bluuebunny/crossref_metadata_2025 huggingface dataset:
A Hybrid Generator with Electromagnetic Transduction for Improving the Power Density of Triboelectric Nanogenerators and Scavenging Wind Energy
Authors: Xin Chuanfu , Guo Hengyu , Shen Fan , Peng Yan , Xie Shaorong , Li Zhongjie , Zhang Quan
Published: April 2022

Due to the low output power of triboelectric nanogenerators (TENGs) in harvesting wind energy, this work proposes a hybridization scheme with electromagnetic generators (EMGs) to improve the power density of TENGs. Then, a novel configuration is designed and experiments of impedance matching and output power are conducted to compare the power density of triboelectric nanogenerators with/without electromagnetic generators under a wind speed of 5.5 m s−1. According to the experimental results, the power density of the hybrid generator is 29.8 times higher than that of the triboelectric nanogenerator without electromagnetic generators (TENG‐WEMGs). To further demonstrate the output performance of the hybrid generator, experiments of charging capacitors and powering electronics are implemented at the same wind speed. Based on the experimental results, a capacitor of 2.2 mF is charged to 25.7 V within 20 s, 170 LEDs are lit, and the Bluetooth tracker is driven to transmit signals in real time. In addition, this work investigates the influences of different resistant loads of EMG on the average power of TENGs. This work can be of great significance to further develop self‐powered sensors.
A Self‐Powered and Efficient Triboelectric Dehydrator for Separating Water‐in‐Oil Emulsions with Ultrahigh Moisture Content
Authors: Li Fangming , Wan Xingfu , Hong Jiaju , Guo Xinyang , Sun Minzheng , Lv Haijia , Wang Hao , Mi Jianchun , Cheng Jia , Pan Xinxiang , Xu Minyi , Wang Zhong Lin
Published: April 2022

Oil–water emulsions are a considerable hazard to the environment, ecology, and human health, if not appropriately treated. This study proposes a self‐powered and efficient triboelectric dehydrator (TED) based on a wind‐driven freestanding rotary triboelectric nanogenerator (FR‐TENG) to separate water‐in‐oil emulsions. This TED can form a high‐voltage electric field in the emulsion when the FR‐TENG is driven by mechanical energy. The dehydration performance of the TED is analyzed in detail through multiphysics‐coupled models and experiments. It is found that the TED can dehydrate water‐in‐oil emulsions with a wide range of initial moisture contents. In particular, even when the initial moisture content is 60%, which is near the phase inversion concentration of the emulsion, the dehydration rate of the TED can still reach 99.41%. In addition, the performance of TED is demonstrated in a simulated situation of wind, suggesting that the present TED has great potential application for separating oil–water emulsions by harvesting environmental energy.
n‐SnOx as a Transparent Electrode and Heterojunction for p‐InP Nanowire Light Emitting Diodes
Authors: Gagrani Nikita , Vora Kaushal , Adhikari Sonachand , Jiang Yuxin , Jagadish Chennupati , Tan Hark Hoe
Published: April 2022

Transparent electronics are rapidly evolving with the development of transparent conducting oxides (TCOs). This work investigates both the electrical and optical properties of n‐type tin oxide (SnOx) film, deposited at various levels of oxygen concentration using magnetron sputtering. The band alignment at InP–SnOx interface is further studied and SnOx deposited at various conditions is used to demonstrate InP nanowire (NW) light emitting diodes (LEDs) to understand the trade‐off between absorption and resistance. It is found that the device with lower resistance but higher absorption outperforms in terms of output power. Emission from the devices consists of two peaks at room temperature due to conduction band‐to‐heavy hole band transition and conduction band‐to‐light hole band transition. Decreasing the operating temperature brings about quite a complex transition in all the devices, which consists of two additional peaks due to Zn acceptor level and zincblende/wurtzite (ZB/WZ) recombination at NW/substrate interface. At temperatures below 208 K, the emission peak from conduction band‐to‐light hole band transition quenches, however the emission peaks from Zn acceptor level and ZB/WZ recombination become prominent. This work lays the foundation for realizing a new generation of efficient transparent electrodes in conjunction with NWs, eliminating the complex epitaxial growth process optimization of NW shell growth, heterostructure and doping.
A Series of Ternary Metal Chloride Superionic Conductors for High‐Performance All‐Solid‐State Lithium Batteries
Authors: Liang Jianwen , van der Maas Eveline , Luo Jing , Li Xiaona , Chen Ning , Adair Keegan R. , Li Weihan , Li Junjie , Hu Yongfeng , Liu Jue , Zhang Li , Zhao Shangqian , Lu Shigang , Wang Jiantao , Huang Huan , Zhao Wenxuan , Parnell Steven , Smith Ronald I. , Ganapathy Swapna , Wagemaker Marnix , Sun Xueliang
Published: April 2022

