The Traitor

The proteolytic activation of protein kinase Cδ (PKCδ) generates a catalytic fragment called PKCδ-CF, which induces cell death. However, the mechanisms underlying PKCδ-CF-mediated cell death are largely unknown. On the basis of an engineering leukemic cell line with inducible expression of PKCδ-CF, here we employ SILAC-based quantitative phosphoproteomics to systematically and dynamically investigate the overall phosphorylation events during cell death triggered by PKCδ-CF expression. Totally, 3000 phosphorylation sites were analyzed. Considering the fact that early responses to PKCδ-CF expression initiate cell death, we sought to identify pathways possibly related directly with PKCδ by further analyzing the data set of phosphorylation events that occur in the initiation stage of cell death. Interacting analysis of this data set indicates that PKCδ-CF triggers complicated networks to initiate cell death, and motif analysis and biochemistry verification reveal that several kinases in the downstream of PKCδ conduct these networks. By analysis of the specific sequence motif of kinase-substrate, we also find 59 candidate substrates of PKCδ from the up-regulated phosphopeptides, of which 12 were randomly selected for <i>in vitro</i> kinase assay and 9 were consequently verified as substrates of PKCδ. To our greatest understanding, this study provides the most systematic analysis of phosphorylation events initiated by the cleaved activated PKCδ, which would vastly extend the profound understanding of PKCδ-directed signal pathways in cell death. The MS data have been deposited to the ProteomeXchange with identifier PXD000225

Surficial geologic map of the Des Moines Lobe of Iowa, Phase 5: Polk County

https://ir.uiowa.edu/igs_ofm/1030/thumbnail.jp

Epigenetic and Post-Translational Mechanisms in Pain: MicroRNA and Phosphorylation

The molecular and neurobiological mechanisms underlying persistent pain are poorly understood. My dissertation research focused on three problems relevant to chronic pain to elucidate epigenetic and post-translational mechanisms. A key issue leading to inadequate pain control is the development of opioid analgesic tolerance. I studied the role of microRNA as an epigenetic regulator of opioid tolerance by targeting the µ opioid receptor (MOR). Employing bioinformatics, a let-7 binding site in MOR 3’UTR was identified, which was experimentally confirmed as a direct target of let-7. Morphine significantly upregulated let-7 expression in human neuroblastoma SH-SY5Y cells and in a mouse model of opioid tolerance. A LNA-let-7 inhibitor decreased brain let-7 levels and partially attenuated opioid antinociceptive tolerance in mice. Mechanistically, let-7 functioned as a mediator translocating and sequestering MOR mRNA to P-bodies, leading to translation repression during opioid tolerance development. Paclitaxel, an effective and frequently used chemotherapeutic agent, produces neuropathic pain as an adverse effect. I found paclitaxel in the low nanomolar range potently triggers intracellular Ca2+ transients, PKA & PKC activation, and substance P release from primary afferent sensory neurons. A specific cellular signaling pathway involving PKA/AKAP150/PKC(ε, βII, & δ) was identified in mediating pain neurotransmitter release and, ultimately, neuropathic pain induced by paclitaxel. Moreover, patients with advanced breast cancer suffer from severe and long-lasting pain, which is extremely difficult to treat. Employing invasive breast cancer MDA-MB-231 cells, I developed a novel cellular model to study nociceptive signaling within the cancer microenvironment. Neuroimmune factors secreted from tumor cells were recognized as contributors to sensory neuron activation. Tumor-induced nociceptor hyperexcitability correlates with the behavioral manifestations of pain seen in vivo, thus validating the model and shedding light on the mechanisms of breast cancer pain. Taken together, these findings provide a better understanding on the specific mechanisms of cancer-related pain and opioid tolerance, which may facilitate the design and development of novel pharmacological treatments for pain relief

H₂ Dissociation on H‑Precovered Ni(100) Surface: Physisorbed State and Coverage Dependence

Hydrogen molecule dissociation on metal surfaces is a prototypical reaction for investigating the gas–surface interaction. To investigate the effect of lattice motion, the embedded cluster model is adopted to construct the quantum Ni(100) lattice, in which 11 Ni atoms are treated quantum mechanically. The direct and steady-state dissociation rates of H2 on H-precovered Ni(100) surface are calculated by quantum instanton method. Both the direct and steady-state dissociation rates on H-precovered Ni(100) are smaller than those on the clean Ni(100). This is because the repulsive interaction between H2 and the preadsorbed H raises the potential energy barrier. Moreover, this repulsive interaction is inversely proportional to the distance between H2 and the preadsorbed H. Owing to the classical relaxation and entropy effect of Ni atoms, the lattice motion promotes H2 dissociation by lowering the free-energy barrier but it hinders H2 recombination by raising the free-energy barrier. There are remarkable kinetic isotope effects for the dissociation process, which is due to the entropy and quantum tunneling effects. However, no kinetic isotope effect is obtained for the recombination process

Table1_Causal associations between autoimmune diseases and sarcopenia-related traits: a bi-directional Mendelian randomization study.XLS

