bluuebunny/crossref_metadata_2025 huggingface dataset:
A functional corona around extracellular vesicles enhances angiogenesis, skin regeneration and immunomodulation
Authors: Wolf Martin , Poupardin Rodolphe W. , Ebner‐Peking Patricia , Andrade André Cronemberger , Blöchl Constantin , Obermayer Astrid , Gomes Fausto Gueths , Vari Balazs , Maeding Nicole , Eminger Essi , Binder Heide‐Marie , Raninger Anna M. , Hochmann Sarah , Brachtl Gabriele , Spittler Andreas , Heuser Thomas , Ofir Racheli , Huber Christian G. , Aberman Zami , Schallmoser Katharina , Volk Hans‐Dieter , Strunk Dirk
Published: April 2022

Nanoparticles can acquire a plasma protein corona defining their biological identity. Corona functions were previously considered for cell‐derived extracellular vesicles (EVs). Here we demonstrate that nano‐sized EVs from therapy‐grade human placental‐expanded (PLX) stromal cells are surrounded by an imageable and functional protein corona when enriched with permissive technology. Scalable EV separation from cell‐secreted soluble factors via tangential flow‐filtration (TFF) and subtractive tandem mass‐tag (TMT) proteomics revealed significant enrichment of predominantly immunomodulatory and proangiogenic proteins. Western blot, calcein‐based flow cytometry, super‐resolution and electron microscopy verified EV identity. PLX‐EVs partly protected corona proteins from protease digestion. EVs significantly ameliorated human skin regeneration and angiogenesis in vivo, induced differential signalling in immune cells, and dose‐dependently inhibited T cell proliferation in vitro. Corona removal by size‐exclusion or ultracentrifugation abrogated angiogenesis. Re‐establishing an artificial corona by cloaking EVs with fluorescent albumin as a model protein or defined proangiogenic factors was depicted by super‐resolution microscopy, electron microscopy and zeta‐potential shift, and served as a proof‐of‐concept. Understanding EV corona formation will improve rational EV‐inspired nano‐therapy design.
Use of quality‐of‐life instruments for people living with HIV: a global systematic review and meta‐analysis
Authors: Zhang Ying , He Christine , Peasgood Tessa , Hulse Emily S. G. , Fairley Christopher K. , Brown Graham , Ofori‐Asenso Richard , Ong Jason J.
Published: April 2022

Introduction

Due to the effectiveness of combined antiretroviral therapy and its growing availability worldwide, most people living with HIV (PLHIV) have a near‐normal life expectancy. However, PLHIV continue to face various health and social challenges that severely impact their health‐related quality‐of‐life (HRQoL). The UNAIDS Global AIDS Strategy discusses the need to optimize quality‐of‐life, but no guidance was given regarding which instruments were appropriate measures of HRQoL. This study aimed to review and assess the use of HRQoL instruments for PLHIV.

Methods

We conducted a global systematic review and meta‐analysis, searching five databases for studies published between January 2010 and February 2021 that assessed HRQoL among PLHIV aged 16 years and over. Multivariable regression analyses were performed to identify factors associated with the choice of HRQoL instruments. We examined the domains covered by each instrument. Random‐effects meta‐analysis was conducted to explore the average completion rates of HRQoL instruments.

Results and discussion

From 714 publications, we identified 65 different HRQoL instruments. The most commonly used instruments were the World Health Organization Quality‐of‐Life‐ HIV Bref (WHOQOL‐HIV BREF)—19%, Medical Outcome Survey‐HIV (MOS‐HIV)—17%, Short Form‐36 (SF‐36)—12%, European Quality‐of‐Life Instrument‐5 Dimension (EQ‐5D)—10%, World Health Organization Quality‐of‐Life Bref (WHOQOL BREF)—8%, Short Form‐12 (SF‐12)—7% and HIV/AIDS Targeted Quality‐of‐Life (HAT‐QOL)—6%. There were greater odds of using HIV‐specific instruments for middle‐ and low‐income countries (than high‐income countries), studies in the Americas and Europe (than Africa) and target population of PLHIV only (than both PLHIV and people without HIV). Domains unique to the HIV‐specific instruments were worries about death, stigma and HIV disclosure. There were no significant differences in completion rates between different HRQoL instruments. The overall pooled completion rate was 95.9% (95% CI: 94.7−97.0, I2 = 99.2%, p < 0.01); some heterogeneity was explained by country‐income level and study type.

Conclusions

A wide range of instruments have been used to assess HRQoL in PLHIV, and the choice of instrument might be based on their different characteristics and reason for application. Although completion rates were high, future studies should explore the feasibility of implementing these instruments and the appropriateness of domains covered by each instrument.
Synergistic impacts of westerlies and monsoon on interdecadal variations of late spring precipitation over the southeastern extension of the Tibetan Plateau
Authors: Wang Jing , Liu Yanju , Song Chengyu , Ding Yihui , Li Qiaoping , Wu Ping , Xu Ying , Xu Xiangde
Published: April 2022

