bluuebunny/crossref_metadata_2025 huggingface dataset:
Germanium‐Bridged 2‐Phenylbenzoheteroles as Luminophores Exhibiting Highly Efficient Solid‐State Fluorescence
Authors: Shimizu Masaki , Ryuse Daiki , Kinoshita Takumi
Published: August 2017

[1]Benzogermolo[3,2‐b]indoles, [1]benzogermolo[3,2‐b]benzofuran, [1]benzogermolo[3,2‐b]benzothiophene, and [1]benzogermolo[3,2‐b]benzothiophene‐S,S‐dioxide were synthesized from the corresponding 3‐bromo‐2‐(2‐bromophenyl)benzoheteroles and characterized. A comparison of the absorption spectra of the Ph2Ge‐ and Ph2Si‐bridged 2‐phenylindoles reveals that the Ge bridge has the effect of slightly widening the HOMO–LUMO energy gap of the bridged 2‐phenylindole π‐system with regard to the Si‐bridged system. Replacement of the indole ring by benzofuran or benzothiophene rings induces blueshifts in the absorption spectrum, whereas the absorption spectrum of the benzothiophene‐S,S‐dioxide derivative was redshifted with respect to the indole derivative. These results are consistent with the changes in the HOMO–LUMO energy gaps calculated by using density functional theory. The Ph2Ge‐bridged indole, benzofuran, and benzothiophene‐S,S‐dioxide derivatives exhibit brilliant fluorescence in the violet‐to‐blue region with good‐to‐excellent quantum yields in toluene (λem=376–439 nm, Φ=0.62–0.99) and powder form (λem=401–451 nm, Φ=0.64–0.80).
Stability of the Greedy Algorithm on the Circle
Authors: Rolla Leonardo T. , Sidoravicius Vladas
Published: August 2017

We consider a single‐server system with service stations in each point of the circle. Customers arrive after exponential times at uniformly distributed locations. The server moves at finite speed and adopts a greedy routing mechanism. It was conjectured by Coffman and Gilbert in 1987 that the service rate exceeding the arrival rate is a sufficient condition for the system to be positive recurrent, for any value of the speed. In this paper we show that the conjecture holds true.© 2017 Wiley Periodicals, Inc.
Influence of IL‐6, IL‐33, and TNF‐α on human mast cell activation: Lessons from single cell analysis by flow cytometry
Authors: Cop Nathalie , Ebo Didier G. , Bridts Chris H. , Elst Jessy , Hagendorens Margo M. , Mertens Christel , Faber Margaretha A. , De Clerck Luc S. , Sabato Vito
Published: August 2017

Background

Mechanisms that govern priming and degranulation of human mast cells (MCs) remain elusive. Besides, most of our knowledge is based on experiments from which data only reflect an average of all stimulated cells. This study aims at investigating the effects of proinflammatory cytokines IL‐6, IL‐33, and TNF‐α on IgE‐dependent and IgE‐independent activation of individual MCs.

Methods

MCs were derived from CD34+ progenitors isolated from 50 mL whole blood from 4 healthy controls and 5 birch pollen allergic patients. Passively sensitized MCs were preincubated with IL‐6, IL‐33, or TNF‐α and stimulated with anti‐IgE/birch pollen allergen or substance P, the latter being a ligand for the G‐protein‐coupled MRGPRX2‐receptor. Activation—i.e., upregulation of CD203c—and anaphylactic degranulation—i.e., appearance of CD63—were measured using flow cytometry.

Results

Preincubation with IL‐33 demonstrated upregulated CD203c density without degranulation. Subsequent IgE‐dependent stimulation (anti‐IgE/birch pollen allergen) resulted in higher appearance of CD63 as compared to cells without preincubation, indicating IL‐33 to exert a priming effect (P = 0.04). IL‐6 only increased allergen‐specific responses but to a lesser extent than IL‐33. Combination of IL‐33/IL‐6 had a synergistic effect, demonstrating more degranulation in response to allergen. TNF‐α had no effect on IgE‐mediated activation, nor synergistic effects with IL‐33. Stimulation with substance P resulted in degranulation that could not be enhanced by preincubation.

Conclusions

In conclusion, IL‐33, and in a lesser extent IL‐6, prime individual MCs for subsequent IgE‐mediated activation. Moreover, this priming effect is synergistic. In contrast, none of the cytokines had a priming effect on MRGPRX2‐mediated activation of MCs. © 2017 International Clinical Cytometry Society
Oncocytic variant of medullary thyroid carcinoma; a rare tumor with numerous diagnostic mimics by fine needle aspiration
Authors: Sams Sharon B. , Tompkins Kenneth D. , Mayson Sarah , Raeburn Christopher D. , Mehrotra Sanjana
Published: August 2017

Oncocytic variant of medullary thyroid carcinoma is rare form of thyroid carcinoma that is easily misdiagnosed on fine needle aspiration specimens due to it is low incidence and cytomorphologic overlap with other more common Hurtle cell lesions. A correct initial diagnosis by fine needle aspiration is imperative as the clinical treatment for medullary carcinoma differs significantly from the mimickers. We present a case of this rare variant tumor that on initial fine needle aspiration was described as a Hurthle cell lesion and was subsequently correctly classified on the resection specimen. In this brief review, we describe the cytomorphologic features of medullary carcinoma, oncocytic variant of medullary carcinoma and it is most common mimickers, and we discuss the ancillary studies required to confirm the diagnosis. This case highlights the importance of a complete clinical history and radiologic correlation, which in conjunction with a careful attention to the cytologic features of the fine needle aspiration sample, should in most cases ensure a correct initial diagnosis.
Timing is everything: Fishing‐season placement may represent the most important angling‐induced evolutionary pressure on Atlantic salmon populations
Authors: Harvey Alison C. , Tang Yongkai , Wennevik Vidar , Skaala Øystein , Glover Kevin A.
Published: August 2017

