bluuebunny/crossref_metadata_2025 huggingface dataset:
Effectiveness and Safety of High‐Dose Biologics in Juvenile Idiopathic Arthritis in the Childhood Arthritis and Rheumatology Research Alliance
Authors: Correll Colleen K. , Shrader Peter , Dennos Anne , Phillips Thomas , Shiff Natalie J. , Verstegen Ruud H. J. , Beukelman Timothy ,   for the Childhood Arthritis and Rheumatology Research Alliance Registry Investigators
Published: June 2021

Objective

To describe high‐dose biologic use when treating juvenile idiopathic arthritis (JIA).

Methods

Patients with JIA enrolled in the Childhood Arthritis and Rheumatology Research Alliance Registry and treated with a biologic after enrollment were eligible. We described the frequency of high‐dose biologic use and characteristics of patients receiving high‐dose biologics. We used regression modeling to compare 6‐month outcomes (using disease activity measures) between those who increased their biologic from standard to high dose (high‐dose group) to those who initiated and remained on standard dosing (no‐change group), and to those who switched biologic agents (biologic‐switch group). We also compared serious adverse events (SAEs) between groups.

Results

A total of 5,352 patients with JIA were treated with biologics following enrollment; 1,080 (20%) had ever received a high‐dose biologic. There were no significant differences in outcomes between the high‐dose group and the biologic‐switch group; both improved disease activity measures, including the clinical Juvenile Arthritis Disease Activity Score 10 (–3.53 and –3.95, respectively; P = 0.68). Although the SAE rates in the high‐dose group and the biologic‐switch group were numerically higher than the no‐change group, the event rates were similar, and neither rate was significantly higher than in the no‐change group (unadjusted incident rate ratio 2.5 [95% confidence interval (95% CI) 0.7–8.5] and 1.8 [95% CI 0.7–4.6], respectively).

Conclusion

Dosing escalation appears to be a reasonable choice to improve disease control, but large, prospective, randomized studies evaluating specific biologic agents are needed.
Relationship Between Body Mass Index and Osteoarthritis for Single and Multisite Osteoarthritis of the Hand, Hip, or Knee: Findings From a Canadian Longitudinal Study on Aging
Authors: Badley Elizabeth M. , Zahid Shatabdy , Wilfong Jessica M. , Perruccio Anthony V.
Published: June 2021

Objective

To determine whether an apparent association between hand osteoarthritis (OA) and adiposity is explained by the presence of OA at other joint sites.

Methods

Data from the Canadian Longitudinal Study on Aging, first cycle, comprehensive cohort, were used. Respondents age 45–85 years (n = 18,279) were asked separate questions about doctor‐diagnosed OA in the hand, hip, or knee. Multinomial logistic regression was used to investigate the relationship between all combinations of hand, hip, and knee OA and body mass index (BMI) and waist‐to‐height ratio (WHtR).

Results

OA was reported by 34.6% of respondents, 28.0% with OA at >1 joint site. Hand OA was not significantly associated with BMI after accounting for OA at other joint sites, with similar findings for WHtR. All joint site combinations containing the knee were strongly associated with BMI, with odds ratios (ORs) ranging from OR 2.92 (95% confidence interval [95% CI] 2.53–3.37) for knee OA only with obesity class I to OR 9.98 (95% CI 7.12–13.88) for multi‐joint knee, hip, hand OA with obesity class II/III. BMI distributions including knee OA were broader and shifted to higher BMI levels than those for hand or hip OA.

Conclusion

Apparent associations between hand OA and BMI may be explained by concurrent OA at other joint sites. Recognizing that OA is a multi‐joint disease is crucial for studies of the associations of adiposity with OA in a particular joint, especially the hand. The association between knee OA and BMI appears to be distinct from those for OA at other joint sites.
Exploring the Associations Among Occupational Balance and Health of Adults With and Without Inflammatory Arthritis
Authors: To‐Miles Flora , Håkansson Carita , Wagman Petra , Backman Catherine L.
Published: June 2021

Objective

Occupational balance is a person's subjective perception of the amount and variation of their everyday activities. Evidence suggests an association between occupational balance and health. However, the impact of arthritis on occupational balance and its association with health is unclear. This exploratory study was undertaken to examine associations between occupational balance and measures of health and between‐group differences in adults with and without inflammatory arthritis (IA).

Methods

In a cross‐sectional study, participants completed the 11‐item Occupational Balance Questionnaire (OBQ‐11) and the Short Form 36 (SF‐36) health survey (physical and mental component summary scores) and provided demographic information. Telomere lengths were analyzed from dried blood spots.

Results

A total of 143 adults participated (67 with IA, 76 from the healthy comparison [HC] group). Occupational balance was higher in the HC group than in the IA group (mean difference 3.5 [95% confidence interval 1.0, 5.9; P = 0.01]), but this difference was not statistically significant when adjusted for physical health. The association between occupational balance and physical health was stronger in the IA group (R2 = 0.17, P = 0.001) than in the HC group (R2 = 0.05, P = 0.05). Occupational balance was associated with mental health (R2 = 0.26, P < 0.001) but not associated with telomere length (R2 = 0.02, P = 0.24).

