bluuebunny/crossref_metadata_2025_split huggingface dataset:
Repurposing metformin: an old drug with new tricks in its binding pockets
Authors: Pryor Rosina , Cabreiro Filipe 
Published: October 2015

Improvements in healthcare and nutrition have generated remarkable increases in life expectancy worldwide. This is one of the greatest achievements of the modern world yet it also presents a grave challenge: as more people survive into later life, more also experience the diseases of old age, including type 2 diabetes (T2D), cardiovascular disease (CVD) and cancer. Developing new ways to improve health in the elderly is therefore a top priority for biomedical research. Although our understanding of the molecular basis of these morbidities has advanced rapidly, effective novel treatments are still lacking. Alternative drug development strategies are now being explored, such as the repurposing of existing drugs used to treat other diseases. This can save a considerable amount of time and money since the pharmacokinetics, pharmacodynamics and safety profiles of these drugs are already established, effectively enabling preclinical studies to be bypassed. Metformin is one such drug currently being investigated for novel applications. The present review provides a thorough and detailed account of our current understanding of the molecular pharmacology and signalling mechanisms underlying biguanide–protein interactions. It also focuses on the key role of the microbiota in regulating age-associated morbidities and a potential role for metformin to modulate its function. Research in this area holds the key to solving many of the mysteries of our current understanding of drug action and concerted effects to provide sustained and long-life health.
0.4–3.0 GHz highly efficient harmonic‐tuned power amplifier
Authors: Ma Chuanhui , Liu Ying , Pan Wensheng , Tang Youxi 
Published: October 2015

An optimisation‐based method is proposed for the design of highly efficient harmonic tuned‐power amplifier (HT‐PA) with multi‐octave bandwidth. The distributed basic matching cell with L‐type structure is utilised to construct the broadband matching network, whose topology and parameters are determined through optimisation. To validate the proposed method, a 0.4–3.0 GHz HT‐PA is implemented and the power added efficiency of 53–72%, output power of more than 40 dBm and 10–12 dB gain are achieved across the frequency band. When tested with 20 MHz long‐term‐evolution advanced signals, the broadband HT‐PA shows about –30 dBc adjacent channel leakage ratio at about 36 dBm average output power, with drain efficiency higher than 36%.
Lateral AlGaN/GaN diode with MIS‐gated hybrid anode for high‐sensitivity zero‐bias microwave detection
Authors: Zhou Qi , Liu Li , Zhou Xingye , Zhang Anbang , Shi Yuanyuan , Wang Zeheng , Wang Yuan Gang , Fang Yulong , Lv Yuanjie , Feng Zhihong , Zhang Bo 
Published: October 2015

A zero‐bias microwave detector using an AlGaN/GaN‐on‐Si lateral diode featuring a recessed metal/Al2O3/III‐nitride (MIS) gated hybrid anode (MG‐HAD) is experimentally demonstrated. The forward turn‐on voltage of the MG‐HAD is determined by the threshold‐voltage of the 2DEG channel beneath the recessed MIS‐gate, and thus the nonlinearity of the device at zero bias can be flexibly modulated by gate recessing. The optimal trench depth of the MIS‐gate for zero‐bias detection was designed and experimentally determined to be ∼23 nm, which enables a high‐curvature coefficient of 78 V−1 at zero bias. The first‐order voltage sensitivity, βV, is as high as 7.8 mV/μW. To the best of the authors' knowledge, these values are the highest reported for GaN‐based zero‐bias detectors to date.
Computational discovery of specificity-conferring sites in non-ribosomal peptide synthetases
Authors: Knudsen Michael , Søndergaard Dan , Tofting-Olesen Claus , Hansen Frederik T. , Brodersen Ditlev Egeskov , Pedersen Christian N. S. 
Published: October 2015

