bluuebunny/crossref_metadata_2025_split huggingface dataset:
Herpesvirus co-infection alters immune responses to human influenza virus infection.
Authors: Souquette Aisha , Oshansky Christine , Tang Li , Wong Sook-san , Jeevan Trushar , Webby Richard , DeVincenzo John , Thomas Paul G. 
Published: January 2023

Abstract
Herpesviruses (HVs) cause lifelong infections, and the majority of humans are infected with at least one; whether co-infection with HVs is beneficial or detrimental to the host is a current debate. We sought to determine if co-infection with HVs alters the magnitude or quality of the immune response to influenza infection, and, if so, the extent to which each virus affects illness outcome. We used a longitudinal study of naturally acquired influenza virus infection and linear regression modeling to determine differences in influenza viral load and shedding, cytokine levels, and severity scores, while taking into account the effects of confounding variables. Our results show co-infection with HVs does not significantly affect influenza virus kinetics or clearance, but Cytomegalovirus is associated with decreased symptom severity and increased antibody titers. Furthermore, co-infection alters cytokine levels involved in each step of the immune response. Changes in plasma and nasal wash cytokines were predominately associated with Herpes simplex virus 1/2 and Epstein-Barr virus co-infection, respectively. The cytokines most affected by HV serostatus in the plasma and nasal wash are MIP1b (adj. R2 = 0.3073) and RANTES (adj. R2 = 0.3604), respectively. The strongest effects on cytokine levels are associated with HV interactions and are primarily found in the plasma. In the nasal wash, co-infection mostly results in decreased levels of cytokines, including those implicated in immunopathology during influenza infection (e.g. IL1, MIP1, TNF-α, IL6). Understanding host-virus interactions during co-infection and how that relationship impacts disease severity can ultimately be used for better prognosis and/or prophylactic measures.
A blood immune suppression index (BISI) based on IL10/IL12 and ARG1/NOS2 ratios is predictive of immune dysfunction and respiratory failure after burn injury in patients
Authors: Stepp Wesley H. , Malfitano Madison , Saklayici Irmak , Jones Samuel W. , Ortiz-Pujols Shiara , Maile Robert , Cairns Bruce A. 
Published: January 2023

Abstract
Few molecular markers exist that can detail the extent of an injury or predict outcomes in burn patients. Understanding the immune status of patients could minimize complications following burn injury by reducing non-emergent surgical interventions when infection risks are high and allowing more aggressive interventions in patients at higher risk for pulmonary compromise. Here we detail a novel molecular signature to identify these at-risk patients. PBMCs from healthy volunteers (n=30) or burn trauma patients (n=110) were isolated under UNC IRB 15-1662 and assayed for IL-10, arginase-1 (ARG1), IL-12 and nitric oxide synthase-2 (NOS2) using quantitative, real-time PCR (qRT-PCR) or Nanostring mRNA arrays. A blood immune suppression index (BISI) was calculated using a ratio of anti- to pro-inflammatory gene expression and molecular pathway analysis of Nanostring data was conducted using Ingenuity Pathway Analysis. PBMCs from severe burn patients had increased expression of the anti-inflammatory mediators interleukin-10 (IL-10) and arginase-1 (ARG1) within the first 48 hours of hospital admission. Conversely, the pro-inflammatory cytokines, interleukin-12 (IL-12) and nitric oxide synthase-2 (NOS2), were markedly down-regulated. The BISI for patients who eventually developed acute lung injury or suffered skin graft failures was increased by 2.2-fold and 3.1-fold, respectively. Further, large-scale mRNA profiling of key immune regulatory markers (n=596 genes) using Nanostring mRNA profiling highlighted key pathways of immune dysfunction that confirmed our initial qRT-PCR findings and added additional immunoregulatory markers that are differentially expressed in conditions of immune dysfunction.
Spatial map of human B cell compartmentalization
Authors: Borghesi Lisa A. , Weisel Nadine , Liu Ailing , Shlomchik Mark J. 
Published: January 2023

