D. J. Reilly

Differential Metabolic Impact of Gastric Bypass Surgery Versus Dietary Intervention in Obese Diabetic Subjects Despite Identical Weight Loss

The enhanced decrease in circulating branched-chain amino acids and their metabolites after gastric bypass occurs by mechanisms other than weight loss. Dissecting the Quick Fix In the Wizard of Oz, when Dorothy encounters a split in the yellow brick road, the Scarecrow assures her that all paths lead to the land of Oz. We’ve witnessed the perils Dorothy met along the path she chose; however, we don’t know what she would have encountered had she followed another route to Oz. Similarly, obese patients with type 2 diabetes can take one of two paths to weight loss—dietary intervention or gastric bypass surgery (GBP). Although the end result—weight loss—is the same, the metabolic shifts that occur en route appear to differ. Now, Laferrère et al. show that in patients with equivalent weight loss, those who underwent GBP displayed a larger decrease in certain circulating amino acids than did subjects who pursued the dietary intervention path. This difference may help to explain why patients who opted for the surgical intervention boasted better improvement in glucose homeostasis—including enhanced insulin sensitivity—than did those who lost weight by controlling their dietary intake. Obese patients with type 2 diabetes strive to lose weight for reasons more momentous than an approaching swimsuit season. Weight loss can improve the body’s ability to metabolize glucose and thus stems the serious complications of diabetes. Patients often can reduce or forgo their diabetes medications. However, in such patients, glycemic control is improved to a greater extent within days after GBP—before weight loss occurs—than after diet-induced shedding of pounds and inches. Precisely why remains a mystery, but research in animal models has revealed that higher-than-normal blood concentrations of branched-chain amino acids (BCAAs) and their metabolites play a role in the loss of insulin sensitivity. Furthermore, recent studies in human patients show a robust positive correlation between insulin resistance and blood levels of BCAAs and their by-products. Finally, obese people have higher circulating concentrations of these amino acids compared to their lean counterparts; the same goes for individuals with versus without diabetes. These observations imply that the rapid reversal of diabetes symptoms in GBP patients may have something to do with BCAA metabolism. Here, the authors measured circulating amounts of a variety of amino acids and acylcarnitines—some of which are produced primarily from BCAA metabolism—to characterize the differential metabolic responses to weight loss induced by GBP versus dietary intervention in obese type 2 diabetes patients. Circulating concentrations of total amino acids, BCAAs, and BCAA metabolites all decreased significantly after GBP but not after dietary intervention, despite equivalent weight loss. These findings were consistent in two patient cohorts, one from the New York Obesity Nutrition Research Center and one from Duke University; in the latter group, the effects were shown to persist for months. These data support the notion that the surgical intervention promoted enhanced BCAA metabolism by mechanisms separate from weight loss and suggest that changes in circulating amino acids pave the road to the correction of glycemic control observed after GBP. Glycemic control is improved more after gastric bypass surgery (GBP) than after equivalent diet-induced weight loss in patients with morbid obesity and type 2 diabetes mellitus. We applied metabolomic profiling to understand the mechanisms of this better metabolic response after GBP. Circulating amino acids (AAs) and acylcarnitines (ACs) were measured in plasma from fasted subjects by targeted tandem mass spectrometry before and after a matched 10-kilogram weight loss induced by GBP or diet. Total AAs and branched-chain AAs (BCAAs) decreased after GBP, but not after dietary intervention. Metabolites derived from BCAA oxidation also decreased only after GBP. Principal components (PC) analysis identified two major PCs, one composed almost exclusively of ACs (PC1) and another with BCAAs and their metabolites as major contributors (PC2). PC1 and PC2 were inversely correlated with pro-insulin concentrations, the C-peptide response to oral glucose, and the insulin sensitivity index after weight loss, whereas PC2 was uniquely correlated with levels of insulin resistance (HOMA-IR). These data suggest that the enhanced decrease in circulating AAs after GBP occurs by mechanisms other than weight loss and may contribute to the better improvement in glucose homeostasis observed with the surgical intervention.

Charge-based quantum computing using single donors in semiconductors

Solid-state quantum computer architectures with qubits encoded using single atoms are now feasible given recent advances in the atomic doping of semiconductors. Here we present a charge qubit consisting of two dopant atoms in a semiconductor crystal, one of which is singly ionized. Surface electrodes control the qubit and a radio-frequency single-electron transistor provides fast readout. The calculated single gate times, of order 50 ps or less, are much shorter than the expected decoherence time. We propose universal one- and two-qubit gate operations for this system and discuss prospects for fabrication and scale up.

A Ge/Si heterostructure nanowire-based double quantum dot with integrated charge sensor.

Yongjie Hu, Hugh O. H. Churchill, David J. Reilly, Jie Xiang, Charles M. Lieber, 3 and Charles M. Marcus Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA Department of Physics, Harvard University, Cambridge, Massachusetts 02138, USA Division of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, USA (Dated: February 1, 2008)One proposal for a solid-state-based quantum bit (qubit) is to control coupled electron spins on adjacent semiconductor quantum dots. Most experiments have focused on quantum dots made from III-V semiconductors; however, the coherence of electron spins in these materials is limited by hyperfine interactions with nuclear spins. Ge/Si core/shell nanowires seem ideally suited to overcome this limitation, because the most abundant nuclei in Ge and Si have spin zero and the nanowires can be chemically synthesized defect-free with tunable properties. Here, we present a double quantum dot based on Ge/Si nanowires in which we can completely control the coupling between the dots and to the leads. We also demonstrate that charge on the double dot can be detected by coupling it capacitively to an adjacent nanowire quantum dot. The double quantum dot and integrated charge sensor serve as an essential building block to form a solid-state qubit free of nuclear spin.