Conclusion

Occupational balance is associated with mental health for all participants and associated with physical health and disease activity in participants with IA. Attention to assessment of and strategies for improving occupational balance in rehabilitation practice and arthritis self‐management programs may contribute to sustaining physical and mental health.
Ultrafast Rechargeable Aqueous Zinc‐Ion Batteries Based on Stable Radical Chemistry
Authors: Tang Mengyao , Zhu Qiaonan , Hu Pengfei , Jiang Li , Liu Rongyang , Wang Jiawei , Cheng Liwei , Zhang Xiuhui , Chen Wenxing , Wang Hua
Published: June 2021

Aqueous zinc‐ion batteries (ZIBs) are a promising candidate for fast‐charging energy‐storage systems due to its attractive ionic conductivity of water‐based electrolyte, high theoretical energy density, and low cost. Current strategies toward high‐rate ZIBs mainly focus on the improvement of ionic or electron conductivity within cathodes. However, enhancing intrinsic electrochemical reaction kinetics of active materials to achieve fast Zn2+ storage has been greatly omitted. Herein, for the first time, stable radical intermediate generation is demonstrated in a typical organic electrode material (methylene blue [MB]), which effectively decreases the reaction energy barrier and enhances the intrinsic kinetics of MB cathode, enabling ultrafast Zn2+ storage. Meanwhile, anionic co‐intercalation essentially avoids MB molecules rearranging their configuration and sharing Zn2+ with adjacent functional groups, thus keeps the structure stable. As a result, Zn–MB batteries exhibit an excellent rate capability up to 500C and ultralong life of 20 000 cycles with a negligible 0.07% capacity decay per cycle at 100C, which is superior to that of most reported aqueous ZIBs batteries. This work provides a novel strategy of stable radical chemistry for ultrafast‐charging aqueous ZIBs, which can be introduced to other appropriate organic materials and multivalent ion battery systems.
Selenium Nanoparticles for Biomedical Applications: From Development and Characterization to Therapeutics
Authors: Ferro Cláudio , Florindo Helena F. , Santos Hélder A.
Published: June 2021

Selenium (Se) is an essential element to human health that can be obtained in nature through several sources. In the human body, it is incorporated into selenocysteine, an amino acid used to synthesize several selenoproteins, which have an active center usually dependent on the presence of Se. Although Se shows several beneficial properties in human health, it has also a narrow therapeutic window, and therefore the excessive intake of inorganic and organic Se‐based compounds often leads to toxicity. Nanoparticles based on Se (SeNPs) are less toxic than inorganic and organic Se. They are both biocompatible and capable of effectively delivering combinations of payloads to specific cells following their functionalization with active targeting ligands. Herein, the main origin of Se intake, its role on the human body, and its primary biomedical applications are revised. Particular focus will be given to the main therapeutic targets that are explored for SeNPs in cancer therapies, discussing the different functionalization methodologies used to improve SeNPs stability, while enabling the extensive delivery of drug‐loaded SeNP to tumor sites, thus avoiding off‐target effects.
Direct Elimination of Detrimental Surface Phases Parasitic to LiNixCo1−xO2 (x = 0.8 and 0.9) with Unique 3D Porous Structures during Synthesis
Authors: Tan Xinghua , Guo Limin , Zhao Tingqiao , Mao Dongdong , Jiang Mingyan , Nie Shuai , Song Luting , Kang Xiaohong , Wang Hanfu , Sun Lianfeng , Chu Weiguo
Published: June 2021

Detrimental rock‐salt and/or spinel surface phases parasitic to Ni‐rich layered oxides with high theoretical capacity are quite formidable which are reported to be eliminated only through alien element dopings and/or surface modifications. Herein, these surface phases are directly eliminated successfully during the synthesis of pristine LiNi0.8Co0.2O2 and LiNi0.9Co0.1O2 using an expanded graphites (EGs) template approach, accompanied by the formation of unique 3D porous structures. The elimination of surface phases may be ascribed to the 3D porous structures formed during the calcination processes at both low and high temperatures, which enables the access of sufficient oxygen to individual nanoparticles and thus promotes the oxidization of Ni2+ to Ni3+ to reduce Li/Ni disordering. Both LiNi0.8Co0.2O2 and LiNi0.9Co0.1O2 show excellent rate capability, long‐term cycling stability, and high initial Coulombic efficiencies (ICEs), such as 210.4 (149) and 222.6 (133) mAh g−1, ICEs of 94.9% and 93.8% at 0.1 C (20 C), and capacity retentions of 74% after 500 cycles at 1 C and 76% after 300 cycles at 1 C, respectively, far better than those synthesized using a conventional sol–gel recipe. This study provides a simple and novel platform for directly synthesizing detrimental surface phases free and chemically stoichiometric Ni‐rich layered oxides with high performance.
Post‐Treatment of Screen‐Printed Silver Nanowire Networks for Highly Conductive Flexible Transparent Films
Authors: Li Dongdong , Lai Wen‐Yong , Feng Fang , Huang Wei
Published: June 2021

Screen printing is an important technique for creating 2D conductive patterns with high conductivity and resolution. Non‐conductive additives are thus required in printable ink formulation in order to achieve appropriate viscosity and rheological behaviors. However, it is still a challenge to recover the conductivity of the printed networks after screen printing, while keeping the integrity of the patterns during repeated water‐washing. Herein, a series of post‐treatments are introduced into the washing process in order to achieve high‐quality silver nanowire (Ag NW) transparent conductive films. Screen‐printed patterns can be well maintained because of the enhanced adhesion between the Ag NW networks and flexible poly(ethylene terephthalate) substrates. High‐performance transparent conductive film with extremely low sheet resistance (0.72 Ω sq−1) is achieved by combining plasma treatment, thermal annealing, and high pressure, making screen‐printed Ag NW conductive networks promising to be used in the next‐generation flexible optoelectronic devices.
Improved Output Performance of Direct‐Current Triboelectric Nanogenerator through Field Enhancing Breakdown Effect
Authors: Chen Shengyang , Liu Di , Zhou Linglin , Li Shaoxin , Zhao Zhihao , Cui Shengnan , Gao Yikui , Li Yanhong , Wang Zhong Lin , Wang Jie
Published: June 2021

