bluuebunny/crossref_metadata_2025 huggingface dataset:
Nostril-specific and structure-based olfactory learning of chiral discrimination in human adults
Authors: Feng Guo , Zhou Wen
Published: January 2019

Practice makes perfect. In human olfaction, such plasticity is generally assumed to occur at the level of cortical synthetic processing that shares information from both nostrils. Here we present findings that challenge this view. In two experiments, we trained human adults unirhinally for the discrimination between odor enantiomers over a course of about 10 to 11 days. Results showed that training-induced perceptual gain was restricted to the trained nostril yet partially generalized to untrained odor enantiomers in a structure- rather than quality- based manner. In other words, learning enhanced the differentiation of chirality (molecular configuration) as opposed to overall odor quality (odor object) per se. These findings argue that, unlike earlier beliefs, one nostril does not readily know what the other learns. Moreover, the initial analytical processing of the structural features of uninarial olfactory input remains plastic in human adults.
SAFETY RULES FOR USE IN ELECTRIC VEHICLE CHARGING INFRASTRUCTURE
Authors: Miličić Juraj , Hederić Željko , Špoljarić Željko , Krstić Dejan
Published: January 2019

Development trend in automotive industry is based on
development of electric vehicles (EV) and supporting infrastructure.
To ensure safety of users and user friendly interfaces, complex systems
of power electronics, high voltage and current levels, as well as
control systems in real time have priority in research and
development. This paper presents an overview of technical solutions and standard procedures related to systems infrastructure for EV power charging, protocols for connections and security systems.
Key words:
electric vehicle, charging infrastructure, standards procedures, connections
Phylogeography and population genetics of the endemic Malagasy bat,Macronycteris commersonis.s. (Chiroptera: Hipposideridae)
Authors: Rakotoarivelo Andrinajoro R. , Goodman Steven M. , Schoeman M. Corrie , Willows-Munro Sandi
Published: January 2019

Macronycteris commersoni(Hipposideridae), a bat species endemic to Madagascar, is widespread across the island and utilizes a range of habitat types including open woodland, degraded habitats, and forested areas from sea level to 1,325 m. Despite being widely distributed, there is evidence thatM. commersoniexhibits morphological and bioacoustic variation across its geographical range. We investigated the fine-scale phylogeographic structure of populations in the western half of the island using extensive spatial sampling and sequence data from two mitochondrial DNA regions. Our results indicated several lineages withinM. commersoni.Individuals collected from northern Madagascar formed a single monophyletic clade (clade C). A second clade (clade B) included individuals collected from the south-western portion of the island. This second clade displayed more phylogeographical partitioning with differences in mtDNA haplotypes frequency detected between populations collected in different bioclimatic regions. Lineage dispersal, genetic divergence, and timing of expansion events ofM.commersoniwere probably associated with Pleistocene climate fluctuations. Our data suggest that the northern and the central western regions of Madagascar may have acted as refugia for this species during periods of cooler and drier climate conditions associated with the Pleistocene.
Introduction of Hydrophobic Ammonium Salts with Halogen Functional Groups for High‐Efficiency and Stable 2D/3D Perovskite Solar Cells
Authors: Liu Guozhen , Zheng Haiying , Xu Xiaoxiao , Xu Shendong , Zhang Xianxi , Pan Xu , Dai Songyuan
Published: January 2019

2D perovskites have attracted extensive attention due to their excellent stability compared with 3D perovskites. However, the intrinsic hydrophilicity of introduced alkylammonium salts effects the humidity stability of 2D/3D perovskites. Devices based on longer chain alkylammonium salts show improvement in hydrophobicity but lower efficiency due to the poorer charge transport among various layers. To solve this issue, two hydrophobic short‐chain alkylammonium salts with halogen functional groups (2‐chloroethylamine, CEA+ and 2‐bromoethylamine, BEA+) are introduced into (Cs0.1FA0.9)Pb(I0.9Br0.1)3 3D perovskites to form 2D/3D perovskite structure, which achieve high‐quality perovskite films with better crystallization and morphology. The optimal 2D/3D perovskite solar cells (PSCs) with 5% CEA+ display a power conversion efficiency (PCE) as high as 20.08% under 1 sun irradiation. Because of the notable hydrophobicity of alkylammonium cations with halogen functional groups and the formed 2D/3D perovskite structure, the optimal PSCs exhibit superior moisture resistance and retain 92% initial PCE after aging at 50 ± 5% relative humidity for 2400 h. This work opens up a new direction for the design of new‐type 2D/3D PSCs with improved performance by employing proper alkylammonium salts with different functional groups.
Progress in Difluoroalkylation of Organic Substrates by Visible Light Photoredox Catalysis
Authors: Lemos Agostinho , Lemaire Christian , Luxen André
Published: January 2019

The selective incorporation of fluorinated motifs, in particular CF2FG (FG=a functional group) and CF2H groups, into organic compounds has attrracted increasing attention since organofluorine molecules are of the utmost importance in the areas of nuclear imaging, pharmaceutical, agrochemical, and material sciences. A variety of synthetic approaches has been employed in late‐stage difluoroalkylation reactions. Visible light photoredox catalysis for the production of CF2FG and CF2H radicals has provided a more sustainable alternative to other conventional radical‐triggered reactions from the viewpoint of safety, cost, availability, and “green” chemistry. A wide range of difluoroalkylating reagents has been successfully implemented in these organic transformations in the presence of transition metal complexes or organic photocatalysts. In most cases, upon excitation via visible light irradiation with fluorescent light bulbs or blue light‐emitting diode (LED) lamps, these photocatalysts can act as both reductive and oxidative quenchers, thus enabling the application of electron‐donor or electron‐acceptor difluoroalkylating reagents for the generation of CF2FG and CF2H radicals. Subsequent radical addition to substrates and additional organic transformations afford the corresponding difluoroalkylated derivatives. The present review describes the distinct strategies for the transition metal‐ and organic‐photocatalyzed difluoroalkylation of a broad range of organic substrates by visible light irradiation reported in the literature since 2014.

