bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating HPV‐negative CIN2+ in the ATHENA trial
Authors: Petry Karl Ulrich , Cox J. Thomas , Johnson Kristin , Quint Wim , Ridder Ruediger , Sideri Mario , Wright Thomas C. , Behrens Catherine M.
Published: February 2016

A post hoc analysis of the ATHENA study was performed to determine whether true HPV‐negative cervical lesions occur and whether they have clinical relevance. The ATHENA database was searched for all CIN2 or worse (CIN2+) cases with cobas HPV‐negative results and comparison was made with Linear Array (LA) and Amplicor to detect true false‐negative HPV results. Immunostaining with p16 was performed on these cases to identify false‐positive histology results. H&E slides were re‐reviewed by the study pathologists with knowledge of patient age, HPV test results and p16 immunostaining. Those with positive p16 immunostaining and/or a positive histopathology review underwent whole tissue section HPV PCR by the SPF10/LiPA/RHA system. Among 46,887 eligible women, 497 cases of CIN2+ were detected, 55 of which tested negative by the cobas® HPV Test (32 CIN2, 23 CIN3/ACIS). By LA and/or Amplicor, 32 CIN2+ (20 CIN2, 12 CIN3/ACIS) were HPV positive and categorized as false‐negatives by cobas HPV; nine of 12 false‐negative CIN3/ACIS cases were p16+. There were 23 cases (12 CIN2, 11 CIN3/ACIS) negative by all HPV tests; seven of 11 CIN3/ACIS cases were p16+. H&E slides were available for six cases for re‐review and all were confirmed as CIN3/ACIS. Tissue PCR was performed on the six confirmed CIN3/ACIS cases (and one without confirmation): four were positive for HPV types not considered oncogenic, two were positive for oncogenic genotypes and one was indeterminate. In summary, subanalysis of a large cervical cancer screening study did not identify any true CIN3/ACIS not attributable to HPV.
Integrated decision strategies for skin sensitization hazard
Authors: Strickland Judy , Zang Qingda , Kleinstreuer Nicole , Paris Michael , Lehmann David M. , Choksi Neepa , Matheson Joanna , Jacobs Abigail , Lowit Anna , Allen David , Casey Warren
Published: February 2016

One of the top priorities of the Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM) is the identification and evaluation of non‐animal alternatives for skin sensitization testing. Although skin sensitization is a complex process, the key biological events of the process have been well characterized in an adverse outcome pathway (AOP) proposed by the Organisation for Economic Co‐operation and Development (OECD). Accordingly, ICCVAM is working to develop integrated decision strategies based on the AOP using in vitro, in chemico and in silico information. Data were compiled for 120 substances tested in the murine local lymph node assay (LLNA), direct peptide reactivity assay (DPRA), human cell line activation test (h‐CLAT) and KeratinoSens assay. Data for six physicochemical properties, which may affect skin penetration, were also collected, and skin sensitization read‐across predictions were performed using OECD QSAR Toolbox. All data were combined into a variety of potential integrated decision strategies to predict LLNA outcomes using a training set of 94 substances and an external test set of 26 substances. Fifty‐four models were built using multiple combinations of machine learning approaches and predictor variables. The seven models with the highest accuracy (89–96% for the test set and 96–99% for the training set) for predicting LLNA outcomes used a support vector machine (SVM) approach with different combinations of predictor variables. The performance statistics of the SVM models were higher than any of the non‐animal tests alone and higher than simple test battery approaches using these methods. These data suggest that computational approaches are promising tools to effectively integrate data sources to identify potential skin sensitizers without animal testing. Published 2016. This article has been contributed to by US Government employees and their work is in the public domain in the USA.
Inhibitory effect of cadmium on estrogen signaling in zebrafish brain and protection by zinc
Authors: Chouchene Lina , Pellegrini Elisabeth , Gueguen Marie‐Madeleine , Hinfray Nathalie , Brion François , Piccini Benjamin , Kah Olivier , Saïd Khaled , Messaoudi Imed , Pakdel Farzad
Published: February 2016

The present study was conducted to assess the effects of Cd exposure on estrogen signaling in the zebrafish brain, as well as the potential protective role of Zn against Cd‐induced toxicity. For this purpose, the effects on transcriptional activation of the estrogen receptors (ERs), aromatase B (Aro‐B) protein expression and molecular expression of related genes were examined in vivo using wild‐type and transgenic zebrafish embryos. For in vitro studies, an ER‐negative glial cell line (U251MG) transfected with different zebrafish ER subtypes (ERα, ERβ1 and ERβ2) was also used. Embryos were exposed either to estradiol (E2), Cd, E2+Cd or E2+Cd+Zn for 72 h and cells were exposed to the same treatments for 30 h. Our results show that E2 treatment promoted the transcriptional activation of ERs and increased Aro‐B expression, at both the protein and mRNA levels. Although exposure to Cd, does not affect the studied parameters when administered alone, it significantly abolished the E2‐stimulated transcriptional response of the reporter gene for the three ER subtypes in U251‐MG cells, and clearly inhibited the E2 induction of Aro‐B in radial glial cells of zebrafish embryos. These inhibitory effects were accompanied by a significant downregulation of the expression of esr1, esr2a, esr2b and cyp19a1b genes compared to the E2‐treated group used as a positive control. Zn administration during simultaneous exposure to E2 and Cd strongly stimulated zebrafish ERs transactivation and increased Aro‐B protein expression, whereas mRNA levels of the three ERs as well as the cyp19a1b remained unchanged in comparison with Cd‐treated embryos. In conclusion, our results clearly demonstrate that Cd acts as a potent anti‐estrogen in vivo and in vitro, and that Cd‐induced E2 antagonism can be reversed, at the protein level, by Zn supplement. Copyright © 2016 John Wiley & Sons, Ltd.
Nanosized titanium dioxide resulted in the activation of TGF‐β/Smads/p38MAPK pathway in renal inflammation and fibration of mice
Authors: Hong F , Wu N , Ge Y , Zhou Y , Shen T , Qiang Q , Zhang Q , Chen M , Wang Y , Wang L , Hong J
Published: February 2016

