bluuebunny/crossref_metadata_2025 huggingface dataset:
Contribution of Pseudomonas aeruginosa Exopolysaccharides Pel and Psl to Wound Infections
Authors: Fleming Derek , Niese Brandon , Redman Whitni , Vanderpool Emily , Gordon Vernita , Rumbaugh Kendra P.
Published: April 2022

Biofilms are the cause of most chronic bacterial infections. Living within the biofilm matrix, which is made of extracellular substances, including polysaccharides, proteins, eDNA, lipids and other molecules, provides microorganisms protection from antimicrobials and the host immune response. Exopolysaccharides are major structural components of bacterial biofilms and are thought to be vital to numerous aspects of biofilm formation and persistence, including adherence to surfaces, coherence with other biofilm-associated cells, mechanical stability, protection against desiccation, binding of enzymes, and nutrient acquisition and storage, as well as protection against antimicrobials, host immune cells and molecules, and environmental stressors. However, the contribution of specific exopolysaccharide types to the pathogenesis of biofilm infection is not well understood. In this study we examined whether the absence of the two main exopolysaccharides produced by the biofilm former Pseudomonas aeruginosa would affect wound infection in a mouse model. Using P. aeruginosa mutants that do not produce the exopolysaccharides Pel and/or Psl we observed that the severity of wound infections was not grossly affected; both the bacterial load in the wounds and the wound closure rates were unchanged. However, the size and spatial distribution of biofilm aggregates in the wound tissue were significantly different when Pel and Psl were not produced, and the ability of the mutants to survive antibiotic treatment was also impaired. Taken together, our data suggest that while the production of Pel and Psl do not appear to affect P. aeruginosa pathogenesis in mouse wound infections, they may have an important implication for bacterial persistence in vivo.
Correlation Analysis of Gut Microbiota and Serum Metabolome With Porphyromonas gingivalis-Induced Metabolic Disorders
Authors: Dong ZhengJie , Lv WanQi , Zhang ChenYang , Chen Si
Published: April 2022

Periodontitis has been demonstrated to increase the risk of metabolic syndrome (MetS), but the underlying mechanism remains unclear. Recent studies have indicated periodontopathic bacteria such as Porphyromonas gingivalis could induce gut microbiota (GM) dysbiosis and aggravate metabolic disorders. However, the effects of microbial metabolites have barely been evaluated. Here, we investigated the alteration of serum metabolome with P. gingivalis-induced metabolic disorders, and explored the correlations of GM and serum metabolites. In this study, we orally administered P. gingivalis ATCC33277 to C57BL/6 mice and performed metagenomic sequencing and untargeted metabolomics with fecal samples and serum collection. In vivo experiments showed a higher proportion of fat mass and worse glucose tolerance in P. gingivalis-administered mice, accompanied with an increase of adipose inflammation and gut permeability, which was similar to HFD-induced obese mice. Metagenomic sequencing indicated a compositional and functional alteration of GM. Untargeted metabolomics revealed an alteration of metabolites in P. gingivalis-administered mice, and most of them were engaged in metabolic pathways, such as tryptophan metabolism and choline metabolism. Correlation analysis between GM and serum metabolome indicated strong relativity with P. gingivalis administration. These results demonstrated some specific microbiota-derived metabolites in the pathogenesis of P. gingivalis-induced metabolic disorders, providing promising targets for the development of novel treatment strategies for MetS.
Fairness in Cardiac Magnetic Resonance Imaging: Assessing Sex and Racial Bias in Deep Learning-Based Segmentation
Authors: Puyol-Antón Esther , Ruijsink Bram , Mariscal Harana Jorge , Piechnik Stefan K. , Neubauer Stefan , Petersen Steffen E. , Razavi Reza , Chowienczyk Phil , King Andrew P.
Published: April 2022

Background

Artificial intelligence (AI) techniques have been proposed for automation of cine CMR segmentation for functional quantification. However, in other applications AI models have been shown to have potential for sex and/or racial bias. The objective of this paper is to perform the first analysis of sex/racial bias in AI-based cine CMR segmentation using a large-scale database.

Methods

A state-of-the-art deep learning (DL) model was used for automatic segmentation of both ventricles and the myocardium from cine short-axis CMR. The dataset consisted of end-diastole and end-systole short-axis cine CMR images of 5,903 subjects from the UK Biobank database (61.5 ± 7.1 years, 52% male, 81% white). To assess sex and racial bias, we compared Dice scores and errors in measurements of biventricular volumes and function between patients grouped by race and sex. To investigate whether segmentation bias could be explained by potential confounders, a multivariate linear regression and ANCOVA were performed.

Results

Results on the overall population showed an excellent agreement between the manual and automatic segmentations. We found statistically significant differences in Dice scores between races (white ∼94% vs. minority ethnic groups 86–89%) as well as in absolute/relative errors in volumetric and functional measures, showing that the AI model was biased against minority racial groups, even after correction for possible confounders. The results of a multivariate linear regression analysis showed that no covariate could explain the Dice score bias between racial groups. However, for the Mixed and Black race groups, sex showed a weak positive association with the Dice score. The results of an ANCOVA analysis showed that race was the main factor that can explain the overall difference in Dice scores between racial groups.

