bluuebunny/crossref_metadata_2025 huggingface dataset:
Quotations as Pictures
Authors: Stern Josef
Published: February 2022

The proposal of a semantics for quotations using explanatory notions drawn from philosophical theories of pictures.

In Quotations as Pictures, Josef Stern develops a semantics for quotations using explanatory notions drawn from philosophical theories of pictures. He offers the first sustained analysis of the practice of quotation proper, as opposed to mentioning. Unlike other accounts that treat quotation as mentioning, Quotations as Pictures argues that the two practices have independent histories, that they behave differently semantically, that the inverted commas employed in both mentioning and quotation are homonymous, that so-called mixed quotation is nothing but subsentential quotation, and that the major problem of quotation is to explain its dual reference or meaning—its ordinary meaning and its metalinguistic reference to the quoted phrase attributed to the quoted subject.

Stern argues that the key to understanding quotation is the idea that quotations are pictures or have a pictorial character. As a phenomenon where linguistic competence meets a nonlinguistic symbolic ability, the pictorial, quotation is a combination of features drawn from the two different symbol systems of language and pictures, which explains the exceptional and sometimes idiosyncratic data about quotation. In light of this analysis of verbal quotation, in the last chapters Stern analyzes scare quotation as a nonliteral expressive use of the inverted commas and explores the possibility of quotation in pictures themselves.
The Digital Multinational
Authors: Nambisan Satish , Luo Yadong
Published: February 2022

How multinational companies can use digital technology to compete in a world where business is driven by the forces of both globalization and deglobalization.

Digital technology has put globalization on steroids; multinational companies now account for one-third of world GDP and one-fourth of world employment. And yet complicating this story of unchecked global capitalism are two contradictory forces. Even as advances in digital technology enable borderless markets, a new nationalism has emerged, reviving protectionism and railing against digital colonialism. In The Digital Multinational, management experts Satish Nambisan and Yadong Luo examine how companies can adopt a dual strategy to cope with this new normal: harnessing the power of digital technology while adapting to the geopolitical realities of particular markets.

Key to success, Nambisan and Luo explain, is the notion of tight and loose coupling to characterize the relationship of the digital multinational to its global partners and subsidiaries. Identifying the tightness-looseness requirements of global business connectivity leads to successful business strategy. Drawing on real-world examples that include Burberry's entrance into the Chinese market, Unilever's AI-powered global talent marketplace, and the Vocal for Local movement in India, they develop a typology of global business contexts; discuss digital strategies for entering new markets, establishing digital platforms, managing globally dispersed activities, and pursuing innovation; and explain how these strategies can be part of a business leader's toolkit. The Digital Multinational is an essential guide to competing in a business world driven by both globalization and deglobalization.
Dogs and wolves differ in their response allocation to their owner/caregiver or food in a concurrent choice procedure
Authors: Isernia Lindsay , Wynne Clive D.L. , House Leanna , Feuerbacher Erica N.
Published: February 2022

Dogs and wolves both show attachment-like behaviors to their owners/caregivers, including exploring more in the presence of the owner/caregiver, and greeting the owner/caregiver more effusively after an absence. Concurrent choice studies can elucidate dogs’ and wolves’ relationship to their owners/caregivers by assessing their preference for the owner/caregiver compared to other stimuli. While previous research has used concurrent choice paradigms to evaluate dogs’ and wolves’ preference between humans giving social interaction or humans giving food, no research has explored their preferences for an owner/caregiver compared to food when the food is not delivered by a human. In the current study, we investigated whether dogs and hand-reared wolves preferred their owner/caregiver or food, unassociated with a human, when they had been equally deprived of each stimulus (at least 4 hours). Each canid experienced four trials; we measured first choice and time spent with each alternative. Dogs overall did not show a preference for the owner or food. Wolves, on the other hand, tended to show a preference for food in both measures. We observed a range of individual variation in both measures, although dogs showed more individual variation. The differences we observed between dogs and wolves align with prior research comparing wolf and dog behavior directed towards humans; however, the reasons for this differential responding could be due to a variety of factors beyond phylogeny.
7,8-Dihydroxyflavone protects neurons against oxygen-glucose deprivation induced apoptosis and activates the TrkB/Akt pathway
Authors: Zhou Qinxiang , Tang Hao , Bai Dingqun , Kong Yuhan
Published: February 2022

Background

7,8-dihydroxyflavone (7,8-DHF), a selective agonist of tropomyosin related kinase receptor B (TrkB), is known to exert protective effects in neurodegenerative diseases. However, the role of 7,8-DHF in TrkB signaling after ischemic stroke has remained elusive.

Methods

In the vitro model of ischemic stroke, we investigated the neuroprotective effect of 7,8-DHF through activation of TrkB signaling. Neurons subjected to oxygen and glucose deprivation/reperfusion were treated with the protein kinase inhibitor K252a and a knockdown of TrkB. Cell counting kit-8 (CCK-8) assay, Flow Cytometric Analysis (FACS), TdT-mediated dUTP nick end labeling (TUNEL) assay were conducted for measuring cell viability and numbers of apoptotic cells. And apoptosis-associated proteins were analyzed by Western blotting.

