Dynamic allostery drives autocrine and paracrine TGF-ß signaling.

TGF-ß, essential for development and immunity, is expressed as a latent complex (L-TGF-ß) non-covalently associated with its prodomain and presented on immune cell surfaces by covalent association with GARP. Binding to integrin αvß8 activates L-TGF-ß1/GARP. The dogma is that mature TGF-ß must physically dissociate from L-TGF-ß1 for signaling to occur. Our previous studies discovered that αvß8-mediated TGF-ß autocrine signaling can occur without TGF-ß1 release from its latent form. Here, we show that mice engineered to express TGF-ß1 that cannot release from L-TGF-ß1 survive without early lethal tissue inflammation, unlike those with TGF-ß1 deficiency. Combining cryogenic electron microscopy with cell-based assays, we reveal a dynamic allosteric mechanism of autocrine TGF-ß1 signaling without release where αvß8 binding redistributes the intrinsic flexibility of L-TGF-ß1 to expose TGF-ß1 to its receptors. Dynamic allostery explains the TGF-ß3 latency/activation mechanism and why TGF-ß3 functions distinctly from TGF-ß1, suggesting that it broadly applies to other flexible cell surface receptor/ligand systems.

Macrophage-Associated PGK1 Phosphorylation Promotes Aerobic Glycolysis and Tumorigenesis.

Macrophages are a dominant leukocyte population in the tumor microenvironment and actively promote cancer progression. However, the molecular mechanism underlying the role of macrophages remains poorly understood. Here we show that polarized M2 macrophages enhance 3-phosphoinositide-dependent protein kinase 1 (PDPK1)-mediated phosphoglycerate kinase 1 (PGK1) threonine (T) 243 phosphorylation in tumor cells by secreting interleukin-6 (IL-6). This phosphorylation facilitates a PGK1-catalyzed reaction toward glycolysis by altering substrate affinity. Inhibition of PGK1 T243 phosphorylation or PDPK1 in tumor cells or neutralization of macrophage-derived IL-6 abrogates macrophage-promoted glycolysis, proliferation, and tumorigenesis. In addition, PGK1 T243 phosphorylation correlates with PDPK1 activation, IL-6 expression, and macrophage infiltration in human glioblastoma multiforme (GBM). Moreover, PGK1 T243 phosphorylation also correlates with malignance and prognosis of human GBM. Our findings demonstrate a novel mechanism of macrophage-promoted tumor growth by regulating tumor cell metabolism, implicating the therapeutic potential to disrupt the connection between macrophages and tumor cells by inhibiting PGK1 phosphorylation.

Nonreciprocal excitation and entanglement dynamics of two giant atoms mediated by a waveguide.

We study the nonreciprocal excitation and entanglement dynamics of two giant atoms (GAs) coupling to a one-dimensional waveguide. With different positions of coupling points, three configurations of two separate GAs, two braided GAs, and two nested GAs are analyzed, respectively. The coupling strengths between different coupling points are considered as complex numbers with phases. For each coupling configuration, the nonreciprocal excitation dynamics and entanglement properties, which results from the phase differences of coupling strength and the phase induced by photon propagation between the two coupling points, are studied both in Markovian and non-Markovian regimes. The analytical solutions for nonreciprocal entanglement degree are given in the Markovian regime. It shows that the steady entanglement can be reached and strongly depends on the phases. Different from the case of the Markovian regime, the entanglement degree shows oscillating behavior in the non-Markovian regime. This work may find applications in the generation and controlling of entanglement in quantum networks based on waveguide quantum electrodynamics.

Frequency tunable single photon diode based on giant atom coupling to a waveguide.

The single photon scattering properties in a waveguide coupling to a giant atom with a three-level system are investigated theoretically. One of the transitions of the giant atom couples to the waveguide at two points while the other one is driven by a classical field. Using the analytical expressions of the single photon scattering amplitudes, the conditions for realizing perfect single photon nonreciprocal scattering are discussed in both Markovian regime and non-Markovian regime. In the Markovian regime, the perfect non-reciprocity can be realized by adjusting the external classical field, the energy dissipation of the giant atom, the phase difference between the two coupling strengths and the accumulated phase resulting from the photon propagating between the two coupling points. In the non-Markovian regime, the non-reciprocal scattering phenomenon becomes more abundant due to the time delay. However, the analytical results show that the perfect non-reciprocity can still be achieved. When the incident photon is resonant with the giant atom, the nonreciprocity can be switched by controlling the classical field. For the non-resonant single photon, one can adjust the Rabi frequency of the classical field to obtain the perfect non-reciprocal single photon transmission. Our work provides a manner to realize a frequency tunable single photon diode.

