bluuebunny/crossref_metadata_2025 huggingface dataset:
Issue Responsiveness in Canadian Politics: Are Parties Responsive to the Climate Change’s Public Salience in Question Period?
Authors: Alvarez R. Michael , Morrier Jacob
Published: July 2022

Are political representatives responsive to their constituents in determining the issues they address? Our paper takes a novel approach to this critical question using innovative data and state-of-the-art methodology. While most previous research on issue responsiveness has looked at the United States and its unique political institutions, we study a multi-party, parliamentary setting: Canada. We focus our analysis on two prominent issues: the environment and climate change. Using transcripts from the House of Commons’ Question Period from 2006 to 2021, we measure the attention political parties attribute to the various issues. We use Google Trends data to measure policy issues’ public salience. We implement an instrumental variable estimation strategy to identify and estimate how the environment and climate change’s public salience drives elite attention. Our analysis demonstrates that public salience significantly affects political parties’ interest in the environment and climate change but unveils appreciable partisan heterogeneity in this regard.
Calculation of Intraocular Lens Optical Power with Enhanced Depth of Focus
Authors: Pershin K. B. , Pashinova N. F. , Tsygankov A. Yu. , Antonov E. A.
Published: July 2022

Relevance.  The new Increased Depth of Focus (EDOF) Intraocular Lens (IOL) technology is designed to improve the correction of visual acuity at a medium distance without compromising distance vision correction and provides a restoration of visual acuity in the distance and at an average distance, but at the same time a lower frequency of side optical phenomena and better contrast sensitivity compared to other multifocal IOLs (MIOL). Regardless of the technology used and the type of lens, the result of surgery and patient satisfaction depend on the optimization of the calculation of the optical strength of the IOL. To date, there is no consensus in the available literature on the choice of a formula for calculating the optical power of known EDOF IOLs.

Aim. Retrospective analysis of the accuracy of 7 formulas for optical power calculation of a new extended depth of focus intraocular lens.

Methods. The retrospective study included 34 patients (62 eyes) with implantation of a new EDOF Tecnis Symfony IOL ZXR00. The mean age of the patients was 61.9 ± 9.4 (39–87) years. IOL optical power range was +5.0 to +30.0 D, target refraction was –0.25 to 0.25 D. The average follow-up period for the patients was 12.3 ± 1.8 months. The SRK/T, Barrett Universal II, Haigis, Hoffer Q, Holladay 2, Olsen, and Kane formulas were retrospectively analyzed for effectiveness using appropriate constants. Each formula was optimized for the study group of patients to achieve an average refractive error as close to zero as possible. For each formula, the mean error (ME), mean absolute error (MAE), standard deviation (SD), median absolute error (MedAE), maximum absolute error (MaxAE), and percentage of eyes within the error range of 0.25, 0.5, 1.0, and 2.0 D were calculated.

Results. The optimized constants were LF = 2.21, a0 = 1.43, a1 = 0.39, a2 = 0.12, personalized ACD=5.68, ACD (Hoffer Q / Holladay 2) = 5.68/5.66, A-constant (SRK/T / Kane) = 119.5/119.4. For the SRK/T, Barrett Universal II, Kane and Haigis formulas the lowest MAE is shown. Application of the Hoffer Q and Holladay 2 formulas are associated with the highest MAE. The Barrett Universal II, SRK/T, Kane, and Haigis formulas were characterized by the highest percentage of reaching refraction of ±0.25 D (64, 62, 59, and 53, respectively). For all of the formulas examined, the frequency of reaching refraction of ±1.00 D was greater than 90% and within ±2.00 D greater than 97%.

Conclusion. This study was the first to retrospectively compare seven formulas for calculating the optical power of a new intraocular lens with an enhanced depth of focus. The SRK/T, Barrett Universal II, Haigis, and Kane formulas are recommended for calculating the optical power of the indicated IOL in clinical practice.
Visual disorders in patients with dyslexia (literature review)
Authors: Rychkova S. I. , Likhvantseva V. G.
Published: July 2022

Background.The ability to read is the key to successful education of schoolchildren and students. At the same time, according to various authors, from 5–10 to 20–30% of the population experience difficulties, characterized as “reading below the level of language proficiency”, “reading difficulties” and “dyslexia”. This work is devoted to the analysis of modern Russian and foreign literature in the field of aetiopathogenesis, diagnosis, clinical manifestations and functional correction of visual disorders in dyslexia.

Aim:to study the literature data on visual impairment in patients with dyslexia.

Materials and methods.The literature analysis of publications available on PubMed, eLibrary, CyberLeninka and Crossref Metadata Search was carried out.

Results.The conducted analysis demonstrates the importance of effective detection of visual disorders in patients with dyslexia, which is necessary for a correct comprehensive assessment of this condition, as well as understanding the causes and nature of difficulties experienced by a child with dyslexia in the process of learning to read. The results of the analysis of studies reveal the possibilities of positive dynamics in the development of reading skills in patients with dyslexia in the process of functional treatment aimed at developing binocular visual functions, improving the functioning of the oculomotor system and the accommodation.

Conclusion.The authors conclude that an in-depth ophthalmic examination and treatment of the identified ophthalmic pathology is of great importance in the overall complex of diagnostic and corrective measures in patients with dyslexia.
Contact lens manufacturing technology
Authors: Yadykin A. A. , Listratov S. V.
Published: July 2022

Currently, the following technologies are used in the production of contact lenses: lathe cut, polymerization in the form (cast molding) and centrifugal molding (spin cast). The last two technologies, due to the low cost of production, have been established in the mass production of soft contact lenses with standard parameters.