Based on multiple long‐term observational and reanalysis datasets, this study investigated the characteristics and physical mechanisms of the interdecadal variations in late spring (i.e., May) precipitation (LSP) over the southeastern extension of the Tibetan Plateau (SETP) since 1900. It was revealed that by and large, LSP over the SETP experienced interdecadal decrease during the period preceding 1927, 1962–1988, and 2004 onwards, but saw an increase during the periods of 1928–1961 and 1989–2003. The atmospheric circulations responsible for interdecadal variations in LSP over the SETP were also analysed. These analyses identified significant synergistic impacts of decreased mid‐latitude upstream westerlies and increased low‐latitude monsoonal southerlies over the Central North Bay of Bengal (CNBOB) on interdecadal variations in precipitation, suggesting striking interactions between extratropical eastward cold air and tropical northward warm/humid air. Further observational and modelling evidence suggested that Atlantic Multidecadal Oscillation (AMO) was likely to be a salient oceanic driver for the interdecadal synergy between upstream westerlies and CNBOB monsoonal southerlies. The elevated sea surface temperature anomalies associated with the warm phase of the AMO could spark favourable local atmospheric anomalies, forcing an upper‐tropospheric, planetary‐scale teleconnection emanating from the east of the North Atlantic sector, which may serve as an effective bridge linking the remote AMO signal and the synergy between westerlies and monsoonal southerlies around the SETP on interdecadal timescales. Our findings provided new insights into the understanding of the synergistic roles of westerlies and monsoons in the modulation of interdecadal LSP over the SETP, prior to the peak Asian summer monsoon season.
Endplate abnormalities, Modic changes and their relationship to alignment parameters and surgical outcomes in the cervical spine
Authors: Baker James D. , Sayari Arash J. , Tao Youping , Louie Philip K. , Basques Bryce A. , Galbusera Fabio , Niemeyer Frank , Wilke Hans‐Joachim , An Howard S. , Samartzis Dino
Published: April 2022

Modic changes (MC) and endplate abnormalities (EA) have been shown to impact preoperative symptoms and outcomes following spinal surgery. However, little is known about how these phenotypes impact cervical alignment. This study aimed to evaluate the impact that these phenotypes have on preoperative, postoperative, and changes in cervical alignment in patients undergoing anterior cervical discectomy and fusion (ACDF). We performed a retrospective study of prospectively collected data of ACDF patients at a single institution. Preoperative magnetic resonance imagings (MRIs) were used to assess for the MC and EA. Patients were subdivided into four groups: MC‐only, EA‐only, the combined Modic‐Endplate‐Complex (MEC), and patients without either phenotype. Pre and postoperative MRIs were used to assess alignment parameters. Associations with imaging phenotypes and alignment parameters were assessed, and statistical significance was set atp < 0.5. A total of 512 patients were included, with 84 MC‐only patients, 166 EA‐only patients, and 71 patients with MEC. Preoperative MC (p = 0.031) and the MEC (p = 0.039) had significantly lower preoperative T1 slope compared to controls. Lower preoperative T1 slope was a risk factor for MC (p = 0.020) and MEC (p = 0.029) and presence of MC (Type II) and the MEC (Type III) was predictive of lower preoperative T1 slope. There were no differences in postoperative alignment measures or patient reported outcome measures. MC and endplate pathologies such as the MEC appear to be associated with worse cervical alignment at baseline relative to patients without these phenotypes. Poor alignment may be an adaptive response to these degenerative findings or may be a risk factor for their development.
Treatment strategies to resectable metachronous colorectal liver metastases after adjuvant oxaliplatin‐based chemotherapy for primary colorectal cancer
Authors: Julio Camille , Benoist Stephane , Allard Marc‐Antoine , Navarro Francis , Pessaux Patrick , Sa Cunha Antonio , Brouquet Antoine ,   French Colorectal Liver Metastases Working Group: Association Française de Chirurgie (AFC)
Published: April 2022

Background

outcome of patients who develop resectable metachronous colorectal liver metastases (CLM) after adjuvant oxaliplatin‐based chemotherapy for Stage III colorectal cancer (CRC) is not well defined and the value of preoperative chemotherapy is controversial.

Methods

From 2006 to 2013, all patients undergoing liver resection for Class I metachronous CLM after adjuvant oxaliplatin‐based chemotherapy for CRC, across 32 French academic centers, were included.

Results

Sixty‐two patients with an average of 2 ± 1 CLM were included. Thirty‐two (52%) patients received preoperative chemotherapy. There was no significant difference in the characteristics of CLM between patients with or without preoperative chemotherapy. After a median follow‐up of 29 months, 3‐year overall and disease‐free survival rates were 79.8% and 34.6%, respectively. The median disease‐free survival was not different in patients with or without preoperative chemotherapy (17 vs. 35 months respectively, p = 0.112). In multivariate analysis, only CEA level > 200 ng/ml was associated with the risk of recurrence (p = 0.027; OR = 4.7, 95% CI = 1.2–18.7).

Conclusion

Liver resection provides a good outcome in patients with limited metachronous CLM after adjuvant oxaliplatin‐based chemotherapy for CRC. The interest of preoperative chemotherapy is not obvious and should be tested in a prospective controlled study.
Sublinear operators on Herz–Hardy spaces with variable exponents
Authors: Ho Kwok‐Pun
Published: April 2022

In this paper, we establish the mapping properties of sublinear operators on Herz–Hardy spaces with variable exponents. We obtain these mapping properties by extending the extrapolation theory to Herz–Hardy spaces with variable exponents. In particular, we study the mapping properties of the multiplier operators, the Littlewood–Paley functions and the parametric Marcinkiewicz integrals on the Herz–Hardy spaces with variable exponents.
Label‐free coronavirus disease 2019 lesion segmentation based on synthetic healthy lung image subtraction
Authors: Fang Chengyijue , Liu Yingao , Liu Ying , Liu Mengqiu , Qiu Xiaohui , Li Yang , Wen Jie , Yang Yidong
Published: April 2022

Purpose

Coronavirus disease 2019 (COVID‐19) has become a global pandemic and is still posing a severe health risk to the public. Accurate and efficient segmentation of pneumonia lesions in computed tomography (CT) scans is vital for treatment decision‐making. We proposed a novel unsupervised approach using a cycle consistent generative adversarial network (cycle‐GAN) which automates and accelerates the process of lesion delineation.