Results

Compared with the Control group, OGD/R group revealed lower cell viability by CCK-8 assay FACS and TUNEL assay showed increased rates of neuronal apoptosis. However, 7,8-DHF treatment increased cell viability and reduced neuronal apoptosis. Western blotting indicated upregulated Bax and cleaved caspase-3 and but downregulated Bcl-2 following OGD/R. Whereas 7,8-DHF treatment downregulated Bax and cleaved caspase-3 but upregulated Bcl-2. These changes were accompanied by a significant increase in the phosphorylation of TrkB and Akt following 7,8-DHF administration. However, the administration of K252a and knockdown of TrkB could alleviate those effects.

Conclusion

Our study demonstrates that activation of TrkB signaling by 7,8-DHF protects neurons against OGD/R injury via the TrkB/Akt pathway, which provides the evidence for the role of TrkB signaling in OGD-induced neuronal damage and may become a potential therapeutic target for ischemic stroke.
No evidence of conditioning of pupillary constriction despite overtraining
Authors: Niehorster Diederick C. , Bengtsson Stina , Brodin Niklas , Rasmussen Anders
Published: February 2022

Eyeblink conditioning is the most popular paradigm for studying classical conditioning in humans. But the fact that eyelids are under voluntary control means it is ultimately impossible to ascertain whether a blink response is ‘conditioned’ or a timed ‘voluntary’ blink response. In contrast, the pupillary response is an autonomic response, not under voluntary control. By conditioning the pupillary response, one might avoid potential volition-related confounds. Several attempts have been made to condition the pupillary constriction and dilation responses, with the earliest published attempts dating back to the beginning of the 20th century. While a few early studies reported successful conditioning of pupillary constriction, later studies have failed to replicate this. The apparatus for recording pupil size, the type of stimuli used and the interval between the stimuli has varied in previous attempts—which may explain the inconsistent results. Moreover, measuring the pupil size used to be cumbersome compared with today when an eyetracker can continuously measure pupil size non-invasively. Here we used an eyetracker to test whether it is possible to condition the autonomic pupillary constriction response by pairing a tone (CS) and a light (US) with a 1s CS-US interval. Unlike in previous studies, our subjects went through multiple training sessions to ensure that any potential lack of conditioning would not be due to too little training. A total of 10 participants went through 2–12 conditioning sessions, each lasting approximately 20 min. One training session consisted of 75 paired, tone + light, trials and 25 randomly interspersed CS alone trials. The eyetracker (Tobii Pro Nano), continuously measured participants’ pupil size. To test statistically whether conditioning of the pupillary response occurred we compared the pupil size after the tone on the first session and the last session. The results showed a complete lack of evidence of conditioning. Though the pupil size varied slightly between participants, the size did not change as a result of the training—irrespective of the number of training sessions. The data replicate previous findings that pupillary constriction does not show conditioning. We conclude that it is not possible to condition pupillary constriction—at least not by pairing a tone and a light. One hypothesis is that when pupillary conditioning has been observed in previous studies, it has been mediated by conditioning of an emotional response.
Incidence and Clinical Implications of Cervical Rib: A Retrospective Study
Authors: Adibatti Mallikarjun Ningappa , Pitchandi Muthiah , Venkatesan Bhuvaneswari
Published: February 2022

Introduction: Cervical ribs are an additional rib, which arise from the costal element of the seventh cervical vertebra. Incidence varies from 0.58-6.2%, incidentally detected on radiographs, but when enlarged can lead to various vascular and neurological symptoms. When it is of sufficient length it can compress the neurovascular bundle leading to Thoracic Outlet Syndrome (TOS) causing vascular and neurological symptoms. Aim: To determine the incidence and morphology of cervical rib in a convenient sample. Materials and Methods: A retrospective observational study was done in 650 radiographs (356 males and 294 females) from January 2016 to January 2019 and the study was conducted at ESIC Medical College and PGIMSR, Chennai, Tamil Nadu, India, and the data was analysed for the incidence and morphology of cervical ribs. Results: Incidence of cervical ribs in females (1.7%) was higher than males (1.12%). In the present study, incidence of cervical ribs was 1.38%, we observed there were seven cases of bilateral cervical ribs and two cases of unilateral cervical rib. Morphologically, cervical ribs had head, neck and tubercle and articulated posteriorly with transverse process and no other significant morphological variations were seen. Conclusion: Knowledge regarding incidence of cervical ribs and other rib anamolies assists the radiologist and surgeons in early diagnosis and management of symptomatic patients in order to avoid neurovascular complications.
Diagnostic Value of Peritoneal Nodules Detected on CECT Abdomen in Management of Ascites of Unknown Origin- A Retrospective Study
Authors: Jukuri Naganarasimharaju , Narra Ramakrishna , Jehendran Mary Varunya , Reddy Yeruva Yeshwanth , Thotakura Mahathi
Published: February 2022