Understanding the relationship between structure, ionic conductivity, and synthesis is the key to the development of superionic conductors. Here, a series of Li3‐3xM1+xCl6 (−0.14 < x ≤ 0.5, M = Tb, Dy, Ho, Y, Er, Tm) solid electrolytes with orthorhombic and trigonal structures are reported. The orthorhombic phase of Li–M–Cl shows an approximately one order of magnitude increase in ionic conductivities when compared to their trigonal phase. Using the Li–Ho–Cl components as an example, their structures, phase transition, ionic conductivity, and electrochemical stability are studied. Molecular dynamics simulations reveal the facile diffusion in the z‐direction in the orthorhombic structure, rationalizing the improved ionic conductivities. All‐solid‐state batteries of NMC811/Li2.73Ho1.09Cl6/In demonstrate excellent electrochemical performance at both 25 and −10 °C. As relevant to the vast number of isostructural halide electrolytes, the present structure control strategy guides the design of halide superionic conductors.
Copolymerization of Sulfur Chains with Vinyl Functionalized Metal−Organic Framework for Accelerating Redox Kinetics in Lithium−Sulfur Batteries
Authors: Zeng Qinghan , Li Xin , Gong Wei , Guo Sijia , Ouyang Yuan , Li Dixiong , Xiao Yingbo , Tan Chao , Xie Lin , Lu Haibin , Zhang Qi , Huang Shaoming
Published: April 2022

Lithium−sulfur batteries (LSBs) are regarded as one of the most promising candidates for energy storage devices. However, the severe shuttling effect of soluble polysulfides (PSs) limits its further application. Metal−organic frameworks (MOFs) have emerged as a new kind of sulfur host for their talents in confining and trapping PSs. However, the shuttle effect has not been fully stressed as a significant drawback for most MOFs that leads to sluggish redox kinetics, resulting in low specific capacity and short lifetime, especially at high sulfur loading. In this work, a MOF‐sulfur copolymer (CNT@UiO‐66‐V‐S) is elaborated by copolymerization of sulfur with vinyl functionalized MOFs. Systematic electrochemical experiments and in situ Raman spectroscopy analysis indicate that the cathode exhibits a radical reaction mechanism and can accelerates LiPSs conversion. The CNT@UiO‐66‐V‐S cathode delivers over 100% improved discharge capacity and lowers decay rate at both low and high (5.6 mg cm–2) sulfur loadings compared to the physically mixed MOF/S cathode. The strategy of MOF‐sulfur copolymerization provides a new solution for promoting reaction kinetics and tackling the shuttle effect, and is expected to inspire the design of advanced sulfur hosts applied for high‐performance LSBs.
Phenazine‐based supramolecular photosensitizing assemblies: A “smart” selectivity control on catalytic activity of Pd(II) nanoparticles
Authors: Singh Aditya , Kumar Manoj , Bhalla Vandana
Published: April 2022

Photosensitizing supramolecular assemblies based on a phenazine derivative (PPA) have been developed, which show a strong affinity toward Pd2+ ions to generate supramolecular ensemble PPA@Pd nanoparticles (NPs). The PPA@Pd NPs catalyse the Suzuki cross‐coupled reaction under mild conditions (aerial conditions, mixed aqueous media, and visible light radiations). Although PPA@Pd NPs exhibit a strong affinity for arylboronic acid and could catalyse homocoupling of arylboronic acid, the preference of PPA assemblies for aryl halide directed the course of reactions toward the formation of cross‐coupled products. The electron‐rich PPA assemblies not only facilitate the oxidative addition step through photoinduced electron transfer to Pd2+ ions but also bring the reactants closer to the catalytic sites by selective interactions with aryl halides in the presence of arylboronic acid under visible light irradiation. The efficiency of PPA@Pd NPs to catalyse the Suzuki cross‐coupled reaction has been demonstrated for the synthesis of unsymmetrically substituted terphenyl derivatives.
Integration of machine learning and first principles models
Authors: Rajulapati Lokesh , Chinta Sivadurgaprasad , Shyamala Bala , Rengaswamy Raghunathan
Published: April 2022

Model building and parameter estimation are traditional concepts widely used in chemical, biological, metallurgical, and manufacturing industries. Early modeling methodologies focused on mathematically capturing the process knowledge and domain expertise of the modeler. The models thus developed are termed first principles models (or white‐box models). Over time, computational power became cheaper, and massive amounts of data became available for modeling. This led to the development of cutting edge machine learning models (black‐box models) and artificial intelligence (AI) techniques. Hybrid models (gray‐box models) are a combination of first principles and machine learning models. The development of hybrid models has captured the attention of researchers as this combines the best of both modeling paradigms. Recent attention to this field stems from the interest in explainable AI (XAI), a critical requirement as AI systems become more pervasive. This work aims at identifying and categorizing various hybrid models available in the literature that integrate machine‐learning models with different forms of domain knowledge. Benefits such as enhanced predictive power, extrapolation capabilities, and other advantages of combining the two approaches are summarized. The goal of this article is to consolidate the published corpus in the area of hybrid modeling and develop a comprehensive framework to understand the various techniques presented. This framework can further be used as the foundation to explore rational associations between several models.
Nutritional status, intestinal parasitic infections, and socio‐environmental conditions in Mbyá‐guaraní children: The current situation in communities incentral Misiones, Argentina
Authors: Zonta María Lorena , Servián Andrea , Panisse Guillermo , Oyhenart Evelia E. , Navone Graciela T.
Published: April 2022

Objectives

Our previous research in Mbyá‐guaraní communities of central Misiones showed high levels of growth stunting and intestinal parasites in children, as well as associations between these variables and deficient sanitary conditions. New studies were necessary to update the present health status of the previously studied Mbyá populations after around two decades. Therefore, we evaluated the current nutritional status, intestinal parasites, and socio‐environmental conditions among Mbyá‐guaraní children from these communities.

Methods

Body weight and height of 102 individuals (aged 2–14) were measured and nutritional status was estimated according to the World Health Organization criteria. Serial fecal samples and anal swabs were analyzed from 75 children (aged 1–14). Socio‐environmental data were obtained from questionnaires.

