Strain rate-dependent failure mechanics of the intervertebral disc under tension/compression and constitutive analysis.

BACKGROUND: The intervertebral disc exhibits not only strain rate dependence (viscoelasticity), but also significant asymmetry under tensile and compressive loads, which is of great significance for understanding the mechanism of lumbar disc injury under physiological loads. OBJECTIVE: In this study, the strain rate sensitive and tension-compression asymmetry of the intervertebral disc were analyzed by experiments and constitutive equation. METHOD: The Sheep intervertebral disc samples were divided into three groups, in order to test the strain rate sensitive mechanical behavior, and the internal displacement as well as pressure distribution. RESULTS: The tensile stiffness is one order of magnitude smaller than the compression stiffness, and the logarithm of the elastic modulus is approximately linear with the logarithm of the strain rate, showing obvious tension-compression asymmetry and rate-related characteristics. In addition, the sensitivity to the strain rate is the same under these two loading conditions. The stress-strain curves of unloading and loading usually do not coincide, and form a Mullins effect hysteresis loop. The radial displacement distribution is opposite between the anterior and posterior region, which is consistent with the stress distribution. By introducing the damage factor into ZWT constitutive equation, the rate-dependent viscoelastic and weakening behavior of the intervertebral disc can be well described.

Vislocas: Vision transformers for identifying protein subcellular mis-localization signatures of different cancer subtypes from immunohistochemistry images.

Proteins must be sorted to specific subcellular compartments to perform their functions. Abnormal protein subcellular localizations are related to many diseases. Although many efforts have been made in predicting protein subcellular localization from various static information, including sequences, structures and interactions, such static information cannot predict protein mis-localization events in diseases. On the contrary, the IHC (immunohistochemistry) images, which have been widely applied in clinical diagnosis, contains information that can be used to find protein mis-localization events in disease states. In this study, we create the Vislocas method, which is capable of finding mis-localized proteins from IHC images as markers of cancer subtypes. By combining CNNs and vision transformer encoders, Vislocas can automatically extract image features at both global and local level. Vislocas can be trained with full-sized IHC images from scratch. It is the first attempt to create an end-to-end IHC image-based protein subcellular location predictor. Vislocas achieved comparable or better performances than state-of-the-art methods. We applied Vislocas to find significant protein mis-localization events in different subtypes of glioma, melanoma and skin cancer. The mis-localized proteins, which were found purely from IHC images by Vislocas, are in consistency with clinical or experimental results in literatures. All codes of Vislocas have been deposited in a Github repository (https://github.com/JingwenWen99/Vislocas). All datasets of Vislocas have been deposited in Zenodo (https://zenodo.org/records/10632698).

Study on potential antigenicity and functional properties of whey protein treated by high hydrostatic pressure based on structural analysis.

High hydrostatic pressure (HHP) is extensively utilized in the field of food processing due to its remarkable ability to preserve the freshness of food. The potential antigenicity of ß-lactoglobulin (ß-LG) in whey protein isolate (WPI, 3%) treated by HHP was detected by enzyme linked immunosorbent assay (ELISA) using monoclonal antibodies. Furthermore, the impact of pressure-induced structural alterations on the emulsification properties and antioxidant activity of WPI was investigated. The findings revealed that pressures exceeding 300 MPa resulted in molecular aggregation, the formation of inter-molecular disulfide bonds, and an increase in surface hydrophobicity (H0). The percentage of ß-sheet decreased along with the pressure. The results showed the increment of α-helix and ß-turn with pressure. ELISA demonstrated a significant reduction in the antigenicity of ß-LG following HHP treatment (100-600 MPa), with a slight recovery observed at 300 MPa. These spatial structural modifications led to the unfolding of the ß-LG molecule, thereby enhancing its digestibility. Moreover, HHP treatment substantially improved the antioxidant properties, with the exposure to hydrophobic amino acids contributing to increased antioxidant properties and emulsion stability.

Dihydroergotamine ameliorates liver fibrosis by targeting transforming growth factor ß type II receptor.

