bluuebunny/crossref_metadata_2025 huggingface dataset:
Wayfinding Tools for People With Visual Impairments in Real-World Settings: A Literature Review of Recent Studies
Authors: Parker Amy T. , Swobodzinski Martin , Wright Julie D. , Hansen Kyrsten , Morton Becky , Schaller Elizabeth
Published: October 2021

A review of 35 peer reviewed articles dated from 2016 to February, 2021 was conducted to identify and describe the types of wayfinding devices that people who are blind, visually impaired or deafblind use while navigating indoors and/or outdoors in dynamic travel contexts. Within this investigation, we discovered some characteristics of participants with visual impairments, routes traveled, and real-world environments that have been included in recent wayfinding research as well as information regarding the institutions, agencies, and funding sources that enable these investigations. Results showed that 33 out of the 35 studies which met inclusionary criteria integrated the use of smart device technology. Many of these devices were supplemented by bluetooth low-energy beacons, and other sensors with more recent studies integrating LIDAR scanning. Identified studies included scant information about participant’s visual acuities or etiologies with a few exceptions, which limits the usability of the findings for this highly heterogeneous population. Themes derived from this study are categorized around the individual traveler’s needs; the wayfinding technologies identified and their perceived efficacy; the contexts and routes for wayfinding tasks; and the institutional support offered for sustaining wayfinding research.
Sustainability of Developed Self-Regulation by Means of Formative Assessment Among Young Adolescents: A Longitudinal Study
Authors: Beekman Kelly , Joosten-Ten Brinke Desirée , Boshuizen Els
Published: October 2021

The present study examined the long-term impact of a formative assessment intervention in primary education on the development of students’ levels of self-regulation, motivation, and self-efficacy after their transition to secondary education. Participants in the study included 695 Dutch sixth graders from 17 schools. A longitudinal design with measurements on three time points was adopted. The first part of the study, consisting of a pretest, the intervention, and posttest, was conducted during the students’ last 7 months in primary education using two experimental conditions, with peer- and self-assessment, and a control condition. A follow-up took place 10 weeks later, after the summer break and at the commencement of the participants’ secondary education. Longitudinal multilevel analyses showed that the development of self-regulation and motivation is significantly positively associated with the formative self- and peer-assessment interventions and continues after the transition to secondary education. Results are discussed with regard to theoretical and practical consequences.
Clinical Characteristics and Management of Patients With McCune-Albright Syndrome With GH Excess and Precocious Puberty: A Case Series and Literature Review
Authors: Zhai Xiao , Duan Lian , Yao Yong , Xing Bing , Deng Kan , Wang Linjie , Feng Feng , Liang Zhiyong , You Hui , Yang Hongbo , Lu Lin , Chen Shi , Wang Renzhi , Pan Hui , Zhu Huijuan
Published: October 2021

Background

McCune-Albright syndrome is a rare disorder characterized by fibrous dysplasia, café au lait skin spots, and hyperfunctioning endocrinopathies. The coexistence of precocious puberty and growth hormone excess in McCune-Albright syndrome is rare. Both conditions can manifest as accelerated growth, and treatments can be more challenging for such patients. This study aimed to describe the clinical manifestations of combined GH excess and PP in the context of McCune-Albright syndrome and analyze the clinical features and treatments of these patients.

Method

Clinical data from 60 McCune-Albright syndrome patients from Peking Union Medical College Hospital were obtained. The demographic characteristics, growth hormone, insulin-like growth factor-1, prolactin, alkaline phosphatase, and sex hormone levels; growth velocity; and bone age data were obtained. The growth velocity Z-score, bone age over chronological age ratio, and predicted adult height Z-score were calculated before and after treatment. Published studies and case reports were systemically searched, and data on demographic, clinical, and biochemical characteristics and treatment outcomes were obtained.

Results

We reviewed seven patients among 60 McCune-Albright syndrome patients at Peking Union Medical College Hospital (5 female) and 39 patients (25 female) from the published literature. Six of the seven patients from Peking Union Medical College Hospital and half of the patients from the published studies were pediatric patients. These patients had increased growth velocity Z-scores and bone age over chronological age ratios. After good control of both conditions, the growth velocity Z-score and bone age over chronological age ratio decreased significantly, and the predicted adult height Z-score increased. The final heights and predicted adult height Z-scores were not impaired in patients with gigantism. All the patients had craniofacial fibrous dysplasia associated with optic and otologic complications.

Conclusion

McCune-Albright syndrome with growth hormone excess and precocious puberty is more common in girls. Patients have accelerated linear growth and advanced skeletal age, and early and good control of both conditions leads to a reduced growth velocity and stabilized bone age. The predicted adult and final heights are not negatively affected when growth hormone excess is diagnosed in pediatric patients.
Spatial Analysis of Incidence of Diagnosed Type 2 Diabetes Mellitus and Its Association With Obesity and Physical Inactivity
Authors: Wu Jinrong , Wang Yang , Xiao Xin , Shang Xianwen , He Mingguang , Zhang Lei
Published: October 2021

Objectives

To investigate the spatial distribution of 10-year incidence of diagnosed type 2 diabetes mellitus (T2DM) and its association with obesity and physical inactivity at a reginal level breakdown.

