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Benzylpenicilloyl/albumin conjugates (BP–HSA) which have lost all antibacterial activity but possess an immunogenic potential were systematically studied by matrix-assisted laser desorption ionization-time of flight-mass spectrometry, polyacrylamide gel electrophoresis and ultraviolet spectrophotometry. The results showed that the conjugation rate was in the range of 8 : 1–18 : 1. The interaction between human serum albumin (HSA) and penicilloic acid (BPA) was firstly studied by using molecular docking. The results showed that at least 8 activity sites existed on HSA for the conjugation of BPA. BP–HSA was imprinted onto a macroporous chitosan/polyvinylpyrrolidone/carbon nanotubes carrier by using surface precipitation polymerization, and a pre-designed hybrid imprinted membrane (CPC-MIM) was obtained to achieve the specific capturing of BP–HSA from human plasma. The morphologies and physical/chemical properties of membranes were systematically characterized by scanning electron microscopy, atomic force microscopy, Fourier translation infrared spectra, differential scanning calorimeter, thermogravimetric analysis and contact angle measurement. The results indicated that CPC-MIM possessed superior properties for the selective adsorption of BP–HSA and it also had a relatively good thermal stability. The adsorption properties of CPC-MIM were evaluated by comparing with other different constituents of membranes. The results revealed that the maximum adsorptive capacity and imprint factor of CPC-MIM were 0.538 μmol cm−3 and 3.3, respectively. Compared with other proteins, CPC-MIM showed a specific adsorption capacity for BP–HSA, and CPC-MIM could selectively capture BP–HSA from human plasma. This study provides a basis for the further research of the allergic mechanism of penicillins, and the generated hybrid imprinted membrane could potentially be an outstanding separation material for the large-scale continuous selective separation of target proteins from a complex matrix.

Pathological angiogenesis plays a critical role in numerous diseases including malignancy. VEGFR-2 is the central regulators in angiogenesis and has become a promising target for anticancer drug design. We have identified a novel biphenyl-aryl urea incorporated with salicyladoxime (BPS-7) as potent VEGFR-2 inhibitor. As a continuation to our previous research, various aromatic-heterocyclic were introduced as hinge-binding fragment via a core-refining approach. Interestingly, many compounds exhibited comparable VEGFR-2 inhibition to Sorafenib. In particular, 12e and 12o displayed excellent VEGFR-2 inhibitory activity with IC₅₀ values of 0.50 nM and 0.79 nM, respectively. Several title compounds showed considerable antiproliferative activity against A549 and SMMC-7721 cells. In addition, molecular docking was performed to rationalize the efficiency of the better compounds. These results will be instructive for further inhibitor design and optimization.

Marine environments are known to be a new source of structurally diverse bioactive molecules. In this paper, we identified a porphyrin derivative of Pyropheophorbide a (PPa) from the mussel Musculus senhousei (M. senhousei) that showed broad anti-influenza A virus activity in vitro against a panel of influenza A viral strains. The analysis of the mechanism of action indicated that PPa functions in the early stage of virus infection by interacting with the lipid bilayer of the virion, resulting in an alteration of membrane-associated functions, thereby blocking the entry of enveloped viruses into host cells. In addition, the anti-influenza A virus activity of PPa was further assessed in mice infected with the influenza A virus. The survival rate and mean survival time of mice were apparently prolonged compared with the control group which was not treated with the drug. Therefore, PPa and its derivatives may represent lead compounds for controlling influenza A virus infection.

Argentine haemorrhagic fever (AHF) is a rodent-borne disease with a lethality as high as ~30%, which is caused by the New World arenavirus, Junín virus (JUNV). It was once a major epidemic in South America and puts millions of people in Argentina at risk. Here, we aimed to develop horse antibodies or antibody fragments against JUNV. Before preparing the horse antibodies, a strategy to efficiently generate horse antisera was established based on comparisons among immunogens and immunization methods in both mice and horses. Antisera against JUNV were finally obtained by vaccinating horses with vesicular stomatitis virus pseudotypes bearing JUNV GP. The horse antibodies IgG and F(ab’)2 were subsequently demonstrated to effectively neutralize vesicular stomatitis virus pseudotypes bearing JUNV GP and to show some cross-neutralization against pathogenic New World arenaviruses. Further research revealed that Asp123 on GP1 is an important site for the binding of antibodies targeting mainly JUNV GP1 for neutralization. Collectively, this study presents an efficient strategy to develop horse antisera against JUNV and provides GP1-specific horse antibodies as potential therapeutics for AHF., Highlights • Junín pseudo-typed virus efficiently stimulates neutralizing antibodies in mice and horses. • Horse immunoglobulin and immunoglobulin fragments potentially neutralize Junín virus. • Horse antibodies show some cross-neutralization against the pathogenic New World arenaviruses. • Asp123 is an important site on glycoprotein 1 for the binding of horse neutralizing antibodies.

