bluuebunny/crossref_metadata_2025 huggingface dataset:
A Novel UHPLC-MS/MS Method for Measuring 8-iso-Prostaglandin F2α in Bronchoalveolar Lavage Fluid
Authors: Holder Cory , Adams Aaron , Allison Claire , Cote Olivia , Lippens Rachel , Blount Benjamin C , Wang Lanqing
Published: August 2021

In August 2019, the Centers for Disease Control and Prevention (CDC) received the first reports of lung injuries that were eventually termed e-cigarette, or vaping, product use–associated lung injury (EVALI). As part of the investigation, CDC laboratories rapidly developed assays for analyzing substances in bronchoalveolar lavage (BAL) fluid collected from EVALI case patients. This report describes the development and validation of a high-throughput isotope dilution UHPLC-MS/MS method for measuring a major oxidative stress biomarker, 8-iso-prostaglandin F2α (8-isoprostane), in BAL fluid samples. The method showed good sensitivity, 17.6 pg/ml LOD, and requires only 50 μl of sample volume. The method had high throughput with an analytical run time of 11 min. The within-day and between-day coefficient of variation (CV) were below 2%. Accuracy, calculated from spiked recovery, at three spiking levels, ranged from 95.5–101.8%. This novel UHPLC-MS/MS method characterizes oxidative stress in lung epithelial tissue and thus helps to elucidate potential pathologic processes.
Interactions Between Specific Immune Status of Pregnant Women and SARS-CoV-2 Infection
Authors: Chen Ruirong , Zhang Shaofen , Su Sheng , Ye Haiyan , Shu Haihua
Published: August 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the Coronavirus Disease 2019 (COVID-19) global pandemic. Because it is a new and highly contagious coronavirus, most people, especially pregnant women, lack immunity. It is therefore important to understand the interaction between why pregnant women are susceptible to SARS-CoV-2 and the specific immune systems of pregnant women. Here, we provide an overview of the changes that occur in the immune system during pregnancy, the activation and response of the immune system in pregnant women with COVID-19, adverse pregnancy outcomes in pregnant women with COVID-19, and the treatment and prevention of COVID-19 in this population.
Anemia of Chronic Disease in Patients With Cardiovascular Disease
Authors: Lanser Lukas , Fuchs Dietmar , Scharnagl Hubert , Grammer Tanja , Kleber Marcus E. , März Winfried , Weiss Günter , Kurz Katharina
Published: August 2021

Objective:Anemia is often found in patients with coronary artery disease (CAD) or acute coronary syndrome (ACS) and related to disease severity. Our study investigated the relationship between anemia, iron homeostasis and inflammation in CAD and examined their influence on the outcome of patients.

Patients and Methods:Markers of immune activation (neopterin, interleukin [IL]-12, IL-6, high sensitive C-reactive protein (hsCRP), fibrinogen, serum amyloid A [SAA]) and iron metabolism (ferritin, transferrin saturation, hemoglobin) were determined in 2,082 patients (68.7 % men, median age 63 years) from the Ludwigshafen Risk and cardiovascular Health (LURIC) cohort. Patients were followed-up for a median of 9.81 years.

Results:960 patients (46.1 %) presented with chronic CAD, 645 patients (31.0 %) had an ACS, and 477 patients (22.9 %) presented with no CAD in coronary angiography (CAG). Anemia (n= 357, 17.1 %) was associated with disease severity (reflected by more progressed stenosis in CAG, CCS, and NYHA classes, and a lower LV-EF), a higher cardio-cerebrovascular event rate and higher levels of inflammatory markers. Interestingly, anemia was only predictive for an adverse outcome in patients with elevated inflammatory markers. Accordingly, anemia of chronic disease (ACD) was associated with a higher cardio-cerebrovascular event-rate in the subsequent 2 years as compared to patients with other types of anemia or without anemia (14.3 vs. 6.1 vs. 4.0%,p< 0.001).

Conclusions:This study confirms that anemia and immune activation are strongly related to cardiovascular disease progression and an adverse outcome. Our data suggest that the association of anemia with disease severity and outcome might mainly be due to underlying inflammation.
Association of Post-operative Systolic Blood Pressure Variability With Mortality After Coronary Artery Bypass Grafting
Authors: Zhou Zhuoming , Chen Jiantao , Fu Guangguo , Zhuang Xiaodong , Hou Jian , Chen Sida , Huang Suiqing , Yue Yuan , Shang Liqun , Wang Keke , Lv Linhua , Liang Mengya , Wu Zhongkai
Published: August 2021

Background: Blood pressure variability (BPV) has long been considered a risk factor for cardiovascular events. We aimed to investigate whether post-operative systolic BPV was associated with early and late all-cause mortality in patients undergoing coronary artery bypass grafting (CABG).

Methods: Clinical variables and blood pressure records within the first 24 h in the post-operative intensive care unit stay from 4,509 patients operated on between 2001 and 2012 were extracted from the Medical Information Mart for Intensive Care III (MIMIC-III) database. BPV was measured as the coefficient of the variability of systolic blood pressure, and we compared patients in the highest quartile with patients in the other three quartiles.

Results: After full adjustment, patients in the highest quartile of BPV were at a higher risk of intensive care unit mortality (OR = 2.02, 95% CI: 1.11–3.69), 30-day mortality (OR = 1.92, 95% CI: 1.22–3.02), and 90-day mortality (HR = 1.64, 95% CI: 1.19–2.27). For 2,892 patients with a 4-year follow-up, the association between a higher post-operative BPV and the risk of 4-year mortality was not significant (HR = 1.17, 95% CI: 0.96–1.42). The results were supported by the comparison of survival curves and remained generally consistent in the subgroup analyses and sensitivity analyses.

