bluuebunny/crossref_metadata_2025 huggingface dataset:
Efecto de la aspersión aérea de cultivos de hoja de coca en el trabajo infantil, la asistencia a la escuela y el rezago escolar en Colombia, 2008-2012
Authors: Rodriguez Claudia
Published: April 2021

Desde 1999, una de las principales estrategias que ha usado el gobierno de Colombia para mitigar la siembra de hoja de coca es la aspersión aérea. Este trabajo evalúa las consecuencias de dicha estrategia dentro del hogar campesino, específicamente el efecto que la aspersión aérea tiene sobre el trabajo infantil y la educación de los niños. Dado que las zonas donde se asperja son diferentes a aquellas en donde no de manera sistemática, se usa un modelo de mínimos cuadrados en dos etapas instrumentando la erradicación aérea con fuertes vientos que dificultaban la aspersión. Esto corrige posibles fuentes de endogeneidad derivadas del sesgo de selección. Los resultados muestran que la aspersión aérea se relaciona con un aumento de un punto porcentual en la probabilidad de trabajar para niños entre 12 y 17 años. Además, la aspersión de cultivos está asociada con un aumento de 0.15 puntos porcentuales en la probabilidad de que los hermanos mayores estén rezagados y de 5 puntos porcentuales en la probabilidad de que los niños dejen de estudiar. Así, los hallazgos de esta investigación sugieren que la guerra contra las drogas, vía aspersión aérea, tiene el potencial para generar nuevas barreras de acceso a la educación.
Association Between Finger-to-Nose Kinematics and Upper Extremity Motor Function in Subacute Stroke: A Principal Component Analysis
Authors: Chen Ze-Jian , He Chang , Xia Nan , Gu Ming-Hui , Li Yang-An , Xiong Cai-Hua , Xu Jiang , Huang Xiao-Lin
Published: April 2021

Background

Kinematic analysis facilitates interpreting the extent and mechanisms of motor restoration after stroke. This study was aimed to explore the kinematic components of finger-to-nose test obtained from principal component analysis (PCA) and the associations with upper extremity (UE) motor function in subacute stroke survivors.

Methods

Thirty-seven individuals with subacute stroke and twenty healthy adults participated in the study. Six kinematic metrics during finger-to-nose task (FNT) were utilized to perform PCA. Clinical assessments for stroke participants included the Fugl-Meyer Assessment for Upper Extremity (FMA-UE), Action Research Arm Test (ARAT), and Modified Barthel Index (MBI).

Results

Three principal components (PC) accounting for 91.3% variance were included in multivariable regression models. PC1 (48.8%) was dominated by mean velocity, peak velocity, number of movement units (NMU) and normalized integrated jerk (NIJ). PC2 (31.1%) described percentage of time to peak velocity and movement time. PC3 (11.4%) profiled percentage of time to peak velocity. The variance explained by principal component regression in FMA-UE (R2 = 0.71) were higher than ARAT (R2 = 0.59) and MBI (R2 = 0.29) for stroke individuals.

Conclusion

Kinematic components during finger-to-nose test identified by PCA are associated with UE motor function in subacute stroke. PCA reveals the intrinsic association among kinematic metrics, which may add value to UE assessment and future intervention targeted for kinematic components for stroke individuals.

Clinical Trial Registration

Chinese Clinical Trial Registry (http://www.chictr.org.cn/) on 17 October 2019, identifier: ChiCTR1900026656.
Novel circGFRα1 Promotes Self-Renewal of Female Germline Stem Cells Mediated by m6A Writer METTL14
Authors: Li Xiaoyong , Tian Geng , Wu Ji
Published: April 2021

Circular RNAs (circRNAs) play important roles in the self-renewal of stem cells. However, their significance and regulatory mechanisms in female germline stem cells (FGSCs) are largely unknown. Here, we identified anN6-methyladenosine (m6A)-modified circRNA, circGFRα1, which is highly abundant in mouse ovary and stage-specifically expressed in mouse FGSC development. Knockdown of circGFRα1 in FGSCs significantly reduced their self-renewal. In contrast, overexpression of circGFRα1 enhanced FGSC self-renewal. Mechanistically, circGFRα1 promotes FGSC self-renewal by acting as a competing endogenous RNA (ceRNA) that sponges miR-449, leading to enhanced GFRα1 expression and activation of the glial cell derived neurotrophic factor (GDNF) signaling pathway. Furthermore, circGFRα1 acts as a ceRNA based on METTL14-mediated cytoplasmic export through the GGACU motif. Our study should help to understand the mechanisms regulating germ cell development, add new evidence on the mechanism of action of circRNA, and deepen our understanding of the development of FGSCs.
Chronic Obstructive Pulmonary Disease and the Cardiovascular System: Vascular Repair and Regeneration as a Therapeutic Target
Authors: Karnati Srikanth , Seimetz Michael , Kleefeldt Florian , Sonawane Avinash , Madhusudhan Thati , Bachhuka Akash , Kosanovic Djuro , Weissmann Norbert , Krüger Karsten , Ergün Süleyman
Published: April 2021

