bluuebunny/crossref_metadata_2025 huggingface dataset:
Incorporating Ontogeny in Physiologically Based Pharmacokinetic Modeling to Improve Pediatric Drug Development: What We Know About Developmental Changes in Membrane Transporters
Authors: Cheung Kit Wun Kathy , van Groen Bianca D. , Burckart Gilbert J. , Zhang Lei , de Wildt Saskia N. , Huang Shiew‐Mei
Published: September 2019

Developmental changes in the biological processes involved in the disposition of drugs, such as membrane transporter expression and activity, may alter the drug exposure and clearance in pediatric patients. Physiologically based pharmacokinetic (PBPK) models take these age‐dependent changes into account and may be used to predict drug exposure in children. As a result, this mechanistic‐based tool has increasingly been applied to improve pediatric drug development. Under the Prescription Drug User Fee Act VI, the US Food and Drug Administration has committed to facilitate the advancement of PBPK modeling in the drug application review process. Yet, significant knowledge gaps on developmental biology still exist, which must be addressed to increase the confidence of prediction. Recently, more data on ontogeny of transporters have emerged and supplied a missing piece of the puzzle. This article highlights the recent findings on the ontogeny of transporters specifically in the intestine, liver, and kidney. It also provides a case study that illustrates the utility of incorporating this information in predicting drug exposure in children using a PBPK approach. Collaborative work has greatly improved the understanding of the interplay between developmental physiology and drug disposition. Such efforts will continue to be needed to address the remaining knowledge gaps to enhance the application of PBPK modeling in drug development for children.
Drug Transporters Expressed in the Human Placenta and Models for Studying Maternal‐Fetal Drug Transfer
Authors: Dallmann André , Liu Xiaomei I. , Burckart Gilbert J. , van den Anker John
Published: September 2019

Tremendous efforts have been directed to investigate the ontogeny of drug transporters in fetuses, neonates, infants, and children based on their importance for understanding drug pharmacokinetics. During development (ie, in the fetus and newborn infant), there is special interest in transporters expressed in the placenta that modulate placental drug transfer. Many of these transporters can decrease or increase drug concentrations in the fetus and at birth, stressing the relevance of elucidating expression in the placenta and potential gestational age‐dependent changes therein. Hence, the main objective of this review was to summarize the current knowledge about expression and ontogeny of transporters in the human placenta in healthy pregnant women. In addition, various in vitro, ex vivo, and in silico models that can be used to investigate placental drug transfer, namely, placental cancer cell lines, ex vivo cotyledon perfusion experiments, and physiologically based pharmacokinetic (PBPK) models, are discussed together with their advantages and shortcomings. A particular focus was placed on PBPK models because these models can integrate different types of information, such as expression data, ontogeny information, and observations obtained from the ex vivo cotyledon perfusion experiment. Such a mechanistic modeling framework may leverage the available information and ultimately help to improve knowledge about the adequacy and safety of pharmacotherapy in pregnant women and their fetuses.
Novel Pyrano[2,3‐d]thiazole and Thiazolo[4,5‐b]pyridine Derivatives: One‐pot Three‐component Synthesis and Biological Evaluation as Anticancer Agents, c‐Met, and Pim‐1 Kinase Inhibitors
Authors: Abdallah Amira E.M. , Mohareb Rafat M. , Ahmed Ebtsam A.
Published: September 2019

Preparation of pyrano[2,3‐d]thiazole and thiazolo[4,5‐b]pyridine derivatives through multicomponent reactions (MCRs) was achieved by the reaction of 2‐(2‐amino‐4,5,6,7‐tetrahydrobenzo[b]thiophen‐3‐yl)thiazol‐4(5H)‐one with various active methylene reagents such as ethyl cyanoacetate or malononitrile in basic conditions containing diverse aromatic aldehyde. Furthermore, this study aims to evaluate the in vitro cytotoxic activity of the synthetic compounds against six cancer cell lines, and all the prepared compounds revealed valuable activity compared with the CHS‐828, which is the 2‐[6‐(4‐chlorophenoxy)hexyl]‐1‐cyano‐3‐pyridin‐4‐ylguanidine as the standard drug. Some of the pyrano[2,3‐d]thiazole and thiazolo[4,5‐b]pyridine derivatives showed the highest antitumor activity towards the six cancer cell lines. Moreover, (c‐Met) enzymatic activity of the most potent compounds showed that compounds 3b 2‐(2‐amino‐4,5,6,7 tetrahydrobenzo[b]thiophen‐3‐yl)‐5‐hydroxy‐7‐(2‐hydroxy‐phenyl)‐7H‐pyrano[2,3‐d]thiazole‐6 carbonitrile and 5e 2‐(2‐amino‐4,5,6,7‐tetrahydrobenzo[b]thiophen‐3‐yl)‐5‐hydroxy‐7‐phenyl‐4,7‐dihydrothiazolo[4,5‐b]pyridine‐6‐carbonitrile were with higher activities than foretinib. Three compounds were selected to examine their Pim‐1 kinase where compounds 3b and 7b showed the highest inhibitions.
Synthesis of some novel pyrazoline‐thiazole hybrids and their antimicrobial activities
Authors: Masoud Doaa M. , Azzam Rasha A. , Hamdy Fatma , Mekawey Amal A.I. , Abdel‐Aziz Hatem A.
Published: September 2019

