Honokiol ameliorates angiotensin II-induced cardiac hypertrophy by promoting dissociation of the Nur77-LKB1 complex and activating the AMPK pathway.

Pathological cardiac hypertrophy is a key contributor to heart failure, and the molecular mechanisms underlying honokiol (HNK)-mediated cardioprotection against this condition remain worth further exploring. This study aims to investigate the effect of HNK on angiotensin II (Ang II)-induced myocardial hypertrophy and elucidate the underlying mechanisms. Sprague-Dawley rats were exposed to Ang II infusion, followed by HNK or vehicle treatment for 4 weeks. Our results showed that HNK treatment protected against Ang II-induced myocardial hypertrophy, fibrosis and dysfunction in vivo and inhibited Ang II-induced hypertrophy in neonatal rat ventricular myocytes in vitro. Mechanistically, HNK suppressed the Ang II-induced Nur77 expression at the transcriptional level and promoted ubiquitination-mediated degradation of Nur77, leading to dissociation of the Nur77-LKB1 complex. This facilitated the translocation of LKB1 into the cytoplasm and activated the LKB1-AMPK pathway. Our findings suggest that HNK attenuates pathological remodelling and cardiac dysfunction induced by Ang II by promoting dissociation of the Nur77-LKB1 complex and subsequent activation of AMPK signalling. This study uncovers a novel role of HNK on the LKB1-AMPK pathway to protect against cardiac hypertrophy.

Operando Spectroscopy Observation of Mo Clusters-Ti3 C2 TX Catalyst/Support Interface's Dynamic Evolution in Hydrogen Evolution Reaction.

The interaction between catalyst and support plays an important role in electrocatalytic hydrogen evolution (HER), which may explain the improvement in performance by phase transition or structural remodeling. However, the intrinsic behavior of these catalysts (dynamic evolution of the interface under bias, structural/morphological transformation, stability) has not been clearly monitored, while the operando technology does well in capturing the dynamic changes in the reaction process in real time to determine the actual active site. In this paper, nitrogen-doped molybdenum atom-clusters on Ti3 C2 TX (MoACs /N-Ti3 C2 TX ) is used as a model catalyst to reveal the dynamic evolution of MoAcs on Ti3 C2 TX during the HER process. Operando X-ray absorption structure (XAS) theoretical calculation and in situ Raman spectroscopy showed that the Mo cluster structure evolves to a 6-coordinated monatomic Mo structure under working conditions, exposing more active sites and thus improving the catalytic performance. It shows excellent HER performance comparable to that of commercial Pt/C, including an overpotential of 60 mV at 10 mA cm-2 , a small Tafel slope (56 mV dec-1 ), and high activity and durability. This study provides a unique perspective for investigating the evolution of species, interfacial migration mechanisms, and sources of activity-enhancing compounds in the process of electroreduction.

Design, synthesis and evaluate of indazolylaminoquinazoline derivatives as potent Tropomyosin receptor kinase (TRK) inhibitors.

Tropomyosin receptor kinases (TRKs), the superfamily of transmembrane receptor tyrosine kinases, have recently become an attractive method for precision anticancer therapies since the approval of Larotrectinib and Entrectinib by FDA. Herein, we reported the discovery of a series of novel indazolylaminoquinazoline and indazolylaminoindazole as TRK inhibitors. The representative compound 30f exhibited good inhibitory activity against TRKWT, TRKG595R and TRKG667C with IC50 values of 0.55 nM, 25.1 nM and 5.4 nM, respectively. The compound also demonstrated potent superior to Larotrectinib antiproliferative activity against a panel of Ba/F3 cell lines transformed with both NTRK wild type and mutant fusions (IC50 = 10-200 nM). In addition, compound 30f exhibited good in vitro metabolic stability (T1/2 = 73.0 min), indicating that the quinazoline derivatives may have better metabolic stability. Finally, the binding mode of compound 30f predicted by molecular docking well explained the good enzyme inhibitory activity of indazolylaminoquinazoline compounds as TRK inhibitor. Thus, compound 30f can be used as a promising lead molecule for further structural optimization.

