bluuebunny/crossref_metadata_2025_split huggingface dataset:
Attention Deficit Hyperactivity Disorder Symptoms in Young Children with Autism Spectrum Disorder
Authors: Hong Ji S. , Singh Vini , Kalb Luke 
Published: October 2020

The purpose of the current study was to examine the prevalence of attention deficit hyperactivity disorder (ADHD) symptoms among young children with autism spectrum disorder (ASD), child and parent‐related demographic and clinical correlates of ADHD symptoms, and the relationships between co‐occurring mental health problems and ADHD symptoms. Data for this cross‐sectional study came from 979 toddlers and preschoolers, ages 1.5–5 years, with ASD. The primary outcome, ADHD symptoms, was measured using the Child Behavior Check List 1.5‐5 (CBCL). Additional information from the medical record included demographics, parenting stress, and Autism Diagnostic Observation Schedule Second Edition. Descriptive and bivariate (ANOVA, Chi‐Square) statistics and multivariate, multinomial regression analyses were used to examine demographic and clinical differences between low, moderate, and high ADHD symptom groups, as defined by 2 ADHD‐related subscales. There were 418 (43%) children in the low ADHD symptom group, 294 (30%) in the moderate ADHD symptom group, and 267 (27%) in the high ADHD symptom group. Those with high ADHD symptoms were less likely to be Black or Hispanic and less likely to have parents with a graduate‐level education compared to those with low ADHD symptoms. Parenting stress and all CBCL DSM‐oriented subscales were positively associated with increasing ADHD symptoms. Among young children with ASD, ADHD symptoms were highly prevalent. The presence of ADHD symptoms was associated with increasing parenting stress and greater levels of other psychopathologies. These data suggest that young children with ASD should be evaluated for ADHD, and mental health as a whole.Lay SummaryWe investigated attention deficit hyperactivity disorder (ADHD) symptoms in toddlers and preschoolers with autism spectrum disorder (ASD) from a large sample with diverse race and socioeconomic background. In our study, we found that ADHD symptoms are highly prevalent in young children with ASD and are associated with increasing parenting stress and greater level of other psychopathologies, both internalizing and externalizing problems.
Homologous Recombination Offers Advantages over Transposition‐Based Systems to Generate Recombinant Baculovirus for Adeno‐Associated Viral Vector Production
Authors: Jacob Aurélien , Brun Laurie , Jiménez Gil Paloma , Ménard Lucie , Bouzelha Mohammed , Broucque Frédéric , Roblin Aline , Vandenberghe Luk H. , Adjali Oumeya , Robin Cécile , François Achille , Blouin Véronique , Penaud‐Budloo Magalie , Ayuso Eduard 
Published: October 2020

AbstractViral vectors have a great potential for gene delivery, but manufacturing is a big challenge for the industry. The baculovirus‐insect cell is one of the most scalable platforms to produce recombinant adeno‐associated virus (rAAV) vectors. The standard procedure to generate recombinant baculovirus is based on Tn7 transposition which is time‐consuming and suffers technical constraints. Moreover, baculoviral sequences adjacent to the AAV ITRs are preferentially encapsidated into the rAAV vector particles. This observation raises concerns about safety due to the presence of bacterial and antibiotic resistance coding sequences with a Tn7‐mediated system for the construction of baculoviruses reagents. Here, a faster and safer method based on homologous recombination (HR) is investigated. First, the functionality of the inserted cassette and the absence of undesirable genes into HR‐derived baculoviral genomes are confirmed. Strikingly, it is found that the exogenous cassette showed increased stability over passages when using the HR system. Finally, both materials generated high rAAV vector genome titers, with the advantage of the HR system being exempted from undesirable bacterial genes which provides an additional level of safety for its manufacturing. Overall, this study highlights the importance of the upstream process and starting biologic materials to generate safer rAAV biotherapeutic products.
Identification two key residues at the intersection of domains of a thioether monooxygenase for improving its sulfoxidation performance
Authors: Ren Shi‐Miao , Liu Feng , Wu Yin‐Qi , Chen Qi , Zhang Zhi‐jun , Yu Hui‐Lei , Xu Jian‐He 
Published: October 2020

