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Disease pathogenesis is always a major topic in biomedical research. With the exponential growth of biomedical information, drug effect analysis for specific phenotypes has shown great promise in uncovering disease-associated pathways. However, this method has only been applied to a limited number of drugs. Here, we extracted the data of 4634 diseases, 3671 drugs, 112 809 disease-drug associations and 81 527 drug-gene associations by text mining of 29 168 919 publications. On this basis, we proposed a 'Drug Set Enrichment Analysis by Text Mining (DSEATM)' pipeline and applied it to 3250 diseases, which outperformed the state-of-the-art method. Furthermore, diseases pathways enriched by DSEATM were similar to those obtained using the TCGA cancer RNA-seq differentially expressed genes. In addition, the drug number, which showed a remarkable positive correlation of 0.73 with the AUC, plays a determining role in the performance of DSEATM. Taken together, DSEATM is an auspicious and accurate disease research tool that offers fresh insights.
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Pesquisa Biomédica , Mineração de Dados , Mineração de Dados/métodos , FenótipoRESUMO
Among the numerous indoor localization methods, Light-Detection-and-Ranging (LiDAR)-based probabilistic algorithms have been extensively applied to indoor localization due to their real-time performance and high accuracy. Nevertheless, these methods are challenged in symmetrical environments when tackling global localization and the robot kidnapping problem. In this paper, a novel hybrid method that combines visual and probabilistic localization results is proposed. Augmented Monte Carlo Localization (AMCL) is improved for position tracking continually. LiDAR-based measurements' uncertainty is evaluated to incorporate discrete visual-based results; therefore, a better diversity of the particle can be maintained. The robot kidnapping problem can be detected and solved by preventing premature convergence of the particle filter. Extensive experiments were implemented to validate the robustness and accuracy performance. Meanwhile, the localization error was reduced from 30 mm to 9 mm during a 600 m tour.
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Robótica , Algoritmos , Método de Monte Carlo , Robótica/métodosRESUMO
We demonstrate a method for quantitative phase (QP) imaging without 2π ambiguity using a spectral domain phase microscopy system. The method is capable of QP measurement of a large dynamic range with a high sensitivity. We determine an integer multiple of 2π to correct wrapped phases by calculating the phase shift difference between the detected interference fringe and simulated fringes. The presented method is quantitatively verified by measuring the vibration generated by a piezo linear stage and mapping the surface topography of a slanted mirror. QP imaging of red blood cells is also performed to demonstrate the method's capacity and application in biological imaging.
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Microscopia/métodos , Razão Sinal-RuídoRESUMO
Due to synergistic effects, combinatorial drugs are widely used for treating complex diseases. However, combining drugs and making them synergetic remains a challenge. Genetic disease genes are considered a promising source of drug targets with important implications for navigating the drug space. Most diseases are not caused by a single pathogenic factor, but by multiple disease genes, in particular, interacting disease genes. Thus, it is reasonable to consider that targeting epistatic disease genes may enhance the therapeutic effects of combinatorial drugs. In this study, synthetic lethality gene pairs of tumors, similar to epistatic disease genes, were first targeted by combinatorial drugs, resulting in the enrichment of the combinatorial drugs with cancer treatment, which verified our hypothesis. Then, conventional epistasis detection software was used to identify epistatic disease genes from the genome wide association studies (GWAS) dataset. Furthermore, combinatorial drugs were predicted by targeting these epistatic disease genes, and five combinations were proven to have synergistic anti-cancer effects on MCF-7 cells through cell cytotoxicity assay. Combined with the three-dimensional (3D) genome-based method, the epistatic disease genes were filtered and were more closely related to disease. By targeting the filtered gene pairs, the efficiency of combinatorial drug discovery has been further improved.
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Descoberta de Drogas/métodos , Epistasia Genética/genética , Neoplasias/tratamento farmacológico , Antineoplásicos/uso terapêutico , Biologia Computacional/métodos , Estudo de Associação Genômica Ampla/métodos , Humanos , Células MCF-7 , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
We demonstrate a method that reduces the noise caused by multi-scattering (MS) photons in an in vivo optical coherence tomography image. This method combines a specially designed image acquisition (i.e., optical coherence tomography scan) scheme and subsequent complex signal processing. For the acquisition, multiple cross-sectional images (frames) are sequentially acquired while the depth position of the focus is altered for each frame by an electrically tunable lens. In the signal processing, the frames are numerically defocus-corrected, and complex averaged. Because of the inconsistency in the MS-photon trajectories among the different electrically tunable lens-induced defocus, this averaging reduces the MS signal. Unlike the previously demonstrated volume-wise multi-focus averaging method, our approach requires the sample to remain stable for only a brief period, approximately 70 ms, thus making it compatible with in vivo imaging. This method was validated using a scattering phantom and in vivo unanesthetized small fish samples, and was found to reduce MS noise even for unanesthetized in vivo measurement.
