bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic background modulates phenotypes of serotonin transporter Ala56 knock-in mice
Authors: Kerr Travis M , Muller Christopher L , Miah Mahfuzur , Jetter Christopher S , Pfeiffer Rita , Shah Charisma , Baganz Nicole , Anderson George M , Crawley Jacqueline N , Sutcliffe James S , Blakely Randy D , Veenstra-VanderWeele Jeremy 
Published: October 2013

Abstract

Background
Previously, we identified multiple, rare serotonin (5-HT) transporter (SERT) variants in children with autism spectrum disorder (ASD). Although in our study the SERT Ala56 variant was over-transmitted to ASD probands, it was also seen in some unaffected individuals, suggesting that associated ASD risk is influenced by the epistatic effects of other genetic variation. Subsequently, we established that mice expressing the SERT Ala56 variant on a 129S6/S4 genetic background display multiple biochemical, physiological and behavioral changes, including hyperserotonemia, altered 5-HT receptor sensitivity, and altered social, communication, and repetitive behavior. Here we explore the effects of genetic background on SERT Ala56 knock-in phenotypes.

Methods
To explore the effects of genetic background, we backcrossed SERT Ala56 mice on the 129 background into a C57BL/6 (B6) background to achieve congenic B6 SERT Ala56 mice, and assessed autism-relevant behavior, including sociability, ultrasonic vocalizations, and repetitive behavior in the home cage, as well as serotonergic phenotypes, including whole blood serotonin levels and serotonin receptor sensitivity.

Results
One consistent phenotype between the two strains was performance in the tube test for dominance, where mutant mice displayed a greater tendency to withdraw from a social encounter in a narrow tube as compared to wildtype littermate controls. On the B6 background, mutant pup ultrasonic vocalizations were significantly increased, in contrast to decreased vocalizations seen previously on the 129 background. Several phenotypes seen on the 129 background were reduced or absent when the mutation was placed on the B6 background, including hyperserotonemia, 5-HT receptor hypersensivity, and repetitive behavior.

Conclusions
Our findings provide a cogent example of how epistatic interactions can modulate the impact of functional genetic variation and suggest that some aspects of social behavior may be especially sensitive to changes in SERT function. Finally, these results provide a platform for the identification of genes that may modulate the risk of ASD in humans.
Control of mRNA stability contributes to low levels of nuclear poly(A) binding protein 1 (PABPN1) in skeletal muscle
Authors: Apponi Luciano H , Corbett Anita H , Pavlath Grace K 
Published: October 2013

AbstractBackgroundThe nuclear poly(A) binding protein 1 (PABPN1) is a ubiquitously expressed proteinthat plays critical roles at multiple steps in post-transcriptional regulation ofgene expression. Short expansions of the polyalanine tract in the N-terminus ofPABPN1 lead to oculopharyngeal muscular dystrophy (OPMD), which is an adult onsetdisease characterized by eyelid drooping, difficulty in swallowing, and weaknessin the proximal limb muscles. Why alanine-expanded PABPN1 leads to muscle-specificpathology is unknown. Given the general function of PABPN1 in RNA metabolism,intrinsic characteristics of skeletal muscle may make this tissue susceptible tothe effects of mutant PABPN1.MethodsTo begin to understand the muscle specificity of OPMD, we investigated thesteady-state levels of PABPN1 in different tissues of humans and mice.Additionally, we analyzed the levels of PABPN1 during muscle regeneration afterinjury in mice. Furthermore, we assessed the dynamics of PABPN1 mRNA decay inskeletal muscle compared to kidney.ResultsHere, we show that the steady-state levels of both PABPN1 mRNA and protein aredrastically lower in mouse and human skeletal muscle, particularly those impactedin OPMD, compared to other tissues. In contrast, PABPN1 levels are increasedduring muscle regeneration, suggesting a greater requirement for PABPN1 functionduring tissue repair. Further analysis indicates that modulation of PABPN1expression is likely due to post-transcriptional mechanisms acting at the level ofmRNA stability.ConclusionsOur results demonstrate that PABPN1 steady-state levels and likely control ofexpression differ significantly in skeletal muscle as compared to other tissues,which could have important implications for understanding the muscle-specificnature of OPMD.
Effects of varying duty cycle and pulse width on high-intensity focused ultrasound (HIFU)-induced transcranial thrombolysis
Authors: Hölscher Thilo , Raman Rema , Fisher David J , Ahadi Golnaz , Zadicario Eyal , Voie Arne 
Published: October 2013

