Discovery of novel NLRP3 inhibitors based on machine learning and physical methods.

The NLRP3 inflammasome plays a crucial role in inflammatory responses, particularly in alcohol-related liver disease (ALD). Given that NLRP3 has emerged as a potential therapeutic target for ALD, the development of effective inhibitors is of great importance. In this study, we trained 11 regression models, and the results showed that LightGBM, Random Forest, and XGBoost performed the best, achieving R² values of 0.774, 0.755, and 0.719, respectively. Using machine learning models and physical methods, we screened more than 11.5 million compounds from Asinex, Princeton, UkrOrgSynthesis, Chemdiv, Chembridge, Alinda, Enamine, and Lifechemicals, which led to the identification of 26 potential NLRP3 inhibitors. Furthermore, molecular dynamics simulations and MMGBSA binding energy calculations confirmed the stability of the interactions between NLRP3 and three key molecules: 19,655,631 (source Chembridge), 38,214,692 (source Chembridge), and Z1180203703 (source Enamine). Additionally, ADMET analysis revealed their favorable pharmacokinetic properties. This study provides insights and candidate molecules for discovering NLRP3 inhibitors, potentially applicable in treating related diseases.

Long-working-distance high-collection-efficiency three-photon microscopy for in vivo long-term imaging of zebrafish and organoids.

Zebrafish and organoids, crucial for complex biological studies, necessitate an imaging system with deep tissue penetration, sample protection from environmental interference, and ample operational space. Traditional three-photon microscopy is constrained by short-working-distance objectives and falls short. Our long-working-distance high-collection-efficiency three-photon microscopy (LH-3PM) addresses these challenges, achieving a 58% fluorescence collection efficiency at a 20 mm working distance. LH-3PM significantly outperforms existing three-photon systems equipped with the same long working distance objective, enhancing fluorescence collection and dramatically reducing phototoxicity and photobleaching. These improvements facilitate accurate capture of neuronal activity and an enhanced detection of activity spikes, which are vital for comprehensive, long-term imaging. LH-3PM's imaging of epileptic zebrafish not only showed sustained neuron activity over an hour but also highlighted increased neural synchronization and spike numbers, marking a notable shift in neural coding mechanisms. This breakthrough paves the way for new explorations of biological phenomena in small model organisms.

Nomogram based on immune-inflammatory indicators and age-adjusted charlson comorbidity index score to predict prognosis of postoperative parotid gland carcinoma patients.

BACKGROUND: Parotid gland carcinoma (PGC) is a rare malignant tumor. The purpose of this study was to investigate the role of immune-inflammatory-nutrition indicators and age-adjusted Charlson comorbidity index score (ACCI) of PGC and develop the nomogram model for predicting prognosis. METHOD: All patients diagnosed with PGC in two tertiary hospitals, treated with surgical resection, from March 2012 to June 2018 were obtained. Potential prognostic factors were identified by univariate and multivariate Cox regression analyses. The nomogram models were established based on these identified independent prognostic factors. The performance of the developed prognostic model was estimated by related indexes and plots. RESULT: The study population consisted of 344 patients with PGC who underwent surgical resection, 285 patients without smoking (82.8%), and 225 patients (65.4%) with mucoepidermoid carcinoma, with a median age of 50.0 years. American Joint Committee on Cancer (AJCC) stage (p < 0.001), pathology (p = 0.019), tumor location (p < 0.001), extranodal extension (ENE) (p < 0.001), systemic immune-inflammation index (SII) (p = 0.004), prognostic nutrition index (PNI) (p = 0.003), ACCI (p < 0.001), and Glasgow prognostic Score (GPS) (p = 0.001) were independent indicators for disease free survival (DFS). Additionally, the independent prognostic factors for overall survival (OS) including AJCC stage (p = 0.015), pathology (p = 0.004), tumor location (p < 0.001), perineural invasion (p = 0.009), ENE (p < 0.001), systemic immune-inflammation index (SII) (p = 0.001), PNI (p = 0.001), ACCI (p = 0.003), and GPS (p = 0.033). The nomogram models for predicting DFS and OS in PGC patients were generated based on these independent risk factors. All nomogram models show good discriminative capability with area under curves (AUCs) over 0.8 (DFS 0.802, and OS 0.825, respectively). Decision curve analysis (DCA), integrated discrimination improvement (IDI), and net reclassification index (NRI) show good clinical net benefit of the two nomograms in both training and validation cohorts. Kaplan-Meier survival analyses showed superior discrimination of DFS and OS in the new risk stratification system compared with the AJCC stage system. Finally, postoperative patients with PGC who underwent adjuvant radiotherapy had a better prognosis in the high-, and medium-risk subgroups (p < 0.05), but not for the low-risk subgroup. CONCLUSION: The immune-inflammatory-nutrition indicators and ACCI played an important role in both DFS and OS of PGC patients. Adjuvant radiotherapy had no benefit in the low-risk subgroup for PGC patients who underwent surgical resection. The newly established nomogram models perform well and can provide an individualized prognostic reference, which may be helpful for patients and surgeons in proper follow-up strategies.

