Theoretical mechanistic study of the reaction of the methylidyne radical with methylacetylene

A detailed doublet potential energy surface for the reaction of CH with CH₃CCH is investigated at the B3LYP/6-311G(d,p) and G3B3 (single-point) levels. Various possible reaction pathways are probed. It is shown that the reaction is initiated by the addition of CH to the terminal C atom of CH₃CCH, forming CH₃CCHCH 1 (1a,1b). Starting from 1 (1a,1b), the most feasible pathway is the ring closure of 1a to CH₃–cCCHCH 2 followed by dissociation to P ₃ (CH₃–cCCCH+H), or a 2,3 H shift in 1a to form CH₃CHCCH 3 followed by C–H bond cleavage to form P ₅ (CH₂CHCCH+H), or a 1,2 H-shift in 1 (1a, 1b) to form CH₃CCCH₂ 4 followed by C–H bond fission to form P ₆ (CH₂CCCH₂+H). Much less competitively, 1 (1a,1b) can undergo 3,4 H shift to form CH₂CHCHCH 5. Subsequently, 5 can undergo either C–H bond cleavage to form P ₅ (CH₂CHCCH+H) or C–C bond cleavage to generate P ₇ (C₂H₂+C₂H₃). Our calculated results may represent the first mechanistic study of the CH + CH₃CCH reaction, and may thus lead to a deeper understanding of the title reaction.     

Molecular dynamics simulation of self-assembled nanocubes in methanol

Molecular dynamics simulations were performed for the hexameric nanocubes of methylated (1₆) and demethylated (2₆) gear-shaped amphiphiles in pure methanol to reveal the difference in structural fluctuation between 1₆ and 2₆. Within our simulation time of 2.0 ns, the cubic structure of 1₆ in methanol is maintained, whereas that of 2₆ is collapsed. We found that the triple π-stacking moieties consisting of the three 3-pyridyl groups in 2₆ are more fluctuated than those in 1₆. This suggests that methyl groups serve to reduce structural fluctuation for nanocubes. We also found that the existence of the solvent molecules near the nanocube is an important factor for the collapse of the 2₆ structure.     

A model of cell firing patterns during epileptic seizures

A simplified model is presented of the dynamics of excitatory and inhibitory neurons in the cerebral cortex. A key feature of the model is that neurons may cease to fire when strongly depolarized (spike inactivation). Computer simulations for different parameters reveal five classes of solutons: a) steady states in which neither excitatory nor inhibitory cells are active, b) steady states in which one or both types of cells fire repetitively, c) states in which one type of cell fluctuates rapidly between bursts of action potentials and inactivity due to strong depolarization, d) rhythmic activity in which both types of cells fire in unison followed by a period of spike inactivation and e) states similar to d but in which the inhibitory cells never produce action potentials. Solutions b, c, d, and e qualitatively resemble the different firing patterns observed during experimental seizures. It is shown that changes in those parameters that are functions of potassium concentration can induce changes in the type of solution. It is therefore proposed that the increase in extracellular potassium concentration during seizures may be responsible for the progressive changes observed in firing patterns and particularly for the transition from tonic to clonic patterns. A method is also outlined for testing the predictions of the model.     

Formation Mechanism of the Free Radical Product and Its Precursor by the Reaction of Dehydro-L-ascorbic Acid with Amino Acid

During the formation of radical A (2) and its precursor (tris(2-deoxy-2-L-ascorbyl)amine, 1) by the reaction of dehydroascorbic acid (DHA) with amino acid, ascorbic acid (AsA) and the reduced red pigment (3) were newly identified, in addition to scorbamic acid (SCA) and the red pigment (4), as intermediate products. The addition of AsA to the DHA-amino acid reaction, as well as to the DHA-SCA reaction, greatly increased the formation of 3 and 1. The reaction of AsA with 4 gave rapidly 3, followed by the gradual production of 1. From these results, a reaction pathway is proposed that 3 formed by the reduction of 4 with AsA is a key intermediate and its condensation with DHA followed by reduction with AsA might produce 2 and 1.     

