Decreased sensitivity to aspirin is associated with altered polyamine metabolism in human prostate cancer cells

Acknowledgments We thank NHS Grampian for financial support of this work.Peer reviewedPublisher PD

How reliable are in vitro IC50 values? Values vary with cytotoxicity assays in human glioblastoma cells

Funding E.D. was funded by an internal research grant from the Polytechnic University of the Marche provided by MIUR (Italian Ministry of University and Research).Peer reviewedPostprin

Viral Coinfections in Kawasaki Disease: A Meta-analysis.

CONTEXT: Viral infections are suspected triggers in Kawasaki disease (KD); however, a specific viral trigger has not been identified. OBJECTIVES: In children with KD, to identify (1) overall prevalence of viral infections; (2) prevalence of specific viruses; and (3) whether viral positivity was associated with coronary artery aneurysms (CAAs) or refractoriness to intravenous immunoglobin (IVIG). DATA SOURCES: We searched Embase, Medline, and Cochrane databases and gray literature. STUDY SELECTION: Eligible studies were conducted between 1999 and 2019, and included children diagnosed with KD who underwent viral testing. DATA EXTRACTION: Two investigators independently reviewed full-text articles to confirm eligibility, extract data, appraise for bias, and assess evidence quality for outcomes using the Grading of Recommendations Assessment Development and Evaluation criteria. We defined viral positivity as number of children with a positive viral test divided by total tested. Secondary outcomes were CAA (z score ≥2.5) and IVIG refractoriness (fever ≥36 hours after IVIG). RESULTS: Of 3189 unique articles identified, 54 full-text articles were reviewed, and 18 observational studies were included. Viral positivity weighted mean prevalence was 30% (95% confidence interval [CI], 14-51) and varied from 5% to 66%, with significant between-study heterogeneity. Individual virus positivity was highest for rhinovirus (19%), adenovirus (10%), and coronavirus (7%). Odds of CAA (odds ratio, 1.08; 95% CI, 0.75-1.56) or IVIG refractoriness (odds ratio, 0.88; 95% CI, 0.58-1.35) did not differ on the basis of viral status. LIMITATIONS: Low or very low evidence quality. CONCLUSIONS: Viral infection was common with KD but without a predominant virus. Viral positivity was not associated with CAAs or IVIG refractoriness

TRIP/NOPO E3 Ubiquitin Ligase Promotes Ubiquitylation of DNA Polymerase η

We previously identified a Drosophila maternal effect-lethal mutant named ‘no poles’ (nopo). Embryos from nopo females undergo mitotic arrest with barrel-shaped, acentrosomal spindles during the rapid cycles of syncytial embryogenesis because of activation of a Chk2-mediated DNA checkpoint. NOPO is the Drosophila homolog of human TNF receptor associated factor (TRAF)-interacting protein (TRIP), which has been implicated in TNF signaling. NOPO and TRIP contain RING domains closely resembling those of known E3 ubiquitin ligases. We herein sought to elucidate the mechanism by which TRIP/NOPO promotes genomic stability by performing a yeast two-hybrid screen to identify potential substrates/interactors. We identified members of the Y-family of DNA polymerases that facilitate replicative bypass of damaged DNA (translesion synthesis) as TRIP interactors. We show that TRIP and NOPO co-immunoprecipitate with human and Drosophila Polη, respectively, from cultured cells. We generated a null mutation in Drosophila Polη (dPolη) and found that dPolη-derived embryos have increased sensitivity to ultraviolet irradiation and exhibit nopo-like mitotic spindle defects. dPolη and nopo interact genetically in that overexpression of dPolηn hypomorphic nopo-derived embryos suppresses nopo phenotypes. We observed enhanced ubiquitylation of Polη by TRIP and NOPO E3 ligases in human cells and Drosophila embryos, respectively, and show that TRIP promotes hPolη localization to nuclear foci in human cells. We present a model in which TRIP/NOPO ubiquitylates Polη to positively regulate its activity in translesion synthesis

The Effect of Glucagon-Like Peptide-2 Receptor Agonists on Colonic Anastomotic Wound Healing

Background. Glucagon-like peptide 2 (GLP-2) is an intestinal specific trophic hormone, with therapeutic potential; the effects on intestinal healing are unknown. We used a rat model of colonic healing, under normoxic, and stress (hypoxic) conditions to examine the effect of GLP-2 on intestinal healing. Methods. Following colonic transection and reanastomosis, animals were randomized to one of six groups (n = 8/group): controls, native GLP-2, long-acting GLP-2 (GLP-2- MIMETIBODY, GLP-2-MMB), animals were housed under normoxic or hypoxic (11%  O2) conditions. Animals were studied five days post-operation for anastomotic strength and wound characteristics. Results. Anastomotic bursting pressure was unchanged by GLP-2 or GLP-2-MMB in normoxic or hypoxic animals; both treatments increased crypt cell proliferation. Wound IL-1β increased with GLP-2; IFNγ with GLP-2 and GLP-2-MMB. IL-10 and TGF-β were decreased; Type I collagen mRNA expression increased in hypoxic animals while Type III collagen was reduced with both GLP-2 agonists. GLP-2 MMB, but not native GLP-2 increased TIMP 1-3 mRNA levels in hypoxia. Conclusions. The effects on CCP, cytokines and wound healing were similar for both GLP-2 agonists under normoxic and hypoxic conditions; anastomotic strength was not affected. This suggests that GLP-2 (or agonists) could be safely used peri-operatively; direct studies will be required

