Targeted blocking of EGFR and GLUT1 by compound H reveals a new strategy for treatment of triple-negative breast cancer and nasopharyngeal carcinoma.

BACKGROUND: Cytoplasmic epidermal growth factor receptor (EGFR) is overexpressed in both nasopharyngeal carcinoma (NPC) and triple-negative breast cancer (TNBC), while clinical outcome and prognosis vary greatly among patients treated with gefitinib, and all patients eventually develop resistance to this agent. Therefore, we propose a new concept for synthesizing multitarget compounds and reveal new therapeutic strategies for NPC and TNBC expressing EGFR. METHODS: Compound H was synthesized in our previous study. Molecular docking, and cell thermal shift assays (CETSAs) and drug affinity responsive target stability(DARTS) were used to confirm the binding of compound H to EGFR and GLUT1. Methylthiazolyldiphenyl-tetrazolium bromide(MTT), annexin V-PE assays, mitochondrial membrane potential (MMP) assays, and animal models were used to evaluate the inhibitory effect of compound H on TNBC cell lines. Energy metabolism tests, Western blotting, and immunofluorescence staining were performed to evaluate the synergistic effects on EGFR- and glucose transporter type 1(GLUT1)-mediated energy metabolism. RESULTS: Compound H can simultaneously act on the EGFR tyrosine kinase ATP-binding site and inhibit GLUT1-mediated energy metabolism, resulting in reductions in ATP, MMP, intra-cellular lactic acid, and EGFR nuclear transfer. The anti-tumor activity of compound H is significantly superior to the combination of GLUT1 inhibitor BAY876 and EGFR inhibitor gefitinib. Compound H has remarkable anti-proliferative effects on TNBC MDA-MB231 cells, and importantly, no obvious toxicity effects of compound H were found in vivo. CONCLUSIONS: Synergistic effects of inhibition of EGFR- and GLUT1-mediated energy metabolism by compound H may present a new strategy for the treatment of TNBC and NPC.

Unveiling antibiotic contamination in surface water: A study of the Huaihe River Basin's Huaibei Plain, a significant Chinese herbal medicine planting region.

The abuse of antibiotics has caused the accumulation of antibiotic residues in environmental media, threatening the ecosystem and human health. Many studies on the distribution of aqueous antibiotics have been reported. However, the pollution status of antibiotics in the environment in Chinese herbal medicine planting areas is rarely comprehensively clarified, resulting in the lack of updated pollution data and conducive suggestions for ecological cultivation and sustainable development of Chinese herbal medicine. Thus, we comprehensively investigated the distribution, profiles, sources, and risks of the antibiotics in the surface water of an important tributary of the Huaihe River Basin, located in Bozhou City, a significant Chinese herbal medicine planting region. Solid-phase extraction coupled with an ultra-performance liquid chromatography-tandem mass spectrometer (SPE-UPLC-MS) was utilized to detect the antibiotics in the water. 27 kinds of antibiotics were identified with total concentrations ranging from 75.01 to 1737.99 ng·L-1, with doxycycline (DC) and doxycycline hydrochloride (DCH) possessed the highest concentration. And DC, DCH, oxilinic acid (OA), sulfamethoxazole (SMZ), clarithromycin (CLA), and roxithromycinum (ROX) were the main antibiotics detected in this basin. Correlation analysis and principal component analysis (PCA) indicated that animal husbandry was the primary source of antibiotics. Furthermore, the ecological risk assessment revealed that certain antibiotics could seriously threaten the survival of aquatic organisms, implying that local Chinese herbal medicines might be at similar growth risk. The drinking risk assessment showed that antibiotics in the water posed low risks for human, and children faced a greater drinking risk than adults. The study can help to facilitate the management of aqueous antibiotic pollution for the ecological cultivation and safe production of Chinese herbal medicine.

Development of a distributed group control strategy for pumping well groups connected by multisource DC microgrids.

