bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of Autism Spectrum Disorder, Neuroticism, and Subjective Well-Being With Cardiovascular Diseases: A Two-Sample Mendelian Randomization Study
Authors: Sun Xingang , Chen Lu , Wang Zhen , Lu Yunlong , Chen Miao , He Yuxian , Xu Hongfei , Zheng Liangrong
Published: June 2021

Background: Previous observational studies have reported an association between psychiatric traits and cardiovascular diseases (CVDs). In this two-sample Mendelian randomization (MR) study, we aimed to investigate the causality between psychiatric traits and CVDs.

Methods: Single-nucleotide polymorphisms (SNPs) associated with autism spectrum disorder (ASD), neuroticism, and subjective well-being at genome-wide significance (P < 1 × 10−8) were identified from genome-wide association studies. Summary-level data of the outcomes, including coronary artery disease (CAD), myocardial infarction (MI), atrial fibrillation (AF), and heart failure (HF), were obtained from several largest datasets. The inverse-variance weighted (IVW) method was used as our main analyses to conduct this MR study. Sensitivity analyses included the weighted median, the MR-robust adjusted profile score (MR-RAPS), and the MR pleiotropy residual sum and outlier (MR-PRESSO) method. Repeated MR analyses using a more relaxed threshold (P < 1 × 10−6) for instruments selection and multivariable MR analyses were also applied to evaluate the robustness of results.

Results: The MR analyses showed that genetic predisposition to ASD was associated with a higher risk of AF [odds ratio (OR), 1.109; 95% confidence interval (CI), 1.023–1.201; P = 0.011] and HF (OR, 1.138; 95% CI, 1.036–1.251; P = 0.007). Neuroticism was casually associated with an increased risk of AF (OR, 1.201; 95% CI, 1.037–1.392; P = 0.015), whereas subjective well-being had a protective effect on HF (OR, 0.732; 95% CI, 0.574–0.933; P = 0.012). No other causal association between psychiatric traits and CVDs was observed. Consistent results were obtained in sensitivity analyses.

Conclusion: This study provided evidence of causal associations of ASD with a higher risk of AF and HF. Besides, neuroticism was casually associated with an increased risk of AF, and subjective well-being was associated with a decreased risk of HF.
Label-Free Multiphoton Microscopy for the Detection and Monitoring of Calcific Aortic Valve Disease
Authors: Tandon Ishita , Quinn Kyle P. , Balachandran Kartik
Published: June 2021

Calcific aortic valve disease (CAVD) is the most common valvular heart disease. CAVD results in a considerable socio-economic burden, especially considering the aging population in Europe and North America. The only treatment standard is surgical valve replacement as early diagnostic, mitigation, and drug strategies remain underdeveloped. Novel diagnostic techniques and biomarkers for early detection and monitoring of CAVD progression are thus a pressing need. Additionally, non-destructive tools are required for longitudinal in vitro and in vivo assessment of CAVD initiation and progression that can be translated into clinical practice in the future. Multiphoton microscopy (MPM) facilitates label-free and non-destructive imaging to obtain quantitative, optical biomarkers that have been shown to correlate with key events during CAVD progression. MPM can also be used to obtain spatiotemporal readouts of metabolic changes that occur in the cells. While cellular metabolism has been extensively explored for various cardiovascular disorders like atherosclerosis, hypertension, and heart failure, and has shown potential in elucidating key pathophysiological processes in heart valve diseases, it has yet to gain traction in the study of CAVD. Furthermore, MPM also provides structural, functional, and metabolic readouts that have the potential to correlate with key pathophysiological events in CAVD progression. This review outlines the applicability of MPM and its derived quantitative metrics for the detection and monitoring of early CAVD progression. The review will further focus on the MPM-detectable metabolic biomarkers that correlate with key biological events during valve pathogenesis and their potential role in assessing CAVD pathophysiology.
Earthquake Early Warning System in Israel—Towards an Operational Stage
Authors: Nof Ran N. , Lior Itzhak , Kurzon Ittai
Published: June 2021

The Geological Survey of Israel has upgraded and expanded the national Israeli Seismic Network (ISN), with more than 110 stations country-wide, as part of the implementation of a governmental decision to build a national Earthquake Early Warning (EEW) system named TRUAA. This upgraded seismic network exhibits a high station density and fast telemetry. The stations are distributed mainly along the main fault systems, the Dead Sea Transform, and the Carmel-Zfira Fault, which may potentially produce Mw7.5 earthquakes. The system has recently entered a limited operational phase, allowing for initial performance estimation. Real-time performance during eight months of operation (41 earthquakes) matches expectations. Alert delays (interval between origin-time and Earthquake Early Warning alert time) are reduced to as low as 3 s, and source parameter errorstatistics are within expected values found in previous works using historical data playbacks. An evolutionary alert policy is implemented based on a magnitude threshold of Mw 4.2 and peak ground accelerations exceeding 2 cm/s2. A comparison between different ground motion prediction equations (GMPE) is presented for earthquakes from Israel and California using median ground motion prediction equations values. This analysis shows that a theoretical GMPE produced the best agreement with observed ground motions, with less bias and lower uncertainties. The performance of this GMPE was found to improve when an earthquake specific stress drop is implemented.
Novel AQP2 Mutations and Clinical Characteristics in Seven Chinese Families With Congenital Nephrogenic Diabetes Insipidus
Authors: Li Qian , Tian Dan , Cen Jing , Duan Lian , Xia Weibo
Published: June 2021

Objective

Mutations in AQP2 (aquaporin-2) lead to rare congenital nephrogenic diabetes insipidus (NDI), which has been limitedly studied in Chinese population.

Methods

Twenty-five subjects from seven families with NDI in a department (Beijing, PUMCH) were screened for AQP2 mutations. Clinical characteristics were described and genotype-phenotype correlation analysis was performed.

