Search

Some Plasmodium falciparum repetitive interspersed families of polypeptides (RIFINs)—variant surface antigens that are expressed on infected erythrocytes1—bind to the inhibitory receptor LAIR1, and insertion of DNA that encodes LAIR1 into immunoglobulin genes generates RIFIN-specific antibodies2,3. Here we address the general relevance of this finding by searching for antibodies that incorporate LILRB1, another inhibitory receptor that binds to β2 microglobulin and RIFINs through their apical domains4,5. By screening plasma from a cohort of donors from Mali, we identified individuals with LILRB1-containing antibodies. B cell clones isolated from three donors showed large DNA insertions in the switch region that encodes non-apical LILRB1 extracellular domain 3 and 4 (D3D4) or D3 alone in the variable–constant (VH–CH1) elbow. Through mass spectrometry and binding assays, we identified a large set of RIFINs that bind to LILRB1 D3. Crystal and cryo-electron microscopy structures of a RIFIN in complex with either LILRB1 D3D4 or a D3D4-containing antibody Fab revealed a mode of RIFIN–LILRB1 D3 interaction that is similar to that of RIFIN–LAIR1. The Fab showed an unconventional triangular architecture with the inserted LILRB1 domains opening up the VH–CH1 elbow without affecting VH–VL or CH1–CL pairing. Collectively, these findings show that RIFINs bind to LILRB1 through D3 and illustrate, with a naturally selected example, the general principle of creating novel antibodies by inserting receptor domains into the VH–CH1 elbow. Plasmodium antigens called RIFINs bind to specific antibodies that incorporate the inhibitory receptor LILRB1 through its D3 domain, illustrating the principle of receptor-containing antibodies.

Over the past two centuries, mammalian chewing and related anatomical features have been among the most discussed of all vertebrate evolutionary innovations1-3. Chief among these features are two characters: the dentary-only mandible, and the tribosphenic molar with its triangulated upper cusps and lower talonid basin3-5. The flexible mandibular joint and the unfused symphysis of ancestral mammals-in combination with transformations of the adductor musculature and palate-are thought to have permitted greater mobility of each lower jaw, or hemimandible6,7. Following the appearance of precise dental occlusion near the origin of the mammalian crown8,9, therians evolved a tribosphenic molar with a craggy topography that is presumed to have been used to catch, cut and crush food. Here we describe the ancestral tribosphenic therian chewing stroke, as conserved in the short-tailed opossum Monodelphis domestica: it is a simple symmetrical sequence of lower tooth-row eversion and inversion during jaw opening and closing, respectively, enacted by hemimandibular long-axis rotation. This sequence is coupled with an eversion-inversion rotational grinding stroke. We infer that the ancestral therian chewing stroke relied heavily on long-axis rotation, including symmetrical eversion and inversion (inherited from the first mammaliaforms) as well as a mortar-and-pestle rotational grinding stroke that was inherited from stem therians along with the tribosphenic molar. The yaw-dominated masticatory cycle of primates, ungulates and other bunodont therians is derived; it is necessitated by a secondarily fused jaw symphysis, and permitted by the reduction of high, interlocking cusps10-12. The development of an efficient masticatory system-culminating in the tribosphenic apparatus-allowed early mammals to begin the process of digestion by shearing and crushing food into small boli instead of swallowing larger pieces in the reptilian manner, which necessitates a long, slow and wholly chemical breakdown. The vast diversity of mammalian teeth has emerged from the basic tribosphenic groundplan13.