Abstract
We have performed a comprehensive analysis of human lymphoid tissue from relatively inaccessible sites including SPL, BM and LN from normal donors. Most of what is known about human B cells comes from blood, a tissue that contains only ~2% of the immune cells in the body. Examination of different tissues from 14 independent donors reveals for the first time the global B cell population structure. We performed unbiased computational clustering on samples stained with antibodies to markers indicative of antigen experience, activation status, and tissue retention. We found that the population structure of splenic B cells is remarkably conserved across a large number of donors who vary by age, gender, environment and history of pathogen exposure. By contrast, blood B cell composition is highly individualized with respect to each donor while BM has a relatively uniform population structure with some individual tailoring. Comparison of paired tissues within individuals further demonstrates that SPL and blood contain largely non-overlapping populations, suggesting geographic segregation of B cell subsets within each person. Recently published Ig clonal tracking studies from this donor cohort demonstrates partitioning of B cell clonal sharing into two broad networks, one across blood rich tissues and the other restricted to portions of the GI tract. Knowledge about the mechanisms that direct the trafficking and retention of discrete B cell subsets to specific tissues has direct implication to how infections are controlled throughout the body. Our findings constitute the basis for a geographic understanding of B cell population structure that will inform studies on the human humoral immune response.
Macrophage-associated lipin-1 enzymatic activity contributes to modified low-density lipoprotein-induced pro-inflammatory signaling and atherosclerosis.
Authors: Vozenilek Aimee E. , Navratil Aaron R. , Green Jonette M. , Coleman David , Blackburn Cassidy M.R. , Finney Alexandra C. , Pearson Brenna H. , Chrast Roman , Finck Brian N. , Klein Ronald L. , Orr A Wayne , Woolard Matthew D. 
Published: January 2023

Abstract
Macrophage proinflammatory responses induced by modified low-density lipoproteins (modLDL) contribute to atherosclerotic progression. How modLDL causes macrophages to become proinflammatory is still enigmatic. Macrophage foam cell formation induced by modLDL requires glycerolipid synthesis. Lipin-1, a key enzyme in the glycerolipid synthesis pathway, contributes to modLDL-elicited macrophage proinflammatory responses in vitro. The objective of this study was to determine if macrophage-associated lipin-1 contributes to atherogenesis and to assess its role in modLDL-mediated signaling in macrophages. We developed mice lacking lipin-1 in myeloid-derived cells and used adeno-associated viral vector 8 expressing the gain-of-function mutation of mouse proprotein convertase subtilisin/kexin type 9 (AAV8-PCSK9) to induce hypercholesterolemia and plaque formation. Mice lacking myeloid-associated lipin-1 had reduced atherosclerotic burden compared to control mice despite similar plasma lipid levels. Stimulation of bone marrow-derived macrophages with modLDL activated a persistent PKCα/βII-ERK1/2-cJun signaling cascade that contributed to macrophage proinflammatory responses that was dependent on lipin-1 enzymatic activity. Our data demonstrate that macrophage-associated lipin-1 is atherogenic, likely through persistent activation of a PKCα/βII-ERK1/2-cJun signaling cascade that contributes to foam cell proinflammatory responses. Taken together these results suggest modLDL-induced foam cell formation and modLDL-induced macrophage proinflammatory responses are not independent consequences of modLDL stimulation, but rather are both directly influenced by enhanced lipid synthesis.
Granulocyte-derived extracellular vesicles activate monocytes and are associated with mortality in ICU patients
Authors: Norris Philip , Inglis Heather C. , Abdel-Mohsen Mohamed , Deng Xutao , Adelman Avril , Schechtman Kenneth B. , Keating Sheila Marie , Cohen Mitchell J. , Jacobs Evan S. , Pillai Satish , Lacroix Jacques , Spinella Philip C. , Danesh Ali 
Published: January 2023

Abstract
To understand how extracellular vesicle (EV) subtypes differentially activate monocytes, a series of in vitro studies were performed. We found that plasma-EVs biased monocytes toward an M1 profile. Culturing monocytes with granulocyte-, monocyte- and endothelial-EVs induced several pro-inflammatory cytokines. In contrast, platelet-EVs induced TGF-β and GM-CSF, and red blood cell (RBC)-EVs did not activate monocytes in vitro. The scavenger receptor CD36 was important for binding of RBC-EVs to monocytes, while blockade of CD36, CD163, CD206, TLR1, TLR2, and TLR4 did not affect binding of plasma-EVs to monocytes in vitro. To identify mortality risk factors, multiple soluble factors and EV subtypes were measured in patients’ plasma at intensive care unit (ICU) admission. Of 43 coagulation factors and cytokines measured, two were significantly associated with mortality, TPA and cystatin C. Of 14 cellular markers quantified on EVs, 4 were early predictors of mortality, including the granulocyte marker CD66b. In conclusion, granulocyte-EVs have potent pro-inflammatory effects on monocytes in vitro. Furthermore, correlation of early granulocyte EV levels with mortality in critically ill patients provides a potential target for intervention in management of the pro-inflammatory cascade associated with critical illness.
The source of fat in a high fat diet affects systemic inflammatory markers and modulates gene expression in intestinal, hepatic and adipose tissues of growing pigs.
Authors: Blais Mylene , Gonzalez Jose Luis Martinez , Pouliot Yves , Gauthier Sylvie , Boutin Yvan , Roy Denis , Marette Andre , Asselin Claude , Lessard Martin 
Published: January 2023

