Self-Assembled Viscoelastic Surfactant Micelles with pH-Responsive Behavior: A New Fracturing-Displacement Integrated Working Fluid for Unconventional Reservoirs.

The integrated fracturing and oil recovery strategy is a new paradigm for achieving sustainable and cost-effective development of unconventional reservoirs. However, a single type of working fluid cannot simultaneously meet the different needs of fracturing and oil displacement processes. Here, we develop a pH-responsive fracturing-displacement integrated working fluid based on the self-assembled micelles of N,N-dimethyl oleoamine propylamine (DOAPA) and succinic acid (SA). By adjusting the pH of the working fluid, the DOAPA and SA molecules can be switched repeatedly between highly viscoelastic wormlike micelles and aqueous low-viscosity spherical micelles. The zero-shear viscosity of the working fluid enriched the wormlike micelles can reach more than 93,100 mPa·s, showing excellent viscoelasticity and sand-carrying properties. The working fluid is easy to gel-break when it encounters oil, generating a low-viscosity liquid without residue. In addition, the system has strong interfacial activity, which can greatly reduce the oil-water interfacial tension to form emulsions and can achieve reversible demulsification and re-emulsification by adjusting pH. Through the designed and fabricated microfluidic chip, it can be visualized that under the synergistic effect of viscoelasticity and interfacial activity DOAPA/SA can effectively expand the swept volume of tight fractured formations, promote pore wetting reversal and crude oil emulsification, and improve the displacement efficiency. The DOAPA/SA meets the design requirements of the fracturing-displacement integrated working fluids and provides a novel method and idea for constructing the integrated working fluids suitable for fracturing and displacement in unconventional reservoirs.

Effect of Bacterial Amyloid Protein Phenol-Soluble Modulin Alpha 3 on the Aggregation of Amyloid Beta Protein Associated with Alzheimer's Disease.

Since the proposal of the brainstem axis theory, increasing research attention has been paid to the interactions between bacterial amyloids produced by intestinal flora and the amyloid ß-protein (Aß) related to Alzheimer's disease (AD), and it has been considered as the possible cause of AD. Therefore, phenol-soluble modulin (PSM) α3, the most virulent protein secreted by Staphylococcus aureus, has attracted much attention. In this work, the effect of PSMα3 with a unique cross-α fibril architecture on the aggregation of pathogenic Aß40 of AD was studied by extensive biophysical characterizations. The results proposed that the PSMα3 monomer inhibited the aggregation of Aß40 in a concentration-dependent manner and changed the aggregation pathway to form granular aggregates. However, PSMα3 oligomers promoted the generation of the ß-sheet structure, thus shortening the lag phase of Aß40 aggregation. Moreover, the higher the cross-α content of PSMα3, the stronger the effect of the promotion, indicating that the cross-α structure of PSMα3 plays a crucial role in the aggregation of Aß40. Further molecular dynamics (MD) simulations have shown that the Met1-Gly20 region in the PSMα3 monomer can be combined with the Asp1-Ala2 and His13-Val36 regions in the Aß40 monomer by hydrophobic and electrostatic interactions, which prevents the conformational conversion of Aß40 from the α-helix to ß-sheet structure. By contrast, PSMα3 oligomers mainly combined with the central hydrophobic core (CHC) and the C-terminal region of the Aß40 monomer by weak H-bonding and hydrophobic interactions, which could not inhibit the transition to the ß-sheet structure in the aggregation pathway. Thus, the research has unraveled molecular interactions between Aß40 and PSMα3 of different structures and provided a deeper understanding of the complex interactions between bacterial amyloids and AD-related pathogenic Aß.

[A new cinnamic acid ester derivative from Liquidambaris Resina].

Twelve compounds were isolated from Liquidambaris Resina by silica gel column chromatography and thin layer chromatography. Their structures were identified on the basis of spectral data, electron capture detector data, and physicochemical properties as(2'R, 3'R)-2',3'-dihydroxy-hydrocinnamyl-(E)-cinnamate(1),(E)-cinnamyl-(E)-cinnamate(2), cinnamic acid(3), 28-norlup-20(29)-en-3-one-17ß-hydroperoxide(4), erythrodiol(5), 13ß,28-epoxy-30-hydroxyolean-1-en-3-one(6),(3ß)-olean-12-ene-3,23-diol(7), 2α,3α-dihydroxy-olean-12-en-28-oic acid(8), 28-hydroxyolean-12-en-3-one(9), 3-epi-oleanolic acid(10), 3-oxo-oleanolic acid(11), and hederagenin(12). Compound 1 was a new cinnamic acid ester derivative and compounds 2-4,6-8, and 12 were isolated from Liquidambaris Resina for the first time. Compounds 4, 5, 10, and 12 exerted inhibitory effects on the proliferation of human umbilical vein endothelial cells(HUVEC) with the IC_(50) values of(17.43±2.17),(35.32±0.61),(27.50±0.80), and(46.30±0.30) µmol·L~(-1), respectively.

