bluuebunny/crossref_metadata_2025 huggingface dataset:
A Single-Cell Characterization of Human Post-implantation Embryos Cultured In Vitro Delineates Morphogenesis in Primary Syncytialization
Authors: Wang Yiming , Jiang Xiangxiang , Jia Lei , Wu Xulun , Wu Hao , Wang Yue , Li Qian , Yu Ruoxuan , Wang Hongmei , Xiao Zhenyu , Liang Xiaoyan
Published: June 2022

Implantation of the human blastocyst is a milestone event in embryonic development. The trophoblast is the first cell lineage to differentiate during implantation. Failures in trophoblast differentiation during implantation are correlated to the defects of pregnancy and embryonic growth. However, many gaps remain in the knowledge of human embryonic development, especially regarding trophoblast morphogenesis and function. Herein, we performed single-cell RNA sequencing (scRNA-seq) analysis on human post-implantation embryos cultured in vitro. A hierarchical model was established, which was characterized by the sequential development of two primitive cytotrophoblast cell (pCTB) subtypes, two primitive syncytiotrophoblast subtypes, and migrative trophoblast cells (MTB) after the trophectoderm . Further analysis characterized cytoskeleton transition of trophoblast cells and morphogenesis, such as irregular nuclei, cell cycle arrest, and cellular aging during implantation. Moreover, we found syncytialization of hTSCs could mimic the morphogenesis, serving as a powerful tool for further understanding of the mechanism during the implantation stage of pregnancy. Our work allows for the reconstruction of trophoblast cell transcriptional transition and morphogenesis during implantation and provides a valuable resource to study pathologies in early pregnancy, such as recurrent implantation failure.
Metabolism-Associated DNA Methylation Signature Stratifies Lower-Grade Glioma Patients and Predicts Response to Immunotherapy
Authors: Yang Guozheng , Shan Dezhi , Zhao Rongrong , Li Gang
Published: June 2022

Metabolism and DNA methylation (DNAm) are closely linked. The value of the metabolism-DNAm interplay in stratifying glioma patients has not been explored. In the present study, we aimed to stratify lower-grade glioma (LGG) patients based on the DNAm associated with metabolic reprogramming. Four data sets of LGGs from three databases (TCGA/CGGA/GEO) were used in this study. By screening the Kendall’s correlation of DNAm with 87 metabolic processes from KEGG, we identified 391 CpGs with a strong correlation with metabolism. Based on these metabolism-associated CpGs, we performed consensus clustering and identified three distinct subgroups of LGGs. These three subgroups were characterized by distinct molecular features and clinical outcomes. We also constructed a subgroup-related, quantifiable CpG signature with strong prognostic power to stratify LGGs. It also serves as a potential biomarker to predict the response to immunotherapy. Overall, our findings provide new perspectives for the stratification of LGGs and for understanding the mechanisms driving malignancy.
Host Preference of Beneficial Commensals in a Microbially-Diverse Environment
Authors: Pérez-Carrascal Olga M. , Choi Rebecca , Massot Méril , Pees Barbara , Narayan Vivek , Shapira Michael
Published: June 2022

Gut bacteria are often described by the neutral term commensals. However, the more we learn about their interactions with hosts, the more apparent it becomes that gut commensals often contribute positively to host physiology and fitness. Whether hosts can prefer beneficial bacteria, and how they do so, is not clear. This is of particular interest in the case of the bacterivore C. elegans, which depends on bacteria as food source, but also as gut colonizers that contribute to its physiology, from development to immunity. It is further unclear to what extent worms living in their microbially-diverse habitats can sense and distinguish between beneficial bacteria, food, and pathogens. Focusing on Enterobacteriaceae and members of closely related families, we isolated gut bacteria from worms raised in compost microcosms, as well as bacteria from the respective environments and evaluated their contributions to host development. Most isolates, from worms or from the surrounding environment, promoted faster development compared to the non-colonizing E. coli food strain. Pantoea strains further showed differential contributions of gut isolates versus an environmental isolate. Characterizing bacterial ability to hinder pathogenic colonization with Pseudomonas aeruginosa, supported the trend of Pantoea gut commensals being beneficial, in contrast to the environmental strain. Interestingly, worms were attracted to the beneficial Pantoea strains, preferring them over non-beneficial bacteria, including the environmental Pantoea strain. While our understanding of the mechanisms underlying these host-microbe interactions are still rudimentary, the results suggest that hosts can sense and prefer beneficial commensals.
Gametogenesis in Plasmodium: Delving Deeper to Connect the Dots
Authors: Dash Manoswini , Sachdeva Sherry , Bansal Abhisheka , Sinha Abhinav
Published: June 2022

In the coming decades, eliminating malaria is the foremost goal of many tropical countries. Transmission control, along with an accurate and timely diagnosis of malaria, effective treatment and prevention are the different aspects that need to be met synchronously to accomplish the goal. The current review is focused on one of these aspects i.e., transmission control, by looking deeper into the event called gametogenesis. In the Plasmodium life cycle, gametocytes are the first life forms of the sexual phase. The transmission of the parasite and the disease is critically dependent on the number, viability and sex ratio of mature gametocytes and their further development inside mosquito vectors. Gametogenesis, the process of conversion of gametocytes into viable gametes, takes place inside the mosquito midgut, and is a tightly regulated event with fast and multiple rounds of DNA replication and diverse cellular changes going on within a short period. Interrupting the gametocyte-gamete transition is ought to restrict the successful transmission and progression of the disease and hence an area worth exploring for designing transmission-blocking strategies. This review summarizes an in-depth and up-to-date understanding of the biochemical and physiological mechanism of gametogenesis in Plasmodium, which could be targeted to control parasite and malaria transmission. This review also raises certain key questions regarding gametogenesis biology in Plasmodium and brings out gaps that still accompany in understanding the spectacular process of gametogenesis.
Performance of a Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry Testing Algorithm for the Rapid Identification of Clinical Filamentous Molds
Authors: Fissel John A. , Holdren-Serrell Carrie K. , Memon Warda , Zhang Sean X.
Published: June 2022

