bluuebunny/crossref_metadata_2025 huggingface dataset:
Standard and optimized carry trades
Authors: Reichenecker Jurij‐Andrei
Published: March 2018

Drawdown periods of standard carry trades are primarily the result of losses in classic carry trade currencies. These periods coincide with an increased financial stress, such as the recent financial crisis. The introduced optimized carry trades employ a dynamic weighting scheme for currencies, which incorporates general risk components. Optimized carry trades are therefore less exposed to losses under financial stress, and provide an enhanced risk‐return profile over the entire and second half of the sample period and during periods of volatile markets. These results find robust statistical evidence. Furthermore, optimized carry trades have a lower correlation with traditional asset classes than standard carry trades. Traditional models of risk are less successful in explaining the returns of optimized carry trades.
Imaging manifestations of sepsis‐associated encephalopathy
Authors: Wu Huiying , Xu Yikai , Xu Wenbiao
Published: March 2018

The purpose of this study was to retrospectively analyze the clinical and imaging data of sepsis‐associated encephalopathy (SAE) following infantile diarrhea. Eight infants were diagnosed with SAE after diarrhea and assessed using computed tomography (CT) and magnetic resonance imaging (MRI). The main symptoms present in each of the eight patients were fever, diarrhea, seizures, and changes in consciousness. From cranial CT examination, five patients showed normal results, two displayed cerebral edema, and one displayed slightly lower density areas in the frontal and parietal lobes. There were four patients examined through MRI: one patient displayed slightly widened cerebral sulci; two displayed edema in the white cerebral matter and basal ganglia with gyriform enhancement after contrast; one displayed an abnormal bilateral signal in the occipital lobes and another in the frontoparietal lobe; and one displayed a diffuse abnormal signal in the white matter of both cerebral hemispheres and basal ganglia. Imaging manifestations of SAE included encephaledema or abnormal signals in the white matter and basal ganglia. CT examination can exclude other cerebral pathologies causing brain dysfunction in early stages. MRI examination can provide more information to aid in the early diagnosis of SAE.
Diagnostic and prognostic value of serum miR‐15a and miR‐16‐1 expression among egyptian patients with prostate cancer
Authors: Zidan Haidy E. , Abdul‐Maksoud Rehab S. , Elsayed Walid S. H. , Desoky Esam A. M.
Published: March 2018

Prostate cancer (PCa) is considered the most common malignancy in men. The aim of this study is to assess the role of serum miR‐15a and miR‐16‐1 expression in PCa development, diagnosis and prognosis aiming to find a specific noninvasive biomarker. This study comprised 70 patients with PCa, 70 patients complaining of benign prostatic hyperplasia (BPH), 30 patients with chronic prostatitis and 70 controls. Circulating miR‐15a and miR‐16‐1 expression was detected by real‐time polymerase chain reaction. Prostate specific antigen levels were measured by enzyme‐linked immunosorbent assay. The expression levels of serum miR‐15a were decreased in PCa patients compared with controls, chronic prostatitis and BPH patients (0.43 ± 0.12, 1.7 ± 0.76, 1.56 ± 0.34 and 1.53 ± 0.65, respectively). The expression levels of serum miR‐16‐1 were decreased in PCa patients compared with controls, chronic prostatitis and BPH patients (0.55 ± 0.23, 2.15 ± 0.87, 2.08 ± 0.54 and 1.96 ±0.61, respectively). Downregulation of miR‐15a and miR‐16‐1 correlated with higher Gleason score (P = 0.002 and P = 0.006, respectively), higher tumor stage (P = 0.001 and P = 0.01, respectively), PCa metastasis (P = 0.002 and P = 0.025, respectively) and lymph node involvement (P = 0.02 and P = 0.007, respectively). Moreover, Receiver operating characteristic curve analysis revealed that combined miR‐15a/miR‐16‐1 and PSA increased the sensitivity and specificity for the diagnosis of PCa (97.1% and 94.3%, respectively) more than prostate specific antigen alone (82.9% sensitivity and 75.7% specificity). Combined serum miR‐15a/miR‐16‐1 expression and PSA level can be used as promising specific noninvasive biomarkers in the diagnosis and prognosis of PCa better than prostate specific antigen alone. © 2018 IUBMB Life, 70(5):437–444, 2018
Osteogenic stimulation of human dental pulp stem cells with a novel gelatin‐hydroxyapatite‐tricalcium phosphate scaffold
Authors: Gu Yingzhi , Bai Yuxing , Zhang Dongliang
Published: March 2018

The aim of the present study was to construct and compare gelatin‐HA‐TCP scaffolds with a gelatin‐only scaffold and to investigate the effect of the scaffold on osteogenic differentiation of human dental pulp stem cells. We developed a novel scaffold for bone tissue engineering via a solution casting/particle washing method, and the physical and mechanical properties of the scaffolds were examined using scanning electron microscopy and a universal testing machine, respectively. Scaffold cytotoxicity toward human dental pulp stem cells (hDPSCs) was evaluated with the CCK8 method, and hDPSC differentiation was evaluated with an alkaline phosphatase activity assay, alizarin red S staining, and reverse transcription‐polymerase chain reaction (RT‐PCR). Our results indicate that the gelatin‐HA‐TCP scaffolds exhibited good homogeneity, interconnected pores, and relatively high mechanical strength and water absorption rates. A significant increase in hDPSC proliferation and ALP activity that stimulated mineralization of the hDPSC‐generated matrix was also seen on gelatin‐HA‐TCP scaffolds compared with the gelatin‐only scaffolds. In addition, RT‐PCR revealed that the gelatin‐HA‐TCP scaffold upregulated gene expression of the osteogenic markers Runx2, bone sialoprotein, and OSX. In conclusion, gelatin‐HA‐TCP scaffolds presented better mechanical properties, cytocompatibility and differentiation‐inducing characteristics than gelatin scaffolds. These results indicate that the novel hydrogel gelatin‐HA‐TCP scaffolds may be a promising biomaterial for bone tissue engineering. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1851–1861, 2018.
Silica coating followed by heat‐treatment of MDP‐primer for resin bond stability to yttria‐stabilized zirconia polycrystals
Authors: Dal Piva Amanda M. O. , Carvalho Ronaldo L. A. , Lima Aline L. , Bottino Marco A. , Melo Renata M. , Valandro Luiz Felipe
Published: March 2018

