Cell Signalling

he fossils described elsewhere in this issue probably left no descendants, are not very old, and were found on a remote island. Despite this, they are among the most outstanding discoveries in palaeoanthropology for half a century. The two papers concerned-by Brown et al. 1 and Morwood et al. 2-appear on pages 1055 and 1087 of this issue, and respectively describe the fossils and their archaeological context. The find is startling.It is of a pygmysized, small-brained hominin, which lived as recently as 18,000 years ago, and which was found on the island of Flores together with stone tools, dwarf elephants and Komodo dragons. Discoveries don't get better than that. The Flores fossils add a new and surprising twig to the hominin family tree, which diverged from the chimpanzee lineage about 7 million years ago. The first African hominins existed 7-1.2 million years ago, were 1-1.5 metres tall, walked upright on two legs (that is, were bipedal), and had chimpanzee-size brains. These early forms comprised as many as six genera and fourteen species, of which the australopithecines are the best known. By 2.5 million years ago, our own genus, Homo, had emerged, with its different body shape, slower growth, greater reliance on meat in the diet, and 'encephalization'-larger brains than expected for body size. These were the first hominins to make stone tools systematically and to colonize Eurasia. They include the familiar names of H. habilis, H. erectus, H. neanderthalensis and, finally, H. sapiens, which put in an appearance about 160,000 years ago. The new fossil is part of this Homo group (Fig. 1). Flores lies to the east of Java, and was probably never connected to the mainland. The presence of 800,000-year-old simple stone tools first attracted attention in 1998 (ref. 3), raising the controversial possibility that H. erectus had produced them and had crossed major sea barriers to reach Flores. Now we have the announcement of the discovery of an 18,000-year-old hominin skeleton from a cave, Liang Bua, on Flores. Although this date is more than 140,000 years after modern humans evolved in Africa, more than 25,000 years after H. sapiens reached Australia, and about 10,000 years after the last known Neanderthal, the

The molecular pathogenesis of follicular lymphoma (FL) was partially revealed 3 decades ago, with the discovery of the translocation that brings BCL2 under the influence of immunoglobulin heavy chain en-hancers in a vast majority of cases. Despite the importance of this seminal observation, it has become increasingly clear that additional genetic alterations need to occur to trigger neoplastic transformation and disease progression. The evolution of FL involves developmental arrest and disruption of the normal function of one or more of epigenetic regulators including KMT2D/MLL2, EZH2 , CBP/ CREBBP , p300/ EP300 , and HIST1H1 in > 95% of cases. B-cells "arrested" in germinal centers acquire dozens of additional genetic aberrations that influence key pathways controlling their physiological development including B Cell Receptor (BCR) signaling, PI3K/AKT, TLR, mTOR, NF-κB, JAK/STAT, MAPK, CD40/CD40L, chemokine, and interleukin signaling. Additionally, most cases of FL do not result from linear accumulation of ge-nomic aberrations, but rather evolve from a common progenitor cell population by diverse evolution, creating multiple FL subclones in one patient. Moreover, one of the subclones might acquire a combination of aberrations involving genes controlling cell survival and proliferation including MDM2, CDKN2A/B, BCL6, MYC, TP53, β2M, FOXO1, MYD88, STAT3, or miR-17-92 , and this can lead to the transformation of an initially indolent FL to an aggressive lymphoma (2%-3% risk per year). The complexity of the disease is also underscored by the importance of its interactions with the microenvironment that can substantially influence disease development and prognosis. Interpreting individual aberrations in relation to their impact on normal processes, their frequency, position in the disease evolution, and the consequences of their (co)occurrence, are the basis for understanding FL pathogenesis. This is necessary for the identification of patients with risk of early progression or transformation, for the development of novel targeted therapies, and for personalized treatment approaches. In this review, we summarize recent knowledge of molecular pathways and microenvironmental components involved in FL biology, and discuss them in the context of physiological B-cell development, FL evolution, and targeted therapies.

The antimicrobial peptide human α-defensin 5 (HD5) is expressed in Paneth cells, secretory epithelial cells in the small intestine. Unlike other characterized defensins, HD5 is stored in secretory vesicles as a propeptide. The storage quantities of HD5 are ∼90-450 µg per cm 2 of mucosal surface area, which is sufficient to generate microbicidal concentrations in the intestinal lumen. HD5 peptides isolated from the intestinal lumen are proteolytically processed forms-HD5(56-94) and HD5(63-94)-that are cleaved at the Arg 55 -Ala 56 and Arg 62 -Thr 63 sites, respectively.We show here that a specific pattern of trypsin isozymes is expressed in Paneth cells, that trypsin colocalizes with HD5 and that this protease can efficiently cleave HD5 propeptide to forms identical to those isolated in vivo. By acting as a prodefensin convertase in human Paneth cells, trypsin is involved in the regulation of innate immunity in the small intestine.