BACKGROUND: The transforming growth factor ß (TGFß) signaling pathway plays a crucial role in the development of liver fibrosis by activating TGFß type II receptor (TGFßR2), followed by the recruitment of TGFßR1 finally triggering downstream signaling pathway. AIM: To find drugs targeting TGFßR2 that inhibit TGFßR1/TGFßR2 complex formation, theoretically inhibit TGFß signaling pathway, and thereby ameliorate liver fibrosis. METHODS: Food and Drug Administration-approved drugs were screened for binding affinity with TGFßR2 by virtual molecular docking. We identified 6 candidates and further explored their potential by Cell Counting Kit-8 (CCK-8) cell cytotoxic experiment to validate toxicity and titrated the best cellular working concentrations. Next, we further demonstrated the detailed molecular working mechanisms using mutagenesis analysis. Finally, we used a mouse model to investigate its potential anti-liver fibrosis effect. RESULTS: We identified 6 drug candidates. Among these 6 drugs, dihydroergotamine (DHE) shows great ability in reducing fibrotic gene expressions such as collagen, p-SMAD3, and α-SMA in TGFß induced cellular model of liver fibrosis in LX-2 cells. Furthermore, we demonstrated that DHE binds to TGFßR2. Moreover, mutation of Leu27, Phe30, Thr51, Ser52, Ile53, and Glu55 of TGFßR2 disrupted the binding of TGFßR2 with DHE. In addition, DHE significantly improved liver fibrosis, as evidenced by Masson's trichrome staining of liver sections. This is further supported by the width and the velocity of the portal vein, and serum markers of liver function. In line with those observations, DHE also decreased macrophages infiltration and extracellular matrix deposition in the liver. CONCLUSION: DHE alleviates liver fibrosis by binding to TGFßR2 thereby suppressing TGFß signaling pathway. We show here that as far as drug repurposing, DHE has great potential to treat liver fibrosis.

Purification and identification of xanthine oxidase inhibitory peptides from enzymatic hydrolysate of α-lactalbumin and bovine colostrum casein.

The development of food-derived Xanthine Oxidase (XO) inhibitors is critical to the treatment of hyperuricemia and oxidative stress-related disease. Few studies report on milk protein hydrolysates' XO inhibitory activity, with the mechanism of their interaction remaining elusive. Here, different commercial enzymes were used to hydrolyze α-lactalbumin and bovine colostrum casein. The two proteins hydrolyzed by alkaline protease exhibited the most potent XO inhibitory activity (bovine casein: IC50 = 0.13 mg mL-1; α-lactalbumin: IC50 = 0.28 mg mL-1). Eight potential XO inhibitory peptides including VYPFPGPI, GPVRGPFPIIV, VYPFPGPIPN, VYPFPGPIHN, QLKRFSFRSFIWR, LVYPFPGPIHN, AVFPSIVGR, and GFININSLR (IC50 of 4.67-8.02 mM) were purified and identified from alkaline protease hydrolysates by using gel filtration, LC-MS/MS and PeptideRanker. The most important role of inhibiting activity of peptides is linked to hydrophobic interactions and hydrogen bonding based on the results of molecular docking and molecular dynamics simulation. The enzymatic hydrolysate of α-lactalbumin and bovine colostrum casein could be a competitive candidates for hyperuricemia-resisting functional food.

PLA-GNN: Computational inference of protein subcellular location alterations under drug treatments with deep graph neural networks.

The aberrant protein sorting has been observed in many conditions, including complex diseases, drug treatments, and environmental stresses. It is important to systematically identify protein mis-localization events in a given condition. Experimental methods for finding mis-localized proteins are always costly and time consuming. Predicting protein subcellular localizations has been studied for many years. However, only a handful of existing works considered protein subcellular location alterations. We proposed a computational method for identifying alterations of protein subcellular locations under drug treatments. We took three drugs, including TSA (trichostain A), bortezomib and tacrolimus, as instances for this study. By introducing dynamic protein-protein interaction networks, graph neural network algorithms were applied to aggregate topological information under different conditions. We systematically reported potential protein mis-localization events under drug treatments. As far as we know, this is the first attempt to find protein mis-localization events computationally in drug treatment conditions. Literatures validated that a number of proteins, which are highly related to pharmacological mechanisms of these drugs, may undergo protein localization alterations. We name our method as PLA-GNN (Protein Localization Alteration by Graph Neural Networks). It can be extended to other drugs and other conditions. All datasets and codes of this study has been deposited in a GitHub repository (https://github.com/quinlanW/PLA-GNN).

Effect of ferulic acid covalent conjugation on the functional properties and antigenicity of ß-lactoglobulin.

Binding to phenolics can improve the functional properties of proteins. Changes in structure, functional properties, and antigenicity of ß-lactoglobulin (ß-LG) after covalent conjugation with ferulic acid (FA) at different mass ratios were reported here. The results of SDS-PAGE and gel exclusion chromatography confirmed that covalent complexes were formed. When the mass ratio of ß-LG and FA was 10:6, the binding content of FA was the highest. Fluorescence spectroscopy, UV-visible absorption spectrometry, and FTIR analysis showed that the structure of the complexes was more stretched compared to native ß-LG. The addition of FA significantly improved the emulsifying property of ß-LG. When the mass ratio was 10:6, the radical scavenging activities of DPPH and ABTS reached 65.06% and 88.22%, respectively, and the antigenicity of ß-LG reduced by about 35%. This study provides novel ß-LG-FA complexes in food systems to reduce the antigenicity of ß-LG and improve functional properties.

