bluuebunny/crossref_metadata_2025 huggingface dataset:
Mentally Ill and Cute as Hell: Menhera Girls and Portrayals of Self-Injury in Japanese Popular Culture
Authors: Seko Yukari , Kikuchi Minako
Published: March 2022

Over the last few decades, self-injury has gained wide visibility in Japanese popular culture frommanga(graphic novel),anime(animation), to digital games and fashion. Among the most conspicuous is the emergence ofmenhera(a portmanteau of “mental health-er”) girls, female characters who exhibit unstable emotionality, obsessive love, and stereotypical self-injurious behaviors such as wrist cutting. Tracing the expansion of this popular cultural slang since 2000, this conceptual article explores three narrative tropes ofmenhera—the sad girl, the mad woman, and the cutie. Within thesemenheranarratives, self-injury functions as a self-sufficient signifier of female vulnerability, monstrosity, and desire for agency. Thesemenheratropes, each with their unique interpretation of self-injury, have evolved symbiotically with traditional gender norms in Japan, while destabilizing long-standing undesirability of sick/detracted female bodies. Themenheranarrative tropes mobilize cultural discourses about female madness and subsequently feed back into the social imaginaries, offering those who self-injure symbolic resources for self-interpretation. We argue that popular cultural narratives of self-injury likemenheramay exert as powerful an influence as clinical discourses on the way we interpret, make sense of, and experience self-injury. Being attentive to cultural representations of self-injury thus can help clinicians move toward compassionate clinical practice beyond the medical paradigm.
A High Precision Machine Learning-Enabled System for Predicting Idiopathic Ventricular Arrhythmia Origins
Authors: Zheng Jianwei , Fu Guohua , Struppa Daniele , Abudayyeh Islam , Contractor Tahmeed , Anderson Kyle , Chu Huimin , Rakovski Cyril
Published: March 2022

Background

Radiofrequency catheter ablation (CA) is an efficient antiarrhythmic treatment with a class I indication for idiopathic ventricular arrhythmia (IVA), only when drugs are ineffective or have unacceptable side effects. The accurate prediction of the origins of IVA can significantly increase the operation success rate, reduce operation duration and decrease the risk of complications. The present work proposes an artificial intelligence-enabled ECG analysis algorithm to estimate possible origins of idiopathic ventricular arrhythmia at a clinical-grade level accuracy.

Method

A total of 18,612 ECG recordings extracted from 545 patients who underwent successful CA to treat IVA were proportionally sampled into training, validation and testing cohorts. We designed four classification schemes responding to different hierarchical levels of the possible IVA origins. For every classification scheme, we compared 98 distinct machine learning models with optimized hyperparameter values obtained through extensive grid search and reported an optimal algorithm with the highest accuracy scores attained on the testing cohorts.

Results

For classification scheme 4, our pioneering study designs and implements a machine learning-based ECG algorithm to predict 21 possible sites of IVA origin with an accuracy of 98.24% on a testing cohort. The accuracy and F1-score for the left three schemes surpassed 99%.

Conclusion

In this work, we developed an algorithm that precisely predicts the correct origins of IVA (out of 21 possible sites) and outperforms the accuracy of all prior studies and human experts.
Discovery of Yaozhuang Stock and Deep Ore Prospecting Implication for the Western Mangling Orefield in North Qinling Terrane, Central China
Authors: Fan Peng , Xi Aihua , Zhou Bin , Chao Xu , Yang Wenbo , Sun Jiaxin , Zhu Hongyu , Wei Li
Published: March 2022

In the western Mangling orefield, the molybdenum (Mo) polymetallic deposits are closely related to the ore-bearing porphyry stocks (individual outcrop size: <1 km2). In this study, we have discovered several granitic stocks at Yaozhuang. Systematic petrologic, zircon U-Pb-Hf isotope and whole-rock geochemical studies show that both the granitic stocks of porphyritic granite (157 ± 2 Ma) and the intruding monzogranite dike (153 ± 1 Ma) were emplaced in the Late Jurassic. These granitic stocks are characterized by high SiO2(66.83–75.63 wt%), high K2O (4.15–5.05 wt%), high Al2O3(12.90–16.93 wt%), and low MgO (0.06–0.73 wt%) and are metaluminous to weakly peraluminous, being highly fractionated I-A-type transition granites. The content of the total rare Earth element (ΣREE) of the porphyritic granite (139.6–161.7 ppm) is lower than that of the monzogranite (151.4–253.6 ppm). The porphyritic granite has weakly negative Eu anomalies (Eu/Eu* = 0.77–0.93), whereas the monzogranite has weakly positive Eu anomalies (Eu/Eu* = 0.97–1.21) and are more enriched in light rare Earth elements. Both of them are enriched in large ion lithophile elements (LILEs, e.g., K, Rb, and Ba) but depleted in high-field-strength elements (HFSEs, e.g., Nb, Ta, Ti, Zr, and Hf). The zircon εHf(t) values of all the samples range from −16.1 to −6.9, and the two-stage model ages (tDM2) are 1.78–2.16 Ga. The magma may have originated from partial melting of the lower crust (more than 40 km in depth) caused by mantle-derived magma underwelling. The plutons and stocks were emplaced into the intersection of the early EW-trending faults and the late (Yanshanian) NE-trending faults. The fertile magma with high water content (H2O > 4%) and high oxygen fugacity (Delta FMQ > 1.5) indicates that the Yaozhuang area has significant potential for porphyry Mo polymetallic ore discovery.
The Impact of Hormonal Contraceptive Use on Serotonergic Neurotransmission and Antidepressant Treatment Response: Results From the NeuroPharm 1 Study
Authors: Larsen Søren Vinther , Ozenne Brice , Köhler-Forsberg Kristin , Poulsen Asbjørn Seenithamby , Dam Vibeke Høyrup , Svarer Claus , Knudsen Gitte Moos , Jørgensen Martin Balslev , Frokjaer Vibe Gedso
Published: March 2022

