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Urea electrolysis is a prospective technology for simultaneous H2 production and nitrogen suppression in the process of water being used for energy production. Its sustainability is currently founded on innocuous N2 products; however, we discovered that prevalent nickel-based catalysts could generally over-oxidize urea into NO2- products with ≈80 % Faradaic efficiencies, posing potential secondary hazards to the environment. Trace amounts of over-oxidized NO3- and N2 O were also detected. Using 15 N isotopes and urea analogues, we derived a nitrogen-fate network involving a NO2- -formation pathway via OH- -assisted C-N cleavage and two N2 -formation pathways via intra- and intermolecular coupling. DFT calculations confirmed that C-N cleavage is energetically more favorable. Inspired by the mechanism, a polyaniline-coating strategy was developed to locally enrich urea for increasing N2 production by a factor of two. These findings provide complementary insights into the nitrogen fate in water-energy nexus systems.

In the present work, a novel series of trifluoromethyl-substituted tetrahydropyran derivatives were rationally designed and synthesized as potent DPP-4 inhibitors with significantly improved duration time of action over current commercially available DPP-4 inhibitors. The incorporation of the trifluoromethyl group on the 6-position of the tetrahydropyran ring of omarigliptin with the configuration of (2R,3S,5R,6S) not only significantly improves the overall pharmacokinetic profiles in mice but also maintains comparable DPP-4 inhibition activities. Further preclinical development of compound 2 exhibited its extraordinary efficacy in vivo and good safety profile. Clinical studies of compound 2 (Haisco HSK7653) are now ongoing in China, which revealed that inhibitor 2 could serve as an efficient candidate with a once-biweekly therapeutic regimen.

The NiOOH catalyst as obtained dynamically from electrodeposition of Ni2+(aq) in the borate-containing electrolyte was observed to exhibit much higher oxygen evolution activity at a near-neutral pH...

The development of a stringent sensor to detect low levels of acetone, yielding the potential for the point-of-care clinical diagnosis of diabetes, is still a great challenge but is urgently required. Most studies have focused on Ti3C2Tx, yet other types of MXenes with good performance are rare. Herein, an emerging kind of MXene, V4C3Tx, has been prepared from V4AlC3 via the selective etching of the Al layer using aqueous HF at room temperature (RT), and its performance as an acetone sensor is presented. A V4C3Tx based acetone sensor delivers good performance, as demonstrated by its low working temperature of 25 °C, low detection limit of 1 ppm (lower than the 1.8 ppm diabetes diagnosis threshold), and high selectivity towards acetone in a mixed gas of acetone and water vapor, hopefully showing promise for application in the much faster and earlier diagnosis of diabetes. V4C3Tx MXene is used for the first time in the field of acetone detection in this work, hopefully opening up a path for the investigation of applications of MXene in gas sensors, and such exciting findings distinguish V4C3Tx as a comparable material to the well-known Ti3C2Tx. In addition, we used DFT calculations to explore the mechanisms that result in the superior selectivity for acetone with respect to water vapor. Hopefully, the proposed mechanisms combining experimental results and theoretical study will shed light on the design and production of new high-performance acetone sensors.

This study aimed to compare the effect of hot roller (HR) drying and hot air (HA) drying on the sensory evaluation, chemical quality, antioxidant activity, and metabolic profile of Yihong Congou black tea processed from E’cha NO1. The Yihong Congou black tea dried with HA obtained higher sensory scores and better chemical qualities such as the hue of tea brew color (a and b), content of theaflavins, thearubigins, water extract, free amino acids, tea polyphenol, and the ratio of polyphenol to amino acids as well as higher antioxidant capacities compared to that dried with HR. The HA drying tea increased the contents of volatile compounds that had positive correlation with sweet and flowery flavor, while the HR drying tea increased the contents of volatile compounds related to fruity flavor. Moreover, non-targeted metabolomics data indicated that the levels of most free amino acids significantly increased, while the levels of most soluble sugars reduced in the HA drying method compared to the HR drying method. The metabolic analysis was also consistent with the above results and revealed that D-ribose and gallic acid were the main characteristic metabolites of HA drying. Our results could provide a technical reference and theoretical guide to processing a high quality of Yihong Congou black tea.

Cobalt oxides (CoOx), despite its wide applications, are notoriously complex on structure, in particular under experimental reduction/oxidation conditions. Here, using the newly developed machine l...