The emerging direct‐current triboelectric nanogenerator (DC‐TENG) does not need to be rectified and is not restricted by a dielectric breakdown compared with an alternating current TENG (AC‐TENG). Furthermore, the charge density of the DC‐TENG reaches an ultrahigh level far beyond that of the AC‐TENG based on a rational design. However, there are always some electrons remaining on the surface of the dielectric after the breakdown process in the DC‐TENG, and therefore a low charge utilization is obtained. Herein, a simple and universal method is proposed through a double‐layer structure design, that is, a triboelectric layer as the friction layer and an electret layer charged through a surface treatment as the field‐enhancing layer to further improve the output performance of the DC‐TENG, which is inspired by the fable “The Crow and the Pitcher.” Owing to the external field‐enhancing breakdown effect, a double improvement in the breakdown efficiency and output charge density is obtained compared with a conventional DC‐TENG. Moreover, a nearly constant output current has been demonstrated for directly powering electronics without a rectifier. This study provides a universal method for optimizing the output performance of a DC‐TENG.
Na Replaces Rb towards High‐Performance Narrow‐Band Green Phosphors for Backlight Display Applications
Authors: Liao Min , Wang Qiang , Lin Qiuming , Xiong Mingxiang , Zhang Xin , Dong Huafeng , Lin Zhiping , Wen Minru , Zhu Daoyun , Mu Zhongfei , Wu Fugen
Published: June 2021

The improvement of high‐performance narrow‐band green phosphors in backlight display applications is still a major challenge. Based on the UCr4C4type of oxide phosphor, the high‐performance narrow‐band green phosphors Rb3M(Li3SiO4)4:Eu2+(M = Rb or Na) are studied in different luminous positions. Benefiting from the replacement of Rb by Na, the change of the local environment in the crystal structure of Rb3Na(Li3SiO4)4:Eu2+(R3NLSO:Eu2+) leads to the decrease of Stokes shift, which improves the quantum efficiency. Moreover, change in the local environment enhances the structural rigidity, which makes the thermal and chemical stability better. The R3NLSO:8%Eu2+phosphor presents a narrow‐band green emission centered at 527 nm, excellent thermal stability (102% @150 °C of the integrated emission intensity at room temperature), and high internal/external quantum efficiency (85.3%/40.4%). The white light‐emitting diode (wLED) using R3NLSO:8%Eu2+phosphor presents a superior luminous efficiency of 128.3 lm W‐1and a wide color gamut. All the results indicate that R3NLSO:8%Eu2+green phosphor has great application prospects in the field of liquid crystal display. This work also provides important guiding significance for the optimization of alkali metal element type of phosphors.
All‐Inorganic Rare‐Earth Halide Double Perovskite Single Crystals with Highly Efficient Photoluminescence
Authors: Zhang Ruiling , Wang Zhongyi , Xu Xin , Mao Xin , Xiong Jin , Yang Yang , Han Keli
Published: June 2021

Halide double perovskites have been regarded as promising alternatives to famous lead halide perovskites in the field of luminescent materials. However, the low‐emission efficiency of pristine ones and the lack of efficient blue emitters remain considerable obstacles for their applications in light‐emitting devices. Here, an air‐stable, all‐inorganic Sc‐based double perovskite Cs2NaScCl6 is reported, which exhibits strong blue emission peaking at 445 nm with an averaged quantum yield of 29.05% (the highest reported value for pristine halide double perovskites). The rare‐earth double perovskite also shows excellent stability against heat and irradiation. Bulk perovskite Cs2NaScCl6 can be an effective host to incorporate Mn2+ ions, yielding interesting tunable dual broadband emission, slightly redshifted blue emission (450 nm) from the host and red emission (635 nm) from Mn2+ d–d transitions. These findings present a new direction toward the design of high‐efficiency, stable, and environmentally friendly perovskite light emitters.
Alkynylazulenes as Building Blocks for Highly Unsaturated Scaffolds
Authors: Elwahy Ahmed H. M. , Hafner Klaus
Published: June 2021

Recently developed routes to the synthesis of mono‐ and polyethynylated azulenes and their transformations into linear oligoazulenes with ethynyl and butadiynyl bridges as well as azulenyl‐substituted benzenes, cyclobutadiene complexes, and azulene‐substituted tetracyanobutadienes are reviewed. The utility of ethynylazulene derivatives for the synthesis of azulene‐substituted heterocycles has also been reviewed.
The decision‐making processes and preferences of older Australians purchasing home support services: An explorative inquiry using a “think‐aloud” technique
Authors: Rahja Miia , Laver Kate , Phillipson Lyn , Comans Tracy , Crotty Maria
Published: June 2021

Consumer‐directed care (CDC) programmes, in principle, provide consumers with choices around who provides care services to them, what services and when. However, literature around consumer behaviour of older adults, especially concerning the factors that may support home care choices, is sparse. The purpose of this study was to understand the decision‐making processes and spending preferences of community‐dwelling seniors assessed eligible for CDC home care services. We completed an explorative inquiry using a “think‐aloud” technique with eligible consumers in South Australia. The inquiry had two components. First, consumers used imitation money to simulate the purchase of home care supports while talking out loud their decision‐making processes. Then, semi‐structured interviews were completed to identify underlying thoughts that informed the decisions made and spending preferences. Fifteen consumers, mean age 82 years (range 70–94), participated. The most frequently prioritised choice was domestic assistance. However, choices were made based on a perceived hierarchy of need (due to limits placed on available budgets for care). Interview data revealed that the decision making and service preferences were also based on limited knowledge about what was available. Consumers revealed perceived value in purchasing expert advice to guide their choices and preference for relational not transactional service delivery.
Molecular Basis for Two Stereoselective Diels–Alderases that Produce Decalin Skeletons**
Authors: Fujiyama Keisuke , Kato Naoki , Re Suyong , Kinugasa Kiyomi , Watanabe Kohei , Takita Ryo , Nogawa Toshihiko , Hino Tomoya , Osada Hiroyuki , Sugita Yuji , Takahashi Shunji , Nagano Shingo
Published: June 2021