Detrital zircons more than 4 billion years old from the Jack Hills metasedimentary belt, Yilgarn craton, Western Australia, are the oldest identified fragments of the Earth's crust 1,2 and are unique in preserving information on the earliest evolution of the Earth. Inclusions of quartz, K-feldspar and monazite in the zircons 3 , in combination with an enrichment of light rare-earth elements 4,5 and an estimated low zircon crystallization temperature 6 , have previously been used as evidence for early recycling of continental crust, leading to the production of granitic melts in the Hadean era. Here we present the discovery of microdiamond inclusions in Jack Hills zircons with an age range from 3,058 6 7 to 4,252 6 7 million years. These include the oldest known diamonds found in terrestrial rocks, and introduce a new dimension to the debate on the origin of these zircons and the evolution of the early Earth 6-10. The spread of ages indicates that either conditions required for diamond formation were repeated several times during early Earth history or that there was significant recycling of ancient diamond. Mineralogical features of the Jack Hills diamonds-such as their occurrence in zircon, their association with graphite and their Raman spectroscopic characteristics-resemble those of diamonds formed during ultrahigh-pressure metamorphism and, unless conditions on the early Earth were unique, imply a relatively thick continental lithosphere and crust-mantle interaction at least 4,250 million years ago. Research on .3,900-Myr-old zircon grains from the Jack Hills has mainly focused on their chemical and isotopic compositions. In this study, we have investigated the mineral inclusions in 1,000 randomly chosen zircon grains, collected from a sample of the Jack Hills conglomerate from the initial 'discovery' site 1. U-Pb ages of the zircon grains were determined using a sensitive high-resolution ion microprobe (SHRIMP II), following the analytical procedure described in detail elsewhere 11,12. Optical examination revealed that about half of the zircon population contains inclusions larger than ,1 mm. These inclusions were further investigated by confocal micro-Raman spectroscopy. A Raman spectrum of a mineral reflects both its structural and chemical properties and can thus be used as a fingerprint for its identification. We have identified apatite, quartz, xenotime, monazite, rutile, biotite, amphibole, K-feldspar and plagioclase inclusions in the Jack Hills zircon, some of which have also been recognized in previous studies 3,4. In addition, we unambiguously identified diamond inclusions in 45 zircon grains, mostly associated with graphite, but in some cases with apatite and quartz. The Raman spectrum of diamond is characterized by a single firstorder band near 1,332 cm 21 with a typical width (full-width at halfmaximum, FWHM) of ,1.7 cm 21 , reflecting a triply degenerate CC stretching vibration with F 2g symmetry, and sometimes by a secondorder feature near 2,600 cm 21 (ref. 13). The Raman spectra of most of the diamond inclusions ('diamond 1') in the Jack Hills zircons Nature

insight review articles "For it is simply a fact of observation that the guiding principle in every cell is embodied in a single atomic association existing only in one copy (or sometimes two)-and a fact of observation that it results in producing events which are paragons of orderliness […] the situation is unprecedented, it is unknown anywhere else except in living matter.

Despite their importance for urban planning [1], traffic forecasting [2], and the spread of biological [3, 4, 5] and mobile viruses [6], our understanding of the basic laws governing human motion remains limited thanks to the lack of tools to monitor the time resolved location of individuals. Here we study the trajectory of 100, 000 anonymized mobile phone users whose position is tracked for a six month period. We find that in contrast with the random trajectories predicted by the prevailing Lévy flight and random walk models [7], human trajectories show a high degree of temporal and spatial regularity, each individual being characterized by a time independent characteristic length scale and a significant probability to return to a few highly frequented locations. After correcting for differences in travel distances and the inherent anisotropy of each trajectory, the individual travel patterns collapse into a single spatial probability distribution, indicating that despite the diversity of their travel history, humans follow simple reproducible patterns. This inherent similarity in travel patterns could impact all phenomena driven by human mobility, from epidemic prevention to emergency response, urban planning and agent based modeling. Given the many unknown factors that influence a population's mobility patterns, ranging from means of transportation to job and family imposed restrictions and priorities, human trajectories are often approximated with various random walk or diffusion models [7, 8]. Indeed, early measurements on albatrosses, bumblebees, deer and monkeys [9, 10] and more recent ones on marine predators [11] suggested that animal trajectory is approximated by a Lévy flight [12, 13], a random walk whose step size ∆r follows a power-law distribution P (∆r) ∼ ∆r −(1+β) with β < 2. While the Lévy statistics for some animals require further study [14], Brockmann et al. [7] generalized this finding to humans, documenting that the distribution of distances between consecutive sight

