Search

Hyperlipidemia results in endothelial dysfunction, which is intimately associated with disturbed mitochondrial homeostasis, and is a real risk factor for cardiovascular diseases (CVDs). Triphenylphosphonium (TPP+)-HT, constructed by linking a mitochondrial-targeting moiety TPP+ to hydroxytyrosol (HT), enters the cell and accumulates in mitochondria and is thus an important candidate drug for preventing hyperlipidemia-induced endothelial injury. In the present study, we found that TPP-HT has a better anti-inflammatory effect than HT. In vivo, TPP-HT significantly prevented hyperlipidemia-induced adverse changes in the serological lipid panel, as well as endothelial and mitochondrial dysfunction of the thoracic aorta. Similarly, in vitro, TPP-HT exhibited similar protective effects in palmitate (PA)-induced endothelial dysfunction, particularly enhanced expression of the mitochondrial ETC complex II, recovered FoxO1 expression in PA-injured human aorta endothelial cells (HAECs) and promoted FoxO1 nuclear translocation. We further demonstrated that FoxO1 plays a pivotal role in regulating ATP production in the presence of TPP-HT by using the siFoxO1 knockdown technique. Simultaneously, TPP-HT enhanced Nrf2 nuclear translocation, consistent with the in vivo findings of immunofluorescence, and the antioxidant effect of TPP-HT was almost entirely blocked by siNrf2. Concomitantly, TPP-HT's anti-inflammatory effects in the current study were primarily mediated via the p38 MAPK/NF-κB signaling pathway in addition to the FoxO1 and Nrf2 pathways. In brief, our findings suggest that mitochondria-targeted TPP-HT prevents lipotoxicity induced endothelial dysfunction by enhancing mitochondrial function and redox balance by promoting FoxO1 and Nrf2 nuclear translocation. [ABSTRACT FROM AUTHOR]

To investigate the nucleation behavior of ammonium sulphate, commonly used as a fertilizer, during cooling crystallization, polythermal methods have been used to determine the metastable zone widths (MSZWs) of ammonium sulphate in aqueous solution from the saturation temperature at 288.15 to 317.15 K under cooling rates of 6.0 to 30.0 K per hour. MSZWs increased with the increasing cooling rate and the saturation temperature. Based on classical nucleation theory, the nucleation potential model linked the MSZWs to the critical nucleation potential and pre-exponential factor. The MSZWs from one saturation temperature or with one cooling rate were used to predict the MSZWs with other saturation temperatures or with other cooling rates, by the nucleation potential model. The estimated MSZWs were compared with the experimental values. Further, according to the characteristics of the electrolyte solution, the supersaturation term in the nucleation potential model was modified by the activity coefficient. The estimated MSZWs showed improved accuracies and a tendency to be positively correlated with both the supersaturation temperature and cooling rate, which was consistent with the experimentally measured MSZWs. [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel cocrystal of metformin hydrochloride with citric acid was synthesized and obtained. • Physicochemical properties and the single-crystal structure of the cocrystal were investigated and determined. • The binding models of the cocrystal were built, simulated, and calculated to investigate the mechanisms of cocrystal formation. • Hirshfeld surface of cocrystal was analyzed to reveal the intermolecular interactions and the strength of molecular packing. Pharmaceutical cocrystals have matured into an effective technique for tuning the physicochemical and mechanical properties of drugs in solid form simultaneously. Herein, in order to provide a novel cocrystal form of oral medicine metformin hydrochloride (MH), citric acid (CA) was selected as an efficient ligand after screening a variety of inorganic and organic acids. Thus, based on the principle of crystal engineering, we report a novel cocrystal: metformin hydrochloride - citric acid (MHCA) after the systematic screening, which was experimentally proved to be constituted with 1:1 stoichiometry. Compared with pure MH, MHCA has been proved higher solubility in water, methanol, and ethanol from 283.15 to 313.15 K. Through single-crystal X-ray diffraction (SC-XRD), the particular molecular structure of MHCA has been determined as the orthorhombic system and Pbca space group. Besides, the binding model of MH-CA was built for investigating the binding energy and stability between two components at 278, 298, and 318 K, which were found to be essential for the prediction and analysis of cocrystals. The contribution of different intermolecular interactions and the strength of molecular packing in the cocrystal also have been investigated by Hirshfeld surface analysis. It was found that the cocrystal structure was mainly stabilized by intermolecular hydrogen bonds existing as N—H···O between components, which indicated that the diffusion-combination trend of molecules enhanced the regular array of cocrystal. The results revealed that the molecules of MH and CA formed supramolecular cocrystals mainly induced by hydrogen bonds after passive contacts, such as co-crystallization or grind. [ABSTRACT FROM AUTHOR]