Methods of production of contact lenses are constantly being improved to obtain products that better meet the requirements of patients in terms of safety, comfort and customization.

The main methods of production of contact lenses are already localized in Russia and remain available to domestic consumers in conditions of geopolitical instability.
Обзор научных публикаций
Authors: Editorial Article
Published: July 2022

Увеличение числа близоруких детей во всем мире, а особенно в регионе Юго-Восточной Азии, стимулирует заинтересованность к методам контроля (замедления прогрессирования) миопии. Цель терапии – снижение риска потери зрения из-за угрожающих осложнений в более позднем возрасте. В нижеприведенных статьях анализируются методы контроля миопии, а также возможные риски, связанные с лечением. Используя ссылку DOI, вы можете ознакомиться с полными текстами этих работ.

Подбор материалов и адаптация перевода: Валерия А. Форбс, магистр оптометрии, Miami Contact Lens Institute, США

Перевод с англ. языка: Артем А. Сологубов, врач-ординатор, Академия постдипломного образования ФГБУ «ФНКЦ ФМБА» России, Россия
The Emerging Applications of Nanotechnology in Neuroimaging: A Comprehensive Review
Authors: Faiz Khunza , Lam Fred C. , Chen Jay , Kasper Ekkehard M. , Salehi Fateme
Published: July 2022

Neuroimaging modalities such as computer tomography and magnetic resonance imaging have greatly improved in their ability to achieve higher spatial resolution of neurovascular and soft tissue neuroanatomy, allowing for increased accuracy in the diagnosis of neurological conditions. However, the use of conventional contrast agents that have short tissue retention time and associated renal toxicities, or expensive radioisotope tracers that are not widely available, continue to limit the sensitivity of these imaging modalities. Nanoparticles can potentially address these shortcomings by enhancing tissue retention and improving signal intensity in the brain and neural axis. In this review, we discuss the use of different types of nanotechnology to improve the detection, diagnosis, and treatment of a wide range of neurological diseases.
Enhancing Drug Utilization Efficiency via Dish-Structured Triboelectric Nanogenerator
Authors: Chen Qu , Deng Wenjing , He Jingjin , Cheng Li , Ren Pei-Gen , Xu Yang
Published: July 2022

Due to the finding of severe side effects and low therapeutic efficacy with cancer chemotherapy, there still remains a great challenge to benefit patients with curative effect. In this work, we designed a self-powered drug delivery system comprising a current source derived from the disk TENG (D-TENG) and a pair of Au electrodes. Thus, cells seeded within the electrode gap could be stimulated by the current followed by D-TENG`s work. Under the rotation frequency of about 7.4 Hz, the peak output current and voltage of the D-TENG reached 3.7 μA and 135 V and achieved an average of 2.8 μA of output current. Furthermore, the D-TENG also showed its good stability to output steady current in a long-term condition. When applying the electric stimulation by this self-powered drug delivery system, a chemotherapy drug, doxorubicin (DOX), had significant uptake by cancer cells. Therefore, utilizing a novel TENG device as a part of chemotherapy would provide a new opportunity in future disease treatment.
Neutrophil Survival Signaling During Francisella tularensis Infection
Authors: Kinkead Lauren C. , Krysa Samantha J. , Allen Lee-Ann H.
Published: July 2022

Neutrophils are the most abundant and shortest-lived leukocytes in humans and tight regulation of neutrophil turnover via constitutive apoptosis is essential for control of infection and resolution of inflammation. Accordingly, aberrant neutrophil turnover is hallmark of many disease states. We have shown in previous work that the intracellular bacterial pathogen Francisella tularensis markedly prolongs human neutrophil lifespan. This is achieved, in part, by changes in neutrophil gene expression. Still unknown is the contribution of major neutrophil pro-survival signaling cascades to this process. The objective of this study was to interrogate the contributions of ERK and p38 MAP kinase, Class I phosphoinositide 3-kinases (PI3K), AKT, and NF-κB to neutrophil survival in our system. We demonstrate that both ERK2 and p38α were activated in F. tularensis-infected neutrophils, but only p38α MAPK was required for delayed apoptosis and the rate of cell death in the absence of infection was unchanged. Apoptosis of both infected and uninfected neutrophils was markedly accelerated by the pan-PI3K inhibitor LY2094002, but AKT phosphorylation was not induced, and neutrophil death was not enhanced by AKT inhibitors. In addition, isoform specific and selective inhibitors revealed a unique role for PI3Kα in neutrophil survival after infection, whereas only simultaneous inhibition of PI3Kα and PI3kδ accelerated death of the uninfected controls. Finally, we show that inhibition of NF-κB triggered rapid death of neutrophil after infection. Thus, we defined roles for p38α, PI3Kα and NF-κB delayed apoptosis of F. tularensis-infected cells and advanced understanding of Class IA PI3K isoform activity in human neutrophil survival.
Gut Microbiota Diversity of Preterm Neonates Is Associated With Clostridioides Difficile Colonization
Authors: Couturier Jeanne , Lepage Patricia , Jolivet Sarah , Delannoy Johanne , Mesa Victoria , Ancel Pierre-Yves , Rozé Jean-Christophe , Butel Marie-José , Barbut Frédéric , Aires Julio
Published: July 2022