Methods

Demographic, behavioral, medical and pharmaceutical and diagnosed T2DM incidence data were collected from a cohort of 232,064 participants who were free of diabetes at enrolment in the 45 and Up Study, conducted in the state of New South Wales (NSW), Australia. We examined the geographical trend and correlation between obesity prevalence, physical inactivity rate and age-and-gender-adjusted cumulative incidence of T2DM, aggregated based on geographical regions.

Result

The T2DM incidence, prevalence of obesity and physical inactivity rate at baseline were 6.32%, 20.24%, and 18.7%, respectively. The spatial variation of T2DM incidence was significant (Moran’s I=0.52; p<0.01), with the lowest incidence of 2.76% in Richmond Valley-Coastal and the highest of 12.27% in Mount Druitt. T2DM incidence was significantly correlated with the prevalence of obesity (Spearman r=0.62, p<0.001), percentage of participants having five sessions of physical activities or less per week (r=0.79, p<0.001) and percentage of participants walked to work (r=-0.44, p<0.001). The geographical variations in obesity prevalence and physical inactivity rate resembled the geographical variation in the incidence of T2DM.

Conclusion

The spatial distribution of T2DM incidence is significantly associated with the geographical prevalence of obesity and physical inactivity rate. Regional campaigns advocating the importance of physical activities in response to the alarming T2DM epidemic should be promoted.
Emerging Roles of T Cells in the Pathogenesis of Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma
Authors: Hirsova Petra , Bamidele Adebowale O. , Wang Haiguang , Povero Davide , Revelo Xavier S.
Published: October 2021

Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. A significant proportion of patients with NAFLD develop a progressive inflammatory condition termed nonalcoholic steatohepatitis (NASH), which may eventually advance to cirrhosis and hepatocellular carcinoma (HCC). NASH is characterized by steatosis, hepatocyte ballooning, and lobular inflammation. Heightened immune cell infiltration is a hallmark of NASH, yet the mechanisms whereby hepatic inflammation occurs in NASH and how it contributes to disease initiation and progression remain incompletely understood. Emerging evidence indicates that intrahepatic T cell immune mechanisms play an integral role in the pathogenesis of NASH and its transition to HCC. In this review, we summarize the current knowledge regarding the T cell-mediated mechanisms of inflammation in NASH. We highlight recent preclinical and human studies implicating various subsets of conventional and innate-like T cells in the onset and progression of NASH and HCC. Finally, we discuss the potential therapeutic strategies targeting T cell-mediated responses for the treatment of NASH.
New Developments in Anterior Laryngeal Recording Technique During Neuromonitored Thyroid and Parathyroid Surgery
Authors: Liu Cheng-Hsin , Huang Tzu-Yen , Wu Che-Wei , Wang Jia Joanna , Wang Ling-Feng , Chan Leong-Perng , Dionigi Gianlorenzo , Chiang Feng-Yu , Tseng Hsin-Yi , Lin Yi-Chu
Published: October 2021

A recurrent laryngeal nerve (RLN) injury resulting in vocal fold paralysis and dysphonia remains a major source of morbidity after thyroid and parathyroid surgeries. Intraoperative neural monitoring (IONM) is increasingly accepted as an adjunct to the standard practice of visual RLN identification. Endotracheal tube (ET) surface recording electrode systems are now widely used for IONM; however, the major limitation of the clinical use of ET-based surface electrodes is the need to maintain constant contact between the electrodes and vocal folds during surgery to obtain a high-quality recording. An ET that is malpositioned during intubation or displaced during surgical manipulation can cause a false decrease or loss of electromyography (EMG) signal. Since it may be difficult to distinguish from an EMG change caused by a true RLN injury, a false loss or decrease in EMG signal may contribute to inappropriate surgical decision making. Therefore, researchers have investigated alternative electrode systems that circumvent common causes of poor accuracy in ET-based neuromonitoring. Recent experimental and clinical studies have confirmed the hypothesis that needle or adhesive surface recording electrodes attached to the thyroid cartilage (transcartilage and percutaneous recording) or attached to the overlying neck skin (transcutaneous recording) can provide functionality similar to that of ET-based electrodes, and these recording methods enable access to the EMG response of the vocalis muscle that originates from the inner surface of the thyroid cartilage. Studies also indicate that, during surgical manipulation of the trachea, transcartilage, percutaneous, and transcutaneous anterior laryngeal (AL) recording electrodes could be more stable than ET-based surface electrodes and could be equally accurate in depicting RLN stress during IONM. These findings show that these AL electrodes have potential applications in future designs of recording electrodes and support the use of IONM as a high-quality quantitative tool in thyroid and parathyroid surgery. This article reviews the major recent developments of newly emerging transcartilage, percutaneous, and transcutaneous AL recording techniques used in IONM and evaluates their contribution to improved voice outcomes in modern thyroid surgery.
A Holistic Study on the Effect of Annealing Temperature and Time on CH3NH3PbI3-Based Perovskite Solar Cell Characteristics
Authors: Ali Akhavan Kazemi Mohammad , Jamali Arash , Sauvage Frédéric
Published: October 2021