Background

Hormonal contraceptive (HC) use has been associated with an increased risk of developing a depressive episode. This might be related to HC’s effect on the serotonergic brain system as suggested by recent cross-sectional data from our group, which show that healthy oral contraceptive (OC) users relative to non-users have lower cerebral serotonin 4 receptor (5-HT4R) levels. Here, we determine if cerebral 5-HT4R binding differs between HC non-users, OC users, and hormonal intrauterine device (HIUD) users among women with an untreated depressive episode. Also, we test if antidepressant drug treatment response and its association with pre-treatment 5-HT4R binding depends on HC status.

Methods

[11C]-SB207145 Positron Emission Tomography imaging data from the NeuroPharm-NP1 Study (NCT02869035) were available from 59 depressed premenopausal women, of which 26 used OCs and 10 used HIUDs. The participants were treated with escitalopram. Treatment response was measured as the relative change in the Hamilton Depression Rating Scale 6 items (rΔHAMD6) from baseline to week eight. Latent variable models were used to evaluate the association between global 5-HT4R binding and OC and HIUD use as well as rΔHAMD6.

Results

We found no evidence of a difference in global 5-HT4R binding between depressed HC users and non-users (p≥0.51). A significant crossover interaction (p=0.02) was observed between non-users and OC users in the association between baseline global 5-HT4R binding and week eight rΔHAMD6; OC users had 3-4% lower binding compared to non-users for every 10% percent less improvement in HAMD6. Within the groups, we observed a trend towards a positive association in non-users (padj=0.10) and a negative association in OC users (padj=0.07). We found no strong evidence of a difference in treatment response between the groups (p=0.13).

Conclusions

We found no difference in 5-HT4R binding between HC users vs. non-users in depressed women, however, it seemed that 5-HT4R settings differed qualitatively in their relation to antidepressant drug treatment response between OC users and non-users. From this we speculate that depressed OC users constitutes a special serotonin subtype of depression, which might have implications for antidepressant drug treatment response.
TERT Promoter Mutations Are an Independent Predictor of Distant Metastasis in Middle Eastern Papillary Thyroid Microcarcinoma
Authors: Parvathareddy Sandeep Kumar , Siraj Abdul K. , Iqbal Kaleem , Qadri Zeeshan , Ahmed Saeeda O. , Al-Rasheed Maha , AlQatie Ahmed A. , Al-Sobhi Saif S. , Al-Dayel Fouad , Al-Kuraya Khawla S.
Published: March 2022

Background

Papillary thyroid microcarcinomas (PTMCs) have been attributed to the recent increased incidence of thyroid cancer. Although indolent, a subset of PTMC could potentially develop distant metastasis (DM). This study aimed to evaluate the clinico-pathological features and molecular characteristics of PTMC and identify the risk factors for DM in PTMC patients from Middle Eastern ethnicity.

Methods

We retrospectively analyzed 210 patients with histologically confirmed PTMC. Clinico-pathological associations for DM, BRAF mutation and TERT mutation were analyzed successfully in 184 patients. Multivariate analysis was performed using Cox proportional hazards model and logistic regression analysis.

Results

Among the PTMC patients included in this cohort, DM was noted in 6.0% (11/184), whereas tumor relapse occurred in 29/184 (15.8%). Of the 11 cases with DM, lung metastasis occurred in 8 cases, bone metastasis in 2 cases and brain metastasis in 1 case. Presence of extrathyroidal extension and male sex were significantly associated with DM. Molecular analysis showed BRAF V600E mutations to be the most frequent, being detected in 45.7% (84/184). TERT promoter mutations were detected in 16 (8.7%) cases and were significantly associated with DM and shorter metastasis-free survival in multivariate analysis.

Conclusions

Our study indicates a surprisingly high frequency of TERT promoter mutation in Saudi patients with PTMC. Identifying TERT promoter mutations as an independent predictor of DM in patients with microcarcinoma could explain the inherent aggressive nature of PTMC from Middle Eastern ethnicity and magnify its role in patient risk stratification, which might help in improving therapeutic strategy for these patients.
Insights Into Genome-Wide Association Study for Diabetes: A Bibliometric and Visual Analysis From 2001 to 2021
Authors: Liu Yang , Wang Yun , Qin Shan , Jin Xinye , Jin Lingzi , Gu Weijun , Mu Yiming
Published: March 2022