Introduction: The aetiology of ascites can be established in a majority of patients with routine clinical examination and conventional laboratory and imaging investigations; but in a minority, the cause may remain undetected even after these examinations. This ascites is termed as ascites of unknown origin. The Contrast Enhanced Computed Tomography (CECT) abdomen of these patients sometimes shows peritoneal nodules which can be useful to establish diagnosis. Aim: To evaluate the diagnostic value of peritoneal nodules detected on CECT abdomen in the management of ascites of unknown origin. Materials and Methods: This retrospective study was conducted in Katuri Medical College and Hospital, Guntur, Andhra Pradesh, India on the data retrieved from the medical records of the patients between January 2019 to January 2021. These patients had already been vainly investigated with basic clinical, laboratory and diagnostic ultrasound examinations for the aetiology of ascites. All the patients who were diagnosed to have peritoneal nodules on CECT abdomen and later underwent laparoscopic tissue diagnosis of these peritoneal nodules were included in the study. The sizes of the peritoneal nodules and the distribution of the pathology were collected from CECT abdomen reports and compared them with the histopathology findings. Statistical analysis and plotting of the Receiver Operating Characteristic (ROC) curve were done using Statistical Package for the Social Sciences (SPSS) version 25.0. Results: Fifty-two patients of ascites of unknown origin with peritoneal nodules were included in the study. Of the total, 36 (69.2%) patients were males and 16 (30.8%) were females. Mean age of the patients was 48 years (22 to 74 years). Tissue diagnosis of the peritoneal nodules revealed that majority of the patients had carcinomatosis peritonei (88.5%) while a minority had tuberculosis (11.5%). A nodule size of more than 5 mm as a sign of malignancy on CECT abdomen had a sensitivity of 93% and a specificity of 83%. Based on the tissue diagnosis of the peritoneal nodules these patients were treated with antituberculosis drugs for tuberculous abdomen and chemotherapy for carcinomatosis peritonei. Conclusion: Detection of peritoneal nodules on CECT abdomen can be helpful in guiding the clinician for further management of ascites of unknown origin.
Conservation and change on Edinburgh's defences
Authors: Lawson John , Reed David , Wallace Colin , Millar Jonathan , Middleton Mike
Published: February 2022

This report presents the results of a historic building survey and archaeological watching brief undertaken between 1998 and 2001 during restoration work, as part of the Scottish Dance Base development, on the Flodden Wall running between Edinburgh's Grassmarket and Johnston Terrace (NGR: NT 252 733). The Flodden Wall is the name given to the 16th-century extension of the capital's town defences, traditionally seen as having been constructed in the months following the defeat at Flodden in 1513. Prior to this project the extent and condition of this particular stretch of the Flodden Wall (the north-western boundary of the Grassmarket and a Scheduled Ancient Monument) was not fully understood. This project has shown that here the Flodden Wall and surrounding area had undergone three major phases of construction and redevelopment, from its origins in the early 16th century to the formation of a drying green (Granny's Green) to the west of the Wall in the late 19th century. In particular the results have demonstrated that the surviving southern section of the Wall here was largely rebuilt during the third quarter of the 18th century, when a complex of buildings was constructed along Kings Stables Road abutting the Wall's western face.
ARID1A‐deficient cells require HDAC6 for progression of endometrial carcinoma
Authors: Megino‐Luque Cristina , Sisó Pol , Mota‐Martorell Natalia , Navaridas Raúl , de la Rosa Inés , Urdanibia Izaskun , Albertí‐Valls Manel , Santacana Maria , Pinyol Miquel , Bonifaci Núria , Macià Anna , Llobet‐Navas David , Gatius Sònia , Matias‐Guiu Xavier , Eritja Núria
Published: February 2022

AT‐rich interactive domain‐containing protein 1A (ARID1A) loss‐of‐function mutation accompanied by a loss of ARID1A protein expression is frequently observed in endometrial carcinomas. However, the molecular mechanisms linking these genetic changes to the altered pathways regulating tumour initiation, maintenance and/or progression remain poorly understood. Thus, the main aim of this study was to analyse the role of ARID1A loss of function in endometrial tumorigenesis. Here, using different endometrial in vitro and in vivo models, such as tumoral cell lines, 3D primary cultures and metastatic or genetically modified mouse models, we show that altered expression of ARID1A is not enough to initiate endometrial tumorigenesis. However, in an established endometrial cancer context, ARID1A loss of function accelerates tumoral progression and metastasis through the disruption of the G2/M cell cycle checkpoint and ATM/ATR‐mediated DNA damage checkpoints, increases epithelial cell proliferation rates and induces epithelial mesenchymal transition through the activation of histone deacetylase 6 (HDAC6). Next, we demonstrated that the inhibition of HDAC6 function, using the HDAC6‐specific inhibitor ACY1215 or by transfection with HDAC6 short hairpin RNA (shRNA), can reverse the migratory and invasive phenotype of ARID1A‐knockdown cells. Further, we also show that inhibition of HDAC6 activity causes an apoptotic vulnerability to etoposide treatments in ARID1A‐deficient cells. In summary, the findings exposed in this work indicate that the inhibition of HDAC6 activity is a potential therapeutic strategy for patients suffering from ARID1A‐mutant endometrial cancer diagnosed in advanced stages.
EM Algorithm
Authors: McLachlan Geoffrey J. , Ng Shu‐Kay , Nguyen Hien D.
Published: February 2022

We supplement the article of Meng (2006) on the EM algorithm and its applications, providing also an update on its more recent developments and applications. The expectation–maximization algorithm, popularly known as the EM algorithm, is a general‐purpose algorithm for maximum‐likelihood estimation in a wide variety of situations best described asincomplete‐dataproblems. The name EM algorithm was given by Dempsteret al. (1997) in a celebrated paper read before the Royal Statistical Society in 1976 and published in its journal in 1977.
Reproducing Kernel Hilbert Space
Authors: Yu Jiahui , Wang Kevin , Liu Anna , Wang Yuedong
Published: February 2022