A series of novel thiazolyl pyrazolines7a‐h,9a‐f, and11a‐fhave been synthesized by the reaction of thioamide derivatives5a,bwith 1‐aryl‐2‐bromoethanones6a‐d, chloroacetones8a‐c, and hydrazonoyl chlorides10a‐c. Additionally, pyrazoles15a‐cand20were prepared starting from enaminone13. These newly synthesized compounds were screened for their in vitro antibacterial activity against four bacterial species. Compound11bshowed a moderate activity againstKlebsiella pneumoniae. Compounds7cand11crevealed a moderate activity againstPseudomonas aeruginosa. In addition, the antifungal activity of the newly synthesized compounds was determined against five fungal strains. Compounds7e,7g, and11eshowed a good activity againstAspergillus flavusandPenicillium expansum.
Substituted quinolinones. 31. Some new pyrano[3,2‐c]quinoline‐3‐carboxamides and their antioxidant activity
Authors: Othman Elham S. , Hassan Heba , Abass Mohamed
Published: September 2019

1‐Ethyl‐4‐hydroxy‐2‐oxo‐1,2‐dihydroquinoline‐3‐carbaldehyde (1) was annulated using malonic acid and/or its ethyl ester to furnish pyrano[3,2‐c]quinoline‐3‐carboxylic acid 2 and its ester 3. Interconversions between acid 2 and ester 3 were successfully carried out. The anticipated pyrano[3,2‐c]quinoline‐3‐carboxamides 5–12 were conveniently attained via condensation of ester 3 with the proper amine. Surprisingly, treatment of ester 3 with dimethylformamide (DMF) in acidic media led to the carboxamide 5. All attempts to convert ester 3 to its corresponding acid hydrazides by interaction with the proper hydrazine derivative led to formation of pyrazolidinediones 15 and 17. Ester 3 underwent cyclo‐condensation with malononitrile dimer affording pyrido[3′,4′:5,6]pyrano[3,2‐c]quinoline derivative 18. The new compounds revealed significant antioxidant effect, which suggests that most of them are possible potent antioxidant agents.
Reactivity and stereoselectivity of oxazolopyridines with a ring‐junction nitrogen atom
Authors: Monier Mohamed , Abdel‐Latif Doaa , El‐Mekabaty Ahmed , Elattar Khaled M.
Published: September 2019

The present study demonstrates a synopsis of the scientific researches reported on the different reactions of oxazolo[3,2‐a]pyridines, besides the preparation of significant fused heterocycles up till now. The different main sections that described the reactivity of the inspected analogues include stereoselective alkylation, reactions involved oxazolidine ring, synthesis of polycyclic systems, indole alkaloids, and alkyl amines. The stereochemical selectivity of oxazolopiperidone lactams is studied, in which the configuration of the stereocenter C8a and substituents at the C8 and C8a effect on the stereoselectivity. On the other hand, the synthetic consequence of the alkylation products provides diverse routes for the synthesis of substituted enantiopure piperidines that are used for the synthesis of natural products, for example, (−)‐rhazinilam, (+)‐eburnamonine, (+)‐aspidospermidine, indole alkaloids such as dihydrocleavamine, nor‐20‐epiuleine, (+)‐dasycarpidone, (+)‐uleine, indoloquinolizidine, (+)‐dihydrocorynantheine, (−)‐dihydrocorynantheol, and indolizines, eg, octahydroindolizines, monomorine I, (−)‐S‐coniceine, and (−)‐R‐coniceine.
Dietary restriction of tyrosine and phenylalanine lowers tyrosinemia associated with nitisinone therapy of alkaptonuria
Authors: Hughes Juliette H. , Wilson Peter J. M. , Sutherland Hazel , Judd Shirley , Hughes Andrew T. , Milan Anna M. , Jarvis Jonathan C. , Bou‐Gharios George , Ranganath Lakshminarayan R. , Gallagher James A.
Published: September 2019

Alkaptonuria (AKU) is caused by homogentisate 1,2‐dioxygenase deficiency that leads to homogentisic acid (HGA) accumulation, ochronosis and severe osteoarthropathy. Recently, nitisinone treatment, which blocks HGA formation, has been effective in AKU patients. However, a consequence of nitisinone is elevated tyrosine that can cause keratopathy. The effect of tyrosine and phenylalanine dietary restriction was investigated in nitisinone‐treated AKU mice, and in an observational study of dietary intervention in AKU patients. Nitisinone‐treated AKU mice were fed tyrosine/phenylalanine‐free and phenylalanine‐free diets with phenylalanine supplementation in drinking water. Tyrosine metabolites were measured pre‐nitisinone, post‐nitisinone, and after dietary restriction. Subsequently an observational study was undertaken in 10 patients attending the National Alkaptonuria Centre (NAC), with tyrosine >700 μmol/L who had been advised to restrict dietary protein intake and where necessary, to use tyrosine/phenylalanine‐free amino acid supplements. Elevated tyrosine (813 μmol/L) was significantly reduced in nitisinone‐treated AKU mice fed a tyrosine/phenylalanine‐free diet in a dose responsive manner. At 3 days of restriction, tyrosine was 389.3, 274.8, and 144.3 μmol/L with decreasing phenylalanine doses. In contrast, tyrosine was not effectively reduced in mice by a phenylalanine‐free diet; at 3 days tyrosine was 757.3, 530.2, and 656.2 μmol/L, with no dose response to phenylalanine supplementation. In NAC patients, tyrosine was significantly reduced (P = .002) when restricting dietary protein alone, and when combined with tyrosine/phenylalanine‐free amino acid supplementation; 4 out of 10 patients achieved tyrosine <700 μmol/L. Tyrosine/phenylalanine dietary restriction significantly reduced nitisinone‐induced tyrosinemia in mice, with phenylalanine restriction alone proving ineffective. Similarly, protein restriction significantly reduced circulating tyrosine in AKU patients.
Influence of Hamstrings on Knee Moments During Loading Response of Gait in Individuals Following ACL Reconstruction
Authors: Lin Paige E. , Sigward Susan M.
Published: September 2019