Results

We identified 9 AQP2 mutations in 13 patients with NDI, including 3 novel AQP2 mutations (p.G165D, p.Q255RfsTer72 and IVS3-3delC). Missense mutations were the most common mutation type, followed by splicing mutations, and frameshift mutations caused by small deletion or insertion. The onset-age in our patients was younger than 1 year old. Common manifestations included polydipsia, polyuria (7/7) and intermittent fever (6/7). Less common presentations included short stature (3/7) and mental impairment (1/7). High osmotic hypernatremia and low osmotic urine were the main biochemical features. Dilation of the urinary tract was a common complication of NDI (3/6). Level of serum sodium in NDI patients with compound het AQP2 mutations was higher than non-compound het mutations.

Conclusion

In the first and largest case series of NDI caused by AQP2 mutation in Chinese population, we identified 9 AQP2 mutations, including 3 novel mutations. Phenotype was found to correlate with genotypes, revealed by higher level of serum sodium in patients with compound het AQP2 mutations than non-compound het mutations. This knowledge broadens genotypic and phenotypic spectrum for rare congenital NDI and provided basis for studying molecular biology of AQP2.
Transferring Complex Scientific Knowledge to Useable Products for Society: The Role of the Global Integrated Ocean Assessment and Challenges in the Effective Delivery of Ocean Knowledge
Authors: Evans Karen , Zielinski Tymon , Chiba S. , Garcia-Soto Carlos , Ojaveer Henn , Park Chul , Ruwa Renison , Schmidt Jörn Oliver , Simcock Alan , Strati Anastasia , Vu Ca Thanh
Published: June 2021

The ocean provides essential services to human wellbeing through climate regulation, provision of food, energy and livelihoods, protection of communities and nurturing of social and cultural values. Yet despite the ocean’s key role for all life, it is failing as a result of unsustainable human practices. The first global integrated assessment of the marine environment, produced by the United Nations under The Regular Process for Global Reporting and Assessment of the State of the Marine Environment, including Socioeconomic Aspects (the World Ocean Assessment), identified an overall decline in ocean health. The second assessment, launched in April 2021, although recognising some bright spots and improvements, stresses ongoing decline in the ocean as a result of many unabated anthropogenic stressors on the ocean. This highlights that society, as a whole, does not fully recognise or value the importance of the ocean to their lives and impacts on the ocean caused by human activities. Further, recognition of the need for immediate and effective solutions for mitigating impacts and enabling ecosystem recovery, and the associated societal changes required is lacking. The United Nations 2030 Agenda for Sustainable Development and the United Nations Decade of Ocean Science for Sustainable Development 2021–2030 both recognize that sustainability is both a desired and essential pathway for ensuring the ocean can continue to provide the services society depends on. The World Ocean Assessment has an important role to play in increasing awareness of the ocean, the changes occurring in the ocean, the human activities causing those changes and the progress being made in reducing and mitigating the impacts of human activities on the marine environment. This paper outlines the knowledge brokering role that the Regular Process provides on ocean issues to all aspects of society from policy makers, ocean managers, ocean users to the public. It identifies the challenges faced by the Regular Process in successfully carrying out that role and lessons learned in achieving widespread uptake and recognition. Within the Decade of Ocean Science for Sustainable Development, solutions in the form of instructions or guidelines for the use of the assessment can be developed and implemented.
The Silent Threat of Non-native Fish in the Amazon: ANNF Database and Review
Authors: Doria Carolina Rodrigues da Costa , Agudelo Edwin , Akama Alberto , Barros Bruno , Bonfim Mariana , Carneiro Laís , Briglia-Ferreira Sylvio Romério , Nobre Carvalho Lucélia , Bonilla-Castillo César Augusto , Charvet Patricia , dos Santos Catâneo Dayana Tamiris Brito , da Silva Hugmar Pains , Garcia-Dávila Carmen Rosa , dos Anjos Hélio Daniel Beltrão , Duponchelle Fabrice , Encalada Andrea , Fernandes Izaias , Florentino Alexandro Cezar , Guarido Paula Carolina Paes , de Oliveira Guedes Tharles Lopes , Jimenez-Segura Luz , Lasso-Alcalá Oscar Miguel , Macean Marc Ruben , Marques Elineide Eugênio , Mendes-Júnior Raimundo Nonato G. , Miranda-Chumacero Guido , Nunes Jorge Luiz Silva , Occhi Thiago Vinícius Trento , Pereira Leonardo Silva , Castro-Pulido William , Soares Lariessa , Sousa Raniere Garcez Costa , Torrente-Vilara Gislene , Van Damme Paul André , Zuanon Jansen , Vitule Jean Ricardo Simões
Published: June 2021