Conclusions: Our findings demonstrated that in patients undergoing CABG, a higher post-operative BPV was associated with a higher risk of early mortality while the association was not significant for late mortality. Post-operative BPV can support doctors in identifying patients with potential hemodynamic instability and making timely clinical decisions.
Shale Reservoir 3D Structural Modeling Using Horizontal Well Data: Main Issues and an Improved Method
Authors: Shu Zhiguo , Wang Guochang , Luo Yang , Wang Chao , Chen Yalin , Zou Xianjun
Published: August 2021

Shale oil and gas fields usually contain many horizontal wells. The key of 3D structural modeling for shale reservoirs is to effectively utilize all structure-associated data (e.g., formation tops) in these horizontal wells. The inclination angle of horizontal wells is usually large, especially in the lateral section. As a result, formation tops in a horizontal well are located at the distinct lateral positions, while formation tops in a vertical well are usually stacked in the same or similar lateral position. It becomes very challenging to estimate shale layer thickness and structural map of multiple formation surfaces using formation tops in horizontal wells. Meanwhile, the large inclination angle of horizontal wells indicates a complicated spatial relation with shale formation surfaces. The 3D structural modeling using horizontal well data is much more difficult than that using vertical well data. To overcome these new challenges in 3D structural modeling using horizontal well data, we developed a method for 3D structural modeling using horizontal well data. The main process included 1) adding pseudo vertical wells at formation tops to convert the uncoupled formation tops to coupled formation tops as in vertical wells, 2) estimating shale thickness by balancing the shale thickness and dip angle change of a key surface, and 3) detecting horizontal well segments landing in the wrong formations and adding pseudo vertical wells to fix them. We used our improved method to successfully construct two structural models of Longmaxi–Wufeng shale reservoirs at a well pad scale and a shale oil/gas field scale. Our research demonstrated that 3D structural modeling could be improved by maximizing the utilization of horizontal well data, thus optimizing the quality of the structural model of shale reservoirs.
Characteristics and Dynamic Process Modeling of the Rainfall-Induced Landslide on August 21, 2020 in Hanyuan County, China
Authors: Yang Weibin , Wang Fulei , Tie Yongbo , Wang Dongpo , Ouyang Chaojun
Published: August 2021

On August 21, 2020, a landslide occurred in Zhonghai village of Hanyuan County, Sichuan Province, China. The landslide is triggered by two successive rounds of heavy rainfall. This landslide can be clearly divided into an initial landslide and a main landslide. The main landslide is activated by the intense impact and overloading of the initial landslide. The depth-integrated continuum method is adopted to simulate the dynamic process. Due to the complicated failure process, it is found that there is no proper unified parameters in Coulomb model which could well reproduce the two successive landslides. It implies that the dynamic process of landslides is highly associated with the characteristics of sliding bodies. Here, an implement of variable frictional coefficients for different parts is proposed and the parameters are calibrated. It is demonstrated that results from numerical modeling match well with the field investigation. The complicated landslides in two different stage can both be efficiently revealed by depth-integrated continuum modeling.
Association Between C-Peptide Level and Subclinical Myocardial Injury
Authors: Chen Ziwei , He Jing , Ma Qiang , Xiao Mingbing
Published: August 2021

Background

Previous studies have confirmed an association between C-peptide levels with the risk of cardiometabolic diseases. However, whether circulating C-peptide was related to subclinical myocardial injury (SC-MI) remains unknown.

Methods

A total of 3,752 participants without a history of cardiovascular diseases were included in our study from National Health and Nutrition Examination Survey III (NHANES III). Multivariable linear regression was performed to explore the correlation between C-peptide and cardiac injury score (CIIS). Multivariate logistic regression was used to examine the association between C-peptide quartile and SC-MI.

Results

Circulating C-peptide was significantly associated with CIIS (β:0.09, 95% confidence interval [CI]: 0.00–0.17; p = 0.041). Compared with the lowest quartile, the highest quartile of circulating C-peptide increased a 1.48-fold risk of SC-MI (Odds ratio = 1.66, 95% CI: 1.18–1.87; p = 0.001).

Conclusions

The level of C-peptide was independently associated with CIIS and SC-MI, which could serve as a new risk factor of SC-MI.
Time Restricted Eating: A Dietary Strategy to Prevent and Treat Metabolic Disturbances
Authors: Schuppelius Bettina , Peters Beeke , Ottawa Agnieszka , Pivovarova-Ramich Olga
Published: August 2021

