bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic rodent models of brain disorders: Perspectives on experimental approaches and therapeutic strategies
Authors: McGraw Christopher M. , Ward Christopher S. , Samaco Rodney C.
Published: September 2017

Neurobehavioral disorders comprised of neurodegenerative, neurodevelopmental, and psychiatric disorders together represent leading causes of morbidity and mortality. Despite significant academic research and industry efforts to elucidate the disease mechanisms operative in these disorders and to develop mechanism‐based therapies, our understanding remains incomplete and our access to tractable therapeutic interventions severely limited. The magnitude of these short‐comings can be measured by the growing list of disappointing clinical trials based on initially promising compounds identified in genetic animal models. This review and commentary will explore why this may be so, focusing on the central role that genetic models of neurobehavioral disorders have come to occupy in current efforts to identify disease mechanisms and therapies. In particular, we will highlight the unique pitfalls and challenges that have hampered success in these models as compared to genetic models of non‐neurological diseases as well as to symptom‐based models of the early 20th century that led to the discovery of all major classes of psychoactive pharmaceutical compounds still used today. Using examples from specific genetic rodent models of human neurobehavioral disorders, we will highlight issues of reproducibility, construct validity, and translational relevance in the hopes that these examples will be instructive toward greater success in future endeavors. Lastly, we will champion a two‐pronged approach toward identifying novel therapies for neurobehavioral disorders that makes greater use of the historically more successful symptom‐based approaches in addition to more mechanism‐based approaches.
Stabilisierung eines niedrigvalenten Eisen(I)‐Ions in einem hochvalenten molekularen Vanadium(V)‐Oxid‐Cluster
Authors: Anjass Montaha H. , Kastner Katharina , Nägele Florian , Ringenberg Mark , Boas John F. , Zhang Jie , Bond Alan M. , Jacob Timo , Streb Carsten
Published: September 2017

Niedrigvalente Eisenzentren sind wichtige Zwischenstufen in chemischen und biochemischen Prozessen. Hier wird das erste Beispiel eines niedrigvalenten Eisen(I)‐Zentrums in einem hochvalenten Polyoxometallat‐Anion beschrieben. Elektrochemische Studien zeigen, dass das Eisen(III)‐funktionalisierte molekulare Vanadium(V)‐oxid (DMA)[FeIIIClVV12O32Cl]3− (DMA=Dimethylammonium) durch zwei wohldefinierte, reversible Eisen‐basierte Reduktionen in die FeI‐Spezies (DMA)[FeIClVV12O32Cl]5− übergeht. Experimentelle und theoretische Studien, einschließlich Elektronenspinresonanz‐Spektroskopie und Dichtefunktionalrechnungen, bestätigen die Bildung der Eisen(I)‐Spezies. Die Studie beschreibt das erste Beispiel des auf den ersten Blick paradoxen Einbettens niedrigvalenter Metallionen in hochvalente Oxometallat‐Anionen und eröffnet neue Möglichkeiten für reduktive Elektronentransferprozesse durch Polyoxometallate.
A Chemical Disruptor of the ClpX Chaperone Complex Attenuates the Virulence of Multidrug‐Resistant Staphylococcus aureus
Authors: Fetzer Christian , Korotkov Vadim S. , Thänert Robert , Lee Kyu Myung , Neuenschwander Martin , von Kries Jens Peter , Medina Eva , Sieber Stephan A.
Published: September 2017

The Staphylococcus aureus ClpXP protease is an important regulator of cell homeostasis and virulence. We utilized a high‐throughput screen against the ClpXP complex and identified a specific inhibitor of the ClpX chaperone that disrupts its oligomeric state. Synthesis of 34 derivatives revealed that the molecular scaffold is restrictive for diversification, with only minor changes tolerated. Subsequent analysis of the most active compound revealed strong attenuation of S. aureus toxin production, which was quantified with a customized MS‐based assay platform. Transcriptome and whole‐proteome studies further confirmed the global reduction of virulence and revealed characteristic signatures of protein expression in the compound‐treated cells. Although these partially matched the pattern of ClpX knockout cells, further depletion of toxins was observed, leading to the intriguing perspective that additional virulence pathways may be directly or indirectly addressed by the small molecule.
Joint model selection of marginal mean regression and correlation structure for longitudinal data with missing outcome and covariates
Authors: Shen Chung‐Wei , Chen Yi‐Hau
Published: September 2017

This work develops a joint model selection criterion for simultaneously selecting the marginal mean regression and the correlation/covariance structure in longitudinal data analysis where both the outcome and the covariate variables may be subject to general intermittent patterns of missingness under the missing at random mechanism. The new proposal, termed “joint longitudinal information criterion” (JLIC), is based on the expected quadratic error for assessing model adequacy, and the second‐order weighted generalized estimating equation (WGEE) estimation for mean and covariance models. Simulation results reveal that JLIC outperforms existing methods performing model selection for the mean regression and the correlation structure in a two stage and hence separate manner. We apply the proposal to a longitudinal study to identify factors associated with life satisfaction in the elderly of Taiwan.
Overcoming interference of plasma phospholipids using HybridSPE for the determination of trimetazidine by UPLC–MS/MS
Authors: Vanol Pravin G. , Yadav Manish , Sanyal Mallika , Shah Priyanka A. , Shrivastav Pranav S.
Published: September 2017