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An analysis of RUC methodology for determining the RVU valuation of sinus surgery
Authors: Smith Kristine A. , Oakley Gretchen , Alt Jeremiah A. , Orlandi Richard R.
Published: January 2019

Background

The Relative Value Scale Update Committee, commonly known as the RUC, is responsible for defining the value of Current Procedural Terminology (CPT) codes. The RUC process uses survey responses reporting operative times to determine procedure reimbursement, but it is limited by low response rates, small sample sizes, and unclear generalizability of the results. By comparing actual reported intraoperative times to the times determined by the RUC process, in this study we sought to assess the performance of RUC methodology in endoscopic sinus surgery (ESS).

Methods

The ESS CPT codes that were reassessed in 2016 using the RUC method were examined in this study. Intraoperative time data for these codes were retrospectively collected from 14 medical facilities, using time stamps in the electronic health record. These actual intraoperative times were compared with the 2016 RUC survey results.

Results

There were 143 RUC physician survey responses and 446 actual procedure times included in the final analysis. There was significant variability within the RUC survey responses (ie, unilateral anterior ethmoidectomy times varied from 5 to 90 minutes). There was also a significant difference between the RUC survey results and actual intraoperative times (p < 0.001). For example, frontal sinus surgeries showed a particularly poor correlation between actual and RUC times.

Conclusion

The RUC process may not accurately estimate or value actual intraoperative times. Real‐world intraoperative times are readily accessible and may be an alternative to survey‐based methodology in the future.
Chiral DMAP‐N‐oxides as Acyl Transfer Catalysts: Design, Synthesis, and Application in Asymmetric Steglich Rearrangement
Authors: Xie Ming‐Sheng , Zhang Ye‐Fei , Shan Meng , Wu Xiao‐Xia , Qu Gui‐Rong , Guo Hai‐Ming
Published: January 2019

A DMAP‐N‐oxide, featuring an α‐amino acid as the chiral source, was developed, synthesized and applied in asymmetric Steglich rearrangement. A series of O‐acylated azlactones afforded C‐acylated azlactones possessing a quaternary stereocenter in high yields (up to 97 % yield) and excellent enantioselectivities (up to 97 % ee). Compared to the widespread use of pyridine nitrogen, which serves as the nucleophilic site in the asymmetric acyl transfer reaction, we discovered that chiral DMAP‐N‐oxides, in which the oxygen now acts as the nucleophilic site, are efficient acyl transfer catalysts. Our finding might open a new door for the development of chiral DMAP‐N‐oxides for asymmetric acyl transfer reactions.
The Effect of β‐Hydrogen Atoms on Iron Speciation in Cross‐Couplings with Simple Iron Salts and Alkyl Grignard Reagents
Authors: Sears Jeffrey D. , Muñoz Salvador B. , Daifuku Stephanie L. , Shaps Ari A. , Carpenter Stephanie H. , Brennessel William W. , Neidig Michael L.
Published: January 2019

The effects of β‐hydrogen‐containing alkyl Grignard reagents in simple ferric salt cross‐couplings have been elucidated. The reaction of FeCl3 with EtMgBr in THF leads to the formation of the cluster species [Fe8Et12]2−, a rare example of a structurally characterized metal complex with bridging ethyl ligands. Analogous reactions in the presence of NMP, a key additive for effective cross‐coupling with simple ferric salts and β‐hydrogen‐containing alkyl nucleophiles, result in the formation of [FeEt3]−. Reactivity studies demonstrate the effectiveness of [FeEt3]− in rapidly and selectively forming the cross‐coupled product upon reaction with electrophiles. The identification of iron‐ate species with EtMgBr analogous to those previously observed with MeMgBr is a critical insight, indicating that analogous iron species can be operative in catalysis for these two classes of alkyl nucleophiles.
A Phase II Trial of Lutikizumab, an Anti–Interleukin‐1α/β Dual Variable Domain Immunoglobulin, in Knee Osteoarthritis Patients With Synovitis
Authors: Fleischmann Roy M. , Bliddal Henning , Blanco Francisco J. , Schnitzer Thomas J. , Peterfy Charles , Chen Su , Wang Li , Feng Sheng , Conaghan Philip G. , Berenbaum Francis , Pelletier Jean‐Pierre , Martel‐Pelletier Johanne , Vaeterlein Ole , Kaeley Gurjit S. , Liu Wei , Kosloski Matthew P. , Levy Gwen , Zhang Lanju , Medema Jeroen K. , Levesque Marc C.
Published: January 2019

Objective

To assess the efficacy and safety of the anti–interleukin‐1α/β (anti–IL‐1α/β) dual variable domain immunoglobulin lutikizumab (ABT‐981) in patients with knee osteoarthritis (OA) and evidence of synovitis.

Methods

Patients (n = 350; 347 analyzed) with Kellgren/Lawrence grade 2–3 knee OA and synovitis (determined by magnetic resonance imaging [MRI] or ultrasound) were randomized to receive placebo or lutikizumab 25, 100, or 200 mg subcutaneously every 2 weeks for 50 weeks. The coprimary end points were change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score at week 16 and change from baseline in MRI‐assessed synovitis at week 26.