The time and annealing temperature for the film crystallization in perovskite solar cells (PSCs) is critical and is at the stake of device optimization. It governs the crystallization process, the film’s morphorlogy and texture and the level of non-radiative defects, which in whole control the power conversion efficiency (PCE). However, deciphering each of these parameters in the device cell characteristics remains not totally clear. In this work, we led a holistic study considering temperature and time for the MAPbI3 crystallization as a free parameter to study how the latter is impacting on the film’s characteristics and how the device figure of merit is affected. The results suggest that the crystallinity level of the grains plays an important role in the photo-current value whereas the morphology and PbI2 impurities resulting from the onset of thermal decomposition of MAPbI3 penalizes the cell photovoltage and the fill factor values. Based on this study, it is highlighted that flash high temperature annealing is beneficial to limit out-of-plane substrate grain boundaries, resulting in a device exhibiting 18.8% power conversion efficiency compared to 18.0% when more standard post-annealing procedure is employed.
Impact Investigation of Stator Seal Leakage on Aerodynamic Performance of Multistage Compressor
Authors: Wang Qi , Zhang Zhou , Hong Qingsong , Ren Lanxue
Published: October 2021

In this paper, a numerical model based on the mass flow rate of seal leakage is presented, and a 3D numerical method of a multistage axial compressor with good engineering practicability is established. Validation consists of modeling a nine-stage axial compressor in all operating rotation speeds and calculating results of the performance characteristic curves in good agreement with test data. Comparisons are made against different cases of seal leakage mass flow rate for analyzing the impact of increasing seal leakage on the aerodynamic performance of the multistage axial compressor. The results indicate that the performance of the nine-stage axial compressor is degenerated faster and faster with seal leakage increasing in all operating working points, and the degeneration of performance of this compressor can be evaluated by the relationships of main performance parameters with the mass flow rate of seal leakage. Comparisons of flow distribution in the compressor for different cases of seal leakage also show that stators located in front stages of the multistage axial compressor are affected more seriously by the increasing seal leakage, and it can be confirmed that relatively larger flow losses in front stages bring significant impact on the decay of aerodynamic performance of a multistage axial compressor.
Utilizing Metagenomic Data and Bioinformatic Tools for Elucidating Antibiotic Resistance Genes in Environment
Authors: Peng Zhangjie , Mao Yujie , Zhang Na , Zhang Lu , Wang Zhi , Han Maozhen
Published: October 2021

Antibiotics resistance genes (ARGs) are mainly caused by the extensive use and abuse of antibiotics and have become a global public health concern. Owing to the development of high-throughput sequencing, metagenomic sequencing has been widely applied to profile the composition of ARGs, investigate their distribution pattern, and track their sources in diverse environments. However, the lack of a detailed transmission mechanism of ARGs limits the management of its pollution. Hence, it’s essential to introduce how to utilize the metagenomic data to obtain an in-depth understanding of the distribution pattern and transmission of ARGs. This review provides an assessment of metagenomic data utilization in ARG studies and summarizes current bioinformatic tools and databases, including ARGs-OAP, ARG analyzer, DeepARG, CARD, and SARG, for profiling the composition of ARGs and tracking the source of ARGs. Several bioinformatic tools and databases were then benchmarked. Our results showed that although SARG is a good database, the application of two or more bioinformatic tools and databases could provide a comprehensive view of ARG profiles in diverse environmental samples. Finally, several perspectives were proposed for future studies to obtain an in-depth understanding of ARGs based on metagenomic data. Our review of the utilization of metagenomic data together with bioinformatic tools and databases in ARG studies could provide insights on exploring the profiles and transmission mechanism of ARG in different environments that mitigate the spread of ARGs and manage the ARGs pollution.
A Framework for Methodological Options to Assess Climatic and Anthropogenic Influences on Streamflow
Authors: Zhang Yu , Wu Xiufeng , Wu Shiqiang , Dai Jiangyu , Yu Lei , Xue Wanyun , Wang Fangfang , Gao Ang , Xue Chen
Published: October 2021

Climate change and human activities are having increasing impacts on the global water cycle, particularly on streamflow. Current methods for quantifying these impacts are numerous and have their merits and limitations. There is a lack of a guide to help researchers select one or more appropriate methods for attribution analysis. In this study, hydrological modeling, statistical analysis, and conceptual approaches were used jointly to develop a methodological options framework consisting of three modules, to guide researchers in selecting appropriate methods and assessing climatic and anthropogenic contributions to streamflow changes. To evaluate its effectiveness, a case study in the Upper Yangtze River Basin (UYRB) of China was conducted. The results suggest that the SWAT-based method is the best approach to quantify the influences of climate change and human activities on streamflow in the UYRB. The comprehensive assessment indicates that climate change is the dominant cause of streamflow changes in the UYRB, and the contribution of climate change, indirect human activities, and direct human activities to streamflow changes is about 7:1:2. The proposed framework is efficient and valuable in assisting researchers to find appropriate methods for attribution analysis of streamflow changes, which can help to understand the water cycle in changing environments.
Cross-Context Responses to Novelty in Rural and Urban Small Mammals
Authors: Mazza Valeria , Czyperreck Inken , Eccard Jana A. , Dammhahn Melanie
Published: October 2021