An improved, precise and reliable ultra‐performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) method has been developed for the quantification of trimetazidine, using trimetazidine‐d8 as the internal standard (IS). Interference owing to plasma phospholipids during sample preparation was overcome using a hybrid solid‐phase extraction–phospholipid ultra cartridge. The mean extraction recovery of trimetazidine (98.66%) and trimetazidine‐d8 (97.63%) from spiked plasma was consistent and reproducible. Chromatographic analysis was performed on a UPLC Ethylene Bridged Hybrid (BEH) C18 (50 × 2.1 mm, 1.7 μm) column with isocratic elution using acetonitrile–5 mm ammonium formate, pH 3.5 (40:60, v/v) as the mobile phase. The parent → product ion transitions for trimetazidine (m/z 267.1 → 181.1) and trimetazidine‐d8 (m/z 275.2 → 181.1) were monitored on a triple quadrupole mass spectrometer with electrospray ionization functioning in the positive multiple reaction monitoring mode. The linearity of the method was established in the concentration range of 0.05–100 ng/mL for trimetazidine. The intra‐batch and inter‐batch accuracy and precision (CV) were 97.3–103.1 and 1.7–5.3%, respectively. Qualitative and quantitative assessment of matrix effect showed no interference of endogenous/exogenous components. The developed method was used to measure plasma trimetazidine concentration for a bioequivalence study with 12 healthy subjects.
A Guide to Quantitative Biomarker Assay Development using Whispering Gallery Mode Biosensors
Authors: Robison Heather M. , Bailey Ryan C.
Published: September 2017

Whispering gallery mode (WGM) sensors are a class of powerful analytical techniques defined by the measurement of changes in the local refractive index at or near the sensor surface. When functionalized with target‐specific capture agents, analyte binding can be measured with very low limits of detection. There are many geometric manifestations of WGM sensors, with chip‐integrated silicon photonic devices first commercialized because of the robust, wafer‐scale device fabrication, facile optical interrogation, and amenability to the creation of multiplexed sensor arrays. Using these arrays, a number of biomolecular targets have been detected in both label‐free and label‐enhanced assay formats. For example, sub‐picomolar detection limits for multiple cytokines were achieved using an enzymatically enhanced sandwich immunoassay that showed high analyte specificity suitable for detection in complex, clinical matrices. This protocol describes a generalizable approach for the development of quantitative, multiplexed immunoassays using silicon photonic microrings as an example WGM platform. © 2017 by John Wiley & Sons, Inc.
Chiral Kagome Lattices from On‐Surface Synthesized Molecules
Authors: Wang Tao , Fan Qitang , Feng Lin , Tao Zhijie , Huang Jianmin , Ju Huanxin , Xu Qian , Hu Shanwei , Zhu Junfa
Published: September 2017

Kagome lattices have attracted much attention owing to their potential applications in spin‐frustrated magnetism and host–guest chemistry. Examples toward the fabrication of 2D Kagome lattices reported previously have in common that the precursor molecules were typically deposited on the surface structurally intact with no chemical reactions accompanied. Herein, by using a combination of synchrotron radiation photoelectron spectroscopy (SRPES) and scanning tunneling microscopy (STM), we demonstrated the fabrication of two types of chiral Kagome lattices from on‐surface synthesized organometallic compounds, which are known as intermediates of Glaser coupling on silver single crystal surfaces. These Kagome lattices are stabilized by the interplay of various intermolecular interactions, including Br⋅⋅⋅Br bonds, C−Br⋅⋅⋅π bonds and π‐π stacking. The chiral transference and host‐guest supramolecular structure in the novel Kagome lattices were also studied. Our studies may pave a new way to engineer complex supramolecular networks through on‐surface reactions.
Large cell neuroendocrine carcinoma of the maxillary sinus on fine needle aspiration cytology: Report of a rare case with a focus on pitfalls in diagnosis
Authors: Kawahara Akihiko , Ono Takeharu , Sumi Akiko , Abe Hideyuki , Takase Yorihiko , Murata Kazuya , Yamaguchi Tomohiko , Naito Yoshiki , Akiba Jun
Published: September 2017

Head and neck large cell neuroendocrine carcinoma (LCNEC) is a rare high‐grade malignant tumor with neuroendocrine differentiation. We report a case of LCNEC causing difficulty in cytological diagnosis. A 60‐year‐old man with right‐sided face pain presented with a swelling at the right cheek, and he complained of right nasal obstruction and lacrimation. Preoperative fine‐needle aspiration cytology (FNAC) showed high cellularity, with a moderate number of clusters of tumor cells on an abundant necrotic background. The clusters were arranged in sheet structures with palisading, and were cohesive with overlapping. The tumor cells had comparatively abundant cytoplasm, with conspicuous large, irregular nucleoli with a fine granular chromatin pattern. Mitotic figures were observed easily. On immunocytochemistry using LBC smear, tumor cells were negative for p40. High‐grade carcinoma other than non‐keratinizing squamous cell carcinoma was suggested from these findings on FNAC. The pretreatment histological biopsy sample revealed tumor cells with solid growth pattern, necrotic materials and large polygonal cells with abundant cytoplasm, fine granular chromatin, and conspicuous nucleoli. Head and neck LCNEC with abundant cytoplasm, fine granular chromatin patterns, prominent nucleoli, and necrotic background were very characteristic of LCNEC. If considered carefully, these findings can enable us to exclude the majority of non‐keratinizing squamous cell carcinomas, and FNAC using ancillary technique can be very useful for proper diagnosis.
Range loss of a threatened grouse species is related to the relative abundance of a mesopredator
Authors: Kämmerle Jim‐Lino , Coppes Joy , Ciuti Simone , Suchant Rudi , Storch Ilse
Published: September 2017

