bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aberrant generation and function of natural killer T (NKT) cell in absence of Utx and Jmjd3
Authors: Wang Jie , Wu Xiaojun , Bosselut Remy , Zhou Li , Mi Qing-Sheng 
Published: January 2023

Abstract
Histone H3 lysine 27 trimethylation (H3K27Me3) demethylases Jmjd3 and Utx, the epigenetic regulators, affects transcription and cell differentiation. But their specific roles in invariant natural killer T (NKT) cells development, maturation and function remain to be explored. Using T cell-specific Utx and Jmjd3 double knock out (DKO) mouse model, we identified that Utx and Jmjd3 deletion results in profound impairment in NKT numbers and maturation of both thymic and peripheral immune organs. DKO thymus NKT cells showed dramatic blockade of maturation at stage 0 and stage 1. Defective expression of Slamf1 (CD150) in DKO CD69+DP thymocytes was identified, suggesting an interrupted DP selecting process. Additionally, we found the impaired expression of PLZF, Tbet, ICOS in DKO NKT cells, which is consistent with the defective NKT sublineage development in those mice. Furthermore, DKO iNKT cells showed significantly defective IFN-r, IL-4 and IL-17 production upon activation. Bone marrow chimera experiment confirmed the major defects of NKT cell development, maturation and function in DKO mice are cell autonomous. Altogether, our present study demonstrates critical contribution of Utx and Jmjd3 in NKT cell development, lineage differentiation and function. Utx and Jmjd3 related epigenetic landscape and gene expression network involved in NKT cell development and function regulation are currently under investigation.
A Long Noncoding RNA, lncRNA205, and an Embedded MicroRNA, MiR-205 have Overlapping and Distinct Contributions to Thymopoiesis and Development
Authors: van Oers Nicolai S , Hoover Ashley R , Du Qiumei , Dozmorov Igor , Raj Prithvi , de la Morena M Teresa , Cleaver Ondine B 
Published: January 2023

Abstract
MiR-205 is an epithelial-specific microRNA (miR) that supports thymopoiesis. This miR positively regulates Forkhead Box N1 (Foxn1) transcription factor expression. MiR-205 is embedded in a long noncoding RNA (lncRNA), termed MIR205HG in humans. Several lncRNAs that contain miRs have independent functional roles in tissue development and/or regeneration. We characterized the transcriptome assembly of the murine locus containing miR-205 and the larger lncRNA. Conditional knockout mice that harbored a targeted deletion of the proximal region of the lncRNA, with miR-205 sequences retained, were developed. The phenotypes in these mice were compared to those with a miR-205 deficiency. The more severe stress-induced thymic atrophy reported in miR-205-deficient mice, compared to littermate controls, is also evident in lncRNA205 knockout lines. In contrast, a lncRNA205 deficiency results in a smaller mouse stature, which may be coupled with a reduced fat but normal lean mass. These phenotypic differences are explained, in part, by the differential regulation of the lncRNA transcript relative to the pre-mature miR-205. Interferon and IL-22, cytokines released following inflammation, transiently reduce miR-205 while increasing the lncRNA. This is partly determined by the DNp63 transcription factor, which controls miR-205 expression. Gene expression comparisons are being undertaken to reveal how the transcriptome is differentially regulated by these two non-coding RNA species. Further, the mechanism by which these noncoding RNAs regulate Foxn1 is being elucidated. Taken together, these findings suggest both overlapping and independent functions for the lncRNA205 and the embedded miR-205.
HDAC3 is required to suppress the CD8-lineage program in DP thymocytes for CD4-lineage T cell commitment
Authors: Philips Rachael Laura , Lee Jeong-Heon , Gaonkar Krutika , Chung Ji Young , Arocha Sinibaldo Romero , Ordog Tamas , Shapiro Virginia 
Published: January 2023

