Ninety percent of clinical drug development fails despite implementation of many successful strategies, which raised the question whether certain aspects in target validation and drug optimization ...are overlooked? Current drug optimization overly emphasizes potency/specificity using structure‒activity-relationship (SAR) but overlooks tissue exposure/selectivity in disease/normal tissues using structure‒tissue exposure/selectivity–relationship (STR), which may mislead the drug candidate selection and impact the balance of clinical dose/efficacy/toxicity. We propose structure‒tissue exposure/selectivity–activity relationship (STAR) to improve drug optimization, which classifies drug candidates based on drug's potency/selectivity, tissue exposure/selectivity, and required dose for balancing clinical efficacy/toxicity. Class I drugs have high specificity/potency and high tissue exposure/selectivity, which needs low dose to achieve superior clinical efficacy/safety with high success rate. Class II drugs have high specificity/potency and low tissue exposure/selectivity, which requires high dose to achieve clinical efficacy with high toxicity and needs to be cautiously evaluated. Class III drugs have relatively low (adequate) specificity/potency but high tissue exposure/selectivity, which requires low dose to achieve clinical efficacy with manageable toxicity but are often overlooked. Class IV drugs have low specificity/potency and low tissue exposure/selectivity, which achieves inadequate efficacy/safety, and should be terminated early. STAR may improve drug optimization and clinical studies for the success of clinical drug development.
Structure‒tissue exposure/selectivity–activity relationship (STAR) selects drug candidates and balances clinical dose/efficacy/toxicity. Display omitted
Most engineering structures serve in complex and harsh dynamic environments and suffer from nonlinear vibrations generated by random excitations such as strong winds and waves, which need to be ...mitigated. To this end, a novel viscoelastic nonlinear energy sink (VNES) device is proposed for the vibration control of structures, whereby the random vibration of a nonlinear oscillator with a VNES device is analyzed in this paper. Specifically, the mathematical model of the structure-VNES is formulated. An approximate technique for the treatment of viscoelastic damping element modeled by the fractional derivative is developed, whereby an equivalent nonlinear system without fractional derivative is derived. The averaged Itô equations associated with the amplitude envelopes are then obtained by resorting to the stochastic averaging method. The closed-form solution of the stationary response is solved from the Fokker–Planck–Kolmogorov (FPK) equation and verified by the Monte Carlo simulation (MCS) data simultaneously. The effects of system parameters and noise intensity on the stationary response are sequentially examined. By comparing the VNES system to the case without attachment and one equipped with the commonly used tuned mass damper (TMD) device, the performance and robustness of the VNES are highlighted. The conclusions of this work may contribute to the efficacy of the application of the VNES in practice.
Nanomedicine usually refers to nanoparticles that deliver the functional drugs and siRNAs to treat cancer. Recent research has suggested that cancer cells can also make nanoparticles that also ...deliver functional molecules in promoting cancer metastasis, which is the leading cause of various cancer mortalities. This nanoparticle is called tumor-derived vesicles, or better-known as tumor-derived exosomes (TEXs). TEXs are nanoscale membrane vesicles (30–140 nm) that are released continuously by various types of cancer cells and contain tumor-derived functional biomolecules, including lipids, proteins, and genetic molecules. These endogenous TEXs can interact with host immune cells and epithelial cells locally and systemically. More importantly, they can reprogram the recipient cells in favor of promoting metastasis through facilitating tumor cell local invasion, intravasation, immune evasion, extravasation, and survival and growth in distant organs. Growing evidence suggests that TEXs play a key role in cancer metastasis. Here, we will review the most recent findings of how cancer cells harness TEXs to promote cancer metastasis through modulating vascular permeability, suppressing systemic immune surveillance, and creating metastatic niches. We will also summarize recent research in targeting TEXs to treat cancer metastasis.
