Virtual screening–based discovery of AI-2 quorum sensing inhibitors that interact with an allosteric hydrophobic site of LsrK and their functional evaluation

Introduction: Quorum sensing (QS) is a bacterial intracellular and intercellular communication system that regulates virulence factor production, biofilm formation, and antibiotic sensitivity. Quorum-sensing inhibitors (QSIs) are a novel class of antibiotics that can effectively combat antibiotic resistance. Autoinducer-2 (AI-2) is a universal signaling molecule that mediates inter- and intraspecies QS systems among different bacteria. Furthermore, LsrK plays an important role in regulating the activity and stability of the intracellular AI-2 signaling pathway. Thus, LsrK is considered an important target for the development of QSIs.Methods: We designed a workflow integrating molecular dynamic (MD) simulations, virtual screening, LsrK inhibition assays, cell-based AI-2-mediated QS interference assays, and surface plasmon resonance (SPR)-based protein affinity assays to screen for potential LsrK kinase inhibitors.Results: MD simulation results of the LsrK/ATP complex revealed hydrogen bonds and salt bridge formation among four key residues, namely, Lys 431, Tyr 341, Arg 319, and Arg 322, which are critical for the binding of ATP to LsrK. Furthermore, MD simulation results indicated that the ATP-binding site has an allosteric pocket that can become larger and be occupied by small molecule compounds. Based on these MD simulation results, a constraint of forming at least one hydrogen bond with Arg 319, Arg 322, Lys 431, or Tyr 341 residues was introduced when performing virtual screening using Glide’s virtual screening workflow (VSW). In the meantime, compounds with hydrophobic group likely to interact with the allosteric hydrophobic pocket are preferred when performing visual inspection. Seventy-four compounds were selected for the wet laboratory assays based on virtual screening and the absorption, distribution, metabolism, and excretion (ADME) properties of these compounds. LsrK inhibition assays revealed 12 compounds inhibiting LsrK by more than 60% at a 200 μM concentration; four of these (Y205-6768, D135-0149, 3284–1358, and N025-0038) had IC50 values below 50 μM and were confirmed as ATP-competitive inhibitors. Six of these 12 LsrK inhibitors exhibited high AI-2 QS inhibition, of which, Y205-6768 had the highest activity with IC50 = 11.28 ± 0.70 μM. The SPR assay verified that compounds Y205-6768 and N025-0038 specifically bound to LsrK. MD simulation analysis of the docking complexes of the four active compounds with LsrK further confirmed the importance of forming hydrogen bonds and salt bridges with key basic amino acid residues including Lys 431, Tyr 341, Arg 319, and Arg 322 and filling the allosteric hydrophobic pocket next to the purine-binding site of LsrK.Discussion: Our study clarified for the first time that there is an allosteric site near the ATP-binding site of Lsrk and that it enriches the structure–activity relationship information of Lsrk inhibitors. The four identified compounds showed novel structures, low molecular weights, high activities, and novel LsrK binding modes, rendering them suitable for further optimization for effective AI-2 QSIs. Our work provides a valuable reference for the discovery of QSIs that do not inhibit bacterial growth, thereby avoiding the emergence of drug resistance

Bose condensation of upper-branch exciton-polaritons in a transferrable microcavity

Exciton-polaritons are composite bosonic quasiparticles arising from the strong coupling of excitonic transitions and optical modes. Exciton-polaritons have triggered wide exploration in the past decades not only due to their rich quantum phenomena such as superfluidity, superconductivity and quantized vortices but also due to their potential applications for unconventional coherent light sources and all-optical control elements. Here, we report the observation of Bose-Einstein condensation of the upper polariton branch in a transferrable WS$_2$ monolayer microcavity. Near the condensation threshold, we observe a nonlinear increase in upper polariton intensity. This sharp increase in intensity is accompanied by a decrease of the linewidth and an increase of the upper polariton temporal coherence, all of which are hallmarks of Bose-Einstein condensation. By simulating the quantum Boltzmann equation, we show that the upper polariton condensation only occurs for a particular range of particle density. We can attribute the creation of Bose condensation of the upper polariton to the following requirements: 1) the upper polariton is more excitonic than the lower one; 2) there is relatively more pumping in the upper branch; and 3) the conversion time from the upper to the lower polariton branch is long compared to the lifetime of the upper polaritons

Increased Mortality Associated with Well-Water Arsenic Exposure in Inner Mongolia, China

We conducted a retrospective mortality study in an Inner Mongolian village exposed to well water contaminated by arsenic since the 1980s. Deaths occurring between January 1, 1997 and December 1, 2004 were classified according to underlying cause and water samples from household wells were tested for total arsenic. Heart disease mortality was associated with arsenic exposure, and the association strengthened with time exposed to the water source. Cancer mortality and all-cause mortality were associated with well-water arsenic exposure among those exposed 10–20 years. This is the first study to document increased arsenic-associated mortality in the Bayingnormen region of Inner Mongolia

Identification of DYNLT1 associated with proliferation, relapse, and metastasis in breast cancer