Novel prognostic nomograms for postoperative patients with oral cavity squamous cell carcinoma in the central region of China.

BACKGROUND: Oral cavity squamous cell carcinoma (OCSCC) is the most common pathological type in oral tumors. This study intends to construct a novel prognostic nomogram model based on China populations for these resectable OCSCC patients, and then validate these nomograms. METHODS: A total of 607 postoperative patients with OCSCC diagnosed between June 2012 and June 2018 were obtained from two tertiary medical institutions in Xinxiang and Zhengzhou. Then, 70% of all the cases were randomly assigned to the training group and the rest to the validation group. The endpoint time was defined as overall survival (OS) and disease-free survival (DFS). The nomograms for predicting the 3-, and 5-year OS and DFS in postoperative OCSCC patients were established based on the independent prognostic factors, which were identified by the univariate analysis and multivariate analysis. A series of indexes were utilized to assess the performance and net benefit of these two newly constructed nomograms. Finally, the discrimination capability of OS and DFS was compared between the new risk stratification and the American Joint Committee on Cancer (AJCC) stage by Kaplan-Meier curves. RESULTS: 607 postoperative patients with OCSCC were selected and randomly assigned to the training cohort (n = 425) and validation cohort (n = 182). The nomograms for predicting OS and DFS in postoperative OCSCC patients had been established based on the independent prognostic factors. Moreover, dynamic nomograms were also established for more convenient clinical application. The C-index for predicting OS and DFS were 0.691, 0.674 in the training group, and 0.722, 0.680 in the validation group, respectively. Besides, the calibration curve displayed good consistency between the predicted survival probability and actual observations. Finally, the excellent performance of these two nomograms was verified by the NRI, IDI, and DCA curves in comparison to the AJCC stage system. CONCLUSION: The newly established and validated nomograms for predicting OS and DFS in postoperative patients with OCSCC perform well, which can be helpful for clinicians and contribute to clinical decision-making.

Effective cryopreservation of human brain tissue and neural organoids.

Human brain tissue models and organoids are vital for studying and modeling human neurological disease. However, the high cost of long-term cultured organoids inhibits their wide-ranging application. It is therefore urgent to develop methods for the cryopreservation of brain tissue and organoids. Here, we establish a method using methylcellulose, ethylene glycol, DMSO, and Y27632 (termed MEDY) for the cryopreservation of cortical organoids without disrupting the neural cytoarchitecture or functional activity. MEDY can be applied to multiple brain-region-specific organoids, including the dorsal/ventral forebrain, spinal cord, optic vesicle brain, and epilepsy patient-derived brain organoids. Additionally, MEDY enables the cryopreservation of human brain tissue samples, and pathological features are retained after thawing. Transcriptomic analysis shows that MEDY can protect synaptic function and inhibit the endoplasmic reticulum-mediated apoptosis pathway. MEDY will enable the large-scale and reliable storage of diverse neural organoids and living brain tissue and will facilitate wide-ranging research, medical applications, and drug screening.

