bluuebunny/crossref_metadata_2025 huggingface dataset:
A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders
Authors: Suzuki Toshimitsu , Suzuki Toshifumi , Raveau Matthieu , Miyake Noriko , Sudo Genki , Tsurusaki Yoshinori , Watanabe Takaki , Sugaya Yuki , Tatsukawa Tetsuya , Mazaki Emi , Shimohata Atsushi , Kushima Itaru , Aleksic Branko , Shiino Tomoko , Toyota Tomoko , Iwayama Yoshimi , Nakaoka Kentaro , Ohmori Iori , Sasaki Aya , Watanabe Ken , Hirose Shinichi , Kaneko Sunao , Inoue Yushi , Yoshikawa Takeo , Ozaki Norio , Kano Masanobu , Shimoji Takeyoshi , Matsumoto Naomichi , Yamakawa Kazuhiro
Published: June 2020

Objective

Neurodevelopmental disorders (NDDs) often associate with epilepsy or craniofacial malformations. Recent large‐scale DNA analyses identified hundreds of candidate genes for NDDs, but a large portion of the cases still remain unexplained. We aimed to identify novel candidate genes for NDDs.

Methods

We performed exome sequencing of 95 patients with NDDs including 51 with trigonocephaly and subsequent targeted sequencing of additional 463 NDD patients, functional analyses of variant in vitro, and evaluations of autism spectrum disorder (ASD)‐like phenotypes and seizure‐related phenotypes in vivo.

Results

We identified de novo truncation variants in nine novel genes; CYP1A1, C14orf119, FLI1, CYB5R4, SEL1L2, RAB11FIP2, ZMYND8, ZNF143, and MSX2. MSX2 variants have been described in patients with cranial malformations, and our present patient with the MSX2 de novo truncation variant showed cranial meningocele and partial epilepsy. MSX2 protein is known to be ubiquitinated by an E3 ubiquitin ligase PJA1, and interestingly we found a PJA1 hemizygous p.Arg376Cys variant recurrently in seven Japanese NDD patients; five with trigonocephaly and one with partial epilepsy, and the variant was absent in 886 Japanese control individuals. Pja1 knock‐in mice carrying p.Arg365Cys, which is equivalent to p.Arg376Cys in human, showed a significant decrease in PJA1 protein amount, suggesting a loss‐of‐function effect of the variant. Pja1 knockout mice displayed moderate deficits in isolation‐induced ultrasonic vocalizations and increased seizure susceptibility to pentylenetetrazole.

Interpretation

These findings propose novel candidate genes including PJA1 and MSX2 for NDDs associated with craniofacial abnormalities and/or epilepsy.
Bioprinting Tissue Analogues with Decellularized Extracellular Matrix Bioink for Regeneration and Tissue Models of Cartilage and Intervertebral Discs
Authors: Vernengo Andrea J. , Grad Sibylle , Eglin David , Alini Mauro , Li Zhen
Published: June 2020

The recent convergence of decellularized extracellular matrix (dECM) methodologies and 3D bioprinting (3DBP) has led to multiple advancements in tissue engineering scaffold design by enabling researchers to recreate a tissue‐specific 3D environment in a custom geometry. The application of 3DBP of dECM for articular cartilage and intervertebral disc (IVD) repair, however, is still burgeoning. While cartilage and IVD tissue each possess unique architectures, they are composed of similar macromolecules and therefore pose similar challenges for the successful application of their matrix bioinks. Herein, the state‐of‐the‐art in cartilage and IVD dECM bioink preparation, material properties, and applications are highlighted. The current major obstacles regarding optimal decellularization and printing methods are discussed, which need to be overcome to enable recapitulation of the hierarchical organization, zone‐specific matrix composition, and anisotropic biomechanical behavior of the native tissues. Finally, a vision is presented for how this field may continue to evolve in the future to empower the fabrication of scaffolds that serve as effective templates for guiding cellular assembly and organization toward the formation of functional cartilage and IVD tissues.
Chirality of Liquid Crystals Formed from Achiral Molecules Revealed by Resonant X‐Ray Scattering
Authors: Lewandowski Wiktor , Vaupotič Nataša , Pociecha Damian , Górecka Ewa , Liz‐Marzán Luis M.
Published: June 2020

Intensive research on chiral liquid crystals (LCs) has been fueled by their actively tunable physicochemical properties and structural complexity, comparable to those of sophisticated natural materials. Herein, recent progress in the discovery of new classes of chiral LCs, enabled by a combination of nano‐ and macroscale investigations is reviewed. First, an overview is provided of liquid crystalline phases, made of chiral and achiral low‐weight molecules, that exhibit chiral structure and/or chiral morphology. Then, recent progress in the discovery of new classes of chiral LCs, particularly enabled by the application of resonant X‐ray scattering is described. It is shown that the method is sensitive to modulations of molecular orientation and therefore provides information hardly accessible by means of other techniques, such as the sense of helical structures or chirality transfer across length scales. Finally, a perspective is presented on the future scope, opportunities, and challenges in the field of chiral LCs, in particular related to nanocomposites.
Direct Conversion of Rice Husks to Nanostructured SiC/C for CO2 Photoreduction
Authors: Weng Wei , Wang Sibo , Xiao Wei , Lou Xiong Wen (David)
Published: June 2020