MiR-509-3p Induces Apoptosis and Affects the Chemosensitivity of Cervical Cancer Cells by Targeting the RAC1/PAK1/LIMK1/Cofilin Pathway.

Chemoresistance is one of the main factors of treatment failure of cervical cancer (CC). Here, we intended to discover the role and mechanism of miR-509-5p in the paclitaxel chemoresistance of CC cells. RT-PCR was conducted to verify miR-509-3p expression. HCC94 and C-33A paclitaxel-resistant CC cell models were constructed. Additionally, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry were performed to verify the viability and apoptosis of HCC94 and C-33A cells after upregulating miR-509-3p. Besides, the downstream target of miR-509-3p was analyzed by bioinformatics, and the targeted relationship between miR-509-3p and RAC1 was identified by the dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Further, the expression of apoptotic proteins (Bcl2, Bax, and Caspase3) and the RAC1/PAK1/LIMK1/Cofilin pathway was monitored by Western blot. The result showed that upregulating miR-509-3p markedly inhibited the viability and promoted the apoptosis of CC cells. On the other hand, miR-509-3p was distinctly downregulated in paclitaxel-resistant HCC94 and C-33A cells (vs. normal cells). The transfection of miR-509-3p mimics notably increased their sensitivity to paclitaxel. Meanwhile, RAC1 was found as the potential target of miR-509-3p in bioinformatics analysis. Moreover, the RAC1/p21 (RAC1) activated kinase 1 (PAK1)/LIM kinase 1 (LIMK1)/Cofilin pathway was significantly activated in paclitaxel-resistant HCC94 and C-33A cells, while miR-509-3p overexpression significantly inactivated this pathway. Additionally, downregulation of RAC1 also partly reversed the paclitaxel-resistance of CC cells and inhibited PAK1/LIMK1/Cofilin. All in all, miR-509-3p enhances the apoptosis and chemosensitivity of CC cells by regulating the RAC1/PAK1/LIMK1/Cofilin pathway.

Galectin-3 induces ovarian cancer cell survival and chemoresistance via TLR4 signaling activation.

Paclitaxel resistance becomes common in patients with aggressive ovarian cancer and results in recurrence after conventional therapy. Galectin-3 is a multifunctional lectin associated with cell migration, cell proliferation, cell adhesion, and cell-cell interaction in tumor cells. Whether circulating galectin-3 is involved in paclitaxel resistance in ovarian cancer remains unknown. The current study investigated the effect of galectin-3 on toll-like receptor 4 (TLR4) signaling and thus paclitaxel resistance. With blood and cancer tissue samples obtained from 102 patients, we identified associations between serum galectin-3 level or TLR4 expression and paclitaxel resistance phenotype. In vitro, treatment with exogenous galectin-3 restored cell survival and migration of SKOV-3 and ES-2 cells was decreased by galectin-3 silencing and paclitaxel treatment. Furthermore, exogenous galectin-3 boosted expression of TLR4, MyD88, and p-p65, as well as interleukin (IL)-6, IL-8, and vascular endothelial growth factor (VEGF) release induced by paclitaxel. Moreover, galectin-3 inhibited the interaction between TLR4 and caveolin-1 (Cav-1) in SKOV-3 and ES-2 cells. In addition, overexpression of Cav-1 dampened the expression of MyD88 and p-p65 stimulated by galectin-3 and enhanced apoptosis in SKOV-3 cells under paclitaxel exposure. In summary, our study elucidated that exogenous galectin-3 might induce paclitaxel resistance through TLR4 signaling activation by inhibiting TLR4-Cav-1 interaction, revealing a novel insight into paclitaxel resistance induction.

