Current landscape of treatments for Wolfram syndrome

Wolfram syndrome is a rare genetic spectrum disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration, and ranges from mild to severe clinical symptoms. There is currently no treatment to delay, halt, or reverse the progression of Wolfram syndrome, raising the urgency for innovative therapeutics for this disease. Here, we summarize our vision for developing novel treatment strategies and achieving a cure for Wolfram-syndrome-spectrum disorder

Skyrmion Gas Manipulation for Probabilistic Computing

The topologically protected magnetic spin configurations known as skyrmions offer promising applications due to their stability, mobility and localization. In this work, we emphasize how to leverage the thermally driven dynamics of an ensemble of such particles to perform computing tasks. We propose a device employing a skyrmion gas to reshuffle a random signal into an uncorrelated copy of itself. This is demonstrated by modelling the ensemble dynamics in a collective coordinate approach where skyrmion-skyrmion and skyrmion-boundary interactions are accounted for phenomenologically. Our numerical results are used to develop a proof-of-concept for an energy efficient ($\sim\mu\mathrm{W}$) device with a low area imprint ($\sim\mu\mathrm{m}^2$). Whereas its immediate application to stochastic computing circuit designs will be made apparent, we argue that its basic functionality, reminiscent of an integrate-and-fire neuron, qualifies it as a novel bio-inspired building block.Comment: 41 pages, 20 figure

Reservoir computing with the frequency, phase and amplitude of spin-torque nano-oscillators

Spin-torque nano-oscillators can emulate neurons at the nanoscale. Recent works show that the non-linearity of their oscillation amplitude can be leveraged to achieve waveform classification for an input signal encoded in the amplitude of the input voltage. Here we show that the frequency and the phase of the oscillator can also be used to recognize waveforms. For this purpose, we phase-lock the oscillator to the input waveform, which carries information in its modulated frequency. In this way we considerably decrease amplitude, phase and frequency noise. We show that this method allows classifying sine and square waveforms with an accuracy above 99% when decoding the output from the oscillator amplitude, phase or frequency. We find that recognition rates are directly related to the noise and non-linearity of each variable. These results prove that spin-torque nano-oscillators offer an interesting platform to implement different computing schemes leveraging their rich dynamical features

Targeting cellular calcium homeostasis to prevent cytokine-mediated beta cell death

AbstractPro-inflammatory cytokines are important mediators of islet inflammation, leading to beta cell death in type 1 diabetes. Although alterations in both endoplasmic reticulum (ER) and cytosolic free calcium levels are known to play a role in cytokine-mediated beta cell death, there are currently no treatments targeting cellular calcium homeostasis to combat type 1 diabetes. Here we show that modulation of cellular calcium homeostasis can mitigate cytokine- and ER stress-mediated beta cell death. The calcium modulating compounds, dantrolene and sitagliptin, both prevent cytokine and ER stress-induced activation of the pro-apoptotic calcium-dependent enzyme, calpain, and partly suppress beta cell death in INS1E cells and human primary islets. These agents are also able to restore cytokine-mediated suppression of functional ER calcium release. In addition, sitagliptin preserves function of the ER calcium pump, sarco-endoplasmic reticulum Ca2+-ATPase (SERCA), and decreases levels of the pro-apoptotic protein thioredoxin-interacting protein (TXNIP). Supporting the role of TXNIP in cytokine-mediated cell death, knock down of TXNIP in INS1-E cells prevents cytokine-mediated beta cell death. Our findings demonstrate that modulation of dynamic cellular calcium homeostasis and TXNIP suppression present viable pharmacologic targets to prevent cytokine-mediated beta cell loss in diabetes.</jats:p

A soluble endoplasmic reticulum factor as regenerative therapy for Wolfram syndrome

Endoplasmic reticulum (ER) stress-mediated cell death is an emerging target for human chronic disorders, including neurodegeneration and diabetes. However, there is currently no treatment for preventing ER stress-mediated cell death. Here, we show that mesencephalic astrocyte-derived neurotrophic factor (MANF), a neurotrophic factor secreted from ER stressed cells, prevents ER stress-mediated β cell death and enhances β cell proliferation in cell and mouse models of Wolfram syndrome, a prototype of ER disorders. Our results indicate that molecular pathways regulated by MANF are promising therapeutic targets for regenerative therapy of ER stress-related disorders, including diabetes, retinal degeneration, neurodegeneration, and Wolfram syndrome

Designing large arrays of interacting spin-torque nano-oscillators for microwave information processing