Could it be that fetal liver cells and adult bone-marrow cells originate from a subset of endothelial cells that line blood vessels in the mouse embryo? Several lines of evidence suggest that this might be the case. During development, haematopoietic stem cells, which give rise to blood cells, and endothelial cells, which line blood vessels, both form from the mesodermal germ-cell layer; exactly how though is debatable. On one hand, a controversial, century-old theory proposes that both haematopoietic and endothelial cells arise from a mesoderm-derived common precursor called haemangioblast. On the other hand, a competing, relatively younger theory proposes that haematopoietic stem cells form from a subset of early endothelial cells known as haemogenic endothelium. The relationship between the haemangioblasts and haemogenic endothelium has never been resolved. In this issue, however, three papers 1-3 clarify the potential relatedness and significance of these cell types.

Elucidating the signalling mechanisms by which obesity leads to impaired insulin action is critical in the development of therapeutic strategies for the treatment of diabetes 1 . Recently, mice deficient for S6 Kinase 1 (S6K1), an effector of the mammalian target of rapamycin (mTOR) that acts to integrate nutrient and insulin signals 2 , were shown to be hypoinsulinaemic, glucose intolerant and have reduced b-cell mass 3 . However, S6K1deficient mice maintain normal glucose levels during fasting, suggesting hypersensitivity to insulin 3 , raising the question of their metabolic fate as a function of age and diet. Here, we report that S6K1-deficient mice are protected against obesity owing to enhanced b-oxidation. However on a high fat diet, levels of glucose and free fatty acids still rise in S6K1-deficient mice, resulting in insulin receptor desensitization. Nevertheless, S6K1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from S6K1 to insulin receptor substrate 1 (IRS1), which blunts S307 and S636/S639 phosphorylation; sites involved in insulin resistance 4,5 . Moreover, wild-type mice on a high fat diet as well as K/K A y and ob/ob (also known as Lep/Lep) mice-two genetic models of obesity-have markedly elevated S6K1 activity and, unlike S6K1-deficient mice, increased phosphorylation of IRS1 S307 and S636/S639. Thus under conditions of nutrient satiation S6K1 negatively regulates insulin signalling.

Reward is important for shaping goal-directed behaviour 1±4. After stimulus±reward associative learning, an organism can assess the motivational value of the incoming stimuli on the basis of past experience (retrospective processing), and predict forthcoming rewarding events (prospective processing) 1±5. The traditional role of the sensory thalamus is to relay current sensory information to cortex. Here we ®nd that non-primary thalamic neurons respond to reward-related events in two ways. The early, phasic responses occurred shortly after the onset of the stimuli and depended on the sensory modality. Their magnitudes resisted extinction and correlated with the learning experience. The late responses

Engulfment and subsequent degradation of apoptotic cells is an essential step that occurs throughout life in all multicellular organisms 1-3 . ELMO/Dock180/Rac proteins are a conserved signalling module for promoting the internalization of apoptotic cell corpses 4,5 ; ELMO and Dock180 function together as a guanine nucleotide exchange factor (GEF) for the small GTPase Rac, and thereby regulate the phagocyte actin cytoskeleton during engulfment 4-6 . However, the receptor(s) upstream of the ELMO/ Dock180/Rac module are still unknown. Here we identify brainspecific angiogenesis inhibitor 1 (BAI1) as a receptor upstream of ELMO and as a receptor that can bind phosphatidylserine on apoptotic cells. BAI1 is a seven-transmembrane protein belonging to the adhesion-type G-protein-coupled receptor family, with an extended extracellular region 7-9 and no known ligands. We show that BAI1 functions as an engulfment receptor in both the recognition and subsequent internalization of apoptotic cells. Through multiple lines of investigation, we identify phosphatidylserine, a key 'eat-me' signal exposed on apoptotic cells 10-13 , as a ligand for BAI1. The thrombospondin type 1 repeats within the extracellular region of BAI1 mediate direct binding to phosphatidylserine. As with intracellular signalling, BAI1 forms a trimeric complex with ELMO and Dock180, and functional studies suggest that BAI1 cooperates with ELMO/Dock180/Rac to promote maximal engulfment of apoptotic cells. Last, decreased BAI1 expression or interference with BAI1 function inhibits the engulfment of apoptotic targets ex vivo and in vivo. Thus, BAI1 is a phosphatidylserine recognition receptor that can directly recruit a Rac-GEF complex to mediate the uptake of apoptotic cells.