Conclusion

We have shown that racial bias can exist in DL-based cine CMR segmentation models when training with a database that is sex-balanced but not race-balanced such as the UK Biobank.
Ubiquitin Carboxyl-Terminal Hydrolase L1 of Cardiomyocytes Promotes Macroautophagy and Proteostasis and Protects Against Post-myocardial Infarction Cardiac Remodeling and Heart Failure
Authors: Wu Penglong , Li Yifan , Cai Mingqi , Ye Bo , Geng Bingchuan , Li Faqian , Zhu Hua , Liu Jinbao , Wang Xuejun
Published: April 2022

Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is a deubiquitinase known to play essential roles in the nervous tissue. Myocardial upregulation of UCHL1 was observed in human dilated cardiomyopathy and several animal models of heart disease, but the (patho)physiological significance of UCHL1 in cardiomyocytes remains undefined. Hence, we conducted this study to fill this critical gap. We produced cardiomyocyte-restricted Uchl1 knockout (CKO) by coupling the Uchl1-floxed allele with transgenic Myh6-Cre in C57B/6J inbred mice. Mice transgenic for Myh6-Cre were used as controls (CTL). Myocardial Uchl1 proteins were markedly reduced in CKO mice but they did not display discernible abnormal phenotype. Ten-week old CTL or CKO mice were subjected to left anterior descending artery ligation (myocardial infarction, MI) or sham surgery (Sham) and characterized at 7- and 28-day after surgery. Compared with Sham mice, significant increases in myocardial UCHL1 proteins were detected in CTL MI but not in CKO MI mice. MI-induced left ventricular (LV) chamber dilation, reduction of ejection fraction (EF) and fractional shortening (FS), and LV anterior wall thinning detected by echocardiography were comparable between the CTL MI and CKO MI groups 7-day post-MI. However, by 28-day post-MI, MI-induced LV chamber dilatation, EF and FS reduction, increases of myocardial ubiquitin conjugates, and increases in the heart weight to body weight ratio and the ventricular weight to body weight ratio were significantly more pronounced in CKO MI than CTL MI mice. As further revealed by LV pressure-volume relationship analyses, CKO MI mice but not CTL MI mice displayed significant decreases in stroke volume, cardiac output, and the maximum rates of LV pressure rising or declining and of LV volume declining, as well as significant increases in LV end-diastolic pressure and Tau, compared with their respective Sham controls. LC3-II flux assays reveal that autophagic flux is decreased in CKO mouse myocardium as well as in cultured Uchl1-deficient cardiomyocytes. In conclusion, UCHL1 of cardiomyocytes is dispensable for development but promotes macroautophagy in cardiomyocytes. Upregulation of UCHL1 in post-MI hearts occurs primarily in the cardiomyocytes and protects against post-MI cardiac remodeling and malfunction likely through supporting autophagic flux and proteostasis during a stress condition.
The Admission (Neutrophil+Monocyte)/Lymphocyte Ratio Is an Independent Predictor for In-Hospital Mortality in Patients With Acute Myocardial Infarction
Authors: Wang Yu , Yuan Miao , Ma Yao , Shao Congcong , Wang Yuan , Qi Mengyao , Ren Bincheng , Gao Dengfeng
Published: April 2022

Purpose

Peripheral differential leukocyte counts are accepted prognostic indicators in patients with acute myocardial infarction (AMI). Herein, we assessed the value of the admission (neutrophil+monocyte)/lymphocyte ratio (NMLR) in predicting in-hospital mortality in these patients.

Materials and Methods

Samples of patients from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database meeting the criteria were included. Receiver operating characteristic (ROC) curves were plotted to explore the predictive value and the optimum cut-off value of admission NMLR. Univariate and multivariate Cox regression analyses and restricted cubic spline (RCS) were performed to determine and visualize the association between admission NMLR and in-hospital mortality. The Kaplan-Meier (KM) method was used to plot survival curves of two groups with different admission NMLR levels.

Results

Samples in the non-survival group had higher admission NMLR values than samples in the survival group (12.11 [7.22–21.05] vs. 6.38 [3.96–11.25], P < 0.05). The area under the ROC curve (AUROC) [0.707 (95% Confidence Interval, 0.677–0.737)] was significantly better than those of other indicators related to peripheral differential leukocyte counts, and the optimal cut-off value was 8.518. Cox regression analysis identified that higher admission NMLR was an independent risk factor for in-hospital mortality. RCS visualized the uptrend and the non-linear relationship between admission NMLR and in-hospital mortality (P-value for non-linearity <0.05). The KM survival curve of the high admission NMLR group was significantly lower than that of the low admission NMLR group (P < 0.001), and the former was associated with an increased risk of in-hospital mortality compared to the latter (Hazard Ratio, 1.452; 95% Confidence Interval, 1.132–1.862; P < 0.05).

Conclusion

An elevated admission NMLR is an independent predictor for high in-hospital mortality in patients with AMI. And it is superior to other leukocyte-related indexes.
Abdominal Aortic Endothelial Dysfunction Occurs in Female Mice With Dextran Sodium Sulfate-Induced Chronic Colitis Independently of Reactive Oxygen Species Formation
Authors: Wu Hao , Hu Tingzi , Zhang Linfang , Xia Xiujuan , Liu Xuanyou , Zhu Qiang , Wang Meifang , Sun Zhe , Hao Hong , Cui Yuqi , Parrish Alan R. , Li De-Pei , Hill Michael A. , Xu Canxia , Liu Zhenguo
Published: April 2022

Background and Objective

Inflammatory bowel disease (IBD) produces significant local and systemic inflammation with increased reactive oxygen species (ROS) formation. IBD Patients are at an increased risk for developing endothelial dysfunction and cardiovascular diseases. The present study tested the hypothesis that IBD impairs aortic endothelial function via ROS formation and investigate potential sex-related differences.

