On well-posedness for nonlinear Schrödinger equations with power nonlinearity in fractional order Sobolev spaces

AbstractWe study the well-posedness for the nonlinear Schrödinger equation (NLS) i∂tu+12Δu=λ|u|p−1u in R1+n, where p>1,λ∈C, and prove that (NLS) is locally well-posed in Hs if 2<s<4 and s/2<p<1+4/(n−2s)+. To obtain a good lower bound for p, we systematically use Strichartz type estimates in fractional order Besov spaces for the time variable

Peripherally restricted transthyretin-based delivery system for probes and therapeutics avoiding opioid-related side effects

Several investigations into the sites of action of opioid analgesics have utilized peripherally acting mu-opioid receptor antagonists (PAMORAs), which have been incorrectly assumed to possess limited permeability across the blood-brain barrier. Unfortunately, the poor pharmacokinetic properties of current PAMORAs have resulted in misunderstandings of the role of central nervous system and gastrointestinal tract in precipitating side effects such as opioid-induced constipation. Here, we develop a drug delivery approach for restricting the passage of small molecules across the blood-brain barrier. This allows us to develop naloxone- and oxycodone-based conjugates that display superior potency, peripheral selectivity, pharmacokinetics, and efficacy in rats compared to other clinically used PAMORAs. These probes allow us to demonstrate that the mu-opioid receptors in the central nervous system have a fundamental role in precipitating opioid-induced constipation. Therefore, our conjugates have immediate use as pharmacological probes and potential therapeutic agents for treating constipation and other opioid-related side effects

レチノインサン ワ ダイチョウ ジョウヒ サイボウ ニ オイテ NF-k B シグナリング オ カッセイカ スル

All-trans retinoic acid(ATRA)は核内受容体であるretinoic acid receptor(RAR)のリガンドであり,消化管を含む多くの組織で重要な生理作用を有している.最近,臨床的なレチノイン酸の使用と炎症性腸疾患との関連が注目されているが,この問題に関する基礎的な検討は行われていない.今回我々は,大腸癌由来細胞株を用いて,炎症・免疫応答において中心的な役割を果たしているnuclear factor- k B(NF-k B)シグナリングに対するATRA の影響について,レポーター遺伝子解析法,リアルタイム定量的 RT-PCR法にて検討を行った.ATRA および他のレチノイド化合物(9-cis retinoic acid,13-cis retinoic acid,AM580,retinol)は,大腸癌由来細胞株において用量依存性に NF-k B を活性化した.また,ATRA はNF-k B の代表的な標的遺伝子であるIL-8の発現を誘導した.RAR の活性化と比較するとNF-k B 活性化に要するATRA の濃度域は高かった.TNF-a によるNF-k B の活性化,IL-8発現誘導は,ATRA をプレインキュベーションすることにより著明に増大し,相乗的な効果が認められた.ATRA はNF-k B サブユニット(RelA,p50)の発現を増大させ,TNF受容体(TNFR1)の発現レベルも上昇させていた.これらの結果より,レチノイン酸は大腸上皮細胞においてNF-k B シグナリングを活性化し,TNF-a に対する感受性を増大させている可能性が示唆された.All-trans retinoic acid(ATRA)is a ligand for the retinoicacid receptor(RAR), a member of the nuclear receptorsuperfamily, and it is well established that RARs play acritical role in the development and differentiation of variousorgans including gastrointestinal tract. Recently, severalcase reports suggested a possible association between theclinical use of retinoic acid and inflammatory bowel diseases.However, it is not known whether ATRA affects the inflammatoryresponse of colonic epithelial cells. In this study,we examined the effect of ATRA on NF-k B activity andIL-8 expression in colonic epithelial cells in vitro. NF-k Bactivation and RAR activation were assessed by the reportergene assay and IL-8 mRNA expression was assessed bythe real-time quantitative RT-PCR. ATRA and other retinoidcompounds(9-cis retinoic acid, 13-cis retinoic acid,AM580 and retinol)activated NF-k B in a dose- and timedependentmanner in colonic cell lines(HCT116, Caco2,SW480, DLD-1, and LS174T). However, compared to RARactivation, much higher concentrations of ATRA wereneeded to activate NF-k B. ATRA also up-regulated theexpression of IL-8, a target gene of NF-k B. ATRA-inducedNF-k B activation was repressed by a MEK inhibitorand a p38 MAP kinase inhibitor. Preincubation with ATRAsignificantly potentiated TNF-a -induced activation of NFkB and TNF-a -induced expression of IL-8. ATRA wasfound to up-regulate the expression of NF-k B subunits(RelA and p50)and TNF-a receptor 1. These results suggestthat ATRA and other retinoid compounds can activateNF-k B signaling and potentiate the inflammatory responseto TNF-a in colonic epithelial cells

