Some features of traffic accidents

Some aspects of urban and rural traffic accidents have been studied at the scene of some accidents in Birmingham and the county of Worcestershire. Accidents to pedestrians are essentially an urban problem, occur mainly at low speed, and most of the serious injury comes from the initial contact with the vehicle, rather than from secondary impacts with the road surface. The characteristics of motor-cycle accidents are more varied; in urban areas there are many side impacts, with consequent injury to the lower limbs, while rural collisions are predominantly front on, with a high incidence of head injury. Accidents to car occupants vary according to the environment.     

Treatment of Hypertension with Clonidine

Clonidine, in a daily dosage of 0·15-4·8 mg., effectively lowered systolic and diastolic pressures in 26 out of 28 impatients with moderate to severe hypertension, including five with primary renal disease. The action of the drug did not depend on posture and was not associated with reduction in renal function. Side-effects were not severe, but mental changes occurred in four patients.Clonidine is a useful alternative to currently available antihypertensive drugs, but further evaluation of its longterm efficacy is required.     

REGIONAL DISTRIBUTION OF MONOAMINES AND THEIR METABOLITES IN THE HUMAN BRAIN

Abstract— Noradrenaline (NA), dopamine (DA). 5-hydroxytryptamine (5-HT), 4-hydroxy, 3-methoxy-phenylethylene glycol (MHPG), homovanillic acid (HVA), 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindolylacetic acid (5-HIAA) were measured in twenty areas of post-mortem brain from ten psychiatrically and neurologically normal patients. There was a marked difference, which did not appear to be related to sex, medication, cause of death or time between death and dissection, in amine and metabolite concentrations between brains. In the cortex, 5-HT, MHPG, HVA. DOPAC and S-HIAA were approximately even in their distribution; NA and DA could not be detected. In sub-cortical areas there were clear differences in the distribution of the three amines accompanied by less marked differences in the distribution of their respective metabolites.     

Advanced Cell Mapping Visualizations for Single Cell Functional Proteomics Enabling Patient Stratification

Highly multiplexed single‐cell functional proteomics has emerged as one of the next‐generation toolkits for a deeper understanding of functional heterogeneity in cell. Different from the conventional population‐based bulk and single‐cell RNA‐Seq assays, the microchip‐based proteomics at the single‐cell resolution enables a unique identification of highly polyfunctional cell subsets that co‐secrete many proteins from live single cells and most importantly correlate with patient response to a therapy. The 32‐plex IsoCode chip technology has defined a polyfunctional strength index (PSI) of pre‐infusion anti‐CD19 chimeric antigen receptor (CAR)‐T products, that is significantly associated with patient response to the CAR‐T cell therapy. To complement the clinical relevance of the PSI, a comprehensive visualization toolkit of 3D uniform manifold approximation and projection (UMAP) and t‐distributed stochastic neighbor embedding (t‐SNE) in a proteomic analysis pipeline is developed, providing more advanced analytical algorithms for more intuitive data visualizations. The UMAP and t‐SNE of anti‐CD19 CAR‐T products reveal distinct cytokine profiles between nonresponders and responders and demonstrate a marked upregulation of antitumor‐associated cytokine signatures in CAR‐T cells from responding patients. Using this powerful while user‐friendly analytical tool, the multi‐dimensional single‐cell data can be dissected from complex immune responses and uncover underlying mechanisms, which can promote correlative biomarker discovery, improved bioprocessing, and personalized treatment development.     

Elastin-like Peptide amphiphiles form nanofibers with tunable length

Peptide amphiphiles (PAs) self-assemble nanostructures with potential applications in drug delivery and tissue engineering. Some PAs share environmentally responsive behavior with their peptide components. Here we report a new type of PAs biologically inspired from human tropoelastin. Above a lower critical solution temperature (LCST), elastin-like polypeptides (ELPs) undergo a reversible inverse phase transition. Similar to other PAs, elastin-like PAs (ELPAs) assemble micelles with fiber-like nanostructures. Similar to ELPs, ELPAs have inverse phase transition behavior. Here we demonstrate control over the ELPAs fiber length and cellular uptake. In addition, we observed that both peptide assembly and nanofiber phase separation are accompanied by a distinctive secondary structure attributed primarily to a type-1 β turn. We also demonstrate increased solubility of hydrophobic paclitaxel (PAX) in the presence of ELPAs. Due to their biodegradability, biocompatibility, and environmental responsiveness, elastin-inspired biopolymers are an emerging platform for drug and cell delivery; furthermore, the discovery of ELPAs may provide a new and useful approach to engineer these materials into stimuli-responsive gels and drug carriers.     

