bluuebunny/crossref_metadata_2025 huggingface dataset:
Environment sensing and response mediated by ABC transporters
Authors: Giuliani Sarah E , Frank Ashley M , Corgliano Danielle M , Seifert Catherine , Hauser Loren , Collart Frank R
Published: August 2011

Background

Transporter proteins are one of an organism’s primary interfaces with the environment. The expressed set of transporters mediates cellular metabolic capabilities and influences signal transduction pathways and regulatory networks. The functional annotation of most transporters is currently limited to general classification into families. The development of capabilities to map ligands with specific transporters would improve our knowledge of the function of these proteins, improve the annotation of related genomes, and facilitate predictions for their role in cellular responses to environmental changes.

Results

To improve the utility of the functional annotation for ABC transporters, we expressed and purified the set of solute binding proteins from Rhodopseudomonas palustris and characterized their ligand-binding specificity. Our approach utilized ligand libraries consisting of environmental and cellular metabolic compounds, and fluorescence thermal shift based high throughput ligand binding screens. This process resulted in the identification of specific binding ligands for approximately 64% of the purified and screened proteins. The collection of binding ligands is representative of common functionalities associated with many bacterial organisms as well as specific capabilities linked to the ecological niche occupied by R. palustris.

Conclusion

The functional screen identified specific ligands that bound to ABC transporter periplasmic binding subunits from R. palustris. These assignments provide unique insight for the metabolic capabilities of this organism and are consistent with the ecological niche of strain isolation. This functional insight can be used to improve the annotation of related organisms and provides a route to evaluate the evolution of this important and diverse group of transporter proteins.
Role of P27-P55 operon from Mycobacterium tuberculosis in the resistance to toxic compounds
Authors: Bianco María V , Blanco Federico C , Imperiale Belén , Forrellad Marina A , Rocha Roxana V , Klepp Laura I , Cataldi Angel A , Morcillo Nora , Bigi Fabiana
Published: August 2011

Background

The P27-P55 (lprG-Rv1410c) operon is crucial for the survival of Mycobacterium
tuberculosis, the causative agent of human tuberculosis, during infection in mice. P55 encodes an efflux pump that has been shown to provide Mycobacterium smegmatis and Mycobacterium bovis BCG with resistance to several drugs, while P27 encodes a mannosylated glycoprotein previously described as an antigen that modulates the immune response against mycobacteria. The objective of this study was to determine the individual contribution of the proteins encoded in the P27-P55 operon to the resistance to toxic compounds and to the cell wall integrity of M. tuberculosis.

Method

In order to test the susceptibility of a mutant of M. tuberculosis H37Rv in the P27-P55 operon to malachite green, sodium dodecyl sulfate, ethidium bromide, and first-line antituberculosis drugs, this strain together with the wild type strain and a set of complemented strains were cultivated in the presence and in the absence of these drugs. In addition, the malachite green decolorization rate of each strain was obtained from decolorization curves of malachite green in PBS containing bacterial suspensions.

Results

The mutant strain decolorized malachite green faster than the wild type strain and was hypersensitive to both malachite green and ethidium bromide, and more susceptible to the first-line antituberculosis drugs: isoniazid and ethambutol. The pump inhibitor reserpine reversed M. tuberculosis resistance to ethidium bromide. These results suggest that P27-P55 functions through an efflux-pump like mechanism. In addition, deletion of the P27-P55 operon made M. tuberculosis susceptible to sodium dodecyl sulfate, suggesting that the lack of both proteins causes alterations in the cell wall permeability of the bacterium. Importantly, both P27 and P55 are required to restore the wild type phenotypes in the mutant.

Conclusions

The results clearly indicate that P27 and P55 are functionally connected in processes that involve the preservation of the cell wall and the transport of toxic compounds away from the cells.
Effect of Qigong on quality of life: a cross-sectional population-based comparison study in Taiwan
Authors: Ho Tsung-Jung , Christiani David C , Ma Tso-Chiang , Jang Tsong-Rong , Lieng Chih-Hui , Yeh Yi-Chun , Lin Shinn-Zong , Lin Jaung-Geng , Lai Jim-Shoung , Lan Tzuo-Yun
Published: August 2011

Background

Qigong, similar to Tai Chi Chuan, is beneficial to health. In Taiwan, Waitankung, a type of Qigong, is as popular as Tai Chi Chuan. This population-based comparison study compares the health-related quality of life between people practicing Waitankung and their comparable community residents.

Methods

A total of 165 individuals practicing Waitankung were matched by age and sex with 660 general individuals for comparison. Information about health-related quality of life, measured by the SF-36, and other basic and health conditions was obtained from the questionnaires. This study used the linear mixed-effect regression model to examine the association between health-related quality of life and the practice of Waitankung.

Results

Compared with either sedentary individuals or individuals practicing other types of exercise, the Waitankung group scored higher for eight and five out of ten SF-36 components, respectively. The Waitankung group scored better in general health, vitality, and physical component summary compared to individuals participating in other types of exercise, even when considering the energy expended by exercise.

Conclusion

The results suggest that Waitankung exercising is significantly associated with health-related quality of life. Waitankung may serve as an exercise choice for middle-aged and older people to improve overall quality of life.
1,3-Propanediol dehydrogenases in Lactobacillus reuteri: impact on central metabolism and 3-hydroxypropionaldehyde production
Authors: Stevens Marc JA , Vollenweider Sabine , Meile Leo , Lacroix Christophe
Published: August 2011

Background

Lactobacillus reuteri metabolizes glycerol to 3-hydroxypropionaldehyde (3-HPA) and further to 1,3-propanediol (1,3-PDO), the latter step catalysed by a propanediol dehydrogenase (PDH). The last step in this pathway regenerates NAD+ and enables therefore the energetically more favourable production of acetate over ethanol during growth on glucose.

