bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protective effects of Heat-killed Lactobacillus sakei CVL-001 on DSS-induced ulcerative colitis in mice
Authors: Kim Dong-Yeon , Lee Tae-Sung , Jung Do-Hyeon , Kim Yeong-Jun , Lee Yun-Ji , Seo In-Su , Song Eun-Jung , Jang Ah-Ra , Park Jong-Hwan 
Published: August 2023

Abstract
Recently, the incidence of Inflammatory Bowel Disease (IBD) is increasing due to westernized lifestyle and eating habits. IBD is a representative gastrointestinal immune disease, and casued by an excessive immune response in the gastrointestinal tract. In recent studies, lactic acid bacteria which known as beneficial intestinal microbiota have protective effects on IBD by various mechanisms. Here, we evaluated the protective effect of Lactobacillus sakei CVL-001 isolated from korean tradtional food kimchi against dextran sulfate sodium-induced colitis in mice. First, administration of Heat-killed (HK) CVL-001 showed protective effects against DSS-induced colitis. Also, colonic mRNA expression levels showed that pro-inflammatory cytokine was downlregulated and anti-inflammatory cytokine was upregulated. Nucleotide-oligomerization domain 2 (NOD2) is well known as innate immune receptor and deeply related to IBD. We found that HK CVL-001 induced a NOD2-dependent regulatory phenotype in mouse bone marrow derived dendritic cell (BMDCs). Especially, we demonstrated that the expression of CD103, which is known as a marker of tolerogenic DC, was expressed mediated by NOD2. In vivo studies, colon administered with HK CVL-001 favoured the expansion of mucosal CD103 DCs and regulatory T cells. However, protective effect was abolished in NOD2 knockout mice. This results indicated that Heat killed L. sakei CVL-001 might be used therapeutic agent and strategy in IBD.
This research was supported by the Mid-Career Researcher Programs (Grant No. 2022R1A2C2012287) of the National Research Foundation of Korea funded by the Ministry of Science and ICT (Information and Communication Technologies).
Akkermansia muciniphila acts synergistically with Btk-deficiency to prevent Type 1 Diabetes
Authors: Verma Sonam , Cohen Lucy S , Olin Ilana Rae , Kendall Peggy L 
Published: August 2023

Abstract
Btk-deficiency eliminates autoreactive B cells, but not normal ones, and protects against Type 1 diabetes (T1D). Surprisingly, we recently found that rederivation of Btk−/−/NOD mice into a cleaner, “barrier” facility resulted in loss of disease protection. This suggests that T1D protection is microbiome dependent in Btk−/− mice. Akkermansia muciniphila (A. muciniphila) was found to be increased in Btk−/−/NOD mice that were protected against disease compared to WT and Btk−/−/NOD that were not protected. A. muciniphila has previously been associated with disease protection in humans and mice under some conditions, although causality and mechanisms are unknown. We previously showed that Btk-deficient K/BxN mice have reduced intestinal IgA, and therefore hypothesized that A. muciniphila escapes suboptimal IgA-coating in Btk−/−/NOD and works synergistically with the loss of autoreactive B cells to protect against T1D. Germ-free female WT NOD and Btk−/−/NOD were gavaged with A. muciniphila at 3–4 weeks. Mice were tested weekly for diabetes to 30 weeks of age. Additional mice were treated in parallel and euthanized at 9–10 weeks to examine the effects on mucosal immunity and autoimmune attack on pancreatic islets. Monocolonization of Btk−/−/NOD with A. muciniphila protected significantly against T1D compared to monocolonized WT NOD. CD19+ GL7+ staining of Peyer’s patches showed small germinal centers in Btk−/−/NOD compared to WT NOD. Thus, A. muciniphila protects against T1D in Btk−/−/NOD but not WT NOD, indicating a synergistic effect. Altogether, the data show that Btk plays a previously unrecognized role in the maintenance of gut health that can have downstream effects on T1D outcomes.
National Institutes of Health Grants R01-DK-084246I Veteran’s Affairs I01-BX-002882 Washington University School of Medicine
Intestinal and skin colonization by Candida albicans contributes to disrupted regulatory T cells in early life
Authors: Greenfield Kara G , Joshi Avni , Knoop Kathryn A 
Published: August 2023

