Folding of N-terminally acetylated α-synuclein upon interaction with lipid membranes.

α-Synuclein (α-syn) is an abundant presynaptic neuronal protein whose aggregation is strongly associated with Parkinson's disease. It has been proposed that lipid membranes significantly affect the α-syn's aggregation process. Extensive studies have been conducted to understand the interactions between α-syn and lipid membranes and have demonstrated that the N-terminus plays a critical role. However, the dynamics of the interactions and the conformational transitions of the N-terminus of α-syn at the atomistic scale details are still highly desired. In this study, we performed extensive enhanced sampling molecular dynamics simulations to quantify the folding and interactions of wild-type (WT) and N-terminally acetylated (AC) α-syn when interacting with lipid structures. We found that N-terminal acetylation significantly increases the helicity of the first few residues in solution or when interacting with lipid membranes. The observations in simulations showed that the binding of α-syn with lipid membranes mainly follows the induced-fit model, where the disordered α-syn binds with the lipid membrane through the electrostatic interactions and hydrophobic contacts with the packing defects; after stable insertion, the N-terminal acetylation promotes the helical folding of the N-terminus to enhance the anchoring, thus increasing the binding affinity. We have shown the critical role of the first N-terminal residue methionine for recognition and anchoring to the negatively charged membrane. Although N-terminal acetylation neutralizes the positive charge of Met1 that may affect the electrostatic interactions of α-syn with membranes, the increase in helicity of the N-terminus should compensate for the binding affinity. This study provides detailed insight into the folding dynamics of α-syn's N-terminus with or without acetylation in solution and upon interaction with lipids, which clarifies how the N-terminal acetylation regulates the affinity of α-syn binding to lipid membranes. It also shows how packing defects and electrostatic effects co-regulate the N-terminus of α-syn folding and its interaction with membranes.

LncRNA HAGLROS promotes breast cancer evolution through miR-135b-3p/COL10A1 axis and exosome-mediated macrophage M2 polarization.

Long non-coding RNAs (lncRNAs) play an important role in breast cancer progression, but the function of lncRNAs in regulating tumor-associated macrophages (TAMs) remains unclear. As carriers of lncRNAs, exosomes play an important role as mediators in the communication between cancer cells and the tumor microenvironment. In this study, we found that lncRNA HAGLROS was highly expressed in breast cancer tissues and plasma exosomes, and its high expression was related to the poor prognosis of breast cancer patients. Functionally, breast cancer cell-derived exosomal lncRNA HAGLROS promotes breast cancer cell proliferation, migration, epithelial-mesenchymal transition (EMT) process and angiogenesis by inducing TAM/M2 polarization. Mechanistically, lncRNA HAGLROS competitively binds to miR-135-3p to prevent the degradation of its target gene COL10A1. Collectively, these results indicated that the lncRNA HAGLROS/miR-135b-3p/COL10A1 axis promoted breast cancer progression, and revealed the interactive communication mechanism between breast cancer cells and TAMs, suggesting that lncRNA HAGLROS may be a potential biomarker and therapeutic target for breast cancer.

TMEM205 induces TAM/M2 polarization to promote cisplatin resistance in gastric cancer.

Cisplatin (DDP) is a basic chemotherapy drug for gastric cancer (GC). With the increase of DDP drug concentration in clinical treatment, cancer cells gradually became resistant. Therefore, it is necessary to find effective therapeutic targets to enhance the sensitivity of GC to DDP. Studies have shown that Transmembrane protein 205 (TMEM205) is overexpressed in DDP-resistant human epidermoid carcinoma cells and correlates with drug resistance, and database analyses show that TMEM 205 is also overexpressed in GC, but its role in cisplatin-resistant gastric cancer remains unclear. In this study, we chose a variety of experiments in vivo and vitro, aiming to investigate the role of TMEM 205 in cisplatin resistance in gastric cancer. The results showed that TMEM 205 promoted proliferation, stemness, epithelial-mesenchymal transition (EMT), migration and angiogenesis of gastric cancer cells through activation of the Wnt/ß-catenin signaling pathway. In addition, TMEM205 promotes GC progression by inducing M2 polarization of tumor-associated macrophages (TAMs). These results suggest that TMEM205 may be an effective target to regulate the sensitivity of GC to DDP, providing a new therapeutic direction for clinical treatment.

Enhancing Prosthetic Control through High-Fidelity Myoelectric Mapping with Molecular Anchoring Technology.

