Cyclic Stress Research Articles

Cyclical heat stress during lactation influences the microstructure of the bovine mammary gland

This study aimed to evaluate the impact of heat stress on mammary epithelial cell (MEC) losses into milk, secretory mammary tissue structure, and mammary epithelial cell activity. Sixteen multiparous Holstein cows (632 ± 12 kg BW) approximately 100 d in milk housed in climate-controlled rooms were paired by body weight and randomly allocated to one of 2 treatments, heat stress (HS) or pair feeding thermoneutral (PFTN) using 2 cohorts. Each cohort was subjected to 2 periods of 4 d each. In period 1, both treatments had ad libitum access to a common total mixed ration and were exposed to a controlled daily temperature-humidity index (THI) of 64. In period 2, HS cows were exposed to controlled cyclical heat stress (THI: 74 to 80), while PFTN cows remained at 64 THI and daily dry matter intake was matched to HS. Cows were milked twice daily, and milk yield was recorded at each milking. Individual milk samples on the last day of each period were used to quantify MEC losses by flow cytometry using butyrophilin as a cell surface marker. On the final day of period 2, individual bovine mammary tissue samples were obtained for histomorphology analysis, assessment of protein abundance, and evaluation of gene expression of targets associated with cellular capacity for milk and milk component synthesis, heat response, cellular proliferation, and autophagy. Statistical analysis was performed using the GLIMMIX procedure of SAS. Milk yield was reduced by 4.3 kg by HS (n = 7) compared with PFTN (n = 8). Independent of treatment, MEC in milk averaged 174 cells/mL (2.9% of total cells). There was no difference between HS vs. PFTN cows for MEC shed or concentration in milk. Alveolar area was reduced 25% by HS, and HS had 4.1 more alveoli than PFTN. Total number of nucleated MEC per area were greater in HS (389 ± 1.05) compared with PFTN (321 ± 1.05); however, cell number per alveolus was similar between groups (25 ± 1.5 vs. 26 ± 1.4). There were no differences in relative fold expression for GLUT1, GLUT8, CSN2, CSN3, LALBA, FASN, HSPA5, and HSPA8 in HS compared with PFTN. Immunoblotting analyses showed a decrease abundance for phosphorylated STAT5 and S6K1, and an increase in LC3 II in HS compared with PFTN. These results suggest that even if milk yield differences and histological changes occur in the bovine mammary gland after 4 d of heat exposure, MEC loss into milk, nucleated MEC number per alveolus, and gene expression of nutrient transport, milk component synthesis, and heat stress related targets are unaffected. In contrast, the abundance of proteins related to protein synthesis and cell survival decreased significantly, while an upregulation of proteins associated with autophagy in HS compared with PFTN.

Evaluation of Strain Sensors Based on Poly(acrylonitrile-co-butadiene) and Polypyrrole Synthesized by the Diffusion Method.

In this study, the functionality of an elastomer composite material containing polypyrrole (PPy) as a stress sensor was evaluated. The material was prepared using the swelling method by diffusing the pyrrole monomer into the elastomer before polymerization. To achieve adequate diffusion, organic solvents with affinity for the elastomer were used. The resulting materials were characterized by scanning electron microscopy (SEM), surface electrical resistance, and thermal and mechanical properties for application as a stress sensor. The simultaneous change in electrical resistance and tension stress was measured using a digital multimeter with electrodes connected to the jaws of a universal mechanical testing machine. The influence of stress cycles on the piezoresistivity of the composite materials was investigated. The obtained PPy/NBR composite presented a good combination of electrical conductivity and mechanical properties. The strain at break remained with mild variation after coating with PPy.

Effect of thermal fluctuations on mold coating delamination during continuous casting of high-alloy (Mn, Al) steel

During the continuous casting of high-alloy (Mn, Al) steels, mold coating delamination occurs specifically at the narrow face (NF) mold corner immediately below the meniscus, different from where mold surface problems are generally known to occur. Most mechanical analyses have been performed assuming negligible thermal fluctuations and steady state interfacial heat fluxes. However, high-alloy steels exhibit larger thermal fluctuations than general steels during continuous casting, attributable to the reaction between the high-alloy steels and mold flux. Therefore, in this study, thermo-mechanical analyses are performed under both steady and fluctuating interfacial heat fluxes to compare the effects of thermal fluctuations on the continuous casting mold, with the results indicating that monotonic stresses are generated under steady interfacial heat fluxes at the corner of the NF mold, whereas cyclic stresses are induced by thermal fluctuations under fluctuating interfacial heat fluxes. Accordingly, the cyclic stresses at the corner of the NF mold, induced by thermal fluctuations, are determined as the major cause of mold coating delamination. These results can be applied to develop methods to reduce mold coating delamination, prevent the degradation of strand quality, and improve mold life.

