Incorporation of physical principles in a machine learning (ML) architecture is a fundamental step toward the continued development of artificial intelligence for inorganic materials. As inspired by the Pauling's rule, we propose that structure motifs in inorganic crystals can serve as a central input to a machine learning framework. We demonstrated that the presence of structure motifs and their connections in a large set of crystalline compounds can be converted into unique vector representations using an unsupervised learning algorithm. To demonstrate the use of structure motif information, a motif-centric learning framework is created by combining motif information with the atom-based graph neural networks to form an atom-motif dual graph network (AMDNet), which is more accurate in predicting the electronic structures of metal oxides such as bandgaps. The work illustrates the route toward fundamental design of graph neural network learning architecture for complex materials by incorporating beyond-atom physical principles.

Introduction

Acid-sensing ion channel 3 (ASIC3) is expressed in synoviocytes, activated by decreases in pH, and reduces inflammation in animal models of inflammatory arthritis. The purpose of the current study was to characterize potential mechanisms underlying the control of inflammation by ASIC3 in fibroblast-like synoviocytes (FLS).

Methods

Experiments were performed in cultured FLS from wild-type (WT) and ASIC3-/- mice, ASIC1-/- mice, and people with rheumatoid arthritis. We assessed the effects of acidic pH with and without interleukin-1β on FLS and the role of ASICs in modulating intracellular calcium [Ca(2+)](i), mitogen activated kinase (MAP kinase) expression, and cell death. [Ca(2+)](i) was assessed by fluorescent calcium imaging, MAP kinases were measured by Western Blots; ASIC, cytokine and protease mRNA expression were measured by quantitative PCR and cell death was measured with a LIVE/DEAD assay.

Results

Acidic pH increased [Ca(2+)](i) and decreased p-ERK expression in WT FLS; these effects were significantly smaller in ASIC3-/- FLS and were prevented by blockade of [Ca(2+)]i. Blockade of protein phosphatase 2A (PP2A) prevented the pH-induced decreases in p-ERK. In WT FLS, IL-1β increases ASIC3 mRNA, and when combined with acidic pH enhances [Ca(2+)](i), p-ERK, IL-6 and metalloprotienase mRNA, and cell death. Inhibitors of [Ca(2+)](i) and ERK prevented cell death induced by pH 6.0 in combination with IL-1β in WT FLS.

Conclusions

Decreased pH activates ASIC3 resulting in increased [Ca(2+)](i), and decreased p-ERK. Under inflammatory conditions, acidic pH results in enhanced [Ca(2+)](i) and phosphorylation of extracellular signal-regulated kinase that leads to cell death. Thus, activation of ASIC3 on FLS by acidic pH from an inflamed joint could limit synovial proliferation resulting in reduced accumulation of inflammatory mediators and subsequent joint damage.

Nonselective Beta blockade (NSBB) is commonly prescribed for liver transplantation (LT) candidates, but its impact on intraoperative hemodynamics is not well understood. In this study, we investigated if preoperative NSBB was associated with severe bradycardia during LT and if severe intraoperative bradycardia was associated with 30-day mortality. Adult patients undergoing LT between 2005 and 2014 were included. Propensity matching was used to control selection bias. Intraoperative hemodynamics were compared between patients with and without preoperative NSBB. Univariate and multivariate methods were used in statistical analysis. Of 1452 patients, 370 who received preoperative NSBB were matched in a 1:1 ratio with those who did not. Propensity matching eliminated all significant differences between the two groups. Patients who received preoperative NSBB had a significantly higher incidence of severe intraoperative bradycardia compared with the non-BB group (9.6% vs 3.2%, P = 0.001, OR 2.95, 95% CI 1.42-6.12, P = 0.004). Intraoperative hypotension and postreperfusion syndrome were not significantly different between the two groups. Severe intraoperative bradycardia was associated with increased 30-day mortality. In conclusion, preoperative NSBB was associated with severe intraoperative bradycardia in LT. In patients who receive preoperative NSBB, severe intraoperative bradycardia should be closely monitored in LT. Further studies assessing safety of preoperative NSBB and intraoperative bradycardia in LT are warranted.