Building on Cram's legacy: stimulated gating in hemicarcerands.

CONSPECTUS: Donald Cram's pioneering Nobel Prize-winning work on host-guest molecules led eventually to his creation of the field of container molecules. Cram defined two types of container molecules: carcerands and hemicarcerands. Host-guest complexes of carcerands, called carceplexes, are formed during their synthesis; once a carceplex is formed, the trapped guest cannot exit without breaking covalent bonds. Cram defined a quantity called constrictive binding, arising from the mechanical force that prevents guest escape. The constrictive binding in carceplexes is high. In contrast, hemicarcerands have low constrictive binding and are able to release the incarcerated guests at elevated temperatures without breaking covalent bonds. We have designed molecules that can switch from carcerand to hemicarcerand through a change in structure that we call gating. The original discovery of gating in container molecules involved our computational studies of a Cram hemicarceplex that was observed to release a guest upon heating. We found that the side portals of this hemicarceplex have multiple thermally accessible conformations. An eight-membered ring that is part of a portal changes from a "chair" to a "boat" structure, leading to the enlargement of the side portal and the release of the guest. This type of gating is analogous to phenomena often observed with peptide loops in enzymes. We refer to this phenomenon as thermally controlled gating. We have also designed and synthesized redox and photochemically controlled gated hemicarceplexes. Gates are built onto host molecules so that the opening or closing of such gates is stimulated by reducing or oxidizing conditions, or by ultraviolet irradiation. In both cases, the appropriate stimuli can produce a carceplex (closed gates) or hemicarceplex (open gates). A hemicarceplex with closed gates behaves like a carceplex, due to its very high constrictive binding energy. When the gates are opened, constrictive binding is dramatically lowered, and guest entrance and exit become facile. This stimulated switching between open and closed states controls access of the guest to the binding site. The experimental and computational investigations of gated hemicarcerands and several potential applications of gated hemicarceplexes are described in this Account

Can acyclic conformational control be achieved via a sulfur-fluorine gauche effect?

The gauche conformation of the 1,2-difluoroethane motif is known to involve stabilising hyperconjugative interactions between donor (bonding, σC-H) and acceptor (antibonding, σ*C-F) orbitals. This model rationalises the generic conformational preference of F-Cβ-Cα-X systems (φFCCX ≈ 60°), where X is an electron deficient substituent containing a Period 2 atom. Little is known about the corresponding Period 3 systems, such as sulfur and phosphorus, where multiple oxidation states are possible. Conformational analyses of β-fluorosulfides, -sulfoxides and -sulfones are disclosed here, thus extending the scope of the fluorine gauche effect to the 3rd Period (F-C-C-S(O) n ; φFCCS ≈ 60°). Synergy between experiment and computation has revealed that the gauche effect is only pronounced in structures bearing an electropositive vicinal sulfur atom (S+-O-, SO2)

Cycloadditions of cyclohexynes and cyclopentyne.

We report the strategic use of cyclohexyne and the more elusive intermediate, cyclopentyne, as a tool for the synthesis of new heterocyclic compounds. Experimental and computational studies of a 3-substituted cyclohexyne are also described. The observed regioselectivities are explained by the distortion/interaction model

Mechanistic analysis of an asymmetric palladium-catalyzed conjugate addition of arylboronic acids to β-substituted cyclic enones.

An asymmetric palladium-catalyzed conjugate addition reaction of arylboronic acids to enone substrates was investigated mechanistically. Desorption electrospray ionization coupled to mass spectrometry was used to identify intermediates of the catalytic cycle and delineate differences in substrate reactivity. Our findings provide evidence for the catalytic cycle proceeding through formation of an arylpalladium(II) cation, subsequent formation of an arylpalladium-enone complex, and, ultimately, formation of the new C-C bond. Reaction monitoring in both positive and negative ion modes revealed that 4-iodophenylboronic acid formed a relatively stable trimeric species under the reaction conditions