Methods and Results

Acute and chronic colitis models were induced in male and female C57BL/6 mice with dextran sodium sulfate (DSS) treatment. Aortic wall stiffness, endothelial function, and ROS levels, as well as serum levels of pro-inflammatory cytokines were evaluated. Acetylcholine (Ach)-induced endothelium-dependent relaxation of abdominal aorta without perivascular adipose tissue (PVAT) was significantly reduced in female mice, not males, with chronic colitis without a change in nitroglycerin-induced endothelium-independent relaxation. PVAT effectively preserved Ach-induced relaxation in abdominal aorta of female mice with chronic colitis. Aortic peak velocity, maximal intraluminal diameters, pulse wave velocity, distensibility and radial strain were preserved in mice with both acute and chronic colitis. Although pro-inflammatory cytokines levels were increased in mice with acute and chronic colitis, aortic ROS levels were not increased.

Conclusion

The data demonstrate that abdominal aortic endothelial function was attenuated selectively in female mice with chronic colitis independent of ROS formation. Further, PVAT played an important role in preserving endothelial function in female mice with chronic colitis.
Current Knowledge on Factor V Leiden Mutation as a Risk Factor for Recurrent Venous Thromboembolism: A Systematic Review and Meta-Analysis
Authors: Eppenberger Daria , Nilius Henning , Anagnostelis Betsy , Huber Carola A. , Nagler Michael
Published: April 2022

Background

Thrombophilia screening is widely done in clinical practice, and it is claimed that the extent of venous thromboembolism (VTE) recurrence risk in patients with common defects is still not fully understood.

Aim

We aimed to summarize data of all observational studies prospectively assessing the association of heterozygous factor V Leiden (FVL) mutation and recurrent VTE in patients with VTE, and to calculate pooled relative risks (RR), overall and in various subgroups.

Methods

We searched MEDLINE and EMBASE databases for cohort studies prospectively assessing VTE recurrence in patients with and without FVL mutation (PROSPERO: CRD42021182800). Data were extracted on cohort and study-level. The methodological quality was assessed using the Newcastle-Ottawa Scale (NOS). RR were calculated overall and in subgroups using a random-effects model.

Results

From 31 cohorts, 24 studies were finally included summarizing 13,571 patients. Heterozygous FVL mutation was identified in 2,840 individuals (21%). The methodological quality was estimated to be high in 20 studies (83%). The overall RR was 1.46 (95% CI: 1.31, 1.64), consistent across subgroups.

Conclusions

Pooling all high-quality epidemiological data, the risk of recurrent VTE was increased by 46% in patients with heterozygous FVL mutation. Against the background of established risk factors, the FVL mutation plays only a marginal role in the risk assessment for recurrent VTE.
Testing and Validating a Faculty Blended Learning Adoption Model
Authors: Antwi-Boampong Ahmed
Published: April 2022

Faculty members are crucial to Blended Learning’s success in higher education. Despite substantial research into the elements that drive faculty adoption of BL, few have developed a model to explain how these factors combine and influence faculty intentions to teach in this mode. This study used data collected from 207 professors from 18 universities across Africa, the United States, Europe, and the Middle East to test and validate a Faculty Blended Learning Adoption Model which was derived from a Grounded Theory study. Four model constructs (institutional hygiene readiness, student BL disposition, faculty technology ready, and Pedagogy Technology Fit for BL) mediated by motivation were tested to predict faculty Blended Learning adoption using structural equation modeling. The results demonstrated an excellent model fit, with three of the six hypotheses in this study being supported. Faculty desire to utilize BL was found to be influenced by faculty technology readiness and task technology fit for BL, but not by institutional hygiene readiness or student BL disposition. This research presents a useful model for university administrators to use in their BL implementations. A thorough understanding of this model can assist decision-makers in identifying the factors that influence future faculty acceptance or resistance to blended learning, as well as helping them in enhancing acceptance and usage.
Study on the CM EMI Generation Characteristics of the Si/SiC Hybrid Switch at Different Switching Patterns and Gate Resistors
Authors: Zhu Yong , Peng Zishun , Dai Yuxing , Zhao Zhenxing , Liu Zeng , Zheng Zijie
Published: April 2022

The switching patterns and gate resistor of the Si/SiC hybrid switch are the key to realizing its own highly efficient and reliable operation. However, as an important performance indicator, the common mode (CM) electromagnetic interference (EMI) noise caused by the Si/SiC hybrid switch lacks comprehensive research, which means that it is not clear how the switching patterns and gate resistor affect CM EMI. In this paper, the Si/SiC hybrid switch-based boost converter is established at first. Then, by analyzing the spectral characteristics of the CM voltage of the Si/SiC hybrid switch, the CM EMI generation characteristics of the Si/SiC hybrid switch at different switching patterns and gate resistors are revealed. Furthermore, the analysis and experimental results can be used to comprehensively guide the design of the gate drive pattern, gate resistor, and EMI suppression strategy.
Effects of the Order Parameter Anisotropy on the Vortex Lattice in UPt3
Authors: Avers K. E. , Gannon W. J. , Leishman A. W. D. , DeBeer-Schmitt L. , Halperin W. P. , Eskildsen M. R.
Published: April 2022

