The synthesis of potential antimalarials. Derivatives of pantoyltaurine

The general hypothesis as to the mode of action of chemotherapeutic agents, which has been formulated by Fildes, Woods, McIlwain, and others (2), offers a rational and useful guide to the design of new drugs. Thus, bacteriostasis is pictured as caused by the blocking of reactions essential to growth by an inhibiting substance which has a structure similar to that of one of the normal enzymes or metabolites essential to the growth of the organism

Towards Regional Assimilation of Lagrangian Data: The Lagrangian Form of the Shallow Water Reduced Gravity Model and its Inverse

Variational data assimilation for Lagrangian geophysical fluid dynamics is introduced. Lagrangian coordinates add numerical difficulties into an already difficult subject, but also offer certain distinct advantages over Eulerian coordinates. First, float position and depth are defined by linear measurement functionals. Second, Lagrangian or ‘comoving’ open domains are conveniently expressed in Lagrangian coordinates. The attraction of such open domains is that they lead to well-posed prediction problems [Bennett and Chua (1999)] and hence efficient inversion algorithms. Eulerian and Lagrangian solutions of the inviscid forward problem in a doubly periodic domain, with North Atlantic mesoscales, are compared and found to be in satisfactory agreement for about one day. Viscous stresses vastly extend the interval of agreement at the cost of considerable complexity, so in this first study the machinery of variational assimilation is developed and tested for inviscid dynamics, simulated data and short assimilation intervals. It was found that the intricate machinery could be consistently developed, managed, and satisfactorily tested at least within the confines of the chosen parameters

Born-Oppenheimer Approximation near Level Crossing

We consider the Born-Oppenheimer problem near conical intersection in two dimensions. For energies close to the crossing energy we describe the wave function near an isotropic crossing and show that it is related to generalized hypergeometric functions 0F3. This function is to a conical intersection what the Airy function is to a classical turning point. As an application we calculate the anomalous Zeeman shift of vibrational levels near a crossing.Comment: 8 pages, 1 figure, Lette

Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series

The largest kindred with inherited prion disease P102L, historically Gerstmann-Sträussler-Scheinker syndrome, originates from central England, with émigrés now resident in various parts of the English-speaking world. We have collected data from 84 patients in the large UK kindred and numerous small unrelated pedigrees to investigate phenotypic heterogeneity and modifying factors. This collection represents by far the largest series of P102L patients so far reported. Microsatellite and genealogical analyses of eight separate European kindreds support multiple distinct mutational events at a cytosine-phosphate diester-guanidine dinucleotide mutation hot spot. All of the smaller P102L kindreds were linked to polymorphic human prion protein gene codon 129M and were not connected by genealogy or microsatellite haplotype background to the large kindred or each other. While many present with classical Gerstmann-Sträussler-Scheinker syndrome, a slowly progressive cerebellar ataxia with later onset cognitive impairment, there is remarkable heterogeneity. A subset of patients present with prominent cognitive and psychiatric features and some have met diagnostic criteria for sporadic Creutzfeldt-Jakob disease. We show that polymorphic human prion protein gene codon 129 modifies age at onset: the earliest eight clinical onsets were all MM homozygotes and overall age at onset was 7 years earlier for MM compared with MV heterozygotes (P = 0.02). Unexpectedly, apolipoprotein E4 carriers have a delayed age of onset by 10 years (P = 0.02). We found a preponderance of female patients compared with males (54 females versus 30 males, P = 0.01), which probably relates to ascertainment bias. However, these modifiers had no impact on a semi-quantitative pathological phenotype in 10 autopsied patients. These data allow an appreciation of the range of clinical phenotype, modern imaging and molecular investigation and should inform genetic counselling of at-risk individuals, with the identification of two genetic modifiers

Schottky-based band lineups for refractory semiconductors

An overview is presented of band alignments for small-lattice parameter, refractory semiconductors. The band alignments are estimated empirically through the use of available Schottky barrier height data, and are compared to theoretically predicted values. Results for tetrahedrally bonded semiconductors with lattice constant values in the range from C through ZnSe are presented. Based on the estimated band alignments and the recently demonstrated p-type dopability of GaN, we propose three novel heterojunction schemes which seek to address inherent difficulties in doping or electrical contact to wide-gap semiconductors such as ZnO, ZnSe, and ZnS

Optical and Radio monitoring of S5 1803+74

The optical (BVRI) and radio (8.4 GHz) light curves of S5 1803+784 on a time span of nearly 6 years are presented and discussed. The optical light curve showed an overall variation greater than 3 mag, and the largest changes occured in three strong flares. No periodicity was found in the light curve on time scales up to a year. The variability in the radio band is very different, and shows moderate oscillations around an average constant flux density rather than relevant flares, with a maximum amplitude of $\sim$30%, without a simultaneous correspondence between optical and radio luminosity. The optical spectral energy distribution was always well fitted by a power law. The spectral index shows small variations and there is indication of a positive correlation with the source luminosity. Possible explanations of the source behaviour are discussed in the framework of current models.Comment: 25 pages, 12 figure