Abstract
MHC-restricted CD4 and CD8 T cells are vital components of the immune system. The decision to generate CD4 or CD8 T cells occurs in the thymus. After positive selection, intermediate thymocytes downregulate CD8 to test coreceptor specificity. Thymocytes develop into CD4 T cells if they experience persistent TCR signaling, while termination of TCR signaling leads to IL-7-mediated CD8-lineage commitment via Runx3. While the general signaling and transcriptional mechanisms are known, the epigenetic mechanisms controlling error-free lineage commitment are largely unknown. We found histone deacetylase 3 (HDAC3) to be critical for generating CD4 T cells, as its deletion leads to the generation of only CD8SP cells. Introduction of an OT-II TCR transgene revealed redirection of MHC class II-restricted cells to the CD8 lineage upon HDAC3 deletion. We found evidence that HDAC3-deficient DP thymocytes are primed for the CD8-lineage, as they exhibit hyperacetylation at CD8-lineage promoting genes and show elevated expression of phosphorylated-STAT5 (pSTAT5). During lineage choice, OT-II expressing HDAC3-deficient cells inappropriately upregulate Runx3. Therefore, HDAC3 functions as a brake in DP thymocytes whose release leads to a developmental bias for CD8 T cells.
The non-receptor protein tyrosine kinase Pyk2 promotes the turnover of mouse monocyte populations at steady-state
Authors: Llewellyn Ryan , Thomas Keena S. , Bouton Amy H 
Published: January 2023

Abstract
Peripheral monocytes, consisting of distinct Ly6C+ and Ly6Cneg subsets in mice, are innate immune effector cells that exhibit a relatively short half-life of 1–3 days. While the differentiation and function of these monocyte subpopulations have been explored extensively, the cellular mechanisms regulating the maintenance and turnover of these populations are not completely understood. The focus of our current study is to investigate the role of proline-rich tyrosine kinase 2 (Pyk2) in the establishment and/or maintenance of monocyte populations at steady-state.
Using a Pyk2 knock-out mouse model (Pyk2−/−), we show for the first time that Pyk2−/− mice exhibit reduced bone marrow (BM) cellularity, resulting in a reduction of total BM monocytes in these mice. Accordingly, Pyk2−/− mice display reduced numbers of BM monocyte progenitors and Ly6C+ monocytes; however, there is no reduction in the representation of Ly6Cneg monocytes in the absence of Pyk2, suggesting that Pyk2 regulates the relative proportion of monocyte subsets normally represented in the BM at steady state. In support of this conclusion, a similar phenotype was observed in the peripheral blood and spleen. Data from reciprocal and mixed BM chimera experiments indicate that the alterations in monocyte populations exhibited by Pyk2−/− mice are due to factors intrinsic to the monocytes. Pyk2 does not appear to regulate the proliferation, differentiation, or egress of monocyte subsets. Instead, experiments using annexin V and cleaved caspase as markers for apoptosis indicate that Pyk2 may promote apoptosis in BM monocytes, thereby acting as an important regulator of turnover in these short-lived effector cells.
Transcription factor IRF8 governs enhancer landscape dynamics during mononuclear phagocyte development
Authors: Kurotaki Daisuke , Nakabayashi Jun , Nishiyama Akira , Sasaki Haruka , Kaneko Naofumi , Kawase Wataru , Ozato Keiko , Suzuki Yutaka , Tamura Tomohiko 
Published: January 2023

Abstract
Monocytes and dendritic cells (DCs) are mononuclear phagocytes essential for innate and adaptive immunity. These phagocytes develop from hematopoietic stem cells via intermediate progenitors, such as granulocyte-monocyte progenitors (GMPs), monocyte-DC progenitors (MDPs), and common monocyte progenitors (cMoPs) or common DC progenitors (CDPs). However, the molecular mechanism underlying their differentiation potential remains incompletely understood. Recent studies suggest that promoter-distal enhancers are key for cell fate decision. In this study, we performed chromatin immunoprecipitation-sequencing (ChIP-seq) analysis of enhancer-related histone modifications in GMPs, MDPs, cMoPs, CDPs, monocytes, DCs, and neutrophils. We found that monocyte- and DC-specific enhancers were gradually established at progenitor stages before the expression of associated genes. Of the transcription factors predicted to bind to these enhancers, IRF8, essential for monocyte and DC development, was found to be required for the establishment of these enhancers, particularly those common to both monocyte and DC lineages. Somewhat unexpectedly, global gene expression patterns were comparable between the remaining Irf8−/− progenitors and their wild-type counterparts. Nevertheless, the enhancer landscapes of Irf8−/− progenitors were significantly distinct from those of wild-type cells, with the enhancer landscapes of Irf8−/− GMPs, MDPs, and cMoPs all remaining similar to that of wild-type GMPs. Our results illustrate the dynamic process by which key transcription factors regulate enhancer formation and thereby direct future gene expression to achieve mononuclear phagocyte development.
Analysis of the Anaphylactic and Immune Reactions by Means of the Isolated Guinea-Pig Lungs
Authors: Manwaring W. H. , Kusama Yoshio 
Published: January 2023

