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The most common causes of chronic liver disease are excess alcohol intake, viral hepatitis and non-alcoholic fatty liver disease, with the clinical spectrum ranging in severity from hepatic inflammation to cirrhosis, liver failure or hepatocellular carcinoma (HCC). The genome of HCC exhibits diverse mutational signatures, resulting in recurrent mutations across more than 30 cancer genes1–7. Stem cells from normal livers have a low mutational burden and limited diversity of signatures8, which suggests that the complexity of HCC arises during the progression to chronic liver disease and subsequent malignant transformation. Here, by sequencing whole genomes of 482 microdissections of 100–500 hepatocytes from 5 normal and 9 cirrhotic livers, we show that cirrhotic liver has a higher mutational burden than normal liver. Although rare in normal hepatocytes, structural variants, including chromothripsis, were prominent in cirrhosis. Driver mutations, such as point mutations and structural variants, affected 1–5% of clones. Clonal expansions of millimetres in diameter occurred in cirrhosis, with clones sequestered by the bands of fibrosis that surround regenerative nodules. Some mutational signatures were universal and equally active in both non-malignant hepatocytes and HCCs; some were substantially more active in HCCs than chronic liver disease; and others—arising from exogenous exposures—were present in a subset of patients. The activity of exogenous signatures between adjacent cirrhotic nodules varied by up to tenfold within each patient, as a result of clone-specific and microenvironmental forces. Synchronous HCCs exhibited the same mutational signatures as background cirrhotic liver, but with higher burden. Somatic mutations chronicle the exposures, toxicity, regeneration and clonal structure of liver tissue as it progresses from health to disease.

FRASER AND KODICEK1have reported, and others hae confirmed2–4, that the kidney is the exclusive site of synthesis of 1,25-dihydroxycholecalciferol (1,25(OH)2D3). The 1-α-hydroxylation of 25-hydroxycholecalciferol (25-OH-D3) occurs in mitochondria1,4,5and is influenced by cytosol6,7, although conflicting data have been reported8. Preparations of whole tubules from the cortex possess 1-α-hydroxylase activity10but the precise localisation of the enzyme along the nephron is not known. In the dog, no evidence of 1-α-hydroxylase was found in medulla, enzymatic activity being observed only in cortical preparations5. In mice given systemic injections of 3H-vitamin D3autoradiography shows the tracer to be present in the proximal tubules9. However, whether hydroxylation occurred at this site was not established. Using single nephron preparations, we have now demonstrated that the major and probably exclusive site of synthesis of 1,25(OH)2D3is the proximal tubule.

Plasmodium falciparum infected erythrocytes containing mature trophozoites and schizonts sequester along venular endothelium1and are not in the peripheral circulation of patients with malaria. Knobs appear on infected erythrocytes and are the points of attachment to endothelium2. Sequestration may protect the parasite from splenic destruction3and may play a role in the pathogenesis of cerebral malaria4. Correlates of sequestration have been developed in vitro using cultured human endothelium5and an amelanotic melanoma cell line6. Knobless strains (K−) of P. falciparum fail to sequester in vivo and to bind to cells in vitro. We now present evidence that the receptor for cytoadherence is the glycoprotein, thrombospondin. Aotus monkey or human erythrocytes containing knobby (K+) but not Aotus erythrocytes containing knobless strains of P. falciparum bind to immobilized thrombospondin. Neither binds to the adhesive proteins laminin, fibronectin, factor VIII/von Wi lie brand factor or vitronectin. Both soluble thrombospondin and anti-thrombospondin antibodies inhibit binding of parasitized Aotus erythrocytes to immobilize thrombospondin and to melanoma cells which secrete thrombospondin.

WE report experiments demonstrating that it is possible to predict quantitatively the level of friction arising when a smooth rubber sphere slides on glass. Analysis of the sliding friction is based on a surface energy approach. Observations show that when a smooth rubber surface advances over glass by a continuous peel process (Schallamach waves) the work done in the region of contact can be calculated in terms of a rate-dependent surface energy and thus an expression found for the tangential frictional stress required to maintain uniform relative motion between the surfaces. In some cases predicted and observed frictional stresses agree to within 10%.