Minimum taxi fleet algorithm considering human spatiotemporal behaviors.

With the development of information technology, more and more travel data have provided great convenience for scholars to study the travel behavior of users. Planning user travel has increasingly attracted researchers' attention due to its great theoretical significance and practical value. In this study, we not only consider the minimum fleet size required to meet the urban travel needs but also consider the travel time and distance of the fleet. Based on the above reasons, we propose a travel scheduling solution that comprehensively considers time and space costs, namely, the Spatial-Temporal Hopcroft-Karp (STHK) algorithm. The analysis results show that the STHK algorithm not only significantly reduces the off-load time and off-load distance of the fleet travel by as much as 81% and 58% and retains the heterogeneous characteristics of human travel behavior. Our study indicates that the new planning algorithm provides the size of the fleet to meet the needs of urban travel and reduces the extra travel time and distance, thereby reducing energy consumption and reducing carbon dioxide emissions. Concurrently, the travel planning results also conform to the basic characteristics of human travel and have important theoretical significance and practical application value.

[Research Progress on Enzyme-free Blood Glucose Sensor].

Blood glucose monitoring is of great significance to diabetic patients, and the development of rapid, accurate and real-time glucose detection technology has become a research hotspot nowadays. This study introduces the concept and classification of the enzyme-free glucose sensor, expounds enzymefree glucose sensor electrode characterization methods and the application progress of different materials in enzyme-free blood glucose sensors. Meanwhile, some problems of enzyme-free glucose sensor existing in the current research and its future application prospects also will be discussed.

Dapagliflozin: a sodium-glucose cotransporter 2 inhibitor, attenuates angiotensin II-induced cardiac fibrotic remodeling by regulating TGFß1/Smad signaling.

BACKGROUND: Cardiac remodeling is one of the major risk factors for heart failure. In patients with type 2 diabetes, sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of the first hospitalization for heart failure, possibly through glucose-independent mechanisms in part, but the underlying mechanisms remain largely unknown. This study aimed to shed light on the efficacy of dapagliflozin in reducing cardiac remodeling and potential mechanisms. METHODS: Sprague-Dawley (SD) rats, induced by chronic infusion of Angiotensin II (Ang II) at a dose of 520 ng/kg per minute for 4 weeks with ALZET® mini-osmotic pumps, were treated with either SGLT2 inhibitor dapagliflozin (DAPA) or vehicle alone. Echocardiography was performed to determine cardiac structure and function. Cardiac fibroblasts (CFs) were treated with Ang II (1 µM) with or without the indicated concentration (0.5, 1, 10 µM) of DAPA. The protein levels of collagen and TGF-ß1/Smad signaling were measured along with body weight, and blood biochemical indexes. RESULTS: DAPA pretreatment resulted in the amelioration of left ventricular dysfunction in Ang II-infused SD rats without affecting blood glucose and blood pressure. Myocardial hypertrophy, fibrosis and increased collagen synthesis caused by Ang II infusion were significantly inhibited by DAPA pretreatment. In vitro, DAPA inhibit the Ang II-induced collagen production of CFs. Immunoblot with heart tissue homogenates from chronic Ang II-infused rats revealed that DAPA inhibited the activation of TGF-ß1/Smads signaling. CONCLUSION: DAPA ameliorates Ang II-induced cardiac remodeling by regulating the TGF-ß1/Smad signaling in a non-glucose-lowering dependent manner.

Lanthanide-Binding Tags for 3D X-ray Imaging of Proteins in Cells at Nanoscale Resolution.

We report the application of lanthanide-binding tags (LBTs) for two- and three-dimensional X-ray imaging of individual proteins in cells with a sub-15 nm beam. The method combines encoded LBTs, which are tags of minimal size (ca. 15-20 amino acids) affording high-affinity lanthanide ion binding, and X-ray fluorescence microscopy (XFM). This approach enables visualization of LBT-tagged proteins while simultaneously measuring the elemental distribution in cells at a spatial resolution necessary for visualizing cell membranes and eukaryotic subcellular organelles.

