Emerging targeted strategies for the treatment of autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a widespread genetic disease that leads to renal failure in the majority of patients. The very first pharmacological treatment, tolvaptan, received Food and Drug Administration approval in 2018 after previous approval in Europe and other countries. However, tolvaptan is moderately effective and may negatively impact a patient's quality of life due to potentially significant side effects. Additional and improved therapies are still urgently needed, and several clinical trials are underway, which are discussed in the companion paper Müller and Benzing (Management of autosomal-dominant polycystic kidney disease-state-of-the-art) Clin Kidney J 2018; 11: i2-i13. Here, we discuss new therapeutic avenues that are currently being investigated at the preclinical stage. We focus on mammalian target of rapamycin and dual kinase inhibitors, compounds that target inflammation and histone deacetylases, RNA-targeted therapeutic strategies, glucosylceramide synthase inhibitors, compounds that affect the metabolism of renal cysts and dietary restriction. We discuss tissue targeting to renal cysts of small molecules via the folate receptor, and of monoclonal antibodies via the polymeric immunoglobulin receptor. A general problem with potential pharmacological approaches is that the many molecular targets that have been implicated in ADPKD are all widely expressed and carry out important functions in many organs and tissues. Because ADPKD is a slowly progressing, chronic disease, it is likely that any therapy will have to continue over years and decades. Therefore, systemically distributed drugs are likely to lead to potentially prohibitive extra-renal side effects during extended treatment. Tissue targeting to renal cysts of such drugs is one potential way around this problem. The use of dietary, instead of pharmacological, interventions is another

Children\u27s implicit recall of junk food, alcohol and gambling sponsorship in Australian sport

BACKGROUND: In Australia, sport is saturated by the promotion of junk food, alcohol and gambling products. This is particularly evident on player jerseys. The effect of this advertising on children, who are exposed to these messages while watching sport, has not been thoroughly investigated. The aim of this research study was to investigate: (1) the extent to which children implicitly recalled shirt sponsors with the correct sporting team; (2) whether children associated some types of sponsors with certain sporting codes more than others; and (3) whether age of the children influenced the correct recall of sponsoring brands and teams. METHOD: This experimental study conducted in New South Wales, Australia used projective techniques to measure the implicit recall of team sponsorship relationships of 85 children aged 5-12 years. Participants were asked to arrange two sets of magnets - one which contained sporting teams and one which contained brand logos - in the manner deemed most appropriate by them. Children were not given any prompts relating to sporting sponsorship relationships. RESULTS: Three quarters (77 %) of the children were able to identify at least one correct shirt sponsor. Children associated alcohol and gambling brands more highly with the more popular sporting code, the National Rugby League compared to the Australian Football League sporting code. Results showed that age had an effect on number of shirt sponsors correctly recalled with 9-12 year olds being significantly more likely than 5-8 year olds to correctly identify team sponsors. CONCLUSIONS: Given children\u27s ability to implicitly recall shirt sponsors in a sporting context, Australian sporting codes should examine their current sponsorship relationships to reduce the number of unhealthy commodity shirt sponsors. While there is some regulation that protects children from the marketing of unhealthy commodity products, these findings suggest that children are still exposed to and recall these sponsorship relationships. Results suggest that the promotion of unhealthy commodity products during sporting matches is contributing to increased awareness amongst children of unhealthy commodity brands. Further investigation is required to examine the extent and impact of marketing initiatives during televised sporting matches on children

Role of 5-HT receptor mechanisms in sub-chronic PCP-induced reversal learning deficits in the rat