Biomechanical studies consistently report smaller knee extensor moments in the surgical limb during loading response (LR) of gait following ACL reconstruction (ACLr). However, this reduction in knee loading is quantified by net joint moments (NJM). As a result, in the presence of greater hamstring activity, the true contribution from the knee extensors may not be reduced. The purpose of this study is to compare hamstring activity and strength and knee joint moments between individuals post‐ACLr and controls. Eighteen individuals 3 months post‐ACLr and matched controls walked and net knee extensor moment peak and impulse and hamstring activity were identified during LR, as well as maximal hamstring strength. A hybrid musculoskeletal model estimated knee flexor moments from joint kinematics and hamstring electromyography. Flexor moments (SIMM) were scaled based on strength. Knee extensor moments were estimated from the sum of the net knee moment and estimated knee flexor moment; estimated extensor moment peaks and impulse were calculated during LR. Repeated measures analysis of variance compared groups and limbs. Smaller net knee extensor moment and greater hamstring activity, as well as deficits in maximal hamstring strength, were observed in the surgical limb (allp < 0.05). When accounting for the torque‐producing capabilities of the knee flexors, estimated knee extensor moment peak and impulse were smaller in the surgical limb. These findings suggest that net knee moments accurately reflect smaller knee extensor loading post‐ACLr. Statement of Clinical Significance: Rehabilitation programs should target increasing knee extensor loading to restore gait mechanics during early rehabilitation. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:378‐386, 2020
Selective Sebaceous Gland Electrothermolysis Using a Single Microneedle Radiofrequency Device for Acne Patients: A Prospective Randomized Controlled Study
Authors: Ahn Ga Ram , Kim Jae Min , Park Su Jung , Li Kapsok , Kim Beom Joon
Published: September 2019

Background and Objectives

The selective electrothermolysis of the sebaceous glands was suggested as a novel therapeutic option for facial acne. However, there has been no randomized controlled trial to evaluate the effectiveness and safety of the monopolar radiofrequency (RF) device using single microneedle with proximal insulation. The objective of the study was to evaluate the efficacy and tolerability of intralesional electrothermolysis using monopolar RF device and proximally‐insulated single microneedle in acne patients.

Study Design/Materials and Methods

The prospective randomized controlled clinical trial was performed to treat moderate‐to‐severe facial acne. Subjects randomized to the treatment group received three treatments at 4‐week intervals with an RF device, whereas the control group received micro‐needling and extraction. For efficacy evaluation, reduction rate of acne lesions were evaluated by two independent physicians.

Results

Sixty‐three patients completed the study and the results showed statistically significant improvement of inflammatory acne at 12 weeks. The number of inflammatory lesions was significantly reduced at 12 weeks (20.86 vs. −5.13; P = 0.03) compared with controls.

Conclusions

Selective sebaceous gland electrothermolysis can be a safe and effective method of achieving consistent improvement in acne. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.
I‐convexity and Q‐convexity in Orlicz–Bochner function spaces endowed with the Orlicz norm
Authors: Gong Wanzhong , Dong Xiaoli , Wang Kangji
Published: September 2019

Some characterizations of I‐convexity and Q‐convexity of Banach space are obtained. Moreover, the criteria is shown for Orlicz–Bochner function spaces endowed with the Orlicz norm being I‐convex as well as being Q‐convex.
Higher Urine bis(Monoacylglycerol)Phosphate Levels in LRRK2 G2019S Mutation Carriers: Implications for Therapeutic Development
Authors: Alcalay Roy N. , Hsieh Frank , Tengstrand Elizabeth , Padmanabhan Shalini , Baptista Marco , Kehoe Caitlin , Narayan Sushma , Boehme Amelia K. , Merchant Kalpana
Published: September 2019

Background

LRRK2 mutations are a common cause of dominantly inherited PD. Previous studies showed decreases in urine levels of didocohexaenoyl (22:6) bis(monoacylglycerol)phosphate in LRRK2‐knockout mice and in non‐human primates treated with LRRK2 kinase inhibitors. We hypothesized that urine levels of bis(monoacylglycerol)phosphate isoforms will be higher in individuals with a PD‐causing gain‐of‐kinase function mutation, LRRK2 G2019S. The objective of this study was to investigate alterations in urinary phospholipids as biomarkers of LRRK2 mutations and Parkinson's disease status/phenotypes.

Methods

Ultra‐performance liquid chromatography–tandem mass spectrometry (UPLC‐MS/MS) was used to assess 54 bioactive phospholipids in urine from the LRRK2 Cohort Consortium (n = 80). To confirm and extend the findings, urine from an independent LRRK2 cohort from Columbia University Irving Medical Center (n = 116) was used. Both cohorts were composed of LRRK2 G2019S carriers and non‐carriers with and without PD.

Results

In each cohort, 4 bis(monoacylglycerol)phosphate isoforms (di‐18:1‐bis[monoacylglycerol]phosphate, didocohexaenoyl [22:6] bis[monoacylglycerol] phosphate, 2,2′‐di‐22:6‐bis[monoacylglycerol]phosphate, and 2,2′‐di‐18:1‐bis[monoacylglycerol]phosphate) were significantly higher (2.5‐ to 4.3‐fold) in G2019S carriers compared with non‐carriers. Interestingly, 2,2′‐di‐18:1‐bis(monoacylglycerol)phosphate levels were marginally higher in LRRK2 carriers with PD than in those without PD (P = 0.045). Moreover, increased 2,2′ and total di‐22:6‐bis(monoacylglycerol)phosphate were associated with worse cognitive status assessed by the Montreal Cognitive Assessment (P = 0.0033 and 0.0144, respectively).

