bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inflammatory markers in relation to pre-pubertal obesity
Authors: Dinov Darina , Khait Albert 
Published: January 2023

Abstract

Background
According to the WHO, current childhood obesity trends are expected to increase to 70 million by 2025. Childhood obesity is becoming a major epidemic with adipokines-TNF-α, IL-6, leptin, and adiponectin-being potentially implicated in the pathogenesis.

Methods
We conducted a literature search of PubMed clinical trials and articles where we searched key terms: ‘pre-pubescent obese children’ cross referenced with ‘TNF-α’ or ‘IL-6’ or ‘hs-CRP’ or ‘adiponectin’.

Research
Thirty-six articles remained in the review after our exclusion criteria was applied. Most of these showed a positive correlation of obesity with TNF-α, IL-6, and hs-CRP. In addition, the research showed a negative correlation with adiponectin. There was one study that we found that showed TNF-α to not be related to obesity and another that showed adiponectin to have a positive correlation rather than negative correlation with obesity. Another contributing study that we evaluated showed that TNF-α causes a decrease in C/EBP-alpha which are gene promoters that downregulate myc. By downregulating this cell cycle regulator there is potential for proliferation of cells leading to increased risk for both obesity and cancer. TNF-α, is one of the primary inflammatory markers that has been implicated in obesity; thus, showing that it could have diagnostic factors in cancer through this downregulation of myc.

Conclusion
A possible consideration for future research is to evaluate the possible relationship between inflammatory markers discussed as diagnostic factors for pediatric cancer. With this potential innovative method, we as a research community can lessen the burden cancer has put on our society.
Induction of class-switched and somatically hypermutated primary and anamnestic antibody responses by TLR-BCR co-engagement in Tcrβ
−/−
Tcrδ
−/−and NSG/B-cell mice
Authors: Rivera Carlos Eduardo , Li Xin , Yan Hui , Chupp Daniel , Taylor Julia , Zan Hong , Xu Zhenming , Casali Paolo 
Published: January 2023

Abstract
Ig gene CSR/SHM as well as plasma cell and memory B cell differentiation are central processes to the maturation of the antibody response and generally depend on T cell help. Prompted by our findings that CSR is efficiently induced by T cell-independent (TI) stimuli in vitro, e.g., dual engagement of TLR/BCR, here we have addressed the induction of TI antibody responses and underlying mechanisms in vivo using Tcrβ−/−Tcrδ−/− mice. These mice lack T cells and, as expected, failed to generate any class-switched antibodies to T-dependent antigens (e.g., NP-CGG and ovalbumin), even in the presence of adjuvants. They, however, displayed circulating IgG2b, IgG3 and IgA, at levels comparable to those in C57BL/6 mice, and to a lesser extent, IgG1 and IgG2a. Further, they generated high-affinity NP-specific IgG2b and IgG3 upon immunization with NP-LPS, but not NP-Ficoll mixed with LPS. The anti-NP-LPS response entailed a high-frequency of (replacement) mutations in the Ig variable region, a hallmark of antibody affinity maturation, CSR and generation of a high number of NP-binding IgG+B cells. Also generated at a high frequency were IgG+NP-specific plasma cells, which homed to the bone marrow, and memory B cells, which were instrumental in mounting an effective anamnestic response. These findings, together with the readily detectable NP-specific response to NP-LPS in immune-deficient NSG mice grafted with highly purified B cells, highlight a previously unsuspected but efficient TI and B cell-intrinsic mechanism, i.e., TLR/BCR co-engagement, in the generation of full-fledged antibody responses. The B cell-intrinsic nature of this mechanism was further emphasized by the failure of mice with B cell-specific Tlr4 deficiency to respond to NP-LPS.
Hepatic CD1d+ B cells reduce immune-mediated drug-induced hepatitis in male BALB/c mice and account for sex bias in hepatitis severity seen in this disease
Authors: Njoku Dolores B. , Nyandjo Maeva , Hamad Abdu , Cottagiri Merylin 
Published: January 2023