In order to develop an affinity HPLC method for screening direct thrombin inhibitors from Traditional Chinese Medicine (TCM), thrombin was immobilized on the glutaraldehyde-modified amino silica gel and was used as thrombin stationary phase. A thrombin affinity column (TAC) was made by packing the thrombin stationary phase into a bare column (2.0 * 1.0 mm, i.d.). The direct thrombin inhibitors could be screened through this TAC column. For the purpose of improvement of the discovery efficiency, a TAC-HPLC-MS/MS system was used to screen thrombin inhibitors from Radix Salviae Miltiorrhiae (RSM), a famous traditional Chinese medicine. After optimization of all the conditions, cryptotanshinone (Cry), dihydrotanshinone I (Dih-I) and tanshinone IIA (Tan-IIA) were screened out and identified as potential active components. The anticoagulant effects of these three compounds were tested by anticoagulant experiments in vitro. Furthermore, the interaction of three compounds with thrombin was studied by molecular docking. The result shows they have the potential to be used as preventive drugs. In short, this method can be used to screen anticoagulant drugs from traditional Chinese medicine, which provides convenience for screening anticoagulant drugs.

VEGFR-2, Tie-2, and EphB4 are essential for both angiogenesis and tumorigenesis. Herein, we developed a series of pyridines incorporated with 1,2,3-triazole as multi-target inhibitors based on the crystal structure alignment of the kinase domain of angiogenic RTKs. Biological results indicated that these multi-target inhibitors displayed considerable potential as novel anti-angiogenic agents. Among them, compound BD7 exhibited the most potent inhibition against the three RTKs simultaneously, and good activity on inhibiting viability of human umbilical endothelial cells. Therefore, 1,2,3-triazole could serve as a promising DFG binding group for multi-target inhibitors of VEGFR-2, Tie-2 and EphB4 bearing pyridine as hinge binding group.

The existence of latent reservoirs of Human Immunodeficiency Virus type-1 (HIV-1) is a major obstacle in eliminating the virus. Thus, an urgent need exists for effective latency reversing agents (LRAs) based on the "shock and kill" strategy. Proteasome inhibitors were recently studied as LRAs, but were considered too toxic for clinical use. Here, we demonstrated that PR-957, a selective immunoproteasome inhibitor, effectively reactivated latent HIV-1 provirus in vitro and ex vivo. Our data also suggests that PR-957 has relatively low cytotoxicity. Furthermore, it does not influence global T cell activation and decreases the expression levels of HIV-1 receptors/co-receptors. We demonstrated synergistic activation of latent HIV-1 with PR-957 and Prostratin (a protein kinase C activator) that alleviated the extent of T cell activation induced by Prostratin. In addition, PR-957 exhibited latency reversing efficacy through activating p-TEFb mediated by HSF-1 pathway. Moreover, PR-957 did not affect the activity of combination antiretroviral therapy (cART) drugs and the PR-957-reactivated virus was effectively inhibited with cART drugs. In conclusion, the immunoproteasome inhibitor PR-957 is a promising candidate LRA for future HIV-1 eradication strategies.

Beamforming is an imaging technique that locates sources by a phased array system. Conventional source model in beamforming is the monopole, and problematic result may appear towards directional sources. As an alternative, a modified beamforming method is proposed in this paper to extend this technique to dipole sources. The method is developed by predefining orientations and selecting direction of maximum output at each scanning point. Simulation and experiment are conducted to illustrate and verify this method, and results are shown to give a proper location of dipole sources.

Background The skeletal muscle mass-to-visceral fat area ratio (SVR) has been linked to arterial stiffness in non-diabetic adults. We examined the association between the SVR and arterial stiffness in patients with type 2 diabetes mellitus (T2DM). Methods Patients with type 2 diabetes mellitus (252 men and 171 women) aged 40–75 years were enrolled and divided into three groups according to SVR tertiles. Arterial stiffness was measured as brachial-ankle pulse wave velocity (baPWV), with baPWV> 1800 mm/s defined as high. Spearman’s partial correlation was used to adjust confounding factors. The odds ratio for high baPWV was determined by multiple logistic regression analyses, and receiver-operating characteristic analysis was conducted. Results SVR was associated with baPWV in Chinese patients with T2DM (Spearman’s partial correlation = − 0.129, P

The scarcity of donor organs may be addressed in the future by using pigs to grow humanized organs with lower potential for immunological rejection after transplantation in humans. Previous studies have demonstrated that interspecies complementation of rodent blastocysts lacking a developmental regulatory gene can generate xenogeneic pancreas and kidney

Objectives: Our aim was to describe the burden of early dcSSc in terms of disability, fatigue and pain in the European Scleroderma Observational Study cohort, and to explore associated clinical features.Methods: Patients completed questionnaires at study entry, 12 and 24 months, including the HAQ disability index (HAQ-DI), the Cochin Hand Function Scale (CHFS), the Functional Assessment of Chronic Illness Therapy-fatigue and the Short Form 36 (SF36). Associates examined included the modified Rodnan skin score (mRSS), current digital ulcers and internal organ involvement. Correlations between 12-month changes were also examined.Results: The 326 patients recruited (median disease duration 11.9 months) displayed high levels of disability [mean (S.D.) HAQ-DI 1.1 (0.83)], with ‘grip’ and ‘activity’ being most affected. Of the 18 activities assessed in the CHFS, those involving fine finger movements were most affected. High HAQ-DI and CHFS scores were both associated with high mRSS (ρ = 0.34, P < 0.0001 and ρ = 0.35, P < 0.0001, respectively). HAQ-DI was higher in patients with digital ulcers (P = 0.004), pulmonary fibrosis (P = 0.005), cardiac (P = 0.005) and muscle involvement (P = 0.002). As anticipated, HAQ-DI, CHFS, the Functional Assessment of Chronic Illness Therapy and SF36 scores were all highly correlated, in particular the HAQ-DI with the CHFS (ρ = 0.84, P < 0.0001). Worsening HAQ-DI over 12 months was strongly associated with increasing mRSS (ρ = 0.40, P < 0.0001), decreasing hand function (ρ = 0.57, P < 0.0001) and increasing fatigue (ρ = −0.53, P < 0.0001).Conclusion: The European Scleroderma Observational Study highlights the burden of disability in early dcSSc, with high levels of disability and fatigue, associating with the degree of skin thickening (mRSS). Impaired hand function is a major contributor to overall disability.

