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Nesfatin-1 is a neuropeptide produced in the hypothalamus. It is known that Nesfatin-1 is involved in food uptake, fat storage, and other metabolic regulation. We hypothesized that Nesfatin-1 may play a role in cardiovascular tissue. Free fatty acids (FFAs) are known to be the risk factor for cardiovascular diseases. FFA-mediated endothelial dysfunction is the critical mechanism of many cardiovascular disorders. The present study explores the protective effects of Nesfatin-1 on FFA-induced endothelial inflammation and the underlying mechanism. We found that significantly increased lactate dehydrogenase release and production of inflammatory factors were observed in FFA-treated human aortic endothelial cells (HAECs), accompanied by the enhanced attachment of U937 monocytes to HAECs and upregulated cell adhesion molecule vascular cell adhesion molecule-1, which were dramatically reversed by the treatment with Nesfatin-1. In addition, the promoted level of nuclear regulator NF-κB p65 and transcriptional function of NF-κB in FFA-treated HAECs were greatly suppressed by HAECs. Growth Factor Independent 1 Transcriptional Repressor 1 (Gfi1), an important negative regulator of NF-κB activity, was significantly downregulated in HAECs by FFAs and was upregulated by Nesfatin-1. Lastly, the inhibitory effects of Nesfatin-1 against FFA-induced NF-κB activation and adhesion of U937 monocytes to HAECs were abolished by the knockdown of Gfi1. In conclusion, our data reveal that Nesfatin-1 inhibited FFA-induced endothelial inflammation mediated by the Gfi1/NF-κB signaling pathway.

A smart in situ-formed wound dressing with excellent antibacterial ability against drug-resistance bacterial, antitumor, and biofilm-eliminating activities to promote effective wound closure is highly desirable in therapeutic and clinical applications. Herein, we designed and developed a multifunctional; shape-adaptable; and pH, temperature, and near-infrared radiation (NIR) multiple responsive cellulose nanofibril (CNF)-based in situ liquid wound dressing, using a pH-sensitive CNF grafted with terminated amino hyperbranched polyamines (HBP-NH2) as a substrate, along with poly(N-isopropylacrylamide) and indocyanine green (ICG) loaded as the temperature and NIR on/off switches, respectively. The 3D nanocage network structure of CNF and the nanocavities in the hyperbranched structure of HBP-NH2 endow the dressing with a high loading capacity for active drugs (doxorubicin and ICG) simultaneously. Moreover, the responsiveness of the dressing to multiple stimuli enables controllable and efficient drug release to the wound area. The bioinspired dressing demonstrates excellent antibacterial activity against common bacteria and methicillin-resistant Staphylococcus aureus, antitumor activity against A375 tumor cells, and biofilm-eliminating capability. In addition, the developed dressing synergistically combines multiple therapeutic strategies for effective wound healing, specifically photothermal therapy, photodynamic therapy, and chemotherapy. The design provides an ideal clinical intervention strategy for irregular tumor postoperative infected wounds.

Pulmonary fibrosis (PF) is a chronic and progressively fatal disease, but clinically available therapeutic drugs are limited due to efficacy and side effects. The possible mechanism of pulmonary fibrosis includes the damage of alveolar epithelial cells II (AEC2), and activation of immune cells such as macrophages. The ions released from bioceramics have shown the activity in stimulating soft tissue derived cells such as fibroblasts, endothelia cells and epithelia cells, and regulating macrophage polarization. Therefore, this study proposes an “ion therapy” approach based on the active ions of bioceramic materials, and investigates the therapeutic effect of bioactive ions derived from calcium silicate (CS) bioceramics on mouse models of pulmonary fibrosis. We demonstrate that silicate ions significantly reduce pulmonary fibrosis by simultaneously regulating the functions of AEC2 and macrophages. This result suggests potential clinical applications of ion therapy for lung fibrosis., Graphical abstract Image 1, Highlights ● A novel treatment of pulmonary fibrosis based on ion therapy using bioactive ionic solution derived from silicate bioceramics (CS) was demonstrated. ● CS solution can stimulate the alveolar epithelial cells to repair damaged lung tissue. ● CS solution can regulate immune cells to inhibit inflammatory factor secretion and reduce the number of inflammatory cells in lung tissue.

Background and Purpose: Intracerebral hemorrhage (ICH) is a devastating subtype of stroke with high mortality and disability. Inflammatory response promotes secondary brain injury after ICH. TREM (triggering receptor expressed on myeloid cells)-1 is a key regulator of inflammation. The aim of this study was to evaluate the role of TREM-1 in neuroinflammatory response after ICH in mice. Methods: CD1 mice (n=275) were used in this study. Mice were subjected to ICH by autologous blood injection. TREM-1 knockout CRISPR was administered intracerebroventricularly to evaluate the role of TREM-1 after ICH. A selective TREM-1 inhibitor, LP17, was administered intranasally 2 hours after ICH. To elucidate TREM-1 signaling pathway, CARD9 (caspase recruitment domain family member 9) activation CRISPR was administered with LP17 and TREM-1 activating anti-mouse TREM-1 monoclonal antibody (mAb) was administered with Rottlerin, a specific PKC (protein kinase C) δ inhibitor. Lastly, to evaluate the role of HMGB1 (high-mobility group box 1) in TREM-1 mediated microglia activation, glycyrrhizin, an inhibitor of HMBG1 was administered with TREM-1 activating mAb. Neurobehavioral test, brain water content, Western blot, immunofluorescence staining, and coimmunoprecipitation was performed. Results: TREM-1 knockout reduced ICH-induced neurobehavioral deficits and neuroinflammatory response. The temporal expression of HMGB1, TREM-1, PKC δ, and CARD9 increased after ICH. TREM-1 was expressed on microglia. Intranasal administration of LP17 significantly decreased brain edema and improved neurobehavioral outcomes at 24 and 72 hours after ICH. LP17 promoted M2 microglia polarization and reduced proinflammatory cytokines after ICH, which was reversed with CARD9 activation CRISPR. TREM-1 mAb increased neurobehavior deficits, proinflammatory cytokines, and reduced M2 microglia after ICH, which was reversed with Rottlerin. HMBG1 interaction with TREM-1 increased after ICH, and glycyrrhizin reduced neuroinflammation and promoted M2 microglia which was reversed with TREM-1 mAb. Conclusions: This study demonstrated that TREM-1 enhanced neuroinflammation by modulating microglia polarization after ICH, and this regulation was partly mediated via PKC δ/CARD9 signaling pathway and increased HMGB1 activation of TREM-1.

Novel lanthanide boride complexes with unique structural and bonding patterns have been observed in recent experiments. Based on extensive first-principles theory calculations, we predict herein the possible existence of half-sandwich C2v LaB14− (1), C1 LaB15 (2), C5v LaB16− (3), and Cs LaB17 (4) which all contain a La center coordinated by a bowl-like Bn ligand (n = 14–17). Detailed bonding analyses indicate that effective d-p coordination interactions exist between the La center and Bn ligand, making these half-sandwich complexes π dually aromatic in nature. Energy decomposition analyses reveal that electrostatic (50.2%) and covalent (49.8%) interactions contribute almost equally to the overall attraction in LaB14− (1), with the La centre serving as both electron donor and acceptor. Molecular dynamics simulations show that both LaB14− (1) (La[B4©B10]−) and LaB17 (4) (La[B©B5©B11]) with multicenter fluxional bonds behave like Wankel motors at finite temperatures.

