HMGA1 sensitizes esophageal squamous cell carcinoma to mTOR inhibitors through the ETS1-FKBP12 axis.

Esophageal carcinoma is amongst the prevalent malignancies worldwide, characterized by unclear molecular classifications and varying clinical outcomes. The PI3K/AKT/mTOR signaling, one of the frequently perturbed dysregulated pathways in human malignancies, has instigated the development of various inhibitory agents targeting this pathway, but many ESCC patients exhibit intrinsic or adaptive resistance to these inhibitors. Here, we aim to explore the reasons for the insensitivity of ESCC patients to mTOR inhibitors. We assessed the sensitivity to rapamycin in various ESCC cell lines by determining their respective IC50 values and found that cells with a low level of HMGA1 were more tolerant to rapamycin. Subsequent experiments have supported this finding. Through a transcriptome sequencing, we identified a crucial downstream effector of HMGA1, FKBP12, and found that FKBP12 was necessary for HMGA1-induced cell sensitivity to rapamycin. HMGA1 interacted with ETS1, and facilitated the transcription of FKBP12. Finally, we validated this regulatory axis in in vivo experiments, where HMGA1 deficiency in transplanted tumors rendered them resistance to rapamycin. Therefore, we speculate that mTOR inhibitor therapy for individuals exhibiting a reduced level of HMGA1 or FKBP12 may not work. Conversely, individuals exhibiting an elevated level of HMGA1 or FKBP12 are more suitable candidates for mTOR inhibitor treatment.

Spinal Lymphatic Dysfunction Aggravates the Recovery Process After Spinal Cord Injury.

We aimed to evaluate the role of the spinal lymphatic system in spinal cord injury and whether it has an impact on recovery after spinal cord injury. Flow cytometry was used to evaluate the changes in the number of microvesicles after spinal cord injury. Evans blue extravasation was used to evaluate the function of the lymphatic system. Evans blue extravasation and immunofluorescence were used to evaluate the permeability of blood spinal cord barrier. The spinal cord edema was evaluated by dry and wet weight.Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay was used to evaluate apoptosis after spinal cord injury. Nuclear factor-kappa B pathway was detected by Western blot. Behavioral tests were used to evaluate limb function. Microvesicles released after spinal cord injury can enter the thoracic duct and then enter the blood through the lymph around the spine. After ligation of the thoracic duct, it can aggravate the neuropathological manifestations and limb function after spinal cord injury. The potential mechanism may involve nuclear factor-kappa B pathway.

Akkermansia muciniphila protects the intestine from irradiation-induced injury by secretion of propionic acid.

Intestinal dysbiosis frequently occurs in abdominal radiotherapy and contributes to irradiation (IR)-induced intestinal damage and inflammation. Akkermansia muciniphila (A. muciniphila) is a recently characterized probiotic, which is critical for maintaining the dynamics of the intestinal mucus layer and preserving intestinal microbiota homeostasis. However, the role of A. muciniphila in the alleviation of radiation enteritis remains unknown. In this study, we reported that the abundance of A. muciniphila was markedly reduced in the intestines of mice exposed to abdominal IR and in the feces of patients who received abdominal radiotherapy. Abundance of A. muciniphila in feces of radiotherapy patients was negatively correlated with the duration of diarrhea in patients. Administration of A. muciniphila substantially mitigated IR-induced intestinal damage and prevented mouse death. Analyzing the metabolic products of A. muciniphila revealed that propionic acid, a short-chain fatty acid secreted by the microbe, mediated the radioprotective effect. We further demonstrated that propionic acid bound to G-protein coupled receptor 43 (GRP43) on the surface of intestinal epithelia and increased histone acetylation and hence enhanced the expression of tight junction proteins occludin and ZO-1 and elevated the level of mucins, leading to enhanced integrity of intestinal epithelial barrier and reduced radiation-induced intestinal damage. Metformin, a first-line agent for the treatment of type II diabetes, promoted intestinal epithelial barrier integrity and reduced radiation intestinal damage through increasing the abundance of A. muciniphila. Together, our results demonstrated that A. muciniphila plays a critical role in the reduction of abdominal IR-induced intestinal damage. Application of probiotics or their regulators, such as metformin, could be an effective treatment for the protection of radiation exposure-damaged intestine.

