bluuebunny/crossref_metadata_2025 huggingface dataset:
An Exploration of the Potential of Machine Learning Tools for Media Analysis to Support Sense-Making Processes in Foresight
Authors: Vignoli Michela , Rörden Jan , Wasserbacher Dana , Kimpeler Simone
Published: March 2022

In view of the many discussions about uncertainty regarding the further development of the coronavirus disease 2019 (COVID-19) pandemic and its effects on the economy and society, we observed that the crisis led to an increased presence of individual researchers and experts making forward-looking statements on the impacts of the COVID-19 pandemic or stating trends in mass media publications. From a strategic foresight research perspective, there is a need to further analyse an increase of future-oriented expert statements in public media in a context of high uncertainty like the impacts of the COVID-19 pandemic and related crises. Given the increasing amount of media texts available for web-based scanning and text analysis, Machine Learning (ML) is a promising approach for text analysis of big data, which also raises high expectations in the field of foresight, particularly in the context of scoping and scanning activities for weak signal detection and text analysis for sense-making processes. In this study, we apply a natural language processing (NLP)-based ML approach to analyse a large corpus of news articles from web sources to explore the potential of applied ML to support sense-making in the field of foresight, specifically for the analysis of future-related statements or predictive statements in media. The results underline the potential of ML approaches as a heuristic tool to support sense-making in foresight processes and research, particularly by pre-structuring large datasets (e.g., news articles around a particular topic of public debate). The ML can provide additional insights for actor analysis associated with a specific topic of public debate from a large data corpus. At the same time, our results show that ML models are limited in their ability to provide solid evidence and that they can also lead to fallacies. Therefore, an ML can only be considered as a heuristic tool supporting specific steps in a sense-making process and development of further research questions, as well as encouraging reflection on the application of ML-based approaches in foresight.
Can Digenic, Tri-Allelic Inheritance of Variants in STAR and CYP11A1 Give Rise to Primary Adrenal Insufficiency? A Case Report
Authors: Ali Naseer , Maharaj Avinaash Vickram , Buonocore Federica , Achermann John C. , Metherell Louise A.
Published: March 2022

An eight-year old South Asian boy presenting with progressive hyperpigmentation was found to have primary adrenal insufficiency (PAI) in the form of isolated glucocorticoid deficiency. Follow up of this boy for nine years, until the age of 17 years showed normal pubertal onset and progression. Molecular evaluation, by targeted next generation sequencing of candidate genes linked to PAI revealed changes in two genes that are intricately linked in the early stages of steroid biosynthesis: compound heterozygous variants in STAR, c.465+1G>A and p.(E99K), plus a heterozygous rs6161 change in CYP11A1. No variants in other known causal genes were detected. The proband’s mother was heterozygous for the c.465+1G>A STAR and rs6161 CYP11A1 variants, while the father was homozygous for the p.(E99K) alteration in STAR but wild-type for CYP11A1. Both parents had normal adrenal cortical function as revealed by short Synacthen tests. The STAR variant c.465+1G>A will lead to abnormal splicing of exon 4 in mRNA and the addition of the p.(E99K) variant, predicted damaging by SIFT and CADD, may be sufficient to cause PAI but this is by no means certain given that the unaffected father is homozygous for the latter change. The rs6161 CYP11A1 variant [c.940G>A, p.(E314K)] has recently been demonstrated to cause PAI in conjunction with a severe rare disruptive change on the other allele, however sequencing of the coding region of CYP11A1 revealed no further changes in this subject. We wondered whether the phenotype of isolated glucocorticoid deficiency had arisen in this child due to tri-allelic inheritance of a heterozygous CYP11A1 change along with the two STAR variants each of which contribute a partial loss-of-function burden that, when combined, is sufficient to cause PAI or if the loss-of-function c.465+1G>A combined with the presumed partial loss-of-function p.(E99K) in STAR could be causative.
Digitalization in Urban Water Governance: Case Study of Bengaluru and Singapore
Authors: Banerjee Chandan , Bhaduri Anik , Saraswat Chitresh
Published: March 2022

Urban water governance aims to ensure equitable access to adequate quality water and related services to rapidly growing urban population while protecting the environment. Rapid urbanization and changing climate are posing challenges to the formal and informal institutions responsible for governing and managing water resources. Complexities existing due to the interaction between societal and environmental subsystems of urban water cycle adds pressure on institutional capabilities to cope up with various uncertainties. Emergence of digital technologies has provided the necessary tools in urban water governance to strengthen capabilities through effective monitoring, decision making, and forecasting. The paper examines how sequencing and leveraging the synergies of different digital technologies can help mitigate various problems and challenges faced in urban water governance. The paper analyses three digital technologies, Smart Water Metering Supervisory Control and Data Acquisition and Flood Alert System (FAS) using the case studies of Bengaluru and Singapore to understand the transformative capabilities of digitalization in urban water governance. It is assumed that the learnings from this study can be generalized to a large extent. The paper indicates that to unlock the full potential and derive best returns of investment, digitalization needs to have broader objectives. Multi-purpose use of digital tools can contribute effectively to the implementation of Integrated Urban Water Management. The results highlighted that societal acceptability of digitalization depends majorly on the mode of implementation and not so much on the technology.
Identification of Branched and Linear Forms of PFOA and Potential Precursors: A User-Friendly SMILES Structure-based Approach
Authors: Richard Ann M. , Hidle Hannah , Patlewicz Grace , Williams Antony J.
Published: March 2022

