bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase III Randomized Trial Comparing the Efficacy of Cediranib As Monotherapy, and in Combination With Lomustine, Versus Lomustine Alone in Patients With Recurrent Glioblastoma
Authors: Batchelor Tracy T. , Mulholland Paul , Neyns Bart , Nabors L. Burt , Campone Mario , Wick Antje , Mason Warren , Mikkelsen Tom , Phuphanich Surasak , Ashby Lynn S. , DeGroot John , Gattamaneni Rao , Cher Lawrence , Rosenthal Mark , Payer Franz , Jürgensmeier Juliane M. , Jain Rakesh K. , Sorensen A. Gregory , Xu John , Liu Qi , van den Bent Martin
Published: August 2013

Purpose

A randomized, phase III, placebo-controlled, partially blinded clinical trial (REGAL [Recentin in Glioblastoma Alone and With Lomustine]) was conducted to determine the efficacy of cediranib, an oral pan–vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, either as monotherapy or in combination with lomustine versus lomustine in patients with recurrent glioblastoma.

Patients and Methods

Patients (N = 325) with recurrent glioblastoma who previously received radiation and temozolomide were randomly assigned 2:2:1 to receive (1) cediranib (30 mg) monotherapy; (2) cediranib (20 mg) plus lomustine (110 mg/m2); (3) lomustine (110 mg/m2) plus a placebo. The primary end point was progression-free survival based on blinded, independent radiographic assessment of postcontrast T1-weighted and noncontrast T2-weighted magnetic resonance imaging (MRI) brain scans.

Results

The primary end point of progression-free survival (PFS) was not significantly different for either cediranib alone (hazard ratio [HR] = 1.05; 95% CI, 0.74 to 1.50; two-sided P = .90) or cediranib in combination with lomustine (HR = 0.76; 95% CI, 0.53 to 1.08; two-sided P = .16) versus lomustine based on independent or local review of postcontrast T1-weighted MRI.

Conclusion

This study did not meet its primary end point of PFS prolongation with cediranib either as monotherapy or in combination with lomustine versus lomustine in patients with recurrent glioblastoma, although cediranib showed evidence of clinical activity on some secondary end points including time to deterioration in neurologic status and corticosteroid-sparing effects.
Optimization of Chemotherapy for Younger Patients With Acute Myeloid Leukemia: Results of the Medical Research Council AML15 Trial
Authors: Burnett Alan K. , Russell Nigel H. , Hills Robert K. , Hunter Ann E. , Kjeldsen Lars , Yin John , Gibson Brenda E.S. , Wheatley Keith , Milligan Donald
Published: August 2013

Purpose

Treatment outcomes in younger patients with acute myeloid leukemia (AML) have improved, but optimization and new combinations are needed. We assess three combinations in induction and consolidation.

Patients and Methods

Younger untreated patients with AML (median age, 49 years; range, 0 to 73 years) were randomly allocated to two induction courses of daunorubicin and cytarabine (DA) with or without etoposide (ADE; n = 1983) or ADE versus fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-Ida; n = 1268), and to amsacrine, cytarabine, etoposide, and then mitoxantrone/cytarabine (MACE-MidAC) or high-dose cytarabine (n = 1,445) 3 g/m2 or 1.5 g/m2 (n = 657) in consolidation, and finally to a fifth course (cytarabine) or not (n = 227).

Results

Overall remission rates were similar for DA versus ADE (84% v 86%; P = .14) and ADE versus FLAG-Ida (86% v 85%; P = .7), with more course 1 remissions after FLAG-Ida (77%) reducing relapse (38% v 55%; P < .001) and improving relapse-free survival (45% v 34%; P = .01), overall and in subgroups, but with increased myelosuppression, reducing participation in the consolidation randomization. Overall outcomes were similar between MACE/MidAc and high-dose cytarabine (1.5/3.0 g/m2), but cytarabine required less supportive care. MACE/MidAc was superior for high-risk patients. A fifth course provided no benefit. The outcome for recipients of only two FLAG-Ida courses were not different from that with DA/ADE with consolidation.

Conclusion

FLAG-Ida is an effective remission induction treatment, with a high complete remission rate after course 1 and reduced relapse. Consolidation with MACE/MidAc is similar overall to high-dose cytarabine, but superior in high-risk patients. Cytarabine at 1.5 g/m2 is equivalent to a 3 g/m2 dose. A fifth course is unnecessary. In patients receiving FLAG-Ida (two courses) and cytarabine (two courses), 8-year survival was 63% for patients with intermediate-risk and 95% for those with favorable-risk disease.
Diagnosis and Treatment of KIT-Mutant Metastatic Melanoma
Authors: Lyle Megan , Long Georgina V.
Published: August 2013

