Femtosecond X-ray protein nanocrystallography

X-ray crystallography provides the vast majority of macromolecular structures, but the success of the method relies on growing crystals of sufficient size. In conventional measurements, the necessary increase in X-ray dose to record data from crystals that are too small leads to extensive damage before a diffraction signal can be recorded. It is particularly challenging to obtain large, well-diffracting crystals of membrane proteins, for which fewer than 300 unique structures have been determined despite their importance in all living cells. Here we present a method for structure determination where single-crystal X-ray diffraction 'snapshots' are collected from a fully hydrated stream of nanocrystals using femtosecond pulses from a hard-X-ray free-electron laser, the Linac Coherent Light Source. We prove this concept with nanocrystals of photosystem I, one of the largest membrane protein complexes. More than 3,000,000 diffraction patterns were collected in this study, and a three-dimensional data set was assembled from individual photosystem I nanocrystals (～200?nm to 2?μm in size). We mitigate the problem of radiation damage in crystallography by using pulses briefer than the timescale of most damage processes. This offers a new approach to structure determination of macromolecules that do not yield crystals of sufficient size for studies using conventional radiation sources or are particularly sensitive to radiation damage.     

Effect of dimethindene, an antihistaminic drug, on the transmembrane potentials of mammalian myocardium

Dimethindene (DMI) decreased the maximum rate of rise of action potential (AP) without changing the resting potential in cat ventricular myocardium. DMI abolished the histamine-induced slow APs in left atria but not in right ventricular papillary muscles of guinea-pig, suggesting that DMI blocked the histamine H1-receptors.     

Operations research (OR), management science (MS), systems science,and Russell Ackoff: The development of two paradigms

The development of OR, MS, and systems science from 1946 through 1980 is seen through a review of Russell Ackoff's work up to approximately the 1980s. Five stages of OR development are distinguished: emergence, expansion of frontiers, institutionalization, controversy, and separation. The latter stages of OR coincide with the early stages in the development of systems science: initial ideas, accumulation of deviants, expansion within OR, and formal launching of systems science. This analysis demonstrates Russell Ackoff's particularly relevant role in the emergence and development of the OR and systems science paradigms.     

Family of disulphide-linked dimers containing the zeta and eta chains of the T-cell receptor and the gamma chain of Fc receptors

Stimulation of T cells by antigen activates many signalling pathways. The capacity for this range of biochemical responses may reside in the complex structure of the seven-chain T-cell antigen receptor (TCR). In addition to the complexity shared by all TCRs, coexpression of zeta (zeta) and the distinct but related eta (eta) chains creates structural diversity among the TCR complexes expressed on a given cell. In most murine T cells that we have studied, about 90% of the heptameric receptor complexes contain a zeta zeta disulphide homodimer, whereas 10% contain a zeta eta disulphide heterodimer. Recent studies suggest that zeta has a critical role in allowing antigen to activate the cell, whereas eta expression has been correlated with the capacity for antigen-induced phosphoinositide turnover. A third zeta-related protein, the gamma (gamma) chain of the Fc epsilon and some Fc gamma receptors, exists as a disulphide homodimer in those complexes. The structural relatedness of zeta and gamma is emphasized by the recent demonstration of zeta zeta in association with CD16 in TCR-negative natural killer cells. Here we identify T cells lacking Fc receptors but coexpressing zeta, gamma, and eta, document the formation of novel heterodimers between zeta and gamma and between eta and gamma and show their association with the TCR. A greater range of homologous coupling structures than previously thought may be one way of achieving the variety of TCR-mediated (and possibly Fc receptor-mediated) biochemical responses and effector functions.     

Oxytocin analogs effective as noncompetitive inhibitors in uterotonic test

Summary Deamino-1-carba-oxytocin analogs with a chemically reactive group in position 4 were demonstrated to act as noncompetitive oxytocin inhibitors in the assay on isolated rat uterus.     

The lack of insulin-binding to simple glycosidic receptors

Summary The results of affinity electrophoresis at pH 8.9 show that insulin does not interact with any of a number of glycosidic ligands which bind various lectins. The results are discussed with respect to some similarities between insulin and concanavalin A.     

Cataract induced by administration of a single dose of sodium selenite to suckling rats

Summary A single dose of sodium selenite to male suckling rats causes permanent or intermittent cataracts. The resistance to the lethal effect of selenite in suckling rats is significantly higher in comparison with adult animals.     

Immunoadjuvant activity of synthetic N-acetyl muramyl dipeptide

Summary The administration of phosphatidyl choline/cholesterol liposomes with entrapped N-acetyl muramyl dipeptide induced in guinea-pigs the development of delayed hypersensitivity to ovalbumin.