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To clarify the effect of sulfur on inclusions and mechanical properties of Ce-Mg treated resulfurized SCr420H steel. Laboratory experiments were conducted to prepare steels with sulfur contents as 0.01%, 0.06%, and 0.132%. Inclusion evolution in liquid steel, MnS precipitation during solidification, and tensile test results of steel after quenching and tempering were investigated. The results showed that due to the limitation of mass transfer in molten steel, composite inclusion that Ce-O-S wrapped by Ce-Ca-Mg-Al-Si-O, which was named transition state inclusions, can form quickly after adding Ce-Mg lump to the molten steel. As the homogenization of molten steel, the difference of sulfur content in steel can lead to the transition state inclusions transformed into different inclusions. With the increase of sulfur content, the quantity of MnS increased significantly, and the morphology of MnS transformed from “stick” to “dendritic + fishbone”, and then to “fishbone”. Tensile test results and fracture analysis indicate that the decline of inclusion spacing as the increase of sulfur content leads to a shorter physical path of crack propagation in steel. Therefore, the increase of sulfur content can bring about a decrease in the strength and plasticity of the steel. From the perspective of inclusion control, making the MnS inclusion precipitate more dispersive and increasing the distance between inclusions can be considered as a method for preventing the decline of mechanical properties in steel with high sulfur content.

Autoimmune diseases (ADs) are characterized by their complexity and a wide range of clinical differences. Despite patients presenting with similar symptoms and disease patterns, their reactions to treatments may vary. The current approach of personalized medicine, which relies on molecular data, is seen as an effective method to address the variability in these diseases. This review examined the pathologic classification of ADs, such as multiple sclerosis and lupus nephritis, over time. Acknowledging the limitations inherent in pathologic classification, the focus shifted to molecular classification to achieve a deeper insight into disease heterogeneity. The study outlined the established methods and findings from the molecular classification of ADs, categorizing systemic lupus erythematosus (SLE) into four subtypes, inflammatory bowel disease (IBD) into two, rheumatoid arthritis (RA) into three, and multiple sclerosis (MS) into a single subtype. It was observed that the high inflammation subtype of IBD, the RA inflammation subtype, and the MS ''inflammation & EGF'' subtype share similarities. These subtypes all display a consistent pattern of inflammation that is primarily driven by the activation of the JAK-STAT pathway, with the effective drugs being those that target this signaling pathway. Additionally, by identifying markers that are uniquely associated with the various subtypes within the same disease, the study was able to describe the differences between subtypes in detail. The findings are expected to contribute to the development of personalized treatment plans for patients and establish a strong basis for tailored approaches to treating autoimmune diseases.

Abstract Background Approximately 25–30% of patients with acute myeloid leukemia (AML) have FMS-like receptor tyrosine kinase-3 (FLT3) mutations that contribute to disease progression and poor prognosis. Prolonged exposure to FLT3 tyrosine kinase inhibitors (TKIs) often results in limited clinical responses due to diverse compensatory survival signals. Therefore, there is an urgent need to elucidate the mechanisms underlying FLT3 TKI resistance. Dysregulated sphingolipid metabolism frequently contributes to cancer progression and a poor therapeutic response. However, its relationship with TKI sensitivity in FLT3-mutated AML remains unknown. Thus, we aimed to assess mechanisms of FLT3 TKI resistance in AML. Methods We performed lipidomics profiling, RNA-seq, qRT-PCR, and enzyme-linked immunosorbent assays to determine potential drivers of sorafenib resistance. FLT3 signaling was inhibited by sorafenib or quizartinib, and SPHK1 was inhibited by using an antagonist or via knockdown. Cell growth and apoptosis were assessed in FLT3-mutated and wild-type AML cell lines via Cell counting kit-8, PI staining, and Annexin-V/7AAD assays. Western blotting and immunofluorescence assays were employed to explore the underlying molecular mechanisms through rescue experiments using SPHK1 overexpression and exogenous S1P, as well as inhibitors of S1P2, β-catenin, PP2A, and GSK3β. Xenograft murine model, patient samples, and publicly available data were analyzed to corroborate our in vitro results. Results We demonstrate that long-term sorafenib treatment upregulates SPHK1/sphingosine-1-phosphate (S1P) signaling, which in turn positively modulates β-catenin signaling to counteract TKI-mediated suppression of FLT3-mutated AML cells via the S1P2 receptor. Genetic or pharmacological inhibition of SPHK1 potently enhanced the TKI-mediated inhibition of proliferation and apoptosis induction in FLT3-mutated AML cells in vitro. SPHK1 knockdown enhanced sorafenib efficacy and improved survival of AML-xenografted mice. Mechanistically, targeting the SPHK1/S1P/S1P2 signaling synergizes with FLT3 TKIs to inhibit β-catenin activity by activating the protein phosphatase 2 A (PP2A)-glycogen synthase kinase 3β (GSK3β) pathway. Conclusions These findings establish the sphingolipid metabolic enzyme SPHK1 as a regulator of TKI sensitivity and suggest that combining SPHK1 inhibition with TKIs could be an effective approach for treating FLT3-mutated AML.