BACKGROUND This study aimed to compare the application value of intraoperative fluorescence navigation technology (FNT) and intraoperative ultrasound (IOUS) in primary liver cancer surgery. MATERIAL AND METHODS Fifty consecutive patients with primary liver cancer scheduled to receive surgical treatment were divided into FNT group and IOUS group. FNT and IOUS were separately used to guide tumor resection and detect new cancerous lesions in the 2 groups. The complete tumor resection rate (R0) resection rate, length of the tumor distance from cutting edge, the diagnostic efficacy of cancerous nodules and the fluorescence imaging characteristics of different types tumors were recorded. RESULTS The R0 resection rate was 100% (25 out of 25 patients) in the FNT group and 96% (24 out of 25 patients) in the IOUS group. In the FNT group, 1 case (4%, 1 out of 25 patients) had cancer tissue that was less than 1 cm from the cutting edge, compared to 7 cases (28%, 7 out of 25 patients) in the IOUS group (P=0.049), which was a significant difference. In the remaining livers of 50 consecutive patients, FNT found 5 new cancerous nodules with a sensitivity of 71.4%, a specificity of 11.1%, and a false-positive rate of 88.9%; for IOUS the results were 42.9%, 88.9%, 11.1%. The fluorescence imaging characteristics of all well-differentiated hepatocellular carcinomas were tumor tissue imaging, but all other types of tumors were ring imaging around the tumor. CONCLUSIONS FNT can improve the R0 resection rate, ensure a safe distance between tumor and cutting edge and can identify more new cancerous nodules compared to IOUS. Thus, FNT could improve the surgical treatment effect for primary liver cancer and hopefully further improve the prognosis of patients.

A DMAP-N-oxide, featuring an α-amino acid as the chiral source, was developed, synthesized and applied in asymmetric Steglich rearrangement. A series of O-acylated azlactones afforded C-acylated azlactones possessing a quaternary stereocenter in high yields (up to 97 % yield) and excellent enantioselectivities (up to 97 % ee). Compared to the widespread use of pyridine nitrogen, which serves as the nucleophilic site in the asymmetric acyl transfer reaction, we discovered that chiral DMAP-N-oxides, in which the oxygen now acts as the nucleophilic site, are efficient acyl transfer catalysts. Our finding might open a new door for the development of chiral DMAP-N-oxides for asymmetric acyl transfer reactions.

Bifunctional chiral DMAP-N-oxides have been reported for the highly enantioselective rearrangement of indolyl carbonates. Using 2.5 mol% of chiral DMAP-N-oxide, diverse oxindoles containing an all-carbon quaternary stereocenter were obtained in excellent yields (up to 98% yield) with high enantioselectivities (up to 96% ee). Compared to the widespread use of chiral DMAP and isothiourea catalysts, in which the nitrogen atom serves as a nucleophilic site, we found that chiral DMAP-N-oxides, which utilize the oxygen atom as a nucleophilic site, were also efficient organocatalysts in this rearrangement.

Ovarian cancer is known for its highest mortality rate in gynecological malignancy. Previous studies demonstrated that thymoquinone (TQ), a bioactive compound isolated from Nigella sativa L., is a potent anti-ovarian cancer agent, which inhibit tumor growth by modulating apoptotic activity. In this study, we found that the effect of chemotherapy on ovarian cancer cells in vitro varies by race/ethnicity. HO-8910 was established from Chinese patient with ovarian serous carcinoma. The results showed that HO-8910 displayed higher resistance to platinum than SKOV3. And further cell variability assay indicated that TQ exhibited dramatically inhibitory activity on HO-8910 and SKOV3. However, apoptosis and cell cycle analysis suggested TQ had multiple mechanisms for its cytotoxic effect. As for HO-8910, TQ could modulated expression level of several pivotal factors involving autophagy, including PI3K, ATG-7, Bectlin-1 and p62, but has little effect on p53, PARP and caspase-3, and no effect on Bax. Our results sustained that TQ was a promising anti-ovarian cancer candidate and its potential application in Chinese patients, even Asian patients , treatment in clinic.

NiFe oxyhydroxide is one of the most promising oxygen evolution reaction (OER) catalysts for renewable hydrogen production, and deciphering the identity and reactivity of the oxygen intermediates on its surface is a key challenge but is critical to the catalyst design for improving the energy efficiency. Here, we screened and utilized in situ reactive probes that can selectively target specific oxygen intermediates with high rates to investigate the OER intermediates and pathway on NiFe oxyhydroxide. Most importantly, the oxygen atom transfer (OAT) probes (e.g., 4-(diphenylphosphino) benzoic acid) could efficiently inhibit the OER kinetics by scavenging the OER intermediates, exhibiting lower OER currents, larger Tafel slopes, and larger kinetic isotope effect (KIE) values, while probes with other reactivities demonstrated much smaller effects. Combining the OAT reactivity with electrochemical kinetic and operando Raman spectroscopic techniques, we identified a resting Fe═O intermediate in the Ni-O scaffold and a rate-limiting O-O chemical coupling step between a Fe═O moiety and a vicinal bridging O. DFT calculation further revealed a longer Fe═O bond formed on the surface and a large kinetic energy barrier of the O-O chemical coupling step, corroborating the experimental results. These results point to a new direction of liberating lattice O and expediting O-O coupling for optimizing NiFe-based OER electrocatalyst.

A pH-dependent dual-binding-site switch in a pair of protein modules is discovered, and the molecular mechanism is elucidated., Many important proteins undergo pH-dependent conformational changes resulting in “on-off” switches for protein function, which are essential for regulation of life processes and have wide application potential. Here, we report a pair of cellulosomal assembly modules, comprising a cohesin and a dockerin from Clostridium acetobutylicum, which interact together following a unique pH-dependent switch between two functional sites rather than on-off states. The two cohesin-binding sites on the dockerin are switched from one to the other at pH 4.8 and 7.5 with a 180° rotation of the bound dockerin. Combined analysis by nuclear magnetic resonance spectroscopy, crystal structure determination, mutagenesis, and isothermal titration calorimetry elucidates the chemical and structural mechanism of the pH-dependent switching of the binding sites. The pH-dependent dual-binding-site switch not only represents an elegant example of biological regulation but also provides a new approach for developing pH-dependent protein devices and biomaterials beyond an on-off switch for biotechnological applications.

