bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of activation-induced autophagy induces hyporesponsiveness in effector T helper cells
Authors: Dowling Samuel Dae , Mocholi Enric , Gruber Ross , Ray Alex , Shafit-Zagardo Bridget , Macian Fernando 
Published: January 2023

Abstract
T cell activation requires the regulation of signaling pathways and metabolic programs downstream of T cell receptor and CD28 engagement. Upon activation, effector CD4+ T helper cells induce autophagy, a lysosomal-mediated protein degradation mechanism. The controlled degradation and recycling of cell components allow effector T helper cells to respond to various types of stimuli. However, it is unknown how autophagy may regulate the antigenic responses and functional capacity of CD4+T cells. We found that inhibiting activation-induced autophagy in CD4+T helper type 1 (TH1) cells induces a hyporesponsive state. This hyporesponsiveness is associated with a reduction in ATP generation and decreased glycolysis and mitochondrial respiration. Moreover, T cells that are unable to upregulate autophagy accumulate a protein tyrosine phosphatase that negatively regulates mitogen-activated protein kinase (MAPK) signaling. In vivo deletion of an essential autophagy-related gene in T cells delayed the onset of and decreased the severity of experimental autoimmune encephalomyelitis. Our data support that autophagy may be necessary for T helper cell activation by regulating signaling pathways and metabolic programs, and the inhibition of this catabolic process may induce tolerance.
New Flow-Based, Multiplex Assays Allow Simultaneous Quantification of 13 Soluble Factors Related to Macrophage/Microglia or B Cell Functions
Authors: Sun Binggang , Rughwani Priyanka , Cohane Kenya , Ji Shaoquan , Taylor Peggy , Jiang Weiping 
Published: January 2023

Abstract
Immune responses are mediated by innate immune cells (e.g., macrophages) and subsequently, adaptive immune cells (e.g., B cells). Macrophages secrete an array of cytokines to effect their functions in host defense, tissue repair and immunoregulation. Pro-inflammatory macrophages (M1) produce cytokines, such as IL-12p70, TNF-α, IL-6, IL-1β, IL-12p40, IL-23, IFN-γ, and IP-10, while anti-inflammatory and tissue repairing macrophages (M2) release a different set of factors, such as IL-4, IL-10, IL-6, Arginase, TARC and IL-1RA. B cells, in addition to antibody production, also secrete an array of cytokines that mediate Th1- and Th2-like immune responses. These cytokines are produced by regulatory B cells (e.g., IL-10, TGF-β1) and B effector cells, namely Be1 (e.g., TNF-α, TNF-β, IFN-γ, and IL-12p70) and Be2 cells (e.g., IL-2, IL-4, IL-6, TNF-α, and IL-13). Other cytokines associated with activation and survival of B cells such as APRIL, BAFF, and CD40L are also important targets in B cell related processes.
We have developed new assay panels targeting macrophage/microglia and B cells, using fluorescence–encoded beads that are suitable for use on general lab flow cytometers. Each panel allows simultaneous quantification of 13 related analytes as shown below.
PanelTargetMacrophage/MicrogliaIL-1β, 1RA, 4, 6, 10, 12p40, 12p70, 23, IFN-γ, TARC, TNF-α, Arginase, IP-10B cellIL-2, 4, 6, 10, 12p70, 13, 17A, IFN-γ, TNF-α, TNF-β, BAFF, APRIL, CD40L
These panels have been validated by detecting expected changes in biological samples. These high quality, low cost and ease of use panels provide an alternative multiplex solution to the biomedical research community.
Developing polymer-drug complex based toll-like receptor (TLR-2/TLR-4) antagonist for modulating gut innate immune system to prevent/treat IBD and colon cancer
Authors: Kesharwani Siddharth Shivkumar , Rajput Mrigendra , Tummala Hemachand 
Published: January 2023