Abstract
Sex modulates severity in autoimmune diseases. In susceptible individuals, drug metabolites induce hepatitis, autoimmunity and liver injury. Drug–induced hepatitis (DIH) is a leading cause of liver failure and is a common reason an approved medication is removed from the consumer market. We previously showed that estrogen and IL-6 promote sex bias by increasing hepatitis severity and by reducing IL-10 and Foxp3+ regulatory T cells in female BALB/c (WT) mice. We also found antibody-independent roles for sex bias via IL-10 and CD1d+B cells in male WT mice with reduced hepatitis. To directly assess the significance of CD1d+B cells in male WT mice with DIH, we induced hepatitis in male and female WT mice and treated them with anti-CD20 after 2 weeks at clinically relevant doses used for treating B cell-associated autoimmune diseases. Hepatitis was induced in female and male WT mice by immunizing them with cytochrome P4502E1 (CYP2E1) epitopes modified by drug metabolites. Splenic and hepatic B cells as well as hepatitis were assessed. Groups were analyzed using Mann-Whitney U. A p value &lt; 0.05 was significant. We found reduced hepatitis in male when compared to female WT mice associated with elevated hepatic follicular CD21/CD35+IgM-B cells (p&lt;0.01) and elevated hepatic and splenic CD1d+B cells (p&lt;0.001) as well as reduced splenic marginal zone CD21/CD35+ IgD+ CD23− B cells in male mice (p&lt;0.05). Anti-CD20 did not abolish sex bias in splenic CD1d+B cells (p&lt;0.05) but reduced hepatic CD1d+B cells (p&lt;0.01), abolished sex bias in the expression of splenic marginal zone B cells and increased DIH in male WT mice (p&lt;0.05). We demonstrate protective roles for hepatic CD1d+B cells in sex bias and in the reduction of hepatitis in male WT mice.
Human germinal center B cells are intrinsically able to discriminate antigen affinity and with T cell help express plasma cell transcription factors
Authors: Saniee Avva , Kwak Kihyuck , Quizon Nicolas , Sohn Haewon , Manzella-Lapeira Javier , Holla Prasida , Lu Jinghua , Xie HengYi , Xu Chenguang , Spillane Katelyn , Tolar Pavel , Pierce Susan K. 
Published: January 2023

Abstract
The selection of GC B cells that express high affinity B cell receptors (BCRs) is driven by the ability of B cells to both signal through the BCR and to extract antigen and present it to follicular helper T cells (T FH cells). Using anti-kappa antibodies of low (KD=3.9×10 −7 ) versus high (KD=2.4×10 −9 ) affinities attached to membranes as surrogate antigens, we show that LZ GC B cells are able to discriminate between these and responded only to the high affinity antigen. In contrast, naïve B cells responded to both high and low affinity antigens. LZ GC B cells engaged membrane associated surrogate antigens through highly dynamic F-actin and ezrin-rich pod-like structures that concentrated BCRs at their contact points. Using DNA-based mechanical force nano-sensors we observed robust pulling forces localized to the contact sites of the pods with the membrane. In contrast, naïve B cells formed flat stable contacts with the membranes and showed only defuse weak pulling forces. GC B cells optimally express transcription factors that drive plasma cell differentiation, namely IRF-4 and PRDM-1, in response to antigen in combination with T FH help while naïve B cells increased IRF-4 and PRDM-1 transcription in response to T FH alone and less so to antigen alone. Thus, LZ GC B cells appear to be intrinsically capable of antigen affinity discrimination and with the acquisition of T FH help BCR-activated LZ GC B cells differentiate into plasma cells.
B lymphocytes are a major source of IL-27 that drives class-switched antibody responses and anti-viral immunity through paracrinic targeting of B cells and T follicular helper cells
Authors: Yan Hui , Wang Rui , Fernandez Maria , Rivera Carlos Eduardo , Sanchez Helia , Li Xiao-Dong , Zhang Nu , Zan Hong , Meng Xiang-Zhi , Kedl Ross , Hunter Christopher A. , Xiang Yan , Casali Paolo , Xu Zhenming 
Published: January 2023