Background Early-life stress increases the risk for posttraumatic stress disorder. However, the epigenetic mechanism of early-life stress-induced susceptibility to posttraumatic stress disorder in adulthood remains unclear. Methods Rat pups were exposed to maternal deprivation during postnatal days 1 to 14 for 3 hours daily and treated with the DNA methyltransferase inhibitor zebularine, L-methionine, or vehicle 7 days before contextual fear conditioning, which was used as a second stress and to mimic the reexperiencing symptom of posttraumatic stress disorder in adulthood. Long-term potentiation, dendritic spine density, DNA methyltransferase mRNA, Reelin gene methylation, and Reelin protein expression in the hippocampal CA1 were measured. Results Maternal deprivation enhanced contextual fear memory in adulthood. Meanwhile, maternal deprivation decreased DNA methyltransferase mRNA and Reelin gene methylation in the hippocampal CA1 on postnatal days 22 and 90. Reelin protein expression was increased in the hippocampal CA1 following contextual fear conditioning in adulthood. Furthermore, compared with rats that experienced maternal deprivation alone, rats also exposed to contextual fear conditioning showed an enhanced induction of hippocampal long-term potentiation and increased dendritic spine density in the hippocampal CA1 following contextual fear conditioning in adulthood. Zebularine pretreatment led to an enhancement of contextual fear memory, hypomethylation of the Reelin gene, and increased Reelin protein expression in adult rats, while L-methionine had the opposite effects. Conclusions Maternal deprivation can epigenetically program second-hit stress-induced Reelin expression and enhance the susceptibility to contextual fear memory in adulthood. These findings provide a new framework for understanding the cumulative stress hypothesis.

Pt single atoms have unique power in enhancing and accelerating OER active NiOOH phase transformation from NiO., Phase transformation of electrode materials widely occurs in electrocatalytic reactions. Metal oxides are promising electrocatalysts for the oxygen evolution reaction (OER); their phase transformation is a key step for the multi-electron OER, and requires extra overpotential. However, little attention has been paid to accelerating and enhancing the phase transformation. Here, we report for the first time that single-atom Pt incorporated into the bulk crystalline phase of porous NiO nanocubes (0.5 wt% Pt/NiO) can greatly promote the active phase (NiOOH) evolution. The Pt doping was achieved by a scalable nanocasting approach using SiO2 as the hard template. In comparison with Pt/NiO samples with PtO2 nanoparticles segregated at the NiO surface (1 wt% Pt), as well as atomistic Pt atoms solely bound at the surface by atomic layer deposition, the bulk Pt doping shows the strongest power in facilitating active phase transformation, which leads to improved OER activity with reduced overpotential and Tafel slope. Experiential data revealed that the charge-transfer from Pt to Ni through O leads to a local weaker Ni–O bond. First principles calculations confirmed that rather than acting as an active site for the OER, monatomic Pt effectively increases the phase transformation rate by reducing the migration barrier of nearby Ni atoms. Our discoveries reveal the relationships of the heteroatom doped structure and phase transformation behavior during the electrochemical process and offer a new route for designing high-performance electrocatalysts.

Processive hydrolysis of crystalline cellulose by cellulases is a critical step for lignocellulose deconstruction. The classic Trichoderma reesei exoglucanase TrCel7A, which has a closed active-site tunnel, starts each processive run by threading the tunnel with a cellulose chain. Loop regions are necessary for tunnel conformation, resulting in weak thermostability of fungal exoglucanases. However, endoglucanase CcCel9A, from the thermophilic bacterium Clostridium cellulosi, comprises a glycoside hydrolase (GH) family 9 module with an open cleft and five carbohydrate-binding modules (CBMs) and hydrolyzes crystalline cellulose processively. How CcCel9A and other similar GH9 enzymes bind to the smooth surface of crystalline cellulose to achieve processivity is still unknown. Our results demonstrate that the C-terminal CBM3b and three CBMX2s enhance productive adsorption to cellulose, while the CBM3c adjacent to the GH9 is tightly bound to 11 glucosyl units, thereby extending the catalytic cleft to 17 subsites, which facilitates decrystallization by forming a supramodular binding surface. In the open cleft, the strong interaction forces between substrate-binding subsites and glucosyl rings enable cleavage of the hydrogen bonds and extraction of a single cellulose chain. In addition, subsite -4 is capable of drawing the chain to its favored location. Cellotetraose is released from the open cleft as the initial product to achieve high processivity, which is further hydrolyzed to cellotriose, cellobiose and glucose by the catalytic cleft of the endoglucanase. On this basis, we propose a wirewalking mode for processive degradation of crystalline cellulose by an endoglucanase, which provides insights for rational design of industrial cellulases.

