alpha Cell Function and Gene Expression Are Compromised in Type 1 Diabetes

Many patients with type 1 diabetes (T1D) have residual beta cells producing small amounts of C-peptide long after disease onset but develop an inadequate glucagon response to hypoglycemia following T1D diagnosis. The features of these residual beta cells and alpha cells in the islet endocrine compartment are largely unknown, due to the difficulty of comprehensive investigation. By studying the T1D pancreas and isolated islets, we show that remnant beta cells appeared to maintain several aspects of regulated insulin secretion. However, the function of T1D alpha cells was markedly reduced, and these cells had alterations in transcription factors constituting alpha and beta cell identity. In the native pancreas and after placing the T1D islets into a non-autoimmune, normoglycemic in vivo environment, there was no evidence of alpha-to-beta cell conversion. These results suggest an explanation for the disordered T1D counterregulatory glucagon response to hypoglycemia

Human islets expressing HNF1A variant have defective beta cell transcriptional regulatory networks

Using an integrated approach to characterize the pancreatic tissue and isolated islets from a 33-year-old with 17 years of type 1 diabetes (T1D), we found that donor islets contained beta cells without insulitis and lacked glucose-stimulated insulin secretion despite a normal insulin response to cAMP-evoked stimulation. With these unexpected findings for T1D, we sequenced the donor DNA and found a pathogenic heterozygous variant in the gene encoding hepatocyte nuclear factor-1alpha (HNF1A). In one of the first studies of human pancreatic islets with a disease-causing HNF1A variant associated with the most common form of monogenic diabetes, we found that HNF1A dysfunction leads to insulin-insufficient diabetes reminiscent of T1D by impacting the regulatory processes critical for glucose-stimulated insulin secretion and suggest a rationale for a therapeutic alternative to current treatment

Bimetallic Palladium Catalysis: Direct Observation of Pd(III)–Pd(III) Intermediates

$PhI(OAc)_2$ is a common oxidant for Pd-catalyzed C−H bond functionalizations. Mechanistic hypotheses since the 1960s have suggested a Pd(II)/Pd(IV) mechanism. Here we present evidence for the relevance of bimetallic Pd(III) complexes to catalysis. A bimetallic Pd(III) acetate was isolated and can afford product by bimetallic reductive elimination.Chemistry and Chemical Biolog

Existence and Stability of Standing Pulses in Neural Networks : I Existence

We consider the existence of standing pulse solutions of a neural network integro-differential equation. These pulses are bistable with the zero state and may be an analogue for short term memory in the brain. The network consists of a single-layer of neurons synaptically connected by lateral inhibition. Our work extends the classic Amari result by considering a non-saturating gain function. We consider a specific connectivity function where the existence conditions for single-pulses can be reduced to the solution of an algebraic system. In addition to the two localized pulse solutions found by Amari, we find that three or more pulses can coexist. We also show the existence of nonconvex ``dimpled'' pulses and double pulses. We map out the pulse shapes and maximum firing rates for different connection weights and gain functions.Comment: 31 pages, 29 figures, submitted to SIAM Journal on Applied Dynamical System

Synthesis and Structure of Solution-Stable One-Dimensional Palladium Wires

One-dimensional metal wires are valuable materials because of their optical and electronic anisotropy, and they have potential utility in devices such as photovoltaic cells and molecular sensors. However, despite more than a century of research, only a few examples exist of well-defined one-dimensional (1D) metal wires that allow for the rational variation of conductivity. Herein we describe the first examples of 1D molecular wires supported by Pd–Pd bonds, the thin-film conductive properties of which can be altered by controlled molecular changes. Wires based on Pd(III) give semiconducting films with a modifiable bandgap, whereas wires based on Pd(2.5) give films that display metallic conductivity above 200 K: a metallic state has not been reported previously for any polymer composed of 1D metal wires. The wires are infinite in the solid state and maintain 1D structures in solution with lengths of up to 750 nm. Solution stability enables thin film coating, a requisite for device fabrication using molecular wires.Chemistry and Chemical Biolog