Enzymes catalyzing [4+2] cycloaddition have attracted increasing attention because of their key roles in natural product biosynthesis. Here, we solved the X‐ray crystal structures of a pair of decalin synthases, Fsa2 and Phm7, that catalyze intramolecular [4+2] cycloadditions to form enantiomeric decalin scaffolds during biosynthesis of the HIV‐1 integrase inhibitor equisetin and its stereochemical opposite, phomasetin. Computational modeling, using molecular dynamics simulations as well as quantum chemical calculations, demonstrates that the reactions proceed through synergetic conformational constraints assuring transition state‐like substrates folds and their stabilization by specific protein‐substrate interactions. Site‐directed mutagenesis experiments verified the binding models. Intriguingly, the flexibility of bound substrates is largely different in two enzymes, suggesting the distinctive mechanism of dynamics regulation behind these stereoselective reactions. The proposed reaction mechanism herein deepens the basic understanding how these enzymes work but also provides a guiding principle to create artificial enzymes.
From Selection to Instruction and Back: Competing Conformational Selection and Induced Fit Pathways in Abiotic Hosts
Authors: Pavlović Radoslav Z. , Lalisse Remy F. , Hansen Alexandar L. , Waudby Christopher A. , Lei Zhiquan , Güney Murat , Wang Xiuze , Hadad Christopher M. , Badjić Jovica D.
Published: June 2021

Two limiting cases of molecular recognition, induced fit (IF) and conformational selection (CS), play a central role in allosteric regulation of natural systems. The IF paradigm states that a substrate “instructs” the host to change its shape after complexation, while CS asserts that a guest “selects” the optimal fit from an ensemble of preexisting host conformations. With no studies that quantitatively address the interplay of two limiting pathways in abiotic systems, we herein and for the first time describe the way by which twisted capsule M‐1, encompassing two conformers M‐1(+) and M‐1(−), trap CX4 (X=Cl, Br) to give CX4⊂M‐1(+) and CX4⊂M‐1(−), with all four states being in thermal equilibrium. With the assistance of 2D EXSY, we found that CBr4 would, at its lower concentrations, bind M‐1 via a M‐1(+)→M‐1(−)→CBr4⊂M‐1(−) pathway corresponding to conformational selection. For M‐1 complexing CCl4 though, data from 2D EXSY measurements and 1D NMR line‐shape analysis suggested that lower CCl4 concentrations would favor CS while the IF pathway prevailed at higher proportions of the guest. Since CS and IF are not mutually exclusive, we reason that our work sets the stage for characterizing the dynamics of a wide range of already existing hosts to broaden our fundamental understanding of their action. The objective is to master the way in which encapsulation takes place for designing novel and allosteric sequestering agents, catalysts and chemosensors akin to those found in nature.
Steaming, boiling after pre‐frying, and stir‐frying influence the fatty acid profiles and oxidative stability of soybean oil blended with docosahexaenoic acid algal oil
Authors: Huang Jianhua , Zhao Zhengmei , Shao Linya , Chang Chang , Sun Xuemei , Wang Xiaosan , Jin Qingzhe , Wang Xingguo
Published: June 2021

The objective of this study was to improve the content of docosahexaenoic acid (DHA) and obtain the blended oils used for different cooking methods (steaming, boiling, and stir‐frying) by blending 0%–15% DHA algal oil into soybean oil. It was shown that the addition of DHA algal oil increased saturated fatty acid (SFA) (1.57%) but decreased monounsaturated fatty acid (MUFA) (0.76%) and polyunsaturated fatty acid (PUFA) (0.68%). Various cooking methods significantly changed the fatty acid (FA) compositions. Steaming is a more effective way to prevent DHA loss and the production of trans‐fatty acid than boiling and stir‐frying. Besides, a positive result from free fatty acid (FFA) and peroxide value also demonstrated that steaming was a better way to protect oils. Overall, the soybean oil blended with 3% DHA algal oil with better oxidative stability and could be recommended for daily application by steaming.
Active airflow of the paranasal sinuses in extinct crocodyliforms: Evidence from a natural cast of the thalattosuchianDakosaurus andiniensis
Authors: Fernández Marta S. , Herrera Yanina
Published: June 2021

The evolution of Thalattosuchia documents the unique shift among Crocodylomorpha from aquatic continental/coastal habitats to a fully pelagic lifestyle. This transition was coupled with deep modification of their skeletons, such as hydrofoil forelimbs, hypocercal tail, and loss of osteoderms. The natural snout casts of the rhacheosaurinCricosaurus araucanensisshowed that it also included changes in the internal anatomy of the snout like the enlargement of nasal glands (probably for salt excretion) and the rearrangement of the paranasal sinus system, including the internalization of the antorbital sinus. Here we described the snout natural cast of the geosaurinDakosaurus andiniensisfrom the Late Jurassic of Patagonia. The information provided by it indicates that, despite having different external morphologies and ecology,D. andiniensisandC. araucanensisshare the same facial anatomy. The new cast preserves a suborbital diverticulum of the antorbital sinus protruding into the orbit through the postnasal fenestra. Its location indicates that it was interleaved with jaw adductor muscles suggesting an active airflow in the paranasal sinus. We provide a putative functional interpretation of this peculiar arrangement where bellow pumps actions of musculature may help drain salt glands. The rearrangement of the paranasal sinuses predates the transition to a completely pelagic‐lifestyle. We proposed a stepwise evolutionary scenario of Thalattosuchia, implying changes in the preorbital region (and orbit orientation) where the internalized antorbital sinus via its subsidiary diverticulum was co‐opted for helping nasal glands drainage. Further scrutiny of facial anatomy of a larger sample of thalattosuchians will help to test this hypothesis.
Gender identification on Twitter
Authors: Ikae Catherine , Savoy Jacques
Published: June 2021