THE notion of “balance” ordinarily implies some underlying insecurity or liability to loss of equilibrium. Thus a pencil set up on its butt end may be technically in stable equilibrium, yet, because the centre of gravity lies some way above the relatively small area of support, we speak of the condition as one of “precarious balance”. The situation of a man standing erect is somewhat similar, though here the posture is maintained by muscular activity which is reflexly adjusted to counter the effects of forces that might disturb the equilibrium. These adjustments are usually so successful, and falling is consequently so unusual, that we tend to forget the inherent insecurity of the posture.

When a man stands, the physiological control of his leg muscles is made simpler than might have been expected by the kinematic design of the knee. Experiments with a working model have shown that a muscle acting as a linear spring produces a propping thrust which is independent of the length of the leg.

Measurements suggest that electrical repulsive forces may be of significance in the boundary lubrication of surfaces by synovial fluid.

This article describes the first direct study of the repulsive forces exerted by charged double layers residing on solid surfaces.

A GLACIATION in the latest part of Precambrian time1is commonly accepted as a major, rapidly waxing and waning event. Most of the northern hemisphere was involved2.

IN a recent communication1, one of us (O. L.) reviewed the results so far obtained, by the oscillographic method, in the study of the non-acoustic function of the vertebrate ear. In that review a preliminary account was given of the reaction to gravitational stimuli and linear accelerations of the otolith organ in the recessus utriculi of the elasmo-branch labyrinth. It was shown that the otolith organ of the utriculus is sensitive to positional changes about any horizontal axis, and to linear acceleration during straight-line translations. The fact that the organ is not restricted to respond to displacements in only one plane of space invited the conclusion that the utriculus may well be the only otolith organ concerned with the maintenance of equilibrium, leaving the otolith organs of the pars inferior of the labyrinth (sacculus and lagena) free for the reception of vibrational stimuli. This function has, in fact, been conclusively demonstrated to be localized in the pars inferior of the labyrinth of bony fish2,3.

FLOR1suggested that parasitic relationships have a specific genetic basis, and that a gene-for-gene relationship exists between host and parasite. Person2,3analysed this relationship and showed it to be valid in several host–parasite systems. Since 1959 numerous reports have appeared which support this validation.

WE report here a new approach to studying the shear behaviour of thin films of oil under conditions of elastohydrodynamic lubrication such as arise at points of contact in ball bearings or between gear teeth. During its passage through the contact the oil is rapidly compressed to pressures in the region of 104bar and then sheared by the sliding motion of the metal surfaces. Hitherto this behaviour has been studied using rolling contact disk machines in which rollers having parallel axes are pressed into contact. Rolling motion generates an oil film of known thickness (∼1 µm) between the hard steel surfaces; superimposed sliding shears the film. At very small sliding speeds—shear rates—the behaviour is linear: the mean shear stress required to shear the film \[taumacr] is proportional to the sliding speed. At higher sliding speeds the mean shear stress reaches a maximum (critical) value \[taumacr]c1. It has been suggested2that the observed behaviour can be explained by the oil exhibiting viscoelastic properties at these high pressures, when the viscosity is known to increase by many orders of magnitude. Unfortunately this hypothesis cannot be tested with certainty by conventional disk machine tests, which do not distinguish unequivocally between viscous and elastic response of the fluid in the contact zone. We report here a different rolling contact experiment which reveals viscoelastic behaviour directly by separating elastic and viscous response of an oil film under elastohydrodynamic conditions.

I TRUST you will allow me space for a short note upon Prof. Lankester's article in last week's issue of NATURE (p. 1), under the above heading. I have no intention of entering into a controversy with Prof. Lankester upon matters of opinion, but I am desirous of correcting statements, made by him in that article, which are inaccurate. In point of fact, the article is based entirely upon a misapprehension as to the purpose and function of the London Society for the Extension of University Teaching, and its position with regard to Gresham College. Prof. Lankester speaks of it as a Lecture Society, and refers to the “innumerable short courses” of lectures given in different halls, Vestry Halls, and others in London. He is evidently here confusing two distinct things. The short courses in large halls are given under the People's Lectures Scheme, which is an entirely different matter, and in connection with which we never use the word “University.” The courses of lectures and classes carried on by the London Society and the Universities Joint Board involve a systematic course of work extending over a full term of ten or twelve weeks. It is a part of the same great movement which is carried on by the University of Cambridge (not by a Lecture Society), and more recently also by the University of Oxford, in different parts of the country.