Time-restricted eating (TRE), a dietary approach limiting the daily eating window, has attracted increasing attention in media and research. The eating behavior in our modern society is often characterized by prolonged and erratic daily eating patterns, which might be associated with increased risk of obesity, diabetes, and cardiovascular diseases. In contrast, recent evidence suggests that TRE might support weight loss, improve cardiometabolic health, and overall wellbeing, but the data are controversial. The present work reviews how TRE affects glucose and lipid metabolism based on clinical trials published until June 2021. A range of trials demonstrated that TRE intervention lowered fasting and postprandial glucose levels in response to a standard meal or oral glucose tolerance test, as well as mean 24-h glucose and glycemic excursions assessed using continuous glucose monitoring. In addition, fasting insulin decreases and improvement of insulin sensitivity were demonstrated. These changes were often accompanied by the decrease of blood triglyceride and cholesterol levels. However, a number of studies found that TRE had either adverse or no effects on glycemic and lipid traits, which might be explained by the different study designs (i.e., fasting/eating duration, daytime of eating, changes of calorie intake, duration of intervention) and study subject cohorts (metabolic status, age, gender, chronotype, etc.). To summarize, TRE represents an attractive and easy-to-adapt dietary strategy for the prevention and therapy of glucose and lipid metabolic disturbances. However, carefully controlled future TRE studies are needed to confirm these effects to understand the underlying mechanisms and assess the applicability of personalized interventions.
Metabolic Syndrome Is Associated With Altered mRNA and miRNA Content in Human Circulating Extracellular Vesicles
Authors: Li Yongxin , Meng Yu , Zhu Xiangyang , Van Wijnen Andre , Eirin Alfonso , Lerman Lilach O.
Published: August 2021

As mediators of intercellular communication, circulating extracellular vehicles (EVs) can modulate tissue and cellular pathways by altering transcription profiles in recipient cells, and their content may reflect the status of their parent cells. However, whether their cargo is altered in the metabolic syndrome (Mets) remains unclear. We hypothesized that MetS altered mRNAs and miRNAs packed within circulating-EVs. EVs were collected from plasma of patients with MetS or age-matched Lean controls (n=4 each). RNA sequencing was performed to identify dysregulated mRNAs and miRNAs, and analyze genes targeted by miRNAs, top pathways, and diseases associated with MetS-EVs. MetS patients showed elevated body weight, blood pressure, glucose, insulin, and liver injury markers levels. 1,446 mRNAs were downregulated and 32 upregulated in MetS- compared to Lean-EVs, whereas 40 miRNAs were selectively enriched and 10 downregulated in MetS-EVs. MetS upregulated in EVs genes involved in apoptosis, mitochondrial regulation, transport, and lipoproteins, but downregulated vessel and heart development, protein complex biogenesis, and angiogenesis. MetS also upregulated miRNAs targeting genes implicated in cellular processes, including oxidation–reduction, and downregulated miRNAs capable of modulating catalytic activity, as well as heart, blood vessel, and skeletal development, transcriptional regulation, apoptosis, and cell cycle. Our study, thus, indicates that human subjects with MetS show modified cargo of circulating EVs, which in turn may modulate several critical cellular functions and fate. These EVs may reflect the anomalous status of their parent cells, and potentially serve as important regulators, biomarkers, and targets in the progression and treatment of MetS.
The Associations of Serum Osteocalcin and Cortisol Levels With the Psychological Performance in Primary Hyperparathyroidism Patients
Authors: Wang Shu-min , He Yang , Zhu Min-ting , Tao Bei , Zhao Hong-yan , Sun Li-hao , Liu Jian-min
Published: August 2021

Objectives

The aim of this study was to investigate factors responsible for the psychological performance in primary hyperparathyroidism (PHPT) patients.

Methods

A group of 38 PHPT patients receiving questionnaires, including Beck Depression Inventory (BDI), State–Trait Anxiety Inventory (STAI), and 36-Item Short Form Survey (SF-36), was evaluated. The relationships between scores of questionnaires and clinical biomarkers were examined. Collinearity and linear regression model were applied to examine variables determining the scores of the questionnaire. In 192 PHPT patients, bivariate and partial correlation were used to analyze the relationships between serum concentrations of parathyroid hormone (PTH), calcium, osteocalcin (OCN), and cortisol.

Results

Among 38 patients receiving questionnaire tests, 50% (19/38) of the patients developed state anxiety, 60.5% (23/38) of the patients had the trait of developing anxiety. In addition, 18.4% (7/38) of the patients developed mild to severe depression. Serum cortisol at 8:00 was negatively and significantly correlated with social function (r = -0.389, p = 0.041) after controlling for age, sex, disease duration, serum PTH, calcium, phosphorus, and 25-hydroxyvitamin D [25(OH)D] concentration. OCN was significantly and negatively correlated with score of STAI-S (r = -0.426, p = 0.027). In the linear regression model for BDI score, variables with statistical significance were serum OCN (β = -0.422, p = 0.019) and cortisol at 0:00 (β = 0.371, p = 0.037). In 192 PHPT patients, the serum concentration of OCN (r = 0.373, p = 0.000) was positively correlated with PTH level. After controlling for age, sex, disease duration, serum 25(OH)D, phosphorus, and calcium concentration, the positive correlation between OCN and PTH was still statistically significant (r = 0.323, p = 0.000). The serum concentration of cortisol at 0:00 was significantly and positively correlated with serum calcium (r = 0.246, p = 0.001) in bivariate correlation analysis. After controlling for age, sex, disease duration, serum PTH, 25(OH)D, and phosphorus concentration, serum cortisol at 0:00 was still positively and significantly correlated with serum calcium (r = 0.245, p = 0.001).

Conclusion

Serum levels of OCN and cortisol, rather than PTH and calcium, are associated with the development of anxiety and depression symptoms in PHPT patients.
The Diagnostic Utility of the Basal Luteinizing Hormone Level and Single 60-Minute Post GnRH Agonist Stimulation Test for Idiopathic Central Precocious Puberty in Girls
Authors: Cao Ruixue , Liu Jinrong , Fu Pinguo , Zhou Yonghai , Li Zhe , Liu Peining
Published: August 2021

Objective

The present study aimed to assess the diagnostic utility of the Luteinizing hormone (LH) levels and single 60-minute post gonadotropin-releasing hormone (GnRH) agonist stimulation test for idiopathic central precocious puberty (CPP) in girls.