One of the most significant challenges in the treatment of fungal infections is the relatively long turnaround time (TAT) required for fungal species identification. The length of TAT to identification can impact patient clinical outcomes by delaying appropriate targeted therapy. Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) has demonstrated exceptional utility in the rapid identification of bacteria and yeasts in the clinical microbiology laboratory. The capability of MALDI-TOF MS for rapid identification of clinical isolates presents an opportunity for significant advancement in the identification of filamentous molds. In this study, we employed a diagnostic algorithm using MALDI-TOF MS for the rapid identification of filamentous molds in order to assess the impact of this technology on TATs. The majority of isolates included in this study were able to be identified by MALDI-TOF MS (78%). Further, these isolates were identified in less than three days from first detection of colony growth. This study demonstrates the utility of MALDI-TOF MS in the rapid identification of filamentous molds in the clinical mycology laboratory.
The microRNA Expression Profiling in Heart Failure: A Systematic Review and Meta-Analysis
Authors: Shen Nan-Nan , Wang Jia-Liang , Fu Yong-ping
Published: June 2022

Background

Heart failure (HF) is a main consequence of cardiovascular diseases worldwide. Abnormal expression levels of microRNAs (miRNAs) in HF are observed in current studies. Novel biomarkers miRNAs may play an important role in the development of HF. Nevertheless, the inconsistency of miRNA expression limits the clinical application. We thus perform this systematic review of the miRNAs expression profiling to identify potential HF biomarkers.

Methods

The electronic databases of Embase, Medline, and Cochrane Library were systematically searched to identify the miRNA expression profiles between HF subjects and non-HF controls before May 26th, 2021. The pooled results were shown as log10 odds ratios (logORs) with 95% confidence intervals (CI) using random-effect models. Subgroup analyses were conducted according to species, region, and sample source. The quality assessment of included studies was independently conducted based on Diagnostic Accuracy Study 2 (QUADAS-2). The sensitivity analysis was conducted based on sample size.

Results

A total of 55 miRNA expression articles reporting 276 miRNAs of HF were included. 47 consistently up-regulated and 10 down-regulated miRNAs were identified in the overall analysis, with the most up-regulated miR-21 (logOR 8.02; 95% CI: 6.76–9.27, P < 0.001) and the most down-regulated miR-30c (logOR 6.62; 95% CI: 3.04–10.20, P < 0.001). The subgroup analysis of sample source identified 35 up-regulated and 10 down-regulated miRNAs in blood sample, the most up-regulated and down-regulated miRNAs were miR-210-3p and miR-30c, respectively. In the region sub-groups, let-7i-5p and miR-129 were most up-regulated and down-regulated in Asian countries, while in non-Asian countries, let-7e-5p and miR-30c were the most dysregulated. It’s worth noting that miR-622 was consistently up-regulated in both Asian and non-Asian countries. Sensitivity analysis showed that 46 out of 58 (79.31%) miRNAs were dysregulated.

Conclusion

A total of 57 consistently dysregulated miRNAs related to HF were confirmed in this study. Seven dysregulated miRNAs (miR-21, miR-30c, miR-210-3p, let-7i-5p, miR-129, let-7e-5p, and miR-622) may be considered as potential non-invasive biomarkers for HF. However, further validation in larger-scale studies are needed to verify our conclusions.
The Use of Noble Gases to Constrain Subsurface Fluid Dynamics in the Hydrocarbon Systems
Authors: Li Yan , Cao Chunhui , Hu Hongyu , Huang Huanfang
Published: June 2022

Geochemical techniques have been widely applied to study the generation and migration of hydrocarbons in sedimentary basins over the last several decades. Diagnostic biomarkers and stable carbon and hydrogen isotopes (such as δ13C and D) are generally used to identify the sources and thermal maturity of hydrocarbons and to reveal the accumulation process and mechanism of oil and gas reservoirs. However, some questions, such as secondary migration processes and pathways of oil and gas, and the relationship between groundwater flow and hydrocarbon transport, remain unclear and challenging. The low abundance and chemical inertness properties allow noble gases to serve as robust tools for tracing subsurface fluid flow. Additionally, they can be used for identifying and quantifying the role of the concomitant groundwater related to the generation and migration of hydrocarbons. This paper reviews the previous modeling work on using noble gases to study the fluid flow, flow paths, and gas/oil-water interactions in hydrocarbon systems. Noble gases from various sources can be readily identified due to their distinct isotopic and elemental signatures. Atmosphere-derived noble gases can be used to evaluate the amount of involved aquifer water associated with the hydrocarbon system and determine the groundwater migration paths and flow rates. Radiogenic noble gases accumulate over time, providing information about the subsurface fluid residence time. Questions concerning the specific trapping sites and mechanisms that affect heavy noble gas adsorption into organic sediments are still unresolved. Investigating the hydrocarbon generation, migration, and subsurface crustal fluid interactions in the hydrocarbon reservoirs can improve our understanding of noble gases as useful tracers in the subsurface environment and provide valuable geological evidence for the exploration and production of petroleum sources.
The Association Between FGF21 and Diabetic Erectile Dysfunction: Evidence from Clinical and Animal Studies
Authors: Yang Song , Zhang Yichun , Lyu Xiaohui , Gu Yuanyuan , Zhang Guodong , Liu Pengcheng , Zheng Yulu , Guo Zheng , Zhang Yanbo , Hou Haifeng
Published: June 2022

