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Background: Pancreatic cancer is a commonly occurring malignant tumor, with pancreatic ductal carcinoma (PDAC) accounting for approximately 95% of cases. According of its poor prognosis, identifying prognostic factors of pancreatic ductal carcinoma can provide physicians with a reliable theoretical foundation when predicting patient survival. Objective: This study aimed to analyze the impact of marital status on survival outcomes of PDAC patients using propensity score matching and machine learning. The goal was to develop a prognosis prediction model specific to married patients with PDAC. Methods: We extracted a total of 206,968 PDAC patient records from the SEER database. To ensure the baseline characteristics of married and unmarried individuals were balanced, we used a 1:1 propensity matching score. We then conducted Kaplan-Meier analysis and Cox proportional-hazards regression to examine the impact of marital status on PDAC survival before and after matching. Additionally, we developed machine learning models to predict 5-year CSS and OS for married patients with PDAC specifically. Results: In total, 24,044 PDAC patients were included in this study. After 1:1 propensity matching, 8,043 married patients and 8,043 unmarried patients were successfully enrolled. Multivariate analysis and the Kaplan-Meier curves demonstrated that unmarried individuals had a poorer survival rate than their married counterparts. Among the algorithms tested, the random forest performed the best, with 0.734 5-year CSS and 0.795 5-year OS AUC. Conclusions: This study found a significant association between marital status and survival in PDAC patients. Married patients had the best prognosis, while widowed patients had the worst. The random forest is a reliable model for predicting survival in married patients with PDAC.

In mass analysis of proteins, mass spectrometry directly measures the mass to charge ratios of ionized proteins and promises higher accuracy than that of indirect approaches measuring other physicochemical properties, provided that the charge states of detected ions are determined. Accurate mass determination of heterogeneously glycosylated proteins is often hindered by unreliable charge determination due to the insufficient resolution of signals from different charge states and inconsistency among mass profiles of ions in individual charge states. Limited charge reduction of a subpopulation of proteoforms using electron transfer/capture reactions (ETnoD/ETnoD) solves this problem by narrowing the mass distribution of examined proteoforms and preserving the mass profile of the precursor charge state in the reduced charge states. However, the limited availability of ETnoD/ETnoD function in commercial instruments limits the application of this approach. Here, utilizing a range of charge-dependent and accuracy-affecting spectral features revealed by a systematic evaluation at levels of both the ensemble and subpopulation of proteoforms based on theoretical models and experiments, we developed a limited charge reduction workflow that enables using collision-induced dissociation and higher energy collisional dissociation, two widely available reactions, as alternatives to ETnoD/ETnoD while providing adequate accuracy. Alternatively, substituting proton transfer charge reduction for ETnoD/ETnoD provides higher accuracy of mass determination. Performing mass selection in a window-sliding manner improves the accuracy and allows profiling of the whole proteoform distribution. The proposed workflow may facilitate the development of universal characterization strategies for more complex and heterogeneous protein systems.

Benzyl alcohol was chosen as a model substrate for Pd/hydrotalcite mediated selective oxidation of alcohols to investigate the roles of palladium precursors (Na2PdCl4, K2PdCl4, PdCl2), reduction reagents (N2H4 and NaBH4), and Pd loading amount in determining structure-activity relationship of flower-like nano-catalyst. XRD analyses show typical characteristic peaks of all hydrotalcites regardless of palladium precursors; whereas TEM studies show a larger mean size of Pd nanoparticles obtained with reducing reagent N2H4 over NaBH4. However, the difference in particle sizes didn't result in a significant difference in benzyl alcohol conversion, but extended to catalytic selectivity where N2H4-reduced Pd/hydrotalcite achieved 94%-96% selectivity over 88%-93% by NaBH4. FTIR-CD3CN surface acidity study suggested that a stronger acidity of N2H4 reduced Pd/hydrotalcite may account for its better selectivity. 3% Pd/hydrotalcite with N2H4 as reducing reagent demonstrated the best catalytic performance; and was successfully extended to oxidation of 17 aromatic and aliphatic alcohols. The conversion of alcohols is strongly dependent on individual alcohol molecular structure and electronic effect; but all reactions showed medium-to-excellent selectivity.