A polysaccharide (PSMP2) was isolated from Salvia miltiorrhiza, and its sulfated derivative (PSMP2-S) was synthesized. The chemical structures of PSMP2 and PSMP2-S were analyzed by various chemical analysis methods and instrumental analysis methods. The ultrastructures and thermal stability were further investigated. In addition, PSMP2 and PSMP2-S had strong immunomodulatory activity and could regulate cytokines (interleukin-2, interleukin-6 and tumor necrosis factor-α), increased the content of short chain fatty acids and effectively reduced the relative abundance of Bacteroides and increased the relative abundance of Firmicutes, significantly increase Muribaculaceae and Lactobacillaceae, and inhibit Lachnospiraceae and Ruminococcaceae, improve the composition of gut microbiota. This study showed that PSMP2 and PSMP2-S might be used as potential natural immune regulators and gut microbiota regulators, and had great development value in the field of food and medicine.

Abstract Adropin is encoded by the energy homeostasis-associated (ENHO) gene and widely present in liver, pancreas, heart, kidney, brain, and vascular tissues. Abnormal adropin is associated with metabolic, inflammatory, immune, and central nervous disorders. Whether adropin is involved in the development of colorectal cancer (CRC) is still unclear. Here, decreased adropin expression of tumor-nest cells in advanced-stage CRC was demonstrated. Adropin expressed by carcinoma cells was negatively correlated with macrophage infiltration in the matrix of CRC tissues. However, tumor macrophages enhanced adropin expression and were positively correlated with tumor invasion and metastasis. ENHO gene transfection into colon cancer (MC38) cells inhibited tumor growth in vivo, accompanying the increase of M1 macrophages. Treatment with low-dose adropin (

Abstract Background Platelet (PLT) count at diagnosis plays an important role in cancer development and progression in solid tumors. However, it remains controversial whether PLT count at diagnosis influences therapeutic outcome in patients with non-acute promyelocytic leukemia (APL) acute myeloid leukemia (AML). Methods This study analyzed the relationship between PLT count at diagnosis and genetic mutations in a cohort of 330 newly diagnosed non-APL AML patients. The impact of PLT count on complete remission, minimal residual disease status and relapse-free survival (RFS) were evaluated after chemotherapy or allogeneic hematopoietic stem cell transplantation (allo-HSCT). Results Our studies showed that patients with DNMT3A mutations have a higher PLT count at diagnosis, while patients with CEBPA biallelic mutations or t(8;21)(q22; q22) translocation had lower PLT count at diagnosis. Furthermore, non-APL AML patients with high platelet count (> 65 × 109/L) at diagnosis had worse response to induction chemotherapy and RFS than those with low PLT count. In addition, allo-HSCT could not absolutely attenuated the negative impact of high PLT count on the survival of non-APL AML patients. Conclusion PLT count at diagnosis has a predictive value for therapeutic outcome for non-APL AML patients.