Erectile dysfunction (ED), a complication of diabetes mellitus (DM), affects 50–75% of men with diabetes. Fibroblast growth factor 21 (FGF21) is a liver-derived metabolic regulator which plays a role in insulin-independent glucose uptake in adipocytes. We designed a clinical study and an animal experiment to investigate the relationship between FGF21 and DM-induced ED. The clinical study enrolled 93 participants aged > 18 years (61 patients with type 2 DM and 32 healthy controls) from Taian City Central Hospital (TCCH) in Shandong Province, China, amongst whom the association between serum FGF21 and diabetic ED was analyzed. To further validate this association, we developed animal model of diabetic ED using Sprague-Dawley (SD) rats. Serum FGF21 concentration and FGF21 mRNA expression in penile samples of the rats were determined with Western blotting and quantitative real-time PCR. Among the 93 participants, the level of serum FGF21 was negatively correlated with the IIEF-5 score (r = -0.74, P < 0.001). The analysis on the performance of FGF21 for ED diagnosis showed that the area under the receiver operating characteristic (ROC) curve was 0.875 (95% confidence interval [CI]: 0.803 to 0.946). In the animal experiment, the levels of serum FGF21, 2-Δ Δ Ct values of FGF21 mRNA expression, and relative levels of FGF21 in penile samples were higher in the ED group compared to the DM and control groups. Our findings demonstrated an association between the FGF21 level and diabetic ED, indicating the potential of this cytokine in predicting diabetic ED.
Impaired Sensitivity to Thyroid Hormones Is Associated With Elevated Blood Glucose in Coronary Heart Disease
Authors: Yu Lu , Li Zhu , Yang Rongrong , Pan Guangwei , Cheng Qi , He Yuanyuan , Liu Yijia , Liu Fanfan , Ma Mei , Yang Tong , Wang Yang , Su Jinyu , Zheng Yanchao , Gao Shan , Xu Qiang , Li Lin , Yu Chunquan
Published: June 2022

Context

Thyroid hormones influence glucose homeostasis through central and peripheral regulation. To date, the association between thyroid hormone sensitivity and elevated blood glucose (EBG) in patients with coronary heart disease (CHD) remains unknown. The purpose of this study was to investigate the association between thyroid hormone sensitivity and risk of EBG in patients with CHD, and to further explore their association in different sexes and ages.

Methods

This large multicenter retrospective study included 30,244 patients with CHD (aged 30–80 years) between 1 January 2014 and 30 September 2020. Parameters representing central and peripheral sensitivity to thyroid hormones were calculated. Central sensitivity to thyroid hormones was assessed by calculating the Thyroid Feedback Quantile-based Index (TFQI), Thyroid-stimulating Hormone Index (TSHI), and Thyrotropin Thyroxine Resistance Index (TT4RI), and Parametric Thyroid Feedback Quantile-based Index (PTFQI); peripheral sensitivity to thyroid hormones was evaluated using the ratio of free triiodothyronine (FT3) /free thyroxine (FT4). Taking normal glucose tolerance (NGT) as a reference, logistic regression was used to analyse the relationship between central and peripheral thyroid hormone sensitivity and EBG in patients with CHD.

Results

Among the 30,244 participants, 15,493 (51.23%) had EBG. The risk of EBG was negatively correlated with TSHI (OR: 0.91; 95%CI: 0.91 to 0.92; P < 0.001), TT4RI (OR: 0.99; 95% CI: 0.99 to 0.99; P<0.001), TFQI (OR: 0.82; 95%CI: 0.80 to 0.84; P <0.001) and PTFQI (OR: 0.76; 95%CI: 0.74 to 0.78; P<0.001). Compared to males and patients aged 60 and below, the OR value for EBG was lower in females and in patients aged over 60 years old. Conversely, EBG risk was positively associated with FT3/FT4 (OR: 1.08; 95% CI: 1.07 to 1.09; P <0.001) and in the sex-categorized subgroups, males had higher OR values than females.

Conclusions

This study showed that thyroid hormone sensitivity is significantly associated with EBG in patients with CHD. This association is higher in females than in males, and the association in those aged over 60 years old is higher than that in patients aged 60 years and below.
Selecting a Project Delivery System for Wastewater Treatment Plants With Related-Indicators Under a Pythagorean Fuzzy Environment
Authors: Li Huimin , Cao Yongchao , Su Limin , Wang Fuqiang
Published: June 2022

Identifying appropriate project delivery systems for wastewater treatment plants (PDSWTPs) plays an important role for wastewater industry decision makers. This study aims to develop a PDSWTP selection model to deal with the related-indicators case by combining the advantages of Pythagorean fuzzy sets and Bonferroni mean operators. The works of this study are as follows: 1) the case with related indicators is innovatively considered as specific to the water industry, and Bonferroni mean operator and Pythagorean fuzzy sets are introduced to PDSWTP selection, which can handle complexity and fuzziness for the actual application. 2) Pythagorean fuzzy weighted Bonferroni mean (PFWBM) and Pythagorean fuzzy weighted geometry Bonferroni mean (PFWGBM) operators are used to aggregate all related indicators in PDSWTP selection, and taking full advantage of PFWBM and PFWGBM operators, a selection framework for PDSWTPs is constructed. 3) To show the robustness, the PDSWTP selection results were given with different parameters in the proposed operators. Finally, a practice example is created, and the results shown are effective and applicable.
A Scoping Review of Species Distribution Modeling Methods for Tick Vectors
Authors: Kopsco Heather L. , Smith Rebecca L. , Halsey Samniqueka J.
Published: June 2022

Background

Globally, tick-borne disease is a pervasive and worsening problem that impacts human and domestic animal health, livelihoods, and numerous economies. Species distribution models are useful tools to help address these issues, but many different modeling approaches and environmental data sources exist.