Summary
Analyses of the anaphylactic and immune reactions by means of perfusion experiments with the isolated guinea-pig lungs show that we are here concerned with three essential factors: Cellular hypersensitiveness, or the anaphylactic response of the hypersensitive fixed pulmonary tissues,Humoral anaphylaxis, or the chemical response (anaphylotoxin formation) of the anaphylactic blood, andHumoral immunity, or the inhibiting or protecting action of the immune blood.
In the 14-day anaphylactic guinea-pig, the fatal bronchial spasm is due, in part to fixed cellular hypersensitiveness, in part to humoral anaphylaxis.
In the 4-week anaphylactic guinea-pig, the fixed cellular hypersensitiveness is usually greater than that of the 14-day anaphylactic guinea-pig. The humoral reaction, however, is usually absent. The fatal bronchial spasm in the 4-week anaphylactic guinea-pig is usually due solely to fixed cellular hypersensitiveness.
The immune guinea-pig usually shows a fixed cellular hypersensitiveness greater than that of the 14-day anaphylactic guinea pig. A fatal bronchial spasm is prevented in the immune guinea-pig, however, by the inhibiting or protecting action of the immune blood.
The immune guinea-pig, therefore, shows a seemingly paradoxical phenomenon, the coexistence of a fixed cellular hypersensitiveness and a humoral immunity.
Experiments with a Possible Bearing Upon Treatment of Typhoid Fever with Typhoid Vaccine Administered Intravenously
Authors: Teague Oscar , McWilliams Helen I. 
Published: January 2023

Summary and Discussion
The intravenous injection of a suitable dose of killed typhoid bacilli in rabbits causes within twenty-four hours a refractory state, which enables them to withstand a dose of living typhoid bacilli that is fatal to normal rabbits. Since antibodies are not demonstrable until four or five days after an injection of antigen, this is not a process of immunization in the accepted sense of the term.
This sudden increase in resistance to living typhoid bacilli bears a certain resemblance to the cure of typhoid fever patients by crisis following the intravenous injection of typhoid vaccine, the reaction in both instances occurring in about twenty-four hours after the injection of the vaccine, which is followed in both cases by a rapid and often extremely high rise in temperature. This suggests that the same factor or factors may be concerned in the two phenomena.
In the preceding article it was shown that the injection of the doses of vaccine used in these experiments does not increase the bacteriolytic power of normal rabbit serum; hence the increased resistance in the treated rabbits is not due to this factor. Nor is it due to an increase in the number of leucocytes in the peripheral blood resulting from the preliminary injection of vaccine; for rabbits that do not show the leucocytosis are also refractory.
The bacteria disappear from the peripheral blood only slightly more rapidly in the treated than in the control animals, there being a rapid decrease in both normal and treated rabbits during the first hour. In the treated animals this decrease continues progressively until the bacteria are very scarce; in the normal controls it appears to be followed by an increase for a short time and then a rapid decrease until the bacteria are very scarce as in the treated rabbits. The cause of this difference in the normal and treated rabbits is not clear but the evidence at hand indicates that it is not due to an increase of the bacteriolytic power of the blood plasma of the treated rabbits.
For the present we wish merely to record the fact that a rabbit becomes more resistant to infection with typhoid bacilli within 24 hours after the intravenous injection of typhoid vaccine and to point out a possible relationship between the phenomenon and the cure of typhoid fever patients by means of the intravenous injection of typhoid vaccine, without attempting to set up any hypothesis as to the mechanism of the process.
The Bacteriolytic Power of Normal Human Sera and Typhoid Patients' Sera for Typhoid Bacilli and an Inquiry Into the Theoretical Basis for the Treatment of Typhoid Fever with Vaccine Administered Intravenously
Authors: Teague Oscar , McWilliams Helen I. 
Published: January 2023