The Anthropocene is the era of urbanization. The accelerating expansion of cities occurs at the expense of natural reservoirs of biodiversity and presents animals with challenges for which their evolutionary past might not have prepared them. Cognitive and behavioral adjustments to novelty could promote animals’ persistence under these altered conditions. We investigated the structure of, and covariance between, different aspects of responses to novelty in rural and urban small mammals of two non-commensal rodent species. We ran replicated experiments testing responses to three novelty types (object, food, or space) of 47 individual common voles (Microtus arvalis) and 41 individual striped field mice (Apodemus agrarius). We found partial support for the hypothesis that responses to novelty are structured, clustering (i) speed of responses, (ii) intensity of responses, and (iii) responses to food into separate dimensions. Rural and urban small mammals did not differ in most responses to novelty, suggesting that urban habitats do not reduce neophobia in these species. Further studies investigating whether comparable response patters are found throughout different stages of colonization, and along synurbanization processes of different duration, will help illuminate the dynamics of animals’ cognitive adjustments to urban life.
Continuous Parameterization of Leaf Area Index and Phenological Phases Within Deciduous Forests Based on Temperature Measurements
Authors: Zolles Anita , Schueler Silvio , Gartner Karl , Scheifinger Gartner
Published: October 2021

The Leaf-Area-Index (LAI) is commonly used to characterize the plant canopy and is a fundamental indication of plant vitality and photosynthetic activity. The forest health status is not only vital for economical reasons, but also has a significant impact on global carbon sequestration. The LAI has a highly dynamic character among deciduous forests and is prone to significant seasonal fluctuations. Accurate continuous LAI measurements do provide valuable information on growth characteristics, but they require considerable measurement effort. In this study, we tested a novel method that would allow for continuous low-effort LAI parameterizations. For our study we used temperature measurements from 2011 to 2019 obtained at two meteorological stations: Station one is an open land station, station two is located inside a forest stand characterized by European beech (measurements were undertaken as part of the ICP Forests program), both are located in Klausen Leopoldsdorf (Austria). We chose the difference in daily maximum temperature between the two sites for our LAI parametrization (LAIpar) since the forest canopy has a significant impact on local radiation conditions. We were able to identify phenological events such as leaf unfolding, the end of leaf growth, and the beginning and end of defoliation by examining at the average course of the year for LAIpar. The resultant LAIpar values were compared to annual values derived from hemispheric photographs taken near the stand temperature sensor. For the years 2011–2017, we found a strong correlation of 0.93 between LAI measures and LAIpar, which dropped to 0.69 after adding the year 2018 and 0.32 after adding 2019. We further compared the phenological events obtained from LAIpar to phenological observations. The impact of forests on their site climate, according to our findings, can be utilized to identify phenological and growth characteristics. The proposed method, however, is not a replacement for conventional LAI measurements.
Role of Prohibitins in Aging and Therapeutic Potential Against Age-Related Diseases
Authors: Belser Misa , Walker David W.
Published: October 2021

A decline in mitochondrial function has long been associated with age-related health decline. Several lines of evidence suggest that interventions that stimulate mitochondrial autophagy (mitophagy) can slow aging and prolong healthy lifespan. Prohibitins (PHB1 and PHB2) assemble at the mitochondrial inner membrane and are critical for mitochondrial homeostasis. In addition, prohibitins (PHBs) have diverse roles in cell and organismal biology. Here, we will discuss the role of PHBs in mitophagy, oxidative phosphorylation, cellular senescence, and apoptosis. We will also discuss the role of PHBs in modulating lifespan. In addition, we will review the links between PHBs and diseases of aging. Finally, we will discuss the emerging concept that PHBs may represent an attractive therapeutic target to counteract aging and age-onset disease.
Identification of Immune-Related Risk Characteristics and Prognostic Value of Immunophenotyping in TNBC
Authors: Yi Jiarong , Shuang Zeyu , Zhong Wenjing , Wu Haoming , Feng Jikun , Zouxu Xiazi , Huang Xinjian , Li Siqi , Wang Xi
Published: October 2021

Background: Triple-negative breast cancer (TNBC) is not sensitive to targeted therapy with HER-2 monoclonal antibody and endocrine therapy due to lack of ER, PR, and HER-2 receptors. TNBC is a breast cancer subtype with the worst prognosis and the highest mortality rate compared with other subtypes.

Materials and Methods: Breast cancer-related data were retrieved from The Cancer Genome Atlas (TCGA) database, and 116 cases of triple-negative breast cancer were identified from the data. GSE31519 dataset was retrieved from Gene Expression Omnibus (GEO) database, comprising a total of 68 cases with TNBC. Survival analysis was performed based on immune score, infiltration score and mutation score to explore differences in prognosis of different immune types. Analysis of differentially expressed genes was conducted and GSEA analysis based on these genes was conducted to explore the potential mechanism.

Results: The findings showed that comprehensive immune typing is highly effective and accurate in assessing prognosis of TNBC patients. Analysis showed that MMP9, CXCL9, CXCL10, CXCL11 and CD7 are key genes that may affect immune typing of TNBC patients and play an important role in prediction of prognosis in TNBC patients.

Conclusion: The current study presents an evaluation system based on immunophenotyping, which provides a more accurate prognostic evaluation tool for TNBC patients. Differentially expressed genes can be targeted to improve treatment of TNBC.
Unraveling the Genetic Architecture of Two Complex, Stomata-Related Drought-Responsive Traits by High-Throughput Physiological Phenotyping and GWAS in Cowpea (Vigna. Unguiculata L. Walp)
Authors: Wu Xinyi , Sun Ting , Xu Wenzhao , Sun Yudong , Wang Baogen , Wang Ying , Li Yanwei , Wang Jian , Wu Xiaohua , Lu Zhongfu , Xu Pei , Li Guojing
Published: October 2021