Multi-functional topology optimization of Victoria cruziana veins.

The growth and development of biological tissues and organs strongly depend on the requirements of their multiple functions. Plant veins yield efficient nutrient transport and withstand various external loads. Victoria cruziana, a tropical species of the Nymphaeaceae family of water lilies, has evolved a network of three-dimensional and rugged veins, which yields a superior load-bearing capacity. However, it remains elusive how biological and mechanical factors affect their unique vein layout. In this paper, we propose a multi-functional and large-scale topology optimization method to investigate the morphomechanics of Victoria cruziana veins, which optimizes both the structural stiffness and nutrient transport efficiency. Our results suggest that increasing the branching order of radial veins improves the efficiency of nutrient delivery, and the gradient variation of circumferential vein sizes significantly contributes to the stiffness of the leaf. In the present method, we also consider the optimization of the wall thickness and the maximum layout distance of circumferential veins. Furthermore, biomimetic leaves are fabricated by using the three-dimensional printing technique to verify our theoretical findings. This work not only gains insights into the morphomechanics of Victoria cruziana veins, but also helps the design of, for example, rib-reinforced shells, slabs and dome skeletons.

The role of extracellular vesicles in traumatic brain injury-induced acute lung injury.

Acute lung injury (ALI), a common complication after traumatic brain injury (TBI), can evolve into acute respiratory distress syndrome (ARDS) and has a mortality rate of 30%-40%. Secondary ALI after TBI exhibits the following typical pathological features: infiltration of neutrophils into the alveolar and interstitial space, alveolar septal thickening, alveolar edema, and hemorrhage. Extracellular vesicles (EVs) were recently identified as key mediators in TBI-induced ALI. Due to their small size and lipid bilayer, they can pass through the disrupted blood-brain barrier (BBB) into the peripheral circulation and deliver their contents, such as genetic material and proteins, to target cells through processes such as fusion, receptor-mediated interactions, and uptake. Acting as messengers, EVs contribute to mediating brain-lung cross talk after TBI. In this review, we aim to summarize the mechanism of EVs in TBI-induced ALI, which may provide new ideas for clinical treatment.

Topology of leaf veins: Experimental observation and computational morphogenesis.

The unique, hierarchical patterns of leaf veins have attracted extensive attention in recent years. However, it remains unclear how biological and mechanical factors influence the topology of leaf veins. In this paper, we investigate the optimization mechanisms of leaf veins through a combination of experimental measurements and numerical simulations. The topological details of three types of representative plant leaves are measured. The experimental results show that the vein patterns are insensitive to leaf shapes and curvature. The numbers of secondary veins are independent of the length of the main vein, and the total length of veins increases linearly with the leaf perimeter. By integrating biomechanical mechanisms into the topology optimization process, a transdisciplinary computational method is developed to optimize leaf structures. The numerical results show that improving the efficiency of nutrient transport plays a critical role in the morphogenesis of leaf veins. Contrary to the popular belief in the literature, this study shows that the structural performance is not a key factor in determining the venation patterns. The findings provide a deep understanding of the optimization mechanism of leaf veins, which is useful for the design of high-performance shell structures.

Mesoscopic dynamic model of epithelial cell division with cell-cell junction effects.

Cell division is central for embryonic development, tissue morphogenesis, and tumor growth. Experiments have evidenced that mitotic cell division is manipulated by the intercellular cues such as cell-cell junctions. However, it still remains unclear how these cortical-associated cues mechanically affect the mitotic spindle machinery, which determines the position and orientation of the cell division. In this paper, a mesoscopic dynamic cell division model is established to explore the integrated regulations of cortical polarity, microtubule pulling forces, cell deformability, and internal osmotic pressure. We show that the distributed pulling forces of astral microtubules play a key role in encoding the instructive cortical cues to orient and position the spindle of a dividing cell. The present model can not only predict the spindle orientation and position, but also capture the morphological evolution of cell rounding. The theoretical results agree well with relevant experiments both qualitatively and quantitatively. This work sheds light on the mechanical linkage between cell cortex and mitotic spindle, and holds potential in regulating cell division and sculpting tissue morphology.

