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Competing Interests: None declared.

Background:  The extent to which educational attainment (EA) influences the risk of varicose veins (VVs), venous thromboembolism (VTE), and phlebitis occurrence, whether this pathway is mediated by obesity-related traits, and the proportion of their mediation is unknown., Methods:  A Mendelian randomization (MR) design was used to genetically investigate the causal effects of EA on the risk of VV, VTE, and phlebitis and to assess the mediating effect of obesity-related traits. Causal effects were estimated using primarily the multiplicative random-effects inverse variance-weighted method. This was supplemented by Cochran's Q-statistic, MR-Egger regression, MR funnel plots, and leave-one-out test to evaluate the reliability of the results. For the individual mediation effect, the coefficient product method was mainly utilized to estimate., Results:  An increase in genetically predicted EA was associated with a lower risk of VV, VTE, and phlebitis, as well as lower body mass index, basal metabolic rate, hip circumference, and waist circumference. As genetically predicted body mass index, basal metabolic rate, hip circumference, and waist circumference increased, the risk of developing VV, VTE, and phlebitis increased, respectively. Body mass index, basal metabolic rate, hip circumference, and waist circumference were identified as mediators of the protective effects of EA on VV, VTE, and phlebitis., Conclusion:  The findings support a causal relationship between higher EA and lower risk of VV, VTE, and phlebitis. Obesity-related traits play a significant mediating role in these pathways, and there are interactions between them, with hip circumference mediating these pathways relatively independently from the other three., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Increasing evidence indicates a close relationship between alterations in human immune cells and plasma metabolites with Rheumatoid Arthritis (RA). However, limited studies have left the causal relationships behind these links unclear., Methods: A bidirectional Mendelian Randomization (MR) study was conducted, combined with mediation analysis, using data from genome-wide association study database covering 731 immune cell phenotypes and 1,400 plasma metabolite traits to explore their causal relationships with RA and potential mediating effects. The primary method used for MR analysis was inverse-variance weighted and False Discovery Rate (FDR) correction was applied to verify the robustness of our results., Results: HLA DR on CD33- HLA DR+ (myeloid cell group) (OR, 1.422; 95% CI, 1.194-1.694; P < 0.001; P FDR = 0.012) increased the risk of developing RA. CD19 on IgD+ CD38- naive (B cell group) (OR, 0.969; 95% CI, 0.954-0.985; P < 0.001; P FDR = 0.021) reduced the risk of developing RA. RA was a risk factor for HLA DR on CD14- CD16+ monocytes (monocyte group) (OR, 1.242; 95% CI, 1.102-1.401; P < 0.001; P FDR  = 0.047). RA was a protective factor for memory B cell %lymphocyte (B cell group) (OR, 0.861; 95% CI, 0.795-0.933; P < 0.001; P FDR  = 0.050), CD4+ CD8dim T cell %lymphocyte (TBNK group) (OR, 0.802; 95% CI, 0.711-0.904; P < 0.001; P FDR  = 0.043), CD4+ CD8dim T cell %leukocyte (TBNK group) (OR, 0.814; 95% CI, 0.726-0.913; P < 0.001; P FDR  = 0.046), CD24 on IgD+ CD24+ B cells (B cell group) (OR, 0.857; 95% CI, 0.793-0.927; P < 0.001; P FDR  = 0.038), and CD24 on unswitched memory B cells (B cell group) (OR, 0.867; 95% CI, 0.797-0.942; P < 0.001; P FDR  = 0.050). Increasing levels of docosatrienoate (22:3n3) (OR, 0.886; 95% CI, 0.838-0.936; P < 0.001; P FDR  = 0.023) significantly reduced the risk of developing RA. The mediating effect of plasma metabolites in this context was not established., Conclusion: This study provides genetic evidence for the intricate relationships between immune cells, plasma metabolites, and RA, highlighting the potential mechanisms involved. This will contribute to future directions in precision medicine and research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Du, Xie and Chai.)

Background:  Given the current debate in clinical research about the relationship between tobacco smoking and the risk of venous thromboembolism (VTE), a Mendelian randomization (MR) study was conducted aimed at elucidating the causal associations of current and past tobacco smoking with the risk of VTE, from the perspective of genetics., Methods:  Two-sample univariate and multivariable MR analyses were designed, using summary-level data from large genome-wide association studies involving European individuals. Causality was primarily assessed using multiplicative fixed-effects or random-effects model and inverse variance weighting, supplemented by MR-Egger regression, MR-PRESSO, Cochran's Q test, and leave-one-out for sensitivity analysis to test the reliability of the results., Results:  In the univariate MR analysis, no significant causal effects were found between current tobacco smoking and the risk of VTE, deep vein thrombosis (DVT), and pulmonary embolism (PE). Similarly, no significant causal effects were found between past smoking and VTE, DVT, and PE. As for the multivariable MR analysis, results were consistent with univariate MR analysis, with no significant causal effect of either current or past tobacco smoking on the risk of VTE, DVT, and PE., Conclusion:  Evidence from both univariate and multivariable MR analyses demonstrated no significant causal relationships between current and past tobacco smoking and VTE, DVT, and PE. This contradicts positive correlations reported in some previous observational studies, which may be explained by other confounding factors. This provided genetic evidence for the conclusion reported in other observational studies that smoking did not affect VTE risk., Competing Interests: None declared., (Thieme. All rights reserved.)