Over the past two centuries, mammalian chewing and related anatomical features have been among the most discussed of all vertebrate evolutionary innovations

In two previously described donors, the extracellular domain of LAIR1, a collagen-binding inhibitory receptor encoded on chromosome 19 (ref. 1), was inserted between the V and DJ segments of an antibody. This insertion generated, through somatic mutations, broadly reactive antibodies against RIFINs, a type of variant antigen expressed on the surface of Plasmodium falciparum-infected erythrocytes. To investigate how frequently such antibodies are produced in response to malaria infection, we screened plasma from two large cohorts of individuals living in malaria-endemic regions. Here we report that 5-10% of malaria-exposed individuals, but none of the European blood donors tested, have high levels of LAIR1-containing antibodies that dominate the response to infected erythrocytes without conferring enhanced protection against febrile malaria. By analysing the antibody-producing B cell clones at the protein, cDNA and gDNA levels, we characterized additional LAIR1 insertions between the V and DJ segments and discovered a second insertion modality whereby the LAIR1 exon encoding the extracellular domain and flanking intronic sequences are inserted into the switch region. By exon shuffling, this mechanism leads to the production of bispecific antibodies in which the LAIR1 domain is precisely positioned at the elbow between the VH and CH1 domains. Additionally, in one donor the genomic DNA encoding the VH and CH1 domains was deleted, leading to the production of a camel-like LAIR1-containing antibody. Sequencing of the switch regions of memory B cells from European blood donors revealed frequent templated inserts originating from transcribed genes that, in rare cases, comprised exons with orientations and frames compatible with expression. These results reveal different modalities of LAIR1 insertion that lead to public and dominant antibodies against infected erythrocytes and suggest that insertion of templated DNA represents an additional mechanism of antibody diversification that can be selected in the immune response against pathogens and exploited for B cell engineering.

Major international projects are underway that are aimed at creating a comprehensive catalogue of all the genes responsible for the initiation and progression of cancer. These studies involve the sequencing of matched tumour-normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false-positive findings that overshadow true driver events. We show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumour-normal pairs and discover extraordinary variation in mutation frequency and spectrum within cancer types, which sheds light on mutational processes and disease aetiology, and in mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and enable the identification of genes truly associated with cancer.

Diverse autoimmune and allergic diseases are associated with polymorphisms in a locus encoding the transcription factor BACH2; here, BACH2 is shown to be a broad regulator of immune activation that stabilizes the differentiation of Treg cells by repressing commitment of CD4+ T cells to alternate cell fates. Polymorphisms within a locus encoding the transcription factor BACH2 are associated with a number of allergic and autoimmune diseases including asthma, multiple sclerosis, Crohn's disease, coeliac disease and type 1 diabetes. This paper identifies a mechanism by which BACH2 might contribute to autoimmunity. Roychoudhuri et al. show how BACH2 limits autoimmunity by repressing alternative cell fates through the stabilization of the differentiation of regulatory T cells. These findings suggest a role for BACH2 as a regulator of CD4+ T-cell differentiation, preventing inflammatory disease by controlling the balance between tolerance and immunity. Through their functional diversification, distinct lineages of CD4+ T cells can act to either drive or constrain immune-mediated pathology. Transcription factors are critical in the generation of cellular diversity, and negative regulators antagonistic to alternate fates often act in conjunction with positive regulators to stabilize lineage commitment1. Genetic polymorphisms within a single locus encoding the transcription factor BACH2 are associated with numerous autoimmune and allergic diseases including asthma2, Crohn’s disease3,4, coeliac disease5, vitiligo6, multiple sclerosis7 and type 1 diabetes8. Although these associations point to a shared mechanism underlying susceptibility to diverse immune-mediated diseases, a function for BACH2 in the maintenance of immune homeostasis has not been established. Here, by studying mice in which the Bach2 gene is disrupted, we define BACH2 as a broad regulator of immune activation that stabilizes immunoregulatory capacity while repressing the differentiation programs of multiple effector lineages in CD4+ T cells. BACH2 was required for efficient formation of regulatory (Treg) cells and consequently for suppression of lethal inflammation in a manner that was Treg-cell-dependent. Assessment of the genome-wide function of BACH2, however, revealed that it represses genes associated with effector cell differentiation. Consequently, its absence during Treg polarization resulted in inappropriate diversion to effector lineages. In addition, BACH2 constrained full effector differentiation within TH1, TH2 and TH17 cell lineages. These findings identify BACH2 as a key regulator of CD4+ T-cell differentiation that prevents inflammatory disease by controlling the balance between tolerance and immunity.