Results

The prevalence of undernutrition was 31.4% and excess of weight was 10.8%. The prevalence of stunting and of overweight reached 30.4% and 8.8%, respectively. About 85% of the children were infected with at least one of the 14 species identified, and around 44% had multiple parasite infections. The most prevalent species wereEnterobius vermicularisand hookworms. Among undernourished children, 88.2% were parasitized by at least one of the potentially pathogenic species detected. Most of the families lived in overcrowded conditions in precarious houses, defecated in latrines, and consumed well water. A higher risk of parasitosis was associated with the source of drinking water.

Conclusions

Although the prevalence of undernutrition and intestinal parasites decreased compared with our previous studies, we still observed the coexistence of stunting, excess weight, and parasitic infections, in a context of socio‐environmental vulnerability.
Novel truncating variants in FGD1 detected in two Danish families with Aarskog–Scott syndrome and myopathic features
Authors: Bayat Allan , Krett Bjørg , Dunø Morten , Torring Pernille Mathiesen , Vissing John
Published: April 2022

Aarskog–Scott syndrome (AAS) is a developmental disorder, caused by disease‐causing hemizygous variants in the FGD1 gene. AAS is characterized by dysmorphic features, genital malformation, skeletal anomalies, and in some cases, intellectual disability and behavioral difficulties. Myopathy has only been reported once in two affected siblings diagnosed with AAS. Only few adult cases have been reported. This article reports four adults with AAS (three male cases and one female carrier) from two unrelated Danish families, all males presented with variable features suggestive of myopathy. All four carried novel hemizygous pathogenic variants in the FGD1 gene; one family presented with the c.2266dup, p.Cys756Leufs*19 variant while the c.527dup; p.Leu177Thrfs*40 variant was detected in the second family. All males had some mild myopathic symptoms or histological abnormalities. Case 1 had the most severe myopathic phenotype with prominent proximal muscular fatigue and exercise intolerance. In addition, he had multiple deletions of mtDNA and low respiratory chain activity. His younger nephew, case 3, had difficulties doing sports in his youth and had a mildly abnormal muscle biopsy and relatively decreased mitochondrial enzyme activity. The singular case from family 2 (case 4), had a mildly myopathic muscle biopsy, but no overt myopathic symptoms. Our findings suggest that myopathic involvement should be considered in AAS.
Early dementia diagnosis, MCI‐to‐dementia risk prediction, and the role of machine learning methods for feature extraction from integrated biomarkers, in particular for EEG signal analysis
Authors: Rossini Paolo Maria , Miraglia Francesca , Vecchio Fabrizio
Published: April 2022

Introduction

Dementia in its various forms represents one of the most frightening emergencies for the aging population. Cognitive decline—including Alzheimer's disease (AD) dementia—does not develop in few days; disease mechanisms act progressively for several years before clinical evidence.

Methods

A preclinical stage, characterized by measurable cognitive impairment, but not overt dementia, is represented by mild cognitive impairment (MCI), which progresses to—or, more accurately, is already in a prodromal form of—AD in about half cases; people with MCI are therefore considered the population at risk for AD deserving special attention for validating screening methods.

Results

Graph analysis tools, combined with machine learning methods, represent an interesting probe to identify the distinctive features of physiological/pathological brain aging focusing on functional connectivity networks evaluated on electroencephalographic data and neuropsychological/imaging/genetic/metabolic/cerebrospinal fluid/blood biomarkers.

Discussion

On clinical data, this innovative approach for early diagnosis might provide more insight into pathophysiological processes underlying degenerative changes, as well as toward a personalized risk evaluation for pharmacological, nonpharmacological, and rehabilitation treatments.
The ecology and physiology of fern gametophytes: A methodological synthesis
Authors: Krieg Christopher P. , Chambers Sally M.
Published: April 2022

All green plants alternate between the gametophyte and sporophyte life stages, but only seed‐free vascular plants (ferns and lycophytes) have independent, free‐living gametophytes. Fern and lycophyte gametophytes are significantly reduced in size and morphological complexity relative to their sporophytic counterparts and have often been overlooked in ecological and physiological studies. Understanding the ecological and physiological factors that directly impact this life stage is of critical importance because the ultimate existence of a sporophyte is dependent upon successful fertilization in the gametophyte generation. Furthermore, previous research has shown that the dual nature of the life cycle and the high dispersibility of spores can result in different geographic patterns between gametophytes and their respective sporophytes. This variation in distribution patterns likely exacerbates the separation of selective pressures acting on gametophyte and sporophyte generations, and can uniquely impact a species’ ecology and physiology. Here, we provide a review of historical and contemporary methodologies used to examine ecological and physiological aspects of fern gametophytes, as well as those that allow for comparisons between the two generations. We conclude by suggesting methodological approaches to answer currently outstanding questions. We hope that the information covered herein will serve as a guide to current researchers and stimulate future discoveries in fern gametophyte ecology and physiology.
Constructing the Single‐Phase Nanotubes with Uniform Dispersion of SiOx and Carbon as Stable Anodes for Lithium‐Ion Batteries
Authors: Gao Yuan , Ling Yang , Peng Yan , Guan Shiyou
Published: April 2022