Methods

Data from 1,492 girls diagnosed with precocious puberty who underwent GnRH agonist stimulation testing between January 1, 2016, and October 8, 2020, were retrospectively reviewed. LH levels and LH/follicle-stimulating hormone (FSH) ratios were measured by immuno-chemiluminescence assay before and at several timepoints after GnRH analogue stimulation testing. Mann–Whitney U test, Spearman’s correlation, χ2 test, and receiver operating characteristic (ROC) analyses were performed to determine the diagnostic utility of these hormone levels.

Results

The 1,492 subjects were split into two groups: an idiopathic CPP group (n = 518) and a non-CPP group (n = 974). Basal LH levels and LH/FSH ratios were significantly different between the two groups at 30, 60, 90, and 120 minutes after GnRH analogue stimulation testing. Spearman’s correlation analysis showed the strongest correlation between peak LH and LH levels at 60 minutes after GnRH agonist stimulation (r = 0.986, P < 0.001). ROC curve analysis revealed that the 60-minute LH/FSH ratio yielded the highest consistency, with an area under the ROC curve (AUC) of 0.988 (95% confidence interval [CI], 0.982–0.993) and a cut-off point of 0.603 mIU/L (sensitivity 97.3%, specificity 93.0%). The cut-off points of basal LH and LH/FSH were 0.255 mIU/L (sensitivity 68.9%, specificity 86.0%) and 0.07 (sensitivity 73.2%, specificity 89.5%), respectively, with AUCs of 0.823 (95% CI, 0.799–0.847) and 0.843 (95% CI, 0.819–0.867), respectively.

Conclusions

A basal LH value greater than 0.535 mIU/L can be used to diagnose CPP without a GnRH agonist stimulation test. A single 60-minute post-stimulus gonadotropin result of LH and LH/FSH can be used instead of a GnRH agonist stimulation test, or samples can be taken only at 0, 30, and 60 minutes after a GnRH agonist stimulation test. This reduces the number of blood draws required compared with the traditional stimulation test, while still achieving a high level of diagnostic accuracy.
The Impact of Helminth Infection on the Incidence of Metabolic Syndrome: A Systematic Review and Meta-Analysis
Authors: Rennie Claire , Fernandez Ritin , Donnelly Sheila , McGrath Kristine CY
Published: August 2021

Background

There are a growing number of publications that report an absence of inflammatory based disease among populations that are endemic to parasitic worms (helminths) demonstrating the ability of these parasites to potentially regulate human immune responses. The aim of this systematic review and meta-analysis was to determine the impact of helminth infection on metabolic outcomes in human populations.

Methods

Using PRISMA guidelines, six databases were searched for studies published up to August 2020. Random effects meta-analysis was performed to estimate pooled proportions with 95% confidence intervals using the Review Manager Software version 5.4.1.

Results

Fourteen studies were included in the review. Fasting blood glucose was significantly lower in persons with infection (MD -0.22, 95% CI -0.40- -0.04, P=0.02), HbA1c levels were lower, although not significantly, and prevalence of the metabolic syndrome (P=0.001) and type 2 diabetes was lower (OR 1.03, 95% CI 0.34-3.09, P<0.0001). Infection was negatively associated with type 2 diabetes when comparing person with diabetes to the group without diabetes (OR 0.44, 95% CI 0.29-0.67, P=0.0001).

Conclusions

While infection with helminths was generally associated with improved metabolic function, there were notable differences in efficacy between parasite species. Based on the data assessed, live infection with S. mansoni resulted in the most significant positive changes to metabolic outcomes.

Systematic Review Registration

Website: PROSPERO Identified: CRD42021227619.
Increasing Genomic Literacy Through National Genomic Projects
Authors: Zimani Ana Nyasha , Peterlin Borut , Kovanda Anja
Published: August 2021

Genomics is an advancing field of medicine, science, ethics, and legislation. Keeping up to date with this challenging discipline requires continuous education and exchange of knowledge between many target groups. Specific challenges in genomic education include tailoring complex topics to diverse audiences ranging from the general public and patients to highly educated professionals. National genomic projects face many of the same challenges and thus offer many opportunities to highlight common educational strategies for improving genomic literacy. We have reviewed 41 current national genomic projects and have identified 16 projects specifically describing their approach to genomic education. The following target groups were included in the educational efforts: the general public (nine projects), patients (six projects), and genomic professionals (16 projects), reflecting the general overall aims of the projects such as determining normal and pathological genomic variation, improving infrastructure, and facilitating personalized medicine. The national genomic projects aim to increase genomic literacy through supplementing existing national education in genomics as well as independent measures specifically tailored to each target group, such as training events, research collaboration, and online resources for healthcare professionals, patients, and patient organizations. This review provides the current state of educational activities within national genomic projects for different target groups and identifies good practices that could contribute to patient empowerment, public engagement, proficient healthcare professionals, and lend support to personalized medicine.
Novel Approaches in the Inhibition of IgE-Induced Mast Cell Reactivity in Food Allergy
Authors: Tontini Chiara , Bulfone-Paus Silvia
Published: August 2021