To determine the author of a text's gender, various feature types have been suggested (e.g., function words, n‐gram of letters, etc.) leading to a huge number of stylistic markers. To determine the target category, different machine learning models have been suggested (e.g., logistic regression, decision tree, k nearest‐neighbors, support vector machine, naïve Bayes, neural networks, and random forest). In this study, our first objective is to know whether or not the same model always proposes the best effectiveness when considering similar corpora under the same conditions. Thus, based on 7 CLEF‐PAN collections, this study analyzes the effectiveness of 10 different classifiers. Our second aim is to propose a 2‐stage feature selection to reduce the feature size to a few hundred terms without any significant change in the performance level compared to approaches using all the attributes (increase of around 5% after applying the proposed feature selection). Based on our experiments, neural network or random forest tend, on average, to produce the highest effectiveness. Moreover, empirical evidence indicates that reducing the feature set size to around 300 without penalizing the effectiveness is possible. Finally, based on such reduced feature sizes, an analysis reveals some of the specific terms that clearly discriminate between the 2 genders.
Is the tropical cyclone surge in Shanghai more sensitive to landfall location or intensity change?
Authors: Wang Shuai , Toumi Ralf , Ye Qinghua , Ke Qian , Bricker Jeremy , Tian Zhan , Sun Laixiang
Published: June 2021

It has been shown that the proportion of intense tropical cyclones (TCs) has been increasing together with a poleward migration of TC track. However, their relative importance to TC surge at landfall remains unknown. Here we examine the sensitivity of TC surge in Shanghai to landfall location and intensity with a new dynamical modelling framework. We find a surge sensitivity of 0.8 m (°N)−1 to landfall location, and 0.1 m (m s−1)−1 to wind speed in Shanghai during landfall. The landfall location and intensity are comparably important to surge variation. However, based on a plausible range of reported trends of TC poleward migration and intensity, the potential surge hazard due to poleward migration is estimated to be about three times larger than that by intensity change. The long‐term surge risk in Shanghai is therefore substantially more sensitive to changes of TC track and landfall location than intensity. This may also be true elsewhere and in the future.
Special volume, preface – 9th International Workshop on Astronomy and Relativistic Astrophysics: From Quarks to Cosmos
Authors: Zen Vasconcellos César A. , Hess Peter O. , Piccinelli Gabriella , Magaña Mariana Vargas , Ureña‐Lopez Luis , Felipe Ricardo Gonzalez , Boller Thomas , Gullberg Steven
Published: June 2021

This special volume includes contributions from some of the most relevant scientists who have participated in the IWARA 2020 Video Conference. The series of meetings known by the acronyms IWARA, STARS, and SMFNS,—more than a congregation of events, students and researchers which in itself would be extremely important for science—became in last years a kind of platform for scientific and academic projects, partnerships and presentation of high‐quality research contributions describing original and unpublished results on several topics related as new phenomena and new states of matter in the Universe, general relativity, gravitation, cosmology, astrophysics, particle and nuclear physics, and topics related. And the scientists participating in this volume, perfectly integrated with this design, bring more than just a glimpse into the technical toolbox of their work, be it theoretical or experimental. In addition to international scientific recognition, these researchers are mentors of students and young researchers, and demonstrate, in these contributions, also glimpses of systematically complex decisions made about the interpretation of data, about which problems are relevant to pursue, thus contributing a lot to the craft of science and its development.
Fluorescence‐based screening for engineered aldo‐keto reductase KmAKR with improved catalytic performance and extended substrate scope
Authors: Qiu Shuai , Xu Shen‐Yuan , Li Shu‐Fang , Meng Kang‐Ming , Cheng Feng , Wang Ya‐Jun , Zheng Yu‐Guo
Published: June 2021

Background

Aldo‐keto reductases‐catalyzed transformations of ketones to chiral alcohols have become an established biocatalytic process step in the pharmaceutical industry. Previously, we have discovered an aldo‐keto reductase (AKR) from Kluyveromyces marxianus that is active to the aliphatic tert‐butyl 6‐substituted (5R/S)‐hydroxy‐3‐oxohexanoates, but it is inactive to aromatic ketones. In order to acquire an excellent KmAKRmutant for ensuring the simultaneous improvement of activity‐thermostability toward tert‐butyl 6‐cyano‐(5R)‐hydroxy‐3‐oxohexanoate ((5R)‐1) and broadening the universal application prospects toward more substrates covering both aliphatic and aromatic ketones, a fluorescence‐based high‐throughput (HT) screening technique was established.

Main Methods and Major Results

The directed evolution of KmAKR variant M5 (KmAKR‐W297H/Y296W/K29H/Y28A/T63M) produced the “best” variant M5‐Q213A/T23V. It exhibited enhanced activity‐thermostability toward (5R)‐1, improved activity toward all 18 test substrates and strict R‐stereoselectivity toward 10 substrates in comparison to M5. The enhancement of enzymatic activity and the extension of substrate scope covering aromatic ketones are proposed to be largely attributed to pushing the binding pocket of M5‐Q213A/T23V to the enzyme surface, decreasing the steric hindrance at the entrance and enhancing the flexibility of loops surrounding the active center. In addition, combined with 0.94 g dry cell weight (DCW) L−1 glucose dehydrogenase from Exiguobacterium sibiricum (EsGDH) for NADPH regeneration, 2.81 g DCW L−1 M5‐Q213A/T23V completely converted (5R)‐1 of up to 450 g L−1 at 120 g g–1 substrates/catalysts (S/C), yielding the corresponding optically pure tert‐butyl 6‐cyano‐(3R,5R)‐dihydroxyhexanoate ((3R,5R)‐2, > 99.5% d.e.p) with a space‐time yield (STY) of 1.08 kg L−1 day−1.