The first ornithischian dinosaur to be found in the Triassic (other than very fragmentary material) was Heterodontosaurus tucki from South Africa, described1 on its skull. The postcranial skeleton of another H. Tucki is described here. Heterodontosaurus is compared with its sympatric contemporary Fabrosaurus, the only other well known Triassic ornithischian, and the interrelationships of early dinosaurs are discussed briefly.

We propose that mammalian homeothermy was was acquired in two steps. The first step enabled mammals to invade a nocturnal niche without an increase in resting metabolic rate. The second step enabled them to invade a diurnal niche and involved the acquisition of higher body temperatures and metabolic rates.

The origin of monotremes—egg-laying mammals from the Australian region—and their relationship to therians (marsupials and placentals) have been intriguing zoological problems. Recently Archer et al.1 described a fragment of a lower jaw of an early Cretaceous monotreme from Australia (Steropodon galmani) and interpreted its teeth as tribosphenic and thus supposedly derived from a relatively advanced stage in therian evolution. This discovery is of major importance, and radically alters currently held opinion that monotremes and therians diverged at the earliest stage of mammalian evolution. We agree that Steropodon is a therian but would argue thai its teeth are not tribosphenic. Steropodon appears to have been derived from therians before the development of tribosphenic teeth, possibly during the Jurassic period.

AS stated in the obituary notice that appeared NATURE (vol. xxxviii. p. 598) at the time of the melancholy accident which caused his death, Wroblewski was engaged in an investigation of the behaviour of hydrogen on compression. The results of this investi gation, as far as it had then advanced, have now been made public (Monatsh. fur Chem., 1888, p. 1067 et seq.). They are of a most important and interesting nature, and form a fitting memorial of the patience and skill of the observer, who most unhappily was not spared to bring this, the last and most complete of a long series of similar investigations, to a close.

THE molar morphology of therian mammals has interested zoologists for nearly a century. Its basic functional significance has been demonstrated by cinefluorographic studies of molar occlusion and jaw movements during mastication in the American opossum (Didelphis marsupialis)1,2, together with a comprehensive study of the molar teeth of Mesozoic mammals.

ATTEMPTS have been made to deduce mandibular movements in primitive mammals from dried skulls and particularly the morphology and wear on the teeth1,2. The work reported here shows that this is not possible. Until mandibular movements are precisely determined for appropriate living mammals, the interpretation of the structure and evaluation of the function of mammalian teeth is extremely difficult. Studies of living mammals are particularly relevant at present because the evolution of pre-Tertiary mammals can now be explained with greater confidence using the recently discovered early mammalian material from the Triassic, Jurassic and Cretaceous.

ALTHOUGH the presence of haemoglobin in free-living flatworms (Turbellaria) has been recorded by several authors1–4, the pigment has not yet been investigated in detail. A large sample of the rhabdoccel. Phaenocora unipunctata (Orsted 1843), was obtained from mud from Coe Fen, Cambridge. These worms were found to contain haemoglobin, and a preliminary examination was made of the properties of this pigment and its distribution within the tissues of the animal.

