Selectivity of natural, synthetic and environmental estrogens for zebrafish estrogen receptors.

International audience: Zebrafish, Danio rerio, is increasingly used as an animal model to study the effects of pharmaceuticals and environmental estrogens. As most of these estrogens have only been tested on human estrogen receptors (ERs), it is necessary to measure their effects on zebrafish ERs. In humans there are two distinct nuclear ERs (hERα and hERβ), whereas the zebrafish genome encodes three ERs, zfERα and two zfERβs (zfERβ1 and zfERβ2). In this study, we established HeLa-based reporter cell lines stably expressing each of the three zfERs. We first reported that estrogens more efficiently activate the zfERs at 28°C as compared to 37°C, thus reflecting the physiological temperature of zebrafish in wildlife. We then showed significant differences in the ability of agonist and antagonist estrogens to modulate activation of the three zfER isotypes in comparison to hERs. Environmental compounds (bisphenol A, alkylphenols, mycoestrogens) which are hER panagonists and hERβ selective agonists displayed greater potency for zfERα as compared to zfERβs. Among hERα selective synthetic agonists, PPT did not activate zfERα while 16α-LE2 was the most zfERα selective compound. Altogether, these results confirm that all hER ligands control in a similar manner the transcriptional activity of zfERs although significant differences in selectivity were observed among subtypes. The zfER subtype selective ligands that we identified thus represent new valuable tools to dissect the physiological roles of the different zfERs. Finally, our work also points out that care has to be taken in transposing the results obtained using the zebrafish as a model for human physiopathology

Fokus na Utjecaj Lorisa Malaguzzija

Prošlo je 20 godina od smrti Lorisa Malaguzzija, čovjeka čije je djelovanje duboko promijenilo kulturu djetinjstva. Njegova misao imala je osobit utjecaj na odgoj i obrazovanje Reggio Emilie, no lokalni utjecaj se brzo proširio i na odgojno-obrazovnu praksu drugih zemalja. Prikupili smo svjedočanstva o njegovu izvornom doprinosu iz različitih europskih zemalja

Fine-tuning language models to find agreement among humans with diverse preferences

Recent work in large language modeling (LLMs) has used fine-tuning to align outputs with the preferences of a prototypical user. This work assumes that human preferences are static and homogeneous across individuals, so that aligning to a a single "generic" user will confer more general alignment. Here, we embrace the heterogeneity of human preferences to consider a different challenge: how might a machine help people with diverse views find agreement? We fine-tune a 70 billion parameter LLM to generate statements that maximize the expected approval for a group of people with potentially diverse opinions. Human participants provide written opinions on thousands of questions touching on moral and political issues (e.g., "should we raise taxes on the rich?"), and rate the LLM's generated candidate consensus statements for agreement and quality. A reward model is then trained to predict individual preferences, enabling it to quantify and rank consensus statements in terms of their appeal to the overall group, defined according to different aggregation (social welfare) functions. The model produces consensus statements that are preferred by human users over those from prompted LLMs (>70%) and significantly outperforms a tight fine-tuned baseline that lacks the final ranking step. Further, our best model's consensus statements are preferred over the best human-generated opinions (>65%). We find that when we silently constructed consensus statements from only a subset of group members, those who were excluded were more likely to dissent, revealing the sensitivity of the consensus to individual contributions. These results highlight the potential to use LLMs to help groups of humans align their values with one another

The (ir)relevance of the abandoned criterion II for the diagnosis of serrated polyposis syndrome:a retrospective cohort study

The World Health Organization (WHO) recently updated the diagnostic criteria for serrated polyposis syndrome (SPS). One of the three previous diagnostic criteria (criterion II 2010) is now abandoned: ≥ 1 serrated polyp (SP) proximal to the sigmoid in a first-degree relative (FDR) of a patient with SPS. Individuals fulfilling this abandoned criterion now receive the same surveillance recommendations as all FDRs of patients with SPS. We aimed to compare the incidence of advanced neoplasia (AN) in FDRs with vs. without fulfillment of the abandoned criterion II 2010. We retrospectively recruited FDRs of patients with SPS who underwent a colonoscopy, and stratified them according to fulfilment of criterion II 2010 at baseline. Our primary and secondary outcomes were AN incidence during surveillance and at baseline, respectively. We included 224 FDRs of patients with SPS, of whom 36 (16%) fulfilled criterion II 2010 at baseline. One hundred and five underwent surveillance after baseline. Criterion II 2010-positive FDRs were at increased risk of AN, both during surveillance (hazard ratio 8.94, 95% CI 2.15–37.1, p =.003) as well as at baseline (adjusted odds-ratio 9.30, 95% CI 3.7–23.3, p <.001). FDRs of patients with SPS that underwent colonoscopy and fulfilled the abandoned criterion II 2010 for SPS diagnosis were at increased risk of AN at baseline and during surveillance in this small, retrospective cohort study. Our results should be interpreted with caution but suggest that adherence to surveillance recommendations for all FDRs of patients with SPS is important, especially for those that would have fulfilled the now abandoned criterion II 2010

Biopsy Sampling in Upper Gastrointestinal Endoscopy : A Survey from 10 Tertiary Referral Centres across Europe