A one‐step and template‐free synthesis of a SiC nanowires/C (SiC‐NW/C) composite from rice husks (RHs) is realized via a molten‐salt‐assisted electrochemical method. The process integrates simultaneously carbonization, electrodeoxidation, nanostructuring, and self‐purification for converting RHs to a SiC‐NW/C hybrid that is assembled from SiC NWs embedded in porous N‐doped graphitic carbon with strong coupling. The SiC‐NW/C nanostructure enables efficient CO2 adsorption and fast separation and transfer of charge carriers. Benefiting from the structural and compositional merits, the SiC‐NW/C composite shows superior activity for photoreduction of CO2 to CO, in the absence of any additional cocatalysts or sacrificial agents. The process proposed herein might help to bridge a closed‐loop carbon cycle in the whole production–utilization of biomass.
In Vivo Enrichment and Elimination of Circulating Tumor Cells by Using a Black Phosphorus and Antibody Functionalized Intravenous Catheter
Authors: Wang Dou , Ge Chenchen , Liang Weiyuan , Yang Qinhe , Liu Quan , Ma Wei , Shi Lulin , Wu Hong , Zhang Yuhua , Wu Zongze , Wei Chaoying , Huang Luodan , Fang Zhiyuan , Liu Liping , Bao Shiyun , Zhang Han
Published: June 2020

The circulating tumor cell (CTC) count is closely related to cancer recurrence and metastasis. The technology that can in vivo destroy CTCs may bring great benefits to patients, which is an urgent clinical demand. Here, a minimally invasive therapeutic intravenous catheter for in vivo enriching and photothermal killing of CTCs is developed. The surface of catheter is modified with anti‐EpCAM antibody and the interior is filled with black phosphorus nanosheets (BPNSs). CTCs in the peripheral blood are captured by the catheter continually with the aid of circulation. The captured CTCs are used for downstream analyses or in vivo eliminated by the near‐infrared (NIR) photothermal effect of BPNSs. A capture efficiency of 2.1% is obtained during the 5 min of treatment, and 100% of the captured CTCs are killed by following NIR light irradiation in both an in vitro closed‐loop circulation system and an in vivo rabbit model. This cost‐effective modality for lowering the CTCs burden can be a good supplement to traditional therapies, which holds great promise as an effective clinical intervention for cancer patients.
Multiple Stimuli Responsive and Identifiable Zwitterionic Ionic Conductive Hydrogel for Bionic Electronic Skin
Authors: Huang Hailong , Han Lu , Fu Xiaobin , Wang Yanling , Yang Zhongli , Pan Likun , Xu Min
Published: June 2020

Bionic electronic skin (E‐skin) is considered to be the best candidate for health monitoring sensor, soft robots, biomedical prostheses, artificial intelligence, and wearable electronics devices. However, most existing studies on bionic E‐skin mainly focus on their strain–stress response. Although some works involved specific response to physiological signals such as temperature, sweat, wet, and so on, most reported E‐skins lack special ability to identify multiple stimuli, which limits their applications in real working environment. In this work, an intelligent zwitterionic ionic conductive hydrogel with double network structure (SAA: NaCl/sodium alginate/poly acrylic‐acrylamide) for bionic E‐skin is developed. The SAA hydrogel as E‐skin not only exhibits high sensitivity to strain–stress, but also demonstrates superior sensing performance in human body motion and physiological signal response. More importantly, the SAA hydrogel possesses excellent identification ability to the superposed signals of multiple stimuli. The type of stimulus can be readily distinguished via electrical signal waveform. The SAA hydrogel should be promisingly applied as multiple stimuli responsive and identifiable bionic E‐skin for sports monitoring, human/machine interfaces, and soft robotics.
Electronic Performance of Polymer Carbon‐Paste Nanoallotropes from 0D to 3D as Novel Gate Electrodes in Water‐Gated Organic Field‐Effect Transistors
Authors: Tamayo Adrián , Muñoz Jose , Mas‐Torrent Marta
Published: June 2020

Water‐gated organic field‐effect transistors (WGOFETs) are expected to have a strong impact in the field of electronic biosensors owing to the synergism between the transduction function of the transistors with the fact that they can be operated in physiological media. Nonetheless, a limited library of gate electrodes has currently been explored for this aim. Herein, different polymer nanocomposite carbon paste gate electrodes (NC‐CPgEs) are successfully exploited for the first time as unusual nonmetal gate electrodes in WGOFET devices employing four types of carbon nanoallotropes with dimensionality ranging from 0D to 3D (i.e., carbon nanohorns, carbon nanotubes, reduced graphene oxide, and graphite, respectively). Interestingly, after an accurate electrochemical and electrical characterization, it is demonstrated that the WGOFETs with the developed NC‐CPgEs reveal excellent behaviors comparable to that achieved with conventional gate electrodes, such as gold or glassy carbon electrodes. Further, depending on the carbon nature the device performance can be tuned, being the devices based on reduced graphene oxide the ones showing a better electrical response. Accordingly, this work can pave the way for widespread applications of NC‐CPgEs for the development of a new generation of WGOFET devices based on carbon nanostructures.
Achieving Balanced Crystallization Kinetics of Donor and Acceptor by Sequential‐Blade Coated Double Bulk Heterojunction Organic Solar Cells
Authors: Wang Yilin , Wang Xiaohui , Lin Baojun , Bi Zhaozhao , Zhou Xiaobo , Naveed Hafiz Bilal , Zhou Ke , Yan Hongping , Tang Zheng , Ma Wei
Published: June 2020