Non-native fish (NNF) can threaten megadiverse aquatic ecosystems throughout the planet, but limited information is available for the Amazon Region. In this study we review NNF data in the Amazonian macroregion using spatiotemporal records on the occurrence and the richness of NNF from a collaborative network of 35 regional experts, establishing the Amazon NNF database (ANNF). The NNF species richness was analyzed by river basin and by country, as well as the policies for each geopolitical division for the Amazon. The analysis included six countries (Brazil, Peru, Bolivia, Ecuador, Venezuela, and Colombia), together comprising more than 80% of the Amazon Region. A total of 1314 NNF occurrence records were gathered. The first record of NNF in this region was in 1939 and there has been a marked increase in the last 20 years (2000–2020), during which 75% of the records were observed. The highest number of localities with NNF occurrence records was observed for Colombia, followed by Brazil and Bolivia. The NNF records include 9 orders, 17 families and 41 species. Most of the NNF species are also used in aquaculture (12 species) and in the aquarium trade (12 species). The most frequent NNF detected were Arapaima gigas, Poecilia reticulata and Oreochromis niloticus. The current data highlight that there are few documented cases on NNF in the Amazon, their negative impacts and management strategies adopted. The occurrence of NNF in the Amazon Region represents a threat to native biodiversity that has been increasing “silently” due to the difficulties of large-scale sampling and low number of NNF species reported when compared to other South American regions. The adoption of effective management measures by decision-makers is urgently needed and their enforcement needed to change this alarming trend and help protect the Amazon’s native fish diversity.
The rs12617336 and rs17574 Dipeptidyl Peptidase-4 Polymorphisms Are Associated With Hypoalphalipoproteinemia and Dipeptidyl Peptidase-4 Serum Levels: A Case-Control Study of the Genetics of Atherosclerotic Disease (GEA) Cohort
Authors: Vargas-Alarcón Gilberto , González-Salazar María del Carmen , Vázquez-Vázquez Christian , Hernández-Díaz Couder Adrián , Sánchez-Muñoz Fausto , Reyes-Barrera Juan , Criales-Vera Sergio A. , Sánchez-Guerra Marco , Osorio-Yáñez Citlalli , Posadas-Sánchez Rosalinda
Published: June 2021

Dipeptidyl peptidase-4 (DPP4) can influence lipid homeostasis and atherosclerosis progression. We aimed to assess the association of DPP4 gene polymorphisms with hypoalphalipoproteinemia and DPP4 serum levels, in a cohort of Mexican individuals. Five DPP4 polymorphisms (rs12617336, rs12617656, rs1558957, and rs3788979, and rs17574) were genotyped in 748 participants with and 745 without hypoalphalipoproteinemia. The associations were evaluated using logistic regression analyses. Under inheritance models adjusted for confounding variables, the rs12617336 (OR = 0.22, Pheterozygote = 0.001) and rs17574 (OR = 0.78, Padditive = 0.022; OR = 0.73, Pdominant = 0.012; OR = 0.73, Pheterozygote = 0.017; OR = 0.72, Pcodominant1 = 0.014) minor alleles were associated with a low risk of hypoalphalipoproteinemia. After the correction for multiple comparisons, the associations were marginal except the association of the rs12617336 that remaining significant. Additionally, both DPP4 minor alleles were associated with protection for the presence of insulin resistance (IR) (OR = 0.17, Pheterozygote = 0.019 for rs12617336 and OR = 0.75, Padditive = 0.049 for rs17574). The rs12617336 minor allele was also associated with a low risk of hyperinsulinemia (OR = 0.11, Pheterozygote = 0.006). Differences in DPP4 levels were observed in individuals with rs17574 genotypes, the rs17574 GG genotype individuals had the lowest levels. Our data suggest that rs12617336 and rs17574 DPP4 minor alleles could be envisaged as protective genetic markers for hypoalphalipoproteinemia, IR, and hyperinsulinemia. The rs17574 GG genotype was associated with the lowest DPP4 levels.
RHIVDB: A Freely Accessible Database of HIV Amino Acid Sequences and Clinical Data of Infected Patients
Authors: Tarasova Olga , Rudik Anastasia , Kireev Dmitry , Poroikov Vladimir
Published: June 2021

Human immunodeficiency virus (HIV) infection remains one of the most severe problems for humanity, particularly due to the development of HIV resistance. To evaluate an association between viral sequence data and drug combinations and to estimate an effect of a particular drug combination on the treatment results, collection of the most representative drug combinations used to cure HIV and the biological data on amino acid sequences of HIV proteins is essential. We have created a new, freely available web database containing 1,651 amino acid sequences of HIV structural proteins [reverse transcriptase (RT), protease (PR), integrase (IN), and envelope protein (ENV)], treatment history information, and CD4+ cell count and viral load data available by the user’s query. Additionally, the biological data on new HIV sequences and treatment data can be stored in the database by any user followed by an expert’s verification. The database is available on the web at http://www.way2drug.com/rhivdb.
Strategies and Future Opportunities for the Prevention, Diagnosis, and Management of Cow Milk Allergy
Authors: Zepeda-Ortega Benjamin , Goh Anne , Xepapadaki Paraskevi , Sprikkelman Aline , Nicolaou Nicolaos , Hernandez Rosa Elena Huerta , Latiff Amir Hamzah Abdul , Yat Miu Ting , Diab Mohamed , Hussaini Bakr Al , Setiabudiawan Budi , Kudla Urszula , van Neerven R. J. Joost , Muhardi Leilani , Warner John O.
Published: June 2021

The prevalence of food allergy has increased over the last 20-30 years, including cow milk allergy (CMA) which is one of the most common causes of infant food allergy. International allergy experts met in 2019 to discuss broad topics in allergy prevention and management of CMA including current challenges and future opportunities. The highlights of the meeting combined with recently published developments are presented here. Primary prevention of CMA should start from pre-pregnancy with a focus on a healthy lifestyle and food diversity to ensure adequate transfer of inhibitory IgG- allergen immune complexes across the placenta especially in mothers with a history of allergic diseases and planned c-section delivery. For non-breastfed infants, there is controversy about the preventive role of partially hydrolyzed formulae (pHF) despite some evidence of health economic benefits among those with a family history of allergy. Clinical management of CMA consists of secondary prevention with a focus on the development of early oral tolerance. The use of extensive Hydrolysate Formulae (eHF) is the nutrition of choice for the majority of non-breastfed infants with CMA; potentially with pre-, probiotics and LCPUFA to support early oral tolerance induction. Future opportunities are, among others, pre- and probiotics supplementation for mothers and high-risk infants for the primary prevention of CMA. A controlled prospective study implementing a step-down milk formulae ladder with various degrees of hydrolysate is proposed for food challenges and early development of oral tolerance. This provides a more precise gradation of milk protein exposure than those currently recommended.
Alternative Complement Pathway Is Activated and Associated with Galactose-Deficient IgA1 Antibody in IgA Nephropathy Patients
Authors: Chiu Yen-Ling , Lin Wei-Chou , Shu Kai-Hsiang , Fang Yi-Wen , Chang Fan-Chi , Chou Yu-Hsiang , Wu Ching-Fang , Chiang Wen-Chih , Lin Shuei-Liong , Chen Yung-Ming , Wu Ming-Shiou
Published: June 2021

Background

Galactose-deficient IgA1 (Gd-IgA1) and alternative complement pathway activation are considered to be involved in the pathogenesis of IgA nephropathy (IgAN). Nevertheless, the relationships between alternative pathway activation and disease activity or Gd-IgA1 level remains unclear.