SiOx is an attractive anode material for lithium‐ion batteries due to its considerable capacity. However, its obvious volume expansion and low conductivity result in poor electrochemical performance. Herein, a novel single‐phase nanotube structure with uniform distribution of nanoscale SiOx units and amorphous carbon matrix was fabricated. The hollow nanotube and homogeneously distributed ultrafine SiOx units greatly alleviate volume changes. The amorphous carbon facilitates electron transport throughout the network and offers a buffer to further reduce the volume expansion of SiOx. Benefiting from this unique structure, as‐prepared single‐phase SiOx/C NTs demonstrate excellent durability and rate capability. Specifically, it delivers a high reversible specific capacity (713 mAh g−1 at 0.1 A g−1 after 200 cycles); negligible capacity decay is confirmed after 500 cycles at high density current (544 mAh g−1 at 1 A g−1 after 500 cycles).
A pH‐Based Single‐Sensor Array for Discriminating Metal Ions in Water
Authors: Bowyer Amy A. , Mai Anthony D. , Guo Haobo , New Elizabeth J.
Published: April 2022

Human activities, such as mining and manufacturing, expose society and the natural environment to harmful levels of metal ions. Recently, optical sensor arrays for metal ion detection have become popular owing to their favourable features, such as facile sample preparation and the requirement of less expensive instrumentation compared to traditional, spectrometry‐based analysis techniques. Sensor arrays usually consist of numerous optical probes that are used in combination to generate unique analyte responses. In contrast, here we present an array that comprises a single fluorescent sensor, Coum4‐DPA, that produces unique responses to metal ions in different pH environments. With this simple sensing platform, we were able to classify 10 metal ions in different water sources and quantify Pb2+ in tap water using just one fluorescent sensor, a few pH buffers and two sets of spectral data. This novel approach significantly decreases time and costs associated with probe synthesis and data collection, making it highly transferrable to real‐world metal sensing applications.
Using weighted communication scoring procedures in naturalistic play samples: Preliminary validation in preschool‐aged boys with autism or fragileXsyndrome
Authors: John Thurman Angela , Hoyos Alvarez Cesar , Nguyen Vivian
Published: April 2022

In the present study, we provide a preliminary evaluation of the validity and reliability of using weighting procedures to measure communication in play samples for preschool‐aged boys with autism or fragile X syndrome (FXS). Because weighting procedure communication scores (WPCSs) reflect growth in both communicative frequency and complexity, establishing the psychometrics of the component scores, in addition to the overall metric, affords investigators the opportunity to describe growth within and across skills. Results, for both groups, provide support regarding the psychometric appropriateness (i.e., convergent validity, divergent validity, and internal consistency) for all WPCSs. That said, a trend was observed for reliability scores to be slightly lower or more variable in boys with autism than in boys with FXS. Finally, although significant associations were observed in the associations between WPCSs across play contexts, contexts effects were observed for all three WPCSs. Together, results from this study provide promising preliminary data indicating the utility of using WPCSs in children with neurodevelopmental disabilities.

Lay Summary: Language supports long‐term positive outcomes; it is important to identify accurate and flexible ways of measuring language in children over time. We considered the effectiveness of using a procedure that considers changes in the number of communication acts and the types of acts produced during a play session by preschool‐aged boys with autism or fragile X syndrome. These procedures were found to be valid and reliable.
Oxidative ligand cleavage in a copper(II) complex containing aniline moiety induced by copper(II) perchlorate in acetonitrile
Authors: Suktanarak Pattira , Leeladee Pannee , Tuntulani Thawatchai
Published: April 2022

Synthetic reaction of a Cu(II) complex containing aniline moiety (Cu(atpa)) (atpa = N‐(anthracen‐9‐ylmethyl)‐2‐((bis(pyridin‐2‐ylmethyl)amino) with an excess Cu(ClO4)2 in CH3CN produced an unusual species, which was not corresponding to the original ligand atpa, Cu(ClO4)2 nor [Cu(atpa)]2+. It was proposed that the new species was generated via electron transfer between aniline‐containing N‐based ligand and Cu(ClO4)2, resulting in oxidative ligand cleavage. Monitoring the reaction of Cu(atpa) with Cu(ClO4)2 for a period of time revealed a gradual decrease of an active species, concomitant with the growth of a variety of organic fractions including 9‐anthraldehyde and anthraquinone compounds. Cu(tpa) (Cu coordinated with tripodal amine ligand without anthracene analogue) was also detected from this reaction. This finding was indicative of an oxidative ligand cleavage via the N‐dealkylation pathway. In addition to oxidative ligand cleavage, the new species was competent to oxidize other substrates such as triphenylphosphine (PPh3) as well.
Entrepreneurial practices and the constitution of environmental value for sustainability
Authors: Gregori Patrick , Holzmann Patrick
Published: April 2022

Environmental value is a central concept in entrepreneurship research addressing issues of sustainability. However, current accounts often reduce environmental value to predefined categories that can be realized through individual business activities and thus underplay the relational and collective efforts for value to be constituted. We address this by blending theories of entrepreneurship as practices of social change with insights from valuation studies. We further invoke the relationality and materiality of practice perspectives and examine how value is constituted in entrepreneurial practices. Drawing on the analysis of visual and textual data, we develop a model of interlocked entrepreneurial practices composed of articulating matters of concern, performing value cuts, and including human actors. These practices give contours to an apparatus of valuation that establishes, enacts, and stabilizes environmental value. Our study contributes to and has implications for rethinking environmental value in entrepreneurship research. It further adds to the discussion of materiality and (non)human agency and value creation in entrepreneurship studies for environmental sustainability.
Do corporate sustainability initiatives improve corporate carbon performance? Evidence from European firms
Authors: Haque Faizul , Ntim Collins G.
Published: April 2022

