A Mechanistic Study of Asymmetric Transfer Hydrogenation of Imines on a Chiral Phosphoric Acid Derived Indium Metal-Organic Framework.

A density functional theory (DFT) study is reported to examine the asymmetric transfer hydrogenation (ATH) of imines catalyzed by an indium metal-organic framework (In-MOF) derived from a chiral phosphoric acid (CPA). It is revealed that the imine and reducing agent (i.e., thiazoline) are simultaneously adsorbed on the CPA through H-bonding to form an intermediate, subsequently, a proton is transferred from thiazoline to imine. The transition state TS-R and TS-S are stabilized on the CPA via H-bonding. Compared to the TS-S, the TS-R has shorter H-bonding distances and longer C-H···π distances, it is more stable and experiences less steric hindrance. Consequently, the TS-R exhibits a lower activation barrier affording to the (R)-enantiomer within 68.1% ee in toluene. Imines with substituted groups such as -NO2, -F, and -OCH3 are used to investigate the substitution effects on the ATH. In the presence of an electron-withdrawing group like -NO2, the electrophilicity of imine is enhanced and the activation barrier is decreased. The non-covalent interactions and activation-strain model (ASM) analysis reveal that the structural distortions and the differential noncovalent interactions of TSs in a rigid In-MOF provide the inherent driving force for enantioselectivity. For -OCH3 substituted imine, the TS-S has the strongest steric hindrance, leading to the highest enantioselectivity. When the solvent is changed from toluene to dichloromethane, acetonitrile, and dimethylsulfoxide with increasing polarity, the activation energies of transition state increase whereas their difference decreases. This implies the reaction is slowed down and the enantioselectivity becomes lower in a solvent of smaller polarity. Among the four solvents, toluene turns out to be the best for the ATH. The calculated results in this study are in fairly good agreement with experimental observations. This study provides a mechanistic understanding of the reaction mechanism, as well as substitution and solvent effects on the activity and enantioselectivity of the ATH. The microscopic insights are useful for the development of new chiral MOFs toward important asymmetric reactions.

A Comprehensive Landscape for Fibril Association Behaviors Encoded Synergistically by Saccharides and Peptides.

Nature provides us a panorama of fibrils with tremendous structural polymorphism from molecular building blocks to hierarchical association behaviors. Despite recent achievements in creating artificial systems with individual building blocks through self-assembly, molecularly encoding the relationship from model building blocks to fibril association, resulting in controlled macroscopic properties, has remained an elusive goal. In this paper, by employing a designed set of glycopeptide building blocks and combining experimental and computational tools, we report a library of controlled fibril polymorphism with elucidation from molecular packing to fibril association and the related macroscopic properties. The growth of the fibril either axially or radially with right- or left-handed twisting is determined by the subtle trade-off of oligosaccharide and oligopeptide components. Meanwhile, visible evidence for the association process of double-strand fibrils has been experimentally and theoretically proposed. Finally the fibril polymorphs demonstrated significant different macroscopic properties on hydrogel formation and cellular migration control.

Flow-driven competition between two capsules passing through a narrow pore.

By incorporating a distance function into the finite element simulation, we investigate the flow-driven competition between two soft capsules passing through a narrow pore, employing the arbitrary Lagrangian-Eulerian formulation to satisfy the boundary conditions for fluid flow and capsule deformation. In our simulations, the motion and deformation of the capsules can be described in an intuitive manner, and the order in which capsules of different sizes pass through a pore can be clearly determined. Meanwhile, when the capsules are near the narrow pore, the change of the flow field is also very interesting and can be expressed intuitively. It is shown that, driven by the Poiseuille flow, the larger capsule has a stronger tendency to pass through the pore than the small one, which can be attributed to the greater resistance and the volume advantage of the larger capsule. In addition, we demonstrate that this tendency can be reversed by changing the inlet velocity and setting the initial position of the smaller capsule closer to the axis of the pore. And as long as the large one passes through first, the small one will offset the axis to the same orientation as the initial, while the large one always moves along the axis.