Allergy is an IgE-dependent type-I hypersensitivity reaction that can lead to life-threatening systemic symptoms such as anaphylaxis. In the pathogenesis of the allergic response, the common upstream event is the binding of allergens to specific IgE, inducing cross-linking of the high-affinity FcεRI on mast cells, triggering cellular degranulation and the release of histamine, proteases, lipids mediators, cytokines and chemokines with inflammatory activity. A number of novel therapeutic options to curb mast cell activation are in the pipeline for the treatment of severe allergies. In addition to anti-IgE therapy and allergen-specific immunotherapy, monoclonal antibodies targeted against several key Th2/alarmin cytokines (i.e. IL-4Rα, IL-33, TSLP), active modification of allergen-specific IgE (i.e. inhibitory compounds, monoclonal antibodies, de-sialylation), engagement of inhibitory receptors on mast cells and allergen-specific adjuvant vaccines, are new promising options to inhibit the uncontrolled release of mast cell mediators upon allergen exposure. In this review, we critically discuss the novel approaches targeting mast cells limiting allergic responses and the immunological mechanisms involved, with special interest on food allergy treatment.
PTK7-Targeting CAR T-Cells for the Treatment of Lung Cancer and Other Malignancies
Authors: Jie Yamin , Liu Guijun , Feng Lina , Li Ying , E Mingyan , Wu Liangliang , Li Yinyin , Rong Guanghua , Li Yongwu , Wei Huafeng , Gu Anxin
Published: August 2021

In spite of impressive success in treating hematologic malignancies, adoptive therapy with chimeric antigen receptor modified T cells (CAR T) has not yet been effective in solid tumors, where identification of suitable tumor-specific antigens remains a major obstacle for CAR T-cell therapy due to the “on target off tumor” toxicity. Protein tyrosine kinase 7 (PTK7) is a member of the Wnt-related pseudokinases and identified as a highly expressed antigen enriched in cancer stem cells (CSCs) from multiple solid tumors, including but not limited to triple-negative breast cancer, non-small-cell lung cancer, and ovarian cancer, suggesting it may serve as a promising tumor-specific target for CAR T-cell therapy. In this study, we constructed three different PTK7-specific CAR (PTK7-CAR1/2/3), each comprising a humanized PTK7-specific single-chain variable fragment (scFv), hinge and transmembrane (TM) regions of the human CD8α molecule, 4-1BB intracellular co-stimulatory domain (BB-ICD), and CD3ζ intracellular domain (CD3ζ-ICD) sequence, and then prepared the CAR T cells by lentivirus-mediated transduction of human activated T cells accordingly, and we sequentially evaluated their antigen-specific recognition and killing activity in vitro and in vivo. T cells transduced with all three PTK7-CAR candidates exhibited antigen-specific cytokine production and potent cytotoxicity against naturally expressing PTK7-positive tumor cells of multiple cancer types without mediating cytotoxicity of a panel of normal primary human cells; meanwhile, in vitro recursive cytotoxicity assays demonstrated that only PTK7-CAR2 modified T cells retained effective through multiple rounds of tumor challenge. Using in vivo xenograft models of lung cancers with different expression levels of PTK7, systemic delivery of PTK7-CAR2 modified T cells significantly prevented tumor growth and prolonged overall survival of mice. Altogether, our results support PTK7 as a therapeutic target suitable for CAR T-cell therapy that could be applied for lung cancers and many other solid cancers with PTK7 overexpression.
Amino Acid Transport and Metabolism in Myeloid Function
Authors: Halaby Marie Jo , McGaha Tracy L.
Published: August 2021

Regulation of amino acid availability and metabolism in immune cells is essential for immune system homeostasis and responses to exogenous and endogenous challenges including microbial infection, tumorigenesis and autoimmunity. In myeloid cells the consumption of amino acids such as arginine and tryptophan and availability of their metabolites are key drivers of cellular identity impacting development, functional polarization to an inflammatory or regulatory phenotype, and interaction with other immune cells. In this review, we discuss recent developments and emerging concepts in our understanding of the impact amino acid availability and consumption has on cellular phenotype focusing on two key myeloid cell populations, macrophages and myeloid derived suppressor cells (MDSCs). We also highlight the potential of myeloid-specific of amino acid transporters and catabolic enzymes as immunotherapy targets in a variety of conditions such as cancer and autoimmune disease discussing the opportunities and limitations in targeting these pathways for clinical therapy.
Needs for Increased Awareness of Gastrointestinal Manifestations in Patients With Human Inborn Errors of Immunity
Authors: Kim Eun Sil , Kim Dongsub , Yoon Yoonsun , Kwon Yiyoung , Park Sangwoo , Kim Jihyun , Ahn Kang Mo , Ahn Soomin , Choe Yon Ho , Kim Yae-Jean , Kim Mi Jin
Published: August 2021