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide and encompasses chronic bronchitis and emphysema. It has been shown that vascular wall remodeling and pulmonary hypertension (PH) can occur not only in patients with COPD but also in smokers with normal lung function, suggesting a causal role for vascular alterations in the development of emphysema. Mechanistically, abnormalities in the vasculature, such as inflammation, endothelial dysfunction, imbalances in cellular apoptosis/proliferation, and increased oxidative/nitrosative stress promote development of PH, cor pulmonale, and most probably pulmonary emphysema. Hypoxemia in the pulmonary chamber modulates the activation of key transcription factors and signaling cascades, which propagates inflammation and infiltration of neutrophils, resulting in vascular remodeling. Endothelial progenitor cells have angiogenesis capabilities, resulting in transdifferentiation of the smooth muscle cellsviaaberrant activation of several cytokines, growth factors, and chemokines. The vascular endothelium influences the balance between vaso-constriction and -dilation in the heart. Targeting key players affecting the vasculature might help in the development of new treatment strategies for both PH and COPD. The present review aims to summarize current knowledge about vascular alterations and production of reactive oxygen species in COPD. The present review emphasizes on the importance of the vasculature for the usually parenchyma-focused view of the pathobiology of COPD.
The Role of School Principals in Promoting Inclusive Schools: A Teachers’ Perspective
Authors: Khaleel Nida , Alhosani Mohamed , Duyar Ibrahim
Published: April 2021

After the enactment and implementation of a series of inclusive education policies in the United Arab Emirates (UAE) and worldwide, a number of challenges have hindered the effective implementation of these policies. The current study investigated the conditions of inclusive schools in the context of the UAE and focused on examining the role of school principals in promoting inclusive schools in the city of Al Ain, UAE. A qualitative research design was employed using a phenomenological approach. A semi-structured interview protocol was used to gather data from the participants. A total of 10 special education and general education teachers, five from public schools and five from private schools, participated in the study. The qualitative data was then refined and analyzed using thematic analysis. The findings demonstrated the key role of principals in creating and promoting inclusive schools when considering the factors that affect the inclusion of students of determination (SODs), referring to students with special needs, and when implementing effective inclusive practices in schools. Principals’ awareness of inclusive education emerged as a significant factor in creating and promoting inclusive schools. These findings shed light on conditions that could promote inclusive schools in the UAE context and increase policymakers’ and practitioners’ in acknowledging the key role played by principals in the effective implementation of inclusive schools. The study recommended a systematic provision of professional development, targeting the enhancement and improvement of principals’ awareness of inclusive education and schools.
Leveraging the Crisis for Equity and Access in the Long Term: A Brief Research Report
Authors: Virella Patricia Marisol , Cobb Casey
Published: April 2021

For years, crises have occurred in and out of schools. School leaders have had to make meaning of these crises and lead during them. Common rhetoric in today’s media describes the educational inequities children have faced as a result of the current crisis, the COVID-19 pandemic. In an effort to understand how school leaders respond to the COVID-19 pandemic, we spoke directly to principals, listening for ways in which they confronted issues of inequity. Our research was guided by the question: How do principals advance equity for students and families while leading during the COVID-19 crisis? This study focuses on the opportunity’s principals have created during the COVID-19 pandemic to address issues of equity in their schools. We present three main findings resulting from our data analysis. Overall, our findings indicate principals acted upon two primary opportunities for achieving equity in their school community. The findings from our study illustrate two specific opportunities principals were presented with as a result of the crisis to engage in equity responses.
Responses to COVID-19 From Non-State School Leaders in Latin America, Sub-Saharan Africa and, India: A Call for Educational Equity
Authors: Cordeiro Paula A. , Gluckman Maxie , Johnson Andy
Published: April 2021

In early 2020, the rapid spread of the COVID-19 pandemic was an unprecedented shock to the global education system, resulting in most educational institutions closing their doors and turning to various forms of remote learning to ensure continuous education for their communities. Since the world has not experienced this scale of school closure before, the goal of this study was to explore what, if anything, non-state schools (NNSs) were doing to support remote learning that may help them to prepare for future events that curtail education. In May 2020, Edify, an international non-governmental organization (INGO) operating in eleven nations in Latin America (LATAM), Sub-Saharan Africa and India conducted a telephone survey with a stratified random sample of 388 school leaders. Since the extent learning had continued across contexts was relatively unknown, the survey aimed to inform the organization's current and future responses to the COVID-19 pandemic and potential future educational interruptions. In addition to identifying the various uses of technology and possible innovations as to how non-state schools can respond when a crisis impacts their operating status, this paper describes three areas of concern expressed by the school leaders: (1) the health and safety of children and adults in their schools; (2) the various challenges of maintaining financial sustainability; and (3) the learning loss of students from the lack of preparedness for such a massive interruption in their school's normal operations.
Explicating the Value of Standardized Educational Achievement Data and a Protocol for Collaborative Analysis of This Data
Authors: Cowie Bronwen , Edwards Frances , Trask Suzanne
Published: April 2021