Regulation of AUXIN RESPONSE FACTOR condensation and nucleo-cytoplasmic partitioning

Auxin critically regulates plant growth and development. Auxin-driven transcriptional responses are mediated through the AUXIN RESPONSE FACTOR (ARF) family of transcription factors. ARF protein condensation attenuates ARF activity, resulting in dramatic shifts in the auxin transcriptional landscape. Here, we perform a forward genetics screen for ARF hypercondensation, identifying an F-box protein, which we named AUXIN RESPONSE FACTOR F-BOX1 (AFF1). Functional characterization of SC

A Fluoride-Derived Electrophilic Late-Stage Fluorination Reagent for PET Imaging

The unnatural isotope fluorine-18 $(^{18}F)$ is used as a positron emitter in molecular imaging. Currently, many potentially useful $^{18}F$-labeled probe molecules are inaccessible for imaging because no fluorination chemistry is available to make them. The 110-minute half-life of $^{18}F$ requires rapid syntheses for which $[^{18}F]$fluoride is the preferred source of fluorine because of its practical access and suitable isotope enrichment. However, conventional $[^{18}F]$fluoride chemistry has been limited to nucleophilic fluorination reactions. We report the development of a palladium-based electrophilic fluorination reagent derived from fluoride and its application to the synthesis of aromatic $^{18}F$-labeled molecules via late-stage fluorination. Late-stage fluorination enables the synthesis of conventionally unavailable positron emission tomography (PET) tracers for anticipated applications in pharmaceutical development as well as preclinical and clinical PET imaging.Chemistry and Chemical Biolog

Livestock grazing and vegetative filter strip buffer effects on runoff sediment, nitrate, and phosphorus losses

Livestock grazing in the Midwestern United States can result in significant levels of runoff sediment and nutrient losses to surface water resources. Some of these contaminants can increase stream eutrophication and are suspected of contributing to hypoxic conditions in the Gulf of Mexico. This research quantified effects of livestock grazing management practices and vegetative filter strip buffers on runoff depth and mass losses of total solids, nitrate-nitrogen (NO3-N), and ortho-phosphorus (PO4-P) under natural hydrologic conditions. Runoff data were collected from 12 rainfall events during 2001 to 2003 at an Iowa State University research farm in central Iowa, United States. Three vegetative buffers (paddock area:vegetative buffer area ratios of 1:0.2, 1:0.1, and 1:0 no buffer [control]) and three grazing management practices (continuous, rotational, and no grazing [control]) comprised nine treatment combinations (vegetative buffer ratio/grazing management practice) replicated in three 1.35 ha (3.34 ac) plot areas. The total 4.05 ha (10.02 ac) study area also included nine 0.4 ha (1.0 ac) paddocks and 27 vegetative buffer runoff collection units distributed in a randomized complete block design. The study site was established on uneven terrain with a maximum of 15% slopes and consisted of approximately 100% cool-season smooth bromegrass. Average paddock and vegetative buffer plant tiller densities estimated during the 2003 project season were approximately 62 million and 93 million tillers ha−1 (153 million and 230 million tillers ac−1), respectively. Runoff sample collection pipe leakage discovered and corrected during 2001 possibly reduced runoff depth and affected runoff contaminant mass losses data values. Consequently, 2001 runoff analysis results were limited to treatment comparisons within the 2001 season and were not compared with 2002 and 2003 data. Analysis results from 2001 showed no significant differences in average losses of runoff, total solids, NO3-N, and PO4-P among the nine vegetative buffer/grazing practice treatment combinations. Results from 2002 indicated significantly higher losses of runoff and total solids from 1:0 no buffer/rotational grazing and 1:0 no buffer/continuous grazing treatment combination plots, respectively, compared among other 2002 season treatment combinations. The 2003 results showed significantly higher runoff and total solids losses from 1:0 no buffer/no grazing treatment combination plots compared among all 2003 treatment combinations and from 1:0.1 vegetative buffer/no grazing treatment combination plots compared among all 2003 treatment combinations and with respective 2002 treatment combinations. However, the 2003 results indicated effective vegetative buffer performance with significantly lower runoff, total solids, and NO3-N losses from the larger 1:0.2 buffer area compared among the smaller 1:0.1 buffer area and 1:0 no buffer treatment combinations. The 2003 results also indicated a highly significant increase in losses of NO3-N from 1:0.1 buffer/no grazing treatment combination plots compared among other 2003 season treatment combinations and with respective 2002 treatment combinations. Overall results from this study suggest a shift from significantly higher 2002 season plot losses of continuous and rotational grazing treatment combinations to significantly higher 2003 season losses of no grazing treatment combinations. We speculate this shift to significantly higher runoff and contaminant losses from no grazing treatment combination plots during 2003 reflects the variability inherent to a complex and dynamic soil-water environment of livestock grazing areas. However, we also hypothesize the environmental conditions that largely consisted of a dense perennial cool-season grass type, high-relief landscape, and relatively high total rainfall depth may not necessarily include livestock grazing activities

