Pre-training of Molecular GNNs via Conditional Boltzmann Generator

Learning representations of molecular structures using deep learning is a fundamental problem in molecular property prediction tasks. Molecules inherently exist in the real world as three-dimensional structures; furthermore, they are not static but in continuous motion in the 3D Euclidean space, forming a potential energy surface. Therefore, it is desirable to generate multiple conformations in advance and extract molecular representations using a 4D-QSAR model that incorporates multiple conformations. However, this approach is impractical for drug and material discovery tasks because of the computational cost of obtaining multiple conformations. To address this issue, we propose a pre-training method for molecular GNNs using an existing dataset of molecular conformations to generate a latent vector universal to multiple conformations from a 2D molecular graph. Our method, called Boltzmann GNN, is formulated by maximizing the conditional marginal likelihood of a conditional generative model for conformations generation. We show that our model has a better prediction performance for molecular properties than existing pre-training methods using molecular graphs and three-dimensional molecular structures.Comment: 4 page

Variational Autoencoding Molecular Graphs with Denoising Diffusion Probabilistic Model

In data-driven drug discovery, designing molecular descriptors is a very important task. Deep generative models such as variational autoencoders (VAEs) offer a potential solution by designing descriptors as probabilistic latent vectors derived from molecular structures. These models can be trained on large datasets, which have only molecular structures, and applied to transfer learning. Nevertheless, the approximate posterior distribution of the latent vectors of the usual VAE assumes a simple multivariate Gaussian distribution with zero covariance, which may limit the performance of representing the latent features. To overcome this limitation, we propose a novel molecular deep generative model that incorporates a hierarchical structure into the probabilistic latent vectors. We achieve this by a denoising diffusion probabilistic model (DDPM). We demonstrate that our model can design effective molecular latent vectors for molecular property prediction from some experiments by small datasets on physical properties and activity. The results highlight the superior prediction performance and robustness of our model compared to existing approaches.Comment: 2 pages. Short paper submitted to IEEE CIBCB 202

Evaluation of internal margins for prostate for step and shoot intensity‐modulated radiation therapy and volumetric modulated arc therapy using different margin formulas

[Purpose] This feasibility study evaluated the intra-fractional prostate motion using an ultrasound image-guided system during step and shoot intensity-modulated radiation therapy (SS-IMRT) and volumetric modulated arc therapy (VMAT). Moreover, the internal margins (IMs) using different margin formulas were calculated. [Methods] Fourteen consecutive patients with prostate cancer who underwent SS-IMRT (n = 5) or VMAT (n = 9) between March 2019 and April 2020 were considered. The intra-fractional prostate motion was observed in the superior–inferior (SI), anterior–posterior (AP), and left–right (LR) directions. The displacement of the prostate was defined as the displacement from the initial position at the scanning start time, which was evaluated using the mean ± standard deviation (SD). IMs were calculated using the van Herk and restricted maximum likelihood (REML) formulas for SS-IMRT and VMAT. [Results] For SS-IMRT, the maximum displacements of the prostate motion were 0.17 ± 0.18, 0.56 ± 0.86, and 0.18 ± 0.59 mm in the SI, AP, and LR directions, respectively. For VMAT, the maximum displacements of the prostate motion were 0.19 ± 0.64, 0.22 ± 0.35, and 0.14 ± 0.37 mm in the SI, AP, and LR directions, respectively. The IMs obtained for SS-IMRT and VMAT were within 2.3 mm and 1.2 mm using the van Herk formula and within 1.2 mm and 0.8 mm using the REML formula. [Conclusions] This feasibility study confirmed that intra-fractional prostate motion was observed with SS-IMRT and VMAT using different margin formulas. The IMs should be determined according to each irradiation technique using the REML margin

Lymph node metastasis from colon carcinoma at 11 years after the initial operation managed by lymph node resection and chemoradiation: A case report and a review of the literature

AbstractINTRODUCTIONLymph node metastasis from colorectal cancer after a disease-free interval (DFI) of >5years is extremely rare, and occurs in <0.6% cases.PRESENTATION OF CASEA 60-year-old man underwent low anterior resection for sigmoid colon cancer. The lesion was an adenocarcinoma with no lymph node metastasis of Stage II. At 9years after the colectomy, he was diagnosed with prostate cancer and was treated with radiation and hormonal therapies; at 11years, he exhibited suddenly elevated carcinoembryonic antigen levels. Computed tomography (CT) and positron emission tomography-CT revealed a 2.0-cm para-aortic lymph nodes swelling invading the small intestine. These lymph nodes and the affected segment of the small intestine were resected, and histopathology of the resected specimen confirmed a metastatic tumor. The patient was administered radiation therapy after 22 cycles of 5-fluorouracil, oxaliplatin and leucovorin. He however presented with a residual lesion in the para-aortic lymph node, but currently, he has been symptom free for 4years.DISCUSSIONA review of the literature indicates that the median survival of all previously reported patients is 12months, and that colon cancer with a long DFI might be a slow growing. One of these patients and our patient both had received radiation and/or hormonal therapy for another cancer, which probably impaired their immune systems, thus resulting in metastatic tumors.CONCLUSIONWe report a case of lymph node metastasis after a DFI of >5years and review relevant literature to assess the significance and possible reasons for delayed colorectal cancer metastases

The plant-derived triterpenoid, cucurbitacin B, but not cucurbitacin E, inhibits the developmental transition associated with ecdysone biosynthesis in Drosophila melanogaster