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As medical safety and drug regulation gain heightened attention, the detection of spurious drug-drug interactions (DDI) has become key in healthcare. Although current research using graph neural networks (GNNs) to predict DDI has shown impressive results, it often fails to account for false DDI in the constructed DDI networks. Such inaccuracies caused by data errors, false alarms, or incorrect drug details can skew the network's structure and hinder the accuracy of GNN-based predictions. To tackle this challenge, we propose ANSM, a network-enhancement method specifically designed to identify and attenuate spurious links between drugs for ensuring the accuracy of DDI networks. ANSM integrates three key components: the feature extractor, the network optimizer, and the discriminative classifier. The feature extractor captures local structural features from drug node pairs, while the network optimizer leverages network information to improve feature extraction and reduce the impact of spurious DDI links. The discriminative classifier then identifies potential spurious links. Experimental results demonstrate that ANSM outperforms state-of-the-art methods in identifying spurious DDI.
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The structural characteristics at the interface of bone implants can guide biological regulation. In this study, a dual-scale hierarchical microstructure is proposed and customized using hybrid machining to achieve temporal dependency osteogenic regulation. It is observed that osteoblasts induced by dual-scale hierarchical structure exhibit adequate protrusion development and rapid cell attachment through the modulation of mechanical forces in the cell growth environment, and further promot the upregulation of the cell membrane receptor PDGFR-α, which is related to cell proliferation. Afterward, transcriptomic analysis reveals that during the differentiation stage, the DSH structure regulates cellular signaling cascades primarily through integrin adhesion mechanisms and then accelerates osteogenic differentiation by activating the TGF-ß pathway and cAMP signaling pathway. Furthermore, the calcium nodules are preferentially deposited within the lower honeycomb-like channels, thereby endowing the proposed dual-scale hierarchical structure with the potential to induce oriented deposition and improve the long-term stability of the implant.
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We demonstrate a deep-learning-based scatterer density estimator (SDE) that processes local speckle patterns of optical coherence tomography (OCT) images and estimates the scatterer density behind each speckle pattern. The SDE is trained using large quantities of numerically simulated OCT images and their associated scatterer densities. The numerical simulation uses a noise model that incorporates the spatial properties of three types of noise, i.e., shot noise, relative-intensity noise, and non-optical noise. The SDE's performance was evaluated numerically and experimentally using two types of scattering phantom and in vitro tumor spheroids. The results confirmed that the SDE estimates scatterer densities accurately. The estimation accuracy improved significantly when compared with our previous deep-learning-based SDE, which was trained using numerical speckle patterns generated from a noise model that did not account for the spatial properties of noise.
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Polarization-sensitive optical coherence tomography (PS-OCT) is a promising biomedical imaging tool for the differentiation of various tissue properties. However, the presence of multiple-scattering (MS) signals can degrade the quantitative polarization measurement accuracy. We demonstrate a method to reduce MS signals and increase the measurement accuracy of Jones matrix PS-OCT. This method suppresses MS signals by averaging multiple Jones matrix volumes measured using different focal positions. The MS signals are decorrelated among the volumes by focus position modulation and are thus reduced by averaging. However, the single scattering signals are kept consistent among the focus-modulated volumes by computational refocusing. We validated the proposed method using a scattering phantom and a postmortem medaka fish. The results showed reduced artifacts in birefringence and degree-of-polarization uniformity measurements, particularly in deeper regions in the samples. This method offers a practical solution to mitigate MS-induced artifacts in PS-OCT imaging and improves quantitative polarization measurement accuracy.
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[This corrects the article on p. 168 in vol. 13, PMID: 35154862.].
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Multiple scattering is one of the main factors that limits the penetration depth of optical coherence tomography (OCT) in scattering samples. We propose a method termed multi-focus averaging (MFA) to suppress the multiple-scattering signals and improve the image contrast of OCT in deep regions. The MFA method captures multiple OCT volumes with various focal positions and averages them in complex form after correcting the varying defocus through computational refocusing. Because the multiple-scattering takes different trajectories among the different focal position configurations, this averaging suppresses the multiple-scattering signal. Meanwhile, the single-scattering takes a consistent trajectory regardless of the focal position configuration and is not suppressed. Hence, the MFA method improves the ratio between the single-scattering signal and multiple-scattering signal, resulting in an enhancement in the image contrast. A scattering phantom and a postmortem zebrafish were measured to validate the proposed method. The results showed that the contrast of intensity images of both the phantom and zebrafish were improved using the MFA method, such that they were better than the contrast provided by the standard single focus averaging method. The MFA method provides a cost-effective solution for contrast enhancement through multiple-scattering reduction in tissue imaging using OCT systems.
