Search Results (49)

Osteoclastogenesis—the activation and differentiation of osteoclasts—is one of the pivotal processes of bone remodeling and is regulated by RANKL/RANK signaling, the decoy function of osteoprotegerin (OPG), and a cascade of pro- and anti-inflammatory cytokines. The disruption of this balance leads to pathological bone loss in diseases such as osteoporosis and rheumatoid arthritis. FFAR4 (Free Fatty Acid Receptor 4), a G protein-coupled receptor for long-chain omega-3 fatty acids, has been confirmed as a key mediator of metabolic and anti-inflammatory effects. This review focuses on how FFAR4 acts as the selective receptor for the omega-3 fatty acid docosahexaenoic acid (DHA). It activates two divergent signaling pathways. The Gαq-dependent cascade facilitates intracellular calcium mobilization and ERK1/2 activation. Meanwhile, β-arrestin-2 recruitment inhibits NF-κB. These collective actions reshape the cytokine environment. In macrophages, DHA–FFAR4 signaling lowers the levels of TNF-α, interleukin-6 (IL-6), and IL-1β while increasing IL-10 secretion. Consequently, the activation of NFATc1 and NF-κB p65 is profoundly suppressed under TNF-α or RANKL stimulation. Additionally, DHA modulates the RANKL/OPG axis in osteoblastic cells by suppressing RANKL expression, thereby reducing osteoclast differentiation in an inflammatory mouse model. Full article

In this paper, a gliding tail decoy for a UAV is proposed, which can be discarded as a decoy when the UAV encounters danger. Based on an aerodynamic model of the tail decoy, a nonlinear dynamics model of the tail decoy gliding in the air is generated, and a three-layer pyramid general design architecture of the tail decoy is established. In order to subsequently analyze the dynamic characteristics and gliding trajectory of the gliding tail decoy, a gliding trajectory simulation software is developed based on the dynamics model of the gliding tail. Selecting the pre-optimized tail shape as the research object, and analyzing the influence of deployment speed and deployment posture angle on the tail trajectory, it was found that a deployment speed of 60 m/s and a deployment posture angle of 8° are more conducive to the tail obtaining a larger gliding distance. In addition, the effectiveness of the optimization method for the gliding tail in this article was verified. It was found that after optimizing the shape of the gliding tail, the lift coefficient increased in the range of 0°~14°, and the gliding distance increased by 4.2%. Full article

Current distance limitations of quantum key distribution (QKD) over fibre optic networks suggest that satellite (free-space optical) QKD networks will be required to enable global quantum communications. However, the operational availability of these systems is limited by background noise and strong attenuation caused by turbulence and adverse weather conditions. Using the decoy-state BB84 QKD protocol, we evaluate the secret key rate for a range of wavelengths, receiver sizes and initial beam waists through a variety of atmospheric conditions. We combine filtering techniques, adaptive optics, and wavelength selection to optimize the performance of satellite QKD. This study is simulation-based. Full article

This review presents current knowledge related to the voltage-dependent anion channel-1 (VDAC1) as a multi-functional mitochondrial protein that acts in regulating both cell life and death. The location of VDAC1 at the outer mitochondrial membrane (OMM) allows control of metabolic cross-talk between the mitochondria and the rest of the cell, and also enables its interaction with proteins that are involved in metabolic, cell death, and survival pathways. VDAC1′s interactions with over 150 proteins can mediate and regulate the integration of mitochondrial functions with cellular activities. To target these protein–protein interactions, VDAC1-derived peptides have been developed. This review focuses specifically on cell-penetrating VDAC1-based peptides that were developed and used as a “decoy” to compete with VDAC1 for its VDAC1-interacting proteins. These peptides interfere with VDAC1 interactions, for example, with metabolism-associated proteins such as hexokinase (HK), or with anti-apoptotic proteins such as Bcl-2 and Bcl-xL. These and other VDAC1-interacting proteins are highly expressed in many cancers. The VDAC1-based peptides in cells in culture selectively affect cancerous, but not non-cancerous cells, inducing cell death in a variety of cancers, regardless of the cancer origin or genetics. They inhibit cell energy production, eliminate cancer stem cells, and act very rapidly and at low micro-molar concentrations. The activity of these peptides has been validated in several mouse cancer models of glioblastoma, lung, and breast cancers. Their anti-cancer activity involves a multi-pronged attack targeting the hallmarks of cancer. They were also found to be effective in treating non-alcoholic fatty liver disease and diabetes mellitus. Thus, VDAC1-based peptides, by targeting VDAC1-interacting proteins, offer an affordable and innovative new conceptual therapeutic paradigm that can potentially overcome heterogeneity, chemoresistance, and invasive metastatic formation. Full article