Passive hydrogen maser (PHM) has the advantages of high frequency stability and low frequency drift. It has been widely used in the navigation system and frequency calibration. Atomic transition signal amplitude of PHM directly determines the system signal to noise ratio, and thus affect system performance, which makes it one of the most important parameters of PHM. Straight solenoid is widely used in PHM to produce the C field for atomic transition. Due to restriction of structural of the physical package, there is improvement potential for homogeneity of magnetic field. This paper discusses the feasibility of multi-section coil for the C field of PHM. Simulation and optimization of the parameters of the multi-section coil is carried out, including length, number of sections, turns, spacing and diameter. Design of multi-section coil with better homogeneity of the C field can be given by the simulation software. Inhomogeneity of about 2% of the C field is realized comparing to about 10% of the straight solenoid. According to the simulation results, several multi-section coils are manufactured. Application and test of these multi-section coils in physical package of hydrogen maser are carried out. Experimental results show that atomic transition signal gain can be increased by about 10%, which is beneficial to the performance of PHM.

cope Resistance of proteins to gastrointestinal digestion may play a role in determining immune-mediated adverse reactions to foods. However, digestion studies have largely been restricted to purified proteins and the impact of food processing and food matrices on protein digestibility is poorly understood. Methods and results Digestibility of a total gliadin fraction (TGF), flour (cv Hereward), and bread was assessed using in vitro batch digestion with simulated oral, gastric, and duodenal phases. Protein digestion was monitored by SDS-PAGE and immunoblotting using monoclonal antibodies specific for celiac-toxic sequences (QQSF, QPFP) and starch digestion by measuring undigested starch. Whereas the TGF was rapidly digested during the gastric phase the gluten proteins in bread were virtually undigested and digested rapidly during the duodenal phase only if amylase was included. Duodenal starch digestion was also slower in the absence of duodenal proteases. Conclusion The baking process reduces the digestibility of wheat gluten proteins, including those containing sequences active in celiac disease. Starch digestion affects the extent of protein digestion, probably because of gluten-starch complex formation during baking. Digestion studies using purified protein fractions alone are therefore not predictive of digestion in complex food matrices.

The aim of this study was to investigate the effect and mechanism of bone morphogenetic protein-6 (BMP-6) on the growth and maturation of mouse follicles in vitro. Preantral follicles isolated from mice were incubated with recombinant human BMP-6 (rhBMP-6) before analysis. BMP-6 expression was detected by immunofluorescence and western blot. Maturation of oocytes was observed microscopically. Estradiol (E2) and progesterone (P4) levels were measured by enzyme-linked immunosorbent assay. Expression of steroidogenesis-related genes was detected by reverse transcription quantitative polymerase chain reaction. There was a marked increase in the preantral follicles maturation in cells incubated with 50 ng/mL of rhBMP-6 for eight days, compared with the control. The levels of E2, P4 and steroidogenesis-related genes were also significantly increased in granulosa cells and theca cells cultured for 6, 10 and 11 days, respectively. Conversely, the preantral follicle maturing rate was remarkably decreased in cells incubated with 50 ng/mL of rhBMP-6 for day 11, accompanied with reduction in E2, P4 levels and steroidogenesis-related genes levels. Meanwhile, compared with the control, the maturing rate was not significantly different in cells incubated with 100 ng/mL of rhBMP-6 for day 8 or day 11. However, the E2 levels and its relevant regulation gene expression all increased significantly, while the P4 content and its relevant regulation gene expression decreased. The results indicate that BMP-6 can promote the maturation of preantral follicles in vitro in a concentration and time-dependent manner and may play a role in the regulation of steroid hormone synthesis and/or secretion.

A series of novel biphenyl–furocoumarin derivatives were synthesized and evaluated for their vasorelaxant activities in vitro against rat mesenteric artery, basilar artery, and renal artery ring models pre-contracted by high KCl. The results showed that compounds 12b, 13b, 13d, 14b, and 14d exhibited good broad spectrum vasorelaxant activities on three kinds of rat artery ring models compared to imperatorin. Noteworthy, most of the compounds had potent good selectivity against mesenteric artery in which compound 14c exhibited highest vasodilation activity (pEC50 = 6.44, E max = 105.8 %). These were suggested that the introduction of biphenyl in imperatorin was useful to improve vasodilation activities. The preliminary structure–activity relationships studies revealed that larger halogen substituent R 1 on phenyl ring and smaller nitrogenous base R 2 were favorable for vasorelaxant activities. In addition, the CoMFA model showed acceptable correlative and predictive abilities (r 2 = 0.875, q 2 = 0.502).