We have used small-angle neutron scattering to determine the vortex lattice phase diagram in the topological superconductor UPt3 for the applied magnetic field along the crystalline c-axis. A triangular vortex lattice is observed throughout the superconducting state, but with an orientation relative to the hexagonal basal plane that changes with field and temperature. At low temperature, in the chiral B phase, the vortex lattice undergoes a non-monotonic rotation with increasing magnetic field. The rotation amplitude decreases with increasing temperature and vanishes before reaching the A phase. Within the A phase an abrupt ±15° vortex lattice rotation was previously reported by Huxley et al., Nature 406, 160-164 (2000). The complex phase diagram may be understood from competing effects of the superconducting order parameter, the symmetry breaking field, and the Fermi surface anisotropy. The low-temperature rotated phase, centered around 0.8 T, reported by Avers et al., Nature Physics 16, 531-535 (2020), can be attributed directly to the symmetry breaking field.
TNF Signaling Acts Downstream of MiR-322/-503 in Regulating DM1 Myogenesis
Authors: Li Meng , Xu Feng , Liu Zhongxian , Wang Chunguang , Zhao Yun , Zhu Guoping , Shen Xiaopeng
Published: April 2022

Myotonic dystrophy type 1 (DM1) is caused by the expanded CUG repeats and usually displays defective myogenesis. Although we previously reported that ectopic miR-322/-503 expression improved myogenesis in DM1 by targeting the toxic RNA, the underlying pathways regulating myogenesis that were aberrantly altered in DM1 and rescued by miR-322/-503 were still unknown. Here, we constructed DM1 and miR-322/-503 overexpressing DM1 myoblast models, which were subjected to in vitro myoblast differentiation along with their corresponding controls. Agreeing with previous findings, DM1 myoblast showed remarkable myogenesis defects, while miR-322/-503 overexpression successfully rescued the defects. By RNA sequencing, we noticed that Tumor necrosis factor (TNF) signaling was the only pathway that was significantly and oppositely altered in these two experimental sets, with it upregulated in DM1 and inhibited by miR-322/-503 overexpression. Consistently, hyperactivity of TNF signaling was detected in two DM1 mouse models. Blocking TNF signaling significantly rescued the myogenesis defects in DM1. On the contrary, TNF-α treatment abolished the rescue effect of miR-322/-503 on DM1 myogenesis. Taking together, these results implied that TNF signaling mediated the myogenesis defects in DM1 and might act downstream of miR-322/-503 in regulating the myogenesis in DM1. Moreover, the inhibition of TNF signaling benefiting myogenesis in DM1 provided us with a novel therapeutic strategy for DM1.
How Does Energy Efficiency Mitigate Carbon Emissions Without Reducing Economic Growth in Post COVID-19 Era
Authors: Li Min , Yao-Ping Peng Michael , Nazar Raima , Ngozi Adeleye Bosede , Shang Meng , Waqas Muhammad
Published: April 2022

A comprehensive analytical study to assess the performance level of industrial functions in the environment has become necessary at the present time. According to existing research, the COVID-19 pandemic resulted in a significant reduction in carbon emissions in 2020. Policymakers are focusing on the discrepancies and negative environmental effect caused by various industries during their routine operations. This study aims to estimate the performance level of energy in the context of the environment of the countries that are members of the European Union This evaluation is performed through a data envelopment analysis (DEA) model, through which we have applied a non-proportional adjustment, taking into account the input of energy and its undesirable output. The DEA model allows dynamic assessment of sources in the field of measuring energy efficiency and its environmental effects. The score of measurement of efficiency lies between zero and one, which means China and Russia are awarded this score of one (1), which shows the highest level of efficiency in clean energy, while Bangladesh (0.19), Uzbekistan (0.09), Mongolia and Cambodia (0.06), and Kyrgyzstan (0.04) are at the lowest level of performance in clean energy. The results of the study showed that clean energy efficiency levels increased in all countries over the study period. The emission level of greenhouse gases in the first world countries was found to be better in the context of improvement in performance enhancement in the sector of the energy mix. Evasion score is measured as 365 kt of CO2. This score for NO2 is 280 kt and for SO2 is 82 kt, whereas it is 23 kt (0.24 kg/cap) of particulate hazardous matter. The higher performance level of energy yields a negative relationship with emissions of gases, with a significant number of 12% for NO2 in 2000, as compared to 13% for SO2 and 14% for PM2.5. Whereas PM10 has the highest concentration (18%). Public policymakers may enhance the facilitation system for better free trade and a result-oriented corporate environment to enhance the performance level of energy in the electric sector.
Interrelationship Among Rice Grain Arsenic, Micronutrients Content and Grain Quality Attributes: An Investigation From Genotype × Environment Perspective
Authors: Moulick Debojyoti , Ghosh Dibakar , Skalicky Milan , Gharde Yogita , Mazumder Muhammed Khairujjaman , Choudhury Shuvasish , Biswas Jayanta Kumar , Santra Subhas Chandra , Brestic Marian , Vachova Pavla , Hossain Akbar
Published: April 2022

Arsenic contamination in the rice agro-ecosystem, its consequent spread into the food chain, and its adverse impact are a global concern. However, assessment of the impact of arsenic contamination on the qualitative aspect of rice in the post-harvest phase has not been attempted. We laid down this particular experiment with the aim to assess how arsenic contamination influences the grain quality attributes and other elemental profiles of four popular rice varieties. The entire field study was conducted in the lower Indo-Gangetic plain from genotype (four) and environment (14 locations) interaction point of view, using the additive main effects and multiplicative interaction model. Our findings indicate that grain arsenic content can influence the grain quality attributes and other elemental profiles in a low to highly significant manner. Amylose content (r = 0.753), cooking time (r = 0.706), and gruel solid loss (r = 0.672, 0.721) were found to be positively correlated with grain arsenic content in high-yielding varieties. Noteworthy variations in micronutrient content like iron (6.63–9.23 mg kg−1), zinc (3.15–5.54 mg kg−1), and copper (2.04–3.86 mg kg−1) as well as soil properties are also visible. Moreover, indigenous rice varieties respond differently than high-yielding varieties. Besides these, a pronounced impact of gene/variety and environment interaction can be seen. The findings clearly indicate that the qualitative aspect of rice is also prone to As contamination. These outcomes will attract the attention of policy-makers and researchers to develop rice varieties that have desirable quality attributes appropriate for the arsenic-contaminated regions of the world for sustainable rice production.
Impact of Environmental Regulation on High-Quality Economic Development
Authors: Ma Xiaowei , Xu Junwei
Published: April 2022