Abstract
In addition to generating antibodies against infections, B lymphocytes produce cytokines to regulate immune functions. Here, we have identified B cells as a major source of cytokine IL-27 (the heterodimer of IL-27p28 and EBI3) by using B cell-deficient mMT and JH mice, mice with B cell-specific deficiency in Ebi3 and NSG mice transplanted with highly purified B cells. IL-27 in turn targets B cells to undergo class-switching to IgG2a, as shown by decreased antigen-specific IgG2a in mice with B cell-specific deficiency IL-27 receptor signaling, leading to defective clearance of vaccinia virus infection. The paracrinic function of IL-27 is recapitulated in vitro by B cell production of IL-27 upon stimulation by a TLR ligand together with CD154 (CD40 ligand) and IL-21, two hallmark stimuli of TFH cells, and IL-27 induction of T-bet and a gene signature similar to that induced by IFNγ, IL-27 collaboration with IFNγ in inducing T-bet and IgG2a, and, finally, selective switching to IgG2a in primed B cells when mixed with IL-27-producing B cells, which display a metabolic program distinct from that in IL-27-responding B cells, i.e., heightened TCA cycle activities and enhanced lactate generation and glutaminolysis. B cell-produced IL-27 also promotes differentiation of TFH cells, as shown by reduced number of TFH cells and defective IL-21 expression in residual TFH cells in mice with B cell-specific deficiency in Ebi3 and, consequently, severe impairments in the germinal center development, class-switching to all Ig isotypes and protective antibody responses to vaccinia virus infection in these mice. Overall, B cell production of IL-27 is a previously unrecognized important regulatory mechanism in the antibody response and anti-viral immunity.
Marijuana THC treatment led to decreased metabolic functions of Staphylococcal enterotoxin B-activated lymphocytes
Authors: Mohammed Amira K. , Alghetaa Hasan F. , Nagarkatti Prakash S. , Nagarkatti Mitzi 
Published: January 2023

Abstract
Studies from our laboratory have shown that Δ9-Tetrahydrocannabinol (THC), an ingredient found in marijuana plant Cannabis sativa, can attenuate acute lung injury induced by Staphylococcus enterotoxin B (SEB). In the current study, we investigated the role of THC on the metabolism of SEB-activated lymphocytes. To this end, we determined metabolic potential of SEB-activated lymphocytes treated with vehicle or THC by performing the Cell Mito Stress Test. The oxygen consumption rate (OCR) in THC-treated cells was decreased when compared to vehicle-treated group whereas the extracellular acidification rate (ECAR) was similar in both the groups. Specifically, electron transport chain inhibitors namely, oligomycin, FCCP and rotenone+antimycinA were added to measure ATP-linked respiration, maximal respiration and non-mitochondrial respiration, respectively. THC treatment led to a significant decrease in the basal respiration, ATP production, proton (H+) leak, maximal respiration, spare respiratory capacity and nonmitochondrial respiration. We also performed the Mito Fuel Flex assay to measure the dependency, capacity and flexibility of cells to oxidize glucose, glutamine and fatty acids. Treatment with inhibitors, BPTES and etomoxir showed a decline in the OCR in SEB+vehicle treated cells demonstrating that glutamine and/or fatty acids serve as major source of fuel in these cells when compared to SEB+THC treated group. However, when UK5099 was added, THC- and vehicle-treated cells showed a reduced response thereby indicating that glucose dependency was similar in both the groups. Together, THC modulates metabolic functions of activated lymphocytes which may affect their signaling, differentiation and toxicity.
Modulation of inflammatory responses in heart failure via activation of alpha-7 nicotinic acetylcholine receptor agonist GTS-21
Authors: Mai Xuyen Kim , Kha Mindy , Chow Sheryl , Cameron Joshua , O’Barr Stephen A. 
Published: January 2023

Abstract
Heart failure (HF) is a prominent health concern amongst the public with prevalence rate being over 5.8 million in the USA. Inflammation and cytokine signaling are two main factors that lead to the pathogenesis of HF because of their effects on the heart and peripheral circulation. The “smoker’s paradox” showed associations between improvements in short-term acute myocardial infarction (MI) and smokers via activation of α7 nicotinic acetylcholine receptor (α7 nAChR) that can inhibit inflammatory responses in HF. Studies showed that the vagus nerve can modulate these inflammatory responses by activating the cholinergic anti-inflammatory pathway via stimulation of α7 nAChR. Hence, stimulation of α7 nAChR with specific agonists can be a potential therapeutic target for HF because it can inhibit pro-inflammatory responses. In this study, the anti-inflammatory effects of 3-(2,4-dimethoxybenzylident)-anabaseine (GTS-21), a partial agonist of α7 nAChR, were observed in an in vivo zebrafish model for HF. For four consecutive days, the zebrafishes were pre-treated with GTS-21 (0.113 μM) for 20 minutes per day. On the fourth day after pre-treatment with GTS-21, the zebrafishes were induced with MI by oligo-[2-(2-ethoxy)- ethoxyethyl)-guanidinium-chloride] (PGH) and survival was recorded. Using reverse transcription PCR (rt-PCR) for analysis, results showed that pre-treatment with GTS-21 modified the gene regulatory protein levels and reduced cytokine expression in the myocardium tissue. Other α7 nAChR agonists were investigated for their potential therapeutic effect in inhibiting inflammatory responses, but GTS-21 was more efficacious in inhibiting cytokine expression. Thus, GTS-21 may be used as a novel therapeutic for HF.
The response of CD8 T cells to antigenic stimulation is controlled by their endogenous circadian clock
Authors: Nobis Chloé , Dubeau-Laramée Geneviève , Cermakian Nicolas , Labrecque Nathalie 
Published: January 2023