We performed DFT calculations to understand CO activation over a χ-Fe5C2 Fischer–Tropsch catalyst. The χ-Fe5C2 catalyst exhibits unique CO activation behaviors, and the BEP relation is nearly valid for this system. The physical basis of this relation mainly originates from the site-dependent charge of the involved surface Fe atoms for the CO activation. This descriptor is also applicable to describe the CO activation on the χ-Fe5C2 catalyst with more complex surface properties involving K promoter, nonstoichiometric termination, and/or carbon vacancy. The insights revealed here might guide the rational catalyst design via surface electronic modification. © American Chemical Society 2018. This is the authors accepted and refereed manuscript to the article.

Seeking for active MnOx material as artificial water splitting catalyst has been a long history since the discovery of PSII system in nature. To date, the highest activity MnOx catalyst reported for oxygen evolution reaction (OER) does however not belong to common MnO2 polymorphs (α-, β-, δ-MnO2), but rather to nascent δ-MnO2 layer produced in situ from spinel under electrochemical conditions with unknown active site structure. Here with the stochastic surface walking (SSW) pathway sampling method, we for the first time resolve the atomic-level mechanism of spinel-to-layer Mn3O4 solid phase transition in aqueous electrolyte. We show that a transient H0.5MnO2 phase is the precursor of transition that forms at high voltage (>1 V), and it undergoes the solid-to-solid phase transition to produce a δ-MnO2 layer, which is accompanied by Mn dissolution, dislocation, layer-breaking, and insertion of water/cations between layers. This leads to the generation of a variety of possible defective structures. We demons...

Cilia loss is common in cancer, and its roles remain unknown. Deng et al. show that cilia loss sensitizes cells to transformation by activating a mevalonate pathway through β-catenin–TCF signaling. The mevalonate pathway inhibitor statin blocks the progression of pancreatic cancer., Although cilia loss and cell transformation are frequently observed in the early stage of tumorigenesis, the roles of cilia in cell transformation are unknown. In this study, disrupted ciliogenesis was observed in cancer cells and pancreatic cancer tissues, which facilitated oncogene-induced transformation of normal pancreatic cells (HPDE6C7) and NIH3T3 cells through activating the mevalonate (MVA) pathway. Disruption of ciliogenesis up-regulated MVA enzymes through β catenin–T cell factor (TCF) signaling, which synchronized with sterol regulatory element binding transcription factor 2 (SREBP2), and the regulation of MVA by β-catenin–TCF signaling was recapitulated in a mouse model of pancreatic ductal adenocarcinoma (PDAC) and human PDAC samples. Moreover, disruption of ciliogenesis by depleting Tg737 dramatically promoted tumorigenesis in the PDAC mouse model, driven by KrasG12D, which was inhibited by statin, an inhibitor of the MVA pathway. Collectively, this study emphasizes the crucial roles of cilia in governing the early steps of the transformation by activating the MVA pathway, suggesting that statin has therapeutic potential for pancreatic cancer treatment.

The aim of this study was to extract and purify anthocyanins from Lycium ruthenicum Murr. and evaluate their tyrosinase inhibitory activity. Response surface methodology was devoted to optimize enzyme-assisted extraction of anthocyanins from L. ruthenicum dried fruits. Extraction at 38 °C for 37 min using water-containing pectinase (52.04 mg/100 g dried fruit) rendered an anthocyanin extraction yield of 19.51 ± 0.21 mg/g. The purified anthocyanins were separated from the extract by macroporous resin XDA-6. Antioxidant tests in vitro suggested that the extract and the purified anthocyanins exhibited a potent 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging capacity, 2,2-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical scavenging capacity, hydroxyl radical scavenging capacity, superoxide radical scavenging capacity, and total reducing power. Thirteen anthocyanins from L. ruthenicum dried fruits were analyzed by HPLC-MS. Moreover, the purified anthocyanins had inhibitory effect on tyrosinase monophenolase (IC50 = 1.483 ± 0.058 mg/mL), and the type of inhibition was competitive inhibition (Ki = 39.83 ± 1.4 mg/mL). The maximum inhibitory activity of the purified anthocyanins (3.00 mg/mL) on tyrosinase diphenolase was 42.16 ± 0.77%, and the type of inhibition was anticompetitive inhibition (Kis = 2.387 ± 0.10 mg/mL). PRACTICAL APPLICATION: The anthocyanins from L. ruthenicum dried fruits can be used as tyrosinase inhibitors in medicine, cosmetics, and food preservation industries.