The proteasome inhibitor bortezomib induces testicular toxicity by upregulation of oxidative stress, AMP-activated protein kinase (AMPK) activation and deregulation of germ cell development in adult murine testis.

Understanding how chemotherapeutic agents mediate testicular toxicity is crucial in light of compelling evidence that male infertility, one of the severe late side effects of intensive cancer treatment, occurs more often than they are expected to. Previous study demonstrated that bortezomib (BTZ), a 26S proteasome inhibitor used to treat refractory multiple myeloma (MM), exerts deleterious impacts on spermatogenesis in pubertal mice via unknown mechanisms. Here, we showed that intermittent treatment with BTZ resulted in fertility impairment in adult mice, evidenced by testicular atrophy, desquamation of immature germ cells and reduced caudal sperm storage. These deleterious effects may originate from the elevated apoptosis in distinct germ cells during the acute phase and the subsequent disruption of Sertoli-germ cell anchoring junctions (AJs) during the late recovery. Mechanistically, balance between AMP-activated protein kinase (AMPK) activation and Akt/ERK pathway appeared to be indispensable for AJ integrity during the late testicular recovery. Of particular interest, the upregulated testicular apoptosis and the following disturbance of Sertoli-germ cell interaction may both stem from the excessive oxidative stress elicited by BTZ exposure. We also provided the in vitro evidence that AMPK-dependent mechanisms counteract follicle-stimulating hormone (FSH) proliferative effects in BTZ-exposed Sertoli cells. Collectively, BTZ appeared to efficiently prevent germ cells from normal development via multiple mechanisms in adult mice. Employment of antioxidants and/or AMPK inhibitor may represent an attractive strategy of fertility preservation in male MM patients exposed to conventional BTZ therapy and warrants further investigation.

Acousto-optically cavity dumped Tm:YAG laser with 54 ns pulses at 200 kHz repetition rate.

In this paper, a cavity dumped Tm:YAG laser was obtained for the first time, whose output pulse width was constant at 54 ns. Maximum repetition rate was 200 kHz, and wavelength was 2013 nm. Its average output power was 595 mW. The laser cavity length was 208 mm with an inserted acousto-optic modulator. Pulses were coupled out of the lateral surface of the cavity when Radio Frequency was added into the modulator. And lens was used to compensate the thermal focal length of Tm:YAG crystal. Numerical calculation of pulse was done.

Diode-pumped acousto-optical cavity-dumped Tm:YAP laser at 1989 nm.

In this paper, we demonstrated a diode-pumped acousto-optical cavity-dumped Tm:YAP laser for the first time. The pulses were coupled out of the lateral surface of the cavity when radio frequency signal was loaded on the acousto-optical modulator. A maximum output power of 1.28 W was obtained with pump power of 40.3 W at a repetition rate of 200 kHz, corresponding to a slope efficiency of 4.7%. The output pulse width of the cavity-dumped Tm:YAP laser was constant at 43 ns, and the wavelength was 1989.8 nm.

Protocol for in situ visualization of mitochondrial ROS and apoptosis in spatially confined cells and sample preparation for biochemical analysis.

Locomotion through spatially confining spaces is an important in vivo migration mode. Here, we present a protocol for in situ visualization of mitochondrial reactive oxygen species and apoptosis in cancer cells during confined migration. We then detail sample preparation of confined cells for transcriptome and immunoblotting analysis by using transwell chambers. This approach allows in situ evaluation of a variety of cellular functions during confined migration and preparation of the samples of confined cells for further biochemical analysis. For complete details on the use and execution of this protocol, please refer to Cai et al.1.

Manifold Learning-Based Common Spatial Pattern for EEG Signal Classification.