This study presents a tapered zero-thickness finite element model together with its parameter identification method for modelling the spindle–holder taper joint in machine tools. In the presented model, the spindle and the holder are modelled as solid elements and the taper joint is modelled as a tapered zero-thickness finite element with stiffness and damping but without mass or thickness. The proposed model considers not only the coupling of adjacent degrees of freedom but also the radial, tangential and axial effects of the spindle–holder taper joint. Based on the inverse relationship between the dynamic matrix and frequency response function matrix of a multi-degree-of-freedom system, this study proposes a combined analytical–experimental method to identify the stiffness matrix and damping coefficient of the proposed tapered zero-thickness finite element. The method extracts those parameters from FRFs of an entire specimen that contains only the spindle–holder taper joint. The simulated FRF obtained from the proposed model matches the experimental FRF quite well, which indicates that the presented method provides high accuracy and is easy to implement in modelling the spindle–holder taper joint.

Recently, we have identified a biphenyl-aryl urea incorporated with salicylaldoxime (BPS-7) as an anti-angiogenesis agent. Herein, we disclosed a series of novel anti-angiogenesis agents with BPS-7 as lead compound through combining diarylureas with N-pyridin-2-ylcyclopropane carboxamide. Several title compounds exhibited simultaneous inhibition effects against three pro-angiogenic RTKs (VEGFR-2, TIE-2 and EphB4). Some of them displayed potent anti-proliferative activity against human vascular endothelial cell (EA.hy926). In particular, two potent compounds (CDAU-1 and CDAU-2) could be considered as promising anti-angiogenesis agents with triplet inhibition profile. The biological evaluation and molecular docking results indicate that N-pyridin-2-ylcyclopropane carboxamide could serve as a hinge-binding group (HBG) for the discovery of multi-target anti-angiogenesis agents. CDAU-2 also exhibited promising anti-angiogenic potency in a tissue model for angiogenesis.

We have investigated the mechanism for embryo development block in vitro and to improve the development rate of golden hamster embryos in vitro. Intracytoplasmic sperm injection (ICSI) technique was used to produce golden hamster ICSI embryos. The changes in the histone acetylation and the expression of histone deacetylase and related genes were analyzed by immunocytochemical staining and real-time PCR both in golden hamster in vivo embryos and in ICSI embryos. Aged oocytes significantly increased the oocyte spontaneous activation rate. In vitro cultured ICSI embryos suffered from severe development block in M199TE medium. Expression of histone deacetylase 1 (HDAC1) was significantly decreased in the nuclei of the arrested ICSI 2-cell embryos, and its nuclear and cytoplasmic expression pattern was also markedly altered. The acetylation level of H4K5, however, was not significantly changed between golden hamster in vivo embryos and ICSI embryos. HSPA1A and MYC, the marker genes for zygotic genome activation (ZGA), were transcriptionally decreased in arrested ICSI 2-cell embryos. Transcription of HDAC1 was also downregulated in these embryos, whereas the mRNA expression of the proapoptotic gene, BAX, was not changed. These results indicate that the golden hamster ICSI embryo development block during ZGA is associated with decreased nuclear expression and altered expression of HDAC1. HSPA1A, MYC, and HDAC1 mRNA levels, which decrease, resulting in ZGA failure.

By taking advantage of microflow injection chemiluminescence analysis, we developed a distinctive microfluidic bioassay method based on G-Quadruplex DNAzyme-enhanced chemiluminescence for the determination of K(+) in human serum. AGRO100, the G-rich oligonucleotide with high hemin binding affinity was primarily selected as a K(+) recognition element. In the presence of K(+), AGRO100 folded into G-quadruplex and bound hemin to form DNAzyme, which catalyzed the oxidation of luminol by H2 O2 to produce chemiluminescence. The intensity of chemiluminescence increased with the K(+) concentration. In the study, the DNAzyme showed both long-term stability and high catalytic activity; other common cations at their physiological concentration did not cause notable interference. With only 6.7 × 10(-13) mol of AGRO100 consumption per sample, a linear response of K(+) ranged from 1 to 300 µmol/L, the concentration detection limit 0.69 µmol/L (S/N = 3) and the absolute detection limit 1.38 × 10(-12) mol were obtained. The precision of 10 replicate measurements of 60 µmol/L K(+) was found to be 1.72% (relative standard deviation). The accuracy of the method was demonstrated by analyzing real human serum samples.

A series of pyridin-3-yl pyrimidines was synthesized and evaluated for their Bcr-Abl inhibitory and anticancer activity. The preliminary results indicated that some compounds were promising anticancer agents. Compounds A2, A8, and A9 exhibited potent Bcr-Abl inhibitory activity, suggesting that aniline containing halogen substituents might be important for biological activity. Molecular docking was carried out to investigate the binding mode of them with Bcr-Abl. Details of synthesis and SAR studies of these compounds are described.

Two new 9-hydroxy-7H-furo[3,2-g]chromen-7-one derivatives were designed, synthesized and evaluated for their in vitro vasodilatory activity. The structures of two compounds were elucidated by infrared, ¹H NMR, and mass spectral data. The in vitro pharmacological evaluation indicated that both of them possessed well vasodilatory activity compared with imperatorin. The molecule docking also showed two target compounds docked well with L-calcium channel (PDB code: 3G43). The result suggested that they would be potential vasodilatory agents for hypertension.

