Hederagenol improves multiple sclerosis by modulating Th17 cell differentiation.

Multiple sclerosis (MS) is a common autoimmune illness that is difficult to treat. The upregulation of Th17 cells is critical in the pathological process of MS. Hederagenol (Hed) has been shown to lower IL-17 levels, although its role in MS pathophysiology is uncertain. In this study, we explore whether Hed could ameliorate MS by modulating Th17 cell differentiation, with the goal of identifying new treatment targets for MS. The experimental autoimmune encephalomyelitis (EAE) mouse model was conducted and Hed was intraperitoneally injected into mice. The weight was recorded and the clinical symptom grade was assessed. Hematoxylin-eosin staining was carried out to determine the extent of inflammation in the spinal cord and liver. The luxol Fast Blue staining was performed to detect the pathological changes in the myelin sheath. Nerve damage was detected using NeuN immunofluorescence staining and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining. Immunohistology approaches were used to study alterations in immune cells in the spinal cord. The proportions of T cell subsets in the spleens were analyzed by flow cytometry. RORγt levels were measured using quantitative real-time PCR or Western blot. The activity of the RORγt promoter was analyzed by Chromatin immunoprecipitation. Hed administration reduced the clinical symptom grade of EAE mice, as well as the inflammatory infiltration, demyelination, and cell disorder of the spinal cord, while having no discernible effect on the mouse weight. In addition, Hed treatment significantly reduced the number of T cells, particularly Th17 cells in the spinal cord and spleen-isolated CD4+ T cells. Hed lowered the RORγt levels in spleens and CD4+ T cells and overexpression of RORγt reversed the inhibitory effect of Hed on Th17 differentiation. Hed decreased nerve injury by modulating Th17 differentiation through the RORγt promoter. Hed regulates Th17 differentiation by reducing RORγt promoter activity, which reduces nerve injury and alleviates EAE.

Reconstruction of Missing Electrocardiography Signals from Photoplethysmography Data Using Deep Neural Network.

ECG helps in diagnosing heart disease by recording heart activity. During long-term measurements, data loss occurs due to sensor detachment. Therefore, research into the reconstruction of missing ECG data is essential. However, ECG requires user participation and cannot be used for continuous heart monitoring. Continuous monitoring of PPG signals is conversely low-cost and easy to carry out. In this study, a deep neural network model is proposed for the reconstruction of missing ECG signals using PPG data. This model is an end-to-end deep learning neural network utilizing WNet architecture as a basis, on which a bidirectional long short-term memory network is added in establishing a second model. The performance of both models is verified using 146 records from the MIMIC III matched subset. Compared with the reference, the ECG reconstructed using the proposed model has a Pearson's correlation coefficient of 0.851, root mean square error (RMSE) of 0.075, percentage root mean square difference (PRD) of 5.452, and a Fréchet distance (FD) of 0.302. The experimental results demonstrate that it is feasible to reconstruct missing ECG signals from PPG.

Insights into the mechanism of the solvolysis of propylene oxide over titanium silicalite-1: a theoretical study.

In order to probe into the mechanism of solvolysis (alcoholysis/hydrolysis) of propylene oxide (PO), the formation of propylene glycol (PG), 1-methoxy-2-propanol (PPM) and 2-methoxy-1-propanol (SPM) over the TS-1 catalyst with tetrahedral Ti and Ti/defect sites was systematically discussed using an embedded quantum mechanical/molecular mechanics (QM/MM) approach. The results showed that the activity of PO solvolysis is closely related to the ring-opening ability of active substances, and the ring-opening ability is in the following order: Si-O(H)-Ti > Ti-OH > 5MR Ti-OOH > Ti-OCH3 (tetrahedral Ti site); 3MR Ti-OOH > Ti-OH > 5MR Ti-OOH > Ti-OCH3 (Ti/defect site). At the tetrahedral site, the concerted mechanism is the dominant pathway for PO ring opening to form PPM, while a competitive relationship exists between stepwise and concerted mechanisms to form PG and SPM. Si-O(H)-Ti exhibits excellent PO ring-opening activity because of its strong Brønsted acidity, but it is difficult to form. At the Ti/defect site, the stepwise mechanism via PO ring opening with 3MR Ti-OOH and then successive hydrolysis/alcoholysis to form product is the dominant pathway. The overall energy barrier of the optimal route is relatively lower as compared to the tetrahedral Ti site. This work opens up a new path for providing more information on the detailed mechanism in the solvolysis of PO over the TS-1 catalyst from a theoretical point of view.