Targeting epidermal growth factor receptor (EGFR) mutants is a promising strategy for treating non-small cell lung cancer (NSCLC). This study focused on the computational identification and characterization of potential EGFR mutant-selective inhibitors using pharmacophore design and validation by deep learning, virtual screening, ADMET (Absorption, distribution, metabolism, excretion and toxicity), and molecular docking-dynamics simulations. A pharmacophore model was generated using Pharmit based on the potent inhibitor JBJ-125, which targets the mutant EGFR (PDB 5D41) and is used for the virtual screening of the Zinc database. In total, 16 hits were retrieved from 13,127,550 molecules and 122,276,899 conformers. The pharmacophore model was validated via DeepCoy, generating 100 inactive decoy structures for each active molecule and ADMET tests were conducted using SWISS ADME and PROTOX 3.0. Filtered compounds underwent molecular docking studies using Glide, revealing promising interactions with the EGFR allosteric site along with better docking scores. Molecular dynamics (MD) simulations confirmed the stability of the docked conformations. These results bring out five novel compounds that can be evaluated as single agents or in combination with existing therapies, holding promise for treating the EGFR-mutant NSCLC. Full article

The rapid advancement of information technology (IT) has given rise to a new era of efficient and fast communication and transactions. However, the increasing adoption of and reliance on IT has led to the exposure of personal and sensitive information online. Safeguarding this information against unauthorized access remains a persistent challenge, necessitating the implementation of improved computer security measures. The core objective of computer security is to ensure the confidentiality, availability, and integrity of data and services. Among the mechanisms developed to counter security threats, authentication stands out as a pivotal defense strategy. Graphical passwords have emerged as a popular authentication approach, yet they face vulnerability to shoulder-surfing attacks, wherein an attacker can clandestinely observe a victim’s actions. Shoulder-surfing attacks present a significant security challenge within the realm of graphical password authentication. These attacks occur when an unauthorized individual covertly observes the authentication process of a legitimate user by shoulder surfing the user or capturing the interaction through a video recording. In response to this challenge, various methods have been proposed to thwart shoulder-surfing attacks, each with distinct advantages and limitations. This study thus centers on reviewing the resilience of existing recognition-based graphical password techniques against shoulder-surfing attacks by conducting a comprehensive examination and evaluation of their benefits, strengths, and weaknesses. The evaluation process entailed accessing pertinent academic resources through renowned search engines, including Web of Science, Science Direct, IEEE Xplore, ProQuest, Scopus, Springer, Wiley Online Library, and EBSCO. The selection criteria were carefully designed to prioritize studies that focused on recognition-based graphical password methods. Through this rigorous approach, 28 studies were identified and subjected to a thorough review. The results show that fourteen of them adopted registered objects as pass-objects, bolstering security through object recognition. Additionally, two methods employed decoy objects as pass-objects, enhancing obfuscation. Notably, one technique harnessed both registered and decoy objects, amplifying the security paradigm. The results also showed that recognition-based graphical password techniques varied in their resistance to different types of shoulder-surfing attacks. Some methods were effective in preventing direct observation attacks, while others were vulnerable to video-recorded and multiple-observation attacks. This vulnerability emerged due to attackers potentially extracting key information by analyzing user interaction patterns in each challenge set. Notably, one method stood out as an exception, demonstrating resilience against all three types of shoulder-surfing attacks. In conclusion, this study contributes to a comprehensive understanding of the efficacy of recognition-based graphical password methods in countering shoulder-surfing attacks by analyzing the diverse strategies employed by these methods and revealing their strengths and weaknesses. Full article

