)/RASSF1A plasmid in the presence or absence of mutated K-Ras by liposome-mediated gene transfer method. Flow cytometry was used to examine the effect of RASSF1A on cell cycle modulation and apoptosis. Meanwhile, trypan blue dye exclusion assays was used to detect the effect of RASSF1A transfection alone and the co-transfection of RASSF1A and K-Ras on cell proliferation.

Results

Promoter methylation of RASSF1A could be detected in 71.05% (27/38) of NPC samples, but not in normal nasopharyngeal epithelia. RASSF1A expression in NPC primary tumors was lower than that in normal nasopharyngeal epithelial (p < 0.01). Expression of RASSF1A was down-regulated in two NPC cell lines. Loss of RASSF1A expression was greatly restored by the methyltransferase inhibitor 5-aza-dC in CNE-2. Ectopic expression of RASSF1A in CNE-2 could increase the percentage of G0/G1 phase cells (p < 0.01), inhibit cell proliferation and induce apoptosis (p < 0.001). Moreover, activated K-Ras could enhance the growth inhibition effect induced by RASSF1A in CNE-2 cells (p < 0.01).

Conclusion

Expression of RASSF1A is down-regulated in NPC due to the hypermethylation of promoter. Exogenous expression of RASSF1A is able to induce growth inhibition effect and apoptosis in tumor cell lines, and this effect could be enhanced by activated K-Ras.
Reply to letter by Bakker et al.
Authors: Fink Mitchell P
Published: January 2010

Many mediators, which regulate inflammatory processes, manifest pro-inflammatory and anti-inflammatory properties, depending upon the conditions under study.
The classification of mental disorder: a simpler system for DSM–V and ICD–11
Authors: Goldberg David
Published: January 2010

This article proposes a simplification to the chapter structure of current classifications of mental disorder, which cause unnecessary estimates of ‘comorbidity’ and pay major attention to symptom similarity as a criterion for deciding on groupings. A simpler system, taking account of recent developments in aetiology, is proposed. There is at present no simple solution to the problems posed by the structure of our classification, but the advantages as well as the shortcomings of changing our approach to diagnosis are discussed.
Cryoglobulin evaluation: best practice?
Authors: Sargur Ravishankar , White Peter , Egner William
Published: December 2009

Cryoglobulins are serum immunoglobulins that precipitate at temperatures below 37°C and re-dissolve on warming. Cryoglobulinaemia leads to variable symptoms including characteristic purpura, ischaemia of extremities, renal failure, peripheral neuropathy, abdominal pain secondary to intestinal ischaemia and arthralgias. Cryoglobulin testing is underutilized in clinical practice. It has been neglected in clinical laboratories and by clinicians due to several factors, such as the length of time it takes for serum cryoglobulin analysis to be performed in the laboratory, the perceived difficulty in getting optimal sampling conditions and a failure to appreciate that even apparently low levels of cryoglobulin can be associated with severe symptoms in some patients. The most important variable confounding standardization of cryoglobulin testing is improper sample handling. A recent report critically appraising the current practice of cryoglobulin evaluation in 137 laboratories in Europe by United Kingdom National External Quality Assurance Scheme (UKNEQAS) illustrated the wide variability in practice. Although many clinical laboratories perform cryoglobulin evaluation, there are widespread differences in the methodology used and the care with which this is carried out and this leads to considerable intralaboratory and interlaboratory variability. The most common sources of error are false-negative results due to loss of cryoprecipitate during transport and storage. Better standardization is needed to avoid missed diagnoses and improve the comparability of results. Laboratories should ensure that sample temperature is maintained at 37°C until the serum is separated. In this article, we briefly review the classification and clinical features of cryoglobulins and suggest best practice guidelines for laboratory detection and identification of cryoglobulins.
The nuclear experience of CPEB: Implications for RNA processing and translational control
Authors: Lin Chien-Ling , Evans Veronica , Shen Shihao , Xing Yi , Richter Joel D.
Published: December 2009