Imrecoxib and celecoxib affect sacroiliac joint inflammation in axSpA by regulating bone metabolism and angiogenesis.

OBJECTIVE: To analyze the changes in the levels of bone metabolism markers related to sacroiliac joint (SIJ) inflammation in patients with axial spondyloarthritis (axSpA) after treatment with imrecoxib and celecoxib and evaluate their relationship with clinical efficacy. METHODS: A total of 120 patients with axSpA with at least 2 magnetic resonance imaging (MRI) SIJ scans during a 12-week follow-up were enrolled. The levels of bone metabolism markers, including dickkopf-1(DKK-1), sclerostin, vascular endothelial growth factor (VEGF), bone morphogenetic protein-2 (BMP-2), osteoprotegerin (OPG), noggin, ß-catenin, and RUNX2, were measured twice, and their association with disease activity and the Spondyloarthritis Research Consortium of Canada (SPARCC) score for SIJ were analyzed by univariate analysis of covariance. RESULTS: A total of 116 patients completed the follow-up. The levels of sclerostin, OPG, noggin, DKK-1, and RUNX2 were increased, whereas those of VEGF and ß-catenin were decreased. The levels of sclerostin and OPG were negatively correlated with disease duration. The levels of VEGF and ß-catenin were significantly decreased (F = 7.866, P = 0.003; F = 4.106, P = 0.047) in patients with disease remission. A decrease in ESR was significantly correlated with decreased levels of Runx2 and SPARCC scores, with the levels of sclerostin being significantly elevated in the SPARCC-reduced group. There were no statistically significant differences between the imrecoxib and celecoxib groups (P> 0.05). CONCLUSION: Imrecoxib and celecoxib affect SIJ inflammation, disease activity, and the course of disease by regulating bone metabolism and angiogenesis in axSpA. Key Points •After treatment with imrecoxib and celecoxib, the levels of sclerostin, OPG, noggin, DKK-1, and RUNX2 were increased, whereas those of VEGF and ß-catenin were decreased, correlating with the course of disease, disease activity, and SIJ inflammation. • A decrease in ESR was significantly correlated with a decrease in the levels of RUNX2 and SIJ inflammation.. • The levels of sclerostin were more significantly elevated in SIJ inflammation remission group.. •Imrecoxib and celecoxib affect SIJ inflammation by regulating bone metabolism and angiogenesis in axSpA..

Microstructure and mechanical properties of the Mg-Gd-Zn alloy prepared by sintering of rapidly-solidified ribbons.

Mg-15Gd-1Zn (wt.%) alloy was successfully prepared via the spark plasma sintering rapid solidification ribbons process. Microstructure investigation showed that the sintered alloys consisted of fine grains, the ß1 phase, and long-perioded stacking ordered phase (LPSO). The sintering temperature and time have a significant effect on the microstructural evolution. A lower sintering temperature (430 °C ) was beneficial for obtaining finer grain sizes with less than 5 µm and a higher content of ß1 phase with a content of 3-15 vol.% and a size-distribution of (10-600) nm. A higher temperature for a longer sintering time, 450-470 °C and 5-10 min, helpfully promoted precipitating the abundantly lamellar LPSO phase, and its content was 2-10 vol.% for LPSO phase with the width of (10-100) nm. The mechanical properties indicated that the fine grain size and supersaturated solid solution contributed at least 50% of the yield stress, and the residual contribution was related to the ß1 phase and LPSO phase strengthening, which were based on their contents and the sizes.

Robust Reconstruction of Electrocardiogram Using Photoplethysmography: A Subject-Based Model.

Electrocardiography and photoplethysmography are non-invasive techniques that measure signals from the cardiovascular system. While the cycles of the two measurements are highly correlated, the correlation between the waveforms has rarely been studied. Measuring the photoplethysmogram (PPG) is much easier and more convenient than the electrocardiogram (ECG). Recent research has shown that PPG can be used to reconstruct the ECG, indicating that practitioners can gain a deep understanding of the patients' cardiovascular health using two physiological signals (PPG and ECG) while measuring only PPG. This study proposes a subject-based deep learning model that reconstructs an ECG using a PPG and is based on the bidirectional long short-term memory model. Because the ECG waveform may vary from subject to subject, this model is subject-specific. The model was tested using 100 records from the MIMIC III database. Of these records, 50 had a circulatory disease. The results show that a long ECG signal could be effectively reconstructed from PPG, which is, to our knowledge, the first attempt in this field. A length of 228 s of ECG was constructed by the model, which was trained and validated using 60 s of PPG and ECG signals. To segment the data, a different approach that segments the data into short time segments of equal length (and that do not rely on beats and beat detection) was investigated. Segmenting the PPG and ECG time series data into equal segments of 1-min width gave the optimal results. This resulted in a high Pearson's correlation coefficient between the reconstructed 228 s of ECG and referenced ECG of 0.818, while the root mean square error was only 0.083 mV, and the dynamic time warping distance was 2.12 mV per second on average.