The gastrointestinal (GI) tract is frequently affected by inborn errors of immunity (IEI), and GI manifestations can be present in IEI patients before a diagnosis is confirmed. We aimed to investigate clinical features, endoscopic and histopathologic findings in IEI patients. This was a retrospective cohort study conducted from 1995 to 2020. Eligible patients were diagnosed with IEI and had GI manifestations that were enough to require endoscopies. IEI was classified according to the International Union of Immunological Societies classification. Of 165 patients with IEI, 55 (33.3%) had GI manifestations, and 19 (11.5%) underwent endoscopy. Among those 19 patients, nine (47.4%) initially presented with GI manifestations. Thirteen patients (68.4%) were male, and the mean age of patients 11.5 ± 7.9 years (range, 0.6 – 26.6) when they were consulted and evaluated with endoscopy. The most common type of IEI with severe GI symptoms was “Disease of immune dysregulation” (31.6%) followed by “Phagocyte defects” (26.3%), according to the International Union of Immunological Societies classification criteria. Patients had variable GI symptoms such as chronic diarrhea (68.4%), hematochezia (36.8%), abdominal pain (31.6%), perianal disease (10.5%), and recurrent oral ulcers (10.5%). During the follow-up period, three patients developed GI tract neoplasms (early gastric carcinoma, mucosa associated lymphoid tissue lymphoma of colon, and colonic tubular adenoma, 15.8%), and 12 patients (63.2%) were diagnosed with inflammatory bowel disease (IBD)-like colitis. Investigating immunodeficiency in patients with atypical GI symptoms can provide an opportunity for correct diagnosis and appropriate disease-specific therapy. Gastroenterologists and immunologists should consider endoscopy when atypical GI manifestations appear in IEI patients to determine if IBD-like colitis or neoplasms including premalignant and malignant lesions have developed. Also, if physicians in various fields are better educated about IEI-specific complications, early diagnosis and disease-specific treatment for IEI will be made possible.
Nasal Administration of Anti-CD3 Monoclonal Antibody (Foralumab) Reduces Lung Inflammation and Blood Inflammatory Biomarkers in Mild to Moderate COVID-19 Patients: A Pilot Study
Authors: Moreira Thais G. , Matos Kimble T. F. , De Paula Giovana S. , Santana Thais M. M. , Da Mata Raquel G. , Pansera Fernando C. , Cortina Andre S. , Spinola Marcelle G. , Baecher-Allan Clare M. , Keppeke Gerson D. , Jacob Jules , Palejwala Vaseem , Chen Karen , Izzy Saef , Healey Brian C. , Rezende Rafael M. , Dedivitis Rogerio A. , Shailubhai Kunwar , Weiner Howard L.
Published: August 2021

Background

Immune hyperactivity is an important contributing factor to the morbidity and mortality of COVID-19 infection. Nasal administration of anti-CD3 monoclonal antibody downregulates hyperactive immune responses in animal models of autoimmunity through its immunomodulatory properties. We performed a randomized pilot study of fully-human nasal anti-CD3 (Foralumab) in patients with mild to moderate COVID-19 to determine if its immunomodulatory properties had ameliorating effects on disease.

Methods

Thirty-nine outpatients with mild to moderate COVID-19 were recruited at Santa Casa de Misericordia de Santos in Sao Paulo State, Brazil. Patients were randomized to three cohorts: 1) Control, no Foralumab (n=16); 2) Nasal Foralumab (100ug/day) given for 10 consecutive days with 6 mg dexamethasone given on days 1-3 (n=11); and 3) Nasal Foralumab alone (100ug/day) given for 10 consecutive days (n=12). Patients continued standard of care medication.

Results

We observed reduction of serum IL-6 and C-reactive protein in Foralumab alonevs. untreated or Foralumab/Dexa treated patients. More rapid clearance of lung infiltrates as measured by chest CT was observed in Foralumab and Foralumab/Dexa treated subjectsvs. those that did not receive Foralumab. Foralumab treatment was well-tolerated with no severe adverse events.

Conclusions

This pilot study suggests that nasal Foralumab is well tolerated and may be of benefit in treatment of immune hyperactivity and lung involvement in COVID-19 disease and that further studies are warranted.
Mitofusin 2 Deficiency Causes Pro-Inflammatory Effects in Human Primary Macrophages
Authors: Khodzhaeva Vera , Schreiber Yannick , Geisslinger Gerd , Brandes Ralf P. , Brüne Bernhard , Namgaladze Dmitry
Published: August 2021

Mitofusin 2 (MFN2) is a mitochondrial outer membrane GTPase, which modulates mitochondrial fusion and affects the interaction between endoplasmic reticulum and mitochondria. Here, we explored how MFN2 influences mitochondrial functions and inflammatory responses towards zymosan in primary human macrophages. A knockdown of MFN2 by small interfering RNA decreased mitochondrial respiration without attenuating mitochondrial membrane potential and reduced interactions between endoplasmic reticulum and mitochondria. A MFN2 deficiency potentiated zymosan-elicited inflammatory responses of human primary macrophages, such as expression and secretion of pro-inflammatory cytokines interleukin-1β, -6, -8 and tumor necrosis factor α, as well as induction of cyclooxygenase 2 and prostaglandin E2 synthesis. MFN2 silencing also increased zymosan-induced nuclear factor kappa-light-chain-enhancer of activated B cells and mitogen-activated protein kinases inflammatory signal transduction, without affecting mitochondrial reactive oxygen species production. Mechanistic studies revealed that MFN2 deficiency enhanced the toll-like receptor 2-dependent branch of zymosan-triggered responses upstream of inhibitor of κB kinase. This was associated with elevated, cytosolic expression of interleukin-1 receptor-associated kinase 4 in MFN2-deficient cells. Our data suggest pro-inflammatory effects of MFN2 deficiency in human macrophages.
A Tale of Two Viruses: Immunological Insights Into HCV/HIV Coinfection
Authors: Gobran Samaa T. , Ancuta Petronela , Shoukry Naglaa H.
Published: August 2021