Abstract
The goal was to test the effects of various combinations of pulse widths (PW) and duty cycles (DC) on high-intensity focused ultrasound (HIFU)-induced sonothrombolysis efficacy using an in vitro flow model. An ExAblate™ 4000 HIFU headsystem (InSightec, Inc., Israel) was used. Artificial blood clots were placed into test tubes inside a human calvarium and exposed to pulsatile flow. Four different duty cycles were tested against four different pulse widths. For all study groups, an increase in thrombolysis efficacy could be seen in association with increasing DC and/or PW (p < 0.0001). Using transcranial HIFU, significant thrombolysis can be achieved within seconds and without the use of lytic drugs in vitro. Longer duty cycles in combination with longer pulse widths seem to have the highest potential to optimize clot lysis efficacy.
Pharmacokinetics and biodistribution of the cyclin-dependent kinase inhibitor -CR8- in mice
Authors: Sallam Hatem , El-Serafi Ibrahim , Meijer Laurent , Hassan Moustapha 
Published: October 2013

Abstract

Background
CR8 is a second generation inhibitor of cyclin-dependent kinases derived from roscovitine. CR8 was shown to be 50–100 fold more potent than roscovitine in inducing apoptosis in different tumor cell lines. In the present investigation, we have established an analytical method for the quantification of CR8 in biological samples and evaluated its bioavailability, biodistribution and pharmacokinetics in mice.

Methods
A liquid chromatography method utilizing UV-detection was used for the determination of CR8. CR8 was administered either orally (100 mg/kg) or i.v. (50 mg/kg) and the animals were sacrificed at different time points. Blood samples and organs were collected, after which the pharmacokinetic parameters were calculated for plasma and organs.

Results
CR8 was eluted at 5 minutes in the high performance liquid chromatography system used. The LLOQ detection was 0.10 μg/ml and linearity was observed within the 0.10-10 μg/ml range (r2 > 0.998). The accuracy and precision were >86%, while the recovery from plasma was >95%. CR8 was stable for 2 months at room temperature in both solution and plasma. CR8 pharmacokinetics was fitted to a two-compartment open model after oral administration and to a one compartment model after i.v. injection. The elimination half-life was about 3 hours. Organ exposure to CR8 (expressed as % AUC organ vs. AUC plasma) was highest in liver (205%), adipose tissue (188%) and kidney (150%) and low in bone marrow (30%) and brain (15%) as compared to plasma. The oral bioavailability of CR8 was found to be essentially 100%.

Conclusions
We have developed a rapid and simple method for the analysis of CR8. CR8 pharmacokinetics pattern showed 100% bioavailability, long half-life and limited distribution to brain and bone marrow, which may allow systemic exposure higher than the IC50 reported for cell death in tumor cell lines. CR8 displays favorable pharmacological properties and is therefore a good candidate for future clinical studies.
An oxidoreductase from ‘Alphonso’ mango catalyzing biosynthesis of furaneol and reduction of reactive carbonyls
Authors: Kulkarni Ram , Chidley Hemangi , Deshpande Ashish , Schmidt Axel , Pujari Keshav , Giri Ashok , Gershenzon Jonathan , Gupta Vidya 
Published: October 2013

Abstract
Two furanones, furaneol (4-hydroxy-2,5-dimethyl-3(2H)-furanone) and mesifuran (2,5-dimethyl-4-methoxy-3(2H)-furanone), are important constituents of flavor of the Alphonso cultivar of mango (Mangifera indica). To get insights into the biosynthesis of these furanones, we isolated an enone oxidoreductase gene from the Alphonso mango. It has high sequence similarity to an alkenal/one oxidoreductase from cucumber (79% identity) and enone oxidoreductases from tomato (73% identity) and strawberry (72% identity). The complete open reading frame was expressed in E. coli and the (his)6-tagged recombinant protein was purified by affinity chromatography. The purified protein assayed with NADH as a reducing agent converted D-fructose-1,6-diphosphate into furaneol, the immediate precursor of mesifuran. The enzyme was also able to convert two highly reactive carbonyls, 3-buten-2-one and 1-penten-3-one, produced by lipid peroxidation in plants, into their saturated derivatives. Expression profiling in various ripening stages of Alphonso fruits depicted an expression maxima at 10 days after harvest stage, shortly before the appearance of the maximum amount of furanones (completely ripe stage, 15 days after harvest). Although no furanones were detected at the 0 day after harvest stage, significant expression of this gene was detected in the fruits at this stage. Overall, the results suggest that this oxidoreductase plays important roles in Alphonso mango fruits.
CD56+ monocytes have a dysregulated cytokine response to lipopolysaccharide and accumulate in rheumatoid arthritis and immunosenescence
Authors: Krasselt Marco , Baerwald Christoph , Wagner Ulf , Rossol Manuela 
Published: October 2013