Chronic T cell activation and accelerated immune senescence are hallmarks of HIV infection, which may contribute to the increased risk of cardiometabolic diseases in people living with HIV (PLWH). T lymphocytes play a central role in modulating adipose tissue inflammation and, by extension, adipocyte energy storage and release. Here, we assessed the CD4+ and CD8+ T cell profiles in the subcutaneous adipose tissue (SAT) and blood of non-diabetic (n = 9; fasting blood glucose [FBG] < 100 mg/dL), pre-diabetic (n = 8; FBG = 100–125 mg/dL) and diabetic (n = 9; FBG ≥ 126 mg/dL) PLWH, in addition to non- and pre-diabetic, HIV-negative controls (n = 8). SAT was collected by liposuction and T cells were extracted by collagenase digestion. The proportion of naïve (TNai) CD45RO−CCR7+, effector memory (TEM) CD45RO+CCR7−, central memory (TCM) CD45RO+CCR7+, and effector memory revertant RA+(TEMRA) CD45RO−CCR7− CD4+ and CD8+ T cells were measured by flow cytometry. CD4+ and CD8+ TEM and TEMRA were significantly enriched in SAT of PLWH compared to blood. The proportions of SAT CD4+ and CD8+ memory subsets were similar across metabolic status categories in the PLWH, but CD4+ T cell expression of the CD69 early-activation and tissue residence marker, particularly on TEM cells, increased with progressive glucose intolerance. Use of t-distributed Stochastic Neighbor Embedding (t-SNE) identified a separate group of predominantly CD69lo TEM and TEMRA cells co-expressing CD57, CX3CR1, and GPR56, which were significantly greater in diabetics compared to non-diabetics. Expression of the CX3CR1 and GPR56 markers indicate these TEM and TEMRA cells may have anti-viral specificity. Compared to HIV-negative controls, SAT from PLWH had an increased CD8:CD4 ratio, but the distribution of CD4+ and CD8+ memory subsets was similar irrespective of HIV status. Finally, whole adipose tissue from PLWH had significantly higher expression of TLR2, TLR8, and multiple chemokines potentially relevant to immune cell homing compared to HIV-negative controls with similar glucose tolerance.

The photocatalytic oxidation of water to molecular oxygen is a key step toward the conversion of solar energy to fuels. Understanding the detailed mechanism and kinetics of this reaction is important for the development of robust catalysts with improved efficiency. TiO2 is one of the best-known photocatalysts as well as a model system for the study of the oxygen evolution reaction (OER). Here we use hybrid density functional based energetic calculations and first-principles molecular dynamics simulations to investigate the pathway and kinetics of the OER on the majority (101) surface of anatase TiO2 in a water environment. Our results show that terminal Ti–OH groups are stable intermediates at the aqueous (101) interface, in accord with the experimental observation that OH radicals are efficiently produced on anatase. Oxidation of Ti–OH gives rise to a second stable intermediate, a surface-bridging peroxo dimer ((O22–)br) composed of one water and one surface lattice oxygen atom, consistent with the surfa...

Herbicide safener, a diverse group of chemicals, is an important tool used to protect plants from herbicidal injury. With the aim of decreasing drift injury of haloxyfop-P-methyl to sensitive plants, the protective effect of four safeners (R-28725, 3-dichloroacetyl oxazolidine and its two optical isomers) was evaluated. Physiological and biochemical tests were conducted under laboratory conditions in Northeast Agricultural University, China, by using seed treatment with safener and soil treatment with haloxyfop-P-methyl, respectively. The maize seeds treated with these safeners were safe from haloxyfop-P-methyl treatment. A positive correlation between growth level and endogenous glutathione (GSH) content, glutathione S-transferases (GST) activity was observed in this research. Enhancement of GSH content, GST activity and affinity of GST to 1-chloro-2,4-dinitrobenzene (CDNB) in maize treated by R-28725 was maximum. However, the detoxification of herbicide was not accompanied by the increase of acetyl-CoA-carboxylase (ACC) activity in maize.

Water splitting driven by solar energy is regarded as the candidate for the next generation of power source. The reaction is however kinetically hindered by the oxygen evolution reaction (OER) involving four proton–electron transfer steps. The ideal OER catalyst should avoid using precious elements, such as Ir, Ru, and Pt, and have a long-term stability under positive bias potential. Recent experiments have shown that most 3d oxides are OER active catalysts, while some can even achieve comparable activities to commercial Ir/Ru catalysts in lab condition. In this article, we review the recent theoretical progress for characterizing the structure of 3d oxides and understanding the photo-electrocatalytic water splitting mechanism over these catalysts. The methodology for global structure exploration, including evolutionary algorithm and stochastic surface walking method, is first introduced together with their applications in exploring the potential energy surface of TiO2 and NiOx systems. The current theoretical approaches to investigate the thermodynamics and kinetics of photo-/electrochemical reactions are discussed and the latest understanding for OER reactions are summarized. WIREs Comput Mol Sci 2016, 6:47–64. doi: 10.1002/wcms.1236 For further resources related to this article, please visit the WIREs website.