Multivariate analysis of prognostic factors in patients with lip squamous cell carcinoma after surgery.

BACKGROUND: Lip squamous cell carcinoma (LSCC) was one of the most common cancer types of head and neck tumors. This study aimed to find more predictors of the prognosis in postoperative LSCC patients. METHODS: A total of 147 LSCC patients between June 2012 and June 2018 were collected from two tertiary care institutions. There were 21 clinicopathological factors included and analyzed in our study. The univariate and multivariate Cox regression analyses were performed to find the independent prognostic factors for predicting progression-free survival (PFS) and overall survival (OS) in postoperative LSCC patients. The role of adjuvant radiotherapy in various subgroups was displayed by Kaplan-Meier plots. RESULTS: The 1-, 3-, and 5-year PFS of postoperative LSCC patients were 88.4%, 70.1%, and 57.8%, respectively. Similarly, the 1-, 3-, and 5-year OS of postoperative LSCC patients were 94.6%, 76.9%, and 69.4%, respectively. The results suggested that postoperative LSCC patients with age at diagnosis ≥ 70 years, grade with moderate or poor differentiate, the American Joint Committee on Cancer (AJCC) stage IV, higher systemic immune-inflammation index (SII), surgical margin < 5, and age-adjusted Charlson Comorbidity Index (ACCI) ≥ 5 tend to have a poorer PFS (all P < 0.05). Besides, postoperative LSCC patients with age at diagnosis ≥ 70 years, AJCC stage IV, higher GPS, higher SII, and ACCI ≥ 5 tend to have a worse OS (all P < 0.05). Additionally, postoperative patients with LSCC in the subgroup of ACCI < 5 and AJCC III-IV stage was more likely to benefit from adjuvant radiotherapy, but not for the other subgroups. CONCLUSION: We identified a series of significant immune-inflammation-related and comorbidity-related clinicopathological factors associated with the prognosis of postoperative LSCC patients by local data from two tertiary care institutions in China, which can be helpful for patients and surgeons to pay more attention to nutrition, inflammation, and complications and finally obtained a better prognosis.

Cold-activated brown fat-derived extracellular vesicle-miR-378a-3p stimulates hepatic gluconeogenesis in male mice.

During cold exposure, activated brown adipose tissue (BAT) takes up a large amount of circulating glucose to fuel non-shivering thermogenesis and defend against hypothermia. However, little is known about the endocrine function of BAT controlling glucose homoeostasis under this thermoregulatory challenge. Here, we show that in male mice, activated BAT-derived extracellular vesicles (BDEVs) reprogram systemic glucose metabolism by promoting hepatic gluconeogenesis during cold stress. Cold exposure facilitates the selective packaging of miR-378a-3p-one of the BAT-enriched miRNAs-into EVs and delivery into the liver. BAT-derived miR-378a-3p enhances gluconeogenesis by targeting p110α. miR-378 KO mice display reduced hepatic gluconeogenesis during cold exposure, while restoration of miR-378a-3p in iBAT induces the expression of gluconeogenic genes in the liver. These findings provide a mechanistic understanding of BDEV-miRNA as stress-induced batokine to coordinate systemic glucose homoeostasis. This miR-378a-3p-mediated interorgan communication highlights a novel endocrine function of BAT in preventing hypoglycemia during cold stress.

A theoretical review on the role of knowledge sharing and intellectual capital in employees' innovative behaviors at work.

