bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk factors for occupational heat‐related illness among California workers, 2000–2017
Authors: Heinzerling Amy , Laws Rebecca L. , Frederick Matt , Jackson Rebecca , Windham Gayle , Materna Barbara , Harrison Robert
Published: October 2020

Background

As climate change increases global temperatures, heat‐related morbidity and mortality are projected to rise. Outdoor workers and those who perform exertional tasks are particularly susceptible to heat‐related illness (HRI). Using workers' compensation data, we aimed to describe rates of occupational HRI in California and identify demographic and occupational risk factors to inform prevention efforts.

Methods

We identified HRI cases during 2000–2017 in the California Workers' Compensation Information System (WCIS) using International Classification of Diseases Ninth and Tenth Revision codes, WCIS nature and cause of injury codes, and HRI keywords. We assigned industry and occupation codes using the NIOSH Industry and Occupation Computerized Coding System (NIOCCS). We calculated HRI rates by sex, age group, year, county, industry, and occupation, and estimated confidence intervals using generalized linear models.

Results

We identified 15,996 HRI cases during 2000–2017 (6.0 cases/100,000 workers). Workers aged 16–24 years had the highest HRI rate (7.6) among age groups, and men (8.1) had a higher rate than women (3.5). Industry sectors with the highest HRI rates were Agriculture, Farming, Fishing, and Forestry (38.6), and Public Administration (35.3). Occupational groups with the highest HRI rates were Protective Services (56.6) and Farming, Fishing, and Forestry (36.6). Firefighters had the highest HRI rate (389.6) among individual occupations.

Conclusions

Workers in certain demographic and occupational groups are particularly susceptible to HRI. Additional prevention efforts, including outreach and enforcement targeting high‐risk groups, are needed to reduce occupational HRI. Workers' compensation data can provide timely information about temporal trends and risk factors for HRI.
Mechanistic Investigations for the Formation of Active Hexafluoroisopropyl Benzoates Involving Aza‐Oxyallyl Cation and Anthranils
Authors: Mukherjee Anirban , Ansari Arshad J. , Rajagopala Reddy S. , Kanti Das Gourab , Singh Ritesh
Published: October 2020

Herein, we report a multicomponent approach to access hexafluoroisopropyl activated esters using anthranil and aza‐oxyallyl cation with hexafluoroisopropyl alcohol (HFIP) under mild reaction conditions. Activated (HFIP) esters synthesized via this approach serve as an important intermediate to obtain coveted 1,4‐benzodiazepine‐3,5‐dione derivatives. The mechanism of the reaction was studied quantum mechanically using density functional theory (DFT) with functional M06‐2X and 6–31G (d, p) basis set. Different pathways were investigated. Calculated results reveal probable involvement of two mechanisms in current transformation.
Color‐ and Dimension‐Tunable Light‐Harvesting Organic Charge‐Transfer Alloys for Controllable Photon‐Transport Photonics
Authors: Han Xixi , Lei Yilong , Liao Qing , Fu Hongbing
Published: October 2020

An electron donor/acceptor pair comprising perylene (Pe) and 9,10‐dicyanoanthracene (DCA) was specifically designed to construct organic charge‐transfer (CT) alloys via weak CT interaction through a solution co‐assembly route. By adjusting the molar ratio between Pe and DCA, we achieve color‐ and dimension‐tunable CT alloy assemblies involving one‐dimensional (1D) (DCA)1−x(Pe)x (0 ≤ x ≤10 %) microribbons and two‐dimensional (2D) (Pe)1−y(DCA)y (0 ≤ y ≤5 %) nanosheets as a consequence of energy transfer from DCA or α‐Pe to Pe‐DCA CT complex. Importantly, dimension‐related optical waveguiding performances are also revealed: continuously adjustable optical loss in 1D (DCA)1−x(Pe)x microribbons and successive conversion from isotropic waveguide to anisotropic waveguide in 2D (Pe)1−y(DCA)y nanosheets. The present work provides a desired platform for in‐depth investigation of light‐harvesting organic CT alloy assemblies, which show promising applications in miniaturized optoelectronic devices.
The Triplet Hydroxyl Radical Complex of Phosphorus Monoxide
Authors: Chu Xianxu , Qian Weiyu , Lu Bo , Wang Lina , Qin Jie , Li Jun , Rauhut Guntram , Trabelsi Tarek , Francisco Joseph S. , Zeng Xiaoqing
Published: October 2020