Associations between estimated glomerular filtration rate and cardiac biomarkers.

BACKGROUND: Chronic kidney disease (CKD) is associated with an increased cardiovascular disease (CVD) mortality risk. Elevation of cardiac biomarkers in patients with renal dysfunction is ambiguous in the diagnosis of CVD. The purpose of this study was to investigate the associations between estimated glomerular filtration rate (eGFR) and cardiac biomarkers, and the influence of renal dysfunction on the cardiac biomarkers. METHODS: We examined the cross-sectional associations of eGFR with cardiac troponin I (cTnI), creatine kinase (CK), CK-MB, lactic dehydrogenase (LDH), hydroxybutyrate dehydrogenase (HBDH), and brain natriuretic peptide (BNP) in 812 adults and 215 child. Spearman correlation and logistic regression analysis were performed to evaluate the associations. RESULTS: For adults, lower eGFR CKD-EPI had significantly higher cTnI, CK-MB, LDH, HBDH, and BNP. There were negative correlations between eGFRCKD-EPI and cTnI, CK-MB, LDH, HBDH, and BNP. After adjustment for potential confounders, as compared with eGFRCKD-EPI  ≥ 90 mL/min/1.73 m2 , eGFRCKD-EPI  < 60 mL/min/1.73 m2 remained associated with a 2.83 (1.08-7.41) [ratio (95% CI)] times higher cTnI and a 6.50 (2.32-18.22) [ratio (95% CI)] times higher HBDH. For child, lower eGFRSchwartz had significant higher CK and CK-MB. There were negative correlations between eGFRSchwartz and CK, and eGFRSchwartz and CK-MB. After adjustment for potential confounders, as compared with eGFRSchwartz  ≥ 90 mL/min/1.73 m2 , eGFRSchwartz  < 90 mL/min/1.73 m2 revealed no significant higher CVD biomarkers. CONCLUSION: Reduced eGFR is associated with elevated cTnI and HBDH among adults without clinically evident CVD, but not child.

Mechanical Roles of F-Actin in the Differentiation of Stem Cells: A Review.

In the development and differentiation of stem cells, mechanical forces associated with filamentous actin (F-actin) play a crucial role. The present review aims to reveal the relationship among the chemical components, microscopic structures, mechanical properties, and biological functions of F-actin. Particular attention is given to the functions of the cytoplasmic and nuclear microfilament cytoskeleton and their regulation mechanisms in the differentiation of stem cells. The distributions of different types of actin monomers in mammal cells and the functions of actin-binding proteins are summarized. We discuss how the fate of stem cells is regulated by intra/extracellular mechanical and chemical cues associated with microfilament-related proteins, intercellular adhesion molecules, etc. In addition, we also address the differentiation-induced variation in the stiffness of stem cells and the correlation between the fate and geometric shape change of stem cells. This review not only deepens our understanding of the biophysical mechanisms underlying the fates of stem cells under different culture conditions but also provides inspirations for the tissue engineering of stem cells.

[Parameter estimation and verification of DSSAT-CROPGRO-Tomato model under different irrigation levels in greenhouse.] / 温室环境不同灌水水平条件下DSSAT-CROPGRO-Tomato模型的调参与验证.