Titanium dioxide nanoparticles (TiO2 NPs) have been demonstrated to damage the kidneys. However, whether chronic nephritis leads to renal fibration or the fibrosis is associated with the activation of TGF‐β/Smads/p38MAPK pathway caused by TiO2 NPs exposure is not well understood. Forty male mice were separately exposed to 0, 2.5, 5, or 10 mg/kg body weight TiO2 NPs for 6 months. Renal biochemical functions and levels of TGF‐β/Smads/p38MAPK pathway‐related markers and extracellular matrix (ECM) expression in the kidneys were investigated. The findings showed that subchronic TiO2 NPs exposure increased levels of urinary creatisix (Cr), N‐acetyl‐glucosaminidase, and vanin‐1, resulted in severe renal inflammation and fibration. Furthermore, TiO2 NP exposure upregulated expression of transforming growth factor‐β1 (TGF‐β1, 0.07‐ to 2.72‐fold), Smad2 (0.42‐ to 1.63‐fold), Smad3 (0.02‐ to 1.94‐fold), ECM (0.15‐ to 2.75‐fold), α‐smooth muscle actin (0.14‐ to 3.06‐fold), p38 mitogen‐activated protein kinase (p38MAPK, 0.11‐ to 3.78‐fold), and nuclear factor‐κB (0.4‐ to 2.27‐fold), and downregulated Smad7 (0.05‐ to 0.61‐fold) expression in mouse kidney. Subchronic TiO2 NPs exposure induced changes of renal characteristics towards inflammation and fibration may be mediated via TGF‐β/Smads/p38MAPK pathway, and the uses of TiO2 NPs should be carried out cautiously, especially in humans. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1452–1461, 2016.
Association of Serum hs‐CRP Levels With the Presence of Obesity, Diabetes Mellitus, and Other Cardiovascular Risk Factors
Authors: Ebrahimi Mahmoud , Heidari‐Bakavoli Ali Reza , Shoeibi Sara , Mirhafez Seyed Reza , Moohebati Mohsen , Esmaily Habibollah , Ghazavi Hamed , Saberi Karimian Maryam , Parizadeh Seyed Mohammad Reza , Mohammadi Maryam , Mohaddes Ardabili Hossein , Ferns Gordon A. , Ghayour‐Mobarhan Majid
Published: February 2016

Background

Diabetes mellitus remains one of the major health problems of the 21st century and is associated with comorbidities including obesity and metabolic abnormalities. The study was conducted to evaluate serum high‐sensitivity C‐reactive protein (hs‐CRP) levels, as a marker of inflammation, in a large sample of Iranian population without a history of cardiovascular or inflammatory disease and cancer, and to relate this to fasting blood glucose (FBG) and the presence of diabetes mellitus.

Methods

The study consisted of 7,762 subjects divided into four groups—nonobese/nondiabetic, obese/nondiabetic, nonobese/diabetic and obese/diabetic—based on the BMI classification and their FBG. Anthropometric characteristics were measured and blood was collected for the evaluation of fasted lipid profile, FBG and serum hs‐CRP levels.

Results

Several clinical and biochemical characteristics were significantly different among the four groups: FBG, P < 0.001; total cholesterol (TC), P < 0.001; and triglyceride (TG), P < 0.001. The subjects with a serum hs‐CRP >3 mg/dl had higher TC (P < 0.001), low‐density lipoprotein cholesterol (LDL‐C, P < 0.001), TG (P < 0.001), fat percentage (P < 0.001), and systolic and diastolic blood pressure (P < 0.001) compared with subjects with a serum hs‐CRP <3 mg/dl. Multivariate analysis showed FBG, LDL‐C, and waist circumference (WC) associated with increased serum hs‐CRP levels (P < 0.001).

Conclusions

FBG, LDL‐C, WC and gender are independently associated with serum hs‐CRP concentrations.
Dysfunction of subtelomeric methylation and telomere length in gallstone disease and gallbladder cancer patients of North Central India
Authors: Poojary Satish S , Mishra Gunja , Gupta Sanjiv , Shrivastav Braj Raj , Tiwari Pramod Kumar
Published: February 2016

Background

Telomeres play an important role in cancer progression. Recently it has been shown that subtelomeric methylation negatively regulates telomere length in various diseases, including cancers. Here, we evaluated the influence of subtelomeric methylation in telomere dysfunction in gallbladder cancer (GBC), and whether this dysfunction is affected by the presence of gallstones.

Methods

Relative telomere length and subtelomeric methylation levels were assessed using monochrome multiplex quantitative polymerase chain reaction and bisulfite sequencing, respectively, in different gallbladder tissue types including different grades of GBC, gallstones and adjacent non‐tumor.

Results

We found telomere length to shorten significantly in overall GBC, but specifically in early grade cancer. We also found D4Z4 and DNF92 subtelomeric sequences to be hypermethylated and hypomethylated, respectively, in GBC; however, their methylation levels differed significantly, only in early grade cancer. We could not find any specific correlation between subtelomeric methylation and telomere length in GBC. Interestingly, telomere length and subtelomeric methylation differed significantly in GBC without gallstones but not in GBC with gallstones.