Phosphorus monoxide (.PO) is a key intermediate in phosphorus chemistry, and its association with the hydroxyl radical (.OH) to yield metaphosphorous acid (cis‐HOPO) contributes to the chemiluminescence in the combustion of phosphines. When photolyzing cis‐HOPO in an Ar‐matrix at 2.8 K, the simplest dioxophosphorane HPO2 and an elusive hydroxyl radical complex (HRC) of .PO form. This prototypical radical‐radical complex reforms into cis‐HOPO at above 12.0 K by overcoming a barrier of 0.28±0.02 kcal mol−1. The vibrational spectra of this HRC and its D‐ and 18O‐isotopologues suggest a structure of .OH⋅⋅⋅OP., for which a triplet spin multiplicity with a binding energy of −3.20 kcal mol−1 has been computed at the UCCSD(T)‐F12a/aug‐cc‐pVTZ level.
Bifunctional Effects of Cation Additive on Na‐O2Batteries
Authors: Zhao Shuo , Wang Chenchen , Du Dongfeng , Li Lin , Chou Shulei , Li Fujun , Chen Jun
Published: October 2020

Aprotic Na‐O2batteries have attracted growing interest owing to their low overpotentials and high energy density. Their cycling stability and Coulombic efficiency are limited, however, by Na dendrite formation and superoxide (O2−) degradation. Here, we present a bifunctional cation additive, the tetrabutylammonium cation (TBA+), to simultaneously protect the Na anode and stabilize the superoxide. The adsorption of TBA+on the Na anode suppresses the dendrite formation in the Na plating and ensures stable anode cycling at high current density in both Ar and oxygen atmospheres. Aprotic Na‐O2batteries with TBA+show increased Coulombic efficiency as well as good rate capability. These are rewarded by the fast desolvation kinetics of O2−and suppression of the disproportionation reaction of O2−with TBA+, as confirmed by molecular dynamics simulation and DFT calculations. This bifunctional effect of this cation additive paves a new avenue for the development of Na‐O2batteries.
In Situ Exploration of the Structural Transition during Morphology‐ and Efficiency‐Conserving Halide Exchange on a Single Perovskite Nanocrystal
Authors: Karimata Izuru , Tachikawa Takashi
Published: October 2020

Controlled fabrication of semiconductor nanostructures with unique physicochemical properties is vital for future technologies. In this study, transformation from red‐emitting metal halide perovskite CH3NH3PbI3 nanocrystals (NCs) to green‐emitting CH3NH3PbBr3 NCs was achieved without significant morphological changes and loss of photoluminescence (PL) efficiency via a controlled halide exchange reaction. In situ single‐particle PL imaging along with detailed structural and elemental characterizations revealed that sudden cooperative transitions between two light‐emitting states via intermediate dark states with >100 s durations during halide exchange originate from two distinct defect‐mediated reconstruction processes with different activation energies (0.072 and 0.40 eV), leading to an isokinetic temperature of ca. 314 K, across a solid‐state miscibility gap between the I‐ and Br‐rich phases inside a single NC.
Molecular Recognition Mediated by Hydrogen Bonding in Aqueous Media
Authors: Dong Jinqiao , Davis Anthony P.
Published: October 2020

Hydrogen bonding is a key governing force in molecular recognition, notably in biological systems. While it has been studied and exploited by supramolecular chemists for many years, most of this work has been conducted in organic solvents. Investigations in water, the biological solvent, have proceeded more slowly, largely because the interaction is weakened by solvation and less easy to detect. Recently it has become appreciated that the problems should be addressed, and work towards the deployment of H‐bonding in water has accelerated. This Minireview discusses a range of synthetic receptors designed to bind organic molecules in aqueous media by combining hydrogen bonding with hydrophobic interactions. Some of these systems are capable of high affinities and selectivities, raising the hope of biomedical applications in the near future.
Two dinuclear copper (II) and nickel (II) complexes based on 4‐(diethylamino)salicylaldehyde: X‐ray structures, spectroscopic, electrochemical, antibacterial, Hirshfeld surfaces analyses, and time‐dependent density functional theory calculations
Authors: Chai Lan‐Qin , Xu Li‐Yan , Zhang Xiao‐Fang , Li Yao‐Xin
Published: October 2020

