Practical Aspects of Carbon-Carbon Cross-Coupling Reactions Using Heteroarenes

The use of cross-coupling reactions for the preparation of alkylated and arylated heteroaromatic compounds has increased tremendously over the past two decades. This has been driven on the one hand by the increasingly complex structures of new drugs, most of which contain one or more heterocyclic motifs. On the other hand, the development of new catalysts and reaction conditions for these reactions has rendered even the most unreactive of heteroarenes amenable to cross-coupling chemistry. Not only have new bulky electron-donating ligands been created that allow the coupling of aryl chlorides under mild conditions, but also the use of ligand-free palladium, in particular at very low doses, sometimes called homeopathic palladium, has served to bring down the cost of these reactions. More recent and enabling developments are the use of catalysts based on cheap metals such as nickel, copper, and iron. Scale-up issues are availability and cost of starting materials, cost of the catalysts (related to cost of the metal and the ligand, intrinsic activity and stability of the catalyst), solvent choice, and removal of the metal t

Beaver Ponds: Resurgent Nitrogen Sinks for Rural Watersheds in the Northeastern United States

Beaver-created ponds and dams, on the rise in the northeastern United States, reshape headwater stream networks from extensive, free-flowing reaches to complexes of ponds, wetlands, and connecting streams. We examined seasonal and annual rates of nitrate transformations in three beaver ponds in Rhode Island under enriched nitrate-nitrogen (N) conditions through the use of 15N mass balance techniques on soil core mesocosm incubations. We recovered approximately 93% of the nitrate N from our mesocosm incubations. Of the added nitrate N, 22 to 39% was transformed during the course of the incubation. Denitrification had the highest rates of transformation (97–236 mg N m−2 d−1), followed by assimilation into the organic soil N pool (41–93 mg N m−2 d−1) and ammonium generation (11–14 mg N m−2 d−1). Our denitrification rates exceeded those in several studies of freshwater ponds and wetlands; however, rates in those ecosystems may have been limited by low concentrations of nitrate. Assuming a density of 0.7 beaver ponds km−2 of catchment area, we estimated that in nitrate-enriched watersheds, beaver pond denitrification can remove approximately 50 to 450 kg nitrate N km−2 catchment area. In rural watersheds of southern New England with high N loading (i.e., 1000 kg km−2), denitrification from beaver ponds may remove 5 to 45% of watershed nitrate N loading. Beaver ponds represent a relatively new and substantial sink for watershed N if current beaver populations persist

Solution-phase racemization in the presence of an enantiopure solid phase.

Solution-phase racemization drives the evolution of single chirality in the solid phase by the "chiral amnesia" process first described by Viedma. The current investigations lay the basis for a better understanding of the mechanism of the solid-phase deracemization by uncoupling the chemical rate processes associated with the interconversion of enantiomers in the solution phase from the physical processes associated with solution-solid phase transfer via dissolution and reaccretion of molecules onto crystals. In addition, the enantiomer concentration profiles presented in this work, together with an analytical treatment of the racemization process in the presence of excess enantiopure solid, unequivocally reconfirm the validity of the Meyerhoffer double solubility rule for systems under solution racemization conditions

Support and Assessment for Fall Emergency Referrals (SAFER 1) trial protocol. Computerised on-scene decision support for emergency ambulance staff to assess and plan care for older people who have fallen: evaluation of costs and benefits using a pragmatic cluster randomised trial

Background: Many emergency ambulance calls are for older people who have fallen. As half of them are left at home, a community-based response may often be more appropriate than hospital attendance. The SAFER 1 trial will assess the costs and benefits of a new healthcare technology - hand-held computers with computerised clinical decision support (CCDS) software - to help paramedics decide who needs hospital attendance, and who can be safely left at home with referral to community falls services. Methods/Design: Pragmatic cluster randomised trial with a qualitative component. We shall allocate 72 paramedics ('clusters') at random between receiving the intervention and a control group delivering care as usual, of whom we expect 60 to complete the trial. Patients are eligible if they are aged 65 or older, live in the study area but not in residential care, and are attended by a study paramedic following an emergency call for a fall. Seven to 10 days after the index fall we shall offer patients the opportunity to opt out of further follow up. Continuing participants will receive questionnaires after one and 6 months, and we shall monitor their routine clinical data for 6 months. We shall interview 20 of these patients in depth. We shall conduct focus groups or semi-structured interviews with paramedics and other stakeholders. The primary outcome is the interval to the first subsequent reported fall (or death). We shall analyse this and other measures of outcome, process and cost by 'intention to treat'. We shall analyse qualitative data thematically. Discussion: Since the SAFER 1 trial received funding in August 2006, implementation has come to terms with ambulance service reorganisation and a new national electronic patient record in England. In response to these hurdles the research team has adapted the research design, including aspects of the intervention, to meet the needs of the ambulance services. In conclusion this complex emergency care trial will provide rigorous evidence on the clinical and cost effectiveness of CCDS for paramedics in the care of older people who have fallen

Bose-Einstein Correlations of Three Charged Pions in Hadronic Z^0 Decays

Bose-Einstein Correlations (BEC) of three identical charged pions were studied in 4 x 10^6 hadronic Z^0 decays recorded with the OPAL detector at LEP. The genuine three-pion correlations, corrected for the Coulomb effect, were separated from the known two-pion correlations by a new subtraction procedure. A significant genuine three-pion BEC enhancement near threshold was observed having an emitter source radius of r_3 = 0.580 +/- 0.004 (stat.) +/- 0.029 (syst.) fm and a strength of \lambda_3 = 0.504 +/- 0.010 (stat.) +/- 0.041 (syst.). The Coulomb correction was found to increase the \lambda_3 value by \~9% and to reduce r_3 by ~6%. The measured \lambda_3 corresponds to a value of 0.707 +/- 0.014 (stat.) +/- 0.078 (syst.) when one takes into account the three-pion sample purity. A relation between the two-pion and the three-pion source parameters is discussed.Comment: 19 pages, LaTeX, 5 eps figures included, accepted by Eur. Phys. J.

Rational Design of Temperature-Sensitive Alleles Using Computational Structure Prediction

Temperature-sensitive (ts) mutations are mutations that exhibit a mutant phenotype at high or low temperatures and a wild-type phenotype at normal temperature. Temperature-sensitive mutants are valuable tools for geneticists, particularly in the study of essential genes. However, finding ts mutations typically relies on generating and screening many thousands of mutations, which is an expensive and labor-intensive process. Here we describe an in silico method that uses Rosetta and machine learning techniques to predict a highly accurate “top 5” list of ts mutations given the structure of a protein of interest. Rosetta is a protein structure prediction and design code, used here to model and score how proteins accommodate point mutations with side-chain and backbone movements. We show that integrating Rosetta relax-derived features with sequence-based features results in accurate temperature-sensitive mutation predictions