2D MEMS-based multilayer Laue lens nanofocusing optics for high-resolution hard x-ray microscopy.

We report on the development of 2D integrated multilayer Laue lens (MLL) nanofocusing optics used for high-resolution x-ray microscopy. A Micro-Electro-Mechanical-Systems (MEMS) - based template has been designed and fabricated to accommodate two linear MLL optics in pre-aligned configuration. The orthogonality requirement between two MLLs has been satisfied to a better than 6 millidegrees level, and the separation along the x-ray beam direction was controlled on a micrometer scale. Developed planar 2D MLL structure has demonstrated astigmatism free point focus of ∼14 nm by ∼13 nm in horizontal and vertical directions, respectively, at 13.6 keV photon energy. Approaching 10 nm resolution with integrated 2D MLL optic is a significant step forward in applications of multilayer Laue lenses for high-resolution hard x-ray microscopy and their adoption by the general x-ray microscopy community.

Blocking Interleukin-1 Beta Reduces the Evolution of Thoracic Aortic Dissection in a Rodent Model.

OBJECTIVE: Thoracic aortic dissection (TAD) is associated with matrix changes, biochemical changes, and inflammatory markers like interleukin-1 beta (IL-1ß). However, the exact mechanism remains unknown. This study aimed to investigate the role of IL-1ß, matrix metalloproteinase (MMP)-2, MMP-9, smooth muscle cell apoptosis, and elastic fibre fracture in the development of TAD in a rat model. METHODS: The TAD rat model was induced by ß-aminopropionitrile (BAPN). TAD was investigated in 112 male Sprague-Dawley rats, which were equally divided into four groups of 28 rats (Control, BAPN, BAPN + IL-1ß, and BAPN + IL-1ß antibody). Systolic blood pressure, survival, and the development of TAD were measured after six weeks. Expression of IL-1ß, MMP-2, and MMP-9 was measured by Western blot. Apoptosis, aortic elastin concentration, and biomechanical characteristics were measured by the TdT mediated dUTP nick end labelling assay, Victoria blue staining, and in vitro testing. RESULTS: During six weeks, the mortality was 0% (0/28) in the control group, 53.6% (15/28) in the BAPN group (p < .001 compared with the control group), 75.0% (21/28) in the BAPN + IL-1ß group (p = .007 compared with the BAPN group), and 35.7% (10/28) in the BAPN + IL-1ß antibody group (p = .023 compared with BAPN group and p < .001 compared with the BAPN + IL-1ß group). IL-1ß treatment deteriorates BAPN induced mortality and aneurysm expansion, which were attenuated by anti-IL-1ß treatment. In BAPN + IL-1ß group, stress and strain parameters were decreased by 13.5%-53.5% and elastin content was decreased by 14%, and IL-1ß, MMP-2, and MMP-9 were expressed higher by 117%, 108%, and 75% when compared with the rats in the BAPN group. Contrarily, in the BAPN + IL-1ß antibody group, the above changes could be completely (strain, elastin content, and expression of MMP-2) or partly (elasticity modulus, stress, and expression of MMP-9) blocked by anti-IL-1ß treatment. CONCLUSION: IL-1ß plays a critical role in TAD formation by altering the expression of MMP-2 and MMP-9, degrading the aortic wall matrix, causing elastic fibre rupture, and changing the stress or strain of the aortic wall. Anti-IL-1ß reduces the later effects and could be one of the molecular targets for prognosis and drug treatment of TAD in the future.

Design, synthesis and identification of N, N-dibenzylcinnamamide (DBC) derivatives as novel ligands for α-synuclein fibrils by SPR evaluation system.