Results

A search throughout the genome of L. reuteri DSM 20016 revealed two putative PDHs encoded by ORFs lr_0030 and lr_1734. ORF lr_1734 is situated in the pdu operon encoding the glycerol conversion machinery and therefore likely involved in 1,3-PDO formation. ORF lr_0030 has not been associated with PDH-activity so far. To elucidate the role of these two PDHs, gene deletion mutant strains were constructed. Growth behaviour on glucose was comparable between the wild type and both mutant strains. However, on glucose + glycerol, the exponential growth rate of Δlr_0030 was lower compared to the wild type and the lr_1734 mutant. Furthermore, glycerol addition resulted in decreased ethanol production in the wild type and Δlr_1734, but not in Δlr_0030. PDH activity measurements using 3-HPA as a substrate revealed lower activity of Δlr_0030 extracts from exponential growing cells compared to wild type and Δlr_1734 extracts.

During biotechnological 3-HPA production using non-growing cells, the ratio 3-HPA to 1,3-PDO was approximately 7 in the wild type and Δlr_0030, whereas this ratio was 12.5 in the mutant Δlr_1734.

Conclusion

The enzyme encoded by lr_0030 plays a pivotal role in 3-HPA conversion in exponential growing L. reuteri cells. The enzyme encoded by lr_1734 is active during 3-HPA production by non-growing cells and this enzyme is a useful target to enhance 3-HPA production and minimize formation of the by-product 1,3-PDO.
An inhibitor of K+ channels modulates human endometrial tumor-initiating cells
Authors: Schickling Brandon M , Aykin-Burns Nukhet , Leslie Kimberly K , Spitz Douglas R , Korovkina Victoria P
Published: August 2011

Background

Many potassium ion (K+) channels function as oncogenes to sustain growth of solid tumors, but their role in cancer progression is not well understood. Emerging evidence suggests that the early progenitor cancer cell subpopulation, termed tumor initiating cells (TIC), are critical to cancer progression.

Results

A non-selective antagonist of multiple types of K+ channels, tetraethylammonium (TEA), was found to suppress colony formation in endometrial cancer cells via inhibition of putative TIC. The data also indicated that withdrawal of TEA results in a significant enhancement of tumorigenesis. When the TIC-enriched subpopulation was isolated from the endometrial cancer cells, TEA was also found to inhibit growth in vitro.

Conclusions

These studies suggest that the activity of potassium channels significantly contributes to the progression of endometrial tumors, and the antagonists of potassium channels are candidate anti-cancer drugs to specifically target tumor initiating cells in endometrial cancer therapy.
The inhibition of fat cell proliferation by n-3 fatty acids in dietary obese mice
Authors: Hensler Michal , Bardova Kristina , Jilkova Zuzana Macek , Wahli Walter , Meztger Daniel , Chambon Pierre , Kopecky Jan , Flachs Pavel
Published: August 2011

Background

Long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) of marine origin exert multiple beneficial effects on health. Our previous study in mice showed that reduction of adiposity by LC n-3 PUFA was associated with both, a shift in adipose tissue metabolism and a decrease in tissue cellularity. The aim of this study was to further characterize the effects of LC n-3 PUFA on fat cell proliferation and differentiation in obese mice.

Methods

A model of inducible and reversible lipoatrophy (aP2-Cre-ERT2 PPARγL2/L2 mice) was used, in which the death of mature adipocytes could be achieved by a selective ablation of peroxisome proliferator-activated receptor γ in response to i.p. injection of tamoxifen. Before the injection, obesity was induced in male mice by 8-week-feeding a corn oil-based high-fat diet (cHF) and, subsequently, mice were randomly assigned (day 0) to one of the following groups: (i) mice injected by corn-oil-vehicle only, i.e."control" mice, and fed cHF; (ii) mice injected by tamoxifen in corn oil, i.e. "mutant" mice, fed cHF; (iii) control mice fed cHF diet with15% of dietary lipids replaced by LC n-3 PUFA concentrate (cHF+F); and (iv) mutant mice fed cHF+F. Blood and tissue samples were collected at days 14 and 42.

Results

Mutant mice achieved a maximum weight loss within 10 days post-injection, followed by a compensatory body weight gain, which was significantly faster in the cHF as compared with the cHF+F mutant mice. Also in control mice, body weight gain was depressed in response to dietary LC n-3 PUFA. At day 42, body weights in all groups stabilized, with no significant differences in adipocyte size between the groups, although body weight and adiposity was lower in the cHF+F as compared with the cHF mice, with a stronger effect in the mutant than in control mice. Gene expression analysis documented depression of adipocyte maturation during the reconstitution of adipose tissue in the cHF+F mutant mice.