Ameliorated in vitro anti-cancer efficacy of methotrexate loaded zinc oxide nanoparticles in breast cancer cell lines MCF-7 & MDA-MB-231 and its acute toxicity study

Traditional therapies often struggle with specificity and resistance in case of cancer treatments. It is therefore important to investigate new approaches for cancer treatment based on nanotechnology. Zinc oxide nanoparticles (ZnONPs) are known to exhibit anti-cancer properties by inducing oxidative stress, apoptosis, and cell cycle arrest. Methotrexate (MTX) a known anti-folate shows specificity to folate receptors and interrupts healthy functioning of cells. This study proposes the use of previously characterized biocompatible Methotrexate loaded Zinc oxide nanoparticles (MTX-ZnONPs) as a dual action therapeutic strategy against breast cancer cell lines, MCF-7 (MTX-sensitive) and MDA-MB-231 (MTX-resistant). To elucidate the cytotoxicity mechanism of MTX-ZnONPs an in depth In vitro study was carried out. In vitro assays, including cell cycle analysis, apoptosis assay, and western blot analysis to study the protein expression were performed. Results of these assays, further supported the anti-cancer activity of MTX-ZnONPs showing apoptotic and necrotic activity in MCF-7 and MDA-MB-231 cell line respectively. In vivo acute oral toxicity study to identify the LD50 in animals revealed no signs of toxicity and mortality up to 550 mg kg−1 body weight of animal, significantly higher LD50 values than anticipated therapeutic levels and safety of the synthesized nanosystem. The study concludes that MTX-ZnONPs exhibit anti-cancer potential against breast cancer cells offering a promising strategy for overcoming resistance.

In-vivo blood pressure sensing with bi-filler nanocomposite

Conductive elastomers present desirable qualities for sensing pressure in-vivo, such as high piezoresistance in tiny volumes, conformability and, biocompatibility. Many electrically conductive nanocomposites however, are susceptible to electrical drift following repeated stress cycles and chemical aging. Here we propose an innovative approach to stabilize nanocomposite percolation network against incomplete recovery to improve reproducibility and facilitate sensor calibration. We decouple the tunnelling-percolation network of highly-oriented pyrolytic graphite (HOPG) nanoparticles from the incomplete viscoelastic recovery of the polydimethylsiloxane (PDMS) matrix by inserting minute amounts of insulating SiO2 nanospheres. SiO2 nanospheres effectively reduce the number of nearest neighbours at each percolation node switching off the parallel electrical pathways that might become activated under incomplete viscoelastic relaxation. We varied the size of SiO2 nanospheres and their filling fraction to demonstrate nearly complete piezoresistance recovery when SiO2 and HOPG nanoparticles have equal diameters (≈400 nm) and SiO2 and HOPG volume fractions are 1 % and 29.5 % respectively. We demonstrate an in-vivo blood pressure sensor based on this bi-filler composite.

Vitamin C Alleviates the Negative Effects of Heat Stress on Reproductive Processes by Regulating Amino Acid Metabolism in Granulosa Cells.