With the rapid growth of technologies, sciences, and globalization, many organizations have modified and updated their managerial policies to meet modern requirements. To survive difficulties and setbacks, especially unexpected crises like the COVID-19 pandemic, many companies turned their attention to employees' knowledge sharing, intellectual capital, and innovative thoughts and behaviors to gain wealth, value, and success. Given the severe shock that the pandemic exerted on many countries' economy, the psycho-emotional and individual aspects of work obtained unprecedented scholarly attention. However, the way knowledge sharing and intellectual capital can interact to foster and enhance innovation at workplaces has remained under-researched. To fill this gap, the present review article presented the theoretical and empirical foundations of these three factors and stressed their possible interplay. In the end, some implications and suggestions for further research were offered to managers and eager researchers to practically and scientifically examine the interplay of knowledge sharing, intellectual capital, and innovative work behaviors.

To explore the mechanism of Maiwei Dihuang decoction in the treatment of non-small cell lung cancer based on network pharmacology combined with LC-MS.

OBJECTIVE: To explore the mechanism of Maiwei Dihuang decoction in the treatment of non-small cell lung cancer (NSCLC) by using network pharmacology and LC-MS technology. METHODS: The effective components in Maiwei Dihuang decoction were detected by liquid chromatography-mass spectrometry (LC-MS). Use the SuperPred database to collect the relevant targets of the active ingredients of Mai Wei Di Tang, and then collect the relevant targets of non-small cell lung cancer from GeneCards, DisgenNET and OMIM databases. On this basis, PPI network construction, GO enrichment analysis and KEGG pathway annotation analysis were carried out for target sites. Finally, AutoDock Vina is used for molecular docking. RESULTS: We further screened 16 effective Chinese herbal compounds through LC-MS combined with ADME level. On this basis, we obtained 77 core targets through protein interaction network analysis. Through GO, KEGG analysis and molecular docking results, we finally screened out the potential targets of Maiwei Dihuang Decoction for NSCLC: TP53, STAT3, MAPK3. CONCLUSION: Maiwei Dihuang decoction may play a role in the treatment of NSCLC by co-regulating TP53/STAT3/MAPK3 signal pathway.

Nomogram for predicting the preoperative lymph node metastasis in resectable pancreatic cancer.

BACKGROUND: Lymph node metastasis (LNM) is a critical prognostic factor in resectable pancreatic cancer (PC) patients, determining treatment strategies. This study aimed to develop a clinical model to adequately and accurately predict the risk of LNM in PC patients. METHODS: 13,200 resectable PC patients were enrolled from the SEER (Surveillance, Epidemiology, and End Results) database, and randomly divided into a training group and an internal validation group at a ratio of 7:3. An independent group (n = 62) obtained from The First Affiliated Hospital of Xinxiang Medical University was enrolled as the external validation group. The univariate and multivariate logistic regression analyses were used to screen independent risk factors for LNM. The minimum Akaike's information criterion (AIC) was performed to select the optimal model parameters and construct a nomogram for assessing the risk of LNM. The performance of the nomogram was assessed by the receiver operating characteristics (ROC) curve, calibration plot, and decision curve analysis (DCA). In addition, an online web calculator was designed to assess the risk of LNM. RESULT: A total of six risk predictors (including age at diagnosis, race, primary site, grade, histology, and T-stage) were identified and included in the nomogram. The areas under the curves (AUCs) [95% confidential interval (CI)] were 0.711 (95%CI: 0.700-0.722), 0.700 (95%CI: 0.683-0.717), and 0.845 (95%CI: 0.749-0.942) in the training, internal validation and external validation groups, respectively. The calibration curves showed satisfied consistency between nomogram-predicted LNM and actual observed LNM. The concordance indexes (C-indexes) in the training, internal, and external validation sets were 0.689, 0.686, and 0.752, respectively. The DCA curves of the nomogram demonstrated good clinical utility. CONCLUSION: We constructed a nomogram model for predicting LNM in pancreatic cancer patients, which may help oncologists and surgeons to choose more individualized clinical treatment strategies and make better clinical decisions.

C11orf54 promotes DNA repair via blocking CMA-mediated degradation of HIF1A.

