Based on the idea of linear programming technique for multidimensional analysis of preference (LINMAP), a novel three-phase LINMAP method is presented for solving hybrid multi-criteria group decision ...making (MCGDM) with dual hesitant fuzzy (DHF) truth degrees and incomplete criteria weights information. Firstly, by simultaneously taking into account the difference between each alternative and all the others for the decision maker (DM), the difference of each alternative between the individual DM and the decision group, and the difference of each alternative between the individual DM and all the others, a tri-objective nonlinear programming model is created to determine the DMs' weights. Secondly, to derive the criteria weights, the objective positive ideal solution (OPIS), and the objective negative ideal solution (ONIS), a new four-objective DHF mathematical programming model is established by minimizing inconsistency and maximizing consistency based on OPIS and ONIS, and a pair of parametric nonlinear programming models are technically established by unequal weighted summation approach for solving the four-objective DHF mathematical programming model, which can provide DMs with more agility and flexible space to change their preference. Thirdly, by considering the distances of each alternative from the OPIS and ONIS for individual DM and the decision group, a minimizing deviation optimal model is established to derive the group ranking order of alternatives. Finally, a new method is put forward for solving hybrid MCGDM with DHF truth degrees, and the validity and practicability of the proposed method is analyzed through a case of water quality monitoring system (WQMS) selection.
The bioeffects of terahertz (THz) radiation received growing attention because of its influence on the interactions between biomolecules. Our work aimed to investigate the effects of THz irradiation ...on cell membrane, especially cell membrane permeability. We found that 0.1 THz irradiation promoted the endocytosis of FM4-64-labeled cells and the inhibition of dynamin attenuated but did not fully abolish the THz promoted endocytosis. Moreover, 0.1 THz irradiation also promoted the transmembrane of the rhodamine, as well as the chemical compounds GDC0941 and H89, evidenced by the confocal microscope observation and the western blotting analysis, respectively. These findings demonstrated 0.1 THz irradiation facilitated the transmembrane transport of small molecules by promoting both the cellular endocytosis and the diffusion process. Our study provided direct evidence that THz could affect the cell membrane permeability, broadened the THz affected cellular physiological processes, and implied its potential application in regulating the cell membrane functions.
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•THz irradiation enhances endocytic activity of neuronal cells•THz irradiation increases the permeation of rhodamine derivatives into cells•THz irradiation promotes the cellular uptake of small drugs GDC0941 and H89
Transport phenomena; Radiation; Membranes
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Previously, we have identified single nucleotide polymorphisms (SNPs) rs7958904 and rs4759314 in long non-coding RNA HOX transcript antisense RNA (HOTAIR) were significantly associated with risk of ...colorectal and gastric cancer, respectively. Here, we aimed to investigate the association between HOTAIR SNPs and cervical cancer (CC) susceptibility. A total of 1209 cases and 1348 controls were enrolled for association study and genotyped with TaqMan allelic discrimination method. The Cancer Genome Atlas (TCGA) database was utilized for in vivo analysis of allele-specific HOTAIR expression. MTT assay was employed for evaluation of allele-specific cell proliferation. The rs7958904 CC genotype was related to an increased risk of cervical cancer compared with the GG/GC genotypes (OR = 1.57, 95% CI = 1.10-2.25). TCGA database showed the CC tissues with rs7958904 CC genotype had higher HOTAIR expression than those with GG genotype (P = 0.046). MTT assay demonstrated a growth-promoting role of rs7958904 C allele on CC cells. Further functional studies on the effect of rs7958904 on biological behavior of CC cells are needed to confirm and extend our findings. In conclusion, HOTAIR rs7958904 might influence CC susceptibility through modulation of CC cell proliferation, and could serve as a diagnostic biomarker.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
MET has been considered as a promising drug target for the treatment of MET-dependent diseases, particularly non-small cell lung cancer (NSCLC). Small molecule MET inhibitors with mainly three types ...of binding modes (Ia/Ib, II, and III) have been developed. In this Review, we provide an overview of the structural features, activation mechanism, and dysregulation pathway of MET and summarize progress on the development and discovery strategies utilized for MET inhibitors as well as mechanisms of acquired resistance to current approved inhibitors. The insights will accelerate discovery of new generation MET inhibitors to overcome clinical acquired resistance.
Colony stimulating factor 1 receptor kinase (CSF1R) is a well validated molecular target for anticancer drug discovery. Herein, we report the design, synthesis, and structure–activity relationship ...study of 2-oxo-3,4-dihydropyrimido4,5-dpyrimidines as new orally bioavailable CSF1R inhibitors. One of the most promising compounds, 3bw, potently inhibits CSF1R kinase with an IC50 value of 3.0 nM, while it is less potent against structurally related epidermal growth factor receptor (EGFR) and other kinases. The kinase inhibition of 3bw was further validated by Western blotting analysis in RAW264.7 macrophages. The molecule also potently blocks macrophage infiltration, abrogates the protumorigenic influences of macrophages, and exhibits reasonable pharmacokinetic profile. Compound 3bw may serve as a new valuable lead compound for future anticancer drug discovery.