Delivering high quality dietary protein at an affordable price is a major aim of the EU-funded CHANCE project. Foods have been formulated with this aim and as part of their nutritional assessment; the bioaccessbility of nutrients following simulated gastroduodenal digestion is being investigated. Nutrimetabolomics approaches can be used to comprehensively and quantitatively analyse nutrients and metabolites. They have been applied to monitor nutrient release from ham, formulated in the CHANCE project, during in vitro digestion. SDS-PAGE analysis shows that constituent ham proteins were broken down to lower molecular weight polypeptides (Mr ≤ 10 kDa) after 120 min simulated gastric digestion which was digested further by subsequent duodenal digestion. Digestion of porteins resulted in the appearance of coalesced lipid droplets associated with the loss of the muscle protein matrix of the ham. Important nutrients, such as choline, creatine, carnosine, sucrose, cholesterol, triacylglyceride and fatty acids (saturated and unsaturated) were identified using 1H NMR. Chance ham is a good source of dietary protein and the combined approach can provide representative data on the bioaccessibility of all detectable nutrients contained in CHANCE ham to human digestive system.

The human cytochrome P450 family 1 enzymes consist of three members, CYP1A1, CYP1A2 and CYP1B1, which are predominantly involved in the phase I metabolism of xenobiotics. Because they have been implicated in carcinogenesis, cancer progression, and drug resistance, the inhibition of these enzymes has been widely considered an effective oncological therapeutic strategy. Some natural and synthetic flavonoids and naphthoflavonoids have been extensively documented to exert pronounced influence in the modulation of CYP1s, including functioning as inhibitors, substrates, and aryl hydrocarbon receptor (AhR) ligands. However, the molecular determinants behind these effects are still unknown. This review summarizes the structural features responsible for the CYP1 inhibitory effects of the reported flavonoids and naphthoflavonoids. Additionally, a three-dimensional quantitative structure–activity relationship (3D-QSAR) study was performed to better understand the effect of their structural properties on biological activities. We hope this review provides a useful foundation for the rational design of potent and selective CYP1 isozyme inhibitors, thereby accelerating the drug discovery process.

Angiogenesis is modulated by a multitude of pro-angiogenic factors including VEGFR-2, Tie-2, and EphB4. Moreover, their crosstalk also had been well elaborated. We have identified several diarylurea-based VEGFR-2 inhibitors as potential anti-angiogenesis agents. As a continuation to our previous research, two series of diaryl malonamide and diaryl thiourea derivatives have been developed as multiplex VEGFR-2/Tie-2/EphB4 inhibitors. Interestingly, the biological evaluation indicated that several compounds bearing trifluoromethyl or trifluoromethoxyl exhibited promising multiplex inhibition against angiogenesis-related VEGFR-2, Tie-2, and EphB4. The representative compound (18a) displayed both potent multi-targeted RTK inhibition and considerable antiproliferative activities against human umbilical vein endothelial cells (EA.hy926). These results will contribute to the discovery of novel muti-targeted anti-angiogenesis agents.

Forkhead O transcription factors (FOXOs) have been implicated in glucose and lipid homeostasis; however, the role of FOXOs in the development of nonalcoholic fatty liver disease (NAFLD) is not well understood. In this study, we designed experiments to examine the effects of two different diets—very high fat diet (HFD) and moderately high fat plus cholesterol diet (HFC)—on wildtype (WT) and liver-specific Foxo1/3/4 triple knockout mice (LTKO). Both diets induced severe hepatic steatosis in the LTKO mice as compared to WT controls. However, the HFC diet led to more severe liver injury and fibrosis compared to the HFD diet. At the molecular levels, hepatic Foxo1/3/4 deficiency triggered a significant increase in the expression of inflammatory and fibrotic genes including Emr1, Ccl2, Col1a1, Tgfb, Pdgfrb, and Timp1. Thus, our data suggest that FOXO transcription factors play a salutary role in the protection against the diet-induced fatty liver disease.

During the data gathering process in sensor networks, lots of transmitted data packets can be lost due to the limiting node energy and the influence of data redundancy. In order to solve this problem, a prediction model is proposed for lost packets based on data reconstruction on lossy links in sensor networks. In this model, retransmission is adopted for data recovery when a random packet loss is predicted while prediction algorithms based on time sequences can be employed for data recovery when a random packet loss cannot be predicted. The operation of the whole system can still be guaranteed with this model when the packet loss probability of the network is lower than 15% while the relative error for data reconstruction remains between 0.17%~0.22% when the packet loss probability is higher than 22%. It is thus proven that this prediction model exhibits a strong stability and flexibility.

The optimisation algorithm based on irreversible data for the job scheduling of dynamic cluster is crucial to the improvement of the cluster rendering throughput and the cluster rendering efficiency. However, the dispatching imbalance of the cluster rendering task on the massive number of cluster rendering nodes will prolong the waiting time for the completion of job. Therefore, we propose dynamic cluster job scheduling optimisation algorithm based on data irreversibility (DCJS_DI). Firstly, we analyse the job scheduling target. Then, we exploit the frame independence with the clustering rendering and further establish the job scheduling model for the irreversible data dynamic cluster. Next, we elaborate on the job scheduling process of the irreversible data dynamic cluster and the dispatching process of the cluster rendering task. Finally, we investigate via simulation results the impacts of the job hunger and the resource fragmentation issue of the traditional job scheduling strategies on the system performance, the impacts of the multi-progress and multi-threading cluster rendering on the job completion time and the resource efficiency of the irreversible data dynamic cluster. We further study the extension of the cluster computation capability and the reliability issue of the cloud service.