Cage-like metallo-borospherenes exhibit unique structures and bonding. Inspired by the newly reported smallest spherical trihedral metallo-borospherene D3h Ta3B12– (1), which contains two equivalent B3 triangles interconnected by three B2 units on the cage surface, we present herein a first-principles theory prediction of the perfect spherical tetrahedral metallo-borospherene Td Ta4B18 (2), which possesses four equivalent B3 triangles interconnected by six B atoms, with four equivalent nonacoordinate Ta centers in four η9-B9 rings as integrated parts of the cage surface. As the well-defined global minimum of the neutral, Ta4B18 (2) possesses four 10c-2e B9(π)–Ta(dσ) and eight 10c-2e B9(π)–Ta(dδ) coordination bonds evenly distributed over four Ta-centered Ta@B9 nonagons, with the remaining 18 valence electrons in nine 22c-2e totally delocalized bonds following the 18-electron principle (1S21P61D10) of a superatom. Such a bonding pattern renders spherical aromaticity to the tetrahedral complex, which can be used as building blocks to form the face-centered cubic crystal Ta4B15 (3). The IR, Raman, and UV–vis spectra of Ta4B18 (2) are theoretically simulated to facilitate its future experimental characterizations.

Label-free radiation pressure force analysis using a microfluidic platform is applied to the differential detection of innate immune cell activation. Murine-derived peritoneal macrophages (IC-21) are used as a model system and the activation of IC-21 cells by lipopolysaccharide (LPS) and interferon gamma (IFN-γ) to M1 pro-inflammatory phenotype is confirmed by RNA gene sequencing and nitric oxide production. The mean cell size determined by radiation pressure force analysis increases slightly after the activation (4 to 6%) and the calculated percentage of population overlaps between the control and the activated group after 14 and 24 h stimulations are at 79% and 77%. Meanwhile the mean cell velocity decreases more significantly after the activation (14% to 15%) and the calculated percentage of population overlaps between the control and the activated group after 14 and 24 h stimulations are only at 14% and 13%. The results demonstrate that the majority of the activated cells acquire a lower velocity than the cells from the control group without changes in cell size. For comparison label-free flow cytometry analysis of living IC-21 cells under the same stimulation conditions are performed and the results show population shifts towards larger values in both forward scatter and side scatter, but the calculated percentage of population overlaps in all case are significant (70% to 83%). Cell images obtained during radiation pressure force analysis by a CCD camera, and by optical microscopy and atomic force microscopy (AFM) reveal correlations between the cell activation by LPS/IFN-γ, the increase in cell complexity and surface roughness, and enhanced back scattered light by the activated cells. The unique relationship predicted by Mie's theory between the radiation pressure force exerted on the cell and the angular distribution of the scattered light by the cell which is influenced by its size, complexity, and surface conditions, endows the cell velocity based measurement by radiation pressure force analysis with high sensitivity in differentiating immune cell activation.

Aim Although Clopidogrel is safe in healthy volunteers, it can induce recurrence of gastric ulcers in high-risk patients. Here, we investigated the protective effect of the natural product, stable gastric pentadecapeptide 157 (BPC 157) on Clopidogrel-induced gastric injury. Methods We used acetic acid to induce gastric ulcer in Sprague Dawley rats. Clopidogrel alone or in combination with BPC 157 or L-NAME (nitric oxide system blockade) were administered after healing of acetic acid-induced ulcer. One percent methylcellulose solution was used as control. Ulcer recurrence rate and the ulcer index were compared between these groups. Gastric mucosal apoptosis rate, microscopic inflammation activity and angiogenesis markers vascular endothelial growth factor A (VEGF-A) and CD34 were examined by TUNEL, histological evaluations (HE) and immunohistochemistry (IHC). Pathways involved, expressions of endoplasmic reticulum (ER) stress apoptosis marker CHOP, angiogenic markers VEGF-A and its receptor VEGFR1, and endothelial NO synthase (eNOS) were all analyzed by Western blot. Results This study indicated that Clopidogrel significantly induced the gastric ulcers recurrence, severe inflammation and ER stress related apoptosis of the gastric mucosa, suppressed the synthesis of angiogenic markers and eNOS. Furthermore, Clopidrogel intervention resulted in the activation of protein kinase B (AKT) and p38 mitogen-activated protein kinase (p38/MAPK). BPC 157 attenuated the gastric mucosal damage caused by Clopidogrel and reversed these molecular effects. However, NO blockade L-NAME weakened the protective effect and thus the molecular effects of BPC 157 on gastric mucosa. Conclusion In conclusion, these results suggest that BPC 157 inhibited Clopidogrel-induced gastric mucosa injury partially by inhibition of gastric mucosa cell ER stress-mediated apoptosis and inflammation, and promoting gastric mucosa angiogenesis via VEGF-A/VEGFR1 mediated-AKT/p38/MAPK signaling pathways.

Quercetin and crocin are the main active constituents of Eucommia and Gardenia species, respectively. This study was conducted to explore the effects of quercetin and crocin on fat reduction and renal fibrosis and the relationship of these compounds with autophagy. First, a model of high-fat diet- and streptozotocin-induced type 2 diabetes was established and then subjected model animals to 8 weeks of metformin, quercetin and crocin gavage. Then, a high glucose-induced rat mesangial cells (RMCs) model was established, and these cells were cocultured with quercetin and crocin. The results showed that quercetin and crocin can decrease fasting blood glucose levels, reduce fat accumulation in the liver, alleviate renal fibrosis, and reduce blood lipid levels. Quercetin and crocin increased autophagy-related protein (LC3, Atg5, Beclin-1 and p-AMPK) levels in the liver and decreased autophagy-related protein (LC3, Atg5, Beclin-1 and p-AMPK) levels in the kidneys. Moreover, quercetin and crocin inhibited the excessive proliferation of RMCs induced by high-glucose (HG) conditions, decreased autophagy-related protein (LC3, Atg5, Beclin-1 and p-AMPK) levels, and decreased TGF-β1 expression. Importantly, cotreatment with quercetin and crocin had a more significant effect than treatment with either compound alone. These results suggest that combined administration of quercetin and crocin can more significantly reduce blood glucose/lipid levels and improve renal fibrosis than administration of either compound alone and that AMPK-dependent autophagy might be involved in this process. Eucommia ulmoides Oliv. and Gardenia could be developed as drugs for Type 2 diabetes treatment.

A biomass bagasse-based hyperbranched adsorbent (BF/HBPA) with high amino density was synthesized using epichlorohydrin (ECH) to cross-link hyperbranched polyamine (HBP-NH2) with bagasse fibre powder (BF). Using this kind of “cross-linking” procedure to synthesize the bagasse-based hyperbranched adsorbent could overcome the disadvantages of the low amino density in the stepwise grafting process, avoiding the requirement of strict preparation conditions and a complicated synthesis process. Thus, the as-prepared BF/HBPA could completely remove low-level Cr(VI) (1.6 mg/L), and showed an outstanding adsorption capacity (330.7 mg/g) for Cr(VI) at high Cr(VI) concentrations (108.3 mg/L) under 30 °C and pH value of 2. BF, as the framework of BF/HBPA cross-linking network, enhanced the adsorption rate (arrived at adsorption equilibrium in 15 min) for Cr(VI) on BF/HBPA. Moreover, BF/HBPA showed a promising regeneration property. After reusing for 10 cycles, the removal rate of BF/HBPA was maintained above 96%. The adsorption mechanism of physical electrostatic adsorption, chemical chelating adsorption and oxidation-reduction were all attributed to the complete removal of low-level Cr(VI) to the Safe Drinking Level (US EPA) (0.05 mg/L).