Funding Information: A. Link reports grants from European Commission “Eu-ropäischer Fond für regionale Entwicklung” (EFRE), outside the submitted work. In Lithuania the work was partly supported by Lithuanian Research Council Grant no APP-2/2016. In Latvia, the methodological support was made available from the project lzp-2018/1-0135. This work was also supported by the NIHR Oxford Biomedical Research Centre (The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care). In Barcelona, we thank the CERCA Programme/Generalitat de Catalunya for the support. Publisher Copyright: © 2020 The Author(s) Published by S. Karger AG, Basel.Background: Guidelines give robust recommendations on which biopsies should be taken when there is endoscopic suggestion of gastric inflammation. Adherence to these guidelines often seems arbitrary. This study aimed to give an overview on current practice in tertiary referral centres across Europe. Methods: Data were collected at 10 tertiary referral centres. Demographic data, the indication for each procedure, endoscopic findings, and the number and sampling site of biopsies were recorded. Findings were compared between centres, and factors influencing the decision to take biopsies were explored. Results: Biopsies were taken in 56.6% of 9,425 procedures, with significant variation between centres (p < 0.001). Gastric biopsies were taken in 43.8% of all procedures. Sampling location varied with the procedure indication (p < 0.001) without consistent pattern across the centres. Fewer biopsies were taken in centres which routinely applied the updated Sydney classification for gastritis assessment (46.0%), compared to centres where this was done only upon request (75.3%, p < 0.001). This was the same for centres stratifying patients according to the OLGA system (51.8 vs. 73.0%, p < 0.001). More biopsies were taken in centres following the MAPS guidelines on stomach surveillance (68.1 vs. 37.1%, p < 0.001). Biopsy sampling was more likely in younger patients in 8 centres (p < 0.05), but this was not true for the whole cohort (p = 0.537). The percentage of procedures with biopsies correlated directly with additional costs charged in case of biopsies (r = 0.709, p = 0.022). Conclusion: Adherence to guideline recommendations for biopsy sampling at gastroscopy was inconsistent across the participating centres. Our data suggest that centre-specific policies are applied instead.publishersversionPeer reviewe

Magnetic fields inferred by Solar Orbiter: A comparison between SO/PHI-HRT and SDO/HMI

Context. The High Resolution Telescope (HRT) of the Polarimetric and Helioseismic Imager on board the Solar Orbiter spacecraft (SO/PHI) and the Helioseismic and Magnetic Imager (HMI) on board the Solar Dynamics Observatory (SDO) both infer the photospheric magnetic field from polarised light images. SO/PHI is the first magnetograph to move out of the Sun–Earth line and will provide unprecedented access to the Sun’s poles. This provides excellent opportunities for new research wherein the magnetic field maps from both instruments are used simultaneously. Aims. We aim to compare the magnetic field maps from these two instruments and discuss any possible differences between them. Methods. We used data from both instruments obtained during Solar Orbiter’s inferior conjunction on 7 March 2022. The HRT data were additionally treated for geometric distortion and degraded to the same resolution as HMI. The HMI data were re-projected to correct for the 3° separation between the two observatories. Results. SO/PHI-HRT and HMI produce remarkably similar line-of-sight magnetograms, with a slope coefficient of 0.97, an offset below 1 G, and a Pearson correlation coefficient of 0.97. However, SO/PHI-HRT infers weaker line-of-sight fields for the strongest fields. As for the vector magnetic field, SO/PHI-HRT was compared to both the 720-second and 90-second HMI vector magnetic field: SO/PHI-HRT has a closer alignment with the 90-second HMI vector. In the weak signal regime (< 600 G), SO/PHI-HRT measures stronger and more horizontal fields than HMI, very likely due to the greater noise in the SO/PHI-HRT data. In the strong field regime (≳600 G), HRT infers lower field strengths but with similar inclinations (a slope of 0.92) and azimuths (a slope of 1.02). The slope values are from the comparison with the HMI 90-second vector. Possible reasons for the differences found between SO/PHI-HRT and HMI magnetic field parameters are discussed.Sección Deptal. de Óptica (Óptica)Fac. de Óptica y OptometríaTRUEBMWi - Bundesministerium für Wirtschaft und Energie (Alemania)AEI/MCIN/10.13039/501100011033Ministerio de ciencia e innovación de EspañaInstituto Astrofísico de Andalucía (España)Agencia Estatal de Investigación (España)Fondo Europeo de Desarrollo Regional (Fondos FEDER)Centre national d'études spatiales (CNES) (Francia)CSIC (Centro Superior de Investigaciones Científicas) (España)pu

Modelling human choices: MADeM and decision‑making

Research supported by FAPESP 2015/50122-0 and DFG-GRTK 1740/2. RP and AR are also part of the Research, Innovation and Dissemination Center for Neuromathematics FAPESP grant (2013/07699-0). RP is supported by a FAPESP scholarship (2013/25667-8). ACR is partially supported by a CNPq fellowship (grant 306251/2014-0)

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong

Optimal utility and probability functions for agents with finite computational precision

When making economic choices, such as those between goods or gambles, humans act as if their internal representation of the value and probability of a prospect is distorted away from its true value. These distortions give rise to decisions which apparently fail to maximise reward, and preferences that reverse without reason. Why would humans have evolved to encode value and probability in a distorted fashion, in the face of selective pressure for reward-maximising choices? Here, we show that under the simple assumption that humans make decisions with finite computational precision – in other words, that decisions are irreducibly corrupted by noise – the distortions of value and probability displayed by humans are approximately optimal in that they maximise reward and minimise uncertainty. In two empirical studies, we manipulate factors that change the reward-maximising form of distortion, and find that in each case, humans adapt optimally to the manipulation. This work suggests an answer to the longstanding question of why humans make “irrational” economic choices