Sequential deposition has great potential to achieve high performance in organic solar cells due to the resulting well‐controlled vertical phase separation. In this work, double bulk heterojunction organic solar cells are fabricated by sequential‐blade cast in ambient conditions. Probed by the in situ grazing incidence X‐ray diffraction and in situ UV–vis absorption measurements, the seq‐blade system exhibits a different tendency from each of the binary films during the film formation process. Due to the extensive aggregation of FOIC, the binary PBDB‐T:FOIC film displays a strong and large phase separation, resulting in low current density (Jsc) and unsatisfactory power conversion efficiency. In the seq‐blade cast system, the bottom layer PBDB‐T:IT‐M produces many crystal nuclei for the top layer PBDB‐T:FOIC, so the PBDB‐T molecules are able to crystallize easily and quickly. Balanced crystallization kinetics between polymer and small molecule and an ideal percolation network in the film are observed. In addition, the balanced crystallization kinetics are favorable toward realizing lower recombination loss through charge transport processes.
Spatio‐temporal calibration of Hargreaves‐Samani model to estimate reference evapotranspiration across U.S. High Plains
Authors: Kukal M.S. , Irmak S. , Walia H. , Odhiambo L.
Published: June 2020

Temperature‐based grass‐reference evapotranspiration (ETo) estimation methods (e.g., Hargreaves−Samani [HS] model) present advantages over combination‐based methods that require full‐suite weather data. The U.S. High Plains region has scarce and short‐term full‐suite weather sites. This data scarcity presents challenges for combination‐based ETo estimation. The performance of HS model against the American Society of Civil Engineers (ASCE) standardized Penman−Monteith (PM) model was assessed using long‐term data at 124 full‐suite weather sites across nine states in the U.S. High Plains. The HS model underestimated ETo at arid (mean bias error [MBE] = −1.68 mm d−1), semi‐arid (MBE = −0.34 mm d−1), and dry subhumid sites (MBE = −0.16 mm d−1) and overestimated ETo at humid sites (MBE = 0.14 mm d−1). There was a significant relationship (p < .01) between HS model performance and aridity index. The HS model performed better (27% lower root mean squared difference [RMSD]) in summer months than the rest of the year at semi‐arid and dry subhumid sites. The model performance was non‐ideal during the summer months in subhumid climates. Spatio‐temporal annual zonal (climate division), monthly zonal, annual site‐specific, and monthly site‐specific calibration resulted in 12, 16, 20, and 26% reduction in RMSD and 11, 16, 17, and 23% reduction in relative error, respectively. Monthly site‐specific calibration performed the best and was used to quantify annual and growing season ETo across the region. The research characterized performance patterns of the HS model over an important agroecosystem‐dominated region. Practical data‐driven strategies were proposed to better estimate PM ETo using limited weather data at any given site (with similar aridity) and time of the year.
Variation of bony labyrinthine morphology in Mio−Plio−Pleistocene and modern anthropoids
Authors: Morimoto Naoki , Kunimatsu Yutaka , Nakatsukasa Masato , Ponce de León Marcia S. , Zollikofer Christoph P. E. , Ishida Hidemi , Sasaki Tomohiko , Suwa Gen
Published: June 2020

Objectives

The bony labyrinth of the inner ear has special relevance when tracking phenotypic evolution because it is often well preserved in fossil and modern primates. Here we track the evolution of the bony labyrinth of anthropoid primates during the Mio−Plio−Pleistocene—the time period that gave rise to the extant great apes and humans.

Materials and Methods

We use geometric morphometrics to analyze labyrinthine morphology in a wide range of extant and fossil anthropoids, including New World and Old World monkeys, apes, and humans; fossil taxa are represented by Aegyptopithecus, Microcolobus, Epipliopithecus, Nacholapithecus, Oreopithecus, Ardipithecus, Australopithecus, and Homo.

Results

Our results show that the morphology of the anthropoid bony labyrinth conveys a statistically significant phylogenetic signal especially at the family level. The bony labyrinthine morphology of anthropoids is also in part associated with size, but does not cluster by locomotor adaptations. The Miocene apes examined here, regardless of inferred locomotor behaviors, show labyrinthine morphologies distinct from modern great apes.

Discussion

Our results suggest that labyrinthine variation contains mixed signals and alternative explanations need to be explored, such as random genetic drift and neutral phenotypic evolution, as well as developmental constraints. The observed pattern in fossil and extant hominoids also suggests that an additional factor, for example, prenatal brain development, could have potentially had a larger role in the evolutionary modification of the bony labyrinth than hitherto recognized.
Successful treatment with artificial pancreas for a patient who attempted suicide using a high‐dose insulin s.c. injection
Authors: Sakurai Toshihiro , Harada Masahiro , Takahashi Takeshi
Published: June 2020

Background

Artificial pancreas is usually used to manage hyperglycemia. We controlled prolonged hypoglycemia induced by insulin overdose using artificial pancreas.

Case Presentation

A 56‐year‐old female patient with type 2 diabetes mellitus was admitted to the emergency department after overdosing on 1,800 units each of insulin aspart and insulin degludec. She had also ingested 2 weeks of anti‐anxiety medication. When the patient arrived at the hospital, her blood glucose level was 30 mg/dL and she was in a coma. Artificial pancreas (STG‐55; Nikkiso, Tokyo, Japan) was used to control blood glucose levels because we were unable to predict the duration or degree of hypoglycemia. Blood glucose levels were safely controlled without the development of hypo‐ or hyperglycemia. Finally, the patient was discharged without any complications on day 7.