Conclusions

This study, thus, suggests that telomere dysfunction and changes in methylation levels may occur earlier in the progression of GBC, while the presence of gallstones may have no influence on telomere length as well as on methylation levels.
A novel method for determination of inorganic oxyanions by electrospray ionization mass spectrometry using dehydration reactions
Authors: Kojima Hirochika , Kurihara Shota , Watanabe Yoshito , Iwamaru Koki , Sato Kiichi , Tsunoda Kin‐ichi , Hotta Hiroki
Published: February 2016

Novel methods for the determination of inorganic oxyanions by electrospray (ES) ionization mass spectrometry have been developed using dehydration reactions between oxyanions and carboxylic acids at the ES interface. Twelve oxyanions (VO3−, CrO42−, MoO42−, WO42−, BO33−, SiO32−, SiO44−, AsO44−, AsO2−, SeO42−, SeO32− and NO2−), out of 16 tested, reacted with at least one of four aminopolycarboxylic acids, i.e. iminodiacetic acid (IDA), nitrilotriacetic acid (NTA), trans‐1,2‐diaminocyclohexane‐N,N,N′,N′‐tetraacetic acid and triethylenetetramine‐N,N,N′,N″,N′″,N′″‐hexaacetic acid, at the ES interface to produce the dehydration products that gave intense mass ion responses, sufficient for trace analysis. As examples, trace determinations of CrVI and silica in water samples were achieved after online ion exchange chromatography, where the dehydration product of CrO42− and NTA (m/z 290) and that of SiO44− and IDA (m/z 192) were measured. The limits of detection of the respective methods were 17 nM (0.83 ng Cr/ml) for CrVI and 0.17 μM (4.8 ng Si/mL) for SiO44−. Copyright © 2016 John Wiley & Sons, Ltd.
Impaired physical function following pediatric LT
Authors: Feldman Amy G. , Neighbors Katie , Mukherjee Shubhra , Rak Melanie , Varni James W. , Alonso Estella M.
Published: February 2016

The purpose of this article is to investigate the spectrum of physical function of pediatric liver transplantation (LT) recipients 12‐24 months after LT. Review data were collected through the functional outcomes group, an ancillary study of the Studies of Pediatric Liver Transplantation registry. Patients were eligible if they had survived LT by 12‐24 months. Children ≥ 8 years and parents completed the Pediatric Quality of Life Inventory™ 4.0 generic core scales, which includes 8 questions assessing physical function. Scores were compared to a matched healthy child population (n = 1658) and between survivors with optimal versus nonoptimal health. A total of 263 patients were included. Median age at transplant and survey was 4.8 years (interquartile range [IQR], 1.3‐11.4 years) and 5.9 years (IQR, 2.6‐13.1 years), respectively. The mean physical functioning score on child and parent reports were 81.2 ± 17.3 and 77.1 ± 23.7, respectively. Compared to a matched healthy population, transplant survivors and their parents reported lower physical function scores (P < 0.001); 32.9% of patients and 35.0% of parents reported a physical function score <75, which is > 1 standard deviation below the mean of a healthy population. Physical functioning scores were significantly higher in survivors with optimal health than those with nonoptimal health (P < 0.01). There was a significant relationship between emotional functioning and physical functioning scores for LT recipients (r = 0.69; P < 0.001). In multivariate analysis, primary disease, height z score < –1.64 at longterm follow‐up (LTF) visit,  > 4 days of hospitalization since LTF visit, and not being listed as status 1 were predictors of poor physical function. In conclusion, pediatric LT recipients 1‐2 years after LT and their parents report lower physical function than a healthy population. Findings suggest practitioners need to routinely assess physical function, and the development of rehabilitation programs may be important. Liver Transplantation 22 495‐504 2016 AASLD
Atrioventricular conduction disturbances immediately after hepatic graft reperfusion and their outcomes in patients undergoing liver transplantation
Authors: Kim Sung‐Hoon , Moon Young‐Jin , Lee Sooho , Jeong Sung‐Moon , Song Jun‐Gol , Hwang Gyu‐Sam
Published: February 2016

Hemodynamic perturbation during hepatic graft reperfusion in patients undergoing liver transplantation (LT) is challenging and is frequently accompanied by bradyarrhythmia and even asystole. However, detailed data on electrocardiographic (ECG) changes during reperfusion are almost nonexistent, although the correct diagnosis by record is important for the treatment. We aimed to identify ECG rhythm disturbances during graft reperfusion and to investigate risk factors and outcomes. Data from 1065 consecutive patients who underwent adult LT were analyzed. The incidence, type, and detailed characteristics of ECG changes immediately after graft reperfusion were assessed using an electronically archived intraoperative ECG database. We analyzed risk factors, postoperative outcomes including major cardiovascular events, 30‐day and 1‐year mortalities of recipients based on the occurrence of atrioventricular (AV) block, and asystole during reperfusion. The typical pattern of postreperfusion bradyarrhythmia was progressive PR interval prolongation until a Mobitz type 1 AV block occurred. The overall incidence of AV block was 5.0% (53/1065), and 30.2% of them (16/53) had initiated as AV block and then progressed into ventricular asystole. Fulminant hepatic failure was a significant predictor for occurrence of AV block (odds ratio [OR], 7.20; 95% confidence interval, 3.38‐15.32; P < 0.001). Patients with AV block showed significantly higher incidence of postoperative major cardiovascular events (P < 0.001) and 30‐day mortality (P = 0.002) than those without AV block, whereas the 1‐year mortality was not different between the 2 groups (P = 0.10). The postreperfusion asystole was consistently preceded by a Mobitz type 1 AV block. The occurrence of AV block and asystole appears to be an important prognosticator. Therefore, maintaining an optimal range of physiological status and gradual unclamping of the vena cava to avoid sudden atrial distension are recommended in high‐risk patients during reperfusion period. Liver Transplantation 22 956–967 2016 AASLD
Biological activity of the bryostatin analog Merle 23 on mouse epidermal cells and mouse skin
Authors: Kelsey Jessica S. , Cataisson Christophe , Chen Jinqiu , Herrmann Michelle A. , Petersen Mark E. , Baumann David O. , McGowan Kevin M. , Yuspa Stuart H. , Keck Gary E. , Blumberg Peter M.
Published: February 2016