This study evaluated the influence of silica coating, primer type and its heat treatment on bond strength durability between resin cement and an yttrium‐stabilized polycrystalline tetragonal zirconia (Y‐TZP). Eighty (80) Y‐TZP blocks were allocated into 16 groups considering four factors: silica coating (without and with); type of primer (RelyX Ceramic Primer, a silane‐based primer; Single Bond Universal, a universal MDP‐based primer); heat treatment of the primer (without and with); aging (without and with). After zirconia treatments, resin cement cylinders (RelyX ARC) (n = 20; N = 320) were built. Half of the samples were tested after 24 h, and another half were subjected to aging (thermocycling 5–55°C/5.000, and storage in water for 6 months). Shear bond strength test and failure analysis were performed. Bond strength data were submitted to four‐way ANOVA and Tukey test (p = 0.05). All factors were statistically significant (p < 0.001) for bond strength (MPa): silica coating (7.3 ± 5.9) > no‐treatment (3.6 ± 4.3); universal primer (6.7 ± 4.8) > silane (4.2 ± 5.8); heat‐treatment (6.5 ± 6.3) > no‐heating (4.4 ± 4.3); no‐aging (8.2 ± 5) > aging (2.7 ± 4.4). Tukey test revealed that the association of silica coating + universal primer + heat‐treatment promoted higher and stable resin bond strength. Silica coating, universal adhesive application and heat treatment improve/increase durability and bond strength of zirconia. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 107B: 104–111, 2019.
Degradation rate of DNA scaffolds and bone regeneration
Authors: Matsumoto Ayako , Kajiya Hiroshi , Yamamoto‐M Nana , Yanagi Tsukasa , Imamura Ayaka , Okabe Koji , Fukushima Tadao , Kido Hirofumi , Ohno Jun
Published: March 2018

Scaffolds implanted into bone defect sites must achieve optimal biodegradation rates while appropriately filling the void as new bone formation progresses. We recently developed a unique biomaterial consisting of salmon deoxyribose nucleic acid (DNA) and protamine, which can be used as an osteoconductive scaffold for tissue engineering. The aim of the present study was to elucidate how the degradation rate of the scaffold affects bone regeneration. We examined the relationships between the degradation rate of salmon DNA scaffolds and new bone formation using a rat skin flank subcutaneous model and rat calvarial defect model. The degradation rates of the scaffolds were proportional to the durations of pretreatment with ultraviolet (UV) light irradiation. The biodegradation rates of the scaffolds were also dependent on the duration of UV irradiation, as tested a subcutaneous tissue implantation. Scaffolds irradiated with UV light for 0.5 h maintained gradual biodegradation of phosphate compared with scaffolds irradiated for 0 or 3 h. In the calvarial defect model, we found that new bone formation was higher in rats treated with scaffolds irradiated with UV light for 0.5 h compared with those irradiated with UV light for 0 or 3.0 h. The present results suggest that bioengineering of scaffolds for biodegradation is important to regenerate bone. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 107B: 122–128, 2019.
Extracellular matrix proteins as diagnostic markers of breast carcinoma
Authors: Giussani Marta , Landoni Elena , Merlino Giuseppe , Turdo Federica , Veneroni Silvia , Paolini Biagio , Cappelletti Vera , Miceli Rosalba , Orlandi Rosaria , Triulzi Tiziana , Tagliabue Elda
Published: March 2018

Changes in amount and composition of extracellular matrix (ECM) are considered a hallmark of tumor development. We tested the hypothesis that abnormal production of ECM components leads to blood‐released ECM molecules representing tumor circulating biomarkers. Candidate genes were selected through class comparison in two publicly available datasets and confirmed in paired normal and tumor associated fibroblasts from breast carcinoma (BC) specimens. Production and release of ECM molecules were evaluated in normal human dermal fibroblasts (NHDFs) treated with conditioned media from three BC cell lines. Plasma samples from healthy donors and from patients with malignant or benign breast disease were tested by ELISA for the presence of collagen 11a1 (COL11A1), collagen oligomeric matrix protein (COMP), and collagen 10a1 (COL10A1). Selected ECM molecules were investigated by IHC in malignant and benign specimens. In silico analysis of gene expression profiles identified 11 ECM genes significantly up‐regulated in tumor versus normal tissue. Western blot analyses revealed increased levels of molecules encoded by three of these genes, COL11A1, COMP, and COL10A1, in cell lysates and supernatants of conditioned NHDFs. Class comparison and class prediction analyses of two independent series of human plasma samples identified the combination of COL11A1, COMP, and COL10A1 as potentially informative in discriminating BC patients from those with benign disease. The three molecules resulted expressed in the stroma of BC tissue samples. Our results indicate that circulating COL11A1, COMP, and COL10A1 may be useful in diagnostic assessment of suspicious breast nodules and ECM molecules could represent an avenue to biomarker identification.
In Vivo Formation of Ethinylestradiol After Intramuscular Administration of Norethisterone Enantate
Authors: Friedrich Christian , Berse Matthias , Klein Stefan , Rohde Beate , Höchel Joachim
Published: March 2018