The BglG group of antiterminators: a growing family of bacterial regulators

The product of the bglG gene of Escherichia coli was among the first bacterial antiterminators to be identified and characterized. Since the elucidation ten years ago of its role in the regulation of the bgl operon of E. coli,a large number of homologies have been discovered in both Gram-positive and Gram-negative bacteria. Often the homologues of BglG in other organisms are also involved in regulating β-glucoside utilization. Surprisingly, in many cases, they mediate antitermination to regulate a variety of other catabolic functions. Because of the high degree of conservation of the cis-acting regulatory elements, antiterminators from one organism can function in another. Generally the antiterminator protein itself is negatively regulated by phosphorylation by a component of the phosphotransferase system. This family of proteins thus represents a highly evolved regulatory system that is conserved across evolutionarily distant genuses.     

非惩罚性报告系统在给药错误管理中的效果研究

?????? 目的 探讨非惩罚性报告系统在护士给药错误管理中的应用效果。方法 回顾性分析某三级乙等综合性医院2006—2012年给药错误报告资料,对实施非惩罚性报告系统前后给药错误的报告和管理情况进行系统的总结和分析。结果 自2008年建立了非惩罚性报告系统以来,护士给药错误报告意识增强,漏报率下降,报告及时性提高,报告人群从护士长普及到临床一线护士,同类给药错误事件发生率下降。结论 建立非惩罚性报告系统,增强护士给药错误的报告意识,护理管理人员能够获得真实数据和信息。     

Morpho-histochemical characterization of salivary gland cells of males of the tick <Emphasis Type="Italic">Rhipicephalus</Emphasis><Emphasis Type="Italic">sanguineus</Emphasis> (Acari: Ixodidae) at different feeding stages: description of new cell types

This study describes the changes undergone by cells of the salivary glands of unfed and feeding (at day two and four post-attachment) Rhipicephalus sanguineus males, as well as new cell types. In unfed males, types I and II acini are observed with cells “undifferentiated”, undefined 1 and 2 (the latter, with atypical granules), a, c1 and c3; type III is composed of cells d and e; and type IV present cells g. In males at day two post-attachment, type I acini exhibit the same morphology of unfed individuals. An increase in size is observed in types II, III, and IV, as cells are filled with secretion granules. Some granules are still undergoing maturation. In type II acinus, cells a, b and c1–c8 are observed. Cells c7 and c8 are described for the first time. Cells c7 are termed as such due to the addition of polysaccharides in the composition of the secretion granules (in unfed individuals, they are termed undefined 1). Type III acini exhibit cells d and e completely filled with granules, and in type IV, cells g contain granules in several stages of maturation. In males at day four post-attachment, type I acini do not exhibit changes. Granular acini exhibit cells with fewer secretion granules, which are already mature. In type II acini, cells a, b, c1–c5 are present, type III exhibit cells d and e, and type IV contain cells g with little or no secretion. This study shows that in the salivary glands of R. sanguineus males, cells a, c1, and c3 of type II acinus, and cells d and e of type III do not exhibit changes in granular content, remaining continuously active during the entire feeding period. This indicates that during the intervals among feeding stages, gland cells reacquire the same characteristics found in unfed individuals, suggesting that they undergo reprogramming to be active in the next cycle.     

The Cyatheaceae (Polypodiopsida) of Peru

A summary is presented of all Peruvian species of scaly tree ferns (Cyatheaceae). A total of 83 species is native to Peru (Sphaeropteris 1 sp., Alsophila sect. Alsophila 9 spp., Alsophila sect. Gymnosphaera 1 sp., Cyathea 72 spp.), with 13 endemic species in Cyathea and one in Alsophila. The following new species are described and illustrated: Alsophila gastonyi, Cyathea chontilla, C. nephele, C. polliculi, and C. praetermissa. The genera Cnemidaria and Trichipteris are no longer recognized and merged in Cyathea. Necessary combinations are made for Cyathea alatissima, C. nervosa, and C. uleana. Cyathea serpens is presented in detail and its relationship is discussed. An artificial key to the Peruvian species of Cyatheaceae is provided.     