Fisheries‐induced evolution can change the trajectory of wild fish populations by selectively targeting certain phenotypes. For important fish species like Atlantic salmon, this could have large implications for their conservation and management. Most salmon rivers are managed by specifying an angling season of predetermined length based on population demography, which is typically established from catch statistics. Given the circularity of using catch statistics to estimate demographic parameters, it may be difficult to quantify the selective nature of angling and its evolutionary impact. In the River Etne in Norway, a recently installed trap permits daily sampling of fish entering the river, some of which are subsequently captured by anglers upstream. Here, we used 31 microsatellites to establish an individual DNA profile for salmon entering the trap, and for many of those subsequently captured by anglers. These data permitted us to investigate time of rod capture relative to river entry, potential body size‐selective harvest, and environmental variables associated with river entry. Larger, older fish entered the river earlier than smaller, younger fish of both sexes, and larger, older females were more abundant than males and vice versa. There was good agreement between the sizes of fish harvested by angling, and the size distribution of the population sampled on the trap. These results demonstrate that at least in this river, and with the current timing of the season, the angling catch reflects the population's demographics and there is no evidence of size‐selective harvest. We also demonstrated that the probability of being caught by angling declines quickly after river entry. Collectively, these data indicate that that the timing of the fishing season, in relation to the upstream migration patterns of the different demographics of the population, likely represents the most significant directional evolutionary force imposed by angling.
Deep Eutectic Solvents Enable the Enhanced Production of n‐3 PUFA‐Enriched Triacylglycerols
Authors: Xu Long , Zhang Li , Li Daoming , Liu Pengzhan , Tan Chin‐Ping , Wang Weifei , Liu Xiangqian , Yang Bo , Lan Dongming , Wang Yonghua
Published: August 2017

Efficient synthesis of n‐3 PUFA‐enriched triacylglycerol (TAG) by the esterification of glycerol with n‐3 PUFA in deep eutectic solvents (DES) is reported. There was a 1.2‐fold increase of TAG yield in DES compared with that in the solvent‐free system. Adsorption of the produced water by DES during esterification contributed to enhance the conversion efficiency by changing the reaction equilibrium. DES also served as an effective solvent for enriching the n‐3 PUFA of TAG in the upper layer of reaction media. A TAG yield of 55% was achieved under the optimal condition. Practical Applications: Enzymatic synthesis of n‐3 PUFA‐enriched triacylglycerol (TAG) is challenged by low yields. Here, deep eutectic solvents show great potential for enhancing the production of n‐3 PUFA‐enriched TAG.

The production of n‐3 PUFA‐enriched triacylglycerol is greatly enhanced in deep eutectic solvents.
Alkyl‐Branched Fatty Compounds: Hydro‐Alkylation of Non‐Activated Alkenes With Haloalkanes Mediated by Ethylaluminum Sesquichloride
Authors: Biermann Ursula , Metzger Jürgen O.
Published: August 2017

The general method for the cationic hydro‐alkyl addition to the nonactivated CC double bond of alkenes mediated by ethylaluminum sesquichloride (Et3Al2Cl3) has been importantly improved and simplified by using haloalkanes (primary, secondary, tertiary) instead of alkyl chloroformates as alkylating agent and performing the reaction without any additional solvent. The protocol is especially suited to perform the hydro‐alkylation of internal double bonds. Reaction of the haloalkane with Et3Al2Cl3 gives an alkyl cation which is added to the alkene; hydride transfer from Et3Al2Cl3 to the adduct carbenium ion gives the saturated addition product. Primary halo alkanes give the same addition product as the respective secondary halo alkane because of 1,2‐H shift yielding the secondary carbenium ions. In the case of 1‐alkenes triethylsilane has to be used as additional hydride donor to avoid di‐ and oligomerization. Special interest has been focused on alkylation of unsaturated fatty compounds, which are important renewable feedstocks, mostly (Z)‐configured such as methyl oleate, high oleic sunflower oil, neopentyl glycol dioleate, but also (E)‐configured, that is, dimethyl (E)‐icos‐10‐enedioate, and with terminal double bond such as methyl 10‐undecenoate. The respective alkyl branched fatty compounds were obtained after simple work‐up with excellent to good yields. The protocol was scaled up without problems to >0.5 mol.

Practical Applications: The synthesis of alkyl‐branched fatty compounds is of high importance since they have interesting properties that make them attractive for use in the cosmetics and lubricant area. We developed an industrially feasible method for the synthesis of well‐defined alkyl branched oleochemicals.

The ethylaluminum sesquichloride (Et3Al2Cl3)‐mediated reaction of non‐activated alkenes with haloalkanes gives the respective hydro alkylation product in excellent to good yields. The reaction protocol allows the synthesis of well‐defined alkyl branched oleochemicals, as for example methyl 9(10)‐isopropylstearate, and can easily be scaled up.
Tandem Ring Opening/Cyclization of trans‐2‐Aryl‐3‐nitrocyclopropane‐1,1‐dicarboxylates with 2‐Aminopyridines: Access to Pyrido[1,2‐a]pyrimidin‐4‐one Derivatives
Authors: Selvi Subramani , Srinivasan Kannupal
Published: August 2017