Based on the connotation of high-quality economic development (HQED) in China, this study uses panel data of 30 provinces (cities and regions) in China from 2005 to 2019 to construct an evaluation index system of HQED with three dimensions of “economic development—social life—ecological environment,” and establishes a fuzzy comprehensive evaluation model to calculate the HQED index. The results show that the high-quality development level of China’s economy shows an upward trend of fluctuation, but the development level is still low and there are obvious regional differences. The eastern region enjoys the highest level of HQED, followed by the central region and western region. The panel data regression model is further established to analyze the impact of environmental regulation on economic development. It is found that there is an inverted u-shaped relationship between environmental regulation and HQED, and there is a “cost compliance” effect between environmental regulation and quantitative economic development. Strict environmental regulation measures will inhibit economic quantity growth. The results of heterogeneity analysis show that environmental regulation has different impacts on the economic development of the three regions due to the differences in resource endowment. The influence of environmental regulation on economic development in eastern China is similar to that in the whole country. However, in the central region, there is an “innovation compensation” effect between environmental regulation and HQED, and a “U” shape relationship between environmental regulation and quantitative economic development. In western China, the enhancement of environmental regulation will inhibit high-quality and quantitative economic development.
Cytokine-Mediated Crosstalk Between Keratinocytes and T Cells in Atopic Dermatitis
Authors: Humeau Mélanie , Boniface Katia , Bodet Charles
Published: April 2022

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by barrier dysfunction, dysregulated immune response, and dysbiosis with increased Staphylococcus aureus colonization. Infiltration of various T helper cell subsets into lesional skin and subsequent cytokine release are a hallmark of AD. Release of cytokines by both T cells and keratinocytes plays a key role in skin inflammation and drives many AD features. This review aims to discuss cytokine-mediated crosstalk between T cells and keratinocytes in AD pathogenesis and the potential impact of virulence factors produced by Staphylococcus aureus on these interactions.
Consequences of Viral Infection and Cytokine Production During Pregnancy on Brain Development in Offspring
Authors: Elgueta Daniela , Murgas Paola , Riquelme Erick , Yang Guang , Cancino Gonzalo I.
Published: April 2022

Infections during pregnancy can seriously damage fetal neurodevelopment by aberrantly activating the maternal immune system, directly impacting fetal neural cells. Increasing evidence suggests that these adverse impacts involve alterations in neural stem cell biology with long-term consequences for offspring, including neurodevelopmental disorders such as autism spectrum disorder, schizophrenia, and cognitive impairment. Here we review how maternal infection with viruses such as Influenza A, Cytomegalovirus, and Zika during pregnancy can affect the brain development of offspring by promoting the release of maternal pro-inflammatory cytokines, triggering neuroinflammation of the fetal brain, and/or directly infecting fetal neural cells. In addition, we review insights into how these infections impact human brain development from studies with animal models and brain organoids. Finally, we discuss how maternal infection with SARS-CoV-2 may have consequences for neurodevelopment of the offspring.
Full-Length Transcriptome Analysis Provides New Insights Into the Diversity of Immune-Related Genes in Portunus trituberculatus
Authors: Zhang Yi , Ni Mengqi , Bai Yunhui , Shi Qiao , Zheng Jinbin , Cui Zhaoxia
Published: April 2022

Generally, invertebrates were thought to solely rely on their non-specific innate immune system to fight against invading microorganisms. However, increasing studies have implied that the innate immune response of invertebrates displayed diversity and specificity owing to the hyper-variable immune molecules in organisms. In order to get an insight into the diversity of immune-related genes in Portunus trituberculatus, a full-length transcriptome analysis of several immune-related tissues (hemocytes, hepatopancreas and gills) in P. trituberculatus was performed and the diversity of several immune-related genes was analyzed. The full-length transcriptome analysis of P. trituberculatus was conducted using a combination of SMRT long-read sequencing and Illumina short-read sequencing. A total of 17,433 nonredundant full-length transcripts with average length of 2,271 bp and N50 length of 2,841 bp were obtained, among which 13,978 (80.18%) transcripts were annotated. Moreover, numerous transcript variants of various immune-related genes were identified, including pattern recognition receptors, antimicrobial peptides, heat shock proteins (HSPs), antioxidant enzymes and vital molecules in prophenoloxidase (proPO)-activating system. Based on the full-length transcriptome analysis, open reading frames (ORFs) of four C-type lectins (CTLs) were cloned, and tissue distributions showed that the four CTLs were ubiquitously expressed in all the tested tissues, and mainly expressed in hepatopancreas and gills. The transcription of the four CTLs significantly increased in several immune-related tissues (hemocytes, hepatopancreas and gills) of P. trituberculatus challenged with Vibrio alginolyticus and displayed different profiles. Moreover, the four CTLs displayed distinct bacterial binding and antibacterial activities. The recombinant protein PtCTL-1 (rPtCTL-1) and rPtCTL-3 displayed bacterial binding and antibacterial activities against all tested bacteria. rPtCTL-2 only showed bacterial binding and antibacterial activities against V. alginolyticus. No obvious bacterial binding or antibacterial activities for PtCTL-4 was observed against the tested bacteria. This study enriches the transcriptomic information on P. trituberculatus and provides new insights into the innate immune system of crustaceans. Additionally, our study provided candidates of antibiotic agents for the prevention and treatment of bacteriosis.
Genetic Engineering and Enrichment of Human NK Cells for CAR-Enhanced Immunotherapy of Hematological Malignancies
Authors: Soldierer Maren , Bister Arthur , Haist Corinna , Thivakaran Aniththa , Cengiz Sevgi Can , Sendker Stephanie , Bartels Nina , Thomitzek Antonia , Smorra Denise , Hejazi Maryam , Uhrberg Markus , Scheckenbach Kathrin , Monzel Cornelia , Wiek Constanze , Reinhardt Dirk , Niktoreh Naghmeh , Hanenberg Helmut
Published: April 2022