Painted environmental surfaces are prone to microbiological colonization with potential coating deterioration induced by the microorganisms. Accurate mechanistic models of these interactions require an understanding of the heterogeneity in which the deterioration processes proceed. Here, unsaturated biofilms (i.e., at air/solid interfaces) of the yeast Papiliotrema laurentii were prepared on polyether polyurethane (PEUR) and polyester-polyether polyurethane (PEST-PEUR) coatings and incubated for up to 33 days at controlled temperature and humidity with no additional nutrients. Transmission micro-Fourier transform infrared microscopy (μFTIR) confirmed preferential hydrolysis of the ester component by the biofilm. Atomic force microscopy combined with infrared nanospectroscopy (AFM-IR) was used to analyze initial PEST-PEUR coating deterioration processes at the single-cell level, including underlying surfaces that became exposed following cell translocation. The results revealed distinct deterioration features that remained localized within ∼10 μm or less of the edges of individual cells and cell clusters. These features comprised depressions of up to ∼300 nm with locally reduced ester/urethane ratios. They are consistent with a formation process initiated by enzymatic ester hydrolysis followed by erosion from water condensation cycles. Further observations included particle accumulation in the broader biofilm vicinity. AFM-IR spectroscopy indicated these to be secondary microplastics consisting of urethane-rich oligomeric aggregates. Overall, multiple contributing factors have been identified that can facilitate differential deterioration rates across the PEST-PEUR surface. Effects of the imposed nutrient conditions on Papiliotrema laurentii physiology were also apparent, with cells developing the characteristics of starvation response, despite the availability of polyester metabolites as a carbon source. The combined results provide new laboratory insights into field-relevant microbiological polymer deterioration mechanisms and biofilm physiology at polymer coating interfaces.

La-doped boron nanoclusters have received considerable attention due to their unique structures and bonding. Inspired by recent experimental observations of the inverse sandwich D8h La2B8 (1) and triple-decker C2v La3B14− (2) and based on extensive global searches and first-principles theory investigations, we present herein the possibility of the perfect cubic La-doped boron clusters Oh La6&[La@B24]+ (3, 1A1g) and Oh La6&[La@B24] (4, 2A2g) which appear to be the embryos of the metallic one-dimensional La10B32 (5) nanowire, two-dimensional La3B10 (6) nanosheet, and three-dimensional LaB6 (7) nanocrystal, facilitating a bottom-up approach to build cubic lanthanide boride nanostructures from gas-phase clusters. Detailed molecular orbital and bonding analyses indicate that effective (d–p)σ, (d–p)π and (d–p)δ covalent coordination interactions exist in La6&[La@B24]+/0 (3/4) clusters, while the 1D La10B32 (5), 2D La3B10 (6), and 3D LaB6 (7) crystals exhibit mainly electrostatic interactions between the trivalent La centers and cubic B24 frameworks, with weak but discernible coordination contributions from La (5d) ← B (2p) back-donations. The IR and Raman spectra of La6&[La@B24]+/0 (3/4) and band structures of La10B32 (5) and La3B10 (6) are computationally simulated to facilitate their future characterizations.

Objectives The association between outcome and kidney injury detected at discharge from the ICU using different biomarkers remains unknown. The objective was to evaluate the association between 1-year survival and kidney injury at ICU discharge. Design Ancillary investigation of a prospective observational study. Setting Twenty-one ICUs with 1-year follow-up. Patients Critically ill patients receiving mechanical ventilation and/or hemodynamic support for at least 24 hours were included. Interventions Serum creatinine, plasma Cystatin C, plasma neutrophil gelatinase-associated lipocalin, urinary neutrophil gelatinase-associated lipocalin, plasma Proenkephalin A 119-159, and estimated glomerular filtration rate (on serum creatinine and plasma Cystatin C) were measured at ICU discharge among ICU survivors. Measurements and main results The association between kidney biomarkers at discharge and mortality was estimated using logistic model with and without adjustment for prognostic factors previously identified in this cohort. Subgroup analyses were performed in patients with discharge serum creatinine less than 1.5-fold baseline at ICU discharge. Among 1,207 ICU survivors included, 231 died during the year following ICU discharge (19.2%). Estimated glomerular filtration rate was significantly lower and kidney injury biomarkers higher at discharge in nonsurvivors. The association between biomarker levels or estimated glomerular filtration rate and mortality remained after adjustment to potential cofounding factors influencing outcome. In patients with low serum creatinine at ICU discharge, 25-47% of patients were classified as subclinical kidney injury depending on the biomarker. The association between kidney biomarkers and mortality remained and mortality was higher than patients without subclinical kidney injury. The majority of patients who developed acute kidney injury during ICU stay had elevated biomarkers of kidney injury at discharge even with apparent recovery based on serum creatinine (i.e., subclinical acute kidney disease). Conclusions Elevated kidney biomarkers measured at ICU discharge are associated with poor 1-year outcome, including in patients with low serum creatinine at ICU discharge.

BRCA1, a multifunctional protein with an important role in DNA double‐strand break repair by homologous recombination (HR), is subjected to ubiquitin‐dependent degradation. To date, several E3 ubiquitin ligases have been identified to govern BRCA1 stability, but the deubiquitinase that counteracts its turnover remains undefined. In this study, we report that the ubiquitin‐specific protease 9X (USP9X) is a bona fide deubiquitinase for BRCA1 in human cancer cells. Reciprocal immunoprecipitation assays demonstrated that USP9X interacted with BRCA1. Depletion of USP9X by short interfering RNAs or inhibition of USP9X by the small‐molecular inhibitor WP1130 significantly reduced BRCA1 protein abundance, without affecting its mRNA levels. In contrast, overexpression of wild‐type USP9X, but not its deubiquitinase activity‐defective mutant (C1566S), resulted in an upregulation of BRCA1 protein levels. Moreover, USP9X depletion reduced the half‐life of BRCA1, accompanied by an increase in its ubiquitination. HR assays showed that knockdown of USP9X significantly reduced HR efficiency, which was partially rescued by reintroduction of BRCA1 into USP9X‐depleted cells. In support of these findings, USP9X knockdown significantly enhanced sensitivity to PARP inhibitor Olaparib and methyl methanesulfonate (MMS). Collectively, these results establish USP9X as a deubiquitinase for BRCA1 and reveal a previously unrecognized role of USP9X in the regulation of HR repair and the sensitivity of cancer cells to DNA‐damaging agents., In this study, we identified USP9X as the first deubiquitinase of BRCA1. Consequently, USP9X regulates BRCA1‐mediated HR repair and confers resistance to DNA‐damaging agents in human cancer cells.

With eco-friendly and sustainable CO2 -derived dimethyl carbonate as the sole solvent, the visible-light-induced cascade radical reactions have been established as a green and efficient tool for constructing various CHF2 /CClF2 /CBrF2 -substituted ring-fused quinazolinones.

A noninvasive fiber material-based wearable electrochemical sensor to continuously monitor the glucose level in sweat is highly desirable for smart fabrics for personal diabetes management. To achieve it, the key challenge is to construct fibers with high stretchability and excellent electrochemical performance. Herein, a highly stretchable Ni-Co metal-organic framework/Ag/reduced graphene oxide/polyurethane (Ni-Co MOF/Ag/rGO/PU) fiber-based wearable electrochemical sensor is fabricated for monitoring the glucose level in sweat continuously with high sensitivity and accuracy. The rGO/PU fiber was simply produced by an improved wet spinning technology, and the Ni-Co MOF nanosheet was coated on its surface to prepare the Ni-Co MOF/Ag/rGO/PU (NCGP) fiber electrode. The Ni-Co MOF has a large specific surface area and high catalytic activity, which enables the fiber sensors with good electrochemical performance with a high sensitivity of 425.9 μA·mM-1·cm-2 and a wide linear range of 10 μM-0.66 mM. More importantly, the NCGP fiber electrode also shows extremely high stretching and bending stability under mechanical deformation. Also, the NCGP fiber electrode has high selectivity and long-time storage stability. Moreover, the NCGP fiber-based three-electrode system was sewn with an absorbent fabric and fixed on a stretchable polydimethylsiloxane film substrate to form a nonenzymatic sweat glucose wearable sensor, which realized real-time monitoring of glucose in human sweat with high accuracy. This indicates that our designed NCGP fiber can be used as a wearable electrochemical sensor for the bio-diagnostics of body sweat.