Due to the alternating loads on pumping units and the integration of new energy sources, multisource DC microgrid pumping unit well groups experience increased fluctuations in voltage and power as well as superimposed peak and valley values. This work presents a distributed control strategy for pumping unit well groups on a multisource DC microgrid based on the weighted moving average algorithm. A centralized control program is implanted in the RTU of the single-well controller of each pumping unit, and communication with each well is realized via SCADA and multicast communication, resulting in a distributed well group system. The real-time power values of the pumping well group are calculated by grouping the power values, and each group is weighted using the total power fluctuation threshold of the well group as the control target. Then, a weighted moving average algorithm is used to predict the next power value and form a table of predicted real-time power spectra. According to the power values in the community power spectrum table, the inverter frequency is proportionally adjusted downwards to reach the power peak before deceleration; after the power peak is crossed, the frequency is increased in the same way to reach the power valley before acceleration. Finally, the peak and valley power values of the bus system level off and further learn to reach the set impulse; ultimately, a stable impulse is formed. In laboratory testing and field application in the Shengli Oilfield XIN-11 block, the group control software module effectively suppressed the active power peak and valley values and voltage fluctuations of the bus system, the active power fluctuation rate range decreased by more than 70%, and the DC bus voltage fluctuation range decreased by more than 80%; moreover, the active power decreased by approximately 6% without additional hardware costs.

Development and validation of a novel lysosome-related LncRNA signature for predicting prognosis and the immune landscape features in colon cancer.

Lysosomes are essential components for managing tumor microenvironment and regulating tumor growth. Moreover, recent studies have also demonstrated that long non-coding RNAs could be used as a clinical biomarker for diagnosis and treatment of colorectal cancer. However, the influence of lysosome-related lncRNA (LRLs) on the progression of colon cancer is still unclear. This study aimed to identify a prognostic LRL signature in colon cancer and elucidated potential biological function. Herein, 10 differential expressed lysosome-related genes were obtained by the TCGA database and ultimately 4 prognostic LRLs for conducting a risk model were identified by the co-expression, univariate cox, least absolute shrinkage and selection operator analyses. Kaplan-Meier analysis, principal-component analysis, functional enrichment annotation, and nomogram were used to verify the risk model. Besides, the association between the prognostic model and immune infiltration, chemotherapeutic drugs sensitivity were also discussed in this study. This risk model based on the LRLs may be promising for potential clinical prognosis and immunotherapeutic responses related indicator in colon cancer patients.

Impact of time-lagging and time-preceding environmental variables on top layer soil moisture in semiarid grasslands.

Top soil moisture (SM) is an important medium connecting the exchange of matter and energy between the ground and the atmosphere. Previous studies of the relationship between SM and environmental factors, especially aerodynamics, have lacked analysis of the variability in the timing of effects. In this study, we analyzed how environmental factors affect SM, as well as soil moisture memory, by observing precipitation, radiation, and wind speed during the 2019 to 2021 growing seasons in grazing prohibited and grazed areas of a semiarid grassland. The results show that there is a clear threshold (7 mm) for the effect of precipitation on SM, that changes in SM across time scales were influenced by preceding precipitation and net radiation in addition to lagging vegetation greening characteristics (NDVI) and wind speed, and that the role of albedo was related to grazing management. The inhibitory effect of albedo on SM and the depletion of SM by NDVI were more pronounced in comparison to other meteorological factors. Wind speed, precipitation, and radiation directly or indirectly influenced SM duration, and these relationships varied with grazing management and annual variation. These results help to clarify the influence of environmental factors on SM, and provide insight for minimizing the degradation of grassland ecosystems in the process of climate change.

Improved in situ characterization of protein complex dynamics at scale with thermal proximity co-aggregation.

Cellular activities are carried out vastly by protein complexes but large repertoire of protein complexes remains functionally uncharacterized which necessitate new strategies to delineate their roles in various cellular processes and diseases. Thermal proximity co-aggregation (TPCA) is readily deployable to characterize protein complex dynamics in situ and at scale. We develop a version termed Slim-TPCA that uses fewer temperatures increasing throughputs by over 3X, with new scoring metrics and statistical evaluation that result in minimal compromise in coverage and detect more relevant complexes. Less samples are needed, batch effects are minimized while statistical evaluation cost is reduced by two orders of magnitude. We applied Slim-TPCA to profile K562 cells under different duration of glucose deprivation. More protein complexes are found dissociated, in accordance with the expected downregulation of most cellular activities, that include 55S ribosome and respiratory complexes in mitochondria revealing the utility of TPCA to study protein complexes in organelles. Protein complexes in protein transport and degradation are found increasingly assembled unveiling their involvement in metabolic reprogramming during glucose deprivation. In summary, Slim-TPCA is an efficient strategy for characterization of protein complexes at scale across cellular conditions, and is available as Python package at https://pypi.org/project/Slim-TPCA/ .