PET imaging of α-synuclein (α-syn) deposition in the brain will be an effective tool for earlier diagnosis of Parkinson's disease (PD) due to α-syn aggregation is the widely accepted biomarker for PD. However, the necessary PET radiotracer for imaging is clinically unavailable until now. The lead compound discovery is the first key step for the study. Herein, we initially established an efficient biologically evaluation system well in highthroughput based on SPR technology, and identified a novel class of N, N-dibenzylcinnamamide (DBC) compounds as α-syn ligands through the assay. These compounds were proved to have high affinities against α-syn aggregates (KD < 10 nM), which well met the requirement of binding activity for the PET probe. These DBC compounds were firstly reported as α-syn ligands herein and the preliminary obtained structure has been further modified into F-labeled ones. Among them, a high-affinity tracer (5-41) with 1.03 nM (KD) has been acquired, indicating its potential as a new lead compound for developing PET radiotracer.

Metrology of a Focusing Capillary Using Optical Ptychography.

The focusing property of an ellipsoidal monocapillary has been characterized using the ptychography method with a 405 nm laser beam. The recovered wavefront gives a 12.5×10.4µm2 focus. The reconstructed phase profile of the focused beam can be used to estimate the height error of the capillary surface. The obtained height error shows a Gaussian distribution with a standard deviation of 1.3 µm. This approach can be used as a quantitative tool for evaluating the inner functional surfaces of reflective optics, complementary to conventional metrology methods.

Extending the depth of field for ptychography using complex-valued wavelets.

Ptychography is a scanning variation of the coherent diffractive imaging method for providing high-resolution quantitative images from specimen with extended dimensions. Its capability of achieving diffraction-limited spatial resolution can be compromised by the sample thickness, which is generally required to be thinner than the depth of field of the imaging system. In this Letter, we present a method to extend the depth of field for ptychography by numerically generating the focus stack from reconstructions with propagated illumination wavefronts and combining the in-focus features to a single sharp image using an algorithm based on the complex-valued discrete wavelet transform. This approach does not require repeated measurements by translating the sample along the optical axis as in the conventional focus stacking method, and offers a computation-efficient alternative to obtain high-resolution images with extended depth of fields, complementary to the multi-slice ptychography.

Extending the depth of field for ptychography using complex-valued wavelets: publisher's note.

This publisher's note corrects an error in Eq. (3) of Opt. Lett.44, 503 (2019).OPLEDP0146-959210.1364/OL.44.000503.

Large Aperture and Wedged Multilayer Laue Lens for X-ray Nanofocusing.

Diffraction optics fabricated from multilayers offer an intriguing alternative to lithography-based zone plates due to their advantages of virtually limitless aspect ratio and extremely small feature size. However, other issues, intrinsic to thin-film deposition, such as film stress and deposition rate instability, for example, limit the total achievable aperture. Over the last decade, Multilayer Laue Lens (MLLs) have progressed from a mere curiosity with initial aperture sizes in the 3-10 µm range, to real beamline-deployed optics with apertures in the 40-50 µm range (X. Huang, et al., Scientific Reports 3, 3562 (2013); E. Nazaretski, et al., Rev. Sci. Instrum. 85, 033707 (2014); E. Nazaretski, et al., Journal of Synchrotron Radiation 24, 1113 (2017)). By optimizing deposition conditions and incorporating new materials, MLLs have now broken the 100 µm thickness milestone. A flat WSi2/Al-Si MLL with a deposition thickness of 102 µm, the largest MLL to date, is reviewed. New large aperture wedged MLLs (wMLL), which were first fabricated by APS in 2006 using the WSi2/Si material system, are presented which demonstrate high focusing efficiency across a broad energy range. These results confirm findings by other groups who have also independently fabricated wMLL (A. J. Morgan, et al., Scientific Reports 5, 9892 (2015); S. Bajt, et al., Nature Light: Science and Applications 7, 17162 (2017)) based on a similar material system.

Measuring Three-Dimensional Strain and Structural Defects in a Single InGaAs Nanowire Using Coherent X-ray Multiangle Bragg Projection Ptychography.