Rheumatoid arthritis (RA) is highly heritable, and previous studies have suggested that genetic variation may affect susceptibility to RA by altering epigenetic modifications (e.g. DNA methylation). Here we examined how genetic variation influences DNA methylation (DNAm) in RA by integrating individual genetic variation and DNAm data. Epigenome‐wide meQTL (methylation quantitative trait loci) analysis was performed on 354 RA patients and 335 controls, scanning 30,101,744 relationships between 62 SNPs and 485,512 DNA methylation sites. Two regulatory relationship pairs (FDR

The study aimed to select the best extraction technology of Angelica dahurica polysaccharides (ADP), characterize its structure, and antioxidant activity. On the basis of the single-factor experiment result, the ultrasonic-assisted extraction (UAE) of ADP was ameliorate using the response surface method. The optimal conditions were: extraction time 32 min, extraction temperature 74°C, ratio of water to material 19 mL/g, extraction power 270 W. The practical extraction rate was 11.21 ± 0.12% (g/g). C-1: Not clear?? g/s??? ADP was purified by column chromatography, and then three polysaccharide fractions (ADP-H, ADP-0.1 and ADP-0.3) were obtained using DEAE-Cellulose 52. The ADP was mainly composed of D-Mannose, D-Glucose, D-Galactose, L-Arabinose, the ADP-H was mainly composed of D-Mannose, D-Glucose, D-Galactose, L-Arabinose, the ADP-0.1 was mainly composed of D-Mannose, D-Galacturonic acid, D-Glucose, D-Galactose, L-Arabinose, and the ADP-0.3 was mainly composed of D-Mannose, L-Rhamnose, D-Galacturonic acid, D-Galactoe, L-Arabinose. The molecular weights of ADP-H, ADP-0.1 and ADP-0.3 were 1.01 × 104 Da, 1.45 × 107 Da and 6.96 × 106 Da. In addition, the purified polysaccharides have certain scavenging ability of DPPH free radical, hydroxyl free radical and ferric reducing power, which can be used as natural products of antioxidants.

Objective: In this study, the response surface method (RSM) was used to optimize the extraction conditions of Glehniae Radix polysaccharides (GLP) by cellulase and ultrasonic-assisted, and its physicochemical properties and immunomodulatory activity were studied. Methods: The factors of enzymolysis time, material to liquid ratio, ultrasonic time, ultrasonic temperature and cellulase additions were selected as influencing factors, the yield of GLP was the evaluation index, and single factor experiments was conducted. Based on single factor results, the optimal extraction process of GLP was obtained by RSM. The physicochemical properties were analyzed by scanning electron microscope (SEM), thermogravimetric analysis-differential scanning calorimetry (TGA-DSC), fourier transform infrared spectroscopy (FT-IR), and high performance liquid chromatography (HPLC), and the immunomodulatory activity of RAW 264.7 macrophage was evaluated by in vitro test. Results: The optimal conditions were as follows: Enzymolysis time was 112 min, material to liquid ratio was 1:30 g·mL−1, ultrasonic time was 41 min, ultrasonic temperature was 65 ℃, and cellulase additions was 2%. Under these conditions, the yield of GLP was 39.58%±0.90%. Besides, GLP was mainly composed of glucose, well thermal stability. The results of in vitro immunomodulatory activity showed that GLP could significantly (P

Phytogenic polysaccharide, a kind of natural macromolecule, is wide spread occurrence in phytogenic cells and has many kinds of biological activities, such as anti-tumor, anti-oxidation, immunomodulation, and etc. The structure of polysaccharide is a key factor affecting its biological activity. Due to the large molecular weight and complex structure of polysaccharide, the in-depth study of polysaccharide is limited. Therefore, this paper introduces the research methods of the primary structure, such as gas chromatography, liquid chromatography, infrared spectroscopy, nuclear magnetic resonance spectroscopy and mass spectrometry, as well as advanced structural analysis methods such as atomic force microscopy, X ray diffraction and circular dichrois, and summarizes the construction of multidimensional fingerprint and molecular model of phytogenic polysaccharides, which provides a new idea for the study of polysaccharide structure and lays a foundation for the development and utilization of polysaccharides.