Method

The workflow includes lung volume segmentation, healthy lung image synthesis, infected and healthy image subtraction, and binary lesion mask generation. The lung volume was first delineated using a pre‐trained U‐net and worked as the input for the following network. A cycle‐GAN was trained to generate synthetic healthy lung CT images from infected lung images. After that, the pneumonia lesions were extracted by subtracting the synthetic healthy lung CT images from the infected lung CT images. A median filter and k‐means clustering were then applied to contour the lesions. The auto segmentation approach was validated on three different datasets.

Results

The average Dice coefficient reached 0.666 ± 0.178 on the three datasets. Especially, the dice reached 0.748 ± 0.121 and 0.730 ± 0.095, respectively, on two public datasets Coronacases and Radiopedia. Meanwhile, the average precision and sensitivity for lesion segmentation on the three datasets were 0.679 ± 0.244 and 0.756 ± 0.162. The performance is comparable to existing supervised segmentation networks and outperforms unsupervised ones.

Conclusion

The proposed label‐free segmentation method achieved high accuracy and efficiency in automatic COVID‐19 lesion delineation. The segmentation result can serve as a baseline for further manual modification and a quality assurance tool for lesion diagnosis. Furthermore, due to its unsupervised nature, the result is not influenced by physicians’ experience which otherwise is crucial for supervised methods.
A method for converting microdosimetric spectra in diamond to tissue in proton therapy
Authors: Yu Songke , Fan Wenjie , Tang Lin , Liao Xianli , Liu Ze
Published: April 2022

Purpose

Diamond has been regarded as a promising microdosimeter in radiation protection and radiotherapy due to its excellent properties. However, as the diamond is not tissue equivalent, a conversion of the measured spectra in the diamond microdosimeter to the tissue site is needed. In this work, we intend to deduce a method for converting the microdosimetric spectra from diamond to tissue in the proton therapy application based on the Chapman–Kolmogorov equation and investigate the validity of this method in spectral conversion.

Methods

The comparison of stopping power and energy deposition distribution of diamond and tissue shows that the conversion of the spectra in diamond to tissue can be performed by a simple scaling factor. Therefore, the equivalence of the energy deposition spectra in the diamond microdosimeter and a tissue site of the same size in the same radiation field was studied first to obtain the scaling factor. Then, the spectra conversion method was derived from the Chapman–Kolmogorov equation and the scaling factor. The Geant4 simulation was employed to settle this study.

Results

Theoretical and Geant4 simulation results indicate that the linear stopping power ratio of diamond to tissue is adequate to convert the microdosimetric spectra in diamond to tissue of identical dimension. The conversion results indicate that the energy deposition spectra converted from diamond to bone agree well with the spectra calculated by Geant4 along the Bragg curve. As for water, a good agreement of the converted and calculated spectra was found at the plateau of the Bragg curve and the distal part of the Bragg peak. At the proximal part of the Bragg peak, the converted and calculated spectrum is poorly coincident.

Conclusions

The method of the energy deposition spectra conversion from the diamond microdosimeter to the tissue site of equal size shows relatively good results in most situations. But the deficiency was also found. Therefore, further investigation is needed to improve the reliability of this method.
Coupled peridynamic model for geometrically nonlinear deformation and fracture analysis of slender beam structures
Authors: Zheng Guojun , Li Lili , Han Fei , Xia Yang , Shen Guozhe , Hu Ping
Published: April 2022

Slender beam structures can experience large displacements, large rotations and fractures, even if the structures are only subjected to small loads. A coupling model of peridynamics (PD) and classical continuum mechanics (CCM) for beam fracture analysis in geometrically nonlinear deformations is developed in this study. Firstly, the formulations of virtually nonlinear strain energy density of each incremental step are obtained by using the updated Lagrangian (UL) formulation and von Karman beam theory, then the nonlinear PD beam parameters are established on the geometrically nonlinear micro‐beam bonds via the principle of virtual work and homogenization. Secondly, the coupling model of PD and CCM for geometrically nonlinear beams is proposed, for which the morphing method is applied to create a balance between the stiffness of geometrically nonlinear CCM beam model and the weighted coefficients of geometrically nonlinear PD beam model. Thirdly, a new fracture criterion for PD beam models considering the effect of geometrical nonlinearity is adopted. Finally, the large deformation and fracture analysis of straight beam, spiral slender beam and complex frame subjected to different loading conditions illustrate the validity and accuracy of the proposed PD‐CCM coupling model.
A class of strain‐displacement elements in upper bound limit analysis
Authors: Makrodimopoulos Athanasios
Published: April 2022