Abstract
Continuous inflammation in the colon often leads to chronic diseases such as inflammatory bowel disease (IBD) and colorectal cancer. Recent evidence strongly suggests the role of Toll-Like Receptors 2 and 4 in the etiology of aforementioned diseases. Therefore, pharmacological inhibition of TLR-2/TLR-4 has been a new promising strategy for preventing inflammation in IBD and colorectal cancer. In the current study, we have developed a novel polymer-drug complex (Ora-Curcumin) as a TLR-2/TLR-4 antagonist to modulate the gut innate immune system. Ora-Curcumin is a molecular complex of curcumin with a hydrophilic polymer Eudrgit® S100 prepared by nano-precipitation. Ora-curcumin is more water soluble (~1000 times) and stable than curcumin in aqueous buffers. It is water soluble only at pHs above 6.8. Therefore, once consumed orally, it is expected to be soluble and functionally available only at the luminal side of the colon where the pH reaches 6.8. In addition, Ora-Curcumin was potent TLR-4 antagonist that significantly inhibited the release of IL-8 and TNF-a from TLR-4 expressing human kidney epithelial cells (HEK293TLR4YFP-MD2) and mouse dendritic cells, respectively, in response to TLR stimulation with Monophosphoryl Lipid A (MPLA) or dead E. coli. The in-vivo potential of Ora-Curcumin in modulation of acute inflammation and intestinal microbiome is currently in progress. To this end, we have developed a unique polymer based water soluble TLR-2/TLR-4 antagonist which also provides enhanced local delivery to colon to prevent or treat IBD and colorectal cancer. As an anti-bacterial and by altering host immune system to control inflammation, Ora-Curcumin is also expected to modulate colon microbiome and improve GI health.
New Lipid Metabolic Targets for Treatment of Inflammation
Authors: Hsu Ku-Lung 
Published: January 2023

Abstract
The human genome contains a vast number of enzymes that lack functional annotation. As a result, our basic understanding of enzymatic pathways that underlie human physiology and pathology remains largely incomplete. Molecular profiling technologies have emerged as an unbiased means to globally examine the biochemical makeup of cells and tissues and identify genes and proteins associated with pathophysiological states. In contrast, global methods for the functional characterization of enzymatic pathways in native biological systems are still lacking. I will describe our efforts to integrate activity-based protein profiling (ABPP) with functional proteomic/metabolomics methods to map novel bioactive lipid networks involved in inflammation. I will describe the development of the first selective and in vivo-active small-molecule inhibitors for the 2-arachidonoylglycerol (2-AG) biosynthetic enzyme, diacylglycerol lipase-beta (DAGLB), along with paired negative-control and tailored activity-based probes for the functional analysis of DAGLB in living systems. We utilize our newly developed chemical probes to discover and show that DAGLB inactivation lowers 2-AG production in mouse peritoneal macrophages, as well as arachidonic acid and eicosanoids in a manner that is distinct and complementary to cytosolic phospholipase-A2. A corresponding reduction in lipopolysaccharide (LPS)-induced TNF-alpha release was observed, indicating that DAGLB serves as a key metabolic hub within a lipid signaling network that regulates proinflammatory responses in macrophages. We will present recent findings that identify DAGLB as a promising anti-inflammatory target for treatment of inflammatory and neuropathic pain.
Host skin T cells survive stem cell transplant conditioning and are functional during acute GVHD
Authors: Divito Sherrie J , Elco Christopher , Guleria Indira , Milford Edgar , Cutler Corey , Kupper Thomas S 
Published: January 2023

Abstract
Graft-versus-host-disease (GVHD) is a major cause of morbidity and mortality in stem cell transplantation (SCT). Acute GVHD is thought to be mediated by donor T cells that target and destroy host tissues. Studies into the host immune system are limited, as it is assumed that host T cells in peripheral tissues such as skin are depleted by conditioning regimens in parallel to T cells in lymphoid organs and blood. However, it is recently appreciated that a high number of memory T cells reside long-term within the organs most affected by GVHD. We investigated whether host skin T cells survive SCT conditioning and are present during acute GVHD. To do so, excess skin biopsy tissue was obtained from patients with acute skin GVHD who had undergone myeloablative or non-myeloablative conditioning and allogeneic SCT with sex-mismatched donor cells. Tissue was stained for T cell markers via immunofluorescence concurrently with in situ hybridization for the X and Y chromosomes. All seventeen patients studied demonstrated persistence of host T cells in skin, often in equal or greater numbers than donor T cells. Host skin T cells survived regardless of myeloablative or non-myeloablative conditioning, of patient age, and of day post-SCT (samples ranged from 12–213 days post-SCT). Comparatively, blood T cell chimerism was 100% donor in nearly all samples, indicating diverging effects of conditioning on T cell compartments. Skin host T cells demonstrated pro-inflammatory cytokine production. These results provide a novel avenue of research into GVHD pathobiology and suggest that alternative conditioning regimens should be employed if host skin T cells are to be targeted.
Obesity predisposes to rapid gastrointestinal graft-versus-host disease lethality after allogeneic hematopoietic stem cell transplantation in mice
Authors: Khuat Lam T , Pai Chien-Chun Steven , Chen Mingyi , Aguilar Ethan George , Dunai Cordelia , Le Catherine T , Raybould Helen E , Abedi Mehrdad , Murphy William J 
Published: January 2023

