CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes

A long-standing paradox in cellular immunology concerns the conditional requirement for CD4+ T-helper (T(H)) cells in the priming of cytotoxic CD8+ T lymphocyte (CTL) responses in vivo. Whereas CTL responses against certain viruses can be primed in the absence of CD4+ T cells, others, such as those mediated through 'cross-priming' by host antigen-presenting cells, are dependent on T(H) cells. A clearer understanding of the contribution of T(H) cells to CTL development has been hampered by the fact that most T(H)-independent responses have been demonstrated ex vivo as primary cytotoxic effectors, whereas T(H)-dependent responses generally require secondary in vitro re-stimulation for their detection. Here, we have monitored the primary and secondary responses of T(H)-dependent and T(H)-independent CTLs and find in both cases that CD4+ T cells are dispensable for primary expansion of CD8+ T cells and their differentiation into cytotoxic effectors. However, secondary CTL expansion (that is, a secondary response upon re-encounter with antigen) is wholly dependent on the presence of T(H) cells during, but not after, priming. Our results demonstrate that T-cell help is 'programmed' into CD8+ T cells during priming, conferring on these cells a hallmark of immune response memory: the capacity for functional expansion on re-encounter with antigen.     

Nanotechnology: high-speed integrated nanowire circuits

Macroelectronic circuits made on substrates of glass or plastic could one day make computing devices ubiquitous owing to their light weight, flexibility and low cost. But these substrates deform at high temperatures so, until now, only semiconductors such as organics and amorphous silicon could be used, leading to poor performance. Here we present the use of low-temperature processes to integrate high-performance multi-nanowire transistors into logical inverters and fast ring oscillators on glass substrates. As well as potentially enabling powerful electronics to permeate all aspects of modern life, this advance could find application in devices such as low-cost radio-frequency tags and fully integrated high-refresh-rate displays.     

A faux 3'-UTR promotes aberrant termination and triggers nonsense-mediated mRNA decay

Nonsense-mediated messenger RNA decay (NMD) is triggered by premature translation termination, but the features distinguishing premature from normal termination are unknown. One model for NMD suggests that decay-inducing factors bound to mRNAs during early processing events are routinely removed by elongating ribosomes but remain associated with mRNAs when termination is premature, triggering rapid turnover. Recent experiments challenge this notion and suggest a model that posits that mRNA decay is activated by the intrinsically aberrant nature of premature termination. Here we use a primer extension inhibition (toeprinting) assay to delineate ribosome positioning and find that premature translation termination in yeast extracts is indeed aberrant. Ribosomes encountering premature UAA or UGA codons in the CAN1 mRNA fail to release and, instead, migrate to upstream AUGs. This anomaly depends on prior nonsense codon recognition and is eliminated in extracts derived from cells lacking the principal NMD factor, Upf1p, or by flanking the nonsense codon with a normal 3'-untranslated region (UTR). Tethered poly(A)-binding protein (Pab1p), used as a mimic of a normal 3'-UTR, recruits the termination factor Sup35p (eRF3) and stabilizes nonsense-containing mRNAs. These findings indicate that efficient termination and mRNA stability are dependent on a properly configured 3'-UTR.     

Earliest evidence of mammalian social behaviour in the basal Tertiary of Bolivia

The vast majority of Mesozoic and early Cenozoic metatherian mammals (extinct relatives of modern marsupials) are known only from partial jaws or isolated teeth, which give insight into their probable diets and phylogenetic relationships but little else. The few skulls known are generally crushed, incomplete or both, and associated postcranial material is extremely rare. Here we report the discovery of an exceptionally large number of almost undistorted, nearly complete skulls and skeletons of a stem-metatherian, Pucadelphys andinus, in the early Palaeocene epoch of Tiupampa in Bolivia. These give an unprecedented glimpse into early metatherian morphology, evolutionary relationships and, especially, ecology. The remains of 35 individuals have been collected, with 22 of these represented by nearly complete skulls and associated postcrania. These individuals were probably buried in a single catastrophic event, and so almost certainly belong to the same population. The preservation of multiple adult, sub-adult and juvenile individuals in close proximity (<1?m(2)) is indicative of gregarious social behaviour or at least a high degree of social tolerance and frequent interaction. Such behaviour is unknown in living didelphids, which are highly solitary and have been regarded, perhaps wrongly, as the most generalized living marsupials. The Tiupampan P.?andinus population also exhibits strong sexual dimorphism, which, in combination with gregariousness, suggests strong male-male competition and polygyny. Our study shows that social interactions occurred in metatherians as early as the basal Palaeocene and that solitary behaviour may not be plesiomorphic for Metatheria as a whole.     