Characterization of protein higher-order structures and dynamics is essential for understanding the biological functions of proteins and revealing the underlying mechanisms. Top-down mass spectrometry (MS) accesses structural information at both the intact protein level and the peptide fragment level. Native top-down MS allows analysis of a protein complex's architecture and subunits' identity and modifications. Top-down hydrogen/deuterium exchange (HDX) MS offers high spatial resolution for conformational or binding interface analysis and enables conformer-specific characterization. A microfluidic chip can provide superior performance for front-end reactions useful for these MS workflows, such as flexibility in manipulating multiple reactant flows, integrating various functional modules, and automation. However, most microchip-MS devices are designed for bottom-up approaches or top-down proteomics. Here, we demonstrate a strategy for designing a microchip for top-down MS analysis of protein higher-order structures and dynamics. It is suitable for time-resolved native MS and HDX MS, with designs aiming for efficient ionization of intact protein complexes, flexible manipulation of multiple reactant flows, and precise control of reaction times over a broad range of flow rates on the submicroliter per minute scale. The performance of the prototype device is demonstrated by measurements of systems including monoclonal antibodies, antibody-antigen complexes, and coexisting protein conformers. This strategy may benefit elaborate structural analysis of biomacromolecules and inspire method development using the microchip-MS approach.

The quaternary structure is an important feature regulating protein function. Native mass spectrometry contributes to untangling quaternary structures by preserving the integrity of protein complexes in the gas phase. Tandem mass spectrometry by collision-induced dissociation (CID) can then be used to release subunits from these intact complexes, thereby providing structural information on the stoichiometry and topology. Cumulatively, such studies have revealed the preferred release of peripheral subunits during CID. In contrast, here we describe and focus on dissociation pathways that release nonperipheral subunits from hetero-complexes in CID at high collision energies. We find that nonperipheral subunits are ejected with a high propensity, as a consequence of sequential dissociation events, upon initial removal of peripheral subunits. Alternatively, nonperipheral subunits can be released directly from a charge-reduced or an elongated intact complex. As demonstrated here for a range of protein assemblies, releasing nonperipheral subunits under controlled conditions may provide unique structural information on the stoichiometry and topology of protein complexes.

Background Blood-brain barrier (BBB) disruption plays a key role in the pathophysiology of acute ischemic stroke. Matrix metalloproteinases-2/9 (MMP-2/9) have been shown to participate in the disruption of the BBB and hemorrhagic transformation after cerebral ischemia. Toll-like receptor 2 (TLR2) may also be correlated with endothelial cell injury during ischemia-reperfusion events. However, the correlation between MMP-2/9 and TLR2 on endothelial cells after ischemia has not yet been evaluated. The aim of the study was to evaluate the impact of TLR2 and MMP-2/9 on tight junction proteins (TJs) after oxygen–glucose deprivation and reoxygenation (OGDR). Materials and methods Rat primary brain microvascular endothelial cells (BMECs) were cultured. Quantitative real-time PCR and western blotting were used to measure the mRNA and proteins expression of TLR2 and MMP-2/-9. The protein expression of TJs was detected by western blotting and immunofluorescence. Results MMP-9 significantly increased after OGDR. Protein and mRNA expression of TLR2 was also upregulated. However, claudin-5, occludin, collagen-Ⅳ, and ZO-1 were decreased after OGDR. When monoclonal anti-TLR2 antibody (T2.5) was added to BMECs after OGDR, MMP-9 was significantly downregulated, whereas occludin and collagen-Ⅳ had a tendency to increase. Conclusion TLR2 antagonist T2.5 is able to downregulate the expression of MMP-9, and may constitute a therapeutic option for restoration of the BBB after OGDR.