PIM-1 kinase is a serine-threonine phosphorylating enzyme with implications in multiple types of malignancies, including prostate, breast, and blood cancers. Developing better search methodologies for PIM-1 kinase inhibitors may be a good strategy to speed up the discovery of an oncological drug approved for targeting this specific kinase. Computer-aided screening methods are promising approaches for the discovery of novel therapeutics, although certain limitations should be addressed. A frequent omission that is encountered in molecular docking is the lack of proper implementation of scoring functions and algorithms on the post-docking results, which usually alters the outcome of the virtual screening. The current study suggests a method for post-processing docking results, expressed either as binding affinity or score, that considers different binding modes of known inhibitors to the studied targets while making use of in vitro data, where available. The docking protocol successfully discriminated between known PIM-1 kinase inhibitors and decoy molecules, although binding energies alone were not sufficient to ensure a successful prediction. Logistic regression models were trained to predict the probability of PIM-1 kinase inhibitory activity based on binding energies and the presence of interactions with identified key amino acid residues. The selected model showed 80.9% true positive and 81.4% true negative rates. The discussed approach can be further applied in large-scale molecular docking campaigns to increase hit discovery success rates. Full article

Osteoarthritis (OA) is the most prevalent joint disease, and it is characterized by cartilage degeneration, synovitis, and bone sclerosis, resulting in swelling, stiffness, and joint pain. TAM receptors (Tyro3, Axl, and Mer) play an important role in regulating immune responses, clearing apoptotic cells, and promoting tissue repair. Here, we investigated the anti-inflammatory effects of a TAM receptor ligand, i.e., growth arrest-specific gene 6 (Gas6), in synovial fibroblasts from OA patients. TAM receptor expression was determined in synovial tissue. Soluble Axl (sAxl), a decoy receptor for the ligand Gas6, showed concentrations 4.6 times higher than Gas6 in synovial fluid of OA patients. In OA fibroblast-like synoviocytes (OAFLS) exposed to inflammatory stimuli, the levels of sAxl in the supernatants were increased, while the expression of Gas6 was downregulated. In OAFLS under TLR4 stimulation by LPS (Escherichia coli lipopolysaccharide), the addition of exogenous Gas6 by Gas6-conditioned medium (Gas6-CM) reduced pro-inflammatory markers including IL-6, TNF-α, IL-1β, CCL2, and CXCL8. Moreover, Gas6-CM downregulated IL-6, CCL2, and IL-1β in LPS-stimulated OA synovial explants. Pharmacological inhibition of TAM receptors by a pan inhibitor (RU301) or by a selective Axl inhibitor (RU428) similarly abrogated Gas6-CM anti-inflammatory effects. Mechanistically, Gas6 effects were dependent on Axl activation, determined by Axl, STAT1, and STAT3 phosphorylation, and by the downstream induction of the suppressors of the cytokine signaling family (SOCS1 and SOCS3). Taken together, our results showed that Gas6 treatment dampens inflammatory markers of OAFLS and synovial explants derived from OA patients associated with SOCS1/3 production. Full article

