Novel and highly potent histamine H3 receptor ligands. Part 2: exploring the cyclohexylamine-based series

Synthesis and biological evaluation of novel and potent cyclohexylamine-based histamine H3 receptor inverse agonists are described. Compounds in this newly identified series exhibited subnanomolar binding affinities for human receptor and no significant interaction with hERG channel. One derivative (10t) demonstrated enhanced in vivo efficiency and preferential brain distribution, both properties suitable for potential clinical evaluation.     

Ecological solidarity as a conceptual tool for rethinking ecological and social interdependence in conservation policy for protected areas and their surrounding landscape

Policy for biodiversity conservation must evolve to cope with the increasing human footprint on natural systems. A major issue here is the need for policy for protected areas, which integrates their surrounding landscape and local human populations in the construction of socially grounded measures. To illustrate current conceptual thinking in this direction we present and provide a conceptual basis for a recent initiative in national park policy in France that is based on "ecological solidarity". In the light of other policy ideas and tools that have recently emerged for the co-construction of conservation policy, we argue that this concept provides an imaginative step towards consolidating ecological and social interdependence in biodiversity policy that goes beyond statutory park boundaries.     

PTBP1 is required for embryonic development before gastrulation

Polypyrimidine-tract binding protein 1 (PTBP1) is an important cellular regulator of messenger RNAs influencing the alternative splicing profile of a cell as well as its mRNA stability, location and translation. In addition, it is diverted by some viruses to facilitate their replication. Here, we used a novel PTBP1 knockout mouse to analyse the tissue expression pattern of PTBP1 as well as the effect of its complete removal during development. We found evidence of strong PTBP1 expression in embryonic stem cells and throughout embryonic development, especially in the developing brain and spinal cord, the olfactory and auditory systems, the heart, the liver, the kidney, the brown fat and cartilage primordia. This widespread distribution points towards a role of PTBP1 during embryonic development. Homozygous offspring, identified by PCR and immunofluorescence, were able to implant but were arrested or retarded in growth. At day 7.5 of embryonic development (E7.5) the null mutants were about 5x smaller than the control littermates and the gap in body size widened with time. At mid-gestation, all homozygous embryos were resorbed/degraded. No homozygous mice were genotyped at E12 and the age of weaning. Embryos lacking PTBP1 did not display differentiation into the 3 germ layers and cavitation of the epiblast, which are hallmarks of gastrulation. In addition, homozygous mutants displayed malformed ectoplacental cones and yolk sacs, both early supportive structure of the embryo proper. We conclude that PTBP1 is not required for the earliest isovolumetric divisions and differentiation steps of the zygote up to the formation of the blastocyst. However, further post-implantation development requires PTBP1 and stalls in homozygous null animals with a phenotype of dramatically reduced size and aberration in embryonic and extra-embryonic structures.     

How to Become a Mentalist: Reading Decisions from a Competitor’s Pupil Can Be Achieved without Training but Requires Instruction

Pupil dilation is implicated as a marker of decision-making as well as of cognitive and emotional processes. Here we tested whether individuals can exploit another’s pupil to their advantage. We first recorded the eyes of 3 "opponents", while they were playing a modified version of the "rock-paper-scissors" childhood game. The recorded videos served as stimuli to a second set of participants. These "players" played rock-paper-scissors against the pre-recorded opponents in a variety of conditions. When players just observed the opponents’ eyes without specific instruction their probability of winning was at chance. When informed that the time of maximum pupil dilation was indicative of the opponents’ choice, however, players raised their winning probability significantly above chance. When just watching the reconstructed area of the pupil against a gray background, players achieved similar performance, showing that players indeed exploited the pupil, rather than other facial cues. Since maximum pupil dilation was correct about the opponents’ decision only in 60% of trials (chance 33%), we finally tested whether increasing this validity to 100% would allow spontaneous learning. Indeed, when players were given no information, but the pupil was informative about the opponent’s response in all trials, players performed significantly above chance on average and half (5/10) reached significance at an individual level. Together these results suggest that people can in principle use the pupil to detect cognitive decisions in another individual, but that most people have neither explicit knowledge of the pupil’s utility nor have they learnt to use it despite a lifetime of exposure.     

Hepatitis B Screening and Vaccination Strategies for Newly Arrived Adult Canadian Immigrants and Refugees: A Cost-Effectiveness Analysis

Background

Immigrants have increased mortality from hepatocellular carcinoma as compared to the host populations, primarily due to undetected chronic hepatitis B virus (HBV) infection. Despite this, there are no systematic programs in most immigrant-receiving countries to screen for chronic HBV infection and immigrants are not routinely offered HBV vaccination outside of the universal childhood vaccination program.