CPEB is a sequence-specific RNA binding protein that promotes polyadenylation-induced translation in early development, during cell cycle progression and cellular senescence, and following neuronal synapse stimulation. It controls polyadenylation and translation through other interacting molecules, most notably the poly(A) polymerase Gld2, the deadenylating enzyme PARN, and the eIF4E-binding protein Maskin. Here, we report that CPEB shuttles between the nucleus and cytoplasm and that its export occurs via the CRM1-dependent pathway. In the nucleus of Xenopus oocytes, CPEB associates with lampbrush chromosomes and several proteins involved in nuclear RNA processing. CPEB also interacts with Maskin in the nucleus as well as with CPE-containing mRNAs. Although the CPE does not regulate mRNA export, it influences the degree to which mRNAs are translationally repressed in the cytoplasm. Moreover, CPEB directly or indirectly mediates the alternative splicing of at least one pre-mRNA in mouse embryo fibroblasts as well as certain mouse tissues. We propose that CPEB, together with Maskin, binds mRNA in the nucleus to ensure tight translational repression upon export to the cytoplasm. In addition, we propose that nuclear CPEB regulates specific pre-mRNA alternative splicing.
Evidence for bacterial origin of heat shock RNA-1
Authors: Kim Dong Seon , Lee Younghoon , Hahn Yoonsoo
Published: December 2009

The heat shock RNA-1 (HSR1) is a noncoding RNA (ncRNA) reported to be involved in mammalian heat shock response. HSR1 was shown to significantly stimulate the heat-shock factor 1 (HSF1) trimerization and DNA binding. The hamster HSR1 sequence was reported to consist of 604 nucleotides (nt) plus a poly(A) tail and to have only a 4-nt difference with the human HSR1. In this study, we present highly convincing evidence for bacterial origin of the HSR1. No HSR1 sequence was found by exhaustive sequence similarity searches of the publicly available eukaryotic nucleotide sequence databases at the NCBI, including the expressed sequence tags, genome survey sequences, and high-throughput genomic sequences divisions of GenBank, as well as the Trace Archive database of whole genome shotgun sequences, and genome assemblies. Instead, a putative open reading frame (ORF) of HSR1 revealed strong similarity to the amino-terminal region of bacterial chloride channel proteins. Furthermore, the 5′ flanking region of the putative HSR1 ORF showed similarity to the 5′ upstream regions of the bacterial protein genes. We propose that the HSR1 was derived from a bacterial genome fragment either by horizontal gene transfer or by bacterial infection of the cells. The most probable source organism of the HSR1 is a species belonging to the order Burkholderiales.
Neuron-type specific regulation of a 3′UTR through redundant and combinatorially acting cis-regulatory elements
Authors: Didiano Dominic , Cochella Luisa , Tursun Baris , Hobert Oliver
Published: December 2009

3′ Untranslated region (UTR)-dependent post-transcriptional regulation has emerged as a critical mechanism of controlling gene expression in various physiological contexts, including cellular differentiation events. Here, we examine the regulation of the 3′UTR of the die-1 transcription factor in a single neuron of the nematode C. elegans. This 3′UTR shows the intriguing feature of being differentially regulated across the animal's left/right axis. In the left gustatory neuron, ASEL, in which DIE-1 protein is normally expressed in adult animals, the 3′UTR confers no regulatory information, while in the right gustatory neuron, ASER, where DIE-1 is normally not expressed, this 3′UTR confers negative regulatory information. Here, we systematically analyze the cis-regulatory architecture of the die-1 3′UTR using a transgenic, in vivo assay system. Through extensive mutagenesis and sequence insertions into heterologous 3′UTR contexts, we describe three 25-base-pair (bp) sequence elements that are both required and sufficient to mediate the ASER-specific down-regulation of the die-1 3′UTR. These three 25-bp sequence elements operate in both a redundant and combinatorial manner. Moreover, there are not only redundant elements within the die-1 3′UTR regulating its left/right asymmetric activity but asymmetric 3′UTR regulation is itself redundant with other regulatory mechanisms to achieve asymmetric DIE-1 protein expression and function in ASEL versus ASER. The features of 3′UTR regulation we describe here may apply to some of the vast number of genes in animal genomes whose expression is predicted to be regulated through their 3′UTR.
When Promotions Meet Operations: Cross-Selling and Its Effect on Call Center Performance
Authors: Armony Mor , Gurvich Itai
Published: December 2009