Methods

Ninety-eight biopsy-diagnosed IgAN, twenty-five primary focal segmental sclerosis (FSGS) patients and forty-two healthy individuals were recruited in this study. Among them, fifty IgAN patients received immunosuppression. Follow-up blood samples at 1 and 3~6 months after immunosuppression were collected. Plasma levels of complement C5a, factor Ba and Gd-IgA1 were measured and analyzed. Immunostaining for complement was performed in twenty-five IgAN and FSGS patients.

Results

At baseline, IgAN patients had higher levels of plasma C5a, factor Ba and Gd-IgA1 than control subjects. Gd-IgA1 levels positively correlated with plasma C5a and factor Ba. In addition, levels of factor Ba and Gd-IgA1 were positively associated with proteinuria and negatively associated with renal function. Immunostaining revealed positive staining for factor Bb and C3c in glomeruli in IgAN patients, but not in FSGS patients. At baseline, patients receiving immunosuppression had more severe proteinuria and higher factor Ba. After 6 months, eGFR declined and proteinuria persisted in patients without immunosuppression. In contrast, patients who received immunosuppression exhibited decreased plasma levels of C5a, factor Ba, and Gd-IgA1 as early as 1 month after treatment. Proteinuria decreased and renal function also remained stable 6 months after immunosuppression.

Conclusions

Our results indicate a close relationship between alternative complement pathway activation, Gd-IgA1 concentration and clinical severity of IgAN. Level of complement factor B may be a potential marker for disease activity and therapeutic target in IgAN patients.
Inflammasomes and Fibrosis
Authors: Zhang Wen-Juan , Chen Shu-Juan , Zhou Shun-Chang , Wu Su-Zhen , Wang Hui
Published: June 2021

Fibrosis is the final common pathway of inflammatory diseases in various organs. The inflammasomes play an important role in the progression of fibrosis as innate immune receptors. There are four main members of the inflammasomes, such as NOD-like receptor protein 1 (NLRP1), NOD-like receptor protein 3 (NLRP3), NOD-like receptor C4 (NLRC4), and absent in melanoma 2 (AIM2), among which NLRP3 inflammasome is the most studied. NLRP3 inflammasome is typically composed of NLRP3, ASC and pro-caspase-1. The activation of inflammasome involves both “classical” and “non-classical” pathways and the former pathway is better understood. The “classical” activation pathway of inflammasome is that the backbone protein is activated by endogenous/exogenous stimulation, leading to inflammasome assembly. After the formation of “classic” inflammasome, pro-caspase-1 could self-activate. Caspase-1 cleaves cytokine precursors into mature cytokines, which are secreted extracellularly. At present, the “non-classical” activation pathway of inflammasome has not formed a unified model for activation process. This article reviews the role of NLRP1, NLRP3, NLRC4, AIM2 inflammasome, Caspase-1, IL-1β, IL-18 and IL-33 in the fibrogenesis.
Bovine Delta Papillomavirus E5 Oncoprotein Interacts With TRIM25 and Hampers Antiviral Innate Immune Response Mediated by RIG-I-Like Receptors
Authors: De Falco Francesca , Cutarelli Anna , Gentile Ivan , Cerino Pellegrino , Uleri Valeria , Catoi Adriana Florinela , Roperto Sante
Published: June 2021

Persistent infection and tumourigenesis by papillomaviruses (PVs) require viral manipulation of various of cellular processes, including those involved in innate immune responses. Herein, we showed that bovine PV (BPV) E5 oncoprotein interacts with a tripartite motif-containing 25 (TRIM25) but not with Riplet in spontaneous BPV infection of urothelial cells of cattle. Statistically significant reduced protein levels of TRIM25, retinoic acid-inducible gene I (RIG-I), and melanoma differentiation-associated gene 5 (MDA5) were detected by Western blot analysis. Real-time quantitative PCR revealed marked transcriptional downregulation of RIG-I and MDA5 in E5-expressing cells compared with healthy urothelial cells. Mitochondrial antiviral signalling (MAVS) protein expression did not vary significantly between diseased and healthy cells. Co-immunoprecipitation studies showed that MAVS interacted with a protein network composed of Sec13, which is a positive regulator of MAVS-mediated RLR antiviral signalling, phosphorylated TANK binding kinase 1 (TBK1), and phosphorylated interferon regulatory factor 3 (IRF3). Immunoblotting revealed significantly low expression levels of Sec13 in BPV-infected cells. Low levels of Sec13 resulted in a weaker host antiviral immune response, as it attenuates MAVS-mediated IRF3 activation. Furthermore, western blot analysis revealed significantly reduced expression levels of pTBK1, which plays an essential role in the activation and phosphorylation of IRF3, a prerequisite for the latter to enter the nucleus to activate type 1 IFN genes. Our results suggested that the innate immune signalling pathway mediated by RIG-I-like receptors (RLRs) was impaired in cells infected with BPVs. Therefore, an effective immune response is not elicited against these viruses, which facilitates persistent viral infection.
A Novel Immune-Related Seventeen-Gene Signature for Predicting Early Stage Lung Squamous Cell Carcinoma Prognosis
Authors: Fan Tao , Lu Zhiliang , Liu Yu , Wang Liyu , Tian He , Zheng Yujia , Zheng Bo , Xue Liyan , Tan Fengwei , Xue Qi , Gao Shugeng , Li Chunxiang , He Jie
Published: June 2021