Conclusions

The observed association of bis(monoacylglycerol)phosphate isoforms with LRRK2 G2019S mutation, PD status among G2019S carriers, and correlation with cognitive decline suggest the potential use of urinary bis(monoacylglycerol)phosphate isoforms as biomarkers for clinical trials of LRRK2‐targeted therapies. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
Inducible nitric oxide synthase inhibitors: A comprehensive update
Authors: Minhas Richa , Bansal Yogita , Bansal Gulshan
Published: September 2019

Inducible nitric oxide synthase (iNOS), which is expressed in response to bacterial/proinflammatory stimuli, generates nitric oxide (NO) that provides cytoprotection. Overexpression of iNOS increases the levels of NO, and this increased NO level is implicated in pathophysiology of complex multifactorial diseases like Parkinson's disease, Alzheimer's disease, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Selective inhibition of iNOS is an effective approach in treatment of such complex diseases. l‐Arginine, being a substrate for iNOS, is the natural lead to develop iNOS inhibitors. More than 200 research reports on development of nitric oxide synthase inhibitors by different research groups across the globe have appeared in literature so far. The first review on iNOS, in 2002, discussed the iNOS inhibitors under two classes that is, amino acid and non‐amino acid derivatives. Other review articles discussing specific chemical classes of iNOS inhibitors also appeared during last decade. In the present review, all reports on both natural and synthetic iNOS inhibitors, published 2002 onwards, are studied, classified, and discussed to provide comprehensive information on iNOS inhibitors. The synthetic inhibitors are broadly classified into two categories that is, arginine and non‐arginine analogs. The latter are further classified into amidines, five‐ or six‐membered heterocyclics, fused cyclics, steroidal type, and chalcones analogs. Structures of the most/significantly potent compounds from each report are provided to know the functional groups important for incurring iNOS inhibitory activity and selectivity. This review is aimed to provide a comprehensive view to the medicinal chemists for rational designing of novel and potent iNOS inhibitors.
Analysis of miRNA‐mRNA regulatory network revealed key genes induced by aflatoxin B1 exposure in primary human hepatocytes
Authors: Zhang Ziyang , Tang Dongyang , Wang Bin , Wang Zhiwei , Liu Mingjiu
Published: September 2019

Background

Aflatoxin B1 (AFB1) exposure is a crucial factor to initiate hepatocellular carcinoma (HCC). However, comprehensive microRNA (miRNA)‐message RNA (mRNA) regulatory network regarding AFB1‐associated HCC is still lacking. This work was aimed to identify miRNA‐mRNA network in primary human hepatocytes after AFB1 exposure.

Methods

A miRNA expression dataset GSE71540 obtained from the gene expression omnibus (GEO) was used to identify differentially expressed miRNAs (DEMs) after AFB1 exposure using GEO2R. Target genes of these DEMs were identified using TargetScan V_7.2, miRDB, PITA, miRanda, and miRTarBase. Gene ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed at Database for Annotation, Visualization and Integrated Discovery (DAVID). miRNA‐mRNA regulatory network was established by analyzing three enriched KEGG pathways significantly correlated with HCC onset and then visualized at CytoScape.

Results

In this work, nine upregulated and nine downregulated DEMs were identified. Functional enrichment analyses showed that these predicted target genes were significantly associated with cancer development. Analysis of three enriched pathways related to the onset of HCC identified 13 and nine target genes for upregulated DEMs and downregulated DEMs, respectively. Subsequently, the miRNA‐mRNA regulatory networks were constructed.

Conclusions

In conclusion, miRNA‐mRNA regulatory network was established, which will help to understand the mechanism underlying the AFB1‐induced onset of HCC.
As one Arkansas CMHC plans to exit, others lament fraying of system
Authors: Enos Gary
Published: September 2019

In an atmosphere of change that Arkansas community mental health providers characterize as “too much too soon,” leaders in the provider community last week described to MHW what they see as a shattering of the state's public mental health system. The most dramatic effect of the strains on the system has been last month's announcement that the Little Rock Community Mental Health Center will close in late September after more than 50 years of service to the community.
Existence and continuous dependence on parameters of radially symmetric solutions to astrophysical model of self‐gravitating particles
Authors: Bors Dorota , Stańczy Robert
Published: September 2019

In this paper, we obtain the existence of a radial solution for some elliptic nonlocal problem with constraints. The problem is described as stationary state of some evolutionary models provided the pressure function conveys some form arising from statistical mechanics. To be more specific, we consider the following forms of the statistics: Michie‐King, Maxwell‐Boltzmann, Fermi‐Dirac, Bose‐Einstein, and polytrope. The most recent models were suggested by H. J. de Vega at al. and P. H. Chavanis et al.. We prove the continuous dependence of stationary solutions on parameters for the given statistics.
Automatic detection of contouring errors using convolutional neural networks
Authors: Rhee Dong Joo , Cardenas Carlos E. , Elhalawani Hesham , McCarroll Rachel , Zhang Lifei , Yang Jinzhong , Garden Adam S. , Peterson Christine B. , Beadle Beth M. , Court Laurence E.
Published: September 2019

Purpose

To develop a head and neck normal structures autocontouring tool that could be used to automatically detect the errors in autocontours from a clinically validated autocontouring tool.

