bluuebunny/crossref_metadata_2025 huggingface dataset:
1,4,7‐Triazacyclononane‐Based Bifunctional Picolinate Ligands for Efficient Copper Complexation
Authors: Guillou Amaury , Lima Luís M. P. , Roger Mélissa , Esteban‐Gómez David , Delgado Rita , Platas‐Iglesias Carlos , Patinec Véronique , Tripier Raphaël
Published: May 2017

Three 1,4,7‐triazacyclononane‐based (tacn‐based) ligands containing picolyl and picolinate pendant arms (no3py, no2pa1py, and no3pa) were synthesized, and their copper(II) complexation properties were studied to evaluate their potentials as chelators for copper radioisotopes. The thermodynamic stability constants of the complexes were determined by potentiometric titrations. These studies evidenced the formation of mononuclear species for no3py and mono‐ and dinuclear species for no2pa1py and no3pa. The pCu values decreased as the number of carboxypicolyl arms increased. The [Cu(no3py)]2+ complex presented a very high stability constant (log KCuL = 27.4) and a very high selectivity towards Zn2+ ions (log KZnL = 17.25). Vis/NIR (NIR = near‐infrared) absorption and electron paramagnetic resonance (EPR) spectroscopy indicated that the three complexes present distorted octahedral geometries with two paramagnetic species, which were identified as the Δ(δδδ) and Λ(δδδ) isomers [and their corresponding enantiomeric forms Λ(λλλ) and Δ(λλλ)] by DFT calculations. The electrochemical properties were investigated by cyclic voltammetry, which revealed quasireversible behavior for the [Cu(no3py)]2+ complex but irreversible Cu2+/Cu+ systems for [Cu(no2pa1py)] and [Cu(no3pa)]–.
PoPD Modified ITO Based Capacitive Immunosensor for Sulphathiazole
Authors: Prusty Arun Kumar , Bhand Sunil
Published: May 2017

A capacitive immunosensor for determination of sulphathaizole (STZ) has been developed on polymer coated indium tin oxide glass chip (ITO). The immunosensor chip was fabricated by polymerizing, ortho‐phenylenediamine (oPD) on ITO followed by surface modification with anti‐sulphathiazole antibody. The developed immunosensor chip was characterized by using Atomic force microscopy (AFM), Cyclicvoltammetry (CV) and Electrochemical impedance spectroscopy (EIS). The capacitive measurement of the developed immunosensor was performed by using EIS in spiked drinking water and milk. The developed sensor showed liner detection range 0.1‐100 μgL−1for STZ with a limit of detection 0.01 μgL−1 in water with recovery between 95–106 %. The biosensor showed excellent selectivity and storage stability upto 4 weeks when preserved at 4 °C.
Effect of intumescent compositions on flammable properties of ethylene vinyl acetate and polypropylene
Authors: Giang Thanhkieu , Hoang Dongquy , Kim Jinhwan
Published: May 2017

An intumescent flame retardant (IFR) system was prepared by 2 ways. Firstly, bis(2,6,7‐trioxa‐1‐phosphabicyclo[2,2,2]octane‐1‐oxa‐4‐hydroxymethyl) phosphonate methyl (bis‐PM) was synthesized and characterized by 1H nuclear magnetic resonance (NMR), 31P NMR, and Fourier transform infrared spectroscopies. This carbonization agent was mixed with melamine (ME), ammonium polyphosphate (APP), and pentaerythritol (PER) to constitute an IFR system. Secondly, an IFR system by reaction was prepared by reaction, and the presence of compositions in product was confirmed by 1H NMR and Fourier transform infrared. Both of systems enhanced the flammable retardation of ethylene vinyl acetate (EVA) and polypropylene (PP). Flammability and thermal behaviors of IFR‐EVA and IFR‐PP were investigated by vertical burning test (UL‐94 V) and thermogravimetric analysis. Results indicated that the IFR systems performed excellent flame retardancy and antidripping ability for PP. At 30 wt% loading, the optimum flame retardant formulations that are bis‐PM/ME: 4/1, bis‐PM/ME/PER: 3/1/1, APP/ME/PER: 3/1/1, and bis‐PM/ME/PER/APP: 1.5/1.5/1/1 give UL‐94 V‐0 rating. However, V‐0 rating results were only obtained for EVA when systems contain bis‐PM/ME: 4/1 and bis‐PM/ME/PER: 3/1/1. The char yield from decomposition of the IFR‐EVA and IFR‐PP has effects on the flame retardancy and antidripping behaviors of EVA and PP.
The novel intracellular protein CREG inhibits hepatic steatosis, obesity, and insulin resistance
Authors: Zhang Quan‐Yu , Zhao Ling‐Ping , Tian Xiao‐Xiang , Yan Cheng‐Hui , Li Yang , Liu Yan‐Xia , Wang Pi‐Xiao , Zhang Xiao‐Jing , Han Ya‐Ling
Published: May 2017

Cellular repressor of E1A‐stimulated genes (CREG), a novel cellular glycoprotein, has been identified as a suppressor of various cardiovascular diseases because of its capacity to reduce hyperplasia, maintain vascular homeostasis, and promote endothelial restoration. However, the effects and mechanism of CREG in metabolic disorder and hepatic steatosis remain unknown. Here, we report that hepatocyte‐specific CREG deletion dramatically exacerbates high‐fat diet and leptin deficiency–induced (ob/ob) adverse effects such as obesity, hepatic steatosis, and metabolic disorders, whereas a beneficial effect is conferred by CREG overexpression. Additional experiments demonstrated that c‐Jun N‐terminal kinase 1 (JNK1) but not JNK2 is largely responsible for the protective effect of CREG on the aforementioned pathologies. Notably, JNK1 inhibition strongly prevents the adverse effects of CREG deletion on steatosis and related metabolic disorders. Mechanistically, CREG interacts directly with apoptosis signal‐regulating kinase 1 (ASK1) and inhibits its phosphorylation, thereby blocking the downstream MKK4/7‐JNK1 signaling pathway and leading to significantly alleviated obesity, insulin resistance, and hepatic steatosis. Importantly, dramatically reduced CREG expression and hyperactivated JNK1 signaling was observed in the livers of nonalcoholic fatty liver disease (NAFLD) patients, suggesting that CREG might be a promising therapeutic target for NAFLD and related metabolic diseases.