Results

The WOMAC pain score at week 16 had improved significantly versus placebo with lutikizumab 100 mg (P = 0.050) but not with the 25 mg or 200 mg doses. Beyond week 16, the WOMAC pain score was reduced in all groups but was not significantly different between lutikizumab‐treated and placebo‐treated patients. Changes from baseline in MRI‐assessed synovitis at week 26 and other key symptom‐ and most structure‐related end points at weeks 26 and 52 were not significantly different between the lutikizumab and placebo groups. Injection site reactions, neutropenia, and discontinuations due to neutropenia were more frequent with lutikizumab versus placebo. Reductions in neutrophil and high‐sensitivity C‐reactive protein levels plateaued with lutikizumab 100 mg, with further reductions not observed with the 200 mg dose. Immunogenic response to lutikizumab did not meaningfully affect systemic lutikizumab concentrations.

Conclusion

The limited improvement in the WOMAC pain score and the lack of synovitis improvement with lutikizumab, together with published results from trials of other IL‐1 inhibitors, suggest that IL‐1 inhibition is not an effective analgesic/antiinflammatory therapy in most patients with knee OA and associated synovitis.
Hypothesis‐driven investigations of diverse pharmacological targets in two mouse models of autism
Authors: Rhine Maya A. , Parrott Jennifer M. , Schultz Maria N. , Kazdoba Tatiana M. , Crawley Jacqueline N.
Published: January 2019

Autism spectrum disorder is a neurodevelopmental syndrome diagnosed primarily by persistent deficits in social interactions and communication, unusual sensory reactivity, motor stereotypies, repetitive behaviors, and restricted interests. No FDA‐approved medical treatments exist for the diagnostic symptoms of autism. Here we interrogate multiple pharmacological targets in two distinct mouse models that incorporate well‐replicated autism‐relevant behavioral phenotypes. Compounds that modify inhibitory or excitatory neurotransmission were selected to address hypotheses based on previously published biological abnormalities in each model. Shank3B is a genetic model of a mutation found in autism and Phelan‐McDermid syndrome, in which deficits in excitatory neurotransmission and synaptic plasticity have been reported. BTBR is an inbred strain model of forms of idiopathic autism in which reduced inhibitory neurotransmission and excessive mTOR signaling have been reported. The GABA‐A receptor agonist gaboxadol significantly reduced repetitive self‐grooming in three independent cohorts of BTBR. The TrkB receptor agonist 7,8‐DHF improved spatial learning in Shank3B mice, and reversed aspects of social deficits in BTBR. CX546, a positive allosteric modulator of the glutamatergic AMPA receptor, and d‐cycloserine, a partial agonist of the glycine site on the glutamatergic NMDA receptor, did not rescue aberrant behaviors in Shank3B mice. The mTOR inhibitor rapamycin did not ameliorate social deficits or repetitive behavior in BTBR mice. Comparison of positive and negative pharmacological outcomes, on multiple phenotypes, evaluated for replicability across independent cohorts, enhances the translational value of mouse models of autism for therapeutic discovery. GABA agonists present opportunities for personalized interventions to treat components of autism spectrum disorder. Autism Res 2019, 12: 401–421 © 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc.

Lay Summary

Many of the risk genes for autism impair synapses, the connections between nerve cells in the brain. A drug that reverses the synaptic effects of a mutation could offer a precision therapy. Combining pharmacological and behavioral therapies could reduce symptoms and improve the quality of life for people with autism. Here we report reductions in repetitive behavior by a GABA‐A receptor agonist, gaboxadol, and improvements in social and cognitive behaviors by a TrkB receptor agonist, in mouse models of autism.
The effects of nifedipine and ivabradine on the functionality of the early rat embryonic heart. Are these drugs a risk in early human pregnancy?
Authors: Ritchie Helen E. , Telenius Carolina , Gustaffson Elin , Webster William S.
Published: January 2019

Background

When the human heart begins its earliest contractions from day 21, it lacks a functional autonomic nerve supply. Instead, contractions are generated by regular calcium transients later augmented by the funny current (If) produced by sinoatrial‐like cells. This study examined effects of blocking these currents in the early rat embryonic heart.

Methods

Rat embryos were incubated in vitro with either the calcium channel blocker nifedipine and/or the funny current (If) blocker ivabradine for 1 hr to examine the effects of these drugs on the activity of the embryonic heart.

Results

On gestational day (GD) 10, nifedipine (0.45–1.8 μM) caused asystole at high concentrations (8/10 embryos at 1.8 μM and 3/10 embryos at 0.9 μM) and markedly increased embryonic heart rate (EHR) in all surviving embryos but likely reduced blood flow due to weak contractions. Ivabradine (1.5 μM) caused a 29% reduction in EHR in GD 10 embryos and a greater than 50% reduction in EHR for GD 11–14 embryos. Combined exposure to both nifedipine and ivabradine resulted in an additive effect. The increased EHR due to nifedipine was reduced by the ivabradine.