It is known that a small fraction of orally administered norethisterone is metabolically converted to ethinylestradiol. This exploratory, open‐label, nonrandomized study was conducted to investigate the systemic exposure to ethinylestradiol after intramuscular administration of norethisterone enantate in comparison with the exposure to ethinylestradiol after administration of a standard combined oral contraceptive. Sixteen healthy premenopausal women received an oral contraceptive (ethinylestradiol 30 μg/levonorgestrel 150 μg) once daily for 21 days and—after a 1‐week washout period—a single intramuscular dose of 200 mg norethisterone enantate. Blood samples to determine ethinylestradiol in serum were taken over 24 hours after the last dose of ethinylestradiol/levonorgestrel and over 8 weeks after administration of norethisterone enantate. Oral equivalent doses of ethinylestradiol were estimated based on area under the concentration–time curves. The ethinylestradiol serum concentrations observed after administration of norethisterone enantate were relatively low: The mean maximum concentration was only 32% of the maximum observed after ethinylestradiol/levonorgestrel (90% confidence interval, 22.5%–44.7%). The maximum oral equivalent dose of ethinylestradiol was markedly lower than 30 μg ethinylestradiol per day (20.3 μg/day; 90% confidence interval, 14.8–28.0 μg/day). The same applied to the average oral equivalent dose of ethinylestradiol for the 8‐week postdose interval (4.41 μg/day; 90% confidence interval, 3.57–5.46 μg/day). To conclude, the study results indicate that metabolic conversion of norethisterone to ethinylestradiol also occurs after intramuscular administration of 200 mg norethisterone enantate, but is associated with a lower exposure to ethinylestradiol than the use of a combined oral contraceptive containing 30 μg ethinylestradiol (plus 150 μg levonorgestrel).
Eosinophils in fungal diseases: An overview
Authors: Figueiredo Rodrigo T , Neves Josiane S
Published: March 2018

Eosinophils are the prominent cells in asthma, allergic bronchopulmonary mycosis (ABPMs), and fungal-sensitization-associated asthma, but their roles in the immunopathology of these disorders are not well understood. Moreover, the immunological mechanisms underlying the molecular direct effector interactions between fungi and eosinophils are rare and not fully known. Here, we provide an overview of eosinophil contributions to allergic asthma and ABPMs. We also revise the major general mechanisms of fungal recognition by eosinophils and consider past and recent advances in our understanding of the molecular mechanisms associated with eosinophil innate effector responses to different fungal species relevant to ABPMs (Alternaria alternata, Candida albicans, and Aspergillus fumigatus). We further examine and speculate about the therapeutic relevance of these findings in fungus-associated allergic pulmonary diseases.

Eosinophil roles in fungal-associated allergic pulmonary disorders: contributions, mechanisms of fungal recognition and potential therapeutic relevance.
Cardiac MR Characterization of left ventricular remodeling in a swine model of infarct followed by reperfusion
Authors: Whitaker John , Tschabrunn Cory M. , Jang Jihye , Leshem Eran , O'Neill Mark , Manning Warren J. , Anter Elad , Nezafat Reza
Published: March 2018

Background

Myocardial infarction (MI) survivors are at risk of complications including heart failure and malignant arrhythmias.

Purpose

We undertook serial imaging of swine following MI with the aim of characterizing the longitudinal left ventricular (LV) remodeling in a translational model of ischemia‐reperfusion‐mediated MI.

Animal Model

Eight Yorkshire swine underwent mid left anterior descending coronary artery balloon occlusion to create an ischemia‐reperfusion experimental model of MI.

Field Strength/Sequences

1.5T Philips Achieva scanner. Serial cardiac MRI was performed at 16, 33, and 62 days post‐MI, including cine imaging, native and postcontrast T1, T2 and dark‐blood late gadolinium enhanced (DB‐LGE) scar imaging.

Assessment

Regions of interest were selected on the parametric maps to assess native T1 and T2 in the infarct and in remote tissue. Volume of enhanced tissue, nonenhanced tissue, and gray zone were assessed from DB‐LGE imaging. Volumes, cardiac function, and strain were calculated from cine imaging.

Statistical Tests

Parameters estimated at more than two timepoints were compared with a one‐way repeated measures analysis of variance. Parametric mapping data were analyzed using a generalized linear mixed model corrected for multiple observations. A result was considered statistically significant at P < 0.05.

Results

All animals developed anteroseptal akinesia and hyperenhancement on DB‐LGE with a central core of nonenhancing tissue. Mean hyperenhancement volume did not change during the observation period, while the central core contracted from 2.2 ± 1.8 ml at 16 days to 0.08 ± 0.19 ml at 62 days (P = 0.008). Native T1 of ischemic myocardium increased from 1173 ± 93 msec at 16 days to 1309 ± 97 msec at 62 days (P < 0.001). Mean radial and circumferential strain rate magnitude in remote myocardium increased with time from the infarct (P < 0.05).

