Using graph-based model to identify cell specific synthetic lethal effects.

Synthetic lethal (SL) pairs are pairs of genes whose simultaneous loss-of-function results in cell death, while a damaging mutation of either gene alone does not affect the cell's survival. This makes SL pairs attractive targets for precision cancer therapies, as targeting the unimpaired gene of the SL pair can selectively kill cancer cells that already harbor the impaired gene. Limited by the difficulty of finding true SL pairs, especially on specific cell types, current computational approaches provide only limited insights because of overlooking the crucial aspects of cellular context dependency and mechanistic understanding of SL pairs. As a result, the identification of SL targets still relies on expensive, time-consuming experimental approaches. In this work, we applied cell-line specific multi-omics data to a specially designed deep learning model to predict cell-line specific SL pairs. Through incorporating multiple types of cell-specific omics data with a self-attention module, we represent gene relationships as graphs. Our approach achieves the prediction of SL pairs in a cell-specific manner and demonstrates the potential to facilitate the discovery of cell-specific SL targets for cancer therapeutics, providing a tool to unearth mechanisms underlying the origin of SL in cancer biology. The code and data of our approach can be found at https://github.com/promethiume/SLwise.

LogD7.4 prediction enhanced by transferring knowledge from chromatographic retention time, microscopic pKa and logP.

Lipophilicity is a fundamental physical property that significantly affects various aspects of drug behavior, including solubility, permeability, metabolism, distribution, protein binding, and toxicity. Accurate prediction of lipophilicity, measured by the logD7.4 value (the distribution coefficient between n-octanol and buffer at physiological pH 7.4), is crucial for successful drug discovery and design. However, the limited availability of data for logD modeling poses a significant challenge to achieving satisfactory generalization capability. To address this challenge, we have developed a novel logD7.4 prediction model called RTlogD, which leverages knowledge from multiple sources. RTlogD combines pre-training on a chromatographic retention time (RT) dataset since the RT is influenced by lipophilicity. Additionally, microscopic pKa values are incorporated as atomic features, providing valuable insights into ionizable sites and ionization capacity. Furthermore, logP is integrated as an auxiliary task within a multitask learning framework. We conducted ablation studies and presented a detailed analysis, showcasing the effectiveness and interpretability of RT, pKa, and logP in the RTlogD model. Notably, our RTlogD model demonstrated superior performance compared to commonly used algorithms and prediction tools. These results underscore the potential of the RTlogD model to improve the accuracy and generalization of logD prediction in drug discovery and design. In summary, the RTlogD model addresses the challenge of limited data availability in logD modeling by leveraging knowledge from RT, microscopic pKa, and logP. Incorporating these factors enhances the predictive capabilities of our model, and it holds promise for real-world applications in drug discovery and design scenarios.

DNA methylation networks underlying mammalian traits.

Using DNA methylation profiles (n = 15,456) from 348 mammalian species, we constructed phyloepigenetic trees that bear marked similarities to traditional phylogenetic ones. Using unsupervised clustering across all samples, we identified 55 distinct cytosine modules, of which 30 are related to traits such as maximum life span, adult weight, age, sex, and human mortality risk. Maximum life span is associated with methylation levels in HOXL subclass homeobox genes and developmental processes and is potentially regulated by pluripotency transcription factors. The methylation state of some modules responds to perturbations such as caloric restriction, ablation of growth hormone receptors, consumption of high-fat diets, and expression of Yamanaka factors. This study reveals an intertwined evolution of the genome and epigenome that mediates the biological characteristics and traits of different mammalian species.

Tora3D: an autoregressive torsion angle prediction model for molecular 3D conformation generation.