We contribute to the business strategy and the environment literature by investigating the influence of corporate sustainability initiatives and corporate carbon performance of European listed firms. We use three‐way fixed‐effects model, and our sample comprises of 2444 firm‐year observations from 12 European countries, covering a 16‐year period (2004–2019). First, we find that corporate sustainability initiatives, a composite measure comprising of emission reduction initiatives, environmental innovations and efficient use of resources, has a positive relationship with corporate carbon performance, in terms of reduced greenhouse gas (GHG) emission intensity. Second, we find that the relationship between corporate sustainability initiatives and corporate carbon performance is stronger for firms in polluting industries. Overall, our evidence lends support for the efficiency‐oriented arguments of the neo‐institutional theory in that organisations respond to climate‐related risks by making substantive engagements in corporate sustainability initiatives, such as emission reduction initiatives, environmental innovations and efficient use of resources, which in turn facilitates organisations' effort to reduce GHG emission and improve corporate carbon performance.
Three‐dimensional printing models improve long‐term retention in medical education of pathoanatomy: A randomized controlled study
Authors: Al‐Badri Nour , Touzet‐Roumazeille Sandrine , Nuytten Alexandra , Ferri Joël , Charkaluk Marie‐Laure , Nicot Romain
Published: April 2022

Craniosynostosis is a rare and complex pathology, and visuospatial skills are necessary for a good understanding of the condition. While the use of three‐dimensional (3D) models has improved the understanding of complex craniofacial anatomy, no study has evaluated the impact of this teaching support on long‐term retention. Our randomized controlled trial was designed to compare the long‐term retention of information with 3D‐printed models of four types of craniosynostosis versus classic 3D reconstructions displayed in two‐dimensional (2D) among undergraduate students. All students benefited from the same standardized course followed by the manipulation of the learning tool associated with the group for 15 min. Long‐term retention was assessed by the capability to properly recognize different types of craniosynostosis 3 weeks after the course. Eighty‐five students were enrolled. Previous educational achievements and baseline visuospatial skills were similar between the groups. The bivariate analysis showed the mean score in the 3D and 2D groups were 11.32 (2.89) and 8.08 (2.81), respectively (p < 0.0001). 3D‐printed models of structures with spatial complexity such as various craniosynostosis patterns improve significantly medical students' long‐term retention, indicating their educational efficacy.
Design, Synthesis, and Biological Evaluation of (+)‐Camphor‐ and (−)‐Fenchone‐Based Derivatives as Potent Orthopoxvirus Inhibitors
Authors: Sokolova Anastasiya S. , Kovaleva Kseniya S. , Kuranov Sergey O. , Bormotov Nikolay I. , Borisevich Sophia S. , Zhukovets Anastasiya A. , Yarovaya Olga I. , Serova Olga A. , Nawrozkij Maxim B. , Vernigora Andrey A. , Davidenko Andrey V. , Khamitov Eduard M. , Peshkov Roman Y. , Shishkina Larisa N. , Maksuytov Rinat A. , Salakhutdinov Nariman F.
Published: April 2022

In this work, a library of (+)‐camphor and (−)‐fenchone based N‐acylhydrazones, amides, and esters, including para‐substituted aromatic/hetaromatic/cyclohexane ring was synthesized, with potent orthopoxvirus inhibitors identified among them. Investigations of the structure‐activity relationship revealed the significance of the substituent at the para‐position of the aromatic ring. Also, the nature of the linker between a hydrophobic moiety and aromatic ring was clarified. Derivatives with p‐Cl, p‐Br, p‐CF3, and p‐NO2 substituted aromatic ring and derivatives with cyclohexane ring showed the highest antiviral activity against vaccinia virus, cowpox, and ectromelia virus. The hydrazone and the amide group were more favourable as a linker for antiviral activity than the ester group. Compounds 3 b and 7 e with high antiviral activity were examined using the time‐of‐addition assay and molecular docking study. The results revealed the tested compounds to inhibit the late processes of the orthopoxvirus replication cycle and the p37 viral protein to be a possible biological target.
Innovative Randomized Phase I Study and Dosing Regimen Selection to Accelerate and Inform Pivotal COVID‐19 Trial of Nirmatrelvir
Authors: Singh Ravi Shankar P. , Toussi Sima S. , Hackman Frances , Chan Phylinda L. , Rao Rohit , Allen Richard , Van Eyck Lien , Pawlak Sylvester , Kadar Eugene P. , Clark Frances , Shi Haihong , Anderson Annaliesa S. , Binks Michael , Menon Sandeep , Nucci Gianluca , Bergman Arthur
Published: April 2022

