The in vivo expression of the globin genes of theβ cistron in γ-,δ-, andδβ-thalassemia heterozygotes

There is considerable evidence suggesting that the switch from to and chain production after birth is due, in part, to silencing of the genes by stage-specific factors which bind to their promoters and to the competition from the adult ( and ) genes for a common enhancer element located in the locus control region. As a consequence one can expect that the increased Hb F production in adults with hereditary persistence of fetal hemoglobin or -thalassemia is directed mainly by -globin genes in cis to the deletion(s) responsible for these conditions. Here we review data on heterozygotes with -, -, or -thalassemia, who also had an^AT mutation, in cis or in trans, which was used as a marker of gene expression. The results show that a deletion affecting adult genes favors the expression of genes in cis, while the deletion of a single gene does not affect the expression of the gene in cis but leads to a faster switch postnatally.     

Is there any quantitative relationship between the synthesis and the breakdown of nucleic acids in living cells?

Zusammenfassung Es wurde untersucht, ob die Biosynthese der Nukleinsäuren in wachsenden Systemen mit dem Abbau von ursprünglich vorhandenen Nukleinsäuren derselben Art gekoppelt ist. Die Versuche wurden mit Bakterien (E. coli) und mit Rattenleber gemacht. Die in der Zelle vorhandenen Nukleinsäuren waren mit P³² markiert, und es wurde der Verlust an Radioaktivität in jeder der beiden Nukleinsäuretypen im Laufe des Wachstums gemessen. Die Resultate wiesen darauf hin, dass das Auftreten von neuen Nukleinsäuremolekeln in der lebenden Zelle ohne den begleitenden Abbau der alten Molekeln stattfinden kann.

---

---

Supported in part by the Scientific Research Fund of the Ministry of Education given to the Synthetic Research Group on Nucleic Acids. The warm encouragement given to this work by Prof.J. Kamahora of this Institute is heartily acknowledged. We are further indebted to Dr.T. Miura, Department of Radiology, University of Osaka Medical School, for his help in this work.     

The use of benzylpenicillinacylase fromEscherichia coli in the resolution of some racemicβ-,γ-,δ- andɛ-amino-acids

Summary The enzymatic hydrolysis of N-phenylacetyl derivatives of racemic amino-acids having the chiral centre removed from the usual -position is examined. The reaction is found to have different degrees of stereoselectivity. In the case of -amino-acids and of -aminovaleric acid, both enantiomers can be obtained in good yields and high optical purity. S-directed stereochemical preference was found for all the substrates examined.     

Open or closed? Dirac,Heisenberg, and the relation between classical and quantum mechanics

This paper describes a long-standing, though little known, debate between Dirac and Heisenberg over the nature of scientific methodology, theory change, and intertheoretic relations. Following Heisenberg's terminology, their disagreements can be summarized as a debate over whether the classical and quantum theories are “open” or “closed.” A close examination of this debate sheds new light on the philosophical views of two of the great founders of quantum theory.     

Cl<Superscript>–</Superscript> affects the function of the GABA cotransporter rGAT1 but preserves the mutal relationship between transient and transport currents

The effects of reducing external Cl- on the electrophysiological properties of the Na+/Cl(-)-dependent GABA transporter rGAT1 expressed in Xenopus oocytes were investigated. In agreement with a recently proposed kinetic scheme, the effects of Cl- are complex but preserve the mutual relationship that links the transport-associated current, I(tr), measured in saturating GABA concentration, and the transient current, I(pre), recorded in the absence of GABA following a voltage step from the holding potential Vh to V. In particular, I(tr) (V) - I(tr) (Vh) = r integral I(pre) (V) dt, where r is the relaxation rate of I(pre) at the same membrane potential and Cl- concentration. The model also predicts a relationship between charge relaxation rate and apparent affinity for GABA, which is also verified in the presence of lowered Na+ or Cl- concentrations. In these conditions, the binding rate of GABA to the transporter is increased. All these effects are consistent with the hypothesis that interaction of the organic substrate with rGAT1 induces a conversion from a capacitive to a conductive mode of operation without strongly altering either the amount or the rate of charge movement.     

The molecular link between β- and γ-secretase activity on the amyloid β precursor protein

Alzheimer’s disease (AD) is characterized by an accumulation in the brain of amyloid β peptides (Aβ). The production of Aβ requires two sequential cleavages induced by β- and γ-secretases on the β-amyloid precursor protein (APP). Altered activity of these secretases is involved in the pathogenesis of AD. The expression and activity of β-secretase (BACE1) is augmented in the brain in late-onset sporadic AD. Mutant presenilin 1 (PS1), the major genetic defect of early-onset familial AD (FAD), alters the activity of γ-secretase, leading to increased production of Aβ42. Here we review the role of oxidative stress as a molecular link between the β- and the γ-secretase activities, and provide a mechanistic explanation of the pathogenesis of sporadic late-onset AD. We also discuss evidence for a role of the same mechanism in the pathogenesis of familial AD carrying PS1 mutations.     

Historical and other considerations regarding the crystal form of sodium-ammonium d- and l-tartrate,potassium d- and l-tartrate,potassium-ammonium d- and l-tartrate,and potassium racemate.—II

In 1914, the physics discipline had reached a very similar stage of development in Australia and Japan. A generation later the paths of development had considerably diverged. A systematic comparison of the evolution of physics in the two countries during these years identifies factors—political, economic and cultural—that led to this divergence, but it also uncovers a number of underlying parallels.     

The Quantification and Differentiation of the Drug Receptor Theory,c. 1910–1960

While historians have dealt with the origins of the concept of drug receptors in the work of Paul Ehrlich (1854–1915) and John N. Langley (1852–1925) as well as with some of its applications in modern pharmaceutical research, the history of the receptor theory as such has been neglected. Discussing major developments and conceptual changes in receptor theory between about 1910 and 1960 (including relevant contributions by A. V. Hill, A. J. Clark, J. H. Gaddum, E. J. Ariëns and others), this paper attempts to fill this gap in historiography. It provides a case study of the unfolding of research under a new paradigm, but it considers also contemporary criticism and scepticism. By the early 1960s, quantitative investigations of drug action and interpretations of the experimental findings in terms of the receptor concept had become constitutive of the emerging field of ‘molecular pharmacology’. Even then, however, receptors were still hypothetical entities.     

Plasma enteroglucagon,peptide YY and gastrin in rats deprived of luminal nutrition,and after urogastrone-EGF administration. A proliferative role for PYY in the intestinal epithelium?

Intestinal tissue mass was significantly reduced throughout the gastrointestinal tract (p<0.001) of=" intravenously=" fed=" (tpn)=" rats.=" urogastrone-epidermal=" growth=" factor,=" (uro-egf),=" reversed=" these=" changes.=" although=" plasma=" enteroglucagon=" and=" gastrin=" levels=" showed=" a=" small=" increase=" with=" uro-egf,=" this=" was=" far=" less=" than=" the=" gut=" tissue=" weight=" change,=" suggesting=" that=" it=" was=" unlikely=" that=" they=" were=" involved=" in=" modulating=" the=" proliferative=" response=" of=" the=" intestine=" to=" uro-egf.=" peptide=" tyrosine=" tyrosine=" (pyy)=" levels=" were=" however=" significantly=" increased=" by=" uro-egf,=" indicating=" that=" pyy=" may=" possibly=" have=" a=" role=" in=" the=" modulation=" of=" intestinal=" cell=">We thank the Cancer Research Campaign for their financial assistance and acknowledge the technical assistance of Mr W. Lenton.