Conclusion: The results of our study provides evidence that CREG is a robust suppressor of hepatic steatosis and metabolic disorders through its direct interaction with ASK1 and the resultant inactivation of ASK1‐JNK1 signaling. This study offers insights into NAFLD pathogenesis and its complicated pathologies, such as obesity and insulin resistance, and paves the way for disease treatment through targeting CREG. (Hepatology 2017;66:834–854)
Risk factors for recurrence of primary biliary cholangitis after liver transplantation in female patients: A Japanese multicenter retrospective study
Authors: Kogiso Tomomi , Egawa Hiroto , Teramukai Satoshi , Taniai Makiko , Hashimoto Etsuko , Tokushige Katsutoshi , Sakisaka Shotaro , Sakabayashi Satomi , Yamamoto Masakazu , Umeshita Koji , Uemoto Shinji
Published: May 2017

Primary biliary cholangitis (PBC) is diagnosed mainly in female individuals, and risk factors for PBC recurrence (rPBC) after liver transplantation (LT) from cadaveric donors have been reported. We conducted a retrospective multicenter study of rPBC in female patients after living‐donor LT (LDLT). A total of 388 female patients undergoing LDLT for end‐stage PBC were enrolled, and the effects of preoperative and operative factors were evaluated. Postoperative factors were evaluated in 312 patients who survived for more than 1 year post‐LDLT. rPBC was defined as abnormal hepatic enzyme levels with typical histological findings in liver biopsies. Fifty‐eight patients (14.9%) developed rPBC with a median of 4.6 (0.8‐14.5) years post‐LT. Cox hazard analysis (P < 0.05) showed that younger recipient age (hazard ratio, 0.95; 95% confidence interval, 0.920‐0.982), shorter operative time (1.00; 0.995‐0.999), higher serum immunoglobulin M level (1.00; 1.001‐1.002), donor sex mismatch (2.45; 1.268‐4.736), human leukocyte antigen B60 (2.56; 1.336‐4.921) and DR8 (1.98; 1.134‐3.448), and initial treatment with cyclosporine A (3.14; 1.602‐6.138) were significantly associated with rPBC. The frequencies of Child‐Turcotte‐Pugh class C (0.46; 0.274‐0.775), the model of end‐stage liver disease score (0.96; 0.914‐0.998), and updated Mayo risk score (1.02; 1.005‐1.033) were significantly lower in rPBC. Posttransplantation use of steroids decreased and that of antimetabolites increased the frequency of rPBC. Conclusion: The timing of LT, recipient conditions, donor characteristics, and immunosuppressive medications may be associated with rPBC in LT recipients. (Hepatology Communications 2017;1:394–405)
Hepatic natural killer T‐cell and CD8+ T‐cell signatures in mice with nonalcoholic steatohepatitis
Authors: Bhattacharjee Jashdeep , Kirby Michelle , Softic Samir , Miles Lili , Salazar‐Gonzalez Rosa‐Maria , Shivakumar Pranav , Kohli Rohit
Published: May 2017

Hepatic inflammation is a key pathologic feature of nonalcoholic steatohepatitis (NASH). Natural killer T (NKT) cells and clusters of differentiation (CD)8+ T‐cells are known to play an important role in obesity‐related adipose tissue inflammation. We hypothesized that these same inflammatory phenotypes would be present in progressive NASH. We used a previously established high‐fat high‐carbohydrate (HFHC) murine obesogenic diet model of progressive NASH to investigate the role of NKT cells and CD8+ T‐cells in C57Bl6/J mice. To better understand the impact of these cell populations, CD1d‐deficient and CD8+ T‐cell‐depleted mice were subjected to an HFHC diet for 16 weeks. C57Bl6/J mice fed an HFHC diet had increased body weight, liver triglyceride content, serum alanine aminotransferase levels, and increased NKT‐cell and CD8+ T‐cell infiltration in the liver. In addition, human liver sections from patients with NASH showed increased CD8+ T‐cells. In comparison, CD1d‐deficient and CD8 T‐cell‐depleted mice fed an HFHC diet had a lower hepatic triglyceride content, lower alanine aminotransferase levels, lower activated resident macrophages and infiltrating macrophages, improved nonalcoholic fatty liver disease activity scores, and reduced α‐smooth muscle actin, collagen type 1 alpha 1, and collagen type 1 alpha 2 messenger RNA expression. Further, while CD1d‐deficient mice were protected against weight gain on the HFHC diet, CD8 T‐cell‐depleted mice gained weight on the HFHC diet. Conclusion: We found that NASH has an immunological signature that includes hepatic infiltrating NKT and CD8+ T‐cells. Depletion of these cells resulted in reduced NASH progression and thus presents novel therapeutic avenues for the treatment of NASH. (Hepatology Communications 2017;1:299–310)
Increased adipose tissue expression of IL‐18R and its ligand IL‐18 associates with inflammation and insulin resistance in obesity
Authors: Ahmad Rasheed , Thomas Reeby , Kochumon Shihab , Sindhu Sardar
Published: May 2017

Introduction

The proinflammatory cytokine IL‐18 is involved in the pathogenesis of metabolic syndrome. While the changes in IL‐18 are known, IL‐18R expression and relationship with IL‐18 and other inflammatory markers in the adipose tissue in obesity/type‐2 diabetes (T2D) remain unclear.