Abstract
Obesity is a form of chronic inflammation, termed “meta-inflammation”, resulting in the development of many chronic diseases such as diabetes and cancer. In this study, we assessed the impact of obesity on recipient graft-versus-host disease (GVHD) outcome post allogeneic HSCT using mouse models. In a model of sclerodermatous chronic GVHD, lean or diet-induced obese (DIO) BALB/c mice received 800 cGy total body irradiation (TBI), bone marrow cells, and splenocytes from H2-identical but minor MHC-mismatched B10.D2 mice. To mimic major MHC mismatch transplant which results in acute GVHD impacting gut, skin and liver, lean or DIO C57BL/6 mice received 1050 cGy TBI, bone marrow cells, and different doses of purified T cells from BALB/c mice. Strikingly, after the minor mismatch HSCT, all DIO mice succumbed to gut pathology while all lean mice survived and developed sclerodermatous GVHD at week 3 post transplant. In both models, pathological assessment indicated marked gut pathology in DIO mice correlating with lethality. Lean mice in the major MHC mismatch strain combination had significantly increased survival and less severe gut pathology compared to the DIO mice. The DIO mice had higher expression of pro-inflammatory cytokines in the gut, liver, visceral fat, and serum post-HSCT. Flow cytometric analysis demonstrated increased numbers of donor CD8+ T cells in the gut of DIO mice compared to lean mice. In an initial evaluation, untreated DIO mice displayed increased gut permeability as well as having limited diversity in their microbiome which would contribute to severe GVHD post-HSCT. Taken together, these results indicate that obesity exacerbates GVHD after allogeneic HSCT primarily affecting the gastrointestinal tract.
Human α1-antitrypsin attenuates injury-induced Inflammation through interacting with high mobility group box-1 (HMGB1)
Authors: Ohayon David E , Schuster Ronen , Mizrahi Mark I , Lior Yotam , Baranovski Boris M , Shahaf Galit , Lewis Eli C 
Published: January 2023

Abstract
HMGB1 is involved in pathologies such as cellular injury and autoimmunity. Indeed, upon binding to immune-related receptors, HMGB1 promotes an inflammatory response, such as that might take part in pancreatic islet destruction during both autoimmune diabetes and islet transplant rejection. Specifically, elevated circulating HMGB1 levels were reported in patients with type 1 diabetes, and increased release of HMGB1 was found to correlate with injury degree and islet allograft survival. The anti-inflammatory and immune-modulatory acute-phase protein human α1-antitrypsin (hAAT) promotes islet survival in both transplantation and autoimmune diabetes models. While AAT binds to damage-released proteins, such as gp96 and HSP70, its tissue protective mechanism remains poorly understood. We now extend this observation that AAT protective activity is related to its interaction with HMGB1. Clinical-grade AAT (Glassia, Kamada Ltd., Israel), diminished recombinant HMGB1-induced inflammatory responses in mouse pancreatic islets (while restoring disrupted insulin inflammation-mediated release). Similar behavior was depicted in HMGB1-stimulated peritoneal macrophages introduced to hAAT. In addition, hAAT modulated HMGB1-inducible surface expression by altering its distribution. Lastly, we show by immunoprecipitation that HMGB1 associated proteins was positive for the presence of AAT, this is also supported by a direct ELISA. Our findings suggest that hAAT is a naturally-occurring regulator of inflammatory responses mediated by extracellular HMGB1, such that preclude outcomes of islet transplantation. hAAT may therefore be considered for therapy of cell damage-mediated pathologies in a clinically-safe manner.
c-Jun N-terminal kinase 1 defective CD4+CD25+FoxP3+ cells prolong pancreatic allograft survival in type 1 diabetic mice
Authors: Tripathi Deepak , Cheekatla Satyanarayana S. , Venkatasubramanian Sambasivan , Paidipally Padmaja , Welch Elwyn , Tvinnereim Amy R. , Vankayalapati Ramakrishna 
Published: January 2023