A key factor for productive DNA-encoded libraries is the chemical diversity of the small molecule moiety attached to an encoding DNA oligomer. The library structure diversity is often limited to DNA-compatible chemical reactions in aqueous media. Herein, we describe a facile process for reducing aryl nitro groups to aryl amines by using sodium dithionite (Na 2 S 2 O 4 ). The new protocol offers simple operation and circumvents the pyrophoric potential of the conventional method (Raney nickel). The utility of this method is demonstrated by the versatile synthesis of benzimidazoles on DNA., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed more than 4 million humans globally, but there is no bona fide Food and Drug Administration-approved drug-like molecule to impede the COVID-19 pandemic. The sluggish pace of traditional therapeutic discovery is poorly suited to producing targeted treatments against rapidly evolving viruses. Here, we used an affinity-based screen of 4 billion DNA-encoded molecules en masse to identify a potent class of virus-specific inhibitors of the SARS-CoV-2 main protease (M pro ) without extensive and time-consuming medicinal chemistry. CDD-1714, the initial three-building-block screening hit (molecular weight [MW] = 542.5 g/mol), was a potent inhibitor (inhibition constant [ K i ] = 20 nM). CDD-1713, a smaller two-building-block analog (MW = 353.3 g/mol) of CDD-1714, is a reversible covalent inhibitor of M pro ( K i = 45 nM) that binds in the protease pocket, has specificity over human proteases, and shows in vitro efficacy in a SARS-CoV-2 infectivity model. Subsequently, key regions of CDD-1713 that were necessary for inhibitory activity were identified and a potent ( K i = 37 nM), smaller (MW = 323.4 g/mol), and metabolically more stable analog (CDD-1976) was generated. Thus, screening of DNA-encoded chemical libraries can accelerate the discovery of efficacious drug-like inhibitors of emerging viral disease targets., Competing Interests: Competing interest statement: A provisional patent involving the molecules described in this paper and their uses has been submitted., (Copyright © 2021 the Author(s). Published by PNAS.)

Hauser's engraver beetle, Ips hauseri, is a serious pest in spruce forest ecosystems in Central Asia. Its monoterpenoid signal production, transcriptome responses and potential regulatory mechanisms remain poorly understood. The quality and quantity of volatile metabolites in hindgut extracts of I. hauseri were found to differ between males and females and among three groups: beetles that were newly emerged, those with a topical application of juvenile hormone III (JHIII) and those that had been feeding for 24 h. Feeding males definitively dominated monoterpenoid signal production in I. hauseri, which uses (4S)-(-)-ipsenol and (S)-(-)-cis-verbenol to implement reproductive segregation from Ipstypographus and Ipsshangrila. Feeding stimulation induced higher expression of most genes related to the biosynthesis of (4S)-(-)-ipsenol than JHIII induction, and showed a male-specific mode in I. hauseri. JHIII stimulated males to produce large amounts of (-)-verbenone and also upregulated the expression of several CYP6 genes, to a greater extent in males than in females. The expression of genes involved in the metabolism of JHIII in females and males was also found to be upregulated. Our results indicate that a species-specific aggregation pheromone system for I. hauseri, consisting of (4S)-(-)-ipsenol and S-(-)-cis-verbenol, can be used to monitor population dynamics or mass trap killing. Our results also enable a better understanding of the bottom-up role of feeding behaviors in mediating population reproduction/aggregation and interspecific interactions., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

A zinc bromide-catalyzed synthesis of 5-substituted tetrazoles via DNA-conjugated nitriles using sodium azide has been developed. The protocol offered moderate to excellent yields of tetrazoles with a broad range of substrates, including a variety of functionalized aromatic, heterocyclic, and aliphatic nitriles. In addition, the electronic effect within the substrate scope was evaluated. DNA fidelity was assessed by ligation efficiency and amplifiability analysis. The ability to generate tetrazoles expands the diversity of heterocycles in the preparation of DNA-encoded chemical libraries.

Objective: Long-chain non-coding RNA (LncRNA) is abnormally expressed in various malignant tumors. In recent years, it has been found that the expression of LncRNA SNHG6 is upregulated in gallbladder carcinoma tissues, which participated in the occurrence and development of gallbladder carcinoma. However, the clinical value of SNHG6 in gallbladder cancer serum is not clear, and there are few studies regulating the biological function of gallbladder carcinoma cells. This study aimed to investigate LncRNA SNHG6 and miR-26b-5p in gallbladder carcinoma and its related mechanisms., Patients and Methods: From February 2017 to February 2019, altogether 68 cases of gallbladder cancer patients admitted to the Yantai Yeda Hospital were collected as a study group, 70 healthy people as a control group. Gallbladder cancer cells and human colorectal mucosa cells were purchased. Sh-SNHG6, si-SNHG6, NC, miR-26b-5p-inhibitor, and miR-26b-5p-mimics were transfected into GBC-SD and NOZ cells. For the detection of SNHG6 and miR-26b-5p in samples we used qRT-PCR, WB was applied for the decreased protein expression of Gli1, Gli2, Shh, Smo, N-cadherin, vimentin, Snail, E-Cadherin, and Gli3 in cells. MTT assay was applied for the detection of cell proliferation, transwell assay for cell invasion, and flow cytometry assay for apoptosis., Results: SNHG6 was highly expressed in gallbladder carcinoma, miR-26b-5p was downregulated, and the area under curve (AUC) of LncRNA SNHG6 and miR-26b-5p was more than 0.8. LncRNA SNHG6 and miR-26b-5p were related to age, sex, tumor invasion, differentiation degree, tumor location, and tumor-node-metastasis (TNM) staging of gallbladder cancer patients. Silencing of SNHG6 and upregulation of miR-26b-5p could promote cell apoptosis, inhibit cell growth, and epithelial-mesenchymal transition (ETM). Silencing of SNHG6 and upregulation of miR-26b-5p could inhibit Gli1, Gli2, Shh, Smo, N-cadherin, vimentin and Snail proteins, and promote upregulation of Gli3 and E-Cadherin expression. Dual-Luciferase report confirmed that SNHG6 and miR-26b-5p have targeted relationship. Rescue experiments showed that after co-transfecting sh-SNHG6+miR-26b-5p-mimics, and si-SNHG6+miR-26b-5p-inhibitor into GBC-SD and NOZ, the proliferation, invasion and apoptosis of cells were not different from those of miR-NC group without transfection sequence., Conclusions: Inhibition of LncRNA SNHG6 expression can upregulate miR-26b-5p mediated Hedgehog signaling pathway, affect epithelial-mesenchymal transition, proliferation and invasion of cells, so LncRNA SNHG6is hoped to be a latent therapeutic target for gallbladder carcinoma.