The Origin and Age of Biogeochemical Trends in Deep Fracture Water of the Witwatersrand Basin,South Africa

Water residing within crustal fractures encountered during mining at depths greater than 500 meters in the Witwatersrand basin of South Africa represents a mixture of paleo-meteoric water and 2.0–2.3 Ga hydrothermal fluid. The hydrothermal fluid is highly saline, contains abiogenic CH ₄ and hydrocarbon, occasionally N ₂ , originally formed at ～ 250–300°C and during cooling isotopically exchanged O and H with minerals and accrued H ₂ , ⁴ He and other radiogenic gases. The paleo-meteoric water ranges in age from ～ 10 Ka to > 1.5 Ma, is of low salinity, falls along the global meteoric water line (GMWL) and is CO ₂ and atmospheric noble gas-rich. The hydrothermal fluid, which should be completely sterile, has probably been mixing with paleo-meteoric water for at least the past ～100 Myr, a process which inoculates previously sterile environments at depths > 2.0 to 2.5 km. Free energy flux calculations suggest that sulfate reduction is the dominant electron acceptor microbial process for the high salinity fracture water and that it is 10 ⁷ times that normally required for cell maintenance in lab cultures. Flux calculations also indicate that the potential bioavailable chemical energy increases with salinity, but because the fluence of bioavailable C, N and P also increase with salinity, the environment remains energy-limited. The ⁴ He concentrations and theoretical calculations indicate that the H ₂ that is sustaining the subsurface microbial communities (e.g. H ₂ -utilizing SRB and methanogens) is produced by water radiolysis at a rate of ～1 nM yr ^?1 . Microbial CH ₄ mixes with abiogenic CH ₄ to produce the observed isotopic signatures and indicates that the rate of methanogenesis diminishes with depth from ～ 100 at < 1 kmbls, to < 0.01 nM yr ^?1 at > 3 kmbls. Microbial Fe(III) reduction is limited due to the elevated pH. The δ¹³C of dissolved inorganic carbon is consistent with heterotrophy rather than autotrophy dominating the deeper, more saline environments. One potential source of the organic carbon may be microfilms present on the mineral surfaces.     

Heat shock protein 70 as an indicator of early lung injury caused by exposure to arsenic

Evidence for the non-enzymatic phosphorylation of bovine serum albumin (BSA) by sodium bis(2-ethyl-2-hydroxybutyrato)oxochromate(V), Na[Cr^VO(ehba)₂], 1, sodium bis(2-hydroxy-2-methylbutyrato)oxochromate(V), Na[Cr^VO(hmba)₂], 2 and potassium dichromate, K₂Cr₂O₇, 3 in the presence of labeled adenosine-5′-triphosphate (ATP) under conditions of physiological pH is presented. Aggregation and extent of phosphorylation of BSA mediated by 1, 2 or 3 seems to increase with the concentration and time of incubation of the reaction mixture containing all the reactants. The [γ-³²P] label in ATP is incorporated into aggregates of BSA in the in vitro reaction of the protein with ATP in the presence of 1, 2 or 3. Phosphorylation of BSA by ATP in the absence of 1, 2 or 3 is negligible. Addition of EDTA reverses aggregation of protein and liberates partially the incorporated phosphate label. The stoichiometry of phosphorylation is found to be the highest and is equal to 12.25 mol PO₄³⁻/mol BSA in the presence of 500 μM of 1, which decreases to 10.56 mol PO₄³⁻/mol BSA after EDTA treatment. Resistance to the removal of phosphate label by EDTA increases with increase in time of incubation. Dialysis of phosphorylated BSA reverses the incorporated [γ-³²P] label only partially, indicating the formation of covalent links of phosphate groups to BSA. Evidence for the site of phosphorylation in the reaction mediated by 1, 2 or 3 being hydroxyl side groups of tyrosine and serine/threonine residues has been gained. Based on the results, a possibility that 1, 2 and 3 mimic the function of tyrosine and serine/threonine kinases has been invoked.     