Governments expect teachers to be able to make sense of and take action on data at various levels of aggregation. In our research we collaborated with 13 teachers from six primary schools and one intermediate school to use a Data Conversation Protocol to analyze and act on mathematics assessment data generated through a standardized assessment tool—the Progressive Achievement Test (PAT). Our intention was to optimize teacher use of this data for pedagogical decision making and action. At team meetings, the teachers co-constructed then refined a taken-as-shared definition for teacher data literacy for instructional action, which acted to inform and anchor our collaborative research. Data were collected in all teacher meetings and via interviews. Initial findings indicate that a ‘Data Conversation Protocol’ is helping teachers to slow down the process of considering, interpreting and making a judgement about their students’ understanding thereby opening up a space for deeper consideration of the range of possible reasons for student responses to assessment items. Students responded positively to teachers’ data informed small group teaching, gaining in understanding and confidence. Teachers considered this confidence translated to more positive engagement with mathematical ideas. Patterns and trends in student responses emerging from the teachers’ collaborative analysis of standard data supported a shift from viewing student responses as linked to student or school characteristics to critical analysis of how their teaching approaches might have contributed to student answers/misunderstandings. This finding has implications for how we might challenge assumptions about students through a willingness to engage critically with student achievement data. The importance of teachers having a rich pedagogical content knowledge as a basis for this was clearly evident.
Supporting Flipped and Gamified Learning With Augmented Reality in Higher Education
Authors: Lu Angel , Wong Crusher S. K. , Cheung Richard Y. H. , Im Tarloff S. W.
Published: April 2021

Chemistry education is challenging when many students cannot see the relevance and interest between what they learn at school and their everyday life outside the curriculum. Due to the prevalence of chemicals in real life, students lose interest in those not-so-novel Chemistry problems as they are satisfied with their rudimentary grasp of knowledge. Therefore, it is of paramount importance to draw students’ attention to those day-to-day Chemistry concepts, a task in which augmented reality (AR) can be a competent pedagogical facilitator. Despite its popularity due to the development of smart devices, educators are still averse to adopting AR in teaching because of the doubts about its pedagogical effectiveness and difficulties in implementation. This paper will demonstrate an AR app developed by City University of Hong Kong (CityU) for a year four undergraduate Chemistry course under two UGC’s project funds and CityU’s Teaching Development Grant that aligns with the university’s Discovery and Innovation-enriched Curriculum. The learning theories and technology stack of development and deployment will be shared in this paper. The consideration during preparation, production, and publishing will also be documented. A pilot survey about students’ perception of the AR showed positive feedback for the AR app in terms of enhancing awareness, learning, understanding, and engagement, which addresses the concerns of retaining students’ engagement during teaching and learning real-life Chemistry. We hope that educators who are interested in adopting AR can gain insights from this AR development experience. This research can act as a foundation for further exploration of applying AR in secondary and tertiary Chemistry education.
Real-Time Dispatching Performance Improvement of Multiple Multi-Energy Supply Microgrids Using Neural Network Based Approximate Dynamic Programming
Authors: Li Bei , Roche Robin
Published: April 2021

In the multi-energy supply microgrid, different types of energy can be scheduled from a “global” view, which can improve the energy utilization efficiency. In addition, hydrogen storage system performs as the long-term storage is considered, which can promote more renewable energy installed in the local consumer side. However, when there are large numbers of grid-connected multi-energy microgrids, the scheduling of these multiple microgrids in real-time is a problem. Because different types of devices, three types of energy, and three types of utility grid networks are considered, which make the dispatching problem difficult. In this paper, a two-stage coordinated algorithm is adopted to operate the microgrids: day-ahead scheduling and real-time dispatching. In order to reduce the time taken to solve the scheduling problem, and improve the scheduling performance, approximate dynamic programming (ADP) is used in real-time operation. Different types of value function approximations (VFA), i.e., linear function, nonlinear function, and neural network are compared to study about the influence of the VFA on the decision results. Offline and online processes are developed to study the impact of the historical data on the regression of VFA. The results show that the neural network based ADP one-step decision algorithm has almost the same performance as the Global optimization algorithm, and the highest performance among all others Local optimization algorithms. The total operation cost relative error is less than 3%, while the running time is only 31% of the Global algorithm. In the neural network based ADP, the key technology is continuously updating the training dataset online, and adopting an appropriate neural network structure, which can at last improve the scheduling performance.
Identification and In Vitro Functional Verification of Two Novel Mutations of GHR Gene in the Chinese Children with Laron Syndrome
Authors: Li Ran , Gong Fengying , Pan Hui , Liang Hanting , Miao Hui , Zhao Yuxing , Duan Lian , Yang Hongbo , Wang Linjie , Chen Shi , Zhu Huijuan
Published: April 2021

Purpose

Laron syndrome (LS) is a severe growth disorder caused byGHRgene mutation or post-receptor pathways defect. The clinical features of these patients collected in our present study were summarized,GHRgene variants were investigated and furtherin vitrofunctional verification was carried out.

Methods

Four patients with LS were collected, their clinical characteristics were summarized, genomic DNA was extracted, andGHRgene was amplified and sequenced. GHR wild type (GHR-WT) and mutant GHR expression plasmids were constructed, and transiently transfected into HepG2 cells and HEK293T cells to observe the subcellular distribution of the GHR protein by immunofluorescence and to determine the expression of GHR and its post-receptor signaling pathway changes by Western blotting.

Results

All of the four patients were male, and the median height was -4.72 SDS. FourGHRgene variants including c.587A>C (p.Y196S), c.766C>T (p.Q256*), c.808A>G (p.I270V) and c.1707-1710del (p.E570Afs*30) were identified, and the latter two were novel mutations. The results of mutant GHR plasmids transfection experiments and immunofluorescence assay showed that the subcellular distribution of GHR-Q256* and GHR-E570Afs*30 mutant proteins in HepG2 and HEK293T cells presented with a unique ring-like pattern, gathering around the nucleus, while GHR-Y196S mutant protein was evenly distributed on HepG2 cell membrane similar to GHR-WT. The GHR protein levels of HepG2 cells transiently transfected with GHR-Y196S, GHR-Q256* and GHR-E570Afs*30 were all significantly lower when compared with cells transfected with GHR-WT (P<0.05). Further mutant GHR post-receptor signal transduction investigation demonstrated that GH induced phosphorylated STAT5 levels of HepG2 cells transfected with three mutant plasmids were all significantly decreased in comparison with that of GHR-WT (P<0.05).

