Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity

A subset of neurons in the brain, known as 'glucose-excited' neurons, depolarize and increase their firing rate in response to increases in extracellular glucose. Similar to insulin secretion by pancreatic beta-cells, glucose excitation of neurons is driven by ATP-mediated closure of ATP-sensitive potassium (K(ATP)) channels. Although beta-cell-like glucose sensing in neurons is well established, its physiological relevance and contribution to disease states such as type 2 diabetes remain unknown. To address these issues, we disrupted glucose sensing in glucose-excited pro-opiomelanocortin (POMC) neurons via transgenic expression of a mutant Kir6.2 subunit (encoded by the Kcnj11 gene) that prevents ATP-mediated closure of K(ATP) channels. Here we show that this genetic manipulation impaired the whole-body response to a systemic glucose load, demonstrating a role for glucose sensing by POMC neurons in the overall physiological control of blood glucose. We also found that glucose sensing by POMC neurons became defective in obese mice on a high-fat diet, suggesting that loss of glucose sensing by neurons has a role in the development of type 2 diabetes. The mechanism for obesity-induced loss of glucose sensing in POMC neurons involves uncoupling protein 2 (UCP2), a mitochondrial protein that impairs glucose-stimulated ATP production. UCP2 negatively regulates glucose sensing in POMC neurons. We found that genetic deletion of Ucp2 prevents obesity-induced loss of glucose sensing, and that acute pharmacological inhibition of UCP2 reverses loss of glucose sensing. We conclude that obesity-induced, UCP2-mediated loss of glucose sensing in glucose-excited neurons might have a pathogenic role in the development of type 2 diabetes.     

PTC124 targets genetic disorders caused by nonsense mutations

Nonsense mutations promote premature translational termination and cause anywhere from 5-70% of the individual cases of most inherited diseases. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease. To address the need for a drug capable of suppressing premature termination, we identified PTC124-a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2-8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.     

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.     

Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia

Chromosomal aberrations are a hallmark of acute lymphoblastic leukaemia (ALL) but alone fail to induce leukaemia. To identify cooperating oncogenic lesions, we performed a genome-wide analysis of leukaemic cells from 242 paediatric ALL patients using high-resolution, single-nucleotide polymorphism arrays and genomic DNA sequencing. Our analyses revealed deletion, amplification, point mutation and structural rearrangement in genes encoding principal regulators of B lymphocyte development and differentiation in 40% of B-progenitor ALL cases. The PAX5 gene was the most frequent target of somatic mutation, being altered in 31.7% of cases. The identified PAX5 mutations resulted in reduced levels of PAX5 protein or the generation of hypomorphic alleles. Deletions were also detected in TCF3 (also known as E2A), EBF1, LEF1, IKZF1 (IKAROS) and IKZF3 (AIOLOS). These findings suggest that direct disruption of pathways controlling B-cell development and differentiation contributes to B-progenitor ALL pathogenesis. Moreover, these data demonstrate the power of high-resolution, genome-wide approaches to identify new molecular lesions in cancer.     

Complex gas hydrate from the Cascadia margin

Natural gas hydrates are a potential source of energy and may play a role in climate change and geological hazards. Most natural gas hydrate appears to be in the form of 'structure I', with methane as the trapped guest molecule, although 'structure II' hydrate has also been identified, with guest molecules such as isobutane and propane, as well as lighter hydrocarbons. A third hydrate structure, 'structure H', which is capable of trapping larger guest molecules, has been produced in the laboratory, but it has not been confirmed that it occurs in the natural environment. Here we characterize the structure, gas content and composition, and distribution of guest molecules in a complex natural hydrate sample recovered from Barkley canyon, on the northern Cascadia margin. We show that the sample contains structure H hydrate, and thus provides direct evidence for the natural occurrence of this hydrate structure. The structure H hydrate is intimately associated with structure II hydrate, and the two structures contain more than 13 different hydrocarbon guest molecules. We also demonstrate that the stability field of the complex gas hydrate lies between those of structure II and structure H hydrates, indicating that this form of hydrate is more stable than structure I and may thus potentially be found in a wider pressure-temperature regime than can methane hydrate deposits.     

