A Dual Inhibitor of DYRK1A and GSK3β for β-Cell Proliferation: Aminopyrazine Derivative GNF4877

Loss of β-cell mass and function can lead to insufficient insulin levels and ultimately to hyperglycemia and diabetes mellitus. The mainstream treatment approach involves regulation of insulin levels; however, approaches intended to increase β-cell mass are less developed. Promoting β-cell proliferation with low-molecular-weight inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) offers the potential to treat diabetes with oral therapies by restoring β-cell mass, insulin content and glycemic control. GNF4877, a potent dual inhibitor of DYRK1A and glycogen synthase kinase 3β (GSK3β) was previously reported to induce primary human β-cell proliferation in vitro and in vivo. Herein, we describe the lead optimization that lead to the identification of GNF4877 from an aminopyrazine hit identified in a phenotypic high-throughput screening campaign measuring β-cell proliferation.     

Indoor heterogeneous photochemistry of furfural drives emissions of nitrous acid

People spend approximately 80% of their time indoor, making the understanding of the indoor chemistry an important task for safety. The high surface-area-to-volume ratio characteristic of indoor environments leads the semi-volatile organic compounds (sVOCs) to deposit on the surfaces. Using a long path absorption photometer (LOPAP), this work investigates the formation of nitrous acid (HONO) through the photochemistry of adsorbed nitrate anions and its enhancement by the presence of furfural. Using a high-resolution proton-transfer-reaction time-of-flight mass spectrometer (PTR-TOF-MS), this work also investigates the surface emissions of VOCs from irradiated films of furfural and a mix of furfural and nitrate anions. Among the emitted VOCs, 2(5H)-furanone/2-Butenedial was observed at high concentrations, leading to maleic anhydride formation after UV irradiation. Moreover, the addition of potassium nitrate to the film formed NO_x and HONO concentrations up to 10 ppb, which scales to ca. 4 ppb for realistic indoor conditions. This work helps to understand the high levels of HONO and NO_x measured indoors.     

Quantum Sensing in a Physiological‐Like Cell Niche Using Fluorescent Nanodiamonds Embedded in Electrospun Polymer Nanofibers

Fluorescent nanodiamonds (fNDs) containing nitrogen vacancy (NV) centers are promising candidates for quantum sensing in biological environments. This work describes the fabrication and implementation of electrospun poly lactic‐co‐glycolic acid (PLGA) nanofibers embedded with fNDs for optical quantum sensing in an environment, which recapitulates the nanoscale architecture and topography of the cell niche. A protocol that produces uniformly dispersed fNDs within electrospun nanofibers is demonstrated and the resulting fibers are characterized using fluorescent microscopy and scanning electron microscopy (SEM). Optically detected magnetic resonance (ODMR) and longitudinal spin relaxometry results for fNDs and embedded fNDs are compared. A new approach for fast detection of time varying magnetic fields external to the fND embedded nanofibers is demonstrated. ODMR spectra are successfully acquired from a culture of live differentiated neural stem cells functioning as a connected neural network grown on fND embedded nanofibers. This work advances the current state of the art in quantum sensing by providing a versatile sensing platform that can be tailored to produce physiological‐like cell niches to replicate biologically relevant growth environments and fast measurement protocols for the detection of co‐ordinated endogenous signals from clinically relevant populations of electrically active neuronal circuits.     

A closed-form solution for the distribution of the sum of Nakagami-m random phase vectors

The distribution of the modulus of the sum of random phase vectors, is of great practical importance in several applications which deal with sums of sinusoidal signals (wireless multipath transmissions, radars, optical communications, etc). In this letter, simple closed-form expressions are presented for the probability density function (PDF), the cumulative distribution function (CDF), the moment generating function (MGF) and the moments of the envelope distribution of the sum of L non-identical random Nakagami-m phase vectors with integer fading parameters. Moreover, the average over this distribution of the Gaussian Q-function and of the squared Q-function, are also presented in closed-form     

Managing Fashion Goods Inventories: Dynamic Recourse for Retailers with Outlet Stores

The proliferation of both online and bricks and mortar outlet stores underscores the observation that secondary markets are readily accessible to retailers of short-life-cycle products. These secondary markets provide recourse channels for retailers to sell excess inventory of out-of-favor items at reduced prices when overstocking occurs in a primary market. We study the problem of determining when a retailer should terminate its primary selling season by selling remaining inventory on a secondary market. The retailer has a single opportunity to procure prior to a primary selling season consisting of multiple periods. Demand in each period is random, but correlated. At the end of each period, any remaining inventory incurs a holding cost. Then, based upon the current level of inventory and the cumulative demand-to-date, the retailer decides either to terminate the primary selling season by selling all or part of the remaining inventory on a secondary market, or to extend the current primary selling season by another period. We develop structural properties of the optimal policy for determining when to terminate the primary selling season, and we develop corresponding implications for procurement.     

Fractal-wavelet image denoising revisited.

The essence of fractal image denoising is to predict the fractal code of a noiseless image from its noisy observation. From the predicted fractal code, one can generate an estimate of the original image. We show how well fractal-wavelet denoising predicts parent wavelet subtress of the noiseless image. The performance of various fractal-wavelet denoising schemes (e.g., fixed partitioning, quadtree partitioning) is compared to that of some standard wavelet thresholding methods. We also examine the use of cycle spinning in fractal-based image denoising for the purpose enhancing the denoised estimates. Our experimental results show that these fractal-based image denoising methods are quite competitive with standard wavelet thresholding methods for image denoising. Finally, we compare the performance of the pixel- and wavelet-based fractal denoising schemes.