AbstractAcCHMO, a cyclohexanone monooxygenase from Acinetobacter calcoaceticus, is a typical Type I Baeyer–Villiger monooxygenase (BVMO). We previously obtained the AcCHMOM6 mutant, which oxidizes omeprazole sulfide (OPS) to the chiral sulfoxide drug esomeprazole. To further improve the catalytic efficiency of the AcCHMOM6 mutant, a focused mutagenesis strategy was adopted at the intersections of the FAD‐binding domain, NADPH‐binding domain, and α‐helical domain based on structural characteristics of AcCHMO. By using focused mutagenesis and subsequent global evolution two key residues (L55 and P497) at the intersections of the domains were identified. Mutant of L55Y improved catalytic efficiency significantly, whereas the P497S mutant alleviated substrate inhibition remarkably. AcCHMOM7 (L55Y/P497S) was obtained by combining the two mutations, which increased the specific activity from 18.5 (M6) to 108 U/g, and an increase in the Ki of the substrate OPS from 34 to 265 μM. The results indicate that catalytic performance can be elevated by modification of the sensitive sites at the intersection of the domains of AcCHMO. The results also provided some insights for the engineering of other Type I BVMOs or other multidomain proteins.
Pharmacokinetics and metabolism of LNP023 in rats by liquid chromatography combined with electrospray ionization–tandem mass spectrometry
Authors: Jiang Xianglan , Pan Rongrong 
Published: October 2020

AbstractIn this study, a simple and sensitive LC–tandem mass spectrometric method was developed and validated for the determination of LNP023 in rat plasma. The plasma sample was precipitated with acetonitrile and then separated on an ACQUITY HSS T3 column (50 mm × 2.1 mm, 1.8 μm) using 0.1% formic acid in water and acetonitrile as the mobile phase. The MS detection was performed in positive multiple‐reaction monitoring mode with precursor‐to‐product ion transitions of m/z 423.3 → 174.1 and m/z 435.3 → 367.1 for LNP023 and olaparib (internal standard), respectively. The developed assay was validated in the linear range of 0.1–1000 ng/mL with correlation coefficient (r) greater than 0.9992. The validation parameters were all within the acceptable limits. The validated method has been successfully used to investigate the pharmacokinetics of LNP023 in rat plasma, and our results indicated that LNP023 showed low clearance and high bioavailability (62.2%). Furthermore, four minor metabolites from rat plasma were detected and identified by LC combined with high‐resolution mass spectrometry. The metabolic pathways were O‐deethylation (M1), hydroxylation (M4), oxidation (M3), and acyl‐glucuronidation (M2).
Association study between genetic variants in retinol metabolism pathway genes and prostate cancer risk
Authors: Cao Dongliang , Meng Yixuan , Li Shuwei , Xin Junyi , Ben Shuai , Cheng Yifei , Wang Meilin , Hua Lixin , Cheng Gong 
Published: October 2020

AbstractBackgroundEvidence suggests that serum retinol level is associated with prostate cancer risk, but the association between genetic variants in the retinol metabolism pathway genes and prostate cancer risk remains unclarified.MethodsSingle‐nucleotide polymorphisms (SNPs) in 31 genes in the retinol metabolism pathway were genotyped to evaluate the association with prostate cancer risk in 4,662 cases and 3,114 controls from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. The gene expression analysis was evaluated using data from the Gene Expression Omnibus (GEO) datasets and the Cancer Genome Atlas (TCGA) database. Data from the Genotype‐Tissue Expression (GTEx) project dataset were utilized to perform the expression quantitative trait loci (eQTL) analysis.ResultsTwo SNPs were significantly associated with prostate cancer risk [rs1330286 in ALDH1A1: odds ratio (OR) = 0.88, 95% confidence interval (CI) = 0.83‐0.94, p = 2.45 × 10−4; rs4646653 in ALDH1A3: OR = 1.17, 95% CI =1.07‐1.27, p = 4.33 × 10−4]. Moreover, the mRNA level of ALDH1A3 was significantly higher in prostate cancer tissues than in normal tissues in both TCGA datasets and GEO datasets (p = 1.63 × 10−12 and p = 4.33 × 10−2, respectively). rs1330286 was an eQTL of ALDH1A1 (P = 2.90 × 10−3).ConclusionOur findings highlight that genetic variants in retinol metabolism pathway genes are associated with prostate cancer risk.
Effect of Transition Metals on the Oxygen Reduction Reaction Activity at Metal‐N3/C Active Sites
Authors: Fruehwald Holly M. , Ebralidze Iraklii I. , Zenkina Olena V. , Easton E. Bradley 
Published: October 2020