Bryostatin 1, a complex macrocyclic lactone, is the subject of multiple clinical trials for cancer chemotherapy. Although bryostatin 1 biochemically functions like the classic mouse skin tumor promoter phorbol 12‐myristate 13‐acetate (PMA) to bind to and activate protein kinase C, paradoxically, it fails to induce many of the typical phorbol ester responses, including tumor promotion. Intense synthetic efforts are currently underway to develop simplified bryostatin analogs that preserve the critical functional features of bryostatin 1, including its lack of tumor promoting activity. The degree to which bryostatin analogs maintain the unique pattern of biological behavior of bryostatin 1 depends on the specific cellular system and the specific response. Merle 23 is a significantly simplified bryostatin analog that retains bryostatin like activity only to a limited extent. Here, we show that in mouse epidermal cells the activity of Merle 23 was either similar to bryostatin 1 or intermediate between bryostatin 1 and PMA, depending on the specific parameter examined. We then examined the hyperplastic and tumor promoting activity of Merle 23 on mouse skin. Merle 23 showed substantially reduced hyperplasia and was not tumor promoting at a dose comparable to that for PMA. These results suggest that there may be substantial flexibility in the design of bryostatin analogs that retain its lack of tumor promoting activity. © 2016 Wiley Periodicals, Inc.
GCV for Tikhonov regularization via global Golub–Kahan decomposition
Authors: Fenu Caterina , Reichel Lothar , Rodriguez Giuseppe
Published: February 2016

Generalized cross validation is a popular approach to determining the regularization parameter in Tikhonov regularization. The regularization parameter is chosen by minimizing an expression, which is easy to evaluate for small‐scale problems, but prohibitively expensive to compute for large‐scale ones. This paper describes a novel method, based on Gauss‐type quadrature, for determining upper and lower bounds for the desired expression. These bounds are used to determine the regularization parameter for large‐scale problems. Computed examples illustrate the performance of the proposed method and demonstrate its competitiveness. Copyright © 2016 John Wiley & Sons, Ltd.
The clinical characteristics and hospital and post‐hospital survival of patients with the obesity hypoventilation syndrome: analysis of a large cohort
Authors: Marik P. E. , Chen C.
Published: February 2016

Objective

The worldwide prevalence of obesity has reached epidemic proportions. Obesity hypoventilation syndrome (OHS) is a common yet largely undiagnosed and mistreated condition that likely carries a high mortality. The aim of this study was to determine the clinical characteristics, hospital outcome, outcome following hospital discharge and predictors of death in a large cohort of patients hospitalized with OHS. OHS is an important condition as many patients with this syndrome are misdiagnosed and receive inappropriate treatment.

Methods

We reviewed the electronic medical records of patients with unequivocal OHS admitted to a 525‐bed tertiary‐care teaching hospital over a 5‐year period. Demographic and clinical data as well as hospital disposition were recorded. In order to determine the patients' post‐discharge status, we linked our database to the database of death certificates of the State Registrar of Vital Records.

Results

We identified 600 patients who met the inclusion criteria for this study. The patients' mean age was 58 ± 15 years with a mean body mass index of 48.2 ± 8.3 kg m−2; 64% were women. Thirty‐seven percent had a history of diabetes and 43% had been misdiagnosed as having chronic obstructive pulmonary disease, while none had been previously diagnosed with OHS. The most common admission diagnoses were respiratory failure, heart failure and sepsis. Ninety (15%) patients died during the index hospitalization. The patients' age, S‐creatinine, respiratory failure, sepsis and admission to the ICU were independent predictors of hospital mortality. The hospital survivors were followed for a mean of 1,174 ± 501 d (3.2 ± 1.3 years) from the index hospitalization. On follow‐up, 98 of the 510 (19%) hospital survivors died, with an overall cumulative mortality of 31.3%. The patients' age, S‐creatinine and admission to the ICU were independent predictors of post‐hospital mortality.

Conclusion

Obesity hypoventilation syndrome is a common disease that is frequently misdiagnosed and mistreated and carries a 3‐year morality, which is significantly worse than that for most cancers combined. Considering the high mortality of this disease, all patients with a body mass index > 35 kg m−2 should be screened for OHS; those patients with both early and established OHS should be referred to a pulmonary and/or sleep specialist for evaluation for non‐invasive positive pressure ventilation, to a dietician for dietary counseling and lifestyle modification and to a bariatric surgeon for evaluation for bariatric surgery.
Microcellular foaming of polylactide and poly(butylene adipate‐co‐terphathalate) blends and their CaCO3 reinforced nanocomposites using supercritical carbon dioxide
Authors: Shi Xuetao , Zhang Guangcheng , Liu Yang , Ma Zhonglei , Jing Zhanxin , Fan Xun
Published: February 2016