Date Conclusion

In this swine model of MI, serial quantitative cardiac MR exams allow characterization of LV remodeling and scar formation.

Level of Evidence: 2

Technical Efficacy: Stage 2

J. Magn. Reson. Imaging 2018;48:808–817.
Constructing short‐duration IDF curves using coupled dynamical–statistical approach to assess climate change impacts
Authors: Vu M. T. , Raghavan S. V. , Liu J. , Liong S.‐Y.
Published: March 2018

This study demonstrates a methodology to construct short‐duration rainfall intensity–duration–frequency (IDF) curves and to quantify the variability in the rainfall intensities for different return periods with respect to the changing climate. A dynamical downscaling approach using the regional climate model (RCM) Weather Research and Forecasting (WRF) has been used to assess present and future climates using the downscaling of an ensemble of three global climate models (GCMs) (CSIRO‐ACCESS1.3, MPI‐ESM‐MR ECHAM6 and NIES‐MIROC5) under the Coupled Model Intercomparison Project phase 5 (CMIP5). Furthermore, a statistical approach using the well‐known simple scaling method has been applied to extend the 6‐hourly WRF precipitation output to the finer temporal scale of 10 min. The short‐duration IDF curves were then constructed for the present and future climates under two representative concentration pathway (RCP) scenarios RCP4.5 and RCP8.5. A preliminary examination for this case study over Bac Ninh, an industrial area in the northern Vietnam, shows that there is a substantial increase in short‐duration rainfall intensity in the future with respect to the baseline climate. The highest increase is towards the end of the century (2071–2100) ranging from 56 to 61% for a 10‐ and 100‐year return period for 24‐hr duration, respectively, while the increase is about 40–45% for the 10‐min duration. These results strongly suggest that severe flooding in the future climate over the study region may be likely. The study results might be useful for policymakers and infrastructure planning and for insurance companies around the study area.
Pharmacists’ perceptions of career opportunities in Australia
Authors: Taylor Hayley , Kyle Greg , Cheong Lynn
Published: March 2018

Background

Anecdotal reports of an oversupply of pharmacy graduates are a growing concern for Australian pharmacists. However, limited data exists regarding pharmacists’ employment experiences and perceptions of current career opportunities in Australia.

Aim

To understand Australian pharmacists’ and pharmacy interns’ employment experiences by exploring their satisfaction and perspectives on current employment opportunities.

Method

An electronic survey was distributed to pharmacists and pharmacy interns across Australia between March and June 2016. National professional organisations for pharmacists assisted with the distribution of the survey. Follow‐up interviews were conducted to further explore survey findings.

Results

A total of 306 individuals completed the survey (83% pharmacists; 17% interns). The majority of pharmacists and interns reported high satisfaction with current employment and professional practice opportunities; however, there is a misalignment between their rated satisfaction and their perspectives on future employment prospects. Key themes that emerged included personal networks for employment, salary and location, and concerns for the future of the profession. The results suggested a confused workforce that are glad to have jobs, but not confident that they could move to other positions if required, or further, that there will be even fewer jobs available in the future.

Conclusion

This study provided valuable insight to the Australian Pharmacist workforce, by improving our understanding of pharmacists’ employment experiences and perspectives. Further exploration of themes identified in this study is required to better inform the future of pharmacy professional practice and employment.
Teach the teacher: Training otolaryngology fellows to become academic educators
Authors: Cramer John D. , Chi David H. , Schaitkin Barry M. , Eibling David E. , Johnson Jonas T.
Published: March 2018

Objectives/Hypothesis

Fellowship is the capstone of academic training and serves as preparation for an academic career. Fellows are expected to educate medical students and residents during and long after fellowship. However, little time is typically spent teaching fellows to become effective educators. We investigate a formal curriculum addressing teaching skills among fellows in otolaryngology–head and neck surgery (OHNS).

Study Design

E‐mail survey.

Methods

We developed and implemented an educational program called Teach the Teacher to build skills as educators for fellows in OHNS. We conducted a survey of fellows from 2014 to 2017 in OHNS who participated in the course. The survey evaluated demographics, teaching experiences, and teaching limitations structured as yes/no and Likert‐style questions (1 = strongly disagree, 5 = strongly agree).

Results

Thirty fellows were surveyed with a response rate was 80%. Fellowship was rated highly as an experience that will make fellows a better academic educator (mean ± standard deviation: 4.54 ± 0.64). The most important components of teaching during fellowship were role modeling (4.67 ± 0.62), followed by teaching psychomotor skills in the operating room (4.29 ± 0.89), diagnostic reasoning (4.25 ± 0.66), and evidence‐based medicine (4.25 ± 0.83). The Teach the Teacher course specifically was rated as a helpful experience (4.00 ± 0.90). The primary limitations to developing teaching skills during fellowship identified were lack of time, patient safety, and inexperience with hospital culture.

Conclusions

Fellowship is a key time to improve skills as academic educators. Fellows value formal efforts to teach academic skills.