Synthesis and biological evaluations of putative metabolically stable analogs of VN/124-1 (TOK-001): head to head anti-tumor efficacy evaluation of VN/124-1 (TOK-001) and abiraterone in LAPC-4 human prostate cancer xenograft model

In a continuing study of our clinical candidate 5 VN/124-1 (TOK-001) and analogs as potential agents for prostate cancer therapy, putative metabolites (10, 15 and 18) of compound 5 were rationally designed and synthesized. However, none of these agents were as efficacious as 5 in several in vitro studies. Using western blot analysis, we have generated a preliminary structure–activity relationship (SAR) of 5 and related analogs as androgen receptor ablative agents (ARAAs). In vivo using the androgen-dependent LAPC-4 prostate cancer xenograft model, we demonstrated for the first time that 5 is more efficacious than the 17-lyase inhibitor 3 (abiraterone)/4 (abiraterone acetate) that is currently in phase III clinical trials. In our desire to optimize the potency of 5, compounds 6 (3ξ-fluoro-) and 9 (3β-sulfamate-) designed to increase the stability and oral bioavailability of 5, respectively were evaluated in vivo. We showed, that on equimolar basis, compound 6 was ∼2-fold more efficacious versus LAPC-4 xenografts than 5, but the toxicity observed with 6 is of concern. These studies further demonstrate the efficacy of 5 in a clinically relevant prostate cancer model and justify its current clinical development as a potential treatment of prostate cancer.     

Polymer-mediated cyclodehydration of alditols and ketohexoses

The polymer PEDOT⁺ (1 or 2) mediates a cyclodehydration reaction with alditols 3, 5, 7, 9, in hydrocarbon solvents, to give cyclic ethers 4, 6, 8, or 10, respectively, in high yield with a trivial isolation protocol. Polymers 1 or 2 also mediate the cyclodehydration of ketohexoses such as d-fructose, but not aldohexoses, to the important industrial intermediate 5-hydroxymethylfurfural (17), under milder conditions when compared to reactions mediated by mineral acids. A cascade reaction with ketohexoses is observed in toluene via cyclodehydration followed by Friedel–Crafts alkylation of the initially formed benzylic alcohol to give 16.     

医院岗位设置管理的做法与体会

目的 探讨医院实施岗位设置管理工作的做法,确保医院岗位设置管理工作顺利实施。方法 按照上级人事部门核准的事业单位岗位设置审核方案,结合自身实际,制定切实可行的医院岗位设置管理实施方案。结果 医院岗位设置管理工作顺利实施,效果显著。结论 要确保医院岗位设置管理工作顺利实施,领导重视是关键,全员参与是保障,公平公开是前提,按需设置是基础,激励约束是目的。     

An analysis of hydrophobic interactions of thymidylate synthase with methotrexate: Free energy calculations involving mutant and native structures bound to methotrexate

Since the human body for many reasons can adapt and become resistant to drugs, it is important to develop and validate computer aided drug design (CADD) methods that could help predict binding affinity changes that can result from these resistant enzymes. The free energy perturbation (FEP) methodology is the most accurate means of estimating relative binding affinities between inhibitors and protein variants. In this paper, we describe the role played by hydrophobic residues lining the active site region, particularly ⁷⁹ Ile and ¹⁷⁶ Phe, in the binding of methotrexate to the Escherichia coli (E. coli) thymidylate synthase (TS) enzyme, using the thermodynamic cycle perturbation (TCP) approach. The computed binding free energy differences on the binding of methotrexate to the native and some mutant E. coli TS structures have been compared with experimental results. Computationally, four different ‘mutations’ have been simulated on the TS enzyme with methotrexate (MTX): ⁷⁹ Ile →  ⁷⁹ Val; ⁷⁹ Ile → ⁷⁹ Ala; ⁷⁹ Ile → ⁷⁹ Leu; and ¹⁷⁶ Phe →  ¹⁷⁶ Ile. The calculated results indicate that in each of these cases, the native residues ( ⁷⁹ Ile and ¹⁷⁶ Phe) interact more favorably with methotrexate than the mutant residues and these results are corroborated by experimental measurements. Binding preference to wild type residues can be rationalized in terms of their better hydrophobic contacts with the phenyl ring of methotrexate.     