With the increasingly early stage lung squamous cell carcinoma (LUSC) being discovered, there is an urgent need for a comprehensive analysis of the prognostic characteristics of early stage LUSC. Here, we developed an immune-related gene signature for outcome prediction of early stage LUSC based on three independent cohorts. Differentially expressed genes (DEGs) were identified using CIBERSORT and ESTMATE algorithm. Then, a 17-immune-related gene (RPRM, APOH, SSX1, MSGN1, HPR, ISM2, FGA, LBP, HAS1, CSF2, RETN, CCL2, CCL21, MMP19, PTGIS, F13A1, C1QTNF1) signature was identified using univariate Cox regression, LASSO regression and stepwise multivariable Cox analysis based on the verified DEGs from 401 cases in The Cancer Genome Atlas (TCGA) database. Subsequently, a cohort of GSE74777 containing 107 cases downloaded from Gene Expression Omnibus (GEO) database and an independent data set consisting of 36 frozen tissues collected from National Cancer Center were used to validate the predictive value of the signature. Seventeen immune-related genes were identified from TCGA cohort, which were further used to establish a classification system to construct cases into high- and low-risk groups in terms of overall survival. This classifier was still an independent prognostic factor in multivariate analysis. In addition, another two independent cohorts and different clinical subgroups validated the significant predictive value of the signature. Further mechanism research found early stage LUSC patients with high risk had special immune cell infiltration characteristics and gene mutation profiles. In conclusion, we characterized the tumor microenvironment and established a highly predictive model for evaluating the prognosis of early stage LUSC, which may provide a lead for effective immunotherapeutic options tailored for each subtype.
How Does B Cell Antigen Presentation Affect Memory CD4 T Cell Differentiation and Longevity?
Authors: Welsh Robin A. , Song Nianbin , Sadegh-Nasseri Scheherazade
Published: June 2021

Dendritic cells are the antigen presenting cells that process antigens effectively and prime the immune system, a characteristic that have gained them the spotlights in recent years. B cell antigen presentation, although less prominent, deserves equal attention. B cells select antigen experienced CD4 T cells to become memory and initiate an orchestrated genetic program that maintains memory CD4 T cells for life of the individual. Over years of research, we have demonstrated that low levels of antigens captured by B cells during the resolution of an infection render antigen experienced CD4 T cells into a quiescent/resting state. Our studies suggest that in the absence of antigen, the resting state associated with low-energy utilization and proliferation can help memory CD4 T cells to survive nearly throughout the lifetime of mice. In this review we would discuss the primary findings from our lab as well as others that highlight our understanding of B cell antigen presentation and the contributions of the MHC Class II accessory molecules to this outcome. We propose that the quiescence induced by the low levels of antigen presentation might be a mechanism necessary to regulate long-term survival of CD4 memory T cells and to prevent cross-reactivity to autoantigens, hence autoimmunity.
SARS-CoV-2 Infection in Spondyloarthritis Patients Treated With Biotechnological Drugs: A Study on Serology
Authors: Ortolan Augusta , Lorenzin Mariagrazia , Cosma Chiara , Cozzi Giacomo , Padoan Andrea , Doria Andrea , Plebani Mario , Ramonda Roberta
Published: June 2021

Objective

Serology could help to define the real extent of SARS-CoV-2 diffusion, especially in individuals considered at higher risk of COVID-19, such as spondyloarthritis (SpA) patients undergoing immunosuppressant. Our aim was to detect, by serology, previous SARS-CoV-2 contact in SpA, compared to health care workers (HCW), and healthy controls.

Methods

Sera from consecutive patients affected by SpA undergoing cytokine-targeted therapy, HCW and healthy controls from 2015 were analysed through chemiluminescent analytical system for the presence of IgG and IgM anti-SARS-CoV-2. Positive patients (IgM or IgG, or both) additionally underwent real-time Polymerase-Chain-Reaction (RT-PCR) to test for active infection. Serology was repeated at 3-months in SpA. Data across 3 groups were compared by Kruskal Wallis/Chi-square, and between 2 groups by Wilcoxon rank test/Chi-Square. P ≤ 0.05 were considered significant.

Results

200 SpA, 95 HCW and 101 controls were recruited. Positive serology was found in 25(12.5%) SpA, 8(8.4%) HCW, 0(0%) controls (p=0.001). SpA patients with positive serology more frequently reported COVID-19-like symptoms than those with negative serology (20% vs. 4%, p=0.009) and 2 had COVID-19 as confirmed by RT-PCR, non severe. No HCW reported symptoms or had positive RT-PCR. In SpA patients, at 3 months, mean IgM titres decreased from 2.76 ± 2.93 to 2.38 ± 2.95 (p=0.001), while IgG titres from 0.89 ± 3.25 to 0.31 ± 0.87 (p=ns).