The main restriction in applying the upper bound theorem in limit analysis by means of the finite element method is that once the displacement field has been discretized, the flow rule and the boundary conditions should be satisfied everywhere throughout the discretized structure. This is to secure mathematically that the result will be a rigorous upper bound of the exact limit load multiplier. So far, only the linear and the quadratic displacement elements with straight sides, which result in constant and linear strains, respectively, satisfy this requirement. In this article, it is proven both theoretically and practically that there is a general class of strain‐displacement triangular elements with straight sides which provide rigorous upper bounds. The interpolation scheme is based on the Bernstein polynomials, and there is no upper restriction of the polynomial order. Both continuous and discontinuous displacements can be considered. The efficiency is examined through plane strain and Kirchhoff plate examples. The generalization to 3D (i.e., tetrahedral elements with plane faces) and other structural conditions is straightforward.
Electrical nanocomposites of PA6/ABS/ABS‐MA reinforced with carbon nanotubes (MWCNTf) for antistatic packaging
Authors: Luna Carlos Bruno Barreto , da Silva Barbosa Ferreira Eduardo , Siqueira Danilo Diniz , Araújo Edcleide Maria , do Nascimento Emanuel Pereira , Medeiros Eliton Souto , de Mélo Tomás Jeferson Alves
Published: April 2022

Herein, we prepared toughened and electrical nanocomposites of polyamide 6 (PA6)/acrylonitrile‐butadiene‐styrene (ABS) compatibilized with maleic anhydride‐grafted acrylonitrile‐butadiene‐styrene (ABS‐MA). Functionalized multi‐walled carbon nanotubes (MWCNTf) were used as conductive nanofillers. Nanocomposites were processed in an internal mixer and injection molded. Torque rheometry, impact strength, elastic modulus, heat deflection temperature (HDT), differential exploratory calorimetry (DSC), melting and crystallization kinetic curves, electrical conductivity, scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were evaluated. Torque increased with the MWCNTf content in the PA6/ABS/ABS‐MA/MWCNTf nanocomposites, suggesting an increase in viscosity. The MWCNTf were well dispersed in the nanocomposites, generating an electrical percolation path. The impact strength of the PA6/ABS/ABS‐MA/MWCNTf nanocomposites was superior to that of pure PA6, indicating improved flexibility and toughness. The addition of 1 pcr of MWCNTf in the PA6/ABS/ABS‐MA system was sufficient for antistatic application, with a 221% higher impact strength, compared to pure PA6. The DSC studies showed that the crystallization temperature of the nanocomposites shifted to higher temperatures. This was due to the MWCNTf that accelerated crystallization. Additionally, the nanocomposites HDT increased by 20°C compared to the PA6 matrix, suggesting a superior thermomechanical strength. The developed nanocomposites show improved mechanical, electrical, and thermomechanical properties. Therefore, they exhibit great technological potential for application in antistatic packaging.
Integrated multicomponent analysis based on UHPLC‐Q‐Exactive Orbitrap‐MS and network pharmacology to elucidate the potential mechanism of Baoyuan decoction against idiopathic pulmonary fibrosis
Authors: Zhang Binbin , Gao Dongyang , Xu Gonghao , Zhu Wenxiang , Liu Jing , Sun Rui , Wang Lu , Zhang Chen , Ding Qi , Shi Yuanyuan
Published: April 2022

Introduction

Idiopathic pulmonary fibrosis (IPF) is a serious lung disease with a high mortality rate. Baoyuan decoction (BYD), a classic medicinal food homology recipe, has anti‐apoptotic effects, enhances immune function, and alleviates fibrosis, suggesting that it may be a potential therapeutic drug for IPF.

Objectives

We aimed to identify the main active ingredients of BYD, determine the basis of its efficacy, prove its anti‐IPF effects, and explore the mechanisms underlying its anti‐IPF effects.

Materials and methods

In this study, the active components of BYD were detected and analysed by ultra‐high‐performance liquid chromatography coupled with hybrid quadrupole Orbitrap mass spectrometry (UHPLC‐Q‐Exactive Orbitrap‐MS). A network pharmacology analysis was performed to determine the potential targets and relevant pathways of BYD in treating IPF. Western blotting and quantitative real‐time polymerase chain reaction (qPCR) were conducted to verify the efficacy of BYD against IPF. Finally, molecular docking and qPCR were performed to identify the central targets of BYD.

Results

A total of 39 components of BYD were identified. After performing the network pharmacology analysis, 35 active components and eight presumptive targets of BYD were found to play a central role in its anti‐IPF effects. The molecular docking results indicated that most of the active components of BYD exhibited good binding activity with these eight central target proteins. In addition, the expression of collagen, α‐SMA, and these eight targets in human pulmonary fibroblast (HPF) cells was suppressed from treatment with BYD.

Conclusion

This study determined the efficacy of BYD against IPF and clarified its multiple‐target and multiple‐pathway mechanisms. Furthermore, the study also provides a new method for exploring the chemical and pharmacological bases of other traditional Chinese medicine (TCM).
Elastic composites fabricating for electromagnetic interference shielding based on MWCNTs and Fe3O4 unique distribution in immiscible NR/NBR blends
Authors: Zhang Xinjin , Fan Chunyan , Ma Yongjie , Zhao Hongying , Sui Jing , Liu Jiwen , Sun Chong
Published: April 2022

Electromagnetic interference (EMI) shielding rubber nanocomposites were fabricated via a simple rubber roll milling technique based on the filler distribution behavior in the immiscible natural rubber (NR) and acrylonitrile‐butadiene (NBR) (50/50) blends with varying amounts of multiwall carbon nanotubes and Fe3O4 nanoparticles. All nanocomposites showed a co‐continuous phase structure, while the distribution behavior of filler was diverse correlated with the filler content and type. The mechanical properties, electrical conductivity, and EMI shielding effectiveness (SE) of rubber composites were characterized. The maximum EMI SE of 29.4 dB at 12.4 GHz was achieved in the rubber composites loaded with 15 phr MWCNTs and 15 phr Fe3O4 nanoparticles. The EMI shielding mechanisms of such materials were also discussed. The observation in this work provided a possible idea to the industrial manufacture electromagnetic interference shielding rubber nanocomposites, and contributed to expanding its application fields with higher mechanical property requirements and flexibility.
Polyhydroxybutyrate: a review of experimental and simulation studies of the effect of fillers on crystallinity and mechanical properties
Authors: Majerczak Katarzyna , Wadkin‐Snaith Dominic , Magueijo Vitor , Mulheran Paul , Liggat John , Johnston Karen
Published: April 2022

