Targeting quiescent leukemic stem cells using second generation autophagy inhibitors

In chronic myeloid leukemia (CML), tyrosine kinase inhibitor (TKI) treatment induces autophagy that promotes survival and TKI-resistance in leukemic stem cells (LSCs). In clinical studies hydroxychloroquine (HCQ), the only clinically approved autophagy inhibitor, does not consistently inhibit autophagy in cancer patients, so more potent autophagy inhibitors are needed. We generated a murine model of CML in which autophagic flux can be measured in bone marrow-located LSCs. In parallel, we use cell division tracing, phenotyping of primary CML cells, and a robust xenotransplantation model of human CML, to investigate the effect of Lys05, a highly potent lysosomotropic agent, and PIK-III, a selective inhibitor of VPS34, on the survival and function of LSCs. We demonstrate that long-term haematopoietic stem cells (LT-HSCs: Lin−Sca-1+c-kit+CD48−CD150+) isolated from leukemic mice have higher basal autophagy levels compared with non-leukemic LT-HSCs and more mature leukemic cells. Additionally, we present that while HCQ is ineffective, Lys05-mediated autophagy inhibition reduces LSCs quiescence and drives myeloid cell expansion. Furthermore, Lys05 and PIK-III reduced the number of primary CML LSCs and target xenografted LSCs when used in combination with TKI treatment, providing a strong rationale for clinical use of second generation autophagy inhibitors as a novel treatment for CML patients with LSC persistence

Long term time variability of cosmic rays and possible relevance to the development of life on Earth

An analysis is made of the manner in which the cosmic ray intensity at Earth has varied over its existence and its possible relevance to both the origin and the evolution of life. Much of the analysis relates to the 'high energy' cosmic rays ($E>10^{14}eV;=0.1PeV$) and their variability due to the changing proximity of the solar system to supernova remnants which are generally believed to be responsible for most cosmic rays up to PeV energies. It is pointed out that, on a statistical basis, there will have been considerable variations in the likely 100 My between the Earth's biosphere reaching reasonable stability and the onset of very elementary life. Interestingly, there is the increasingly strong possibility that PeV cosmic rays are responsible for the initiation of terrestrial lightning strokes and the possibility arises of considerable increases in the frequency of lightnings and thereby the formation of some of the complex molecules which are the 'building blocks of life'. Attention is also given to the well known generation of the oxides of nitrogen by lightning strokes which are poisonous to animal life but helpful to plant growth; here, too, the violent swings of cosmic ray intensities may have had relevance to evolutionary changes. A particular variant of the cosmic ray acceleration model, put forward by us, predicts an increase in lightning rate in the past and this has been sought in Korean historical records. Finally, the time dependence of the overall cosmic ray intensity, which manifests itself mainly at sub-10 GeV energies, has been examined. The relevance of cosmic rays to the 'global electrical circuit' points to the importance of this concept.Comment: 18 pages, 5 figures, accepted by 'Surveys in Geophysics

Is it time for studying real-life debiasing? Evaluation of the effectiveness of an analogical intervention technique.

The aim of this study was to initiate the exploration of debiasing methods applicable in real-life settings for achieving lasting improvement in decision making competence regarding multiple decision biases. Here, we tested the potentials of the analogical encoding method for decision debiasing. The advantage of this method is that it can foster the transfer from learning abstract principles to improving behavioral performance. For the purpose of the study, we devised an analogical debiasing technique for 10 biases (covariation detection, insensitivity to sample size, base rate neglect, regression to the mean, outcome bias, sunk cost fallacy, framing effect, anchoring bias, overconfidence bias, planning fallacy) and assessed the susceptibility of the participants (N = 154) to these biases before and 4 weeks after the training. We also compared the effect of the analogical training to the effect of 'awareness training' and a 'no-training' control group. Results suggested improved performance of the analogical training group only on tasks where the violations of statistical principles are measured. The interpretation of these findings require further investigation, yet it is possible that analogical training may be the most effective in the case of learning abstract concepts, such as statistical principles, which are otherwise difficult to master. The study encourages a systematic research of debiasing trainings and the development of intervention assessment methods to measure the endurance of behavior change in decision debiasing

