Based on the prognosis model of immunogenes, the prognosis model was constructed to predict the invasion of immune genes and immune cells related to primary liver cancer and its experimental validation.

Background: Primary liver cancer (PLC) is a prevalent malignancy of the digestive system characterized by insidious symptom onset and a generally poor prognosis. Recent studies have highlighted a significant correlation between the initiation and prognosis of liver cancer and the immune function of PLC patients. Purpose: Revealing the expression of PLC-related immune genes and the characteristics of immune cell infiltration provides assistance for the analysis of clinical pathological parameters and prognosis of PLC patients. Methods: PLC-related differentially expressed genes (DEGs) with a median absolute deviation (MAD > 0.5) were identified from TCGA and GEO databases. These DEGs were intersected with immune-related genes (IRGs) from the ImmPort database to obtain PLC-related IRGs. The method of constructing a prognostic model through immune-related gene pairs (IRGPs) is used to obtain IRGPs and conduct the selection of central immune genes. The central immune genes obtained from the selection of IRGPs are validated in PLC. Subsequently, the relative proportions of 22 types of immune cells in different immune risk groups are evaluated, and the differential characteristics of PLC-related immune cells are verified through animal experiments. Results: Through database screening and the construction of an IRGP prognosis model, 84 pairs of IRGPs (P < 0.001) were ultimately obtained. Analysis of these 84 IRGPs revealed 11 central immune genes related to PLC, showing differential expression in liver cancer tissues compared to normal liver tissues. Results from the CiberSort platform indicate differential expression of immune cells such as naive B cells, macrophages, and neutrophils in different immune risk groups. Animal experiments demonstrated altered immune cell proportions in H22 tumor-bearing mice, validating findings from peripheral blood and spleen homogenate analyses. Conclusion: Our study successfully predicted and validated PLC-related IRGs and immune cells, suggesting their potential as prognostic indicators and therapeutic targets for PLC.

BET bromodomain inhibitors PFI-1 and CPI-203 suppress the development of follicular lymphoma via regulating Wnt/ß-catenin signaling.

Objective: Follicular lymphoma (FL) is an indolent B-cell lymphoproliferative disorder, characterized by a lymphoid follicular pattern of growth. PFI-1 or CPI-203 has been known to effectively promote the inhibition of primary effusion lymphoma progression. This study aimed at investigating the anti-tumor properties of PFI-1 and CPI-203 on FL cells and uncover the underlying mechanism of action. Methods: FL cells were treated with PFI-1 and CPI-203, and the treated cells were evaluated for their cell viability, cell cycle and apoptosis using CCK8, flow cytometry, and Western blot assays. A xenograft mouse model was used for assessing the in vivo effects of CPI-203 on tumorigenesis. Results: PFI-1 or CPI-203 showed potential inhibitory effects on the cell viability of DOHH2 and RL cells in a dose-response-dependent manner. Furthermore, PFI-1 and CPI-203 inhibited cell growth, induced apoptosis of FL cells in vitro, and facilitated the translocation of ß-catenin into cytoplasm both in vitro and in vivo. After engrafted with FL cells, CPI-203-treated mice got a longer duration of survival and a smaller tumor size than control mice. Mechanistically, PFI-1 and CPI-203 impede the activity of ß-catenin and its downstream molecules by regulating the DVL2/GSK3ß axis. Conclusion: In conclusion, PFI-1 and CPI-203 may serve as potential anti-tumor inhibitors for the therapy of FL.

Quality of evidence supporting the role of hyperbaric oxygen therapy for diabetic foot ulcers.

The goal of this overview of systematic reviews (SRs) and meta-analyses (MAs) was to methodically gather, evaluate and summarize the data supporting the use of hyperbaric oxygen therapy (HBOT) to treat diabetic foot ulcers (DFUs). The Cochrane Library, Embase, PubMed, Web of Science and Embase were all searched thoroughly to identify SRs/MAs that qualified. AMSTAR-2 tool, PRISMA checklists and GRADE system were applied by two reviewers independently to assess the methodological quality, reporting and evidence quality of the included SRs/MAs, respectively. Eleven SRs/MAs were enrolled in this overview. According to AMSTAR-2, a very low methodological quality assessment was given to the included SRs/MAs due to the limitations of items 2, 4 and 7. For the PRISMA, the overall quality of reporting is not satisfactory due to missing reporting on protocol, search, as well as additional analysis. The majority of outcomes had low- to moderate-quality evidence, and no high-quality evidence was found to support the role of HBOT for DFUs, according to GRADE. To conclude, the potential of HBOT in treating DFUs is supported by evidence of low to moderate quality. More rigorously designed, high-level studies are needed in the future to determine the evidence for HBOT for DFU, including the timing, frequency and duration of HBOT interventions.