YesRationale: 5-HT receptor mechanisms have been suggested to mediate improvements in cognition in schizophrenia. Aim: To investigate the involvement of 5-HT receptor mechanisms in sub-chronic PCP-induced reversal learning deficits in female rats, a task of relevance to schizophrenia. Methods: Adult female hooded-Lister rats were trained to perform an operant reversal learning task and then received sub-chronic PCP (2 mg/kg) or vehicle i.p. twice daily for seven days, followed by 7-days washout. Rats then received an acute dose of the 5-HT7 receptor antagonist SB-269970A (1.0, 3.0, 10.0 mg/kg; i.p.) or vehicle. In experiment 2, PCP-treated rats received the selective 5-HT2C receptor antagonist, SB-243213A acutely (1.0, 3.0, 10.0 mg/kg; i.p.) or vehicle. In experiment 3, PCP-treated rats received the 5-HT1A receptor partial agonist, buspirone (0.15625, 0.3125, 0.625 mg/kg, i.p.) in combination with the selective 5-HT1A receptor antagonist WAY-100635 (0.3, 1.0 mg/kg). Results: In all experiments sub-chronic PCP significantly impaired reversal phase performance (P<0.01-0.001), with no effect in the initial phase. SB-269970A at 3.0 and 10.0 mg/kg significantly improved the PCP-induced deficit (P<0.05). SB-243213A also significantly attenuated the deficit at 10 mg/kg (P<0.05). In experiment 3, buspirone attenuated the deficit with significant effects at 0.3125 mg/kg and 0.625 mg/kg (P<0.05). WAY-100635 at 0.3 and 1.0 mg/kg produced a partial attenuation of buspirone’s effect as buspirone (0.3125 mg/kg) in the presence of WAY-100635 did not significantly reverse the PCP-induced deficit. Conclusions: These studies implicate the role of 5-HT7, 5-HT2C and 5-HT1A receptors in the improvement of cognitive dysfunction of relevance to schizophrenia

The Epstein-Barr Virus Episome Maneuvers between Nuclear Chromatin Compartments during Reactivation.

The human genome is structurally organized in three-dimensional space to facilitate functional partitioning of transcription. We learned that the latent episome of the human Epstein-Barr virus (EBV) preferentially associates with gene-poor chromosomes and avoids gene-rich chromosomes. Kaposi's sarcoma-associated herpesvirus behaves similarly, but human papillomavirus does not. Contacts on the EBV side localize to OriP, the latent origin of replication. This genetic element and the EBNA1 protein that binds there are sufficient to reconstitute chromosome association preferences of the entire episome. Contacts on the human side localize to gene-poor and AT-rich regions of chromatin distant from transcription start sites. Upon reactivation from latency, however, the episome moves away from repressive heterochromatin and toward active euchromatin. Our work adds three-dimensional relocalization to the molecular events that occur during reactivation. Involvement of myriad interchromosomal associations also suggests a role for this type of long-range association in gene regulation.IMPORTANCE The human genome is structurally organized in three-dimensional space, and this structure functionally affects transcriptional activity. We set out to investigate whether a double-stranded DNA virus, Epstein-Barr virus (EBV), uses mechanisms similar to those of the human genome to regulate transcription. We found that the EBV genome associates with repressive compartments of the nucleus during latency and with active compartments during reactivation. This study advances our knowledge of the EBV life cycle, adding three-dimensional relocalization as a novel component to the molecular events that occur during reactivation. Furthermore, the data add to our understanding of nuclear compartments, showing that disperse interchromosomal interactions may be important for regulating transcription

PhylOTU: a high-throughput procedure quantifies microbial community diversity and resolves novel taxa from metagenomic data.

Microbial diversity is typically characterized by clustering ribosomal RNA (SSU-rRNA) sequences into operational taxonomic units (OTUs). Targeted sequencing of environmental SSU-rRNA markers via PCR may fail to detect OTUs due to biases in priming and amplification. Analysis of shotgun sequenced environmental DNA, known as metagenomics, avoids amplification bias but generates fragmentary, non-overlapping sequence reads that cannot be clustered by existing OTU-finding methods. To circumvent these limitations, we developed PhylOTU, a computational workflow that identifies OTUs from metagenomic SSU-rRNA sequence data through the use of phylogenetic principles and probabilistic sequence profiles. Using simulated metagenomic data, we quantified the accuracy with which PhylOTU clusters reads into OTUs. Comparisons of PCR and shotgun sequenced SSU-rRNA markers derived from the global open ocean revealed that while PCR libraries identify more OTUs per sequenced residue, metagenomic libraries recover a greater taxonomic diversity of OTUs. In addition, we discover novel species, genera and families in the metagenomic libraries, including OTUs from phyla missed by analysis of PCR sequences. Taken together, these results suggest that PhylOTU enables characterization of part of the biosphere currently hidden from PCR-based surveys of diversity