Mammalian generalist mesopredators can reach high densities in forest–farmland mosaic landscapes in the absence of top‐down control. The abundance of generalist mesopredators is a potentially limiting factor for prey populations, especially ground breeding birds such as grouse. High mesopredator abundance has been associated with reduced reproductive success in grouse. There is little evidence, however, on how variation in mesopredator abundance affects grouse population trends while considering other environmental covariates. We make use of range maps spanning two decades (1993–2013) of a locally threatened capercaillie (Tetrao urogallus) population in the Black Forest, Germany, to assess whether range loss of grouse in forest–farmland mosaic landscapes can be explained by a gradient in red fox abundance, while accounting for other potential determinants of grouse range loss. We show that capercaillie range persistence was favored by increasing snow cover, decreasing index of red fox abundance, slightly increasing index for soil quality, and increasing population connectivity. Red fox abundance had the largest relative impact in areas already facing an elevated capercaillie extinction risk due to unsuitable site conditions, dense forests, or lack of connectivity, but the negative effect was compensated under otherwise optimal conditions. This indicates that the relative importance of predator abundance for prey population dynamics is mediated by environmental attributes, emphasizing the threat to remnant populations but also indicating potential for species conservation.
Quantitative models of Rhipicephalus (Boophilus) ticks: historical review and synthesis
Authors: Wang Hsiao‐Hsuan , Corson Michael S. , Grant William E. , Teel Pete D.
Published: September 2017

Several tick species, in what is now known as the subgenus Boophilus in the genus Rhipicephalus, are economically important ectoparasites of livestock and other ungulates; as vectors of pathogens that kill cattle, they remain among the most studied ticks in the world. Researchers have developed quantitative computer models of Rhipicephalus ticks since the early 1970s to study complex biological and ecological relationships that influence management or eradication of ticks and tick‐borne diseases. We review the 45‐yr history of Rhipicephalus (Boophilus) models, which were developed and applied first in Australia, 10 yr later in North and South America, then soon after in Africa. Models progressed from analytical models of a portion of tick life cycles, to simulation models of complete life cycles or ecoclimatic indices, to the current emphasis on GIS‐based bioclimatic envelope models estimated from remotely sensed data and tick presence records. Earlier models were used primarily to predict effects of management techniques, such as use of sterile hybrid ticks, pasture rotation, acaricides, vaccines, and resistant cattle, while more recent models have been used to predict the potential for range expansion, especially due to global climate change and wildlife hosts, as well as in the face of competition with other tick species. We summarize characteristics of these models and compare those of population dynamics and bioclimatic envelope models. We discuss the past and present utility of these models and provide a perspective on future Rhipicephalus (Boophilus) modeling efforts.
Using Fourier series to estimate periodic patterns in dynamic occupancy models
Authors: Fidino Mason , Magle Seth B.
Published: September 2017

Some of the most impressive adaptations of organisms are in response to periodic environmental variability. To capture these temporal dynamics, statistical models that estimate the spatiotemporal distribution of a species typically include categorical seasonal covariates, temporally varying parameters, or smoothing splines. While these techniques provide a useful starting point, they may require many parameters to estimate and are not well suited for making predictions. Here, we present a technique that uses Fourier series to estimate periodic signals in dynamic occupancy models, and parameterize these models with data from a large‐scale long‐term camera trapping study of medium to large mammals in Chicago, Illinois,USA. Our periodic models captured up to 75% of the temporal variability in species colonization rates and performed similar to dynamic occupancy models with temporally varying parameters. Overall, this method can partition variability between periodic and non‐periodic sources and estimate the proportion of temporal variability that is attributable to a periodic source in a model‐based framework. Further, practitioners can use this method to incorporate prior knowledge on a species' natural history (e.g., natal dispersal and migration). This will, in turn, create more biologically reasonable models for conservation and management applications.
Population dynamics of two beaver species in Finland inferred from citizen‐science census data
Authors: Brommer J. E. , Alakoski R. , Selonen V. , Kauhala K.
Published: September 2017

A species' distribution and abundance in both space and time play a pivotal role in ecology and wildlife management. Collection of such large‐scale information typically requires engagement of volunteer citizens and tends to consist of non‐repeated surveys made with a survey effort varying over space and time. We here used a hierarchical single‐census open population N‐mixture model, which was recently developed to handle such challenging census data, to describe the dynamics in the Finnish population sizes of the reintroduced native Eurasian beaver (Castor fiber) and the invasive North American beaver (Castor canadensis). The numbers of beaver winter lodges (i.e., family groups) were counted by volunteers in the municipalities of Finland every third year during 1995–2013. The dynamics of both species followed Gompertz logistic growth with immigration. Initial abundance of North American beavers increased with proximity to the introduction sites as well as with the amount of water in the municipality. The intensively hunted North American beaver population declined and the Eurasian beaver population increased during the study period. The model generated reasonable estimates of both total Finnish and local numbers of lodges, corrected for the incomplete detection. We conclude that the single‐census N‐mixture model approach has clear potential when using citizen‐science data for understanding spatio‐temporal dynamics of wild populations.
Affinity capillary electrophoresis for the assessment of binding affinity of carbohydrate‐based cholera toxin inhibitors
Authors: Aizpurua‐Olaizola Oier , Sastre Torano Javier , Pukin Aliaksei , Fu Ou , Boons Geert Jan , de Jong Gerhardus J. , Pieters Roland J.
Published: September 2017

