Variation in FTO contributes to childhood obesity and severe adult obesity

We identified a set of SNPs in the first intron of the FTO (fat mass and obesity associated) gene on chromosome 16q12.2 that is consistently strongly associated with early-onset and severe obesity in both adults and children of European ancestry with an experiment-wise P value of 1.67 x 10(-26) in 2,900 affected individuals and 5,100 controls. The at-risk haplotype yields a proportion of attributable risk of 22% for common obesity. We conclude that FTO contributes to human obesity and hence may be a target for subsequent functional analyses.     

Evidence for an unusual multifunctional protoreceptor in hormone action

Summary Contrary to the techniques of mere association, column chromatography has revealed a protoreceptor that accepts aldosterone agonists and antagonists only in the physiological target, the kidney, and is absent in non-targets, liver and serum; it is furthermore different from the aldosterone specific receptor in renal cytosol.Supported in part by grants from the CNRS AI 03 1917 and UER Broussais Hôtel Dieu.     

How could models possibly provide how-possibly explanations?

One puzzle concerning highly idealized models is whether they explain. Some suggest they provide so-called ‘how-possibly explanations’. However, this raises an important question about the nature of how-possibly explanations, namely what distinguishes them from ‘normal’, or how-actually, explanations? I provide an account of how-possibly explanations that clarifies their nature in the context of solving the puzzle of model-based explanation. I argue that the modal notions of actuality and possibility provide the relevant dividing lines between how-possibly and how-actually explanations. Whereas how-possibly explanations establish claims of possible explanations, how-actually explanations establish claims of actual ones. Models, in turn, simply provide evidence for these claims.     

Jaws and teeth of the earliest bony fishes

Extant jawed vertebrates, or gnathostomes, fall into two major monophyletic groups, namely chondrichthyans (cartilaginous fishes) and osteichthyans (bony fishes and tetrapods). Fossil representatives of the osteichthyan crown group are known from the latest Silurian period, 418 million years (Myr) ago, to the present. By contrast, stem chondrichthyans and stem osteichthyans are still largely unknown. Two extinct Palaeozoic groups, the acanthodians and placoderms, may fall into these stem groups or the common stem group of gnathostomes, but their relationships and monophyletic status are both debated. Here we report unambiguous evidence for osteichthyan characters in jaw bones referred to the late Silurian (423-416-Myr-old) fishes Andreolepis hedei and Lophosteus superbus, long known from isolated bone fragments, scales and teeth, and whose affinities to, or within, osteichthyans have been debated. The bones are a characteristic osteichthyan maxillary and dentary, but the organization of the tooth-like denticles they bear differs from the large, conical teeth of crown-group osteichthyans, indicating that they can be assigned to the stem group. Andreolepis and Lophosteus are thus not only the oldest but also the most phylogenetically basal securely identified osteichthyans known so far.     

Generation of optical 'Schrödinger cats' from photon number states

Schr?dinger's cat is a Gedankenexperiment in quantum physics, in which an atomic decay triggers the death of the cat. Because quantum physics allow atoms to remain in superpositions of states, the classical cat would then be simultaneously dead and alive. By analogy, a 'cat' state of freely propagating light can be defined as a quantum superposition of well separated quasi-classical states-it is a classical light wave that simultaneously possesses two opposite phases. Such states play an important role in fundamental tests of quantum theory and in many quantum information processing tasks, including quantum computation, quantum teleportation and precision measurements. Recently, optical Schr?dinger 'kittens' were prepared; however, they are too small for most of the aforementioned applications and increasing their size is experimentally challenging. Here we demonstrate, theoretically and experimentally, a protocol that allows the generation of arbitrarily large squeezed Schr?dinger cat states, using homodyne detection and photon number states as resources. We implemented this protocol with light pulses containing two photons, producing a squeezed Schr?dinger cat state with a negative Wigner function. This state clearly exhibits several quantum phase-space interference fringes between the 'dead' and 'alive' components, and is large enough to become useful for quantum information processing and experimental tests of quantum theory.     

Charge- and size-based separation of macromolecules using ultrathin silicon membranes

Commercial ultrafiltration and dialysis membranes have broad pore size distributions and are over 1,000 times thicker than the molecules they are designed to separate, leading to poor size cut-off properties, filtrate loss within the membranes, and low transport rates. Nanofabricated membranes have great potential in molecular separation applications by offering more precise structural control, yet transport is also limited by micrometre-scale thicknesses. This limitation can be addressed by a new class of ultrathin nanostructured membranes where the membrane is roughly as thick (approximately 10 nm) as the molecules being separated, but membrane fragility and complex fabrication have prevented the use of ultrathin membranes for molecular separations. Here we report the development of an ultrathin porous nanocrystalline silicon (pnc-Si) membrane using straightforward silicon fabrication techniques that provide control over average pore sizes from approximately 5 nm to 25 nm. Our pnc-Si membranes can retain proteins while permitting the transport of small molecules at rates an order of magnitude faster than existing materials, separate differently sized proteins under physiological conditions, and separate similarly sized molecules carrying different charges. Despite being only 15 nm thick, pnc-Si membranes that are free-standing over 40,000 microm2 can support a full atmosphere of differential pressure without plastic deformation or fracture. By providing efficient, low-loss macromolecule separations, pnc-Si membranes are expected to enable a variety of new devices, including membrane-based chromatography systems and both analytical and preparative microfluidic systems that require highly efficient separations.     

A role for mitochondria in NLRP3 inflammasome activation

An inflammatory response initiated by the NLRP3 inflammasome is triggered by a variety of situations of host 'danger', including infection and metabolic dysregulation. Previous studies suggested that NLRP3 inflammasome activity is negatively regulated by autophagy and positively regulated by reactive oxygen species (ROS) derived from an uncharacterized organelle. Here we show that mitophagy/autophagy blockade leads to the accumulation of damaged, ROS-generating mitochondria, and this in turn activates the NLRP3 inflammasome. Resting NLRP3 localizes to endoplasmic reticulum structures, whereas on inflammasome activation both NLRP3 and its adaptor ASC redistribute to the perinuclear space where they co-localize with endoplasmic reticulum and mitochondria organelle clusters. Notably, both ROS generation and inflammasome activation are suppressed when mitochondrial activity is dysregulated by inhibition of the voltage-dependent anion channel. This indicates that NLRP3 inflammasome senses mitochondrial dysfunction and may explain the frequent association of mitochondrial damage with inflammatory diseases.