Abstract
The bacteriolytic action of the sera of typhoid patients has been studied extensively by two methods: first, by determining the greatest dilution of the serum that will kill a given dose of typhoid bacilli and secondly, by determining the greatest dilution of the serum that, with the addition of rabbit or guinea pig complement, will kill a given dose of typhoid bacilli. By both of these methods the titers of the patients' sera were found to be higher than those of normal human sera; with the addition of complement the patients' sera sometimes killed typhoid bacilli at a dilution of 1/500,000 or even 1/1,000,000. Korte and Steinberg (1) say that the (bacteriolytic) amboceptor content of the serum rises during the first weeks of the disease and falls towards convalescence. Denison (2) obtained similar results. The latter found that complement remains constant throughout the disease no matter what spectacular increase or decrease the immune bodies might show.
Hay Fever
Authors: Cooke Robert A. , Flood Edward P. , Coca Arthur F. 
Published: January 2023

Abstract
Since the etiological relation of the pollens of certain plants to hay fever and some forms of asthma was established, a number of investigators have studied the question of the nature of the active substances in the pollens, as well as the mechanism of the curative or alleviating effect of the two forms of specific treatment (with “antitoxin”—“pollantin” of Dunbar—and with active immunization as first practised by Noon).
Originally, both of these methods of treatment were based upon the assumption that the active substances of the pollens are toxins (toxalbumins) to which the former method induced a passive immunization, while the latter, as already indicated, caused an active immunization by the production of specific antibodies.
This conception has been supplanted by the theory of Wolff-Eisner (1),1 according to which the clinical manifestations of hay fever are expressions of hypersensitiveness to an otherwise non-toxic constituent of the pollens.
Serum LTB4, HODE13 and PLA2G7 as biomarkers of cardiovascular disease in SLE
Authors: Baig Sahar , Ding Huihua , McMahon Maureen , Mohan Chandra 
Published: January 2023

Abstract

Background
Cardiovascular complications are the most serious ones associated with lupus, and are thought to be caused by inflammation which results from autoimmunity. This study uses a metabolomic screen to identify metabolites that are elevated in SLE patients with and without CVD. Four of metabolites elevated in the initial screen have been selected for validation by ELISA.

Methods
27 serum samples (10 healthy controls, 8 with SLE and plaque progression, 9 with SLE and no plaque progression) were screened for elevated metabolites. Four of the most significantly elevated metabolites were selected for validation in another cohort of 85 serum samples (25 healthy controls, 53 with lupus nephritis, 7 with both lupus nephritis and cardiovascular disease).

Results
Metabolomic screening of the initial cohort demonstrated that several lipoxygenase metabolites (and HODE 13) were elevated in SLE patients who developed CVD compared to other SLE patients (p &lt; .05) and healthy controls (p &lt; .05). Based on this, LOX15, LTB4, and PLA2G7 (as well as HODE13) were selected for ELISA validation. Serum PLA2G7 correlated positively with number and increase of atherosclerotic plaques, as well as smoking history (p&lt;.05 and &lt;.01, respectively). LTB4 correlated positively with coronary artery disease (p&lt;.05) and HODE13 correlated positively with hypertension and SLEDAI (p&lt;.05).

Conclusions
Serum LTB4, HODE13 and PLA2G7 exhibit potential as biomarkers distinguishing between SLE patients who are or are not at risk of developing cardiovascular complications. Longitudinal studies are in progress to assess the clinical utility of these novel markers.
Identification of protein biomarkers in cerebrospinal fluid(CSF) of Neuro Psychiatric SLE(NPSLE) patients using SOMA scan assay.
Authors: Vanarsa Kamala , Hanly John , Mok C.C. , Mohan Chandra 
Published: January 2023

Abstract

Background
Neurological manifestations of systemic lupus erythematosus (NPSLE) include a wide spectrum of symptoms like seizures, meningitis and psychosis. Clinical diagnosis of NPSLE is challenging due to the lack of objective diagnostic tests. Here, we explore if CSF proteins may have diagnostic value in NPSLE.

Methods
24 CSF samples (8 healthy + 8 neuro controls (NC) + 8 NPSLE) were screened using an aptamer-based platform for about 1100 proteins. A subset of the differentially expressed CSF proteins was selected for validation in two different cohorts, Caucasian controls (N=54) & NPSLE (N= 25) and Chinese controls (N=15) & SLE (N= 17).

Results
The initial aptamer-based screen revealed 8 CSF proteins to be elevated in NPSLE vs healthy, at fold change &gt;2, and p &lt;0.05. All 8 proteins were validated by ELISA. Total IgM, Lipocalin 2, M-CSF were significantly elevated in the CSF of NPSLE when compared to controls, in both Caucasian and Chinese patients (range of fold change: 16–1.2; p &lt; 0.05). CSF HCC-s, DAN and Angiostatin were significantly elevated in Caucasian NPSLE patients only (range of fold change: 2.3–1.8; p &lt; 0.05). Total C3 and albumin in CSF did not show any difference in disease groups in both cohorts, as assayed by ELISA.