Developing tools for the study of protein carbohydrate interactions is an important goal in glycobiology. Cholera toxin inhibition is an interesting target in this context, as its inhibition may help to fight against cholera. For the study of novel ligands an affinity capillary electrophoresis (ACE) method was optimized and applied. The method uses unlabeled cholera toxin B‐subunit (CTB) and unlabeled carbohydrate ligands based on ganglioside GM1‐oligosaccharides (GM1os). In an optimized method at pH 4, adsorption of the protein to the capillary walls was prevented by a polybrene‐dextran sulfate‐polybrene coating. Different concentrations of the ligands were added to the BGE. CTB binding was observed by a mobility shift that could be used for dissociation constant (Kd) determination. The Kd values of two GM1 derivatives differed by close to an order of magnitude (600 ± 20 nM and 90 ± 50 nM) which was in good agreement with the differences in their reported nanomolar IC50 values of an ELISA‐type assay. Moreover, the selectivity of GM1os towards CTB was demonstrated using Influenza hemagglutinin (H5) as a binding competitor. The developed method can be an important platform for preclinical development of drugs targeting pathogen‐induced secretory diarrhea.
Evaluation of out‐of‐plane seismic performance of column‐to‐column precast concrete cladding panels in one‐storey industrial buildings
Authors: Belleri Andrea , Cornali Fabrizio , Passoni Chiara , Marini Alessandra , Riva Paolo
Published: September 2017

Recent earthquakes in Italy (L'Aquila 2009 and Emilia 2012) highlighted the vulnerability of precast cladding panels, typically associated with a connection system not designed to account for displacement and rotation compatibility between the panels and the supporting structure. Experimental investigations were performed in the past to investigate the in‐plane performance of cladding panels and design recommendations have been made accordingly; however, in the case of out‐of‐plane seismic loads, the load demand is commonly evaluated in the design practice by means of formulations for nonstructural components.

This paper summarizes the results obtained from parametric analyses conducted to estimate the out‐of‐plane load demand in column‐to‐column cladding panels typical of one‐storey commercial and industrial buildings. Empirical equations suitable for both new and existing panels are proposed and compared with the design equations given in Eurocode 8 and ASCE 7. The paper also considers the effects of the development of plastic hinges at the column base and of the roof flexibility on the load demand in panel‐to‐column connections. The roof flexibility may generate the torsion of the panels; consequently, an analytical procedure to account for such effects is proposed. Finally, general design recommendations are made.
RC structures cyclic behavior simulation with a model integrating plasticity, damage, and bond‐slip
Authors: Alfarah Bashar , Murcia‐Delso Juan , López‐Almansa Francisco , Oller Sergio
Published: September 2017

The behavior of reinforced concrete structures under severe demands, as strong ground motions, is highly complex; this is mainly due to the complexity of concrete behavior and to the strong interaction between concrete and steel, with several coupled failure modes. On the other hand, given the increasing awareness and concern on the worldwide seismic risk, new developments have arisen in earthquake engineering; nonetheless, some developments are mainly based on simple analytical tools that are widely used, given their moderate computational cost. This research aims to provide a solid basis for validation and calibration of such developments by using computationally efficient continuum mechanics‐based tools. Within this context, this paper presents a model for 3D simulation of cyclic behavior of RC structures. The model integrates a bond‐slip model developed by one of the authors and the damage variable evolution methodology for concrete damage plastic model developed by some authors. In the integrated model, a new technique is derived for efficient 3D analysis of bond‐slip of 2 or more crossing reinforcing bars in beam‐column joints, slabs, footings, pile caps, and other similar members. The analysis is performed by implementing the bond‐slip model in a user element subroutine of Abaqus and the damage variable evolution methodology in the original concrete damage plastic model in the package. Two laboratory experiments consisting of a column and a frame subjected to cyclic displacements up to failure are simulated with the proposed formulation.
MicroRNA‐324‐5p regulates stemness, pathogenesis and sensitivity to bortezomib in multiple myeloma cells by targeting hedgehog signaling
Authors: Tang Bo , Xu Aoshuang , Xu Jian , Huang Haifan , Chen Lei , Su Yan , Zhang Lannan , Li Junying , Fan Fengjuan , Deng Jun , Tang Liang , Sun Chunyan , Hu Yu
Published: September 2017

Chromosome 17p deletions are present in 10% of patients with newly diagnosed multiple myeloma (MM), and are associated with inferior prognosis. miR‐324‐5p is located on chromosome 17p, and shows diverse functions in different types of cancers. However, its role in MM is largely unknown. Here we found the expression of miR‐324‐5p was decreased in MM, especially in del(17p) MM. In contrast, the expression of hedgehog (Hh) signaling components was elevated, indicating a correlation between miR‐324‐5p and Hh signaling in MM. Hh signaling is important for the pathogenesis of MM and maintenance of MM stem cell compartment. Indeed, overexpression of miR‐324‐5p significantly decreased Hh signaling components Smo and Gli1, and functionally reduced cell growth, survival as well as stem cell compartment in MM. Moreover, miR‐324‐5p potentiated the anti‐MM efficacy of bortezomib through regulating the activities of multidrug‐resistance proteins and the expression of Bcl‐2 family genes. Consistent results were obtained in vivo. Finally, miR‐324‐5p overcame the protective effect of bone marrow stromal cells on MM cells. Taken together, our data demonstrate that miR‐324‐5p is essential for MM pathogenesis and downregulation of miR‐324‐5p is a novel mechanism of Hh signaling activation in MM. Therefore, targeting miR‐324‐5p provides a potential therapeutic strategy for MM.
Novel carbonic anhydrase IX‐targeted therapy enhances the anti‐tumour effects of cisplatin in small cell lung cancer
Authors: Bryant Jennifer L , Gieling Roben G , Meredith Suzanne L , Allen Tiffany‐Jayne , Walker Leanne , Telfer Brian A , Supuran Claudiu T , Williams Kaye J , White Anne
Published: September 2017

