Structure of blood coagulation factor VIII in complex with an anti-C1 domain pathogenic antibody inhibitor.

Antibody inhibitor development in hemophilia A represents the most significant complication resulting from factor VIII (fVIII) replacement therapy. Recent studies have demonstrated that epitopes present in the C1 domain contribute to a pathogenic inhibitor response. In this study, we report the structure of a group A anti-C1 domain inhibitor, termed 2A9, in complex with a B domain-deleted, bioengineered fVIII construct (ET3i).

Sedimentation Velocity Analytical Ultracentrifugation of Oxidized Recombinant Full-Length Factor VIII.

Anti-drug antibodies to coagulation factor VIII (fVIII), often termed inhibitors, present the greatest economical and treatment related obstacle in the management of hemophilia A. Although several genetic and environmental risk factors associated with inhibitor development have been identified, the precise mechanisms responsible for the immune response to exogenous fVIII therapies remain undefined. Clinical trials suggest there is an increased immunogenic potential of recombinant fVIII compared to plasma-derived products.

The 3.2 Å structure of a bioengineered variant of blood coagulation factor VIII indicates two conformations of the C2 domain.

Background: Coagulation factor VIII represents one of the oldest protein-based therapeutics, serving as an effective hemophilia A treatment for half a century. Optimal treatment consists of repeated intravenous infusions of blood coagulation factor VIII (FVIII) per week for life. Despite overall treatment success, significant limitations remain, including treatment invasiveness, duration, immunogenicity, and cost.

Human-mediated extirpation of the unique Chatham Islands sea lion and implications for the conservation management of remaining New Zealand sea lion populations.

While terrestrial megafaunal extinctions have been well characterized worldwide, our understanding of declines in marine megafauna remains limited. Here, we use ancient DNA analyses of prehistoric (<1450-1650 AD) sea lion specimens from New Zealand's isolated Chatham Islands to assess the demographic impacts of human settlement. These data suggest there was a large population of sea lions, unique to the Chatham Islands, at the time of Polynesian settlement.

Invader or resident? Ancient-DNA reveals rapid species turnover in New Zealand little penguins.

The expansion of humans into previously unoccupied parts of the globe is thought to have driven the decline and extinction of numerous vertebrate species. In New Zealand, human settlement in the late thirteenth century AD led to the rapid demise of a distinctive vertebrate fauna, and also a number of 'turnover' events where extinct lineages were subsequently replaced by closely related taxa. The recent genetic detection of an Australian little penguin (Eudyptula novaehollandiae) in southeastern New Zealand may potentially represent an additional 'cryptic' invasion.

Phytophthora niederhauserii sp. nov., a polyphagous species associated with ornamentals, fruit trees and native plants in 13 countries.

A non-papillate, heterothallic Phytophthora species first isolated in 2001 and subsequently from symptomatic roots, crowns and stems of 33 plant species in 25 unrelated botanical families from 13 countries is formally described here as a new species. Symptoms on various hosts included crown and stem rot, chlorosis, wilting, leaf blight, cankers and gumming. This species was isolated from Australia, Hungary, Israel, Italy, Japan, the Netherlands, Norway, South Africa, Spain, Taiwan, Turkey, the United Kingdom and United States in association with shrubs and herbaceous ornamentals grown mainly in greenhouses.

Terminal Schwann cells participate in the competition underlying neuromuscular synapse elimination.

The competitive processes that result in elimination/pruning of developing synapses are incompletely understood. Serial electron microscopy was used to image postnatal mouse neuromuscular junctions where elimination is well studied and events at every synaptic contact can be examined. Glial or Schwann cells (SCs) are shown to have two activities during elimination: their processes separate nerve terminals from each other and from the muscle fiber; they contact the plaque of acetylcholine receptors, apposing this surface as closely as the nerve, limiting the area where synaptic transmission occurs.

Rate constants and branching ratios for the reaction of CH radicals with NH3: a combined experimental and theoretical study.