Methods

An autocontouring tool based on convolutional neural networks (CNN) was developed for 16 normal structures of the head and neck and tested to identify the contour errors from a clinically validated multiatlas‐based autocontouring system (MACS). The computed tomography (CT) scans and clinical contours from 3495 patients were semiautomatically curated and used to train and validate the CNN‐based autocontouring tool. The final accuracy of the tool was evaluated by calculating the Sørensen–Dice similarity coefficients (DSC) and Hausdorff distances between the automatically generated contours and physician‐drawn contours on 174 internal and 24 external CT scans. Lastly, the CNN‐based tool was evaluated on 60 patients' CT scans to investigate the possibility to detect contouring failures. The contouring failures on these patients were classified as either minor or major errors. The criteria to detect contouring errors were determined by analyzing the DSC between the CNN‐ and MACS‐based contours under two independent scenarios: (a) contours with minor errors are clinically acceptable and (b) contours with minor errors are clinically unacceptable.

Results

The average DSC and Hausdorff distance of our CNN‐based tool was 98.4%/1.23 cm for brain, 89.1%/0.42 cm for eyes, 86.8%/1.28 cm for mandible, 86.4%/0.88 cm for brainstem, 83.4%/0.71 cm for spinal cord, 82.7%/1.37 cm for parotids, 80.7%/1.08 cm for esophagus, 71.7%/0.39 cm for lenses, 68.6%/0.72 for optic nerves, 66.4%/0.46 cm for cochleas, and 40.7%/0.96 cm for optic chiasm. With the error detection tool, the proportions of the clinically unacceptable MACS contours that were correctly detected were 0.99/0.80 on average except for the optic chiasm, when contours with minor errors are clinically acceptable/unacceptable, respectively. The proportions of the clinically acceptable MACS contours that were correctly detected were 0.81/0.60 on average except for the optic chiasm, when contours with minor errors are clinically acceptable/unacceptable, respectively.

Conclusion

Our CNN‐based autocontouring tool performed well on both the publically available and the internal datasets. Furthermore, our results show that CNN‐based algorithms are able to identify ill‐defined contours from a clinically validated and used multiatlas‐based autocontouring tool. Therefore, our CNN‐based tool can effectively perform automatic verification of MACS contours.
Cluster analysis of time evolution (CAT) for quantitative susceptibility mapping (QSM) and quantitative blood oxygen level‐dependent magnitude (qBOLD)‐based oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) mapping
Authors: Cho Junghun , Zhang Shun , Kee Youngwook , Spincemaille Pascal , Nguyen Thanh D. , Hubertus Simon , Gupta Ajay , Wang Yi
Published: September 2019

Purpose

To improve the accuracy of QSM plus quantitative blood oxygen level‐dependent magnitude (QSM + qBOLD or QQ)‐based mapping of the oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) using cluster analysis of time evolution (CAT).

Methods

3D multi‐echo gradient echo and arterial spin labeling images were acquired in 11 healthy subjects and 5 ischemic stroke patients. DWI was also carried out on patients. CAT was developed for analyzing signal evolution over TE. QQ‐based OEF and CMRO2 were reconstructed with and without CAT, and results were compared using region of interest analysis and a paired t‐test.

Results

Simulations demonstrated that CAT substantially reduced noise error in QQ‐based OEF. In healthy subjects, QQ‐based OEF appeared less noisy and more uniform with CAT than without CAT; average OEF with and without CAT in cortical gray matter was 32.7 ± 4.0% and 37.9 ± 4.5%, with corresponding CMRO2 of 148.4 ± 23.8 and 171.4 ± 22.4 μmol/100 g/min, respectively. In patients, regions of low OEF were confined within the ischemic lesions defined on DWI when using CAT, which was not observed without CAT.

Conclusion

The cluster analysis of time evolution (CAT) significantly improves the robustness of QQ‐based OEF against noise.
Single‐Voxel 1H MR spectroscopy of cerebral nicotinamide adenine dinucleotide (NAD+) in humans at 7T using a 32‐channel volume coil
Authors: Bagga Puneet , Hariharan Hari , Wilson Neil E. , Beer Joanne C. , Shinohara Russell T. , Elliott Mark A. , Baur Joseph A. , Marincola Francesco M. , Witschey Walter R. , Haris Mohammad , Detre John A. , Reddy Ravinder
Published: September 2019

Purpose

Reliable monitoring of tissue nicotinamide adenine dinucleotide (NAD+) concentration may provide insights on its roles in normal and pathological aging. In the present study, we report a 1H MRS pulse sequence for the in vivo, localized 1H MRS detection of NAD+ from the human brain.

Methods

Studies were carried out on a 7T Siemens MRI scanner using a 32‐channel product volume coil. The pulse sequence consisted of a spectrally selective low bandwidth E‐BURP‐1 90° pulse. PRESS localization was achieved using optimized Shinnar‐Le Roux 180° pulses and overlapping gradients were used to minimize the TE. The reproducibility of NAD+ quantification was measured in 11 healthy volunteers. The association of cerebral NAD+ with age was assessed in 16 healthy subjects 26–78 years old.

Results

Spectra acquired from a voxel placed in subjects' occipital lobe consisted of downfield peaks from the H2, H4, and H6 protons of the nicotinamide moiety of NAD+ between 8.9–9.35 ppm. The mean ± SD within‐session and between‐session coefficients of variation were found to be 6.14 ± 2.03% and 6.09 ± 3.20%, respectively. In healthy volunteers, an age‐dependent decline of the NAD+ levels in the brain was also observed (β = −1.24 μM/y, SE = 0.21, P < 0.001).