Objective

We conducted a scoping review that examined all available research employing species distribution models to predict occurrence and map tick species to understand the diversity of model strategies, environmental predictors, tick data sources, frequency of climate projects of tick ranges, and types of model validation methods.

Design

Following the PRISMA-ScR checklist, we searched scientific databases for eligible articles, their references, and explored related publications through a graphical tool (www.connectedpapers.com). Two independent reviewers performed article selection and characterization using a priori criteria.

Results

We describe data collected from 107 peer-reviewed articles that met our inclusion criteria. The literature reflects that tick species distributions have been modeled predominantly in North America and Europe and have mostly modeled the habitat suitability for Ixodes ricinus (n = 23; 21.5%). A wide range of bioclimatic databases and other environmental correlates were utilized among models, but the WorldClim database and its bioclimatic variables 1–19 appeared in 60 (56%) papers. The most frequently chosen modeling approach was MaxEnt, which also appeared in 60 (56%) of papers. Despite the importance of ensemble modeling to reduce bias, only 23 papers (21.5%) employed more than one algorithm, and just six (5.6%) used an ensemble approach that incorporated at least five different modeling methods for comparison. Area under the curve/receiver operating characteristic was the most frequently reported model validation method, utilized in nearly all (98.9%) included studies. Only 21% of papers used future climate scenarios to predict tick range expansion or contraction. Regardless of the representative concentration pathway, six of seven genera were expected to both expand and retract depending on location, while Ornithodoros was predicted to only expand beyond its current range.

Conclusion

Species distribution modeling techniques are useful and widely employed tools for predicting tick habitat suitability and range movement. However, the vast array of methods, data sources, and validation strategies within the SDM literature support the need for standardized protocols for species distribution and ecological niche modeling for tick vectors.
Crosstalk Between Histone and m6A Modifications and Emerging Roles of m6A RNA Methylation
Authors: Xu Zibin , Xie Tingfei , Sui Xiaolu , Xu Yunpeng , Ji Lecai , Zhang Yanzi , Zhang Aisha , Chen Jihong
Published: June 2022

RNA, like DNA and proteins, has been discovered to undergo dynamic and reversible chemical alterations, increasing the diversity and functional complexity of the molecule. N-6-methyladenosine (m6A) RNA methylation serves as a bridge between transcription and translation and is critical for many diseases’ progression. There is a complex interrelationship between m6A modifications and other epigenetic modifications. Their crosstalk significantly affects transcriptional outputs, translation, recruitment of chromatin modifiers, as well as the deployment of the m6A methyltransferase complex at target sites. This article outlines the potential function of m6A RNA methylation in epigenetics and summarizes its interactions with histone modifications.
Dietary Mannan Oligosaccharides Enhance the Non-Specific Immunity, Intestinal Health, and Resistance Capacity of Juvenile Blunt Snout Bream (Megalobrama amblycephala) Against Aeromonas hydrophila
Authors: Ding Zhujin , Wang Xu , Liu Yunlong , Zheng Yancui , Li Hongping , Zhang Minying , He Yang , Cheng Hanliang , Xu Jianhe , Chen Xiangning , Zhao Xiaoheng
Published: June 2022

Mannan oligosaccharides (MOS) have been studied and applied as a feed additive, whereas their regulation on the growth performance and immunity of aquatic animals lacks consensus. Furthermore, their immunoprotective effects on the freshwater fish Megalobrama amblycephala have not been sufficiently studied. Thus, we investigated the effects of dietary MOS of 0, 200, and 400 mg/kg on the growth performance, non-specific immunity, intestinal health, and resistance to Aeromonas hydrophila infection in juvenile M. amblycephala. The results showed that the weight gain rate of juvenile M. amblycephala was not significantly different after 8 weeks of feeding, whereas the feed conversion ratio decreased in the MOS group of 400 mg/kg. Moreover, dietary MOS increased the survival rate of juvenile M. amblycephala upon infection, which may be attributed to enhanced host immunity. For instance, dietary MOS increase host bactericidal and antioxidative abilities by regulating the activities of hepatic antimicrobial and antioxidant enzymes. In addition, MOS supplementation increased the number of intestinal goblet cells, and the intestine was protected from necrosis of the intestinal folds and disruption of the microvilli and junctional complexes, thus maintaining the stability of the intestinal epithelial barrier. The expression levels of M. amblycephala immune and tight junction-related genes increased after feeding dietary MOS for 8 weeks. However, the upregulated expression of immune and tight junction-related genes in the MOS supplemental groups was not as notable as that in the control group postinfection. Therefore, MOS supplementation might suppress the damage caused by excessive intestinal inflammation. Furthermore, dietary MOS affected the richness and composition of the gut microbiota, which improved the gut health of juvenile M. amblycephala by increasing the relative abundance of beneficial gut microbiota. Briefly, dietary MOS exhibited significant immune protective effects to juvenile M. amblycephala, which is a functional feed additive and immunostimulant.
Risk of Ankylosing Spondylitis in Patients With Endometriosis: A Population-Based Retrospective Cohort Study
Authors: Yin Zhihua , Low Hui-Ying , Chen Brian Shiian , Huang Kuo-Shu , Zhang Yue , Wang Yu-Hsun , Ye Zhizhong , Wei James Cheng-Chung
Published: June 2022

Objectives

Previous research has shown a possible relationship between endometriosis and autoimmune diseases. However, the relationship between endometriosis and ankylosing spondylitis (AS) is lacking. Therefore, we intended to find possible associations between endometriosis and AS using ICD-9 coding data in a population-based retrospective cohort study in Taiwan.