In adults, Clostridioides difficile infections are associated with alterations of the intestinal bacterial populations. Although preterm neonates (PN) are frequently colonized by C. difficile, limited data are available regarding the relationship between C. difficile and the intestinal microbiota of this specific population. Therefore, we studied the intestinal microbiota of PN from two multicenter cohorts using high-throughput sequencing of the bacterial 16S rRNA gene. Our results showed that alpha diversity was significantly higher in children colonized by C. difficile than those without colonization. Beta diversity significantly differed between the groups. In multivariate analysis, C. difficile colonization was significantly associated with the absence of postnatal antibiotherapy and higher gestational age. Taxa belonging to the Lachnospiraceae, Enterobacteriaceae, Oscillospiraceae families and Veillonella sp. were positively associated with C. difficile colonization, whereas Bacteroidales and Bifidobacterium breve were negatively associated with C. difficile colonization. After adjustment for covariables, Clostridioides, Rothia, Bifidobacterium, Veillonella, Eisenbergiella genera and Enterobacterales were more abundant in the gut microbiota of colonized children. There was no significant association between C. difficile colonization and necrotizing enterocolitis in PN. Our results suggest that C. difficile colonization in PN is related to the establishment of physiological microbiota.
Vaccination Is Associated With Shorter Time to Target Cycle Threshold Value in Patients With SARS-CoV-2 Omicron Variant
Authors: Wu Jiajun , Wei Yong , Shen Feng , Zhu Shun , Lu Yingying , Tian Xue , Zhang Pengyu
Published: July 2022

Background

Limited data are available on the responses to vaccination for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant in the Chinese population. This study aimed to investigate whether vaccination could alter the disease course of SARS-CoV-2 Omicron variant.

Methods

A retrospective cohort included 142 patients who had no or mild symptoms and were admitted to our department for centralized isolation after being locally infected with SARS-CoV-2 Omicron variant from March 4 to 30, 2022, in Shanghai, China.

Results

Of the 142 subjects with the mean age of 43.1 years, 53.5% were male and 90.8% had been vaccinated before the infection. Comparing the vaccinated with the unvaccinated patients, there was no difference in patient characteristics, but patients with vaccination had shorter time to target cycle threshold value (TtCT) (vaccinated vs. unvaccinated, 12.6 ± 3.4 vs. 14.8 ± 4.7 days, P = 0.039). There was no difference in TtCT between heterogeneous and homologous vaccination. Of subjects with homologous vaccination, 43.1% were vaccinated with CoronaVac (Sinovac Life Science), 47.2% with Sinopharm BBIBP-CorV, 4.9% with Sinopharm WIBP, 3.3% with CanSinoBio, and 1.6% with Zhifei Longcom. No difference in TtCT was observed among different vaccines. Comparing two-dose primary vaccination with three-dose booster vaccination, we found no difference in TtCT either.

Conclusion

Vaccination is associated with shorter TtCT in patients with SARS-CoV-2 Omicron variant.
Colistin Susceptibility in Companion Animal-Derived Escherichia coli, Klebsiella spp., and Enterobacter spp. in Japan: Frequent Isolation of Colistin-Resistant Enterobacter cloacae Complex
Authors: Sato Toyotaka , Harada Kazuki , Usui Masaru , Yokota Shin-ichi , Horiuchi Motohiro
Published: July 2022

Transmission of colistin-resistant Enterobacterales from companion animals to humans poses a clinical risk as colistin is a last-line antimicrobial agent for treatment of multidrug-resistant Gram-negative bacteria including Enterobacterales. In this study, we investigated the colistin susceptibility of 285 Enterobacterales (including 140 Escherichia coli, 86 Klebsiella spp., and 59 Enterobacter spp.) isolated from companion animals in Japan. We further characterized colistin-resistant isolates by multilocus sequence typing (MLST), phylogenetic analysis of hsp60 sequences, and population analysis profiling, to evaluate the potential clinical risk of companion animal-derived colistin-resistant Enterobacterales to humans in line with the One Health approach. All E. coli isolates were susceptible to colistin, and only one Klebsiella spp. isolate (1.2%, 1/86 isolates) was colistin resistant. Enterobacter spp. isolates were frequently colistin resistant (20.3%, 12/59 isolates). In colistin-resistant Enterobacter spp., all except one isolate exhibited colistin heteroresistance by population analysis profiling. These colistin-heteroresistant isolates belonged to clusters I, II, IV, VIII, and XII based on hsp60 phylogeny. MLST analysis revealed that 12 colistin-resistant Enterobacter spp. belonged to the Enterobacter cloacae complex; five Enterobacter kobei (four ST591 and one ST1577), three Enterobacter asburiae (one ST562 and two ST1578), two Enterobacter roggenkampii (ST606 and ST1576), and Enterobacter hormaechei (ST1579) and E. cloacae (ST765) (each one strain). Forty-two percent of the colistin-resistant E. cloacae complex isolates (predominantly ST562 and ST591) belonged to lineages with human clinical isolates. Four E. kobei ST591 isolates were resistant to third-generation cephalosporines, aminoglycosides, and fluroquinolones but remained susceptible to carbapenems. In conclusion, our study is the first to our knowledge to report the frequent isolation of the colistin-resistant E. cloacae complex from companion animals. Furthermore, a subset of isolates belonged to human-associated lineages with resistance to multiple classes of antibiotics. These data warrant monitoring carriage of the colistin-resistant E. cloacae complex in companion animals as part of a domestic infection control procedure in line with the One Health approach.
An Artificial Intelligence Algorithm With 24-h Holter Monitoring for the Identification of Occult Atrial Fibrillation During Sinus Rhythm
Authors: Kim Ju Youn , Kim Kyung Geun , Tae Yunwon , Chang Mineok , Park Seung-Jung , Park Kyoung-Min , On Young Keun , Kim June Soo , Lee Yeha , Jang Sung-Won
Published: July 2022