Polyhydroxybutyrate (PHB) is a sustainable polymer that is a promising candidate for replacing petroleum‐based plastics in food packaging. Fillers are used to improve the mechanical properties of PHB composites, simultaneously changing the crystallinity of the polymer matrix. However, it is not well understood how fillers affect crystallisation and microstructure, and thus the resulting mechanical properties of the composite. This review summarises simulation work on polymer nucleation and crystallisation and how nucleation is influenced by different types of polymer–filler interfaces. Experimental studies of PHB composites with a wide variety of fillers are reviewed to find trends between the filler type, crystallinity and mechanical properties. It is clear that fillers act as nucleants that increase the number of spherulites while reducing spherulite size. This behaviour is apparent for almost all fillers regardless of filler chemistry or topology. However, the data obtained from the literature do not seem to produce strong conclusions about the effect of the degree of crystallinity on the tensile properties of PHB–filler composites, although there are some weak trends that indicate the importance of microstructure. In order to enable prediction and control of PHB composite properties, further systematic studies are required to elucidate the effect of specific filler types and the connection between crystallinity, microstructure and mechanical properties. © 2022 The Authors. Polymer International published by John Wiley & Sons Ltd on behalf of Society of Industrial Chemistry.
In‐liquid plasma synthesis of iron–nitrogen‐doped carbon nanoflakes with high catalytic activity
Authors: Kondo Hiroki , Hamaji Ryo , Amano Tomoki , Ishikawa Kenji , Sekine Makoto , Hiramatsu Mineo , Hori Masaru
Published: April 2022

Flake‐shaped carbon nanomaterials with nitrogen (N) and iron (Fe) addition, so‐called carbon nanoflakes (CNFLs), were synthesized by the in‐liquid plasma using two different kinds of additive agents, such as hemin and iron (II) phthalocyanine (FePc). According to scanning electron microscopy images and Raman spectra, CNFLs with a size of at least 100 nm order were formed regardless of types of additive agents, and crystallinity of six‐membered ring structures was improved as additive agents increased. Photoelectron spectra showed that pyridinic N contents increased from 1.05% to 2.02% with increasing FePc, while those decreased from 0.34% to 0.14% with hemin. In the oxygen reduction reaction, onset potential values also increased from 0.71 to 0.79 eV with increasing FePc, while those decreased from 0.60 to 0.47 eV with hemin. These results suggested that the catalytic activity of CNFLs was effectively improved by the increase of pyridinic N by the in‐liquid plasma synthesis with FePc. In contrast, the electron transfer numbers reached 3.81 when hemin increased, although those were less than 2.88 in the cases using FePc. These results mean that the in‐liquid plasma synthesis method of CNFLs using FePc has the potential to further improve its catalytic activity.
Meta‐analysis of apple (Malus × domestica Borkh.) fruit and juice quality traits for potential use in hard cider production
Authors: VanderWeide Joshua , van Nocker Steve , Gottschalk Christopher
Published: April 2022

Societal Impact Statement

The production of hard cider is a burgeoning industry in North America. However, traditional European cider‐specific apples are largely unsuitable for production in modern systems and have not been widely adopted. Evaluation of the biochemical variability in apples can provide a better characterization of varieties for use in hard cider production. Many varieties exhibited extensive variability in biochemical traits. Varieties with high phenolics and acidity displayed greater plasticity of these traits between seasons, which supports the concept of “vintage quality” and opens new marketing opportunities. This study provides valuable insight for apple producers to integrate cider‐specific and nonspecific varieties into their production systems.

The North American fermented beverage market has undergone extensive growth in the fermented apple juice (hard cider) sector over the last decade. Traditional hard cider producing regions such as England, France, and Spain have historically utilized cider‐specific apples that have desirable balances between sugar, organic acid, and phenolics. However, in North America, culinary apples (lower acidity and phenolics) are predominantly used, and information distinguishing the varieties with novel use for hard cider production is lacking.

In this study, we evaluated variation of four major apple biochemical traits (total soluble solids, pH, titratable acidity, and total phenolics) as they relate to use for hard cider production by using a meta‐analysis approach. We analyzed the variation in cider quality traits across 47 published works and more than 800 unique apple varieties, including an additional analysis of 142 varieties from cider apple germplasms in the United States.

The biochemical traits of many varieties exhibited plasticity, and the characterization of a subset of varieties using two cider classification system revealed that most belonged to the “sweet” or “sharp” (acidic) categories rather than “bitter” (high phenolic content). We also compared the classification of a subset of varieties from two US germplasm resources across two seasons and found varieties that have high percent phenolics and/or malic acid experienced greater biochemical plasticity and potential classification change across vintages.

