Geochemical Characteristics and Significance of Organic Matter in Hydrate-Bearing Sediments from Shenhu Area, South China Sea.

Rock-Eval pyrolysis and the biomarker composition of organic matter were systematically studied in hydrate-bearing sediments from the Shenhu area, South China Sea. The n-alkane distribution patterns revealed that the organic matter in the sediments appeared to originate from mixed sources of marine autochthonous input, terrestrial higher plants, and ancient reworked organic matter. The low total organic carbon contents (average < 0.5%) and the low hydrogen index (HI, <80 mg HC/g TOC) suggested the poor hydrocarbon-generation potential of the deposited organic matter at a surrounding temperature of <20 °C in unconsolidated sediments. The abnormally high production index and the fossil-originated unresolved complex mixture (UCM) accompanied by sterane and hopane of high maturity indicated the contribution of deep hydrocarbon reservoirs. Preliminary oil-to-source correlation for the extracts implied that the allochthonous hydrocarbons in the W01B and W02B sediments might have originated from the terrestrial source rocks of mature Enping and Wenchang formations, while those of W03B seem to be derived from more reduced and immature marine source rocks such as the Zhuhai formation. The results of the organic extracts supported the previous identification of source rocks based on the isotopic composition of C2+ hydrate-bound gases. The biomarker of methanogens, squalane, was recognized in the sediments of this study, possibly suggesting the generation of secondary microbial gases which are coupled with the biodegradation of the deep allochthonous hydrocarbons.

Oral multivalent epitope vaccine, based on UreB, HpaA, CAT, and LTB, for prevention and treatment of Helicobacter pylori infection in C57BL / 6 mice.

BACKGROUND: As the resistance of Helicobacter pylori to traditional triple therapy is gradually revealed, an increasing number of people are focusing on vaccine treatments for H. pylori infection. Epitope vaccines are a promising strategy for the treatment of H. pylori infection, and multivalent vaccines will be more effective than monovalent vaccines. MATERIALS AND METHODS: In this study, we designed a multivalent vaccine named LHUC, which consists of the adjuvant LTB as well as three Th cell epitopes (HpaA154-171 , UreB237-251, and UreB546-561 ) and five B-cell epitopes (UreB349-363 , UreB327-334 , CAT394-405 , CAT387-397, and HpaA132-141 ) from UreB, HpaA, and catalase. In BALB/c mice, the specificity and immunogenicity of the fusion peptide LHUC and the neutralization of H. pylori urease and catalase by the specific IgG elicited by LHUC were evaluated. The preventive and therapeutic effects of LHUC were evaluated in C57BL/6 mice infected with H. pylori. RESULTS: The results showed that compared with LTB and PBS, LHUC induced specific IgG and IgA antibody production in mice, and IgG antibodies significantly inhibited the H. pylori urease and catalase activities in vitro. Additionally, by detecting the levels of IFN-γ, IL-4, and IL-17 in lymphocyte supernatants, we proved that LHUC could activate Th1, Th2, and Th17 mixed T-cell immune responses in vivo. Finally, a C57BL/6 mouse model of gastric infection with H. pylori was established. The results showed that compared with the effects of LTB and PBS, the prevention and treatment effects of oral inoculation with LHUC significantly inhibited bacterial colonization. CONCLUSIONS: In conclusion, LHUC, a multivalent vaccine based on multiple H. pylori antigens, is a promising and safe vaccine that can effectively reduce the colonization of H. pylori in the stomach.

Down-regulation of FTX promotes the differentiation of osteoclasts in osteoporosis through the Notch1 signaling pathway by targeting miR-137.

BACKGROUND: Osteoporosis (OP) is one of the commonly seen bone diseases with low bone mineral densities and trauma fractures. Accumulative studies have demonstrated that the occurrence of OP is closely related to osteoclasts differentiation. LncRNA FTX has been demonstrated to inhibit the development of some human cancers. However, its potential functions in human OP remains to be elusive. METHODS: The expressions of FTX and miR-137 in bone and serum samples of patients with or without OP were measured. Bioinformatics analysis, RIP assays and luciferase reporter assays were performed to examine the upstream and downstream transactional factors of miR-137. Functional assays were conducted to check the roles of the Notching1 signaling pathway OP. RESULTS: FTX was suppressed in OP samples and serums, however, miR-137 was greatly elevated. FTX reduced osteoclast-genesis and inhibited osteogenic differentiation by targeting miR-137. This also inhibited the Notch1 signaling pathway. CONCLUSION: Our experiments and results pointed out that lncRNA FTX up-regulated miR-137 in OP through the Notch1 signaling pathway.

MiR-137 promotes TLR4/NF-κB pathway activity through targeting KDM4A, inhibits osteogenic differentiation of human bone marrow mesenchymal stem cells and aggravates osteoporosis.