Coronavirus disease 2019 (COVID‐19) is a continued leading cause of hospitalization and death. Safe, efficacious COVID‐19 antivirals are needed urgently. Nirmatrelvir (PF‐07321332), the first orally bioavailable, severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) Mpro inhibitor against the coronaviridae family, has demonstrated potent preclinical antiviral activity and benign safety profile. We report safety, tolerability, and pharmacokinetic data of nirmatrelvir with and without ritonavir as a pharmacokinetic enhancer, from an accelerated randomized, double‐blind, placebo‐controlled, phase I study. Two interleaving single‐ascending dose (SAD) cohorts were evaluated in a three‐period crossover. Multiple‐ascending dose (MAD) with nirmatrelvir/ritonavir twice daily (b.i.d.) dosing was evaluated over 10 days in five parallel cohorts. Safety was assessed, including in a supratherapeutic exposure cohort. Dose and dosing regimen for clinical efficacy evaluation in phase II/III clinical trials were supported by integrating modeling and simulations of SAD/MAD data with nonclinical data and a quantitative systems pharmacology model (QSP). In SAD, MAD, and supratherapeutic exposure cohorts, nirmatrelvir/ritonavir was safe and well‐tolerated. Nirmatrelvir exposure and half‐life were considerably increased by ritonavir, enabling selection of nirmatrelvir/ritonavir dose and regimen for phase II/III trials (300/100 mg b.i.d.), to achieve concentrations continuously above those required for 90% inhibition of viral replication in vitro. The QSP model suggested that a 5‐day regimen would significantly decrease viral load in SARS‐CoV‐2‐infected patients which may prevent development of severe disease, hospitalization, and death. In conclusion, an innovative and seamless trial design expedited establishment of phase I safety and pharmacokinetics of nirmatrelvir/ritonavir, enabling high confidence in phase II/III dose selection and accelerated pivotal trials’ initiation (NCT04756531).
Applying Modeling and Simulations for Rational Dose Selection of Novel Toll‐Like Receptor 7/8 Inhibitor Enpatoran for Indications of High Medical Need
Authors: Klopp‐Schulze Lena , Shaw Jamie V. , Dong Jennifer Q. , Khandelwal Akash , Vazquez‐Mateo Cristina , Goteti Kosalaram
Published: April 2022

Dual toll‐like receptor (TLR) 7 and TLR8 inhibitor enpatoran is under investigation as a treatment for lupus and coronavirus disease 2019 (COVID‐19) pneumonia. Population pharmacokinetic/pharmacodynamic (PopPK/PD) model‐based simulations, using PK and PD (inhibition of ex vivo‐stimulated interleukin‐6 (IL‐6) and interferon‐α (IFN‐α) secretion) data from a phase I study of enpatoran in healthy participants, were leveraged to inform dose selection for lupus and repurposed for accelerated development in COVID‐19. A two‐compartment PK model was linked to sigmoidal maximum effect (Emax) models with proportional decrease from baseline characterizing the PD responses across the investigated single and multiple doses, up to 200 mg daily for 14 days (n = 72). Concentrations that maintain 50/60/90% inhibition (IC50/60/90) of cytokine secretion (IL‐6/IFN‐α) over 24 hours were estimated and stochastic simulations performed to assess target coverage under different dosing regimens. Simulations suggested investigating 25, 50, and 100 mg enpatoran twice daily (b.i.d.) to explore the anticipated therapeutic dose range for lupus. With 25 mg b.i.d., > 50% of subjects are expected to achieve 60% inhibition of IL‐6. With 100 mg b.i.d., most subjects are expected to maintain almost complete target coverage for 24 hours (> 80% subjects IC90,IL‐6 = 15.5 ng/mL; > 60% subjects IC90,IFN‐α = 22.1 ng/mL). For COVID‐19, 50 and 100 mg enpatoran b.i.d. were recommended; 50 mg b.i.d. provides shorter IFN‐α inhibition (median time above IC90 = 13 hours/day), which may be beneficial to avoid interference with the antiviral immune response. Utilization of PopPK/PD models initially developed for lupus enabled informed dose selection for the accelerated development of enpatoran in COVID‐19.
Restoring ornithine transcarbamylase (OTC) activity in an OTC‐deficient mouse model using LUNAR‐OTC mRNA
Authors: Yu Hailong , Brewer Edward , Shields Michael , Crowder Michael , Sacchetti Cristiano , Soontornniyomkij Benchawanna , Dou Dandan , Clemente Brenda , Sablad Marciano , Chivukula Padmanabh , Hughes Steve , Roberts Scott , Rajappan Kumar , Tannis Steve , Sekulovich Rose , Parker Suezanne , Limphong Pattraranee
Published: April 2022

Ornithine transcarbamylase (OTC) catalyses the reaction from ornithine to citrulline in the urea cycle. Ornithine transcarbamylase deficiency (OTCD) results in episodes of hyperammonemia. Arcturus Therapeutics developed a lipid nanoparticle (LNP)‐encapsulated OTC‐mRNA (LUNAR‐OTC) that results in a replacement enzyme and is currently undergoing clinical trials. In this study, the efficacy of LUNAR OTC‐mRNA drug in the spfash mouse model was examined by measuring the OTC enzyme activity and protein expression in the liver and plasma of OTC‐mRNA‐treated mice. Using purified citrulline‐D4 as the substrate improved the sensitivity of the OTC activity assay and allowed us to quantify the ornithine‐D4 product from the mouse plasma samples. OTC activity in the liver showed a clear dose response: The lowest dose, 0.3 mg/kg, resulted in higher activity than that of the untreated group, and the highest dose, 3 mg/kg, resulted in completely restored OTC activity in the liver. OTC activity in plasma was also dose‐dependent. A clear positive correlation between the OTC activity in the liver and that in the plasma suggests that the plasma OTC activity assay may serve as a surrogate for measuring OTC activity in liver biopsy samples. In addition, the OTC protein expression levels correlated well with the OTC activity in liver samples, but there was no quantifiable OTC protein in the plasma samples. This finding suggests that the sensitivity of the OTC activity assay is superior to that of the protein expression assay. Overall, the results of this study suggest that the OTC activity assay described here can be used as a clinical pharmacodynamic endpoint to measure the effectiveness of OTCD treatment.
Building a spectral cytometry toolbox: Coupling fluorescent proteins and antibodies to microspheres
Authors: Monard Simon
Published: April 2022