Ultimately, this work provides information regarding the variability in apple biochemical traits and also suggests a unique opportunity for producers to market “vintage” quality.
Structure‐based analysis and evolution of a monomerized red‐colored chromoprotein from the Olindias formosa jellyfish
Authors: Zhai Le , Nakashima Ryosuke , Shinoda Hajime , Ike Yoshimasa , Matsuda Tomoki , Nagai Takeharu
Published: April 2022

GFP‐like chromoproteins (CPs) with non‐fluorescence ability have been used as bioimaging probes. Existing CPs have voids in the optical absorption window which limits their extensibility. The development of new CP color is therefore ongoing. Here, we cloned CPs from the jellyfish, Olindias formosa, and developed a completely non‐fluorescent monomeric red CP, R‐Velour, with an absorption peak at 528 nm. To analyze the photophysical properties from a structural aspect, we determined the crystal structure of R‐Velour at a 2.1 Å resolution. R‐Velour has a trans‐chromophore similar to the green fluorescence protein, Gamillus, derived from the same jellyfish. However, in contrast to the two coplanar chromophoric rings in Gamillus, R‐Velour has a large torsion inducing non‐fluorescence property. Through site‐directed mutagenesis, we surveyed residues surrounding the chromophore and found a key residue, Ser155, which contributes to the generation of four‐color variants with the bathochromic and hypsochromic shift of the absorption peak, ranging from 506 to 554 nm. The recently proposed spectrum shift theory, based on the Marcus–Hush model, supports the spectrum shift of these mutants. These findings may support further development of R‐Velour variants with useful absorption characteristics for bioimaging, including fluorescence lifetime imaging and photoacoustic imaging.
Synthetic antibodies block receptor binding and current‐inhibiting effects of α‐cobratoxin from Naja kaouthia
Authors: Miersch Shane , de la Rosa Guillermo , Friis Rasmus , Ledsgaard Line , Boddum Kim , Laustsen Andreas H. , Sidhu Sachdev S.
Published: April 2022

Each year, thousands of people fall victim to envenomings caused by cobras. These incidents often result in death due to paralysis caused by α‐neurotoxins from the three‐finger toxin (3FTx) family, which are abundant in elapid venoms. Due to their small size, 3FTxs are among the snake toxins that are most poorly neutralized by current antivenoms, which are based on polyclonal antibodies of equine or ovine origin. While antivenoms have saved countless lives since their development in the late 18th century, an opportunity now exists to improve snakebite envenoming therapy via the application of new biotechnological methods, particularly by developing monoclonal antibodies against poorly neutralized α‐neurotoxins. Here, we describe the use of phage‐displayed synthetic antibody libraries and the development and characterization of six synthetic antibodies built on a human IgG framework and developed against α‐cobratoxin – the most abundant long‐chain α‐neurotoxin from Naja kaouthia venom. The synthetic antibodies exhibited sub‐nanomolar affinities to α‐cobratoxin and neutralized the curare‐mimetic effect of the toxin in vitro. These results demonstrate that phage display technology based on synthetic repertoires can be used to rapidly develop human antibodies with drug‐grade potencies as inhibitors of venom toxins.
Nucleoside analog GS‐441524: pharmacokinetics in different species, safety, and potential effectiveness against Covid‐19
Authors: Rasmussen Henrik Berg , Thomsen Ragnar , Hansen Peter Riis
Published: April 2022

GS‐441524, the parent nucleoside of remdesivir, has been proposed to be effective against Covid‐19 based on in vitro studies and studies in animals. However, randomized clinical trials of the agent to treat Covid‐19 have not been conducted. Here, we evaluated GS‐441524 for Covid‐19 treatment based on studies reporting pharmacokinetic parameters of the agent in mice, rats, cats, dogs, monkeys, and the single individual in the first‐in‐human trial supplemented with information about its activity against severe acute respiratory syndrome coronavirus 2 and safety. A dosing interval of 8 h was considered clinically relevant and used to calculate steady‐state plasma concentrations of GS‐441524. These ranged from 0.27 to 234.41 μM, reflecting differences in species, doses, and administration routes. Fifty percent maximal inhibitory concentrations of GS‐441524 against severe acute respiratory syndrome coronavirus 2 ranged from 0.08 μM to above 10 μM with a median of 0.87 μM whereas concentrations required to produce 90% of the maximal inhibition of the virus varied from 0.18 µM to more than 20 µM with a median of 1.42 µM in the collected data. Most of these concentrations were substantially lower than the calculated steady‐state plasma concentrations of the agent. Plasma exposures to orally administered GS‐441524, calculated after normalization of doses, were larger for dogs, mice, and rats than cynomolgus monkeys and humans, probably reflecting interspecies differences in oral uptake with reported oral bioavailabilities below 8.0% in cynomolgus monkeys and values as high as 92% in dogs. Reported oral bioavailabilities in rodents ranged from 12% to 57%. Using different presumptions, we estimated human oral bioavailability of GS‐441524 at 13% and 20%. Importantly, doses of GS‐441524 lower than the 13 mg/kg dose used in the first‐in‐human trial may be effective against Covid‐19. Also, GS‐441524 appears to be well‐tolerated. In conclusion, GS‐441524 has potential for oral treatment of Covid‐19.
Analysis of MTG‐IRS observations and general channel selection for numerical weather prediction models
Authors: Coopmann O. , Fourrié N. , Guidard V.
Published: April 2022