Analysis of Serum Metabolomics in Rats with Osteoarthritis by Mass Spectrometry.

Osteoarthritis is a common multifactorial chronic disease that occurs in articular cartilage, subchondral bone, and periarticular tissue. The pathogenesis of OA is still unclear. To investigate the differences in serum metabolites between OA and the control group, liquid chromatography/mass spectrometry (LC/MS)-based metabolomics was used. To reveal the pathogenesis of OA, 12 SD male rats were randomly divided into control and OA groups using collagenase to induce OA for modeling, and serum was collected 7 days after modeling for testing. The OA group was distinguished from the control group by principal component analysis and orthogonal partial least squares-discriminant analysis, and six biomarkers were finally identified. These biomarkers were metabolized through tryptophan metabolism, glutamate metabolism, nitrogen metabolism, spermidine metabolism, and fatty acid metabolism pathways. The study identified metabolites that may be altered in OA, suggesting a role in OA through relevant metabolic pathways. Metabolomics, as an important tool for studying disease mechanisms, provides useful information for studying the metabolic mechanisms of OA.

Chemotherapy exacerbates ovarian cancer cell migration and cancer stem cell-like characteristics through GLI1.

BACKGROUND: Despite the great clinical response to the first-line chemotherapeutics, metastasis still happens among most of the ovarian cancer patients within 2 years. METHODS: Using multiple human ovarian cancer cell lines, a transwell co-culture system of the carboplatin or VP-16-challenged feeder and receptor cells was established to demonstrate the chemotherapy-exacerbated migration. The migration and cancer stem cell (CSC)-like characteristics were determined by wound healing, transwell migration, flow cytometry and sphere formation. mRNA and protein expression were identified by qPCR and western blot. Bioinformatics analysis was used to investigate the differentially expressed genes. GLI1 expression in tissue samples was analysed by immunohistochemistry. RESULTS: Chemotherapy was found to not only kill tumour cells, but also trigger the induction of CSC-like traits and the migration of ovarian cancer cells. EMT markers Vimentin and Snail in receptor cells were upregulated in the microenvironment of chemotherapy-challenged feeder cells. The transcription factor GLI1 was upregulated by chemotherapy in both clinical samples and cell lines. Follow-up functional experiments illustrated that inhibiting GLI1 reversed the chemotherapy-exacerbated CSC-like traits, including CD44 and CD133, as well as prevented the migration of ovarian cancer cells. CONCLUSIONS: Targeting GLI1 may improve clinical benefits in the chemotherapy-exacerbated metastasis in ovarian cancer treatment.

Electrocatalytically Active Fe-(O-C2 )4 Single-Atom Sites for Efficient Reduction of Nitrogen to Ammonia.

Single-atom catalysts have demonstrated their superiority over other types of catalysts for various reactions. However, the reported nitrogen reduction reaction single-atom electrocatalysts for the nitrogen reduction reaction exclusively utilize metal-nitrogen or metal-carbon coordination configurations as catalytic active sites. Here, we report a Fe single-atom electrocatalyst supported on low-cost, nitrogen-free lignocellulose-derived carbon. The extended X-ray absorption fine structure spectra confirm that Fe atoms are anchored to the support via the Fe-(O-C2 )4 coordination configuration. Density functional theory calculations identify Fe-(O-C2 )4 as the active site for the nitrogen reduction reaction. An electrode consisting of the electrocatalyst loaded on carbon cloth can afford a NH3 yield rate and faradaic efficiency of 32.1 µg h-1 mgcat. -1 (5350 µg h-1 mgFe -1 ) and 29.3 %, respectively. An exceptional NH3 yield rate of 307.7 µg h-1 mgcat. -1 (51 283 µg h-1 mgFe -1 ) with a near record faradaic efficiency of 51.0 % can be achieved with the electrocatalyst immobilized on a glassy carbon electrode.