Based on the greenhouse experiment in Shenyang, the growth, development, and yield formation of tomato under different irrigation levels were simulated by growth model DSSAT-CROPGRO-Tomato. The optimal scheme of parameter estimation and model validation was determined. There were four treatments in this experiment. Irrigation upper limit of whole growth season was set as field capacity, while the lower limit was 50% (W1), 60% (W2), 70% (W3), and 80% of field capacity (CK), respectively. The relevant genetic coefficients were estimated by DSSAT-GLUE, a program package for parameter estimation in DSSAT. The differences between simulated and observed values of phenological phase, canopy height, shoot dry matter, tomato fresh mass, leaf area index (LAI), and soil moisture were analyzed to determine the accuracy of simulation. The results showed that the estimated value of genetic parameter of tomato (thermal time for final pod load appeared greater variability under optimal genetic coefficient of tomato, PODUR) had large variability, with the coefficient of variation being 11.5%. When the CROPGRO-Tomato model was applied to the greenhouse in different regions, the PODUR should be estimated adequately. Otherwise, the accuracy of simulation would be affected. In the process of model application, the observation data of sufficient irrigation treatment should be selected for estimating genetic parameters, which could improve the simulation precision. The absolute relative error and standard root mean square error were 8.7% and 10.5%, respectively. The simulation results of LAI and soil moisture showed that the higher the irrigation level was, the higher accuracy of simulation was. By leave-one-out cross validation, the overall error validation ranged from 10.5% to 12.5%. Our results indicated that the growth, development, and yield formation of tomato could be accurately simulated by DSSAT CROPGRO-Tomato model under different irrigation conditions in Shenyang greenhouse.

High-speed spinning disks on flexible threads.

A common spinning toy, called "buzzer", consists of a perforated disk and flexible threads. Despite of its simple construction, a buzzer can effectively transfer translational motions into high-speed rotations. In the present work, we find that the disk can be spun by hand at an extremely high rotational speed, e.g., 200,000 rpm, which is much faster than the previously reported speed of any manually operated device. We explore, both experimentally and theoretically, the detailed mechanics and potential applications of such a thread-disk system. The theoretical prediction, validated by experimental measurements, can help design and optimize the system for, e.g., easier operation and faster rotation. Furthermore, we investigate the synchronized motion of multiple disks spinning on a string. Distinctly different twist waves can be realized by the multi-disk system, which could be exploited in the control of mechanical waves. Finally, we develop two types of manually-powered electric generators based on the thread-disk system. The high-speed rotation of the rotors enables a pulsed high current, which holds great promise for potential applications in, for instance, generating electricity and harvesting energy from ocean waves and other rhythmic translational motions.

A Dynamic Biochemomechanical Model of Geometry-Confined Cell Spreading.

Cell spreading is involved in many physiological and pathological processes. The spreading behavior of a cell significantly depends on its microenvironment, but the biochemomechanical mechanisms of geometry-confined cell spreading remain unclear. A dynamic model is here established to investigate the spreading of cells confined in a finite region with different geometries, e.g., rectangle, ellipse, triangle, and L-shape. This model incorporates both biophysical and biochemical mechanisms, including actin polymerization, integrin-mediated binding, plasma viscoelasticity, and the elasticity of membranes and microtubules. We simulate the dynamic configurational evolution of a cell under different geometric microenvironments, including the angular distribution of microtubule forces and the deformation of the nucleus. The results indicate that the positioning of the cell-division plane is affected by its boundary confinement: a cell divides in a plane perpendicular to its minimal principal axis of inertia of area. In addition, the effects of such physical factors as the adhesive bond density, membrane tension, and microtubule number are examined on the cell spreading dynamics. The theoretical predictions show a good agreement with relevant experimental results. This work sheds light on the geometry-confined spreading dynamics of cells and holds potential applications in regulating cell division and designing cell-based sensors.

ARISTOLOCHIA BRACTEOLATE RETZ. ATTENUATES HYPERURICEMIA IN A METABOLIC ARTHRITIS RAT MODEL.

BACKGROUND: The leaves of Aristolochia bracteolata Retz. has been documented in the folk medicine literature for its anti-arthritic activity. The target of the research envisaged was to elucidate the activity of A. bracteolata extract on hyperuricemic condition in arthritis rat model. MATERIALS AND METHODS: Dried and powdered plant leaves were extracted using ether and chloroform. Potassium oxonate was injected intra-articularly to produce arthritis. The hyperuricemic effect, of A. bracteolate was analyzed by studying levels of uric acid in serum as well as in urine of arthritis induced rats. Effects of plant extracts were also studied on BUN (blood urea nitrogen) levels and fraction of uric acid excreted. RESULTS: Results indicate that administration of A. bracteolata presented substantial change in uric acid concentration, augmented by potassium oxonate administration in rats. The reduction in levels of uric acid levels was nearly same as allopurinol. The investigation also revealed that the primary plant extract has nephroprotective effect by enhancing the production of Prostaglandin E2 and Interleukin-1. Histological studies of rat kidney slices indicated the safety of the present plant extract. CONCLUSION: The crude extract of A. bracteolate can be used to reduce hyperuricemia in metabolic arthritis produced in rat model, without inducing any potential damaging effects.