In the original version of [this article][1] ([1][2]), there are errors in Figs. 1D and H and 5B. Specifically, in Fig. 1D, the same migration assay image was used in the second and seventh panels, and an overlapping image was used in the third and fourth panels. In addition, the same migration

PROteolysis TArgeting Chimeras (PROTACs) have emerged as a new and promising modality utilizing an event-driven MOA, whereby protein levels could be modulated by PROTAC-induced degradation by hijacking the ubiquitin-proteasome system. Starting from 2001, many target proteins have been studied, such as BET and kinase families as well as nuclear receptors. Bruton's tyrosine kinase (BTK) is an essential component of BCR pathway, which plays an important role in development, activation, proliferation, and survival of B lymphocytes. Ibrutinib is an irreversible inhibitor of BTK, and shows promising activity against multiple B lymphocyte derived malignancies. However, there remains a big concern about the development of Ibrutinib induced resistance by BTK C481S mutant. In our study, HSK26784 was found as a novel orally available BTK-PROTAC molecule, which could selectively degrade the BTK proteins. HSK26784 selectively degraded BTK proteins in Mino cell lines, with a half degradation concentration (DC50) of 22.9 nM. HSK26784 also effectively induced BTK degradation in mouse spleen, with a DC50 of 3.8 mg/kg. In addition, HSK26784 significantly inhibit the expression of CD69 on human PBMC cells after ex vivo BCR stimulation. HSK26784 could inhibit cell proliferation in many malignant B cell lines. In Ibrutinib sensitive cell lines, the inhibitory activity of HSK26784 is similar to that of Ibrutinib. While in the Ibrutinib non-sensitive cell lines, HSK26784 was more potent than Ibrutinib. Importantly, in the xenograft models, HSK26784 could also inhibit the tumor growth in a dose dependent manner. And HSK26784 achieved much better therapeutic effects than Ibrutinib. HSK26784 could inhibit the kinase activity of BTK wt and BTK C481S mutant, with IC50 of 11 nM and 14 nM respectively. It indicated that the efficacy of HSK26784 in BTK wt and BTK C481S mutant was comparable. HSK26784 showed good orally bioavailability in different species. The oral bio availabilities in mice, rats and dogs were 15.4 %, 11.8 % and 12.8 % respectively. In conclusion, HSK26784 is a promising BTK PROTAC degrader with better efficacy than Ibrutinib in multiple B lymphocytes. Citation Format: Meilin Qian, Fei Ye, Chen Zhang, Jianming Wang, Yuanli Zhang, Yangyang Cui, Linli Li, Xiaoli Gou, Jia Ni. HSK26784: An oral PROTAC-BTK degrader for multiple B lymphocyte derived malignancies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3761.

Oxide Chemistry Below the Surface Although metal oxides, such as titanium dioxide (TiO 2 ), are used for catalytic oxidation reactions and photocatalysis, the O 2 does not react directly with substrates. Vacancies in the surface region of the TiO 2 rutile phase can transfer a negative charge to adsorbed O 2 to create more reactive species. By contrast, in anatase—the phase associated with nanoscale TiO 2 particles—subsurface vacancies form. Setvin et al. (p. 988 ) used a scanning tunneling microscopy tip to pull these vacancies to the surface in a niobiumdoped anatase crystal and followed the transformation of adsorbed O 2 − into a peroxo species and a bridging O 2 dimer.

Nickel ferrite, NiFe2O4, is a material with interesting physical properties and useful technological applications. We have used Density-functional theory with on-site Coulomb repulsion U term to study the structure, electronic properties, and energetics of the NiFe2O4(001) surface and its interaction with water both in the absence and in the presence of surface oxygen vacancies. In a humid environment, water adsorbs dissociatively on the surface oxygen vacancies leading to the formation of surface hydroxyls. At high temperature, water desorbs leaving a surface containing oxygen vacancies. These defects could represent useful reactive sites for various catalytic reactions.

Summary Presynaptic endosomes reportedly participate in synaptic vesicle (SV) recycling. However, it remains unclear whether they differentially regulate SV biogenesis and synaptic transmission in different types of synapses and how they are implicated in diseases. Using cryo-electron tomography and endocytic tracing, we uncover different endocytic modes and dynamics associated with distinct SV morphology between glutamatergic and GABAergic synapses. We further find that cathepsin D (CatD), a lysosomal storage disease (LSD) protein, is selectively located in GABAergic presynaptic endosomes. Inactivation of CatD results in enlarged presynaptic endosomes, reduces the readily releasable pool, and impairs synaptic transmission in GABAergic, but not glutamatergic, synapses. Moreover, CatD-deficient mice exhibit hyperactivity and increased sensitivity to seizure, mimicking epileptic behavior in CatD-related LSD patients. These data reveal an important role for presynaptic endosomal CatD in regulating GABAergic SV biogenesis and provide mechanistic insights for understanding the synaptic pathology and behavioral defects in CatD-associated LSD.

Although the rhizomes of Rheum nobile Hook. f. et Thoms (Polygonaceae) are widely used in Tibetan medicine, no previous investigations regarding the biological activities and rarely chemical constituents of this plant have been reported. As part of an ongoing search for novel bioactive agents, a phytochemical investigation of R. nobile led to the isolation of two new compounds Rheumone B (1) and piceatannol-4′-O-β-D-(6″-O-acetyl)-glucoside (2), together with 15 known compounds by gel filtration over Sephadex LH-20 and preparative HPLC. Their structures were determined by combined spectroscopic methods. Compounds 1–10 were evaluated for their ability to scavenge 2,2-diphenyl-1-picrylhydzyl (DPPH) radical and compounds 7–10 showed relatively strong scavenging abilities with IC50 values from 2.76 μM to 11.80 μM. In conclusion, naphthalene glycosides, stilbene glycosides, flavanols, especially anthraquinones are main chemical constituents of this plant. The ability to scavenge DPPH radical of compound 8 was the highest among compounds 1–10.