Perfluorooctanoic acid (PFOA) and related compounds are per- and polyfluorinated alkyl substances (PFASs) of concern from toxicological, environmental, and regulatory perspectives. In 2019, the Conference of the Parties to the Stockholm Convention on Persistent Organic Pollutants listed PFOA, its salts, and PFOA-related compounds in Annex A to the Convention. Additionally, the listing specifically included PFOA branched isomers and compounds containing a perfluoroheptyl (C7F15)C moiety, with some noted exclusions. A draft updated “Indicative List” of 393 PFASs (335 with defined structures), each specified as falling within or outside the listing, was released for comment in 2021. The U.S. Environmental Protection Agency’s CompTox Chemicals Dashboard has published a curated PFAS list containing more than 10,700 structures. Applying the PFOA and related compounds listing definition to screen this list required a structure-based approach capable of discerning salts and branched or linear forms of the (C7F15)C moiety. A PFOA SMILES workflow and associated Excel macro file, developed to address this need, applies a series of text substitution rules to a set of canonicalized SMILES structure representations to convert branched forms of the (C7F15)C moiety to linear forms to aid their detection. The approach correctly classified each Stockholm Convention draft Indicative List structure relative to the PFOA and related compounds definition, and accurately discerned branched and linear forms of the (C7F15)C moiety in over 10,700 PFAS structures with 100% sensitivity (no false negatives) and 99.7% accuracy (35 false positives). Approximately 20% of structures in the large PFAS list fell within the PFOA and related compounds definition, and 10% of those were branched. The present work highlights the need to computationally detect branched forms of PFASs and promotes the use of unambiguous, structure-based definitions, along with tools that are publicly available and easy to use, to support clear communication and regulatory action within the PFAS community.
Coastal Ecosystem Services Modeling in Latin America to Guide Conservation and Restoration Strategies: The Case of Mangroves in Guatemala and El Salvador
Authors: Hernández-Blanco Marcello , Moritsch Monica , Manrow Marilyn , Raes Leander
Published: March 2022

We modeled the coastal protection and blue carbon ecosystem services provided by the mangroves of the Paz River Basin (El Salvador and Guatemala) using InVEST Coastal Vulnerability and Coastal Blue Carbon Models, with the goal of supporting the Regional Coastal Biodiversity Project of the International Union for the Conservation of Nature, in determining potential priority mangrove areas for conservation and restoration. To quantify the relative coastal protection that mangroves provide, we combined maps of different aspects of vulnerability, including ecological, physical, and social data. We also estimated carbon stocks, net sequestration, and the economic value of carbon sequestration as a service in 2050 and 2100. We then developed a combined index of coastal protection and carbon sequestration services to highlight potential priority conservation and restoration areas for mangroves. We found that in Guatemala the coastal protection service was provided in greater quantity in the province of Moyuta, while in El Salvador this service was the highest in the provinces of San Francisco Menéndez, Jujutla and Acajutla, which also had the greatest total carbon stock. In the Paz River Basin, we estimate there are approximately 1,741 hectares of mangroves that provide the highest coastal protection and carbon sequestration services. Furthermore, we identified 318.9 hectares across both countries where mangroves could potentially be restored.
Combined Analysis of RRBS DNA Methylome and Transcriptome Reveal Novel Candidate Genes Related to Porcine Clostridium perfringens Type C-Induced Diarrhea
Authors: Huang Xiaoyu , Yang Qiaoli , Yan Zunqiang , Wang Pengfei , Shi Hairen , Li Jie , Shang Xuefeng , Gun Shuangbao
Published: March 2022

Clostridium perfringenstype C (Cp) is one of the principal microorganisms responsible for bacterial diarrhea in neonatal and pre-weaning piglets. To better understand the molecular effects of Cp infection, we performed a genome-wide comparison of the changes in DNA methylation and gene expression in Cp infected resistant and susceptible piglets. We characterized the pattern of changes in methylation and found 6485, 5968, and 6472 differentially methylated regions (DMRs) of piglets infected with Cp in IR vs. IC, IS vs. IC, and IS vs. IR groups, respectively. These methylation changes for genes mainly involved in immune and inflammatory responses, cell adhesion, and activation of transcription factors. Gene ontology and KEGG pathway analyses showed that the differentially methylated genes (DMGs) were associated with negative regulation of transcription, apoptotic processes, protein binding, and kinase activity. In addition, they were enriched in immunity-related pathways, such as MAPK signaling pathway, Toll-like receptor signaling pathway, and NF-kappa B signaling pathway. Integrative analysis identified 168, 198, and 7 mRNAs showing inverse correlations between methylation and expression with Cp infection. Altered DNA methylation and expression of various genes suggested their roles and potential functional interactions upon Cp infection, 14 immune-associated mRNAs with differential methylation and transcriptional repression were identified in IS vs. IR, commonly revealing that the differentially expressed genes (DEGs)LBP,TBX21, andLCN2were likely involved in the piglets against Cp infection. The present results provide further insight into the DNA methylation epigenetic alterations ofC. perfringenstype C infected piglet ileum tissues, and may advance the identification of biomarkers and drug targets for predicting susceptibility to and controllingC. perfringenstype C-induced piglet diarrhea.
Genome-wide Association Study for Starch Pasting Properties in Chinese Spring Wheat
Authors: Tian Yousheng , Sang Wei , Liu Pengpeng , Liu Jindong , Xiang Jishan , Cui Fengjuan , Xu Hongjun , Han Xinnian , Nie Yingbin , Kong Dezhen , Li Weihua , Mu Peiyuan
Published: March 2022