Antiferroelectric-based dielectric capacitors are receiving tremendous attention for their outstanding energy-storage performance and extraordinary flexibility in collecting pulsed powers. Nevertheless, the in situ atomic-scale structural-evolution pathway, inherently coupling to the energy storage process, has not been elucidated for the ultimate mechanistic understanding so far. Here, time- and atomic-resolution structural phase evolution in antiferroelectric PbZrO 3 during storage of energy from the electron-beam illumination is reported. By employing state-of-the-art negative-spherical-aberration imaging technique, the quantitative transmission electron microscopy study presented herein clarifies that the hierarchical evolution of polar oxygen octahedra associated with the unit-cell volume change and polarization rotation accounts for the stepwise antiferroelectric-to-ferroelectric phase transition. In particular, an unconventional ferroelectric category-the ferrodistortive phase characteristic of a unique cycloidal polarization order-is established during the dynamic structure investigation. Through clarifying the atomic-scale phase transformation pathway, findings of this work unveil a new territory to explore novel ferrodistortive phases in energy-storage materials with the nonpolar-to-polar phase transitions., (© 2020 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Hypofunction of the serotonin (5-HT) 5-HT 2C receptor (5-HT 2C R) has been implicated in a variety of disorders including substance use disorders. As such, approaches to enhance 5-HT 2C R signaling display therapeutic potential. In the present study, we show that disruption of the 5-HT 2C R interaction with the protein phosphatase and tensin homolog (PTEN) via peptidomimetics enhances 5-HT 2C R-mediating signaling in vitro and potentiates selective 5-HT 2C R agonists in behavioral rodent models. Overall, the present study provides further evidence that 5-HT 2C R activity can be modulated through an allosteric protein-protein interaction. This work provides the groundwork for the continued exploration of protein-protein interactions that can allosterically modulate this critical receptor and other important G protein-coupled receptors (GPCRs) for new therapeutic development through mechanisms that may display clinical utility.

We investigated the effects of different types of early feeding on rumen fermentation parameters and the bacterial community in calves. Fifty-four Holstein calves were assigned to three treatments and fed whole milk (M), pasteurized waste milk (WM), or milk replacer (MR). Male calves were slaughtered at the age of two months to measure the stomach masses. The female calves were followed for six months to determine the body weight, blood indices, rumen fermentation, and ruminal bacterial community. At the age of two months, the average daily gain was lower, but the concentration of total volatile fatty acids was greater in the MR group. Starter intake and stomach mass were lower, but the isovalerate molar proportion was greater in the WM group. The blood indices and ruminal bacterial community of the WM group differed from those of the other groups. At the age of six months, the ruminal propionate molar proportion was lower, but the ruminal pH and acetate/propionate ratio were greater in the MR group. In conclusion, calves fed WM had different rumen fermentation and bacterial community during the weaning period, whereas feeding MR produced a long-lasting effect on the rumen environment.

A multistep protocol for the synthesis of 3,5-disubstituted 1,2,4-oxadiazoles on DNA-chemical conjugates has been developed. A set of six DNA-connected aryl nitriles were converted to corresponding amidoximes with hydroxylamine followed by the O-acylation with a series of aryl and aliphatic carboxylic acids. After cyclodehydration of the O-acyl amidoximes by heating at 90 °C in pH 9.5 borate buffer for 2 h, the desired oxadiazole products were observed in 51-92% conversion with the cleavage of O-acylamidoximes as the major side-product. The reported protocol paves the way for the synthesis of oxadiazole core-focused DNA-encoded chemical libraries.

A hypodiboric acid system for the reduction of nitro groups on DNA-chemical conjugates has been developed. This transformation provided good to excellent yields of the reduced amine product for a variety of functionalized aromatic, heterocyclic, and aliphatic nitro compounds. DNA tolerance to reaction conditions, extension to decigram scale reductions, successful use in a DNA-encoded chemical library synthesis, and subsequent target selection are also described.

DNA-encoded chemical libraries have emerged as a cost-effective alternative to high-throughput screening (HTS) for hit identification in drug discovery. A key factor for productive DNA-encoded libraries is the chemical diversity of the small molecule moiety attached to an encoding DNA oligomer. The library structure diversity is often limited to DNA-compatible chemical reactions in aqueous media. Herein, we describe a facile process for reducing aryl nitro groups to aryl amines. The new protocol offers simple operation and circumvents the pyrophoric potential of the conventional method (Raney nickel). The reaction is performed in aqueous solution and does not compromise DNA structural integrity. The utility of this method is demonstrated by the versatile synthesis of benzimidazoles on DNA.