III-As nanowires are candidates for near-infrared light emitters and detectors that can be directly integrated onto silicon. However, nanoscale to microscale variations in structure, composition, and strain within a given nanowire, as well as variations between nanowires, pose challenges to correlating microstructure with device performance. In this work, we utilize coherent nanofocused X-rays to characterize stacking defects and strain in a single InGaAs nanowire supported on Si. By reconstructing diffraction patterns from the 21̅1̅0 Bragg peak, we show that the lattice orientation varies along the length of the wire, while the strain field along the cross-section is largely unaffected, leaving the band structure unperturbed. Diffraction patterns from the 011̅0 Bragg peak are reproducibly reconstructed to create three-dimensional images of stacking defects and associated lattice strains, revealing sharp planar boundaries between different crystal phases of wurtzite (WZ) structure that contribute to charge carrier scattering. Phase retrieval is made possible by developing multiangle Bragg projection ptychography (maBPP) to accommodate coherent nanodiffraction patterns measured at arbitrary overlapping positions at multiple angles about a Bragg peak, eliminating the need for scan registration at different angles. The penetrating nature of X-ray radiation, together with the relaxed constraints of maBPP, will enable the in operando imaging of nanowire devices.

Discovery and anti-inflammatory evaluation of benzothiazepinones (BTZs) as novel non-ATP competitive inhibitors of glycogen synthase kinase-3ß (GSK-3ß).

Glycogen synthase kinase-3ß (GSK-3ß) has been identified to promote inflammation and its inhibitors have also been proven to treat some inflammatory mediated diseases in animal models. Non-ATP competitive inhibitors inherently have better therapeutical value due to their higher specificity than ATP competitive ones. In this paper, we designed and synthesized a series of new BTZ derivatives as non-ATP competitive GSK-3ß inhibitors. Kinetic analysis revealed two typical compounds 6j and 3j showed the different non-ATP competitive mechanism of substrate competition or allosteric modulation to GSK-3ß, respectively. As expected, the two compounds showed good specificity in a panel test of 16 protein kinases, even to the closest enzymes, like CDK-1/cyclin B and CK-II. The in vivo results proved that both compounds can greatly attenuate the LPS-induced acute lung injury (ALI) and diminish inflammation response in mice by inhibiting the mRNA expression of IL-1ß and IL-6. Western blot analysis demonstrated that they negatively regulated GSK-3ß, and the mechanism of the observed beneficial effects of the inhibitors may involve both the increased phosphorylation of the Ser9 residue on GSK-3ß and protein expression of Sirtuin 1 (SIRT1). The results support that such novel BTZ compounds have a protective role in LPS-induced ALI, and might be attractive candidates for further development of inflammation pharmacotherapy, which greatly thanks to their inherently high selectivities by the non-ATP competitive mode of action. Finally, we proposed suggesting binding modes by Docking study to well explain the impacts of compounds on the target site.

Achieving diffraction-limited nanometer-scale X-ray point focus with two crossed multilayer Laue lenses: alignment challenges.

We discuss misalignment-induced aberrations in a pair of crossed multilayer Laue lenses used for achieving a nanometer-scale x-ray point focus. We thoroughly investigate the impacts of two most important contributions, the orthogonality and the separation distance between two lenses. We find that misalignment in the orthogonality results in astigmatism at 45° and other inclination angles when coupled with a separation distance error. Theoretical explanation and experimental verification are provided. We show that to achieve a diffraction-limited point focus, accurate alignment of the azimuthal angle is required to ensure orthogonality between two lenses, and the required accuracy is scaled with the ratio of the focus size to the aperture size.

Hard x-ray scanning imaging achieved with bonded multilayer Laue lenses.