In order to understand the genetic basis of starch pasting viscosity characteristics of Chinese spring wheat, we assessed the genetic variation of RVA parameters determined by the Rapid Visco Analyser in a panel of 192 Chinese spring wheat accessions grown in Er’shi, Shihezi and Zhaosu during 2012 and 2013 cropping seasons. A genome-wide association study with 47,362 single nucleotide polymorphism (SNP) markers was conducted to detect marker-trait associations using mixed linear model. Phenotypic variations of RVA parameters ranged from 1.6 to 30.7% and broad-sense heritabilities ranged from 0.62 to 0.91. Forty-one SNP markers at 25 loci were significantly associated with seven RVA traits in at least two environments; among these, 20 SNPs were located in coding sequences (CDS) of 18 annotation genes, which can lead to discovering novel genes underpinning starch gelatinization in spring wheat. Haplotype analysis revealed one block for breakdown (BD) on chromosome 3B and two blocks for pasting temperature (T) on chromosome 7B. Cultivars with superior haplotypes at these loci showed better starch pasting viscosity than the average of all cultivars surveyed. The identified loci and associated markers provide valuable sources for future functional characterization and genetic improvement of starch quality in wheat.
Impact of Pre-Anthesis Drought Stress on Physiology, Yield-Related Traits, and Drought-Responsive Genes in Green Super Rice
Authors: Ahmad Hassaan , Zafar Syed Adeel , Naeem Muhammad Kashif , Shokat Sajid , Inam Safeena , Rehman Malik Attique ur , Naveed Shahzad Amir , Xu Jianlong , Li Zhikang , Ali Ghulam Muhammad , Khan Muhammad Ramzan
Published: March 2022

Optimum soil water availability is vital for maximum yield production in rice which is challenged by increasing spells of drought. The reproductive stage drought is among the main limiting factors leading to the drastic reduction in grain yield. The objective of this study was to investigate the molecular and morphophysiological responses of pre-anthesis stage drought stress in green super rice. The study assessed the performance of 26 rice lines under irrigated and drought conditions. Irrigated treatment was allowed to grow normally, while drought stress was imposed for 30 days at the pre-anthesis stage. Three important physiological traits including pollen fertility percentage (PFP), cell membrane stability (CMS), and normalized difference vegetative index (NDVI) were recorded at anthesis stage during the last week of drought stress. Agronomic traits of economic importance including grain yield were recorded at maturity stage. The analysis of variance demonstrated significant variation among the genotypes for most of the studied traits. Correlation and principal component analyses demonstrated highly significant associations of particular agronomic traits with grain yield, and genetic diversity among genotypes, respectively. Our study demonstrated a higher drought tolerance potential of GSR lines compared with local cultivars, mainly by higher pollen viability, plant biomass, CMS, and harvest index under drought. In addition, the molecular basis of drought tolerance in GSR lines was related to upregulation of certain drought-responsive genes including OsSADRI, OsDSM1, OsDT11, but not the DREB genes. Our study identified novel drought-responsive genes (LOC_Os11g36190, LOC_Os12g04500, LOC_Os12g26290, and LOC_Os02g11960) that could be further characterized using reverse genetics to be utilized in molecular breeding for drought tolerance.
Genome-Wide Identification and Expression Analysis of the Thioredoxin (Trx) Gene Family Reveals Its Role in Leaf Rust Resistance in Wheat (Triticum aestivum L.)
Authors: Bhurta Ramesh , Hurali Deepak T. , Tyagi Sandhya , Sathee Lekshmy , Adavi B Sandeep , Singh Dalveer , Mallick Niharika , Chinnusamy Viswanathan , Vinod  , Jha Shailendra K.
Published: March 2022

Bread wheat (Triticum aestivum L.; Ta) is the staple cereal crop for the majority of the world’s population. Leaf rust disease caused by the obligate fungal pathogen, Puccinia triticina L., is a biotrophic pathogen causing significant economic yield damage. The alteration in the redox homeostasis of the cell caused by various kinds of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in response to pathogenic infections is controlled by redox regulators. Thioredoxin (Trx) is one of the redox regulators with low molecular weight and is thermostable. Through a genome-wide approach, forty-two (42) wheat Trx genes (TaTrx) were identified across the wheat chromosome groups A, B, and D genomes containing 12, 16, and 14 Trx genes, respectively. Based on in silico expression analysis, 15 TaTrx genes were selected and utilized for further experimentation. These 15 genes were clustered into six groups by phylogenetic analysis. MicroRNA (miRNA) target analysis revealed eight different miRNA-targeted TaTrx genes. Protein–protein interaction (PPI) analysis showed TaTrx proteins interact with thioredoxin reductase, peroxiredoxin, and uncharacterized proteins. Expression profiles resulting from quantitative real-time PCR (qRT-PCR) revealed four TaTrx genes (TaTrx11-5A, TaTrx13-5B, TaTrx14-5D, and TaTrx15-3B) were significantly induced in response to leaf rust infection. Localization of ROS and its content estimation and an assay of antioxidant enzymes and expression analysis suggested that Trx have been involved in ROS homeostasis at span 24HAI-72HAI during the leaf rust resistance.
Integration of Transcriptomic and Metabolomic Data to Compare the Hepatotoxicity of Neonatal and Adult Mice Exposed to Aristolochic Acid I
Authors: Fang Zhi-e , Wang Chunyu , Niu Ming , Liu Tingting , Ren Lutong , Li Qiang , Li Zhiyong , Wei Ziying , Lin Li , Mu Wenqing , Gao Yuan , Xiao Xiaohe , Bai Zhaofang
Published: March 2022