Three-dimensional (3D) conformations of a small molecule profoundly affect its binding to the target of interest, the resulting biological effects, and its disposition in living organisms, but it is challenging to accurately characterize the conformational ensemble experimentally. Here, we proposed an autoregressive torsion angle prediction model Tora3D for molecular 3D conformer generation. Rather than directly predicting the conformations in an end-to-end way, Tora3D predicts a set of torsion angles of rotatable bonds by an interpretable autoregressive method and reconstructs the 3D conformations from them, which keeps structural validity during reconstruction. Another advancement of our method over other conformational generation methods is the ability to use energy to guide the conformation generation. In addition, we propose a new message-passing mechanism that applies the Transformer to the graph to solve the difficulty of remote message passing. Tora3D shows superior performance to prior computational models in the trade-off between accuracy and efficiency, and ensures conformational validity, accuracy, and diversity in an interpretable way. Overall, Tora3D can be used for the quick generation of diverse molecular conformations and 3D-based molecular representation, contributing to a wide range of downstream drug design tasks.

Centenarian clocks: epigenetic clocks for validating claims of exceptional longevity.

Claims surrounding exceptional longevity are sometimes disputed or dismissed for lack of credible evidence. Here, we present three DNA methylation-based age estimators (epigenetic clocks) for verifying age claims of centenarians. The three centenarian clocks were developed based on n = 7039 blood and saliva samples from individuals older than 40, including n = 184 samples from centenarians, 122 samples from semi-supercentenarians (aged 105 +), and 25 samples from supercentenarians (aged 110 +). The oldest individual was 115 years old. Our most accurate centenarian clock resulted from applying a neural network model to a training set composed of individuals older than 40. An epigenome-wide association study of age in different age groups revealed that age effects in young individuals (age < 40) are correlated (r = 0.55) with age effects in old individuals (age > 90). We present a chromatin state analysis of age effects in centenarians. The centenarian clocks are expected to be useful for validating claims surrounding exceptional old age.

Reconstruction of three-dimensional objects in layered composite structures from multimode orbital angular momentum.

Because of helical phase wavefront distribution, vortex electromagnetic waves are considered to carry more information and additional degrees of freedom than traditional spherical waves. Therefore, a vortex wave carrying orbital angular momentum (OAM) can improve inversion and imaging accuracy. In this work, we revisit the reconstruction of three-dimensional objects in layered composite structures extended with OAM. In forward modeling, the concentric uniform circle array is used to generate electromagnetic vortex beams. To analyze the difference of vortex beams, the electric field radiation pattern and phase pattern distribution of OAM waves with different modes are calculated. Then, the scattered field of layered media illuminated by different OAM beams is determined by the dyadic Green's function and the stabilized biconjugate gradient technique with a fast Fourier transform algorithm. In the inversion, the variational Born iterative method is used to reconstruct targets in layered composite structures, and multiple OAM modes are used to improve the reconstruction results. The numerical results prove that the permittivity of the target can be better reconstructed by using the multiple OAM modes rather than the traditional spherical wave. With the increase of OAM mode number, the reconstructed target parameters are closer to the true value. We expect that our results will provide a better understanding of the OAM and pave the way for the improvement of inversion and optical imaging technology using vortex waves.

Simulate Deutsch-Jozsa algorithm with metamaterials.

During the past few years, a lot of efforts have been devoted in studying optical analog computing with artificial structures. Up to now, much of them are primarily focused on classical mathematical operations. How to use artificial structures to simulate quantum algorithm is still to be explored. In this work, an all-dielectric metamaterial-based model is proposed and realized to demonstrate the quantum Deutsch-Jozsa algorithm. The model is comprised of two cascaded functional metamaterial subblocks. The oracle subblock encodes the detecting functions (constant or balanced), onto the phase distribution of the incident wave. Then, the original Hadamard transformation is performed with a graded-index subblock. Both the numerical and experimental results indicate that the proposed metamaterials are able to simulate the Deutsch-Jozsa problem with one round operation and a single measurement of the output eletric field, where the zero (maximum) intensity at the central position results from the destructive (constructive) interference accompanying with the balance (constant) function marked by the oracle subblock. The proposed computational metamaterial is miniaturized and easy-integration for potential applications in communication, wave-based analog computing, and signal processing systems.

Automatic Hip Fracture Identification and Functional Subclassification with Deep Learning.