Background

Subclinical atrial fibrillation (AF) is one of the pathogeneses of embolic stroke. Detection of occult AF and providing proper anticoagulant treatment is an important way to prevent stroke recurrence. The purpose of this study was to determine whether an artificial intelligence (AI) model can assess occult AF using 24-h Holter monitoring during normal sinus rhythm.

Methods

This study is a retrospective cohort study that included those who underwent Holter monitoring. The primary outcome was identifying patients with AF analyzed with an AI model using 24-h Holter monitoring without AF documentation. We trained the AI using a Holter monitor, including supraventricular ectopy (SVE) events (setting 1) and excluding SVE events (setting 2). Additionally, we performed comparisons using the SVE burden recorded in Holter annotation data.

Results

The area under the receiver operating characteristics curve (AUROC) of setting 1 was 0.85 (0.83–0.87) and that of setting 2 was 0.84 (0.82–0.86). The AUROC of the SVE burden with Holter annotation data was 0.73. According to the diurnal period, the AUROCs for daytime were 0.83 (0.78–0.88) for setting 1 and 0.83 (0.78–0.88) for setting 2, respectively, while those for nighttime were 0.85 (0.82–0.88) for setting 1 and 0.85 (0.80–0.90) for setting 2.

Conclusion

We have demonstrated that an AI can identify occult paroxysmal AF using 24-h continuous ambulatory Holter monitoring during sinus rhythm. The performance of our AI model outperformed the use of SVE burden in the Holter exam to identify paroxysmal AF. According to the diurnal period, nighttime recordings showed more favorable performance compared to daytime recordings.
Estimating the Water Budget of the Upper Blue Nile River Basin With Water and Energy Processes (WEP) Model
Authors: Abebe Sintayehu A. , Qin Tianling , Zhang Xin , Li Chenhao , Yan Denghua
Published: July 2022

Understanding the spatial and temporal distributions and variations of basin water budget components is essential for effective water resources management. Due to a lack of basic hydro-meteorological information, the Upper Blue Nile River Basin (UBNRB) remains poorly understood in quantifying its hydrologic fluxes and associated dynamics. This study used a physically based distributed hydrologic model, WEP. We used multi-year land use information to better estimate the water budget components (evapotranspiration, runoff and storage) of the UBNRB. WEP simulation was validated at two main sections of the Upper Blue Nile river monthly from 1992 to 2014 (23 years). Results show that the basin stores a significant amount of water during the long rainy season (June to September) due to higher precipitation and limited evapotranspiration. However, it loses this storage through evapotranspiration during the dry season (October to February). The overall basin precipitation is 1,051 mm per year. Evapotranspiration accounts for 58% of the annual water budget, runoff is 25% and storage is 18%. The findings reported in this study can shed some light on understanding the UBNRB water budget dynamics and inform water management practitioners.
Studies of Teaching and Learning English-Speaking Skills: A Review and Bibliometric Analysis
Authors: Wang Juan , Abdullah Rohaya , Leong Lai-Mei
Published: July 2022

This study conducted a comprehensive historical review and bibliometric analysis of the literature on English-speaking (ES) education and mapped the current state of the field, trends, and emerging topics, as well as identified gaps where further research is needed. We retrieved 361 sample documents on ES teaching and learning in Scopus (2010–2021) under certain conditions and analyzed the extracted data using Excel and VOSviewer 1.6.17 from the perspectives of the number of yearly publications, countries, authors, citation numbers, and keywords. The findings show that the number of publications on ES education increased from 2010 to 2021, but there was a lack of sustained engagement with this topic by researchers. Countries with an ESL or EFL context focused more on the subject of ES, although studies from native ES countries were more influential. The research topics showed a multidimensional trend, covering communicative skills, language knowledge, assessment, teaching or learning methods, ICT-related applications, and cognitive factors, of which ICT-related applications (such as flipped classrooms, blended learning, and e-learning) and cognitive factors (such as motivation, anxiety, and affect) were the areas of focus. Students in higher institutions, rather than children, became the main research subject of ES education over the period studied.
The Perceived Usefulness of Gamified E-Learning: A Study of Undergraduate Students With Implications for Higher Education
Authors: Aguilos Veronica , Fuchs Kevin
Published: July 2022