Drought is one of the most devasting and frequent abiotic stresses in agriculture. While many morphological, biochemical and physiological indicators are being used to quantify plant drought responses, stomatal control, and hence the transpiration and photosynthesis regulation through it, is of particular importance in marking the plant capacity of balancing stress response and yield. Due to the difficulties in simultaneous, large-scale measurement of stomatal traits such as sensitivity and speed of stomatal closure under progressive soil drought, forward genetic mapping of these important behaviors has long been unavailable. The recent emerging phenomic technologies offer solutions to identify the water relations of whole plant and assay the stomatal regulation in a dynamic process at the population level. Here, we report high-throughput physiological phenotyping of water relations of 106 cowpea accessions under progressive drought stress, which, in combination of genome-wide association study (GWAS), enables genetic mapping of the complex, stomata-related drought responsive traits “critical soil water content” (θcri) and “slope of transpiration rate declining” (KTr). The 106 accessions showed large variations in θcri and KTr, indicating that they had broad spectrum of stomatal control in response to soil water deficit, which may confer them different levels of drought tolerance. Univariate GWAS identified six and fourteen significant SNPs associated with θcri and KTr, respectively. The detected SNPs distributed in nine chromosomes and accounted for 8.7–21% of the phenotypic variation, suggesting that both stomatal sensitivity to soil drought and the speed of stomatal closure to completion were controlled by multiple genes with moderate effects. Multivariate GWAS detected ten more significant SNPs in addition to confirming eight of the twenty SNPs as detected by univariate GWAS. Integrated, a final set of 30 significant SNPs associated with stomatal closure were reported. Taken together, our work, by combining phenomics and genetics, enables forward genetic mapping of the genetic architecture of stomatal traits related to drought tolerance, which not only provides a basis for molecular breeding of drought resistant cultivars of cowpea, but offers a new methodology to explore the genetic determinants of water budgeting in crops under stressful conditions in the phenomics era.
RNA Sequencing Reveals Phenylpropanoid Biosynthesis Genes and Transcription Factors for Hevea brasiliensis Reaction Wood Formation
Authors: Meng Xiangxu , Wang Yue , Li Jia , Jiao Nanbo , Zhang Xiujie , Zhang Yuanyuan , Chen Jinhui , Tu Zhihua
Published: October 2021

Given the importance of wood in many industrial applications, much research has focused on wood formation, especially lignin biosynthesis. However, the mechanisms governing the regulation of lignin biosynthesis in the rubber tree (Hevea brasiliensis) remain to be elucidated. Here, we gained insight into the mechanisms of rubber tree lignin biosynthesis using reaction wood (wood with abnormal tissue structure induced by gravity or artificial mechanical treatment) as an experimental model. We performed transcriptome analysis of rubber tree mature xylem from tension wood (TW), opposite wood (OW), and normal wood (NW) using RNA sequencing (RNA-seq). A total of 214, 1,280, and 32 differentially expressed genes (DEGs) were identified in TW vs. NW, OW vs. NW, and TW vs. OW, respectively. GO and KEGG enrichment analysis of DEGs from different comparison groups showed that zeatin biosynthesis, plant hormone signal transduction, phenylpropanoid biosynthesis, and plant–pathogen interaction pathways may play important roles in reaction wood formation. Sixteen transcripts involved in phenylpropanoid biosynthesis and 129 transcripts encoding transcription factors (TFs) were used to construct a TF–gene regulatory network for rubber tree lignin biosynthesis. Among them, MYB, C2H2, and NAC TFs could regulate all the DEGs involved in phenylpropanoid biosynthesis. Overall, this study identified candidate genes and TFs likely involved in phenylpropanoid biosynthesis and provides novel insights into the mechanisms regulating rubber tree lignin biosynthesis.
singlecellVR: Interactive Visualization of Single-Cell Data in Virtual Reality
Authors: Stein David F. , Chen Huidong , Vinyard Michael E. , Qin Qian , Combs Rebecca D. , Zhang Qian , Pinello Luca
Published: October 2021

Single-cell assays have transformed our ability to model heterogeneity within cell populations. As these assays have advanced in their ability to measure various aspects of molecular processes in cells, computational methods to analyze and meaningfully visualize such data have required matched innovation. Independently, Virtual Reality (VR) has recently emerged as a powerful technology to dynamically explore complex data and shows promise for adaptation to challenges in single-cell data visualization. However, adopting VR for single-cell data visualization has thus far been hindered by expensive prerequisite hardware or advanced data preprocessing skills. To address current shortcomings, we present singlecellVR, a user-friendly web application for visualizing single-cell data, designed for cheap and easily available virtual reality hardware (e.g., Google Cardboard, ∼$8). singlecellVR can visualize data from a variety of sequencing-based technologies including transcriptomic, epigenomic, and proteomic data as well as combinations thereof. Analysis modalities supported include approaches to clustering as well as trajectory inference and visualization of dynamical changes discovered through modelling RNA velocity. We provide a companion software package, scvr to streamline data conversion from the most widely-adopted single-cell analysis tools as well as a growing database of pre-analyzed datasets to which users can contribute.
Molecular Characterization of the Highest Risk Adult Patients With Acute Myeloid Leukemia (AML) Through Multi-Omics Clustering
Authors: Nguyen Trinh , Pepper John W , Nguyen Cu , Fan Yu , Hu Ying , Chen Qingrong , Yan Chunhua , Meerzaman Daoud
Published: October 2021

Background: Acute myeloid leukemia (AML) is a clinically heterogeneous group of cancers. While some patients respond well to chemotherapy, we describe here a subgroup with distinct molecular features that has very poor prognosis under chemotherapy. The classification of AML relies substantially on cytogenetics, but most cytogenetic abnormalities do not offer targets for development of targeted therapeutics. Therefore, it is important to create a detailed molecular characterization of the subgroup most in need of new targeted therapeutics.