Methods

We, therefore, determined the adipose tissue expression of IL‐18R and IL‐18 mRNA/protein in lean, overweight, and obese individuals with and without T2D, 15 each, using qRT‐PCR, immunohistochemistry, and confocal microscopy. Data (mean ± SEM) were analyzed using unpaired t‐test and Pearson's correlation (r); all P values ≤0.05 were considered statistically significant.

Results

We found the upregulated gene/protein expression of IL‐18R and IL‐18 in non‐diabetic obese/overweight as compared with lean individuals (P < 0.05). BMI correlated positively (P < 0.05) with the adipose tissue expression of IL‐18R (mRNA: r = 0.90 protein: r = 0.84) and IL‐18 (mRNA: r = 0.84 protein: r = 0.80). Similarly, in T2D individuals, gene and protein expression of IL‐18R/IL‐18 was significantly higher in obese as compared with overweight/lean individuals. The BMI was associated with the changes in both IL‐18R (mRNA: r = 0.55 protein: r = 0.50) and IL‐18 (mRNA: r = 0.53 protein: r = 0.57) expression. IL‐18R/IL‐18 gene expression in the adipose tissue was positively associated (P < 0.05) with local gene expression of other inflammatory markers including CD11c, CD86, CD68, CD163, TNF‐α, and CCL5. Homeostatic model assessment of insulin resistance (HOMA‐IR) was higher in diabetic/non‐diabetic obese and it correlated with BMI (P < 0.05). IL‐18R and IL‐18 mRNA/protein expression in obesity was associated with HOMA‐IR only in non‐diabetics.

Conclusions

The adipose tissue IL‐18R/IL‐18 expression is enhanced in obesity which associates with proinflammatory gene signature and insulin resistance in these individuals.
A new transcript in the TCRB locus unveils the human ortholog of the mouse pre‐Dß1 promoter
Authors: Lethé Bernard , Snauwaert Sylvia , Bricard Orian , Schröder David , Gomard Tiphanie , Hames Gérald , Muller Catherine , Lurquin Christophe , Gauthy Emilie , Essaghir Ahmed , Vandekerckhove Bart , Coulie Pierre G.
Published: May 2017

Introduction

While most transcripts arising from the human T Cell Receptor locus reflect fully rearranged genes, several germline transcripts have been identified. We describe a new germline transcript arising from the human TCRB locus.

Methods

cDNA sequencing, promoter, and gene expression analyses were used to characterize the new transcript.

Results

The new germline transcript encoded by the human TCRB locus consists of a new exon of 103 bp, which we named TRBX1 (X1), spliced with the first exon of gene segments Cß1 or Cß2. X1 is located upstream of gene segment Dß1 and is therefore deleted from a V‐DJ rearranged TCRB locus. The X1‐Cß transcripts do not appear to code for a protein. We define their transcription start and minimal promoter. These transcripts are found in populations of mature T lymphocytes from blood or tissues and in T cell clones with a monoallelic TCRB rearrangement. In immature thymocytes, they are already detectable in CD1a−CD34+CD4−CD8− cells, therefore before completion of the TCRB rearrangements.

Conclusions

The X1 promoter appears to be the ortholog of the mouse pre‐Dß1 promoter (PDß1). Like PDß1, its activation is regulated by Eß in T cells and might facilitate the TCRB rearrangement process by contributing to the accessibility of the Dß1 locus.
Silver nanoparticle deposited implants to treat osteomyelitis
Authors: Nandi Samit Kumar , Shivaram Anish , Bose Susmita , Bandyopadhyay Amit
Published: May 2017

In this study, electrolytically deposited strongly adherent silver nanoparticles on stainless‐steel (SS) implants were used for in situ osteomyelitis treatment. Samples were heat treated to enhance adhesion of silver on 316 L SS. Ex vivo studies were performed to measure silver‐release profiles from the 316 L SS screws inserted in equine cadaver bones. No change in the release profiles of silver ions were observed in vitro between the implanted screws and the control. In vivo studies were performed using osteomyelitic rabbit model with 3 mm diameter silver‐deposited 316 L SS pins at two different doses of silver: high and low. Infection control ability of the pins for treating osteomyelitis in a rabbit model was measured using bacteriologic, radiographic, histological, and scanning electron microscopic studies. Silver‐coated pins, especially high dose, offered a promising result to treat infection in animal osteomyelitis model without any toxicity to major organs. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1073–1083, 2018.
Lack of Effect of Rivipansel on QTc Interval in Healthy Adult African American Male Subjects
Authors: Tammara Brinda K. , Plotka Anna , Shafer Frank E. , Readett David R. J. , Riley Steve , Korth‐Bradley Joan M.
Published: May 2017