The quinazoline‐type ligand 2‐(4‐diethylamino‐2‐hydroxyphenyl)‐4‐methyl‐1,2‐dihydroquinazoline 3‐oxide (HL1; H is the deprotonatable hydrogen) was prepared. Two 2‐D supramolecular complexes [Cu2(L2)2(NO3)2] (1) and [Ni2(L2)2(CH3COO)2] (2) (L2 = 1‐(2‐{[(E)‐(4‐diethylamino‐2‐hydroxybenzylidene]amino} phenyl)ethanone oxime) were synthesized using HL1 and characterized by elemental analysis, spectroscopic methods, and single‐crystal X‐ray diffraction studies. It revealed that 1 had coordinated two nitrate ions whereas 2 had acetate ions. In the crystal structures, six‐coordinated Cu (II) complex 1 formed an infinite 2‐D and X‐shaped 3‐D supramolecular frameworks. Simultaneously, Ni (II) complex 2 assembled into wavy 2‐D networks. Furthermore, electrochemical properties and antimicrobial activities of all compounds were as well investigated. Afterwards, the electrophilic and nucleophilic attack sites identified by electrostatic potential (ESP) calculations confirmed that hydrogen bonds were observed in the optimized structure of the crystal, and the closest contact between the active atoms of both complexes was confirmed through Hirshfeld surface analysis and time‐dependent density functional theory (TD‐DFT) calculations.
The effect of 3D structure design on fire behavior of polyethylene terephthalate glycol containing aluminum hypophosphite and melamine cyanurate
Authors: Zárybnická Lucie , Mácová Petra , Machová Dita , Rychlý Jozef , Viani Alberto
Published: October 2020

Effect of the shape of 3D printed samples on fire behavior of polyethylene terephthalate glycol (PET‐G) and PET‐G additivated with a mix of aluminum hypophosphite (AHP) and melamine cyanurate as flame retardant, was investigated. The additives improved fire performance (e.g., maximum average rate of heat emission, total oxygen consumption, heat release rate indices) irrespective of structural complexity, favoring carbonaceous char formation. However, at increasing structural complexity, they promoted higher release of smoke, compared to neat PET‐G, because of a change in the prevalent retardation mechanism, which became dominated by the flame inhibition action of AHP. Consequently, the synergistic effect obtained combining the two additives, was hindered. Impact of product design on mechanisms of fire retardation helps in devising engineering solutions aimed at meeting required level of fire‐safety performance, which should be tailored to the specific product.
Phase equilibria and surface tension in castor oil‐based polyols‐water–methanol mixture: Thermodynamic basis
Authors: Moon Junho , Yang Han Earl , Lee Chan Hee , Choi Ji Su , Oh Jeong Seok
Published: October 2020

Considering the current environmental issues with petro‐polymers, castor oil is a promising green alternative to the polyols to be used as the main raw material for polyurethane. However, the basic information regarding the processability of castor oil‐based polyol (CP) such as its miscibility in different solvents is still elusive. Herein we have investigated the phase equilibria and surface tension of various CP solutions using thermo‐optical analysis and pendent drop method, respectively. The modified double lattice (MDL) model was employed to theoretically describe those phase equilibria and surface behaviors. The phase diagrams of CPs/methanol binary systems represent upper critical solution temperature (UCST) behaviors, and CPs/methanol/water ternary systems show Treybal Type 2 behaviors. The surface tension results exhibit preferential solvent adsorption, which means affinity of the solvent to be present in surface is higher than that of the polymer. The calculated results showed good agreement with the experimental observations.
Age‐Related Effects on Social Cognition in Adults with Autism Spectrum Disorder: A Possible Protective Effect on Theory of Mind
Authors: Zıvralı Yarar Esra , Howlin Patricia , Charlton Rebecca , Happé Francesca
Published: October 2020

Impaired social cognition has been suggested to underlie the social communication difficulties that define autism spectrum disorder (ASD). In typical development, social cognition may deteriorate in older age, but age effects in ASD adults have been little explored. In the present study, we compared groups of younger and older adults with and without ASD (n = 97), who completed a set of social cognition tasks assessing theory of mind (ToM), and self‐report measures of empathy and alexithymia. While typically developing (TD) younger adults outperformed elderly TD and younger ASD participants, younger and older ASD adults did not differ in their ToM performance, and the elderly ASD and TD groups performed equivalently. By contrast, ASD adults reported lower empathy scores and higher levels of alexithymia symptoms compared to TD adults regardless of age. The difference between ASD and TD groups in self‐reported empathy scores was no longer significant when alexithymia was covaried (with the exception of the Perspective Taking subscore). Results suggest a possible age‐protective effect on ToM in the ASD group. In addition, empathy difficulties appear to be associated with alexithymia rather than ASD per se. Possible interpretations are discussed, and future directions for autism aging research are proposed.