We study cross-selling operations in call centers. The following questions are addressed: How many customer-service representatives are required (staffing), and when should cross-selling opportunities be exercised (control) in a way that will maximize the expected profit of the center while maintaining a prespecified service level target? We tackle these questions by characterizing control and staffing schemes that are asymptotically optimal in the limit, as the system load grows large. Our main finding is that a threshold priority control, in which cross-selling is exercised only if the number of callers in the system is below a certain threshold, is asymptotically optimal in great generality. The asymptotic optimality of threshold priority reduces the staffing problem to a solution of a simple deterministic problem in one regime and to a simple search procedure in another. We show that our joint staffing and control scheme is nearly optimal for large systems. Furthermore, it performs extremely well, even for relatively small systems.
Exploiting Market Size in Service Systems
Authors: Kumar Sunil , Randhawa Ramandeep S.
Published: December 2009

We study a profit-maximizing firm providing a service to price and delay sensitive customers. We are interested in analyzing the scale economies inherent in such a system. In particular, we study how the firm's pricing and capacity decisions change as the scale, measured by the potential market for the service, increases. These decisions turn out to depend intricately on the form of the delay costs seen by the customers; we characterize these decisions up to the dominant order in the scale for both convex and concave delay costs. We show that when serving customers on a first-come, first-served basis, if the customers' delay costs are strictly convex, the firm can increase its utilization and extract profits beyond what it can do when customers' delay costs are linear. However, with concave delay costs, the firm is forced to decrease its utilization and makes less profit than in the linear case. While studying concave delay costs, we demonstrate that these decisions depend on the scheduling policy employed as well. We show that employing the last-come, first-served rule in the concave case results in utilization and profit similar to the linear case, regardless of the actual form of the delay costs.
Feasting on Leftovers: Strategic Use of Shortages in Price Competition Among Differentiated Products
Authors: Porteus Evan L. , Shin Hyoduk , Tunca Tunay I.
Published: December 2009

Two single-product firms with different quality levels and fixed limited capacities engage in sequential price competition in an essentially deterministic model where customers have heterogeneous valuations for both products. We develop conditions under which the leader (she) can take strategic advantage of her limited capacity by pricing relatively low, purposefully creating shortages and leaving some leftovers for the follower (him) to feast on, avoiding direct competition. The extent to which the leader benefits in this Leftovers Equilibrium depends on operational variables such as the capacity levels of the two firms and the sequence in which customers arrive at the market. We spell out the details for three different known arrival sequences within a specific subset of plausible fixed-capacity levels. The follower's strategic shadow price can be positive even when not all his capacity is used, and the leader's can be negative when all her capacity is used. We illustrate that Leftovers Equilibria can arise when some of our assumptions are relaxed.
On the Impact of Forward Markets on Investments in Oligopolistic Markets with Reference to Electricity
Authors: Murphy Frederic , Smeers Yves
Published: December 2009

Allaz and Vila made the seminal contribution that forward contracts mitigate market power on the spot market. This result is widely quoted and elaborated in studies of restructured power markets, where generators can potentially exploit the special characteristics of this industry in order to extract higher prices. Allaz-Vila established their result under the assumption that the production capacities of the players are infinite. We show that the Allaz-Vila result does not hold when capacities are endogenous and constraining generation. Specifically, a forward market can enhance or mitigate market power when capacities are endogenous and demand is unknown at the time of investment. We also show that forward markets do not mitigate market power when capacities are endogenous and demand is known at the time of investment. Our results complement other work that shows that forward markets systematically enhance market power in some symmetric capacity-constrained markets.
Impact of a Pharmaceutical Care Intervention on Blood Pressure Control in a Chain Pharmacy Practice
Authors: Robinson J Daniel , Segal Richard , Lopez Larry M , Doty Randell E
Published: December 2009

BACKGROUND

Hypertension affects over 50 million Americans, with only 50% of patients being adequately controlled. Several pharmacist counseling and pharmacist-physician comanagement studies have documented that community pharmacist interventions improve blood pressure (BP) management.