L-type calcium channel (LTCC) blockers are used as cardiac antiarrhythmics or antihypertensives. In our previous research, we have reported a furanocoumarin, imperatorin, which exhibited potent vasodilatory effects. The possible mechanism might involve with inhibition against LTCC. In order to further investigate the pharmacologic mechanism of imperatorin for interaction with LTCC, the homology modeling of LTCC was performed using MODELLER 9.9 program with potassium channels as templates. The binding mode of imperatorin to LTCC was further investigated by molecular docking. Molecular docking results indicated that imperatorin occupied the same binding site as verapamil and hydrogen bond interaction played important role in blocker-channel binding. Docking studies provided useful information to understand the action mechanism of imperatorin. The results described here will be helpful in the development of novel potential LTCC blockers.

A novel class of Nilotinib derivatives, B1-B20, were synthesized in high yields using various substituted anilines. All the title compounds were evaluated for their inhibitory activities against Bcr-Abl and antiproliferative effects on human leukemia cell (K562). The pharmacological results indicated that some compounds exhibited promising anticancer activity. In particular, compound B14 containing tertiary amine side chain exhibited Bcr-Abl inhibitory activity similar to that of Nilotinib. It was suggested that the introduction of the tertiary amine moiety could improve Bcr-Abl inhibitory activity and antitumor effects.

Active biogenesis of cytoplasmic lipid droplets (LDs) is reported in different types of cancer cells. LDs are linked to cancer cell proliferation, apoptosis and differentiation. The chemical nature of lipids in LDs is poorly understood and revealing their chemical composition may provide novel information of lipid metabolism in cancers. Gradient ultracentrifugation was performed to isolate LDs from five nervous system tumour cell lines. Nile red staining was used to estimate the size of LDs and validate the isolation procedure. 1H NMR spectroscopy was performed from the chloroform/methanol extracts of whole cells and the isolated LDs. NMR lipid signal intensity from different lipid species was measured to compare the lipid compositions. The average diameter of LDs in cancer cells was 0.21±0.02 μm, with a widely varying size range up to 1.48 μm. 1H NMR spectroscopic analysis revealed that the LDs contain phosphatidylcholine, cholesterol and cholesterol ester with saturated, mono-unsaturated and polyunsaturated fatty acid species. The content of the isolated LDs differed between the tumor cell lines with variability seen in unsaturated fatty acids, cholesterol and lipids containing choline head groups however the mean fatty acid chain length remained similar across the cell lines. The lipid composition of LDs was also found to be different from whole cell extracts. In conclusion, we have shown that the composition of LDs differs between tumour cell lines, suggesting a functional link between these structures and cancer specific pathways.

Prostate cancer (PCa) is a metastatic malignant cancer driven by complex pathological mechanisms and characterized by poor long-term prognosis. Metastasis is the main cause of death of PCa patients, yet the molecular mechanisms of this process are poorly understood. In the present study, positive co-expression of RON and c-Met was observed in human clinical PCa tissues (biopsy material), as detected by immunohistochemical staining and quantitative real-time PCR. We investigated this further in PCa cells, demonstrating that the inhibition of RON and c-Met with foretinib (GSK1363089) suppressed metastasis and promoted the reversal of the epithelial-to-mesenchymal transition (EMT) in PCa cells. Furthermore, the invasion and migration of PCa cells were enhanced by the exogenous activation of RON with MSP and c-Met with HGF, whereas silencing of RON and c-Met attenuated the invasion and metastasis of the PCa cells. Our data also demonstrated that HGF/c-Met, but not the MSP-RON signaling pathway may be the dominant mechanism for PCa EMT. We further revealed that RON and c-Met facilitate metastasis via ERK1/2 signaling. These findings indicate that RON and c-Met facilitate metastasis through ERK1/2 signaling and that targeting RON and c-Met with foretinib may be an attractive therapeutic option for suppressing PCa metastasis.

Aims: Metabolite levels can be measured non-invasively using in vivo 1H magnetic resonance spectroscopy (MRS). These tumour metabolite profiles are highly characteristic for tumour type in childhood brain tumours; however, the relationship between metabolite values and conventional histopathological characteristics has not yet been fully established. This study systematically tests the relationship between metabolite levels detected by MRS and specific histological features in a range of paediatric brain tumours. Methods: Single-voxel MRS was performed routinely in children with brain tumours along with the clinical imaging prior to treatment. Metabolites were quantified using LCModel. Histological features were assessed semi-quantitatively for 27 children on H&E and immunostained slides, blind to the metabolite values. Statistical analysis included 2-tailed independent-samples t tests and 2-tailed Spearman rank correlation tests. Results: Ki67, cellular atypia, and mitosis correlated positively with choline metabolites, and phosphocholine in particular. Apoptosis and necrosis were both associated with lipid levels, with the relationship dependent on the use of long or short echo time MRS acquisitions. Neuronal components correlated negatively and glial components positively with N-acetyl-aspartate. Glial components correlated positively with myoinositol. Conclusion: Metabolite levels in children's brain tumours measured by MRS are closely associated with key histological features routinely assessed by histopathologists in the diagnostic process. This further elucidates our understanding of this important non-invasive diagnostic tool and strengthens our understanding of the relationship between metabolites and histological features.

The persistence of HIV in resting memory CD4+ T cells at a latent state is considered as the major barrier on the path to achieve a cure for HIV. Proteasome inhibitors (PIs) were previously reported as latency reversing agents (LRAs) but the mechanism underlying this function is yet unclear. Here we demonstrate that PIs reactivate latent HIV ex vivo without global T cell activation, and may facilitate host innate immune responses. Mechanistically, latent HIV reactivation induced by PIs is mediated by heat shock factor 1 (HSF1) via the recruitment of the heat shock protein (HSP) 90-positive transcriptional elongation factor b (p-TEFb) complex. Specifically, HSP90 downstream HSF1 gives positive feedback to the reactivation process through binding to cyclin-dependent kinase 9 (CDK9) and preventing it from undergoing degradation by the proteasome. Overall, these findings suggest proteasome inhibitors as potential latency reversing agents. In addition, HSF1/HSP90 involved in HIV transcription elongation, may serve as therapeutic targets in HIV eradication.