Fluorescent proteins (FPs) have become an essential tool for biological research. Since the isolation and description of GFP, hundreds of fluorescent proteins have been discovered and created with various characteristics. The excitation of these proteins ranges from ultra‐violet (UV) up to near infra‐RED (NIR). Using conventional cytometry with each detector assigned to each fluorochrome, great care must be taken when selecting the optimal bandpass filters to minimalize the spectral overlap. In the last 8 years, several companies have released full spectrum flow cytometers which eliminates the need to change optical filters for analyzing FPs. This addressed at least part of the problem however, the laser wavelengths in commercial instruments are generally not ideal for all fluorescent proteins yet do allow the separation of at least six FPs. Another technical challenge is to have convenient single color controls. If four different FPs are being used in an experiment, single color controls will be needed to compensate or unmix the data. In the case of cultured cells this will involve having each of the FPs expressed in cell lines separately with a parental cell line expressing none. In the case of in vivo experiments, colonies of animals may need to be maintained expressing each FP along with a wildtype animal. This represents a considerable expense and inconvenience. An appealing alternative is to produce and purify FPs and covalently couple to polystyrene microspheres. Such microspheres are ready to use and can be stored at 4°C for months or even years without any deterioration in fluorescence. The same procedure can be used to couple antibodies to these particles. Here we describe this procedure which can be executed in any lab without any special equipment or skills.
Erythroid side scatter: A parameter that improves diagnostic accuracy of flow cytometry myelodysplastic syndrome scoring
Authors: Johansson Ulrika , Rolf Nina , Futhee Natasha , Stewart Andrew
Published: April 2022

Background: Flow cytometry immunophenotyping (FCM) is a benchmark test for integrated diagnosis of myelodysplastic syndromes (MDS). Our department's FCM‐MDS‐score follows international guidelines and additionally includes the maturing erythroid (mEry) side scatter (SSC)/lymphocyte SSC ratio (mErySSCr), often increased in MDS patients. A recent exploratory computational flow analysis study highlighted mErySSC as the top feature for separating MDS from non‐MDS. Thus, we sought to systematically evaluate the diagnostic accuracy of mErySSCr in conventional diagnostic FCM as used currently in‐house.

Methods: Historical MDS (n = 93), chronic myelomonocytic leukemia (CMML; n = 27) and non‐neoplastic cytopenia (n = 57) cohorts were created. Differences between these cohorts and LG‐MDS entities were mapped and the mErySSCr cut‐off was refined. Prospective bone marrows (n = 213) received for marrow failure work‐up were used to determine the sensitivity and specificity of mErySSCr, both as a sole parameter and as a component of the MDS‐score.

Results: Low‐grade (LG)‐MDS mErySSCr differed more prominently from controls (p = <0.0001) than high‐grade (HG)‐MDS (p = 0.024). CMML and controls had a similar mErySSCr. As sole parameter, mErySSCr specificity was 91.1% (n = 112 non‐MDS diagnoses) and sensitivity was 36% for LG‐MDS (n = 36) and 25% for new HG‐MDS diagnoses (n = 16). The specificity of the MDS‐score was similar if mErySSCr was omitted (81.3% with and 82.1% without). The MDS‐score sensitivity for new HG‐MDS diagnoses and CMML (n = 17) was 100%, and was not affected by mErySSCr. The score sensitivity for LG‐MDS however, dropped from 86.1% to 72.2% when mErySSCr was excluded.

Conclusion: mErySSCr increases the diagnostic accuracy of flow‐based MDS scoring in our setting, particularly for LG‐MDS.
An energy‐efficient data management scheme for industrial IoT
Authors: Ghaderi Ali , Movahedi Zeinab
Published: April 2022

Industry 4.0 is the emerging trend of manufacturing technologies towards smart factories. The industrial internet of things (IIoT) plays a primordial role to achieve the objectives of Industry 4.0, by enabling the cyber‐physical production systems to communicate and cooperate with each other and with humans both internally and across the participants of the supply chain. The Publish/Subscribe is the communication model used commonly in IIoT networks, in which the data generated by sensors are cached in a central controller to be subsequently consumed by actuators. However, the traditional centralized data management is inappropriate for real applications because of its communication overhead and inability to cope with strict delay requirements of IIoT applications and energy constraints of IIoT networks. To address these issues, we propose an energy‐efficient data management scheme (EDMS), in which a set of IoT nodes are selected to cache data distributedly, so that the network energy consumption is optimized while the constraints on data access latency and nodes' cache capacity are met. In this measure, the extra IoT nodes not involved in data transmission nor in data caching are switched off to prolong the network lifetime. We model the aforementioned optimization problem as an integer linear programming (ILP) considering the realistic constraints and characteristics of IIoT networks and solve it using the CPLEX tool. Moreover, we propose a metaheuristic algorithm based on ant colony optimization to solve the aforementioned problem in a timely manner. Simulation results show that EDMS outperforms significantly alternative solutions in terms of energy consumption, data latency, and cache utilization.
Observed and modelled tidal bar sedimentology reveals preservation bias against mud in estuarine stratigraphy
Authors: Braat Lisanne , Pierik Harm Jan , van Dijk Wout M. , van de Lageweg Wietse I. , Brückner Muriel Z. M. , van der Meulen Bas , Kleinhans Maarten G.
Published: April 2022