A 52-year-old man has unresectable locally recurrent melanoma of the left foot ( Fig 1 ) and pulmonary metastases. Nine months before this presentation, he underwent a wide local excision and sentinel node biopsy for an acral melanoma on his left heel. Pathology disclosed Breslow thickness of 4.8 mm, Clark level IV, and tumor ulceration with a mitotic rate of 37 mitoses/mm2. Both sentinel nodes in the left groin were positive for melanoma cells, which expressed S100, HMB45, and melan A. At subsequent left inguinal dissection, seven more nodes showed no additional nodal metastases. Within 3 months of his original surgery, the patient developed a local recurrence in the foot, and over the subsequent 6 months, he underwent serial local excisions and topical diphencyprone treatment. A recent staging scan showed at least 20 foci of in-transit disease in the left lower leg and foot, as well as a solitary lung metastasis (12 mm). His Eastern Cooperative Oncology Group performance status is 1, with no significant comorbidities. High-resolution melt followed by sequencing of an in-transit metastasis showed there is no BRAF exon 15 mutation. However, Sanger sequencing of KIT exons 9, 11, 13, and 17, performed as screening for a clinical trial enrolling patients with metastatic acral and mucosal melanomas, showed an exon 13 K642E mutation.
CAF-1 promotes Notch signaling through epigenetic control of target gene expression during Drosophila development
Authors: Yu Zhongsheng , Wu Honggang , Chen Hanqing , Wang Ruoqi , Liang Xuehong , Liu Jiyong , Li Changqing , Deng Wu-Min , Jiao Renjie
Published: August 2013

The histone chaperone CAF-1 is known for its role in DNA replication-coupled histone deposition. However, loss of function causes lethality only in higher multicellular organisms such as mice and flies, but not in unicellular organisms such as yeasts, suggesting that CAF-1 has other important functions than histone deposition during animal development. Emerging evidence indicates that CAF-1 also has a role in higher order chromatin organization and heterochromatin-mediated gene expression; it remains unclear whether CAF-1 has a role in specific signaling cascades to promote gene expression during development. Here, we report that knockdown of one of the subunits of Drosophila CAF-1, dCAF-1-p105 (Caf1-105), results in phenotypes that resemble those of, and are augmented synergistically by, mutations of Notch positive regulatory pathway components. Depletion of dCAF-1-p105 leads to abrogation of cut expression and to downregulation of other Notch target genes in wing imaginal discs. dCAF-1-p105 is associated with Suppressor of Hairless [Su(H)] and regulates its binding to the enhancer region of E(spl)mβ. The association of dCAF-1-p105 with Su(H) on chromatin establishes an active local chromatin status for transcription by maintaining a high level of histone H4 acetylation. In response to induced Notch activation, dCAF-1 associates with the Notch intracellular domain to activate the expression of Notch target genes in cultured S2 cells, manifesting the role of dCAF-1 in Notch signaling. Together, our results reveal a novel epigenetic function of dCAF-1 in promoting Notch pathway activity that regulates normal Drosophila development.
Characterization of known protein complexes using k-connectivity and other topological measures
Authors: Gallagher Suzanne R , Goldberg Debra S
Published: August 2013

Many protein complexes are densely packed, so proteins within complexes often interact with several other proteins in the complex. Steric constraints prevent most proteins from simultaneously binding more than a handful of other proteins, regardless of the number of proteins in the complex. Because of this, as complex size increases, several measures of the complex decrease within protein-protein interaction networks. However,k-connectivity, the number of vertices or edges that need to be removed in order to disconnect a graph, may be consistently high for protein complexes. The property ofk-connectivity has been little used previously in the investigation of protein-protein interactions. To understand the discriminative power ofk-connectivity and other topological measures for identifying unknown protein complexes, we characterized these properties in knownSaccharomyces cerevisiaeprotein complexes in networks generated both from highly accurate X-ray crystallography experiments which give an accurate model of each complex, and also as the complexes appear in high-throughput yeast 2-hybrid studies in which new complexes may be discovered. We also computed these properties for appropriate random subgraphs. We found that clustering coefficient, mutual clustering coefficient, and k-connectivity are better indicators of known protein complexes than edge density, degree, or betweenness. This suggests new directions for future protein complex-finding algorithms.
The interferential mistakes as problem of communication and possible ways to solve them in teaching Russian language as
Authors: Янченко  , Yanchenko Vladislav
Published: August 2013

The article describes the concept of interference and its manifestation in communication practice as well as the role of the phenomenon in teaching foreign students. The author analyses the causes and types of interference errors and offers exercises aimed at preventing such mistakes. The author further stresses the need of a large number of communicative exercises that help foreign students to achieve mastery in Russian.
Three-flow Vortex Tubes — Ecologically Significant Alternative to Burning of Oil-associated Gas on Torches
Authors: Гусев  , Gusev A. , Жидков  , Zhidkov Dmitriy , Жидков  , Zhidkov M. , Девисилов  , Devisilov Vladimir , Рябов  , Ryabov A.
Published: August 2013

The practical aspects related to application of three-flow vortex pipes in the systems of low-temperature separation of associated petroleum gas before its giving in the main pipelines are considered in this paper. The conclusion is drawn that due to the use of these pipes the extinguishing of field torches is becoming rather profitable, improving thereby the ecological situation while developing of oil fields.
Studying the Effect of Salicylic and Paraaminobenzoyny Acids on Biological Sewage Treatment of Organic Synthesis Production
Authors: Пантюкова  , Pantyukova M.
Published: August 2013

The influence of salicylic and paraaminobenzoyny acids on active silt microorganisms’ vital functions has been investigated. The value of oxygen’s chemical consumption being the integrated indicator of water bodies’ condition was chosen as indicator of these

acids’ efficacy on active silt biocenosis. It has been established that these acids don´t provide the active silt stimulation.
Conspicuous Consumption and Dynamic Pricing
Authors: Rao Raghunath Singh , Schaefer Richard
Published: August 2013