Myoelectric control utilizes electrical signals generated from the voluntary contraction of remaining muscles in an amputee's stump to operate a prosthesis. Precise and agile control requires low-level myoelectric signals (below 10% of maximum voluntary contraction, MVC) from weak muscle contractions such as phantom finger or wrist movements, but imbalanced calcium concentration in atrophic skin can distort the signals. This is due to poor ionic-electronic coupling between skin and electrode, which often causes excessive muscle contraction, fatigue, and discomfort during delicate tasks. To overcome this challenge, a new strategy called molecular anchoring is developed to drive hydrophobic molecular effectively interact with and embed into stratum corneum for high coupling regions between ionic fluxes and electronic currents. The use of hydrophobic poly(N-vinyl caprolactam) gel has resulted in an interface impedance of 20 kΩ, which is 1/100 of a commercial acrylic-based electrode, allowing the detection of ultralow myoelectric signals (≈1.5% MVC) that approach human limits. With this molecular anchoring technology, amputees operate a prosthesis with greater dexterity, as phantom finger and wrist movements are predicted with 97.6% accuracy. This strategy provides the potential for a comfortable human-machine interface when amputees accomplish day-to-day tasks through precise and dexterous myoelectric control.

Primary hepatic angiosarcoma with noncirrhotic portal hypertension: A case report.

Background: Primary hepatic angiosarcoma (PHA) is a rare malignant tumor of mesothelial tissue origin in the liver. The diagnosis of PHA relies on pathology, and it is frequently misdiagnosed as multiple hepatic hemangioma. Noncirrhotic portal hypertension is a relatively rare pathological manifestation, and there are few reports of PHA as an uncommon cause of noncirrhotic portal hypertension. Case summary: A 36-year-old male was admitted with abnormal liver function and suspected drug-induced liver injury (DILI), initially manifesting as multifocal hepatic hemangioma. The liver biopsy revealed features of noncirrhotic portal hypertension (NCPH), and the patient was eventually diagnosed with multifocal hepatic angiosarcoma. Conclusion: Patients with PHA may present with NCPH in the liver due to injury to hepatic sinusoids; therefore, it is necessary to consider the possibility of unsampled vascular malignancy when hepatic masses are identified, and the histology is consistent with PHA.

TLR8 agonist partially improves IFN-γ deficiency of NK cells in chronic hepatitis B through the synergy of monocytes.

BACKGROUND: Natural killer (NK) cells exhibit a selective deficiency of IFN-γ production in chronic hepatitis B (CHB). Toll-like receptor 8 (TLR8) agonists could induce IFN-γ production in immune cells, although their effects on the deficiency in NK cells remain unclear. AIMS: To investigate TLR8 expression in NK cells and the effect of TLR8 agonists in patients with CHB METHODS: We enrolled 32 patients with CHB and 19 healthy controls to assess TLR8 expression and IFN-γ production in NK cells. The sorted NK cells and monocytes were co-cultured to compare the extent of IFN-γ and IL-10 production after TLR8 agonist ssRNA40 stimulation. The synergic effect of NK cells and monocytes was assessed by blocking IL-12 and IL-18. We recruited another 22 patients with CHB undergoing nucleotide analogue (NA) therapy to explore the impact of antiviral treatment on the ssRNA40-mediated response of NK cells. RESULTS: In patients with CHB, TLR8 expression in NK cells was up-regulated, accompanied by insufficient IFN-γ production. The enhanced IFN-γ secretion by ssRNA40 in NK cells depended on monocyte-derived IL-12 and IL-18. NK cells displayed an imbalanced response to ssRNA40 in patients with CHB with a weak increase in IFN-γ despite a higher IL-10 production. The response was improved in patients with CHB undergoing NA therapy. CONCLUSIONS: In patients with CHB, targeting TLR8 partially rescues the IFN-γ insufficiency in NK cells. However, NK cells show an inhibitory response to TLR8 agonist stimulation. TLR8 agonist combined with NA may enhance the antiviral effect of NK cells.

PD-L1/p-STAT3 promotes the progression of NSCLC cells by regulating TAM polarization.

PD-L1 is closely related to the immune escape process of tumour cells, and targeted PD-L1 clinical immunotherapy has been implemented. However, whether PD-L1 is involved in TAM/M2 polarization in the TME of NSCLC and its specific mechanism remain unclear. In order to clarify the specific role of PD-L1 in NSCLC and to seek new treatments for NSCLC, we designed a series of experimental studies. After constructing the co-culture system and conditioned medium system, the proliferation, apoptosis, metastasis, angiogenesis, EMT process and stemness of NSCLC were detected by MTT, flow cytometry, Transwell, endothelial cell tube formation and western blot assays. The results showed that αPD-L1 reversed TAM/M2 polarization by suppressing STAT3 phosphorylation in TAM/M2, therapy inhibiting NSCLC cell migration, angiogenesis, EMT process and stemness. However, αPD-L1 had no effect on the proliferation and apoptosis abilities of NSCLC cells. In vivo experiments showed that αPD-L1 inhibited lung metastasis of NSCLC and reversed TAM/M2 polarization in TME. The study investigates the mechanism by which PD-L1 regulates TAMs polarization in TME and promotes malignant progression of NSCLC, providing a new theoretical basis for PD-L1 targeted therapy of NSCLC.

