Nesprin interchain associations control nuclear size

Nesprins-1/-2/-3/-4 are nuclear envelope proteins, which connect nuclei to the cytoskeleton. The largest nesprin-1/-2 isoforms (termed giant) tether F-actin through their N-terminal actin binding domain (ABD). Nesprin-3, however, lacks an ABD and associates instead to plectin, which binds intermediate filaments. Nesprins are integrated into the outer nuclear membrane via their C-terminal KASH-domain. Here, we show that nesprin-1/-2 ABDs physically and functionally interact with nesprin-3. Thus, both ends of nesprin-1/-2 giant are integrated at the nuclear surface: via the C-terminal KASH-domain and the N-terminal ABD-nesprin-3 association. Interestingly, nesprin-2 ABD or KASH-domain overexpression leads to increased nuclear areas. Conversely, nesprin-2 mini (contains the ABD and KASH-domain but lacks the massive nesprin-2 giant rod segment) expression yields smaller nuclei. Nuclear shrinkage is further enhanced upon nesprin-3 co-expression or microfilament depolymerization. Our findings suggest that multivariate intermolecular nesprin interactions with the cytoskeleton form a lattice-like filamentous network covering the outer nuclear membrane, which determines nuclear size.     

A Middle Miocene hominoid from Thailand and orangutan origins

The origin of orangutans has long been debated. Sivapithecus is considered to be the closest ancestor of orangutans because of its facial-palatal similarities, but its dental characteristics and postcranial skeleton do not confirm this phylogenetic position. Here we report a new Middle Miocene hominoid, cf. Lufengpithecus chiangmuanensis n. sp. from northern Thailand. Its dental morphology relates it to the Pongo clade, which includes Lufengpithecus, Sivapithecus, Gigantopithecus, Ankarapithecus and possibly Griphopithecus. Our new species displays striking dental resemblances with living orangutans and appears as a more likely candidate to represent an ancestor of this ape. In addition, it originates from the geographic area of Pleistocene orangutans. But surprisingly, the associated flora shows strong African affinities, demonstrating the existence of a temporary floral and faunal dispersal corridor between southeast Asia and Africa during the Middle Miocene, which may have played a critical role in hominoid dispersion.     

The Ehrenfest Classification of Phase Transitions: Introduction and Evolution

The first classification of general types of transition between phases of matter, introduced by Paul Ehrenfest in 1933, lies at a crossroads in the thermodynamical study of critical phenomena. It arose following the discovery in 1932 of a suprising new phase transition in liquid helium, the “lambda transition,” when W. H. Keesom and coworkers in Leiden, Holland observed a λhaped “jump” discontinuity in the curve giving the temperature dependence of the specific heat of helium at a critical value. This apparent jump led Ehrenfest to introduce a classification of phase transitions on the basis of jumps in derivatives of the free energy function. This classification was immediately applied by A.J. Rutgers to the study of the transition from the normal to superconducting state in metals. Eduard Justi and Max von Laue soon questioned the possibility of its class of “second-order phase transitions” -- of which the “lambda transition was believed to be the arche type -- but C.J. Gorter and H.B.G. Casimir used an “order parameter to demonstrate their existence in superconductors. As a crossroads of study, the Ehrenfest classification was forced to undergo a slow, adaptive evolution during subsequent decades. During the 1940s the classification was increasingly used in discussions of liquid-gas, order-disorder, paramagnetic-ferromagnetic and normal-super-conducting phase transitions. Already in 1944 however, Lars Onsagers solution of the Ising model for two-dimensional magnets was seen to possess a derivative with a logarithmic divergence rather than a jump as the critical point was approached. In the 1950s, experiments further revealed the lambda transition in helium to exhibit similar behavior. Rather than being a prime example of an Ehrenfest phase transition, the lambda transition was seen to lie outside the Ehrenfest classification. The Ehrenfest scheme was then extended to include such singularities, most notably by A. Brain Pippard in 1957, with widespread acceptance. During the 1960s these logarithmic infinities were the focus of the investigation of “scaling” by Leo Kadanoff, B. Widom and others. By the 1970s, a radically simplified binary classification of phase transitions into “first-order” and “continuous” transitions was increasingly adopted.     