Method

Data for this retrospective cohort study were collected from the Taiwan National Health Insurance Research Database (NHIRD) between 2000–2012. We collected 13,145 patients with endometriosis and a 78,870 non-endometriosis comparison cohort. Diagnoses of endometriosis and AS were defined by the International Classification of Diseases-9 (ICD-9-CM) code for at least 3 outpatients or 1 hospitalization. Propensity score matching by comorbidities, corticosteroids, and non-steroidal anti-inflammatory drugs (NSAIDs) usage were done for baseline comparability. Cox proportional hazard models were used to evaluate crude and adjusted hazard ratios.

Results

The cumulative incidence of AS was higher in patients with endometriosis compared to the non-endometriosis comparison cohort (log-rank test, p = 0.015). The adjusted hazard ratio (aHR) of incidental AS in patients with endometriosis was 1.61 (95% CI = 1.11 to 2.35) in comparison to the non-endometriosis comparison cohort. An increased risk of AS was also observed in subjects with major depressive disorder (aHR = 5.05, 95% CI = 1.85 to 13.78). Stratified analyses of age subgroups showed consistent results. NSAID users had a lower risk of AS than NSAID non-users (aHR 4.57 vs 1.35, p for interaction = 0.031).

Conclusions

In this retrospective population-based cohort study, we found a higher risk of AS in patients with endometriosis. We suggest that clinicians should pay attention to the occurrence of AS in patients with endometriosis.
Murine Q Fever Vaccination Model Reveals Sex Dimorphism in Early Phase Delayed-Type Hypersensitivity Responses
Authors: Binette Picabo , Tesfamariam Mahelat , Cockrell Diane , Heinzen Robert A. , Richards Crystal , Shaia Carl , Long Carrie Mae
Published: June 2022

Delayed-type hypersensitivity (DTH) responses to microbial vaccines and related components are a major roadblock for widespread licensing of whole cell vaccines such as that of Q fever. Q fever is a zoonotic disease caused by the intracellular bacteriumCoxiella burnetii. The only currently licensed vaccine, Q-Vax®, is a whole cell inactivated formulation that is associated with a potentially severe dermal post vaccination DTH response in previously sensitized individuals. To investigate the underlying immunologic mechanisms of this response and better represent the early-phase DTH response observed in humans, a murine sensitization and skin testing model was developed and employed. Female C57Bl/6J mice displayed the most robust early-phase DTH responses following sensitization and elicitation compared to their male counterparts and other mouse strains. Immunologic responses were measured within the skin, draining lymph nodes, and serum following both sensitization and elicitation with Q fever whole cell vaccines. Local immunologic responses in the dermis were characterized by inflammation primarily involving neutrophils, macrophages, and T cells. Secondary lymphoid organ profiling revealed distinct immunological signatures following both sensitization and elicitation with a sex-based dichotomy in T cell phenotypes and antigen presenting cell numbers. Beyond providing a post-Q fever vaccination DTH model that recapitulates early-phase DTH events, these data suggest that sex is a primary factor influencing the magnitude and composition of the ensuing response.
As in Real Estate, Location Matters: Cellular Expression of Complement Varies Between Macular and Peripheral Regions of the Retina and Supporting Tissues
Authors: Zauhar Randy , Biber Josef , Jabri Yassin , Kim Mijin , Hu Jian , Kaplan Lew , Pfaller Anna M. , Schäfer Nicole , Enzmann Volker , Schlötzer-Schrehardt Ursula , Straub Tobias , Hauck Stefanie M. , Gamlin Paul D. , McFerrin Michael B. , Messinger Jeffrey , Strang Christianne E. , Curcio Christine A. , Dana Nicholas , Pauly Diana , Grosche Antje , Li Mingyao , Stambolian Dwight
Published: June 2022

The cellular events that dictate the initiation of the complement pathway in ocular degeneration, such as age-related macular degeneration (AMD), is poorly understood. Using gene expression analysis (single cell and bulk), mass spectrometry, and immunohistochemistry, we dissected the role of multiple retinal and choroidal cell types in determining the complement homeostasis. Our scRNA-seq data show that the cellular response to early AMD is more robust in the choroid, particularly in fibroblasts, pericytes and endothelial cells. In late AMD, complement changes were more prominent in the retina especially with the expression of the classical pathway initiators. Notably, we found a spatial preference for these differences. Overall, this study provides insights into the heterogeneity of cellular responses for complement expression and the cooperation of neighboring cells to complete the pathway in healthy and AMD eyes. Further, our findings provide new cellular targets for therapies directed at complement.
Fucosylation Promotes Cytolytic Function and Accumulation of NK Cells in B Cell Lymphoma
Authors: Tong Xing , Ru Yuhua , Fu Jianhong , Wang Ying , Zhu Jinjin , Ding Yiyang , Lv Fulian , Yang Menglu , Wei Xiya , Liu Chenchen , Liu Xin , Lei Lei , Wu Xiaojin , Guo Lingchuan , Xu Yang , Li Jie , Wu Peng , Gong Huanle , Chen Jia , Wu Depei
Published: June 2022