Building smart cities requires three-dimensional (3D) modelling to facilitate the planning and management of built environments. This requirement leads to high demand for data on vertical dimensions, such as building height, that are critical for the construction of 3D city models. Despite increasing recognition of the importance of such data, their acquisition in a low-cost and efficient manner remains a daunting task. Big data, particularly street view images (SVIs), provide an opportunity to efficiently solve this problem. In this study, we aim to derive information on building height from openly available SVIs by using single view metrology. Unlike other methods using multisource inputs, our method capitalizes on deep neural networks to extract a set of features – such as vanishing points, line segments, and semantic segmentation maps – for single view measurement and then estimates the height from single SVIs. The minimal input required by the method increases its competitiveness in large-scale estimation of building heights, especially in areas with difficulty to obtain the conventional remote sensing data. In addition to experiments that demonstrate the effectiveness and efficiency of the proposed method, we also conduct a thorough analysis of uncertainties and errors brought by the method, thereby providing guidance for its future applications. 1 Source code: https://github.com/yzre/SIHE. [ABSTRACT FROM AUTHOR]

We have proposed a new tumor sensitization and targeting (TST) framework, named in vivo computation, in our previous investigations. The problem of TST for an early and microscopic tumor is interpreted from the computational perspective with nanorobots being the “natural” computing agents, the high-risk tissue being the search space, the tumor targeted being the global optimal solution, and the tumor-triggered biological gradient field (BGF) providing the aided knowledge for fitness evaluation of nanorobots. This natural computation process can be seen as on-the-fly path planning for nanorobot swarms with an unknown target position, which is different from the traditional path planning methods. Our previous works are focusing on the TST for a solitary lesion, where we proposed the weak priority evolution strategy (WP-ES) to adapt to the actuating mode of the homogeneous magnetic field used in the state-of-the-art nanorobotic platforms, and some in vitro validations were performed. In this paper, we focus on the problem of TST for multifocal tumors, which can be seen as a multimodal optimization problem for the “natural” computation. To overcome this issue, we propose a sequential targeting strategy (Se-TS) to complete TST for the multiple lesions with the assistance of nanorobot swarms, which are maneuvered by the external actuating and tracking devices according to the WP-ES. The Se-TS is used to modify the BGF landscape after a tumor is detected by a nanorobot swarm with the gathered BGF information around the detected tumor. Next, another nanorobot swarm will be employed to find the second tumor according to the modified BGF landscape without being misguided to the previous one. In this way, all the tumor lesions will be detected one by one. In other words, the paths of nanorobots to find the targets can be generated successively with the sequential modification of the BGF landscape. To demonstrate the effectiveness of the proposed Se-TS, we perform comprehensive simulation studies by enhancing the WP-ES based swarm intelligence algorithms using this strategy considering the realistic in-body constraints. The performance is compared against that of the “brute-force” search, which corresponds to the traditional systemic tumor targeting, and also against that of the standard swarm intelligence algorithms from the algorithmic perspective. Furthermore, some in vitro experiments are performed by using Janus microparticles as magnetic nanorobots, a two-dimensional microchannel network as the human vasculature, and a magnetic nanorobotic control system as the external actuating and tracking system. Results from the in silico simulations and in vitro experiments verify the effectiveness of the proposed Se-TS for two representative BGF landscapes. [ABSTRACT FROM AUTHOR]