Self-Reporting Joule Heating Modulated Stiffness of Polymeric Nanocomposites for Shape Reconfiguration.

Shape reconfigurable devices, e.g., foldable phones, have emerged with the development of flexible electronics. But their rigid frames limit the feasible shapes for the devices. To achieve freely changeable shapes yet keep the rigidity of devices for user-friendly operations, stiffness-tunable materials are desired, especially under electrical control. However, current such systems are multilayer with at least a heater layer and a structural layer, leading to complex fabrication, high cost, and loss of reprocessability. Herein, we fabricate covalent adaptable networks-carbon nanotubes (CAN-CNT) composites to realize Joule heating controlled stiffness. The nanocomposites function as stiffness-tunable matrices, electric heaters, and softening sensors all by themselves. The self-reporting of softening is used to regulate the power control, and the sensing mechanism is investigated by simulating the CNT-polymer chain interactions at the nanoscale during the softening process. The nanocomposites not only have adjustable mechanical and thermodynamic properties but also are easy to fabricate at low cost and exhibit reprocessability and recyclability benefiting from the dynamic exchange reactions of CANs. Shape and stiffness control of flexible display systems are demonstrated with the nanocomposites as framing material, where freely reconfigurable shapes are realized to achieve convenient operation, wearing, or storage, fully exploiting their flexible potential.

PD­L1 mediates triple­negative breast cancer evolution via the regulation of TAM/M2 polarization.

Tumor­associated macrophages/M2­type (TAM/M2) play a key role in the metastasis and angiogenesis of cancer, and are considered to be critical targets for cancer treatment. However, it remains unclear whether α­programmed death­ligand 1 (αPD­L1; PD­L1 inhibitor) inhibits tumor progression via targeting TAMs. In the present study, it was demonstrated that αPD­L1 significantly inhibited IL­13­induced TAM/M2 polarization in vitro. Moreover, αPD­L1 inhibited the epithelial­mesenchymal transition (EMT) process and the stemness of triple­negative breast cancer (TNBC) cells, which were mediated via the reversal of TAM/M2 polarization. This therefore inhibited the migration and angiogenesis of TNBC cells. Furthermore, αPD­L1 prevented STAT3 phosphorylation and nuclear translocation, which resulted in the arrest of TAM/M2 polarization. In vivo experiments further demonstrated that αPD­L1 reduced the number of lung metastases without affecting tumor growth. Moreover, αPD­L1 reduced the expression levels of TAM/M2, EMT, stemness and vascular markers in tumor tissues. In summary, these data suggest that αPD­L1 plays a vital role in the anti­metastasis and anti­angiogenesis of TNBC in vitro and in vivo via the inhibition of TAM/M2 polarization. These findings may thus provide a novel therapeutic strategy for clinically refractory TNBC.

[Ginsenoside Rg3 Regulates Cisplatin Resistance in Gastric Cancer by Wnt/ß-catenin Signaling Pathway].

Objective To investigate the inhibitory effect of ginsenoside Rg3 combined with cisplatin (DDP) on DDP-resistant cell line SGC-7901/DDP and their molecular mechanism.Methods SGC-7901/DDP cells were divided into four groups including a control group,a ginsenoside Rg3 (40 µg/ml) treatment group,a DDP (1.40 µg/ml) treatment group,and a drug combination treatment group.The proliferation ability of SGC-7901/DDP cells was detected by MTT,EdU,and colony formation assays.The apoptosis ability of SGC-7901/DDP cell was detected by flow cytometry and Hoechst 33342 staining.The protein levels of apoptosis-related markers were detected by Western blotting.The migration ability of SGC-7901/DDP cells was detected by wound healing and Transwell assays.The expression levels of proteins in epithelial-mesenchymal transformation (EMT) and Wnt/ß-catenin signaling pathway were determined by Western blotting and immunofluorescence staining.Results Compared with the ginsenoside Rg3 or the DDP treatment groups,the drug combination treatment group inhibited the proliferation (t=8.062,P=0.001;t=7.090,P=0.002),colony formation (t=8.062,P=0.001;t=6.144,P=0.004),and migration (t=7.424,P=0.002;t=4.317,P=0.013),and promoted the apoptosis (t=5.530,P=0.031;t=6.036,P=0.026) of SGC-7901/DDP cells.Compared with the ginsenoside Rg3 and the DDP treatment groups,the drug combination treatment group down-regulated the expression levels of EMT-associated proteins including vimentin (t=24.450,P<0.001;t=14.750,P<0.001),Snail (t=29.640,P<0.001;t=70.700,P<0.001),Slug (t=89.230,P<0.001;t=87.360,P<0.001),matrix metalloproteinase (MMP) 2 (t=84.540,P<0.001;t=67.120,P<0.001),and MMP9 (t=19.010,P<0.001;t=10.890,P<0.001),as well as those of Wnt/ß-catenin signaling pathway related proteins including Wnt (t=35.480,P<0.001;t=14.670,P<0.001),ß-catenin (t=155.800,P<0.001;t=118.100,P<0.001),C-myc (t=20.870,P<0.001;t=3.334,P=0.029),and cyclin D1 (t=5.007,P=0.008;t=8.347,P=0.001).Meanwhile,it up-regulated the expression of epithelial cells including E-cadherin (t=36.450,P<0.001;t=33.810,P<0.001) and ZO-1 (t=37.060,P<0.001;t=37.030,P<0.001).Conclusion Ginsenoside Rg3 enhanced the sensitivity of SGC-7901/DDP cells to DDP by inhibiting the activity of Wnt/ß-catenin signaling pathway.