C11orf54 is an ester hydrolase highly conserved across different species. C11orf54 has been identified as a biomarker protein of renal cancers, but its exact function remains poorly understood. Here we demonstrate that C11orf54 knockdown decreases cell proliferation and enhances cisplatin-induced DNA damage and apoptosis. On the one hand, loss of C11orf54 reduces Rad51 expression and nuclear accumulation, which results in suppression of homologous recombination repair. On the other hand, C11orf54 and HIF1A competitively interact with HSC70, knockdown of C11orf54 promotes HSC70 binding to HIF1A to target it for degradation via chaperone-mediated autophagy (CMA). C11orf54 knockdown-mediated HIF1A degradation reduces the transcription of ribonucleotide reductase regulatory subunit M2 (RRM2), which is a rate-limiting RNR enzyme for DNA synthesis and DNA repair by producing dNTPs. Supplement of dNTPs can partially rescue C11orf54 knockdown-mediated DNA damage and cell death. Furthermore, we find that Bafilomycin A1, an inhibitor of both macroautophagy and chaperone-mediated autophagy, shows similar rescue effects as dNTP treatment. In summary, we uncover a role of C11orf54 in regulating DNA damage and repair through CMA-mediated decreasing of HIF1A/RRM2 axis.

Nomograms for predicting overall survival and cancer-specific survival in elderly patients with epithelial ovarian cancer.

BACKGROUND: Epithelial ovarian cancer (EOC) is one of the most fatal gynecological malignancies among elderly patients. We aim to construct two nomograms to predict the overall survival (OS) and cancer-specific survival (CSS) in elderly EOC patients. METHODS: Elderly patients with EOC between 2000 and 2019 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. Enrolled patients were randomly divided into the training and validation set at a ratio of 2:1. The OS and CSS were recognized as endpoint times. The independent prognostic factors from the multivariate analysis were used to establish nomograms for predicting the 3-, 5- and 10-year OS and CSS of elderly EOC patients. The improvement of predictive ability and clinical benefits were evaluated by consistency index (C-index), receiver operating characteristic (ROC), calibration curve, decision curve (DCA), net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Finally, the treatment efficacy of surgery and chemotherapy in low-, medium-, and high-risk groups were displayed by Kaplan-Meier curves. RESULTS: Five thousand five hundred eighty-eight elderly EOC patients were obtained and randomly assigned to the training set (n = 3724) and validation set (n = 1864). The independent prognostic factors were utilized to construct nomograms for OS and CSS. Dynamic nomograms were also developed. The C-index of the OS nomogram and CSS nomogram were 0.713 and 0.729 in the training cohort. In the validation cohort, the C-index of the OS nomogram and CSS nomogram were 0.751 and 0.702. The calibration curve demonstrated good concordance between the predicted survival rates and actual observations. Moreover, the NRI, IDI, and DCA curves determined the outperformance of the nomogram compared with the AJCC stage system. Besides, local tumor resection had a higher benefit on the prognosis in all patients. Chemotherapy had a better prognosis in the high-risk groups, but not for the medium- risk and low-risk groups. CONCLUSIONS: We developed and validated nomograms for predicting OS and CSS in elderly EOC patients to help gynecologists to develop an appropriate individualized therapeutic schedule.

Generation of neural organoids for spinal-cord regeneration via the direct reprogramming of human astrocytes.

Organoids with region-specific architecture could facilitate the repair of injuries of the central nervous system. Here we show that human astrocytes can be directly reprogrammed into early neuroectodermal cells via the overexpression of OCT4, the suppression of p53 and the provision of the small molecules CHIR99021, SB431542, RepSox and Y27632. We also report that the activation of signalling mediated by fibroblast growth factor, sonic hedgehog and bone morphogenetic protein 4 in the reprogrammed cells induces them to form spinal-cord organoids with functional neurons specific to the dorsal and ventral domains. In mice with complete spinal-cord injury, organoids transplanted into the lesion differentiated into spinal-cord neurons, which migrated and formed synapses with host neurons. The direct reprogramming of human astrocytes into neurons may pave the way for in vivo neural organogenesis from endogenous astrocytes for the repair of injuries to the central nervous system.