Abstract
CD4+CD25+FoxP3+ cells (Tregs) inhibit inflammatory immune responses to allografts. Here we found that co-transplantation of allogeneic pancreatic islets with Tregs that are defective in JNK1 signaling prolong the islet allograft survival in the liver parenchyma of the T1D mice. Deletion of the JNK1 in Tregs increased the expression of anti-apoptotic molecules Mcl-1, Bcl-Xl and anti-inflammatory cytokine IL-10 production. JNK1−/− Tregs persist for long period in the transplanted liver and prolong the islet allograft survival compared to WT Tregs. JNK1−/− Tregs demonstrated improved control of allo-inflammation compared to WT Tregs in the T1D liver upon co-transplantation. JNK1−/− Tregs specifically inhibit IL-17 and IL-21 medited alloimmune response. Inhibition of alloimmune response by JNK1−/− Tregs independently mediated through the LAG3 on its cell surface and the increased production of IL-10. Our study identifies a novel role of JNK1 signaling in the Tregs function and co-transplantation of JNK1 deficient Tregs enhances the islet allograft survival in the liver parenchyma of T1D mice.
Spontaneous Agglutination in Typhoid and Paratyphoid Cultures and Its Bearing Upon Absorption of Agglutinins
Authors: Teague Oscar , McWilliams Helen I. 
Published: January 2023

Abstract
In carrying out some experiments involving the injection of living typhoid bacilli in rabbits and the plating several hours later of the rabbits' blood in nutrient agar, we observed that some of the colonies developing upon the plates showed spontaneous agglutination when rubbed up in a drop of saline solution upon a glass slide. A number of the colonies were fished into small tubes of nutrient broth and after twenty-four hours' incubation yielded, instead of the usual turbid growth characteristic of the typhoid bacillus, flocculi throughout the broth and a flocculent sediment. We at first thought that this change in the typhoid strain had been brought about by its sojourn in the body of the rabbit; however, upon plating the original typhoid culture and fishing a number of the colonies into broth we observed a similar type of growth in some of the tubes.
The Absorption of Antigen: A Repetition of Work Reported by Doerr and Pick
Authors: Smith G. H. , Cook M. W. 
Published: January 2023

Abstract
The question of the parenteral absorption of antigen has been studied by Doerr and Pick (1). By comparing the reaction in normal and sensitized animals they hoped to determine whether or not in sensitized animals the anaphylactic poison was produced from the antigen. Doerr and Pick injected rabbits, sensitized and normal, with anti-cholera horse serum intravenously. The rabbits were bled at intervals and the sera tested for precipitable horse serum and for agglutinins for the cholera vibrio. Their titrations for precipitinogen and agglutinins indicate, in their opinion, that there is no essential difference in the rate of disappearance of antigen from the circulation of the normal and sensitized rabbits.
To approach the subject from a somewhat different point of view, Doerr and Pick measured the rate of absorption of antigen from the peritoneal cavity of normal and sensitized guineapigs. The amount of antigen absorbed into the circulation was titrated as in the rabbit experiments.
The Action of Formaldehyde on Diphtheria Toxin
Authors: Bunney William Edward 
Published: January 2023

Summary
Additional evidence is offered which indicates that toxoid formation is not the result of the direct action of free formaldehyde on the diphtheria toxin. Results are obtained which suggest that the formation of toxoid by the action of formaldehyde on diphtheria toxin may depend upon a compound resulting from the reaction between formaldehyde and the amino group in an amino acid. A possible method for making acceptable toxoid from lower grade diphtheria toxins is suggested.
Advantages and Disadvantages of the Buffered Diluent for Diphtheria Toxin
Authors: Bunney William E. , White Benjamin 
Published: January 2023