How do firms develop marketing strategy when consumers seek to satisfy both quality and status-related considerations? We develop an analytical model to study this issue, examining both pricing and product management decisions in markets for conspicuous durable goods. Our analysis yields many interesting and nontrivial insights. First, we demonstrate that high intrinsic quality indirectly generates exclusivity via pricing effects; in turn, this exclusivity generates considerable social payoffs where consumers value status. This insight reverses the direction of causality in the existing literature, wherein only status considerations matter and mere price increases may enhance consumer utility. Second, our dynamic model indicates that where consumers prioritize status benefits, producers incur substantial price depreciation in equilibrium. Third, we examine the product management strategies used by firms to preserve early adopter exclusivity. Finally, we discuss the boundary conditions of our results as well as our results' implications for managerial and policy issues.
On the Value of Input Efficiency, Capacity Efficiency, and the Flexibility to Rebalance Them
Authors: Plambeck Erica L. , Taylor Terry A.
Published: August 2013

A common characteristic of basic material manufacturers (which account for 85% of all industrial energy use) and of cleantech manufacturers is that they are price takers in their input and output markets. Variability in those prices has implications for how much a manufacturer should invest in three fundamental types of process improvement. Input price variability reduces the value of improving input efficiency (output produced per unit input) but increases that of capacity efficiency (the rate at which a production facility can convert input into output). Output price variability increases the value of capacity efficiency, but it increases the value of input efficiency if and only if the expected margin is small. Moreover, as the expected input cost rises, the value of input efficiency decreases. A third type of process improvement is to develop flexibility in input efficiency versus capacity efficiency (the ability to respond to a rise in input cost or fall in output price by increasing input-efficiency at the expense of capacity efficiency). The value of this flexibility decreases with variability in input and output prices if and only if the expected margin is thin. Together, these results suggest that a carbon tax or cap-and-trade system may reduce investment by basic material manufacturers in improving energy efficiency.
OM Forum—Business Model Innovation for Sustainability
Authors: Girotra Karan , Netessine Serguei
Published: August 2013

A systematic approach to innovating business models can help identify new business models that encourage sustainable use of products and services, or facilitate wider adoption of new environmentally friendly technologies. This paper provides a brief summary of a conceptual framework that we have developed to systematize the study and identification of new business models. Our approach advocates that the key to identifying new business models is understanding the context of decision making in existing models and the associated inefficiencies. We propose a three-step approach: First, existing business models must be audited for identifying information and incentive misalignment inefficiencies that destroy value. Next, new business models can be identified by changing the context of the decision associated with the most consequential of these inefficiencies. We conjecture that four elements of the decision context are most significant: WHAT decisions are made, WHEN they are made, WHO makes them, and WHY they are made. We provide a set of idea triggers to stimulate brainstorming of new business models by changing one of these four Ws. Finally, we advise that generated business models should be analyzed and experimented with to identify the most promising ones. We close the paper by describing the design of a pedagogical program based on this framework.
Current Methods for Fluorescence-Based Universal Sequence-Dependent Detection of Nucleic Acids in Homogenous Assays and Clinical Applications
Authors: Faltin Bernd , Zengerle Roland , von Stetten Felix
Published: August 2013

BACKGROUND

Specific and sensitive nucleic acid (NA) testing in research and clinical diagnostics is usually performed by use of labeled oligonucleotide probes. However, the use of target-specific fluorogenic probes increases the cost of analysis. Therefore, universal sequence-dependent (USD) NA detection methods have been developed to facilitate cost-effective target detection using standardized reagents.

CONTENT

We provide a comprehensive review of the current methods for fluorescence-based USD NA detection. Initially, we focus on the emergence of these methods as a means to overcome the shortcomings of common NA detection methods, such as hydrolysis probes and molecular beacons. Thereafter, we provide a critical evaluation of the individual detection methods. These methods include (a) target amplification with bipartite primers introducing a universal detection tag to the amplicon (UniPrimer PCR, universal fluorescence energy transfer probe PCR, attached universal duplex probe PCR, and universal strand displacement amplification) or combined with bipartite probes comprising a universal detection region (mediator probe PCR, universal strand displacement amplification, universal quenching probe PCR) and (b) amplification-independent assays employing either a universal variant of the invader assay or universal NA hybridization sensors. We discuss differences between the methods and review clinical applications.

The current methods for USD NA testing are cost-effective and flexible and have concordant analytical performance in comparison with common probe-based techniques. They can detect any target sequence by the simple use of a label-free, low-cost primer or probe combined with a universal fluorogenic reporter. The methods differ in the number of target specificities, capability of multiplexing, and incubation requirements (isothermal/thermocycling). Extensive clinical applications comprise detection of single-nucleotide polymorphisms, study of gene expression, in situ PCR, and quantification of pathogen load.
Polymorphisms of TCF7L2 gene in South Brazilian women with polycystic ovary syndrome: a cross-sectional study
Authors: Ramos Ramon Bossardi , Wiltgen Denusa , Spritzer Poli Mara
Published: August 2013

Objective

To assess whetherTCF7L2single nucleotide polymorphisms rs7903146 C/T and rs11196236 C/T are associated with polycystic ovary syndrome (PCOS) in South Brazilian women.

Design

Cross-sectional study.

Methods

Two hundred PCOS patients and 102 non-hirsute, ovulatory controls were genotyped by real-time PCR. Haplotypes were constructed from the combination of both polymorphisms. Frequencies were inferred using the PHASE 2.1.1 software.