Delivering high quality dietary protein at an affordable price is a major aim of the EU-funded CHANCE project. Foods have been formulated with this aim and as part of their nutritional assessment; the bioaccessbility of nutrients following simulated gastroduodenal digestion is being investigated. Nutrimetabolomics approaches can be used to comprehensively and quantitatively analyse nutrients and metabolites. They have been applied to monitor nutrient release from ham, formulated in the CHANCE project, during in vitro digestion. SDS-PAGE analysis shows that constituent ham proteins were broken down to lower molecular weight polypeptides (Mr ≤ 10 kDa) after 120 min simulated gastric digestion which was digested further by subsequent duodenal digestion. Digestion of porteins resulted in the appearance of coalesced lipid droplets associated with the loss of the muscle protein matrix of the ham. Important nutrients, such as choline, creatine, carnosine, sucrose, cholesterol, triacylglyceride and fatty acids (saturated and unsaturated) were identified using 1H NMR. Chance ham is a good source of dietary protein and the combined approach can provide representative data on the bioaccessibility of all detectable nutrients contained in CHANCE ham to human digestive system.

HSF1, a conserved heat shock factor, has emerged as a key regulator of mammalian transcription in response to cellular metabolic status and stress. To our knowledge, it is not known whether HSF1 regulates viral transcription, particularly HIV-1 and its latent form. Here we reveal that HSF1 extensively participates in HIV transcription and is critical for HIV latent reactivation. Mode of action studies demonstrated that HSF1 binds to the HIV 5′-LTR to reactivate viral transcription and recruits a family of closely related multi-subunit complexes, including p300 and p-TEFb. And HSF1 recruits p300 for self-acetylation is also a committed step. The knockout of HSF1 impaired HIV transcription, whereas the conditional over-expression of HSF1 improved that. These findings demonstrate that HSF1 positively regulates the transcription of latent HIV, suggesting that it might be an important target for different therapeutic strategies aimed at a cure for HIV/AIDS.

To verify whether FN1 and ZNF438 are the androgen receptor(AR) target genes in LNCaP-AI cells and investigate the effects of AR exerts on FN1 and ZNF438 gene expression.ChIP-PCR and agarose gel electrophoresis were performed to verify the fact that AR acted on FN1 and ZNF438 gene. Subsequently, LNCaP-AI cells were treated with dihydrotestosterone(DHT)and lentivirus transfection to down-regulate AR expression. The expression of FN1 and ZNF438 gene in mRNA and protein levels were analyzed by RT-qPCR and Western blot.FN1 and ZNF438 gene enrichment of AR-ChIP group were 7.274±0.290 and 6.843±0.078, significantly higher than the IgG-ChIP group of 1.004±0.113 and 1.000±0.014 (t(FN1)=34.91, t(ZNF438)=128.377, P0.05). Differences were statistical significance. After DHT stimulation, the expression of FN1 and ZNF438 gene in mRNA and protein levels were 0.434±0.050 and 0.069±0.042, significantly lower than the control group of 1.000±0.016 and 1.025±0.277 (t(FN1)=18.532, t(ZNF438)=5.905, P0.05). Differences were statistical significance. Moreover, after AR down-regulation, the expression of FN1 and ZNF438 gene in mRNA and protein levels were 17.579±4.415 and 1.895±0.424, significantly higher than the control group of 1.028±0.445 and 1.041±0.190 (t(FN1)=6.461, t(ZNF438)=3.184, P0.05). Differences were statistical significance.FN1 and ZNF438 gene are AR negatively regulated target genes in LNCaP-AI cells. The study might provide a new sight to further explore the mechanism of LNCaP-AI cells grow in androgen-depleted conditions.

SESN3 has been implicated in multiple biological processes including protection against oxidative stress, regulation of glucose and lipid metabolism. However, little is known about the factors and mechanisms controlling its gene expression at the transcriptional level. We performed in silico phylogenetic footprinting analysis of 5 kb upstream regions of a diverse set of human SESN3 orthologs for the identification of high confidence conserved binding motifs (BMo). We further analyzed the predicted BMo by a motif comparison tool to identify the TFs likely to bind these discovered motifs. Predicted TFs were then integrated with experimentally known protein-protein interactions and experimentally validated to delineate the important transcriptional regulators of SESN3. Our study revealed high confidence set of BMos (integrated with DNase I hypersensitivity sites) in the upstream regulatory regions of SESN3 that could be bound by transcription factors from multiple families including FOXOs, SMADs, SOXs, TCFs and HNF4A. TF-TF network analysis established hubs of interaction that include SMAD3, TCF3, SMAD2, HDAC2, SOX2, TAL1 and TCF12 as well as the likely protein complexes formed between them. We show using ChIP-PCR as well as over-expression and knock out studies that FOXO3 and SOX2 transcriptionally regulate the expression of SESN3 gene. Our findings provide an important roadmap to further our understanding on the regulation of SESN3.