The reaction between CH radicals and NH(3) molecules is known to be rapid down to at least 23 K {at which temperature k = (2.21 ± 0.17) × 10(-10) cm(3) molecule(-1) s(-1): Bocherel ; et al.

Low temperature kinetics: the association of OH radicals with O2.

We report the first measurements of rate constants for the reaction in which OH radicals associate with O(2) to form HO(3). Our recent measurements (Science, 2010, 328, 1258) have shown that the HO-O(2) bond dissociation energy is only (12.3 ± 0.

The thermodynamics of the elusive HO3 radical.

The role of HO3 as a temporary reservoir of atmospheric OH radicals remains an open question largely because of the considerable uncertainty in the value of the dissociation energy of the HO-O2 bond (D0) or, equivalently, the standard enthalpy of formation of HO3 (Delta(f)H;{\overline{);\circ }}$$). Using a supersonic flow apparatus, we have observed by means of laser-induced fluorescence the decay of OH radicals in the presence of O2 at temperatures between 55.7 and 110.

An experimental confirmation of the products of the reaction between CN radicals and NH3.

By comparing H-atom yields from the reactions of CN with C(2)H(2) and NH(3), it has been confirmed that the latter reaction produces insignificant amounts of H-atoms, implying that it proceeds exclusively to HCN + NH(2).

A theoretical analysis of the reaction between CN radicals and NH3.

The reaction between CN radicals and NH3 molecules has been studied experimentally over an unusually wide range of temperature (25-716 K). Below 295 K, the rate constant exhibits a strong negative dependence on temperature; that is, it increases sharply as the temperature is lowered. The present work analyses the kinetics of this reaction theoretically, both to explain this unusual temperature-dependence and to identify the major products of the reaction--which have not been well established by experiment.

The temperature-dependence of elementary reaction rates: beyond Arrhenius.

The rates of chemical reactions and the dependence of their rate constants on temperature are of central importance in chemistry. Advances in the temperature-range and accuracy of kinetic measurements, principally inspired by the need to provide data for models of combustion, atmospheric, and astrophysical chemistry, show up the inadequacy of the venerable Arrhenius equation--at least, over wide ranges of temperature. This critical review will address the question of how to reach an understanding of the factors that control the rates of 'non-Arrhenius' reactions.

Understanding reactivity at very low temperatures: the reactions of oxygen atoms with alkenes.

A remarkable number of reactions between neutral free radicals and neutral molecules have been shown to remain rapid down to temperatures as low as 20 kelvin. The rate coefficients generally increase as the temperature is lowered. We examined the reasons for this temperature dependence through a combined experimental and theoretical study of the reactions of O(3P) atoms with a range of alkenes.

Rate coefficients for reaction and for rotational energy transfer in collisions between CN in selected rotational levels (X 2Sigma+, v=2, N=0, 1, 6, 10, 15, and 20) and C2H2.

Rate coefficients (ktot,Ni) are reported (a) for total removal (reactive+inelastic) of CN(X2Sigma+,v=2,Ni) radicals from selected rotational levels (Ni=0, 1, 6, 10, 15, and 20) and (b) for state-to-state rotational energy transfer (ki-->f) between levels Ni and other rotational levels Nf in collisions with C2H2. CN radicals were generated by pulsed laser photolysis of NCNO at 573 nm. A fraction of the radicals was then promoted to a selected rotational level in v=2 using a tunable infrared "pump" laser operating at approximately 2.

The temperature-dependence of rapid low temperature reactions: experiment, understanding and prediction.

Despite the success of the CRESU (Cinétique de Réaction en Ecoulement Supersonique Uniforme) method in measuring rate coefficients for neutral-neutral reactions of radicals down close to the very low temperatures prevalent in dense interstellar clouds (ISCs), there are still many reactions of potential importance in the chemistry of these objects for which there have been no measurements of low temperature rate coefficients. One important class of reactions is that between atomic and molecular free radicals and unsaturated hydrocarbons; that is, alkynes and alkenes. Based on semi-empirical arguments and correlations of 'room temperature' rate coefficients, k(298 K), for reactions of this type with the difference between the ionisation energy of the alkyne/alkene and the electron affinity of the radical, we suggest which reactions between the radicals, C(3P), O(3P), N(4S), CH, C2H and CN, and carbon chain molecules (Cn) and cyanopolyynes (HC2nCN and NCC2nCN) are likely to be fast at the temperature of dense ISCs.

