Exploring Optimal Reaction Conditions Guided by Graph Neural Networks and Bayesian Optimization

The optimization of organic reaction conditions to obtain the target product in high yield is crucial to avoid expensive and time-consuming chemical experiments. Advancements in artificial intelligence have enabled various data-driven approaches to predict suitable chemical reaction conditions. However, for many novel syntheses, the process to determine good reaction conditions is inevitable. Bayesian optimization (BO), an iterative optimization algorithm, demonstrates exceptional performance to identify reagents compared to synthesis experts. However, BO requires several initial randomly selected experimental results (yields) to train a surrogate model (approximately 10 experimental trials). Parts of this process, such as the cold-start problem in recommender systems, are inefficient. Here, we present an efficient optimization algorithm to determine suitable conditions based on BO that is guided by a graph neural network (GNN) trained on a million organic synthesis experiment data. The proposed method determined 8.0 and 8.7% faster high-yield reaction conditions than state-of-the-art algorithms and 50 human experts, respectively. In 22 additional optimization tests, the proposed method needed 4.7 trials on average to find conditions higher than the yield of the conditions recommended by five synthesis experts. The proposed method is considered in a situation of having a reaction dataset for training GNN

The interaction of gremlin-1 with cancer cells is independent of VEGFR2 expression.

<p>(A) Gremlin-1 does not interact with HUVECs as measured by flow cytometry. (B) RT-PCR analysis of VEGFR2 mRNA indicates the presence of VEGFR2 in HUVECs but not in A549 or HeLa cells. (C) Immunoblot analysis using a VEGFR2 antibody indicates that A549 and HeLa cells do not express VEGFR2.</p

Characterization of gremlin-1-transfected A549 cell lines.

<p>(A) RT-PCR and western blot analyses indicate gremlin-1 mRNA and protein are expressed in gremlin-1-A549 cells but not mock-A549 cells. (B) E-cadherin protein expression is reduced in gremlin-1-A549 cells and this effect is attenuated upon addition of the neutralizing antibody GRE1. (C) Gremlin-1-A549 cells show increased invasiveness in cell invasion assays as compared to mock-A549 cells. The cells on the underside of the ECM membrane were stained and counted. ***P<0.001, Student's <i>t</i> test. (D) Gremlin-1-A549 cells show increased migration compared to mock-A549 cells and this effect is attenuated upon the addition of the neutralizing antibody GRE1. **P<0.01, ***P<0.001, Student's <i>t</i> test. (E) Gremlin-1-A549 cells display an increased growth rate compared to mock-A549 cells as determined by MTS proliferation assay. The neutralizing antibody GRE1 addition blocks this effect. *P<0.05 versus mock-A549, Student's <i>t</i> test. (F) Gremlin-1-A549 cells injected subcutaneously in nude mice have an increased rate of tumor growth <i>in vivo</i> as compared with injection of mock-A549 cells. Tumor volume is depicted as the average ± standard deviation. *P<0.05 versus mock-A549, Student's <i>t</i> test.</p

Gremlin-1 interacts with human cancer cell lines.

<p>Cells were incubated with gremlin-1, in the presence or absence of the neutralizing antibody GRE1 as described. The four cancer cell lines interacted directly with gremlin-1 and this interaction was inhibited upon the addition of the neutralizing antibody GRE1.</p

Gremlin-1 induces the scattering and migration of A549 cells <i>in vitro</i>.

<p>(A) A549 cells appear fibroblast-like after incubation with gremlin-1 for 3 days. (B) E-cadherin protein expression is reduced in A549 cells after incubation with gremlin-1 for 3 days. (C) E-cadherin immunofluorescence (green) in A549 cells is reduced after incubation with gremlin-1 for 3 days. Nuclei were counterstained with DAPI (blue) and actin filaments were counterstained with rhodamine-phalloidin (red). (D) Migration of A549 cells after incubation with gremlin-1 only or gremlin-1 plus GRE1. Addition of the neutralizing antibody GRE1 abolishes gremlin-1 induced migration. **P<0.01, ***P<0.001, Student's <i>t</i> test.</p

Addition of the neutralizing antibody GRE1 does not interrupt the interaction between gremlin-1 and BMPs.

<p>(A) Interaction of gremlin-1 with BMP-2, BMP-4, and BMP-7 as measured by enzyme immunoassay. The neutralizing antibody GRE1 does not affect the interaction between gremlin-1 and BMPs. *P<0.05, Student's <i>t</i> test. (B) The interaction of gremlin-1 with A549 cells is unaffected by treatment with a 10 times molar excess of BMP-2, BMP-4, and BMP-7 as measured by flow cytometry.</p

Representative images of a true intimal flap and flow artifact.

<p>A-B. Intimal flap. The coronal 3D-PD image (A) shows the intimal flap (black arrows) as a linear structure crossing the arterial lumen with clear continuity to the arterial wall (inbox, arrow head). Anteroposterior view of right VA angiography (B) shows irregular luminal narrowing and VasoCT (inbox) shows the intimal flap on a coronal plane image (white arrows). C-D. Flow artifact. The coronal 3D-PD image (C) shows a curvilinear structure (dotted arrow) which gradually fades away towards the endpoint without continuity with the arterial wall. Lateral view of left VA angiography (D) shows normal findings.</p

Diagnosis of dissection using 3D-HR-MRI with or without 3D-PD.

<p>Diagnosis of dissection using 3D-HR-MRI with or without 3D-PD.</p

Cochlear innervation defects in <i>Pten-</i>deficient mice.

<p>(A, B) Patterns of cochlear innervation were assessed by NeuroVue-tracing at E18.5. (A) In <i>Pax2^Cre/+</i>;<i>Pten^loxP/loxP</i> mice, nerve innervation was evident in the apical and basal turns of the cochlea in wild-type (a, c) and <i>Pten</i> cKO (b, d) mice. <i>Pten</i>-deficient inner ears displayed sparse radial fibers, a disorganized pattern, and loss of spiral ganglia in the cochlea (arrowheads in b, d). Abnormal innervation was distributed evenly throughout the cochlea. M, modiolus; R, radial fibers; SG, spiral ganglion. Scale bar: 100 µm. (B) <i>Neurog1^Cre/+</i>;<i>Pten^loxP/loxP</i> mice were administered tamoxifen as an IP injection to perform tamoxifen-inducible deletion of <i>Pten</i> between E8.5 and E11.5. Neuronal abnormalities were seen in <i>Pax2^Cre/+</i>;<i>Pten^loxP/loxP</i> mice and similar innervation defects in <i>Neurog1^Cre/+</i>;<i>Pten^loxP/loxP</i> mice revealed spacing or several gathered radial fibers and a disorganized pattern in the innervation of the cochlea (arrowheads in b, d). The innervation defects were distributed evenly throughout the cochlea. M, modiolus; R, radial fibers; SG, spiral ganglion. Scale bar: 100 µm. (C, D) Neuronal loss in the spiral ganglion in <i>Pax2^Cre/+</i>;<i>Pten^loxP/loxP</i> mice at E18.5. (C) Neurofilament immunoreactivity (arrows) and (D) the number of the spiral ganglia were significantly decreased in <i>Pten</i> cKO mice compared to wild-type mice at E18.5 (3 cochleae, <i>P</i><0.01). M, modiolus; R, radial fibers; SG, spiral ganglion. Scale bar: 100 µm.</p

Diagnostic Criteria for Cervicocephalic Arterial Dissection.

<p>Diagnostic Criteria for Cervicocephalic Arterial Dissection.</p