Substantial confusion

In this paper I defend, against Eric Scerri’s objections, the following theses: (i) that Lavoisier and Mendeleev shared a ‘core conception’ of chemical element, and (ii) that this core conception underwrites referential continuity in the names of particular elements.     

T-type calcium channel regulation by specific G-protein betagamma subunits

Low-voltage-activated (LVA) T-type calcium channels have a wide tissue distribution and have well-documented roles in the control of action potential burst generation and hormone secretion. In neurons of the central nervous system and secretory cells of the adrenal and pituitary, LVA channels are inhibited by activation of G-protein-coupled receptors that generate membrane-delimited signals, yet these signals have not been identified. Here we show that the inhibition of alpha1H (Ca(v)3.2), but not alpha(1G) (Ca(v)3.1) LVA Ca2+ channels is mediated selectively by beta2gamma2 subunits that bind to the intracellular loop connecting channel transmembrane domains II and III. This region of the alpha1H channel is crucial for inhibition, because its replacement abrogates inhibition and its transfer to non-modulated alpha1G channels confers beta2gamma2-dependent inhibition. betagamma reduces channel activity independent of voltage, a mechanism distinct from the established betagamma-dependent inhibition of non-L-type high-voltage-activated channels of the Ca(v)2 family. These studies identify the alpha1H channel as a new effector for G-protein betagamma subunits, and highlight the selective signalling roles available for particular betagamma combinations.     

Origin of Saturn's rings and inner moons by mass removal from a lost Titan-sized satellite

The origin of Saturn's rings has not been adequately explained. The current rings are more than 90 to 95 per cent water ice, which implies that initially they were almost pure ice because they are continually polluted by rocky meteoroids. In contrast, a half-rock, half-ice mixture (similar to the composition of many of the satellites in the outer Solar System) would generally be expected. Previous ring origin theories invoke the collisional disruption of a small moon, or the tidal disruption of a comet during a close passage by Saturn. These models are improbable and/or struggle to account for basic properties of the rings, including their icy composition. Saturn has only one large satellite, Titan, whereas Jupiter has four large satellites; additional large satellites probably existed originally but were lost as they spiralled into Saturn. Here I report numerical simulations of the tidal removal of mass from a differentiated, Titan-sized satellite as it migrates inward towards Saturn. Planetary tidal forces preferentially strip material from the satellite's outer icy layers, while its rocky core remains intact and is lost to collision with the planet. The result is a pure ice ring much more massive than Saturn's current rings. As the ring evolves, its mass decreases and icy moons are spawned from its outer edge with estimated masses consistent with Saturn's ice-rich moons interior to and including Tethys.     

A redox switch in angiotensinogen modulates angiotensin release

Blood pressure is critically controlled by angiotensins, which are vasopressor peptides specifically released by the enzyme renin from the tail of angiotensinogen-a non-inhibitory member of the serpin family of protease inhibitors. Although angiotensinogen has long been regarded as a passive substrate, the crystal structures solved here to 2.1?? resolution show that the angiotensin cleavage site is inaccessibly buried in its amino-terminal tail. The conformational rearrangement that makes this site accessible for proteolysis is revealed in our 4.4?? structure of the complex of human angiotensinogen with renin. The co-ordinated changes involved are seen to be critically linked by a conserved but labile disulphide bridge. Here we show that the reduced unbridged form of angiotensinogen is present in the circulation in a near 40:60 ratio with the oxidized sulphydryl-bridged form, which preferentially interacts with receptor-bound renin. We propose that this redox-responsive transition of angiotensinogen to a form that will more effectively release angiotensin at a cellular level contributes to the modulation of blood pressure. Specifically, we demonstrate the oxidative switch of angiotensinogen to its more active sulphydryl-bridged form in the maternal circulation in pre-eclampsia-the hypertensive crisis of pregnancy that threatens the health and survival of both mother and child.