Energy transfer in thermal and hyperthermal collisions between CN(X2Sigma+, v = 2) in selected rotational levels (Ni = 0, 1, 6, 10, 15 and 20) and N2.

We report rate coefficients (k(tot,N(i))) for total removal of CN(X(2)Sigma(+), v = 2, N(i)) radicals from selected rotational levels (N(i) = 0, 1, 6, 10, 15 and 20) and for state-to-state rotational energy transfer (k(i-->f)) between levels N(i) and other rotational levels N(f) in single collisions with N(2). CN radicals have been generated using two sources: (a) the pulsed laser photolysis of ICN at 266 nm, which generates translationally 'hot' CN radicals; and (b) the pulsed laser photolysis of NCNO at 570 nm, which generates CN radicals with translational energies close to the average value at 298 K. Comparison of the values of k(tot,N(i)) obtained using these two sources of CN demonstrates: firstly, that the same results are obtained as long as time is allowed for the translationally hot CN radicals generated from ICN to be thermalised before radicals are promoted to a specific rotational level in v = 2 using a tuneable infrared 'pump' laser operating at ca.

Reactions at very low temperatures: gas kinetics at a new frontier.

Advances in experimental techniques, especially the development of the CRESU (Cinétique de Réaction en Ecoulement Supersonique Uniforme) method, allow many gas-phase molecular processes to be studied at very low temperatures. This Review focuses on the reactions of molecular and atomic radicals with neutral molecules. Rate constants for almost 50 such reactions have been measured at temperatures as low as 13 K by using the CRESU method.

Investigating the Presence of Biotic Agents Associated with Mundulla Yellows.

The role of biotic agents in the dieback syndrome Mundulla Yellows (MY) was investigated by analysis of 40 Eucalyptus camaldulensis, E. leucoxylon, or E. cladocalyx trees and soil samples from South Australia and Victoria, Australia.

Kinetics of the radical-radical reaction, O(3P(J)) + OH(X2Pi omega) --> O2 + H, at temperatures down to 39 K.

The kinetics of the reaction between O atoms and OH radicals, both in their electronic ground state, have been investigated at temperatures down to ca. 39 K. The experiments employed a CRESU (Cinétique deRéaction en Ecoulement Supersonique Uniforme) apparatus to attain low temperatures.

Rotational energy transfer in collisions between CO(X 1Sigma+, v= 2 , J = 0, 1, 4, and 6) and He at temperatures from 294 to 15 K.

Infrared-vacuum ultraviolet double resonance experiments have been implemented in the ultracold environment provided by a Cinetique de Reaction en Ecoulement Supersonique Uniforme apparatus. With this technique rate coefficients of two kinds have been measured for rotational energy transfer in collisions between CO and He: (a) those for total removal from the selected rotational states J = 0, 1, 4, and 6 in the vibronic state X 1Sigma+, v = 2, and (b) those for transfer between selected initial and specific final states. Using different Laval nozzles, results have been obtained at several different temperatures: 294, 149, 63, 27, and 15 K.

Relaxation of H2O from its /04>- vibrational state in collisions with H2O, Ar, H2, N2, and O2.

We report rate coefficients at 293 K for the collisional relaxation of H2O molecules from the highly excited /04>(+/-) vibrational states in collisions with H2O, Ar, H2, N2, and O2. In our experiments, the mid R:04(-) state is populated by direct absorption of radiation from a pulsed dye laser tuned to approximately 719 nm. Evolution of the population in the (/04>(+/-)) levels is observed using the combination of a frequency-quadrupled Nd:YAG laser, which selectively photolyses H2O(/04>(+/-)), and a frequency-doubled dye laser, which observes the OH(v=0) produced by photodissociation via laser-induced fluorescence.