China is a big country in the production and consumption of rice in the world. However, for a long time, China's rice processing is only in the primary processing state that meets people's demand for rations, and the level of comprehensive utilization of deep processing and its by-products is low. This paper reviews the main raw and by-products of rice, such as rice protein, rice starch and by-products of rice processing (including broken rice, rice bran and rice husk), aiming to further improve the comprehensive utilization of rice resources and increase the added value of rice and its by-products to create more economic and social benefits. The vigorously developing and promoting the deep processing technology of rice and its by-products will extend the rice industry chain and greatly increasing the added value of rice, make full use of resources to supplement the shortage of high-quality edible oil, protein, starch and other products.

Delivery of therapeutics into the solid tumor microenvironment is a major challenge for cancer nanomedicine. Administration of certain exogenous enzymes which deplete tumor stromal components has been proposed as a method to improve drug delivery. Here we present a protein-free collagen depletion strategy for drug delivery into solid tumors, based on activating endogenous matrix metalloproteinases (MMP-1 and -2) using nitric oxide (NO). Mesoporous silica nanoparticles (MSN) were loaded with a chemotherapeutic agent, doxorubicin (DOX) as well as a NO donor ( S-nitrosothiol) to create DN@MSN. The loaded NO results in activation of MMPs which degrade collagen in the tumor extracellular matrix. Administration of DN@MSN resulted in enhanced tumor penetration of both the nanovehicle and cargo (DOX), leading to significantly improved antitumor efficacy with no overt toxicity observed.

Lanthanide-boron binary clusters possess interesting structures and bonding which may provide insights into designing new boride nanomaterials. Inspired by the recently discovered mono-decker inverse sandwich D9h La2B9- (1A'1) (1) and based on the extensive first-principles theory calculations, we predict herein the possible existence of a series of bi-decker inverse sandwich di-lanthanide boron complexes including D9d La2[B18] (3A1g) (2), D9d La2[B18]2- (1A1g) (3), and C2h La2[B2@B18] (1Ag) (4) which all contain a tubular Bn ligand (n = 18, 20) sandwiched by two La atoms at the two ends. In these novel clusters, La2[B2@B18] (4) as a tubular molecular rotor with the smallest core-shell structure reported to date in boron-based nanoclusters possesses a B2-bar rotating constantly and almost freely inside the B18 tube around it at room temperature. Detailed bonding analyses indicate that these complexes are stablized by effective (d-p)σ, (d-p)π, and (d-p)δ coordination interactions between the La centers and Bn bi-decker ligand. Six multi-center fluxional σ-bonds between the B2-core and B18 tube in La2[B2@B18] (4) are found to be responsible for its unique fluxional behaviors. The IR and Raman spectra of the concerned species are simulated to facilitate their experimental characterization.

Cage-like and core-shell metallo-borospherenes exhibit interesting structures and bonding. Based on extensive global searches and first-principles theory calculations, we predict herein the perfect tetrahedral cage-like Td La4B24 (1) and core-shell Td La4B29 (2), Td La4B29+ (3), and Td La4B29- (4) which all possess the same geometrical symmetry as their carbon fullerene counterpart Td C28, with four equivalent interconnected B6 triangles on the cage surface and four nona-coordinate La centers in four conjoined η9-B9 rings. In these tetra-La-doped boron complexes, La4[B@B4@B24]0/+/- (2/3/4) in the structural motif of 1+4+28 contain a B-centered tetrahedral Td B@B4 core in a La-decorated tetrahedral La4B24 shell, with the negatively charged tetra-coordinate B- at the center being the boron analog of tetrahedral C in Td CH4 (B-~C). Detailed orbital and bonding analyses indicate that these Td lanthanide boride complexes are spherically aromatic in nature with a universal La--B9 (d-p) σ and (d-p) δ coordination bonding pattern. The IR, Raman, and UV-Vis or photoelectron spectra of these novel metallo-borospherenes are computationally simulated to facilitate their spectral characterizations.

A CRISPR-Cas–driven positive feedback circuit with exponential dynamic enables ultrasensitive detection of genomic DNA., Artificial nucleic acid circuits with precisely controllable dynamic and function have shown great promise in biosensing, but their utility in molecular diagnostics is still restrained by the inability to process genomic DNA directly and moderate sensitivity. To address this limitation, we present a CRISPR-Cas–powered catalytic nucleic acid circuit, namely, CRISPR-Cas–only amplification network (CONAN), for isothermally amplified detection of genomic DNA. By integrating the stringent target recognition, helicase activity, and trans-cleavage activity of Cas12a, a Cas12a autocatalysis-driven artificial reaction network is programmed to construct a positive feedback circuit with exponential dynamic in CONAN. Consequently, CONAN achieves one-enzyme, one-step, real-time detection of genomic DNA with attomolar sensitivity. Moreover, CONAN increases the intrinsic single-base specificity of Cas12a, and enables the effective detection of hepatitis B virus infection and human bladder cancer–associated single-nucleotide mutation in clinical samples, highlighting its potential as a powerful tool for disease diagnostics.

Background: Paclitaxel, a natural diterpenoid compound, has anti-tumor effect by acting on tubulin, whereas coumarin, another kind of natural product, has anti-tumor effect, along with some other effects, such as anti-bacterial-., Moreover, it also possesses fluorescence. Objective: Multi targeting is an effective strategy in drug design to combat tumor. Therefore, a combination of paclitaxel with other active molecular drugs for exploring the novel lead with multi-functions is in demand. Materials and Methods: To synthsize paclitaxel-coumarin conjugate via click chemistry and to investigate anticancer activity by MTT assay and the scratch test. Results and Discussion: The results of MTT assay showed that compared tothe paclitaxel, the anti-tumor activity of the conjugate was significantly improved. The results of flow cytometry showed that the conjugate had a stronger ability to induce apoptosis. The scratch test results showed that the conjugate had better anti- metastasis ability than paclitaxel. Conclusion: These findings indicated that paclitaxel and coumarin had a synergistic effect, which paved the way for the development of paclitaxel through fluorescence.

The current study aimed to investigate whether sarpogrelate and rosuvastatin possess anti-arterial injury, and attempted to elucidate the mechanism of action underlying this activity. Sarpogrelate, a 5-hydroxytryptamine type 2A antagonist, is extensively used to prevent arterial thrombosis; however, its effects on atherosclerosis remain unknown. In the present study, sarpogrelate combined with rosuvastatin or rosuvastatin alone were administered to male ApoE-/- mice fed a high-fat diet (HFD) for 8 weeks. Metabolic parameters in the blood samples were analyzed using an automatic analyzer. Aortic tissues were stained with hematoxylin and eosin for morphological analysis. The expression levels of oxidized-low density lipoprotein (LDL) specific scavenging receptors, lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and cluster of differentiation 68 were detected via immunostaining. mRNA expression levels of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α were determined via reverse transcription-quantitative PCR analysis, while protein expression levels of LOX-1 and phosphor(p)-ERK were determined via western blot analysis. The results demonstrated that sarpogrelate combined with rosuvastatin treatment significantly decreased total cholesterol and LDL cholesterol levels in the serum, and alleviated intimal hyperplasia and lipid deposition, accompanied by decreased inflammatory cell infiltration and lower expression levels of inflammatory cytokines, compared with rosuvastatin monotherapy or HFD treatment. Furthermore, sarpogrelate combined with rosuvastatin treatment significantly decreased the expression levels of LOX-1 and p-ERK. Taken together, these results suggest that the positive effects of sarpogrelate combined with rosuvastatin treatment on aortic injury may be associated with the regulation of the LOX-1/p-ERK signaling pathway. Sarpogrelate and rosuvastatin synergistically decreased aortic damage in ApoE-/- HFD mice, and thus provide a basis for the treatment of aortic injury caused by hyperlipidemia with sarpogrelate.

