Expression of the pair-rule gene homologs runt, Pax3/7, even-skipped-1 and even-skipped-2 during larval and juvenile development of the polychaete annelid Capitella teleta does not support a role in segmentation

<p>Abstract</p> <p>Background</p> <p>Annelids and arthropods each possess a segmented body. Whether this similarity represents an evolutionary convergence or inheritance from a common segmented ancestor is the subject of ongoing investigation.</p> <p>Methods</p> <p>To investigate whether annelids and arthropods share molecular components that control segmentation, we isolated orthologs of the <it>Drosophila melanogaster </it>pair-rule genes, <it>runt</it>, <it>paired </it>(<it>Pax3/7</it>) and <it>eve</it>, from the polychaete annelid <it>Capitella teleta </it>and used whole mount <it>in situ </it>hybridization to characterize their expression patterns.</p> <p>Results</p> <p>When segments first appear, expression of the single <it>C. teleta runt </it>ortholog is only detected in the brain. Later, <it>Ct-runt </it>is expressed in the ventral nerve cord, foregut and hindgut. Analysis of <it>Pax </it>genes in the <it>C. teleta </it>genome reveals the presence of a single <it>Pax3/7 </it>ortholog. <it>Ct-Pax3/7 </it>is initially detected in the mid-body prior to segmentation, but is restricted to two longitudinal bands in the ventral ectoderm. Each of the two <it>C. teleta eve </it>orthologs has a unique and complex expression pattern, although there is partial overlap in several tissues. Prior to and during segment formation, <it>Ct-eve1 </it>and <it>Ct-eve2 </it>are both expressed in the bilaterial pair of mesoteloblasts, while <it>Ct-eve1 </it>is expressed in the descendant mesodermal band cells. At later stages, <it>Ct-eve2 </it>is expressed in the central and peripheral nervous system, and in mesoderm along the dorsal midline. In late stage larvae and adults, <it>Ct-eve1 </it>and <it>Ct-eve2 </it>are expressed in the posterior growth zone.</p> <p>Conclusions</p> <p><it>C. teleta eve, Pax3/7 </it>and <it>runt </it>homologs all have distinct expression patterns and share expression domains with homologs from other bilaterians. None of the pair-rule orthologs examined in <it>C. teleta </it>exhibit segmental or pair-rule stripes of expression in the ectoderm or mesoderm, consistent with an independent origin of segmentation between annelids and arthropods.</p

A Zebrafish Chemical Suppressor Screening Identifies Small Molecule Inhibitors of the Wnt/β-catenin Pathway

SummaryGenetic screening for suppressor mutants has been successfully used to identify important signaling regulators. Using an analogy to genetic suppressor screening, we developed a chemical suppressor screening method to identify inhibitors of the Wnt/β-catenin signaling pathway. We used zebrafish embryos in which chemically induced β-catenin accumulation led to an “eyeless” phenotype and conducted a pilot screening for compounds that restored eye development. This approach allowed us to identify geranylgeranyltransferase inhibitor 286 (GGTI-286), a geranylgeranyltransferase (GGTase) inhibitor. Our follow-up studies showed that GGTI-286 reduces nuclear localization of β-catenin and transcription dependent on β-catenin/T cell factor in mammalian cells. In addition to pharmacological inhibition, GGTase gene knockdown also attenuates the nuclear function of β-catenin. Overall, we validate our chemical suppressor screening as a method for identifying Wnt/β-catenin pathway inhibitors and implicate GGTase as a potential therapeutic target for Wnt-activated cancers

Safety, tolerability, pharmacokinetics, and pharmacodynamics of the afucosylated, humanized anti-EPHA2 antibody DS-8895a: a first-in-human phase I dose escalation and dose expansion study in patients with advanced solid tumors