A Multi-Mitochondrial Anticancer Agent that Selectively Kills Cancer Cells and Overcomes Drug Resistance.

Mitochondria are double-membrane-bound organelles involved mainly in supplying cellular energy, but also play roles in signaling, cell differentiation, and cell death. Mitochondria are implicated in carcinogenesis, and therefore dozens of lethal signal transduction pathways converge on these organelles. Accordingly, mitochondria provide an alternative target for cancer management. In this study, F16, a drug that targets mitochondria, and chlorambucil (CBL), which is indicated for the treatment of selected human neoplastic diseases, were covalently linked, resulting in the synthesis of a multi-mitochondrial anticancer agent, FCBL. FCBL can associate with human serum albumin (HSA) to form an HSA-FCBL nanodrug, which selectively recognizes cancer cells, but not normal cells. Systematic investigations show that FCBL partially accumulates in cancer cell mitochondria to depolarize mitochondrial membrane potential (MMP), increase reactive oxygen species (ROS), and attack mitochondrial DNA (mtDNA). With this synergistic effect on multiple mitochondrial components, the nanodrug can effectively kill cancer cells and overcome multiple drug resistance. Furthermore, based on its therapeutic window, HSA-FCBL exhibits clinically significant differential cytotoxicity between normal and malignant cells. Finally, while drug dosage and drug resistance typically limit first-line mono-chemotherapy, HSA-FCBL, with its ability to compromise mitochondrial membrane integrity and damage mtDNA, is expected to overcome those limitations to become an ideal candidate for the treatment of neoplastic disease.

Chirality-dependent flutter of Typha blades in wind.

Cattail or Typha, an emergent aquatic macrophyte widely distributed in lakes and other shallow water areas, has slender blades with a chiral morphology. The wind-resilient Typha blades can produce distinct hydraulic resistance for ecosystem functions. However, their stem may rupture and dislodge in excessive wind drag. In this paper, we combine fluid dynamics simulations and experimental measurements to investigate the aeroelastic behavior of Typha blades in wind. It is found that the chirality-dependent flutter, including wind-induced rotation and torsion, is a crucial strategy for Typha blades to accommodate wind forces. Flow visualization demonstrates that the twisting morphology of blades provides advantages over the flat one in the context of two integrated functions: improving wind resistance and mitigating vortex-induced vibration. The unusual dynamic responses and superior mechanical properties of Typha blades are closely related to their biological/ecosystem functions and macro/micro structures. This work decodes the physical mechanisms of chirality-dependent flutter in Typha blades and holds potential applications in vortex-induced vibration suppression and the design of, e.g., bioinspired flight vehicles.

PAQR3 controls autophagy by integrating AMPK signaling to enhance ATG14L-associated PI3K activity.

The Beclin1-VPS34 complex is recognized as a central node in regulating autophagy via interacting with diverse molecules such as ATG14L for autophagy initiation and UVRAG for autophagosome maturation. However, the underlying molecular mechanism that coordinates the timely activation of VPS34 complex is poorly understood. Here, we identify that PAQR3 governs the preferential formation and activation of ATG14L-linked VPS34 complex for autophagy initiation via two levels of regulation. Firstly, PAQR3 functions as a scaffold protein that facilitates the formation of ATG14L- but not UVRAG-linked VPS34 complex, leading to elevated capacity of PI(3)P generation ahead of starvation signals. Secondly, AMPK phosphorylates PAQR3 at threonine 32 and switches on PI(3)P production to initiate autophagosome formation swiftly after glucose starvation. Deletion of PAQR3 leads to reduction of exercise-induced autophagy in mice, accompanied by a certain degree of disaggregation of ATG14L-associated VPS34 complex. Together, this study uncovers that PAQR3 can not only enhance the capacity of pro-autophagy class III PI3K due to its scaffold function, but also integrate AMPK signal to activation of ATG14L-linked VPS34 complex upon glucose starvation.