The Infrared Sounder (IRS) is an infrared Fourier transform spectrometer that will be on board the Meteosat Third Generation series of the future European Organization for the Exploitation of Meteorological Satellites geostationary satellites and will have a unique four‐dimensional look at the atmosphere. After its planned launch in 2024, it will be able to measure the radiance emitted by the Earth at the top of the atmosphere using 1,960 channels in two spectral bands between 680–1,210 cm (long‐wave infrared) and 1,600–2,250 cm (mid‐wave infrared) at a spectral sampling of 0.6 cm. It will perform measurements over the full Earth disk with high spatial and temporal resolution of 4 km at nadir and 30 min over Europe. Thus, the huge amount of data from IRS will present challenges, particularly in data transmission, data storage, and assimilation into numerical weather prediction (NWP) models. To reduce the volume of data, various methods are available, including spatial sampling, principal component analysis, and channel selection. The latter technique will be discussed in this paper by proposing general channel selection to provide NWP models. The objective of this selection is to improve essential variables for NWP such as temperature, humidity, skin temperature, and ozone. This work has required the development of a large observation database and takes into account the main developments in assimilation techniques, including the use of full observation‐error covariance matrices or the assimilation of ozone in global models, for example. This study performs a specific analysis of the sensitivity of IRS observations and proposes a first general selection of 300 channels for NWP models. This selection allows us to reduce the analysis error in the troposphere by 48% in temperature, 65% in humidity, and 17% in ozone.
Predefined‐time tracking control for high‐order nonlinear systems with control saturation
Authors: Gong Youmin , Guo Yanning , Li Dongyu , Ma Guangfu , Ran Guangtao
Published: April 2022

In this paper, an innovative predefined‐time tracking control algorithm is proposed for high‐order nonlinear systems with control saturation and disturbance, which can directly calculate the upper bound of settling‐time by user‐defined parameters. First, a predefined‐time observer based on tracking differentiator is applied to handle the disturbance. Next, a new predefined‐time tracking control algorithm is designed using the backstepping method, and a novel auxiliary dynamic system is designed to deal with the control saturation. The stability of the closed‐loop system is analyzed applying Lyapunov function‐like method. The derivative of the virtual controller is obtained by the first‐order filter to reduce the computation burden. It is worth mentioning that, different from the exiting results, all parameters related to settling‐time in each virtual controller can be selected differently, and it can improve the flexibility of the controller design. Finally, the robustness and effectiveness of the investigated algorithm have been demonstrated by two typical numerical simulations.
DisCrit Literacies: Early Childhood Teachers Critically Reading School as Text and Imagining an Otherwise
Authors: Beneke Margaret R. , Machado Emily , Taitingfong Jordan
Published: April 2022

In this participatory case study, we explored the critical literacy practices of early‐career early childhood teachers in a year‐long inquiry group, examining how they collectively read school as text through DisCrit literacies. Bridging literature from Disability Critical Race Theory (DisCrit) and critical literacies scholarship, DisCrit literacies involve practices of critically reading school itself as text and uncovering intersecting systems of ableism and racism. We describe teachers’ collective engagement in DisCrit literacies, in which they: (a) deconstructed literacy practices and broader schooling mechanisms through repeated shared readings; (b) implicated themselves through critical readings of literacy classroom artifacts; and (c) identified and designed spaces of subversion and refusal in their literacy classrooms. Across each of these practices, early career early childhood teachers in our study used critical reading practices rooted in interdependence and presumptions of competence to redesign literacy routines. Ultimately, DisCrit literacies supported teachers in dismantling systems of regulation and classification in their early literacy classrooms, and—in solidarity with multiply‐marginalized children— imagining otherwise possibilities. We conclude with implications for teacher education and research, exploring how we might use DisCrit literacies to move toward humanizing early literacy spaces with and for multiply‐marginalized young children.
Estimation of vaccine efficacy for variants that emerge after the placebo group is vaccinated
Authors: Follmann Dean , Fay Michael , Magaret Craig
Published: April 2022

SARS‐CoV‐2 continues to evolve and the vaccine efficacy against variants is challenging to estimate. It is now common in phase III vaccine trials to provide vaccine to those randomized to placebo once efficacy has been demonstrated, precluding a direct assessment of placebo controlled vaccine efficacy after placebo vaccination. In this work, we extend methods developed for estimating vaccine efficacy post placebo vaccination to allow variant specific time varying vaccine efficacy, where time is measured since vaccination. The key idea is to infer counterfactual strain specific placebo case counts by using surveillance data that provide the proportions of the different strains. This blending of clinical trial and observational data allows estimation of strain‐specific time varying vaccine efficacy, or sieve effects, including for strains that emerge after placebo vaccination. The key requirements are that the surveillance strain distribution accurately reflects the strain distribution for a placebo group throughout follow‐up after placebo group vaccination, and that at least one strain is present before and after placebo vaccination. For illustration, we develop a Poisson approach for an idealized design under a rare disease assumption and then use a proportional hazards model to address staggered entry, staggered crossover, and smoothly varying strain specific vaccine efficacy. We evaluate these methods by theoretical work and simulations, and demonstrate that useful estimation of the efficacy profile is possible for strains that emerge after vaccination of the placebo group. An important principle is to incorporate sensitivity analyses to guard against misspecification of the strain distribution.
Tumor Customized 2D Supramolecular Nanodiscs for Ultralong Tumor Retention and Precise Photothermal Therapy of Highly Heterogeneous Cancers
Authors: Lin Peng , Xue Yucheng , Mu Xueluer , Shao Youyou , Lu Qian , Jin Xiangang , Yinwang Eloy , Zhang Zengjie , Zhou Hao , Teng Wangsiyuan , Sun Hangxiang , Chen Weida , Shi Wei , Shi Cangyi , Zhou Xianfeng , Jiang Xuesheng , Yu Xiaohua , Ye Zhaoming
Published: April 2022

