bluuebunny/crossref_metadata_2025_split huggingface dataset:
Progress in Difluoroalkylation of Organic Substrates by Visible Light Photoredox Catalysis
Authors: Lemos Agostinho , Lemaire Christian , Luxen André 
Published: January 2019

AbstractThe 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.magnified image
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

BackgroundThe 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).MethodsThe 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.ResultsThere 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.ConclusionThe 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

AbstractA 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

AbstractThe 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

ObjectiveTo 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.MethodsPatients (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.ResultsThe 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.ConclusionThe 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 SummaryMany 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

BackgroundWhen 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.MethodsRat 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.ResultsOn 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.ConclusionThe 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

AbstractConsumption 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

AbstractOptimization 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

AbstractIntracellular 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

AbstractSolvent‐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

AbstractBackgroundIt 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.MethodsPatients 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.ResultsOf 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 &lt; 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 &lt; 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.ConclusionThis 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

AbstractKnowledge 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.