Conclusions

Two novelGHRgene mutations (I270V and E570Afs*30) were found in our patients with LS. GHR mutations influenced the subcellular distribution and GHR protein levels, then led to the impaired post-receptor signal transduction, suggesting that theGHRmutations contributed to the pathological condition of LS patients.
Glycated Hemoglobin (HbA1c) Concentrations Among Children and Adolescents With Diabetes in Middle- and Low-Income Countries, 2010–2019: A Retrospective Chart Review and Systematic Review of Literature
Authors: Chen Xiuli , Pei Zhou , Zhang Miaoying , Xu Zhenran , Zhao Zhuhui , Lu Wei , Chen Linqi , Luo Feihong , Chen Ting , Sun Chengjun
Published: April 2021

Objectives

To explore the glycemic control [represented by glycated hemoglobin (HbA1c) concentrations] in children with diabetes mellitus (DM) in east China and middle- and low-income countries, from 2010 to 2019.

Methods

Retrospective data of children with DM from two hospital-based health records were reviewed. Data on HbA1c concentrations, hospitalization due to diabetic ketoacidosis, and patient demographics were collected and analyzed. A systematic review was subsequently performed to analyze publications that report HbA1c concentrations in patients aged <18 years. Patients’ characteristics extracted from each publication were used to generate simulated individual data for pooled analysis. HbA1c estimates were derived from steady-state iterations.

Results

Data of 843 diabetic children (aged 11.2 ± 3.9 years) with 2,658 HbA1c measures were retrieved from the two hospitals during the period 2010–2020. The duration of diabetes in the patients was 4.4 ± 2.8 years, and their HbA1c was 8.1 ± 2.2%. Patients who were internal migrants had significantly higher HbA1c concentration than resident patients (8.4 vs. 7.9%). The literature review yielded 1,164 publications, and the majority (74.1%) of patient data were published in high-income countries. The patient data extracted from these publications generated 486,416 HbA1c concentration estimates between 2005 and 2019. The average HbA1c concentration during the 15 years was 9.07 ± 2.15%. The mean HbA1c concentrations among children were 8.23, 8.73, 9.20, and 10.11% in high-income country (HIC), upper-middle income country (UMIC), lower-middle income country (LMIC), and low-income country (LIC) respectively. The mean rate of optimized glycemic control (HbA1c <7.5%) among children was 32.4, 27.5, 21.7, and 12.7% in HIC, UMIC, LMIC, and LIC, respectively.

Conclusions

The current study indicated that there is substantial room for improvement in glycemic control in children with DM worldwide, especially in middle- and low-income countries.
Islet-Resident Dendritic Cells and Macrophages in Type 1 Diabetes: In Search of Bigfoot’s Print
Authors: Zirpel Henner , Roep Bart O.
Published: April 2021

The classical view of type 1 diabetes assumes that the autoimmune mediated targeting of insulin producing ß-cells is caused by an error of the immune system. Malfunction and stress of beta cells added the target tissue at the center of action. The innate immune system, and in particular islet-resident cells of the myeloid lineage, could function as a link between stressed ß-cells and activation and recognition by the adaptive immune system. We survey the role of islet-resident macrophages and dendritic cells in healthy islet homeostasis and pathophysiology of T1D. Knowledge of islet-resident antigen presenting cells in rodents is substantial, but quite scarce in humans, in particular regarding dendritic cells. Differences in blood between healthy and diseased individuals were reported, but it remains elusive to what extend these contribute to T1D onset. Increasing our understanding of the interaction between ß-cells and innate immune cells may provide new insights into disease initiation and development that could ultimately point to future treatment options. Here we review current knowledge of islet-resident macrophages and dendritic cells, place these in context of current clinical trials, and guide future research.
Overstory Longleaf Pines and Hardwoods Create Diverse Patterns of Energy Release and Fire Effects During Prescribed Fire
Authors: Whelan Andrew W. , Bigelow Seth W. , O’Brien Joseph J.
Published: April 2021