Astrocytes and microglia-targeted Danshensu liposomes enhance the therapeutic effects on cerebral ischemia-reperfusion injury.

Cerebral ischemia-reperfusion injury (CI/RI) is the main cause of disability and death in stroke without satisfactory therapeutic effect. Inflammation mediated by activation of astrocytes and microglia is the main pathological mechanism of CI/RI. Danshensu (DSS) has been shown to exert anti-inflammatory effects against brain injury. However, limited by its poor cellular permeability and low bioavailability, it is still needed the new DSS preparations with the ability to cross the blood-brain barrier (BBB) and target inflammatory glial cells. In this study, we developed phosphatidylserine (PS) and transferrin (TF) modified liposomes carrying DSS (TF/PS/DSS-LPs) to improve the therapeutic efficacy against ischemic stroke. First, TF molecules targeted transferrin receptor (TfR) that is overexpressed in the BBB. Following the liposomes enter the brain, PS modification allowed the liposomes to target and bind to the overexpressed phosphatidylserine-specific receptors (PSRs) on the surface of astrocytes and microglia. Furthermore, it enhanced the uptake of TF/PS/DSS-LPs by astrocytes and microglia, while polarizing astrocytes from A1 to A2 and microglia from M1 to M2, reducing neuronal inflammation, and ultimately ameliorating cerebral ischemic injury. Thus, TF/PS/DSS-LPs could potentially serve as a promising strategy for the CI/RI treatment.

[Mechanism of Zhenwu Decoction in improving renal inflammatory injury in mice with DN of spleen-kidney Yang deficiency syndrome by regulating ROCK/IKK/NF-κB pathway].

To investigate the intervention effect and mechanism of Zhenwu Decoction on diabetic nephropathy(DN) mice of spleen-kidney Yang deficiency syndrome based on the Rho-associated coiled-coil kinase(ROCK)/IκB kinase(IKK)/nuclear factor-κB(NF-κB) pathway. Ninety-five 7-week-old db/db male mice and 25 7-week-old db/m male mice were fed adaptively for one week. The DN model of spleen-kidney Yang deficiency syndrome was induced by Dahuang Decoction combined with hydrocortisone by gavage, and then the model was evaluated. After modeling, they were randomly divided into a model group, high-dose, medium-dose, and low-dose Zhenwu Decoction groups(33.8, 16.9, and 8.45 g·kg~(-1)·d~(-1)), and an irbesartan group(25 mg·kg~(-1)·d~(-1)), with at least 15 animals in each group. The intervention lasted for eight weeks. After the intervention, body weight and food intake were measured. Serum crea-tinine(Scr), blood urea nitrogen(BUN), fasting blood glucose(FBG), urinary albumin(uALb), and urine creatinine(Ucr) were determined. The uALb/Ucr ratio(ACR) and 24 h urinary protein(UTP) were calculated. Renal pathological morphology was evaluated by HE staining and Masson staining. The levels of key molecular proteins in the ROCK/IKK/NF-κB pathway were detected by Western blot. Enzyme-linked immunosorbent assay(ELISA) was used to detect interleukin-1ß(IL-1ß), interleukin-6(IL-6), interleukin-8(IL-8), interleukin-10(IL-10), and tumor necrosis factor-α(TNF-α). Compared with the blank group, the model group showed increased content of BUN, uALb, and SCr, increased values of 24 h UTP and ACR, decreased content of Ucr(P<0.05), enlarged glomeruli, thickened basement membrane, mesangial matrix proliferation, inflammatory cell infiltration, and collagen fiber deposition. The protein expression of ROCK1, ROCK2, IKK, NF-κB, phosphorylated IKK(p-IKK), phosphorylated NF-κB(p-NF-κB), and phosphorylated inhibitor of NF-κB(p-IκB) increased(P<0.05), while the protein expression of inhibitor of NF-κB(IκB) decreased(P<0.05). The levels of inflammatory factors IL-1ß, IL-6, IL-8, and TNF-α increased(P<0.05), while the level of IL-10 decreased(P<0.05). Compared with the model group, the groups with drug treatment showed decreased levels of BUN, uALb, SCr, 24 h UTP, and ACR, increased level of Ucr(P<0.05), and improved renal pathological status to varying degrees. The high-and medium-dose Zhenwu Decoction groups and the irbesartan group showed reduced protein expression of ROCK1, ROCK2, IKK, NF-κB, p-IKK, p-NF-κB, and p-IκB in the kidneys(P<0.05), increased protein expression of IκB(P<0.05), decreased levels of serum inflammatory factors IL-1ß, IL-6, IL-8, and TNF-α(P<0.05), and increased level of IL-10(P<0.05). Zhenwu Decoction can significantly improve renal function and renal pathological damage in DN mice of spleen-kidney Yang deficiency syndrome, and its specific mechanism may be related to the inhibition of inflammatory response by down-regulating the expression of key molecules in the ROCK/IKK/NF-κB pathway in the kidney.