Abstract
Introduction
Peripheral blood monocytes are no longer regarded as a homogeneous cell population, but can be differentiated both phenotypically and functionally into various subpopulations. In rheumatoid arthritis, the subpopulation of CD14bright/CD16+ monocyte is expanded and prone towards generation of Th17 cells. CD56+ monocytes represent a different subpopulation, which is also expanded in conditions associated with autoimmunity like inflammatory bowel diseases. The aim of the study was the quantification and functional characterization of the CD56+ monocyte subset in rheumatoid arthritis (RA).

Methods
Frequencies of peripheral blood monocyte subpopulations were analyzed by flow cytometry in 86 healthy controls and 75 RA patients. In 16 patients, anti-tumor necrosis factor (TNF) therapy was initiated, and the CD56+ monocyte frequency was monitored longitudinally. Lipopolysaccharide (LPS)-induced cytokine production of CD56+ and CD56– monocytes was determined by intracellular staining or cytokine secretion assays.

Results
In healthy individuals, 8.6% ± 0.6 of the monocytes co-expressed CD56, with the majority of CD56+ monocytes being CD14bright (7.9% ± 0.5), while only a minor population was CD14dim (0.7% ± 0.1). We found a strong positive correlation between an individual’s age and the frequency of CD56+ monocytes. Upon stimulation with LPS, CD56+ monocytes became more frequently positive for TNF, IL-10 and IL-23 than CD56– monocytes. In addition, CD56+ monocytes spontaneously produced more reactive oxygen intermediates than CD56- monocytes. In RA patients, the frequency of CD56+ monocytes was significantly higher than in healthy controls (12.2% ± 0.9 vs. 7.9% ± 0.5, p = 0.0002), and this difference most pronounced in RA patients below 40 years of age (11.1% ± 1.6 vs. 4.1% ± 0.4, P < 0.0001). Treatment of the patients with an anti-TNF blocking agent significantly reduced CD56+ monocyte frequencies (baseline 12.4% vs. 24 weeks treatment 8.0%, P = 0.0429), and the magnitude of this decrease was found to correlate with the change in disease activity under the therapy.

Conclusion
The CD14bright/CD56+ monocyte subset is expanded in aging individuals as well as in patients with RA. The pro-inflammatory production of cytokines and reactive oxygen species as well as the elimination of those cells in patients with a good response towards TNF inhibiting agents indicates a possible contribution of those monocytes in the inflammatory response in RA.
ACPA fine-specificity profiles in early rheumatoid arthritis patients do not correlate with clinical features at baseline or with disease progression
Authors: van Beers Joyce JBC , Willemze Annemiek , Jansen Jeroen J , Engbers Gerard HM , Salden Martin , Raats Jos , Drijfhout Jan W , van der Helm-van Mil Annette HM , Toes Rene EM , Pruijn Ger JM 
Published: October 2013

Abstract
Introduction
Autoantibodies against citrullinated peptides/proteins (ACPA) are found in approximately 75% of the sera of patients with rheumatoid arthritis (RA). The RA-specific ACPA are frequently present prior to disease onset and their presence associates with a more erosive disease course. ACPA can therefore be used to aid the diagnosis and prognosis of RA. Recently, it became clear that ACPA are very heterogeneous, both in an individual patient and among different patients. The aim of this study was to investigate whether clinically meaningful ACPA profiles exist in early RA patients.

Methods
Twenty citrullinated peptides and the corresponding non-citrullinated control peptides were immobilized on microarray sensor chips. Sera from 374 early arthritis patients were analyzed by surface plasmon resonance imaging (i SPR) of biomolecular interactions on the sensor chip.

Results
Cluster analysis of the reactivities with the citrullinated peptides, after subtraction of the reactivities with the corresponding control peptides confirmed the heterogeneity of the ACPA response in RA and revealed 12 distinct ACPA profiles. The association of the 5 most frequent profiles with clinical features at diagnosis and during the disease course was examined, showing no statistically significant associations.