Level of Evidence

NA. Laryngoscope, 128:2034–2048, 2018
Chemical Synthesis of Rare Natural Bile Acids: 11α‐Hydroxy Derivatives of Lithocholic and Chenodeoxycholic Acids
Authors: Namegawa Kazunari , Iida Kyoko , Omura Kaoru , Ogawa Shoujiro , Hofmann Alan F. , Iida Takashi
Published: March 2018

A method for the preparation of 11α‐hydroxy derivatives of lithocholic and chenodeoxycholic acids, recently discovered to be natural bile acids, is described. The principal reactions involved were (1) elimination of the 12α‐mesyloxy group of the methyl esters of 3α‐acetate‐12α‐mesylate and 3α,7α‐diacetate‐12α‐mesylate derivatives of deoxycholic acid and cholic acid with potassium acetate/hexamethylphosphoramide; (2) simultaneous reduction/hydrolysis of the resulting △11‐3α‐acetoxy and △11‐3α,7α‐diacetoxy methyl esters with lithium aluminum hydride; (3) stereoselective 11α‐hydroxylation of the △11‐3α,24‐diol and △11‐3α,7α,24‐triol intermediates with B2H6/tetrahydrofuran (THF); and (4) selective oxidation at C‐24 of the resulting 3α,11α,24‐triol and 3α,7α,11α,24‐tetrol to the corresponding C‐24 carboxylic acids with NaClO2 catalyzed by 2,2,6,6‐tetramethylpiperidine 1‐oxyl free radical (TEMPO) and NaClO. In summary, 3α,11α‐dihydroxy‐5β‐cholan‐24‐oic acid and 3α,7α,11α‐trihydroxy‐5β‐cholan‐24‐oic acid have been synthesized and their nuclear magnetic resonance (NMR) spectra characterized. These compounds are now available as reference standards to be used in biliary bile acid analysis.
Decreasing ALT donor site morbidity with the keystone flap
Authors: Turin Sergey Y. , Spitz Jamie A. , Alexander Karina , Ellis Marco F.
Published: March 2018

Background

The anterolateral thigh (ALT) flap is a workhorse flap for a variety of wounds. The primary disadvantage of ALT flaps is donor site morbidity associated with large skin paddle defects. We present a strategy of managing the donor site with the Keystone flap to avoid skin grafts in cases where primary closure is not possible.

Methods

A retrospective, multi‐institutional review from December 2015 to March 2017 based on a single surgeon's experience was performed. Inclusion criteria were harvest of an ALT flap and closure of the thigh donor site with a keystone flap.

Results

Six patients underwent reconstruction of the ALT donor site with a keystone flap. The average width of the ALT skin paddle was 7.8 cm (range 7–8 cm) and the defects could not be closed primarily or with wide undermining. Surface area of the ALT flaps averaged 96.8 cm2 (range 64–152 cm2). Mean patient BMI was 24.6 (range 16–37). Keystone flap dimensions averaged 9.5 × 17.8 cm. There were no major donor or recipient site complications, and one ×minor complication of delayed wound healing. No patients exhibited decreased range of motion at the hip or knee.

Conclusions

Primary closure of the ALT donor site is preferred, but becomes difficult as skin paddle width approaches 8 cm. Managing the ALT flap donor site with a keystone flap is safe, does not appear to have significant morbidity, and can allow the surgeon to avoid the morbidity and secondary donor site associated with skin grafting.
Separating the coherence transfer from chemical shift evolution in high‐resolution pure shift COSY NMR
Authors: Aguilar Juan A. , Belda Raquel , Gaunt Benjamin R. , Kenwright Alan M. , Kuprov Ilya
Published: March 2018

Recent developments in data sampling and processing techniques have made it possible to acquire 2‐dimensional NMR spectra of small molecules at digital resolutions in both dimensions approaching the intrinsic limitations of the equipment and sample on a realistic timescale. These developments offer the possibility of enormously increased effective resolution (peak dispersion) and the ability to effectively study samples where peak overlap was previously a limiting factor. Examples of such spectra have been produced for a number of 2‐dimensional techniques including TOCSY and HSQC. In this paper, we investigate some of the problems in applying such techniques to COSY spectra and suggest a modification to the classic experiment that alleviates some of these problems.
Current developments in homonuclear and heteronuclear J‐resolved NMR experiments
Authors: Parella Teodor
Published: March 2018

From the first days of NMR, it is known that J‐resolved methods offer a simple spectral representation, where the J information is represented along the highly‐resolved indirect dimension. A comprehensive compilation of an entire family of new homonuclear and heteronuclear J‐resolved NMR experiments is presented. The methods are classified according to different features of pulse sequence design, involving broadband vs frequencyselective nature and homonuclear vs heteronuclear experiments. In addition, modern features in NMR pulse sequence development are also discussed. Some examples include the incorporation of broadband homonuclear decoupling techniques, the use of perfect‐echo elements to produce highly specific spin manipulations, the simultaneous measurement of multiple coupling constants and their signs, or the simultaneous measurement of scalar and residual dipolar coupling constants in a single NMR spectrum. Each reported J‐resolved experiment is discussed and illustrated with examples. As concluded in the work, it is recommended the incorporation of all these novel J‐resolved methods to the standard library of small‐molecule NMR tools to be available in any NMR lab.
Porphyrin–peptide conjugates in biomedical applications
Authors: Biscaglia Francesca , Gobbo Marina
Published: March 2018