Conclusion

The STG‐55 artificial pancreas was very useful and convenient for controlling blood glucose levels in our insulin overdose patient.
Synthesis, Characterization, and Reactivity of a Hypervalent‐Iodine‐Based Nitrooxylating Reagent
Authors: Calvo Roxan , Le Tellier Antoine , Nauser Thomas , Rombach David , Nater Darryl , Katayev Dmitry
Published: June 2020

Herein, the synthesis and characterization of a hypervalent‐iodine‐based reagent that enables a direct and selective nitrooxylation of enolizable C−H bonds to access a broad array of organic nitrate esters is reported. This compound is bench stable, easy‐to‐handle, and delivers the nitrooxy (‐ONO2) group under mild reaction conditions. Activation of the reagent by Brønsted and Lewis acids was demonstrated in the synthesis of nitrooxylated β‐keto esters, 1,3‐diketones, and malonates, while its activity under photoredox catalysis was shown in the synthesis of nitrooxylated oxindoles. Detailed mechanistic studies including pulse radiolysis, Stern–Volmer quenching studies, and UV/Vis spectroelectrochemistry reveal a unique single‐electron‐transfer (SET)‐induced concerted mechanistic pathway not reliant upon generation of the nitrate radical.
Prognostic values of the clinicopathological characteristics and survival outcomes in micropapillary urothelial carcinoma of the bladder: A SEER database analysis
Authors: Jin Di , Jin Kun , Qiu Shi , Zhou Xianghong , Yuan Qiming , Yang Lu , Wei Qiang
Published: June 2020

Purpose

To study prognostic values of the clinicopathological characteristics and survival outcomes in micropapillary urothelial carcinoma (MPUC) of the urinary bladder.

Method

We used the national Surveillance, Epidemiology, and End Results database (2004‐2016) to compare MPUC with transitional cell carcinoma (TCC) and to investigate prognostic values of clinicopathological characteristics, as well as survival outcomes, in MPUC of the urinary bladder. A multivariable Cox proportional hazard model, subgroup analyses, and propensity score matching were used.

Results

In all, 519 patients with MPUC and 154 453 patients with TCC were enrolled. Compared with TCC, patients with MPUC had a higher rate of muscle invasive disease (P < .001), lymph node metastasis (P < .001), and distal metastasis (P < .001), as well as higher tumor grade (P < .001). According to the survival analyses, the MPUC group also had lower survival probability in both cancer‐specific mortality (CSM) (P < .0001) and overall mortality (OM) analyses (P < .0001). Cox proportional hazard regression showed that the MPUC group had a higher risk of OM (hazard ratios [HR] = 1.39, 95% confidence intervals [CI] = 1.22‐1.57, P < .0001), although the CSM (HR = 1.18, 95% CI = 1.00‐1.40, P = .0505) in that group was fair. In the subgroup analysis, only MPUC patients without distal metastasis faced a higher risk of CSM (HR = 1.33, 95% CI = 1.101.61, P < .0001).

Conclusions

Micropapillary urothelial carcinoma prognosis is poorer than that of TCC. Micropapillary urothelial carcinoma is an independent prognostic factor for OM in patients with urinary bladder cancer.
Numerical and Experimental Study on Mixing in Chaotic Micromixers with Crossing Structures
Authors: Fuwad Ahmed , Hossain Shakhawat , Ryu Hyunil , Ansari Mubashshir Ahmad , Khan Muhammad Saiful Islam , Kim Kwang-Yong , Jeon Tae-Joon , Kim Sun Min
Published: June 2020

Two chaotic micromixers (Models A and B) based on the split‐and‐recombine principle using multilayer microchannels are proposed and the mixing performance was analyzed numerically and experimentally for a wide range of Reynolds numbers. The fluid flow and mixing performance were numerically analyzed by solving Navier‐Stokes equations. Micromixers were fabricated using a soft‐lithography technique. As working fluids, water and a dye/water mixture were used. Quantitative and qualitative analyses were performed using confocal scanning microscopy and image processing techniques. The micromixers could enhance the mixing performance by expanding the interfaces between the working fluids to be mixed. The results confirm the superior mixing index of Model B compared to that of Model A.
Chemical Looping Steam Methane Reforming via Ni‐ferrite Supported on Cerium and Zirconium Oxides
Authors: Garai Mohammad Hadi Safari , Khosravi-Nikou Mohammad Reza , Shariati Ahmad
Published: June 2020

Pure hydrogen was produced by means of chemical looping steam methane reforming with novel oxygen carriers. Ni‐ferrite, Ni‐ferrite‐ZrO2, and Ni‐ferrite‐CeO2 were synthesized as oxygen carriers and characterized by X‐ray diffraction (XRD), Brunauer‐Emmett‐Teller (BET) method, scanning electron microscopy (SEM), dynamic light scattering (DLS), and hydrogen temperature‐programmed reduction (H2‐TPR). The performances of the as‐synthesized oxygen carriers in the cyclic oxidation‐reduction were investigated in the packed‐bed microreactor at a defined temperature range and under atmospheric pressure. Ni0.39Fe2.61O4‐ZrO2 exhibited the best performance and maximum methane conversion among the other oxygen carriers. In addition, high selectivities for H2 and CO were reached.
Atomization and Mixing Characteristics of Swirl‐Flow Atomizers in the Refining Industry
Authors: Jin Haozhe , Xu Henghui , Yu Chenyang , Liu Xiaofei , Wang Chao , Ou Guofu
Published: June 2020

Swirl atomizers are commonly used by refining and chemical companies to wash out ammonium chloride deposits. Experiments and numerical simulation were performed to investigate the atomization and mixing characteristics of swirl atomizers. The volume‐of‐fluid Lagrangian method was applied in the simulation, and its results were compared with experimental data to validate its accuracy. Results demonstrated that the entrainment effect of the airflow changed the atomization angle and coverage area of water. Momentum exchanges between water and airflow promoted the fracture of liquid membranes and formed small droplets.
Differential Effects of Nitrogen Substitution in 5‐ and 6‐Membered Aromatic Motifs
Authors: Levandowski Brian J. , Abularrage Nile S. , Raines Ronald T.
Published: June 2020

Invited for the cover of this issue is the group of Ronald T. Raines at the Massachusetts Institute of Technology. The image depicts the consequence of replacing carbon with nitrogen in aromatic systems, represented by Kekulé’s allegorical snake. Read the full text of the article at 10.1002/chem.202000825.
Transformation of COUPY Fluorophores into a Novel Class of Visible‐Light‐Cleavable Photolabile Protecting Groups
Authors: López‐Corrales Marta , Rovira Anna , Gandioso Albert , Bosch Manel , Nonell Santi , Marchán Vicente
Published: June 2020