Therapeutic Inflammatory Monocyte Modulation Using Immune-Modifying Microparticles

Negatively charged immune-modifying microparticles bind to the scavenger receptor MARCO on inflammatory monocytes, resulting in their apoptosis and reduced inflammatory damage in a range of diseases. A New Frontier in Immune Modulation Inflammatory monocytes markedly potentiate the immune pathology observed in many diseases, yet no therapy exists that specifically inhibits these cells. The therapeutic accessibility of monocytes in the bloodstream and their inherent propensity to engulf particulate material suggest that highly negatively charged microparticles might provide a readily translatable solution to this problem. These microparticles, referred to as immune-modifying microparticles (IMPs), may be derived from numerous compounds, including the biodegradable polymer poly(lactic-co-glycolic acid) (PLGA-IMP), already used in humans for inter alia dissolvable sutures. Getts et al. now show that upon infusion, IMPs bind to a receptor with a positive domain on inflammatory monocytes, resulting in monocyte sequestration in the spleen and apoptosis through a similar pathway observed for senescing leukocytes. This safe monocyte clearance pathway culminated in substantially reduced inflammatory tissue damage in mouse models of West Nile virus encephalitis, experimental autoimmune encephalomyelitis, peritonitis, colitis, and myocardial infarction. Together, the data suggest that IMPs could transform the treatment of acute inflammation. Indeed, phase 1/2 testing is planned to begin in 2014, with rapid translation supported by the availability of clinical-grade PLGA. Inflammatory monocyte-derived effector cells play an important role in the pathogenesis of numerous inflammatory diseases. However, no treatment option exists that is capable of modulating these cells specifically. We show that infused negatively charged, immune-modifying microparticles (IMPs), derived from polystyrene, microdiamonds, or biodegradable poly(lactic-co-glycolic) acid, were taken up by inflammatory monocytes, in an opsonin-independent fashion, via the macrophage receptor with collagenous structure (MARCO). Subsequently, these monocytes no longer trafficked to sites of inflammation; rather, IMP infusion caused their sequestration in the spleen through apoptotic cell clearance mechanisms and, ultimately, caspase-3–mediated apoptosis. Administration of IMPs in mouse models of myocardial infarction, experimental autoimmune encephalomyelitis, dextran sodium sulfate–induced colitis, thioglycollate-induced peritonitis, and lethal flavivirus encephalitis markedly reduced monocyte accumulation at inflammatory foci, reduced disease symptoms, and promoted tissue repair. Together, these data highlight the intricate interplay between scavenger receptors, the spleen, and inflammatory monocyte function and support the translation of IMPs for therapeutic use in diseases caused or potentiated by inflammatory monocytes.

Density-Dependent Spin Polarization in Ultra-Low -Disorder Quantum Wires

There is controversy as to whether a one-dimensional (1D) electron gas can spin polarize in the absence of a magnetic field. Together with a simple model, we present conductance measurements on ultra-low-disorder quantum wires supportive of a spin polarization at B=0. A spin energy gap is indicated by the presence of a feature in the range (0.5-0.7)x2e(2)/h in conductance data. Importantly, it appears that the spin gap is not constant but a function of the electron density. Data obtained using a bias spectroscopy technique are consistent with the spin gap widening further as the Fermi level is increased.

Fast single-charge sensing with a rf quantum point contact

We report high-bandwidth charge sensing measurements using a GaAs quantum point contact embedded in a radio frequency impedance matching circuit (rf-QPC). With the rf-QPC biased near pinch-off where it is most sensitive to charge, we demonstrate a conductance sensitivity of 5×10−6e2∕hHz−1∕2 with a bandwidth of 8MHz. Single-shot readout of a proximal few-electron double quantum dot is investigated in a mode where the rf-QPC back action is rapidly switched.

Rapid Single-Shot Measurement of a Singlet-Triplet Qubit

We report repeated single-shot measurements of the two-electron spin state in a GaAs double quantum dot. The readout allows measurement with a fidelity above 90% with a approximately 7 micros cycle time. Hyperfine-induced precession between singlet and triplet states of the two-electron system are directly observed, as nuclear Overhauser fields are quasistatic on the time scale of the measurement cycle. Repeated measurements on millisecond to second time scales reveal the evolution of the nuclear environment.

Suppressing Spin Qubit Dephasing by Nuclear State Preparation

Coherent spin states in semiconductor quantum dots offer promise as electrically controllable quantum bits (qubits) with scalable fabrication. For few-electron quantum dots made from gallium arsenide (GaAs), fluctuating nuclear spins in the host lattice are the dominant source of spin decoherence. We report a method of preparing the nuclear spin environment that suppresses the relevant component of nuclear spin fluctuations below its equilibrium value by a factor of ∼70, extending the inhomogeneous dephasing time for the two-electron spin state beyond 1 microsecond. The nuclear state can be readily prepared by electrical gate manipulation and persists for more than 10 seconds.

Dispersive readout of a few-electron double quantum dot with fast RF gate sensors.

We report the dispersive charge-state readout of a double quantum dot in the few-electron regime using the in situ gate electrodes as sensitive detectors. We benchmark this gate sensing technique against the well established quantum point contact charge detector and find comparable performance with a bandwidth of ∼ 10 MHz and an equivalent charge sensitivity of ∼ 6.3 × 10(-3) e/sqrt[Hz]. Dispersive gate sensing alleviates the burden of separate charge detectors for quantum dot systems and promises to enable readout of qubits in scaled-up arrays.

Many-body spin-related phenomena in ultra low-disorder quantum wires

Zero length quantum wires (or point contacts) exhibit unexplained conductance structure close to