Aristolochic acid (AA) is a group of structurally related compounds what have been used to treat various diseases in recent decades. Aristolochic acid I (AAI), an important ingredient, has been associated with tumorigenesis. Recently, some studies indicated that AAI could induce liver injury in mice of different age, but comprehensive mechanisms of AAI-induced differences in liver injury in various age groups have not yet been elucidated. This study aims to evaluate the causal relationship between AAI-induced liver injury and age based on neonatal mice and adult mice. A survival experiment indicated that all neonatal mice survived. Moreover, the adult mice in the high-dose AAI group all died, whereas half of the adult mice in the low-dose AAI group died. In observation experiments, AAI induced more severe liver injury in neonatal mice than adult mice under long-term than short-term exposure. Furthermore, integrated metabolomics and transcriptomics indicated that AAI disturbing steroid hormone biosynthesis, arachidonic acid metabolism, the drug metabolism-cytochrome P450 pathway and glycerophospholipid metabolism induced neonatal mice liver injury. The important role of age in AAI-induced liver injury was illustrated in our study. This study also lays a solid foundation for scientific supervision of AA safety.
Mechanistic Insights Into the Immune Pathophysiology of COVID-19; An In-Depth Review
Authors: Shafqat Areez , Shafqat Shameel , Salameh Sulaiman Al , Kashir Junaid , Alkattan Khaled , Yaqinuddin Ahmed
Published: March 2022

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), which causes coronavirus-19 (COVID-19), has caused significant morbidity and mortality globally. In addition to the respiratory manifestations seen in severe cases, multi-organ pathologies also occur, making management a much-debated issue. In addition, the emergence of new variants can potentially render vaccines with a relatively limited utility. Many investigators have attempted to elucidate the precise pathophysiological mechanisms causing COVID-19 respiratory and systemic disease. Spillover of lung-derived cytokines causing a cytokine storm is considered the cause of systemic disease. However, recent studies have provided contradictory evidence, whereby the extent of cytokine storm is insufficient to cause severe illness. These issues are highly relevant, as management approaches considering COVID-19 a classic form of acute respiratory distress syndrome with a cytokine storm could translate to unfounded clinical decisions, detrimental to patient trajectory. Additionally, the precise immune cell signatures that characterize disease of varying severity remain contentious. We provide an up-to-date review on the immune dysregulation caused by COVID-19 and highlight pertinent discussions in the scientific community. The response from the scientific community has been unprecedented regarding the development of highly effective vaccines and cutting-edge research on novel therapies. We hope that this review furthers the conversations held by scientists and informs the aims of future research projects, which will potentially further our understanding of COVID-19 and its immune pathogenesis.
In-Depth Immunophenotyping With Mass Cytometry During TB Treatment Reveals New T-Cell Subsets Associated With Culture Conversion
Authors: Chedid Carole , Andrieu Thibault , Kokhreidze Eka , Tukvadze Nestani , Biswas Samanta , Ather Md. Fahim , Uddin Mohammad Khaja Mafij , Banu Sayera , De Maio Flavio , Delogu Giovanni , Endtz Hubert , Goletti Delia , Vocanson Marc , Dumitrescu Oana , Hoffmann Jonathan , Ader Florence
Published: March 2022

Tuberculosis (TB) is a difficult-to-treat infection because of multidrug regimen requirements based on drug susceptibility profiles and treatment observance issues. TB cure is defined by mycobacterial sterilization, technically complex to systematically assess. We hypothesized that microbiological outcome was associated with stage-specific immune changes in peripheral whole blood during TB treatment. The T-cell phenotypes of treated TB patients were prospectively characterized in a blinded fashion using mass cytometry after Mycobacterium tuberculosis (Mtb) antigen stimulation with QuantiFERON-TB Gold Plus, and then correlated to sputum culture status. At two months of treatment, cytotoxic and terminally differentiated CD8+ T-cells were under-represented and naïve CD4+ T-cells were over-represented in positive- versus negative-sputum culture patients, regardless of Mtb drug susceptibility. At treatment completion, a T-cell immune shift towards differentiated subpopulations was associated with TB cure. Overall, we identified specific T-cell profiles associated with slow sputum converters, which brings new insights in TB prognostic biomarker research designed for clinical application.
Reduction of Cell Surface T-Cell Receptor by Non-Mitogenic CD3 Antibody to Mitigate Murine Lupus
Authors: Morita Masashi , Mizui Masayuki , Masuyama Satoshi , Tsokos George C. , Isaka Yoshitaka
Published: March 2022