Conclusions

A fluorescence‐based HT screening system was developed to tailor KmAKR's activity, thermostability and substrate scope. The “best” variant M5‐Q213A/T23V holds great potential application for the synthesis of aliphatic/aromatic R‐configuration alcohols.
The GLP‐1/GIP dual‐receptor agonist DA5‐CH inhibits the NF‐κB inflammatory pathway in the MPTP mouse model of Parkinson's disease more effectively than the GLP‐1 single‐receptor agonist NLY01
Authors: Lv MiaoJun , Xue GuoFang , Cheng HuiFeng , Meng PengFei , Lian Xia , Hölscher Christian , Li DongFang
Published: June 2021

The GLP‐1 receptor agonist exendin‐4 has recently shown good effects in a phase II clinical trial in Parkinson's disease (PD) patients. Here, a comparison of the new GLP‐1/GIP dual receptor agonist DA5‐CH and NLY01, a 40 kDa pegylated form of exendin‐4, on motor impairments and reducing inflammation in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) PD mouse model is provided. The drug groups received either DA5‐CH or NLY01 (25 nmol/kg) i.p. after daily MPTP intraperitoneal injection. Both drugs showed improvements in motor activity, open field experiments, rotarod tests, and gait analysis, but DA5‐CH was more potent. Tyrosine hydroxylase expression in dopaminergic neurons was much reduced by MPTP and improved by DA5‐CH, while NLY01 showed weak effects. When analyzing levels of α‐synuclein (α‐Syn), DA5‐CH reduced levels effectively while NLY01 had no effect. When measuring the levels of the inflammation markers Toll‐like receptor 4 (TLR4), specific markers of microglia activation (Iba‐1), the marker of astrocyte activation glial fibrillary acidic protein (GFAP), nuclear factor‐κB (NF‐κB), tumor necrosis factor (TNF‐α), and transforming growth factor β1 (TGF‐β1), DA5‐CH was very effective in reducing the chronic inflammation response, while NLY01 did not show significant effects. Levels of key growth factors such as Glial cell‐derived neurotrophic factor (GDNF) and Brain‐derived neurotrophic factor (BDNF) were much reduced by MPTP, and DA5‐CH was able to normalize levels in the brain, while NLY01 showed little effect. The levels of pro‐inflammatory cytokines (IL‐6 and IL‐Iβ) were much reduced by DA5‐CH, too, while NLY01 showed no effect. In a separate experiment, we tested the ability of the two drugs to cross the blood‐brain barrier. After injecting fluorescin‐labelled peptides peripherally, the fluorescence in brain tissue was measured. It was found that the pegylated NLY01 peptide did not cross the BBB in meaningful quantities while exendin‐4 and the dual agonist DA5‐CH did. The results show that DA5‐CH shows promise as a therapeutic drug for PD.
Worse capecitabine treatment outcome in patients with a low skeletal muscle mass is not explained by altered pharmacokinetics
Authors: Molenaar‐Kuijsten Laura , Jacobs Bart Albertus Wilhelmus , Kurk Sophie Alberdine , May Anne Maria , Dorlo Thomas Petrus Catharina , Beijnen Jacob Hendrik , Steeghs Neeltje , Huitema Alwin Dagmar Redmar
Published: June 2021

Background

A low skeletal muscle mass (SMM) has been associated with increased toxicity and shorter survival in cancer patients treated with capecitabine, an oral prodrug of 5‐fluorouracil (5‐FU). Capecitabine and its metabolites are highly water‐soluble and, therefore, more likely to distribute to lean tissues. The pharmacokinetics (PK) in patients with a low SMM could be changed, for example, by reaching higher maximum plasma concentrations. In this study, we aimed to examine whether the association between a low SMM and increased toxicity and shorter survival could be explained by altered PK of capecitabine and its metabolites.

Methods

Previously, a population PK model of capecitabine and metabolites in patients with solid tumors was developed. In our analysis, we included patients from this previous analysis for which evaluable abdominal computed tomography (CT)‐scans were available. SMM was measured on CT‐scans, by single slice evaluation at the third lumbar vertebra, using the Slice‐o‐Matic software. The previously developed population PK model was extended with SMM as a covariate, to assess the association between SMM and capecitabine and metabolite PK.

Results

PK and SMM data were available from 151 cancer patients with solid tumors. From the included patients, 55% had a low SMM. No relevant relationships were found between SMM and the PK parameters of capecitabine and, the active and toxic metabolite, 5‐FU. SMM only correlated with the PK of the, most hydrophilic, but inactive and non‐toxic, metabolite α‐fluoro‐β‐alanine (FBAL). Patients with a low SMM had a smaller apparent volume of distribution and lower apparent clearance of FBAL.