AbstractThe roles of various transition and post‐transition metals in model non‐precious‐metal catalysts for the oxygen reduction reaction (ORR) are reported after being prepared via a molecularly defined terpyridine unit covalently attached to a carbon black support. We previously reported the use of a terpyridine‐modified iron‐based catalyst that allowed for the controlled deposition of highly active nitrogen functionalities on the carbon support, which adopts a Fe−N3/C active site formation. In this work, we expand on this idea by altering the metal center in the predefined active sites M−N3/C and compare the ORR reactivity of the isostructural set of catalysts, where M=Fe, Co, Ni, Mn, and Sn. The results show that the iron‐based material was the most active catalyst in acid, whereas the cobalt‐based catalyst was most active in base. In addition, nickel‐ and manganese‐based materials showed promising activity for the ORR in both acidic and basic media. We demonstrate that, with a suitable templating bis‐chelating nitrogenous ligand, the M−N3/C active site geometry is adopted with a wide range of non‐precious‐metal centers on a Vulcan carbon surface, and the resulting catalysts are ORR active in a range of conditions, further confirming the tunability and versatility of the N3 site. As expected, post‐transition metals, such as tin, do not coordinate to the N3 nitrogenous ligand under synthetic conditions and deposits tin oxides(s). This study confirms the generality of the phenomenon of M−N3/C as an ORR catalytic site.
Generation of Oxidoreductases with Dual Alcohol Dehydrogenase and Amine Dehydrogenase Activity
Authors: Tseliou Vasilis , Schilder Don , Masman Marcelo F. , Knaus Tanja , Mutti Francesco G. 
Published: October 2020

AbstractThe l‐lysine‐ϵ‐dehydrogenase (LysEDH) from Geobacillus stearothermophilus naturally catalyzes the oxidative deamination of the ϵ‐amino group of l‐lysine. We previously engineered this enzyme to create amine dehydrogenase (AmDH) variants that possess a new hydrophobic cavity in their active site such that aromatic ketones can bind and be converted into α‐chiral amines with excellent enantioselectivity. We also recently observed that LysEDH was capable of reducing aromatic aldehydes into primary alcohols. Herein, we harnessed the promiscuous alcohol dehydrogenase (ADH) activity of LysEDH to create new variants that exhibited enhanced catalytic activity for the reduction of substituted benzaldehydes and arylaliphatic aldehydes to primary alcohols. Notably, these novel engineered dehydrogenases also catalyzed the reductive amination of a variety of aldehydes and ketones with excellent enantioselectivity, thus exhibiting a dual AmDH/ADH activity. We envisioned that the catalytic bi‐functionality of these enzymes could be applied for the direct conversion of alcohols into amines. As a proof‐of‐principle, we performed an unprecedented one‐pot “hydrogen‐borrowing” cascade to convert benzyl alcohol to benzylamine using a single enzyme. Conducting the same biocatalytic cascade in the presence of cofactor recycling enzymes (i.e., NADH‐oxidase and formate dehydrogenase) increased the reaction yields. In summary, this work provides the first examples of enzymes showing “alcohol aminase” activity.
Structural Transformations and Spin‐Crossover in [FeL2]2+ Salts (L=4‐{tert‐Butylsulfanyl}‐2,6‐di{pyrazol‐1‐yl}pyridine): The Influence of Bulky Ligand Substituents
Authors: Kulmaczewski Rafal , Bamiduro Faith , Shahid Namrah , Cespedes Oscar , Halcrow Malcolm A. 
Published: October 2020