Conclusions

Serology revealed that exposure to SARS-CoV-2 in SpA patients and HCW was higher than expected based on reported symptoms. In SpA, anti-cytokine therapy could act as a protective factor for a severe disease course. However, a seroconversion was not observed at 3-months.
Resistance Mutations to BTK Inhibitors Originate From the NF-κB but Not From the PI3K-RAS-MAPK Arm of the B Cell Receptor Signaling Pathway
Authors: Smith C. I. Edvard , Burger Jan A.
Published: June 2021

Since the first clinical report in 2013, inhibitors of the intracellular kinase BTK (BTKi) have profoundly altered the treatment paradigm of B cell malignancies, replacing chemotherapy with targeted agents in patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenström’s macroglobulinemia. There are over 20 BTKi, both irreversible and reversible, in clinical development. While loss-of-function (LoF) mutations in theBTKgene cause the immunodeficiency X-linked agammaglobulinemia, neither inherited, nor somaticBTKdriver mutations are known. Instead, BTKi-sensitive malignancies are addicted to BTK. BTK is activated by upstream surface receptors, especially the B cell receptor (BCR) but also by chemokine receptors, and adhesion molecules regulating B cell homing. Consequently, BTKi therapy abrogates BCR-driven proliferation and the tissue homing capacity of the malignant cells, which are being redistributed into peripheral blood. BTKi resistance can develop over time, especially in MCL and high-risk CLL patients. Frequently, resistance mutations affect the BTKi binding-site, cysteine 481, thereby reducing drug binding. Less common are gain-of-function (GoF) mutations in downstream signaling components, including phospholipase Cγ2 (PLCγ2). In a subset of patients, mechanisms outside of the BCR pathway, related e.g. to resistance to apoptosis were described. BCR signaling depends on many proteins including SYK, BTK, PI3K; still based on the resistance pattern, BTKi therapy only selects GoF alterations in the NF-κB arm, whereas an inhibitor of the p110δ subunit of PI3K instead selects resistance mutations in the RAS-MAP kinase pathway. BTK and PLCγ2 resistance mutations highlight BTK’s non-redundant role in BCR-mediated NF-κB activation. Of note, mutations affecting BTK tend to generate clone sizes larger than alterations in PLCγ2. This infers that BTK signaling may go beyond the PLCγ2-regulated NF-κB and NFAT arms. Collectively, when comparing the primary and acquired mutation spectrum in BTKi-sensitive malignancies with the phenotype of the corresponding germline alterations, we find that certain observations do not readily fit with the existing models of BCR signaling.
The Yin and Yang of Type 1 Regulatory T Cells: From Discovery to Clinical Application
Authors: Sayitoglu Ece Canan , Freeborn Robert Arthur , Roncarolo Maria Grazia
Published: June 2021

Regulatory T cells are essential players of peripheral tolerance and suppression of inflammatory immune responses. Type 1 regulatory T (Tr1) cells are FoxP3-regulatory T cells induced in the periphery under tolerogenic conditions. Tr1 cells are identified as LAG3+CD49b+mature CD4+T cells that promote peripheral tolerance through secretion of IL-10 and TGF-β in addition to exerting perforin- and granzyme B-mediated cytotoxicity against myeloid cells. After the initial challenges of isolation were overcome by surface marker identification,ex vivoexpansion of antigen-specific Tr1 cells in the presence of tolerogenic dendritic cells (DCs) and IL-10 paved the way for their use in clinical trials. With one Tr1-enriched cell therapy product already in a Phase I clinical trial in the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT), Tr1 cell therapy demonstrates promising results so far in terms of efficacy and safety. In the current review, we identify developments in phenotypic and molecular characterization of Tr1 cells and discuss the potential of engineered Tr1-like cells for clinical applications of Tr1 cell therapies. More than 3 decades after their initial discovery, Tr1 cell therapy is now being used to prevent graft versus host disease (GvHD) in allo-HSCT and will be an alternative to immunosuppression to promote graft tolerance in solid organ transplantation in the near future.
Emerging New Approaches in Desensitization: Targeted Therapies for HLA Sensitization
Authors: Choi Ashley Y. , Manook Miriam , Olaso Danae , Ezekian Brian , Park Jaeberm , Freischlag Kyle , Jackson Annette , Knechtle Stuart , Kwun Jean
Published: June 2021

There is an urgent need for therapeutic interventions for desensitization and antibody-mediated rejection (AMR) in sensitized patients with preformed or de novo donor-specific HLA antibodies (DSA). The risk of AMR and allograft loss in sensitized patients is increased due to preformed DSA detected at time of transplant or the reactivation of HLA memory after transplantation, causing acute and chronic AMR. Alternatively, de novo DSA that develops post-transplant due to inadequate immunosuppression and again may lead to acute and chronic AMR or even allograft loss. Circulating antibody, the final product of the humoral immune response, has been the primary target of desensitization and AMR treatment. However, in many cases these protocols fail to achieve efficient removal of all DSA and long-term outcomes of patients with persistent DSA are far worse when compared to non-sensitized patients. We believe that targeting multiple components of humoral immunity will lead to improved outcomes for such patients. In this review, we will briefly discuss conventional desensitization methods targeting antibody or B cell removal and then present a mechanistically designed desensitization regimen targeting plasma cells and the humoral response.
Impacts of Seagrass on Benthic Microalgae and Phytoplankton Communities in an Experimentally Warmed Coral Reef Mesocosm
Authors: Tew Kwee Siong , Kuo Jimmy , Cheng Jing-O , Ko Fung-Chi , Meng Pei-Jie , Mayfield Anderson B. , Liu Pi-Jen
Published: June 2021

The effects of seagrass on microalgal assemblages under experimentally elevated temperatures (28°C) and CO2 partial pressures (pCO2; 800 μatm) were examined using coral reef mesocosms. Concentrations of nitrate, ammonium, and benthic microalgal chlorophyll a (chl-a) were significantly higher in seagrass mesocosms, whereas phytoplankton chl-a concentrations were similar between seagrass and seagrass-free control mesocosms. In the seagrass group, fewer parasitic dinoflagellate OTUs (e.g., Syndiniales) were found in the benthic microalgal community though more symbiotic dinoflagellates (e.g., Cladocopium spp.) were quantified in the phytoplankton community. Our results suggest that, under ocean acidification conditions, the presence of seagrass nearby coral reefs may (1) enhance benthic primary productivity, (2) decrease parasitic dinoflagellate abundance, and (3) possibly increase the presence of symbiotic dinoflagellates.
Determination of Thermal Expansion, Defect Formation Energy, and Defect-Induced Strain of α-U Via ab Initio Molecular Dynamics
Authors: Beeler Benjamin , Mahbuba Khadija , Wang Yuhao , Jokisaari Andrea
Published: June 2021