Abstract
Perturbations of the mucosal immune system and the microbiota can lead to allergic disorders with a lifelong impact. With up to 90% of cases diagnosed by age 6, atopic dermatitis represents a unique allergic disorder during early life. Diagnosis of atopic dermatitis is associated with an increased risk for other allergic disorders throughout life. The opportunistic fungal species Candida albicans is often found as part of a dysbiotic microbiota and its presence is associated with increased risk of atopy. While adult mice are unable to be stably colonized with C. albicans without the use of antibiotics, we have found that mice exposed to C. albicans prior to weaning maintain long term colonization in the gut and on the skin. In mice colonized in early life with C. albicans in the GI tract, FoxP3+ T cells were significantly decreased post-weaning in the mesenteric lymph node as well as in the small intestine and colon lamina propria. Colonization by C. albicans resulted in an increased Th17 response, with increased RORγt+ and c-Maf+ T cells in the colon lamina propria. In a clinical observation study, we found C. albicans colonization in the intestine of prematurely born infants, suggesting colonization of the human GI tract with C. albicans may frequently occur. As the microbiota develops with age, the presence of C. albicans may impact the normal course of increasing complexity and diversity in this ecosystem. The establishment of regulatory T cells in early life is vital to maintaining tolerance to commensal organisms throughout life; this disruption in regulatory T cells potentially links colonization by C. albicans to the development of atopy and allergic responses.
Supported by grants from Mayo Clinic Center for Individualized Medicine
Progressive accumulation of hyperinflammatory NKG2Dlow NK cells in early life defines a novel endotype of severe atopic dermatitis
Authors: Waggoner Stephen N , Ohayon David E , DeVore Stanley B , Chang Wan Chi , Krishnamurthy Durga , Seelamneni Harsha , Grashel Brittany , Spagna Daniel , Martin Lisa J , Biagini Jocelyn M , Khurana Hershey Gurjit K 
Published: August 2023

Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease that often precedes the development of food allergy, asthma, and allergic rhinitis. The prevailing paradigm holds that a reduced frequency and function of natural killer (NK) cell contributes to AD pathogenesis, yet the underlying mechanisms and contributions of NK cells to allergic co-morbidities remain ill-defined. Herein, longitudinal analysis of circulating NK cells in a well-defined early life cohort of children with AD revealed a progressive accumulation of NK cells with low expression of the activating receptor NKG2D that was linked to more severe AD and sensitivity to allergens. This was most notable in children co-sensitized to food and aero allergens, a risk factor for development of asthma. Importantly, low expression of NKG2D on NK cells was paradoxically associated with depressed cytolytic function but exaggerated release of the proinflammatory cytokine TNF-a. These observations provide important new insights into a potential pathophysiological mechanism of atopic march involving altered NK cell functional responses and define a novel endotype of severe AD.
5U19AI70235 (GKKH, JBM, LJM); American Heart Association (DEO); R01AI148080, R01AR073228 (SNW), 5T32GM063483 (SBD)
Trends in current students learning-unknown unknowns!
Authors: Fazal Nadeem , Graefen Bahar , Aliyeva Leyla , Uzoma Emeakoroha , Arceo Adriel , Loya Egwin , Najafova Nurana 
Published: August 2023