Small cell lung cancer (SCLC) has an extremely poor prognosis and methods of improving chemotherapeutic intervention are much sought after. A promising approach lies in inhibiting the tumour‐associated enzyme, carbonic anhydrase IX (CA IX), which supports tumour cell survival. The aim of this study was to assess the potential of CA IX inhibition using 4‐(3′‐(3″,5″‐dimethylphenyl)ureido)phenyl sulfamate (S4), for the treatment of human SCLC alone and in combination with cisplatin chemotherapy. Treating SCLC cell lines (DMS 79 and COR‐L24) with 100 µM S4 reduced viability in vitro and enhanced cell death when combined with 7 µM cisplatin, most prominently under hypoxic conditions (0.1% O2). When either cell line was grown as a xenograft tumour in nude mice, intraperitoneal injection of 50 mg/kg S4 alone and in combination with 3 mg/kg cisplatin led to significantly reduced tumour growth. Combination therapy was superior to single agents and response was greatly accentuated when administering repeated doses of cisplatin in DMS 79 tumours. The mechanism of therapeutic response was investigated in vitro, where S4 treatment increased apoptosis under hypoxic conditions in both DMS 79 and COR‐L24 cells. DMS 79 tumours receiving S4 in vivo also displayed increased apoptosis and necrosis. Combining S4 with cisplatin reduced both the area of hypoxia and CA IX‐positive cells within tumours and increased necrosis, suggesting hypoxia‐specific targeting. This study presents a novel, targeted approach to improving current SCLC therapy via inhibition of CA IX, which enhances apoptosis and significantly inhibits xenograft tumour growth when administered alone and in combination with cisplatin chemotherapy.
Nrf2 transfection enhances the efficacy of human amniotic mesenchymal stem cells to repair lung injury induced by lipopolysaccharide
Authors: Zhang Shouqin , Jiang Wei , Ma Lijie , Liu Yuhao , Zhang Xiangyu , Wang Sheng
Published: September 2017

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are clinical emergencies with no effective pharmaceutical treatment. This study aims to determine the protective effects of Nrf2‐transfected human amniotic mesenchymal stem cells (hAMSCs) against lipopolysaccharide (LPS)‐induced lung injury in mice. hAMSCs stably transfected with Nrf2 or green fluorescent protein control were transplanted into male C57BL/6 mice via the tail vein 4 h after intratracheal instillation of LPS. At 3, 7, and 14 days after cell transplantation, total lung injury score (the Smith score) was determined by hematoxylin and eosin staining. Lung fibrosis was assessed by Masson's trichrome staining. Alveolar epithelial apoptosis was determined by terminal deoxynucleotidyl transferase dUTP nick end labeling staining. The plasma levels of interleukin (IL)‐1β, IL‐6, and IL‐10 were determined by enzyme‐linked immunosorbent assays (ELISA). The homing and differentiation of hAMSCs into type II alveolar epithelial (AT II) cells were examined by immunofluorescent staining and/or western blot analysis. Nrf2, mRNA, and protein expression in lungs were examined by qRT‐PCR and western blot analysis, and DNA‐binding activity of Nrf2 was detected by ELISA. We found that, compared with control hAMSCs, treatment with Nrf2‐overexpressing hAMSCs led to further reduced lung injury, lung fibrosis, and inflammation in LPS‐challenged mice. Nrf2‐overexpressing hAMSCs also exhibited increased cell retention in the lung, more efficient differentiation into AT II cells, and more prominent effects on the increased mRNA and protein expression as well as DNA‐binding activity of Nrf2 than control. These results support Nrf2‐overexpressing hAMSCs as a potential cell‐based therapy for clinical ALI/ARDS.
Effects of Rolapitant Administered Intravenously or Orally on the Pharmacokinetics of Digoxin (P‐glycoprotein Substrate) and Sulfasalazine (Breast Cancer Resistance Protein Substrate) in Healthy Volunteers
Authors: Wang Xiaodong , Zhang Zhi‐Yi , Arora Sujata , Hughes Lorraine , Wang Jing , Powers Daniel , Christensen Jennifer , Lu Sharon , Kansra Vikram
Published: September 2017

Rolapitant is a selective and long‐acting neurokinin‐1 receptor antagonist approved in an oral formulation in combination with other antiemetic agents for the prevention of delayed chemotherapy‐induced nausea and vomiting in adults. Four open‐label phase 1 studies evaluated the safety and drug–drug interactions of a single dose of rolapitant given intravenously (166.5 mg) or orally (180 mg) with oral digoxin (0.5 mg) or sulfasalazine (500 mg), probe substrates for the P‐glycoprotein (P‐gp) and breast cancer resistance protein (BCRP), respectively. Administration of intravenous rolapitant with the substrates did not result in clinically significant effects on digoxin and sulfasalazine pharmacokinetics. In contrast, peak concentration and area under the curve for last quantifiable plasma concentrations increased by 71% (geometric mean ratio [GMR], 1.71; 90% confidence interval [CI], 1.49–1.95) and 30% (GMR, 1.30; 90%CI, 1.19–1.42), respectively, when rolapitant was coadministered orally with digoxin compared with digoxin alone; they increased by 140% (GMR, 2.40; 90%CI, 2.02–2.86) and 127% (GMR, 2.27; 90%CI, 1.94–2.65), respectively, when rolapitant was given orally with sulfasalazine compared with sulfasalazine alone. Adverse events were mild to moderate in severity in the absence or presence of rolapitant. There were no abnormal clinical laboratory or electrocardiogram findings. Thus, whether administered orally or intravenously, rolapitant was safe and well tolerated. Patients taking oral rolapitant with P‐gp and BCRP substrates with a narrow therapeutic index should be monitored for potential adverse events; although increased plasma concentrations of these substrates may raise the risk of toxicity, they are not contraindicated.
Synthesis of Novel Diverse Methoxybenzenes‐substituted 2H/4H‐chromene Derivatives in the Presence of InBr3 (5 mol%) and their Cytotoxic Activity
Authors: K. Ratnakar Reddy , D. Krishna Swaroop , N. Ravikumar , G. Sravanthi Devi , Y. Poornachandra , N. Jagadeesh Babu , C. Ganesh Kumar , Banda Narsaiah
Published: September 2017