The extracellular matrix has drawn considerable interest in tissue engineering not only acts as a bioactive three-dimensional scaffold but also regulates cell behaviors through providing biochemical signals. Extracellular matrix-based biomaterials, mainly derived from xenogeneic tissues, have shown positive outcomes in promoting cutaneous wound healing. However, such extracellular matrices only contain low doses of growth factors, which limit their therapeutic efficiency. Recent reports demonstrated that cell sheets made from mesenchymal stem cell can accelerate wound repair through enhanced re-epithelialization and angiogenesis, but its clinical translation is hindered by several limitations, such as the risk of aberrant immune responses and cost implications. In this study, acellular extracellular matrices were prepared from CuCl 2 -conditioned mesenchymal stem cell sheets and their in vivo wound healing properties were evaluated in a mouse model of full-thickness skin defect. We found that extracellular matrices derived from CuCl 2 -conditioned mesenchymal stem cell sheets have a compact surface with thick solid-like cross-sectional structure. Moreover, CuCl 2 dramatically enriched the extracellular matrices with collagen I, collagen III, transforming growth factor-β1, vascular endothelial growth factor, and basic fibroblast growth factor via hypoxia-inducible factor-1α activation. And as a consequence, the resulting extracellular matrices showed markedly improved in vivo wound healing potency through early adipocyte mobilization, enhanced granulation tissues formation, rapid re-epithelialization, and augmented angiogenesis. Therefore, we consider that the extracellular matrix derived from CuCl 2 -conditioned mesenchymal stem cell sheets has the potential for clinical translation and may lead to a novel strategy for wound management.

We theoretically investigate high-order harmonic generation (HHG) from solids in two-color fields. It is found that under the premise of maintaining the same amplitude, the intensity of the second plateau can be enhanced by two to three orders in a proper two-color field compared with the result in the monochromatic field with the same frequency as the driving pulse of the two-color field. This can be attributed to the fact that most excited electrons can be driven to the top of the first conduction band due to the larger vector potential of the two-color fields, which leads to the higher electron population of upper conduction bands. Moreover, we also find that isolated attosecond pulses can be generated from solids by choosing a proper two-color field that allows the electrons to reach the top of the first conduction band only once. This work provides a promising method for extending the range of solid HHG spectra in experiments.

Canine mammary tumors are the most common neoplasms in intact female dogs. The surgery cannot always solve the problem, chemotherapy are recommend to these patients. However, chemotherapy could always fail because of multidrug resistance (MDR). Through stepwise increasing 5-Fluorouracil (5-FU) concentration in the culture medium, a 5-FU-resistant canine mammary tumor cell line CMT7364/5-FU was established to disclose the molecular mechanism of the drug resistance. Cell morphology, cell sensitivity to drugs, growth curves, expression of proteins, and chemo-sensitivity in vivo were compared between the parental cell line and resistant cell line. As compared it to its parental cell line (CMT7364), CMT7364/5-FU showed different morphology, cross-resistant to other chemo-drugs and a prolonged population doubling time (PDT). The drug efflux pump proteins (ABCB1 and ABCG2) in CMT7364/5-FU were up-regulated. In vivo, the similar result revealed that CMT7364/5-FU cell line was more resistant to 5-FU. In conclusion, a 5-FU-resistant canine mammary tumor cell line (CMT7364/5-FU) was successfully established, it can serve as a good model for researching the mechanism of MDR and screening effective agents to reverse drug resistance.

MSC treatment can promote cutaneous wound repair through multiple mechanisms, and paracrine mediators secreted by MSC are responsible for most of its therapeutic benefits. Recently, MSC sheet composed of live MSCs and their secreted ECMs was reported to promote wound healing; however, whether its ECM alone could accelerate wound closure remained unknown. In this study, Nc-ECM and Cc-ECM were prepared from nonconditioned and CoCl 2 -conditioned MSC sheets, respectively, and their wound healing properties were evaluated in a mouse model of full-thickness skin defect. Our results showed that Nc-ECM can significantly promote wound repair through early adipocyte recruitment, rapid reepithelialization, enhanced granulation tissue growth, and augmented angiogenesis. Moreover, conditioning of MSC sheet with CoCl 2 dramatically enriched its ECM with collagen I, collagen III, TGF- β 1, VEGF, and bFGF via activation of HIF-1 α and hence remarkably improved its ECM's in vivo wound healing potency. All the Cc-ECM-treated wounds completely healed on day 7, while Nc-ECM-treated wounds healed about 85.0% ± 8.6%, and no-treatment wounds only healed 69.8% ± 9.6% ( p < 0.05). Therefore, we believe that such growth factor-reinforced ECM fabricated from chemically hypoxic MSC sheet has the potential for clinical translation and will lead to a MSC-derived, cost-effective, bankable biomaterial for wound management.

By using the density functional theory, the study of reaction termination mechanism of two (CH3)2 (CN)C--CH2-- (CN)CH was carried out at the B3LYP/6-31G(d) level. The initiator AIBN was used. Reactants, coupled intermediates, transition states and disproportionation products were optimized at the B3LYP/6-31G(d) level. Then the total energies corrected by zero-point energy, vibrational frequencies and electronic structures were calculated, the transition states structure was also verified. The results show that it forms the energy-rich adducts a through the coupling termination. Then, the disproportionation product P[p1 (CH3)2 (CN) C-CH=CHCN + p2 (CH3)2 (CN)C-CH2-CH2CN] formed via hydrogen shift and dissociation. The reactions of coupling termination and disproportionation termination are all exothermic reactions, and the coupled product has lower energy. The rate constant of step a→TS→P k(298.15 K) = 2.71 x 10(-59) at the normal atmospheric temperature. Disproportionation termination occurs more easily with the reaction temperature rising, so the proportion of disproportionation products is increasing. Also, the analysis of infrared spectrogram of each species in reaction process shows chemical change of free radicals in the whole termination reaction. The authors give the HOMO-LUMO in this paper to verify the accuracy of biradical coupling termination and structures. It has important guiding significance to controlling the free radicals termination methods of acrylonitrile monomer.