Abstract
Circadian clocks control various aspects of the immune system in mammals but their role in the adaptive immune response remains poorly defined. Our previous work showed that the CD8 T cell response to vaccination with dendritic cells loaded with the OVA peptide (DC-OVA) varies according to the time of day. In this study, we have identified the clock involved in the in vivo CD8 T cell response and have started to uncover how the circadian clock affects this response. Using Kb-OVA tetramer staining, we found that the higher expansion of OVA-specific CD8 T cells in response to DC-OVA vaccination done in the middle of the day is abolished when CD8 T cells are deficient for the essential clock gene Bmal1. Similarly, the rhythm of cytokine production by CD8 T cells was abolished. Moreover, the observed rhythm impacts the ability to control an infectious challenge (by Listeria monocytogenes) as shown by a day/night variation in bacterial load in WT but not CD8 T cell-specific Bmal1 KO mice. In contrast, the rhythm of CD8 T cell response was not affected when Bmal1 KO DCs were used to vaccinate mice, confirming the role of the CD8 T cell clock in this rhythm. To assess whether the circadian clock affected the magnitude of the CD8 T cell response by modulating the affinity of the T cells recruited in the response, we measured CD8 T cell sensitivity to restimulation with various doses of OVA peptide. A stronger T cell expansion in response to antigen presentation correlated with an increased EC50, suggesting that the CD8 T cell clock acts by recruiting CD8 T cell clones bearing TCR with different affinities for the antigen. In conclusion, the CD8 T cell clock is essential for the rhythm of the CD8 T cell response and affects the affinity of the antigen-specific CD8 T cell response.
Neuroprotective roles of fractalkine in multiple sclerosis: Characterization of novel humanized animal model
Authors: Cardona Sandra M. , Kim Sangwon V. , Torres Vanessa , Hung Chiung-Yu , Church Kaira , Cleary Ian , Mendiola Andrew S. , Saville Stephen , Watowich Stephanie S. , Parker-Thornburg Jan , Littman Dan R. , Ransohoff Richard M. , Cardona Astrid E. 
Published: January 2023

Abstract
Multiple sclerosis (MS), an inflammatory demyelinating disease of the CNS is the leading cause of nontraumatic neurological disability in young adults. Immune mediated destruction of the myelin and oligodendrocytes are considered its primary pathology, but progressive axonal loss is the major cause of neurological disability. In an effort to understand microglia function in CNS inflammation, our laboratory showed that Fractalkine/CX3CR1 signaling regulates microglia neurotoxicity during neurodegeneration.
Fractalkine (FKN), a transmembrane chemokine expressed in the CNS by neurons signals through its unique receptor, CX3CR1 present in microglia. During EAE, CX3CR1 deficiency confers exacerbated disease, severe inflammation and neuronal loss. The CX3CR1 human polymorphism I249/M280 present in ~20% of the population exhibits reduced adhesion for FKN conferring defective signaling whose role in microglia function and effect on neurons during MS remains unsolved.
The aim of this study is to assess the effect of weaker signaling through hCX3CR1I249/M280 during EAE. We hypothesize that dysregulated microglial responses in absence of CX3CR1 signaling enhance neuronal/axonal damage.
We generated an animal model replacing the mouse CX3CR1 locus for the hCX3CR1I249/M280 variant. Upon EAE induction, these mice exhibit exacerbated EAE defined by severe inflammation and neuronal loss. We also observed that mice with aberrant CX3CR1 signaling are unable to produce FKN and CNTF during EAE as WT mice. Our results provide validation of defective function of the hCX3CR1I249/M280 variant and the foundation to broaden the understanding of microglia dysfunction during neuroinflammation.
ADAMTS7 extracellular matrix enzyme expression is required for optimal influenza-specific CD8+T cell immunity.
Authors: Stambas John , McMahon Meagan , Ye Siying , Dlugolenski Daniel , Tripp Ralph A. , McCulloch Daniel 
Published: January 2023