Rivipansel is a pan‐selectin inhibitor in phase 3 development for the treatment of vaso‐occlusive crises in patients with sickle cell disease. This single‐dose, randomized, 3‐period, 3‐treatment (400 mg moxifloxacin open‐label, 4 g rivipansel–blinded, and placebo‐blinded) crossover study evaluated the effect of rivipansel on the QT/QTc interval in 48 healthy male African American subjects (age, 21–53 years; weight, 60–115 kg). Time‐matched, placebo‐adjusted change from baseline QT interval using Fridericia's correction method (QTcF) was determined using a repeated‐measures mixed‐effects model. The highest upper bound of the 2‐sided 90% confidence interval (CI) for QTcF change was 3.22 milliseconds 3 hours postdose. Moxifloxacin showed the anticipated QTcF effect, indicating that the study had adequate sensitivity to detect changes in the QTcF interval. The study concluded that no QTcF effect was demonstrated with rivipansel compared with placebo, as the upper bound of the 2‐sided 90%CI was less than 10 milliseconds at all times. Exposure–response modeling for rivipansel concentrations and change from baseline in QTcF data corroborated a lack of effect with rivipansel compared with placebo. Single doses of rivipansel 4 g by intravenous infusion over 20 minutes were well tolerated in this study.
Functional phosphatome requirement for protein homeostasis, networked mitochondria, and sarcomere structure in C. elegans muscle
Authors: Lehmann Susann , Bass Joseph J. , Barratt Thomas F. , Ali Mohammed Z. , Szewczyk Nathaniel J.
Published: May 2017

Background

Skeletal muscle is central to locomotion and metabolic homeostasis. The laboratory worm Caenorhabditis elegans has been developed into a genomic model for assessing the genes and signals that regulate muscle development and protein degradation. Past work has identified a receptor tyrosine kinase signalling network that combinatorially controls autophagy, nerve signal to muscle to oppose proteasome‐based degradation, and extracellular matrix‐based signals that control calpain and caspase activation. The last two discoveries were enabled by following up results from a functional genomic screen of known regulators of muscle. Recently, a screen of the kinome requirement for muscle homeostasis identified roughly 40% of kinases as required for C. elegans muscle health; 80 have identified human orthologues and 53 are known to be expressed in skeletal muscle. To complement this kinome screen, here, we screen most of the phosphatases in C. elegans.

Methods

RNA interference was used to knockdown phosphatase‐encoding genes. Knockdown was first conducted during development with positive results also knocked down only in fully developed adult muscle. Protein homeostasis, mitochondrial structure, and sarcomere structure were assessed using transgenic reporter proteins. Genes identified as being required to prevent protein degradation were also knocked down in conditions that blocked proteasome or autophagic degradation. Genes identified as being required to prevent autophagic degradation were also assessed for autophagic vesicle accumulation using another transgenic reporter. Lastly, bioinformatics were used to look for overlap between kinases and phosphatases required for muscle homeostasis, and the prediction that one phosphatase was required to prevent mitogen‐activated protein kinase activation was assessed by western blot.

Results

A little over half of all phosphatases are each required to prevent abnormal development or maintenance of muscle. Eighty‐six of these phosphatases have known human orthologues, 57 of which are known to be expressed in human skeletal muscle. Of the phosphatases required to prevent abnormal muscle protein degradation, roughly half are required to prevent increased autophagy.

Conclusions

A significant portion of both the kinome and phosphatome are required for establishing and maintaining C. elegans muscle health. Autophagy appears to be the most commonly triggered form of protein degradation in response to disruption of phosphorylation‐based signalling. The results from these screens provide measurable phenotypes for analysing the combined contribution of kinases and phosphatases in a multi‐cellular organism and suggest new potential regulators of human skeletal muscle for further analysis.
Effect of the height‐to‐diameter ratio on the mass transfer and mixing performance of a biotrickling filter
Authors: Ordaz Alberto , Figueroa‐González Ivonne , San‐Valero Pau , Gabaldón Carmen , Quijano Guillermo
Published: May 2017

BACKGROUND

Biotrickling filters (BTFs) are among the most widely used biological technologies for air pollution control. The pollutant removal rate in BTFs relies to a large extent on its gas–liquid mass transfer performance. Therefore, knowledge of the design parameters affecting the mass transfer and mixing performance of full‐scale BTFs is of paramount importance.

RESULTS

This work showed that the height‐to‐diameter (H/D) ratio is an important parameter in the design of BTFs devoted to air pollution control. The H/D ratio significantly affected the mass transfer and mixing performance of the BTF with and without additional stirring in the holding tank. It was observed that under the same liquid velocity, the mass transfer coefficient (kLa) and the mixing time (tmix) can be optimized only by selecting an adequate H/D ratio. Additional stirring in the holding tank also affected kLa and tmix, this effect being different for each H/D ratio tested.

CONCLUSIONS

The H/D ratio should be considered in the design of full‐scale BTFs since this parameter will significantly affect the mass transfer and mixing performance, regardless of the agitation conditions prevailing in the holding tank. As far as the authors know this is first report addressing the combined effect of the H/D ratio, liquid velocity and holding tank stirring on kLa and tmix in BTFs devoted to air pollution control. © 2017 Society of Chemical Industry
One‐Pot Three‐Component Synthesis of 6H‐chromeno[4,3‐b] or Cyclopenta[b]furo[3,2‐f]quinoline Derivatives
Authors: Li Zhe , Li Xiao‐Jing , Liu Jian‐Quan , Wang Xiang‐Shan
Published: May 2017

Two series of furo[3,2‐f]quinoline‐2‐carboxylate were obtained via a three‐component reaction of aldehydes, 5‐aminobenzofuran‐2‐carboxylate, and 4‐hydroxy‐2H‐chromen‐2‐one or cyclopentane‐1,3‐dione in DMF under catalyst‐free condition in high yields. This one‐pot three‐component reaction provided an efficient method for the synthesis of fused polycyclic heterocycles for bioactive screening.
Influence of Molecular Weight on the Creep Resistance of Almost Molten Polyethylene Blends
Authors: Andersson Mattias G. , Städler Roman , Hagstrand Per‐Ola , Gkourmpis Thomas , Andersson Mats R. , Müller Christian
Published: May 2017