BackgroundBreast cancer (BC) is the most common malignant disease worldwide. Although the survival rate is improved in recent years, the prognosis is still bleak once recurrence and metastasis occur. It is vital to investigate more efficient biomarkers for predicting the metastasis and relapse of BC. DYNLT1 has been reported that participating in the progression of multiple cancers. However, there is still a lack of study about the correlation between DYNLT1 and BC.MethodsIn this study, we evaluated and validated the expression pattern and prognostic implication of DYNLT1 in BC with multiple public cohorts and BC tumor microarrays (TMAs) of paraffin-embedded tissues collected from the Affiliated Hospital of Jining Medical University. The response biomarkers for immune therapy, such as tumor mutational burden (TMB), between different DYNLT1 expression level BC samples were investigated using data from the TCGA-BRCA cohort utilizing public online tools. In addition, colony formation and transwell assay were conducted to verify the effects of DYNLT1 in BC cell line proliferation and invasion.ResultsThe results demonstrated that DYNLT1 overexpressed in BC and predicted poor relapse-free survival in our own BC TMA cohort. In addition, DYNLT1 induced BC development by promoting MDA-MB-231 cell proliferation migration, and metastasis.ConclusionAltogether, our findings proposed that DYNLT1 could be a diagnostic and prognostic indicator in BC

Well Water Arsenic Exposure, Arsenic Induced Skin-Lesions and Self-Reported Morbidity in Inner Mongolia

Residents of the Bayingnormen region of Inner Mongolia have been exposed to arsenic-contaminated well water for over 20 years, but relatively few studies have investigated health effects in this region. We surveyed one village to document exposure to arsenic and assess the prevalence of arsenic-associated skin lesions and self-reported morbidity. Five-percent (632) of the 12,334 residents surveyed had skin lesions characteristics of arsenic exposure. Skin lesions were strongly associated with well water arsenic and there was an elevated prevalence among residents with water arsenic exposures as low as 5 μg/L-10 μg/L. The presence of skin lesions was also associated with self-reported cardiovascular disease

Relaxation Studies on Power Equipment

This paper describes a method of studying and modeling the dielectric relaxation for stationary power apparatus in an interconnected network to get the necessary aging indicators. The polarization phenomenon was studied using Recovery Voltage (RVM) and Polarization Current (PCM) Measurements on individual power apparatus and on network with other connected apparatus. Because of dielectric absorption in composite insulation, all RVM responses showed a single peak response and the response was linear with charging voltage. PCM decreased monotonically with a sudden drop in the initial period and after 100 s, it decreased very slowly and the response was linear with charging voltage. The responses were analyzed by modeling the dielectric function as an exponential function and as two-time dependent fractional power law function to determine suitable aging parameters. Exponential function model was found to fit both responses to get an equivalent electrical circuit of the system. Interrelation of RVM and PCM was established in most of the cases. Predicted dielectric response function for generator was more linear with time than for transformers and cable. In the frequency plane, it was found to have distinct regions of relaxation spectrum. Studies indicated that the parameters of fit for RVM response with each charging period differed from all RVM responses

Relaxation and frequency response analysis studies on power equipment

The main objective of this research project is to study the relaxation processes in various power apparatus of two power-generating plants with Recovery Voltage Measurement (RVM) and Polarization Current Measurement (PCM) techniques and to develop an automated technqiue to identify winding faults and severity of a transformer using Frequency Response Analysis (FRA) technqiue.Master of Engineerin

Advancements of Artificial Intelligence Techniques in the Realm About Library and Information Subject—A Case Survey of Latent Dirichlet Allocation Method

To investigate the advancements of artificial intelligence techniques in the realm of library and information subject, we have chosen the Latent Dirichlet Allocation method as a case study to explore its current study status and implementations. Traditional theme mining analyses utilize methods such as word frequency statistics, co-occurrence analysis, community detection, and citation analysis to capture external quantitative features of words or documents. In contrast, the Latent Dirichlet Allocation theme modelling method employs a three-layer Bayesian structure of document-topic-word to describe the themes of documents and the semantic relationships among words, enabling a better exploration of latent semantic information in text. This method plays a pivotal role in fine-grained knowledge extraction and analysis. We systematically review more than a decade of relevant literature in the realm about library and information subject. Through content analysis, we construct an analytical architecture for the implementation of the Latent Dirichlet Allocation method. This architecture, viewed from the perspective of the implementation process of Latent Dirichlet Allocation, comprehensively summarizes the core stages and technical challenges, including text pre-processing, model construction (i.e., theme model selection and optimal theme number determination), and model solving. Additionally, we provide a comprehensive overview of the current study status of the Latent Dirichlet Allocation method across various implementation domains, such as theme exploration, knowledge organization, academic evaluation, sentiment analysis, and recommendation study. Our findings indicate that the Latent Dirichlet Allocation method has formed a mature analytical process in the realm of library and information subject, with ongoing growth in study interest

Distribution and Environmental Impact Factors of Phytoplankton in the Bay of Bengal during Autumn

In order to better understand the effects of environmental factors and water mixing on the phytoplankton community structure in the Bay of Bengal, a field investigation was conducted from October to December 2016. A total of 276 species from 68 genera were identified, including Bacillariophyta (81 species), Miozoa (188 species), Cyanobacteria (four species), and Ochrophyta (three species). The abundance and distribution of dominant cyanobacteria gradually decreased along the latitude. This is evidenced in the vertical direction, which shows that cyanobacteria were affected by changes in environmental factors caused by the vertical mixing of seawater. The relationship between stratified N:P and phytoplankton also revealed that the changes in the vertical direction of the water deeply affected the phytoplankton community structure in the Bay of Bengal. The regions with strong vertical stratification were more favorable for the growth of cyanobacteria, while the regions with weak vertical stratification were more favorable for the growth of diatoms and dinoflagellates. According to the canonical correspondence analysis, nitrogen, silicates, phosphates, vertical stratification, and temperature were key control factors for phytoplankton communities. However, changes in these chemical parameters in the study area were also caused by the seawater cycle process