Hundreds of research and review articles concerning genome-wide association study (GWAS) in diabetes have been published in the last two decades. We aimed to evaluate the hotspots and future trends in GWAS in diabetes research through bibliometric analysis. Accordingly, 567 research and review articles published between 2001 and 2021 were included. A rising trend was noted in the annual number of publications and citations on GWAS in diabetes during this period. Harvard University and Harvard Medical School have played leading roles in genome research. Hotspot analyses indicated that DNA methylation and genetic variation, especially in type 2 diabetes mellitus, are likely to remain the research hotspots. Moreover, the identification of genetic phenotypes associated with adiposity, metabolic memory, pancreatic islet, and inflammation is the leading trend in this research field. Through this review, we provide predictions on the main research trends in the future so as to shed light on new directions and ideas for further investigations on the genetic etiology of diabetes for its prevention and treatment.
Towards Achieving Environmental Sustainability: The Role of Nuclear Energy, Renewable Energy, and ICT in the Top-Five Carbon Emitting Countries
Authors: Azam Anam , Rafiq Muhammad , Shafique Muhammad , Yuan Jiahai
Published: March 2022

In the era of globalization, the incidence of global warming emerges from the issue of climate change, which attracts the attention of several scholars to attain sustainability with respect to ensuring sufficient energy access and diminishing environmental adversities. However, in view of these circumstances, this study examines the heterogenous impacts of nuclear energy, renewable energy, and information and communication technologies (ICTs) on pollution emissions reduction for the top-five emitter countries, covering the data from the period from 1995–2017. This study employs an advanced panel quantile regression model that takes into account both unobserved individual heterogeneity and distributional heterogeneity. The findings illustrate that the effect of all the selected explanatory variables on CO2 emissions is heterogenous along the quantiles. Our outcome supports the notion that nuclear energy consumption is insignificant in contributing to lower environmental pollution. Renewable energy consumption and ICT significantly decrease the carbon emissions of emitter economies, but the negative influence is more robust at the quantiles level (0.30–0.80) and (0.10, 0.20), both factors correct the environmental pollution in the five emitter countries. Finally, the findings of the study provide crucial policy recommendations to policymakers.
Multi-Objective Optimization of a T-Shaped Anti-Sloshing Baffle Based on NSGA-II
Authors: Lei Yu , Zhang Licheng , Zhong Shengzhi , Huang Bin
Published: March 2022

Unlike the solid cargo in the truck, the liquid in the tank truck fluctuates with the movement of the vehicle. Most of the current research study focuses on the transverse shock caused by the sloshing liquid and control of the liquid movement in the lateral direction. However, the movement of the fluid in the longitudinal direction also harms the vehicle dynamic. It is caused by the acceleration or deceleration of the truck. To lower the risk, the T-shaped anti-sloshing baffle is designed based on the current research study. To improve the conflict performance of the anti-sloshing baffle, the approximation model and multi-objective optimization method are initiated. The relationship between the anti-sloshing effect and the structural parameters of the anti-sloshing baffle is established by the Kriging method. The NSGA-II is initiated to minimize the maximum pressure caused by the moving liquid and the increasing mass of the anti-sloshing baffle. The maximum pressure is decreased by 40.97%, and the anti-sloshing baffle mass is decreased by 2.77%. With the optimized anti-sloshing baffle, the maximum pressure, waving damping time, and the baffle mass are decreased; the force on the tank walls and baffles is distributed more evenly, and the safety of the truck is improved.
Grey Wolf Optimization–Based Deep Echo State Network for Time Series Prediction
Authors: Chen Xiaojuan , Zhang Haiyang
Published: March 2022

The Echo State Network (ESN) is a unique type of recurrent neural network. It is built atop a reservoir, which is a sparse, random, and enormous hidden infrastructure. ESN has been successful in dealing with a variety of non-linear issues, including prediction and classification. ESN is utilized in a variety of architectures, including the recently proposed Multi-Layer (ML) architecture. Furthermore, Deep Echo State Network (DeepESN) models, which are multi-layer ESN models, have recently been proved to be successful at predicting high-dimensional complicated non-linear processes. The proper configuration of DeepESN architectures and training parameters is a time-consuming and difficult undertaking. To achieve the lowest learning error, a variety of parameters (hidden neurons, input scaling, the number of layers, and spectral radius) are carefully adjusted. However, the optimum training results may not be guaranteed by this haphazardly created work. The grey wolf optimization (GWO) algorithm is introduced in this study to address these concerns. The DeepESN based on GWO (GWODESN) is utilized in trials to forecast time series, and therefore the results are compared with the regular ESN, LSTM, and ELM models. The findings indicate that the planned model performs the best in terms of prediction.
Renewable Energy and CO2 Emissions in Top Natural Resource Rents Depending Countries: The Role of Governance
Authors: Szetela Beata , Majewska Agnieszka , Jamroz Paweł , Djalilov Bekhzod , Salahodjaev Raufhon
Published: March 2022

This study analyzes the relationship between renewable energy and CO2 emissions in top natural resource depending countries over the period 2000–2015. An important contribution of this study is to assess the role of governance. The Ordinary Least Squares Fixed effects Generalized Least Squares methods and two-step GMM estimators are used for panel data. The empirical results show that renewable energy has significant negative impact on per capita CO2 emissions. The estimates show that 1 percentage point increase in renewable energy consumption leads to 1.25% decrease in CO2 emissions per capita. We also find that renewable energy consumption decreases CO2 emissions faster in countries with higher rule of law and voice and accountability. gross domestic product per capita has inverted U-shaped relationship with CO2 emissions.
Mitonuclear Mismatch is Associated With Increased Male Frequency, Outcrossing, and Male Sperm Size in Experimentally-Evolved C. elegans
Authors: Bever Brent W. , Dietz Zachary P. , Sullins Jennifer A. , Montoya Ariana M. , Bergthorsson Ulfar , Katju Vaishali , Estes Suzanne
Published: March 2022