Although photolabile protecting groups (PPGs) have found widespread applications in several fields of chemistry, biology and materials science, there is a growing interest in expanding the photochemical toolbox to overcome some of the limitations of classical caging groups. In this work, the synthesis of a new class of visible‐light‐sensitive PPGs based on low‐molecular weight COUPY fluorophores with several attractive properties, including long‐wavelength absorption, is reported. Besides being stable to spontaneous hydrolysis in the dark, COUPY‐based PPGs can be efficiently photoactivated with yellow (560 nm) and red light (620 nm) under physiological‐like conditions, thereby offering the possibility of unmasking functional groups from COUPY photocages under irradiation conditions in which other PPGs remain stable. Additionally, COUPY photocages exhibit excellent cellular uptake and accumulate selectively in mitochondria, opening the door to the delivery of caged analogues of biologically active compounds into these organelles.
A multicountry assessment in Eurasia: Alignment of physician perspectives on palliative care integration in pediatric oncology with World Health Organization guidelines
Authors: Ehrlich Bella S. , Movsisyan Narine , Batmunkh Tsetsegsaikhan , Kumirova Ella , Borisevich Marina V. , Kirgizov Kirill , Graetz Dylan E. , McNeil Michael J. , Yakimkova Taisiya , Vinitsky Anna , Ferrara Gia , Li Chen , Lu Zhaohua , Kaye Erica C. , Baker Justin N. , Agulnik Asya ,   for the ADAPT Research Group
Published: June 2020

Background

The World Health Organization (WHO) advocates for early integration of palliative care for all children with life‐threatening illness. Provider awareness and misperceptions, however, can impede this imperative. In the Eurasian region, little is known about physician knowledge and perspectives on palliative care.

Methods

The Assessing Doctors' Attitudes on Palliative Treatment survey was developed as an evidence‐based and culturally relevant assessment of physician perceptions on palliative care integration into childhood cancer care in Eurasia. Iteratively tested by American and Eurasian palliative care experts, the survey was culturally adapted, translated, and piloted in English, Russian, and Mongolian. The survey was distributed to physicians caring for children with cancer. Fifteen statements were scored in accordance with WHO guidelines to evaluate provider knowledge. The statistical analysis was complemented by a qualitative analysis of open‐ended responses.

Results

This study received 424 responses from 11 countries in Eurasia. The mean alignment between provider perspectives and WHO recommendations was 70% (range, 7%‐100%). Significant independent predictors of higher alignment included country, prior palliative care education, and greater experience with patient death. Respondents primarily described palliative care as end‐of‐life care and symptom management. Two‐thirds of respondents (67%) reported not feeling confident about delivering at least 1 component of palliative care.

Conclusions

This is the first study assessing physician perspectives and knowledge of palliative care in Eurasia and reveals wide variability in alignment with WHO guidelines and limited confidence in providing palliative care. Study findings will inform targeted educational interventions, which must be tailored to the local political, economic, and cultural context.
Insulin resistance and breast cancer incidence and mortality in postmenopausal women in the Women’s Health Initiative
Authors: Pan Kathy , Chlebowski Rowan T. , Mortimer Joanne E. , Gunther Marc J. , Rohan Thomas , Vitolins Mara Z. , Adams‐Campbell Lucile L. , Ho Gloria Y. F. , Cheng Ting‐Yuan David , Nelson Rebecca A.
Published: June 2020

Background

Insulin resistance is associated with higher all‐cause and cancer‐specific mortality in postmenopausal women. However, to the authors' knowledge, information regarding insulin resistance and breast cancer mortality risk is limited. Therefore, the authors examined associations between insulin resistance and breast cancer incidence and mortality in a subsample of Women's Health Initiative participants.

Methods

A total of 22,837 postmenopausal women with fasting baseline glucose and insulin levels were followed for incident breast cancer and breast cancer mortality. Breast cancers were verified by medical record review and serial National Death Index linkage–enhanced mortality findings. Insulin resistance was estimated using the homeostatic model assessment of insulin resistance (HOMA‐IR). Multivariable Cox proportional hazards models were used to compute hazard ratios (HRs) with 95% confidence intervals (95% CIs) for quartile comparisons. Outcomes included breast cancer incidence, deaths from breast cancer, and deaths after breast cancer (breast cancer followed by death from any cause).

Results

During a median of 19.8 years of follow‐up of 1328 breast cancer cases, there were 512 deaths reported, 151 of which were from breast cancer. Breast cancer incidence was higher in women in the highest HOMA‐IR quartile (HR, 1.34; 95% CI, 1.12‐1.61 [P for trend = .003]). Although HOMA‐IR was not found to be associated with risk of death from breast cancer (HR, 1.04; 95% CI, 0.60‐1.79), women in the highest versus those in the lowest HOMA‐IR quartile were at a higher risk of death after breast cancer (HR, 1.78; 95% CI, 1.32‐2.39 [P for trend <.001]).