Study of biomechanical, anatomical, and physiological properties of scorpion stingers for developing biomimetic materials.

Through natural selection, many animal organs have evolved superior mechanical properties and elegant hierarchical structures adaptive to their multiple biological functions. We combine experiments and theory to investigate the composition-structure-property-function relations of scorpion stingers. Their hierarchical structures and functionally gradient mechanical properties were revealed. Slow motion analysis of the penetration process of a scorpion stinger was performed to examine the refined survival skills of scorpions. An experiment-based mechanics model of the stinger was proposed, the results of which revealed an optimized range of penetration angle in an insertion event. Both theoretical and numerical results are in good agreement with our experimental measurements. The analysis method and physical insights of this work are potentially important for investigating a general class of sharp-edge biological materials, e.g., cattle horns, spider fangs, cat claws, and plant thorns.

Biomechanical tactics of chiral growth in emergent aquatic macrophytes.

Through natural selection, many plant organs have evolved optimal morphologies at different length scales. However, the biomechanical strategies for different plant species to optimize their organ structures remain unclear. Here, we investigate several species of aquatic macrophytes living in the same natural environment but adopting distinctly different twisting chiral morphologies. To reveal the principle of chiral growth in these plants, we performed systematic observations and measurements of morphologies, multiscale structures, and mechanical properties of their slender emergent stalks or leaves. Theoretical modeling of pre-twisted beams in bending and buckling indicates that the different growth tactics of the plants can be strongly correlated with their biomechanical functions. It is shown that the twisting chirality of aquatic macrophytes can significantly improve their survivability against failure under both internal and external loads. The theoretical predictions for different chiral configurations are in excellent agreement with experimental measurements.

[Chemical constituents from flowers of Scabiosa tschilliensis].

Twenty-two compounds were isolated from the flowers of Scabiosa tschilliensis. Their structures were identified by spectroscopic methods as octacosanol (1), stearic acid (2), ß-sitosterol (3), oleanolic acid (4), apigenin (5), luteolin (6), daucosterol (7), kaempferol-3-O-ß-D-6-O-(p-hydroxycinnamoyl) -glucopyranoside (8), kaempferol-3-O-ß-D- (3, 6-di-p-(hydroxycinnamoyl) -glucopyranoside (9), apigenin-7-O-ß-D-glucopyranoside (10), luteolin-4'-O-ß-D-glucopyranoside (11), apigenin-7-O-rutinoside (12), luteolin-7-O-ß-D-glucopyranoside (13), apigenin-4'-O-ß-D-glucopyranoside (14), caffeic acid methyl ester (15), loganin (16), adenosine (17), luteolin-6-C-ß-D-glycopyranosyl (18), sweroside (19), sylvestrosides I (20), sylvestrosides II (21), urceolide (22). Among them, compounds 1, 2, 7-9, 12, 15, 17-18, 20-22 were isolated from the genus Scabiosa for the first time, and compounds 1-4, 6-9, 11-12, 14-22 were isolated from this plant for the first time. 13C-NMR data of 22 were reported for the first time.

Structures, properties, and functions of the stings of honey bees and paper wasps: a comparative study.

Through natural selection, many animal organs with similar functions have evolved different macroscopic morphologies and microscopic structures. Here, we comparatively investigate the structures, properties and functions of honey bee stings and paper wasp stings. Their elegant structures were systematically observed. To examine their behaviors of penetrating into different materials, we performed penetration-extraction tests and slow motion analyses of their insertion process. In comparison, the barbed stings of honey bees are relatively difficult to be withdrawn from fibrous tissues (e.g. skin), while the removal of paper wasp stings is easier due to their different structures and insertion skills. The similarities and differences of the two kinds of stings are summarized on the basis of the experiments and observations.