Litter from pine trees in open woodlands is an important fuel for surface fires, but litter from hardwood species may quell fire behavior. Lower intensity fires favor hardwood over longleaf pine regeneration, and while overstory hardwoods are important sources of food and shelter for many wildlife species, too many could result in canopy closure and a loss of ground layer diversity. Although some researchers have found synergies in fire effects when leaves of different species are combined, field tests of effects of tree guild diversity on fire behavior are lacking from the literature. We used neighborhood modeling to understand how diverse overstory trees in longleaf pine forests affect fire radiative energy density (FRED), and to determine the effect on top-kill of shrub-form hardwood trees. We measured the effects of three guilds of overstory trees (longleaf pine, upland oaks, and mesic oaks) on FRED, and related FRED to post-fire damage in four guilds of understory hardwoods (sandhill oaks, upland oaks, mesic oaks, and fleshy-fruited hardwoods). We found that FRED increased 33–56% near overstory longleaf pine but decreased 23–37% near overstory mesic oaks. Additive models of FRED performed well and no synergies or antagonisms were present. Seventy percent of stems of understory hardwoods survived fire with energy release typical of dormant-season fires in canopy gaps and near overstory mesic oaks. We also found that among understory trees >2 m tall, upland and sandhill oaks were more likely than mesic oaks or fleshy-fruited hardwoods to avoid top-kill. We conclude that neighborhood models provide a method to predict longleaf pine forest structure and composition that allows for the ecological benefits of overstory hardwoods while maintaining ground-layer diversity. To maintain hardwood control, fire practitioners may need to select fire weather conditions to increase fire behavior especially during dormant-season burns.
Disorder of Sexual Development Males With XYY in Blood Have Exactly X/XY/XYY Mosaicism in Gonad Tissues
Authors: Yang Yongjia , Chen Fang , Luo Zhenqing , Zheng Yu , Zheng Jiayong , Fu Yuyan , Chen Weijian , Luo Haiyan
Published: April 2021

Y chromosome represents masculinization. The extra Y chromosome of XYY patients usually leads to over-masculinization phenotypes. The occurrence of several DSD cases with XYY in blood is controversial. Is XYY associated with disorder of sex development (DSD)? What is the mechanism behind DSD in males with XYY in blood? To this end, this study retrospectively analyzed blood-karyotype data of 4,437 DSD male children and karyotypes data of 6,259 newborn males as the control. Exome sequencing (ES) was performed to test whether the patients with DSD and with XYY in blood had other variants on known DSD-genes. Testicular biopsy was performed. Fluorescence in situ hybridization (FISH) was used to test whether a sex chromosome mosaicism was present in the oral epithelial cells or gonad tissue of patients with DSD and with XYY in blood. Among 4,437 DSD males who received cytogenetic evaluation, 14 patients with 47,XYY were identified. By contrast, five individuals among the 6,259 controls had 47,XYY. XYY in blood is more frequent among males with DSD than in other males (p = 0.004). The XYY karyotypes were confirmed again by GTG-banding in blood samples and by FISH performed on oral epithelial cells. ES on seven XYY DSD patients was successfully performed, but results did not identify any pathogenic variant on 55 known DSD genes. Gonad biopsy (n = 3) revealed testicular dysplasia and true hermaphroditism. FISH of gonad tissues (n = 3) showed that all of the samples had mosaic for X/XY/XYY. This study is the first to investigate the relationship between XYY in blood and DSD. The knowledge that XYY is in the blood and in oral cells have X/XY/XYY mosaicism in gonadal tissue is new for both researchers and clinicians who seek to understand the genetic basis of DSD males.
Increased Pentraxin 3 Levels Correlate With IVIG Responsiveness and Coronary Artery Aneurysm Formation in Kawasaki Disease
Authors: Kitoh Toshiyuki , Ohara Tsuyoshi , Muto Taichiro , Okumura Akihisa , Baba Reizo , Koizumi Yusuke , Yamagishi Yuka , Mikamo Hiroshige , Daigo Kenji , Hamakubo Takao
Published: April 2021

Kawasaki disease (KD) is a febrile disease of childhood characterized by systemic vasculitis that can lead to coronary artery lesions (CAL). This was a prospective cohort study to determine the levels of the pentraxin 3 (PTX3), soluble CD24-Subtype (Presepsin) and N-terminal pro-brain natriuretic peptide (NT-pro BNP) in consecutive KD patients. From January 2013 to March 2015, all patients with KD admitted to Aichi Medical University Hospital who provided consent had their plasma saved before IVIG administration. In total, 97 cases were registered. 22 cases of incomplete KD were excluded from the outcome analysis. The total 75 cases were used for statistical analyses. A PTX3 threshold of >7.92 ng/ml provided a specificity of 88.5 %, a sensitivity of 94.4 %, and a likelihood ratio as high as 15.92 for the diagnosis of KD compared with febrile non-KD controls. Although an echocardiographic diagnosis of CAL in the early course of the disease was confirmed in 24 cases, it was not in the remaining 51 cases. Neither NT-proBNP nor Presepsin had statistical significance for the prediction of the echocardiographic CAL diagnosis. Only PTX3 was significantly predictive of the echocardiographic CAL diagnosis (p=0.01). The PTX3 level was significantly higher in the intravenous immunoglobulin (IVIG) non-responders (45.9±7.45) than in the IVIG responders (17.0 ± 1.46 ng/ml) (p< 0.001). The PTX3 level also correlated with the number of IVIG treatment courses needed to resolve fever (R² =0.64). Persistent CAL (pCAL) formation was observed in three cases; one of aneurysm only and two aneurysms with dilatations. The patients with pCAL had significantly higher PTX3 levels (85 ± 8.4 ng/ml) than patients without pCAL (22 ± 2.2 ng/ml) (p< 0.0001). In terms of pCAL prediction, the area under the curve (AUC) of receiver operating characteristic ROC curve of PTX3 was 0.99, and it was significantly greater than that of Presepsin (0.67) or NT-proBNP (0.75). PTX3 is a soluble pattern recognition molecule that acts as a main component of the innate immune system. These data suggest that PTX3 can be utilized as a definitive biomarker for the prediction of IVIG resistance and subsequent CAL formation in patients with KD.
Virus Caused Imbalance of Type I IFN Responses and Inflammation in COVID-19
Authors: Zhang Jintao , Zhao Chunyuan , Zhao Wei
Published: April 2021