8 typically slower than ϳ1 km s −1 ) might differ significantly from what is assumed by current modelling efforts 27 . The expected equation-of-state differences among small bodies (ice versus rock, for instance) presents another dimension of study; having recently adapted our code for massively parallel architectures (K. M. Olson and E.A, manuscript in preparation), we are now ready to perform a more comprehensive analysis.

by in situ X-ray observations based on the same pressure scale in the previous study . The overpressure was calculated using these boundaries. We observed the pressure to drop during the transformation by 1-2 GPa, but this would not affect the transformation rate significantly because the overpressure is very large in the present study. This has been confirmed in the post-spinel transformation 7 .

Sir-Gottfried and Wilson 1 remark critically that "SSK [sociology of scientific knowledge] accounts often treat only the earliest phases of a scientific development, when the evidence is uncertain, and largely ignore subsequent convincing confirmations". This is true of controversy studies in SSK, but not of one of the books at issue, my own Constructing Quarks 2. There I documented and analysed the history of the establishment of the standard model as the 'new orthodoxy' in elementary particle physics. Ellis 3 makes a similar mistake, and adds that he would "also like [me] to document and compare more thoroughly the rejection by the scientific community of false 'discoveries'". I have published essays on discredited 'discoveries' of magnetic monopoles and isolated quarks, and on the ultimately unsuccessful theoretical arguments that the new particles (the J/psi and so on) were manifestations of quark colour rather than charm (see, for example, ref. 4). The analysis in those essays goes along the same lines as that of Constructing Quarks, and if Ellis wants to dispute it, I will be happy to respond. Capasso 5 is mistaken in asserting that successful technology "validates the specific theories on which it is founded". A machine works because it works, not because of what anybody thinks about it 6. And, as I believe Gottfried and Wilson recognize, Capasso's idea that technology owes everything to prior science is as historically misleading as its inverse. In short, the continuing criticism of science studies in your pages remains wide of its mark.

One of the important morphometric variables assessed in the comparisons between the bony labyrinths of Neanderthals and modern humans is the sagittal labyrinthine index. This index expresses what percentage of the posterior semicircular canal is situated inferiorly to the plane of the lateral semicircular canal. Its formula, as given in the legend to Fig. 2 of the above Letter, is incorrect and should be i=ðs þ i Þ 3 100. M View publication stats View publication stats

After insertion into the endoplasmic reticulum (ER), proteins that fail to fold there are destroyed. Through a process termed dislocation such misfolded proteins arrive in the cytosol, where ubiquitination, deglycosylation and finally proteasomal proteolysis dispense with the unwanted polypeptides. The machinery involved in the extraction of misfolded proteins from the ER is poorly defined. The human cytomegalovirus-encoded glycoproteins US2 and US11 catalyse the dislocation of class I major histocompatibility complex (MHC) products, resulting in their rapid degradation. Here we show that US11 uses its transmembrane domain to recruit class I MHC products to a human homologue of yeast Der1p, a protein essential for the degradation of a subset of misfolded ER proteins. We show that this protein, Derlin-1, is essential for the degradation of class I MHC molecules catalysed by US11, but not by US2. We conclude that Derlin-1 is an important factor for the extraction of certain aberrantly folded proteins from the mammalian ER.

I was appalled when I read a report in Nature last year about proposals by the Indian government to encourage universities to teach astrology (Nature 411, 227; 200110.1038/35077282), but never thought that anything similar might occur in the West. ... To read this story in full you ...

We describe a protocol to rapidly and reliably visualize blood vessels in experimental animals. Blood vessels are directly labeled by cardiac perfusion using a specially formulated aqueous solution containing 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI), a lipophilic carbocyanine dye, which incorporates into endothelial cell membranes upon contact. By lateral diffusion, DiI also stains membrane structures, including angiogenic sprouts and pseudopodial processes that are not in direct contact. Tissues can be immediately examined by conventional and confocal fluorescence microscopy. High-quality serial optical sections using confocal microscopy are obtainable from thick tissue sections, especially at low magnification, for three-dimensional reconstruction. It takes less than 1 h to stain the vasculature in a whole animal. Compared with alternative techniques to visualize blood vessels, including space-occupying materials such as India ink or fluorescent dye-conjugated dextran, the corrosion casting technique, endothelial cell-specific markers and lectins, the present method simplifies the visualization of blood vessels and data analysis.