ObjectiveTo investigate the expression of soluble vascular endothelial growth factor receptor-1 (sFlt-1) and placental growth factor (PLGF) in the fetal growth restriction (FGR) cases and the intervention mechanism of tetramethylpyrazine.MethodsA total of 60 fetal growth restriction cases that admitted to our hospital were randomly divided into ligustrazine intervention group (group A) and nutritional support group (group B). A total of 50 healthy pregnant women were also enrolled as control group (group C). Expression level of maternal serum sFlt1, PLGF and fetal growth parameters including HC, AC, FL, BPD, EFW as well as placenta PLGF, sFlt-1 mRNA expression were recorded and compared among the three groups. A total of 15 SD rats were selected and were divided into three groups, TMP group, alcohol and tobacco group and blank control group. Three groups of rats were dissected on the twentieth day of gestation.ResultsExpression level of sFlt-1 and PLGF in group A was not significantly different from that of group C (P>0.05); but significant difference in SFlt1 and PLGF expression level was observed between group C and group B (P0.05). There was significant difference in PLGF between FGR group with treatment and FGR group without treatment or control group (P

Mixed nickel–iron oxides have recently emerged as promising electrocatalysts for water oxidation because of their low cost and high activity, but the composition and structure of the catalyst’s active phase under working conditions are not yet fully established. We present here density functional theory calculations with on-site Coulomb repulsion of the energetics of the oxygen evolution reaction (OER) on selected surfaces of pure and mixed Ni–Fe oxides that are possible candidates for the catalyst’s active phase. The investigated surfaces are pure β-NiOOH(0115) and γ-NiOOH(101), Fe-doped β-NiOOH(0115) and γ-NiOOH(101), NiFe2O4(001), and Fe3O4(001). We find that Fe-doped β-NiOOH(0115) has by far the lowest overpotential (η = 0.26 V), followed by NiFe2O4(001) (η = 0.42 V). Our results indicate that Fe-doped β-NiOOH and, to a lesser extent, NiFe2O4 could be the phases responsible for the enhanced OER activity of NiOx when it is doped with Fe.

The BF3·Et2O-catalyzed formal [3 + 2] reaction of aziridinofullerenes with various carbonyl compounds for the easy preparation of fullerooxazolidines has been developed. Moreover, the reaction of aziridinofullerene with ethyl formate affords the simplest fullerooxazole without substituent.

The facile one-step reaction of [60]fullerene with isocyanates/isothiocyanates in the presence of ferric perchlorate generates a series of oxazolidinofullerenes/thiazolidinofullerenes, which are difficult to prepare by common methods. The direct dissolution approach plays an important role in the efficient synthesis of oxazolidinofullerenes/thiazolidinofullerenes. A possible reaction mechanism for the product formation is proposed.

While Scanning Tunneling Microscopy (STM) has evolved as an ideal tool to study surface chemistry at the atomic scale, the identification of adsorbed species is often not straightforward. This paper describes a way to reliably identify H2O, CO and O2 on the TiO2 anatase (101) surface with STM. These molecules are of a key importance in the surface chemistry of this and many other (photo-) catalytic materials. They exhibit a wide variety of contrasts in STM images, depending on the tip condition. With clean, metallic tips the molecules appear very similar, i.e., as bright, dimer-like features located in the proximity of surface Ti5c atoms. However, each species exhibits a specific response to the electric field applied by the STM tip. It is shown that this tip–adsorbate interaction can be used to reliably ascertain the identity of such species. The tip–adsorbate interactions, together with comparison of experimental and calculated STM images, are used to analyse and revisit the assignments of molecular adsorbed species reported in recent studies.

A novel polymer membrane (TPP-M) with strong light harvesting ability within the entire visible- light spectrum has been prepared, in which the meso-tetrakis(4-cyanophenyl) porphyrin (TPP-1) as a functional unit is highly crosslinked through an aromatic nitrile trimerization reaction. The designed triazine framework controls the size of the -conjugation and retains the excellent photophysical properties of monomeric porphyrin, such as strong absorption and high singlet oxygen quantum yield. Due to these excellent photophysical properties and low solubility in common organic solvents, polyporphyrin membranes, as efficient singlet oxygen (O-1(2)) sensitizers, could be easily recycled and reused for the photo-oxidation of 1,5-dihydroxynaphthalene (DHN). image

Surfactant imbibition experiments were carried out with four surfactants and effects of interfacial tension and surface wettability on oil recovery were studied. A convenient imbibition process with quartz sands was used, and the experimental results suggest that anionic and non-ionic surfactants have higher oil recovery than cationic surfactant, and the sand surface wettability plays an important role in influencing oil recovery during spontaneous imbibition. Altering the wettability of oil sand surface from oil-wet to water-wet can enhance the oil recovery of imbibition process. The maximum ultimate imbibition recovery appeared in the area where both contact angle and interfacial tension were low.