A tandem ring‐opening/cyclization reaction of trans‐2‐aryl‐3‐nitrocyclopropane‐1,1‐dicarboxylates with 2‐aminopyridines was discovered. The reaction did not require the assistance of any catalyst and proceeded more efficiently in water than in organic solvents. This strategy afforded pyrido[1,2‐a]pyrimidin‐4‐one derivatives having a carboxylate group at C3 in 62–90 % yields.
Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance
Authors: Gaggini Melania , Carli Fabrizia , Rosso Chiara , Buzzigoli Emma , Marietti Milena , Della Latta Veronica , Ciociaro Demetrio , Abate Maria Lorena , Gambino Roberto , Cassader Maurizio , Bugianesi Elisabetta , Gastaldelli Amalia
Published: August 2017

Plasma concentrations of amino acids (AAs), in particular, branched chain AAs (BCAAs), are often found increased in nonalcoholic fatty liver disease (NAFLD); however, if this is due to increased muscular protein catabolism, obesity, and/or increased insulin resistance (IR) or impaired tissue metabolism is unknown. Thus, we evaluated a) if subjects with NAFLD without obesity (NAFLD‐NO) compared to those with obesity (NAFLD‐Ob) display altered plasma AAs compared to controls (CTs); and b) if AA concentrations are associated with IR and liver histology. Glutamic acid, serine, and glycine concentrations are known to be altered in NAFLD. Because these AAs are involved in glutathione synthesis, we hypothesized they might be related to the severity of NAFLD. We therefore measured the AA profile of 44 subjects with NAFLD without diabetes and who had a liver biopsy (29 NAFLD‐NO and 15 NAFLD‐Ob) and 20 CTs without obesity, by gas chromatography–mass spectrometry, homeostasis model assessment of insulin resistance, hepatic IR (Hep‐IR; Hep‐IR = endogenous glucose production × insulin), and the new glutamate–serine–glycine (GSG) index (glutamate/[serine + glycine]) and tested for an association with liver histology. Most AAs were increased only in NAFLD‐Ob subjects. Only alanine, glutamate, isoleucine, and valine, but not leucine, were increased in NAFLD‐NO subjects compared to CTs. Glutamate, tyrosine, and the GSG‐index were correlated with Hep‐IR. The GSG‐index correlated with liver enzymes, in particular, gamma‐glutamyltransferase (R = 0.70), independent of body mass index. Ballooning and/or inflammation at liver biopsy were associated with increased plasma BCAAs and aromatic AAs and were mildly associated with the GSG‐index, while only the new GSG‐index was able to discriminate fibrosis F3‐4 from F0‐2 in this cohort. Conclusion: Increased plasma AA concentrations were observed mainly in subjects with obesity and NAFLD, likely as a consequence of increased IR and protein catabolism. The GSG‐index is a possible marker of severity of liver disease independent of body mass index. (Hepatology 2018;67:145‐158).
Blockade of transforming growth factor‐β signaling enhances oncolytic herpes simplex virus efficacy in patient‐derived recurrent glioblastoma models
Authors: Esaki Shinichi , Nigim Fares , Moon Esther , Luk Samantha , Kiyokawa Juri , Curry William , Cahill Daniel P. , Chi Andrew S. , Iafrate A. John , Martuza Robert L. , Rabkin Samuel D. , Wakimoto Hiroaki
Published: August 2017

Despite the current standard of multimodal management, glioblastoma (GBM) inevitably recurs and effective therapy is not available for recurrent disease. A subset of tumor cells with stem‐like properties, termed GBM stem‐like cells (GSCs), are considered to play a role in tumor relapse. Although oncolytic herpes simplex virus (oHSV) is a promising therapeutic for GBM, its efficacy against recurrent GBM is incompletely characterized. Transforming growth factor beta (TGF‐β) plays vital roles in maintaining GSC stemness and GBM pathogenesis. We hypothesized that oHSV and TGF‐β inhibitors would synergistically exert antitumor effects for recurrent GBM. Here we established a panel of patient‐derived recurrent tumor models from GBMs that relapsed after postsurgical radiation and chemotherapy, based on GSC‐enriched tumor sphere cultures. These GSCs are resistant to the standard‐of‐care temozolomide but susceptible to oHSVs G47Δ and MG18L. Inhibition of TGF‐β receptor kinase with selective targeted small molecules reduced clonogenic sphere formation in all tested recurrent GSCs. The combination of oHSV and TGF‐βR inhibitor was synergistic in killing recurrent GSCs through, in part, an inhibitor‐induced JNK‐MAPK blockade and increase in oHSV replication. In vivo, systemic treatment with TGF‐βR inhibitor greatly enhanced the antitumor effects of single intratumoral oHSV injections, resulting in cures in 60% of mice bearing orthotopic recurrent GBM. These results reveal a novel synergistic interaction of oHSV therapy and TGF‐β signaling blockade, and warrant further investigations aimed at clinical translation of this combination strategy for GBM patients.
Identification and characterization of metformin on peptidomic profiling in human visceral adipocytes
Authors: Gao Yao , Wang XingYun , Huang FangYan , Cui XianWei , Li Yun , Wang Xing , Cao Yan , Xu PengFei , Xie KaiPeng , Tang RanRan , Zhang Le , Ji ChenBo , You LiangHui , Guo XiRong
Published: August 2017