Gamification is about applying gaming strategies and game elements to improve learning, and thus, making it more engaging for individuals. The application of gamification in higher education aims to incentivize students and is said to improve the efficiency of self-paced learning. The study aims to explore the perceived usefulness and challenges of gamified learning in the context of a massive open online course. A qualitative exploratory study design was adopted to collect empirical data from 19 undergraduate students about their experiences with gamified learning. An inductive approach was used to interpret the results thematically. A total of four themes emerged from the data analysis. The collected data revealed that Students’ competitive behavior has a significant effect on Students’ marks in the activities. Moreover, instant gratification from immediate feedback and evaluation was perceived as highly motivating for the students. The article concludes by presenting implications for educators, policymakers, and education researchers derived from the academic and practical discussions based on the findings.
ERα and ERβ Homodimers in the Same Cellular Context Regulate Distinct Transcriptomes and Functions
Authors: Song Dandan , He Huan , Indukuri Rajitha , Huang Zhiqiang , Stepanauskaite Lina , Sinha Indranil , Haldosén Lars-Arne , Zhao Chunyan , Williams Cecilia
Published: July 2022

The two estrogen receptors ERα and ERβ are nuclear receptors that bind estrogen (E2) and function as ligand-inducible transcription factors. They are homologues and can form dimers with each other and bind to the same estrogen-response element motifs in the DNA. ERα drives breast cancer growth whereas ERβ has been reported to be anti-proliferative. However, they are rarely expressed in the same cells, and it is not fully investigated to which extent their functions are different because of inherent differences or because of different cellular context. To dissect their similarities and differences, we here generated a novel estrogen-dependent cell model where ERα homodimers can be directly compared to ERβ homodimers within the identical cellular context. By using CRISPR-cas9 to delete ERα in breast cancer MCF7 cells with Tet-Off-inducible ERβ expression, we generated MCF7 cells that express ERβ but not ERα. MCF7 (ERβ only) cells exhibited regulation of estrogen-responsive targets in a ligand-dependent manner. We demonstrated that either ER was required for MCF7 proliferation, but while E2 increased proliferation via ERα, it reduced proliferation through a G2/M arrest via ERβ. The two ERs also impacted migration differently. In absence of ligand, ERβ increased migration, but upon E2 treatment, ERβ reduced migration. E2 via ERα, on the other hand, had no significant impact on migration. RNA sequencing revealed that E2 regulated a transcriptome of around 800 genes via each receptor, but over half were specific for either ERα or ERβ (417 and 503 genes, respectively). Functional gene ontology enrichment analysis reinforced that E2 regulated cell proliferation in opposite directions depending on the ER, and that ERβ specifically impacted extracellular matrix organization. We corroborated that ERβ bound to cis-regulatory chromatin of its unique proposed migration-related direct targets ANXA9 and TFAP2C. In conclusion, we demonstrate that within the same cellular context, the two ERs regulate cell proliferation in the opposite manner, impact migration differently, and each receptor also regulates a distinct set of target genes in response to E2. The developed cell model provides a novel and valuable resource to further complement the mechanistic understanding of the two different ER isoforms.
A Transformation in City-Descriptive Input Data for Urban Climate Models
Authors: Lipson Mathew J. , Nazarian Negin , Hart Melissa A. , Nice Kerry A. , Conroy Brooke
Published: July 2022

In urban climate studies, datasets used to describe urban characteristics have traditionally taken a class-based approach, whereby urban areas are classified into a limited number of typologies with a resulting loss of fidelity. New datasets are becoming increasingly available that describe the three-dimensional structure of cities at sub-metre micro-scale resolutions, resolving individual buildings and trees across entire continents. These datasets can be used to accurately determine local characteristics without relying on classes, but their direct use in numerical weather and climate modelling has been limited by their availability, and because they require processing to conform to the required inputs of climate models. Here, we process building-resolving datasets across large geographical extents to derive city-descriptive parameters suitable as common model inputs at resolutions more appropriate for local or meso-scale modelling. These parameter values are then compared with the ranges obtained through the class-based Local Climate Zone framework. Results are presented for two case studies, Sydney and Melbourne, Australia, as open access data tables for integration into urban climate models, as well as codes for processing high-resolution and three-dimensional urban datasets. We also provide an open access 300 m resolution building morphology and surface cover dataset for the Sydney metropolitan region (approximately 5,000 square kilometres). The use of building resolving data to derive model inputs at the grid scale better captures the distinct heterogenetic characteristics of urban form and fabric compared with class-based approaches, leading to a more accurate representation of cities in climate models. As consistent building-resolving datasets become available over larger geographical extents, we expect bottom-up approaches to replace top-down class-based frameworks.
Uncertainty Analysis of Premature Death Estimation Under Various Open PM2.5 Datasets
Authors: Liu Jing , Li Shenxin , Xiong Ying , Liu Ning , Zou Bin , Xiong Liwei
Published: July 2022

