Multiple Organ System Defects and Transcriptional Dysregulation in the Nipbl+/− Mouse, a Model of Cornelia de Lange Syndrome

Cornelia de Lange Syndrome (CdLS) is a multi-organ system birth defects disorder linked, in at least half of cases, to heterozygous mutations in the NIPBL gene. In animals and fungi, orthologs of NIPBL regulate cohesin, a complex of proteins that is essential for chromosome cohesion and is also implicated in DNA repair and transcriptional regulation. Mice heterozygous for a gene-trap mutation in Nipbl were produced and exhibited defects characteristic of CdLS, including small size, craniofacial anomalies, microbrachycephaly, heart defects, hearing abnormalities, delayed bone maturation, reduced body fat, behavioral disturbances, and high mortality (75–80%) during the first weeks of life. These phenotypes arose despite a decrease in Nipbl transcript levels of only ∼30%, implying extreme sensitivity of development to small changes in Nipbl activity. Gene expression profiling demonstrated that Nipbl deficiency leads to modest but significant transcriptional dysregulation of many genes. Expression changes at the protocadherin beta (Pcdhb) locus, as well as at other loci, support the view that NIPBL influences long-range chromosomal regulatory interactions. In addition, evidence is presented that reduced expression of genes involved in adipogenic differentiation may underlie the low amounts of body fat observed both in Nipbl+/− mice and in individuals with CdLS

People with more extreme attitudes towards science have self-confidence in their understanding of science, even if this is not justified.

Acknowledgements: We thank Patrick Sturgis and Sarah Cunningham-Burley for advice on survey design and on the manuscript.Funder: Genetics Society; funder-id: http://dx.doi.org/10.13039/100013562People differ greatly in their attitudes towards well-evidenced science. What characterises this variation? Here, we consider this issue in the context of genetics and allied sciences. While most prior research has focused on the relationship between attitude to science and what people know about it, recent evidence suggests that individuals with strongly negative attitudes towards specific genetic technologies (genetic modification (GM) technology and vaccines) commonly do not objectively understand the science, but, importantly, believe that they do. Here, using data from a probability survey of United Kingdom adults, we extend this prior work in 2 regards. First, we ask whether people with more extreme attitudes, be they positive or negative, are more likely to believe that they understand the science. Second, as negativity to genetics is commonly framed around issues particular to specific technologies, we ask whether attitudinal trends are contingent on specification of technology. We find (1) that individuals with strongly positive or negative attitudes towards genetics more strongly believe that they well understand the science; but (2) only for those most positive to the science is this self-confidence warranted; and (3) these effects are not contingent on specification of any particular technologies. These results suggest a potentially general model to explain why people differ in their degree of acceptance or rejection of science, this being that the more someone believes they understand the science, the more confident they will be in their acceptance or rejection of it. While there are more technology nonspecific opponents who also oppose GM technology than expected by chance, most GM opponents fit a different demographic. For the most part, opposition to GM appears not to reflect a smokescreen concealing a broader underlying negativity

The derivation of questions.

All scripts and data are available at doi: 10.5281/zenodo.7289133. (PDF)</p

The survey contents, demographics, and fieldwork.

All scripts and data are available at doi: 10.5281/zenodo.7289133. (PDF)</p

Correlations between attitudinal scores and the 12 knowledge questions.

All scripts and data are available at doi: 10.5281/zenodo.7289133. (XLSX)</p

Hartigan and Hartigan dip tests on scientific knowledge scores for those most sceptical on various measures.

For Trust, Hype, and GM, these are class −2. For vaccine, it is those who will not have it. All scripts and data are available at doi: 10.5281/zenodo.7289133. (PDF)</p

Replication of all results when knowledge is defined by 10 biology questions and subjective understanding is defined by the 4 genetic questions.

All scripts and data are available at doi: 10.5281/zenodo.7289133. In this instance, consult zip archive S_results_2.zip. (PDF)</p

Point estimates of seasonal dengue incidence for Iquitos.

<p>Point estimates of seasonal dengue incidence for Iquitos.</p

LifeTime and improving European healthcare through cell-based interceptive medicine

AUTEURS : LifeTime Community Working GroupsInternational audienceHere we describe the LifeTime Initiative, which aims to track, understand and target human cells during the onset and progression of complex diseases, and to analyse their response to therapy at single-cell resolution. This mission will be implemented through the development, integration and application of single-cell multi-omics and imaging, artificial intelligence and patient-derived experimental disease models during the progression from health to disease. The analysis of large molecular and clinical datasets will identify molecular mechanisms, create predictive computational models of disease progression, and reveal new drug targets and therapies. The timely detection and interception of disease embedded in an ethical and patient-centred vision will be achieved through interactions across academia, hospitals, patient associations, health data management systems and industry. The application of this strategy to key medical challenges in cancer, neurological and neuropsychiatric disorders, and infectious, chronic inflammatory and cardiovascular diseases at the single-cell level will usher in cell-based interceptive medicine in Europe over the next decade