Conclusion

Dietary LC n-3 PUFA could reduce both hypertrophy and hyperplasia of fat cells in vivo. Results are in agreement with the involvement of fat cell turnover in control of adiposity.
Synchronous double primary malignant tumor of the gallbladder and liver: a case report
Authors: Kim Ji Won , Han Jae Woong , Jung So Young , Jung Jae Pil , Kim Jeong Won
Published: August 2011

We report a case of synchronous double primary tumor of gallbladder and liver. A 63-year-old male was admitted to the hospital complaining of abdominal discomfort. Enhanced computed tomography of the abdomen showed acute cholecystitis with tiny gallbladder stones and a 2.2 cm size enhanced nodule in the left lobe of the liver. Under the impression of acute cholecystitis with gall bladder stones and hepatocellular carcinoma of the left Liver, the patient underwent a laparotomy. At laparotomy, a mass was palpated on the surface of the neck portion of the gall bladder. Intraoperative frozen diagnosis revealed adenocarcinoma of the gall bladder. The patient was diagnosed as having gall bladder cancer and hepatocellular carcinoma, so extended cholecystectomy with dissection of regional lymph nodes and left hemihepatectomy were performed. Histological examination revealed moderated differentiated adenocarcinoma of gallbladder and hepatocellular carcinoma of liver. To our knowledge, the simultaneous occurrence of primary malignant tumor of the gallbladder and liver has never been published before. The patient is doing well with no evidence of recurrence 17 months after surgery.
Melatonin reduces LH, 17 beta-estradiol and induces differential regulation of sex steroid receptors in reproductive tissues during rat ovulation
Authors: A Chuffa Luiz Gustavo , Seiva Fábio RF , Fávaro Wagner José , Teixeira Giovana R , Amorim João PA , Mendes Leonardo O , Fioruci Beatriz A , Pinheiro Patrícia Fernanda F , Fernandes Ana Angélica H , Franci Janete AA , Delella Flávia K , Martinez Marcelo , Martinez Francisco E
Published: August 2011

Background

Melatonin is associated with direct or indirect actions upon female reproductive function. However, its effects on sex hormones and steroid receptors during ovulation are not clearly defined. This study aimed to verify whether exposure to long-term melatonin is able to cause reproductive hormonal disturbances as well as their role on sex steroid receptors in the rat ovary, oviduct and uterus during ovulation.

Methods

Twenty-four adult Wistar rats, 60 days old (+/- 250 g) were randomly divided into two groups. Control group (Co): received 0.9% NaCl 0.3 mL + 95% ethanol 0.04 mL as vehicle; Melatonin-treated group (MEL): received vehicle + melatonin [100 μg/100 g BW/day] both intraperitoneally during 60 days. All animals were euthanized by decapitation during the morning estrus at 4 a.m.

Results

Melatonin significantly reduced the plasma levels of LH and 17 beta-estradiol, while urinary 6-sulfatoximelatonin (STM) was increased at the morning estrus. In addition, melatonin promoted differential regulation of the estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR) and melatonin receptor (MTR) along the reproductive tissues. In ovary, melatonin induced a down-regulation of ER-alpha and PRB levels. Conversely, it was observed that PRA and MT1R were up-regulated. In oviduct, AR and ER-alpha levels were down-regulated, in contrast to high expression of both PRA and PRB. Finally, the ER-beta and PRB levels were down-regulated in uterus tissue and only MT1R was up-regulated.

Conclusions

We suggest that melatonin partially suppress the hypothalamus-pituitary-ovarian axis, in addition, it induces differential regulation of sex steroid receptors in the ovary, oviduct and uterus during ovulation.
Self-assembled monolayer of designed and synthesized triazinedithiolsilane molecule as interfacial adhesion enhancer for integrated circuit
Authors: Wang Fang , Li Yanni , Wang Yabin , Cao Zhuo
Published: August 2011

Self-assembled monolayer (SAM) with tunable surface chemistry and smooth surface provides an approach to adhesion improvement and suppressing deleterious chemical interactions. Here, we demonstrate the SAM comprising of designed and synthesized 6-(3-triethoxysilylpropyl)amino-1,3,5-triazine-2,4-dithiol molecule, which can enhance interfacial adhesion to inhibit copper diffusion used in device metallization. The formation of the triazinedithiolsilane SAM is confirmed by X-ray photoelectron spectroscopy. The adhesion strength between SAM-coated substrate and electroless deposition copper film was up to 13.8 MPa. The design strategy of triazinedithiolsilane molecule is expected to open up the possibilities for replacing traditional organosilane to be applied in microelectronic industry.
Strong convergence theorems for system of equilibrium problems and asymptotically strict pseudocontractions in the intermediate sense
Authors: Duan Peichao , Zhao Jing
Published: August 2011

Let "Equation missing" be N uniformly continuous asymptotically λ
i
-strict pseudocontractions in the intermediate sense defined on a nonempty closed convex subset C of a real Hilbert space H. Consider the problem of finding a common element of the fixed point set of these mappings and the solution set of a system of equilibrium problems by using hybrid method. In this paper, we propose new iterative schemes for solving this problem and prove these schemes converge strongly.