The most common route to improve the creep resistance of low density polyethylene (LDPE) is crosslinking, which however results in volatile decomposition products that must be removed. Blends of LDPE and an additive‐like amount of a linear polyethylene are found to offer improved creep resistance. Above the melting temperature of LDPE, Tm ≈ 111 °C, a load‐bearing network of higher‐melting crystallites—connected through tie chains and trapped entanglements—provides additional form stability. The molecular weight of the linear polyethylene is found to be critical for the ability to arrest creep, which is correlated with the probability of tie chain formation as well as cocrystallization of the two polyethylenes. A number of high‐density polyethylenes (HDPE) and one ultrahigh molecular weight polyethylene (UHMW‐PE) are explored. For blends of LDPE and 2 wt% of the linear polyethylene, an HDPE with a weight‐average molecular weight Mw of 16 kg mol−1 is found to be sufficient to arrest creep at 115 °C. Further improvement in terms of creep resistance is obtained in case of UHMW‐PE with creep fracture occurring only at a stress of 12 kPa at 115 °C.

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Therapeutic Targeting of Poly(ADP‐Ribose) Polymerase‐1 (PARP1) in Cancer: Current Developments, Therapeutic Strategies, and Future Opportunities
Authors: Rajawat Jyotika , Shukla Nidhi , Mishra Durga Prasad
Published: May 2017

Poly(ADP‐ribose) polymerase‐1 (PARP‐1) plays a central role in numerous cellular processes including DNA repair, replication, and transcription. PARP interacts directly, indirectly or via PARylation with various oncogenic proteins and regulates several transcription factors thereby modulating carcinogenesis. Therapeutic inhibition of PARP is therefore perceived as a promising anticancer strategy and a number of PARP inhibitors (PARPi) are currently under development and clinical evaluation. PARPi inhibit the DNA repair pathway and thus form the concept of synthetic lethality in cancer therapeutics. Preclinical and clinical studies have shown the potential of PARPi as chemopotentiator, radiosensitizer, or as adjuvant therapeutic agents. Recent studies have shown that PARP‐1 could be either oncogenic or tumor suppressive in different cancers. PARP inhibitor resistance is also a growing concern in the clinical setting. Recently, changes in the levels of PARP‐1 activity or expression in cancer patients have provided the basis for consideration of PARP‐1 regulatory proteins as potential biomarkers. This review focuses on the current developments related to the role of PARP in cancer progression, therapeutic strategies targeting PARP‐associated oncogenic signaling, and future opportunities in use of PARPi in anticancer therapeutics.
Refining genotype–phenotype correlation in Alström syndrome through study of primary human fibroblasts
Authors: Chen Jian‐Hua , Geberhiwot Tarekegn , Barrett Timothy G. , Paisey Richard , Semple Robert K.
Published: May 2017

Background

Alström syndrome (AS), featuring retinal dystrophy, neuronal deafness, cardiomyopathy, metabolic syndrome, and diffuse fibrosis, is caused by biallelic mutations in the centrosomal protein ALMS1. Genotype–phenotype correlation has been suggested without assessment of ALMS1 expression.

Methods

ALMS1 expression (real‐time PCR and immunocytochemistry) and cilia formation (immunocytochemistry) were assessed in fibroblasts from deeply phenotyped volunteers diagnosed with AS recruited from a dedicated AS Service. Exome sequencing was used in two participants without convincing biallelic ALMS1 mutations, and BBS2 (Bardet–Biedl syndrome 2) protein expression was assessed in one patient with biallelic BBS2 mutations. Hedgehog‐induced GLI1 expression and PDGFA signaling was assessed using quantitative real‐time PCR, immunoblotting, or immunostaining of fixed cells after stimulation.

Results

In 16 of the patient cell lines examined, ALMS1 protein was undetectable (14 with biallelic loss‐of‐function (LoF) mutations), and in two, ALMS1 staining was equivocal (one with biallelic LoF mutations). In five lines, ALMS1 expression was normal using at least one fixation method (one with biallelic LoF mutations). These differences were not accounted for by major differences in ALMS1 mRNA expression. Exome sequencing of two participants with normal ALMS1 expression identified biallelic LoF BBS2 mutations in one. No second, known ciliopathy mutation was found in the other patient, who had one LoF ALMS1 mutation. Phenotypes were milder or atypical in participants with preserved ALMS1 immunostaining, even when two with likely alternative genetic diagnoses were excluded. All cells studied developed normal cilia, ALMS1 and BBS2 mutant cells showed normal Hedgehog‐induced upregulation of GLI1 expression, and PDGFA signaling was normal in ALMS1‐deficient cells.