Abstract4‐(tert‐Butylsulfanyl)‐2,6‐di(pyrazol‐1‐yl)pyridine (L) was obtained in low yield from a one‐pot reaction of 2,4,6‐trifluoropyridine with 2‐methylpropane‐2‐thiolate and sodium pyrazolate in a 1:1:2 ratio. The materials [FeL2][BF4]2⋅solv (1[BF4]2⋅solv) and [FeL2][ClO4]2⋅solv (1[ClO4]2⋅solv; solv=MeNO2, MeCN or Me2CO) exhibit a variety of structures and spin‐state behaviors including thermal spin‐crossover (SCO). Solvent loss on heating 1[BF4]2⋅x MeNO2 (x≈2.3) occurs in two steps. The intermediate phase exhibits hysteretic SCO around 250 K, involving a “reverse‐SCO” step in its warming cycle at a scan rate of 5 K min−1. The reverse‐SCO is not observed in a slower 1 K min−1 measurement, however, confirming its kinetic nature. The final product [FeL2][BF4]2⋅0.75 MeNO2 was crystallographically characterized, and shows abrupt but incomplete SCO at 172 K which correlates with disorder of an L ligand. The asymmetric unit of 1[BF4]2⋅y Me2CO (y≈1.6) contains five unique complex molecules, four of which undergo gradual SCO in at least two discrete steps. Low‐spin 1[ClO4]2⋅0.5 Me2CO is not isostructural with its BF4− congener, and undergoes single‐crystal‐to‐single‐crystal solvent loss with a tripling of the crystallographic unit cell volume, while retaining the P
space group. Three other solvate salts undergo gradual thermal SCO. Two of these are isomorphous at room temperature, but transform to different low‐temperature phases when the materials are fully low‐spin.
Pnictogen‐Functionalised C1 Ligands: MC‐ARn (n=0, 1, 2, 3)
Authors: Colebatch Annie L. , Frogley Benjamin J. , Hill Anthony F. , Onn Chee S. 
Published: October 2020

AbstractThe chemistry of transition metal carbynes, LnM≡CR, has historically been dominated by species bearing hydrocarbyl or amino ‘R’ substituents, with other elements appearing only sporadically. In recent years, carbynes and related ‘C1’ species bearing other main‐group substituents, particularly heavier elements of the p‐block, have begun to emerge. This review details the chemistry of heavier pnictogen‐functionalised C1 ligands, MCARn (A=P, As, Sb, Bi; n=0–3), including their syntheses, properties and reactivities, and how these are distinguished from more traditional carbyne complexes. Recent developments in the closely related phospha‐isonitrile LnM(CPR), cya‐phosphide and cya‐arside ligands, LnM(C≡A) (A=P, As), are also discussed.
Ablation of paroxysmal and persistent atrial fibrillation in the very elderly real‐world data on safety and efficacy
Authors: Willy Kevin , Wasmer Kristina , Dechering Dirk G. , Köbe Julia , Lange Philipp S. , Bögeholz Nils , Ellermann Christian , Reinke Florian , Frommeyer Gerrit , Eckardt Lars 
Published: October 2020