MSC: 47H05; 47H09; 47H10.
Glycoprotein is enough for sindbis virus-derived DNA vector to express heterogenous genes
Authors: Zhu Wuyang , Li Jiangjiao , Tang Li , Wang Huanqin , Li Jia , Fu Juanjuan , Liang Guodong
Published: August 2011

To investigate the necessity and potential application of structural genes for expressing heterogenous genes from Sindbis virus-derived vector, the DNA-based expression vector pVaXJ was constructed by placing the recombinant genome of sindbis-like virus XJ-160 under the control of the human cytomegalovirus (CMV) promoter of the plasmid pVAX1, in which viral structural genes were replaced by a polylinker cassette to allow for insertion of heterologous genes. The defect helper plasmids pVaE or pVaC were developed by cloning the gene of glycoprotein E3E26KE1 or capsid protein of XJ-160 virus into pVAX1, respectively. The report gene cassette pVaXJ-EGFP or pV-Gluc expressing enhanced green fluorescence protein (EGFP) or Gaussia luciferase (G.luc) were constructed by cloning EGFP or G.luc gene into pVaXJ. EGFP or G.luc was expressed in the BHK-21 cells co-transfected with report gene cassettes and pVaE at levels that were comparable to those produced by report gene cassettes, pVaC and pVaE and were much higher than the levels produced by report gene cassette and pVaC, suggesting that glycoprotein is enough for Sindbis virus-derived DNA vector to express heterogenous genes in host cells. The method of gene expression from Sindbis virus-based DNA vector only co-transfected with envelop E gene increase the conveniency and the utility of alphavirus-based vector systems in general.
Support vector machine prediction of enzyme function with conjoint triad feature and hierarchical context
Authors: Wang Yong-Cui , Wang Yong , Yang Zhi-Xia , Deng Nai-Yang
Published: August 2011

Background

Enzymes are known as the largest class of proteins and their functions are usually annotated by the Enzyme Commission (EC), which uses a hierarchy structure, i.e., four numbers separated by periods, to classify the function of enzymes. Automatically categorizing enzyme into the EC hierarchy is crucial to understand its specific molecular mechanism.

Results

In this paper, we introduce two key improvements in predicting enzyme function within the machine learning framework. One is to introduce the efficient sequence encoding methods for representing given proteins. The second one is to develop a structure-based prediction method with low computational complexity. In particular, we propose to use the conjoint triad feature (CTF) to represent the given protein sequences by considering not only the composition of amino acids but also the neighbor relationships in the sequence. Then we develop a support vector machine (SVM)-based method, named as SVMHL (SVM for hierarchy labels), to output enzyme function by fully considering the hierarchical structure of EC. The experimental results show that our SVMHL with the CTF outperforms SVMHL with the amino acid composition (AAC) feature both in predictive accuracy and Matthew’s correlation coefficient (MCC). In addition, SVMHL with the CTF obtains the accuracy and MCC ranging from 81% to 98% and 0. 82 to 0. 98 when predicting the first three EC digits on a low-homologous enzyme dataset. We further demonstrate that our method outperforms the methods which do not take account of hierarchical relationship among enzyme categories and alternative methods which incorporate prior knowledge about inter-class relationships.

Conclusions

Our structure-based prediction model, SVMHL with the CTF, reduces the computational complexity and outperforms the alternative approaches in enzyme function prediction. Therefore our new method will be a useful tool for enzyme function prediction community.
A methodology for utilization of predictive genomic signatures in FFPE samples
Authors: Freedman Jennifer A , Augustine Christina K , Selim Angelica M , Holshausen Kirsten C , Wei Zhengzheng , Tsamis Katherine A , Hsu David S , Dressman Holly K , Barry William T , Tyler Douglas S , Nevins Joseph R
Published: August 2011

Background

Gene expression signatures developed to measure the activity of oncogenic signaling pathways have been used to dissect the heterogeneity of tumor samples and to predict sensitivity to various cancer drugs that target components of the relevant pathways, thus potentially identifying therapeutic options for subgroups of patients. To facilitate broad use, including in a clinical setting, the ability to generate data from formalin-fixed, paraffin-embedded (FFPE) tissues is essential.

Methods

Patterns of pathway activity in matched fresh-frozen and FFPE xenograft tumor samples were generated using the MessageAmp Premier methodology in combination with assays using Affymetrix arrays. Results generated were compared with those obtained from fresh-frozen samples using a standard Affymetrix assay. In addition, gene expression data from patient matched fresh-frozen and FFPE melanomas were also utilized to evaluate the consistency of predictions of oncogenic signaling pathway status.

Results

Significant correlation was observed between pathway activity predictions from paired fresh-frozen and FFPE xenograft tumor samples. In addition, significant concordance of pathway activity predictions was also observed between patient matched fresh-frozen and FFPE melanomas.

Conclusions

Reliable and consistent predictions of oncogenic pathway activities can be obtained from FFPE tumor tissue samples. The ability to reliably utilize FFPE patient tumor tissue samples for genomic analyses will lead to a better understanding of the biology of disease progression and, in the clinical setting, will provide tools to guide the choice of therapeutics to those most likely to be effective in treating a patient's disease.
A cross‐sectional assessment of population demographics, HIV risks and human rights contexts among men who have sex with men in Lesotho
Authors: Baral Stefan , Adams Darrin , Lebona Judith , Kaibe Bafokeng , Letsie Puleng , Tshehlo Relebohile , Wirtz Andrea , Beyrer Chris
Published: August 2011

Background

Evidence is increasing of high HIV risks among southern African men who have sex with men (MSM). This represents the first study of HIV risks and human rights contexts among MSM in Lesotho.

Methods

Two hundred and fifty‐two men who reported ever having anal sex with another man were accrued with snowball sampling and were administered a structured quantitative instrument in October and November 2009.