Heat stress-induced biochemical alterations in ovarian follicles compromise the function of granulosa cells (GCs) and the developmental competence of oocytes. Summer heat stress can have a far-reaching negative impact on overall fertility and reproductive success. Together with the heat stress, the rise of assisted reproductive technologies (ART), potential confounding hazards of in vitro handling and the absence of systemic body support in ART makes it imperative to study the heat stress ameliorative effects of vitamin C under in vitro conditions. Using in vitro heat stress treatment of 43 °C for two hours in bovine GCs, we studied the effects of vitamin C on cell growth, oxidative stress, apoptosis and cell cycle progression together with a comprehensive metabolomics profiling. This study investigates the molecular milieu underlying the vitamin C (VC)-led alleviation of heat-related disruptions to metabolic processes in bovine GCs. The supplementation of VC ameliorated the detrimental effects of heat stress by reducing oxidative stress and apoptosis while restoring cell proliferation. Normal cell function restoration in treated GCs was demonstrated through the finding of significantly high levels of progesterone. We observed a shift in the metabolome from biosynthesis to catabolism, mostly dominated by the metabolism of amino acids (decreased tryptophan, methionine and tyrosine) and the active TCA cycle through increased Succinic acid. The Glutathione and tryptophan metabolism were important in ameliorating the inflammation and metabolism nexus under heat stress. Two significant enzymes were identified, namely tryptophan 2,3-dioxygenase (TDO2) and mitochondrial phenylalanyl-tRNA synthetase (FARS2). Furthermore, our findings provide insight into the significance of B-complex vitamins in the context of heat stress during VC supplementation. This study underscores the importance of VC supplementation in heat stress and designates multiple metabolic intervention faucets in the context of ameliorating heat stress and enhancing reproductive efficiency.

Twinning–Detwinning-Dominated Cyclic Deformation Behavior of a High-Strength Mg-Al-Sn-Zn Alloy during Loading Reversals: Experiment and Modeling

The deformation behavior of a high-strength Mg-Al-Sn-Zn alloy under loading reversals has been thoroughly examined through a combination of experimental measurements and crystal plasticity modeling. We focused on an age-treated alloy fortified by distributed Mg2Sn particles and Mg17Al12 precipitates, which underwent two distinct loading cycles: tension-compression-tension (TCT) and compression-tension-compression (CTC), aligned with the extrusion direction (ED). The initial and deformed microstructures of the alloy were analyzed using the electron backscattering diffraction (EBSD) technique. Notably, the alloy displays tensile and compressive yield strengths (YS) of 215 MPa and 160 MPa, respectively, with pronounced anelastic behavior observed during unloading and reverse loading phases. Utilizing the elasto-viscoplastic self-consistent model incorporating a twinning–detwinning scheme (EVPSC-TDT), the cyclic stress–strain responses and resultant textures of the alloy were accurately captured. The predicted alternation between various slip and twinning modes during plastic deformation was used to interpret the observed behaviors. It was found that prismatic <a> slip plays an important role during the plastic deformation of the studied alloy, and its relative activity in tensile loading processes accounts for up to ~66% and ~67% in the TCT and CTC cases, respectively. Moreover, it was discerned that detwinning and twinning behaviors are predominantly governed by stresses within the parent grain, and they can concurrently manifest during the reverse tensile loading phase in the TCT case. After cyclic deformation, the area fractions of residual twins were determined to be 7.51% and 0.93% in the TCT and CTC cases, respectively, which is a result of the varied twinning–detwinning behavior of the alloy in different loading paths.

Multifunctional nanogel loaded with cerium oxide nanozyme and CX3CL1 protein: Targeted immunomodulation and retinal protection in uveitis rat model

Effectively addressing retinal issues represents a pivotal aspect of blindness-related diseases. Novel approaches involving reducing inflammation and rebalancing the immune response are paramount in the treatment of these conditions. This study delves into the potential of a nanogel system comprising polyethylenimine-benzene boric acid-hyaluronic acid (PEI-PBA-HA). We have evaluated the collaborative impact of cerium oxide nanozyme and chemokine CX3CL1 protein for targeted immunomodulation and retinal protection in uveitis models. Our nanogel system specifically targets the posterior segment of the eyes. The synergistic effect in this area reduces oxidative stress and hampers the activation of microglia, thereby alleviating the pathological immune microenvironment. This multifaceted drug delivery system disrupts the cycle of oxidative stress, inflammation, and immune response, suppressing initial immune cells and limiting local retinal structural damage induced by excessive immune reactions. Our research sheds light on interactions within retinal target cells, providing a promising avenue for the development of efficient and innovative drug delivery platforms.

Influence of Composite Lay-Up and Cyclic Load Parameters on the Fatigue Behaviour of Flexible Composite Elements.