BACKGROUND:Erythropoietin-producing hepatocellular receptor A2 (EPHA2) is overexpressed on the cell surface in many cancers and predicts poor prognosis. DS-8895a is a humanized anti-EPHA2 IgG1 monoclonal antibody afucosylated to enhance antibody-dependent cellular cytotoxicity activity. We conducted a two-step, phase I, multicenter, open-label study to determine the safety, tolerability, and pharmacokinetics of DS-8895a in patients with advanced solid tumors.METHODS:Step 1 was a dose escalation cohort in advanced solid tumor patients (six dose levels, 0.1-20 mg/kg) to determine Step 2 dosing. Step 2 was a dose expansion cohort in EPHA2-positive esophageal and gastric cancer patients. DS-8895a was intravenously administered every 2 weeks for the duration of the study, with a 28-day period to assess dose-limiting toxicity (DLT). Safety, pharmacokinetics, tumor response, and potential biomarkers were evaluated.RESULTS:Thirty-seven patients (Step 1: 22, Step 2: 15 [9: gastric cancer, 6: esophageal cancer]) were enrolled. Although one DLT (Grade 4 platelet count decreased) was observed in Step 1 (dose level 6, 20 mg/kg), the maximum tolerated dose was not reached; the highest dose (20 mg/kg) was used in Step 2. Of the 37 patients, 24 (64.9%) experienced drug-related adverse events (AEs) including three (8.1%) with Grade ≥ 3 AEs. Infusion-related reactions occurred in 19 patients (51.4%) but were manageable. All patients discontinued the study (evident disease progression, 33; AEs, 4). Maximum and trough serum DS-8895a concentrations increased dose-dependently. One gastric cancer patient achieved partial response and 13 patients achieved stable disease. Serum inflammatory cytokines transiently increased at completion of and 4 h after the start of DS-8895a administration. The proportion of CD16-positive natural killer (NK) cells (CD3-CD56+CD16+) decreased 4 h after the start of DS-8895a administration, and the ratio of CD3-CD56+CD137+ to CD3-CD56+CD16+ cells increased on day 3.CONCLUSIONS:Twenty mg/kg DS-8895a infused intravenously every 2 weeks was generally safe and well tolerated in patients (n = 21) with advanced solid tumors. The exposure of DS-8895a seemed to increase dose-dependently and induce activated NK cells

Suzaku wide-band observations of SN 1006

We report on the wide band spectra of SN 1006 as observed by Suzaku. Thermal and nonthermal emission are successfully resolved thanks to the excellent spectral response of Suzaku's X-ray CCD XIS. The nonthermal emission cannot be reproduced by a simple power-law model but needs a roll-off at 5.7$\times 10^{16}$ Hz = 0.23 keV. The roll-off frequency is significantly higher in the northeastern rim than in the southwestern rim. We also have placed the most stringent upper limit of the flux above 10 keV using the Hard X-ray Detector.Comment: 16 pages, 8 figures, PASJ, in pres

Phosphoinositide 3-kinase signaling pathway mediated by p110α regulates invadopodia formation

Inhibition of p110α or of the downstream PI3K signaling pathway components PDK1 and Akt, as well as phosphoinositide sequestration, blocks invadopodia formation in breast cancer cells

深穴金型におけるPVDコーティング膜厚の均一化: 対向デュアルビーム・アーク蒸着法の開発

金沢大学理工研究域機械工学系対向デュアルビーム・アーク蒸着装置によって金型の深穴内面へTiN膜を生成し，膜厚分布を検証している．従来のPVDコーティングでは膜生成が不可能であったL（長さ）/D（内径）＝5の深穴において，本製法では全面にTiN膜を生成することができる．また，深穴の奥部でも、入口部と同等の組成および塑性変形硬さが得られる．深穴を有する粉末成形用金型へ適用した結果、従来比10倍以上の寿命向上を実現している．出版者照会後に全文公

Intracrine activity involving NAD-dependent circadian steroidogenic activity governs age-associated meibomian gland dysfunction

新たなイントラクライン機構を用いた加齢性眼疾患治療へ --眼局所のホルモンの加齢変化とサーカディアンリズムが鍵--. 京都大学プレスリリース. 2022-02-14.Canonically, hormones are produced in the endocrine organs and delivered to target tissues. However, for steroids, the concept of tissue intracrinology, whereby hormones are produced in the tissues where they exert their effect without release into circulation, has been proposed, but its role in physiology/disease remains unclear. The meibomian glands in the eyelids produce oil to prevent tear evaporation, which reduces with aging. Here, we demonstrate that (re)activation of local intracrine activity through nicotinamide adenine dinucleotide (NAD+)-dependent circadian 3β-hydroxyl-steroid dehydrogenase (3β-HSD) activity ameliorates age-associated meibomian gland dysfunction and accompanying evaporative dry eye disease. Genetic ablation of 3β-HSD nullified local steroidogenesis and led to atrophy of the meibomian gland. Conversely, reactivation of 3β-HSD activity by boosting its coenzyme NAD+ availability improved glandular cell proliferation and alleviated the dry eye disease phenotype. Both women and men express 3β-HSD in the meibomian gland. Enhancing local steroidogenesis may help combat age-associated meibomian gland dysfunction

K0(K0ˉ)K^0(\bar{K^0}) Production in Two-Photon Processes at TRISTAN

We have carried out an inclusive measurement of $K^0(\bar{K^0})$ production in two-photon processes at TRISTAN. The mean $\sqrt{s}$ was 58 GeV and the integrated luminosity was 199 pb$^{-1}$. High-statistics $K_s$ samples were obtained under such conditions as no-, anti-electron, and remnant-jet tags. The remnant-jet tag, in particular, allowed us, for the first time, to measure the cross sections separately for the resolved-photon and direct processes.Comment: 20 pages, Latex format, 4 figures and KEK-mark included. Table 1 revised. To be published in Phys. Lett.