THE movements of the hyoid bone and the larynx during swallowing are only well established for man1–3. Their movements, if any, during mastication in man and in other mammals have been neglected. The hyoid is suspended from the cranium, above and behind, by the posterior suprahyoid muscles (stylohyoid and the posterior belly of digastric) and from the symphyseal region of the jaw in front by the anterior suprahyoid muscles (anterior belly of digastric, mylohyoid, geniohyoid and the more inferior fibres of genioglossus). The infrahyoid, or ‘strap’ muscles of the neck connect the hyoid with the sternum directly by the sternohyoid and indirectly through the thyroid cartilage of the larynx (thyrohyoid and sternothyroid) as well as with the scapula (omohyoid). This arrangement of the hyoid apparatus is found in all mammals, except that the digastric may not have a direct hyoid connection4: a situation occasionally found in man2. These three groups of muscles (anterior and posterior suprahyoids and infrahyoids) are recognised, on the basis of anatomical, cinematographic5 and electromyographic6 studies of human deglutition, as acting in combination first to elevate and then to depress the hyoid and larynx in swallowing. The posterior suprahyoids and the infrahyoids are also classically regarded1,2 as acting to “stabilise”1 or “fix”2 the hyoid so that the anterior suprahyoids, and particularly the anterior belly of digastric6,7, can pull the symphyseal region of the jaw towards the hyoid and open the mouth. Mandibular depression follows the power stroke8 of every chewing cycle. The classical view of the hyoid apparatus is of a somewhat immobile bone and a group of muscles whose only active role is in swallowing. This concept may have led to the view that, since the omohyoid in man made such an uncertain contribution to hyoid movement or control of hyoid position, a “specific”1and “speculative”2 function should be attributed to this muscle; namely the tensing of the cervical fascia to assist prolonged inspiration during forced respiration. The latest edition of Gray's Anatomy2 comments, “so far no useful data in regard to the hyoid musculature as a whole have been contributed by electromyographers” (page 508).

IN reference to the portrait of Brahe engraved in NATURE (vol. xv. p. 406), and to Mr. Dreyer's remarks on it (vol. xv. p. 530), I have the pleasure of sending you the following particulars. In the first place I have permission from Herr Friis, of Copenhagen, the learned editor of Tichonis Brahei et ad eum doctorum virorum Epistolae. Havniae, 1876, &c., to publish an important letter from himself:—

LAURIE1,2 found that formate, acetate and lactate were the chief excretory products from the carbohydrate metabolism of Moniliformis dubius, and we have found lactate and succinate to be the most important excretory products of Polymorphous minutus, an acanthocephalan parasite of domestic ducks3. Succinate has been reported as an intermediary metabolite of the carbohydrate metabolism of M. dubius4,5, and so we decided to analyse for excretory products, in particular succinate, the medium in which specimens of M. dubius had been incubated.

The Soils of Europe Illustrated Diagnosis and Systematics. By Prof. Dr. Walter L. Kubiena. Pp. 318 + 26 plates. (Madrid: Consejo Superior de Investigaciones Cientificas; London: Thomas Murby and Co., 1953.) n.p.

I HAVE read Mr. Hutchins's communication (p. 368) with considerable interest. Mr. Hutchins is at the head of the Forest Department which has been recently established by the Cape Government, and the improved method of riding that he has adopted, in accordance with the views expressed in my recent paper, have evidently been of service to him in traversing the very rough country to enable him to carry out his duties. Mr. Hutchins's experiences so closely agree with my own that I can-say little in criticism of his letter. I think, however, that he will find that the gain from the lengthened crank advocated by me cannot be explained by the very simple formula that he gives. My son and I went very carefully into this matter at the time I prepared my paper, and I think if Mr. Hutchins refers to it he will find, if we consider the mechanical advantage apart from the gain in nerve waste, the mathematical analysis of ankling given by lengthened crank both give the only explanation which would be satisfactory to a mathematician. In our explanation the weight of the leg plays a very important part, and it follows therefore that a heavy legged man gets most from our system of riding.

THE growth of ionization currents with distance at constant low values of E/p (E is the field, p the gas pressure) at high values of p has been investigated in this laboratory primarily to obtain precise determinations of the ionization coefficients α and ω/α in conditions when special attention was paid to the state of the gas and cathode surface. Some of the results obtained preliminary to the main part of this investigation are, however, of general interest.