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We analyzed the particle size distribution of soil aggregates in 0-20 and 20-40 cm soil layers of rice-wheat rotation field based on a field plot test with two treatments, conventional straw returning (CK) and straw returning with the addition of straw decomposition promoting microbial inoculants (IT). We evaluated the water stability indices of soil aggregates (the number of soil water stable large aggregates R0.25, the average weight diameter MWD, and the geometric average diameter GMD), and measured the contents of soil organic carbon (SOC), total nitrogen (TN), and total phosphorus (TP) in the soil aggregates of ＜0.053, 0.053-0.25, 0.25-1, ＞1 mm. The results showed that: 1) The number of aggregates ＜0.053, 0.053-0.25, ＞0.25 mm in the 0-20 and 20-40 cm soil layers under IT decreased by 10.0% and 6.8%, increased by 3.0% and 5.7%, and 17.9% and 26.1% compared with CK, respectively. IT effectively increased R0.25, MWD, and GMD by 26.4%, 20.0%, 18.2% and 18.2%, 10.5%, 10.0% in 0-20 and 20-40 cm soil, respectively. 2) Compared to CK, the TP content of 0.25-1 mm aggregates in 0-20 and 20-40 cm soil under IT was significantly increased by 40.3% and 37.5%, respectively, without difference in TN and SOC contents. There was no significant difference in nutrient contents of the other aggregates between the treatments. The contents of SOC and TN in large aggregates (>0.25 mm) were higher than those in silty aggregates (<0.053 mm). Compared to CK, the cumulative contribution rates of SOC, TN and TP of <0.053 mm aggregates under IT were decreased in two soil layers. There was no significant difference in the nutrient cumulative contribution rates of 0.053-0.25 mm aggregates between treatments. The cumulative contribution rates of SOC, TN, and TP of large aggregates (>0.25 mm) under IT were 32.1%, 19.6%, 52.8% and 22.8%, 11.8%, 42.9% higher than those under CK in 0-20 and 20-40 cm soils, respectively. 3) The number of <0.053 mm aggregates was significantly negatively correlated with SOC and TP contents, while that of 0.053-0.25 mm aggregates was negatively correlated with nutrient content. The number of large aggregates (>0.25 mm) were significantly positively correlated with SOC, TN, and TP contents. In conclusion, straw returning with microbial-inoculant addition could promote the formation of soil macroaggregates (>0.25 mm), and improve the water stability of soil aggregates, increasing nutrient contents in soil macroaggregates, with the nutrients transferring from silty aggregates to macroaggregates.

Population genomics reveals that natural variation in PRDM16 contributes to cold tolerance in domestic cattle.

Environmental temperature serves as a major driver of adaptive changes in wild organisms. To discover the mechanisms underpinning cold tolerance in domestic animals, we sequenced the genomes of 28 cattle from warm and cold areas across China. By characterizing the population structure and demographic history, we identified two genetic clusters, i.e., northern and southern groups, as well as a common historic population peak at 30 kilo years ago. Genomic scan of cold-tolerant breeds determined potential candidate genes in the thermogenesis-related pathways that were under selection. Specifically, functional analysis identified a substitution of PRDM16 (p.P779L) in northern cattle, which maintains brown adipocyte formation by boosting thermogenesis-related gene expression, indicating a vital role of this gene in cold tolerance. These findings provide a basis for genetic variation in domestic cattle shaped by environmental temperature and highlight the role of reverse mutation in livestock species.

Direct Reprogramming of Mouse Fibroblasts into Melanocytes.

The loss of function of melanocytes leads to vitiligo, which seriously affects the physical and mental health of the affected individuals. Presently, there is no effective long-term treatment for vitiligo. Therefore, it is imperative to develop a convenient and effective treatment for vitiligo. Regenerative medicine technology for direct reprogramming of skin cells into melanocytes seems to be a promising novel treatment of vitiligo. This involves the direct reprogramming of the patient's skin cells into functional melanocytes to help ameliorate the loss of melanocytes in patients with vitiligo. However, this method needs to be first tested on mice. Although direct reprogramming is widely used, there is no clear protocol for direct reprogramming into melanocytes. Moreover, the number of available transcription factors is overwhelming. Here, a concentrated lentivirus packaging system protocol is presented to produce transcription factors selected for reprogramming skin cells to melanocytes, including Sox10, Mitf, Pax3, Sox2, Sox9, and Snai2. Mouse embryonic fibroblasts (MEFs) were infected with the concentrated lentivirus for all these transcription factors for the direct reprogramming of the MEFs into induced melanocytes (iMels) in vitro. Furthermore, these transcription factors were screened, and the system was optimized for direct reprogramming to melanocytes. The expression of the characteristic markers of melanin in iMels at the gene or protein level was significantly increased. These results suggest that direct reprogramming of fibroblasts to melanocytes could be a successful new therapeutic strategy for vitiligo and confirm the mechanism of melanocyte development, which will provide the basis for further direct reprogramming of fibroblasts into melanocytes in vivo.