Prognostic value of Mortalin correlates with roles in epithelial-mesenchymal transition and angiogenesis in lung adenocarcinoma.

Mortalin is involved in the malignant phenotype of many cancers. However, the specific molecular mechanisms involving Mortalin in lung adenocarcinoma remain unclear. In this study, we showed that both Mortalin mRNA and protein are overexpressed in lung adenocarcinoma. In addition, Mortalin overexpression was positively correlated with poor overall survival. In vitro experiments showed that Mortalin silencing inhibited the proliferation, colony formation and migration abilities of A549 and H1299 cells. Mortalin promotes EMT progression, angiogenesis and tumor progression by activating the Wnt/ß-catenin signaling pathway. In vivo experiments further confirmed that Mortalin promoted malignant progression of lung adenocarcinoma. Taken together, our data suggest that Mortalin represents an attractive prognostic marker and therapeutic target in lung adenocarcinoma patients.

Mortalin promotes breast cancer malignancy.

Mortalin is a member of the heat shock protein 70 (HSP70) family that promotes the development of many cancers. It is reportedly a tumor promoter, but the mechanism of Mortalin in breast cancer is unclear. We designed a series of experiments to explore the correlation between Mortalin and the malignancy of breast cancer, and to assess the potential of Mortalin as a novel therapeutic target in breast cancer. The expression level of Mortalin in breast cancer tissues was detected. Then, we did a series of functional experiment. The findings indicated that Mortalin facilitates the proliferation, metastasis, and endothelial-to-mesenchymal transition (EMT) process of breast cancer. In our research, Mortalin is regulated EMT process and malignant progression of breast cancer through Wnt/ß-Catenin signaling pathway. The findings imply that Mortalin significantly promotes the progression of breast cancer malignancy and reduces patient survival, suggesting that Mortalin as a biomarker and prognostic factor in breast cancer.

Ground-glass Opacity Associated With Endobronchial Leech / Opacidad de vidrio esmerilado asociada a una sanguijuela endobronquial

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Condroma endobronquial: un caso atípico de obstrucción bronquial / Endobronchial chondroma: An unusual case of bronchial obstruction

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Sphingosine kinase 1/sphingosine 1-phosphate signalling pathway as a potential therapeutic target of pulmonary hypertension.

Pulmonary hypertension is characterized by extensive vascular remodelling, leading to increased pulmonary vascular resistance and eventual death due to right heart failure. The pathogenesis of pulmonary hypertension involves vascular endothelial dysfunction and disordered vascular smooth muscle cell (VSMC) proliferation and migration, but the exact processes remain unknown. Sphingosine 1-phosphate (S1P) is a bioactive lysophospholipid involved in a wide spectrum of biological processes. S1P has been shown to regulate VSMC proliferation and migration and vascular tension via a family of five S1P G-protein-coupled receptors (S1P1-SIP5). S1P has been shown to have both a vasoconstrictive and vasodilating effect. The S1P receptors S1P1 and S1P3 promote, while S1P2 inhibits VSMC proliferation and migration in vitro in response to S1P. Moreover, it has been reported recently that sphingosine kinase 1 and S1P2 inhibitors might be useful therapeutic agents in the treatment of empirical pulmonary hypertension. The sphingosine kinase 1/S1P signalling pathways may play a role in the pathogenesis of pulmonary hypertension. Modulation of this pathway may offer novel therapeutic strategies.