While studies of the adaptor SH3BP2 have implicated a role in receptor-mediated signaling in mast cells and lymphocytes, they have failed to identify its function or explain why SH3BP2 missense mutations cause bone loss and inflammation in patients with cherubism. We demonstrate that Sh3bp2 "cherubism" mice exhibit trabecular bone loss, TNF-alpha-dependent systemic inflammation, and cortical bone erosion. The mutant phenotype is lymphocyte independent and can be transferred to mice carrying wild-type Sh3bp2 alleles through mutant fetal liver cells. Mutant myeloid cells show increased responses to M-CSF and RANKL stimulation, and, through mechanisms of increased ERK 1/2 and SYK phosphorylation/activation, they form macrophages that express high levels of TNF-alpha and osteoclasts that are unusually large. M-CSF and RANKL stimulation of myeloid cells that overexpress wild-type SH3BP2 results in similar large osteoclasts. This indicates that the mutant phenotype reflects gain of SH3BP2 function and suggests that SH3BP2 is a critical regulator of myeloid cell responses to M-CSF and RANKL stimulation.

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IntroductionCoronavirus disease 2019 (COVID-19) is a new viral disease. Uncontrolled inflammation called “cytokine storm” is reported to contribute to disease pathogenesis as well as sepsis. We aimed to identify cytokines related to the pathogenesis of COVID-19 through a proteomics analysis of 1463 plasma proteins, validate these cytokines, and compare them with sepsis.Materials and MethodsIn a derivation cohort of 306 patients with COVID-19, 1463 unique plasma proteins were measured on days 1, 4, and 8. Cytokines associated with disease severity and prognosis were derived. In a validation cohort of 62 COVID-19 patients and 38 sepsis patients treated in the intensive care unit [ICU], these derived cytokines were measured on days 1 (day of ICU admission), 2-3, and 6-8 (maximum: 3 time points/patient). Derived cytokines were compared with healthy controls and between COVID-19 and sepsis patients, and the associations with prognosis were evaluated. The time to wean off mechanical ventilation (MV) was evaluated only for COVID-19.ResultsIL-6, amphiregulin, and growth differentiation factor (GDF)-15 were associated with disease severity and prognosis in the derivation cohort. In the validation cohort, IL-6 and GDF-15 were elevated in COVID-19 and sepsis on day 1, and the levels of these cytokines were higher in sepsis than in COVID-19. IL-6 and GDF-15 were associated with prognosis in sepsis. Cox proportional hazards model with time as a dependent covariate showed a significant relationship between plasma GDF-15 level and time to wean off MV (hazard ratio, 0.549 [95% confidence level, 0.382–0.789]). The GDF-15 level at ICU admission predicted late recovery.ConclusionGDF-15 and IL-6 derived from proteomics analysis were related with disease severity of COVID-19. Their values were higher in sepsis than in COVID-19 and were associated with prognosis in sepsis. In COVID-19 patients treated in the ICU, GDF-15 was associated with the time to wean off MV and better predicted late recovery.

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Introduction: Cytokines compose a network and play crucial roles in the pathogenesis and prognosis of sepsis. Adipose tissue is an important immune endocrine organ that releases adipocytokines. This study aimed to evaluate adipocytokines in sepsis from a network perspective. Materials and Methods: This retrospective study of 37 patients with sepsis and 12 healthy controls was conducted from February 2014 to July 2015. Blood samples were collected from patients on days 1 (within 24 h of diagnosis), 2, 4, 6, 8, 11, and 15 and from healthy controls. Adipocytokines (adiponectin, leptin, resistin, chemerin, visfatin, vaspin, CXCL-12/SDF-1, angiotensinogen), inflammatory cytokines (IL-1b, IL-4, IL-6, IL-8, IL-10, IL-12/IL-23p40, TNF-a, monocyte chemotactic protein [MCP-1]), and plasminogen activator inhibitor-1 were measured. Acute Physiology and Chronic Health Evaluation II score was evaluated on day 1, and Sequential Organ Failure Assessment (SOFA) score and Japanese Association for Acute Medicine (JAAM) and International Society of Thrombosis and Hemostasis overt disseminated intravascular coagulation (DIC) scores were assessed at the times of blood sampling. Results: Hierarchical clustering analysis showed the cluster formed by resistin, IL-6, IL-8, MCP-1, and IL-10 on days 1, 2, and 4 represented the cytokine network throughout the acute phase of sepsis. Each cytokine in this network was significantly associated with SOFA and JAAM DIC scores over the acute phase. A Cox proportional hazards model focusing on the acute phase showed a significant relation of these five cytokines with patient prognosis. Conclusions: Adipocytokines and an inflammatory cytokine profile assessed over time in sepsis patients showed that resistin was involved in an inflammatory cytokine network including IL-6, IL-8, IL-10, and MCP-1 in the acute phase of sepsis, and this network was associated with severity and prognosis of sepsis.

Mo K-edge EXAFS, TEM and FT-IR of adsorbed NO were performed to further investigate the nature of the active sites on the CoMo/HY-Al2O3 catalyst containing citric acid and phosphorus, which had significantly higher HDS activity compared to the conventional CoMoP/Al2O3 catalyst. The results showed that the new catalyst has multiple layers of MoS2 slabs and the edges of MoS2 are mainly occupied by Co _ Mo _ S phases. XPS and FT-IR were used to investigate the sulfiding behavior of Co and Mo in the formation process of the active sites during sulfidation. The results showed that addition of citric acid to the impregnation solution postponed the sulfidation of Co at low temperatures, thereby increasing formation of the Co _ Mo _ S phase.