Nearly 2.3 million individuals worldwide are coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Odds of HCV infection are six times higher in people living with HIV (PLWH) compared to their HIV-negative counterparts, with the highest prevalence among people who inject drugs (PWID) and men who have sex with men (MSM). HIV coinfection has a detrimental impact on the natural history of HCV, including higher rates of HCV persistence following acute infection, higher viral loads, and accelerated progression of liver fibrosis and development of end-stage liver disease compared to HCV monoinfection. Similarly, it has been reported that HCV coinfection impacts HIV disease progression in PLWH receiving anti-retroviral therapies (ART) where HCV coinfection negatively affects the homeostasis of CD4+ T cell counts and facilitates HIV replication and viral reservoir persistence. While ART does not cure HIV, direct acting antivirals (DAA) can now achieve HCV cure in nearly 95% of coinfected individuals. However, little is known about how HCV cure and the subsequent resolution of liver inflammation influence systemic immune activation, immune reconstitution and the latent HIV reservoir. In this review, we will summarize the current knowledge regarding the pathogenesis of HIV/HCV coinfection, the effects of HCV coinfection on HIV disease progression in the context of ART, the impact of HIV on HCV-associated liver morbidity, and the consequences of DAA-mediated HCV cure on immune reconstitution and HIV reservoir persistence in coinfected patients.
Geostatistical Seismic Inversion for Temperature and Salinity in the Madeira Abyssal Plain
Authors: Azevedo Leonardo , Matias Luís , Turco Francesco , Tromm Renan , Peliz Álvaro
Published: August 2021

A two-dimensional multichannel seismic reflection profile acquired in the Madeira Abyssal Plain during June 2016 was used in a modeling workflow comprising seismic oceanography processing, geostatistical inversion and Bayesian classification to predict the probability of occurrence of distinct water masses. The seismic section was processed to image in detail the fine scale structure of the water column using seismic oceanography. The processing sequence was developed to preserve, as much as possible, the relative seismic amplitudes of the data and enhance the shallow structure of the water column by effectively suppressing the direct arrival. The migrated seismic oceanography section shows an eddy at the expected Mediterranean Outflow Water depths, steeply dipping reflectors, which indicate the possible presence of frontal activity or secondary dipping eddy structures, and strong horizontal reflections between intermediate water masses suggestive of double diffuse processes. We then developed and applied an iterative geostatistical seismic oceanography inversion methodology to predict the spatial distribution of temperature and salinity. Due to the lack of contemporaneous direct measurements of temperature and salinity we used a global ocean model as spatial constraint during the inversion and nearby contemporaneous ARGO data to infer the expected statistical properties of both model parameters. After the inversion, Bayesian classification was applied to all temperature and salinity models inverted during the last iteration to predict the spatial distribution of three distinct water masses. A preliminary interpretation of these probabilistic models agrees with the expected ocean dynamics of the region.
Biomechanical Properties of 3D-Printed Cervical Interbody Fusion Cage With Novel SF/nHAp Composites
Authors: Chen Shuang , Meng Yi , Wu Guozhi , Liu Zhize , Lian Xiaodong , Hu Jianyu , Yang Dongfang , Zhang Guiqi , Li Kun , Zhang Hao
Published: August 2021

Anterior cervical discectomy and fusion (ACDF) is a commonly used surgical method for the treatment of cervical spondylosis. As ACDF surgery is widely used in clinics, identifying suitable materials to design and prepare cervical interbody fusion cages is a hot research topic. Here, we describe a new three-dimensional (3D) printing approach to create stretchable and tough silk fibroin/nano-hydroxyapatite (SF/nHAp) composites with tunable mechanical properties. The compressive strength of the novel composites with biomimetic structure could reach more than 128 MPa. More importantly, the composites were prepared using 30% silk fibroin and 70% hydroxyapatite, a composition similar to the human bone tissue. Finite element analysis results indicate that the stress distribution of SF/nHAp composite cervical interbody fusion cages in vivo is more uniform than that of commercial Ti alloy cages. This study evaluates the effectiveness of SF/nHAp composites for application in cervical interbody fusion cages and in the field of bone tissue engineering.
Exploration of Nonlinear Optical Properties of Triphenylamine-Dicyanovinylene Coexisting Donor-π-Acceptor Architecture by the Modification of π-Conjugated Linker
Authors: Khan Muhammad Usman , Khalid Muhammad , Asim Sumreen , Momina  , Hussain Riaz , Mahmood Khalid , Iqbal Javed , Akhtar Muhammad Nadeem , Hussain Amjad , Imran Muhammad , Irfan Ahmad , Ali Akbar , Rehman Muhammad Fayyaz ur , Jiang Yang , Lu Changrui
Published: August 2021