To gain insight into the effect of metformin on losing weight from peptidomic perspective and to screen potential active peptides for reducing fat lipid deposition. After determining the proper concentration of metformin on human primary visceral adipocytes, we constructed a comparative peptidomic profiling between control and metformin treatment group (n = 3) using a stable isobaric labeling strategy involving tandem mass tag reagents, followed by liquid chromatography tandem mass spectrometry. We identified and quantified 3065 non‐redundant peptides, 304 of which were differentially expressed after metformin treatment, 206 peptides were up regulated and 98 peptides were down regulated significantly. Gene ontology (GO) enrichment and pathway analysis were performed to study differentially peptides though their precursor proteins. We concluded three peptides located within the functional domains of their precursor proteins could be candidate bioactive peptides for obesity. On one hand, these results confirmed the versatile effects of metformin on adipocyte and advance our current understanding of metformin, on the other hand, these identified peptides might play putative roles in treatment of obesity.
Assessment of advanced hepatic MR elastography methods for susceptibility artifact suppression in clinical patients
Authors: Wang Jin , Glaser Kevin J. , Zhang Tianhui , Shan Qungang , He Bingjun , Chen Jun , Yin Meng , Dzyubak Bogdan , Kugel Jennifer L. , Kruse Scott A. , Grimm Roger C. , Venkatesh Sudhakar K. , Ehman Richard L.
Published: August 2017

Purpose

To assess the success rate, image quality, and the ability to stage liver fibrosis of a standard 2D gradient‐recalled echo (GRE) and four different spin‐echo (SE) magnetic resonance elastography (MRE) sequences in patients with different liver iron concentrations.

Materials and Methods

A total of 332 patients who underwent 3T MRE examinations that included liver fat and iron quantification were enrolled, including 136 patients with all five MRE techniques. Thirty‐four patients had biopsy results for fibrosis staging. The liver stiffness, region of interest area, image quality, and success rate of the five sequences were compared in 115/136 patients. The area under the receiver operating characteristic curves (AUCs) and the accuracies for diagnosing early‐stage fibrosis and advanced fibrosis were compared. The effect of BMI (body mass index), the R2* relaxation time, and fat fraction on the image quality and liver stiffness measurements were analyzed.

Results

The success rates were significantly higher in the four SE sequences (99.1–100%) compared with GRE MRE (85.3%) (all P < 0.001). There were significant differences of the mean ROI area between every pair of sequences (all P < 0.0001). There were no significant differences in the AUC of the five MRE sequences for discriminating advanced fibrosis (10 P‐values ranging from 0.2410–0.9171). R2* had a significant effect on the success rate and image quality for the noniron 2D echo‐planar imaging (EPI), 3D EPI and 2D GRE (all P < 0.001) sequences. BMI had a significant effect on the iron 2D EPI (P = 0.0230) and iron 2D SE (P = 0.0040) sequences.

Conclusion

All five techniques showed good diagnostic performance in staging liver fibrosis. The SE MRE sequences had higher success rates and better image quality than GRE MRE in 3T clinical hepatic imaging.

Level of Evidence: 3

Technical Efficacy: Stage 5

J. Magn. Reson. Imaging 2018;47:976–987.
MRI characterization of brown adipose tissue under thermal challenges in normal weight, overweight, and obese young men
Authors: Deng Jie , Neff Lisa M. , Rubert Nicholas C. , Zhang Bin , Shore Richard M. , Samet Jonathan D. , Nelson Paige C. , Landsberg Lewis
Published: August 2017

Purpose

To implement quantitative Dixon magnetic resonance imaging (MRI) methods for brown adipose tissue (BAT) characterization at inactive and cold‐activated states in normal weight, overweight, and obese subjects. The hypotheses are that MRI characteristics of BAT would differentiate between nonobese and obese subjects, and activation of BAT in response to thermal challenges that are detected by MRI would be correlated with BAT activity measured by positron emission tomography / computed tomography (PET/CT).

Materials and Methods

Fifteen male subjects (20.7 ± 1.5 years old) including six normal weight, five overweight, and four obese subjects participated in the study. A multiecho Dixon MRI sequence was performed on a 1.5T scanner. MRI was acquired under thermoneutral, nonshivering thermogenesis, and subsequent warm‐up conditions. Fat fraction (FF), R2*, and the number of double bonds (ndb) were measured by solving an optimization problem that fits in‐ and out‐of‐phase MR signal intensities to the fat‐water interference models. Imaging acquisition and postprocessing were performed by two MRI physicists. In each subject, Dixon MRI measurements of FF, R2*, and ndb were calculated for each voxel within all BAT regions of interest (ROIs) under each thermal condition. Mean FF, R2*, and ndb were compared between nonobese (ie, normal‐weight/overweight) and obese subjects using the two‐sample t‐test. Receiver operating characteristic (ROC) analyses were performed to differentiate nonobese vs. obese subjects. BAT MRI measurement changes in response to thermal condition changes were compared with hypermetabolic BAT volume/activity measured by PET/CT using the Pearson's correlation. In addition, BAT MRI measurements were compared with body adiposity using the Pearson's correlation. P < 0.05 was considered statistically significant.

Results

Obese subjects showed higher FF and lower R2* than nonobese subjects under all three thermal conditions (P < 0.01). ROC analyses demonstrated that FF and R2* were excellent predictors for the differentiation of nonobese from obese subjects (100% specificity and 100% sensitivity). FF changes under thermal challenges were correlated with hypermetabolic BAT volume (r = –0.55, P = 0.04 during activation, and r = 0.72, P = 0.003 during deactivation), and with BAT activity (r = 0.69, P = 0.006 during deactivation), as measured by PET/CT. FF and R2* under all three thermal conditions were highly correlated with body adiposity (P ≤ 0.002).

Conclusion

MRI characteristics of BAT differentiated between nonobese and obese subjects in both inactivated and activated states. BAT activation detected by Dixon MRI in response to thermal challenges were correlated with glucose uptake of metabolically active BAT.