Assessments of premature deaths caused by PM2.5 exposure have important scientific significance and provide valuable information for future human health–oriented air pollution prevention. PM2.5 concentration data are particularly vital and may cause great uncertainty in premature death assessments. This study constructed an index of deviation frequency to compare differences in premature deaths assessed by five sets of extensively used PM2.5 concentration remote sensing datasets. Then, a preferred combination project of the PM2.5 dataset was proposed by selecting relatively high-accuracy PM2.5 concentration datasets in areas with significant differences. Based on this project, an index of uncertainty was constructed to quantify the effects of using different PM2.5 datasets on premature death assessments. The results showed that there were significant differences in PM2.5 attributable to premature deaths assessed by different datasets from 2000 to 2016, and the differences were most obvious in 2004. Spatially, differences were most significant in Jilin, Fujian, Liaoning, Hebei, Shanxi, Hubei, Sichuan, and Yunnan. The differences were caused by PM2.5 concentration; therefore, in order to reduce uncertainty in subsequent premature death assessments because of using different PM2.5 concentration data, the CGS3 dataset was recommended for Jilin, Sichuan, Yunnan, and Fujian, and the CHAP dataset was recommended for Liaoning, Hebei, Shanxi, and Hubei, and for other regions, CGS3, CHAP, or PHD datasets were more applicable. The CHAP dataset was the best selection for premature death assessments in the whole area. Based on the preferred combination project of the PM2.5 dataset, uncertainty in annual premature death assessments could be reduced by 31 and 159% in the whole and local area, respectively. The research results will provide a scientific basis for a reasonable selection of PM2.5 concentration remote sensing datasets in air pollution premature death assessments in China.
Feeding Patterns of Three Widespread Carnivores—The Wolf, Snow Leopard, and Red Fox—in the Trans-Himalayan Landscape of India
Authors: Shrotriya Shivam , Reshamwala Hussain S. , Lyngdoh Salvador , Jhala Yadvendradev V. , Habib Bilal
Published: July 2022

The Trans-Himalayan landscape is an extreme cold desert with limited diversity and a low density of wild prey. The landscape has three widespread carnivores—the wolfCanis lupus chanco, snow leopardPanthera uncia, and red foxVulpes vulpes—competing for similar prey. We studied predation patterns, dietary competition, and niche segregation of three sympatric carnivores in the Indian Trans-Himalayas. The Himalayan or wooly wolf is one of the oldest lineages and has adapted to extreme cold. We further studied the prey selection of the wolf in the high-altitude environment. We collected 1,600 carnivore scats (wolf = 542, snow leopard = 31, and red fox = 1,027), and additional data on 573 snow leopard scats from literature was used in the analyses. We found that livestock was a major contributor to the wolf (56.46%) and snow leopard diet (30.01%). The wolf consumed blue sheep (8.26%) and ibex (3.13%), whereas the snow leopard subsisted on blue sheep (30.79%) and ibex (17.15%), relatively more frequently. The red fox preyed upon small species like pika and marmots (18.85 %); however, livestock carrions (16.49%), fruits and seeds (15.05%), and human-derived material (11.89%) were also consumed frequently. The dietary niche of three carnivore species highly overlapped (Pianka's index = 0.503, simulated mean = 0.419,p= 0.15) due to livestock. The carnivores segregated their diet in prey items originating from the wild. We tested a relationship between carnivore diet variations and prey/predator functional traits using RLQ ordination. Predator morphology traits like body size, weight, and habitat preference significantly affected the prey selection (p< 0.05). The wolf and snow leopard avoided the competition through habitat selection, while the red fox coexisted by exploiting a broader niche. The wolf showed site-specific variation in prey preferences albeit no prey selection at the landscape level (G2 = 6.79,df= 12,p= 0.87). The wolf preferred wild prey over domestic species at the wild prey rich site. The carnivores in this pastoralist landscape have adapted to exploit livestock resources despite facing persecution. Therefore, managing livestock and simultaneously restoring wild prey is crucial for the conservation of the carnivore guild in the Trans-Himalayan ecosystem.
Case Report: Whole-Exome Sequencing-Based Copy Number Variation Analysis Identified a Novel DRC1 Homozygous Exon Deletion in a Patient With Primary Ciliary Dyskinesia
Authors: Liu Ying , Lei Cheng , Wang Rongchun , Yang Danhui , Yang Binyi , Xu Yingjie , Lu Chenyang , Wang Lin , Ding Shuizi , Guo Ting , Liu Shaokun , Luo Hong
Published: July 2022

Objective: Whole-exome sequencing (WES) based copy number variation (CNV) analysis has been reported to improve the diagnostic rate in rare genetic diseases. In this study, we aim to find the disease-associated variants in a highly suspected primary ciliary dyskinesia (PCD) patient without a genetic diagnosis by routine WES analysis.

Methods: We identified the CNVs using the “Exomedepth” package in an undiagnosed PCD patient with a negative result through routine WES analysis. RNA isolation, PCR amplification, and Sanger sequencing were used to confirm the variant. High-speed video microscopy analysis (HSVA) and immunofluorescence analysis were applied to detect the functional and structural deficiency of nasal cilia and sperm flagella. Papanicolaou staining was employed to characterize the morphology of sperm flagella.

Results: NC_000002.11(NM_145038.5): g.26635488_26641606del, c.156-1724_244-2550del, r.156_243del, p. (Glu53Asnfs*13), a novel DRC1 homozygous CNV, was identified by WES-based CNV analysis rather than routine variants calling, in a patient from a non-consanguineous family. HSVA results showed no significant change in ciliary beating frequency but with reduced beating amplitude compared with normal control, and his spermatozoa were almost immotile. The diagnosis of multiple morphological abnormalities of the sperm flagella (MMAF) was established through sperm motility and morphology analysis. PCR amplification and Sanger sequencing confirmed the novel variant of DRC1. Immunofluorescence showed that both cilia and sperm flagella were deficient in protein expression related to the dynein regulatory complex.