Reproducing kernel Hilbert space (RKHS) has a wide range of applications in many fields including statistics and machine learning. We provide a gentle introduction to RKHS with some examples. We also discuss the tensor products of RKHSs.
Bayesian Additive Regression Trees, Computational Approaches
Authors: Chipman Hugh , George Edward , Hahn Richard , McCulloch Robert , Pratola Matthew , Sparapani Rodney
Published: February 2022

Methods based on binary trees play a fundamental role in modern data science. In this article, we give a very focused review of basic Bayesian approaches to tree modeling. Bayesian approaches have some fundamental advantages. Complex models are enhanced with meaningful prior specifications, and Markov chain Monte Carlo provides a framework for useful stochastic search of the model space along with some sense of uncertainty. Bayesian approaches require a specification of a prior in tree space and computation of a high and variable dimension posterior. We provide some computational details that are not readily available in the literature. We also review a few more recent extensions of the basic approaches to illustrate the power and potential of the overall approach.
Complementarities of Survey and Population Registers
Authors: Zhang Li‐Chun
Published: February 2022

Survey data collected by sampling or census and register data recorded administratively can be used on an equal footing for creating frames, estimating population parameters, and evaluating statistics. Instead of conducting a population census, census‐like statistics can be produced with less cost by combining survey sampling and population registers. The cost can be further reduced and timeliness improved by fully register‐based approaches, where audit sampling inference can provide valid uncertainty measures.
Futility Analysis
Authors: Freidlin Boris , Korn Edward L.
Published: February 2022

To balance patient interests against the need for acquiring evidence, ongoing randomized clinical trials (RCTs) are monitored to allow stopping as soon as the clinical question is answered with sufficiently high confidence. Most RCTs are designed to demonstrate superiority of an experimental over a standard treatment. In this case, for ethical, scientific, and economic reasons, it is important to stop a trial early (for “futility”) when there is no longer a reasonable chance that the experimental arm will be shown to be better than the standard arm if the trial were continued. Futility monitoring is a widely accepted component of clinical trial design. This article provides a review of commonly used futility procedures and discusses the practical aspects of their implementation across the range of trial designs.
Cereal Architecture and Its Manipulation
Authors: Dixon Laura E. , van Esse Wilma , Hirsz Dominique , Willemsen Viola , McKim Sarah M.
Published: February 2022

Our lives depend on an incredibly small number of cereal species whose grain provides more calories to our diet than any other source. The extraordinary productivity of cultivated cereals reflects millennia of selection, recent directed breeding, and modern agricultural practices. Here, we examine selected architectural and agronomic features of major cereal body parts: leaf, branch, inflorescence, stem, and root; and discuss how their manipulation enhanced crop performance. Highlighting synergistic research across laboratory models and field‐based systems, we consider how diversified molecular circuitry, novel regulators and conserved components of genetic, hormonal, and molecular mechanisms control cereal architecture. Lastly, we emphasise the agricultural importance of developmental decisions during cereal growth and propose future perspectives for robust architectural improvement, made ever more urgent by our accelerating climate crisis.
Pectin‐Mediated Plant Immunity
Authors: Wang Duoduo , Yang Lirong , Silva Christian J. , Sarwar Rehman , Chen Yupeng , Blanco‐Ulate Barbara
Published: February 2022

The plant cell wall, a dynamic and complex structure surrounding every plant cell, serves not only as a passive structural barrier but also as an active monitoring system for protection against biotic and abiotic stresses. Plants monitor and maintain the status of their cell wall integrity (CWI) through the perception of signal molecules derived from pathogens or the plant cell walls themselves via pattern recognition receptors (PRRs) localised on the plasma membrane. PRRs in turn trigger a cascade of responses, including cell wall remodelling, to adapt to environmental stimuli. Pectin is the most abundant and structurally complex polysaccharide in the plant cell wall. Emerging evidence has revealed new features of pectin and challenged the classic primary cell wall model, providing an opportunity to revisit the role of pectin and CWI during plant–pathogen interactions. Here we present an overview of recent findings on the relationships between pectin metabolism and cell wall‐mediated immunity along with the underlying regulatory mechanisms. We propose future studies to reveal the fine structural and dynamic changes of specific wall polymers with improved temporal‐spatial resolution for a better understanding of pectin‐mediated plant immunity at the cellular and molecular level. Finally, we conclude that manipulating pectin composition and structure using advanced molecular breeding strategies, such as CRISPR editing technologies, can be a viable approach to develop novel crop genotypes with improved disease resistance.
Development of an independent MU calculation software for radiotherapy treatments with stereotactic cones
Authors: Campos Guilherme Filipe Pinto , Souto Ana Catarina Santos , Lencart Joana Borges , Cunha Luís Paulo Teixeira , Dias Anabela Gregório
Published: February 2022

Purpose

Development of an independent MU calculator (StereoCalc) with and without heterogeneity corrections for stereotactic treatments, in a Varian TrueBeam STx LINAC using stereotactic cones, with flattening filter‐free photon energies.

Methods

Multiple depth curves and output factors were measured, following the dosimetry formalism for small fields proposed by the TRS‐483. The developed StereoCalc imports and processes the beam data files and calculates the patient plans with and without heterogeneity correction. Validation of the developed software was carried out using phantoms. The accuracy of the StereoCalc software was verified in stereotactic patient plans.

Results

A maximum difference of 2.47% and 2.07% was obtained in the phantom validation tests with and without heterogeneity correction, respectively. The mean percentual difference of StereoCalc from cone dose calculation (CDC) in the clinical testing was 2.86% ±1.27% and 0.78% ±0.48% with and without heterogeneity correction, respectively. The largest differences found were 7.34% and 1.98%, respectively.