Edge-Preserving Median Filter and Weighted Coding with Sparse Nonlocal Regularization for Low-Dose CT Image Denoising Algorithm.

The impulse noise in CT image was removed based on edge-preserving median filter algorithm. The sparse nonlocal regularization algorithm weighted coding was used to remove the impulse noise and Gaussian noise in the mixed noise, and the peak signal-to-noise ratio (PSNR) and structural similarity index (SSIM) were calculated to evaluate the quality of the denoised CT image. It was found that in nine different proportions of Gaussian noise and salt-and-pepper noise in Shepp-Logan image and CT image processing, the PSNR and SSIM values of the proposed denoising algorithm based on edge-preserving median filter (EP median filter) and weighted encoding with sparse nonlocal regularization (WESNR) were significantly higher than those of using EP median filter and WESNR alone. It was shown that the weighted coding algorithm based on edge-preserving median filtering and sparse nonlocal regularization had potential application value in low-dose CT image denoising.

Down-regulated miR-374c and Hsp70 promote Th17 cell differentiation by inducing Fas expression in experimental autoimmune encephalomyelitis.

OBJECTIVE: Fas is a positive regulator of Th17 cells differentiation in experimental autoimmune encephalomyelitis (EAE). However, its upstream regulators are still not fully determined. This study was designed to explore the upstream regulators of Fas in regulating Th17 cells differentiation in EAE. METHODS: The mouse model of EAE was established by myelin oligodendrocyte glycoprotein injection. Th17 cells differentiation was induced by IL-23, IL-6 and TGF-ß. RESULTS: Down-regulated Hsp70 and miR-374c and up-regulated Fas were observed in the spleen and brain of EAE mice. Hsp70 overexpression evidently reduced Fas protein level, but not mRNA level. The luciferase reporter assay indicated that miR-374c targets Fas. Overexpression of miR-374c down-regulated the mRNA and protein level of Fas. The concentration of IL-17A in CD4+ T-cells was reduced by miR-374c or Hsp70 overexpression, and Fas overexpression altered this trend. Hsp70 did not regulate the expression of miR-374c, and likewise, miR-374c did not regulate the expression of Hsp70. Further results suggested that Hsp70 and miR-374c regulated Fas expression through different ways to affect Th17 cells differentiation in EAE. CONCLUSIONS: This study suggested that down-regulated miR-374c and Hsp70 promote Th17 cell differentiation by inducing Fas expression in EAE.

ORY-1001 Suppresses Cell Growth and Induces Apoptosis in Lung Cancer Through Triggering HK2 Mediated Warburg Effect.

ORY-1001, an inhibitor of covalent lysine (K)-specific demethylase 1A (KDM1A), has been used as a therapy for the treatment of acute leukemia. However, the underlying mechanisms of anticancer are still not fully elucidated. Here, we report that KDM1A is highly expressed in lung cancers, where it appears to drive aggressive growth. Furthermore, lung cancer patients with higher KDM1A levels have worse survival outcomes than patients with lower KDM1A levels. Interestingly, ORY-1001significantly inhibited the cell proliferation, colony formation, cell cycle, and induced apoptosis, by regulating the Warburg effect through controlling Hexokinases 2 (HK2) expression. In summary, these results indicate that ORY-1001 could inhibit the growth of lung cancer cells via regulating the Warburg effect by controlling HK2.

Anti-N-methyl-D-aspartate receptor encephalitis: A case report.

RATIONALE: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an auto-immune and paraneoplastic encephalitis with prominent neuropsychiatric manifestations. The N-methyl-D-aspartate receptor is located in the forebrain and hippocampus and plays a role in learning and memory. PATIENT CONCERNS: A 29-year-old female patient with anti-NMDAR encephalitis, was reported and we also reviewed the literature and summarised the characteristics of the cases. DIAGNOSES: In the present study, we reported 1 patient with anti-NMDAR encephalitis diagnosed by the detection of anti-NMDAR antibodies in serum and cerebrospinal fluid (CSF). INTERVENTIONS: The patient received glucocorticoids and anti-epilepsy treatment as well as human immunoglobulin treatment. OUTCOMES: After treatment, the patient gradually regained consciousness and was discharged after 3 months of rehabilitation. At the follow-up 2 months later, the patient had the sequelae of memory impairment and limb movement disorders. LESSONS: An accurate early diagnosis and active treatment are crucial to the improvement in the prognosis of patients with anti-NMDAR receptor encephalitis.

