Unidirectional Cross-Activation of GRPR by MOR1D Uncouples Itch and Analgesia Induced by Opioids

SummarySpinal opioid-induced itch, a prevalent side effect of pain management, has been proposed to result from pain inhibition. We now report that the μ-opioid receptor (MOR) isoform MOR1D is essential for morphine-induced scratching (MIS), whereas the isoform MOR1 is required only for morphine-induced analgesia (MIA). MOR1D heterodimerizes with gastrin-releasing peptide receptor (GRPR) in the spinal cord, relaying itch information. We show that morphine triggers internalization of both GRPR and MOR1D, whereas GRP specifically triggers GRPR internalization and morphine-independent scratching. Providing potential insight into opioid-induced itch prevention, we demonstrate that molecular and pharmacologic inhibition of PLCβ3 and IP3R3, downstream effectors of GRPR, specifically block MIS but not MIA. In addition, blocking MOR1D-GRPR association attenuates MIS but not MIA. Together, these data suggest that opioid-induced itch is an active process concomitant with but independent of opioid analgesia, occurring via the unidirectional cross-activation of GRPR signaling by MOR1D heterodimerization

Report of the third Asian Prostate Cancer study meeting.

The Asian Prostate Cancer (A-CaP) study is an Asia-wide initiative that was launched in December 2015 in Tokyo, Japan, with the objective of surveying information about patients who have received a histopathological diagnosis of prostate cancer (PCa) and are undergoing treatment and clarifying distribution of staging, the actual status of treatment choices, and treatment outcomes. The study aims to clarify the clinical situation for PCa in Asia and use the outcomes for the purposes of international comparison. Following the first meeting in Tokyo in December 2015, the second A-CaP meeting was held in Seoul, Korea, in September 2016. This, the third A-CaP meeting, was held on October 14, 2017, in Chiang Mai, Thailand, with the participation of members and collaborators from 12 countries and regions. In the meeting, participating countries and regions presented the current status of data collection, and the A-CaP office presented a preliminary analysis of the registered cases received from each country and region. Participants discussed ongoing challenges relating to data input and collection, institutional, and legislative issues that may present barriers to data sharing, and the outlook for further patient registrations through to the end of the registration period in December 2018. In addition to A-CaP-specific discussions, a series of special lectures were also delivered on the situation for health insurance in the United States, the correlation between insurance coverage and PCa outcomes, and the outlook for robotic surgery in the Asia-Pacific region. Members also confirmed the principles of authorship in collaborative studies, with a view to publishing original articles based on A-CaP data in the future

Austrian Syndrome with a Delayed Onset of Heart Failure

A 59-year-old man treated with pneumococcal meningitis 4 months ago was hospitalized for acute heart failure and performed aortic valve replacement by rupture of aortic valve. The frequent association of pneumococcal meningitis and endocarditis is known as Austrian syndrome. Though Austrian syndrome is a clinically rare disease, the evolution of pneumococcal endocarditis is very aggressive and associated with high mortality, and early recognition for evidence of endocardial lesion in patients with pneumococcal meningitis is important to reduce the complications and mortality rate

Revisiting the Tianwen Yellow Pumice (TYP) Eruption of Changbaishan Volcano: Tephra Correlation, Eruption Timing and Its Climatostratigraphical Context

Changbaishan volcano (China/North Korea) is one of the most active and hazardous volcanic centers in Northeast Asia. Despite decades of intensive research, the eruption history of this stratovolcano remains poorly constrained. One of the major puzzles is the timing of the eruption that produced the Tianwen Yellow Pumice (TYP) deposit at the caldera rim. Here we identify a new cryptotephra layer in sediment core 13PT-P4 from the East Sea. Grain-specific major, minor, and trace element analyses of glass shards allow a clear correlation of this distal tephra to the proximal TYP deposit of Changbaishan. Age-depth modeling using radiocarbon (14C) dates of sediment bulk organic fractions and other tephrochronological markers from the sediment sequence constraints the age of the cryptotephra and thus the TYP eruption to 29,948–29,625 cal yr BP (95.4% confidence interval). Our findings lead to a revision of the history of Changbaishan explosive activity, and show that the volcano has been particularly active during ca. 51–24 ka BP in the last 100 ka. Using high resolution palaeo-proxy records, we find the TYP tephra almost coeval with regional to hemispheric-scale climatic changes known as Heinrich Event 3 (H3). With its precise age determination and wide geographic dispersion, the tephra offers a key isochron for dating records of past climatic changes and addressing the phasing relationships in environmental response to H3 across East Asia

Measuring Complex Refractive Indices of a Nanometer-Thick Superconducting Film Using Terahertz Time-Domain Spectroscopy with a 10 Femtoseconds Pulse Laser

