Preliminary study on spallation target characteristics in an Accelerator-Driven system.

This study aims to investigate the neutronic characteristics of spallation targets for Accelerator-Driven subcritical System (ADS) and find the optimal target design for reducing the strength of the required beam current. All the calculations were conducted using the MCNP6.1 with cross-section library ENDF/B-VII. In this study, the influence of several parameters on spallation targets is investigated, such as neutron production with various spallation target layouts, spallation neutron distribution with different proton beam energy levels, and spallation neutron spectrum.

SNARE protein SEC22B regulates early embryonic development.

The highly conserved SNARE protein SEC22B mediates diverse and critical functions, including phagocytosis, cell growth, autophagy, and protein secretion. However, these characterizations have thus far been limited to in vitro work. Here, we expand our understanding of the role Sec22b plays in vivo. We utilized Cre-Lox mice to delete Sec22b in three tissue compartments. With a germline deletion of Sec22b, we observed embryonic death at E8.5. Hematopoietic/endothelial cell deletion of Sec22b also resulted in in utero death. Notably, mice with Sec22b deletion in CD11c-expressing cells of the hematopoietic system survive to adulthood. These data demonstrate Sec22b contributes to early embryogenesis through activity both in hematopoietic/endothelial tissues as well as in other tissues yet to be defined.

Burnup computations of online-refueling process for pebble-bed reactors using layer-mixed-shell fuel movement model.

This study aims to propose a model for dynamically simulating the online-refueling process in pebble-bed reactor (PBR) using MCNPX. PBR has a special feature of online-refueling which can greatly reduce the outage time and enable a higher burnup in spent fuel. However, this feature also results in the dynamical fuel movements which may significantly increase the difficulty and the computational time in computer simulation. Therefore, an appropriate model is necessary to be proposed to simulate the burnup characteristics of online-refueling and to reduce the computational time simultaneously. All the calculations in this study were performed using MCNPX 2.7.0 with the ENDF/B-VII continuous energy nuclear data library. The PBR model was built according to the core design of HTR-10 but adopted some reasonable assumptions. The refueling process was emulated by utilizing the fuel loading scenario of the once through then out (OTTO) in combination with the layer-mixed-shell fuel movement. Additionally, the layer-mixed-shell fuel movement considered the concept of fuel channels, where the fuel pebbles only move in the same fuel channel, such that the burnup characteristics of fuel pebbles in both radial and axial direction can be identified separately. The core was divided into 9 fuel zones with a fixed volume and 3 fuel channels with a variety of fuel zones. Furthermore, the number of fuel zones in each fuel channel was determined based on the relative residence time of fuel pebbles in the core. The results revealed that the core can achieve an equilibrium fuel cycle after refueling several times, and after that all the core characteristics can nearly maintain unchanged between different cycles. Although the refueling process was modeled based on the OTTO fuel loading scenario instead of the multi-pass one, the discharged burnup can still reach the target burnup of the spent fuel for HTR-10, i.e. 72 GWd/tHM. In addition, the average discharged burnup under the equilibrium fuel cycle is approximate to 80 GWd/tHM, which also coincides the design value of the spent fuel for HTR-10. Therefore, the layer-mixed-shell movement model can consider the fuel movements in either radial or axial directions simultaneously and enable a more accurate prediction to the real refueling process of HTR-10 than our previous studies.

Murine Models of Steroid Refractory Graft-versus-Host Disease.

Corticosteroids are the first line therapy for acute graft-versus-host disease (GVHD). However, the outcome of steroid refractory GVHD (SR-GVHD) is poor due to a lack of effective treatments. The development of therapies for SR-GVHD is limited by an incomplete understanding of its pathophysiology partly because of the absence of clinically relevant animal models of SR-GVHD. Here we addressed the need for a SR-GVHD animal model by developing both MHC matched multiple minor histocompatibility antigens (miHAs) mismatched and MHC mismatched haploidentical murine models of SR-GVHD. We demonstrate that animals can develop SR-GVHD regardless of whether steroids are initiated early or late post allogeneic bone marrow transplantation (allo-BMT). In general, we observed increased GVHD specific histopathological damage of target organs in SR-GVHD animals relative to steroid responsive animals. Interestingly, we found no significant differences in donor T cell characteristics between steroid refractory and responsive animals suggesting that donor T cell independent mechanisms may play more prominent roles in the pathogenesis of SR-GVHD than was considered previously.

Regulating Damage from Sterile Inflammation: A Tale of Two Tolerances.

The severity of immunopathology from non-infectious inflammation is mainly understood and is managed by targeting immune cells. However, the role of target tissues in determining damage severity has been largely overlooked. Here, we discuss the concept of 'tissue tolerance' for tissue-intrinsic programs that ameliorate organ damage in the setting of sterile immunopathology.

Tissue tolerance: a distinct concept to control acute GVHD severity.

Target tissue damage occurs as a consequence of pathological immune responses following allogeneic stem cell transplantation resulting in acute graft-versus-host disease (GVHD). Among those who study infections in plants, it is well recognized that tissues play a distinct role from the immune system in mediating disease severity. Recently, this has also been appreciated in mammals. However, the severity of immunopathology in the context of alloimmune diseases such as acute GVHD has been mainly understood and managed by direct targeting of immune cells to generate immune tolerance. The role of tissue-intrinsic factors that might contribute to regulation of acute GVHD severity has been largely overlooked. Here, we introduce the concept of "tissue tolerance" to discuss the tissue-specific programs that contribute to target tissue resilience, repair, and regeneration, and mitigate severity of acute GVHD without altering the load or function of alloreactive immune cells.