Correlation between conventional ultrasound features combined with contrast-enhanced ultrasound patterns and pathological prognostic factors in malignant non-mass breast lesions.

OBJECTIVE: To investigate the correlation between ultrasound performance and prognostic factors in malignant non-mass breast lesions (NMLs). MATERIALS AND METHODS: This study included 106 malignant NMLs in 104 patients. Different US features and contrast enhancement patterns were evaluated. Prognostic factors, including histological types and grades, axillary lymph node and peritumoral lymphovascular status, estrogen and progesterone receptor status and the expression of HER-2 and Ki-67 were determined. A chi-square test and logistic regression analysis were used to analyse possible associations. RESULTS: Lesion size (OR: 3.08, p = 0.033) and posterior echo attenuation (OR: 8.38, p < 0.001) were useful in reflecting malignant NMLs containing an invasive carcinoma component. Posterior echo attenuation (OR: 7.51, p = 0.003) and unclear enhancement margin (OR: 6.50, p = 0.018) were often found in tumors with axillary lymph node metastases. Peritumoural lymphovascular invasion mostly exhibited posterior echo attenuation (OR: 3.84, p = 0.049) and unclear enhancement margin (OR: 8.68, p = 0.042) on ultrasound images. Perfusion defect was a comparatively accurate enhancement indicator for negative ER (OR: 2.57, p = 0.041) and PR (OR: 3.04, p = 0.008) expression. Calcifications (OR: 3.03, p = 0.025) and enlarged enhancement area (OR: 5.36, p = 0.033) imply an increased risk of positive HER-2 expression. Similarly, Calcifications (OR: 4.13, p = 0.003) and enlarged enhancement area (OR: 11.05, p < 0.001) were valid predictors of high Ki-67 proliferation index. CONCLUSION: Ultrasound performance is valuable for non-invasive prediction of prognostic factors in malignant NMLs.

A Knowledge Map of the Relationship between Diabetes and Stroke: A Bibliometric Analysis Study.

INTRODUCTION: The correlation between diabetes and stroke has been studied extensively in epidemiological research. Here we used bibliometric software to visualize and analyze the literature related to diabetic stroke to provide an overview of the current state of research, hot spots, and future trends in the field. METHODS: Based on the Web of Science Core Collection(WoSCC) database, we collected studies related to diabetic stroke from 2007 to May 2022. We used CiteSpace (version 6.1.R5), VOSviewer, and Sci-mago Graphica to create knowledge maps and conduct visual analyses on authors, countries, in-stitutions, cited references, and keywords, and Origin for statistical analysis. RESULTS: We included a total of 5171 papers on diabetic stroke from the WoSCC database. Overall, there was a steady increase in the number of publications, with a high number of emerging scientists. The United States was the most productive and influential country, which dominated national col-laborations. The most common subject category was "neurology". In total, 12 major clusters were generated from the cited references. Keywords analysis showed that keywords related to post-stroke injury and treatment are those with the highest burst intensity and latest burst time. CONCLUSIONS: Individual disease treatment remains a hot topic and how to balance acute stroke treatment and glycemic control is currently a difficult clinical problem. At the same time, the mechanism of their interaction and the prevention and treatment of related causative factors remain a hot topic of current and future research.