Natural killer (NK) cells have been demonstrated as a promising cellular therapy as they exert potent anti-tumor immune responses. However, applications of NK cells to tumor immunotherapy, especially in the treatment of advanced hematopoietic and solid malignancies, are still limited due to the compromised survival and short persistence of the transferred NK cells in vivo. Here, we observed that fucosyltransferase (FUT) 7 and 8 were highly expressed on NK cells, and the expression of CLA was positively correlated with the accumulation of NK cells in clinical B cell lymphoma development. Via enzyme-mediated ex vivo cell-surface fucosylation, the cytolytic effect of NK cells against B cell lymphoma was significantly augmented. Fucosylation also promoted NK cell accumulation in B cell lymphoma-targeted tissues by enhancing their binding to E-selectin. Moreover, fucosylation of NK cells also facilitated stronger T cell anti-tumor immune responses. These findings suggest that ex vivo fucosylation contributes to enhancing the effector functions of NK cells and may serve as a novel strategy for tumor immunotherapy.
Glucocorticoids Bind to SARS-CoV-2 S1 at Multiple Sites Causing Cooperative Inhibition of SARS-CoV-2 S1 Interaction With ACE2
Authors: Sarker Hassan , Panigrahi Rashmi , Hardy Eugenio , Glover J. N. Mark , Elahi Shokrollah , Fernandez-Patron Carlos
Published: June 2022

Dexamethasone may reduce mortality in COVID-19 patients. Whether dexamethasone or endogenous glucocorticoids, such as cortisol, biochemically interact with SARS-CoV-2 spike 1 protein (S1), or its cellular receptor ACE2, is unknown. Using molecular dynamics (MD) simulations and binding energy calculations, we identified 162 druggable pockets in various conformational states of S1 and all possible binding pockets for cortisol and dexamethasone. Through biochemical binding studies, we confirmed that cortisol and dexamethasone bind to S1. Limited proteolysis and mass spectrometry analyses validated several MD identified binding pockets for cortisol and dexamethasone on S1. Interaction assays indicated that cortisol and dexamethasone separately and cooperatively disrupt S1 interaction with ACE2, through direct binding to S1, without affecting ACE2 catalytic activity. Cortisol disrupted the binding of the mutant S1 Beta variant (E484K, K417N, N501Y) to ACE2. Delta and Omicron variants are mutated in or near identified cortisol-binding pockets in S1, which may affect cortisol binding to them. In the presence of cortisol, we find increased inhibition of S1 binding to ACE2 by an anti-SARS-CoV-2 S1 human chimeric monoclonal antibody against the receptor binding domain. Whether glucocorticoid/S1 direct interaction is an innate defence mechanism that may have contributed to mild or asymptomatic SARS-CoV-2 infection deserves further investigation.
IgG Anti-Spike Antibodies and Surrogate Neutralizing Antibody Levels Decline Faster 3 to 10 Months After BNT162b2 Vaccination Than After SARS-CoV-2 Infection in Healthcare Workers
Authors: Decru Bram , Van Elslande Jan , Steels Sophie , Van Pottelbergh Gijs , Godderis Lode , Van Holm Bram , Bossuyt Xavier , Van Weyenbergh Johan , Maes Piet , Vermeersch Pieter
Published: June 2022

Background

IgG anti-spike (S) antibodies arise after SARS-CoV-2 infection as well as vaccination. Levels of IgG anti-S are linked to neutralizing antibody titers and protection against (re)infection.

Methods

We measured IgG anti-S and surrogate neutralizing antibody kinetics against Wild Type (WT) and 4 Variants of Concern (VOC) in health care workers (HCW) 3 and 10 months after natural infection (“infection”, n=83) or vaccination (2 doses of BNT162b2) with (“hybrid immunity”, n=17) or without prior SARS-CoV-2 infection (“vaccination”, n=97).

Results

The humoral immune response in the “vaccination” cohort was higher at 3 months, but lower at 10 months, compared to the “infection” cohort due to a faster decline. The “hybrid immunity” cohort had the highest antibody levels at 3 and 10 months with a slower decline compared to the “vaccination” cohort. Surrogate neutralizing antibody levels (expressed as %inhibition of ACE-2 binding) showed a linear relation with log10 of IgG anti-S against WT and four VOC. IgG anti-S corresponding to 90% inhibition ranged from 489 BAU/mL for WT to 1756 BAU/mL for Beta variant. Broad pseudoneutralization predicted live virus neutralization of Omicron BA.1 in 20 randomly selected high titer samples.

Conclusions

Hybrid immunity resulted in the strongest humoral immune response. Antibodies induced by natural infection decreased more slowly than after vaccination, resulting in higher antibody levels at 10 months compared to vaccinated HCW without prior infection. There was a linear relationship between surrogate neutralizing activity and log10 IgG anti-S for WT and 4 VOC, although some VOC showed reduced sensitivity to pseudoneutralization.
EGR2 Deletion Suppresses Anti-DsDNA Autoantibody and IL-17 Production in Autoimmune-Prone B6/lpr Mice: A Differential Immune Regulatory Role of EGR2 in B6/lpr Versus Normal B6 Mice
Authors: Dai Rujuan , Wang Zhuang , Heid Bettina , Eden Kristin , Reilly Christopher M. , Ahmed S. Ansar
Published: June 2022