Conclusion

The results suggest that exposure to nifedipine in human pregnancy 3–4 weeks postfertilization may cause a direct effect on the embryonic heart resulting in reduced blood flow leading to abnormal heart and/or blood vessel development and/or embryonic death. Accidental exposure to ivabradine in the organogenic period would be expected to cause embryonic bradycardia, hypoxia, malformations, and embryonic death. This drug is currently contraindicated in pregnancy.
Determination of thiacloprid, thiamethoxam and imidacloprid in tea samples by quenching terbium luminescence
Authors: Llorent‐Martínez E.J. , Soler‐Gallardo M.I. , Ruiz‐Medina A.
Published: January 2019

Consumption of herbal teas, infusions and other plant‐related products has always been popular due to the related health benefits. However, the safety of these products needs to be assessed, for example monitoring the potential presence of contaminants such as pesticides. In this paper, we report an analytical method for determining three neonicotinoid insecticides − thiacloprid, thiamethoxam, and imidacloprid − that are widely used worldwide. This method is based on quenching by analytes of the luminescence signal of terbium ions. Terbium presents a time‐resolved luminescence signal at 256/545 nm/nm, which is quenched by the presence of low concentrations of the selected analytes. Detection limits of 0.1, 0.2 or 0.75 μg ml−1 were obtained for thiamethoxam, thiacloprid and imidacloprid, respectively. Recovery experiments in different teas (green tea, black tea, chamomile, peppermint) were performed at concentrations lower than the maximum residue limits established by the European Union and the Codex Alimentarius for tea samples. In all cases, satisfactory recovery yields were observed, and the results were compared with a chromatographic reference method. The proposed method therefore proved suitable for quantifying these insecticides, fulfilling the current legislation.
Mucin‐coating technologies for protection and reduced aggregation of cellular production systems
Authors: Shurer Carolyn R. , Head Shelby E. , Goudge Marc C. , Paszek Matthew J.
Published: January 2019

Optimization of host‐cell production systems with improved yield and production reliability is desired to meet the increasing demand for biologics with complex posttranslational modifications. Aggregation of suspension‐adapted mammalian cells remains a significant problem that can limit the cellular density and per volume yield of bioreactors. Here, we propose a genetically encoded technology that directs the synthesis of antiadhesive and protective coatings on the cellular surface. Inspired by the natural ability of mucin glycoproteins to resist cellular adhesion and hydrate and protect cell and tissue surfaces, we genetically encode new cell‐surface coatings through the fusion of engineered mucin domains to synthetic transmembrane anchors. Combined with appropriate expression systems, the mucin‐coating technology directs the assembly of thick, highly hydrated barriers to strongly mitigate cell aggregation and protect cells in suspension against fluid shear stresses. The coating technology is demonstrated on suspension‐adapted human 293‐F cells, which resist clumping even in media formulations that otherwise would induce extreme cell aggregation and show improved performance over a commercially available anticlumping agent. The stable biopolymer coatings do not show deleterious effects on cell proliferation rate, efficiency of transient transfection with complementary DNAs, or recombinant protein expression. Overall, our mucin‐coating technology and engineered cell lines have the potential to improve the single‐cell growth and viability of suspended cells in bioreactors.
The role of assembly parameters on polyplex poly(beta‐amino ester) nanoparticle transfections
Authors: Wilson David R. , Suprenant Mark P. , Michel John H. , Wang Ellen B. , Tzeng Stephany Y. , Green Jordan J.
Published: January 2019

Intracellular delivery of nucleic acids to mammalian cells using polyplex nanoparticles (NPs) remains a challenge both in vitro and in vivo, with transfections often suffering from variable efficacy. To improve reproducibility and efficacy of transfections in vitro using a next‐generation polyplex transfection material poly(beta‐amino ester)s (PBAEs), the influence of multiple variables in the preparation of these NPs on their transfection efficacy was explored. The results indicate that even though PBAE/pDNA polyplex NPs are formed by the self‐assembly of polyelectrolytes, their transfection is not affected by the manner in which the components are mixed, facilitating self‐assembly in a single step, but timing for self‐assembly of 5–20 min is optimal. In addition, even though the biomaterials are biodegradable in water, their efficacy is not affected by up to eight freeze‐thaw cycles of the polymer. It was found that there is a greater stability of nucleic acid‐complexed polymer as a polyplex nanoparticle compared with free polymer. Finally, by exploring multiple buffer systems, it was identified that utilization of divalent cation magnesium or calcium acetate buffers at pH 5.0 is optimal for transfection using these polymeric materials, boosting transfection several folds compared with monovalent cations. Together, these results can improve the reproducibility and efficacy of PBAE and similar polyplex nanoparticle transfections and improve the robustness of using these biomaterials for bioengineering and biotechnology applications.
Constitutively solvent‐tolerant Pseudomonas taiwanensis VLB120∆C∆ttgV supports particularly high‐styrene epoxidation activities when grown under glucose excess conditions
Authors: Volmer Jan , Lindmeyer Martin , Seipp Julia , Schmid Andreas , Bühler Bruno
Published: January 2019

Solvent‐tolerant bacteria represent an interesting option to deal with the substrate and product toxicity in bioprocesses. Recently, constitutive solvent tolerance was achieved for Pseudomonas taiwanensis VLB120 via knockout of the regulator TtgV, making tedious adaptation unnecessary. Remarkably,
ttgV knockout increased styrene epoxidation activities of
P. taiwanensis VLB120Δ
C. With the aim to characterize and exploit the biocatalytic potential of
P. taiwanensis VLB120Δ
C and VLB120Δ
CΔ
ttgV, we investigated and correlated growth physiology, native styrene monooxygenase (StyAB) gene expression, whole‐cell bioconversion kinetics, and epoxidation performance. Substrate inhibition kinetics was identified but was attenuated in two‐liquid phase bioreactor setups. StyA fusion to the enhanced green fluorescent protein enabled precise enzyme level monitoring without affecting epoxidation activity. Glucose limitation compromised
styAB expression and specific activities (30–40 U/g
CDW for both strains), whereas unlimited batch cultivation enabled specific activities up to 180 U/g
CDW for VLB120Δ
CΔ
ttgV strains, which is unrivaled for bioreactor‐based whole‐cell oxygenase biocatalysis. These extraordinarily high specific activities of constitutively solvent‐tolerant
P. taiwanensis VLB120∆
C∆
ttgV could be attributed to its high metabolic capacity, which also enabled high expression levels. This, together with the high product yields on glucose and biomass obtained qualifies the VLB120∆
ttgV strain as a highly attractive tool for the development of ecoefficient oxyfunctionalization processes and redox biocatalysis in general.
Long-term functional outcomes and quality of life in patients with Hirschsprung's disease
Authors: Meinds R J , van der Steeg A F W , Sloots C E J , Witvliet M J , de Blaauw I , van Gemert W G , Trzpis M , Broens P M A
Published: January 2019