Abstract
Never in the history of academics there has been such a wave of uncertainty, unpredictability, unrest, and unforeseeable challenges in learning methods adopted by academic departments. The traditional big barrier between instructor and students is becoming arbitrary. At one end instructors are experimenting all the modern tools and gadgets on the other end the students are responding with such a prominent variability making the statistical methods unreliable. Instructors are trying a plethora of modern available learning methods within a very short period of time and are equally met with a challenging students’ learning styles. The current teaching environment with millennial, generation x and z are further complicating the equation. We at Chicago State University College of Pharmacy surveyed both instructors and students over the last four years. Our hypothesis was that the academic stability and standardization has lost its value with frequent and untimely use of tsunami of new learning methods. Data was analyzed from two major departments of College of Pharmacy including basic sciences and clinical practice. This includes data of students from year one pharmacy to year four pharmacy. Our results suggest that instructors are becoming impulsive in changing their teaching methods without giving each method a deserved testing time and evaluation period. Likewise the students are becoming more self-directed, and are taking their learning in their own hands. This see-saw type of educational environment is taking root in academic settings and adding to frustrations and burnouts, both for Instructors as well as the students. We suggest that the instructors should bring the changes in their teaching styles in a slow, perpetual and steady way.
Funds from CTRE Chicago State University to Nadeem Fazal and to Bahar Graefen from Fulbright Association.
Bridging statistics and life sciences education for immunologists: Exploring significantly impactful teaching strategies and collaborations
Authors: Singh Jastaranpreet , White Bethany 
Published: August 2023

Abstract
The widespread misuse of statistics is one of the contributing factors to reproducibility concerns in immunological research. However, not all immunologists have the statistical expertise to choose the best methods to evaluate and represent their experiments, and the formal statistics training required by undergraduate and graduate immunology curricula is often quite limited. How can we prepare immunologists for statistical practice in research? We previously developed a second-year undergraduate course to integrate statistics instruction with research design to improve the quantitative training of life sciences students. In a Scholarship of Teaching and Learning (SoTL) study conducted within the course, student attitudes and self-efficacies for statistics, as well as their abilities to recognize and handle problems related to statistical practice in life sciences research, were assessed through surveys administered at the beginning and end of the course (n=126). Here, we present our team-teaching model and strategies for promoting meaningful connections between statistics and immunological research through course design, activities and assessments. We also highlight the results from our SoTL study, which have guided the development of several specialized immunology courses focusing on statistical practice and experimental design at the University of Toronto. We hope that insights from this teaching partnership and our SoTL findings will help inform future quantitative course offerings and training initiatives, and ultimately, better prepare students to effectively engage with statistics in immunological research.
Using lung-on-a-chip to characterize HIF-1α-dependent inflammatory responses during acute Streptococcus pneumoniae infection
Authors: Kang Hellen , Rosin Nicole , Sinha Sarthak , Biernaskie Jeff , Gillrie Mark 
Published: August 2023

Abstract
Current models used to study Streptococcus pneumoniae (SP) infections do not account for complex organ microenvironments or species-specific signaling pathways. To address this, we created a vascularized 3D lung-on-a-chip (LoC) that better recapitulates the physiologic lung, including cellular components, immune cell recruitment, blood flow, and oxygen tension. Hypoxia inducible factor 1-alpha (HIF-1α) is a transcription factor known to activate inflammatory pathways during infectious diseases, but its role in acute SP infection remains unclear. LoC was used to validate HIF-1α upregulation and characterize its role in immune cell recruitment. Whole human blood with fluorescently-labeled immune cells were perfused in LoC +/− BAY 87-2243 (HIF-1α chemical inhibitor). HIF1α-dependent inflammatory mediators involved in SP infection were identified by scRNA-seq and confirmed at the protein level by Western blot and ELISA. Preliminary studies of LoC stimulated with SP demonstrated HIF-1α early target gene activation. LoC showed increased CD15+-neutrophil recruitment from perfused whole blood in microvessels to tissue and airway during SP infection, partially mediated by HIF-1α. IL-17C was identified as the top differentially expressed gene activated by SP and 2D protein analysis showed increased IL-17C levels during HIF-1α knockdown, suggesting that HIF-1α is a negative regulator of IL-17C transcription. These preliminary findings suggest that HIF-1α mediates immune cell recruitment during acute SP infection and support the use of LoC as a pre-clinical human model that can identify key mediators during pneumonia.
Unraveling novel crosstalk between distinct neutrophil subsets and soluble plasma factors in sepsis and ARDS
Authors: Parthasarathy Upasana , Kuang Yi , Thakur Gunjan , Hogan John , Wyche Thomas , Norton James , Sana Theodore , Beakes Caroline , Shyong BaoJen , Zhang Rena , Filbin Michael , Christiani David , White Cory , Martinelli Roberta 
Published: August 2023