Conclusions

Higher levels of insulin resistance in postmenopausal women are associated with higher breast cancer incidence and higher all‐cause mortality after breast cancer.
Automated Synthesis and Purification of Guanidine‐Backbone Oligonucleotides
Authors: Skakuj Kacper , Bujold Katherine E. , Mirkin Chad A.
Published: June 2020

This protocol describes a method based on iodine and a base as mild coupling reagents to synthetize deoxyribonucleic guanidines (DNGs)—oligodeoxynucleotide analogues with a guanidine backbone. DNGs display unique properties, such as high cellular uptake with low toxicity and increased stability against nuclease degradation, but have been impeded in their development by the requirement for toxic and iterative manual synthesis protocols. The novel synthesis method reported here eliminates the need for the toxic mercuric chloride and pungent thiophenol that were critical to previous DNG synthesis methods and translates their synthesis to a MerMadeTM12 automated oligonucleotide synthesizer. This method can be used to synthesize DNG strands up to 20 bases in length, along with 5′‐DNG‐DNA‐3′ chimeras, at 1‐ to 5‐μmol scales in a fully automated manner. We also present detailed and accessible instructions to adapt the MerMadeTM12 oligonucleotide synthesizer to enable the parallel synthesis of DNG and DNA/RNA oligonucleotides. Because DNG linkages alter the overall charge of the oligonucleotides, we also describe purification strategies to generate oligonucleotides with varying lengths and numbers of DNGs, based on extraction or preparative‐scale gel electrophoresis, along with methods to characterize the final products. Overall, this article provides an overview of the synthesis, purification, and handling of DNGs and mixed‐charge DNG‐DNA oligonucleotides. © 2020 Wiley Periodicals LLC.

Basic Protocol 1: Preparation of a MerMadeTMsynthesizer for guanidine couplings

Basic Protocol 2: Synthesis of DNG strands on a MerMadeTMsynthesizer

Basic Protocol 3: Purification of DNG strands using preparative acetic acid urea (AU) PAGE

Basic Protocol 4: Characterization of DNG strands using MALDI‐TOF MS

Basic Protocol 5: Characterization of DNG strands using AU PAGE

Support Protocol 1: Synthesis of initiator‐functionalized CPG

Support Protocol 2: Synthesis of thiourea monomer
Impact of Disease on Plasma and Lung Exposure of Chloroquine, Hydroxychloroquine and Azithromycin: Application of PBPK Modeling
Authors: Rowland Yeo Karen , Zhang Mian , Pan Xian , Ban Ke Alice , Jones Hannah M. , Wesche David , Almond Lisa M.
Published: June 2020

We use a mechanistic lung model to demonstrate that accumulation of chloroquine (CQ), hydroxychloroquine (HCQ), and azithromycin (AZ) in the lungs is sensitive to changes in lung pH, a parameter that can be affected in patients with coronavirus disease 2019 (COVID‐19). A reduction in pH from 6.7 to 6 in the lungs, as observed in respiratory disease, led to 20‐fold, 4.0‐fold, and 2.7‐fold increases in lung exposure of CQ, HCQ, and AZ, respectively. Simulations indicated that the relatively high concentrations of CQ and HCQ in lung tissue were sustained long after administration of the drugs had stopped. Patients with COVID‐19 often present with kidney failure. Our simulations indicate that renal impairment (plus lung pH reduction) caused 30‐fold, 8.0‐fold, and 3.4‐fold increases in lung exposures for CQ, HCQ, and AZ, respectively, with relatively small accompanying increases (20 to 30%) in systemic exposure. Although a number of different dosage regimens were assessed, the purpose of our study was not to provide recommendations for a dosing strategy, but to demonstrate the utility of a physiologically‐based pharmacokinetic modeling approach to estimate lung concentrations. This, used in conjunction with robust in vitro and clinical data, can help in the assessment of COVID‐19 therapeutics going forward.
Toward a Consolidated Lignin Biorefinery: Preserving the Lignin Structure through Additive‐Free Protection Strategies
Authors: Karlsson Maria , Giummarella Nicola , Lindén Pär A. , Lawoko Martin
Published: June 2020

As part of the continuing efforts in lignin‐first biorefinery concepts, this study concerns a consolidated green processing approach to obtain high yields of hemicelluloses and lignin with a close to native molecular structure, leaving a fiber fraction enriched in crystalline cellulose. This is done by subcritical water extraction of hemicelluloses followed by organosolv lignin extraction. This initial report focuses on a detailed characterization of the lignin component, with the aim of unravelling processing strategies for the preservation of the native linkages while still obtaining good yields and high purity. To this effect, a static cycle process is developed as a physical protection strategy for lignin, and advanced NMR analysis is applied to study structural changes in lignin. Chemical protection mechanisms in the cyclic method are also reported and contrasted with the mechanisms in a reference batch extraction process where the role of homolytic cleavage in subsequent repolymerization reactions is elucidated.
Development of noise correction method of environmental magnetic field with reference magnetic sensor for magnetocardiography
Authors: Ogata Kuniomi , Kandori Akihiko
Published: June 2020

In recent years, a magnetocardiography (MCG) with superconducting quantum interference device with noise level of 50 fT/√ Hz is used for arrhythmia diagnosis. The MCG is usually installed in a multilayered magnetically shielded room (MSR). In the MCG close to some magnetic noise sources like direct current (dc)‐electrified railway, the MCG can stably measure the magnetic field by increasing the number of layers of MSR. However, increasing the number of layers in the MSR increases the cost and weight. We developed the method to correct the environmental magnetic field (EMF) in the MCG that considers the reduction response of each EMF reduction technology of the MCG including the MSR by referring to the signal measured by the reference magnetic sensor outside the MSR. The effect of the correction was evaluated for each channel of the MCG by using the EMF signal from the dc‐electrified railway as the magnetic noise source. The average value of the correction effect was 18.1 dB, the standard deviation (SD) was 4.1 dB, and the 2SD range was from 9.8 to 26.4 dB. From these results, it is suggested that the developed method has the possibility to improve the EMF in the MCG by more than 9 dB.
Transcriptional meta‐analysis of regulatory B cells
Authors: Dubois Florian , Limou Sophie , Chesneau Mélanie , Degauque Nicolas , Brouard Sophie , Danger Richard
Published: June 2020