Lay Summary

People with autism spectrum disorder (ASD) have difficulties with social understanding. Some age‐related studies in typical development have shown a decline in social understanding in older age. We investigated whether a similar pattern is present in adults with ASD. We found that understanding what someone is thinking was not worse in older versus younger autistic adults. Also, we reported further evidence suggesting that emotional empathy difficulties were related to difficulties with understanding one's own emotions rather than with autism itself. Autism Res 2021, 14: 911–920. © 2020 International Society for Autism Research and Wiley Periodicals LLC.
Interaction between Maternal Immune Activation and Antibiotic Use during Pregnancy and Child Risk of Autism Spectrum Disorder
Authors: Holingue Calliope , Brucato Martha , Ladd‐Acosta Christine , Hong Xiumei , Volk Heather , Mueller Noel T. , Wang Xiaobin , Fallin M. Daniele
Published: October 2020

Prenatal exposure to maternal immune activation (MIA) has been implicated as a risk factor for the development of autism spectrum disorder (ASD), though the conditions under which this elevated risk occurs are unclear. Animal literature demonstrates that antibiotic use, which affects the composition of the maternal gut microbiota, modifies the effect of MIA on neurodevelopmental outcomes in the offspring. The aim of this study was to assess whether antibiotic use during pregnancy modifies the association between MIA and subsequent risk of ASD, in a prospective birth cohort with 116 ASD cases and 860 typically developing (TD) child controls. There was no evidence of interaction between fever or genitourinary infection and antibiotic use on the odds of ASD in unadjusted or adjusted analyzes. However, we found evidence of an interaction between flu, specifically in second trimester, and antibiotic use at any point during pregnancy on the odds of ASD in the child. Among women who received an antibiotic during pregnancy, flu in trimester two was not associated with ASD (adjusted odds ratio [aOR] = 0.99 [0.43–2.28]). Among women who were not exposed to an antibiotic at any point during pregnancy, flu in second trimester was significantly associated with increased odds of ASD (aOR = 4.05 [1.14–14.38], P = .03), after adjustment for child sex, child birth year, maternal age, gestational age, C‐section delivery, and low birthweight. These findings should be treated as hypothesis‐generating and suggest that antibiotic use may modify the influence that MIA has on autism risk in the child.

Lay Summary

We looked at whether the association between activation of the immune system during pregnancy and risk of the child developing autism spectrum disorder (ASD) differed among women who did or did not take an antibiotic at any point during pregnancy. We examined 116 children with ASD and 860 without ASD and found that flu in second trimester was associated with increased ASD, but only among women who did not take an antibiotic during pregnancy. No other immune activation exposures seemed to interact with antibiotic use.
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 Summary

We 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

Viral 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

AcCHMO, 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

In 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

Background

Evidence 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.

Methods

Single‐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.

Results

Two 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).

Conclusion

Our 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

The 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

The 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

4‐(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

The 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

Background

The 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.

Hypothesis

PVI is comparably safe in the very elderly with similar recurrence and complication rates.

Methods

We 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.

Results

Acute 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.

Conclusion

PVI 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

Photopharmacology, 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

A 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

Aims

High 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 results

The 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'.

Conclusions

The 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.
Divergent SARS‐CoV‐2‐specific T‐ and B‐cell responses in severe but not mild COVID‐19 patients
Authors: Oja Anna E. , Saris Anno , Ghandour Cherien A. , Kragten Natasja A.M. , Hogema Boris M. , Nossent Esther J. , Heunks Leo M.A. , Cuvalay Susan , Slot Ed , Linty Federica , Swaneveld Francis H. , Vrielink Hans , Vidarsson Gestur , Rispens Theo , van der Schoot Ellen , van Lier René A.W. , Ten Brinke Anja , Hombrink Pleun
Published: October 2020