15 new bromotyrosine‐derived compounds, pseudoceroximes A–E (1–5), pseudocerolides A–E (6–10), 13‐ketohemifistularin 3 (11), and ceratinines J–M (12–15), were isolated from a Pseudoceratina sp. marine sponge collected in the South China Sea. The planar structures of all compounds were established based on extensive NMR spectroscopic analyses and HRESIMS data. Their absolute configurations were assigned by a combination of modified Mosher's method, ECD calculations and a single‐crystal X‐ray diffraction experiment. Pseudoceroximes A–D (1–4) represent the first examples of the oxime‐type bromotyrosine derivatives possessing the 2‐oxazolidone ring. Pseudoceroximes A (1) and B (2) and pseudocerolide C (8) showed antibacterial activity against methicillin‐resistant Staphylococcus aureus ATCC 43300 with MIC values of 5.2–7.1 µm. Additionally, pseudoceroximes B (2) and D (4) exhibited moderate antiproliferative activity against two human glioma cell lines U87MG and U251. [ABSTRACT FROM AUTHOR]

The checkerboard is a frequently used pattern in camera calibration, an essential process to get intrinsic parameters for more accurate information from images. An automatic checkerboard detection method that can detect multiple checkerboards in a single image is proposed. It contains a corner extraction approach using self-correlation and a structure recovery solution using constraints related to adjacent corners and checkerboard block edges. The method utilizes the central symmetric feature of the checkerboard crossings as well as the spatial relationship of neighboring checkerboard corners and the grayscale distribution of their neighboring pixels. Five public datasets are used in the experiments to evaluate the method. Results show high detection rates and a short average runtime of the proposed method. In addition, the camera calibration accuracy also presents the effectiveness of the proposed detection method with reprojected pixel errors smaller than 0.5 pixels. [ABSTRACT FROM AUTHOR]

The RNA-binding protein LIN-28 was first found to control developmental timing in Caenorhabditis elegans. Later, it was found to play important roles in pluripotency, metabolism, and cancer in mammals. Here we report that a low dosage of lin-28 enhanced stress tolerance and longevity, and reduced germline stem/progenitor cell number in C. elegans. The germline LIN-28 -regulated microRNA let-7 was required for these effects by targeting akt-1/2 and decreasing their protein levels. AKT-1/2 and the downstream DAF-16 transcription factor were both required for the lifespan and germline stem cell effects of lin-28. The pathway also mediated dietary restriction induced lifespan extension and reduction in germline stem cell number. Thus, the LIN-28/let-7/AKT/DAF-16 axis we delineated here is a program that plays an important role in balancing reproduction and somatic maintenance and their response to the environmental energy level-a central dogma of the 'evolutionary optimization' of resource allocation that modulates aging. [ABSTRACT FROM AUTHOR]