Results

Of the participants, 96.4% (240/249) were ethnic Basotho with a mean age of 26.3 years (range 18‐56), 49.6% (124/250) were currently employed, and 95.2% (238/250) had at least a secondary‐level education. Self‐reported HIV prevalence was 11.6% (22/190); 54.5% (128/235) reported being tested for HIV in the last year. HIV knowledge was low; only 3.7% (8/212) of MSM knew that receptive anal intercourse was the highest risk for HIV and that a water‐based lubricant was most appropriate to use with condoms.

Bivariate associations of wearing condoms during last intercourse with men include: having easy access to condoms (OR 3.1, 95% CI 1.2‐8.5, p < 0.05); being older than 26 years (OR 2.3, 95% CI 1.3‐4.2, p < 0.01); knowing that receptive anal intercourse is higher risk than insertive anal intercourse (OR 2.6, 95% CI 1.2‐5.9, p < 0.05); wearing condoms with female sexual partners (OR 3.5, 95% 1.4‐8.3, p < 0.01); using water‐based lubricants (OR 2.8, 95% CI 1.4‐5.5, p < 0.01); being less likely to report having been diagnosed with a sexually transmitted infecton (OR 0.21, 95% CI 0.06‐0.76, p < 0.05); and being more likely to have been tested for HIV in the last year (OR 2.0, 95% CI 1.2‐3.6, p > 0.05).

Human rights abuses were common: 76.2% (170/223) reported at least one abuse, including rape (9.8%, 22/225), blackmail (21.3%, 47/221), fear of seeking healthcare (22.2%, 49/221), police discrimination (16.4%, 36/219), verbal or physical harassment (59.8%, 140/234), or having been beaten (18.9%, 43/228).

Conclusions

MSM in Lesotho are at high risk for HIV infection and human rights abuses. Evidence‐based and rights‐affirming HIV prevention programmes supporting the needs of MSM should be developed and implemented.
Postural control deficits in people with fibromyalgia: a pilot study
Authors: Jones Kim D , King Laurie A , Mist Scott D , Bennett Robert M , Horak Fay B
Published: August 2011

Introduction

Postural instability and falls are increasingly recognized problems in patients with fibromyalgia (FM). The purpose of this study was to determine whether FM patients, compared to age-matched healthy controls (HCs), have differences in dynamic posturography, including sensory, motor, and limits of stability. We further sought to determine whether postural instability is associated with strength, proprioception and lower-extremity myofascial trigger points (MTPs); FM symptoms and physical function; dyscognition; balance confidence; and medication use. Last, we evaluated self-reported of falls over the past six months.

Methods

In this cross-sectional study, we compared middle-aged FM patients and age-matched HCs who underwent computerized dynamic posturography testing and completed the Fibromyalgia Impact Questionnaire-Revised (FIQR) and balance and fall questionnaires. All subjects underwent a neurological and musculoskeletal examination. Descriptive statistics were used to characterize the sample and explore the relationships between variables. The relationships between subjective, clinical and objective variables were evaluated by correlation and regression analyses.

Results

Twenty-five FM patients and twenty-seven HCs (combined mean age ± standard deviation (SD): 48.6 ± 9.7 years) completed testing. FM patients scored statistically lower on composite sensory organization tests (primary outcome; P < 0.010), as well as with regard to vestibular, visual and somatosensory ratio scores on dynamic posturography. Balance confidence was significantly different between groups, with FM patients reporting less confidence than HCs (mean ± SD: 81.24 ± 19.52 vs. 98.52 ± 2.45; P < 0.001). Interestingly, 76% to 84% of FM patients had gastrocnemius and/or anterior tibialis MTPs. Postural stability was best predicted by dyscognition, FIQR score and body mass index. Regarding falls, 3 (11%) of 27 HCs had fallen only once during the past 6 months, whereas 18 (72%) of 25 FM patients had fallen at least once. Fifteen FM patients (60%) reported falling at least three times in the past six months.

Conclusions

In this study, we report that middle-aged FM patients have consistent objective sensory deficits on dynamic posturography, despite having a normal clinical neurological examination. Further study is needed to determine prospective fall rates and the significance of lower-extremity MTPs. The development of interventions to improve balance and reduce falls in FM patients may need to combine balance training with exercise and cognitive training.
Clustered Genomic Alterations in Chromosome 7p Dictate Outcomes and Targeted Treatment Responses of Lung Adenocarcinoma WithEGFR-Activating Mutations
Authors: Yuan Shinsheng , Yu Sung-Liang , Chen Hsuan-Yu , Hsu Yi-Chiung , Su Kang-Yi , Chen Huei-Wen , Chen Chih-Yi , Yu Chong-Jen , Shih Jin-Yuan , Chang Yih-Leong , Cheng Chiou-Ling , Hsu Chung-Ping , Hsia Jiun-Yi , Lin Chien-Yu , Wu Guani , Liu Chia-Hsin , Wang Chin-Di , Yang Kang-Chung , Chen Yi-Wei , Lai Yi-Ling , Hsu Chu-Chun , Lin Tai-Ching , Yang Tsung-Ying , Chen Kun-Cheieh , Hsu Kuo-Hsuan , Chen Jeremy J.W. , Chang Gee-Chen , Li Ker-Chau , Yang Pan-Chyr
Published: August 2011

Purpose

Although epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been proven more effective for patients with lung adenocarcinoma with EGFR-activating mutation rather than wild type, the former group still includes approximately 30% nonresponders. The molecular basis of this substantial response heterogeneity is unknown. Our purpose was to seek molecular aberrations contributing to disease progression at the genome-wide level and identify the prognostic signature unique to patients with EGFR-activating mutation.