Objective: To analyze the expression of phosphatidylinositol 3 kinase (PI3-K), protein kinase B (PKB) and glycogen synthase kinase 3 beta (GSK-3 β) in skeletal muscle tissue of gestational diabetes mellitus (GDM)., Methods: A total of 90 cases of pregnant women were divided into observation group and control group according to the occurrence of GDM with 45 cases in either, and the expression of PI3-K, PKB, GSK-3 β mRNA expression in skeletal muscle tissue was compared between two groups., Results: The total PI3-K p85 protein was significantly higher in the observation group compared with the control group, the activity of PI3-K was lower than that of the latter; The total PKB, GSK-3 β protein in skeletal tissue had no significant difference between two groups, while the serine phosphorylation levels of PKB and GSK-3β were significantly lower in observation group compared with the control group., Conclusions: The downregulation of PI3-K, PKB and GSK-3βin skeletal tissue of GDM caused by phosphorylation dysfunction of signaling molecules is the reason for insulin resistance and transporter function decline which lead to GDM., (Copyright © 2014 Hainan Medical College. Published by Elsevier B.V. All rights reserved.)

Objectives: The aims of the study were to (i) quantify the sales of over-the-counter (OTC) ophthalmic chloramphenicol from all community pharmacies in Wales and investigate the impact on primary care prescriptions up to 5 years after reclassification and (ii) investigate the temporal relationship between items supplied OTC and on NHS primary care prescriptions., Methods: Primary care prescription data (2004-2010) and OTC sales data (2005-2010) for ophthalmic chloramphenicol were obtained. The quantity sold OTC was calculated from pharmacy wholesale records and sales data from a large pharmacy multiple. Spearman's rank correlation for prescription and OTC supplies of ophthalmic chloramphenicol was calculated for data from January 2008 to December 2010., Key Findings: OTC supply of chloramphenicol eye drops and ointment were both highest in 2007-2008 and represented 68% (57,708/84,304) and 48% (22,875/47,192) of the corresponding prescription volume, respectively. There was a steady year-on-year increase in the combined supply of OTC ophthalmic chloramphenicol and that dispensed on prescription from 144,367 items in 2004-2005 to 210,589 in 2007-2008 before stabilising in 2008-2009 and 2009-2010. A significant positive correlation was observed between prescription items and OTC sales of chloramphenicol eye drops and ointment combined (r=0.7, P<0.001)., Conclusion: OTC availability increased the total quantity of ophthalmic chloramphenicol supplied in primary care compared to that seen prior to reclassification. Although growth in the sales of ophthalmic chloramphenicol OTC has stabilised and the supply pattern mirrors primary care prescribers, further work is required to investigate whether use is appropriate and whether the publication of updated practice guidance has changed this., (© 2013 The Authors. IJPP © 2013 Royal Pharmaceutical Society.)

To prepare beta-cyclodextrin (beta-CD)-deoxyrhaponti inclusion complex by the homogeneous method, and characterize the inclusion complex with ultraviolet-visible spectrum and fluorescence spectroscopy, in order to determine the inclusion rate, the ratio of subject-object, the binding constant of supra-molecular system and the thermodynamic function. The results showed that the designed method was so rational that the inclusion complex was successfully prepared. The ultraviolet-visible spectrophotometry method was adoptedto determine the inclusion rate of 38%, and the ratio of subject-object of 2: 1. The thermodynamic parameters of this inclusion complex: deltaH(0), deltaS(0) was all smaller than zero, which indicated that the main acting forces generated by the inclusion complex were hydrogen bonding and Vander Waals' force. deltaG(0) < 0 and deltaG(0) were directly proportional to the reaction temperature, which suggested that the reaction would spontaneously increase with the temperature rise. The polarization fluorescence method was used to quantitatively prove the non-covalent inclusion complex generated during the interaction between beta-CD interacting with DES. The results could also provide reference for studies on cyclodextrin supra-molecular system.

The etiology of epilepsy is a very complicated, multifactorial process that is not completely understood. Therefore, the availability of epilepsy animal models induced by different mechanisms is crucial in advancing our knowledge and developing new therapeutic regimens for this disorder. Considering the advantages of zebrafish, we have developed a seizure model in zebrafish larvae using ginkgotoxin, a neurotoxin naturally occurring in Ginkgo biloba and hypothesized to inhibit the formation of the neurotransmitter γ-aminobutyric acid (GABA). We found that a 2-hour exposure to ginkgotoxin induced a seizure-like behavior in zebrafish larvae. This seizure-like swimming pattern was alleviated by the addition of either pyridoxal-5'-phosphate (PLP) or GABA and responded quickly to the anti-convulsing activity of gabapentin and phenytoin, two commonly prescribed anti-epileptic drugs (AEDs). Unexpectedly, the ginkgotoxin-induced PLP depletion in our experimental setting did not affect the homeostasis of folate-mediated one-carbon metabolism, another metabolic pathway playing a crucial role in neural function that also relies on the availability of PLP. This ginkgotoxin-induced seizure behavior was also relieved by primidone, which had been tested on a pentylenetetrazole-induced zebrafish seizure model but failed to rescue the seizure phenotype, highlighting the potential use and complementarity of this ginkgotoxin-induced seizure model for AED development. Structural and morphological characterization showed that a 2-hour ginkgotoxin exposure did not cause appreciable changes in larval morphology and tissues development. In conclusion, our data suggests that this ginkgotoxin-induced seizure in zebrafish larvae could serve as an in vivo model for epileptic seizure research and potential AED screening.