The global expansion of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as one of the greatest public health challenges and imposes a great threat to human health. Innate immunity plays vital roles in eliminating viruses through initiating type I interferons (IFNs)-dependent antiviral responses and inducing inflammation. Therefore, optimal activation of innate immunity and balanced type I IFN responses and inflammation are beneficial for efficient elimination of invading viruses. However, SARS-CoV-2 manipulates the host’s innate immune system by multiple mechanisms, leading to aberrant type I IFN responses and excessive inflammation. In this review, we will emphasize the recent advances in the understanding of the crosstalk between host innate immunity and SARS-CoV-2 to explain the imbalance between inflammation and type I IFN responses caused by viral infection, and explore potential therapeutic targets for COVID-19.
Anaplasmataceae: Dichotomous Autophagic Interplay for Infection
Authors: Patterson LaNisha L. , Byerly Caitlan D. , McBride Jere W.
Published: April 2021

Autophagy is a vital conserved degradative process that maintains cellular homeostasis by recycling or eliminating dysfunctional cellular organelles and proteins. More recently, autophagy has become a well-recognized host defense mechanism against intracellular pathogens through a process known as xenophagy. On the host-microbe battlefield many intracellular bacterial pathogens have developed the ability to subvert xenophagy to establish infection. Obligately intracellular bacterial pathogens of the Anaplasmataceae family, including Ehrlichia chaffeensis, Anaplasma phaogocytophilium and Orientia tsutsugamushi have developed a dichotomous strategy to exploit the host autophagic pathway to obtain nutrients while escaping lysosomal destruction for intracellular survival within the host cell. In this review, the recent findings regarding how these master manipulators engage and inhibit autophagy for infection are explored. Future investigation to understand mechanisms used by Anaplasmataceae to exploit autophagy may advance novel antimicrobial therapies and provide new insights into how intracellular microbes exploit autophagy to survive.
Human Milk Drives the Intimate Interplay Between Gut Immunity and Adipose Tissue for Healthy Growth
Authors: van den Elsen Lieke W. J. , Verhasselt Valerie
Published: April 2021

As the physiological food for the developing child, human milk is expected to be the diet that is best adapted for infant growth needs. There is also accumulating evidence that breastfeeding influences long-term metabolic outcomes. This review covers the potential mechanisms by which human milk could regulate healthy growth. We focus on how human milk may act on adipose tissue development and its metabolic homeostasis. We also explore how specific human milk components may influence the interplay between the gut microbiota, gut mucosa immunity and adipose tissue. A deeper understanding of these interactions may lead to new preventative and therapeutic strategies for both undernutrition and other metabolic diseases and deserves further exploration.
Microneme Proteins 1 and 4 From Toxoplasma gondii Induce IL-10 Production by Macrophages Through TLR4 Endocytosis
Authors: Ricci-Azevedo Rafael , Mendonça-Natividade Flavia Costa , Santana Ana Carolina , Alcoforado Diniz Juliana , Roque-Barreira Maria Cristina
Published: April 2021

The protozoan parasiteToxoplasma gondiimodulates host cell responses to favor its success in the early stage of infections by secreting proteins from its apical organelles. Some of these proteins, including microneme proteins (MICs) 1 and 4, trigger pro-inflammatory host cell responses. The lectins MIC1 and MIC4 interact with N-linked glycans on TLR2 and TLR4, activating NF-κB and producing IL-12, TNF-α, and IL-6. Interestingly, MIC1 and MIC4 also trigger secretion of the anti-inflammatory cytokine IL-10 through mechanisms as yet unknown. Herein, we show that the ability of these MICs to induce macrophages to produce IL-10 depends on TLR4 internalization from the cell surface. Macrophages subjected to blockade of endocytosis by Dynasore continued to release TNF-α, but failed to produce IL-10, in response to MIC1 or MIC4 exposure. Similarly, IL-10 was not produced by Dynasore-conditionedT. gondii-infected macrophages. Furthermore, MIC1- or MIC4-stimulated macrophages gained transient tolerance to LPS. We report a previously undiscovered mechanism by which well-definedT. gondiicomponents inhibit a host inflammatory response.
Latent Cytomegalovirus-Driven Recruitment of Activated CD4+ T Cells Promotes Virus Reactivation
Authors: Jackson Sarah E. , Chen Kevin C. , Groves Ian J. , Sedikides George X. , Gandhi Amar , Houldcroft Charlotte J. , Poole Emma L. , Montanuy Inmaculada , Mason Gavin M. , Okecha Georgina , Reeves Matthew B. , Sinclair John H. , Wills Mark R.
Published: April 2021