The great clinical success of chimeric antigen receptor (CAR) T cells has unlocked new levels of immunotherapy for hematological malignancies. Genetically modifying natural killer (NK) cells as alternative CAR immune effector cells is also highly promising, as NK cells can be transplanted across HLA barriers without causing graft-versus-host disease. Therefore, off-the-shelf usage of CAR NK cell products might allow to widely expand the clinical indications and to limit the costs of treatment per patient. However, in contrast to T cells, manufacturing suitable CAR NK cell products is challenging, as standard techniques for genetically engineering NK cells are still being defined. In this study, we have established optimal lentiviral transduction of primary human NK cells by systematically testing different internal promoters for lentiviral CAR vectors and comparing lentiviral pseudotypes and viral entry enhancers. We have additionally modified CAR constructs recognizing standard target antigens for acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) therapy—CD19, CD33, and CD123—to harbor a CD34-derived hinge region that allows efficient detection of transduced NK cells in vitro and in vivo and also facilitates CD34 microbead-assisted selection of CAR NK cell products to >95% purity for potential clinical usage. Importantly, as most leukemic blasts are a priori immunogenic for activated primary human NK cells, we developed an in vitro system that blocks the activating receptors NKG2D, DNAM-1, NKp30, NKp44, NKp46, and NKp80 on these cells and therefore allows systematic testing of the specific killing of CAR NK cells against ALL and AML cell lines and primary AML blasts. Finally, we evaluated in an ALL xenotransplantation model in NOD/SCID-gamma (NSG) mice whether human CD19 CAR NK cells directed against the CD19+ blasts are relying on soluble or membrane-bound IL15 production for NK cell persistence and also in vivo leukemia control. Hence, our study provides important insights into the generation of pure and highly active allogeneic CAR NK cells, thereby advancing adoptive cellular immunotherapy with CAR NK cells for human malignancies further.
Randomized, Double-Blind, Reference-Controlled, Phase 2a Study Evaluating the Immunogenicity and Safety of OVX836, A Nucleoprotein-Based Influenza Vaccine
Authors: Leroux-Roels Isabel , Waerlop Gwenn , Tourneur Jessika , De Boever Fien , Maes Catherine , Bruhwyler Jacques , Guyon-Gellin Delphine , Moris Philippe , Del Campo Judith , Willems Paul , Leroux-Roels Geert , Le Vert Alexandre , Nicolas Florence
Published: April 2022

OVX836 is a recombinant protein-based vaccine targeting the highly conserved influenza nucleoprotein (NP), which aims to confer a broad-spectrum protection against influenza. In a Phase 1 study, OVX836, administered intramuscularly, has been found safe and immunogenic. The 90µg and 180µg dose levels were selected to be further evaluated in this randomized, monocenter, reference-controlled (Influvac Tetra™: quadrivalent seasonal influenza subunit vaccine), parallel group, double-blind, Phase 2a study in 300 healthy volunteers, aged 18-65 years, during the 2019/2020 flu season. Safety, influenza-like illness episodes (ILI; based on the Flu-PRO® questionnaire) and immunogenicity were assessed up to 180 days post-vaccination. OVX836 was safe and presented a reactogenicity profile similar to Influvac Tetra. It induced a significant increase in terms of NP-specific interferon-gamma (IFNγ) spot forming cells (SFCs), NP-specific CD4+ T-cells (essentially polyfunctional cells) and anti-NP IgG responses. OVX836 was superior to Influvac Tetra for all immunological parameters related to NP, and the 180µg dose was significantly superior to the 90µg dose for SFCs and CD4+ T-cells expressing IFNγ. Both the CD4+ T-cell and the anti-NP IgG responses persisted up to Day 180. An efficacy signal was observed with OVX836 at 180µg through reduction of ILI episodes occurring during the flu season as of 14 days post-vaccination. In conclusion, these results encourage further clinical evaluation of OVX836 in order to confirm the signal of efficacy on ILIs and/or laboratory-confirmed influenza cases. NCT04192500 (https://clinicaltrials.gov/ct2/show/study/NCT04192500)
Skin Interstitial Fluid and Plasma Multiplex Cytokine Analysis Reveals IFN-γ Signatures and Granzyme B as Useful Biomarker for Activity, Severity and Prognosis Assessment in Vitiligo
Authors: Ng Chau Yee , Chiu Yen-Chuan , Chan Yu-Pei , Lin Yu-Jr , Chung Pei-Han , Chung Wen-Hung , Ku Cheng-Lung
Published: April 2022

Background

The course of vitiligo is unpredictable, with periods of disease flare-ups and prolonged recovery periods. It is essential to establish a biomarker profile as a substitute marker for disease activity to predict disease activity, severity, and prognosis prediction. The use of localized skin interstitial fluid as biomarkers has recently gained interest, but extensive studies of the association between skin interstitial fluid, plasma, and the disease course is lacking. This study aims to evaluate the cytokine expression profiles in the skin and plasma and the utility of the biomarker panel in assessing disease activity, severity, and prognosis in patients with vitiligo.