Abstract
While high fat diets have been associated with increased level of inflammation and metabolic health impairment, new evidences show that the source of fat plays an important role on these outcomes. In order to investigate the specific role of dairy fats on metabolic health, a model of growing pigs was used. A total of 40 pigs aged 6 weeks were fed a low fat diet, or high fat diets (17.5% fat) containing either lard only, a combination of lard and butter (butter: 4.5% fat; lard: 13% fat) or a combination of lard and cheddar cheese (cheddar: 4.5% fat; lard: 13% fat) for 10 weeks. After 5 and 10 weeks, blood samples were collected to determine hyperlipidemia and inflammatory markers level. After 10 weeks, pigs were euthanized to collect intestinal, hepatic and adipose tissues to measure the expression of a selection of genes involved in inflammation, oxidative stress and energy metabolism by qPCR. Blood levels of IL-1β and TNF-α were decreased in pigs fed either butter or cheddar compared to the lard-only high fat diet (P &lt; 0.05), while no changes were observed in the level of blood lipids. To visualize the impact of dairy fats on gene expression, a Heatmap of gene expression was drawn and showed that both butter and cheddar affected gene expression in jejunum, while butter specifically modulated the gene expression in liver and fat tissues, and cheddar specifically changed gene expression in colon. In conclusion, replacement of lard for dairy fats in a high fat diet protects from systemic inflammation and changes gene expression in pig intestinal, hepatic and adipose tissues.
A missense mutation impairs ITK function in a patient with severe Epstein-Barr virus disease.
Authors: Dowdell K. C. , Howe Matthew , Roy Amitava , Niemela Julie , Wilson Wyndham , McElwee Joshua , Cohen Jeffrey 
Published: January 2023

Abstract
T cells are critical in controlling EBV. IL-2-inducible T cell kinase (ITK) is an integral component of T cell signaling and modulates cytotoxic function. ITK activation leads to ITK mediated phosphorylation of phospholipase C (PLC)-γ, resulting in an intracellular calcium flux, activation of ERK, and translocation of NF-κB and NFAT into the nucleus. ITK is expressed in cells critical for controlling EBV infection, including T cells, NK cells, and invariant NKT (iNKT) cells. Mutations in ITK have been previously reported in 9 patients, ranging from 5 to 18 years of age who presented with low numbers of CD4 T and iNKT cells and EBV driven B cell lymphoproliferation. Here we identify a patient with a previously unreported homozygous missense mutation (ITK NM_005546 c.1618G&gt;A p.D540N) in a highly conserved residue in the kinase domain of ITK. This patient presented at age 22 with lung nodules due to lymphomatoid granulomatosis with EBV-positive large tumor cells. She was treated with interferon and cytotoxic chemotherapy and her disease ultimately went into remission. She has since had persistent elevation of EBV DNA in the blood, low CD4 T cells, low NK cells, and nearly absent iNKT cells. Stimulation of her T cells resulted in reduced ITK signaling with diminished PLC-γ and Erk activation, and impaired calcium flux. Western blot analysis showed normal levels of ITK, indicating that the mutation affects the function, but not the stability of ITK. The patient’s CD8 T cells were impaired for degranulation, while her NK cells had reduced expression of the NK cell receptor, NKG2D. Our findings highlight the critical role of ITK to modulate T cell activation and control EBV driven B cell lymphoproliferation.
Cardiac damage after experimental blunt chest trauma and multiple trauma with hemorrhagic shock
Authors: Kalbitz Miriam , Weber Birte , Braun Christian , Lackner Ina , Haffner-Luntzer Melanie , Huber-Lang Markus , Gebhard Florian 
Published: January 2023

Abstract

INTRODUCTION
Heart injury represents an independent predictor for a poor outcome after trauma. However, molecular mechanisms of depressed cardiac function after trauma remains elusive.

METHODS
Multiple trauma (PTHS) included a blast-wave induced blunt chest trauma, traumatic brain injury and closed femoral fracture as well as pressure controlled hemorrhagic shock. In vitro studies were performed using human cardiomyocytes (Cellular Dynamics). Data were analyzed by one-way ANOVA analysis of variance followed by Dunnett’s multiple comparison test.