EEG signal classification using Riemannian manifolds has shown great potential. However, the huge computational cost associated with Riemannian metrics poses challenges for applying Riemannian methods, particularly in high-dimensional feature data. To address these, we propose an efficient ensemble method called MLCSP-TSE-MLP, which aims to reduce the computational cost while achieving superior performance. MLCSP of the ensemble utilizes a Riemannian graph embedding strategy to learn intrinsic low-dimensional sub-manifolds, enhancing discrimination. TSE uses the Euclidean mean as the reference point for tangent space mapping and reducing computational cost. Finally, the ensemble incorporates the MLP classifier to offer improved classification performance. Classification results conducted on three datasets demonstrate that MLCSP-TSE-MLP achieves significant superior performance compared to various competing methods. Notably, the MLCSP-TSE module achieves a remarkable increase in training speed and exhibits much lower test time compared to traditional Riemannian methods. Based on these results, we believe that the proposed MLCSP-TSE-MLP is a powerful tool for handling high-dimensional data and holds great potential for practical applications.

Analytical solution of a pollutant transport model for unsaturated soil considering the effects of consolidation and temperature.

The migration behavior of pollutants is affected by consolidation and temperature when using thermal desorption technology to clean contaminated sites. Based on a one-dimensional consolidation model for unsaturated soil and the traditional heat conduction equation, a pollutant transport model accounting for the combined effects of consolidation and temperature was established in this paper. An analytical solution was obtained by using the separation of variables method and the integral transformation method. In addition, the correctness of the proposed model was verified via a comparison between the existing analytical solution and the theoretical model. Finally, adopting benzene as the research object, the influence of different factors on pollutant migration was studied. It was found that the growth rate of the pollutant concentration increased with increasing consolidation pressure, and the final pollutant concentration decreased with increasing consolidation pressure. The pollutant concentration increment due to temperature first increased and then decreased with increasing migration distance. The higher the Soret coefficient and volumetric moisture content are, the higher the pollutant concentration.

Hypercomplex Graph Neural Network: Towards Deep Intersection of Multi-modal Brain Networks.

The multi-modal neuroimage study has provided insights into understanding the heteromodal relationships between brain network organization and behavioral phenotypes. Integrating data from various modalities facilitates the characterization of the interplay among anatomical, functional, and physiological brain alterations or developments. Graph Neural Networks (GNNs) have recently become popular in analyzing and fusing multi-modal, graph-structured brain networks. However, effectively learning complementary representations from other modalities remains a significant challenge due to the sophisticated and heterogeneous inter-modal dependencies. Furthermore, most existing studies often focus on specific modalities (e.g., only fMRI and DTI), which limits their scalability to other types of brain networks. To overcome these limitations, we propose a HyperComplex Graph Neural Network (HC-GNN) that models multi-modal networks as hypercomplex tensor graphs. In our approach, HC-GNN is conceptualized as a dynamic spatial graph, where the attentively learned inter-modal associations are represented as the adjacency matrix. HC-GNN leverages hypercomplex operations for inter-modal intersections through cross-embedding and cross-aggregation, enriching the deep coupling of multi-modal representations. We conduct a statistical analysis on the saliency maps to associate disease biomarkers. Extensive experiments on three datasets demonstrate the superior classification performance of our method and its strong scalability to various types of modalities. Our work presents a powerful paradigm for the study of multi-modal brain networks.

Membrane behavior of clay considering the effect of fixed charges.

Membrane efficiency coefficient of clay is evaluated with considering the effect of fixed charges adsorbed on clay mineral surfaces. By virtue of the concept of chemical potential, the ionic concentration of pore water is calculated. An equation is first proposed to calculate the Donnan osmotic pressure based on the activity of water (H2O), and then a new method is developed to determine the membrane efficiency coefficient, based on the theoretical chemo-osmotic pressure difference. The proposed method is used to calculate the membrane efficiency coefficients of geosynthetic clay liners (GCLs) with different bentonite contents and porosities under different KCl concentrations. The calculated results are compared to those of van't Hoff equation, showing that if skeletal deformation is excluded, the proposed model and van't Hoff equation with average ion concentration difference yield practically the same results; if the deformation is considered, however, van't Hoff equation yields smaller membrane coefficients.

IGFBP1 Sustains Cell Survival during Spatially-Confined Migration and Promotes Tumor Metastasis.