Human cytomegalovirus (HCMV) infection is not cleared by the initial immune response but persists for the lifetime of the host, in part due to its ability to establish a latent infection in cells of the myeloid lineage. HCMV has been shown to manipulate the secretion of cellular proteins during both lytic and latent infection; with changes caused by latent infection mainly investigated in CD34+ progenitor cells. Whilst CD34+ cells are generally bone marrow resident, their derivative CD14+ monocytes migrate to the periphery where they briefly circulate until extravasation into tissue sites. We have analyzed the effect of HCMV latent infection on the secretome of CD14+ monocytes, identifying an upregulation of both CCL8 and CXCL10 chemokines in the CD14+ latency-associated secretome. Unlike CD34+ cells, the CD14+ latency-associated secretome did not induce migration of resting immune cell subsets but did induce migration of activated NK and T cells expressing CXCR3 in a CXCL10 dependent manner. As reported in CD34+ latent infection, the CD14+ latency-associated secretome also suppressed the anti-viral activity of stimulated CD4+ T cells. Surprisingly, however, co-culture of activated autologous CD4+ T cells with latently infected monocytes resulted in reactivation of HCMV at levels comparable to those observed using M-CSF and IL-1β cytokines. We propose that these events represent a potential strategy to enable HCMV reactivation and local dissemination of the virus at peripheral tissue sites.
Triple-Negative Breast Cancer Cells Recruit Neutrophils by Secreting TGF-β and CXCR2 Ligands
Authors: SenGupta Shuvasree , Hein Lauren E. , Xu Yang , Zhang Jason , Konwerski Jamie R. , Li Ye , Johnson Craig , Cai Dawen , Smith Janet L. , Parent Carole A.
Published: April 2021

Tumor associated neutrophils (TANs) are frequently detected in triple-negative breast cancer (TNBC). Recent studies also reveal the importance of neutrophils in promoting tumor progression and metastasis during breast cancer. However, the mechanisms regulating neutrophil trafficking to breast tumors are less clear. We sought to determine whether neutrophil trafficking to breast tumors is determined directly by the malignant potential of cancer cells. We found that tumor conditioned media (TCM) harvested from highly aggressive, metastatic TNBC cells induced a polarized morphology and robust neutrophil migration, while TCM derived from poorly aggressive estrogen receptor positive (ER+) breast cancer cells had no activity. In a three-dimensional (3D) type-I collagen matrix, neutrophils migrated toward TCM from aggressive breast cancer cells with increased velocity and directionality. Moreover, in a neutrophil-tumor spheroid co-culture system, neutrophils migrated with increased directionality towards spheroids generated from TNBC cells compared to ER+ cells. Based on these findings, we next sought to characterize the active factors secreted by TNBC cell lines. We found that TCM-induced neutrophil migration is dependent on tumor-derived chemokines, and screening TCM elution fractions based on their ability to induce polarized neutrophil morphology revealed the molecular weight of the active factors to be around 12 kDa. TCM from TNBC cell lines contained copious amounts of GRO (CXCL1/2/3) chemokines and TGF-β cytokines compared to ER+ cell-derived TCM. TCM activity was inhibited by simultaneously blocking receptors specific to GRO chemokines and TGF-β, while the activity remained intact in the presence of either single receptor inhibitor. Together, our findings establish a direct link between the malignant potential of breast cancer cells and their ability to induce neutrophil migration. Our study also uncovers a novel coordinated function of TGF-β and GRO chemokines responsible for guiding neutrophil trafficking to the breast tumor.
Case Report: Resetting the Humoral Immune Response by Targeting Plasma Cells With Daratumumab in Anti-Phospholipid Syndrome
Authors: Pleguezuelo Daniel E. , Díaz-Simón Raquel , Cabrera-Marante Oscar , Lalueza Antonio , Paz-Artal Estela , Lumbreras Carlos , Serrano Hernández Antonio
Published: April 2021

Introduction

Monoclonal antibodies (mAb) targeting plasma cells are malignant gammopathy designed and approved therapies. In recent years, these antibodies have also been increasingly introduced for non-malignant conditions such as autoimmune-mediated diseases. The Anti-Phospholipid Syndrome (APS) is an immune-mediated disorder in which autoantibodies against phospholipid associated proteins could elicit the activation of the coagulation cascade in specific situations. Therefore, the mainstream treatment for APS patients is the use of anticoagulant therapy. However, there are refractory patients who would benefit from targeting the antibodies rather than their effects. Rituximab, a B-cell depleting mAb, and intravenous immunoglobulins (IVIG) have been used in APS patients without showing a clear beneficial effect or a significant drop in anti-phospholipid antibody (aPL) levels.

Clinical case

We present our first APS case treated with daratumumab, an anti-CD38 mAb, in a 21-year-old patient with APS who presented with recurrent venous thromboembolic events despite adequate anticoagulant therapy. She tested positive for lupus anticoagulant, anti-cardiolipin IgG, anti-beta-2-glycoprotein-I IgG and anti-phosphatidylserine/prothrombin IgG and IgM. She was administered one dose weekly of daratumumab for 4 weeks. The treatment showed an adequate safety profile and was well tolerated. The patient was discharged after undergoing a clinically significant improvement. After the therapy, her levels of positive aPL declined significantly and most continued to decrease during the next three months. The patient experienced a new thrombotic episode two years after the therapy associated with poor adherence to antithrombotic therapy.