Abstract
Sepsis is a life-threatening condition caused by an aberrant immune response to infection and subsequent organ dysfunction. Further, due to shared mechanisms such as severe inflammation and endothelial dysfunction, sepsis remains the most common etiology in acute respiratory distress syndrome (ARDS) patients. Despite multiple efforts to identify a distinct signature to support the development of new therapeutics, sepsis remains a significant unmet clinical need. While singular components of the dysregulated immune response have been explored, studies linking different data layers are lacking. Using an integrated systems immunology approach, we evaluated neutrophil phenotypes and related changes in soluble plasma factors in sepsis versus healthy donors. Results from our studies identify differentially expressed mature and immature neutrophil subsets in sepsis patients. Further, we show that expression of neutrophil CD10 is associated with factors such as pentraxin-3, angiopoietin-2, and lysophosphatidylcholines, in the sepsis cohort. These findings detail a novel correlation between increased presence of immature neutrophils and endothelial dysfunction/metabolic alterations in sepsis patients. Additionally, we profiled the neutrophil landscape and evaluated levels of soluble plasma factors, in a subset of ARDS patients and healthy donors. Here, we present distinct findings that reveal a novel crosstalk between neutrophil subsets and parameters indicative of endothelial dysfunction, in sepsis and ARDS patients. Overall, our study reinforces the importance of data integration and provides novel insights that could help inform future mechanistic studies, early patient stratification and treatment options.
IRF3 in adipose tissue inflammation and metabolism
Authors: Zhang Yongliang 
Published: August 2023

Abstract
Dysfunction of adipocytes and adipose tissue is a primary defect in obesity and obesity-associated metabolic diseases. Interferon regulatory factor 3 (IRF3) has been implicated in adipogenesis. However, the role of IRF3 in obesity and obesity associated disorders still remains unclear. Here we show that IRF3 expression in human adipose tissue was positively associated with insulin sensitivity and negatively associated with type 2 diabetes. In mouse preadipocytes, IRF3 not only acts as a brake negatively regulating the adipogenic transcriptional network centered on the PPARg pathway, but also is important for the functionality of adipocytes. In macrophages, IRF3 inhibits inflammatory cytokine expression through IFNb/IL-10 axis, thereby restraining adipose tissue inflammation in obesity. Mice deficient in IRF3 developed obesity and type 2 diabetes spontaneously associated with increased adipose tissue inflammation. This study demonstrates that IRF3 regulates the biology of multiple cell types including adipocytes and macrophages to prevent the development of obesity and obesity-related complications, hence, could be a target for therapeutic interventions for prevention and treatment of obesity-associated metabolic disorders.
National Medical Research Council of Singapore
Dominant CD40 Receptor (CD40R) Antagonist Antibodies as Novel Approach to Treating Autoimmune Diseases
Authors: LaMontagne Russell W , Olivier Ken , Weaver Bruce 
Published: August 2023

Abstract
The CD40R-CD40 ligand pathway is a key co-stimulatory pathway for driving T cell-dependent B cell activation and humoral immune responses. This pathway has been implicated in the pathogenesis of several autoimmune diseases including autoimmune thyroiditis, type 1 diabetes, Crohn’s disease, inflammatory bowel disease, psoriasis, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus and Sjogren’s syndrome. Although the use of anti-CD40 ligand antibodies have shown benefits in patients, their use has been linked to the development of thromboembolic events, ADCC issues and low efficacy with poor antagonism in vivo. Two novel IgG2 CD40R antagonists developed by BITT have differentiated mechanisms of action including the formation of inhibitory anti-parallel dimers of the surface receptor. Several unique features include: ligand independence, Fc receptor independence, potency with ligand present and selectivity to rapidly proliferating cells. Multiple BITT antibodies showed strong antagonist activity in B-cell proliferation assays. Two BITT CD40 antagonists were selected for testing in a humanized NSG Mouse Model of graft verse host disease. The BITT CD40R antagonists were compared to isotype control and a known IgG1 CD40R antagonist. The BITT antibodies showed better B cell depletion and better inhibition of IgG levels – including a unique ability to selectively deplete activated (CD86+ cells) and younger B cells making early IgM antibodies. This selective action could result in more potent immune-suppressive function at the site of inflammation and a reduced possibility of developing side effects.
β-defensin-1 regulates influenza virus infection in human bronchial epithelial cells through the STAT3 signaling Pathway
Authors: Othumpangat Sreekumar , Noti John D 
Published: August 2023