AbstractBackgroundThe role and technique of catheter ablation of atrial fibrillation (AF) in the elderly is unclear. While in young patients pulmonary vein isolation (PVI) has evolved as first option, in older patients decision is often made in favor of drugs as higher complication rates and less benefit are suspected. Therefore, data on PVI of paroxysmal and persistent AF in these patients is still sparse but of eminent importance.HypothesisPVI is comparably safe in the very elderly with similar recurrence and complication rates.MethodsWe enrolled all patients (n = 146) aged >75 years who underwent a first PVI over a period of 10 years (2009‐2019) from our prospective single‐center ablation registry. Mean follow‐up time was 231 ± 399 days.ResultsAcute ablation success defined as complete PVI and sinus rhythm at the end of the ablation procedure was high (99%). Severe periprocedural complications occurred in 3.3% (stroke/TIA n = 2; 1.3%; pericardial effusion n = 3; 2%). In 4.6% of patients symptomatic sick‐sinus‐syndrome was unmasked after PVI resulting in pacemaker implantation. There were no deaths related to PVI. Recurrence rate of symptomatic AF was 37.3% resulting in a Re‐PVI and/or substrate ablation in 32 pts (20.9%). During follow‐up pacemaker implantation plus atrioventricular node ablation was performed in 10 pts (6.8%). There was a trend toward lower recurrence rates with single‐shot devices (cryoballoon, multielectrode phased‐radiofrequency ablation catheter) than with point‐by‐point radiofrequency while complication rates did not differ.ConclusionPVI for AF is a feasible treatment option also in patients >75 years with a reasonable success and safety profile. Higher success rates occurred in patients treated with a single‐shot device as compared to point‐by‐point ablation.
Implantable Optofluidic Systems for Wireless In Vivo Photopharmacology
Authors: Qazi Raza , Yeon Kim Choong , Kang Inho , Binazarov Dauren , McCall Jordan G. , Jeong Jae‐Woong 
Published: October 2020

AbstractPhotopharmacology, which uses chemical photoswitches for the optical manipulation of biological process, holds immense potential for neuroscience and clinical medicine due to its high specificity, fast response, and versatility. However, enabling photopharmacology in living subjects has been an arduous undertaking mainly because of limitations of the available tools. Conventional approaches to drug delivery and photostimulation involve the use of bulky, rigid, and tethered implants in the form of metal cannulas and optical fibers. These prevent highly precise, spatially matching stimulation with drugs and light, aggravates adverse tissue responses, and causes undue stress in the freely‐moving subject. Recent advances in materials science and device engineering have led to the development of miniaturized, standalone multimodal implants referred to as “optofluidic” devices, which allow wireless delivery of both light and drugs. Herein, we review state‐of‐the‐art wireless optofluidic systems, which can open up new horizons for in vivo photopharmacology, and discuss future directions for further technology developments.
Catalytic, Kinetic, and Mechanistic Insights into the Fixation of CO2 with Epoxides Catalyzed by Phenol‐Functionalized Phosphonium Salts
Authors: Hu Yuya , Wei Zhihong , Frey Anna , Kubis Christoph , Ren Chang‐Yue , Spannenberg Anke , Jiao Haijun , Werner Thomas 
Published: October 2020

AbstractA series of hydroxy‐functionalized phosphonium salts were studied as bifunctional catalysts for the conversion of CO2 with epoxides under mild and solvent‐free conditions. The reaction in the presence of a phenol‐based phosphonium iodide proceeded via a first order rection kinetic with respect to the substrate. Notably, in contrast to the aliphatic analogue, the phenol‐based catalyst showed no product inhibition. The temperature dependence of the reaction rate was investigated, and the activation energy for the model reaction was determined from an Arrhenius‐plot (Ea=39.6 kJ mol−1). The substrate scope was also evaluated. Under the optimized reaction conditions, 20 terminal epoxides were converted at room temperature to the corresponding cyclic carbonates, which were isolated in yields up to 99 %. The reaction is easily scalable and was performed on a scale up to 50 g substrate. Moreover, this method was applied in the synthesis of the antitussive agent dropropizine starting from epichlorohydrin and phenylpiperazine. Furthermore, DFT calculations were performed to rationalize the mechanism and the high efficiency of the phenol‐based phosphonium iodide catalyst. The calculation confirmed the activation of the epoxide via hydrogen bonding for the iodide salt, which facilitates the ring‐opening step. Notably, the effective Gibbs energy barrier regarding this step is 97 kJ mol−1 for the bromide and 72 kJ mol−1 for the iodide salt, which explains the difference in activity.
Stratified Treatment of Heart Failure with preserved Ejection Fraction: rationale and design of the STADIA‐HFpEF trial
Authors: Scheffer Mariëlle , Driessen‐Waaijer Annet , Hamdani Nazha , Landzaat Jochem W.D. , Jonkman Nini H. , Paulus Walter J. , van Heerebeek Loek 
Published: October 2020