Abstract
Motivation: By using a class of large modular enzymes known as Non-Ribosomal Peptide Synthetases (NRPS), bacteria and fungi are capable of synthesizing a large variety of secondary metabolites, many of which are bioactive and have potential, pharmaceutical applications as e.g. antibiotics. There is thus an interest in predicting the compound synthesized by an NRPS from its primary structure (amino acid sequence) alone, as this would enable an in silico search of whole genomes for NRPS enzymes capable of synthesizing potentially useful compounds.
Results: NRPS synthesis happens in a conveyor belt-like fashion where each individual NRPS module is responsible for incorporating a specific substrate (typically an amino acid) into the final product. Here, we present a new method for predicting substrate specificities of individual NRPS modules based on occurrences of motifs in their primary structures. We compare our classifier with existing methods and discuss possible biological explanations of how the motifs might relate to substrate specificity.
Availability and implementation: SEQL-NRPS is available as a web service implemented in Python with Flask at http://services.birc.au.dk/seql-nrps and source code available at https://bitbucket.org/dansondergaard/seql-nrps/.
Contact: micknudsen@gmail.com or cstorm@birc.au.dk
Supplementary information: Supplementary data are available at Bioinformatics online.
Murine allergic rhinitis and nasal T
h2
activation are mediated via TSLP- and IL-33-signaling pathways
Authors: Akasaki Shoko , Matsushita Kazufumi , Kato Yukinori , Fukuoka Ayumi , Iwasaki Naruhito , Nakahira Masakiyo , Fujieda Shigeharu , Yasuda Koubun , Yoshimoto Tomohiro 
Published: October 2015

Abstract
Thymic stromal lymphopoietin (TSLP) and IL-33 are epithelium-derived proallergic cytokines that contribute to allergic diseases. Although the involvement of TSLP in allergic rhinitis (AR) is suggested, the exact role of TSLP in AR is poorly understood. Furthermore, the relative contribution of TSLP and IL-33 in nasal allergic responses has not been described. In this study, we examined the roles of TSLP and IL-33 in AR by analyzing acute and chronic AR models. Acute AR mice were intraperitoneally immunized with ragweed, then intranasally challenged with ragweed pollen for four consecutive days. Chronic AR mice were nasally administrated ragweed pollen on consecutive days for 3 weeks. In both models, TSLP receptor (TSLPR)-deficient mice showed defective sneezing responses and reduced serum ragweed-specific IgE levels compared with wild-type (WT) mice. Analyses of bone-marrow chimeric mice demonstrated that hematopoietic cells were responsible for defective sneezing in TSLPR-deficient mice. In addition, FcεRI + -cell-specific TSLPR-deficient mice showed partial but significant reduction in sneezing responses. Of note, T h2 activation and nasal eosinophilia were comparable between WT and TSLPR-deficient mice. ST2- and IL-33-deficient mice showed defective T h2 activation and nasal eosinophilia to acute, but not chronic, ragweed exposure. TSLPR and ST2 double-deficient mice showed defective T h2 activation and nasal eosinophilia even after chronic ragweed exposure. These results demonstrate that TSLPR signaling is critical for the early phase response of AR by controlling the IgE-mast-cell/basophil pathway. The IL-33/ST2 pathway is central to nasal T h2 activation during acute allergen exposure, but both TSLPR and ST2 contribute to T h2 responses in chronically allergen-exposed mice.
Rapid Diagnosis of Mediastinal Tuberculosis with Polymerase Chain Reaction Evaluation of Aspirated Material Taken by Endobronchial Ultrasound–Guided Transbronchial Needle Aspiration
Authors: Senturk Aysegul , Arguder Emine , Hezer Habibe , Babaoglu Elif , Kilic Hatice , Karalezli Aysegul , Hasanoglu H. Canan 
Published: October 2015