T-cells are critically involved in the pathogenesis of systemic lupus erythematosus. Although treatment with the anti-CD3 antibody has been reported to be effective in several autoimmune disease animal models including lupus, the immunosuppressive mechanisms remain obscure because of its pleiotropicin vivokinetics. In this study, a conventional anti-CD3 (2C11C) and a non-mitogenic anti-CD3 with a manipulated Fc region (2C11S) were compared to elucidate the underlying mechanism of action. The efficacy and safety of 2C11Sin vivowere demonstrated by sustained TCR reduction for a longer period as compared to 2C11C and no induction of cytokine release or T-cell depletion. Anti-CD3s were administered to NZB/W F1 (BWF1) mice at different time points for individual periods. The short-term treatment with 2C11S in the early phase of lupus suppressed the autoantibody associated with the reduction of germinal center B-cells. Treatment in the late phase attenuated lupus nephritis without affecting autoantibodies or differentiation of effector T-cells. The effect of reduced TCR in the development of autoimmunity was examined by CD3ζ heterozygous-deficient mice, in which T-cells had reduced TCR intensity but showed normal TCR signaling response. Autoantibody and lupus nephritis were attenuated significantly in CD3ζ heterozygous-deficient lupus-prone mice. Collectively, the reduction of surface TCR by non-mitogenic anti-CD3 could sufficiently suppress the development of lupus.
Sea Levels Dynamical Downscaling and Climate Change Projections at the Uruguayan Coast
Authors: Jackson Michelle , Fossati Monica , Solari Sebastian
Published: March 2022

This work implements a dynamical downscaling approach, based on a set of nested two-dimensional hydrodynamic models, to quantify the expected changes in the total sea level climate and its components for the Uruguayan coast, using surface wind and sea level pressure projections from global climate models generated during the Phase 5 of the Coupled Models Inter-Comparison Project, considering three time horizons: historical period (1986-2005), short term (2027-2045) and long term (2082-2100), and the future scenarios RCP 4.5 and RCP 8.5. It is concluded that the main contribution to the projected changes in the area is the regional mean sea level rise, followed in importance by the effect that the increase in the water depth has on the amplitude of the tidal components. Moreover, it is concluded that changes in the meteorological residuals (or surges), associated with potential changes in the atmospheric circulation patterns, are negligible in the study area. The obtained results reinforce the need to resort to dynamic downscaling for projecting total sea level changes in areas characterized by wide and shallow continental shelfs and estuaries, as this approach allows to resolve the interactions that may arise between tides, surges and the mean sea level rise, something that cannot addressed with an approach based solely on statistical downscaling.
Non HCV-Related Mixed Cryoglobulinemic Vasculitis With Biopsy-Proven Renal Involvement: The Effects of Rituximab
Authors: Fenoglio Roberta , Sciascia Savino , Rossi Daniela , Naretto Carla , Alpa Mirella , Roccatello Dario
Published: March 2022

In the countries where HCV infection is still endemic, about 90% of subjects with mixed cryoglobulinemia had previously been infected with HCV and about 80% are RNA positive. Remarkable results in severe HCV-related cryoglobulinemic vasculitis have been obtained with Rituximab. Details of the clinical characteristics and effective treatment of non HCV-related cryogloulinemic syndromes are presently lacking. This paper reports on a prospective single-Center open study aimed at evaluating the clinical presentation and effects of Rituximab administered alone in patients with severe non HCV-related cryoglobulinemic syndrome. The study group included 11 patients followed for at least 6 months. Three patients had type I cryoglobulinemia, 6 had type II and the remaining 2 patients had type III. Mean cryocrit was 2.5%. Four out of 11 patients had symptomatic sicca complex with anti-SSA (Ro)/anti SSB (La) antibodies. All 11 patients presented with biopsy-proven renal involvement, 4 out of 11 with leukocytoclastic vasculitis, and 8 with involvement of the peripheral nervous system. Renal biopsy revealed diffuse membranoproliferative glomerulonephritis (MPGN) in 9 out of 11 patients. Extracapillary proliferation and necrosis of the glomerular tuft was observed in 1 of these 9 cases. Interstitial nephritis together with mesangial expansion and capillary immune deposits were observed in 1 patient. Prevalent interstitial fibrosis and glomerular sclerosis were detected in the remaining case. Patients underwent treatment with rituximab alone. After 6 months we observed a remarkable improvement in the necrotizing skin ulcers and a substantial amelioration of the electrophysiological parameters of motor and sensory peripheral neuropathy. Improvement in both renal function (from 2.8 to 1.4 mg/dl, p < 0.001) and proteinuria (from 4.2 g/24 to 0.4 g/24 h, p < 0.001) was found in 10 out of 11 patients, while 1 could not be fully treated because of a severe infusion reaction and sudden development of anti-Rituximab antibodies. Good renal response was confirmed at the end of follow-up (38.4 months). Three patients had a relapse at 6, 12, and 48 months, respectively. In our cohort the administration of 4 once-weekly infusions of Rituximab followed by 2 more infusions after 1 and 2 months proved to be effective in the management of these rare patients.
Mechanisms Underlying the Interaction Between Chronic Neurological Disorders and Microbial Metabolites via Tea Polyphenols Therapeutics
Authors: Hong Mengyu , Cheng Lu , Liu Yanan , Wu Zufang , Zhang Peng , Zhang Xin
Published: March 2022