Conclusions

No alterations in PK of capecitabine and the active and toxic metabolite 5‐FU were observed in patients with a low SMM. Therefore, the previously identified increased toxicity and shorter survival in patients with a low SMM, could not be explained by changes in pharmacokinetic characteristics of capecitabine and metabolites.
Tricuspid clip implantation using the MitraClip system–A step‐by‐step guide
Authors: Kaple Ryan K. , Agarwal Vratika , Azarbal Amir , Sugeng Lissa , Tang Gilbert H. L.
Published: June 2021

Many novel percutaneous interventions are being developed for application in the tricuspid valve position. At the present time, there are no commercially available devices for this application. There has been mounting evidence supporting the safety and efficacy of using the MitraClip system on the tricuspid valve. This review summarizes the peer reviewed data available to date supporting this procedure, outlines the step‐by‐step maneuvers using the MitraClip system for this application, and imaging techniques used prior to and during the procedure.
Random Packing Performance in Continuous Foam Fractionation
Authors: Gu Qianfeng , Xue Xiaochen , Darwesh Osama M. , Habimana Pascal , Liu Wei , Wu Zhaoliang , Li Zhiqiang
Published: June 2021

The #25 teller rosette (TR) random packing was used to enhance foam drainage in foam fractionation under continuous steady‐state conditions and tested using sodium dodecyl sulfate (SDS) as a model surfactant. A column without the #25 TR served as control. The results demonstrated that the #25 TR was capable of enhancing the foam drainage and enrichment ratio while reducing the liquid holdup. The experiment was set up with optimized feed flow rate, liquid pool height, air flow rate, and SDS feed concentration. The enrichment ratio obtained by the #25 TR column was 1.76 times higher compared with the control column. Based on the mass balances and equilibrium relationship, a new method for graphical illustration of theoretical stages is also presented.
Prediction of Thermal Behavior of Polycarbonate/Cerium Oxide Composite Films
Authors: Larosa Claudio , Saldābola Rūta , Zicāns Jānis , Merijs Meri Remo , Eggenhöffner Roberto , Converti Attilio
Published: June 2021

Thermal effects in polycarbonate (PC) induced by lanthanide oxide nanoparticles (NPs) dispersed by blending were studied using thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). DSC data proved the occurrence of solvent‐induced crystallization of polymer doped with cerium oxide (ceria). TGA was performed to predict PC flammability properties in composites with 5–15 wt % ceria NPs at various heating rates. Decomposition was represented by first‐order reactions and the Arrhenius equation. A model was formulated for thin samples subject to uniform heat irradiation, which is based on PC softening and decomposition into several products. This is an attempt to predict composite film burning behavior assuming constant heat transmission to samples.
In Situ Electrochemical Investigations of Inherently Chiral 2,2′‐Biindole Architectures with Oligothiophene Terminals
Authors: Malacrida Claudia , Scapinello Luca , Cirilli Roberto , Grecchi Sara , Penoni Andrea , Benincori Tiziana , Ludwigs Sabine
Published: June 2021

The synthesis and characterization of three new inherently chiral N,N′‐dipropyl‐3,3′‐diheteroaryl‐2,2′‐biindole monomers, nicknamed Ind2T4, Ind2T6 and Ind2Ph2T4, which differ in the number of thiophenes as terminals, are reported. In addition to a full monomer characterization, stable electroactive oligomeric films were obtained by electro‐oxidation upon cycling to potentials which activate the thiophene terminals. Cyclic voltammetry, UV‐Vis‐NIR spectroelectrochemistry and in situ conductance measurements show that oligomeric films of Ind2T6 present the best stability and electrochromic switching performance. Enantioselective tests with a chiral ferrocene amine clearly show the potential as chiral selectors for analytical and sensing purposes.
Pathways of the Extremely Reactive Iron(IV)‐oxido complexes with Tetradentate Bispidine Ligands
Authors: Abu‐Odeh Mahmud , Bleher Katharina , Johnee Britto Neethinathan , Comba Peter , Gast Michael , Jaccob Madhavan , Kerscher Marion , Krieg Saskia , Kurth Marius
Published: June 2021

The nonheme iron(IV)‐oxido complex trans‐N3‐[(L1)FeIV=O(Cl)]+, where L1 is a derivative of the tetradentate bispidine 2,4‐di(pyridine‐2‐yl)‐3,7‐diazabicyclo[3.3.1]nonane‐1‐one, is known to have an S=1 electronic ground state and to be an extremely reactive oxidant for oxygen atom transfer (OAT) and hydrogen atom abstraction (HAA) processes. Here we show that, in spite of this ferryl oxidant having the “wrong” spin ground state, it is the most reactive nonheme iron model system known so far and of a similar order of reactivity as nonheme iron enzymes (C−H abstraction of cyclohexane, −90 °C (propionitrile), t1/2=3.5 sec). Discussed are spectroscopic and kinetic data, supported by a DFT‐based theoretical analysis, which indicate that substrate oxidation is significantly faster than self‐decay processes due to an intramolecular demethylation pathway and formation of an oxido‐bridged diiron(III) intermediate. It is also shown that the iron(III)‐chlorido‐hydroxido/cyclohexyl radical intermediate, resulting from C−H abstraction, selectively produces chlorocyclohexane in a rebound process. However, the life‐time of the intermediate is so long that other reaction channels (known as cage escape) become important, and much of the C−H abstraction therefore is unproductive. In bulk reactions at ambient temperature and at longer time scales, there is formation of significant amounts of oxidation product – selectively of chlorocyclohexane – and it is shown that this originates from oxidation of the oxido‐bridged diiron(III) resting state.
Self‐Assembled Cationic Polypeptide Supramolecular Nanogels for Intracellular DNA Delivery
Authors: Pottanam Chali Sharafudheen , Hüwel Sabine , Rentmeister Andrea , Ravoo Bart Jan
Published: June 2021