Background Endobronchial ultrasound–guided transbronchial needle aspiration (EBUS-TBNA) is a diagnostic method for tuberculosis (TB). This study was conducted to determine the efficiency of polymerase chain reaction (PCR) testing for detecting TB lymphadenitis in samples obtained by EBUS-TBNA. Materials and Methods A total of 93 consecutive patients with hilar/mediastinal lymphadenopathies and diagnosed with granulomatous diseases through histopathological evaluation were included in the study. The specimens provided by EBUS-TBNA were evaluated through pathological, microbiological, and molecular tests. Results Eighty-nine (95.7%) of the 93 patients had histopathologically granulomatous diseases by EBUS-TBNA. Tuberculosis was diagnosed in 27 (30.3%) patients and sarcoidosis was diagnosed in 62 (69.7%) patients. Four (4.3%) patients were diagnosed through mediastinoscopy. Endobronchial ultrasound–guided transbronchial needle aspiration had an overall diagnostic efficiency in TB of 96.9%, a sensitivity of 90.9%, and a specificity of 100%. Mycobacterium tuberculosis PCR was positive in 17 of the 30 patients. The sensitivity of PCR was 56.7%, the specificity was 100%, and the general efficiency of the test was 96.4%. Conclusions As a result, the use of M. tuberculosis PCR in the EBUS-TBNA specimens provides a rapid and an accurate diagnosis of TB. Therefore, we recommend the use of M. tuberculosis PCR in the EBUS-TBNA specimens as a rapid diagnostic method for mediastinal lymphadenopathies in patients with suspected TB.
A Low Glycemic Index Staple Diet Reduces Postprandial Glucose Values in Asian Women with Gestational Diabetes Mellitus
Authors: Hu Zhi-Geng , Tan Rong-Shao , Jin Di , Li Wei , Zhou Xiao-Yan 
Published: October 2015

Background A low glycemic index (GI) diet is beneficial for glucose control in patients with diabetes mellitus. This study aimed to investigate the influence of a low-GI diet on postprandial glucose levels in women with gestational diabetes mellitus (GDM). Methods Pregnant women with GDM were randomized to receive a normal diabetic control diet or a low-GI staple diet for 5 days. A low-GI staple food was used to replace rice in lunch and dinner for the low-GI staple diet group, whereas the total energy and carbohydrate levels remained equal in both groups. Fasting and postprandial glucose levels were determined daily. Results A total of 140 pregnant women with GDM were included in the study, including 66 in the low-GI staple diet group and 74 in the normal diabetic diet control group. No differences existed in baseline characteristics between the 2 groups (all P > 0.05). After dietary intervention, glucose levels were significantly reduced in the low-GI staple diet group (all P < 0.01) and the control group (all P < 0.008). Postintervention glucose values after breakfast, lunch, and dinner were significantly reduced in the treatment group compared with those in the control group (all P < 0.05). The percentage changes from baseline of all glucose values were significantly greater in the treatment group than in the control group (all P < 0.05). Conclusions A low-GI staple diet significantly reduces postprandial glucose levels in women with GDM.
Early-Onset Type 2 Diabetes Mellitus is Associated to HNF4A T130I Polymorphism in Families of Central Spain
Authors: Cieza-Borrella Clara , Díaz-Soto Gonzalo , Martínez-Pino Isabel , Puig-Domingo Manuel , González-Sarmiento Rogelio 
Published: October 2015