N-acetylmuramic acid 6-phosphate lyases (MurNAc etherases): role in cell wall metabolism, distribution, structure, and mechanism

MurNAc etherases cleave the uniqued-lactyl ether bond of the bacterial cell wall sugar N-acetylmuramic acid (MurNAc). Members of this newly discovered family of enzymes are widely distributed among bacteria and are required to utilize peptidoglycan fragments obtained either from the environment or from the endogenous cell wall (i.e., recycling). MurNAc etherases are strictly dependent on the substrate MurNAc possessing a free reducing end and a phosphoryl group at C6. They carry a single conserved sugar phosphate isomerase/sugar phosphate- binding (SIS) domain to which MurNAc 6-phosphate is bound. Two subunits form an enzymatically active homodimer that structurally resembles the isomerase module of the double-SIS domain protein GlmS, the glucosamine 6-phosphate synthase. Structural comparison provides insights into the two-step lyase-type reaction mechanism of MurNAc etherases: β-elimination of the D-lactic acid substituent proceeds through a 2,3-unsaturated sugar intermediate to which water is subsequently added. Received 31 August 2007; received after revision 12 October 2007; accepted 1 November 2007     

A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3

To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P < 10(-4) in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping (10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 (P = 2.5 x 10(-13) overall; P = 6.9 x 10(-12) replication), and rs16892766, at 8q23.3 (P = 3.3 x 10(-18) overall; P = 9.6 x 10(-17) replication), which tags a plausible causative gene, EIF3H. These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition.     

Dynamic control of positional information in the early Drosophila embryo

Morphogen gradients contribute to pattern formation by determining positional information in morphogenetic fields. Interpretation of positional information is thought to rely on direct, concentration-threshold-dependent mechanisms for establishing multiple differential domains of target gene expression. In Drosophila, maternal gradients establish the initial position of boundaries for zygotic gap gene expression, which in turn convey positional information to pair-rule and segment-polarity genes, the latter forming a segmental pre-pattern by the onset of gastrulation. Here we report, on the basis of quantitative gene expression data, substantial anterior shifts in the position of gap domains after their initial establishment. Using a data-driven mathematical modelling approach, we show that these shifts are based on a regulatory mechanism that relies on asymmetric gap-gap cross-repression and does not require the diffusion of gap proteins. Our analysis implies that the threshold-dependent interpretation of maternal morphogen concentration is not sufficient to determine shifting gap domain boundary positions, and suggests that establishing and interpreting positional information are not independent processes in the Drosophila blastoderm.     

A new orang-utan relative from the Late Miocene of Thailand

The fossil record of the living great apes is poor. New fossils from undocumented areas, particularly the equatorial forested habitats of extant hominoids, are therefore crucial for understanding their origins and evolution. Two main competing hypotheses have been proposed for orang-utan origins: dental similarities support an origin from Lufengpithecus, a South Chinese and Thai Middle Miocene hominoid; facial and palatal similarities support an origin from Sivapithecus, a Miocene hominoid from the Siwaliks of Indo-Pakistan. However, materials other than teeth and faces do not support these hypotheses. Here we describe the lower jaw of a new hominoid from the Late Miocene of Thailand, Khoratpithecus piriyai gen. et sp. nov., which shares unique derived characters with orang-utans and supports a hypothesis of closer relationships with orang-utans than other known Miocene hominoids. It can therefore be considered as the closest known relative of orang-utans. Ancestors of this great ape were therefore evolving in Thailand under tropical conditions similar to those of today, in contrast with Southern China and Pakistan, where temperate or more seasonal climates appeared during the Late Miocene.