The effects of denervation and stimulation upon synaptic ultrastructure

Quantitative studies of synaptic ultrastructure were made in the upper layers of cat cerebral cortex. Tissues were from intact cortex and from long-term (chronic) undercut cortex with or without electrical stimulation. The synaptic effects of chronic electrical stimulation of denervated cortex are most readily understood as growth and remodeling of synaptic elements. Associated with chronic stimulation were increases in: symmetric membrane contacts; areas of round and flat vesicle containing terminals; dendritic shaft contacts; and synaptic contact lengths. Even without stimulation there were indications of synaptic plasticity in denervated cortex; compared with intact cortex, synapses having symmetric membrane contacts showed an increase in bouton area and an increase in synaptic contacts on dendritic shafts. These data are consistent with the observations of others in which axonal terminal growth occurred after deafferentation. But it appears that chronic electrical stimulation in the adult nervous system promotes significantly more plasticity than occurs without stimulation. In a functional sense stimulation in the present experiments produced effective inhibition which did not occur with denervation alone. Thus the plasticity observed with stimulation had both structural and functional components.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50005/1/901780107_ftp.pd

Molecular mechanisms of developmentally programmed crinophagy in Drosophila

At the onset of metamorphosis, Drosophila salivary gland cells undergo a burst of glue granule secretion to attach the forming pupa to a solid surface. Here, we show that excess granules evading exocytosis are degraded via direct fusion with lysosomes, a secretory granule-specific autophagic process known as crinophagy. We find that the tethering complex HOPS (homotypic fusion and protein sorting); the small GTPases Rab2, Rab7, and its effector, PLEKHM1; and a SNAP receptor complex consisting of Syntaxin 13, Snap29, and Vamp7 are all required for the fusion of secretory granules with lysosomes. Proper glue degradation within lysosomes also requires the Uvrag-containing Vps34 lipid kinase complex and the v-ATPase proton pump, whereas Atg genes involved in macroautophagy are dispensable for crinophagy. Our work establishes the molecular mechanism of developmentally programmed crinophagy in Drosophila and paves the way for analyzing this process in metazoans

Post-Renal Transplant Diabetes Mellitus in Korean Subjects: Superimposition of Transplant-Related Immunosuppressant Factors on Genetic and Type 2 Diabetic Risk Factors

Postrenal transplantation diabetes mellitus (PTDM), or new-onset diabetes after organ transplantation, is an important chronic transplant-associated complication. Similar to type 2 diabetes, decreased insulin secretion and increased insulin resistance are important to the pathophysiologic mechanism behind the development of PTDM. However, β-cell dysfunction rather than insulin resistance seems to be a greater contributing factor in the development of PTDM. Increased age, family history of diabetes, ethnicity, genetic variation, obesity, and hepatitis C are partially accountable for an increased underlying risk of PTDM in renal allograft recipients. In addition, the use of and kinds of immunosuppressive agents are key transplant-associated risk factors. Recently, a number of genetic variants or polymorphisms susceptible to immunosuppressants have been reported to be associated with calcineurin inhibition-induced β-cell dysfunction. The identification of high risk factors of PTDM would help prevent PTDM and improve long-term patient outcomes by allowing for personalized immunosuppressant regimens and by managing cardiovascular risk factors

Oleic, Linoleic and Linolenic Acids Increase ROS Production by Fibroblasts via NADPH Oxidase Activation

The effect of oleic, linoleic and γ-linolenic acids on ROS production by 3T3 Swiss and Rat 1 fibroblasts was investigated. Using lucigenin-amplified chemiluminescence, a dose-dependent increase in extracellular superoxide levels was observed during the treatment of fibroblasts with oleic, linoleic and γ-linolenic acids. ROS production was dependent on the addition of β-NADH or NADPH to the medium. Diphenyleneiodonium inhibited the effect of oleic, linoleic and γ-linolenic acids on fibroblast superoxide release by 79%, 92% and 82%, respectively. Increased levels of p47phox phosphorylation due to fatty acid treatment were detected by Western blotting analyses of fibroblast proteins. Increased p47phox mRNA expression was observed using real-time PCR. The rank order for the fatty acid stimulation of the fibroblast oxidative burst was as follows: γ-linolenic > linoleic > oleic. In conclusion, oleic, linoleic and γ-linolenic acids stimulated ROS production via activation of the NADPH oxidase enzyme complex in fibroblasts

Evaluation of a Rapid Immunochromatographic ODK-0901 Test for Detection of Pneumococcal Antigen in Middle Ear Fluids and Nasopharyngeal Secretions

Since the incidence of penicillin-resistant Streptococcus pneumoniae has been increasing at an astonishing rate throughout the world, the need for accurate and rapid identification of pneumococci has become increasingly important to determine the appropriate antimicrobial treatment. We have evaluated an immunochromatographic test (ODK-0901) that detects pneumococcal antigens using 264 middle ear fluids (MEFs) and 268 nasopharyngeal secretions (NPSs). A sample was defined to contain S. pneumoniae when optochin and bile sensitive alpha hemolytic streptococcal colonies were isolated by culture. The sensitivity and specificity of the ODK-0901 test were 81.4% and 80.5%, respectively, for MEFs from patients with acute otitis media (AOM). In addition, the sensitivity and specificity were 75.2% and 88.8%, respectively, for NPSs from patients with acute rhinosinusitis. The ODK-0901 test may provide a rapid and highly sensitive evaluation of the presence of S. pneumoniae and thus may be a promising method of identifying pneumococci in MEFs and NPSs