OBJECTIVE

To determine whether community pharmacists can improve clinical endpoints including hypertension control, drug therapy dosing, adherence to prescribed regimens, adverse drug reaction incidence, patient understanding, response to therapy, and quality-of-life.

METHODS

The program included the education and training of a group of 18 chain community pharmacists in hypertension therapies, monitoring, and management. Protocols and documentation tools were based on nationally accepted clinical practice guidelines for hypertension in place at the time of the study. Pharmaceutical care (PC) was then compared with usual care (UC) over a 12-month period.

RESULTS

The study initially enrolled 180 PC and 196 UC patients, with 44% (PC) and 32% (UC) of the patients reporting a final BP measurement. A larger proportion (50%) of PC patients who had poorly controlled hypertension at baseline (>140/90 mm Hg) were controlled compared with UC patients (22%). The average reduction in systolic BP was 9.9 mm Hg in PC patients compared with 2.8 mm Hg in UC patients (p < 0.05). Changes in diastolic BP were similar in the PC and UC groups. Based on patient self-report, PC patients were more likely to say that they take their medicines as prescribed compared with UC patients (p < 0.05). The 1- to 6-month antihypertensive adherence rate was higher in PC patients (0.91 ± 0.15) compared to UC patients (0.78 ± 0.30) (p = 0.02); there was no significant difference in adherence rate during the 7- to 12-month period.

CONCLUSIONS

Community pharmacists can positively affect patient medication adherence during the 6-month period following counseling by a pharmacist along with an improvement in patient BP. However, there is much room for improvement in PC programs and in the number of patients who properly adhere to their medications.
Lofexidine, an α2-Receptor Agonist for Opioid Detoxification
Authors: Gish Emily C , Miller Jamie L , Honey Brooke L , Johnson Peter N
Published: December 2009

Objective:

To review the pharmacology, toxicology, pharmacokinetics, efficacy, adverse effects, drug interactions, and dosage guidelines for lofexidine, an α2-agonist, for opioid detoxification.

Data Sources:

Primary literature was identified through a MEDLINE search (1950–September 2009), EMBASE (1988–Juty 2009), International Pharmaceutical Abstracts (1970–September 2009), and the Cochrane Library (1996–September 2009) using the key words lofexidine and opioid withdrawal. Abstracts were included in the absence of published results of studies.

Study Selection and Data Extraction:

Studies published in English-language literature reporting on animal and human pharmacology, toxicology, and pharmacokinetics were included in addition to clinical trials using lofexidine for opioid detoxification in comparison to placebo or active controls.

Data Synthesis:

Lofexidine is an α2-agonist structurally related to clonidine. It is not an effective antihypertensive agent; however, it decreases the sympathetic outflow responsible for many opioid withdrawal symptoms. Nine clinical studies were reviewed representing 354 patients receiving lofexidine including a recent Phase 3 clinical trial. Eight studies involved comparisons of lofexidine to an opioid receptor agonist or clonidine for opioid detoxification. In these trials, lofexidine dosing was titrated to a maximum of 1.6–3.2 mg/day in divided doses for a total of 5–18 days. The data suggest that lofexidine has positive efficacy in reducing opioid withdrawal symptoms and is at least as effective as the opioid receptor agonists utilized for detoxification. Not all withdrawal symptoms are alleviated by α2-agonists, with many patients complaining of insomnia and aching. The most common adverse event with lofexidine in the Phase 3 trial was insomnia. Hypotension was also reported; however, the studies comparing clonidine with lofexidine suggest decreased incidence and severity of adverse events with lofexidine.