Biological age (BA) has been proposed to evaluate the aging status instead of chronological age (CA). Our study shows evidence that there might be multiple "clocks" within the whole-body system: systemic aging drivers/clocks overlaid with organ/tissue-specific counterparts. We utilize multi-omics data, including clinical tests, immune repertoire, targeted metabolomic molecules, gut microbiomes, physical fitness examinations, and facial skin examinations, to estimate the BA of different organs (e.g., liver, kidney) and systems (immune and metabolic system). The aging rates of organs/systems are diverse. People's aging patterns are different. We also demonstrate several applications of organs/systems BA in two independent datasets. Mortality predictions are compared among organs' BA in the dataset of the United States National Health and Nutrition Examination Survey. Polygenic risk score of BAs constructed in the Chinese Longitudinal Healthy Longevity Survey cohort can predict the possibility of becoming centenarian. [Display omitted] • Constructing biological ages of organs/systems using multi-omics features • Organs and systems are aging at different rates • Specific biological age could predict disease of corresponding organs • Biological ages of organs and systems have diverse genetic architectures Nie et al. estimate biological ages of organs and systems using 402 multi-omics features from 4,066 individuals and demonstrate several applications. They find that organs and systems are aging at different rates, and biological ages could be utilized for population stratification, mortality prediction, and phenotypes of genetic association studies. [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel cocrystal of lenalidomide with nicotinamide was predicted and synthesized. • Systematic physicochemical properties such as solubility, dissolution and stability were studied. • The anomalous thermal phase transition process of the cocrystal was firstly investigated. Lenalidomide (LDM), widely used for the treatment of transfusion-dependent anaemia, has low oral bioavailability due to its poor aqueous solubility. Herein, we selected nicotinamide (NIC) as a coformer and synthesized a novel pharmaceutical cocrystal: lenalidomide-nicotinamide cocrystal (LNC) with a 1:1 stoichiometric ratio for enhancing the physicochemical properties of LDM, such as solubility and stability. For evaluating the ability to form cocrystal of LDM and NIC, a model of hydrogen-bond propensity (HBP) was utilized to calculate the hydrogen bond formation possibility for every hydrogen bond pair based on the existing structural information in the database. Afterward, solid-state grinding and liquid-assisted grinding methods were conducted to synthesize LNC, which were then characterized using powder X-ray diffraction, thermal and spectroscopic analysis. Besides, in the heating process, an interesting and anomalous phenomenon called thermal phase transition of the cocrystal was firstly observed and visualized by the hot stage microscope. Notably, the second thermal stage controlled by the vapor pressure of NIC was further determined experimentally and theoretically, which means that intermolecular hydrogen bonds gradually break when NIC occurs phase transition (from liquid to gas). Further, the physicochemical stability of cocrystal was proved reliable after being tested under accelerated stability conditions of 40 °C/75% RH for one month. Compared to lenalidomide and their physical mixture (molar ratio of 1:1), the dissolution and solubility of LNC have also been improved. [ABSTRACT FROM AUTHOR]

Aging is characterized by the loss of homeostasis and the general decline of physiological functions, accompanied by various degenerative diseases and increased rates of mortality. Aging targeting small molecule screens have been performed many times, however, few have focused on endogenous metabolic intermediates—metabolites. Here, using C. elegans lifespan assays, we conducted a worm metabolite screen and identified an eukaryotes conserved metabolite, myo-inositol (MI), to extend lifespan, increase mobility and reduce fat content. Genetic analysis of enzymes in MI metabolic pathway suggest that MI alleviates aging through its derivative PI(4,5)P2. MI and PI(4,5)P2 are precursors of PI(3,4,5)P3, which is negatively related to longevity. The longevity effect of MI is dependent on the tumor suppressor gene, daf-18 (homologous to mouse Pten), independent of its classical pathway downstream genes, akt or daf-16. Furthermore, we found MI effects on aging and lifespan act through mitophagy regulator PTEN induced kinase-1 (pink-1) and mitophagy. MI's anti-aging effect is also conserved in mouse, indicating a conserved mechanism in mammals. Phosphatidylinositol 3-kinase catalyzes the reaction from PI(4,5)P2 to PI(3,4,5)P3 and is encoded by the age-1 gene known to regulate lifespan. Here the researchers found that the metabolite myo-inositol, which can be converted to PI(3,4,5)P3 extends worm lifespan and alleviates worm as well as mouse health decline during aging. [ABSTRACT FROM AUTHOR]