Transition metals anchored on two-dimensional p-BN support with center-coordination scaling relationship descriptor for spontaneous visible-light-driven photocatalytic nitrogen reduction.

Solar energy has the potential to revolutionize the production of ammonia, as it could provide a reliable and uninterrupted source of energy for the chemical reaction involved. However, improving the catalytic performance of catalysts often leads to a reduction in their band gaps, which results in insufficient photogenerated electron potential to realize the nitrogen reduction reaction (NRR), and thus the development of NRR efficient photocatalysts remains a great challenge. Herein, based on the density functional theory (DFT), a series of single-atom photocatalysts with transition metals (TMs) doped on porous boron nitride (p-BN) nanosheet are proposed for NRR. Among them, Re-B3@p-BN could effectively catalyze gas-phase N2 through the corresponding pathways with limiting potentials of 0.31 V. Meanwhile, it exhibits excellent light absorption efficiency under illumination and could spontaneously catalyse nitrogen fixation reactions due to the suitable forbidden band and high photogenerated electron potential. Moreover, a linear relationship descriptor based on the intrinsic properties has been established, using a machine learning approach by considering the combined effects of the central metal atom and the coordination atoms. This descriptor could help accelerate the development of rational and improved 2D NRR photocatalysts with high catalytic activity and high selectivity.

Innovative co-treatment technology for effective disposal of electrolytic manganese residue.

Electrolytic manganese residue (EMR) stockpiles contain significant amounts of Mn2+ and NH4+-N which pose a risk of environmental pollution. For EMR safe disposal, an innovative approach is proposed that involves direct sodium silicate-sodium hydroxide (Na2SiO3-NaOH) collaborative technology. This approach utilises Na2SiO3 and NaOH as the solidifying agent and activator, respectively, to treat EMR without hazardous effects. The study also provides insights into the kinetics of Mn2+ leaching under the effect of Na2SiO3-NaOH. Leaching efficiency was determined by varying parameters such as stirring rate, reaction temperature, pH of the initial solution, Na2SiO3 concentration, and reaction time to investigate the efficacy of this method. The study indicates that the co-treatment technology of Na2SiO3-NaOH can achieve maximum solidification efficiencies of 99.7% and 98.2% for Mn2+ and NH4+-N, respectively. The process can successfully solidify Mn2+ by synthesising Mn(OH)2 and MnSiO3 in an alkaline environment under optimal conditions including stirring rate of 450 rpm, initial solution pH of 8, test temperature of 40 °C, test time of 420 min, and Na2SiO3 content of 5%. The findings of this study have confirmed that surface chemistry plays a vital role in regulating the test rate and the proposed equation accurately describes Mn2+ leaching kinetics. Overall, the co-treatment technology involving Na2SiO3-NaOH is a viable solution for EMR resource utilisation without compromising environmental safety. This method has the potential to be implemented for other waste streams with comparable compositions, ultimately promoting the sustainable management of waste.

The prognostic index PRIMA-PI combined with Ki67 as a better predictor of progression of disease within 24 months in follicular lymphoma.