Patients and Methods

We first investigated the molecular differences between tumors with EGFR-activating mutation and wild-type tumors by conducting high-density array comparative genomic hybridization on a collection of 138 adenocarcinoma tissues. We then used an independent group of 114 patients to validate the clinical relevance of copy-number alterations (CNAs) in predicting overall and disease-free survival. Finally, focusing on 23 patients with EGFR mutation receiving EGFR-TKI treatment, we investigated the association between CNAs and response to EGFR-TKIs.

Results

We identified chromosome regions with differential CNAs between tumors with EGFR-activating mutation and wild-type tumors and found the aberration sites to cluster highly on chromosome 7p. A cluster of six representative chromosome 7p genes predicted overall and disease-free survival for patients with EGFR-activating mutation but not for those with wild type. Importantly, simultaneous presence of more genes with increased CNAs in this cluster correlated with less favorable response to EGFR-TKIs in patients with EGFR-activating mutation.

Conclusion

Our results shed light on why responses to EGFR-TKIs are heterogeneous among patients with EGFR-activating mutation. They may lead to better patient management in this population.
American Society of Clinical Oncology Policy Statement: Opportunities in the Patient Protection and Affordable Care Act to Reduce Cancer Care Disparities
Authors: Moy Beverly , Polite Blase N. , Halpern Michael T. , Stranne Steven K. , Winer Eric P. , Wollins Dana S. , Newman Lisa A.
Published: August 2011

Patients in specific vulnerable population groups suffer disproportionately from cancer. The elimination of cancer disparities is critically important for lessening the burden of cancer. The Patient Protection and Affordable Care Act provides both opportunities and challenges for addressing cancer care disparities and access to care. The American Society of Clinical Oncology (ASCO) advocates for policies that ensure access to cancer care for the underserved. Such policies include insurance reform and the reduction of economic barriers to quality health care. Building on ASCO's prior statement on disparities in cancer care (2009), this article summarizes elements of the health care law that are relevant to cancer disparities and provides recommendations for addressing major provisions in the law. It outlines specific strategies to address insurance reform, access to care, quality of care, prevention and wellness, research on health care disparities, and diversity in the health care workforce. ASCO is committed to leading efforts toward the improvement of cancer care among the most vulnerable patients.
We All Want It, but We Don't Know What It Is: Toward a Standard of Affordability for Health Insurance Premiums
Authors: Muennig Peter , Sampat Bhaven , Tilipman Nicholas , Brown Lawrence D. , Glied Sherry A.
Published: August 2011

The 2010 Patient Protection and Affordable Care Act (P.L. 111-148), or ACA, requires that U.S. citizens either purchase health insurance or pay a fine. To offset the financial burden for lower-income households, it also provides subsidies to ensure that health insurance premiums are affordable. However, relatively little work has been done on how such affordability standards should be set. The existing literature on affordability is not grounded in social norms and has methodological and theoretical flaws. To address these issues, we developed a series of hypothetical vignettes in which individual and household sociodemographic characteristics were varied. We then convened a panel of eighteen experts with extensive experience in affordability standards to evaluate the extent to which each vignette character could afford to pay for one of two health insurance plans. The panel varied with respect to political ideology and discipline. We find that there was considerable disagreement about how affordability is defined. There was also disagreement about what might be included in an affordability standard, with substantive debate surrounding whether savings, debt, education, or single parenthood is relevant. There was also substantial variation in experts' assessed affordability scores. Nevertheless, median expert affordability assessments were not far from those of ACA.
Relative Affordability of Health Insurance Premiums Under CHIP Expansion Programs and the ACA
Authors: Gresenz Carole Roan , Laugesen Miriam J. , Yesus Ambeshie , Escarce José J.
Published: August 2011

Affordability is integral to the success of health care reforms aimed at ensuring universal access to health insurance coverage, and affordability determinations have major policy and practical consequences. This article describes factors that influenced the determination of affordability benchmarks and premium-contribution requirements for Children's Health Insurance Program (CHIP) expansions in three states that sought to universalize access to coverage for youth. It also compares subsidy levels developed in these states to the premium subsidy schedule under the Affordable Care Act (ACA) for health insurance plans purchased through an exchange. We find sizeable variability in premium-contribution requirements for children's coverage as a percentage of family income across the three states and in the progressivity and regressivity of the premium-contribution schedules developed. These findings underscore the ambiguity and subjectivity of affordability standards. Further, our analyses suggest that while the ACA increases the affordability of family coverage for families with incomes below 400 percent of the federal poverty level, the evolution of CHIP over the next five to ten years will continue to have significant implications for low-income families.
Swatting flies: modelling wound healing and inflammation in Drosophila
Authors: Razzell William , Wood Will , Martin Paul
Published: August 2011

Aberrant wound healing can lead to a variety of human pathologies, from non-healing chronic wounds that can become dangerously infected, to exuberant fibrotic healing in which repair is accompanied by excessive inflammation. To guide therapeutic intervention, we need a better understanding of the fundamental mechanisms driving tissue repair; this will require complementary wound-healing studies in several model organisms. Drosophila has been used to model genetic aspects of numerous human pathologies, and is being used increasingly to gain insight into the molecular and genetic aspects of tissue repair and inflammation, which have classically been modelled in mice or cultured cells. This review discusses the advantages and disadvantages of Drosophila as a wound-healing model, as well as some exciting new research opportunities that will be enabled by its use.
The ferret as a model organism to study influenza A virus infection
Authors: Belser Jessica A. , Katz Jacqueline M. , Tumpey Terrence M.
Published: August 2011