Highlights Structural characteristics of PZMP4 were analyzed by HPGPC, GC, FT-IR, GC-MS, NMR, SEM and AFM. PZMP4 mainly consisted of (1→4)-linked GalpA with three branches boned to O-3. The branches included (1→3)-linked Araf, (1→2)-linked Rhap, and terminated with GalpA.

Traditional Chinese Medicine (TCM) has some advantages, such as a multi-component, multi-target, and overall action, which makes the research on the compatibility of TCM formula a key and difficult point. On the contrary, network pharmacology (NP) uses high-throughput screening, computer simulation, and network database retrieval to reveal the drug–gene–target–disease interaction network, predict the mechanism of action of drugs through network relationships, and evaluate the efficacy and adverse reactions of drugs, thereby determining drugs with high efficiency and low toxicity. Therefore, the TCM formula has its unique TCM theories, and this paper primarily introduces the status quo of TCM compound prescriptions using TCM theories and NP, namely, the treatment theory of TCM (the core of TCM treatment and the principle of compatibility of TCM), as the theoretical guidance to evaluate drug's properties, efficacy, and toxicity. In addition, this study aims to predict drug's mechanism of action, interaction relationship, and matching selection to provide a high-efficiency and low-toxicity TCM formula and new insights into the follow-up study of TCM formula.

Iron deficiency anemia can lead to a variety of functional disorders, which is one of the highest incidence of nutrient deficiency diseases. The direct addition of iron to food will not only brings difficulties to the production of products, but also brings damages to human body. In recent years, international studies have shown that polysaccharide iron complex (PIC) not only has a variety of pharmacological activities of polysaccharide itself, but also has the function of supplementing iron, so it is a good iron supplement. With the advantages of good solubility, high iron content, low gastrointestinal irritation and high bioavailability, PIC is an effective iron supplement for iron deficiency anemia and has attracted more and more attention. In this paper, the different preparation methods, structural characterization, biological activities and clinical applications of PIC synthesized by natural polysaccharides from plant were reviewed, in order to provide theoretical basis for the development and application of PIC.

Polygonatum sibiricum polysaccharides (PSPs) have important biological functions, such as antioxidation, immunomodulatory, and hypolipidemic functions. Different extraction methods have effects on their structures and activities. In this study, six extraction methods, including hot water extraction (HWE), alkali extraction (AAE), ultrasound-assisted extraction (UAE), enzyme-assisted extraction (EAE), microwave-assisted extraction (MAE), and freeze–thaw-assisted extraction (FAE) were used to extract PSPs, and their structure–activity relationships were analyzed. The results showed that all six PSPs had similar functional group compositions, thermal stability, and glycosidic bond compositions. PSP-As (PSPs extracted by AAE) exhibited better rheological properties due to their higher molecular weight (Mw). PSP-Es (PSPs extracted by EAE) and PSP-Fs (PSPs extracted by FAE) had better lipid-lowering activity due to their lower Mw. PSP-Es and PSP-Ms (PSPs extracted by MAE), which do not contain uronic acid and have a moderate Mw, had better 1,1-diphenyl-2-picrylhydrazyl (DPPH)-radical-scavenging activity. On the contrary, PSP-Hs (PSPs extracted by HWE) and PSP-Fs, with the Mw of uronic acid, had the best OH-radical-scavenging activity. The high-Mw PSP-As had the best Fe2+-chelating ability. In addition, mannose (Man) may play an important role in the immunomodulatory activity. These results indicate that different extraction methods affect the structure and biological activity of polysaccharides to varying degrees, and these results are helpful for understanding the structure–activity relationship of PSPs.