The conjugation of peptides to porphyrins and related tetrapyrrole based macrocycles have extended their applications in biological systems, where the photophysical properties of these molecules and their ability to coordinate metals can be exploited for detecting and opposing to the onset of important diseases. This review presents a survey of the published literature over last years on biomedical applications of these hybrid compounds, mostly in the field of photodynamic therapy (PDT), but also in sensing key metabolites and peculiar structures of biomolecules in living systems. Peptides based strategies to improve the efficacy of the photosensitizer (PS) in PDT will be discussed, as well as solutions to overcome some limitations recently emerged in the use of peptides as delivery vehicles. An overview on possible application of porphyrin–peptide conjugates in detection of biomarkers of physiological and pathological states will be also presented.
Site‐Specific Systematic Analysis of Lysine Modification Crosstalk
Authors: Xu Hao‐Dong , Wang Li‐Na , Wen Ping‐Ping , Shi Shao‐Ping , Qiu Jian‐Ding
Published: March 2018

Research has revealed that post‐translational modifications (PTMs) that occur at lysine (PLMs) can cooperatively regulate various biological processes by crosstalk. However, the trend of the crosstalk between multiple PLMs and the properties of PLM crosstalk require additional investigation. Here, the crosstalk among acetylation, succinylation, and SUMOylation is systematically studied in a site‐specific waz. First, crosstalk between SUMOylation is detected and succinylation is found to be underexpressed, whereas succinylation tends to crosstalk with acetylation and SUMOylation on the same lysine residue while PLM crosstalk is tissue‐specific across different species. Further analysis reveals that different PLMs tend to occur crosstalk at diverse subcellular compartments and structural regions, and they participate in distinct biological processes and functions. Additionally, short‐term evolutionary analysis shows that there is no additional evolutionary pressure on PLMs crosstalk sites, as found by comparison with singly modified sites. Finally, phylogenetic classification reveals that genes with co‐occupied lysine crosstalk are more likely to have higher evolutionary similarity and possess a tendency to cluster in the specific branch. The integrated approach reported here has the potential for large‐scale prioritization of in situ crosstalk of PLM candidates and provides a profound understanding of the underlying relationship between different lysine modifications.
A Deep Proteomics Perspective Into Grape Berry Quality Traits During Ripening
Authors: Martínez‐Esteso María José , Bru Martínez Roque
Published: March 2018

Discovery‐based proteomics studies have an important role in the understanding of the biochemical processes that occur during grape berry ripening. The ripening process is relevant in determining grape berry quality. For a proteome analysis of grape berry ripening, Kambiranda et al. (2018) applied a label‐free mass spectrometry–based quantitative approach. The authors reported the identification of proteins associated with the production flavor, aroma and ethylene production. Despite the valuable contribution of discovery‐based proteomics studies, the picture is still incomplete. Future efforts in gaining proteome coverage would benefit the identification of proteins associated with grape berry quality traits.
Aromaticity in heterocyclic analogues of benzene: Dissected NICS and current density analysis
Authors: Báez‐Grez R. , Rabanal‐León Walter A. , Alvarez‐Thon Luis , Ruiz Lina , Tiznado W. , Pino‐Rios R.
Published: March 2018

The magnetic aromaticity of 6‐membered monoheterocycles containing Group 13 to 16 elements (C5H5X, where X = SiH, GeH, N, P, As, O+, S+, Se+) was assessed by using 2 magnetic descriptors: the π‐electron contribution to the out‐of‐plane component of the nucleus‐independent chemical shifts (NICSzz,π) and ring current strength. The results show that both descriptors lead to the same conclusion regarding magnetic aromaticity. However, they do not agree with the predictions obtained by isotropic NICS, which is a most commonly used method. Ring current strength and NICSπ predict that benzene is the most aromatic molecule of the series, with an only slightly less aromatic pyridine. Additionally, aromaticity decreases when going down in the same group of the periodic system. The only exception is the pyrylium cation, which is predicted as the least aromatic species of this series.
Behavioral symptoms and psychiatric disorders in child and adolescent long‐term survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only
Authors: Liu Wei , Cheung Yin Ting , Brinkman Tara M. , Banerjee Pia , Srivastava Deokumar , Nolan Vikki G. , Zhang Hongmei , Gurney James G. , Pui Ching‐Hon , Robison Leslie L. , Hudson Melissa M. , Krull Kevin R.
Published: March 2018

Background

Prevalence of emotional, behavioral, and psychiatric outcomes in child and adolescent survivors of childhood acute lymphoblastic leukemia treated on a chemotherapy‐only protocol were not well defined.

Methods

Self‐ and parent‐reported emotional and behavioral symptoms were assessed for 161 survivors of childhood acute lymphoblastic leukemia (51.0% female; mean [SD] age 12.1[2.6] years; 7.5[1.6] years post‐diagnosis). Age‐ and sex‐adjusted scores were calculated for standardized measures and compared with 90th percentile of norms. Frequencies of survivor psychiatric disorders from structured diagnostic interviews with parents were compared with the general population. Parent emotional distress and post‐traumatic stress symptoms were assessed. Associations between child symptoms/disorders and parent distress were examined with log‐binomial models, adjusting for highest parent education.

Results

Compared with population expectations (10%), more survivors self‐reported symptoms of inattention (27.9; 95% CI, 21.0%‐35.7%), hyperactivity/impulsivity (26.0%; CI, 19.2%‐33.6%), and oppositional‐defiant behavior (20.1%; CI, 14.1%‐27.3%). Parents reported survivors with more symptoms of inattention (23.6%; CI, 17.2%‐31.0%), higher frequencies of obsessive‐compulsive disorder (10.3% vs 2%) and oppositional defiant disorder (16.0% vs 9.5%), but not attention‐deficit/hyperactivity disorder (7.1% vs 7.8%) or generalized anxiety disorder (3.2% vs 4.1%), compared with national norms. Parent‐report of child anxiety disorders was associated with parent self‐reported emotional distress but not survivor self‐report of anxiety.