Foamed polylactide (PLA), PLA–PBAT (poly (butylene adipate‐co‐terphathalate)) blend and their composites with CaCO3 were prepared in a batch process using supercritical carbon dioxide (CO2) at 12 MPa and 45°C. The solubility of CO2 and its diffusion patterns in different PLA samples was investigated. PLA systems had a relatively high CO2 solubility related to the carboxyl groups. CO2 desorption behaviors in PLA systems first followed the Fickian diffusion mechanism in short time and then decreased slowly to a plateau. The addition of both PBAT and CaCO3 into PLA impeded the desorption of CO2. In the presence of second phase PBAT, nanoparticles CaCO3 and dissolved CO2, the PLA crystallization behavior investigated by DSC technique was greatly changed. As the desorption time increased, the gas induced crystallinity slightly decreased in consequence of less CO2 content in each system and thus less plasticization effect. The cell morphology of foamed PLA and PLA composites showed interesting microstructure patterns. The prepared pure PLA foam exhibits a typical bimodal structure because of the foaming in both the amorphous and crystalline zones. With PBAT and CaCO3 into PLA, the composite foam presented significant increase in cell uniformity and cell density. With less CO2 content in each PLA sample, the cell structure showed interesting variation. Pure PLA foam presented transition from bimodal structure to more uniform cell structure with decreased cell density. In contract, PLA–PBAT foam show unfoamed regions because of none CO2 left in the separated PBAT phase. Copyright © 2016 John Wiley & Sons, Ltd.
Morphometric human embryonic brain features according to developmental stage
Authors: Kobayashi Ami , Ishizu Koichi , Yamada Shigehito , Uwabe Chigako , Kose Katsumi , Takakuwa Tetsuya
Published: February 2016

Objectives

The present study investigated linear, area, and volume measurements of human brain samples according to Carnegie stages (CS) in an attempt to select suitable morphometric features that reflect embryonic development.

Methods

Using magnetic resonance imaging, we measured seven linear segments, three separate areas, and three regional volumes in 101 samples between CS13 and 23. Brain volume was determined via manual segmentation of the magnetic resonance image, whereby a formula was generated to estimate the volume of each linear measurement.

Results

All parameters correlated with crown‐rump length. Bitemporal length and mesencephalic height increased linearly according to the CS, and a high correlation between bitemporal length and both whole‐brain (r = 0.98) and prosencephalon (r = 0.99) volumes was found when brain cavity volume was excluded.

Conclusion

Morphometric data related to human embryonic stages are valuable for correcting and comparing sonographic data. The present approach may contribute to improvements in prenatal diagnostics by enabling the selection of more suitable measurements during early embryonic stages. © 2016 John Wiley & Sons, Ltd.
Myocardial effects of fetal endoscopic tracheal occlusion in lambs with CDH
Authors: Zambaiti Elisa , Bussani Rossana , Calcaterra Valeria , Zandonà Lorenzo , Silvestri Furio , Peiró José Luis , Marotta Mario , Andreatta Erika , Pelizzo Gloria
Published: February 2016

Introduction

Fetal endoscopic tracheal occlusion in congenital diaphragmatic hernia (CDH) may reduce pulmonary hypertension and ameliorate postnatal cardiac output. The effects of sustained early (ETO) and late (LTO) tracheal occlusion on left ventricular (LV) cells in the lamb model have not been described.

Materials and methods

CDH was created in lambs at 70 days' gestation (term = 145 days). ETO (85 days) or LTO (105 days) was sustained till term. After cesarean section (140 days) fetuses were euthanized and hearts harvested. LV myocardial cells were studied by histological and immunofluorescence (TGF‐beta 1, endothelin‐1) assays in CDH, ETO, LTO, and the control group (two subjects per group). Small intramyocardial arteries were evaluated by traditional histology.

Results

LV myocardial histology in CDH and LTO was similar. ETO‐induced LV myocardial cell enlargement and increased endothelin‐1 and TGF‐beta 1 staining; a weaker immunofluorescence signal was observed in LTO compared with ETO. Myocardial vascular wall thickness was greater in CDH than in controls. ETO was associated with a vascular wall thickness within the range of controls.

Conclusion

With only two fetuses in each group, only an explorative evaluation was possible. The time point at which TO is performed seems to have an effect on cardiac morphology. Functional studies as well as confirmation in clinical samples are mandatory. © 2016 John Wiley & Sons, Ltd.
Structure of iron saturated C‐lobe of bovine lactoferrin at pH 6.8 indicates a weakening of iron coordination
Authors: Rastogi Nilisha , Singh Avinash , Singh Prashant K. , Tyagi Tapesh K. , Pandey Sada , Shin Kouichirou , Kaur Punit , Sharma Sujata , Singh Tej P.
Published: February 2016