Design of Gallic Acid-Glutamine Conjugate and Chemical Implications for Its Potency Against Alzheimer's Amyloid-ß Fibrillogenesis.

Epigallocatechin-3-gallate (EGCG) has been widely recognized as a potent inhibitor of Alzheimer's amyloid-ß (Aß) fibrillogenesis. We found that gallic acid (GA) has superior inhibitory effects over EGCG at the same mass concentrations and assumed the pivotal role of the carboxyl group in GA. Therefore, we designed five GA-derivatives to investigate the significance of carboxyl groups in modulating Aß fibrillogenesis, including carboxyl-amidated GA (GA-NH2), GA-glutamic acid conjugate (GA-E), and GA-E derivatives with amidated either of the two carboxyl groups (GA-Q and GA-E-NH2) or with two amidated-carboxyl groups (GA-Q-NH2). Intriguingly, only GA-Q shows significantly stronger potency than GA and extends the life span of the AD transgenic nematode by over 30%. Thermodynamic studies reveal that GA-Q has a strong binding affinity for Aß42 with two binding sites, one stronger (site 1, Ka1 = 3.1 × 106 M-1) and the other weaker (site 2, Ka2 = 0.8 × 106 M-1). In site 1, hydrogen bonding, electrostatic interactions, and hydrophobic interactions all have contributions, while in site 2, only hydrogen bonding and electrostatic interactions work. The two sites are confirmed by molecular simulations, and the computations specified the key residues. GA-Q has strong binding to Asp23, Gly33, Gly38, Ala30, Ile31, and Leu34 via hydrogen bonding and electrostatic interactions, while it interacts with Phe19, Ala21 Gly25, and Asn27 via hydrophobic interactions. Consequently, GA-Q destroys Asp23-Lys28 salt bridges and restricts ß-sheet/bridge structures. The thermodynamic and molecular insight into the GA-Q functions on inhibiting Aß fibrillogenesis would pave a new way to the design of potent molecules against Alzheimer's amyloid.

Association between time in range, a novel measurement of glycemic control and islet secretory function in chinese patients with type 2 diabetes mellitus-An observational study.

AIMS: To explore the association between dynamic islet secretory function and TIR (time in range), a new valuable metric of glycemic control in type 2 diabetes (T2D). METHODS: In this observational study 256 patients with type 2 diabetes were included and continuous glucose monitoring system (CGMS) were applied to monitor blood glucose and also the calculation of TIR [the time spent in an individual's target glucose range (usually 3.9-10 mmol/L)]. The participants were divided into 3 groups according to the tertiles of TIR, 85 cases with TIR ≥ 65.05% (T1 group), 86 cases with 41.84 < TIR ≤ 65.05% (T2 group) and 85 cases with TIR < 41.84% (T3 group). Serum glucagon (GLA0h, GLA0.5h, GLA1h, GLA2h, GLA3h), C-peptide (Cp0h, Cp0.5h, Cp1h, Cp2h, Cp3h) concentration at different time points were measured after a 100 g standard steamed buns meal test to assess the pancreatic alpha cell and beta cell function. Spearman correlation analysis and multivariate linear stepwise regression analysis were adopted for statistical analysis. RESULTS: The average age and diabetes duration of all the participants were separately 56.09 ± 13.8 years and 8.0 (4.0,15.0) years. Compared with patients in T1 group, participants in group T2 and T3 tend to have a lower concentration of C-peptide at all time points, as well as GLA0h, GLA2h and GLA3h (p < 0.05). TIR was positively correlated with C-peptide at different time points, area under the curve of C-peptide in half an hour (AUCCp0.5h), GLA0h, GLA3h, area under the curve of glucagon in half an hour (AUCGLA0.5h)(rs = 0.263, 0.414, 0.510, 0.587, 0.528, 0.360, 0.259, 0.144 and 0.208, respectively, p < 0.05) and was negatively correlated with the increment of serum glucagon from baseline at 0.5 h, 1 h and 2 h after the standard energy loaded(△GLA0.5h, △GLA1h, △GLA2h)(rs = -0.152,-0.172 and -0.203, respectively, p < 0.05). Cp2h, Cp0h and GLA0h were independent factors for TIR (ß = 6.558,-6.930, 0.247, respectively, p < 0.01). CONCLUSION: Both islet alpha cell and beta cell secretory function have important influence on TIR, a novel vital index of glycemic fluctuation.