Depression promotes hepatocellular carcinoma progression through a glucocorticoid-mediated upregulation of PD-1 expression in tumor-infiltrating NK cells.

There is a growing belief that depression was positively associated with the progression of liver cancer. However, the driving molecular events behind the depression in liver cancer are poorly understood and need to be elucidated. Since hyperactivity of the hypothalamic-pituitary-adrenal axis during depression leads to the excessive release of glucocorticoids (GCs), which suppress the activity of natural killer (NK) cells, we hypothesized that high levels of GCs during depression may inhibit function of tumor-infiltrating NK cells during the progress of the liver cancer. Using chronic unpredictable mild stress-induced depressed mice model, we showed that the progression of liver cancer was significantly accelerated in the depressed mice. The high levels of GCs were observed in both depressed mice and depressed patients with liver cancer. Importantly, the expression of programmed death (PD)-1 on NK cells was specifically increased in the tumor microenvironment rather than that in blood or spleen. Coculture studies demonstrated that the expression of PD-1 was significantly increased and cytotoxicity of NK92 cells was remarkably decreased by the dexamethasone treatment through PD-L1-dependent pathway. To the best of our knowledge, we first found that PD-1/PD-L1-mediated exhaustion of infiltrated NK cells promoted hepatocellular carcinoma progression under depression and provided a novel strategy for GC-mediated antidepressant therapy in patients with liver cancer.

5-FU preferably induces apoptosis in BRAF V600E colorectal cancer cells via downregulation of Bcl-xL.

Fluorouracil (5-FU) which has been widely used in postoperative adjuvant therapy in patients with colon cancer, remains the main backbone of combination treatment of patients with colon cancer. However, the efficacy of 5-FU alone in colorectal cancer patients with BRAFV600E is not clear. In this study, we demonstrated that BRAFV600E confers sensitivity to 5-FU in vitro and in vivo xenograft model, using the paired isogenic colorectal cancer cell lines RKO with either BRAF Wild Type (WT)(+/-) or mutant (Mut) (600E/-). Our results revealed 5-FU preferably induces marked apoptosis in BRAF-mutant colorectal cancer cells, through attenuating expression of Bcl-xL and activation caspase-3/9 pathway, eventually conferring the anti-tumor efficacy of 5-FU in vitro and in vivo. Meanwhile, expression of Bcl-xL remained unchanged in BRAF WT group after treatment of 5-FU, although low extent of anti-tumor activity of 5-FU still being observed. In conclusion, these results provided a better understanding of clinical outcome of 5-FU between BRAF WT and mutant colorectal cancer patients, and suggested the inhibition of Bcl-xL might present an alternative strategy to enhance the therapeutic efficacy of 5-FU in colorectal cancer patients with BRAF mutation.

Flow-induced translocation of vesicles through a narrow pore.

We use finite element method to investigate the flow-induced translocation of vesicles through a narrow pore from a dynamic point of view. In order to complete the coupling between fluid flow and the vesicle membranes, we employ the fluid-structure interactions with the arbitrary Lagrangian-Eulerian method. Our results demonstrate that the vesicle shows similar shape change from bullet-like to dumbbell-like, dumbbell-like to bulb-like, and bulb-like to parachute-like if it is pushed by flow field to pass through a narrow pore smaller than its size. We further find that the strain energy exhibits a higher peak and a lower peak in the whole translocation process, where the higher peak corresponds to the dumbbell-like shape and the lower peak corresponds to the parachute-like shape due to more stretching of the membrane for the dumbbell-like shape than that of the parachute-like shape. The translocation time of the vesicle from one side to the other side of the narrow pore decreases with the increase of inlet velocity, but the strain energy exhibits an increase, which implies that the vesicle needs more time to complete the translocation with the lower inlet velocity, but the requirement for the mechanical properties of the membrane is lower. Our work answers the mapping between the positions of the vesicles and deformed states with the stress distribution and change of strain energy, which can provide helpful information on the utilization of vesicles in pharmaceutical, chemical, and physiological processes.