Impact of dietary sucralose and sucrose-sweetened water intake on lipid and glucose metabolism in male mice.

AIMS: Overconsumption of sugar-sweetened beverages (SSBs) is associated with an increased risk of metabolic disorders, including obesity and diabetes. However, accumulating evidence also suggests the potential negative impact of consuming nonnutritive sweeteners (NNSs) on weight and glycaemic control. The metabolic effects of sucralose, the most widely used NNS, remain controversial. This study aimed to compare the impact of intake of dietary sucralose (acceptable daily intake dose, ADI dose) and sucrose-sweetened water (at the same sweetness level) on lipid and glucose metabolism in male mice. MATERIALS AND METHODS: Sucralose (0.1 mg/mL) or sucrose (60 mg/mL) was added to the drinking water of 8-week-old male C57BL/6 mice for 16 weeks, followed by oral glucose and intraperitoneal insulin tolerance tests, and measurements of bone mineral density, plasma lipids, and hormones. After the mice were sacrificed, the duodenum and ileum were used for examination of sweet taste receptors (STRs) and glucose transporters. RESULTS: A significant increase in fat mass was observed in the sucrose group of mice after 16 weeks of sweetened water drinking. Sucrose consumption also led to increased levels of plasma LDL, insulin, lipid deposition in the liver, and increased glucose intolerance in mice. Compared with the sucrose group, mice consuming sucralose showed much lower fat accumulation, hyperlipidaemia, liver steatosis, and glucose intolerance. In addition, the daily dose of sucralose only had a moderate effect on T1R2/3 in the intestine, without affecting glucose transporters and plasma insulin levels. CONCLUSION: Compared with mice consuming sucrose-sweetened water, daily drinking of sucralose within the ADI dose had a much lower impact on glucose and lipid homeostasis.

Network Pharmacology Analysis and Experimental Validation to Explore the Anti-inflammatory Mechanism of Asiatic Acid on Alcoholic Steatohepatitis.

Objective: The mechanism of action of asiatic acid (AA) on alcoholic steatohepatitis (ASH) was investigated using network pharmacology and experiments. Methods: Through data retrieval, network construction, and enrichment analysis, the potential mechanism of AA in the treatment of alcoholic steatohepatitis was explored. Animal and cell models were established in this study. Animal Model. The mouse model was divided into six groups: normal group; model group; low, medium, and high AA group; and silibinin-positive group. Cell Model. An in vitro inflammatory model of RAW264.7 cells was established by alcohol stimulation. Results: Compared with the model group, the low, medium, and high AA group showed decreased serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglyceride (TG), and total cholesterol (T-CHO). The inflammatory factor tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1ß), and interleukin 6 (IL-6) in a dose-dependent manner were decreased. In addition, hematoxylin-eosin staining showed that liver tissue damage and inflammatory cell infiltration in mice were significantly reduced with increasing doses. Further, oil red staining showed that lipid accumulation in hepatocytes in the low, medium, and high AA group was significantly reduced, with increasing dose. In addition, in the cellular model, real-time reverse transcriptase-polymerase chain reaction (Real-Time RT-PCR) and enzyme-linked immunosorbent assay (ELISA) results showed that AA could alleviate alcohol-induced cellular inflammation, while western blot and immunofluorescence results showed that AA might alleviate alcohol-induced cellular inflammation by inhibiting the nuclear factor-κB (NF-κB) pathway. Conclusion: This study provides multiple lines of evidence that asiatic acid may alleviate alcoholic hepatitis in mice by modulating the NF-κB pathway.

Diagnosis of pulmonary tuberculosis via identification of core genes and pathways utilizing blood transcriptional signatures: a multicohort analysis.