RESULTS
4h after PTHS in mice plasma concentration of pro-inflammatory cytokines such as MCP-1 and chemokine KC were significantly increased in comparison to sham treated animals. Plasma concentration of cardiac troponin levels were significantly increased early after experimental PTHS. HMGB1 staining provided significant increase in left ventricular tissue after PTHS. Distribution of the gap junction protein connexin 43 (Cx43) was was disintegrated in histological sections.
In presence of TNF reactive oxygen species were significantly increased in human cardiomyocytes, indicating a redox imbalance indicative of an oxidative state. Furthermore, presence of TNF in cultured human cardiomyocytes was associated with increased expression of the NLRP3 inflammasome and increased concentration of troponin in supernatant, which is specific marker for cardiac cell damage.

DISCUSSION
The cellular and subcellular events demonstrated in this report may explain molecular mechanisms associated with cardiac dysfunction after trauma. Better understanding of cardiac damage and molecular mechanisms of cardiac dysfunction after trauma will improve patient care in future.
TLR3 contributes to degeneration of dopamine neurons in an MPTP mouse model of Parkinson’s disease
Authors: Chung Young Cheul , Jeong Jaeyeong , Jin Byung Kwan 
Published: January 2023

Abstract
Toll like receptor 3 (TLR3), a pattern recognition receptor, is highly expressed in the brain. However, its role in neurodegenerative diseases is unknown. The present study investigated the effects of TLR 3 on dopamine (DA) neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease (PD). Here we show that TLR3-deficient mice are resistant to MPTP neurotoxicity. TH immunohistochemical analysis revealed that number of nigral TH+ neurons and striatal density of TH+ fibers were significantly maintained in MPTP-treated TLR3−/− mice, compared to MPTP-treated TLR3+/+ control mice. The observed neuroprotection was accompanied by reducing blood brain barrier (BBB) leakage and infiltration of immune cells such as CD-3+ T cells in the substantia nigra (SN). Moreover, genetic deletion of IKK-β (IKK-β−/−) in microglia, the downstream signaling of TLR3 and inhibitor of NF-κB kinase subunit beta (IκB) rescued dopamine neurons in the SN of MPTP-treated mice, compared to MPTP-treated IKK-β+/+ control mice. Similar to TLR3−/− mice, number of CD-3+ T cells were significantly attenuated in MPTP-treated IKK-β−/− mice, compared to MPTP-treated IKK-β+/+ control mice. Collectively, these results suggest that TLR 3 via IKK-β signaling pathway may play a crucial role in degeneration of dopamine neurons in the MPTP mouse model of PD.
Prenatal Maternal Immune Activation Sensitizes the Neuroinflammatory Responses to Neonatal Hypoxic-Ischemic Brain Injury
Authors: Kuan Chia-Yi , Chen Hong-Ru 
Published: January 2023

Abstract
Epidemiological evidence suggests that prenatal maternal immune activation (MIA) is a risk factor for autism spectrum disorders (ASD). Yet, because not all human MIA offspring develop ASD, we hypothesize that “second hits” may be needed to induce severe brain damage and disruption of the neural network. We tested this hypothesis using an established MIA model with Poly I:C (20 mg/kg) intraperitoneally injected at mid pregnancy (E12.5) in C57BL/6 mice. The offspring were challenged by mild hypoxia-ischemia (HI) at P10 as the second hit. We found that MIA alone infrequently caused clusters of amoeboid microglial cells (AMCs) expressing a high level of Complement component 3 (C3) in the offspring brains. Elevated NFkB signaling and a higher basal level of IL-6, IL-17 and MMP9 mRNA were also detected in the P11 MIA offspring brains. When challenged by HI, the MIA offspring showed significantly greater NFkB activity, TUNEL-positive apoptosis, and mRNAs for pro-inflammatory cytokines including IL-6, IL-17, TNFα, IL-23, TSPO and MCP-1 at 24 h post-injury, when compared to those injured by HI alone. At 7 d recovery, the MIA/HI-injured mice showed more AMCs, monocyte infiltration, and greater brain atrophy than singularly MIA- or HI-injured mice. Finally, the MIA/HI-injured mouse brains showed a significant reduction of PSD95 and synaptotagmin/PSD-96 punctates, correlated with greater C3 expression in the hippocampal CA2/3 region than MIA alone or HI-injured counterparts. Together, these results suggest that MIA elevates the inflammatory activity in the offspring brain, and acts as a primer to sensitize the neuroinflammatory responses to a secondary insult, leading to greater brain damage, and potentially ASD-like cognitive deficits.
Absence of CD137L decreases mechanical hypersensitivity and functional recovery time following sciatic nerve crush
Authors: Wakley Alexa A. , Cao Ling 
Published: January 2023