Conclusion

A significant minority of survivors have long‐term psychiatric morbidity, multi‐informant assessment is important to understand these symptom profiles and to inform selection of appropriate interventions. Interventions targeting inattention and oppositional behavior in children and emotional distress in parents are warranted in families with survivors who display behavioral problems.
Policy Insights From Party History
Authors: Skidmore Max J.
Published: March 2018

Max J. Skidmore examines party history in the United States, specifically discussing three books: two treatments of the Republican Party, Lewis Gould's The Republicans: A History of the Grand Old Party; and Heather Cox Richardson's To Make Men Free: A History of the Republican Party. He also examines a broader analysis by Nancy MacLean, Democracy in Chains. He concludes, and demonstrates, that party history—even the history of a single party—can provide considerable insight into the character of American public policy, its development, and its strengths and weaknesses. Supplementing formal party history by discussing deliberate efforts external to the party to influence its orientation provides yet greater insights.
Two Inside Views of a Most Bizarre Election—With a Forthright Analysis From Outside
Authors: Skidmore Max J.
Published: March 2018

Editor Max J. Skidmore reviews two books on the 2016 elections and provides his own analysis of the Trump presidency and its effect on policies.
Fused dimerization increases expression, solubility, and activity of bacterial dehydratase enzymes
Authors: Rullán‐Lind Carlos , Pietri Ruth B. , Vázquez‐Cintrón Melvin , Baerga‐Ortiz Abel
Published: March 2018

FabA and FabZ are the two dehydratase enzymes in Escherichia coli that catalyze the dehydration of acyl intermediates in the biosynthesis of fatty acids. Both enzymes form obligate dimers in which the active site contains key amino acids from both subunits. While FabA is a soluble protein that has been relatively straightforward to express and to purify from cultured E. coli, FabZ has shown to be mostly insoluble and only partially active. In an effort to increase the solubility and activity of both dehydratases, we made constructs consisting of two identical subunits of FabA or FabZ fused with a naturally occurring peptide linker, so as to force their dimerization. The fused dimer of FabZ (FabZ‐FabZ) was expressed as a soluble enzyme with an ninefold higher activity in vitro than the unfused FabZ. This construct exemplifies a strategy for the improvement of enzymes from the fatty acid biosynthesis pathways, many of which function as dimers, catalyzing critical steps for the production of fatty acids.
PBOV1 as a potential biomarker for more advanced prostate cancer based on protein and digital histomorphometric analysis
Authors: Carleton Neil M. , Zhu Guangjing , Gorbounov Mikhail , Miller M. Craig , Pienta Kenneth J. , Resar Linda M. S. , Veltri Robert W.
Published: March 2018

Background

There are few tissue‐based biomarkers that can accurately predict prostate cancer (PCa) progression and aggressiveness. We sought to evaluate the clinical utility of prostate and breast overexpressed 1 (PBOV1) as a potential PCa biomarker.

Methods

Patient tumor samples were designated by Grade Groups using the 2014 Gleason grading system. Primary radical prostatectomy tumors were obtained from 48 patients and evaluated for PBOV1 levels using Western blot analysis in matched cancer and benign cancer‐adjacent regions. Immunohistochemical evaluation of PBOV1 was subsequently performed in 80 cancer and 80 benign cancer‐adjacent patient samples across two tissue microarrays (TMAs) to verify protein levels in epithelial tissue and to assess correlation between PBOV1 proteins and nuclear architectural changes in PCa cells. Digital histomorphometric analysis was used to track 22 parameters that characterized nuclear changes in PBOV1‐stained cells. Using a training and test set for validation, multivariate logistic regression (MLR) models were used to identify significant nuclear parameters that distinguish Grade Group 3 and above PCa from Grade Group 1 and 2 PCa regions.

Results

PBOV1 protein levels were increased in tumors from Grade Group 3 and above (GS 4 + 3 and ≥ 8) regions versus Grade Groups 1 and 2 (GS 3 + 3 and 3 + 4) regions (P = 0.005) as assessed by densitometry of immunoblots. Additionally, by immunoblotting, PBOV1 protein levels differed significantly between Grade Group 2 (GS 3 + 4) and Grade Group 3 (GS 4 + 3) PCa samples (P = 0.028). In the immunohistochemical analysis, measures of PBOV1 staining intensity strongly correlated with nuclear alterations in cancer cells. An MLR model retaining eight parameters describing PBOV1 staining intensity and nuclear architecture discriminated Grade Group 3 and above PCa from Grade Group 1 and 2 PCa and benign cancer‐adjacent regions with a ROC‐AUC of 0.90 and 0.80, respectively, in training and test sets.

Conclusions

Our study demonstrates that the PBOV1 protein could be used to discriminate Grade Group 3 and above PCa. Additionally, the PBOV1 protein could be involved in modulating changes to the nuclear architecture of PCa cells. Confirmatory studies are warranted in an independent population for further validation.
The composition of prostate core matrisome in vivo and in vitro unveiled by mass spectrometric analysis
Authors: Ojalill Marjaana , Rappu Pekka , Siljamäki Elina , Taimen Pekka , Boström Peter , Heino Jyrki
Published: March 2018

Background

The composition and organization of extracellular matrix (ECM) are important regulators of cell behavior. In particular in the prostate, this central role of the ECM is further stressed by the fact that several potential markers of prostate stem cells are matrix receptors.