A New Ichnospecies of Arthrophycus from the Upper Cambrian-Lower Tremadocian of Northwest Argentina: Implications for the Arthrophycid Lineage and Potential in Ichnostratigraphy

A new ichnospecies of Arthrophycus Hall 1852, A. minimus , is described from Upper Cambrian-Lower Tremadocian, shallow-marine strata of northwest Argentina. This new ichnospecies consists of small, long, regularly annulated hypichnial elements displaying subcircular to squarish cross-section and a ventral median groove. Side branches are occasionally present, but palmate, fan-like structures and scribbling patterns are absent. We adopt a relatively narrow diagnosis of Arthrophycus , suggesting that roughly annulated, cylindrical structures should not be included in this ichnogenus, unless other diagnostic features (i.e., squarish cross-section, median groove, zipper-like annulations) are also present. Arthrophycus is a common ichnotaxon in Ordovician-Silurian shallow-marine siliciclastic environments. Post-Paleozoic occurrences are removed from Arthrophycus . Arthrophycus has been proposed as a biostratigraphic index fossil in Ordovician-Silurian rocks. The presence of A. minimus in the Santa Rosita Formation of northwest Argentina indicates that Arthrophycus ranges at least from the Upper Cambrian-Lower Tremadocian with probable representatives in the Lower Cambrian and, therefore, its biostratigraphic utility is extended. Arthrophycus minimus represents the first Cambrian occurrence exhibiting not only fine, diagnostic morphologic features, but also the classical Arthrophycus behavioral pattern in dense monoichnospecific assemblages. The exploratory behavioral pattern displayed by A. minimus is simpler than that of the younger ichnospecies, particularly A. brogniartii, A. alleghaniensis, and A. lateralis . This is consistent with the basal position of A. minimus within the arthrophycid lineage.     

基本药物制度实施与乡镇卫生院补偿机制转变

目的 了解乡镇卫生院各项收支及药品补偿状况,探讨基本药物制度实施后,取消药品加成对乡镇卫生院的影响。方法 收集华东三省49家乡镇卫生院财务及药品收支数据,对定量资料进行统计分析。结果 乡镇卫生院主要的补偿渠道依然是药品收入,乡镇卫生院收入增长主要归因于增加药品收入。在财政补助收入大幅增加的情况下,乡镇卫生院对药品收入的依赖程度有所降低。结论 基本药物制度的实施对乡镇卫生院的平稳运行有影响,可采取加强财政补助、建立综合补偿机制、遏制药品价格虚高等措施保证乡镇卫生院在改革中的平稳运行。     

Cosynthesis of erythromycin A N-oxide by mutants ofSaccharopolyspora erythraea blocked in erythromycin production

The production of erythromycin A (1) and free erythronolide B (2) inSaccharopolyspora erythraea BTCC-2 is accompanied by formation of erythromycin A N-oxide (3) and other minor components, the ratio of yields of1 and3 being 97:3. Erythromycin-blocked mutants of type I (impaired in some unidentified steps prior to lactone synthesis) and type II (accumulating only2) cosynthesized both1 and the accompanying metabolites, but the ratio of1 and3 changed to 70:30. In pure cultures of type I, exogenous2 was converted to1 and minor components in ratios typical of the strain BTCC-2, whereas mutants of type II were effective convertors of1 to3.     

A monograph of <Emphasis Type="Italic">Ascogrammitis</Emphasis>, a new genus of grammitid ferns (Polypodiaceae)

This paper describes Ascogrammitis, a new genus of grammitid ferns formerly combined under Terpsichore. Seventeen species are recognized, including five new ones: A. clavigera, A. colombiensis, A. loxensis, A. oxapampensis, and A. tungurahuae. New combinations are made for A. alan-smithii, A. anfractuosa, A. angustipes, A. athyrioides, A. clathrata, A. cuencana, A. david-smithii, A. dilatata, A. nana, A. pichinchae, A. pichinchensis, A. stuebelii, and a lectotype is chosen for Polypodium induens. A key is provided to distinguish the species, and illustrations are provided for 12 species. The genus occurs primarily in neotropical cloud forests, with the greatest diversity in the Andes. Ascogrammitis is one of two monophyletic groups of grammitid ferns that are consistently associated with Acrospermum, an epibiotic bitunicate ascomycete that produces black clavate fruiting bodies.     

Photo-Arbuzov Rearrangements of Benzyl Phosphites. Preparation of Acyclic Nucleoside Phosphonates Related to HPMPA

Abstract

Photo-Arbuzov rearrangement of the benzylic phosphite 18 affords the benzylphosphonate 19 which is converted to the bromo derivative 21. The latter is a common precursor for the preparation of a series of branched-chain, acyclic nucleoside-based, benzylphosphonic acids, 25, 28, 32, and 35.