This work is dedicated to the design of flexible composite elements, specifically leaf springs. The design of these flexible composite elements took in consideration the technologies, materials and intermediate goods that are available and useable in laboratory manufacturing and the possibility for the transfer of gained knowledge to industrial practice. This work deals with individual types of materials and their processability and usability for the manufacturing of composite products exposed to cyclic stress. The impact of the designed lay-up diagrams and cyclic load boundary on the fatigue behaviour of manufactured specimens was used to evaluate the effect of cyclic stressing. Based on this assessment, a conclusion and recommendation were formulated for the serial manufacturing of flexible composite elements.

Fatigue properties of spot joints of metal-plastic composites with DP 800 steel prepared by ultrasound resistance spot welding

The aim of this work is to analyze the properties of spot joints of metal-plastic composites (Litecor) with DP 800 steel. The joints were made using ultrasound resistance spot welding technology. A metallographic analysis of the joints was carried out, and the basic areas of the weld structure were determined. The separation and decomposition of the polymer core was also illustrated, with no observed diffusion between the Litecor covers and the polypropylene core. Fatigue tests were the main goal of this work, therefore a fatigue curve was determined and the mechanisms of fatigue failure at various levels of fatigue load were analyzed. The tests were carried out at a frequency of 30 Hz, the cycle asymmetry coefficient was R = 0.1 and the limit number of cycles was 2 × 106. Fatigue failure mechanisms specific to particular levels of fatigue load were demonstrated, which were: 2.2, 1.9, 1.5, 1.2, and 1 kN. For joints subjected to fatigue shear has been demonstrated that the boundary between low-cycle and high-cycle fatigue is located at a cyclic shear stress level of approximately 132 MPa. However, with the assumed limit number of fatigue cycles, the fatigue shear strength was 70.576 MPa. Macro- and microscopic fractographic analysis was carried out for joints after fatigue tests in order to demonstrate the mechanisms of failure at individual levels of cyclic load.

Effect of SiC particle content on the mechanical behavior and deformation mechanism of SiCp/Al composite under high-frequency dynamic loading

SiCp/Al composites exhibit excellent structural properties but suffer from inherent brittleness, which has brought rigorous challenges on the materials processing. Ultrasonic-vibration-assisted approach offers a promising solution to improve the processability. However, the underlying mechanisms of mechanical response and defect suppression under ultrasonic action have been rarely studied for SiCp/Al composites, hindering the development of high-efficiency processing. This work aims to investigate the mechanical behavior and microstructural evolution in this class of composites with varying SiC volume fractions up to 45% under high-frequency dynamic load induced by ultrasonic vibration. The results showed that the deformation stress of SiCp/Al composites under ultrasonic compression was significantly reduced to only about 1/10 of that under conventional quasi-static loading. Moreover, as the SiC fractions increasing, this ultrasonic softening effect of SiCp/Al became more pronounced. The plastic limit of SiCp/Al with 45% SiC fraction nearly doubled under ultrasonic compression without any macroscopic cracks. The subsequent nanoindentation tests revealed a transition in work-hardening behavior of SiCp/Al with different SiC fractions under ultrasonic loading. Microstructure characterization was conducted to analyze the grain refinement, recrystallization, and deformation textures within the deformed areas, revealing the deformation mechanism of SiCp/Al under different loading mode. TEM observations confirmed the distribution of dislocations in Al matrix and dense stacking faults in SiC particles after ultrasonic compression, indicating that the plastic behaviors were enhanced in both Al matrix and SiC phase under the high-frequency cyclic stress. This research revealed the distinct deformation mechanisms of SiCp/Al composites under high-frequency dynamic loading, exhibiting extremely low deformation stress accompanied with significantly enhanced plasticity. The results provide theoretical insights for the high-efficiency processing and rapid property regulation of particle-reinforced-composites based on ultrasonic-vibration-assisted technologies.