Methods and findings

A cost-effective analysis was performed to compare four HBV screening and vaccination strategies with no intervention in a hypothetical cohort of newly-arriving adult Canadian immigrants. The strategies considered were a) universal vaccination, b) screening for prior immunity and vaccination, c) chronic HBV screening and treatment, and d) combined screening for chronic HBV and prior immunity, treatment and vaccination. The analysis was performed from a societal perspective, using a Markov model. Seroprevalence estimates, annual transition probabilities, health-care costs (in Canadian dollars), and utilities were obtained from the published literature. Acute HBV infection, mortality from chronic HBV, quality-adjusted life years (QALYs), and costs were modeled over the lifetime of the cohort of immigrants. Costs and QALYs were discounted at a rate of 3% per year. Screening for chronic HBV infection, and offering treatment if indicated, was found to be the most cost-effective intervention and was estimated to cost $40,880 per additional QALY gained, relative to no intervention. This strategy was most cost-effective for immigrants < 55 years of age and would cost < $50,000 per additional QALY gained for immigrants from areas where HBV seroprevalence is ≥ 3%. Strategies that included HBV vaccination were either prohibitively expensive or dominated by the chronic HBV screening strategy.

Conclusions

Screening for chronic HBV infection from regions where most Canadian immigrants originate, except for Latin America and the Middle East, was found to be reasonably cost-effective and has the potential to reduce HBV-associated morbidity and mortality.     

Whole Mount RNA Fluorescent in situ Hybridization of Drosophila Embryos

Assessing the expression pattern of a gene, as well as the subcellular localization properties of its transcribed RNA, are key features for understanding its biological function during development. RNA in situ hybridization (RNA-ISH) is a powerful method used for visualizing RNA distribution properties, be it at the organismal, cellular or subcellular levels ¹. RNA-ISH is based on the hybridization of a labeled nucleic acid probe (e.g. antisense RNA, oligonucleotides) complementary to the sequence of an mRNA or a non-coding RNA target of interest ². As the procedure requires primary sequence information alone to generate sequence-specific probes, it can be universally applied to a broad range of organisms and tissue specimens ³. Indeed, a number of large-scale ISH studies have been implemented to document gene expression and RNA localization dynamics in various model organisms, which has led to the establishment of important community resources ^4-11. While a variety of probe labeling and detection strategies have been developed over the years, the combined usage of fluorescently-labeled detection reagents and enzymatic signal amplification steps offer significant enhancements in the sensitivity and resolution of the procedure ¹². Here, we describe an optimized fluorescent in situ hybridization method (FISH) employing tyramide signal amplification (TSA) to visualize RNA expression and localization dynamics in staged Drosophila embryos. The procedure is carried out in 96-well PCR plate format, which greatly facilitates the simultaneous processing of large numbers of samples.     

Influence of atmospheric modes of variability on the limnological characteristics of large lakes south of the Alps: a new emerging paradigm

Winter air and spring surface water temperatures, spring epilimnetic phosphorus, and hypolimnetic oxygen in the deep lakes south of the Alps (Garda, Iseo, Como, Lugano, and Maggiore) showed a high degree of temporal coherence. The common temporal patterns were originating from the effects caused by winter climate, and from corresponding synchronisms in the interannual variations in the extent of the spring water renewal and replenishment of nutrients. In turn, the sequence of linked causal events was triggered by two atmospheric modes of variability relevant for the Mediterranean region, i.e. the East Atlantic pattern (EA) and the Eastern Mediterranean Pattern (EMP). In contrast, there were no significant relationships of air and water temperatures with the North Atlantic Oscillation. In oligotrophic lakes, which were characterised by weak vertical nutrient gradients, the spring replenishment of P was negligible and difficult to detect (Maggiore), or detectable but of minor importance (Garda and Como) compared to that measured in more enriched lakes (Iseo and Lugano). The applicability of EA and EMP in the study of the impact of climate on aquatic ecosystems will require to be tested by expanding the number, typology, and geographical location of water bodies in the Alpine and Mediterranean regions.     

Interaction of tumour cells with their microenvironment: ion channels and cell adhesion molecules. A focus on pancreatic cancer

Cancer must be viewed as a ‘tissue’, constituted of both transformed cells and a heterogeneous microenvironment, the ‘tumour microenvironment’ (TME). The TME undergoes a complex remodelling during the course of multistep tumourigenesis, hence strongly contributing to tumour progression. Ion channels and transporters (ICTs), being expressed on both tumour cells and in the different cellular components of the TME, are in a strategic position to sense and mediate signals arising from the TME. Often, this transmission is mediated by integrin adhesion receptors, which are the main cellular receptors capable of mediating cell-to-cell and cell-to-matrix bidirectional signalling. Integrins can often operate in conjunction with ICT because they can behave as functional partners of ICT proteins. The role of integrin receptors in the crosstalk between tumour cells and the TME is particularly relevant in the context of pancreatic cancer (PC), characterized by an overwhelming TME which actively contributes to therapy resistance. We discuss the possibility that this occurs through integrins and ICTs, which could be exploited as targets to overcome chemoresistance in PC.