The number of hydroxyl groups and existence of characteristic structural groups in tea polyphenols (TP) make them have antioxidant activity, which gives TP anti-inflammatory effects, toward protecting the intestinal flora and brain neurons. Host-associated microbial metabolites are emerging as dominant modifiers of the central nervous system. As yet, the investigations on host-microbiota crosstalking remain challenging, studies focusing on metabolites such as serotonin, short-chain fatty acids, and others have pinpointed multiple actionable signaling pathways relevant to host health. However, there are still complexities and apparent limitations inherent in transforming complex human diseases to corresponding animal models. Here, we choose to discuss several intestinal metabolites with research value, as crucial areas for assessing TP-mediated chronic brain diseases interactions with microbial.
Failure Mode Structured Preventive Maintenance Scheduling With Changing Failure Rates in Industry 4.0 Environment
Authors: Alamri Theyab O. , Mo John P. T.
Published: March 2022

Critical manufacturing systems consist of many different components working together. Each component is important to the operation and performance of the whole system. It is crucial to have a sound maintenance plan to ensure continuous production output. The strategy of current research is to focus on the failure mode modelling of the manufacturing system and divide it according to failure mode in production blocks. The preventive replacement intervals are determined using mean time to failure values of components, with group replacements of components within the production blocks to prevent unexpected functional breakdown failures. With the implementation of Industry 4.0 infrastructure, the mean time to failure values of components are constantly updated. The multi-mode mathematical model developed in this paper is able to adjust the preventive replacement schedule dynamically to suit changing system conditions. The results indicate that preventive replacement of components can achieve consistent minimum system reliability of 90% while minimizing system costs due to maintenance and downtime. Novelty of the approach lies in developing a holistic preventive maintenance schedule using failure mode and effects analysis for a complete system. The approach not only improves maintainability and reliability, lowers the cost of maintenance, but also keeps continuity of production.
PMCA-Based Detection of Prions in the Olfactory Mucosa of Patients With Sporadic Creutzfeldt–Jakob Disease
Authors: Cazzaniga Federico Angelo , Bistaffa Edoardo , De Luca Chiara Maria Giulia , Portaleone Sara Maria , Catania Marcella , Redaelli Veronica , Tramacere Irene , Bufano Giuseppe , Rossi Martina , Caroppo Paola , Giovagnoli Anna Rita , Tiraboschi Pietro , Di Fede Giuseppe , Eleopra Roberto , Devigili Grazia , Elia Antonio Emanuele , Cilia Roberto , Fiorini Michele , Bongianni Matilde , Salzano Giulia , Celauro Luigi , Quarta Federico Giuseppe , Mammana Angela , Legname Giuseppe , Tagliavini Fabrizio , Parchi Piero , Zanusso Gianluigi , Giaccone Giorgio , Moda Fabio
Published: March 2022

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare neurodegenerative disorder caused by the conformational conversion of the prion protein (PrPC) into an abnormally folded form, named prion (or PrPSc). The combination of the polymorphism at codon 129 of the PrP gene (coding either methionine or valine) with the biochemical feature of the proteinase-K resistant PrP (generating either PrPSc type 1 or 2) gives rise to different PrPSc strains, which cause variable phenotypes of sCJD. The definitive diagnosis of sCJD and its classification can be achieved only post-mortem after PrPSc identification and characterization in the brain. By exploiting the Real-Time Quaking-Induced Conversion (RT-QuIC) assay, traces of PrPSc were found in the olfactory mucosa (OM) of sCJD patients, thus demonstrating that PrPSc is not confined to the brain. Here, we have optimized another technique, named protein misfolding cyclic amplification (PMCA) for detecting PrPSc in OM samples of sCJD patients. OM samples were collected from 27 sCJD and 2 genetic CJD patients (E200K). Samples from 34 patients with other neurodegenerative disorders were included as controls. Brains were collected from 26 sCJD patients and 16 of them underwent OM collection. Brain and OM samples were subjected to PMCA using the brains of transgenic mice expressing human PrPC with methionine at codon 129 as reaction substrates. The amplified products were analyzed by Western blot after proteinase K digestion. Quantitative PMCA was performed to estimate PrPSc concentration in OM. PMCA enabled the detection of prions in OM samples with 79.3% sensitivity and 100% specificity. Except for a few cases, a predominant type 1 PrPSc was generated, regardless of the tissues analyzed. Notably, all amplified PrPSc were less resistant to PK compared to the original strain. In conclusion, although the optimized PMCA did not consent to recognize sCJD subtypes from the analysis of OM collected from living patients, it enabled us to estimate for the first time the amount of prions accumulating in this biological tissue. Further assay optimizations are needed to faithfully amplify peripheral prions whose recognition could lead to a better diagnosis and selection of patients for future clinical trials.
Learning Suction Graspability Considering Grasp Quality and Robot Reachability for Bin-Picking
Authors: Jiang Ping , Oaki Junji , Ishihara Yoshiyuki , Ooga Junichiro , Han Haifeng , Sugahara Atsushi , Tokura Seiji , Eto Haruna , Komoda Kazuma , Ogawa Akihito
Published: March 2022