Background

It is unclear whether functional outcomes improve or deteriorate with age following surgery for Hirschsprung's disease. The aim of this cross-sectional study was to determine the long-term functional outcomes and quality of life (QoL) in patients with Hirschsprung's disease.

Methods

Patients with pathologically proven Hirschsprung's disease older than 7 years were included. Patients with a permanent stoma or intellectual disability were excluded. Functional outcomes were assessed according to the Rome IV criteria using the Defaecation and Faecal Continence questionnaire. QoL was assessed by means of the Child Health Questionnaire Child Form 87 or World Health Organization Quality of Life questionnaire 100. Reference data from healthy controls were available for comparison.

Results

Of 619 patients invited, 346 (55·9 per cent) responded, with a median age of 18 (range 8–45) years. The prevalence of constipation was comparable in paediatric and adult patients (both 22·0 per cent), and in patients and controls. Compared with controls, adults with Hirschsprung's disease significantly more often experienced straining (50·3 versus 36·1 per cent; P = 0·011) and incomplete evacuation (47·4 versus 27·2 per cent; P < 0·001). The prevalence of faecal incontinence, most commonly soiling, was lower in adults than children with Hirschsprung's disease (16·8 versus 37·6 per cent; P < 0·001), but remained higher than in controls (16·8 versus 6·1 per cent; P = 0·003). Patients with poor functional outcomes scored significantly lower in several QoL domains.

Conclusion

This study has shown that functional outcomes are better in adults than children, but symptoms of constipation and soiling persist in a substantial group of adults with Hirschsprung's disease. The persistence of defaecation problems is an indication that continuous care is necessary in this specific group of patients.
Study of degradation behavior of besifloxacin, characterization of its degradation products by LC–ESI–QTOF–MS and their in silico toxicity prediction
Authors: Salunke Nishant , Kharkar Prashant S. , Pandita Nancy
Published: January 2019

Knowledge and understanding of the stability profile of a drug is important as it affects its safety and efficacy. In the present work, besifloxacin, a new, fourth‐generation fluoroquinolone antibiotic, was subjected to different forced‐degradation conditions as per International Conference on Harmonization (ICH) guidelines such as hydrolysis (acid, base and neutral), oxidation, thermal and photolysis. The drug degraded under acidic, basic, oxidative and photolytic conditions while it was found to be stable under dry heat and neutral hydrolytic conditions. In total, five degradation products (DPs) were formed under different conditions—DP1 and DP2 (photolysis), DP3 (oxidation), DP4 (acidic), DP3 and DP5 (basic). The chromatographic separation of besifloxacin and its degradation products was achieved on a Sunfire C18 (250 mm × 4.6 mm, 5 μm) column with 0.1% aqueous formic acid–acetonitrile as a mobile phase. The gradient RP‐HPLC method was developed and validated as per ICH guidelines. The degradation products were characterized with the help of LC–ESI–QTOF mass spectrometric studies and the most likely degradation pathway of the drug was proposed. In silico toxicity assessment of the drug and its degradation products was carried out, which indicated that DP3 and DP4 carry a mutagenicity alert.
Development of a rapid HPLC method for quantification of the copper tetramibi tetraflourborate in a kit for preparation of Technetium 99 m Sestamibi Injection
Authors: de Bitencourt Fernanda Gobbi , Petersen Guilherme Oliveira , Garcia Cássia Virginia
Published: January 2019

Radiopharmaceuticals are radioactive compounds that can be used for diagnostic and therapeutic purposes. Technetium (99mTc) Sestamibi is the most commercialized radiopharmaceutical in the world. It includes a coordination complex consisting of the radioisotope 99 m technetium bound to six copper tetramibi tetrafluorborate ligands, and is mainly used to image the myocardium via scintigraphy. As radiopharmaceuticals are regarded as drugs, they are subject to the same regulations; therefore, the objective of this study was to develop a quantification method for the active pharmaceutical ingredient before their complexation with the radioisotope by employing high‐performance liquid chromatography (HPLC) methodology. A simple and efficient method (retention time = 2.5 min) was developed and validated for copper tetramibi tetrafluorborate in the final product using a buffer and organic solvent mixtures (ACN–methanol–ammonium sulfate buffer) and a C18 column. The analytical protocol was fast, taking around 30 min until evaluation of results. The validation parameters were evaluated with satisfactory results: in terms of linearity r > 0.99 (160–240 μg/mL) and no deviation was observed. The RSD of precision was <5%, and an average recovery of 99% was observed for accuracy. The proposed method was thus considered adequate for routine analysis in the pharmaceutical industries.
Long noncoding RNA DNAJC3‐AS1 promotes osteosarcoma progression via its sense‐cognate gene DNAJC3
Authors: Liang Ridong , Liu Zezheng , Chen Zhixu , Yang Yang , Li Yuejun , Cui Zhifei , Chen Ajuan , Long Zhenxue , Chen Jinbin , Lu Jiachun , Huang Bin , Li Qingchu
Published: January 2019