IAPs protect host target tissues from graft-versus-host disease in mice.

Inhibitors of apoptosis proteins (IAPs) regulate apoptosis, but little is known about the role of IAPs in the regulation of immunity. Development of IAP inhibition by second mitochondria-derived activator of caspase (SMAC) mimetics is emerging as a novel therapeutic strategy to treat malignancies. We explored the role of IAPs in allogeneic immunity with 2 distinct yet complementary strategies, namely, chemical and genetic approaches, in clinically relevant models of experimental bone marrow transplantation (BMT). The small-molecule pan-IAP inhibitor SMAC mimetic AT-406 aggravated gastrointestinal graft-versus-host disease (GVHD) in multiple models. The role of specific IAPs in various host and donor cellular compartments was explored by utilizing X-linked IAP (XIAP)- and cellular IAP (cIAP)-deficient animals as donors or recipients. Donor T cells from C57BL/6 cIAP1-/- or XIAP-/- animals demonstrated equivalent GVHD severity and allogeneic responses, both in vivo and in vitro, when compared with B6 wild-type (B6-WT) T cells. By contrast, when used as recipient animals, both XIAP-/- and cIAP1-/- animals demonstrated increased mortality from GVHD when compared with B6-WT animals. BM chimera studies revealed that cIAP and XIAP deficiency in host nonhematopoietic target cells, but not in host hematopoietic-derived cells, is critical for exacerbation of GVHD. Intestinal epithelial cells from IAP-deficient animals showed reduced levels of antiapoptotic proteins as well as autophagy-related protein LC3 after allogeneic BMT. Collectively, our data highlight a novel immune cell-independent but target tissue-intrinsic role for IAPs in the regulation of gastrointestinal damage from GVHD.

Genome-Wide STAT3 Binding Analysis after Histone Deacetylase Inhibition Reveals Novel Target Genes in Dendritic Cells.

STAT3 is a master transcriptional regulator that plays an important role in the induction of both immune activation and immune tolerance in dendritic cells (DCs). The transcriptional targets of STAT3 in promoting DC activation are becoming increasingly understood; however, the mechanisms underpinning its role in causing DC suppression remain largely unknown. To determine the functional gene targets of STAT3, we compared the genome-wide binding of STAT3 using ChIP sequencing coupled with gene expression microarrays to determine STAT3-dependent gene regulation in DCs after histone deacetylase (HDAC) inhibition. HDAC inhibition boosted the ability of STAT3 to bind to distinct DNA targets and regulate gene expression. Among the top 500 STAT3 binding sites, the frequency of canonical motifs was significantly higher than that of noncanonical motifs. Functional analysis revealed that after treatment with an HDAC inhibitor, the upregulated STAT3 target genes were those that were primarily the negative regulators of proinflammatory cytokines and those in the IL-10 signaling pathway. The downregulated STAT3-dependent targets were those involved in immune effector processes and antigen processing/presentation. The expression and functional relevance of these genes were validated. Specifically, functional studies confirmed that the upregulation of IL-10Ra by STAT3 contributed to the suppressive function of DCs following HDAC inhibition.

SAG/Rbx2-Dependent Neddylation Regulates T-Cell Responses.

Neddylation is a crucial post-translational modification that depends on the E3 cullin ring ligase (CRL). The E2-adapter component of the CRL, sensitive to apoptosis gene (SAG), is critical for the function of CRL-mediated ubiquitination; thus, the deletion of SAG regulates neddylation. We examined the role of SAG-dependent neddylation in T-cell-mediated immunity using multiple approaches: a novel T-cell-specific, SAG genetic knockout (KO) and chemical inhibition with small-molecule MLN4924. The KO animals were viable and showed phenotypically normal mature T-cell development. However, in vitro stimulation of KO T cells revealed significantly decreased activation, proliferation, and T-effector cytokine release, compared with WT. Using in vivo clinically relevant models of allogeneic bone marrow transplantation also demonstrated reduced proliferation and effector cytokine secretion associated with markedly reduced graft-versus-host disease. Similar in vitro and in vivo results were observed with the small-molecule inhibitor of neddylation, MLN4924. Mechanistic studies demonstrated that SAG-mediated effects in T cells were concomitant with an increase in suppressor of cytokine signaling, but not NF-κB translocation. Our studies suggest that SAG is a novel molecular target that regulates T-cell responses and that inhibiting neddylation with the clinically available small-molecule MLN4924 may represent a novel strategy to mitigate T-cell-mediated immunopathologies, such as graft-versus-host disease.

Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease.

The effect of alterations in intestinal microbiota on microbial metabolites and on disease processes such as graft-versus-host disease (GVHD) is not known. Here we carried out an unbiased analysis to identify previously unidentified alterations in gastrointestinal microbiota-derived short-chain fatty acids (SCFAs) after allogeneic bone marrow transplant (allo-BMT). Alterations in the amount of only one SCFA, butyrate, were observed only in the intestinal tissue. The reduced butyrate in CD326(+) intestinal epithelial cells (IECs) after allo-BMT resulted in decreased histone acetylation, which was restored after local administration of exogenous butyrate. Butyrate restoration improved IEC junctional integrity, decreased apoptosis and mitigated GVHD. Furthermore, alteration of the indigenous microbiota with 17 rationally selected strains of high butyrate-producing Clostridia also decreased GVHD. These data demonstrate a heretofore unrecognized role of microbial metabolites and suggest that local and specific alteration of microbial metabolites has direct salutary effects on GVHD target tissues and can mitigate disease severity.