An Analytical Method for Mechanical Analysis of Offshore Pipelines during Lifting Operation.

The lifting operation of offshore pipelines is an important step in ocean pipeline engineering. An effective analytical method is developed for investigating the mechanical properties of the pipeline based on mechanical, physical, and geometric relationships. By using the shooting and the secant methods to transform the boundary value problem into an initial value one and then solving them with the Runge-Kutta method, the deformation and mechanical properties of the pipeline are calculated. Furthermore, based on the Det Norske Veritas (DNV) offshore standard, the mechanical properties of the pipeline are checked. The finite element method (FEM) by Orcaflex is employed to verify the accuracy of the analytical model. The effects of some factors such as the current velocity and lifting point position on the mechanical properties of the pipeline are analyzed based on the analytical model. The results indicate that the change in current velocity during the lifting process has a minimal effect on the pipeline, but the change in lifting point position significantly affects the deformation and mechanical properties of the pipeline.

Additive-optimized micro-structure in cellulose acetate butyrate-based reverse osmosis membrane for desalination.

Progress toward the high water flux of cellulose acetate butyrate (CAB)-based reverse osmosis (RO) membrane is a bottleneck for desalination and mitigation of fresh water shortage. Here, we develop an "optimization of formulation-induced structure" strategy using acetone (solvent), triethyl phosphate (pore-inducing agent), glycerin and n-propanol (boosters), which achieves a state-of-the-art salt rejection of 97.1% and permeate flux of 8.73 L m-2·h-1, ranking top among CAB-based RO membrane. Compared with reported literatures, it represents high separation performance for different concentrations (20-100 mg L-1) of Rhodamine B and Congo red, different ion types (NaCl and MgCl2), different time (600 min), and resistance to feed pressure changes. The key is the appropriate viscosity of the casting solution (995.52 mPa s), the synergy between the components and additives, contributing to the formation of "jellyfish"-like microscopic pore structure with the lowest surface roughness (Ra = 16.3) and good hydrophilicity. The proposed correlation mechanism between additive-optimized micro-structure and desalination provides a promising prospect for CAB-based RO membrane.

A Finite/Spectral Element Hybrid Method for Modeling and Band-Gap Characterization of Metamaterial Sandwich Plates.

In this study, elastic metamaterial sandwich plates with axially deformed Timoshenko beam cores, considering both the out-of-plane and in-plane deformations of the face plates, are designed and the vibration band-gap properties are explored. The beam cores act as local resonators that can bear axial force, bending moment and shearing force. The finite element method (FEM) and the spectral element method (SEM) are combined to create the finite/spectral element hybrid method (FE-SEHM) for establishing the dynamic model and calculating the frequency response functions (FRFs) of the elastic metamaterial sandwich plate with axially deformed beam cores. It is observed that the metamaterial sandwich plate possesses both the axial and transverse vibration band-gaps of the beams, and the two kinds of band-gaps are independent. Compared with the metamaterial sandwich plates with rod cores, those with axially deformed beam cores have more extensive application ranges for vibration reduction.

The Effect of Cyclosporin A on Aspergillus niger and the Possible Mechanisms Involved.

Aspergillus niger is one of the major pathogenic fungi causing postharvest grape decay. The development of antifungal agents is beneficial to reduce the loss of grapes during storage. The aim of this study was to investigate the antifungal mechanism of cyclosporin A (CsA). It was indicated that the rot development on grapes caused by A. niger was almost completely inhibited with CsA in vivo at a concentration of 200 mg/L. The transcriptomic analysis revealed that the expression levels of genes involved in rRNA processing and ribosome biogenesis were down-regulated, whereas those related to ß-glucosidases and chitinases were up-regulated. The results implied that CsA may disturb rRNA and ribosome formation to obstruct protein synthesis, accelerate chitin and glucan degradation to destruct cell walls, and ultimately reduce postharvest decay caused by A. niger in grapes. This study evaluated the potential of CsA as a grape preservative and provided new insights into the mechanisms underlying the molecular response in A. niger with the treatment of CsA.