Conclusion: This report identifies a novel DRC1 disease-associated variant by WES-based CNV analysis from a highly suspected PCD patient with MMAF. Our findings not only expand the genetic spectrum of PCD with MMAF but suggest that in combination with CNV analysis might improve the efficiency of genetic tests.
Pyruvate Supports RET-Dependent Mitochondrial ROS Production to Control Mycobacterium avium Infection in Human Primary Macrophages
Authors: Røst Lisa Marie , Louet Claire , Bruheim Per , Flo Trude Helen , Gidon Alexandre
Published: July 2022

Macrophages deploy a variety of antimicrobial programs to contain mycobacterial infection. Upon activation, they undergo extensive metabolic reprogramming to meet an increase in energy demand, but also to support immune effector functions such as secretion of cytokines and antimicrobial activities. Here, we report that mitochondrial import of pyruvate is linked to production of mitochondrial ROS and control of Mycobacterium avium (M. avium) infection in human primary macrophages. Using chemical inhibition, targeted mass spectrometry and single cell image analysis, we showed that macrophages infected with M. avium switch to aerobic glycolysis without any major imbalances in the tricarboxylic acid cycle volume or changes in the energy charge. Instead, we found that pyruvate import contributes to hyperpolarization of mitochondria in infected cells and increases production of mitochondrial reactive oxygen species by the complex I via reverse electron transport, which reduces the macrophage burden of M. avium. While mycobacterial infections are extremely difficult to treat and notoriously resistant to antibiotics, this work stresses out that compounds specifically inducing mitochondrial reactive oxygen species could present themself as valuable adjunct treatments.
Dual Antigen T Cell Engagers Targeting CA9 as an Effective Immunotherapeutic Modality for Targeting CA9 in Solid Tumors
Authors: Tatari Nazanin , Zhang Xiaoyu , Chafe Shawn C. , McKenna Dillon , Lawson Keith A. , Subapanditha Minomi , Shaikh Muhammad Vaseem , Seyfrid Mathieu , Savage Neil , Venugopal Chitra , Moffat Jason , Singh Sheila K.
Published: July 2022

Glioblastomas (GBM), the most common malignant primary adult brain tumors, are uniformly lethal and are in need of improved therapeutic modalities. GBM contain extensive regions of hypoxia and are enriched in therapy resistant brain tumor-initiating cells (BTICs). Carbonic anhydrase 9 (CA9) is a hypoxia-induced cell surface enzyme that plays an important role in maintenance of stem cell survival and therapeutic resistance. Here we demonstrate that CA9 is highly expressed in patient-derived BTICs. CA9+ GBM BTICs showed increased self-renewal and proliferative capacity. To target CA9, we developed dual antigen T cell engagers (DATEs) that were exquisitely specific for CA9-positive patient-derived clear cell Renal Cell Carcinoma (ccRCC) and GBM cells. Combined treatment of either ccRCC or GBM cells with the CA9 DATE and T cells resulted in T cell activation, increased release of pro-inflammatory cytokines and enhanced cytotoxicity in a CA9-dependent manner. Treatment of ccRCC and GBM patient-derived xenografts markedly reduced tumor burden and extended survival. These data suggest that the CA9 DATE could provide a novel therapeutic strategy for patients with solid tumors expressing CA9 to overcome treatment resistance.
Host-Related Factors as Targetable Drivers of Immunotherapy Response in Non-Small Cell Lung Cancer Patients
Authors: Baci Denisa , Cekani Elona , Imperatori Andrea , Ribatti Domenico , Mortara Lorenzo
Published: July 2022

Despite some significant therapeutic breakthroughs leading to immunotherapy, a high percentage of patients with non-small cell lung cancer (NSCLC) do not respond to treatment on relapse, thus experiencing poor prognosis and survival. The unsatisfying results could be related to the features of the tumor immune microenvironment and the dynamic interactions between a tumor and immune infiltrate. Host–tumor interactions strongly influence the course of disease and response to therapies. Thus, targeting host-associated factors by restoring their physiologic functions altered by the presence of a tumor represents a new therapeutic approach to control tumor development and progression. In NSCLC, the immunogenic tumor balance is shifted negatively toward immunosuppression due to the release of inhibitory factors as well as the presence of immunosuppressive cells. Among these cells, there are myeloid-derived suppressor cells, regulatory T cells that can generate a tumor-permissive milieu by reprogramming the cells of the hosts such as tumor-associated macrophages, tumor-associated neutrophils, natural killer cells, dendritic cells, and mast cells that acquire tumor-supporting phenotypes and functions. This review highlights the current knowledge of the involvement of host-related factors, including innate and adaptive immunity in orchestrating the tumor cell fate and the primary resistance mechanisms to immunotherapy in NSCLC. Finally, we discuss combinational therapeutic strategies targeting different aspects of the tumor immune microenvironment (TIME) to prime the host response. Further research dissecting the characteristics and dynamic interactions within the interface host–tumor is necessary to improve a patient fitness immune response and provide answers regarding the immunotherapy efficacy, with the aim to develop more successful treatments for NSCLC.
A Novel Immune-Related Gene Signature to Identify the Tumor Microenvironment and Prognose Disease Among Patients With Oral Squamous Cell Carcinoma Patients Using ssGSEA: A Bioinformatics and Biological Validation Study
Authors: Chen Yun , Feng Yunzhi , Yan Fei , Zhao Yaqiong , Zhao Han , Guo Yue
Published: July 2022