The bilobal lactoferrin is an approximately 76 kDa glycoprotein. It sequesters two Fe3+ ions together with two
ions. The C‐terminal half (residues, Tyr342–Arg689, C‐lobe) of bovine lactoferrin (BLF) (residues Ala1–Arg689) was prepared by limited proteolysis using trypsin. Both C‐lobe and intact BLF were saturated to 100%. Both of them retained up to nearly 85% of iron at pH 6.5. At pH 5.0, C‐lobe retained 75% of iron whereas intact protein could retain only slightly more than 60%. At pH 4.0 both contained 25% iron and at pH 2.0 they were left with iron concentration of only 10%. The structure of iron saturated C‐lobe was determined at 2.79 Å resolution and refined to Rcryst and Rfree factors of 0.205 and 0.273, respectively. The structure contains two crystallographically independent molecules, A and B. They were found to have identical structures with an r.m.s. shift of 0.5 Å for their Cα atoms. A high solvent content of 66% was observed in the crystals. The average value of an overall B‐factor was 68.0 Å2. The distance of 2.9 Å observed for the coordination bond between Fe3+ ion and Ne2 of His595 appeared to be considerably longer than the normally observed values of 1.9–2.2 Å. This indicated that the coordination bond involving His595 may be absent. Other coordination distances were observed in the range of 2.1–2.3 Å. Based on the present structure of iron saturated C‐lobe, it may be stated that His595 is the first residue to dissociate from ferric ion when the pH is lowered. Proteins 2016; 84:591–599. © 2016 Wiley Periodicals, Inc.
Structure prediction using sparse simulated NOE restraints with Rosetta in CASP11
Authors: Ovchinnikov Sergey , Park Hahnbeom , Kim David E. , Liu Yuan , Wang Ray Yu‐Ruei , Baker David
Published: February 2016

In CASP11 we generated protein structure models using simulated ambiguous and unambiguous nuclear Overhauser effect (NOE) restraints with a two stage protocol. Low resolution models were generated guided by the unambiguous restraints using continuous chain folding for alpha and alpha‐beta proteins, and iterative annealing for all beta proteins to take advantage of the strand pairing information implicit in the restraints. The Rosetta fragment/model hybridization protocol was then used to recombine and regularize these models, and refine them in the Rosetta full atom energy function guided by both the unambiguous and the ambiguous restraints. Fifteen out of 19 targets were modeled with GDT‐TS quality scores greater than 60 for Model 1, significantly improving upon the non‐assisted predictions. Our results suggest that atomic level accuracy is achievable using sparse NOE data when there is at least one correctly assigned NOE for every residue. Proteins 2016; 84(Suppl 1):181–188. © 2016 Wiley Periodicals, Inc.
Molecular modeling of antibodies for the treatment of TNFα‐related immunological diseases
Authors: Pierri Ciro Leonardo , Bossis Fabrizio , Punzi Giuseppe , De Grassi Anna , Cetrone Michela , Parisi Giovanni , Tricarico Domenico
Published: February 2016

Therapeutic monoclonal antibodies (mAbs) have high efficacy in treating TNFα‐related immunological diseases. Other than neutralizing TNFα, these IgG1 antibodies exert Fc receptor‐mediated effector functions such as the complement‐dependent cytotoxicity (CDC) and antibody‐dependent cell cytotoxicity (ADCC). The crystallizable fragment (Fc) of these IgG1 contains a single glycosylation site at Asn 297/300 that is essential for the CDC and ADCC. Glycosylated antibodies lacking core fucosylation showed an improved ADCC. However, no structural data are available concerning the ligand‐binding interaction of these mAbs used in TNFα‐related diseases and the role of the fucosylation. We therefore used comparative modeling for generating complete 3D mAb models that include the antigen‐binding fragment (Fab) portions of infliximab, complexed with TNFα (4G3Y.pdb), the Fc region of the human IGHG1 fucosylated (3SGJ) and afucosylated (3SGK) complexed with the Fc receptor subtype FcγRIIIA, and the Fc region of a murine immunoglobulin (1IGT). After few thousand steps of energy minimization on the resulting 3D mAb models, minimized final models were used to quantify interactions occurring between FcγRIIIA and the fucosylated/afucosylated Fc fragments. While fucosylation does not affect Fab‐TNFα interactions, we found that in the absence of fucosylation the Fc–mAb domain and FcγRIIIA are closer and new strong interactions are established between G129 of the receptor and S301 of the Chimera 2 Fc mAb; new polar interactions are also established between the Chimera 2 Fc residues Y299, N300, and S301 and the FcγRIIIA residues K128, G129, R130, and R155. These data help to explain the reduced ADCC observed in the fucosylated mAbs suggesting the specific AA residues involved in binding interactions.
Taurolidine and congeners activate hTRPA1 but not hTRPV1 channels and stimulate CGRP release from mouse tracheal sensory nerves
Authors: Kichko Tatjana I. , Pfirrmann Rolf W. , Reeh Peter W.
Published: February 2016

Taurolidine has long been in clinical use as an antimicrobial irrigation that does not impede wound healing. It can even be administered intravenously (30 g/day) to treat sepsis or to exert newly recognized antineoplastic actions. Only one irritant effect is reported, that is, to temporarily induce burning pain of unknown origin when applied to body cavities or peripheral veins. The structure of the molecule suggested the chemoreceptor channel TRPA1 as a potential target, which was verified measuring stimulated CGRP release from sensory nerves of the isolated mouse trachea and calcium influx in hTRPA1‐transfected HEK293 cells. With both methods, the concentration–response relationship of taurolidine exceeded the threshold value below 500 μmol/L and 100 μmol/L, respectively, and reached saturation at 1 mmol/L. The clinical 2% taurolidine solution did not evoke greater or longer lasting responses. The reversible tracheal response was abolished in TRPA1−/− but retained in TRPV1−/− mice. Consistently, hTRPV1‐HEK showed no calcium influx as a response, likewise native HEK293 cells and hTRPA1‐HEK deprived of extracellular calcium did not respond to taurolidine 1 mmol/L. The metabolite taurultam and its oxathiazine derivative, expected to cause less burning pain, showed weak tracheal irritancy only at 10 mmol/L, acting also through hTRPA1 but not hTRPV1. In conclusion, taurolidine, its metabolite, and a novel derivative showed no unspecific cellular effects but selectively, concentration‐dependently and reversibly activated the irritant receptor TRPA1 in CGRP‐expressing, thus nociceptive, neurons. The clinical solution of 2% taurolidine (~70 mmol/L) can, thus, rightly be expected to cause transient burning pain and neurogenic inflammation.
Preclinical and translational evaluation of coagulation factor IXa as a novel therapeutic target
Authors: Ankrom Wendy , Wood Harold B. , Xu Jiayi , Geissler Wayne , Bateman Tom , Chatterjee Manash S. , Feng Kung‐I , Metzger Joseph M. , Strapps Walter R. , Tadin‐Strapps Marija , Seiffert Dietmar , Andre Patrick
Published: February 2016