Periodic density functional theory calculations are performed to study the hydrostatic compression effects on the structure, electronic, and thermodynamic properties of the energetic polyazide 4,4',6,6'-tetra(azido)hydrazo-1,3,5-triazine (TAHT) in the range of 0-100 GPa. At the ambient pressure, the local density approximation/Ceperley-Alder exchange-correlation potential parameterized by Perdew and Zunger relaxed crystal structure compares well with the experimental results. The predicted heat of sublimation is 38.68 kcal/mol, and the evaluated condensed phase of formation (414.04 kcal/mol) approximates to the experimental value. The detonation velocity and detonation pressure for the solid TAHT are calculated to be 7.44 km/s and 23.71 GPa, respectively. When the pressure is exerted less than 35 GPa, the crystal structure and geometric parameters change slightly. However, at 36 GPa, the molecular structure, band structure, and density of states change abnormally because of the azide-tetrazole transformation that has not been observed in gas phase or polar solvents. The azido group cyclizes to form a five-membered tetrazole ring that is coplanar with the riazine ring and contributes to a larger conjunction system. As the pressure augments further to 80 GPa, the hydrogen transfer is found and a new covalent bond H2-N9 is formed. In the studied pressure range, the band gap decreases generally except for some breaks due to the molecular transformation and drops to nearly zero at 100 GPa, which means the electronic character of the crystal changes toward a metallic system. An analysis of the electronic structure shows that an applied pressure increases the impact sensitivity of TAHT., (Copyright © 2012 Wiley Periodicals, Inc.)

A new polynitro cage compound 2, 4, 6, 8, 10, 12, 13, 14, 15-nonanitro-2, 4, 6, 8, 10, 12, 13, 14, 15-nonaazaheptcyclo [5.5.1.1(3,11).1(5,9)] pentadecane (NNNAHP) was designed in the present work. Its molecular structure was optimized at the B3LYP/6-31 G(d,p) level of density functional theory (DFT) and crystal structure was predicted using the Compass and Dreiding force fields and refined by DFT GGA-RPBE method. The obtained crystal structure of NNNAHP belongs to the P-1 space group and the lattice parameters are a = 9.99 Å, b = 10.78 Å, c = 9.99 Å, α = 90.01°, β = 120.01°, γ = 90.00°, and Z = 2, respectively. Based on the optimized crystal structure, the band gap, density of state, thermodynamic properties, infrared spectrum, strain energy, detonation characteristics, and thermal stability were predicted. Calculation results show that NNNAHP has detonation properties close to those of CL-20 and is a high energy density compound with moderate stability.

Triton X-114 temperature transition extraction has been considered to be a simple and cost-effective strategy to eliminate endotoxin from plasmid preparations. However, a repeated cooling-heating process may promote the degradation of plasmid DNA. Based on the finding that the cloud point of Triton X-114 solution increases substantially in the presence of small amounts of sodium dodecyl sulfate (SDS) and that electrolytes decrease the cloud point of Triton X-114-SDS solution drastically, we designed a Triton X-114 isothermal extraction method for removing endotoxin from plasmid samples and found that it has the same endotoxin removal efficiency when compared with the temperature transition extraction method., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Ab initio calculations have been performed using the complete basis set model (CBS-QB3) to study the reaction mechanism of butane radical (C(4)H(9)•) with oxygen (O(2)). On the calculated potential energy surface, the addition of O(2) to C(4)H(9)• forms three intermediates barrierlessly, which can undergo subsequent isomerization or decomposition reaction leading to various products: HOO• + C(4)H(8), C(2)H(5)• + CH(2)CHOOH, OH• + C(3)H(7)CHO, OH• + cycle-C(4)H(8)O, CH(3)• + CH(3)CHCHOOH, CH(2)OOH• + C(3)H(6). Five pathways are supposed in this study. After taking into account the reaction barrier and enthalpy, the most possible reaction pathway is C(4)H(9)• + O(2) → IM1 → TS5 → IM3 → TS6 → IM4 → TS7 → OH• + cycle-C(4)H(8)O.

A new polynitro cage compound with the framework of HNIW and a tetrazole unit, i.e., 10-(1-nitro-1, 2, 3, 4-tetraazol-5-yl)) methyl-2, 4, 6, 8, 12-hexanitrohexaazaisowurtzitane (NTz-HNIW) has been proposed and studied by density functional theory (DFT) and molecular mechanics methods. Properties such as IR spectrum, heat of formation, thermodynamic properties, and crystal structure were predicted. The compound belongs to the Pbca space group, with the lattice parameters a = 15.07 Å, b = 12.56 Å, c = 18.34 Å, Z = 8, and ρ = 1.990 g·cm(-3). The stability of the compound was evaluated by the bond dissociation energies and results showed that the first step of pyrolysis is the rupture of the N-NO(2) bond in the side chain. The detonation properties were estimated by the Kamlet-Jacobs equations based on the calculated crystal density and heat of formation, and the results were 9.240 km·s(-1) for detonation velocity and 40.136 GPa for detonation pressure. The designed compound has high thermal stability and good detonation properties and is probably a promising high energy density compound (HEDC).