Regulatory B cells (Bregs) have the ability to regulate inflammation in various pathological situations, making them key players in immune regulation. Several mechanisms have been described and we recently identified a GZMB expressing Breg population in kidney transplanted patients who tolerate a kidney graft. To further investigate their biology and mechanisms, we conducted a transcriptomic analysis by RNAseq of these cells and we performed the first weighted meta‐analysis of publicly available transcriptomic data from published Breg studies both in humans and mice. We identified two distinct and unique transcriptional signatures of 126 and 93 genes, respectively, associated with these Bregs. While we highlighted genes coding for proteins with potent involvement in regulatory functions, proliferation, and coding for transcription factors, the comparison between humans and mice did not allow identifying a common pattern. Thus, our results suggest distinct species‐restricted Breg transcriptional signatures in humans and mice.
Enantioselective Reformatsky Reaction of Ketones Catalyzed by Chiral Indolinylmethanol
Authors: Luo Renshi , Chen Miao‐Miao , Ouyang Lu , Chan Albert S. C. , Lu Gui
Published: June 2020

A reliable and practical Reformatsky reaction of ethyl iodide acetate with ketones for the synthesis of chiral β‐hydroxyl carbonyl compounds in good yields and excellent enantioselectivities is presented. A readily available dihydroindole derivative was used as chiral catalyst, ethyl iodide acetate was the nucleophile, and Me2Zn was the zinc source. The presence of air was found to be essential for the efficient construction of new carbon–carbon bonds through a radical pathway.
Electroanalytical Sensor for Diabetic Foot Ulcer Monitoring with Integrated Electronics for Connected Health Application
Authors: Roy Souradeep , Nagabooshanam Shalini , Krishna Kushagra , Wadhwa Shikha , Chauhan Nidhi , Jain Utkarsh , Kumar Ranjit , Mathur Ashish , Davis James
Published: June 2020

L‐tyrosine is an amino acid, the concentration of which is found to be highly elevated in patients suffering from diabetic foot ulcer (DFU). The latter proves to be fatal when it turns out chronic and may lead to amputation. The conventional clinical diagnostic methods are costly and time consuming, in which case, the condition of patient(s) may deteriorate long before proper treatment commences. Herein, we report the development of smart band‐aid for real time monitoring of L‐tyrosine by employing enzymatic bio‐sensor using α‐MnO2/tyrosinase. The smart band‐aid was further integrated with portable electronics capable of wireless data transmission to a personal digital assistant, and its tyrosine sensing performance was evaluated. Anodic current was found to vary linearly with the concentrations of L‐tyrosine in the range of 5 nM–500 μM. The developed sensor displayed a limit of detection and sensitivity of 0.71 nM and 0.67 μA/nM/mm2 respectively, with a stability of 25 days. The developed sensor was validated using a commercial impedance analyzer. The impedance response was found to be consistent with the cyclic voltammogram obtained and demonstrated to be a linear function of tyrosine concentration. The developed sensing platform combines early diagnosis with connected health technologies, thus, fitting well into modern healthcare needs.
Purification of low‐abundance lysozyme in egg white via free‐flow electrophoresis with gel‐filtration chromatography
Authors: Dong Shuang , Jiang Ziqin , Liu Zhen , Chen Ling , Zhang Qiang , Tian Youli , Sohail Amir , Khan Muhammad Idrees , Xiao Hua , Liu Xiaoping , Wang Yuxing , Li Honggen , Wu Hanyu , Liu Weiwen , Cao Chengxi
Published: June 2020

As an effective separation tool, free‐flow electrophoresis has not been used for purification of low‐abundance protein in complex sample matrix. Herein, lysozyme in complex egg white matrix was chosen as the model protein for demonstrating the purification of low‐content peptide via an FFE coupled with gel fitration chromatography (GFC). The crude lysozyme in egg while was first separated via free‐flow zone electrophoresis (FFZE). After that, the fractions with lysozyme activity were condensed via lyophilization. Thereafter, the condensed fractions were further purified via a GFC of Sephadex G50. In all of the experiments, a special poly(acrylamide‐ co‐acrylic acid) (P(AM‐co‐AA)) gel electrophoresis and a mass spectrometry were used for identification of lysozyme. The conditions of FFZE were optimized as follows: 130 μL/min sample flow rate, 4.9 mL/min background buffer of 20 mM pH 5.5 Tris‐Acetic acid, 350 V, and 14 °C as well as 2 mg/mL protein content of crude sample. It was found that the purified lysozyme had the purity of 80% and high activity as compared with its crude sample with only 1.4% content and undetectable activity. The recoveries in the first and second separative steps were 65% and 82%, respectively, and the total recovery was about 53.3%. The reasons of low recovery might be induced by diffusion of lysozyme out off P(AM‐co‐AA) gel and co‐removing of high‐abundance egg ovalbumin. All these results indicated FFE could be used as alternative tool for purification of target solute with low abundance.
Quantification of imatinib and related compounds using capillary electrophoresis‐tandem mass spectrometry with field‐amplified sample stacking
Authors: Zhao Tingting , Wang Lingyu , Chen David Da Yong
Published: June 2020