Results and conclusions

The distribution of rs7903146 (PCOS, 54.4% CC; 28.5% CT; 17.1% TT; controls, 51.0% CC; 37.0% CT; 12.0% TT) and rs11196236 (PCOS, 4.3% CC; 33.5% CT; 62.2% TT; controls, 3.2% CC; 35.5% CT; 61.3% TT) was similar between the groups. rs7903146 and rs11196236 were not in linkage disequilibrium (|D′|=0.34;r2=0.07). PCOS participants were younger, with higher age-adjusted BMI, waist circumference, blood pressure, triglycerides, insulin, homeostasis model assessment index to estimate insulin resistance and total testosterone, and lower HDL-C and sex hormone binding globulin vs controls. In PCOS, no differences between genotypes and haplotypes were found for clinical and metabolic variables. However, for each T (rs7903146) and T (rs11196236) allele added to the haplotypes, a variation of 5.87 cm in waist (Ptrend=0.01), 10.7 mg/dl in total cholesterol (Ptrend=0.03), and 10.3 mg/dl in LDL-C (Ptrend=0.01) was recorded.TCF7L2variants are probably not implicated in PCOS development in South Brazilian women.
Elevated hepatic chemerin mRNA expression in human non-alcoholic fatty liver disease
Authors: Döcke S , Lock J F , Birkenfeld A L , Hoppe S , Lieske S , Rieger A , Raschzok N , Sauer I M , Florian S , Osterhoff M A , Heller R , Herrmann K , Lindenmüller S , Horn P , Bauer M , Weickert M O , Neuhaus P , Stockmann M , Möhlig M , Pfeiffer A F H , von Loeffelholz C
Published: August 2013

Objective

Adipose tissue-derived factors link non-alcoholic fatty liver disease (NAFLD) with obesity, which has also been reported for circulating chemerin. On the other hand, hepatic chemerin and chemokine-like receptor 1 (CMKLR1) mRNA expression has not yet been studied in an extensively characterized patient collective.

Design

This study was cross-sectional and experimental in design.

Methods

Liver tissue samples were harvested from 47 subjects and histologically examined according to the NAFLD activity score (NAS). The concentrations of chemerin and CMKLR1 were measured using semi-quantitative real-time PCR, and the concentration of serum chemerin was measured using ELISA. To evaluate potential effects of chemerin and CMKLR1, cultured primary human hepatocytes (PHHs) were exposed to selected metabolites known to play a role in NAFLD (insulin, glucagon, palmitoic acid, and interleukin-6 (IL6)).

Results

Chemerin andCMKLR1mRNA levels were elevated in the human liver. Their expression was correlated with the NAS (R2=0.543;P<0.001 andR2=0.355;P=0.014 respectively) and was significantly elevated in patients with definite non-alcoholic steatohepatitis (NASH) (P<0.05 respectively). Linear regression analysis confirmed an independent association of liver fibrosis, steatosis, inflammation, and hepatocyte ballooning with hepatic chemerin mRNA expression (P<0.05 respectively). The expression of hepatic chemerin and CMKLR1 was correlated with the measures of obesity (P<0.05). The incubation of PHHs with IL6 significantly increased the expression ofCMKLR1mRNA (P=0.027), while that of chemerin remained unaffected (P>0.05). None of the other metabolites showed an influence (P>0.05).

Conclusion

This is the first study to show that chemerin mRNA expression is significantly elevated in the liver of NASH patients and that CMKLR1 expression is upregulated in liver inflammation, whereby IL6 could play a causal role.
Determinants of serum T4 and T3 at the time of diagnosis in nosological types of thyrotoxicosis: a population-based study
Authors: Carlé Allan , Knudsen Nils , Pedersen Inge Bülow , Perrild Hans , Ovesen Lars , Rasmussen Lone Banke , Laurberg Peter
Published: August 2013

Objective

To characterize thyroid hormone levels at the time of diagnosis in the nosological types of thyrotoxicosis diagnosed in the population and to analyze determinants for serum thyroxine (T4) and tri-iodothyronine (T3).

Design

Population-based study of thyrotoxicosis at disease onset.

Methods

In the period 1997–2000, we prospectively identified all patients diagnosed with incident primary overt thyrotoxicosis in a Danish population cohort and classified patients into ten well-defined nosological types of disease (n=1082). Untreated levels of serum T3, T4, and T3:T4ratio were compared and related to sex, age, level of iodine deficiency, smoking status, alcohol intake, iodine supplement use, co-morbidity, and TSH receptor antibodies (TRAbs) in multivariate models.

Results

Graves' disease (GD) patients had much higher levels of T3and higher T3:T4ratio at diagnosis compared with other thyrotoxic patients, but with a profound negative association between hormone levels and age. In GD, patients diagnosed in the area with more severe iodine deficiency had lower levels of T3and T4. TRAb-negative GD patients had biochemically mild thyrotoxicosis. Higher age was also associated with lower degree of biochemical thyrotoxicosis in nodular toxic goiter. We found no association between serum T3and T4and sex, smoking habits, iodine supplements, alcohol intake, or co-morbidity in any type of thyrotoxicosis.

Conclusions

The study gives new insight into the hormonal presentation of thyrotoxicosis and showed that young age, positive TRAb levels, but also residency in the area with higher iodine intake was positively associated with biochemical disruption in GD.
Monocentric study of 112 consecutive patients with childhood onset GH deficiency around and after transition
Authors: Courtillot Carine , Baudoin Roselyne , Du Souich Tatiana , Saatdjian Lucile , Tejedor Isabelle , Pinto Graziella , Léger Juliane , Polak Michel , Golmard Jean-Louis , Touraine Philippe , _ _
Published: August 2013

Objectives

Our aim was to analyze a large cohort of childhood onset GH deficiency (CO-GHD) adults from a unique adult center, in order to analyze their clinical management and to study the metabolic and bone status in relation to GHD and to the other pituitary deficits, and to evaluate these parameters during the long-term follow-up.