A Simplified Model to Predict the Repeated Shear Strain during the Cyclic Triaxial Test by Using an Elastic Coefficient-Damping Ratio System

Some researchers in past years have tried to develop a simplified method for analyzing soil liquefaction. However, the correctness of the pore water pressure in the model will affect the results. In addition, the formulas derived are not easy, and the exact parameters of the model are difficult to obtain. This study used a mass-spring-damping system to simulate the repeated strain of liquefaction cyclic triaxial tests. Because the model is simple and the parameters are easy to understand and obtain, it also shows the extensibility of this model. During the parameter study, damping coefficient c and spring coefficient k parameters decreased with the increasing cyclic number. Preliminary results of the research show that this model can further simulate the repeated strain obtained by cyclic triaxial tests without considering the variation of effective stress during cyclic loading. Four samples were used to verify the model’s correctness, and their boring sites were found in Yunlin areas, Taiwan. Simulation results show that the spring-damping system is feasible for simulated cyclic triaxial tests because the simulated results correlate to the testing results in trend. Generally, the first cycle number simulation will be less accurate because the pore water pressure of the specimen changes rapidly when the performance has just started. In contrast, the increase in subsequent cycles may be biased due to cyclic stress variation and soil plasticity during simulation. In the future, pure sand specimens created in the laboratory will be suggested for simulation.

Increasing concentrations of dietary threonine, tryptophan, and glycine improve growth performance and intestinal health with decreasing stress responses in broiler chickens raised under multiple stress conditions

The current study aimed to compare the effects of increasing concentrations of dietary threonine (Thr), tryptophan (Trp), and glycine (Gly) on growth performance, stress biomarkers, and intestinal function in broiler chickens under multiple stress conditions. Five hundred sixty broiler chickens at 21 d old were randomly allotted to 5 treatments with 8 replicates. Birds in a positive control (PC) treatment were raised under low stock density (16.9 birds/m2 per cage) with recommended environmental conditions, whereas birds in 4 treatments were subjected to multiple stress conditions: a cyclic heat stress of 30 ± 0.3 °C for 10 h and 23 ± 0.2 °C for 14 h per day with high stock density (25.3 birds/m2 per cage). A basal diet was assigned to both PC and negative control (NC) treatments. Three additional diets were individually formulated to contain double concentrations of digestible Thr, Trp, or Gly + Ser compared with their concentrations in the basal diet. The experiment lasted for 14 d. Results showed that NC treatment had less growth performance (P < 0.001), jejunal goblet cell counts (P = 0.018), and trans-epithelial electrical resistance (TEER; P < 0.001), but greater (P = 0.026) feather corticosterone (CORT) concentrations than PC treatment. Thr treatment showed the least (P < 0.001) feed conversion ratio (FCR) among treatments under multiple stress conditions. Thr, Trp, and Gly treatments had less (P = 0.026) feather CORT concentrations, but had greater (P < 0.001) TEER than NC treatment. In conclusion, increasing concentrations of dietary Thr, Trp, or Gly improve the growth performance and intestinal health in broiler chickens with decreasing stress response under multiple stress conditions.

Effect of Magnesium Chloride Solution as an Antifreeze Agent in Clay Stabilization during Freeze-Thaw Cycles

Freeze-thaw cycles significantly impact construction by altering soil properties and stability, which can lead to delays and increased costs. While soil-stabilizing additives are vital for addressing these issues, stabilized soils remain susceptible to volume changes and structural alterations, ultimately reducing their strength after repeated freeze-thaw cycles. This study aims to introduce a different approach by employing magnesium chloride (MgCl2) as an antifreeze and soil stabilizer additive to enhance the freeze-thaw resilience of clay soils. We investigated the efficiency of MgCl2 solutions at concentrations of 4%, 9%, and 14% on soil by conducting tests such as Atterberg limits, standard proctor compaction, unconfined compression, and freeze-thaw cycles under extreme cold conditions (−10 °C and −20 °C), alongside microstructural analysis with SEM, XRD, and FTIR. The results showed that MgCl2 reduces the soil’s liquid limit and plasticity index while enhancing its compressive strength and durability. Specifically, soil treated with a 14% MgCl2 solution maintained its volume and strength at −20 °C, with similar positive outcomes observed for samples treated with 14% and 9% MgCl2 solutions at −10 °C. This underlines MgCl2’s potential to enhance soil stability during initial stabilization and, most importantly, preserve it under cyclic freeze-thaw stresses, offering a solution to improve construction practices in cold environments.