Level of Evidence: 1

Technical Efficacy: Stage 3

J. Magn. Reson. Imaging 2018;47:936–947.
Effects of ultrasound treatment on physico‐chemical, functional properties and antioxidant activity of whey protein isolate in the presence of calcium lactate
Authors: Jiang Zhanmei , Yao Kun , Yuan Xiangying , Mu Zhishen , Gao Zengli , Hou Juncai , Jiang Lianzhou
Published: August 2017

BACKGROUND

The aim of this study was to investigate the effects of ultrasound applied at various powers (0, 200, 400, 600 or 800 W) and for different times (20 or 40 min) on the physico‐chemical, functional properties and antioxidant activities of whey protein isolate (WPI) dispersions in the presence of 1.20 mmol L−1 calcium lactate.

RESULTS

Surface hydrophobicity and free sulfhydryl group of the WPI dispersions containing 1.2 mmol L−1 calcium lactate were significantly enhanced after sonication. Furthermore, particle size of WPI dispersions containing 1.20 mmol L−1 calcium lactate was minimised after sonication. Scanning electron microscopy of sonicated WPI suspensions containing 1.20 mmol L−1 calcium lactate showed that WPI microstructure had significantly changed. After WPI dispersions were treated by sonication assisted with calcium lactate, its gel strength enhanced and solubility decreased. Gel strength of sonicated WPI dispersions (600 W, 40 min) was the maximum among all the WPI treatments. Emulsification activity of sonicated WPI dispersions reduced while its emulsion stability increased. The DPPH radical scavenging activity and ferrous reducing power of sonicated WPI dispersions mostly increased.

CONCLUSION

Ultrasound treatments induced structural changes in WPI molecules, leading to different microstructure and improved gel strength of WPI in the presence of calcium lactate. © 2017 Society of Chemical Industry
Simple and rapid determination of zaltoprofen in human plasma by manual‐shaking‐assisted dispersive liquid–liquid microextraction followed by liquid chromatography with ultraviolet detection
Authors: Han Se Young , Jeong Kyung Min , Yoo Da Eun , Jin Yan , Kim Eun Mi , Kim Su Hyun , Lee Seok‐Yong , Kim Se‐Hyung , Zhao Jing , Lee Jeongmi
Published: August 2017

A readily applicable method was developed to determine the concentration level of zaltoprofen, a non‐steroidal antiinflammatory drug from the propionic acid family, in human plasma. This method is based on manual‐shaking‐assisted dispersive liquid–liquid microextraction coupled with liquid chromatography with ultraviolet detection. Factors affecting the extraction efficiency were screened and optimized by experimental design using fractional factorial and central composite designs, respectively. Optimal conditions were: 220 μL of C2H4Cl2 (extraction solvent), 5 mL of 3.75% w/v NaCl aqueous solution at pH 2.0, and manual shaking for 13 s (65 times). The resulting extraction method yielded a reasonable enrichment factor of 18.0 (±0.6, n = 3) and extraction recovery of 86.0% (±3.3%, n = 3). The established method was validated for selectivity, linearity, precision, accuracy, matrix effect, recovery, dilution integrity, and stability, and it met the acceptable criteria for all of the tested parameters. Specifically, the method was linear in the range of 0.16–50.0 mg/L, precise (< 8.8% RSD), accurate (–7.5–5.6% deviation), and showed negligible matrix effects (96.1–106.4%) with high absolute recovery (94.5–97.7%). Compared with previous methods involving labor‐intensive liquid–liquid extraction or non‐specific protein precipitation, our method allows the simple, rapid, and efficient determination of zaltoprofen using the most affordable analytical instrument, liquid chromatography with ultraviolet detection.
Evaluation of poly([2‐(acryloyloxy)ethyl]trimethylammonium chloride) cationic polymer capillary coating for capillary electrophoresis and electrokinetic chromatography separations
Authors: McGettrick Julie R. , Palmer Christopher P.
Published: August 2017

Capillary electrophoresis and electrokinetic chromatography are typically carried out in unmodified fused‐silica capillaries under conditions that result in a strong negative zeta potential at the capillary wall and a robust cathodic electroosmotic flow. Modification of the capillary wall to reverse the zeta potential and mask silanol sites can improve separation performance by reducing or eliminating analyte adsorption, and is essential when conducting electrokinetic chromatography separations with cationic latex nanoparticle pseudo‐stationary phases. Semipermanent modification of the capillary walls by coating with cationic polymers has proven to be facile and effective. In this study, poly([2‐(acryloyloxy)ethyl]trimethylammonium chloride) polymers were synthesized by reversible addition‐fragmentation chain transfer polymerization and used as physically adsorbed semipermanent coatings for capillary electrophoresis and electrokinetic chromatography separations. An initial synthesis of poly([2‐(acryloyloxy)ethyl]trimethylammonium chloride) polymer coating produced strong and stable anodic electroosmotic flow of –5.7 to –5.4 × 10−4 cm2/V⋅s over the pH range of 4–7. Significant differences in the magnitude of the electroosmotic flow and effectiveness were observed between synthetic batches, however. For electrokinetic chromatography separations, the best performing batches of poly([2‐(acryloyloxy)ethyl]trimethylammonium chloride) polymer performed as well as the commercially available cationic polymer polyethyleneimine, whereas polydiallylammonium chloride and hexadimethrine bromide did not perform well.
Ursolic Acid, a Natural Nutraceutical Agent, Targets Caspase3 and Alleviates Inflammation‐Associated Downstream Signal Transduction
Authors: Ma Xiaoyao , Zhang Yuan , Wang Zengyong , Shen Yunbing , Zhang Man , Nie Quandeng , Hou Yuanyuan , Bai Gang
Published: August 2017

Scope

Ursolic acid (UA) is a pentacyclicterpenoid carboxylic acid that is present in a wide variety of plant foods. There are many beneficial health effects that are attributed to the properties of UA. However, the specific cellular targets of UA and the mechanism underlying downstream signal transduction processes linked to the anti‐inflammation pathway have not been thoroughly elucidated to date.