Through a solvothermal reaction between the corresponding nickel(II) sulfate, π-electron rich tri-carboxylate ligand 4-(2′,3′-dicarboxylphenoxy) benzoic acid (H3L) and 1,2-bis (4-pyridyl) ethylene (bpe) molecule, a novel three-dimensional (3D) nickel-based coordination polymer (Ni-CP), namely [Ni3(L)2(bpe)3(H2O)4]·(H2O)6 (1) was successfully constructed. The structure was established by single-crystal X-ray diffraction, which reveals that 1 features a new 3,4,4-connected topology with the point symbol of (105·12) (4·102)2 (4·85)2. Subsequently, some studies on optical properties of compound 1 were carried out. Interestingly, the results suggest that compound 1 exhibits excellent applications as a fluorescent sensor for the recognition of Hacac via a fluorescence quenching approach. The detection limit can be as low as 10.19 µM. The possible mechanisms of the fluorescence turn-off effect were also discussed in detail. This work presents a case for monitoring Hacac concentrations in water samples.

A novel Cu(II) coordination polymer (compound 1) formulated as [Cu(HL)(bpy)]·H2O (H3L = 4-(2′,3′-Dicarboxylphenoxy) benzoic acid, bpy = 2,2′-bipyridine) has been successfully prepared via solvothermal methods and characterized by structural analyses. Crystallographic research reveals that compound 1 exhibits a 1D metal-carboxylate chain, which self-assembles into a final 3D supramolecular network through the interchain hydrogen bonds. Further investigation indicates that compound 1 possesses excellent chemical stability. It maintains good stability in various solvents and aqueous solution with pH range of 2–11 for two weeks. The luminescence investigations manifest that compound 1 can be used as a multi-responsive fluorescence sensor for sensing acetylacetone (Hacac), CrO42− and Cr2O72− with high selectivity, sensitivity and excellent anti-interference ability through luminescence quenching. Furthermore, the probable mechanisms of selective detection have been explored in detail.

Brain edema is a vital contributor to early brain injury after subarachnoid hemorrhage (SAH), which is responsible for prolonged hospitalization and poor outcomes. Pharmacological therapeutic targets on edema formation have been the focus of research for decades. Pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to participate in neural development and brain injury. Here, we used PACAP knockout CRISPR to demonstrate that endogenous PACAP plays an endogenous neuroprotective role against brain edema formation after SAH in rats. The exogenous PACAP treatment provided both short- and long-term neurological benefits by preserving the function of the blood–brain barrier and glymphatic system after SAH. Pretreatment of inhibitors of PACAP receptors showed that the PACAP-involved anti-edema effect and neuroprotection after SAH was facilitated by the selective PACAP receptor (PAC1). Further administration of adenylyl cyclase (AC) inhibitor and sulfonylurea receptor 1 (SUR1) CRISPR activator suggested that the AC–cyclic adenosine monophosphate (cAMP)–protein kinase A (PKA) axis participated in PACAP signaling after SAH, which inhibited the expression of edema-related proteins, SUR1 and aquaporin-4 (AQP4), through SUR1 phosphorylation. Thus, PACAP may serve as a potential clinical treatment to alleviate brain edema in patients with SAH. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-020-00925-3) contains supplementary material, which is available to authorized users.

International audience; Rationale: Subclinical acute kidney injury (sub-AKI) refers to patients with low serum creatinine but elevated alternative biomarkers of AKI. Its incidence and outcome in critically ill patients remain, however, largely unknown. Plasma proenkephalin A 119–159 (penKid) has been proposed as a sensitive biomarker of glomerular function.Objectives: In this ancillary study of two cohorts, we explored the incidence and outcome of sub-AKI based on penKid.Methods: A prospective observational study in ICUs was conducted. FROG-ICU (French and European Outcome Registry in ICUs) enrolled 2,087 critically ill patients, and AdrenOSS-1 (Adrenomedullin and Outcome in Severe Sepsis and Septic Shock-1) enrolled 583 septic patients. The primary endpoint was 28-day mortality after ICU admission. Sub-AKI was defined by an admission penKid concentration above the normal range (i.e., >80 pmol/L) in patients not meeting the definition of AKI. A sensitivity analysis was performed among patients with estimated glomerular filtration rate above 60 ml/min/1.73 m2 at ICU admission.Measurements and Main Results: In total, 6.1% (122/2,004) and 6.7% (39/583) of patients from the FROG-ICU and AdrenOSS-1 cohorts met the definition of sub-AKI (11.6% and 17.5% of patients without AKI). In patients without AKI or with high estimated glomerular filtration rate, penKid was associated with higher mortality (adjusted standardized hazard ratio [HR], 1.4 [95% confidence interval, 1.1–1.8]; P = 0.010; and HR, 1.6 [95% confidence interval, 1.3–1.8]; P

Intracellular reactive oxygen species (ROS) accumulation during culture process compromise cord blood-derived hematopoietic stem/progenitor cells (CB-HSPCs) proliferation potential dramatically. In this work, the effects of hyperoside (Hyp) on CD34+ cells were investigated by the analysis of cell expansion and secondary expansion potential, with the objective to optimize the culture conditions for ex vivo expansion of HSPCs. The results showed that the expansion of total cells treated with 1 μM Hyp reached 54.9 ± 9.6 folds, which was significantly higher than that of control cells (42.0 ± 8.1 folds, P

Lac is a type of natural resin secreted by lac insects and is widely used in the military and other industries because of its excellent adhesion and insulation properties. The main ingredients of lac are lactones and lactides, which are formed from hydroxy fatty acids and sesquiterpene esters. In this study, we measured lac secretion rates by the insect Kerria chinensis at different developmental stages and identified lac secretion-minimum and lac secretion-active stages of the insect. We then analyzed transcriptomes of lac secretion-minimum and lac secretion-active stages of the insect. Based on expression profiles of genes in different stages of the insect, we identified pathways and genes that are potentially involved in lac synthesis and secretion in K. chinensis. Our study lays a foundation for future studies to reveal the molecular mechanisms and pathways of lac synthesis and secretion in this beneficial insect.

We report the surface modification of 4-n-pentyl-4’-cyanobiphenyl (5CB) droplets in aqueous solution by the adsorption of sulfated β-CD/tetradecyl sulfate sodium (SC14S) complexes at the 5CB-aqueous interface, followed by the coating of poly(diallyldimethylammonium chloride) (PDADMAC) through electrostatic interaction. The PDADMAC/sulfate β-CD/SC14S complex-coated 5CB droplets are highly stable in aqueous solution. We show that bile acids are able to penetrate into the PDADMAC coating and displace the SC14S from the cavity of the β-CD immobilized at the surface of the 5CB droplets through the competitive host-guest recognition, consequently inducing the radial-to-bipolar configuration transition of the 5CB droplets. The integration of PDADMAC/sulfate β-CD/SC14S complex-coated 5CB droplets in microfluidic channels allows the selective detection of bile acids in a small sample volume (1 μL) in the presence of ascorbic acid, uric acid, creatinine and urea by observing the configuration transition of the 5CB droplets. The detection limit of the miniaturized 5CB droplet-based sensor platform for bile acids can be tuned by the number density of 5CB droplets.