We provide a partial test of the mitonuclear sex hypothesis with the first controlled study of how male frequencies and rates of outcrossing evolve in response to mitonuclear mismatch by allowing replicate lineages of C. elegans nematodes containing either mitochondrial or nuclear mutations of electron transport chain (ETC) genes to evolve under three sexual systems: facultatively outcrossing (wildtype), obligately selfing, and obligately outcrossing. Among facultatively outcrossing lines, we found evolution of increased male frequency in at least one replicate line of all four ETC mutant backgrounds tested—nuclear isp-1, mitochondrial cox-1 and ctb-1, and an isp-1 IV; ctb-1M mitonuclear double mutant—and confirmed for a single line set (cox-1) that increased male frequency also resulted in successful outcrossing. We previously found the same result for lines evolved from another nuclear ETC mutant, gas-1. For several lines in the current experiment, however, male frequency declined to wildtype levels (near 0%) in later generations. Male frequency did not change in lines evolved from a wildtype control strain. Additional phenotypic assays of lines evolved from the mitochondrial cox-1 mutant indicated that evolution of high male frequency was accompanied by evolution of increased male sperm size and mating success with tester females, but that it did not translate into increased mating success with coevolved hermaphrodites. Rather, hermaphrodites’ self-crossed reproductive fitness increased, consistent with sexually antagonistic coevolution. In accordance with evolutionary theory, males and sexual outcrossing may be most beneficial to populations evolving from a state of low ancestral fitness (gas-1, as previously reported) and less beneficial or deleterious to those evolving from a state of higher ancestral fitness (cox-1). In support of this idea, the obligately outcrossing fog-2 V; cox-1 M lines exhibited no fitness evolution compared to their ancestor, while facultatively outcrossing lines showed slight upward evolution of fitness, and all but one of the obligately selfing xol-1 X; cox-1 M lines evolved substantially increased fitness—even beyond wildtype levels. This work provides a foundation to directly test the effect of reproductive mode on the evolutionary dynamics of mitonuclear genomes, as well as whether compensatory mutations (nuclear or mitochondrial) can rescue populations from mitochondrial dysfunction.
Identification of Key microRNAs and Genes in Infantile Hemangiomas
Authors: Fu Cong , Yang Kun , Zou Yuqing , Huo Ran
Published: March 2022

Infantile hemangiomas (IHs) are the most frequent vascular tumors that occur during infancy. Microribonucleic acids (miRNAs) have been demonstrated as critical regulators of gene expression in various diseases. However, the function of miRNAs in IH still remains largely unknown. In the present study, we performed a miRNA microarray analysis of IH and identified 68 differentially expressed miRNAs (DEMs). In addition, miRNA-gene networks and protein-protein interactions were constructed, and the hub miRNAs and genes of IH were screened out. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were used for biological analysis of DEMs and differentially expressed genes (DEGs). The pathway enrichment analysis of DEMs revealed several tumor-related pathways, including proteoglycans in cancer, signaling pathway regulating pluripotency of stem cells and TGF-beta signaling pathway. DEGs were mainly enriched in biological processes, including intracellular signal transduction, cell adhesion, and cell death. KEGG pathway analysis indicated that DEGs were enriched in tumorigenesis- and angiogenesis-related pathways such as proteoglycans in cancer, MAPK signaling pathway and Rap1 signaling pathway. Collectively, this study first established a comprehensive miRNA-gene network in IH, which should provide novel insights into IH pathogenesis and be beneficial to the understanding of neovascularization-related disorders.
Targeting the Retinoid X Receptor Pathway Prevents and Ameliorates Murine Chronic Graft-Versus-Host Disease
Authors: Thangavelu Govindarajan , Zaiken Michael C. , Mohamed Fathima A. , Flynn Ryan , Du Jing , Rhee Stephanie Y. , Riddle Megan J. , Aguilar Ethan G. , Panoskaltsis-Mortari Angela , Sanders Martin E. , Blazar Bruce R.
Published: March 2022

Most allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients receive peripheral blood stem cell grafts resulting in a 30%–70% incidence of chronic graft-versus-host disease (cGVHD), a major cause of mortality and morbidity in long-term survivors. While systemic steroids remain the standard of care for first-line therapy, patients may require long-term administration, and those with steroid-resistant or refractory cGVHD have a worse prognosis. Although durable and deep responses with second-line therapies can be achieved in some patients, there remains an urgent need for new therapies. In this study, we evaluated the efficacy of IRX4204, a novel agonist that activates RXRs and is in clinical trials for cancer treatment to prevent and treat cGVHD in two complementary murine models. In a major histocompatibility complex mismatched, non-sclerodermatous multiorgan system model with bronchiolitis obliterans, IRX4204 prevented and reversed cGVHD including associated pulmonary dysfunction with restoration of germinal center T-follicular helper: T-follicular regulatory cell balance. In a minor histocompatibility antigen disparate sclerodermatous model, IRX4204 treatment significantly prevented and ameliorated skin cGVHD by reducing Th1 and Th17 differentiation due to anti-inflammatory properties. Together, these results indicate that IRX4204 is a promising therapeutic option to treat cGVHD with bronchiolitis obliterans or sclerodermatous manifestations.
TMT-Based Quantitative Proteomics Analysis of Synovial Fluid-Derived Exosomes in Inflammatory Arthritis
Authors: Huang Yukai , Liu Yuqi , Huang Qidang , Sun Shanmiao , Ji Zhuyi , Huang Lixin , Li Zhi , Huang Xuechan , Deng Weiming , Li Tianwang
Published: March 2022

Objectives

To compare the proteomics of synovial fluid (SF)-derived exosomes in rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), gout, and osteoarthritis (OA) patients.