Superconducting thin films are widely applied in various fields, including switching devices, because of their phase transition behaviors in relation to temperature changes. Therefore, it is important to quantitatively determine the optical constant of a superconducting material in the thin-film state. We performed a terahertz time-domain spectroscopy, based on a 10 femtoseconds pulse laser, to measure the optical constant of a superconducting GdBa2Cu3O7-x (GdBCO) thin film in the terahertz region. We then estimated the terahertz refractive indices of the 70 nm-thick GdBCO film using a numerical extraction process, even though the film thickness was approximately 1/10,000 times smaller than the terahertz wavelength range of 200 mu m to 1 mm. The resulting refractive indices of the GdBCO thin film were consistent with the theoretical results using the two-fluid model. Our work will help to further understand the terahertz optical properties of superconducting thin films with thicknesses under 100 nm, as well as provide a standard platform for characterizing the optical properties of thin films without the need of Kramers-Kronig transformation at the terahertz frequencies

Small molecule inhibition of CBP/catenin interactions eliminates drug resistant clones in acute lymphoblastic leukemia

Drug resistance in acute lymphoblastic leukemia (ALL) remains a major problem warranting new treatment strategies. Wnt/catenin signaling is critical for the self-renewal of normal hematopoietic progenitor cells. Deregulated Wnt signaling is evident in chronic and acute myeloid leukemia, however little is known about ALL. Differential interaction of catenin with either the Kat3 coactivator CREBBP (CBP) or the highly homologous EP300 (p300) is critical to determine divergent cellular responses and provides a rationale for the regulation of both proliferation and differentiation by the Wnt signaling pathway. Usage of the coactivator CBP by catenin leads to transcriptional activation of cassettes of genes that are involved in maintenance of progenitor cell self-renewal. However, the use of the coactivator p300, leads to activation of genes involved in the initiation of differentiation. ICG-001 is a novel small molecule modulator of Wnt/catenin signaling, which specifically binds to the N-terminus of CBP and not p300, within amino acids 1–110, thereby disrupting the interaction between CBP and catenin. Here, we report that selective disruption of the CBP/β- and γ-catenin interactions using ICG-001 leads to differentiation of pre-B ALL cells and loss of self-renewal capacity. Survivin, an inhibitor-of-apoptosis protein, was also downregulated in primary ALL after treatment with ICG-001. Using ChIP assay, we demonstrate occupancy by CBP of the survivin promoter, which is decreased by ICG-001 in primary ALL. CBP-mutations have been recently identified in a significant percentage of ALL patients, however, almost all of the identified mutations reported occur C-terminal to the binding site for ICG-001. Importantly, ICG-001, regardless of CBP mutational status and chromosomal aberration, leads to eradication of drug-resistant primary leukemia in combination with conventional therapy in vitro and significantly prolongs the survival of NOD/SCID mice engrafted with primary ALL. Therefore, specifically inhibiting CBP/catenin transcription represents a novel approach to overcome relapse in ALL

Tlr2 and the nlrp3 inflammasome mediate il-1β production in prevotella nigrescens-infected dendritic cells

Prevotella nigrescens is an oral pathogen that is frequently observed in the subgingival plaque of periodontitis patients. Interleukin-1β (IL-1β) is known to be involved in the immunopathology of periodontal diseases and has been implicated in the destruction of bone. In this study, we investigated the mechanism of IL-1β production by P. nigrescens in murine bone marrow-derived dendritic cells (BMDCs). Our results showed that a host receptor, Toll-like receptor 2 (TLR2), but not TLR4 is required for pro-IL-1β induction and nucleotide-binding oligomerization domain like receptor pyrin domain containing 3 (NLRP3) priming in BMDCs in response to P. nigrescens and activation of the NLRP3 inflammasome is necessary for processing of pro-IL-1β into mature IL-1β. In addition, an inhibitor assay revealed that production of reactive oxygen species, P2X7R activity, and release of cathepsin B are involved in IL-1β production in BMDCs in response to P. nigrescens. © The author(s).1

Algae decorated TiO2/Ag hybrid nanofiber membrane with enhanced photocatalytic activity for Cr(VI) removal under visible light

Algae as an abundant natural biomass, more attention has been paid to explore its potential application in environmental pollutants treatment. This work prepared the algae-TiO2/Ag bionano hybrid material by loading algae cells on the ultrafine TiO2/Ag chitosan hybrid nanofiber mat. For the first time, the synergistic photocatalytic effect of fresh algae and TiO2/Ag nanomaterial was investigated by removal of Cr(VI). The addition of algae significantly improved the photo-removal of Cr(VI) in the system with TiO2/Ag hybrid nanomaterial under visible light irradiation. Meanwhile, the photocatalytic mechanism was studied. The photogenerated reactive oxygen species were quantified and the addition of algae apparently decreased the yields of •OH to 31.0 µM, while improved the yields of 1O2 and O2•− in the reaction system with TiO2/Ag hybrid nanofiber mats. The change of superoxide dismutase activity and malondialdehyde content in algae indicated that TiO2/Ag could impose oxidative stress and cause lipid peroxidation in algae cells. During the course of irradiation, algae released substances could act as scavenger for holes, thus inhibited the recombination of hole/electron and enhanced the photocatalytic reduction of Cr(VI) by electrons on TiO2 surface. Algae was simultaneously photodegraded in the system and the resulting O2•−, organic free radicals could promote the reduction of Cr(VI). This functional hybrid nanofiber mat was easily recovered and maintained a great photocatalytic activity on the five successive cycles. This algae-photocatalyst hybrid material has promising applications potential in heavy metal removal and organic pollutants treatment