Background: Progression of disease within 24 months (POD24) is a risk factor for poor survival in follicular lymphoma (FL), and there is currently no optimal prognostic model to accurately predict patients with early disease progression. How to combine traditional prognostic models with new indicators to establish a new prediction system, to predict the early progression of FL patients more accurately is a future research direction. Methods: This study retrospectively analyzed patients with newly diagnosed FL patients in Shanxi Provincial Cancer Hospital from January 2015 to December 2020. Data from patients undergoing immunohistochemical detection (IHC) were analyzed using χ2 test and multivariate Logistic regression. Also, we built a nomogram model based on the results of LASSO regression analysis of POD24, which was validated in both the training set and validation set, and additional external validation was performed using a dataset (n = 74) from another center, Tianjin Cancer Hospital. Results: The multivariate Logistic regression results suggest that high-risk PRIMA-PI group, Ki-67 high expression represent risk factors for POD24 (P<0.05). Next, PRIMA-PI and Ki67 were combined to build a new model, namely, PRIMA-PIC to reclassify high and low-risk groups. The result showed that the new clinical prediction model constructed by PRIMA-PI with ki67 has a high sensitivity to the prediction of POD24. Compared to PRIMA-PI, PRIMA-PIC also has better discrimination in predicting patient's progression-free survival (PFS) and overall survival (OS). In addition, we built nomogram models based on the results of LASSO regression (histological grading, NK cell percentage, PRIMA-PIC risk group) in the training set, which were validated using internal validation set and external validation set, we found that C-index and calibration curve showed good performance. Conclusion: As such, the new predictive model-based nomogram established by PRIMA-PI and Ki67 could well predict the risk of POD24 in FL patients, which boasts clinical practical value.

Prognostic nomograms for gastric carcinoma after D2 + total gastrectomy to assist decision-making for postoperative treatment: based on Lasso regression.

OBJECTIVE: This study aimed to establish novel nomograms that could be used to predict the prognosis of gastric carcinoma patients who underwent D2 + total gastrectomy on overall survival (OS) and progression-free survival (PFS). METHODS: Lasso regression was employed to construct the nomograms. The internal validation process included bootstrapping, which was used to test the accuracy of the predictions. The calibration curve was then used to demonstrate the accuracy and consistency of the predictions. In addition, the Harrell's Concordance index (C-index) and time-dependent receiver operating characteristic (t-ROC) curves were used to evaluate the discriminative abilities of the new nomograms and to compare its performance with the 8th edition of AJCC-TNM staging. Furthermore, decision curve analysis (DCA) was performed to assess the clinical application of our model. Finally, the prognostic risk stratification of gastric cancer was conducted with X-tile software, and the nomograms were converted into a risk-stratifying prognosis model. RESULTS: LASSO regression analysis identified pT stage, the number of positive lymph nodes, vascular invasion, neural invasion, the maximum diameter of tumor, the Clavien-Dindo classification for complication, and Ki67 as independent risk factors for OS and pT stage, the number of positive lymph nodes, neural invasion, and the maximum diameter of tumor for PFS. The C-index of OS nomogram was 0.719 (95% CI: 0.690-0.748), which was superior to the 8th edition of AJCC-TNM staging (0.704, 95%CI: 0.623-0.783). The C-index of PFS nomogram was 0.694 (95% CI: 0.654-0.713), which was also better than that of the 8th edition of AJCC-TNM staging (0.685, 95% CI: 0.635-0.751). The calibration curves, t-ROC curves, and DCA of the two nomogram models showed that the prediction ability of the two nomogram models was outstanding. The statistical difference in the prognosis between the low- and high-risk groups further suggested that our model had an excellent risk stratification performance. CONCLUSION: We reported the first risk stratification and nomogram for gastric carcinoma patients with total gastrectomy in Chinese population. Our model could potentially be used to guide treatment selections for the low- and high-risk patients to avoid delayed treatment or unnecessary overtreatment.

Novel synergistic mechanism of 11-keto-ß-boswellic acid and Z-Guggulsterone on ischemic stroke revealed by single-cell transcriptomics.

Although strides have been made, the challenge of preventing and treating ischemic stroke continues to persist globally. For thousands of years, the natural substances Frankincense and Myrrh have been employed in Chinese and Indian medicine to address cerebrovascular diseases, with the key components of 11-keto-ß-boswellic acid (KBA) and Z-Guggulsterone (Z-GS) being the active agents. In this study, the synergistic effect and underlying mechanism of KBA and Z-GS on ischemic stroke were examined using single-cell transcriptomics. Fourteen cell types were identified in KBA-Z-GS-treated ischemic penumbra, and microglia and astrocytes account for the largest proportion. They were further re-clustered into six and seven subtypes, respectively. GSVA analysis reflected the distinct roles of each subtype. Pseudo-time trajectory indicated that Slc1a2 and Timp1 were core fate transition genes regulated by KBA-Z-GS. In addition, KBA-Z-GS synergistically regulated inflammatory reactions in microglia and cellular metabolism and ferroptosis in astrocytes. Most notably, we established an innovative drug-gene synergistic regulation pattern, and genes regulated by KBA-Z-GS were divided into four categories based on this pattern. Finally, Spp1 was demonstrated as the hub target of KBA-Z-GS. Taken together, this study reveals the synergistic mechanism of KBA and Z-GS on cerebral ischemia, and Spp1 may be the synergistic target for that. Precise drug development targeting Spp1 may offer a potential therapeutic approach for treating ischemic stroke.