Methods

Exosomes were separated from SF by the Exoquick kit combined ultracentrifugation method. Tandem mass tags (TMT)-labeled liquid chromatography mass spectrometry (LC-MS/MS) technology was used to analyze the proteomics of SF-derived exosomes. Volcano plot, hierarchical cluster, gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted.

Results

A total of 1,678 credible proteins were detected. Sixty-nine differentially expressed proteins were found in gout, compared with OA, axSpA, and RA simultaneously. Twenty-five proteins were found highly expressed in gout uniquely, lysozyme C and protein S100-A9 included, whose bioinformatic analysis was significantly involved in “neutrophil degranulation” and “prion diseases”. Eighty-four differentially expressed proteins were found in axSpA, compared with OA, gout, and RA simultaneously. Thirty-nine proteins were found highly expressed in axSpA uniquely, RNA-binding protein 8A and protein transport protein Sec24C included, whose bioinformatic analysis was significantly involved in “acute-phase response” and “citrate cycle”. One hundred and eighty-four differentially expressed proteins were found in RA, compared with OA, gout, and axSpA simultaneously. Twenty-eight proteins were found highly expressed in RA uniquely, pregnancy zone protein (PZP) and stromelysin-1 included, whose bioinformatic analysis was significantly involved in “serine-type endopeptidase inhibitor activity” and “complement and coagulation cascades”. Enzyme-linked immunosorbent assay (ELISA) result showed that the exosome-derived PZP level of SF in RA was higher than that in OA (p < 0.05).

Conclusion

Our study for the first time described the protein profiles of SF-derived exosomes in RA, axSpA, gout, and OA patients. Some potential biomarkers and hypothetical molecular mechanisms were proposed, which may provide helpful diagnostic and therapeutic insights for inflammatory arthritis (IA).
N6-Methyladenosine Regulator-Mediated Immue Patterns and Tumor Microenvironment Infiltration Characterization in Glioblastoma
Authors: Xiong Wu , Li Cong , Wan Bowen , Zheng Ziyang , Zhang Yingfei , Wang Siming , Fan Jin
Published: March 2022

Background

Epigenetic modifications, according to emerging evidence, perform a critical role for cellular immune response and tumorigenesis. Nonetheless, the role of N6-methyladenosine modification in shaping of the glioblastoma tumor microenvironment is unknown.

Methods

N6-methyladenosine(m6A) methylation patterns in GBM patients were evaluated via multiple omics analysis of 15 m6A regulators and systematically correlated with tumor immune features. For quantification of N6-methyladenosine methylation patterns of individual patients, GM-score was developed and correlated with clinical and immunological characteristics.

Results

Glioblastoma has two different m6A methylation patterns that are strongly associated with TME characteristics, tumor subtype, immunotherapy response, and patient prognosis. High-GM-score is associated with an immune tolerance phenotype dominated by the IDH1 wild molecular subtype and the Mesenchymal tissue subtype, as well as a high infiltration of immune cells and stromal cells and a poor prognosis. Furthermore, despite higher immune checkpoint expression, individuals with a high-GM-score have a poorer response to anti-CTLA4 immunotherapy regimens due to T-cells dysfunctional. Low-GM-score individuals had an immunodeficient phenotype dominated by IDH mutant molecular subtypes and Proneural tissue subtypes, with less immune cell infiltration and a better prognosis. Furthermore, patients with low-GM-scores had higher microsatellite instability (MSI) and t-cell exclusion scores, as well as a better response to anti-CTLA4 immunotherapy regimens.

Conclusion

This study demonstrated that m6A modification patterns play an important role in the shaping of TME complexity and diversity. The GM-score could identify m6A modification patterns in individual patients, resulting in a more personalization and efficacious anti-tumor immunotherapy strategy.
Natural SARS-CoV-2 Infection Affects Neutralizing Activity in Saliva of Vaccinees
Authors: Garziano Micaela , Utyro Olga , Poliseno Mariacristina , Santantonio Teresa Antonia , Saulle Irma , Strizzi Sergio , Lo Caputo Sergio , Clerici Mario , Introini Andrea , Biasin Mara
Published: March 2022

Background

SARS-CoV-2 transmission mainly occurs through exposure of the upper airway mucosa to infected secretions such as saliva, which are excreted by an infected person. Thus, oral mucosal immunity plays a central role in the prevention of and early defense against SARS-CoV-2 infection. Although virus-specific antibody response has been extensively investigated in blood samples of SARS-CoV-2-infected patients and vaccinees, local humoral immunity in the oral cavity and its relationship to systemic antibody levels needs to be further addressed.