Uranium (U) is often alloyed with molybdenum (Mo) or zirconium (Zr) in order to stabilize its high-temperature body-centered cubic phase for use in nuclear reactors. However, in all metallic fuel forms, the α phase of U remains in some fraction. This phase decomposition due to temperature or compositional variance can play an outsized role on fuel performance and microstructural evolution. Relatively little is known about fundamental point defect properties in α-U at non-zero temperatures, from either computational or experimental studies. This work performs the first thorough evaluation of the α phase of U via ab initio molecular dynamics (AIMD). A number of thermophysical properties are calculated as a function of temperature, including equilibrium lattice parameters, thermal expansion, and heat capacity. These results indicate a two-region behavior, with the transition at 400 K. The thermal expansion/contraction in the a/b direction occurs rapidly from 100 up to 400 K, after which a more linear and gradual change in the lattice constant takes place. The volumetric expansion matches experiments quantitatively, but the individual lattice constant expansion only matches experiments qualitatively. Point defect formation energies and induced lattice strains are also determined as a function of temperature, providing insight on defect populations and the fundamentals of irradiation growth in α-U. Interstitials induce significantly more strain than vacancies, and the nature of that strain is highly dependent on the individual lattice directions. The direction of point defect-induced lattice strain is contrary to the irradiation growth behavior of α-U. This work shows that isolated point defects cannot be the primary driving force responsible for the significant irradiation-induced growth of α-U observed experimentally.
Quality of and Recommendations for Relevant Clinical Practice Guidelines for COVID-19 Management: A Systematic Review and Critical Appraisal
Authors: Wang Yun-Yun , Huang Qiao , Shen Quan , Zi Hao , Li Bing-Hui , Li Ming-Zhen , He Shao-Hua , Zeng Xian-Tao , Yao Xiaomei , Jin Ying-Hui
Published: June 2021

Background: The morbidity and mortality of coronavirus disease 2019 (COVID-19) are still increasing. This study aimed to assess the quality of relevant COVID-19 clinical practice guidelines (CPGs) and to compare the similarities and differences between recommendations.

Methods: A comprehensive search was conducted using electronic databases (PubMed, Embase, and Web of Science) and representative guidelines repositories from December 1, 2019, to August 11, 2020 (updated to April 5, 2021), to obtain eligible CPGs. The Appraisal of Guidelines for Research and Evaluation (AGREE II) tool was used to evaluate the quality of CPGs. Four authors extracted relevant information and completed data extraction forms. All data were analyzed using R version 3.6.0 software.

Results: In total, 39 CPGs were identified and the quality was not encouragingly high. The median score (interquartile range, IQR) of every domain from AGREE II for evidence-based CPGs (EB-CPGs) versus (vs.) consensus-based CPG (CB-CPGs) was 81.94% (75.00–84.72) vs. 58.33% (52.78–68.06) in scope and purpose, 59.72% (38.89–75.00) vs. 36.11% (33.33–36.11) in stakeholder involvement, 64.58% (32.29–71.88) vs. 22.92% (16.67–26.56) in rigor of development, 75.00% (52.78–86.81) vs. 52.78% (50.00–63.89) in clarity of presentation, 40.63% (22.40–62.50) vs. 20.83% (13.54–25.00) in applicability, and 58.33% (50.00–100.00) vs. 50.00% (50.00–77.08) in editorial independence, respectively. The methodological quality of EB-CPGs were significantly superior to the CB-CPGs in the majority of domains (P < 0.05). There was no agreement on diagnosis criteria of COVID-19. But a few guidelines show Remdesivir may be beneficial for the patients, hydroxychloroquine +/– azithromycin may not, and there were more consistent suggestions regarding discharge management. For instance, after discharge, isolation management and health status monitoring may be continued.

Conclusions: In general, the methodological quality of EB-CPGs is greater than CB-CPGs. However, it is still required to be further improved. Besides, the consistency of COVID-19 recommendations on topics such as diagnosis criteria is different. Of them, hydroxychloroquine +/– azithromycin may be not beneficial to treat patients with COVID-19, but remdesivir may be a favorable risk-benefit in severe COVID-19 infection; isolation management and health status monitoring after discharge may be still necessary. Chemoprophylaxis, including SARS-CoV 2 vaccines and antiviral drugs of COVID-19, still require more trials to confirm this.
The Antimicrobial Peptide Mastoparan X Protects Against Enterohemorrhagic Escherichia coli O157:H7 Infection, Inhibits Inflammation, and Enhances the Intestinal Epithelial Barrier
Authors: Zhao Xueqin , Wang Lei , Zhu Chunling , Xia Xiaojing , Zhang Shouping , Wang Yimin , Zhang Huihui , Xu Yanzhao , Chen Shijun , Jiang Jinqing , Liu Shanqin , Wu Yundi , Wu Xilong , Zhang Gaiping , Bai Yueyu , Fotina Hanna , Hu Jianhe
Published: June 2021