A series of novel 2‐(trifluoromethyl)‐2H/4H‐chromene‐3‐carboxylate isomers 3 and 4 functionalized with diverse methoxybenzenes 2 at position 4 in compound 3 and position 2 in compound 4 were prepared in different proportions by nucleophilic substitution on ethyl 2‐hydroxy‐2‐(trifluoromethyl)‐2H‐chromene‐3‐carboxylate 1 in single step promoted by Indium (III) bromide (5 mol%) a Lewis acid. Regiospecific isomers 3k, 3l, 3m, and 3n prepared by using sterically bulk 1,3,5‐trimethoxy benzene substrate 2e in this reaction. Further, isomers 3a and 4a independently on reaction with amines, only compound 3a could give Michael addition products 5a–c. All the compounds 3a–n, 4a–j, and 5a–c were screened for cytotoxic activity against four human cancer cell lines and found to show high activity at micromolar concentration. The compounds 4h and 5a–c showed promising cytotoxic activity against the tested cancer cell lines. Further, these compounds 4h and 5a–c were docked with protein (1SA0) on colchicine‐binding site of β tubulin suggesting that tubulin inhibition could be the possible mechanism of action for these compounds.
Synthesis and Antimicrobial Activity of 2‐(4‐(Hydroxyalkyl)‐1H‐1,2,3‐triazol‐1‐yl)‐N‐substituted propanamides
Authors: Kaushik C.P. , Luxmi Raj
Published: September 2017

A series of 21 2‐(4‐(hydroxyalkyl)‐1H‐1,2,3‐triazol‐1‐yl)‐N‐substituted propanamides (1,4‐disubstituted 1,2,3‐triazoles having amide linkage and hydroxyl group) have been synthesized from click reaction between terminal alkyne and 2‐azido‐N‐substituted propanamide (generated in situ from reaction of 2‐bromo‐N‐substituted propanamide and sodium azide) and characterized by FTIR, 1H NMR, 13C NMR spectroscopy, and HRMS. All the newly synthesized triazoles were tested in vitro for antimicrobial activity against four bacterial cultures – Escherichia coli, Enterobacter aerogenes, Klebsiella pneumoniae, and Staphylococcus aureus – and two fungal cultures – Candida albicans and Aspergillus niger. The synthesized 1,4‐disubstituted 1,2,3‐triazoles displayed moderate to good antimicrobial potential against the tested strains.
Sterically Hindered N‐Heterocyclic Salts Utilized as Antimicrobial Agents
Authors: Ndlovu Slindile N. P. , Ibrahim Halliru , Bala Muhammad D.
Published: September 2017

By the adoption of annulated ring systems for their steric bulkiness, a new series of symmetric N‐heterocyclic imidazolium and perimidium salts were synthesized. Also, corresponding asymmetric ferrocenyl N‐functionalized series were prepared as salts. All the reported salts were fully characterized. The reported X‐ray structure of 4,5‐diphenyl‐1,3‐dimethyl‐1H‐imidazol‐3‐ium iodide (2a) shows that it crystallized in the orthorhombic space group P212121. Low to moderate antimicrobial activities were observed with both sets of salts against important clinical isolates of Staphylococcus aureus, Bacillus subtilis, and Enterococcus faecalis and Escherichia coli, Pseudomonas aeruginosa, and Salmonella enterica. The results were benchmarked against meropenem. Both 1,3‐propyl‐1H‐phenanthro[9,10‐d]imidazol‐3‐ium iodide (3b) and 1‐ferrocenyl‐3‐propyl‐1H‐perimidin‐3‐ium iodide (9b) showed high antimicrobial activities against all tested Gram‐positive bacterial strains, with minimum inhibitory concentration values ranging from 8 to 4 μg/mL (meropenem = 0.5–0.125 μg/mL), while all the salts showed little or no activity against Gram‐negative bacterial strains. In general, the asymmetric ferrocenyl‐containing salts exhibited higher activities than the symmetric ones.
CXCL10 is upregulated in synovium and cartilage following articular fracture
Authors: Furman Bridgette D. , Kent Collin L. , Huebner Janet L. , Kraus Virginia B. , McNulty Amy L. , Guilak Farshid , Olson Steven A.
Published: September 2017