AbstractAimsHigh myocardial stiffness in heart failure with preserved ejection fraction (HFpEF) is attributed to comorbidity‐induced structural and functional remodelling through inflammation and oxidative stress affecting coronary microvascular endothelial cells and cardiomyocytes, which augments interstitial fibrosis and cardiomyocyte stiffness. In murine and human HFpEF myocardium, sodium glucose co‐transporter 2 (SGLT2) inhibition ameliorates cardiac microvascular endothelial cell and cardiomyocyte oxidative stress, while enhancing myocardial protein kinase G activity and lowering titin‐based cardiomyocyte stiffness. Failure of previous HFpEF outcome trials refocuses attention to improving pathophysiological insight and trial design with better phenotyping of patients and matching of therapeutic targets to prevailing pathogenetic mechanisms. SGLT2 inhibition could represent a viable therapeutic option especially in HFpEF patients in whom high diastolic left ventricular (LV) stiffness is predominantly caused by elevated cardiomyocyte stiffness and associated endothelial dysfunction, whereas HFpEF patients with extensive myocardial fibrosis might be less responsive. This study aims to investigate a stratified treatment approach, using dapagliflozin in heart failure patients with preserved ejection fraction without evidence of significant myocardial fibrosis.Methods and resultsThe Stratified Treatment to Ameliorate DIAstolic left ventricular stiffness in early Heart Failure with preserved Ejection Fraction (STADIA‐HFpEF) is a Phase II, randomized, 2 × 2 crossover trial, evaluating the efficacy of 13 weeks of treatment with dapagliflozin 10 mg od in 26 patients with HFpEF, with normal cardiac magnetic resonance imaging‐derived extracellular volume. The co‐primary endpoint is echocardiographically derived change in E/e'/LV end‐diastolic volume index and change in mean LV e'.ConclusionsThe STADIA‐HFpEF trial will be the first study to evaluate the direct effects of dapagliflozin on amelioration of LV stiffness, using histological phenotyping to discern early HFpEF.
Heart Failure Association of the European Society of Cardiology update on sodium–glucose co‐transporter 2 inhibitors in heart failure
Authors: Seferović Petar M. , Fragasso Gabriele , Petrie Mark , Mullens Wilfried , Ferrari Roberto , Thum Thomas , Bauersachs Johann , Anker Stefan D. , Ray Robin , Çavuşoğlu Yuksel , Polovina Marija , Metra Marco , Ambrosio Giuseppe , Prasad Krishna , Seferović Jelena , Jhund Pardeep S. , Dattilo Giuseppe , Čelutkiene Jelena , Piepoli Massimo , Moura Brenda , Chioncel Ovidiu , Ben Gal Tuvia , Heymans Stephane , Jaarsma Tiny , Hill Loreena , Lopatin Yuri , Lyon Alexander R. , Ponikowski Piotr , Lainščak Mitja , Jankowska Ewa , Mueller Christian , Cosentino Francesco , Lund Lars H. , Filippatos Gerasimos S. , Ruschitzka Frank , Coats Andrew J.S. , Rosano Giuseppe M.C. 
Published: October 2020

The Heart Failure Association (HFA) of the European Society of Cardiology (ESC) has recently issued a position paper on the role of sodium–glucose co‐transporter 2 (SGLT2) inhibitors in heart failure (HF). The present document provides an update of the position paper, based of new clinical trial evidence. Accordingly, the following recommendations are given:• Canagliflozin, dapagliflozin empagliflozin, or ertugliflozin are recommended for the prevention of HF hospitalization in patients with type 2 diabetes mellitus and established cardiovascular disease or at high cardiovascular risk.• Dapagliflozin or empagliflozin are recommended to reduce the combined risk of HF hospitalization and cardiovascular death in symptomatic patients with HF and reduced ejection fraction already receiving guideline‐directed medical therapy regardless of the presence of type 2 diabetes mellitus.