Purpose Type 2 diabetes mellitus (type 2 DM) and maturity-onset diabetes of the young present some similar clinical and biochemical characteristics that make them difficult to differentiate. Currently, the polymorphism T130I (rs1800961) in the HNF4A (hepatocyte nuclear factor 4A) gene has been described as a risk factor to type 2 DM and shows an autosomal dominant inheritance pattern associated to β-cell function decrease. The aim of the present work was to characterize the phenotypic profile of the T130I carrier and noncarrier relatives included in 3 unrelated families. Methods We studied GCK, HNF1A, and HNF4A genes by polymerase chain reaction and sequencing in 3 unrelated subjects from Valladolid, Spain, in which maturity-onset diabetes of the young was suspected. We collected genetic, clinical, and biochemical data from these subjects and their relatives in order to check the presence of the T130I polymorphism. Results The heterozygous T130I mutation was the unique functional gene variation that could explain diabetes phenotype. We observed significant differences in glucose metabolism, lipid profile, and Homeostasis Model Assessment index when we compared T130I mutation carriers and noncarriers. Diabetes diagnosed in T130I mutation carriers was related to stressful situations in an earlier age and tightly associated with gestational diabetes. Fasting plasma glucose and HbA1c levels increased with age in all carriers ( r = 0.69 and r = 0.66, P < 0.01), respectively. Conclusions Our study supports the T130I variant in HNF4A as a major susceptibility genotype associated with early-onset type 2 DM. Healthy carriers of this mutation require a stricter control in the population of central Spain.
Interrelationships among Cortisol, 17-Hydroxyprogesterone, and Androstenendione Exposures in the Management of Children with Congenital Adrenal Hyperplasia
Authors: Sarafoglou Kyriakie , Zimmerman Cheryl L. , Gonzalez-Bolanos Maria T. , Willis Brian A. , Brundage Richard 
Published: October 2015

Hydrocortisone is the standard replacement therapy for children with congenital adrenal hyperplasia (CAH). Relationships between cortisol exposures and pharmacodynamic responses of 17-hydroxyprogesterone and androstenedione exposures have not been systematically evaluated. Objectives (1) Assess individual oral hydrocortisone pharmacokinetics; (2) relate the observed cortisol exposure in each subject to the observed exposures of 17-hydroxyprogesterone and androstenedione; (3) determine potential individualized treatment regimens based on each subject's pharmacokinetic and pharmacodynamic parameters. Methods Thirty-four patients (18 boys, 16 girls, aged 1.4 to 18.1 years) with CAH underwent 6-hour pharmacokinetic studies. Results were analyzed by noncompartmental methods to obtain the area under the curve (AUC) for cortisol, 17-hydroxyprogesterone, and androstenedione; maximum concentration and time-to-maximum concentration for cortisol; and minimum and time-to-minimum concentration for 17-hydroxyprogesterone and androstenedione. Results Mean (SD) cortisol half-life and Cmax were 1.01 (0.20) hours and 24.4 (5.4) μg/dL, respectively. The AUCs for cortisol, 17-hydroxyprogesterone and androstenedione were 40.8 (14.5) μg hour/dL, 29,490 (23,539) ng hour/dL, and 680 (795) ng hour/dL, respectively. No significant relationships existed between cortisol AUCs and the AUCs of either 17-hydroxyprogesterone ( P = 0.32) or androstenedione ( P = 0.99); nor were there differences between the change-from-baseline concentrations for cortisol with either 17-hydroxyprogesterone ( P = 0.80) or androstenedione ( P = 0.40). Cortisol simulations indicated that although four daily doses decreased 24-hour hypercortisolemia and hypocortisolemia, substantial periods of each remained. Conclusions Concentration profiles of cortisol, 17-hydroxyprogesterone, and androstenedione are highly variable in children with CAH, and knowledge of them can assist in personalizing the therapy of CAH patients. Hydrocortisone's rapid half-life and the lack of a sustained-released product make it difficult to closely approximate normal circadian profiles.
Assessment of a Possible Link between Hyperhomocysteinemia and Hyperuricemia
Authors: Cohen Eytan , Levi Amos , Vecht-Lifshitz Susan E. , Goldberg Elad , Garty Moshe , Krause Ilan 
Published: October 2015