Can screening and brief intervention lead to population-level reductions in alcohol-related harm?

A distinction is made between the clinical and public health justifications for screening and brief intervention (SBI) against hazardous and harmful alcohol consumption. Early claims for a public health benefit of SBI derived from research on general medical practitioners' (GPs') advice on smoking cessation, but these claims have not been realized, mainly because GPs have not incorporated SBI into their routine practice. A recent modeling exercise estimated that, if all GPs in England screened every patient at their next consultation, 96% of the general population would be screened over 10 years, with 70-79% of excessive drinkers receiving brief interventions (BI); assuming a 10% success rate, this would probably amount to a population-level effect of SBI. Thus, a public health benefit for SBI presupposes widespread screening; but recent government policy in England favors targeted versus universal screening, and in Scotland screening is based on new registrations and clinical presentation. A recent proposal for a national screening program was rejected by the UK National Health Service's National Screening Committee because 1) there was no good evidence that SBI led to reductions in mortality or morbidity, and 2) a safe, simple, precise, and validated screening test was not available. Even in countries like Sweden and Finland, where expensive national programs to disseminate SBI have been implemented, only a minority of the population has been asked about drinking during health-care visits, and a minority of excessive drinkers has been advised to cut down. Although there has been research on the relationship between treatment for alcohol problems and population-level effects, there has been no such research for SBI, nor have there been experimental investigations of its relationship with population-level measures of alcohol-related harm. These are strongly recommended. In this article, conditions that would allow a population-level effect of SBI to occur are reviewed, including their political acceptability. It is tentatively concluded that widespread dissemination of SBI, without the implementation of alcohol control measures, might have indirect influences on levels of consumption and harm but would be unlikely on its own to result in public health benefits. However, if and when alcohol control measures were introduced, SBI would still have an important role in the battle against alcohol-related harm

National identity in fragile states: insights from tertiary students in Melanesia and Timor-Leste

The challenges of nation building in Melanesia and Timor-Leste have often been neglected in the regional focus on state-building challenges. High levels of ethno-linguistic diversity, combined with an array of regional, historical and cultural divisions, continue to present obstacles to the creation of a cohesive sense of national political community leading these nations to be labelled ‘fragile’. This paper presents the findings of a comparative study on the attitudes of tertiary students in Melanesia and Timor-Leste to national identity and nation building. A strong pan-Melanesian pattern of group identification was identified, common to Papua New Guinea, Solomon Islands and Vanuatu. The ongoing importance of traditional authority and custom in informing conceptions of political community and identity was evident in all four case study sites, but was in each case matched by indicators of respect for modern state authority. The survey also reveals some significant gender differences in key attitudes towards national identity, including the role of traditional authorities. Most importantly, the study reveals high degrees of national pride, and faith in democratic principles and citizenship; but conversely, low levels of pride in contemporary democratic performance and inter-group tolerance

The Nihoku Ecosystem Restoration Project: A case study in predator exclusion fencing, ecosystem restoration, and seabird translocation