Glycogen synthase kinase-3 (GSK-3) isoforms α and β have diverse roles within cell biology, and have been linked with multiple diseases that include prominent CNS conditions such as Alzheimer’s disease and several psychiatric disorders. In this study, motivated by computation, we aimed to identify novel ATP-binding site inhibitors of GSK-3 with CNS-active potential. A ligand screening (docking) protocol against GSK-3β was first optimized, employing an active/decoy benchmarking set, with the final protocol selected based on statistical performance analysis. The optimized protocol involved pre-filtering of ligands using a three-point 3D-pharmacophore, followed by Glide-SP docking applying hinge region hydrogen bonding constraints. Using this approach, the Biogenic subset of the ZINC15 compound database was screened, focused on compounds with potential for CNS-activity. Twelve compounds (generation I) were selected for experimental validation using in vitro GSK-3β binding assays. Two hit compounds, 1 and 2, with 6-amino-7H-benzo[e]perimidin-7-one and 1-(phenylamino)-3H-naphtho[1,2,3-de]quinoline-2,7-dione type scaffolds were identified with IC₅₀ values of 1.63 µM and 20.55 µM, respectively. Ten analogues of 2 (generation II) were selected for structure activity relationship (SAR) analysis and revealed four low micromolar inhibitors (<10 µM), with 19 (IC₅₀ = 4.1 µM)~five times more potent than initial hit compound 2. Selectivity screening of low micromolar inhibitors 14 and 19 (comparing aryl- and alkyl-substituents) against 10 homologous kinases revealed unique selectivity profiles, with both compounds more potent against the GSK-3α isoform (IC₅₀s~2 µM) and, additionally, inhibitors of PKBβ (IC₅₀s < 25 µM). Compound 14 also inhibited ERK2 and 19, PKCγ, but generally good selectivity for GSK-3 isoforms over the other kinases was observed. The compounds had excellent predicted oral bioavailability and CNS-activity profiles, presenting promising candidates for future testing in cellular models of disease. Full article

Fascin is an actin-bundling protein overexpressed in various invasive metastatic carcinomas through promoting cell migration and invasion. Therefore, blocking Fascin binding sites is considered a vital target for antimetastatic drugs. This inspired us to find new Fascin binding site blockers. First, we built an active compound set by collecting reported small molecules binding to Fascin’s binding site 2. Consequently, a high-quality decoys set was generated employing DEKOIS 2.0 protocol to be applied in conducting the benchmarking analysis against the selected Fascin structures. Four docking programs, MOE, AutoDock Vina, VinaXB, and PLANTS were evaluated in the benchmarking study. All tools indicated better-than-random performance reflected by their pROC-AUC values against the Fascin crystal structure (PDB: ID 6I18). Interestingly, PLANTS exhibited the best screening performance and recognized potent actives at early enrichment. Accordingly, PLANTS was utilized in the prospective virtual screening effort for repurposing FDA-approved drugs (DrugBank database) and natural products (NANPDB). Further assessment via molecular dynamics simulations for 100 ns endorsed Remdesivir (DrugBank) and NANPDB3 (NANPDB) as potential binders to Fascin binding site 2. In conclusion, this study delivers a model for implementing a customized DEKOIS 2.0 benchmark set to enhance the VS success rate against new potential targets for cancer therapies. Full article

Cytochrome P450s are heme-containing enzymes capable of the oxidative transformation of a wide range of organic substrates. A protein scaffold that coordinates the heme iron, and the catalytic pocket residues, together, determine the reaction selectivity and regio- and stereo-selectivity of the P450 enzymes. Different substrates also affect the properties of P450s by binding to its catalytic pocket. Modulating the redox potential of the heme by substituting iron-coordinating residues changes the chemical reaction, the type of cofactor requirement, and the stereoselectivity of P450s. Around hundreds of P450s are experimentally characterized, therefore, a mechanistic understanding of the factors affecting their catalysis is increasingly vital in the age of synthetic biology and biotechnology. Engineering P450s can enable them to catalyze a variety of chemical reactions viz. oxygenation, peroxygenation, cyclopropanation, epoxidation, nitration, etc., to synthesize high-value chiral organic molecules with exceptionally high stereo- and regioselectivity and catalytic efficiency. This review will focus on recent studies of the mechanistic understandings of the modulation of heme redox potential in the engineered P450 variants, and the effect of small decoy molecules, dual function small molecules, and substrate mimetics on the type of chemical reaction and the catalytic cycle of the P450 enzymes. Full article

The influence of environmental factors on prey discrimination of bait-attracted white sharks was studied over a six-year period (2008–2013) at Dyer Island Nature Reserve (Gansbaai, South Africa). Across 240 bait-attracted feeding events observed in this period, both immature and mature white sharks were attracted by the seal-shaped decoy rather than the tuna bait, except for the years 2008 and 2011. Tide ranges, underwater visibility, water temperature, and sea conditions were, in decreasing order, the factors which drove white sharks to select the seal-shaped decoy. High tide lowered the minimum depth from which sharks could approach seals close to the shore, while extended visibility helped the sharks in making predatory choices towards the more energy-rich prey source, the odorless seal-shaped decoy. On the contrary, warmer water is associated with an increase in phytoplankton that reduces underwater visibility and increases the diversity of teleosts including tuna—a known prey of white sharks—driving the sharks to favor the tuna bait. Overall, sea conditions were almost always slightly rough, ensuring a good average underwater visibility. Recommendations for future research work at this site are presented. Full article