Deep learning has been widely used for inferring robust grasps. Although human-labeled RGB-D datasets were initially used to learn grasp configurations, preparation of this kind of large dataset is expensive. To address this problem, images were generated by a physical simulator, and a physically inspired model (e.g., a contact model between a suction vacuum cup and object) was used as a grasp quality evaluation metric to annotate the synthesized images. However, this kind of contact model is complicated and requires parameter identification by experiments to ensure real world performance. In addition, previous studies have not considered manipulator reachability such as when a grasp configuration with high grasp quality is unable to reach the target due to collisions or the physical limitations of the robot. In this study, we propose an intuitive geometric analytic-based grasp quality evaluation metric. We further incorporate a reachability evaluation metric. We annotate the pixel-wise grasp quality and reachability by the proposed evaluation metric on synthesized images in a simulator to train an auto-encoder–decoder called suction graspability U-Net++ (SG-U-Net++). Experiment results show that our intuitive grasp quality evaluation metric is competitive with a physically-inspired metric. Learning the reachability helps to reduce motion planning computation time by removing obviously unreachable candidates. The system achieves an overall picking speed of 560 PPH (pieces per hour).
Phosphorylation of Spastin Promotes the Surface Delivery and Synaptic Function of AMPA Receptors
Authors: Chen Li , Wang Hanjie , Cha Shuhan , Li Jiong , Zhang Jiaqi , Wu Jiaming , Guo Guoqing , Zhang Jifeng
Published: March 2022

Synaptic plasticity is essential for cognitive functions such as learning and memory. One of the mechanisms involved in synaptic plasticity is the dynamic delivery of AMPA receptors (AMPARs) in and out of synapses. Mutations of SPAST, which encodes SPASTIN, a microtubule-severing protein, are considered the most common cause of hereditary spastic paraparesis (HSP). In some cases, patients with HSP also manifest cognitive impairment. In addition, mice with Spastin depletion exhibit working and associative memory deficits and reduced AMPAR levels. However, the exact effect and molecular mechanism of Spastin on AMPARs trafficking has remained unclear. Here, we report that Spastin interacts with AMPAR, and phosphorylation of Spastin enhances its interaction with AMPAR subunit GluA2. Further study shows that phosphorylation of Spastin can increase AMPAR GluA2 surface expression and the amplitude and frequency of miniature excitatory synaptic currents (mEPSC) in cultured hippocampal neurons. Moreover, phosphorylation of Spastin at Ser210 is crucial for GluA2 surface expression. Phosphorylation of Spastin K353A, which obliterates microtubule-severing activity, also promotes AMPAR GluA2 subunit trafficking to the surface and increases the amplitude and frequency of mEPSCs in cultured neurons. Taken together, our data demonstrate that Spastin phosphorylation promotes the surface delivery of the AMPAR GluA2 subunit independent of microtubule dynamics.
Identification of Neuronal Cells in Sciatic Nerves of Adult Rats
Authors: Liu Yisheng , Zhou Songlin , Zhao Lili , Gu Xiaosong
Published: March 2022

Prior research generally confirms that there are no neuronal cell bodies in the adult sciatic nerve. However, we occasionally find some neuronal cells in adult rat sciatic nerves, either intact or crush-injured. By whole-mount staining and optical imaging of the hyalinized sciatic nerves for Stmn2 (a specific marker for neuronal cells), we found those neuronal cells with irregular distribution in the sciatic nerves in both crushed model and normal rats. We investigated the identity of those cells and established a cultured sciatic nerve model. Immunohistochemistry evidence both in vivo and in vitro illustrated that some of those cells are mature neurons in sciatic nerves. With single-cell sequencing of neuronal cells in adeno-associated virus (AAV)-infected sciatic nerves, we identified that some of those cells are a kind of neuronal stem-like cells. Then we constructed a Nestin-CreERT2 rat line and traced those cells with fluorescence labeling which was induced by tamoxifen. Interesting, we proved that neuronal stem-like cells could proliferate by combination of EdU incorporation with staining in the sciatic nerves of transgenic rats. Together, the discovery of neuronal cells in adult sciatic nerves will make us aware of the distribution of neurons in the peripheral nervous system. Especially our data suggest that neuronal stem-like cells could proliferate in the sciatic nerves of adult rats.
RNA N6-Methyladenosine Modifications and Its Roles in Alzheimer’s Disease
Authors: Zhang Runjiao , Zhang Yizhou , Guo Fangzhen , Li Sha , Cui Huixian
Published: March 2022

The importance of epitranscriptomics in regulating gene expression has received widespread attention. Recently, RNA methylation modifications, particularly N6-methyladenosine (m6A), have received marked attention. m6A, the most common and abundant type of eukaryotic methylation modification in RNAs, is a dynamic reversible modification that regulates nuclear splicing, stability, translation, and subcellular localization of RNAs. These processes are involved in the occurrence and development of many diseases. An increasing number of studies have focused on the role of m6A modification in Alzheimer’s disease, which is the most common neurodegenerative disease. This review focuses on the general features, mechanisms, and functions of m6A methylation modification and its role in Alzheimer’s disease.
Sulforaphane Attenuates Chronic Intermittent Hypoxia-Induced Brain Damage in Mice via Augmenting Nrf2 Nuclear Translocation and Autophagy
Authors: Li Xiucui , Ying Huiya , Zhang Zilong , Yang Zijing , You Cancan , Cai Xiaohong , Lin Zhongdong , Xiao Yanfeng
Published: March 2022