Methods and results

Chemical biology strategies such as target fishing, click reaction synthesis of a UA probe and molecular imaging were used to identify potential target proteins of UA. Cysteinyl aspartate specific proteinase 3 (CASP3) and its downstream signaling pathway were verified as potential targets by molecular docking, intracellular enzyme activity evaluation and accurate pathway analysis. The results indicated that UA acted on CASP3, ERK1 and JNK2 targets, alleviated inflammation‐associated downstream multiple signal transduction factors, including ERK1, NF‐κB and STAT3, and exhibited anti‐inflammation activities.

Conclusion

As a natural dietary supplement, UA demonstrated anti‐inflammation activity via inhibition of CASP3 and shows the potential to improve the therapy effect of several inflammation‐associated diseases.
Modeling ion recombination in liquid ionization chambers — Improvement and analysis of the two‐dose‐rate method
Authors: Andersson Jonas , Tölli Heikki
Published: August 2017

Purpose

The use of liquid ionization chambers can provide useful information to endeavors with radiation dosimetry for highly modulated beams. Liquid ionization chambers may be particularly suitable for computed tomography applications where conventional ionization chambers do not present a high enough sensitivity for the spatial resolution required to characterize common X‐ray beams. Due to the sensitivity, which leads to high charge densities, liquid ionization chambers can suffer from large recombination losses leading to degradation in signal to dose rate linearity. To solve this problem, a two‐dose‐rate method for general recombination correction has been proposed for liquid ionization chambers. However, the valid range of recombination losses that the method can accurately account for has been found to vary depending on radiation quality. The present work provides an in‐depth analysis of the performance of the two‐dose‐rate method. Furthermore, the soundness of applying gas theory to liquids is investigated by using the two‐dose‐rate method.

Methods

In the present work, the two‐dose‐rate method for general recombination correction of liquid ionization chambers used in continuous beams is studied by employing theory for gas‐filled ionization chambers. An approximate relation for the general collection efficiency containing a material‐specific parameter that is traceable to liquids has been derived for theoretical and experimental investigation alongside existing theory. Furthermore, the disassociation between initial and general recombination in the method is analyzed both theoretically and experimentally.

Results

The results indicate that liquids and gases share general recombination characteristics, where the liquids investigated (isooctane and tetramethylsilane) to a large extent mimic the behavior theoretically expected in gases. Furthermore, it is shown that the disassociation between initial and general recombination in the two‐dose‐rate method is an approximation that depends on the relation between initial recombination and the collecting electric field strength at the dose rates used.

Conclusions

Due to the approximation used to separate initial and general recombination the valid range of collection efficiencies for the two‐dose‐rate method will not only depend on the model used to describe general recombination but also on the type of liquid and radiation beam quality. As there is no robust theory for initial recombination in liquids to apply, the valid range of general collection efficiencies for the two‐dose‐rate method should be experimentally evaluated for each radiation dosimetry application.
Different nerve ultrasound patterns in charcot‐marie‐tooth types and hereditary neuropathy with liability to pressure palsies
Authors: Padua Luca , Coraci Daniele , Lucchetta Marta , Paolasso Ilaria , Pazzaglia Costanza , Granata Giuseppe , Cacciavillani Mario , Luigetti Marco , Manganelli Fiore , Pisciotta Chiara , Piscosquito Giuseppe , Pareyson Davide , Briani Chiara
Published: August 2017

Introduction

Nerve ultrasound in Charcot–Marie–Tooth (CMT) disease has focused mostly on the upper limbs. We performed an evaluation of a large cohort of CMT patients in which we sonographically characterized nerve abnormalities in different disease types, ages, and nerves.

Methods

Seventy patients affected by different CMT types and hereditary neuropathy with liability to pressure palsies (HNPP) were evaluated, assessing median, ulnar, fibular, tibial, and sural nerves bilaterally. Data were correlated with age.

Results

Nerve dimensions were correlated with CMT type, age, and nerve site. Nerves were larger in demyelinating than in axonal neuropathies. Nerve involvement was symmetric.

Discussion

CMT1 patients had larger nerves than did patients with other CMT types. Patients with HNPP showed enlargement at entrapment sites. Our study confirms the general symmetry of ultrasound nerve patterns in CMT. When compared with ultrasound studies of nerves of the upper limbs, evaluation of the lower limbs did not provide additional information. Muscle Nerve 57: E18–E23, 2018
Pregnancy outcomes in mothers of offspring with inherited bone marrow failure syndromes
Authors: Giri Neelam , Reed Helen D. , Stratton Pamela , Savage Sharon A. , Alter Blanche P.
Published: August 2017

Background

Children with inherited bone marrow failure syndromes (IBMFSs) may be symptomatic in utero, resulting in maternal and fetal problems during the pregnancy. Subsequent pregnancies by their mothers should be considered “high risk”.

Methods

We retrospectively analyzed outcomes of 575 pregnancies in 165 unaffected mothers of offspring with Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond–Blackfan anemia (DBA), and Shwachman–Diamond syndrome (SDS) for events noted during pregnancy, labor, and delivery. We compared outcomes of pregnancies with affected and unaffected offspring within each group of mothers and with the general population.