PURPOSE: To investigate the feasibility of automatic identification and classification of hip fractures using deep learning, which may improve outcomes by reducing diagnostic errors and decreasing time to operation. MATERIALS AND METHODS: Hip and pelvic radiographs from 1118 studies were reviewed, and 3026 hips were labeled via bounding boxes and classified as normal, displaced femoral neck fracture, nondisplaced femoral neck fracture, intertrochanteric fracture, previous open reduction and internal fixation, or previous arthroplasty. A deep learning-based object detection model was trained to automate the placement of the bounding boxes. A Densely Connected Convolutional Neural Network (or DenseNet) was trained on a subset of the bounding box images, and its performance was evaluated on a held-out test set and by comparison on a 100-image subset with two groups of human observers: fellowship-trained radiologists and orthopedists; senior residents in emergency medicine, radiology, and orthopedics. RESULTS: The binary accuracy for detecting a fracture of this model was 93.7% (95% confidence interval [CI]: 90.8%, 96.5%), with a sensitivity of 93.2% (95% CI: 88.9%, 97.1%) and a specificity of 94.2% (95% CI: 89.7%, 98.4%). Multiclass classification accuracy was 90.8% (95% CI: 87.5%, 94.2%). When compared with the accuracy of human observers, the accuracy of the model achieved an expert-level classification, at the very least, under all conditions. Additionally, when the model was used as an aid, human performance improved, with aided resident performance approximating unaided fellowship-trained expert performance in the multiclass classification. CONCLUSION: A deep learning model identified and classified hip fractures with expert-level performance, at the very least, and when used as an aid, improved human performance, with aided resident performance approximating that of unaided fellowship-trained attending physicians.Supplemental material is available for this article.© RSNA, 2020.

Poly(dimethylsilylene)diacetylene-Guided ZIF-Based Heterostructures for Full Ku-Band Electromagnetic Wave Absorption.

Zeolitic imidazolate frameworks (ZIFs), a group of metal-organic frameworks (MOFs), hold promise as building blocks in electromagnetic (EM) wave absorbing/shielding materials and devices. In this contribution, we proposed a facile strategy to synthesize three-dimensional ZIF-67-based hierarchical heterostructures through coordinated reaction of a preceramic component, poly(dimethylsilylene)diacetylene (PDSDA) with ZIF-67, followed by carbonizing the PDSDA-wrapped ZIF at high temperature. The introduction of PDSDA leads to controllable generation of a surface network containing branched carbon nanotubes and regional distributed graphitic carbons, in addition to the nanostructures with a well-defined size and porous surface made by cobalt nanoparticles. The surface structures can be tailored through variations in pyrolysis temperatures, therefore enabling a simple and robust route to facilitate a suitable structural surface. The heterostructure of the ZIF nanocomplex allows the existence of dielectric loss and magnetic loss, therefore yielding a significant improvement on EM wave absorption with a minimum reflection coefficient (RCmin) of -50.9 dB at 17.0 GHz at a thickness of 1.9 mm and an effective absorption bandwidth (EAB) covering the full Ku-band (12.0-18.0 GHz).

Implementing Quantum Search Algorithm with Metamaterials.

Metamaterials, artificially structured electromagnetic (EM) materials, have enabled the realization of many unconventional EM properties not found in nature, such as negative refractive index, magnetic response, invisibility cloaking, and so on. Based on these man-made materials with novel EM properties, various devices are designed and realized. However, quantum analog devices based on metamaterials have not been achieved so far. Here, metamaterials are designed and printed to perform quantum search algorithm. The structures, comprising of an array of 2D subwavelength air holes with different radii perforated on the dielectric layer, are fabricated using a 3D-printing technique. When an incident wave enters in the designed metamaterials, the profile of beam wavefront is processed iteratively as it propagates through the metamaterial periodically. After ≈N roundtrips, precisely the same as the efficiency of quantum search algorithm, searched items will be found with the incident wave all focusing on the marked positions. Such a metamaterial-based quantum searching simulator may lead to remarkable achievements in wave-based signal processors.