Conclusion

We demonstrated the feasibility and robustness of a newly developed 1H MRS technique to measure localized cerebral NAD+ at 7T MRI using a commercially available RF head coil. This technique may be further applied to detect and quantify NAD+ from different regions of the brain as well as from other tissues.
The Effects of Regulated Area Location and Size on the Effectiveness of a Catch-and-Release Season for a Riverine Black Bass
Authors: Sammons Steven M.
Published: September 2019

Catch-and-release areas are an extension of the concept of aquatic protected areas, which implement protective measures at a broad spatial scale in an attempt to increase conservation efforts. Also, catch-and-release areas are commonly used to regulate sport fisheries, particularly in specific areas during the spawning season. However, the size and location of catch-and-release areas are rarely evaluated in terms of their effects on the success of these regulations in protecting these species. Empirical exploitation data were used with an age-structured model to explore changes in population biomass and size structure of Shoal Bass Micropterus cataractae in the Flint River, Georgia, with simulated changes in the location and size of catch-and-release areas during the spawning season. Annual exploitation of Shoal Bass with no catch-and-release area was 0.257 and was reduced 0–21% when a catch-and-release regulation was simulated in a specific reach. Models predicted significant increases in population biomass and size structure using catch-and-release reaches as short as 33 km, but this was contingent upon which specific reaches were designated as catch and release. As area size increased, population biomass and size structure of the population increased, but the rate of increase depended upon the specific areas incorporated. Designation of the entire reach would decrease annual exploitation by 50%, but large portions of the study area could be designated as catch and release with little changes in population biomass or size structure due to low harvest rates. This study illuminated the importance of spatial patterns of harvest in determining effectiveness of catch-and-release areas, which should be an important consideration in the placement of such aquatic protected areas.
Distributed inexact dual consensus ADMM for network resource allocation
Authors: Jian Long , Hu Jiangping , Wang Jun , Shi Kaibo
Published: September 2019

This paper investigates two novel distributed algorithms based on alternating direction method of multipliers (ADMM) for network resource allocation of N agents. The main objective is to derive an optimal allocation that minimizes a global objective expressed as a sum of locally known separable convex objective functions. Based on a communication matrix, the dual resource allocation problem is changed into a consensus optimization problem, in which each agent broadcasts the outcome of its local processing to all his neighbors. In this paper, we first propose a new distributed dual consensus ADMM (DC‐ADMM) algorithm to address this consensus problem. Moreover, by applying an inexact step for each ADMM update, a distributed inexact DC‐ADMM (IDC‐ADMM) is also developed, which enables agents to perform cheap computation at each iteration. Finally, numerical simulations are delivered to illustrate and validate the proposed algorithm.
Modeling of 1,3‐Butadiene Solution Polymerizations Catalyzed by Neodymium Versatate
Authors: Vasconcelos Mateus K. , Brandão Amanda L.T. , Dutra Luciana S. , Nele Márcio , Pinto José Carlos
Published: September 2019

The control of polymerization conditions and final properties of polybutadiene produced through solution polymerizations constitute an important industrial challenge, which can be tackled with help of mathematical models. For this reason, the present work focus on the development of a phenomenological mathematical model, and estimation of the respective model parameters, in order to describe the kinetics of 1,3‐butadiene solution polymerizations catalyzed by neodymium versatate. The proposed model can be used to predict some important final properties of polybutadiene resins, including the cis‐content and average molecular weights, and the evolution of operation conditions that are used at plant site to monitor the course of the reaction, including the reaction temperature and pressure. Given the low required computation times, the proposed model can be used for purposes of monitoring and control in actual industrial sites. POLYM. ENG. SCI., 59:2290–2300, 2019. © 2019 Society of Plastics Engineers
The effect of polylactic acid (PLA)/poly‐d‐lactidestereocomplex on the thermal and mechanical properties of various PLA/rubber blends
Authors: Phattarateera Supanut , Pattamaprom Cattaleeya
Published: September 2019

This study investigated the effect of polylactic acid (PLA)/poly‐d‐lactide (PDLA) stereocomplex (ST) on the improvement of the mechanical and thermal properties of various rubber‐toughened PLAs. In this work, natural rubber (NR), synthetic polyisoprene rubber (IR), silicone rubber (SI), acrylic rubber (ACM), acrylic core–shell rubber (CSR), thermoplastic copolyester (TPE) and thermoplastic polyurethane (TPU) were chosen as the toughening agents. 5 wt% PDLA was melt‐blended with PLA to form ST crystals in the presence of 15 wt% rubber in an internal mixer at 180 °C and 50 rpm. It was found that the melting temperature of ST crystal (Tm,sc) and the impact strength of ST/rubber blends were strongly correlated with the rubber domain size. For the blends of ST with compatible rubbers (ACM, CSR, TPE and TPU), the rubber domain sizes tended to be smaller with higher Tm,sc and higher impact strength than the blends with incompatible rubbers (NR, IR and SI). However, the presence of ST crystals in PLA/incompatible rubber blends, especially the blends with NR and IR, led to a significant increase in the rubber domain size and plunges in tensile toughness and impact strength. On the other hand, the presence of these crystals in PLA/compatible blends did not change the rubber size or the impact strength significantly compared with those without ST crystals except in the case of ST/ACM, which resulted in a large increase in the impact strength. Among all rubber types, CSR provided the highest impact strength for both the PLA and ST systems. © 2019 Society of Chemical Industry
Subcutaneous mepolizumab in children aged 6 to 11 years with severe eosinophilic asthma
Authors: Gupta Atul , Pouliquen Isabelle , Austin Daren , Price Robert G. , Kempsford Rodger , Steinfeld Jonathan , Bradford Eric S. , Yancey Steven W.
Published: September 2019

Objectives

There are no published reports for anti‐interleukin‐5 therapy in children <12 years with asthma. The primary objective of this study was to characterize the pharmacokinetics and pharmacodynamics of mepolizumab following subcutaneous (SC) administration in children 6 to 11 years‐of‐age with severe eosinophilic asthma.