One new Co(II) coordination polymer was prepared by the hydrothermal method based on a semi-rigid tricarboxylate acid, 4-(2′,3′-dicarboxylphenoxy) benzoic acid (H3L) as [H2bpe][Co(HL)2(bpe)(H2O)2]·(H2O)4 (1) (bpe = 1,2-bis(4-pyridyl) ethylene). This compound has been characterized by single crystal and powder X-ray diffraction, elemental analysis, IR spectra, thermogravimetric analysis, and fluorescent properties. In particular, it is found that compound 1 possesses excellent chemical stability. More importantly, this material could act as a novel “turn-on” fluorescent probe for highly selectively sensitizing ascorbic acid (AA) and “turn-off” sensor for recognizing acetylacetone (Hacac) in the aqueous phase. Both proposed sensing systems showed excellent performance with high sensitivity and selectivity as well as good reusability. The detection limits are as low as 2.60 nM and 57.5 μM, respectively. In addition, the possible mechanism were detailedly discussed.

Plants suffer from combined stress of sulfur deficiency and cadmium toxicity in some agricultural lands. However, little is known about the reaction in plants, such as responses in antioxidant enzymes and non-protein thiol compounds, to such combined stress. Therefore, in this study, four treatments, S-sufficiency (TS−Cd), S-deficiency (T−S−Cd), Cd stress (TS+Cd) and combined stress of S-deficiency and Cd stress (T−S+Cd), were set up to investigate (1) the effects of sulfur deficiency or sulfur sufficiency on Cd toxicity to kidney bean cultivar seedlings and the related mechanisms, and (2) the responses of two kidney bean cultivars to combined stress of S-deficiency and Cd-tolerance. The results showed significant increases in hydrogen peroxide (H2O2) and malondialdehyde contents and significant increases in antioxidant enzyme (superoxide dismutase, catalase, peroxidase, and glutathione S-transferase) activities and non-protein thiol compounds (non-protein thiols, reduced glutathione, phytochelatins) synthesis in the plants in TS+Cd and T−S+Cd. On the tissue level, higher proportion of Cd was found to be immobilized/deposited in roots, while on the sub-cell level, higher proportion of Cd was located in cell walls and vacuole fractions with lower in cell organelles. Taken together, the results indicated that Cd detoxification was achieved by the two kidney bean cultivars through antioxidant enzyme activation, non-protein thiol compound synthesis and sub-cellular compartmentalization. In addition, the results indicated that sufficient S supply helped to relieve Cd toxicity, which is of special significance for remediation or utilization of Cd-contaminated soils as S is a plant essential nutrient.

Background Although the interaction between the gut microbiota and central nervous system (CNS) is well-known, the effects of gut microbiota on different brain regions remain obscure. New method In present study, we developed a simple and sensitive high-performance liquid chromatography-tandem mass spectrometry with atmospheric pressure chemical ionization in positive mode (LC-APCI+-MS/MS) for simultaneous detection of 12 analytes in the rodent’ brain with different housing conditions Results The results showed that male mice in XZ group had significantly higher brain levels of dehydroepiandrosterone (DHEA), androstenedione (A4), testosterone (T), progesterone (P), corticosterone (CORT), aldosterone (ALD) and 11-dehydrocorticosterone (11-DHC) than those in SPF group. CORT level was higher in the left prefrontal cortex, whereas ALD and 11-DHC levels were higher in the left hypothalamus than in the right symmetrical areas in both groups. DHEA and CORT levels were highest in the striatum than in the prefrontal cortex, hippocampus, hypothalamus, regardless of the region and group (XZ and SPF). Comparison with existing methods These results demonstrated that the method developed in this study provides, for the first time, direct quantitation of neurosteroids in male mice brain. Conclusions DHEA levels showed a left-lateralized pattern in the hippocampus and hypothalamus. Mice in the XZ group showed significantly elevated levels of CORT and/or its metabolites, ALD and 11-DHC in brain than mice in the SPF group. Insanitation living conditions increased more diverse gut microbiota.

Protein crystallization is a delicate process that is always sensitive to environmental factors. When the environmental factors are not well controlled or not controlled at all, identical crystallization droplets from the same mother liquid may yield different crystallization results. One environmental factor, the weather conditions during crystallization solution preparation, is not usually considered as a parameter for protein crystallization. In this paper, it is shown that the weather parameters during preparation of the crystallization experiment, including the ambient temperature, humidity, pressure and particulate matter in the air, can all affect the reproducibility of lysozyme crystallization. An identical lysozyme crystallization experiment was repeated for an entire year, and the weather conditions when each crystallization experiment was set up were recorded along with the crystallization results. Among the parameters recorded, the humidity during the experiment setup showed the strongest effect on lysozyme crystallization. On the basis of these results, it is suggested that the weather conditions during crystallization solution preparation should be considered as a potential factor that can influence protein crystallization.

The effect of support on electrocatalytic activity of Cu nanoparticles (NPs) towards CO2 electroreduction to hydrocarbon fuels (CH4 and C2H4) is investigated for three types of nanostructured carbons: single wall carbon nanotubes (SWNT), reduced graphene oxide (RGO) and onion-like carbon (OLC). Cu/SWNT, Cu/RGO and Cu/OLC composite catalysts are synthesized and characterized by X-ray diffraction analysis, transmission electron microscopy and electrochemical surface area measurements. Electrocatalytic activities of the synthesized materials, as measured in an electrochemical cell connected to a gas chromatograph, are compared to that of Cu NPs supported on Vulcan carbon. All four catalysts demonstrate higher activity towards C2H4 generation vs CH4, with production of the latter mostly suppressed on Cu NPs supported on nanostructured substrates. Onset potentials for C2H4 vs CH4 generation demonstrate 200 mV positive shifts for Cu/SWNT, Cu/RGO, and Cu/OLC catalysts. The Cu/OLC catalyst is found to be superior to the other two nanostructured catalysts in terms of stability, activity and selectivity towards C2H4 generation. Its faradaic efficiency reached 60% at −1.8 V vs Ag/AgCl. The enhanced stability and activity of the Cu/OLC catalyst can be attributed to the unique catalyst design, wherein a shell of OLC surrounds the Cu NPs. Such a configuration enables the outer layer to act as a filter that protects the Cu surface from adsorption of undesirable species, enhances its electrocatalytic performance, and improves its viability in CO2 electroreduction reaction. The enhanced selectivity of the Cu/OLC catalyst towards the C2H4 production is most likely related to the enhanced electrocatalytic activity of the OLC support towards the CO2 electroreduction to CO. Higher CO surface concentration from CO2 electroreduction on the OLC support, rather than a greater number of available sites for CO dimerization, likely originated this behavior. CO molecules generate on surfaces of OLCs, dimerize on Cu NP (100) planes, and, subsequently, yield additional C2H4 molecules. Both the reduction of the CO2 to CO on the surface of OLCs and reduction of “extra” CO molecules to C2H4 on the surface of Cu NPs are expected to lead to an increase in the local pH, which is also beneficial for the C2H4 production.