Influenza is a human pathogen that continues to pose a public health threat. The use of small mammalian models has become indispensable for understanding the virulence of influenza viruses. Among numerous species used in the laboratory setting, only the ferret model is equally well suited for studying both the pathogenicity and transmissibility of human and avian influenza viruses. Here, we compare the advantages and limitations of the mouse, ferret and guinea pig models for research with influenza A viruses, emphasizing the multifarious uses of the ferret in the assessment of influenza viruses with pandemic potential. Research performed in the ferret model has provided information, support and guidance for the public health response to influenza viruses in humans. We highlight the recent and emerging uses of this species in influenza virus research that are advancing our understanding of virus-host interactions.
Development and validation of a yeast high-throughput screen for inhibitors of Aβ42 oligomerization
Authors: Park Sei-Kyoung , Pegan Scott D. , Mesecar Andrew D. , Jungbauer Lisa M. , LaDu Mary Jo , Liebman Susan W.
Published: August 2011

Recent reports point to small soluble oligomers, rather than insoluble fibrils, of amyloid β (Aβ), as the primary toxic species in Alzheimer’s disease. Previously, we developed a low-throughput assay in yeast that is capable of detecting small Aβ42 oligomer formation. Specifically, Aβ42 fused to the functional release factor domain of yeast translational termination factor, Sup35p, formed sodium dodecyl sulfate (SDS)-stable low-n oligomers in living yeast, which impaired release factor activity. As a result, the assay for oligomer formation uses yeast growth to indicate restored release factor activity and presumably reduced oligomer formation. We now describe our translation of this assay into a high-throughput screen (HTS) for anti-oligomeric compounds. By doing so, we also identified two presumptive anti-oligomeric compounds from a sub-library of 12,800 drug-like small molecules. Subsequent biochemical analysis confirmed their anti-oligomeric activity, suggesting that this form of HTS is an efficient, sensitive and cost-effective approach to identify new inhibitors of Aβ42 oligomerization.
Guide RNA biogenesis involves a novel RNase III family endoribonuclease inTrypanosoma brucei
Authors: Madina Bhaskara Reddy , Kuppan Gokulan , Vashisht Ajay A. , Liang Yu-He , Downey Kurtis M. , Wohlschlegel James A. , Ji Xinhua , Sze Sing-Hoi , Sacchettini James C. , Read Laurie K. , Cruz-Reyes Jorge
Published: August 2011

The mitochondrial genome of kinetoplastids, including species ofTrypanosomaandLeishmania, is an unprecedented DNA structure of catenated maxicircles and minicircles. Maxicircles represent the typical mitochondrial genome encoding components of the respiratory complexes and ribosomes. However, most mRNA sequences are cryptic, and their maturation requires a unique U insertion/deletion RNA editing. Minicircles encode hundreds of small guide RNAs (gRNAs) that partially anneal with unedited mRNAs and direct the extensive editing.Trypanosoma bruceigRNAs and mRNAs are transcribed as polycistronic precursors, which undergo processing preceding editing; however, the relevant nucleases are unknown. We report the identification and functional characterization of a close homolog of editing endonucleases, mRPN1 (mitochondrial RNA precursor-processing endonuclease 1), which is involved in gRNA biogenesis. Recombinant mRPN1 is a dimeric dsRNA-dependent endonuclease that requires Mg2+, a critical catalytic carboxylate, and generates 2-nucleotide 3′ overhangs. The cleavage specificity of mRPN1 is reminiscent of bacterial RNase III and thus is fundamentally distinct from editing endonucleases, which target a single scissile bond just 5′ of short duplexes. An inducible knockdown of mRPN1 inT. bruceiresults in loss of gRNA and accumulation of precursor transcripts (pre-gRNAs), consistent with a role of mRPN1 in processing. mRPN1 stably associates with three proteins previously identified in relatively large complexes that do not contain mRPN1, and have been linked with multiple aspects of mitochondrial RNA metabolism. One protein, TbRGG2, directly binds mRPN1 and is thought to modulate gRNA utilization by editing complexes. The proposed participation of mRPN1 in processing of polycistronic RNA and its specific protein interactions in gRNA expression are discussed.
Lack of Evidence for Direct Corticospinal Contributions to Control of the Ipsilateral Forelimb in Monkey
Authors: Soteropoulos Demetris S. , Edgley Steve A. , Baker Stuart N.
Published: August 2011