Cytoplasmic lipid droplets (LDs) are dynamic cellular organelles; their accumulation is associated with several cellular processes, such as cell proliferation, apoptosis and necrosis. 1H Nuclear Magnetic Resonance (NMR) spectroscopy detects resonances from lipids present in cytoplasmic (LDs); an understanding of the relationship between LD characteristics and NMR lipid signals is important. In this study, five nervous system cancer cell lines were investigated. Nile red staining was used to measure the diameter of LDs. High-resolution magic angle spinning NMR (HR-MAS) was performed on harvested cell pellets to quantify the patterns of lipid signals. LDs were present in all five cell lines with different morphology. An average LD diameter of approximately 0.2 μm was found in all cell types. Diameter of the largest LDs varied across the cell lines. The intensity of NMR lipid signals varied greatly between cell types, and a good correlation was found between total volume of LDs and the proton NMR lipid signal intensity at 0.9 and 1.3 ppm. The correlation implied that little NMR signal is detected from LDs of diameters less than approximately 0.34 μm, most likely due to restriction of rotational motion of the lipids.

As a continuation to our previous work in developing anticancer agents, eighteen symmetrical biphenyl derivatives structurally related to taspine were synthesized and evaluated in vitro and in vivo. All the compounds were prepared with varied substitutions in the phenyl ring of aniline moiety. The cytotoxicity and anticancer activity of biphenyls was evaluated against various human tumor and normal cell line. Antiproliferative assays indicated that some of them exhibited potent anticancer activity. The potent antiproliferative activity of these compounds against ECV304 suggested that these biphenyls could be served as antiangiogenic agents. The highly active compound (2) also exhibited potent growth inhibition against cancer cell lines in vivo. Our findings demonstrated that these symmetrical biphenyl derivatives would be a promising candidate as novel anticancer agents.

Neuraminidase (NA) is a major glycoprotein of influenza virus which is essential for viral infection. It offers a potential target for antiviral drug development. To develop potent NA inhibitors, pharmacophore models were generated by genetic algorithm with linear assignment for hypermolecular alignment of data sets. 3D-QSAR studies were carried out on 49 molecules. Both comparative molecular field analysis (q2 = 0.720 and r2 = 0.947) and comparative molecular similarity indices analysis (q2 = 0.644 and r2 = 0.885) yielded reasonable results. A preliminary pharmacokinetic profile of these neuraminidase inhibitors was predicted using Volsurf module.

To investigate the effect of Euphorbia fischeriana extract on latent HIV reactivation and the pathway involved in this process and discuss the value of Euphorbia fischeriana extract in eliminating HIV.Fresh tissues of Euphorbia fischeriana root were crushed into powder after quick freezing with liquid nitrogen and extracted with acetone followed by a three-day vacuum freeze-drying for dehydration of the extract. The extract (EFE) was separated using RP-C18 column with high-performance liquid chromatography (HPLC) and identified with mass spectrometry (MS). The activity of reactivated latent HIV was analyzed by fluorescence-activated cell sorting in a J-Lat 10.6 cell model treated with EFE (50 µg/mL) for 24 h, using TNF-α (10 ng/mL) as the positive control. The effect of a NF-κB pathway inhibitor (Bay 11-7082) on EFE activity was tested. The changes in P65 expression in the cell nuclei within 2 h and HIV protein p24 expression within 24 h were analyzed by Western blotting in cells treated with EFE.EFE was obtained by one-step acetone extraction, and the concentration of prostratin in the extract was around 0.53 mmol/L. About 50% of the cells showed HIV reactivation after treatment with 50 µg/mL EFE for 24 h accompanied by a significantly increased p24 expression. The activity of EFE in reactivating latent HIV was inhibited by Bay 11-7082 in a concentration-dependent manner, and p65 accumulation was detected in the cell nuclei within 2 h.EFE we obtained contains the active compounds of prostratin and its analogues and shows a strong capacity to reactivate latent HIV through classical NF-κB pathway.

Angiogenesis is required for invasive tumor growth and metastasis and constitutes an important point in the control of cancer progression. Its inhibition may be a valuable approach to cancer therapy. Antiangiogenic agents are designed to attack the tumor vasculature and cut off the tumor's supply of nutrients. Systemic blockade of angiogenesis has been recently approved for the treatment of several types of human cancers. Antiangiogenic therapy presents various advantages as compared to conventional treatment. Vascular endothelial growth factor (VEGF) is considered to be one of the most important regulators of angiogenesis and a key target in anticancer treatment. VEGF binding to its receptor (VEGFR) leads to cell proliferation and new vascular formation by tyrosine kinase (TK) pathway. VEGF/VEGFR pathway is becoming attractive target for anticancer drug design. It is believed to be important in the control of angiogenesis. Antiangiogenic therapy based on inhibition of VEGFR was reported to be powerful clinical strategies. In this review, the authors describe the existing literature regarding VEGFR inhibitors in the last few years. We attempt to cover all essential publications on the medicinal chemistry in terms of chemical structure, pharmacological profile and structure-activity relationships.

Chlorine-free is not only one of the new concepts of green chemistry, but also a problematical task for chemical processes in industrial utility. During the past several decades, we devoted ourselves to the study of chlorine-free organic synthesis. Herein, we describe an efficient chlorine-free copper-catalyzed oxidative approach providing 1,3,4-oxadiazoles in good yields from readily available starting materials. This transformation requires only a green and inexpensive reagent to afford the structurally useful motifs, and has a broad functional groups tolerance.