Methods: We used a multi-omics approach to identify a molecular subgroup with the worst response to chemotherapy, and to identify promising drug targets specifically for this AML subgroup.

Results: Multi-omics clustering analysis resulted in three primary clusters among 166 AML adult cancer cases in TCGA data. One of these clusters, which we label as the high-risk molecular subgroup (HRMS), consisted of cases that responded very poorly to standard chemotherapy, with only about 10% survival to 2 years. The gene TP53 was mutated in most cases in this subgroup but not in all of them. The top six genes over-expressed in the HRMS subgroup included E2F4, CD34, CD109, MN1, MMLT3, and CD200. Multi-omics pathway analysis using RNA and CNA expression data identified in the HRMS subgroup over-activated pathways related to immune function, cell proliferation, and DNA damage.

Conclusion: A distinct subgroup of AML patients are not successfully treated with chemotherapy, and urgently need targeted therapeutics based on the molecular features of this subgroup. Potential drug targets include over-expressed genes E2F4, and MN1, as well as mutations in TP53, and several over-activated molecular pathways.
Macrophage Selenoproteins Restrict Intracellular Replication of Francisella tularensis and Are Essential for Host Immunity
Authors: Markley Rachel L. , Restori Katherine H. , Katkere Bhuvana , Sumner Sarah E. , Nicol McKayla J. , Tyryshkina Anastasia , Nettleford Shaneice K. , Williamson David R. , Place David E. , Dewan Kalyan K. , Shay Ashley E. , Carlson Bradley A. , Girirajan Santhosh , Prabhu K. Sandeep , Kirimanjeswara Girish S.
Published: October 2021

The essential micronutrient Selenium (Se) is co-translationally incorporated as selenocysteine into proteins. Selenoproteins contain one or more selenocysteines and are vital for optimum immunity. Interestingly, many pathogenic bacteria utilize Se for various biological processes suggesting that Se may play a role in bacterial pathogenesis. A previous study had speculated that Francisella tularensis, a facultative intracellular bacterium and the causative agent of tularemia, sequesters Se by upregulating Se-metabolism genes in type II alveolar epithelial cells. Therefore, we investigated the contribution of host vs. pathogen-associated selenoproteins in bacterial disease using F. tularensis as a model organism. We found that F. tularensis was devoid of any Se utilization traits, neither incorporated elemental Se, nor exhibited Se-dependent growth. However, 100% of Se-deficient mice (0.01 ppm Se), which express low levels of selenoproteins, succumbed to F. tularensis-live vaccine strain pulmonary challenge, whereas 50% of mice on Se-supplemented (0.4 ppm Se) and 25% of mice on Se-adequate (0.1 ppm Se) diet succumbed to infection. Median survival time for Se-deficient mice was 8 days post-infection while Se-supplemented and -adequate mice was 11.5 and >14 days post-infection, respectively. Se-deficient macrophages permitted significantly higher intracellular bacterial replication than Se-supplemented macrophages ex vivo, corroborating in vivo observations. Since Francisella replicates in alveolar macrophages during the acute phase of pneumonic infection, we hypothesized that macrophage-specific host selenoproteins may restrict replication and systemic spread of bacteria. F. tularensis infection led to an increased expression of several macrophage selenoproteins, suggesting their key role in limiting bacterial replication. Upon challenge with F. tularensis, mice lacking selenoproteins in macrophages (TrspM) displayed lower survival and increased bacterial burden in the lung and systemic tissues in comparison to WT littermate controls. Furthermore, macrophages from TrspM mice were unable to restrict bacterial replication ex vivo in comparison to macrophages from littermate controls. We herein describe a novel function of host macrophage-specific selenoproteins in restriction of intracellular bacterial replication. These data suggest that host selenoproteins may be considered as novel targets for modulating immune response to control a bacterial infection.
Unraveling the Effects of a Talimogene Laherparepvec (T-VEC)-Induced Tumor Oncolysate on Myeloid Dendritic Cells
Authors: Tijtgat Jens , De Munck Jolien , Dufait Inès , Schwarze Julia Katharina , Van Riet Ivan , Franceschini Lorenzo , Breckpot Karine , Aerts Joeri L. , Neyns Bart , Tuyaerts Sandra
Published: October 2021

T-VEC, a HSV-1 derived oncolytic virus, is approved for the treatment of advanced melanoma. The mechanisms that underly the systemic anti-tumor effect that is seen following intratumoral injection have not yet been studied but are likely to be mediated by myeloid dendritic cells (myDC) that initiate an adaptive immune response. In this study we could demonstrate that T-VEC is non-toxic for human myDC. T-VEC and a T-VEC oncolysate of melanoma cell lines were able to mature human myDC. myDC were able to take up lysed melanoma cells and cross-present melanoma-derived tumor antigens to antigen-specific T cells. Our results support the possible role of myDC as mediators of an adaptive anti-tumor effect and intratumoral co-administration of T-VEC plus autologous myDC could be a complementary treatment option. A clinical trial that investigates this hypothesis is currently ongoing.
UnAIDed Class Switching in Activated B-Cells Reveals Intrinsic Features of a Self-Cleaving IgH Locus
Authors: Dalloul Iman , Laffleur Brice , Dalloul Zeinab , Wehbi Batoul , Jouan Florence , Brauge Baptiste , Derouault Paco , Moreau Jeanne , Kracker Sven , Fischer Alain , Durandy Anne , Le Noir Sandrine , Cogné Michel
Published: October 2021