Factors Affecting Adoption of Improved Crops by Rural Farmers in Niger

Improved crops are advocated to meet the dual challenge of food security and the fight against poverty in developing countries. As most poor people in developing countries live in rural areas and depend on agriculture for their livelihood, an important key to get them out of poverty is to increase agricultural productivity by using technologies such as improved crops. However, the rate of improved crops adoption remains surprisingly low in Niger, one of the world poorest countries. In this paper, we examine the factors affecting adoption of improved crops by rural farmers focusing on Niger. Using the 2014’s National Survey on Households Living Conditions and Agriculture, we investigate the effect of farmers’ socioeconomic characteristics, the farm’s quality, the geographic location, the production system, the access to improved seeds and the land tenure on the probability to use improved crops rather than local crops. Our results suggest that the ownership of a government land title is the most important driver in the adoption of improved crops by rural farmers. In addition, being a female, educated, practicing polyculture, having access to improved seed increase the probability to adopt improved crops. In contrast, household size, operating on the parcel for a long period and the parcel size reduces the probability to use improved crops. These determinants of improved crops adoption should be considered in Niger’s agricultural policy to succeed in the dissemination of improved crops among rural farmers. Keywords: Adoption, Improved crops, Farm, Farmer, Nige

Bridging reproductive and microbial ecology: a case study in arbuscular mycorrhizal fungi

Offspring size is a key trait for understanding the reproductive ecology of species, yet studies addressing the ecological meaning of offspring size have so far been limited to macro-organisms. We consider this a missed opportunity in microbial ecology and provide what we believe is the first formal study of offspring-size variation in microbes using reproductive models developed for macro-organisms. We mapped the entire distribution of fungal spore size in the arbuscular mycorrhizal (AM) fungi (subphylum Glomeromycotina) and tested allometric expectations of this trait to offspring (spore) output and body size. Our results reveal a potential paradox in the reproductive ecology of AM fungi: while large spore-size variation is maintained through evolutionary time (independent of body size), increases in spore size trade off with spore output. That is, parental mycelia of large-spored species produce fewer spores and thus may have a fitness disadvantage compared to small-spored species. The persistence of the large-spore strategy, despite this apparent fitness disadvantage, suggests the existence of advantages to large-spored species that could manifest later in fungal life history. Thus, we consider that solving this paradox opens the door to fruitful future research establishing the relationship between offspring size and other AM life history traits

Arbuscular Mycorrhizal Fungi and Plant Chemical Defence : Effects of Colonisation on Aboveground and Belowground Metabolomes

Arbuscular mycorrhizal fungal (AMF) colonisation of plant roots is one of the most ancient and widespread interactions in ecology, yet the systemic consequences for plant secondary chemistry remain unclear. We performed the first metabolomic investigation into the impact of AMF colonisation by Rhizophagus irregularis on the chemical defences, spanning above- and below-ground tissues, in its host-plant ragwort (Senecio jacobaea). We used a non-targeted metabolomics approach to profile, and where possible identify, compounds induced by AMF colonisation in both roots and shoots. Metabolomics analyses revealed that 33 compounds were significantly increased in the root tissue of AMF colonised plants, including seven blumenols, plant-derived compounds known to be associated with AMF colonisation. One of these was a novel structure conjugated with a malonyl-sugar and uronic acid moiety, hitherto an unreported combination. Such structural modifications of blumenols could be significant for their previously reported functional roles associated with the establishment and maintenance of AM colonisation. Pyrrolizidine alkaloids (PAs), key anti-herbivore defence compounds in ragwort, dominated the metabolomic profiles of root and shoot extracts. Analyses of the metabolomic profiles revealed an increase in four PAs in roots (but not shoots) of AMF colonised plants, with the potential to protect colonised plants from below-ground organisms

Polarized citizen preferences for the ethical allocation of scarce medical resources in 20 countries.