Synthesis and biophysical evaluation of minor-groove binding C-terminus modified pyrrole and imidazole triamide analogs of distamycin

Five polyamide derivatives with rationally modified C-terminus moieties were synthesized and their DNA binding specificity and affinity determined. A convergent approach was employed to synthesize polyamides containing an alkylaminopiperazine (4 and 5), a truncated piperazine (6), or an alkyldiamino-C-terminus moiety (7 and 8) with two specific objectives: to investigate the effects of number of potential cationic centers and steric bulk at the C-terminus. CD studies confirmed that compounds 4, 5, 7, and 8 bind in the minor groove of DNA. The alkylpiperazine containing compounds (4 and 5) showed only moderate binding to DNA with DeltaT(m) values of 2.8 and 8.3 degrees C with their cognate sequence, respectively. The alkyldiamino compounds (7 and 8) were more impressive producing a DeltaT(m) of >17 and >22 degrees C, respectively. Compound 6 (truncated piperazine) did not stabilize its cognate DNA sequence. Footprints were observed for all compounds (except compound 6) with their cognate DNA sequence using DNase I footprinting, with compound 7 producing a footprint of 0.1 microM at the expected 5'-ACGCGT-3' site. SPR analysis of compound 7 binding to 5'-ACGCGT-3', 5'-ACCGGT-3', and 5'-AAATTT-3' produced binding affinities of 2.2x10(6), 3.3x10(5), and 1x10(5)M(-1), respectively, indicating a preference for its cognate sequence of 5'-ACGCGT-3'. These results are in good agreement with the footprinting data. The results indicate that steric crowding at the C-terminus is important with respect to binding. However, the number of cationic centers within the molecule may also play a role. The alkyldiamino-containing compounds (7 and 8) warrant further investigation in the field of polyamide research.     

Analysis of TaALMT1 traces the transmission of aluminum resistance in cultivated common wheat (Triticum aestivum L.)

Allele diversities of four markers specific to intron three, exon four and promoter regions of the aluminum (Al) resistance gene of wheat (Triticum aestivum L.) TaALMT1 were compared in 179 common wheat cultivars used in international wheat breeding programs. In wheat cultivars released during the last 93 years, six different promoter types were identified on the basis of allele size. A previous study showed that Al resistance was not associated with a particular coding allele for TaALMT1 but was correlated with blocks of repeated sequence upstream of the coding sequence. We verified the linkage between these promoter alleles and Al resistance in three doubled haploid and one intercross populations segregating for Al resistance. Molecular and pedigree analysis suggest that Al resistance in modern wheat germplasm is derived from several independent sources. Analysis of a population of 278 landraces and subspecies of wheat showed that most of the promoter alleles associated with Al resistance pre-existed in Europe, the Middle East and Asia prior to dispersal of cultivated germplasm around the world. Furthermore, several new promoter alleles were identified among the landraces surveyed. The TaALMT1 promoter alleles found within the spelt wheats were consistent with the hypothesis that these spelts arose on several independent occasions from hybridisations between non-free-threshing tetraploid wheats and Al-resistant hexaploid bread wheats. The strong correlation between Al resistance and Al-stimulated malate efflux from the root apices of 49 diverse wheat genotypes examined was consistent with the previous finding that Al resistance in wheat is conditioned primarily by malate efflux. These results demonstrate that the markers based on intron, exon and promoter regions of TaALMT1 can trace the inheritance of the Al resistance locus within wheat pedigrees and track Al resistance in breeding programmes. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Presence of transient helical segments in the galanin-like peptide evident from (1)H NMR, circular dichroism, and prediction studies

Galanin and its newly discovered relative galanin-like peptide (GALP) are neuropeptides that are implicated in the neuroendocrine regulation of body weight and reproduction. GALP encompasses within its sequence the first 13 residues of galanin, known to be crucial to binding and activation of galanin receptor (GalR) subtypes. Using 2D-NMR and circular dichroism spectroscopy we demonstrated that GALP does not adopt a preferred conformation in pure water alone. However, it shows characteristics of transient turn-like structures in two distinct regions of its sequence, 11-23 and 41-49. These transient ordered structures, nascent helices, probably form stable helical structures upon addition of the helix-inducing solvent, trifluoroethanol, as determined by circular dichroism studies. Secondary structure prediction methods also predict the presence of two helical regions in the sequence of GALP overlapping reasonably with those regions identified as nascent helical structures by experimental methods.     

Crystal structures of flax rust avirulence proteins AvrL567-A and -D reveal details of the structural basis for flax disease resistance specificity

The gene-for-gene mechanism of plant disease resistance involves direct or indirect recognition of pathogen avirulence (Avr) proteins by plant resistance (R) proteins. Flax rust (Melampsora lini) AvrL567 avirulence proteins and the corresponding flax (Linum usitatissimum) L5, L6, and L7 resistance proteins interact directly. We determined the three-dimensional structures of two members of the AvrL567 family, AvrL567-A and AvrL567-D, at 1.4- and 2.3-A resolution, respectively. The structures of both proteins are very similar and reveal a beta-sandwich fold with no close known structural homologs. The polymorphic residues in the AvrL567 family map to the surface of the protein, and polymorphisms in residues associated with recognition differences for the R proteins lead to significant changes in surface chemical properties. Analysis of single amino acid substitutions in AvrL567 proteins confirm the role of individual residues in conferring differences in recognition and suggest that the specificity results from the cumulative effects of multiple amino acid contacts. The structures also provide insights into possible pathogen-associated functions of AvrL567 proteins, with nucleic acid binding activity demonstrated in vitro. Our studies provide some of the first structural information on avirulence proteins that bind directly to the corresponding resistance proteins, allowing an examination of the molecular basis of the interaction with the resistance proteins as a step toward designing new resistance specificities.