We reviewed recent progress on understanding how tumor-derived exosomes (TEXs) promote metastasis through facilitating tumor cell local invasion, intravasation, immune evasion, extravasation, and growth in distant organs. Display omitted
Straw returning is an effective management measure to improve or maintain soil fertility in agricultural ecosystems. This study investigated the effects of straw returning combined with compound ...fertilizer on the bacterial community, enzyme activities, and soil nutrients' contents in a rape-rice rotation soil aggregates. To do so, a 5-year field trial (November 2016 to October 2021) was carried out in a paddy soil with three treatments: no straw + no fertilization (CK), compound fertilizer (F), and straw returning + compound fertilizer (SF). Soil aggregates were classified into mega-aggregates (> 2 mm), macro-aggregates (0.25-2 mm), micro-aggregates (0.053-0.25 mm), and silt-clay (< 0.053 mm) using the wet sieve method. High-throughput sequencing was employed to characterize the bacterial community, and Pearson correlation coefficient was used to identify the relationships among bacterial community, organic carbon, nitrogen, phosphorus, and enzyme activities in soil aggregates. Compared with F, the results showed that straw returning increased the content of > 2 mm aggregates by 3.17% and significantly decreased the content of 0.053-0.25 mm aggregates by 20.27%. The contents of organic carbon and total nitrogen in > 0.053 mm straw amended aggregates increased by 15.29 and 18.25%, respectively. Straw returning significantly increased the urease activity of > 0.053 mm aggregates with an average of 43.08%, while it decreased the phosphatase and invertase activities of soil aggregates by 7.71-40.66%. The Shannon indices of the bacterial community in each particle sizes soil aggregates decreased by an average of 1.16% and the Chao indices of the bacterial community in < 2 mm aggregates increased by an average of 3.90% in straw amended soils. Nevertheless, the relative abundances of Chloroflexi and Nitrospirotain in all soil aggregates increased by 6.17-71.77% in straw amended soils. Altogether, our findings suggest that straw returning is an efficient approach to enhance soil structure, carbon and nitrogen contents, and the richness of soil bacterial diversity.
Clearance of bacteria by macrophages involves internalization of the microorganisms into phagosomes, which are then delivered to endolysosomes for enzymatic degradation. These spatiotemporally ...segregated processes are not known to be functionally coupled. Here, we show that lysosomal degradation of bacteria sustains phagocytic uptake. In Drosophila and mammalian macrophages, lysosomal dysfunction due to loss of the endolysosomal Cl− transporter ClC-b/CLCN7 delayed degradation of internalized bacteria. Unexpectedly, defective lysosomal degradation of bacteria also attenuated further phagocytosis, resulting in elevated bacterial load. Exogenous application of bacterial peptidoglycans restored phagocytic uptake in the lysosomal degradation-defective mutants via a pathway requiring cytosolic pattern recognition receptors and NF-κB. Mammalian macrophages that are unable to degrade internalized bacteria also exhibit compromised NF-κB activation. Our findings reveal a role for phagolysosomal degradation in activating an evolutionarily conserved signaling cascade, which ensures that continuous uptake of bacteria is preceded by lysosomal degradation of microbes.
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•Vesicular Cl− transporters drive phagolysosomal degradation of internalized bacteria•Lysosomal degradation is required for sustained bacteria phagocytosis by macrophages•Lysosomal degradation activates cytosolic PRRs and NF-κB to sustain phagocytosis•NF-κB couples phagolysosomal degradation to sustained clearance of bacteria
Macrophages clear bacteria by phagosomal internalization and subsequent lysosomal degradation of the microbes. Wong et al. find that defective lysosomal degradation attenuates further phagocytosis, resulting in elevated bacterial load. Cytosolic pattern recognition receptors and NF-κB signal to couple phagolysosomal degradation to sustained phagocytic bacterial clearance.
As an attractive strategy developed rapidly in recent years, nanocrystals are used to deliver insoluble drugs. PEGylation may further prolong the circulation time of nanoparticles and improve the ...therapeutic outcome of drugs. In this study, paclitaxel (PTX) nanocrystals (PTX-NCs) and PEGylated PTX nanocrystals (PEG-PTX-NCs) were prepared using antisolvent precipitation augmented by probe sonication. The characteristics and antitumor efficacy of nanocrystals were investigated. The results indicated that the nanocrystals showed rod-like morphology, and the average particle size was 240 nm and 330 nm for PTX-NCs and PEG-PTX-NCs, respectively. The PEG molecules covered the surface of nanocrystals with an 11.54 nm fixed aqueous layer thickness (FALT), much higher than that of PTX-NCs (0.2 nm). PEG-PTX-NCs showed higher stability than PTX-NCs under both storage and physiological conditions. In breast cancer xenografted mice, PEG-PTX-NCs showed significantly better tumor inhibition compared to saline (p < 0.001) and PTX-NC groups (p < 0.05) after intravenous administration. In a model of lung tumor metastasis quantified by the luciferase activity, the PEG-PTX-NCs group showed higher anticancer efficacy not only than saline and PTX-NCs groups, but also than Taxol®, achieving an 82% reduction at the end of the experiment. These studies suggested the potential advantages of PEGylated PTX nanocrystals as alternative drug delivery systems for anticancer therapy.