Abstract
CD137 Ligand (CD137L), a tumor necrosis factor superfamily molecule, is involved in immune responses such as migration, proliferation and production of cytokines. To investigate the involvement of CD137L in pain development and nerve regeneration following peripheral nerve injury, we examined various pain-like and functional recovery-related behavioral responses in CD137L knockout (KO) mice and wild type (WT) B6 mice following sciatic nerve crush (SNC). Male and female B6 WT and CD137LKO mice underwent a sham or SNC surgery and were evaluated for hypersensitivity (von Frey, Hargreaves & cold water tail withdrawal tests), sensory (pin prick assay) and motor (hind limb grip strength, toe spread reflex and toe spacing score) functional recovery. Behaviors were assessed before surgery and on post-surgery days 1–77. On post-SNC Day 1, both KO and WT mice showed increased hypersensitivity and decreased sensory and functional responses. By Day 7, CD137LKO mice showed reduced mechanical hypersensitivity compared to WT and were responding at sham levels by Day 42, whereas WT controls reached sham levels by Days 56–63. Lack of CD137L did not alter warm or cold thermal hypersensitivity. Grip strength improved in both strains beginning on Day 7, but CD137LKO mice reached sham levels faster than WT controls (Day 17 vs. Day 70). No differences were found on toe spread reflex and toe spacing scores. Finally, pin prick scores revealed that sensory recovery in both strains of mice emerged on Day 7, but the CD137LKO mice responded similar to shams by Day 28, one week earlier than WT. Together, these results suggest that CD137L mediates the sensory hypersensitivity and impedes the restoration of sensory and motor functions following peripheral nerve injury.
A novel variant in ATM gene causes ataxia telangiectasia revealed by whole-exome sequencing
Authors: Alonazi Noufa Afri 
Published: January 2023

Abstract
Ataxia-Telangiectasia (A-T) is an autosomal recessive disorder caused by variants in ATM gene and characterized by progressive neurologic impairment, cerebellar ataxia, and oculo-cutaneous telangiectasia. Immunodeficiency with a recurrent sinopulmonary infections are observed in patients with A-T. Here, we report a novel stop codon variant, c.5944 C&gt;T (p.Gln1982*), revealed by whole-exome sequencing in a 9- year old boy. He presented with recurrent upper respiratory tract infections, failure to thrive, developmental delay, ataxic gait, and bulbar telangiectasia.
Effects of HMGB1 gene silencing on respiratory syncytial virus-induced inflammatory response
Authors: Kempaiah Kempaiah Rayavara , Kurosky Alexander , Hosakote Yashoda Madaiah 
Published: January 2023

Abstract
Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections among infants and young children worldwide. High mobility group box 1 protein (HMGB1) is a redox-sensitive multifunctional protein that serves as both DNA regulatory protein and an extracellular cytokine signaling molecule that mediates the activation of innate and adaptive immune responses to infection, injury and inflammation. The goal of this study is to investigate the effect of HMGB1 gene silencing using short interfering RNA (siRNA) in RSV-induced airway inflammation. Studies were conducted in airway epithelial cells, human lung carcinoma cell line (A549) and normal small alveolar epithelial (SAE) cells. Cells were transfected with siRNA followed by infection with RSV, and NFκB, Nrf2, HDAC1 and catalase expression were determined. HMGB1-siRNA achieved a reduction of ~60–70% in nuclear HMGB1 expression in the airway epithelial cells. The Knockdown of nuclear HMGB1 was found to worsen inflammation in RSV-infected lung epithelial cells, highlighting a role for intracellular HMGB1 in cellular protection. We also found that HMGB1 gene silencing resulted in decreased HMGB1 release with significant downregulation of Nrf2, catalase and HDAC1 and increased NFκB and MAPK expression. These results indicated that downregulation of nuclear HMGB1 by siRNA might not only decrease its proinflammatory extracellular role by reducing its release but also serve to maintain its beneficial intracellular role, thus protecting against RSV -induced airway inflammation. Understanding the role of HMGB1 and associated cellular signaling in RSV-induced lung inflammation may pave the way for the development of novel therapeutic interventions.