Previous studies have reported that deletion of the transcription factor, early growth response protein 2 (EGR2), in normal C57BL/6 (B6) resulted in the development of lupus-like autoimmune disease. However, increased EGR2 expression has been noted in human and murine lupus, which challenges the notion of the autoimmune suppressive role of EGR2 in B6 mice. In this study, we derived both conditional EGR2-/-B6/lprand EGR2-/-B6 mice to elucidate the immune and autoimmune regulatory roles of EGR2 in autoinflammation (B6/lpr) versus physiologically normal (B6) conditions. We found that conditional EGR2 deletion increased spleen weight, enhanced T cell activation and IFNγ production, and promoted germinal center B cells and LAG3+regulatory T cells development in both B6/lpr and B6 mice. Nevertheless, EGR2 deletion also showed strikingly differential effects in these two strains on T lymphocyte subsets profile, Foxp3+Tregs and plasma cell differentiation, anti-dsDNA autoantibodies and immunoglobulins production, and on the induction of IL-17 inin vitroactivated splenocytes. Specifically, EGR2 deletion in B6/lpr mice significantly decreased serum levels of anti-dsDNA autoantibodies, total IgG, IgM, IgG1, and IgG2a with reduced plasma cells differentiation. Furthermore, EGR2 deletion in B6/lpr mice had no obvious effect on IgG immunocomplex deposition, medium caliber vessel, and glomeruli inflammation but increased complement C3 immunocomplex deposition and large caliber vessel inflammation in the kidneys. Importantly, we demonstrated that EGR2 deletion in B6/lpr mice significantly reduced pathogenic CD4-CD8-CD3+B220+double negative T cells, which correlated with the reduced anti-dsDNA autoantibodies in serum and decreased IL-17 production in splenocytes of EGR2-/-B6/lpr mice. Together, our data strongly suggest that the role of EGR2 is complex. The immunoregulatory role of EGR2 varies at normal or autoinflammation conditions and should not be generalized in differential experimental settings.
T-Follicular-Like CD8+ T Cell Responses in Chronic HIV Infection Are Associated With Virus Control and Antibody Isotype Switching to IgG
Authors: Romero-Martín Luis , Tarrés-Freixas Ferran , Pedreño-López Núria , de la Concepción Maria L. Rodríguez , Cunyat Francesc , Hartigan-O'Connor Dennis , Carrillo Jorge , Mothe Beatriz , Blanco Julià , Ruiz-Riol Marta , Brander Christian , Olvera Alex
Published: June 2022

T cell responses are considered critical for the in vivo control of HIV, but the contribution of different T cell subsets to this control remains unclear. Using a boosted flow cytometric approach that is able to differentiate CD4+ and CD8+ T cell Th1/Tc1, Th2/Tc2, Th17/Tc17, Treg and Tfh/Tfc-like HIV-specific T cell populations, we identified CD8+ Tfc responses that were related to HIV plasma viral loads and associated with rate of antibody isotype class switching to IgG. This favorable balance towards IgG responses positively correlated with increased virus neutralization, higher avidity of neutralizing antibodies and more potent antibody-dependent cell cytotoxicity (ADCC) in PBMCs from HIV controllers compared to non-controllers. Our results identified the CD8+ Tfc-like T-cell response as a component of effective virus control which could possibly be exploited therapeutically.
Effects of Late Pleistocene Climatic Fluctuations on the Phylogeographic and Demographic History of Japanese Scad (Decapterus maruadsi)
Authors: Wang Qing-Hua , Wu Ren-Xie , Li Zhong-Lu , Niu Su-Fang , Zhai Yun , Huang Min , Li Biao
Published: June 2022

The Late Pleistocene-Holocene climate fluctuations have greatly influenced the phylogeographic structure and historical dynamics of many marine organisms in the western Pacific marginal seas. Here, we investigated the impact of Pleistocene glacial-interglacial cycles on the phylogeographic structure and demographic dynamics of Decapterus maruadsi, an economically important fish along the coast of the East China Sea (ECS) and northern South China Sea (NSCS). We obtained 430 concatenated sequences (Cyt b + control region, 1548–1554 bp) of D. maruadsi, including 246 newly sampled from the ECS and 184 previously determined from the NSCS. Genetic structure and phylogenetic analysis demonstrated a lack of significant population structure among 16 populations. Moreover, there was no significant differentiation among populations from Chinese coastal waters and northern Vietnam. Neutrality tests, unimodal mismatch distributions, Bayesian skyline plots, and the star-like haplotype networks all indicated a recent demographic expansion for D. maruadsi population during the Late Pleistocene-Holocene, explaining the low genetic diversity in D. maruadsi along the southeast coast of China. Notably, phylogenetic analyses and net genetic distances based on Cyt b jointly confirmed that 57 Cyt b haplotypes identified as D. maruadsi from the previously defined Sundaland-Rosario-Ranong clade actually represented D. russelli. These results not only reveal the complex effects of Pleistocene-Holocene climate fluctuations on the phylogeographic structure and demographic history of D. maruadsi but also provide useful genetic information for the management of genetic resources.
Ultrasound-Guided Selective Bronchial Intubation: A Feasibility Study in Pediatric Animal Model
Authors: Gomes Sara Hora , Miranda Alice , Pêgo José Miguel , Costa Patrício S. , Correia-Pinto Jorge
Published: June 2022

Objective

Selective one-lung ventilation used to optimize neonatal and pediatric surgical conditions is always a demanding task for anesthesiologists, especially during minimally invasive thoracoscopic surgery. This study aims to introduce an ultrasound-guided bronchial intubation and exclusion technique in a pediatric animal model.

Methods

Seven rabbits were anesthetized and airway ultrasound acquisitions were done.