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is the causative agent of the current coronavirus disease 2019 (COVID‐19) pandemic. Understanding the immune response that provides specific immunity but may also lead to immunopathology is crucial for the design of potential preventive and therapeutic strategies. Here, we characterized and quantified SARS‐CoV‐2‐specific immune responses in patients with different clinical courses. Compared to individuals with a mild clinical presentation, CD4+ T‐cell responses were qualitatively impaired in critically ill patients. Strikingly, however, in these patients the specific IgG antibody response was remarkably strong. Furthermore, in these critically ill patients, a massive influx of circulating T cells into the lungs was observed, overwhelming the local T‐cell compartment, and indicative of vascular leakage. The observed disparate T‐ and B‐cell responses could be indicative of a deregulated immune response in critically ill COVID‐19 patients.
Solar energy and TiO2 nanotubes: Biodiesel production from waste cooking olive oil
Authors: Khaligh Nader Ghaffari , Mihankhah Taraneh , Shahnavaz Zohreh , Zaharani Lia , Johan Mohd Rafie
Published: October 2020

TiO2 nanotubes have been used as practical heterogeneous nano‐catalyst for biodiesel production from waste cooking olive oil using solar energy. Several critical parameters namely the reaction time and temperature and volume ratio of methanol to oil were optimized to obtain high‐quality biodiesel fuel. By using an optimum volume ratio of methanol to WCOO of 8.0:1.0 at 60°C within 4 h, the highest conversion of 91.2 ± 0.7% was obtained. Solar energy was applied to heat the reaction vessel by parabolic trough reflectors, and photovoltaic panels were employed to power a small electric motor for the stirring of the reaction mixture. After completion of the reaction, the nanocatalyst was separated by a centrifuge. The catalyst could be reused up to four times with a 3% reduction in yield of the final product. The variation of five pollutant emissions for a blend of biodiesel: diesel (20:80 vol/vol %) showed a net decrease of the total hydrocarbons, carbon monoxide, and carbon dioxide emissions compared to the pure diesel fuel.
Impact of an 0.2 km3 Rock Avalanche on Lake Eibsee (Bavarian Alps, Germany) – Part II: Catchment Response to Consecutive Debris Avalanche and Debris Flow
Authors: Knapp Sibylle , Anselmetti Flavio S. , Lempe Bernhard , Krautblatter Michael
Published: October 2020

The ~0.2 km3 Eibsee rock avalanche impacted Paleolake Eibsee and completely displaced its waters. This study analyses the lake impact and the consequences, and the catchment response to the landslide. A quasi‐3D seismic reflection survey, four sediment cores from modern Lake Eibsee, reaching far down into the rock avalanche mass, nine radiocarbon ages, and geomorphic analysis allow us to distinguish the main rock avalanche event from a secondary debris avalanche and debris flow. The highly fluidized debris avalanche formed a megaturbidite and multiple swashes that are recorded in the lake sediments. The new calibrated age for the Eibsee rock avalanche of ~4080–3970 cal yr BP indicates a coincidence with rockslides in the Fernpass cluster and subaquatic landslides in Lake Piburg and Lake Plansee, and raises the possibility that a large regional earthquake triggered these events. We document a complex history of erosion and sedimentation in Lake Eibsee, and demonstrate how the catchment response and rebirth of the lake are revealed through the complementary application of geophysics, sedimentology, radiocarbon dating, and geomorphology. © 2020 The Authors. Earth Surface Processes and Landforms published by John Wiley & Sons Ltd
An exploration of genetic association tests for disease risk and age at onset
Authors: Martin Eden R. , Gao Xiaoyi R. , Li Yi‐Ju
Published: October 2020

Risk genes influence the chance of an individual developing disease over their lifetime, although the age at onset (AAO) genes influence disease timing. These two categories are not disjoint; a gene that influences AAO might also appear to influence the risk. When an allele influences both AAO and risk, a reasonable question is whether we would have more power to detect association using a statistical test based on risk or AAO. To address this question, we compared power analytically for the Cochran–Armitage trend case–control test for risk and a linear regression case‐only test for AAO. We also used simulations to compare the power of these tests with a 2‐degree of freedom joint test (which combines the risk and AAO statistics) and the Cox proportional hazards survival model testing AAO (with censored data in controls). We found that when there is little heterogeneity, the case–control risk test has more power than the case‐only AAO test (with equivalent sample sizes), but when the model is complex (e.g., with heterogeneity or reduced penetrance), the relationship reverses. The joint test generally outperforms the risk or AAO test alone and ultimately is our recommendation as a powerful alternative in many scenarios.