Cell migration is a pivotal step in metastatic process, which requires cancer cells to navigate a complex spatially-confined environment, including tracks within blood vessels and in the vasculature of target organs. Here it is shown that during spatially-confined migration, the expression of insulin-like growth factor-binding protein 1 (IGFBP1) is upregulated in tumor cells. Secreted IGFBP1 inhibits AKT1-mediated phosphorylation of mitochondrial superoxide dismutase (SOD2) serine (S) 27 and enhances SOD2 activity. Enhanced SOD2 attenuates mitochondrial reactive oxygen species (ROS) accumulation in confined cells, which supports tumor cell survival in blood vessels of lung tissues, thereby accelerating tumor metastasis in mice. The levels of blood IGFBP1 correlate with metastatic recurrence of lung cancer patients. This finding reveals a unique mechanism by which IGFBP1 sustains cell survival during confined migration by enhancing mitochondrial ROS detoxification, thereby promoting tumor metastasis.

Laser Additively Manufactured Iron-Based Biocomposite: Microstructure, Degradation, and In Vitro Cell Behavior.

A too slow degradation of iron (Fe) limits its orthopedic application. In this study, calcium chloride (CaCl2) was incorporated into a Fe-based biocomposite fabricated by laser additive manufacturing, with an aim to accelerate the degradation. It was found that CaCl2 with strong water absorptivity improved the hydrophilicity of the Fe matrix and thereby promoted the invasion of corrosive solution. On the other hand, CaCl2 could rapidly dissolve once contacting the solution and release massive chloride ion. Interestingly, the local high concentration of chloride ion effectively destroyed the corrosion product layer due to its strong erosion ability. As a result, the corrosion product layer covered on the Fe/CaCl2 matrix exhibited an extremely porous structure, thus exhibiting a significantly reduced corrosion resistance. Besides, in vivo cell testing proved that the Fe/CaCl2 biocomposite also showed favorable cytocompatibility.

DW-FBCSP: EEG emotion recognition algorithm based on scale distance weighted optimization.

Emotion calibration is measured by the valence and arousal scales and the ideal center is used to directly divide valence arousal into high scores and low scores. This division method has a big classification and labeling defect, and the influence of emotion stimulation material on the subjects cannot be accurately measured. To address this problem, this paper proposes an EEG emotion recognition algorithm (DW-FBCSP: Distance Weighted Filter Bank Common Spatial Pattern) based on scale distance weighted optimization to optimize the classification according to the distance of the scores from ideal center. This method is a natural extension of CSP that optimize the user's EEG signal projection matrix. Then, the LDA classifier is used to recognize emotions using the features set which fused the selected features and the features extracted by the projection matrix. The results show that the mean correct rate of the valence and arousal achieves 81.14% and 84.45% using the DEAP dataset. The results demonstrate that our proposed method outperforms better than some other results published in recent years.

TGFß signaling hyperactivation-induced tumorigenicity during the derivation of neural progenitors from mouse ESCs.

Clinical therapies of pluripotent stem cells (PSCs)-based transplantation have been hindered by frequent development of teratomas or tumors in animal models and clinical patients. Therefore, clarifying the mechanism of carcinogenesis in stem cell therapy is of great importance for reducing the risk of tumorigenicity. Here we differentiate Oct4-GFP mouse embryonic stem cells (mESCs) into neural progenitor cells (NPCs) and find that a minority of Oct4+ cells are continuously sustained at Oct4+ state. These cells can be enriched and proliferated in a standard ESC medium. Interestingly, the differentiation potential of these enriched cells is tightly restricted with much higher tumorigenic activity, which are thus defined as differentiation-resistant ESCs (DR-ESCs). Transcriptomic and epigenomic analyses show that DR-ESCs are characterized by primordial germ cell-like gene signatures (Dazl, Rec8, Stra8, Blimp1, etc.) and specific epigenetic patterns distinct from mESCs. Moreover, the DR-ESCs possess germ cell potential to generate Sycp3+ haploid cells and are able to reside in sperm-free spermaduct induced by busulfan. Finally, we find that TGFß signaling is overactivated in DR-ESCs, and inhibition of TGFß signaling eliminates the tumorigenicity of mESC-derived NPCs by inducing the full differentiation of DR-ESCs. These data demonstrate that these TGFß-hyperactivated germ cell-like DR-ESCs are the main contributor for the tumorigenicity of ESCs-derived target cell therapy and that inhibition of TGFß signaling in ESC-derived NPC transplantation could drastically reduce the risk of tumor development.