Results

The rates of miscarriage (12–20%), elective abortion (5–10%), and live birth (68–78%) among mothers of all IBMFS groups were similar and comparable with general population rates but recurrent miscarriages (≥2) were significantly more common in mothers of offspring with DBA and SDS. Offspring with FA were more frequently born small for gestational age (SGA) than unaffected babies (39% vs. 4%) and had fetal malformations (46%) with 18% having three or more, often necessitating early delivery and surgery; offspring with DC had higher rates of SGA (39% vs. 8%) and fetal distress (26% vs. 3%); and offspring with DBA had fetal hypoxia (19% vs. 1%) leading to preterm and emergency cesarean deliveries (26% vs. 6%). Offspring with early‐onset severe phenotypes had the most prenatal and peripartum adverse events.

Conclusion

We identified the high‐risk nature of pregnancies in mothers with IBMFS‐affected fetuses, suggesting the need for prepregnancy counseling and monitoring of subsequent pregnancies by high‐risk fetal–maternal specialists.
An analysis of inpatient pediatric sickle cell disease: Incidence, costs, and outcomes
Authors: Bou‐Maroun Laura M. , Meta Fabien , Hanba Curtis J. , Campbell Andrew D. , Yanik Gregory A.
Published: August 2017

Objective

To identify characteristics of pediatric sickle cell disease (SCD) hospitalizations and to examine admission demographics and medical expenditures.

Methods

Admissions with SCD were identified from the 2009 and 2012 releases of the Healthcare and Cost Utilization Project's Kids Inpatient Database. Disease‐specific secondary diagnoses including acute chest syndrome (ACS), vaso‐occlusive pain crisis (VOC), splenic sequestration, and stroke/transient ischemic attack were analyzed for patient and hospital demographics. Analytical endpoints included total healthcare expenditures and mortality.

Results

We reviewed 75,234 inpatient hospitalizations with a diagnosis of SCD. Over $900,000,000 was spent annually in associated healthcare expenditure. The median length of hospitalization stay (LOS) for all admissions was 3 days (interquartile range [IQR] 2–5 days). VOC was the most frequent secondary diagnosis, recording 48,698 total hospitalizations and a median LOS of 3 days (IQR 2–6 days). Of the 8,490 hospitalizations with ACS, the infant population had a significantly higher mortality rate compared to other age groups (2% vs. 0.3%, P < 0.001). Cerebral vascular accidents incurred the second highest median hospitalization cost ($18,956), behind ACS ($22,631). A high proportion of Caucasian patients died during hospitalization for VOC (0.4% vs. 0.1%, P = 0.014) and ACS (4% vs. 0.2%, P < 0.001) when compared to non‐Caucasians.

Conclusion

Inpatient hospitalizations for secondary manifestations of pediatric SCD were associated with significant healthcare expenditures. Patients with an increased statistical risk for death during hospitalization included Caucasians with SCD complications of ACS and VOC, and patients <1‐year‐old with ACS. Further research is needed to substantiate the associated clinical significance of these findings.
Fetal isovolumetric time intervals as a marker of abnormal cardiac function in fetal anemia from homozygous alpha thalassemia‐1 disease
Authors: Tongprasert Fuanglada , Srisupundit Kasemsri , Luewan Suchaya , Traisrisilp Kuntharee , Jatavan Phudit , Tongsong Theera
Published: August 2017

Objective

To determine whether fetal isovolumetric time intervals can be an early sonographic marker of fetal anemia in fetuses with homozygous alpha thalassemia‐1.

Methods

Pregnancies at risk for fetal homozygous alpha thalassemia‐1 disease at 18–22 weeks were recruited before cordocentesis for hemoglobin typing. Isovolumetric contraction time (ICT) and isovolumetric relaxation time (IRT) intervals were measured by placing pulsed wave Doppler sample volume within the left ventricle to obtain the mitral and aortic waveform. Time intervals were compared between the affected group of homozygous alpha thalassemia‐1 fetuses and the unaffected group.

Results

Among 70 fetuses at risk, 28 cases were diagnosed as affected by homozygous alpha thalassemia‐1 disease. Mean ICT and ICT + IRT intervals in the affected group were significantly longer than in the unaffected group (47.9 ± 12.5 ms vs 35.0 ± 6.7 ms, p < 0.001; and 96.2 ± 13.6 ms vs 80.9 ± 10.6 ms, p < 0.001. ICT effectively predicted affected fetuses with 71.4% sensitivity and 78.6% specificity using a cutoff value ≥40 ms.

Conclusions

Isovolumetric contraction time was significantly prolonged in fetal anemia from homozygous alpha thalassemia‐1 during the early stage of hydropic changes. Because of its simple measurement and high efficacy, ICT can be a useful marker for prenatal screening of abnormal cardiac function in fetal anemia. © 2017 John Wiley & Sons, Ltd.
The Emergence of Second‐Generation Lethal Injection Protocols: A Brief History and Review
Authors: Malcom Daniel R. , Romanelli Frank
Published: August 2017

The history of capital punishment in the United States is long and controversial. In many cases, lethal injection has brought medical personnel, ethically and professionally charged with preserving life, into the arena of assisting the state in taking life. U.S. Supreme Court decisions, including Baze v. Rees (2008) and Glossip v. Gross (2015), have evaluated and condoned lethal injection protocols. Despite the judicial validation of some midazolam‐containing protocols, controversy exists about the level of unconsciousness provided due to the ceiling effects of the drug. Drug shortages, induced in part by manufacturers under pressure by death penalty opponents and governments opposed to capital punishment, have forced states to sometimes use creative means to obtain medications for use in lethal injection, even proposing to allow inmates to supply their own drugs for use in execution. Others have resorted to using compounding pharmacies and enacting tougher execution secrecy laws to protect the identities of those involved in the process. Professional organizations representing health care team members, including nursing, medicine, and pharmacy, among others, have roundly denounced the medicalization of capital punishment. Legal challenges continue to mount at all levels, leading to an uncertain future for lethal injection.
Poly(2‐oxazoline)s: A comprehensive overview of polymer structures and their physical properties
Authors: Glassner Mathias , Vergaelen Maarten , Hoogenboom Richard
Published: August 2017