Single-Cell RNA Sequencing Reveals Unique Alterations in the Immune Panorama and Treg Subpopulations in Mice during the Late Stages of Echinococcus granulosus Infection.

Cystic echinococcosis (CE) is a common zoonotic parasitic disease that seriously impacts public health. However, the full spectrum of immune cell changes in Echinococcus granulosus infection, especially the negative immune regulation of subpopulations of regulatory T (Treg) cells, are not yet well understood. In this study, we used single-cell RNA sequencing and immunome repertoire (IR) sequencing to analyze 53,298 cells from the spleens and peripheral blood mononuclear cells (PBMCs) of healthy and E. granulosus-infected mice. We used immunofluorescence combined with RNA fluorescence in situ hybridization and quantitative real-time PCR to verify the sequencing results. Our results showed tissue-specific immune system alterations in mice infected with E. granulosus. E. granulosus-infected mice induced a subpopulation of CD4+ cells with type I interferon production potential. Furthermore, there were six different Treg cell subpopulations in vivo at three stages of differentiation, and Treg subpopulations of different classes and different stages of differentiation showed tissue specificity. After infection, the Lag3hi Treg and Gpr83+Igfbp4+ naive Treg subpopulations were specifically induced in PBMCs and the spleen, respectively. Furthermore, T follicular helper 2 (Tfh2) cells with high expression of Cxxc5 and Spock2 were found in E. granulosus-infected mice. Our data uncovered changes in the full spectrum of immune cells in mice following the late stages of E. granulosus infection, including subpopulations of cells that have not been emphasized in previous studies. These results further enrich the study of the bidirectional immunomodulatory mechanism and offer a different perspective for subsequent studies of infection in E. granulosus.

Feasibility of low-carbon electrolytic manganese residue-based supplementary cementitious materials.

In this work, the electrolytic manganese residues (EMR) were used as sulfate activators for fly ash and granulated blast-furnace slag to fabricate highly reactive supplementary cementitious materials (SCMs). The findings promote the implementation of a win-win strategy for carbon reduction and waste resource utilisation. The effects of EMR dosing on the mechanical properties, microstructure and CO2 emission of the EMR-doped cementitious materials are investigated. The results show that low dosing EMR (5 %) produced more ettringite, fostering early strength development. The fly ash-doped mortar strength increases and then decreases with the addition of EMR from 0 to 5 % to 5-20 %. It was found that blast furnace slag contributes less to strength than fly ash. Moreover, the sulfate activation and the micro-aggregate effect compensate for the EMR-induced dilution effect. The significant increase in strength contribution factor and direct strength ratio at each age verifies the sulfate activation of EMR. The lowest EIF90 value of 5.4 kg∙MPa-1∙m3 was achieved for the fly ash-doped mortar with 5 % EMR, suggesting the synergistic effect between fly ash and EMR optimised the mechanical properties while maintaining lower CO2 emissions.