Activation-induced deaminase (AID) is the major actor of immunoglobulin (Ig) gene diversification in germinal center B-cells. From its first description, it was considered as mandatory for class switch recombination (CSR), and this discovery initiated a long quest for all of the AID-interacting factors controlling its activity. The mechanisms focusing AID-mediated DNA lesions to given target sequences remain incompletely understood with regards the detailed characterization of optimal substrates in which cytidine deamination will lead to double strand breaks (DSBs) and chromosomal cleavage. In an effort to reconsider whether such CSR breaks absolutely require AID, we herein provide evidence, based on deep-sequencing approaches, showing that this dogma is not absolute in both human and mouse B lymphocytes. In activated B-cells from either AID-deficient mice or human AID-deficient patients, we report an intrinsic ability of the IgH locus to undergo “on-target” cleavage and subsequent synapsis of broken regions in conditions able to yield low-level CSR. DNA breaks occur in such conditions within the same repetitive S regions usually targeted by AID, but their repair follows a specific pathway with increased usage of microhomology-mediated repair. These data further demonstrate the role of AID machinery as not initiating de novo chromosomal cleavage but rather catalyzing a process which spontaneously initiates at low levels in an appropriately conformed IgH locus.
Regulatory T Cells in Pregnancy Adverse Outcomes: A Systematic Review and Meta-Analysis
Authors: Green Samantha , Politis Marina , Rallis Kathrine S. , Saenz de Villaverde Cortabarria Alba , Efthymiou Athina , Mureanu Nicoleta , Dalrymple Kathryn V. , Scottà Cristiano , Lombardi Giovanna , Tribe Rachel M. , Nicolaides Kypros H. , Shangaris Panicos
Published: October 2021

Background

Several studies report the role of Regulatory T-cells (Tregs) in the pathophysiology of pregnancy adverse outcomes.

Objective

The aim of this systematic review and meta-analysis was to determine whether there is an association between regulatory T cell levels and pregnancy adverse outcomes (PAOs), including pre-eclampsia and preterm birth (PTB).

Method

Literature searches were conducted in PubMed/MEDLINE, Embase, and Cochrane CENTRAL databases. Inclusion criteria were original articles (clinical trials, case-control studies and cohort studies) comparing Tregs, sampled from the decidua or maternal blood, in healthy pregnant women versus women with pre-eclampsia or PTB. The outcome was standardised mean difference (SMD) in Treg numbers. The tau-squared (Tau²), inconsistency index (I²), and chi-squared (χ²) test quantified heterogeneity among different studies. Analyses were performed in RevMan software V.5.4.0 for Mac using a random-effects model with outcome data reported with 95% confidence intervals (CI). This study was prospectively registered with PROSPERO (CRD42020205469). PRISMA guidelines were followed.

Results

From 4,085 unique studies identified, 36 were included in qualitative synthesis, and 34 were included in quantitative synthesis (meta-analysis). In total, there were 1,783 participants in these studies: healthy controls=964, pre-eclampsia=759, PTB=60. Thirty-two studies compared Tregs in healthy pregnant women and women with pre-eclampsia, and 30 of these sampled Tregs from peripheral blood showing significantly higher Treg numbers in healthy pregnancies (SMD; 1.46; 95% CI, 1.03–1.88; I²=92%). Four studies sampled Tregs from the maternal decidua showing higher Tregs in healthy pregnancies (SMD, 0.76; 95% CI, -0.13–1.65; I²=84%). No difference was found in the number of Tregs between early versus late pre-eclampsia (SMD,-1.17; 95% CI, -2.79–0.44; I²=94%). For PTB, two studies compared Tregs sampled from the peripheral blood with a tendency for higher Tregs in healthy pregnancies but this did not reach significance (SMD, 2.18; 95% CI, -1.34–5.70; I²=96%). Subcohort analysis using Treg analysis (flow cytometry vs. qPCR vs. immunofluorescence tissue staining) showed similar associations.

Conclusion

Lower Tregs in pregnancy, sampled from the maternal peripheral blood, are associated with pre-eclampsia. There is a need for further studies to confirm a relationship between low Tregs and PTB. As the precise mechanisms by which Tregs may mediate pre-eclampsia and PTB remain unclear, further fundamental research is necessary to elucidate the underlying processes and highlight the causative link.