Background/Aim Hyperhomocysteinemia and hyperuricemia are both considered risk factors for coronary artery disease. However, the relationship between the 2 has not yet been thoroughly investigated. This study aimed to evaluate this relationship more closely. Material and Methods This study is a retrospective cross-sectional analysis of data from a screening center in Israel assessing 16,477 subjects, within an age range of 20 to 80 years. Results The mean age of the study sample was 46 years, and 68% were males. Hyperuricemia was found in 24.9% and 14.6% of subjects with elevated and normal homocysteine serum levels, respectively ( P < 0.001). A positive association was found between homocysteine serum levels and uric acid serum levels. Compared with subjects with normal homocysteine serum levels, those with hyperhomocysteinemia had an odds ratio (OR) for hyperuricemia of 1.7 (95% confidence interval [CI], 1.5–1.9) and 1.6 (95% CI, 1.1–2.5) for males and females, respectively. After multivariate adjustment for age, hypertension, body mass index, estimated glomerular filtration rate, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and thiazide use, the association remained significant in males (OR, 1.5; 95% CI, 1.3–1.7; P < 0.001) but not in females (OR, 0.9; 95% CI, 0.6–1.6; P = 0.82). Conclusions This large cohort showed a significant association between hyperhomocysteinemia and hyperuricemia. Sex differences were observed. This study suggests that accelerated atherosclerosis may be a consequence of the combined effect of these 2 factors.
Renal Elasticity Quantification by Acoustic Radiation Force Impulse Applied to the Evaluation of Kidney Diseases
Authors: Zaffanello Marco , Piacentini Giorgio , Bruno Costanza , Brugnara Milena , Fanos Vassilios 
Published: October 2015

For centuries, clinicians have used palpation to evaluate abdominal organs. After exploring almost all the different methods of interaction between x-rays, ultrasound, and magnetic fields on tissues, recent interest has focused on the evaluation of their mechanical properties. Acoustic radiation force impulse (ARFI) is a recent, established ultrasound-based diagnostic technique that allows physicians to obtain a measure of the elastic properties of an organ. Shear wave velocity, obtained by the ARFI technique, depends on the elasticity of tissues. To date, there are studies on the ARFI technique applied to normal kidneys, chronic kidney diseases, and kidney transplants. Mechanical properties of the kidney, such as stiffness and deformity, depend on various conditions that alter its histology, in particular the amount of fibrosis in the renal parenchyma; urinary pressure and renal blood perfusion may be other important contributing factors. Unfortunately, the ARFI technique applied to native renal pathologies is still limited, and not all studies are comparable because they used different methods. Therefore, the results reported in recent literature encourage further improvement of this method and the drawing up of standardized guidelines of investigation.
Thiazolidinediones Inhibit Mouse Osteoblastic MC3T3-E1 Cell Proliferation in Part through the Wnt Signaling Pathway
Authors: Duan Miao , Zhou Bowen , Zhou Xinrong , Yuan Gang 
Published: October 2015

Background Peroxisome proliferator-activated receptor γ (PPARγ) and Wnt play different roles in bone homeostasis. Thiazolidinediones are PPARγ agonists that cause bone mineral density loss. This study investigated the relationship between PPARγ and Wnt/β-catenin signaling in mouse osteoblastic MC3T3-E1 cells. Methods MC3T3-E1 cells were treated with either pioglitazone (Pio) or rosiglitazone (Rosi), thiazolidinediones, for 24 hours at 10 to 40-μM concentrations. Recombinant mouse Wnt3a protein (50 ng/mL) for 6 hours was also used to treat the 20-μM Pio and Rosi pretreated cells. Cell proliferation was measured by MTT, and apoptosis with flow cytometry using annexin V/propidium iodide staining; reverse transcriptase–polymerase chain reaction measured mRNA expression levels of LRP5/6 (low-density lipoprotein–related protein 5/6), glycogen synthase kinase 3β (GSK3β), TCF7L2 (transcription factor 7–like 2), PPARγ, and cyclin D1, and Western blots detected β-catenin and p-GSK3β proteins. Results Pioglitazone and Rosi decreased MC3T3-E1 cell viability by 28.07% and 18.14% at 20 μM, respectively ( P < 0.05). Apoptosis increased compared with controls (7.21%), after 20-μM treatment with Pio or Rosi, to 10.45% and 12.10%, respectively ( P < 0.05). Both Pio and Rosi decreased β-catenin protein levels and increased p-GSK3β, but the LRP5/6, GSK3β, and TCF7L2 mRNA levels were constant. Upon activation of the Wnt pathway by mouse Wnt3a protein, β-catenin and p-GSK3β protein levels were reversed, accompanied with increased proliferation, but apoptosis remained high. Conclusions Activation of PPARγ in osteoblasts accompanied Wnt signaling suppression. Activation of Wnt signaling alleviated the PPARγ proliferation decreases but not the apoptosis increases. The thiazolidinedione PPARγ agonists act in part through inhibition of the Wnt signaling pathway, showing there is a relationship between PPARγ and Wnt signaling.
Clinical Predictors of Progressive Beta-Cell Failure in Type 2 Diabetes
Authors: Irace Concetta , Tripolino Cesare , Carallo Claudio , Scavelli Faustina Barbara , Valle Elisabetta Della , Cortese Claudio , Gnasso Agostino 
Published: October 2015