Poly(2‐oxazoline)s (PAOx) are of increasing importance for a wide range of applications, mostly in the biomedical field. This review describes the synthesis of 2‐oxazoline monomers and their cationic ring‐opening polymerization, and gives a comprehensive overview of all reported PAOx homopolymers. In the second part of the review, the polymer properties of these PAOx homopolymers with varying side‐chain structures are discussed. Altogether, this review intends to serve as an encyclopedia for poly(2‐oxazoline)s enabling the straightforward selection of a polymer structure with the desired properties for a certain application. © 2017 Society of Chemical Industry
MALDI Imaging‐Guided Microproteomic Analyses of Heterogeneous Breast Tumors—A Pilot Study
Authors: Alberts Deborah , Pottier Charles , Smargiasso Nicolas , Baiwir Dominique , Mazzucchelli Gabriel , Delvenne Philippe , Kriegsmann Mark , Kazdal Daniel , Warth Arne , De Pauw Edwin , Longuespée Rémi
Published: August 2017

Matrix‐assisted laser desorption/ionization (MALDI) imaging is an ideal tool to study intratumor heterogeneity (ITH) and its implication in prognostic stratification of patients. However, there are some drawbacks concerning protein identification. On the other hand, laser microdissection (LMD)‐based microproteomics allows retrieving thousands of protein identifications from small tissue pieces. As a proof of concept, the authors combine these two complementary approaches to analyze heterogeneous regions in breast tumors. Invasive ductal breast cancer FFPE tissue sections from five patients are analyzed by MALDI imaging and the dataset is processed by segmentation. Heterogeneous regions within tumors are processed by LMD‐based microproteomics, in duplicates. Liquid chromatography‐tandem mass spectrometry data are classified by hierarchical clustering. Heterogeneous tissue regions are discriminated on the basis of their actual molecular heterogeneity. The dataset is correlated with MALDI imaging to identify m/z values discriminating heterogeneous regions. The molecular characterization of cell clones in tumors related to bad patient outcome could have great impact for pathology. A combined application of LMD‐based microproteomics and MALDI imaging for ITH studies is presented.
Cyclic oligomer design with de novo αβ‐proteins
Authors: Lin Yu‐Ru , Koga Nobuyasu , Vorobiev Sergey M. , Baker David
Published: August 2017

We have previously shown that monomeric globular αβ‐proteins can be designed de novo with considerable control over topology, size, and shape. In this paper, we investigate the design of cyclic homo‐oligomers from these starting points. We experimented with both keeping the original monomer backbones fixed during the cyclic docking and design process, and allowing the backbone of the monomer to conform to that of adjacent subunits in the homo‐oligomer. The latter flexible backbone protocol generated designs with shape complementarity approaching that of native homo‐oligomers, but experimental characterization showed that the fixed backbone designs were more stable and less aggregation prone. Designed C2 oligomers with β‐strand backbone interactions were structurally confirmed through x‐ray crystallography and small‐angle X‐ray scattering (SAXS). In contrast, C3‐C5 designed homo‐oligomers with primarily nonpolar residues at interfaces all formed a range of oligomeric states. Taken together, our results suggest that for homo‐oligomers formed from globular building blocks, improved structural specificity will be better achieved using monomers with increased shape complementarity and with more polar interfaces.
Thermal hazard investigation of a pharmaceutical intermediate
Authors: Zhao Ralph , Muzzio Dan , Vickery Tom , Fisher Elizabeth , Artino Laura , Yin Jay , Hinksmon Joe , Fine Adam
Published: August 2017

During the process development of a pharmaceutical advanced intermediate, new chemistry using an aqueous workup resulted in the discovery of a new hydrated crystal form of this intermediate. This hydrated crystal form showed thermal instability at a relatively low temperature compared to the original anhydrous form. Thermal stability and associated process safety hazards were investigated in order to ensure process safety and transportation safety of this intermediate. © 2017 American Institute of Chemical Engineers Process Saf Prog 37: 263–267, 2018
Brief Report: A Differential Transcriptomic Profile of Ex Vivo Expanded Adult Human Hematopoietic Stem Cells Empowers Them for Engraftment Better than Their Surface Phenotype
Authors: Psatha Nikoletta , Georgolopoulos Grigorios , Phelps Susan , Papayannopoulou Thalia
Published: August 2017

Transplantation of small cord blood (CB) units, or of autologous ex vivo-genetically modified adult hematopoietic stem cells (HSC), face the common challenge of suboptimal HSC doses for infusion and impaired engraftment of the transplanted cells. Ex vivo expansion of HSCs, using either cell-based coculture approaches or especially small molecules have been successfully tested mainly in CB and in prolonged cultures. Here, we explored whether innovative combinations of small molecules can sufficiently, after short culture, expand adult HSCs while retaining their functionality in vivo. We found that 5-day cultured cells, in the presence of the small molecule combinations tested, achieved higher engraftment levels in NSG mice than both their uncultured and their cytokine only-cultured counterparts. Surprisingly, the engraftment levels were neither concordant to the numbers of phenotypically similar HSCs expanded under different small molecule combinations, nor explained by their distinct companion cells present. Transcriptomic comparative analysis of sorted, phenotypically similar, ex vivo generated HSCs transplanted in equal numbers, suggested that HSCs generated under expansion conditions that maintain low expression of the Rap1/Ras/PI3K-AKT pathway exhibit a superior functional profile in vivo.