Systematic Review Registration

PROSPERO, identifier CRD42020205469.
Type I Interferons Are Involved in the Intracellular Growth Control of Mycobacterium abscessus by Mediating NOD2-Induced Production of Nitric Oxide in Macrophages
Authors: Ahn Jae-Hun , Park Ji-Yeon , Kim Dong-Yeon , Lee Tae-Sung , Jung Do-Hyeon , Kim Yeong-Jun , Lee Yeon-Ji , Lee Yun-Ji , Seo In-Su , Song Eun-Jung , Jang Ah-Ra , Yang Soo-Jin , Shin Sung Jae , Park Jong-Hwan
Published: October 2021

Mycobacterium abscessus(MAB) is one of the rapidly growing, multidrug-resistant non-tuberculous mycobacteria (NTM) causing various diseases including pulmonary disorder. Although it has been known that type I interferons (IFNs) contribute to host defense against bacterial infections, the role of type I IFNs against MAB infection is still unclear. In the present study, we show that rIFN-β treatment reduced the intracellular growth of MAB in macrophages. Deficiency of IFN-α/β receptor (IFNAR) led to the reduction of nitric oxide (NO) production in MAB-infected macrophages. Consistently, rIFN-β treatment enhanced the expression of iNOS gene and protein, and NO production in response to MAB. We also found that NO is essential for the intracellular growth control of MAB within macrophages in an inhibitor assay using iNOS-deficient cells. In addition, pretreatment of rIFN-β before MAB infection in mice increased production of NO in the lungs at day 1 after infection and promoted the bacterial clearance at day 5. However, when alveolar macrophages were depleted by treatment of clodronate liposome, rIFN-β did not promote the bacterial clearance in the lungs. Moreover, we found that a cytosolic receptor nucleotide-binding oligomerization domain 2 (NOD2) is required for MAB-induced TANK binding kinase 1 (TBK1) phosphorylation and IFN-β gene expression in macrophages. Finally, increase in the bacterial loads caused by reduction of NO levels was reversed by rIFN-β treatment in the lungs of NOD2-deficient mice. Collectively, our findings suggest that type I IFNs act as an intermediator of NOD2-induced NO production in macrophages and thus contribute to host defense against MAB infection.
The Use of Induced Pluripotent Stem Cells to Study the Effects of Adenosine Deaminase Deficiency on Human Neutrophil Development
Authors: Tsui Michael , Min Weixian , Ng Stephanie , Dobbs Kerry , Notarangelo Luigi D. , Dror Yigal , Grunebaum Eyal
Published: October 2021

Inherited defects that abrogate the function of the adenosine deaminase (ADA) enzyme and consequently lead to the accumulation of toxic purine metabolites cause profound lymphopenia and severe combined immune deficiency. Additionally, neutropenia and impaired neutrophil function have been reported among ADA-deficient patients. However, due to the rarity of the disorder, the neutrophil developmental abnormalities and the mechanisms contributing to them have not been characterized. Induced pluripotent stem cells (iPSC) generated from two unrelated ADA-deficient patients and from healthy controls were differentiated through embryoid bodies into neutrophils. ADA deficiency led to a significant reduction in the number of all early multipotent hematopoietic progenitors. At later stages of differentiation, ADA deficiency impeded the formation of granulocyte colonies in methylcellulose cultures, leading to a significant decrease in the number of neutrophils generated from ADA-deficient iPSCs. The viability and apoptosis of ADA-deficient neutrophils isolated from methylcellulose cultures were unaffected, suggesting that the abnormal purine homeostasis in this condition interferes with differentiation or proliferation. Additionally, there was a significant increase in the percentage of hyperlobular ADA-deficient neutrophils, and these neutrophils demonstrated significantly reduced ability to phagocytize fluorescent microspheres. Supplementing iPSCs and methylcellulose cultures with exogenous ADA, which can correct adenosine metabolism, reversed all abnormalities, cementing the critical role of ADA in neutrophil development. Moreover, chemical inhibition of the ribonucleotide reductase (RNR) enzyme, using hydroxyurea or a combination of nicotinamide and trichostatin A in iPSCs from healthy controls, led to abnormal neutrophil differentiation similar to that observed in ADA deficiency, implicating RNR inhibition as a potential mechanism for the neutrophil abnormalities. In conclusion, the findings presented here demonstrate the important role of ADA in the development and function of neutrophils while clarifying the mechanisms responsible for the neutrophil abnormalities in ADA-deficient patients.
Slit2-Mediated Metabolic Reprogramming in Bone Marrow-Derived Macrophages Enhances Antitumor Immunity
Authors: Kaul Kirti , Benej Martin , Mishra Sanjay , Ahirwar Dinesh K. , Yadav Marshleen , Stanford Kristin I. , Jacob Naduparambil K. , Denko Nicholas C. , Ganju Ramesh K.
Published: October 2021

Slit2 exerts antitumor effects in various cancers; however, the underlying mechanism, especially its role in regulating the immune, especially in the bone marrow niche, system is still unknown. Elucidating the behavior of macrophages in tumor progression can potentially improve immunotherapy. Using a spontaneous mammary tumor virus promoter-polyoma middle T antigen (PyMT) breast cancer mouse model, we observed that Slit2 increased the abundance of antitumor M1 macrophage in the bone marrow upon differentiation in vitro. Moreover, myeloablated PyMT mice injected with Slit2-treated bone marrow allografts showed a marked reduction in tumor growth, with enhanced recruitment of M1 macrophage in their tumor stroma. Mechanistic studies revealed that Slit2 significantly enhanced glycolysis and reduced fatty acid oxidation in bone marrow-derived macrophages (BMDMs). Slit2 treatment also altered mitochondrial respiration metabolites in macrophages isolated from healthy human blood that were treated with plasma from breast cancer patients. Overall, this study, for the first time, shows that Slit2 increases BMDM polarization toward antitumor phenotype by modulating immune-metabolism. Furthermore, this study provides evidence that soluble Slit2 could be developed as novel therapeutic strategy to enhance antitumor immune response.