Methods

We established 12 fibroblastic cell lines from cancerous and non‐cancerous areas of six prostates and allowed the cells to produce ECM under cell culture conditions. We also performed a proteome wide analysis of the ECM components by mass spectrometry. To study the in vitro activation of fibroblastic cells we compared the differences between the ECM produced in cell culture by six non‐cancerous‐tissue‐derived fibroblasts and the in vivo matrisome from the corresponding non‐cancerous tissue of prostate.

Results

Our results suggest that at tissue level the ECM is mainly produced by fibroblastic cells and that it contains standard collagen I fibrils and fibril‐associated proteins. Beaded‐filament forming collagen VI is also abundant and basement membranes potentially contain five laminin subtypes and collagens XV and XVIII. As the main finding, we also detected differences when in vivo and in vitro matrisomes were compared. Only 65 out of 206 proteins were found to be common for both in vivo and in vitro samples. Majority of the 55 proteins, which were solely detected in in vivo samples, were considered to be plasma derived. Eighty‐six proteins were solely found from in vitro fibroblast‐derived ECM, and most of them were related to matrix remodeling or growth factor action, proposing that the activation of fibroblasts in cell culture may remarkably modify their gene expression profile. Finally, in comparison to traditional 2D in vitro cell culture, the ECM composition of 3D spheroid culture was analyzed. The matrisome in spheroid culture did not resemble the in vivo ECM more closely than in monolayer culture.

Conclusions

Artificial activation of ECM remodeling seems to be a distinctive feature in in vitro models. In conclusion the constitution of ECM produced by prostate derived fibroblasts in vitro is similar, but not identical to the prostate ECM in vivo as shown here by mass spectrometric analysis.
Efficacy of artichoke leaf extract in non‐alcoholic fatty liver disease: A pilot double‐blind randomized controlled trial
Authors: Panahi Yunes , Kianpour Parisa , Mohtashami Reza , Atkin Stephen L. , Butler Alexandra E. , Jafari Ramezan , Badeli Roghayeh , Sahebkar Amirhossein
Published: March 2018

Non‐alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide and is potentially treatable, though there are few therapeutic agents available. Artichoke leaf extract (ALE) has shown potential as a hepatoprotective agent. This study sought to determine if ALE had therapeutic utility in patients with established NAFLD. In this randomized double‐blind placebo‐controlled parallel‐group trial, 100 subjects with ultrasound‐diagnosed NAFLD were randomized to either ALE 600 mg daily or placebo for a 2‐month period. NAFLD response was assessed by liver ultrasound and serological markers including the aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio and AST to platelet ratio index (APRI) score. Ninety patients completed the study (49 ALE and 41 placebo) with no side effects reported. ALE treatment compared with placebo: Doppler sonography showed increased hepatic vein flow (p < .001), reduced portal vein diameter (p < .001) and liver size (p < .001), reduction in serum ALT (p < .001) and AST (p < .001) levels, improvement in AST/ALT ratio and APRI scores (p < .01), and reduction in total bilirubin. ALE supplementation reduced total cholesterol, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, non‐high‐density lipoprotein cholesterol, and triglyceride concentrations (p = .01). This study has shown beneficial effects of ALE supplementation on both ultrasound liver parameters and liver serum parameters (ALT, AST, APRI ratio, and total bilirubin) in patients with NAFLD.
Inflammation and clozapine concentrations
Authors: Lam Y. W. Francis
Published: March 2018

Although clozapine is highly effective in managing patients with treatment‐resistant schizophrenia, it possesses a highly variable pharmacokinetic profile influenced by multiple factors. These variables include altered metabolic status as a result of drug‐drug interactions, as well as patient‐specific factors such as smoking1 and infection.2 The mechanism of infection‐related changes in clozapine pharmacokinetics is thought to be related to release of inflammatory cytokines that act as inhibitors of cytochrome P‐450 enzymes.3,4 Two recent case reports discussed the occurrence of elevated serum clozapine concentrations in patients with inflammatory conditions.5
On the achievement of high fidelity and scalability for large‐scale diagonalizations in grid‐based DFT simulations
Authors: Choi Sunghwan , Kim Woo Youn , Yeom Min Sun , Ryu Hoon
Published: March 2018

Recent advance in high performance computing (HPC) resources has opened the possibility to expand the scope of density functional theory (DFT) simulations toward large and complex molecular systems. This work proposes a numerically robust method that enables scalable diagonalizations of large DFT Hamiltonian matrices, particularly with thousands of computing CPUs (cores) that are usual these days in terms of sizes of HPC resources. The well‐known Lanczos method is extensively refactorized to overcome its weakness for evaluation of multiple degenerate eigenpairs that is the substance of DFT simulations, where a multilevel parallelization is adopted for scalable simulations in as many cores as possible. With solid benchmark tests for realistic molecular systems, the fidelity of our method are validated against the locally optimal block preconditioned conjugated gradient (LOBPCG) method that is widely used to simulate electronic structures. Our method may waste computing resources for simulations of molecules whose degeneracy cannot be reasonably estimated. But, compared to LOBPCG method, it is fairly excellent in perspectives of both speed and scalability, and particularly has remarkably less (< 10%) sensitivity of performance to the random nature of initial basis vectors. As a promising candidate for solving electronic structures of highly degenerate systems, the proposed method can make a meaningful contribution to migrating DFT simulations toward extremely large computing environments that normally have more than several tens of thousands of computing cores.