Conclusions

The results obtained in this work show that the MU calculated with StereoCalc software is in good agreement with the values calculated by the treatment planning systems, both in static fields and arcs. We have also improved the software to consider heterogeneity corrections calculations. As expected, and as a major achievement of this work, some differences were observed when heterogeneities were considered. StereoCalc proved to be a powerful tool that can be integrated into the specific quality assurance program in a medical physics department for independent verification in stereotactic treatment with cones.
Diffusion spectrum imaging predicts hippocampal sclerosis in mesial temporal lobe epilepsy patients
Authors: Wang Zhen‐Ming , Wei Peng‐Hu , Zhang Miao , Wu Chunxue , Shan Yi , Yeh Fang‐Cheng , Shan Yongzhi , Lu Jie
Published: February 2022

Objectives

Epileptic patients suffer from seizure recurrence after surgery due to the challenging localization. Improvement of the noninvasive imaging‐based approach for a better definition of the abnormalities would be helpful for a better outcome.

Methods

The quantitative anisotropy (QA) of diffusion spectrum imaging (DSI) is a quantitative scalar of evaluating the water diffusivity. Herein, we investigated the association between neuronal diameters or density acquired in literature and QA of DSI as well as the seizure localization in temporal lobe epilepsy. Thirty healthy controls (HCs) and 30 patients with hippocampal sclerosis (HS) were retrospectively analyzed. QA values were calculated and interactively compared between the areas with different neuronal diameter/density acquired from literature in the HCP‐1021 template. Diagnostic tests were performed on Z‐transformed asymmetry indices (AIs) of QA (which exclude physical asymmetry) among HS patients to evaluate its clinical value.

Results

The QA values in HCs conformed with different pyramidal cell distributions ranged from giant to small; corresponding groups were the motor‐sensory, associative, and limbic groups, respectively. Additionally, the QA value was correlated with the neuronal diameter/density in cortical layer IIIc (correlation coefficient with diameter: 0.529, p = 0.035; density: −0.678, p = 0.011). Decreases in cingulum hippocampal segments (Chs) were consistently observed on the sclerosed side in patients. The area under the curve of the Z‐transformed AI in Chs to the lateralization of HS was 0.957 (sensitivity: 0.909, specificity: 0.895).

Interpretation

QA based on DSI is likely to be useful to provide information to reflect the neuronal diameter/density and further facilitate localization of epileptic tissues.
Nusinersen efficacy data for 24‐month in type 2 and 3 spinal muscular atrophy
Authors: Pane Marika , Coratti Giorgia , Pera Maria Carmela , Sansone Valeria A. , Messina Sonia , d'Amico Adele , Bruno Claudio , Salmin Francesca , Albamonte Emilio , De Sanctis Roberto , Sframeli Maria , Di Bella Vincenzo , Morando Simone , Palermo Concetta , Frongia Anna Lia , Antonaci Laura , Capasso Anna , Catteruccia Michela , Longo Antonella , Ricci Martina , Cutrona Costanza , Pirola Alice , Bravetti Chiara , Pedemonte Marina , Brolatti Noemi , Bertini Enrico , Mercuri Eugenio ,   Italian ISMAC group
Published: February 2022

The study reports real world data in type 2 and 3 SMA patients treated for at least 2 years with nusinersen. Increase in motor function was observed after 12 months and during the second year. The magnitude of change was variable across age and functional subgroup, with the largest changes observed in young patients with higher function at baseline. When compared to natural history data, the difference between study cohort and untreated patients swas significant on both Hammersmith Functional Motor Scale and Revised Upper Limb Module both at 12 months and at 24 months.
Development and Performance Analysis of Pneumatic Soft‐Bodied Bionic Flipper
Authors: Zhao Wenchuan , Zhang Yu , Lim Kian Meng , Luo Jun , Wang Ning
Published: February 2022

The sea lion fore flipper has superior underwater movement performance. Its structural characteristics and propulsion mechanism are drawn, combined with the large deformation and hyperelastic properties of silicone, a pneumatic soft‐bodied bionic flipper with strong underwater mobility, good environmental adaptability, and flexible attitude transformation. Based on Yeoh's second‐order constitutive model of silicone, the nonlinear dynamic analysis of the main limb of the bionic flipper is carried out, and the deformation analysis theoretical model is established. Then, the force analysis of infinitesimal and integral of the wing fin of the bionic flipper is analyzed by the blade element theory, to obtain the theoretical model of underwater propulsion dynamic performance. The superiority of the hydrodynamic performance of the bionic flipper is analyzed and confirmed using the bidirectional fluid–structure coupling numerical simulation algorithm. An experimental test platform is built to test the physical model of the bionic flipper. The motion and dynamic characteristics curves of the bionic flipper are obtained and compared with the corresponding numerical simulation results. The results show that the theoretical model and numerical simulation are accurate, and the structure is feasible, which can provide methods and references for the research and implementation of the underwater propeller.
Unclonable Anti‐Counterfeiting Labels Based on Plasmonic‐Patterned Nanostructures
Authors: Tang Zilun , Liu Xiaopeng , Liu Xiaochun , Wu Jianyu , Lin Wenjing , Lin Xiaofeng , Yi Guobin
Published: February 2022