Conclusions:

Lofexidine appears to be a promising agent for opioid detoxification. If approved, it would be the first nonopioid agent approved for this indication. Further large-scale controlled studies are needed to identify the safest, most effective dosage regimen required to achieve opioid detoxification.
Raltegravir-Based HAART Regimen in a Patient with Large B-Cell Lymphoma
Authors: Fulco Patricia Pecora , Hynicka Lauren , Rackley Dwight
Published: December 2009

Objective:

To describe the antiretroviral management of a patient diagnosed simultaneously with HIV/AIDS and diffuse large B-cell lymphoma, focusing on the drug-drug interactions between highly active antiretroviral therapy (HAART) and concomitant cancer chemotherapy.

Case Summary:

A 55-year-old white man was recently diagnosed with HIV/AIDS and presented 1 month later with complaints of nausea, vomiting, abdominal pain, double vision, right eye discomfort/swelling, and a 3.6-kg weight loss. An excisional biopsy of a right inguinal lymph node confirmed a new diagnosis of diffuse large B-cell lymphoma. HAART and a chemotherapeutic regimen, including cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) with intrathecal methotrexate, was to be initiated. As the potential for multiple drug-drug interactions existed, raltegravir, abacavir, and lamivudine were chosen for the initial HAART regimen. The patient achieved and maintained an undetectable viral load throughout 6 CHOP cycles.

Discussion:

HAART improves the chemotherapeutic response in patients with HIV and lymphoma. Multiple drug-drug interactions are possible in patients who are to receive CHOP and HAART. Cyclophosphamide and vincristine are metabolized via the CYP3A4 isoenzyme. Protease inhibitors (Pls) and nonnucleoside reverse transcriptase inhibitors both inhibit and induce CYP3A4, with the potential for altered chemotherapeutic and cytotoxic effects. When Pls are combined with CHOP, mortality is reduced, but increased adverse effects are demonstrated. Raltegravir, an integrase inhibitor, is eliminated via glucuronidation and results in minimal drug-drug interactions. Raltegravir improves virologic and immunologic responses in HAART-naïve patients and thus would be a suitable alternative for preventing chemotherapeutic-HAART interactions.

Conclusions:

There is limited information published regarding the potential for interactions between HAART and cancer chemotherapy. While further research is necessary, it is important for clinicians to consider the potential for drug-drug interactions when designing a HAART regimen concurrently with chemotherapy. KEY WORDS: abacavir, antiretroviral therapy, CYP3A4, diffuse large B-cell lymphoma, drug interactions, highly active antiretroviral therapy, integrase inhibitor, lamivudine, nonnucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors, protease inhibitors, raltegravir, tumor lysis syndrome.
Structuralism and Kabbalah: Sciences of Mysticism or Mystifications of Science?
Authors: Levi Jerome M.
Published: December 2009

This paper argues that Kabbalah, the generic term for Jewish mysticism, and structuralism, as articulated in anthropology by Claude Lévi-Strauss, share a number of unexpected theoretical foundations. These include the idea that surface diversity conceals underlying unity, truth is hidden within a layered model of reality, and linguistic and mathematical relationships constitute elementary structures enabling diverse and seemingly unconnected orders to be correlated with each other systematically. Yet if Kabbalah and structuralism are so similar, does this imply that Kabbalah is scientific or, as David Maybury-Lewis suggests, that structuralism is akin to mysticism?
Manipulating Cartographies: Plurinationalism, Autonomy, and Indigenous Resurgence in Bolivia
Authors: Gustafson Bret
Published: December 2009

Latin American indigenous movements increasingly speak of “plurinationalism” in demands for state transformation. The concept—as yet solidified in legal or territorial orders—exists in tension with disputed meanings of “autonomy,” raising questions about indigenous territorial rights, citizenship, and natural resources. Bolivia’s new constitution elevates both concepts to official status in the context of struggles over natural gas. Following David Maybury-Lewis’s call for rethinking the state, I consider how Bolivians are rethinking historicities of space to transform cartographies of a “plurinational state.” Though raising fears of ethnic partitioning, the Guaraní case suggests that hybrid plural and indigenous territorialities are emergent.
Indigenous Dialectics at Garage Sales and in Traditional Tales
Authors: Fast Phyllis A.
Published: December 2009