Design and methods

Observational retrospective cohort study on 112 consecutive CO-GHD adults transferred to our unit from 1st January 1994 to 1st March 2012. Evaluation of GHD in pediatrics and after transition was conducted following consensus guidelines. Data recorded from pediatric and adult files were GH doses, pituitary magnetic resonance imaging and function, and metabolic and bone status.

Results

Most patients presented with severe CO-GHD (64%) associated with other pituitary deficits (66%). CO-GHD was acquired in 56%, congenital in 33%, and idiopathic in 11% cases. Most patients (83%) stopped GH before transfer, at 16.3 years (median), despite persistence of GHD. Median age at transfer was 19.4 years. After transfer, GHD persisted in 101 patients and four of the 11 resolutive GHD were non idiopathic. IGF1 level was <−2 SDS in 70% of treated patients at transfer and in 34% of them after 3 years of treatment. Follow-up showed improvement in lipid profile and bone mineral density in severely persistent GHD patients under GH therapy. In multivariate analysis, the associated pituitary deficits seemed stronger determinant factors of metabolic and bone status than GHD.

Conclusions

This study raises concern about discontinuation of GH replacement therapy in pediatrics in severely persistent GHD patients and about the often insufficient dose of GH in the treatment of adult patients.
Genome-Wide Prediction of Traits with Different Genetic Architecture Through Efficient Variable Selection
Authors: Wimmer Valentin , Lehermeier Christina , Albrecht Theresa , Auinger Hans-Jürgen , Wang Yu , Schön Chris-Carolin
Published: August 2013

In genome-based prediction there is considerable uncertainty about the statistical model and method required to maximize prediction accuracy. For traits influenced by a small number of quantitative trait loci (QTL), predictions are expected to benefit from methods performing variable selection [e.g., BayesB or the least absolute shrinkage and selection operator (LASSO)] compared to methods distributing effects across the genome [ridge regression best linear unbiased prediction (RR-BLUP)]. We investigate the assumptions underlying successful variable selection by combining computer simulations with large-scale experimental data sets from rice (Oryza sativa L.), wheat (Triticum aestivum L.), and Arabidopsis thaliana (L.). We demonstrate that variable selection can be successful when the number of phenotyped individuals is much larger than the number of causal mutations contributing to the trait. We show that the sample size required for efficient variable selection increases dramatically with decreasing trait heritabilities and increasing extent of linkage disequilibrium (LD). We contrast and discuss contradictory results from simulation and experimental studies with respect to superiority of variable selection methods over RR-BLUP. Our results demonstrate that due to long-range LD, medium heritabilities, and small sample sizes, superiority of variable selection methods cannot be expected in plant breeding populations even for traits like FRIGIDA gene expression in Arabidopsis and flowering time in rice, assumed to be influenced by a few major QTL. We extend our conclusions to the analysis of whole-genome sequence data and infer upper bounds for the number of causal mutations which can be identified by LASSO. Our results have major impact on the choice of statistical method needed to make credible inferences about genetic architecture and prediction accuracy of complex traits.
Architectural and Functional Diversity of Polycomb Group Response Elements in Drosophila
Authors: Brown J Lesley , Kassis Judith A
Published: August 2013

Polycomb group response elements (PREs) play an essential role in gene regulation by the Polycomb group (PcG) repressor proteins in Drosophila. PREs are required for the recruitment and maintenance of repression by the PcG proteins. PREs are made up of binding sites for multiple DNA-binding proteins, but it is still unclear what combination(s) of binding sites is required for PRE activity. Here we compare the binding sites and activities of two closely linked yet separable PREs of the Drosophila engrailed (en) gene, PRE1 and PRE2. Both PRE1 and PRE2 contain binding sites for multiple PRE–DNA-binding proteins, but the number, arrangement, and spacing of the sites differs between the two PREs. These differences have functional consequences. Both PRE1 and PRE2 mediate pairing-sensitive silencing of mini-white, a functional assay for PcG repression; however, PRE1 requires two binding sites for Pleiohomeotic (Pho), whereas PRE2 requires only one Pho-binding site for this activity. Furthermore, for full pairing-sensitive silencing activity, PRE1 requires an AT-rich region not found in PRE2. These two PREs behave differently in a PRE embryonic and larval reporter construct inserted at an identical location in the genome. Our data illustrate the diversity of architecture and function of PREs.
Accumulation of Spontaneous Mutations in the CiliateTetrahymena thermophila
Authors: Long Hong-An , Paixão Tiago , Azevedo Ricardo B R , Zufall Rebecca A
Published: August 2013