Long noncoding RNAs have been proved to play essential roles in tumor development and progression. In this study, we focused on DNAJC3‐AS1 and investigated its biological function and clinical significance in osteosarcoma. We detected the expression of DNAJC3‐AS1 in 30 pairs of matched osteosarcoma and adjacent nontumorous specimens and osteosarcoma cell lines and analyzed association between DNAJC3‐AS1 levels and clinicopathological factors. We found that DNAJC3‐AS1 expression was up‐regulated in osteosarcoma. High level of DNAJC3‐AS1 was correlated with high differentiated degree (P = 0.018) and advanced Enneking stage (P = 0.016). Mechanistically, DNAJC3‐AS1 enhanced cell proliferation, migration, and invasion in vitro and in vivo and reduced sensitivity of osteosarcoma to cisplatin. These effects of DNAJC3‐AS1 were reversed by down‐regulation of its sense‐cognate gene DNAJC3. Thus, DNAJC3‐AS1 promotes osteosarcoma development and progression by regulating DNAJC3 and might be a biomarker and therapeutic target for osteosarcoma.
Quinazolin‐4(3H)‐one‐Based Hydroxamic Acids: Design, Synthesis and Evaluation of Histone Deacetylase Inhibitory Effects and Cytotoxicity
Authors: Hieu Doan Thanh , Anh Duong Tien , Hai Pham‐The , Thuan Nguyen Thi , Huong Le‐Thi‐Thu , Park Eun Jae , Young Ji A. , Soon Kang Jong , Phuong Dung Phan Thi , Han Sang‐Bae , Nam Nguyen‐Hai
Published: January 2019

The present article describes the synthesis and biological activity of various series of novel hydroxamic acids incorporating quinazolin‐4(3H)‐ones as novel small molecules targeting histone deacetylases. Biological evaluation showed that these hydroxamic acids were potently cytotoxic against three human cancer cell lines (SW620, colon; PC‐3, prostate; NCI−H23, lung). Most compounds displayed superior cytotoxicity than SAHA (suberoylanilide hydroxamic acid, Vorinostat) in term of cytotoxicity. Especially, N‐hydroxy‐7‐(7‐methyl‐4‐oxoquinazolin‐3(4H)‐yl)heptanamide (5b) and N‐hydroxy‐7‐(6‐methyl‐4‐oxoquinazolin‐3(4H)‐yl)heptanamide (5c) (IC50 values, 0.10–0.16 μm) were found to be approximately 30‐fold more cytotoxic than SAHA (IC50 values of 3.29–3.67 μm). N‐Hydroxy‐7‐(4‐oxoquinazolin‐3(4H)‐yl)heptanamide (5a; IC50 values of 0.21–0.38 μm) was approximately 10‐ to 15‐fold more potent than SAHA in cytotoxicity assay. These compounds also showed comparable HDAC inhibition potency with IC50 values in sub‐micromolar ranges. Molecular docking experiments indicated that most compounds, as represented by 5b and 5c, strictly bound to HDAC2 at the active binding site with binding affinities much higher than that of SAHA.
Bivalirudin with a post‐procedure infusion versus heparin monotherapy for the prevention of stent thrombosis
Authors: Shah Rahman , Latham Samuel B. , Porta Jennifer M. , Naz Arshi , Matin Khalid , Rao Sunil V.
Published: January 2019

Objectives

To evaluate the efficacy of post‐primary percutaneous coronary intervention (PCI) bivalirudin infusion (at full PCI dose) to prevent stent thrombosis (ST) compared with heparin monotherapy.

Background

Early randomized controlled trials (RCTs) have shown that compared with heparin use, bivalirudin use during primary PCI is associated with an increased risk of ST. However, bivalirudin was stopped in those trials at the end of the procedure and glycoprotein IIb/IIIa inhibitors (GPIs) were routinely used with heparin. The increased risk of ST may be eliminated by continuing bivalirudin infusion post‐procedure for few hours. Indeed, in most recent trials, a trend of lower ST risk has been observed with a post‐procedure infusion of bivalirudin compared with heparin monotherapy (without the routine use of GPI).

Methods

Relevant RCTs were included and risk ratios (RRs) were calculated using random effect models. The primary outcome of interest was the risk of early definite ST.

Results

Four RCTs involving 13,505 patients were included in this meta‐analysis. Compared with heparin monotherapy, bivalirudin (with a post‐procedure infusion) was associated with a 55% decrease in the risk of early definite ST (RR: 0.45, 95% confidence interval: 0.23–0.85; P = 0.015). There was no difference in the risk of early ST between bivalirudin (with a post‐procedure infusion) and heparin with GPI.

Conclusions

For primary PCI, a bivalirudin‐based anticoagulant strategy (with post procedure infusion) is associated with a lower risk of early definite ST compared with treatment with heparin monotherapy (without GPI).
Predictors of clinical outcomes after coronary implantation of bioresorbable polymer sirolimus‐eluting Ultimaster stents in all‐comers: A report of 1,727 cases
Authors: Tadano Yutaka , Kotani Jun‐ichi , Kashima Yoshifumi , Hachinohe Daisuke , Watanabe Tomohiko , Sugie Takuro , Kaneko Umihiko , Kobayashi Ken , Kanno Daitaro , Fujita Tsutomu
Published: January 2019

Background

Although bioresorbable polymer sirolimus‐eluting Ultimaster stents (BP‐SESs) are likely useful for percutaneous coronary interventions (PCIs), the clinical data from real‐world cases are insufficient. Furthermore, the predictors of adverse clinical outcomes after BP‐SES implantation have not been fully investigated.

