Multigenome DNA sequence conservation identifies Hox cis-regulatory elements

To learn how well ungapped sequence comparisons of multiple species can predict cis-regulatory elements in Caenorhabditis elegans, we made such predictions across the large, complex ceh-13/lin-39 locus and tested them transgenically. We also examined how prediction quality varied with different genomes and parameters in our comparisons. Specifically, we sequenced ∼0.5% of the C. brenneri and C. sp. 3 PS1010 genomes, and compared five Caenorhabditis genomes (C. elegans, C. briggsae, C. brenneri, C. remanei, and C. sp. 3 PS1010) to find regulatory elements in 22.8 kb of noncoding sequence from the ceh-13/lin-39 Hox subcluster. We developed the MUSSA program to find ungapped DNA sequences with N-way transitive conservation, applied it to the ceh-13/lin-39 locus, and transgenically assayed 21 regions with both high and low degrees of conservation. This identified 10 functional regulatory elements whose activities matched known ceh-13/lin-39 expression, with 100% specificity and a 77% recovery rate. One element was so well conserved that a similar mouse Hox cluster sequence recapitulated the native nematode expression pattern when tested in worms. Our findings suggest that ungapped sequence comparisons can predict regulatory elements genome-wide

Transcription factor redundancy and tissue-specific regulation: Evidence from functional and physical network connectivity

Two major transcriptional regulators of Caenorhabditis elegans bodywall muscle (BWM) differentiation, hlh-1 and unc-120, are expressed in muscle where they are known to bind and regulate several well-studied muscle-specific genes. Simultaneously mutating both factors profoundly inhibits formation of contractile BWM. These observations were consistent with a simple network model in which the muscle regulatory factors drive tissue-specific transcription by binding selectively near muscle-specific targets to activate them. We tested this model by measuring the number, identity, and tissue-specificity of functional regulatory targets for each factor. Some joint regulatory targets (218) are BWM-specific and enriched for nearby HLH-1 binding. However, contrary to the simple model, the majority of genes regulated by one or both muscle factors are also expressed significantly in non-BWM tissues. We also mapped global factor occupancy by HLH-1, and created a genetic interaction map that identifies hlh-1 collaborating transcription factors. HLH-1 binding did not predict proximate regulatory action overall, despite enrichment for binding among BWM-specific positive regulatory targets of hlh-1. We conclude that these tissue-specific factors contribute much more broadly to the transcriptional output of muscle tissue than previously thought, offering a partial explanation for widespread HLH-1 occupancy. We also identify a novel regulatory connection between the BWM-specific hlh-1 network and the hlh-8/twist nonstriated muscle network. Finally, our results suggest a molecular basis for synthetic lethality in which hlh-1 and unc-120 mutant phenotypes are mutually buffered by joint additive regulation of essential target genes, with additional buffering suggested via newly identified hlh-1 interacting factors

Central Nervous System Parasitosis and Neuroinflammation Ameliorated by Systemic IL-10 Administration in Trypanosoma brucei-Infected Mice

Peer reviewedPublisher PD

Reconstructing a metazoan genetic pathway with transcriptome-wide epistasis measurements

RNA-sequencing (RNA-seq) is commonly used to identify genetic modules that respond to perturbations. In single cells, transcriptomes have been used as phenotypes, but this concept has not been applied to whole-organism RNA-seq. Also, quantifying and interpreting epistatic effects using expression profiles remains a challenge. We developed a single coefficient to quantify transcriptome-wide epistasis that reflects the underlying interactions and which can be interpreted intuitively. To demonstrate our approach, we sequenced four single and two double mutants of Caenorhabditis elegans. From these mutants, we reconstructed the known hypoxia pathway. In addition, we uncovered a class of 56 genes with HIF-1–dependent expression that have opposite changes in expression in mutants of two genes that cooperate to negatively regulate HIF-1 abundance; however, the double mutant of these genes exhibits suppression epistasis. This class violates the classical model of HIF-1 regulation but can be explained by postulating a role of hydroxylated HIF-1 in transcriptional control

COVID-19 vaccine hesitancy in eight European countries: prevalence, determinants and heterogeneity

We examine heterogeneity in COVID-19 vaccine hesitancy across eight European countries. We reveal striking differences across countries, ranging from 6.4% of adults in Spain to 61.8% in Bulgaria reporting being hesitant. We experimentally assess the effectiveness of different messages designed to reduce COVID-19 vaccine hesitancy. Receiving messages emphasizing either the medical benefits or the hedonistic benefits of vaccination significantly increases COVID-19 vaccination willingness in Germany, whereas highlighting privileges contingent on holding a vaccination certificate increases vaccination willingness in both Germany and the United Kingdom. No message has significant positive effects in any other country. Machine learning-based heterogeneity analyses reveal that treatment effects are smaller or even negative in settings marked by high conspiracy beliefs and low health literacy. In contrast, trust in government increases treatment effects in some groups. The heterogeneity in vaccine hesitancy and responses to different messages suggests that health authorities should avoid one-size-fits-all vaccination campaigns

Assessing the perceived effect of non-pharmaceutical interventions on SARS-Cov-2 transmission risk: an experimental study in Europe

We conduct a large (N = 6567) online experiment to measure the features of non-pharmaceutical interventions (NPIs) that citizens of six European countries perceive to lower the risk of transmission of SARS-Cov-2 the most. We collected data in Bulgaria (n = 1069), France (n = 1108), Poland (n = 1104), Italy (n = 1087), Spain (n = 1102) and Sweden (n = 1097). Based on the features of the most widely adopted public health guidelines to reduce SARS-Cov-2 transmission (mask wearing vs not, outdoor vs indoor contact, short vs 90 min meetings, few vs many people present, and physical distancing of 1 or 2 m), we conducted a discrete choice experiment (DCE) to estimate the public’s perceived risk of SARS-CoV-2 transmission in scenarios that presented mutually exclusive constellations of these features. Our findings indicate that participants’ perception of transmission risk was most influenced by the NPI attributes of mask-wearing and outdoor meetings and the least by NPI attributes that focus on physical distancing, meeting duration, and meeting size. Differentiating by country, gender, age, cognitive style (reflective or intuitive), and perceived freight of COVID-19 moreover allowed us to identify important differences between subgroups. Our findings highlight the importance of improving health policy communication and citizens’ health literacy about the design of NPIs and the transmission risk of SARS-Cov-2 and potentially future viruses

iSPOT: A Web Tool for the Analysis and Recognition of Protein Domain Specificity

Methods that aim at predicting interaction partners are very likely to play an important role in the interpretation of genomic information. iSPOT (iSpecificity Prediction Of Target) is a web tool (accessible at http://cbm.bio.uniroma2.it/iSPOT) developed for the prediction of protein-protein interaction mediated by families of peptide recognition modules. iSPOT accesses a database of position specific residue-residue interaction frequencies for members of the SH3 and PDZ protein domain families. The software utilises this database to provide a score for any potential domain peptide interaction