Conclusions
Compared to the detection of ACPA in RA sera by CCP-based assays, ACPA profiling in early arthritis patients did not reveal associations with disease activity and progression scores.
Treatment for mild cognitive impairment: systematic review
Authors: Cooper Claudia , Li Ryan , Lyketsos Constantine , Livingston Gill 
Published: October 2013

BackgroundMore people are presenting with mild cognitive impairment (MCI), frequently a precursor to dementia, but we do not know how to reduce deterioration.AimsTo systematically review randomised controlled trials (RCTs) evaluating the effects of any intervention for MCI on cognitive, neuropsychiatric, functional, global outcomes, life quality or incident dementia.MethodWe reviewed 41 studies fitting predetermined criteria, assessed validity using a checklist, calculated standardised outcomes and prioritised primary outcome findings in placebo-controlled studies.ResultsThe strongest evidence was that cholinesterase inhibitors did not reduce incident dementia. Cognition improved in single trials of: a heterogeneous psychological group intervention over 6 months; piribedil, a dopamine agonist over 3 months; and donepezil over 48 weeks. Nicotine improved attention over 6 months. There was equivocal evidence that Huannao Yicong improved cognition and social functioning.ConclusionsThere was no replicated evidence that any intervention was effective. Cholinesterase inhibitors and rofecoxib are ineffective in preventing dementia. Further good-quality RCTs are needed and preliminary evidence suggests these should include trials of psychological group interventions and piribedil.Declarations of interestC.L. has received grant support (research or continuing medical education) from NIMH, NIA, Associated Jewish Federation of Baltimore, Weinberg Foundation, Forest, GlaxoSmithKline, Eisai, Pfizer, AstraZeneca, Lilly, Ortho-McNeil, Bristol-Myers Squibb, Novartis, National Football League (NFL), Elan, Functional Neuromodulation; and has been a consultant/advisor to AstraZeneca, GlaxoSmithKline, Eisai, Novartis, Forest, Supernus, Adlyfe, Takeda, Wyeth, Lundbeck, Merz, Lilly, Pfizer, Genentech, Elan, NFL Players Association, NFL Benefits Office, Avanir, Zinfandel, Bristol-Myers Squibb; and received honorarium or travel support from Pfizer, Forest, GlaxoSmithKline, Health Monitor.
Sunitinib Versus Sorafenib in Advanced Hepatocellular Cancer: Results of a Randomized Phase III Trial
Authors: Cheng Ann-Lii , Kang Yoon-Koo , Lin Deng-Yn , Park Joong-Won , Kudo Masatoshi , Qin Shukui , Chung Hyun-Cheol , Song Xiangqun , Xu Jianming , Poggi Guido , Omata Masao , Pitman Lowenthal Susan , Lanzalone Silvana , Yang Liqiang , Lechuga Maria Jose , Raymond Eric 
Published: October 2013

Purpose Open-label, phase III trial evaluating whether sunitinib was superior or equivalent to sorafenib in hepatocellular cancer. Patients and Methods Patients were stratified and randomly assigned to receive sunitinib 37.5 mg once per day or sorafenib 400 mg twice per day. Primary end point was overall survival (OS). Results Early trial termination occurred for futility and safety reasons. A total of 1,074 patients were randomly assigned to the study (sunitinib arm, n = 530; sorafenib arm, n = 544). For sunitinib and sorafenib, respectively, median OS was 7.9 versus 10.2 months (hazard ratio [HR], 1.30; one-sided P = .9990; two-sided P = .0014); median progression-free survival (PFS; 3.6 v 3.0 months; HR, 1.13; one-sided P = .8785; two-sided P = .2286) and time to progression (TTP; 4.1 v 3.8 months; HR, 1.13; one-sided P = .8312; two-sided P = .3082) were comparable. Median OS was similar among Asian (7.7 v 8.8 months; HR, 1.21; one-sided P = .9829) and hepatitis B–infected patients (7.6 v 8.0 months; HR, 1.10; one-sided P = .8286), but was shorter with sunitinib in hepatitis C–infected patients (9.2 v 17.6 months; HR, 1.52; one-sided P = .9835). Sunitinib was associated with more frequent and severe adverse events (AEs) than sorafenib. Common grade 3/4 AEs were thrombocytopenia (29.7%) and neutropenia (25.7%) for sunitinib; hand-foot syndrome (21.2%) for sorafenib. Discontinuations owing to AEs were similar (sunitinib, 13.3%; sorafenib, 12.7%). Conclusion OS with sunitinib was not superior or equivalent but was significantly inferior to sorafenib. OS was comparable in Asian and hepatitis B–infected patients. OS was superior in hepatitis C–infected patients who received sorafenib. Sunitinib-treated patients reported more frequent and severe toxicity.
A Prognostic DNA Methylation Signature for Stage I Non–Small-Cell Lung Cancer
Authors: Sandoval Juan , Mendez-Gonzalez Jesus , Nadal Ernest , Chen Guoan , Carmona F. Javier , Sayols Sergi , Moran Sebastian , Heyn Holger , Vizoso Miguel , Gomez Antonio , Sanchez-Cespedes Montse , Assenov Yassen , Müller Fabian , Bock Christoph , Taron Miquel , Mora Josefina , Muscarella Lucia A. , Liloglou Triantafillos , Davies Michael , Pollan Marina , Pajares Maria J. , Torre Wenceslao , Montuenga Luis M. , Brambilla Elisabeth , Field John K. , Roz Luca , Lo Iacono Marco , Scagliotti Giorgio V. , Rosell Rafael , Beer David G. , Esteller Manel 
Published: October 2013