BackgroundPedigree data (family history) are indispensable for genetics studies and the assessment of individuals' disease susceptibility. With the popularity of genetics testing, the collection of pedigree data is becoming more common. However, it can be time-consuming, laborious, and tedious for clinicians to investigate all pedigree data for each patient. A self-service robot could inquire about patients' family history in place of professional clinicians or genetic counselors. ObjectiveThe aim of this study was to develop a mobile-based and self-service tool to collect and visualize pedigree data, not only for professionals but also for those who know little about genetics. MethodsThere are 4 main aspects in the iPed construction, including interface building, data processing, data storage, and data visualization. The user interface was built using HTML, JavaScript libraries, and Cascading Style Sheets (version 3; Daniel Eden). Processing of the submitted data is carried out by PHP programming language. MySQL is used to document and manage the pedigree data. PHP calls the R script to accomplish the visualization. ResultsiPed is freely available to all users through the iPed website. No software is required to be installed, no pedigree files need to be prepared, and no knowledge of genetics or programs is required. The users can easily complete their pedigree data collection and visualization on their own and through a dialogue with iPed. Meanwhile, iPed provides a database that stores all users’ information. Therefore, when the users need to construct new pedigree trees for other genetic traits or modify the pedigree trees that have already been created, unnecessary duplication of operations can be avoided. ConclusionsiPed is a mobile-based and self-service tool that could be used by both professionals and nonprofessionals at any time and from any place. It reduces the amount of time required to collect, manage, and visualize pedigree data.

A novel polysaccharide (ZOP) was extracted from Zingiber officinale with ultrasonic assisted extraction method. ZOP monosaccharide composition and mole ratio is GlcA: GalA: Glc: Gal: Ara = 1.97:1.15:94.33:1.48:1.07. Then, the particle size of ZOP-NPs prepared by nano-precipitation method was 230.5 nm, and the polydispersity index (PDI) was 0.260. Using ZOP and ZOP-NPs as reductants and stabilizers, ZOP-AgNPs and ZOP-NPs-AgNPs were prepared. They were characterized by ultraviolet-visible spectrophotometer (UV-Vis), fourier transform infrared spectroscopy (FT-IR), scanning electron microscope (SEM), transmission electron microscope (TEM), and X-ray diffraction (XRD). The silver chelation rate of polysaccharide silver nanoparticles (AgNPs) ranged from 68.70 to 82.12%. ZOP-AgNPs (0.5%, w/v; 1%, w/v) and ZOP-NPs-AgNPs (0.5%, w/v; 1%, w/v) exhibited a narrow particle size distribution of 31.1, 34.6, 25.1 and 27.6 nm, respectively. And the zeta potential values of them were−19.4,−21.6,−19.7,−23.8mV, respectively. The antioxidant and antibacterial activities of ZOP-NPs-AgNPs were superior to those of ZOP, ZOP-NPs and ZOP-AgNPs.

Organogels are excellent drug carrier for controlled release. Organogels based on amino acid derivatives has been widely used in the area of drug delivery. In this study, a series of the organogel system based on amino acid derivatives gelators was designed and prepared to investigate the structure-property correlation in organogels. To investigate the factors that influence the property of drug release, we varied the formulation in the organogels: gelator structure, gelator concentration, volume of antigelation solvent, and drug loading. Through the Box–Behnken tests, the optimum organogel formulation in vitro was obtained. The self-healing properties of the organogel have been utilised for injection of a model lipophilic risperidone in situ, and sustained release of the drug has been studied over about one week in vivo. In conclusion, the gelation ability of gelators could be adjusted by the gelator structure. Gel property is related with the whole composition of the formulation. As drug carrier, the drug release property of organogels is affected by multiple factors. Our investigation of the gel release property will play a theoretical guiding role in the application in the in situ drug delivery system.

The preparation conditions of Glehniae Radix polysaccharide-iron complex (GLP80-Fe) were optimized and the physicochemical properties were characterized by Ultraviolet-visible spectroscopy (UV-Vis), Fourier Transform Infrared Spectroscopy (FT-IR), X-ray diffraction (XRD), Transmission electron microscope (TEM), Thermogravimetric analyzer, and Differential scanning calorimetry (TGA-DSC), respectively. The stability and reducibility of GLP80 and GLP80-Fe were analyzed, and the monosaccharide composition was determined by gas chromatograph (GC). In vitro antioxidant activity of GLP80 and GLP80-Fe were evaluated by determining the radical (DPPH and hydroxyl radical) scavenging abilities. The results showed that the highest iron content of GLP80-Fe (15.61%±0.04) was obtained at the optimum conditions: reaction temperature was 38.0°C, reaction time was 3.0 h, FeCl3 addition was 2.9 mL and pH was 9. GLP80-Fe was a complex with β-FeOOH as the core and polysaccharides on its surface, and it was stable at pH 3 ~ 14. GC showed that the major monosaccharides were mannose (Man) and galactose (Gal) with a ratio of 1:5.15. In vitro free-radical scavenging activity of GLP80-Fe was significantly better than GLP80. The IC50 of GLP80-Fe against DPPH and hydroxyl radical were 3.785 mg/mL and 1.460 mg/mL, respectively.