Herein this study, plasmonic‐patterned nanostructures are applied to fabricate unclonable anti‐counterfeiting labels. Patterned Au nanoparticles (AuNPs) are constructed by the skillful combination of diblock copolymer polystyrene‐block‐poly(4‐vinyl pyridine) (PS‐b‐P4VP) self‐assembly with shadow mask lithography to provide a simple and universal approach for large‐area fabrication of patterned nanostructures. The AuNP pattern can be made visible by increasing the nanoparticle size. A surface‐enhanced Raman spectroscopy (SERS)‐based physical unclonable function (PUF) security label with a large encoding capacity is fabricated by depositing malachite green (MG) on the surface. The broadening of the size distribution of the AuNPs after their growth and the increased disorder in their arrangement confer the security label with unique and unclonable characteristics. The as‐prepared optical PUF security label is read out by a confocal Raman spectrometer to extract binary codes, which are then authenticated through comparison. These SERS‐based PUF security labels, which combine patterning with stochastic spectral encoding, not only provide rich and diverse patterns but are also promising for anti‐counterfeiting applications in areas such as rigid silicon‐based optoelectronic materials and devices.
Nano/Microplastics Capture and Degradation by Autonomous Nano/Microrobots: A Perspective
Authors: Urso Mario , Pumera Martin
Published: February 2022

The growing use of plastic materials has led to the continuous accumulation of wastes in marine environments, which fragment into hazardous micro‐and nanoplastics. These plastic particles absorb toxic organic pollutants on their surface, support bacterial biofilms growth, and propagate through the food chain, posing serious risks for human health. Therefore, nano/microplastics pollution has become a global issue, making their definitive elimination compulsory. Self‐propelled nano/microrobots have demonstrated efficient removal of nano/microplastics from water, combining enhanced physicochemical properties of nano/microscale materials and active motion. During the last year, the potential of this technology to degrade nano/microplastics has been investigated. Here, the most advanced strategies for nano/microplastics capture and subsequent degradation by autonomous nano/microrobots are critically reviewed. A short introduction to the main propulsion mechanisms and experimental techniques for studying nano/microplastics degradation is also provided. Forthcoming challenges in this research field are discussed proactively. This perspective inspires future nano/microrobotic designs and approaches for water purification from nano/microplastics and other emerging pollutants.
Micropathological Chip Modeling the Neurovascular Unit Response to Inflammatory Bone Condition
Authors: Neto Estrela , Monteiro Ana Carolina , Leite Pereira Catarina , Simões Miguel , Conde João Pedro , Chu Virginia , Sarmento Bruno , Lamghari Meriem
Published: February 2022

Organ‐on‐a‐chip in vitro platforms accurately mimic complex microenvironments offering the ability to recapitulate and dissect mechanisms of physiological and pathological settings, revealing their major importance to develop new therapeutic targets. Bone diseases, such as osteoarthritis, are extremely complex, comprising of the action of inflammatory mediators leading to unbalanced bone homeostasis and de‐regulation of sensory innervation and angiogenesis. Although there are models to mimic bone vascularization or innervation, in vitro platforms merging the complexity of bone, vasculature, innervation, and inflammation are missing. Therefore, in this study a microfluidic‐based neuro‐vascularized bone chip (NVB chip) is proposed to 1) model the mechanistic interactions between innervation and angiogenesis in the inflammatory bone niche, and 2) explore, as a screening tool, novel strategies targeting inflammatory diseases, using a nano‐based drug delivery system. It is possible to set the design of the platform and achieve the optimized conditions to address the neurovascular network under inflammation. Moreover, this system is validated by delivering anti‐inflammatory drug‐loaded nanoparticles to counteract the neuronal growth associated with pain perception. This reliable in vitro tool will allow understanding the bone neurovascular system, enlightening novel mechanisms behind the inflammatory bone diseases, bone destruction, and pain opening new avenues for new therapies discovery.
A Smart Near‐Infrared Carbon Dot‐Metal Organic Framework Assemblies for Tumor Microenvironment‐Activated Cancer Imaging and Chemodynamic‐Photothermal Combined Therapy
Authors: Bai Yulong , Zhao Jingjin , Zhang Liangliang , Wang Shulong , Hua Jing , Zhao Shulin , Liang Hong
Published: February 2022

Tumor microenvironment (TME)‐activated cancer imaging and therapy is a key to achieving accurate diagnosis and treatment of cancer and reducing the side effects. Herein, smart near‐infrared carbon dot‐metal organic framework MIL‐100 (Fe) assemblies are constructed to achieve TME‐activated cancer imaging and chemodynamic‐photothermal combined therapy. First, a near‐infrared emission carbon dot (RCDs) is developed using glutathione (GSH) as the precursor. Then, the RCDs@MIL‐100 self‐assemblies are obtained using RCDs, FeCl3, and trimesic acid solutions as raw materials. After the RCDs@MIL‐100 enters the TME, a high concentration of GSH reduces Fe3+ to Fe2+ and drains the GSH, triggering the collapse of RCDs@MIL‐100 skeleton and the release of RCDs and Fe2+, at which time the RCDs fluorescence is restored and in an “on” state to illuminate the tumor cells, which achieved cancer imaging. The released Fe2+ reacts with H2O2 in the TME to form highly reactive hydroxyl radicals (•OH) by Fenton reaction, which achieves the chemodynamic therapy of tumors. Thus, efficient synergistic chemodynamic‐photothermal dual mode therapy is achieved under fluorescence imaging guidance with TME response.
Predicting the Effects of Waning Vaccine Immunity Against COVID‐19 through High‐Resolution Agent‐Based Modeling
Authors: Truszkowska Agnieszka , Zino Lorenzo , Butail Sachit , Caroppo Emanuele , Jiang Zhong‐Ping , Rizzo Alessandro , Porfiri Maurizio
Published: February 2022