Abrupt onset of a second energy gap at the superconducting transition of underdoped Bi2212

The superconducting gap--an energy scale tied to the superconducting phenomena--opens on the Fermi surface at the superconducting transition temperature (T(c)) in conventional BCS superconductors. In underdoped high-T(c) superconducting copper oxides, a pseudogap (whose relation to the superconducting gap remains a mystery) develops well above T(c) (refs 1, 2). Whether the pseudogap is a distinct phenomenon or the incoherent continuation of the superconducting gap above T(c) is one of the central questions in high-T(c) research. Although some experimental evidence suggests that the two gaps are distinct, this issue is still under intense debate. A crucial piece of evidence to firmly establish this two-gap picture is still missing: a direct and unambiguous observation of a single-particle gap tied to the superconducting transition as function of temperature. Here we report the discovery of such an energy gap in underdoped Bi2Sr2CaCu2O8+delta in the momentum space region overlooked in previous measurements. Near the diagonal of Cu-O bond direction (nodal direction), we found a gap that opens at T(c) and has a canonical (BCS-like) temperature dependence accompanied by the appearance of the so-called Bogoliubov quasi-particles, a classical signature of superconductivity. This is in sharp contrast to the pseudogap near the Cu-O bond direction (antinodal region) measured in earlier experiments.     

Controlled exchange interaction between pairs of neutral atoms in an optical lattice

Ultracold atoms trapped by light offer robust quantum coherence and controllability, providing an attractive system for quantum information processing and for the simulation of complex problems in condensed matter physics. Many quantum information processing schemes require the manipulation and deterministic entanglement of individual qubits; this would typically be accomplished using controlled, state-dependent, coherent interactions among qubits. Recent experiments have made progress towards this goal by demonstrating entanglement among an ensemble of atoms confined in an optical lattice. Until now, however, there has been no demonstration of a key operation: controlled entanglement between atoms in isolated pairs. Here we use an optical lattice of double-well potentials to isolate and manipulate arrays of paired (87)Rb atoms, inducing controlled entangling interactions within each pair. Our experiment realizes proposals to use controlled exchange coupling in a system of neutral atoms. Although 87Rb atoms have nearly state-independent interactions, when we force two atoms into the same physical location, the wavefunction exchange symmetry of these identical bosons leads to state-dependent dynamics. We observe repeated interchange of spin between atoms occupying different vibrational levels, with a coherence time of more than ten milliseconds. This observation demonstrates the essential component of a neutral atom quantum SWAP gate (which interchanges the state of two qubits). Its 'half-implementation', the root SWAP gate, is entangling, and together with single-qubit rotations it forms a set of universal gates for quantum computation.     

A reversible wet/dry adhesive inspired by mussels and geckos

The adhesive strategy of the gecko relies on foot pads composed of specialized keratinous foot-hairs called setae, which are subdivided into terminal spatulae of approximately 200 nm (ref. 1). Contact between the gecko foot and an opposing surface generates adhesive forces that are sufficient to allow the gecko to cling onto vertical and even inverted surfaces. Although strong, the adhesion is temporary, permitting rapid detachment and reattachment of the gecko foot during locomotion. Researchers have attempted to capture these properties of gecko adhesive in synthetic mimics with nanoscale surface features reminiscent of setae; however, maintenance of adhesive performance over many cycles has been elusive, and gecko adhesion is greatly diminished upon full immersion in water. Here we report a hybrid biologically inspired adhesive consisting of an array of nanofabricated polymer pillars coated with a thin layer of a synthetic polymer that mimics the wet adhesive proteins found in mussel holdfasts. Wet adhesion of the nanostructured polymer pillar arrays increased nearly 15-fold when coated with mussel-mimetic polymer. The system maintains its adhesive performance for over a thousand contact cycles in both dry and wet environments. This hybrid adhesive, which combines the salient design elements of both gecko and mussel adhesives, should be useful for reversible attachment to a variety of surfaces in any environment.