Abstract
Previous work by Bunney and White (1) on the buffered diluent described by Glenny, Pope and Waddington (2) substantiated their description of its properties to a degree encouraging further study. Diphtheria toxin diluted in this borax-boric acid solution1 did not lose toxicity in ten weeks at room temperature. Inasmuch as such a diluent might be valuable to the research scientist interested in diphtheria toxin, as well as to those concerned with either the preparation or the use of diphtheria toxin in the Schick test the subject was investigated further. The additional data gained in this study are presented in the present paper.
I. Use of the Glenny Diluent in the Study of Diphtheria Toxin
There is need for a suitable diluent for use in studying the chemistry of diphtheria toxin, in which purified toxin could be dissolved in high or low concentrations with equal confidence, with little fear of deterioration under convenient precautions.
The Toxicity of Certain Normal Sera for the Guinea Pig
Authors: Field Madeleine E. 
Published: January 2023

Abstract
The effect of age upon the primary toxicity of normal serum has usually been referred to in the literature in the course of other observations. Zinsser (1), in this connection, stated that goat serum which had stood at room temperature for three days was still hemolytic and hemagglutinating when injected in doses of from 2 to 5 cc. into rabbits but had often lost its power to produce respiratory distress and death. Zipf and Wagenfeld (2) observed a fall in the systemic blood pressure of rabbits only after an intravenous injection of 2 cc. of very fresh serum. Hyde (3) noticed that ox serum became inactive for the guinea pig with age, losing its hemolytic activity and its ability to produce necrotic skin areas and cause death after standing at room temperature for ten days. DeKruif (4), also, states that normal serum which had been freed from contact with the clot will remain toxic for only about twenty-two hours.
Heredity of the Agglutinogens M and N of Landsteiner and Levine
Authors: Wiener Alexander S. , Vaisberg Maurice , Director Mas Lederer 
Published: January 2023

Summary and Conclusions
Specimens of blood of 131 families with 642 children were examined for the agglutinogens A, B, M, and N. The agglutinogens M and N seem to be inherited entirely independently of the agglutinogens A and B, confirming the observation of Landsteiner and Levine.
Concerning the heredity of the agglutinogens M and N, two exceptions to the theory of a single pair of allelomorphic genes were found, but in neither case could the possibility of illegitimacy be excluded. Concerning the heredity of the agglutinogens A and B, one exception to the Bernstein theory was found, but here again the possibility of illegitimacy could not be excluded. Considering the size of the series of cases studied (642 children), a certain percentage of illegitimacies is rather to be expected. Since the agglutinogens A, B, M, and N together can detect one third of all illegitimacies, the three exceptions found would imply the presence of only nine illegitimacies. We therefore believe that our results speak well for the theories of heredity discussed.
Neurokinin A augments SynCAM expression and IL-10 release from mast cells
Authors: Sumpter Tina L. , Alwine Jeremy , Rao Mekhala , Falo Louis D. , Larregina Adriana T. 
Published: January 2023

Abstract
Cutaneous mast cells (MCs) initiate innate and adaptive immune responses. In the skin, MCs reside proximal to peripheral nerve fibers, forming a functional synapse mediated, in part, by Synaptic Cell Adhesion Molecule (SynCAM). Within the synapse, MC function is likely affected by the release of soluble neuropeptides. We and others have demonstrated that the immune functions of MCs are affected by the neuropeptides from the tachykinin family. Substance P promotes MC-inflammatory functions, whereas the role of neurokinin A (NKA) in MC biology is hereto unknown. In this study, the capacity for NKA to regulate MC stasis and IgE-initiated MC activation was evaluated. In bone marrow derived (BM) MCs, NKA increased expression of SynCAM, but not expression of other cell adhesion molecules, such as ICAM or NCAM. In IgE-activated MCs, NKA did not affect SynCAM expression. However, NKA promoted IL-10 secretion resulting in the inhibition of IgE-initiated STAT5 phosphorylation and nuclear localization, leading to the inhibition of type 2 cytokine release. STAT5 phosphorylation was restored in NKA treated BMMCs by neutralizing IL-10. In vivo, intradermal administration of NKA increased the density of MCs in the skin. In spite of this increase in MCs, NKA reduced IgE-initiated passive cutaneous anaphylaxis. Our data indicates that NKA strengthens the formation of the MC-neuron synapse and down-regulates MC pro-inflammatory functions.