Abstract
Extracellular matrix (ECM) enzymes including the ADAMTS (A disintegrin-like and metalloproteinase with thrombospondin-1 motifs) family have been shown to regulate influenza-specific immunity. ADAMTS7, a largely uncharacterised ECM enzyme with broad tissue distribution has been associated with coronary heart disease and arthritis, however its role in viral immunity remains undefined. We assessed the contribution of ADAMTS7 to influenza-specific immunity using Adamts7−/− mice. Adamts7−/− mice intranasally infected with influenza virus showed increased weight loss and had higher viral loads when compared to WT controls. We also observed fewer influenza-specific CD8+ T cells and changes in cytokine production following primary and secondary infection suggesting ADAMTS7 expression is a key regulator of viral immunity.
Influenza-Induced Interferon-γ Promotes Alveolar Macrophage Depletion during Secondary Pneumococcal Infection
Authors: Bansal Shruti , Yajjala Vijaya Kumar , Bauer Christopher , Sun Keer 
Published: January 2023

Abstract
Secondary bacterial pneumonia is a significant cause of influenza-associated morbidity and mortality. Animal studies have shown that this viral/bacterial synergy is due to suppression of antibacterial immunity by influenza-induced cytokines, i.e., type I IFN and IFN-γ. However, it is not clear which of these pathways is most critical in the pathogenesis. In this study, we have performed comparative analyses of antibacterial immunity in type I IFN receptor-1 (IFNAR1)−/−, IFN-γ−/− and WT mice super-challenged with S. pneumoniae on day seven after PR8 infection. While nearly all WT and IFNAR1−/− mice succumbed, IFN-γ−/− animals fully survived from PR8/S. pneumoniae coinfection. In agreement, despite a temporary reduction at 24 h, lung bacterial burden in IFNAR1−/− mice was comparable to WT controls at 72 h after coinfection. At the same time, bacterial burden diminished in IFN-γ−/− mice. Rather than attenuated inflammatory cytokine response or neutrophil recruitment, the heightened bacterial burden is consistent with diminished alveolar macrophage (AM) numbers in IFNAR1−/− and WT mice after coinfection. Furthermore, we have used “macrophages insensitive to IFN-γ” (MIIG) mice, which express a dominant negative mutant IFN-γ receptor (IFN-γR) in macrophage lineage cells, to examine the direct effect of IFN-γ on macrophages. Similar to IFN-γR−/− mice, MIIG mice exhibited significantly increased AM numbers and bacterial clearance compared with WT controls at 72 h, as well as complete survival from coinfection. Together, these results indicate that by acting directly on macrophages/monocytes to reduce AM survival, IFN-γ plays a predominant role in inhibiting antibacterial immunity during post-influenza pneumococcal infection.
Keratinocytes affect biology of Langerhans cells through mRNA transfer
Authors: Su Qingtai , Igyártó Botond 
Published: January 2023

Abstract
Dendritic cell (DC) subsets might acquire specific immune functions based on their tissue of residence. Langerhans cells (LCs), a specific DC population located in the epidermis, are in close contact with epidermal keratinocytes (KCs), providing us with an easily accessible model to dissect the effect of epithelial cells on infiltrating DCs. Using microarray analysis, RT-qPCR, histology and flow cytometry, we showed that many of the KC-specific molecules, such as keratins and adhesion molecules, can be detected in LCs at mRNA and protein levels. To determine whether these KC-specific genes are accessible for transcription in LCs, we performed ATAC-seq on flow-purified LCs. We found that chromatin loci of these genes were in the closed conformation in LCs. Therefore, these data support the active transport of mRNAs from the KCs to LCs. Furthermore, we also showed that KC-specific expression of Cre, driven by the KRT14 promoter, can lead to genetic recombination and expression of YFP in the LCs. Additionally, YFP+ LCs could be readily identified in LC-depleted KRT14-YFP mice reconstituted with WT bone marrow, which further supports the material transfer from KCs to LCs. Of note, we found that tunneling nanotubes could be one of the potential mechanisms mediating the material transfer. The transfer of material between epithelial cells and epithelia-associated DCs was not limited to mice or to KC-to-LC transfer.
Taken together, these data suggest that the epithelial environment might have a long-term effect on DC biology and that genetic tools specifically targeting epithelial cells also affect tissue-resident immune cells, which adds another layer of complexity to data interpretation.