Abstract Epigenome‐wide association study (EWAS) has been applied to analyze DNA methylation variation in complex diseases for a decade, and epigenome as a research target has gradually become a hot topic of current studies. The DNA methylation microarrays, next‐generation, and third‐generation sequencing technologies have prepared a high‐quality platform for EWAS. Here, the progress of EWAS research is reviewed, its contributions to clinical applications, and mainly describe the achievements of four typical diseases. Finally, the challenges encountered by EWAS and make bold predictions for its future development are presented.

Programmed death-1 (PD-1) is a cell surface receptor that functions as a T cell checkpoint and plays a central role in regulating T cell exhaustion. Binding of PD-1 to its ligand, programmed death-ligand 1 (PD-L1), activates downstream signaling pathways and inhibits T cell activation. Moreover abnormally high PD-L1 expression on tumor cells and antigen-presenting cells in the tumor microenvironment mediates tumor immune escape, and the development of anti-PD-1/PD-L1 antibodies has recently become a hot topic in cancer immunotherapy. Here, we review the structure of PD-1 and PD-L1, the function of the PD-1/PD-L1 signaling pathway, the application of PD-1 or PD-L1 monoclonal antibodies and future directions for anti-PD-1/PD-L1 antibodies with combination therapies. Cancer immunotherapy using PD-1/PD-L1 immune checkpoint blockade may require more studies, and this approach may be curative for patients with many types of cancer in the future.

As a mental disease in modern society, depression shows an increasing occurrence, with low cure rate and high recurrence rate. It has become the most disabling disease in the world. At present, the treatment of depression is mainly based on drug therapy combined with psychological therapy, physical therapy, and other adjuvant therapy methods. Antidepressants are primarily administered peripherally (oral and intravenous) and have a slow onset of action. Antidepressant active ingredients, such as neuropeptides, natural active ingredients, and some chemical agents, are limited by factors such as the blood–brain barrier (BBB), first-pass metabolism, and extensive adverse effects caused by systemic administration. The potential anatomical link between the non-invasive nose–brain pathway and the lesion site of depression may provide a more attractive option for the delivery of antidepressant active ingredients. The purpose of this article is to describe the specific link between intranasal administration and depression, the challenges of intranasal administration, as well as studies of intranasal administration of antidepressant active ingredients.

Most proteins given orally have low bioavailability and are easily eliminated by rapid metabolism in vivo. In order to immobilize the drug at the site of administration and delay its release, a natural, gentle release system was designed. In this study, a heteropolysaccharide (ZOP) was isolated from Zingiber officinale using an ultrasonic assisted extraction method. ZOP Ara = 1.97: 1.15: 94.33: 1.48: 1.07. The ZOP/Chitosan (CS) composite hydrogel was synthesized using epichlorohydrin (ECH) as a cross-linking agent. The structure, morphology, and water-holding capacity of the composite hydrogel were characterized. The data showed that the addition of ZOP improved the hardness and water-holding capacity of the material. A swelling ratio test showed that the prepared hydrogel was sensitive to pH and ionic strength. In addition, the degradation rate of the hydrogel in a phosphate-buffered saline (PBS) solution with a pH value of 1.2 was higher than that in PBS with pH value of 7.4. Similarly, the release kinetics of Bovine serum albumin (BSA) showed higher release in an acidic system by the hydrogel composed of ZOP/CS. The hydrogel prepared by this study provided a good microenvironment for protein delivery. In summary, this composite polysaccharide hydrogel is a promising protein-drug-delivery material.