Purpose Non–small-cell lung cancer (NSCLC) is a tumor in which only small improvements in clinical outcome have been achieved. The issue is critical for stage I patients for whom there are no available biomarkers that indicate which high-risk patients should receive adjuvant chemotherapy. We aimed to find DNA methylation markers that could be helpful in this regard. Patients and Methods A DNA methylation microarray that analyzes 450,000 CpG sites was used to study tumoral DNA obtained from 444 patients with NSCLC that included 237 stage I tumors. The prognostic DNA methylation markers were validated by a single-methylation pyrosequencing assay in an independent cohort of 143 patients with stage I NSCLC. Results Unsupervised clustering of the 10,000 most variable DNA methylation sites in the discovery cohort identified patients with high-risk stage I NSCLC who had shorter relapse-free survival (RFS; hazard ratio [HR], 2.35; 95% CI, 1.29 to 4.28; P = .004). The study in the validation cohort of the significant methylated sites from the discovery cohort found that hypermethylation of five genes was significantly associated with shorter RFS in stage I NSCLC: HIST1H4F, PCDHGB6, NPBWR1, ALX1, and HOXA9. A signature based on the number of hypermethylated events distinguished patients with high- and low-risk stage I NSCLC (HR, 3.24; 95% CI, 1.61 to 6.54; P = .001). Conclusion The DNA methylation signature of NSCLC affects the outcome of stage I patients, and it can be practically determined by user-friendly polymerase chain reaction assays. The analysis of the best DNA methylation biomarkers improved prognostic accuracy beyond standard staging.
Effect of Increasing Glutathione With Cysteine and Glycine Supplementation on Mitochondrial Fuel Oxidation, Insulin Sensitivity, and Body Composition in Older HIV-Infected Patients
Authors: Nguyen Dan , Hsu Jean W , Jahoor Farook , Sekhar Rajagopal V 
Published: October 2013

Abstract

Background
HIV-infected patients are reported to have impaired oxidation of fatty acids despite increased availability, suggesting a mitochondrial defect. We investigated whether diminished levels of a key mitochondrial antioxidant, glutathione (GSH), was contributing to defective fatty acid oxidation in older HIV-infected patients, and if so, the metabolic mechanisms contributing to GSH deficiency in these patients.

Methods
In an open-label design, 8 older GSH-deficient HIV-infected males were studied before and after 14 days of oral supplementation with the GSH precursors cysteine and glycine. A combination of stable-isotope tracers, calorimetry, hyperinsulinemic-euglycemic clamp, and dynamometry were used to measure GSH synthesis, fasted and insulin-stimulated (fed) mitochondrial fuel oxidation, insulin sensitivity, body composition, anthropometry, forearm-muscle strength, and lipid profiles.

Results
Impaired synthesis contributed to GSH deficiency in the patients and was restored with cysteine plus glycine supplementation. GSH improvement was accompanied by marked improvements in fasted and fed mitochondrial fuel oxidation. Associated benefits included improvements in insulin sensitivity, body composition, anthropometry, muscle strength, and dyslipidemia.

Conclusions
This work identifies 2 novel findings in older HIV-infected patients: 1) diminished synthesis due to decreased availability of cysteine and glycine contributes to GSH deficiency and can be rapidly corrected by dietary supplementation of these precursors and 2) correction of GSH deficiency is associated with improvement of mitochondrial fat and carbohydrate oxidation in both fasted and fed states and with improvements in insulin sensitivity, body composition, and muscle strength. The role of GSH on ameliorating metabolic complications in older HIV-infected patients warrants further investigation. (J Clin Endocrinol Metab 99: 169–177, 2014)