Objectives

This study evaluated the 1‐year clinical outcomes after BP‐SES implantation in real‐world PCI cases and identified the predictors of adverse outcomes.

Methods

In this single‐center, all‐comers study, we consecutively implanted BP‐SESs in all patients who required coronary stents between October 2015 and August 2016. We conducted a clinical follow‐up assessment of these patients.

Results

The sample comprised 1,727 patients; 67% were men, the mean age was 72 years, and 37% had diabetes. Of the 2,085 lesions detected, 88% were type B2/C lesions, 4% were chronic total occlusions (CTOs), and 23% were bifurcations. The cumulative incidences of target lesion revascularization (TLR) and target lesion failure (TLF) at 1‐year were 2.4% and 5.2%, respectively. A multivariate analysis revealed that hemodialysis (HD) (hazard ratio [HR] 8.40) and CTO (HR 4.21) were independent predictors of TLR. Stent sizes ≤2.5 mm were not associated with either TLR or TLF.

Conclusions

The current study indicates that patients on HD and those with CTO were more likely to experience adverse clinical outcomes after BP‐SES implantation. In contrast, small vessel diameter was not significantly related to adverse outcomes. The 1‐year clinical outcomes after BP‐SES implantation were found to be favorable among all‐comer PCI cases, including patients receiving HD and those with in‐stent restenosis.
Enantioselective Addition of Alkynyl Ketones to Nitroolefins Assisted by Brønsted Base/H‐Bonding Catalysis
Authors: Campano Teresa E. , Iriarte Igor , Olaizola Olatz , Etxabe Julen , Mielgo Antonia , Ganboa Iñaki , Odriozola José M. , García Jesús M. , Oiarbide Mikel , Palomo Claudio
Published: January 2019

Various sets of enolizable alkynyl ketones (including methyl ynones with α‐aryl, α‐alkenyl, and α‐alkoxy groups) were able to react smoothly with nitroolefins with the assistance of bifunctional Brønsted base/H‐bond catalysts to provide adducts with two consecutive tertiary stereocenters in a highly diastereo‐ and enantioselective fashion. Further transformation of the obtained adducts into optically active acyclic and polycyclic molecules, including some with intricate carbon skeletons, was also demonstrated.
Amphiphilicity Regulation of AgI Nanoclusters: Self‐Assembly and Its Application as a Luminescent Probe
Authors: Shen Jinglin , Wang Zhi , Xia Congxin , Sun Di , Yuan Shiling , Xin Xia
Published: January 2019

Research on the self‐assembly of various amphiphilic molecules is a relatively new research area and of great significance. However, new kinds of metal‐nanocluster (NC)‐based amphiphilic molecule have rarely been explored. Herein, hydrophobic cation 1‐hexadecyl‐3‐methylimidazolium (C16mim+) was chosen to modify hydrophilic (NH4)6[Ag6(mna)6] (Ag6‐NCs, H2mna=2‐mercaptonicotinic acid) and Ag6@C16mim‐NCs were obtained. Ag6@C16mim‐NCs displayed thermotropic liquid crystal and thermofluorescent properties. Moreover, the Ag6@C16mim‐NCs exhibits benign amphiphilicity, and it can self‐assemble into ordered nanosheets and nanorods through aggregation in water/dimethyl sulfoxide (DMSO) binary solvent mixtures, whereas single Ag6‐NCs do not. Meanwhile, the Ag6@C16mim‐NCs also displays aggregation‐induced emission properties owing to the restriction of intramolecular vibrations of the capping ligands. Furthermore, the luminescent aggregates could detect arginine selectively with the detection limit at 28 μm. This study introduces a new kind of metal‐NC‐based amphiphilic molecule in a supramolecular self‐assembly field, and they have potential to be used as optical materials in applied research.
Tailoring Covalent Organic Frameworks To Capture Water Contaminants
Authors: Fernandes Soraia P. S. , Romero Vanesa , Espiña Begoña , Salonen Laura M.
Published: January 2019

Covalent organic frameworks (COFs) are attractive materials receiving increasing interest in the literature due to their crystallinity, large surface area, and pore uniformity. Their properties can be tailored towards specific applications by judicious design of COF building blocks, giving access to tailor‐made pore sizes and surfaces. In this Concept article, developments in the field of COFs that have allowed these materials to be explored for contaminant adsorption are discussed. Strategies to obtain water‐stable materials with highly ordered structures and large surface areas are reviewed. Post‐synthetic modification approaches, by which pore surfaces can be tuned to target specific contaminants, are described. Recent advances in COF formulations, crucial for future implementation in adsorption devices, are highlighted. At the end, future challenges which need to be addressed to allow for the deployment of COFs for the capture of water contaminants will be discussed.
N‐Heterocyclic Carbene Catalyzed Synthesis of Dihydroxybenzophenones from β‐Methylenals and Aurones
Authors: Chen Kun‐Quan , Luo Zhi , Gao Zhong‐Hua , Ye Song
Published: January 2019

N‐heterocyclic carbene catalyzed synthesis of 2,2′‐dihydroxybenzophenones from β‐methylenals and aurones was developed. The cleavage of the C−O bond by a retro‐Michael addition is the key step from the spirocyclic intermediate to final product.
Chiral porphyrin imine manganese complex as catalyst for asymmetric epoxidation of styrene derivatives
Authors: Ananthi Nallamuthu , Enoch I.V. Muthu Vijayan
Published: January 2019