Cistanche tubulosa alleviates ischemic stroke-induced blood-brain barrier damage by modulating microglia-mediated neuroinflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Ischemic stroke (IS) has both high morbidity and mortality. Previous research conducted by our group demonstrated that the bioactive ingredients of the traditional medicinal and edible plant Cistanche tubulosa (Schenk) Wight (CT) have various pharmacological effects in treating nervous system diseases. However, the effect of CT on the blood-brain barrier (BBB) after IS are still unknown. AIM OF THE STUDY: This study aimed to identify CT's curative effect on IS and explore its underlying mechanism. MATERIALS AND METHODS: IS injury was established in a rat model of middle cerebral artery occlusion (MCAO). Gavage administration of CT at dosages of 50, 100, and 200 mg/kg/day was carried out for seven consecutive days. Network pharmacology was used for predicting the pathways and potential targets of CT against IS, and subsequent studies confirmed the relevant targets. RESULTS: According to the results, both neurological dysfunction and BBB disruption were exacerbated in the MCAO group. Moreover, CT improved BBB integrity and neurological function and protected against cerebral ischemia injury. Network pharmacology revealed that IS might involve neuroinflammation mediated by microglia. Extensive follow-up studies verified that MCAO caused IS by stimulating the production of inflammatory factors and microglial infiltration. CT was found to influence neuroinflammation via microglial M1-M2 polarization. CONCLUSION: These findings suggested that CT may regulate microglia-mediated neuroinflammation by reducing MCAO-induced IS. The results provide theoretical and experimental evidence for the efficacy of CT therapy and novel concepts for the prevention and treatment of cerebral ischemic injuries.

Prediction of Compressive Strength of Fly Ash-Slag Based Geopolymer Paste Based on Multi-Optimized Artificial Neural Network.

The fly ash-slag geopolymer is regarded as one of the new green cementitious materials that can replace cement, but it is difficult to predict its mechanical properties by conventional methods. Therefore, in the present study, the back propagation (BP) artificial neural network technique is used to predict the compressive strength of the fly ash-slag geopolymer. In this paper, data from the published literature were collected as the training set and the experimental results from laboratory experiments were used as the test set. Eight input parameters were determined, as follows: the percentage of fly ash, the percentage of slag, the water-cement ratio, the curing age, the modulus of alkali activator, the mass ratio of NaOH to Na2SiO3 and the moles of Na2O and SiO2 in the alkali activator. Three multilayer artificial neural network models were constructed using the Levenberg-Marquardt (LM), Bayesian regularization (BR) and scaled conjugate gradient (SCG) algorithms to compare the prediction accuracy of the compressive strength of the fly ash-slag geopolymer paste at different ages (3, 7, and 28 d). It was concluded that the training set error of the BR-BP neural network was the smallest. Ultimately, the hyperparameter optimization of the BR-BP neural network was carried out to compare the training set and the test set errors before and after the optimization, and the results show that the BR-BP neural network model with hyperparameter optimization had the highest prediction accuracy.

New Insights into the Structural and Binding Properties on Aß Mature Fibrils Due to Histidine Protonation Behaviors.

Histidine tautomeric behaviors have been considered origin factors for controlling the structure and aggregation properties of misfolding peptides. Except for tautomeric behaviors, histidine protonation behaviors definitely have the same capacities due to the net charge changes and the various N/N-H orientations on imidazole rings. However, such phenomena are still unknown. In the current study, Aß mature fibrils substituted with various protonation states were performed by molecular dynamics simulations to investigate the structure and binding properties. Our results show that all kinds of protonation states can increase the ΔG1 stability and decrease ΔG2 and ΔG3 stabilities. A significantly higher averaged ß-sheet content was detected in (εεp), (εpp), and (ppp) fibrils in one, two, and three protonation stages, respectively. Impressively, we found that the substituted fibril with specific protonated states can control the N-terminus structural properties. Further analysis confirmed that H6 and H13 are more important than H14 since the H-bond donor and receptor cooperate among C1/C3/C8_H6, C1/C3/C8_H13, and C1/C3/C8_E11. Furthermore, the mechanism of protonation behaviors was discussed. The current study is helpful for understanding the histidine protonation behaviors on one, two, and three protonation stages, which provides new horizons for exploring the origin of protein folding and misfolding.

Hierarchical DNA branch assembly-encoded fluorescent nanoladders for single-cell transcripts imaging.