Conclusions

The treatment with daratumumab showed an adequate safety profile, was well tolerated and led to a significant clinical improvement. Levels of aPL lowered on therapy and the next three months and then rose again during follow-up. Further investigation is needed to better elucidate the role and optimal timing and doses of daratumumab in treatment of refractory APS.
Microbial Community Characteristics Largely Unaffected by X-Ray Computed Tomography of Sediment Cores
Authors: Ewton Erica , Klasek Scott , Peck Erin , Wiest Jason , Colwell Frederick
Published: April 2021

X-ray computed tomography (CT) scanning is used to study the physical characteristics of soil and sediment cores, allowing scientists to analyze stratigraphy without destroying core integrity. Microbiologists often work with geologists to understand the microbial properties in such cores; however, we do not know whether CT scanning alters microbial DNA such that DNA sequencing, a common method of community characterization, changes as a result of X-ray exposure. Our objective was to determine whether CT scanning affects the estimates of the composition of microbial communities that exist in cores. Sediment cores were extracted from a salt marsh and then submitted for CT scanning. We observed a minimal effect of CT scanning on microbial community composition in the sediment cores either when the cores were examined shortly after recovery from the field or after the cores had been stored for several weeks. In contrast, properties such as sediment layer and marsh location did affect microbial community structure. While we observed that CT scanning did not alter microbial community composition as a whole, we identified a few amplicon sequence variants (13 out of 7,037) that showed differential abundance patterns between scanned and unscanned samples among paired sample sets. Our overall conclusion is that the CT-scanning conditions typically used to obtain images for geological core characterization do not significantly alter microbial community structure. We stress that minimizing core exposure to X-rays is important if cores are to be studied for biological properties. Future investigations might consider variables, such as the length and energy of radiation exposure, the volume of the core, or the degree, to which microbial communities are stressed as important factors in assessing the impact of X-rays on microbes in geological cores.
Duck Hepatitis A Virus Type 1 Induces eIF2α Phosphorylation-Dependent Cellular Translation Shutoff via PERK/GCN2
Authors: Liu Yuanzhi , Cheng Anchun , Wang Mingshu , Mao Sai , Ou Xumin , Yang Qiao , Wu Ying , Gao Qun , Liu Mafeng , Zhang Shaqiu , Huang Juan , Jia Renyong , Zhu Dekang , Chen Shun , Zhao Xinxin , Yu Yanling , Liu Yunya , Zhang Ling , Tian Bin , Pan Leichang
Published: April 2021

Duck hepatitis A virus type 1 (DHAV-1) is one of the most deadly pathogens that endanger the duck industry. Most viruses usually turn off host translation after infection to facilitate viral replication and translation. For the first time report to our knowledge, DHAV-1 can induce eIF2α phosphorylation and inhibit cellular translation in duck embryo fibroblasts (DEFs). Moreover, the activity of DHAV-1 in the cells caused obvious eIF2α phosphorylation, which has nothing to do with the viral protein. Subsequently, we screened two kinases (PERK and GCN2) that affect eIF2α phosphorylation through inhibitors and shRNA. Notably, the role of GCN2 in other picornaviruses has not been reported. In addition, when the phosphorylation of eIF2α induced by DHAV-1 is inhibited, the translation efficiency of DEFs restores to a normal level, indicating that DHAV-1 induced cellular translation shutoff is dependent on eIF2α phosphorylation.
Heme Oxygenase-1 Induction in Human BeWo Trophoblast Cells Decreases Toxoplasma gondii Proliferation in Association With the Upregulation of p38 MAPK Phosphorylation and IL-6 Production
Authors: Almeida Marcos Paulo Oliveira , Mota Caroline Martins , Mineo Tiago Wilson Patriarca , Ferro Eloisa Amália Vieira , Barbosa Bellisa Freitas , Silva Neide Maria
Published: April 2021

Heme oxygenase-1 (HO-1) enzyme exerts beneficial effects at the maternal-fetal interface, especially in trophoblasts, being involved in survival and maturation of these cell phenotypes. Trophoblast cells play essential roles throughout pregnancy, being the gateway for pathogens vertically transmitted, such as Toxoplasma gondii. It was previously shown that HO-1 activity was involved in the control of T. gondii infection in vivo; however, its contribution in trophoblast cells during T. gondii infection, remain undefined. Thus, this study aimed to investigate the influence of HO-1 in T. gondii-infected BeWo and HTR-8/SVneo human trophoblast cells. For this purpose, trophoblast cells were infected and the HO-1 expression was evaluated. T. gondii-infected BeWo cells were treated with hemin or CoPPIX, as inducers of HO-1, or with bilirubin, an end-product of HO-1, and the parasitism was quantified. The involvement of p38 MAPK, a regulator of HO-1, and the cytokine production, were also evaluated. It was found that T. gondii decreased the HO-1 expression in BeWo but not in HTR-8/SVneo cells. When treated with the HO-1 inducers or bilirubin, BeWo cells reduced the parasite proliferation. T. gondii also decreased the p38 MAPK phosphorylation in BeWo cells; on the other hand, HO-1 induction sustained its activation. Finally, the IL-6 production was upregulated by HO-1 induction in T. gondii-infected cells, which was associated with the control of infection.
Gastrointestinal Microenvironment and the Gut-Lung Axis in the Immune Responses of Severe COVID-19
Authors: Yang Yun , Huang Weishan , Fan Yubo , Chen Guo-Qiang
Published: April 2021

The global pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an unprecedented threat to the human health. A close association of the digestive tract is implied by the high frequency of gastrointestinal syndromes among COVID-19 patients. A better understanding of the role of intestinal microenvironment in COVID-19 immunopathology will be helpful to improve the control of COVID-19 associated morbidity and mortality. This review summarizes the immune responses associated with the severity of COVID-19, the current evidence of SARS-CoV-2 intestinal tropism, and the potential involvement of gut microenvironment in COVID-19 severity. Additionally, we discuss the therapeutic potential of probiotics as an alternative medicine to prevent or alleviate severe COVID-19 outcome.