New chiral porphyrin imine was synthesized from (S)‐3‐benzyl‐2‐methyl‐4‐phenylbutanal according to dipyrromethane method using trifluoroacetic acid, BF3 etherate, and p‐chloranil. Manganese complex of this chiral porphyrin imine ligand was used as catalyst in the asymmetric epoxidation of styrene derivatives possessing different substituents. Styrene derivatives possessing electron withdrawing groups gave the corresponding chiral epoxides in high yield up to 98% and ee up to 99%. The mechanism for the catalytic asymmetric epoxidation was also discussed based on transfer of oxygen.
Catheter ablation of atrial fibrillation—A key role in heart failure therapy?
Authors: Tose Costa Paiva Beatriz , Fischer Thomas H. , Brachmann Johannes , Busch Sonia
Published: January 2019

Atrial fibrillation (AF) and heart failure (HF) are epidemic cardiac diseases and are often detected in the same patient. Recent evidence suggests that this is not a mere coincidence but that the strategy of AF treatment may impact HF development. This review comprehensively summarizes current trial data on rhythm and rate control strategies in atrial fibrillation with a special focus on catheter ablation of AF in HF patients. For a long time, rate and rhythm control strategies for AF have been regarded as equal regarding long term mortality. Decision making has been based on the symptoms of patients. Current trials, however, show that the treatment strategy of AF and its effectiveness may significantly impact survival of HF patients. The benefits of rhythm control in HF patients may have been masked by side effects of antiarrhythmic drugs. If rhythm control, however, is achieved by catheter ablation, a reduction of HF related mortality can be observed. As catheter ablation of AF may reduce mortality in HF patients, AF ablation should be preferred over medical treatment in HF patients. In general, HF patients may profit most from rigorous AF treatment.
Association of obesity phenotypes with electrocardiographic subclinical myocardial injury in the general population
Authors: Vasim Izzah , Ahmad Muhammad I. , Mongraw‐Chaffin Morgana , Soliman Elsayed Z.
Published: January 2019

Background

As the debate continues about whether obesity in metabolically healthy individuals is associated with poor outcomes or not, investigating the association between the obesity phenotypes and markers of subclinical myocardial injury will help identify those at risk for future cardiovascular events (cardiovascular disease [CVD]).

Hypothesis

We hypothesize that obesity phenotypes including metabolically healthy obesity (MHO) is associated with subclinical myocardial injury (SC‐MI).

Methods

This analysis included 3423 participants (57.85 ± 13.06 years, 53.3% women) without known CVD from National Health and Nutrition Examination Survey (NHANES) III. Multivariable logistic regression models were used to examine the cross‐sectional association between four obesity phenotypes (metabolically healthy nonobese (MHNO) [reference], metabolically unhealthy nonobese (MUNO), MHO, and metabolically unhealthy obese (MUO) with SC‐MI. SC‐MI was defined from the 12‐lead electrocardiogram as cardiac infarction/injury score ≥ 10 units. Metabolic syndrome (MetS) was defined according to the International Diabetes Federation consensus definition. Obesity was defined as body mass index ≥30 kg/m2.

Results

MUO was associated with higher odds of SC‐MI compared with MHNO (odds ratio [OR], 1.53; 95% confidence interval [CI], 1.22‐1.92, P = 0.0005). This association was stronger in men vs women (OR [95% CI]: 2.20 [1.58‐2.07] vs 1.08 [0.79‐1.48]), respectively; interaction P‐value = 0.002) but was consistent in subgroups stratified by age and race. There was no significant association of MHO or MUNO with SC‐MI compared with MHNO, but there was a trend toward higher odds of SC‐MI in the MUNO group (P‐value for trend across MHNO, MUNO, and MUO = 0.0002).

Conclusions

Our findings suggest that a combination of obesity and MetS confers worse prognosis and early preventive strategies aimed at weight loss and management of MetS components may decrease the risk of future poor outcomes.
Comparisons of efficacy, safety, and recurrence risk factors of paroxysmal and persistent atrial fibrillation catheter ablation using robotic magnetic navigation system
Authors: Zhao Xiao‐Xi , Li Ku‐Lin , Wang Ru‐Xing , Zheng Jie , Liu Xiao‐Yu , Dang Shi‐Peng , Yu Zhi‐Ming , Zhang Chang‐Ying , Yang Xiang‐Jun
Published: January 2019

Background

No data exist on comparisons of efficacy, safety, and recurrence risk factors of paroxysmal and persistent atrial fibrillation (AF) ablation using robotic magnetic navigation system (MNS), respectively.

Methods

About 151 AF patients were prospectively enrolled and divided into paroxysmal AF group (n = 102) and persistent AF group (n = 49). Circumferential pulmonary vein antrum isolation (CPVI) was performed in all patients. Linear ablation at the left atrial roof and mitral isthmus was performed in patients with persistent AF in addition to CPVI. The procedural time, X‐ray exposure time, acute and long‐term success rates of CPVI, and procedure‐related complications were analyzed. The AF recurrence rates in the two groups were compared during 1 year, and Cox regression was used to analyze the recurrence risk factors.

Results

The acute success rates of CPVI in the two groups were 98.04% and 97.96%, respectively. There were no significant differences in the procedural time, X‐ray exposure time, and ablation time between the two groups (P > 0.05). No serious complications appeared in either group. The AF ablation success rates were 70.6% and 57.1% for the paroxysmal and persistent groups respectively at 12‐month follow‐up (P = 0.102). AF duration and coronary heart disease prior to ablation were associated with the higher AF recurrence in patients with persistent AF.

Conclusion

Ablation using MNS is effective and safe both in patients with paroxysmal and persistent AF. AF duration and coronary heart disease prior to ablation are two independent risk factors of AF recurrence in patients with persistent AF postoperatively.