Novel anthraquinone derivatives trigger endoplasmic reticulum stress response and induce apoptosis.

Background: Endoplasmic reticulum (ER) stress is a therapeutic target in cancer given its regulation of bioenergetics and cell death. Methodology & results: We synthesized 14 ER stress-triggered anthraquinone derivatives by introducing an amino group at the 3-position side chain of the lead compound obtained previously. Most of the anthraquinone derivatives exhibited good antitumor activity due to their ability to induce ER damage through cytoplasmic vacuoles. The mechanisms of ER stress caused by compound KA-4c were related to increasing the expression levels of the ATF6 and Bip proteins and upregulating CHOP and cleaved PARP. Conclusion: Compound KA-4c triggers ER stress response and induces apoptosis via the ATF6-CHOP signaling pathway.

Research on Robot Screwing Skill Method Based on Demonstration Learning.

A robot screwing skill learning framework based on teaching-learning is proposed to improve the generalization ability of robots for different scenarios and objects, combined with the experience of a human operation. This framework includes task-based teaching, learning, and summarization. We teach a robot to twist and gather the operation's trajectories, define the obstacles with potential functions, and counter the twisting of the robot using a skill-learning-based dynamic movement primitive (DMP) and Gaussian mixture model-Gaussian mixture regression (GMM-GMR). The hole-finding and screwing stages of the process are modeled. In order to verify the effectiveness of the robot tightening skill learning model and its adaptability to different tightening scenarios, obstacle avoidance trends and tightening experiments were conducted. Obstacle avoidance and tightening experiments were conducted on the robot tightening platform for bolts, plastic bottle caps, and faucets. The robot successfully avoided obstacles and completed the twisting task, verifying the effectiveness of the robot tightening skill learning model and its adaptability to different tightening scenarios.

Efficacy, immunogenicity and safety of COVID-19 vaccines in older adults: a systematic review and meta-analysis.

Background: Older adults are more susceptible to severe health outcomes for coronavirus disease 2019 (COVID-19). Universal vaccination has become a trend, but there are still doubts and research gaps regarding the COVID-19 vaccination in the elderly. This study aimed to investigate the efficacy, immunogenicity, and safety of COVID-19 vaccines in older people aged ≥ 55 years and their influencing factors. Methods: Randomized controlled trials from inception to April 9, 2022, were systematically searched in PubMed, EMBASE, the Cochrane Library, and Web of Science. We estimated summary relative risk (RR), rates, or standardized mean difference (SMD) with 95% confidence interval (CI) using random-effects meta-analysis. This study was registered with PROSPERO (CRD42022314456). Results: Of the 32 eligible studies, 9, 21, and 25 were analyzed for efficacy, immunogenicity, and safety, respectively. In older adults, vaccination was efficacious against COVID-19 (79.49%, 95% CI: 60.55-89.34), with excellent seroconversion rate (92.64%, 95% CI: 86.77-96.91) and geometric mean titer (GMT) (SMD 3.56, 95% CI: 2.80-4.31) of neutralizing antibodies, and provided a significant protection rate against severe disease (87.01%, 50.80-96.57). Subgroup and meta-regression analyses consistently found vaccine types and the number of doses to be primary influencing factors for efficacy and immunogenicity. Specifically, mRNA vaccines showed the best efficacy (90.72%, 95% CI: 86.82-93.46), consistent with its highest seroconversion rate (98.52%, 95% CI: 93.45-99.98) and GMT (SMD 6.20, 95% CI: 2.02-10.39). Compared to the control groups, vaccination significantly increased the incidence of total adverse events (AEs) (RR 1.59, 95% CI: 1.38-1.83), including most local and systemic AEs, such as pain, fever, chill, etc. For inactivated and DNA vaccines, the incidence of any AEs was similar between vaccination and control groups (p > 0.1), while mRNA vaccines had the highest risk of most AEs (RR range from 1.74 to 7.22). Conclusion: COVID-19 vaccines showed acceptable efficacy, immunogenicity and safety in older people, especially providing a high protection rate against severe disease. The mRNA vaccine was the most efficacious, but it is worth surveillance for some AEs it caused. Increased booster coverage in older adults is warranted, and additional studies are urgently required for longer follow-up periods and variant strains.