Strong experimental evidence implicates the corticospinal tract in voluntary control of the contralateral forelimb. Its potential role in controlling the ipsilateral forelimb is less well understood, although anatomical projections to ipsilateral spinal circuits are identified. We investigated inputs to motoneurons innervating hand and forearm muscles from the ipsilateral corticospinal tract using multiple methods. Intracellular recordings from 62 motoneurons in three anesthetized monkeys revealed no monosynaptic and only one weak oligosynaptic EPSP after stimulation of the ipsilateral corticospinal tract. Single stimulus intracortical microstimulation of the primary motor cortex (M1) in awake animals failed to produce any responses in ipsilateral muscles. Strong stimulation (>500 μA, single stimulus) of the majority of corticospinal axons at the medullary pyramids revealed only weak suppressions in ipsilateral muscles at longer latencies than the robust facilitations seen contralaterally. Spike-triggered averaging of ipsilateral muscle activity from M1 neural discharge (184 cells) did not reveal any postspike effects consistent with monosynaptic corticomotoneuronal connections. We also examined the activity of 191 M1 neurons during ipsilateral or contralateral “reach to precision grip” movements. Many cells (67%) modulated their activity during ipsilateral limb movement trials (compared with 90% with contralateral trials), but the timing of this activity was best correlated with weak muscle activity in the contralateral nonmoving arm. We conclude that, in normal adults, any inputs to forelimb motoneurons from the ipsilateral corticospinal tract are weak and indirect and that modulation of M1 cell firing seems to be related primarily to control of the contralateral limb.
Neuroaxonal Dystrophy in Calcium-Independent Phospholipase A2β Deficiency Results from Insufficient Remodeling and Degeneration of Mitochondrial and Presynaptic Membranes
Authors: Beck Goichi , Sugiura Yuki , Shinzawa Koei , Kato Shinsuke , Setou Mitsutoshi , Tsujimoto Yoshihide , Sakoda Saburo , Sumi-Akamaru Hisae
Published: August 2011

Infantile neuroaxonal dystrophy (INAD) is a fatal neurodegenerative disease characterized by the widespread presence of axonal swellings (spheroids) in the CNS and PNS and is caused by gene abnormality in PLA2G6 [calcium-independent phospholipase A2β (iPLA2β)], which is essential for remodeling of membrane phospholipids. To clarify the pathomechanism of INAD, we pathologically analyzed the spinal cords and sciatic nerves of iPLA2β knock-out (KO) mice, a model of INAD. At 15 weeks (preclinical stage), periodic acid-Schiff (PAS)-positive granules were frequently observed in proximal axons and the perinuclear space of large neurons, and these were strongly positive for a marker of the mitochondrial outer membrane and negative for a marker of the inner membrane. By 100 weeks (late clinical stage), PAS-positive granules and spheroids had increased significantly in the distal parts of axons, and ultrastructural examination revealed that these granules were, in fact, mitochondria with degenerative inner membranes. Collapse of mitochondria in axons was accompanied by focal disappearance of the cytoskeleton. Partial membrane loss at axon terminals was also evident, accompanied by degenerative membranes in the same areas. Imaging mass spectrometry showed a prominent increase of docosahexaenoic acid-containing phosphatidylcholine in the gray matter, suggesting insufficient membrane remodeling in the presence of iPLA2β deficiency. Prominent axonal degeneration in neuroaxonal dystrophy might be explained by the collapse of abnormal mitochondria after axonal transportation. Insufficient remodeling and degeneration of mitochondrial inner membranes and presynaptic membranes appear to be the cause of the neuroaxonal dystrophy in iPLA2β-KO mice.
Opposing Synaptic Regulation of Amyloid-β Metabolism by NMDA ReceptorsIn Vivo
Authors: Verges Deborah K. , Restivo Jessica L. , Goebel Whitney D. , Holtzman David M. , Cirrito John R.
Published: August 2011

The concentration of amyloid-β (Aβ) within the brain extracellular space is one determinant of whether the peptide will aggregate into toxic species that are important in Alzheimer's disease (AD) pathogenesis. Some types of synaptic activity can regulate Aβ levels. Here we demonstrate two distinct mechanisms that are simultaneously activated by NMDA receptors and regulate brain interstitial fluid (ISF) Aβ levels in opposite directions in the living mouse. Depending on the dose of NMDA administered locally to the brain, ISF Aβ levels either increase or decrease. Low doses of NMDA increase action potentials and synaptic transmission which leads to an elevation in synaptic Aβ generation. In contrast, high doses of NMDA activate signaling pathways that lead to ERK (extracellular-regulated kinase) activation, which reduces processing of APP into Aβ. This depression in Aβ via APP processing occurs despite dramatically elevated synaptic activity. Both of these synaptic mechanisms are simultaneously active, with the balance between them determining whether ISF Aβ levels will increase or decrease. NMDA receptor antagonists increase ISF Aβ levels, suggesting that basal activity at these receptors normally suppresses Aβ levelsin vivo. This has implications for understanding normal Aβ metabolism as well as AD pathogenesis.
Coordination of High Gamma Activity in Anterior Cingulate and Lateral Prefrontal Cortical Areas during Adaptation
Authors: Rothé Marie , Quilodran René , Sallet Jérôme , Procyk Emmanuel
Published: August 2011

The anterior cingulate cortex (ACC) and the lateral prefrontal cortex (LPFC) process complementary information for planning and evaluating behavior. This suggests at least that processes in these two areas are coordinated during behavioral adaptation. We analyzed local field potentials recorded in both regions in two monkeys performing a problem-solving task that alternated exploration and repetitive behaviors with the specific prediction that neural activity should reveal interareal coordination mainly during exploration. Both areas showed increased high gamma power after errors in exploration and after rewards in exploitation. We found that high gamma (60–140 Hz) power increases in ACC were followed by a later increase in LPFC only after negative feedback (errors) or first positive feedback (correct) during the exploration period. The difference in latencies between the two structures disappeared in repetition period. Simultaneous recordings revealed correlations between high gamma power in the two areas around feedback; however, correlations were observed in both exploration and repetition. In contrast, postfeedback beta (10–20 Hz) power in ACC and LPFC correlated more frequently during repetition. Together, our data suggest that the coordination between ACC and LPFC activity is expressed during adaptive as well as stable behavioral periods but with different modes depending on the behavioral period.