Scholars of indigenous peoples have searched for inherent patterns of cultural behavior that have survived globalization. This study explores the underpinning dynamics of garage sales and doing garage sailing that may be reflected in traditional northern Athabascan narratives. Patterns of plot, humor, and acceptable character behavior mask competitive actions in the guise of sharing resources, nullifying status, and reinforcing notions of metaphysical powers. Likewise, garage sales, symbolic of poverty-level shopping, epitomize the unequal relationships between the rich and the poor, and have become yet another idiom for the multiple hegemonies endured or fantasized by indigenous peoples.
Death ante ora parentum in Virgil's Aeneid
Authors: O'Sullivan Timothy M.
Published: December 2009

Virgil's Aeneid includes a number of scenes in which children die in front of their parents. While the motif has a Homeric precedent, Virgil's invention of a formula ( ante ora parentum : "before the faces of one's parents") suggests a particular interest in the theme. An analysis of scenes where the formula recurs (such as Aeneas's shipwreck, the fall of Troy, and the lusus Troiae ) reveals a metapoetic resonance behind the motif, with the parent-child relationship acting as a metaphor for authorial influence and artistic creation. Thus the threat that Aeneas might die as Anchises looks on, for instance, evokes Virgil's own precarious position in relation to his "father," Homer. Aeneas's well-known transition into a father-figure as the poem progresses comes with the risk that he may become the parent who sees his own child die; Virgil exploits this transition, too, as a vehicle for self-reflection, concerned about the reception of his "child," the Aeneid, in the Augustan age.
Proving Power: Signs and Sign-inference in Thucydides' Archaeology
Authors: Reynolds Joshua J.
Published: December 2009

Contrary to a common view, Thucydides' remarks about signs (σημεῖα; τεκμήρια) in the Archaeology are part of a coherent methodology. To see this, a distinction should be drawn between signs that serve as probable evidence for descriptions of past deeds, and signs that serve as an infallible standard for evaluating deeds. In response to the tradition of archaic pessimism, which emphasizes the fallibility of signs, Thucydides takes his evaluative inferences to be infallible because the signs that support them are the conditions sufficient to create power and greatness. Thucydides' optimism, however, is qualified, as the History in general shows that a guarantee of power and greatness is not a guarantee of success.
A Wolf at the Table: Sympotic Perjury in Archilochus
Authors: Gagné Renaud
Published: December 2009

The epode of the eagle and the fox (Archilochus 172-181W) stages a rich and multifaceted play of reflections between the biographical narrative of the poet's persona and the oblique meanings of an ainos . It frames in this context the central event that motivates the murderous verse attacks launched by Archilochus against Lycambes and his daughters: the breaking of an oath. By investigating the theme of perjury in this poem, this paper proposes to cast new light on the imagery and the structure of the text, as well as on its performative and social significance.
Magnesian Inviolability
Authors: Sosin Joshua D.
Published: December 2009

In 221/20 the citizens of Magnesia on the Maeander sought to create crowned games in honor of Artemis Leukophryene. The goddess had appeared to them and Delphi instructed that "it is more agreeable and better for those who revere Apollo Pythios and Artemis Leukophryene and treat the city and territory of the Magnesians on the Maeander as sacred and inviolable." But why it took Magnesia more than a decade to secure asylia and inaugurate the enhanced games has remained a puzzle. It has been thought since Kern (1901) that the Magnesians first attempted to win acceptance of inviolability and the games in 221/20, that their invitations were almost universally snubbed, and that the city did not succeed in securing international recognition until 208/7. This paper argues that there was no failed campaign of invitations in 221, that Magnesia did not canvass the Greek world until 208/7.