Methods

In this prospective cohort study, 86 patients and 34 healthy controls were recruited from the outpatient department of a tertiary medical center from March 2019 to September 2021. All patients were of Asian ethnicity. Two independent investigators evaluated disease activity and severity with longitudinal follow-ups for treatment response for a-12 month period. Ultrasensitive multiplex cytokine panel and single-molecule counting technology immunoassays were used to study the cytokine expression in skin interstitial fluid and plasma.

Results

IFN-γ and its’ signature cytokines, including CXCL9, CXCL10, and GzmB, are most highly expressed in the vitiligo patients’ lesion skin interstitial fluid and plasma compared to healthy control. By way of comparison, no significant changes in IL-1β, IL-13, IL-15, IL-17A, IL-18 were observed. Receiver operating characteristic analysis revealed that IFN-γ is the most sensitive and specific marker in predicting disease activity, followed by CXCL10 and GzmB. CXCL-9 was sensitive and specific in diagnosing vitiligo disease severity. The decrease in IFN-γ expression level is positively correlated with the treatment response.

Conclusion

IFN-γ, CXCL9, CXCL10, and GzmB are highly expressed in vitiligo patients’ lesion skin and plasma and may serve as biomarkers for the clinical activity, severity, and prognosis prediction in vitiligo patients. Among all, IFN-γ exerts the highest predictive value in disease activity and treatment response, supporting the critical role of IFN-γ in the pathogenesis of vitiligo.
Acute Silica Exposure Triggers Pulmonary Inflammation Through Macrophage Pyroptosis: An Experimental Simulation
Authors: Yin Haoyu , Fang Lei , Wang Lifeng , Xia Yu , Tian Jiaqi , Ma Lan , Zhang Jing , Li Ning , Li Weixiu , Yao Sanqiao , Zhang Lin
Published: April 2022

Silica is an essential substrate of various materials, and inhaling silica induces pulmonary diseases potentially associated with macrophage pyroptosis. Utilizing silica of micro- and nano- sizes, we explored the role of macrophage pyroptosis in silica-induced pulmonary inflammation. Under the transmission electron microscopy, we found that the internalization of silica nanoparticle induced membrane rupture and increased the number of intracellular vacuoles, and both sizes of silica could suppress cell viability and proliferation. Also, silica-exposed macrophages generated higher levels of ROS, together with the upregulated expression of NLRP3, ASC, Caspase-1, GSDMD, IL-1β, and IL-6. However, the expression of these proteins was suppressed after removing ROS or NLRP3. In addition, we found increased expression of TLR4 and NF-κB responsible for silica recognition and pyroptosis priming after silica exposure. For in vivo studies, we established animal model by intratracheally instilling 5 mg of silica into mice with/without NLRP3 inhibition. Four weeks later, we found diffused infiltration of inflammatory cells and enhanced collagen hyperplasia partially reversed by additional treatment with MCC950, so as the expression of pyroptotic molecules and proinflammatory cytokines. In particular, the dual immunofluorescent staining showed co-expression of macrophage-specific biomarker F4/80 and NLRP3 within the cells, and silica of nano-size showed more potent toxicity and pathogenicity than that of the micro-sized particles both in vitro and in vivo. To sum up, macrophage pyroptosis is an upstream event of silica-induced pulmonary inflammation promoted by ROS through the TLR4/NLRP3/NF-κB signaling axis.
Case Report: Diagnostic and Therapeutic Challenges in Severe Mechanobullous Epidermolysis Bullosa Acquisita
Authors: Schauer Franziska , Nyström Alexander , Kunz Manfred , Hübner Stefanie , Scholl Sarah , Athanasiou Ioannis , Alter Svenja , Fischer Judith , Has Cristina , Kiritsi Dimitra
Published: April 2022

Collagen VII is the main constituent of the anchoring fibrils, important adhesive structures that attach the epidermis to the dermal extracellular matrix. Two disorders are caused by dysfunction of collagen VII, both characterized by skin and mucosa fragility, epidermolysis bullosa acquisita (EBA) and dystrophic epidermolysis bullosa (DEB). EBA and DEB share high clinical similarities with significant difference in patients’ age of onset and pathogenesis. Our patients presented with severe and recalcitrant mechanobullous EBA with characteristic DIF, IIF and ELISA diagnostics. But in both women recessive COL7A1 variants were also found, in a monoallelic state. Collagen VII from EBA keratinocytes of our cases was significantly more vulnerable to proteolytic degradation than control keratinocytes, hinting that the heterozygous pathogenic variants were sufficient to destabilize the molecule in vitro. Thus, even if the amount and functionality of mutant and normal type VII collagen polypeptides is sufficient to assure dermal-epidermal adhesion in healthy individuals, the functionally-impaired proteins are probably more prone to development of autoantibodies against them. Our work suggests that testing for COL7A1 genetic variants should be considered in patients with EBA, which either have a patient history hinting towards underlying dystrophic epidermolysis bullosa or pose therapeutic challenges.
Seasonal Distributions of Methane in a Populous Urban Coastal Sea Area
Authors: Tseng Hsiao-Chun , Lin Chia-Chia , Pan Hui-Juan , Han Yokie Tai Yuh , Gong Gwo-Ching
Published: April 2022