A series of N(4)-substituted thiosemicarbazones (TSCs) bearing pyrrole unit (1a-1e) were synthesized and fully characterized by elemental analyses, infrared spectra, 1H nuclear magnetic resonance and single crystal X-ray diffraction. The compounds were assessed as potential chemotherapeutic agents. All newly synthesized compounds were screened for their anticancer activity against lung cancer PC-9, esophageal cancer Eca-109 and gastric cancer SGC-7901 cell lines. The results of MTT, Terminal deoxynucleotidyl transferase dUTP nick end labeling and fluorescence-activated cell sorting assays indicated that all the prepared compounds exhibited cytotoxicity against PC-9, Eca-109 and SGC-7901 cells in vitro. All the compounds significantly induced cancer cell apoptosis accompanied by increasing the Bax/Bcl-2 ratio and activation of caspase-3. The structure-activity association was discussed and the potential pre-clinical trials may be conducted. The present findings have a great potential in biomedical applications of novel N(4)-substituted TSCs.

Glass hollow fiber membrane precursor was well prepared using glass and polyvinylidene fluoride (PVDF) as starting materials by non-solvent-induced phase separation. The spinning dope including glass powders and PVDF was obtained firstly. Then the hollow fiber membrane precursors were spinning via dry-wet spinning method. The parameters about preparation process were listed. The viscosity of spinning dope were also measured. The results showed that the viscosity increased with a function of the content of PVDF. The suitable viscosity for spinning technology was selected. The scanning electron microscopy showed that the glass powders with the diameter of several micrometer were connected by PVDF binder. The water flux was also tested, and it decreased with the time. The preparation technology of glass hollow fiber membrane precursor could provide support for the glass hollow fiber membrane via sintering process.

The thermal degradation kinetics and pyrolysis characteristics of a chitosan-Zn complex have been studied by Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA) and pyrolysis gas-chromatography/mass spectrometry (Py-GC/MS). FTIR analysis showed that the absorptions associated with the O H, N H, C O and C C bonds shifted to lower frequencies and became much less intense at high temperatures. Furthermore, several new peaks appeared at 3049, 2332, 2202 and 600–900 cm−1 under these conditions. TGA experiments indicated that the thermal degradation of the chitosan-Zn complex occurred over two stages. The kinetic triplets of the second thermal degradation stage were estimated by Flynn–Wall–Ozawa, Kissinger–Akahira–Sunose and Coats–Redfern methods, and the most plausible kinetic model was F 3 ( [ ( 1 − α ) − 2 − 1 ] / 2 ), i.e., a third-order reaction. The Py-GC/MS results indicated that the pyrolysis of the chitosan-Zn complex was very complicated, producing many volatile products, including carbon dioxide, acetic acid and nitrogen-containing aromatic heterocyclic compounds. Compared with chitosan, the decomposition of the chitosan-Zn complex was easier and more thorough.

Normalization of the tumor microenvironment is a promising approach to render conventional chemotherapy more effective. Although passively targeted drug nanocarriers have been investigated to this end, actively targeted tumor priming remains to be explored. In this work, we demonstrate an effective tumor priming strategy using metronomic application of nanoparticles actively targeted to tumor neovasculature. F56 peptide-conjugated paclitaxel-loaded nanoparticles (F56-PTX-NP) were formulated from PEGylated polylactide using an oil in water emulsion approach. Metronomic F56-PTX-NP specifically targeted tumor vascular endothelial cells (ECs), pruned vessels with strong antiangiogenic activity and induced thrombospondin-1 (TSP-1) secretion from ECs. The treatment induced tumor vasculature normalization as evidenced by significantly increased coverage of basement membrane and pericytes. The tumor microenvironment was altered with enhanced pO2, lower interstitial fluid pressure, and enhanced vascular perfusion and doxorubicin delivery. A "normalization window" of at least 9 days was induced, which was longer than other approaches using antiangiogenic agents. Together, these results show that metronomic, actively-targeted nanomedicine can induce tumor vascular normalization and modulate the tumor microenvironment, opening a window of opportunity for effective combination chemotherapies.

Curcumin is potentially therapeutic for malignant diseases. The mechanisms of this effect might involve a combination of antioxidant, immunomodulatory, proapoptotic, and antiangiogenic activities. However, the exact mechanisms are not fully understood. In the present study, we provided evidences that curcumin suppressed the expression of enhancer of zeste homolog 2 (EZH2) in lung cancer cells both transcriptionally and post-transcriptionally. Curcumin inhibited the expression of EZH2 through microRNA (miR)-let 7c and miR-101. Curcumin decreased the expression of NOTCH1 through the inhibition of EZH2. There was a reciprocal regulation between EZH2 and NOTCH1 in lung cancer cells. These observations suggest that curcumin inhibits lung cancer growth and metastasis at least partly through the inhibition of EZH2 and NOTCH1.

Environments with varying temperatures have been shown to beneficially increase the probability of obtaining protein crystals. Therefore, a cycling temperature strategy (CTS) has been proposed for protein crystallization screening. During the practical application of this strategy, it is necessary to know the effective temperature range that promotes crystallization to design a suitable temperature program. In this paper, the effects of different temperature ranges on lysozyme crystallization (or more specifically, nucleation) were investigated. The results show that a small periodic variation in the temperature range of as little as 0.4 K can have a significant effect on the crystallization success rate under some crystallization concentration conditions, confirming that crystallization of lysozyme is very sensitive to temperature variation. Because practical protein crystallization is always performed in an environment with slight temperature variations, the sensitivity of protein crystallization to temperature may provide an explanation for the poor reproducibility of protein crystallization. Further investigation of the CTS on lysozyme crystallization showed that a cycling temperature strategy exerts an effect on protein crystallization by altering the supersaturation caused by changes in temperature.

A composite of (Mo0.9Cr0.1)Si2+15vol% ZrO2 was prepared with powder metallurgy and pres-sure-less sintering, aiming at applications of high temperature structural materials. Mechanical properties of the composites were assessed with hardness, fracture toughness Kc and KIC tested using indentation fracture and SEVNB methods, flexure strength at room temperature and 1200˚C, and isothermal oxidation at 1400˚C. The results showed that the native silica oxide on the silicide feedstock surface, and in turn, the SiO2 in the sintered bulks was significantly re-duced in terms of Cr-alloying. (Mo0.9Cr0.1)Si2 and (Mo0.9Cr0.1)Si2+15vol% ZrO2 composite exhib-ited enhanced sinterability, owing to the formation of (Cr, Mo)5Si3. Fracture toughness of the composite was increased by a factor of 1.6 of that of the monolithic silicide. Mechanical prop-erty of the composite was not affected by Cr addition. However, the high temperature oxidation resistance was greatly improved in the (Mo0.9Cr0.1)Si2+15vol%ZrO2 composite compared with the as-sintered MoSi2+15vol%ZrO2. The Cr-alloying effects on feedstock native oxides, micro-structure, mechanical property and high temperature oxidation resistance were discussed.

Peripheral painful neuropathy is one of the most common complications in diabetes and necessitates improved treatment. Secoisolariciresinol diglycoside (SDG), a predominant lignan in flaxseed, has been shown in our previous studies to exert antidepressant-like effect. As antidepressant drugs are clinically used to treat chronic neuropathic pain, this work aimed to investigate the potential analgesic efficacy of SDG against diabetic neuropathic pain in a mouse model of type 1 diabetes. We subjected mice to diabetes by a single intraperitoneal (i.p.) injection of streptozotocin (STZ, 200 mg/kg), and Hargreaves test or von Frey test was used to assess thermal hyperalgesia or mechanical allodynia, respectively. Chronic instead of acute SDG treatment (3, 10 or 30 mg/kg, p.o., twice per day for three weeks) ameliorated thermal hyperalgesia and mechanical allodynia in diabetic mice, and these analgesic actions persisted about three days when SDG treatment was terminated. Although chronic treatment of SDG to diabetic mice did not impact on the symptom of hyperglycemia, it greatly attenuated excessive oxidative stress in sciatic nerve and spinal cord tissues, and partially counteracted the condition of weight decrease. Furthermore, the analgesic actions of SDG were abolished by co-treatment with the reactive oxygen species donor tert-butyl hydroperoxide (t-BOOH), but potentiated by the reactive oxygen species scavenger phenyl-N-tert-butylnitrone (PBN). These findings indicate that chronic SDG treatment can correct neuropathic hyperalgesia and allodynia in mice with type 1 diabetes. Mechanistically, the analgesic actions of SDG in diabetic mice may be associated with its antioxidant activity.