Unusual self-diffusion behaviors of polymer adsorbed on rough surfaces.

We investigate the diffusion dynamics of a single polymer strongly adsorbed on surfaces in an extremely broad chain length and surface roughness by means of molecular dynamics simulations. Our simulations demonstrate that with the increase in chain length, the diffusion dynamics of polymer chains exhibits three regimes: the Rouse dynamics with D ∼ N-1 when the lateral size of polymer chains is smaller than a half of distance between obstacles on rough surfaces; the reptationlike dynamics with D ∼ N-1.5 and τr ∼ N3 when the obstacles inhibit the freely Rouse behavior of polymer chains; and the quasi-Rouse dynamics with D ∼ N-1 and τr ∼ N2.5 when the height of obstacles is smaller than twice the vertical size of polymer chains, where D, N, and τr are the diffusion coefficient, chain length, and end-to-end vector relaxation time of polymer chains, respectively. The long chains have sufficient conformation entropy to form loops to hop over short obstacles, which could dramatically reduce the confinement from obstacles on the rough surfaces and changes the diffusion and relaxation dynamics of polymer chains from the reptationlike dynamics to the quasi-Rouse dynamics. Our results reveal the whole diffusion dynamics of polymer chains strongly adsorbed on rough surfaces and clarify the corresponding transition mechanism, which is significant for the understanding of the physical nature and the development of the corresponding applications.

Increased Serum Levels of Cortisol and Inflammatory Cytokines in People With Depression.

This cross-sectional study aimed at measuring the correlation and association between serum levels of cortisol, inflammatory cytokines, and depression and to measure the detection accuracy of serum levels of cortisol in serum samples. In total, 89 male participants were recruited into this study from June 15, 2017, to September 31, 2017. The Hamilton Depression Rating Scale, Beck Anxiety Inventory, and Pittsburgh Sleep Quality Index were used to investigate the mental health status of the participants. Serum concentrations of cortisol and inflammatory cytokines were determined. The serum cortisol concentration, anxiety level, and sleep quality were included in the final logistic regression model. Serum cortisol was able to accurately distinguish between patients with depression and those without depression. There was a significant positive correlation between serum cortisol levels and Hamilton Depression Rating Scale scores.

Effects of surface roughness on the self-diffusion dynamics of a single polymer.

We employ molecular dynamics simulations to simulate the diffusion dynamics of a single polymer adsorbed on surfaces with different roughnesses, which are characterized by the separation distance between obstacles and the height of obstacles. Our simulations demonstrate that for strong adsorption and when the confinement of obstacles is strong enough for all chains, the scaling exponent α of the diffusion coefficient on the chain length exhibits three cases with increase of the height of obstacles: a Rouse plateau with α ≈ -1 (the lateral motion of the polymer chains is free), a reptationlike plateau with α ≈ -1.5 (the polymer chains can hardly stride over the obstacles in the perpendicular direction) and a transition from the Rouse plateau to the reptationlike plateau with -1.5 < α < -1 (the obstacles hinder the lateral motion of the polymer chains). However, with increase of the separation distance between obstacles, the confinement from the obstacles exhibits a decrease (more lateral motions of the polymer chains are allowed), which results in a higher plateau (no longer separate reptationlike dynamics). Our results clarify the effects of surface roughness on the diffusion mechanism of polymer chains strongly adsorbed on solid surfaces in dilute solutions and the resulting transition mechanism from the Rouse scaling to the reptationlike scaling, which is significant for the understanding of the physical nature and the development of the corresponding applications.

Conformational Heterogeneity and FRET Data Interpretation for Dimensions of Unfolded Proteins.