Methane (CH4) is an important greenhouse gas, and its concentrations in aquatic areas are heavily influenced by anthropogenic activities, especially human-induced eutrophication, polluted river discharge and wastewater treatment plant (WWTP) effluents. Although coastal areas and estuaries contribute large amounts of global oceanic CH4 emissions, the relative contributions of different sources have not been well determined. The Tamsui River located in northern Taiwan is an urban river flowing through populated cities and thus likely carries large amounts of contaminants, such as nutrients and organic matter to the estuary. In this study, we characterized the spatial distribution and seasonal variations in CH4 in the Tamsui River estuary adjacent marine areas. The sea-to-air CH4 fluxes were also estimated to quantify the strength of the study area as an atmospheric CH4 source. Our results showed that CH4 concentrations in coastal sea areas were influenced by WWTP effluents, sediment and freshwater inputs. Thus, river discharge and nutrient levels as well as strong vertical mixing and disturbances might increase CH4 concentrations and emissions. The seasonal surface CH4 concentrations and sea-to-air CH4 fluxes were 13.7 ± 18.7 nM and 41.7 ± 68.0 μmol m-2 d-1 in autumn; 29.3 ± 19.8 nM and 61.3 ± 44.6 μmol m-2 d-1 in spring; 21.8 ± 13.9 nM and 37.0 ± 26.2 μmol m-2 d-1 in summer; and 27.0 ± 21.4 nM and 85.9 ± 75.4 μmol m-2 d-1 in winter.
Clinical Significance of Haplo-Fever and Cytokine Profiling After Graft Infusion in Allogeneic Stem Cell Transplantation From Haplo-Identical Donors
Authors: Wang Lining , Dai Bo , Gao Wenhui , Wang Jing , Wan Ming , Wang Runshu , Wang Ling , Jiang Jieling , Blaise Didier , Hu Jiong
Published: April 2022

Allogeneic stem cell transplantation from haplo-identical donors (haplo-HSCT) has become a well-established therapeutic option for hematological malignancies. The fever of unknown origin (haplo-fever) early after the infusion of T cell repleted graft, which returned to normal right after post-transplantation cyclophosphamide (PTCy), is a unique clinical feature in patients undergoing haplo-HSCT. In the current study, the characteristics of haplo-fever and cytokine profiles during haplo-fever were retrospectively analyzed in a cohort of 37 patients undergoing T cell repleted haplo-HSCT with PTCy as graft versus host disease (GvHD) prophylaxis. In total, 33 patients (89.2%) developed haplo-fever from day 0 to day +7. Patients with high peak temperatures tended to have a lower incidence of chronic GvHD (cGvHD) (p = 0.07), moderate to severe cGvHD (p = 0.08), and superior GvHD and relapse-free survival (GRFS, p = 0.04). During the haplo-fever, there were significant increases in multiple cytokines, such as interferon gamma, interleukin (IL) 6, IL2, IL2 receptor, IL8, IL10, IL17, and tumor necrosis factor (TNF). The increases in IL2 receptor (p = 0.037) and TNF (p < 0.001) on day +4 were correlated with the lower risk of cGvHD. Increased TNF > 1.8055-fold on day +4 was the best predictive threshold for cGvHD, and was correlated with a lower incidence of cGvHD (p < 0.001), moderate to severe cGvHD (p = 0.003), and superior GRFS (p < 0.001). These observations may reflect the early reactivation of donor T cells after haplo graft infusion, which would potentially be eliminated by PTCy. Further studies with larger independent cohorts of patients are warranted, to clarify the clinical significance of haplo-fever, and day +4 TNF as a potential biomarker to predict GvHD and GRFS.
Effects of Virtual Reality Education on Procedural Pain and Anxiety During Venipuncture in Children: A Randomized Clinical Trial
Authors: Ryu Jung-Hee , Han Sung-Hee , Hwang Sang Mee , Lee Jiyoun , Do Sang-Hwan , Kim Jin-Hee , Park Jin-Woo
Published: April 2022

Background

Venipuncture is one of the most frequent and frightening medical procedures for children. This randomized clinical trial aimed to evaluate whether pre-procedural immersive virtual reality (VR) education could decrease pain and anxiety during venipuncture procedure of children.

Methods

Sixty children scheduled for venipuncture at the phlebotomy unit were randomized into either the control or VR group. Before the procedure, children of the control group received conventional simple verbal instructions, whereas those of the VR group experienced a 4-min VR education regarding venipuncture. The primary outcome was the pain and anxiety of pediatric patients assessed with the children’s hospital of eastern ontario pain scale. Secondary outcomes were parental satisfaction, venipuncture time, repeated procedure and procedural difficulty rated by phlebotomists.

Results

The pain and anxiety score during the procedure was significantly lower in the VR group than in the control group (median [IQR], 6.0 [5.0–7.0] vs. 8.0 [6.0–9.8], P = 0.001). Parental satisfaction about the procedural process were higher in the VR group than in the control group (P = 0.029), and the degree of procedural difficulty was lower in the VR group, compared to the control group (P = 0.026).

Conclusion

The preprocedural VR education significantly reduced pain and anxiety of children and decreased the procedural difficulty of phlebotomists during venipuncture procedure.

Clinical Trial Registration

University hospital Medical Information Network Clinical Trials Registry (registration number: UMIN000042968, date of registration: January 9, 2021, URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000049043).