Extradiol dioxygenases (EDOs) catalyze the meta cleavage of catechol into 2-hydroxymuconaldehyde, a critical step in the degradation of aromatic compounds in the environment. In the present work, a novel thermophilic extradiol dioxygenase from Thermomonospora curvata DSM43183 was cloned, expressed, and characterized by phylogenetic and biochemical analyses. This enzyme exhibited excellent thermo-tolerance, displaying optimal activity at 50 °C, remaining >40% activity at 70 °C. Structural modeling and molecular docking demonstrated that both active center and pocket-construction loops locate at the C-terminal domain. Site-specific mutants D285A, H205V, F301V based on a rational design were obtained to widen the entrance of substrates; resulting in significantly improved catalytic performance for all the 3 mutants. Compared to the wild-type, the mutant D285A showed remarkably improved activities with respect to the 3,4-dihydroxyphenylacetic acid, catechol, and 3-chlorocatechol, by 17.7, 6.9, and 3.7-fold, respectively. The results thus verified the effectiveness of modeling guided design; and confirmed that the C-terminal loop structure indeed plays a decisive role in determining catalytic ring-opening efficiency and substrate specificity of the enzyme. This study provided a novel thermostable dioxygenase with a broad substrate promiscuity for detoxifying environmental pollutants and provided a new thinking for further enzyme engineering of EDOs.

Background Bortezomib (BZM), alone or in combination with other chemotherapies, has displayed strong anticancer effects in several cancers. The efficacy of the combination of BZM and mitoxantrone (MTX) in treating prostate cancer remains unknown. Methods Anticancer effects of combination of BZM and MTX were determined by apoptosis and proliferation assay in vivo and in vitro. Expression of β-Catenin and its target genes were characterized by western blot and Real-time PCR. Results BZM significantly enhanced MTX-induced antiproliferation in vivo and in vitro. Mice administered a combination of BZM and MTX displayed attenuated tumor growth and prolonged survival. BZM significantly attenuated MTX-induced apoptosis. Moreover, the combination of BZM and MTX contributed to inhibition of the Wnt/β-Catenin signaling pathway compared to monotherapy. Conclusions This study demonstrates that BZM enhances MTX-induced anti-tumor effects by inhibiting the Wnt/β-Catenin signaling pathway in prostate cancer cells.

A highly efficient supported metal catalyst, Pd/Ni-Al hydrotalcite with flower-like structure was synthesized and applied for catalytic oxidation of benzyl alcohols; affording >99 % conversion and 94–100 % selectivity in a base-free solution. The surface basicity and cation-oxygen mode in the layer of hydrotalcite were found to be pronouncedly associated with the changes of morphologies of the Ni-Al hydrotalcites. Compared to negligible activity by Ni-Al hydrotalcite itself, low efficiency by Pd nanoparticles or its simple mixture with Ni-Al hydrotalcite, a significant enhancement in the catalytic activity by the Pd deposited on flower-like Ni-Al hydrotalcites suggested a synergistic effect occurred between Pd and well-structured Ni-Al hydrotalcite. A plausible mechanism for the catalytic reaction involving the formation of metal-alkoxide and metal-hydroperoxide intermediates was postulated based on the control reactions, FTIR and XPS analysis and Hammett experiment.

Blood–brain barrier (BBB) destruction is associated with a variety of neurological diseases. Brain microvascular endothelial cells (BMECs) are the key constituent of BBB. Both matrix metalloproteinases-2/9 (MMP-2/9) and toll-like receptor-2 (TLR2) are coexpressed in BMECs and have been shown to play important roles in BBB breakdown. It is unknown whether TLR2 can regulate MMP-2/9 in BMECs. In this study, Pam3CSK4 was used to activate TLR2, and the expression of MMP-2/9 and tight junctions (TJs) in BBB was measured by quantitative real-time PCR and western blotting. Phosphoproteins were determined by western blotting. The inhibitors of mitogen-activated protein kinases (MAPKs) and NF-κB were used to identify the signaling pathways by which TLR2 regulates the expression of MMP-2/9 in BMECs. This study showed that Pam3CSK4 upregulated the mRNA and protein expression of MMP-9 and downregulated MMP-2 and TJ expression in BMECs simultaneously. Pam3CSK4 also induced the phosphorylation of MAPKs and NF-κB signaling pathways in BMECs. MMP-9 expression was found to decrease by pretreatment with inhibitors of ERK1/2 and JNK but not p38. However, the mRNA and protein expression of MMP-2 and MMP-9 increased after addition of a NF-κB inhibitor. Our results indicated that Pam3CSK4 was able to upregulate MMP-9 expression through ERK1/2 and JNK signaling pathways, but the NF-κB signaling pathway negatively regulated the effect of TLR2 on MMP-2 and MMP-9 expression in BMECs. The finding provides novel insight into the molecular mechanism of MMP-2/9 expression in BMECs.