Material and Methods

We fine-tuned a virus neutralization assay (vNTA) to measure the neutralizing activity (NA) of plasma and saliva samples from 20 SARS-CoV-2-infected (SI), 40 SARS-CoV-2-vaccinated (SV), and 28 SARS-CoV-2-vaccinated subjects with a history of infection (SIV) using the “wild type” SARS-CoV-2 lineage B.1 (EU) and the Delta (B.1.617.2) strains. To validate the vNTA results, the presence of neutralizing antibodies (NAbs) to the spike receptor binding domain (RBD) was evaluated with an ELISA assay.

Results

NA to SARS-CoV-2 lineage B.1 (EU) was present in plasma samples from all the tested subjects, with higher titers in SIV compared to both SI and SV. Conversely, NA was detected in saliva samples from 10.3% SV, 45% SI, and 92.6% SIV, with significantly lower titers in SV compared to both SI and SIV. The detection of NAbs in saliva reflected its reduced NA in SV.

Discussion

The difference in NA of plasma vs. saliva was confirmed in a vNTA where the SARS-CoV-2 B.1 and Delta strains were tested head-to-head, which also revealed a reduced NA of both specimens compared to the B.1 variant.

Conclusions

The administration of SARS-CoV-2 vaccines was associated with limited virus NA in the oral cavity, as measured in saliva and in comparison to plasma. This difference was more evident in vaccinees without a history of SARS-CoV-2 infection, possibly highlighting the importance of local exposure at the site of virus acquisition to effectively prevent the infection and block its spread. Nevertheless, the presence of immune escape mutations as possibly represented by the SARS-CoV-2 Delta variant negatively affects both local and systemic efficacy of NA associated with vaccination.
On the Origin of Neutrophil Extracellular Traps in COVID-19
Authors: Pastorek Michal , Dúbrava Martin , Celec Peter
Published: March 2022

Despite ongoing vaccination COVID-19 is a global healthcare problem because of the lack of an effective targeted therapy. In severe COVID-19 manifesting as acute respiratory distress syndrome, uncontrolled innate immune system activation results in cytokine deregulation, damage-associated molecular patterns release upon tissue damage and high occurrence of thrombotic events. These pathomechanisms are linked to neutrophil function and dysfunction, particularly increased formation of neutrophil extracellular traps (NETs). While the association of NETs and severity of COVID-19 has been shown and proved, the causes of NETs formation are unclear. The aim of this review is to summarize potential inducers of NETs formation in severe COVID-19 and to discuss potential treatment options targeting NETs formation of removal.
Potential Roles of Long Noncoding RNAs as Therapeutic Targets in Organ Transplantation
Authors: Salehi Saeedeh , Afzali Shima , Shahi Abbas , Amirzargar Ali Akbar , Mansoori Yaser
Published: March 2022

Organ transplantation is the most preferred treatment option for end-stage organ diseases; however, allograft rejection is the major hurdle in successful long-term transplant survival. In spite of developing better HLA matching and more effective immunosuppressive regimen, one-year graft survival has been increased by nearly 90% and the incidence of acute rejection by one-year post-transplantation has been decreased by 12.2% in the last decades, chronic allograft rejection has remained as one of the major obstacles to the long-lasting survival of the transplanted allograft. Therefore, seemingly preventing the allograft rejection and inducing immunological tolerance against transplanted allografts is one of the primary goals in transplantation research to enable long-lasting graft survival. Various mechanisms such as long noncoding RNAs (lncRNAs) have been proposed that induce immune tolerance by modulating the gene expression and regulating innate and adaptive immune responses during transplantation. Besides, because of involvement in regulating epigenetic, transcriptional, and post-translational mechanisms, lncRNAs could affect allograft status. Therefore, these molecules could be considered as the potential targets for prediction, prognosis, diagnosis, and treatment of graft rejection. It is suggested that the noninvasive predictive biomarkers hold promise to overcome the current limitations of conventional tissue biopsy in the diagnosis of rejection. Hence, this review aims to provide a comprehensive overview of lncRNAs and their function to facilitate diagnosis, prognosis, and prediction of the risk of graft rejection, and the suggestive therapeutic choices after transplantation.
Role of Dynamic Actin Cytoskeleton Remodeling in Foxp3+ Regulatory T Cell Development and Function: Implications for Osteoclastogenesis
Authors: Dohnke Sebastian , Moehser Stephanie , Surnov Alexey , Kurth Thomas , Jessberger Rolf , Kretschmer Karsten , Garbe Annette I.
Published: March 2022

In T cells, processes such as migration and immunological synapse formation are accompanied by the dynamic reorganization of the actin cytoskeleton, which has been suggested to be mediated by regulators of RhoGTPases and by F-actin bundlers. SWAP-70 controls F-actin dynamics in various immune cells, but its role in T cell development and function has remained incompletely understood. CD4+ regulatory T (Treg) cells expressing the transcription factor Foxp3 employ diverse mechanisms to suppress innate and adaptive immunity, which is critical for maintaining immune homeostasis and self-tolerance. Here, we propose Swap-70 as a novel member of the Foxp3-dependent canonical Treg cell signature. We show that Swap-70-/- mice have increased numbers of Foxp3+ Treg cells with an effector/memory-like phenotype that exhibit impaired suppressor function in vitro, but maintain overall immune homeostasis in vivo. Upon formation of an immunological synapse with antigen presenting cells in vitro, cytosolic SWAP-70 protein is selectively recruited to the interface in Treg cells. In this context, Swap-70-/- Treg cells fail to downregulate CD80/CD86 on osteoclast precursor cells by trans-endocytosis and to efficiently suppress osteoclastogenesis and osteoclast function. These data provide first evidence for a crucial role of SWAP-70 in Treg cell biology and further highlight the important non-immune function of Foxp3+ Treg cells in bone homeostasis mediated through direct SWAP-70-dependent mechanisms.
Two CIDP Variants Patients With Anti-Caspr1 Antibodies in South China
Authors: Li Chong , Zheng Hui , Yuan Chao , Li Yanran , Hu Yafang , Jiang Haishan
Published: March 2022