Knowledge of the rate and fitness effects of mutations is essential for understanding the process of evolution. Mutations are inherently difficult to study because they are rare and are frequently eliminated by natural selection. In the ciliate Tetrahymena thermophila, mutations can accumulate in the germline genome without being exposed to selection. We have conducted a mutation accumulation (MA) experiment in this species. Assuming that all mutations are deleterious and have the same effect, we estimate that the deleterious mutation rate per haploid germline genome per generation is U = 0.0047 (95% credible interval: 0.0015, 0.0125), and that germline mutations decrease fitness by s = 11% when expressed in a homozygous state (95% CI: 4.4%, 27%). We also estimate that deleterious mutations are partially recessive on average (h = 0.26; 95% CI: –0.022, 0.62) and that the rate of lethal mutations is <10% of the deleterious mutation rate. Comparisons between the observed evolutionary responses in the germline and somatic genomes and the results from individual-based simulations of MA suggest that the two genomes have similar mutational parameters. These are the first estimates of the deleterious mutation rate and fitness effects from the eukaryotic supergroup Chromalveolata and are within the range of those of other eukaryotes.
Imprints of Natural Selection Along Environmental Gradients in Phenology-Related Genes ofQuercus petraea
Authors: Alberto Florian J , Derory Jérémy , Boury Christophe , Frigerio Jean-Marc , Zimmermann Niklaus E , Kremer Antoine
Published: August 2013

We explored single nucleotide polymorphism (SNP) variation in candidate genes for bud burst from Quercus petraea populations sampled along gradients of latitude and altitude in Western Europe. SNP diversity was monitored for 106 candidate genes, in 758 individuals from 32 natural populations. We investigated whether SNP variation reflected the clinal pattern of bud burst observed in common garden experiments. We used different methods to detect imprints of natural selection (FST outlier, clinal variation at allelic frequencies, association tests) and compared the results obtained for the two gradients. FST outlier SNPs were found in 15 genes, 5 of which were common to both gradients. The type of selection differed between the two gradients (directional or balancing) for 3 of these 5. Clinal variations were observed for six SNPs, and one cline was conserved across both gradients. Association tests between the phenotypic or breeding values of trees and SNP genotypes identified 14 significant associations, involving 12 genes. The results of outlier detection on the basis of population differentiation or clinal variation were not very consistent with the results of association tests. The discrepancies between these approaches may reflect the different hierarchical levels of selection considered (inter- and intrapopulation selection). Finally, we obtained evidence for convergent selection (similar for gradients) and clinal variation for a few genes, suggesting that comparisons between parallel gradients could be used to screen for major candidate genes responding to natural selection in trees.
Empirical Complexities in the Genetic Foundations of Lethal Mutagenesis
Authors: Bull James J , Joyce Paul , Gladstone Eric , Molineux Ian J
Published: August 2013

From population genetics theory, elevating the mutation rate of a large population should progressively reduce average fitness. If the fitness decline is large enough, the population will go extinct in a process known as lethal mutagenesis. Lethal mutagenesis has been endorsed in the virology literature as a promising approach to viral treatment, and several in vitro studies have forced viral extinction with high doses of mutagenic drugs. Yet only one empirical study has tested the genetic models underlying lethal mutagenesis, and the theory failed on even a qualitative level. Here we provide a new level of analysis of lethal mutagenesis by developing and evaluating models specifically tailored to empirical systems that may be used to test the theory. We first quantify a bias in the estimation of a critical parameter and consider whether that bias underlies the previously observed lack of concordance between theory and experiment. We then consider a seemingly ideal protocol that avoids this bias—mutagenesis of virions—but find that it is hampered by other problems. Finally, results that reveal difficulties in the mere interpretation of mutations assayed from double-strand genomes are derived. Our analyses expose unanticipated complexities in testing the theory. Nevertheless, the previous failure of the theory to predict experimental outcomes appears to reside in evolutionary mechanisms neglected by the theory (e.g., beneficial mutations) rather than from a mismatch between the empirical setup and model assumptions. This interpretation raises the specter that naive attempts at lethal mutagenesis may augment adaptation rather than retard it.
Overcompensation in Response to Herbivory in Arabidopsis thaliana: The Role of Glucose-6-Phosphate Dehydrogenase and the Oxidative Pentose-Phosphate Pathway
Authors: Siddappaji Madhura H , Scholes Daniel R , Bohn Martin , Paige Ken N
Published: August 2013

That some plants benefit from being eaten is counterintuitive, yet there is now considerable evidence demonstrating enhanced fitness following herbivory (i.e., plants can overcompensate). Although there is evidence that genetic variation for compensation exists, little is known about the genetic mechanisms leading to enhanced growth and reproduction following herbivory. We took advantage of the compensatory variation in recombinant inbred lines of Arabidopsis thaliana, combined with microarray and QTL analyses to assess the molecular basis of overcompensation. We found three QTL explaining 11.4, 10.1, and 26.7% of the variation in fitness compensation, respectively, and 109 differentially expressed genes between clipped and unclipped plants of the overcompensating ecotype Columbia. From the QTL/microarray screen we uncovered one gene that plays a significant role in overcompensation: glucose-6-phosphate-1-dehydrogenase (G6PDH1). Knockout studies of Transfer-DNA (T-DNA) insertion lines and complementation studies of G6PDH1 verify its role in compensation. G6PDH1 is a key enzyme in the oxidative pentose-phosphate pathway that plays a central role in plant metabolism. We propose that plants capable of overcompensating reprogram their transcriptional activity by up-regulating defensive genes and genes involved in energy metabolism and by increasing DNA content (via endoreduplication) with the increase in DNA content feeding back on pathways involved in defense and metabolism through increased gene expression.
Spargel/dPGC-1 Is a New Downstream Effector in the Insulin–TOR Signaling Pathway in Drosophila
Authors: Mukherjee Subhas , Duttaroy Atanu
Published: August 2013

