On Steam Pipe Network Modeling and Flow Rate Calculation

AbstractThe paper demonstrates the method to set up the pipe network hydraulic-thermal synthetic mode by applying hydraulic and thermal models of single pipe, and proposes the algorithm based on searching for the problem that iterative calculation sometimes cannot derive convergent reasonable result as well. Compared the calculated values with the measurements, it shows the validation of the model and effectiveness of the algorithm

Dibutyl 5-[(4-ethoxycarbonylphenyl)diazenyl]benzene-1,3-dicarboxylate

In the title compound, C25H30N2O6, the dihedral angle between the aromatic rings is 3.79 (1) Å and the N=N bond shows a trans conformation. Both butyl side chains show evidence of disorder

Metformin Treatment Does Not Inhibit Growth of Pancreatic Cancer Patient-Derived Xenografts

There is currently tremendous interest in developing anti-cancer therapeutics targeting cell signaling pathways important for both cancer cell metabolism and growth. Several epidemiological studies have shown that diabetic patients taking metformin have a decreased incidence of pancreatic cancer. This has prompted efforts to evaluate metformin, a drug with negligible toxicity, as a therapeutic modality in pancreatic cancer. Preclinical studies in cell line xenografts and one study in patient-derived xenograft (PDX) models were promising, while recently published clinical trials showed no benefit to adding metformin to combination therapy regimens for locally advanced and metastatic pancreatic cancer. PDX models in which patient tumors are directly engrafted into immunocompromised mice have been shown to be excellent preclinical models for biomarker discovery and therapeutic development. We evaluated the response of four PDX tumor lines to metformin treatment and found that all four of our PDX lines were resistant to metformin. We found that the mechanisms of resistance may occur through lack of sustained activation of adenosine monophosphate-activated protein kinase (AMPK) or downstream reactivation of the mammalian target of rapamycin (mTOR). Moreover, combined treatment with metformin and mTOR inhibitors failed to improve responses in cell lines, which further indicates that metformin alone or in combination with mTOR inhibitors will be ineffective in patients, and that resistance to metformin may occur through multiple pathways. Further studies are required to better understand these mechanisms of resistance and inform potential combination therapies with metformin and existing or novel therapeutics

Original Article Triptolide induces anti-inflammatory cellular responses

Abstract: Tripterygium wilfordii Hook F. has been used for centuries in traditional Chinese medicine to treat rheumatoid arthritis, an autoimmune disease associated with increased production of the pro-inflammatory cytokine, tumor necrosis factor (TNF)-α. Triptolide is a compound originally purified from T. wilfordii Hook F. and has potent anti-inflammatory and immunosuppressant activities. In this study, we investigated the effect of triptolide on the global gene expression patterns of macrophages treated with lipopolysaccharide (LPS). We found that LPS stimulation resulted in >5-fold increase in expression of 117 genes, and triptolide caused a >50% inhibition in 47 of the LPS-inducible 117 genes. A large portion of the genes that were strongly induced by LPS and significantly inhibited by triptolide were pro-inflammatory cytokine and chemokine genes, including TNF-α, IL-1β, and IL-6. Interestingly, LPS also induced the expression of micro-RNA-155 (miR-155) precursor, BIC, which was inhibited by triptolide. Confirming the cDNA array results, we demonstrated that triptolide blocked the induction of these pro-inflammatory cytokines as well as miR-155 in a dose-dependent manner. Profound inhibition of pro-inflammatory cytokine expression was observed at concentrations as low as 10-50 nM. However, triptolide neither inhibited the phosphorylation or degradation of IBα after LPS stimulation, nor affected the DNAbinding activity of NF-B. Surprisingly, we found that triptolide not only inhibited NF-B-regulated reporter transcription, but also dramatically blocked the activity of other transcription factors. Our study offers a plausible explanation of the therapeutic mechanism of T. wilfordii Hook F

The E3 Ubiquitin Ligase SCF(Cyclin F) Transmits AKT Signaling to the Cell-Cycle Machinery

The oncogenic AKT kinase is a key regulator of apoptosis, cell growth, and cell-cycle progression. Despite its important role in proliferation, it remains largely unknown how AKT is mechanistically linked to the cell cycle. We show here that cyclin F, a substrate receptor F-box protein for the SCF (Skp1/Cul1/F-box) family of E3 ubiquitin ligases, is a bona fide AKT substrate. Cyclin F expression oscillates throughout the cell cycle, a rare feature among the 69 human F-box proteins, and all of its known substrates are involved in proliferation. AKT phosphorylation of cyclin F enhances its stability and promotes assembly into productive E3 ligase complexes. Importantly, expression of mutant versions of cyclin F that cannot be phosphorylated by AKT impair cell-cycle entry. Our data suggest that cyclin F transmits mitogen signaling through AKT to the core cell-cycle machinery. This discovery has potential implications for proliferative control in malignancies where AKT is activated

VprBP/DCAF1 Regulates the Degradation and Nonproteolytic Activation of the Cell Cycle Transcription Factor FoxM1