Conclusion

Milder or atypical presentations of AS should prompt genetic evaluation for alternative, clinically overlapping ciliopathies. A subgroup of patients with bona fide ALMS1 defects have milder phenotypes due to residual ALMS1 expression, which may be more important than mutation site.
Numerical simulation of a discontinuous gallery lining's behavior, and its interaction with rock
Authors: Salehnia F. , Sillen X. , Li X. L. , Charlier R.
Published: May 2017

Deep excavation in some geological media needs lining of the gallery. This could limit the extent of the so‐called excavation damaged zone and the resulting convergence of the material due to tunneling. Boom clay, the reference potential host rock in Belgium for disposal of high‐level radioactive waste, is one of these media for which lining of the gallery walls is essential. A correct simulation of the lining behavior in the course of the excavation process, where the rock comes into contact with the lining, and in the long term, remains a significant challenge in analysis of the whole coupled phenomena of rock in interaction with the lining. This study aims to numerically model the lining behavior. The main objective is to develop a model that could realistically simulate the behavior of a discontinuous lining made of concrete segments. We propose to numerically analyze the response of the blocks in contact with each other and in interaction with rock, with the use of zero‐thickness interface elements. To validate the developed model and a proposed approach, a particular analysis compares the obtained results with the available in situ measurements. This study then discusses the deficiency of the simplistic model that considers a continuous lining. In addition, regarding the contact mechanism on the interface between the rock and the lining, the obtained results demonstrate an interesting relation between the contact phenomena and the shear banding within the rock around the gallery. Copyright © 2017 John Wiley & Sons, Ltd.
Numerical implementation of anisotropic damage mechanics
Authors: Nairn John A. , Hammerquist Chad C. , Aimene Yamina E.
Published: May 2017

This paper describes implementation of anisotropic damage mechanics in the material point method. The approach was based on previously proposed, fourth‐rank anisotropic damage tenors. For implementation, it was convenient to recast the stress update using a new damage strain partitioning tensor. This new tensor simplifies numerical implementation (a detailed algorithm is provided) and clarifies the connection between cracking strain and an implied physical crack with crack opening displacements. By using 2 softening laws and 3 damage parameters corresponding to 1 normal and 2 shear cracking strains, damage evolution can be directly connected to mixed tensile and shear fracture mechanics. Several examples illustrate interesting properties of robust anisotropic damage mechanics such as modeling of necking, multiple cracking in coatings, and compression failure. Direct comparisons between explicit crack modeling and damage mechanics in the same material point method code show that damage mechanics can quantitatively reproduce many features of explicit crack modeling. A caveat is that strengths and energies assigned to damage mechanics materials must be changed from measured material properties to apparent properties before damage mechanics can agree with fracture mechanics.
Exome sequencing reveals novel genetic loci influencing obesity‐related traits in Hispanic children
Authors: Sabo Aniko , Mishra Pamela , Dugan‐Perez Shannon , Voruganti V. Saroja , Kent Jack W. , Kalra Divya , Cole Shelley A. , Comuzzie Anthony G. , Muzny Donna M. , Gibbs Richard A. , Butte Nancy F.
Published: May 2017

Objective

To perform whole exome sequencing in 928 Hispanic children and identify variants and genes associated with childhood obesity.

Methods

Single‐nucleotide variants (SNVs) were identified from Illumina whole exome sequencing data using integrated read mapping, variant calling, and an annotation pipeline (Mercury). Association analyses of 74 obesity‐related traits and exonic variants were performed using SeqMeta software. Rare autosomal variants were analyzed using gene‐based association analyses, and common autosomal variants were analyzed at the SNV level.

Results

(1) Rare exonic variants in 10 genes and 16 common SNVs in 11 genes that were associated with obesity traits in a cohort of Hispanic children were identified, (2) novel rare variants in peroxisome biogenesis factor 1 (PEX1) associated with several obesity traits (weight, weight z score, BMI, BMI z score, waist circumference, fat mass, trunk fat mass) were discovered, and (3) previously reported SNVs associated with childhood obesity were replicated.

Conclusions

Convergence of whole exome sequencing, a family‐based design, and extensive phenotyping discovered novel rare and common variants associated with childhood obesity. Linking PEX1 to obesity phenotypes poses a novel mechanism of peroxisomal biogenesis and metabolism underlying the development of childhood obesity.
Impact of induction chemotherapy, hyperfractionated accelerated radiotherapy and high‐dose thiotepa on brain volume loss and functional status of children with primitive neuroectodermal tumour
Authors: Szychot Elwira , Seunarine Kiran , Mankad Kshitij , Thust Steffi , Clark Chris , Gaze Mark N. , Michalski Antony
Published: May 2017

Background

The introduction of aggressive chemo‐radiotherapy regimens has improved overall survival in children with primitive neuroectodermal tumours (PNET). However, these combinations may result in neurotoxicity. Previously reported magnetic resonance imaging abnormalities in children receiving intensive sequential chemotherapy, hyperfractionated accelerated radiotherapy (HART) and high‐dose thiotepa prompted us to investigate the degree of brain volume loss and patients’ functional status after therapy.

Methods

We retrospectively reviewed clinico‐radiological data of children with PNET treated in this way at our centre.

Results

We studied 14 children treated between December 2009 and April 2013. Data were not complete for one child. Performance status was severely restricted in four children, and mildly to moderately impaired in 7 of the 13 children. Eleven of 13 children showed mild‐to‐severe generalised neuroparenchymal atrophy, in 7 of whom neuroparenchymal volume loss was moderate to severe. Of these seven, six had received high‐dose thiotepa. There was no correlation between brain volume loss and Lansky performance status. However, unexpected neurotoxicities, such as symptoms of transverse myelitis, were observed.