Hydrotalcites with different cations were synthesized by co-precipitation method and characterized using different techniques. The catalytic activity of the hydrotalcites was studied using hydroxylation of phenol by H 2O 2 as a model reaction. The CuNiAl ternary hydrotalcite was found to be the best catalyst in this work; and the effects of reaction temperature, ratio of substrate:catalyst, H 2O 2 concentration, solvent and pH value of the medium were investigated. The results showed that under optimal reaction conditions, the conversion of phenol can reach up to 62.8%, with catechol and hydroquinone as the main products. The substrate scope was expanded to other phenol-derivatives, such as m-cresol and 3-ethylphenol. A plausible reaction mechanism was proposed based on the control reactions and XPS analysis. The CuNiAl hydrotalcite shows high toxicity (the 48 h LC 50 value of CuNiAl hydrotalcite was 2.12 mg/L) in the acute toxicity tests of Daphnia magna. However, after simple filtration of the solid catalyst, the 48 h LC 50 value of the remaining solution was increased to 83.46 mg/L. In all, the as-synthesized CuNiAl35 hydrotalcite offers a novel biodegradation pathway for in situ treatment of phenol-contaminated water or other phenolic pollutions when applied together with dioxygenases for further degradation of resulting catechols or hydroquinones.

A simple and eco-friendly approach was used to prepare α-Fe2O3@graphene oxide (α-Fe2O3@GO) nanocomposites with different iron oxide content in lower temperature. The nanocomposites were characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy, field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM) and nitrogen adsorption–desorption techniques. The results show that α-Fe2O3 nanoparticles with particle sizes of 60–100 nm are uniformly anchored on the surface of GO nanosheets at lower hydrothermal reaction. The specific surface area of α-Fe2O3@GO (114.57 m2/g) was about threefold larger than that of pure iron oxide (33.37 m2/g). Moreover, α-Fe2O3@GO nanocomposites with optimal mass ratio (8:1) between iron oxide and GO, which exhibited enhanced response to 100 ppm ethanol (14.82) in comparison with pure α-Fe2O3 (3.48) at 260 °C. The improved sensitive performance is in contact with larger surface area and incremental active sites in interface owing to introducing GO. The results reveal that GO is crucial to improve gas sensing performance.

ZnSnO3 hollow microspheres were synthesized by a simple one-pot template-free and general in-situ precipitation method combined with subsequent dehydration treatment. The prepared ZnSnO3 hollow microspheres were characterized using scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and the thermogravimetric-differential scanning calorimetry analysis (TG-DSC). The results showed that ZnSnO3 hollow microspheres with diameter ranging from 1.3 to 1.6 μm were constructed by small nanoparticles with diameter of about 70 nm. The investigation on the evolution formation revealed that the orientation and morphology of the products were carefully controlled by adjusting the amount of the addition of NaOH and the growth time, and a possible formation mechanism of the hollow structure was proposed. Moreover, the as-fabricated sensors based on the ZnSnO3 hollow microspheres showed superior gas-sensing properties for the detection of ethanol than ZnSnO3 solid spheres and can detect ethanol in the real life.