Kenkiyak oilfield in kazakstan is a low porosity, extremely low permeability and overpressure carbonate reservoir. There are different reservoir and fracture characteristics in different region. The formation pressure decline seriously and water cannot be injected into the low permeability zone. Referring to the domestic and oversea research achievement, integrating regional geologic characteristics, numerical simulation results and reservoir engineering research results, we optimize a series of the development technology policy, including the reasonable gas and water injection modes and injection opportunity, the suitable well patterns and well spacing. Meanwhile, the development mode of energy supplement in the extremely low permeability and overpressure reservoir is explored.

This work explores thoroughly the reaction network of the partial oxidation of phenylmethanol at the TiO(2)-solvent interface under photocatalytic conditions by using a first-principles continuum solvation method. We demonstrate that the photocatalytic oxidation of phenylmethanol has a complex reaction network with dual pathways. The dimer pathway dominates the mechanism under aerobic conditions and a [C(6)H(5)CH(OH)O](2) peroxo dimer is the key intermediate, the decomposition of which leads to an unusual O exchange phenomenon.

As a model system of 2-D oxide material, layered δ-MnO2 has important applications in Li ion battery systems. δ-MnO2 is also widely utilized as a precursor to synthesize other stable structure variants in the MnO2 family, such as α-, β-, R-, and γ-phases, which are 3-D interlinked structures with different tunnels. By utilizing the stochastic surface walking (SSW) pathway sampling method, we here for the first time resolve the atomistic mechanism and the kinetics of the layer-to-tunnel transition of MnO2, that is, from δ-MnO2 to the α-, β-, and R-phases. The SSW sampling determines the lowest-energy pathway from thousands of likely pathways that connects different phases. The reaction barriers of layer-to-tunnel phase transitions are found to be low, being 0.2-0.3 eV per formula unit, which suggests a complex competing reaction network toward different tunnel phases. All the transitions initiate via a common shearing and buckling movement of the MnO2 layer that leads to the breaking of the Mn-O framework and the formation of Mn(3+) at the transition state. Important hints are thus gleaned from these lowest-energy pathways: (i) the large pore size product is unfavorable for the entropic reason; (ii) cations are effective dopants to control the kinetics and selectivity in layer-to-tunnel transitions, which in general lowers the phase transition barrier and facilitates the creation of larger tunnel size; (iii) the phase transition not only changes the electronic structure but also induces the macroscopic morphology changes due to the interfacial strain.

The overexpression of interleukin-8 (IL-8) is closely associated with poor tumor differentiation, metastasis and tumor progression. This study aimed to examine the effects and mechanisms of action of SN38 (a metabolite of the camptothecin derivative, CPT-11) on IL-8 expression in HCT8 cells, using ELISA, CCK-8 and western blot analysis. Among jatrorrhizine, evodiamine, 5-fluorouracil and SN38, SN38 was found to inhibit the proliferation of HCT8 cells in a dose-dependent manner, but to increase IL-8 secretion from HCT8 cells. Of the other agents, evodiamine was found to inhibit both IL-8 secretion and cell proliferation, and jatrorrhizine was found to increase IL-8 secretion without any obvious inhibitory effect on cell proliferation. Further experiments revealed that the increased activation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK)1/2 and c-Jun N-terminal kinase (JNK) by SN38 contributed to the decreased cell proliferation and to the overexpression of IL-8 induced by SN38. Our results suggested that the MAPK pathways are activated by SN38, resulting in the upregulation of IL-8 expression and in the inhibition of cell proliferation in an IL-8-independent manner. Thus, the potential benefit of the use of a combination of camptothecin-11 with other chemical drugs with inhibitory effects on IL-8 expression, should be paid more attention in treating colon cancer.

In this work, a robust brefeldin A-synthesizing fungus, Eupenicillium brefeldianum ZJB082702, was bred from a Murraya paniculata endophytic fungus E. brefeldianum A1163. Using one-factor-at-a-time experimental design, optimization of media composition for E. brefeldianum ZJB082702 fermenting brefeldin A was conducted. Outcomes indicated that mixed carbon source and mixed nitrogen source were of c ritical importance to brefeldin A fermentation. After 6d culture in the optimized fermentation media, composed of (gl(-1)) 13.33 starch, 26.67 glucose, 1.0 yeast extract powder, 1.0 corn steep liquor, 0.5 soybean meal, 0.75 NaNO(3), 2.5 malt extract, 6.0 CaCO(3), 3.0 MgSO(4), 4.0 KH(2)PO(4), 1.0 × 10(-2) CuSO(4), brefeldin A yield peaked at 1304.7 mgl(-1), 648.2 mgl(-1) in 500 ml baffled flask and 15 l stirred fermentor respectively, formed as a growth associated type of secondary metabolite based on fermentation profile analysis.

The paper analyzed the adsorption conditions of uranium on carboxylic acid fiber. The isotherms were drawn, and Langmuir and Freundlich equations were deduced. The adsorption kinetics of UO22+on carboxylic fiber was researched. The rate constant of adsorption was obtained and the apparent activation energy was determined. This research provides a theoretical basis for new adsorbents of uranium in nuclear wastes.