High-tech electronic, optics, and storage devices require organic compounds with nonlinear optical (NLO) properties. This study designed D-π-A based dyes with donor triphenylamine (TPA) and acceptor dicyanovinylene (DCV) species by structurally modifying π-conjugated linkers. Our density functional theory (DFT) computations analyzed the impact of structural variations on the nonlinear optical (NLO) response of newly designed dyes. The B3LYP/6-31G(d,p) level determined the quantic chemical insights: frontier molecular orbital (FMOs), natural bond orbitals (NBOs), and nonlinear optical (NLO) properties of the designed dyes (DPTM-1 to DPTM-12). UV-Vis analysis based on the TD-DFT/CAM-B3LYP/6-311+G(d,p) level explored the optoelectronic properties. DPTM-1 and DPTM-5 showed the highest red-shifted absorption band at 519 and 506 nm. NBO analysis shows that DPTM-1 to DPTM-12 dyes have positive values for all donors (D) and π-spacers but negative values for acceptors (A). The π-spacers act as a conveyer between donor and acceptor moieties; thus, electrons were transferred smoothly from D to A units, which resulted in a charge separation state. Our calculations show the extent of NLO response in terms of electronic transitions, polarizability <α>, and first hyperpolarizability (β) values. The highest value of βtotal was 110,509.23 a.u. manifested in DPTM-6 due to 2,5-dimethyloxazole as a second π-linker, twice that of R (66,275.95 a.u.). Also, DPTM-6 and DPTM-8 exhibit the lowest energy band gap of 2.06 and 2.04 eV, respectively. In short, all DPTM-1 to DPTM-12 dyes manifested maximum absorption, lowest energy band gap, greater charge transfer from donor to the acceptor, and better first hyperpolarizability values as compared to the R and showed good NLO response. The present work represents new compounds with remarkable NLO properties and their applications in modern high-tech devices.
Current Update on Intrinsic and Acquired Colistin Resistance Mechanisms in Bacteria
Authors: Gogry Firdoos Ahmad , Siddiqui Mohammad Tahir , Sultan Insha , Haq Qazi Mohd. Rizwanul
Published: August 2021

Colistin regained global interest as a consequence of the rising prevalence of multidrug-resistant Gram-negative Enterobacteriaceae. In parallel, colistin-resistant bacteria emerged in response to the unregulated use of this antibiotic. However, some Gram-negative species are intrinsically resistant to colistin activity, such as Neisseria meningitides, Burkholderia species, and Proteus mirabilis. Most identified colistin resistance usually involves modulation of lipid A that decreases or removes early charge-based interaction with colistin through up-regulation of multistep capsular polysaccharide expression. The membrane modifications occur by the addition of cationic phosphoethanolamine (pEtN) or 4-amino-l-arabinose on lipid A that results in decrease in the negative charge on the bacterial surface. Therefore, electrostatic interaction between polycationic colistin and lipopolysaccharide (LPS) is halted. It has been reported that these modifications on the bacterial surface occur due to overexpression of chromosomally mediated two-component system genes (PmrAB and PhoPQ) and mutation in lipid A biosynthesis genes that result in loss of the ability to produce lipid A and consequently LPS chain, thereafter recently identified variants of plasmid-borne genes (mcr-1 to mcr-10). It was hypothesized that mcr genes derived from intrinsically resistant environmental bacteria that carried chromosomal pmrC gene, a part of the pmrCAB operon, code three proteins viz. pEtN response regulator PmrA, sensor kinase protein PmrAB, and phosphotransferase PmrC. These plasmid-borne mcr genes become a serious concern as they assist in the dissemination of colistin resistance to other pathogenic bacteria. This review presents the progress of multiple strategies of colistin resistance mechanisms in bacteria, mainly focusing on surface changes of the outer membrane LPS structure and other resistance genetic determinants. New handier and versatile methods have been discussed for rapid detection of colistin resistance determinants and the latest approaches to revert colistin resistance that include the use of new drugs, drug combinations and inhibitors. Indeed, more investigations are required to identify the exact role of different colistin resistance determinants that will aid in developing new less toxic and potent drugs to treat bacterial infections. Therefore, colistin resistance should be considered a severe medical issue requiring multisectoral research with proper surveillance and suitable monitoring systems to report the dissemination rate of these resistant genes.
Switching to a Dual-Drug Regimen in HIV-Infected Patients Could Be Associated With Macrophage Activation?
Authors: Vassallo Matteo , Durant Jacques , Fabre Roxane , Ticchioni Michel , Lotte Laurene , Sindt Audrey , Puchois Annick , De Monte Anne , Cezar Renaud , Corbeau Pierre , Pradier Christian
Published: August 2021

Objectives: The aim of this study was to evaluate the effect on immune activation of switching from a triple-drug to a dual-drug regimen in HIV-1 infected patients on successful combination antiretroviral treatment (cART). Immunadapt is a prospective study evaluating the impact of cART simplification on immune activation.

Methods: We prospectively collected blood samples in HIV-1 infected patients on stable and successful cART switching from triple to dual regimens as a simplifying strategy. We compared immune activation markers: high sensitivity CRP, IL-1, IL-6, IL-8, IP-10, MCP-1, TNF-alpha, soluble CD14 (sCD14), soluble CD163 (sCD163), lipopolysaccharide binding protein, and D-dimer before cART change and at least 6 months after the switch. Patients were stratified according to low or high risk factors of immune activation (low CD4 nadir, previous AIDS-defining condition or very-low-level viremia during follow-up).

Results: From April 2019 to May 2020, 20 subjects were included (mean age 57 years, 25 years since HIV infection, CD4 666 cells/mm3, CD8 766 cells/mm3, CD4/CD8 0.94, CD4 nadir 326 cells/mm3, 15% with AIDS, 18 years on cART, 6 cART regimens received, current cART duration: 56 months). Fourteen patients were prescribed Dolutegravir + Rilpivirine and six received Dolutegravir + Lamivudine. After 6.9 months, a significant sCD163 increase (+ 25.5% vs. + 0.5%, p = 0.02) was observed in subjects with high risk factors, despite maintaining a viral load <50 cp/ml.

Conclusion: cART simplification in favor of dual therapy is associated with macrophage activation in patients at risk of immune activation despite sustained virological control. Risk factors should thus be considered before generalizing such strategies.