Fe3O4-TiO2 heterostructures were synthesized through co-precipitation method based on TiO2 nanobelts. X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), vibration sample magnetometry (VSM) were used to characterize the heterostructure nanocomposites. The results of XRD proved that the TiO2 nanobelt was anatase which was the most suitable crystal form for photocatalysis. SEM and TEM analysis indicated that Fe3O4 nanoparticles were adhere to TiO2 nanobelts which have one-dimensional structure with 100–200 nm in width. The VSM measurements showed that the photocatalyst can be easily recovered by an extemal magnetic field. X-ray photoelectron spectroscopy (XPS) of Ag@Fe3O4-TiO2 nanocomposites studies confirm that Ag is in Ag0 state. Finally, the photodegradation of rhodamine B (RhB) by the obtained magnetic photocatalyst was investigated via UV–vis absorption spectra. The photocatalytic activity of the composites was observed to be lower compared to bare TiO2 due to the higher degree of recombination reactions after combined with Fe3O4 nanoparticles. After coated the composite of 15% Fe3O4-TiO2 with Ag, the new nanocomposite of Ag@Fe3O4-TiO2 can be easily recovered after photocatalysis by an extemal magnetic field and showed enhanced photocatalytic activity. The mechanisms for the exhibited enhanced photocatalytic effect of Ag nanoparticle decorated Fe3O4-TiO2 nanocomposites with surface heterostructures are discussed.

Enzymatic conversion of abundant fatty acids (FAs) through fatty acid hydratases (FAHs) presents an environment-friendly and efficient route for production of high-value hydroxy fatty acids (HFAs). However, a limited diversity was achieved among HFAs to date with respect to chain length and hydroxy group position, due to high substrate- and regio-selectivity of hydratases. In this study, we compared two highly similar FAHs from Lactobacillus acidophilus: FA-HY2 has narrow substrate scope and strict regioselectivity, whereas FA-HY1 utilize longer chain substrates and hydrate various double bond positions. We reveal three active-site residues that play remarkable role in directing substrate specificity and regioselectivity of hydration. When these residues on FA-HY2 are mutated to the corresponding residues in FA-HY1, we observe a significant expansion of substrate scope and distinct shift and enhancement in hydration of double bonds towards omega-end of FAs. A three-residue mutant of FA-HY2 (TM-FA-HY2; T391S/H393S/I378P) displayed an impressive reversal of regioselectivity towards linoleic acid, shifting ratio of the HFA product regioisomers (10-OH:13-OH) from 99:1 to 12:88. Although kcat values are still low in comparison to wild-type FA-HY1, TM-FA-HY2 exhibited about 60-fold increase in catalytic efficiency (kcat/Km) compared to wild-type FA-HY2. Important changes in regioselectivity were also observed with mutant enzymes for arachidonic acid and C18 PUFAs. In addition, TM-FA-HY2 variant exhibited high conversion rates for cis-5, cis-8, cis-11, cis-14, cis-17-eicosapentaenoic acid (EPA) and cis-8, cis-11, cis-14-eicosatrienoic acid (ETA) at preparative scale and enabled isolation of 12-hydroxy products with moderate yields. Furthermore, we demonstrated the potential of microalgae as a source of diverse FAs for HFA production. Our study paves the way for tailor-made FAH design and for efficient conversion of FA sources into diverse range of HFAs with high potential for various applications from polymer industry to medical field.

The nanocomposites of g-C3N4 supported by Fe3O4 nanoparticles (Fe3O4/g-C3N4) have been fabricated through a simple hydrothermal route in a water–ethanol system. The nanocomposites were characterized by X-ray diffraction, and transmission electron microscopy, Fourier transform infrared, and thermogravimetric analysis, respectively. The results showed that g-C3N4 nanosheets were decorated randomly by Fe3O4 nanoparticles with average diameters of 7 nm. The photocatalytic activities were evaluated in terms of the efficiencies of photodecomposition of Rhodamine B in aqueous solution under visible light illumination. The as-synthesized Fe3O4/g-C3N4 nanocomposites showed unprecedented photodecomposition efficiency compared with pure g-C3N4 under visible-light. The Fe3O4/g-C3N4 nanocomposites with improved photocatalytic activities would have a great potential in removing organic dyes from polluted water.