Anaerobic Fungi Isolated From Bactrian Camel Rumen Contents Have Strong Lignocellulosic Bioconversion Potential.

This study aims to obtain anaerobic fungi from the rumen and fecal samples and investigates their potential for lignocellulosic bioconversion. Multiple anaerobic strains were isolated from rumen contents (CR1-CR21) and fecal samples (CF1-CF10) of Bactrian camel using the Hungate roll tube technique. After screening for fiber degradability, strains from rumen contents (Oontomyces sp. CR2) and feces (Piromyces sp. CF9) were compared with Pecoramyces sp. F1 (earlier isolated from goat rumen, having high CAZymes of GHs) for various fermentation and digestion parameters. The cultures were fermented with different substrates (reed, alfalfa stalk, Broussonetia papyrifera leaves, and Melilotus officinalis) at 39°C for 96 h. The Oontomyces sp. CR2 had the highest total gas and hydrogen production from most substrates in the in vitro rumen fermentation system and also had the highest digestion of dry matter, neutral detergent fiber, acid detergent fiber, and cellulose present in most substrates used. The isolated strains provided higher amounts of metabolites such as lactate, formate, acetate, and ethanol in the in vitro rumen fermentation system for use in various industrial applications. The results illustrated that anaerobic fungi isolated from Bactrian camel rumen contents (Oontomyces sp. CR2) have the highest lignocellulosic bioconversion potential, suggesting that the Bactrian camel rumen could be a good source for the isolation of anaerobic fungi for industrial applications.

Antifungal Mechanism of MTE-1, a Novel Oligosaccharide Ester, against Ustilaginoidea virens.

Ustilaginoidea virens is a pathogenic fungus that causes false smut disease in rice during the flowering stage through stamen filaments. Currently, there is a need to develop safe and effective antifungal agents for the control of this disease. In our preliminary experiments, we found that MTE-1, a new trisaccharide ester, exhibits significant inhibitory activity against U. virens. Hence, the effects and inhibitory mechanism of MTE-1 in U. virens were investigated. Results showed that the MTE-1 inhibited the hyphae growth of U. virens with an IC50 of 5.67 µg/mL. Similarly, MTE-1 disrupted the endomembrane system in U. virens, especially the plasma membrane, mitochondria, and lipidosome. Moreover, transcriptome and proteome analysis indicated that MTE-1 inhibited the growth of U. virens by inhibiting the synthesis of lipids, altering the primary metabolic pathways including carbohydrates and amino acid metabolism, and affecting the intracellular redox dyshomeostasis, thus leading to the disorder of active oxygen metabolism. These findings lay the foundation for the future application of MTE-1-derived agents in the management of antifungal diseases.

Molecular Details of Actinomycin D-Treated MRSA Revealed via High-Dimensional Data.

Methicillin-resistant Staphylococcus aureus (MRSA) is highly concerning as a principal infection pathogen. The investigation of higher effective natural anti-MRSA agents from marine Streptomyces parvulus has led to the isolation of actinomycin D, that showed potential anti-MRSA activity with MIC and MBC values of 1 and 8 µg/mL, respectively. Proteomics-metabolomics analysis further demonstrated a total of 261 differential proteins and 144 differential metabolites induced by actinomycin D in MRSA, and the co-mapped correlation network of omics, indicated that actinomycin D induced the metabolism pathway of producing the antibiotic sensitivity in MRSA. Furthermore, the mRNA expression levels of the genes acnA, ebpS, clfA, icd, and gpmA related to the key differential proteins were down-regulated measured by qRT-PCR. Molecular docking predicted that actinomycin D was bound to the targets of the two key differential proteins AcnA and Icd by hydrogen bonds and interacted with multiple amino acid residues of the proteins. Thus, these findings will provide a basic understanding to further investigation of actinomycin D as a potential anti-MRSA agent.

Investigation on flow field characteristics in an open-pit coal mine.