Most anti-angiogenic therapies currently being evaluated target the vascular endothelial growth factor (VEGF) pathway, however, the tumor vasculature can acquire resistance to VEGF-targeted therapy by shifting to other angiogenesis mechanisms. Therefore, other therapeutic agents that block non-VEGF angiogenic pathways need to be evaluated. Here, we identified ferulic acid as a novel fibroblast growth factor receptor 1 (FGFR1) inhibitor and a novel agent with potential anti-angiogenic and anti-cancer activities. Ferulic acid demonstrated inhibition of endothelial cell proliferation, migration and tube formation in response to basic fibroblast growth factor 1 (FGF1). In ex vivo and in vivo angiogenesis assays, ferulic acid suppressed FGF1-induced microvessel sprouting of rat aortic rings and angiogenesis. To understand the underlying molecular basis, we examined the effects of ferulic acid on different molecular components and found that ferulic acid suppressed FGF1-triggered activation of FGFR1 and phosphatidyl inositol 3-kinase (PI3K)-protein kinase B (Akt) signaling. Moreover, ferulic acid directly inhibited proliferation and blocked the PI3K-Akt pathway in melanoma cell. In vivo, using a melanoma xenograft model, ferulic acid showed growth-inhibitory activity associated with inhibition of angiogenesis. Taken together, our results indicate that ferulic acid targets the FGFR1-mediated PI3K-Akt signaling pathway, leading to the suppression of melanoma growth and angiogenesis.

e21705 Background: TQ-B3101 is a novel compound, which deacetylated metabolite targets to receptor tyrosine kinases including ALK, ROS1 and MET. Preclinical studies showed TQ-B3101 had a better Inhibition activity and duration compared with equimolar crizotinib. Methods: Patients (pts) with advanced solid tumor failed to standard therapy were enrolled into dose escalation and expansion cohorts. TQ-B3101 was orally administered at doses of 100~300mg QD or 200~350mg BID in a 28-day cycle, then received the same dose until disease progression or intolerable toxicity. Dose escalation was based on dose-limiting toxicities (DLTs) in the first cycle and used “3+3” design to get the maximal tolerated dose (MTD) or recommended phase II dose (RP2D). Other objectives included safety and pharmacokinetics (PK) for all pts, and objective response rate (ORR) for ALK+, ROS1+ and MET amplification pts. Results: As of 20 Dec 2019, 30 pts (median age 51.3, males: 16, females: 14, ALK+: 19, ROS1+: 6, MET amplification: 2, lung cancer: 27, asymptomatic brain metastasis: 8, ECOG PS 1: 30) were enrolled into 7 dose escalation cohorts and 2 dose expansion cohorts (350mg BID/ 300mg BID). One DLT (grade 3 ALT increased) occurred at 350 mg BID. The MTD has not been reached. The most common grade 3 adverse events were neutrophils count decreased (20%), ALT increased (6.67%), leucocyte counts decreased (3.33%) and QT internal prolongation (3.33%). Grade 3 adverse events rate were 40% in 350mg BID cohort and 16.67% in 300mg BID cohort. PK analyses indicated TQ-B3101 metabolized into its deacetylated product rapidly, and exposure (Cmax and AUC) of which generally increased in a dose-proportional manner. Tumor response was evaluated in 24 pts with ALK+/ROS1+/MET amplification. ORR were 62.5% (15/24) in all cohorts, and 87.5% (7/8) in 350mg BID cohort. In 8 pts with brain metastases at baseline, ORR was 62.5% (5/8) . In 22 pts without brain metastases at baseline, the incidence of brain metastasis was 4.55% (1/22). 1 patient with MET amplification is evaluable and the tumor response is PR. Conclusions: TQ-B3101 was well tolerated and showed preliminary antitumor activity in ALK+, ROS1+ and MET amplification pts. Recommended phase II dose (RP2D) might be 300mg BID according longtime safety data. Further anti-tumor research in pts with ROS1+ is under going as multicenter clinical study in China. (NCT03972189). Clinical trial information: NCT03019276.

In this research, a strain with broad-spectrum antimicrobial activities was isolated from the gastrointestinal tract of hairtail (Trichiurus haumela) and identified as Bacillus siamensis JFL15 through morphological, 16S rRNA, and average nucleotide identity analyses. The genome of B. siamensis JFL15 was sequenced, and three gene clusters involved in the biosynthesis of surfactin (srf), bacillibactin (dhb), and fengycin (fen) were predicted through antiSMASH analysis. The combined genomics-metabolics profiling of the strain revealed 20 active compounds, which belong to four main types of cyclic lipopeptides produced by Bacillus species: bacillibactin, iturin, fengycin, and surfactin. Among these lipopeptides, two high-purity antifungal components, namely, components b and c, were successfully identified as iturin A and bacillomycin F. The minimum inhibitory concentrations (MICs) of iturin A for Magnapothe grisea, Rhizoctorzia solani, and Colletotrichum gloeosporioides were 125.00, 62.50, and 125.00 μg/ml, respectively, whereas the MICs of bacillomycin F for these three organisms were 62.50, 31.25, and 62.50 μg/ml, respectively. The mechanism of bacillomycin F and iturin A against M. grisea was also investigated. Scanning electron microscopy (SEM) indicated that the surface of the hypha treated with iturin A or bacillomycin F became sunk, lumpy, and wrinkled. The diversity of the identified and predicted compounds from B. siamensis JFL15 suggested that this strain might be a promising biocontrol agent for an effective and environmentally friendly control of pathogenic microorganisms. To the best of our knowledge, this study is the first to describe cyclic lipopeptides purified and identified from B. siamensis.

The stimulator of interferon genes (STING) is a key adaptor protein mediating innate immune defense against DNA viruses. To investigate the role of STING in acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF), we isolated primary peripheral blood mononuclear cells (PBMCs) from patients and healthy controls (HCs). Raw264.7 and A549 cells were infected with herpes simplex virus type 1 (HSV-1). Mice with bleomycin-induced lung fibrosis were infected with HSV-1 to stimulate acute exacerbation of the lung fibrosis. Global gene expression profiling revealed a substantial downregulation of interferon-regulated genes (downstream of STING) in the AE-IPF group compared with the HC and stable IPF groups. The PBMCs of the AE-IPF group showed significantly reduced STING protein levels, increased levels of endoplasmic reticulum (ER) stress markers, and elevated apoptosis. HSV-1 infection decreased STING expression and stimulated the ER stress pathways in Raw264.7 and A549 cells in a time- and dose-dependent manner. HSV-1 infection exacerbated the bleomycin-induced lung injury in mice. In the primary bone marrow-derived macrophages of mice treated with bleomycin and HSV-1, STING protein expression was substantially reduced; ER stress was stimulated. Tauroursodeoxycholic acid, a known inhibitor of ER stress, partially reversed those HSV-1-mediated adverse effects in mice with bleomycin-induced lung injury. STING levels in PBMCs increased after treatment in patients showing improvement but remained at low levels in patients with deterioration. Viral infection may trigger ER stress, resulting in STING deficiency and AE-IPF onset.