A mathematico-physically valid formulation is required to infer properties of disordered protein conformations from single-molecule Förster resonance energy transfer (smFRET). Conformational dimensions inferred by conventional approaches that presume a homogeneous conformational ensemble can be unphysical. When all possible-heterogeneous as well as homogeneous-conformational distributions are taken into account without prejudgment, a single value of average transfer efficiency 〈E〉 between dyes at two chain ends is generally consistent with highly diverse, multiple values of the average radius of gyration 〈Rg〉. Here we utilize unbiased conformational statistics from a coarse-grained explicit-chain model to establish a general logical framework to quantify this fundamental ambiguity in smFRET inference. As an application, we address the long-standing controversy regarding the denaturant dependence of 〈Rg〉 of unfolded proteins, focusing on Protein L as an example. Conventional smFRET inference concluded that 〈Rg〉 of unfolded Protein L is highly sensitive to [GuHCl], but data from SAXS suggested a near-constant 〈Rg〉 irrespective of [GuHCl]. Strikingly, our analysis indicates that although the reported 〈E〉 values for Protein L at [GuHCl] = 1 and 7 M are very different at 0.75 and 0.45, respectively, the Bayesian Rg2 distributions consistent with these two 〈E〉 values overlap by as much as 75%. Our findings suggest, in general, that the smFRET-SAXS discrepancy regarding unfolded protein dimensions likely arise from highly heterogeneous conformational ensembles at low or zero denaturant, and that additional experimental probes are needed to ascertain the nature of this heterogeneity.

Flow-induced polymer separation through a nanopore: effects of solvent quality.

Using a hybrid simulation method that combines a lattice-Boltzmann approach for the flow and a molecular dynamics model for the polymer, we investigated the effect of solvent quality on the flow-induced polymer translocation through a nanopore. We demonstrate the nontrivial dependence of the translocation dynamics of polymers on the solvent quality, i.e., the enhancement in the polymer insolubility increases the critical velocity flux and shortens the translocation time. Accordingly, we propose a new strategy to separate polymers with different solubilities via their translocations in the nanopore by adjusting the velocity flux of the flow, which appears to be promising for the design of micro-scaled polymer separation devices.

The influence of polymer architectures on the dewetting behavior of thin polymer films: from linear chains to ring chains.

The dewetting behavior of ring polystyrene (RPS) film and linear polystyrene (LPS) film on silanized Si substrates with different grafting densities and PDMS substrate was investigated. Results showed that polymer architectures greatly influenced the dewetting behavior of the thin polymer film. On the silanized Si substrate with 69% grafting density, RPS chains exhibited stronger adsorption compared with LPS chains, and as a result the wetting layer formed more easily. For LPS films, with a decreased annealing temperature, the stability of the polymer film changed from non-slip dewetting via apparent slip dewetting to apparently stable. However, for RPS films, the polymer film stability switched from apparent slip dewetting to apparently stable. On the silanized Si substrate with 94% grafting density, the chain adsorption became weaker and the dewetting processes were faster than that on the substrate with 69% grafting density at the same experimental temperature for both the LPS and RPS films. Moreover, on the PDMS substrate, LPS films always showed non-slip dewetting, while the dewetting kinetics of RPS films switched from non-slip dewetting to slip dewetting behaviour. Forming the wetting layer strongly influenced the stability and dewetting behavior of the thin polymer films.

Synthesis of Si/SiO2 core-shell nanowire arrays and broadband anti-reflection effects in diluted Si nanowire arrays by adjusting dielectric shell thickness.

A low filling ratio and enhanced absorption is needed to enable the full potential of Si nanowire (NW) arrays for optoelectronic applications. In this paper, we report a versatile, scalable fabrication technique that uses nanosphere lithography (NSL) patterning for the synthesis of vertically aligned Si and Si/SiO2 NW arrays. The optical reflection of the NW arrays can be substantially suppressed by the addition of the transparent shell. Meanwhile, by the finite-difference time-domain (FDTD) simulation, we find that the absorption enhancement in the core Si NW can be obtained by adding the transparent shell. The special absorption enhancement of the Si NW arrays with a core-shell structure can be theoretically understood by modal analysis. The absorption in such Si NW array structures is very sensitive to the thickness of transparent coating. By the addition of a SiO2 shell layer, the absorption in the inner Si NW array can be substantially enhanced. Furthermore, significant absorption enhancement and broadband anti-reflection effects can be achieved by the diluted Si NWs combined with the single dielectric shell.