The potential waning of the vaccination immunity to COVID‐19 could pose threats to public health, as it is tenable that the timing of such waning would synchronize with the near‐complete restoration of normalcy. Should also testing be relaxed, a resurgent COVID‐19 wave in winter 2021/2022 might be witnessed. In response to this risk, an additional vaccine dose, the booster shot, is being administered worldwide. A projected study with an outlook of 6 months explores the interplay between the rate at which boosters are distributed and the extent to which testing practices are implemented, using a highly granular agent‐based model tuned on a medium‐sized US town. Theoretical projections indicate that the administration of boosters at the rate at which the vaccine is currently administered could yield a severe resurgence of the pandemic. Projections suggest that the peak levels of mid‐spring 2021 in the vaccination rate may prevent such a scenario to occur, although exact agreement between observations and projections should not be expected due to the continuously evolving nature of the pandemic. This study highlights the importance of testing, especially to detect asymptomatic individuals in the near future, as the release of the booster reaches full speed.
A Bionic‐Homodimerization Strategy for Optimizing Modulators of Protein–Protein Interactions: From Statistical Mechanics Theory to Potential Clinical Translation
Authors: Yan Jin , Zheng Xiaoqiang , You Weiming , He Wangxiao , Xu Guang‐Kui
Published: February 2022

Emerging protein–protein interaction (PPI) modulators have brought out exciting ability as therapeutics in human diseases, but its clinical translation has been greatly hampered by the limited affinity. Inspired by the homodimerize structure of antibody, the homodimerization contributes hugely to generating the optimized affinity is conjectured. Herein, a statistical‐mechanics‐theory‐guided method is established to quantize the affinity of ligands with different topologies through analyzing the change of enthalpy and the loss of translational and rotational entropies. A peptide modulator for p53‐MDM2 termed CPAP is used to homodimerize connecting, and this simple homodimerization can significantly increase the affinity. To realize the cellular internalization and tumor accumulation, DimerCPAP and MonoCPAP are nanoengineered into gold(I)‐CPAP supermolecule by the aurophilic interaction‐driven self‐assembly. Nano‐DimerCPAP potently suppressed tumor growth in lung cancer allograft model and a patient‐derived xenograft model in more action than Nano‐MonoCPAP, while keeping a favorable drug safety profile. This work not only presents a physico‐mechanical method for calculating the affinity of PPI modulators, but also provides a simple yet robust homodimerization strategy to optimize the affinity of PPI modulators.
Influence of thermal runaway in styrene–acrylonitrile bulk copolymerization revealed by computational fluid dynamics modeling
Authors: Yang Ya‐Nan , Zhou Yin‐Ning , Ouyang Bo , Wu Yi‐Yang , Zhang Xi‐Bao , Luo Zheng‐Hong
Published: February 2022

The computational fluid dynamics (CFD) and kinetic‐based moment methods coupled approach is adopted to simulate the bulk copolymerization of styrene–acrylonitrile (SAN) in a stirred tank reactor. Numerical simulations are carried out to investigate the impacts of impeller speed, monomer ratio, initiator ratio, and initial reaction temperature on the copolymerization process and product properties. Particularly, the Chaos theory is selected as a criterion for evaluating the occurrence of the thermal runaway. The Flory's and Stockmayer's distributions are employed to calculate chain length distribution and copolymer composition distribution of copolymer. The simulation results highlight that the appearance of thermal runaway can be postponed by properly increasing the rotation speed, decreasing the initiator loadings, initial acrylonitrile contents and initial reactor temperature. Furthermore, significant differences exist in the product properties that predicted by the ideal and non‐ideal models, which demonstrates that the temperature heterogeneity plays a crucial role in SAN copolymerization. This study could offer references for the safe operation and design of polymerization processes.
Personalizing Deep Brain Stimulation Using Advanced Imaging Sequences
Authors: Neudorfer Clemens , Kroneberg Daniel , Al‐Fatly Bassam , Goede Lukas , Kübler Dorothee , Faust Katharina , van Rienen Ursula , Tietze Anna , Picht Thomas , Herrington Todd M. , Middlebrooks Erik H. , Kühn Andrea , Schneider Gerd‐Helge , Horn Andreas
Published: February 2022

Objective

With a growing appreciation for interindividual anatomical variability and patient‐specific brain connectivity, advanced imaging sequences offer the opportunity to directly visualize anatomical targets for deep brain stimulation (DBS). The lack of quantitative evidence demonstrating their clinical utility, however, has hindered their broad implementation in clinical practice.

Methods

Using fast gray matter acquisition T1 inversion recovery (FGATIR) sequences, the present study identified a thalamic hypointensity that holds promise as a visual marker in DBS. To validate the clinical utility of the identified hypointensity, we retrospectively analyzed 65 patients (26 female, mean age = 69.1 ± 12.7 years) who underwent DBS in the treatment of essential tremor. We characterized its neuroanatomical substrates and evaluated the hypointensity's ability to predict clinical outcome using stimulation volume modeling and voxelwise mapping. Finally, we determined whether the hypointensity marker could predict symptom improvement on a patient‐specific level.