Conclusion

Measurement of brain volume loss in patients treated with HART and high‐dose thiotepa may not be sufficient to predict function. However, correlation of brain volume loss due to late neurotoxicity with performance decline may be more obvious over longer period of follow‐up. The combination of HART and myeloablative courses of thiotepa is associated with severe neurotoxicity and subsequent decline in performance status in a significant proportion of patients.
Proteomics show antigen presentation processes in human immune cells after AS03‐H5N1 vaccination
Authors: Galassie Allison C. , Goll Johannes B. , Samir Parimal , Jensen Travis L. , Hoek Kristen L. , Howard Leigh M. , Allos Tara M. , Niu Xinnan , Gordy Laura E. , Creech C. Buddy , Hill Heather , Joyce Sebastian , Edwards Kathryn M. , Link Andrew J.
Published: May 2017

Adjuvants enhance immunity elicited by vaccines through mechanisms that are poorly understood. Using a systems biology approach, we investigated temporal protein expression changes in five primary human immune cell populations: neutrophils, monocytes, natural killer cells, T cells, and B cells after administration of either an Adjuvant System 03 adjuvanted or unadjuvanted split‐virus H5N1 influenza vaccine. Monocytes demonstrated the strongest differential signal between vaccine groups. On day 3 post‐vaccination, several antigen presentation‐related pathways, including MHC class I‐mediated antigen processing and presentation, were enriched in monocytes and neutrophils and expression of HLA class I proteins was increased in the Adjuvant System 03 group. We identified several protein families whose proteomic responses predicted seroprotective antibody responses (>1:40 hemagglutination inhibition titer), including inflammation and oxidative stress proteins at day 1 as well as immunoproteasome subunit (PSME1 and PSME2) and HLA class I proteins at day 3 in monocytes. While comparison between temporal proteomic and transcriptomic results showed little overlap overall, enrichment of the MHC class I antigen processing and presentation pathway in monocytes and neutrophils was confirmed by both approaches.
Benchmarking a computational design method for the incorporation of metal ion‐binding sites at symmetric protein interfaces
Authors: Hansen William A. , Khare Sagar D.
Published: May 2017

The design of novel metal‐ion binding sites along symmetric axes in protein oligomers could provide new avenues for metalloenzyme design, construction of protein‐based nanomaterials and novel ion transport systems. Here, we describe a computational design method, symmetric protein recursive ion‐cofactor sampling (SyPRIS), for locating constellations of backbone positions within oligomeric protein structures that are capable of supporting desired symmetrically coordinated metal ion(s) chelated by sidechains (chelant model). Using SyPRIS on a curated benchmark set of protein structures with symmetric metal binding sites, we found high recovery of native metal coordinating rotamers: in 65 of the 67 (97.0%) cases, native rotamers featured in the best scoring model while in the remaining cases native rotamers were found within the top three scoring models. In a second test, chelant models were crossmatched against protein structures with identical cyclic symmetry. In addition to recovering all native placements, 10.4% (8939/86013) of the non‐native placements, had acceptable geometric compatibility scores. Discrimination between native and non‐native metal site placements was further enhanced upon constrained energy minimization using the Rosetta energy function. Upon sequence design of the surrounding first‐shell residues, we found further stabilization of native placements and a small but significant (1.7%) number of non‐native placement‐based sites with favorable Rosetta energies, indicating their designability in existing protein interfaces. The generality of the SyPRIS approach allows design of novel symmetric metal sites including with non‐natural amino acid sidechains, and should enable the predictive incorporation of a variety of metal‐containing cofactors at symmetric protein interfaces.
Road‐Centered Map‐Aided Localization for Driverless Cars Using Single‐Frequency GNSS Receivers
Authors: Tao Zui , Bonnifait Philippe , Frémont Vincent , Ibanez‐Guzman Javier , Bonnet Stéphane
Published: May 2017

Accurate localization with high availability is a key requirement for autonomous vehicles. It remains a major challenge when using automotive sensors such as single‐frequency Global Navigation Satellite System (GNSS) receivers, a lane detection camera, and proprioceptive sensors. This paper describes a method that enables the estimation of stand‐alone single‐frequency GNSS errors by integrating the measurements from a forward‐looking camera matched with lane markings stored in a digital map. It includes a parameter identification method for a shaping model, which is evaluated using experimental data. An algebraic observability study is then conducted to prove that the proposed state vector is fully observable in a road‐oriented frame. This observability property is the basis to develop a road‐centered Extended Kalman filter (EKF) that can maintain the observability of every component of the state vector on any road, whatever its orientation. To accomplish this, the filter needs to handle road changes, which it does using bijective transformations. The filter was implemented and tested intensely on an experimental vehicle for driverless valet parking services. Field results have shown that the performance of the estimation process is better than solutions based on EKF implemented in a fixed working frame. The proposed filter guarantees that the drift along the road direction remains bounded. This is very important when the vehicle navigates autonomously. Furthermore, the road‐centered modeling improves the accuracy, consistency, and robustness of the localization solver.
Hybrid actuation with complementary allocation for depth control of a Lagrangian sea‐floor imaging platform
Authors: Snyder William , Roman Chris , Licht Stephen
Published: May 2017

A hybrid depth control approach, which utilizes both active buoyancy control and a bi‐directional vertical thruster, is presented for the Shallow Water Lagrangian Imaging Float. The approach is shown to reduce propulsion power and increase tracking accuracy compared to a single actuator system. Results are presented from field trials at Cordell Bank Marine Sanctuary and Scott Reef Nature Reserve at depths up to 60 m. Using heuristically tuned controllers, the hybrid actuation approach reduces average propulsion power by 65% with respect to a thruster‐only system, and by 73% with respect to a piston‐only system. A further 58% reduction in power consumption, and a 26% reduction in mean tracking error, is realized by combining state feedback control with a pair of complementary filters. The complementary filters are used to allocate vertical force command between the two actuation modes. Simulations are used to demonstrate that the power savings compared to a thruster‐only system result from elimination of steady state trim errors that are otherwise inevitable in field deployments. The control architecture described allows the user to directly tune (a) the time constant of the desired first‐order system dynamics and (b) the frequency cutoff between control using the “slow” active buoyancy system and control using the “fast” bi‐directional thruster. The results indicate that hybrid actuation and complementary filtering for control allocation are enabling technologies for energy‐constrained deep water platforms.
Detection of aircraft below the horizon for vision‐based detect and avoid in unmanned aircraft systems
Authors: Molloy Timothy L. , Ford Jason J. , Mejias Luis
Published: May 2017