Martensitic stainless steel containing 13% Cr–4% Ni suffers cavitation erosion (CE) as the common material of hydro turbine impellers. Two 13% Cr–4% Ni stainless steel samples were obtained by ...different melting and heating processes. One was of relatively low toughness but high ductility (LTHD), and the other was of relatively high toughness but low ductility (HTLD). This paper is to clarify the relationship between the mechanical properties and the CE resistance of the experimental steel samples. The CE of the two materials was studied using an ultrasonic vibration cavitation erosion rig. Mass loss, morphological observation, nanoindentation characterization, and tensile tests were employed to clarify the erosion mechanism. The results showed that LTHD stainless steel had slightly higher ductility, but lower toughness than HTLD material. The mass loss method verified that the CE resistance of LTHD material was higher than that for the HTLD material. In addition, both materials had an incubation stage of 2 h in the distilled water. The SEM revealed that material removal was preferentially initiated from the grain boundaries and slip zone after the incubation period. The ductility could delay the fracture of the material, which contributed more to cavitation erosion resistance than the toughness of the materials. The hardness test showed few relationships with the CE resistance.
The reliability estimation of a structure with viscoelastic nonlinear energy sink (VNES) subjected to random excitation is investigated in this paper. An approximate technique for the treatment of ...viscoelastic damping element modelled by the fractional derivative is first developed, whereby an equivalent nonlinear system with amplitude-variant stiffness and damping elements. The equivalent system is converted to averaged Itô differential equations by virtue of the stochastic averaging theory, from which the backward Kolmogorov (BK) equation of the system is then derived and solved to yield the conditional reliability function (CRF) and probability density distribution of the first-passage failure. The applicability of the analytical prediction is conducted by Monte Carlo simulation (MCS) simultaneously. Sensitivity analyses with respect to the input noise intensity and main parameters of structure-VNES are sequentially examined in detail. In general, the conclusions of this work will contribute to promoting the application of VNES in engineering structures.
The high concentration of arsenic (As) in paddy soil has seriously threatened the growth of rice and human food safety. Biological soil crusts (BSC), which are ubiquitous in paddy fields, have been ...shown a high ability to capture trace metal elements. In the present study, we investigated the effectiveness and mechanism of BSC for immobilizing As, and tested their potential to alleviate the stress of As on rice germination. It is found that BSC can remove 77.8% of arsenic in solution with 3.5 mg L−1 initial As concentration. The As content in BSC reached 514.5 mg kg−1 after 216 h exposure, and the entrapped As was mainly distributed in BSC as a non-EDTA-exchangeable fraction, which might be intracellularly accumulated. Proteobacteria and Bacteroidetes were the dominant phyla in BSC after being exposed to As, playing a significant role in tolerating As and As biogeochemical cycling. The presence of BSC notably promoted the germination rate (18.3%) and dry biomass (103.4%) of rice seeds under 3.5 mg L−1 As stress while reducing the As content in plant roots (8.2–34.3%) and shoots (8.7–47.6%). These findings demonstrate that BSC have a great entrapping effect on As and highlight the importance of BSC in alleviating the stress on rice germination by As, providing a potential nature-based and low-cost strategy to decontaminate paddy fields polluted with As.
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•Biological soil crusts were capable of entrapping high concentration arsenic.•The captured arsenic was mainly immobilized in the non-EDTA-exchangeable form.•Biological soil crusts application alleviated the stress of arsenic on rice germination.•Biological soil crusts application decreased arsenic accumulation in rice seedlings.
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