The benefits of novel oral anticoagulants are hampered by bleeding. Since coagulation factor IX (fIX) lies upstream of fX in the coagulation cascade, and intermediate levels have been associated with reduced incidence of thrombotic events, we evaluated the viability of fIXa as an antithrombotic target. We applied translational pharmacokinetics/pharmacodynamics (PK/PD) principles to predict the therapeutic window (TW) associated with a selective small molecule inhibitor (SMi) of fIXa, compound 1 (CPD1, rat fIXa inhibition constant (Ki, 21 nmol/L) relative to clinically relevant exposures of apixaban (rat fXa Ki 4.3 nmol/L). Concentrations encompassing the minimal clinical plasma concentration (Cmin) of the 5 mg twice daily (BID) dose of apixaban were tested in rat arteriovenous shunt (AVS/thrombosis) and cuticle bleeding time (CBT) models. An Imax and a linear model were used to fit clot weight (CW) and CBT. The following differences in biology were observed: (1) antithrombotic activity and bleeding increased in parallel for apixaban, but to a lesser extent for CPD1 and (2) antithrombotic activity occurred at high (>99%) enzyme occupancy (EO) for fXa or moderate (>65% EO) for fIXa. translational PK/PD analysis indicated that noninferiority was observed for concentrations of CPD1 that provided between 86% and 96% EO and that superior TW existed between 86% and 90% EO. These findings were confirmed in a study comparing short interfering (si)RNA‐mediated knockdown (KD) modulation of fIX and fX mRNA. In summary, using principles of translational biology to relate preclinical markers of efficacy and safety to clinical doses of apixaban, we found that modulation of fIXa can be superior to apixaban.
ADME studies of [5‐3H]‐2′‐O‐methyluridine nucleoside in mice: a building block in siRNA therapeutics
Authors: Lozac'h Frederic , Christensen Jesper , Faller Thomas , van de Kerkhof Esther , Krauser Joel , Garnier Maxime , Litherland Karine , Catoire Alexandre , Natt Francois , Hunziker Jurg , Swart Piet
Published: February 2016

The chemical modification 2′‐O‐methyl of nucleosides is often used to increase siRNA stability towards nuclease activities. However, the metabolic fate of modified nucleosides remains unclear. Therefore, the aim of this study was to determine the mass balance, pharmacokinetic, and absorption, distribution, metabolism, and excretion (ADME)‐properties of tritium‐labeled 2′‐O‐methyluridine, following a single intravenous dose to male CD‐1 mice. The single intravenous administration of [5‐3H]‐2′‐O‐methyluridine was well tolerated in mice. Radioactivity was rapidly and widely distributed throughout the body and remained detectable in all tissues investigated throughout the observation period of 48 h. After an initial rapid decline, blood concentrations of total radiolabeled components declined at a much slower rate. [3H]‐2′‐O‐Methyluridine represented a minor component of the radioactivity in plasma (5.89% of [3H]‐AUC0‐48 h). Three [3H]‐2′‐O‐methyluridine metabolites namely uridine (M1), cytidine (M2), and uracil (M3) were the major circulating components representing 32.8%, 8.11%, and 23.6% of radioactivity area under the curve, respectively. The highest concentrations of total radiolabeled components and exposures were observed in kidney, spleen, pineal body, and lymph nodes. The mass balance, which is the sum of external recovery of radioactivity in excreta and remaining radioactivity in carcass and cage wash, was complete. Renal excretion accounted for about 52.7% of the dose with direct renal excretion of the parent in combination with metabolism to the endogenous compounds cytidine, uracil, cytosine, and cytidine.
Magnetic phase transitions in ZnO doped by transition metals
Authors: Yuldashev Shavkat , Yalishev Vadim , Yunusov Ziyodbek , Kwon Younghae , Kang Tae Won
Published: February 2016

In this work we present the results on experimental study of magnetic phase transitions in ZnO thin films doped by Mn and Co by using the thermal diffusivity and specific heat measurements. The inverted lambda‐shaped peaks observed in the temperature dependencies of the thermal diffusivity demonstrate the existence of the second order phase transitions in these samples. The magnetic entropy derived from the specific heat gives the number of magnetic ions involved in the magnetic ordering. (© 2016 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Evidence of exchange interaction of localized carriers and transition metals in diluted II‐VI nanostructures: ODMR study
Authors: Baranov P. G. , Romanov N. G. , Tolmachev D. O. , Gurin A. S. , Namozov B. R. , Kusrayev Yu. G. , Karczewski G. , Orlinskii S. , De Mello Donega C. , Schmidt J.
Published: February 2016

Optically detected magnetic resonance study of (CdMn)Te/(CdMg)Te quantum wells allowed to reveal the formation of exchange‐coupled complexes consisting of Mn ions and localized holes in quantum wells with excess hole concentration and the directional electron tunneling towards wider wells in multiple quantum well structures. The existence of a distribution of Mn‐hole complexes that differ in a number of Mn ions interacting with a localized hole is justified.