Summary Experimental large-scale screens for drug repositioning are limited by restriction to in vitro conditions and lack of applicability to real human conditions. Here, we developed an in silico screen in human in vivo conditions using a reference of single gene mutations' non-tissue-specific "core transcriptome signatures" (CSs) of 8,476 genes generated from the TCGA database. We developed the core-signature drug-to-gene (csD2G) software to scan 3,546 drug treatment profiles against the reference signatures. csD2G significantly outperformed conventional cell line-based gene perturbation signatures and existing drug-repositioning methods in both coverage and specificity. We highlight this with 3 demonstrated applications: (1) repositioned category of psychiatric drugs to inhibit the TGF-β pathway; (2) antihypertensive calcium channel blockers predicted to activate AMPK and inhibit AKT pathways, and validated by clinical electronic medical records; and (3) 7 drugs predicted and validated to selectively target the AKT-FOXO and AMPK pathways and thus regulate worm lifespan. Graphical Abstract Highlights • Non-tissue-specific core signatures (CSs) were generated for 8,476 human genes • csD2G repositions drugs through drug-gene CS modules and specificity mapping • Calcium blockers predicted to target AKT and AMPK are validated by medical records • Seven drugs were repositioned to selectively target AKT and AMPK and extend lifespan Xu et al. generated core transcriptome signatures representing single-gene mutations for 8,476 human genes from the cancer transcriptomes in the TCGA database and developed a drug-repositioning method to predict high-specificity candidate target genes for 1,938 drugs. Applied to targeting aging pathways, 7 lifespan-extending drugs are found and functionally validated. [ABSTRACT FROM AUTHOR]

[Display omitted] • The induction time and metastable zone width of MET-HCl were measured in four hydroxylic solvents. • Based on the modified Sangwal's theory, the interfacial energy and critical nucleation parameters was calculated and discussed. • The role of solvent in crystal nucleation was investigated with the solvent–solute interaction by DFT method. Metformin hydrochloride (MET-HCl) was applied as a model compound to investigate the nucleation behavior in four hydroxylic solvents based on the experimental and simulated methods. Over 320 induction time experiments were measured in four solvents, and the induction time increased in the order: water < methanol < ethanol < n-propanol. The metastable zone widths were determined with different cooling rates and saturation temperatures. According to classical nucleation theory, the nucleation kinetics and thermodynamic parameters (interfacial energy, critical nucleus size and Gibbs free energy) were estimated. The result indicates that the nucleation rate of MET-HCl in water was highest among four solvents. The density functional theory (DFT) calculation was applied to reveal the solvent–solute interaction in crystal nucleation, showing the binding energies increased in the order: water < methanol < ethanol < n-propanol. The simulation results combined with experimental data suggested that the stronger the interactions of solvent–solute molecules, the more difficult the nucleation becomes. [ABSTRACT FROM AUTHOR]

• Identify and characterize apremilast forms B and E. • Determine the solubility of apremilast polymorphs in three binary solvents. • Analyze thermodynamic property by Wilson, NRTL and UNIQUAC models. • Explore the Gibbs energy of solvation and solute-solvent interaction by molecular simulation. The polymorphism of apremilast has been investigated. Two polymorphs have been identified and characterized by differential scanning calorimeter, fourier transform infrared spectroscopy, and powder X-ray diffractometer. Solubilities of apremilast forms B and E in three binary solvents of methanol-water, acetonitrile-water, and acetonitrile-methanol have been measured using the static method at a temperature ranging from 288.15 K to 328.15 K under standard atmospheric pressure. Subsequently, the solubility data have been analyzed using the Wilson, NRTL, and UNIQUAC thermodynamic models, respectively. Furthermore, the Gibbs energy of solution and the radial distribution function have been calculated using the molecular simulation method to evaluate the dissolution mechanism. The Gibbs energy of solution reveals that the rank of solute-solvent interaction correlated well with solubility order in binary solvent mixtures, and the radial distribution function indicates that weakening of solvent-solvent interaction led to an increase in solubility. [Display omitted] [ABSTRACT FROM AUTHOR]