BACKGROUND: Blood transcriptomics can be used for confirmation of tuberculosis diagnosis or sputumless triage, and a comparison of their practical diagnostic accuracy is needed to assess their usefulness. In this study, we investigated potential biomarkers to improve our understanding of the pathogenesis of active pulmonary tuberculosis (PTB) using bioinformatics methods. METHODS: Differentially expressed genes (DEGs) were analyzed between PTB and healthy controls (HCs) based on two microarray datasets. Pathways and functional annotation of DEGs were identified and ten hub genes were selected. They were further analyzed and selected, then verified with an independent sample set. Finally, their diagnostic power was further evaluated between PTB and HCs or other diseases. RESULTS: 62 DEGs mostly related to type I IFN pathway, IFN-γ-mediated pathway, etc. in GO term and immune process, and especially RIG-I-like receptor pathway were acquired. Among them, OAS1, IFIT1 and IFIT3 were upregulated and were the main risk factors for predicting PTB, with adjusted risk ratios of 1.36, 3.10, and 1.32, respectively. These results further verified that peripheral blood mRNA expression levels of OAS1, IFIT1 and IFIT3 were significantly higher in PTB patients than HCs (all P < 0.01). The performance of a combination of these three genes (three-gene set) had exceeded that of all pairwise combinations of them in discriminating TB from HCs, with mean AUC reaching as high as 0.975 with a sensitivity of 94.4% and a specificity of 100%. The good discernibility capacity was evaluated d via 7 independent datasets with an AUC of 0.902, as well as mean sensitivity of 87.9% and mean specificity of 90.2%. In regards to discriminating PTB from other diseases (i.e., initially considered to be possible TB, but rejected in differential diagnosis), the three-gene set equally exhibited an overall strong ability to separate PTB from other diseases with an AUC of 0.999 (sensitivity: 99.0%; specificity: 100%) in the training set, and 0.974 with a sensitivity of 96.4% and a specificity of 98.6% in the test set. CONCLUSION: The described commonalities and unique signatures in the blood profiles of PTB and the other control samples have considerable implications for PTB biosignature design and future diagnosis, and provide insights into the biological processes underlying PTB.

Dual-specificity Tyrosine Phosphorylation-regulated Kinase Inhibitor ID-8 Promotes Human Somatic Cell Reprogramming by Activating PDK4 Expression.

BACKGROUND: Human induced pluripotent stem cells (hiPSCs) hold great potentials in disease modeling, drug screening and cell therapy. However, efficiency and costs of hiPSCs preparation still need to be improved. METHODS: We screened the compounds that target signaling pathways, epigenetic modifications or metabolic-process regulation to replace the growth factors. After small molecule treatment, TRA-1-60, which is a cell surface antigen expressed by human embryonic stem cells (hESCs), staining was performed to quantify the efficiency of somatic cell reprogramming. Next, small molecule cocktail-induced ESCs or iPSCs were examined with pluripotent markers expression. Finally, Genome-wide gene expression profile was analyzed by RNA-seq to illustrate the mechanism of human somatic cell reprogramming. RESULT: Here, we found that a dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) inhibitor ID-8 robustly enhanced human somatic cell reprogramming by upregulation of pyruvate dehydrogenase kinase 4 (PDK4) and activation of glycolysis. Furthermore, we identified a novel growth-factor-free hiPSC generation system using small molecules ID-8 (I) and TGFß signal pathway agonist Kartogenin (K). Importantly, we developed IK medium combined with low-dose bFGF to support the long-term expansion of human pluripotent stem cells. IK-iPSCs showed pluripotency and normal karyotype. CONCLUSIONS: Our studies may provide a novel growth-factor-free culture system to facilitate the generation of hiPSCs for multiple applications in regenerative medicine. In Brief Xu et at. found that a dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) inhibitor ID-8 robustly enhanced human somatic cell reprogramming by upregulation of PDK4 and activation of glycolysis. Furthermore, we established a novel growth-factor-free hiPSC generation system using small molecules ID-8/Kartogenin (IK). IK medium combined with Low-dose bFGF (IKB medium) supported the long-term expansion of human pluripotent stem cells. Highlights ID-8 Enhanced Reprogramming of Human Fibroblasts and Astrocytes Establishment of the Growth-factor-free Reprogramming System Using Small Molecule Compounds IK IKB Medium Maintained the Long-term Expansion of Human Pluripotent Stem Cells ID-8 Promoted Human Somatic Cell Reprogramming by Activating PDK4 Expression.