In this paper, the atmospheric flow field characteristics in a deep open-pit mine are investigated numerically and theoretically. A theoretical model on the recirculation length based on the energy equation is used, and a total variation diminishing (TVD) difference scheme with second-order accuracy is used to solve the NS equations with a standard two-equation k-ε turbulence model. The effects of elevated inner dump on the flow field characteristics of the open-pit mine are analyzed detailedly with the same inflow parameters. The results show that a recirculation zone exists in the open-pit mine due to the reflux from the high-pressure zone to the low-pressure zone. As the height of the inner dump increases, the flow becomes more complicated, and the low-pressure zone and the recirculation zone become bigger. The elevated inner dump makes it difficult for the internal fluid to flow to the outside, which results in the increase of the dust concentration. At last, the influences of key parameters on flow filed are conducted by normalizing the depth of the lowest direct current flow on the windward slope. The sensitivity analysis is done by study each influencing factor. This paper offers an effective way to study the flow field characteristics in an open-pit coal mine, which is essential to the dust pollution control of open-pit mine.

A new circulating accumulation emission model for assessing dust emission from open pit mine.

To reduce the inaccuracy of using the monitoring data outside the pit to evaluate the unorganized emission dust source of open pit mine, the circulating accumulation emission model is established. Based on the model, the monitoring data in the pit can be converted into the dust emission from the pit. The main conclusions include: (1) the circulating accumulation emission model is suitable for the dust diffusion process in open pit mine. The ratio of diffusion [Formula: see text] and the ratio of surplus [Formula: see text] were used to simulate the dust diffusion process in open pit mine, containing emission, retention and diffusion. (2) The initial value of the dust in the pit before the team operation has little influence on the final stable value. (3) When the external dust enters the pit, it will accumulate under the action of eddy current. The dust background value in the pit is different from that outside the pit. (4) The dust emission from the pit can be calculated from the monitoring data in the pit based on the circulating accumulation emission model. The model can deal with environmental changes such as the wind direction and speed, without arranging a lot of external monitoring equipment like the traditional external monitoring methods.

Multi-Omics Analysis Reveals Anti-Staphylococcus aureus Activity of Actinomycin D Originating from Streptomyces parvulus.

Staphylococcus aureus (S. aureus) is a common pathogen that causes various serious diseases, including chronic infections. Discovering new antibacterial agents is an important aspect of the pharmaceutical field because of the lack of effective antibacterial drugs. In our research, we found that one anti-S. aureus substance is actinomycin D, originating from Streptomyces parvulus (S. parvulus); then, we further focused on the anti-S. aureus ability and the omics profile of S. aureus in response to actinomycin D. The results revealed that actinomycin D had a significant inhibitory activity on S. aureus with a minimum inhibitory concentration (MIC) of 2 µg/mL and a minimum bactericidal concentration (MBC) of 64 µg/mL. Bacterial reactive oxygen species (ROS) increased 3.5-fold upon treatment with actinomycin D, as was measured with the oxidation-sensitive fluorescent probe DCFH-DA, and H2O2 increased 3.5 times with treatment by actinomycin D. Proteomics and metabolomics, respectively, identified differentially expressed proteins in control and treatment groups, and the co-mapped correlation network of proteomics and metabolomics annotated five major pathways that were potentially related to disrupting the energy metabolism and oxidative stress of S. aureus. All findings contributed to providing new insight into the mechanisms of the anti-S. aureus effects of actinomycin D originating from S. parvulus.

Effects of Duodenal 5-Hydroxytryptophan Perfusion on Melatonin Synthesis in GI Tract of Sheep.

The purpose of this study is to investigate the potential effects of 5-hydroxytryptophan (5-HTP) duodenal perfusion on melatonin (MT) synthesis in the gastrointestinal (GI) tract of sheep. 5-hydroxytryptophan is a precursor in the melatonin synthetic pathway. The results showed that this method significantly increased melatonin production in the mucosa of all segments in GI tract including duodenum, jejunum, ileum, cecum and colon. The highest melatonin level was identified in the colon and this indicates that the microbiota located in the colon may also participate in the melatonin production. In addition, portion of the melatonin generated by the GI tract can pass the liver metabolism and enters the circulation via portal vein. The current study provides further evidence to support that GI tract is the major site for melatonin synthesis and the GI melatonin also contributes to the circulatory melatonin level since plasma melatonin concentrations in 5-HTP treated groups were significantly higher than those in the control group. In conclusion, the results show that 10-50 mg of 5-HTP flowing into the duodenum within 6 h effectively improve the production of melatonin in the GI tract and melatonin concentration in sheep blood circulation during the day.