This is the final version. Available from SAGE Publications via the DOI in this record. Data Availability Statement: Data and code are open and available at https://github.com/ bencebago/ventilators.Objective. When medical resources are scarce, clinicians must make difficult triage decisions. When these decisions affect public trust and morale, as was the case during the COVID-19 pandemic, experts will benefit from knowing which triage metrics have citizen support. Design. We conducted an online survey in 20 countries, comparing support for 5 common metrics (prognosis, age, quality of life, past and future contribution as a health care worker) to a benchmark consisting of support for 2 no-triage mechanisms (first-come-first-served and random allocation). Results. We surveyed nationally representative samples of 1000 citizens in each of Brazil, France, Japan, and the United States and also self-selected samples from 20 countries (total N = 7599) obtained through a citizen science website (the Moral Machine). We computed the support for each metric by comparing its usability to the usability of the 2 no-triage mechanisms. We further analyzed the polarizing nature of each metric by considering its usability among participants who had a preference for no triage. In all countries, preferences were polarized, with the 2 largest groups preferring either no triage or extensive triage using all metrics. Prognosis was the least controversial metric. There was little support for giving priority to healthcare workers. Conclusions. It will be difficult to define triage guidelines that elicit public trust and approval. Given the importance of prognosis in triage protocols, it is reassuring that it is the least controversial metric. Experts will need to prepare strong arguments for other metrics if they wish to preserve public trust and morale during health crises. Highlights: We collected citizen preferences regarding triage decisions about scarce medical resources from 20 countries.We find that citizen preferences are universally polarized.Citizens either prefer no triage (random allocation or first-come-first served) or extensive triage using all common triage metrics, with "prognosis" being the least controversial.Experts will need to prepare strong arguments to preserve or elicit public trust in triage decisions

A new species of Stenobiella Tillyard (Neuroptera, Berothidae) from Australia

Stenobiella variola sp. n., a new species of beaded lacewing (Neuroptera: Berothidae), is described and figured from south-eastern Australia. A preliminary key to Stenobiella species is presented

The Effects of Hyperacute Serum on the Elements of the Human Subchondral Bone Marrow Niche

Mesenchymal stem cells (MSCs) are widely used in laboratory experiments as well as in human cell therapy. Their culture requires animal sera like fetal calf serum (FCS) as essential supplementation; however, animal sera pose a risk for clinical applications. Human blood derivatives, for example, platelet-rich plasma (PRP) releasates, are potential replacements of FCS; however, it is unclear which serum variant has the best effect on the given cell or tissue type. Additionally, blood derivatives are commonly used in musculoskeletal diseases like osteoarthritis (OA) or osteonecrosis as "proliferative agents" for the topical MSC pool. Hyperacute serum (HAS), a new serum derivative, has been designed to approximate the natural coagulation cascade with a single-step, additive-free preparation method. We investigated the effects of HAS on monolayer MSC cultures and in their natural niche, in 3D subchondral bone and marrow explants. Viability measurements, RT-qPCR evaluation for gene expression and flow cytometry for cell surface marker analysis were performed to compare the effects of FCS-, PRP-, or HAS-supplemented culture media. Monolayer MSCs showed significantly higher metabolic activity following 5 days' incubation in HAS, and osteoblast-specific mRNA expression was markedly increased, while cells also retained their MSC-specific cell surface markers. A similar effect was observed on bone and marrow explants, which was further confirmed with confocal microscopy analysis. Moreover, markedly higher bone marrow preservation was observed with histology in case of HAS supplementation compared to FCS. These findings indicate possible application of HAS in regenerative solutions of skeletal diseases like OA or osteonecrosis

Effect of having private health insurance on the use of health care services: the case of Spain

Background: Several stakeholders have undertaken initiatives to propose solutions towards a more sustainable health system and Spain, as an example of a European country affected by austerity measures, is looking for ways to cut healthcare budgets. Methods: The aim of this paper is to study the effect of private health insurance on health care utilization using the latest micro-data from the European Community Household Panel (ECHP), the Spanish National Health Survey (SNHS) and the European Union Statistics on Income and Living Conditions (EU-SILC). We use matching techniques based on propensity score methods: single match, four matches, bias-adjustment and allowing for heteroskedasticity. Results: The results demonstrate that people with a private health insurance, use the public health system less than individuals without double health insurance coverage. Conclusions: Our conclusions are useful when policy makers design public-private partnership policie