We report scanning hard x-ray imaging with a monolithic focusing optic consisting of two multilayer Laue lenses (MLLs) bonded together. With optics pre-characterization and accurate control of the bonding process, we show that a common focal plane for both MLLs can be realized at 9.317 keV. Using bonded MLLs, we obtained a scanning transmission image of a star test pattern with a resolution of 50 × 50 nm2. By applying a ptychography algorithm, we obtained a probe size of 17 × 38 nm2 and an object image with a resolution of 13 × 13 nm2. The significant reduction in alignment complexity for bonded MLLs will greatly extend the application range in both scanning and full-field x-ray microscopies.

Electrochemical (de)lithiation of silver ferrite and composites: mechanistic insights from ex situ, in situ, and operando X-ray techniques.

The structure of pristine AgFeO2 and phase makeup of Ag0.2FeO1.6 (a one-pot composite comprised of nanocrystalline stoichiometric AgFeO2 and amorphous γ-Fe2O3 phases) was investigated using synchrotron X-ray diffraction. A new stacking-fault model was proposed for AgFeO2 powder synthesized using the co-precipitation method. The lithiation/de-lithiation mechanisms of silver ferrite, AgFeO2 and Ag0.2FeO1.6 were investigated using ex situ, in situ, and operando characterization techniques. An amorphous γ-Fe2O3 component in the Ag0.2FeO1.6 sample is quantified. Operando XRD of electrochemically reduced AgFeO2 and Ag0.2FeO1.6 composites demonstrated differences in the structural evolution of the nanocrystalline AgFeO2 component. As complimentary techniques to XRD, ex situ X-ray Absorption Spectroscopy (XAS) provided insight into the short-range structure of the (de)lithiated nanocrystalline electrodes, and a novel in situ high energy X-ray fluorescence nanoprobe (HXN) mapping measurement was applied to spatially resolve the progression of discharge. Based on the results, a redox mechanism is proposed where the full reduction of Ag+ to Ag0 and partial reduction of Fe3+ to Fe2+ occur on reduction to 1.0 V, resulting in a Li1+yFeIIIFeIIyO2 phase. The Li1+yFeIIIFeIIyO2 phase can then reversibly cycle between Fe3+ and Fe2+ oxidation states, permitting good capacity retention over 50 cycles. In the Ag0.2FeO1.6 composite, a substantial amorphous γ-Fe2O3 component is observed which discharges to rock salt LiFe2O3 and Fe0 metal phase in the 3.5-1.0 V voltage range (in parallel with the AgFeO2 mechanism), and reversibly reoxidizes to a nanocrystalline iron oxide phase.

[Changes in 25-hydroxyvitamin D3 level in children with Henoch-Schönlein purpura].

OBJECTIVE: To examine the changes in 25-hydroxyvitamin D3 [25-(OH)D3] level in children with Henoch-Schönlein purpura (HSP) and its clinical significance. METHODS: A total of 92 HSP children were included in this study, and were divided into HSP nephritis (HSPN) group (31 cases) and HSP group (61 cases) based on the presence or absence of HSPN. Alternatively, the patients were divided into purpura alone group (22 cases), purpura with joint symptoms group (joint symptom group, 24 cases), purpura with gastrointestinal symptoms group (gastrointestinal symptom group, 20 cases), and purpura with joint and gastrointestinal symptoms (mixed group, 26 cases) based on their clinical symptoms. In addition, 42 healthy children were selected as healthy control group. The level of 25-(OH)D3 in each group was measured using enzyme-linked immunoassay. RESULTS: The 25-(OH)D3 level in the HSP and HSPN groups was significantly lower than that in the healthy control group (P<0.05), and the 25-(OH)D3 level in the HSPN group was significantly lower than that in the HSP group (P<0.05). Although there was no significant difference in the 25-(OH)D3 level between the joint symptom, gastrointestinal symptom, and mixed groups (P=0.22), the 25-(OH)D3 level in the three groups was all significantly lower than that in the purpura alone group (P<0.05). CONCLUSIONS: The level of 25-(OH)D3 is reduced in children with HSP, particularly those with HSPN or with joint and gastrointestinal symptoms. Therefore, the reduction in 25-(OH)D3 level may serve as a predictor of whether HSP is associated with other impairments.