In this work, the properties of the synthesized high-nitrogen compounds 4,4',6,6'-tetra(azido)azo-1,3,5-triazine (TAAT) and 4,4',6,6'-tetra(azido)hydrazo-1,3,5-triazine (TAHT), and a set of designed bridged triazines with similar bridges were studied theoretically to facilitate further developments for the molecules of interests. The gas-phase heats of formation were predicted based on the isodesmic reactions by using the DFT-B3LYP/AUG-cc-PVDZ method. The estimates of the condensed-phase heats of formation and heats of sublimation were estimated in the framework of the Politzer approach. Calculation results show that the method gives a good estimation for enthalpies, in comparison with available experimental data for TAAT and TAHT. The crystal density has been computed using molecular packing calculations. The calculated detonation velocities and detonation pressures indicate that -NF(2), -NO(2), -N═N-, and -N═N(O)- groups are effective structural units for improving the detonation performance of the bridged triazines. The synthesized TAAT and TAHT are not preferred energetic materials due to their inferior detonation performance. The p→π conjugation effect between the triazine rings and bridges makes the molecule stable as a whole. The electrostatic behavior of the bridged triazines is characterized by an anomalous surface potential imbalance when incorporating the strongly electron-withdrawing -NF(2) and -NO(2) groups into the molecule. An analysis of the bond dissociation energies shows that all these derivatives have good thermal stability over RDX and HMX, and the -NH-NH- bridge is more helpful for improving the stability than -N═N(O)- and -N═N- bridges. Considering the detonation performance and thermal stability, three bridged triazines may be considered as the potential candidates of high-energy density materials (HEDMs).

Polynitro cage compound 4-trinitroethyl-2,6,8,10,12-pentanitrohexaazaisowurtzitane has the same framework with but higher stability than CL-20 and is a potential new high energy density compound (HEDC). In this paper, the B3LYP/6-31G(d,p) method of density functional theory (DFT) has been used to study its heat of formation, IR spectrum, and thermodynamic properties. The stability of the compound was evaluated by the bond dissociation energies. The calculated results show that the first step of pyrolysis is the rupture of the N-NO(2) bond in the side chain and verify the experimental observation that the title compound has better stability than CL-20. The crystal structure obtained by molecular mechanics belongs to the P2(1)2(1)2(1) space group, with lattice parameters a = 12.59 Å, b = 10.52 Å, c = 12.89 Å, Z = 4, and ρ = 2.165 g·cm(-3). Both the detonation velocity of 9.767 km·s(-1) and the detonation pressure of 45.191 GPa estimated using the Kamlet-Jacobs equation are better than those of CL-20. Considering that this cage compound has a better detonation performance and stability than CL-20, it may be a superior HEDC.

The derivatives of DPO (2,5-dipicryl-1,3,4-oxadiazole) are optimized to obtain their molecular geometries and electronic structures at the DFT-B3LYP/6-31G* level. The bond length is focused to primarily predict thermal stability and the pyrolysis mechanism of the title compounds. Detonation properties are evaluated using the modified Kamlet-Jacobs equations based on the calculated densities and heats of formation. It is found that there are good linear relationships between density, detonation velocity, detonation pressure, and the number of azido, nitrate, and nitramine groups. According to the largest exothermic principle, the relative specific impulse is investigated by calculating the enthalpy of combustion (ΔH(comb)) and the total heat capacity (C(p,gases)). It is found that the introduction of -N(3), -ONO(2), and -NNO(2) groups could increase the specific impulses and II-4, II-5, and III-5 are potential candidates for High Energy Density Materials (HEDMs). The effect of the azido, nitrate, and nitramine groups on the structure and the properties is discussed., (Copyright © 2010 Wiley Periodicals, Inc.)

Aliphatic polynitrates are studied using the density functional theory B3LYP method with basis set 6-31G*. The assigned infrared spectrum is obtained and is used to compute the thermodynamic properties based on the frequencies scaled by 0.96 and the principle of statistic thermodynamics. On comparison of the theoretical densities with the experimental ones, the reliability of this theoretical method is tested. Detonation properties are evaluated using the modified Kamlet-Jacobs equations based on the calculated densities and heats of formation. According to the largest exothermic principle, the relative specific impulse (Is) is investigated by calculating the enthalpy of combustion (ΔH(comb)) and the total heat capacity (C(p,gases)). It is found that the introduction of methylene nitrate group could decrease the specific impulses on whole. Moreover, in combination with the energetic properties, xylitol pentanitrate, mannitol hexanitrate, volemitol heptanitrate, and 1,2,3,4,5,6,7,8-octanitrate n-octane are potential candidates for high energy density compounds.