Coriolus is the dried fruiting body of Coriolus versicolor (L. ex Fr.) Quel. C. versicolor (CV) is a worldwide-distributed fungus, which is common and widely used in primitive forests in the northern hemisphere. Polysaccharide, as the main active ingredient in CV, has a variety of biological activities, such as promoting immune function, antivirus, antitumor, anti-diabetes, and so on. However, Coriolus versicolor polysaccharide (CVP) faces the problems of a single extraction method, lack of research on separation and purification, and the research on structural characterization is limited to the primary structure. Furthermore, the existing research results have not been systematically reviewed. Therefore, this paper summarizes the research status of CVP in terms of extraction technology, separation and purification, structural characterization, and pharmacological activity in recent years, in order to provide a theoretical basis for in-depth research, development, and utilization of CVP.

Rheumatoid arthritis (RA) is a complex autoimmune disease. Recent studies have identified the DNA methylation loci associated with RA and found that DNA methylation was a potential mediator of genetic risk. Parkinson's disease (PD) is a common neurodegenerative disease. Several studies have indicated that DNA methylation levels are linked to PD, and genes related to the immune system are significantly enriched in PD-related methylation modules. Although recent studies have provided profound insights into the DNA methylation of both RA and PD, no shared co-methylation relationships have been identified to date. Therefore, we sought to identify shared co-methylation relationships linked to RA and PD. Here, we calculated the Pearson's correlation coefficient (PCC) of 225,239,700 gene pairs and determined the differences and similarities between the two diseases. The global co-methylation change between in PD cases and controls was larger than that between RA cases and controls. We found 337 gene pairs with large changes that were shared between RA and PD. This co-methylation relationship study represents a new area of study for both RA and PD and provides new ideas for further study of the shared biological mechanisms of RA and PD.

The molecular mechanism that maintains the pluripotency of embryonic stem cells (ESCs) is not well understood but may be reflected in complex biological networks. However, there have been few studies on the effects of transcriptional and post-transcriptional regulation during the development of ESCs from the perspective of computational systems biology. In this study, we analyzed the topological properties of the "core" pluripotency transcription factors (TFs) OCT4, SOX2 and NANOG in protein-protein interaction networks (PPINs). Further, we identified synergistic interactions between these TFs and microRNAs (miRNAs) in PPINs during ESC development. Results show that there were significant differences in centrality characters between TF-targets and non-TF-targets in PPINs. We also found that there was consistent regulation of multiple "core" pluripotency TFs. Based on the analysis of shortest path length, we found that the module properties were not only within the targets regulated by common or multiple "core" pluripotency TFs but also between the groups of targets regulated by different TFs. Finally, we identified synergistic regulation of these TFs and miRNAs. In summary, the synergistic effects of "core" pluripotency TFs and miRNAs were analyzed using computational methods in both human and mouse PPINs.

Traditional permutation (TradPerm) tests are usually considered the gold standard for multiple testing corrections. However, they can be difficult to complete for the meta-analyses of genetic association studies based on multiple single nucleotide polymorphism loci as they depend on individual-level genotype and phenotype data to perform random shuffles, which are not easy to obtain. Most meta-analyses have therefore been performed using summary statistics from previously published studies. To carry out a permutation using only genotype counts without changing the size of the TradPerm P-value, we developed a Monte Carlo permutation (MCPerm) method. First, for each study included in the meta-analysis, we used a two-step hypergeometric distribution to generate a random number of genotypes in cases and controls. We then carried out a meta-analysis using these random genotype data. Finally, we obtained the corrected permutation P-value of the meta-analysis by repeating the entire process N times. We used five real datasets and five simulation datasets to evaluate the MCPerm method and our results showed the following: (1) MCPerm requires only the summary statistics of the genotype, without the need for individual-level data; (2) Genotype counts generated by our two-step hypergeometric distributions had the same distributions as genotype counts generated by shuffling; (3) MCPerm had almost exactly the same permutation P-values as TradPerm (r = 0.999; P