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The ability to respond to physical stress that disrupts normal physiological homeostasis at an older age embraces the concept of resilience to aging. A physical stressor could be used to induce physiological responses that are age-related, since resilience declines with increasing age. Increased fat and sugar intake is a nutritional stress with a high prevalence of obesity in older people. In order to determine the effect of this type of diet on resilience to aging, 18-month-old C57BL/6J male mice were fed a diet high in saturated fat (lard) and sucrose (HFS) for ten months. At the end of the 10-month study, mice fed the HFS diet showed increased cognitive impairment, decreased cardiac function, decreased strength and agility, and increased severity of renal pathology compared to mice fed a rodent chow diet low in saturated fat and sucrose (LFS). The degree of response aligned with decreased resilience to the long-term adverse effects of the diet with characteristics of accelerated aging. This observation suggests additional studies could be conducted to investigate the relationship between an accelerated decline in resilience to aging and enhanced resilience to aging under different dietary conditions.
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Here we demonstrate a long-depth-of-focus imaging method using polarization sensitive optical coherence tomography (PS-OCT). This method involves a combination of Fresnel-diffraction-model-based phase sensitive computational refocusing and Jones-matrix based PS-OCT (JM-OCT). JM-OCT measures four complex OCT images corresponding to four polarization channels. These OCT images are computationally refocused as preserving the mutual phase consistency. This method is validated using a static phantom, postmortem zebrafish, and ex vivo porcine muscle samples. All the samples demonstrated successful computationally-refocused birefringence and degree-of-polarization-uniformity (DOPU) images. We found that defocusing induces polarization artifacts, i.e., incorrectly high birefringence values and low DOPU values, which are substantially mitigated by computational refocusing.
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[This corrects the article on p. 2975 in vol. 13.].
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Background: Disruption of metabolic and bioenergetic homeostasis related to mitochondrial dysfunction is a key driver of aging biology. Therefore, targeting mitochondrial function would be a rational approach to slowing aging. Elamipretide (Elam, a.k.a. SS-31) is a peptide known to target mitochondria and suppress mammalian signs of aging. The present study was designed to examine the phenotypic effects of long-term Elam treatment on aging in C57BL/6 mice starting at 18 months of age. Methods: Mice were fed regular chow (RC diet) or a diet high in fat and sugar (HF diet) and treated with 3 mg/kg of Elam or saline subcutaneously 5 days per week for 10 months. Physiological performance assessments were conducted at 28 months of age. Results: Elam improved the physical performance of males but not females, while in females Elam improved cognitive performance and enhanced the maintenance of body weight and fat mass. It also improved diastolic function in both males and females, but to a greater extent in males. The HF diet over 10 months had a negative effect on health span, as it increased body fat and decreased muscle strength and heart function, especially in females. Conclusions: Elam enhanced healthy aging and cardiac function in both male and female mice, although the specific effects on function differed between sexes. In females, the treatment led to better cognitive performance and maintenance of body composition, while in males, performance on a rotating rod was preserved. These overall observations have translational implications for considering additional studies using Elam in therapeutic or preventive approaches for aging and age-related diseases.
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SIGNIFICANCE: The scattering and polarization characteristics of various organs of in vivo wildtype zebrafish in three development stages were investigated using a non-destructive and label-free approach. The presented results showed a promising first step for the usability of Jones-matrix optical coherence tomography (JM-OCT) in zebrafish-based research. AIM: We aim to visualize and quantify the scatter and polarization signatures of various zebrafish organs for larvae, juvenile, and young adult animals in vivo in a non-invasive and label-free way. APPROACH: A custom-built polarization-sensitive JM-OCT setup in combination with a motorized translation stage was utilized to investigate live zebrafish. Depth-resolved scattering (intensity and attenuation coefficient) and polarization (birefringence and degree of polarization uniformity) properties were analyzed. OCT angiography (OCT-A) was utilized to investigate the vasculature label-free and non-destructively. RESULTS: The scatter and polarization signatures of the zebrafish organs such as the eye, gills, and muscles were investigated. The attenuation coefficient and birefringence changes between 1- and 2-month-old animals were evaluated in selected organs. OCT-A revealed the vasculature of in vivo larvae and juvenile zebrafish in a label-free manner. CONCLUSIONS: JM-OCT offers a rapid, label-free, non-invasive, tissue specific, and three-dimensional imaging tool to investigate in vivo processes in zebrafish in various development stages.