The oncogenic transcription factor FoxM1 plays a vital role in cell cycle progression, is activated in numerous human malignancies, and is linked to chromosome instability. We characterize here a cullin 4-based E3 ubiquitin ligase and its substrate receptor, VprBP/DCAF1 (CRL4VprBP), which we show regulate FoxM1 ubiquitylation and degradation. Paradoxically, we also found that the substrate receptor VprBP is a potent FoxM1 activator. VprBP depletion reduces expression of FoxM1 target genes and impairs mitotic entry, whereas ectopic VprBP expression strongly activates a FoxM1 transcriptional reporter. VprBP binding to CRL4 is reduced during mitosis, and our data suggest that VprBP activation of FoxM1 is ligase independent. This implies a nonproteolytic activation mechanism that is reminiscent of, yet distinct from, the ubiquitin-dependent transactivation of the oncoprotein Myc by other E3s. Significantly, VprBP protein levels were upregulated in high-grade serous ovarian patient tumors, where the FoxM1 signature is amplified. These data suggest that FoxM1 abundance and activity are controlled by VprBP and highlight the functional repurposing of E3 ligase substrate receptors independent of the ubiquitin system

Mine earthquake mechanism of extremely thick strata based on focalmemchanism analysis

In the Ordos mining area of North China, the Jurassic coal seam is commonly overlain by extremely thick cretaceous sandstone strata. Based on the seismic displacement field and relative moment tensor inversion method, this paper investigates the mine earthquake mechanism and roof fracture characteristics of coal seams under extremely thick strata. In this study, by using seismic source groups as units and microseismic stations as objects, the source mechanism of mine earthquakes is inverted by constructing an inversion matrix, which greatly improves the inversion efficiency and accuracy. The focal mechanism of large-energy mine earthquakes located in solid coal section and goaf section under extremely thick strata is calculated. The characteristics of roof fracture evolution and the influence of vibration wave radiation are quantitatively analyzed. The results show that the extremely thick strata of Cretaceous goaf start to break when the panel below retreats along goaf. During this period, the surface subsidence increases rapidly, and the significant mine earthquakes with energy above 100 kJ begin to occur, and the mine earthquake distribution is more concentrative than that in the solid coal stage. Most of the large-energy mine earthquakes are located behind the goaf, which is closely related to the breakage and slide of the thick roof. Roof tension rupture accounts for more than 85% of the mine earthquakes. During mining along goaf, the seismic sources tend to expand upward, and more shear slip ruptures are presented compared with that in the solid coal mining stage. The strike of the fracture surface has a similar direction or an angle of “X” with the advancing direction. However, compared with that in the solid coal stage, the angle of “X” during mining along goaf increases from 30° to 45°. For the source rupture surface, the dip angle of between 0°−30° accounts for about 50% of the total. The failure type of roof is dominated by horizontal separation tension and roof rotation compression. The generated P waves mostly propagate to the goaf below, which causes a minor influence on the mining face. Only a small part of the P waves propagate to the surrounding working face, which may pose a great impact on the working face. The prevention and control strategy on the extremely-thick-strata type mine earthquakes can be conducted by weakening the integrity of thick strata and making thick strata break in tiers, aiming to reduce the rockburst risks to the working face induced by the breakage of the whole thick strata

MAP kinase phosphatase 1 controls innate immune responses and suppresses endotoxic shock

Septic shock is a leading cause of morbidity and mortality. However, genetic factors predisposing to septic shock are not fully understood. Excessive production of proinflammatory cytokines, particularly tumor necrosis factor (TNF)-α, and the resultant severe hypotension play a central role in the pathophysiological process. Mitogen-activated protein (MAP) kinase cascades are crucial in the biosynthesis of proinflammatory cytokines. MAP kinase phosphatase (MKP)-1 is an archetypal member of the dual specificity protein phosphatase family that dephosphorylates MAP kinase. Thus, we hypothesize that knockout of the Mkp-1 gene results in prolonged MAP kinase activation, augmented cytokine production, and increased susceptibility to endotoxic shock. Here, we show that knockout of Mkp-1 substantially sensitizes mice to endotoxic shock induced by lipopolysaccharide (LPS) challenge. We demonstrate that upon LPS challenge, Mkp-1−/− cells exhibit prolonged p38 and c-Jun NH2-terminal kinase activation as well as enhanced TNF-α and interleukin (IL)-6 production compared with wild-type cells. After LPS challenge, Mkp-1 knockout mice produce dramatically more TNF-α, IL-6, and IL-10 than do wild-type mice. Consequently, Mkp-1 knockout mice develop severe hypotension and multiple organ failure, and exhibit a remarkable increase in mortality. Our studies demonstrate that MKP-1 is a pivotal feedback control regulator of the innate immune responses and plays a critical role in suppressing endotoxin shock

In silico APC/C substrate discovery reveals cell cycle-dependent degradation of UHRF1 and other chromatin regulators

The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase and critical regulator of cell cycle progression. Despite its vital role, it has remained challenging to globally map APC/C substrates. By combining orthogonal features of known substrates, we predicted APC/C substrates in silico. This analysis identified many known substrates and suggested numerous candidates. Unexpectedly, chromatin regulatory proteins are enriched among putative substrates, and we show experimentally that several chromatin proteins bind APC/C, oscillate during the cell cycle, and are degraded following APC/C activation, consistent with being direct APC/C substrates. Additional analysis revealed detailed mechanisms of ubiquitylation for UHRF1, a key chromatin regulator involved in histone ubiquitylation and DNA methylation maintenance. Disrupting UHRF1 degradation at mitotic exit accelerates G1-phase cell cycle progression and perturbs global DNA methylation patterning in the genome. We conclude that APC/C coordinates crosstalk between cell cycle and chromatin regulatory proteins. This has potential consequences in normal cell physiology, where the chromatin environment changes depending on proliferative state, as well as in disease. Copyright