Peridynamic numerical investigation of asymmetric strain-controlled fatigue behaviour using the kinetic theory of fracture

Numerical fatigue process modelling is complex and still an open task. Discontinuity caused by fatigue cracks requires special finite element techniques based on additional parameters, the selection of which has a strong effect on the simulation results. Moreover, the calculation of fatigue life according to empirical material coefficients (e.g., Paris law) does not explain the process, and coefficients should be set from experimental testing, which is not always possible. A new nonlocal continuum mechanics formulation without spatial derivative of coordinates, namely, peridynamics (PD), which was created 20 y ago, provides new opportunities for modelling discontinuities, such as fatigue cracks. The fatigue process can be better described by using the atomistic approach-based kinetic theory of fracture (KTF), which includes the process temperature, maximum and minimum stresses, and loading frequency in its differential fatigue damage equation. Standard 316L stainless steel specimens are tested, and then the KTF-PD fatigue simulation is run in this study. In-house MATLAB code, calibrated from the material S‒N curve, is used for the KTF-PD simulation. A novel KTF equation based on the cycle stress‒strain hysteresis loop is proposed and applied to predict fatigue life. The simulation results are compared with the experimental results, and good agreement is observed for both symmetric and asymmetric cyclic loading.

Behavior of group of geosynthetic encased granular piles with tire chips- aggregates mixture under static and cyclic loading – A model study

The current study addresses the dual challenges of improving the performance of soft soil beds subjected to static and cyclic stresses and managing the environmental impact of waste tire disposal. This research contributes valuable insights into the sustainable use of recycled tire chips in granular pile construction, coupled with the efficacy of combi-grid encasement for improved soft ground under static and cyclic loading conditions. A series of laboratory model tests were carried out on a group of granular piles to examine the principal parameters, such as the selection of geosynthetic materials and cyclic loading characteristics, including cyclic loading amplitude (qca) and cyclic loading frequency (f). The granular pile composition consists of (25% tire chips + 75% aggregates). The performance of granular piles on improved ground is assessed based on the settlement reduction ratio (Sc,r), accumulation of excess pore water pressure (Pexc), and stress concentration ratio (n). The key findings from static model tests are that the load-bearing capacity is significantly increased with installing a group of ordinary granular piles (= 58%) and substantially increased with combi-grid encasement (= 335%). The effectiveness of ordinary granular piles (OGP) in enhancing the performance of a soft soil bed becomes greater when subjected to lower cyclic loading frequencies (f) and smaller cyclic loading amplitudes (qca). The incorporation of combi-grid encasement greatly enhanced the cyclic performance of a group of granular piles by substantially minimizing cyclic-induced settlement (Sc) across both principle parameters f and qca. This study also examines the increased cyclic stresses on the improved soft bed, resulting in the accumulation of excess pore water pressure (Pexc) development, which is reduced to a greater extent with the help of combi-grid encasement across both principle parameters.

Environmental aging effects on mechanical behavior of an hemp based biocomposite material for structural strengthening

Biocomposites are innovative materials usually made of natural fibers embedded in a natural matrix. The mechanical behavior of such materials when exposed to the environmental agents (i.e. UV radiations, high/low temperature, variable humidity conditions) is a crucial issue. This paper is aimed to investigate an hemp based biocomposite for structural strengthening, addressing a gap in the existing literature concerning the mechanical characterization of the composite constituents (i.e. hemp ropes and natural matrices) under accelerated weathering conditions. In particular, this research involves the mechanical behavior assessment of hemp ropes, four distinct types of matrices (i.e. two organic binder based matrices and two mortar based matrices) and the hemp/matrix interface. Tensile tests, three point bending tests, uniaxial compression tests and pull-out tests are carried out to characterize these components. To simulate accelerated weathering, samples of the biocomposite constituents are subjected to cycles of hygrothermal stress and UV radiation using an accelerated weathering testing apparatus. Subsequently, experimental mechanical tests are performed on the aged biocomposite components, and their mechanical properties are assessed and compared to those of the non-aged materials. The results reveal that aging leads to a significant reduction in the mechanical properties of the hemp ropes, and varying effects on the mechanical properties of matrices depending on their nature (organic binder-based or mortar-based matrices).

Physical and mental preparedness for large animal practice

Veterinary medicine, specifically large animal practice, is a highly physical job with inherent physical danger. Being in good physical shape and cultivating good fitness habits can de­crease our risk of injury. Physical fitness will affect our perfor­mance. For example, measurements of grip strength have been shown to be indicative of accuracy in transrectal bovine palpa­tion pregnancy diagnosis at the student level. This session also covers acute and chronic stress and tools we can use to com­plete stress cycles.