The objective of this study was to investigate the expression of the chemokine CXCL10 and its role in joint tissues following articular fracture. We hypothesized that CXCL10 is upregulated following articular fracture and contributes to cartilage degradation associated with post‐traumatic arthritis (PTA). To evaluate CXCL10 expression following articular fracture, gene expression was quantified in synovial tissue from knee joints of C57BL/6 mice that develop PTA following articular fracture, and MRL/MpJ mice that are protected from PTA. CXCL10 protein expression was assessed in human cartilage in normal, osteoarthritic (OA), and post‐traumatic tissue using immunohistochemistry. The effects of exogenous CXCL10, alone and in combination with IL‐1, on porcine cartilage explants were assessed by quantifying the release of catabolic mediators. Synovial tissue gene expression of CXCL10 was upregulated by joint trauma, peaking one day in C57BL/6 mice (25‐fold) versus 3 days post‐fracture in MRL/MpJ mice (15‐fold). CXCL10 protein in articular cartilage was most highly expressed following trauma compared with normal and OA tissue. In a dose dependent manner, exogenous CXCL10 significantly reduced total matrix metalloproteinase (MMP) and aggrecanase activity of culture media from cartilage explants. CXCL10 also trended toward a reduction in IL‐1α‐stimulated total MMP activity (p = 0.09) and S‐GAG (p = 0.09), but not NO release. In conclusion, CXCL10 was upregulated in synovium and chondrocytes following trauma. However, exogenous CXCL10 did not induce a catabolic response in cartilage. CXCL10 may play a role in modulating the chondrocyte response to inflammatory stimuli associated with joint injury and the progression of PTA. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1220–1227, 2018.
Photodynamic therapy for glioblastoma: A preliminary approach for practical application of light propagation models
Authors: Dupont Clément , Vignion Anne‐Sophie , Mordon Serge , Reyns Nicolas , Vermandel Maximilien
Published: September 2017

Purpose

Photodynamic therapy (PDT) is a promising treatment modality to be added in the management of glioblastoma multiforme (GBM). Light distribution modeling is required for planning and optimizing PDT. Several models have been developed to predict the light propagation inside biological tissues. In the present study, two analytical methods of light propagation emitted from a cylindrical fiber source were evaluated: a discrete and a continuous method.

Methods

The two analytical approaches were compared according to their fluence rate results. Several cylindrical diffuse lengths were evaluated, and the relative deviation in the fluence rates was estimated. Moreover, a sensitivity analysis was conducted to compute the variance of each analytical model.

Results

The discrete method provided fluence rate estimations closer to the Monte‐Carlo simulations than the continuous method. The sensitivity study results did not reveal significant differences between the variance of the two analytical models.

Conclusions

Although the discrete model provides relevant light distribution, the heterogeneity of GBM tissues was not considered. With the improvement in parallel computing that drastically decreased the computing time, replacing the analytical model by a Monte‐Carlo GPU‐accelerated code appeared relevant to the GBM case. Nonetheless, the analytical modeling may still function in the optimization algorithms, which might be used in the Photodynamic treatment planning system. Lasers Surg. Med. 50:523–534, 2018. © 2017 Wiley Periodicals, Inc.
Ca2+ Induced Crosslinking of AIE‐Active Polyarylene Ether Nitrile into Fluorescent Polymeric Nanoparticles for Cellular Bioimaging
Authors: Wang Pan , Jia Kun , Zhou Xuefei , Guan Xiaotian , Wang Lianhui , Tian Yuan , Wu Chunhui , Liu Xiaobo
Published: September 2017

Biocompatible fluorescent polymeric nanoparticles (FPNs) are promising luminescent probes in cellular bioimaging, while the fabrication of high‐quantum‐yield FPN using nonconjugated heterochain polymers derived from step‐growth polymerization is still in its infancy. Herein, the nonconjugated polyarylene ether nitrile (PEN) is endowed with aggregation‐induced emission (AIE) feature by incorporation of an AIEgen named of 1,2‐di(4‐hydroxyphenyl)‐1,2‐diphenylethene into macromolecular backbone. Furthermore, the AIE‐active PEN is crosslinked into water soluble fluorescent nanospheres showing good biocompatibility and strong emission ≈480 nm with a quantum yield of 21% in the presence of Ca2+, which allows the successful bioimaging of cancer cells. Due to the facile fabrication of FPNs and their effective bioimaging performance, the current work will open the way for the biomedical applications of various high performance polyarylene ethers.
Immobilizing Organic‐Based Molecular Switches into Metal–Organic Frameworks: A Promising Strategy for Switching in Solid State
Authors: Gui Bo , Meng Yi , Xie Yang , Du Ke , Sue Andrew C.‐H. , Wang Cheng
Published: September 2017

Organic‐based molecular switches (OMS) are essential components for the ultimate miniaturization of nanoscale electronics and devices. For practical applications, it is often necessary for OMS to be incorporated into functional solid‐state materials. However, the switching characteristics of OMS in solution are usually not transferrable to the solid state, presumably because of spatial confinement or inefficient conversion in densely packed solid phase. A promising way to circumvent this issue is harboring the functional OMS within the robust and porous environment of metal–organic frameworks (MOFs) as their organic components. In this feature article, recent research progress of OMS‐based MOFs is briefly summarized. The switching behaviors of OMS under different stimuli (e.g., light, redox, pH, etc.) in the MOF state are first introduced. After that, the technological applications of these OMS‐based MOFs in different areas, including CO2 adsorption, gas separation, drug delivery, photodynamic therapy, and sensing, are outlined. Finally, perspectives and future challenges are discussed in the conclusion.
Time‐periodic solution to the compressible nematic liquid crystal flows in periodic domain
Authors: Yang Ying , Tao Qiang
Published: September 2017

In this paper, we consider the time‐periodic solution to a simplified version of Ericksen‐Leslie equations modeling the compressible hydrodynamic flow of nematic liquid crystals with a time‐periodic external force in a periodic domain in
. By using an approach of parabolic regularization and combining with the topology degree theory, we establish the existence of the time‐periodic solution to the model under some smallness and symmetry assumptions on the external force. Then, we give the uniqueness of the periodic solution of this model.
Synthetic breast phantoms from patient based eigenbreasts
Authors: Sturgeon Gregory M. , Park Subok , Segars William Paul , Lo Joseph Y.
Published: September 2017

Purpose

The limited number of 3D patient‐based breast phantoms available could be augmented by synthetic breast phantoms in order to facilitate virtual clinical trials (VCTs) using model observers for breast imaging optimization and evaluation.