Results

Anatomical characterization suggested that the identified hypointensity constituted the terminal part of the dentatorubrothalamic tract. Overlap between DBS stimulation volumes and the hypointensity in standard space significantly correlated with tremor improvement (R2 = 0.16, p = 0.017) and distance to hotspots previously reported in the literature (R2 = 0.49, p = 7.9e‐4). In contrast, the amount of variance explained by other anatomical atlas structures was reduced. When accounting for interindividual neuroanatomical variability, the predictive power of the hypointensity increased further (R2 = 0.37, p = 0.002).

Interpretation

Our findings introduce and validate a novel imaging‐based marker attainable from FGATIR sequences that has the potential to personalize and inform targeting and programming in DBS for essential tremor. ANN NEUROL 2022;91:613–628
RGMa Signal in Macrophages Induces Neutrophil‐Related Astrocytopathy in NMO
Authors: Iwamoto Shosuke , Itokazu Takahide , Sasaki Atsushi , Kataoka Hirotoshi , Tanaka Shinji , Hirata Takeshi , Miwa Keiko , Suenaga Toshihiko , Takai Yoshiki , Misu Tatsuro , Fujihara Kazuo , Yamashita Toshihide
Published: February 2022

Objective

Repulsive guidance molecule‐a (RGMa) is a glycosylphosphatidylinositol‐linked glycoprotein which has multiple functions including axon growth inhibition and immune regulation. However, its role in the pathophysiology of neuromyelitis optica (NMO) is poorly understood. Perivascular astrocytopathy, which is induced by the leakage of aquaporin‐4 (AQP4)‐specific IgG into the central nervous system parenchyma, is a key feature of NMO pathology. We investigated the RGMa involvement in the pathology of NMO astrocytopathy, and tested a therapeutic potential of humanized anti‐RGMa monoclonal antibody (RGMa‐mAb).

Methods

Using a clinically relevant NMO rat model, we evaluated the therapeutic effect of a RGMa‐mAb by behavioral testing, immunohistochemistry, and gene expression assay. We further performed in vitro experiments to address the RGMa‐signaling in macrophages.

Results

In both NMO rats and an NMO‐autopsied sample, RGMa was expressed by the spared neurons and astrocytes, whereas its receptor neogenin was expressed by infiltrating macrophages. AQP4‐IgG‐induced astrocytopathy and clinical exacerbation in NMO rats were ameliorated by RGMa‐mAb treatment. RGMa‐mAb treatment significantly suppressed neutrophil infiltration, and decreased the expression of neutrophil chemoattractants. Interestingly, neogenin‐expressing macrophages accumulated in the lesion expressed CXCL2, a strong neutrophil chemoattractant, and further analysis revealed that RGMa directly regulated CXCL2 expression in macrophages. Finally, we found that our NMO rats developed neuropathic pain, and RGMa‐mAb treatment effectively ameliorated the severity of neuropathic pain.

Interpretation

RGMa signaling in infiltrated macrophages is a critical driver of neutrophil‐related astrocytopathy in NMO lesions, and RGMa‐mAb may provide an efficient therapeutic strategy for NMO‐associated neuropathic pain and motor deficits in patients with NMO. ANN NEUROL 2022;91:532–547
Ultra‐Tough Elastomers from Stereochemistry‐Directed Hydrogen Bonding in Isosorbide‐Based Polymers
Authors: Petersen Shannon R. , Prydderch Hannah , Worch Joshua C. , Stubbs Connor J. , Wang Zilu , Yu Jiayi , Arno Maria C. , Dobrynin Andrey V. , Becker Matthew L. , Dove Andrew P.
Published: February 2022

The remarkable elasticity and tensile strength found in natural elastomers are challenging to mimic. Synthetic elastomers typically feature covalently cross‐linked networks (rubbers), but this hinders their reprocessability. Physical cross‐linking via hydrogen bonding or ordered crystallite domains can afford reprocessable elastomers, but often at the cost of performance. Herein, we report the synthesis of ultra‐tough, reprocessable elastomers based on linear alternating polymers. The incorporation of a rigid isohexide adjacent to urethane moieties affords elastomers with exceptional strain hardening, strain rate dependent behavior, and high optical clarity. Distinct differences were observed between isomannide and isosorbide‐based elastomers where the latter displays superior tensile strength and strain recovery. These phenomena are attributed to the regiochemical irregularities in the polymers arising from their distinct stereochemistry and respective inter‐chain hydrogen bonding.
Short Synthesis of (+)‐Actinobolin: Simple Entry to Complex Small‐Molecule Inhibitors of Protein Synthesis
Authors: Tharra Prabhakara R. , Mikhaylov Andrey A. , Švejkar Jiří , Gysin Marina , Hobbie Sven N. , Švenda Jakub
Published: February 2022

We report a concise synthesis of the naturally occurring protein synthesis inhibitor (+)‐actinobolin (1). The densely functionalized and stereochemically complex molecular structure of 1 was assembled from (−)‐quinic acid, L‐threonine, and L‐alanine as the principal components. Our route is based around a convergent strategy that features conjugate addition of an α‐amino radical in the key fragment‐coupling step. The dramatically simplified synthesis of (+)‐actinobolin proceeding in 9 steps with 18 % overall yield has practical implications for analog preparation, as demonstrated herein.