The decoy state quantum key distribution (QKD) protocol is proven to be an effective strategy against the photon number splitting attack. It was shown that the 1-decoy state protocol, easier to implement in the practical QKD system, outperforms the 2-decoy state protocol for block sizes of up to ${10}^8$ bits. How intensity fluctuations influence the performance of the 1-decoy state protocol with finite resources remains a pending issue. In this paper, we present a finite-key analysis of the 1-decoy state protocol with intensity fluctuations and obtain the secret key rate formula about intensity fluctuations. Our numerical simulation results show that the stronger the intensity fluctuations, the lower the secret key rate for a small data block size of a few bits. Our research can provide theoretical implications for the selection of data size in the QKD system with intensity fluctuations. Full article

Systemic sclerosis (SSc) is an autoimmune disease with completely undefined etiology and treatment difficulties. The expression of both protein coding and non-coding RNAs is dysregulated during disease development. We aimed to examine a possible regulatory axis implemented in the control of chitinase-3 like protein 1 (CHI3L1) or YKL-40, an inflammation-associated glycoprotein, shown to be elevated in SSc. A panel of seven miRNAs and three lncRNAs potentially involved in the control of CHI3L1 were selected on the basis of in silico analysis. TagMan assay was used to evaluate the expression levels of miRNAs and RT-qPCR for lncRNAs in white blood cells (WBCs) and plasma from SSc patients and healthy controls. Among the eight screened miRNAs, miR-30e-5p (p = 0.04) and miR-30a-5p (p = 0.01) were significantly downregulated in WBCs and plasma of SSc patients, respectively. On the contrary, the expression of the metastasis associated lung adenocarcinoma transcript 1 (MALAT1) (p = 0.044) and the Nuclear enriched abundant transcript 1 (NEAT1) (p = 0.008) in WBCs was upregulated compared to the controls. Increased levels of MALAT1 and NEAT1 could be associated with the downregulation of miR-30e-5p and miR-30a-5p expression in WBCs and plasma. We present novel data on the involvement of a possible regulatory axis lncRNAs/miR-30e/CHI3L1 in SSc and hypothesize that MALAT1 and NEAT1 could act as miR-30e-5p and miR-30a-5p decoys. This may be a reason for the increased serum levels of CHI3L1 in SSc patients. Full article

DNA is a molecular target for the treatment of several diseases, including cancer, but there are few docking methodologies exploring the interactions between nucleic acids with DNA intercalating agents. Different docking methodologies, such as AutoDock Vina, DOCK 6, and Consensus, implemented into Molecular Architect (MolAr), were evaluated for their ability to analyze those interactions, considering visual inspection, redocking, and ROC curve. Ligands were refined by Parametric Method 7 (PM7), and ligands and decoys were docked into the minor DNA groove (PDB code: 1VZK). As a result, the area under the ROC curve (AUC-ROC) was 0.98, 0.88, and 0.99 for AutoDock Vina, DOCK 6, and Consensus methodologies, respectively. In addition, we proposed a machine learning model to determine the experimental ∆T_m value, which found a 0.84 R² score. Finally, the selected ligands mono imidazole lexitropsin (42), netropsin (45), and N,N′-(1H-pyrrole-2,5-diyldi-4,1-phenylene)dibenzenecarboximidamide (51) were submitted to Molecular Dynamic Simulations (MD) through NAMD software to evaluate their equilibrium binding pose into the groove. In conclusion, the use of MolAr improves the docking results obtained with other methodologies, is a suitable methodology to use in the DNA system and was proven to be a valuable tool to estimate the ∆T_m experimental values of DNA intercalating agents. Full article