Target therapy for highly heterogeneous cancers represents a major clinical challenge due to the lack of recurrent therapeutic targets identified in these tumors. Herein, the authors report a tumor‐customized targeting photothermal therapy (PTT) strategy for highly heterogeneous cancers, by which 2D supramolecular self‐assembled nanodiscs are modified with tumor‐specific binding peptides identified by phage display techniques. Taking osteosarcoma (OS) as a model heterogeneous cancer, an OS targeting peptide (OTP) is first selected after biopanning and is demonstrated to successfully bind to this heterogeneous cancer cells/tissues. Successful conjugation of OTP to heptamethine cyanine (Cy7)‐based 2D nanodiscs Cy7‐TCF (2‐dicyanomethylene‐3‐cyano‐4,5,5‐trimethyl‐2,5‐dihydrofuran,TCF) enables the 2D nanodiscs to specifically target the heterogeneous tumor. Notably, a single dose injection of this targeted nanodisc (T‐ND) not only effectively induces enhanced photothermal tumor ablation under near‐infrared light, but also exhibits sevenfold increase of tumor retention time (more than 24 days) compared to generic nanomedicine. Thus, the authors’ findings suggest that the combination of phage display‐based affinity peptides selection and 2D supramolecular nanodiscs leads to the development of a platform technology for highly heterogeneous cancers precise therapy, offering specific tumor targeting, ultralong tumor retention, and precise PTT.
Large‐Scale Production of Ligand‐Engineered Robust Lead Halide Perovskite Nanocrystals by a Droplet‐Based Microreactor System
Authors: Geng Yuhao , Guo Jiazhuang , Wang Huiqing , Ling Si Da , Chen Zhuo , Chen Su , Xu Jianhong
Published: April 2022

Cesium lead halide perovskite nanocrystals (CLHP NCs) have a wide range of potential applications benefited from the properties of high photoluminescence quantum yield (PLQY), wide luminous gamut, and narrow half peak width. However, due to the ionic nature and sensitivity to moisture, oxygen, or heat, perovskite nanocrystals are too fragile to maintain their crystal structure and optical properties. This work proposes solutions to two key issues in the development of CLHP NCs. First, a productive droplet‐based microreactor system is designed to accomplish the scale‐up production of CLHP NCs, obtaining sub‐gram high‐purity nanocrystal powders in a single production process. Second, CLHP NCs which are stable in polar solvents, air environment, and high temperature by using 3‐aminopropyl triethoxysilane (APTES) as basic ligand are obtained. Wrapped with Si–O–Si generated by APTES, the CLHP NCs exhibit a longer fluorescence lifetime and higher quantum yield. Especially, the PLQY of CsPbBr3@APTES can be stable at higher than 90% for more than 10 days. The Si–O–Si protective layer can also suppress the anion exchange between CsPbBr3 and CsPbI3, maintaining the monochromaticity of nanocrystal luminescence. Eventually, full‐spectrum quantum light‐emitting diode (QLED) beads with robust nanocrystals are fabricated. The gamut of CsPbX3@APTES encompasses 140% of the NTSC color gamut standard.
Context modeling for cyber‐physical systems
Authors: Daun Marian , Tenbergen Bastian
Published: April 2022

When developing cyber‐physical systems (CPS), the context is of vital importance. CPS interact with the world not only through sensing the environment and acting upon it (like embedded systems) but also by communicating with other CPS (like systems in the Internet of Things [IoT]). This means that the context interactions CPS must deal with are much greater than regular embedded or IoT systems: On the one hand, external systems and human users constrain the specific interaction among them. On the other hand, properties of these external systems, human users, and laws, regulations, or standards constrain the way the CPS must be developed. In this paper, we propose a comprehensive, ontologically grounded context modeling framework to systematically explore the problem space in which a CPS under development will operate. This allows for the systematic elicitation of requirements for the CPS, early validation and verification of its properties, and safety assessment of its context interactions at runtime.
Freestanding Helical Nanostructured Chiro‐Photonic Crystal Film and Anticounterfeiting Label Enabled by a Cholesterol‐Grafted Light‐Driven Molecular Motor
Authors: Bao Jinying , Wang Zizheng , Shen Chen , Huang Rui , Song Chenjie , Li Zhaozhong , Hu Wei , Lan Ruochen , Zhang Lanying , Yang Huai
Published: April 2022

Design and fabrication of freestanding chiro‐photonic crystal film with the ability to change color over the whole visible light spectrum is appealing for anticounterfeiting technology and smart labels. Utilizing a newly synthesized light‐responsive molecular motor functionalized with cholesterol (chol‐MM) on the rotor, novel light‐controlled photonic crystal is prepared by doping the novel chol‐MM into liquid crystals (LCs). Thanks to the liquid crystalline cholesterol substituent, the chol‐MM can be triggered by visible light (420 nm). At the same time, the miscibility of chol‐MM in LC matrix is significantly enhanced. Integrating the chol‐MM with thermochromic hydrogen‐bonded LC matrix, thermal and light dual‐responsive cholesteric LC (CLC) material is prepared, in which the nanoscale helical pitch is tunable by photo‐induced molecular motions of chol‐MM. More importantly, utilizing UV‐initiated polymerization of the visible light‐modulated CLC material, structural colored photonic crystal films with arbitrary colorful patterns are fabricated. Such freestanding helical nanostructured labels have potential in the application of encrypted communication and anticounterfeiting.