Methods

These synthetic breast phantoms were developed using Principal Component Analysis (PCA) to reduce the number of dimensions needed to describe a training set of images. PCA decomposed a training set of M breast CT volumes (with millions of voxels each) into an M‐1‐dimensional space of eigenvectors, which we call eigenbreasts. Each of the training breast phantoms was compactly represented by the mean image plus a weighted sum of eigenbreasts. The distribution of weights observed from training was then sampled to create new synthesized breast phantoms.

Results

The resulting synthesized breast phantoms demonstrated a high degree of realism, as supported by an observer study. Two out of three experienced physicist observers were unable to distinguish between the synthesized breast phantoms and the patient‐based phantoms. The fibroglandular density and noise power law exponent of the synthesized breast phantoms agreed well with the training data.

Conclusions

Our method extends our series of digital breast phantoms based on breast CT data, providing the capability to generate new, statistically varying ensembles consisting of tens of thousands of virtual subjects. This work represents an important step toward conducting future virtual trials for task‐based assessment of breast imaging, where it is vital to have a large ensemble of realistic phantoms for statistical power as well as clinical relevance.
Fast 3D rosette spectroscopic imaging of neocortical abnormalities at 3 T: Assessment of spectral quality
Authors: Schirda Claudiu V. , Zhao Tiejun , Yushmanov Victor E. , Lee Yoojin , Ghearing Gena R. , Lieberman Frank S. , Panigrahy Ashok , Hetherington Hoby P. , Pan Jullie W.
Published: September 2017

Purpose

To use a fast 3D rosette spectroscopic imaging acquisition to quantitatively evaluate how spectral quality influences detection of the endogenous variation of gray and white matter metabolite differences in controls, and demonstrate how rosette spectroscopic imaging can detect metabolic dysfunction in patients with neocortical abnormalities.

Methods

Data were acquired on a 3T MR scanner and 32‐channel head coil, with rosette spectroscopic imaging covering a 4‐cm slab of fronto‐parietal‐temporal lobes. The influence of acquisition parameters and filtering on spectral quality and sensitivity to tissue composition was assessed by LCModel analysis, the Cramer‐Rao lower bound, and the standard errors from regression analyses. The optimized protocol was used to generate normative white and gray matter regressions and evaluate three patients with neocortical abnormalities.

Results

As a measure of the sensitivity to detect abnormalities, the standard errors of regression for Cr/NAA and Ch/NAA were significantly correlated with the Cramer‐Rao lower bound values (R = 0.89 and 0.92, respectively, both with P < 0.001). The rosette acquisition with a duration of 9.6 min, produces a mean Cramer‐Rao lower bound (%) over the entire slab of 4.6 ± 2.6 and 5.8 ± 2.3 for NAA and Cr, respectively. This enables a Cr/NAA standard error of 0.08 (i.e., detection sensitivity of 25% for a 50/50 mixed gray and white matter voxel). In healthy controls, the regression of Cr/NAA versus fraction gray matter in the cingulate differs from frontal and parietal regions.

Conclusions

Fast rosette spectroscopic imaging acquisitions with regression analyses are able to identify metabolic differences across 4‐cm slabs of the brain centrally and over the cortical periphery with high efficiency, generating results that are consistent with clinical findings. Magn Reson Med 79:2470–2480, 2018. © 2017 International Society for Magnetic Resonance in Medicine.
High spatio‐temporal resolution in functional MRI with 3D echo planar imaging using cylindrical excitation and a CAIPIRINHA undersampling pattern
Authors: van der Zwaag Wietske , Reynaud Olivier , Narsude Mayur , Gallichan Daniel , Marques José P.
Published: September 2017

Purpose

The combination of 3D echo planar imaging (3D‐EPI) with a 2D‐CAIPIRINHA undersampling scheme provides high flexibility in the optimization for spatial or temporal resolution. This flexibility can be increased further with the addition of a cylindrical excitation pulse, which exclusively excites the brain regions of interest. Here, 3D‐EPI was combined with a 2D radiofrequency pulse to reduce the brain area from which signal is generated, and hence, allowing either reduction of the field of view or reduction of parallel imaging noise amplification.

Methods

3D‐EPI with cylindrical excitation and 4 × 3‐fold undersampling in a 2D‐CAIPIRINHA sampling scheme was used to generate functional MRI (fMRI) data with either 2‐mm or 0.9‐mm in‐plane resolution and 1.1‐s temporal resolution over a 5‐cm diameter cylinder placed over both temporal lobes for an auditory fMRI experiment.

Results

Significant increases in image signal‐to‐noise ratio (SNR) and temporal SNR (tSNR) were found for both 2‐mm isotropic data and the high‐resolution protocol when using the cylindrical excitation pulse. Both protocols yielded highly significant blood oxygenation level–dependent responses for the presentation of natural sounds.

Conclusion

The higher tSNR of the cylindrical excitation 3D‐EPI data makes this sequence an ideal choice for high spatiotemporal resolution fMRI acquisitions. Magn Reson Med 79:2589–2596, 2018. © 2017 International Society for Magnetic Resonance in Medicine.