Reports were scanned in black and white at a resolution of 600 dots per inch and were converted to text using Adobe Paper Capture Plug-in.Newell’s Shearwater (Puffinus auricularis newelli; NESH) and Hawaiian Petrel (Pterodroma sandwichensis; HAPE) are both listed under the Endangered Species Act of 1973 and are declining due to collisions with power lines and structures, light attraction, predation by feral cats, pigs, rats, and introduced Barn Owls, habitat degradation by feral ungulates (pigs, goats) and invasive exotic plants. Protection of NESH and HAPE on their nesting grounds and reduction of collision and lighting hazards are high priority recovery actions for these species. Given the challenges in protecting nesting birds in their rugged montane habitats, it has long been desirable to also create breeding colonies of both species in more accessible locations that offer a higher level of protection. Translocation of birds to breeding sites within predator exclusion fences was ranked as priority 1 in the interagency 5-year Action Plan for Newell’s Shearwater and Hawaiian Petrel. In 2012, funding became available through several programs to undertake this action at Kilauea Point National Wildlife Refuge (KPNWR), which is home to one of the largest seabird colonies in the main Hawaiian Islands. The project was named the “Nihoku Ecosystem Restoration Project” after the area on the Refuge where the placement of the future colony was planned. The Nihoku Ecosystem Restoration Project is a result of a large partnership between multiple government agencies and non-profit groups who have come together to help preserve the native species of Hawaii. There were four stages to this multi-faceted project: permitting and biological monitoring, fence construction, restoration and predator eradication, followed by translocation of the birds to the newly secured habitat. The translocation component is expected to last five years and involve up to 90 individuals each of NESH and HAPE. Prior to fence construction, baseline monitoring data were collected in order to provide a record of initial site conditions and species diversity. Surveys were conducted quarterly from 2012-2014, investigating diversity and richness of plant, invertebrate, mammalian, and avian species. A 650 m (2130 ft) long predator proof fence was completed at Nihoku in September 2014, enclosing 2.5 ha (6.2 ac), and all mammalian predators were eradicated by March 2015. From 2015-2017, approximately 40% of the fenced area (~1 ha) was cleared of non-native vegetation using heavy machinery and herbicide application. A water catchment and irrigation system was installed, and over 18,000 native plants representing 37 native species were outplanted in the restoration area. The plant species selected are low-in-stature, making burrow excavation easier for seabirds while simultaneously providing forage for Nene (Branta sandvicensis). Habitat restoration was done in phases (10-15% of the project per year) and will be continued until the majority of the area has been restored. In addition to habitat restoration, 50 artificial burrows were installed in the restoration to facilitate translocation activities. From 2012-2017 potential source colonies of NESH and HAPE were located by the Kauai Endangered Seabird Recovery Project (KESRP) with visual, auditory, and ground searching methods at locations around Kauai. The sites that were selected as source colonies for both species were Upper Limahuli Preserve (owned by the National Tropical Botanical Garden; NTBG) and several sites within the Hono o Na Pali Natural Area Reserve system. These sites had high call rates, high burrow densities to provide an adequate source of chicks for the translocation, and had active predator control operations in place to offset any potential impacts of the monitoring. Translocation protocols were developed based on previous methods developed in New Zealand; on the ground training was done by the translocation team by visiting active projects in New Zealand. In year one, 10 HAPE and eight NESH were translocated, and the goal is to translocate up to 20 in subsequent years for a cohort size of 90 birds of each species over a five year period. Post-translocation monitoring has been initiated to gauge the level of success, and social attraction has been implemented in an attempt to attract adults to the area. It is anticipated that the chicks raised during this project will return to breed at Nihoku when they are 65-6 years old; for the first cohort released in 2015 this would be starting in 2020. Once this occurs, Nihoku will be the first predator-free breeding area of both species in Hawaii.This project and manuscript are part of a large collaboration that spans beyond the agencies mentioned. Many individuals were consulted for advice and input along the way. For botanical and invertebrate advice, we thank: David Burney, Lida Burney, Natalia Tangalin, Emory Griffin‐Noyes, Kawika Winter, Kim Starr, Forest Starr, Sheldon Plentovich and Keren Gunderson. For assistance with translocation training and predator exclusion fence technical advice we thank Helen Gummer, John McLennan, Lindsay Wilson, and Darren Peters. For reviewing documents related to this project, and for feedback on techniques we thank the seabird hui, particularly Fern Duvall, Jay Penniman, Megan Laut, Darcy Hu and Cathleen Bailey. For their on the ground assistance at KPNWR, we thank: Shannon Smith, Chadd Smith, Warren Madeira, Rob Petersen, Jennifer Waipa, Padraic Gallagher, Carolyn Rushforth, Kristina Macaulay, Jimmy Macaulay, and Jillian Cosgrove. We would also like to thank Chris Mottley, Kyle Pias and the entire predator control team in Hono o Na Pali NAR and Kawika Winter, Chiemi Nagle, Merlin Edmonds and the entire predator control team in Upper Limahuli Preserve. We would also like to thank the Kaua‘i Island Utility Co‐operative (KIUC) for the funding that they provide – through a Habitat Conservation Plan – to provide predator control and seabird monitoring at several of the sites used for translocation. Lastly, we would like to thank all of the endangered seabird technicians within the Kauaʻi Endangered Seabird Recovery Project for all of their hard work in montane colonies. Mahalo

Role of Polyamine-Induced Dimerization of Antizyme in Its Cellular Functions

Funding: This work was supported by grants from the Russian Science Foundation (grant # 17-74-20049—synthesis of C-methylated Spd analogues, ITC studies of dimerization of OAZ1, and frameshifting experiments), the Russian Science Foundation (grant # 19-74-10086—isolation of OAZ1, electrophoresis studies of dimerization of OAZ1), and the Academy of Finland (grants # 292574 and # 315487). Acknowledgments: The authors thank A. Karppinen, A. Korhonen, T. Reponen, M. Salminkoski, and S.D. Negrya for their skillful technical assistance.Peer reviewedPublisher PD