Phosphorylation of glycogen synthase kinase-3 beta at serine 9 confers cisplatin resistance in ovarian cancer cells.

Cisplatin is commonly used in the treatment of advanced ovarian carcinoma. A major limitation of the use of cisplatin is the development of resistance in tumors. Glycogen synthase kinase-3 beta (GSK-3beta) is a multi-functional serine/threonine kinase. Its activity is regulated negatively by the phosphorylation of serine 9 (pGSK-3beta-ser-9) and positively by the phosphorylation of tyrosine 216 (pGSK-3beta-tyr-216). We compared the expression/phosphorylation of GSK-3beta between the cisplatin-sensitive ovarian carcinoma cell line A2780 and its cisplatin-resistant derivative CP70. The expression levels of total GSK-3beta and pGSK-3beta-tyr-216 were similar in these cells; however, CP70 cells had a much higher expression of pGSK-3beta-ser-9 than A2780 cells. Lithium chloride, which is a GSK-3beta inhibitor and stimulates pGSK-3beta-ser-9, significantly increased the IC50 of cisplatin and counteracted cisplatin-induced apoptosis of A2780 and CP70 cells. In contrast, overexpression of a constitutively active S9A GSK-3beta mutant increased the sensitivity of CP70 cells to cisplatin and significantly enhanced cisplatin-mediated apoptosis. It is suggested that the cisplatin-resistance of CP70 cells is mediated by stabilizing p53. We demonstrated that GSK-3beta negatively regulated the expression of p53. Therefore, pGSK-3beta-ser-9 may confer the cisplatin resistance of ovarian carcinomas through the stabilization of p53 expression. Our study establishes a potential role of GSK-3beta in the development of cisplatin resistance in initially sensitive tumors.

Hepatitis B X-interacting protein promotes cisplatin resistance and regulates CD147 via Sp1 in ovarian cancer.

Ovarian cancer is the highest mortality rate of all female reproductive malignancies. Drug resistance is a major cause of treatment failure in malignant tumors. Hepatitis B X-interacting protein acts as an oncoprotein, regulates cell proliferation, and migration in breast cancer. We aimed to investigate the effects and mechanisms of hepatitis B X-interacting protein on resistance to cisplatin in human ovarian cancer cell lines. The mRNA and protein levels of hepatitis B X-interacting protein were detected using RT-PCR and Western blotting in cisplatin-resistant and cisplatin-sensitive tissues, cisplatin-resistant cell lines A2780/CP and SKOV3/CP, and cisplatin-sensitive cell lines A2780 and SKOV3. Cell viability and apoptosis were measured to evaluate cellular sensitivity to cisplatin in A2780/CP cells. Luciferase reporter gene assay was used to determine the relationship between hepatitis B X-interacting protein and CD147. The in vivo function of hepatitis B X-interacting protein on tumor burden was assessed in cisplatin-resistant xenograft models. The results showed that hepatitis B X-interacting protein was highly expressed in ovarian cancer of cisplatin-resistant tissues and cells. Notably, knockdown of hepatitis B X-interacting protein significantly reduced cell viability in A2780/CP compared with cisplatin treatment alone. Hepatitis B X-interacting protein and cisplatin cooperated to induce apoptosis and increase the expression of c-caspase 3 as well as the Bax/Bcl-2 ratio. We confirmed that hepatitis B X-interacting protein up-regulated CD147 at the protein expression and transcriptional levels. Moreover, we found that hepatitis B X-interacting protein was able to activate the CD147 promoter through Sp1. In vivo, depletion of hepatitis B X-interacting protein decreased the tumor volume and weight induced by cisplatin. Taken together, these results indicate that hepatitis B X-interacting protein promotes cisplatin resistance and regulated CD147 via Sp1 in ovarian cancer cell lines. Impact statement We found that hepatitis B X-interacting protein (HBXIP) was able to activate the CD147 promoter through Sp1. In vivo, depletion of HBXIP decreased the tumor volume and weight induced by CP. Taken together, these results indicate that HBXIP promotes cisplatin resistance and regulated CD147 via Sp1 in ovarian cancer cell lines.