Laboratory model test study of the hydrological effect on granite residual soil slopes considering different vegetation types.

The problems caused by the interaction between slopes and hydrologic environment in traffic civil engineering are very serious in the granite residual soil area of China, especially in Guangdong Province. Against the background of two heavy rainfall events occurring during a short period due to a typhoon making landfall twice or even two typhoons consecutively making landfall, laboratory model tests were carried out on the hydrological effects of the granite residual soil slope considering three vegetation types under artificial rainfall. The variation in slope surface runoff, soil moisture content and rain seepage over time was recorded during the tests. The results indicate that surface vegetation first effectively reduces the splash erosion impact of rainwater on slopes and then influences the slope hydrological effect through rainwater forms adjustment. (1) The exposed slope has weak resistance to two consecutive heavy rains, the degree of slope scouring and soil erosion damage will increase greatly during the second rainfall. (2) The multiple hindrances of the stem leaf of Zoysia japonica plays a leading role in regulating the hydrological effect of slope, the root system has little effect on the permeability and water storage capacity of slope soil, but improves the erosion resistance of it. (3) Both the stem leaf and root system of Nephrolepis cordifolia have important roles on the hydrological effect. The stem leaf can stabilize the infiltration of rainwater, and successfully inhibit the surface runoff under continuous secondary heavy rainfall. The root system significantly enhances the water storage capacity of the slope, and greatly increases the permeability of the slope soil in the second rainfall, which is totally different from that of the exposed and Zoysia japonica slopes. (4) Zoysia is a suitable vegetation species in terms of slope protection because of its comprehensive slope protection effect. Nephrolepis cordifolia should be cautiously planted as slope protection vegetation. Only on slopes with no stability issues should Nephrolepis cordifolia be considered to preserve soil and water.

Atranones from Stachybotrys chartarum and their antitumor activities in MG-63 human osteosarcoma cells.

Two new atranones T and U (1 and 2), and three known analogues atranone B (3), atranone Q (4), and stachatranone C (5) were isolated from the toxigenic fungus Stachybotrys chartarum. Their structures and absolute configurations were elucidated by spectroscopic data and calculated ECD analyses. The cytotoxicities of all the atranones (1-5) were evaluated against MG-63 human osteosarcoma cell lines. Compound 4 exhibited significant cytotoxic effect against MG-63 with IC50 value of 8.6 µM, being more active than the positive control, 5-FU (IC50 10.4 µM). Morphological features of apoptosis activities were evaluated in 4-treated MG-63 cells. Compound 4 effectively induced apoptosis of MG-63, which was associated with G0/G1-phase cell cycle arrest. Flow cytometric analysis showed that the treatment by 4 significantly induced MG-63 cell apoptosis in a dose-dependent manner.

Nondestructive In Situ Measurement Method for Kernel Moisture Content in Corn Ear.

Moisture content is an important factor in corn breeding and cultivation. A corn breed with low moisture at harvest is beneficial for mechanical operations, reduces drying and storage costs after harvesting and, thus, reduces energy consumption. Nondestructive measurement of kernel moisture in an intact corn ear allows us to select corn varieties with seeds that have high dehydration speeds in the mature period. We designed a sensor using a ring electrode pair for nondestructive measurement of the kernel moisture in a corn ear based on a high-frequency detection circuit. Through experiments using the effective scope of the electrodes' electric field, we confirmed that the moisture in the corn cob has little effect on corn kernel moisture measurement. Before the sensor was applied in practice, we investigated temperature and conductivity effects on the output impedance. Results showed that the temperature was linearly related to the output impedance (both real and imaginary parts) of the measurement electrodes and the detection circuit's output voltage. However, the conductivity has a non-monotonic dependence on the output impedance (both real and imaginary parts) of the measurement electrodes and the output voltage of the high-frequency detection circuit. Therefore, we reduced the effect of conductivity on the measurement results through measurement frequency selection. Corn moisture measurement results showed a quadric regression between corn ear moisture and the imaginary part of the output impedance, and there is also a quadric regression between corn kernel moisture and the high-frequency detection circuit output voltage at 100 MHz. In this study, two corn breeds were measured using our sensor and gave R² values for the quadric regression equation of 0.7853 and 0.8496.