A kind of novel ZnSnO3/SnO2 hollow urchin nanostructure was synthesized by a facile, eco-friendly two-step liquid-phase process. The structure, morphology, and composition of samples were characterized using X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), and nitrogen adsorption–desorption techniques. The results revealed that many tiny needle-like SnO2 nanowires with the average diameter of 5 nm uniformly grew on the surface of the ZnSnO3 hollow microspheres and the ZnSnO3/SnO2 hollow urchin nanostructures with different SnO2 content also were successfully prepared. In order to comprehend the evolution process of the ZnSnO3/SnO2 hollow urchin nanostructures, the possible growth mechanism of samples was illustrated via several experiments in different reaction conditions. Moreover, the gas-sensing performance of as-prepared samples was investigated. The results showed that ZnSnO3/SnO2 hollow urchin nanostructures with high response to various concentration levels of acetone enhanced selectivity, satisfying repeatability, and good long-term stability for acetone detection. Specially, the 10 wt% ZnSnO3/SnO2 hollow urchin nanostructure exhibited the best gas sensitivity (17.03 for 50 ppm acetone) may be a reliable biomarker for the diabetes patients, which could be ascribed to its large specific surface area, complete pore permeability, and increase of chemisorbed oxygen due to the doping of SnO2.

Based on the BBV model [A. Barrat, M. Barthelemy, A. Vespignani, Phys. Rev. Lett. 92 (22) (2004)], we propose a weighted group preferential model, which is generated by the group preferential mechanism. We derive analytically the various statistical properties, such as the distribution of degree, strength and weight, the degree-strength relationship. Finally, we provide a contrast with the BBV model on the synchronization robustness and fragility through numerical simulation.

The effects of cathepsin L on claudin-1 expression were investigated under hyperthermic condition in a blood-brain barrier (BBB) model in vitro, in order to estimate the potential effects of hyperthermia on BBB dysfunction.Brain microvascular endothelial cells (BMECs) and astrocytes were obtained from rat brain. The BBB models were randomly divided into a sham (37°C) group, a 39°C group, a 37°C+cathepsin L group and a 39°C+cathepsin L group. The permeability of BBB was judged. The expressions of cathepsin L in astrocytes and claudin-1 in BMECs were detected using immunohistochemistry method and western blot assay.The permeability of BBB models was higher in the 39°C group than in the sham group. The cathepsin L expression in astrocytes was higher in the 39°C group than in the sham group (P0.01), whereas the claudin-1 expression in BMECs was lower in the 39°C group than in the sham group (P0.01). The claudin-1 expression in BMECs was significantly lower in the 37°C+cathepsin L group than in the sham group (P0.01). At the same time point, the claudin-1 expression in BMECs was significantly lower in the 39°C+cathepsin L group than in the 37°C+cathepsin L group (P0.01).Hyperthermia can probably decrease claudin-1 expression in BMECs by upregulating cathepsin L expression in astrocytes in a BBB model in vitro.

Social media check-in data as a geo-tagged information source have been used for revealing spatio-temporal patterns in the field of social and urban study, such as human behavior or public issues. This paper investigates a case study and presents a new method of representing the mobility of people within a city from check-in data. By dividing the data in a temporal sequence, this study examines the overall mobility in the case study city through the gradient/difference of population density with a series of time after computing the population density from the check-in data using an incorporated Thiessen polygon method. By classifying check-in data with their geo-tags into several groups according to travel purposes, and partitioning the data according to administrative district boundaries, various moving patterns for those travel purposes in those administrative districts are identified by scrutinizing a series of spatial geometries of a weighted standard deviational ellipse (WSDE). Through deep analyses of those data by the adopted approaches, the general pattern of mobility in the case city, such as people moving to the central urban area from the suburb from 4 am to 8 am, is ascertained, and different characteristics of movement in those districts are also depicted. Furthermore, it can tell that in which district less movement is likely for a certain purpose (e.g., for dinner or entertainment). This study has demonstrated the availability of the proposed methodology and check-in data for investigating intra-urban human mobility.

We study and generalize the copying model of Kumar et al. [Stochastic models for the Web graph, FOCS 2000]. The basic idea is that a new Web is often made by copying an old one, and then changing some of the links. Our main contributions are as follows: we show that (1) the copying model of Kumar et al. does generate a power-law degree distribution as stated in Kumar et al. [Stochastic models for the Web graph, FOCS 2000]; (2) We generalize the Kumar et al. copying process. We prove that this generalized model has a power-law degree distribution and give the exact solution from the perspective of Markov chain.