An enzyme capable of hydrolyzing organophosphate compounds is of biological as well as environmental significance. We evaluated the possibility of human cytosolic aminopeptidase P (hcAMPP) as an attractive bioscavenger candidate by measuring the enzymatic rates of hydrolysis for a wide variety of organophosphorus compounds. The comparison of substrate specificity exhibited by hcAMPP and E. coli aminopeptidase P (E. coli AMPP) was studied. We cloned, expressed, and purified hcAMPP from HeLa cells and AMPP from Escherichia coli. The pH-rate profiles of hcAMPP were measured in the presence of organophosphate compound 3 or 5. All of the organophosphorus compounds, 1-19, were synthesized by using the approach of phosphorus chemistry described in a previous publication. The relative activity of hcAMPP and E. coli AMPP in hydrolyzing a series of organophosphorus analogues, 1-17, was evaluated in a spectrophotometric assay by monitoring the difference of accumulation of 4-nitrophenol at 400 nm. The overall substrate preference of hcAMPP is as follows: methylphosphonates>ethylphosphonates> or =organophosphates. Interestingly, the observed enhancement in the activity of hcAMPP with methyl phosphonates, 8, 10, 12, and 13, suggests that there is particularly special about the substructure of both methyl moiety and P=O ligand, since the values of specific activity with hcAMPP for the methylphosphonates 8, 10, 12, and 13 are 2- to 73-fold greater than those for the ethylphosphonates 14-17 and the organophosphates 1-7. Similarly, in E. coli AMPP toward ethylphosphonates 14-17, the results indicate that the regions of both MeO moiety and P=O ligand may be located in the vicinity of the substrate-binding site, which have not been altered within the active site of enzyme upon mutation of Trp88, Arg153, and Arg370. These studies demonstrate that E. coli AMPP and hcAMPP display different substrate preference toward organophosphorus compounds. Evidence here, therefore, represents the first example of hcAMPP that might serve as a valuable bioscavenger candidate as E. coli AMPP due to the promise from the hydrolysis of these toxic chemicals.

Objective: To investigate the influence of RNA interference (RNAi) on the expression of aquaporin-1 (AQP1) gene and to investigate the feasibility of gene therapy for pleural effusion., Methods: Two recombinant plasmids with shRNAs targeting the AQP1 gene, AQP1-1-pGenesil and AQP1-2-pGenesil-1 were constructed. Pleural mesothelial cells were obtained from rats, cultured, and randomly divided into 5 groups: blank control group, Lipofectamine 2000 control group, HK negative control group, AQP1-1-pGenesil-1 transfected group, and AQP1-2-pGenesil-1 transfected group. RT-PCR and Western blotting were used to detect the mRNA and protein expression of AQP1., Results: The mRNA expression levels of aquaporin-1 of the AQP1-1-pGenesil-1 and AQP1-2-pGenesil-1 transfected groups were inhibited by 83.5% and 90.9% respectively, and the protein expression levels of the AQP1-1-pGenesil-1 and AQP1-2-pGenesil-1 transfected groups were inhibited by 41.2% and 67.6% respectively., Conclusion: RNAi can successfully inhibit the expression of AQP1 and has the feature of sequence correlation of shRNA in the cultured rat pleural mesothelial cells. It may be used as a potential new approach for gene therapy of pleural effusion.

125I-labeled rat amylin binds to specific sites in the cortex of rat kidney, which can be distinguished from those for 125I-labeled salmon calcitonin (sCT) and 125I-labeled rat alpha-calcitonin gene-related peptide (alpha-CGRP) on the basis of regional distribution. These sites have a high affinity (approximately 1 nM) for amylin, and 125I-amylin binding is potently inhibited by the peptide antagonists AC413 and sCT-(8-32), whereas CGRP-(8-37) is a poor inhibitor of binding. Furthermore, incubation with guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) inhibits 125I-amylin binding by > 90%, indicating that binding is dependent on coupling to G proteins. In renal cortex, amylin stimulated adenylyl cyclase activity three- to fourfold, and this was inhibited by AC413 and sCT-(8-32) but not by CGRP-(8-37). Amylin activated plasma renin twofold, and this was blunted by prior administration of AC413 but not CGRP-(8-37). We speculate that amylin may play an important role in renal physiology and that in states of hyperamylinemia, as found in obesity and the insulin resistance syndrome, this peptide may be involved in the genesis and development of hypertension.

In experimental diabetes, the mesenteric vascular tree undergoes hypertrophy, and this is associated with an increase in mesenteric angiotensin-converting enzyme (ACE) levels. The aim of this study was to determine if inhibition of mesenteric ACE by ACE inhibition would influence diabetes-associated mesenteric vascular hypertrophy. Control or streptozocin-induced diabetic rats were randomized to receive no drug or the ACE inhibitor perindopril. In addition, other diabetic rats were randomized to receive either low-dose insulin that does not alter glycemic control or high-dose insulin, administered as a silastic pellet to achieve euglycemia. After 3 weeks, animals were killed for measurement of mesenteric ACE, vessel weight, and wall:lumen ratio. Diabetes was associated with increased mesenteric ACE levels, increased vessel weight, and an increase in the wall:lumen ratio. ACE inhibition, despite no effect on glycemic control, food intake, urinary urea excretion, or gut weight, prevented the increase in mesenteric ACE levels and attenuated mesenteric vascular hypertrophy as assessed by weight or wall:lumen ratio. The increase in staining by an antibody to the endothelial product, von Willebrand factor, in diabetic rats was totally prevented by perindopril treatment. Euglycemia but not low-dose insulin therapy in the diabetic rats normalized mesenteric vessel ACE, weight, and wall:lumen ratio. In conclusion, ACE inhibition may have a specific role in preventing diabetes-associated vascular hypertrophy, an important process in the genesis of micro- and macrovascular diabetic complications.

In this paper, we extend the binary Gray code to symbolic Gray code. We then show that this symbolic Gray code can be used as a multikey hashing function for storing symbolic records. The record stored at location k and the record stored at location k + 1 will be nearest neighbors if this hashing function is used. Thus, this symbolic Gray code hashing function exhibits some kind of clustering property which will group similar records together. This property is a desirable property for designing nearest neighbor searching (also called best match searching) systems. There are many other interesting properties of this hashing function. For instance, there exists an address-to-key transformation which can be used to determine the record stored at certain location k if this hashing function is used. Besides, if there are totally M records, we only have to reserve exactly M locations; there are no collisions and wasting of memory storage. At the end of this paper, it is shown that the resulting file exhibits the multiple-attribute tree structure.