Abstract
To develop intervention strategies it is necessary to understand the host response to influenza A virus (IAV) infection. The primary barriers for invading respiratory pathogens are the airway epithelial cells of the respiratory tract and several antimicrobial peptides are produced by these cells. The antimicrobial peptide, β-defensin-1, has antiviral activity against both enveloped and non-enveloped viruses. Significant downregulation of β-defensin-1 gene (DEFB1) expression was observed when human bronchial epithelial cells (HBEpCs) were exposed to IAV. HBEpCs overexpressing DEFB1 caused a significant reduction in IAV, that was confirmed by IAV matrix gene analysis, plaque assay, and confocal microscopy. DEFB1 expression after transfection with two micro RNAs (miRNAs), hsa-miR-186-5p and hsa-miR-340-5p, provided evidence that DEFB1 expression could be modulated by these miRNAs and hsa-miR-186-5p had a higher binding efficiency with DEFB1. Overexpression of DEFB1 in IAV infected HBEpCs led to increased NF-κB expression. In a PCR array analysis of 84 transcription factors, either overexpressing DEFB1 or siRNA silencing of DEFB1 expression significantly modulated the expression of signal transducer and activator of transcription 3 (STAT3). In addition, Ingenuity Pathway Analysis (IPA) integrated with PCR array data showed that the JAK1/STAT3 pathway was significantly altered in cells overexpressing DEFB1, suggesting this to be one of the pathways by which defensin regulates IAV replication in HBEpCs. In conclusion, the reduction in IAV copy number in DEFB1 overexpressing cells suggests that β-defensin-1 plays a key role in regulating IAV survival through STAT3 and is a potential target for antiviral drug development.
No funding
Obesity is associated with impaired immune history to influenza
Authors: Abd Alhadi Marwa , Friedman Lilach M , Karlsson Erik A , Cohen-Lavi Liel , Burkovitz Anat , Schultz-Cherry Stacey , Noah Terry L , Weir Samuel S , Shulman Lester M , Beck Melinda A , Hertz Tomer 
Published: August 2023

Abstract
Obesity is a risk factor of severe disease and mortality for both influenza and SARS-CoV-2. While previous studies show that obese individuals generate antibody responses following influenza vaccination, infection rates within the obese group were twice as high compared to the healthy-weight group. To investigate the hypothesis that obesity impacts immune memory to infections and vaccines, we profiled the baseline immune history of obese and healthy-weight adults vaccinated with 2010–11 seasonal influenza vaccine to influenza antigens. Despite extensive heterogeneity in baseline immune history profiles in both groups, there were striking differences between obese and healthy controls, especially towards A/H1N1 strains and the 2009 pandemic virus (Cal09). Individuals with obesity had lower IgG and IgA magnitude and breadth towards a panel of A/H1N1 whole viruses and hemagglutinin proteins from 1933–2009, but increased IgG magnitude and breadth towards linear peptides from the Cal09 H1 and N1 proteins. Age was also associated with A/H1N1 baseline immune history, with young individuals with obesity more likely to have reduced A/H1N1 baseline immune history. We further found that IgG baseline immune history was associated with baseline and post-vaccination protective antibody responses, as measured by micro-neutralization and hemagglutinin inhibition assays. Taken together our findings suggest that increased susceptibility of obese subjects to influenza infection may be in-part mediated by obesity-associated differences in the memory antibody repertoire, which cannot be ameliorated by seasonal vaccination. Overall, these data have vital implications for the next generation of influenza and SARS-CoV-2 vaccines.