Smooth Muscle Overexpression of PGC1α Attenuates Atherosclerosis in Rabbits.

[Figure: see text].

Distribution of serum Thrombospondin-2, a novel tumor marker, in general population and cancer patients in China.

PURPOSE: Distribution of serum thrombospondin-2 in general population and cancer patients in China have not been reported. METHODS: This study evaluated the expression level of serum thrombospondin-2 in general population and various cancer patients, the 95% confidence interval was used for the derivation of reference range. The comparison of the expression levels in controls for age and gender was performed. The associations between candidate biomarkers (thrombospondin-2 [THBS2]) expression and tumor metastasis status were also explored. RESULTS: 125 healthy controls and 193 various cancer patients were enrolled. The mean ± SD in serum THBS2 levels in general population was 42.37 ± 12.24 ng/ml, there was no significant sex and age difference, the reference range is 18.37-66.36 ng/ml. Most cancer patients present a decreased serum THBS2 level except hepatoma and lymphoma which most patients showed a relatively high level of THBS2. There was no statistical difference of serum THBS2 level between metastasis and non-metastasis group in breast, lung, cervical, colorectal cancer, nasopharyngeal carcinoma and hepatoma (P > 0.05) while a significant negative correlation was observed in ovarian cancer (P = 0.0209). CONCLUSIONS: The distribution of serum THBS2 displayed an obvious heterogeneity among various cancers comparing to health controls, ovarian cancer patients detected with low THBS2 expression may be more prone to develop metastasis in China.

Genistein suppresses allergic contact dermatitis through regulating the MAP2K2/ERK pathway.

Genistein is one of the main components of soybeans and has been reported to be a potential candidate for the treatment of obesity, cancer, osteoporosis and cardiovascular diseases. Recently, genistein has been shown to have therapeutic effects on some chronic skin diseases, but its underlying mechanisms remain unclear. In this study, we evaluated the role of genistein in alleviating squaric acid dibutylester (SADBE)-induced allergic contact dermatitis (ACD) in mice, and elucidated the potential molecular mechanisms in human keratinocyte (HaCaT) cell line. The impacts of genistein on the production of pro-inflammatory chemokines and cytokines including CXCL9, TSLP, TNF-α, IL-1ß and IL-6 in the skin and serum of ACD mice were assessed, as well as the phosphorylation of components in the MAPK and JAK-STAT3 signaling pathways in the skin and dorsal root ganglions (DRGs). The results showed that genistein exerted protective effects on skin damage and inflammatory cell infiltration. Moreover, genistein significantly inhibited the increased expressions of pro-inflammatory factors in skin and peripheral blood, and down-regulated the levels of p-ERK, p-p38 and p-STAT3 in skin and DRGs. Furthermore, genistein inhibited the phosphorylation of ERK and STAT3 to downregulate the expression of cytokines and chemokines, and feedback downregulate phospho-p38 in TNF-α/IFN-γ-induced HaCaT cells. The genistein-mediated inhibitory effect on the MAPK pathway can be reversed by siMAP2K2 but not by siMAP2K4. Altogether, our findings demonstrated that genistein exhibits strong antipruritic and anti-inflammatory effects in ACD mice by inhibiting the production of pro-inflammatory cytokines and intracellular MAP2K2/ERK cell signaling, which makes genistein a potentially valuable candidate for the treatment of skin conditions and systemic syndromes in the setting of contact dermatitis.