Mud plays a pivotal role in estuarine ecology and morphology. However, field data on the lateral and vertical depositional record of mud are rare. Furthermore, numerical morphodynamic models often ignore mud due to long computational times and simplifications of mixed depositional processes. This study aims to understand the spatial distribution, formative conditions and preservation of mud deposits in the intertidal zone of bars in high‐energy sand‐dominated estuaries, and to elucidate the effects of mud on morphology, ecology and stratigraphic architecture. To meet these objectives, field data (historic bathymetry, bio‐morphological maps and sediment cores of the shoal of Walsoorden, Western Scheldt estuary, the Netherlands) were combined with complementary hydro‐morphodynamic numerical modelling (Delft3D). Based on the field observations, two types of mud deposits were distinguished: (1) mudflat deposits, which are thick (>10 cm) mud beds at the surface associated with high elevations and low accumulation rates; and (2) mud drapes, which are thin (millimetre to centimetre) buried laminae that form and preserve at a wide range of elevations and energy conditions. Model results show that deposition on mudflats occurs just after high‐tide slack water in areas shielded from high flood velocities, suggesting that mud accumulation is mostly controlled by elevation, flow velocity and flow direction. Mud accumulation increases shoal elevation, sometimes to supratidal levels. This reduces flow over the shoal, which in turn reduces chute channel formation, stabilises bar morphology and decreases local tidal prism. These effects further promote mud deposition and vegetation settling. Although observations show that mud cover at the surface is relatively high (20%–40% of the intertidal area), mud constitutes only a small percentage of the total estuary volume (ca 5%) revealing that only a small fraction is preserved in the stratigraphy. Due to this mismatch between surface and subsurface expression of mud, interpretations of estuarine stratigraphy risk underestimating the influence of mud at the surface on morphodynamics and habitats.
Climate change mitigation and improvement of water quality from the restoration of a subtropical coastal wetland
Authors: Iram Naima , Maher Damien T. , Lovelock Catherine E. , Baker Tallis , Cadier Charles , Adame Maria F.
Published: April 2022

Coastal wetland restoration is an important activity to achieve greenhouse gas (GHG) reduction targets, improve water quality, and reach the Sustainable Development Goals. However, many uncertainties remain in connection with achieving, measuring, and reporting success from coastal wetland restoration. We measured levels of carbon (C) abatement and nitrogen (N) removal potential of restored coastal wetlands in subtropical Queensland, Australia. The site was originally a supratidal forest composed of Melaleuca spp. that was cleared and drained in the 1990s for sugarcane production. In 2010, tidal inundation was reinstated, and a mosaic of coastal vegetation (saltmarshes, mangroves, and supratidal forests) emerged. We measured soil GHG fluxes (CH4, N2O, CO2) and sequestration of organic C in the trees and soil to estimate the net C abatement associated with the reference, converted, and restored sites. To assess the influence of restoration on water quality improvement, we measured denitrification and soil N accumulation. We calculated C abatement of 18.5 Mg CO2−eq ha−1 year−1 when sugarcane land transitioned to supratidal forests, 11.0 Mg CO2−eq ha−1 year−1 when the land transitioned to mangroves, and 6.2 Mg CO2−eq ha−1 year−1 when the land transitioned to saltmarshes. The C abatement was due to tree growth, soil accumulation, and reduced N2O emissions due to the cessation of fertilization. Carbon abatement was still positive, even accounting for CH4 emissions, which increased in the wetlands due to flooding and N2O production due to enhanced levels of denitrification. Coastal wetland restoration in this subtropical setting effectively reduces CO2 emissions while providing additional cobenefits, notably water quality improvement.
Community size structure varies with predator–prey size relationships and temperature across Australian reefs
Authors: Coghlan Amy Rose , Blanchard Julia L. , Heather Freddie J. , Stuart‐Smith Rick D. , Edgar Graham J. , Audzijonyte Asta
Published: April 2022

Climate change and fisheries exploitation are dramatically changing the abundances, species composition, and size spectra of fish communities. We explore whether variation in ‘abundance size spectra’, a widely studied ecosystem feature, is influenced by a parameter theorized to govern the shape of size‐structured ecosystems—the relationship between the sizes of predators and their prey (predator–prey mass ratios, or PPMRs). PPMR estimates are lacking for avast number of fish species, including at the scale of trophic guilds. Using measurements of 8128 prey items in gut contents of 97 reef fish species, we established predator–prey mass ratios (PPMRs) for four major trophic guilds (piscivores, invertivores, planktivores, and herbivores) using linear mixed effects models. To assess the theoretical predictions that higher community‐level PPMRs leads to shallower size spectrum slopes, we compared observations of both ecosystem metrics for ~15,000 coastal reef sites distributed around Australia. PPMRs of individual fishes were remarkably high (median ~71,000), with significant variation between different trophic guilds (~890 for piscivores; ~83,000 for planktivores), and ~8700 for whole communities. Community‐level PPMRs were positively related to size spectrum slopes, broadly consistent with theory, however, this pattern was also influenced by the latitudinal temperature gradient. Tropical reefs showed a stronger relationship between community‐level PPMRs and community size spectrum slopes than temperate reefs. The extent that these patterns apply outside Australia and consequences for community structure and dynamics are key areas for future investigation.