Hypothesis

Mepolizumab SC pharmacokinetics and pharmacodynamics in children with severe eosinophilic asthma are comparable with adults.

Study Design

Multinational, nonrandomised, open‐label (NCT02377427).

Patient Selection

Children 6 to 11 years‐of‐age with severe eosinophilic asthma (blood eosinophil count ≥150 cells/µL at screening or ≥300 cells/µL <12 months of screening) and ≥2 exacerbations in the prior year.

Methodology

Children received mepolizumab SC 40 mg (bodyweight <40 kg) or 100 mg (≥40 kg) every 4 weeks for 12 weeks.

Results

Thirty‐six children received mepolizumab (40 mg, n = 26; 100 mg, n = 10). Mepolizumab exposures were higher and apparent clearance lower than predicted based on prior existing data. Derived mepolizumab exposures normalized to mean bodyweight for the 40 mg and 100 mg dose groups were 454 μg * day/mL and 675 μg * day/mL, respectively. At week 12, blood eosinophils were reduced by 89% and 83% from baseline to 42 and 55 cells/µL, respectively. Mepolizumab was well tolerated; no new safety signals were observed compared with previous adult/adolescent studies.

Conclusion

In children 6 to 11 years‐of‐age with severe eosinophilic asthma, mepolizumab SC 40 or 100 mg provided bodyweight‐adjusted drug exposure within twofold of target adult exposure as well as marked reductions to blood eosinophil counts similar to adults, and although not designed to evaluate efficacy outcomes, demonstrated a positive clinical profile.
Clinical features and outcomes associated with tracheostomy in congenital diaphragmatic hernia
Authors: Al Baroudi Sahar , Collaco Joseph M. , Lally Pamela A. , Harting Matthew T. , Jelin Eric B.
Published: September 2019

Introduction

The purpose of this study was to examine the clinical features/outcomes associated with tracheostomy in infants with congenital diaphragmatic hernia (CDH).

Methods

The study population consisted of liveborn infants reported to the CDH Study Group registry between 2007 and 2017. Subjects were identified as having a tracheostomy if they were discharged or transferred to another hospital with tracheostomy and/or on mechanical ventilation. Multivariate mixed models were used for analyses.

Results

The registry population consisted of 5434 subjects, of whom 230 (4.2%) underwent tracheostomy placement. Only 3830 (70.5%) infants survived until discharge/transfer. The median age of tracheostomy placement was 3.3 months (range, 1.3‐13.4 when known; n = 58 out of 154 survivors). The mortality rate among subjects with tracheostomy was 32.8% with a median of 37 days (range, 8‐189 when known; n = 32 out of 75 deceased) ensuing between tracheostomy placement and death. The clinical features found to be associated with increased odds ratio of tracheostomy placement included male sex, birth weight, 5‐minute APGAR score, defect size, liver in chest, ECMO use, cardiac abnormality, other congenital abnormalities, pulmonary hypertension, and the presence of a feeding tube. There was center variation in the rate of tracheostomy placement, which may be partially accounted for by disease severity, but not center size.

Conclusion

There are several clinical features that are associated with increased likelihood of tracheostomy placement. Most deaths in subjects with tracheostomies occurred outside the immediate postoperative period. The utility of a standardized protocol for tracheostomy in infants with CDH should be considered.
Aggregation of zinc‐free p53 is inhibited by Hsp90 but not other chaperones
Authors: Wu Huiwen , Dyson H. Jane
Published: September 2019

The structured DNA‐binding domain (DBD) of p53 is a well‐known client protein of the chaperone Hsp90. The p53 DBD contains a single zinc ion, coordinated by the side chains of Cys176, His179, Cys238, and Cys242; zinc coordination plays a structural role to stabilize the DBD and is required for its DNA binding. The ambiguous nature of the p53‐Hsp90 interaction, together with the stabilizing role of the zinc in the structure of the DBD, prompted us to examine the interaction of Hsp90 with zinc‐free p53 DBD. NMR spectroscopy and native gel electrophoresis did not show any apparent preference for the interaction of the destabilized zinc‐free form of p53 DBD with Hsp90. Intriguingly, however, at lower protein concentrations, closer to physiological concentrations, the addition of Hsp90, but not other chaperones such as Hsp70, Hsp40, p23, and HOP, appears to slow or prevent the aggregation of zinc‐free p53 DBD. This result suggests that part of the function of the Hsp90‐p53 interaction in the cell may be to stabilize the apoprotein in the absence of zinc.
Alteration of insulin signaling to control insect pest by using transformed bacteria expressing dsRNA
Authors: Al Baki Abdullah , Jung Jin Kyo , Kim Yonggyun
Published: September 2019

BACKGROUND

Insulin/insulin‐like growth factor signaling (IIS) is known to mediate larval growth and adult reproduction in the legume pod borer, Maruca vitrata (Lepidoptera: Crambidae). Four IIS components (InR, FOXO, Akt, and TOR) play crucial roles in the IIS pathway.