Conclusion
Several novel proteins were noted to be elevated in NPSLE CSF, relative to control subjects with other neurological symptoms. Further studies are warranted to establish the specificity of CSF IgM, Lipocalin 2, M-CSF, HCC-s, DAN and Angiostatin for NPSLE and to understand their pathogenic relevance.
Neuropsychiatric lupus is lipocalin-2 dependent
Authors: Mike Elise V. , Cuda Carla , Makinde Hadijat , Perlman Harris , Putterman Chaim 
Published: January 2023

Abstract
Neuropsychiatric manifestations of systemic lupus erythematosus (NPSLE) affect approximately 40% of patients. Lipocalin-2 (LCN2), an acute-phase reactant protein, is an established urinary biomarker in lupus patients. Previous studies using LCN2-deficient mice have demonstrated its role in glial migration and chemokine regulation in the brain. We therefore hypothesized that LCN2 is involved in NPSLE pathogenesis. We investigated the lupus prone B6.Sle1.Sle3 (Sle1,3) mouse and the effects of LCN2 deficiency on the development of the neuropsychiatric phenotype exhibited by this strain. Sle1,3, B6.LCN2KO, B6, and Sle1,3-LCN2KO mice (6–10 month old; n=5–10/group) underwent comprehensive neurobehavioral assessment, and brains were evaluated by flow cytometry and RNA sequencing.
Sle1,3 mice exhibited significant impairment in spatial (p&lt;0.04) and recognition (p&lt;0.02) memory when compared with B6 mice, and these deficits were attenuated in Sle1,3-LCN2KO mice (p&lt;0.001, p&lt;0.02). Furthermore, Sle1,3 mice demonstrated anhedonia, and this depression-like behavior was significantly reduced with LCN2 deficiency (p=0.01). Flow cytometry showed a significant increase in brain infiltrating CD8+ T cells in Sle1,3 mice, with a reduction in infiltration in the Sle1,3-LCN2KO strain (p=0.06). Preliminary analysis of RNA sequencing from sorted microglia revealed genes involved in cognition and memory that were differentially expressed in Sle1,3 mice were restored to background B6 expression levels in Sle1,3-LCN2KO mice.
Our findings establish the Sle1,3 mouse as an NPSLE model and demonstrate that LCN2 deficiency attenuates neurobehavioral deficits and regulates microglial expression of genes essential to NPSLE development.
Loss of circadian rhythmicity of renin-angiotensin-aldosterone system and sodium and potassium balance in lupus nephritis mice
Authors: Mishra Rakesh K. , Bethunaickan Ramalingam , Zhang Weijia , Davidson Anne 
Published: January 2023

Abstract

Background
The mammalian circadian system regulates numerous physiological processes including immune responses. We found a disturbance of expression of key clock transcriptional regulators in the kidneys of mice with SLE nephritis. The purpose of this study was to determine how this abnormality affected transcriptional regulation of renally expressed genes and immune cell homeostasis.

Methods
We studied NZB/W mice at the age of 12 weeks (without proteinuria) and &gt;30 weeks (with proteinuria). Kidneys, urine and blood were harvested at 4 hour intervals. Kidneys were perfused with PBS and used to generate RNA and single cells for flow cytometry analysis. Blood pressure was measured by the tail-cuff method. Urine Na and K were measured by Charles River Lab. Blood and urine aldosterone was measured by ELISA.

Results
Kidneys of young mice displayed a normal circadian pattern of expression of the master transcriptional regulators of circadian rhythm including Bmal1, Clock, Per and Cry. By contrast, the nephritic mice had attenuated rhythm of these genes with dampened BMAL1 expression. To investigate whether timed regulation of renal function was disrupted SLE nephritis mice we compared urinary Na and K excretion during the night versus the day. Young mice exhibited significant day/night differences in urinary Na and K. In contrast, SLE mice did not exhibit a day/night difference in urinary Na and K. In parallel, SLE mice lost the normal circadian rhythm of plasma aldosterone levels and blood pressure with a spike in blood pressure during the day instead of at night.

Conclusion
These data show that the circadian clock mechanism is disrupted in the setting of renal inflammation resulting in dysregulation of normal renal physiologic functions.