Schwann cells play critical roles in peripheral neuropathies; however, the regulatory mechanisms of their homeostasis remain largely unknown. Here, we show that nucleoporin Seh1, a component of ...nuclear pore complex, is important for Schwann cell homeostasis. Expression of Seh1 decreases as mice age. Loss of Seh1 leads to activated immune responses and cell necroptosis. Mice with depletion of Seh1 in Schwann cell lineage develop progressive reduction of Schwann cells in sciatic nerves, predominantly non-myelinating Schwann cells, followed by neural fiber degeneration and malfunction of the sensory and motor system. Mechanistically, Seh1 safeguards genome stability by mediating the interaction between SETDB1 and KAP1. The disrupted interaction after ablation of Seh1 derepresses endogenous retroviruses, which triggers ZBP1-dependent necroptosis in Schwann cells. Collectively, our results demonstrate that Seh1 is required for Schwann cell homeostasis by maintaining genome integrity and suggest that decrease of nucleoporins may participate in the pathogenesis of periphery neuropathies.
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•Seh1 is essential for Schwann cell homeostasis and peripheral sensory function•Loss of Seh1 activates necroptosis in a ZBP1-dependent manner•Seh1 represses ERV expression by mediating the interaction between SETDB1 and KAP1•Reverse transcriptase inhibitor alleviates the abnormality in periphery nerves
Wu et al. demonstrate that nucleoporin Seh1 is essential for Schwann cell homeostasis and peripheral sensory function. They find that loss of Seh1 derepresses ERV production and activates necroptosis in Schwann cells, which can be rescued by reverse transcriptase inhibitors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Platensimycin, an active metabolite of Streptomyces platensis, was initially discovered by a combination of RNA interferin induced gene-silencing and library screening to microbial extracts. ...Platensimycin selectively inhibits beta - ketoacyl-acyl carrier protein (ACP) synthase II (FabF) that is recognized as an effective broad-spectrum antibiotic against drug-resistant microorganism strains. Its novel scaffold and extraordinary antibacterial activity have drawn great attentions in recent years. So far, a number of synthetic strategies have been explored for the total synthesis of platensimycin. Moreover, many analogues have been investigated in terms of structure-activity relationships (SAR). This review provides a detailed overview of updated studies on platensimycin, focusing on various total and formal synthetic strategies, development of analogues, and the structure-activity relationships.
A series of 2-acylated and 2-alkylated amino-5-(4-(benzyloxy)phenyl)thiophene-3-carboxylic acid derivatives were synthesized and evaluated for anti-tubercular activity. Among these compounds,
10d,
...15,
12h and
12k inhibited
Mycobacterium tuberculosis (Mtb) growth with MIC values between 1.9 and 7.7 μM and low toxicity against VERO cells. The four compounds were also tested against multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) clinical strains, which were found to show moderate activity. In addition, molecular docking simulation was performed to position compounds
10d,
15,
12h and
12k into
mtFabH active site to predict the probable binding mode. These studies thus suggest that the designed 2-amino-5-phenylthiophene-3-carboxylic acid scaffold may serve as new promising template for further elaboration as anti-TB drugs.
A series of 2-acylated and 2-alkylated amino-5-(4-(benzyloxy)phenyl)thiophene-3-carboxylic acid derivatives (
10a-m,
15,
12a–k) were designed and synthesized for anti-tubercular activity.
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► Thiophene-3-carboxylic acid derivatives were designed for anti-tubercular activity. ► Compounds
10d,
15,
12h and
12k exhibited potent activity and low toxicity. ► The four compounds were also tested against MDR-TB and XDR-TB clinical strains. ► Docking was performed to predict binding mode between inhibitors and
mtFabH.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The estrogen-related receptors (ERRs), comprising ERRα, ERRβ and ERRγ, are the members of the nuclear receptor superfamily, which have been functionally implicated in estrogen signal pathway in ...various patterns. However, no natural ligand of ERRs has been identified to data, so identification of the synthetic modulators (inverse agonist and agonist) of ERRs would be highly effective in the treatment of estrogen-related pathologies, such as diabetes, breast cancer and osteoporosis. This review summarizes the structures and biological functions of ERR subtypes, and the progress in designing the small molecular modulators of ERRs as well as the detailed description of available co-crystal structures of the LBD of ERRs in three distinct states: unligand, inverse agonist bound, and agonist bound.
Many classic visual monocular SLAM (simultaneous localization and mapping) systems have been developed over the past decades, yet most of them fail when dynamic scenarios dominate. DM-SLAM is ...proposed for handling dynamic objects in environments based on ORB-SLAM2. This article mainly concentrates on two aspects. Firstly, we proposed a distribution and local-based RANSAC (Random Sample Consensus) algorithm (DLRSAC) to extract static features from the dynamic scene based on awareness of the nature difference between motion and static, which is integrated into initialization of DM-SLAM. Secondly, we designed a candidate map points selection mechanism based on neighborhood mutual exclusion to balance the accuracy of tracking camera pose and system robustness in motion scenes. Finally, we conducted experiments in the public dataset and compared DM-SLAM with ORB-SLAM2. The experiments corroborated the superiority of the DM-SLAM.
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