RESULTS

RNA interference (RNAi) against any of these four IIS component genes was effective in suppressing each target mRNA level by either hemocoelic injection or oral administration using gene‐specific double‐stranded RNAs (dsRNAs). These RNAi treatments interfered with larval growth, leading to small pupae or significant larval mortality. For massive production of dsRNA, transformed bacteria expressing dsRNAs of these four IIS components were prepared with L4440 expression vector and HT115 strain of Escherichia coli. The transformed bacteria killed the larvae in a dose‐dependent manner by feeding administration. An ultra‐sonication pretreatment was performed to impair bacterial membrane and increase dsRNA release from the bacteria in insect intestine. This pretreatment increased the insecticidal activity of these recombinant bacteria. To further increase dsRNA toxicity, its mixture with Bacillus thuringiensis (Bt) was prepared and showed significant increase of Bt insecticidal activity in the laboratory. The bacterial mixture also showed a high control efficacy (83.3%) in an adzuki bean (Vigna angularis) field infested by M. vitrata. Furthermore, such a dsRNA effect was specific for M. vitrata, but not for non‐target insects.

CONCLUSION

The bacteria expressing dsRNA specific to IIS components can be used to develop dsRNA insecticide. © 2019 Society of Chemical Industry
Direct Growth of Unidirectional Graphene Nanoribbons on Vicinal Ge(001)
Authors: Li Panlin , Wang Tianbo , Yang Yuekun , Wang Yalan , Zhang Miao , Xue Zhongying , Di Zengfeng
Published: September 2019

Long, highly oriented, semiconducting graphene nanoribbons (GNRs) are fabricated by chemical vapor deposition (CVD) on Ge(001) substrate. However, these anisotropic nanoribbons are apt to randomly distribute on Ge surface, which hinders their scalable applications in high‐performance graphene electronic devices. In this work, it is proved that the alignment of GNRs is closely related to the miscut angle of vicinal Ge(001) substrate. By investigating the growth behaviors of the GNRs on vicinal Ge(001) substrates with 0°, 4°, 8°, and 12° miscut toward Ge[111], it can be found that GNRs tend to nucleate along the orientation perpendicular to the miscut direction with the increase of miscut angle, and unidirectional GNRs are successfully synthesized on 12° miscut Ge(001) surface. Moreover, the shape of GNRs is also tuned by the miscut angle, which undoubtedly affects the aspect ratio of these GNRs. These promising results demonstrate that synthesizing unidirectional GNRs by the proposed method may promote the application of graphene in future nanoelectronic devices.
Memory‐type multivariate charts with fixed and variable sampling intervals for process mean when covariance matrix is unknown
Authors: Haq Abdul , Khoo Michael B. C.
Published: September 2019

Memory‐type multivariate charts have been widely recognized as a potentially powerful process monitoring tool because of their excellent speed in detecting small‐to‐moderate shifts in the mean vector of a multivariate normally distributed process, namely, the multivariate EWMA (MEWMA), double MEWMA, Crosier multivariate CUSUM (MCUSUM), and Pignatiello and Runger MCUSUM charts. These multivariate charts are based on the assumption that the covariance matrix is known in advance; but, it may not be known in practice. It is thus not possible to use these multivariate charts unless a large Phase I dataset is available from an in‐control process. In this paper, we propose multivariate charts with fixed and variable sampling intervals for the process mean vector when the covariance matrix is estimated from sample. Using the Monte Carlo simulation method, the run length characteristics of the multivariate charts are computed. It is shown that the in‐control and out‐of‐control run length performances of the proposed multivariate charts are robust to the changes in the process covariance matrix, while the existing multivariate charts are not. A real dataset is taken to explain the implementation of the proposed multivariate charts.
On the normalized Laplacian of Möbius phenylene chain and its applications
Authors: Lei Lan , Geng Xianya , Li Shuchao , Peng Yingjun , Yu Yuantian
Published: September 2019

Let denote a molecular graph of linear [n] phenylene with n hexagons and n squares, and let the Möbius phenylene chain be the graph obtained from the by identifying the opposite lateral edges in reversed way. Utilizing the decomposition theorem of the normalized Laplacian characteristic polynomial, we study the normalized Laplacian spectrum of , which consists of the eigenvalues of two symmetric matrices ℒ
R and ℒ
Q of order 3n. By investigating the relationship between the roots and coefficients of the characteristic polynomials of the two matrices above, we obtain an explicit closed‐form formula of the multiplicative degree‐Kirchhoff index as well as the number of spanning trees of . Furthermore, we determine the limited value for the quotient of the multiplicative degree‐Kirchhoff index and the Gutman index of .
Comparison between the vascular control technique and conventional technique for reducing operative blood loss during robot‐assisted myomectomy
Authors: Song Taejong , Han Young Gi , Sung Ji‐Hee
Published: September 2019

Background

This retrospective study aimed to compare the surgical outcomes and morbidity of the vascular control technique in robotic myomectomy with the conventional technique.

Methods

Thirty‐two consecutive patients who underwent robotic myomectomy using laparoscopic vascular clamps in 2017 to 2019 (the practice change cohort) were retrospectively comparted with 32 case‐matched consecutive patients who underwent the conventional robotic myomectomy (the historical cohort). The primary outcome was the operative blood loss and hemoglobin change.

Results

The two cohorts had similar baseline characteristics. The mean operative blood loss and hemoglobin changes were lower in the practice change cohort than in the historical cohort (P < .001 and P = .005, respectively). Other postoperative outcomes were similar between two cohorts.

Conclusion

The vascular control technique in robotic myomectomy appears to be effective and safe in the management of selective patients with symptomatic myomas.