PURPOSE: As the global population ages rapidly, osteoporotic fractures have become an important public health problem. Previous studies have suggested that miR-137 is involved in the regulation of bone formation, but its specific regulatory mechanism remains unclear. In this study, we aimed to explore the expression, role, and regulatory mechanism of miR-137 in the osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs). METHODS: hBMSCs were induced into osteoblasts at first, and the expression level of miR-137 at different time points was detected. After knockdown and overexpression of miR-137, the effect of miR-137 on the osteogenic differentiation of hBMSCs was examined through alkaline phosphatase (ALP) staining and Alizarin Red staining. Western blotting was performed to detect the expression of runt-related transcription factor 2 (Runx2), osteocalcin (OCN), and toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway. Bioinformatics websites were used to predict the target binding sites for miR-137 and KDM4A, and the results were validated using luciferase reporter gene experiments. Moreover, the ALP activity, calcium nodule formation, and activation of Runx2, OCN, and TLR4/NF-κB pathways were observed after knockdown of KDM4A. RESULTS: The expression of miR-137 decreased during osteogenic differentiation. Knockdown of miR-137 expression increased the osteogenic ability of hBMSCs, while overexpression of it weakened the ability. Through the activation of the TLR4/NF-κB pathway, miR-137 inhibited osteogenic differentiation. KDM4A was identified as a predicted target gene of miR-137. After knocking down KDM4A expression, the osteogenic ability of hBMSCs was diminished, and the TLR4/NF-κB pathway was activated. Furthermore, the osteogenic ability of hBMSCs was partially restored and the activation level of TLR4/NF-κB was reduced after miR-137 knockdown. CONCLUSION: MiR-137 enhances the activity of the TLR4/NF-κB pathway by targeting KDM4A, thereby inhibiting the osteogenic differentiation of hBMSCs and exacerbating osteoporosis.

Anomaly traffic detection based on feature fluctuation for secure industrial internet of things.

The detection of anomaly traffic in internet of things (IoT) is mainly based on the original binary data at the traffic packet level and the structured data at the session flow level. This kind of dataset has a single feature extraction method and relies on prior manual knowledge. It is easy to lose critical information during data processing, which reduces the validity and robustness of the dataset. In this paper, we first construct a new anomaly traffic dataset based on the traffic packet and session flow data in the Iot-23 dataset. Second, we propose a feature extraction method based on feature fluctuation. Our proposed method can effectively solve the disadvantage that the data collected in different scenarios have different characteristics, which leads to the feature containing less information. Compared with the traditional anomaly traffic detection model, experiments show that our proposed method based on feature fluctuation has stronger robustness, can improve the accuracy of anomaly traffic detection and the generalization ability of the traditional model, and is more conducive to the detection of anomalous traffic in IoT.

Trends in insulin resistance: insights into mechanisms and therapeutic strategy.

The centenary of insulin discovery represents an important opportunity to transform diabetes from a fatal diagnosis into a medically manageable chronic condition. Insulin is a key peptide hormone and mediates the systemic glucose metabolism in different tissues. Insulin resistance (IR) is a disordered biological response for insulin stimulation through the disruption of different molecular pathways in target tissues. Acquired conditions and genetic factors have been implicated in IR. Recent genetic and biochemical studies suggest that the dysregulated metabolic mediators released by adipose tissue including adipokines, cytokines, chemokines, excess lipids and toxic lipid metabolites promote IR in other tissues. IR is associated with several groups of abnormal syndromes that include obesity, diabetes, metabolic dysfunction-associated fatty liver disease (MAFLD), cardiovascular disease, polycystic ovary syndrome (PCOS), and other abnormalities. Although no medication is specifically approved to treat IR, we summarized the lifestyle changes and pharmacological medications that have been used as efficient intervention to improve insulin sensitivity. Ultimately, the systematic discussion of complex mechanism will help to identify potential new targets and treat the closely associated metabolic syndrome of IR.

A bone substitute composed of polymethyl-methacrylate bone cement and Bio-Gene allogeneic bone promotes osteoblast viability, adhesion and differentiation.

BACKGROUND: Increasing reports on new cement formulations that address the shortcomings of PMMA bone cements and various active components have been introduced to improve the biological activity of PMMA cement. OBJECTIVE: Evaluating the biological properties of PMMA cements reinforced with Bio-Gene allogeneic bone. METHODS: The MC3T3-E1 mouse osteoblast-like cells were utilized to determine the effects of Bio-Gene + PMMA on osteoblast viability, adhesion and differentiation. RESULTS: The combination of allogeneic bone and PMMA increased the number of adherent live cells compared to both control group and PMMA or Bio-Gene group. Scanning electron microscopy observed that the number of cells adhered to Bio-Gene + PMMA was larger than Bio-Gene and PMMA group. Compared with the control and PMMA or Bio-Gene group, the level of ALP and the number of calcium nodules after osteoinduction was remarkably enhanced in Bio-Gene + PMMA group. Additionally, the combination of Bio-Gene and PMMA induced the protein expression of osteocalcin, osterix and collagen I. CONCLUSION: The composition of PMMA and allogeneic bone could provide a more beneficial microenvironment for osteoblast proliferation, adhesion and differentiation. PMMA bone cement reinforced with Bio-Gene allogeneic bone may act as a novel bone substitute to improve the biological activity of PMMA cement.