Insulin and target of rapamycin (TOR) signaling pathways converge to maintain growth so a proportionate body form is attained. Insufficiency in either insulin or TOR results in developmental growth defects due to low ATP level. Spargel is the Drosophila homolog of PGC-1, which is an omnipotent transcriptional coactivator in mammals. Like its mammalian counterpart, Spargel/dPGC-1 is recognized for its role in energy metabolism through mitochondrial biogenesis. An earlier study demonstrated that Spargel/dPGC-1 is involved in the insulin–TOR signaling, but a comprehensive analysis is needed to understand exactly which step of this pathway Spargel/PGC-1 is essential. Using genetic epistasis analysis, we demonstrated that a Spargel gain of function can overcome the TOR and S6K mediated cell size and cell growth defects in a cell autonomous manner. Moreover, the tissue-restricted phenotypes of TOR and S6k mutants are rescued by Spargel overexpression. We have further elucidated that Spargel gain of function sets back the mitochondrial numbers in growth-limited TOR mutant cell clones, which suggests a possible mechanism for Spargel action on cells and tissue to attain normal size. Finally, excess Spargel can ameliorate the negative effect of FoxO overexpression only to a limited extent, which suggests that Spargel does not share all of the FoxO functions and consequently cannot significantly rescue the FoxO phenotypes. Together, our observation established that Spargel/dPGC-1 is indeed a terminal effector in the insulin–TOR pathway operating below TOR, S6K, Tsc, and FoxO. This led us to conclude that Spargel should be incorporated as a new member of this growth-signaling pathway.
TORC1 Signaling Is Governed by Two Negative Regulators in Fission Yeast
Authors: Ma Ning , Liu Qingbin , Zhang Lili , Henske Elizabeth P , Ma Yan
Published: August 2013

The target of rapamycin (TOR) is a highly conserved protein kinase that regulates cell growth and metabolism. Here we performed a genome-wide screen to identify negative regulators of TOR complex 1 (TORC1) in Schizosaccharomyces pombe by isolating mutants that phenocopy Δtsc2, in which TORC1 signaling is known to be up-regulated. We discovered that Δnpr2 displayed similar phenotypes to Δtsc2 in terms of amino acid uptake defects and mislocalization of the Cat1 permease. However, Δnpr2 and Δtsc2 clearly showed different phenotypes in terms of rapamycin supersensitivity and Isp5 transcription upon various treatments. Furthermore, we showed that Tor2 controls amino acid homeostasis at the transcriptional and post-transcriptional levels. Our data reveal that both Npr2 and Tsc2 negatively regulate TORC1 signaling, and Npr2, but not Tsc2, may be involved in the feedback loop of a nutrient-sensing pathway.
Rare Variants in Hypermutable Genes Underlie Common Morphology and Growth Traits in WildSaccharomyces paradoxus
Authors: Roop Jeremy I , Brem Rachel B
Published: August 2013

Understanding the molecular basis of common traits is a primary challenge of modern genetics. One model holds that rare mutations in many genetic backgrounds may often phenocopy one another, together explaining the prevalence of the resulting trait in the population. For the vast majority of phenotypes, the role of rare variants and the evolutionary forces that underlie them are unknown. In this work, we use a population of Saccharomyces paradoxus yeast as a model system for the study of common trait variation. We observed an unusual, flocculation and invasive-growth phenotype in one-third of S. paradoxus strains, which were otherwise unrelated. In crosses with each strain in turn, these morphologies segregated as a recessive Mendelian phenotype, mapping either to IRA1 or to IRA2, yeast homologs of the hypermutable human neurofibromatosis gene NF1. The causal IRA1 and IRA2 haplotypes were of distinct evolutionary origin and, in addition to their morphological effects, associated with hundreds of stress-resistance and growth traits, both beneficial and disadvantageous, across S. paradoxus. Single-gene molecular genetic analyses confirmed variant IRA1 and IRA2 haplotypes as causal for these growth characteristics, many of which were independent of morphology. Our data make clear that common growth and morphology traits in yeast result from a suite of variants in master regulators, which function as a mutation-driven switch between phenotypic states.
Predicting Functionally Informative Mutations inEscherichia coliBamA Using Evolutionary Covariance Analysis
Authors: Dwyer Robert S , Ricci Dante P , Colwell Lucy J , Silhavy Thomas J , Wingreen Ned S
Published: August 2013

The essential outer membrane β-barrel protein BamA forms a complex with four lipoprotein partners BamBCDE that assembles β-barrel proteins into the outer membrane of Escherichia coli. Detailed genetic studies have shown that BamA cycles through multiple conformations during substrate assembly, suggesting that a complex network of residues may be involved in coordinating conformational changes and lipoprotein partner function. While genetic analysis of BamA has been informative, it has also been slow in the absence of a straightforward selection for mutants. Here we take a bioinformatic approach to identify candidate residues for mutagenesis using direct coupling analysis. Starting with the BamA paralog FhaC, we show that direct coupling analysis works well for large β-barrel proteins, identifying pairs of residues in close proximity in tertiary structure with a true positive rate of 0.64 over the top 50 predictions. To reduce the effects of noise, we designed and incorporated a novel structured prior into the empirical correlation matrix, dramatically increasing the FhaC true positive rate from 0.64 to 0.88 over the top 50 predictions. Our direct coupling analysis of BamA implicates residues R661 and D740 in a functional interaction. We find that the substitutions R661G and D740G each confer OM permeability defects and destabilize the BamA β-barrel. We also identify synthetic phenotypes and cross-suppressors that suggest R661 and D740 function in a similar process and may interact directly. We expect that the direct coupling analysis approach to informed mutagenesis will be particularly useful in systems lacking adequate selections and for dynamic proteins with multiple conformations.
Hypocretin-1 Deficiency in a Girl With ROHHAD Syndrome
Authors: Dhondt Karlien , Verloo Patrick , Verhelst Hélène , Van Coster Rudy , Overeem Sebastiaan
Published: August 2013