Background and Objectives

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is considered an immune-mediated heterogeneous disease that involves both cellular and humoral immunity. The advent of the new concept of node-paranodopathy in recent years has boosted the identification of more antibody-positive CIDP variants patients. Cases of Caspr1 autoantibodies are the least common. Here, we reported two patients with Caspr1 autoantibodies and summarized their clinical features and treatment responses.

Methods

Do statistical analyses on the clinical manifestations and laboratory examinations obtained from two patients identified in this study, and eight patients with anti-Caspr1 antibodies reported in previous research. And based on the developed scoring standard, draw the radar charts and line graphs.

Results

Similar to other studies, the two patients we mentioned had a subacute and severe onset, distal phenotype, sensory ataxia, and severe pain. Differently, they had severe pain accompanying cold sense and coarse tremor in both hands, which may be a typical symptom for the anti-Caspr1 positive patient in south China. And we drew the line and radar graph for two China patients based on five aspects, muscle strength, sensory nerve, cranial nerve, laboratory tests, and NCS examinations. The two visual data charts offered new complementary means for the diagnostic assessment of CIDP variants.

Conclusion

Pain with cold sense, coarse tremor in hands, and CSF protein levels greater than 3g/L may be the source of the distinct symptoms observed in patients with anti-Caspr1 autoantibodies in south China.
Seeking Relevant Biomarkers in Common Variable Immunodeficiency
Authors: Ho Hsi-en , Cunningham-Rundles Charlotte
Published: March 2022

Common variable immunodeficiency (CVID) is the most common symptomatic form of primary immunodeficiency. More than 50% of patients in some series suffer from autoimmune or inflammatory complications (the “CVID+” phenotype), and these are not adequately addressed by current treatments. Despite major advancements in genetics, the pathogenesis of the CVID+ phenotype has remained unexplained for most patients, necessitating the need for relevant biomarkers in both the clinic and research settings. In the clinics, reduced isotype-switched memory B cells (≤ 0.55% of B cells) and reduced T cells (CD4) can be utilized to identify those with increased complication risks. Additionally, condition-specific markers have also been suggested for lymphoma (normal or elevated IgM) and progressive interstitial lung disease (increased BAFF, normal or elevated IgM). Additional biomarkers have provided insights into disease pathogenesis, demonstrating wider systemic inflammation (increased LBP, sCD14, and sCD25; expanded ILC3), mucosal defects (increased zonulin, I-FABP), and perhaps reduced anti-inflammatory capability (reduced HDL) in CVID. Most recently, efforts have revealed elevated circulating bioactive bacterial DNA levels – marking microbial translocation and potentially linking the causation of multiple inflammatory changes previously observed in CVID. The implementation of high throughput profiling techniques may accelerate the search of relevant biomarker profiles in CVID and lead to better clinical risk stratification, revealing disease insights, and identifying potential therapeutic targets.
The Inflammatory Cytokine Imbalance for Miscarriage, Pregnancy Loss and COVID-19 Pneumonia
Authors: Vesce Fortunato , Battisti Chiara , Crudo Michele
Published: March 2022

Pregnancy can be defined a vascular event upon endocrine control. In the human hemo-chorial placentation the chorionic villi penetrate the wall of the uterine spiral arteries, to provide increasing amounts of nutrients and oxygen for optimal fetal growth. In any physiological pregnancy the natural maternal response is of a Th1 inflammatory type, aimed at avoiding blood loss through the arteriolar wall openings. The control of the vascular function, during gestation as in any other condition, is achieved through the action of two main types of prostanoids: prostaglandin E2 and thromboxane on the one hand (for vasoconstriction and coagulation), prostacyclin on the other (for vasodilation and blood fluidification). The control of the maternal immune response is upon the responsibility of the fetus itself. Indeed, the chorionic villi are able to counteract the natural maternal response, thus changing the inflammatory Th1 type into the anti-inflammatory Th2. Clinical and experimental research in the past half century address to inflammation as the leading cause of abortion, pregnancy loss, premature delivery and related pulmonary, cerebral, intestinal fetal syndromes. Increased level of Interleukin 6, Interleukin 1-beta, Tumor Necrosis Factor-alfa, Interferon-gamma, are some among the well-known markers of gestational inflammation. On the other side, COVID-19 pneumonia is a result of extensive inflammation induced by viral replication within the cells of the respiratory tract. As it may happen in the uterine arteries in the absence of an effective fetal control, viral pneumonia triggers pulmonary vascular coagulation. The cytokines involved in the process are the same as those in gestational inflammation. As the fetus breathes throughout the placenta, fetal death from placental thrombosis is similar to adult death from pulmonary thrombosis. Preventing and counteracting inflammation is mandatory in both conditions. The most relevant literature dealing with the above-mentioned concepts is reviewed in the present article.
A Comprehensive Atlas of Immunological Differences Between Humans, Mice, and Non-Human Primates
Authors: Bjornson-Hooper Zachary B. , Fragiadakis Gabriela K. , Spitzer Matthew H. , Chen Han , Madhireddy Deepthi , Hu Kevin , Lundsten Kelly , McIlwain David R. , Nolan Garry P.
Published: March 2022