Arrays of spin-torque nano-oscillators are promising for broadband microwave signal detection and processing, as well as for neuromorphic computing. In many of these applications, the oscillators should be engineered to have equally-spaced frequencies and equal sensitivity to microwave inputs. Here we design spin-torque nano-oscillator arrays with these rules and estimate their optimum size for a given sensitivity, as well as the frequency range that they cover. For this purpose, we explore analytically and numerically conditions to obtain vortex spin-torque nano-oscillators with equally-spaced gyrotropic oscillation frequencies and having all similar synchronization bandwidths to input microwave signals. We show that arrays of hundreds of oscillators covering ranges of several hundred MHz can be built taking into account nanofabrication constraints

Role of non-linear data processing on speech recognition task in the framework of reservoir computing

The reservoir computing neural network architecture is widely used to test hardware systems for neuromorphic computing. One of the preferred tasks for bench-marking such devices is automatic speech recognition. However, this task requires acoustic transformations from sound waveforms with varying amplitudes to frequency domain maps that can be seen as feature extraction techniques. Depending on the conversion method, these may obscure the contribution of the neuromorphic hardware to the overall speech recognition performance. Here, we quantify and separate the contributions of the acoustic transformations and the neuromorphic hardware to the speech recognition success rate. We show that the non-linearity in the acoustic transformation plays a critical role in feature extraction. We compute the gain in word success rate provided by a reservoir computing device compared to the acoustic transformation only, and show that it is an appropriate benchmark for comparing different hardware. Finally, we experimentally and numerically quantify the impact of the different acoustic transformations for neuromorphic hardware based on magnetic nano-oscillators.Comment: 13 pages, 5 figure

A phase Ib/IIa clinical trial of dantrolene sodium in patients with Wolfram syndrome

BACKGROUNDWolfram syndrome is a rare ER disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is no treatment for Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting ER calcium homeostasis, including dantrolene sodium, may be beneficial.METHODSBased on results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, we assembled what we believe is the first-ever clinical trial in pediatric and adult Wolfram syndrome patients with an open-label phase Ib/IIa trial design. The primary objective was to assess the safety and tolerability of dantrolene sodium in adult and pediatric Wolfram syndrome patients. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic β cell functions, visual acuity, quality-of-life measures related to vision, and neurological functions.RESULTSDantrolene sodium was well tolerated by Wolfram syndrome patients. Overall, β cell functions were not significantly improved, but there was a significant correlation between baseline β cell functions and change in β cell responsiveness (R2, P = 0.004) after 6-month dantrolene therapy. Visual acuity and neurological functions were not improved by 6-month dantrolene sodium. Markers of inflammatory cytokines and oxidative stress, such as IFN-γ, IL-1β, TNF-α, and isoprostane, were elevated in subjects.CONCLUSIONThis study justifies further investigation into using dantrolene sodium and other small molecules targeting the ER for treatment of Wolfram syndrome.TRIAL REGISTRATIONClinicalTrials.gov identifier NCT02829268FUNDINGNIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK112921, DK113487, DK020579), NIH/National Center for Advancing Translational Sciences (NCATS) (TR002065, TR000448), NIH training grant (F30DK111070), Silberman Fund, Ellie White Foundation, Snow Foundation, Unravel Wolfram Syndrome Fund, Stowe Fund, Eye Hope Foundation, Feiock Fund, Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from NIH/NCATS, Bursky Center for Human Immunology & Immunotherapy Programs

Bounds on Supersymmetry from Electroweak Precision Analysis

The Standard Model global fit to precision data is excellent. The Minimal Supersymmetric Standard Model can also fit the data well, though not as well as the Standard Model. At best, supersymmetric contributions either decouple or only slightly decrease the total chi^2, at the expense of decreasing the number of degrees of freedom. In general, regions of parameter space with large supersymmetric corrections from light superpartners are associated with poor fits to the data. We contrast results of a simple (oblique) approximation with full one-loop results, and show that for the most important observables the non-oblique corrections can be larger than the oblique corrections, and must be taken into account. We elucidate the regions of parameter space in both gravity- and gauge-mediated models which are excluded. Significant regions of parameter space are excluded, especially with positive supersymmetric mass parameter mu. We give a complete listing of the bounds on all the superpartner and Higgs boson masses. For either sign of mu, and for all supersymmetric models considered, we set a lower limit on the mass of the lightest CP-even Higgs scalar, mh > 78 GeV. Also, the first and second generation squark masses are constrained to be above 280 (325) GeV in the supergravity (gauge-mediated) model.Comment: 32 pages, 12 figures; SLAC-PUB number change