Molecular Insight into Cu2+-Induced Conformational Transitions of Amyloid ß-Protein from Fast Kinetic Analysis and Molecular Dynamics Simulations.

Cu2+-mediated amyloid ß-protein (Aß) aggregation is implicated in the pathogenesis of Alzheimer's disease, so it is of significance to understand Cu2+-mediated conformational transitions of Aß. Herein, four Aß mutants were created by using the environment-sensitive cyanophenylalanine to respectively substitute F4, Y10, F19, and F20 residues of Aß40. By using stopped-flow fluorescence spectroscopy and molecular dynamics (MD) simulations, the early stage conformational transitions of the mutants mediated by Cu2+ binding were investigated. The fast kinetics unveils that Cu2+ has more significant influence on the conformational changes of N-terminal (F4 and Y10) than on the central hydrophobic core (CHC, F19, and F20) under different pH conditions (pH 6.6-8.0), especially Y10. Interestingly, lag periods of the conformational transitions are observed for the F19 and F20 mutants at pH 8.0, indicating the slow response of the two mutation sites on the conformational transitions. More importantly, significantly longer lag periods for F20 than for F19 indicate the conduction of the transition from F19 to F20. The conduction time (difference in lag period) decreases from 4.5 s at Cu2+ = 0 to undetectable (<1 ms) at Cu2+ = 10 µM. The significant difference in the response time of F19 and F20 and the fast local conformational changes of Y10 imply that the conformational transitions of Aß start around Y10. MD simulations support the observation of hydrophobicity increase at N-terminal during the conformational transitions of Aß-Cu2+. It also reveals that Y10 is immediately approached by Cu2+, supporting the speculation that the starting point of conformational transitions of Aß is near Y10. The work has provided molecular insight into the early stage conformational transitions of Aß40 mediated by Cu2+.

Time in Range, as a Novel Metric of Glycemic Control, Is Reversely Associated with Presence of Diabetic Cardiovascular Autonomic Neuropathy Independent of HbA1c in Chinese Type 2 Diabetes.

OBJECTIVE: The objective of this study is to investigate the relationship between time in range (TIR), a new metric of continuous glucose monitoring (CGM) and cardiovascular autonomic neuropathy (CAN) in individuals with type 2 diabetes mellitus (T2DM). METHODS: A total of 349 individuals with T2DM were enrolled in this study. Evaluating by the standard cardiac autonomic reflex tests (CARTs), there were 228 diabetic individuals without cardiovascular autonomic neuropathy (without confirmed CAN) including absent CAN (n = 83 cases) and early CAN (n = 83 cases) and early CAN (n = 83 cases) and early CAN (n = 83 cases) and early CAN (. RESULTS: The total presence of CAN was 34.67% (definite CAN 31.23% and severe CAN 3.44%). Patients with more severe CAN had lower TIR (P < 0.001). With increasing quartiles of TIR, the presence of CAN by severity declined (P < 0.001). With increasing quartiles of TIR, the presence of CAN by severity declined (P < 0.001). With increasing quartiles of TIR, the presence of CAN by severity declined (P < 0.001). With increasing quartiles of TIR, the presence of CAN by severity declined (. CONCLUSION: TIR is associated with the presence of CAN independent of HbA1c and GV metrics in Chinese type 2 diabetes.

Design of Multifunctional Agent Based on Basified Serum Albumin for Efficient In Vivo ß-Amyloid Inhibition and Imaging.

Theranostics, the combination of therapeutics and diagnostics, has emerged as a sophisticated, integrated, and advanced tool in the prevention and treatment of serious diseases, such as Alzheimer's disease (AD). However, the preclinical research of an AD theranostic molecule is in its infancy and needs to be explored in depth. Herein, a multifunctional theranostic agent is designed and fabricated by conjugating an Aß-specific near-infrared (NIR) fluorescence probe (F) and by coupling a BBB penetrable peptide (Penetratin, Pen) onto the basified human serum albumin (HSA-B) that has been recently proven as an effective amyloid-ß (Aß) inhibitor. Such an elaborately constructed HSA-B-based molecule (HSA-BFP) possesses high potency on inhibiting Aß fibrillogenesis, for example, increasing SH-SY5Y cell viability from 66.5 to 93%. In addition, HSA-BFP exhibits favorable stability in the "off-on" NIR imaging of Aß plaques and achieves a 2-fold increase of BBB permeability after the Pen modification. More importantly, in vivo assays with the AD model C. elegans CL2006 indicate that HSA-BFP can specifically image Aß deposits, decrease amyloid accumulation, and attenuate Aß-triggered paralysis. Thus, HSA-B has been proven as a potent and versatile platform for the development of AD theranostic agents.