A quantification method for imatinib (IM), its major metabolite N‐desmethyl imatinib (NDI), and a degradation by‐product was developed using CE–MS combined with an online concentration technique. The use of multiple reaction monitoring (MRM)–MS/MS further improved the sensitivity of this technology. Liquid–liquid extraction (LLE) using tertiary butyl methyl ether yielded high recovery and reproducibility for the pretreatment of serum samples. The recovery rate exceeded 83% for all three analytes, and was 90% for IM. To improve quantification results, a conductivity‐induced online analyte concentration technique, field‐amplified sample stacking (FASS), was used. The S/N ratios were improved at least 10‐fold when compared with conventional capillary zone electrophoresis. The detection limits were 0.2 ng/mL for IM, 0.4 ng/mL for NDI, and 4 ng/mL for the degradation by‐product. These results are superior to those previously obtained by other reported methods. The new method was validated in terms of its selectivity, intra‐ and interday repeatability and accuracy, and sample storage stability, following the guidelines issued by the European Medicines Agency. Considering the convenient pretreatment procedure (LLE), superior sensitivity, and fast analysis speed (<15 min), this method can be useful in the determination of imatinib levels in blood.
Hydrogen: Hype or a Glide Path to Decarbonizing Natural Gas?
Authors: Russo Thomas N.
Published: June 2020

Existing technologies that produce blue hydrogen with carbon capture, use, and storage (CCUS) could be a bridge to widespread production of green H2, which is produced with renewable energy without carbon dioxide (CO2) emissions. By incenting and encouraging higher production of blue H2, which primarily uses natural gas, and green H2, the transportation sector could be decarbonized to combat the adverse effects of climate change. Such a program would require tax incentives for blue H2 production and help decarbonize natural gas by blending it with H2 for use in the heating and power sectors. Tax incentives on green H2 production would also encourage more companies to use and improve alkaline and proton exchange membrane electrolyzers. One of the advantages of such an approach is that residential and industrial consumers in various countries could be given a choice in selecting an electric vehicle (EV) with H2‐powered fuel cells or battery‐powered EVs.
False‐positive reverse transcriptase polymerase chain reaction screening for SARS‐CoV‐2 in the setting of urgent head and neck surgery and otolaryngologic emergencies during the pandemic: Clinical implications
Authors: Katz Andrew P. , Civantos Francisco J. , Sargi Zoukaa , Leibowitz Jason M. , Nicolli Elizabeth A. , Weed Donald , Moskovitz Alexander E. , Civantos Alyssa M. , Andrews David M. , Martinez Octavio , Thomas Giovana R.
Published: June 2020

Background

No reports describe falsepositive reverse transcriptase polymerase chain reaction (RT‐PCR) for novel coronavirus in preoperative screening.

Methods

Preoperative patients had one or two nasopharyngeal swabs, depending on low or high risk of viral transmission. Positive tests were repeated.

Results

Forty‐three of 52 patients required two or more preoperative tests. Four (9.3%) had discrepant results (positive/negative). One of these left the coronavirus disease (COVID) unit against medical advice despite an orbital abscess, with unknown true disease status. The remaining 3 of 42 (7.1%) had negative repeat RT‐PCR. Although ultimately considered falsepositives, one was sent to a COVID unit postoperatively and two had urgent surgery delayed. Assuming negative repeat RT‐PCR, clear chest imaging, and lack of subsequent symptoms represent the “gold standard,” RT‐PCR specificity was 0.97.

Conclusions

If false positives are suspected, we recommend computed tomography (CT) of the chest and repeat RT‐PCR. Validated serum immunoglobulin testing may ultimately prove useful.
Microbiomics, Metabolomics, Predicted Metagenomics, and Hepatic Steatosis in a Population‐Based Study of 1,355 Adults
Authors: Alferink Louise J.M. , Radjabzadeh Djawad , Erler Nicole S. , Vojinovic Dina , Medina‐Gomez Carolina , Uitterlinden André G. , de Knegt Robert J. , Amin Najaf , Ikram M. Arfan , Janssen Harry L.A. , Kiefte‐de Jong Jessica C. , Metselaar Herold J. , van Duijn Cornelia M. , Kraaij Robert , Darwish Murad Sarwa
Published: June 2020

Background and Aims

Previous small studies have appraised the gut microbiome (GM) in steatosis, but large‐scale studies are lacking. We studied the association of the GM diversity and composition, plasma metabolites, predicted functional metagenomics, and steatosis.

Approach and Results

This is a cross‐sectional analysis of the prospective population‐based Rotterdam Study. We used 16S ribosomal RNA gene sequencing and determined taxonomy using the SILVA reference database. Alpha diversity and beta diversity were calculated using the Shannon diversity index and Bray–Curtis dissimilarities. Differences were tested across steatosis using permutational multivariate analysis of variance. Hepatic steatosis was diagnosed by ultrasonography. We subsequently selected genera using regularized regression. The functional metagenome was predicted based on the GM using Kyoto Encyclopedia of Genes and Genomes pathways. Serum metabolomics were assessed using high‐throughput proton nuclear magnetic resonance. All analyses were adjusted for age, sex, body mass index, alcohol, diet, and proton‐pump inhibitors. We included 1,355 participants, of whom 472 had steatosis. Alpha diversity was lower in steatosis (P = 1.1∙10−9), and beta diversity varied across steatosis strata (P = 0.001). Lasso selected 37 genera of which three remained significantly associated after adjustment (Coprococcus3: β = −65; Ruminococcus Gauvreauiigroup: β = 62; and Ruminococcus Gnavusgroup: β = 45, Q‐value = 0.037). Predicted metagenome analyses revealed that pathways of secondary bile‐acid synthesis and biotin metabolism were present, and D‐alanine metabolism was absent in steatosis. Metabolic profiles showed positive associations for aromatic and branched chain amino acids and glycoprotein acetyls with steatosis and R. Gnavusgroup, whereas these metabolites were inversely associated with alpha diversity and Coprococcus3.

Conclusions

We confirmed, on a large‐scale, the lower microbial diversity and association of Coprococcus and Ruminococcus Gnavus with steatosis. We additionally showed that steatosis and alpha diversity share opposite metabolic profiles.