Dynamic Interactions Between Groundwater Level and Discharge by Phreatophytes

Many traditional models that predict plant–groundwater use based on groundwater level variations, such as the White method, make various simplifying assumptions. For example, these models often neglect the role of plant hydraulic redistribution, a process that can contribute up to 80% of transpiration. Thus, this work aims to avoid such assumptions and subsequently explore the dynamic interactions between groundwater levels and phreatophytic vegetation, including plant nocturnal transpiration, hydraulic redistribution, and response to atmospheric conditions, in shallow-groundwater ecosystems using Loblolly pine (Pinus taeda) as a model species. The model scenarios are formulated using a stomatal-optimization model coupled to the soil–plant–atmosphere continuum. Flow through soil and groundwater are described using the Richards equation and a linear reservoir approximation, respectively, with groundwater in contact with an external water body of fixed elevation. Results show that nocturnal transpiration, mediated by plant residual conductance, and hydraulic redistribution, are able to reduce groundwater levels at night and alter the groundwater recharge rate. Projected atmospheric conditions of increased carbon dioxide and elevated temperature have opposing effects on groundwater levels, which tend to roughly cancel each other under a projected scenario of 500 ppm carbon dioxide and 1.5 oC warming. Such detailed modeling can be used to provide further insights into coupled interactions between vegetation, climate and groundwater levels in phreatophyte-dominated ecosystems

A qualitative investigation of obese men\u27s experiences with their weight

Objectives: To investigate obese men\u27s health behaviors and strategies for change. Methods: Qualitative interviews with 36 men (BMI 30 and over). Results: All men felt personally responsible for their weight gain. Sedentary lifestyles, stress, lack of worklife balance and weight-based stigma were all significant causes of weight gain and barriers to weight loss. These factors also contributed to men\u27s unwillingness to seek help for their overweight. Conclusion: Addressing the self-blame and stigma associated with obesity is important in developing strategies to improve the health and well-being of obese men

Insensitivity of alkenone carbon isotopes to atmospheric CO₂ at low to moderate CO₂ levels

Atmospheric pCO2 is a critical component of the global carbon system and is considered to be the major control of Earth’s past, present and future climate. Accurate and precise reconstructions of its concentration through geological time are, therefore, crucial to our understanding of the Earth system. Ice core records document pCO2 for the past 800 kyrs, but at no point during this interval were CO2 levels higher than today. Interpretation of older pCO2 has been hampered by discrepancies during some time intervals between two of the main ocean-based proxy methods used to reconstruct pCO2: the carbon isotope fractionation that occurs during photosynthesis as recorded by haptophyte biomarkers (alkenones) and the boron isotope composition (δ11B) of foraminifer shells. Here we present alkenone and δ11B-based pCO2 reconstructions generated from the same samples from the Plio-Pleistocene at ODP Site 999 across a glacial-interglacial cycle. We find a muted response to pCO2 in the alkenone record compared to contemporaneous ice core and δ11B records, suggesting caution in the interpretation of alkenone-based records at low pCO2 levels. This is possibly caused by the physiology of CO2 uptake in the haptophytes. Our new understanding resolves some of the inconsistencies between the proxies and highlights that caution may be required when interpreting alkenone-based reconstructions of pCO2

Young people’s recall and perceptions of gambling advertising and intentions to gamble on sport

Background There has been an increased international policy focus on the factors that may contribute to, and prevent, the normalization of gambling for young people. However, there is still limited research, which investigates the role of advertising in shaping young people’s gambling attitudes and consumption intentions. Methods Mixed methods study of 111 young people aged 11–16 years recruited from community basketball stadiums in Victoria, Australia, between May and July 2018. Interviewer-assisted surveys investigated recall and awareness of sports betting brands, perceptions of promotional strategies, intention to gamble, and reasons for betting on particular sports. Quantitative data were analyzed using descriptive statistics and χ2 tests. Thematic analyses were used to interpret qualitative responses. Results Young people had high recall and awareness of advertising, with most able to name at least one betting brand (n = 90, 81.1%), and many demonstrating a high awareness of the distinct characteristics (such as colors and appeal strategies) of different brands. A fifth of young people (n = 25, 22.5%) expressed intentions to gamble at 18 years, with boys significantly more likely than girls to state they would gamble (χ2 = 10.90, p = .001). Young people perceived that advertising strategies associated with inducement promotions would be the most influential in encouraging individuals to gamble. While many young people took promotions at face value, there was evidence that some were able to critically engage with and challenge the messages within marketing. Discussion and conclusions Current regulatory structures appear to be ineffective in limiting young people’s recall and awareness of gambling advertising. Lessons from tobacco control support the application of precautionary approaches as a more effective way to limit young people’s development of positive gambling attitudes and behaviors