Animal models are an integral part of the drug development and evaluation process. However, they are unsurprisingly imperfect reflections of humans, and the extent and nature of many immunological differences are unknown. With the rise of targeted and biological therapeutics, it is increasingly important that we understand the molecular differences in the immunological behavior of humans and model organisms. However, very few antibodies are raised against non-human primate antigens, and databases of cross-reactivity between species are incomplete. Thus, we screened 332 antibodies in five immune cell populations in blood from humans and four non-human primate species generating a comprehensive cross-reactivity catalog that includes cell type-specificity. We used this catalog to create large mass cytometry universal cross-species phenotyping and signaling panels for humans, along with three of the model organisms most similar to humans: rhesus and cynomolgus macaques and African green monkeys; and one of the mammalian models most widely used in drug development: C57BL/6 mice. As a proof-of-principle, we measured immune cell signaling responses across all five species to an array of 15 stimuli using mass cytometry. We found numerous instances of different cellular phenotypes and immune signaling events occurring within and between species, and detailed three examples (double-positive T cell frequency and signaling; granulocyte response to Bacillus anthracis antigen; and B cell subsets). We also explore the correlation of herpes simian B virus serostatus on the immune profile. Antibody panels and the full dataset generated are available online as a resource to enable future studies comparing immune responses across species during the evaluation of therapeutics.
Evaluation of a Multi-Season, Community-Based Larval Source Management Program on Bioko Island, Equatorial Guinea
Authors: García Guillermo A. , Fuseini Godwin , Mba Nlang Jose Antonio , Nsue Maye Valeriano Olo , Bela Nestor Rivas , Wofford Rachel N. , Weppelmann Thomas A. , Matulis Graham , Efiri Prudencio Bibang , Smith Jordan M. , Rivas Matilde Riloha , Phiri Wonder Philip , von Fricken Michael E.
Published: March 2022

Background

In 2015 and 2016, the Bioko Island Malaria Control Project (BIMCP) introduced a pilot larvicide program, which recruited local volunteers to assess the sustainability and effectiveness of community-led larval source management. This study evaluates the effectiveness of the community-led LSM program to determine if this type of intervention could be used as a sustainable malaria control method on Bioko Island.

Methods

The pilot program was split into two phases, both taking place between February and December, with phase I in 2015 and phase II in 2016. During phase I, the BIMCP team assisted in identifying and treating Anopheles species mosquito breeding habitats. During phase II, community volunteers, with supervision from designated community leaders, identified and treated breeding habitats. Larval source management took place at thirteen locations around the Island during both phases. Human landing catches were conducted at seven sentinel sites once every month for the duration of the study period to determine average nightly biting rates.

Results

During phase I, 1,033 breeding sites were identified with a 100% treatment coverage rate. Only 970 breeding sites were identified in phase II with a 75% treatment coverage rate, a significant decrease from phase I (p<0.001). Between phase I and phase II, larvicide usage also decreased by 45% (95% CI: 32, 59%, p=0.003). However, excluding the sentinel site Balboa, vector density showed a nonsignificant (p=0.272) relationship between phase I and phase II.

Conclusion

Overall, community-based larval source management can be effective with strong operational management and oversight. However, repeated training and evaluation will be necessary to monitor the effectiveness and sustainability of such interventions.
Influences of the 1855 AD Huanghe (Yellow River) Relocation on Sedimentary Organic Carbon Burial in the Southern Yellow Sea
Authors: Liu Jianying , Li Da-Wei , Ding Yang , Ge Tiantian , Chen Weifang , Huh Chih-An , Zhao Meixun
Published: March 2022

The Huanghe (Yellow River) supplies large amount of sediments and terrestrial organic carbon (OC) to the eastern Chinese marginal seas. A relocation of the Huanghe outlet from the southern Yellow Sea (YS) to the Bohai Sea occurred in 1855 AD, however, detailed knowledge about the impact of this relocation on sedimentary source and OC burial in Chinese marginal seas is still critically lacking. In this study, we present total OC content and its isotope (δ13C), along with bulk total organic carbon (TOC)/total nitrogen (TN) molar ratio and lipid biomarker contents, in a sediment core HH12 from the southern YS with sediment age spanning the last 300 years. We find that TOC and terrestrial lipid biomarker mass accumulation rates were lower between 1855 AD and 1950 AD than that prior to 1855 AD in core HH12; and in accordance, both TOC/TN ratio and δ13C records indicate a gradual decrease of terrigenous source contributions to sedimentary OC. This suggests that the relocation of the Huanghe outlet reduced the transport of terrestrial OC to the southern YS. However, the δ13C record also indicates a relative increase of terrestrial OC contribution to sedimentary OC after 1950 AD, and the most likely explanation is increased contributions from the old Huanghe delta erosion and Korean rivers. Future studies should focus on better constraining the variations of terrestrial and marine endmembers with δ13C and Δ14C analyses of specific biomarkers to examine these linkages.