Liquefaction resistance and small strain stiffness of silty sand: Effects of host sand gradation and fines content

In this paper, a well designed experimental study comprising undrained cyclic triaxial and bender element tests was carried out on five sand-silt mixtures with three grain size ratios (Rd) and three sand uniformity coefficients (Cus). The results reveal that at given fines content (FC) and void ratio, the liquefaction resistance (CRR) of the mixtures decreases as Rd increases from 9.7 to 27.8 or Cus from 1.50 to 4.46, and the CRR of the mixture at the highest Rd or Cus becomes as low as nearly 50% of that at the lowest Rd or Cus. The equivalent relative density (Dr*) based on the binary packing theory can be utilized to capture the coupled effects of host sand gradation and FC on the CRR of sand-silt mixtures. A novel finding is that a universal relationship exists between the liquefaction resistance and the shear modulus normalized by the minimum void ratio function of host sand (GN') for different FCs, initial effective confining pressures, sample preparation methods (SPMs), and host sand gradations. Based on the comprehensive laboratory test data, the empirical CRR15-GN' correlation is proposed and further adjusted for the field liquefaction triggering analysis based on the shear wave velocity (Vs). Soil can be considered non-liquefiable when its equivalent shear wave velocity exceeds 225 m/s or the applied cyclic stress ratio (CSR) is below 0.088. Comparisons with the previously established liquefaction triggering boundary curves validate the applicability of the proposed curve for initial evaluation of the liquefaction resistance of sandy soils, indicating laboratory studies can complement in-situ investigations for Vs-based liquefaction assessment.

Comprehensive dry eye therapy: overcoming ocular surface barrier and combating inflammation, oxidation, and mitochondrial damage

BackgroundDry Eye Disease (DED) is a prevalent multifactorial ocular disease characterized by a vicious cycle of inflammation, oxidative stress, and mitochondrial dysfunction on the ocular surface, all of which lead to DED deterioration and impair the patients’ quality of life and social functioning. Currently, anti-inflammatory drugs have shown promising efficacy in treating DED; however, such drugs are associated with side effects. The bioavailability of ocular drugs is less than 5% owing to factors such as rapid tear turnover and the presence of the corneal barrier. This calls for investigations to overcome these challenges associated with ocular drug administration.ResultsA novel hierarchical action liposome nanosystem (PHP-DPS@INS) was developed in this study. In terms of delivery, PHP-DPS@INS nanoparticles (NPs) overcame the ocular surface transport barrier by adopting the strategy of “ocular surface electrostatic adhesion-lysosomal site-directed escape”. In terms of therapy, PHP-DPS@INS achieved mitochondrial targeting and antioxidant effects through SS-31 peptide, and exerted an anti-inflammatory effect by loading insulin to reduce mitochondrial inflammatory metabolites. Ultimately, the synergistic action of “anti-inflammation-antioxidation-mitochondrial function restoration” breaks the vicious cycle associated with DED. The PHP-DPS@INS demonstrated remarkable cellular uptake, lysosomal escape, and mitochondrial targeting in vitro. Targeted metabolomics analysis revealed that PHP-DPS@INS effectively normalized the elevated level of mitochondrial proinflammatory metabolite fumarate in an in vitro hypertonic model of DED, thereby reducing the levels of key inflammatory factors (IL-1β, IL-6, and TNF-α). Additionally, PHP-DPS@INS strongly inhibited reactive oxygen species (ROS) production and facilitated mitochondrial structural repair. In vivo, the PHP-DPS@INS treatment significantly enhanced the adhesion duration and corneal permeability of the ocular surface in DED mice, thereby improving insulin bioavailability. It also restored tear secretion, suppressed ocular surface damage, and reduced inflammation in DED mice. Moreover, it demonstrated favorable safety profiles both in vitro and in vivo.ConclusionIn summary, this study successfully developed a comprehensive DED management nanosystem that overcame the ocular surface transmission barrier and disrupted the vicious cycle that lead to dry eye pathogenesis. Additionally, it pioneered the regulation of mitochondrial metabolites as an anti-inflammatory treatment for ocular conditions, presenting a safe, efficient, and innovative therapeutic strategy for DED and other inflammatory diseases.