Escherichia coli can cause intestinal diseases in humans and livestock, destroy the intestinal barrier, exacerbate systemic inflammation, and seriously threaten human health and animal husbandry development. The aim of this study was to investigate whether the antimicrobial peptide mastoparan X (MPX) was effective against E. coli infection. BALB/c mice infected with E. coli by intraperitoneal injection, which represents a sepsis model. In this study, MPX exhibited no toxicity in IPEC-J2 cells and notably suppressed the levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), myeloperoxidase (MPO), and lactate dehydrogenase (LDH) released by E. coli. In addition, MPX improved the expression of ZO-1, occludin, and claudin and enhanced the wound healing of IPEC-J2 cells. The therapeutic effect of MPX was evaluated in a murine model, revealing that it protected mice from lethal E. coli infection. Furthermore, MPX increased the length of villi and reduced the infiltration of inflammatory cells into the jejunum. SEM and TEM analyses showed that MPX effectively ameliorated the jejunum damage caused by E. coli and increased the number and length of microvilli. In addition, MPX decreased the expression of IL-2, IL-6, TNF-α, p-p38, and p-p65 in the jejunum and colon. Moreover, MPX increased the expression of ZO-1, occludin, and MUC2 in the jejunum and colon, improved the function of the intestinal barrier, and promoted the absorption of nutrients. This study suggests that MPX is an effective therapeutic agent for E. coli infection and other intestinal diseases, laying the foundation for the development of new drugs for bacterial infections.
Gullies and Moraines Are Islands of Biodiversity in an Arid, Mountain Landscape, Asgard Range, Antarctica
Authors: Solon Adam J. , Mastrangelo Claire , Vimercati Lara , Sommers Pacifica , Darcy John L. , Gendron Eli M. S. , Porazinska Dorota L. , Schmidt S. K.
Published: June 2021

Cold, dry, and nutrient-poor, the McMurdo Dry Valleys of Antarctica are among the most extreme terrestrial environments on Earth. Numerous studies have described microbial communities of low elevation soils and streams below glaciers, while less is known about microbial communities in higher elevation soils above glaciers. We characterized microbial life in four landscape features (habitats) of a mountain in Taylor Valley. These habitats varied significantly in soil moisture and include moist soils of a (1) lateral glacial moraine, (2) gully that terminates at the moraine, and very dry soils on (3) a southeastern slope and (4) dry sites near the gully. Using rRNA gene PCR amplicon sequencing of Bacteria and Archaea (16S SSU) and eukaryotes (18S SSU), we found that all habitat types harbored significantly different bacterial and eukaryotic communities and that these differences were most apparent when comparing habitats that had macroscopically visible soil crusts (gully and moraine) to habitats with no visible crusts (near gully and slope). These differences were driven by a relative predominance of Actinobacteria and a Colpodella sp. in non-crust habitats, and by phototrophic bacteria and eukaryotes (e.g., a moss) and predators (e.g., tardigrades) in habitats with biological soil crusts (gully and moraine). The gully and moraine also had significantly higher 16S and 18S ESV richness than the other two habitat types. We further found that many of the phototrophic bacteria and eukaryotes of the gully and moraine share high sequence identity with phototrophs from moist and wet areas elsewhere in the Dry Valleys and other cold desert ecosystems. These include a Moss (Bryum sp.), several algae (e.g., a Chlorococcum sp.) and cyanobacteria (e.g., Nostoc and Phormidium spp.). Overall, the results reported here broaden the diversity of habitat types that have been studied in the Dry Valleys of Antarctica and suggest future avenues of research to more definitively understand the biogeography and factors controlling microbial diversity in this unique ecosystem.
Antifungal Combination of Ethyl Acetate Extract of Poincianella pluviosa (DC.) L. P. Queiros Stem Bark With Amphotericin B in Cryptococcus neoformans
Authors: Andriani Gabriella Maria , Morguette Ana Elisa Belotto , Spoladori Laís Fernanda Almeida , Pereira Patrícia Morais Lopes , Cabral Weslei Roberto Correia , Fernandes Bruna Terci , Tavares Eliandro Reis , Almeida Ricardo Sérgio , Lancheros Cesar Armando Contreras , Nakamura Celso Vataru , Mello João Carlos Palazzo , Yamauchi Lucy Megumi , Yamada-Ogatta Sueli Fumie
Published: June 2021

Cryptococcus neoformans is the leading cause of cryptococcosis, an invasive and potentially fatal infectious disease. Therapeutic failures are due to the increase in antifungal resistance, the adverse effects of drugs, and the unavailability of therapeutic regimens in low-income countries, which limit the treatment of cryptococcosis, increasing the morbidity and mortality associated with these infections. Thus, new antifungal drugs and innovative strategies for the cryptococcosis treatment are urgently needed. The aim of the present study was to evaluate the effect of ethyl acetate fraction (EAF) of Poincianella pluviosa stem bark on planktonic and biofilm mode of growth of C. neoformans. Furthermore, the interaction between the EAF and amphotericin B (AmB) was evaluated in vitro and in Galleria mellonella infection model. Minimal inhibitory concentrations (MICs) of EAF ranged from 125.0 to >1,000.0 μg/ml and >1,000.0 μg/ml for planktonic and sessile cells, respectively. The combination between EAF and AmB exhibited a synergistic fungicidal activity toward C. neoformans, with a fractional inhibitory concentration index (FICI) ranging from 0.03 to 0.06 and 0.08 to 0.28 for planktonic and sessile cells, respectively. Microscopy analyses of planktonic C. neoformans cells treated with EAF, alone or combined with AmB, revealed morphological and ultrastructural alterations, including loss of integrity of the cell wall and cell membrane detachment, suggesting leakage of intracellular content, reduction of capsule size, and presence of vacuoles. Moreover, EAF alone or combined with AmB prolonged the survival rate of C. neoformans-infected G. mellonella larvae. These findings indicate that P. pluviosa may be an important source of new compounds that can be used as a fungus-specific adjuvant for the treatment of cryptococcosis.