Spatial visualization of single-cell transcripts is limited by signal specificity and multiplexing. Here, we report hierarchical DNA branch assembly-encoded fluorescent nanoladders, which achieve denoised and highly multiplexed signal amplification for single-molecule transcript imaging. This method first offers independent RNA-primed rolling circle amplification without nonspecific amplification based on circular DNAzyme. It then executes programmable DNA branch assembly on these amplicons to encode virtual signals for visualizing numbers of targets by FISH. In theory, more virtual signals can be encoded via the increase of detection spectral channels and repeats of the same sequences on barcode. Our method almost eliminates nonspecific amplification in fixed cells (reducing nonspecific spots of single cells from 16 to nearly zero), and achieves simultaneous quantitation of nine transcripts by using only two detection spectral channels. We demonstrate accurate RNA profiling in different cancer cells, and reveal diverse localization patterns for spatial regulation of transcripts.

Concentration Effect, Structural Properties, and Driving Force on Aß28 Dimerization with and without Zn2+ Cooperation: Learning from Replica Exchange Sampling.

Zn2+ is a very important factor in promoting the formation of amyloid beta (Aß) aggregates and amyloid plaques. The Zn2+ -bound Aß species generate amorphous or low molecular-weight oligomers. However, it is a lack of studies to approach the starting structural features (dimerization) in Aß nucleation processes with and without Zn2+ , which is the key point in understanding Zn2+ -induced nucleation mechanisms. To better understand the effect of concentration, structural properties, and the driving force, 14 independent replica exchange molecular dynamics simulations were performed in Aß28 dimerization with and without Zn2+ (zAß28 ) cooperation. Our scanning results show that the aggregation propensity is easier in Aß28 -Aß28 and Aß28 -zAß28 systems than zAß28 -zAß28 system. In binding property, the Aß28 -Aß28 model (-61.5 kcal mol-1 ) is stronger than zAß28 -zAß28 (-26.6 kcal mol-1 ) and Aß28 -zAß28 (-7.24 kcal mol-1 ) models. Further analysis confirmed that H13 and H14 residues play specific roles in the three systems. The key point is the orientation of N atom of the imidazole ring in histidine residues. Furthermore, we discovered different driving forces for each system. Our current study contributes to the understanding of how the Aß28 dimer interacts with Zn2+ , which could lead to new insights into Zn2+ -induced nucleation mechanisms.

Frankincense-Myrrh treatment alleviates neuropathic pain via the inhibition of neuroglia activation mediated by the TLR4/MyD88 pathway and TRPV1 signaling.

BACKGROUND: Neuroglia are important modulators of neuronal functionality, and thus play an integral role in the pathogenesis and treatment of neuropathic pain (NP). According to traditional Chinese medicine, Frankincense-Myrrh is capable of "activating blood and dissipating blood stasis", and as such these two biological compounds are commonly used to treat NP, however, the mechanisms underlying the efficacy of such treatment are unclear. PURPOSE: This study aimed to further elucidate the protective effects associated with the Frankincense-Myrrh treatment of NP. METHODS: A chronic sciatic nerve compression injury (CCI) model of NP was established, after which animals were gavaged with Frankincense, Myrrh, Frankincense-Myrrh, or the positive control drug pregabalin for 14 days. Network pharmacology approaches were used to identify putative pathways and targets associated with the Frankincense-Myrrh-mediated treatment of NP, after which these targets were subjected to in-depth analyses. The impact of TLR4 blockade on NP pathogenesis was assessed by intrathecally administering a TLR4 antagonist (LRU) or the MyD88 homodimerization inhibitory peptide (MIP). RESULTS: Significant alleviation of thermal and mechanical hypersensitivity in response to Frankincense and Myrrh treatment was observed in NP model mice, while network pharmacology analyses suggested that the pathogenesis of NP may be related to TLR4/MyD88-mediated neuroinflammation. Consistently, Frankincense-Myrrh treatment was found to reduce TLR4, MyD88, and p-p65 expression in spinal dorsal horn neuroglia from treated animals, in addition to inhibiting neuronal TRPV1 and inflammatory factor expression. Intrathecal LRU and MIP delivery were sufficient to alleviate thermal and mechanical hyperalgesia in these CCI model mice, with concomitant reductions in neuronal TRPV1 expression and neuroglial activation in the spinal dorsal horn. CONCLUSION: These data suggest that Frankincense-Myrrh treatment was sufficient to alleviate NP in part via inhibiting TLR4/MyD88 pathway and TRPV1 signaling activity. Blocking TLR4 and MyD88 activation may thus hold value as a means of treating NP.