In colloidal cobalt doped ZnO nanocrystals, several nm in diameter, the interaction between the magnetic ions and the shallow donor electron in the confined system of ZnO quantum dots has been revealed. Direct evidence of interaction of Co ions with the interstitial Li shallow donor in the ZnO nanocrystal core and hyperfine coupling with 1H in the quantum dot shell have been demonstrated. (© 2016 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Application of the difference spectroscopy for studying of complex acceptors in CdTe
Authors: Bagaev Victor , Krivobok Vladimir , Nikolaev Sergey , Onischenko Evgeny , Pruchkina Anna
Published: February 2016

Wavelength modulation of the excitation source combined with the analysis of the differential PL signal have been applied to studying of electronic spectra of acceptors in compensated CdTe:Cl, CdTe:Ag,Cl single crystals. For the Cl‐related complex acceptor with an activation energy of ∼121 meV (A‐center), the energies of eight excited states are measured. In the case of tetrahedral AgCdacceptor the splitting of 2P3/2 (Γ8) and 2S3/2 (Γ8) states has been revealed for AgCd centres located at a short distances (5‐7 nm) from a hydrogen‐like donor (ClTe). A method allowing a simple symmetry test for acceptors in a diverse zinc‐blende compound semiconductor is proposed. (© 2016 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Acceleration Factor Constant Principle and the Application under ADT
Authors: Wang Hao‐Wei , Xi Wen‐Jun
Published: February 2016

Accelerated degradation test (ADT) has become an efficient approach to evaluate the reliability for highly reliable products. However, when modeling accelerated degradation data with degradation models, it is difficult to exactly figure out the changing rules of parameters with stress variables varying. At present, the changing rules are mainly assumed according to engineering experience or subjective judgements, which probably results in inaccurately extrapolating the reliability. To figure out the changing rules of parameters with stress variables varying, the acceleration factor constant principle and its application under ADT are studied in the paper. It is well known that the acceleration factor between any two different stress levels should be a constant under an effective ADT. For each degradation model, its parameters should obey special changing rules to satisfy that the acceleration factor maintains a constant throughout an ADT. Taking three extensively used stochastic process models as examples, including Wiener process model, gamma process model, and inverse Gaussian process model, the method of deducing the changing rules of the parameters according to the acceleration factor constant principle was demonstrated. A simulation test was conducted to validate the deduced changing rules of the parameters for the three stochastic process models. An illustrative example involving self‐regulating heating cables was used to illustrate the application of the acceleration factor constant principle under ADT. Results indicate that the acceleration factor constant principle offers an appealing and credible approach to help model accelerated degradation data. Copyright © 2016 John Wiley & Sons, Ltd.
The fragility of standard inferential approaches in principal stratification models relative to direct likelihood approaches
Authors: Frumento Paolo , Mealli Fabrizia , Pacini Barbara , Rubin Donald B.
Published: February 2016

Many empirical settings involve the specification of models leading to complicated likelihood functions, for example, finite mixture models that arise in causal inference when using Principal Stratification (PS). Traditional asymptotic results cannot be trusted for the associated likelihood functions, whose logarithms are not close to being quadratic and may be multimodal even with large sample sizes. We first investigate the shape of the likelihood function with models based on PS by providing diagnostic tools for evaluating ellipsoidal approximations based on the second derivatives of the log‐likelihood at a mode. In these settings, inference based on standard approximations is inappropriate, and other forms of inference are required. We explore the use of a direct likelihood approach for parsimonious model selection and, specifically, propose comparing values of scaled maximized likelihood functions under competitive models to select preferred models. An extensive simulation study provides guidelines, for calibrating the use of scaled log‐likelihood ratio statistics, as functions of the complexity of the models being compared.
Modeling lightcurves for improved classification of astronomical objects
Authors: Faraway Julian , Mahabal Ashish , Sun Jiayang , Wang Xiao‐Feng , Wang Yi G. , Zhang Lingsong
Published: February 2016

Many synoptic surveys are observing large parts of the sky multiple times. The resulting time series of light measurements, called lightcurves, provide a wonderful window to the dynamic nature of the Universe. However, there are many significant challenges in analyzing these lightcurves. We describe a modeling‐based approach using Gaussian process regression for generating critical measures for the classification of such lightcurves. This method has key advantages over other popular nonparametric regression methods in its ability to deal with censoring, a mixture of sparsely and densely sampled curves, the presence of annual gaps caused by objects not being visible throughout the year from a given position on Earth and known but variable measurement errors. We demonstrate that our approach performs better by showing it has a higher correct classification rate than past methods popular in astronomy. Finally, we provide future directions for use in sky‐surveys that are getting even bigger by the day. © 2016 Wiley Periodicals, Inc. Statistical Analysis and Data Mining: The ASA Data Science Journal, 2016
The crown joules: Resource peaks and monetary hegemony
Authors: Sager Jalel
Published: February 2016

Global energy and monetary systems appear to be deeply linked. Whereas mainstream economics focuses on the exchange aspects of the energy trade over the more structural aspects, the biophysical view of ecological economics and the historical economic thought exemplified by William Jevons help explain why monetary hegemony has correlated with large energy surpluses in the past. When such surpluses begin to decline, dramatic changes in monetary and financial systems often ensue—as was the case in the twentieth‐century United Kingdom and United States and, I argue, as is the case in twenty‐first‐century China. Considering energy and finance as linked systems allows us to more clearly understand the contemporary global economic and climate impasse—and to include China's monetary role in the new century as part of a larger solution.