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare and complex pediatric syndrome, essentially caused by dysfunction of 3 vital systems regulating endocrine, respiratory, and autonomic nervous system functioning. The clinical spectrum of ROHHAD is broad, but sleep/wake disorders have received relatively little attention so far, although the central hypothalamic dysfunction would make the occurrence of sleep symptoms likely. In this case report, we expand the phenotype of ROHHAD with a number of striking sleep symptoms that together can be classified as a secondary form of narcolepsy. We present a 7-year-old girl with ROHHAD who displayed the classic features of narcolepsy with cataplexy: excessive daytime sleepiness with daytime naps, visual hallucinations, and partial cataplexy reflected in intermittent loss of facial muscle tone. Nocturnal polysomnography revealed sleep fragmentation and a sleep-onset REM period characteristic for narcolepsy. The diagnosis was confirmed by showing an absence of hypocretin-1 in the cerebrospinal fluid. We discuss potential pathophysiological implications as well as symptomatic treatment options.
Unexpected Relationship Between Tympanometry and Mortality in Children With Nontraumatic Coma
Authors: Gwer Samson , Chengo Eddie , Newton Charles R.J.C. , Kirkham Fenella J.
Published: August 2013

OBJECTIVE:

We sought to further examine the relationship between tympanometry and mortality after noting an unexpected association on assessment of baseline data of a study whose primary aim was to investigate the utility of noninvasive tympanic membrane displacement measurement for monitoring intracranial pressure in childhood coma.

METHODS:

We recruited children who presented with acute nontraumatic coma to the high-dependency unit of Kilifi District Hospital on the rural coast of Kenya. We excluded children with sickle cell disease, epilepsy, and neurodevelopmental delay. We performed tympanometry on the right ear before tympanic membrane displacement analyzer measurements. All children were managed according to standard World Health Organization guidelines.

RESULTS:

We recruited 72 children with a median age of 3.2 years (interquartile range [IQR]: 2.0–4.3 years); 31 (43%) were female. Thirty-eight (53%) had cerebral malaria, 8 (11%) acute bacterial meningitis, 4 (6%) sepsis, and 22 (30%) encephalopathy of unknown etiology. Twenty (28%) children died. Tympanometry was normal in 25 (35%) children. Adjusting for diagnosis and clinical features of increased intracranial pressure, both associated with death on univariable analysis, children with abnormal tympanometry had greater odds of dying than did those with normal tympanometry (adjusted odds ratio: 17.0; 95% confidence interval: 1.9–152.4; P = .01). Children who died had a lower compliance (0.29 mL; IQR: 0.09–0.33 mL) compared with those who survived (0.48 mL; IQR: 0.29–0.70 mL) (P < .01).

CONCLUSIONS:

Abnormal tympanometry appears to be significantly associated with death in children with acute nontraumatic coma. This finding needs to be explored further through a prospective study that incorporates imaging and intensive physiologic monitoring.
Wouter J. Hanegraaff and Jeffrey J. Kripal (eds.), Hidden Intercourse: Eros and Sexuality in the History of Western Esotericism.
Authors: Johnston Jay
Published: August 2013

Wouter J. Hanegraaff and Jeffrey J. Kripal (eds.), Hidden Intercourse: Eros and Sexuality in the History of Western Esotericism. Brill, Leiden and Boston, 2008, pp. 544, ISBN: 978 90 04 16872 2; ISSN: 1871 1405.
Wilburn Hansen, When Tengu Talk: Hirata Atsutane’s Ethnography of the Other World.
Authors: Cusack Carole M.
Published: August 2013

Wilburn Hansen, When Tengu Talk: Hirata Atsutane’s Ethnography of the Other World, University of Hawai’i Press, Honolulu, 2008, pp. 268, ISBN: 978-0-8248-3209-4 (hbk).
Norman Simms, Masks in the Mirror: Marranism in Jewish Experience.
Authors: Hartney Christopher
Published: August 2013

Norman Simms, Masks in the Mirror: Marranism in Jewish Experience, Peter Lang, New York, 2006, pp. 142, ISBN: 0-8204-8120-3.
Dungog
Authors: Boer Roland
Published: August 2013

This article makes use of Henri Lefebvre's highly influential threefold distinction of space to interpret the spatial dynamics of the Uniting (formerly Methodist) church of Dungog in the Hunter Valley foothills. Lefebvre ditsinguished between spatial practice (perceived space), representations of space (overtly conceived space) and spaces of representation (covertly lived space). The study proceeds to analyse the journey to and arrival in Dungog in terms of spatial practice. Then it explores the interactions between the other two types of space in the relations between, on the one hand, the Uniting and Presbyterian churches and, on the other hand, within the former Wesleyan Church itself. Apart from noting how the relations of space change when the item of analysis shifts (as one would expect with Lefebvre's dialectical approach), the study also presents a neglected way of analysing the religious dynamics of a country town.