In insects, some sterols are essential not only for cell membrane homeostasis, but for biosynthesis of the steroid hormone ecdysone. Dietary sterols are required for insect development because insects cannot synthesize sterols de novo. Therefore, sterol-like compounds that can compete with essential sterols are good candidates for insect growth regulators. In this study, we investigated the effects of the plant-derived triterpenoids, cucurbitacin B and E (CucB and CucE) on the development of the fruit fly, Drosophila melanogaster. To reduce the effects of supply with an excess of sterols contained in food, we reared D. melanogaster larvae on low sterol food (LSF) with or without cucurbitacins. Most larvae raised on LSF without supplementation or with CucE died at the second or third larval instar (L2 or L3) stages, whereas CucB-administered larvae mostly died without molting. The developmental arrest caused by CucB was partially rescued by ecdysone supplementation. Furthermore, we examined the effects of CucB on larval-prepupal transition by transferring larvae from LSF supplemented with cholesterol to that with CucB just after the L2/L3 molt. L3 larvae raised on LSF with CucB failed to pupariate, with a remarkable developmental delay. Ecdysone supplementation rescued the developmental delay but did not rescue the pupariation defect. Furthermore, we cultured the steroidogenic organ, the prothoracic gland (PG) of the silkworm Bombyx mori, with or without cucurbitacin. Ecdysone production in the PG was reduced by incubation with CucB, but not with CucE. These results suggest that CucB acts not only as an antagonist of the ecdysone receptor as previously reported, but also acts as an inhibitor of ecdysone biosynthesis

Distinct Roles of Zmynd17 and PGC1α in Mitochondrial Quality Control and Biogenesis in Skeletal Muscle

Maintaining skeletal muscle mitochondrial quality is important not only for muscle activity but also for systemic metabolism. Exercise has long been recognized to have a positive impact on muscle mitochondrial quality. Although exercise triggers various changes in the mitochondrial dynamics, its molecular basis remains to be elucidated. We have previously reported that inactivation of the muscle-specific protein, zinc finger MYND domain-containing protein 17 (Zmynd17), results in mitochondrial abnormalities. To investigate the link between Zmynd17 activity and exercise-induced mitochondrial maintenance, we observed the effect of consecutive exercise on the mitochondrial quality in Zmynd17-deficient muscles. Zmynd17-deficient mice displayed abnormal mitochondrial morphology in limb muscles, which remarkably improved upon voluntary exercise. Interestingly, morphological abnormalities in mitochondria were even more apparent when PGC1α, a regulator of exercise-induced mitochondrial biogenesis, was overexpressed in Zmynd17-KO limb muscle. These abnormalities were also ameliorated by voluntary exercise. Our results show that neither the effect of consecutive exercise on mitochondrial quality nor PGC1α-induced mitochondrial biogenesis are mediated through Zmynd17 activity, thereby suggesting the existence of a complex mechanism of mitochondrial quality control in muscles

Temporal Effects of Cyclic Stretching on Distribution and Gene Expression of Integrin and Cytoskeleton by Ligament Fibroblasts In Vitro

Cyclic stretching is pivotal to maintenance of the ligaments. However, it is still not clear when ligament fibroblasts switch on expression of genes related to the mechanotransduction pathway in response to cyclic stretching. This in vitro study investigated, using ligament fibroblasts, the time-dependent changes in distribution and gene expression of β1 integrin, the cytoskeleton, and collagens after the application of 6% cyclic stretching at a frequency of 0.1 Hz for 3 hr on silicon membranes. We carried out confocal laser scanning microscopy to demonstrate changes in distribution of these components as well as quantitative real-time RT-PCR to quantify levels of these gene expression both during application of cyclic stretching and at 0, 2, 6, 12, and 18 hr after the termination of stretching. Control (unstretched) cells were used at each time point. Within 1 hr of the application of stretching, the fibroblasts and their actin stress fibers became aligned in a direction perpendicular to the major axis of stretch, whereas control (unstretched) cells were randomly distributed. In response to cyclic stretching, upregulation of actin at the mRNA level was first observed within 1 hr after the onset of stretching, while upregulation of β1 integrin and type I and type III collagens was observed between 2 and 12 hr after the termination of stretching. These results indicate that the fibroblasts quickly modify their morphology in response to cyclic stretching, and subsequently they upregulate the expression of genes related to the mechanotransduction pathway mainly during the resting period after the termination of stretching

On the origin and evolution of the asteroid Ryugu: A comprehensive geochemical perspective

Presented here are the observations and interpretations from a comprehensive analysis of 16 representative particles returned from the C-type asteroid Ryugu by the Hayabusa2 mission. On average Ryugu particles consist of 50% phyllosilicate matrix, 41% porosity and 9% minor phases, including organic matter. The abundances of 70 elements from the particles are in close agreement with those of CI chondrites. Bulk Ryugu particles show higher δ18O, Δ17O, and ε54Cr values than CI chondrites. As such, Ryugu sampled the most primitive and least-thermally processed protosolar nebula reservoirs. Such a finding is consistent with multi-scale H-C-N isotopic compositions that are compatible with an origin for Ryugu organic matter within both the protosolar nebula and the interstellar medium. The analytical data obtained here, suggests that complex soluble organic matter formed during aqueous alteration on the Ryugu progenitor planetesimal (several 10’s of km), <2.6 Myr after CAI formation. Subsequently, the Ryugu progenitor planetesimal was fragmented and evolved into the current asteroid Ryugu through sublimation