Oral squamous cell carcinoma (OSCC) is the most invasive oral malignancy in adults and is associated with a poor prognosis. Accurate prognostic models are urgently needed, however, knowledge of the probable mechanisms behind OSCC tumorigenesis and prognosis remain limited. The clinical importance of the interplay between the immune system and tumor microenvironment has become increasingly evident. This study explored immune-related alterations at the multi-omics level to extract accurate prognostic markers linked to the immune response and presents a more accurate landscape of the immune genomic map during OSCC. The Cancer Genome Atlas (TCGA) OSCC cohort (n = 329) was used to detect the immune infiltration pattern of OSCC and categorize patients into two immunity groups using single-sample gene set enrichment analysis (ssGSEA) and hierarchical clustering analysis. Multiple strategies, including lasso regression (LASSO), Cox proportional hazards regression, and principal component analysis (PCA) were used to screen clinically significant signatures and identify an incorporated prognosis model with robust discriminative power on the survival status of both the training and testing set. We identified two OSCC subtypes based on immunological characteristics: Immunity-high and immunity low, and verified that the categorization was accurate and repeatable. Immunity_ high cluster with a higher immunological and stromal score. 1047 differential genes (DEGs) integrate with immune genes to obtain 319 immue-related DEGs. A robust model with five signatures for OSCC patient prognosis was established. The GEO cohort (n = 97) were used to validate the risk model’s predictive value. The low-risk group had a better overall survival (OS) than the high-risk group. Significant prognostic potential for OSCC patients was found using ROC analysis and immune checkpoint gene expression was lower in the low-risk group. We also investigated at the therapeutic sensitivity of a number of frequently used chemotherapeutic drugs in patients with various risk factors. The underlying biological behavior of the OSCC cell line was preliminarily validated. This study characterizes a reliable marker of OSCC disease progression and provides a new potential target for immunotherapy against this disease.
Selenium Deficiency Leads to Inflammation, Autophagy, Endoplasmic Reticulum Stress, Apoptosis and Contraction Abnormalities via Affecting Intestinal Flora in Intestinal Smooth Muscle of Mice
Authors: Wang Fuhan , Sun Ni , Zeng Hanqin , Gao Yuan , Zhang Naisheng , Zhang Wenlong
Published: July 2022

Selenium (Se) is a micronutrient that plays a predominant role in various physiological processes in humans and animals. Long-term lack of Se will lead to many metabolic diseases. Studies have found that chronic Se deficiency can cause chronic diarrhea. The gut flora is closely related to the health of the body. Changes in environmental factors can cause changes in the intestinal flora. Our study found that Se deficiency can disrupt intestinal flora. Through 16s high-throughput sequencing analysis of small intestinal contents of mice, we found that compared with CSe group, the abundance of Lactobacillus, Bifidobacterium, and Ileibacterium in the low selenium group was significantly increased, while Romboutsia abundance was significantly decreased. Histological analysis showed that compared with CSe group, the small intestine tissues of the LSe group had obvious pathological changes. We examined mRNA expression levels in the small intestine associated with inflammation, autophagy, endoplasmic reticulum stress, apoptosis, tight junctions, and smooth muscle contraction. The mRNA levels of NF-κB, IκB, p38, IL-1β, TNF-α, Beclin, ATG7, ATG5, LC3α, BaK, Pum, Caspase-3, RIP1, RIPK3, PERK, IRE1, elF2α, GRP78, CHOP2, ZO-1, ZO-2, Occludin, E-cadherin, CaM, MLC, MLCK, Rho, and RhoA in the LSe group were significantly increased. The mRNA levels of IL-10, p62 BcL-2 and BcL-w were significantly decreased in the LSe group compared with the CSe group. These results suggest that changes in the abundance of Lactobacillus, bifidobacterium, ileum, and Romboutsia may be associated with cellular inflammation, autophagy, endoplasmic reticulum stress, apoptosis, tight junction, and abnormal smooth muscle contraction. Intestinal flora may play an important role in chronic diarrhea caused by selenium deficiency.
Proprotein Convertases and the Complement System
Authors: Dobó József , Kocsis Andrea , Dani Ráhel , Gál Péter
Published: July 2022

Proteins destined for secretion - after removal of the signal sequence - often undergo further proteolytic processing by proprotein convertases (PCs). Prohormones are typically processed in the regulated secretory pathway, while most plasma proteins travel though the constitutive pathway. The complement system is a major proteolytic cascade in the blood, serving as a first line of defense against microbes and also contributing to the immune homeostasis. Several complement components, namely C3, C4, C5 and factor I (FI), are multi-chain proteins that are apparently processed by PCs intracellularly. Cleavage occurs at consecutive basic residues and probably also involves the action of carboxypeptidases. The most likely candidate for the intracellular processing of complement proteins is furin, however, because of the overlapping specificities of basic amino acid residue-specific proprotein convertases, other PCs might be involved. To our surprise, we have recently discovered that processing of another complement protein, mannan-binding lectin-associated serine protease-3 (MASP-3) occurs in the blood by PCSK6 (PACE4). A similar mechanism had been described for the membrane protease corin, which is also activated extracellularly by PCSK6. In this review we intend to point out that the proper functioning of the complement system intimately depends on the action of proprotein convertases. In addition to the non-enzymatic components (C3, C4, C5), two constitutively active complement proteases are directly activated by PCs either intracellularly (FI), or extracellularly (MASP-3), moreover indirectly, through the constitutive activation of pro-factor D by MASP-3, the activity of the alternative pathway also depends on a PC present in the blood.