Introduction: Behaviors of swimming rodents are not uniform, exhibiting large variations, which may underlie the individual differences in swimming exercise-induced benefits. The study aimed to monitor individualized swimming behavior and evaluate its biological significance. Methods: A swimming tank which can monitor individualized rodent swimming behavior during exercise was established. A total of 45 mice were subjected to swimming training for 1 month (1 h per day) and the swimming behaviors of each mouse were recorded. Results: The swimming behaviors of mice displayed considerable variations in aspects of distance, velocity, and area preference. For example, nearly one-third of mice preferred to swim in central area and most of the mice exhibited an even area distribution. Long-term exercise training improved cardiac systolic function and decreased blood pressure in mice, but hardly changed swimming behaviors. Analyses of the relationship between swimming behavior and cardiovascular adaptations to exercise training revealed that swimming behavior indicated the biological effects of swimming training. Specifically, mice which preferred swimming at the central zone or were trainable in behavior during 1-month training exhibited better outcomes in cardiac function and blood pressure post long-term exercise. Mechanistically, a centralized swimming behavior indicated a smaller stress during exercise, as evidenced by a milder activation of hypothalamic-pituitary-adrenal axis. Discussion: These results suggest that swimming behavior during training indicates individualized adaptations to long-term exercise, and highlight a biological significance of swimming behavior monitoring in animal studies., Competing Interests: Authors SH and XC were employed by Chengdu Techman Software Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yu, Liu, Li, He, Hu, Sun, Yan, Zhao, Cheng, Li, Gao, Liu and Zhang.)

Not all individuals age at the same rate. Methods such as the 'methylation clock' are invasive, rely on expensive assays of tissue samples and infer the ageing rate by training on chronological age, which is used as a reference for prediction errors. Here, we develop models based on convoluted neural networks through training on non-invasive three-dimensional (3D) facial images of approximately 5,000 Han Chinese individuals that achieve an average difference between chronological or perceived age and predicted age of ±2.8 and 2.9 yr, respectively. We further profile blood transcriptomes from 280 individuals and infer the molecular regulators mediating the impact of lifestyle on the facial-ageing rate through a causal-inference model. These relationships have been deposited and visualized in the Human Blood Gene Expression-3D Facial Image (HuB-Fi) database. Overall, we find that humans age at different rates both in the blood and in the face, but do so coherently and with heterogeneity peaking at middle age. Our study provides an example of how artificial intelligence can be leveraged to determine the perceived age of humans as a marker of biological age, while no longer relying on prediction errors of chronological age, and to estimate the heterogeneity of ageing rates within a population.

The RNA-binding protein LIN-28 was first found to control developmental timing in Caenorhabditis elegans. Later, it was found to play important roles in pluripotency, metabolism, and cancer in mammals. Here we report that a low dosage of lin-28 enhanced stress tolerance and longevity, and reduced germline stem/progenitor cell number in C. elegans. The germline LIN-28-regulated microRNA let-7 was required for these effects by targeting akt-1/2 and decreasing their protein levels. AKT-1/2 and the downstream DAF-16 transcription factor were both required for the lifespan and germline stem cell effects of lin-28. The pathway also mediated dietary restriction induced lifespan extension and reduction in germline stem cell number. Thus, the LIN-28/let-7/AKT/DAF-16 axis we delineated here is a program that plays an important role in balancing reproduction and somatic maintenance and their response to the environmental energy level-a central dogma of the 'evolutionary optimization' of resource allocation that modulates aging., (© 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

A new approach to measure the 3D profile of a texture object is proposed utilizing light field imaging, in which three key steps are required: a disparity map is first obtained by detecting the slopes in the epipolar plane image with the multilabel technique; the intrinsic parameters of the light field camera are then extracted by camera calibration; at last, the relationship between disparity values and real distances is built up by depth calibration. In the last step, a linear calibration method is proposed to achieve accurate results. Furthermore, the depth error is also investigated and compensated for by reusing the checkerboard pattern. The experimental results are in good agreement with the 3D models, and also indicate that the light field imaging is a promising 3D measurement technique.