Obstructive sleep apnea–hypopnea syndrome (OSAHS), typically characterized by chronic intermittent hypoxia (CIH), is associated with neurocognitive dysfunction in children. Sulforaphane (SFN), an activator of nuclear factor E2-related factor 2 (Nrf2), has been demonstrated to protect against oxidative stress in various diseases. However, the effect of SFN on OSAHS remains elusive. In this research, we investigated the neuroprotective role of SFN in CIH-induced cognitive dysfunction and underlying mechanisms of regulation of Nrf2 signaling pathway and autophagy. CIH exposures for 4 weeks in mice, modeling OSAHS, contributed to neurocognitive dysfunction, manifested as increased working memory errors (WMEs), reference memory errors (RMEs) and total memory errors (TEs) in the 8-arm radial maze test. The mice were intraperitoneally injected with SFN (0.5 mg/kg) 30 min before CIH exposure everyday. SFN treatment ameliorated neurocognitive dysfunction in CIH mice, which demonstrates less RME, WME, and TE. Also, SFN effectively alleviated apoptosis of hippocampal neurons following CIH by decreased TUNEL-positive cells, downregulated cleaved PARP, cleaved caspase 3, and upregulated Bcl-2. SFN protects hippocampal tissue from CIH-induced oxidative stress as evidenced by elevated superoxide dismutase (SOD) activities and reduced malondialdehyde (MDA). In addition, we found that SFN enhanced Nrf2 nuclear translocation to hold an antioxidative function on CIH-induced neuronal apoptosis in hippocampus. Meanwhile, SFN promoted autophagy activation, as shown by increased Beclin1, ATG5, and LC3II/LC3I. Overall, our findings indicated that SFN reduced the apoptosis of hippocampal neurons through antioxidant effect of Nrf2 and autophagy in CIH-induced brain damage, which highlights the potential of SFN as a novel therapy for OSAHS-related neurocognitive dysfunction.
Fractional-Order Traveling Wave Approximations for a Fractional-Order Neural Field Model
Authors: González-Ramírez Laura R.
Published: March 2022

In this work, we establish a fractional-order neural field mathematical model with Caputo's fractional derivative temporal order α considering 0 < α < 2, to analyze the effect of fractional-order on cortical wave features observed preceding seizure termination. The importance of this incorporation relies on the theoretical framework established by fractional-order derivatives in which memory and hereditary properties of a system are considered. Employing Mittag-Leffler functions, we first obtain approximate fractional-order solutions that provide information about the initial wave dynamics in a fractional-order frame. We then consider the Adomian decomposition method to approximate pulse solutions in a wider range of orders and longer times. The former approach establishes a direct way to investigate the initial relationships between fractional-order and wave features, such as wave speed and wave width. In contrast, the latter approach displays wave propagation dynamics in different fractional orders for longer times. Using the previous two approaches, we establish approximate wave solutions with characteristics consistent with in vivo cortical waves preceding seizure termination. In our analysis, we find consistent differences in the initial effect of the fractional-order on the features of wave speed and wave width, depending on whether α <1 or α>1. Both cases can model the shape of cortical wave propagation for different fractional-orders at the cost of modifying the wave speed. Our results also show that the effect of fractional-order on wave width depends on the synaptic threshold and the synaptic connectivity extent. Fractional-order derivatives have been interpreted as the memory trace of the system. This property and the results of our analysis suggest that fractional-order derivatives and neuronal collective memory modify cortical wave features.
Factors Associated With Severity of Delirium Complicating COVID-19 in Intensive Care Units
Authors: Madonna Domenico , Enrico Paolo , Ciappolino Valentina , Boscutti Andrea , Colombo Elisa , Turtulici Nunzio , Cantù Filippo , Cereda Guido , Delvecchio Giuseppe , De Falco Stefano , Chierichetti Monica , Savioli Monica , Grasselli Giacomo , Brambilla Paolo
Published: March 2022

The clinical outcome of the disease provoked by the SARS-CoV-2 infection, COVID-19, is largely due to the development of interstitial pneumonia accompanied by an Acute Respiratory Distress Syndrome (ARDS), often requiring ventilatory support therapy in Intensive Care Units (ICUs). Current epidemiologic evidence is demonstrating that the COVID-19 prognosis is significantly influenced by its acute complications. Among these, delirium figures as one of the most frequent and severe, especially in the emergency setting, where it shows a significantly negative prognostic impact. In this regard, the aim of our study is to identify clinical severity factors of delirium complicating COVID-19 related-ARDS. We performed a comparative and correlation analysis using demographics, comorbidities, multisystemic and delirium severity scores and anti-delirium therapy in two cohorts of ARDS patients with delirium, respectively, due to COVID-19 (n = 40) or other medical conditions (n = 39). Our results indicate that delirium in COVID-19-related ARDS is more severe since its onset despite a relatively less severe systemic condition at the point of ICU admission and required higher dosages of antipsychotic and non-benzodiazepinic sedative therapy respect to non-COVID patients. Finally, the correlation analysis showed a direct association between the male gender and maximum dosage of anti-delirium medications needed within the COVID-19 group, which was taken as a surrogate of delirium severity. Overall, our results seem to indicate that pathogenetic factors specifically associated to severe COVID-19 are responsible for the high severity of delirium, paving the way for future research focused on the mechanisms of the cognitive alterations associated with COVID-19.