Results

Tracheal tube progression along the trachea to the right bronchus and positioning of the bronchial blocker in the left bronchus were successfully done with consistent ultrasound identification of relevant anatomical structures.

Conclusion

The study provided a new application of ultrasound in airway management. More advanced experimental studies are needed since this technique has the potential for translation to pediatric anesthesia.
Longitudinal Analysis of Biologic Correlates of COVID-19 Resolution: Case Report
Authors: Bruiners Natalie , Guerrini Valentina , Ukey Rahul , Dikdan Ryan J. , Yang Jason H. , Mishra Pankaj Kumar , Onyuka Alberta , Handler Deborah , Vieth Joshua , Carayannopoulos Mary , Guo Shuang , Pollen Maressa , Pinter Abraham , Tyagi Sanjay , Feingold Daniel , Philipp Claire , Libutti Steven K. , Gennaro Maria Laura
Published: June 2022

While the biomarkers of COVID-19 severity have been thoroughly investigated, the key biological dynamics associated with COVID-19 resolution are still insufficiently understood. We report a case of full resolution of severe COVID-19 due to convalescent plasma transfusion. Following transfusion, the patient showed fever remission, improved respiratory status, and rapidly decreased viral burden in respiratory fluids and SARS-CoV-2 RNAemia. Longitudinal unbiased proteomic analysis of plasma and single-cell transcriptomics of peripheral blood cells conducted prior to and at multiple times after convalescent plasma transfusion identified the key biological processes associated with the transition from severe disease to disease-free state. These included (i) temporally ordered upward and downward changes in plasma proteins reestablishing homeostasis and (ii) post-transfusion disappearance of a subset of monocytes characterized by hyperactivated Interferon responses and decreased TNF-α signaling. Monitoring specific dysfunctional myeloid cell subsets in peripheral blood may provide prognostic keys in COVID-19.
Infants' Prefrontal Hemodynamic Responses and Functional Connectivity During Joint Attention in an Interactive-Live Setting
Authors: Naoi Nozomi , Minagawa Yasuyo , Yamamoto Jun-ichi , Kojima Shozo
Published: June 2022

The present study examined cerebral hemodynamic responses and functional connectivity during joint attention either initiated by infants (Initiating Joint Attention, IJA condition) or by their partner (Responding to Joint Attention, RJA condition). To capture responses to natural social cues in infants aged 7–12 months using functional near-infrared spectroscopy (fNIRS), we employed an interactive-live paradigm for IJA and RJA. During the measurement, an adult sat facing an infant, and objects, such as small stuffed animals, paired with sound toys were presented to the right or left side of the screen. In the RJA condition, the adult gazed at the infants' eyes and then to the objects to encourage the infants to follow the adult's gaze. On the other hand, in the IJA condition, the adult followed the infant's gaze as it shifted to the presented object. Our results indicate that the concentration of oxy-Hb in the bilateral ventral prefrontal region had significantly decreased, then followed by an increase in the right dorsal prefrontal region in the RJA. In addition, a selective activation in the bilateral dorsal prefrontal region was seen in the IJA condition. Moreover, the infants exhibited increased functional connectivity especially within the right ventral prefrontal region during RJA condition when compared with IJA conditions. These findings suggest that RJA and IJA recruit specific brain networks localized in the prefrontal cortex of infants.
EBV Exploits RNA m6A Modification to Promote Cell Survival and Progeny Virus Production During Lytic Cycle
Authors: Yanagi Yusuke , Watanabe Takahiro , Hara Yuya , Sato Yoshitaka , Kimura Hiroshi , Murata Takayuki
Published: June 2022

N6-methyladenosine (m6A) mediates various biological processes by affecting RNA stability, splicing, and translational efficiency. The roles of m6A modification in Epstein-Barr virus (EBV) infection in the lytic phase are unclear. Here, knockout of the m6A methyltransferase, N6-methyladenosine methyltransferase-like 3 (METTL3), or inhibition of methylation by DAA or UZH1a decreased the expression of viral lytic proteins and reduced progeny virion production. Interestingly, cell growth and viability were decreased by induction of the lytic cycle in METTL3-knockout or inhibitor-treated cells. Apoptosis was induced in those conditions possibly because of a decreased level of the anti-apoptotic viral protein, BHRF1. Therefore, m6A shows potential as a target of lytic induction therapy for EBV-associated cancers, including Burkitt lymphoma.
Discovery of Drug Candidates for Specific Human Disease Based on Natural Products of Gut Microbes
Authors: Wang Cheng-Yu , Wen Qing-Feng , Wang Qiao-Qiao , Kuang Xia , Dong Chuan , Deng Zi-Xin , Guo Feng-Biao
Published: June 2022

The beneficial metabolites of the microbiome could be used as a tool for screening drugs that have the potential for the therapy of various human diseases. Narrowing down the range of beneficial metabolite candidates in specific diseases was primarily a key step for further validation in model organisms. Herein, we proposed a reasonable hypothesis that the metabolites existing commonly in multiple beneficial (or negatively associated) bacteria might have a high probability of being effective drug candidates for specific diseases. According to this hypothesis, we screened metabolites associated with seven human diseases. For type I diabetes, 45 out of 88 screened metabolites had been reported as potential drugs in the literature. Meanwhile, 18 of these metabolites were specific to type I diabetes. Additionally, metabolite correlation could reflect disease relationships in some sense. Our results have demonstrated the potential of bioinformatics mining gut microbes' metabolites as drug candidates based on reported numerous microbe-disease associations and the Virtual Metabolic Human database. More subtle methods would be developed to ensure more accurate predictions.