Demographic events such as migration, and evolutionary events like mutation and recombination, have contributed to the genetic variations that are found in the human genome. During the evolution and differentiation of human populations, different functional genes and pathways (a group of genes that act together to perform specific biological tasks) would have displayed different degrees of genetic diversity or evolutionary conservatism. To query the genetic differences of functional genes or pathways in populations, we have developed the human gene population genetic difference (HGPGD) database. Currently, 11 common population genetic features, 18,158 single human genes, 220 KEGG (Kyoto Encyclopedia of Genes and Genomes) human pathways and 4,639 Gene Ontology (GO) categories (3,269 in biological process; 862 in molecular function; and 508 in cellular component) are available in the HGPGD database. The 11 population genetic features are related mainly to three aspects: allele frequency, linkage disequilibrium pattern, and transferability of tagSNPs. By entering a list of Gene IDs, KEGG pathway IDs or GO category IDs and selecting a population genetic feature, users can search the genetic differences between pairwise HapMap populations. We hope that, when the researchers carry out gene-based, KEGG pathway-based or GO category-based research, they can take full account of the genetic differences between populations. The HGPGD database (V1.0) is available at http://www.bioapp.org/hgpgd.

Growing evidence from epidemiological studies indicates the association between rheumatoid arthritis (RA) and measles. However, the exact mechanism for this association is still unclear now. We consider that the strong association between both diseases may be caused by shared genetic pathways. We performed a pathway analysis of large-scale RA genome-wide association studies (GWAS) dataset with 5,539 cases and 20,169 controls of European descent. Meanwhile, we evaluated our findings using previously identified RA loci, protein-protein interaction network and previous results from pathway analysis of RA and other autoimmune diseases GWAS. We confirmed four pathways including Cytokine-cytokine receptor interaction, Jak-STAT signaling, T cell receptor signaling and Cell adhesion molecules. Meanwhile, we highlighted for the first time the involvement of Measles and Intestinal immune network for IgA production pathways in RA. Our results may explain the strong association between RA and measles, which may be caused by the shared genetic pathway. We believe that our results will be helpful for future genetic studies in RA pathogenesis and may significantly assist in the development of therapeutic strategies.

OBJECTIVE: Candidate gene association studies and genome-wide association studies (GWAs) have identified a large number of single nucleotide polymorphisms (SNPs) loci affecting susceptibility to rheumatoid arthritis (RA). However, for the same locus, some studies have yielded inconsistent results. To assess all the available evidence for association, we performed a meta-analysis on previously published case-control studies investigating the association between SNPs and RA. METHODS: Two hundred and sixteen studies, involving 125 SNPs, were reviewed. For each SNP, three genetic models were considered: the allele, dominant and recessive effects models. For each model, the effect summary odds ratio (OR) and 95% CIs were calculated. Cochran's Q-statistics were used to assess heterogeneity. If the heterogeneity was high, a random effects model was used for meta-analysis, otherwise a fixed effects model was used. RESULTS: The meta-analysis results showed that: (1) 30, 28 and 26 SNPs were significantly associated with RA (P

Detecting and interpreting certain system-level characteristics associated with human population genetic differences is a challenge for human geneticists. In this study, we conducted a population genetic study using the HapMap genotype data to identify certain special Gene Ontology (GO) categories associated with high/low genetic difference among 11 Hapmap populations. Initially, the genetic differences in each gene region among these populations were measured using allele frequency, linkage disequilibrium (LD) pattern, and transferability of tagSNPs. The associations between each GO term and these genetic differences were then identified. The results showed that cellular process, catalytic activity, binding, and some of their sub-terms were associated with high levels of genetic difference, and genes involved in these functional categories displayed, on average, high genetic diversity among different populations. By contrast, multicellular organismal processes, molecular transducer activity, and some of their sub-terms were associated with low levels of genetic difference. In particular, the neurological system process under the multicellular organismal process category had low levels of genetic difference; the neurological function also showed high evolutionary conservation between species in some previous studies. These results may provide a new insight into the understanding of human evolutionary history at the system-level.