Background:Sarcopenia is common in patients with autoimmune diseases (ADs); however, the causal associations between ADs and sarcopenia remain unclear. Therefore, this study investigated the causal associations using bi-directional Mendelian randomization analysis.Methods:Exposure-related single-nucleotide polymorphisms (SNPs) were extracted from genome-wide association studies (GWASs). GWAS statistics for common ADs [Crohn’s disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriasis (PSO), and multiple sclerosis (MS)] and sarcopenia-related traits [hand grip strength (HGS), appendicular fat-free mass (FFM), and walking pace] were obtained from public datasets. Inverse-variance weighting as the main method was used to evaluate the causal effect.Results:Genetically predicted CD had causal effects on whole-body FFM (β = −0.005, p = 0.001), leg FFM (βleft = −0.006, p = 1.8E-4; βright = −0.007, p = 2.0E-4), and arm FFM (βleft = −0.005, p = 0.005; βright = −0.005, p = 0.001), while RA had causal effects on 8 sarcopenia-related traits, namely, HGS (βleft = −2.06, p = 2.8E-38; βright = −2.311, p = 2E-20), whole-body FFM (β = −0.842, p = 4.7E-10), leg FFM (βleft = −0.666, p = 2.6E-6; βright = −0.073, p = 2.1E-3), arm FFM (βleft = −0.63, p = 4.4E-6; βright = −0.736, p = 4.4E-8), and walking pace (β = −1.019, p = 6.2E-14). In the reverse direction, HGS (odds ratio [OR]left = 10.257, p = 3.6E-5; ORright = 16.445, p = 3.7E-7) had causal effects on CD, while HGS (ORleft = 0.994, p = 0.004; ORright = 0.993, p = 1.4E-4), leg FFM (ORleft = 1.003, p = 0.005; ORright = 1.005, p = 1.9E-4), and walking pace (OR = 0.985, p = 5.7E-5) were causally associated with RA. No evidence showed causal associations of UC, SLE, PSO, or MS with sarcopenia-related traits.Conclusion:Our study demonstrated that the genetic susceptibility to CD and RA was associated with high risk of sarcopenia, and some sarcopenia-related traits had causal effects on CD or RA.</p

Let-7 micro RNAs and opioid tolerance

This chapter will focus on the role of microRNAs (miRs) in regulating the actions of opioid drugs through the opioid receptors. Opioids, such as morphine, are analgesics that are used for treating many forms of acute and chronic pain. However, their chronic use is limited by undesirable effects such as opioid tolerance. The mu opioid receptor (MOR) is the primary receptor responsible for opioids' analgesia and antinociceptive tolerance. The long 3'-untranslated region (3'-UTR) of MOR mRNA is of great interest since this region may contain elements for the post-transcriptional regulation of receptor expression, such as altering the stability of mRNA, influencing translational efficiency, and controlling mRNA transport. MicroRNAs are small non-coding RNA molecules that exert their functions through base-pairing with partially complementary sequences in the 3'-UTR of target mRNAs, resulting in decreased polypeptide formation from those mRNAs. Since the discovery of the first miR, lin-4 in Caenorhabditis elegans, hundreds of miRs have been identified from humans to viruses, which have provided a crucial and pervasive layer of post-transcriptional gene regulation. The nervous system is a rich source of miR expression, with a diversity of miR functions in fundamental neurobiological processes including neuronal development, plasticity, metabolism, and apoptosis. Recently, the let-7 family of miRs is found to be a critical regulator of MOR function in opioid tolerance. Let-7 is the first identified human miR. Its family members are highly conserved across species in sequence and function. In the review, we will present a brief review of the opioid receptors, their regulation, and opioid tolerance as well as an overview of miRs and a perspective how miRs may interact with MOR and serve as a regulator of opioid tolerance

Biomimetic Approach to the Catalytic Enantioselective Synthesis of Flavonoids

Herein is reported the direct asymmetric addition of phenol nucleophiles to benzopyrylium salts as a means to produce enantioenriched flavonoid-like compounds. This enantioselective C–C bond construction was achieved through a chiral anion phase-transfer strategy that mimics the proposed biosynthesis of this structurally diverse set of natural products. The utility of this methodology was demonstrated in enantioselective synthesis of a 2,8-dioxabicyclo[3.3.1]­nonane and a 2,4-diarylbenzopyran

Efficient Mo(VI)-Catalyzed Hydration of Nitrile with Acetaldoxime

<div><p></p><p>A method for the selective hydration of nitrile to amide by employing commercially available acetaldoxime and inexpensive oxometallate such as molybdate, vanadate, and tungstate in environmentally friendly water is described. Under this protocol, nitriles including aromatic nitriles, heterocyclic nitriles, and aliphatic nitriles were converted into the corresponding amides in good to excellent yields.</p> <p>[Supplementary materials are available for this article. Go to the publisher's online edition of <i>Synthetic Communications®</i> for the following free supplemental resource(s): Full experimental and spectral details.]</p> </div

Synthesis of 1‑Amino‑2<i>H</i>‑quinolizin-2-one Scaffolds by Tandem Silver Catalysis

An efficient tandem cycloisomerization–amination reaction catalyzed by silver is described. This rapid and atom-economic reaction delivered 1-amino-2H-quinolizin-2-one scaffolds in high yields under mild conditions. The reaction could be extended to an asymmetric version albeit with moderate enantioselective excess of the products. In addition, the products can be easily reduced into various azabicycles containing 4-pyridones, which are important building blocks in organic synthesis

2017_SI2_PIs_Meeting_ACI-1440811.pdf

We have developed a Bound Preserving Discontinuous Galerkin advection method for modeling the advection diffusion equation that governs the temperature in computational models of convection in the Earth's mantle. This new algorithm prevents overshoot in the temperature at the tips of subducting slabs, which heretofore have lead to very large errors in the viscosity at the slab tip, due to the fact that the viscosity has a steep gradient near the slab tip and the viscosity depends exponentially on the temperature. We are now using this new algorithm to model subducting slabs