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Tomografia de Coerência Óptica , Peixe-Zebra , Animais , Birrefringência , Refração OcularRESUMO
Label-free metabolic imaging of non-alcoholic fatty liver disease (NAFLD) mouse liver is demonstrated ex vivo by dynamic optical coherence tomography (OCT). The NAFLD mouse is a methionine choline-deficient (MCD)-diet model, and two mice fed the MCD diet for 1 and 2 weeks are involved in addition to a normal-diet mouse. The dynamic OCT is based on repeating raster scan and logarithmic intensity variance (LIV) analysis that enables volumetric metabolic imaging with a standard-speed (50,000 A-lines/s) OCT system. Metabolic domains associated with lipid droplet accumulation and inflammation are clearly visualized three-dimensionally. Particularly, the normal-diet liver exhibits highly metabolic vessel-like structures of peri-vascular hepatic zones. The 1-week MCD-diet liver shows ring-shaped highly metabolic structures formed with lipid droplets. The 2-week MCD-diet liver exhibits fragmented vessel-like structures associated with inflammation. These results imply that volumetric LIV imaging is useful for visualizing and assessing NAFLD abnormalities.
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The zebrafish is a valuable vertebrate animal model in pre-clinical cancer research. A Jones matrix optical coherence tomography (JM-OCT) prototype operating at 1310 nm and an intensity-based spectral-domain OCT setup at 840 nm were utilized to investigate adult wildtype and a tumor-developing zebrafish model. Various anatomical features were characterized based on their inherent scattering and polarization signature. A motorized translation stage in combination with the JM-OCT prototype enabled large field-of-view imaging to investigate adult zebrafish in a non-destructive way. The diseased animals exhibited tumor-related abnormalities in the brain and near the eye region. The scatter intensity, the attenuation coefficients and local polarization parameters such as the birefringence and the degree of polarization uniformity were analyzed to quantify differences in tumor versus control regions. The proof-of-concept study in a limited number of animals revealed a significant decrease in birefringence in tumors found in the brain and near the eye compared to control regions. The presented work showed the potential of OCT and JM-OCT as non-destructive, high-resolution, and real-time imaging modalities for pre-clinical research based on zebrafish.
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Pharmaceutical intervention of aging requires targeting multiple pathways, thus there is rationale to test combinations of drugs targeting different but overlapping processes. In order to determine if combining drugs shown to extend lifespan and healthy aging in mice would have greater impact than any individual drug, a cocktail diet containing 14 ppm rapamycin, 1000 ppm acarbose, and 1000 ppm phenylbutyrate was fed to 20-month-old C57BL/6 and HET3 4-way cross mice of both sexes for three months. Mice treated with the cocktail showed a sex and strain-dependent phenotype consistent with healthy aging including decreased body fat, improved cognition, increased strength and endurance, and decreased age-related pathology compared to mice treated with individual drugs or control. The severity of age-related lesions in heart, lungs, liver, and kidney was consistently decreased in mice treated with the cocktail compared to mice treated with individual drugs or control, suggesting an interactive advantage of the three drugs. This study shows that a combination of three drugs, each previously shown to enhance lifespan and health span in mice, is able to delay aging phenotypes in middle-aged mice more effectively than any individual drug in the cocktail over a 3-month treatment period.
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Acarbose , Sirolimo , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Fenilbutiratos/farmacologia , Sirolimo/farmacologiaRESUMO
We present deep convolutional neural network (DCNN)-based estimators of the tissue scatterer density (SD), lateral and axial resolutions, signal-to-noise ratio (SNR), and effective number of scatterers (ENS, the number of scatterers within a resolution volume). The estimators analyze the speckle pattern of an optical coherence tomography (OCT) image in estimating these parameters. The DCNN is trained by a large number (1,280,000) of image patches that are fully numerically generated in OCT imaging simulation. Numerical and experimental validations were performed. The numerical validation shows good estimation accuracy as the root mean square errors were 0.23%, 3.65%, 3.58%, 3.79%, and 6.15% for SD, lateral and axial resolutions, SNR, and ENS, respectively. The experimental validation using scattering phantoms (Intralipid emulsion) shows reasonable estimations. Namely, the estimated SDs were proportional to the Intralipid concentrations, and the average estimation errors of lateral and axial resolutions were 1.36% and 0.68%, respectively. The scatterer density estimator was also applied to an in vitro tumor cell spheroid, and a reduction in the scatterer density during cell necrosis was found.