Vision‐based aircraft detection technology may provide a credible sensing option for automated detect and avoid in small‐to‐medium size fixed‐wing unmanned aircraft systems (UAS). Reliable vision‐based aircraft detection has previously been demonstrated in sky‐region sensing environments. This paper describes a novel vision‐based system for detecting aircraft below the horizon in the presence of ground clutter. We examine the performance of our system on a data set of 63 near collision encounters we collected between a camera‐equipped manned aircraft and a below‐horizon target. In these 63 encounters, our system successfully detects all aircraft, at an average detection range of 1890 m (with a standard error of 43 m and no false alarms in 1.1 h). Furthermore, our system does not require access to inertial sensor data (which significantly reduces system cost) and operates at over 12 frames per second.
Intrinsic Notch Effect Leads to Breakdown of Griffith Criterion in Graphene
Authors: Liu Feng , Tang Qiheng , Wang Tzu‐Chiang
Published: May 2017

Due to lack of the third dimension in 3D bulk materials, the crack tip in graphene locates on several atoms implying that its fracture behavior can be closely associated with its lattice structure, i.e., the bond length and angle. As the bond length reflects the discrete nature of the atomic structure, theoretical discussion is focused on the concomitant size effect at the nanoscale with few or no reports about the influence of the bond angle. Through the comparisons between theoretical calculations and experimental data, here it is first demonstrated that the bond angle is essential for understanding the fracture behavior in graphene, serving as an intrinsic notch reducing the stress singularity near the crack tip (the intrinsic notch effect), leading to the breakdown of the Griffith criterion in graphene. The work provides a framework for the studying of the brittle fracture in 2D materials, which gives rise to the more reliable device design based on 2D materials. More importantly, the significance of the intrinsic notch effect is profound and far‐reaching, paving the way to a more comprehensive and deep understanding of the mechanical properties in nano as well as nanostructured materials.
Dynamic Self‐Assembly of Homogenous Microcyclic Structures Controlled by a Silver‐Coated Nanopore
Authors: Gao Rui , Lin Yao , Ying Yi‐Lun , Liu Xiao‐Yuan , Shi Xin , Hu Yong‐Xu , Long Yi‐Tao , Tian He
Published: May 2017

The self‐assembly of nanoparticles is a challenging process for organizing precise structures with complicated and ingenious structures. In the past decades, a simple, high‐efficiency, and reproducible self‐assembly method from nanoscale to microscale has been pursued because of the promising and extensive application prospects in bioanalysis, catalysis, photonics, and energy storage. However, microscale self‐assembly still faces big challenges including improving the stability and homogeneity as well as pursuing new assembly methods and templates for the uniform self‐assembly. To address these obstacles, here, a novel silver‐coated nanopore is developed which serves as a template for electrochemically generating microcyclic structures of gold nanoparticles at micrometers with highly homogenous size and remarkable reproducibility. Nanopore‐induced microcyclic structures are further applied to visualize the diffusion profile of ionic flux. Based on this novel strategy, a nanopore could potentially facilitate the delivery of assembled structures for many practical applications including drug delivery, cellular detection, catalysis, and plasmonic sensing.
Ultralight Multifunctional Carbon‐Based Aerogels by Combining Graphene Oxide and Bacterial Cellulose
Authors: Li Chao , Wu Zhen‐Yu , Liang Hai‐Wei , Chen Jia‐Fu , Yu Shu‐Hong
Published: May 2017

Nanostructured carbon aerogels with outstanding physicochemical properties have exhibited great application potentials in widespread fields and therefore attracted extensive attentions recently. It is still a challenge so far to develop flexible and economical routes to fabricate high‐performance nanocarbon aerogels, preferably based on renewable resources. Here, ultralight and multifunctional reduced graphene oxide/carbon nanofiber (RGO/CNF) aerogels are fabricated from graphene oxide and low‐cost, industrially produced bacterial cellulose by a three‐step process of freeze‐casting, freeze‐drying, and pyrolysis. The prepared RGO/CNF aerogel possesses a very low apparent density in the range of 0.7–10.2 mg cm−3 and a high porosity up to 99%, as well as a mechanically robust and electrically conductive 3D network structure, which makes it to be an excellent candidate as absorber for oil clean‐up and an ideal platform for constructing flexible and stretchable conductors.
Vertical Charge Transport via Small Polaron Hopping within TIPS‐Pentacene Lamellar Single Crystal
Authors: Wang Jiawei , Liu Tianjun , Dong Ji , Li Molin , He Jun , Jiang Chao
Published: May 2017

A modified liquid method is employed to grow an ultralarge 6,13‐bis(triisopropylsilylethynyl)pentacene crystal, ensuring fabrication and measurements of the two terminal devices. The hole transport mechanism is studied by analyzing the space charge limited currents (SCLCs) at various temperatures. Modified SCLC theory with a small polaron hopping model is developed and employed to successfully simulate the I–V curves. Values of effective hopping distance, transfer integral, and reorganization energy are extracted and reasonably discussed. A scenario is suggested that hopping transport takes place from one molecule to its nearest neighbor along the c‐axis, with every molecule acting as a trapping center.