Blau syndrome with good Reponses to Tocilizumab: A case report and focused literature review.

OBJECTIVES: Blau syndrome (BS), a rare auto-inflammatory granulomatous disease, is a progressive disorder. Usually the maintenance dose of glucocorticoid may not be tapered below 15 mg per day while immunosuppressives is used. There has been some experience with biologic agents in refractory BS patients. The objective of this study is to describe the case of a BS patient benefiting from Tocilizumab, a humanized monoclonal antibody against interleukin 6 receptor. METHODS: We report the first Chinese patient with BS who was resistant to currently available therapies but had rapid quiescence after using Tocilizumab. We also conducted a systematic literature review about the current treatments of BS. RESULTS: A 13-year-old Chinese boy with BS, whose uveitis got worsened when treated with Infliximab, was well-controlled after taking Tocilizumab and prednisone was tapered off to a dose of 8mg per day. We identified 29 manuscripts providing 45 BS cases. Among these patients, 24 underwent biological treatments and 22 of them recovered. In these 29 manuscripts, the biological agents used to treat refractory BS included Etanercept, Infliximab, Adalimumab, Canakinumab and Anakinra. CONCLUSIONS: Case reports on the use of biological agents have yielded mixed results. The diversity of the symptoms may be due to functional differences in NOD2 mutations. For BS patients with fever, lymphadenopathy and hepatosplenomegaly, Tocilizumab may be a better choice.

Inhibition of 6-phosphogluconate Dehydrogenase Reverses Cisplatin Resistance in Ovarian and Lung Cancer.

Cisplatin (DDP) is currently one of the most commonly used chemotherapeutic drugs for treating ovarian and lung cancer. However, resistance to cisplatin is common and it often leads to therapy failure. In addition, the precise mechanism of cisplatin resistance is still in its infancy. In this study, we demonstrated that the oxidative pentose phosphate pathway enzyme 6-phosphogluconate dehydrogenase (6PGD) promotes cisplatin resistance. We showed that cisplatin-resistant cancer cells (C13∗ and A549DDP), had higher levels of 6PGD compared to their cisplatin-sensitive counterparts (OV2008 and A549). Furthermore, ovarian and lung cancer patients with higher 6PGD levels have worse survival outcomes relative to patients with lower 6PGD expression. Interestingly, we found that the upregulation of 6PGD in cisplatin-resistant cells was due to the decreased expression of miR-206 and miR-613, which we found to target this enzyme. We further demonstrate that suppressing 6PGD using shRNA, inhibitor or miR-206/miR-613, either as single agents or in combination, could sensitize cisplatin-resistant cancer cells to cisplatin treatment and thereby improving the therapeutic efficacy of cisplatin. Taken together, our results suggest that 6PGD serves as a novel potential target to overcome cisplatin resistance.

[Tuberous sclerosis complex with refractory epilepsy: a clinicopathologic study of 14 cases].

OBJECTIVE: To study the clinicopathologic features of tuberous sclerosis complex (TSC). METHODS: The clinicopathologic data of the patients diagnosed as TSC with refractory epilepsy and resection of epileptic focus were retrospectively analyzed. RESULTS: Fourteen cases were included, the mean age was (15.8±12.9) years, with a male predominance (male to female ratio=10:4). Frontal lobe was the most common (13/14) site of involvement. MRI showed multiple patchy long T1 and long T2 signals. CT images showed multiple subependymal high density calcified nodules in nine cases. Histology showed mild to severe disruption of the cortical lamination, cortical and subcortical tubers with giant cells and/or dysmorphic neurons. The giant cells showed strong immunoreactivity for vimentin and nestin, while the dysmorphic neurons partially expressed MAP2 and NF. Vimentin also stained strongly the "reactive" astrocytes. Thirteen cases had follow-up information: Engel class I in six cases, Engel class II in six cases, and Engel class III in one case. CONCLUSIONS: Diagnosis of TSC relies on combined pathologic, clinical and neuroradiological features. Immunohistochemical staining can be helpful. Resection of epileptic focus is an effective method to treat refractory epilepsy in TSC.