[Biomechanical study of polymethyl methacrylate bone cement and allogeneic bone for strengthening sheep vertebrae].

OBJECTIVE: To investigate the feasibility and mechanical properties of polymethyl methacrylate (PMMA) bone cement and allogeneic bone mixture to strengthen sheep vertebrae with osteoporotic compression fracture. METHODS: A total of 75 lumbar vertebrae (L 1-L 5) of adult goats was harvested to prepare the osteoporotic vertebral body model by decalcification. The volume of vertebral body and the weight and bone density before and after decalcification were measured. And the failure strength, failure displacement, and stiffness were tested by using a mechanical tester. Then the vertebral compression fracture models were prepared and divided into 3 groups ( n=25). The vertebral bodies were injected with allogeneic bone in group A, PMMA bone cement in group B, and mixture of allogeneic bone and PMMA bone cement in a ratio of 1∶1 in group C. After CT observation of the implant distribution in the vertebral body, the failure strength, failure displacement, and stiffness of the vertebral body were measured again. RESULTS: There was no significant difference in weight, bone density, and volume of vertebral bodies before decalcification between groups ( P>0.05). After decalcification, there was no significant difference in bone density, decreasing rate, and weight between groups ( P>0.05). There were significant differences in vertebral body weight and bone mineral density between pre- and post-decalcification in 3 groups ( P<0.05). CT showed that the implants in each group were evenly distributed in the vertebral body with no leakage. Before fracture, the differences in vertebral body failure strength, failure displacement, and stiffness between groups were not significant ( P>0.05). After augmentation, the failure displacement of group A was significantly greater than that of groups B and C, and the failure strength and stiffness were less than those of groups B and C, the failure displacement of group C was greater than that of group B, and the failure strength and stiffness were less than those of group B, the differences between groups were significant ( P<0.05). Except for the failure strength of group A ( P>0.05), the differences in the failure strength, failure displacement, and stiffness before fracture and after augmentation in the other groups were significant ( P<0.05). CONCLUSION: The mixture of allogeneic bone and PMMA bone cement in a ratio of 1∶1 can improve the strength of the vertebral body of sheep osteoporotic compression fractures and restore the initial stiffness of the vertebral body. It has good mechanical properties and can be used as one of the filling materials in percutaneous vertebroplasty.

MiR-582-3p alleviates osteoarthritis progression by targeting YAP1.

Osteoarthritis (OA) is a widespread degenerative joint disease that affects more than 350 million people worldwide. Although YAP1 has been proved to play a key role in OA, the biological function and mechanism of YAP1 in OA still need further investigation. In the present study, we demonstrated that YAP1 was highly expressed in OA rat chondrocytes. Recently, growing microRNAs (miRNAs) have been reported to play important roles in OA development. Among them, miR-582-3p is one of the few significantly downregulated miRNAs and attracted our attention. Functional investigations indicated that miR-582-3p inhibited chondrocyte apoptosis, reduced the proinflammatory cytokine production and suppressed extracellular matrix (ECM) degradation. Subsequently, molecular mechanism exploration implied that YAP1 is a downstream target of miR-582-3p. Furthermore, rescue assays revealed that YAP1 amplification can reverse miR-582-3p mimic-mediated effects on chondrocyte apoptosis, inflammatory response, and ECM degradation. Moreover, the OA rat model was established to explore the function of miR-582-3p/YAP1 axis in vivo. The results showed that YAP1 overexpression can recover the effects induced by injection of AAV-miR-582-3p mimic on OA progression. To sum up, these findings implied a crucial role of miR-582-3p/YAP1 axis in OA, which may provide a promising therapeutic strategy for OA.

Pyrrolopyrazines as selective spleen tyrosine kinase inhibitors.

We describe the discovery of several pyrrolopyrazines as potent and selective Syk inhibitors and the efforts that eventually led to the desired improvements in physicochemical properties and human whole blood potencies. Ultimately, our mouse model revealed unexpected toxicity that precluded us from further advancing this series.

Rational design of highly selective spleen tyrosine kinase inhibitors.

A novel approach to design selective spleen tyrosine kinase (Syk) inhibitors is described. Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of autoimmune diseases such as asthma, rheumatoid arthritis, and SLE. Fostamatinib, a Syk inhibitor that successfully completed phase II clinical trials, also exhibits some undesirable side effects. More selective Syk inhibitors could offer safer, alternative treatments. Through a systematic evaluation of the kinome, we identified Pro455 and Asn457 in the Syk ATP binding site as a rare combination among sequence aligned kinases and hypothesized that optimizing the interaction between them and a Syk inhibitor molecule would impart high selectivity for Syk over other kinases. We report the structure-guided identification of three series of selective spleen tyrosine kinase inhibitors that support our hypothesis and offer useful guidance to other researchers in the field.