Bad expression influences time to androgen escape in prostate cancer

<b>OBJECTIVE</b>: To assess the role of selected downstream Bcl-2 family members (Bad, Bax, Bcl-2 and Bcl-xL) in the development of androgen-independent prostate cancer (AIPC), as androgen-deprivation therapy is the treatment of choice in advanced prostate cancer, yet patients generally relapse and progress to an AI state within 18–24 months. <b>PATIENTS, MATERIALS AND METHODS</b>: The patient cohort was established by retrospectively selecting patients with prostate cancer who had an initial response to androgen-deprivation therapy, but subsequently relapsed with AIPC. In all, 58 patients with prostate cancer were included with matched androgen-dependent (AD) and AI prostate tumours available for immunohistochemical analysis; two independent observers using a weighted-histoscore method scored the staining. Changes in Bad, Bax, Bcl-2 and Bcl-xL expression during transition to AIPC were evaluated and then correlated to known clinical variables. <b>RESULTS</b>: High Bad expression in AD tumours was associated with an increased time to biochemical relapse (<i>P</i> = 0.007) and a trend towards improved overall survival (<i>P</i> = 0.053). There were also trends towards a decrease in Bad (<i>P</i> = 0.068) and Bax (<i>P</i> = 0.055) expression with progression to AIPC. There were no significant results for Bcl-2 or Bcl-xL. <b>CONCLUSION</b>: There is evidence to suggest that Bad expression levels at diagnosis influence time to biochemical relapse and overall survival, and that levels of pro-apoptotic proteins Bad and Bax fall during AIPC development. Bad might therefore represent a possible positive prognostic marker and potential therapeutic target for AIPC in the future

Air Pollution Exposure in Relation to the Commute to School: A Bradford UK Case Study

Walking School Buses (WSBs) provide a safe alternative to being driven to school. Children benefit from the contribution the exercise provides towards their daily exercise target, it gives children practical experience with respect to road safety and it helps to relieve traffic congestion around the entrance to their school. Walking routes are designed largely based in road safety considerations, catchment need and the availability of parent support. However, little attention is given to the air pollution exposure experienced by children during their journey to school, despite the commuting microenvironment being an important contributor to a child’s daily air pollution exposure. This study aims to quantify the air pollution exposure experienced by children walking to school and those being driven by car. A school was chosen in Bradford, UK. Three adult participants carried out the journey to and from school, each carrying a P-Trak ultrafine particle (UFP) count monitor. One participant travelled the journey to school by car while the other two walked, each on opposite sides of the road for the majority of the journey. Data collection was carried out over a period of two weeks, for a total of five journeys to school in the morning and five on the way home at the end of the school day. Results of the study suggest that car commuters experience lower levels of air pollution dose due to lower exposure and reduced commute times. The largest reductions in exposure for pedestrians can be achieved by avoiding close proximity to traffic queuing up at intersections, and, where possible, walking on the side of the road opposite the traffic, especially during the morning commuting period. Major intersections should also be avoided as they were associated with peak exposures. Steps to ensure that the phasing of lights is optimised to minimise pedestrian waiting time would also help reduce exposure. If possible, busy roads should be avoided altogether. By the careful design of WSB routes, taking into account air pollution, children will be able to experience the benefits that walking to school brings while minimizing their air pollution exposure during their commute to and from school

Enzyme-catalyzed cationic epoxide rearrangements in quinolone alkaloid biosynthesis.

Epoxides are highly useful synthons and biosynthons for the construction of complex natural products during total synthesis and biosynthesis, respectively. Among enzyme-catalyzed epoxide transformations, a reaction that is notably missing, in regard to the synthetic toolbox, is cationic rearrangement that takes place under strong acid. This is a challenging transformation for enzyme catalysis, as stabilization of the carbocation intermediate upon epoxide cleavage is required. Here, we discovered two Brønsted acid enzymes that can catalyze two unprecedented epoxide transformations in biology. PenF from the penigequinolone pathway catalyzes a cationic epoxide rearrangement under physiological conditions to generate a quaternary carbon center, while AsqO from the aspoquinolone pathway catalyzes a 3-exo-tet cyclization to forge a cyclopropane-tetrahydrofuran ring system. The discovery of these new epoxide-modifying enzymes further highlights the versatility of epoxides in complexity generation during natural product biosynthesis

Cell wall perturbation sensitizes fungi to the antimalarial drug chloroquine.