Flow-induced translocation of star polymers through a nanopore.

We study the flow-induced translocation of the star polymers through a nanopore using a hybrid simulation method that incorporates a lattice-Boltzmann approach for the fluid into a molecular dynamics model for the polymer. Our simulation demonstrates the existence of an optimal forward arm number of the star polymers captured by the nanopore, and illustrates its significance in determining the critical velocity flux of the star polymer translocation through the nanopore. Importantly, we find that the critical velocity flux of the star polymers is independent of the arm polymerization degree, but exhibits a linear dependence on the arm number. Based on previous scaling arguments and our simulation results, we conclude a linear dependence of the critical velocity flux on the arm number of the star polymers, which can successfully describe the dynamics of the star polymer translocation. Our simulation results rationalize the experimental results for the dependence of the critical velocity flux on the arm polymerization degree and the arm number of the star polymers, which provide new insights for the characterization and the purification of the star polymers.

Effects of nanopore size on the flow-induced star polymer translocation.

We study the effects of the nanopore size on the flow-induced capture of the star polymer by a nanopore and the afterward translocation, using a hybrid simulation method that couples point particles into a fluctuating lattice-Boltzmann fluid. Our simulation demonstrates that the optimal forward arm number decreases slowly with the increase of the length of the nanopore. Compared to the minor effect of the length of the nanopore, the optimal forward arm number obviously increases with the increase of the width of the nanopore, which can clarify the current controversial issue for the optimal forward arm number between the theory and experiments. In addition, our results indicate that the critical velocity flux of the star polymer is independent of the nanopore size. Our work bridges the experimental results and the theoretical understanding, which can provide comprehensive insights for the characterization and the purification of the star polymers.

Influence of film structure on the dewetting kinetics of thin polymer films in the solvent annealing process.

On a non-wetting solid substrate, the solvent annealing process of a thin polymer film includes the swelling process and the dewetting process. Owing to difficulties in the in situ analysis of the two processes simultaneously, a quantitative study on the solvent annealing process of thin polymer films on the non-wetting solid substrate is extremely rare. In this paper, we design an experimental method by combining spectroscopic ellipsometry with optical microscopy to achieve the simultaneous in situ study. Using this method, we investigate the influence of the structure of swollen film on its dewetting kinetics during the solvent annealing process. The results show that for a thin PS film with low Mw (Mw = 4.1 kg mol(-1)), acetone molecules can form an ultrathin enriched layer between the PS film and the solid substrate during the swelling process. The presence of the acetone enriched layer accounts for the exponential kinetic behavior in the case of a thin PS film with low Mw. However, the acetone enriched layer is not observed in the case of a thin PS film with high Mw (Mw = 400 kg mol(-1)) and the slippage effect of polymer chains is valid during the dewetting process.

Flow-induced polymer translocation through a nanopore from a confining nanotube.

We study the flow-induced polymer translocation through a nanopore from a confining nanotube, using a hybrid simulation method that couples point particles into a fluctuating lattice-Boltzmann fluid. Our simulation illustrates that the critical velocity flux of the polymer linearly decreases with the decrease in the size of the confining nanotube, which corresponds well with our theoretical analysis based on the blob model of the polymer translocation. Moreover, by decreasing the size of the confining nanotube, we find a significantly favorable capture of the polymer near its ends, as well as a longer translocation time. Our results provide the computational and theoretical support for the development of nanotechnologies based on the ultrafiltration and the single-molecule sequencing.