Depth-resolved photochemical production of hydrogen peroxide in the global ocean using remotely sensed ocean color

Hydrogen peroxide (H2O2) is an important reactive oxygen species (ROS) in natural waters, affecting water quality via participation in metal redox reactions and causing oxidative stress for marine ecosystems. While attempts have been made to better understand H2O2 dynamics in the global ocean, the relative importance of various H2O2 sources and losses remains uncertain. Our model improves previous estimates of photochemical H2O2 production rates by using remotely sensed ocean color to characterize the ultraviolet (UV) radiation field in surface water along with quantitative chemical data for the photochemical efficiency of H2O2 formation. Wavelength- and temperature-dependent efficiency (i.e., apparent quantum yield, AQY) spectra previously reported for a variety of seawater sources, including coastal and oligotrophic stations in Antarctica, the Pacific Ocean at Station ALOHA, the Gulf of Mexico, and several sites along the eastern coast of the United States were compiled to obtain a “marine-average” AQY spectrum. To evaluate our predictions of H2O2 photoproduction in surface waters using this single AQY spectrum, we compared modeled rates to new measured rates from Gulf Stream, coastal, and nearshore river-outflow stations in the South Atlantic Bight, GA, United States; obtaining comparative differences of 33% or less. In our global model, the “marine-average” AQY spectrum was used with modeled solar irradiance, together with satellite-derived surface seawater temperature and UV optical properties, including diffuse attenuation coefficients and dissolved organic matter absorption coefficients estimated with remote sensing-based algorithms. The final product of the model, a monthly climatology of depth-resolved H2O2 photoproduction rates in the surface mixed layer, is reported for the first time and provides an integrated global estimate of ∼21.1 Tmol yr−1 for photochemical H2O2 production. This work has important implications for photo-redox reactions in seawater and improves our understanding of the role of solar irradiation on ROS cycling and the overall oxidation state in the oceans

The MafA transcription factor becomes essential to islet β-cells soon after birth

The large Maf transcription factors, MafA and MafB, are expressed with distinct spatial-temporal patterns in rodent islet cells. Analysis of Mafa(-/-) and pancreas-specific Mafa(∆panc) deletion mutant mice demonstrated a primary role for MafA in adult β-cell activity, different from the embryonic importance of MafB. Our interests here were to precisely define when MafA became functionally significant to β-cells, to determine how this was affected by the brief period of postnatal MafB production, and to identify genes regulated by MafA during this period. We found that islet cell organization, β-cell mass, and β-cell function were influenced by 3 weeks of age in Mafa(Δpanc) mice and compromised earlier in Mafa(Δpanc);Mafb(+/-) mice. A combination of genome-wide microarray profiling, electron microscopy, and metabolic assays were used to reveal mechanisms of MafA control. For example, β-cell replication was produced by actions on cyclin D2 regulation, while effects on granule docking affected first-phase insulin secretion. Moreover, notable differences in the genes regulated by embryonic MafB and postnatal MafA gene expression were found. These results not only clearly define why MafA is an essential transcriptional regulator of islet β-cells, but also why cell maturation involves coordinated actions with MafB