Journal ArticleResearch Support, Non-U.S. Gov'tCopyright © 2015 by the American Society for Microbiology.Post print version deposited in accordance with SHERPA RoMEO guidelines.Chloroquine (CQ) has been a mainstay of antimalarial drug treatment for several decades. Additional therapeutic actions of CQ have been described, including some reports of fungal inhibition. Here we investigated the action of CQ in fungi, including the yeast model Saccharomyces cerevisiae. A genomewide yeast deletion strain collection was screened against CQ, revealing that bck1Δ and slt2Δ mutants of the cell wall integrity pathway are CQ hypersensitive. This phenotype was rescued with sorbitol, consistent with cell wall involvement. The cell wall-targeting agent caffeine caused hypersensitivity to CQ, as did cell wall perturbation by sonication. The phenotypes were not caused by CQ-induced changes to cell wall components. Instead, CQ accumulated to higher levels in cells with perturbed cell walls: CQ uptake was 2- to 3-fold greater in bck1Δ and slt2Δ mutants than in wild-type yeast. CQ toxicity was synergistic with that of the major cell wall-targeting antifungal drug, caspofungin. The MIC of caspofungin against the yeast pathogen Candida albicans was decreased 2-fold by 250 μM CQ and up to 8-fold at higher CQ concentrations. Similar effects were seen in Candida glabrata and Aspergillus fumigatus. The results show that the cell wall is critical for CQ resistance in fungi and suggest that combination treatments with cell wall-targeting drugs could have potential for antifungal treatment.University of NottinghamMinistry of Higher Education Malaysi

Pengantrian Meja pada Restoran Menggunakan Fasilitas Short Message Service

Perkembangan restoran saat ini semakin pesat dengan bertambah banyaknya jenis- jenis masakan baik masakan Indonesia mau pun di luar Indonesia seperti China, Jepang dan Amerika. Dengan adanya berbagai macam masakan ini, membuat ketertarikan pengunjung untuk mencoba. Hal ini membuat pengunjung rela mengantri demi masakan yang mereka sukai. Perancangan sistem ini menggunakan simulasi denah mau pun data. Simulasi denah menggunakan tiga meja dengan kapasitas masing-masing dua, empat dan enam kursi. Simulasi data dengan menggunakan data menu yang telah ditentukan terlebih dahulu. Sistem dirancang dengan menggunakan mikrokontroler sebagai pusat pemrosesan data. Pendataan dalam proses pengantrian masih manual. Perancangan alat pengantrian meja pada restoran menggunakan fasilitas SMS ini meliputi pembuatan simulasi denah restoran, LED sebagai penanda ada tidaknya pengunjung dan software yang berguna untuk proses pengiriman SMS dan untuk menjalankan simulasi. Perancangan ini dibuat untuk membantu meringankan kerja resepsionis dan membuat Kenyamanan pengunjung dalam proses pengantrian. Hasil pengujian sistem memperlihatkan bahwa simulasi yang dilakukan berjalan dengan baik

Aging Effects of Caenorhabditis elegans Ryanodine Receptor Variants Corresponding to Human Myopathic Mutations

Delaying the decline in skeletal muscle function will be critical to better maintenance of an active life-style in old age. The skeletal muscle ryanodine receptor, the major intracellular membrane channel through which calcium ions pass to elicit muscle contraction, is central to calcium ion balance, and is hypothesized to be a significant factor for age-related decline in muscle function. The nematode Caenorhabditis elegans is a key model system for the study of human aging and strains with modified C. elegans ryanodine receptors corresponding to human myopathic variants linked with malignant hyperthermia and related conditions were generated. The altered response of these strains to pharmacological agents reflected results of human diagnostic tests for individuals with these pathogenic variants. Involvement of nerve cells in the C. elegans responses may relate to rare medical symptoms concerning the central nervous system that have been associated with ryanodine receptor variants. These single amino acid modifications in C. elegans also conferred a reduction in lifespan and an accelerated decline in muscle integrity with age, supporting the significance of ryanodine receptor function for human aging