Objectives The aim of the study was to identify factors associated with progressive beta-cell failure in a cohort of nonselected subjects with type 2 diabetes. Methods Two hundred twenty-four medical records were evaluated. Progressive beta-cell failure was defined as the following: glycated hemoglobin is higher than 7.5% despite combined drug therapy and appropriate diet (ie, isocaloric or hypocaloric diet depending on body weight) and absence of any illness causing acute hyperglycemia. The following factors were considered as possible predictors: diabetes-related symptoms, fasting plasma glucose at the onset of disease, family history of type 2 diabetes, number of visits per year, and residency. Further potential predictors were disease duration, age, body mass index, estimated glomerular filtration rate, and hypertension and/or hyperlipidemia at the enrollment in the study. Results The prevalence of beta-cell failure was 41%. Independent predictors of failure were longer disease duration (hazard ratio [HR] for each year of diabetes, 1.03; confidence intervals (CIs), 1.01–1.05; P = 0.03), history of hypertension (HR, 1.90; CIs, 1.73–2.89; P = 0.04), hyperlipidemia (HR, 1.65; CIs, 1.06–2.58; P = 0.03), residence in suburb (HR, 1.78; CIs, 1.06–3.01; P = 0.03), and presence of symptoms at the onset of disease (HR, 2.47; CIs, 1.51–4.03; P = 0.0001). Conclusions Patients with long disease duration, hypertension, and hyperlipidemia who are residents in suburbs and had diabetes-related symptoms at diagnosis might deserve intensive treatment to obtain adequate and stable glycemic control.
Elevated Human Endothelial Cell-Specific Molecule-1 Level and Its Association with Coronary Artery Disease in Patients with Hypertension
Authors: Xiong Chang , Zhao Zi-wen , Chen Zhao-yang , Wu Ling-zhen , Luo Yu-kun , Hu Fu-dong , Lin Chao-gui , Chen Liang-long 
Published: October 2015

Background Endothelial dysfunction plays an important role in the pathophysiology of coronary artery disease (CAD). Previous studies suggested that human endothelial cell-specific molecule-1 (endocan) may be a novel endothelial dysfunction marker. This study aims to investigate the relationship between serum endocan level and the presence and severity of CAD in patients with hypertension. Methods A total of 190 eligible hypertension patients were enrolled in this study. Serum endocan level was measured by enzyme-linked immunosorbent assay. The presence and severity of CAD were evaluated by coronary angiography. Results Hypertensive patients with CAD had significantly higher serum endocan level than those without CAD (1.63 ± 0.51 ng/mL vs 1.31 ± 0.65 ng/mL, P < 0.05). Multivariate logistic regression revealed that serum endocan level was independently associated with the presence of CAD (odds ratio, 2.662; 95% confidence interval, 1.560–4.544; P < 0.001). Spearman rank correlation analysis demonstrated that serum endocan level was associated with SYNergy between PCI with TAXUS and Cardiac Surgery score (r = 0.349, P = 0.001). Conclusions Serum endocan level is independently correlated with the presence and severity of CAD in hypertension patients, and those with high endocan level may have an increased risk of developing atherosclerosis.