Supramolecular nanogels are an emerging class of polymer nanocarriers for intracellular delivery, due to their straightforward preparation, biocompatibility, and capability to spontaneously encapsulate biologically active components such as DNA. A completely biodegradable three‐component cationic supramolecular nanogel was designed exploiting the multivalent host‐guest interaction of cyclodextrin and adamantane attached to a polypeptide backbone. While cyclodextrin was conjugated to linear poly‐L‐lysine, adamantane was grafted to linear as well as star shaped poly‐L‐lysine. Size control of nanogels was obtained with the increase in the length of the host and guest polymer. Moreover, smaller nanogels were obtained using the star shaped polymers because of the compact nature of star polymers compared to linear polymers. Nanogels were loaded with anionic model cargoes, pyranine and carboxyfluorescein, and their enzyme responsive release was studied using protease trypsin. Confocal microscopy revealed successful transfection of mammalian HeLa cells and intracellular release of pyranine and plasmid DNA, as quantified using a luciferase assay, showing that supramolecular polypeptide nanogels have significant potential in gene therapy applications.
Prognostic impact of resistance to bortezomib and/or lenalidomide in carfilzomib‐based therapies for relapsed/refractory multiple myeloma: The Kyoto Clinical Hematology Study Group, multicenter, pilot, prospective, observational study in Asian patients
Authors: Kawaji‐Kanayama Yuka , Kobayashi Tsutomu , Muramatsu Ayako , Uchiyama Hitoji , Sasaki Nana , Uoshima Nobuhiko , Nakao Mitsushige , Takahashi Ryoichi , Shimura Kazuho , Kaneko Hiroto , Kiyota Miki , Wada Katsuya , Chinen Yoshiaki , Hirakawa Koichi , Fuchida Shin‐ichi , Shimazaki Chihiro , Matsumura‐Kimoto Yayoi , Mizutani Shinsuke , Tsukamoto Taku , Shimura Yuji , Horiike Shigeo , Taniwaki Masafumi , Kuroda Junya ,   Kyoto Clinical Hematology Study Group (KOTOSG) Investigators
Published: June 2021

Background

Combinatory strategies with carfilzomib (CFZ), a second‐generation proteasome inhibitor, plus dexamethasone (DEX) with or without lenalidomide (LEN) have shown promising efficacy for patients with relapsed/refractory multiple myeloma (RRMM) in pivotal clinical trials. However, their effects on patients who were resistance to bortezomib (BTZ) and/or LEN have not been fully evaluated in a daily practice setting.

Aims

To evaluate the real‐world efficacy and safety of CFZ‐based treatments; that is, CFZ with LEN plus DEX (KRD therapy) and CFZ with DEX (KD therapy), in Asian patients, we conducted a multicenter pilot prospective observational study in the Kyoto Clinical Hematology Study Group.

Methods and Results

All 50 patients with RRMM enrolled in this study were treated with CFZ‐based treatments between 2017 and 2019. KRD and KD were administered to 31 and 19 patients, respectively. The overall response rates (ORRs) were 80.6% with KRD and 73.7% with KD. Two‐year progression‐free survival (PFS) and overall survival (OS) were 58.5% and 79.7% with KRD, and 23.1% and 52.6% with KD. By multivariate analysis, refractoriness to BTZ and to LEN were identified as independent unfavorable factors for both PFS and OS. The common non‐hematologic AEs included hypertension (42.0%), fever (24.0%), fatigue (24.0%), and infection (16.0%). No serious heart failure was observed. This study is registered as UMIN000025108.

Conclusion

This study suggests the need of the development of novel CFZ‐containing strategy which can overcome the refractoriness to BTZ and/or LEN, while both KRD and KD were shown to be mostly feasible in Asian patients in a daily practice setting.
Ship‐iceberg discrimination from Sentinel‐1 synthetic aperture radar data using parallel convolutional neural network
Authors: Song Lan , Peters Dennis K. , Huang Weimin , Power Desmond
Published: June 2021

Ships and icebergs are similar in size and intensity in SAR images, so it is difficult to distinguish them in remote sensing images. Deep learning is a technique based on neural networks, which has played an important role in image information processing. In order to address the challenge of ship and iceberg classification, we present a convolutional neural network (CNN) based classification method for iceberg and ship discrimination from Sentinel‐1 SAR images with different polarizations and incidence angles. The method is based on the fixed constant false alarm rate (CFAR) detector and the CNN model has three input channels, then the model was trained using parallel algorithm. The CNN is trained using 1443 images and tested using 161 images. The CNN model is also compared with support vector machine (SVM) and k nearest neighbors (kNN) using the same dataset. Comparison shows the CNN‐based method performs the best, and it achieved a validation accuracy of 96%.
Accelerated Reaction Engineering of Photo(bio)catalytic Reactions through Parallelization with an Open‐Source Photoreactor
Authors: Winkler Christoph K. , Simić Stefan , Jurkaš Valentina , Bierbaumer Sarah , Schmermund Luca , Poschenrieder Silvan , Berger Sarah A. , Kulterer Elisa , Kourist Robert , Kroutil Wolfgang
Published: June 2021

Photobiocatalysis is an alternative approach in synthesis that has received much attention in the recent years. Due to the youth of the topic, only few reactor systems are commercially available. To allow a parallel parameter‐screening approach as often used in the optimization of biocatalytic processes, a photoreactor was developed that can illuminate up to 24 samples at well‐defined reaction conditions. The device‘s optical features and temperature regulation have been thoroughly characterized and its application was demonstrated in four examples, specifically three photobiocatalytic and one photocatalytic process: (i) Light‐dependent decarboxylation using a photodecarboxylase; (ii) Reduction of protochlorophyllide using a protochlorophyllide oxidoreductase; (iii) Photosynthetic oxygen production performed by cyanobacteria; and (iv) (−)‐Riboflavin‐catalyzed (E/Z)‐isomerization of cinnamic acid derivatives.